JP2000309590A - Substituted 7-oxabicyclo [2.2.1] heptane-2,3-dicarboxylic acid derivative, protein phosphatase inhibitor, and medicament - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain a new compound useful for a low molecular inhibitor having inhibiting activities against dephosphorilase 2B of serine/threonine protein, and exhibiting the selectivity from types 1 and 2A, and also useful for a biochemical research reagent and an immunosuppresant. SOLUTION: This new compound is represented by formula I [X is carboxyl or two Xs form C(O)OC(O) together with each other; R1 is a (substituted) alkyl, a (substituted) aryloxy or the like; R2 and R3 are each H, a (substituted) alkyl, a (substituted) aryloxy or the like], e.g. 1,5-dibenzoyloxymethyl-7- oxybicyclo[2.2.1]heptane-2,3-dicarboxylic anhydride. The compound of formula I is obtained by an addition reaction of maleic anhydride to a compound of formula II, a following hydrogenation of the product, and optional hydrolysis of the hydrogenated product. The compound of formula I has an inhibiting activity against dephosphorilase 2B of serine/threonine protein, stronger than that of cantharidin.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention relates to a substituted 7-oxabicyclo [2.2.1] heptane-2,3-dicarboxylic acid derivative, a substituted 7-oxabicyclo [2.2.1] heptane-2,3. The present invention relates to a protein phosphatase inhibitor and a medicament containing a dicarboxylic acid derivative or a salt thereof as an active ingredient, particularly an immunosuppressant.

[0002]

2. Description of the Related Art Serine / threonine protein phosphatase that removes the phosphoryl groups of serine and threonine phosphorylated in proteins are known to be of type 1, 2A and 2B. Of these, okadaic acid, microcystin, caliculin A, tautomycin, etc., which strongly inhibit types 1 and 2A, are widely used as research reagents for elucidating intracellular signal transduction systems, but have strong toxicity and cancer promoters. It is known to show activity. On the other hand, cyclosporin A and FK506, which are widely used clinically to suppress rejection in organ transplantation, bind to a protein called immunophilin in cells, and this complex forms serine / threonine protein dephosphorylation. It has been shown that inhibition of oxidase 2B (calcineurin) inhibits the proliferation of T cells and exerts an immunosuppressive effect (F.
McKeon, Cell, 66, p823-826, 1991, Nobuhiro Takahashi, separate volume Nikkei Science, 106, p120-130, 1993). Therefore, a selective inhibitor of serine / threonine protein phosphatase 2B is expected to be an excellent immunosuppressant as well as a biochemical research reagent. However, serine / threonine protein phosphatase 2B alone
No compound has been known so far, which strongly inhibits the compound 1 and exhibits high selectivity for type 1 and type 2A, and its development has been desired.

[0003]

An object of the present invention is to provide a low-molecular-weight inhibitor that inhibits serine / threonine protein phosphatase 2B, and a novel immunosuppressant.

[0004]

SUMMARY OF THE INVENTION Cantharidin (7-oxabicyclo [2.2.1] heptane-2,3-dimethyl)
-2,3-dicarboxylic anhydride) has been reported to have an extremely low inhibitory activity on serine / threonine protein phosphatase 2B (RE Honkanen, FE).
BS Lett., 330, p283-286, 1993), cantharidin itself more strongly inhibited types 1 and 2A and was a highly toxic compound. Therefore, the present inventors have conducted intensive studies and as a result,
7 having a substituent at the 1- and 5- and / or 6-positions
-Oxabicyclo [2.2.1] heptane-2,3-dicarboxylic acid derivative has a stronger inhibitory activity on serine / threonine protein phosphatase 2B than cantharidin,
Furthermore, they have found that they show selectivity for type 1 and type 2A, and completed the present invention.

That is, the present invention provides the following general formula [I]

[0006]

Embedded image

[0007] (wherein, X is two X either or adjacent shows the carboxyl group -C together (O) OC (O) - . To form a group represented by Also, R ¹ is substituted An alkyl group which may have a group, an alkenyl group which may have a substituent, an alkynyl group which may have a substituent, or an aryl group which may have a substituent, a substituent An optionally substituted acyl group, an optionally substituted acyloxy group, an optionally substituted alkoxy or aryloxycarbonyl group, an optionally substituted alkoxy or aryl Oxycarbonyloxy group, alkyl or arylthiocarbonyl group which may have a substituent, aminocarbonyl group which may have a substituent, aminocarbonyloxy group which may have a substituent, substituent To Alkyl or arylsulfonyl group which may be substituted, alkyl or arylsulfinyl group which may have a substituent, alkoxyl group which may have a substituent, aryloxy group which may have a substituent Represents an alkyl or arylthio group which may have a substituent, a carboxyl group, a cyano group, a nitro group, an amino group which may have a substituent, R ² and R ³ are each independently a hydrogen atom, An alkyl group which may have a substituent, an alkenyl group which may have a substituent, an alkynyl group which may have a substituent, or an aryl group which may have a substituent, An acyl group which may have a group, an acyloxy group which may have a substituent, an alkoxy or aryloxycarbonyl group which may have a substituent, a substituent An optionally substituted alkoxy or aryloxycarbonyloxy group, an optionally substituted alkyl or arylthiocarbonyl group, an optionally substituted aminocarbonyl group, An aminocarbonyloxy group, an alkyl or arylsulfonyl group which may have a substituent, an alkyl or arylsulfinyl group which may have a substituent, an alkoxyl group which may have a substituent, It represents an aryloxy group which may have a group, an alkylthio group which may have a substituent, a carboxyl group, a cyano group, a nitro group, a halogen atom, and an amino group which may have a substituent. However, R ² and R ³ are not simultaneously hydrogen atoms.) Substituted 7-oxabicyclo [2.2.1]
A heptane-2,3-dicarboxylic acid derivative is provided.

Further, the present invention provides the following general formula [I]

[0009]

Embedded image

[0010] (wherein, X is two X either or adjacent shows the carboxyl group -C together (O) OC (O) - . To form a group represented by Also, R ¹ is substituted An alkyl group which may have a group, an alkenyl group which may have a substituent, an alkynyl group which may have a substituent, or an aryl group which may have a substituent, a substituent An optionally substituted acyl group, an optionally substituted acyloxy group, an optionally substituted alkoxy or aryloxycarbonyl group, an optionally substituted alkoxy or aryl Oxycarbonyloxy group, alkyl or arylthiocarbonyl group which may have a substituent, aminocarbonyl group which may have a substituent, aminocarbonyloxy group which may have a substituent, substituent To Alkyl or arylsulfonyl group which may be substituted, alkyl or arylsulfinyl group which may have a substituent, alkoxyl group which may have a substituent, aryloxy group which may have a substituent Represents an alkyl or arylthio group which may have a substituent, a carboxyl group, a cyano group, a nitro group, an amino group which may have a substituent, R ² and R ³ are each independently a hydrogen atom, An alkyl group which may have a substituent, an alkenyl group which may have a substituent, an alkynyl group which may have a substituent, or an aryl group which may have a substituent, An acyl group which may have a group, an acyloxy group which may have a substituent, an alkoxy or aryloxycarbonyl group which may have a substituent, a substituent An optionally substituted alkoxy or aryloxycarbonyloxy group, an optionally substituted alkyl or arylthiocarbonyl group, an optionally substituted aminocarbonyl group, An aminocarbonyloxy group, an alkyl or arylsulfonyl group which may have a substituent, an alkyl or arylsulfinyl group which may have a substituent, an alkoxyl group which may have a substituent, It represents an aryloxy group which may have a group, an alkylthio group which may have a substituent, a carboxyl group, a cyano group, a nitro group, a halogen atom, and an amino group which may have a substituent. However, R ² and R ³ are not simultaneously hydrogen atoms.) Substituted 7-oxabicyclo [2.2.1]
Provided are a protein phosphatase inhibitor, an immunosuppressant, and a medicament comprising a heptane-2,3-dicarboxylic acid derivative or a salt thereof as an active ingredient.

[0011]

BEST MODE FOR CARRYING OUT THE INVENTION The compound represented by the above general formula [I] can be obtained by an addition reaction of a corresponding furan derivative represented by the following general formula [II] with maleic anhydride, followed by hydrogenation and, if desired, hydrolysis. Obtained by a decomposition reaction.

[0012]

Embedded image

(Wherein, X, R ¹ , R ² and R ³ are the same as described above)

In the present specification, the alkyl group in the "alkyl group which may have a substituent (s)" may be linear, branched or cyclic, and may be, for example, an alkyl group having 1 to 30 carbon atoms. Typically, methyl, ethyl, propyl,
Isopropyl, butyl, isobutyl, s-butyl, t-butyl, pentyl, isopentyl, neopentyl, hexyl, heptyl, octyl, nonyl, decyl, cyclopropyl, cyclobutyl,
Cyclopentyl, cyclohexyl, cycloheptyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl, hexadecyl, 14-methylpentadecyl, 6-methylpentadecyl, octadecyl, icosyl, tetracosyl And so on.

In the present specification, the alkenyl group in the "alkenyl group optionally having substituent (s)" may be any of linear, branched and cyclic, and is, for example, an alkenyl group having 2 to 30 carbon atoms. Allyl, vinyl, crotyl, 1-penten-1-yl, 2-penten-1-yl,
3-penten-1-yl group, 1-hexen-1-yl group, 2-
Hexen-1-yl group, 3-hexen-1-yl group, 2-cyclohexenyl group, 2-cyclopentenyl group, 8-heptadecen-1-yl group, 8,11-heptadecadien-1-yl group, 8, 11,14-heptadecatrien-1-yl group, 4,
7,10,13-nonadecatetraen-1-yl group, 9-octadecene-1-yl group, 9,12-octadecadien-1-yl group, 9,12,15-octadecatriene-1-yl group Il group,
6,9,12-octadecatrien-1-yl group, 5,8,1
1,14-icosatetraen-1-yl group, 5,8,11,1
4,17-icosapentaen-1-yl group, 4,7,10,1
3,16,19-docosahexaen-1-yl group and the like.

In the present specification, the alkynyl group in the “optionally substituted alkynyl group” may be any of linear, branched and cyclic, and is, for example, an alkynyl group having 2 to 30 carbon atoms. Ethynyl group, propargyl group,
1-pentyn-1-yl group, 2-pentyn-1-yl group, 3-
Pentin-1-yl group, 1-octin-1-yl group, 8-heptadecin-1-yl group and the like.

In the present specification, the aryl group in the "aryl group optionally having substituent (s)" includes a heteroaryl group, for example, a phenyl group, a naphthyl group, an anthranyl group, a pyrenyl group, a biphenyl group. , Pyridyl, pyrimidinyl, pyrazinyl, pyridanidyl, piperazinyl, pyrazolyl, imidazolyl, quinylyl, pyrrolyl, indolyl, furyl and the like.

In the present specification, the acyl group in "acyl group optionally having substituent (s) or acyloxy group optionally having substituent (s)" means linear, branched, cyclic, saturated, It may be unsaturated aliphatic or aromatic,
For example, an acyl group having 2 to 30 carbon atoms, specifically, an acetyl group, a propionyl group, an isopropionyl group, a pivaloyl group, an oleoyl group, a cyclohexylcarbonyl group, an acroyl group, a crotonoyl group, a benzoyl group, a naphthoyl group, a nicotinoyl group, and the like Is raised.

In the present specification, the alkoxy or aryloxycarbonyl group in the “optionally substituted alkoxy or aryloxycarbonyl group or the optionally substituted alkoxy or aryloxycarbonyloxy group” is Linear, branched, cyclic, saturated, unsaturated, aliphatic or aromatic, for example, methoxycarbonyl, ethoxycarbonyl, propyloxycarbonyl, isopropyloxycarbonyl, butoxycarbonyl, s- Butoxycarbonyl group, t-butoxycarbonyl group, cyclopentyloxycarbonyl group, cyclohexyloxycarbonyl group, benzyloxycarbonyl group, allyloxycarbonyl group, phenyloxycarbonyl group, pyridyloxycarbonyl group and the like Group.

In the present specification, the alkyl or arylthiocarbonyl group in the “alkyl or arylthiocarbonyl group optionally having substituent (s)” is a straight-chain, branched, cyclic, saturated or unsaturated aliphatic group. Or may be aromatic, for example, a methylthiocarbonyl group,
Ethylthiocarbonyl group, propylthiocarbonyl group,
Groups such as isopropylthiocarbonyl group, butylthiocarbonyl group, t-butylthiocarbonyl group, cyclopentyloxythiocarbonyl group, cyclohexyloxythiocarbonyl group, benzylthiocarbonyl group, phenylthiocarbonyl group and pyridylthiocarbonyl group.

In the present specification, the aminocarbonyl group in the “aminocarbonyl group which may have a substituent or the aminocarbonyloxy group which may have a substituent” is an unsubstituted carbamoyl group or a substituent. An alkyl group which may have a substituent, an aromatic group which may have a substituent, a hydroxyl group, an alkoxyl group which may have a substituent, an amino group which may have a substituent, and the like. Represents a substituted carbamoyl group, for example, carbamoyl group, ethylaminocarbonyl group, propylaminocarbonyl group,
Isopropylaminocarbonyl group, butylaminocarbonyl group, t-butylaminocarbonyl group, cyclopentylaminocarbonyl group, cyclohexylaminocarbonyl group, benzylaminocarbonyl group, phenylaminocarbonyl group, pyridylaminocarbonyl group, benzyloxyaminocarbonyl group, hydroxyaminocarbonyl And hydrazinocarbonyl groups.

In the present specification, the alkyl or arylsulfonyl group in the “alkyl or arylsulfonyl group optionally having substituent (s)” may be a straight-chain, branched, cyclic, saturated, unsaturated aliphatic or Any aromatic group may be used, for example, methanesulfonyl group, ethanesulfonyl group, benzenesulfonyl group, cyclohexanesulfonyl group, naphthalenesulfonyl group and the like.

In the present specification, the alkyl or arylsulfinyl group in the “optionally substituted alkyl or arylsulfinyl group” is a straight-chain, branched, cyclic, saturated or unsaturated aliphatic or Any of aromatic groups may be used, and examples thereof include groups such as a methanesulfinyl group, an ethanesulfinyl group, a benzenesulfinyl group, a cyclohexanesulfinyl group, and a naphthalenesulfinyl group.

[0024] In the present specification, in the "optionally substituted alkoxyl group or aryloxy group",
An alkoxyl group or an aryloxy group is linear,
Any of branched, cyclic, saturated, unsaturated aliphatic or aromatic, for example, an alkoxyl group or aryloxy group having 2 to 30 carbon atoms, specifically a methoxy group,
Examples include ethoxy, propyloxy, t-butoxy, allyloxy, cyclopentyloxy, cyclohexyloxy, benzyloxy, and phenoxy groups.

In the present specification, the alkyl or arylthio group in the “alkyl or arylthio group optionally having substituent (s)” is a straight-chain, branched, cyclic, saturated, unsaturated aliphatic or aromatic group. Any tribe may be
For example, an alkyl or arylthio group having 2 to 30 carbon atoms, specifically, methylthio, ethylthio, propylthio, t-butylthio, allylthio, cyclopentylthio, cyclohexylthio, benzylthio, phenylthio and the like can be mentioned. .

In the present specification, the “amino group optionally having substituent (s)” means an unsubstituted amino group, an alkyl group,
Shows an amino group substituted with an aromatic group and the like, for example, ethylamino group, propylamino group, isopropylamino group, butylamino group, t-butylamino group, benzylamino group, phenylamino group, pyridylamino group, piperazinyl group, Groups such as an indolinyl group and a dimethylamino group.

The above alkyl, alkenyl, alkynyl, aryl, acyl, acyloxy, alkoxy or aryloxycarbonyl, alkoxy or aryloxycarbonyloxy, alkylthio or arylthiocarbonyl, aminocarbonyl, aminocarbonyl Examples of the substituent which the oxy group, alkoxyl group or aryloxy group, alkyl or arylthio group, alkyl or arylsulfonyl group, alkyl or arylsulfinyl group, amino group and the like may have include, for example, an alkyl group, an alkenyl group and an alkynyl Group, aryl group, acyl group, acyloxy group, alkoxy or aryloxycarbonyl group, alkoxy or aryloxycarbonyloxy group, alkyl Thio or arylthiocarbonyl group, aminocarbonyl group, aminocarbonyloxy group, alkoxyl group or aryloxy group, alkyl or arylthio group, alkyl or arylsulfonyl group, alkyl or arylsulfinyl group, and specific examples thereof are Same as above. Other substituents include halogen atoms, nitro groups, amino groups (acyl groups, alkoxy or aryloxycarbonyl groups, carbamoyl groups, substituted sulfonyl groups, alkyl groups, cycloalkyl groups, aryl groups, and the like as substituents. And aralkyl groups such as a benzyl group, a phenethyl group and a naphthylmethyl group, in addition to groups such as a cyano group, a hydroxyl group and a carboxyl group.

In the present specification, the "halogen atom" includes a fluorine atom, a chlorine atom, a bromine atom and an iodine atom.

Pharmaceutically acceptable salts include inorganic or organic bases, for example, alkali metal salts such as sodium salt and potassium salt, alkaline earth metal salts such as calcium salt and magnesium salt, ammonium salt, triethylamine salt and ethanol. Examples thereof include aliphatic or heterocyclic aromatic amine salts such as amine salts, lysine salts, arginine salts, quinoline salts, and pyridine salts, and quaternary ammonium salts such as tetramethylammonium salts.

The compound of the present invention can be used in various forms for administration as a medicament, for example, tablets, capsules, powders, oral preparations such as granules or liquids, injections, rectum preparations, and the like. Parenteral preparations such as external preparations for the skin and inhalants.

The solid preparation can be produced as it is in the form of tablets, capsules, granules or powder, but it can also be produced using appropriate additives.
Examples of such additives include sugars such as lactose or glucose, starches such as fatty acids such as stearic acid,
For example, inorganic salts such as magnesium metasilicate aluminate or anhydrous calcium phosphate, synthetic polymers such as polyvinylpyrrolidone or polyalkylene glycol, fatty acid salts such as calcium stearate or magnesium stearate, alcohols such as stearyl alcohol or benzyl alcohol, Examples thereof include synthetic cellulose derivatives such as methylcellulose, ethylcellulose, carboxymethylcellulose and hydroxypropylmethylcellulose, and other commonly used additives such as water, gelatin, talc, vegetable oil, and gum arabic.

The liquid preparation is prepared by using an appropriate additive usually used in liquid preparations such as water, alcohols or plant-derived oils such as soybean oil, peanut oil or sesame oil, and is used as a suspension, syrup or injection. And so on.

In particular, as a suitable solvent for administration as an injection, for example, distilled water for injection, lidocaine hydrochloride aqueous solution, physiological saline, glucose aqueous solution, ethanol, liquid for intravenous injection (for example, citric acid and sodium citrate) And the like, an electrolyte solution and the like, or a mixed solution thereof. These injections may be in the form of a powder which is dissolved in advance, or a powder to which an appropriate additive has been added, which is dissolved at the time of use.

In order to prepare a rectal preparation, the active ingredient and a suppository base such as cocoa butter, a fatty acid tri-, di- or monoglyceride, or polyethylene glycol are heated, melted, poured into a mold and cooled. The active ingredient may be dissolved in polyethylene glycol, soybean oil or the like and then coated with a gelatin film.

To prepare an external preparation for skin, the active ingredient is added to petrolatum, beeswax, liquid paraffin, polyethylene glycol and the like, and if necessary, heated and kneaded to obtain an ointment, or rosin, alkyl acrylate or the like. After kneading with an adhesive such as an ester polymer, it is spread on a nonwoven fabric such as polyethylene to form a tape.

To produce an inhalant, the active ingredient is dissolved or dispersed in a propellant such as chlorofluorocarbon gas and filled into a pressure-resistant container to form an aerosol.

The actually preferred dose of the compound of the present invention varies depending on the kind of the composition, the frequency of application and the age, weight, and condition of the patient, but is usually about 1 to 5 times a day.
00 mg, and it is desirable to administer once or several times.

Hereinafter, the present invention will be described in detail with reference to Reference Examples, Examples and Test Examples, but it goes without saying that the present invention is not limited to these.

[0039]

【Example】

Reference Example 1

[0041]

Embedded image

Dimethylformamide (DMF) (3.56 mL, 46.0
mmol) was added little by little at 0 ° C. to phosphorus oxychloride (3.80 mL, 46.0 mmol), and the mixture was stirred for 30 minutes to synthesize a Vilsmeier reagent. To the Vilsmeier reagent, 3-benzoyloxymethylfuran (6.17 g, 30.7 mmol) obtained by benzoylation of 3-furanmethanol by a conventional method was added dropwise while cooling so as not to exceed 20 ° C, and the mixture was stirred for 1.5 hours. afterwards,
The mixture was returned to room temperature and further stirred for 20 hours. The reaction solution was poured into saturated aqueous sodium hydrogencarbonate cooled to 0 ° C., stirred for 2.5 hours, and extracted with ether. The organic layer was dried over magnesium sulfate and concentrated, and then purified by silica gel column chromatography (hexane: ethyl acetate = 8: 1) to give 3-benzoyloxymethyl-2-formylfuran and 4-benzoyloxymethyl-2. -Mixture with formylfuran (5.28 g, 75
%) As colorless crystals. The mixture was recrystallized from benzene and washed with ether to give 3-benzoyloxymethyl-2-formylfuran as colorless crystals. mp. 69-71 ° C IR (KBr, cm ^-1 ) 2820, 1720, 1670, 1580, 1520, 1450,
1270, 1120 ¹ H-NMR (250 MHz, CDCl ₃ ) δ 5.60 (2H, s), 6.72 (1H, d,
J = 1.6 Hz), 7.41-7.56 (3H, m), 7.63 (1H, s), 8.03-8.
09 (2H, m), 9.92 (1H, s) ¹³ C-NMR (125 MHz, CDCl ₃ ) δ 57.5, 113.5, 128.4, 12
9.5, 129.7, 131.0, 133.3, 147.2, 148.5, 166.0, 17
8.8 Mass (CI) m / z 231 (M ⁺ +1), 106.

3-benzoyloxymethyl-2-formylfuran (1.504 g, 6.53 mmol) was dissolved in ethanol (38 mL),
At 0 ° C., sodium borohydride (371 mg, 9.80 mmol) was added. After stirring at room temperature for 2.5 hours, 1N hydrochloric acid was added at 0 ° C. to terminate the reaction. Saturated aqueous sodium bicarbonate was added for neutralization, and the mixture was extracted with ethyl acetate. The organic layer was dried over magnesium sulfate and concentrated, and then purified by silica gel column chromatography (hexane: ethyl acetate = 3: 1) to transfer 3-benzoyloxymethyl-2-hydroxymethylfuran and a benzoyl group. A mixture of -benzoyloxymethyl-3-hydroxymethylfuran (976 mg, 64%) was obtained as colorless crystals. This mixture (247 mg, 1.06 mmol) was dissolved in dichloromethane (10 mL), and triethylamine (147 μL,
1.1 mmol) and N, N-dimethylaminopyridine (DMAP) (12.
8 mg, 0.11 mmol), and cooled to 0 ° C.
7 μL, 1.59 mmol) were added with stirring. After stirring for 1.5 hours, 1N hydrochloric acid was added to the reaction solution to terminate the reaction. Then, the mixture was neutralized with saturated aqueous sodium hydrogen carbonate and extracted with dichloromethane. After the organic layer was dried over magnesium sulfate and concentrated, silica gel column chromatography (hexane:
Purification with ethyl acetate (4: 1) gave 2,3-di (benzoyloxymethyl) furan (252 mg, 53%) as a pale yellow oil. IR (neat, cm ^-1 ) 2950, 1720, 1610, 1460, 1280, 1100 ¹ H-NMR (250 MHz, CDCl ₃ ) δ 5.36 (2H, s), 5.44 (2H,
s), 6.53 (1H, d, J = 1.8 Hz), 7.38 (1H, d, 1.8 Hz), 7.
39-7.53 (4H, m), 7.56-7.68 (2H, m), 8.00-8.18 (4H, m) ¹³ C-NMR (125 MHz, CDCl ₃ ) δ 56.7, 57.8, 112.0, 12
0.3, 128.9, 129.7, 129.8, 130.0, 130.6, 133.0, 13
3.1, 143.0, 147.9, 162.4, 166.2, 166.4 Mass (EI) m / s 336 (M ⁺ ), 105.

On the other hand, a mixture of 3-benzoyloxymethyl-2-formylfuran and 4-benzoyloxymethyl-2-formylfuran (a mixture of 800 mg, 3.48 mmol, 1: 1) was dissolved in ethanol (15 mL). C. and cooled while stirring and sodium borohydride (194 mg, 5.22 mmol) was added. After stirring at room temperature for 1.5 hours, the mixture was cooled to 0 ° C. and 1N hydrochloric acid was added to terminate the reaction. Saturated aqueous sodium bicarbonate was added for neutralization, and the mixture was extracted with ethyl acetate. The organic layer was dried over magnesium sulfate, concentrated, and then subjected to silica gel column chromatography (hexane: ethyl acetate = 4: 1) and preparative high-performance liquid chromatography (TSKgel silica 60, hexane: isopropyl alcohol = 50: 1). Purified, 4-benzoyloxymethyl
2-Hydroxymethylfuran (107 mg, 26%) was obtained as a colorless oil. IR (neat, cm ^-1 ) 3370, 2950, 1720, 1610, 1460, 128
0, 1280, 1110 ¹ H-NMR (500 MHz, CDCl ₃ ) δ 1.94 (1H, s), 4.59 (2H,
s), 5.19 (2H, s), 6.42 (1H, s), 7.42-7.45 (2H, m), 7.
51 (1H, s), 7.54-7.57 (1H, m), 8.03-8.05 (2H, m) ¹³ C-NMR (125 MHz, CDCl ₃ ); δ 57.5, 58.2, 108.8, 12
1.3, 128.3, 129.6, 130.0, 133.0, 141.5, 155.0, 16
6.5 Mass (EI) m / s 232 (M ⁺ ), 110, 105.

4-benzoyloxymethyl-2-hydroxymethylfuran (273 mg, 1.18 mmol), triethylamine (32
9 μL, 2.36 mmol), a solution of DMAP (14.2 mg, 0.12 mmol) in dichloromethane (6.8 mL) was added at 0 ° C. benzoyl chloride (181 μL,
1.29 mmol) was added and stirred for 1.5 hours. The reaction was quenched with 1N hydrochloric acid to terminate the reaction, and then neutralized with saturated aqueous sodium hydrogen carbonate, and extracted with dichloromethane. The organic layer was dried over magnesium sulfate, concentrated, and purified by silica gel column chromatography (hexane: ethyl acetate = 2: 1) to give 2,4-di (benzoyloxymethyl) furan (37
5.1 mg, 95%) as a pale yellow oil. IR (neat, cm ^-1 ) 2950, 1720, 1610, 1460, 1280, 1100 ¹ H-NMR (250 MHz, CDCl ₃ ) δ 5.14 (2H, s), 5.21 (2H,
s), 6.53 (1H, s), 7.32 (1H, s), 7.33-7.45 (4H, m), 7.
48-7.61 (2H, m), 7.92-7.96 (4H, m) ¹³ C-NMR (125 MHz, CDCl ₃ ) δ 58.1, 58.4, 111.7, 12
1.5, 128.9, 129.7, 129.8, 129.8, 130.1, 130.6, 13
3.1, 133.1, 150.4, 162.3, 166.2, 166.4 Mass (EI) m / s 336 (M ⁺ ), 105

Embodiment 1

[0047]

Embedded image

2,4-di (benzoyloxymethyl) furan (3
55 mg, 1.06 mmol) was added with maleic anhydride (310 mg, 3.18 mmol), and the mixture was stirred in toluene (2 mL) at room temperature for 12 hours. Further, maleic anhydride (87.5 mg, 890 μmol) was added and the mixture was stirred for 183 hours. After concentrating the reaction solution, it was purified by silica gel column chromatography (hexane: ethyl acetate = 4: 1) to give 1,5-dibenzoyloxymethyl-7-oxabicyclo [2.2.1] hept-5-ene. -2,3-Dicarboxylic anhydride (297 mg, 64%) was obtained as a colorless oil. IR (KBr, cm ^-1 ) 3100, 2975, 1865, 1830, 1785, 1720,
1700, 1600, 1580, 1450, 1270, 1120, 710, 680 ¹ H-NMR (250 MHz, CDCl ₃ ) δ 3.36 (1H, d, J = 7.0 Hz),
3.57 (1H, d, J = 7.0 Hz), 4.79 (1H, d, J = 13 Hz), 5.03 (2
H, d, J = 1.5 Hz), 5.16 (1H, d, J = 13 Hz), 5.47 (1H,
s), 6.42 (1H, S), 7.26-7.50 (4H, m), 7.56-7.62 (2H,
m), 8.01-8.07 (4H, m) ¹³ C-NMR (125 MHz, CDCl ₃ ) δ 50.7, 51.1, 59.3, 61.
0, 82.8, 91.8, 128.5, 128.6, 129.0, 129.2, 129.7,
129.8, 133.1, 133.4, 133.6, 148.2, 165.9, 166.0, 1
67.8, 169.3 Mass (EI) m / s 337, 307, 105.

Dissolve 1,5-dibenzoyloxymethyl-7-oxabicyclo [2.2.1] hept-5-ene-2,3-dicarboxylic anhydride (28 mg, 64 μmol) in tetrahydrofuran (THF) (1 mL) Then, 10% palladium / carbon (10 mg) was added, and the mixture was stirred at room temperature under a hydrogen atmosphere for 2 hours. The reaction solution was filtered through celite and then concentrated, and a mixed solvent of hexane-ethyl acetate (5: 1) was added to precipitate an oily precipitate, whereby 1,5-dibenzoyloxymethyl-7-oxabicyclo [2.2 .1] Heptane-2,3-
The dicarboxylic anhydride (5 mg, 14%) was obtained as a colorless oil. IR (neat, cm ^-1 ) 2970, 1865, 1830, 1785, 1720, 160
0, 1580, 1450, 1270, 1120, 710 ¹ H-NMR (500 MHz, CDCl ₃ ) δ 1.47 (1H, dd, J = 12.4 Hz,
5.5 Hz), 2.28 (1H, ddd, J = 12.4 Hz, 12.4 Hz, 5.5 H
z), 2.93-2.96 (1H, m), 3.33 (1H, d, J = 7.5 Hz), 3.78 (1
H, d, J = 7.5 Hz), 4.26 (1H, dd, J = 11.8 Hz, 9.4 Hz),
4.52 (1H, dd, J = 11.8 Hz, 5.8 Hz), 4.89 (1H, d, J = 6.5
Hz), 4.95 (1H, d, J = 6.5 Hz), 5.10 (1H, d, J = 4.9 Hz),
7.45-7.50 (4H, m), 7.60-7.62 (2H, m), 8.02-8.06 (4H, m
m) ¹³ C-NMR (125 MHz, CDCl ₃ ); δ 33.6, 39.7, 46.5, 50.
6, 61.2, 62.5, 80.8, 87.2, 127.5, 127.7, 128.2, 12
8.2, 128.6, 128.9, 132.4, 132.6, 164.7, 165.2, 16
7.7, 170.1 Mass (CI) m / s 437 (M ⁺ +1), 315, 123, 105.

Embodiment 2

[0051]

Embedded image

2,3-di (benzoyloxymethyl) furan (3
Maleic anhydride (324 mg, 3.3 mmol) was added to 70 mg, 1.1 mmol), and the mixture was stirred in toluene (2 mL) at room temperature for 68 hours. further,
Maleic anhydride (108 mg, 1.1 mmol) was added and the mixture was stirred for 216 hours. After concentrating the reaction solution, it was purified by silica gel column chromatography (hexane: ethyl acetate = 4: 1) to give 1,6-dibenzoyloxymethyl-7-oxabicyclo [2.2.1] hept-5-ene. -2,3-dicarboxylic anhydride (304.
(5 mg, 63%) as a colorless oil. IR (neat, cm ^-1 ) 2820, 1865, 1830, 1720, 1705, 160
0, 1580, 1450, 1270, 1120, 710 ¹ H-NMR (250 MHz, CDC
l ₃ ) δ 3.41 (1H, d, J = 6.9 Hz), 3.55 (1H, d, J = 6.9 H
z), 5.05 (2H, d, J = 2.0 Hz), 5.67 (2H, d, J = 2.0 Hz),
5.48 (1H, d, J = 2.5 Hz), 6.53 (1H, d, J = 1.3 Hz), 7.40
-7.48 (4H, m), 7.55-7.63 (2H, m), 7.96-8.03 (4H, m) ¹³ C-NMR (125 MHz, CDCl ₃ ); δ 49.7, 52.3, 59.1, 60.
7, 82.1, 91.0, 128.6,128.7, 129.0, 129.1, 129.6, 1
29.8, 133.5, 133.7, 134.5, 146.9, 165.5, 165.9, 16
7.8, 169.1 Mass (EI) m / s 337, 307.

1,6-Dibenzoyloxymethyl-7-oxabicyclo [2.2.1] hept-5-ene-2,3-dicarboxylic anhydride (94.4 mg, 220 μmol) was dissolved in THF (1.5 mL). And 5% rhodium / alumina (10 mg) were added, and the mixture was stirred at room temperature under a hydrogen atmosphere for 2 hours. The reaction solution was filtered through celite and then concentrated, and a mixed solvent of hexane-ethyl acetate (5: 1) was added to precipitate an oily precipitate, whereby 1,6-dibenzoyloxymethyl-7
-Oxabicyclo [2.2.1] heptane-2,3-dicarboxylic anhydride (78.3 mg, 83%) was obtained as a colorless oil. IR (neat, cm ^-1 ) 2820, 1865, 1830, 1785, 1720, 160
0, 1580, 1450, 1270, 1120, 755, 710, 680 ¹ H-NMR (500 MHz, CDCl ₃ ) δ 1.47 (1H, dd, J = 12.8 Hz,
5.5 Hz), 2.89 (1H, ddd, J = 12.4 Hz, 12.4 Hz, 5.5 H
z), 2.95 -2.99 (1H, m), 3.39 (1H, d, J = 7.5 Hz), 3.67
(1H, d, J = 7.5 Hz), 4.29 (1H, dd, J = 12.0 Hz, 9.3 H
z), 4.61 (1H, dd, J = 12.0 Hz, 5.5 Hz), 4.87 (1H, d, J
= 13.0 Hz), 4.95 (1H, d, J = 13.0Hz), 5.04 (1H, d, J = 5.
5 Hz), 7.40-7.47 (4H, m), 7.54-7.61 (2H, m), 7.95-8.
02 (4H, m) ¹³ C-NMR (125 MHz, CDCl ₃ ) δ 32.8, 40.6, 4
7.2, 51.9, 62.0, 63.5, 79.8, 89.5, 128.5, 128.7, 1
29.0, 129.2, 129.5, 129.7, 133.3, 133.6, 165.6, 16
6.1, 169.4, 170.5 Mass (EI) m / z 436 (M ⁺ ), 315, 122, 105; High Resolut
ion Mass Calcd for 436.12, Found 436.1140.

Reference Example 2

[0055]

Embedded image

3-furanmethanol (2.04 g, 20.7 mmol)
Into, 4-phenylbutanoic acid (3.24 g, 19.7 mmol), N, N'-dicyclohexylcarbodiimide (DCC) (8.56 g, 41.5 mmol),
DMAP (1.25 g, 10.4 mmol) was added, and the mixture was stirred in THF (20 mL) at room temperature for 27 hours. After the reaction solution was filtered through celite, 1N hydrochloric acid was added and the mixture was stirred for 10 minutes, and the precipitated urea was removed by filtration. The organic layer was dried over magnesium sulfate, concentrated, and then purified by silica gel column chromatography (hexane: ethyl acetate = 3: 1) to give 3- (4-phenylbutanoyloxymethyl) furan (3.48 g, 69%) Was obtained as a colorless oil. IR (neat, cm ^-1 ) 2926, 2853, 1740, 1600, 1500, 148
0, 1430, 1140, 1040 ¹ H-NMR (250 MHz, CDCl ₃ ) δ 1.96
(2H, quint, J = 7.5 Hz), 2.34 (2H, t, J = 7.5 Hz), 2.64
(2H, t, J = 7.5 Hz), 4.98 (2H, s), 6.42 (1H, d, J = 1.3
Hz), 7.17-7.47 (7H, m) ¹³ C-NMR (125 MHz, CDCl ₃ ) δ 26.5, 33.6, 35.1, 57.
6, 110.5, 120.5, 126.0, 128.4, 128.5, 141.3, 141.5,
143.4, 173.3 Mass (EI) m / s 244 (M ⁺ ), 163, 117, 81.

Phosphorus oxytrichloride (1.48 mL, 14.7 mmol) was added little by little to DMF (1.14 mL, 14.7 mmol) at 0 ° C. and stirred for 30 minutes to synthesize a Vilsmeier reagent. Vilsmeier reagent 3- (4
-Phenylbutanoyloxymethyl) furan (1.8g, 7.37m
mol) was slowly added dropwise while cooling so as not to exceed 20 ° C, and the mixture was stirred for 30 minutes, and further stirred at room temperature for 70 hours. The reaction solution was poured into saturated aqueous sodium hydrogencarbonate cooled to 0 ° C., stirred for 4 hours, and extracted with ether. The organic layer was dried over magnesium sulfate, concentrated, and then purified by silica gel column chromatography (hexane: ethyl acetate = 7: 1) to give 2-formyl-3- (4-phenylbutanoyloxymethyl) furan (1.48 g, 74%) and 2-formyl-4- (4-phenylbutanoyloxymethyl) furan (503 mg, 25%) as colorless oils.

2-formyl-3- (4-phenylbutanoyloxymethyl) furan IR (neat, cm ^-1 ) 2926, 2853, 1740, 1670, 1600, 148
0, 1450, 1430, 1270, 1140 ¹ H-NMR (250 MHz, CDCl ₃ ) δ 1.98 (2H, quint, J = 7.5 H
z), 2.39 (2H, t, J = 7.5Hz,), 2.66 (2H, t, J = 7.5Hz,),
5.33 (2H, s), 6.61 (1H, d, J = 1.0 Hz), 7.17-7.28 (4H,
m), 7.60 (2H, d, J = 1.25 Hz), 9.85 (1H, s) ¹³ C-NMR (125 MHz, CDCl ₃ ) δ 26.3, 33.3, 35.0, 56.
9, 113.4, 126.0, 128.4, 128.4, 130.9, 141.1, 147.2,
148.5, 172.9, 178.7 Mass (CI) m / s 273 (M ⁺ 1), 255, 163, 109, 91.

2-formyl-4- (4-phenylbutanoyloxymethyl) furan IR (neat, cm ^-1 ) 2820, 1740, 1670, 1600, 1520, 145
0, 1270, 1140 ¹ H-NMR (250 MHz, CDCl ₃ ) δ 1.93 (2H, quint, J = 7.5 H
z), 2.35 (2H, t, J = 7.5Hz,), 2.64 (2H, t, J = 7.5Hz),
5.00 (2H, s), 7.14-7.31 (5H, m), 7.70 (2H, s), 9.63 (1
(H, s) ¹³ C-NMR (125 MHz, CDCl ₃ ) δ 26.3, 33.4, 35.0, 56.
7, 120.9, 123.5, 126.0, 128.4, 128.4, 141.1, 146.7,
153.2, 173.1, 177.8 Mass (EI) m / s 272 (M ⁺ ), 255, 163, 109, 91.

2-Formyl-3- (4-phenylbutanoyloxymethyl) furan (1.46 g, 5.35 mmol) was added to THF-methanol-
Dissolved in a mixed solvent of acetic acid (20: 20: 1 v / v) (30.8 mL) and stirred at 0 ° C. with sodium cyanoborohydride (672 mg, 1
(0.7 mmol), and the mixture was further stirred at room temperature for 18 hours. After adding saturated aqueous sodium hydrogen carbonate to the reaction mixture and extracting with ethyl acetate, the organic layer was dried over magnesium sulfate and concentrated. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 3: 1) to give 2-hydroxymethyl-
3- (4-phenylbutanoyloxymethyl) furan (1.21 g,
83%) as a colorless oil. IR (neat, cm ^-1 ) 3450, 2940, 2853, 1740, 1600, 150
0, 1450, 1260, 1200, 1120, 1023, 754, 692 ¹ H-NMR (250 MHz, CDCl ₃ ) δ 1.92 (2H, quint, J = 7.5 H
z), 2.32 (2H, t, J = 7.5Hz), 2.61 (2H, t, J = 7.5Hz),
4.67 (2H, d, J = 6.3 Hz), 5.01 (2H, s), 6.36 (1H, d, J =
(6.3 Hz) 7.12-7.35 (6H, m) ¹³ C-NMR (125 MHz, CDCl ₃ ) δ 26.3, 33.6, 35.0, 55.
5, 57.5, 111.6, 117.0, 126.0, 128.4, 128.4, 141.2,
142.2, 152.7, 174.0 Mass (EI) m / s 274 (M ⁺ ), 257, 163, 111.

2-Hydroxymethyl-3- (4-phenylbutanoyloxymethyl) furan (1.02 g, 3.72 mmol), triethylamine (1.04 mL, 7.44 mmol) and DMAP (45 mg, 0.37 mmol) were added to dichloromethane (30 mL). Dissolve and benzoyl chloride at 0 ° C
(573 μL, 4.09 mmol) and stirred for 23 hours. To the reaction solution
After the reaction was terminated by adding 1N hydrochloric acid, the mixture was neutralized by adding saturated aqueous sodium hydrogen carbonate, and extracted with dichloromethane. The organic layer was dried over magnesium sulfate and concentrated, and then purified by silica gel column chromatography (hexane: ethyl acetate = 4: 1) to give 2-benzoyloxymethyl-3- (4-phenylbutanoyloxymethyl) furan. (1.19 g, 85%) was obtained as a colorless oil. IR (neat, cm ^-1 ) 2940, 2853, 1740, 1600, 1500, 146
0, 1260, 1140, 1100, 940, 754, 792 ¹ H-NMR (250 MHz, CDCl ₃ ) δ 1.93 (2H, quint, J = 7.5 H
z), 2.32 (2H, t, J = 7.5Hz), 2.61 (2H, t, J = 7.5Hz),
5.10 (2H, s), 5.38 (2H, s), 6.43 (1H, d, J = 1.8Hz), 7.
12-7.55 (9H, m), 8.01-8.05 (2H, m) ¹³ C-NMR (125 MHz, CDCl ₃ ) δ 26.4, 33.5, 35.0, 56.
5, 57.1, 111.8, 120.1, 126.0, 128.3, 128.3, 128.4,
129.7, 129.8, 133.1, 141.3, 143.0, 147.7, 166.1, 1
73.2 Mass (CI) m / s 379 (M ⁺ +1), 257.

On the other hand, 2-formyl-4- (4-phenylbutanoyloxymethyl) furan (390 mg, 1.43 mmol) was mixed with THF-methanol-acetic acid (20: 20: 1 v / v) in a mixed solvent (17.5 mL). Dissolved in
While stirring at 0 ° C., sodium cyanoborohydride (225 m
g, 3.58 mmol). Thereafter, the mixture was stirred at room temperature for 23 hours. After adding saturated aqueous sodium hydrogen carbonate to the reaction mixture and extracting with ethyl acetate, the organic layer was dried over magnesium sulfate and concentrated.
The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 3: 1) to give 2-hydroxymethyl-4- (4-phenylbutanoyloxymethyl) furan (287 mg, 73%) as a colorless oil. As obtained. IR (neat, cm ^-1 ) 3450, 2940, 2853, 1740, 1500, 146
0, 1260, 1200, 1120, 1023, 754, 692 ¹ H-NMR (250 MHz, CDCl ₃ ) δ 1.96 (2H, quint, J = 7.5 H
z), 2.34 (2H, t, J = 7.5Hz), 2.64 (2H, t, J = 7.5Hz),
4.58 (2H, s), 4.94 (2H, s), 6.33 (1H, s) 7.14-7.31 (5
H, m), 7.43 (1H, s) ¹³ C-NMR (125 MHz, CDCl ₃ ) δ 26.4, 33.6, 35.1, 57.
5, 57.6, 108.7, 121.3, 126.0, 128.4, 128.5, 141.3,
141.5, 154.9, 173.3 Mass (EI) m / s 274 (M ⁺ ), 257, 163.

2-hydroxymethyl-4- (4-phenylbutanoyloxymethyl) furan (280 mg, 1.02 mmol), triethylamine (284 μL, 2.04 mmol), DMAP (10.3 mg, 0.10 mmol)
Was dissolved in dichloromethane (8 mL), benzoyl chloride (189 μL, 1.34 mmol) was added with stirring at 0 ° C., and the mixture was stirred at room temperature for 57 hours. After 1N hydrochloric acid was added to the reaction solution to terminate the reaction, saturated aqueous sodium hydrogen carbonate was added to neutralize the mixture, and the mixture was extracted with dichloromethane. The organic layer was dried over magnesium sulfate and concentrated, and then purified by silica gel column chromatography (hexane: ether acetate = 3: 1) to give 2-benzoyloxymethyl-4- (4-phenylbutanoyloxymethyl) furan. (361 mg, 94%) was obtained as a colorless oil. IR (neat, cm ^-1 ) 2820, 1720, 1600, 1500, 1450, 127
0, 710 ¹ H-NMR (250 MHz, CDCl ₃ ) δ 1.96 (2H, quint, J = 7.5 H
z), 2.35 (2H, t, J = 7.5Hz), 2.64 (2H, t, J = 7.5Hz),
3.92 (1H, s), 4.96 (2H, s), 5.27 (2H, s), 6.51 (1H, s)
s), 7.14-7.47 (8H, m), 8.03-8.06 (2H, m) ¹³ C-NMR (125 MHz, CDCl ₃ ) δ 26.4, 33.5, 35.1, 57.
5, 58.4, 111.6, 121.5, 126.0, 128.4, 128.4, 128.5,
129.6, 129.8, 133.1, 141.3, 142.1, 150.4, 166.2, 1
73.2 Mass (CI) m / s 379 (M ⁺ +1), 163, 105.

Embodiment 3

[0065]

Embedded image

To 2-benzoyloxymethyl-4- (4-phenylbutanoyloxymethyl) furan (350 mg, 925 μmol) was added maleic anhydride (272 mg, 2.78 mmol), and the mixture was stirred at room temperature under an argon atmosphere for 17 hours. Thereafter, maleic anhydride (91 mg, 925 μmol) and toluene (0.5 mL) were further added, and the mixture was stirred for 72 hours. After concentrating the reaction solution, hexane-ethyl acetate (2:
By adding the mixed solvent of 1), excess maleic anhydride was crystallized and removed. Thereafter, the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 3: 1) to give 1-benzoyloxymethyl-5- (4-phenylbutanoyloxymethyl) -7-oxabicyclo [2.2.1]
Hept-5-ene-2,3-dicarboxylic anhydride (441 mg, 68%) was obtained as a colorless oil. IR (neat, cm ^-1 ) 3100, 2950, 1865, 1780, 1730, 160
0, 1500, 1450, 1270, 920, 710 ¹ H-NMR (250 MHz, CDCl ₃ ) δ 1.97 (2H, quint, J = 7.5 H
z), 2.37 (2H, t, J = 7.5Hz), 2.66 (2H, t, J = 7.5Hz),
3.32 (1H, d, J = 7.0 Hz), 3.46 (1H, d, J = 7.0 Hz), 4.75
(2H, s), 4.77 (1H, d, J = 12.8Hz), 5.16 (1H, d, J = 12.8Hz)
Hz), 5.36 (1H, s), 6.33 (1H, s), 7.15-7.59 (8H, m),
8.02-8.06 (2H, m) ¹³ C-NMR (125 MHz, CDCl ₃ ) δ 26.2, 33.2, 35.0, 50.
7, 51.0, 58.8, 61.0, 82.7, 91.7, 126.0, 128.4, 12
8.4, 128.5, 129.2, 129.8, 132.9, 133.5, 140.9, 165.
8, 167.7, 169.3, 172.9 Mass (EI) m / s 378, 163, 105.

1-benzoyloxymethyl-5- (4-phenylbutanoyloxymethyl) -7-oxabicyclo [2.2.1] hept-5-ene-2,3-dicarboxylic anhydride (200 mg, 420 μm
l) was added 5% rhodium / alumina (15 mg) and THF-ether (1:
1) The mixture was stirred in a mixed solvent (6 mL) under a hydrogen atmosphere at room temperature for 63 hours. The reaction solution was filtered through celite and concentrated, and hexane-
A mixed solvent of ether (10: 1) was added to precipitate an oily precipitate, which was washed with ether to give 1-benzoyloxymethyl-5- (4-phenylbutanoyloxymethyl) -7-oxabicyclo [2.2.1] Heptane-2,3-dicarboxylic anhydride (125m
g, 62%) as a colorless oil. IR (neat, cm ^-1 ) 2950, 1865, 1780, 1730, 1600, 150
0, 1450, 1280, 1240, 1110, 980, 930, 760, 720 ¹ H-NMR (250 MHz, CDCl ₃ ) δ 1.32 (1H, dd, J = 13.0 Hz,
5.7 Hz), 1.98 (2H, quint, J = 7.5 Hz), 2.18 (1H, t, J
= 13.0 Hz), 2.37 (2H, t, J = 7.5 Hz), 2.67 (2H, d, J = 7.
5 Hz), 2.73-2.79 (1H, m), 3.25 (1H, d, J = 7.5 Hz), 3.
64 (1H, d, J = 7.5Hz), 4.00 (1H, dd, J = 12 Hz, 9.5 Hz),
4.23 (1H, dd, J = 12 Hz, 5.5 Hz), 4.74 (1H, d, J = 12.5
Hz), 4.86 (1H, d, J = 12.5 Hz), 4.99 (1H, d, 4.5 Hz),
7.17-7.33 (5H, m), 7.43-7.49 (2H, m), 7.56-7.59 (1H,
m), 8.02-8.05 (2H, m) ¹³ C-NMR (125 MHz, CDCl ₃ ) δ 26.3, 33.3, 34.6, 35.
0, 40.5, 47.5, 51.6, 62.2, 62.9, 81.8, 88.2, 126.
2, 128.5, 128.5, 128.5, 129.3, 129.8, 133.5, 141.
0, 165.7, 168.7, 171.1, 173.1 Mass (EI) m / z 478 (M ⁺ ), 315, 147, 105; High Resolut
ion Mass Calcd for 478.16, Found 478.1634.

Embodiment 4

[0069]

Embedded image

2-benzoyloxymethyl-3- (4-phenyl)
Butanoyloxymethyl) furan (487mg, 1.29mol)
Water Maleic acid (379 mg, 3.86 mmol) was added and dissolved in toluene (3 mL).
The mixture was stirred in the medium for 146 hours. After concentrating the reaction solution,
Excess by adding a mixed solvent of ethyl acetate-ethyl acetate (3: 1).
Crystallized maleic anhydride was removed. Then,
Ricagel column chromatography (hexane: ethyl acetate
7: 2) to give 1-benzoyloxime
Tyl-6- (4-phenylbutanoyloxymethyl) -7-oxa
Bicyclo [2.2.1] hept-5-ene-2,3-dicarboxylic anhydride
(314 mg, 51%) was obtained as a colorless oil. IR (neat, cm^-1) 2950, 1865, 1780, 1730, 1600, 150
0, 1450, 1270, 920, 710 ¹H-NMR (250 MHz, CDCl_Three) δ
1.92 (2H, quint, J = 7.5Hz), 2.32 (2H, t, J = 7.5Hz),
2.62 (2H, t, J = 7.5Hz), 3.37 (1H, d, J = 7.0 Hz), 3.43
(1H, d, J = 7.0 Hz), 4.79, (2H, s), 4.98 (2H, s), 5.45
(1H, d, J = 1.8 Hz), 6.45 (1H, d, J = 1.8 Hz), 7.13-7.59
(8H, m), 7.99-8.02 (2H, m)¹³ C-NMR (125 MHz, CDCl_Three) δ 26.2, 33.2, 35.0, 49.
6, 52.3, 58.6, 60.6, 82.0, 90.9, 126.2, 128.4, 12
8.4, 128.5, 128.6, 129.1, 129.7, 133.5, 134.1, 140.
9, 165.4, 167.8, 169.1, 172.8 Mass (EI) m / s 379, 105.

1-benzoyloxymethyl-6- (4-phenylbutanoyloxymethyl) -7-oxabicyclo [2.2.1] hept-5-ene-2,3-dicarboxylic anhydride (249 mg, 523 mmol)
5% rhodium / alumina (15 mg) was added to THF-ether (1:
1) The mixture was stirred in a mixed solvent (6 mL) under a hydrogen atmosphere at room temperature for 2 hours. The reaction solution was filtered through celite and concentrated to give 1-benzoyloxymethyl-6- (4-phenylbutanoyloxymethyl) -7-oxabicyclo [2.2.1] heptane-2,3-
The dicarboxylic anhydride (250 mg, 100%) was obtained as a colorless oil. IR (neat, cm ^-1 ) 2950, 1865, 1780, 1730, 1600, 150
0, 1450, 1110, 980, 920, 760, 710 ¹ H-NMR (250 MHz, CDCl ₃ ) δ 1.34 (1H, dd, J = 12.0 Hz,
5.0 Hz), 1.92 (2H, quint, J = 7.5 Hz), 2.24-2.37 (3H,
m), 2.63 (2H, t, J = 7.5 Hz), 2.70-2.79 (1H, m), 3.30
(1H, d, J = 7.5 Hz), 3.54 (1H, d, J = 7.5 Hz), 3.97 (1H,
dd, J = 12.0 Hz, 7.5 Hz), 4.34 (1H, dd, J = 12.0 Hz, 5.
0 Hz), 4.77 (1H, d, J = 12.0 Hz), 4.95 (1H, d, J = 12.0
Hz), 5.00 (1H, d, 5.0 Hz), 7.12-7.30 (5H, m), 7.42-
7.48 (2H, m), 7.55-7.58 (1H, m), 8.00-8.03 (2H, m) ¹³ C-NMR (125 MHz, CDCl ₃ ) δ 26.1, 32.8, 33.3, 34.
9, 40.3, 47.1, 51.8, 61.9, 62.8, 79.7, 89.1, 126.
1, 128.4, 128.5, 129.3, 129.7, 133.4, 141.0, 165.
5, 169.4, 170.4, 172.9 Mass (EI) m / z 478 (M ⁺ ), 315, 147, 105; High Resolut
ion Mass Calcd for 478.16, Found 478.1641.

Reference Example 3

[0073]

Embedded image

3-furanmethanol (1.80 g, 18.3 mmol)
In 4- (4-methoxyphenyl) butanoic acid (3.56 g, 1.83 mmo
l), DCC (9.44 g, 45.8 mmol) and DMAP (1.22 g, 9.2 mmol) were added, and the mixture was stirred in THF (20 mL) at room temperature for 118 hours. After the reaction solution was filtered through celite, 1N hydrochloric acid was added and the mixture was stirred for 10 minutes, and the precipitated urea was removed by filtration. Next, the filtrate was extracted with ether, the organic layer was dehydrated with magnesium sulfate, concentrated, and purified by silica gel column chromatography (hexane: ethyl acetate = 4: 1) to give 3- [4- (4-methoxyphenyl). Butanoyloxymethyl] furan (3.89g,
77%) as a colorless oil. IR (neat, cm ^-1 ) 3060, 3030, 3000, 2950, 2835, 173
5, 1602, 1510, 1460, 1240, 1020, 810, 740, 1180, 1
160, 1140 ¹ H-NMR (250 MHz, CDCl ₃ ) δ 1.57 (2H, quint, J = 7.5 H
z), 2.33 (2H, t, J = 7.5Hz), 2.56 (2H, t, J = 7.5Hz),
3.79 (3H, s), 4.98 (2H, s), 6.42 (1H, d, J = 1.0Hz), 6.
82 (2H, d, J = 8.5 Hz), 7.07 (2H, d, J = 8.5 Hz), 7.40 (1
H, s), 7.47 (1H, d, J = 1.0 Hz) ¹³ C-NMR (125 MHz, CDCl ₃ ) δ 26.7, 33.5, 34.1, 55.
2, 57.5, 110.5, 113.8, 120.5, 129.3, 133.4, 141.6,
143.4, 157.9, 173.3 Mass (EI) m / s 274 (M ⁺ ), 193, 147, 121, 81.

Dimethylformamide (DMF) (1.12 mL, 14.5
To 8 mmol), phosphorus oxychloride (1.47 mL, 14.6 mmol) was added at 0 ° C., followed by stirring for 30 minutes to synthesize a Vilsmeier reagent. Vilsmei
3- [4- (4-Methoxyphenyl) butanoyloxymethyl] furan (2.0 g, 7.29 mmol) was slowly added dropwise to the er reagent while cooling so that the temperature did not exceed 20 ° C., and the mixture was stirred for 30 minutes. For 22 hours. The reaction solution was poured into saturated aqueous sodium hydrogencarbonate cooled to 0 ° C., stirred for 3 hours, and extracted with ether. After the organic layer was dried over magnesium sulfate and concentrated, silica gel column chromatography (hexane:
By purifying with ethyl acetate = 7: 1), 2-formyl-3-
[4- (4-Methoxyphenyl) butanoyloxymethyl] furan (1.47 g, 67%) was obtained as a colorless oil. IR (neat, cm ^-1 ) 3060, 3030, 3000, 2950, 2835, 174
0, 1695, 1610, 1510, 1480, 1380, 1250, 1180, 1140,
1040, 790 ¹ H-NMR (250 MHz, CDCl ₃ ) δ 1.94 (2H, quint, J = 7.5 H
z), 2.34 (2H, t, J = 7.5Hz,), 2.60 (2H, t, J = 7.5Hz,),
3.78 (3H, s), 5.33 (2H, s), 6.61 (2H, d, J = 1.5 Hz),
6.82 (2H, d, J = 8.8 Hz), 7.08 (2H, d, J = 8.8 Hz), 7.61
(1H, d, J = 1.5 Hz), 9.85 (1H, s) ¹³ C-NMR (125 MHz, CDCl ₃ ) δ 26.6, 33.3, 34.1, 55.
2, 56.9, 113.4, 113.8, 129.3, 131.0, 133.2, 147.2,
148.5, 157.9, 173.0, 178.7 Mass (EI) m / s 302 (M ⁺ ), 193, 147, 121, 109.

2-Formyl-3- [4- (4-methoxyphenyl) butanoyloxymethyl] furan (1.4 g, 4.63 mmol) was added to THF-
It was dissolved in a mixed solvent (20.5 mL) of methanol-acetic acid (20: 20: 1 v / v), and sodium cyanoborohydride (582 mg, 9.26 mmol) was added while stirring at 0 ° C. Thereafter, the mixture was stirred at room temperature for 42 hours. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was dried over magnesium sulfate and concentrated, and then purified by silica gel column chromatography (hexane: ethyl acetate = 3: 1) to give 2-hydroxymethyl-3- [4- (4-methoxyphenyl) butanoyl. [Oxymethyl] furan (1.27 g, 91%) was obtained as a colorless oil. IR (neat, cm ^-1 ) 3450, 3060, 3030, 3000, 2940, 282
0, 1735, 1615, 1510, 1480, 1250, 1180, 1150, 1040,
810, 735 ¹ H-NMR (250 MHz, CDCl ₃ ) δ 1.92 (2H, quint, J = 7.5 H
z), 2.28 (2H, t, J = 7.5Hz), 2.53 (2H, t, J = 7.5Hz),
2.72 (1H, t, J = 6.5 Hz), 3.78 (3H, s), 4.67 (2H, d, J =
6.5 Hz), 5.07 (2H, s), 6.38 (1H, d, J = 1.8 Hz) 6.81 (2
H, d, J = 8.5 Hz), 7.05 (2H, d, J = 8.5 Hz), 7.35 (1H, d,
J = 1.8 Hz) ¹³ C-NMR (125 MHz, CDCl ₃ ) δ 26.6, 33.6, 34.1, 55.
2, 55.5, 57.4, 111.6, 113.8, 117.0, 129.3, 133.3,
142.2, 152.7, 157.9, 174.0 Mass (EI) m / s 304 (M ⁺ ), 193, 147, 121, 110.

2-hydroxymethyl-3- [4- (4-methoxyphenyl) butanoyloxymethyl] furan (800 mg, 2.63 mm
ol) in dichloromethane solution (25 mL) at 0 ° C. was added triethylamine (753 μL, 3.15 mmol), DMAP (32 mg, 0.26 mmol), and benzoyl chloride (442 μL, 3.15 mmol), and then at room temperature.
Stirred for 22 hours. The reaction was quenched by the addition of 1N hydrochloric acid, neutralized with saturated aqueous sodium bicarbonate and extracted with dichloromethane. The organic layer was dried over magnesium sulfate and concentrated, and then purified by silica gel column chromatography (hexane: ethyl acetate = 7: 2) to give 2-benzoyloxymethyl-3- [4- (4-methoxyphenyl) butamate. [Noyloxymethyl] furan (1.01 g, 94%) was obtained as a colorless oil. IR (neat, cm ^-1 ) 3060, 3030, 3000, 2960, 1730, 161
5, 1515, 1460, 1250, 1180, 1150, 1040, 810, 735 ¹ H-NMR (250 MHz, CDCl ₃ ) δ 1.89 (2H, quint, J = 7.5 H
z), 2.30 (2H, t, J = 7.5Hz), 2.55 (2H, t, J = 7.5Hz), 3.
78 (3H, s), 5.10 (2H, s), 5.38 (2H, s), 6.43 (1H, d, J
= 1.8Hz), 6.81 (2H, d, J = 8.6 Hz), 7.05 (2H, d, J = 8.6
Hz), 7.38-7.44 (3H, m), 7.51-7.55 (1H, m), 8.01-8.05
(2H, m) ¹³ C-NMR (125 MHz, CDCl ₃ ) δ 26.6, 33.5, 34.1, 55.
2, 56.6, 57.1, 111.8, 113.8, 120.1, 128.3, 129.3,
129.7, 129.8, 133.1, 133.3, 143.0, 147.7, 157.9, 1
66.1, 173.2 Mass (EI) m / s 408 (M ⁺ ), 193, 147, 121, 105.

Embodiment 5

[0079]

Embedded image

2-benzoyloxymethyl-3- [4- (4-methoxyphenyl) butanoyloxymethyl] furan (974 mg,
To 2.39 mol) was added maleic anhydride (702 mg, 7.15 mmol). The mixture was stirred in toluene (1 mL) for 145 hours under an argon atmosphere. After concentrating the reaction solution, hexane-ethyl acetate (3: 1)
By adding a mixed solvent of the above, excess maleic anhydride was crystallized and removed. Thereafter, the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 2: 1) to give 1-benzoyloxymethyl-6- [4- (4-methoxyphenyl) butanoyloxymethyl] -7-oxabicyclo [ 2.2.1] Hept-5-ene-2,3-dicarboxylic anhydride (82
(3 mg, 68%) as a colorless oil. IR (neat, cm ^-1 ) 3060, 3000, 2950, 2850, 1870, 178
0, 1730, 1610, 1520, 1460, 1250, 1180, 1150, 1120,
1040, 710 ¹ H-NMR (250 MHz, CDCl ₃ ) δ 1.89 (2H, quint, J = 7.5 H
z), 2.30 (2H, t, J = 7.5Hz), 2.56 (2H, t, J = 7.5Hz), 3.
17 (1H, d, J = 6.9 Hz), 3.42 (1H, d, J = 6.9 Hz), 3.78 (3
H, s), 4.79 (2H, s), 4.97 (2H, s), 5.44 (1H, d, J = 1.5
Hz), 6.45 (1H, d, J = 1.5 Hz), 6.64 (2H, d, J = 8.6 H
z), 7.06 (2H, d, J = 8.6 Hz), 7.42-7.48 (2H, m), 7.56-
7.62 (1H, m), 7.99-8.02 (2H, m) ¹³ C-NMR (125 MHz, CDCl ₃ ) δ 26.4, 33.1, 34.0, 49.
6, 52.3, 55.2, 58.5, 60.4, 60.6, 90.9, 113.9, 128.
6, 129.1, 129.3, 129.7, 132.9, 133.5, 134.4, 146.7,
158.0, 165.4, 167.8, 169.1, 172.8 Mass (EI) m / s 408, 193, 147, 121, 105.

1-benzoyloxymethyl-6- [4- (4-methoxyphenyl) butanoyloxymethyl] -7-oxabicyclo [2.2.1] hept-5-ene-2,3-dicarboxylic anhydride ( 78
4%, 1.55 mol) and 5% rhodium / alumina (15 mg) and THF-
In a mixed solvent of ether (1: 1) (3 mL) under a hydrogen atmosphere at room temperature 3.
Stir for 5 hours. The reaction solution was filtered through celite and concentrated to give 1-benzoyloxymethyl-6- [4- (4-methoxyphenyl) butanoyloxymethyl] -7-oxabicyclo [2.2.1] heptane-2,3. -Dicarboxylic anhydride (783m
g, 100%) as a colorless oil. IR (neat, cm ^-1 ) 3060, 3030, 3000, 2950, 2850, 187
0, 1780, 1730, 1610, 1520, 1450, 1250, 1180, 1150,
1120, 1040, 710 ¹ H-NMR (250 MHz, CDCl ₃ ) δ 1.34 (1H, dd, J = 12 Hz, 5
Hz), 1.89 (2H, quint, J = 7.5 Hz), 2.25-2.37 (3H, m),
2.57 (2H, t, J = 7.5 Hz), 2.69-2.82 (1H, m), 3.30 (1H,
d, J = 7.5 Hz), 3.53 (1H, d, J = 7.5 Hz), 3.78 (3H, s),
3.97 (1H, dd, J = 12.0 Hz, 9.0 Hz), 4.35 (1H, dd, J = 1
2.0 Hz, 5.5 Hz), 4.77 (1H, d, J = 13.0 Hz), 4.99 (1H,
d, J = 13.0 Hz), 5.01 (1H, d, 5.5 Hz), 6.81 (2H, d, J =
8.6 Hz), 7.06 (2H, d, J = 8.6 Hz), 7.42-7.49 (2H, m),
7.56-7.62 (1H, m), 8.01-8.04 (2H, m) ¹³ C-NMR (125 MHz, CDCl ₃ ) δ 26.4, 32.8, 33.2, 34.
0, 40.3, 47.1, 51.8, 55.2, 61.9, 62.8, 79.7, 89.1,
113.8, 128.5, 129.3, 129.3, 129.8, 133.0, 133.4,
158.0, 165.5, 169.3, 170.4, 173.0 Mass (EI) m / z 508 (M ⁺ ), 403, 315, 193, 147, 121, 10
5; High Resolution Mass Calcd for 508.17, Found 50
8.1718.

Reference Example 4

[0083]

Embedded image

A solution of 3-benzoyloxymethyl-2-hydroxymethylfuran (1.267 g, 5.46 mmol) in ether (9 mL)
To the mixture was added pyridine (50 μL) and phenyl isocyanate (0.59 mL, 5.461 mmol) at 0 ° C., and the mixture was stirred for 27 hours. An additional 60
After refluxing at 30 ° C. for 30 minutes, the reaction solution was concentrated. Silica gel chromatography of the residue (hexane: ethyl acetate = 5: 1)
To give 3-benzoyloxymethyl-2-phenylcarbamoyloxymethylfuran (1.745 g, 91.0%) as colorless crystals. mp 76.0-76.5 ° C IR (KBr, cm ^-1 ) 3380, 3100, 1730, 1600, 1530, 1500 ¹ H-NMR (500 MHz, CDCl ₃ ); δ 5.29 (2H, s), 5.34 (2H,
s), 6.52 (1H, d, J = 1.8 Hz), 6.64 (1H, brs), 7.06 (1H,
t, J = 7.3 Hz), 7.29 (2H, dd, J = 7.9, 7.3 Hz), 7.35 (2
H, d, J = 7.9 Hz), 7.39 (2H, dd, J = 7.4, 7.1 Hz), 7.41
(1H, d, J = 1.8 Hz), 7.53 (1H, t, J = 7.4 Hz), 8.03 (2H,
d, J = 7.1 Hz) ¹³ C-NMR (CDCl ₃ , 125 MHz) δ 56.9, 57.7, 112.0, 11
8.7, 120.1, 123.9, 128.5, 129.1, 129.7, 130.0, 13
7.6, 143.0, 147.9, 152.8, 166.4 Mass (CI) m / z 352 (M ⁺⁺ 1), 230, 215, 105, 77. Example 6

[Formula 17] 3-benzoyloxymethyl-2-phenylcarbamoyloxymethylfuran (252.0 mg, 0.718 mmol) in toluene
(1.0 mL), maleic anhydride (211.1 mg, 2.154 mmol) was added, and the mixture was stirred at 70 ° C. for 20 hours. In addition, maleic anhydride (70.
4 mg, 0.718 mmol) and stirred for 1 hour. The reaction mixture was concentrated and purified by silica gel chromatography (hexane: ethyl acetate = 3: 1) to give 6-benzoyloxymethyl-1-phenylcarbamoyloxymethyl-7-oxabicyclo [2.
2.1] Hept-5-ene-2,3-dicarboxylic anhydride (135.7 mg,
42.1%) as colorless crystals. ¹ H-NMR (250 MHz, CDCl ₃ ); δ 3.32 (1H, d, J = 7.0 Hz),
3.41 (1H, d, J = 7.0 Hz), 4.77 (1H, d, J = 13.0 Hz), 4.
91 (1H, d, J = 13.0 Hz), 4.98 (2H, s), 5.40 (1H, d, J = 1.
5 Hz), 6.46 (1H, s), 6.63 (1H, s), 7.01 (1H, t, J = 6.8
Hz), 7.1-7.3 (4H, m), 7.39 (2H, dd, J = 7.5, 7.0 Hz),
7.50 (1H, t, J = 7.5 Hz), 7.94 (2H, d, J = 7.0 Hz) .6-benzoyloxymethyl-1-phenylcarbamoyloxymethyl-7-oxabicyclo [2.2.1] hept-5- To a mixed solution of ene-2,3-dicarboxylic anhydride (135.7 mg, 0.302 mmol) in THF (1.6 mL) and ether (0.8 mL) was added 5% Rh-Al ₂ O ₃ (15 mg), and a hydrogen atmosphere was added. The mixture was stirred at room temperature for 17 hours. After the reaction solution was filtered through celite and concentrated, it was purified by thin-layer silica gel chromatography (hexane: ethyl acetate = 2: 1, 1% acetic acid) to give 6-benzoyloxymethyl-1-phenylcarbamoyloxymethyl-7-oxabicyclo. [2.2.1] Heptane-2,3
-Dicarboxylic anhydride (9.4 mg, 6.9%) was obtained as colorless crystals. mp 95-97 ° C IR (KBr, cm ^-1 ) 3420, 1800, 1740, 1600, 1550 ¹ H-NMR (500 MHz, CDCl ₃ ) δ1.47 (1H, dd, J = 12.4, 5.3
Hz), 2.37 (1H, dd, J = 12.4, 12.0 Hz), 2.83 (1H, m),
3.35 (1H, d, J = 7.5 Hz), 3.61 (1H, d, J = 7.5 Hz), 4.31
(1H, dd, J = 12.0, 8.8 Hz), 4.55 (1H, dd, J = 12.0 Hz,
5.5 Hz), 4.70 (1H, d, J = 12.8 Hz), 4.84 (1H, d, J = 12.
8 Hz), 5.03 (1H, d, J = 5.3 Hz), 6.74 (1H, brs), 7.07 (1
H, t, J = 7.8 Hz), 7.30 (2H, dd, J = 7.9, 7.8 Hz), 7.35
(2H, d, J = 7.9 Hz), 7.46 (2H, dd, J = 7.9, 7.5 Hz), 7.
59 (1H, t, J = 7.5 Hz), 8.01 (2H, d, J = 7.9 Hz) ¹³ C-NMR (CDCl ₃ , 125 MHz) δ 33.04, 40.51, 51.38, 6
2.30, 63.51, 65.85, 79.92, 89.14, 118.74, 123.84,
128.78, 129.09, 129.58, 133.69, 137.37, 166.24, 16
9.25, 170.40 Mass (EI) m / z 451 (M ⁺ ), 331, 119, 105, 77.

Reference Example 5

[0086]

Embedded image

To a solution of 4-benzoyloxymethyl-2-hydroxymethylfuran (315.8 mg, 1.37 mmol) in ether was added
At 50 ° C, pyridine (50 μL) and phenyl isocyanate
(0.15 mL, 1.37 mmol) was added and the mixture was stirred at room temperature for 42 hours. After further refluxing at 60 ° C. for 30 minutes, the reaction solution was concentrated, and the residue was subjected to silica gel chromatography (hexane: ethyl acetate = 5: 5).
Purification was performed in 1) to give 4-benzoyloxymethyl-2-phenylcarbamoyloxymethylfuran (399.7 mg, yield 84.0%) as colorless crystals. mp 120-121 ° C IR (KBr, cm ^-1 ) 3350, 2380, 1730, 1600, 1550, 1500 ¹ H-NMR (500 MHz, CDCl ₃ ); δ 5.12 (2H, s), 5.19 (2H,
s), 6.57 (1H, s), 6.73 (1H, brs), 7.06 (1H, t, J = 7.4
Hz), 7.29 (2H, dd, J = 8.2, 7.5 Hz), 7.37 (2H, d, J = 7.9
Hz), 7.42 (2H, dd, J = 7.9, 7.4 Hz), 7.53 (1H, s), 7.
55 (1H, t, J = 7.5Hz), 8.04 (2H, d, J = 8.2 Hz) ¹³ C-NMR (CDCl ₃ , 125 MHz) δ 58.1, 58.6, 111.6, 11
8.7, 121.5, 123.6, 128.4, 129.0, 129.6, 123.0, 13
3.7, 137.5, 142.2, 150.5, 152.9, 166.4 Mass (CI) m / z 352 (M ⁺ +1), 233, 215, 105, 77.

Embodiment 7

[0089]

Embedded image

To a toluene solution (0.8 mL) of 4-benzoyloxymethyl-2-phenylcarbamoyloxymethylfuran (130.7 mg, 0.39 mmol) was added maleic anhydride (114.8 mg, 1.1
7 mmol) and stirred at 70 ° C. for 19 hours. Further, maleic anhydride (38.3 mg, 0.39 mmol) was added, and the mixture was stirred for 4 hours. The reaction mixture is concentrated and chromatographed on silica gel (hexane:
Purified with ethyl acetate = 3: 1), 5-benzoyloxymethyl-1-phenylcarbamoyloxymethyl-7-oxabicyclo [2.2.1] hept-5-ene-2,3-dicarboxylic anhydride (8
3.1 mg, 49.7%) as colorless crystals. ¹ H-NMR (250 MHz, CDCl ₃ ) δ 3.31 (1H, d, J = 7.5 Hz),
3.55 (1H, d, J = 7.5 Hz), 4.59 (1H, d, J = 12.5 Hz), 5.02
(2H, d, J = 2.5 Hz), 5.09 (1H, d, J = 12.5 Hz), 5.46 (1
H, s), 6.42 (1H, s), 6.71 (1H, brs), 7.09 (1H, t, J =
7.5 Hz), 7.1-7.3 (4H, m), 7.47 (2H, dd, J = 7.5, 7.5 H
z), 7.61 (1H, t, J = 7.5 Hz), 8.03 (2H, d, J = 7.5 Hz) Mass (CI) m / z 451 (M ⁺ +2), 307, 232, 215, 105.

5-benzoyloxymethyl-1-phenylcarbamoyloxymethyl-7-oxabicyclo [2.2.1] hept-5-ene-2,3-dicarboxylic anhydride (83.1 mg, 0.185 mmol
l) in a mixed solution of THF (1.0 mL) and ether (0.5 mL) was added 5% R
h-Al ₂ O ₃ (15 mg) was added, and the mixture was stirred at room temperature under a hydrogen atmosphere for 14 hours. After the reaction solution was filtered through celite and concentrated, the obtained crystals were washed with ether, and further recrystallized with a mixed solvent of hexane: ethyl acetate = 3: 1 to give 5-benzoyloxymethyl-1-phenylcarbamoyloxymethyl-. 7-oxabicyclo [2.2.1] heptane-2,3-dicarboxylic anhydride (10.0 mg,
12.0%) as colorless crystals. mp 80-81 ° C ¹ H-NMR (500 MHz, CDCl ₃ ) δ 1.39 (1H, dd, J = 6.4, 5.7
Hz), 2.23 (1H, m), 2.9 (1H, m), 3.27 (1H, d, J = 7.5 H
z), 3.76 (1H, d, J = 7.5 Hz), 4.26 (1H, dd, J = 11.8, 9.
3 Hz), 4.52 (1H, dd, J = 11.8, 5.8 Hz), 4.62 (1H, d, J
= 12.5 Hz), 4,74 (1H, d, J = 12.5 Hz), 5.07 (1H, d, J =
4.9 Hz), 6.72 (1H, brs), 7.09 (1H, t, J = 7.3 Hz), 7.3
2 (2H, dd, J = 7.3, 6.2 Hz), 7.34 (2H, d, J = 6.2 Hz),
7.49 (2H, dd, J = 7.5, 7.1 Hz), 7.62 (1H, t, J = 7.5 Hz),
8.02 (2H, d, J = 7.1 Hz).

Test Example 1

The inhibition tests of the above compounds on serine / threonine protein phosphatase type 1, 2A and 2B were carried out according to the methods described below, and the results are shown in Table 1.

Serine / threonine protein phosphatase 1
The inhibitory activity on (PP-1) and serine / threonine protein phosphatase 2A (PP-2A) was measured using a serine / threonine phosphatase assay kit 1 manufactured by UBI according to the following method. Commercially available enzyme (PP-2
A ₁ , UBI, 0.05 μg or PP-1, UBI, 0.1un
It), using a reaction buffer (PP-2A buffer: 50 mM Tris-HCl, pH 7.0, 0.1 mM EGTA, 0.1% β-mercaptoethanol, 1 mg / mL for bovine serum albumin containing 1 mg / mL bovine serum albumin) Buffer: 20 mM MOPS, pH 7.5, 1 mM MgCl ₂ , 60 mM β-mercaptoethanol, containing 0.1 mg / mL bovine serum albumin)
Medium, in the presence of test compound, phosphorylated peptide as substrate
(KRpTIRR, 250 μM) at 37 ° C. for 20 minutes. After the reaction, a malachite green solution (100 μL) was added, the mixture was allowed to stand at room temperature for 15 minutes, and the absorbance at 630 nm was measured with a plate reader to quantify the generated inorganic phosphate. Based on the measurement results, the inhibition rate of the protein phosphatase activity of each test compound (based on the results obtained without any compound) was calculated. The inhibitory activity on serine / threonine protein phosphatase 2B (PP-2B) was measured according to the following method. Commercially available enzyme (PP-2
B, manufactured by UBI, 1 μg) and using a reaction buffer (50 mM Tris-
Hydrochloric acid, pH 7.0, 0.03 mM calcium chloride, 1 mM nickel chloride, 0.1 μM calmodulin, 0.1 mg / mL bovine serum albumin), in the presence of the test compound, the substrate paranitrophenyl phosphate (0.9 mg / mL) And 37 ° C for 30 minutes. After the reaction, a 13% aqueous solution of dipotassium phosphate was added, and the absorbance at 415 nm was measured with a plate reader to quantify the generated paranitrophenol. Based on the measurement results, the inhibition rate of the protein phosphatase activity of each test compound (based on the results obtained without any compound) was calculated. Further PP-2B
For, the concentration of the compound showing 50% inhibition was described as the IC ₅₀ value.

[0095]

Embedded image

Table 1. Inhibitory activity on PP1, PP2A and PP2B 化合物 Compound concentration Inhibition rate (%) IC ₅₀ value ( μM) Compound (mM) PP1 PP2A PP2B PP2B 化合物 Compound 1 1 0 0 96 50 0.1 0 0 68 Compound 2 1 43 52 95 250 0.1 10 2 27 Compound 3 1 15 21 87 50 0.1 4 0 83 Compound 4 1 41 42 94 60 0.1 22 2 81 Compound 5 1 21 28 81 30 0.1 7 4 89 Compound 6 1 0 40 98 100 0.1 0 4 51 Compound 7 1 0 7 92 300 0.1 0 0 35 ─────────────────────────────── Cantharidin 1 93 97 23 1000 << (Comparative example) 0.1 80 96 3 ───────────────────────────────

From the above results, it was found that the compound according to the present invention exhibited a protein phosphatase inhibitory activity.

[0098]

The compound according to the present invention inhibits serine / threonine protein phosphatase 2B, and thus is useful not only as a biochemical research reagent but also as an immunosuppressant.

Claims (4)

[Claims] [Claim 1] The following general formula [I] (Wherein X represents a carboxyl group or 2
X together form a group represented by -C (O) OC (O)-. Further, R ¹ may be an alkyl group which may have a substituent, an alkenyl group which may have a substituent, an alkynyl group which may have a substituent, or may have a substituent. A good aryl group, an acyl group which may have a substituent, an acyloxy group which may have a substituent, an alkoxy or aryloxycarbonyl group which may have a substituent, Optionally substituted alkoxy or aryloxycarbonyloxy group, optionally substituted alkyl or arylthiocarbonyl group, optionally substituted aminocarbonyl group, optionally substituted amino Carbonyloxy group, optionally substituted alkyl or arylsulfonyl group, optionally substituted alkyl or arylsulfinyl An optionally substituted alkoxyl group, an optionally substituted aryloxy group, an optionally substituted alkyl or arylthio group, a carboxyl group, a cyano group, a nitro group, Represents an amino group which may have a group, R ² , R ³
Are each independently a hydrogen atom, an alkyl group which may have a substituent, an alkenyl group which may have a substituent,
An alkynyl group which may have a substituent, an aryl group which may have a substituent, an acyl group which may have a substituent, an acyloxy group which may have a substituent, An alkoxy or aryloxycarbonyl group optionally having a group, an alkoxy or aryloxycarbonyloxy group optionally having a substituent,
An alkyl or arylthiocarbonyl group which may have a substituent, an aminocarbonyl group which may have a substituent, an aminocarbonyloxy group which may have a substituent, Alkyl or arylsulfonyl group, an alkyl or arylsulfinyl group which may have a substituent, an alkoxyl group which may have a substituent, an aryloxy group which may have a substituent, a substituent Represents an alkylthio group, a carboxyl group, a cyano group, a nitro group, a halogen atom, or an amino group which may have a substituent. However, R ² and R ³ are not simultaneously hydrogen atoms.)-Substituted 7-oxabicyclo [2.2.1] heptane-
2,3-dicarboxylic acid derivatives. 2. The following general formula [I] (Wherein X represents a carboxyl group or 2
X together form a group represented by -C (O) OC (O)-. Further, R ¹ may be an alkyl group which may have a substituent, an alkenyl group which may have a substituent, an alkynyl group which may have a substituent, or may have a substituent. A good aryl group, an acyl group which may have a substituent, an acyloxy group which may have a substituent, an alkoxy or aryloxycarbonyl group which may have a substituent, Optionally substituted alkoxy or aryloxycarbonyloxy group, optionally substituted alkyl or arylthiocarbonyl group, optionally substituted aminocarbonyl group, optionally substituted amino Carbonyloxy group, optionally substituted alkyl or arylsulfonyl group, optionally substituted alkyl or arylsulfinyl An optionally substituted alkoxyl group, an optionally substituted aryloxy group, an optionally substituted alkyl or arylthio group, a carboxyl group, a cyano group, a nitro group, Represents an amino group which may have a group, R ² , R ³
Are each independently a hydrogen atom, an alkyl group which may have a substituent, an alkenyl group which may have a substituent,
An alkynyl group which may have a substituent, an aryl group which may have a substituent, an acyl group which may have a substituent, an acyloxy group which may have a substituent, An alkoxy or aryloxycarbonyl group optionally having a group, an alkoxy or aryloxycarbonyloxy group optionally having a substituent,
An alkyl or arylthiocarbonyl group which may have a substituent, an aminocarbonyl group which may have a substituent, an aminocarbonyloxy group which may have a substituent, Alkyl or arylsulfonyl group, an alkyl or arylsulfinyl group which may have a substituent, an alkoxyl group which may have a substituent, an aryloxy group which may have a substituent, a substituent Represents an alkylthio group, a carboxyl group, a cyano group, a nitro group, a halogen atom, or an amino group which may have a substituent. However, R ² and R ³ are not simultaneously hydrogen atoms.)-Substituted 7-oxabicyclo [2.2.1] heptane-
A protein phosphatase inhibitor comprising a 2,3-dicarboxylic acid derivative or a salt thereof as an active ingredient. 3. The following general formula [I] (Wherein X represents a carboxyl group or 2
X together form a group represented by -C (O) OC (O)-. Further, R ¹ may be an alkyl group which may have a substituent, an alkenyl group which may have a substituent, an alkynyl group which may have a substituent, or may have a substituent. A good aryl group, an acyl group which may have a substituent, an acyloxy group which may have a substituent, an alkoxy or aryloxycarbonyl group which may have a substituent, Optionally substituted alkoxy or aryloxycarbonyloxy group, optionally substituted alkyl or arylthiocarbonyl group, optionally substituted aminocarbonyl group, optionally substituted amino Carbonyloxy group, optionally substituted alkyl or arylsulfonyl group, optionally substituted alkyl or arylsulfinyl An optionally substituted alkoxyl group, an optionally substituted aryloxy group, an optionally substituted alkyl or arylthio group, a carboxyl group, a cyano group, a nitro group, Represents an amino group which may have a group, R ² , R ³
Are each independently a hydrogen atom, an alkyl group which may have a substituent, an alkenyl group which may have a substituent,
An alkynyl group which may have a substituent, an aryl group which may have a substituent, an acyl group which may have a substituent, an acyloxy group which may have a substituent, An alkoxy or aryloxycarbonyl group optionally having a group, an alkoxy or aryloxycarbonyloxy group optionally having a substituent,
An alkyl or arylthiocarbonyl group which may have a substituent, an aminocarbonyl group which may have a substituent, an aminocarbonyloxy group which may have a substituent, Alkyl or arylsulfonyl group, an alkyl or arylsulfinyl group which may have a substituent, an alkoxyl group which may have a substituent, an aryloxy group which may have a substituent, a substituent Represents an alkylthio group, a carboxyl group, a cyano group, a nitro group, a halogen atom, or an amino group which may have a substituent. However, R ² and R ³ are not simultaneously hydrogen atoms.)-Substituted 7-oxabicyclo [2.2.1] heptane-
An immunosuppressant comprising a 2,3-dicarboxylic acid derivative or a pharmaceutically acceptable salt thereof as an active ingredient. 4. The following general formula [I] (Wherein X represents a carboxyl group or 2
X together form a group represented by -C (O) OC (O)-. Further, R ¹ may be an alkyl group which may have a substituent, an alkenyl group which may have a substituent, an alkynyl group which may have a substituent, or may have a substituent. A good aryl group, an acyl group which may have a substituent, an acyloxy group which may have a substituent, an alkoxy or aryloxycarbonyl group which may have a substituent, Optionally substituted alkoxy or aryloxycarbonyloxy group, optionally substituted alkyl or arylthiocarbonyl group, optionally substituted aminocarbonyl group, optionally substituted amino Carbonyloxy group, optionally substituted alkyl or arylsulfonyl group, optionally substituted alkyl or arylsulfinyl An optionally substituted alkoxyl group, an optionally substituted aryloxy group, an optionally substituted alkyl or arylthio group, a carboxyl group, a cyano group, a nitro group, Represents an amino group which may have a group, R ² , R ³
Are each independently a hydrogen atom, an alkyl group which may have a substituent, an alkenyl group which may have a substituent,
An alkynyl group which may have a substituent, an aryl group which may have a substituent, an acyl group which may have a substituent, an acyloxy group which may have a substituent, An alkoxy or aryloxycarbonyl group optionally having a group, an alkoxy or aryloxycarbonyloxy group optionally having a substituent,
An alkyl or arylthiocarbonyl group which may have a substituent, an aminocarbonyl group which may have a substituent, an aminocarbonyloxy group which may have a substituent, Alkyl or arylsulfonyl group, an alkyl or arylsulfinyl group which may have a substituent, an alkoxyl group which may have a substituent, an aryloxy group which may have a substituent, a substituent Represents an alkylthio group, a carboxyl group, a cyano group, a nitro group, a halogen atom, or an amino group which may have a substituent. However, R ² and R ³ are not simultaneously hydrogen atoms.)-Substituted 7-oxabicyclo [2.2.1] heptane-
A medicament comprising a 2,3-dicarboxylic acid derivative or a pharmaceutically acceptable salt thereof as an active ingredient.