JP2000159747A - New thiol derivative, its production and use - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain the subject safe new compound having excellent matrix metalloprotease(MMP) inhibitory action and its sustainability, and useful as a preventive/therapeutic agent for arthrosis deformans, chronic arthrorheumatism osteoporosis, cancer, periodontosis, corneal ulcer, and the like. SOLUTION: This new compound is a compound of formula I [rings A and B are each a (substituted) homocyclic or heterocyclic ring; R1 is H, a (substituted) hydrocarbon group, acyl or the like; X1 is a lone pair, (substituted) bivalent 1-3C aliphatic hydrocarbon group or the like; X2 is a lone pair, (substituted) bivalent 1-3C aliphatic hydrocarbon group or the like; Y is H, a (substituted) hydrocarbon group, halogen, carboxyl, an acyl or the like; m is 0 or 1; n is 1-3; q1 is 1 to 2n+4; q2 is 0 to 2n+3], e.g. 3-mercapto-1-(4- phenoxybenzyl)pyrrolidine-2,5-dione. The compound of formula I is obtained, for example, by reaction between a compound of formula II (L is an eliminable group) or formula III and a compound of the formula: R1SH.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention has excellent matrix metalloprotease inhibitory activity and is useful as a therapeutic or prophylactic agent for osteoarthritis and rheumatoid arthritis, and as an inhibitor for metastasis, invasion and proliferation of various cancers. New thiol derivatives.

[0002]

2. Description of the Related Art Matrix metalloprotease (MM)
P) is an endopeptidase that is physiologically important in tissue remodeling, and its protease activity is strictly controlled. However, in pathological conditions, their control is disrupted, causing excessive degradation of the extracellular matrix, leading to joint diseases such as osteoarthritis and rheumatoid arthritis,
It is involved in the pathogenesis of many diseases such as bone diseases such as osteoporosis, periodontal disease, tumor invasion and metastasis, and corneal ulceration.
Currently, at least 15 types of MMPs are known, and the collagenases (MMP-1, 8, 1
3), gelatinase group (MMP-2, 9), stromelysin group (MMP-3, 10), membrane type MMP group (MT1, 2, 3, 4-MMP), and other groups (MMP-7, 11, 12, 18). Among these, MMP-13 belonging to the collagenase group
It has been reported that the expression site is almost limited to cartilage and bone tissue, and its production is increased in joint diseases and the like. Furthermore, MMP-13 is expected to be deeply involved in bone and joint diseases, because it has a stronger collagen-degrading effect than other collagenases. Many MMP inhibitors have been reported (Current Pharmaceutical Design,
2, 624-661 (1996), Expert Opinion on Therapeutic P
atents, 6, 1305-1315 (1996)), and many thiol derivatives have recently been reported (WO97-3783, WO97-38007,
WO97-48685, EP818443, WO98-3164, WO98-3166, WO98-
6696, WO98-8814, WO98-12211, WO98-23588, Bioorgani
c & Medicinal Chemistry Letters, 8,1157-1162 (199
8), Bioorganic & Medicinal Chemistry Letters, 8, 1
163-1168 (1998)). In addition, many compounds showing inhibitory activity against MMP-13 have been reported, and hydroxamic acid derivatives (British Journal of Pharmacology, 121,
540-546 (1997), WO97-31892, WO98-15525, WO98-1650
6, WO98-16520), carboxylic acid derivatives (Journal of Clin)
ical Investigation, 99, 1534-1545 (1997), WO98-671
1, WO98-9934, WO98-17643) and thiol derivatives (WO
98-3164, WO98-3166).

[0003]

SUMMARY OF THE INVENTION There is a demand for the development of new compounds that are more satisfactory in terms of effect, sustainability, safety and the like than conventional MMP inhibitors and the like.

[0004]

Means for Solving the Problems The present inventors have conducted various studies and found that the formula

Embedded image (Wherein Y is the same or different and each represents a hydrogen atom,
An optionally substituted hydrocarbon group, a halogen atom, a carboxyl group, an acyl group, an optionally substituted hydroxy group, an optionally substituted amino group, SR ⁵ (R ⁵ is a hydrogen atom, Represents an optionally substituted hydrocarbon group, an acyl group or an optionally substituted heterocyclic group), an oxo group, a thioxo group, an optionally substituted imino group, a nitro group or a cyano group, and n is 1 to 3 And q ₂ represents an integer of 0 to 2n + 3. The nitrogen atom on the ring represented by the formula

Embedded image (Wherein, ring A and ring B are the same or different and each represents an optionally substituted homo- or heterocyclic ring;
The substituent of the ring (or ring B) may be bonded to a substitutable position on ring B (or ring A) to form a condensed ring with ring A, ring B and X ² , and X ¹ is a bond An optionally substituted divalent C _1-3 aliphatic hydrocarbon group or —NR ³ —
(R ³ represents a hydrogen atom, an optionally substituted hydrocarbon group or an acyl group), and X ² represents a bond, an optionally substituted divalent C _1-3 aliphatic hydrocarbon group, −NR ⁴ −
(R ⁴ represents a hydrogen atom, an optionally substituted hydrocarbon group or an acyl group), —O— or —S (O) p—
(P represents 0, 1 or 2). ) Is substituted,

[0005]

Embedded image (Wherein each symbol is as defined above) on a substitutable carbon atom on the ring represented by

Embedded image (Wherein R ¹ is the same or different and each represents a hydrogen atom,
An optionally substituted hydrocarbon group, an acyl group, an optionally substituted heterocyclic group or SR ² (R ² is a hydrogen atom, an optionally substituted hydrocarbon group, an acyl group or an optionally substituted M represents the same or different and each represents 0 or 1, and q ₁ represents 1 to 2n + 4. )) Is a compound of the formula (1) which has significant chemical structural features where the group represented by

Embedded image (Wherein, ring A and ring B are the same or different and each represents an optionally substituted homo- or heterocyclic ring;
The substituent of the ring (or ring B) may be bonded to a substitutable position on the ring B (or ring A) to form a condensed ring together with the ring A, the ring B and X ² , and R ¹ is The same or different, a hydrogen atom, an optionally substituted hydrocarbon group, an acyl group, an optionally substituted heterocyclic group or SR ² (R ²
Represents a hydrogen atom, a hydrocarbon group which may be substituted, an acyl group or a heterocyclic group which may be substituted), and X ¹ represents a bond, a divalent C _{1- which} may be substituted. ₃ aliphatic hydrocarbon group, or -NR ³ - (R ³ is a hydrogen atom, an optionally substituted hydrocarbon group or an acyl group) indicates, X ² is a bond, divalent optionally substituted C _1-3
Aliphatic hydrocarbon group, -NR ⁴ - (R ⁴ represents a hydrogen atom, optionally substituted hydrocarbon group or an acyl group), -
O- or -S (O) p- (p represents 0, 1 or 2), and Y is the same or different and is a hydrogen atom, a hydrocarbon group which may be substituted, a halogen atom,
A carboxyl group, an acyl group, an optionally substituted hydroxy group, an optionally substituted amino group, SR ⁵ (R ⁵
Represents a hydrogen atom, an optionally substituted hydrocarbon group, an acyl group or an optionally substituted heterocyclic group), an oxo group, a thioxo group, an optionally substituted imino group, a nitro group or a cyano group And m is the same or different and each represents 0 or 1, n represents an integer of 1 to 3, q ₁ represents 1 to 2n + 4, and q ₂ represents 0 to 2n
+3, and the sum of q ₁ and q ₂ represents 2n + 4. ) Or a salt thereof show unexpectedly excellent MMP inhibitory activity (particularly MMP-13 inhibitory activity) and excellent durability and safety based on its unique chemical structure, Based on these findings, they have found that they can be used as preventive and therapeutic agents for osteoarthritis, rheumatoid arthritis, osteoporosis, cancer, periodontal disease, corneal ulcer and the like, and have completed the present invention.

That is, the present invention relates to (1) the above formula (I)
Or a salt thereof (provided that, when the ring B is a nitrogen-containing heterocyclic ring, X ² is bonded to a substitutable position other than the nitrogen atom on the ring B), (2) the ring A and the ring B (3) The compound according to the above (1), which is an optionally substituted benzene ring, (3) R ¹ is the same or different and each is a hydrogen atom, an optionally substituted lower alkyl group,-(C =
O) -R ⁶ (R ⁶ is a hydrogen atom, optionally substituted hydrocarbon group, an optionally substituted amino group or an optionally substituted hydroxy group) or SR ² (R ² is claimed the compounds of the above (1), wherein a section 1 the same significance as described), (4) R ¹ is the same or different formula

Embedded image (Wherein each symbol has the same meaning as described in the above (1)) or

Embedded image (Wherein each symbol has the same meaning as described in the above (1)), the compound according to the above (1), and (5) the methylene group optionally substituted with X ^{1 according} to the above (1) Compound,
(6) The compound according to the above (1), wherein X ² is —O—,
(7) Formula in formula [I]

Embedded image The group represented by

Embedded image (R ⁷ to R ¹¹ are the same or different and each represents a hydrogen atom, a lower alkyl group which may be substituted, a hydroxy group which may be substituted, an amino group which may be substituted or SR ¹² (R ¹² is A hydrogen atom, a hydrocarbon group which may be substituted, an acyl group or a heterocyclic group which may be substituted)).
The compound according to the above (1), which is a group represented by the following meaning:

(8) Equation in equation [I]

Embedded image The group represented by

Embedded image (R ¹³ to R ²⁵ are the same or different and each is a hydrogen atom, a lower alkyl group which may be substituted, a hydroxy group which may be substituted, an amino group which may be substituted or SR ¹² (R ¹² is A hydrogen atom, a hydrocarbon group which may be substituted, an acyl group or a heterocyclic group which may be substituted), and other symbols have the same meanings as in claim 1). 1) The compound according to the above,
(9) The compound according to the above (1), wherein m is 0,

Equation (10)

Embedded image (Wherein each symbol has the same meaning as described in the above (1)), the compound according to the above (1),

Embedded image (Wherein L represents a leaving group, and other symbols have the same meanings as described in the above (1)) or a salt thereof and a compound represented by the formula R ¹ SH (wherein R ¹ is (1) a compound represented by the formula (1) or a salt thereof:

Embedded image (Wherein each symbol has the same meaning as described in the above (1)) or a method for producing a compound thereof or a salt thereof,

Embedded image (Wherein each symbol has the same meaning as described in the above (1)) or a salt thereof, or a compound represented by the formula

Embedded image (Wherein each symbol has the same meaning as described in the above (1)) or a salt thereof, and a compound represented by the formula R ¹ SH (wherein R ¹ has the same meaning as described in the above (1)). ) Or a salt thereof,

Embedded image (Wherein each symbol has the same meaning as described in the above (1)) or a method for producing the compound represented by the formula (I), or (13) the compound represented by the above formula (I) or a salt thereof. A pharmaceutical composition comprising: (14) a matrix metalloprotease inhibitor comprising the compound according to (13) or a salt thereof; and (15) a modification comprising the compound according to (13) or a salt thereof. The present invention relates to an agent for preventing or treating osteoarthritis, rheumatoid arthritis, osteoporosis, cancer, periodontal disease, or corneal ulcer. Further, when the compound (I) or a salt thereof contains an asymmetric carbon in the structure, both the optically active form and the racemic form are included in the scope of the present invention, and the compound (I) or a salt thereof may be a hydrate, an anhydrous form. Any of Japanese products may be used.

Hereinafter, the present invention will be described in detail. “A ring and B ring” The A ring and the B ring are the same or different, and each represents an homocyclic ring or a hetero ring which may have the same or different substituent. Further, the substituent on ring A (or ring B) is B
A ring (or ring A) bonded to a substitutable position on the ring (A),
The condensed ring may be formed together with the ring B and X ² described below.
The "homocycle or heterocycle" includes, for example, (i) one selected from a nitrogen atom, a sulfur atom and an oxygen atom in addition to a carbon atom.
One or two heteroatoms, preferably one to three
Aromatic heterocyclic ring or non-aromatic heterocyclic ring, or (i
i) Cyclic hydrocarbons consisting of carbon atoms (homocycles) and the like are included. As the "aromatic heterocycle", for example, a 5- or 6-membered aromatic heterocycle containing 1 to 3 heteroatoms selected from a nitrogen atom, an oxygen atom and a sulfur atom in addition to a carbon atom (for example, pyridine , Pyrazine, pyrimidine, pyridazine, pyrrole, imidazole, pyrazole, triazole, thiophene, furan, thiazole, isothiazole, oxazole and isoxazole rings)
And so on. Preferred aromatic heterocycles include, for example, pyridine, pyrazine and thiophene rings.
For example, pyrrole and thiazole rings are also included. In particular, (i) containing one or two nitrogen atoms other than carbon atoms
Membered nitrogen-containing heterocyclic ring (eg, pyridine, pyrazine ring, etc.) or (ii) 5 containing one sulfur atom other than carbon atom
A membered aromatic heterocycle (for example, a thiophene ring or the like) is preferred.

The "non-aromatic heterocyclic ring" includes, for example, a 5- to 9-membered non-aromatic heterocyclic ring containing 1 to 3 hetero atoms selected from nitrogen, oxygen and sulfur atoms in addition to carbon atoms. Heterocycles, preferably 5- or 6-membered non-aromatic heterocycles and the like are included. Specific examples of the "non-aromatic heterocycle" include, for example, tetrahydropyridine, dihydropyridine, tetrahydropyrazine, tetrahydropyrimidine, tetrahydropyridazine, dihydropyran, dihydropyrrole, dihydroimidazole, dihydropyrazole, dihydrothiophene, dihydrofuran, dihydrothiazole, Dihydroisothiazole, dihydrooxazole, dihydroisoxazole, piperidine, piperazine, hexahydropyrimidine, hexahydropyridazine, tetrahydropyran, morpholine, pyrrolidine, imidazolidine, pyrazolidine, tetrahydrothiophene, tetrahydrofuran, tetrahydrothiazole, tetrahydroisothiazole, tetrahydrooxazole, Tetrahydroisoxazole ring etc. It is.

The "cyclic hydrocarbon (homocycle)" includes, for example, a 3- to 10-membered (preferably 5- to 9-membered) cyclic hydrocarbon, more preferably a 5- or 6-membered cyclic hydrocarbon. included. For example, benzene, C _3-10 cycloalkene (eg, cyclobutene, cyclopentene, cyclohexene, cycloheptene, cyclooctene, etc.), C _3-10 cycloalkane (eg, cyclobutane,
Cyclopentane, cyclohexane, cycloheptane, cyclooctane, etc.). As the cycloalkene, C _5-6 cycloalkene (eg, cyclopentene, cyclohexene, etc.) is preferable, and as the cycloalkane, C _5-6 cycloalkane (eg, cyclohexane, cyclopentane, etc.) is preferable. As the ring A and the ring B, for example, a 6-membered homocyclic ring such as a benzene ring or a cyclohexene ring is preferable, and a benzene ring or the like is particularly preferable.

Examples of the substituent which the “homocyclic or heterocyclic ring” represented by the rings A and B may have include, for example,
(I) a halogen atom (for example, fluorine, chlorine, bromine, iodine, etc.), (ii) an optionally substituted alkyl group,
(Iii) an optionally halogenated alkoxy group (for example, methoxy, difluoromethoxy, trichloromethoxy, trifluoromethoxy, ethoxy, 2,2,2-
Trifluoroethoxy, perfluoroethoxy, propoxy, isopropoxy, butoxy, isobutoxy, t-
Butoxy, perfluorobutoxy, pentyloxy, hexyloxy groups and the like, and C _1-6 alkoxy groups which may be substituted with halogen atoms such as fluorine and chlorine), (i
v) optionally halogenated alkylthio groups (for example, C ₁ which may be substituted by halogen atoms such as fluorine and chlorine such as methylthio, difluoromethylthio, trifluoromethylthio, ethylthio, propylthio, isopropylthio and butylthio groups) _-6 alkylthio groups (particularly C _1-4 alkylthio groups), (v) aryl groups (eg, C _6-14 aryl groups such as phenyl, naphthyl, anthryl, phenanthryl), (vi) acyloxy groups (eg, (C _1-3 acyloxy group such as formyloxy, acetoxy, propionyloxy group, etc.), (vii)
Hydroxy group, (viii) nitro group, (ix) cyano group,
(X) amino group, (xi) mono - or di - alkylamino group (e.g., methylamino, ethylamino, propylamino, dimethylamino, mono- such diethylamino group - or di -C _1-6 alkylamino group (especially , A mono- or di-C _1-4 alkylamino group), (xii) a cyclic amino group (for example, which may contain 1 to 3 hetero atoms such as an oxygen atom and a sulfur atom in addition to a nitrogen atom. And a 9-membered cyclic amino group (eg, pyrrolidino, piperidino, morpholino group, etc.), (xiii) an acylamino group (eg, formylamino group, or a acetylamino, propionylamino, butyrylamino group, etc.
_1-6 alkyl - carbonyl amino group), (xiv) such as lower alkyl-substituted carbamoylamino group (ethylcarbamoyl amino group) (xv) alkylsulfonyl group (e.g., methylsulfonylamino, ethylsulfonylamino, propylsulfonyl amino group, etc. C, such as _1-6 alkylsulfonylamino group) of, (xvi) alkoxy - carbonyl group (e.g., methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl, C _1-6 alkoxy, such as iso-butoxycarbonyl group - carbonyl group) , (Xvii) carboxyl group, (xviii) alkyl-
Carbonyl group (eg, C _1-6 alkyl-carbonyl group such as methylcarbonyl, ethylcarbonyl, butylcarbonyl, etc.), (xix) carbamoyl group, (xx) mono- or di-alkyl-carbamoyl group (eg, methylcarbamoyl, A mono- or di-C _1-6 alkyl-carbamoyl group such as ethylcarbamoy, propylcarbamoyl, butylcarbamoyl, diethylcarbamoyl, dibutylcarbamoyl, etc.), (xxi) an alkylsulfonyl group (eg, methylsulfonyl, ethylsulfonyl group, C _1-6 alkylsulfonyl group such as propylsulfonyl group), (xxii) oxo group, (xxiii) thioxo group and the like. The "optionally substituted alkyl group" includes, for example, (a) methyl or ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, etc. In addition to the branched alkyl group, (b) halogenated C _1-6
Alkyl group (for example, chloromethyl, difluoromethyl, trichloromethyl, trifluoromethyl, 2-bromoethyl, 2,2,2-trifluoroethyl, perfluoroethyl, 3,3,3-trifluoropropyl, perfluorobutyl group ), (C) C substituted with an amino group
_1-6 alkyl group (e.g., aminomethyl and 2-aminoethyl group), (d) mono- - or di -C _1-6 C _1-6 alkyl group substituted with an alkylamino group (e.g., methylaminomethyl Dimethylaminomethyl, 2-methylaminoethyl, 2-dimethylaminoethyl, etc.), (e) a C _1-6 alkyl group substituted with a carboxyl group (for example,
Carboxymethyl, carboxyethyl, etc.), (f) C
A C _1-6 alkyl group substituted with a _1-6 alkoxy-carbonyl group (e.g., methoxycarbonylethyl, ethoxycarbonylethyl group, etc.), (g) a C _1-6 alkyl group substituted with a hydroxy group (e.g., hydroxy (H) C substituted with a C _{6-14 aryl} group such as methyl or hydroxyethyl group
_1-6 alkyl group (for example, benzyl and the like), (i) C _1-6 alkyl group substituted with C _1-6 alkoxy group (for example, methoxymethyl, methoxyethyl and the like), or (j) C
_And a C _1-6 alkyl group substituted with a _7-15 aralkyloxy group (eg, benzyloxymethyl).

Preferred substituents which the rings A and B may have are, for example, halogen atom, alkyl group which may be substituted, alkoxy group which may be halogenated, mono- and di-. Examples thereof include an alkylamino group and an alkylthio group which may be halogenated. More preferred substituents that the ring A and the ring B may have include, for example, a halogen atom, an optionally substituted C _1-4 alkyl group, an optionally halogenated C _1-4
Examples include an alkoxy group, a mono- or di-C _1-4 alkylamino group, a C _1-4 alkylthio group which may be halogenated, and the like. Of these, a halogen atom, a C _1-4 alkyl group which may be substituted, a C _1-4 alkoxy group which may be halogenated, and the like are particularly preferable.

The substituents on ring A and ring B may be substituted at any substitutable position on the ring. When there are two or more substituents, the substituents may be the same or different. And the number thereof may be about 1 to 4. The number of substituents is preferably about 1 to 3.
When the ring A and the ring B have a nitrogen atom, they may form a quaternary ammonium salt, for example, a halide ion (eg, Cl ⁻ , Br ⁻ , I ^−, etc.), a sulfate ion, a hydroxy ion, etc. It may form a salt with an ion. The ring A and the ring B are each preferably an optionally substituted benzene ring. Examples of the substituent of the “optionally substituted benzene ring” include the above-mentioned A
The same substituents as those exemplified for the ring and the ring B are exemplified. The substituent of ring A (or ring B) is bonded to a substitutable position on ring B (or ring A) to form ring A or ring B
Specific examples of the case where a condensed ring is formed together with a ring and X ² described below include, for example, a ring such as fluorene, anthracene, dibenzofuran, dibenzopyran, dibenzodioxane, carbazole, acridine, and phenothiazine. Is, for example, the expression

Embedded image (Wherein, ring A and ring B have the same meanings as described above, and X ² has the same meaning as described later). More preferably, for example, the formula

Embedded image (Wherein, ring A and ring B have the same meanings as described above), and the like.

Regarding “R ¹ ”, R ¹ is the same or different and is a hydrogen atom, an optionally substituted hydrocarbon group, an acyl group, an optionally substituted heterocyclic group or SR ² (R ² is a hydrogen atom , An optionally substituted hydrocarbon group, an acyl group or an optionally substituted heterocyclic group). Examples of the “hydrocarbon group” of the “optionally substituted hydrocarbon group” represented by R ¹ include, for example, an alkyl group, an alkenyl group, an alkynyl group, a cycloalkyl group, and an aryl group. Alkyl, cycloalkyl and aryl groups, especially alkyl groups, are commonly used. As the “alkyl group”, a linear or branched one having 1 to 6 carbon atoms is used, and preferably a carbon atom such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, etc. A linear or branched alkyl group of the formulas 1 to 4 is used. Examples of the "alkenyl group" include ethenyl, propenyl, isopropenyl, butenyl, isobutenyl, and sec-butenyl.
And an alkenyl group having 6 to 4 carbon atoms, preferably ethenyl, propenyl, isopropenyl or the like.
Alkenyl group is used. Examples of the “alkynyl group” include those having 2 to 6 carbon atoms such as ethynyl, propynyl, isopropynyl, butynyl, isobutynyl, and sec-butynyl.
And an alkynyl group having 2 to 4 carbon atoms such as ethynyl, propynyl and isopropynyl is preferably used. As the “cycloalkyl group”, for example, a C _3-8 cycloalkyl group such as cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl is used, and preferably, a C _3-6 cycloalkyl group such as cyclopropyl and cyclobutyl is used.
As the "aryl group", an aryl group having 6 to 14 carbon atoms such as phenyl, naphthyl, anthryl, and phenanthryl is used, and an aryl group having 6 to 10 carbon atoms such as phenyl and naphthyl is preferably used.

Examples of the "substituent" of the "optionally substituted hydrocarbon group" represented by R ¹ include (i) a halogen atom (eg, fluorine, chlorine, bromine, iodine, etc.), (ii) An) an alkyl group which may have a substituent,
(Iii) cycloalkyl group (for example, cyclopropyl,
(C _3-8 cycloalkyl groups such as cyclobutyl, cyclopentyl, cyclohexyl and the like), (iv) optionally substituted aryl groups, (v) optionally halogenated alkoxy groups (eg methoxy, difluoro Methoxy, trichloromethoxy, trifluoromethoxy, ethoxy, 2,2,2-trifluoroethoxy, perfluoroethoxy, propoxy, isopropoxy, butoxy, isobutoxy, t-butoxy, perfluorobutoxy, pentyloxy, hexyloxy, C _{3 -8} cycloalkyloxy, fluorine such as a heterocyclyloxy group,
C _1-6 which may be substituted by a halogen atom such as chlorine
Alkoxy group, etc.), (vi) nitro group, (vii) cyano group, (viii) hydroxy group, (ix) aryloxy group (for example, C _6-14 such as phenoxy and naphthyloxy group)
Aryloxy group), (x) aralkyloxy group (for example, C _6-14 aryl group-C _1-4 alkyloxy group such as benzyloxy and phenethyloxy group), (x
i) an alkylthio group which may be halogenated (for example, C ₁ which may be substituted with a halogen atom such as fluorine or chlorine such as methylthio, difluoromethylthio, trifluoromethylthio, ethylthio, propylthio, isopropylthio and butylthio groups); _-6 alkylthio group (particularly C _1-4 alkylthio group), (xii) amino group,
(Xiii) a formyl group, an amino group mono- or di-substituted with an alkyl group which may be substituted (for example, mono- or di-C such as methylamino, ethylamino, propylamino, dimethylamino, diethylamino group and the like) _1-6
Alkylamino group (particularly, mono- or di- _C1-4 alkylamino group), formylamino group, pyrimidinylmethylamino group, etc., (xiv) cyclic amino group (for example, oxygen atom, sulfur atom, etc. other than nitrogen atom) 1 heteroatom
Or a 5- to 9-membered cyclic amino group (eg, pyrrolidino, piperidino, morpholino group, etc.) which may contain from 3 to 3, (xv) an alkyl-carbonylamino group (eg, acetylamino, propionylamino, butyrylamino group, etc.) carbonyl amino group), (xvi) alkoxy - - C _1-6 alkyl such as C _1-6 alkoxycarbonylamino group, such as carbonyl group (e.g., ethoxycarbonylamino group) (xvii) aryl - carbonyl amino group (e.g., A C _6-14 aryl-carbonylamino group such as a benzoylamino group, (xviii) an acyloxy group (eg, a C _1-3 acyloxy group such as a formyloxy, acetoxy, propionyloxy group), (xix) an aminocarbonyloxy group Group, (xx) mono- or di-alkylamino-carbo Nyloxy group (for example, mono- or di-C _1-6 alkylamino-carbonyloxy group such as methylaminocarbonyloxy, ethylaminocarbonyloxy, dimethylaminocarbonyloxy group and diethylamino-carbonyloxy group), (xxi) alkylsulfonyl An amino group (eg, a methylsulfonylamino, ethylsulfonylamino, propylsulfonylamino group, etc.
_1-6 alkylsulfonylamino group, etc.), (xxii) alkoxy-carbonyl group (for example, methoxycarbonyl,
Carbonyl group), (xxiii) aralkyloxy - - ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl, C _1-6 alkoxy, such as isobutoxycarbonyl group carbonyl group (e.g., C _7-15 aralkyloxycarbonyl such as benzyloxycarbonyl group - (Xxiv) aryloxy-carbonyl group (eg, C _6-14 aryloxy-carbonyl group such as phenoxycarbonyl group), (xxv) carboxyl group, (x
xvi) alkyl-carbonyl groups (e.g., methylcarbonyl, ethylcarbonyl, butylcarbonyl, etc.
_1-6 alkyl - carbonyl group), (xxvii) cycloalkyl - carbonyl group (e.g., cyclopentyl carbonyl, C _3-8 cycloalkyl such as cyclohexyl group - carbonyl group), (xxviii) aryl -
A carbonyl group (for example, a C _6-14 aryl-carbonyl group such as a benzoyl group), a (xxix) carbamoyl group,
(Xxx) a thiocarbamoyl group, (xxxi) a mono- or di-alkyl-carbamoyl group (for example, a mono- or di-C _1- group such as a methylcarbamoyl, ethylcarbamoyl, propylcarbamoyl, butylcarbamoyl, diethylcarbamoyl, dibutylcarbamoyl group and the like). ₆ alkyl-
Carbamoyl group), (xxxii) alkylsulfonyl group (for example, methylsulfonyl, ethylsulfonyl group,
Propyl such as C _1-6 alkylsulfonyl group such as sulfonyl group), (xxxiii) cycloalkyl sulfonyl group (e.g., cyclopentylsulfonyl, such as a C _3-8 cycloalkyl sulfonyl group such as a cyclohexyl sulfonyl group), (xxxiv) an arylsulfonyl group (Eg, C _6-14 arylsulfonyl groups such as phenylsulfonyl and naphthylsulfonyl groups), (xxxv) aralkylsulfonyl groups (eg, C _7-15 aralkylsulfonyl groups such as benzylsulfonyl groups), and (xxxvi) substituted. And a 5- or 6-membered heterocyclic group which may be used.

Examples of the “optionally substituted 5- or 6-membered heterocyclic group” represented as “substituent” of the “optionally substituted hydrocarbon group” for R ¹ include, for example,
Examples thereof include a 5- or 6-membered aromatic heterocyclic group and a saturated or unsaturated 5- or 6-membered non-aromatic heterocyclic group. Examples of the "5- or 6-membered aromatic heterocyclic group" include furyl, thienyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, imidazolyl,
Pyrazolyl, 1,2,3-oxadiazolyl, 1,2,4-
Oxadiazolyl, 1,3,4-oxadiazolyl, furazanyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,3-triazolyl, 1,2,4- Triazolyl, tetrazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl and the like. Examples of the above “5- or 6-membered non-aromatic heterocyclic group” include pyrrolidinyl, tetrahydrofuryl, tetrahydrothienyl, piperidyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl, piperazinyl and the like. These non-aromatic heterocyclic groups may be further condensed with another aromatic or non-aromatic homocyclic or heterocyclic ring. Examples of the “substituent” of the “optionally substituted 5- or 6-membered heterocyclic group” represented as the “substituent” of the “optionally substituted hydrocarbon group” represented by R ¹ include, for example, The same substituents as the “substituent” of the “optionally substituted homocyclic or heterocyclic ring” represented by the above-mentioned ring A and ring B are exemplified.

Further, as the "substituent" of the "optionally substituted hydrocarbon group" for R ¹ ,

Embedded image (Wherein each symbol has the same meaning as described above). The number of substituents of the “optionally substituted hydrocarbon group” represented by R ¹ is 1 to 5 (preferably 1
Or 2), and when there are two or more substituents, the substituents may be the same or different.

The “optionally substituted alkyl group” described as the “substituent” of the “optionally substituted hydrocarbon group” for R ¹ includes the aforementioned ring A and ring B And the same as the “alkyl group optionally having substituent (s)” described as the substituent that the “homocyclic ring or heterocyclic ring” may have. Examples of the “aryl group” of the “optionally substituted aryl group” described as the “substituent” of the “optionally substituted hydrocarbon group” represented by R ¹ include, for example, phenyl,
6 carbon atoms such as naphthyl, anthryl and phenanthryl
And aryl groups having 6 to 10 carbon atoms, such as phenyl and naphthyl. Examples of the “substituent” of the “aryl group which may have a substituent” described as the “substituent” of the “optionally substituted hydrocarbon group” represented by R ¹ include, for example, (i ) halogen atoms such as fluorine and chlorine, (ii) methyl, ethyl, halogenated which may be C _1-4 alkyl group such as trifluoromethyl group or (iii) methoxy,, C _1-4 such as an ethoxy group And an alkoxy group.

The "acyl group" represented by R ¹ includes, for example,-(C = O) -R ⁶ , -SO ₂ -R ⁶ , -SO-
R ⁶ , — (C ＝ O) NR ⁶ R ²⁷ , — (C） O) O—R ⁶ ,
- (C = S) O- R 6, - (C = S) NR 6 R 27, - (P
_{^{= O) (OR 6) 2}} , - (P = O) (OR 6) (OR 27)
(R ⁶ represents a hydrogen atom or an optionally substituted hydrocarbon group, an optionally substituted amino group or an optionally substituted hydroxy group, and R ²⁷ represents a hydrogen atom or a lower alkyl group (for example, methyl , Ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert
Preferred are C _1-6 alkyl groups such as -butyl, pentyl, hexyl and the like, and particularly C _1-3 alkyl groups such as methyl, ethyl, propyl and isopropyl. ). ).

The "optionally substituted hydrocarbon group" represented by R ⁶ is, for example, the same as the above-mentioned "optionally substituted hydrocarbon group" represented by R ¹ And the like. As the “substituent” of the “optionally substituted amino group” represented by R ⁶ ,
For example, an optionally substituted hydrocarbon group, an optionally substituted hydroxy group, an acyl group and the like can be mentioned.
Examples of the “optionally substituted hydrocarbon group” as the “substituent” of the “optionally substituted amino group” represented by R ⁶ include, for example, the above “substituted substituted” represented by R ¹ And the like, and the like. Examples of the “optionally substituted hydroxy group” as the “substituent” of the “optionally substituted amino group” represented by R ⁶ include, for example, (i)
Hydroxy group, (ii) C _1-6 alkoxy group (for example, methoxy, ethoxy, propoxy, isopropoxy, butoxy, t-butoxy group, etc.), (iii) C _6-14 aryloxy group (for example, phenyloxy, naphthyl) An oxy group), (iv) a C _1-6 alkyl-carbonyloxy group (eg, formyloxy, acetoxy, propionyloxy group, etc.) and (v) a C _6-14 aryl-carbonyloxy group (eg, benzyloxy, naphthyl) -Carbonyloxy group and the like, and preferably a hydroxy group and a C _1-6 alkoxy group (for example, methoxy, ethoxy, propoxy, isopropoxy group and the like).

As the "acyl group" as the "substituent" of the "optionally substituted amino group" represented by R ⁶ ,
For example, - (C = O) -R 28, -SO 2 -R 28, -SO
^{-R 28, - (C = O} ) NR 28 R 29, - (C = O) O-R
^{28, - (C = S)} O-R 28, - (C = S) NR 28 R 29,
(R ²⁸ represents a hydrogen atom or a hydrocarbon group which may have a substituent, and R ²⁹ represents a hydrogen atom or a lower alkyl group (eg, methyl, ethyl, propyl, isopropyl,
Preferred are C _1-6 alkyl groups such as butyl, isobutyl, sec-butyl, tert-butyl, pentyl and hexyl, and particularly preferred are C _1-3 alkyl groups such as methyl, ethyl, propyl and isopropyl. ). ). Examples of the “optionally substituted hydrocarbon group” represented by R ²⁸ include the same as the aforementioned “optionally substituted hydrocarbon group” represented by R ¹ . Things. “C _1-6 alkoxy group” exemplified as “hydroxy group which may have a substituent” as “substituent” of “amino group which may be substituted” represented by R ⁶ , “C _{The “6-14} aryloxy group”, “C _1-6 alkyl-carbonyloxy group” and “C _6-14 aryl-carbonyloxy group” may further have a “substituent represented by R ¹ ” The substituent may be the same as the “substituent” of the “good hydrocarbon group”, and the substituent is preferably a halogen atom (eg, fluorine, chlorine, bromine, etc.). Examples of the “optionally substituted hydroxy group” represented by R ⁶ include the aforementioned R ⁶
And the same as "hydroxy group optionally having substituent (s)" as "substituent" of "amino group which may be substituted" represented by Further, R ⁶ and R ²⁷ are taken together to form a cyclic amino group (for example, a 5- to 9-membered cyclic amino group which may contain 1 to 3 hetero atoms such as an oxygen atom and a sulfur atom in addition to a nitrogen atom ( For example,
Pyrrolidino, piperidino, morpholino group, etc.).

The “heterocyclic group” of the “optionally substituted heterocyclic group” represented by R ¹ includes, for example, an oxygen atom other than a carbon atom as an atom (ring atom) constituting a ring system.
Aromatic heterocyclic group containing at least one (preferably 1 to 4, more preferably 1 to 2) of 1 to 3 (preferably 1 to 2) heteroatoms selected from a sulfur atom, a nitrogen atom and the like And saturated or unsaturated non-aromatic heterocyclic groups. Examples of the “aromatic heterocyclic group” include aromatic monocyclic heterocyclic groups (for example, furyl, thienyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, imidazolyl, pyrazolyl,
1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, furzanil, 1,
2,3-thiadiazolyl, 1,2,4-thiadiazolyl,
1,3,4-thiadiazolyl, 1,2,3-triazolyl,
5- or 6-membered aromatic monocyclic heterocyclic group and aromatic condensed heterocyclic group such as 1,2,4-triazolyl, tetrazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl and the like (for example, benzofuranyl, isobenzofuran) Nyl, benzothienyl, indolyl, isoindolyl, 1H-indazolyl, benzindazolyl, benzoxazolyl, 1,2-benzoisoxazolyl, benzothiazolyl, benzopyranyl, 1,2-benzoisothiazolyl, 1H-benzotria Zolyl, quinolyl, isoquinolyl, cinnolinyl, quinazolinyl, quinoxalinyl, phthalazinyl, naphthyridinyl, purinyl, buteridinyl, carbazolyl, α-carbolinyl, β-carbolinyl, γ-carbolinyl, acridinyl, phenoxazinyl, phenothiazini , Phenazinyl, phenoxathiinyl, thianthrenyl, phenatridinyl, phenatrolinyl, indolizinyl, pyrrolo [1,2- b ] pyridazinyl, pyrazolo [1,5- a ] pyridyl, imidazo [1,2- a ] pyridyl, imidazo [1 , 5- a ] Pyridyl, imidazo [1,2- b ] pyridazinyl, imidazo [1,2- a ] pyrimidinyl, 1,2,4-triazolo [4,3- a ] pyridyl, 1,2,4-triazolo [4,3
- b] pyridazinyl, etc.) 8-12 membered aromatic fused Hajime Tamaki such as (preferably, the 5 or 6-membered aromatic monocyclic heterocyclic group and is heterocyclic or said fused with a benzene ring 5 And a 6-membered aromatic monocyclic heterocyclic group in which two identical or different heterocyclic rings are condensed). Examples of the above “non-aromatic heterocyclic group” include 3- to 8-membered (preferably, oxiranyl, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, tetrahydrofuryl, tetrahydrothienyl, piperidyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl, piperazinyl, etc.) (5-6 membered) saturated or unsaturated (preferably saturated) non-aromatic heterocyclic group.

The “substituent” of the “optionally substituted heterocyclic group” represented by R ¹ includes, for example, a ring A and a ring B
In addition to the same substituents that may be possessed by the "homocyclic or heterocyclic ring" represented by the ring, and the like, and the above formula
In [I], a group represented by Y (Y is as defined above) or a group represented by the formula:

Embedded image (Each symbol has the same meaning as described above). The “substituent” of the “optionally substituted heterocyclic group” represented by R ¹ may be substituted at any substitutable position on the ring, and when there are two or more substituents Has the same or different substituents,
The number may be about 1 to 3. The number of substituents is preferably about 1 to 2.

"SR ² represented by R ¹ (R ² is a hydrogen atom,
It represents a hydrocarbon group which may be substituted, an acyl group or a heterocyclic group which may be substituted. )) As the “optionally substituted hydrocarbon group” represented by R ² , for example, the same as those described above as the “optionally substituted hydrocarbon group” represented by R ¹ And the like. "SR ² (R ² is a hydrogen atom, optionally substituted hydrocarbon group, an acyl group or an optionally substituted heterocyclic group.)" Represented by R ¹ is represented by R ² in As the “acyl group”, for example, those similar to the aforementioned “acyl group” represented by R ¹ and the like can be mentioned. "SR ² (R ² is a hydrogen atom, optionally substituted hydrocarbon group, an acyl group or an optionally substituted heterocyclic group.)" Represented by R ¹ is represented by R ² in As the “optionally substituted heterocyclic group”, for example, those similar to the above-mentioned “optionally substituted heterocyclic group” represented by R ¹ and the like can be mentioned. R ¹
Are, for example, a hydrogen atom, a lower alkyl group which may be substituted,-(C = O) -R ⁶ (R ⁶ has the same meaning as described above) or SR ² (R ² has the same meaning as described above) Are preferably used.

The "optionally substituted lower alkyl group" as a preferable example of R ¹ includes (a) methyl, ethyl, propyl, isopropyl, butyl, isobutyl, and
(b) In addition to a linear or branched alkyl group having 1 to 6 carbon atoms such as c-butyl and tert-butyl, (b) a halogenated C _1-6 alkyl group (for example, chloromethyl, difluoromethyl, Trichloromethyl, trifluoromethyl, 2
-Bromoethyl, 2,2,2-trifluoroethyl, perfluoroethyl, 3,3,3-trifluoropropyl, perfluorobutyl, etc.), (c) a C _1-6 alkyl group substituted by an amino group ( For example, aminomethyl, 2-
Amino and ethyl group), (d) mono- - or di -C _1-6 alkylamino C _1-6 alkyl group substituted by group (e.g., methylaminomethyl, dimethylaminomethyl, 2-
(E) a C _1-6 alkyl group substituted with a carboxyl group (eg, carboxymethyl, carboxyethyl group, etc.), (f) a C _1-6 alkoxy-carbonyl A C _1-6 alkyl group substituted with a group (for example, methoxycarbonylethyl, ethoxycarbonylethyl, t-butoxycarbonylmethyl group, etc.), (g) a C _1-6 substituted with a hydroxy group
Alkyl groups (eg, hydroxymethyl, hydroxyethyl groups, (h) C _1-6 alkyl groups substituted with C _{6-14 aryl} groups (eg, benzyl), (i) substituted with C _1-6 alkoxy groups A substituted C _1-6 alkyl group (eg, methoxymethyl, methoxyethyl, etc.) or (j) a C _1-6 alkyl group substituted with a C _7-15 aralkyloxy group (eg, benzyloxymethyl, etc.). can give.

R ¹ is more preferably (1) a hydrogen atom, (2) a C _1-6 alkoxy-carbonyl group (especially ethoxycarbonyl, t-butoxycarbonyl, etc.) or a C _{6-14 aryl} group (especially phenyl, etc.). )) _May be substituted with a C _1-6 alkyl group or (3)-(C ＝ O) -R ^6a
(R ^6a is a C _1-6 alkyl group (especially methyl or the like) or C 6
_{And 6-14} aryl groups (particularly phenyl and the like) and the like.

Further, as R ¹ , the formula

Embedded image (Wherein each symbol is as defined above) or

Embedded image (Wherein each symbol has the same meaning as described above) is also a preferred example.

With respect to “X ¹ ”, X ¹ is a bond, an optionally substituted divalent C _1-3 aliphatic hydrocarbon group or —NR ³ — (R ³ is a hydrogen atom, and may be substituted A hydrocarbon group or an acyl group). X ¹ represents an optionally substituted divalent C _1-3.
The “divalent C _1-3 aliphatic hydrocarbon group” of the “aliphatic hydrocarbon group” refers to a hydrogen atom bonded to the same or different carbon atom of a saturated or unsaturated C _1-3 aliphatic hydrocarbon. The groups formed by removing each one (two in total) are shown. In particular,
(I) C _1-3 alkylene group (for example, -CH _2- , -CH ₂
CH ₂ —, —CH ₂ CH ₂ CH ₂ —, —CH (CH ₃ ) —CH ₂
-) And (ii) a C _2-3 alkenylene group (for example, -C
H = CH—, —CH ＝ CH—CH ₂ —, etc.) (iii) C _2-3 alkynylene group (for example,

Embedded image Etc.) are used. Among them, a C _1-3 alkylene group (for example, —CH ₂ —, —CH ₂ CH ₂ —, —CH ₂ CH
₂ CH ₂ — or —CH (CH ₃ ) —CH ₂ —) is widely used. Preferably -CH ₂ - it is universal.

[0030] As "substituents" of represented by X ¹ "divalent C _1-3 aliphatic which may be substituted hydrocarbon group", for example, represented by R ¹ " The same as the “substituent” of the “hydrocarbon group optionally having substituent (s)” (provided that, as the substituent of the optionally substituted hydrocarbon group represented by R ¹ ,

Embedded image (Wherein each symbol has the same meaning as described above), a group represented by “a divalent C _1-3 aliphatic hydrocarbon group which may have a substituent” is excluded from the substituents. In addition, an oxo group, a thioxo group and the like can be mentioned. X ¹ represented by "-NR ³ -" as "R ^3", "an optionally substituted hydrocarbon group" represented by, for example, has a "substituent represented by R ¹ And the like may be the same as the "hydrocarbon group which may be substituted" (provided that, as a substituent of the hydrocarbon group represented by R ¹ , a group represented by the formula

Embedded image (Wherein each symbol has the same meaning as described above), the group represented by R ¹ is excluded from the substituent of the hydrocarbon group represented by R ¹ ). “Acyl group” represented by “R ³ ” of “—NR ³ —” represented by X ¹
Examples thereof include those similar to the “acyl group” represented by R ¹ . X ¹ is preferably an optionally substituted methylene group. As the “substituent” of the “optionally substituted methylene group”, for example, “an optionally substituted divalent C _1-3 aliphatic hydrocarbon group” represented by X ¹ And the same as the “substituent” of the above. As X ¹ , an unsubstituted methylene group is particularly preferably used.

Regarding “X ² ”, X ² is a bond, an optionally substituted divalent C _1-3 aliphatic hydrocarbon group or —NR ⁴ — (R ⁴ is a hydrogen atom, and may be substituted Represents a hydrocarbon group or an acyl group), -O
-Or -S (O) p- (p represents 0, 1 or 2)
Is shown. Examples of the “optionally substituted divalent C _1-3 aliphatic hydrocarbon group” represented by X ² include the aforementioned X ¹
And the same as the “optionally substituted divalent C _1-3 aliphatic hydrocarbon group”. Examples of the “optionally substituted hydrocarbon group” represented by “R ⁴ ” of “—NR ⁴ —” represented by X ² include, for example, “optionally substituted hydrocarbon group” represented by the aforementioned R ³ And the same as the “good hydrocarbon group”. Examples of the “acyl group” represented by “R ⁴ ” of “—NR ⁴ —” represented by X ² include, for example, those similar to the “acyl group” represented by R ¹ . As X ² , —O— is particularly preferably used.

As for “Y”, Y is the same or different and each represents a hydrogen atom, an optionally substituted hydrocarbon group, a halogen atom, a carboxyl group, an acyl group, an optionally substituted hydroxy group, A good amino group, SR ⁵ (R ⁵ is a hydrogen atom,
A hydrocarbon group, an acyl group or a heterocyclic group which may be substituted), an oxo group, a thioxo group, an imino group which may be substituted, a nitro group or a cyano group. Examples of the “optionally substituted hydrocarbon group” represented by Y include, for example, those similar to the “optionally substituted hydrocarbon group” represented by R ³ . As the “halogen atom” represented by Y, for example, fluorine, chlorine, bromine, iodine and the like can be mentioned. As the “acyl group” represented by Y, for example, those similar to the “acyl group” represented by R ¹ can be mentioned. Examples of the "optionally substituted hydroxy group" represented by Y include, for example, "optionally substituted hydroxy group" as the "substituent" of the "optionally substituted amino group" represented by R ⁶ And the same as the “good hydroxy group”. Examples of the “optionally substituted amino group” represented by Y include, for example, the same as the “optionally substituted amino group” represented by R ⁶ . Examples of the “optionally substituted hydrocarbon group” as “R ⁵ ” of “SR ⁵ ” represented by Y include the aforementioned R
^{And the same} as the “optionally substituted hydrocarbon group” represented by ³ . Examples of the “acyl group” as “R ⁵ ” of “SR ⁵ ” represented by Y include those similar to the “acyl group” represented by R ¹ . Examples of the “optionally substituted heterocyclic group” as “R ⁵ ” of “SR ⁵ ” represented by Y include the aforementioned R
^{And the same} as the “optionally substituted heterocyclic group” represented by ¹ (however, the “substituent” of the “optionally substituted heterocyclic group” represented by the above R ¹⁾ Medium, Y
(Y is as defined above) and a group represented by the formula

Embedded image (Each symbol is as defined above) is a group represented by R ⁵
Excluding from the substituents of the “optionally substituted heterocyclic group”).

Examples of the substituent of the “optionally substituted imino group” represented by Y include the “optionally substituted hydrocarbon group” and “acyl group” represented by R ^4. And the like. Y is preferably a hydrogen atom, a lower alkyl group which may be substituted,
An optionally substituted hydroxy group, an optionally substituted amino group, SR ¹² (R ¹² is a hydrogen atom, an optionally substituted hydrocarbon group, an acyl group or an optionally substituted heterocyclic group; Or an oxo group. Examples of the above-mentioned "optionally substituted lower alkyl group" as a preferable example of Y include, for example, (a) methyl, ethyl, propyl, isopropyl, butyl, isobutyl,
In addition to linear or branched alkyl groups having 1 to 6 carbon atoms such as sec-butyl and tert-butyl, (b) a halogenated C _1-6 alkyl group (for example, chloromethyl, difluoromethyl, Trichloromethyl, trifluoromethyl,
2-bromoethyl, 2,2,2-trifluoroethyl,
Perfluoroethyl, 3,3,3-trifluoropropyl, perfluorobutyl, etc.), (c) a C _1-6 alkyl group substituted with an amino group (for example, aminomethyl, 2-
Amino and ethyl group), (d) mono- - or di -C _1-6 alkylamino C _1-6 alkyl group substituted by group (e.g., methylaminomethyl, dimethylaminomethyl, 2-
(E) a C _1-6 alkyl group substituted with a carboxyl group (eg, carboxymethyl, carboxyethyl group, etc.), (f) a C _1-6 alkoxy-carbonyl A C _1-6 alkyl group substituted with a group (for example, methoxycarbonylethyl, ethoxycarbonylethyl, t-butoxycarbonylmethyl group, etc.), (g) a C _1-6 substituted with a hydroxy group
An alkyl group (eg, hydroxymethyl, hydroxyethyl group), (h) a C _1-6 alkyl group (eg, benzyl) substituted with a C _{6-14 aryl} group, and (i) a C _1-6 alkoxy group. A substituted C _1-6 alkyl group (eg, methoxymethyl, methoxyethyl, etc.) or (j) a C _1-6 alkyl group substituted with a C _7-15 aralkyloxy group (eg, benzyloxymethyl, etc.) Is raised.

Examples of the above-mentioned “optionally substituted hydroxy group” as a preferred example of Y include, for example, R ⁶
And the same as the “optionally substituted hydroxy group” as the “substituent” of the “optionally substituted amino group”. Examples of the above-mentioned “optionally substituted amino group” as a preferable example of Y include, for example, those similar to the “optionally substituted amino group” represented by R ⁶ . As the “optionally substituted hydrocarbon group” as “R ¹² ” of the above “SR ¹² ” as a preferred example of Y, for example, the “optionally substituted hydrocarbon” represented by R ³ And the like. “R” of “SR ¹² ” represented by Y
As the “acyl group” as “ ¹² ”, for example, the aforementioned R ¹
And the same as the “acyl group” represented by Examples of the “optionally substituted heterocyclic group” as “R ¹² ” of “SR ¹² ” represented by Y include the aforementioned R
^{And the same} as the “optionally substituted heterocyclic group” represented by ¹ (however, the “substituent” of the “optionally substituted heterocyclic group” represented by the above R ¹⁾ Medium, Y
(Y is as defined above) and a group represented by the formula

Embedded image (Each symbol is as defined above) is a group represented by R ¹²
Excluding from the substituents of the “optionally substituted heterocyclic group”).

More preferably, Y is, for example, an unsubstituted C _1-6 alkyl group (eg, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, etc.) or a hydroxy group. C
Examples thereof include a _1-6 alkyl group (eg, hydroxymethyl, hydroxyethyl group, etc.), a C _1-6 alkyl group substituted with an alkoxy group (eg, benzyloxymethyl, methoxymethyl group, etc.), and an oxo group.

Regarding “m”, m represents the same or different and represents 0 or 1. m
Is preferably 0.

Regarding “n”, n represents an integer of 1 to 3. n is 1 or 2
Is preferable, and 1 is more preferable.

Regarding “q ₁ and q ₂ ”, q ₁ represents an integer of 1 to 2n + 4, and q ₂ represents 0 to 2
n + 3, and the sum of q ₁ and q ₂ indicates 2n + 4. q ₁ is preferably 1.

The partial structure of the compound represented by the formula [I]
And a formula which is a partial structure in the above formula [I]

Embedded image Preferably, as the group represented by, for example, a formula

Embedded image (R ⁷ to R ¹¹ are the same or different and are each a hydrogen atom, a lower alkyl group which may be substituted, a hydroxy group which may be substituted, an amino group which may be substituted or SR ¹² (R ¹² is Shows the same meaning as above)
Other symbols have the same meanings as described above).

The “optionally substituted lower alkyl group” represented by R ⁷ to R ¹¹ includes, for example, (a) methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl (B) a halogenated C _1-6 alkyl group (for example, chloromethyl, etc.), in addition to a linear or branched alkyl group having 1 to 6 carbon atoms such as
Difluoromethyl, trichloromethyl, trifluoromethyl, 2-bromoethyl, 2,2,2-trifluoroethyl, perfluoroethyl, 3,3,3-trifluoropropyl, perfluorobutyl, etc.), (c) amino (D) mono- or di-substituted C _1-6 alkyl group (eg, aminomethyl, 2-aminoethyl group, etc.)
A C _1-6 alkyl group substituted with a C _1-6 alkylamino group (for example, methylaminomethyl, dimethylaminomethyl, 2-methylaminoethyl, 2-dimethylaminoethyl group, etc.), (e) a carboxyl group C _1-6 alkyl group (e.g., carboxymethyl, carboxymethyl ethyl group), (f) C _1-6 alkoxy - C _1-6 alkyl group substituted with a carbonyl group (e.g., methoxycarbonylethyl, ethoxycarbonyl Ethyl, t-butoxycarbonylmethyl group), (g) a C _1-6 alkyl group substituted with a hydroxy group (eg, hydroxymethyl, hydroxyethyl group, etc.), and (h) a C _{6-14 aryl} group substituted with a C _{6-14 aryl} group. C
_1-6 alkyl group (for example, benzyl and the like), (i) C _1-6 alkyl group substituted with C _1-6 alkoxy group (for example, methoxymethyl, methoxyethyl and the like), or (j) C
_And a C _1-6 alkyl group substituted with a _7-15 aralkyloxy group (eg, benzyloxymethyl). The “optionally substituted hydroxy group” represented by R ⁷ to R ¹¹ includes, for example, “substituted” as the “substituent” of the “optionally substituted amino group” represented by R ^6. And the like. Examples of the “optionally substituted amino group” represented by R ⁷ to R ¹¹ include the aforementioned R ⁶
And the same as the “optionally substituted amino group” represented by

More preferably, R ⁷ to R ¹¹ are, for example, an unsubstituted C _1-6 alkyl group (for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl,
sec-butyl, tert-butyl, etc.), a C _1-6 alkyl group substituted with a hydroxy group (eg, hydroxymethyl, hydroxyethyl group, etc.), a C _1-6 alkyl group substituted with an alkoxy group (eg, benzyl) Oxymethyl and methoxymethyl groups) or oxo groups. Formula which is a partial structure in the above formula [I]

Embedded image As the group represented by, for example,

Embedded image (R ¹³ to R ²⁵ are the same or different and are each a hydrogen atom, a lower alkyl group which may be substituted, a hydroxy group which may be substituted, an amino group which may be substituted or SR ¹² (R ¹² is R ¹³ to R ²⁵ are also preferred.
As the "optionally substituted lower alkyl group" represented by, for example, (a) methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-
(B) halogenated C _1-6 alkyl groups (for example, chloromethyl, difluoromethyl, trichloromethyl, trifluoromethyl) , 2-bromoethyl,
2,2,2-trifluoroethyl, perfluoroethyl, 3,3,3-trifluoropropyl, perfluorobutyl, etc.), (c) a C _1-6 alkyl group substituted with an amino group (for example, amino methyl and 2-aminoethyl group), (d) mono- - or di -C _1-6 alkylamino C _1-6 alkyl group substituted by group (e.g., methylaminomethyl, dimethylaminomethyl, 2-methylamino Ethyl, 2-dimethylaminoethyl, etc.), (e) a C _1-6 alkyl group substituted with a carboxyl group (eg, carboxymethyl, carboxyethyl group, etc.), and (f) a C _1-6 alkoxy-carbonyl group. Substituted C _1-6 alkyl group (for example, methoxycarbonylethyl, ethoxycarbonylethyl, t-butoxycarbonylmethyl group, etc.),
(g) a C _1-6 alkyl group substituted with a hydroxy group (for example, hydroxymethyl, hydroxyethyl group, etc.),
(h) a C _1-6 alkyl group substituted with a C _{6-14 aryl} group (eg, benzyl, etc.); and (i) a C _1-6 alkyl group substituted with a C _1-6 alkoxy group (eg, methoxymethyl , Methoxyethyl and the like), or (j) a C _1-6 alkyl group substituted with a C _7-15 aralkyloxy group (for example, benzyloxymethyl and the like).

The “optionally substituted hydroxy group” represented by R ¹³ to R ²⁵ includes, for example, a “substituent” of the “optionally substituted amino group” represented by R ^6. And the same as the "optionally substituted hydroxy group". Examples of the “optionally substituted amino group” represented by R ¹³ to R ²⁵ include, for example, those similar to the “optionally substituted amino group” represented by R ⁶ . More preferably, as R ¹³ to R ²⁵ , for example, an unsubstituted C _1-6 alkyl group (eg, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, etc.) or a hydroxy group C _1-6 alkyl group (eg, hydroxymethyl, hydroxyethyl group, etc.), C _1-6 alkyl group substituted with alkoxy group (eg, benzyloxymethyl, methoxymethyl group, etc.)
Or an oxo group. Further, the formula which is a partial structure in the above formula [I]

Embedded image Formulas described as preferred examples of the group represented by

Embedded image (Wherein each symbol is as defined above), particularly preferably

Embedded image (Wherein each symbol has the same meaning as described above). Preferred examples of the compound represented by the formula [I] include, for example, the following formulas [Ia], [Ib], and [I]
c], formula [Id], formula [Ie], formula [If], formula [I
g], a compound represented by the formula [Ih], a formula [Ii], a formula [XXXIV] or a formula [XXXVII]. In the compound represented by the formula [I], both the A ring and the B ring are benzene rings, R ¹ is an acyl group, X ¹ is methylene, X ² is an oxygen atom, n
Is particularly preferred.

The optically active form of the compound represented by the formula [I]
When the compound represented by the formula [I] or a salt thereof contains an asymmetric carbon in the structure, an optically active substance is obtained.

Embedded image (Wherein each symbol has the same meaning as described above), or a salt thereof is preferably used.

Next, a method for producing the compound (I) of the present invention or a salt thereof will be described. The compound (I) or a salt thereof of the present invention can be produced by the following methods (A) to (N).

(Method A) Formula represented by compound (I) of the present invention

Embedded image (In the formula, q _1a represents 1 to 2n + 2, q _2a represents 0 to 2n + 1, the sum of q _1a and q _2a represents 2n + 2, and other symbols have the same meanings as described above.) The compound or a salt thereof is, for example, a compound of the formula

Embedded image (II) (wherein each symbol is as defined above) or a salt thereof and a compound represented by the formula

Embedded image (III) (wherein q _1a represents 1 to 2n + 2, and q _2a represents 0
To indicate the 2n + 1, the sum of q _1a and q _2a shows the 2n + 2. ) Or a salt thereof, or

Embedded image (IV) (wherein each symbol has the same meaning as described above) or a salt thereof, and can be produced.

In this reaction, 1 to 5 mol, preferably 1 to 3 mol of compound [III] or its salt or compound [IV] or its salt is used per 1 mol of compound [II] or its salt. . The reaction solvent is benzene, toluene, aromatic hydrocarbons such as xylene, organic acids such as acetic acid, organic acid anhydrides such as acetic anhydride, N,
Amides such as N-dimethylformamide and N, N-dimethylacetamide are used. This reaction is generally performed under dehydration conditions. In this reaction, addition of an acid advantageously promotes the reaction. As such an acid, inorganic acids such as hydrochloric acid and sulfuric acid, and organic acids such as methanesulfonic acid, benzenesulfonic acid, toluenesulfonic acid, oxalic acid, fumaric acid, and maleic acid are preferable. The amount of the acid used varies depending on the type of the compound and the solvent used, and other reaction conditions, but is usually 0.01 to 1 mol, preferably 0.05 to 0.1 mol, per 1 mol of the compound. The reaction temperature is usually 0 to 200 ° C, preferably 50 to 150 ° C. The reaction time is usually 30 minutes to 48 hours, preferably 1 to 24 hours. The compound [II] is produced by the method shown in the below-mentioned method N, and the compounds [III] to [IV] are commercially available or sulfur-substituted acid anhydrides and dicarboxylic acids produced by the below-mentioned method D and the like.

(Method B) The compound (I) of the present invention or a salt thereof is, for example, a compound represented by the formula

Embedded image (II) wherein each symbol is as defined above, or a salt thereof.

Embedded image (V) (wherein each symbol is as defined above) or a salt thereof, or

Embedded image (VI) (wherein each symbol has the same meaning as described above) or a salt thereof, and

Embedded image (VII) (wherein each symbol is as defined above) or a salt thereof, or a compound represented by the formula

Embedded image (VIII) (wherein each symbol has the same meaning as described above) or a salt thereof, and the compound of the above formula [VII]
Or a compound represented by the formula [VIII] or a salt thereof and R ¹
It can be produced by reacting a compound represented by SH (R ¹ has the same meaning as described above) or a salt thereof.

The compound represented by the formula [II] or a salt thereof is reacted with the compound represented by the formula [V] or the formula [VI] or a salt thereof to obtain a compound represented by the formula [VII] or the formula [VIII]. In order to produce the compound or a salt thereof, a method similar to the above (Method A) or the like is used. The formula [VI
In a reaction for producing a compound represented by the formula [I] or a salt thereof from a compound represented by the formula [I] or the formula [VIII] or a salt thereof, the compound represented by the formula [VII] or the formula [VII]
1] to 1 mol, preferably 1 to 3 mol of the compound represented by R ¹ SH (R ¹ has the same meaning as described above) or a salt thereof per 1 mol of the compound represented by I] or a salt thereof.
Use moles. Examples of R ¹ SH include inorganic sulfur such as hydrogen sulfide, sodium hydrosulfide, and sodium sulfide and salts thereof, organic sulfur acids such as thioacetic acid and thiobenzoic acid and salts thereof, methyl mercaptan, benzyl mercaptan,
Aliphatic mercaptans such as triphenylmethylmercaptan and 3-mercaptopropionic acid derivatives, aromatic mercaptans such as thiophenol and thioureas are used. Reaction solvents are methanol, alcohols such as ethanol, dioxane, ethers such as tetrahydrofuran, benzene, toluene, aromatic hydrocarbons such as xylene, esters such as ethyl acetate, chloroform, halogenated hydrocarbons such as dichloromethane, Nitriles such as acetonitrile, amides such as N, N-dimethylformamide and N, N-dimethylacetamide, and sulfoxides such as dimethylsulfoxide are used. In this reaction, addition of a base advantageously promotes the reaction. Such bases include inorganic bases (eg, alkali metal hydroxides such as sodium hydroxide and potassium hydroxide, alkali metal bicarbonates such as sodium hydrogen carbonate and potassium hydrogen carbonate, and alkali metal carbonates such as sodium carbonate and potassium carbonate). Salts, alkali metal hydrides such as sodium hydride, potassium hydride, alkoxides such as sodium amide, sodium methoxide, sodium ethoxide, etc.), organic bases (amines such as trimethylamine, triethylamine, diisopropylethylamine, etc., cyclic compounds such as pyridine) Amines etc. are used

In this reaction, instead of using a base, R
^The compound represented by ¹ SH (R ¹ has the same meaning as described above) or a salt thereof is converted into, for example, an alkali metal salt, an alkaline earth metal salt, or the like, and this is converted into a compound of the formula [VII] or [VII]
I] or a salt thereof. The amount of the base used depends on the compound used, the type of the solvent and other reaction conditions.
^{The amount is 1} to 10 mol, preferably 1 to 5 mol, per 1 mol of the compound represented by ¹ SH (R ¹ has the same meaning as described above) or a salt thereof. The reaction temperature is about -50 to 20
The reaction is carried out at 0 ° C, preferably in the range of -20 to 100 ° C. The reaction time varies depending on the type of the compound, the reaction temperature and the like, but is 1 to 72 hours, preferably 1 to 24 hours.

(Method C) The formula included in the compound (I) of the present invention

Embedded image (In the formula, q _2b represents 2n + 3, and other symbols have the same meanings as described above.)

Embedded image (Wherein each symbol is as defined above) or a salt thereof and an oxidizing agent.

Examples of the oxidizing agent used in this reaction include general disulfide bond-forming reagents such as those shown in New Experimental Chemistry Lecture 15, Oxidation and Reduction (Maruzen), for example, chlorine, bromine, and the like.
Halogens such as iodine, N-halogen carboximides or sulfonamides such as N-chlorosuccinimide, chromic acid, lead tetraacetate, potassium permanganate,
Metal oxidizing agents such as iron chloride, organic peroxides such as metachloroperbenzoic acid and peracetic acid, hydrogen peroxide and air oxidation are used. In this reaction, 1 to 5 mol of an oxidizing agent is usually used per 1 mol of compound [IX] or a salt thereof,
Preferably, 1 to 2 mol is used. Reaction solvents include ethers such as dioxane and tetrahydrofuran; aromatic hydrocarbons such as benzene, toluene and xylene; esters such as ethyl acetate; halogenated hydrocarbons such as chloroform and dichloromethane; nitriles such as acetonitrile; N-dimethylformamide, N, N-
Amides such as dimethylacetamide and sulfoxides such as dimethylsulfoxide are used.

In this reaction, the addition of a base advantageously promotes the reaction. Such bases include inorganic bases (such as alkali metal hydroxides such as sodium hydroxide and potassium hydroxide,
Alkali metal bicarbonates such as sodium bicarbonate and potassium bicarbonate; alkali metal carbonates such as sodium carbonate and potassium carbonate; halides such as sodium iodide and potassium iodide; alkali metals such as sodium hydride and potassium hydride Hydride, sodium amide,
Examples thereof include alkoxides such as sodium methoxide and sodium ethoxide, and organic bases (amines such as trimethylamine, triethylamine, diisopropylethylamine, and cyclic amines such as pyridine). The amount of the base depends on the compound used, the type of solvent,
The compound [IX] usually varies depending on other reaction conditions.
Or 0.1 to 20 mol, preferably 1 to 2 mol, per 1 mol of a salt thereof. Reaction temperature is -20 to 2
00 ° C, preferably 0 to 100 ° C. The reaction time is generally 1 minute to 24 hours, preferably 1 minute to 5 hours.

(Method D) The formula included in the compound (I) of the present invention

Embedded image ( _Wherein , q _1c represents an integer of 1 to 2n + 2, q _2c represents an integer of 0 to 2n + 1, and the sum of q _1c and q _2c is 2
n + 2, and other symbols are as defined above)
The compound represented by or a salt thereof is, for example, a compound represented by the formula

Embedded image (Wherein each symbol is as defined above) or a salt thereof and a compound represented by the formula

Embedded image (Wherein each symbol has the same meaning as described above) or a salt thereof.

In this reaction, first, the compound [X] or a salt thereof is reacted with various acid anhydrides or acid halides to produce the corresponding acid anhydride. The reagent used is an acid anhydride or acid halide of a common organic acid such as acetic acid and benzoic acid. This reaction was carried out using compound [X] or a salt thereof 1
1 to 50 moles of reagent are used per mole. Reaction solvents include aromatic hydrocarbons such as benzene, toluene and xylene, or organic acids such as acetic acid, nitriles such as acetonitrile, N, N-dimethylformamide,
Amides such as N, N-dimethylacetamide are used, but an acid anhydride of a reagent can also be used as a solvent. The reaction temperature varies depending on the compound [X] or a salt thereof used, and other conditions, but is preferably 0 to 200 ° C, preferably
20-150 ° C. The reaction time is 30 minutes to 24 hours, preferably 1 to 10 hours. From the obtained acid anhydride and compound [II] or a salt thereof, the above (Method A)
Compound [Ic] or a salt thereof can be produced in the same manner as in the above.

In the compound represented by the compound [Ic], R ¹
Can be hydrolyzed with an acid or a base to produce a compound wherein R ¹ is H. Acids used are inorganic acids such as hydrochloric acid, sulfuric acid and nitric acid; bases are alkali metal hydroxides such as sodium hydroxide and potassium hydroxide; alkali metal hydrogen carbonates such as sodium hydrogen carbonate and potassium hydrogen carbonate; sodium carbonate And alkali metal carbonates such as potassium carbonate, alkoxides such as sodium amide, sodium methoxide and sodium ethoxide, and organic amines such as ammonia, methylamine and ethylamine. Compounds in this reaction is represented by the compounds [Ic], R ¹
3 but in a compound represented by 20 to in the inorganic acid aqueous solution 50-fold volume relative to compound 1g acyl group (usually 10 to 30%) or a compound [Ic], R ¹ is 1 mole of the compound of the acyl group The reaction is carried out in an aqueous solution containing from 10 to 10 mol of the above base. Further, from the solubility of the compound, an organic solvent can be added to the above aqueous solution to carry out the reaction, or the reaction can be carried out in an organic solvent. Organic solvents used include alcohols such as methanol and ethanol, organic acids such as acetic acid, ethers such as dioxane and tetrahydrofuran, nitriles such as acetonitrile, and amides such as N, N-dimethylformamide and N, N-dimethylacetamide. And sulphoxides such as dimethylsulphoxide. The reaction temperature is 0 to 200 ° C, preferably 20 to 150 ° C, depending on the compound represented by the compound [Ic] in which R ¹ is an acyl group and other conditions. The reaction time is 30 minutes to 48 hours, preferably 1 to 24 hours.

The compound represented by the formula (X) or a salt thereof is represented by the formula

Embedded image (Wherein, L ¹ represents a leaving group, R ^a represents a same or different and each optionally substituted hydrocarbon group, Y is as defined above) or a salt thereof And a sulfur nucleophile, followed by hydrolysis. Here, L ¹ in compound [XI]
Examples of the leaving group represented by are hydroxy, a halogen atom (eg, chlorine, bromine, iodine, etc.), and a substituted sulfonyloxy (eg, methanesulfonyloxy, p
-Toluenesulfonyloxy, etc.), acyloxy (acetoxy, benzoyloxy, etc.), an oxy group substituted with a heterocyclic ring or an aryl group (succinimide, benzotriazole, quinoline, 4-nitrophenyl, etc.). Examples of the optionally substituted hydrocarbon group represented by R ^a include, for example, those similar to the “optionally substituted hydrocarbon group” represented by R ¹ above, and in particular, methyl, C such as ethyl and propyl
_1-4 alkyl groups are preferably used. Examples of the sulfur nucleophile include inorganic sulfur such as hydrogen sulfide, sodium hydrosulfide and sodium sulfide and salts thereof, organic sulfur acids and salts thereof such as thioacetic acid and thiobenzoic acid, benzyl mercaptan, triphenylmethyl mercaptan, and 3-mercapto. Mercaptans such as propionic acid derivatives or thioureas are used. Examples of the base include inorganic bases (such as alkali metal hydroxides such as sodium hydroxide and potassium hydroxide, alkali metal bicarbonates such as sodium hydrogen carbonate and potassium hydrogen carbonate, alkali metal carbonates such as sodium carbonate and potassium carbonate, and cesium carbonate Cesium salts such as sodium hydride, alkali metal hydrides such as potassium hydride, alkoxides such as sodium amide, sodium methoxide, sodium ethoxide, etc.), organic bases (amines such as trimethylamine, triethylamine, diisopropylethylamine, pyridine) And the like are used.

In this reaction, compound [XI] or a salt thereof 1
1 to 5 moles, preferably 1 mole, of sulfur nucleophile per mole
To 3 moles. The base is also used in an amount of 1 to 5 mol, preferably 1 to 3 mol. Reaction solvents are methanol, alcohols such as ethanol, dioxane, ethers such as tetrahydrofuran, benzene, toluene, aromatic hydrocarbons such as xylene, esters such as ethyl acetate, chloroform, halogenated hydrocarbons such as dichloromethane, Nitriles such as acetonitrile, amides such as N, N-dimethylformamide and N, N-dimethylacetamide, and sulfoxides such as dimethylsulfoxide are used. The reaction temperature varies depending on the compound used and other conditions, but is from -20 to
The temperature is 200 ° C, preferably 0 to 150 ° C. The reaction time is generally 5 minutes to 24 hours, preferably 5 minutes to 6 hours. Compound [X] or a salt thereof can be produced by hydrolyzing the obtained sulfur-substituted product with an acid or a base.
Inorganic acids such as hydrochloric acid, sulfuric acid, nitric acid, and the like,
As the base, an inorganic base (such as an alkali metal hydroxide such as sodium hydroxide or potassium hydroxide, an alkali metal bicarbonate such as sodium hydrogen carbonate or potassium hydrogen carbonate,
Alkali metal carbonates such as sodium carbonate and potassium carbonate).

This reaction is carried out in an aqueous solution of the above-mentioned inorganic acid (usually 10 to 30%) per 1 g of the sulfur-substituted product or in an aqueous solution containing 3 to 10 mol of the above-mentioned base per 1 mol of the sulfur-substituted product. Done. Further, the reaction can be carried out by adding an organic solvent to the above aqueous solution due to the solubility of the compound. Organic solvents used include alcohols such as methanol and ethanol, organic acids such as acetic acid, ethers such as dioxane and tetrahydrofuran, nitriles such as acetonitrile, N, N-dimethylformamide, N, N
Amides such as dimethylacetamide and sulfoxides such as dimethylsulfoxide. The reaction temperature depends on the sulfur substituent used and other conditions,
The temperature is 0 to 200 ° C, preferably 20 to 150 ° C. The reaction time is 30 minutes to 48 hours, preferably 1 to 24 hours.

Compound [XI] can be obtained by using a commercially available halogenated dicarboxylic acid derivative or a corresponding aminodicarboxylic acid derivative by a method known in the literature, for example, Heterocycles 24.
(5) 1331 (1986), Journal of Organic Chemistry 58 (5) 1159 (19 )
93) or the corresponding hydroxy form is obtained by a known method such as the acylation or alkylation method shown in Organic Functional Group Preparations (Academic Press). Those appropriately converted to the above-mentioned leaving groups can be used.

(Method E) Formula represented by compound (I) of the present invention

Embedded image (In the formula, q _2d represents 0 to 2, and other symbols have the same meanings as described above.)

Embedded image (Wherein each symbol has the same meaning as described above) or a salt thereof and R ¹ SH (R ¹ has the same meaning as described above)
Or a salt thereof in the presence of a base.

In this reaction, 1 to 5 moles, preferably 1 to 3 moles of a compound represented by R ¹ SH (R ¹ has the same meaning as described above) or a salt thereof per mole of compound [XII] or a salt thereof. Mol, 1 to 5 mol of base, preferably 1
To 3 moles. Examples of the compound represented by R ¹ SH (R ¹ has the same meaning as described above) include, for example, inorganic sulfides such as hydrogen sulfide, sodium hydrosulfide, and sodium sulfide; methyl mercaptan, ethyl mercaptan, and mercaptopropionic acid derivatives Aliphatic mercaptans, such as
Organic sulfur acids such as thioacetic acid and thiobenzoic acid; aromatic mercaptans such as thiophenol; and thioureas. Examples of the base include alkali metal hydroxides such as sodium hydroxide and potassium hydroxide, alkali metal bicarbonates such as sodium bicarbonate and potassium bicarbonate,
Alkali metal carbonates such as sodium carbonate and potassium carbonate, cesium salts such as cesium carbonate, alkali metal hydrides such as sodium hydride and potassium hydride, alkoxides such as sodium amide, sodium methoxide and sodium ethoxide, trimethylamine, triethylamine And amines such as diisopropylethylamine and cyclic amines such as pyridine. The reaction solvent used is alcohols such as methanol and ethanol, ethers such as dioxane and tetrahydrofuran, aromatic hydrocarbons such as benzene, toluene and xylene, esters such as ethyl acetate, chloroform,
Examples include halogenated hydrocarbons such as dichloromethane, nitriles such as acetonitrile, amides such as N, N-dimethylformamide and N, N-dimethylacetamide, and sulfoxides such as dimethylsulfoxide.
In this reaction, instead of using a base, the compound represented by R ¹ SH may be converted into, for example, an alkali metal salt or an alkaline earth metal salt, and this may be reacted with compound [XII] or a salt thereof. The reaction temperature depends on the compound used [XI
I] or its salt and other conditions,
It is 0 to 200 ° C, preferably 0 to 150 ° C. The reaction time is 5 minutes to 24 hours, preferably 5 minutes to 6 hours.

The compound represented by the formula [XII] or a salt thereof is, for example,

Embedded image (Wherein each symbol is as defined above) or a salt thereof and a compound represented by the formula

Embedded image (Wherein each symbol is as defined above) or a salt thereof to produce an amide, followed by hydrolysis and imidation.

In this reaction, first, the compound [XII
I] or a salt thereof is condensed with compound [II] or a salt thereof to produce an amide. These are known amidation reactions,
For example, it can be produced by the method shown in Experimental Chemistry Course 22, Organic Synthesis IV (Maruzen). As the condensing agent, for example, dicyclohexylcarbodiimide (DCC), diethyl cyanophosphate (DEPC), diphenylphosphoryl azide (DPPA) and the like are used. When these condensing agents are used, the solvent is usually (e.g., ethers, esters, hydrocarbons, amides such as tetrahydrofuran, dioxane, dimethoxyethane, ethyl acetate, benzene, toluene, N, N-dimethylformamide, and dimethyl sulfoxide). , Sulfoxides).
This reaction may be promoted in the presence of a base,
The reaction is carried out at 0 to 100 ° C, preferably at 0 to 60 ° C. The reaction time is usually 30 minutes to 96 hours, preferably 1 to 72 hours. The amounts of compound [II] or a salt thereof and the condensing agent to be used are respectively 1 to 5 mol, preferably 1 to 3 mol, per 1 mol of compound [XIII] or a salt thereof. Examples of the base include alkylamines such as triethylamine, and cyclic amines such as N-methylmorpholine and pyridine. The amount of the base is 1 to 5 mol, preferably 1 to 5 mol, per 1 mol of compound [XIII] or a salt thereof. Or 3 moles.

The obtained ester is hydrolyzed to produce a carboxylic acid. Acids or bases are used for the hydrolysis. The acid used is an inorganic acid such as hydrochloric acid, sulfuric acid or nitric acid, and the base is an inorganic base (alkali metal hydroxide such as sodium hydroxide or potassium hydroxide, alkali metal bicarbonate such as sodium hydrogen carbonate or potassium hydrogen carbonate) Alkali metal carbonates such as sodium carbonate and potassium carbonate). This reaction was performed with 1 g of the ester.
The reaction is carried out in an aqueous solution of the above-mentioned inorganic acid (usually 10 to 30%) or an aqueous solution containing 3 to 10 mol of the above-mentioned base per 1 mol of the ester. Further, the reaction can be carried out by adding an organic solvent to the above aqueous solution due to the solubility of the compound. Organic solvents used include alcohols such as methanol and ethanol, organic acids such as acetic acid, ethers such as dioxane and tetrahydrofuran, nitriles such as acetonitrile, and amides such as N, N-dimethylformamide and N, N-dimethylacetamide. And sulphoxides such as dimethylsulphoxide. The reaction temperature varies depending on the ester used and other conditions, but is 0 to 200 ° C, preferably 20 ° C.
To 150 ° C. Reaction time is 30 minutes to 48 hours,
Preferably, it is 1 to 24 hours.

The obtained carboxylic acid is condensed to give a compound [X
II] or a salt thereof can be produced. In this reaction, 10 to 50 times the volume of a condensing agent is used as a reaction solvent for 1 g of carboxylic acid. As the condensing agent, anhydrides of general organic acids such as acetic anhydride and benzoic anhydride are used.
In this reaction, addition of a base advantageously promotes the reaction. The base used is preferably an alkali metal salt of an organic acid corresponding to the condensing agent used, such as sodium acetate and potassium acetate. The amount used is 0.1 to 1 mol of carboxylic acid. The reaction temperature varies depending on the carboxylic acid used and other conditions, but is 20 to 200 ° C, preferably 50 to 150 ° C. The reaction time is 5 minutes to 24 hours, preferably 5 minutes to 5 hours. As the compound [VIII], a commercially available epoxy succinic acid derivative is mainly used.

(Method F) Formulas included in the compound (I) of the present invention

Embedded image (In the formula, q _2e represents 2n + 1, and other symbols have the same meanings as described above.)
For example, the expression

Embedded image (Wherein each symbol has the same meaning as described above) or a salt thereof can be produced in the presence of a base by the same method as described in the above Method C.

The compound represented by the formula (XIV) or a salt thereof is, for example,

Embedded image (Wherein each symbol is as defined above) or a salt thereof,

Embedded image (Wherein each symbol is as defined above) or a salt thereof to form an amide, and then R ¹ S
H (wherein, R ¹ has the same meaning as described above) or a salt thereof, followed by imidization. In the amidation reaction, 1 to 5 mol, preferably 1 to 2 mol of compound [II] or a salt thereof is reacted with 1 mol of compound [XV] or a salt thereof. Reaction solvents are methanol, alcohols such as ethanol, dioxane, ethers such as tetrahydrofuran, benzene, toluene, aromatic hydrocarbons such as xylene, esters such as ethyl acetate, chloroform, halogenated hydrocarbons such as dichloromethane,
Examples thereof include nitriles such as acetonitrile, amides such as N, N-dimethylformamide and N, N-dimethylacetamide, and sulfoxides such as dimethylsulfoxide. The reaction temperature varies depending on the compound [XV] or a salt thereof or other conditions, but is from -20 to 100 ° C, preferably from 0 to 100 ° C. The reaction time is 5 minutes to 5 hours, preferably 5 minutes to 1 hour. The obtained amide form can be converted into an adduct by the same method as described in the above (Method B), and further condensed by the same method as described in the (Method E) to produce compound [XIV] or a salt thereof.
As the compound [XV], a commercially available itaconic anhydride derivative or the like is mainly used.

(Method G) Compound (I) of the present invention or a salt thereof may be, for example, a compound represented by the formula

Embedded image (Wherein L ² represents a leaving group, and other symbols have the same meanings as described above) or a salt thereof and R ¹ S
It can be produced by reacting a compound represented by H (R ¹ has the same meaning as described above) or a salt thereof in the presence of a base. The leaving group represented by L ^2, for example, those similar to the leaving group of the L ¹ and the like.

The compound represented by the formula (XVI) or a salt thereof is, for example,

Embedded image (Wherein each symbol has the same meaning as described above) or a salt thereof. That is,
Compound [XVI] or a salt thereof decarboxylates compound [XVII] or a salt thereof, reacts a dicarbonyl compound produced in the system with a nucleophile or a reducing agent to give a hydroxy form, and converts this to a leaving group. Can be manufactured.

The decarboxylation reaction is carried out with 1 g of compound [XVII].
The reaction is carried out in a solvent of from 100 to 100 times, preferably from 20 to 50 times by volume. The solvent used is preferably nitriles such as acetonitrile, but dioxane, ethers such as tetrahydrofuran, benzene, toluene,
Aromatic hydrocarbons such as xylene; esters such as ethyl acetate; halogenated hydrocarbons such as chloroform and dichloromethane; N, N-dimethylformamide;
Examples include amides such as N-dimethylacetamide, sulfoxides such as dimethyl sulfoxide, and water. The reaction temperature varies depending on the compound [XVII] used, its salt or other conditions, but it is 0 to 200 ° C, preferably 20 to 150 ° C. Reaction time is 5 minutes to 24
Time, preferably 5 minutes to 1 hour. In the nucleophilic reaction and the reduction reaction, 1 to 5 mol, preferably 1 to 3 mol of a nucleophile or a reducing agent is used per 1 mol of [XVII] or a salt thereof. Organometallic reagents such as organolithium, organozinc, organoaluminum and Grignard reagents are used as the nucleophile. As the reducing agent, metal hydrides such as sodium borohydride and lithium aluminum hydride are suitable, but other reagents for reducing ketone compounds to alcohols are generally described in, for example, New Experimental Chemistry Lecture 15 Oxidation and Reduction (Maruzen). Reagents and the like can be used. Solvents used are alcohols such as methanol and ethanol, ethers such as dioxane and tetrahydrofuran, benzene, toluene, aromatic hydrocarbons such as xylene, esters such as ethyl acetate,
Examples include halogenated hydrocarbons such as chloroform and dichloromethane, nitriles such as acetonitrile, amides such as N, N-dimethylformamide and N, N-dimethylacetamide, and sulfoxides such as dimethylsulfoxide. The reaction temperature varies depending on the reagents used and other conditions, but is −100 to 200 ° C., preferably −
78-100 ° C. Reaction time is 5 minutes to 24
Time, preferably 5 minutes to 10 hours. Compound [XVI] can be produced by converting the obtained hydroxy form into various leaving groups. Examples of the leaving group include a halogen atom (eg, chlorine, bromine, iodine, etc.), a substituted sulfonyloxy (eg, methanesulfonyloxy, p-toluenesulfonyloxy, etc.), an acyloxy (acetoxy, benzoyloxy, etc.), a heterocyclic or aryl group (An oxy group substituted with succinimide, benzotriazole, quinoline, 4-nitrophenyl, etc.). Regarding halogen atoms, thionyl chloride, thionyl bromide, phosphorus trichloride, phosphorus pentachloride, inorganic acid halides such as phosphorus oxychloride, hydrochloric acid,
Hydrohalic acids such as hydrobromic acid can be used. For other leaving groups, the compound of method D [X
It can be produced by a known method as described in the preparation method of [I]. For example, the latter reaction using acylation is performed by reacting the corresponding halide 1 with respect to 1 mol of the hydroxy form or a salt thereof.
1 to 5 mol, preferably 1 to 2 mol, base 1 to 5 mol, preferably 1 to 3 mol. For example, it may be used as a solvent depending on the type of base such as pyridine. Reaction solvents are dioxane, ethers such as tetrahydrofuran, benzene, toluene, aromatic hydrocarbons such as xylene, esters such as ethyl acetate,
Halogenated hydrocarbons such as chloroform and dichloromethane, nitriles such as acetonitrile, amides such as N, N-dimethylformamide and N, N-dimethylacetamide, and sulfoxides such as dimethyl sulfoxide are used. Sodium hydroxide as a base,
Alkali metal hydroxides such as potassium hydroxide, alkali metal bicarbonates such as sodium hydrogen carbonate and potassium hydrogen carbonate, alkali metal carbonates such as sodium carbonate and potassium carbonate, cesium salts such as cesium carbonate, sodium hydride, hydrogen Alkali metal hydrides such as potassium iodide, alkoxides such as sodium amide, sodium methoxide and sodium ethoxide, amines such as trimethylamine, triethylamine and diisopropylethylamine, and cyclic amines such as pyridine are used. The reaction temperature varies depending on the substrate used and other conditions, but is preferably from -20 to 200 ° C, preferably from 0 to 100 ° C.
° C. The reaction time is 30 minutes to 48 hours, preferably 1 to 24 hours. The obtained compound [XVI] is reacted with various sulfur nucleophiles by the same method as described in the above (Method D), and among the compounds represented by the compound [I], a compound wherein R ¹ is not H or a salt thereof; The compound represented by compound [I], wherein R ¹ is H, or a salt thereof can be produced by deprotection.

The compound represented by the formula (XVII) or a salt thereof is, for example,

Embedded image (Wherein each symbol is as defined above) or a salt thereof and a compound represented by the formula

Embedded image (Wherein each symbol has the same meaning as described above), or a salt thereof, or a compound represented by the formula

Embedded image (Wherein, X ₁ represents a halogen atom, and other symbols have the same meanings as described above), or a salt thereof, to give an amide form, followed by base treatment. it can.

The halogen atom represented by X ₁ includes, for example, fluorine, chlorine, bromine, iodine and the like.
In this reaction, the compound [XVIII] or a salt thereof is condensed with the compound [XIX] or a salt thereof with a condensing agent, or the amide compound is reacted with the acid halide compound [XX] or a salt thereof in the presence of a base. Can be manufactured. The former is the same as the method described in (Method E) above. The latter reaction is carried out using the compound [XVIII]
Alternatively, 1 to 5 mol, preferably 1 to 2 mol of compound [XX] or a salt thereof is used per 1 mol of the salt.
Examples of the base include alkali metal hydroxides such as sodium hydroxide and potassium hydroxide, alkali metal bicarbonates such as sodium hydrogen carbonate and potassium hydrogen carbonate, alkali metal carbonates such as sodium carbonate and potassium carbonate, and cesium such as cesium carbonate. Salts, sodium hydride, alkali metal hydrides such as potassium hydride, sodium amide,
Alkoxides such as sodium methoxide and sodium ethoxide, amines such as trimethylamine, triethylamine and diisopropylethylamine, and cyclic amines such as pyridine are used. The amount of the base used is 1 to 1 mol of the compound [XVIII] or a salt thereof.
To 10 mol, preferably 1 to 5 mol. For example, it may be used as a solvent depending on the type of base such as pyridine. Reaction solvents include ethers such as dioxane and tetrahydrofuran; aromatic hydrocarbons such as benzene, toluene and xylene; esters such as ethyl acetate; halogenated hydrocarbons such as chloroform and dichloromethane; nitriles such as acetonitrile; N-
Examples include amides such as dimethylformamide and N, N-dimethylacetamide, and sulfoxides such as dimethylsulfoxide. The reaction temperature depends on the compound used [XV
III] or its salt and other conditions,
The temperature is from -20 to 200 ° C, preferably from 0 to 100 ° C. The reaction time is 5 minutes to 48 hours, preferably 5 minutes to 24 hours. The compound [XVII] or a salt thereof can be produced by treating the obtained amide with a base.

In this reaction, 1 to 3 mol, preferably 1 to 2 mol of a base is used per 1 mol of the amide. As the base, sodium hydroxide, alkali metal hydroxides such as potassium hydroxide, sodium hydrogen carbonate, alkali metal hydrogen carbonate such as potassium hydrogen carbonate, sodium carbonate,
Alkali metal carbonates such as potassium carbonate, cesium salts such as cesium carbonate, alkali metal hydrides such as sodium hydride and potassium hydride, alkoxides such as sodium amide, sodium methoxide and sodium ethoxide are used. Reaction solvents are methanol, alcohols such as ethanol, dioxane, ethers such as tetrahydrofuran, benzene, toluene, aromatic hydrocarbons such as xylene, esters such as ethyl acetate, chloroform, halogenated hydrocarbons such as dichloromethane, Nitriles such as acetonitrile, N, N-
Amides such as dimethylformamide and N, N-dimethylacetamide, and sulfoxides such as dimethylsulfoxide are used. The reaction temperature varies depending on the amide compound used and other conditions, but is -20 to 200 ° C.
Preferably it is 0 to 100 ° C. The reaction time is 5 minutes to 48 hours, preferably 10 minutes to 5 hours.

The compound represented by the formula (XVIII) or a salt thereof is, for example,

Embedded image Wherein Y is as defined above, or a salt thereof, and a compound represented by the formula

Embedded image (Wherein each symbol has the same meaning as described above) or a salt thereof.

Compound [XVIII] or a salt thereof is compound [XXI] or a salt thereof with carbonyl compound [XX]
II], an imine compound can be prepared in a system and reduced with an appropriate reducing agent to produce the compound. Suitable reducing agents include, for example, sodium borohydride, lithium borohydride, sodium cyanoborohydride, and sodium triacetoxyborohydride. In this reaction, the compound [XXI] or a carbonyl compound per 1 mol of a salt thereof is used.
[XXII] 1 to 5 mol, preferably 1 to 2 mol, and 0.5 to 10 mol, preferably 0.5 to 3 mol, of a reducing agent are used. Reaction solvents are methanol, alcohols such as ethanol, dioxane, ethers such as tetrahydrofuran, benzene, toluene, aromatic hydrocarbons such as xylene, esters such as ethyl acetate, chloroform, halogenated hydrocarbons such as dichloromethane, Examples thereof include nitriles such as acetonitrile, amides such as N, N-dimethylformamide and N, N-dimethylacetamide, and sulfoxides such as dimethylsulfoxide. During the preparation of the imine, dehydration conditions using a molecular sieve or the addition of an acid accelerates the progress of the reaction. As the acid used at this time, acetic acid, trifluoroacetic acid and the like are preferable. The reaction temperature in the preparation of the imine is used [XX
0] to 200 ° C., preferably 0 to 15 ° C., depending on the compound represented by formula I] or a salt thereof and other conditions.
0 ° C. The reaction time is 30 minutes to 48 hours, preferably 1 to 24 hours. The reaction temperature in the reduction reaction is -20 to 150 ° C, preferably 0 to 10 ° C.
0 ° C. The reaction time is 30 minutes to 24 hours, preferably 30 minutes to 12 hours. As the compound [XXI], a commercially available amino acid derivative or the like is mainly used, and the compound [XXI]
[I] is a product manufactured by the method N or a commercially available product.

(Method H) Formula represented by compound (I) of the present invention

Embedded image (Wherein, R ¹ ′ represents an optionally substituted hydrocarbon group, an acyl group or an optionally substituted heterocyclic group, and other symbols have the same meanings as described above) Or a salt thereof, for example, of the formula

Embedded image (Wherein R ¹ ′ has the same meaning as described above) or a salt thereof and a compound represented by the above formula (IX) or a salt thereof in the same manner as described in the above (Method C). It can be produced by a method or a reaction known per se.

The compound represented by the formula (XXIII) or a salt thereof is commercially available or for example,

Embedded image (Wherein each symbol is as defined above) or a salt thereof and a method known in the literature (for example, Organic Chemistry of Bivalent Sulfur)
Vol1 p32 (Chem. Publ. Co. New York), Organic Functional Group Preparations 1 (Academic) and the like. Examples of the “optionally substituted hydrocarbon group” represented by R ¹ ′ include the above-mentioned R ^{1 ′}
And has the same meaning as the “optionally substituted hydrocarbon group”. The “acyl group” represented by R ¹ ′ has, for example, the same meaning as the “acyl group” represented by R ¹ .
The “optionally substituted heterocyclic group” represented by R ¹ ′ has, for example, the same meaning as the “optionally substituted heterocyclic group” represented by R ¹ .

(Method I) The formula included in the compound (I) of the present invention

Embedded image (Wherein q _2f represents 0 to 2n + 2, and other symbols have the same meanings as described above) or a salt thereof, for example,

Embedded image (Wherein L ³ represents a leaving group, and other symbols have the same meanings as described above) or a salt thereof and R ¹ S
It can be produced by subjecting a compound represented by H (R ¹ has the same meaning as described above) or a salt thereof to a nucleophilic reaction. As the leaving group represented by L ³ , for example, L ¹
And the same as the leaving group represented by. The reaction can be carried out according to a method similar to the above (Method G).

The compound represented by the formula (XXV) or a salt thereof is, for example,

Embedded image (Wherein each symbol has the same meaning as described above) or a salt thereof, which can be produced by converting a secondary hydroxy group into a leaving group.

In this reaction, first, the compound [XXV]
I] or the salt thereof is protected with a primary hydroxy group to produce a protected intermediate. As the protecting group used in this reaction, all commonly used protecting groups for a hydroxy group are used. At the same time, a triphenylmethyl group, a diphenylmethyl group, a t-phenylmethyl group, A butyldimethylsilyl group, a t-butyldiphenylsilyl group and the like are preferable. In the reaction, a halide having such a substituent, for example, triphenylmethyl chloride or the like is condensed with compound [XXVI] or a salt thereof in the presence of a base to produce a protected intermediate. In this reaction, 1 to 5 mol, preferably 1 to 3 mol, 1 to 10 mol, preferably 1 to 5 mol of a halide is used per 1 mol of compound [XXVI] or a salt thereof. As the base, sodium hydroxide, alkali metal hydroxides such as potassium hydroxide, sodium hydrogen carbonate, alkali metal hydrogen carbonate such as potassium hydrogen carbonate, sodium carbonate,
Alkali metal carbonates such as potassium carbonate, cesium salts such as cesium carbonate, alkali metal hydrides such as sodium hydride and potassium hydride, alkoxides such as sodium amide, sodium methoxide and sodium ethoxide, trimethylamine, triethylamine, diisopropylethylamine And cyclic amines such as pyridine. The reaction solvent is dioxane,
Ethers such as tetrahydrofuran; aromatic hydrocarbons such as benzene, toluene and xylene; esters such as ethyl acetate; halogenated hydrocarbons such as chloroform and dichloromethane; nitriles such as acetonitrile; N, N-dimethylformamide; Amides such as N, N-dimethylacetamide and sulfoxides such as dimethyl sulfoxide are used. The reaction temperature varies depending on the substrate used and other conditions.
00 ° C, preferably 0 to 100 ° C. The reaction time is 1 to 48 hours, preferably 1 to 24 hours. In the obtained intermediate, a secondary hydroxy group can be converted to a leaving group in the same manner as in the above (Method G).

The obtained active intermediate can be deprotected to produce compound [XXV] or a salt thereof. In this reaction, deprotection is performed under acidic conditions or catalytic hydrogenation. Examples of the catalyst used in the method by catalytic hydrogenation include platinum black, platinum oxide, a platinum catalyst such as platinum carbon, palladium black, palladium oxide, palladium barium sulfate, a palladium catalyst such as palladium carbon, reduced nickel, nickel oxide, Nickel catalysts such as Raney nickel and Urushibara nickel are exemplified. As the solvent,
For example, methanol, ethanol, propanol, alcohols such as isopropanol, tetrahydrofuran,
Ethers such as dioxane and esters such as ethyl acetate are preferably used. The reaction temperature is between 0 ° C and 2
It is carried out at 00 ° C, preferably at 20 ° C to 110 ° C. The reaction time is generally 0.5 to 48 hours, preferably 1 to 16 hours. The reaction is usually carried out under normal pressure, but if necessary under pressure (3 to 10 atm). The amount of the catalyst used depends on the type of the catalyst, but is usually 0.1 to 20% (w
/ W). The deprotection reaction under acidic conditions includes acids such as inorganic acids such as hydrochloric acid, sulfuric acid and nitric acid, formic acid, acetic acid,
Common organic acids such as trifluoroacetic acid and methanesulfonic acid; and Lewis acids. Reaction solvents are methanol, alcohols such as ethanol, dioxane, ethers such as tetrahydrofuran, benzene, toluene, aromatic hydrocarbons such as xylene, esters such as ethyl acetate, chloroform, halogenated hydrocarbons such as dichloromethane, Nitriles such as acetonitrile, amides such as N, N-dimethylformamide and N, N-dimethylacetamide, sulfoxides such as dimethylsulfoxide, and water are used. This reaction is carried out using 1 to 100 mol, preferably 1 to 10 mol of the above acid per 1 mol of the active intermediate. Further, it is used as a solvent depending on the kind of the acid. The reaction temperature varies depending on the substrate to be used and other conditions, but is -20 to 200 ° C, preferably 0 to 100 ° C.
° C. The reaction time is 5 minutes to 24 hours, preferably 5 minutes to 10 hours.

The compound represented by the formula (XXVI) or a salt thereof is, for example,

Embedded image (Wherein each symbol has the same meaning as described above) or a salt thereof, by subjecting the compound to a reaction similar to the above-mentioned production method (G) or a reaction known per se.

The compound represented by the formula (XXVII) or a salt thereof is, for example,

Embedded image (Wherein each symbol has the same meaning as described above) or a salt thereof, followed by a deprotection reaction.

This reaction is carried out by various methods.
For example, a method of reducing by the same method as the above-mentioned catalytic hydrogenation is preferably used.

The compound represented by the formula (XXVIII) or a salt thereof is, for example,

Embedded image (Wherein each symbol has the same meaning as described above) or a salt thereof can be produced by subjecting the compound to a reaction similar to the above-mentioned production method (G) and a reaction known per se. Compound
For [XXIX], commercially available amino acid derivatives such as serine are mainly used.

(Method J) The formula included in the compound (I) of the present invention

Embedded image (Wherein each symbol is as defined above) or a salt thereof, for example,

Embedded image (Wherein each symbol is as defined above) or a salt thereof,

Embedded image (Wherein each symbol has the same meaning as described above) or a salt thereof. This reaction can be carried out by the method described in the above (Method A) or a method analogous thereto. Compound
[XXX] is, for example, commercially available thiodisuccinic acid.

(Method K) The formula included in the compound (I) of the present invention

Embedded image (Wherein each symbol is as defined above) or a salt thereof, for example,

Embedded image (Wherein L ⁴ represents a leaving group, and other symbols have the same meanings as described above) or a salt thereof and R ¹ S
It can be produced by reacting a compound represented by H (R ¹ has the same meaning as described above) or a salt thereof. The leaving group represented by L ⁴ includes, for example, those similar to the leaving group represented by L ¹ above. This reaction can be carried out in the same manner as described in the above (Method G).

The compound represented by the above formula (XXXI) or a salt thereof is, for example,

Embedded image And a compound represented by the formula

Embedded image (Wherein each symbol is as defined above) or a salt thereof is reacted to form an imide form, and the protecting group is deprotected to convert the amino form and the amino group to halogen. can do.

In this reaction, first, compound [XXXII] or a salt thereof and compound [II] or a salt thereof are condensed by the same method as described in the above (Method E) to produce an imide compound. In this step, cyclization also proceeds at the same time. An amino compound or a salt thereof can be produced by deprotecting the obtained imide compound. This reaction is carried out in 1 g of the imide compound in a 10-fold volume of an appropriate organic acid solvent, an aqueous solution of an inorganic acid, or a mixed solution. As the organic acid, trifluoroacetic acid and the like are preferable. Hydrochloric acid, sulfuric acid and the like are used as the inorganic acid. The reaction temperature is -20 to 100C, preferably -20 to 50C. Reaction time is 1 minute to 2 minutes
4 hours, preferably 1 minute to 12 hours. The obtained amino compound or a salt thereof is prepared by a method known in the literature, for example, Heterocycles 24 (5) 1331 (1986), Journal of Organic Chemistry 58.
(5) Compound [XXXI] can be produced by substituting with halogen by the method described in 1159 (1993). In this reaction, a diazotizing agent such as sodium nitrite is used in an amount of 1 to 10 moles, preferably 1 to 3 moles, in the presence of 1 to 100 moles of a halogen acid relative to 1 mole of the amino compound or a salt thereof.
Molar reaction. As the halogen acid, hydrogen chloride, hydrogen bromide, hydrogen iodide and the like are preferable. The reaction solvent is preferably a nitrile such as acetonitrile or water. Reaction temperature is -5
It is 0 to 100 ° C, preferably -20 to 50 ° C. The reaction time is 30 minutes to 24 hours, preferably 30 minutes.
Minutes to 12 hours.

The compound represented by the above formula (XXXIII) or a salt thereof is, for example,

Embedded image From the compound represented by the following formula or a salt thereof (tetrahedron asymmetry 6 (6) 1249 (1
995)).

(Method L) The formula included in the compound (I) of the present invention

Embedded image (Wherein each symbol has the same meaning as described above) or a salt thereof is, for example, a compound represented by the formula

Embedded image (Wherein L ⁵ represents a leaving group, and each symbol has the same meaning as described above) or a salt thereof, and R ¹ SH (R ¹ has the same meaning as described above). It can be produced by reacting a compound or a salt thereof. This reaction can be carried out by the method described in the above (Method G) or a method analogous thereto. The leaving group represented by L ^5, for example, those similar to the leaving group represented by the L1 and the like.

The compound represented by the above formula (XXXV) or a salt thereof is, for example, a compound represented by the formula

Embedded image (Wherein each symbol is as defined above) or a salt thereof and a compound represented by the formula

Embedded image (IIa) (in the formula, L ⁶ represents a leaving group, and other symbols have the same meanings as described above) or a salt thereof, thereby converting a hydroxy group to a leaving group. Can be manufactured. Examples of the leaving group represented by L ⁶ include a halogen atom (eg, chlorine, bromine, iodine, etc.), a substituted sulfonyloxy (eg, methanesulfonyloxy, p-toluenesulfonyloxy, etc.), an acyloxy (acetoxy, benzoyl) Oxy), a heterocycle or an aryl group (succinimide,
Oxy group substituted with benzotriazole, quinoline, 4-nitrophenyl, etc.). The compound [XXXVI] or a salt thereof may be used as it is, or may be subjected to the reaction as, for example, an alkali metal salt such as lithium, sodium, or potassium.
In this reaction, 1 to 10 mol of compound [IIa] or a salt thereof is added to 1 mol of compound [XXXVI] or a salt thereof,
Preferably 1 to 5 moles are reacted. Usually, the reaction is performed in a solvent. As the solvent, for example, halogenated hydrocarbons such as dichloromethane and chloroform, nitriles such as acetonitrile, ethers such as dimethoxyethane and tetrahydrofuran, dimethylformamide, dimethylsulfoxide, hexamethylphosphoramide and the like are used. Addition of a base favors the reaction. As such a base, for example, sodium hydrogen carbonate, potassium hydrogen carbonate, sodium carbonate, potassium carbonate, sodium hydride, potassium hydride, sodium amide, sodium methoxide, triethylamine, diisopropylethylamine, pyridine and the like are used.
The amount of the base varies depending on the type of the compound to be used, the type of the solvent, and other reaction conditions, but is usually a compound [XXXV
I] or 1 to 10 mol, preferably 1 to 5 mol, per 1 mol of the salt. The reaction is carried out at a temperature of about -50 to 200 ° C, preferably -20 to 150 ° C. The reaction time varies depending on the type of the compound, the reaction temperature and the like, but is 1 to 72 hours, preferably 1 to 24 hours. Compound [XXXVI] is a commercially available 5- or 6-membered ring amide substituted with a hydroxy group, for example, (S) -4-hydroxypyrrolidin-2-one, (R)
-4-hydroxypyrrolidin-2-one (both daiso-
Co., Ltd.), 3-hydroxy-piperidin-2-one (Aldrich) and methods known in the literature, for example, synthesis
614 (1978), tetrahedron asymmetry 3
(11) Those manufactured according to 1431 (1992) can be used. As the compound [IIa], a commercially available compound, a compound produced by the method N, and the like are used.

(Method M) Formula represented by compound (I) of the present invention

Embedded image (Wherein each symbol is as defined above) or a salt thereof, for example,

Embedded image (Wherein L ⁷ represents a leaving group, and other symbols have the same meanings as described above) or a salt thereof in the same manner as in the above method G. L above
The leaving group represented by ^7, for example, those similar to the leaving group represented by L ¹ and the like.

The compound represented by the above formula [XXXVIII] or a salt thereof is, for example,

Embedded image (Wherein, Bz represents a benzyl group, and the other symbols have the same meanings as described above), or a catalytic hydrogenation known per se (for example, the same as in the above method I).
To give a saturated hydroxy form, which is converted into a leaving group.

The above compound [XXXIX] or a salt thereof can be produced according to the method described in the literature (Journal of American Chemical Society 75 3413 (1953)). For example, the expression

Embedded image (Wherein, R ^b represents a hydrocarbon group which may be substituted, and Y has the same meaning as described above) or a salt thereof, from which a reduced amino compound is prepared in the same manner as in the above method G. It can be produced by reacting the obtained amino compound with the oxalic acid diester derivative in the presence of a base. As the optionally substituted hydrocarbon group represented by R ^b , for example, those similar to the optionally substituted hydrocarbon group represented by R ¹ described above can be used. It is preferably used. In this reaction, 1 to 3 moles, preferably 1 to 2 moles of oxalic acid diester and base are used per 1 mole of the reduced amino compound. Various oxalic acid diester derivatives are possible, but a benzyl derivative which can be deprotected by catalytic hydrogenation is preferable. Examples of the base include alkali metal hydroxides such as sodium hydroxide and potassium hydroxide, alkali metal bicarbonates such as sodium hydrogen carbonate and potassium hydrogen carbonate, alkali metal carbonates such as sodium carbonate and potassium carbonate, and cesium such as cesium carbonate. Salts, alkali metal hydrides such as sodium hydride and potassium hydride, alkoxides such as sodium amide, sodium methoxide and sodium ethoxide, amines such as trimethylamine, triethylamine and diisopropylethylamine, and cyclic amines such as pyridine are used. . Reaction solvents are methanol, alcohols such as ethanol, dioxane, ethers such as tetrahydrofuran, benzene, toluene, aromatic hydrocarbons such as xylene, esters such as ethyl acetate, chloroform, halogenated hydrocarbons such as dichloromethane, Nitriles such as acetonitrile, N, N-
Amides such as dimethylformamide and N, N-dimethylacetamide, sulfoxides such as dimethylsulfoxide, and water are used. The reaction temperature varies depending on the substrate used and other conditions, but is 0 to 200 ° C.
Preferably it is 0 to 150 ° C. The reaction time is 1 to 24 hours, preferably 1 to 12 hours.

(Method N) The above formula [II] or [II
a] is included in the compound represented by the formula

Embedded image (Wherein, R ²⁶ has the same meaning as the substituent of ring B in the above formula [I], and R ³⁰ represents an amino group or a halogen) or a salt thereof, for example,

Embedded image (Wherein, R ²⁶ has the same meaning as described above, and W represents a cyano group or an aldehyde group) or a salt thereof, which is subjected to a reduction reaction or a halogenation reaction known per se. it can.

Compound [XXXXII] is obtained when W is a nitrile.
Reduction was performed with a suitable reducing agent as described in a known method, for example, New Experimental Chemistry Course 15 Oxidation and Reduction (Maruzen) to obtain a benzylamine compound [XXXXI]. As the reducing agent, general nitrile reducing reagents such as metal hydride compounds such as lithium aluminum hydride are used. In this reaction, 0.5 to 3 reducing agents are used per 1 mol of the compound [XXXXII].
Mole, preferably 0.5 to 1 mole. The reaction solvent is dioxane, ethers such as tetrahydrofuran,
Aromatic hydrocarbons such as benzene, toluene and xylene are used. The reaction temperature is -50 to 100C, preferably 0 to 80C. The reaction time is 0.5 to 24 hours, preferably 0.5 to 12 hours. When W is an aldehyde, compound [XXXXII] is a known method, for example, Experimental Chemistry Lecture 20 (Maruzen), Journal of American Chemical Society 81475.
After converting the oxime with hydroxylamine in the same manner as described in (1959), it was reduced with a suitable reducing agent to obtain a benzylamine derivative [XXXXI]. The oxime preparation uses from 1 to 3 mol, preferably from 1 to 2 mol, of hydroxylamine per mol of aldehyde. This reaction is promoted by the addition of a base. Alkali metal hydroxides such as sodium hydroxide and potassium hydroxide as bases,
Sodium bicarbonate, alkali metal bicarbonates such as potassium bicarbonate, sodium carbonate, alkali metal carbonates such as potassium carbonate, alkoxides such as sodium amide, sodium methoxide, sodium ethoxide,
Amines such as trimethylamine, triethylamine and diisopropylethylamine, and cyclic amines such as pyridine are used. The amount used is 1 to 5 mol, preferably 1 to 3 mol, per 1 mol of the aldehyde.
Reaction solvents include alcohols such as methanol and ethanol; ethers such as dioxane and tetrahydrofuran; nitriles such as acetonitrile; amides such as N, N-dimethylformamide and N, N-dimethylacetamide; sulfoxides such as dimethylsulfoxide; Water or the like is used. The reaction temperature is 0 to 20
0 ° C., preferably 0 to 150 ° C., and the reaction time is 1 to 48 hours, preferably 1 to 24 hours. As described in New Experimental Chemistry Lecture 15 Oxidation and Reduction (Maruzen), a common oxime reducing reagent such as catalytic hydrogenation and a metal hydride compound such as lithium aluminum hydride can be used. The reaction conditions are the same as in the nitrile reduction. When W is an aldehyde, it was reduced with a suitable reducing agent to a hydroxy form, and then the hydroxy group was halogenated with a suitable halogenating agent to give benzyl halide [XXXXI]. As the reducing agent, a common aldehyde reducing agent such as sodium borohydride, lithium aluminum hydride, and the like described in New Experimental Chemistry Course 15 Oxidation and Reduction is suitable. The reaction conditions are the same as for the above nitriles.
As the halogenating agent, inorganic acid halides such as thionyl chloride, thionyl bromide, phosphorus trichloride, phosphorus pentachloride, and phosphorus oxychloride, and hydrohalic acids such as hydrochloric acid and hydrobromic acid can be used. In this reaction, the halogenating agent is used in an amount of 1 to 3 mol, preferably 1 to 1.5 mol, per 1 mol of the alcohol. This reaction is promoted by the addition of a base. As the base, amines such as trimethylamine, triethylamine and diisopropylethylamine, and cyclic amines such as pyridine are used. As the reaction solvent, ethers such as dioxane and tetrahydrofuran, aromatic hydrocarbons such as benzene, toluene and xylene, esters such as ethyl acetate, and halogenated hydrocarbons such as chloroform and dichloromethane are used. The reaction temperature is -50 to 100C, preferably -20 to 50C. The reaction time is 30 minutes to 24 hours, preferably 30 minutes to 10 hours.

Further, the above compound [XXXXXXII] is
Commercially available or, for example,

Embedded image Wherein W is as defined above, and X is a halogen atom, or a salt thereof,

Embedded image (Wherein, R ²⁶ has the same meaning as described above) or a salt thereof and a literature method known per se ((Journal of Organic Chemistry 59 (18) 5414 )
(1994), Bio-Organic and Medicinal Chemistry 615 (1998)) or those produced by a method equivalent thereto.

When the compound (I) is obtained in a free state by the above method, for example, an inorganic acid (for example, hydrochloric acid, sulfuric acid, hydrobromic acid, etc.), an organic acid (for example, methanesulfonic acid, benzene) Sulfonic acid, toluene sulfonic acid,
Oxalic acid, fumaric acid, maleic acid, tartaric acid, etc.), inorganic bases (eg, alkali metals such as sodium and potassium, alkaline earth metals such as calcium and magnesium, aluminum or ammonium, etc.) or organic bases (eg, trimethylamine, triethylamine, pyridine) , Picoline, ethanolamine, diethanolamine, triethanolamine, dicyclohexylamine, N, N'-dibenzylethylenediamine, etc.), and when compound (I) is obtained in the form of a salt, It can also be converted into the free form or other salts according to the method. Compound (I) or a salt thereof obtained by the above method can be separated and purified by a means known per se (eg, concentration,
Solvent extraction, column chromatography, recrystallization, etc.).

The compound which is the starting compound of the compound (I) of the present invention may form a salt. These salts include, for example, inorganic acids (for example, hydrochloric acid, phosphoric acid, hydrobromic acid, sulfuric acid and the like). Salts or organic acids (eg, acetic acid, formic acid,
Salts with propionic acid, fumaric acid, maleic acid, succinic acid, tartaric acid, citric acid, malic acid, oxalic acid, benzoic acid, methanesulfonic acid, benzenesulfonic acid and the like are used. Further, when these compounds have an acidic group such as —COOH, an inorganic base (for example, an alkali metal or alkaline earth metal such as sodium, potassium, calcium, or magnesium, ammonia, or the like) or an organic base (for example, triethylamine or the like) Tri-C
_{With 1-3} alkylamines). In each of the above reactions, when the starting compound has an amino group, a carboxyl group, or a hydroxyl group as a substituent, a protecting group generally used in peptide chemistry or the like is introduced into these groups. Alternatively, the desired compound can be obtained by removing the protecting group as necessary after the reaction. Examples of the amino-protecting group include C _1-6 alkyl-carbonyl _optionally having a substituent (eg, formyl, methylcarbonyl, ethylcarbonyl and the like), phenylcarbonyl, C _1-6 alkyl-oxycarbonyl ( For example, methoxycarbonyl,
For example, ethoxycarbonyl), phenyloxycarbonyl (eg, benzooxycarbonyl), C _7-10 aralkyl-carbonyl (eg, benzyloxycarbonyl), trityl, phthaloyl and the like are used. As these substituents, halogen atoms (eg, fluorine, chlorine, bromine, iodine, etc.), C _1-6 alkyl-carbonyl (eg, methylcarbonyl, ethylcarbonyl, butylcarbonyl, etc.), nitro group and the like are used. The number of substituents is about 1 to 3.

Examples of the carboxyl-protecting group include C _1-6 alkyl which may have a substituent (for example, methyl, ethyl, n-propyl, i-propyl, n-butyl, tert-butyl, etc.) , Phenyl, trityl, silyl and the like are used. These substituents include a halogen atom (eg, fluorine, chlorine, bromine, iodine, etc.), C
_1-6 alkyl-carbonyl (eg, formyl, methylcarbonyl, ethylcarbonyl, butylcarbonyl, etc.), nitro group and the like are used, and the number of substituents is about 1 to 3. Examples of the hydroxyl-protecting group include C _1-6 alkyl which may have a substituent (eg, methyl, ethyl, n-propyl, i-propyl, n
-Butyl, tert-butyl, etc.), phenyl, C _7-10 aralkyl (eg, benzyl, etc.), C _1-6 alkylcarbonyl (eg, formyl, methylcarbonyl, ethylcarbonyl, etc.), phenyloxycarbonyl (eg, benzoxy Carbonyl), C _7-10 aralkyl-carbonyl (eg, benzyloxycarbonyl), pyranyl, furanyl, silyl and the like.
As these substituents, halogen atoms (for example, fluorine, chlorine, bromine, iodine, etc.), C _1-6 alkyl, phenyl, C _7-10 aralkyl, nitro group and the like are used, and the number of substituents is 1 to There are about four.

As a method for removing the protecting group, a method known per se or a method analogous thereto can be used. For example, acid, base, reduction, ultraviolet light, hydrazine, phenylhydrazine, sodium N-methyldithiocarbamate, tetrabutylammonium A method of treating with fluoride, palladium acetate or the like is used.

The compound (I) of the present invention or a salt thereof has an excellent MMP inhibitory action, particularly an MMP-13 inhibitory action. The compound (I) or a salt thereof of the present invention has low toxicity and is safe. Therefore, excellent MMP inhibitory action,
In particular, the compound (I) of the present invention or a salt thereof having an MMP-13 inhibitory activity can be used for deforming joints in mammals (for example, mice, rats, hamsters, rabbits, cats, dogs, cows, sheep, monkeys, humans, etc.). Disease, rheumatoid arthritis, osteoporosis, cancer, periodontal disease, corneal ulcer, pathological bone resorption (such as Paget's disease), nephritis, arteriosclerosis, emphysema,
It is useful as a safe preventive and therapeutic agent for cirrhosis, autoimmune diseases (Crohn's disease, Sjogren's disease, etc.), cancer metastasis, contraception and the like.

The preparation containing the compound (I) of the present invention or a salt thereof may be any of solid preparations such as powders, granules, tablets and capsules, and liquid preparations such as syrups, emulsions and injections. The prophylactic / therapeutic preparation of the present invention can be produced by a conventional method such as mixing, kneading, granulating, tableting, coating, sterilizing treatment, emulsification, etc., depending on the form of the preparation.
In addition, regarding the production of the preparation, for example, each section of the Japanese Pharmacopoeia Act general provisions of the preparation can be referred to. In the preparation of the present invention, the content of compound (I) or a salt thereof varies depending on the form of the preparation.
%, Preferably about 0.1 to 50% by weight, more preferably about 0.5 to 20% by weight.

When the compound (I) of the present invention or a salt thereof is used as the above-mentioned drug, it may be used as it is or as an appropriate pharmacologically acceptable carrier such as an excipient (eg,
Starch, lactose, sucrose, calcium carbonate, calcium phosphate, etc.), binders (eg, starch, gum arabic, carboxymethylcellulose, hydroxypropylcellulose, crystalline cellulose, alginic acid, gelatin,
Polyvinylpyrrolidone, etc.), lubricants (eg, stearic acid, magnesium stearate, calcium stearate, talc, etc.), disintegrants (eg, calcium carboxymethylcellulose, talc, etc.), diluents (eg, water for injection, physiological saline, etc.), Additives (stabilizer, preservative, colorant, fragrance, dissolution aid, emulsifier,
Buffer, isotonic agent, etc.) in the form of powders, solids such as fine granules, granules, tablets, capsules or liquids such as injections, orally or parenterally. Can be administered. The dose varies depending on the type of compound (I) or a pharmaceutically acceptable salt thereof, the route of administration, symptoms, age of the patient, and the like. For example, when administered orally to an adult patient with osteoarthritis, Weight 1 per day
About 0.00 as a compound (I) or a salt thereof per kg
5 to 50 mg, preferably about 0.05 to 10 mg, more preferably about 0.2 to 4 mg can be divided and administered in 1 to 3 times.

[0106]

BEST MODE FOR CARRYING OUT THE INVENTION The present invention will be described below in more detail with reference to examples and reference examples, but the present invention is not limited by the examples and does not depart from the scope of the present invention. May be changed.

Elution in column chromatography in Examples was performed by TLC (Thin Layer C) unless otherwise specified.
hromatography, thin layer chromatography). In the TLC observation, using 60F ₂₅₄ Merck (Merck) manufactured as a TLC plate. For the detection, a color reaction with a UV detector or phosphomolybdic acid was employed. As silica gel for column chromatography, silica gel 60 (7
0-230 mesh). The preparative TLC plates were used 60F ₂₅₄ manufactured by Merck. YMC Pack ODS SH-
343-5 or YMC Pack ODS S-363 I-15 (manufactured by YMC) was used. Room temperature is usually about 10 ° C to 35 ° C
Means temperature in ° C.

The NMR (nuclear magnetic resonance) spectrum is a Varian Gemini-200 type spectrometer ( ¹ H-NMR: 200 MHz).
Or Bruker DPX-300 spectrometer ( ¹ HN
(MR: 300 MHz). All δ values are shown in ppm using tetramethylsilane as an internal standard. Abbreviations in this specification are as follows. CDCl ₃ : deuterated chloroform, DMSO-d ₆ : deuterated dimethyl sulfoxide,
Hz: Hertz, J: Coupling constant, m: Multiplet, q: Quartet, t: Triplet, d: Doublet, s: Singlet, br: Broad, dd: Double doublet, dq: Double quartet.

[0109]

EXAMPLES Example 1 3-mercapto-1- (4-phenoxybenzyl) pyrrolidine-2,5-dione 4-phenoxybenzylamine hydrochloride (0.50 g, 2.1 mmol) was dissolved in chloroform (50 ml), and saturated sodium hydrogen carbonate was added. Washed with water. After drying over anhydrous magnesium sulfate, chloroform was concentrated under reduced pressure, 50 ml of toluene and 0.38 g (2.6 mmol) of thiomalic acid were added to the residue, and the mixture was heated under reflux for 5 hours.
After concentrating the toluene, 50 ml of acetic acid was added to the residue, and the mixture was heated under reflux overnight. After concentrating the reaction solution, the residue was subjected to silica gel column chromatography, eluted with chloroform, and concentrated to dryness to give 3-mercapto-1. -(4-phenoxybenzyl)
0.21 g (yield 32%) of pyrrolidine-2,5-dione was obtained as a colorless oil. ¹ H-NMR (200 MHz, CDCl ₃ ) δ: 7.40-6.90 (9 H, m), 4.70 (1 H, d, J = 14.0 Hz), 4.58 (1 H, d, J
= 14.0Hz), 3.95-3.86 (1H, m), 3.17 (1H, dd, J = 18.6,9.0Hz),
2.57 (1H, dd, J = 18.6,4.2Hz), 2.56 (1H, d, J = 4.6Hz)

Example 2 3-ethylthio-1- (4-phenoxybenzyl) pyrrolidine-2,5-dione 5.90 g (29.6 mmol) of 4-phenoxybenzylamine and 2.94 g (30 mmol) of maleic anhydride were dissolved in 50 ml of acetic acid. And stirred at 130 ° C. overnight. After concentration of the reaction solution, the residue was subjected to silica gel column chromatography, and eluted with chloroform.
Concentrate to dryness to give 4-phenoxybenzylmaleimide 2.60 g
(Yield 32%) as a white powder. ¹ H-NMR (200 MHz, CDCl ₃ ) δ: 7.40-6.90 (9H, m), 6.71 (2H, s), 4.65 (2H, s) 0.10 g (0.36 mmol) of 4-phenoxybenzylmaleimide in ethanol 10 ml Dissolved in ethyl mercaptan 0.040 g
(0.43 mmol) was added and the mixture was stirred at room temperature for 4 hours. After concentrating the reaction solution, the residue was subjected to silica gel column chromatography, eluted with chloroform, and concentrated to dryness to give 3-ethylthio-1- (4-phenoxybenzyl) pyrrolidine-2,5.
0.10 g (82% yield) of -dione was obtained as a colorless oil. ¹ H-NMR (200 MHz, CDCl ₃ ) δ: 7.40-6.90 (9 H, m), 4.68 (1 H, d, J = 14.0 Hz), 4.60 (1 H, d, J
= 14.0Hz), 3.75 (1H, dd, J = 9.0,3.7Hz), 3.15 (1H, dd, J = 18.
0,9.0Hz), 2.95-2.65 (2H, m), 2.54 (1H, dd, J = 18.0,3.7Hz),
1.29 (3H, t, J = 7.4Hz)

Example 3 3- [2- (ethoxycarbonyl) ethylthio] -1- (4-phenoxybenzyl) pyrrolidine-2,5-dione In the same manner as in Example 2, 0.10 g of 4-phenoxybenzylmaleimide was obtained. 0.36 mmol) and 0.14 g (yield) of oily 3- [2- (ethoxycarbonyl) ethylthio] -1- (4-phenoxybenzyl) pyrrolidine-2,5-dione from 0.06 g (0.43 mmol) of ethyl 3-mercaptopropionate. 95%) as a colorless oil. ¹ H-NMR (200 MHz, CDCl ₃ ) δ: 7.40-6.90 (9 H, m), 4.68 (1 H, d, J = 14.0 Hz), 4.60 (1 H, d, J
= 14.0Hz), 4.16 (2H, q, J = 7.1Hz), 3.80 (1H, dd, J = 10.0,3.8H
z), 3.26-2.94 (3H, m), 2.68 (2H, t, J = 6.0Hz), 2.51 (1H, dd, J
= 18.0,4.0Hz), 1.26 (3H, t, J = 7.2Hz)

Example 4 3-benzylthio-1- (4-phenoxybenzyl) pyrrolidine-2,5-dione In the same manner as in Example 2, 0.28 g (1.0 mmol) of 4-phenoxybenzylmaleimide and 0.12 g of benzylmercaptan
From g (1.0 mmol), 0.42 g of 3-benzylthio-1- (4-phenoxybenzyl) pyrrolidine-2,5-dione was obtained almost quantitatively as a colorless oil. ¹ H-NMR (300 MHz, CDCl ₃ ) δ: 7.39-7.25 (9H, m), 7.10 (1
H, m), 7.02-6.91 (4H, m), 4.66.
(1H, d, J = 14.1 Hz), 4.60 (1H,
d, J = 14.1 Hz), 4.20 (1H, d, J = 1)
3.5Hz), 3.84 (1H, d, J = 13.5H)
z), 3.51 (1H, dd, J = 9.2, 3.8H)
z), 2.97 (1H, dd, J = 18.8, 9.2H
z), 2.41 (1H, dd, J = 18.8, 3.8H
z)

Example 5 3-acetylthio-1- (4-
Phenoxybenzyl) pyrrolidine-2,5-dione S-acetylmercaptosuccinic anhydride1.00 g (5.70 mmol,
Was dissolved in 30 ml of acetic acid, and 1.20 g (5.70 mmol) of 4-phenoxybenzylamine hydrochloride and 795 μl (5.70 mmol) of triethylamine were added thereto, followed by heating and stirring at 100 ° C. for 14 hours. The reaction solution is concentrated under reduced pressure, and the residue is purified three times by silica gel column chromatography (elution solvent).
Ethyl acetate: hexane (20:80), chloroform and ethyl acetate: hexane (20:80)) and the desired fraction were concentrated under reduced pressure to give 3-acetylthio-1- (4-phenoxybenzyl) pyrrolidine-2. 0.80 g of 5,5-dione (40% yield)
Was obtained as a yellow oil. ¹ H-NMR (300 MHz, CDCl ₃ ) δ: 7.37 (2 H, d, J = 8.5 Hz), 7.32 (2 H, d, J = 7.6 Hz), 7.11 (1 H,
t, J = 7.6Hz), 7.00 (2H, d, J = 8.5Hz), 6.94 (2H, d, J = 8.5Hz),
4.72 (1H, d, J = 14.1Hz), 4.65 (1H, d, J = 14.1Hz), 4.23 (1H, d
d, J = 9.6,5.6Hz), 3.25 (1H, dd, J = 18.5,9.6Hz), 2.72 (1H, d
d, J = 18.5,5.6Hz), 2.39 (3H, s)

Example 6 3-benzoylthio-1- (4
-Phenoxybenzyl) pyrrolidine-2,5-dione 1.00 g (3.60 mmol) of 4-phenoxybenzylmaleimide and 0.50 g of thiobenzoic acid (3.60 m
mol) to give 3-benzoylthio-1- (4-phenoxybenzyl) pyrrolidine-2,5-dione (0.87 g, yield 58%) as a white powder. ¹ H-NMR (300 MHz, CDCl ₃ ) δ: 7.91 (2H, d, J = 7.4 Hz), 7.62 (1H, dd, J = 7.6, 7.6 Hz), 7.47
(2H, dd, J = 7.7,7.6Hz), 7.41 (2H, d, J = 8.5Hz), 7.33 (2H, dd,
J = 7.7,7.6Hz), 7.11 (1H, dd, J = 7.6,7.4Hz), 7.01 (2H, d, J =
8.5Hz), 6.95 (2H, d, J = 8.5Hz), 4.78 (1H, d, J = 14.1Hz), 4.70
(1H, d, J = 14.1Hz), 4.41 (1H, dd, J = 9.5,5.5Hz), 3.34 (1H, d
d, J = 18.5,9.5Hz), 2.84 (1H, dd, J = 18.5,5.5Hz)

Example 7 3-acetylthio-4-methyl-1- (4-phenoxybenzyl) pyrrolidine-2,5-
Dione 2-amino-3-methylsuccinic acid 3.00 g (manufactured by Sigma, 20.4 g)
was dissolved in 163 ml of 2.5 N hydrobromic acid, cooled to -10 ° C, 7.28 g (61.2 mmol) of potassium bromide was added, and 3.52 g (51.0 mmol) of sodium nitrite was stirred over 1.5 hours. The mixture was added and further stirred at -5 ° C for 1.5 hours. After adding sodium chloride, the mixture was extracted five times with ethyl acetate and dried over anhydrous sodium sulfate. After concentration to dryness, the residue was dissolved in ethanol (100 ml), concentrated sulfuric acid (1.00 ml) was added, and the mixture was heated under reflux for 10 hours. After concentration, the residue was dissolved in ethyl acetate, saturated aqueous sodium hydrogen carbonate, water,
After washing with saturated saline, it was dried over anhydrous sodium sulfate.
After concentration, the residue was subjected to silica gel column chromatography, eluted with hexane: ethyl acetate (95: 5), and concentrated to give diethyl 2-bromo-3-methylsuccinate (4.53 g, yield 83%) as a colorless oil. . ¹ H-NMR (300 MHz, CDCl ₃ ) δ: 4.44 (1 H, d, J = 9.4 Hz), 4.23 (2 H, m), 4.16 (2 H, q, J = 7.2 H
z), 3.12 (1H, dq, J = 9.4,7.2Hz), 1.40 (3H, d, J = 7.2Hz), 1.29
(3H, t, J = 7.2Hz), 1.25 (3H, t, J = 7.2Hz)

Diethyl 2-bromo-3-methylsuccinate
2.27 g (8.49 mmol) was dissolved in 110 ml of ethanol, and 1.45 g (12.7 mmol) of potassium thioacetate was added. After stirring at 50 ° C. for 2 hours, 0.49 g (4.25 mmol) of potassium thioacetate was further added. Stirred for hours. The reaction solution was concentrated, dissolved in ethyl acetate, washed with water and saturated saline, and dried over anhydrous sodium sulfate. After concentration, the residue was subjected to silica gel column chromatography, and hexane: ethyl acetate (90: 10-80: 20)
And concentrated to dryness to give 1.80 g (80% yield) of diethyl 2-acetylthio-3-methylsuccinate as a colorless oil. ¹ H-NMR (300 MHz, CDCl ₃ ) δ: 4.56 (1 H, d, J = 5.7 Hz), 4.17 (4 H, m), 3.24 (1 H, dq, J = 5.7,
7.2Hz), 2.39 (3H, s), 1.26 (3H, t, J = 7.2Hz), 1.26 (3H, d, J =
7.2Hz), 1.26 (3H, t, J = 7.2Hz)

1.80 g (6.86 mmol) of diethyl 2-acetylthio-3-methylsuccinate was dissolved in 20.0 ml of acetic acid and 20.0 ml of concentrated hydrochloric acid and stirred at 100 ° C. for 1.5 hours. After concentrating the reaction solution, toluene was added and concentrated, and powdered from ether-hexane,
1.00 g (89% yield) of 2-mercapto-3-methylsuccinic acid was obtained as a white powder. ¹ H-NMR (300 MHz, DMSO-d ₆ ) δ: 3.42 (1 H, m), 3.13 (1 H, m), 2.71 (1 H, m), 1.15 (3 H, d, J = 7.
2Hz) 0.950 g of 2-mercapto-3-methylsuccinic acid (5.79 mmo
l) was dissolved in 15.0 ml of acetic anhydride and stirred at 100 ° C. for 1 hour. After concentrating the reaction solution, toluene was added thereto, and the mixture was concentrated to dryness.
0.963 g of acetylthio-4-methylsuccinic anhydride (yield 88
%) As a colorless oil. ¹ H-NMR (300 MHz, CDCl ₃ ) δ: 3.93 (1 H, d, J = 8.3 Hz), 3.17 (1 H, m), 2.44 (3 H, s), 1.49 (3
(H, d, J = 7.2Hz) 0.930 g of 3-acetylthio-4-methylsuccinic anhydride (4.
After dissolving 94 mmol) in 25.0 ml of dichloromethane, 1.16 g (4.94 mmol) of 4-phenoxybenzylamine hydrochloride and 1.03 ml (7.41 mmol) of triethylamine were added, and the mixture was stirred at room temperature for 2 hours, and the reaction solution was concentrated to dryness. After dissolving the residue in 15.0 ml of acetic anhydride, 1.00 g of sodium acetate was added and the mixture was stirred at 100 ° C for 20 minutes. The reaction solution was concentrated, dissolved in ethyl acetate, washed with water and saturated saline, and dried over anhydrous sodium sulfate. After concentration, the residue was subjected to silica gel column chromatography, eluted with hexane: ethyl acetate (75:25), concentrated to dryness, and 3-acetylthio-4-methyl-1- (4-phenoxybenzyl) pyrrolidine-2,5-dione. 0.491 g (yield 27%) was obtained as a colorless oil. ¹ H-NMR (300 MHz, CDCl ₃ ) δ: 7.35 (4H, m), 7.11 (1H, m),
7.00 (2H, m), 6.94 (2H, d, J = 8.
7 Hz), 4.72 (1H, d, J = 14.1 Hz),
4.63 (1H, d, J = 14.1 Hz), 3.85
(1H, d, J = 6.4 Hz), 2.85 (1H,
m), 2.40 (3H, s), 1.40 (3H, d, J
= 7.2Hz)

Example 8 3-mercapto-4-methyl-
1- (4-phenoxybenzyl) pyrrolidine-2,5-
Dione 3-acetylthio-4-methyl-1 obtained in Example 7
After dissolving 0.360 g (0.974 mmol) of-(4-phenoxybenzyl) -pyrrolidine-2,5-dione in 20.0 ml of acetic acid and 10.0 ml of concentrated hydrochloric acid, the mixture was stirred at 100 ° C for 30 minutes. After adding toluene to the reaction solution and concentrating it to dryness, the residue was subjected to silica gel column chromatography, eluted with hexane: ethyl acetate (80:20), concentrated to dryness, and 3-mercapto-4-methyl-1- (4- (Phenoxybenzyl) -pyrrolidine-2,5-dione 0.208
g (65% yield) as a colorless oil. ¹ H-NMR (300 MHz, CDCl ₃ ) δ: 7.33 (4 H, m), 7.11 (1 H, m), 7.00 (2 H, m), 6.93 (2 H, d, J = 8.
3Hz), 4.67 (1H, d, J = 13.9Hz), 4.61 (1H, d, J = 13.9Hz), 3.48
(1H, dd, J = 5.3,5.3Hz), 2.67 (1H, dq, J = 5.3,7.2Hz), 2.44 (1
(H, d, J = 5.3Hz), 1.41 (3H, d, J = 7.2Hz)

Example 9 10.0 g (75.7 mmol, Tokyo Chemical Industry) of 3-hydroxy-4- [2- (methoxycarbonyl) ethylthio] -1- (4-phenoxybenzyl) pyrrolidine-2,5-dione cis-epoxysuccinic acid Was dissolved in 200 ml of ethanol, 2.00 ml of concentrated sulfuric acid was added, and the mixture was heated under reflux for 4 hours. After concentration, the reaction solution was dissolved in ethyl acetate and washed with water and saturated saline. After drying over anhydrous sodium sulfate, the mixture was concentrated to dryness and diethyl ester 1
3.5 g (95% yield) was obtained as a colorless oil. ¹ H-NMR (300 MHz, CDCl ₃ ) δ: 4.27 (4 H, q, J = 7.2 Hz), 3.70 (2 H, s), 1.31 (6 H, t, J = 7.2 H
z) After dissolving 4.00 g (21.30 mmol) of the obtained diethyl ester in 200 ml of ethanol, 21.30 ml of a 1N aqueous sodium hydroxide solution
(21.30 mmol) was added, and the mixture was stirred at room temperature for 2 hours. After the reaction solution was concentrated, a saturated saline solution was added, the pH was adjusted to 2.0 with 1N hydrochloric acid, and the mixture was extracted five times with ethyl acetate. The ethyl acetate layer was washed with saturated saline, dried over anhydrous sodium sulfate, concentrated to dryness, and ethyl-hydrogen-cis-epoxysuccinic acid 1.92 g (yield)
56%) as a colorless oil. ¹ H-NMR (300 MHz, CDCl ₃ ) δ: 4.32 (2 H, m), 3.80 (1 H, d, J = 4.5 Hz), 3.76 (1 H, d, J = 4.9 H)
z), 1.33 (3H, t, J = 7.2Hz) ethyl-hydrogen-cis-epoxysuccinic acid 0.679g
(4.24 mmol) was dissolved in 20.0 ml of N, N-dimethylformamide, and then 0.845 g of 4-phenoxybenzylamine (4.24 mmol)
l), 0.634 ml (4.24 mmol) of diethyl cyanophosphate and 0.591 ml (4.24 mmol) of triethylamine were added, and the mixture was stirred at room temperature for 2 hours. After concentrating the reaction solution, it was dissolved in ethyl acetate and 10%
The extract was washed with aqueous citric acid, saturated aqueous sodium hydrogen carbonate, water and saturated saline, and then dried over anhydrous sodium sulfate. After concentration, the residue was subjected to silica gel column chromatography, and hexane:
Elution with ethyl acetate (70:30), concentration to dryness, and ethyl-cis-3- (4-phenoxybenzylcarbamoyl) -2-
0.870 g (60% yield) of oxirane-carboxylate was obtained as a colorless oil. ¹ H-NMR (300 MHz, CDCl ₃ ) δ: 7.34 (2 H, m), 7.25 (2 H, d, J = 8.5 Hz), 7.11 (1 H, m), 6.98 (4
H, m), 6.77 (1H, m), 4.45 (1H, dd, J = 14.7,6.4Hz), 4.35 (1H, d
d, J = 14.7,5.7Hz), 4.16 (2H, q, J = 7.2Hz), 3.74 (1H, d, J = 4.9
Hz), 3.72 (1H, d, J = 4.9 Hz), 1.25 (3H, t, J = 7.2 Hz) ethyl-cis-3- (4-phenoxybenzylcarbamoyl) -2-oxirane-carboxylate 0.770 g (2.26
was dissolved in 30.0 ml of methanol, and 2.49 ml (2.49 mmol) of a 1N aqueous sodium hydroxide solution was added thereto, followed by stirring at room temperature for 2 hours. The reaction solution was adjusted to pH 2.0, concentrated, added with ethyl acetate, and washed with water and saturated saline. After drying over anhydrous sodium sulfate, the mixture was concentrated to dryness and cis-3- (4-phenoxybenzylcarbamoyl) -2-oxiranecarboxylic acid 0.650 g
(92% yield) as a white powder. ¹ H-NMR (300 MHz, DMSO-d ₆ ) δ: 8.54 (1 H, m), 7.38 (2 H, m), 7.27 (2 H, d, J = 8.3 Hz), 7.13 (1
H, m), 6.98 (2H, m), 6.94 (2H, d, J = 8.3Hz), 4.29 (1H, dd, J = 1
5.1,6.4Hz), 4.23 (1H, dd, J = 15.1,5.7Hz), 3.79 (1H, d, J = 4.
9Hz), 3.76 (1H, d, J = 4.9Hz) cis-3- (4-phenoxybenzylcarbamoyl)-
0.250 g (0.80 mmol) of 2-oxiranecarboxylic acid was treated with acetic anhydride
After dissolving in 5.00 ml, add 0.250 g of sodium acetate,
For 5 minutes. The reaction solution was concentrated, dissolved in ethyl acetate, washed with water and saturated saline, and dried over anhydrous sodium sulfate. After concentration, the residue was subjected to silica gel column chromatography, eluted with hexane: ethyl acetate (70: 30-60: 40), concentrated, and powdered from hexane-ethyl acetate to give 3,4-
0.129 g (55% yield) of epoxy-1- (4-phenoxybenzyl) -pyrrolidine-2,5-dione was obtained as a white powder. ¹ H-NMR (300 MHz, CDCl ₃ ) δ: 7.33 (2 H, m), 7.26 (2 H, d, J = 8.3 Hz), 7.11 (1 H, m), 6.99 (2
H, m), 6.93 (2H, d, J = 8.7 Hz), 4.54 (2H, s), 4.05 (2H, s) 3,4-epoxy-1- (4-phenoxybenzyl) -pyrrolidine-2,5 0.20 g (0.745 mmol) of dione in N, N
-Dissolve in 10.0 ml of dimethylformamide and add potassium carbonate
0.309 g (2.24 mmol) and 0.248 ml (2.24 mmol) of methyl 3-mercaptopropionate were added, and the mixture was stirred at room temperature for 10 minutes. Three
After adding N hydrochloric acid, the mixture was extracted twice with ethyl acetate. The ethyl acetate layer was washed with water and saturated saline, and then dried over anhydrous sodium sulfate. After concentration, the residue was subjected to silica gel column chromatography, eluted with hexane: ethyl acetate (50:50), and concentrated to dryness to give 3-hydroxy-4- [2- (methoxycarbonyl) ethylthio] -1- (4-phenoxy). Benzyl)
0.153 g (yield 49%) of pyrrolidine-2,5-dione was obtained as a colorless oil. ¹ H-NMR (300 MHz, CDCl ₃ ) δ: 7.34 (4 H, m), 7.12 (1 H, m), 7.00 (2 H, m), 6.93 (2 H, d, J = 8.
3Hz), 4.67 (1H, d, J = 14.1Hz), 4.63 (1H, d, J = 14.1Hz), 4.46
(1H, m), 3.78 (1H, d, J = 5.3Hz), 3.71 (3H, s), 3.48 (1H, d, J =
3.0Hz), 3.09 (2H, m), 2.75 (2H, t, J = 7.0Hz)

Example 10 3-acetylthiomethyl-
1- (4-phenoxybenzyl) pyrrolidine-2,5-dione 4-phenoxybenzylamine hydrochloride 1.90 g (8.90 mmol)
Was dissolved in ethyl acetate and washed with saturated aqueous sodium carbonate. The organic layer was concentrated under reduced pressure, dissolved in 100 ml of toluene, added with 1.00 g (8.90 mmol) of itaconic anhydride and stirred at room temperature for 4 hours. 2.50 ml (19.8 mmol) of triethylamine and 1.30 ml (19.8 mmol) of thioacetic acid were added, and the mixture was further stirred at room temperature for 16 hours. The reaction solution was concentrated under reduced pressure, dissolved in ethyl acetate, washed twice with water, dilute hydrochloric acid, water and saturated saline, and the organic layer was dried over anhydrous sodium sulfate. After concentration under reduced pressure, the residue was subjected to silica gel column chromatography, the fraction eluted with ethyl acetate-hexane (10: 90-50: 50) was concentrated, dissolved in 50 ml of toluene, and 10 ml of acetic anhydride was added.
The mixture was heated and stirred at 100 ° C. for 3 hours. After concentrating the reaction solution under reduced pressure, the residue was subjected to silica gel column chromatography, and the fraction eluted with ethyl acetate-hexane (20: 80-30: 70) was subjected to high performance liquid chromatography (elution solvent: 60% acetonitrile / 0.05% (Trifluoroacetic acid). The desired fraction was concentrated under reduced pressure, extracted twice with ethyl acetate, and the obtained organic layer was washed with saturated saline and dried over anhydrous sodium sulfate. The solution was concentrated under reduced pressure to give 0.536 g (16% yield) of 3-acetylthiomethyl-1- (4-phenoxybenzyl) pyrrolidine-2,5-dione as a brown oil. ¹ H-NMR (300 MHz, CDCl ₃ ) δ: 7.33 (4 H, m), 7.11 (1 H, t, J = 7.4 Hz), 6.99 (2 H, d, J = 7.7 H)
z), 6.93 (2H, d, J = 8.6Hz), 4.65 (1H, d, J = 14.1Hz), 4.59 (1H,
d, J = 14.1Hz), 3.42 (1H, dd, J = 13.4,4.1Hz), 3.25-3.09 (2H,
m), 2.83 (1H, dd, J = 18.4,8.8H), 2.45 (1H, dd, J = 18.4,4.8H)
z), 2.34 (3H, s)

Example 11 3-[(tetrahydro-2-furanyl) methyldithio] -1- (4-phenoxybenzyl)
Pyrrolidin-2,5-dione tetrahydrofurfuryl bromide (5.00 g, 30.0 mmol) was dissolved in ethanol (30 ml), thiourea (2.30 g, 30.0 mmol) was added, and the mixture was heated under reflux for 16 hours. After concentrating the reaction solution under reduced pressure,
It was dissolved in 30 ml of a 1N aqueous sodium hydroxide solution and heated at 100 ° C. for 1.5 hours. After cooling, the mixture was extracted with ethyl acetate, and the organic layer was washed with water and saturated saline and dried over anhydrous sodium sulfate. This solution was concentrated under reduced pressure to obtain 0.208 g of a brown oil. The obtained oil was dissolved in 20 ml of methanol, and 0.552 g (1.80 mmol) of 3-mercapto-1- (4-phenoxybenzyl) pyrrolidine-2,5-dione obtained in Example 1 was dissolved.
l), 0.178 g (1.80 mmol) of triethylamine and an excessive amount of iodine were added, and the mixture was stirred at room temperature for 1 hour. After concentration under reduced pressure, the residue was dissolved in ethyl acetate, washed with water, an aqueous solution of sodium thiosulfate, and saturated saline, and then dried over anhydrous sodium sulfate. After concentration under reduced pressure, the residue was purified by silica gel column chromatography three times (elution solvent: ethyl acetate: hexane (30: 70-5
0:50), chloroform and ethyl acetate: hexane (20: 8
0)) and high performance liquid chromatography (elution solvent: 6
(0% acetonitrile / 0.05% trifluoroacetic acid). The desired fraction was concentrated under reduced pressure, extracted twice with ethyl acetate, and the obtained organic layers were combined, washed with saturated aqueous sodium hydrogen carbonate and saturated saline, and dried over anhydrous sodium sulfate. The solution was concentrated under reduced pressure to give 3-[(tetrahydro-2-furanyl) methyldithio] -1- (4-
Phenoxybenzyl) pyrrolidine-2,5-dione 0.045
g (6% yield) was obtained as a brown oil. ¹ H-NMR (300 MHz, CDCl ₃ ) δ: 7.38 (2H, d, J = 8.5 Hz), 7.31 (2H, d, J = 7.9 Hz), 7.11 (1H,
m), 6.99 (2H, d, J = 7.9Hz), 6.93 (2H, d, J = 8.5Hz), 4.70 (0.5
H, d, J = 14.0Hz), 4.69 (0.5H, d, J = 14.0Hz) 4.63 (0.5H, d, J = 1
4.0Hz), 4.62 (0.5H, d, J = 14.0Hz), 4.09-3.68 (4H, m), 3.17
(0.5H, dd, J = 18.8,2.7Hz), 3.14 (0.5H, dd, J = 18.8,2.7Hz),
2.95 (0.5H, dd, J = 18.8,4.2Hz), 2.92 (0.5H, dd, J = 18.8,4.2
Hz), 2.81 (0.5H, dd, J = 13.4, 6.7Hz), 2.67 (1H, m), 2.52 (0.5
H, dd, J = 13.4,7.4Hz), 2.06-1.82 (3H, m), 1.61-1.43 (1H,
m)

Example 12 3,3′-Dithiobis [1-
(4-phenoxybenzyl) pyrrolidine-2,5-dione] 0.100 g (0.35 g) of 3-mercapto-1- (4-phenoxybenzyl) pyrrolidine-2,5-dione obtained in Example 1.
was dissolved in 100 ml of ethanol, and 0.15 g of iodine (0.60 mm
ol) was added and left at room temperature for 1 hour. After concentrating the reaction solution under reduced pressure, high performance liquid chromatography (elution solvent: 60%
Purification was performed using acetonitrile / 0.01 M phosphate buffer (pH 6.3). The desired fraction is concentrated under reduced pressure, and concentrated with ethyl acetate.
After extraction twice, the obtained organic layer was washed with saturated saline and dried over anhydrous sodium sulfate. This solution was concentrated under reduced pressure to obtain 0.062 g (yield 31%) of 3,3'-dithiobis [1- (4-phenoxybenzyl) hydroxy-2,5-dione] as a white powder. ¹ H-NMR (300 MHz, CDCl ₃ ) δ: 7.33 (8 H, m), 7.11 (2 H, td, J = 7.6, 2.6 Hz), 6.95 (8 H, m),
4.63 (4H, brs.), 4.02 (1H, dd, J = 9.2,4.8Hz), 3.82 (1H, dd, J
= 9.1,4.6Hz), 3.13 (1H, dd, J = 18.9,9.1Hz), 3.03 (1H, dd, J =
18.8,9.2Hz), 2.86 (1H, dd, J = 18.9,4.6Hz), 2.74 (1H, dd, J =
(18.8,4.8Hz)

Example 13 3,3 '-[Dithiobis (methylene)] bis [1- (4-phenoxybenzyl) pyrrolidine-2,5-dione] 3-acetylthiomethyl-1- obtained in Example 10
(4-phenoxybenzyl) pyrrolidine-2,5-dione
0.300 g (0.80 mmol) was dissolved in methanol 3 ml, 28% sodium methoxide methanol solution 3 ml was added,
For a minute. The reaction solution was acidified by adding 1N hydrochloric acid, and water was further added. After extracting twice with ethyl acetate, the obtained organic layer was washed with saturated aqueous sodium carbonate and saturated brine, and dried over anhydrous sodium sulfate. After concentration under reduced pressure, the residue was subjected to silica gel column chromatography, and the fraction eluted with ethyl acetate: hexane (50:50) was concentrated under reduced pressure to give 3,3.
0.059 g of 3 '-[dithiobis (methylene)] bis [1- (4-phenoxybenzyl) pyrrolidine-2,5-dione] (yield 2
0%) as a colorless oil. ¹ H-NMR (300 MHz, CDCl ₃ ) δ: 7.33 (8H, t, J = 8.5 Hz), 7.10 (2H, t, J = 7.5 Hz), 6.99 (4H,
d, J = 8.6Hz), 6.92 (4H, d, J = 8.6Hz), 4.63 (2H, s), 4.62 (2H,
s), 3.10-2.74 (8H, m), 2.59 (1H, dd, J = 18.3,5.0Hz), 2.53 (1
(H, dd, J = 18.3,5.0Hz)

Example 14 3,3'-thiobis [1- (4
-Phenoxybenzyl) pyrrolidine-2,5-dione] 4-phenoxybenzylamine hydrochloride 1.00 g (4.20 mmol)
Was dissolved in ethyl acetate and washed with saturated aqueous sodium hydrogen carbonate. The organic layer was concentrated under reduced pressure, dissolved in 50 ml of toluene, added with 0.506 g of thiodisuccinic acid (1.90 mmol, manufactured by Tokyo Chemical Industry Co., Ltd.), and dehydrated and heated under reflux for 4 hours. After the reaction solution was concentrated under reduced pressure, 50 ml of acetic acid was added, and the mixture was stirred at 120 ° C for 11 hours. The reaction solution was concentrated under reduced pressure, dissolved in ethyl acetate, washed with water and saturated saline, and dried over anhydrous sodium sulfate. After concentration, the residue was subjected to silica gel column chromatography, and the fraction eluted with ethyl acetate-hexane (20: 80-30: 70) was concentrated under reduced pressure to give 3,3′-thiobis [1- (4-phenoxybenzyl). ) Pyrrolidine-2,5-dione] 0.180 g (8% yield)
Was obtained as a yellow oil. ¹ H-NMR (300 MHz, CDCl ₃ ) δ: 7.33 (8H, m), 7.11 (2H, m), 6.95 (8H, m), 4.64 (4H, brs),
4.61 (1H, dd, J = 9.3,4.3Hz), 4.08 (1H, dd, J = 9.3,4.3Hz), 3.
16 (2H, dd, J = 18.8,9.3Hz), 2.71 (1H, dd, J = 18.8,4.3Hz), 2.
43 (1H, dd, J = 18.8,4.3Hz)

Example 15 4-acetylthio-1- (4
-Phenoxybenzyl) pyrrolidin-2-one glycine ethyl ester hydrochloride (2.79 g, 20.0 mmol) was dissolved in methanol (30 ml), and triethylamine (2.23 g, 20.0 mmol) was dissolved.
l) was added and the mixture was stirred at room temperature for 10 minutes. Then, 4.96 g (20.0 mmol) of 4-phenoxybenzaldehyde was added and the mixture was stirred for 5 hours.
After adding 0.378 g (10.0 mmol) of sodium borohydride little by little and stirring at room temperature for 2 hours, the reaction solution was concentrated, saturated aqueous sodium hydrogen carbonate was added, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with water and concentrated, and the residue was mixed with 50 ml of ether and 10 ml of a 4N hydrogen chloride ethyl acetate solution, and stirred at room temperature for 30 minutes. The crystallized product was collected by filtration and washed with ether to obtain a reduced amino form hydrochloride (5.49 g, yield 85%) as a white powder. ¹ H-NMR (200 MHz, DMSO-d ₆ ) δ: 10.2-9.6 (1 H, m), 7.62-6.97 (9 H, m), 4.30-4.10 (4 H, m),
4.00-3.82 (2H, m), 1.23 (3H, t, J = 7.1Hz) The obtained amine form 5.00 g (16.0 mmol) in chloroform 50 ml
Under ice cooling, triethylamine (3.46 g, 34.0 mmol) was added, and the mixture was stirred for 10 minutes.Then, ethyl malonate ethyl chloride (2.57 g, 1 ml) was added.
(7.0 mmol) was added dropwise and the mixture was stirred at room temperature overnight. The mixture was acidified with 2N hydrochloric acid, extracted, and the chloroform layer was washed with water, concentrated, and then subjected to silica gel chromatography to give hexane:
Eluted with ethyl acetate (70:30), 3.40 g of amide (55% yield)
Was obtained as a pale yellow oil. ¹ H-NMR (200 MHz, CDCl ₃ ) δ: 7.40-6.90 (9 H, m), 4.65 (1 H, s), 4.61 (1 H, s), 4.27-4.10
(4H, m), 4.06 (1H, s), 3.98 (1H, s), 3.58 (1H, s), 3.48 (1H, s
s), 1.35-1.20 (6H, m) 3.40 g (8.51 mmol) of the obtained amide was dissolved in 30 ml of ethanol, and a 20% sodium ethoxide ethanol solution 2.90 m
l (8.51 mmol) was added and the mixture was stirred at room temperature for 1 hour. After the reaction solution was concentrated at low temperature, the residue was acidified by adding 2N hydrochloric acid, and extracted with ethyl acetate. The ethyl acetate layer was washed with water, concentrated at a low temperature, and a mixed solution of ethyl acetate: hexane (1: 5) was added to the residue, and the mixture was stirred for 10 minutes. 2.34 g of the on-isomer (78% yield) was obtained as a white powder. ¹ H-NMR (200 MHz, CDCl ₃ ) δ: 7.40-6.90 (9H, m), 4.57 (2H, s), 4.41 (2H, q, J = 7.1H
z), 3.88 (2H, s), 1.41 (3H, t, J = 7.1 Hz) 0.353 g (1.00 mmol) of the obtained pyrrolidin-2-one was dissolved in 10 ml of acetonitrile, and 0.5 ml of water was added to the solution. 30 ° C
For a minute. After concentrating the reaction solution, 10 ml of methanol was added, and 0.038 g (1.00 mmol) of sodium borohydride was added little by little at room temperature, followed by stirring for 1 hour. After the reaction solution was concentrated, the residue was extracted with ethyl acetate and saturated aqueous sodium hydrogen carbonate. The ethyl acetate layer was washed with water, concentrated, subjected to silica gel column chromatography, and eluted with methanol: chloroform (3:97) to obtain 0.280 g (yield: 99%) of an alcohol as a colorless oil. ¹ H-NMR (200 MHz, CDCl ₃ ) δ: 7.40-6.90 (9H, m), 4.57-4.45 (1H, m), 4.45 (2H, s), 3.53
(1H, dd, J = 10.7,5.7Hz), 3.21 (1H, dd, J = 10.7,2.1Hz), 2.75
(1H, dd, J = 17.4,6.5Hz), 2.44 (1H, dd, J = 17.4,2.5Hz), 2.32
-2.24 (1H, m) 0.120 g (0.42 mmol) of the obtained alcohol compound in 10 ml of pyridine
Dissolved in methanesulfonyl chloride 0.115 g (1.00 mmol)
Was added and stirred at 50 ° C. for 2 hours. After the reaction solution was concentrated, the residue was acidified by adding 2N hydrochloric acid, and extracted with ethyl acetate. The ethyl acetate layer was washed with water and concentrated, and a hexane: ethyl acetate (5: 1) mixture was added to the residue, followed by stirring for 30 minutes. The crystallized product was collected by filtration and washed with the same solution to obtain 0.120 g (yield 79%) of a mesylate compound as a white powder. ¹ H-NMR (200 MHz, CDCl ₃ ) δ: 7.40-6.95 (9H, m), 5.35-5.25 (1H, m), 4.47 (2H, brs), 3.
67 (1H, dd, J = 12.0,5.6Hz), 3.53 (1H, dd, J = 12.0,2.2Hz), 3.
02 (3H, s), 2.89 (1H, dd, J = 17.9,6.7Hz) 2.71 (1H, dd, J = 17.
0.090 g (0.25 mmol) of the obtained mesylate was dissolved in 5 ml of N, N-dimethylformamide, and 0.085 g of potassium thioacetate was added.
g (0.75 mmol) was added and the mixture was stirred at 70 ° C. for 1 hour. The reaction solution was poured into water and extracted with ethyl acetate. The ethyl acetate layer was washed with water and concentrated. The residue was subjected to silica gel column chromatography, and eluted with hexane: ethyl acetate (60:40).
Acetylthio-1- (4-phenoxybenzyl) pyrrolidin-2-one (0.055 g, yield 64%) was obtained as a white powder. ¹ H-NMR (200 MHz, CDCl ₃ ) δ: 7.40-6.95 (9 H, m), 4.44 (2 H, brs), 4.13-3.98 (1 H, m), 3.
76 (1H, dd, J = 10.7,7.5Hz), 3.17 (1H, dd, J = 10.7,4.9Hz), 2.
92 (1H, dd, J = 17.4,8.9Hz), 2.42 (1H, dd, J = 17.4,6.0Hz), 2.
32 (3H, s)

Example 16 4-benzoylthio-1-
(4-phenoxybenzyl) pyrrolidin-2-one 0.100 g (0.28 mmol) of the mesylate obtained in Example 15,
0.046 g (0.66 mmol) of thiobenzoic acid, 0.092 g of potassium carbonate
(0.66 mmol) was dissolved in 10 ml of N, N-dimethylformamide and stirred at 80 ° C. for 2 hours. The reaction solution was poured into water and extracted with ethyl acetate. The ethyl acetate layer was washed with water, concentrated, and the residue was subjected to silica gel column chromatography, eluted with hexane: ethyl acetate (70:30) to give 4-benzoylthio-1- (4-phenoxybenzyl) pyrrolidine-2-. on
0.052 g (46% yield) was obtained as a colorless oil. ¹ H-NMR (200 MHz, CDCl ₃ ) δ: 7.92-6.90 (14H, m), 4.47 (2H, s), 4.33-4.20 (1H, m), 3.8
8 (1H, dd, J = 10.7,7.5Hz), 3.29 (1H, dd, J = 10.7,4.8Hz), 3.0
3 (1H, dd, J = 17.4,9.0Hz), 2.56 (1H, dd, J = 17.4,5.9Hz)

Example 17 4-mercapto-1- (4-
Phenoxybenzyl) pyrrolidin-2-one 25 mg (0.07 mmol) of 4-acetylthio-1- (4-phenoxybenzyl) pyrrolidin-2-one obtained in Example 15
l) was dissolved in a mixture of 5 ml of acetic acid and 1 ml of concentrated hydrochloric acid and stirred at 100 ° C for 2 hours. After the reaction solution was concentrated, the residue was extracted with ethyl acetate and saturated aqueous sodium hydrogen carbonate. The ethyl acetate layer was washed with water and concentrated, and the residue was subjected to silica gel column chromatography, eluted with chloroform, and 4-mercapto-1- (4-phenoxybenzyl) pyrrolidine-2-yl.
20 mg (95% yield) were obtained as a colorless oil. ¹ H-NMR (200 MHz, CDCl ₃ ) δ: 7.40-6.93 (9 H, m), 4.48 (1 H, d, J = 14.7 Hz), 4.40 (1 H, d, J
= 14.7Hz), 3.66 (1H, dd, J = 9.8,7.1Hz), 3.61-3.47 (1H, m),
3.17 (1H, dd, J = 9.8,4.8Hz), 2.92 (1H, dd, J = 17.1,8.1Hz),
2.42 (1H, dd, J = 17.1,6.1Hz), 1.87 (1H, d, J = 6.8Hz)

Example 18 4-Pivaloyloxymethylthio-1- (4-phenoxybenzyl) pyrrolidine-2-
On 80 mg (0.27 mmol) of 4-mercapto-1- (4-phenoxybenzyl) pyrrolidin-2-one obtained in Example 17
Is dissolved in 5 ml of chloroform and 60% sodium hydride oil
11 mg (0.27 mmol), pivaloyloxymethyl chloride 41 mg
(0.27 mmol) was added and the mixture was stirred at room temperature for 1 hour. The mixture was extracted by gently adding water, the chloroform layer was washed with water, concentrated, and the residue was subjected to silica gel column chromatography, eluted with hexane: ethyl acetate (70:30) to give 4-pivaloyloxymethylthio-1. 63 mg (78% yield) of-(4-phenoxybenzyl) pyrrolidin-2-one was obtained as a colorless oil. ¹ H-NMR (200 MHz, CDCl ₃ ) δ: 7.40-6.93 (11 H, m), 4.48 (1 H, d, J = 14.8 Hz), 4.39 (1 H, d,
J = 14.8Hz), 4.02-3.90 (1H, m), 3.77 (1H, dd, J = 10.6,7.4H
z), 3.13 (1H, dd, J = 10.6,4.6Hz), 2.93 (1H, dd, J = 17.4,8.9H
z), 2.43 (1H, dd, J = 17.4,5.8Hz), 1.20 (9H, s)

Example 19 4,4'-Dithiobis [1-
(4-phenoxybenzyl) pyrrolidin-2-one] A 30-ml separatory funnel was charged with 30 ml of ethyl acetate and 30 ml of water.
80 mg (0.27 mmol) of 4-mercapto-1- (4-phenoxybenzyl) pyrrolidin-2-one obtained in 7, iodine 6
8 mg (0.27 mmol) and 45 mg (0.27 mmol) of potassium iodide were added, and the mixture was shaken at room temperature for 5 minutes. After liquid separation, the ethyl acetate layer was washed with an aqueous solution of sodium hydrogen sulfite, washed with water and concentrated to dryness. Hexane was added to the residue, and after stirring, the crystallized product was collected by filtration, and 63 mg of 4,4′-dithiobis [1- (4-phenoxybenzyl) piperidin-2-one] (78% yield) was obtained as a white powder. Obtained. ¹ H-NMR (200 MHz, CDCl ₃ ) δ: 7.40-6.90 (18 H, m), 4.50 (1 H, d, J = 14.7 Hz), 4.48 (1 H, d,
J = 14.7Hz), 4.38 (1H, d, J = 14.7Hz), 4.35 (1H, d, J = 14.7Hz),
3.65-3.53 (2H, m), 3.53-3.37 (2H, m), 3.31-3.22 (2H, m), 2.
85 (1H, dd, J = 8.0,2.9Hz), 2.77 (1H, dd, J = 7.8,3.1Hz), 2.49
(2H, dd, J = 17.6,4.4Hz)

Example 20 Trans-4-acetylthio-5-hydroxymethyl-1- (4-phenoxybenzyl) pyrrolidin-2-one While stirring with ice cooling, 13.5 ml (185 mmol) of thionyl chloride was added to 52 ml of methanol for 30 minutes. After that, O-benzyl-D, L-serine 10.0 g (51.2 mmol) was added, and the mixture was added at room temperature for 15 minutes.
Stirred for hours. After concentration of the reaction solution, toluene was added and concentrated.
After adding methanol and concentrating, adding ether to make powder, O-benzyl-D, L-serine methyl ester hydrochloride 1
2.0 g (95% yield) was obtained as a white powder. ¹ H-NMR (300 MHz, DMSO-d ₆ ) δ: 8.71 (3 H, s), 7.35 (5 H, m), 4.58 (1 H, d, J = 12.1 Hz), 4.49
(1H, d, J = 12.1Hz), 4.35 (1H, t, J = 3.4Hz), 3.85 (2H, d, J = 3.4
Hz), 3.74 (3H, s) O-benzyl-D, L-serine methyl ester hydrochloride 9.50 g
After dissolving (38.7 mmol) in 160 ml of methanol, 8.09 ml (58.1 mmol) of triethylamine and 6.78 ml (38.7 mmol) of 4-phenoxybenzaldehyde were added, and the mixture was stirred at room temperature for 20 hours. Further, 1.46 g (38.7 mmol) of sodium borohydride was added, and the mixture was stirred at room temperature for 2.5 hours. After concentrating the reaction solution, ethyl acetate was added, washed with water and saturated saline, and dried over anhydrous sodium sulfate. After concentration, the concentrate was subjected to silica gel column chromatography, and hexane: ethyl acetate (80: 20-60: 4
Eluted with 0), concentrated to dryness, and N- (4-phenoxybenzyl)
-O-benzyl-D, L-serine methyl ester 13.0 g (yield
86%) as a colorless oil. ¹ H-NMR (300 MHz, CDCl ₃ ) δ: 7.30 (9 H, m), 7.08 (1 H, m), 6.98 (4 H, m), 4.54 (1 H, d, J = 1
2.4Hz), 4.50 (1H, d, J = 12.4Hz), 3.86 (1H, d, J = 12.8Hz), 3.7
3 (3H, s), 3.70 (3H, m), 3.51 (1H, t, J = 4.9Hz) N- (4-phenoxybenzyl) -O-benzyl-D, L-serine methyl ester 13.0g (33.2mmol A) chloroform 1
After dissolving in 30 ml, 5.55 ml of triethylamine (39.8 mmo
l), 5.10 ml (39.8 mmol) of ethylmalonyl chloride were added, and the mixture was stirred at room temperature for 1 hour. After concentrating the reaction solution, ethyl acetate was added, washed with water and saturated saline, and dried over anhydrous sodium sulfate. After concentration, the residue was subjected to silica gel column chromatography, and hexane: ethyl acetate (70: 30-60: 40)
, Concentrated to dryness, and N- (ethylmalonyl) -N- (4-
Phenoxybenzyl) -O-benzyl-D, L-serine methyl ester (14.3 g, yield 85%) was obtained as a colorless oil. ¹ H-NMR (300 MHz, CDCl ₃ ) δ: 7.28 (9 H, m), 7.12 (1 H, m), 6.98 (4 H, m), 4.72 (3 H, m), 4.4
1 (2H, s), 4.18 (2H, q, J = 7.2Hz), 3.97 (2H, m), 3.71 (3H, s),
3.47 (1H, d, J = 15.3Hz), 3.39 (1H, d, J = 15.3Hz), 1.25 (3H,
t, J = 7.2Hz) N- (ethylmalonyl) -N- (4-phenoxybenzyl)-
O-benzyl-D, L-serine methyl ester 2.40 g (4.75m
mol) was dissolved in 30.0 ml of methanol, and 240 mg of 10% palladium on activated carbon and 30 ml of concentrated hydrochloric acid were added.
Stirred for hours. After filtering the catalyst, the mixture was concentrated to dryness, and N- (ethylmalonyl) -N- (4-phenoxybenzyl) -D, L-
1.90 g (96% yield) of serine methyl ester was obtained as a colorless oil. ¹ H-NMR (300 MHz, CDCl ₃ ) δ: 7.33 (4 H, m), 7.13 (1 H, m), 7.01 (4 H, m), 4.64 (1 H, d, J = 1
6.8Hz), 4.58 (1H, d, J = 16.8Hz), 4.21 (2H, q, J = 7.2Hz), 4.13
(2H, m), 3.93 (1H, m), 3.72 (3H, s), 3.56 (1H, d, J = 15.8Hz),
3.45 (1H, d, J = 15.8Hz), 1.29 (3H, t, J = 7.2Hz) N- (ethylmalonyl) -N- (4-phenoxybenzyl)-
After dissolving 1.90 g (4.57 mmol) of D, L-serine methyl ester in 20.0 ml of ethanol, 1.79 ml (4.57 mmol) of a 20% sodium ethoxide ethanol solution was added, and the mixture was stirred at room temperature for 1 hour. After concentrating the reaction solution, ethyl acetate was added, and the mixture was washed with 10% aqueous citric acid, water and saturated saline, and then dried over anhydrous sodium sulfate. After concentration, dissolved in 40.0 ml of acetonitrile,
μl was added and the mixture was heated under reflux for 30 minutes. After concentration of the reaction solution, dissolved in 30.0 ml of methanol, sodium borohydride 159m
g (4.20 mmol) was added with stirring, and the mixture was further stirred at room temperature for 1 hour. After adding 1N hydrochloric acid, the mixture was extracted twice with ethyl acetate. The ethyl acetate layer was washed with water and saturated saline, and then dried over anhydrous sodium sulfate. After concentration, the residue was subjected to silica gel column chromatography, eluted with chloroform: methanol (95: 5), concentrated to dryness, and cis-4-hydroxy-5-hydroxymethyl-1- (4-phenoxybenzyl) -pyrrolidine-2-yl. 520 mg (36% yield) were obtained as a white powder. ¹ H-NMR (300 MHz, CDCl ₃ ) δ: 7.34 (2 H, m), 7.19 (2 H, d, J = 8.3 Hz), 7.11 (1 H, m), 6.97 (4
H, m), 4.97 (1H, d, J = 15.1Hz), 4.61 (1H, m), 4.07 (1H, d, J = 1
5.1Hz), 3.92 (2H, m), 3.55 (1H, m), 3.49 (1H, m), 3.06 (1H,
s), 2.76 (1H, dd, J = 17.2,7.5Hz), 2.54 (1H, dd, J = 17.2,4.9H
z) cis-4-hydroxy-5-hydroxymethyl-1-
(4-phenoxybenzyl) -pyrrolidin-2-one 500m
g (1.60 mmol) was dissolved in 15.0 ml of chloroform, and then 491 mg (1.76 mmol) of trityl chloride and 401 μl of triethylamine were dissolved.
(2.88 mmol), 7.82 mg of 4-dimethylaminopyridine (0.0
64 mmol) and stirred at room temperature for 9 hours. After concentrating the reaction solution, ethyl acetate was added, washed with water and saturated saline, and dried over anhydrous sodium sulfate. After concentration, the mixture was subjected to silica gel column chromatography, and hexane: ethyl acetate (70: 3
0-60: 40), concentrated to dryness and 700 mg (79% yield) of cis-4-hydroxy-1- (4-phenoxybenzyl) -5-trityloxymethyl-pyrrolidin-2-one as a colorless oil. Obtained as a product. ¹ H-NMR (300 MHz, CDCl ₃ ) δ: 7.33 (19 H, m), 7.11 (1 H, m), 6.98 (2 H, m), 6.87 (2 H, d, J =
8.3Hz), 4.94 (1H, d, J = 14.7Hz), 4.55 (1H, m), 3.58 (2H, m),
3.47 (1H, dd, J = 10.0,3.4Hz), 3.40 (1H, dd, J = 10.0,5.7Hz),
2.77 (1H, dd, J = 17.3,7.9Hz), 2.63 (1H, dd, J = 17.3,5.7Hz),
2.48 (1H, d, J = 6.8Hz) cis-4-hydroxy-1- (4-phenoxybenzyl)
-5-Trityloxymethyl-pyrrolidin-2-one 35
After 0 mg (0.630 mmol) was dissolved in 14.0 ml of chloroform, 439 μl (3.15 mmol) of triethylamine and 244 μl (3.15 mmol) of methanesulfonyl chloride were added under ice cooling, and the mixture was stirred at room temperature for 1 hour. After concentrating the reaction solution, ethyl acetate was added, washed with water and saturated saline, and dried over anhydrous sodium sulfate. After concentration, the residue was subjected to silica gel column chromatography, eluted with hexane: ethyl acetate (40: 60-30: 70), concentrated to dryness,
400 mg (100% yield) of cis-4-methanesulfonyloxy-1- (4-phenoxybenzyl) -5-trityloxymethyl-pyrrolidin-2-one was obtained as a colorless oil. ¹ H-NMR (300 MHz, CDCl ₃ ) δ: 7.41 (6 H, m), 7.31 (11 H, m), 7.12 (1 H, m), 6.99 (2 H, m), 6.
88 (4H, m), 5.29 (1H, m), 4.95 (1H, d, J = 15.1Hz), 3.69 (1H,
m), 3.52 (1H, dd, J = 10.6,2.6Hz), 3.39 (1H, dd, J = 10.6,4.1H
z), 3.31 (1H, d, J = 15.1Hz), 3.11 (1H, dd, J = 16.6, 7.2Hz), 2.
92 (3H, s), 2.85 (1H, dd, J = 16.6, 7.9 Hz) cis-4-methanesulfonyloxy-1- (4-phenoxybenzyl) -5-trityloxymethyl-pyrrolidin-2-one 400 mg ( After dissolving 0.630 mmol) in 2.00 ml of ether, 4.00 ml of formic acid was added, and the mixture was stirred at room temperature for 1 hour. After concentrating the reaction solution, it was subjected to silica gel column chromatography, eluted with hexane: ethyl acetate (10: 90-0: 100), concentrated to dryness, and cis-5-hydroxymethyl-4-methanesulfonyloxy-1-. 121 mg (yield 49%) of (4-phenoxybenzyl) -pyrrolidin-2-one was obtained as a colorless oil. ¹ H-NMR (300 MHz, CDCl ₃ ) δ: 7.35 (2H, m), 7.21 (2H, d, J =
8.3 Hz), 7.12 (1H, m), 7.01 (2
H, m), 6.96 (2H, d, J = 8.7 Hz),
5.35 (1H, m), 4.90 (1H, d, J = 1
5.1 Hz), 4.13 (1H, d, J = 15.1H)
z), 3.89 (2H, m), 3.77 (1H,
m), 3.10 (3H, s), 2.84 (2H,
m), 2.04 (1H, s) cis-5-hydroxymethyl-4-methanesulfonyloxy-1- (4-phenoxybenzyl) -pyrrolidine-2
-One 121 mg (0.309 mmol) was dissolved in N, N-dimethylformamide 5 ml, and potassium thioacetate 70.6 mg (0.618 mmol) was dissolved.
l) was added thereto, and the mixture was stirred at 50 ° C for 1.5 hours. Further, 141 mg (1.24 mmol) of potassium thioacetate was added, and the mixture was stirred at 70 ° C for 3 hours. After concentrating the reaction solution, ethyl acetate was added, washed with water and saturated saline, and dried over anhydrous sodium sulfate. After concentration, the concentrate was subjected to silica gel column chromatography, eluted with hexane: ethyl acetate (10:90), concentrated to dryness, and trans-4-acetylthio-5-hydroxymethyl-1- (4-phenoxybenzyl) -pyrrolidine-2 was obtained. 17.1 mg (15% yield) of -one was obtained as a colorless oil. ¹ H-NMR (300 MHz, CDCl ₃ ) δ: 7.34 (2 H, m), 7.21 (2 H, d, J = 8.3 Hz), 7.11 (1 H, m), 6.98 (4
H, m), 4.90 (1H, d, J = 15.3Hz), 4.11 (1H, d, J = 15.3Hz), 4.03
(1H, m), 3.80 (1H, dd, J = 12.3,3.2Hz), 3.71 (1H, dd, J = 12.3,
2.5Hz), 3.38 (1H, m), 3.10 (1H, dd, J = 17.3, 9.0Hz), 2.37 (1
H, dd, J = 17.3,4.1Hz), 2.30 (3H, s)

Example 21 (S) -4-acetylthio-1
-(4-phenoxybenzyl) pyrrolidin-2-one (R) -4-hydroxy-2-pyrrolidone 700 mg (6.9 mmol,
Daiso) and 4-phenoxybenzyl chloride 4.5
0 g (20.8 mmol) was dissolved in dimethyl sulfoxide 6.0 ml,
Under ice cooling, after adding 1.20 g of powdered potassium hydroxide,
Stirred at room temperature for 14 hours. After adding ethyl acetate, add 6
Twice, followed by washing with a saturated saline solution. The ethyl acetate layer was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography to give ethyl acetate:
Elution with methanol (100: 0-99: 1) gave 365 mg (19% yield) of (R) -4-hydroxy-1- (4-phenoxybenzyl) pyrrolidin-2-one as a light brown oil. . ¹ H-NMR (300 MHz, CDCl ₃ ) δ: 7.36-6.95 (9H, m), 4.51-4.48 (1H, m), 4.45 (2H, s), 3.53
(1H, dd, J = 10.8,5.6Hz), 3.21 (1H, dd, J = 10.8,1.9Hz), 2.75
(1H, dd, J = 17.3,6.5Hz), 2.44 (1H, dd, J = 17.3,2.2Hz), 2.07
(1H, brs). (R) -4-hydroxy-1- (4-phenoxybenzyl)
To a mixture of 300 mg (1.1 mmol) of pyrrolidin-2-one, 207 μl (1.5 mmol) of triethylamine and 1.5 ml of chloroform, a mixture of 115 μl (1.5 mmol) of methanesulfonyl chloride and 1.5 ml of chloroform was added dropwise under ice cooling, and 30 ml of ice was added under ice cooling. Stirred for minutes. The reaction solution was concentrated under reduced pressure, ethyl acetate was added to the residue, and the mixture was washed six times with water and then with saturated saline, and the ethyl acetate layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure.
372 mg (97% yield) of (R) -4-methanesulfonyloxy-1- (4-phenoxybenzyl) pyrrolidin-2-one was obtained as a brown oil. ¹ H-NMR (300 MHz, CDCl ₃ ) δ: 7.37-6.96 (9 H, m), 5.32-5.27 (1 H, m), 4.50 (1 H, d, J = 14.
7Hz), 4.44 (1H, d, J = 14.7Hz), 3.66 (1H, dd, J = 11.9,5.7Hz),
3.52 (1H, dd, J = 11.9,2.0Hz), 3.02 (3H, s), 2.87 (1H, dd, J = 1
7.9, 6.8 Hz), 2.71 (1H, dd, J = 17.9, 2.5 Hz) .369 ml of cesium carbonate (1.1 mmol) was added to a solution of 89 μl (1.2 mmol) of thioacetic acid in 1.0 ml of methanol at room temperature, and the mixture was concentrated under reduced pressure. Thereafter, 2.0 ml of N, N-dimethylformamide was added to the residue to prepare a cesium thioacetate salt solution. This solution was prepared using the (R) -4-methanesulfonyloxy-1 obtained above.
-(4-phenoxybenzyl) pyrrolidin-2-one 372m
g (1.0 mmol) and N, N-dimethylformamide (3.0 ml), and the mixture was stirred at room temperature for 6 hours.
(0.2 mmol) and 67 mg (0.2 mmol) of cesium carbonate.
After stirring at room temperature for 15 hours, ethyl acetate was added, and water was added six times.
Subsequently, the extract was washed with saturated saline, the ethyl acetate layer was dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue obtained was subjected to silica gel column chromatography to give ethyl acetate.
The crude product was eluted with hexane (18:82), and the obtained crude product was purified by preparative thin-layer silica gel chromatography (eluent: ethyl acetate: hexane (1: 1)) to give (S) -4- Acetylthio-1- (4-phenoxybenzyl) pyrrolidine-
80.3 mg of 2-one (23% yield) was obtained as a colorless oil. ¹ H-NMR (300 MHz, CDCl ₃ ) δ: 7.36-6.94 (9H, m), 4.45 (1H, d, J = 14.7 Hz), 4.39 (1H, d, J
= 14.7Hz), 4.07-4.02 (1H, m), 3.74 (1H, dd, J = 10.6,7.5Hz),
3.16 (1H, dd, J = 10.6,4.9Hz), 2.90 (1H, dd, J = 17.4,8.9Hz),
2.41 (1H, dd, J = 17.4,6.0Hz), 2.31 (3H, s).

Example 22 (S) -4-mercapto-1-
(4-phenoxybenzyl) pyrrolidin-2-one (S) -4-acetylthio-1- (4) obtained in Example 21
-Phenoxybenzyl) pyrrolidin-2-one 8 mg (0.02m
mol), 0.1 ml of concentrated hydrochloric acid and 0.1 ml of acetic acid at 100 ° C. for 2 hours.
Stirred for 0 minutes. Ethyl acetate was added to the reaction solution, and water was used five times.
Subsequently, the mixture was washed with saturated saline, and the ethyl acetate layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give (S) -4-mercapto-1- (4-phenoxybenzyl) pyrrolidine-2-.
6.9 mg (99% yield) were obtained as a colorless oil. ¹ H-NMR (300 MHz, CDCl ₃ ) δ: 7.37-6.95 (9 H, m), 4.47 (1 H, d, J = 14.6 Hz), 4.40 (1 H, d,
J = 14.7Hz), 3.65 (1H, dd, J = 10.0,7.2Hz), 3.60-3.48 (1H,
m), 3.16 (1H, dd, J = 10.0,5.1Hz), 2.91 (1H, dd, J = 17.1,8.1H
z), 2.41 (1H, dd, J = 17.1, 6.2Hz), 1.87 (1H, d, J = 6.7Hz).

Example 23 (4S, 4'S) -4,4'-Dithiobis [1- (4-phenoxybenzyl) pyrrolidine-2
-One] (S) -4-acetylthio-1- (4) obtained in Example 21.
-Phenoxybenzyl) pyrrolidin-2-one 4 mg (0.01 m
mol), 2 drops of concentrated hydrochloric acid and 2 drops of acetic acid were stirred at 100 ° C. for 5 minutes. Ethyl acetate was added to the reaction solution, and twice with water, 0.25M
Wash with potassium iodide-aqueous solution of iodine, 5% aqueous solution of sodium sulfite, then saturated brine, dry the ethyl acetate layer with anhydrous sodium sulfate, and concentrate under reduced pressure (4S, 4'S)
-4,4'-Dithiobis [1- (4-phenoxybenzyl) pyrrolidin-2-one] (2 mg, yield 30%) was obtained as a pale yellow powder. ¹ H-NMR (300 MHz, CDCl ₃ ) δ: 7.36-6.94 (18H, m), 4.47 (2H, d, J = 14.7 Hz), 4.38 (2H, d,
J = 14.7Hz), 3.61 (2H, dd, J = 10.7,6.9Hz), 3.53-3.47 (2H,
m), 3.27 (2H, dd, J = 10.7,3.5Hz), 2.82 (2H, dd, J = 17.5,8.2H
z), 2.49 (2H, dd, J = 17.5,4.4Hz).

Example 24 (R) -4-acetylthio-1
-(4-Phenoxybenzyl) pyrrolidin-2-one In the same manner as in Example 21, (R) -4-acetylthio-1- (4) was obtained from (S) -4-hydroxy-2-pyrrolidone (manufactured by Daiso). -Phenoxybenzyl) pyrrolidine-
The 2-one was obtained as a pale yellow oil. (S) -4-hydroxy-1- (4-phenoxybenzyl)
Pyrrolidin-2-one (21% yield) ¹ H-NMR (300 MHz, CDCl ₃ ) δ: 7.37-6.94 (9H, m), 4.54-4.48 (1H, m), 4.48 (1H, d, J = 14) .
6Hz), 4.42 (1H, d, J = 14.6Hz), 3.53 (1H, dd, J = 10.8,6.5Hz),
3.21 (1H, dd, J = 10.8,2.1Hz), 2.75 (1H, dd, J = 17.3,6.5Hz),
2.44 (1H, d, J = 17.3,2.4Hz), 2.05 (1H, brs). (S) -4-methanesulfonyloxy-1- (4-phenoxybenzyl) pyrrolidin-2-one (98% yield) ¹ H-NMR (300 MHz, CDCl ₃ ) δ: 7.37-6.96 (9 H, m), 5.32-5.27 (1 H, m), 4.49 (1 H, d, J = 14.
7Hz), 4.43 (1H, d, J = 14.7Hz), 3.66 (1H, dd, J = 11.9,5.7Hz),
3.52 (1H, dd, J = 11.9,2.0 Hz), 3.02 (3H, s), 2.88 (1H, dd, J =
17.9,6.8Hz), 2.71 (1H, dd, J = 17.9,2.5Hz). (R) -4-acetylthio-1- (4-phenoxybenzyl) pyrrolidin-2-one (44% yield) ¹ H- NMR (300 MHz, CDCl ₃ ) δ: 7.37-6.95 (9H, m), 4.46 (1H, d, J = 14.6 Hz), 4.40 (1H, d, J
= 14.6Hz), 4.11-4.01 (1H, m), 3.75 (1H, dd, J = 10.6,7.5H
z), 3.17 (1H, dd, J = 10.6,4.9Hz), 2.91 (1H, dd, J = 17.4,9.0H
z), 2.42 (1H, dd, J = 17.4,6.0Hz), 2.32 (3H, s).

Example 25 (R) -4-Mercapto-1-
(4-phenoxybenzyl) pyrrolidin-2-one Obtained in Example 24 by a method similar to that in Example 22.
(R) -4-acetylthio-1- (4-phenoxybenzyl) pyrrolidin-2-one 10 mg (0.03 mmol) to (R) -4-
8.1 mg (92% yield) of mercapto-1- (4-phenoxybenzyl) pyrrolidin-2-one was obtained as a colorless oil. ¹ H-NMR (300 MHz, CDCl ₃ ) δ: 7.37-6.95 (9 H, m), 4.47 (1 H, d, J = 14.7 Hz), 4.40 (1 H, d, J
= 14.7Hz), 3.65 (1H, dd, J = 10.0,7.2Hz), 3.60-3.48 (1H, m),
3.16 (1H, dd, J = 10.0,5.1Hz), 2.91 (1H, dd, J = 17.1,8.1Hz),
2.42 (1H, dd, J = 17.0,6.2Hz), 1.87 (1H, d, J = 6.7Hz).

Example 26 (4R, 4'R) -4,4'-Dithiobis [1- (4-phenoxybenzyl) pyrrolidin-2-one] Was
From (R) -4-acetylthio-1- (4-phenoxybenzyl) pyrrolidin-2-one 10 mg (0.03 mmol) to (4R, 4′R)
6.9 mg (79% yield) of -4,4'-dithiobis [1- (4-phenoxybenzyl) pyrrolidin-2-one] was obtained as a white powder. ¹ H-NMR (300 MHz, CDCl ₃ ) δ: 7.36-6.94 (18H, m), 4.46 (2
H, d, J = 14.7 Hz), 4.42 (2H, d, J)
= 14.7 Hz), 3.60 (2H, dd, J = 10.
7, 6.9 Hz), 3.52-3.45 (2H, m),
3.27 (2H, dd, J = 10.7, 3.5 Hz),
2.81 (2H, dd, J = 17.5, 8.2 Hz),
2.48 (2H, dd, J = 17.5, 4.4 Hz).

Example 27 3-acetylthio-1-
(4-phenoxybenzyl) pyrrolidin-2-one 3.20 g (16.2 mmol) of 4-phenoxybenzaldehyde, β-
Alanine benzyl ester p-toluenesulfonate 6.00
After stirring a mixture of g (17.1 mmol), 2.40 ml (17.1 mmol) of triethylamine and 150.0 ml of methanol at room temperature for 22 hours, 0.517 g (13.7 mmol) of sodium borohydride was added little by little. After stirring at room temperature for 10 minutes, ethyl acetate was added to the residue obtained by concentration under reduced pressure, and saturated aqueous sodium hydrogen carbonate was added.
And then once with water and then with saturated saline, and the ethyl acetate layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give 5.70 g (yield 98%) of the amine compound as a colorless oil. . ¹ H-NMR (300 MHz, CDCl ₃ ) δ: 7.35 to 6.93 (14H, m), 5.13 (2H, s), 3.76 (2H, s), 2.92 (2H,
t, J = 6.3 Hz), 2.59 (2H, t, J = 6.4 Hz) obtained amine form 5.70 g (15.9 mmol), oxalic acid dibenzyl ester 4.50 g (16.7 mmol), tetrahydrofuran 150.0
At room temperature, 667 mg of 60% sodium hydride oily (1 mg
6.7 mmol) was added three times after washing with hexane, and the mixture was heated with stirring at 95 ° C. for 2 hours, cooled and concentrated under reduced pressure, and ethyl acetate was added to the obtained residue. After washing with brine, the ethyl acetate layer was dried over anhydrous sodium sulfate, and concentrated under reduced pressure. Ethyl acetate was added to the obtained residue, and the crystallized product was collected by filtration, yielding 3.10 g of the benzyl ester derivative (yield 47). %) As a white powder. ¹ H-NMR (300 MHz, CDCl ₃ ) δ: 8.80 (1 H, brs), 7.38-6.94 (14 H, m), 5.26 (2 H, s), 4.63 (2
H, s), 3.89 (2H, s) .The obtained benzyl ester form 3.50 g (8.40 mmol), 10% palladium on activated carbon 1.80 g, ethyl acetate 100 ml, ethanol 10
The 0 ml mixture was stirred under a hydrogen atmosphere at room temperature for 3 hours. After filtering off the insoluble matter, the residue obtained by concentrating under reduced pressure was added with ethyl acetate, washed twice with a saturated aqueous solution of sodium hydrogencarbonate and with a saturated saline solution, and the ethyl acetate layer was dried over anhydrous sodium sulfate. Ethyl acetate was added to the residue obtained by concentration under reduced pressure,
The crystallized product was collected by filtration to obtain 1.70 g (yield 72%) of 3-hydroxy-1- (4-phenoxybenzyl) pyrrolidin-2-one as a white powder. ¹ H-NMR (300 MHz, DMSO-d ₆ ) δ: 7.41-6.96 (9 H, m), 5.56 (1 H, d, J = 5.6 Hz), 4.37 (1 H, d, J =
15.2Hz), 4.31 (1H, d, J = 15.2Hz), 4.19-4.12 (1H, m), 3.22-
3.06 (2H, m), 2.31-2.21 (1H, m), 1.76-1.63 (1H, m) .3-hydroxy-1- (4-phenoxybenzyl) pyrrolidin-2-one 50 mg (0.2 mmol), methanesulfonyl Chloride 15 μl (0.2 mmol), triethylamine 54 μl (0.2 mmol) was added to a mixture of chloroform 1.0 ml, and the mixture was stirred at room temperature for 5 minutes, concentrated under reduced pressure, and ethyl acetate was added to the obtained residue. The extract was washed with saturated saline, the ethyl acetate layer was dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by preparative thin-layer silica gel chromatography (developing solvent: ethyl acetate: hexane (33:67)). This gave 52 mg (81% yield) of 3-methanesulfonyloxy-1- (4-phenoxybenzyl) pyrrolidin-2-one as a colorless oil ¹ H-NMR (300 MHz, CDCl ₃ ) δ: 7.38- 6.96 (9H, m), 5.23 (1H, t, J = 7.8 Hz), 4.47 (1H, d, J
= 14.6Hz), 4.41 (1H, d, J = 14.5Hz), 3.41-3.21 (2H, m), 3.31
(3H, s), 2.61-2.50 (1H, m), 2.30-2.17 (1H, m) .52 mg (0.1 mmol) of 3-methanesulfonyloxy-1- (4-phenoxybenzyl) pyrrolidin-2-one, thiol A mixture of potassium acetate (20 mg, 0.2 mmol) and N, N-dimethylformamide (1.0 ml) was stirred at room temperature for 12 hours, and concentrated under reduced pressure. Ethyl acetate was added to the obtained residue, and the mixture was saturated with water three times and then saturated. After washing with brine, the ethyl acetate layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give 3-acetylthio-1-.
(4-phenoxybenzyl) pyrrolidin-2-one 41 mg
(84% yield) as a colorless oil. ¹ H-NMR (300 MHz, CDCl ₃ ) δ: 7.37-6.95 (9 H, m), 4.50 (1 H, d, J = 14.6 Hz), 4.41 (1 H, d, J
= 14.6Hz), 4.25 (1H, t, J = 8.6Hz), 3.35-3.23 (2H, m), 2.65-
2.54 (1H, m), 2.39 (3H, s), 2.07-1.94 (1H, m).

Example 28 3-benzoylthio-1-
(4-Phenoxybenzyl) pyrrolidin-2-one To a solution of 64 μl (0.5 mmol) of thiobenzoic acid in 1.0 ml of methanol was added 24 mg (0.2 mmol) of cesium carbonate at room temperature, and the solvent was distilled off under reduced pressure to remove cesium thiobenzoate. Was prepared. Example
3-methanesulfonyloxy-1- (4-
Phenoxybenzyl) pyrrolidin-2-one 163 mg (0.452
mmol) and 2.0 ml of N, N-dimethylformamide, the salt was added, and the mixture was stirred at room temperature for 3 days.
4 μl (0.5 mmol) and 24 mg (0.2 mmol) of cesium carbonate were added. After further stirring at room temperature for 3 hours, 64 μl of thiobenzoic acid (0.
5 mmol) and 24 mg (0.2 mmol) of cesium carbonate,
Ethyl acetate was added and twice with saturated aqueous sodium hydrogen carbonate,
The extract was washed with water and saturated saline, and the ethyl acetate layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The obtained residue was separated by thin-layer silica gel chromatography (developing solvent: ethyl acetate: hexane (1: 1)). ) To give 3-benzoylthio-
1- (4-phenoxybenzyl) pyrrolidin-2-one 13
3 mg (73% yield) was obtained as a colorless oil. ¹ H-NMR (300 MHz, CDCl ₃ ) δ: 7.98-7.95 (2H, m), 7.59-6.97 (12H, m), 4.54 (1H, d, J = 1
4.8Hz), 4.47 (1H, t, J = 8.3Hz), 4.46 (1H, d, J = 14.8Hz), 3.42
-3.30 (2H, m), 2.78-2.65 (1H, m), 2.17-2.05 (1H, m)

Example 29 3-mercapto-1- (4-
Phenoxybenzyl) pyrrolidin-2-one 41.2 mg (0.1 mmo) of 3-acetylthio-1- (4-phenoxybenzyl) pyrrolidin-2-one obtained in Example 27
l), a mixture of concentrated hydrochloric acid (0.5 ml) and acetic acid (0.5 ml) was stirred at 100 ° C. for 8 minutes, cooled, concentrated under reduced pressure, and ethyl acetate was added to the obtained residue. , And the ethyl acetate layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give 3-mercapto-1- (4-phenoxybenzyl) pyrrolidin-2-one (35.6 mg, yield 98%) as a colorless oil. As obtained. ¹ H-NMR (300 MHz, CDCl ₃ ) δ: 7.37-6.95 (9H, m), 4.48 (1
H, d, J = 14.6 Hz), 4.40 (1H, d, J)
= 14.6 Hz), 3.72-3.66 (1H, m),
3.40-3.19 (2H, m), 2.52-2.39
(1H, m), 2.32 (1H, d, J = 4.3H)
z), 1.96-1.85 (1H, m).

Example 30 4-acetylthio-1-
(4- (4'-Fluorophenoxy) benzyl) pyrrolidin-2-one 10.0 g (83.9 mmol) of 4-amino-3-hydroxybutyric acid was dissolved in 400 ml of xylene, and 124 ml of hexamethyldisilazane (5 ml) was dissolved.
87 mmol), 1 drop of trimethylsilyl chloride, and 16.5
Heated to reflux for an hour. After concentration of the reaction solution, the residue was washed with diisopropyl ether to obtain 12.6 g (yield 87%) of 4-trimethylsilyloxypyrrolidin-2-one as a brown powder. ¹ H-NMR (300 MHz, CDCl ₃ ) δ: 6.62 (1 H, brs), 4.52 (1 H, brs), 3.57 (1 H, brd), 3.23 (1
H, brd), 2.52 (1H, m), 2.25 (1H, m), 0.11 (9H, brs)

5.0 g of 4-fluorobenzaldehyde (40.3 m
mol), 4.5 g (40.3 mmol) of 4-fluorophenol and 5.6 g (40.3 mmol) of potassium carbonate in N, N-dimethylformamide
After dissolving in 100 ml, the mixture was stirred at 120 ° C for 14.5 hours. After adding cold water to the reaction solution and extracting twice with ethyl acetate, the obtained organic layer was washed with water and saturated saline, and dried over anhydrous sodium sulfate. After concentration under reduced pressure, the residue was subjected to silica gel column chromatography, the fraction eluted with hexane: ethyl acetate (97: 3) was concentrated under reduced pressure, and the residue was washed with hexane.
7.7 g (88% yield) of (4'-fluorophenoxy) benzaldehyde was obtained as a white powder. ¹ H-NMR (300 MHz, CDCl ₃ ) δ: 9.93 (1 H, s), 7.85 (2 H, d, J = 8.8 Hz), 7.09 (2 H, d, J = 7.9 H)
z), 7.05 (2H, d, J = 7.9Hz), 7.03 (2H, d, J = 8.8Hz)

After dissolving 2.0 g (9.3 mmol) of 4- (4′-fluorophenoxy) benzaldehyde in 40 ml of methanol,
422 mg (11.2 mmol) of sodium borohydride was slowly added, and the mixture was stirred at room temperature for 2 hours. The reaction solution was acidified by adding dilute hydrochloric acid, concentrated under reduced pressure, extracted twice with ethyl acetate, and the obtained organic layer was washed with water and saturated saline, and dried over anhydrous sodium sulfate. After concentration under reduced pressure, the residue was washed with hexane to give 1.7 g of 4- (4'-fluorophenoxy) benzyl alcohol (85% yield) as a white powder. ¹ H-NMR (300 MHz, CDCl ₃ ) δ: 7.33 (2H, d, J = 8.7 Hz), 7.01 (2H, d, J = 10.3 Hz), 6.99 (2
H, d, J = 8.7Hz), 6.96 (2H, d, J = 10.3Hz), 4.67 (2H, d, J = 5.6H
z), 1.64 (1H, t, J = 5.6Hz)

1.7 g (7.9 mmol) of 4- (4′-fluorophenoxy) benzyl alcohol was dissolved in chloroform.
Stir in an ice bath. 639 μl (7.9 mmol) of pyridine and 632 μl (8.7 mmol) of thionyl chloride were slowly added, and 0.5
The mixture was stirred for an additional 2 hours at room temperature. The reaction solution was concentrated under reduced pressure, water was added, and the mixture was extracted twice with ethyl acetate. The obtained organic layer was washed with water and saturated saline, and dried over anhydrous sodium sulfate. The mixture was concentrated under reduced pressure to obtain 1.7 g (yield 91%) of 4- (4'-fluorophenoxy) benzyl chloride as a colorless oil. ¹ H-NMR (300 MHz, CDCl ₃ ) δ: 7.33 (2H, d, J = 8.6 Hz), 7.01 (2H, d, J = 7.6 Hz), 6.99 (2H,
d, J = 7.6Hz), 6.93 (2H, d, J = 8.6Hz), 4.56 (2H, s)

4-trimethylsilyloxypyrrolidine-
1.25 g (7.2 mmol) of 2-one and 1.70 g (7.2 mmol) of 4- (4′-fluorophenoxy) benzyl chloride were dissolved in 20.0 ml of dimethyl sulfoxide, and 475 mg (7.2 mmol) of powdered potassium hydroxide was added to the catalyst. After adding an amount of potassium iodide, the mixture was stirred at room temperature for 5.5 hours. After water was added to the reaction solution and the mixture was extracted twice with ethyl acetate, the obtained organic layer was washed four times with water and subsequently with a saturated saline solution and dried over anhydrous sodium sulfate. After concentration under reduced pressure, the residue was subjected to silica gel column chromatography and eluted with chloroform: methanol (98: 2) to give 914 mg of 4-hydroxy-1- (4- (4′-fluorophenoxy) benzyl) pyrrolidin-2-one. (Yield 42
%) As a brown powder. ¹ H-NMR (300 MHz, CDCl ₃ ) δ: 7.20 (2H, d, J = 8.6 Hz), 7.01 (2H, d, J = 10.6 Hz), 6.99 (2
H, d, J = 10.6Hz), 6.92 (2H, d, J = 8.6Hz), 4.91 (1H, m), 4.49 (1
H, d, J = 14.9Hz), 4.41 (1H, d, J = 14.8Hz), 3.53 (1H, dd, J = 10.
8,5.6Hz), 3.21 (1H, dd, J = 10.8,2.0Hz), 2.75 (1H, dd, J = 17.
4,6.6Hz), 2.44 (1H, dd, J = 17.4,2.4Hz), 2.10 (1H, d, J = 4.3H
z)

914 mg of 4-hydroxy-1- (4- (4′-fluorophenoxy) benzyl) pyrrolidin-2-one
After dissolving (3.0 mmol) in 20 ml of pyridine, 464 μl (6.0 mmol) of methanesulfonyl chloride was added, and the mixture was stirred at 50 ° C. for 1 hour. After adding water to the reaction solution and extracting twice with ethyl acetate,
The obtained organic layer was washed twice with water and subsequently with a saturated saline solution, and the ethyl acetate layer was dried over anhydrous sodium sulfate. After concentration under reduced pressure, the residue was triturated with hexane-ethyl acetate, and 4-methanesulfonyloxy-1- (4- (4′-fluorophenoxy) benzyl) pyrrolidin-2-one926
mg (81% yield) was obtained as a grey-brown powder. ¹ H-NMR (300 MHz, CDCl ₃ ) δ: 7.19 (2H, d, J = 8.5 Hz), 7.02 (2H, d, J = 10.7 Hz), 7.00 (2
H, d, J = 10.7Hz), 6.93 (2H, d, J = 8.5Hz), 5.29 (1H, m), 4.49 (1
H, d, J = 14.9Hz), 4.43 (1H, d, J = 14.8Hz), 3.66 (1H, dd, J = 11.
9,5.7Hz), 3.52 (1H, dd, J = 11.9,2.0Hz), 3.03 (3H, s), 2.75
(1H, dd, J = 17.9,6.8Hz), 2.71 (1H, dd, J = 17.9,2.6Hz)

4-Methanesulfonyloxy-1- (4-
(4′-fluorophenoxy) benzyl) pyrrolidine-2
926 mg (2.4 mmol) of -one was dissolved in 30 ml of ethanol, and 822 mg (7.2 mmol) of potassium thioacetate was added, followed by heating under reflux for 1 hour. The reaction solution was concentrated under reduced pressure, water was added, and the mixture was extracted twice with ethyl acetate. The obtained organic layer was washed with water and saturated saline, and dried over anhydrous sodium sulfate. After concentration under reduced pressure,
The residue was subjected to silica gel column chromatography,
Elution with hexane: ethyl acetate (70:30) gave 834 mg of 4-acetylthio-1- (4- (4′-fluorophenoxy) benzyl) pyrrolidin-2-one (97% yield) as a pale yellow oil. Was. ¹ H-NMR (300 MHz, CDCl ₃ ) δ: 7.18 (2H, d, J = 8.6 Hz), 7.02 (2H, d, J = 9.7 Hz), 7.00 (2H,
d, J = 9.7Hz), 6.92 (2H, d, J = 8.6Hz), 4.45 (1H, d, J = 15.1Hz),
4.40 (1H, d, J = 15.1Hz), 4.05 (1H, m), 3.75 (1H, dd, J = 10.6,
7.6Hz), 3.17 (1H, dd, J = 10.6,5.0Hz), 2.91 (1H, dd, J = 17.4,
9.0Hz), 2.42 (1H, dd, J = 17.4,6.1Hz), 2.32 (3H, s)

Example 31 4-mercapto-1- (4-
(4′-fluorophenoxy) benzyl) pyrrolidine-2
-One 4-acetylthio-1- (4-
(4′-fluorophenoxy) benzyl) pyrrolidine-2
250 mg (0.7 mmol) of -one was dissolved in a mixture of 4 ml of acetic acid and 1 ml of concentrated hydrochloric acid, and the mixture was stirred at 100 ° C for 3 hours. The reaction solution was concentrated under reduced pressure, ethyl acetate was added, and the mixture was washed twice with water and then with saturated saline, and the organic layer was dried over anhydrous sodium sulfate. After concentration under reduced pressure, the residue was subjected to silica gel column chromatography, and eluted with hexane: ethyl acetate (70: 30-50: 50) to give 4-mercapto-1- (4- (4′-fluorophenoxy) Benzyl) pyrrolidin-2-one 163 mg (73% yield)
Was obtained as a colorless oil. ¹ H-NMR (300 MHz, CDCl ₃ ) δ: 7.21 (2H, d, J = 8.6 Hz), 7.02 (2H, d, J = 10.2 Hz), 7.00 (2
H, d, J = 10.2Hz), 6.93 (2H, d, J = 8.6Hz), 4.47 (1H, d, J = 14.7H
z), 4.39 (1H, d, J = 14.7Hz), 3.65 (1H, dd, J = 10.0,7.2Hz), 3.
54 (1H, m), 3.16 (1H, dd, J = 10.0,5.0Hz), 2.92 (1H, dd, J = 17.
1,8.1Hz), 2.42 (1H, dd, J = 17.1,6.1Hz), 1.86 (1H, d, J = 6.7H
z)

Example 32 4-Acetylthio-1- (4
-(4'-chlorophenoxy) benzyl) pyrrolidine-2
In a manner similar to that of Example 30, 4-on was prepared from 4-fluorobenzaldehyde and 4-chlorophenol.
1.72 g (6.8) of (4'-chlorophenoxy) benzyl chloride
mmol) and 4-trimethylsilyloxypyrrolidine-2-
From 1.20 g (6.8 mmol) of 4-acetylthio-1- (4-
(4′-chlorophenoxy) benzyl) pyrrolidine-2-
702 mg (27% yield) of ON were obtained as a light brown powder. ¹ H-NMR (300 MHz, CDCl ₃ ) δ: 7.30 (2H, d, J = 8.9 Hz), 7.20 (2H, d, J = 8.5 Hz), 6.96 (2H,
d, J = 8.5Hz), 6.94 (2H, d, J = 8.9Hz), 4.46 (1H, d, J = 15.2Hz),
4.41 (1H, d, J = 15.2Hz), 4.06 (1H, m), 3.76 (1H, dd, J = 10.6,
7.5Hz), 3.18 (1H, dd, J = 10.6,5.0Hz), 2.92 (1H, dd, J = 17.4,
9.0Hz), 2.43 (1H, dd, J = 17.4,6.1Hz), 2.32 (3H, s)

Example 33 4-mercapto-1- (4-
(4′-chlorophenoxy) benzyl) pyrrolidine-2-
In the same manner as in Example 31, 4-mercapto was prepared from 253 mg (0.7 mmol) of 4-acetylthio-1- (4- (4′-chlorophenoxy) benzyl) pyrrolidin-2-one obtained in Example 32. 209 mg (93% yield) of -1- (4- (4'-chlorophenoxy) benzyl) pyrrolidin-2-one was obtained as a colorless oil. ¹ H-NMR (300 MHz, CDCl ₃ ) δ: 7.29 (2H, d, J = 8.8 Hz), 7.22 (2H, d, J = 8.5 Hz), 6.96 (2H,
d, J = 8.5Hz), 6.94 (2H, d, J = 8.8Hz), 4.48 (1H, d, J = 14.7Hz),
4.40 (1H, d, J = 14.7Hz), 3.66 (1H, dd, J = 10.0,7.2Hz), 3.55
(1H, m), 3.17 (1H, dd, J = 10.0,5.0Hz), 2.92 (1H, dd, J = 17.1,
8.1Hz), 2.42 (1H, dd, J = 17.1,6.1Hz), 1.87 (1H, d, J = 6.7Hz)

Example 34 4-acetylthio-1- (4
-(4'-bromophenoxy) benzyl) pyrrolidine-2
In a manner similar to that of Example 30, 4-on was prepared from 4-fluorobenzaldehyde and 4-bromophenol.
1.92 g of (4'-bromophenoxy) benzyl chloride (6.5
mmol) and 4-trimethylsilyloxypyrrolidine-2-
From 1.10 g (6.5 mmol) of 4-acetylthio-1- (4-
(4′-bromophenoxy) benzyl) pyrrolidine-2-
955 mg (35% yield) of ON were obtained as a light brown powder. ¹ H-NMR (300 MHz, CDCl ₃ ) δ: 7.44 (2H, d, J = 8.9 Hz), 7.20 (2H, d, J = 8.5 Hz), 6.96 (2H,
d, J = 8.5Hz), 6.89 (2H, d, J = 8.9Hz), 4.46 (1H, d, J = 14.9Hz),
4.41 (1H, d, J = 14.9Hz), 4.06 (1H, m), 3.76 (1H, dd, J = 10.6,
7.5Hz), 3.18 (1H, dd, J = 10.6,5.0Hz), 2.92 (1H, dd, J = 17.4,
9.0Hz), 2.43 (1H, dd, J = 17.4,6.1Hz), 2.32 (3H, s)

Example 35 4-mercapto-1- (4-
(4′-bromophenoxy) benzyl) pyrrolidine-2-
On From the 4-acetylthio-1- (4- (4′-bromophenoxy) benzyl) pyrrolidin-2-one 330 mg (0.8 mmol) obtained in Example 34 by the same method as in Example 31, 4-mercapto 240 mg (79% yield) of -1- (4- (4'-bromophenoxy) benzyl) pyrrolidin-2-one was obtained as a colorless oil. ¹ H-NMR (300 MHz, CDCl ₃ ) δ: 7.44 (2H, d, J = 8.9 Hz), 7.23 (2H, d, J = 8.6 Hz), 6.96 (2H,
d, J = 8.6Hz), 6.88 (2H, d, J = 8.9Hz), 4.48 (1H, d, J = 14.8Hz),
4.40 (1H, d, J = 14.8Hz), 3.66 (1H, dd, J = 10.0,7.2Hz), 3.55
(1H, m), 3.17 (1H, dd, J = 10.0,5.0Hz), 2.92 (1H, dd, J = 17.1,
8.1Hz), 2.43 (1H, dd, J = 17.1,6.1Hz), 1.87 (1H, d, J = 6.7Hz)

Example 36 4-Acetylthio-1- (4
-(4'-methoxyphenoxy) benzyl) pyrrolidine-
2-One prepared from 4-fluorobenzaldehyde and 4-methoxyphenol in the same manner as in Example 30.
1.75 g of (4'-methoxyphenoxy) benzyl chloride
(7.0 mmol) and 4-trimethylsilyloxypyrrolidine-
From 1.21 g (7.0 mmol) of 2-one to 4-acetylthio-1-
866 mg (33% yield) of (4- (4'-methoxyphenoxy) benzyl) pyrrolidin-2-one were obtained as a brown oil. ¹ H-NMR (300 MHz, CDCl ₃ ) δ: 7.15 (2H, d, J = 8.4 Hz), 6.9
8 (2H, d, J = 9.0 Hz), 6.89 (2H,
d, J = 8.4 Hz), 6.89 (2H, d, J = 9.
0 Hz), 4.45 (1H, d, J = 15.1 Hz),
4.38 (1H, d, J = 15.1 Hz), 4.05
(1H, m), 3.81 (3H, s), 3.74 (1
H, dd, J = 10.6, 7.6 Hz), 3.16 (1
H, dd, J = 10.6, 5.0 Hz), 2.91 (1
H, dd, J = 17.4, 9.0 Hz), 2.41 (1
H, dd, J = 17.4, 6.0 Hz), 2.31 (3
H, s)

Example 37 4-mercapto-1- (4
-(4'-methoxyphenoxy) benzyl) pyrrolidine-
2-one In the same manner as in Example 31, 4-acetylthio-1- (4- (4′-methoxyphenoxy) benzyl) pyrrolidin-2-one obtained in Example 36 was converted from 291 mg (0.9 mmol) to 4 291 mg of mercapto-1- (4- (4'-methoxyphenoxy) benzyl) pyrrolidin-2-one (98% yield)
Was obtained as a colorless oil. ¹ H-NMR (300 MHz, CDCl ₃ ) δ: 7.17 (2H, d, J = 8.4 Hz), 6.98 (2H, d, J = 9.0 Hz), 6.90 (2H,
d, J = 8.4Hz), 6.89 (2H, d, J = 9.0Hz), 4.45 (1H, d, J = 14.7Hz),
4.39 (1H, d, J = 14.7Hz), 3.81 (3H, s), 3.64 (1H, dd, J = 10.0,
7.3Hz), 3.53 (1H, m), 3.15 (1H, dd, J = 10.0,5.1Hz), 2.91 (1H
H, dd, J = 17.1,8.1Hz), 2.42 (1H, dd, J = 17.1,6.2Hz), 1.86 (1
(H, d, J = 6.8Hz)

Example 38 trans-4-acetylthio-5-benzyloxymethyl-1- (4-phenoxybenzyl) pyrrolidin-2-one N- (ethylmalonyl) -N-synthesized in Example 20
(4-phenoxybenzyl) -O-benzyl-D, L-serine methyl ester 14.3 g (28.3 mmol) was added to ethanol 14
After dissolving in 0 ml, 20% sodium ethoxide ethanol solution
11.1 ml (28.3 mmol) was added, and the mixture was stirred at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure, 10% citric acid aqueous solution was added, and the mixture was extracted twice with ethyl acetate. The organic layer was washed twice with water, saturated brine, and dried over anhydrous sodium sulfate. After concentrating to dryness under reduced pressure, dissolve in 220 ml of acetonitrile, add 700 ml of water and add
Heated to reflux for an hour. After the reaction solution was concentrated under reduced pressure, it was dissolved in 165 ml of methanol, and sodium borohydride 9 was stirred.
87 mg (26.1 mmol) was added little by little, and the mixture was further stirred at room temperature for 1 hour. After the reaction solution was concentrated under reduced pressure, water was added, and the mixture was extracted three times with ethyl acetate. The organic layer was washed twice with water and subsequently with a saturated saline solution, and then dried over anhydrous sodium sulfate. After concentration under reduced pressure, the residue was subjected to silica gel column chromatography, eluted with hexane: ethyl acetate (20: 80-0: 100), and cis-5-benzyloxymethyl-4-hydroxy-1-
(4-phenoxybenzyl) pyrrolidin-2-one 8.32
g (yield 73%) was obtained as a colorless oil. ¹ H-NMR (300 MHz, CDCl ₃ ) δ: 7.34 (7H, m), 7.12 (3H, m), 6.98 (2H, m), 6.92 (2H, d,
J = 8.3Hz), 4.80 (1H, d, J = 15.3Hz), 4.53 (1H, m), 4.48 (1H,
d, J = 11.9Hz), 4.40 (1H, d, J = 11.9Hz), 4.00 (1H, d, J = 15.3H)
z), 3.71 (1H, m), 3.65 (2H, m), 2.74 (1H, dd, J = 17.0, 7.9H
z), 2.53 (1H, dd, J = 17.0, 6.0Hz)

After dissolving 500 mg (1.24 mmol) of cis-5-benzyloxymethyl-4-hydroxy-1- (4-phenoxybenzyl) pyrrolidin-2-one in 20 ml of chloroform, 864 μl (6.20 mmol) of triethylamine was added under ice-cooling. Add 480 μl (6.20 mmol) of methanesulfonyl chloride and add 1
Stirred for hours. After concentrating the reaction solution under reduced pressure, ethyl acetate was added, and the mixture was washed with water and saturated saline and dried over anhydrous sodium sulfate. After concentration under reduced pressure, the residue was subjected to silica gel column chromatography, and hexane: ethyl acetate (30: 70-20: 80) was used.
Eluted with cis-5-benzyloxymethyl-4-methanesulfonyloxy-1- (4-phenoxybenzyl)
560 mg (94% yield) of pyrrolidin-2-one were obtained as a colorless oil. ¹ H-NMR (300 MHz, CDCl ₃ ) δ: 7.34 (7H, m), 7.13 (3H, m), 7.00 (2H, m), 6.92 (2H, d,
J = 8.7Hz), 5.27 (1H, m), 4.85 (1H, d, J = 15.1Hz), 4.47 (1H, m
d, J = 11.9Hz), 4.42 (1H, d, J = 11.9Hz), 4.06 (1H, d, J = 15.1H)
z), 3.82 (1H, m), 3.66 (2H, m), 2.98 (3H, s), 2.91 (1H, dd,
J = 17.0, 6.6Hz), 2.76 (1H, dd, J = 17.0, 7.9Hz)

After dissolving 560 mg (1.16 mmol) of 5-benzyloxymethyl-4-methanesulfonyloxy-1- (4-phenoxybenzyl) pyrrolidin-2-one in 20 ml of ethanol, 265 mg (2.32 mmol) of potassium thioacetate was added. After heating under reflux for 4 hours, potassium thioacetate 265 mg (2.32 mmo
l) was added and the mixture was heated under reflux for 2 hours. After concentrating the reaction solution under reduced pressure, ethyl acetate was added, and the mixture was washed with water and saturated saline and dried over anhydrous sodium sulfate. After concentration under reduced pressure, the residue was subjected to silica gel column chromatography, eluted with hexane: ethyl acetate (60: 40-50: 50), and trans-4-acetylthio-5-benzyloxymethyl-1- (4-phenoxybenzyl) ) 245 mg (46% yield) of pyrrolidin-2-one were obtained as a colorless oil. ^{1 H-NMR (300MHz, CDCl} 3) δ: 7.32 (7H, m), 7.14 (2H, d, J = 8.7Hz), 7.10 (1H, m), 6.
98 (2H, m), 6.92 (2H, d, J = 8.7Hz), 4.88 (1H, d, J = 15.3Hz),
4.49 (1H, d, J = 12.1Hz), 4.39 (1H, d, J = 12.1Hz), 3.99 (1H, d, J = 12.1Hz)
d, J = 15.3Hz), 3.99 (1H, m), 3.57 (2H, m), 3.45 (1H, m), 3.
13 (1H, dd, J = 17.8, 9.1Hz), 2.33 (1H, m), 2.29 (3H, s)

Example 39 trans-5-benzyloxymethyl-4-mercapto-1- (4-phenoxybenzyl) pyrrolidin-2-one trans-4-acetylthio-5 obtained in Example 38
Benzyloxymethyl-1- (4-phenoxybenzyl) pyrrolidin-2-one (145 mg, 0.314 mmol) in acetic acid (1 m)
and 1 ml of concentrated hydrochloric acid, and the mixture was stirred at 100 ° C. for 20 minutes.
After placing the reaction solution in ice water, it was extracted twice with ethyl acetate,
The obtained organic layer was washed twice with water and subsequently with a saturated saline solution, and then dried over anhydrous sodium sulfate. After concentration under reduced pressure,
The residue was subjected to silica gel column chromatography, eluted with hexane: ethyl acetate (50:50), and trans-5-benzyloxymethyl-4-mercapto-1- (4-phenoxybenzyl) pyrrolidin-2-one (34.2 mg, yield). (26% rate)
Was obtained as a colorless oil. ¹ H-NMR (300 MHz, CDCl ₃ ) δ: 7.33 (7 H, m), 7.15 (2 H, d, J = 8.7 Hz), 7.10 (1 H, m), 6.
98 (2H, m), 6.92 (2H, d, J = 8.7Hz), 4.91 (1H, d, J = 15.1Hz),
4.46 (1H, d, J = 11.9Hz), 4.42 (1H, d, J = 11.9Hz), 3.97 (1H,
d, J = 15.1Hz), 3.50 (2H, m), 3.42 (2H, m), 3.05 (1H, dd, J = 1
7.3, 7.9Hz), 2.36 (1H, dd, J = 17.3, 4.9Hz), 1.79 (1H, d, J
= 6.8Hz)

Example 40 4-acetylthio-1- (3
-Phenoxybenzyl) pyrrolidin-2-one 1.23 g (5.6 mmol) of 3-phenoxybenzyl chloride prepared from 3-phenoxybenzaldehyde (manufactured by Tokyo Chemical Industry Co., Ltd.) and 4-trimethylsilyloxypyrrolidine- in the same manner as in Example 30. From 0.97 g (5.6 mmol) of 2-one, 704 mg (37% yield) of 4-acetylthio-1- (3-phenoxybenzyl) pyrrolidin-2-one was obtained as a colorless oil. ¹ H-NMR (300 MHz, CDCl ₃ ) δ: 7.38-7.28 (3H, m), 7.12 (1H, t, J = 7.4 Hz), 7.02-6.86 (5
H, m), 4.48 (1H, d, J = 14.9Hz), 4.39 (1H, d, J = 14.9Hz), 4.05
(1H, m), 3.75 (1H, dd, J = 10.6,7.5Hz), 3.17 (1H, dd, J = 10.6,
4.9Hz), 2.91 (1H, dd, J = 17.4,8.9Hz), 2.41 (1H, dd, J = 17.4,
5.9Hz), 2.31 (3H, s)

Example 41 4-mercapto-1- (3-
Phenoxybenzyl) pyrrolidin-2-one From the 4-acetylthio-1- (3-phenoxybenzyl) pyrrolidin-2-one 200 mg (0.59 mmol) obtained in Example 40 in the same manner as in Example 31, 104 mg (59% yield) of mercapto-1- (3-phenoxybenzyl) pyrrolidin-2-one was obtained as a colorless oil. ¹ H-NMR (300 MHz, CDCl ₃ ) δ: 7.38-7.26 (3H, m), 7.12 (1H, t, J = 7.4 Hz), 7.03-6.87 (5
H, m), 4.48 (1H, d, J = 14.9Hz), 4.40 (1H, d, J = 14.9Hz), 3.65
(1H, dd, J = 10.1,7.2Hz), 3.53 (1H, m), 3.16 (1H, dd, J = 10.1,
5.0Hz), 2.91 (1H, dd, J = 17.1,8.1Hz), 2.41 (1H, dd, J = 17.1,
6.1Hz), 1.84 (1H, d, J = 6.8Hz)

Examples 42 and 43 3-Acetylthio-1- (4-phenoxybenzyl) piperidine-
2,6-dione and 3-acetylthio-1- [4- (4
-Bromophenoxy) benzyl] piperidine-2,6-dione The method described in the literature (Tetrahedron Asymmetry Vol. 6, No. 6, p.
α-phenyl N-tert synthesized according to p1249-1252, 1995)
-Butyloxycarbonylglutamate 4.91 g (1
4.9 mmol), 4.28 g (22.3 mmol) of 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride, 15.8 ml (113.1 mmol) of triethylamine, 3.56 g (17.9 mmol) of 4-phenoxybenzylamine, and 77 ml of chloroform Was stirred at 55 ° C. for 30 minutes, 2.41 g (17.9 mmol) of 1-hydroxybenzotriazole was added, and the mixture was stirred at 55 ° C. for 2 nights. The reaction solution was concentrated under reduced pressure, and ethyl acetate was added to the residue.
3 times with saturated aqueous sodium hydrogen carbonate, once with saturated saline,
It was washed three times with a 10% aqueous citric acid solution and then once with a saturated saline solution. After drying the ethyl acetate layer with anhydrous sodium sulfate,
After concentration under reduced pressure, the residue was subjected to silica gel column chromatography and eluted with ethyl acetate: hexane (25:75) to give 3- (tert-butyloxycarbonylamino) -1
1.46 g (24% yield) of-(4-phenoxybenzyl) piperidine-2,6-dione was obtained as a brown oil. ¹ H-NMR (300 MHz, CDCl ₃ ) δ: 7.35-6.89 (9H, m), 5.40 (1H, brs), 4.93 (1H, d, J = 13.8H
z), 4.88 (1H, d, J = 13.8Hz), 4.31-4.26 (1H, m), 2.93-2.85 (1
H, m), 2.78-2.66 (1H, m), 2.51-2.47 (1H, m), 1.88-1.73 (1H,
m), 1.46 (9H, s).

3- (tert-butyloxycarbonylamino) -1- (4-phenoxybenzyl) piperidine-2,
1.21 g (3.0 mmol) of 6-dione was dissolved in 15 ml of trifluoroacetic acid, and immediately concentrated under reduced pressure.Ethyl acetate was added to the obtained residue, and the mixture was washed with saturated aqueous sodium hydrogen carbonate, water, and saturated saline in this order. The ethyl acetate layer was dried over anhydrous sodium sulfate, and concentrated under reduced pressure.
The crystallized product was collected by filtration to obtain 823 mg (90% yield) of 3-amino-1- (4-phenoxybenzyl) piperidine-2,6-dione as a pale blue powder. ¹ H-NMR (300 MHz, CDCl ₃ ) δ: 7.36-6.89 (9H, m), 4.91 (2H, s), 3.53 (1H, dd, J = 12.4,
5.1Hz), 2.94-2.85 (1H, m), 2.74-2.61 (1H, m), 2.27-2.18 (1
H, m), 1.87-1.72 (1H, m).

800 mg (2.6 mmol) of 3-amino-1- (4-phenoxybenzyl) piperidine-2,6-dione was suspended in 2 ml of ethyl acetate, and 2 ml of a 25% hydrogen bromide in acetic acid was added.
Immediately under reduced pressure, ethyl acetate was added to the obtained residue, and the crystallized product was collected by filtration. 3-Amino-1- (4-phenoxybenzyl) piperidine-2,6-dione hydrobromide 88
1 mg was prepared. The thus obtained 3-amino-
1- (4-phenoxybenzyl) piperidine-2,6-dione hydrobromide 1.20 g (3.1 mmol), 8.84 N aqueous hydrogen bromide 7 ml
(61.4 mmol), a mixture of 7 ml of acetonitrile and 7 ml of water at -5 ° C.
Then, an aqueous solution prepared by adding 103 water to 1.83 g (15.4 mmol) of potassium bromide and 530 mg (7.7 mmol) of sodium nitrite was added dropwise over 1 hour. Then acetonitrile 2
1 ml and 14 ml of water were added, and the mixture was stirred at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure, and ethyl acetate was added to the residue.
It was washed once with saturated saline. The ethyl acetate layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography, and eluted with ethyl acetate: hexane (10:90) to give 3-bromo-1- (4- 424 mg of a mixture of phenoxybenzyl) piperidine-2,6-dione and 3-bromo-1- [4- (4-bromophenoxy) benzyl] piperidine-2,6-dione (about 2: 1) as a pale purple oil Obtained. ¹ H-NMR (300 MHz, CDCl ₃ ) δ: 7.43-7.40 (0.7H, m), 7.12-7.07 (0.7H, m), 7.35-6.85
(7.3H, m), 4.97 (1H, d, J = 13.8Hz), 4.88 (1H, d, J = 13.8Hz),
4.72 (1H, t, J = 3.1Hz), 3.12-3.00 (1H, m), 2.81-2.73 (1H,
m), 2.44-2.20 (2H, m).

3-Bromo-1- (4-phenoxybenzyl) piperidine-2,6-dione and 3-bromo-1-
[4- (4-bromophenoxy) benzyl] piperidine-
200 mg of a mixture of 2,6-dione (about 2: 1), 67 mg (0.6 mmol) of potassium thioacetate, 2 ml of N, N-dimethylformamide
The mixture was stirred at room temperature for 30 minutes, concentrated under reduced pressure, ethyl acetate was added to the obtained residue, and the mixture was washed with water three times and then with saturated saline, and the ethyl acetate layer was dried over anhydrous sodium sulfate. Thereafter, the residue obtained by concentrating under reduced pressure was subjected to high performance liquid chromatography (elution solvent: 65% acetonitrile / 0.01N
Phosphate buffer (pH 6.3)).
108 mg of-(4-phenoxybenzyl) piperidine-2,6-dione as a pale blue oil and 63 mg of 3-acetylthio-1- [4- (4-bromophenoxy) benzyl] piperidine-2,6-dione as a pale blue oil Obtained as a red oil.
3-acetylthio-1- (4-phenoxybenzyl) piperidine-2,6-dione (Example 42) ¹ H-NMR (300 MHz, CDCl ₃ ) δ: 7.35-6.90 (9H, m), 4.96 (1H, d) , J = 13.7Hz), 4.88 (1H, d,
J = 13.8Hz), 4.45 (1H, dd, J = 9.7,4.9Hz), 2.91-2.70 (2H, m),
2.42 (3H, s), 2.32-2.26 (1H, m), 2.14-2.04 (1H, m). 3-acetylthio-1- [4- (4-bromophenoxy)
Benzyl] piperidine-2,6-dione (Example 43) ¹ H-NMR (300 MHz, CDCl ₃ ) δ: 7.42-7.27 (4H, m), 6.91-6.85 (4H, m), 4.95 (1H, d, J = 1
3.8Hz), 4.88 (1H, d, J = 13.8Hz), 4.44 (1H, dd, J = 9.8,4.9H
z), 2.90-2.70 (2H, m), 2.41 (3H, s), 2.34-2.23 (1H, m), 2.14
-2.01 (1H, m).

Example 44 3-benzoylthio-1-
(4-phenoxybenzyl) piperidine-2,6-dione 3-bromo-1- (4-phenoxybenzyl) piperidine-2,6-dione and 3 obtained in the same manner as in Example 42.
100 mg of a mixture of bromo-1- [4- (4-bromophenoxy) benzyl] piperidine-2,6-dione (about 5: 1)
To 3-benzoylthio-1-
(4-phenoxybenzyl) piperidine-2,6-dione 8
6 mg was obtained as a pale yellow oil. ¹ H-NMR (300 MHz, CDCl ₃ ) δ: 8.00-7.95 (2H, m), 7.65-6.86 (12H, m), 5.00 (1H, d, J = 1
3.7Hz), 4.93 (1H, d, J = 13.7Hz), 4.67 (1H, dd, J = 9.7,4.9),
2.98-2.76 (2H, m), 2.44-2.13 (2H, m).

Example 45 3-mercapto-1- (4-
Mixture of phenoxybenzyl) piperidine-2,6-dione and 1- [4- (4-bromophenoxy) benzyl] -3-mercaptopiperidin-2,6-dione 3-bromo- obtained as in Example 42 1- (4-phenoxybenzyl) piperidine-2,6-dione and 3
-Bromo-1- [4- (4-bromophenoxy) benzyl] piperidine-2,6-dione mixture (about 2: 1) 150 m
g, potassium thioacetate (50 mg, 0.4 mmol) and N, N-dimethylformamide (2 ml) were stirred at room temperature for 45 minutes, and concentrated under reduced pressure. Ethyl acetate was added to the residue, and water was added.
It was washed twice with saturated saline. The ethyl acetate layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue obtained was dissolved in a mixed solution of 1 ml of acetic acid and 1 ml of concentrated hydrochloric acid, and stirred at 100 ° C for 25 minutes. Ethyl acetate was added to the residue obtained by concentration under reduced pressure, three times with water, saturated aqueous sodium hydrogen carbonate solution,
Wash with phosphate buffer (pH 6.8) followed by saturated saline,
The ethyl acetate layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue obtained was purified by preparative thin-layer silica gel chromatography (developing solvent: ethyl acetate: hexane (2: 1)) to give 3-mercapto- 1- (4-phenoxybenzyl) piperidine-2,6-dione and 1- [4- (4-
A mixture of bromophenoxy) benzyl] -3-mercaptopiperidine-2,6-dione (about 2: 1) was obtained. ¹ H-NMR (300 MHz, CDCl ₃ ) δ: 7.43-7.40 (0.7H, m), 7.15-7.07 (0.7H, m), 7.35-6.85
(7.3H, m), 4.96 (1H, d, J = 13.8Hz), 4.89 (1H, d, J = 13.8Hz),
3.97-3.93 (1H, m), 2.99-2.88 (1H, m), 2.75-2.65 (1H, m), 2.
40 (1H, d, J = 4.6Hz), 2.39-2.27 (1H, m), 2.09-1.96 (1H, m).

Example 46 3-acetylthio-1- (4
-Phenoxybenzyl) piperidin-2-one 3-hydroxy-2-piperidone 700 mg (6.1 mmol, manufactured by Aldrich), powdered potassium hydroxide 512 mg (9.1 mm
ol), 1.33 g (6.1 mmol) of phenoxybenzyl chloride was added to a mixture of 6 ml of dimethyl sulfoxide under ice cooling, and the mixture was added at room temperature.
Stirred for 16 hours. After adding ethyl acetate, the mixture was washed six times with 1N hydrochloric acid and water, and subsequently with a saturated saline solution. The ethyl acetate layer was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography, and eluted with ethyl acetate: n-hexane (20:80) to give 3-hydroxy-ethyl acetate.
1- (4-phenoxybenzyl) piperidin-2-one 78
1 mg (43% yield) was obtained as a pale yellow oil. ¹ H-NMR (300 MHz, CDCl ₃ ) δ: 7.35-6.95 (9 H, m), 4.60 (1 H, d, J = 14.5 Hz), 4.49 (1 H, d,
J = 14.5Hz), 4.13-4.06 (1H, m), 3.26-3.22 (2H, m), 2.30-2.2
6 (1H, m), 1.93-1.69 (4H, m).

From 909 mg (3.1 mmol) of 3-hydroxy-1- (4-phenoxybenzyl) piperidin-2-one, 3-methansulfonyloxy-1-
(4-phenoxybenzyl) piperidin-2-one 1.13 g
(99% yield) as a pale yellow oil. ¹ H-NMR (300 MHz, CDCl ₃ ) δ: 7.37-6.96 (9 H, m), 5.06 (1 H, dd, J = 7.9, 5.7 Hz), 4.58 (1
H, d, J = 14.6Hz), 4.52 (1H, d, J = 14.4Hz), 3.31 (3H, s), 3.29-
3.20 (2H, m), 2.27-1.81 (4H, m) .3-methanesulfonyloxy-1- (4-phenoxybenzyl) piperidin-2-one 400 mg (1.1 mmol), potassium thioacetate 146 mg (1.3 mmol), A mixture of 4 ml of N, N-dimethylformamide was stirred at room temperature for 1 hour, then concentrated under reduced pressure, and ethyl acetate was added to the obtained residue. Washed with saturated saline. After drying the ethyl acetate layer with anhydrous sodium sulfate,
The residue obtained by concentration under reduced pressure was subjected to silica gel column chromatography, and eluted with ethyl acetate: hexane (20:80) to elute 328 mg of 3-acetylthio-1- (4-phenoxybenzyl) piperidin-2-one. (Yield 87%)
Obtained as a pale brown oil. ¹ H-NMR (300 MHz, CDCl ₃ ) δ: 7.36 to 6.94 (9 H, m), 4.60 (1 H, d, J = 14.5 Hz), 4.54 (1 H, d, J
= 14.4Hz), 4.29 (1H, dd, J = 7.7,5.5Hz), 3.34-3.21 (2H, m),
2.38 (3H, s), 2.30-2.20 (1H, m), 2.00-1.81 (3H, m).

Example 47 3-benzoylthio-1-
(4-phenoxybenzyl) piperidin-2-one 3-methanesulfonyloxy-1 obtained in Example 46
-(4-phenoxybenzyl) piperidin-2-one 200m
g (0.5 mmol), a mixture of thiobenzoic acid 75 μl (0.6 mmol), cesium carbonate 87 mg (0.3 mmol) and N, N-dimethylformamide 1 ml was stirred at room temperature for 15 hours, and then thiobenzoic acid 6 μl (0.1 mm
ol) and 9 mg (0.03 mmol) of cesium carbonate, and the mixture was stirred at room temperature for 1 hour. Ethyl acetate was added to the residue obtained by concentration under reduced pressure, and the mixture was added twice with water and twice with a saturated aqueous sodium hydrogen carbonate solution.
It was washed twice with saturated saline. The ethyl acetate layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue obtained was subjected to silica gel column chromatography, and eluted with ethyl acetate: hexane (8:92) to give 3-benzoylthio-
1- (4-phenoxybenzyl) piperidin-2-one 18
2 mg (82% yield) was obtained as a pale red oil. ¹ H-NMR (300 MHz, CDCl ₃ ) δ: 7.99-7.96 (2H, m), 7.60-6.95 (12H, m), 4.64 (1H, d, J = 1
4.5Hz), 4.58 (1H, d, J = 14.4Hz), 4.51 (1H, dd, J = 7.8,5.8H
z), 3.41-3.26 (2H, m), 2.40-2.30 (1H, m), 2.11-1.86 (3H,
m).

Example 48 3-mercapto-1- (4-
Phenoxybenzyl) piperidin-2-one 3-mercapto-1-one was obtained in the same manner as in Example 29 from 127 mg (0.4 mmol) of 3-acetylthio-1- (4-phenoxybenzyl) piperidin-2-one obtained in Example 46. (4-
108 mg of phenoxybenzyl) piperidin-2-one (yield
96%) as a brown oil. ¹ H-NMR (300 MHz, CDCl ₃ ) δ: 7.37-6.94 (9 H, m), 4.61 (1 H, d, J = 14.5 Hz), 4.50 (1 H, d,
J = 14.5Hz), 3.84-3.78 (1H, m), 3.34-3.20 (2H, m), 2.60 (1H, m
d, J = 4.2Hz), 2.28-1.70 (4H, m).

Example 49 S-[(3R) -5-oxo-1- (4-phenoxybenzyl) pyrrolidinyl] thiocarbamate The (R) -4-mercapto-1- (4-phenoxybenzyl) obtained in Example 25. ) Pyrrolidin-2-one 400mg (1.34mmo
l) was dissolved in 10 ml of chloroform, and N-chlorocarbonyl was dissolved.
118.7 μl (1.47 mmol) of isocyanate in 2 ml of chloroform
The solution was added dropwise at -18 to -12 ° C, and after completion of the addition, the mixture was stirred at the same temperature for 30 minutes, heated to 0 ° C over 1 hour, and stirred at room temperature for 12 hours. After the reaction solution was concentrated under reduced pressure, it was dissolved in ethyl acetate, and 6N
After washing with hydrochloric acid and saturated saline, it was dried over anhydrous sodium sulfate. After concentration under reduced pressure, the residue was purified by preparative thin-layer chromatography (developing solvent: n-hexane: ethyl acetate (1: 3)) to give the title compound (212 mg, yield 46%) as a white solid. ¹ H-NMR (300 MHz, CDCl ₃ ) δ: 7.36-6.94 (9H, m), 5.59 (2H, br), 4.43 (2H, s), 4.08-4.0
3 (1H, m), 3.78 (1H, dd, J = 10.7,7.3Hz), 3.27 (1H, dd, J = 10.
7,4.6Hz), 2.93 (1H, dd, J = 17.4,8.9Hz), 2.47 (1H, dd, J = 17.
4,5.7Hz)

Example 50 S-[(3R) -5-oxo-1- (4-phenoxybenzyl) pyrrolidinyl] methylthiocarbamate (R) -4-mercapto-1- (4-phenoxybenzyl) obtained in Example 25 ) Pyrrolidin-2-one 220 mg (0.74 mmo
l) in 2 ml of chloroform, 50 mg (0.88 mmol) of methyl isocyanate, 0.5 μl of triethylamine (catalytic amount)
Was added and stirred under a nitrogen atmosphere for 20 minutes. The reaction solution was concentrated under reduced pressure, dissolved in chloroform, washed with water, and dried over anhydrous sodium sulfate. After concentration under reduced pressure, the residue was purified by preparative thin-layer chromatography (developing solvent: n-hexane: ethyl acetate (1: 2, 1: 3)), and powdered from n-hexane: ethyl acetate to give 198 mg of the title compound. (76% yield) as a white powder. Elemental analysis _{(%): C 19 H 20} N 2 O 3 S · 0.5H 2 O Calculated: C, 62.44; H, 5.79 ; N, 7.66 Found: C, 62.46; H, 5.87 ; N, 7.66

Example 51 S-[(3R) -5-oxo-1- (4-phenoxybenzyl) pyrrolidinyl] ethylthiocarbamate In the same manner as in Example 50, the (R) -4- obtained in Example 25.
Mercapto-1- (4-phenoxybenzyl) pyrrolidin-2-one 150 mg (0.501 mmol), ethyl isocyanate 8
7.2 μl (1.10 mmol), triethylamine 13.9 μl (0.102 mmo
From l), 122 mg (66% yield) of the title compound were obtained as colorless needles. Elemental analysis _{(%): C 20 H 22} N 2 O 3 S Calculated: C, 64.84; H, 5.99 ; N, 7.56 Found: C, 84.88; H, 6.04 ; N, 7.65

Example 52 S- [5-oxo-1- (4
-Phenoxybenzyl) -3-pyrrolidinyl] propylcarbamothioate 4-mercapto-1- (4-phenoxybenzyl) pyrrolidine-2 obtained in Example 17 in the same manner as in Example 50.
-100 mg (0.33 mmol), 34 μl of propyl isocyanate
(0.37 mmol), 47 μl (0.33 mmol) of triethylamine,
110 mg (yield 87%) of the title compound was obtained as colorless needles. ¹ H-NMR (200 MHz, CDCl ₃ ) δ: 7.40-6.90 (9H, m), 5.45-5.30 (1H, m), 4.43 (2H, s), 4.15
-4.00 (1H, m), 3.79 (1H, dd, J = 7.4,10.0Hz), 3.27 (1H, dd, J =
4.8,10,0Hz), 3.30-3.15 (2H, m), 2.92 (1H, dd, J = 8.8,16.0H
z), 2.46 (1H, dd, J = 6.0, 18.0Hz), 1.65-1.45 (2H, m), 0.92 (3
(H, t, J = 7.4Hz)

Example 53 S- [5-oxo-1- (4
-Phenoxybenzyl) -3-pyrrolidinyl] phenylcarbamothioate 4-mercapto-1- (4-phenoxybenzyl) pyrrolidine-2 obtained in Example 17 in the same manner as in Example 50.
-One 100 mg (0.33 mmol), phenyl isocyanate 36 μl
(0.33 mmol), 47 μl of triethylamine (0.33 mmol),
The title compound (120 mg, yield 87%) was obtained as colorless needles. ¹ H-NMR (200 MHz, CDCl ₃ ) δ: 7.52-6.90 (15H, m), 4.45 (2
H, s), 4.22-4.08 (1H, m), 3.85.
(1H, dd, J = 7.1, 12.0 Hz), 3.34
(1H, dd, J = 4.2, 12.0 Hz), 2.98
(1H, dd, J = 8.8, 18.0 Hz), 2.53
(1H, dd, J = 5.2, 18.0 Hz)

Example 54 S-[(3R) -5-oxo-1- (4-phenoxybenzyl) pyrrolidinyl] benzylthiocarbamate The (R) -4-mercapto-1- (4) obtained in Example 25
-Phenoxybenzyl) pyrrolidin-2-one 200 mg (0.6
7 mmol) dissolved in chloroform 2 ml, benzyl isocyanate 99 μl (0.80 mmol), triethylamine 0.5 μl
(Amount of catalyst) was added, and the mixture was stirred for 1 hour under a nitrogen atmosphere. The reaction solution was concentrated under reduced pressure, and purified by preparative thin-layer chromatography (developing solvent: chloroform: methanol (20: 1)).
n-Hexane: Powdered from ethyl acetate to give the title compound
217 mg (75% yield) were obtained as a white powder. ¹ H-NMR (300 MHz, CDCl ₃ ) δ: 7.37-6.94 (14H, m), 5.71 (1H, br), 4.40 (4H, bs), 4.15-
4.06 (1H, m), 3.79 (1H, dd, J = 10.7,7.3Hz), 3.28 (1H, dd, J = 1
0.7,4.8Hz), 2.92 (1H, dd, J = 17.4,8.9Hz), 2.46 (1H, dd, J = 1
(7.4,6.0Hz)

Example 55 S-[(3R) -5-oxo-1- (4-phenoxybenzyl) pyrrolidinyl] acetylthiocarbamate 264 mg (1.76 mmol) of silver cyanate, 125 μl of acetyl chloride
(1.76 mmol) was added to 4 ml of toluene, and the mixture was stirred at 70 ° C. for 30 minutes. After cooling the reaction solution, the supernatant was used and the (R)-obtained in Example 25 was used.
After dissolving 220 mg (0.74 mmol) of 4-mercapto-1- (4-phenoxybenzyl) pyrrolidin-2-one, 5.1 μl (catalytic amount) of triethylamine was added, and the mixture was stirred at room temperature for 20 minutes. The reaction solution was concentrated under reduced pressure, dissolved in ethyl acetate, washed twice with water and saturated brine, and dried over anhydrous sodium sulfate. After concentration under reduced pressure, the residue was purified by preparative thin-layer chromatography (developing solvent: n-hexane: ethyl acetate (1: 2)) and powdered from n-hexane: ethyl acetate to give 193 mg of the title compound (yield 68). %) As a white powder. ¹ H-NMR (300 MHz, CDCl ₃ ) δ: 8.40 (1 H, s), 7.37-6.95 (9 H, m), 4.44 (2 H, s), 4.40 (4 H, b
s), 4.12-4.02 (1H, m), 3.78 (1H, dd, J = 10.7,7.7Hz), 3.26 (1H
H, dd, J = 10.7,5.0Hz), 2.95 (1H, dd, J = 17.5,9.1Hz), 2.50 (1
H, dd, J = 17.5,6.2Hz), 2.05 (3H, s)

Example 56 S-[(3R) -5-oxo-1- (4-phenoxybenzyl) pyrrolidinyl] benzoylthiocarbamate The (R) -4-mercapto-1- (4-phenoxy) obtained in Example 25. (Benzyl) pyrrolidin-2-one 220 mg (0.74 mmo
l) was dissolved in 2 ml of chloroform, 113 μl (0.81 mmol) of benzoyl isocyanate and 5.1 μl (catalytic amount) of triethylamine were added, and the mixture was stirred under a nitrogen atmosphere for 30 minutes. The reaction solution was concentrated under reduced pressure, dissolved in ethyl acetate, washed twice with water and saturated brine, and dried over anhydrous sodium sulfate.
After concentration under reduced pressure, the residue was purified by preparative thin-layer chromatography (developing solvent: n-hexane: ethyl acetate 1: 2) to give the title compound (230 mg, yield 70%) as a colorless oil. ¹ H-NMR (300 MHz, CDCl ₃ ) δ: 7.97-6.92 (14H, m), 4.47-4.32 (2H, m), 4.14-4.04 (1H,
m), 3.79 (1H, dd, J = 10.7,7.8Hz), 3.29 (1H, dd, J = 10.7,5.1H
z), 2.93 (1H, dd, J = 17.5,9.0Hz), 2.51 (1H, dd, J = 17.5,6.2H
z),

Example 57 O-ethyl S-[(3R)
-5-oxo-1- (4-phenoxybenzyl) pyrrolidinyl] imidothiodicarbonate 220 mg of (R) -4-mercapto-1- (4-phenoxybenzyl) pyrrolidin-2-one obtained in Example 25 (0.74 mmol)
l) in 2 ml of chloroform, 93 μl (0.81 mmol) of ethyl isocyanatoformate, 5.1 μl of triethylamine
(Amount of catalyst) was added, and the mixture was stirred under a nitrogen atmosphere for 30 minutes. The reaction mixture was concentrated under reduced pressure, and purified by preparative thin-layer chromatography (developing solvent: n-hexane: ethyl acetate 1: 2) to give n-
Hexane: Powdered from ethyl acetate to give the title compound 214m
g (yield 70%) was obtained as a white powder. ¹ H-NMR (300 MHz, CDCl ₃ ) δ: 7.69 (1H, bs), 7.37-6.94 (9
H, m), 4.43 (2H, s), 4.24 (2H,
q, J = 7.1 Hz), 4.07-4.03 (1H,
m), 3.79 (1H, dd, J = 10.7, 7.7H
z), 3.25 (1H, dd, J = 10.7, 5.1H
z), 2.94 (1H, dd, J = 17.5, 9.1H
z), 2.50 (1H, dd, J = 17.5, 6.3H
z), 1.31 (3H, t, J = 7.1 Hz)

Example 58 Ethyl [(｛[(3R)-
5-oxo-1- (4-phenoxybenzyl) pyrrolidinyl] sulfanyl {carbonyl) amino] acetate (R) -4- obtained in Example 25 in the same manner as in Example 50.
Mercapto-1- (4-phenoxybenzyl) pyrrolidin-2-one 300 mg (1.00 mmol), isocyanatoacetic acid ethyl ester 246 μl (2.20 mmol), triethylamine 41.7 μl
(0.300 mmol) to give 417 mg (yield 97%) of the title compound as a colorless oil. Elemental analysis _{(%): C 22 H 24} N 2 O 5 S · 0.4H 2 O Calculated: C, 60.64; H, 5.74 ; N, 6.43 Found: C, 60.60; H, 5.70 ; N, 6.43

Example 59 [({[(3R) -5-oxo-1- (4-phenoxybenzyl) pyrrolidinyl] sulfanyl} carbonyl) amino] acetic acid Ethyl obtained in Example 58 [({[(3R) −5-
Oxo-1- (4-phenoxybenzyl) pyrrolidinyl] sulfanyl {carbonyl) amino] acetate 22
After dissolving 5 mg (0.525 mmol) in a mixture of 3 ml of acetic acid and 3 ml of concentrated hydrochloric acid,
The mixture was heated and stirred at 100 ° C. for 25 minutes. The reaction solution was placed in ice water and extracted twice with ethyl acetate. The ethyl acetate layer was washed three times with water.
After washing once with a saturated saline solution, it was dried over anhydrous sodium sulfate. After concentration under reduced pressure, the residue was subjected to silica gel column chromatography, and the fraction eluted with chloroform: methanol (95: 5) was concentrated and powdered from ether to give 123 mg of the title compound.
(59% yield) as a white powder. Elemental analysis _{(%): C 20 H 20} N 2 O 5 S Calculated: C, 59.99; H, 5.03 ; N, 7.00 Found: C, 59.81; H, 4.92 ; N, 7.07

Example 60 Ethyl 3-[(｛[(3
R) -5-Oxo-1- (4-phenoxybenzyl) pyrrolidinyl] sulfanyl {carbonyl) amino] propanoate (R) -4-mercapto-1- (4-phenoxybenzyl) pyrrolidine-2- obtained in Example 25. 200mg (0.67mmo
l) was dissolved in 2 ml of chloroform, 106 μl (0.80 mmol) of ethyl 3-isocyanatopropionate and 0.5 μl (catalytic amount) of triethylamine were added, and the mixture was stirred for 30 minutes under a nitrogen atmosphere. After concentrating the reaction solution under reduced pressure, preparative thin-layer chromatography (developing solvent: chloroform: methanol (20: 1))
The title compound (243 mg, yield 82%) was obtained as a colorless oil. ¹ H-NMR (300 MHz, CDCl ₃ ) δ: 7.37-6.94 (9H, m), 5.94 (1H, br), 4.43 (2H, s), 4.16 (2H,
q, J = 7.1Hz), 4.09-4.02 (1H, m), 3.76 (1H, dd, J = 10.6,7.5H
z), 3.53 (2H, br) 3.25 (1H, dd, J = 10.6,5.0Hz), 2.91 (1H, dd,
J = 17.3,8.9Hz), 2.53 (2H, t, J = 5.9Hz), 2.45 (1H, dd, J = 17.
4,6.2Hz), 1.26 (3H, t, J = 7.1Hz)

Example 61 N-({[(3R) -5-oxo-1- (4-phenoxybenzyl) pyrrolidinyl]
Sulfanyl｝ carbonyl) -β-alanine Ethyl 3-[(｛[(3R) -5 obtained in Example 60.
261 mg (0.59 mmol) of -oxo-1- (4-phenoxybenzyl) pyrrolidinyl] sulfanyl {carbonyl) amino] propanoate was dissolved in 3 ml of a mixture of concentrated hydrochloric acid and acetic acid (1: 1), and the mixture was stirred at 100 ° C. for 30 minutes. The reaction solution was concentrated under reduced pressure, dissolved in ethyl acetate, washed with 1N hydrochloric acid and saturated saline, and then dried over anhydrous sodium sulfate. After concentration under reduced pressure, the residue was purified by preparative thin-layer chromatography (developing solvent: chloroform: methanol (10: 1)) to give the title compound 170
mg (70% yield) as a colorless oil. ¹ H-NMR (300 MHz, DMSO-d ₆ ) δ: 8.31 (1 H, br), 7.42-6.95 (9 H, m), 4.39 (1 H, d, J = 15.1 H
z), 4.33 (1H, d, J = 15.1Hz), 3.98-3.90 (1H, m), 3.71 (1H, dd,
J = 10.4,7.3Hz), 3.26 (2H, t, J = 6.5Hz), 3.16 (1H, dd, J = 10.
4,4.5Hz), 2.83 (1H, dd, J = 17.0,8.6Hz), 2.36 (2H, t, J = 6.9H
z), 2.27 (1H, dd, J = 17.0,5.6Hz)

Example 62 S-[(3R) -5-oxo-1- (4-phenoxybenzyl) pyrrolidinyl] dimethylcarbamothioate The (R) -4-mercapto-1- (4-) obtained in Example 25. Phenoxybenzyl) pyrrolidin-2-one 200 mg (0.67 mmo
l), N, N-dimethylcarbonyl chloride 68 μl (0.73
mmol) in 1 ml of chloroform.
A solution of 2 μl (0.73 mmol) of chloroform in 1 ml was added dropwise at 0 ° C., and after completion of the addition, the mixture was stirred at room temperature for 1 hour. Next, 27 mg (0.67 mmol) of 60% sodium hydride was added, and the mixture was stirred at room temperature for 10 minutes, concentrated under reduced pressure, dissolved in ethyl acetate, washed twice with water, and washed with a saturated saline solution. It was dried over anhydrous sodium sulfate. After concentration under reduced pressure, the residue was purified by preparative thin-layer chromatography (developing solvent: n-hexane: ethyl acetate (1: 2)) to give the title compound (153 mg, yield 62%) as a pale-yellow oil. Elemental analysis _{(%): C 20 H 22} N 2 O 3 S · 0.1H 2 O Calculated: C, 64.52; H, 6.01 ; N, 7.52 Found: C, 64.38; H, 6.05 ; N, 7.41

Example 63 S-[(3R) -5-oxo-1- (4-phenoxybenzyl) pyrrolidinyl] 4
-Morpholine carbothioate (R) -4-obtained in Example 25 in the same manner as in Example 62.
Mercapto-1- (4-phenoxybenzyl) pyrrolidin-2-one 150 mg (0.501 mmol), morpholinecarbonyl chloride 451 μl (3.85 mmol), 60% sodium hydride 140 mg
(3.50 mmol) to give 185 mg (90% yield) of the title compound as a colorless oil. Elemental analysis _{(%): C 22 H 24} N 2 O 4 S · 0.3H 2 O Calculated: C, 63.23; H, 5.93 ; N, 6.70 Found: C, 63.09; H, 5.95 ; N, 6.66

Example 64 S-[(3R) -5-oxo-1- (4-phenoxybenzyl) pyrrolidinyl] propanethioate (R) -4-mercapto-1- (4-phenoxy) obtained in Example 25 (Benzyl) pyrrolidin-2-one 200 mg (0.67 mmo
l), 64 μl (0.73 mmol) of propionyl chloride were dissolved in 2 ml of chloroform, and 102 μl of triethylamine (0.73 mmol
l) A solution of chloroform in 1 ml was added dropwise at 0 ° C.
Stirred at C for 1 hour. The reaction solution was concentrated under reduced pressure, dissolved in ethyl acetate, washed with water and saturated saline, and dried over anhydrous sodium sulfate. After concentration under reduced pressure, preparative thin-layer chromatography (developing solvent: n-hexane: ethyl acetate
(1: 1)) to give the title compound (228 mg, yield 96%) as a pale pink oil. ¹ H-NMR (300 MHz, CDCl ₃ ) δ: 7.37-6.95 (9 H, m), 4.46 (1 H, d, J = 14.7 Hz), 4.40 (1 H, d, J
= 14.7Hz), 4.10-4.01 (1H, m), 3.76 (1H, dd, J = 10.7,7.5Hz),
3.17 (1H, dd, J = 10.7,5.0Hz), 2.92 (1H, dd, J = 17.4,9.0Hz),
2.55 (2H, t, J = 7.5Hz), 2.42 (1H, dd, J = 17.4,6.0Hz), 1.16 (3
(H, t, J = 7.5Hz)

Example 65 S-[(3R) -5-oxo-1- (4-phenoxybenzyl) pyrrolidinyl]
Butanethioate 200 mg (0.67 mmol) of (R) -4-mercapto-1- (4-phenoxybenzyl) pyrrolidin-2-one obtained in Example 25.
l), 76 μl (0.73 mmol) of butyryl chloride in chloroform
The solution was dissolved in 2 ml, and a solution of 102 μl (0.73 mmol) of triethylamine in 1 ml of chloroform was added dropwise at 0 ° C., and after completion of the addition, the mixture was stirred at 0 ° C. for 1 hour. The reaction solution was concentrated under reduced pressure, dissolved in ethyl acetate, washed with water and saturated saline, and dried over anhydrous sodium sulfate. After concentration under reduced pressure, preparative thin-layer chromatography (developing solvent: n-hexane: ethyl acetate (1: 1))
The title compound was obtained as a colorless oily substance (228 mg, yield 92%). ¹ H-NMR (300 MHz, CDCl ₃ ) δ: 7.37-6.95 (9 H, m), 4.47 (1 H, d, J = 14.7 Hz), 4.39 (1 H, d, J
= 14.7Hz), 4.10-4.01 (1H, m), 3.76 (1H, dd, J = 10.7,7.5Hz),
3.16 (1H, dd, J = 10.7,4.9Hz), 2.92 (1H, dd, J = 17.4,8.9Hz),
2.51 (2H, t, J = 7.4Hz), 2.42 (1H, dd, J = 17.4,5.9Hz), 1.73-
1.60 (2H, m), 1.16 (3H, t, J = 7.5Hz)

Example 66 S- [5-oxo-1- (4
-Phenoxybenzyl) -3-pyrrolidinyl] pentanethioate 4-mercapto-1- (4-phenoxybenzyl) pyrrolidine-2 obtained in Example 17 in the same manner as in Example 64.
-One 100 mg (0.33 mmol), valeric chloride 48 mg (0.40 mmo
l) and 57 μl (0.40 mmol) of triethylamine gave 78 mg (62% yield) of the title compound as a colorless oil. ¹ H-NMR (200 MHz, CDCl ₃ ) δ: 7.40-6.90 (9 H, m), 4.48 (1 H, d, J = 16.0 Hz), 4.40 (1 H, d, J
= 14.0Hz), 4.12-3.97 (1H, m), 3.77 (1H, dd, J = 7.5,10.0Hz),
3.17 (1H, dd, J = 4.9,10.0Hz), 2.93 (1H, dd, J = 8.9,16.0Hz),
2.53 (2H, t, J = 7.8Hz), 2.43 (1H, dd, J = 6.0,18.0Hz), 1.70-
1.55 (2H, m), 1.42-1.24 (2H, m), 0.90 (3H, t, J = 7.3Hz)

Example 67 S-[(3R) -5-oxo-1- (4-phenoxybenzyl) pyrrolidinyl] 2
-Methylpropanethioate 200 mg of (R) -4-mercapto-1- (4-phenoxybenzyl) pyrrolidin-2-one obtained in Example 25 (0.67 mmol
l), 77 μl (0.73 mmol) of isobutyryl chloride was dissolved in 2 ml of chloroform, and 102 μl (0.73 mmol) of triethylamine was dissolved.
Was added dropwise at 0 ° C.
For 1 hour. The reaction solution was concentrated under reduced pressure, dissolved in ethyl acetate, washed with water and saturated saline, and dried over anhydrous sodium sulfate. After concentration under reduced pressure, preparative thin-layer chromatography (developing solvent: n-hexane: ethyl acetate
(1: 1)) to give 223 mg (yield 91%) of the title compound as a colorless oil. ¹ H-NMR (300 MHz, CDCl ₃ ) δ: 7.06-6.95 (9 H, m), 4.47 (1 H, d, J = 14.6 Hz), 4.39 (1 H, d, J
= 14.7Hz), 4.07-3.73 (1H, m), 3.76 (1H, dd, J = 10.6,7.4Hz),
3.15 (1H, dd, J = 10.6,4.8Hz), 2.92 (1H, dd, J = 17.4,8.9Hz),
2.77-2.63 (1H, m), 2.42 (1H, dd, J = 17.4,5.8Hz), 1.19-1.15
(6H, m)

Example 68 S- [5-oxo-1- (4
-Phenoxybenzyl) -3-pyrrolidinyl] 2-phenylethanethioate 4-mercapto-1- (4-phenoxybenzyl) pyrrolidine-2 obtained in Example 17 in the same manner as in Example 64.
-One 100 mg (0.33 mmol), phenylacetyl chloride 57 m
g (0.37 mmol), triethylamine 57 μl (0.40 mmol),
The title compound (61 mg, yield 44%) was obtained as a colorless oil. ¹ H-NMR (200 MHz, CDCl ₃ ) δ: 7.40-6.90 (14 H, m), 4.45 (1 H, d, J = 14.8 Hz), 4.36 (1 H, d,
J = 14.7Hz), 4.10-3.95 (1H, m), 3.79 (2H, s), 3.74 (1H, dd, J =
7.5,10.0Hz), 3.14 (1H, dd, J = 4.9,10,0Hz), 2.90 (1H, dd, J =
9.0,18.0Hz), 2.40 (1H, dd, J = 6.1,18.0Hz)

Example 69 S- [5-oxo-1- (4
-Phenoxybenzyl) -3-pyrrolidinyl]-(4
-Chlorophenyl) ethanethioate 4-mercapto-1- (4-phenoxybenzyl) pyrrolidine-2 obtained in Example 17 in the same manner as in Example 64.
-One 100 mg (0.33 mmol), p-chlorophenylacetyl chloride 76 mg (0.40 mmol), triethylamine 57 μl (0.40 mm
ol) to give the title compound (85 mg, yield 57%) as a colorless oil. ¹ H-NMR (200 MHz, CDCl ₃ ) δ: 7.40-6.90 (13 H, m), 4.45 (1 H, d, J = 14.7 Hz), 4.37 (1 H, d,
J = 14.7Hz), 4.10-3.95 (1H, m), 3.75 (2H, s), 3.74 (1H, dd, J =
7.5,10.0Hz), 3.13 (1H, dd, J = 4.9,12.0Hz), 2.90 (1H, dd, J =
(8.8, 18.0Hz), 2.38 (1H, dd, J = 5.9,20.0Hz)

Example 70 S- [5-oxo-1- (4
-Phenoxybenzyl) -3-pyrrolidinyl] 2,2
-Diphenylethanethioate 4-mercapto-1- (4-phenoxybenzyl) pyrrolidine-2 obtained in Example 17 in the same manner as in Example 64.
-One 50 mg (0.17 mmol), diphenylacetyl chloride 58
mg (0.25 mmol) and 57 μl (0.40 mmol) of triethylamine gave 57 mg (69% yield) of the title compound as a colorless oil. ¹ H-NMR (200 MHz, CDCl ₃ ) δ: 7.40-6.90 (19 H, m), 5.13 (1 H, s), 4.45 (1 H, d, J = 14.5 H
z), 4.36 (1H, d, J = 14.7Hz), 4.14-4.00 (1H, m), 3.77 (1H, dd,
J = 7.4,10.0Hz), 3.16 (1H, dd, J = 4.8,12.0Hz), 2.92 (1H, dd,
J = 8.9,18.0Hz), 2.41 (1H, dd, J = 5.9,18.0Hz)

Example 71 Ethyl 3-oxo-3-
{[(3R) -5-oxo-1- (4-phenoxybenzyl) pyrrolidinyl] sulfanyl} propanoate (R) -4-mercapto-1- (4-phenoxybenzyl) pyrrolidin-2-one obtained in Example 25 200mg (0.67mmo
l), ethyl-3-chloro-3-oxopropionate 94
μl (0.73 mmol) was dissolved in 1 ml of chloroform, and a solution of 102 μl (0.73 mmol) of triethylamine in 1 ml of chloroform was added at 0 ° C.
After the addition was completed, the mixture was stirred at 0 ° C. for 1 hour. The reaction solution was concentrated under reduced pressure, dissolved in ethyl acetate, washed twice with water and saturated brine, and dried over anhydrous sodium sulfate. After concentration under reduced pressure, the residue was purified by preparative thin-layer chromatography (developing solvent: n-hexane: ethyl acetate (1: 2)) to give the title compound (175 mg, yield 63%) as a colorless oil. ¹ H-NMR (300 MHz, CDCl ₃ ) δ: 7.37-6.95 (9 H, m), 4.43 (2 H, s), 4.19 (2 H, q, J = 7.1 Hz),
4.14-4.09 (1H, m), 3.78 (1H, dd, J = 10.7,7.5Hz), 3.55 (2H,
s), 3.20 (1H, dd, J = 10.7,4.8Hz), 2.94 (1H, dd, J = 17.4,8.9H
z), 2.44 (1H, dd, J = 17.4,5.9Hz), 1.27 (3H, t, J = 7.1Hz)

Example 72 124 μl (0.73 mmol) of tert-butyl 3-oxo-3-{[(3R) -5-oxo-1- (4-phenoxybenzyl) pyrrolidinyl] sulfanyl} propanoate mono-tert-butyl malonate After dissolving in 1 ml of acetonitrile, adding 130 mg (0.73 mmol) of N, N-carbonyldiimidazole and stirring for 1 hour, the (R) -4-mercapto-1- (4-phenoxybenzyl) pyrrolidine obtained in Example 25 was obtained. A solution of 200 mg (0.67 mmol) of 2-one in 1 ml of acetonitrile was added and stirred for 10 minutes. The reaction solution was concentrated under reduced pressure, dissolved in ethyl acetate, and added with 0.1N hydrochloric acid.
After washing with saturated saline twice, it was dried over anhydrous sodium sulfate. After concentration under reduced pressure, the residue was purified by preparative thin-layer chromatography (developing solvent: n-hexane: ethyl acetate (1: 2)) to give the title compound (180 mg, yield 61%) as a colorless oil. ¹ H-NMR (300 MHz, CDCl ₃ ) δ: 7.37-6.95 (9 H, m), 4.43 (2 H, s), 4.14-4.06 (1 H, m), 3.78
(1H, dd, J = 10.7,7.5Hz), 3.47 (2H, s), 3.20 (1H, dd, J = 10.7,
4.8Hz), 2.93 (1H, dd, J = 17.4,9.0Hz), 2.44 (1H, dd, J = 17.4,
5.9Hz), 1.53 (9H, s)

Example 73 3-oxo-3-{[(3
R) -5-oxo-1- (4-phenoxybenzyl) pyrrolidinyl] sulfanyl {propanoic acid tert-butyl 3-oxo-3- obtained in Example 72
{[(3R) -5-oxo-1- (4-phenoxybenzyl) pyrrolidinyl] sulfanyl} propanoate 22
4 mg (0.51 mmol) and 203 μl (1.28 mmol) of triethylsilane were dissolved in a mixture of 2 ml of trifluoroacetic acid and 2 ml of chloroform and stirred for 5 days. The reaction solution was concentrated under reduced pressure, dissolved in ethyl acetate, washed with 1N hydrochloric acid, a mixed solution of 1N hydrochloric acid and saturated saline, and then dried over anhydrous sodium sulfate. After concentration under reduced pressure, powdered from ethyl acetate to give 151 m of the title compound.
g (yield 77%) was obtained as a white powder. ¹ H-NMR (300 MHz, DMSO-d ₆ ) δ: 7.42-6.97 (9 H, m), 4.40 (1 H, d, J = 15.1 Hz), 4.35 (1 H, d, J
= 15.1Hz), 4.11-4.02 (1H, m), 3.76 (1H, dd, J = 10.6,7.4Hz),
3.66 (2H, s), 3.16 (1H, dd, J = 10.6,4.3Hz), 2.90 (1H, dd, J = 1
7.1,8.8Hz), 2.30 (1H, dd, J = 17.1,5.2Hz)

Example 74 Ethyl 4-oxo-4-
{[(3R) -5-oxo-1- (4-phenoxybenzyl) pyrrolidinyl] sulfanyl} butanoate 113 μl (0.88 mmol) was dissolved in 1 ml of acetonitrile, and N, N-carbonyldiimidazole 130 mg (0.73 mmol) and stirred for 30 minutes.
A solution of 200 mg (0.67 mmol) of (R) -4-mercapto-1- (4-phenoxybenzyl) pyrrolidin-2-one obtained in 1 ml of acetonitrile in 1 ml was added and stirred for 10 minutes. The reaction solution was concentrated under reduced pressure, dissolved in ethyl acetate, washed twice with 1N hydrochloric acid and with a saturated saline solution, and then dried over anhydrous sodium sulfate. After concentration under reduced pressure, the residue was purified by preparative thin-layer chromatography (developing solvent: n-hexane: ethyl acetate (1: 2)),
The title compound (236 mg, yield 75%) was obtained as a white solid. ¹ H-NMR (300 MHz, CDCl ₃ ) δ: 7.37-6.95 (9H, m), 4.43 (2
H, s), 4.11-4.04 (3H, m), 3.75.
(1H, dd, J = 10.6, 7.5 Hz), 3.17
(1H, dd, J = 10.6, 5.0 Hz), 2.91
(1H, dd, J = 17.4, 8.9 Hz), 2.86
(2H, t, J = 7.1 Hz), 2.62 (2H, t,
J = 6.9 Hz), 2.42 (1H, dd, J = 17.
4,6.0 Hz), 1.24 (3H, t, J = 7.1H)
z)

Example 75 4-oxo-4-{[(3
R) -5-oxo-1- (4-phenoxybenzyl) pyrrolidinyl] sulfanyldibutanoic acid 200 mg of (R) -4-mercapto-1- (4-phenoxybenzyl) pyrrolidin-2-one obtained in Example 25 ( 0.67mmo
l), 67 mg (0.67 mmol) of succinic anhydride was dissolved in 2 ml of THF,
Add 27 mg (0.67 mmol) of 60% sodium hydride, and add
Stirred for hours. The reaction solution was concentrated under reduced pressure, dissolved in ethyl acetate, washed with 1N hydrochloric acid and saturated saline, and then dried over anhydrous sodium sulfate. After concentration under reduced pressure, preparative thin-layer chromatography (developing solvent: chloroform: methanol)
(5: 1)) to give the title compound (163 mg, yield 61%) as a pale-brown oil. Elemental analysis (%): C ₂₁ H ₂₁ NO ₅ S · 0.1H ₂ O Calculated: C, 62.85; H, 5.32; N, 3.49 Found: C, 62.80; H, 5.12; N, 3.52

Example 76 (3R) -5-oxo-1-
(4-phenoxybenzyl) pyrrolidinyl methyldithiocarbamate 220 mg (0.74 mmol) of (R) -4-mercapto-1- (4-phenoxybenzyl) pyrrolidin-2-one obtained in Example 25
l) was dissolved in 2 ml of chloroform, 59 mg (0.81 mmol) of methyl isothiocyanate and 5.1 μl (catalytic amount) of triethylamine were added, and the mixture was stirred under a nitrogen atmosphere for 12 hours. The reaction mixture was concentrated under reduced pressure, and then purified by preparative thin-layer chromatography (developing solvent: n-hexane: ethyl acetate (1: 2)) to give the title compound (75 mg, yield 27%) as a colorless oil. Was. ¹ H-NMR (300 MHz, CDCl ₃ ) δ: 8.30-7.98 (1H, m), 7.35-6.92 (9H, m), 4.56-4.49 (1H,
m), 4.44 (1H, d, J = 14.8Hz), 4.36 (1H, d, J = 14.7Hz), 3.89 (1H, d, J = 14.7Hz)
H, dd, J = 11.1,6.9Hz), 3.37 (1H, dd, J = 11.1,3.0Hz), 3.19 (3
H, d, J = 7.8Hz), 3.02 (1H, dd, J = 17.9,8.9Hz), 2.55 (1H, dd, J
= 17.7,4.0Hz)

Example 77 (3R) -5-oxo-1-
(4-phenoxybenzyl) pyrrolidinyl ethyldithiocarbamate 220 mg of (R) -4-mercapto-1- (4-phenoxybenzyl) pyrrolidin-2-one obtained in Example 25 (0.74 mmol)
l) was dissolved in chloroform 2 ml, and ethyl isothiocyanate 71 μl (0.81 mmol) and a previously prepared triethylamine 5.1 μl (catalyst amount) and acetic acid 2.1 μl (catalyst amount) in chloroform 0.1 ml solution were added thereto. Stirred. The reaction solution was concentrated under reduced pressure, and dissolved in ethyl acetate.
After washing with 0.1N hydrochloric acid and a saturated saline solution, it was dried over anhydrous sodium sulfate. After concentration under reduced pressure, preparative thin-layer chromatography (developing solvent: n-hexane: ethyl acetate (1: 2))
Then, 211 mg (74% yield) of the title compound was obtained as a pale pink oily substance. ¹ H-NMR (300 MHz, CDCl ₃ ) δ: 7.61-6.91 (10H, m), 4.51-4.38 (3H, m), 3.91-3.84 (1H,
m), 3.74-3.32 (3H, m), 3.06-2.97 (1H, m), 2.55-2.48 (1H,
m), 1.26 (3H, t, J = 7.2Hz)

Example 78 (4R) -4-[(Methoxycarbonyl) disulfanyl] -2-oxo-1- (4
-Phenoxybenzyl) pyrrolidine 50 mg of (R) -4-mercapto-1- (4-phenoxybenzyl) pyrrolidin-2-one obtained in Example 25 (0.17 mmol
l) was dissolved in 1 ml of methanol, and 17 μl (0.18 mmol) of methoxycarbonylsulfenyl chloride was added.
Stirred for hours. The reaction solution was concentrated under reduced pressure, dissolved in ethyl acetate, washed with water and saturated saline, and dried over anhydrous sodium sulfate. The mixture was concentrated under reduced pressure to give the title compound (62 mg, yield 95%) as a pale-brown oil. Elemental analysis (%): C ₁₉ H ₁₉ NO ₄ S ₂ Calculated: C, 58.59; H, 4.92; N, 3.60 Found: C, 58.29; H, 4.95; N, 3.61

Example 79 (4R) -4- (Ethyldisulfanyl) -1- (4-phenoxybenzyl) -2-
Pyrrolidinone (4R) -4-[(methoxycarbonyl) disulfanyl] -2-oxo-1- (4-phenoxybenzyl) pyrrolidine obtained in Example 78 220 mg (0.57 mmol)
l) was dissolved in a mixture of chloroform (1 ml) and methanol (1 ml), ethanethiol (209 μl, 2.82 mmol) and triethylamine (0.4 μl, catalytic amount) were added, and the mixture was stirred at room temperature under a nitrogen atmosphere for 30 minutes. The reaction solution was concentrated under reduced pressure, dissolved in ethyl acetate, washed with water and saturated saline, and dried over anhydrous sodium sulfate. After concentration under reduced pressure, preparative thin-layer chromatography (developing solvent: n-hexane: ethyl acetate (1: 2))
The title compound was obtained as colorless oil (140 mg, yield 69%). Elemental analysis (%): C ₁₉ H ₂₁ NO ₂ S ₂ Calculated: C, 63.48; H, 5.89; N, 3.90 Found: C, 63.31; H, 5.91; N, 4.09

Example 80 (4R) -4- (Hexyldisulfanyl) -1- (4-phenoxybenzyl) -2
-Pyrrolidinone 200 mg (0.51 mmol) of (4R) -4-[(methoxycarbonyl) disulfanyl] -2-oxo-1- (4-phenoxybenzyl) pyrrolidine obtained in Example 78 was added to a mixture of 1 ml of chloroform and 1 ml of methanol. Dissolve, 1-hexanethiol 362 μl (2.57 mmol), triethylamine 0.4 μl
(Amount of catalyst) was added, and the mixture was stirred at room temperature for 30 minutes under a nitrogen atmosphere.
The reaction solution was concentrated under reduced pressure, dissolved in ethyl acetate, and added with water
After washing with 1N hydrochloric acid and saturated saline, it was dried over anhydrous sodium sulfate. After concentration under reduced pressure, the residue was purified by preparative thin-layer chromatography (developing solvent: n-hexane: ethyl acetate (1: 1)) to give the title compound (157 mg, yield 74%) as a colorless oil. ¹ H-NMR (300 MHz, CDCl ₃ ) δ: 7.37-6.96 (9 H, m), 4.47 (1 H, d, J = 14.7 Hz), 4.41 (1 H, d, J
= 14.7Hz), 3.64-3.51 (2H, m), 3.33 (1H, dd, J = 9.9,3.5Hz),
2.83 (1H, dd, J = 17.4,8.0Hz), 2.65 (1H, t, J = 7.3Hz), 2.56 (1
H, dd, J = 17.5,4.8Hz), 1.68-1.57 (2H, m), 1.40-1.27 (6H,
m), 0.88 (3H, t, J = 6.7Hz)

Example 81 (4R) -4- (tert-
Butyldisulfanyl) -1- (4-phenoxybenzyl) -2-pyrrolidinone (4R) -4-[(methoxycarbonyl) disulfanyl] -2-oxo-1- (4-phenoxybenzyl) obtained in Example 78. Dissolve 220 mg (0.57 mmol) of pyrrolidine in a mixture of 1 ml of chloroform and 1 ml of methanol to give 2-methyl-2-
319 µl (2.83 mmol) of propanethiol and 0.4 µl (catalytic amount) of triethylamine were added, and the mixture was stirred at room temperature for 30 minutes under a nitrogen atmosphere. The reaction solution was concentrated under reduced pressure, dissolved in ethyl acetate, washed twice with water and saturated brine, and dried over anhydrous sodium sulfate. After concentration under reduced pressure, preparative thin-layer chromatography (developing solvent: n-hexane: ethyl acetate (1:
Purification by 2)) afforded 183 mg (84% yield) of the title compound as a white solid. Elemental analysis (%): C ₂₁ H ₂₅ NO ₂ S ₂ Calculated: C, 65.08; H, 6.50; N, 3.61 Found: C, 65.02; H, 6.26; N, 3.65

Example 82 Ethyl 2-{[(3R)-
5-oxo-1- (4-phenoxybenzyl) pyrrolidinyl] disulfanyl {acetate (4R) -4-[(methoxycarbonyl) disulfanyl] -2-oxo-1- (4-phenoxybenzyl) obtained in Example 78 ) 220 mg (0.57 mmol) of pyrrolidine were dissolved in a mixture of 1 ml of chloroform and 1 ml of methanol, and 68 µl (0.62 mmol) of ethyl 2-mercaptoacetate and 0.4 µl (catalytic amount) of triethylamine were added, followed by stirring at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure, dissolved in ethyl acetate, the insolubles were removed by filtration, washed with water and saturated saline, and dried over anhydrous sodium sulfate. After concentration under reduced pressure, preparative thin-layer chromatography (developing solvent: n-hexane: ethyl acetate (1: 2))
The title compound was obtained as a colorless oil (51 mg, yield 22%). Elemental analysis (%): C ₂₁ H ₂₃ NO ₄ S ₂ Calculated: C, 60.41; H, 5.55; N, 3.35 Found: C, 60.32; H, 5.53; N, 3.45

Example 83 2-{[(3R) -5-oxo-1- (4-phenoxybenzyl) pyrrolidinyl] disulfanyl} acetic acid (4R) -4-[(methoxycarbonyl) diacetic acid obtained in Example 78 Sulfanyl] -2-oxo-1- (4-phenoxybenzyl) pyrrolidine 220 mg (0.57 mmol)
l) was dissolved in 2 ml of methanol, and 39 μl of mercaptoacetic acid was dissolved.
(0.57 mmol) and 0.8 μl (catalytic amount) of triethylamine were added, and the mixture was stirred at room temperature for 3 hours. After concentrating the reaction solution under reduced pressure,
It was dissolved in ethyl acetate, washed with 1N hydrochloric acid, and dried over anhydrous sodium sulfate. After concentration under reduced pressure, preparative thin-layer chromatography (developing solvent: chloroform: methanol)
(5: 1)) and trituration from ethyl acetate to give the title compound (136 mg, yield 62%) as a white powder. ¹ H-NMR (300 MHz, DMSO-d ₆ ) δ: 7.41-6.97 (9 H, m), 4.43 (1 H, d, J = 14.8 Hz), 4.32 (1 H, d, J
= 14.8Hz), 3.86-3.16 (7H, m), 2.85 (1H, dd, J = 17.4,8.2Hz),
2.31 (1H, dd, J = 17.4,3.7Hz)

Example 84 Ethyl 3-{[(3R)-
5-oxo-1- (4-phenoxybenzyl) pyrrolidinyl] disulfanyl} propanoate (4R) -4-[(methoxycarbonyl) disulfanyl] -2-oxo-1- (4-phenoxybenzyl) obtained in Example 78 ) 200 mg (0.51 mmol) of pyrrolidine were dissolved in a mixture of 1 ml of chloroform and 1 ml of methanol, and 332 µl (2.57 mmol) of ethyl 3-mercaptopropionate and 0.4 µl (catalytic amount) of triethylamine were added, followed by stirring at room temperature for 30 minutes. After concentrating the reaction solution under reduced pressure, it was dissolved in ethyl acetate,
After washing with 1N hydrochloric acid and saturated saline, it was dried over anhydrous sodium sulfate. After concentration under reduced pressure, the residue was purified by preparative thin-layer chromatography (developing solvent: n-hexane: ethyl acetate (1: 2)) to give the title compound (72 mg, yield 33%) as a colorless oil. ¹ H-NMR (300 MHz, CDCl ₃ ) δ: 7.36 to 6.95 (9 H, m), 4.47 (1 H, d, J = 14.7 Hz), 4.40 (1 H, d, J
= 14.7Hz), 4.14 (2H, q, J = 7.1Hz), 3.65-3.54 (2H, m), 3.36-
3.30 (1H, m), 2.92-2.79 (3H, m), 2.68 (2H, t, J = 7.0Hz), 2.52
(1H, dd, J = 17.5,4.4Hz), 1.26 (3H, t, J = 7.0Hz)

Example 85 3-{[(3R) -5-oxo-1- (4-phenoxybenzyl) pyrrolidinyl] disulfanyl} propanoic acid (4R) -4-[(methoxycarbonyl) obtained in Example 78 Disulfanyl] -2-oxo-1- (4-phenoxybenzyl) pyrrolidine (200 mg, 0.51 mmol) was dissolved in methanol (2 ml), and 3-mercaptopropionic acid (45 μl, 0.51
mmol) and 0.4 μl (catalytic amount) of triethylamine, and the mixture was stirred at room temperature for 4 hours. The reaction solution was concentrated under reduced pressure, and purified by preparative thin-layer chromatography (developing solvent: chloroform: methanol (10: 1)) to obtain 188 mg (yield 91%) of the title compound as a colorless oil. ¹ H-NMR (300 MHz, DMSO-d ₆ ) δ: 7.41-6.95 (9 H, m), 4.43 (1 H, d, J = 14.8 Hz), 4.31 (1 H, d, J
= 14.9Hz), 3.78-3.71 (1H, m), 3.65 (1H, dd, J = 10.7,6.7Hz),
3.25 (1H, dd, J = 10.7,2.9Hz), 2.89-2.78 (3H, m), 2.57 (2H,
t, J = 6.8Hz), 2.31 (1H, dd, J = 17.3,3.8Hz),

Example 86 2-{[(3R) -5-oxo-1- (4-phenoxybenzyl) pyrrolidinyl] disulfanyl} benzoic acid (R) -4-mercapto-1- (obtained in Example 25) 4-phenoxybenzyl) pyrrolidin-2-one 200 mg (0.67 mmo
l) was dissolved in 3 ml of 95% ethanol, and 226 mg of O-carboxyphenyl O-carboxybenzenethiol sulfonate was dissolved.
(0.67 mmol), and the mixture was stirred at room temperature for 12 hours. The reaction mixture was concentrated under reduced pressure, dissolved in chloroform, insoluble materials were removed by filtration, and the residue was purified by preparative thin-layer chromatography (developing solvent: chloroform: methanol (8: 1)) to give 185 mg of the title compound.
(61% yield) as a colorless oil. Elemental analysis _{(%): C 24 H 21} NO 4 S 2 · 0.25H 2 O
Calculated: C, 63.20; H, 4.75; N, 3.07 Actual: C, 63.05; H, 4.66; N, 2.97

Example 87 (4R) -4-[(2-Nitrophenyl) disulfanyl] -1- (4-phenoxybenzyl) -2-pyrrolidinone (R) -4-mercapto-1 obtained in Example 25 -(4-phenoxybenzyl) pyrrolidin-2-one 200 mg (0.67 mmo
l) was dissolved in 2 ml of acetic acid, 133 mg (0.70 mmol) of 2-nitrobenzenesulfenyl chloride was added, and the mixture was stirred at room temperature for 15 minutes. The reaction solution was concentrated under reduced pressure, and dissolved in ethyl acetate.
After washing twice with water and saturated saline, preparative thin-layer chromatography (developing solvent: n-hexane: ethyl acetate (1: 1
Purification was performed under 2)) to give the title compound (272 mg, yield 90%) as a pale-yellow oil. Elemental analysis (%): C ₂₃ H ₂₀ N ₂ O ₄ S ₂ Calculated: C, 61.04; H, 4.45; N, 6.19 Found: C, 60.99; H, 4.51; N, 6.05

Example 88 (4-amino-2-methyl-
5-pyrimidinyl) methyl ((Z) -4-hydroxy-
1-methyl-2-{[(3R) -5-oxo-1- (4
-Phenoxybenzyl) pyrrolidinyl] disulfanyl {-1-butenyl) formamide 100 mg of (4R) -4-[(methoxycarbonyl) disulfanyl] -2-oxo-1- (4-phenoxybenzyl) pyrrolidine obtained in Example 78. (0.26 mmol) was dissolved in ethanol 1 ml, thiamine hydrochloride 87 mg (0.26 mmol), 10N
Sodium hydroxide aqueous solution 77μl (0.77mmol), acetic acid 15μl
(0.26 mmol) and 1 ml of ethanol and stirred at room temperature for 20 minutes. The reaction solution was concentrated under reduced pressure, dissolved in ethyl acetate, washed with a saturated aqueous solution of sodium hydrogen carbonate and saturated saline, and then dried over anhydrous sodium sulfate. After concentration under reduced pressure, preparative thin-layer chromatography (developing solvent:
Purification with chloroform: methanol (10: 1)) gave 68 mg (yield 45%) of the title compound as a white foam. Elemental analysis _{(%): C 29 H 33} N 5 O 4 S 2 · 0.5H 2 O Calculated: C, 59.16; H, 5.82 ; N, 11.89 Found: C, 59.14; H, 5.99 ; N , 11.97

Example 89 (4R) -4- (Methylsulfanyl) -1- (4-phenoxybenzyl) -2-pyrrolidinone The (R) -4-mercapto-1- (4-phenoxybenzyl) obtained in Example 25. ) Pyrrolidin-2-one 220 mg (0.74 mmo
l), 50 μl (0.81 mmol) of iodomethane was dissolved in 2 ml of THF, and 6
29 mg (0.74 mmol) of 0% sodium hydride was added, and the mixture was stirred at room temperature under a nitrogen atmosphere for 10 minutes. After concentrating the reaction solution under reduced pressure,
It was dissolved in ethyl acetate, washed with 0.1N hydrochloric acid and saturated saline, and then dried over anhydrous sodium sulfate. After concentration under reduced pressure,
Purification by preparative thin-layer chromatography (developing solvent: n-hexane: ethyl acetate (1: 2)) gave 180 mg (yield 78%) of the title compound as a colorless oil. Elemental analysis (%): C ₁₈ H ₁₉ NO ₂ S Calculated: C, 68.98; H, 6.11; N, 4.47 Found: C, 68.80; H, 6.00; N, 4.57

Example 90 (4R) -4-[(2-Hydroxyethyl) sulfanyl] -1- (4-phenoxybenzyl) -2-pyrrolidinone (R) -4-mercapto-1-obtained in Example 25 (4-phenoxybenzyl) pyrrolidin-2-one 200 mg (0.67 mmo
l), 47 μl (0.67 mmol) of 2-bromoethanol were dissolved in 2 ml of THF, 27 mg (0.67 mmol) of 60% sodium hydride was added, and the mixture was stirred at room temperature for 10 minutes. The reaction solution was concentrated under reduced pressure, dissolved in ethyl acetate, washed with 1N hydrochloric acid and saturated saline, and then dried over anhydrous sodium sulfate. After concentration under reduced pressure, the residue was purified by preparative thin-layer chromatography (developing solvent: chloroform: methanol (15: 1)) to give the title compound (149 mg, yield 65%) as a pale-brown oil. Elemental analysis (%): C ₁₉ H ₂₁ NO ₃ S Calculated: C, 66.45; H, 6.16; N, 4.08 Found: C, 66.30; H, 6.08; N, 4.05

Example 91 2-{[(3R) -5-oxo-1- (4-phenoxybenzyl) pyrrolidinyl] sulfanyl} acetic acid (R) -4-mercapto-1- (4-) obtained in Example 25 Phenoxybenzyl) pyrrolidin-2-one 199mg (0.66mmo
l), 47 mg (0.66 mmol) of bromoacetic acid were dissolved in 2 ml of THF, and 60%
27 mg (1.33 mmol) of sodium hydride was added, and the mixture was stirred at room temperature for 10 minutes. The reaction solution was concentrated under reduced pressure, dissolved in ethyl acetate, washed twice with 1N hydrochloric acid and with a saturated saline solution, and then dried over anhydrous sodium sulfate. After concentration under reduced pressure, preparative thin-layer chromatography (developing solvent: chloroform: methanol)
(1: 3)) to give 138 mg (yield 58%) of the title compound as a pale brown oil. Elemental analysis (%): C ₁₉ H ₁₉ NO ₄ S · 0.8 H ₂ O Calculated: C, 61.37; H, 5.58; N, 3.76 Found: C, 61.15; H, 5.32; N, 3.95

Example 92: Ethyl 3-{[(3R)-
5-oxo-1- (4-phenoxybenzyl) pyrrolidinyl] sulfanyl} propanoate (R) -4- obtained in Example 25 in the same manner as in Example 89.
Mercapto-1- (4-phenoxybenzyl) pyrrolidin-2-one 150 mg (0.501 mmol), ethyl 3-bromopropionate 70.7 μl (0.551 mmol), 60% sodium hydride 20.0 m
From g (0.501 mmol), 145 mg (yield 72%) of the title compound was obtained as a colorless oil. ¹ H-NMR (300 MHz, CDCl ₃ ) δ: 7.34 (2 H, m), 7.20 (2 H, d, J = 8.3 Hz), 7.11 (1 H, m), 7.01 (2
H, m), 6.97 (2H, d, J = 8.3Hz), 4.43 (2H, s), 4.15 (1H, q, J = 7.2
Hz), 3.61 (1H, dd, J = 10.2,7.5Hz), 3.49 (1H, m), 3.19 (1H, d
d, J = 10.2,5.3Hz), 2.86 (1H, dd, J = 17.0,8.3Hz), 2.79 (2H,
t, J = 7.2Hz), 2.57 (2H, t, J = 7.2Hz), 2.43 (1H, dd, J = 17.0,6.
4Hz), 1.26 (3H, t, J = 7.2Hz)

Example 93 3-{[(3R) -5-oxo-1- (4-phenoxybenzyl) pyrrolidinyl] sulfanyl} propanoic acid In the same manner as in Example 89, the (R)-obtained in Example 25 was obtained. 4-
Mercapto-1- (4-phenoxybenzyl) pyrrolidin-2-one 150 mg (0.501 mmol), 3-bromopropionic acid
76.6 μl (0.501 mmol), 60% sodium hydride 40.1 mg (1.00
mmol) to give 71.5 mg (38% yield) of the title compound as a white powder. ¹ H-NMR (300 MHz, CDCl ₃ ) δ: 7.34 (2H, m), 7.20 (2H, d, J = 8.5H
z), 7.11 (1H, m), 7.00 (2H, m), 6.96 (2H, d, J = 8.5Hz), 4.43 (2
H, s), 3.62 (1H, dd, J = 10.0,7.7Hz), 3.51 (1H, m), 3.19 (1H, d
d, J = 10.0,5.1Hz), 2.88 (1H, dd, J = 17.3,8.3Hz), 2.79 (2H,
t, J = 7.1Hz), 2.63 (2H, t, J = 7.1Hz), 2.47 (1H, dd, J = 17.3,6.
0Hz)

Example 94 4-[(4-Bromobenzyl) sulfanyl] -1- (4-phenoxybenzyl)
-2-Pyrrolidinone 4-mercapto-1- (4-phenoxybenzyl) pyrrolidine-2 obtained in Example 17 in the same manner as in Example 89.
-One 80 mg (0.27 mmol), p-bromobenzyl bromide 67
From 110 mg (0.27 mmol) and 12 mg (0.30 mmol) of 60% sodium hydride, 110 mg (yield 87.9%) of the title compound was obtained as a colorless oil. ¹ H-NMR (200 MHz, CDCl ₃ ) δ: 7.45-6.90 (13 H, m), 4.44 (1 H, d, J = 14.6 Hz), 4.35 (1 H, d,
J = 14.7Hz), 3.67 (2H, s), 3.46 (1H, dd, J = 7.3,8.0Hz), 3.32-
3.19 (1H, m), 3.10 (1H, dd, J = 5.2,10.0Hz), 2.76 (1H, dd, J =
(8.4, 18.0Hz), 2.39 (1H, dd, J = 6.2,22.0Hz)

Example 95 Methyl 4-(｛[(3R)
-5-oxo-1- (4-phenoxybenzyl) pyrrolidinyl] sulfanyldimethyl) benzoate 500 mg (1.67) of (R) -4-mercapto-1- (4-phenoxybenzyl) pyrrolidin-2-one obtained in Example 25. mmo
l), 383 mg of methyl 4- (bromomethyl) -benzoate
(1.67 mmol) was dissolved in 5 ml of THF, and 60% sodium hydride 67
mg (1.67 mmol) was added, and the mixture was stirred at room temperature under a nitrogen atmosphere for 10 minutes. The reaction solution was concentrated under reduced pressure, and dissolved in ethyl acetate.
After washing with water and saturated saline, it was dried over anhydrous sodium sulfate. After concentration under reduced pressure, the residue was purified by silica gel column chromatography and n-hexane: ethyl acetate (2: 1 to
1: 1) The eluted fraction was concentrated to give the title compound (645 mg, yield 86%) as a yellow oil. Elemental analysis (%): C ₂₆ H ₂₅ NO ₄ S Calculated: C, 69.78; H, 5.63; N, 3.13 Found: C, 69.64; H, 5.72; N, 3.35

Example 96 4-({[(3R) -5-oxo-1- (4-phenoxybenzyl) pyrrolidinyl]]
Sulfanyl {methyl) benzoic acid Methyl 4-({[(3R) -5-
Oxo-1- (4-phenoxybenzyl) pyrrolidinyl] sulfanyldimethyl) benzoate 250 mg (0.56 mm
ol) and 234 mg (5.59 mmol) of lithium hydroxide monohydrate were stirred at room temperature for 1 hour in a mixture of 2 ml of methanol, 1 ml of water and 1.5 ml of THF. Ethyl acetate was added to the reaction solution, washed with 1N hydrochloric acid, a mixture of 1N hydrochloric acid and saturated saline, and then dried over anhydrous sodium sulfate. After concentration under reduced pressure, the residue was purified by preparative thin-layer chromatography (developing solvent: chloroform: methanol (8: 1)) to give 178 mg (yield 73%) of the title compound as a colorless glassy substance. Elemental analysis _{(%): C 25 H 23} NO 4 S · 0.1H 2 O Calculated: C, 68.97; H, 5.37 ; N, 3.21 Found: C, 68.89; H, 5.32 ; N, 3.35

Example 97 1- (4-Phenoxybenzyl) -4-{[2- (phenylsulfonyl) ethyl] sulfanyl} -2-pyrrolidinone (R) -4-mercapto-1- (obtained in Example 25) 4-phenoxybenzyl) pyrrolidin-2-one 150 mg (0.501 mm
ol) in THF (15 ml), and after cooling with ice, under an argon gas atmosphere,
168 mg (1.00 mmol) of phenylvinyl sulfone and 56.0 μl (0.400 mmol) of triethylamine were added, and the mixture was stirred at room temperature for 48 hours. After adding ethyl acetate to the reaction solution, the mixture was washed with water and saturated saline, and then dried over anhydrous sodium sulfate. After concentration under reduced pressure, the residue was subjected to silica gel column chromatography, and the fraction eluted with hexane: ethyl acetate (20: 80-10: 90) was concentrated under reduced pressure, and powdered from diethyl ether to give the title compound 101m
g (43% yield) was obtained as a white powder. Elemental analysis (%): C ₂₅ H ₂₅ NO ₄ S ₂ Calculated: C, 64.21; H, 5.39; N, 3.00 Found: C, 64.18; H, 5.61; N, 2.99

Example 98 (4R) -4-[(Methoxymethyl) sulfanyl] -1- (4-phenoxybenzyl) -2-pyrrolidinone The (R)-obtained in Example 25 in the same manner as in Example 64.
4-mercapto-1- (4-phenoxybenzyl) pyrrolidin-2-one 150 mg (0.501 mmol), chloromethyl methyl ether 190 μl (2.51 mmol), triethylamine 349 μl
(2.51 mmol) to give 158 mg (yield 92%) of the title compound as a colorless oil. Elemental analysis (%): C ₁₉ H ₂₁ NO ₃ S Calculated: C, 66.45; H, 6.16; N, 4.08 Found: C, 66.53; H, 5.87; N, 4.41

Example 99 (4R) -4-[(3-oxo-1,3-dihydro-2-benzofuran-1-yl)
Sulfanyl] -1- (4-phenoxybenzyl) -2
-Pyrrolidinone 180 mg (0.60 mmol) of (R) -4-mercapto-1- (4-phenoxybenzyl) pyrrolidin-2-one obtained in Example 25.
l), 99.3 mg (0.66 mmol) of O-formylbenzenebenzoic acid were dissolved in 2 ml of trifluoroacetic acid, and the mixture was stirred at room temperature for 17 hours. The reaction solution was concentrated under reduced pressure, dissolved in ethyl acetate, washed twice with a saturated aqueous solution of sodium hydrogencarbonate, washed with a saturated saline solution, and dried over anhydrous sodium sulfate. After concentration under reduced pressure, the residue was purified by preparative thin-layer chromatography (developing solvent: n-hexane: ethyl acetate (1: 1)) to give 224 mg of the title compound.
(86% yield) as a colorless oil. Elemental analysis (%): C ₂₅ H ₂₁ NO ₄ S Calculated: C, 69.59; H, 4.91; N, 3.25 Found: C, 69.83; H, 4.82; N, 3.35

Example 100 N-({[(3R) -5
Oxo-1- (4-phenoxybenzyl) pyrrolidinyl] sulfanyldimethyl) acetamide 180 mg (0.60 mmo) of (R) -4-mercapto-1- (4-phenoxybenzyl) pyrrolidin-2-one obtained in Example 25.
l), 58.9 mg (0.66 mmol) of acetamide methanol were dissolved in 1 ml of trifluoroacetic acid, and the mixture was stirred at room temperature for 30 minutes. The reaction solution was concentrated under reduced pressure, dissolved in ethyl acetate, washed twice with a saturated aqueous solution of sodium hydrogencarbonate, washed with a saturated saline solution, and dried over anhydrous sodium sulfate. After concentration under reduced pressure, the residue was purified by preparative thin-layer chromatography (developing solvent: chloroform: methanol (9: 1)) to give the title compound (167 mg, yield 75%).
Was obtained as a pale brown oil. Elemental analysis _{(%): C 20 H 22} N 2 O 3 S Calculated: C, 64.84; H, 5.99 ; N, 7.56 Found: C, 64.89; H, 6.26 ; N, 7.76

Example 101 2,2-Dimethyl-N-
({[(3R) -5-oxo-1- (4-phenoxybenzyl) pyrrolidinyl] sulfanyl} methyl) propanamide (R) -4-mercapto-1- (4-phenoxybenzyl) pyrrolidine obtained in Example 25 -2-one 220mg (0.74mmo
l), N-hydroxyacetamide methanol 108.1 mg (0.81 mm
ol) was dissolved in 2 ml of trifluoroacetic acid and stirred at room temperature for 10 minutes. The reaction solution was concentrated under reduced pressure, and dissolved in ethyl acetate.
The extract was washed twice with a saturated aqueous solution of sodium hydrogen carbonate and saturated saline, and then dried over anhydrous sodium sulfate. After concentration under reduced pressure, the residue was purified by preparative thin-layer chromatography (developing solvent: n-hexane: acetone (1: 1)) to give 209 mg of the title compound.
(69% yield) as a pale brown oil. Elemental analysis (%): C ₂₃ H ₂₈ N ₂ O ₃ S · 0.1H ₂ O Calculated: C, 66.67; H, 6.85; N, 6.76 Found: C, 66.55; H, 6.94; 6.67

Example 102 N-(｛[(3R) -5
Oxo-1- (4-phenoxybenzyl) pyrrolidinyl] sulfanyl {methyl) benzamide 220 mg (0.74 mmol) of (R) -4-mercapto-1- (4-phenoxybenzyl) pyrrolidin-2-one obtained in Example 25.
l), N-hydroxybenzamide methanol 116.7 mg (0.77
mmol) was dissolved in 2 ml of trifluoroacetic acid and stirred at room temperature for 10 minutes. After concentrating the reaction mixture under reduced pressure, preparative thin-layer chromatography (developing solvent: n-hexane: ethyl acetate (1:
Purify in 3)) and triturate from ethyl acetate to give the title compound
172 mg (54% yield) was obtained as a white powder. Elemental analysis (%): C ₂₅ H ₂₄ N ₂ O ₃ S · 0.1H ₂ O Calculated: C, 69.13; H, 5.61; N, 6.44 Found: C, 69.11; H, 5.61; N, 6.34

Example 103 Ethyl ｛[(3R) -5
-Oxo-1- (4-phenoxybenzyl) pyrrolidinyl] sulfanyl} methylcarbamate 200 mg (0.67 mmol) of (R) -4-mercapto-1- (4-phenoxybenzyl) pyrrolidin-2-one obtained in Example 25.
l), 88 mg (0.73 mmol) of N- (hydroxymethyl) urethane
Was dissolved in 2 ml of trifluoroacetic acid and stirred at room temperature for 10 minutes. The reaction solution was concentrated under reduced pressure, and dissolved in ethyl acetate.
After washing with water and saturated saline, it was dried over anhydrous sodium sulfate. After concentration under reduced pressure, the residue was purified by preparative thin-layer chromatography (developing solvent: n-hexane: ethyl acetate (1: 2)) to give the title compound (177 mg, yield 66%) as a pale-yellow oil. Elemental analysis (%): C ₂₁ H ₂₄ N ₂ O ₄ S · 0.1H ₂ O Calculated: C, 62.69; H, 6.06; N, 6.96 Found: C, 62.45; H, 6.07; 6.91

Example 104 2-({[(3R) -5-
Oxo-1- (4-phenoxybenzyl) pyrrolidinyl] sulfanyldimethyl) -1H-isoindole-
1,3 (2H) -dione 220 mg (0.74 mmol) of (R) -4-mercapto-1- (4-phenoxybenzyl) pyrrolidin-2-one obtained in Example 25.
l), 176 mg (0.74 mmol) of N- (bromomethyl) phthalimide
l) in 2 ml of THF and 29 mg of 60% sodium hydride (0.74 m
mol), and the mixture was stirred at room temperature under a nitrogen atmosphere for 50 minutes. The reaction mixture was concentrated under reduced pressure, dissolved in ethyl acetate, and added with 0.1N hydrochloric acid.
After washing twice with a saturated saline solution, it was dried over anhydrous sodium sulfate. After concentration under reduced pressure, the residue was purified by preparative thin-layer chromatography (developing solvent: n-hexane: ethyl acetate (1: 2)) to give the title compound (253 mg, yield 75%) as a colorless oil. Elemental analysis (%): C ₂₆ H ₂₂ N ₂ O ₄ S · 0.1H ₂ O Calculated: C, 67.83; H, 4.86; N, 6.08 Found: C, 67.74; H, 4.97; 6.05

Example 105 3-{[(3R) -5-oxo-1- (4-phenoxybenzyl) pyrrolidinyl]
Sulfanyl｝ -2,5-pyrrolidindione 150 mg (0.50 mmol) of (R) -4-mercapto-1- (4-phenoxybenzyl) pyrrolidin-2-one obtained in Example 25.
l) was dissolved in 1.5 ml of chloroform, and 54 mg of maleimide (0.55
mmol) and 7 μl (catalytic amount) of triethylamine, and added at room temperature.
Stir for 2 hours. The reaction solution was concentrated under reduced pressure, dissolved in ethyl acetate, washed twice with water and saturated brine, and dried over anhydrous sodium sulfate. After concentration under reduced pressure, the residue was purified by preparative thin-layer chromatography (developing solvent: chloroform: methanol (8: 1)) to give the title compound (165 mg, yield 83%) as a milky white powder. Elemental analysis value (%): C ₂₁ H ₂₀ N ₂ O ₄ S · 0.2H ₂ O Calculated value: C, 63.04; H, 5.13; N, 7.00 Observed value: C, 63.00; H, 4.99; N, 6.94

Example 106 1-methyl-3-{[(3
R) -5-oxo-1- (4-phenoxybenzyl) pyrrolidinyl] sulfanyl {-2,5-pyrrolidinedione (R) -4-mercapto-1- (4-phenoxybenzyl) pyrrolidine obtained in Example 25 2-one 150mg (0.50mmo
l) was dissolved in 1.5 ml of chloroform, 61 mg (0.55 mmol) of N-methylmaleimide and 7 μl (catalytic amount) of triethylamine were added, and the mixture was stirred at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure, dissolved in ethyl acetate, washed three times with water and saturated brine, and dried over anhydrous sodium sulfate. After concentration under reduced pressure, the residue was purified by preparative thin-layer chromatography (developing solvent: chloroform: methanol (15: 1)) to give the title compound (155 m).
g (75% yield) as a pale yellow oil. Elemental analysis _{(%): C 22 H 22} N 2 O 4 S · 0.3H 2 O Calculated: C, 63.53; H, 5.47 ; N, 6.73 Found: C, 63.28; H, 5.40 ; N, 6.50

Example 107 O-ethyl S-[(3
R) -5-oxo-1- (4-phenoxybenzyl) pyrrolidinyl] carbanothioate (R) -4-mercapto-1- (4) obtained in Example 25
-Phenoxybenzyl) pyrrolidin-2-one 180 mg (0.6
(0 mmol) was dissolved in 1 ml of chloroform, 63 μl (0.66 mmol) of ethyl chloroformate was added at 0 ° C., followed by dropwise addition of a solution of 92 μl (0.66 mmol) of triethylamine in 1 ml of chloroform. . The reaction solution was concentrated under reduced pressure, dissolved in ethyl acetate, washed twice with water and saturated brine, and dried over anhydrous sodium sulfate. After concentration under reduced pressure, preparative thin-layer chromatography (developing solvent: n-
Hexane: ethyl acetate (1: 2)) to give the title compound 1
84 mg (83% yield) was obtained as a pale yellow oil. Elemental analysis _{(%): C 20 H 21} NO 4 S · 0.1H 2 O Calculated: C, 64.35; H, 5.72 ; N, 3.75 Found: C, 64.15; H, 5.71 ; N, 3.84

Example 108 S- [6-oxo-1-
(4-phenoxybenzyl) -3-piperidinyl] ethanethioate The method described in the literature (Arch. Pharm. (Weinheim) 316, pp 719-
723, 1983), 5-{[tert-butyl (dimethyl) silyl] oxy} -2-piperidinone 179m
g (0.78 mmol), 34 mg (0.86 mmol) of 60% sodium hydride,
149 μl (0.82 mmol) of 4-phenoxybenzyl chloride
The mixture was stirred in 2 ml of THF at room temperature for 16 hours. After the reaction solution was concentrated under reduced pressure, ethyl acetate was added, and the mixture was washed twice with water and saturated brine, and then dried over anhydrous sodium sulfate. After concentration under reduced pressure, the resulting 5-{[tert-butyl (dimethyl) silyl] oxy} -1- (4-phenoxybenzyl) -2-
Piperidinone was dissolved in 1 ml of THF, and 1.74 ml (1.74 mmol) of a 1 M tetrabutylammonium fluoride solution in THF was added, followed by stirring at room temperature for 30 minutes. After concentrating the reaction solution under reduced pressure,
Preparative thin-layer chromatography (developing solvent: methanol:
Ethyl acetate (1: 9)) (83% yield, two steps) to give 5-hydroxy-1- (4-phenoxybenzyl)-.
187 mg (0.628 mmol) of 2-piperidinone, triethylamine
131 μl (0.94 mmol), 73 μl methanesulfonyl chloride
(0.94 mmol) was stirred in 2 ml of chloroform at room temperature for 15 minutes. After concentrating the reaction solution under reduced pressure, ethyl acetate was added and
After washing twice with saturated saline, drying over anhydrous sodium sulfate and concentration under reduced pressure were obtained (87% yield). 6-oxo-1- (4-phenoxybenzyl) -3-piperidinyl methanesulfonate 205 mg (0.55 mmol) was dissolved in DMF (2 ml), and potassium thioacetate (106 mg, 0.93 mmol) was added.
Stir for 2 hours. Ethyl acetate was added to the reaction solution, and water was used five times.
After washing with saturated saline, it was dried over anhydrous sodium sulfate.
After concentration under reduced pressure, the residue was purified by preparative thin-layer chromatography (developing solvent: n-hexane: ethyl acetate (2: 1)) to obtain 97 mg (yield 50%) of the title compound as a pale yellow oil. Elemental analysis _{(%): C 20 H 21} NO 3 S Calculated: C, 67.58; H, 5.95 ; N, 3.94 Found: C, 67.33; H, 5.90 ; N, 3.80

Example 109 1- (4-Phenoxybenzyl) -5-sulfanyl-2-piperidinone S- [6-oxo-1- (4-phenoxybenzyl) -3-piperidinyl] ethanethioate obtained in Example 108 20 mg (0.056 mmol) is dissolved in 0.2 ml of ethanol,
80 μl (1.13 mmol) of acetyl chloride was slowly added. Thereafter, the mixture was stirred at 50 ° C. for 1 hour, and the reaction solution was concentrated under reduced pressure, dissolved in ethyl acetate, and washed with a saturated saline solution.
Dry over anhydrous sodium sulfate. After concentration under reduced pressure, the residue was purified by preparative thin-layer chromatography (developing solvent: n-hexane: ethyl acetate (2: 3)) to give 14 mg of the title compound (78% yield).
Was obtained as a colorless oil. ¹ H-NMR (300 MHz, CDCl ₃ ) δ: 7.36 to 6.95 (9 H, m), 4.59 (1 H, d, J = 14.6 Hz), 4.50 (1 H, d, J
= 14.6Hz), 3.51-3.43 (1H, m), 3.25-3.13 (2H, m), 2.71-2.45
(2H, m), 2.25-2.16 (1H, m), 1.90-1.77 (1H, m), 1.62-1.59 (1
H, m)

Example 110 S- [2-oxo-1-
(4-phenoxybenzyl) -4-piperidinyl] ethanethioate S- [2-oxo-1- (4-phenoxybenzyl) -4- Piperidinyl] ethanethioate was obtained. ¹ H-NMR (200 MHz, CDCl ₃ ) d: 7.40-6.90 (9 H, m), 4.62 (1 H, d, J = 14.7 Hz), 4.52 (1 H, d, J
= 14.5Hz), 3.92-3.78 (1H, m), 3.32 (1H, d, J = 5.2Hz), 3.29 (1H
H, d, J = 5.3Hz), 2.87 (1H, dd, J = 5.7,16.0Hz), 2.50 (1H, dd, J
= 9.1,18.0Hz), 2.33 (3H, s), 2.25-2.05 (1H, m), 1.95-1.76
(1H, m)

Example 111 1- (4-Phenoxybenzyl) -4-sulfanyl-2-piperidinone S- [2-oxo-1- (4-
Phenoxybenzyl) -4-piperidinyl] 14 mg (82.6% yield) of 1- (4-phenoxybenzyl) -4-sulfanyl-2-piperidinone from 20 mg (0.054 mmol) of ethanethioate in the same manner as in Example 184. As obtained. ¹ H-NMR (200 MHz, CDCl ₃ ) d: 7.40-6.90 (9 H, m), 4.66 (1 H, d, J = 14.4 Hz), 4.48 (1 H, d, J
= 14.6Hz), 3.45-3.20 (3H, m), 2.92 (1H, dd, J = 5.3,18.0Hz),
2.48 (1H, dd, J = 9.1,18.0Hz), 2.25-2.10 (1H, m), 1.90-1.70
(1H, m), 1.67 (1H, d, J = 6.5Hz)

Example 112 4-acetylthio-1-
[4- (2'-Fluorophenoxy) benzyl] pyrrolidin-2-one In a manner similar to that in Example 30, 4- (4-fluorobenzaldehyde) prepared from 4-fluorophenol
1.67 g of (2'-fluorophenoxy) benzyl chloride
(8.1 mmol) and 4-trimethylsilyloxypyrrolidine-
From 1.70 g (9.8 mol) of 2-one to 4-acetylthio-1-
[4- (2'-Fluorophenoxy) benzyl] pyrrolidin-2-one (396 mg, yield 17%) was obtained as a brown oil. Elemental analysis (%): as C ₁₉ H ₁₈ NO ₃ SF Calculated: C, 63.49; H, 5.05; N, 3.9
0; S, 8.92 Found: C, 63.24; H, 5.11; N, 3.8
5; S, 9.01

Example 113 4-mercapto-1- [4
-(2'-Fluorophenoxy) benzyl] pyrrolidin-2-one In the same manner as in Example 31, 4-acetylthio-1- [4- (2'-fluorophenoxy) benzyl] pyrrolidine obtained in Example 112. -2-one 112mg (0.30mm
ol), 97.0 mg of 4-mercapto-1- [4- (2′-fluorophenoxy) benzyl] pyrrolidin-2-one
(98% yield) as a colorless oil. ¹ H-NMR (300 MHz, CDCl ₃ ) δ: 7.20 (2H, d, J = 8.5 Hz), 7.17-7.03 (4H, m), 6.94 (2H, d, J =
8.5Hz), 4.47 (1H, d, J = 14.7Hz), 4.40 (1H, d, J = 14.7Hz), 3.6
4 (1H, dd, J = 10.0,7.2Hz), 3.53 (1H, m), 3.16 (1H, dd, J = 10.
0,5.0Hz), 2.91 (1H, dd, J = 17.1,8.1Hz), 2.42 (1H, dd, J = 17.
1,6.1Hz), 1.86 (1H, d, J = 6.7Hz)

Example 114 4-acetylthio-1-
[4- (3′-Fluorophenoxy) benzyl] pyrrolidin-2-one In a manner similar to that in Example 30, prepared from 4-fluorobenzaldehyde and 3-fluorophenol.
1.73 g of (3'-fluorophenoxy) benzyl chloride
(7.3 mmol) and 4-trimethylsilyloxypyrrolidine-
From 1.90 g (11 mmol) of 2-one to 4-acetylthio-1-
[4- (3'-Fluorophenoxy) benzyl] pyrrolidin-2-one (664 mg, yield 25%) was obtained as a brown oil. Elemental analysis (%): as C ₁₉ H ₁₈ NO ₃ SF Calculated: C, 63.49; H, 5.05; N, 3.9
0; S, 8.92 found: C, 63.19; H, 5.08; N, 3.7.
9; S, 9.00

Example 115 4-Mercapto-1- [4
-(3'-Fluorophenoxy) benzyl] pyrrolidin-2-one In the same manner as in Example 31, 4-acetylthio-1- [4- (3'-fluorophenoxy) benzyl] pyrrolidine obtained in Example 112. -2-one 205mg (0.60mm
ol), 143 mg of 4-mercapto-1- [4- (3′-fluorophenoxy) benzyl] pyrrolidin-2-one
(75% yield) as a colorless oil. ¹ H-NMR (300 MHz, CDCl ₃ ) δ: 7.28 (1 H, m), 7.24 (2 H, d, J = 8.5 Hz), 7.00 (2 H, d, J = 8.5 H
z), 6.79 (2H, ddd, J = 11.4,8.3,2.5Hz), 6.69 (1H, ddd, J = 10.
2,2.3,2.3Hz), 4.49 (1H, d, J = 14.8Hz), 4.42 (1H, d, J = 14.8H
z), 3.67 (1H, dd, J = 10.1,7.2Hz), 3.55 (1H, m), 3.18 (1H, dd,
J = 10.1,5.0Hz), 2.92 (1H, dd, J = 17.1,8.1Hz), 2.43 (1H, dd,
J = 17.1,6.1Hz), 1.88 (1H, d, J = 6.7Hz)

Example 116 (S) -4-Acetylthio-1- [4- (4′-fluorophenoxy) benzyl]
Pyrrolidin-2-one 4-acetylthio-1- [4-
(4'-Fluorophenoxy) benzyl] pyrrolidine-
Using 2-one as a chiral column (CHIRAL manufactured by Daicel Chemical Industries, Ltd.)
(S) -4-Acetylthio-1-) was separated by HPLC using CEL OD 20 × 250 mm (mobile phase hexane: ethanol (90:10), flow rate 10 ml / min, detection 254 nm).
[4- (4′-Fluorophenoxy) benzyl] pyrrolidin-2-one was obtained. ¹ H-NMR (300 MHz, CDCl ₃ ) δ: 7.18 (2H, d, J = 8.5 Hz), 7.04 (2H, dd, J = 9.3, 8.0 Hz), 6.97
(2H, dd, J = 9.3,4.7Hz), 6.92 (2H, d, J = 8.5Hz), 4.45 (1H, d, J
= 15.2Hz), 4.39 (1H, d, J = 15.2Hz), 4.05 (1H, m), 3.75 (1H, d
d, J = 10.6,7.6Hz), 3.17 (1H, dd, J = 10.6,5.0Hz), 2.91 (1H, d
d, J = 17.4,9.0Hz), 2.42 (1H, dd, J = 17.4,6.1Hz), 2.32 (3H,
s)

Example 117 (R) -4-acetylthio-1- [4- (4′-fluorophenoxy) benzyl]
Pyrrolidin-2-one In a manner similar to that in Example 116, 4-acetylthio-1- [4- (4′-fluorophenoxy) benzyl] pyrrolidin-2-one synthesized in Example 30 was subjected to HPLC using a chiral column. By dividing, (R) -4
-Acetylthio-1- [4- (4'-fluorophenoxy) benzyl] pyrrolidin-2-one was obtained. ¹ H-NMR (300 MHz, CDCl ₃ ) δ: 7.18 (2H, d, J = 8.5 Hz), 7.04 (2H, dd, J = 9.3, 8.0 Hz), 6.97
(2H, dd, J = 9.3,4.7Hz), 6.92 (2H, d, J = 8.5Hz), 4.45 (1H, d, J
= 15.2Hz), 4.39 (1H, d, J = 15.2Hz), 4.05 (1H, m), 3.75 (1H, d
d, J = 10.6,7.6Hz), 3.17 (1H, dd, J = 10.6,5.0Hz), 2.91 (1H, d
d, J = 17.4,9.0Hz), 2.42 (1H, dd, J = 17.4,6.2Hz), 2.32 (3H,
s)

Example 118 (R) -4-Mercapto-
1- [4- (4′-Fluorophenoxy) benzyl] pyrrolidin-2-one In the same manner as in Example 31, (R) -4-acetylthio-1- [4- (4 (R) -4-Mercapto-1- [4- (4′-fluorophenoxy) benzyl] pyrrolidin-2-one was obtained from '-fluorophenoxy) benzyl] pyrrolidin-2-one. ¹ H-NMR (300 MHz, CDCl ₃ ) δ: 7.22-6.91 (8H, m), 4.47 (1H, d, J = 14.7 Hz), 4.39 (1H, d, J
= 14.7Hz), 3.64 (1H, dd, J = 10.0,7.2Hz), 3.59-3.48 (1H, m),
3.16 (1H, dd, J = 10.0,5.0Hz), 2.91 (1H, dd, J = 17.1,8.1Hz),
2.42 (1H, dd, J = 17.0,6.1Hz), 1.86 (1H, d, J = 6.7Hz)

Example 119 4-acetylthio-1-
[4- (2 ′, 4′-difluorophenoxy) benzyl] pyrrolidin-2-one 4- (2 ′, 4) prepared from 4-fluorobenzaldehyde and 2,4-difluorophenol in the same manner as in Example 30. From 1.83 g (7.2 mmol) of '-difluorophenoxy) benzyl chloride and 1.50 g (8.6 mmol) of 4-trimethylsilyloxypyrrolidin-2-one, 4-acetylthio-1- [4- (2', 4'-difluorophenoxy)
[Benzyl] pyrrolidin-2-one (288 mg, yield 10%) was obtained as a white powder. Elemental analysis value (%): as C ₁₉ H ₁₇ NO ₃ SF ₂ Calculated value: C, 60.47; H, 4.54; N, 3.7
1; S, 8.50 Found: C, 60.69; H, 4.64; N, 3.8
1: S, 8.49

Example 120 4-Mercapto-1- [4
-(2 ', 4'-Difluorophenoxy) benzyl] pyrrolidin-2-one By a method similar to that in Example 31, 4-acetylthio-1- [4- (2', 4'-) obtained in Example 119. Difluorophenoxy) benzyl] pyrrolidin-2-one 10mg
(0.26 mmol) from 4-mercapto-1- [4- (2 ′,
4'-Difluorophenoxy) benzyl] pyrrolidine-
60.0 mg of 2-one (69% yield) was obtained as a white powder. ¹ H-NMR (300 MHz, CDCl ₃ ) δ: 7.19 (2 H, d, J = 8.5 Hz), 7.06 (1 H, ddd, J = 14.5, 9.0, 5.5 H
z), 7.00-6.88 (2H, m), 6.89 (2H, d, J = 8.5Hz), 4.46 (1H, d, J =
14.7Hz), 4.38 (1H, d, J = 14.7Hz), 3.64 (1H, dd, J = 10.0,7.2H
z), 3.53 (1H, m), 3.15 (1H, dd, J = 10.0,5.0Hz), 2.90 (1H, dd,
J = 17.1,8.1Hz), 2.41 (1H, dd, J = 17.1,6.1Hz), 1.85 (1H, d, J
= 6.7Hz)

Example 121 4-acetylthio-1-
[4- (3 ′, 4′-Difluorophenoxy) benzyl] pyrrolidin-2-one 4- (3 ′, 4) prepared from 4-fluorobenzaldehyde and 3,4-difluorophenol in the same manner as in Example 30. From 1.90 g (7.5 mmol) of '-difluorophenoxy) benzyl chloride and 1.60 g (9.0 mmol) of 4-trimethylsilyloxypyrrolidin-2-one, 4-acetylthio-1- [4- (3', 4'-difluorophenoxy)
[Benzyl] pyrrolidin-2-one (506 mg, yield 19%) was obtained as a pale brown powder. Elemental analysis value (%): as C ₁₉ H ₁₇ NO ₃ SF ₂ Calculated value: C, 60.47; H, 4.54; N, 3.7
1; S, 8.50 Found: C, 60.45; H, 4.51; N, 3.7
8; S, 8.48

Example 122 4-Mercapto-1- [4
-(3 ', 4'-Difluorophenoxy) benzyl] pyrrolidin-2-one By a method similar to that in Example 31, 4-acetylthio-1- [4- (3', 4'-) obtained in Example 121. Difluorophenoxy) benzyl] pyrrolidin-2-one 100m
g (0.26 mmol) from 4-mercapto-1- [4-
(3 ′, 4′-Difluorophenoxy) benzyl] pyrrolidin-2-one (55.0 mg, yield 63%) was obtained as a white powder. ¹ H-NMR (300 MHz, CDCl ₃ ) δ: 7.24 (2H, d, J = 8.5 Hz), 7.12 (1H, dd, J = 18.8, 9.1 Hz), 6.9
6 (2H, d, J = 8.5Hz), 6.83 (1H, ddd, J = 11.2,6.6,2.9Hz), 6.72
(1H, m), 4.49 (1H, d, J = 14.8Hz), 4.40 (1H, d, J = 14.8Hz), 3.6
7 (1H, dd, J = 10.0,7.2Hz), 3.55 (1H, m), 3.17 (1H, dd, J = 10.
0,5.0Hz), 2.92 (1H, dd, J = 17.1,8.1Hz), 2.43 (1H, dd, J = 17.
1,6.1Hz), 1.87 (1H, d, J = 6.7Hz)

Example 123 (R) -4-Acetylthio-1- [4- (4′-methylphenoxy) benzyl] pyrrolidin-2-one (1) In the same manner as in Example 30, 4-fluorobenzaldehyde was prepared. 4-prepared from 4-cresol
5.00 g of (4'-methylphenoxy) benzaldehyde (24
was dissolved in ethanol (60 ml) and water (30 ml), and sodium acetate (3.90 g (47 mmol), hydroxylammonium chloride 2.1) was dissolved.
0 g (31 mmol) was added, and the mixture was heated under reflux for 2 hours. The reaction solution was concentrated under reduced pressure, water was added, and the mixture was extracted twice with ethyl acetate. The obtained organic layer was washed with water and saturated saline, and dried over anhydrous sodium sulfate. After concentration under reduced pressure, the residue was diluted with hexane-
Solidified with ethyl acetate. 100m of this powder in methanol
The mixture was dissolved in l, 250 mg of 10% palladium carbon was added, and the mixture was stirred at room temperature under a hydrogen atmosphere. The reaction solution was filtered, concentrated under reduced pressure, added with water, extracted twice with ethyl acetate, and the obtained organic layer was washed with saturated aqueous sodium hydrogen carbonate and saturated brine, and dried over anhydrous sodium sulfate. After filtration, a 4N solution of hydrochloric acid in ethyl acetate was added to obtain 4.50 g (yield 76%) of 4- (4′-methylphenoxy) benzylamine hydrochloride as a white powder. ¹ H-NMR (300 MHz, CD ₃ OD) δ: 8.23 (2H, brs), 7.46 (2H, d, J = 8.6 Hz), 7.22 (2H, d, J = 8.3)
Hz), 7.00 (2H, d, J = 8.6Hz), 6.91 (2H, d, J = 8.3Hz), 4.11 (0.5
H, brs), 3.99 (1.5H, brs), 2.33 (3H, s), (2) A mixed solvent of 4.50 g (18 mmol) of 4- (4'-methylphenoxy) benzylamine hydrochloride in 25 ml of tetrahydrofuran and 50 ml of acetonitrile And 2.8 ml (20 mmol) of triethylamine was added thereto, followed by stirring at room temperature for 40 minutes. To this solution, 4.00 g (25 mmol) of (S) -O-acetylmalic anhydride (manufactured by Tokyo Chemical Industry Co., Ltd.) was added, and the mixture was stirred at room temperature for 4.5 hours. The reaction solution was concentrated under reduced pressure, dissolved in 50 ml of acetyl chloride, and heated under reflux for 3 hours. After concentration under reduced pressure, ethyl acetate was added, and the mixture was washed with saturated aqueous sodium hydrogen carbonate and saturated brine, and dried over anhydrous sodium sulfate. After concentration under reduced pressure, the residue was subjected to silica gel column chromatography and eluted with hexane: ethyl acetate (80: 20-75: 25) to give (S) -3-acetoxy-1- [4- (4 ′). -Methylphenoxy) benzyl]
3.80 g (60% yield) of pyrrolidine-2,5-dione were obtained as a yellow oil. ¹ H-NMR (300 MHz, CDCl ₃ ) δ: 7.34 (2H, d, J = 8.6 Hz), 7.14 (2H, d, J = 8.2 Hz), 6.91 (2H,
d, J = 8.6Hz), 6.90 (2H, d, J = 8.2Hz), 5.45 (1H, dd, J = 8.7,4.8
Hz), 4.68 (1H, d, J = 13.2 Hz), 4.63 (1H, d, J = 13.2 Hz), 3.16 (1
H, dd, J = 18.3,8.7Hz), 2.67 (1H, dd, J = 18.3,4.8Hz), 2.33 (3
H, s), 2.16 (3H, s) (3) (S) -3-acetoxy-1- [4- (4'-
3.60 g (10 mmol) of methylphenoxy) benzyl] pyrrolidine-2,5-dione was dissolved in a mixed solvent of 40 ml of tetrahydrofuran and 20 ml of ethanol, and the mixture was stirred at -18 to -13 ° C. 386mg sodium borohydride (10mmo
l) was added and the mixture was stirred at -18 to -13 ° C for 8 hours. At the lowest temperature after the reaction, saturated aqueous sodium hydrogen carbonate and saturated saline were added, and the mixture was extracted three times with ethyl acetate. The obtained organic layer was washed with saturated saline and dried over anhydrous sodium sulfate. After concentration under reduced pressure, the residue was treated with 50 ml of trifluoroacetic acid and triethylsilane.
1.6 ml (10 mmol) was added, and the mixture was stirred at room temperature for 35 minutes. 2.8 ml (20 mmol) of triethylamine was added, and the mixture was stirred at room temperature for 40 minutes. To a solution obtained by adding 15 ml (0.20 mol) of acetyl chloride to 30 ml of ethanol, a residue that was concentrated under reduced pressure after the reaction was added,
The mixture was heated and stirred at 50 ° C. for 2 hours. After concentration under reduced pressure, the residue was subjected to silica gel column chromatography and eluted with hexane: acetone (50:50) to give (S) -4-hydroxy-1- [4- (4′-methylphenoxy) benzyl ]
2.20 g (73% yield) of pyrrolidin-2-one were obtained as a white powder. ¹ H-NMR (300 MHz, CDCl ₃ ) δ: 7.18 (2H, d, J = 8.5 Hz), 7.14 (2H, d, J = 8.3 Hz), 6.93 (2H,
d, J = 8.5Hz), 6.90 (2H, d, J = 8.3Hz), 4.49 (1H, m), 4.44 (2H,
s), 3.52 (1H, dd, J = 10.9,5.6Hz), 3.20 (1H, dd, J = 10.9,1.9H
z), 2.74 (1H, dd, J = 17.4,6.6Hz), 2.44 (1H, dd, J = 17.4,2.3H
z), 2.35 (1H, brs), 2.33 (3H, s) (4) (S) -4-hydroxy-1- [4- (4'-
Methylphenoxy) benzyl] pyrrolidin-2-one 2.
00g (6.7 mmol) was dissolved in 15 ml of chloroform, 0.73 ml (9.4 mmol) of methanesulfonyl chloride was added, and the mixture was stirred under ice cooling. To this, a solution of 1.3 ml (9.4 mmol) of triethylamine dissolved in 5 ml of chloroform was added dropwise over 10 minutes, and the mixture was further stirred under ice cooling for 3 hours. After concentration under reduced pressure, ethyl acetate was added, and the mixture was washed three times with water and further with a saturated saline solution, and dried over anhydrous sodium sulfate. After concentration under reduced pressure, the residue was washed with ethyl acetate-hexane, and 2.40 g of (S) -4-methanesulfonyloxy-1- [4- (4′-methylphenoxy) benzyl] pyrrolidin-2-one (yield) 95%) as a white powder. ¹ H-NMR (300 MHz, CDCl ₃ ) δ: 7.18 (2H, d, J = 8.6 Hz), 7.15 (2H, d, J = 8.6 Hz), 6.94 (2H,
d, J = 8.3Hz), 6.91 (2H, d, J = 8.3Hz), 5.29 (1H, m), 4.49 (1H,
d, J = 15.0Hz), 4.42 (1H, d, J = 15.0Hz), 3.66 (1H, dd, J = 12.0,
5.7Hz), 3.52 (1H, dd, J = 12.0,2.0Hz), 3.02 (3H, s), 2.87 (1
H, dd, J = 17.9,6.8Hz), 2.71 (1H, dd, J = 17.9,2.5Hz), 2.34 (3
H, s) (5) 1.30 g (8.3 mmol) of cesium carbonate was dispersed in 10 ml of N, N-dimethylformamide, and 2.1 ml (30 mmo) of thioacetic acid was dispersed.
l) was added and the mixture was stirred at room temperature for several minutes. Thereafter, a degassing operation was performed under reduced pressure to prepare a cesium thioacetate salt solution.
(S) -4-methanesulfonyloxy-1- [4-
(4′-Methylphenoxy) benzyl] pyrrolidine-2
-One 2.20 g (5.9 mmol) in N, N-dimethylformamide
The solution was dissolved in 10 ml, the prepared cesium thioacetate salt solution was added, and the mixture was further degassed under reduced pressure. This solution was stirred at room temperature under a nitrogen atmosphere for 61 hours. Water was added to the reaction solution, and the mixture was extracted three times with ethyl acetate. The obtained organic layer was washed three times with water and further with a saturated saline solution, and dried over anhydrous sodium sulfate. After concentration under reduced pressure, the residue was subjected to silica gel column chromatography, and hexane: ethyl acetate was used.
(80: 20-70: 30), and the eluate was treated with activated carbon to give (R) -4-acetylthio-1- [4- (4′-methylphenoxy) benzyl] pyrrolidin-2-one 1.70.
g (81% yield) was obtained as a pale red oil. ¹ H-NMR (300 MHz, CDCl ₃ ) δ: 7.17 (2H, d, J = 8.4 Hz), 7.13 (2H, d, J = 8.3 Hz), 6.93 (2H,
d, J = 8.4Hz), 6.91 (2H, d, J = 8.3Hz), 4.45 (1H, d, J = 14.7Hz),
4.38 (1H, d, J = 14.7Hz), 4.05 (1H, m), 3.75 (1H, dd, J = 10.7,
7.6Hz), 3.16 (1H, dd, J = 10.7,5.0Hz), 2.91 (1H, dd, J = 17.4,
9.0Hz), 2.41 (1H, dd, J = 17.4,6.0Hz), 2.34 (3H, s), 2.32 (3
H, s)

Example 124 (R) -4-Acetylthio-1- [4- (4'-ethylphenoxy) benzyl] pyrrolidin-2-one In the same manner as in Example 123, 4-fluorobenzaldehyde and 4-ethyl 4-prepared from phenol
(4'-methylphenoxy) benzylamine and (S)-
(R) -4-Acetylthio-1- [4- (4′-ethylphenoxy) benzyl] pyrrolidin-2-one was obtained as a pale red oil from O-acetylmalic anhydride. ¹ H-NMR (300 MHz, CDCl ₃ ) δ: 7.17 (4H, d, J = 8.5 Hz), 6.92 (2H, d, J = 8.6 Hz), 6.92 (2H,
d, J = 8.5Hz), 4.46 (1H, d, J = 14.7Hz), 4.39 (1H, d, J = 14.7H
z), 4.05 (1H, m), 3.75 (1H, dd, J = 10.6,7.5Hz), 3.16 (1H, dd,
J = 10.6,5.0Hz), 2.91 (1H, dd, J = 17.4,8.9Hz), 2.63 (2H, q, J
= 7.6Hz), 2.42 (1H, dd, J = 17.4,6.0Hz), 2.31 (3H, s), 1.24 (3
(H, t, J = 7.6Hz)

Example 125 (R) -4-acetylthio-
1- [4- (4-chlorophenoxy) benzyl] pyrrolidin-2-one (1) 30.0 g (233 mmol) of 4-chlorophenol, 28.9 g (233 mmol) of 4-fluorobenzaldehyde, potassium carbonate
From 32.2 g (233 mmol), 51.8 g (96% yield) of 4- (4-chlorophenoxy) benzaldehyde was obtained as pale yellow prism crystals. ¹ H-NMR (300 MHz, CDCl ₃ ) δ: 9.93 (1 H, s), 7.86 (2 H, d, J = 8.7 H
z), 7.38 (2H, d, J = 9.0Hz), 7.04 (4H, m) (2) 4- (4-chlorophenoxy) benzaldehyde
46.5 g (200 mmol), 17.4 g of hydroxylamine hydrochloride (250 mmo
l), 25.2 g (300 mmol) of sodium bicarbonate, 4- (4
-Chlorophenoxy) benzaldoxime 47.9 g (yield 9
7%) as a white powder. ¹ H-NMR (300 MHz, CDCl ₃ ) δ: 8.11 (1 H, s), 7.55 (2 H, d, J = 8.7 H
z), 7.32 (2H, d, J = 9.1 Hz), 6.98 (4H, m) (3) After adding 22.8 g (600 mmol) of lithium aluminum hydride to 800 ml of diethyl ether, 4- (4-chlorophenoxy) A solution of 46.9 g (189 mmol) of benzaldoxime in 200 ml of diethyl ether was added dropwise with stirring over 1 hour. Water was added to the reaction solution under ice-cooling, filtered through celite, and the precipitate was washed with ethyl acetate. The organic layer was washed with water and saturated saline, and then dried over anhydrous sodium sulfate. After concentrating under reduced pressure, dissolving in ethyl acetate, 4N hydrochloric acid / ethyl acetate 80 ml
Was added and allowed to stand. The precipitate was collected by filtration, washed several times with diethyl ether, and dried to obtain 43.7 g (86% yield) of 4- (4-chlorophenoxy) benzylamine hydrochloride as a white powder. ¹ H-NMR (300 MHz, DMSO-d ₆ ) δ: 8.42 (2 H, br s), 7.53 (2 H, d, J = 8.3 Hz), 7.46 (2 H, d, J = 8.
9Hz), 7.08 (2H, d, J = 8.3Hz), 7.02 (2H, d, J = 8.9Hz), 4.00 (2
(H, s) (4) As in Example 123, 30.0 g (111 mmol) of 4- (4-chlorophenoxy) benzylamine hydrochloride, 15.5 ml (111 mmol) of triethylamine, 20.2 g of (S) -O-acetylmalic anhydride g (128 mmol), (S) -3-acetoxy-1
39.4 g (95% yield) of-[4- (4-chlorophenoxy) benzyl] succinimide was obtained as a colorless oil. ¹ H-NMR (300 MHz, CDCl ₃ ) δ: 7.36 (2H, d, J = 8.7 Hz), 7.28 (2H, d, J = 9.0 Hz), 6.93 (4H,
m), 5.45 (1H, dd, J = 8.9,4.9Hz), 4.70 (1H, d, J = 14.3Hz), 4.6
4 (1H, d, J = 14.3Hz), 3.17 (1H, dd, J = 18.5,8.9Hz), 2.68 (1H,
dd, J = 18.5, 4.9 Hz), 2.16 (3H, s) (5) (S) -3-acetoxy-1- [4- (4-chlorophenoxy) benzyl] succinimide 39.0 g (104 mmol),
After reduction with 3.93 g (104 mmol) of sodium borohydride and 16.6 ml (104 mmol) of triethylsilane, respectively,
14.8 g (yield 45%) of (S) -4-hydroxy-1- [4- (4-chlorophenoxy) benzyl] pyrrolidin-2-one was obtained as a pale yellow oil. Elemental analysis _{(%) C 17 H 16 NO} 3 Cl · 0.3H 2 O Calculated C, 63.18; H, 5.18; N, 4.33 Found C, 63.13; H, 5.06; N, 4.34 (6) ( S) -4-Hydroxy-1- [4- (4-chlorophenoxy) benzyl] pyrrolidin-2-one 14.5 g (45.6
mmol), 4.94 ml (63.8 mmol) of methanesulfonyl chloride,
From 8.90 ml (63.8 mmol) of triethylamine, 14.6 g (yield 81%) of (S) -4-methanesulfonyloxy-1- [4- (4-chlorophenoxy) benzyl] pyrrolidin-2-one was obtained as a white powder. . Elemental analysis value (%) Calculated value for C ₁₈ H ₁₈ NO ₅ SCl · 0.2H ₂ O C, 54.12; H, 4.64; N, 3.51 Actual value C, 54.09; H, 4.59; N, 3.43 (7) ( S) -4-Methanesulfonyloxy-1- [4-
(4-Chlorophenoxy) benzyl] pyrrolidin-2-one 14.0 g (35.4 mmol), thioacetic acid 12.7 ml (177 mmol), cesium carbonate 8.07 g (24.8 mmol), (R) -4-acetylthio-
11.7 g (88% yield) of 1- [4- (4-chlorophenoxy) benzyl] pyrrolidin-2-one was obtained as a brown oil. Elemental analysis value (%) C ₁₉ H ₁₈ NO ₃ SCl · 0.25H ₂ O
Calculated C, 59.99; H, 4.90; N, 3.68 Found C, 59.96; H, 4.78; N, 3.67

Example 126 (R) -4-Mercapto-1
-[4- (4-chlorophenoxy) benzyl] pyrrolidine-
8.55 ml of acetyl chloride (120 mmo)
l) was added dropwise over 30 minutes with stirring. Example 12 was added to this solution.
(R) -4-acetylthio-1- [4- (4- (4-
Chlorophenoxy) benzyl] pyrrolidin-2-one 2.26
After dissolving g (6.01 mmol), the mixture was heated and stirred at 50 ° C. for 1.5 hours. After the reaction solution was concentrated under reduced pressure, ethyl acetate was added, and the mixture was washed with water and saturated saline, and then dried over anhydrous sodium sulfate. After concentration under reduced pressure, the residue was subjected to silica gel column chromatography, and the fraction eluted with hexane: ethyl acetate (40:60) was concentrated under reduced pressure to give (R) -4-mercapto-1- [4- (4-chloroform). 1.29 g (phenoxy) benzyl] pyrrolidin-2-one (64% yield) was obtained as a pale red oil. Elemental analysis _{(%) C 17 H 16 NO} 2 SCl · 0.2H 2 O Calculated C, 60.51; H, 4.90; N, 4.15 Found C, 60.41; H, 4.96; N, 4.12

Example 127 4-acetylthio-1-
[4- (4'-Methylphenoxy) benzyl] pyrrolidin-2-one 1.97 g of 4- (4'-methylphenoxy) benzyl chloride prepared from 4-fluorobenzaldehyde and 4-cresol in the same manner as in Example 30. (8.9 mmol) and 4
-Trimethylsilyloxypyrrolidin-2-one 1.50 g
(8.9 mmol) from 4-acetylthio-1- [4- (4′-
Methylphenoxy) benzyl] pyrrolidin-2-one 39
7 mg (12% yield) was obtained as a white powder. Elemental analysis _{(%): C 20 H 21} NO 3 S Calculated: C, 67.58; H, 5.95 ; N, 3.9
4; S, 9.02 found: C, 67.53; H, 5.94; N, 4.1.
5; S, 9.05

Example 128 4-Mercapto-1- [4
-(4'-methylphenoxy) benzyl] pyrrolidine-
2-One 103 mg (0.30 mmol) of 4-acetylthio-1- [4- (4'-methylphenoxy) benzyl] pyrrolidin-2-one obtained in Example 127 in the same manner as in Example 31.
From l), 87 mg of 4-mercapto-1- [4- (4′-methylphenoxy) benzyl] pyrrolidin-2-one (yield 9
6%) as a colorless oil. ¹ H-NMR (300 MHz, CDCl ₃ ) δ: 7.18 (2H, d, J = 8.5 Hz), 7.14 (2H, d, J = 8.4 Hz), 6.93 (2H,
d, J = 8.5Hz), 6.91 (2H, d, J = 8.4Hz), 4.46 (1H, d, J = 14.7Hz),
4.39 (1H, d, J = 14.7Hz), 3.64 (1H, dd, J = 10.0,7.3Hz), 3.53
(1H, m), 3.16 (1H, dd, J = 10.0,5.1Hz), 2.91 (1H, dd, J = 17.1,
8.1Hz), 2.42 (1H, dd, J = 17.1,6.2Hz), 2.34 (3H, s) 1.86 (1H,
d, J = 6.7Hz)

Example 129 4-Acetylthio-1-
[4- (4 ′-(Trifluoromethyl) phenoxy) benzyl] pyrrolidin-2-one 4- [4 prepared from 4-fluorobenzaldehyde and 4- (trifluoromethyl) phenol in the same manner as in Example 30. From 382 mg (1.3 mmol) of '-(trifluoromethyl) phenoxy] benzyl chloride and 338 mg (2.0 mmol) of 4-trimethylsilyloxypyrrolidin-2-one, 4-acetylthio-1- {4- [4'-(trifluoromethyl) Phenoxy] benzyl @ pyrrolidin-2-one
95.0 mg (18% yield) was obtained as a colorless oil. ¹ H-NMR (300 MHz, CDCl ₃ ) δ: 7.58 (2H, d, J = 8.7 Hz), 7.25 (2H, d, J = 8.5 Hz), 7.05 (2H,
d, J = 8.7Hz), 7.02 (2H, d, J = 8.5Hz), 4.49 (1H, d, J = 15.0Hz),
4.42 (1H, d, J = 15.0Hz), 4.07 (1H, m), 3.78 (1H, dd, J = 10.6,
7.5Hz), 3.19 (1H, dd, J = 10.6,5.0Hz), 2.93 (1H, dd, J = 17.5,
9.0Hz), 2.44 (1H, dd, J = 17.4,6.0Hz), 2.33 (3H, s)

Example 130 4-Mercapto-1- ｛4
-[4 '-(Trifluoromethyl) phenoxy] benzyl} pyrrolidin-2-one By the same method as in Example 31, 4-acetylthio-1- {4- [4'-(tri Fluoromethyl) phenoxy] benzyl {pyrrolidin-2-one (58.0 mg, 0.14 mmol) to 4-mercapto-1- {4-
[4 '-(trifluoromethyl) phenoxy] benzyl} pyrrolidin-2-one (46.0 mg, yield 89%) was obtained as a colorless oil. ¹ H-NMR (300 MHz, CDCl ₃ ) δ: 7.58 (2H, d, J = 8.7 Hz), 7.27 (2H, d, J = 8.7 Hz), 7.04 (2H,
d, J = 8.4Hz), 7.02 (2H, d, J = 8.4Hz), 4.52 (1H, d, J = 14.8Hz),
4.42 (1H, d, J = 14.8Hz), 3.68 (1H, dd, J = 10.0,7.2Hz), 3.56
(1H, m), 3.19 (1H, dd, J = 10.0,5.0Hz), 2.94 (1H, dd, J = 17.1,
8.1Hz), 2.43 (1H, dd, J = 17.1,6.1Hz), 1.87 (1H, d, J = 6.7Hz)

Example 131 4-Acetylthio-1-
[4- (4'-Ethoxycarbonylphenoxy) benzyl] pyrrolidin-2-one 4- (4'-chloromethylphenoxy) prepared from 4-fluorobenzaldehyde and ethyl 4-hydroxybenzoate in the same manner as in Example 30. ) Ethyl benzoate and 4-trimethylsilyloxypyrrolidin-2-one to 4-acetylthio-1- [4- (4'-ethoxycarbonylphenoxy) benzyl] pyrrolidin-2-one
(17% yield) as a colorless oil. ¹ H-NMR (300 MHz, CDCl ₃ ) δ: 8.02 (2H, d, J = 8.8 Hz), 7.24 (2H, d, J = 8.6 Hz), 7.02 (2H,
d, J = 8.6Hz), 6.98 (2H, d, J = 8.8Hz), 4.49 (1H, d, J = 14.9Hz),
4.42 (1H, d, J = 14.9Hz), 4.56 (2H, q, J = 7.1Hz), 4.07 (1H, m),
3.78 (1H, dd, J = 10.6,7.5Hz), 3.19 (1H, dd, J = 10.6,4.9Hz),
2.93 (1H, dd, J = 17.4,8.9Hz), 2.44 (1H, dd, J = 17.4,6.0Hz),
2.32 (3H, s), 1.39 (3H, t, J = 7.1Hz)

Example 132 4-Mercapto-1- [4
-(4'-ethoxycarbonylphenoxy) benzyl]
Pyrrolidin-2-one 4-Acetylthio-1- [4- (4'-ethoxycarbonylphenoxy) benzyl] pyrrolidin-2-one obtained in Example 131 in the same manner as in Example 31.
From 8 mg (0.26 mmol), 4-mercapto-1- [4-
(4′-Ethoxycarbonylphenoxy) benzyl] pyrrolidin-2-one (100 mg) was obtained almost quantitatively as a pale yellow oil. ¹ H-NMR (300 MHz, CDCl ₃ ) δ: 8.01 (2H, d, J = 8.8 Hz), 7.27 (2H, d, J = 8.5 Hz), 7.02 (2H,
d, J = 8.5Hz), 6.98 (2H, d, J = 8.8Hz), 4.51 (1H, d, J = 14.8Hz),
4.42 (1H, d, J = 14.8Hz), 4.36 (2H, q, J = 7.1Hz), 3.68 (1H, dd,
J = 10.1,7.2Hz), 3.56 (1H, m), 3.19 (1H, dd, J = 10.1,5.0Hz),
2.93 (1H, dd, J = 17.1,8.1Hz), 2.43 (1H, dd, J = 17.1,6.0Hz),
1.88 (1H, d, J = 6.7Hz), 1.48 (3H, t, J = 7.1Hz)

Example 133 4-Acetylthio-1-
[4- (4′-Carboxyphenoxy) benzyl] pyrrolidin-2-one (1) 4- (4′-chloro) prepared from 4-fluorobenzaldehyde and benzyl 4-hydroxybenzoate by the same method as in Example 30. From 6.20 g (18 mmol) of benzyl methylphenoxy) benzoate and 3.00 g (18 mmol) of 4-trimethylsilyloxypyrrolidin-2-one 4-methanesulfonyloxy-1- [4- (4′-benzyloxycarbonylphenoxy) benzyl] pyrrolidine -2-
471 mg (5% yield) were obtained as a brown oil. ¹ H-NMR (300 MHz, CDCl ₃ ) δ: 8.05 (2H, d, J = 8.8 Hz), 7.48-7.32 (5H, m), 7.25 (2H, d, J =
8.5Hz), 7.03 (2H, d, J = 8.5Hz), 6.98 (2H, d, J = 8.8Hz), 5.35
(2H, s), 5.30 (1H, m), 4.50 (2H, s), 3.69 (1H, dd, J = 12.0,5.6
Hz), 3.55 (1H, dd, J = 12.0,1.9Hz), 3.03 (3H, s), 2.89 (1H, d
d, J = 17.9,6.8Hz), 2.72 (1H, dd, J = 17.9,2.4Hz) (2) 4-Methanesulfonyloxy-1- [4-
471 mg (1.1 mmol) of (4′-benzyloxycarbonylphenoxy) benzyl] pyrrolidin-2-one was dissolved in 20 ml of tetrahydrofuran, 24.0 mg of 10% palladium carbon was added, and the mixture was stirred at room temperature under a hydrogen atmosphere for 2.5 hours. After the reaction solution was filtered and concentrated under reduced pressure, the residue was triturated with hexane-ethyl acetate to give 4-methanesulfonyloxy-1- [4
-(4'-Carboxyphenoxy) benzyl] pyrrolidin-2-one (240 mg, yield 59%) was obtained as a white powder. ¹ H-NMR (300 MHz, CDCl ₃ ) δ: 8.08 (2H, d, J = 8.7 Hz), 7.27 (2H, d, J = 8.6 Hz), 7.06 (2H,
d, J = 8.6Hz), 7.01 (2H, d, J = 8.7Hz), 5.31 (1H, m), 4.51 (2H,
s), 3.71 (1H, dd, J = 12.0,5.6Hz), 3.57 (1H, dd, J = 12.0,2.0H
z), 3.04 (3H, s), 2.91 (1H, dd, J = 18.0,6.9Hz), 2.74 (1H, dd,
J = 18.0, 2.2Hz) (3) 4-Methanesulfonyloxy-1- [4-
240 mg (0.59 mmol) of (4′-carboxylphenoxy) benzyl] pyrrolidin-2-one was dissolved in 20 ml of ethanol, and 822 mg (3.0 mmol) of potassium thioacetate was added, followed by heating under reflux for 2 hours. The reaction solution was concentrated under reduced pressure, 5% aqueous sodium hydrogen sulfate was added, and the mixture was extracted twice with ethyl acetate. The obtained organic layer was washed with water and saturated saline, and dried over anhydrous sodium sulfate. After concentration under reduced pressure, the residue was subjected to silica gel column chromatography, eluted with chloroform: methanol (98: 2), and again subjected to silica gel column chromatography, and eluted with hexane: ethyl acetate (40:60) And 4-acetylthio-1- [4- (4'-carboxylphenoxy) benzyl] pyrrolidin-2-one 103m
g (yield 45%) was obtained as a pale yellow powder. ¹ H-NMR (300 MHz, CDCl ₃ ) δ: 8.07 (2H, d, J = 8.8 Hz), 7.26 (2H, d, J = 8.4 Hz), 7.04 (2H,
d, J = 8.4Hz), 7.01 (2H, d, J = 8.8Hz), 4.51 (1H, d, J = 14.8Hz),
4.43 (1H, d, J = 14.8Hz), 4.07 (1H, m), 3.79 (1H, dd, J = 10.6,
7.5Hz), 3.20 (1H, dd, J = 10.6,5.0Hz), 2.94 (1H, dd, J = 17.4,
9.0Hz), 2.44 (1H, dd, J = 17.4,6.0Hz), 2.33 (3H, s)

Example 134 4-Acetylthio-1-
[4- (4′-Aminocarbonylphenoxy) benzyl] pyrrolidin-2-one (1) 4-prepared in the same manner as in Example 133
Methanesulfonyloxy-1- [4- (4'-carboxylphenoxy) benzyl] pyrrolidin-2-one 310 m
g (0.76 mmol) was dissolved in 5 ml of thionyl chloride, and
Stirred for hours. The reaction solution was concentrated under reduced pressure, 5 ml of tetrahydrofuran and 1 ml of concentrated aqueous ammonia were added, and the mixture was stirred at room temperature for 1.5 hours. The reaction solution was concentrated under reduced pressure, diluted hydrochloric acid was added, and the mixture was extracted twice with ethyl acetate. The obtained organic layer was washed with water and saturated saline, and dried over anhydrous sodium sulfate. After concentration under reduced pressure, the residue was triturated with hexane-ethyl acetate,
4-methanesulfonyloxy-1- [4- (4′-aminocarbonylphenoxy) benzyl] pyrrolidine-2-
147 mg (48% yield) were obtained as a white powder. ¹ H-NMR (300 MHz, DMSO-d ₆ ) δ: 7.87 (2H, d, J = 8.2 Hz), 7.27 (2H, d, J = 8.2 Hz), 7.04 (2H,
d, J = 8.5Hz), 6.98 (2H, d, J = 8.5Hz), 5.29 (1H, m), 4.53 (1H, b
rs), 4.41 (2H, s), 3.97 (1H, brs), 3.69 (1H, dd, J = 11.5,5.4H
z), 3.41 (1H, d, J = 11.5Hz), 3.30 (1H, m), 3.21 (3H, s), 2.91
(1H, dd, J = 17.9,6.9Hz) (2) 4-Methanesulfonyloxy-1- [4-
(4'-Aminocarbonylphenoxy) benzyl] pyrrolidin-2-one (147 mg, 0.36 mmol) was dissolved in ethanol (20 ml), and potassium thioacetate (123 mg, 1.1 mmol) was added.
The mixture was refluxed for 5 hours. The reaction solution was concentrated under reduced pressure, water was added, and the mixture was extracted twice with ethyl acetate. The obtained organic layer was washed with water and saturated saline, and dried over anhydrous sodium sulfate. After concentration under reduced pressure, the residue was subjected to silica gel column chromatography, and chloroform: methanol (98: 2-95: 5)
And eluted with 4-acetylthio-1- [4- (4'-aminocarbonylphenoxy) benzyl] pyrrolidine-2-
62.0 mg (45% yield) of ON were obtained as a white powder. ¹ H-NMR (300 MHz, CDCl ₃ ) δ: 7.80 (2H, d, J = 8.7 Hz), 7.24 (2H, d, J = 8.5 Hz), 7.01 (2H,
d, J = 8.7Hz), 7.01 (2H, d, J = 8.5Hz), 5.90 (2H, brs), 4.49 (1
(H, d, J = 14.9Hz), 4.42 (1H, d, J = 14.9Hz), 4.07 (1H, m), 3.78
(1H, dd, J = 10.6,7.5Hz), 3.20 (1H, dd, J = 10.6,4.9Hz), 2.93
(1H, dd, J = 17.4,6.0Hz), 2.43 (1H, dd, J = 17.4,6.0Hz), 2.33
(3H, s)

Example 135 4-Mercapto-1- [4
-(4'-Aminocarbonylphenoxy) benzyl] pyrrolidin-2-one In the same manner as in Example 31, 4-acetylthio-1- [4- (4'-carboxamidophenoxy) benzyl] obtained in Example 134. 23.0 mg of pyrrolidin-2-one
(0.060 mmol) from 4-mercapto-1- [4- (4 ′
-Aminocarbonylphenoxy) benzyl] pyrrolidin-2-one (22.0 mg) was obtained almost quantitatively as a colorless oil. ¹ H-NMR (300 MHz, CDCl ₃ ) δ: 7.79 (2H, d, J = 8.7 Hz), 7.27 (2H, d, J = 8.6 Hz), 7.02 (2H,
d, J = 8.6Hz), 7.02 (2H, d, J = 8.7Hz), 5.90-5.60 (2H, brd), 4.
51 (1H, d, J = 14.8Hz), 4.42 (1H, d, J = 14.8Hz), 3.68 (1H, dd, J
= 10.0,7.3Hz), 3.57 (1H, m), 3.19 (1H, dd, J = 10.0,5.0Hz),
2.93 (1H, dd, J = 17.1,8.1Hz), 2.43 (1H, dd, J = 17.1,6.0Hz),
1.88 (1H, d, J = 6.7Hz)

Example 136 4-Acetylthio-1-
[4- (4′-Hydroxyphenoxy) benzyl] pyrrolidin-2-one (1) 4-methanesulfonyloxy-1- [4- (4′-methoxyphenoxy) benzyl] prepared by the same method as in Example 36. 1.16 g of pyrrolidin-2-one (3.1 m
mol) was dissolved in 25 ml of chloroform, and boron tribromide (3M
(Dichloromethane solution) (4 ml) was added and the mixture was stirred at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure, ethyl acetate was added, washed with water and saturated saline, and dried over anhydrous sodium sulfate. After concentration under reduced pressure, the residue was subjected to silica gel column chromatography, eluted with ethyl acetate, and 933 mg of 4-methanesulfonyloxy-1- [4- (4′-hydroxyphenoxy) benzyl] pyrrolidin-2-one ( (80% yield) as a gray powder. ¹ H-NMR (300 MHz, CDCl ₃ ) δ: 7.15 (2H, d, J = 8.5 Hz), 6.91 (2H, d, J = 9.0 Hz), 6.88 (2H,
d, J = 8.5Hz), 6.82 (2H, d, J = 9.0Hz), 5.35 (1H, s), 5.28 (1H,
m), 4.49 (1H, d, J = 14.7 Hz), 4.41 (1H, d, J = 14.7 Hz), 3.66 (1
H, dd, J = 12.0,5.6Hz), 3.52 (1H, dd, J = 12.0,1.8Hz), 3.02 (3
H, s), 2.88 (1H, dd, J = 18.0,6.8Hz), 2.72 (1H, dd, J = 18.0,2.
4Hz) (2) 4-Methanesulfonyloxy-1- [4-
933 mg (2.5 mmol) of (4′-hydroxyphenoxy) benzyl] pyrrolidin-2-one was dissolved in 50 ml of ethanol,
1.40 g (13 mmol) of potassium thioacetate was added, and the mixture was heated under reflux for 2 hours. The reaction solution was concentrated under reduced pressure, water was added, and the mixture was extracted twice with ethyl acetate. The obtained organic layer was washed with water and saturated saline, and dried over anhydrous sodium sulfate. After concentration under reduced pressure, the residue was subjected to silica gel column chromatography, eluted with hexane: ethyl acetate (50:50), and again subjected to silica gel column chromatography, eluted with chloroform, and 4-acetylthio-1 − [4- (4′-
434 mg (yield 49%) of hydroxyphenoxy) benzyl] pyrrolidin-2-one was obtained as a colorless oil. Elemental analysis (%): C ₁₉ H ₁₉ NO ₄ S Calculated: C, 63.85; H, 5.36; N, 3.9
2; S, 8.97 found: C, 63.66; H, 5.16; N, 4.0.
5; S, 8.86

Example 137 4-Mercapto-1- [4
-(4'-Hydroxyphenoxy) benzyl] pyrrolidin-2-one In the same manner as in Example 31, 4-acetylthio-1- [4- (4'-hydroxyphenoxy) benzyl] pyrrolidine obtained in Example 136. -2-one 58.0mg (0.1
6 mmol) from 4-mercapto-1- [4- (4′-hydroxyphenoxy) benzyl] pyrrolidin-2-one 3
5.0 mg (68% yield) was obtained as a white powder. ¹ H-NMR (300 MHz, CDCl ₃ ) δ: 8.42 (1 H, s), 7.09 (2 H, d, J = 8.5 Hz), 6.81 (2 H, d, J = 8.5 H)
z), 6.79 (4H, d, J = 4.7Hz), 4.37 (1H, d, J = 14.7Hz), 4.31 (1H,
d, J = 14.7Hz), 3.58 (1H, dd, J = 10.0,7.2Hz), 3.47 (1H, m), 3.
09 (1H, dd, J = 10.0,5.0Hz), 2.84 (1H, dd, J = 17.0,8.1Hz), 2.
34 (1H, dd, J = 17.0,6.1Hz), 1.83 (1H, d, J = 6.7Hz)

Example 138 4-Acetylthio-1-
[4- (4′-Ethoxyphenoxy) benzyl] pyrrolidin-2-one A compound prepared from 4-fluorobenzaldehyde and 4-ethoxyphenol in the same manner as in Example 30.
1.83 g of (4'-ethoxyphenoxy) benzyl chloride
(7.0 mmol) and 4-trimethylsilyloxypyrrolidine-
1.20 g (7.0 mmol) of 2-one to 4-acetylthio-1-
[4- (4'-Ethoxyphenoxy) benzyl] pyrrolidin-2-one (667 mg, yield 25%) was obtained as a yellow oil. Elemental analysis (%): C ₂₁ H ₂₃ NO ₄ S Calculated: C, 65.43; H, 6.01; N, 3.6
3: S, 8.32 Found: C, 65.61; H, 5.93; N, 3.7.
5; S, 8.29

Example 139 4-Mercapto-1- [4
-(4'-Ethoxyphenoxy) benzyl] pyrrolidin-2-one In the same manner as in Example 31, 4-acetylthio-1- [4- (4'-ethoxyphenoxy) benzyl] pyrrolidine obtained in Example 138. -2-one 192mg (0.50mm
ol) from 128 mg of 4-mercapto-1- [4- (4′-ethoxyphenoxy) benzyl) pyrrolidin-2-one
(75% yield) as a colorless oil. ¹ H-NMR (300 MHz, CDCl ₃ ) δ: 7.17 (2H, d, J = 8.6 Hz), 6.96 (2H, d, J = 9.1 Hz), 6.89 (2H,
d, J = 8.6Hz), 6.87 (2H, d, J = 9.1Hz), 4.45 (1H, d, J = 14.7Hz),
4.38 (1H, d, J = 14.7Hz), 4.02 (2H, q, J = 7.0Hz), 3.63 (1H, dd,
J = 10.0,7.2Hz), 3.52 (1H, m), 3.15 (1H, dd, J = 10.0,5.1Hz),
2.91 (1H, dd, J = 17.0,8.2Hz), 2.42 (1H, dd, J = 17.0,6.2Hz),
1.86 (1H, d, J = 6.8Hz), 1.42 (3H, t, J = 7.0Hz)

Example 140 4-acetylthio-1-
{4- [4 '-(trifluoromethoxy) phenoxy]
Benzyl @ pyrrolidin-2-one 1.85 g of 4- [4 ′-(trifluoromethoxy) phenoxy] benzyl chloride prepared from 4-fluorobenzaldehyde and 4- (trifluoromethoxy) phenol in the same manner as in Example 30. 6.1 mmol) and 1.60 g (9.2 mmol) of 4-trimethylsilyloxypyrrolidin-2-one
To 4-acetylthio-1- {4- [4 '-(trifluoromethoxy) phenoxy] benzyl} pyrrolidine-2
639 mg (25% yield) of -one was obtained as a white powder. Elemental analysis (%): Calculated _{C 20 H 18 NO 4 SF 3} : C, 56.46; H, 4.26; N, 3.2
9; S, 7.54 Found: C, 56.57; H, 4.26; N, 3.4
7; S, 7.51

Example 141 4-Mercapto-1- ｛4
-[4 ′-(Trifluoromethoxy) phenoxy] benzyl} pyrrolidin-2-one By a method similar to that in Example 31, 4-acetylthio-1- {4- [4 ′-(tri Fluoromethoxy) phenoxy] benzyl @ pyrrolidine-2-
From 160 mg (0.40 mmol) of 4-mercapto-1- ｛4
-[4 '-(Trifluoromethoxy) phenoxy] benzyl} pyrrolidin-2-one 102 mg (71% yield) was obtained as a colorless oil. ¹ H-NMR (300 MHz, CDCl ₃ ) δ: 7.23 (2H, d, J = 8.5 Hz), 7.19 (2H, d, J = 8.5 Hz), 7.00 (2H,
d, J = 8.5Hz), 6.97 (2H, d, J = 8.5Hz), 4.49 (1H, d, J = 14.8Hz),
4.40 (1H, d, J = 14.8Hz), 3.66 (1H, dd, J = 10.0,7.2Hz), 3.55
(1H, m), 3.17 (1H, dd, J = 10.0,5.0Hz), 2.92 (1H, dd, J = 17.1,
8.1Hz), 2.43 (1H, dd, J = 17.1,6.1Hz), 1.87 (1H, d, J = 6.7Hz)

Example 142 4-acetylthio-1-
[4- (4′-Nitrophenoxy) benzyl] pyrrolidin-2-one In a manner similar to that in Example 30, 4-hydroxybenzaldehyde was prepared from p-dinitrobenzene.
(4′-nitrophenoxy) benzyl chloride and 4-trimethylsilyloxypyrrolidin-2-one to give 4-acetylthio-1- [4- (4′-nitrophenoxy) benzyl] pyrrolidin-2-one (8% yield). Obtained as a yellow oil. ¹ H-NMR (300 MHz, CDCl ₃ ) δ: 8.21 (2H, d, J = 9.2 Hz), 7.30 (2H, d, J = 8.5 Hz), 7.06 (2H,
d, J = 8.5Hz), 7.02 (2H, d, J = 9.2Hz), 4.48 (2H, s), 4.08 (1H,
m), 3.80 (1H, dd, J = 10.6,7.6Hz), 3.21 (1H, dd, J = 10.6,5.0H
z), 2.93 (1H, dd, J = 17.4,9.0Hz), 2.45 (1H, dd, J = 17.4,6.1H
z), 2.34 (3H, s)

Example 143 4-Mercapto-1- [4
-(4'-nitrophenoxy) benzyl] pyrrolidine-
2-One In the same manner as in Example 31, 5-2.0 mg (0.13 mmol) of 4-acetylthio-1- [4- (4′-nitrophenoxy) benzyl] pyrrolidin-2-one obtained in Example 142.
From l), 34.0 mg (yield 73%) of 4-mercapto-1- [4- (4′-nitrophenoxy) benzyl] pyrrolidin-2-one was obtained as a yellow oil. ¹ H-NMR (300 MHz, CDCl ₃ ) δ: 8.21 (2H, d, J = 9.2 Hz), 7.32
(2H, d, J = 8.5 Hz), 7.06 (2H, d,
J = 8.5 Hz), 7.01 (2H, d, J = 9.2H)
z), 4.54 (1H, d, J = 14.9 Hz);
42 (1H, d, J = 14.9 Hz), 3.69 (1
H, dd, J = 10.0, 7.2 Hz), 3.58 (1
H, m), 3.20 (1H, dd, J = 10.0, 5.
0 Hz), 2.94 (1H, dd, J = 17.1, 8.
1 Hz), 2.44 (1H, dd, J = 17.1,6.
0 Hz), 1.89 (1H, d, J = 6.6 Hz)

Example 144 4-acetylthio-1-
[4- (4′-acetaminophenoxy) benzyl] pyrrolidin-2-one (1) 4 prepared by the same method as in Example 142.
-Hydroxy-1- [4- (4'-nitrophenoxy)
[Benzyl] pyrrolidin-2-one 1.86 g (5.7 m
mol) was dissolved in 40 ml of pyridine, 10 ml of acetic anhydride was added, and the mixture was stirred at room temperature for 14 hours. The reaction solution was concentrated under reduced pressure, water was added, and the mixture was extracted twice with ethyl acetate. The obtained organic layer was washed with water and saturated saline, and dried over anhydrous sodium sulfate. After concentration under reduced pressure, the residue was triturated with hexane-ethyl acetate, and 1.80 g of 4-acetoxy-1- [4- (4′-nitrophenoxy) benzyl] pyrrolidin-2-one was obtained.
(85% yield) as a brown powder. ¹ H-NMR (300 MHz, CDCl ₃ ) δ: 8.22 (2H, d, J = 9.2 Hz), 7.29 (2H, d, J = 8.5 Hz), 7.07 (2H,
d, J = 8.5Hz), 7.02 (2H, d, J = 9.2Hz), 5.29 (1H, m), 4.51 (2H,
s), 3.68 (1H, dd, J = 11.5,6.0Hz), 3.28 (1H, dd, J = 11.5,2.0H
z), 2.85 (1H, dd, J = 17.9,7.2Hz), 2.57 (1H, dd, J = 17.9,2.5H
z), 2.06 (3H, s) (2) 4-acetoxy-1- [4- (4′-nitrophenoxy) benzyl] pyrrolidin-2-one 1.80 g (4.9 m
mol) was dissolved in a mixed solvent of 100 ml of methanol and 10 ml of tetrahydrofuran, and 90.0 mg of 10% palladium on carbon was added. The reaction solution was filtered and concentrated under reduced pressure.
1.67 g (90% yield) of acetoxy-1- [4- (4'-aminophenoxy) benzyl] pyrrolidin-2-one hydrochloride was obtained as a white powder. ¹ H-NMR (300 MHz, CD ₃ OD) δ: 7.35 (2H, d, J = 8.9 Hz), 7.30 (2H, d, J = 8.6 Hz), 7.11 (2H,
d, J = 8.9Hz), 7.02 (2H, d, J = 8.6Hz), 5.27 (1H, m), 4.52 (1H,
d, J = 14.9Hz), 4.44 (1H, d, J = 14.9Hz), 3.73 (1H, dd, J = 11.7,
5.7Hz), 3.33 (1H, dd, J = 11.7,1.5Hz), 2.90 (1H, dd, J = 18.0,
(7.1Hz), 2.47 (1H, dd, J = 18.0,1.8Hz), 2.02 (3H, s) (3) 4-acetoxy-1- [4- (4'-aminophenoxy) benzyl] pyrrolidin-2-one Hydrochloride 324m
g (0.86 mmol) was dissolved in chloroform (10 ml), triethylamine (360 μl (2.6 mmol), acetyl chloride (122 μl (1.7 mmol)).
l) was added and the mixture was stirred at room temperature for 14 hours. The reaction solution was concentrated under reduced pressure, ethyl acetate was added, and the mixture was washed with water and saturated saline, and dried over anhydrous sodium sulfate. After concentration under reduced pressure, the residue was subjected to silica gel column chromatography, eluted with ethyl acetate, and 265 mg of 4-acetoxy-1- [4- (4'-acetoaminophenoxy) benzyl] pyrrolidin-2-one (yield 81%) as a white powder. ¹ H-NMR (300 MHz, CDCl ₃ ) δ: 7.46 (2H, d, J = 8.9 Hz), 7.25 (1 H, brs), 7.17 (2 H, d, J = 8.5
Hz), 6.97 (2H, d, J = 8.9Hz), 6.93 (2H, d, J = 8.5Hz), 5.25 (1H,
m), 4.48 (1H, d, J = 15.7 Hz), 4.42 (1H, d, J = 15.7 Hz), 3.63 (1
H, dd, J = 11.6,6.0Hz), 3.24 (1H, dd, J = 11.6,1.9Hz), 2.82 (1
H, dd, J = 17.8,7.2Hz), 2.53 (1H, dd, J = 17.8,2.4Hz), 2.18 (3
H, s), 2.04 (3H, s) (4) 4-acetoxy-1- [4- (4'-acetaminophenoxy) benzyl] pyrrolidin-2-one 265m
g (0.69 mmol) was dissolved in 10 ml of ethanol and 1 ml of chloroform, 330 mg (3.5 mmol) of guanidine hydrochloride and 481 μl (3.5 mmol) of triethylamine were added, and the mixture was stirred at room temperature for 5 days. The reaction solution was concentrated under reduced pressure, ethyl acetate was added, washed with water and saturated saline, and dried over anhydrous sodium sulfate. After concentration under reduced pressure, the residue was triturated with hexane-ethyl acetate,
200 mg of 4-hydroxy-1- [4- (4′-acetaminophenoxy) benzyl] pyrrolidin-2-one (yield 85
%) As a white powder. ¹ H-NMR (300 MHz, CDCl ₃ ) δ: 7.45 (2 H, d, J = 8.9 Hz), 7.19 (2 H, d, J = 8.5 Hz), 7.15 (1 H, b
rs), 6.96 (2H, d, J = 8.9Hz), 6.92 (2H, d, J = 8.5Hz), 4.51 (1H,
m), 4.47 (1H, d, J = 14.9 Hz), 4.40 (1H, d, J = 14.9 Hz), 3.53 (1
H, dd, J = 10.9,5.6Hz), 3.21 (1H, dd, J = 10.9,1.8Hz), 2.75 (1
H, dd, J = 17.4,6.6Hz), 2.44 (1H, dd, J = 17.4,2.3Hz), 2.12 (3
H, s), 2.09 (1H, brs) (5) In the same manner as in Example 30, 159 mg of 4-hydroxy-1- [4- (4′-acetaminophenoxy) benzyl] pyrrolidin-2-one (0.47mmol)
To 4-acetylthio-1- [4- (4'-acetoaminophenoxy) benzyl] pyrrolidin-2-one 190 mg
(46% yield) as a yellow oil. ¹ H-NMR (300 MHz, CDCl ₃ ) δ: 7.46 (2H, d, J = 8.9 Hz), 7.17 (2H, d, J = 8.5 Hz), 7.14 (1H, b
rs), 6.98 (2H, d, J = 8.9Hz), 6.93 (2H, d, J = 8.5Hz), 4.46 (1H,
d, J = 14.7Hz), 4.39 (1H, d, J = 14.7Hz), 4.06 (1H, m), 3.75 (1
H, dd, J = 10.7,7.6Hz), 3.18 (1H, dd, J = 10.7,4.9Hz), 2.92 (1
H, dd, J = 17.4,8.9Hz), 2.42 (1H, dd, J = 17.4,6.0Hz), 2.32 (3
H, s), 2.18 (3H, s)

Example 145 4-Mercapto-1- [4
-(4'-Acetaminophenoxy) benzyl] pyrrolidin-2-one In the same manner as in Example 31, 4-acetylthio-1- [4- (4'-acetoaminophenoxy) benzyl obtained in Example 144 ] 23.0 mg of pyrrolidin-2-one
(0.060 mmol) from 4-mercapto-1- [4- (4 ′
-Acetaminophenoxy) benzyl] pyrrolidine-2
22.0 mg of -one were obtained almost quantitatively as a colorless oil. ¹ H-NMR (300 MHz, CD ₃ OD) δ: 7.52 (2H, d, J = 9.0 Hz), 7.25 (2H, d, J = 8.5 Hz), 6.94 (2H,
d, J = 9.0Hz), 6.94 (2H, d, J = 8.5Hz), 4.48 (1H, d, J = 14.9Hz),
4.37 (1H, d, J = 14.9Hz), 3.73 (1H, dd, J = 10.4,7.2Hz), 3.59
(1H, m), 3.18 (1H, dd, J = 10.4,4.6Hz), 2.92 (1H, dd, J = 17.1,
8.1Hz), 2.35 (1H, dd, J = 17.1,5.4Hz), 2.11 (3H, s), 1.29 (1
H, brs)

Example 146 4-acetylthio-1-
[4- (4'-methylsulfonylaminophenoxy) benzyl] pyrrolidin-2-one (1) 4-hydroxy-1- obtained in Example 144
[4- (4′-Aminophenoxy) benzyl] pyrrolidin-2-one hydrochloride (300 mg, 0.80 mmol) in chloroform 20m
335 μl (2.4 mmol) of triethylamine and 93.0 μl (1.2 mmol) of methanesulfonyl chloride, and added at room temperature.
Stir for 7 hours. The reaction solution was concentrated under reduced pressure, ethyl acetate was added, and the mixture was washed with water and saturated saline, and dried over anhydrous sodium sulfate. After concentration under reduced pressure, the residue was subjected to silica gel column chromatography, eluted with ethyl acetate, and 285 mg of 4-acetoxy-1- [4- (4′-methylsulfonylaminophenoxy) benzyl] pyrrolidin-2-one ( (85% yield) as a pale brown oil. ¹ H-NMR (300 MHz, CDCl ₃ ) δ: 7.23 (2H, d, J = 8.8 Hz), 7.21 (2H, d, J = 8.2 Hz), 6.99 (2H,
d, J = 8.8Hz), 6.96 (2H, d, J = 8.2Hz), 6.55 (1H, brs), 5.27 (1H
H, m), 4.46 (2H, s), 3.64 (1H, dd, J = 11.5,6.0Hz), 3.25 (1H, d
d, J = 11.5,2.0Hz), 3.01 (3H, s), 2.83 (1H, dd, J = 17.8,7.2H
z), 2.55 (1H, dd, J = 17.8, 2.5 Hz), 2.05 (3H, s) (2)
Acetoxy-1- [4- (4′-methylsulfonylaminophenoxy) benzyl] pyrrolidin-2-one 285 mg
(0.50 mmol), 4-acetylthio-1- [4- (4 ′
-Methylsulfonylaminophenoxy) benzyl] pyrrolidin-2-one (59.0 mg, yield 20%) was obtained as a white powder. ¹ H-NMR (300 MHz, CDCl ₃ ) δ: 7.22 (2H, d, J = 8.8 Hz), 7.21 (2H, d, J = 8.6 Hz), 6.99 (2H,
d, J = 8.8Hz), 6.96 (2H, d, J = 8.6Hz), 6.27 (1H, brs), 4.44 (2H
H, s), 4.06 (1H, m), 3.76 (1H, dd, J = 10.7,7.7Hz), 3.18 (1H, d
d, J = 10.7,5.0Hz), 3.01 (3H, s), 2.92 (1H, dd, J = 17.4,9.0H
z), 2.42 (1H, dd, J = 17.4,6.0Hz), 2.32 (3H, s)

Example 147 4-Mercapto-1- [4
-(4'-Methylsulfonylaminophenoxy) benzyl] pyrrolidin-2-one In the same manner as in Example 31, 4-acetylthio-1- [4- (4'-methylsulfonylaminophenoxy) obtained in Example 146. ) Benzyl] pyrrolidin-2-one from 38.0 mg (0.090 mmol) was converted to 4-mercapto-1- [4
-(4'-Methylsulfonylaminophenoxy) benzyl] pyrrolidin-2-one (28.0 mg, yield 79%) was obtained as a white powder. ¹ H-NMR (300 MHz, CDCl ₃ ) δ: 7.22 (2H, d, J = 8.7 Hz), 7.21 (2H, d, J = 9.0 Hz), 6.99 (2H,
d, J = 9.0Hz), 6.96 (2H, d, J = 8.7Hz), 6.33 (1H, s), 4.49 (1H,
d, J = 14.7Hz), 4.40 (1H, d, J = 14.7Hz), 3.66 (1H, dd, J = 10.0,
7.2Hz), 3.55 (1H, m), 3.17 (1H, dd, J = 10.0,5.0Hz), 3.00 (3
H, s), 2.92 (1H, dd, J = 17.1,8.1Hz), 2.42 (1H, dd, J = 17.1,6.
0Hz), 1.87 (1H, d, J = 6.7Hz)

Example 148 4-Acetylthio-1-
[4- (4'-Ethylaminocarbonylaminophenoxy) benzyl] pyrrolidin-2-one (1) 4-hydroxy-1- obtained in Example 144
[4- (4'-Aminophenoxy) benzyl] pyrrolidin-2-one hydrochloride (300 mg, 0.80 mmol) in chloroform 10m
Then, 223 μl (1.6 mmol) of triethylamine and 317 μl (3.2 mmol) of ethyl cyanate were added, and the mixture was stirred at room temperature for 14 hours. The reaction solution was concentrated under reduced pressure, ethyl acetate was added, and the mixture was washed with water and saturated saline, and dried over anhydrous sodium sulfate. After concentration under reduced pressure, the residue was subjected to silica gel column chromatography and eluted with hexane-ethyl acetate (30: 70-0: 100) to give 4-acetoxy-1- (4- (4′-ethylaminocarbonyl). 278 mg (85% yield) of aminophenoxy) benzyl) pyrrolidin-2-one were obtained as a white powder. ¹ H-NMR (300 MHz, CDCl ₃ ) δ: 7.26 (2H, d, J = 8.7 Hz), 7.17 (2H, d, J = 8.4 Hz), 6.93 (2H,
d, J = 8.7Hz), 6.92 (2H, d, J = 8.4Hz), 6.66 (1H, s), 5.26 (1H,
m), 4.91 (1H, brs), 4.45 (2H, s), 3.64 (1H, dd, J = 11.6,6.0H
z), 3.27 (3H, m), 2.82 (1H, dd, J = 17.8,7.2Hz), 2.54 (1H, dd,
J = 17.8, 2.3 Hz), 2.04 (3H, s), 1.16 (3H, t, J = 7.0 Hz) (2) Hereinafter, 4-acetoxy-1- [4- ( 4'-ethylaminocarbonylaminophenoxy) benzyl] pyrrolidin-2-one 27
From 8 mg (0.68 mmol), 4-acetylthio-1- [4-
(4′-Ethylaminocarbonylaminophenoxy) benzyl] pyrrolidin-2-one 107 mg (37% yield) was obtained as a white powder. ¹ H-NMR (300 MHz, CDCl ₃ ) δ: 7.26 (2H, d, J = 8.8 Hz), 7.18 (2H, d, J = 8.5 Hz), 6.97 (2H,
d, J = 8.8Hz), 6.94 (2H, d, J = 8.5Hz), 6.29 (1H, brs), 4.66 (1
H, brt), 4.46 (1H, d, J = 14.8Hz), 4.39 (1H, d, J = 14.8Hz), 4.0
6 (1H, m), 3.76 (1H, dd, J = 10.6,7.5Hz), 3.30 (2H, m), 3.17 (1
H, dd, J = 10.6,5.0Hz), 2.92 (1H, dd, J = 17.4,8.9Hz), 2.42 (1
H, dd, J = 17.4,6.0Hz), 2.32 (3H, s), 1.16 (3H, t, J = 7.2Hz)

Example 149 4-Mercapto-1- [4
-(4'-ethylaminocarbonylaminophenoxy)
Benzyl] pyrrolidin-2-one In the same manner as in Example 31, 4-acetylthio-1- [4- (4'-ethylaminocarbonylaminophenoxy) benzyl] pyrrolidine- obtained in Example 148.
From 2-7.0 mg (0.060 mmol) of 2-one, 4-mercapto-1
6.00 mg of-[4- (4'-ethylaminocarbonylaminophenoxy) benzyl] pyrrolidin-2-one (yield 26
%) As a pale brown oil. ¹ H-NMR (300 MHz, CDCl ₃ ) δ: 7.26 (2H, d, J = 8.7 Hz), 7.18 (2H, d, J = 8.5 Hz), 6.95 (2H,
d, J = 8.7Hz), 6.93 (2H, d, J = 8.5Hz), 6.47 (1H, s), 4.78 (1H,
t, J = 5.7Hz), 4.46 (1H, d, J = 14.8Hz), 4.39 (1H, d, J = 14.8H
z), 3.66 (1H, dd, J = 10.1,7.3Hz), 3.54 (1H, m), 3.29 (2H, qd,
J = 7.1,5.7Hz), 3.17 (1H, dd, J = 10.1,5.0Hz), 2.91 (1H, dd, J
= 17.1,8.1Hz), 2.42 (1H, dd, J = 17.1,6.1Hz), 1.87 (1H, d, J =
6.7Hz), 1.15 (3H, t, J = 7.1Hz)

Example 150 4-acetylthio-1-
(2-nitro-4-phenoxybenzyl) pyrrolidine-2
-On (1) 4-chloro-2-nitrobenzaldehyde 5.00
g (27 mmol) was dissolved in 50 ml of pyridine, and 3.80 g (4
0 mmol) and 7.40 g (54 mmol) of potassium carbonate, and added at 100 ° C.
For 2.5 hours. Thereafter, 5.30 g of copper (II) oxide (67 mm
ol) and heated at 120 ° C. for 15.5 hours. The reaction solution was concentrated under reduced pressure, ethyl acetate was added, and the insoluble material was removed by filtration. The filtrate was washed with a saturated aqueous solution of sodium carbonate, water, and a saturated saline solution, and dried over anhydrous sodium sulfate. After concentration under reduced pressure, the residue was subjected to silica gel column chromatography, eluted with hexane: ethyl acetate (97: 3), and 4.80 g (yield 73%) of 2-nitro-4-phenoxybenzaldehyde was obtained as a yellow oil. As obtained. ¹ H-NMR (300 MHz, CDCl ₃ ) δ: 10.48 (1 H, s), 7.88 (1 H, d, J = 8.4 Hz), 7.45 (1 H, d, J = 7.5 H)
z), 7.43 (1H, d, J = 7.5Hz), 7.25 (1H, dd, J = 7.4,7.4Hz), 7.14
(1H, dd, J = 8.4,1.8Hz), 7.10 (2H, d, J = 8.7Hz), 7.10 (2H, d, J
= 8.7 Hz), 6.89 (1H, d, J = 1.8 Hz) (2) In the same manner as in Example 30, 2-acetyl-4-phenoxybenzyl chloride was converted to 4-acetylthio-1- (2-nitro -4-phenoxybenzyl) pyrrolidin-2-one (11% yield) was obtained as a colorless oil. ¹ H-NMR (300 MHz, CDCl ₃ ) δ: 7.39 (1 H, d, J = 8.2 Hz), 7.35 (1 H, d, J = 7.8 Hz), 7.27 (1 H,
d, J = 7.5Hz), 7.15 (1H, ddd, J = 7.5,7.5,0.5Hz), 7.08 (1H, d
d, J = 8.2,2.0Hz), 6.96 (2H, dd, J = 7.8,0.5Hz), 6.84 (1H, d, J
= 2.0Hz), 4.51 (2H, s), 4.02 (1H, m), 3.81 (1H, dd, J = 10.7,7.
6Hz), 3.23 (1H, dd, J = 10.7,4.9Hz), 2.83 (1H, dd, J = 17.4,8.
9Hz), 2.34 (1H, dd, J = 17.4,6.0Hz), 2.32 (3H, s)

Example 151 4-acetylthio-1-
(3-nitro-4-phenoxybenzyl) pyrrolidine-2
-On (1) 1.90 g (40 mmol) of sodium hydride (60% oil) was dispersed in 20 ml of N, N-dimethylformamide and stirred at room temperature for 10 minutes. 3.80 g (40 mmol) of phenol was added to N, N-
A solution dissolved in 20 ml of dimethylformamide was added, and the mixture was further stirred at room temperature for 10 minutes. To this solution was added 4-chloro-
7.40 g (40 mmol) of 3-nitrobenzaldehyde was added, and the mixture was heated with stirring at room temperature for 10 minutes and further at 120 ° C. for 1 hour. Ethyl acetate was added to the reaction solution, washed with water and saturated saline, and dried over anhydrous sodium sulfate. After concentration under reduced pressure, the residue was subjected to silica gel column chromatography and eluted with hexane-ethyl acetate (90:10) to give 3-nitro-4-phenoxybenzaldehyde (6.50 g, yield 67%) as a yellow oil. As obtained. ¹ H-NMR (300 MHz, CDCl ₃ ) δ: 9.97 (1H, s), 8.44 (1H, d, J =
2.1 Hz), 7.97 (1H, dd, J = 8.8,
2.1Hz), 7.48 (2H, d, J = 7.7H)
z), 7.45 (1H, d, J = 7.4 Hz), 7.3
0 (1H, dd, J = 7.4, 7.4 Hz), 7.14
(1H, d, J = 7.7 Hz), 7.05 (1H, d,
(J = 8.8 Hz) (2) Hereinafter, in the same manner as in Example 30, 1.04 g of 3-nitro-4-phenoxybenzyl chloride
(3.9 mmol) to 4-acetylthio-1- (3-
344 mg (20% yield) of nitro-4-phenoxybenzyl) pyrrolidin-2-one were obtained as a pale yellow oil. ¹ H-NMR (300 MHz, CDCl ₃ ) δ: 7.82 (1 H, d, J = 2.1 Hz), 7.41 (1 H, d, J = 8.6 Hz), 7.38 (2 H,
d, J = 7.9Hz), 7.20 (1H, dd, J = 7.4,7.4Hz), 7.06 (2H, d, J = 7.9
Hz), 6.98 (1H, d, J = 8.6Hz), 4.55 (1H, d, J = 15.1Hz), 4.40 (1
H, d, J = 15.1Hz), 4.08 (1H, m), 3.81 (1H, dd, J = 10.5,7.4Hz),
3.22 (1H, dd, J = 10.5,4.7Hz), 2.93 (1H, dd, J = 17.5,8.9Hz),
2.44 (1H, dd, J = 17.5,5.7Hz), 2.34 (3H, s)

Example 152 4-Acetylthio-1-
(3-Methylsulfonylamino-4-phenoxybenzyl) pyrrolidin-2-one Using 3-nitro-4-phenoxybenzaldehyde synthesized in Example 151, as in Example 146,
-Acetylthio-1- (3-methylsulfonylamino-
4-phenoxybenzyl) pyrrolidin-2-one (yield 5
%) As a colorless oil. ¹ H-NMR (300 MHz, CDCl ₃ ) δ: 7.49 (1 H, d, J = 1.9 Hz), 7.40 (1 H, d, J = 7.9 Hz), 7.36 (1 H,
d, J = 8.1Hz), 7.19 (1H, dd, J = 7.9,7.9Hz), 7.00 (2H, d, J = 8.1
Hz), 6.97 (1H, dd, J = 8.3,1.9Hz), 6.85 (1H, d, J = 8.3Hz), 6.8
5 (1H, brs), 4.44 (2H, s), 4.07 (1H, m), 3.79 (1H, dd, J = 10.6,
7.5Hz), 3.22 (1H, dd, J = 10.6,5.0Hz), 3.01 (3H, s), 2.92 (1
H, dd, J = 17.4,9.0Hz), 2.43 (1H, dd, J = 17.4,6.1Hz), 2.33 (3
H, s)

Example 153 4-Mercapto-1- (3
-Methylsulfonylamino-4-phenoxybenzyl)
Pyrrolidin-2-one 4-acetylthio-1- (3-methylsulfonylamino-4-phenoxybenzyl) pyrrolidin-2-one obtained in Example 152 in the same manner as in Example 31.
From 0 mg (0.090 mmol), 34.0 mg (yield 97%) of 4-mercapto-1- (3-methylsulfonylamino-4-phenoxybenzyl) pyrrolidin-2-one was obtained as a colorless oil. ¹ H-NMR (300 MHz, CDCl ₃ ) δ: 7.50 (1 H, d, J = 2.0 Hz), 7.39 (1 H, d, J = 7.5 Hz), 7.36 (1 H,
d, J = 8.1Hz), 7.18 (1H, dd, J = 7.5,7.5Hz), 6.99 (3H, m), 6.86
(1H, d, J = 8.3Hz), 6.85 (1H, brs), 4.51 (1H, d, J = 15.0Hz), 4.
40 (1H, d, J = 15.0Hz), 3.71 (1H, dd, J = 10.1,7.2Hz), 3.57 (1
H, m), 3.22 (1H, dd, J = 10.1,5.0Hz), 3.01 (3H, s), 2.93 (1H, d
d, J = 17.2,8.2Hz), 2.43 (1H, dd, J = 17.2,6.0Hz), 1.91 (1H,
d, J = 6.9Hz)

Example 154 4-Acetylthio-1-
(4-phenylthiobenzyl) pyrrolidin-2-one 1.61 g (6.9 mmol) of 4-phenylthiobenzyl chloride prepared from 4-fluorobenzaldehyde and thiophenol in the same manner as in Example 30 and 4-trimethylsilyloxypyrrolidine- From 1.80 g (10 mmol) of 2-one to 4
716 mg (29% yield) of -acetylthio-1- (4-phenylthiobenzyl) pyrrolidin-2-one was obtained as a brown oil. Elemental analysis (%): C ₁₉ H ₁₉ NO ₂ S ₂ Calculated: C, 63.83; H, 5.36; N, 3.9
2: S, 17.94 Found: C, 63.86; H, 5.11; N, 3.9.
9; S, 17.77

Example 155 4-Mercapto-1- (4
-Phenylthiobenzyl) pyrrolidin-2-one By a method similar to that in Example 31, 4-acetylthio-1- (4-phenylthiobenzyl) obtained in Example 154
From 130 mg (0.36 mmol) of pyrrolidin-2-one, 4-mercapto-1- (4-phenylthiobenzyl) pyrrolidine-
69.0 mg of 2-one (61% yield) was obtained as a colorless oil. ¹ H-NMR (300 MHz, CDCl ₃ ) δ: 7.38-7.26 (7H, m), 7.17 (2H, d, J = 8.3 Hz), 4.47 (1H, d, J =
14.9Hz), 4.40 (1H, d, J = 14.9Hz), 3.64 (1H, dd, J = 10.0,7.2H
z), 3.54 (1H, m), 3.16 (1H, dd, J = 10.0,5.0Hz), 2.92 (1H, dd,
J = 17.1,8.1Hz), 2.42 (1H, dd, J = 17.1,6.1Hz), 1.86 (1H, d, J
= 6.7Hz),

Example 156 4-Acetylthio-1-
[4- (2′-pyridyloxy) benzyl] pyrrolidin-2-one In a manner similar to that in Example 30, prepared from 4-fluorobenzaldehyde and 2-hydroxypyridine.
420 mg of (2'-pyridyloxy) benzyl chloride (1.9 m
mol) and 494 mg (2.9 mmol) of 4-trimethylsilyloxypyrrolidin-2-one from 4-acetylthio-1- [4-
(2′-pyridyloxy) benzyl] pyrrolidine-2-
47.0 mg (yield 7%) were obtained as a pale yellow powder. ¹ H-NMR (300 MHz, CDCl ₃ ) δ: 8.20 (1 H, dd, J = 5.0, 1.9 Hz), 7.70 (1 H, ddd, J = 8.8, 6.9,
1.9Hz), 7.26 (2H, d, J = 8.5Hz), 7.11 (2H, d, J = 8.5Hz), 7.00
(1H, dd, J = 6.9,5.0Hz), 6.92 (1H, d, J = 8.8Hz), 4.50 (1H, d, J
= 14.7Hz), 4.42 (1H, d, J = 14.7Hz), 4.07 (1H, m), 3.78 (1H, d
d, J = 10.6,7.6Hz), 3.21 (1H, dd, J = 10.6,5.0Hz), 2.93 (1H, d
d, J = 17.4,9.0Hz), 2.43 (1H, dd, J = 17.4,6.0Hz), 2.32 (3H,
s)

Example 157 4-Acetylthio-1-
[4- (3'-thienyloxy) benzyl] pyrrolidin-2-one (1) 7.50 g (61 mmo) of 4-hydroxybenzaldehyde
l) and 3-bromothiophene 10.0 g (61 mmol), potassium carbonate 3.40 g (25 mmol), and copper powder 500 mg, and mixed with no solvent 140
Heated at C for 44 hours. The reaction mixture was poured into an aqueous sodium hydroxide solution, and extracted three times with ethyl acetate. The obtained organic layer was washed with a saturated aqueous sodium carbonate solution, water, and saturated saline, and dried over anhydrous sodium sulfate. After concentration under reduced pressure, the residue was subjected to silica gel column chromatography, and eluted with hexane: ethyl acetate (70:30).
1.70 g of (3′-thienyloxy) benzaldehyde (yield
14%) as a yellow oil. ¹ H-NMR (300 MHz, CDCl ₃ ) δ: 9.93 (1 H, s), 7.85 (2 H, d, J = 8.6 Hz), 7.33 (1 H, dd, J = 5.1,
3.3Hz), 7.11 (2H, d, J = 8.6Hz), 6.87 (1H, dd, J = 5.1,1.4Hz),
6.84 (1H, dd, J = 3.3, 1.4 Hz) (2) Hereinafter, 4-
1.30 g of (3′-thienyloxy) benzyl chloride (5.8 m
mol) and 1.20 g (7.0 mmol) of 4-trimethylsilyloxypyrrolidin-2-one from 4-acetylthio-1- [4-
(3′-thienyloxy) benzyl] pyrrolidine-2-
521 mg (26% yield) were obtained as a brown oil. ¹ H-NMR (300 MHz, CDCl ₃ ) δ: 7.26 (1H, dd, J = 5.2, 3.3 Hz), 7.18 (2H, d, J = 8.6 Hz), 7.00
(2H, d, J = 8.6Hz), 6.85 (1H, dd, J = 5.2,1.5Hz), 6.62 (1H, dd,
J = 3.3,1.5Hz), 4.46 (1H, d, J = 14.7Hz), 4.39 (1H, d, J = 14.7H
z), 4.05 (1H, m), 3.75 (1H, dd, J = 10.6,7.6Hz), 3.16 (1H, dd,
J = 10.6,5.0Hz), 2.92 (1H, dd, J = 17.4,9.0Hz), 2.42 (1H, dd,
J = 17.4,6.0Hz), 2.32 (3H, s)

Example 158 4-Mercapto-1- [4
-(3'-thienyloxy) benzyl] pyrrolidine-2
In a manner similar to that in Example 31, 100 mg (0.30 mmol) of 4-acetylthio-1- [4- (3′-thienyloxy) benzyl] pyrrolidin-2-one obtained in Example 157.
From 74.0 mg of 4-mercapto-1- [4- (3′-thienyloxy) benzyl] pyrrolidin-2-one (yield 81)
%) As a colorless oil. ¹ H-NMR (300 MHz, CDCl ₃ ) δ: 7.27 (1H, dd, J = 5.2, 3.2 Hz), 7.20 (2H, d, J = 8.6 Hz), 7.01
(2H, d, J = 8.6Hz), 6.84 (1H, dd, J = 5.2,1.5Hz), 6.63 (1H, dd,
J = 3.2,1.5Hz), 4.47 (1H, d, J = 14.7Hz), 4.40 (1H, d, J = 14.7H
z), 3.65 (1H, dd, J = 10.0,7.2Hz), 3.54 (1H, m), 3.16 (1H, dd,
J = 10.0,5.0Hz), 2.92 (1H, dd, J = 17.1,8.1Hz), 2.42 (1H, dd,
J = 17.1,6.1Hz), 1.86 (1H, d, J = 6.7Hz)

Example 159 4-Acetylthio-1-
(4-benzylbenzyl) pyrrolidin-2-one (1) After dissolving 5.07 g (22.4 mmol) of 4-benzoylbenzoic acid in 50 ml of N, N-dimethylformamide, 3.10 g (22.4 mmol) of potassium carbonate and 2.79 of methyl iodide ml (44.8 mmol)
Was added, and the mixture was stirred at room temperature for 14 hours. After concentrating the reaction solution under reduced pressure, ethyl acetate was added, and the mixture was washed with water and saturated saline, and then dried over anhydrous sodium sulfate. After concentration under reduced pressure,
Crystallization from hexane-ethyl acetate gave 4-benzoylbenzoic acid methyl ester (4.28 g, yield 80%) as colorless needles. ¹ H-NMR (300 MHz, CDCl ₃ ) δ: 8.15 (2H, d, J = 8.3 Hz), 7.84 (2H, d, J = 8.3 Hz), 7.81 (2H,
m), 7.62 (1H, m), 7.50 (2H, m), 3.97 (3H, s) (2) To a mixture of 24 ml of chloroform and 40 ml of trifluoroacetic acid was added 1.89 g (49.9 mmol) of sodium borohydride. After that, 2.00 g of 4-benzoylbenzoic acid methyl ester (8.
32 mmol), and the mixture was stirred at room temperature for 5 hours. Further, 945 mg (25.0 mmol) of sodium borohydride was added, and the mixture was stirred for 16 hours. After concentrating the reaction solution under reduced pressure, ethyl acetate was added, and the mixture was washed with saturated aqueous sodium hydrogen carbonate, water, and saturated saline, and then dried over anhydrous sodium sulfate. After concentration under reduced pressure, the residue was subjected to silica gel column chromatography, and the fraction eluted with hexane: ethyl acetate (100: 0-90: 10) was concentrated under reduced pressure to give 1.81 g of methyl 4-benzylbenzoate (96% yield). %) As a colorless oil. ¹ H-NMR (300 MHz, CDCl ₃ ) δ: 7.95 (2H, d, J = 8.3 Hz), 7.15-7.33 (7H, m), 4.03 (2H, s),
3.89 (3H, s) (3) 1.76 g of methyl 4-benzylbenzoate (7.
After dissolving 78 mmol) in 40 ml of diethyl ether, 591 mg (15.6 mmol) of lithium aluminum hydride was added, and the mixture was stirred at room temperature for 1 hour. Water was added to the reaction mixture under ice-cooling, and the mixture was extracted three times with ethyl acetate. The ethyl acetate layer was washed twice with water and once with saturated saline, and then dried over anhydrous sodium sulfate. The mixture was concentrated under reduced pressure to obtain 1.57 g (quantitative yield) of 4-benzylbenzyl alcohol as a colorless oil. ¹ H-NMR (300 MHz, CDCl ₃ ) δ: 7.28 (4H, m), 7.19 (5H, m), 4.65 (2H, s), 3.98 (2H, s) (4) 1.52 g of 4-benzylbenzyl alcohol ( 7.67mm
ol) in chloroform, pyridine 620 μl under ice cooling
(7.67 mmol), and 615 μl of thionyl chloride (8.44 mmol)
Was added dropwise over 30 minutes, followed by stirring at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure, ethyl acetate was added, washed with water and saturated saline, and dried over anhydrous sodium sulfate. It was concentrated under reduced pressure to obtain 1.68 g (quantitative yield) of 4-benzylbenzyl chloride as a colorless oil. ¹ H-NMR (300 MHz, CDCl ₃ ) δ: 7.29 (4H, m), 7.19 (5H, m), 4.56 (2H, s), 3.98 (2H, s) (5) As in Example 30, 4 -Benzylbenzyl chloride 1.60 g (7.38 mmol), 4-trimethylsilyloxypyrrolidin-2-one 1.28 g (7.38 mmol), powdered potassium hydroxide 414 mg (7.38 mmol), 4-hydroxy-
1- (4-benzylbenzyl) pyrrolidin-2-one 51
0 mg (25% yield) was obtained as a white powder. ¹ H-NMR (300 MHz, CDCl ₃ ) δ: 7.28 (2 H, m), 7.13-7.23 (7 H, m), 4.47 (1 H, m), 4.44 (2 H, m
s), 3.95 (2H, s), 3.49 (1H, dd, J = 10.9, 5.7 Hz), 3.18 (1H, dd,
J = 10.9,1.9Hz), 2.73 (1H, dd, J = 17.3,6.4Hz), 2.42 (1H, dd,
J = 17.3,2.3Hz), 2.14 (1H, brs) (6) 460 mg (1.63 mmol) of 4-hydroxy-1- (4-benzylbenzyl) pyrrolidin-2-one, 454 μl (3.26 mmol) of triethylamine, methanesulfonyl Chloride
252 μl (3.26 mmol) to 4-methanesulfonyloxy-1
-(4-benzylbenzyl) pyrrolidin-2-one 534m
g (yield 91%) was obtained as a white powder. ¹ H-NMR (300 MHz, CDCl ₃ ) δ: 7.29 (2H, m), 7.13-7.23 (7H, m), 5.26 (1H, m), 4.48 (1H,
d, J = 14.9Hz), 4.43 (1H, d, J = 14.9Hz), 3.96 (2H, s), 3.63 (1
H, dd, J = 11.7,5.7Hz), 3.49 (1H, dd, J = 11.7,2.1Hz), 2.95 (3
H, s), 2.86 (1H, dd, J = 18.1,6.8Hz), 2.70 (1H, dd, J = 18.1,2.
(6 Hz) (7) 500 mg (1.39 mmol) of 4-methanesulfonyloxy-1- (4-benzylbenzyl) pyrrolidin-2-one
Then, 331 mg (70% yield) of 4-acetylthio-1- (4-benzylbenzyl) pyrrolidin-2-one was obtained as a white powder from 318 mg (2.78 mmol) of potassium thioacetate. ¹ H-NMR (300 MHz, CDCl ₃ ) δ: 7.29 (2H, m), 7.13-7.23 (7
H, m), 4.42 (2H, s), 4.04 (1H,
m), 3.96 (2H, s), 3.72 (1H, dd,
J = 10.9, 7.5 Hz), 3.15 (1H, dd,
J = 10.9, 5.1 Hz), 2.91 (1H, dd,
J = 17.3, 9.1 Hz), 2.41 (1H, dd,
J = 17.3, 6.0 Hz), 2.30 (3H, s)

Example 160 4-Mercapto-1- (4
-Benzylbenzyl) pyrrolidin-2-one 4-acetylthio-1- (4-
(Benzylbenzyl) pyrrolidin-2-one 200 mg (0.589 mm
ol) was treated as in Example 31 to give 4-mercapto-
1- (4-benzylbenzyl) pyrrolidin-2-one 147m
g (yield 84%) was obtained as a white powder. ¹ H-NMR (300 MHz, CDCl ₃ ) δ: 7.29 (2H, m), 7.13-7.23 (7H, m), 4.43 (2H, s), 3.97 (2H,
s), 3.62 (1H, dd, J = 9.8,7.2Hz), 3.51 (1H, m), 3.14 (1H, dd, J
= 9.8,5.1Hz), 2.90 (1H, dd, J = 17.0,8.3Hz), 2.41 (1H, dd, J =
17.0,6.2Hz), 1.85 (1H, d, J = 6.8Hz)

Example 161 4-acetylthio-1-
(4-benzoylbenzyl) pyrrolidin-2-one (1) After dissolving 2.00 g (8.32 mol) of methyl 4-benzoylbenzoate obtained in Example 159 in 25 ml of nitromethane, 9.10 ml (83.2 mmol) of trimethyl orthoformate was dissolved. ), 3.37 ml (83.2 mmol) of anhydrous methanol, 147 μl (1.66 mmol) of trifluoromethanesulfonic acid, and the mixture was heated under reflux for 4 hours with stirring.
3.37 ml (83.2 mmol) of anhydrous methanol was added, and the mixture was heated under reflux with stirring for 16 hours. After adding saturated aqueous sodium hydrogen carbonate to the reaction solution, the mixture was extracted twice with ethyl acetate.
The extract was washed once with saturated saline and dried over anhydrous sodium sulfate. After concentration under reduced pressure, the residue was subjected to silica gel column chromatography to obtain 4-methoxycarbonylbenzophenone dimethyl acetal with hexane: ethyl acetate (95: 5), and the raw material methyl ester was obtained with hexane: ethyl acetate (90:10). 680 mg was recovered. The same reaction was repeated for the recovered raw materials to obtain 2.32 g (97% yield) of 4-methoxycarbonylbenzophenone dimethyl acetal as a colorless oily substance. ¹ H-NMR (300 MHz, CDCl ₃ ) δ: 7.96 (2H, d, J = 8.7 Hz), 7.58 (2H, d, J = 8.7 Hz), 7.48 (2H,
m), 7.19-7.33 (3H, m), 3.88 (3H, s), 3.13 (6H, s) ), To obtain 2.05 g (quantitative yield) of 4-hydroxymethylbenzophenone dimethyl acetal as a colorless oil in the same manner as in Example 159. ¹ H-NMR (300 MHz, CDCl ₃ ) δ: 7.50 (4H, m), 7.29 (4H, m), 7.21 (1H, m), 4.65 (2H, s), 3.1
3 (6H, s) (3) 2.00 g (7.74 mmol) of 4-hydroxymethylbenzophenone dimethyl acetal, 626 μl of pyridine (7.74 mmol)
l) and 621 μl (8.51 mmol) of thionyl chloride in Example 159
And treated with 4-benzoylbenzyl chloride 93
0 mg (52% yield) was obtained as a colorless oil. ¹ H-NMR (300 MHz, CDCl ₃ ) δ: 7.81 (4H, m), 7.59 (1 H, m), 7.51 (4H, m), 4.65 (2H, s) (4) 900 mg of 4-benzoylbenzyl chloride (3.90 mm
ol), 535 mg (3.90 mmol) of 4-trimethylsilyloxypyrrolidin-2-one, 219 mg of powdered potassium hydroxide
(3.90 mmol), 200 mg (17% yield) of 4-hydroxy-1- (4-benzoylbenzyl) pyrrolidin-2-one was obtained as a brown powder. ¹ H-NMR (300 MHz, CDCl ₃ ) δ: 7.79 (4 H, m), 7.60 (1 H, m), 7.48 (2 H, m), 7.36 (2 H, d, J = 8.
3Hz), 4.64 (1H, d, J = 15.3Hz), 4.55 (1H, m), 4.51 (1H, d, J = 1
5.3Hz), 3.57 (1H, dd, J = 10.9,5.7Hz), 3.24 (1H, dd, J = 10.9,
2.1Hz), 2.78 (1H, dd, J = 17.3,6.4Hz), 2.47 (1H, dd, J = 17.3,
2.3Hz), 1.99 (1H, brs) (5) 4-hydroxy-1- (4-benzoylbenzyl) pyrrolidin-2-one 180 mg (0.609 mmol), triethylamine 170 μl (1.22 mmol), methanesulfonyl chloride
94.3 μl (1.22 mmol) to 4-methanesulfonyloxy-
1- (4-benzoylbenzyl) pyrrolidin-2-one
249 mg (quantitative yield) were obtained as a colorless oil. ¹ H-NMR (300 MHz, CDCl ₃ ) δ: 7.79 (4 H, m), 7.61 (1 H, m), 7.49 (2 H, m), 7.35 (2 H, d, J = 7.
9Hz), 5.32 (1H, m), 4.61 (1H, d, J = 15.1Hz), 4.55 (1H, d, J = 1
5.1Hz), 3.71 (1H, dd, J = 11.9,5.9Hz), 3.57 (1H, dd, J = 11.9,
1.9Hz), 3.04 (3H, s), 2.91 (1H, dd, J = 18.1,6.8Hz), 2.75 (1H
H, dd, J = 18.1,2.5Hz) (6) 227 mg (0.609 mmo) of 4-methanesulfonyloxy-1- (4-benzoylbenzyl) pyrrolidin-2-one
l) and potassium thioacetate (140 mg, 1.23 mmol) from 4-acetylthio-1- (4-benzoylbenzyl) pyrrolidine-2
138 mg (64% yield) of -one was obtained as a colorless oil. ¹ H-NMR (300 MHz, CDCl ₃ ) δ: 7.80 (4 H, m), 7.61 (1 H, m), 7.49 (2 H, m), 7.35 (2 H, d, J = 8.
3Hz), 4.61 (1H, d, J = 15.1Hz), 4.48 (1H, d, J = 15.1Hz), 4.09
(1H, m), 3.80 (1H, dd, J = 10.6,7.5Hz), 3.21 (1H, dd, J = 10.6,
4.9Hz), 2.96 (1H, dd, J = 17.5,9.9Hz), 2.46 (1H, dd, J = 17.5,
5.9Hz), 2.32 (3H, s)

Example 162 4-Mercapto-1- (4
-Benzoylbenzyl) pyrrolidin-2-one 4-acetylthio-1- (4-
Benzoylbenzyl) pyrrolidin-2-one 108 mg (0.306
mmol) was treated in the same manner as in Example 31 to give 4-mercapto-1- (4-benzoylbenzyl) pyrrolidin-2-one.
77.2 mg (81% yield) were obtained as a colorless oil. ¹ H-NMR (300 MHz, CDCl ₃ ) δ: 7.80 (4 H, m), 7.60 (1 H, m), 7.49 (2 H, m), 7.37 (2 H, d, J = 8.
3 Hz), 4.61 (1H, d, J = 15.1 Hz), 4.51 (1H, d, J = 15.1 Hz), 3.69
(1H, dd, J = 10.0,7.2Hz), 3.59 (1H, m), 3.20 (1H, dd, J = 10.0,
4.9Hz), 2.95 (1H, dd, J = 17.2,8.1Hz), 2.45 (1H, dd, J = 17.2,
6.9Hz), 1.90 (1H, d, J = 6.4Hz)

Example 163 4-Acetylthio-1-
(4-phenoxymethylbenzyl) pyrrolidin-2-one (1) 4-hydroxymethylbenzoic acid methyl ester
After dissolving 5.00 g (30.1 mmol) in 75 ml of chloroform, 2.43 ml (30.1 mmol) of pyridine was added under ice-cooling, and 10 ml of a chloroform solution of 2.42 ml (33.1 mmol) of thionyl chloride was added with stirring.
The mixture was added dropwise over 0 minutes, and the mixture was stirred for 30 minutes under ice cooling and for 2 hours at room temperature. The reaction solution was concentrated under reduced pressure, and ethyl acetate was added.
The extract was washed once with saturated saline and dried over anhydrous sodium sulfate. After concentration under reduced pressure, the residue was dissolved in 75 ml of N, N-dimethylformamide, 2.83 g (30.1 mmol) of phenol and 4.16 g (30.1 mmol) of potassium carbonate were added, and the mixture was stirred at room temperature for 40 hours. After the reaction solution was concentrated under reduced pressure, ethyl acetate was added, and the mixture was washed twice with water and once with a saturated saline solution, and then dried over anhydrous sodium sulfate. After concentration under reduced pressure, the residue was subjected to silica gel column chromatography. The fraction eluted with hexane: ethyl acetate (95: 5) was concentrated under reduced pressure, and crystallized from hexane-ethyl acetate to give 5.35 g of methyl 4-phenoxymethylbenzoate.
(73% yield) as colorless needles. ¹ H-NMR (300 MHz, CDCl ₃ ) δ: 8.06 (2H, d, J = 8.3 Hz), 7.51 (2H, d, J = 8.3 Hz), 7.30 (2H,
m), 6.96 (3H, m), 5.13 (2H, s), 3.92 (3H, s) (2) Methyl 4-phenoxymethylbenzoate
5.35 g (22.1 mmol) and lithium aluminum hydride 839 mg (2
As in Example 159, 4.22 g (89% yield) of 4-phenoxymethylbenzyl alcohol was obtained from 2.1 mmol) as a white powder. ¹ H-NMR (300 MHz, CDCl ₃ ) δ: 7.41 (4H, m), 7.29 (2H, m), 6.96 (3H, m), 5.07 (2H, s), 4.7
0 (2H, s) (3) 4-phenoxymethylbenzyl alcohol 2.00
g (9.33 mmol), pyridine 755 μl (9.33 mmol), thionyl chloride 749 μl (10.3 mmol) were treated in the same manner as in Example 159 to give 4-phenoxymethylbenzyl chloride 2.20 g (quantitative yield) as a colorless oil. Obtained. ¹ H-NMR (300 MHz, CDCl ₃ ) δ: 7.42 (4H, m), 7.29 (2H, m), 6.97 (3H, m), 5.07 (2H, s), 4.6
0 (2H, s) (4) As in Example 30, 1.40 g (6.00 mmol) of 4-phenoxymethylbenzyl chloride, 1.04 g (6.00 mmol) of 4-trimethylsilyloxypyrrolidin-2-one, and powdered hydroxide From 396 mg (7.06 mmol) of potassium, 710 mg (40% yield) of 4-hydroxy-1- (4-phenoxymethylbenzyl) pyrrolidin-2-one was obtained as a white powder. Elemental analysis (%) Calcd C as _{C 18 H 19 NO 3, 72.71} ; H, 6.44; N, 4.71 Found C, 72.46; H, 6.45; N, 4.54 (5) 4- hydroxy-1- (4 Phenoxymethylbenzyl) pyrrolidin-2-one 650 mg (2.19 mmol), triethylamine 610 μl (4.38 mmol), methanesulfonyl chloride 339 μl (4.38 mmol) from 4-methanesulfonyloxy-1- (4-phenoxymethylbenzyl) pyrrolidine-2. 760 mg (92% yield) of -one was obtained as a white powder. Elemental analysis value (%) Calculated value for C ₁₉ H ₂₁ NO ₅ S · 0.1 H ₂ O C, 60.49; H, 5.66; N, 3.71 Actual value C, 60.46; H, 5.84; N, 3.61 (6) 4 -Methanesulfonyloxy-1- (4-phenoxymethylbenzyl) pyrrolidin-2-one 710 mg (1.
89 mmol) and 432 mg (3.78 mmol) of potassium thioacetate gave 464 mg (69% yield) of 4-acetylthio-1- (4-phenoxymethylbenzyl) pyrrolidin-2-one as a white powder. ¹ H-NMR (300 MHz, CDCl ₃ ) δ: 7.42 (2H, d, J = 7.9 Hz), 7.23-7.34 (4H, m), 6.97 (3H, m),
5.05 (2H, s), 4.51 (1H, d, J = 14.7Hz), 4.42 (1H, d, J = 14.7H
z), 4.05 (1H, m), 3.75 (1H, dd, J = 10.6,7.5Hz), 3.17 (1H, dd,
J = 10.6,4.9Hz), 2.93 (1H, dd, J = 17.3,8.9Hz), 2.43 (1H, dd,
J = 17.3,6.0Hz), 2.31 (3H, s)

Example 164 4-Mercapto-1- (4
-Phenoxymethylbenzyl) pyrrolidin-2-one 4-acetylthio-1- (4-
(Phenoxymethylbenzyl) pyrrolidin-2-one 230mg
After dissolving (0.647 mmol) in 23 ml of methanol, 132 μl (0.647 mmol) of a 28% methanol solution of sodium methoxide was added,
Stirred at room temperature for 0.5 hour. After adjusting the pH of the reaction solution to 2.0, the mixture was concentrated under reduced pressure, ethyl acetate was added, and then twice with water.
After washing once with a saturated saline solution, it was dried over anhydrous sodium sulfate. After concentration under reduced pressure, the mixture was powdered from hexane-ethyl acetate to give 156 mg (77% yield) of 4-mercapto-1- (4-phenoxymethylbenzyl) pyrrolidin-2-one as a white powder. ¹ H-NMR (300 MHz, CDCl ₃ ) δ: 7.42 (2H, d, J = 7.9 Hz), 7.24-7.33 (4H, m), 6.97 (3H, m),
5.05 (2H, s), 4.50 (1H, d, J = 14.9Hz), 4.45 (1H, d, J = 14.9H
z), 3.64 (1H, dd, J = 10.2,7.2Hz), 3.53 (1H, m), 3.16 (1H, dd,
J = 10.2,5.1Hz), 2.92 (1H, dd, J = 17.2,8.1Hz), 2.43 (1H, dd,
J = 17.2,6.2Hz), 1.86 (1H, d, J = 6.8Hz)

Example 165 4-Acetylthio-1-
(4-benzyloxybenzyl) pyrrolidin-2-one (1) 4.96 g of 4-hydroxybenzyl alcohol (40.0 g)
mmol) in 100 ml of N, N-dimethylformamide,
5.52 g (40.0 mmol) of potassium carbonate, 4.76 m of benzyl bromide
l (40.0 mmol) was added, and the mixture was stirred at room temperature for 14 hours. After concentrating the reaction solution under reduced pressure, ethyl acetate was added, and the mixture was washed twice with water and once with a saturated saline solution, and then dried over anhydrous sodium sulfate.
After concentration under reduced pressure, the residue was subjected to silica gel column chromatography, and a fraction eluted with hexane: ethyl acetate (60:40) was collected.
Concentrated under reduced pressure, powdered from hexane-ethyl acetate,
3.92 g of 4-benzyloxybenzyl alcohol (46% yield)
Was obtained as a white powder. ¹ H-NMR (300 MHz, CDCl ₃ ) δ: 7.26-7.46 (7H, m), 6.97 (2H, d, J = 8.3 Hz), 5.07 (2H, s),
4.62 (2H, s) (2) 2.00 g of 4-benzyloxybenzyl alcohol
(9.33 mmol), pyridine 755 μl (9.33 mmol), and thionyl chloride 749 μl (10.3 mmol) were treated in the same manner as in Example 159 to give 4-benzyloxybenzyl chloride 2.17 g (quantitative yield) as a colorless oil. Was. ¹ H-NMR (300 MHz, CDCl ₃ ) δ: 7.28-7.45 (7 H, m), 6.95 (2 H, d, J = 8.3 Hz), 5.07 (2 H, s),
4.56 (2H, s) (3) As in Example 30, 1.40 g (6.00 mmol) of 4-benzyloxybenzyl chloride, 1.04 g (6.00 mmol) of 4-trimethylsilyloxypyrrolidin-2-one, and powdered hydroxide From 396 mg (7.06 mmol) of potassium, 420 mg (yield 24%) of 4-hydroxy-1- (4-benzyloxybenzyl) pyrrolidin-2-one was obtained as a white powder. Elemental analysis value (%) Calculated value for C ₁₈ H ₁₉ NO ₃ · 0.1 H ₂ O C, 72.27; H, 6.47; N, 4.68 Actual value C, 72.22; H, 6.23; N, 4.54 (4) 4- Hydroxy-1- (4-benzyloxybenzyl) pyrrolidin-2-one (370 mg, 1.24 mmol), triethylamine (346 μl, 2.48 mmol), methanesulfonyl chloride (192 μl, 2.48 mmol) were converted to 4-methanesulfonyloxy-1- (4-benzyl Oxybenzyl) pyrrolidine-2
348 mg (75% yield) of -one were obtained as a white powder. Elemental analysis (%) Calcd C as _{C 19 H 21 NO 5 S,} 60.78; H, 5.64; N, 3.73 Found C, 60.58; H, 5.77; N, 3.58 (5) 4- methanesulfonyloxy -1 -(4-benzyloxybenzyl) pyrrolidin-2-one 298 mg (0.79
From 4 mmol) and 181 mg (1.59 mmol) of potassium thioacetate, 171 mg (yield 61%) of 4-acetylthio-1- (4-benzyloxybenzyl) pyrrolidin-2-one was obtained as a white powder. ¹ H-NMR (300 MHz, CDCl ₃ ) δ: 7.29-7.46 (5H, m), 7.15 (2H, d, J = 8.5 Hz), 6.94 (2H, d, J =
8.5Hz), 5.05 (2H, s), 4.42 (1H, d, J = 14.5Hz), 4.36 (1H, d, J =
14.5Hz), 4.03 (1H, m), 3.72 (1H, dd, J = 10.6,7.5Hz), 3.14 (1H
H, dd, J = 10.6,4.9Hz), 2.91 (1H, dd, J = 17.3,9.0Hz), 2.41 (1
H, dd, J = 17.3,6.0Hz), 2.30 (3H, s)

Example 166 4-Mercapto-1- (4
-Benzyloxybenzyl) pyrrolidin-2-one 4-acetylthio-1- (4-
(Benzyloxybenzyl) pyrrolidin-2-one 100 mg
(0.281 mmol) was treated in the same manner as in Example 164 to give 4-mercapto-1- (4-benzyloxybenzyl) pyrrolidin-2-one (46.1 mg, yield 52%) as a white powder. ¹ H-NMR (300 MHz, CDCl ₃ ) δ: 7.29-7.46 (5H, m), 7.17 (2
H, d, J = 8.5 Hz), 6.94 (2H, d, J =
8.5 Hz), 5.05 (2H, s), 4.43 (1
H, d, J = 14.5 Hz), 4.38 (1H, d, J)
= 14.5 Hz), 3.62 (1H, dd, J = 10.
0, 7.4 Hz), 3.51 (1H, m), 3.13
(1H, dd, J = 10.2, 5.1 Hz), 2.91
(1H, dd, J = 17.2, 8.1 Hz), 2.41
(1H, dd, J = 17.2, 6.2 Hz), 1.84
(1H, d, J = 6.8Hz)

Example 167 4-Acetylthio-1-
(4-phenethylbenzyl) pyrrolidin-2-one (1) trans-4-stilbenecarboxaldehyde
4.75 g (22.8 mmol) was dissolved in a mixture of methanol 100 ml and tetrahydrofuran 100 ml, and then 10% palladium activated carbon 450 m
After adding g, the mixture was stirred at room temperature for 3 hours under a hydrogen atmosphere.
After removing the catalyst by filtration, the filtrate was concentrated under reduced pressure, dissolved in methanol (40 ml), added with sodium borohydride (431 mg, 11.4 mmol), and stirred at room temperature for 0.5 hour. The reaction solution was adjusted to pH 3.0, concentrated under reduced pressure, and extracted twice with ethyl acetate.
The ethyl acetate layer was washed twice with water and once with saturated saline, and then dried over anhydrous sodium sulfate. After concentration under reduced pressure, the residue was subjected to silica gel column chromatography, and the fraction eluted with hexane: ethyl acetate (70:30) was concentrated under reduced pressure to give 4-phenethylbenzyl alcohol (4.34 g, yield 90%) as a white powder. Obtained. ¹ H-NMR (300 MHz, CDCl ₃ ) δ: 7.24-7.31 (4H, m), 7.19 (5H, m), 4.66 (2H, s), 2.92 (4H,
s) (2) 2.00 g of 4-phenethylbenzyl alcohol (9.42
mmol), pyridine 762 μl (9.42 mmol), thionyl chloride 7
59 μl (10.4 mmol) were treated as in Example 159 to give 4
-Phenethylbenzyl chloride (2.24 g, yield quantitative) was obtained as a colorless oil. ¹ H-NMR (300 MHz, CDCl ₃ ) δ: 7.28 (4H, m), 7.18 (5H, m), 4.57 (2H, s), 2.91 (4H, s) (3) As in Example 30, 4 From 1.38 g (6.00 mmol) of phenethylbenzyl chloride, 1.04 g (6.00 mmol) of 4-trimethylsilyloxypyrrolidin-2-one, and 396 mg (7.06 mmol) of powdered potassium hydroxide, 4-hydroxy-1- (4-phenethyl 730 mg (yield 41%) of benzyl) pyrrolidin-2-one was obtained as a white powder. Elemental analysis (%) Calculated for C ₁₉ H ₂₁ NO ₂ C, 77.26; H, 7.17; N, 4.74 Found C, 77.30; H, 7.05; N, 4.65 (4) 4-hydroxy-1- (4 -Phenethylsibenzyl) pyrrolidin-2-one 600 mg (2.03 mmol), triethylamine 566 μl (4.06 mmol), methanesulfonyl chloride 314 μl (4.06 mmol) to 4-methanesulfonyloxy-
1- (4-phenethylbenzyl) pyrrolidin-2-one
542 mg (yield 72%) was obtained as a white powder. Elemental analysis (%) Calcd C as _{C 20 H 23 NO 4 S,} 64.32; H, 6.21; N, 3.75 Found C, 64.38; H, 6.12; N, 3.77 (5) 4- methanesulfonyloxy -1 -(4-phenethylbenzyl) pyrrolidin-2-one 500 mg (1.34 mmo
l) and potassium thioacetate 306 mg (2.68 mmol) from 4-acetylthio-1- (4-phenethylbenzyl) pyrrolidine-2
339 mg (72% yield) of -one were obtained as a white powder. Elemental analysis (%) Calculated for C ₂₁ H ₂₃ NO ₂ S Calculated C, 71.35; H, 6.56; N, 3.96 Found C, 71.53; H, 6.37; N, 3.95

Example 168 4-Mercapto-1- (4
-Phenethylbenzyl) pyrrolidin-2-one 4-acetylthio-1- (4-
(Phenethylbenzyl) pyrrolidin-2-one 200 mg (0.566
mmol) was treated in the same manner as in Example 31, to give 4-mercapto-1- (4-phenethylbenzyl) pyrrolidin-2-one.
154 mg (87% yield) were obtained as a white powder. ¹ H-NMR (300 MHz, CDCl ₃ ) δ: 7.24-7.31 (3H, m), 7.13-7.
23 (6H, m), 4.47 (1H, d, J = 14.7)
Hz), 4.40 (1H, d, J = 14.7 Hz),
3.62 (1H, dd, J = 9.8, 7.2 Hz),
3.52 (1H, m), 3.14 (1H, dd, J =
9.8, 4.9 Hz), 2.92 (1H, dd, J = 1)
7.0, 8.3 Hz), 2.91 (4H, s), 2.4
2 (1H, dd, J = 17.0, 6.2 Hz), 1.8
5 (1H, d, J = 6.8 Hz)

Example 169 S- [5-oxo-1- (4
-Phenoxyphenethyl) -3-pyrrolidinyl] ethanethioate 1.3 ml (6.64 mmol) of 4-phenoxyphenethylamine in O-
The solution was added to a solution of 1.0 g (6.32 mmol) of acetylmalic anhydride in 6.5 ml of THF and stirred for 1.3 hours. After concentrating the reaction solution under reduced pressure,
It was dissolved in 5 ml of acetyl chloride and stirred at 60 ° C. for 12 hours. The reaction solution was concentrated under reduced pressure, and dissolved in ethyl acetate.
The extract was washed twice with water and a saturated aqueous solution of sodium hydrogencarbonate and then with a saturated saline solution, and then dried over anhydrous sodium sulfate. After concentration under reduced pressure, powdered and obtained from ethyl acetate (yield 75%),
2,5-dioxo-1- (4-phenoxyphenethyl)-
1.3 g (3.68 mmol) of 3-pyrrolidinyl acetate was dissolved in a mixed solvent of 6.5 ml of ethanol and 13 ml of THF, and 696 mg (18.40 mmol) of sodium borohydride was added at -18 ° C to give -18 to -9.
Stirred at C for 5 hours. A saturated aqueous sodium hydrogen carbonate solution and ethyl acetate were added to the reaction solution, and the mixture was partitioned. The ethyl acetate layer was washed with saturated saline and dried over anhydrous sodium sulfate. After concentration under reduced pressure, the residue was dissolved in trifluoroacetic acid (13 ml), triethylsilane (705 μl, 4.42 mmol) was added, and the mixture was stirred at room temperature for 30 minutes. The reaction solution was concentrated under reduced pressure, dissolved in ethyl acetate, washed twice with a saturated aqueous solution of sodium hydrogencarbonate, washed with a saturated saline solution, and dried over anhydrous sodium sulfate. After concentration under reduced pressure, the residue was purified by silica gel column chromatography.
A fraction eluted with -hexane: ethyl acetate (3: 2 to 1: 1) could be concentrated (2 strokes, yield: 71%), and 5-oxo-1- (4-phenoxyphenethyl) -3-pyrrolidinyl acetate 1.48. g (4.
36 mmol) in 62 ml of acetyl chloride (87 ml) in 10 ml of ethanol
(mmol) was dissolved in the solution prepared dropwise, and the mixture was stirred at 50 ° C for 1.5 hours. The reaction solution was concentrated under reduced pressure, and powdered from ethyl acetate (yield 80%) to obtain 4-hydroxy-1- (4-
Phenoxyphenethyl) -2-pyrrolidinone 995 mg (3.35
mmol), 363 μl of methanesulfonyl chloride (4.69 mmol)
Was dissolved in 10 ml of chloroform, and triethylamine 6 was added at 0 ° C.
A solution of 54 μl (4.69 mmol) in 5 ml of chloroform was added dropwise over 5 minutes. After completion of the dropwise addition, the mixture was stirred at 0 ° C. for 10 minutes. The reaction solution was concentrated under reduced pressure, dissolved in ethyl acetate, washed twice with water and saturated brine, and dried over anhydrous sodium sulfate.
Concentration under reduced pressure (yield 91%), 5-oxo-1- (4
-Phenoxyphenethyl) -3-pyrrolidinyl methanesulfonate 500 mg (1.33 mmol) was dissolved in a mixed solvent of DMF 10 ml and ethanol 10 ml, and potassium thioacetate 304 mg (2.
66 mmol) and stirred at 90 ° C. for 4 hours. Solvent under reduced pressure
After evaporating to half the volume, add ethyl acetate to the reaction solution and add
After washing with saturated saline twice, it was dried over anhydrous sodium sulfate. After concentration under reduced pressure, the residue was purified by silica gel column chromatography, and the fraction eluted with n-hexane: ethyl acetate (2: 1) was concentrated to give the title compound (404 mg, yield 85%) as a brown oil. Elemental analysis _{(%): C 20 H 21} NO 3 S · 0.25H 2 O Calculated: C, 66.73; H, 6.02 ; N, 3.89 Found: C, 66.79; H, 5.98 ; N, 3.76

Example 170 1- (4-Phenoxyphenethyl) -4-sulfanyl-2-pyrrolidinone S- [5-oxo-1- (4-phenoxyphenethyl) -3-pyrrolidinyl] ethanethioate obtained in Example 169 91 mg (0.26 mmol), ethanol 1 ml and acetyl
Dissolve in a mixture of 365 μl (5.14 mmol) of chloride and at 50 ° C. 1.
After stirring for 5 hours, the reaction solution was concentrated under reduced pressure, and then subjected to preparative thin-layer chromatography (developing solvent: n-hexane: ethyl acetate).
(1: 2)) to give the title compound (64 mg, yield 79%) as a colorless oil. ¹ H-NMR (300 MHz, CDCl3) δ: 7.35-6.93 (9H, m), 3.65-3.41 (4H, m), 3.16 (1H, dd, J = 1
0.0,5.1Hz), 2.85-2.78 (3H, m), 2.32 (1H, dd, J = 16.9,6.2H
z), 1.84 (1H, d, J = 7.0Hz)

Example 171 4-Acetylthio-1-
(4-phenylsulfinylbenzyl) pyrrolidine-2-
ON (1) 4-Hydroxy-1- obtained in Example 154
(4-phenylthiobenzyl) pyrrolidin-2-one 32
4 mg (1.08 mmol) was dissolved in a mixture of 7 ml of acetic acid and 2 ml of 30% aqueous hydrogen peroxide, and the mixture was stirred at room temperature for 1 hour. After adding ethyl acetate to the reaction solution, the mixture was washed twice with water and once with a saturated saline solution, and dried over anhydrous sodium sulfate. After concentration under reduced pressure, the residue was subjected to silica gel column chromatography, and hexane: acetone was added.
(30: 70-0: 100) The eluted fraction was concentrated under reduced pressure to obtain 239 mg of 4-hydroxy-1- (4-phenylsulfinylbenzyl) pyrrolidin-2-one (70% yield) as a colorless oil. Was. ¹ H-NMR (300 MHz, CDCl ₃ ) δ: 7.62 (4 H, m), 7.46 (3 H, m), 7.34 (2 H, d, J = 8.3 Hz), 4.57 (1
H, d, J = 15.3Hz), 4.50 (1H, m), 4.40 (1H, d, J = 15.3Hz), 3.50
(1H, dd, J = 10.9,5.7Hz), 3.18 (1H, dd, J = 10.9,1.7Hz), 2.71
(1H, dd, J = 17.3,6.4Hz), 2.42 (1H, dd, J = 17.3,2.5Hz) (2) 4-hydroxy-1- (4-phenylsulfinylbenzyl) pyrrolidin-2-one 215 mg (0.682 mmo
l), 286 μl (2.04 mmol) of triethylamine, 158 μl (2.04 mmol) of methanesulfonyl chloride to 4-methanesulfonyloxy-1- (4-phenylsulfinylbenzyl)
198 mg (74% yield) of pyrrolidin-2-one were obtained as a colorless oil. ¹ H-NMR (300 MHz, CDCl ₃ ) δ: 7.64 (4 H, m), 7.47 (3 H, m), 7.33 (2 H, d, J = 8.3 Hz), 5.28 (1
H, m), 4.53 (1H, d, J = 17.2Hz), 4.48 (1H, d, J = 17.2Hz), 3.64
(1H, dd, J = 12.1,5.5Hz), 3.50 (1H, br d, J = 12.1Hz), 3.00 (3
H, s), 2.87 (1H, dd, J = 18.1,6.9Hz), 2.71 (1H, dd, J = 18.1,2.
(3 Hz) (3) 4-methanesulfonyloxy-1- (4-phenylsulfinylbenzyl) pyrrolidin-2-one 180 m
g (0.457 mmol) and potassium thioacetate (104 mg, 0.915 mmol) to give 4-acetylthio-1- (4-phenylsulfinylbenzyl) pyrrolidin-2-one (129 mg, yield 76%) as a colorless oil. Elemental analysis _{(%) C 19 H 19 NO} 3 Calculated C as _{S 2, 61.10; H, 5.13} ; N, 3.75 Found C, 61.05; H, 5.22; N, 3.83

Example 172 4-Mercapto-1- (4
-Phenylsulfinylbenzyl) pyrrolidin-2-one The 4-acetylthio-1- (4-
(Phenylsulfinylbenzyl) pyrrolidin-2-one 6
From 0.0 mg (0.161 mmol) and 229 μl (3.22 mmol) of acetyl chloride, 4-mercapto-1-
(4-phenylsulfinylbenzyl) pyrrolidine-2-
17.9 mg (yield 34%) were obtained as a colorless oil. ¹ H-NMR (300 MHz, CDCl ₃ ) δ: 7.64 (4 H, m), 7.47 (3 H, m), 7.35 (2 H, d, J = 7.9 Hz), 4.51 (1
H, d, J = 15.1Hz), 4.43 (1H, d, J = 15.1Hz), 3.63 (1H, dd, J = 9.
6,7.5Hz), 3.55 (1H, m), 3.14 (1H, dd, J = 9.6,4.5Hz), 2.91 (1
H, dd, J = 17.2,8.1Hz), 2.41 (1H, dd, J = 17.2,5.9Hz), 1.86 (1
(H, d, J = 6.8Hz)

Example 173 4-Acetylthio-1-
(4-phenylsulfonylbenzyl) pyrrolidin-2-one (1) 4-hydroxy-1- obtained in Example 154
(4-phenylthiobenzyl) pyrrolidin-2-one 28
0 mg (0.935 mmol) was dissolved in a mixture of 7 ml of acetic acid and 2 ml of 30% hydrogen peroxide solution, and the mixture was stirred at 70 ° C. for 1 hour. After adding ethyl acetate to the reaction solution, the mixture was washed twice with water and once with a saturated saline solution, and dried over anhydrous sodium sulfate. After concentration under reduced pressure, toluene was added, and the mixture was concentrated to dryness again under reduced pressure, powdered from ethyl acetate to give 310 mg of 4-hydroxy-1- (4-phenylsulfonylbenzyl) pyrrolidin-2-one (quantitative yield). Obtained as a white powder. Elemental analysis (%) Calcd C as _{C 17 H 17 NO 4 S,} 61.61; H, 5.17; N, 4.23 Found C, 61.31; H, 4.95; N, 4.21 (2) 4- hydroxy-1- ( 310 mg (0.935 mmol) of 4-phenylsulfonylbenzyl) pyrrolidin-2-one,
From 430 μl (3.10 mmol) of triethylamine and 240 μl (3.10 mmol) of methanesulfonyl chloride, 359 mg (94% yield) of 4-methanesulfonyloxy-1- (4-phenylsulfonylbenzyl) pyrrolidin-2-one was obtained as a colorless oil. . Elemental analysis (%) Calculated for C ₁₈ H ₁₉ NO ₆ S ₂ C, 52.80; H, 4.68; N, 3.
42, C, 52.82; H, 4.57; N, 3.
47 (3) 4-methanesulfonyloxy-1- (4-phenylsulfonylbenzyl) pyrrolidin-2-one 280 mg
(0.684 mmol) and 156 mg (1.37 mmol) of potassium thioacetate
-Acetylthio-1- (4-phenylsulfonylbenzyl) pyrrolidin-2-one (175 mg, yield 66%) was obtained as a white powder. Elemental analysis (%) Calculated for C ₁₉ H ₁₉ NO ₄ S ₂ C, 58.59; H, 4.92; N, 3.60 Found C, 58.59; H, 4.85; N, 3.68

Example 174 4-Mercapto-1- (4
-Phenylsulfonylbenzyl) pyrrolidin-2-one 4-acetylthio-1- (4-
(Phenylsulfonylbenzyl) pyrrolidin-2-one 90.
From 0 mg (0.231 mmol) and 365 μl (5.14 mmol) of acetyl chloride,
In the same manner as in Example 126, 4-mercapto-1- (4
-Phenylsulfonylbenzyl) pyrrolidin-2-one 6
1.2 mg (76% yield) was obtained as a white powder. Elemental analysis _{(%) C 17 H 17 NO} 3 Calculated C as _{S 2, 58.77; H, 4.93} ; N, 4.03 Found C, 58.79; H, 4.93; N, 4.03

Example 175 (4S, 5S) -4-acetylthio-5-methyl-1- (4-phenoxybenzyl) pyrrolidin-2-one (1) As in Example 20, L-alanine methyl ester hydrochloride 2.34 g (15.0 mmol), triethylamine 3.14 ml
(22.5 mmol), 2.63 ml of 4-phenoxybenzaldehyde (1
From 5.0 mmol), 4.31 g (quantitative yield) of N- (4-phenoxybenzyl) -L-alanine methyl ester was obtained as a colorless oil. ¹ H-NMR (300 MHz, CDCl ₃ ) δ: 7.27-7.37 (4H, m), 7.09 (1H, m), 6.98 (4H, m), 3.77 (1H,
d, J = 12.8Hz), 3.74 (3H, s), 3.64 (1H, d, J = 12.8Hz), 3.40 (1
(H, q, J = 6.8 Hz), 1.33 (3H, d, J = 6.8 Hz) (2) N- (4-phenoxybenzyl) -L-alanine methyl ester 4.21 g (14.8 mmol), triethylamine 2.
48 ml (17.8 mmol), ethyl malonyl chloride 2.28 ml (17.8
mmol) to 5.11 g of N- (ethylmalonyl) -N- (4-phenoxybenzyl) -L-alanine methyl ester (yield 86
%) As a colorless oil. ¹ H-NMR (300 MHz, CDCl ₃ ) δ: 7.20-7.40 (4H, m), 7.13 (1H, m), 6.97-7.04 (4H, m), 4.66
(1H, q, J = 7.2Hz), 65 (1H, d, J = 17.3Hz), 4.50 (1H, d, J = 17.3H
z), 4.19 (1H, q, J = 7.2Hz), 3.69 (3H, s), 3.47 (1H, d, J = 15.5H
z), 3.39 (1H, d, J = 15.5Hz), 1.41 (3H, d, J = 7.2Hz), 1.28 (3H,
(t, J = 7.2 Hz) (3) N- (ethylmalonyl) -N- (4-phenoxybenzyl) -L-alanine methyl ester 5.00 g (12.5 mmo
l) and 4.91 ml of 20% sodium ethoxide ethanol solution (1
2.5 mmol), and after decarboxylation, sodium borohydride
473 mg (12.5 mmol) to (5S) -4-hydroxy-5-
Methyl-1- (4-phenoxybenzyl) -pyrrolidine-
3.61 g (97% yield) of 2-one was obtained as a colorless oil. ¹ H-NMR (300 MHz, CDCl ₃ ) (only main peaks are described) δ: 7.33 (2H, m), 7.19 (2 H, m), 7.10 (1 H, m), 6.97-7.03 (4H,
m), 4.95 (1H, d, J = 15.1 Hz), 4.35 (1H, m), 3.97 (1H, d, J = 15.1)
Hz), 3.60 (1H, m), 2.70 (1H, dd, J = 17.0, 6.6Hz), 2.47 (1H, d
d, J = 17.0,3.4Hz), 1.22 (3H, d, J = 6.8Hz) (4) (5S) -4-hydroxy-5-methyl-1-
(4-phenoxybenzyl) pyrrolidin-2-one 3.50 g
(11.8 mmol), 3.28 ml (23.5 mmol) of triethylamine, 1.81 ml (23.5 mmol) of methanesulfonyl chloride to (5
S) -4-Methanesulfonyloxy-5-methyl-1-
(4-phenoxybenzyl) -pyrrolidin-2-one 3.87
g (87% yield) was obtained as a colorless oil. This was separated by preparative high performance liquid chromatography (column: YMC Pack S-363 I-15
ODS, mobile phase: 42% acetonitrile / 0.01M phosphate buffer p
H6.3, flow rate: 20 ml / min, detection: 214 nm), and the eluted fractions of the two peaks were each concentrated and then extracted twice with ethyl acetate. The ethyl acetate layer was washed with water and saturated saline, dried over anhydrous sodium sulfate, and concentrated (4R, 5S) -4.
1.20 g of methanesulfonyloxy-5-methyl-1- (4-phenoxybenzyl) pyrrolidin-2-one (recovery 3
(1S) as a colorless oil, and 2.08 g of (4S, 5S) -4-methanesulfonyloxy-5-methyl-1- (4-phenoxybenzyl) pyrrolidin-2-one (54% recovery) as a white powder. Got each. (4R, 5S) -4-methanesulfonyloxy-5-methyl-1- (4-phenoxybenzyl) pyrrolidin-2-one ¹ H-NMR (300 MHz, CDCl ₃ ) δ: 7.34 (2H, m), 7.21 ( 2H, d, J = 8.7Hz), 7.11 (1H, m), 6.98 (4
H, m), 4.97 (1H, d, J = 15.1Hz), 4.90 (1H, m), 3.98 (1H, d, J = 1
5.1Hz), 3.73 (1H, dq, J = 1.5,6.8Hz), 2.97 (3H, s), 2.95 (1H,
dd, J = 18.1,6.8Hz), 2.66 (1H, dd, J = 18.1,2.3Hz), 1.23 (3H,
d, J = 6.8 Hz) (4S, 5S) -4-methanesulfonyloxy-5-methyl-1- (4-phenoxybenzyl) pyrrolidine-2-
On ¹ H-NMR (300 MHz, CDCl ₃ ) δ: 7.35 (2 H, m), 7.18 (2 H, d, J = 8.3 Hz), 7.12 (1 H, m), 7.01 (2
H, m), 6.95 (2H, d, J = 8.3Hz), 5.21 (1H, m), 4.98 (1H, d, J = 15.
1Hz), 3.96 (1H, d, J = 15.1Hz), 3.80 (1H, m), 3.06 (3H, s), 2.8
3 (1H, dd, J = 17.3,6.4Hz), 2.74 (1H, dd, J = 17.3,4.0Hz), 1.2
8 (3H, d, J = 6.4Hz) (4R, 5S) -4-methanesulfonyloxy-5-methyl-1- (4-phenoxybenzyl) pyrrolidine-2-
After dissolving 1.00 g (2.66 mmol) of ON in 30 ml of ethanol, 608 mg (5.33 mmol) of potassium thioacetate was added, and the mixture was heated under reflux with stirring for 13 hours. After concentrating the reaction solution, ethyl acetate was added,
After washing with water and saturated saline, it was dried over anhydrous sodium sulfate. After concentration, the residue was subjected to silica gel column chromatography, eluted with hexane: ethyl acetate (60:40), concentrated to dryness, and treated with (4S, 5S) -4-acetylthio-5-methyl-.
1- (4-phenoxybenzyl) pyrrolidin-2-one 20
7 mg (22% yield) was obtained as a colorless oil. ¹ H-NMR (300 MHz, CDCl ₃ ) δ: 7.34 (2H, m), 7.20 (2H, d, J =
8.3 Hz), 7.11 (1H, m), 7.01 (2
H, m), 6.96 (2H, m), 4.93 (1H,
d, J = 15.1 Hz), 4.18 (1H, m), 3.
96 (1H, d, J = 15.1 Hz), 3.84 (1
H, m), 2.82 (1H, dd, J = 17.0, 8.
3Hz), 2.45 (1H, dd, J = 17.0, 9.
1 Hz), 2.34 (3H, s), 1.13 (3H,
d, J = 6.4 Hz)

Example 176 (4S, 5S) -4-mercapto-5-methyl-1- (4-phenoxybenzyl)
Pyrrolidin-2-one 120 mg (0.338 mmol) of (4S, 5S) -4-acetylthio-5-methyl-1- (4-phenoxybenzyl) -pyrrolidin-2-one obtained in Example 175 was obtained in the same manner as in Example 31. The same treatment is carried out to give (4S, 5S) -4-mercapto-5-
Methyl-1- (4-phenoxybenzyl) -pyrrolidine-
81.2 mg (yield 77%) of 2-one was obtained as a colorless oil. ¹ H-NMR (300 MHz, CDCl ₃ ) δ: 7.34 (2 H, m), 7.20 (2 H, d, J = 8.3 Hz), 7.11 (1 H, m), 7.00 (2
H, m), 6.96 (2H, d, J = 8.3Hz), 4.96 (1H, d, J = 15.1Hz), 3.95 (1
H, d, J = 15.1Hz), 3.65 (1H, m), 3.58 (1H, m), 2.84 (1H, dd, J = 1
7.0,7.5Hz), 2.46 (1H, dd, J = 17.0,7.7Hz), 1.52 (1H, d, J = 7.
5Hz), 1.23 (3H, d, J = 6.4Hz)

Example 177 (4R, 5S) -4-acetylthio-5-methyl-1- (4-phenoxybenzyl)
Pyrrolidin-2-one 1.50 g (4.00 mmol) of (4S, 5S) -4-methanesulfonyloxy-5-methyl-1- (4-phenoxybenzyl) pyrrolidin-2-one obtained in Example 175 and thioacetic acid 914 mg (8.00 mmol) of potassium was treated in the same manner as in Example 175 to give (4R, 5S) -4-acetylthio-5-methyl-1- (4-phenoxybenzyl) pyrrolidine-2-
596 mg (42% yield) were obtained as a colorless oil. ¹ H-NMR (300 MHz, CDCl ₃ ) δ: 7.34 (2 H, m), 7.19 (2 H, d, J = 8.3 Hz), 7.11 (1 H, m), 7.00 (2
H, m), 6.96 (2H, m), 4.95 (1H, d, J = 15.1Hz), 3.95 (1H, d, J = 1
5.1Hz), 3.68 (1H, m), 3.39 (1H, m), 3.02 (1H, dd, J = 17.7,8.9
Hz), 2.39 (1H, dd, J = 17.7, 5.7 Hz), 2.31 (3H, s), 1.26 (3H, d,
(J = 6.4Hz)

Example 178 (4R, 5S) -4-Mercapto-5-methyl-1- (4-phenoxybenzyl) pyrrolidin-2-one (4R, 5S) -4-acetylthio- obtained in Example 177 301 mg (0.847 mmol) of 5-methyl-1- (4-phenoxybenzyl) pyrrolidin-2-one was treated in the same manner as in Example 31 to give (4R, 5S) -4-mercapto-5-methyl-1- ( 4-phenoxybenzyl) pyrrolidine-2-
210 mg (79% yield) was obtained as a colorless oil. ¹ H-NMR (300 MHz, CDCl ₃ ) δ: 7.34 (2 H, m), 7.21 (2 H, d, J = 8.7 Hz), 7.11 (1 H, m), 7.00 (2
H, m), 96 (2H, d, J = 8.7Hz), 4.96 (1H, d, J = 15.1Hz), 3.96 (1H,
d, J = 15.1Hz), 3.33 (1H, m), 3.03 (1H, m), 2.95 (1H, m), 2.39
(1H, dd, J = 16.2,6.8Hz), 1.75 (1H, d, J = 6.8Hz), 1.25 (3H, d,
(J = 6.4Hz)

Example 179 Trans-4-acetylthio-5-isobutyl-1- (4-phenoxybenzyl)
Pyrrolidin-2-one (1) D, L-leucine 6.56 g (50.0 m
mol), methanol 50 ml, thionyl chloride 13.0 ml (180 m
mol), 8.93 g (98% yield) of D, L-leucine methyl ester hydrochloride was obtained as a white powder. ¹ H-NMR (300 MHz, D ₂ O) δ: 4.17 (1 H, t, J = 6.8 Hz), 3.87 (3 H, s), 1.90 (1 H, m), 1.78 (2
H, m), 00 (3H, d, J = 6.0 Hz), 0.99 (3H, d, J = 6.0 Hz) (2) 2.73 g of D, L-leucine methyl ester hydrochloride (15.
0 mmol), 3.14 ml (22.5 mmol) of triethylamine, 2.63 ml (15.0 mmol) of 4-phenoxybenzaldehyde, 420 mg (11.1 mmol) of sodium borohydride, and N- (4-phenoxybenzyl) -D, L-leucine methyl ester 4.34g
(88% yield) as a colorless oil. ¹ H-NMR (300 MHz, CDCl ₃ ) δ: 7.30 (4H, m), 7.08 (1H, m), 6.97
(4H, m), 3.78 (1H, d, J = 12.8Hz), 3.73 (3H, s), 3.58 (1H, d, J = 12.8Hz), 3.31 (1H, t, J = 7.2Hz),
1.78 (1H, m), 1.48 (2H, t, J = 7.2Hz), 0.92 (3H, d, J = 6.8Hz),
0.85 (3H, d, J = 6.4Hz) (3) N- (4-phenoxybenzyl) -D, L-leucine methyl ester 4.34g (13.3mmol), triethylamine
2.22 ml (16.0 mmol), ethyl malonyl chloride 2.05 ml (1
6.0 mmol) from N- (ethylmalonyl) -N- (4-phenoxybenzyl) -D, L-leucine methyl ester 5.24 g
(89% yield) as a colorless oil. ¹ H-NMR (300 MHz, CDCl ₃ ) (only main peaks are described) δ: 7.21-7.38 (4H, m), 7.12 (1H, m), 6.91-7.03 (4H, m), 4.86
(1H, m), 4.63 (1H, d, J = 17.3Hz), 4.50 (1H, d, J = 17.3Hz), 4.1
9 (2H, q, J = 7.2Hz), 3.62 (3H, s), 3.47 (1H, d, J = 15.5Hz), 3.4
2 (1H, d, J = 15.5Hz), 1.88 (1H, m), 1.60 (2H, m), 1.28 (3H, t, J
= 7.2Hz), 0.91 (3H, d, J = 6.4Hz), 0.84 (3H, d, J = 6.0Hz) (4) N- (ethylmalonyl) -N- (4-phenoxybenzyl) -D, L -Leucine methyl ester 5.24 g (11.9 mm
ol), 4.66 ml of a 20% sodium ethoxide ethanol solution (1
1.9 mmol), and after decarboxylation, 450 mg (11.9 mmol) of sodium borohydride was reacted to give 4-hydroxy-5
-Isobutyl-1- (4-phenoxybenzyl) pyrrolidin-2-one (3.52 g, yield 87%) was obtained as a colorless oil. ¹ H-NMR (300 MHz, CDCl ₃ ) (only main peaks are described) δ: 7.33 (2H, m), 7.18 (2H, d, J = 8.7 Hz), 7.10 (1 H, m), 6.97 (4
H, m), 4.96 (1H, d, J = 15.3Hz), 4.37 (1H, m), 3.97 (1H, d, J = 1
5.3Hz), 3.49 (1H, m), 2.67 (1H, dd, J = 17.0, 5.9Hz), 2.47 (1
H, dd, J = 17.0,1.9Hz), 1.70 (2H, m), 1.40 (1H, m), 0.94 (3H,
d, J = 6.4Hz), 0.81 (3H, d, J = 6.4Hz) (5) 4-Hydroxy-5-isobutyl-1- (4-
Phenoxybenzyl) pyrrolidin-2-one 3.30 g (9.72 m
mol), 2.71 ml (19.4 mmol) of triethylamine and 1.50 ml (19.4 mmol) of methanesulfonyl chloride, followed by preparative high performance liquid chromatography in the same manner as in Example 175 to give cis-5-isobutyl-4-methane Sulfonyloxy-1- (4-phenoxybenzyl) pyrrolidine-2-
2.63 g (65% yield) of ON were obtained as a white powder. ¹ H-NMR (300 MHz, CDCl ₃ ) δ: 7.34 (2H, m), 7.17 (2H, d, J = 8.7 Hz), 7.11 (1 H, m), 6.98 (4
H, m), 5.26 (1H, m), 5.02 (1H, d, J = 15.3Hz), 3.96 (1H, d, J = 1
5.3Hz), 3.68 (1H, m), 3.06 (3H, s), 2.82 (1H, dd, J = 17.9,2.8
Hz), 2.75 (1H, dd, J = 17.9, 5.5Hz), 1.70 (1H, m), 1.67 (1H,
m), 1.47 (1H, m), 0.94 (3H, d, J = 6.4Hz), 0.79 (3H, d, J = 6.4H
z) (6) cis-5-isobutyl-4-methanesulfonyloxy-1- (4-phenoxybenzyl) pyrrolidine-2
-1.00 g (2.40 mmol) and potassium thioacetate 548 mg (4.80 m
mol) from trans-4-acetylthio-5-isobutyl-1- (4-phenoxybenzyl) pyrrolidine-2-
227 mg (24% yield) were obtained as a colorless oil. ¹ H-NMR (300 MHz, CDCl ₃ ) δ: 7.34 (2H, m), 7.19 (2H, d, J = 8.7 H
z), 7.11 (1H, m), 6.99 (4H, m), 5.02 (1H, d, J = 15.3Hz), 3.86
(1H, d, J = 15.3Hz), 3.81 (1H, m), 3.30 (1H, m), 3.09 (1H, dd, J
= 17.7,7.9Hz), 2.37 (1H, dd, J = 17.7,2.3Hz), 2.29 (3H, s),
1.77 (1H, m), 1.42 (2H, m), 0.92 (3H, d, J = 6.8Hz), 0.80 (3H, m
d, J = 6.8Hz)

Example 180 trans-5-isobutyl-4-mercapto-1- (4-phenoxybenzyl) pyrrolidin-2-one The trans-4-acetylthio- obtained in Example 179
227 mg (0.571 mmol) of 5-isobutyl-1- (4-phenoxybenzyl) pyrrolidin-2-one was treated in the same manner as in Example 31 to give trans-5-isobutyl-4-mercapto-1- (4-phenoxybenzyl). ) Pyrrolidin-2-one
165 mg (81% yield) were obtained as a colorless oil. ¹ H-NMR (300 MHz, CDCl ₃ ) δ: 7.34 (2H, m), 7.24 (2H, d, J = 8.3 Hz), 7.11 (1H, m), 6.99 (4
H, m), 5.03 (1H, d, J = 15.1Hz), 3.88 (1H, d, J = 15.1Hz), 3.29
(1H, m), 3.23 (1H, m), 3.03 (1H, dd, J = 17.3,7.9Hz), 2.38 (1H
H, dd, J = 17.3,2.6Hz), 1.78 (1H, d, J = 6.8Hz), 1.68 (1H, m),
1.48 (1H, m), 1.28 (1H, m), 0.93 (3H, d, J = 6.8Hz), 0.85 (3H, m
(d, J = 6.4Hz)

Example 181 trans-4-acetylthio-5-benzyl-1- (4-phenoxybenzyl) pyrrolidin-2-one (1) As in Example 20, D, L-phenylalanine 8.2
6 g (50.0 mmol), methanol 50 ml, thionyl chloride 13.
From 0 ml (180 mmol), 10.6 g (98% yield) of D, L-phenylalanine methyl ester hydrochloride was obtained as a white powder. ¹ H-NMR (300 MHz, D ₂ O) δ: 7.45 (3H, m), 7.34 (2H, m),
4.46 (1H, m), 3.87 (3H, s), 3.3
9 (1H, dd, J = 14.3, 5.9 Hz), 3.2
7 (1H, dd, J = 14.3, 7.5 Hz) (2) D, L-phenylalanine methyl ester hydrochloride
3.24 g (15.0 mmol), 3.14 ml of triethylamine (22.5 mmo
l), 2.63 ml of 4-phenoxybenzaldehyde (15.0 mmo
l), from 496 mg (13.1 mmol) of sodium borohydride,
4.05 g (yield 75%) of-(4-phenoxybenzyl) -D, L-phenylalanine methyl ester was obtained as a colorless oil. ¹ H-NMR (300 MHz, CDCl ₃ ) δ: 7.21-7.36 (5H, m), 7.14-7.20 (4H, m), 7.09 (1H, m), 6.99
(2H, m), 6.92 (2H, d, J = 8.3Hz), 3.78 (1H, d, J = 12.8Hz), 3.66
(3H, s), 3.60 (1H, d, J = 12.8Hz), 3.54 (1H, t, J = 6.8Hz), 2.99
(1H, dd, J = 13.6,6.4Hz), 2.94 (1H, dd, J = 13.6,7.5Hz) (3) N- (4-phenoxybenzyl) -D, L-phenylalanine methyl ester 4.05 g (11.2 mmol ), 1.87 ml (13.4 mmol) of triethylamine, ethylmalonyl chloride
From 1.72 ml (13.4 mmol), N- (ethylmalonyl) -N-
5.34 g (100% yield) of (4-phenoxybenzyl) -D, L-phenylalanine methyl ester was obtained as a colorless oil. ¹ H-NMR (300 MHz, CDCl ₃ ) (only main peaks are described) δ: 7.23-7.38 (6H, m), 7.06-7.19 (4H, m), 6.99 (2H, m), 6.90
(2H, d, J = 8.7Hz), 4.41 (1H, d, J = 16.8Hz), 4.28 (1H, dd, J = 9.
4,5.7Hz), 4.21 (2H, q, J = 7.2Hz), 3.83 (1H, d, J = 16.8Hz), 3.
66 (3H, s), 3.46 (1H, d, J = 14.9Hz), 3.38 (1H, d, J = 14.9Hz),
3.36 (1H, m), 3.25 (1H, m), 1.29 (3H, t, J = 7.2Hz) (4) N- (ethylmalonyl) -N- (4-phenoxybenzyl) -D, L-phenylalanine methyl Ester 5.34
g (11.2 mmol), 20% sodium ethoxide ethanol solution
After treatment with 4.39 ml (11.2 mmol), and after decarboxylation, 424 mg (11.2 mmol) of sodium borohydride was reacted to give 5-benzyl-4-hydroxy-1- (4-phenoxybenzyl) pyrrolidine-2-yl. 3.93 g (94% yield) of ON were obtained as a colorless oil. ¹ H-NMR (300 MHz, CDCl ₃ ) (only main peaks are described) δ: 7.20-7.38 (5H, m), 7.08-7.19 (5H, m), 7.01 (2H, m), 6.96
(2H, d, J = 8.7Hz), 5.02 (1H, d, J = 15.1Hz), 4.22 (1H, m), 3.93
(1H, d, J = 15.1Hz), 3.73 (1H, dt, J = 5.3,7.5Hz), 3.00 (2H, d,
J = 7.5Hz), 2.63 (1H, dd, J = 17.0,6.4Hz), 2.44 (1H, dd, J = 17.
0,3.4Hz), 1.84 (1H, d, J = 4.5Hz) (5) 5-benzyl-4-hydroxy-1- (4-phenoxybenzyl) pyrrolidin-2-one 3.70 g (9.91mmo
l), 2.76 ml (19.8 mmol) of triethylamine and 1.53 ml (19.8 mmol) of methanesulfonyl chloride, followed by preparative high performance liquid chromatography in the same manner as in Example 175 to give cis-5-benzyl-4-methane Sulfonyloxy-1- (4-phenoxybenzyl) pyrrolidin-2-one
1.65 g (37% yield) was obtained as a white powder. ¹ H-NMR (300 MHz, CDCl ₃ ) δ: 7.22-7.39 (5H, m), 7.14 (3H, m), 7.02 (4H, m), 6.94 (2H,
d, J = 8.7Hz), 5.09 (1H, m), 5.06 (1H, d, J = 15.1Hz), 4.01 (1H, m
m), 3.75 (1H, d, J = 15.1 Hz), 3.05 (2H, d, J = 6.8 Hz), 2.87 (3H,
s), 2.74 (2H, d, J = 6.0 Hz) (6) cis-5-benzyl-4-methanesulfonyloxy-1- (4-phenoxybenzyl) pyrrolidine-2-
ON 1.35 g (2.99 mmol) and potassium thioacetate 683 mg (5.98 mmo
From l), trans-4-acetylthio-5-benzyl-1- (4-phenoxybenzyl) pyrrolidin-2-one
327 mg (25% yield) were obtained as a colorless oil. Elemental analysis (%) Calculated as C ₂₆ H ₂₅ NO ₃ S.0.2H ₂ O C, 71.76; H, 5.88; N, 3.22 Observed C, 71.71; H, 6.02; N, 2.97

Example 182 trans-5-benzyl-
4-mercapto-1- (4-phenoxybenzyl) pyrrolidin-2-one trans-4-acetylthio- obtained in Example 181
185 mg (0.429 mmol) of 5-benzyl-1- (4-phenoxybenzyl) pyrrolidin-2-one was treated in the same manner as in Example 31 to give trans-5-benzyl-4-mercapto-1
-(4-phenoxybenzyl) pyrrolidin-2-one 135m
g (81% yield) was obtained as a colorless oil. Elemental analysis value (%) Calculated value as C ₂₄ H ₂₃ NO ₂ S · 0.2H ₂ O C, 73.33; H, 6.00; N, 3.56 Actual value C, 73.41; H, 6.16; N, 3.56

Example 183 Trans-4-acetylthio-5-propylaminocarbonyloxymethyl-1-
(4-phenoxybenzyl) pyrrolidin-2-one 122 ml of propyl isocyanate (1.43
mmol) and 0.36 ml of a 4N hydrogen chloride ethyl acetate solution (1.
Cis-5-Hydroxymethyl-4-methanesulfonyloxy-1- (4-phenoxybenzyl) pyrrolidin-2-one obtained in Example 20 while adding and stirring.
280 mg (0.72 mmol) were added. After stirring at room temperature overnight, the reaction solution was concentrated and subjected to silica gel column chromatography.
Elution with methanol: chloroform (3:97) yielded 320 mg (94% yield) of cis-4-methanesulfonyloxy-5-propylaminocarbonyloxymethyl-1- (4-phenoxybenzyl) pyrrolidin-2-one as a colorless oil. Obtained as a product.
300 mg (0.63 mmol) of the obtained cis-mesylate was dissolved in 15 ml of ethanol, and 360 mg (3.15 mmol) of potassium thioacetate was added, followed by stirring at 90 ° C. for 3 hours. After concentration of the reaction solution, ethyl acetate and water were added to the residue for extraction, and the ethyl acetate layer was washed with water.
Concentrate and subject the residue to silica gel column chromatography, eluting with ethyl acetate: n-hexane (30:70).
31 mg (22% yield) of trans-4-acetylthio-5-propylaminocarbonyloxymethyl-1- (4-phenoxybenzyl) pyrrolidin-2-one was obtained as a colorless oil. ¹ H-NMR (200 MHz, CDCl ₃ ) d: 7.40-6.90 (9 H, m), 5.01 (1 H, d, J = 15.7 Hz), 4.87-4.65 (1
H, m), 4.42-4.32 (1H, m) 4.21-3.95 (3H, m), 3.52-3.45 (1H, m
m), 3.20-3.08 (2H, m), 3.05 (1H, dd, J = 8.9,17.8Hz) 2.37 (1
(H, dd, J = 4.0,22.0Hz), 2.30 (3H, s), 1.60-1.45 (2H, m), 0.92
(3H, t, J = 7.5Hz).

Example 184 trans-4-Mercapto-5-propylaminocarbonyloxymethyl-1-
(4-phenoxybenzyl) pyrrolidin-2-one trans-4-acetylthio- obtained in Example 183
5-propylaminocarbonyloxymethyl-1- (4
-Phenoxybenzyl) pyrrolidin-2-one 57 mg (0.13
was dissolved in 5 ml of methanol, and 24 μl (0.13 mmol) of a 28% methanol solution of sodium methoxide was added.
For a minute. After concentration of the reaction solution, ethyl acetate and dilute hydrochloric acid were added to the residue for extraction, the ethyl acetate layer was washed with water, concentrated, the residue was subjected to silica gel column chromatography, and ethyl acetate: n-hexane (30:70). Eluted, trans-4
-Mercapto-5-propylaminocarbonyloxymethyl-1- (4-phenoxybenzyl) pyrrolidine-2-
On 23 mg (44% yield) was obtained as a colorless oil. ¹ H-NMR (200 MHz, CDCl ₃ ) d: 7.40-6.90 (9 H, m), 5.02 (1 H, d, J = 15.0 Hz), 4.87-4.65 (1
H, m), 4.30-4.10 (2H, m) 3.99 (1H, d, J = 15.0Hz), 3.51-3.35
(2H, m), 3.19-3.08 (2H, m), 3.00 (1H, dd, J = 8.3,16.0Hz), 2.
39 (1H, dd, J = 5.2,16.0Hz), 1.87 (1H, d, J = 6.9Hz), 1.60-1.4
3 (2H, m), 0.92 (3H, t, J = 7.4Hz)

Example 185 trans-4-acetylthio-5- (tetrahydro-2H-pyran-2-yl) oxymethyl-1- (4-phenoxybenzyl) pyrrolidine-
2-one cis-5-hydroxymethyl-4 obtained in Example 20
Dissolve 200 mg (0.51 mmol) of -methanesulfonyloxy-1- (4-phenoxybenzyl) pyrrolidin-2-one in 5 ml of chloroform, add 51 mg (0.61 mmol) of dihydropyran and one drop of concentrated hydrochloric acid, and stir at room temperature for 3 hours. did. Saturated aqueous sodium hydrogen carbonate solution was added to the reaction solution for extraction, the chloroform layer was washed with water and concentrated. The residue was subjected to silica gel column chromatography, eluted with chloroform, and 5- (tetrahydro-2H-pyran-2-yl). Oxymethyl 210
mg (87% yield) as a colorless oil. The obtained 5- (tetrahydro-2H-pyran-2-yl) oxymethyl compound 2
In a similar manner to that of Example 183, trans-4-acetylthio-5- (tetrahydro-2H-pyran-2-yl) oxymethyl-1- (4- Phenoxybenzyl) pyrrolidin-2-one (40 mg, yield 21%) was obtained as a colorless oil. ¹ H-NMR (200 MHz, CDCl ₃ ) d: 7.40-6.90 (18 H, m), 5.09 (1 H, d, J = 15.2 Hz), 4.83 (1 H, d,
J = 15.1Hz), 4.66-4.63 (1H, m), 4.39-4.35 (1H, m), 4.19 (1H, m
d, J = 15.0Hz), 4.05-3.40 (12H, m), 3.21-3.06 (2H, m), 2.40-
2.39 (2H, m), 2.30 (3H, s), 2.29 (3H, s), 1.80-1.45 (12H, m).

Example 186 trans-4-acetylthio-5-ethoxycarbonylmethylaminocarbonyl-
1- (4-phenoxybenzyl) pyrrolidin-2-one cis-5-hydroxymethyl-4 obtained in Example 20
-Methanesulfonyloxy-1- (4-phenoxybenzyl) pyrrolidin-2-one 500 mg (1.28 mmol) in acetone
The mixture was dissolved in 20 ml, and while stirring under ice cooling, the Jones reagent was added dropwise until the orange color of the reaction solution became stable, and the mixture was further stirred under ice cooling for 2 hours. After adding 1 ml of 2-propanol, ethyl acetate and water were added for extraction. The ethyl acetate layer was washed with water and concentrated, and the residue was crystallized by adding ethyl acetate and n-hexane to obtain a 5-carboxylic acid compound (450 mg, yield 87%) as a white powder. 300 mg (0.74 mmol) of the obtained carboxylic acid compound was dissolved in 15 ml of N, N-dimethylformamide, and 153 mg (0.80 mmol of 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide was dissolved.
l), 108 mg (0.80 mmol) of hydroxybenzotriazole was added, and the mixture was stirred at room temperature for 15 minutes. Glycine ethyl ester hydrochloride 112 mg (0.80 mmol), triethylamine 8
A solution of 1 mg (0.80 mmol) in 3 ml of dimethylformamide was added dropwise at room temperature, and the mixture was stirred for 3 hours. Ethyl acetate and diluted hydrochloric acid were added to the reaction solution for extraction, and the ethyl acetate layer was washed with water.
After concentration, the residue was subjected to silica gel column chromatography, and eluted with chloroform: methanol (98: 2).
160 mg (44% yield) of an ethoxycarbonylmethylaminocarbonyl compound was obtained as a colorless oil. 170 mg (0.35 mmol) of the obtained 5-ethoxycarbonylmethylaminocarbonyl compound,
From 198 mg (1.73 mmol) of potassium thioacetate, trans-4-acetylthio-5-ethoxycarbonylmethylaminocarbonyl-1- (4-phenoxybenzyl) pyrrolidin-2-one 41 mg (yield 25%) in the same manner as in Example 183. ) Was obtained as a colorless oil. ¹ H-NMR (200 MHz, CDCl ₃ ) d: 7.40-6.90 ( ¹⁰ H, m), 5.17 (1 H, d, J = 15.1 Hz), 4.26-3.80
(5H, m), 4.24 (2H, q, J = 7.2Hz), 3.05 (1H, dd, J = 8.1,18.0H
z), 2.34 (1H, dd, J = 1.5,18.0Hz), 2.33 (3H, s), 1.30 (3H, t, J
= 7.2Hz)

Example 187 Trans-5-aminocarbonyl-4-acetylthio-1- (4-phenoxybenzyl) pyrrolidin-2-one In the same manner as in Example 186, carboxylic acid 578 mg (1.43
mmol) and concentrated aqueous ammonia to give 220 mg (46% yield) of the amide. Further, trans-5-aminocarbonyl-4-acetylthio-1- (4-phenoxybenzyl) pyrrolidin-2-one 28 mg (yield 14) was obtained from the obtained amide 220 mg (0.54 mmol) and potassium thioacetate 310 mg (2.72 mmol). %) As a white powder. ^{1 H-NMR (200MHz, CDCl} 3) d: 7.40-6.90 (9H, m), 6.73 (1H, brs), 5.66 (1H, brs), 5.19
(1H, d, J = 15.3Hz), 3.98 (1H, d, J = 8.9Hz), 3.85 (1H, d, J = 15.
4Hz), 3.77 (1H, s), 3.05 (1H, dd, J = 9.0,17.8Hz), 2.35 (1H, d
d, J = 1.4,18.0Hz), 2.33 (3H, s)

Example 188 trans-5-aminocarbonyl-4-mercapto-1- (4-phenoxybenzyl) pyrrolidin-2-one trans-5-aminocarbonyl-4-acetylthio-1-one obtained in Example 187 (4-phenoxybenzyl)
Example 57 from 57 mg (0.13 mmol) of pyrrolidin-2-one
Trans-5-aminocarbonyl-4-
23 mg (44% yield) of mercapto-1- (4-phenoxybenzyl) pyrrolidin-2-one was obtained as a colorless oil. ¹ H-NMR (200 MHz, CDCl ₃ ) d: 7.40-6.90 (9H, m), 5.84 (1
H, brs), 5.68 (1H, brs), 5.14
(1H, d, J = 14.8 Hz), 3.88 (1H,
d, J = 14.7 Hz), 3.72 (1H, d, J =
4.1 Hz), 3.62-3.48 (1H, m),
07 (1H, dd, J = 8.2, 18.0), 2.39
(1H, dd, J = 5.0, 18.0 Hz), 2.04
(1H, d, J = 7.2Hz)

Example 189 trans-4-acetylthio-5- (2-hydroxyethyl) aminocarbonyl-
1- (4-phenoxybenzyl) pyrrolidin-2-one In the same manner as in Example 186, carboxylic acid 700 mg (1.73
180 mg of amide form (yield 2 mmol) and 2-aminoethanol.
3%). Further, trans-4-acetylthio-5- (2-hydroxyethyl) aminocarbonyl-1- (4-phenoxybenzyl) pyrrolidine-2- was obtained from the obtained amide form 160 mg (0.36 mmol) and potassium thioacetate 163 mg (1.43 mmol).
52 mg (34% yield) were obtained as a white powder. ¹ H-NMR (200 MHz, CDCl ₃ ) d: 7.40-6.85 ( ¹⁰ H, m), 5.11 (1 H, d, J = 15.1 Hz), 4.00-3.94
(1H, m), 3.86 (1H, d, J = 15.4Hz), 3.80-3.70 (3H, m), 3.60-3.
30 (2H, m), 3.08 (1H, dd, J = 8.0,18.0Hz), 2.34 (1H, dd, J = 2.
0,18.0Hz), 2.32 (3H, s)

Example 190: trans-5- (2-hydroxyethyl) aminocarbonyl-4-mercapto-1
-(4-phenoxybenzyl) pyrrolidin-2-one trans-4-acetylthio- obtained in Example 189
5- (2-hydroxyethyl) aminocarbonyl-1-
(4-phenoxybenzyl) pyrrolidin-2-one 25 mg
(0.058 mmol) and trans-5- (2-hydroxyethyl) aminocarbonyl-4- in the same manner as in Example 184.
5 mg of mercapto-1- (4-phenoxybenzyl) pyrrolidin-2-one (22% yield) was obtained as a colorless oil. ¹ H-NMR (200 MHz, CDCl ₃ ) d: 7.42-6.89 (9H, m), 6.30-6.17 (1H, m), 5.07 (1H, d, J = 14.
7Hz), 3.91 (1H, d, J = 14.7Hz), 3.78-3.30 (6H, m), 3.08 (1H, d
d, J = 8.0,18,0Hz), 2.38 (1H, dd, J = 5.2,18.0Hz), 2.03 (1H,
d, J = 7.0Hz)

Example 191 Trans-4-acetylthio-5- (4-pyridylmethyl) aminocarbonyl-1-
(4-phenoxybenzyl) pyrrolidin-2-one In the same manner as in Example 186, carboxylic acid derivative 600 mg (1.48
(mmol) and 4-aminomethylpyridine 320 mg
(44% yield). The obtained amide form 300 mg (0.61 mmo
l) and 346 mg (3.00 mmol) of potassium thioacetate
4-acetylthio-5- (4-pyridylmethyl) aminocarbonyl-1- (4-phenoxybenzyl) pyrrolidine-
98 mg of 2-one (34% yield) was obtained as a colorless oil. ¹ H-NMR (200 MHz, CDCl ₃ ) d: 8.60-8.57 (2H, m), 7.40-6.90 (12H, m), 5.14 (1H, d, J = 1
5.4Hz), 4.51 (1H, d, J = 6.1Hz), 3.93 (1H, d, J = 8.8Hz), 3.89
(1H, d, J = 15.3Hz), 3.76 (1H, s), 3.06 (1H, dd, J = 9.1,18.0H
z), 2.36 (1H, dd, J = 1.5,18.0Hz), 2.34 (3H, s)

Example 192 trans-4-Mercapto-5- (4-pyridylmethyl) aminocarbonyl-1-
(4-phenoxybenzyl) pyrrolidin-2-one trans-4-acetylthio- obtained in Example 191
5- (4-pyridylmethyl) aminocarbonyl-1- (4
-Phenoxybenzyl) pyrrolidin-2-one 50 mg (0.11
mmol) in the same manner as in Example 184.
23 mg (yield 48%) of mercapto-5- (4-pyridylmethyl) aminocarbonyl-1- (4-phenoxybenzyl) pyrrolidin-2-one was obtained as a colorless oil. ¹ H-NMR (200 MHz, CDCl ₃ ) d: 8.59-8.50 (2H, m), 7.40-6.90 (11H, m), 6.88-6.65 (1H,
m), 5.04 (1H, d, J = 15.0Hz), 4.46 (2H, d, J = 6.2Hz), 3.87 (1H,
d, J = 14.6Hz), 3.75 (1H, d, J = 4.3Hz), 3.62-3.45 (1H, m), 3.0
4 (1H, dd, J = 8.2,18.0Hz), 2.36 (1H, dd, J = 5.4,18.0Hz), 2.0
5-1.95 (1H, m)

Example 193 4-Acetylthio-1-
[(1-benzoyl-4-piperidyl) methyl] pyrrolidin-2-one 2.28 g (0.02 mol) of 4-aminomethylpiperidine and 2.12 g (0.02 mol) of benzaldehyde are dissolved in 20 ml of toluene, and heated under reflux for 2 hours while dehydrating. did. After concentrating the reaction solution, chloroform (20 ml) and triethylamine (2.23 g, 0.022 mol) were added, and while stirring under ice cooling, benzoyl chloride (2.81 g, 0.022 mol) was added dropwise. After stirring for 2 hours, the reaction solution was concentrated, 30 ml of acetic acid and 10 ml of water were added, and the mixture was stirred at room temperature for 30 minutes. After concentrating the reaction solution, diethyl ether and water were added thereto, and the mixture was separated. The aqueous layer was made basic with an aqueous sodium hydroxide solution and then extracted with chloroform. The chloroform layer was washed with water and concentrated to give 1-benzoyl-4-aminomethylpiperidine (2.71 g, yield 62.1%) as a colorless oil.
From the obtained 1-benzoyl-4-aminomethylpiperidine, 4-acetylthio-1 was obtained in the same manner as in Example 123.
-[(1-Benzoyl-4-piperidyl) methyl] pyrrolidin-2-one was obtained. ¹ H-NMR (200 MHz, CDCl ₃ ) d: 7.39 (5H, s), 4.81-4.55 (1 H, m), 4.13-4.00 (1 H, m), 4.00
-3.62 (1H, m), 3.89 (1H, dd, J = 7.3,12.0Hz), 3.31 (1H, dd, J =
4.5,12.0Hz), 3.35-3.01 (2H, m), 3.00-2.75 (2H, m), 2.87 (1H
H, dd, J = 8.8,18.0Hz), 2.38 (1H, dd, J = 5.6,18.0Hz), 2.35 (3
H, s), 2.13-1.80 (1H, m), 1.80-1.50 (2H, m), 1.40-1.15 (2H,
m).

Example 194 Trans-4-acetylthio-3-methyl-1- (4-phenoxybenzyl) pyrrolidin-2-one 0.70 g of the pyrrolidin-2-one compound obtained in Example 15 (2.
(0 mmol) was dissolved in 15 ml of acetonitrile, 0.5 ml of water was added, and 9
Stirred at 0 ° C. for 20 minutes. After concentration of the reaction solution, 15 ml of tetrahydrofuran and 0.32 g of 1,1-diethoxytrimethylamine (2.
2 mmol) and stirred at 80 ° C. for 30 minutes. After concentrating the reaction solution,
To the residue was added 15 ml of 2-propanol, and 0.15 g (4.0 mmol) of sodium borohydride was added with stirring at room temperature. 1
After stirring for an hour, the reaction solution was concentrated, and the residue was extracted with ethyl acetate and saturated aqueous sodium hydrogen carbonate. The ethyl acetate layer was washed with water, concentrated and subjected to silica gel column chromatography, and eluted with methanol: chloroform (3:97) to obtain 0.41 g (yield 68.1%) of an alcohol as a colorless oil.
0.36 g (1.2 mmol) of the obtained alcohol was dissolved in 10 ml of pyridine, and 0.28 g (2.4 mmol) of methanesulfonyl chloride was added, followed by stirring at 50 ° C. for 2 hours. After the reaction solution was concentrated, the residue was acidified by adding 2N hydrochloric acid and extracted with ethyl acetate.
After concentrating the ethyl acetate layer, the residue was subjected to silica gel column chromatography, and eluted with ethyl acetate: n-hexane (60:40) to obtain a cis-mesylate compound (0.12 g, yield 26.2%) as a colorless oil. 38 mg (0.1 mmol) of the obtained cis-mesylate
Was dissolved in 2 ml of N, N-dimethylformamide, and 57 mg (0.5 mmol) of potassium thioacetate was added thereto, followed by stirring at 45 ° C. overnight. Ethyl acetate and water were added to the reaction solution, and the mixture was extracted. The ethyl acetate layer was washed with water, concentrated, and the residue was subjected to silica gel column chromatography, eluted with ethyl acetate: n-hexane (30:70), and trans-4- Acetylthio-3-methyl-1
-(4-phenoxybenzyl) pyrrolidin-2-one 24 mg
(68% yield) as a colorless oil. ¹ H-NMR (200 MHz, CDCl ₃ ) d: 7.40-6.90 (9 H, m), 4.49 (1 H, d, J = 14.7 Hz), 4.37 (1 H, d, J
= 14.7Hz), 4.30-4.20 (1H, m), 3.66 (1H, dd, J = 10.7,6.6Hz),
3.12 (1H, dd, J = 10.7,4.3Hz), 2.92-2.78 (1H, m), 2.33 (3H,
s), 1.20 (3H, d, J = 7.3Hz)

Example 195 trans-4-Mercapto-3-methyl-1- (4-phenoxybenzyl) pyrrolidin-2-one The trans-4-acetylthio- obtained in Example 194
From 4-methyl-1- (4-phenoxybenzyl) pyrrolidin-2-one (20 mg, 0.056 mmol), trans-4-mercapto-3-methyl-1- (4-
Phenoxybenzyl) pyrrolidin-2-one 17 mg (yield 97
%) As a colorless oil. ¹ H-NMR (200 MHz, CDCl ₃ ) d: 7.40-6.90 (9 H, m), 4.52 (1 H, d, J = 14.6 Hz), 4.37 (1 H, d, J
= 14.7Hz), 3.71-3.56 (2H, m), 3.19-3.05 (1H, m), 2.80-2.67
(1H, m), 1.44 (1H, d, J = 7.9Hz), 1.26 (3H, d, J = 7.3Hz)

Example 196 S- [5-oxo-1-
(4-phenoxybenzoyl) -3-pyrrolidinyl]
Dissolve 3.0 g (29.67 mmol) of ethanethioate 4-hydroxy-2-pyrrolidone and 5050 mg (74.18 mmol) of imidazole in 15 ml of DMF, and add te
rt-butyldimethylchlorosilane 5366 mg (35.60 mmol)
Was added and stirred at room temperature for 24 hours. Ethyl acetate was added to the reaction solution, washed four times with water and saturated brine, and dried over anhydrous sodium sulfate. After concentration under reduced pressure, n-hexane:
4- (yield 89%) obtained by powdering from ethyl acetate (1: 1).
{[(Tert-butyl (dimethyl) silyl] oxy} -2
-Dissolve 400 mg (1.86 mmol) of pyrrolidinone in 4 ml of THF,
Add 89 mg (2.23 mmol) of 60% sodium hydride with
After stirring for 4 minutes, THF 4 ml, 4-phenoxybenzoic acid 477 mg
(2.23 mmol), 389 μl of oxalyl chloride (4.46 mmol), DM
A 4-phenoxybenzoyl chloride solution prepared from 5 μl of F (catalytic amount) was added, and the mixture was immediately brought to room temperature and stirred for 2 hours. The reaction solution was concentrated under reduced pressure, and dissolved in ethyl acetate.
The extract was washed with water, a saturated aqueous solution of sodium hydrogencarbonate and saturated saline, and then dried over anhydrous sodium sulfate. After concentrating under reduced pressure, the residue was purified by preparative thin-layer chromatography (developing solvent: n-hexane: ethyl acetate (3: 1)), dissolved in ethyl acetate, saturated aqueous sodium hydrogen carbonate solution three times, and saturated saline solution. And then dried over anhydrous sodium sulfate. 100 mg (0.244 mmol) of 1- (4-phenoxybenzoyl) -4-{[(tert-butyl (dimethyl) silyl] oxy} -2-pyrrolidinone obtained after concentration under reduced pressure (yield 26%) was added to TH.
After dissolving in 1 ml of F, 244 μl (0.24 mmol) of 1M tetrabutylammonium fluoride in THF was added at 0 ° C., and the mixture was stirred at the same temperature for 15 minutes. After concentrating the reaction solution under reduced pressure, preparative thin-layer chromatography (developing solvent: n-hexane: ethyl acetate)
(1: 2)) (78% yield), 4-hydroxy-1
-(4-phenoxybenzoyl) -2-pyrrolidinone 30
mg (0.10 mmol), N, N, N ', N'-tetramethylazodicarboxamide 26.1 mg (0.15 mmol), tributylphosphine 38 μl
(0.15 mmol) was dissolved in 0.5 ml of toluene, and 7.2 μl (0.10 mmol) of thiolacetic acid was added at 0 ° C., and the mixture was immediately brought to room temperature and stirred for 20 hours. 7.2 μl (0.10 mmol) of thiolacetic acid was added again, and the mixture was further stirred for 24 hours. The reaction solution was concentrated under reduced pressure, dissolved in ethyl acetate, washed twice with water and saturated brine, and dried over anhydrous sodium sulfate. After concentration under reduced pressure, the residue was purified by preparative thin-layer chromatography (developing solvent: n-hexane: ethyl acetate (1: 1)) to obtain 7 mg (yield 19%) of the title compound as a yellow oil. ¹ H-NMR (300 MHz, CDCl ₃ ) δ: 7.65-6.95 (9H, m), 4.33 (1
H, dd, J = 11.9, 6.9 Hz), 4.23-
4.14 (1H, m), 3.86 (1H, dd, J = 1
1.9, 5.0 Hz), 3.09 (1H, dd, J = 1)
8.2, 8.2 Hz), 2.61 (1H, dd, J = 1)
8.1, 5.8 Hz), 2.38 (3H, s)

Example 197 4.8 g (25.44 mmol) of S-((3R) -5-oxo-1- {4-[(phenylsulfonyl) amino] benzyl} pyrrolidinyl) ethanethioate 4-nitrobenzylamine hydrochloride;
(S)-(-)-O-acetylmalic anhydride 4.4 g (27.98 mmol),
Triethylamine 3 at 0 ° C in a mixture of 40 ml of acetonitrile
A solution of 547 μl (25.44 mmol) in 20 ml of THF was added dropwise. Immediately after the completion of the dropwise addition, the mixture was immediately brought to room temperature and stirred for 1.5 hours. The reaction mixture was concentrated under reduced pressure, dissolved in 50 ml of acetyl chloride, and
Stir for 2 hours. The reaction solution was concentrated under reduced pressure, dissolved in ethyl acetate, washed with water, a saturated aqueous solution of sodium hydrogen carbonate, and saturated saline, and then dried over anhydrous sodium sulfate. After concentration under reduced pressure, the residue was purified by silica gel column chromatography, and the fraction eluted with n-hexane: ethyl acetate (3: 1 to 2: 3) was concentrated (51% yield), (3S) -1- 2.0 g (6.84 mmol) of (4-nitrobenzyl) -2,5-dioxopyrrolidinyl acetate was dissolved in a mixed solvent of 11.5 ml of ethanol and 23 ml of THF, and 259 mg of sodium borohydride at -10 ° C.
(6.84 mmol), and the mixture was stirred at -13 to -10 ° C for 1 hour. Again, 259 mg (6.84 mmol) of sodium borohydride was added, and the mixture was further stirred at -13 to -10 ° C for 2.5 hours.To the reaction solution, a saturated aqueous solution of sodium hydrogen carbonate, ethyl acetate, and saturated saline were added, and the mixture was partitioned. The mixture was extracted twice with ethyl acetate, and the organic layers were combined and dried over anhydrous sodium sulfate. After concentration under reduced pressure, dissolved in trifluoroacetic acid 15 ml, triethylsilane 1093 μl
(6.84 mmol) was added and the mixture was stirred at room temperature for 10 minutes. The reaction mixture was concentrated under reduced pressure, dissolved in ethyl acetate, twice with a saturated aqueous sodium hydrogen carbonate solution, and twice with a saturated aqueous sodium hydrogen carbonate solution.
It was washed with 0.1N hydrochloric acid and saturated saline twice and dried over anhydrous sodium sulfate. After concentration under reduced pressure, chloroform 10 ml
Dissolved in acetic anhydride 1292 μl (13.67 mol), pyridine 1107
μl (13.67 mmol) was added, and the mixture was stirred at room temperature for 5 hours. The reaction mixture was concentrated under reduced pressure, dissolved in ethyl acetate, and concentrated with 1N hydrochloric acid.
After washing with saturated saline twice, it was dried over anhydrous sodium sulfate. After concentration under reduced pressure, the residue was purified by silica gel column chromatography, and n-hexane: ethyl acetate (33:67) was used.
The eluted fraction was concentrated (3 steps, 48% yield) to give (3S)-
1- (4-nitrobenzyl) -5-oxopyrrolidinyl acetate 200 mg (0.72 mmol) in the presence of 10% palladium-added carbon 258 mg, formic acid 1 ml and 1N hydrochloric acid in ethyl acetate
In a mixed solvent of 2 ml, vigorously stirred for 1 hour under a hydrogen atmosphere,
The reaction solution was filtered through celite, concentrated under reduced pressure, dissolved in ethyl acetate, washed with a saturated aqueous solution of sodium hydrogencarbonate and brine, and dried over anhydrous sodium sulfate. 0.5 ml of a 4N hydrochloric acid solution in ethyl acetate was added, and the mixture was concentrated under reduced pressure (yield: 82%). (3S) -1- (4-aminobenzyl)
-5mg-oxopyrrolidinyl acetate hydrochloride 167mg
(0.59 mmol), benzenesulfonyl chloride 82 μl (0.6
4 mmol) was dissolved in 2 ml of chloroform, and 172 μl (1.23 mmol) of triethylamine was added dropwise at 0 ° C. After dropping, 3 ° C at 0 ° C
Stirred for 0 minutes. The reaction solution was concentrated under reduced pressure, dissolved in ethyl acetate, washed with 0.1N hydrochloric acid and saturated saline, and then dried over anhydrous sodium sulfate. Concentrate under reduced pressure and preparative thin-layer chromatography (developing solvent: n-hexane: ethyl acetate
(1: 2)) (yield 71%), 130 mg (0.37 mmol) of (3S) -5-oxo-1- {4-[(phenylsulfonyl) amino] benzyl} pyrrolidinyl acetate was obtained.
519 μl (7.3 mmol) of acetyl chloride was added dropwise to 1 ml of ethanol to dissolve the solution, and the mixture was stirred at 50 ° C. for 1.5 hours. The reaction mixture was concentrated under reduced pressure to obtain (92% yield) N- (4-
{[(4S) -4-hydroxy-2-oxopyrrolidinyl] methyl} phenyl) benzenesulfonamide 116 mg (0.
335 mmol), 44 μl of methanesulfonyl chloride (0.57 mmo
l) was dissolved in 1 ml of acetonitrile, and a solution of 79.4 μl (1.07 mmol) of triethylamine in 1 ml of acetonitrile was added dropwise at 0 ° C. After completion of the dropwise addition, the mixture was stirred at 0 ° C. for 10 minutes, and again a solution of 44 μl (0.57 mmol) of methanesulfonyl chloride and 79.4 μl (1.07 mmol) of triethylamine in 0.5 ml of acetonitrile was added dropwise. After completion of the dropwise addition, the mixture was further stirred at 0 ° C. for 10 minutes. The reaction solution was concentrated under reduced pressure, dissolved in ethyl acetate, washed with water and saturated saline, and then dried over anhydrous sodium sulfate. It was concentrated under reduced pressure and purified by preparative thin-layer chromatography (developing solvent: chloroform: methanol (10: 1)).
(Yield 9%), 13 mg (0.03 mmol) of (3S) -5-oxo-1- {4-[(phenylsulfonyl) amino] benzyl} pyrrolidinyl methanesulfonate was dissolved in 1 ml of DMF, and 8 mg (0.02 mmol) of cesium carbonate was dissolved. , Thiolacetic acid 11μl (0.15mmo
l) DMF (1 ml) was added, and the mixture was stirred at room temperature for 24 hours under a nitrogen atmosphere. Again, a solution of 10 mg (0.03 mmol) of cesium carbonate and 4 μl (0.06 mmol) of thiolacetic acid in 1 ml of DMF was added, and the mixture was stirred under a nitrogen atmosphere at room temperature for 11 days. Ethyl acetate was added to the reaction solution, which was washed three times with water and saturated saline, and then dried over anhydrous sodium sulfate. After concentration under reduced pressure, preparative thin-layer chromatography (developing solvent: n-hexane: ethyl acetate (1:
Purification by 2)) yielded 1.6 mg (13% yield) of the title compound as a colorless oil. ¹ H-NMR (300 MHz, CDCl ₃ ) δ: 7.88-7.01 (9 H, m), 6.74 (1 H, m), 4.51-4.06 (2 H, m), 4.08
-3.99 (1H, m), 3.82-3.67 (1H, m), 3.23-3.08 (1H, m), 2.90 (1
H, dd, J = 17.4,8.9Hz), 2.52-2.35 (1H, m), 2.31 (3H, s)

Example 198 S-｛(3R) -1- [4
-(1,3-benzodioxol-5-yloxy) benzyl] -5-oxopyrrolidinyl} ethanethioate 3.0 g (24.17 mmol) of 4-fluorobenzaldehyde, 3,4
3.3 g (24.17 mmol) of methylenedioxyphenol and 3.3 g (24.17 mmol) of potassium carbonate were stirred in 20 ml of DMF at 120 ° C. for 22 hours, ethyl acetate was added to the reaction solution, and the mixture was washed four times with water and saturated brine. Then, it was dried over anhydrous sodium sulfate. After concentration under reduced pressure, the residue was purified by silica gel column chromatography, and the fraction eluted with n-hexane: ethyl acetate (92: 8) was concentrated (yield 25%). 2.9 g of sole-5-yloxy) benzaldehyde (11.95 mmo
l), hydroxylamine hydrochloride 1030 mg (14.82 mmol),
1486 mg (17.57 mmol) of sodium bicarbonate in ethanol 41 m
l, stirred in a mixed solvent of water (6 ml) at 60 ° C for 1 hour, concentrated under reduced pressure, dissolved in ethyl acetate, washed twice with water, washed with saturated saline, and dried over anhydrous sodium sulfate. did.
After concentration under reduced pressure, 684 μl of acetic acid (11.95 mmol), in the presence of 258 mg of carbon with 10% palladium, in vigorously stirring for 2 hours in 55 ml of methanol under a hydrogen atmosphere, the reaction solution was filtered through Celite, and concentrated under reduced pressure. In ethyl acetate, 3 ml of a 4N hydrochloric acid solution in ethyl acetate was added dropwise, concentrated under reduced pressure, and then powdered from ethyl acetate (2 steps, yield: 77%) to give 4- (1,3-benzodioxole-). 5-yloxy) benzylamine hydrochloride 2.0 g (7.15 mmol), (S)-(-)-O-acetylmalic anhydride
1244mg (7.87mmol), acetonitrile 10ml mixture at 0 ℃
Then, a solution of 996 μl (7.15 mmol) of triethylamine in 5 ml of THF was added dropwise. Immediately after the completion of the dropwise addition, the mixture was immediately brought to room temperature and stirred for 2 hours. After concentrating the reaction solution under reduced pressure, acetyl chloride 20 ml
And stirred at 60 ° C. for 30 minutes. The reaction solution was concentrated under reduced pressure, dissolved in ethyl acetate, washed with water, a saturated aqueous solution of sodium hydrogen carbonate, and saturated saline, and then dried over anhydrous sodium sulfate. After concentration under reduced pressure, the residue is purified by silica gel column chromatography and n-hexane: ethyl acetate
(3: 1) The eluted fraction was concentrated (92% yield), (3S) -1
1592 mg (4.15 mmol) of-[4- (1,3-benzodioxol-5-yloxy) benzyl] -2,5-dioxopyrrolidinyl acetate was dissolved in a mixed solvent of 7 ml of ethanol and 14 ml of THF. 314mg sodium borohydride at ℃
(8.30 mmol) was added, and the mixture was stirred at -14 to -10 ° C for 3 hours. A saturated aqueous sodium hydrogen carbonate solution, ethyl acetate and saturated saline were added to the reaction solution, and the mixture was partitioned. The aqueous layer was extracted twice with ethyl acetate, and the organic layers were combined and dried over anhydrous sodium sulfate. After concentration under reduced pressure, the residue was dissolved in 9 ml of trifluoroacetic acid, and 663 μl (4.15 mmol) of triethylsilane was added thereto, followed by stirring at room temperature for 30 minutes. The reaction solution was concentrated under reduced pressure, dissolved in ethyl acetate, washed with a saturated aqueous solution of sodium hydrogen carbonate and saturated saline, and then dried over anhydrous sodium sulfate. After concentration under reduced pressure,
A solution prepared by adding 639 μl (83 mmol) of acetyl chloride dropwise to 15 ml of ethanol was dissolved in the solution, followed by stirring at 50 ° C. for 1.5 hours. After the reaction solution was concentrated under reduced pressure, it was purified by silica gel column chromatography, and n-hexane: acetone (55: 4
5) The eluted fraction was concentrated (3 steps, yield 34%) to obtain (4S)
250 mg (0.76 mmol) of -1- [4- (1,3-benzodioxol-5-yloxy) benzyl] -4-hydroxy-2-pyrrolidinone, 82 μl of methanesulfonyl chloride
(1.07 mmol) was dissolved in 2 ml of chloroform, and a solution of 149 μl (1.07 mmol) of triethylamine in 1 ml of chloroform was added at 0 ° C. to 10 ml.
Dropped over minutes. After completion of the dropwise addition, the mixture was stirred at 0 ° C. for 10 minutes. The reaction solution was concentrated under reduced pressure, and dissolved in ethyl acetate.
After washing with water and saturated saline, it was dried over anhydrous sodium sulfate. Concentrated under reduced pressure (quantitative), (3S) -1-
[4- (1,3-benzodioxol-5-yloxy) benzyl] -5-oxopyrrolidinyl methanesulfonate 200 mg (0.53 mmol) was dissolved in DMF 1 ml, cesium carbonate 22 mg (0.37 mmol), thiol acetic acid 191 μl (2.67 mmol)
DMF (1 ml) was added, and the mixture was stirred at room temperature under a nitrogen atmosphere for 48 hours. Ethyl acetate was added to the reaction solution, and the mixture was washed five times with water and saturated brine, and then dried over anhydrous sodium sulfate. After concentration under reduced pressure, preparative thin-layer chromatography (developing solvent: n
-Hexane: ethyl acetate (1: 1)) to give the title compound 8
8 mg (43% yield) was obtained as a brown oil. ¹ H-NMR (300 MHz, CDCl ₃ ) δ: 7.17-6.47 (7H, m), 5.97 (2
H, s), 4.44 (1H, d, J = 14.6 Hz),
4.38 (1H, d, J = 14.7 Hz), 4.09-
4.00 (1H, m), 3.74 (1H, dd, J = 1)
0.6, 7.5 Hz), 3.15 (1H, dd, J = 1)
0.6, 4.9 Hz), 2.91 (1H, dd, J = 1)
7.4, 9.0 Hz), 2.41 (1H, dd, J = 1)
7.4, 6.0 Hz), 2.31 (3H, s)

Example 199 (R) -4-Acetylthio-1- [4- (4′-bromophenoxy) benzyl] pyrrolidin-2-one In the same manner as in Example 125, 4-fluorobenzaldehyde and 4-bromobenzaldehyde were used. 4-prepared from phenol
(4'-bromophenoxy) benzylamine and (S)-
(R) -4-Acetylthio-1- [4- (4′-bromophenoxy) benzyl] pyrrolidin-2-one was obtained as a pale orange powder from O-acetylmalic anhydride. ¹ H-NMR (200 MHz, CDCl ₃ ) δ: 7.44 (2H, d, J = 9.0 Hz), 7.20 (2H, d, J = 8.7 Hz), 6.96 (2H,
d, J = 8.7Hz), 6.89 (2H, d, J = 9.0Hz), 4.43 (2H, s), 4.14-3.98
(1H, m), 3.76 (1H, dd, J = 10.6,7.5Hz), 3.17 (1H, dd, J = 10.6,
5.0Hz), 2.92 (1H, dd, J = 17.4,8.9Hz), 2.43 (1H, dd, J = 17.4,
6.0Hz), 2.32 (3H, s)

Example 200 (R) -4-mercapto-
1- [4- (4′-Bromophenoxy) benzyl] pyrrolidin-2-one In the same manner as in Example 126, the (R) -4-acetylthio-1- [4- (4 '-Bromophenoxy) benzyl] pyrrolidin-2-one 200m
g (0.48 mmol) from (R) -4-mercapto-1- [4
-(4'-bromophenoxy) benzyl] pyrrolidine-
180 mg of 2-one (77% yield) was obtained as a pale pink oil. ¹ H-NMR (200 MHz, CDCl ₃ ) δ: 7.44 (2H, d, J = 9.0 Hz), 7.23 (2H, d, J = 8.7 Hz), 6.96 (6H,
d, J = 8.7Hz), 6.88 (2H, d, J = 9.0Hz), 4.49 (1H, d, J = 14.9Hz),
4.37 (1H, d, J = 14.9Hz), 3.66 (1H, dd, J = 9.8,7.2Hz), 3.55-
3.46 (1H, m), 3.17 (1H, dd, J = 9.8,4.8Hz), 2.93 (1H, dd, J = 1
7.2,8.0Hz), 2.43 (1H, dd, J = 17.2,6.1Hz), 1.87 (1H, d, J = 6.
7Hz)

Example 201 4-acetylthio-1-
(2-dibenzofuranmethyl) pyrrolidin-2-one (1) 10.0 g (60 mmol) of dibenzofuran was added to chloroform 3
The mixture was dissolved in 00 ml and stirred under ice cooling. 9.8 ml of titanium tetrachloride (89
mmol) was added dropwise over 30 minutes, and the mixture was further stirred under ice cooling for 1.5 hours. To this solution, 8.1 ml (89 mmol) of dichloromethyl methyl ether was added dropwise over 30 minutes, and the mixture was further stirred under ice cooling for 2.5 hours. Ice was slowly added to the reaction solution, and the mixture was stirred for 1 hour while returning to room temperature. After concentrating under reduced pressure, extracting twice with ethyl acetate, the obtained organic layer was washed with water and saturated saline, and dried over anhydrous sodium sulfate. After concentration under reduced pressure, the residue was subjected to silica gel column chromatography and eluted with hexane: ethyl acetate (95: 5) to give 3.50 g (yield 30%) of 2-dibenzofurancarboxaldehyde as an orange powder . ¹ H-NMR (300 MHz, CDCl ₃ ) δ: 10.14 (1 H, s), 8.51 (1 H, d, J = 1.4 Hz), 8.03 (1 H, d, J = 8.5 H)
z), 8.03 (1H, dd, J = 8.2,1.0Hz), 7.70 (1H, d, J = 8.5Hz), 7.63
(1H, d, J = 8.2Hz), 7.54 (1H, ddd, J = 7.2,7.2,1.4Hz), 7.42 (1
(H, ddd, J = 7.4,7.4,1.0Hz) (2) In the same manner as in Example 30, 1.22 g (5.6 mmol) of 2-chloromethyldibenzofuran and 1.16 g of 4-trimethylsilyloxypyrrolidin-2-one were obtained. (6.7mol)
To obtain 4-acetylthio-1- (2-dibenzofuranmethyl) pyrrolidin-2-one (537 mg, yield 29%) as a brown oil. ¹ H-NMR (300 MHz, CDCl ₃ ) δ: 7.95 (1 H, d, J = 7.4 Hz), 7.84 (1 H, d, J = 1.4 Hz), 7.57 (1 H,
d, J = 8.2Hz), 7.53 (1H, d, J = 8.4Hz), 7.47 (1H, ddd, J = 7.4,7.
4,1.4Hz), 7.35 (2H, m), 4.67 (1H, d, J = 14.6Hz), 4.56 (1H, d,
J = 14.6Hz), 4.06 (1H, m), 3.78 (1H, dd, J = 10.7,7.5Hz), 3.19
(1H, dd, J = 10.7,4.8Hz), 2.95 (1H, dd, J = 17.5,9.0Hz), 2.46
(1H, dd, J = 17.5,5.9Hz), 2.28 (3H, s)

Example 202 4-Mercapto-1- (2
-Dibenzofuranmethyl) pyrrolidin-2-one In the same manner as in Example 31, 4-acetylthio-1- (2-dibenzofuranmethyl) obtained in Example 201
From 282 mg (0.80 mmol) of pyrrolidin-2-one, 4-mercapto-1- (2-dibenzofuranmethyl) pyrrolidine-
207 mg (87% yield) of 2-one was obtained as a colorless oil. ¹ H-NMR (300 MHz, CDCl ₃ ) δ: 7.95 (1 H, d, J = 7.4 Hz), 7.85 (1 H, d, J = 1.4 Hz), 7.57 (1 H,
d, J = 8.2Hz), 7.53 (1H, d, J = 8.5Hz), 7.47 (1H, ddd, J = 7.4,7.
3,1.4Hz), 7.35 (2H, m), 4.66 (1H, d, J = 14.6Hz), 4.59 (1H, d,
J = 14.6Hz), 3.68 (1H, dd, J = 10.2,7.2Hz), 3.54 (1H, m), 3.19
(1H, dd, J = 10.2,5.1Hz), 2.95 (1H, dd, J = 17.1,8.2Hz), 2.45
(1H, dd, J = 17.1,6.1Hz), 1.85 (1H, d, J = 6.8Hz)

Example 203 4-acetylthio-1-
[4- (N-phenyl-NP-toluenesulfonyl) aminobenzyl] pyrrolidin-2-one (1) 20.0 g (148 mmol) of acetanilide and 13.9 g (76.5 mmol) of 4-bromobenzonitrile are heated at 120 ° C. under a nitrogen atmosphere. , And further dissolve copper (I) oxide (23.0 g, 161 mmol), potassium carbonate
18.0 g (130 mmol) was added and the mixture was stirred at 200 ° C. for 18 hours under a nitrogen atmosphere. Ethyl acetate was added to the reaction solution, followed by filtration. The ethyl acetate layer was washed with water and saturated saline, and dried over anhydrous sodium sulfate. After concentration under reduced pressure, the residue was subjected to silica gel column chromatography. The fraction eluted with hexane: ethyl acetate (80:20) was concentrated under reduced pressure, and crystallized from hexane-ethyl acetate to give 5.51 g of 4-cyano-N-phenylaniline ( (Yield 37%)
Was obtained as pale yellow needles. ¹ H-NMR (300 MHz, CDCl ₃ ) δ: 7.48 (2H, d, J = 8.7 Hz), 7.36 (2H, m), 7.17 (2H, m), 7.12 (1
H, m), 6.97 (2H, d, J = 8.7Hz), 6.07 (1H, s) (2) 1.00 g of 4-cyano-N-phenylaniline (5.15
mmol) in 40 ml of toluene, 618 mg (15.5 mmol) of 60% sodium hydride, p-toluenesulfonyl chloride
2.95 g (15.5 mmol) was added, and the mixture was heated and stirred at 100 ° C. for 3 days.
After water was added to the reaction solution, the mixture was extracted twice with ethyl acetate. The ethyl acetate layer was washed with water and saturated saline, and then dried over anhydrous sodium sulfate. After concentration under reduced pressure, the residue was subjected to silica gel column chromatography, eluted with hexane: ethyl acetate (80:20), and 510 mg of 4-cyano-N-phenylaniline as a raw material was obtained.
After recovering the desired product, 4-cyano-N-phenyl-N
-P-Toluenesulfonylaniline was obtained. The recovered raw material is subjected to the same reaction, and 4-cyano-N-phenyl-N
A total of 1.47 g (82% yield) of -p-toluenesulfonylaniline was obtained as a pale yellow powder. ¹ H-NMR (300 MHz, CDCl ₃ ) δ: 7.61 (2H, d, J = 8.3 Hz), 7.56 (2H, d, J = 8.7 Hz), 7.38 (3H,
m), 7.34 (2H, d, J = 8.7Hz), 7.30 (2H, d, J = 8.3Hz), 7.21 (2H, d
m), 2.44 (3H, s) (3) After dissolving 1.26 g (3.62 mmol) of 4-cyano-N-phenyl-NP-toluenesulfonylaniline in a mixture of 36.2 ml of toluene and 7.24 ml of dichloromethane under an argon atmosphere. The mixture was cooled to -78 ° C, and 5.43 ml (5.43 mmol) of a 1 M solution of diisobutylaluminum hydride in toluene was added. After stirring at -78 ° C for 0.5 hour, the mixture was further stirred at room temperature for 2 hours. After adding 7.24 ml of methanol and 7.24 ml of 2N hydrochloric acid to the reaction solution,
The mixture was extracted twice with ethyl acetate, and the ethyl acetate layer was washed twice with water and once with saturated saline, and then dried over anhydrous sodium sulfate.
After concentration under reduced pressure, the residue was subjected to silica gel column chromatography, and the fraction eluted with hexane: ethyl acetate (80: 20-70: 30) was concentrated under reduced pressure to give 4-formyl-N-phenyl-N-p.
1.04 g (82% yield) of toluenesulfonylaniline was obtained as a pale yellow powder. ¹ H-NMR (300 MHz, CDCl ₃ ) δ: 9.94 (1 H, s), 7.79 (2 H, d, J = 8.3 Hz), 7.62 (2 H, d, J = 8.3 H)
z), 7.40 (2H, d, J = 8.3Hz), 7.36 (3H, m), 7.29 (2H, d, J = 8.3H
z), 7.25 (2H, m), 2.44 (3H, s) (4) 1.00 g (2.85 mmol) of 4-formyl-N-phenyl-Np-toluenesulfonylaniline in methanol 200
After dissolution in ml, sodium borohydride 108 mg (2.85 mmol)
Was added and stirred at room temperature for 0.5 hour. After concentrating the reaction solution under reduced pressure, ethyl acetate was added, and the mixture was washed with water and saturated saline and dried over anhydrous sodium sulfate. After concentration under reduced pressure, 1.05 g (yield quantitative) of 4-hydroxymethyl-N-phenyl-N-p-toluenesulfonylaniline was obtained as a colorless oil. ¹ H-NMR (300 MHz, CDCl ₃ ) δ: 7.58 (2H, d, J = 8.3 Hz), 7.20
−7.35 (11H, m), 4.67 (2H, d, J =
5.8 Hz), 2.43 (3H, s), 1.69 (1
(H, t, J = 5.8 Hz) (5) 4-hydroxymethyl-N-phenyl-Np
1.05 g (2.85 mmol) of toluenesulfonylaniline, 231 μl of pyridine (2.85 mmol), 229 μl of thionyl chloride (3.14 m
mol) was treated in the same manner as in Example 159 to give 4-chloromethyl-N-phenyl-Np-toluenesulfonylaniline (1.05 g, quantitative yield) as a colorless oil. ¹ H-NMR (300 MHz, CDCl ₃ ) δ: 7.59 (2H, d, J = 8.3 Hz), 7.21-7.36 (11H, m), 4.54 (2H, s),
2.44 (3H, s) (6) As in Example 30, 4-chloromethyl-N-
Phenyl-Np-toluenesulfonylaniline 1.05 g
(2.82 mmol), 4-trimethylsilyloxypyrrolidine-
494 mg (2.85 mmol) of 2-one, powdered potassium hydroxide 1
From 60 mg (2.85 mmol), 4-hydroxy-1- [4- (N-
439 mg (35% yield) of phenyl-Np-toluenesulfonylamino) benzyl] pyrrolidin-2-one was obtained as a brown oil. ¹ H-NMR (300 MHz, CDCl ₃ ) δ: 7.57 (2 H, d, J = 8.3 Hz), 7.15 to 7.35 (11 H, m), 4.50 (1 H, m),
4.48 (1H, d, J = 15.1Hz), 4.40 (1H, d, J = 15.1Hz), 3.51 (1H, d
d, J = 10.9,5.5Hz), 3.19 (1H, dd, J = 10.9,1.9Hz), 2.73 (1H, d
d, J = 17.3,6.4Hz), 2.44 (3H, s), 2.42 (1H, dd, J = 17.3,2.3H
z) (7) 4-hydroxy-1- [4- (N-phenyl-N
-P-toluenesulfonylamino) benzyl] pyrrolidin-2-one 390 mg (0.893 mmol), triethylamine 374 μl
(2.68 mmol), 208 μl of methanesulfonyl chloride (2.68 mmo
l) to 4-methanesulfonyloxy-1- [4- (N-phenyl-Np-toluenesulfonylamino) benzyl]
419 mg (91% yield) of pyrrolidin-2-one were obtained as a colorless oil. ¹ H-NMR (300 MHz, CDCl ₃ ) δ: 7.57 (2H, d, J = 8.3 Hz), 7.15-7.35 (11H, m), 5.28 (1H, m),
4.48 (1H, d, J = 15.6Hz), 4.42 (1H, d, J = 15.6Hz), 3.65 (1H, d
d, J = 12.1,5.5Hz), 3.50 (1H, dd, J = 12.1,1.9Hz), 2.98 (3H,
s), 2.86 (1H, dd, J = 17.9,6.8Hz), 2.70 (1H, dd, J = 17.9,2.3H
z), 2.44 (3H, s) (8) 4-Methanesulfonyloxy-1- [4- (N-
Phenyl-Np-toluenesulfonylamino) benzyl] pyrrolidin-2-one (350 mg, 0.680 mmol) and potassium thioacetate (155 mg, 1.36 mmol) were converted to 4-acetylthio-1-.
[4- (N-phenyl-Np-toluenesulfonylamino) benzyl] pyrrolidin-2-one (268 mg, yield 80%) was obtained as a colorless oil. ¹ H-NMR (300 MHz, CDCl ₃ ) δ: 7.57 (2H, d, J = 8.3 Hz), 7.20-7.36 (9H, m), 7.16 (2H, d, J =
(8.3Hz), 4.45 (1H, d, J = 15.1Hz), 4.39 (1H, d, J = 15.1Hz), 4.0
5 (1H, m), 3.74 (1H, dd, J = 10.6,7.7Hz), 3.16 (1H, dd, J = 10.
6,4.9Hz), 2.90 (1H, dd, J = 17.5,8.9Hz), 2.44 (3H, s), 2.40
(1H, m), 2.31 (3H, s)

Example 204 4-Mercapto-1- [4
-(N-phenyl-Np-toluenesulfonylamino)
Benzyl] pyrrolidin-2-one 4-acetylthio-1- [4-
(N-phenyl-Np-toluenesulfonylamino) benzyl] pyrrolidin-2-one (120 mg, 0.243 mmol) and acetyl chloride (345 μl, 4.85 mmol) were prepared in the same manner as in Example 126, using 4-mercapto-1- [ 4- (N-phenyl-N-
p-toluenesulfonylamino) benzyl] pyrrolidine-
65.3 mg of 2-one (59% yield) was obtained as a white powder. ¹ H-NMR (300 MHz, CDCl ₃ ) δ: 7.57 (2 H, d, J = 8.3 Hz), 7.15 to 7.36 (11 H, m), 4.45 (1 H, d, J
= 15.5Hz), 4.40 (1H, d, J = 15.5Hz), 3.64 (1H, dd, J = 10.2,7.4
Hz), 3.54 (1H, m), 3.16 (1H, dd, J = 10.2, 4.9Hz), 2.90 (1H, d
d, J = 17.3,8.1Hz), 2.44 (3H, s), 2.40 (1H, dd, J = 17.3,6.0H
z), 1.86 (1H, d, J = 6.4Hz)

Reference Example 1 Production of Recombinant Human MMP-13 Enzyme A paper by Freije, JM et al. (Journal of Biological Chemistr
y, 269: 16766-16773, 1994), and human MMP-13 cDNA was obtained by a PCR method known per se. Obtained human MMP
PBlueBac4 (Invitrogen) incorporating Ba-13 cDNA and Bacu
The lovirus vector Bac-N-Blue (Invitrogen) was co-transfected into Sf9 cells to obtain an MMP-13 expressing recombinant virus. The obtained recombinant virus is transferred to High-Five cells (Inv
(3), and the culture supernatant on the third day was used as an enzyme solution.

Reference Example 2 Method for MMP-13 Inhibitory Activity Recombinant human MMP-13, 200 mM sodium chloride, 20 mM calcium chloride, 0.1% Brij35, 1 mM 2-mercaptoethanol, 200 mM Tris-HCl buffer ( pH 7.5) and 40 μM MOCAc-Pro-Leu-Gly-
The reaction was started by adding 25 μl of Leu-A ₂ pr (DNP) -Ala-Arg-NH ₂ (manufactured by Peptide Research Laboratories), incubated at 37 ° C. for 2 hours, and then 500 mM sodium acetate-hydrochloric acid buffer. (PH3.0) 1
The reaction was stopped by adding 00 μl. MOCAc-Pro-Leu-G released
The amount of ly was measured at an excitation wavelength of 330 nm and a fluorescence wavelength of 405 nm using a fluorometer (MTP-32 / F2: manufactured by Corona Electric Co., Ltd.). In addition, the fluorescence measurement value of the same reaction without adding a sample was set to 100%, and the concentration of each sample required for 50% inhibition was shown as an IC ₅₀ value. The structural formulas and IC ₅₀ values of the compounds of the examples are described below.

[Table 1]

[Table 2]

[Table 3]

[Table 4]

[Table 5]

[Table 6]

[Table 7]

[Table 8]

[Table 9]

[Table 10]

[Table 11]

[Table 12]

[Table 13]

Reference Example 3 Method of Measuring Cartilage Collagen Degradation Inhibitory Activity Nasal cartilage was aseptically excised from a slaughtered cow, and 5% heat-inactivated fetal bovine serum, penicillin G 100 units / ml, streptomycin 100 units / ml were added. Using a modified Dulbecco's modified Eagle's medium, the cells were pre-cultured for 3 days at 37 ° C, 5% carbon dioxide, and 95% air. After completion of the preculture, a cartilage piece weighing about 10 mg was prepared, and human recombinant interleukin-1β (IL-1β:
(Zenzyme) and a test compound were added to 100 μl of the culture solution. Change the culture medium every week for a total of 3
After culturing for a week, the total amount of hydroxyproline released into the culture solution and the amount of hydroxyproline in the remaining cartilage pieces were measured to determine the collagen degradation rate. The activity of the test compound to inhibit collagen degradation was determined by the following equation. Formula: Collagen degradation inhibitory activity (%) = 100 x (Ci-Cs)
/ (Ci-Cc) (where Cc indicates the collagen degradation rate when neither IL-1β nor the test compound is contained, Ci indicates the collagen degradation rate when IL-1β is added, and Cs indicates IL- 1 shows the collagen decomposition rate when both 1β and the test compound are added, and shows the collagen decomposition inhibitory activity of the compounds of the examples below.

[Table 14]

[0329]

EFFECT OF THE INVENTION The compound (I) or a salt thereof has an excellent MMP inhibitory action, especially an MMP-13 inhibitory action, and therefore has an osteoarthritis, rheumatoid arthritis, osteoporosis, cancer,
Safe prevention and treatment of periodontal disease, corneal ulcer, pathological bone resorption (eg, Paget's disease), nephritis, arteriosclerosis, emphysema, cirrhosis, autoimmune diseases (eg, Crohn's disease, Sjogren's disease), cancer metastasis, contraception, etc. Useful as a medicine.

──────────────────────────────────────────────────続 き Continued on the front page (51) Int.Cl. ⁷ Identification symbol FI theme coat ゛ (Reference) A61K 31/45 A61K 31/45 31/5375 31/5375 A61P 1/16 A61P 1/16 5/38 5 / 38 13/12 13/12 15/00 15/00 19/08 19/08 29/00 29/00 35/00 35/00 43/00 111 43/00 111 C07D 207/273 C07D 207/273 207/40 207/40 211/76 211/76 401/04 401/04 403/12 403/12 405/04 405/04 405/12 405/12 409/12 409/12 (72) Inventor Koji Yoshimura Tsukuba, Ibaraki 1-7-9 Kasuga 9 Takeda Kasuga Heights 101

Claims (15)

[Claims] (1) Formula (1) [In the formula, ring A and ring B are the same or different and each represents an optionally substituted homo- or heterocyclic ring, and the substituents of ring A and ring B are bonded to each other to form ring A, ring B, X ^Two
And R ¹ may be the same or different and are each a hydrogen atom, an optionally substituted hydrocarbon group, an acyl group, an optionally substituted heterocyclic group or SR ² (R ² Represents a hydrogen atom, a hydrocarbon group which may be substituted, an acyl group or a heterocyclic group which may be substituted), and X ¹ represents a bond, optionally substituted 2
A monovalent C _1-3 aliphatic hydrocarbon group or —NR ³ — (R ³ represents a hydrogen atom, an optionally substituted hydrocarbon group or an acyl group), and X ² represents a bond, substituted Divalent C _1-3 aliphatic hydrocarbon group which may be substituted, —NR ⁴ — (R ⁴ represents a hydrogen atom, an optionally substituted hydrocarbon group or an acyl group), —O— or —S ( O) p- (p is 0, 1
Or 2), wherein Y is the same or different and each is a hydrogen atom, an optionally substituted hydrocarbon group, a halogen atom, a carboxyl group, an acyl group, an optionally substituted hydroxy group, An optionally substituted amino group, SR ⁵ (R ⁵ represents a hydrogen atom, an optionally substituted hydrocarbon group, an acyl group or an optionally substituted heterocyclic group), an oxo group, a thioxo group, a substituted Represents an imino group, a nitro group or a cyano group, m represents the same or different and represents 0 or 1, n represents an integer of 1 to 3, q ₁ represents an integer of 1 to 2n + 4, q ₂ Represents an integer of 0 to 2n + 3, and the sum of q ₁ and q ₂ represents 2n + 4. However, when the ring B is a nitrogen-containing heterocyclic ring, X ² is bonded to a substitutable position other than the nitrogen atom on the ring B. Or a salt thereof. 2. The compound according to claim 1, wherein each of the ring A and the ring B is an optionally substituted benzene ring. (3) R ¹ is the same or different and each is a hydrogen atom, an optionally substituted lower alkyl group,-(C =
O) -R ⁶ (R ⁶ is a hydrogen atom, optionally substituted hydrocarbon group, an optionally substituted amino group or an optionally substituted hydroxy group) or SR ² (R ² is claimed The compound according to claim 1, which has the same significance as described in item 1.). 4. A compound according to claim 1, wherein R ¹ is the same or different. (Wherein each symbol has the same meaning as described in claim 1) or a formula (Wherein each symbol has the same meaning as described in claim 1). 5. The compound according to claim 1, wherein X ¹ is an optionally substituted methylene group. 6. The compound according to claim 1, wherein X ² is —O—. 7. A compound of the formula [I] The group represented by is (R ⁷ to R ¹¹ are the same or different and each represents a hydrogen atom, a lower alkyl group which may be substituted, a hydroxy group which may be substituted, an amino group which may be substituted or SR ¹² (R ¹² is A hydrogen atom, a hydrocarbon group which may be substituted, an acyl group or a heterocyclic group which may be substituted), and other symbols are as defined in claim 1). The compound according to claim 1, which is a group. 8. A compound of the formula [I] The group represented by is (R ¹³ to R ²⁵ are the same or different and are each independently a hydrogen atom, a lower alkyl group which may be substituted, a hydroxy group which may be substituted, an amino group which may be substituted or SR ¹² (R ¹² is A hydrogen atom, an optionally substituted hydrocarbon group, an acyl group or an optionally substituted heterocyclic group), and the other symbols have the same meanings as in claim 1). 2. The compound according to 1. 9. The compound according to claim 1, wherein m is 0. 10. The formula: (Wherein each symbol has the same meaning as described in claim 1). 11. A compound of the formula (Wherein L represents a leaving group, and other symbols are as defined in claim 1)
The meaning is as described. And a salt thereof, and a compound represented by the formula: R ¹ SH (wherein R ¹ has the same meaning as in claim 1) or a salt thereof. Formula 10 (Wherein each symbol has the same meaning as described in claim 1) or a method for producing a salt thereof. 12. A compound of the formula (Wherein each symbol is as defined in claim 1) or a salt thereof, or a compound represented by the formula: (Wherein each symbol has the same meaning as in claim 1) or a salt thereof and a formula R ¹ SH (wherein, R ¹ has the same meaning as in claim 1). A compound represented by the formula: or a salt thereof, (Wherein each symbol has the same meaning as described in claim 1) or a method for producing a salt thereof. 13. A compound of the formula [In the formula, ring A and ring B are the same or different and each represents an optionally substituted homo- or heterocyclic ring, and the substituents of ring A and ring B are bonded to each other to form ring A, ring B, X ^Two
And R ¹ may be the same or different and are each a hydrogen atom, an optionally substituted hydrocarbon group, an acyl group, an optionally substituted heterocyclic group or SR ² (R ² Represents a hydrogen atom, a hydrocarbon group which may be substituted, an acyl group or a heterocyclic group which may be substituted), and X ¹ represents a bond, optionally substituted 2
A monovalent C _1-3 aliphatic hydrocarbon group or —NR ³ — (R ³ represents a hydrogen atom, an optionally substituted hydrocarbon group or an acyl group), and X ² represents a bond, substituted Divalent C _1-3 aliphatic hydrocarbon group which may be substituted, —NR ⁴ — (R ⁴ represents a hydrogen atom, an optionally substituted hydrocarbon group or an acyl group), —O— or —S ( O) p- (p is 0, 1
Or 2), wherein Y is the same or different and each is a hydrogen atom, an optionally substituted hydrocarbon group, a halogen atom, a carboxyl group, an acyl group, an optionally substituted hydroxy group, An optionally substituted amino group, SR ⁵ (R ⁵ represents a hydrogen atom, an optionally substituted hydrocarbon group, an acyl group or an optionally substituted heterocyclic group), an oxo group, a thioxo group, a substituted Represents an imino group, a nitro group or a cyano group, m represents the same or different and represents 0 or 1, n represents an integer of 1 to 3, q ₁ represents an integer of 1 to 2n + 4, q ₂ Represents an integer of 0 to 2n + 3, and the sum of q ₁ and q ₂ represents 2n + 4. Or a salt thereof. 14. A matrix metalloprotease inhibitor comprising the compound according to claim 13 or a salt thereof. 15. An agent for preventing or treating osteoarthritis, rheumatoid arthritis, osteoporosis, cancer, periodontal disease, or corneal ulcer, comprising the compound according to claim 13 or a salt thereof.