JPS63264453A - Azetidinone derivative - Google Patents

Abstract

NEW MATERIAL:A compound expressed by formula I (R<1> is H or protecting group of OH; R<2> and R<3> are H, lower alkyl or aryl; X is O or S; Y is imino, alkylimino, O or S; R<4> is alkyl, aralkyl, aryl, etc.; R<5> is H, protecting group of amide, etc.). EXAMPLE:(3S, 4R)-3-[ (R)-1-tert-butyldimethylsilyloxyethyl ]-4-[[ (S)-1-( p- nitrobenzyloxycarbonyl )pyrrolidin-3-ylthio ]carbonylmethyl ]-2-azetidinone. USE:A synthetic intermediate for carbapenem derivatives capable of exhibiting powerful antimicrobial activity. PREPARATION:A compound expressed by formula II (R<6> is a leaving group and lower acyloxy, arylcarbonyloxy, etc.) is reacted with a compound expressed by formula III (R<7>-R<9> are methyl, ethyl, phenyl, etc.) in the presence of a catalyst (e.g. trimethylsilyl trifluoromethanesulfonate) to afford the aimed compound expressed by formula I.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a novel azetidinone derivative having the general formula fl) and a method for synthesizing the same.

In the formula, R1 represents a hydrogen atom or a hydroxyl group-protecting group, and the protecting group is not particularly limited as long as it is a hydroxyl-protecting group used in the reaction of β-lactam antibiotic derivatives, but formyl, acetyl, Acyl groups such as chloroacetyl, propionyl, butyryl, isobutyryl, benzoyl;
Silyl groups such as trimethylsilyl, t-butyldimethylsilyl, and triphenylsilyl: Aralkyl groups such as benzyl and p-nitrobenzyl: benzyloxycarbinyl, p-bromobenzyloxycarbonyl, p-nitrobenzyloxycarbonyl, 0-nitro Benzyloxycarbonyl, allyloxycarbinyl, 2-chloroallyloxycarbonyl, 2-methylallyloxycarbonyl, 21212-tribromoethoxycarbonyl, 21
2.2-)! Alkoxycarbonyl groups such as J dichlorothoxycarbonyl, t-butoxycarbonyl, 2-(trimethylsilyl)ethoxycarbonyl, tetrahydropyranyl, methoxymethyl, 1-ethoxyethyl,
It is an ether group such as 2-(trimethylsilyl)ethoxymethyl. R2 represents a hydrogen atom, a lower alkyl group having 1 to 3 carbon atoms such as methyl, ethyl, propyl, isozoropyl, or a phenyl group, and R3 represents a hydrogen atom, methyl, ethyl, propyl, isopropyl, etc. having 1 to 3 carbon atoms. represents an alkyl group or a phenyl group, X represents an oxygen atom or a sulfur atom, and Y represents an imino group, an alkylimino group (an alkyl group having 1 to 4 carbon atoms such as methyl, ethyl, butyl, Benznow, p-
aralkyl group such as nitrobenzyl), an oxygen atom or a sulfur atom, and R4 is a straight-chain or branched substituted alkyl group (there is no particular limitation as a hydroxyl-protecting group, and a common alcoholic hydroxyl group) Protecting groups can be used, preferably alkyl groups such as methyl, ethyl, propyl, aralkyl groups such as benzyl, p-nitrobenzyl, tonoacyl groups such as formyl, acetyl, propionyl, benzoyl, hensyloxycarbonyl, p-nitrobenzyl, etc.
-Alkoxycarbonyl groups such as -nitrobenzyloxycarbonyl, and trialkylsilyl groups such as trimethylsilyl and t-butyldimethylsilyl. ) 2-hydroxyethyl group, 3-hydroxypropyl group, 2-hydroxy-1-methylethyl group, or 3-hydroxy-
Indicates a hydroxyalkyl group such as 1-methylpropyl group. As the linear or branched substituted alkyl group for protecting the amino group, there are no particular limitations on the protecting group for the amino group, and general amine protecting groups can be used. Preferably, formyl, acetyl, and chloroacetyl are used. , fropionyl, hensoylinato acyl group, t-butoxycarbonyl, 2,2.2-trichloroethoxycarbonyl, 2-()IJmethylsilyl)ethoxycarbonyl, benzyloxycarbinyl, p-nitrobenzyloxycarbonyl, 0-nitrobenzyloxy alkoxycarbonyl groups such as carbonyl) 2-aminoethyl, 2-amino-1-methylethyl, 2-amino-1-ethylethyl, 3-aminopropyl, 3-amino-1-methylpropyl, 2-amino-2 -Methyl ethyl or 2-N-methylaminoethyl, 2-N-methylamino-
Indicates an aminoalkyl group such as 1-methylethyl. A linear or branched substituted alkyl group in which the hydroxyl group is decorated with an aminoalkyl group, the amine group of which may be protected, and the protecting group for the amine group is not particularly limited, but the preferred ones are those listed above. can be given. The substituted alkyl group whose hydroxyl group is modified with an aminoalkyl group is preferably <2
-(2-aminoethoxy)ethyl, 2-(2-aminoethoxy)-1-methylethyl, 2-(3-aminopropoxy)ethyl, 3-(2-aminoethoxy)propyl,
3-(2=amineethoxy)-1-methylpropyl, etc.

Aralkyl groups include benzyl, p-methoxybenzyl, m-nitrobenzyl, 0-methylbenzyl, p-bromobenzyl, and p-aminobenzyl, and aryl groups include phenyl, 1-naphthyl, 2-naphthyl, p- Nitrophenyl, m-cal? xyphenyl, Q
-Hydroxyphenyl and p-methoxyphenyl are also L (
ham-ethoxycarbonylphenyl e, the alicyclic heterocyclic group is substituted or unsubstituted in which a nitrogen atom, oxygen atom, sulfur atom, sulfinyl group, sulfonyl group, or carbonyl group may be present on the ring carbon silver. 4-membered ring to 8
Represents a cycloaliphatic amine residue forming a membered ring, and the substituents bonded to the ring carbon atoms are an alkyl group, an alkoxyalkyl group, a 7anoalkyl group, a halogenoalkyl group, an alkoxy group, a hydroxyl group, an amino group, a halogen atom, A ring nitrogen atom selected from the group consisting of an acyloxy group, an acylamino group, a cyano group, an at group, a carboxyl group, an alkoxycarbonyl group, a carbamoyl group, an alkylthio group, an alkylsulfinyl group, an alkylsulfonyl group, or a nitro group. Substituents bonded to are alkyl groups, alkenyl groups, alkynyl groups, cycloalkyl groups, cycloalkylalkyl groups, aryl groups, aralkyl groups, acyl groups, phenacyl groups, sulfo groups: alkoxysulfonyl groups, alkylsulfonyl groups, alkenylsulfonyl groups , alkynylsulfonyl group, cycloalkylsulfonyl group, cycloalkylalkylsulfonyl group, arylsulfonyl group: aralkylsulfonyl group, heteroarylsulfonyl group, heteroaralkylsulfonyl group, alkyl group, R1) is a hydrogen atom or an imino group protecting group ) or differently represents a hydrogen atom or a lower alkyl group,
Z represents an imino group optionally substituted with an oxygen atom, a sulfur atom, or a lower alkyl group. ); Halogen atom, lower aliphatic acyloxy group, lower aliphatic acylamino group, cyan group, azide group, carboxyl group, lower alkoxycarbonyl group,
Carbamoyl group, lower alkylthio group, lower alkylsulfinyl group, lower alkylsulfonyl group, nitro group may be the same or different and represent a hydrogen atom or a lower alkyl group. ) may be substituted with one selected from the group consisting of: Preferred examples of the alicyclic heterocyclic group include azetidinyl, hyrolysinyl, hyheridinyl, morpholinyl, tetrahydropyrimidinyl, thiazolisonyl, oxazolidinyl, hexahyP-ropyrimidinyl, imidazolidinyl, or octahydroazosinyl, which may have a substituent; Substituents bonded to carbon atoms are preferably straight-chain or branched lower alkyl groups such as, for example, methyl, ethyl, propyl, inpropyl, butyl, isobutyl, (8)-butyl, t-butyl, pentyl, inventyl, etc. groups, such as cycloalkyl groups such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,
For example, lower alkoxyalkyl groups such as methoxymethyl, ethoxymethyl, n-propoxymethyl, impropoxymethyl, n-butoxymethyl, methoxyethyl, 3-methoxypropyl, 2-methoxypropyl, 4-ethoxybutyl, e.g. alkoxycargenyl alkyl group such as nylethyl, methoxycarbonylpropyl, ethoxycarbonylmethyl, t-butoxycarbinylmethyl,
Cyano lower alkyl groups, such as cyanomethyl, cyanoethyl, 3-cyanopropyl, 2-cyanopropyl, 4-cyanobutyl, - e.g. trifluoromethyl, 2
-fluoroethyl, 2,2,2-trifluoromethyl,
2-chloroethyl, 2-7” lomoethyl, 3-fluoropropyl, 2-fluoropropyl, 4-chlorobutyl,
a halogeno lower alkyl group such as 3-fluorobutyl,
For example, linear or branched lower alkoxy groups such as methoxy, ethoxy, propoxy, inpropoxy, butoxy, isobutoxy, rich-butoxy, 1-butoxy, hydroxyl groups, amino groups, such as fluorine, chlorine, bromine, iodine. halogen atoms such as, for example, lower aliphatic acyloxy groups such as acetoxy, propionyloxy, butyryloxy, imbutyryloxy, such as acetylamino,
Lower aliphatic acylamino groups such as propionylamino, butyrylamino, imbutyrylamino, cyanide groups, asodo groups, carboxyl groups, e.g. evamethoxycarbonyl,
Ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, imbutoxycarbonyl, crown-butoxycarbonyl, t-butoxypower/l/, 1? Lower alkoxycarbonyl group, carbamoyl group, such as methylthio, ethylthio,
Straight-chain or branched lower alkylthio groups such as propylthio, isopropylthio, butylthio, isobutylthio, straight chain such as methylsulfinyl, ethylsulfinyl, flobylsulfinyl, isopropylsulfinyl, butylsulfinyl, isoditylsulfinyl a linear or branched lower alkylsulfinyl group; nitro group, the substituents attached to the ring nitrogen atom being preferably selected from the group consisting of nitro groups, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, of the formula -butyl, t-butyl, pentyl, isopentyl. Straight or branched lower alkyl groups such as vinyl,
Lower alkenyl groups such as allyl, 1-propenyl, isopropenyl, 2-butenyl, 2-pentenyl, e.g.
'lower alkynyl groups such as ethynyl, 2-propynyl, 2-butynyl, 4-pentynyl, e.g. cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl;
Cyclo-lower alkyl groups such as cycloheptyl, e.g. cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, cycloheptylmethyl, 2-cyclopentylethyl, 2-cyclohexylethyl, 3-cyclomethylpropyl, 2-cyclopentylpropyl , 3-cyclohexylpropyl, 2-cyclohexylzolobyl, 4-cyclopentylbutyl, 3
- lower cycloalkylalkyl groups such as cyclohexylbutyl, aryl groups such as phenyl, naphthyl, aralkyl groups such as benol, phenethyl, 3-phenylpropyl, such as formyl, acetyl,
Lower aliphatic acyl groups such as propionyl, butyryl, isobutyryl, acryloyl, methacryloyl, crotonoyl, incrotonoyl, propioloyl, methylpropioloyl, such as cyclopropanecarbonyl, cyclobutanecarbonyl, cyclopentanecarbonyl, cyclohexanecarbinyl Lower cycloalkanecarbonyl groups, such as cyclopropylacetyl, cyclobutylacetyl, cyclopentylacetyl, cyclohexylacetyl, 3-cyclobeny/tylpropionyl, 3-
Lower cycloalkylalkanoyl groups such as cyclohexylpropionyl, 4-cyclopentylbutyryl, 4-cyclohexylbutyryl, aromatic acyl groups such as benzoyl, 1-naphthoyl, 2-naphthoyl, e.g. phenylacetyl, 1-naphthyl Acetyl, 3-phenylpropionyl, hydratroboyl, cinnamoyl,
Aromatic acyl groups such as phenylpropioloyl, e.g. furoyl, thenoyl, nicotinoyl, innicotinoyl, heterocyclic acyl groups such as 4-thiazolecarbonyl, 5-pipericinecarbonyl, 2-pipedinecarbinyl, e.g. 2-che Nylacetyl, 3-(2-chenyl)
Heterocycloaliphatic acyl groups such as phlopionyl, 4-thiazolyl acetyl, 2-pyridylacetyl, 4-bilizolacetyl, 5-pyrimidylacetyl, e.g. 1-anolidinecarbonyl, 1-azetidinecarbonyl, 3 -azetidine carbonyl, 1-pyrrolidine carbonyl, 2-pyrrolidine carbonyl, 3-pyrrolidine carbonyl, 1-
piperidine carbonyl, 2-piperidine carbonyl, 4
- a heterocyclyl carbonyl group such as pipericine carbonyl, 4-morpholine carbonyl or e.g. 1-
Azilinonylacetyl, 1-azetinonylacetyl, 3
-Azetinonylacetyl, 1-pyrrolidinylacetyl,
Heterocyclyl fatty acids such as 2-pyrrolidinyl acetyl, 3-pyrrolidinyl acetyl, 3-(2-piOIJdinyl)propionyl, piperidinoacetyl, 2-piperidinyl acetyl, 4-piperidinyl acetyl, morpholinoacetyl Acyl groups such as group acyl groups, 7-enacyl groups, sulfo groups, such as methoxysulfonyl, ethoxysulfonyl, phenylsulfonyl, impropoxysulfonyl, lower alkoxysulfonyl groups, such as methylsulfonyl, ethylsulfonyl, furobylsulfonyl, isopropylsulfonyl , butylsulfonyl, linear or branched lower alkylsulfonyl groups such as imbutylsulfonyl, lower alkenylsulfonyl groups such as evaarylsulfonyl, impropenylsulfonyl, 2-butenylsulfonyl, e.g. Sulfonyl, 2-provinylsulfonyl, 2-butynyl/I/
Lower alkynylsulfonyl group, e.g.) J
Lower cycloalkylsulfonyl ts of d cyclopropylsulfonyl, cyclobutylsulfonyl, cyclopentylsulfonyl, cyclohexylsulfonyl, Example Lt
d cyclopropylmethylsulfonyl, cyclopentylethylsulfonyl, cyclomethylmethylsulfonyl, cyclohexylmethylsulfonyl, 2-cyclopentylethylsulfonyl, 2-cyfhexylethylsulfonyl,
Lower cycloalkylsulfonyl such as 3-cyclopentylpropylsulfonyl, 2-cyclopentylpropylsulfonyl, f, fi phenylsulfonyl, 1-1-
Arylsulfonyl groups such as 7-tylsulfonyl, 2-naphthylsulfonyl, e.g. benzylsulfonyl, phenethylsulfonyl, 3-phenylpropylsulfonyl,
Aralkylsulfonyl groups such as 2-phenylpropylsulfonyl, for example if 2-fethylsulfonyl,
4-thiazolylsulfonyl, 2-pyrinolsulfonyl, 4-pyridylsulfonyl, younaheteroarylsulfonyl group, e.g. 2-thenylmethylsulfonyl, 3-
Heteroaralkylsulfonyl groups such as (2-IF-enyl)furobylsulfonyl, 4-thiazolylmethylsulfonyl, 2-bi+J, /lmethylsulfonyl, 4-pyridylmethylsulfonyl, HIO formula -〇=N -R1) group (wherein HIO is a hydrogen atom or a lower alkyl group such as methyl, ethyl, propyl, isopropyl, R1) is a hydrogen atom or a group such as allyloxycarbonyl, 2-methylallyloxycarbonyl, 2-chloro Allyloxycarbonyl, 2,2.2
- Alkoxycarbonyl groups such as trichloroethoxycarzenyl, 2,2.2-toIJ bromoethoxycarbonyl are examples! d p-Nitropenoloxycarbonyl, io-1aralkyloxycarbonyl group of 0-nitropenoloxycarbonyl. ) or differently represents a hydrogen atom or a lower alkyl group such as methyl, ethyl, propyl, isopropyl, and Z is an oxygen atom, a sulfur atom or a hydrogen atom such as methyl, ethyl, propyl, isopropyl,
Indicates an imino group optionally substituted with a lower alkyl group such as inpropyl. ), for example methoxycarbonyl, ethoxycarbinyl, butoxycarbonyl, 2,2.
2- IJ Chlorethoxycarbonyl, 2. ．． 2.
consisting of a lower alkoxycarbonyl group such as 2-bromoethoxycarbonyl or an aralkyloxycarbonyl group such as pennoloxycarbonyl, phenethyloxycarbonyl, p-nitrobenzyloxycarbonyl, 0-nitrobenzyloxycarbonyl The substituents attached to the nitrogen atom are preferably selected from the group consisting of lower alkyl groups such as methyl, ethyl, propyl, impropyl, e.g. methoxy, ethoxy, propoxy, impropoxy. lower alkoxy groups, hydroxyl groups, amine groups such as halogen atoms such as fluorine, chlorine, bromine; lower aliphatic acyloxy groups such as acetoxy, propioni, ruoxy, butyryloxy, imbutyryloxy, such as acetylamino, propionyl; lower aliphatic acylamino groups such as amino, butyrylamino, and imbutyrylamino; cyano groups; acid groups; carboxyl groups; r-class alkoxycarbonyl groups such as methoxycarbinyl, ethoxycarbinyl, propoxycarbonyl, and impropoxycarbonyl; , carbamoyl groups, such as lower alkylthio groups such as methylthio, ethylthio, furohylthio, isopropylthio, e.g. evamethylsulfinyl, ethylsulfinyl, propylsulfinyl, impropylsulfinyl, lower alkylsulfinyl groups, e.g. evamethylsulfonyl, ethylsulfonyl, propyl A lower alkylsulfonyl group such as sulfonyl, isopropylsulfonyl, a nitro group, which may be the same or different, represents a hydrogen atom or a lower alkyl group such as methyl, ethyl, propyl, isopropyl. ) may be further substituted with a selection from the group consisting of

As an alicyclic heterocyclic substituted alkyl group, the heterocycle is the above-mentioned alicyclic monocyclic ring, and the substituents bonded to the ring carbon atoms and nitrogen atoms have the same meanings as above, and the alkyl group is methyl, It is a lower alkyl group such as 1-i substituted ethyl, 2-substituted ethyl, and 1-substituted propyl.

Examples of aromatic heterocyclic groups include pyridyl, pyrimidinyl, trianonyl, chenyl, furyl, thiazolyl, and imidazolyl, which may have substituents, and examples of the substituents include alkyl groups such as methyl, ethyl, and propyl, methoxy, and ethoxy. , alkoxy groups such as propoxy, amine groups, alkylamino groups such as methylamine, ethylamino and propylamino, noalkylamino groups such as trimethylamine and noethylamino, hydroxyl groups, acetoxy,
7 lower alkanoyl groups such as propionyl oxine,
These include nitro groups, halogen atoms such as fluorine, chlorine, and bromine, and alkoxycarbonyl groups such as hamethoxycarbonyl, p-nitrobe/-)yloxycarbonyl, and t-butoyaccarbonyl.

R5 represents a hydrogen atom, an oxalo group with a carboxyl group attached as a protecting group for an amide group (the protecting group for a carboxy group is not particularly limited, and represents a protecting group for a carboxy group used in a β-lactam-based drug substance). Preferably lower alkyl groups such as methyl, ethyl and t-butyl, aralkyl groups such as benzhydryl, benzyl, p-nitrobenzyl and 0-nitrobenzyl, allyl, 2-chloroallyl, 2
- Alkenyl groups such as methylallyl, 2,2.2-trichloroethyl N 2+2+2- halogenated alkyl groups such as tribromoethyl, 2-(trimethylsilyl)
Such as ethyl group. ), protected carboxy group (
The carboxyl group) protecting group indicates a protecting group for the carboxyne group in the case of the aforementioned oxalo group. ) Carboxymethyl group, 1
-carboxy-2-methyl-1-proenyl group, -carboxy-2-methyl-2-propenyl group, etc.; Furthermore, there are no particular limitations on the protecting group for the amide group of the azetidinone ring, and it is a general protecting group for the amide group. Preferred are trialkylsilyl groups such as trimethylsilyl and t-butyldimethylsilyl, and triarylsilyl groups such as triphenylsilyl. - Although there are no particular limitations regarding the steric configuration of the general formula (ll), preferred C is an azetidinone derivative having a steric configuration that can lead to a configuration similar to the 5,6,8 position of chenamycin.R4 When there is an asymmetric carbon in , there is no particular limitation on its steric configuration.

Among the azetidinones having the general formula (lie), R1 is preferably t-butyldimethylsilyl, methoxymethyl,
1-ethoxyethyl, chloroacetyl, trimethylsilyl, noceranitropendyloxycarbonyl, allyloxycarbonyl, 2゜2.2-IJ chloroethoxycarbonyl, t-butoxycarbonyl group, and R2 and R3 are hydrogen atoms. , X and Y are oxygen atoms or sulfur atoms; R4 is benzyl, phenyl,
2-(p-Nitrobenzyloxy-nitroquine)ethyl, 2-(t-butyldimethylsilyloxy)-1-
Methyl ethyl, 2-(p-nitrobenzyloxycarbinyl)aminoethyl, 2-acetamiP-ethyl, 2-acetamido-1-methylethyl, 2-[:2-(p-nitrobenzyloxycarbinyl)ethoxy2-1- Methyl ethyl, 1-(p-nitrobenzyloxycarbonyl)pyrrolidin-3-yl, 1-acetylpyrrolidine-3
-yl, 1-[,N-(p-nitrobenzyloxycarbonyl)acetimidoyl]pyrrolidin-3-yl, 1
- (N-(p-nitrobenzyloxycarbonyl)formimidoyl]pyrrolinon-3-yl, 3.4,
5.6-tetrahydro-2-methyl-1,3-pyrimidin-5-yl, 3,4,5.6-tetrahydro-2-methyl-3-(p-nitrobenzyloxycarbinyl) 1
．． 3-pyrimidin-5-yl, 1-[1-(p-nitrobenzyloxycarvinyl)pyrrolidin-3-yl]ethyl, 1-(1-acetylpyrrolidin-3-yl)ethyl, 1-1:1- CN-(1)-nitrobenzyloxycarbinyl)formimidoyl]pyrrolidin-3-yl]ethyl, 1-(i-(N-(p-nitrobenzyloxycarbinyl)acetimidoyl)pyrrolidin-3-yl ] Ethyl, 1-(4-CN-(p-nitrobenzyloxycarbonyl)formimidoyl 3morpholine-2-
yl]ethyl, 1-(4-(N-(p-nitrobenzyloxycarvinyl)acetimidoyl 3morpholine-2
-yl]ethyl, 1-[:4-(p-nitropenzyloxycarbonyl)morpholin-2-yl]ethyl, 1-
(4-acetylmorpholin-2-yl)ethyl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, 2-chenyl, 3-chenyl, 1,2.4-triazol-3-yl, thiazol-2-yl, etc., and R5 is a hydrogen atom, p-nitrobenzyloxycarbonylmethyl, p-nitrobenoloxyoxalyl, 2-
Methyl-1-(p-nitropenoloxycarbonyl)
-1-7'lopenyl, 2-methyl-1-(p-nitrobenzyloxycarbinyl)-2-propenyl, 2-methyl-1-(phthoxycarbonyl)-1-propenyl, 2-methyl-( 0-nitrobenzyloxycarbonyl)-1-propenyl, 2-methyl-1-nophenylmethyloxycarbonyl-1-propenyl, 2-methyl-1
-allyloxycarbonyl-2-propenyl, 2-methyl-1-(2,2゜2-) IJ Chlorethyloxycarbonyl)-2-flobenyl, 2-methyl-1-)
IJ methylsilyloxycarbonyl-2-propenyl, t-butyldimethylsilyl group, etc.

A compound having the general formula (Il) is a compound having the general formula (Ill'-
A compound having r (wherein R1 and R5 have the same meanings as described above, R6 is a freeing group, formyloxy, acetoxy,
Lower acyloxy groups such as propionyloxy; arylcarbonyloxy groups such as hendiyloxy, naphthoyloxy, p-methoxybenzoyloxy; sulfonyloxy groups such as methylsulfonyloxy, ethylsulfonyloxy, benzenesulfonyloxy, p-toluenesulfonyloxy Acylthio groups such as niacetylthio, propioni, ruthio, benzoylthio, and 0-methylbenzoylthio: represent halogen atoms such as chlorine, bromine, and iodine. ) Compounds with the general formula are prepared by total reaction.

RRR5iCRRC-YRQl [l (wherein p, 2, R5,
represent the same or different methyl, ethyl, t-butyl, or phenyl groups. ) The reaction between the compound (Ill and (IID) is a trifluoromethanesulfonic acid triallysilyl ester, such as trifluoromethanesulfonic acid trimethylsilyl ester, or a boron trifluoride ether complex, zinc iodide, titanium tetrachloride, tin chloride, aluminum chloride, etc. The reaction is carried out in an aprotic solvent such as hexane, benzene, toluene, methylene chloride, chloroform, 1,2-dichloroethane, tetrahydrofuran, dioxane, acetonitrile or diethyl ether in the presence of a catalyst selected from -20°C to 80°C, and the reaction time is 1 hour to 7 days.When R5 is a trimethylsilyl group, after the reaction is completed, it can be easily treated with water or with potassium fluoride in alcohol. i
The CN-silyl group can be eliminated.

Further, when R1 is a protecting group for a hydroxyl group in the general formula (I), a compound in which R1 is a hydrogen atom can be obtained by removing the protecting group according to a conventional method.

This new method of introducing an acetate group into the 4-position of azetidinone by reacting the α-silylacetate mark with a 4-position heterosubstituted azetidinone compound (nlTh) in the presence of trimethylsilyl fluoromethanesulfonic acid has the following characteristics: has. Recently (A, G, M, Bar
re'ut and? -Q+xayle.

Chem, Comm, 1981, 1076)
A new method has been developed in which a 4-acetoxyazetidinone compound is subjected to a total reaction with silyl enol ether or 0-silyl ketene acetal to generate carbon-carbon viscosity at the 4-position of azetidinone. O-silyl ketene acetal is obtained by treating a ketone or ester with a strong base to deprotonate it and then silylating it with trimethylchloride.

In this method, if the starting ketone or ester has a base-labile functional group in its molecule, it is usually difficult to synthesize the desired silyl enol ether or 0-silyl ketene acetal. Additionally, in general, 7lyl ninol ether or Q-nolyl ketene acetal is easily hydrolyzed and returns to its original ketone or ester, so care must be taken when handling it.

The present inventors have shown that the ester, thioester, amyl, which is easily derived from α-silylacetic acid ((), cedar barks the carbon-carbon bond at the 4-position of azetidinone in exactly the same way as the 0-silyl ketene acetal described above. The α-silylacetic acid ester, thioester, or amide used in this reaction can be prepared by reacting α-silylacetic acid chloride with an alcohol, mercaptan, or amine, or by reacting α-silylacetic acid with an appropriate alcohol, mercaptan, or amine. It can be obtained by reacting in the presence of a condensing agent.Since the reaction conditions are harmonious, α-silylacetic acid derivatives having various functional groups can be obtained, and the stability of the compound is also good, making it easy to handle and use by chromatography. Therefore, azetidinone (Il), which is difficult to synthesize by the method of A, G, M, Barrett, etc., can also be synthesized in one step using an appropriate α-silylacetic acid derivative.

New azetidinone derivatives having the general formula CIIe obtainable according to the invention are illustrated in Table 1. However, this does not limit the present invention.

Table 1 The abbreviations in the table are shown below.

PNZ: p-nitrobenzyloxycarbonyl group O
NZ: o-nitrobenzyloxycarbonyl group PN
B: p-nitrobenzyl group ONB 20-nitrobenzyl group TMS: trimethylsilyl The azetidinone derivative having the general formula (II Th) obtained by the basic invention can be led to a carbapenem derivative by the method shown below.

That is, if R5 of the general formula (Il is a hydrogen atom, the nitrogen atom of the nitrogen atom is an alkoxyoxalyl group + S) and the compound (■
and when R5 is a 1-alkoxycarbonyl-2-methyl-2-propenyl group, the compound CVD is treated with a base to form the 1-alkoxycarbonyl-2-methyl-1-propenyl compound ~1, and then oxidized with ozone to form the compound ( Leads to ■ (■) (■) [In the formula, R4, R2, R5, P, ", X and Y have the same meanings as described above. R represents a protecting group for a carboxy group.] Compound (■ By reacting with triethyl phosphite, it is possible to lead to the carbapenem derivative (■). If necessary, the protecting group R1 of the hydroxyl group of compound (Viij)
, H4 contains a protecting group for the amine group, and when the protecting group and the protecting group R for the carboxyl group are removed by a conventional method ((therefore, when removed, a carbapenem derivative exhibiting a strong antibacterial activity typified by chenamycin can be obtained.

As is clear from the above, compounds having the general formula fil are important intermediates in the synthesis of useful carbapenem derivatives.

Reference examples and examples of the present invention are shown below.

Example 1 (3S,4R)-3-C(R1-1-tert-butyldimethylsilyl quinethyl)-4-[C(31-1-
(p-nitrobenzyloxycarbonyl)pyrrolinone-
3-ylthio]carbonylmethyl]-2-azetidinone (3R,4R)-4-acetoxy-3-((R1-1-
tert-butyldimethylsilyloxyethyl]-1-
()limethylsilyl)-2-azetidinone 180+W(
0,50 mmole), (Sl-1-(1)-=trobenzyloxycarbonyl)-3-(toIJ methylnrylacetylthio)pyrrolidine 414 mV (1,00
mmole ) was dissolved in 3 mi of methylene chloride, then 15 mV (0.07 mmole ) Yr of trifluoromethanesulfonic acid trimethylsilyl ester was added, and the mixture was allowed to stand at room temperature for 15 hours. After the reaction is complete, pour the reaction solution into aqueous sodium bicarbonate solution (while stirring. Separate the organic layer, wash with water,
After drying, the solvent is distilled off. The obtained residue was separated by preparative thin layer chromatography [developing solvent: chloroform-ethyl acetate (6:1)], and the obtained solid 18
5 (yield 67%) was recrystallized from hexypone-ethyl acetate to obtain a pure product having a melting point of 104-106°C.

IR spectrum CHCt3CrfL-1:aX 3410.1775.1685 NMR spectrum (CDC/!, 3) δppm: 0.
08 (61 (, s), 0.88 (9H, s), 1.19
(3B.

d, J=6Hz), 1.7-2.5 (2H, m),
2.7-3.0 (2H, m), 3.53 (2H, t, J
=7Hz), 32-4.4 (6H, m), 5.19 (2
H,s), 6.15 (LH.

br ), 7.42 (2H, d), 8.20 (2H,
d) Example 2 (3R,4R)-4-acetoxy-3-(fRl-te
rt -butyldimethylsilyloxyethyl) -1-
(1-methoxycarbonyl-2-methyl-1-propenyl)-2-azetidinone 1.04 F (2,61 mm
ole), )rimethylsilylacetic acid pennor ester 1.74 f (7,84 mmn1e) was dissolved in methylene chloride 121e, and then trifluoromethanesulfonic acid trimethylsilyl ester 50q (0,23 s
mole) and left at room temperature for 7 days. The entire reaction solution was washed with sodium bicarbonate, and the organic layer was separated, washed with water, dried, and then the solvent was distilled off. The obtained residue is separated and purified by liquid chromatography using Rover Column-B (E, manufactured by Merck & Co.). Elution was carried out with hexane-ethyl acetate (4:1) mixed solvent, starting material azetidinone 109 vty (8.6%)
) was recovered, and then the target product 693 m9 (yield 55
%) was obtained as an oil.

Engineering F, Spectrum V company foot '5 cn-': 1740
(br,) NMR extinction (CDC43) δppm
: 0.09 (6H, s), 0.89 (9H, S), 1
．． 23 (3H.

d, J = 6.5 Hz), 1.85 (3H, s
), 2.10 (3JS), 2.67 (2H, d, J=7
Hz), 2.85 (IH.

ad, J = 6.5, 2.5 Hz), 3.6
4 (3H, s), 39-4.5 (2H, n), 4.90
(IH, d, J=12Hz), ), 06 (I H+
d + J = 12 Hz), 7.28 (5I4.
s) Example 3 (3R,4R)-4-acetoxy-3 described in Reference Example 1
-(fRl-1-tart-butyldimethylsilyloxyethyl)-1-trimethylsilyl-2-azetidinone 1.109 (3,06 mmole) and trimethylsilylthioacetic acid S-phenyl ester 961 mg (
20 ml of methylene chloride (4,29 mmole); Cool the solution to -20°C, add 0.07 mt (0.0
,32mmole) Add f. 4 at -10° to 5°C
After stirring for 5 hours, water is added to terminate the reaction. Wash the methylene chloride layer with diluted sodium bicarbonate solution and saturated saline. The residue after solvent distillation was dissolved in 2.5 ml of emenol, and
Add 58 ml (1,00 mmole) of Hicalum and stir at room temperature for 15 hours. The reaction solution was diluted with ethyl acetate, washed with water and saturated brine, and the solvent was distilled off. The residue is purified using a Roper column (E, manufactured by Merck & Co.). The portion eluted with a hexane-ethyl acetate (2:1) mixed solvent was collected to obtain 961 mg (83% wicking) of the desired product as crystals.

Recrystallization from hexane gave needle-shaped crystals with a melting point of 94-95°C.

Elemental analysis value Calculated value as C4, H29NO5S81:
C, 60, 12: H, 7, 70: N, 3.69: S,
8.45 actual value: C, 60, 1): H, 7, 72; N
, 3.67: S , 8.54 from s hector νnuJ
01cI7L-1:aX 3160.3000, 1767.1726.1703N
MR spectrum (CDC73) δppm: 0.08 (
6H, s), 0.88 (9H, s), 1.21 (3H
.

d, J=6Hz), 2.7-3.2 (3H, m),
4.0 (IH.

m), 4.18 (IH, quintet, J=6Hz)
, 6.10(LH,br,s), 7.4(5I(,s)
Example 4 (33,4R)-4-[(2-(p-nitrobenzyloxycarbonylamino)ethylthio]carbonylmethyl)-3-CtPJ-1-(p-nitrobenzyloxycarbonylamino)ethylthio2- Azetinonone (3R,4R)-4-acetoxy-3-((R1-1-
(p-nitrobenzyloxycarponyloxy)ethyl)-1-()limethylsilyl)-2-azetidinone 30
W (0,051 mmole) and S-(:2-(N
-(p-nitrobenzyloxycarbonyl)-N-(trimethylsilyl)amine]ethyl](trimethylsilyl)ethanethioate 47 ml (0,106 mmol
Dissolve e) in 0.5 ml of methylene chloride, and add 3 (0,014 mmole) f of trimethylsilylmethanesulfonic acid trimethylsilyl ester under a stream of phoneme. After leaving it at room temperature for 24 hours, the reaction solution? : Pour into 5 liters of sodium bicarbonate solution under cooling and stirring, and stir for 10 minutes.

Extract with ethyl acetate, wash with saturated brine, dry, and then evaporate the solvent. The residue was purified by preparative thin layer chromatography on silica gel [developing solvent: benzene-ethyl acetate (1:2)] to obtain 29 mq (yield: 69%) of the desired product as an oil.

IRX Pect/'M"HC'5crrL-':
3460, 3420°aX 1763.1750 (sh,), 1730 (sh,),
1685NMR spectrum (CDC13) δppm:
1.40 (3H, d, J=6Hz), 2.6-3.6
(7H, m), 3.91 (LH, m), 5.13 (2H
, s), 5.19 (2E.

S), 4.9-5.5 (2H, m), 6.67 (I
H, br, s), 7.45 (2a, a), 7.48 (2
1(,d), 8.16(2I(.

d), 8.19 (21'l, d) Example 5 -2-azetidinone (3R,4Fl)-4-acetoxy-3- [(published-1-
(p-nitrobenzyloxycarbyloxy)ethyl)-1-(trimethylsilyl)-2-azetidinone 53
ml (0,125 mmole) and (Sl-1-(
p-nitrobenzyloxycarbonyl)-3-(J-lymethylsilylacetylthio)pyrrolidine 1031)Wi
(0,25 mmole) was dissolved in 1 mt of methylene chloride, and this solution was added with 5 μm of trifluoromethanesulfonic acid trimethylsilyl ester (0,023=ole).
f and the mixture was kept at room temperature under a nitrogen atmosphere for 28 hours.

After the reaction, dilute with chloroform and wash with diluted sodium bicarbonate solution.

After drying, the solvent was distilled off, and the resulting residue was dissolved in 3 ml of tetrahydrofuran-water (4:1), 3η of pyridine-p-toluenesulfonate was added, and the mixture was allowed to stand at room temperature for 30 minutes. Ethyl acetate was added, washed with water, dried, and the solvent was distilled off. The resulting residue was subjected to preparative thin layer chromatography on silica gel [developing solvent: benzene-ethyl acetate (2:1)].
Purification was performed to obtain the target product 67 (yield: 87) as a solid. Recrystallization from benzene was performed to obtain plate crystals having a melting point of 54 to 56°C.

Elemental analysis value C27H2801) Calculated value as N4S:
C, 52,59:H, 4,58:N, 9.09:S, 5
．． 20 Actual value: C, 52, 88; 3, 4.54; N
, 8.93: S, 5.47ER spectrum νc1(ctz-1・max ”α.

3410.1760.1688 The specific optical rotation [α] is also 5' + 5.3° (C = 0.55
, cHct3) NMR spectrum (CDC43) δp
pm: 1.44 (3H, d, J=6Hz), 1.6~
2.7 (2H, m), 2.7~4.5 (10H, m
), 5.19 (2H, s), 5.22 (2H, s),
6.35 (IH, br, ), 7.47 (2I (.

d), 7.51(2H,'d), 8.20(4I(,d
) Example 6 Benzyloxycarbonyl)acetimidoyl]pyrrolidin-3-ylthio]carbonylmethyl]bonyloxy)ethyl2-azetidinone (3R,4R)-4-acetoxy-3-C(R1-1-(p-nitrobene) Noroxycarbonyloxy)ethyl)-1-()limethylsilyl)-2-azetidinone 50 Tnry (0,1)
8 mmole) and (Sl-1-(N-(p-nitrobenzyloxycarbonyl)acetimidoyl)-3-
()Limethylsilylacetylthio)pyrrolidine 103■
(0.24 mmole) was dissolved in 0.8 mmole of methylene chloride, and 63 mmole (0.28 mmole) of trifluoromethanesulfonic acid trimethylsilyl ester was added thereto, and the mixture was allowed to stand at room temperature under a nitrogen atmosphere for 14 hours. The reaction solution was cooled on ice, and 5 ml of aqueous sodium bicarbonate was added thereto, followed by stirring for 10 minutes. After extraction with ethyl acetate, washing with water, and drying, the solvent was distilled off, and the resulting residue was purified by preparative thin layer chromatography on silica gel [developing solvent: benzene-ethyl acetate (1:2)] to obtain the desired product 45. (2) (yield 58%) was obtained as an oil.

IR spectrum CHCt5 knee 1: 3380,16
80ma=(NMR spectrum # (CDC45) δppm: 1.4
1(3!(, d, J=6.5Hz), 1°7~2.5(
2H.

m), 2.27 (3H, s), 2.84 (2H, d
, J=7Hz), 3.01(LHldd, J=8+
2.5Hz), 3.3-4.2 (5H, m), 5.1 (
LH, m), 5.17 (2H, s), 5.20 (2H,
s), 6.32 (L H, br, ), 7.51 (
4H, d), 8.17 (2H, d), 8.20 (2H,
d) Example 7 Tyrsilyloxy)ethyl:] -1-(fRl-1-
(p-nitrobenzyloxycarbonyl)-2-,7'
thyl-'l-propenyl']-4-C (phenylthio)
Cal? Nylmethyl]-2-azetidinone0OPNB (3R,4R3)-4-acetoxy-3-[(Oka-1-
(tar”u-butyldimethylsilyloxy)ethyl]
-1-C(PJ-1-(p-nitropenzyloxycarbonyl)-2-methyl-2-propenyl)-2-azetidinone 358"! (0,69 mmole), S-phenyl() IJ methylsilyl)ethanethiony ) 2
60 m'! (1,16 mmole), trifluoromethanesulfonic acid trimethylsilyl ester 25”q
(0,1)3 mmole) f Dissolved in 12 methylene chloride solution and allowed to stand under nitrogen atmosphere for 41 hours. The reaction solution was poured into dilute 1-basic acid aqueous solution under water-cooling and stirring, and extracted with chloroform. After drying, the solvent is distilled off, and the residue is separated and purified by liquid chromatography using Roper Column B (E, manufactured by Merck & Co.). Elute with a mixed solvent of hexane-benzene-ethyl acetate (6:6:1) to obtain 67 μm of starting material azetidinone (recovered 1
9%: cis: trans = 1 = 2), followed by 30 objects
1 (yield 71%) was obtained as an oil.

Engineering R spectrum shiCHCt3c7IL-1:aX 1750 (sh, ), 1740.1695 specific optical rotation [α
) D-50°C (=l, Q 4 , CHCA3) Nagii B spectrum (CDCl2) δppm: 0.03 (3
H,s), 0.06 (3H,s), 0.85 (9I(
.

S), 1.18 (3H, d, J=6Hz), 1.85 (
3H.

br, s ), 2.86 (LH, dd, J = 15.7H
z), 3.00 (IH, dd, J=5.2.5Hz),
3.20(1)(.

dd, J=15.5.5Hz), 3.9~4.6 (2
H, m ), 4.78 (LH, s), 4.87 (LH
, br, s ), 5.02 (IH, br, ), 5.20
(2H, s), 7.36 (5H.

S), 7.45 (2H, d), 8.16 (2H, d) Example S Lopenzyloxycarponylmethyl)-4-azetidinone (3R,4R8)-4-acetoxy-3-C (PJ- 1
-(tert-butyldimethylsilyloxy)ethyl]
-1-(p-nitrobenzyloxylponylmethyl)
-2-Azetidinone 751n9 (0,156mmol
e), S-phenyl(trimethylsilyl)ethanethimanate 52 mg (0.27 mmole), trifluoromethanesulfonic acid trimethylsilyl ester 6 m9
(0,027 mmole) f Dissolved in methylene chloride and allowed to stand still under a nitrogen atmosphere for 43 hours. The reaction solution was poured into a water-cooled sodium bicarbonate solution and extracted with chloroform.

The oil obtained by distilling off the solvent was separated by preparative thin layer chromatography on silica gel [developing solvent: chloroform-ethyl acetate (10:1)] to obtain the target product s7mq (
Yield 64%)') Obtained as an oil. 18 mg (24%) of starting azetidinone was recovered.

IR spectrum U"H"'5crrt-': 175
0,1690ax NMR (CDCt,) δ ppm: 0.07 (
6H, s), 0.87 (9H, s), 1.23 (3)!
.

d, J = 5.5 Hz), 2.90 (IH, d
d, J=5.5°2.5Hz), 3.12 (2H, d
, J=6.5Hz), 4.08(2H,s), 3
．． 9-4.4 (2H, m), 5.15 (2H.

S), 7.34 (5H, s), 7.36 (2H, d),
8.07 (2H, d) Example 9 Dinone (3R,,4R)-4,-acetoxy-3-((R-1
-(tert-butyldimethylsilyloxy)ethyl]
-1-()limethylsilyl)-2-azetidinone 500
mg (1,39 mmole) and S-phenyl 2
-(trimethylsilyl)propanethioate 662 m
g (2,78 mmole) of methylene chloride 5 me
40 mg (0.18 mmole) of trifluoromethanesulfonic acid trimethylsilyl ester dissolved in
In addition, let stand overnight in a room under a nitrogen atmosphere. After washing the reaction solution with water, the solvent was distilled off, and the residue was dissolved in 2 smg of tetrahydro7ran-water (4:1) and stirred at room temperature for 30 minutes. Acetic ester was added, washed with water, dried, and the solvent was distilled off. The resulting residue was separated and purified using silica gel columnography [eluting with cyclohexane-ethyl acetate (4:1)] to obtain 310 mg of the target compound A. (Yield 57%) and Compound B 135my (Yield 2s%) were obtained as oils.

Compound A: Engineering R spectrum vCHCt5 c! rL-': 34
30, 1765.

ax NMR spectrum (CDCl2) δppm: 0.08
(6!(,'s), 0.87(9H,s), 1.20
(3H.

d, J = 6) 1z), 1.32 (3H<, d, J==
6Hz), 2.7-3.2 (2H, m),
3.94 (LH, dd,, ding = 6.

2 Hz), 4.20 (IH, dq, J=6.5Hz
), 590(IH,br,s), 7.41(5I(,S
) Compound B: IR spectrum k νCHC45Cm-1: aX 3430.1765.1695 NMR spectrum (CDCl2) δppm: 0.08
(6H, s), 0.87 (9H, s), 1.22 (3H
.

d, J=6Hz), 1.32 (3H, d, J=8Hz)
, 2.5-3.1 (2H, m), 3.76 (IH,
dd, J=8°2 Hz), 4.18 (L H, q
uipt, J = 6 Hz), 6.05 (I H,
br,s), 7.41(5H,s) Example 10 (3S,4R)-3-((R1-1-(tert,-butyldume4S)-2-carbamoyl-1-(p-nitropentyloxy carbinyl)pyrrolidin-3-ylthio]carbonyl]ethyl)-2-7zeticinone(3R,4R)-4-acetoxy-3-[(published-1=(
tart-butyldimethylsilyloxy)ethyl]-1
-(trimethylsilyl)-2-azetidine 7550”
? (1,53mmole) and (2S l 4s
) -2-(N,N-His()IJ methylsilyl)
carbamoyl)-1-(p-nitrobenzyloxycarbonyl)-4-(2-'()limethylsilyl)propionylthio]pyrrolidine 1.839 (3,06 mmol
e) in 10 ml of methylene chloride, then 50 ml of trifluoromethanesulfonic acid trimethylsilyl ester
(0.23 mmole) was added and allowed to stand at room temperature for 15 hours. After the reaction is complete, pour the reaction solution into water with stirring. The organic layer is separated, washed with water, dried, and the solvent is distilled off. The resulting residue was subjected to column chromatography using silica gel, and benzene-ethyl acetate (1:2)
Elution with a mixed solvent yielded the target product 7081rNi (yield: 57) as an oil. This product is a mixture of two isomers A and B based on the steric coordination (IC) of the methyl group in the 4-position (f1) chain of azetidinone. Isomer A was separated by chromatography.

Spectral data of isomer A
0.3410+aX 3330.1757.1690 (br,), 1668 spectra (dy-DMF) δppm: 0
．． 08 (6H, s), 0.85 (9H, s), 1.16
(3H.

d, J=6Hz), 1.23(3H, d, J=6.5H
z), 2.0-4.6 (IOH, m), 5.20 (2H
, s), 617 (IH, br, ), 6.67 (2H, b
r, ), 7.47 (2Jd), 8.15 (2I(,
d) Reference Example 1 tert-butyldimethylsilyloxyethyl]-1-
Trimethylsilyl-2-azetinonone (3R,4R)-4-acetoquine-3-[:(PJ
-1-tert-butyldimethylsilyloxyethyl]
-2-Azetidinone 507 (0,174mole) and triethylamine 724.6f (0,244zcle)
)'s Tetrahirofuran 500mA! Add 26.57 (0,244 moles) of trimethylchlorosilane to the solution. The reaction temperature was returned to room temperature and stirred for 2 hours. The deposited precipitate was removed by filtration using Celite, and further washed twice with ether.

The PR and washing liquid are combined, the solvent is distilled off, ether is added to the residue, and the insoluble matter is removed. The solvent of the P solution is distilled off, and the target object 62
．． :1 (yield: 100%) was obtained as a semi-solid.

I3 spectrum, nu,)ot, -1: 1770,
1745aX N: P1 spectrum (CDCl2) δppm: 0
．． 06 (6H, s), 0.26 (9H, s), 0.85
(9H.

S), 1.19(3)(,d, J=6Hz), 2.03
(3H.

S), 3.07 (LH, dd, J=3.IHz), 4.
13' (IH, dq, J=3.6Hz), 6.04 (L
H,d.

J=IHz) Reference Example 2 Pyrrolidine 55 sodium hydride 182 mt (4,16 mm
After washing with diluted bexane, suspend in 5 ml of ether and add 500 μl of trimethylsilylacetic acid (
3,79 mmole). When the generation of hydrogen gas has subsided, 481 cm (3.79 mmole) of oxalyl chloride is added dropwise to the resulting emulsion while stirring at the same temperature.

After 15 minutes, 500 μ(Sl-3-mercapto-1-(p-nitrobenzyloxycarbonyl)pyrrolidine) (1
, 77 mmole) and ethyldiisopropylamine 2
29 W (1,77 mmole)'f: A solution of 5 mt of methylene chloride was slowly added dropwise.

After stirring at the same temperature for 30 minutes, the mixture was poured into aqueous sodium bicarbonate solution, the organic layer was separated, washed with water, dried, and the solvent was distilled off. The resulting residue was purified by liquid chromatography using a Rover column-Bi (chloroform-ethyl acetate (10:1)) to obtain the desired product 282η (yield 38%) as an oil.

NMR spectrum (CDCl2) δppm: 0.15
(9H, s), 2.30 (2H, s), 1.7-2.5
(2H, m), 3°54 (2H, t, J=6.5Hz)
, 3.1-4.2 (3H, m), 5.20 (2H, s)
, 7.50(2)E.

d), 8.17 (2,, H, d) Reference example 3 Chill 55 sodium hydride 237 mt (5,41 mt
tole) with hexane and add 6.5 liters of ether.

To this suspension, 650 W (4.93 mmole) f of trimethylsilylacetic acid is added while cooling on ice and stirring.

After the generation of hydrogen gas subsided, 626 mt (4.93 mm) of oxalyl chloride was added to the resulting emulsion while stirring at the same temperature.
ole) dropwise. After 15 minutes, 2537 nq (2,30 mmol) of thiophenol was added to the resulting emulsion under water cooling and stirring.
le ) and diisopropylethylamine 298■ (2,
30 mmole) of a 6.5 ml solution of methylene chloride is slowly added dropwise. After stirring at the same temperature for 30 minutes, the reaction solution was poured into diluted sodium bicarbonate solution, the separated organic layer was washed with water, dried, and the solvent was distilled off.

The resulting residue was separated and purified by liquid chromatography using a Rover column-Bt (benzene-hexane (1:1)) to obtain the desired product 206 cm (yield: 40 cm) as an oily substance.

NMR spectrum (CDCl2) δppm: 0.06
(9)1. s), 2.34 (2H, s), 7.30 (5
H,s) Reference row 4 Zetidinone (3S,4R)-3-C(R1-1-tert-butyldimethylsilyloxyethyl)-4-((tsI-1
-(P-nitrobenzyloxycarbonyl)pyrrolinon-3-ylthio]car? A 3 ml methylene chloride solution of 57.7 q (0.105 mmole) of triethylamine and 57.7 q (0.105 mmole) of [nylmethyl]-2-azetidinone was cooled on ice, and 73 μl of p-di)lobenoloxyoxalyl chloride was added under a nitrogen stream. (0.30mm
ole) and stir for 1 hour. The reaction solution was 0.1
Pour into MIJ acid buffer solution (pH 7.2) and wash the organic layer with saturated saline. The residue after the solvent was distilled off was treated with silica gel 1.
32, and the portion eluted with a benzene-ethyl acetate mixed solvent (12:1 to 4:1) was collected to obtain 67.8 mt (yield: 83%) of the desired product as an oily substance. .

IR spectrum CHCl30-1:aX 1800.1754.1695.16821-IMR spectrum (CDCl2) δppm: 0.03 (3H,
s), 0.13 (3H, s), 0.85 (9H.

S), 1.23 (3H, d, J=6Hz), 1.5-2
．． 5 (2H, m), 3.0-5.0 (10H, m)
, 5.23 (2JS), 5.43 (2H,s), 7.
50 (2H, d, J=8Hz), 7.56 (2H, d
, J=8Hz), 8.22 (4H.

d, J=8Hz) Reference row 5 (5R,63)-6-((R1-1-tert-butyldimethylsilyloxyethyl)-2-[:(S+-1-
(p-nitrobenzyloxycarbonyl)pyrrolidine-
3-ylthio]carbapen-2-em-3-carboxylic acid p-nitrobennorester (33,4R)-3-(
(El-1-tert-butyldimethylsilyloxyethyl)-1-(p-nitrobenzyloxyoxalyl)
-4-[:(sl-1-(p-nitrobenzyloxycarvinyl)pyrrolidin-3-ylthio]carbonylmethyl]-2-azetidinone 190 mg (0.25 mmol)
e), triethyl phosphite 2somy (1,smmo
la ), and hy-r-quinone l Om9 (0,09
mmole ) in 20 ml of toluene at 95°C for 15 min.
Heat for an hour. The raw material disappeared on thin layer chromatography, and (36,4R)-3-C(R1-1-tert-butyldimethylsilyloxyethyl)-1-CI-(p-
nitrobenzyloxycarbinyl)triethoxyphosphoranylidenemethyl)-4-((s+-t-(p-nitrobenzyloxycarbinyl)pyrrolinon-3-ylthio]carbonylmethyl]-2-azetidinone and the desired carbapenem Compounds are recognized.

The solvent and excess triethyl phosphite were distilled off under reduced pressure, and 20ml of toluene was again added to the remaining oily substance, and the mixture was heated at 95°C for 5 minutes.
The mixture is heated for 7 hours to terminate the cyclization reaction of the phosphorane compound. The shallow residue after solvent distillation is purified using a Rover column. The fraction eluted with a mixed solvent of benzene-ethyl acetate (2:1) was collected, and 151.5 cm (yield: 83) of the desired product was obtained as an oily substance.

IR spectrum HCt3cIrL-': 17
70, 1695ax NMR spectrum (CDCtρδppm: 0.07(
6H, s), 0.87 (9H, s), 1.24 (3)
1゜d, J=6H2), L, S~2.8 (2H, m
), 2.8-4.5 (IOH, m), 5.14 (IH,
d, J=14Fiz), 5.18 (2H, s), 5.4
1 (IH, d, J = 14Hz), 7.46 (2H, d,
J=9Hz), 7.61 (2H, d.

J = 9Hz), 8.17 (4H, d, J = 9Hz) Reference row 6 Thio) carbonylmethylcou-2-azetidinone (3S,
4R)-3-C(Pi-1-tart-butyldimethylsilyloxyethyl)-4-C(phenylthio)carbonylmethylcou-2-azetizonone 747■(1,97m
mole) and triethylamine 398■ (3,94m
A solution of 20ml of methylene chloride was cooled on ice.
Under a nitrogen stream, add 960 mg (3.94 mmole) of p-nitrobe/zyloxyoxalyl chloride,
Stir for 2 hours. 0.1 M IJ acid buffer (pH 7.2) is added to the reaction solution to terminate the reaction, and the organic layer is washed with water. After drying, the solvent is distilled off and the residue is subjected to column chromatography using 15 grams of silica gel. Collect the part eluted with hexane-ethyl acetate (6:1 to 3:1),
Target product of 1.0329 (yield: 89)? Obtained as an oil.

IR spectrum νCHCt5 cm-': ax 1805.1757, 1699, 1609, 1522°NMR spectrum (CDC7,3) δppm Knee 0.
02 (3H, s), 0.04 (3H, s), 0.08 (
9H,s), 1. ], 4 (3H, d, J=6Hz), 3
．． 1) (LH, ad, J=15.8Hz), 3.35(
LH,t.

J=3Hz), 3.43(1)1. dd, J=15.4
Hz), 4.29 (qd, J=6.3Hz), 4.64
(IHlddd.

J=8.4.3Hz), 5.37(2H,s), 7.5
2 (2H, d, J=8Hz), 8.16 (2H
, d, J = 8Hz) Reference example flusilyloxyethyl)-2-(phenylthio)carbapen-2-em-3-carboxylic acid p-nitrobenzyl ester (33,4R)-3-C(R1-1-tert -butyldimethylsilyloxy)-1-(p-nitrobenzyloxyoxalyl)-4-[:(phenylthio)carbonylmethyl]-2-azetidinone 1)4 m9(0,
194 anole) and 258 mg (1.55 mmole) of triethyl sulfite were dissolved in 10 ml of toluene, a catalytic amount of hydroquinone was added, and the mixture was heated at 100°C under a nitrogen stream.
Heat for 18 hours. Obtained by distilling off the solvent under reduced pressure.

The residue was chromatographed using a Lorber column (E, manufactured by Merck & Co., Ltd.) [Developing solvent: hexane-acetone (3
, 5:1) to obtain 95 cm of the desired product (yield: 88) as a solid. Recrystallization was performed from an acetone-hexane mixed solvent to obtain colorless needle crystals with a melting point of 144 to 145.5°C.

Elemental analysis value Calculated value as C28H34N206SS1: C, 60, 62: H, 6, 18: N, 5.05: S
, 5.78 Actual value: C, 60, 50: H, 6, llN
, 4.77:S, 5.91) R spectrum synuJ0
1cIrL-1:ax 1777. 1697.1524 NMR spectrum (CDCl2) δppm: 0.06
(6H, s), 0.83 (9H, s), 1.1 D (
3H1d, J=6Hz), 2.63(2H,d, J=
10Hz]・, 3.05 (IH, dd, J=4.2H
z), 4.04 (LH.

dd, J = 10, 2 Hz), 4. i'+
(IH, dq+J=4+6 Hz), 5.22 (IH
,d,,1i=14H2),5.50(1g,ci,J
=14Hz), 7.2-7.7 (5H, rrr),
7.64 (2H, dlJ=9Hz), 8.19 (2H,
d.

J=9Hz) Reference Example 8 Thioate (CI(ρ3SICH2CO8CH2CH2NHPNZ
2-(p-nitrobenzyloxycargonylamino)ethanethiol 512 μm (2,00 mmole), trimethylsilylacetic acid 264 μm (2,00 mmole),
Dicyclohexylcarbodiimide F455 mg (2,20
mmole ), 4-dimethylaminopyridine 10η
was dissolved in benzene 10s + 13, and dissolved at room temperature under a nitrogen stream for 5
．． Stir for 5 hours. Add 100 m9 of water and stir for 10 minutes to decompose excess dicyclohexylcarbodiimide. Insoluble matter was removed by filtration, and the filtrate was passed through a silica gel 3F column. The mixture was flushed with a mixed solvent of benzene-ethyl acetate (1:1), and the collected solution was evaporated under reduced pressure. Low 9 residue
- Purification by chromatography using column B, eluting with a hexane-ethyl acetate (2:1) mixed solvent to obtain the target product 455rn9 (yield 61%) as crystals. Recrystallized from hexane-benzene mixed solvent, melting point 49-50
A pure product with ℃ was obtained.

Elemental analysis value Calculated value as C15H2°N205SS1: C, 48, 63; H, 5, 98: N, 7.56; S
, 8.65 actual value: C, 48, 53: E, 6.28:
N, 7.44:S, 8.67IE (spectrum ν model number"art-': 3340.1719.166O NMR spectrum (cDcz3) δppm: 0.15
(9H, s), 2.32 (2H, s), 2.6-3.6
(4H, m), 5.18 (2H, s), ~5.2 (I
H, br, ), 7.48 (2EI, d), 8.2o (
2a, a) Reference Example 9 Trito-5-(2-(p-nitrobenzyloxycargonylamino)ethyl](trimethylsilyl)ethanethioate 4
1) n9(0,1)1 mmole), bis(trimethylsilyl)trifluoroacetamide 86■(0,33m
mole), 4-dimethylaminopyricne (1) was dissolved in 1.3 rni of tetrahydro7rane and left to stand at room temperature under a nitrogen stream for 30 hours. After the reaction is complete, the solvent is distilled off under pressure at room temperature, and the residue is dissolved in benzene-ethyl acetate (10:1) and quickly passed through a 300-inch column of silica gel. The solvent was distilled off under reduced pressure to obtain the desired product 47 (yield 96%) as an oil.

IR spectrum 1) qcm-': 1702,
1678aX NMP, spectrum (CDC73) δppm: 0.1
3 (9H, s), 0.28 (9H, s), 2.30
(2H.

S), 2.7-3.5 (4H, m), 5.20 (2
H, s), 7.48 (2H, d), 8.19 (2H, a
) Reference Example 10 Zetidinone (3s, 4R)-4-C[:2-(p-nitrobenzyloxycarponylamino)ethylthio]carbonylmethyl, l-3-((Fil-1-(p-nitrobenzyloxycarbonyl) oxy)ethyl-2-azetidino/3
58■ (Q, 449 mmole) to methylene chloride 8
184 μg (1,82 mmole) of triethylamine and 443 mg (1,82 mmole) p-nitrobenzyloxyoxalyl chloride were dissolved in 100 μg (1,82 mmole) of triethylamine while stirring at 0°C.
mmole). After stirring at the same temperature for 1 hour,
The reaction solution was diluted with 0.1 M phosphate buffer (pH 7,2) at 2C.
1 g K was removed, the organic layer was separated, and the aqueous layer was further extracted with methylene chloride. The organic layers are combined, washed with brine, dried, and the solvent is distilled off. The residue was subjected to column chromatography using silica gel 52 and eluted with a mixed solvent of hexane-ethyl acetate (1:1) to obtain the desired product 351 (yield 73%). : Obtained as an oil. Further elution was carried out with a hexane-ethyl acetate (1:3) mixed solvent to obtain 75 μm of starting material.
(21%) was recovered.

IR spectrum v"Ct5c!rL-': 18
08, 1749.

ax 1718 (br,), 1700 (sh,), 1682 (
sh,) NMR spectrum (cDc13) δppm:
1.40 (3H, d, J=6.5Hz), 2.7-3.
7 (7H.

m), 4.5 (IH, m), 5.13 (2H, s), 5
．． 19 (2H, s), 5.35 (2H, s), 4.9~
5.4 (2H.

m), 7.43 (2H, d), 7.46 (2a, a),
7.50 (2B, d), 8.15 (2H, d), 8.1
7(4H,a) Reference Example 1) (38,4R)-4-[(2-(p-nitrobenzyloxycarnylamino)ethylthio]carbonylmethyl)-3-((R1-1-(p-nitro benzyloxycarbonyloxy)ethyl) -1-(p-nitrobenzyloxyoxalyl)-2-azetidinone 230 m9
(0.29 mmole) and triethyl phosphite 287
ms+ (1,73mmole) f toluene 23m
1 in a nitrogen atmosphere at 90° C. for 1 hour. The solvent and volatile substances are distilled off at the same temperature under reduced pressure, and to the resulting residue are added 8 TIPy of HyP quinone and 10 ml of toluene, and the mixture is heated at 100° C. for 44 hours under a nitrogen atmosphere. After the reaction is complete, the solvent is completely distilled off under reduced pressure and the resulting residue is purified using a Rover column. Elute with benzene-ethyl acetate mixed solvent to obtain crystalline target product 90 mq, (yield 40%) t
-4. Recrystallization was performed with a mixed solvent of ethyl acetate-benzene-hexane to obtain prism crystals with a melting point of 148 to 150°C.

Elemental analysis value Calculated value as C34H51016N5S:
C, 53,33:H, 4,08:N, 9.15:S,
4.19 actual measurement value: C, 53, 19:B, 4.07:N
, 9.13:S, 4.43IR spectrum νC””5
cfrL-1: 3450, 1780.

ax 1740 (sh,), 1718.1700 (sh,) Specific optical rotation [α几5+66° (c=o, s 1. cHct
3) NMR spectrum (CDCl2) δppm: 1.
47 (3H, d, J=6Hz), 2.7~3.7 (7
H, m), 4.2o (IH, m), ~5.1 (IH, m
), 5.16 (2H.

S), 5.22 (2H, s), 5.18 (L H, d
, J=14Hz\5.47 (IH, d, J=14H
z), 7.45 (2H, d), 7.49 (2a, a),
7.60 (2H, d), 8.20 (6I(.

d) Reference Example 12 (3s, 4a)-4-C((s+-1-1:N-(p-
Nitrobenzyloxycarbonyl)acetimidoyl]
pyrrolidin-3-ylthio]carbonylmethyl]-3-
((R1-1-(p-nitrobenzyloxycarbonyloxy)ethyl)-L-((p-nitrobenzyloxy)oxalyl-2-azetidino(3s, 4l-4-C
[:(s+-1-1:N-(p-nitrobenzyloxycarbonyl)acetimidoyl)pyrrolidin-3-ylthio]calnylmethyl]-3-([B-1-(p-nitrobenzyloxycarbonyloxy) ) Ethylcou 2-
Azetinonone 150 m9 (0.23 mmole)
was dissolved in 5 m of tetrahydrofuran, and under a nitrogen stream,
While stirring at -78°C, add 0.15 ml of i5% n-butyllithium hexane solution! (0.24 mmole
) Drop f. After stirring for 2 minutes, p-nitrobenoloxyoxalyl chloride 84rn9 (0.34m
Add mole).

After stirring for 4 minutes, 7 rul of 0.1 M +) acid buffer (PH7,1) was added to the reaction solution, and the mixture was extracted with ethyl acetate.

After drying, the solvent is distilled off and the residue is subjected to column chromatography using silica gel 42. Elution with a mixed solvent of be/zene-ethyl acetate (1:5) yielded 61m9 of the target product (yield 31%)'! Obtained in oil form.

IR spectrum, CHCl3cTL-1°ax 1810.1753.1682 (br,) NMR spectrum (cDcz3) δppm: 1.42 (3H, d,
J=6.5Hz), 1.8-2.5 (2H.

m), 2.26 (3H, s), 2.8-4.2 (8H
, m), ~4.5 (IH, m), 5.17 (2H, s
), 5.21 (2!(.

S), 5.37 (2H, s), ~5.2 (LH, m),
7.52 (6H, br, d), 8.15 (2E, d)
, 8.19 (4H,d) Reference Example 13 Stell(3s,+R)-3-(tn-x-(p-nitrobenzyloxycarbonyloxy)ethyl, 1-4-[[(s
+-1-(p-nitrobenzyloxycarbonyl)pyrrolicin-3-ylthio]carvinylmethyl) -1-(
128 m9 (0,155 mmole of p-nitrobenzyloxyoxalyl)-2-azetidinone, 155 mg (0,934 mmole) of triethyl phosphite, and 7 mmole of hydroquinone (0,06 mmole) were dissolved in 13 m1 of toluene and heated at 90° under a nitrogen stream. Heat for 1.5 hours. When the raw materials have disappeared, the solvent and excess triethyl phosphite are distilled off under reduced pressure, and the resulting residue is dissolved again in 13 g of toluene and heated at 100° C. for 80 hours under a nitrogen stream. The solvent is distilled off and the product is separated and purified using a Roper column. Elution with a mixed solvent of ethyl acetate-pe/zene (1:1) gave 69.6 ml of the desired product (yield 56.6%) as an oil.

IR spectrum νCH”'S C7rL-': 1
778, 1745.

aX 1695.1690 (sh,) NMR spectrum (CDC23) δppm: 1.47
(3H, d, J=6Hz), L7~2.7 (2H, m
), 2.9-4.5 (10H, m ), 5.18 (
2H, s), 5.21 (2H, s), 5.19 (IH,
d, J=14Hz), 5.45(IH, d, J=14H
z), 7.47 (4H, d), 7.58 (2H, d),
8.17(6H,a)□Reference Example 14 Lucilylacetylthio)pyrrolisine (Sl-3-mercapto-1-(N-p-nitrobenzyloxycarbinyl)acetimidoyl)pyrrolisif 1.40 f (4 , 33 mmole) was dissolved in Cef 281 and heated at 10°C.
m9 (4,34 mmole), N,N'-socycloheylcarbodiimide 980 # (4,75 mmole
le) and dimethylaminopyridine to 1
Stir for 3 hours. Water Q, add 5 ml f and 1 at room temperature
After stirring for 0 minutes, the solids were removed by filtration. Solution F was passed through a column of 4F of silica gel, and the column was further flushed with a mixed solvent of benzene and ethyl acetate (3:2).

The eluates are combined and the solvent is distilled off under reduced pressure at room temperature, and the resulting residue is purified by chromatography using a Rover column Bi. Elution with a mixed solvent of ethyl acetate and benzene (1:1) gave 937 ml of the desired product (yield: 49) as an oil.

Engineering R spectrum 1) qcrn-': 1670,1
550ax NMR spectrum (CDCl2) δppm: 0.16
(9H, s), 1.6-2.8 (2H, m), 2.
30 (5H, s), 3.3-4.2 (5H, m),
5.17 (2H.

S), 7.51 (2a, d), 8.15 (2a, d) Reference Example 15 (3s, 4R)-3-(:(n-1-(p-nitrobenzyloxycar?nyloxy)ethyl: ]-4-CC(
Sl-1-(p-nitropenzyloxycaryl)pyrrolidin-3-ylthio]carbonylmethyl, l-1-
(p-nitrobenzyloxyoxalyl)-2-azetidinone (3S,4R)-3-1: (io1-(p-nitrobenozyloxycarbonyloxy)ethyl)-4-(Cts
+-1-(p-nitropenzyloxycarbonyl) Hio +) , :/No-3-ylthio]cargonylmethyl]-2-azetidinone 182K (0,295mm+1e
) was dissolved in 10 m/m of methylene chloride, stirred at 0°C, and then dissolved in 1,4-diazobicyclo(2,2,2)octane.
) 0■ (0.98 mmole) Then p-nitropenzyloxyoxalyl chloride 450η (1.85 mmole
ole). After 1 hour, the reaction solution was poured into 40 mJ of 0.1M phosphate buffer H (p+(7,t),
Extract with methylene chloride. After washing with saturated brine and drying, the solvent is distilled off. The residue was subjected to column chromatography using silica gel to obtain a concentration of 10 to 17.5%.
Elution with ethyl acetate-benzene yielded the desired product 169 cm (yield 169.5%) as an oil.

IR spectrum v”HC'5 crrt-1: 18
05, 1745.

ax 1695.1690 (sh, ) ) IMR spectrum (cDcz5) δppm: 1.
42(3!(.

d, J=5.5Hz), 1.5-2.5 (2H, m
), 2.7-4.2 (9H, m), ~4.5 (LH,
m), 5.17 (2H.

S), 5.20 (2H, s), 5.36 (2H, s),
7.47 (4H, d), 7.52 (2I (, d), 8.
18(6H,d) Reference Example 16 (3S,4R)-4-((tsl-1-(N-(p-nitrobe/zyloxycar-nyl)acetoimiryl]pyrrolidin-3-ylthio]cardenylmethyl)-3 −(
[R1-1-(p-nitrobenzyloxycargonyloxy)ethyl)-1-(p-nitrobenzyloxyoxalyl)-2-azetidinone 972■ (1,12 mmo
le ), triethyl phosphite 1, 1 2 f
(6,75 mmole) toluene, 80
:N1ll'ic was dissolved and heated at 90°C for 2 hours under a nitrogen stream. The residue obtained by distilling off the solvent under reduced pressure is purified using a Rover column. Elution was carried out with a mixed solvent of ethyl acetate-chloroform-methanol (30:10:1) to obtain the desired product 961cm (yield: 84%) as an oil.

IR spectrum CHCl3CTL-i.

ax 1750.1680.1640 Reference Example 17 Ethyl]carbapen-2-M-3-carboxylic acid p-
Nitrobenzyl ester (3s, 4R)-4-CC(s+-t-(n-(p-nitrobenzyloxycarbonyl)acetimidoyl]pyrrolidin-3-ylthio]car?nylmethyl)-a-C
(PJ-1-(p-nitrobenzyloxycarbonyloxy)ethyl)-1-(1-(p-nitrobenzyloxycarbonyl)triethyloxyphosphoranylidenemethyl)-2-azetidinone 197■, hydroquinone 20
■ A mixture of 20 toluene was heated at 100℃ under a nitrogen stream for 4 hours.
Heated for 4 hours.

The solvent is distilled off under reduced pressure, and the residue is purified using a Rover column. Ethyl acetate-chloroform-methanol (3
0:10:1) Elute with mixed solvent to obtain starting material 16+rq
(8%) was recovered, and then the target product 93■ (yield 58%)
It is good as an oily substance.

IR spectrum νCEC23': 1780,17
44° [1690 (sh,), 1676 specific optical rotation [α], +68° (C=Q, l 7 , c
Hct3) NMR spectrum (CDCA3) δppm
: 1.48 (3H, d, J = 6.5Hz), 2.31 (
3H, s), 1.8-2.6 (2H, m), 3.0
~4.5 (9H, m), 5.16 (2E, s), 5
．． 20 (2Fi, s), 5.14 (ILd, J=14H
z), 5.43 (IH, d, J=14)! z), ~5.
2 (IH, m), 7.50 (4H, d), 7.57 (
2H.

d), 8.17 (6B, a) Reference Example 18 Lugenic acid (5R,63)-2-[(Sl-1-CN-(1-nitropenyloxycarbonyl)acetimidoyl]pyrrolidin-3-ylthio) -6-[(E-1-(p-nitrobenzyloxycarbonyloxy)ethyl]carbapene-2-emucarboxylic acid p-nitrobenzyl ester 485 μm was added to 25 mA of tetrahydrofuran and 0.1
Dissolve in a mixed solution of 25 mg of M-phosphate buffer (pH 7.1), add 1.42 mg of 10%/f radium-carbon, and stir for 70 minutes under normal pressure of hydrogen. After the reaction is completed, the catalyst is filtered off, 15 mg of the above buffer solution is added to the P solution, and the mixture is washed with ethyl acetate. After concentrating the aqueous layer at room temperature under reduced pressure to approximately 100%, HP20AG (Mitsubishi Kasei Corporation) is
The fractions eluted with 3thiacetone and water were collected and freeze-dried to obtain the desired product in the form of a white powder 1) 5cm (yield 58cm).
I got it.

IR spectrum νKBr CnL-1:ax 3400.1760.1675 NMR spectrum (D20) δppm: 1.29 (3
H, d, J=6.5Hz), 1.8-2.7 (2H.

m), 2.29 (3H, s), 3.22 (2H, d
, J=9.5Hz), 3.3~4.4 (8H, m
) Reference Example 19 (3R,4R8)-4-acetoxy-3- [(Published-1-
1-C(R1-1-(p-nitrobenoloxycarboazetidinone 6α-[(ju-1-tert-butyldimethylsilyloxyethyl)penicillanic acid p-nitrobenzyl ester lβ-oxide 51)■(1, 00mmole)
'jc Dissolved in 3 QmJ of toluene, 744 ■ trimethyl phosphite (6,00 mmole), 240 ■ acetic acid.
(4,00 mmole) and heated at 90°C for 5 hours. After the reaction was completed, the solvent was distilled off under reduced pressure, and the remaining residue was subjected to column chromatography using 10 g of silica gel.
r. Elution with a benzene-ethyl acetate (20:1) mixed solvent gave 479 ml of the desired product (yield 92%) as an oil. The product is about 1 diisomer with 4R and 4B coordination.
:1 mixture.

NMR spectrum (CDCl2) δ1) 1) m: (
(4R)-isomer] 0.02(3H,s), 0.06(
3H,s), 0.84(9I(.

S), 1.26 (3, H, d, J=6Hz), 1.83
(3H.

br, s), 1.99 (3H, s), 3.09 (IH,
dd, J=4.5, 1.5Hz), 4.2 (LH, m)
, 4.80 (IH, s), 4.89 (LH, br, s
), 5.00 (LH, br, ), 5.20 (2H, s
), 6.42 (IH, d, J = 1.51 (z), 7.4
5 (2B, a), 8.16 (2H, d): (: (4S)
-isomer, IO,04(3H,s), 0.08(3H
, s), 0.84 (9H, s), 1.34 (3a, a.

J = 6Hz), 2.08 (3H, s), 3.35 (LH
, dd.

J=8, 4.5 Hz), 4.2 (IH, m), 4
．． 75(II(.

S), 4.89 (L H, br, s), 5.00
(LH, br, ), 5.20 (2H, s), 6.17
(LH, d, J=4.5Hz), 7.45 (2H, d)
, 8.16 (2H,a) Reference Example 20 (3R,4R8)-4-acetoxy-3-(:(R1-
1-(tert-butyldimethylsilyloxy)ethyl]-1-(1-(p-nitrobenzyloxycarbonyl)-2-methyl-1-propenyl-2-azetidinone (3R,4Rs)-4-acetoxy-3- [:(R-1
-(t, ert-butyldimethylsilyloxy)ethyl]-1-((io1-(p-nitrobenzyloxycarbonyl)-2-methyl-2-propenyl)-2-azetidinone 78 ■ Triethylamine dissolved in total methylene chloride The solvent was distilled off under reduced pressure and the resulting oil was subjected to preparative thin layer chromatography on silica gel [developing solvent: ethyl acetate-hexane (1:
4)) to obtain the desired product 75■ (yield: 96) as an oil. This material is a 1:1 mixture of the 3,4-) lance and 3,4-cis isomers.

IR spectrum ν”””3crL-': 1764
, 1755 (sh,).

aX 1737(sh,), 1725(sh,), 1720(
sh,).

1700 (sh), 163 O NMRx vector (CDC23) δppm: [trans isomer] -0,03 (3B, s), 0.03 (3H
.

S), 0.83 (9H, s), x, 27 (3H, d, J
=6Hz), 1.97 (3H, s), 2. ol(3E,
s), 2.22 (3H, s), 3.19 (IH, dd,
J = 6.5.1.5Hz), 4.1 (IH, m), 5
．． 27 (2H, s), 6.19 (IE.

d, J=1,5EZ), 7.53 (2H, d), 8.2
0 (2H, d) [cis isomer] 0.06 (3H, s)
, 0.10 (3H, s), 0.86 (9H, s), 1.
36 (3H, d, J=6Hz), 1.97 (3H, S)
, 2.06 (3H, S), 2.22 (3H.

S), 3.37 (IH2dd, J=8.4.5Hz),
4.3 (IH, m), 5.27 (2H, s), 6.24
(LH, d.

J = 4.5 Hz), 7.52 (2a, d), 8.
20 (2H, d) Reference Example 21 (3R,4R8)-4-acetoxy-3-[(sentence-1-
(tart-butyldimethylsilyloxy)ethyl]-
1-(1-(p-nitropenoloxycarbonyl)-
2-Methyl-1-propenylcou-2-azetidinone 15
6■ was dissolved in 25 mj of methylene chloride and cooled to -78°C. After passing ozone through for 15 minutes and allowing it to stand at the same temperature for 100 minutes, the furnace was blown with soot to remove excess ozone. After adding 0.2 ml of dimethyl sulfide to the reaction solution and raising the temperature to room temperature, the solvent was distilled off under reduced pressure. The residue was dissolved in a benzene-hexane (1:1) mixed solvent, washed twice with water, dried, and the solvent was distilled off.

149 ml of the oily target product (yield 100%) was obtained.

This material is a 1:1 mixture of the 3,4-) lance and 3,4-cis isomers.

IR spectrum CHCt3crrL-1:ax 1820.1758i1713 NMR spectrum (CDCl2) δppm: [trans isomer] -0,01 (3H,s), 0.07 (
3LS), 0.81 (9H, s), 1.28 (3H, d
, J==6Hz), 2.08(3H,s), 3.27(
LH, t, J=2Hz), 4.3 (LH, m), 5.3
7 (2H, s), 6.67 (IH, d, J=2Hz),
7.53 (2H, d), 8.20 (2H, d) [cis isomer] 0.03 (3H, s), 0.08 (3
H, s), 0.86 (9H, s), 1.29 (3H, d
, J=6Hz), 3.56 (IH, dd, J=6.5.
5.5Hz), 4.3(LH.

m), 5.37(2H,s), 6281(
LH, d, J = 5.5 Hz), 7.53 (2a, d),
8.20(2H,d) Reference Example 22 (tart-butyldimethylsilyloxy)ethyl]-
1-(p-nitropenzyloxycargenylmethyl)-
2-azetidinone (3R,4R8)-4-acetoxy-3-((R-x-
(tert-butyldimethylsilyloxy)ethyl]-
1-C(1)-nitrobenzyloxy)oxalyl-2-azetidinone 1491) 17 (0,30 mmol
e), triethyl phosphite 224■ (1,35 mmol
e) was dissolved in 3 ml of toluene and heated at 90°C for 2 hours. The solvent was distilled off under reduced pressure to give (3R,4R8)-4-
Acetoxy-3-(ln-1-(tert-butyldimethylsilyloxy)ethyl)-1-[:1-(p-nitropenoloxycarbonyl)triethoxyphosphoranylidenemethyl]-2-azetidinone was obtained as an oil. Ta.

IR spectrum CHC25cIrL-1:1774
．． 1752ax 3 ml of tetrahydrofuran was added to the oil obtained above.

Dissolve in 1 ml of water, add 3 ml of p-toluenesulfonic acid, and let stand at room temperature for 5 minutes. After diluting with ethyl acetate, washing with water, and drying, the solvent was distilled off, and the residue was purified by preparative thin layer chromatography on silica gel (C developing solvent: ethyl acetate-benzene (1 nia)) to obtain the desired product 1). 81)
v (yield 82%) was obtained as an oil. This substance is 3.4
-) It is a 1=1 mixture of lance isomer and 3,4-cis isomer.

IR spectrum CHCt3cIrL-': 17
74, 1752ax NMR spectrum (CDCl2) δppm: [trans isomer 3 0.04 (3E, s), 0.08 (3I (
.

S), 0.86 (9H, s), 1.26 (3H, d, J
=6Hz), 2.03(3H,s), 3.24(LH
,aa,,y=4.5,1.5Hz),4.1)
(2H,s), 4.2(LH.

m), 5.22 (2E, s), 5.93 (LH, d, J
= 1.5Hz), 7.47 (2H, d), 8.19 (2
H, d) [cis isomer] 0.08 (3H, s), 0
．． 10 (3H, s), 0.86 (9H, s), 1.36
(3H, d, J=6Hz), 2.08 (3E, s), 3
．． 44 (1) (, dd, J=8.5, 4.5H
z), 3.93 (IH, d, J=18Hz), 4.2
4 (IH.

d, J=18Hz), 4.3(LH,m), 5.22(
2H.

S), 6°03 (LH, d, J==4.5RZ), 7°47 (2Ld), 8.19 (2H, d)

Claims (1)

[Claims] (1) General formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (I) [In the formula, R^1 is a hydrogen atom or a hydroxyl protecting group, R
^2 and R^3 are the same or different hydrogen atoms, lower alkyl groups or aryl groups, X is an oxygen atom or sulfur atom, Y is an imino group or alkylimino group, oxygen atom or sulfur atom, R^4 is an alkyl group, an alkyl group having a substituent, an aralkyl group, an alicyclic heterocyclic substituted alkyl group, an alicyclic heterocyclic group, an aryl group, or an aromatic heterocyclic group, and R^5 is a hydrogen atom or an amide group. Indicates a protecting group. However, when X and Y are oxygen atoms and R^4 is an alkyl group or an aralkyl group, R^5 is a protecting group for the amide group. An azetidinone derivative having the following.