JPS6058987A - Novel beta-lactam compound and production thereof - Google Patents

Abstract

NEW MATERIAL:A compound of formula I (R1 is H or 1-hydroxyethyl, etc.; R2 is H or a protecting group of the amino group; R3 is H or a protecting group of the carboxyl group; R4 and R5 are H, lower alkyl aralkyl, etc.) and a salt thereof. EXAMPLE:2-[2-Carbamoylpyrrolidin-4-ylthio]-6-(1-hydroxyethyl)-penem-3- carboxylic acid. USE:Useful as an antimicrobial agent and an intermediate therefor, and capable of exhibiting improved activity against Gram-negative bacteria, microorganisms producing beta-lactamases, etc. PREPARATION:A sulfoxide of formula II (R6 is lower alkyl) is reacted with a mercaptan of formula III (R8 is a protecting group of the amino group) or a reactive derivative thereof in an inert solvent at 0 deg.C or below, and the protecting groups, e.g. OH, amino and carboxyl groups, are removed by the well-known method to give the aimed compound of formula I .

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention is based on the general formula [eco], where 几! represents a hydrogen atom, a 1-hydroxyethyl group, or a l-hydroxyethyl group whose hydroxyl group is protected with a protective group, 几2 represents a hydrogen atom or a protective group for an amino group, and Ra represents a hydrogen atom or a protective group for a carboxyl group. Show.

1L4, R5 represents a hydrogen atom, a lower alkyl group, an aralkyl group, a substituted lower alkyl group, or 4 and Rs represent an alkylene group bonded to the group, and together with the adjacent arsenic atom, a 4- to 7-membered cyclic Represents an amino group. ] The present invention relates to a novel β-lactam compound represented by the above, a pharmacologically acceptable salt thereof, and a method for producing the same.

In the general formula CI], various commonly used protecting groups can be used as the protecting group for the hydroxyl group toward ILl or the protecting group for the amine group in R2, but preferably, for example, te
Lower alkoxycarbonyl groups such as rt -butyloxycarbonyl, e.g. 2-ethyloxycarbonyl iodide, halogenoalkoxycarbonyl groups such as 2,2°2-trichloroethyloxycarbonyl, e.g. benzyloxycarbonyl, p-methoxybenzyloxy carbonyl, 0-nitrobenzyloxycarbonyl, p-
Aralkyloxycarbonyl groups such as nitrobenzyloxycarbonyl, e.g. trimethylsilyl, tert
- a trialkylsilyl group such as butyldimethylsilyl.

Furthermore, as the protecting group for the carboxyl group in R8, various commonly used protecting groups are possible, but straight chain or branched chains such as methyl, ethyl, isopropyl, and tert-butyl are preferable. lower alkyl group,
For example, halogenated lower alkyl groups such as 2-ethyl iodide, 2,2,2-trichloroethyl, lower alkoxymethyl groups such as methoxymethyl, ethoxymethyl, isobutoxymethyl, e.g. acetoxymethyl, propionyloxymethyl, butylene lyloxymethyl, pivaloyloxymethyl0) aliphatic low aliphatic acyloxymethyl groups, such as l-methoxycarbonyloxyethyl,
A 1-lower alkoxycarbonyloxyethyl group such as 1-ethoxycarbonyloxyethyl, an aralkyl group such as benzyl, p-methoxybenzyl, o-nitrobenzyl, p-nitrobenzyl, a benzhydryl group, or a phthalidyl group.

R4 and R6 are the same or different,
Examples of the lower alkyl group include a methyl group, an ethyl group, an n-propyl group, and an iso group.

Examples of substituted lower alkyl groups include methyl, ethyl, and n-propyl groups substituted with a hydroxyl group, a di-lower alkylamino group (lower alkyl has 1 to 4 carbon atoms), a carbamoyl group, etc. Number of carbon atoms: 1-4
The lower alkyl group of
Examples of the ~7-membered cyclic amino group include an azetidino group, a piperidino group, a pyrrolidino group, and the like.

The carboxylic acid compound in which R8 is a hydrogen atom in the general formula CI] can be made into a pharmacologically acceptable salt form, if necessary. Examples of such salts include salts of inorganic metals such as pallium, sodium, potassium, calcium, and magnesium, and ammonium salts such as ammonium, cyclohexylammonium, diisopropylammonium, and triethylammonium, but sodium is preferred. salt and potassium salt.

The β-lactam compound represented by the general formula [I] of the present invention belongs to penem derivatives and has various 2-carbamoylpyrrolidin-4-ylthio atoms or various 〇-substituted -l at the 2-position thereof.
-It is a novel compound having a hydroxyethyl group, and the present invention has been achieved by discovering that these compounds have strong antibacterial activity and are useful compounds as pharmaceuticals, or are important intermediates for compounds exhibiting antibacterial activity. completed.

The method for producing the compound of the present invention will be described in detail below.

General formula [■] [In the formula, Rt and R8 have the same meanings as above. R
6 represents a substituted or unsubstituted lower alkyl group. 1 and the general formula [m] [wherein R8
represents a protecting group for an amino group. R4°R6 has the same meaning as above. ] By reacting a mercaptan represented by the formula [■] or a reactive derivative thereof in an inert solvent, a compound of the general formula [■] [wherein 1t1.几s, R4, 几5 and 几8 have the same meanings as above. ] A β-lactam compound represented by the following can be produced.

The lower alkyl group in R6 of the general formula [1[] is,
Preferably, it is a linear or branched alkyl group having 1 to 4 carbon atoms. Substituents for the substituted lower alkyl group include hydroxyl group, lower alkoxy group (01-C4), lower alkoxycarbonyloxy group (C2-C5), lower alkanoyloxy group (02-C5), amine group, mono- or di-lower Alkylamino group, lower alkanoyl t/M
(02-C6), lower alkoxycarbonylamino group (
02 to C6), an aralkyloxycarbonyloxy group, an aralkyloxycarbonylamino group, and the like.

The inert solvent used in this reaction is N.

N-dimethylformamide, hexamethylphosphoramide, acetonitrile, tetrahydrofuran, dioxane and the like can be mentioned.

The reaction temperature is 0°C or lower, but it is preferably carried out in the range of -20°C to -40°C.

When the mercaptan of general formula [111] itself is used as a raw material compound in this reaction, it is generally desirable to carry out the reaction in the presence of a base. Examples of bases include alkali metal bases such as potassium hydroxide, potassium hydride, sodium hydroxide, potassium hydroxide, sodium amide, potassium amide, sodium methoxide, potassium methoxide, pyridine, various lutidines, triethylamine,
Organic bases such as diisopropylethylamine can be mentioned, and organic bases such as diisopropylamine are preferred.

The amount of base needs to be sufficient for the reaction to proceed sufficiently, but it is usually 1 to 1.5 per mole of mercaptan [■].
Use moles.

When a reactive derivative of mercaptan [111] is used as a raw material compound in this reaction, suitable reactive derivatives include alkali metal salts of mercaptan [■], particularly sodium salts or potassium salts.

The reaction of mercaptan [i[l] or its reactive derivatives proceeds satisfactorily! The amount of moss is necessary and a large excess can be used, but usually 1.5 to 4.0 mol is used per 1 mol of the sulfoxide of general formula [11].

After the reaction is completed, the resultant can be taken out using conventional organic chemistry techniques.

Next, the obtained compound represented by the general formula [M] was subjected to a reaction for removing the protecting group for the hydroxyl group, a reaction for removing the protecting group for the amino group, and a reaction for removing the protecting group for the carboxyl group according to the method of Koga. If necessary, a β-lactam compound represented by the general formula LID can be obtained by appropriately combining treatments or by simultaneously performing a reaction to remove these binding groups.

The method for removing a protecting group varies depending on the type of protecting group, but it is removed by a generally known method.

For example, in the general formula [■], a protecting group for a hydroxyl group and a protecting group for an amino group at R+.
〉Compounds that have a halogenoalkoxycarbonyl group, aralkyloxycarbonyl group, and compounds where the carboxyl group in 几8 is a halogenoalkyl group, aralkyl group, or penshydryl group can be subjected to an appropriate reduction reaction to remove the protective group. can do. - Such reduction reactions include acetic acid, when the protecting group is a halogenoalkoxycarbonyl group or a halogenoalkyl group.
Reduction using an organic solvent such as tetrahydrofuran or methanol and zinc is suitable, and when the protecting group is an aralkyloxycarbonyl group, an aralkyl group, or a benzhydryl group, a catalytic reduction reaction using a catalyst such as platinum or palladium-carbon is preferable. suitable. Suitable solvents used in this catalytic reduction reaction include lower alcohols such as methanol and ethanol, ethers such as tetrahydrofuran and dioxane, acetic acid, or a mixed solvent of these organic solvents and water. The reaction temperature is 0°
C-100°C, but preferably O''C to 40°C. Hydrogen pressure can be carried out under normal pressure or increased pressure.

After the reaction is completed, the resultant can be taken out using conventional organic chemistry techniques.

Note that the compound represented by the general formula [I] has optical isomers and stereoisomers based on asymmetric carbon atoms, and these isomers are all represented by a single formula for convenience, but this does not mean that the present invention The scope of the description of the invention is not limited.

However, compounds in which the carbon atom at position 5 has a diagonal coordination can be preferably selected.

General formula [v] in which 1 is a 1-hydroxyethyl group in the general formula CD [wherein 2, Ra, 4 and R6 have the same meanings as above. ] Regarding the compound represented by, preferred steric configurations include (5R, 68, 8B) coordination, (5R, 68, 8R
) coordination, (51L,6R,88) coordination and (5R,6
S, 88) Compounds having coordination can be mentioned.

As particularly preferable steric configurations, compounds with (5R, 6R, 8IL) and (5R, 68, 8R) configurations can be selected.

On the other hand, for the 2'-carbamoylpyrrolidin-4'-ylthio group, the (2°s, 4's) coordination, (2°s
, 4°n) coordination, (2'lL, 4°S) coordination, (2° 几.

There are four types of stereoisomers with the 4°R) coordination, and the general formula [I]
Although the general formulas such as [2'8, 4'S] coordination, [2'8, 4'S] coordination, [ 2'
Compounds with ⇠, 4'⇠] coordination can be mentioned.

When producing an isomer having such a coordination, corresponding isomers can be used in the starting compound [■] and/or [■].

The compounds of the present invention represented by the general formula CI] are a group of novel penem derivatives having various 2-carbamoylpyrrolidin-4-ylthio groups at the 2-position, and these compounds exhibit excellent antibacterial activity and are useful as pharmaceuticals. or an important mesohedron of compounds that exhibit these activities.

Examples of the compound having the general formula [1] obtained by the present invention include the compounds described below.

(1) 2-[2-carbamoylpyrrolidin-4-ylthio]-6-(1-hydroxyethyl)-penemu-8-carboxylic acid (2) 2-[(2-N-methylcarbamoyl)pyrrolidin-4-ylthio] '-6-(1-hydroxyethyl)-penem-3-carboxylic acid (8) 2-CC2-N-
ethylcarbamoyl)pyrrolidin-4-ylthio]-6
-(1-hydroxyethyl)-penem-3-carboxylic acid (4) 2 [(2-N-n-propylcarbamoyl)
pyrrolidin-4-ylthio]-6-(1-hydroxyethyl)-penem-3-carboxylic acid (5J 2-[(2-
N-isopropylcarbamoyl)pyrrolidin-4-ylthio]-6-(1-hydroxyethyl)-penem-8-
Carboxylic acid pyrrolidin-4-ylthio]-6-(1-hydroxyethyl)-penem-3-carboxylic acid (7) 2-[(2-
N-isobutylcarbamoyl)pyrrolidin-4-ylthio]-6-(1-hydroxyethyl)-penem-8-carboxylic acid (8) 2-[(2-N,N-dimethylcarbamoyl)pyrrolidin-4-ylthio]- 6-(1-hydroxyethyl)-penem-3-carboxylic acid <93 2-4(2-N,N-diethylcarbamoyl)
pyrrolidin-4-ylthio]-6-(1-hydroxyethyl)-penem-8-carboxylic acid (10)2C(2-N,N-')-n-
pyrrolidin-4-ylthio]-
6-(1-hydroxyethyl)-penem-3-carboxylic acid (11) 2-[(2-N,N-diisopropylcarbamoyl)pyrrolidin-4-ylthio]-6carboxylic acid (12) 2 [(2-N . -ylthioco-6-(l-hydroxyethyl)-penem-3-carboxylic acid (14) 2-[(2'-N-methyl-N-ethylcarbamoyl)pyrrolidin-4-ylthio]-6-(1-
hydroxyethyl)-penem-3-carboxylic acid (15) 2 [(2-N-n-butyl-N -)L
tylcarbamoyl)pyrrolidin-4-ylthio]-6-
(1-Hydroxyethyl)-penem-3-carboxylic acid (16) 2 [(2-N-n-butyl-N-ethyl J
LIcarbamoyl)pyrrolidin-4-ylthio]-6-
(1-hydroxyethyl)-penem-3-carboxylic acid (17) 2-[(2-N-(2-hydroxyethyl)
carbamoyl)pyrrolidin-4-ylthio]-6-(1
-Hydroxyethyl)-penem-8-carboxylic acid (18) 2-[(2-N-(2-N,N-dimethylaminoethyl)carbamoyl)pyrrolidin-4-yltothi-3-6-(1-1nitro xyethyl)-penem-8
-Carboxylic acid (19) 2-[(2-N-(carbamoylmethyl)carbamoyl)pyrrolidin-4-ylthio]-6-(1-
hydroxyethyl)-penem-8-carboxylic acid (20) 2-[(2-N-benzylcarbamoyl)pyrrolidin-4-ylthio 3-6-(1-hydroxyethyl)-pei,mu-3-carboxylic acid (21) 2 1:(
2N (2-H)'ooxyethyl)-8-methylcarbamoyl)pyrrolidin-4-ylthio]-6-(1-hydroxyethyl)-penemu8-carboxylic acid (22) 2-[(2-N-(2 -N,N-dimethylaminoethyl)-N-methylcarbamoyl)pyrrolidine-
4-ylthio]-6-(1-hydroxyethyl)-penem-8-carboxylic acid (2B) 2-[('1-N-benzyl-N-methylcarbamo-fl)pyrrolidin-4-ylthio]-6-( 1-hydroxyethyl)-penem-8
-carboxylic acid (24) 2 [(2N (2-human oxyethyl JL+
)-N-ethylcarbamoyl)pyrrolidin-4-ylthio]-6-(1-hydroxyethyl)-pe-8-carboxylic acid (25) 2-12-N--benzyl-N-ethylcarbamoyl)pyrrolidine- 4-ylthio]-6-(1-
hydroxyethyl)-penem-8-carboxylic acid (26) 2-[(2-N-(2-N,N-diethylamineethyl)carbamoyl)pyrrolidin-4-ylthio]
-6-(1-hydroxyethyl)-penem-8-carboxylic acid (27) 2-[(2-4-(2-N,N-dimethylaminoethyl)-N-ethylcarbamoyl)pyrrolidine-4
-ylthio]-6-(1-hydroxyethyltwopenem-3-carboxylic acid (28) 2-[(2-N-(2-N
, N-xy-laminoethyl)-h-ethylcarbamo,yl)pyrrolidin-4-ylthio]-6-(1
-hydroxyethyl)-penem-3-carboxylic acid (29
) 2-[(2-N=(8-1'Q, N-dimethylaminopropyl)carbamoyl)pyrrolidin-4-ylthio]-6-(1-hydroxyethyl)-penem-3-carboxylic acid (80) 2 -[(2-N-(8-N,N-diethyl
Aminopropyl)carbamoyl)pyrrolidin-4-ylthio]-6-(1-hydroxyethyl)-penem-3
-Carboxylic acid (81) 2-[<2-N-(a-hydroxypropyl)carbamoyl)pyrrolidin-4-ylthio, l-
6-(1-hydroxyethyl)-penem-3-carboxylic acid (82) 2-[(2-N-(2-humanoxy-1-methylethyl)carbamoyl)pyrrolidin-4-ylthio)-6-( 1-hydroxyethyl)-penem-3-carboxylic acid (88) 2-4(2-he-(2-hydroxypropyl)
carbamoyl)pyrrolidin-4-ylthio)-6,-(
1-Hydroxyethyl)-penem-8-carboxylic acid (84) 2-[(2-N-(2-carbamoylethyl)carbamoyl)pyrrolidin-4-ylthio]-6-(
1-hydroxyethyl)-penem-3-carboxylic acid (35) 2- [< 2- (1-azetidinecarbonyl))pyrrolidin-4-ylthio 3-6-(1-hydroxyethyl)-bay, mu 8- Carboxylic acid (86)
2-[(2-(1-pyrrolidinecarbonyl))pyrrolidin-4-ylthio]-6-(1-hydroxyethyl)
-penem-3-carboxylic acid 17) 2- [(2-(1
-piperidinecarbonyl))pyrrolidin-4-ylthio]-6-(1-hydroxyethyl)-penem-3-carboxylic acid (88) 2-C2-carbamoylpyrrolidine-4
-ylthio]-penemoo 3-carboxylic acid (89) 2-12-fi, N-dimethylcarbamoylpyrrolidin-4-ylthiocopenemoo 3-carboxylic acid (40) 2-C(2-(i-piperidinecarbonyl)
) Pyrrolidin-4-ylthio]-penemu-3-carboxylic acid In this exemplified compound, stereoisomers exist as shown in Section 0a, and although they are given a single name, they are not limited in any way by this. .

However, as a preferable uncontained skeleton having a 6-(1-hydroxyethyl) group, (5R, 438
, 8K) Kunihii, (5R, 6 几.

8ft) coordination.

In addition, for the pyrrolidinylthio group which is a substituent at the 8-position, preferred examples are (2'S, 4'S) coordination, (2'
B, 4'IL) coordination.

The raw material compound represented by the general formula [■] is represented by the general formula [W] [wherein! , Ra, and Re have the same meanings as above. ] It can be produced by 8-oxidizing the compound represented by the following with a mild oxidizing agent.

Examples of mild oxidizing agents include perbenzoic acid, meta-chloroperbenzoic acid, hydrogen peroxide, selenium dioxide, sodium meta-periodate, etc., but preferred are substituted perbenzoic acids such as meta-chloroperbenzoic acid. I can give you benzoic acid.

Note that the raw material compound represented by the general formula CM] can be produced by various methods that have already been reported.
It can be produced according to the method described in JP-A-686 and JP-A-56-81591.

10,000, Raw material mercaptan [■] can be produced by various methods, but for example, by the method shown below, 2'B A mercaptan [Dlal, [I[Ib] with coordination can be produced.

1 About 8 1183 7 6 [■a] 8 12 Lr [lbl 上゛1111) [11b] [In the formula, Kashima R6 and R8 have the same meaning as above. R7 represents a carboxyl group-protecting group, and 几9 represents a thiol group-protecting group. [Process] This process can be easily achieved by a commonly used protection reaction of the amino group of various known amino acids, such as a method of reacting with arylmethyloxycarbonyl chloride etc. in the presence of a base, or S-acyl-4゜6 Examples include a filtration method using -cymethyl-2-mercaptopyrimidine and the like.

Process Various known methods for obtaining an ester from a carboxylic acid are possible, and for example, the reaction can be achieved by reacting the carboxylic acid 2 with various alkyl halides or aralkyl halides in the presence of a base.

Process: Various known methods are possible for converting a hydroxyl group into a protected thiol group. For example, after deriving a hydroxyl group into an active ester form, various thiolating reagents such as thioacetic acid, thiobenzoic acid, trityl mercaptan, etc. and the presence of a base are used. This can be achieved by reacting below.

This step can also be obtained by reacting an alcohol derivative with a thiolating reagent such as thioacetic acid in an inert solvent such as tetrahydrofuran in the presence of triphenylphosphine and dienalazodicarboxylate.

Step D: Various known methods for converting an ester into a carboxyl group are possible, such as alkaline hydrolysis, an acid method using trifluoroacetic acid, hydrobromic acid, etc., and a reductive method using zinc. This can be done by

Step E Various known methods are possible for converting carboxylic acid into an amide group, but for example, converting a carboxylic acid group into an active ester derivative using a halogenating agent, an acylating agent, etc.
In the general formula E, lta and R5 have the same meanings as above.

] This is achieved by a method of treating with an amine represented by:

1r Step Various known methods for deprotecting thiol protecting groups are possible. For example, when the thiol protecting group is an acyl group, it can be removed by a method such as alkaline hydrolysis.

Step G Various known oxidation reactions for converting hydroxyl groups into carbonyl groups are possible, and this can be achieved, for example, by oxidation reactions such as chromic acid-sulfuric acid in acetone.

(2) Step Although various known reduction reactions for converting a carbonyl group into a hydroxyl group are possible, for example, by treating with sodium borohydride, etc., it is possible to obtain a mixture of compounds 3 and 9, in which the steric hydroxyl groups of 3 are different. can.

Although the production ratio of 3 and 9 varies depending on the conditions, each compound can be obtained as a unified product by purification such as recrystallization and chromatography.

The isomerization of the 4-position hydroxyl group can be achieved through the steps G and (2) described above, but it can also be achieved by the method through the steps (2) and J described below.

+, J Engineering, hifi alcohol ulB 7t9 was reacted with 4 acids in the presence of triphenylphosphine and diethyl asodicarboxylate in an inert solvent such as tetrahydrofuran to give formyloxy derivative 1;k15. This can be achieved by subsequently removing the small lumyl group by a method such as alkaline hydrolysis.

1 (Step 1) A commonly used method for deprotecting amino groups is known, for example, a method using an acid such as acetic acid or arsenic acid.
(Reductive method using lead, lithium, liquid red ammonia, etc.) [F] (C by reduction etc.)
can be done.

In addition, cis-4-hydroxy-1-)-bulin was used as a compound for the production of 2'2' It can be produced by combining the L'l and C5 reactions described in the production of the 7di, 2'F3 form with the method for producing the S form.

The novel β-lactam compound of the present invention represented by the general formula
It has excellent antibacterial activity against a wide range of pathogenic bacteria, including Durum-positive bacteria such as Streptococcus pyrogens and Streptococcus faecalis, and Gram-negative bacteria such as Escherichia coli, Proteus mirabilis, Selassia marcescens, and Pseudomonas aeruginosa. They are compounds useful as antibacterial agents, or are important intermediates in the synthesis of compounds that exhibit antibacterial activity.

Another characteristic of the compound of the present invention is that it has excellent antibacterial activity against β-lactamase-producing bacteria.

Dosage forms for using the compound of the present invention as an antibacterial agent to treat bacterial infections include, for example, tablets, capsules,
Examples include oral administration using powders, syrups, etc., and parenteral administration via intravenous injection, intramuscular injection, rectal administration, etc.

In addition, if necessary, dipeptidase inhibitors such as sodium Z-7-(L-amino-2-carboxyethylthio)-2-(2,2-dimethylcyclopropaneylpoxamide)-2-hebutenoate It can be administered in combination with the compounds described in Publication No. 56-81518).

゛Dosage varies depending on symptoms, age, body weight, dosage form, number of administrations, etc., but is usually about 200 to 800 mg per day for adults.
007n? Administer in one or several doses. The amount can be reduced or increased as necessary.

Next, the present invention will be explained in more detail with reference to Examples and Reference Examples, but the present invention is of course not limited to these in any way.

The meanings of the abbreviations used in the following Examples and Reference Examples are as follows.

PNZ: p-nitropenzyloxycarbonyl group PNB
: p-Nitrobenzyl group Ph : Phenyl group AC=C Niacetyl S Dimethanesulfonyl group PMB : p-Methoxybenzyl group Example 1 (5R,68,811L)-2-ethylsulfi-6-(1-hydroxyethyl) -A solution of penem-8-carboxylic acid p-nitrobenzyl ester (82 ml) in dry acetonitrile (0.6 m) was added to a solution of diisopropylethylamine (22 ml) in dry acetonitrile (0.2 ml) at -40°C under a nitrogen atmosphere. and then (28, 48)-
A solution of 1-p-nitropenzyloxycarbonyl-2-carbamoyl-4-mercaptopyrrolidine (54) in dry dimethylformamide (0.5 mg) was added, and -40
Stir at ~-45°C for 10 minutes, add water to the reaction mixture, extract with ethyl acetate, wash with saturated saline, dry with sulfur salt, evaporate the solvent,
The residue was purified by silica gel chromatography.
Rin, 6S.

8R, 2'S, 4'8)-2-[(1-P-nitrobenzyloxycarbonyl-2-carbamoyl)pyrrolidin-4-ylthio]-6-(1-hydroxyethyl)-penem-3-carboxylic acid p-Nitrobenzyl ゛,
-Ester was obtained.

[αbo=+32°CC=0.22, Tnp)IR
v"""cm': 1780.1680.160
8.1517゜ax 1881, 185O NIiiiR(ODOzs) δ: 1.18(an, d
, J = (Jz), 5.22 (2EI.

S), 5.79 (ILs) Example 2 5% palladium-carbon (117W9) was suspended in ethanol (2.2tri)-1420 (2.2ml), hydrogenated at room temperature and normal pressure for 1 hour, filtered and washed with water. and suspended in phosphate buffer PH6.86 (8.0ml),
(5]L, 68,8IL, 2'S, 4'S)-2-C
(1-1'l-nitrobenzyloxycarbonyl-2-
carbamoyl)pyrrolidin-4-ylthio]-6-(1
-Hydroxyethyl)-penem-3-carboxylic acid p-nitrobenzyl ester (89ray) in dioxane (
This mixture was hydrogenated at room temperature and normal pressure for 4.5 hours. After removing the catalyst, the tetrahydrofuran was distilled off under reduced pressure, the residual liquid was washed with ethyl acetate, and the aqueous layer was The organic solvent was distilled off again under reduced pressure, and the remaining liquid was converted to C! IIF-
Purified by 20P column chromatography, (5R
,6S,8R,2'S,4'8)2[2-carbamoylpyrrolidin-4-ylthio]-6-(1-hydroxyethyl)-penem-3-carboxylic acid was obtained.

KBr ■几ν -1: t762.165o, 1577.1.
376111aX J NMR (D20) δ: 1.29 (8M, d, J=a
5H2), 1.75-1.89 (In, m), 2.62
~2.87 (111, m), 8.00 ~ 8.09 (I
n.

m), 8.88-8.48 (In, m), 8.65-8
．． 92 (2H, m), 8.90 (IH, dd, J
=l, 4Hz and J=511z), 4.17-4.
80 (IIi, m), 5.68 (IH, d, J = 1.4
Hz) Example 8 (5,68+8K)-2-ethylsulfinyl-6-
(l-hydroxyethyl)-penem-8-carboxylic acid p
--- Trobenzyl ester (45 #IP) in a solution of dry acetonitrile (0,8 Tnt) under a nitrogen stream at -40
At 'C', a solution of diisopropylethylamine (801'lr) in dry acetate and nitrile (0,8d) was added, and then (2'8
, 4'8) -1'-p-nitrobenzyloxycarbonyl-2-dimethylcarbamoyl-4'-mercaptopyrrolidine (81■) in dry acetonitrile (0,6r
nt) and stirred at -40 to -45°C for 10 minutes, the reaction solution was diluted with ethyl acetate, washed with saturated saline, dried with sulfur salt, the solvent was distilled off, and the residue was purified by silica gel chromatography. ,68°8R,2'S,4'
p-nitrobenzyl-2-[(1-p-nitrobenzyloxycarbonyl-2-N,N-dimethylcarbamoyl)pyrrolidin-4-ylthio]-6-(1-hydroxyethyl)-penemu 3-carboxylate An ester was obtained.

[α]D=+52°(C=0.48, CHGts
) ILLνCk'cta max, -1:1781311700.1660,16
07°1400, 1825.1114.1011018
N CD (3za) δ: 1.82 (8H, d, J=
5Hz), 2.96 (8L8), 8.08 (8H,s
), 8.72 (In, da, J=1,5H2an
d J=611z), 5.20 (2 to 5s),
5.70 (IJ Hi, d.

J = 1.5Hz) e e 5% palladium-carbon (204119) was suspended in 112U (8.8 ml) of ethanol (8.8 ml), hydrogenated at room temperature and normal pressure for 1 hour, filtered, washed with water, and dissolved in phosphoric acid. Suspend in buffer y PH1.86 (5.1ml), (51L, 68.8L, 2'S, 4'S)-
2-[(1-p-nitrobenzyloxycarbonyl-2
-h,N-dimethylcarbamoyl)pyrrolidin-4-ylthio]-6-(1-hydroxyethyl)-penem-8
-Carboxylic acid p-nitrobenzyl ester (68#v)
of tetrahydrofuran (7.7 mA) and the mixture was hydrogenated at room temperature and normal pressure for 3 hours.
After evaporation, tetrahydrofuran was distilled off under reduced pressure, the residual liquid was washed with ethyl acetate, the aqueous layer was again distilled off under reduced pressure to remove the organic solvent, and the residual liquid was purified by tillF-20P column chromatography. 5R, 68, 8 liters, 2'S.

4'S)-2-[2-N,N-dimethylcarbamoylpyrrolidin-4-ylthio]-6-(1-hydroxyethyl)-penem-3-carboxylic acid was obtained.

20 λ, naxnm: 822.255Br 1几ν -1: 1765.1645.1580,15
08.1867m&X cm Nhm(D 20 ) δ: ], 29(8H, d, J
=6.4flz), 1.94-2.08(lH,tn)
, 2.98-8.15 (In, In), 2.98 (8H
, S), 8, O5C3M, 8), 8.58-8.62
(lit, m), 8.88-8.98 (IR, n]
), 8.94 (In, dd, J=1.4Hz and J=
(iRz) 4.06-4.80 (8n, m), 5.7
1 (In, d, J = 1.4Hz) Example 5 (5R,6s,5R)-2-ethylsulfinyl-6
-(1-Hydroxyethyl)-penem-3-carboxylic acid p-nitrobenzyl ester (32η) was added to a solution of dry acetonitrile (0,6rn1.) at -40°C under a nitrogen stream.
Add a solution of diisopropylethylamine (22W9) in dry acetonitrile (0.2 mg) and add (2'
S, 4'8) -1'-P-nitrobenzyloxycarbonyl-2'-(1-pyrrolidinecarbonyl)-
Add a solution of 4'-mercaptopyrrolidine (68#) in dry acetonitrile (0,5 ml) and heat at -40 to -45°.
The reaction mixture was stirred at C for 10 minutes, diluted with ethyl acetate, washed with saturated saline, dried with salt water, and the solvent was distilled off. The residue was purified by silica gel chromatography.
R,2'S,4'5)-2-[:[1-P-nitropenzyloxycarbonyl-2-(1-pyrrolidinecarbonyl)]]pyrrolidin-4-ylthio-6-(1-hydroxyethyl)-penem -8-carboxylic acid p-nitrobenzyl ester was obtained.

[α brother 7 = +48° (C = 0.81, CHOz
a) 14'lu, L8bb, IIID NMR (CDCza) δ: 1.86 (811, d,
J=6), 5.22 (2H, s), 5.75 (IH,
d, J = 1.5Rz) Example 6 5% palladium-carbon (90mg>'t) Suspended in ethanol (1,77m), hydrogenated at room temperature and normal pressure for 1 hour, and filtered. , washed with water, suspended in phosphate buffer PH6,86 (2.8 ml),
(5R, 68, 8R, 2'8゜4'S)-2-[[1
-P-nitrobenzyloxycarbonyl-2-(1-pyrrolidinecarbonyl)]]pyrrolidin-4-ylthio]
-6(l-Hydroxyethyl)-penem-8-carphonic acid p-nitrobenzyl ester (80 ml) was added to a solution of tetrahydrofuran (8,4+n7 ml), and this mixture was hydrogenated at room temperature and normal pressure for 3.5 hours. Then, tetrahydrofuran was distilled off under reduced pressure, the residual liquid was washed with ethyl acetate, the aqueous layer was again distilled off under reduced pressure to remove the organic solvent, and the residual liquid was purified by CLIP-20P column chromatography to obtain (5R, 68,
8[L, 2'8.4'8)-2-[[2-(1-pyrrolidinecarbonyl)]]pyrrolidin-4-ylthio]-
6(1-hydroxyethyl)-penem-3-carboxylic acid was obtained.

Br I几ν −1: 1765.1686.1582.18
65max NMR (D2(J)δ: 1.29 (3H,d,
, T==6.4flz), 1.80~2.08(5L
m), 2.88~8.05 (Iff, m), 8.84~
8.61 (5ft.

m), 8.64-8.74 (lfi, m), 8.98 (
ILL, dd, J==l, 4Hz and J-6H2
), 4.04 (IL quin, J=6.6fl
Z), 4.24 (IL quin, J=(i,
3), 4.40 (lli, t, J=8.2H
z ), 5.70 (ILd, J = 1.411z) Example 7 2 2-(2-p-nitrobenzyloxyluponylaminoethylsulfinyl)-6-(1-p-nitrobenzyloxycarbonyloxy ethyl)-penem-3-carboxylic acid p-nitrobenzyl ester (80ff?) in dry acetonitrile (0.75d) under a nitrogen stream.
Add a solution of diisopropylethylamine (3,8η) in dry acetonitrile (0,251 nt) at −40°C;
Further, a solution of (28,48)-1-p-nitrobenzyloxycarbonyl-2-carbamoyl-4-mercaptopyrrolidine (72W) in dry dimethylformamide (0,5g) was added and the mixture was heated at -20 to -800 for 20 minutes. Stir and
The reaction solution was diluted with ethyl acetate, washed with saturated saline, dried with salt water, and the solvent was distilled off. The residue was purified by silica gel chromatography to obtain (2'S, 4'S)-2-
[(1-p-nitrobenzyloxycarbonyl-2-carbamoyl)pyrrolidin-4-ylthio]-6-(1-
p-nitrobenzyloxycarbonyloxy)ethyl-
Penem-8-force 7L+phonic acid-P-nitrobenzyl ester was obtained.

11t""" -1:1794.174L1698,1
605゜mthX cm 1516, 1840.1258. l107NMR(l
107N) δppm: 1.49 (8H,d,
J=6.5)+8.95(In, dd, J==l,5
Hz and J = 7Hz), 5.25 (4L!
I+), 5.68 (IIi, d, J= 1.5
) Example 8 5% palladium-carbon (160M') was suspended in ethanol (8mg) Il+(J (8mg), hydrogenated at room temperature and normal pressure for 1 hour, filtered, washed with water, and suspended in phosphate buffer C (8ml)). Dokusaze, (2'S, 4
'S)-2-[(1-P-nitrobenzyloxycarbonyl-2-carbamoyl)pyrrolidin-4-ylthio)-6-(1-P--nitrobenzyloxycarbonyloxy)-ethyl-penem-3-carvone Acid P-nitrobenzyl ester (40q) (D tetrahydrofuran (
4,5+d) and the mixture was hydrogenated at room temperature and normal pressure for 5 hours.

After removing the catalyst, tetrahydrofuran was distilled off under reduced pressure, and the residual liquid was purified by UIliP-201' column chromatography to obtain (2'S, 4'S)-2-C(2'-carbamoyl)pyrrolidine 4- [ylthio]-6-(1-hydroxyethyl)-penem-3-carboxylic acid was obtained.

λ”0Mm: 821, 252 ax IRvKB”-r: 1770.1688.159
0.1874111aX crn NMR (D20) δPPm: 1.26 (8L d
, J=6.5), lz), 1.95-2.22(
ILm), 2.79-2.98 (ill, m>, 8
．． 26-8.41 (in, m), 8.60-8.77 (
111, In), 8.90 (Ill, dd.

J=1.4. Eiz and J=7tiz), 3.97~
4.04 (IH, m), 4.15-4.85 (211,
m), 5.67 (In, d, J= 1.4 H
z) Example 9 Jq 2-ebursulfinylpenem-3-carboxylic acid P
- To a solution of dry acetonitrile (0.75 mg) of nitrobenzyl varnish f) 24~) was added M solution of dry acetonitrile (0.25 mjt) of diisopropylethylamine (0.25 times mol) at -40°C under a nitrogen stream. A solution of (28,48)-1-'p-nitropenzyloxycarponyl-2-carbamoyl-4-mercaptopyrrolidine (2.2 times mol) in dry dimethylformamide (0.5 ml) Add -20 to -4
After stirring at 0°C for 40 minutes, the reaction solution was diluted with ethyl acetate, washed with saturated brine, dried with sulfur salt, the solvent was distilled off, and the residue was purified by silica gel chromatography using 2'S.

4'8)-2-[(1-, P-nitrobenzyloxycarbonyl-2-carbamoyl)pyrrolidin-4-ylthio"-he-3-carvone rR-p-nitrobenzyl ester was obtained.

IRv"j0'x-": 1780.1700.1
675+ 1600°ax 505 NMI ((UDeza) δppm: 4.40 (
ln, t, J = 7Hz), 5.25 (2M,
s), 5.87 (IH, d, J= 13.6Hz
), 5.75 (IH, dd, J = 1.5Hz
and J=3.5Hz), 7.47(2H,d,
J=9Hz), 7.57(2Ld, J=9H
z), 8.16(411,d, J=91(Z)) The following compounds can be synthesized in a similar manner to the methods described in Examples 1 to 6.

■ (5 liters, 6B, 8 liters, 21S, 4'R) 2
-(2-carbamoylpyrrolidin-4-ylthio)-6
-(1-Hydroxyethyl)-penem-3-carboxylic acid (5ft, 68,3R,2'几,4'5)-2-(
2-Carbamoylpyrrolidin-4-ylthio)-6-(
1-Hydroxyethyl)-penem-8-carboxylic acid
-carbamoylpyrrolidin-4-ylt)-6-(1
-hydroxyethyl)-penem-3-carboxylic acid■ (5R,68,8B,2'S,4'R)-2-(
2-N,N-dimethylcarbamoylpyrrolidin-4-ylthio 3-6-(1-hydroxyethyl)-penem-8
-carboxylic acid■ (5R,68,8R,2'R,4'8)-2-(2
-N,N-dimethyl-carbamoylpyrrolidin-4-ylthio l-6-(1-hydroxyethyl)-penem-3
-Carboxylic acid■ (5R, 6S, 8L, 2'R, 4'R
)-2-(2-N,N-dimethylcarbamoylpyrrolidin-4-ylthio)-6-(1-hydroxyethyl-penem-8-carboxylic acid (5R, 68, 8R, 2'S, 4') -2-
[(2-(1-pyrrolidinecarbonyl)pyrrolidine)-
4-ylthioE-6-(1-hydroxyethyl)-3-
Carboxylic acid■ (5R,68,8R,2'几,4'8)-2-[(
2-(1-pyrrolidinecarbonyl)pyrrolidine)-4-
ylthio]-6-(1-hydroxyethyl)-8-carboxylic acid (5R,6S,81L,2'R,4'R)-2-
[(2-(i-pyrrolidinecarbonyl)pyrrolidine)-
4-ylthio]-6-'(1-hydroxyethyl)-3
-Carboxylic acid reference example 1-1 trans-4-hydroxy-L-proline 6.55f,
Triethylamine 7.5- is dissolved in 15 g of water, and 5-p-nitropenzyloxycarbonyl-4 is added to the solution at room temperature.
,6-dimethyl-2-mercaptopyrimidine 15.95
A dioxane 85-solution of F was added dropwise, and the mixture was left at room temperature for 1
．． Stir for 5 hours and set aside overnight. The reaction solution was cooled with water for 2N.
After adding 80 m of sodium hydroxide and extracting with ether, the ether layer was washed with 20 m of sodium hydroxide, the alkaline aqueous layers were combined, acidified with hydrochloric acid using 100 tnt of 2N aqueous hydrochloric acid, and extracted with ethyl acetate. The ethyl acetate layer was sequentially washed with 2N hydrochloric acid, dried with sodium sulfate, and the solvent was distilled off.
The obtained crude crystals were purified by repulping with ethyl acetate to obtain trans-1-CP-nitrobenzyloxycarbonyl)-4.
-Hydroxy-L-proline was obtained.

m, p, 184.8~185.5° CIRNu"'
(cm-'): 8800 (br), 1788
, 1660°ax 1605, 1520.1B40.1205.1172.
1070.965 Reference Example 1-2 Trans-1-(P-nitrobenzyloxycarbonyl)-4-hydroxy-L-florin 8.1Of, l-ethylamine 1.10f was dried in tetrahydrofuran 40
A solution of ethyl chloroformate (1.2°F) in dry tetrahydrofuran was added dropwise at -25°C to -85°C, and after stirring for 50 minutes, concentrated ammonia water (lO) was added at -25°C to -40°C. - was added dropwise. Gradually raise the temperature to room temperature,
After further stirring for 1 hour, the reaction solution was concentrated under reduced pressure. After adding 20 d of water and 50 rnt of ether to the residue and cooling with water, the resulting white crystals were separated, washed successively with cold water and cold ether, and dried under reduced pressure to give trans-1-(p-nitrobenzyloxycarbonyl)-4-hydroxy-L- Prolinamide was obtained.

m, p, 168.8-164.0℃ IRNuj0'(cm''): 8460.8B70
．． 8200.1687°1640, 1621, 15
89, 1B41, 1180, 1078 Reference Example 1-
3 trans-1-(P-nitrobenzyloxycarbonyl)-4-hydroxy-L-prolinamide 2.82 g,
To a suspension of 1.67 g of triethylamine in 40 g of dry tetrahydrofuran was added 1.8 g of methanesulfonyl chloride at room temperature.
Add 9F dry tetrahydro 7ran 10-solution dropwise,
After stirring for an hour, the reaction solution was concentrated under reduced pressure. Add 30ml of water and 80ml of ether to the residue, cool with water, filter the white crystals, wash with cold water and cold ether, and dry under reduced pressure to obtain trans-1-(P-nitrobenzyloxycarbonyl)-
4-methanesulfonyloxy-L-prolinamide was obtained.

m, P, 149.5-151'C N'''' (cm 1): 3400,8225.171
5.1675゜iRma Engineering 1520.1840.1170.1185 Reference Example 1-4 To a suspension of 50% sodium hydride 874 ~ in dry dimethylformamide 18, add a solution of thioacetic acid e642q in dry dimethylformamide 14 under a nitrogen stream. , 25 at room temperature
Stir for 1 minute, add 975 kg of sodium iodide to this solution, and then add 2.52 g of trans-1-(p-nitrobenzyloxycarbonyl)-4-methanesulfonyloxy-L-prolinamide to 12 m of dry dimethylformamide.
Solution A was added and the mixture was heated and stirred at 70°C for 6 hours. The reaction solution was poured into cold brine and extracted with benzene. The extract was sequentially washed with a 10% aqueous sodium sulfite solution and brine, dried with mirabilite, and the solvent was distilled off. The resulting crude crystals were repulfed with a mixed solvent of tetrahydrofuran and benzene. cis-1-(p-nitropenzyloxycarbonyl)-4-acetylthio-L
- Prolinamide was obtained.

+11. P, 168.5~169.5℃ IR work 4°'
(cm-',): 8B50, 8180, 17
15, 1690.

1688, 1510.1880.1100 Reference Example 1-5 Cis-1-(p-nitropenzyloxycarbonyl)-
4-Acetylthio-L-prolinamide (950 ~) was dissolved in methanol (95%), and IN-sodium hydroxide water bath solution (2.59 mg) in an argon stream was added at room temperature, and the mixture was stirred for 15 minutes. - Add aqueous hydrochloric acid solution (2,59 mA) to neutralize, distill methanol off under reduced pressure, collect precipitated crystals and wash with water to remove cis-1-(p-nitrobenzyloxycarbonyl)-
4-Mercapto-L-prolinamide was obtained.

"-P, 158-162°C Reference Example 2-1 Trans-1-(p-nitropenzyloxycarbonyl)-4-hydroxy-L-prolinamide 2.11 was diluted with 100 rsl of acetone, and the excess amount Jeans (
Jones) reagent was added under water cooling, and the mixture was stirred at room temperature for 1.5 hours. The reaction solution was diluted with ethyl acetate; washed with water and dried with mirabilite to obtain B-(p-nitrobenzyloxycarbonyl)-4-oxo-L-prolinamide. ln, p, 156 ~158°C Reference Example 2-2 0.9f of l-(p-nitrobenzyloxycarbonyl)-4-oxo-L-prolinamide was dissolved in methanol 60-
160 IF of sodium borohydride was added and stirred for 30 minutes.

The reaction solution was concentrated under reduced pressure to about l〇-, extracted with a mixed solvent of tetrahydrofuran-ethyl acetate (1:i), and washed with water.
Glauber's salt drying. The hot medium was distilled off, and the residue was purified by silica gel chromatography to obtain 1-(p-nitrobenzyloxycarbonyl)-4
-Cis and trans isomers of hydroUxy-L-prolinamide were obtained (ratio of cis and trans isomers was 1
0:l).

Cis isomer m, p, 150-151.5°C Trans isomer is the same as that obtained in Reference Example 1-2, m, p, and IR
matched.

Reference example 2・-3 cis-1-(p-nitrobenzyloxycarbonyl)-
4-Hydroxy-L-fo! J Namide 0.81
From F, trans-1-(p-nitrobenzyloxycarbonyl)-4-mercapto-L-prolinamide was obtained in the same manner as Reference Example 1-8, Reference Example 1-4, and T-groove side 1-5.

El ynj1m(,ko'): 1705.1685.
1515.14B5゜1400, 1342, 111
8 Reference Example 8-1 Trans-1-(p-nitrobenzyloxycarbonyl)-4-hydroxy-L-florin (15,01) Triethylamine (18.5 ml) was dissolved in dry dimethylpolamide (150 ml), Under continuous air flow, p-methoxybenyl chloride (12,C; 6 mg) was added dropwise,
The reaction solution was stirred at 7°C''C-1θ for 10 hours. The reaction solution was diluted with ethyl acetate (500 yd), precipitated with water, dried with mirabilite, and distilled off. The residue was crystallized from ether and trans-1-(p-
nitrobenzyloxycarbonyl)-4-hydroxy-
L-proline-1)-methoxybenzyl ester as fζ
Ta.

m, p, 88~85"0 1fLyn age (ffi'): 84B0.17
35.1705.1510°1840, 1245,
116 (1 Reference Example 3-2 1'ΔIJ, PNZ trans-1-(p-nitrobenzyloxycarbonyl)-4-hydroxy-L-proline-p-methoxybenzyl ester (8,61/), triphenylphosphine (7,8611) in dry tetrahydrofuran (20 mg)
), then water-cooled and under a nitrogen stream, a solution of diethyl azodicarbonate (5,22F) in dry tetrahydrofuran (5G) was added dropwise and stirred for 80 minutes, then thioacetic acid (2,28F) was added dropwise, and the mixture was cooled with water. The mixture was stirred for 1 hour and then at room temperature for 8 hours, and the reaction solution was concentrated. The residue was subjected to silica gel column chromatography to obtain cis-1-(p-nitrobenzyloxycarbonyl)-4-acetylthio-L-proline-p-methoxybenzyl ester.

IRfil” (cy++’): 1740 (Sh)
, 1715.1520°ax 1405 , 1848 , 112O NMR δ (CDOzs): 2.81 (8R, s),
8.79 (8H, 8), 5.10 (2L 8 ), 5.
24 (2H, s), 7.49 (211, d, J=9, Q
Hz), 8.18 (211L, d, J=9.0
fiz) Reference Example 8-3 cis-1-(p-nitropenzyloxycarbonyl)-
4-acetylthio-L-proline-P-methoxybenzyl ester (9,761), anisole (4,82F)
was stirred with trifluoroacetic acid (85 mg) for 80 minutes at room temperature.

The residue was subjected to silica gel column chromatography to obtain cis-1-(p-nitrobenzyloxycarbonyl)-4-acetylthio-L-proline.

m, P, 107-109°C IRNu”1 (m 1): 1725.1685.1
660 (8h).

ax 1B40.1180.1110 Reference Example 3-4 Cis-1-(p-nitropenzyloxycarbonyl)
-4-acetylthio-L-proline (+8(ly)) was dissolved in dry tetrahydrofuran (2d) and dimethylamine hydrochloride (48'9), N, N-') methyl7'i,/hi') syn (78q ) and dicyclohexylcarbodiimide (152η) were sequentially added and stirred overnight.

Insoluble matter was removed in an oven, the P solution was diluted with ethyl acetate, diluted with dilute hydrochloric acid,
Washed sequentially with water, dried with Glauber's salt, distilled off the solvent, and subjected the residue to silica gel column chromatography.
)-1-(P-nitrobenzyloxycarbonyl)-
2-dimethylcarbamoyl-4-acetylthiopyrrolidine was obtained.

IR"In(crr'): 1705.1650,1
515,1400゜&! 1840.11l1 05Nδ (CDOza): 2.82 (8L8), 2
．． 97 (8H, 11), 8.11 (811, 8), 5.
21 (2H, s), 8.18 (2Ld, J = 8.5H7
) ["lr +5.21' (C=0-8T97 seh
) Reference Example 8-5 (28,48)-1-(P-nitrobenzyloxycarbonyl)-2-dimethylcarbamoyl-4-acetylthiopyrrolidine (40) was dissolved in methanol (4-), and IN-Na0 The mixture (0,1d) was stirred at room temperature for 15 minutes. Then IN-MCL (0.11 rpl) was added and concentrated under reduced pressure. Dilute the concentrated solution with ethyl acetate, wash with water,
-IJ-rm&mff1##a+I/suQARl-1-
(p-nitrobenzyloxycarbonyl)-2-dimethylcarbamoyl-4-mercaptopyrrolidine was obtained.

fil+n-r.

Ill,, 1aX(on), 1705.1650
．． 1515.1400゜1840, 1165.1105 Brown mδ (CDCza): 1.90 (lli,
d, J=8H7), 2.97Ct3kL, 8),
3.08 (8J=L, S), 5.19 (21 Sat +
S), 7.48<2kL, d, J=9Hz), 8.15
(211,d, J=9Hz) Reference Example 4-1 Oxalyl chloride (0.2m6) in dry methylene chloride C5ml> Dimethyl sulfoxide (0.85ml) in dry methylene chloride in #5 solution at -60 to -70°C Melt [(1
-) was added dropwise, and after 10 minutes, a dry methylene chloride bath solution (10 mg) of trans-1-(p-nitrobenzyloxycarbonyl)-4-hydroxy-2-zololine p-methoxybenzyl ester (860~) was added to - It was added dropwise at below 50°C and stirred for 15 minutes. Next, triethylamine (1
, 01g) was added dropwise, heated to room temperature, diluted with methylene chloride, washed with diluted hydrochloric acid, dried with sodium sulfate, evaporated the solvent, and subjected the residue to silica gel column chromatography.
-nitrobenzyloxycarbonyl)-4-oxo-L
-Proline p-methoxybenzyl ester IR""(m-'): 1762.1740.17
10.1512ax 1B45.1245.1155 NMItδ (0, DCzs): 8.78 (8M, s)
, 8.95(2)1. s), 5.08 (2H, s)
, 6.85 (2H, d, J=9Hz), 8.12 (2f
t, d, J=9Hz) Reference Example 4-2 Q 1'NZ 1-(p-nitrobenzyloxycarbonyl)-4-oxo-L-proline P-methoxybenzyl ester (
650~) in ethanol (45m) and at room temperature,
Add sodium borohydride (8619) in two portions. After 30 minutes, it was concentrated under reduced pressure at below 80°, the concentrated solution was diluted with ethyl acetate, washed with water, dried with sodium sulfate, and the solvent was distilled off. -Nitrobenzyloxycarbonyl)-4-hydroxy-L-proline p-methoxybenzyl ester and trans-1-(p-nitrobenzyloxycarbonyl)-4-hydroxy-L-proline P-methoxybenzyl ester were obtained.

Trans form: II'L, NMR was consistent with the spectral data of the compound of Reference Example 8-1.

Cis form: IRnL x”'(crn'):
8400 (br), 1725.1515, 1405.
1850.1250.1170゜120 Hatake Jin δ (Ckaza): 8.78 (8Ls), 5.0
8(2H,S), 6.82(211,d, J=
9Hz), 8.12 (2R, d, J = 9Hz)
Reference Example 4-3 Cis-1-(p-nitropenzyloxycarbonyl)-
Reference Examples 3-2 and 3 using 4-hydroxy-L-proline p-methoxybenzyl ester (610my)
Trans-1-(P-nitroben-L-proline) was obtained by the method of -3 and Hinata.

IR4axr11 (cngo): ~8000,170
0.1515,1480°1400.1B45.120
5,1165.1115mtδ (ODC18): 2
．． 82(8)1,8), 5.20(2-tf, br
, s ), 7.42 (211, d , J=gnz
), 8.12 (2n, d, J=911Z) Reference Example 4-4 us.

P'NZ a) trans-1-(p-nitrobenzyloxycarbonyl)-4-acetylthio-L-proline (180~)
C2S, 4R by the same method as Reference Example 3-4 using
]-1-(p-nitropenzyloxycarbonyl)-2
-dimethylcarbamoyl-4-acetylthiopyrrolidine (100w) was obtained.

IRfll” (crIV'): 1700.1655
．． 1515.1400°ax 1840, 1115 [α] Sweet 82.8° (G = 0.875. Acetone) b
)Thioacetate-1/rust conductor obtained in &) above (80my
) by the same method as Reference Example 3-5 [28,4R]
-1-(1)-nitrobenzyloxycarbonyl)-2
-Dimethylcarbamoyl-4-mercaptopyrrolidine was obtained.

filrn -t ++ 1 liter (crn), 1700, 1650, 1510
．． 1420°ax 1400, [140, 1120 mtδ(C1)Ozll): 1.77(ltl, d
, J=7Hy, ), 2.97 (8H,,8), 8.16
(8) i, s), 5.22 (2H, s), 8.16
(211, d, J = 8.5Hz) Reference example 5-
Reference example 1-1 from 1 P to 2 Hz cis-4-hydroxy-D-proline
and 8 Cis-1-p-nitrobenzyloxycarbonyl-4-hydroxy-D- obtained by the same method as 1
Prolinol-methoxybenzyl ester (166-)
triphenylphosphine (202η) was dissolved in dry tetrahydrofuran (1,fim) and then formic acid (27η) was dissolved in dry tetrahydrofuran (1,fim).
Add ri. Furthermore, diethyl azodicarbonate (18
4MI) was added at room temperature under a nitrogen stream, and after stirring for 30 minutes, the solvent was distilled off.

The residue was purified by silica gel chromatography and trans-1-p-2I-lobenzyloxycarbonyl-4-
Formyloxy-D-proline-p-methoxybenodif
- Obtained ester.

i1m IR(z'): 1720.1515.1402,
1842°ax 1245.1165.1120 Drawing δtcDOtt+>: g, 7e (an, s),
4.50 (2H, t, J=gRz), 5.08 (2LI
8), 5.15 (2fi, ABq, J= 1
6H2), 5.41 (in, m), 7.97 (11i,
11) Reference Example 5-2 trans-1-p-nitropenzyloxycarbonyl-
4-formyloxy-D-proline-P-methoxybenzyl ester (215) was dissolved in tetrahydrofuran (i,
iv), add IN-Na (JR water 0.98-mL), stir for 10 minutes, dilute with ethyl acetate, and wash with saturated brine. After drying the sodium sulfate, the solvent is distilled off. The residue is purified by thin layer chromatography. Then, trans-1-p-nitrobenzyloxycarbonyl-4-hydroxy-D-proline-p-methoxybenzyl ester was obtained.

■RmBxm (Crn''): 8425 (br),
17B5.1705.1510゜1400, 1B40
．． 1240.1162mδ (CDOzs): 2.8
8 (2H, m), 8.58 (2ft, d, J=g, 5.
tlz), 8.78 (8ft, s), 5.08 (24
:L,! 1), 5.07 (211, ABq, J =
taHz), 6.78 (21i, d, J =
914z), 6.77 (2M, d, J = 9Hz),
8.00 (2L d , J=8.5Hz), 8.0
7 (2ft, d, J=8.5JlllZ) Reference Example 5-8 s-coNZ a) Trans-tp-nitrobenzyloxycarbonyl-4-hydroxy-D-proline-p-methoxybenzyl ester (110k ), Reference Example 8-2.8-8 and 8-
[2R.

4K]-1-p-nitropenzyloxycarbonyl-2
-dimethylcarbamoyl-4-acetylthiovirolidine was obtained.

IR"'m (cm-"): 1705.1650.1
515.1485°ax 1840, 1115 [α]D-7.88° (0=0.210.acetone)b
) Thioacetate a conductor (421J9) obtained in a) above
[2 liters, 4 R] in the same manner as in Reference Example 8-5 using
-1-p-nitrobenzyloxycarbonyl-2-dimethylcarbamoyl-4-mercaptopyrrolidine was obtained.

IR”””(cnV'): 1710.1660.15
25.1440゜m & [2R,4)-1-p by the same method as Example 8-2.8-8.1-2 and 1-5.
40 pieces of -nitropenzyloxycarbonyl-2-carbamoyl-4-acetylthiopyrrolidine were obtained.

I bow A,”’(cnV’): 1685.1515
, 1400, 1840°110 [α], +89.6° (e=0.298, DMF)
b) Thioacetate derivative obtained in &) above (4011F
) using the same method as in Reference Example 1-5, [2, 4
R]-1-p-nitrobenzyloxycarbonyl-2-
Carbamoyl-4-mercaptopyrrolidine was obtained.

IRNuj0'(m-'): 8200, 1'710
, 1655, 1512°ax 1840 , 1115 Reference example 6 From cis-4-hydroxy-D-proline Reference example 1-1
In the same manner as in 1-2, carbonyl)-4-hydroxy-D-prolinamide 8101F) was dissolved in dry tetrahydrofuran 1- with liphenylphosphine 89ON12, and diethylazocarboxylate 260#IF was dissolved in dry tetrahydrofuran (1-) with water cooling. l-) Add common solution and stir for 80 minutes. Then Thio I [1151119
A solution of dry tetrahydrofuran (0.51 nt) was added thereto, and the mixture was stirred for 1 hour under water cooling, and then stirred at room temperature for 8 hours. The reaction solution was concentrated under reduced pressure and purified by silica gel chromatography to obtain trans-1-(p-nitrobenzyloxycarbonyl)-4-acetylthio-D-prolinamide 270M.
I got a 9. This was then treated in the same manner as Reference Example -5 to obtain trans-1-(p-nitropenzyloxycarbonyl)-4-mercapto-D-prolinamide.

IR"""(cm-"): 1695 (8tl), 1
682.1515゜nax 1895, 1840, 1115 Reference Example 7 a) Cis-4-hydroxy-D-proline (800■)
Reference example 1-1.8-1゜8-2.8-8 and 8-
[2 liters, 4a]-1-(P-nitrobenzyloxycarbonyl)-2-dimethylcarbamoyl-4-acetylthiopyrrolidine (45η) was obtained in the same manner as in Example 4.

IRfjlm (cm-1): 1700.1650.
1520.1400゜nthx 1845,1120 Island O [α: 1D-29,6° ((!=0.215.70 tons) b) Thioacetate derivative obtained in a) above (80#+
2) by the same method as in Reference Example 8-6 [2E, ,
4S]-1-(P-nitrobenzyloxycarbonyl)-2-dimethylcarbamoyl-4-mercaptopyrrolidine was obtained.

IR, SA4” (z-1) m 1'710 * 16
55 + 1520, 1480 +1405, 18
47, 1122 Reference Example 8 ■ NZ a) Cis-1-(p-nitrobenzyloxycarbonyl)-4-7 cetylthio L-bouline (184"F
) was dissolved in dry methylene chloride (1,5d), dimethylformamide (0,05-) was added, oxalyl chloride (0,1 rnt) was added dropwise under water cooling and a nitrogen stream, and the mixture was stirred for 1 hour at room temperature. . The solvent was distilled off under reduced pressure, dry benzene (15 m) was added to the residue, and the solvent was distilled off again. The residue was dried under reduced pressure. This was dissolved again in dry tetrahydrofuran (2-) and added dropwise to a solution of pyrrolidine (71-) in dry tetrahydrofuran (2-) under water cooling and a nitrogen stream.

After stirring for 80 minutes, diluted with ethyl acetate, washed successively with IN-hydrochloric acid and water, dried with sodium sulfate, distilled off the solvent, and purified with silica gel chromatography.28.48)-1-(P-Nitrobenzyloxycarbonyl)- 2-(1-pyrrolidinecarbonyl)-4-acetylthiopyrrolidine was obtained.

IR, 4 staves (m-'): 1705.1640.15
16.1480°1400, 1842.111O NMRδCODOtm): 2.81 (8H, s),
4.08 (211, dd.

J = (3 and gIliz), 4.68 (lli
, t, J=3Hz), 5.19 (2H, 8),
7.48 (211, d, J=9Hz), 8.18 (2H
, d, J=91Lz)b) Using the thioacetate-1 derivative (150~) obtained above, (28,48)-1-p-nitrobenzyloxycarbonyl was prepared in the same manner as in Reference Example 3-5. -2-(1-pyrrolidinecarbonyl)-4-mercaptopyrrolidine was obtained.

■几”””(cy+-'): 1708.1645,1
520,1440゜11aX 1405, 1850.1170.1115 Reference example 9-1 (8 liters, 41 L)-8-((几)1-tert-butyldimethylsilyloxyethyl)-4-acetoxy-2-
Azetidinone (2,10f) in dioxane (12,2m
) of ethyltrithiocarbonate potassium salt (1,29y) in water (12,2
The solution of d) was added and pressed for 20 minutes at the same temperature. The reaction solution was diluted with methylene chloride, washed with water, dried with sulfate, and the solvent was distilled off. The residue was crystallized from ether-n-hexane (Bf
L,4R)-8-((R)-1-tert-butyldimethylsilyloxyethyl)-4-ethylthiothiocarbonylthio-2-azetidinone was obtained.

Nu'ol.

El ν' −1,1771,173L1874.12
88゜mt%xcrn 1258, 1230.1140.1128 width °IR (O
DOts ) δ: 0.16 (6) 1. s), 0.90
(911,!l), 1.21(8H,cl, J=6
1Z), 1.86 (8Li, t, J=7,5n
z), 5.67 (In, d, J = Jtlz) Reference Example 9
-2 P-nitrobenzylglyoxylate monohydrate (1,
85y) was azeotropically dehydrated with dry Jlli Hensen (40+x/), leaving a residue (8It, 4B) -8((
fL) 1-1;ert-15''le')f')ruoxyethyl)-4-ethylthiothiorubonylte2-
2-Azetidinone (2,29F) in dry benzene (80
At 8.5 o'clock, the ILU was refluxed, the reaction solution was filtered, and the M medium was distilled off. The remaining solution was dissolved in dry tetrahydrofuran (21 mA), and 2,6-lutidine (
Add 1.01y), add thionyl chloride (1.12f) at -10 to -15°C under a violet atmosphere, and incubate for 15 minutes at the same temperature.
After stirring, the reaction solution was diluted with methylene chloride, washed successively with dilute hydrochloric acid and water, and dried with salt. Evaporate the solvent at room temperature,
The residue was dissolved in dry tetrahydrofuran (5-), further trinoenylphosphine CB, 271) was added and dissolved, the mixture was left at room temperature for 2 days, diluted with methylene chloride, washed with saturated diluted water, washed with water, and washed with diluted sodium chloride. After drying and evaporating the solvent, the residue was purified by silica gel column chromatography to obtain (8K, 4R)' 8 ((R) 1
-1ert-butyldimethylsilyloxyethyl)-4
-ethylthiothiocarbonylthio-1-(1-p-nitrobenzyloxycarbonylphosphoranylidenemethyl)
-2-Azetidinone was obtained.

lR3C11lCt8゜m, xcn-1, 1752, 1617 (Sh), 160
4.18481190, 1105.1078 Reference example 9-8 (8K, 4R) -8((R) -1-tert
-butyldimethylsilyloxyethyl)-4-ethylthiothiocarbonylthio-1-(1-P-nitrobenzyloxycarbonylphosphoranylidenemethyl)-2-azetidinone (1,60 g) in dry methylene chloride (58,
Boron trifluoride-
Ether complex (16,68F) was added, and the reaction mixture was stirred at the same temperature for 1 hour. The reaction solution was washed with saturated heavy water, washed with water, dried with sulfur salt, and the solvent was distilled off. The residue was purified by silica gel column chromatography to give (B K , 4 R) -8-
((R) -1-Hydroxyethyl)-4-ethylthiothiocarbonylthio-1-(1-p-nitrobenzyloxycarbonylphosphoranylidenemethyl)-2-azetidinone was obtained.

IIL, OHO/jl.

max cm-1, 1759, 1622, 1608 (S
h) l 1476°1414, 1848.1192.1
104, 1080 Reference Example 9-4 (8B, 4B)-8-((R)-1- and droxyethyl)-4-ethylthiothiocarbonylthio 1-(1-
Drying of p-nitropendyloxycarbonylphosphoranylidenemethyl)-2-azetidinone (2,70y) (J
- Bistrimethylsilylacetamide (8,911) was added to a solution of xylene (185 mJ) at room temperature under a nitrogen stream, stirred at the same temperature for 10 minutes, and further 2.6-sheet
t-butiJl/-4/ti-JL/-phenol (8
6'W) was added, the mixture was refluxed for 5 hours, the solvent was distilled off, the residue was diluted with ethyl acetate, diluted hydrochloric acid was added, and the mixture was stirred at room temperature for 80 minutes. The ethyl acetate layer was washed with saturated brine and dried with salt and water. , the solvent was distilled off, and the residue was purified by silica gel column chromatography (5R.

68.3R)-2-ethylthio-6-(1-hydroxyethyl)-penem-8-carboxylic acid p-nitrobenzyl ester was obtained.

■几、Nujoj　.

max,, -1, 1780, 1747, 1698, 16
09°1510, 1487, 1888, 1846
, 1886, 12B0.

1200.1128.110B, 1050.976, 8
58°748, 716.692 NMR (CDOtg) δ: 8.71 (IL dd
, J=1.5Hz and J=(i,5Hz
), 5.64 (IL d , J=1.5.Liz )
Reference Example 9-6 (5 liters, 68.8R)-2-ethylthio-6-(1-hydroxyethyl)-penem-8-carboxylic acid-p-nitrobenzyl ester (26tTjv) in dry methylene chloride (28ml) m- in the bath solution at -45℃ under nitrogen stream
Add chloroperbenzoic acid (144), -20 to -40
The reaction mixture was stirred at ℃ for 2 hours, washed with saturated heavy water, washed with water, dried with sulfur salt, solvent distilled off, and the residue was purified by silica gel chromatography. hydroxyethyl)-penem-
8-carboxylic acid p-nitrobenzyl ester was obtained.

01Bjt", n, x, -1: 1798.170B, 1605.
1517°1447.1877.1844.1815.
1172, 1112° 104B, 965. 824 kmELccDOts): 5.74(/)l, d,
J=1.5Hz), 5.87 (IH, d, J=l, 5
E17. ) Reference Example 10 2-(2-p-nitrobenzyloxycarbonylaminoethyl)thio-6-(1-p-nitrobenzyloxycarbonyloxyethyl)-penem-8-carboxylic acid p-
To a solution of nitrobenzyl ester (44(1?)) in dry methylene chloride (5g) was added m-chloroperbenzoic acid (l16#9) at -40°C under a stream of nitrogen gas, and the mixture was heated at -15 to -25°C.
After stirring for 40 minutes at Ethylsulfini Jl/)
-6-(1-p-nitrobenzyloxycarbonyloxyethyl)-penem-3-carboxylic acid p-nitrobenzyl ester was obtained.

IRy C11CLs.

max crn-” -1798,1712* 16
0'/+1520 Reference Example 11 2-Ethylthio-penem-3-carboxylic acid P-nitrobenzyl ester (0.2 mmol) was added to RIFN in dry methylene chloride (2 td) at -20°C under a stream of arsenic.
After adding l-ri-O-benzene MW acid (0.22 mmoJ) and stirring at the same temperature for 1 hour, the reaction solution was diluted with ethyl acetate and then diluted with 5% sodium bicarbonate solution and saturated brine. The residue was purified by silica gel column chromatography to obtain 2-ethylsulfinyl-penem-3-carvone Wp-nitrobenzyl ester.

noat.

IRν −t, 1784.1696. IGO8,1
518aXem

Claims (1)

[Claims] (IJ General formula: IJ [In the formula, ILl represents a hydrogen atom, an l-hydroxyethyl group, or an l-hydroxyethyl group whose hydroxyl group is protected with a protecting group, and ILl represents a hydrogen atom or Represents a protecting group for an amino group, R8 represents a hydrogen atom or a protective group for a carboxyl group. IL4 and R5 represent a hydrogen atom, a lower alkyl group, an aralkyl group, a substituted lower alkyl group, or IL4 and R6 are bonded to each other. (2) R1 is a hydrogen atom or 1- The β-lactam compound and pharmacologically acceptable salt thereof according to claim 1, which is a hydroxyethyl group and R2 and R8 are hydrogen atoms. (3) General formula [1] [wherein, A symbol indicates a hydrogen atom, ■-hydroxyethyl group or a l-hydroxyethyl group whose hydroxyl group is protected and is closed by an R1 group, IL2 indicates a hydrogen atom or a protecting group for an amino group, and 佽 indicates a hydrogen atom or a carboxyl group. R4 and R5 represent a hydrogen atom, a lower alkyl group, an aralkyl group, a substituted lower alkyl group, or R4 and R6 represent an alkylene chain that is bonded to each other, and together with the M contacting element atom, 4 to represents a 7-membered cyclic amino group.] In producing a β-lactam compound represented by a), general formula [111] [wherein loss and Ra have the same meanings as in 61, R6
represents a substituted or unsubstituted lower alkyl group. ] Sulfoxide represented by the general formula [111] [wherein,
几8 represents a protecting group for an amino group, and 14 and 6 have the same meanings as above. ] In the general formula [11']c formula, R1, 几a,
R4, R5 and R8 have the same meaning as above. ] When producing a β-lactam compound represented by the following and desiring a β-lactam compound in which R1 is a hydrogen atom or a 1-hydroxyethyl group, or a β-lactam compound in which R2 and/or R8 are a hydrogen atom, Then, the reaction for removing the protecting group for carboxyl group, the reaction for removing the protecting group for hydroxyl group, and the reaction for removing the protecting group for amino group R8 are appropriately combined as necessary, or the reactions are performed to simultaneously remove these protecting groups. The above general formula [13
A method for producing a β-lactam compound represented by and a pharmacologically acceptable salt thereof.