JPS60233076A - Novel beta-lactam and its preparation - Google Patents

Abstract

NEW MATERIAL:A compound of formula I [R1 is H, protecting group for OH; R2 is H, protecting group for NH2; R3 is H, protecting group for COOH; R4 is H, alkyl; Y is NR5R6 (R5, R6 are H, alkyl, alkenyl, pyridyl), formula II (R7 is H, alkyl), alkoxy, OH, hydrazino, NHOR8 (R8 is R1, alkyl)] or its salt. EXAMPLE:(5S,6S,8R,2'S,4'S )-3[4-( 2-Dimethylaminecarbonyl )pyrrolidinylthio]-6-(1- hydroxyethyl)-1-azabicyclo[3.2.0]-hepto-2-ene-7-one-carboxylic acid. USE:Antibacterial showing activity against a wide range of disease causative bacteria and a synthetic intermediate of other antibiotics. PREPARATION:The reaction of a reactive ester of an alcohol of formula III with a mercaptan derivative of formula IV is carried out in the presence of a base to give the compound of formula I.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to novel β-lactam compounds or salts thereof, and methods for their production. For more details, please refer to the general formula CI
) [In the formula, R1 is a hydrogen atom or a hydroxyl group protecting group, R2
represents a hydrogen atom or a protecting group for an amino group, R8 represents a hydrogen atom or a protective group for a carboxyl group, and R4 represents a hydrogen atom or a 01-C8 alkyl group.

Y represents the general formula (2) (wherein Rs and Rs are the same or different and represent a hydrogen atom, a C1-Ca alkyl group, a lower alkenyl group, an aryl lower alkyl group, a substituted C1-C6 alkyl group, or a pyridyl group) or R5 and R6 represent an alkylene chain bonded to each other, or represent an alkylene chain via an oxygen atom, a sulfur atom, or a lower alkyl-substituted nitrogen atom, and together with the adjacent nitrogen atom, form an 8- to 7-membered ring. represents an unsubstituted or substituted cyclic amino group which may have a double bond.), a group represented by the general formula (8) (
In the formula, R7 represents a hydrogen atom or a lower alkyl group. )
represented by an anidyl group, protected or unprotected hydroxyl group, lower alkoxyl group, 1, unsubstituted or lower alkyl-substituted hydrazino group, or general formula (4) % formula % (4) (wherein R8 is hydrogen Indicates a group represented by atom, a hydroxyl group protecting group, or a lower alkyl group. ] A novel β-lactam compound or its salt represented by
and their manufacturing methods.

In the general formula CI), various commonly used protecting groups can be used as the protecting group for the hydroxyl group in R1 or the protecting group for the amino group in R2, but preferably, for example, tert-butyloxy. Lower alkoxycarbonyl groups such as carbonyl, e.g. 2-! ethyloxycarbonyl trichloroethyloxycarbonyl, 2゜2.2-trichloroethyloxycarbonyl ionahalogenoalkoxycarbonyl group, examples: t-benzyloxycarbonyl, p-methoxybenzyloxycarbonyl, 0-nitrobenzyloxycarbonyl,
Aralkyloxycarbonyl groups such as p-nitrobenzyloxycarbonyl, e.g. trimethylsilyl, te
A trialkylsilyl group such as rt-butyldimethylsilyl.

In addition, as a protecting group for the carboxyl group in R8,
Suitable examples include methyl, ethyl, isopropyl, ter
Straight-chain, young, and branched lower chain-like chains of t-butyl are examples of ζi2-ethethyl iodide, 2.2-
a halogeno lower alkyl group such as 1-lichloroethyl,
Lower alkoxymethyl groups such as methoxymethyl, ethoxymethyl, isobutoxymethyl, lower aliphatic acyloxymethyl groups such as acetoxymethyl, propionyloxymethyl, butyryloxymethyl, pivaloyloxymethyl, e.g. 1- Methoxycarbonyloxyethyl, 1-lower alkoxycarbonyloxyethyl groups such as 1-ethoxycarbonyloxyethyl; and aralkyl groups such as benzyl, p-methoxybenzyl, 〇-nitrobenzyl, p-nitrobenzyl, and benzhydryl. or phthalidyl group.

Examples of the lower alkyl group in R4 include methyl,
Ethyl, n-propyl, etc. can be mentioned.

Regarding Y, when Y is an amino group represented by the above general formula (2), R6 and R6 are the same or different from each other.

In R5'□ and R6, examples of the 01-C6 alkyl group include methyl, ethyl, n-zorobyl, isopropyl, n-butyl, t-butyl, etc., and examples of the lower alkenyl group include C8-C4 alkenyl such as propenyl and butenyl. The aryl lower alkyl group is substituted with a phenyl group, substituted phenyl group, pyridyl group or substituted pyridyl group, such as benzyl, substituted benzyl, phenethyl, 2-pyridylmethyl, 8-pyridylmethyl, 4-pyridylmethyl. An alkyl group having 1 to 8 carbon atoms is substituted with a substituted 01-C6 alkyl group, such as a hydroxyl group, a 01-C8-alkylamino group, a carbamoyl group, a mono- or 01-Cm alkyl-substituted aminocarbonyl group, or a protected Alternatively, a carbon atom containing 1 to 5 carbon atoms substituted with a substituent such as an unprotected carboxyl group. Examples of the straight-chain or branched alkyl group include 2-pyridyl, 8-pyridyl and 4-pyridyl groups. .

Rs and R6 represent an alkylene chain bonded to each other, or represent an alkylene chain via an oxygen atom, a sulfur atom or a Cs-Cm alkyl-substituted nitrogen atom,
When indicating an unsubstituted or substituted cyclic amino group which may have a double bond in an 8- to 7-membered ring together with the adjacent nitrogen atom, the! Examples of the amino group include saturated cyclic amino groups such as cyasiridino group, azetidino group, pyrrolidino group, piperidino group, etc.; for example, 8-azabicyclo(8,2
, 2) cyclic a,mino groups having a crosslinked structure such as nonan-8-yl group; unsaturated cyclic amino groups such as pyrrolyl group, 8-pyrrolinyl group, etc.; e.g. morpholino group, thiomorpholino group, Oxygen like N-methylpiperazino group! Examples include a cyclic amino group having a sulfur atom, a sulfur atom, or an alkyl-substituted nitrogen atom in the ring. Furthermore, examples of substituents for each of these cyclic a- and mino groups include (
14,Ca alkyl group, carbamoyl group-mono- or di-C1-mary-substituted aminocarbonyl group, and hydroxyl group.

Examples of the unsubstituted or lower alkyl group-substituted guanidyl group include guanidyl groups and guanidyl groups substituted with alkyl groups having 1 to 8 carbon atoms such as methyl, ethyl, n-propyl, and isopropyl; more specifically, for example, N
, N''-tetramethylguanidyl group, etc.

Examples of lower alkoxyl groups include alkoxyl groups having 1 to 8 carbon atoms such as methoxy, ethoxy, n-propoxy, and isopropoxy.

For hydrazino groups, for example, hydrazino, 2', 2
'-Dimethylhydrazino, trimethylhydrazino, etc., unsubstituted or (() refers to hydrazino groups in which an alkyl group having 1 to 8 carbon atoms such as methyl, ethyl, n-propyl, isopropyl, etc. is substituted with 1 to 8 carbon atoms) I can do it.

Regarding R8 represented by the general formula (4), the island is, for example, a protecting group commonly used as a protecting group for a hydrogen atom or a hydroxyl group, or 01 of methyl, ethyl, n-propyl, etc.
~C8 alkyl group. In addition, when Y is a protected hydroxyl group, examples of the protecting group include those commonly used as protecting groups for carboxyl groups.

In the general formula CI), -C00Ra or -co
A carboxylic acid compound in which the group represented by y is a carboxyl group can be made into a pharmacologically acceptable salt form, if necessary. Examples of such salts include salts of inorganic metals such as lithium, sodium, potassium, calcium, and magnesium, and ammonium salts such as ammonium, cyclohexylammonium, diisopropylammonium, and triethylammonium, preferably sodium salts. salt and potassium salt.

The β-lacta A compound represented by the general formula (I) of the present invention is a new compound belonging to carbapenem (1-azabicyclo[8,2,0]hept-2-en-7-one-2-carboxylic acid) derivatives. be. Since chenamycin is an antibiotic that exhibits strong antibacterial activity against Gram-positive bacteria and Gram-positive bacteria, synthetic research on carbapenem derivatives related to chenamycin has been widely conducted.

As a result of repeated research on the synthesis of carbapenems or penem derivatives, the present inventors have found that the 8'-position side chain of the carbapenem skeleton can be easily derived from 4-hydroxyproline with various substituents, that is, various substitutions at the 2-position. A general formula containing a substituted pyrrolidinyl group with a substituted carbonyl group [! ]
The present invention was completed by discovering that the compound represented by the following formula has strong antibacterial activity and is a useful compound as a medicine, or is an important intermediate for a compound exhibiting antibacterial activity.

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

General formula [■] [In the formula, R1 and R4 have the same meanings as above, and R9 represents a carboxyl group protecting group. A reactive ester of alcohol represented by the general formula [m] [wherein R2 has the same meaning as above and Y' is a group represented by the above general formula (2), an unsubstituted or lower alkyl-substituted guanidyl group A hydroxyl group protected with a dicarboxyl protecting group, a lower aflecoxyl group, an unsubstituted hydrazino group or a lower alkyl-substituted hydrazino group, or general formula (4')-NHO
A mercaptan represented by R-8 (4-) (in the formula, R'8 represents a hydroxyl-protecting group or a lower alkyl group) is added in an inert solvent in the presence of a base. By reacting with
s and Y' have the same meanings as above. ] To produce a β-lactam compound represented by 'Q
hru.

Here, the reactive ester of alcohol refers to, for example, substituted or unsubstituted arylsulfonic acid ester, lower alkanesulfonic acid ester, halogeno lower alkanesulfonic acid ester, or diarylphosphory!quacid ester of alcohol [''I[). , or a halide that is an ester with halogen hydrogen. Examples of substituted or unsubstituted arylsulfonic acid esters include benzenesulfonic acid ester, p-toluenesulfonic acid ester, p-nitrobenzene, and sulfonic acid. Thousand stell, p-b, mouth.

For example, lower primary alkanesulfonic acid esters include methane s5-
Phonic acid ester, ethanesulfonic diacid ester rxt
Examples of halogeno-lower alkanesulfonic acid esters include trifluorometabisulfonic acid esters; examples of diarylphosphoric acid esters include diphenylphosphoric acid esters; and examples of halides include chlorine, Examples include bromine and iodide. Preferred examples of such reactive esters of alcohols include p-trienesulfonic acid ester, methane, sulfonic acid ester, and diphenylphosphoric acid ester. .

The protecting group for the carboxyl group in R9 corresponds to the protecting group in Rs, and similar examples can be given as suitable protecting groups.

The inert solvent used in this reaction is dioxane, tetrahydrofuran, lofuran, dimethylformamide, dimethylsulfoxide, acetonitrile, hexamethylphosphoramide, etc., or a mixture of two or more of them! Suitable examples include acetonitrile, dimethylformamide, and dichloromethane. 'Bases include various bases such as sodium carbonate, potassium carbonate, sodium hydride, hydrogenated 1 (rum, potassium butoxide, pyridine, various lutidines, 4-dimethylaminopyridine, triethylamine, diisopropylethylamine, etc.) However, organic bases such as diisopropylethylamine are preferred.

The amount of base needs to be sufficient for the reaction to proceed sufficiently, and usually 1 to 2 equivalents are used per t mole of mercaptan (m). The raw material mercaptan (m) needs to be in an amount sufficient for the reaction to proceed sufficiently. Although it can be used in a large excess amount, it is usually used in an amount of 1 to 2 equivalents relative to the compound represented by the general formula (II). It can be done by

The reaction temperature is carried out in the range of -78°C to 60°C.
The range of ability from ℃ to 40℃ is suitable □.

In addition, after the reaction is completed, the resultant can be taken out by ordinary organic chemical methods.

Next, from the obtained compound represented by the general formula [IV], a reaction for removing the hydroxyl protecting group in R1, a reaction for removing the amino protecting group in R2, and a protection reaction for the carboxyl group are carried out according to known methods. A β-lactam compound represented by the general formula CI) can be obtained by performing a reaction for removing the group R9 and a reaction for removing the protecting group on Y' in an appropriate combination as necessary.

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

For example, a compound of the general formula [1] in which the hydroxyl group-protecting group and/or the amino group-protecting group is a halogenoalkoxycarbonyl group or an aralkyloxycarbonyl group,
Compounds whose carboxyl protecting group is a halogenoalkyl group, aralkyl group or benzhydryl group can be removed by subjecting them to an appropriate reduction reaction. For such a reduction reaction, when the protecting group is an aralkyloxycarbonyl group or a halogenoalkyl group, reduction with an organic solvent such as acetic acid, tetrahydrofuran, or methanol and zinc is suitable. In the case of a group, an aralkyl group, or a benzhydryl group, a catalytic reduction reaction using a catalyst such as platinum or palladium-carbon is suitable. The solvents used in this catalytic reduction reaction include lower alcohols such as methanol and ethanol, ethers such as tetrahydrofuran and dioxane, acetic acid, or these organic solvents, and water, phosphoric acid, and morpholinopropanesulfonic acid. A mixed solvent with a buffer solution such as the following is suitable. The reaction temperature is θ℃~100℃, but 0℃
~40°C is preferred.

In addition, the water-based process can be carried out at normal pressure or under increased pressure.

In particular, when the protecting group is an O-nitrobenzyl group, an O-nitrobene, or a zyloxycarbonyl group, these can also be removed by photoreaction.

In addition, after the reaction is completed, the resultant can be taken out by ordinary organic chemical methods.

In addition, the 5th and 6th positions of the compound represented by the general formula (,T)
and the 8-position, or the 4-position when R4 is an alkyl group, and the 8-position side chain, the 2'-position and the 4-position.
All carbons at position ′ are asymmetric carbons. Therefore, the general formula C
The compound represented by I) has optical isomers and stereoisomers based on asymmetric carbon atoms, and all of these isomers are represented by a single formula. The scope of the description is not limited. However, preferred examples include compounds in which the carbon atom at position 5 has the R coordination, which is the same coordination as that of chenamycin (5R, 6S) or (5R, 6R). Regarding the 8-position, Compound No. 1 having R coordination can be selected as a suitable one.

Compounds with 4R coordination can be mentioned as suitable compounds. There are four types of isomers, but among them, the preferred steric configurations are (2'5.4'S) coordination, (
2'R, 4'R) coordination metal compounds can be mentioned.

1. When producing an isomer having such coordination,
can be found in the starting compound [■, ] and/or Cm).

Compounds that are raw material compounds (ID has already been reported and can be produced by various methods) can be prepared using the general formula [where R4 is a hydrogen atom]. They are known per se or can be obtained according to the methods described therein.

(1) Japanese Unexamined Patent Application Publication No. 55-27169 (Ka Journal of American Chemical Society 4 (J,
Am, Chem, Soc,) Volume 108, @67
pp. 65-6767 (1981) (Sushi Journal of Chemical Society Part I (J, Ch.
em, Soc, Perkin I) 11964-9
68 pages (1981) Also Tetrahedron Letters
nLettera) R12fl 98-229 th
(1982) or the method described in European Patent Publication No. 70204. , ] Using the compound represented by as a raw material, the above-mentioned documents (1) to
Compound (n) can be synthesized according to the method described in (8).

Furthermore, general formula (b) obtained by the method described in European Patent Publication No. 70204 [wherein DAM represents a di-p-ayucylmethyl group]. ] Arndt Einster) (A
rndt-Einstert) reaction, etc., and then convert the ethynyl group to l-hydroxyethyl group by oxymerculation reaction, etc., and if necessary, carry out carboxyl group protection, deprotection reaction, and hydroxyl group protection. The general formula (C
) [wherein R1 and DAM are as described above. Compound (II) can be obtained from the compound represented by the following method according to method i described in JP-A-57-167964.

The DAM group on the nitrogen of compound LC) is cerium ammonium nitrate.
nitrate) in an inert solvent such as acetonitrile-water at 10 to 80"C. - can also be ε, which combines □protection reactions.

Further, compounds in which R4 is an alkyl group in the general formula (II) include, for example, Hetero-cycles (HeterO-cycles).
es) @ vol. 21, p. 29 (1984), or by the known method described in JP-A-58-26887, or in accordance with the method.

Compounds represented by the general formula (V) which can be used as raw material compounds for compounds in which R4 is an alkyl group in the general formula (n) [wherein R1 has the same meaning as above, and ``dark'' represents a lower alkyl group] can be produced, for example, by the following route.

(d) (f) [In the formula, *R(, has the same meaning as above, R1° represents a protecting group for a carboxyl group, and TBDMS represents a t-butyldimethylsilyl group.) Compound (e) and ( f) is (8R,
4R)-4-acetoxy-8-((R)-4-(t-butyldimethylsilyloxy)ethyl]-2-azetidinone (d) by the method described in JP-A-55-78656, that is, chlorination. In the presence of diethylaluminium and zinc, the general formula % formula % [wherein RO4 and Rto have the same meaning as above,
X represents a halogen atom. ] Halogeno fatty acid esters represented by and ethers such as tetrahydrofuran, dioxane, diethyl ether,
It is obtained as a mixture by reacting in a solvent such as aromatic hydrocarbons such as benzene and toluene, or in a mixed solvent of these and hexane.

Separation and purification of each isomer (e) and (f) can be performed by silica gel column chromatography.

Compounds (e) and (f) have a hydroxyl group, a carboxyl group,
Alternatively, compound (n) can be derived by appropriately combining nitrogen atom protection and deprotection reactions as necessary.

An example of the method for producing the raw material compound (n) is shown in the scheme below, and each step will be explained.

-n' (2) , , @ (i) (j) [In the formula, -R1, R4, and R9 have the same meanings as described above, sapon represents a hydroxyl group-protecting group, and ph represents a phenyl group. ] From the compound (2) mentioned above, JP-A-57-167964
The reaction described in the publication or heterocycles (Het.
erocycles) @ Volume 14, No. 1805-1
Compound (
You can get the season.

Furthermore, compound (i) is compound th) with tetrahedron.
It can be obtained, for example, by reaction with a diazotizing agent such as carboxybenzenesulfone azide in the presence of a base, as described in Letters, pages 81-84 (1980).

Further, compound (j) can be obtained by subjecting compound (i) to a ring-closing reaction in the presence of a metal salt catalyst such as dirhodium tetrakis acetate or by photoreaction.

Finally, the starting compound represented by general formula (na) can be obtained by reacting compound (j) with diphenylphosphoryl chloride in an inert solvent in the presence of a base.

The compound t that corresponds to the -m number of the supercarbapenem m rumor body
j) From raw material compound @tnia] No. I4 can be combined by reacting it with each mercap body instead of heating it as it is.
, and then it becomes cloudy with the name Hi and 1 expressed by the general formula Ci].

For optically active reactions, #1, for example, (its) is desired, the original S and b8β-→reimu complex (2) use the intrinsic form with the corresponding stereochemistry. thing*
, ib, Kamisouyu t and m-.On the other hand, raw material mercaptan (II) can be produced by various methods. Sotonton = 4-hydroxy-proline 1
As a raw material compound, a mercaptan with 1-s coordination [
It is possible to produce a mixture of a), (mbl, and llc).

2 4 6 ~ ~ ゛　. , 3. , 1t 7′ R.

~ 1t 12 (mb) 11 8 ~ [In the formula, Y''' has the same meaning as the definition of Y' excluding the hydroxyl group and lower alkoxy group protected with a carboxyl group protecting group, and RIO is the same as the above-mentioned has the same meaning as

R11 represents an amino group protecting group, and R12 represents a thiol group protecting group. ] Human process (can be easily achieved by a protection reaction of the amino group of various known amino acids used)
For example, a method of reacting with 1-lylmethyloxycarbonyl chloride etc. in the presence of a base, or
, 6-dimethyl-2-mercaptopyrimidine, and the like.

Step B: Various known methods for obtaining an ester from a carboxylic acid are possible; for example, in the presence of a base, a carboxylic acid
This can be achieved by reacting with various alkyl halides or aralkyl halides.

Step C 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 a base are used. This can be achieved by reacting in the presence of

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

Step D Various known methods for converting esters into carboxyl groups are possible; for example, alkaline hydrolysis, an acid method using trifluoroacetic acid, hydrobromic acid, etc., or a reductive method using zinc. can.

Step E Various known methods are possible for converting carboxylic acid into an amide group. For example, converting a carboxylic acid group into an active ester derivative using a halogenating agent, an acylating agent, etc.
This can be achieved by a method of treating various amine derivatives represented by the general formula [wherein Y'' has the same meaning as above].

Step F Various known deprotection methods for thiol protecting groups are possible; for example, when the thiol protecting group is an acyl group,
It can be removed by methods such as alkaline hydrolysis.

Step C 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 romic acid-sulfuric acid in acetone, and the like.

Step H: Although various known reduction reactions for converting carbo and nyl groups into hydroxyl groups are possible, for example, by treatment with sodium borohydride etc., a mixture of compounds 9 with different steric hydroxyl groups of compounds 3 and 8 is obtained. be able to.

Although the production ratio of 8 and 9 varies depending on the conditions, each compound can be obtained as a single compound by purification such as recrystallization and chromatography.

Isomerization of the 4-position hydroxyl group can be achieved through the above steps G and H, but it can also be achieved by a method that involves steps I and J described below.

Steps I and J: The alcohol derivative is reacted with formic acid in an inert solvent such as tetrahydrofuran in the presence of triphenylphosphine and diethyl azodicarboxylate to form the formyloxy derivative IJ, and then the formyl group is converted by a method such as alkaline hydrolysis. This can be achieved by removing the .

K step Various commonly used methods for deprotecting amino groups are possible, including methods using acids such as trifluoroacetic acid and hydrobromic acid, reductive methods using zinc or lithium-liquid ammonia, etc. Alternatively, it can be achieved by catalytic reduction or the like.

In addition, Y in the general formula CI) is a protected or unprotected hydroxyl group,
Alternatively, when it is a lower alkoxyl group, the raw material mercaptan (m) can be obtained by subjecting the compound or 10 to Step F.

In addition, in the production of 2'R-mercaptan Cut), cis-4-hydroxy-D-proline was used as a raw material compound and the method for producing the 21S-mercaptan described above was followed, namely,
It can be produced by combining the reactions described in the production of the 2'S form.

Among the novel β-lactam compounds represented by the general formula CD of the present invention, compounds in which R1, Rg and Ra are hydrogen atoms include Staphylococcus aureus, Staphylococcus evidermizois, Streptococcus.
pyrogens, Nodalum-positive bacteria such as Streptococcus faecalis, Escherichia coli, Proteus
It is a compound useful as an antibacterial agent, having excellent antibacterial activity against a wide range of pathogenic bacteria, including Gram-negative bacteria such as P. mirabilis, Serratia marcesiscens, and Pseudomonas aeruginosa. Furthermore, it is a unique compound that has excellent antibacterial activity against β-lactamase-producing bacteria. Other compounds of the present invention are important synthetic intermediates for synthesizing compounds exhibiting antibacterial activity as described above.

In addition, although the compounds of the present invention vary depending on each compound,
Characteristics include generally high physicochemical stability and excellent solubility in water.

The compound of the present invention can be administered as an antibacterial agent to treat bacterial infections, for example, by oral administration in the form of tablets, capsules, powders, syrups, etc., or non-administered by intravenous injection, intramuscular injection, rectal administration, etc. Oral administration is mentioned. The dosage varies depending on symptoms, age, body weight, dosage form, number of administrations, etc., but it is usually about 100 mg per day for adults.
Administer ~8000q once or in divided doses. The amount can be reduced or increased as necessary.

The compound of the present invention may also be used as a dipeptidase inhibitor such as sodium Z-7-(L-amino-2-cal-resistant xyethylthio)-2-(2,2-dimethylcyclopropanecarboxamide)-2-hebutenoate. (Unexamined Japanese Patent Publication No. 56-
It can be administered in combination with the compound group described in Japanese Patent No. 81518).

It is not limited in any way.

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

PNZ: p-nitropenzyloxycarbonyl group P
MZ: p-methoxybenzyloxycarbonyl group P
MB2 1)-Methoxybenzyl group PNB: p-
Nitrobenzyl group Ph: phenyl group, AC niacetyl group MS dimethanesulfonyl group tBu: t-butyl group -Me: methyl group -Et
: Ethyl group Reference example 1-1 trans-4-hydroxy-L-proline (6,55F
), triethylamine (7.5 mg) in water (15 sd)
A dioxane (85sd) solution of 5-p-nitrobenzyloxycarbonyl-4゜6-dimethyl-2-mercaptopyrimidine (15,95F) was added dropwise to this at room temperature, and the mixture was stirred for 1.5 hours at room temperature. , - The device was installed at night. 2N-sodium hydroxide (80 m
), extracted with ether, washed the ether layer with IN-sodium hydroxide (20-), combined the alkaline aqueous layers, and extracted with ether.
The mixture was made acidic with N-hydrochloric acid (100 mg), and extracted with ethyl acetate. The ethyl acetate layer was sequentially washed with 2N hydrochloric acid, dried with mirabilite, and the solvent was distilled off. The resulting crude crystals were washed with ethyl acetate while heating to give trans 1-(p-nitrobenzyloxycarbonyl)-4-hydroxy- - Florin was obtained.

m, p, 184.8-185.5℃ 1660, 1605.1520.1840°1205,
1172.1070.965 Reference Example 1-2 Trans-1-(p-nitrobenzyloxycarbonyl)-4-hydroxy-L-florin (15,0f)) ethylamine (18,5-) was dissolved in dry dimethylformamide (150d ), p-methoxybenzyl chloride (12,66s+g) was added dropwise under a nitrogen stream, and the mixture was stirred at 7°C for 10 hours. The reaction solution was diluted with ethyl acetate (500
gIt), washed with water, dried with mirabilite, and distilled off the solvent, and the residue was crystallized from ether to obtain trans-1-(p-nitrobenzyloxycarbonyl)-4-hydroxy-L-proline-p-methoxybenzyl ester. the law of nature.

m, p, 88~85"C IR""(cm'): 84g0.1785.1
705°ax 1510.1840.1245.1160 Reference Example 1-3 Trans-1-(p-nitrobenzyloxycarbonyl)-4-hydroxy-proline-p-methoxybenzyl ester (8,6F)-triphenylphosphine (
7,861), dried tetrahydrofuran (20wt)
Diethyl azodicarboxylate (5,22F) was dissolved in dry tetrahydrofuran (5,22F) under water cooling and nitrogen flow.
-) After adding the solution dropwise and stirring for 80 minutes, thioacetic acid (2,28F) was added dropwise, and the mixture was stirred for 1 hour under water cooling and then at room temperature for 8 hours. The reaction solution was concentrated and the residue was subjected to silica gel column chromatography. and cis-1-(p-nitrobenzyloxycarbonyl)-4-acetylthio-L-
Proline-p-methoxybenzyl ester was obtained.

IRmaX (ffi-1): 1740 (ah), 1
715°152G, 1405.1848.112ONM
Ra (CDCts): 2.81 (8H, s), 8.
79 (8H, s), 5.10 (2H, s), 5.24 (
2H, 8), 7.49 (2H, d, J=9.0Hz),
8.18 (2H, d, J=9.0Hz), Reference Example 1-
4 cis-1-(p-nitrobenzyloxycarbonyl)-
4-acetylthio-L-proline-P-methoxybenzyl ester (9,761F), anisole (4,82f
) was stirred with trifluoroacetic acid (85v) for 80 minutes at room temperature.

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

m, p, 107-109°C 166G (sh), 1840.1180°110 Reference Example 1-5 Cis-1-(p-nitrobenzyloxycarbonyl)-
4-7 Cetylthio L-proline (180+v) was dissolved in dry tetrahydrofuran (2-), dimethylamine hydrochloride (48)-N,N-dimethyJ rareminopiI3dine (78q), dicyclohexylcarbodiimide (15
2q) were sequentially added and stirred overnight.

Insoluble matter was removed, the solution was diluted with ethyl acetate, diluted with diluted hydrochloric acid,
Washed sequentially with water, dried with Glauber's salt, distilled off the solvent, and subjected the residue to silica gel chromatography.25.45)-1-
(p-nitrobenzyloxycarbonyl)-2-dimethylcarbamoyl-4-acetylthiopyrrolidine was obtained.

This compound was prepared by dissolving 200 ml of raw material carboxylic acid in 1.8 ml of dry methylene chloride, adding 1 drop of dimethylformamide, then adding 0.12 ml of oxalyl chloride dropwise while cooling with water, stirring at room temperature for 1 hour, and then distilling off the solvent. . After thoroughly drying the residue under vacuum, it was dissolved in dry tetrahydrofuran (1-1), and a solution of dimethylamine in tetrahydrofuranthine (10 M) was added to the solution under water cooling.
It can also be obtained by dropping the solution for 2 d, washing the layer for 15 minutes in the order of dilute HCt and water, and drying and distilling off the solvent.

□ 1400, 1840.1105 NMRa (Cl105N: 2.82 (8H, s), 2
．． 97 (BH, B), 8.11 (8H, a), 5.21
(♀H,s), 8.18(2H,d.

J=8.5Hz) (a')D + 5.21' (C=0.879 acetone) Reference Example 1-6 Cis-1-(p-nitrobenzyloxycarbonyl)-
4-Acetylthio-L-proline (277w9) was dissolved in dry methylene chloride (1.5 sd), then oxalyl chloride (0.15 ad) and a catalytic amount of dimethylformamide were added and stirred at room temperature for 1.5 hours. The solvent of the reaction solution was distilled off, dry benzene was added to the residue, and then the benzene was distilled off to remove the remaining oxalyl chloride.

On the other hand, pyrrole (51 sv) was dissolved in dry tetrahydrofuran (2-) and cooled with water under a nitrogen stream to give 1.60 mmol.
/sg non-n-butyllithium hexane solution (0,47-
) and stirred for 40 minutes. This was added to a solution of the above-mentioned reaction residue dissolved in dry tetrahydrofuran (2-) under water cooling under a nitrogen stream, and stirred for 10 minutes. The reaction solution was diluted with methylene chloride, washed with water, dried with sulfur salt, the solvent was distilled off, and the residue was purified by silica gel thin layer chromatography. pyrrolyl)carbonyl 4-abutylthiopyrrolidine was obtained.

IRCHCt8(♂') :1710.1525. I.J.
45°ax 1278.1120 NMRa (CDCza): 2.8B (8H, s),
5.28 (2H, s) 6.85 (2H, d, J
= 2Hz), 7.51 (2H, d, J = 9Hz) Reference Example 1-7 (2S, 4S)-1-p-nitrobenzyloxycarbonyl-2-hydroxycarbonyl-4-acetylthiopyrrolidine (868q) Dissolved in dry methylene chloride (8d), then added oxalyl chloride (0.8m ) and a catalytic amount of dimethylformamide, stirred at room temperature for 1.5 hours, evaporated the reaction solution, added dry benzene to the residue,
Then, benzene was distilled off to remove remaining oxalyl chloride. On the other hand, 4-carbamoylpiperidine (128v)
was dissolved in dry tetrahydrofuran (8TId), then bistrimethylsilylacetamide (0,25-) was added, and the mixture was stirred for 8 hours in a nitrogen stream.

Next, triethylamine (101 st) was added, and to this was added a solution of the previously mentioned reaction residue dissolved in dry tetrahydrofuran (8 m) under ice-cooling in a nitrogen stream, and the solution was added with ice-cooling in a nitrogen stream.
Stir for 5 minutes.

Add methylene chloride to the reaction solution, wash with brine, dilute hydrochloric acid,
Washing with salt water, washing with heavy water, washing with salt water, drying with salt water, distilling off the solvent, and purifying the residue by silica gel thin layer chromatography to give (25,45)-1-1)-nitrobenzyloxycarbonyl-2- (4-Carbamoylpiperidinyl)carbonyl-4-acetylthiopyrrolidine was obtained.

IRyCH""Ctsm-'): 8440
, 1695.

ax 1655, 1525.1860°12O NMRa (CDCts): 2.85 (8H, s
), 5.21 (2H, s), 5.98 (2H, s) 7
．． 52 (2H, d, , J=9Hz), 8.22
(2H, d, J = 7Hz) Reference Example 1-8 (2S, 45)-1-(p-nitrobenzyloxycarbonyl)-2-dimethylcarbamoyl-4-acetylthiopyrrolidine (40q) in methanol (4m) Add 1N-NaOH (0.1mg) and leave at room temperature for 15 minutes.
Stir for a minute. Then I N-HCtC0,1-)
and concentrated under reduced pressure. The concentrated solution was diluted with ethyl acetate, washed with water, dried with mirabilite, and the solvent was distilled off to give 2S, 4S)-1-(p
-nitrobenzyloxycarbonyl)-2-dimethylcarbamoyl-4-mercaptopyrrolidine was obtained.

1400, 1840.1165.11l105N a
(CDCza): 1.90 (IH, d, J=
8Hz), 2.97 (8H, s), 8.08 (8H,
s), 5.19 (2H, S), 7.48 (2H, d, J=9Hz), 8.15 (2H
, d, J=9Hz) The following thioacetates were obtained in the same manner as in Reference Example 1-6 using the corresponding amines.

Reference Example 2-1 Trans-1-(p-nitrobenzyloxycarbonyl)-4-hydroxy-proline 8.1Of,) ethylamine 1.10f was dried in tetrahydrofuran 40.
A solution of 1.20 f of ethyl chloroformate in dry tetrahydrofuran was added dropwise at -26°C to -85'C, and after stirring for 50 minutes, the solution was dissolved at -26°C to -85'C.
10 g 1 t of concentrated ammonia water was added dropwise at ℃.

The temperature was gradually raised to room temperature, and after further stirring for 1 hour, the reaction solution was concentrated under reduced pressure. Add 20 m of water and 50 m of ether to the residue, collect the resulting white crystals, wash with cold water and cold ether, and dry under reduced pressure to obtain trans-1-(p-nitrobenzyloxycarbonyl)-4-hydroxy-L. - Prolinamide was obtained.

m, 1), 168.8-164.0"C1687, 16
40,1621°1589.1841.1180°078 Reference Example 2-2 Trans-1-(p-nitrobenzyloxycarbonyl)-4-hydroxy-prolinamide 2.8211
1 To a suspension of 1.67 fi of triethylamine in dry tetrahydrofuran (4C) was added dropwise a solution of methanesulfonyl chloride 1,891 in dry tetrahydrofuran (10) at room temperature, and after stirring for 1 hour, the reaction solution was concentrated under reduced pressure. Add 80% of water and 80% of ether to the residue, collect the resulting white crystals, wash with cold water and cold ether, and dry under reduced pressure to give trans-1-(1)-nitrobenzyloxycarbonyl)-4- Methanesulfonyloxy-prolinamide was obtained.

m, p, 149.5-1. ．． 51°C 1715, 1675, 1520° 1840, 117@, 1185 Reference Example 2-a 874 kg of 50% sodium hydride and 18 sdl of dry dimethylformamide! Add 642s of thioacetic acid to the suspension under a nitrogen stream.
Add a solution of dry dimethylformamide 14-v and stir at room temperature for 25 minutes.
and trans-1-(9-nitrobenzyloxycarbonyl)-4-methanesulfonyloxy-L-
A solution of prolinamide 2.52F in dry dimethylformamide 12 was added, and the mixture was heated and stirred at 70°C for 6 hours. The reaction solution was poured with cold brine and extracted with benzene, the extract was sequentially washed with a 10% aqueous sodium sulfite solution and brine, dried with mirabilite, and extracted with benzene.
The solvent was distilled off, and the resulting crude crystals were heated and washed with a mixed solvent of tetrahydrofuran and benzene to give cis-1-(p-nitrobenzyloxycarbonyl)-4-thioacetoxy-
-prolinamide was obtained.

m, p, 168.5-169.5℃ 1690, 1688.1510.1880°100 [α) D-28° (C=0.884, DMF)
Reference Example 2-4 (25,48)-1-(p-nitrobenzyloxycarbonyl)-2-carbamoyl-4-acetylthiopyrrolidine (950q) was dissolved in methanol (95 mg) and dissolved in an aqueous IN-sodium hydroxide solution in an argon stream. (2,59
mg) was added at room temperature, and the mixture was stirred for 15 minutes.

Add IN-hydrochloric acid aqueous solution (2,59 sd) to the reaction solution, neutralize it, and distill off methanol under reduced pressure. The precipitated crystals were collected and washed with water to give (25, as )-1-(p
-nitrobenzyloxycarbonyl)-2-carbamoyl-4-merkabutopyrrolidine was obtained.

m, p, 158 to 162°C Reference Example 8-1 A solution of dimethyl sulfoxide (0.85 sd) in dry methylene chloride (Smg) at -60 to -70"C to a solution of oxalyl chloride (0.2 mg) in dry methylene chloride (Smg) (1-
) was added dropwise, and after 10 minutes, a dry methylene chloride solution (10 sd) of trans-1-(p-nitrobenzyloxycarbonyl)-4-hydroxy-L-proline p-methoxybenzyl ester (860q) was added at -50°C or below. and stirred for 16 minutes.

Next, triethylamine (1,01F) was added dropwise, warmed to room temperature, diluted with methylene chloride, washed with diluted hydrochloric acid, dried with sodium sulfate, and the solvent was distilled off. The residue was subjected to silica gel column chromatography. -nitrobenzyloxycarbonyl) (75) = 4-oxo-proline p-methoxybenzyl ester 1512, 1845.1245°155 Island formation δ (CDCza): 8.78 (8 views, 8), f
ll, 95≦2H,s), 5.08(2H,s), 6.
85 (,2H1d, J=9Hz), 8, 12 (2H=d
-J=9Hz) Reference Example 8-2 HO.

↓NZ 1-(p-nitrobenzyloxycarbonyl)-4-oxo-L-proline p-methoxybenzyl ester (
650sv) in ethanol (45mg) and add sodium borohydride (86q) in two portions at room temperature. After 80 minutes, concentrate under reduced pressure at 80°C or less, dilute the concentrated solution with ethyl acetate, wash with water, dry Glauber's salt, and distill off the solvent.
The residue was subjected to silica gel column chromatography to obtain cis-1-(1)-nitrohensyloxycarbonyl)-
4-Nitroxy-proline p-methoxybenzyl ester (450sp) and trans-1-(p-nitrobenzyloxycarbonyl)-4-hydroxy-
Proline p-methoxybenzyl ester (19 (lv)
) was obtained.

Trans form: IR and NMR were consistent with the spectral data of the compound of Reference Example 1-2.

Cis body: IR”m (cts-”): 8400 (
br), 1725, 1515.14os, 185G.

1250.1170.112O NMRa (CDCza): 8.78 (8H, ss),
5.08 (2H, s), 6.82 (2H, d.

J=9Hz), 8.12 (2H, d, J=9Hz) Reference Example 8-8 Cis-1-(p-nitrobenzyloxycarbonyl)-
Reference Examples 1-a and 1-4 using 4-hydroxy-proline p-methoxybenzyl ester (610q)
Trans-1-(p-nitrobenzyloxycarbonyl)-4-acetylthio-L-proline was obtained in the same manner as above.

Reference Example 8-4 a) trans-1-(p-nitrobenzyloxycarbonyl)-4-acetylthio-proline (180-v
) using the same method as in Reference Example 1-6 to prepare (25,4
R)-1-(1)-nitrobenzyloxycarbonyl)
-2-dimethylcarbamoyl-4-acetylthiopyrrolidine (100~) was obtained.

1400, 1840.1115 [α) D +82.8 ° (C”'0.875. Acetone) b) Thioacetate derivative obtained in a) above (80
q) by the same method as Reference Example 1-8 (2S, 4R)
-1-(p-nitrobenzyloxycarbonyl)-2-
Dimethylcarbamoyl-4-mercaptopyrrolidine was obtained.

1420, 1400.1840.112ONMRa(C
DCts): 1.77 (IH, d, J=7Hz),
2.91 (8H, ra), 8.16 (8H, !1), 5
．． 22 (2H, s), 8.16 (2H, d, J=8.5Hz) The following thioacetates and mercaptans were obtained in the same manner as in Reference Example 8-4 using the respective corresponding amines. .

-8 NZ, Reference Example 4-1 Cis-1-p-nitrobenzyloxycarbonyl-4- obtained from cis-4-hydroxy-D-proline by the same method as in NZ Reference Examples 1-1 and l-2 Hydroxy-D-proline-p-methoxybenzyl ester (166q), triphenylphosphine (201v)
e Dissolved in dry tetrahydrofuran (1,5-) and then added formic acid (27 sv). Furthermore, diethyl azodicarboxylate (184 sv) was added at room temperature under a nitrogen stream,
After stirring for 80 minutes, the solvent was distilled off. The residue was purified by silica gel chromatography to obtain trans-1-p-nitrobenzyl 1oxycarbonyl-4-formyloxy-D-proline-p-methoxybenzyl ester.

1842, 1245.1165.112ONMRa (
CDCLs): 8.76 (8H,s), 4.50
(2H9t, J=8Hz), 5.08 (2H,s)
, 5.15 (2H, ABq J=16Hz), 5.41
(IH, m), 7.97 (IH, s) Reference Example 4-2 trans-t-p-nitrobenzyloxycarbonyl-
4-Formyloxy-D-proline-p-methoxybenzyl ester (215q) was dissolved in tetrahydrofuran (1,
1sd), added 1N-NaOH water 0698-, stirred for 10 minutes, diluted with ethyl acetate, and washed with saturated brine. After drying the Glauber's salt, the solvent was distilled off. The residue was purified by thin layer chromatography to obtain trans-1-1)-nitrobenzyloxycarbonyl-4-hydroxy-D-proline-p-methoxybenzyl ester.

1705, 1610.1400.1840°1240,
1162 NMRa (CDCts): ji! , 8B (2H,
m), 8.58 (2H, d, J=8.5Hz)
, 8.78 (8H, s), 5.08 (2H, s), 5.
07 (2H, ABq, J-18Hz), 6.7
8 (2H, d, J-9Hz), 6.77 (2H, d, J=9Hz), 8.00 (
2H, d, J=8.5Hz), 8.07(2)f
, d, J=8.5Hz) Reference Example 4-8 a) Using trans-1-p-nitrobenzyloxycarbonyl-4-hydroxy-D-florin-p-methoxybenzyl ester (110v), Reference Example 1- 1.1-
(2R, 4R) − by the same method as 4 and 1-6
l-p-nitrobenzyloxycarbonyl-2-dimethylcarbamoyl-4-acetylthiopyrrolidine was obtained.

1486, 1840.1115 0 [α) D -7,88° (C = 0.210, acetone] b) Thioacetate derivative obtained in a) above (42q
) using the same method as in Reference Example 1-8 (2R, 4R
)-1-p-nitrobenzyloxycarbonyl-2-dimethylcarbamoyl-4-mercaptopyrrolidine was obtained.

1440, 1847.1180.1122 Reference Example 4-4 PNZ PNZ a) Trans-1-1)-nitrobenzyloxycarbonyl-4-hydroxy-D-proline-p-methoxybenzyl ester (110q) was used, Reference Example 1-8.1-4 and 2-
[2R04R]-1-1-nitropenzyloxycarbonyl-2-carbamoyl-4-acetylthiopyrrolidine 40q was obtained in the same manner as in Example 1.

1840, 1110 [α)D+89.6°(C=0.298.DMF)b)
(2R,4R)-1 in the same manner as in Reference Example 1-8 using the thioacetate derivative (40 Misaki) obtained in a) above.
-p-nitrobenzyloxycarbonyl-2-carbamoyl-4-mercaptopyrrolidine was obtained.

1655, 1612.1840°116 Reference Example 6-1 NZ a) Cis-4-hydroxy-D-proline (800sr
) from Reference Examples 1-1.1-2゜1-8.1-4 and l
(2R,4SJ-1-(p-nitrobenzyloxycarbonyl)-2-dimethylcarbamoyl-4-acetylthiopyrrolidine (45q)) was obtained in the same manner as in -6.

1400, 1845.1120 0 [α) D -29,6° (c = 0.215.acetone) b] Thioacetate derivative obtained in a) above (80q)
was prepared by the same method as in Reference Example 1-8 (2R,45]-1
-(p-nitrobenzyloxycarbonyl)-2-dimethylcarbamoyl-4-mercaptopyrrolidine was obtained.

1480, 1405.1847°122 The following thioacetates and mercaptans were obtained in the same manner as in Reference Example 5-1 using the corresponding amines.

NZ Reference Example 6-1 Using trans-1-1)-nitrobenzyloxycarbonyl-4-hydroxy-proline (500q) and p-nitrobenzyl bromide (888sv), Reference Example 1
Trans-tp-nitrobenzyloxycarbonyl-4-hydroxy-L-broline-p-nitrobenzyl ester was obtained in the same manner as in Example 2-2.

1706, 1520.1425.140G.

1842, 116O NMRa (CDCA8): 2.2G (8H, m)
, 8.67 (2H.

d, J=8Hz), 4.60(2f(,t, J=8
Hz), 5.15 (2H, s), 5j! 8(1!H,A
Bq),? -47 (4H, d, J=8.5Hz), &
15 (4H, d, J=8.5Hz) Reference Example 6-2 Trans-1-p-nitrobenzyloxycarbonyl-
4-Hydroxy-L-proline-p-nitrobenzyl ester & cis-1-p-nitrobenzyloxycarbonyl-4- by the same method as Reference Examples 1-3 and 1-8
Mercapto-L-proline-p-nitrobenzyl ester was obtained.

1510, 1480.140G, 1840°105 Reference Example 6-8 0 NZ a) Cis-1-1)-nitrobenzyloxycarbonyl-4-mercapto-L-proline-p-nitrobenzyl ester (115q) was dried in tetrahydrofuran. (8-
) and added triethylamine (80w),
Ethyl chloroformate (28,5η) was added dropwise under water cooling, and 10
After stirring for a minute, dilute with ethyl acetate, wash successively with dilute hydrochloric acid and water, and dry mirabilite. The solvent was evaporated and cis-1-p-nitrobenzyloxycarbonyl-4-ethoxycarbonylthio-L-proline-p-nitrobenzyl ester (188
q) was obtained.

1525, 1405.1850°1160.1015. 850 b) Dissolve the ester derivative (188 sv) obtained in a) above in a tetrahydrofuran-water (1:t) mixture (5-), add IN-NaOH water (0,26-), and dissolve at room temperature for 2.5 sv. After stirring for an hour, IN-HCt(0,8-) was added, extracted with ethyl acetate, washed with water, dried with sodium sulfate, and the solvent was distilled off. The residue was subjected to silica gel thin layer chromatography to obtain cis-1-p-
Nitrobenzyloxycarbonyl-4-ethoxycarbonylthio-L-proline was obtained.

1B40.1165.1145 NMRa (CDCl2): 1.80 (8H, t, J
=7f(z), 4.28(2H,Q,J=7Hz), 5.24(2H,s), 7.50(2H,d,J=9Hz), 8.17(2H,d,J =9Hz) Reference Example 6-4 NZ, a) Cis-1-1-nitrobenzyloxycarbonyl-4-ethoxycarbonylthio-L-proline (72
sv) was dissolved in dry tetrahydrofuran (8-), triethylamine (40 sv) was added, ethyl chloroformate (41 q) was added dropwise under water cooling, and after stirring for 15 minutes, methylamine (40%) aqueous solution (1, 5 mg) was added dropwise and stirred for an additional 15 minutes.

The reaction solution was diluted with ethyl acetate, washed with dilute hydrochloric acid and water, and dried with mirabilite. Evaporate the solvent [2S.

45) -1-p-m=trobenzyloxycarbonyl-
2-Methylcarbamoyl-4-ethoxycarbonylthiopyrrolidine was obtained.

1660.1520.1425゜1405, 1845.1180゜16O NMRa (CDCts): 1.80 (8H, t, J
= 8Hz), 2.80 (8H, d, J = 5Hz), 4.27 (2H, Q, J = 8Hz) 5.22 (2H, s), 7.48 (2H, d.

J=9H2), 8.18 (2H,d, J=9Hz
)b) Methylcarbamoyl derivative (8) obtained in a) above
2sv) was dissolved in a mixture of methanol and water (1:1) (4-), IN-NaOHO, 25- was added thereto, and the mixture was heated at room temperature for 8
After stirring for 0 minutes, IN-HCLo, 27- was added, extracted with ethyl acetate, washed with water, dried with sodium sulfate, and the solvent was distilled off ["2S, 4
S)-1-9-nitropenzyloxycarbonyl-2-
Methylcarbamoyl-4-mercaptopyrrolidine was obtained.

1650, 1510.1840.1165NMRδ(C
DC2a): 2.79 (8H, d, J=5H
z ), 4.27 (2H, t, J = 8Hz), 5.28 (2H, s), 7.50 (2H, d, J = 9Hz), 8.20 (2H, d, J = 9Hz) The following thiocarbonates were obtained in the same manner as in Reference Example 6-4 a) using the corresponding amines.

1 NZ The following mercaptan was obtained in the same manner as in Reference Example 1-8 or 6-4.

Reference Example 8-1 a) Trans-4-hydroxy-proline (10F
) and 5-p-methoxybenzyloxycarbonyl-4,
6-dimethyl-2-mercaptopyrimidine (28,2f
) using the same method as in Reference Example it to transform trans-1.
-(p-methoxybenzyloxycarbonyl)-4-hydroxy-L-proline was obtained.

1480.1855.1245.1170°122 NMRa (CDCts): 2.28 (2H, m), 8
, '18 (8H1s1.5.00 (2H,S), 6J8
(2H, d, J = 9Hz), 7-20 (2H, d, J = 9Hz) b) Using the proline derivative (0,57f) obtained in a) above and benzylamine (0,2159), the reference example Trans-1-p-methoxybenzyloxycarbonyl-4-hydroxy-benzylprolinamide was obtained in the same manner as in 2-1.

1248, 1165.112G, 101025N a
(CDCts): 8.76 (8H, s), 4.8
5 (4) f, m), 4-96 (2H, s), 6.79 (
2H, d, J = 9Hz), 7.20 (5H, 8) C) Benzylprolinamide obtained in b) above (0,5F
) and in the same manner as in Reference Example 1-8 (2S, 4
S)-1-p-methoxybenzyloxycarbonyl-2
-Benzylcarbamoyl-4-acetylthiopyrrolidine was obtained.

240 δ (CDCts): 2.2'l (8■, S), 8.8
2 (8H, s), 4.42 (2H, d, J-6Hz), 5.05 (2
H, s), 6.87 (2H, d, J = 8Hz), 7.28 (2H, d, J = 8Hz), 7.28 (5H, ss) Reference Example 8-2 a) (2S, 4S ) 1-p-me)! Dibenzyloxycarbonyl-2-benzylcarbamoyl-4-1 cetylthiopyrrolidine (177 cape) and anisole (86sv
) was dissolved in 0.5 m of trifluoroacetic acid and stirred at room temperature for 30 minutes. The reaction solution was concentrated under reduced pressure, diluted with ethyl acetate,
After washing with heavy sound water and water, dry with mirabilite. The solvent was distilled off, and the remaining liquid was subjected to silica gel thin layer chromatography to obtain (23,4
s)-2-benzylcarbamoyl-4-acetylthiopyrrolidine was obtained.

1400.1!15G, 1120°95O NMRa (CDCA8): 2.2g (!lH,s)
, 8.88 (2H, m), 4.42 (2H, d, J = (Hz), Reference Example 9-1 1-(di-p-ayucylmethyl)-8-ethynyl-4-
Carboxymethyl-2-azetidinone is l-(di-p-
Ayucylmethyl)-B-ethynyl-4-carboxy-2
-Azetidinone in the same manner as described in JP-A No. 1858-222089.

1510.1800.1180.1080°2O NMRa (CDCta): 2j16 (2H, d, 1=6
Hz) 8.78 (6H, 8), 5.80 (IH, s),
6.78 (4H, d, J=9.0Hz>, 7.08 (
4H, d, J=9.0Hz) Reference Example 9-2 1-(di-p-ayucylmethyl)-8-ethynyl-4-
Carboxymethyl-2-azetidinone (2,8f) was dissolved in dry dimethylformamide (50m), triethylamine (1,5,d) was added, then p-methoxybenzyl chloride (1,8f) was added dropwise to 70" After stirring at C for 8 hours, diluted with ethyl acetate and ether, washed sequentially with dilute hydrochloric acid and water, dried with sodium sulfate, distilled off the solvent, and chromatographed on silica gel to give l-(di-p-ayucylmethyl)-8-ethynyl-4-p. -Methoxybenzyloxycarbonylmethyl-
2-azetidinone was obtained.

1250, 1175.1010 88N a CCDCts): 2.86 (2H, d
, J=6.5Hz 1.8.72 (6H,s), 8
．． 75 (8H, s), 4.88 (!H, S), 5.78
(IH, 8) Reference Example 9-8 1-(di-p-ayucylmethyl)-8-ethynyl-4-
p-Methoxybenzyloxycarbonylmethyl-2-azetidinone (2,851) was prepared using JP-A Ws58-9946.
1-(di-p-ayucylmethyl)-8-(1-hydroxyethyl)-4-1) in the same manner as the method described in Publication No. 8
-Methokylebenzyloxycarbonylmethyl-2-azetidinone (2,6f) was obtained.

151G, 1247.1178.1080°2O NMRa (CDCAII): 1.2g (8H,
d, J=6.5Hz 1.2.42 (12H, dJ
=7Hz), 8.77 (9H, s) 4.95 (2H, s), 5.78 (IH, s) Reference Example 9
-4 1-(di-p-ayucylmethyl)-8-(1-hydroxyethyl)-4-I)-methoxybenzyloxycarbonylmethyl-2-azetidinone (2,6F) was dissolved in dry methylene chloride (151ml/g), 4-dimethylaminopyridine (1,22f) was added, and a solution of p-nitrobenzyl chloroformate (1,8F) in dry methylene chloride (7-) was added dropwise under water cooling, and after stirring at room temperature for 1 hour, chloride was added. Methylene and water were added, and the methylene chloride layer was sequentially washed with IN-hydrochloric acid, water, 5% sodium bicarbonate solution, and water, dried with sodium sulfate, and the solvent was distilled off.
l-(p-anisylmethyl)-3-(1-p-nitrobenzyloxycarbonyloxyethyl)-4-p-methoxybenzyloxycarbonylmethyl-2-azetidinone (2,2#) was obtained by silica gel chromatography. .

1a50.1245.1175.1 ([ONMRa (
CDCza): 1.85 (8H, d, J2 6.5
Hz), 2.40 (2H, d, J=6.5Hz
), 8.09 (IH, dd , J = 2.5 and 6H2), 8.78 (6H, s), 8.77 (8H, s
), 4.91 (2H, s), 5.18 (2H, s), 5
．． 71 (IH, s) Reference Example 9-6 1-(di-p-ayucylmethyl)-8-(1-p-nitrobenzyloxycarbonyloxyethyl)-4-p-
Methoxybenzyloxycarbonylmethyl-2-azetidinone (2,2F) was dissolved in dry methylene chloride (20m), m-dimethoxybenzene (0,88F) and trifluoroacetic acid (2,5t-t) were added, and the mixture was heated to room temperature for 4 hours. After stirring for hours, the solvent was distilled off, and the oily residue was subjected to silica gel chromatography.
Nitrobenzyloxycarbonyloxyethyl)-4-
Carboxymethyl-2-azetidinone (1,75f) was obtained.

1510, 1250.1180.101085N a
(CDCza): 1.85 (8H, d, J==6
．． 5Hz 1.2.85 (2H, d, J=6.5
Hz), 8.10 (IH, m), 8.78 (6H, s
\5, '16 (2H, s), 5.75 (IH, s), 6
．． 78 (4H, d, J = 9Hz), 7.46 (2H, d, J = 9Hz), 8.10 (2
H, d, J = 9Hz) Reference Example 9-6 1-(di-p-ayucylmethyl)-8-(1-1)-nitrobenzyloxycarbonyloxyethyl)-4-carboxymethyl-2-azetidinone (o , sy) in dry methylene chloride (20 mg) and to this is added N-methylmorpholine (0.17 m). Next one ten
Cool to below °C and ethyl chloroformate (0,15 m )
was added dropwise and stirred for 80 minutes.

Meanwhile, t-butyl-(p-nitrobenzyl)malonate (0,81F) was dissolved in dry tetrahydrofuran (15Wt).
Sodium hydride (50
% purity) (0.14f) was added, and the mixture was stirred for 30 minutes. This solution was added dropwise to the previously prepared mixed acid anhydride solution at -10°C or below, and stirred for 1 hour.

The temperature was raised to room temperature, the reaction solution was concentrated under reduced pressure, the concentrated solution was diluted with cold water and ethyl acetate, washed with IN-hydrochloric acid and water, and dried with sodium sulfate. The solvent was distilled off, and the residue was purified by silica gel chromatography to obtain 1-(di-p-ayucylmethyl)
-8-(1-p-nitrobenzyloxycarbonyloxyethyl)-4-CB-t-butoxycarbonyl-8-
(p-nitrobenzyloxycarbonyl)-2-oxopropyl-2-azetidinone was obtained.

1845, 125O NMR δ (CDC/, a): 1-88 (9H, a)
, 8. y5 (6H, g), 5.17 (4H, S), 6.
1'l (IH, br, a), 6.77 (4H, d,
J=8.58Z), 7.45(4H,d, J=9Hz
), 8.15 (4H, d, J = 9Hz) Reference Example 9-7 1-(di-p-ayucylmethyl)-8-(1-1-nitrobenzyloxycarbonyloxyethyl)-4-(g
-t-Butoxycarbonyl-8-(p-nitrobenzyloxycarbonyl)-2-oxopropyl]-2-7 zetidinone (2,8f) was dried in methylene chloride (120m
g), trifluoroacetic acid (10v) was added, and the mixture was stirred at room temperature for 1 hour.

The reaction solution was washed with aqueous sodium bicarbonate and water, dried over sodium sulfate, and the solvent was distilled off. The residue was purified by silica gel chromatography, and 1
-(di-p-ayucylmethyl)-8-(1-1)-nitrobenzyloxycarbonyloxyethyl)-4-(8
-(p-nitrobenzyloxycarbonyl)-8-oxopropyl-2-azetidinone was obtained.

1610.1510.1B45.125ONMRa (
CDC4g): 1.41 (8H, d, J=6.5H
2), 2.61 (2H, d, J = 6.5H2), 8.2
7 (2H, s), 8.76 (6H, 8), 5.77 (I
H,s), 6.82 (4H,d.

J = 9Hz) □, 7.47 (2H, d, J = 9Hz),
7.58 (21(,d, J=9Hz), 8.20(
4H, d, J = 9Hz) Reference Example 9-8 □ 1-(di-p-ayucylmethyl)-8-(1-p-nitrobendi-leoxycarbonyloxyethyl)-4-(
8-(1)-nitrobenzyloxycarbonyl)-2-
From oxopropyl-2-azetidinone, JP-A-58-
p-Nitrobenzyl-5,6-trans-8-(diphenylphosphoryl)-6-(1-p-nitrobenzyloxycarbonyloxyethyl)-1-azabicyclo(1, 2,0)
Hept-2-en-7-one-2-carboxylate was obtained.

1517.1480. ．． 1B45.1295.

1255.1180.1158. 965NMRδ(C
DCAa): 1.46 (8H, d, J=6.5)T
z), 8.24 (2H, br, d, J=8.5Hz),
8.40 (IH, dd, J=8.0 and g, 5Hz)
, 6.24 (2H0s), 5, 82 (2H, ABq, J=18Hz), 7.28 (
IOH, s) 7.58 (4H, d, J = 8.51 (Z), s, 14 (
2H, a, J=s, 6Hz), 8.28 (2H, dJ=
8.5Hz) Also (8R,4S)-1-(di-p-ayucylmethyl)
-8-ethynyl-4-carboxy-2-azetidinone [
Specific optical rotation [α] o = + S a, ao (c =
(5R,65,8R)-p-nitrobenzyl-8-(
diphenylphosphoryloxy)-6-(1-p-nitrobenzyloxycarbonyloxyethyl)-1-azabicyclo(8,!,0)-hept-2-en-7-one-
2-carboxylate was obtained.

Reference Example 1O-1 (1) (2a) (2b) Dry tetrahydrofuran 20- is added to activated zinc 1.88F (20 mM), and then a 15% n-hexane solution of diethylaluminium chloride (88-) is cooled with water. , under a nitrogen stream, and (8R,4R)-4-acetoxy-
8-((R)-1-(t-butyldimethylsilyloxy)ethyl]-2-1 zetidinone (1) 1.49f (5,
2mM) and benzyl-a-bromopropionate8.
A solution of 78 f (15.8 mM) dissolved in dry tetrahydrofuran 18.8- was added dropwise over a period of 30 to 40 minutes.
Then stir for another hour. Under water cooling, pyridine 2.8-
Then 18.2 m of water, 26.5 m of ethyl acetate, and IN-
18.2-hydrochloric acid was added and filtered on Celite.

The furnace solution was washed with water, the organic layer was dried with sodium sulfate, the solvent was distilled off, and the resulting oily residue was subjected to silica gel column chromatography to obtain 4-(1-benzyloxycarbonyl)ethyl-8-((R)- A mixture of 1-(t-butyldimethylsilyloxy)ethyl-2-acetidinone was obtained.

Separation of isomers was achieved by Rho 76 ram chromatography (silica gel) eluting with 1.5% isopropanol/n-hexane to give (2a) and (2b) as oils.

Isomer (2a) NMRa (CDCts): 0.06 (6H, s)
, 0.87 (9) 1.8), 1.08 (8H, d, J-
6,5H2), 1.18 (8H, d, J=7.0H2)
,8.91(li(,dd,J=2.2 and 5.5H
2) 1, i, t7 (2H, q, J=6Hz), 5.12 (2H
, s), 7J5 (5H, s) isomer (2b) 1252.1100. 885 NMRδ (CDCLa): 0.06 (6H, B),
0.87 (98,8), 1.16 (8H, d, J
= 6.5Hz), 1.19 (8H, d, J = 7.0H
z), 8.71 (IH, dd, J=2 and 10Hz), 5.14 (2H, 11).

7.85 (5H, s) Reference Example 1O-2 (2a) (8a) (128) 4-(l-benzyloxycarbonyl)ethyl-8-(
(R)-1'-(t-butifredimethylsilyloxy)ethyl]-2-azetidinone (2a) (200W9)
was dissolved in dry dimethylformamide (2-), triethyl Jl/7mine (121v) was added thereto, t-butyldimethylsilyl chloride (151+v) was added, and the mixture was stirred at room temperature overnight. The reaction solution was diluted with ethyl acetate, washed with water, dried with sodium sulfate, and purified by silica gel chromatography to obtain 4-(
1-benzyloxycarbonyl)ethyl-8-((R)
-1-(1-butyldimethylsilyloxy)ethyl)
-1-('t-butyldimethylsilyl)-2-azetidinone (3a) was obtained.

1255.885 Reference Example 1O-3 (8a) 4-(1-benzyloxycarbonyl)ethyl-8-(
(R)-1-(t-Butyldimethylsilyloxy)ethyl)-1-(t-butyldimethylsilyl)-2-azetidinone (184■) was dissolved in methanol 4- and 10%
Stir with palladium-carbon (20 sv) under normal pressure hydrogen gas for 2 hours. The catalyst was removed, the liquid was concentrated under reduced pressure, and 4-
(1-carboxy)ethyl-8-((R)-1-(t-
butyldimethylsilyloxy)ethyl)-1-(t-
Butyldimethylsilyl)-2-azetidinone (4a) was obtained.

1255, 1048.887 Reference Example 1O-4 (4a) (5a) 4-(l-carboxy)ethyl-8-[■ Zetidinone 1
(4R, 5R, 6
S,8R)-p-nitrobenzyl-4-methyl-6-(
l-hydroxyethyl)-1-azabicyclo(8,2,
0')-hepto-8,7-thion-2-carboxylate (5a) was obtained.

1750.1605.1520.

1850.1217.1180 Example 1-1 a) (5R,6S,8R)-p-nitrobenzyl-8-
(Diphenylphosphoryloxy-6-(1-1)-nitrobenzyloxycarbonyloxyethyl)-1-azabicyclo(8,2,0')hept-2-en-7-one-2-carboxylate (122q) was dissolved in dry acetonitrile (8-), diisopropylethylamine (811q) was added under water cooling in a nitrogen stream, and then [2S
.

4S]-1-1-nitrobenzyloxycarbonyl-2
-Dimethylaminecarbonyl-4-mercaptopyrrolidine (60w) was added, and the mixture was stirred for 1 hour. The reaction solution was diluted with ethyl acetate, washed with water, dried over magnesium sulfate, and the solvent was distilled off. The residual liquid was purified by silica gel thin layer chromatography to obtain (5R, 6S, 8R, 2'S, 4
'5)-p-nitrobenzyl-8-(4-(1-1)-
Nitrobenzyloxycarbonyl-2-dimethylaminecarbonyl)pyrrolidinylthio)-6-(1-1)-nitrobenzyloxycarbonyloxyethyl)-1-azabicycloC8,2,0.]]]Hepto-2-ene-7 −
One-2 carboxylate (9511P) was obtained.

1650.1605. 1515°1842.1257 NMRa (CDCts): 1.49 (8H, d, J=
6Hz), 2.99 (8H, s), 8.11 (8H, s
), 5.25 (4H, S), 5.28 and 5.46 (2H, ABq, J==14H
z), 7.58 (4H, d, J=8.5Hz), 7.6
2 (2H, d, J=8.5Hz), 8.18
(6H, d, J=8.5Hz) [α)D +7.
7° (C=OJO8, acetone)b) (5R,6S
, 8R, 2・S, 4′S) -1)-Nitrobenzyl-
! l-(4-(1-1)-nitrobenzyloxycarbonyl-2-dimethylaminecarbonyl)pyrrolidinylthio)-6-(1-p-nitrobenzyloxycarbonyloxyethyl)-1-azabicycloCB, 2.0 ”
3Hept-2-en-7-one-2-carboxylate (95 cape) was dissolved in dioxane (20v) and morpholinopropanesulfonic acid 1ik solution (pH = 7.0).

10-) and platinum oxide (Cape 35) were added and hydrogenated for 6.5 hours under a hydrogen pressure of 8.5 atm.

After filtering the catalyst, dioxane was distilled off under reduced pressure, the residual liquid was washed with ethyl acetate, the aqueous layer was again distilled off under reduced pressure, the organic solvent was distilled off, and the residual liquid was subjected to polymer chromatography (CHP-20P).
), the parts eluted with water (5R, 6S, 8R
,2'S,4'5)-8-C4-(2-dimethylaminecarbonyl)pyrrolidinylthio)-6-(1-hydroxyethyl)-1-azabicyclo(8,2,0')hept-2- En-7-one-2-carboxylic acid was obtained.

1252, 118O NMRa (D20) 2 1.25 (8H, d,
J=6.4Hz), 1.81~1.96 (IH
,m), 2.96(8t(,s), 8.08(8H,s),8.
14-8.20 (8H, m), 8.81-8.41 (2H, m), 8.62-8.72
(IH, m), 8.90-4.00 (IH, m), 4
．． 14-4.26 (2H, m), 4.68 (IH,
t, J==8.5Hz) Example 1-2 a) (5R,6S,8R)-1) -'-trobenzyl-8-(diphenylphosphoryloxy)-6-(1-1
)-nitropenzyloxycarbonyloxyethyl)-
1-AzabicycloC8,2,0')hept-2-ene-
7-one-2-carboxylate (129η) and (28
(5R,6S, 8R, 2・S.

4'R)-p-nitrobenzyl-8-(4-(1-p-
Nitrobenzyloxycarbonyl-2-dimethylaminecarbonyl)pyrrolidinylthio)-6-(1-1-nitrobenzyloxycarbonyloxyethyl)-1-azabicyclo(8,2,0]hept-2-ene-7- On-
2-carboxylate (40 mW) was obtained.

1650.1520.1400°1845.1260.118O NMRa (CDCts): 1.48 (8H, d, J=
6Hz), 2.96 (8H, s), 8.12 (8B, s
), 5.22 (4H, S), 7.44, 7.50 and 7.58 (2H, d, J=8.5Hz, respectively),
8.17 (6H, d, J=8.5Hz) [α) D+
s 1.1° (c=o, 19s, acetone) b) (
5R,6S,8R,2'S,4'R)-p-nitrobenzyl-8-C4-(1-p-nitrobenzyloxycarbonyl-2-dimethylaminecarbonyl)pyrrolidinylthio)-6-(1- 1)-Nitropenzyloxycarbonyloxyethyl)-1-azabicycloCB, 2.0
) Hept-2-en-7-one-2-carboxylate (40 cape) was prepared by the same method as in Example 1-t(b) (5R,6S,8R,2'S,4'R)-8 -C4-
(2-dimethylaminecarbonyl)pyrrolidinylthio)
-6-(1-hydroxyethyl)-1-azabicyclo(
8,2,0) Hept-2-ene-7-o-carboxylic acid was obtained.

Example 1-8 H a) (5R,6S,8R)-p-nitrobenzyl-8-
(diphenylphosphoryloxy)-6-(1-p-nitrobenzyloxycarbonyloxyethyl)-1-azabicyclo(8,2,0)hept-2-en-7-one-
2-carboxylate (61sv) and (2R,4S)-
(5R, 6S, 8R, 2'R) in the same manner as in Example 1-1 (a) using 1-p-nitrobenzyloxycarbonyl-2-dimethylaminecarbonyl-4-mercaptopyrrolidine (81sy).

4'5)-p-nitrobenzyl-8-(4-(1-p-
Nitropendyloxycarbonyl-2-dimethylaminecarbonyl)pyrrolidinylthio)-6-(1-p-nitropenzyloxycarbonyloxyethyl) = 1-azabicyclo(8,2,0)hept-2- En-7-on-
2-carboxylate (87 cape) was obtained.

1650, 1520.1400゜1B45.1260.118O NMRa (CDCA8): 1,49 (8H, d
J=6.5Hz), 2.98 (8H, s), 8.16
(8H, S), 5.27 (4H, s), 5.19 and 5.47 (2H, ABq, J=14Hz), 7.
50.7.55.7.64 (each 2H, d, J = 8.5
H2), 8.20 (4H, d, J=8.5Hz), 8.
22 (2H, d, J = 8.5Hz) 9 (a) D +26.8° (C = 0.248.acetone) b) (5R, 6S, 8R, 2'R, 4'5) -p
-Nitrobenzyl-8-C4-(1-1) -Nitrobenzyloxycarbonyl-2-dimethylaminecarbonyl)pyrrolidinyl]-6-(1-1)-Nitrobenzyloxycarbonyloxyethyl)-1-azabicyclo( 8,2,0') hept-2-en-7-one-2-carboxylate (87q) was converted into (5R06S, 8R,2・R,4'5 )
-8-(4-(2-dimethylaminecarbonyl)pyrrolidinylthio)-6-(1-hydroxyethyl)-1-azabicycloCB, 2.0]hept-2-en-7-one-2-carboxylic acid I got it.

Example 1-4 a) (5R, 6S, 8R) I)-=)abenzyl-3
-(diphenylphosphoryloxy)-6-(1-1)-
Nitrobenzyloxycarbonyloxyethyl)-1-
Azabicyclo(8,2,0)hept-2-en-7-one-2-carboxylene) (76sv) and (2R,4R
)-1-p-Nitrobenzyloxycarbonyl-2-dimethylaminecarbonyl-4-mercaptopyrrolidine (89q) in the same manner as in Example 1-1 (a) (5R,6S,8R,2.k .

4'R)-p-nitrobenzyl-8-C4-(1-p-
Nitrobenzyloxycarbonyl-2-dimethylaminecarbonyl)pyrrolidinylthio)-6-(1-p-nitrobenzyloxycarbonyloxyethyl)-1-azabicyclo(8,,2,0)hept-2-ene-7- (85w) was obtained.

1650, 1520.1440°1842, 1260.112O NMRa (CDCza): 1.49 (8H, d
, J=6.5Hz), 2.98 (8H,s), 8.09
(8H, a), 5.25 (4H, s), 5.26 and 5.44 (2H, ABq, J=14Hz), 8.2
0 (6H, d, J=8.5Hz) [α)D +28. B
o (C=0.829.acetone) b) (5R, 6S,
8R,2'R,4'R)-1)-nitrobenzyl-8-
(4-(1-1)-nitrobenzyloxycarbonyl-2-dimethylaminecarbonyl)pyrrolidinylthio)
-6-(1-p-nitrobenzyloxycarbonyloxyethyl)-1-azabicyclo(8,2,0'l hept-2-en-7-one-2-carboxylate (85w
I) was prepared by the same method as in Example 1-1 (b).
R, 6S, 8R, 2'R, 4'R)-8-(4-(2-
dimethylaminecarbonyl)pyrrolidinylthio)-6-
(1-hydroxyethyl)-1-azabicycloCB, 2
゜0] Hept-2-en-7-one-2-carboxylic acid was obtained.

Example 2 a) (4R, 5R, 6S, 8R)-p-: Trobenzyl-4-methyl-6-("1-hydroxyethyl) was converted into 1-azebicyclo[8°2.0]hept-8,7 −
Sion-2-carboxylate (58) was dissolved in dry acetonitrile (6-), diisopropylethylamine (574) was added under water cooling in a nitrogen stream, and then diphenylchlorophosphate (48 sv) was added, and after stirring for 2.5 hours ( 25.451)-1-1)-Nitropenzyloxycarbonyl-2-dimethylaminecarbonyl-4-mercaptopyrrolidine (57q) was added and stirred for 1 hour.The reaction solution was diluted with ethyl acetate. The mixture was diluted, washed with water, dried over magnesium sulfate, and the solvent was distilled off.

The residue was purified by silica gel thin layer zovt-graphy (4R, 5R, 6S, 8R).

2'5,4'S)-1)-nitrobenzyl-8-(
4-(1-1)-nitrobenzyloxycarbonyl-2
-dimethylaminecarbonyl)pyrrolidinylthio]-4
-Methyl-6-(1-hydroxyethyl)-1-azabicyclo(8,2,0')hept-2-dyn-7-one-2-carboxylate (85,+v) was obtained.

1520, 1402.1842.1185°11O NMRa (CDC28): 1.8'0 (BH, d, J
=7.0Hz), 1.85 (3H, d, J=6.
5Hz), -.

199 (8H1s), □ 8.02 (8H, d, J&1'5Hz), 6J1 (2H
, s), 6.20 and 5.4 B (2H, ABq, J=14Hz),
7:6 r (2H, a L J=8.5H2), 7.
64 (2H, d, J=8.5H1), 8.20 (4H
Cod, J=8.5H2) b) (4R, 5R, 6S, 8
R,2・5.4・5)-p-nitrobenzyl-8-(4
-(1-p-nitrobenzyloxycarbonyl-2-
dimethylaminecarbonyl-pyro1'dinylthio]-
4-Methyl-6-(l-hydroxyethyl)-t-azabicyclo(8,2゜0]hept-2-en-7-one-'2-carpoxylate (25q) was mixed with tetrahydrofuran (1,9m) and ethano This solution was hydrogenated for 1 hour under normal hydrogen pressure in morpholinopropylene antisulfonic acid buffer (pH = 7.0.1.9sd), and then filtered. 10% palladium on carbon (80η) washed with water was added, and hydrogenation was carried out at room temperature for 8 hours under hydrogen pressure. After filtering the catalyst, tetrahydrocefuran and ethanol were distilled off under reduced pressure, the remaining liquid was washed with ethyl acetate, the aqueous layer was again distilled off under reduced pressure to remove the organic solvent, and the remaining liquid was subjected to 4-mer chromatography (CHP- 20P), the parts eluted with water (4R, 5R, 6S, 8R
,2'S,4'5)-8-C4-(2-dimethylaminecarbonyl)pyrrolidinylthio]-4-methyl-6-(
1-hydroxyethyl)-1-azabicyclo(8,2,
0] hept-2-en-7-one-2-carboxylic acid was obtained.

NMRJ (D20): '1.2M8H, dJ=7.0
Hz), 1.29 (8H, d, J=6.5Hz
), 1.92 (IH, m), 2.99 (8H, s), 8.06 (8H, a) Example 8 a) (4R,5R,6S,8R)-p-nitrobenzyl-4- Methyl-6-(1- and droxyethyl)-1-azebicyclo[8°2.0]hept-8,7-sion-2
-Carboxylate (61 sv) was dissolved in dry acetonitrile (6-), diisopropylethylamine (72 W) and then diphenyl chlorophosphate (55 Misaki) were added under nitrogen flow and water cooling, and after stirring for 2.5 hours [2S
.

45)-1-1)-nitrobenzyloxycarbonyl-
2-(1-pyrrolidinecarbonyl)-4-mercaptopyrrolidine (77q) was added, and the mixture was stirred for 11 hours.

The reaction solution was diluted with ethyl acetate, washed with water, dried over magnesium sulfate, the solvent was distilled off, and the residue was purified by silica gel thin layer chromatography.
's, 4'5)-p-nitrobenzyl-8-(1-1-
Nitrobenzyloxycarbonyl-2-(1-1-, azabicyclo(8,2,0)-hept-2-en-7-one-2-carboxylate (51q) was obtained.

1525, 1440.1B50.1210°tii.

NMRa (CDCA8): 1.80 (8H, d
, J=7.0Hz), 1.84(8H,d, J=6.5
Hz), 5.21 (2H, +ri, 5.20 and 5.4
4(2H, ABq, J=t4Hz), 7.50(21(
, d, J=8.5Hz), 7.64(2H, d, J=8
．． 5Hz), 8.20 (4H, d, J=8.5Hz)b
) (4R, 5R, 6S, 8R, 2'S, 4'5)-p
-Nitrobenzyl-8=(1-p-nitrobenzyloxycarbonyl-2-(1-pyrrolidinecarbonyl)pyrrolidin-4-y, ruthio)-4-methyl-6-(1-hydroxyethyl)-1-azabicyclo[ 8°2.0')
Hept-2-en-7-one-2-carboxylate (50 sv) was dissolved in tetrahydrofuran (8,9 m) and ethanol (0,6-), and this solution was added to morpholinopropanesulfonic acid buffer (pH = 7). .0, 8.9
- After hydrogenation at room temperature for 1 hour under normal hydrogen pressure in -
10% palladium-carbon (60v) subjected to perhydration was added, and hydrogenation was carried out at room temperature for 4.5 hours under normal hydrogen pressure. After filtering the catalyst, tetrahydrofuran and ethanol were 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 subjected to polymer chromatography (CHP-20P). From the part eluted with 2% tetrahydrofuran aqueous solution (4R, 5R, 6S,
8R,2'5.4'5)=p-C2-(1-pyrrolidinecarbonyl)pyrrolidin-4-ylthio]-4-methyl-6,, -(1- and droxyethyl)-1-azabicycloC8,2 ,0) hepto-2-ni-7-one-2-
Carboxylic acid was obtained.

NMRa (DilO): 1.20 (8H, d, J
=7.0Hz), 1.28 (8B, d, J=
6.5Hz), 1.95 (6H, m), 8.46 (6H, m), 8.72 (IH, dd, J=6.5 and 12H2>,
4.02 (LH, quintet.

J=6.5Hz) Example 4 a) (5R, 6S, 8R) 9-neat ohensyl-3-(diphenylphosphoryloxy)-6-(1-
p-nitrobenzyloxycarbonyloxyethyl)-
1-Azabicyclo(8,2,0')hept-2-enecyone-2-carboxylate (172q) was dissolved in dry acetonitrile (2.8 mg) and diisopropylethylamine (59q) was dissolved in dry acetonitrile (2.8 mg) under ice cooling in a nitrogen stream. Add the solution of Q, 7+v) and then [2S.

4S)-1-1)-nitrobenzyloxycarbonyl-
A solution of 2-(8-pyrrolinyl-1-carbonyl-4-mercaptopyrrolidine (944)) in dry acetonitrile (1-) was added, and the mixture was stirred for 15 minutes.

The reaction solution was diluted with ether, washed with water, the insoluble matter in the ether layer was dissolved in methylene chloride, and the ether layer was dried with magnesium sulfate, and the solvent was distilled off. The residue was purified by silica gel thin layer chromatography. 5R, 6S, = 8
R,2'3.4'5)-1)-nitrobenzyl-8-(
4-(1-p-nitropenzyloxycarbonyl-2-
(8-pyrrolinyl-1-carbonyl)pyrrolidinylthio)-6-(1-1-nitrobenzyloxycarbonyloxyethyl)-1-azabirecro(8,2,(1)hept-2-en-7-one -2-carboxylene) (1
82 Cape) was obtained.

17G8.1660.1628゜NMRa (CDCjJ): 1.49 (''8H,
d, J=6.2Hz) 5.26 (4H, Sl), 8.18 (6H, d, J=8.8Hz) □ b) (5R, 6S, 8R, 2・S, 4・5) − p-Nitrobenzyl-8-(4-(1-1-nitrobenzyloxycarbonyl-2-(3-pyrrolinyl]l'carbonyl))pyrrolidinylthio)-6-(1-p-nitrobenzyloxycarbonyloxyethyl )-1-azabicyclo(8,2,0)hept-2-en-7-one-2-carboxylate (182-F) was dissolved in tetrahydrofuran (
12,6m)-ethanol (2-), and add morpholinopropanesulfonic acid buffer (1) H7,0 to this solution.
, t 2.6 mg) for 1 hour under hydrogen pressure at room temperature and pressure: Add filtered and water-washed 10% palladium-carbon (219 Misaki) and hydrogenate for 7 hours at room temperature under hydrogen pressure. Added.

After filtering the catalyst, tetrahydrofuran and ethanol were distilled off under reduced pressure, the residual liquid was washed with ethyl acetate, the aqueous layer was again distilled off with the organic solvent under reduced pressure, and the residual liquid was subjected to polymer chromatography (CHP-20P). From the portion eluted with 2% tetrahydrofuran (5R, ss, sR.

2'5.4'S) -8-(4-(2-(8-pyrroline-1-carbonyl)pyrrolidinylthio)-6-(1-hydroxyethyl)-1-azabicyclo(8,2,0) Hept-2-en-7-one-2-carboxylic acid was obtained.

1595, 1450.1880°245 NfvlRa (D20): 1.26 (8H, d, J
= 6.4Hz), 8.18 (IH, dd, J = 2.1 and 9.QHz), 8°77 (tH, dd, J = 7.0 and 12.0H2), 5.89 (2H, br, s) Example 5 a) (5R,65,8R)-p-=trobenzyl-3-
(diphenylphosphoryloxy)-6-(1-1)-nitrobenzyloxycarbonyloxyethyl)-1-azabicyclo('8.2.0')hept-2-ene-7-
on-2-carboxylate (68119) and (2S
, 45) -1-p-nitrobenzyloxycarbonyl-
2-Carbamoylmethylamine carbonyl-4-mercaptopyrrolidine (88sv) was treated in the same manner as in Example 1-1 (a), and the resulting crystalline (5R, 6S, 8R
,2'5.4'5)-1)-nitrobenzyldi11-(
'4-(1-p-nitrobenzyloxycarbonyl-2
-carbamoylmethylaminecarbonyl,)pyrrolidinylthio]-6-(1-p-nitrobenzyloxycarbonyloxyethyl)-1-azabicyclo(8,2,0)
hept-2-en-7-one-2-carboxylate (
61y) was obtained by filtration.

1745...! te10・1670・16B5.1510.1845゜27O Nlla a (CI) Cza) 2 1.5G (8H
, d, J=6.5Hz), 5.28(4)1.8
), 7.50 (4H, d, J = 8.5Hz), 8.21 (6
H, d, J = 8.5H2) m, p, 184-189℃ (
decomposition) b) (5R,sS,sR,2'S,4'5)-p-nitrobenzyl-a-e4-< t-p-nitrobenzyloxycarbonyl-2-carbamoylmethylaminecarbonyl)pyrrolidinylthio) -6-(1-1-nitrobenzyloxycarbonyloxyethyl)-1-azabicyclo("8.2.0)hept-2-en-7-one-
Dissolve 2-carboxylate (80v) in tetrahydrofuran (8,1-)-dimethylpholumamide (1-), and add this solution to a monomorpholinopropanesulfonic acid buffer (pH 7,0, a, t-) at room temperature. , atmospheric hydrogen pressure 1
After hydrogenation for an hour, 10% palladium-carbon (87q), which had been filtered and washed with water, was added, and hydrogenation was carried out under normal hydrogen pressure at room temperature for 5 hours.

After filtering the catalyst, tetrahydrofuran was distilled off under reduced pressure, the residual liquid was washed with methylene chloride, the organic solvent was distilled off from the aqueous layer under reduced pressure, and the residual liquid was subjected to polymer chromatography (CHP-
(5R, 6S) from the part that is eluted with water when applied to
, 8R, 2・5.4・5)-8-(4-(2-carbamoylmethylaminecarbonyl)pyrrolidinylthio)-6
-(1-hydroxyethyl)-1-azabicyclo(8,
2,0) hept-2-en-7-one-2-carboxylic acid was obtained.

1890.1220.1180゜104O NFaa (D20): 1.26 (8H, d, J-6
-6Hz), 1.86 (IH, m), 8.20 (2H, dd, J=7.5 and 14.7Hz
), 8.88 (IH, dd.

J=8.0 and 5.7Hz), 4.02 (IH,t, J=9.0H2) The following compounds were obtained from the corresponding mercaptan derivatives.

Examples R, R, R, Y Physical properties UVk"Onm: 297 ax Example A R8R@R@Y Physical properties UV"nm: 298 ax NMRδ (D! 0): 1.27 (8H, d
, J = 7 Hz), 5-68 (8H-m) UV
i" nm: 298 ax Measurement point RI R1Rs Y
Shizu --- Sono Kazuichi Rumor --,, 1 Eyu,,,,,,,,,.

Physical properties Uv, H, o nm: 297 ax UVIH'Onm: 297 ax Br IRy (c++s') = 1755e1685,159
0-1870-1240ax Example m RI Rt Rs Y Akebono 11-1-□ Delivery item-m---1-■----1-
■---------Familiarity---Yu,,,Engineer,,,,1.
．． 1 Physical property example points R, R, R3Y Physical properties m, p, 179-18.2c (decomposition) Example Todoroki RIR1R3'Y, 9□F, □, 2.21.2-■--□1 section Open-□Threshold ■ Garden-- Mountain properties Ui: FxMm: 298 Example 1111 RI R18 Y Physical properties UVA" nm: 298 ax Example A RI R1R, Y Physical properties m, p, 167-169°C (decomposition ) Measurement point RI R1R1y Value 2 C8 Physical properties m, p, 196-199℃ (decomposition) m, p, 168-170℃ (decomposition) UvλH2Onm: 800 !I breath ax Example Todoroki R,R,R ,・7 CH.

Iris B C material properties m, p, 98-101℃ Example points RI R1RI Y cHI 4 electrical properties m, p, 172-1750 q UVλH"nm: 800 ax J=6.91'izJ, X!! ,92(8tt,s),
8.18 (8fl, 8) Example A R, R, R, Y Physical properties Example wild goose R, R, R, Y Physical properties UVλH! Onm: 800 ax NMRδ (D, 0): 1.26 (8H, deJ=6.
8Hz)-2-78(8H1s)e8.09(8H,S
), 8.89 (IH, Q, J=2.6H2) Example A
R1 for R3'1' Physical property Uvknax"m' 297 Example point R1R2R3Y Physical property UVIH"nm: 298 ax UVλ"Onm: 298 ax Example point R, R, R, Y g+i,' HHH・-NH-0 Physical properties 1jVl"Onm: 2gg ax UVλ"Onm: 245.800 ax z8b Example A R, R, R, Y Physical properties 8.60 (lfl, (1, J=2.2flZJ Example 凰 RIR, R, Y B2 10HH Physical properties m, p, 189-191'C (decomposition) Example 1a R8Rz Rs Y Physical properties 8.84 (11-1, m) Example EAR, R, R, Y Physical properties Example Light R1R2R Breath Y Physical Properties Br IRν (Reduction: l750.1650.1600.1
440.1895aX Example ex RIRl Rs Y Physical properties NMRJ (CDCem): 1.48 (-8H, d, J
=5.9Hz), 5.25(4H,8)-8,15(6
H, d, J=8.6Hz) UVλH” nm:
29B ax J=2.6 64h 5. QfiZJ Sea F Core Example/Ffi R1 Bird R,Y Physical Properties NMRa (CDCe Ri:' 1.50 (8H, d, J=
6.2Hz), 5.28(4)1.3)-8,19(6
M, d, J=8.1Hz)UVI”0-12
97 ax Example A Rs Rm Rm Y Cl.

Physical properties J = (iflZ), 1.81L8fl, a, J = 71'
izJ Example AR, R, R, Y 41 'HHH-N)CONH.

Physical properties NMRδ (CDCJ=): 1.47 (8H, d, J=
6.2Hz), 5.26 (4H, s).

8.16 (6H, d, J=8.6Hz)UVl”Onm
: 298 ax NMRδ (D*0): 1.26 (8H, d, J=6.
8Hz) Example/IER, Bird RI Y Physical property example RlR, R, Y Physical property 8 no UVA” Onm: 207; 299ax NMRδ (Dρ): 1.25 (8H, d, J=6.6
Hz), 1.85 (IH, rn) Example R, R, R
,Y PNZ PNZ PNB -0PNB 4 ・HHH-0H PNZ PNZ PNB -OCH.

, 45 HH)I-OCH.

physicality PNZ PNZ PNB-NHN Tow 46 HHH-NHN Tow PNZ PNZ PNB -NHN (CH,).

7 HHH-NHN (CH, 9゜Physical properties m, I), 184-187℃ (decomposition) m, p, 187-L89C (decomposition) UVIH"nm: 800 ax Practical example A RIR, R, Y 48, , , , , , , , , , , , , , ,
, , , , , , , , , , , , ・1) -H"Hge 1° deviation -□ Physical properties IRνKBr (cfn-'): 174B, 1697.
18B0.1240.1180ax Example & RI B, 'R* Y PNZ PNZ PNB -NHOPNB9 HHH-NHOH PNZ PNZ PNB -NHOCH.

0 HHH-NHOCH3 Physical properties m, 1), 149-152℃ (decomposition) UVAH”nm
: 800 ax Br IRν (cIn-'): 1750.1680,160
0,1400,1120ax m, p, 188-189.6c (decomposition) NMR δ (D!
0): 8.70 (OH, S) Example A R1R, R3
Y Physical properties Example A RIR, R3 Physical properties UVl"Onm: 800 ax Example A R1 Peng R, Y Physical properties 4.14-4.29 (2fi, m) Example points Rt Ra A Physical properties 9 [α ] ゎ +87.8° (c=0.244, acetone) UVl"Onm: 298 ax Example A R, R, A \PNZ 5 \H Physical properties 2 (+2) D +57.6' (c=0. 279.ycetone) Example point RlR,A Physical property 5 [α) +48.7° (C=0.858.acetone)
UVl"Onm: 287 ax Example A Rs Rt Rs'" HPNZ PNB, N'\10H e 9 HHHN'\10H e Physical properties CHcl.

IRν (r++-): 1770.1695.1650
．． 1520.1840ax Br IRν (Country-): 1750.16B0.1605.
1875.1240ax Example/Pi Rs RIRs Y 2O・ □ ) I HHNHCH, CON Chicken Sex Br IRν (cIR=): 1750.1670.1600
．． 1890.1245ax Example R, R, R, Y HPNZ PNB NCH, C0NH.

e 1 HHHNCH, CON8e Physical properties UVλ"Onm: 292 ITYfi X Br IRν (is-'): 1752.1645.1600
．． 1885.1245ax Example A Rs R1Rs Y Physical properties [a) 26-45° (cm0.l l, CHCgs
)UVI"Onm: 298 nax IRyKBr(cm-'): 1750.1640.1
610.1460-1880ax NMRδ (DzO): 1.25 (8H, d, J=6H
z), 1.27 (8H, d.

J=7.5Hz), 5.85 (2H, br, s) Example R1 R, Y Physical properties Example points R, RlR, Y Physical properties Br IRν C6R-'): 1.760.1615. 1B
90.1245.1100ax Examples & R, R, R, Y (-1) Physical properties Examples R1 uniformity R3Y, M M M -NN-CH.

physicality ■ Examples & R1R2 also Y B2 HHH-0CR.

Physical property UV1H! 0nrn: 2g6 ax Br IRy (Lyn”): 1735.1602-1B9
0ax Example seed Rs R2Rs Y B2 HHH-IC) Physical properties [α] 26-88° (C=0.l l, CHCJ,)
tJV)"Onm: 288 ax Example A R,R,R,Y Physical propertiesUVl,W,::nm: 28B The following compound can be synthesized by a method similar to that shown in the above example. .

l　H″″NHC, H5 2H-NH-nC4H.

8H-NH-ic4 bird 4H-N(nC,H,).

5H-N(IC5Hy)t 6 H-N (nC4H,)2 7 H-N (i C4Hll)! 11 H-N/'\--ph CH.

12H-NCH,-Ph C,H.

13H-N(CM, -Ph).

14 H-N% N (C1H1+) Goose 16 H-N/to ψ/N (C, 搗) 2CM.

16 H-N/X/N (for C) 1 Fortune telling 21 17　H-N　/X/N　(C!H5)tC crystal 18 H-N //X/A-N (C8).

19 H-N"\/\N (C crystal) 2 ′□　■-8～. □ 8 ,,・Mount C Compound point R4Y 28 H-N 4-1OH store crystal 29 H-N (%OH).

a　a　H-N')-OH 0H 881 (N/Heli/C0NII.

89 H-N% C0NHCH.

40 H-N, /'\7■intermediate) 41 H-N/in/\CONH2 42H-N/4ν^, C0NH Compound base to H R4Y 48 H-N/\l\α)N (CHs) a44 CH3
-H/'-/ 46 CH, -NH.

47　C　-N/-\, MeOH Yam CH.

48　C　-NHCH, CON Toki 49 CH, -N-CH, CONH.

♂H3 Compound & R4Y 2OC Toki-NQ (-) 56 CH, -0CH3 56CH3-NCH,C0N1(CH.

57 G8 -NCH, C0NHCH3CH3 58C) f, -6 → CO Peng Continuation of page 1 [phase] Int, C1,' Identification code Internal reference number 0 Inventor Masuhiro Kato 4-2 Takashi, Takarazuka City No. 1 Written amendment to proceedings within Sumitomo Chemical Co., Ltd. (voluntary) January 10, 1985 1. Indication of the case 1987 Patent Application No. 191167 2. Title of the invention 3. Relationship with the person making the amendment Patent Applicant's address: 5-15-5 Kitahama, Higashi-ku, Osaka Contents of amendment (1) In the following sections of the specification, the term "carbamoyl" is replaced with "a-carbonyl."

The following is added between the second and first lines from the bottom of page 78 of the same book:

[1515, 1480, 1400, 1845°1205.
1165 NMRδ (CDCA!3): 2.82 (8H, s
), 5.20 (2H, br, s ), 7.42 (
2H,d.

J=9Hz), 8.12 (2H, d, J=9H
z)'' In the following passages of the same book, the term ``carbamoyl'' is replaced with ``aminocarbonyl.''

(2) In the following parts of the same book, all references to ``amine carbonyl'' are replaced with ``aminocarbonyl.''

(3) In the following parts of the same book, all references to ``pyrrolidinecarbonyl'' are replaced with ``pyrrolidinylcarbonyl.''

(4) In the following section □ of the same book, all references to ``amine carbonyl'' are replaced with ``aminocarbonyl.''

□ LA complete)

Claims (1)

[Scope of Claims] (1) General formula 4 [wherein, R1 is a hydrogen atom or a hydroxyl group-protecting group,
2 represents a hydrogen atom or a protecting group for an amino group, Ra represents a hydrogen atom or a protective group for a carboxyl group, and R4 represents a hydrogen atom or a 01-C8 alkyl group. Y is m set ′′- hydrogen atom, C1-C5 alkyl group, lower thylkenyl group,
aryl lower alkyl group, substituted C1-C5 alkyl group,
or represents a pyridyl group, or R5 and R6 represent an alkylene chain packed together, or an oxygen atom,
AJ! via a sulfur atom or a lower alkyl substituted nitrogen atom! /K represents a lene chain and indicates an unsubstituted or substituted cyclic amino group which may have a double bond within an 8- to 7-membered ring together with the adjacent nitrogen atom. ), a group represented by the general formula (wherein R7 represents a hydrogen atom or a lower thylkyl group,
), a protected or unprotected hydroxyl group, a lower alkoxyl group, an electroless or lower alkyl-substituted hydrazino group, or a guanidyl group represented by the general formula % (in the formula, R8 is a hydrogen atom, a protecting group for a hydroxyl group, or a lower alkyl group) A β-lactam compound or a salt thereof. (2) Claim f! where Rt, R2 and R8 are hydrogen atoms! ! ! IQ-β-lactam compound or salt thereof. (8) Y is a group represented by the general formula, a guanidyl group, a hydroxyl group, a lower alkoxyl group, an unsubstituted or lower alkyl substituted hydrazino group represented by the general formula, or a general formula -NHORaa (wherein, Rsa is a hydrogen atom or (representing a lower alkyl group) β- according to claim 2, which is a group represented by
Lactam compounds or their salts. (4) Claim 2, wherein Y is a group represented by the general formula! −
Lactam compounds or their salts. (ω) R6 and R6 represent an alkylene chain packed with each other, and are an unsubstituted or substituted cyclic amino group having a double bond in a 3- to 7-membered ring together with the adjacent nitrogen atom, Claim No. 4 The β-lactam compound or salt thereof according to claim 5. (6) The β-lactam compound or salt thereof according to claim 5, wherein the cyclic amino group is a 5- to 6-membered cyclic amino group. ) Rs and R6 are the same or different, 7, C
! The l-lactam compound or salt thereof according to claim 4, which is a -C5 alkyl group. @Y is a general formula,,. Claims 1 and 2 are guanidyl groups represented by
A β-nilactam compound or a salt thereof as described in . (9) The β-lactam compound or salt thereof according to claim 2, wherein Y is an unsubstituted or lower alkyl-substituted hydrazino group. (Conflict General Introduction. [In the formula, R1 is a hydrogen atom or a hydroxyl group protecting group, R2
represents a hydrogen atom or a protecting group for the syl group of an amino group, and R
4 represents a hydrogen atom or a lower alkyl group. Y is the general formula □ - (wherein Rs and R6 are the same or different and represent a hydrogen atom, a CI -Cs alkyl group, a lower alkenyl group, an aryl lower alkyl group, a substituted C1-C6 alkyl group, or a pyridine JLI group) or 'R1I and R6
represents an alkylene chain packed with each other, or represents an alkylene chain via an oxygen atom, a sulfur atom, or a lower alkyl-substituted nitrogen atom, and has 21 bonds in an 8- to 7-membered ring together with the adjacent nitrogen atom. represents an optionally unsubstituted or substituted cyclic amino group. ), a guanidyl group represented by the general formula (in the formula, R7 represents a hydrogen atom or a lower alkyl group), a protected or unprotected hydroxyl group, a lower alkoxyl group, an unsubstituted or lower alkyl-substituted hydrazino group , or represents a group represented by the general formula % formula % (wherein R8 represents a hydrogen atom, a hydroxyl group, a protecting group, or a lower alkyl group), or a salt thereof. In doing so, the general formula [wherein R1 and R4 have the same considerations as above,
represents a carboxyl group protecting group. ] and the general formula [wherein Rg has the same meaning as above, Y' is the general formula (wherein R6 and R6 have the same meaning as above)]
A group represented by, a guanidyl group substituted with a snowless or lower alkyl group, a hydroxyl-1 lower alkoxyl group protected with a carboxyl group protecting group, an unsubstituted or lower alkyl-substituted hydrazino group, or the general formula % formula % ( In the formula, R'8 represents a hydroxyl protecting group or a lower alkyl group. ] in the presence of a base to form a compound of the general formula [wherein R1, R2, R4, R9 and Y. have the same meanings as above. ] ・Produce a β-lactam compound represented by Rt,
R2 and/or Rs are hydrogen atoms, or protection on Y', removal/reaction with removal of groups, and/
Alternatively, a method for producing the β-lactam compound or a salt thereof, which comprises appropriately combining reactions for removing and removing protecting groups of amino groups, or subjecting these protecting groups to reactions for simultaneously removing them.