JPS6254427B2 - - Google Patents

Description

[Detailed description of the invention]

3-1 Object of the invention The present invention is a method for producing carbapenem derivatives.
It is known that carbapenem derivatives represented by thienamycin exhibit excellent antibacterial activity.
However, since carbapenem derivatives cannot be obtained in good yield by fermentation, they are produced by chemical synthesis. A practical synthesis method is a ring-closing reaction using an intramolecular Wittig reaction (RJ Ponsford et al., Chem Comm.1085
(1980)) and a method via the intramolecular ring-closing reaction of carbene produced by the decomposition reaction of diazo compounds (BGChristensen et al., J.Am.Chem.Soc 102
6161 (1980)) is known. The inventors have discovered a practical method for synthesizing carbapenem derivatives that requires fewer steps than these synthetic methods, and has completed the present invention. The present invention is based on the formula A compound having the formula P(R ⁶ ) ₃ (2) is reacted with a compound having the formula and then heating this compound. This is a method for producing a carbapenem derivative having the following. In the above formula, R ¹ represents a hydrogen atom or a hydroxyl group protecting group, R ² and R ³ are the same or different and represent a hydrogen atom, an alkyl group or a phenyl group,
R ⁴ is an alkyl group that may have a substituent, an aralkyl group that may have a substituent, an aryl group that may have a substituent, or an alicyclic heterocyclic group that may have a substituent , represents an alicyclic heterocyclic substituted alkyl group which may have a substituent or an aromatic heterocyclic group which may have a substituent, R ⁵ represents a hydrogen atom or a protecting group for a carboxy group, R ⁶ represents an alkoxy group, an aryloxy group or a dialkylamino group. The hydroxyl group-protecting group of R ¹ is not particularly limited and is a general alcoholic hydroxyl group-protecting group,
Tri-substituted silyl groups such as trimethylsilyl, t-butyldimethylsilyl, triphenylsilyl, t-butoxydimethylsilyl or t-butoxydiphenylsilyl; such as benzyl, 4-nitrobenzyl, 2-nitrobenzyl or 4-methoxybenzyl. Aralkyl group; benzyloxycarbonyl, 4-nitrobenzyloxycarbonyl, 2-nitrobenzyloxycarbonyl,
Aryloxycarbonyl, 2-chloroallyloxycarbonyl, 2-methylallyloxycarbonyl, 2,2,2-trichloroethoxycarbonyl, t-butoxycarbonyl, diphenylmethoxycarbonyl or 2-(trimethylsilyl)
Substituted oxycarbonyl groups such as ethoxycarbonyl; tetrahydropyranyl, methoxymethyl, 1
Examples include ether groups such as -ethoxyethyl or 2-(trimethylsilyl)ethoxymethyl, or chloroacetyl groups. Examples of the alkyl group for R ² and R ³ include methyl, ethyl, propyl or isopropyl. The optionally substituted alkyl group of R ⁴ is, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, s-butyl or t-
Butyl is mentioned, and its substituents include, for example, a protected hydroxyl group (the protecting group has the same meaning as the protecting group for R ¹ described above), a protected amino group, or

[Formula] Groups are mentioned. The protecting group for the protected amino group is not particularly limited, and general amino group protecting groups can be used, such as acyl groups such as formyl, acetyl, chloroacetyl, propionyl, or benzoyl, or t-butoxycarbonyl, 2 ,2,2
Substituted oxycarbonyls include -tribromoethoxycarbonyl, 2-(trimethylsilyl)ethoxycarbonyl, benzyloxycarbonyl, 4-nitrobenzyloxycarbonyl, and 2-nitrobenzyloxycarbonyl. mentioned above

In the [Formula] group, R ⁷ , R ⁸ and R ⁹ are hydrogen atoms; protecting groups for amino groups (same meanings as above); alkyl groups such as methyl or ethyl; R ⁸ and R ⁹ are taken together to form a ring via adjacent nitrogen atoms -( _CH2 )n- group (n represents 2, 3, 4, 5 or 6) or ^R7 and ^R8 are taken together to form a ring to form a ring via adjacent nitrogen atoms. -( _CH2 )p- group (p represents 2 or 3). The aralkyl group which may have a substituent for R ⁴ is, for example, benzyl, 4-methoxybenzyl, 3-
Nitrobenzyl, 2-methylbenzyl, 4-brombenzyl, 4-aminobenzyl, 2-tenyl,
Examples include 3-tenyl or furfuryl. The aryl group which may have a substituent for R ⁴ is, for example, phenyl, 4-nitrophenyl, 3-carboxyphenyl, 2-hydroxyphenyl, 4-
Mention may be made of methoxyphenyl, 3-ethoxycarbonylmethylphenyl, 1-naphthyl or 2-naphthyl. The alicyclic heterocyclic group of R ⁴ is a substituted or unsubstituted 4- to 8-membered ring in which a nitrogen atom, an oxygen atom, a sulfur atom, a sulfinyl group, a sulfonyl group, or a carbonyl group may be present in the ring carbon chain. rings, such as azetidinyl, pyrrolidinyl, piperidyl,
Examples include morpholinyl, tetrahydropyrimidinyl, thiazolidinyl, oxazolinidyl, tetrahydropyrimidine, hexahydropyrimidinyl, imidazolidinyl or octahydroazocinyl, and the substituents bonded to the ring carbon atoms are alkyl groups, cycloalkyl groups, alkoxyalkyl groups,
Alkoxycarbonylalkyl group, cyanoalkyl group, halogenoalkyl group, alkoxy group, hydroxyl group, amino group, halogen atom, acyloxy group,
Acylamino group, cyano group, azide group, carboxy group, alkoxycarbonyl group, carbamoyl group, alkylthio group, alkylsulfinyl group,
selected from the group consisting of an alkylsulfonyl group or a nitro group, and the substituent bonded to the ring nitrogen atom is an alkyl group, an alkenyl group, an alkynyl group, a cycloalkyl group, a cycloalkylalkyl group, an aryl group, an aralkyl group. , acyl group, phenacyl group, sulfo group; alkoxysulfonyl group, alkylsulfonyl group, alkenylsulfonyl group, alkynylsulfonyl group, cycloalkylsulfonyl group, cycloalkylalkylsulfonyl group, arylsulfonyl group; aralkylsulfonyl group, heteroarylsulfonyl group, heteroaralkylsulfonyl group, formula

[Formula] Group (wherein R ¹⁰ represents a hydrogen atom or a lower alkyl group, and R ¹¹ represents a hydrogen atom or a protecting group for an imino group), Formula

[Formula] group (wherein R ¹² and R ¹³ are the same or different and represent a hydrogen atom or a lower alkyl group, and Z represents an imino group optionally substituted with an oxygen atom, a sulfur atom, or a lower alkyl group). ), an alkoxycarbonyl group or an aralkyloxycarbonyl group. The substituents attached to the ring carbon atoms of the alicyclic heterocycles may be linear or branched, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, t-butyl, bentyl, isopentyl. Lower alkyl groups such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl; for example methoxymethyl, ethoxymethyl, propoxymethyl, isopropoxymethyl, butoxymethyl, methoxyethyl, 3-methoxypropyl, 2-methoxypropyl , 4-ethoxybutyl; alkoxycarbonylalkyl groups such as methoxycarbonylmethyl, ethoxycarbonylmethyl, t-butoxycarbonylmethyl, benzyloxycarbonylethyl, methoxycarbonylpropyl; e.g. cyanomethyl, cyanoethyl, 3 -cyanopropyl, 2-
cyano-lower alkyl groups such as cyanopropyl, 4-cyanobutyl; e.g. trifluoromethyl,
2-fluoroethyl, 2,2,2-trifluoroethyl, 2-chloroethyl, 2-promoethyl,
3-fluoropropyl, 2-fluoropropyl,
Halogeno lower alkyl groups such as 4-chlorobutyl, 3-fluorobutyl; e.g. methoxy, ethoxy, propoxy, isopropoxy, butoxy,
Linear or branched lower alkoxy groups such as isobutoxy, sec-butoxy, t-butoxy; hydroxyl groups; amino groups; halogen atoms such as fluorine, chlorine, bromine, iodine; e.g. acetoxy, propionyloxy, Lower aliphatic acyloxy groups such as butyryloxy and isobutyryloxy; lower aliphatic acylamino groups such as acetylamino, propionylamino, butyrylamino and isobutyrylamino; cyano group; azide group; carboxy group; e.g. methoxycarbonyl,
Ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl,
lower alkoxycarbonyl groups such as isobutoxycarbonyl, sec-butoxycarbonyl, t-butoxycarbonyl; carbamoyl groups; linear or branched chains such as methylthio, ethylthio, propylthio, isopropylthio, butylthio, isobutylthio; lower alkylthio group;
Straight-chain or branched lower alkylsulfinyl groups such as methylsulfinyl, ethylsulfinyl, propylsulfinyl, isopropylsulfinyl, butylsulfinyl, isobutylsulfinyl; e.g. Examples include linear or branched lower alkylsulfonyl groups or nitro groups such as methylsulfonyl, ethylsulfonyl, propylsulfonyl, isopropylsulfonyl, butylsulfonyl, and isobutylsulfonyl. Substituents bonded to the ring nitrogen atom of the alicyclic heterocyclic group include, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, t-
Straight-chain or branched lower alkyl groups such as butyl, pentyl, isopentyl; e.g. vinyl, allyl, 1-propenyl, isopropenyl,
Lower alkenyl groups such as 2-butenyl, 2-pentenyl; e.g. ethynyl, 2-propynyl, 2
-lower alkynyl groups such as butynyl, 4-pentynyl; e.g. cyclopropyl, cyclobutyl,
Cyclo-lower alkyl groups such as cyclopentyl, cyclohexyl, cyclohebutyl; e.g. cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, cyclohebutylmethyl, 2-cyclopentylethyl, 2-
Lower cycloalkylalkyl groups such as cyclohexylethyl, 3-cyclopentylpropyl, 2-cyclopentylpropyl, 3-cyclohexylpropyl, 2-cyclohexylpropyl, 4-cyclopentylbutyl, 3-cyclohexylbutyl; aryl groups such as phenyl, naphthyl, etc. aralkyl groups such as benzyl, phenethyl, 3-phenylpropyl; e.g. formyl, acetyl, propionyl, butyryl, isobutyryl, acryloyl, methacryloyl, crotonoyl, isocrotonoyl, propioloyl,
Lower aliphatic acyl groups such as methylpropioloyl, e.g. cyclopropanecarbonyl, cyclobutanecarbonyl, cyclopentanecarbonyl, lower cycloalkanecarbonyl groups such as cyclohexanecarbonyl, e.g. cyclopropylacetyl, cyclobutylacetyl, cyclopentylacetyl, cyclohexylacetyl , 3-cyclopentylpropionyl, 3-cyclohexylpropionyl, 4-cyclopentylbutyryl, lower cycloalkylalkanoyl groups such as 4-cyclohexylbutyryl, aromatic acyl groups such as benzoyl, 1-naphthoyl, 2-naphthoyl, e.g. Phenylacetyl, 1-naphthylacetyl,
3-phenylpropionyl, hydratropoyl,
Aroaliphatic acyl groups such as cinnamoyl, phenylpropioloyl, e.g. furoyl, thenoyl, nicotinoyl, isonicotinoyl, 4-thiazolecarbonyl, 5-pyrimidinecarbonyl,
Heterocyclic carbonyl groups such as 2-pyrazinecarbonyl, e.g. 2-thienyl acetyl, 3-(2-
Heterocycloaliphatic acyl groups such as thienyl)propionyl, 4-thiazolyl acetyl, 2-pyridylacetyl, 4-pyridylacetyl, 5-pyrimidylacetyl, e.g. 1-aziridinecarbonyl,
1-Azetidinecarbonyl, 3-azetidinecarbonyl, 1-pyrrolidinecarbonyl, 2-pyrrolidinecarbonyl, 3-pyrrolidinecarbonyl, 1
-heterocyclylcarbonyl groups such as piperidinecarbonyl, 2-piperidinecarbonyl, 4-piperidinecarbonyl, 4-morpholinecarbonyl or e.g. 1-aziridinyl acetyl, 1
-Azetidinyl acetyl, 3-azetidinyl acetyl, 1-pyrrolidinyl acetyl, 2-pyrrolidinyl acetyl, 3-pyrrolidinyl acetyl, 3-
Acyl groups such as heterocyclyl aliphatic acyl groups such as (2-pyrrolidinyl)propionyl, piperidinoacetyl, 2-piperidinyl acetyl, 4-piperidinyl acetyl, morpholinoacetyl; phenacyl group; fluoro group; e.g. methoxysulfonyl , ethoxysulfonyl, propoxysulfonyl, isopropoxysulfonyl; lower alkoxysulfonyl groups such as methylsulfonyl,
Straight-chain or branched lower alkylsulfonyl groups such as ethylsulfonyl, propylsulfonyl, isopropylsulfonyl, butylsulfonyl, isobutylsulfonyl; lower alkenylsulfonyl groups such as allylsulfonyl, isopropenylsulfonyl, 2-butenylsulfonyl groups; lower alkynylsulfonyl groups such as ethynylsulfonyl, 2-propynylsulfonyl, 2-butynylsulfonyl; lower cycloalkylsulfonyl groups such as cyclopropylsulfonyl, cyclobutylsulfonyl, cyclopentylsulfonyl, cyclohexylsulfonyl; e.g. cyclopropyl; Methylsulfonyl, cyclobutylmethylsulfonyl, cyclopentylmethylsulfonyl, cyclohexylmethylsulfonyl, 2-
Lower cycloalkylalkylsulfonyl groups such as cyclopentylethylsulfonyl, 2-cyclohexylethylsulfonyl, 3-cyclopentylpropylsulfonyl, 2-cyclopentylpropylsulfonyl; e.g. phenylsulfonyl, 1-
Arylsulfonyl groups such as naphthylsulfonyl, 2-naphthylsulfonyl; aralkylsulfonyl groups such as benzylsulfonyl, phenethylsulfonyl, 3-phenylpropylsulfonyl, 2-phenylpropylsulfonyl; e.g. 2-thienylsulfonyl, 4 - heteroarylsulfonyl groups such as thiazolylsulfonyl, 2-pyridylsulfonyl, 4-pyridylsulfonyl;
For example, 2-thienylmethylsulfonyl, 3-(2
-thienyl)propylsulfonyl, 4-thiazolylmethylsulfonyl, 2-pyridylmethylsulfonyl, 4-pyridylmethylsulfonyl; a heteroaralkylsulfonyl group;

[Formula] Group (wherein R ¹⁰ is a hydrogen atom or a lower alkyl group such as methyl, ethyl, propyl, or isopropyl, R ¹¹ is a hydrogen atom or a protecting group for an imino group, such as allyloxycarbonyl, 2-methyl allyloxycarbonyl,
2-chloroallyloxycarbonyl, 2,2,2
-Trichloroethoxycarbonyl, 2,2,2-
It represents an alkoxycarbonyl group such as tribromoethoxycarbonyl or an aralkyloxycarbonyl group such as 4-nitrobenzyloxycarbonyl or 2-nitrobenzyloxycarbonyl. ); expression

[Formula] Group (wherein R ¹² and R ¹³ are the same or different and are hydrogen atoms or, for example, methyl,
It represents a lower alkyl group such as ethyl, propyl, isopropyl, and Z is an imino group optionally substituted with an oxygen atom, a sulfur atom, or a lower alkyl group such as methyl, ethyl, propyl, isopropyl, or a protected The protecting group has the same meaning as the above-mentioned protecting group for the amino group. ); for example, methoxycarbonyl,
ethoxycarbonyl, butoxycarbonyl, 2,
2,2-trichloroethoxycarbonyl, 2,
Lower alkoxycarbonyl groups such as 2,2-tribromoethoxycarbonyl or e.g. benzyloxycarbonyl, phenethyloxycarbonyl, 4-nitrobenzyloxycarbonyl, 2-
Examples include aralkyloxycarbonyl groups such as nitrobenzyloxycarbonyl. The heterocycle in the alicyclic heterocyclic substituted alkyl group of R ⁴ is the alicyclic heterocycle described above, and the substituents bonded to the ring carbon atoms and nitrogen atoms have the same meanings as described above, and the alkyl group is methyl. , 1-substituted ethyl, 2-substituted ethyl, 1-substituted propyl and other lower alkyl groups. Examples of the aromatic heterocyclic group which may have a substituent for R ⁴ include pyridyl, pyrimidinyl, triazinyl,
Examples include thienyl, furyl, thiazolyl, or imidazolyl, and substituents include alkyl groups such as methyl, ethyl, and propyl; alkoxy groups such as methoxy, ethoxy, and propoxy; amino groups; and alkyl groups such as methylamino, ethylamino, and propylamino. Amino group; dialkylamino group such as dimethylamino and diethylamino; hydroxyl group; lower alkanoyloxy group such as acetoxy and propionyloxy; nitro group; fluorine, chlorine,
Halogen atoms such as bromine; for example, methoxycarbonyl, 4-nitrobenzyloxycarbonyl,
Examples include alkoxycarbonyl groups such as t-butoxycarbonyl. The carboxyl group-protecting group for R ₅ is not particularly limited, and includes carboxyl group-protecting groups used in β-lactam antibiotics, preferably lower alkyl groups such as methyl, ethyl, and t-butyl; Aralkyl groups such as benzyl, diphenylmethyl, 4-nitrobenzyl, 2-nitrobenzyl; alkenyl groups such as allyl, 2-chlorallyl, 2-methylallyl; 2,2,2-trichloroethyl, 2,2,2-tribromoethyl Examples include halogenated alkyl groups such as and 2-(trimethylsilyl)ethyl groups. Examples of the alkoxy group for R ⁶ include methoxy, ethoxy, propoxy, isopropoxy, butoxy or sec-butoxy. Examples of the aryloxy group for R ⁶ include phenoxy, 4-tolyloxy, and 4-methoxyphenyloxy. Examples of the alkyl group in the dialkylamino group of R ⁶ include methyl, ethyl, propyl, isopropyl, butyl or t-butyl. In general formulas (1) to (4), R ¹ is preferably trimethylsilyl, t-butyldimethylsilyl, t-butoxydimethylsilyl, t-butoxydiphenylsilyl, 4-nitrobenzyl, 4-nitrobenzyloxycarbonyl, allyloxy carbonyl,
Examples include 2,2,2-tribromoethyloxycarbonyl, 1-ethoxyethyl or chloroacetyl. Examples of R ² and R ³ include a hydrogen atom or methyl. R ⁴ is an alkyl group such as methyl, ethyl or t-butyl; 2-hydroxyethyl or 2-hydroxy-1-methylethyl with a hydroxy group protected; 2-aminoethyl with an amino group protected;
2-amino-1-methylethyl;

[Formula] Methyl group substituted with group; Benzyl group; Aryl group such as phenyl or 2-naphthyl; 1-(4-nitrobenzyloxycarbonyl)pyrrolidin-3-yl, 1-acetylpyrrolidin-3-yl, 1 -[N-(4-nitrobenzyloxycarbonyl)acetimidoyl]pyrrolidin-3-yl, 1-[N-methylacetimidoyl]pyrrolidin-3-yl, 1-[N-(4-
nitrobenzyloxycarbonyl)formimidoyl]pyrrolidin-3-yl, 1-[N-methylformimidoyl]pyrrolidin-3-yl, 3,
4,5,6-tetrahydro-2-methyl-1,3
-pyrimidin-5-yl or 3,4,5,6
-Alicyclic heterocyclic group such as -tetrahydro-2-methyl-3-(4-nidrobenzyloxycarbonyl)-1,3-pyrimidin-5-yl; 1-[1-
(4-nitrobenzyloxycarbonyl)pyrrolidin-3-yl]ethyl, 1-(1-acetylpyrrolidin-3-yl)ethyl, 1-[1-[N-
(4-nitrobenzyloxycarbonyl)formimidoyl]pyrrolidin-3-yl]ethyl, 1
-[1-[N-(4-nitrobenzyloxycarbonyl)acetimidoyl]pyrrolidin-3-yl]ethyl, 1-[4-[N-(4-nitrobenzyloxycarbonyl)formimidoyl]morpholine-2 -yl]ethyl, 1-[4-[N-(4-
nitrobenzyloxycarbonyl)acetimidoyl]morpholin-2-yl]ethyl, 1-[4
-(4-nitrobenzyloxycarbonyl)morpholin-2-yl]ethyl or alicyclic heterocyclic group substituted alkyl group such as 1-(4-acetylhylfolin-2-yl)ethyl or 2-pyridyl,
3-pyridyl, 4-pyridyl, 2-thienyl, 3
-thienyl, 2-furyl, 3-furyl, 1,2,
Examples include aromatic heterocyclic groups such as 4-triazol-3-yl and 2-thiazolyl. R ⁵ is a hydrogen atom or methyl, t-butyl, benzyl, diphenylmethyl, 4-nitrobenzyl, 2-nitrobenzyl, allyl, 2-chloroallyl, 2,2,2-trichloroethyl, 2,2,
Examples include carboxyl group-protecting groups such as 2-tribromoethyl and 2-(trimethylsilyl)ethyl. R ⁶ is an alkoxy group such as methoxy, ethoxy, propoxy, isopropoxy, butoxy or sec-butoxy; an aryloxy group such as phenoxy, 4-tolyloxy or 4-methoxyphenyloxy; or dimethylamino, diethylamino, dipropylamino, Examples include dialkylamino groups such as diisopropylamino, dibutylamino, di-sec-butylamino, and di-tert-butylamino. Preferred compounds having general formula (4) are illustrated in Table 1.

【table】

【table】

【table】

【table】

[Table] There are no particular limitations on the steric configurations of general formulas (1), (3), and (4), but those having the steric configuration represented by thienamycin are preferred. When R ⁴ has an asymmetric carbon atom, its steric configuration is not particularly limited. The compound having general formula (1), which is a starting material used in the present invention, can be obtained as follows. Compound (9) is obtained by reacting azetidinone derivative (5) with thioester of trimethylsilylacetic acid (6) or trimethylsilyl enol ether of acetic acid thioester in the presence of trimethylsilyl ester of trifluoromethanesulfonic acid. On the other hand, compound (8) is a mercaptan derivative. Compound (9) is obtained by reacting (R ⁴ SH) in the presence of a condensing agent such as dicyclohexylcarbodiimide or diphenylphosphoryl azide and triethylamino. Then, when compound (9) is reacted with alkoxyoxalyl chloride, the compound
(10) is obtained. In the above formula, R ² , R ³ and R ⁴ have the same meanings as described above, R ¹⁶ represents the hydroxyl group protecting group R ¹ described above, and R ¹⁷ represents the carboxy group protecting group R ⁵ described above. . R 1 and/or R ¹ in formula (1) can be obtained by removing R ¹⁶ and/or R ¹⁷ of compound (10) according to a conventional method.
Alternatively, compounds in which R ⁵ is hydrogen are obtained. Compounds having formulas (3) and (4) are synthesized by the method shown below. A compound having formula (1) and a compound having formula (2) are combined in an aprotic solvent such as hexane, benzene,
After heating at 50 to 150°C for 5 to 50 hours in toluene, xylene, chloroform, methylene chloride, 1,2-dichloroethane, ethyl acetate, tetrahydrofuran, dioxane, acetonitrile, or dimethylformamide, the solvent and low-boiling substances are removed under reduced pressure. By distilling off, a compound having formula (3) is obtained. At this time, depending on the reaction temperature and time, a compound having general formula (4) may also be produced at the same time. Compound (3) was further dissolved in the above aprotic solvent at 80°C.
A compound having general formula (4) is obtained by heating at ~150°C for 10 hours to 5 days. Furthermore, the compound
Compound (4) can be directly obtained by maintaining a mixed solution of compounds (1) and (2) at a reaction temperature of 80 to 150°C for 10 hours to 5 days without isolating (3). Note that compound (3) is a new compound. 3-3 Effect of the invention The practical methods for synthesizing carbapenem derivatives known so far include a method using an intramolecular ring-closing reaction by an intramolecular Wittig reaction (hereinafter referred to as the Ponsford method) and a method using a decomposition reaction of a diazo compound. There is a method that involves an intramolecular ring-closing reaction of carbene (hereinafter referred to as the Christensen method). In order to compare this method with the Ponsford method and the Christensen method, the synthesis steps of the same carbapenem derivative (12) from the same starting material (11) are shown below. This method The first to fourth steps are the steps already described, and the fifth step is a step of removing the t-butyldimethylsilyl group with potassium fluoride. Ponsford method (RJPonsford et al., Chem
Comm.1085 (1980) When compound (11) is reacted with a mercaptan derivative in the presence of a condensing agent, the thioester of (11) is obtained (first step), which is then reacted with 4-nitrobenzylglyoxylate to give an alcohol form (step 1). Step 2), this alcohol form is led to a chloride using thionyl chloride (Step 3). The phosphonium salt obtained by reacting this chloride with triphenylphosphine is treated with a base to lead to a phosphoranylidene compound (fourth step), which is then heated (intramolecular Wittig reaction) to obtain a carbapenem derivative (fifth step). Step), and then the t-butyldimethylsilyl group, which is a protective group for this hydroxyl group, is removed with potassium fluoride to obtain compound (12). Christensen method Compound (11) is reacted with carbonyl diimidazole to activate the carboxy group of (11) (first step), and this is reacted with magnesium salt of mono-4-nitrobenzyl malonic acid to form a β-ketocarboxylic acid ester derivative. (Second step) The t-butyldimethylsilyl group, which is a protective group for the hydroxyl group, is removed using potassium fluoride (Third step). The activated methylene of the resulting hydroxy-β-ketoester is removed using tosyl azide. Diazotization (4th step), heating the resulting diazo compound in the presence of rhodium acetate, and intramolecular ring closure of the resulting carbene to obtain a 2-ketocarbapenam derivative (5th step)
Step), reacting (Pho) ₂ POCl with this in the presence of a base to activate the carbonyl group (step 6),
Then, by reacting this with a mercaptan derivative (R ⁴ SH), compound (12) is obtained. Comparing this method with the Ponsford method, this method yields compound (12) from compound (11) in 5 steps, but
In the Ponsford method, (11) to (12) are obtained in 6 steps. In addition, in the Ponsford method, when R ⁴ is an electron-withdrawing group such as a phenyl group, a carbapenem derivative can be obtained in good yield through intramolecular Wittig reaction (fifth step); however, when R ⁴ is an electron-donating group such as an alkyl group, In such cases, the intramolecular Wittig reaction (5th step) yields carbapenem derivatives only in low yields (T. Kametani et al., JCS
Perkin I 964 (1981)). This method is a method for producing carbapenem derivatives that is superior to the Ponsford method in that it requires fewer steps and provides an intramolecularly closed ring product in good yield regardless of the type of substituent for R ⁴ . Comparing this method with Christensen's method,
In the Christensen method, (11) to (12) are obtained in 7 steps, which is a larger number of steps than this method. Although the Christensen method is an excellent method for practical synthesis of carbapenem derivatives, it is inferior to this method in that it requires more steps. From the above, the present method is superior to the practical methods for synthesizing carbapenem derivatives known so far. In addition, when R ¹ and/or R ⁵ of compound (4) obtained by this method is a protecting group, the carbapenem derivative having excellent antibacterial activity can be obtained by removing the protecting group according to a conventional method. I can lead you to. Examples and reference examples are given below to further illustrate the present invention. Example 1 (3S,4R)-3-[(R)-1-tert-butyldimethylsilyloxyethyl]-4-[(butylthio)carbonylmethyl]-1-[1-(4-nitrobenzyloxycarbonyl) trimethoxyphosphoranylidenemethyl]-2-azetidinone (3S,4R)-3-[(R)-1-tert-butyldimethylsilyloxyethyl]-4-(butylthio)
Carbonylmethyl-1-(4-nitrobenzyl)
Oxyoxalyl-2-azetidinone 61mg
(0.11 mmole) and trimethyl phosphite 107 mg
A 7 ml solution of (0.86 mmole) in ethyl acetate is stirred at 70-80° C. for 65 hours under nitrogen flow. The solvent and excess trimethyl phosphite were distilled off under reduced pressure to give 69 mg (yield
95%) of the crude target product was obtained as an oil. IR spectrum ν ^CHCl3 _nax cm ^-1 : 1740, 1675,
1631, 1520, 1343 NMR spectrum (CDCl ₃ ) δppm: 0.05 (6H,
s), 0.85 (9H, s), 0.90 (3H, t, J=
6Hz), 1.23 (3H, d, J=6Hz), ~1.5
(4H, m), 2.5-3.1 (5H, m), 3.87 (9H,
d, J=12Hz), ~4.0 (2H, m), 5.0~5.4
(2H, m), 7.48and7.54 (2H, d),
8.15and8.19(2H,d) Example 2 (5R,6S)-6-[(R)-1-(tert-butyldimethylsilyloxy)ethyl]-2-(butylthio)carbapen-2-em-3 -carboxylic acid 4
-Nitrobenzyl ester Crude (3S,4R)-3-[(R) described in Example 1
-1-tert-butyldimethylsilyloxyethyl]-4-(butylthio)carbonylmethyl-1-
[1-(4-nitrobenzyloxycarbonyl)trimethoxyphosphoranylidenemethyl]-2-azetidinone 69 mg (0.10 mmole) and hydroquinone 5
A solution of mg (0.05 mmole) in 9 ml of xylene is heated at 120° C. for 21 hours under a nitrogen stream. The solvent was distilled off under reduced pressure, and the residue was subjected to thin layer chromatography [Developing solvent:
10mg purified with hexane-ethyl acetate (1.5:1)
The desired product (yield 18%) was obtained as an oily substance. IR spectrum ν ^CHCl _3nax cm ^-1 : 1768, 1695,
1605, 1520, 1345 NMR spectrum (CDCl ₃ ) δppm: 0.00 (6H,
s), 0.80 (9H, s), 0.86 (3H, t, J=
6Hz), 1.18 (3H, d, J=6Hz), ~1.5
(4H, m), 2.77 (2H, t-like, J=6
Hz), 3.0 to 3.2 (3H, m), 4.0 to 4.3 (2H,
m), 5.17 (1H, d, J = 14Hz), 5.42
(1H, d, J = 14Hz), 7.59 (2H, d, J =
9Hz), 8.16 (2H, d, J = 9Hz) Example 3 (5R, 6S)-6-[(R)-1-tert-butyldimethylsilyloxyethyl]-2-(isopropylthio)carbapene-2- Em-3-carboxylic acid 4-nitrobenzyl ester (3S,4R)-3-[(R)-1-tert-butyldimethylsilyloxyethyl]-4-[(isopropylthio)carbonylmethyl]-1-(4-nitrobenzyloxyoxalyl)-2-azetidinone 55
mg (0.10 mmole), triethyl phosphite 100 mg
(0.60 mmole), 3 mg of hydroquinone in xylene
Heat in 5.5 ml at 120°C under nitrogen stream for 15 hours. The oil obtained by distilling off the solvent and volatile substances under reduced pressure is dissolved again in 5.5 ml of xylene and heated at 120° C. for 70 hours under a nitrogen stream. After the reaction, the solvent was distilled off under reduced pressure and the resulting residue was separated and purified by preparative silica gel thin layer chromatography [developing solvent: hexane-ethyl acetate (3:1)] to obtain 26.6 mg of the target product (yield). 51%) was obtained as an oil. IR spectrum ν ^CHCl3 _nax cm ^-1 : 1768, 1690 NMR spectrum (CDCl ₃ ) δppm: 0.08 (6H,
s), 0.87 (9H, s), 1.25 (3H, d, J=
6Hz), 1.35 (6H, br.d, J=7Hz), 2.9~
3.6 (3H, m), 3.9-4.4 (2H, m), 5.20
(1H, d, J = 14Hz), 5.45 (1H, d, J =
14Hz), 7.62 (2H, d), 8.19 (2H, d) Example 4 (5R, 6S)-6-[(R)-1-tert-butyldimethylsilyloxyethyl]-2-(phenylthio)-carbapene -2-M-3-carboxylic acid 4-nitrobenzyl ester (3S,4R)-3-[(R)-1-tert-butyldimethylsilyloxyethyl]-1-(4-nitrobenzyloxyoxalyl)-4-[(phenylthio)carbonylmethyl]-2-azetinone
511mg (0.872mmole) and trimethyl phosphite
A solution of 1.03 g (8.46 mmole) in 50 ml of ethyl acetate is stirred at 70° C. for 4 days under nitrogen flow. The residue obtained by distilling off the solvent was subjected to chromatography using a Lorber column (manufactured by E. Merck & Co., Ltd.) [developing solvent: benzene-ethyl acetate (1:3)], and 158 mg of the target product containing some impurities was separated. (3S,
4R)-3-[(R)1-tert-butyldimethylsilyloxyethyl]-1-[1-(4-nitrobenzyloxycarbonyl)trimethoxyphosphoranylidenemethyl]-4-[(phenylthio)carbonylmethyl] 176 mg (yield 29%) of -2-azetidinone is obtained. The mixture containing the target compound was further chromatographed using a Lorber column [developing solvent: hexane-acetone (3.5:
1)] to obtain 103 mg (yield 21%) of the target product as a solid. This was recrystallized from acetone-hexane mixed solvent to obtain colorless needle crystals with a melting point of 144-145.5°C. Triethoxyphosphonium ylide IR spectrum ν ^CHCl3 _nax cm ^-1 : 1740, 1695
，
1636, 1520, 1345 NMR spectrum (CDCl ₃ ) δppm: 0.00 (6H,
s), 0.87 (9H, s), 1.26 (3H, d, J=
6Hz), 2.7-3.5 (3H, m), 3.84 (9H, d,
J=12Hz), ~4.2 (2H, m), 4.9~5.5
(2H, m), 7.36 (5H, s), 7.53 (2H, d,
J=9Hz), 8.17 (2H, d, J=9Hz) Carbapenem Elemental analysis value C ₂₈ H ₃₄ N ₂ O ₆ As SSi Calculated value: C, 60.62; H, 6.18; N, 5.05
; S, 5.78 Actual value: C, 60.50; H, 6.11; N, 4.77
;S, 5.91 IR spectrum ν ^nujol _nax cm ^-1 : 1777, 1697
, 1524 NMR spectrum (CDCl ₃ ) δppm: 0.06 (6H,
s), 0.83 (9H, s), 1.15 (3H, d, J=
6Hz), 2.63 (2H, d, J=10Hz), 3.05
(1H, dd, J=4,2Hz) 4.04 (1H, dd,
J = 10, 2Hz), 4.19 (1H, dd, J = 4.6
Hz), 5.22 (1H, d, J = 14Hz), 5.50
(1H, d, J=14Hz), 7.2~7.7 (5H, m),
7.64 (2H, d, J = 9Hz), 8.19 (2H, d,
J=9Hz) (3S,4R)-3-[(R)-1-tert-butyldimethylsilyloxyethyl]-1-[1-(4
-nitrobenzyloxycarbonyl)trimethoxyphosphoranylidenemethyl-4-[(phenylthio)carbonylmethyl]-2-azetidinone
19 mg (0.027 mmole) and a catalytic amount of hydroquinone are stirred in 2 ml of xylene at 120° C. for 4 hours under a nitrogen stream. After the reaction was completed, the solvent was distilled off, and the residue was purified using a Lorber column [developing solvent: hexane-acetone (3.5:1)] to give 7.5 mg (yield: 45
%) of the target product was obtained as a solid. (3S,4R)-3-[(R)-1-tert-butyldimethylsilyloxyethyl]-1-(4-nitrobenzyloxyoxalyl)-4-[(phenylthio)carbonylmethyl]-2-azetidinone 114 mg ( 0.194 mmole) and triethyl phosphite
A solution of 258 mg (1.55 mmole) in 10 ml of toluene is stirred at 100°C for 18 hours under nitrogen flow. The residue obtained by distilling off the solvent was purified in the same manner as in ) to obtain 95 mg (yield 38%) of the target product as crystals. ), use 324 mg of triisopropyl phosphite instead of triethyl phosphite.
(1.56 mmole), 83 mg (yield 77%) of the target product was obtained as crystals. ) in the reaction of 195 mg of trimethyl phosphite instead of triethyl phosphite.
A similar reaction was carried out using (1.56 mmole) to obtain 37 mg (yield 34%) of the target product as crystals. Example 5 (5R,6S)-6-[(R)-1-tert-butyldimethylsilyloxyethyl]-2-[2-(4-nitrobenzyloxycarbonylamino)ethylthio]carbapen-2-em-3 -Carboxylic acid 4-nitrobenzyl ester (3S,4R)-3-[(R)-1-tert-butyldimethylsilyloxyethyl]-4-[[2-(4-nitrobenzyloxycarbonylamino)ethylthio]carbonylmethyl]-1-(4- Nitrobenzyloxyoxalyl)-2-azetidinone 165mg
(0.23 mmole), triethyl phosphite 229 mg
(1.38 mmole), 4 mg of hydroquinone in toluene
Heat in 16.5 ml at 90°C under nitrogen stream for 30 hours. The residue obtained by distilling off toluene under reduced pressure is separated and purified by liquid chromatography using Rover Column-B (manufactured by E. Merck & Co.). Benzene-
Elute with ethyl acetate (2:1) mixed solvent to obtain the target product.
107 mg (yield 68%) was obtained as a solid. Recrystallized from benzene-hexane, melting point 65-67℃
A pure product with . IR spectrum ν ^CHCl3 _nax cm ^-1 : 3450, 1770
，
1715, 1696 (sh.) NMR spectrum (CDCl ₃ ) δppm: 0.09 (6H,
s), 0.88 (9H, s), 1.23 (3H, d, J=
6Hz), 2.7~3.7 (6H, m), 3.9~4.5 (2H,
m), 5.13 (2H, s), 5.15 (1H, d, J=
14Hz), 5.39 (1H, d, J = 14Hz), 7.41
(2H, d), 7.56 (2H, d), 8.13 (4H, d) Example 6 (5R, 6S)-6-[(R)-1-tert-butyldimethylsilyloxyethyl]-2-[( S)-1-
(4-nitrobenzyloxycarbonyl)pyrrolidin-3-ylthio]carbapen-2-em-3-carboxylic acid 4-nitrobenzyl ester (3S,4R)-3-[(R)-1-tert-butyldimethylsilyloxyethyl]-1-(4-nitrobenzyloxyoxalyl)-4-[[(S)-1-(4
-nitrobenzyloxycarbonyl)pyrrolidin-3-ylthio]carbonylmethyl]-2-azetidinone 190 mg (0.25 mmole), triethyl phosphite 250 mg (1.5 mmole), and hydroquinone 10 mg
(0.09 mmole) in 20 ml of toluene is heated at 95°C for 15 hours. The raw material disappears on thin layer chromatography,
(3S,4R)-3-[(R)-1-tert-butyldimethylsilyloxyethyl]-1-[1-(4-nitrobenzyloxycarbonyl)triethoxyphosphoranylidenemethyl]-4-[[( S)-1-(4-nitrobenzyloxycarbonyl)pyrrolidine-3-
Ilthio]carbonylmethyl]-2-azetidinone and the desired carbapenem compound are observed. The solvent and excess triethyl phosphite are distilled off under reduced pressure, and 20 ml of toluene is again added to the remaining oily substance and heated at 95°C for 57 hours to terminate the cyclization reaction of the phosphorane compound. The residue after evaporation of the solvent is purified using a Rover column. Collect the part eluted with a benzene-ethyl acetate (2:1) mixed solvent,
151.5 mg (yield 83%) of the target product was obtained as an oily substance. IR spectrum ν ^CHCl3 _nax cm ^-1 : 1770, 1695 NMR spectrum (CDCl ₃ ) δppm: 0.07 (6H,
s), 0.87 (9H, s), 1.24 (3H, d, J=
6Hz), 1.6-2.8 (2H, m), 2.8-4.5
(10H, m), 5.14 (1H, d, J = 14Hz),
5.18 (2H, s), 5.41 (1H, d, J=14
Hz), 7.46 (2H, d, J=9Hz), 7.61
(2H, d, J=9Hz), 8.17 (4H, d, J=
9Hz) Example 7 (5R,6S)-6-[(R)-1-tert-butyldimethylsilyloxyethyl]-2-[(S)-1-
[N-(4-nitrobenzyloxycarbonyl)
Acetimidoyl]pyrrolidin-3-ylthio]carbapen-2-em-3-carboxylic acid
4-Nitrobenzyl ester (3S,4R)-3-[(R)-tert-butyldimethylsilyloxyethyl]-1-(4-nitrobenzyloxyoxalyl)-4-[[(S)-1-[N-
(4-nitrobenzyloxycarbonyl)acetimidoyl]pyrrolidin-3-ylthio]carbonylmethyl]-2-azetidinone 99mg
(0.14mmole), triethyl phosphite 139mg
(0.84 mmole) and hydroquinone 4 mg
(0.04 mmole) was dissolved in 10 ml of toluene and heated at 95°C for 24 hours under a nitrogen stream. The residue obtained by distilling off the solvent was purified by preparative silica gel thin layer chromatography [developing solvent: benzene-ethyl acetate (3:1) mixed solvent] to obtain 71 mg of the target product (yield 75%). was obtained as an oil. IR spectrum ν ^CHCl3 _nax cm ^-1 : 1773, 1690
(sh.
), 1675 NMR spectrum (CDCl ₃ ) δppm: 0.09 (6H,
s), 0.88 (9H, s), 1.23 (3H, d, J=
6Hz), 2.28 (3H, s), 1.5~2.5 (2H,
m), 2.9-4.5 (10H, m), 5.16 (2H, s),
5.17 (1H, d, J = 14Hz), 5.40 (1H, d,
J=14Hz), 7.49 (2H, d), 7.56 (2H,
d), 8.15 (4H, d) Example 8 (5R, 6s)-2-[(S)-1-[N-(4-nitrobenzyloxycarbonyl)acetimidoyl]pyrrolidin-3-ylthio]-6 -[(R)-
1-(trimethylsilyloxy)ethyl]carbapen-2-em-3-carboxylic acid 4-nitrobenzyl ester (3S,4R)-4-[[(S)-1-[N-(4-nitrobenzyloxycarbonyl)acetimidoyl]pyrrolidin-3-ylthio]carbonylmethyl]-1-(4-nitrobenzyloxy oxalyl)-3-[(R)-1-(trimethylsilyloxy)ethyl]-2-azetidinone 180mg
(0.24mmole), triethyl phosphite 200mg
(1.20mmole), hydroquinone 7.5mg, toluene
Heat 15 ml of the mixture at 105°C under nitrogen for 50 hours. The residue obtained by distilling off the solvent under reduced pressure is purified using Rover Column A. Elute with benzene-ethyl acetate (1:2) mixed solvent to obtain the title compound.
109 mg (yield 63%) was obtained. Recrystallization was performed from a benzene-isopropyl ether mixed solvent to obtain crystals with a melting point of 95-96°C. Specific optical rotation [α] ²⁵ _D +84° (C = 0.72, CHCl ₃ ) IR spectrum ν ^nujol _nax cm ^-1 : 1781, 1693,
1670 NMR spectrum ( _CDCl3 ) δppm: 0.15
(9H), 1.27 (3H, d, J=6Hz), 2.28
(3H, s), 1.9~2.6 (2H, m), 3.0~4.5
(10H, m), 5.17 (2H, s), 5.18 (1H,
d, J = 13.5Hz), 5.44 (1H, d, J = 13.5
Hz), 7.51 (2H, d), 7.60 (2H, d), 8.17
(4H, d) Example 9 (5R, 6S)-2-[2-(4-nitrobenzyloxycarbonylamino)ethylthio]-6-
[(R)-1-trimethylsilyloxyethyl]
Carbapen-2-M-3-carboxylic acid 4-nitrobenzyl ester (3S,4R)-4-[[2-(4-nitrobenzyloxycarbonylamino)ethylthio]carbonylmethyl]-1-(4-nitrobenzyloxyoxalyl)-3-[(R)-1-trimethylsilyloxyethyl ]-2-Azetidinone 114mg
(0.16 mmole), triethyl phosphite 164 mg
(0.99 mmole) and hydroquinone 3 mg
(0.03 mmole) was dissolved in 15 ml of toluene and heated at 100°C for 24 hours under a nitrogen stream. After the reaction is complete, the solvent is distilled off under reduced pressure and the residue is purified using a Lorber column. Elution with a benzene-ethyl acetate (2:1) mixed solvent gave 43 mg (yield 40%) of the target product as a solid. Recrystallization from benzene-hexane yielded a pure product with a melting point of 105-106°C. IR spectrum ν ^CHCl3 _nax cm ^-1 : 1773, 1718
，
1700 (sh.) NMR spectrum (CDCl ₃ ) δppm: 0.14 (9H,
s), 1.26 (3H, d, J=6Hz), 2.8-3.7
(7H, m), 3.9-4.5 (2H, m), 5.15 (2H,
s), 5.18 (1H, d, J = 14Hz), 5.44
(1H, d, J=14Hz), ~5.3 (1H, br.),
7.43 (2H, d), 7.59 (2H, d), 8.17
(4H, d) Example 10 (5R, 6S)-6-[(R)-1-(4-nitrobenzyloxycarbonyloxy)ethyl]-2-
[(S)-1-(4-nitrobenzyloxycarbonyl)pyrrolidin-3-ylthio]carbapen-2-em-3-carboxylic acid 4-nitrobenzyl ester (3S,4R)-3-[(R)-1-(4-nitrobenzyloxycarbonyloxy)ethyl]-4-
[(S)-1-(4-nitrobenzyloxycarbonyl)pyrrolidin-3-ylthio]carbonylmethyl]-1-(4-nitrobenzyloxyoxalyl)-2-azetidinone 128 mg (0.155 mmole), triethyl phosphite 155 mg (0.934 mmole) and 7 mg (0.06 mmole) of hydroquinone in 13 ml of toluene
Dissolve in and heat at 90° under a nitrogen stream for 1.5 hours.
Once the raw materials had disappeared, the solvent and excess triethyl phosphite were distilled off under reduced pressure, and the resulting residue was dissolved again in 13 ml of toluene and heated at 100°C under a nitrogen stream for 80 min.
Heat for an hour. The solvent is distilled off and the product is separated and purified using a Rover column. Elution with a mixed solvent of ethyl acetate and benzene (1:1) yielded 69.6 mg (yield 56.6%) of the desired product as an oil. IR spectrum ν ^CHCl3 _nax cm ^-1 : 1778, 1745
，
1695, 1690 (sh.) NMR spectrum (CDCl ₃ ) δppm: 1.47 (3H,
d, J=6Hz), 1.7~2.7 (2H, m), 2.9~
4.5 (10H, m), 5.18 (2H, s), 5.21
(2H, s), 5.19 (1H, d, J=14Hz), 5.45
(1H, d, J=14Hz), 7.47 (4H, d), 7.58
(2H, d), 8.17 (6H, d) Example 11 (5R, 6S)-2-[2-(4-nitrobenzyloxycarbonylamino)ethylthio]-6-
[(R)-1-(4-nitrobenzyloxycarbonyloxy)ethyl]carbapen-2-em-
3-carboxylic acid 4-nitrobenzyl ester (3S,4R)-4-[[2-(4-nitrobenzyloxycarbonylamino)ethylthio]carbonylmethyl]-3-[(R)-1-(4-nitrobenzyloxycarbonyloxy)ethyl]-1- (4-
230 mg (0.29 mmole) of nitrobenzyloxyoxalyl-2-azetidinone and 287 mg (1.73 mmole) of triethyl phosphite are heated in 23 ml of toluene at 90° C. for 1 hour under a nitrogen atmosphere. 8 mg of hydroquinone and 10 ml of toluene were added to the residue obtained by distilling off the solvent and volatile substances at the same temperature under reduced pressure.
Heat at 100℃ under nitrogen atmosphere for 44 hours. After the reaction is completed, the solvent is 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 material 90 mg
(yield 40%). Recrystallize with ethyl acetate-benzene-hexane mixed solvent, melting point 148-150℃
Obtained prismatic crystals. Elemental analysis value C ₃₄ H ₃₁ O ₁₆ N ₅ Calculated value as S: C, 53.33; H, 4.08; N, 9.15
; S, 4.19 Actual value: C, 53.19; H, 4.07; N, 9.13
;S, 4.43 IR spectrum ν ^CHCl3 _nax cm ^-1 : 3450, 1780
，
1740 (sh.), 1718, 1700 (sh.) Specific rotation [α] ²⁵ _D +66° (C = 0.81, CHCl ₃ ) NMR spectrum (CDCl ₃ ) δppm: 1.47 (3H,
d, J=6Hz), 2.7-3.7 (7H, m), 4.20
(1H, m), ~5.1 (1H, m), 5.16 (2H,
s), 5.22 (2H, s), 5.18 (1H, d, J=
14Hz), 5.47 (1H, d, J = 14Hz), 7.45
(2H, d), 7.49 (2H, d), 7.60 (2H,
d), 8.20 (6H, d) Example 12 (3S,4R)-3-[(R)-1-(4-nitrobenzyloxycarbonyloxy)ethyl]-1-
[1-(4-nitrobenzyloxycarbonyl)
Triisopropoxyphosphoranylidenemethyl]
-4-[(phenylthio)carbonylmethyl]-
2-azetidinone (3S,4R)-3-[(R)-1-(4-nitrobenzyloxycarbonyloxy)ethyl]-1-(4
-Nitrobenzyloxyoxalyl)-4-[(phenylthio]carbonylmethyl]-2-azetidinone 147 mg (0.225 mmole) and triisopropyl phosphite 234 mg (1.13 mmole) were dissolved in 3 ml of benzene and heated at 70°C under nitrogen flow for 1.5 hours. Stir.The residue obtained by distilling off the solvent is transferred to Rover Column A.
(manufactured by E. Merck). Benzene-
The target product was eluted with ethyl acetate (3:1) mixed solvent.
161 mg (85% yield) was obtained as an oil. IR spectrum ν ^CHCl3 _nax cm ^-1 : 1748, 1700
，
1630 Example 13 (5R,6S)-6-[(R)-1-(4-nitrobenzyloxycarbonyloxy)ethyl]-2-
(Phenylthio)carbapen-2-m-3-
Carboxylic acid 4-nitrobenzyl ester (3S,4R)-3-[(R)-1-(4-nitrobenzyloxycarbonyloxy)ethyl]-1-[1
-(4-nitrobenzyloxycarbonyl)triisopropyloxyphosphoranylidenemethyl]-
4-[(phenylthio)carbonylmethyl]-2-
55 mg of azetidinone and 3 mg of hydroquinone are heated in 5 ml of toluene at 105°C under a nitrogen stream for 48 hours.
Toluene was distilled off under reduced pressure, and the residue was purified with silica gel 5.
Subjected to column chromatography using g. 5
% ethyl acetate-benzene mixed solvent to obtain 27 mg (yield 67%) of the desired product as an oil. IR spectrum ν ^CHCl3 _nax cm ^-1 : 1779, 1745
，
1700 NMR spectrum ( _CDCl3 ) δppm: 1.41 (3H,
d, J = 6Hz), 2.65 (2H, d, J = 9
Hz), 3.24 (1H, dd, J=8, 25Hz), 4.03
(1H, td, J=9, 2.5Hz), ~5.0 (1H,
m), 5.14 (2H, s), 5.21 (1H, d, J=
14Hz), 5.48 (1H, d, J = 14Hz), ~7.4
(5H, m), 7.42 (2H, d), 7.60 (2H,
d), 8.14 (2H, d), 8.18 (2H, d) Example 14 (3S, 4R)-4-[[(S)-1-[N(4-nitrobenzyloxycarbonyl)acetimidoyl]pyrrolidine -3-ylthio]carbonylmethyl]-3-[(R)-1-(4-nitrobenzyloxycarbonyloxy)ethyl]-1-[1-
(4-nitrobenzyloxycarbonyl)triethoxyphosphoranylidenemethyl]-2-azetidinone (3S,4R)-4-[[(S)-1-[N-(4-nitrobenzyloxycarbonyl)acetimidoyl]pyrrolidin-3-ylthio]carbonylmethyl]-3-[(R)-1- (4-nitrobenzyloxycarbonyloxy)ethyl]-1-(4-nitrobenzyloxyoxalyl)-2-azetidinone
972mg (1.12mmole) triethyl phosphite 1.12g
(6.75 mmole) was dissolved in 80 ml of toluene 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 with a mixed solvent of ethyl acetate-chloroform-methanol (30:10:1) yielded 961 mg of the target product.
(yield 84%) was obtained as an oil. IR spectrum ν ^CHCl3 _nax cm ^-1 : 1750, 1680
，
1640 Example 15 (5R,6S)-2-[(S)-1-[N-(4-nitrobenzyloxycarbonyl)acetimidoyl]pyrrolidin-3-ylthio]-6-[(R)-
1-(4-nitrobenzyloxycarbonyloxy)ethyl]carbapen-2-em-3-carboxylic acid 4-nitrobenzyl ester (3S,4R)-4-[[(S)-1-[N-(4-nitrobenzyloxycarbonyl)acetimidoyl]pyrrolidin-3-ylthio]carbonylmethyl]-3-[(R)-1- (4-nitrobenzyloxycarbonyloxy)ethyl]-1-[1-(4-
A mixture of 197 mg of nitrobenzyloxycarbonyl)triethyloxyphosphoranylidenemethyl]-2-azetidinone, 20 mg of hydroquinone, and 20 ml of toluene was heated at 100° C. for 44 hours under a nitrogen stream. The solvent is distilled off under reduced pressure, and the residue is purified using a Rover column. By elution with a mixed solvent of ethyl acetate-chloroform-methanol (30:10:1), 16 mg (8%) of the starting material was recovered, and then 93 mg (yield 58%) of the desired product was obtained as an oil. IR spectrum ν ^CHCl3 _nax cm ^-1 : 1780, 1744
，
1690 (sh.), 1676 Specific optical rotation [α] ²⁵ _D +68° (C = 0.17, CHCl ₃ ) NMR spectrum (CDCl ₃ ) 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 (2H,
s), 5.20 (2H, s), 5.14 (1H, d, J=
14Hz), 5.43 (1H, d, J = 14Hz), 5.2
(1H, m), 7.50 (4H, d), 7.57 (2H,
d), 8.17 (6H, d) Example 16 (5R, 6S)-2-[(R)-1-[(R)-4-(4-
nitrobenzyloxycarbonyl)morpholin-2-yl]ethylthio]-6[(R)-1-(t
-butyldimethylsilyloxy)ethyl]carbapenem-3-carboxylic acid 4-nitrobenzyl ester (3S,4R)-3-[(R)-1-t-butyldimethylsilyloxyethyl]-4-carboxymethyl-2-azetidinone and (R)-4-(4-nitrobenzyloxycarbonyl)-2- When a compound obtained by reacting [(R)-1-mercaptoethyl]morpholine in the same manner as in Reference Example 1 is reacted with 4-nitrobenzyloxyoxalyl chloride in the same manner as in Reference Example 2, (3S,4R)- 3-[(R)-1-t-
butyldimethylsilyloxyethyl]-4-
[(R)-1-[(R)-4-(4-nitrobenzyloxycarbonyl)-morpholin-2-yl]ethylthiocarbonylmethyl]-1-(4-nitrobenzyloxyoxalyl)-2-azetidinone can get. When this compound was subjected to reaction treatment in the same manner as in Example 1, the desired product was obtained as an oil with a yield of 80%. IR spectrum ν ^CHCl3 _nax cm ^-1 : 3450, 1778
，
1700 NMR spectrum ( _CDCl3 ) δppm: 0.08 (6H,
s), 0.88 (9H, s), 1.25 (3H, d, J=
7Hz), 1.35 (3H, d, J=7Hz), 2.5-4.5
(13H, m), 5.23 (2H, s), 5.20 (1H,
d, J = 14Hz), 5.51 (1H, d, J = 14
Hz), 7.48 (2H, d), 7.63 (2H, d), 8.21
(4H, d) Example 17 (1R,5R,6S)-6-[(R)-1-(tert-butyldimethylsilyloxy)ethyl]-1-methyl-2-(phenylthio)carbapen-2-em -3-carboxylic acid 4-nitrobenzyl ester (3S,4R)-3-[(R)-1-(tert-butyldimethylsilyloxy)ethyl]-4-[(R)-1-
[(phenylthio)carbonyl]ethyl]-1-(4
-Nitrobenzyloxyoxalyl)-2-azetidinone 320mg (0.52mmole) was dissolved in toluene 25ml, triethyl phosphite 432mg.
(2.60 mmole) and 15 mg of hydroquinone were added, and the mixture was heated under reflux for 24 hours under a nitrogen atmosphere. The residue obtained by distilling off the solvent is subjected to column chromatography using 10 g of silica gel. Elution with a 5% ethyl acetate-benzene mixed solvent gave 235 mg (yield 78%) of the title compound as an oil. IR spectrum ν ^CHCl3 _nax cm ^-1 : 1775, 1695 NMR spectrum (CDCl ₃ ) δppm: 0.06 (6H,
s), 0.85 (9H, s), 1.23 (6H, d, J=
6Hz), ~2.9 (1H, m), 3.07 (1H, dd, J
=4.2Hz), ~4.1 (2H, m), 5.20 (1H,
d, J = 14Hz), 5.45 (1H, d, J = 14
Hz), 7.2-7.7 (5H, m), 7.61 (2H, d),
8.17 (2H, d) Reference example 1 (3S,4R)-3-[(R)-(1-tert-butyldimethylsilyloxy)ethyl]-4-(butylthio)carbonylmethyl]-2-azetidinone (3S,4R)-3-[(R)-(1-tert-butyldimethylsilyloxy)ethyl]-4-carboxymethyl-2-azetidinone 542 mg (1.89 mmole),
Butyl mercaptan 212 mg (2.36 mmole), triethylamine 381 mg (3.77 mmole) and diphenylphosphoryl azide 1.04 g (3.78 mmole) N,N
-Leave the 10 ml solution of dimethylformamide at room temperature overnight. The reaction mixture is diluted with ethyl acetate, washed several times with water, dried, and the solvent is distilled off. residue 1.25
g was subjected to column chromatography using 23 g of silica gel, and hexane-ethyl acetate (4:1~
2:1) Collect the part eluted with mixed solvent and collect 649 mg.
The title compound (yield 96%) was obtained. Recrystallization from hexane gave colorless needles with a melting point of 56.5-57°C. Elemental analysis value C ₁₇ H ₃₃ NO ₃ Calculated value as SSi: C, 56.78; H, 9.25; N, 3.90
; S, 8.92 Actual value: C, 56.88; H, 9.15; N, 3.87
;S, 9.08 IR spectrum ν ^Nujol _nax cm ^-1 : 3160, 3090,
1762,
1722, 1683 NMR spectrum (CDCl ₃ ) δppm: 0.06 (6H,
s), 0.89 (9H, s), 0.6-1.8 (7H, m),
1.16 (3H, d, J=6Hz), 2.7~3.2 (5H,
m), 3.9 (1H, m), 4.15 (1H, quintet, J
=6Hz), 6.4 (1H, br.s) Reference example 2 (3S,4R)-3-[(R)-1-(tert-butyldimethylsilyloxy)ethyl]-4-[(butylthio)carbonylmethyl] -1-(4-nitrobenzyloxyoxalyl)-2-azetidinone (3S,4R)-3-[(R)-(1-tert-butyldimethylsilyloxy)ethyl]-4-(butylthio)carbonylmethyl-2-azetidinone 150mg
(0.418 mmole) in 1,2-dichloroethane was cooled on ice, and while stirring under a nitrogen stream, 1,4-
Diazabicyclo[2,2,2]octane 140mg
(1.25 mmol) and 305 mg (1.25 mmole) of 4-nitrobenzyloxyoxal chloride are added sequentially.
After continuing stirring for 2 hours, 0.1M phosphate buffer (PH7.2) is added to terminate the reaction. Add methylene chloride, wash the organic layer with water, and dry. After evaporating the solvent, 232 mg of the residue was subjected to column chromatography using 6 g of silica gel, and the portion eluted with a hexane-ethyl acetate (5:1) mixed solvent was collected.
132 mg (56% yield) of the title compound was obtained as an oil. IR spectrum ν ^CHCl3 _nax cm ^-1 : 1802, 1756
，
1687, 1520, 1346 NMR spectrum (CDCl ₃ , 100MHz) δppm:
-0.01 (3H, s), 0.08 (3H, s), 0.80
(9H, s), 0.90 (3H, t, J=6Hz), 1.19
(3H, d, J=6Hz), ~1.5 (4H, m),
2.90 (2H, t, J=6Hz), 3.00 (1H, dd,
J=15,8Hz), 3.33(1H,t,J=3
Hz), 3.40 (1H, dd, J=15, 4Hz), 4.31
(1H, qd, J=6,3Hz), 4.61 (1H,
ddd, J = 8, 4, 3Hz), 5.40 (2H, s),
7.58 (2H, d, J=9Hz), 8.23 (2H, d,
J=9Hz) Reference example 3 (3S,4R)-3-[(R)-1-(tert-butyldimethylsilyloxy)ethyl]-4-[(isopropylthio)carbonylmethyl]-2-azetidinone (3S,4R)-3-[(R)-1-(tert-butyldimethylsilyloxy)ethyl]-4-carboxymethyl-2-azetidinone 1.15 mg
(4.00mmole), isopropyl mercaptan 380mg
(5.00mmole), triethylamine 808mg
(8.00mmole), diphenylphosphoryl azide 2.20
g (8.00 mmole) in 20 mg of dimethylformamide and left at room temperature for 15 hours. After the reaction is complete, the reaction solution is poured into ice water, extracted twice with ethyl acetate, and washed with water. After drying, the solvent was distilled off and the resulting residue was subjected to chromatography using 30 g of silica gel. Elution was performed with a hexane-ethyl acetate (3:1) mixed solvent to obtain 1.06 g (yield 77%) of the title compound as a solid. Recrystallize from hexane,
A pure product was obtained with a melting point of 87-90°C. Elemental analysis value C ₁₆ H ₃₁ NO ₃ Calculated value as SSi: C, 55.61; H, 9.04; N, 4.05
; S, 9.28 Actual value: C, 55.71; H, 8.92; N, 4.25
;S, 9.24 IR spectrum ν ^CHCl3 _nax cm ^-1 : 3420, 1756,
1670 NMR spectrum ( _CDCl3 ) δppm: 0.08 (6H,
s), 0.88 (9H, s), 1.18 (3H, d, J=
6Hz), 1.30 (6H, d, J=7Hz), ~2.8
(3H, m), 3.64 (1H, m), 3.8~4.4 (2H,
m), 6.3 (1H, br) Reference example 4 (3S,4R)-3-[(R)-(1-tert-butyldimethylsilyloxy)ethyl]-4-[(isopropylthio)carbonylmethyl]-1 -(4-nitrobenzyloxyoxalyl)-2-azetidinone (3S,4R)-3-[(R)-(1-tert-butyldimethylsilyloxy)ethyl]-4-[(isopropylthio)carbonylmethyl]-2-azetidinone 708 mg (2.05 mmole) was dissolved in 30 ml of methylene chloride. After melting and stirring under ice cooling, 689 mg (6.15 mmole) of 1,4-diazabicyclo[2,2,2]octane and then 1.50 g (6.15 mmole) of 4-nitrobenzyloxyoxalyl chloride were added. After 1.5 hours, pour the reaction solution into 20 ml of 0.1M phosphate buffer (PH7.2), separate the organic layer, and wash with water. After drying, the solvent is distilled off and the resulting residue is subjected to chromatography using 20 g of silica gel. Elution was performed with a mixed solvent of hexane-ethyl acetate (5:1 to 4:1) to obtain 1.12 g (yield 99%) of the title compound as an oil. IR spectrum ν ^CHCl3 _nax cm ^-1 : 1804, 1755,
1695 NMR spectrum (CDCl ₃ ) δppm: −0.03 (3H,
s), 0.05 (3H, s), 0.80 (9H, s), 1.18
(3H, d, J = 6Hz), 1.30 (6H, br.d, J
= 7Hz), 2.96 (1H, dd, J = 15, 8Hz),
3.32 (1H, dd, J = 15, 4Hz), 3.33 (1H,
t, J=3Hz), 3.65 (1H, m), ~4.3
(1H, m), ~4.6 (1H, m), 5.40 (2H,
s), 7.56 (2H, d), 8.17 (2H, d) Reference example 5 (3S, 4R)-3-[(R)-(1-tert-butyldimethylsilyloxy)ethyl]-4-[(phenylthio ) carbonylmethyl]-2-azetidinone (3S,4R)-4-acetoxy-3-[(R)-1
-(tert-butyldimethylsilyloxy)ethyl]-1-trimethylsilyl-2-azetidinone
1.10g (3.06mmole) and 961mg of trimethylsilylthioacetic acid S-phenyl ester
(4.29 mmole) in 20 ml of methylene chloride solution at −20°C.
Cool to 0.07 ml of trifluoromethanesulfonic acid trimethylsilyl ester under a nitrogen stream.
(0.32 mmole). After stirring at -10° to 5°C for 4.5 hours, water is added to terminate the reaction. Wash the methylene chloride layer with diluted sodium bicarbonate solution and saturated saline.
Dissolve the residue after solvent distillation in 2.5 ml of ethanol,
Add 58 mg (1.00 mmole) of potassium fluoride and stir at room temperature.
Stir for 1.5 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 Rover column (manufactured by E. Merck). The portion eluted with a hexane-ethyl acetate (2:1) mixed solvent was collected and yielded 961 mg of the title compound.
(yield 83%) was obtained as crystals. Recrystallization from hexane gave needle-shaped crystals with a melting point of 94-95°C. Elemental analysis value C ₁₉ H ₂₉ NO ₃ Calculated value as SSi: C, 60.12; H, 7.70; N, 3.69
; S, 8.45 Actual value: C, 60.11; H, 7.72; N, 3.67
;S, 8.54 IR spectrum ν ^nujol _nax cm ^-1 : 3160, 3000,
1767,
1726, 1703 NMR spectrum (CDCl ₃ ) δppm: 0.08 (6H,
s), 0.88 (9H, s), 1.21 (3H, d, J=
6Hz), 2.7-3.2 (3H, m), 4.0 (1H, m),
4.18 (1H, quintet, J=6Hz), 6.10 (1H,
br.s), 7.4(5H,s) Reference example 6 (3S,4R)-3-[(R)-(1-tert-butyldimethylsilyloxy)ethyl]-1-(4-nitrobenzyloxyoxalyl) -4-[(phenylthio)carbonylmethyl]-2-azetidinone (3S,4R)-3-[(R)-(1-tert-butyldimethylsilyloxy)ethyl]-4-[(phenylthio)carbonylmethyl]-2-azetidinone 747
mg (1.97 mmole) and triethylamino 398 mg
A solution of (3.94 mmole) in methylene chloride (20 ml) was cooled with ice, and 960 mg (3.94 mmole) of 4-nitrobenzyloxyoxalyl chloride was added under a nitrogen stream, followed by stirring for 2 hours. Add 0.1M phosphate buffer (PH
7.2) is added to terminate the reaction, and the organic layer is washed with water. After drying, the solvent was distilled off and the residue was purified using silica gel 15
Calm chromatography using g. The fraction eluted with hexane-ethyl acetate (6:1 to 3:1) was collected to give 1.032 g (89% yield) of the title compound as an oil. IR spectrum ν ^CHCl3 _nax cm ^-1 : 1805, 1757,
1699, 1609, 1522, 1344 NMR spectrum (CDCl ₃ ) δppm: −0.02 (3H,
s), 0.04 (3H, s), 0.08 (9H, s), 1.14
(3H, d, J=6Hz), 3.11 (1H, dd, J=
15,8Hz), 3.35 (1H, t, J=3Hz), 3.43
(1H, dd, J = 15, 4Hz), 4.29 (qd, J =
6,3Hz), 4.64 (1H, ddd, J=8,4,
3Hz), 5.37 (2H, s), 7.52 (2H, d, J
= 8 Hz), 8.16 (2H, d, J = 8 Hz) Reference example 7 (3S, 4R)-3-[(R)-1-(tert-butyldimethylsilyloxy)ethyl]-4-[2-(4
-nitrobenzyloxycarbonylamino)ethylthio]carbonylmethyl]-2-azetidinone (3S,4R)-3-[(R)-1-(tert-butyldimethylsilyloxy)ethyl]-4-carboxymethyl-2-azetidinone 1.00g
(3.48 mmole), 2-(4-nitrobenzyloxycarbonylamino)ethanethiol 1.07 g
(4.18 mmole) was dissolved in 20 ml of benzene, and dicyclohexylcarboimide 861 was dissolved while stirring at room temperature.
mg (4.18 mmole) and then 10 mg (0.082 mmole) of 4-dimethylaminopyridine. 2 hours later
The formed insoluble solid was removed, the solvent was distilled off from the liquid, and the residue was subjected to column chromatography using 40 g of silica gel. Elution with benzene-ethyl acetate (1:1) mixed solvent yielded 1.59 g of the title compound.
(yield 87%) was obtained as an oil. IR spectrum ν ^CHCl3 _nax cm ^-1 : 3390, 1746,
1715, 1673 NMR spectrum (CDCl ₃ ) δppm: 0.07 (6H,
s), 0.87 (9H, s), 1.17 (3H, d, J=
6Hz), 2.7-3.6 (7H, m), 3.8-4.4 (2H,
m), 5.12 (2H, s), 5.88 (1H, br.t, J=
6Hz), 6.91 (1H, s), 7.41 (2H, d),
8.10 (2H, d) Reference example 8 (3S,4R)-3-[(R)-1-(tert-butyldimethylsilyloxy)ethyl]-4-[[2-(4
-nitrobenzyloxycarbonylamino)ethylthio]carbonylmethyl]-1-(4-nitrobenzyloxyoxalyl)-2-azetidinone (3S,4R)-3-[(R)-(tert-butyldimethylsilyloxy)ethyl]-4-[[2-(4-nitrobenzyloxycarbonylamino)ethylthio]carbonylmethyl]-2-azetidinone 500 mg
(0.95 mmole) in 6 ml of methylene chloride,
288 mg of triethylamine under stirring at °C
(2.85 mmole) Then 694 mg (2.85 mmole) of 4-nitrobenzyloxyoxalyl chloride is added. After 1 hour, 10 ml of 0.1M phosphate buffer (PH7.0) is added to the reaction solution, the organic layer is separated, dried, and the solvent is distilled off. The residue was subjected to column chromatography using 8 g of silica gel and eluted with a hexane-ethyl acetate (1:1) mixed solvent to obtain the title compound.
642 mg (92% yield) was obtained as an oil. IR spectrum ν ^CHCl3 _nax cm ^-1 : 3450, 1802,
1745
(sh.), 1715, 1700 (sh.) NMR spectrum (CDCl ₃ ) δppm: −0.02 (3H,
s), 0.05 (3H, s), 0.80 (9H, s), 1.18
(3H, d, J=6Hz), 2.8−3.6 (7H, m),
~4.25 (1H, m), ~4.6 (1H, m), 5.15
(2H, s), 5.36 (2H, s), 7.46 (2H,
d), 7.54 (2H, d), 8.17 (2H, d), 8.19
(2H, d) Reference example 9 (3S,4R)-3-[(R)-1-(tert-butyldimethylsilyloxy)ethyl]-4-[(S)-1
-(4-nitrobenzyloxycarbonyl)pyrrolidin-3-ylthio]carbonylmethyl]
-2-azetidinone (3R,4R)-4-acetoxy-3-[(R)-1
-(tert-butyldimethylsilyloxy)ethyl]-1-(trimethylsilyl)-2-azetidinone 180 mg (0.50 mmole), (S)-1-(4-nitrobenzyloxycarbonyl)-3-(trimethylsilylacetylthio)pyrrolidine 414mg
(1.00 mmole) was dissolved in 3 ml of methylene chloride, then 15 mg (0.07 mmole) of trifluoromethanesulfonic acid trimethylsilyl ester was added, and the mixture was heated at room temperature.
Leave 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 and purified by preparative thin layer chromatography [developing solvent: chloroform-ethyl acetate (6:1)], and 185 mg (yield 67%) of the resulting solid was re-purified from hexane-ethyl acetate. A pure product was crystallized and had a melting point of 104-106°C. IR spectrum ν ^CHCl3 _nax cm ^-1 : 3410, 1775,
1685 NMR spectrum ( _CDCl3 ) δppm: 0.08 (6H,
s), 0.88 (9H, s), 1.19 (3H, d, J=
6Hz), 1.7-2.5 (2H, m), 2.7-3.0 (2H,
m), 3.53 (2H, t, J=7Hz), 3,2~
4.4 (6H, m), 5.19 (2H, s), 6.15 (1H,
br), 7.42 (2H, d), 8.20 (2H, d) Reference example 10 (3S, 4R)-3-[(R)-1-(tert-butyldimethylsilyloxy)ethyl]-1-(4- nitrobenzyloxyoxalyl)-4-[[(S)-
1-(4-nitrobenzyloxycarbonyl)
Pyrrolidin-3-ylthio]carbonylmethyl]-2-azetidinone (3S,4R)-3-[(R)-1-(tert-butyldimethylsilyloxy)ethyl]-4-[[(S)-1
-(4-nitrobenzyloxycarbonyl)pyrrolidin-3-ylthio]carbonylmethyl]-2
- 57.7 mg (0.105 mmole) of azetidinone and 33 mg (0.33 mmole) of triethylamine in methylene chloride 3
ml solution was cooled on ice, and under nitrogen flow, 73 mg of 4-nitrobenzyloxyoxalyl chloride was added.
(0.30 mmole) and stir for 1 hour. Pour the reaction solution into 0.1M phosphate buffer (PH7.2) and wash the organic layer with saturated saline. The residue after evaporation of the solvent was subjected to column chromatography using 1.3 g of silica gel, and a benzene-ethyl acetate mixed solvent (12:1 to
4:1) was collected and the title compound 67.8
mg (yield 83%) was obtained as an oil. IR spectrum ν ^CHCl3 _nax : 1800, 1754, 1695
，
1682 NMR spectrum (CDCl ₃ ) 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 (2H, s), 5.43
(2H, s), 7.50 (2H, d, J=8Hz), 7.56
(2H, d, J=8Hz), 8.22 (4H, d, J=
8Hz) Reference example 11 (3S,4R)-3-[(R)-1-(tert-butyldimethylsilyloxy)ethyl]-4-[[(S)-
1-[N-(4-nitrobenzyloxycarbonyl)acetimidoyl]pyrrolidin-3-ylthio]carbonylmethyl]-2-azetidinone (3S,4R)-3-[(R)-1-(tert-butyldimethylsilyloxy)ethyl]-4-carboxymethyl-2-azetidinone 267 mg (0.93 mmole)
and (S)-3-mercapto-1-[N-(4-nitrobenzyloxycarbonyl)acetimidoyl]pyrrolidine (330 mg (1.02 mmole)) were dissolved in 5 ml of benzene and dicyclohexyldicarboimide was dissolved.
Add 210 mg (1.02 mmole) followed by 5 mg (0.041 mmole) of 4-dimethylaminopyridine. After stirring at room temperature for 1 hour, the formed insoluble solid was removed,
The solvent is distilled off from the liquid. The obtained oil was subjected to column chromatography using 15 g of silica gel, and benzene-ethyl acetate (1:2 to 1:5)
Elution with a mixed solvent yielded 495 mg of the title compound (yield 90
%) was obtained as an oil. IR spectrum ν ^CHCl3 _nax cm ^-1 : 3410, 1760
，
1677 NMR spectrum (CDCl ₃ ) δppm: 0.09 (6H,
s), 0.88 (9H, s), 1.20 (3H, d, J=
6.5Hz), 2.29 (3H, s), 1.5~2.5 (2H,
m), 2.7-3.0 (2H, m), 3.3-4.4 (8H,
m), 5.18 (2H, s), 6.27 (1H, br.s),
7.52 (2H, d), 8.17 (2H, d) Reference example 12 (3S, 4R)-3-[(R)-(1-tert-butyldimethylsilyloxy)ethyl]-1-(4-nitrobenzyloxy oxalyl)-4-[[(S)-
1-[N-nitrobenzyloxycarbonyl)
Acetimidoyl]pyrrolidin-3-ylthio]carbonylmethyl]-2-azetidinone (3S,4R)-3-[(R)-1-(tert-butyldimethylsilyloxy)ethyl]-4-[(S)-1-
[N-(4-nitrobenzyloxycarbonyl)acetimidoyl]pyrrolidin-3-ylthio]carbonylmethyl]-2-azetidinone 185 mg
(0.31 mmole) was dissolved in 5 ml of tetrahydrofuran, and while stirring at -78°C under a nitrogen stream, 15% n-
Butyl lithium hexane solution 0.20ml
(0.32 mmole) dropwise. After stirring for 2 minutes at the same temperature, 120 mg (0.49 mmole) of p-nitrobenzyloxyoxalyl chloride is added. After stirring for 4 minutes, add 0.1M phosphate buffer (PH7.1) to the reaction solution.
Add 10ml and extract with ethyl acetate. After drying, the solvent is distilled off and the residue is subjected to chromatography using 6 g of silica gel. After eluting impurities with a mixed solvent of benzene-ethyl acetate (8:1), elution was carried out with a mixed solvent of benzene-ethyl acetate (4:1 to 3:1) to obtain 99 mg (yield 45%) of the title compound as an oil. obtained as. (Benzene-ethyl acetate (1:2~
1:5) further elute with mixed displacement to obtain starting compound 51
mg (28%) was recovered. ) IR spectrum ν ^CHCl3 _nax cm ^-1 : 1808, 1756,
1689 NMR spectrum (CDCl ₃ ) δppm: −0.03 (3H,
s), 0.08 (3H, s), 0.82 (9H, s), 1.20
(3H, d, J=6.5Hz), 2.29 (3H, s), 1.5
~2.5 (2H, m), 3.0 ~ 4.7 (10H, m), 5.17
(2H, s), 5.36 (2H, s), 7.51 (2H,
d), 7.53 (2H, d), 8.18 (2H, d), 8.22
(4H, d) Reference example 13 (3S,4R)-4-[[(S)-1-(N-(4-nitrobenzyloxycarbonyl)acetimidoyl]pyrrolidin-3-ylthio]carbonylmethyl]-1 -(4-nitrobenzyloxyoxalyl)-3-[(R)-1-(trimethylsilyloxy)ethyl]-2-azetidinone (3S,4R)-3-[(R)-1-(tert-butyldimethylsilyloxy)ethyl]-4-[[(S)-1
-[N-(4-nitrobenzyloxycarbonyl)
Acetimidoyl [pyrrolidin-3-ylthio]
Carbonylmethyl]-1-(4-nitrobenzyloxyoxalyl)-2-azetidinone 240mg
(0.30 mmole) in 5 ml of acetonitrile,
Boron trifluoride ether complex with stirring at 0°C
Add 130mg (0.92mmole). After 20 minutes, the reaction solution was mixed with 10 ml of 0.1 M phosphate buffer (PH7.1) and ethyl acetate.
Pour 10ml into a stirring medium and separate the ethyl acetate layer.
After drying over magnesium sulfate, the solvent was distilled off under reduced pressure to obtain 210 mg of the desilylated product as an oil. Dissolve the desilylated product in 3 ml of tetrahydrofuran, and add 154 mg (0.60 mmole) of bis(trimethylsilyl)trifluoroacetamide and 4-(dimethylamino).
Add 2 mg of pyridine and leave at room temperature for 45 minutes. After the reaction is complete, the solvent is distilled off under reduced pressure, and the residue is chromatographed on 2 g of silica gel. Elution with a benzene-ethyl acetate (2:1) mixed solvent gave 191 mg (yield: 84%) of the desired product as an oil. IR spectrum ν ^CHCl3 _nax cm ^-1 : 1803, 1758,
1685 NMR spectrum (CDCl ₃ ) δppm: 0.15 (9H,
s), 1.15 (3H, d, J = 6.5Hz), 2.22
(3H, s), 1.5~2.5 (2H, m), 3.0~4.7
(10H, m), 5.15 (2H, s), 5.30 (2H,
s), 7.51 (2H, d), 7.53 (2H, d), 8.16
(2H, d), 8.20 (2H, d) Reference example 14 (3S, 4R)-3-[(R)-1-(p-nitrobenzyloxycarbonyloxy)ethyl]-4-
[[(S)-1-(4-nitrobenzyloxycarbonyl)pyrrolidin-3-ylthio]carbonylmethyl]-1-(4-nitrobenzyloxyoxalyl)-2-azetidinone (3S,4R)-3-[(R)-1-(4-nitrobenzyloxycarbonyloxy)ethyl]-4-
[[(S)-1-(4-nitrobenzyloxycarbonyl)pyrrolidin-3-ylthio]carbonylmethyl]-2-azetidinone 182 mg (0.295 mmole)
was dissolved in 10 ml of methylene chloride, and while stirring at 0°C, 110 mg (0.98 mmole) of 1,4-diazabicyclo[2,2,2]octane was added, followed by 450 mg of 4-nitrobenzyloxyoxalyl chloride.
(1.85 mmole). After 1 hour, the reaction solution was
Pour into 40 ml of 0.1M phosphate buffer (PH7.1) and extract with methylene chloride. After washing with saturated brine and drying, the solvent is distilled off. The residue is silica gel 5
Column chromatography using 10 g
Elution with ~17.5% ethyl acetate-benzene gave 169 mg (69.5% yield) of the title compound as an oil. IR spectrum ν ^CHCl3 _nax cm ^-1 : 1805, 1745,
1695, 1690 NMR spectrum (CDCl ₃ ) δppm: 1.42 (3H,
d, J=6.5Hz), 1.5~2.5 (2H, m), 2.7~
4.2 (9H, m), ~4.5 (1H, m), 5.17
(2H, s), 5.20 (2H, s), 5.36 (2H,
s), 7.47 (4H, d), 7.52 (2H, d), 8.18
(6H, d) Reference example 15 (3S,4R)-3-[(R)-1-hydroxyethyl]-4-[[2-(4-nitrobenzyloxycarbonylmethyl)ethylthio]carbonylmethyl]-1- (4-nitrobenzyloxyoxalyl)-2-azetidinone (3S,4R)-3-[(R)-(1
-tert-butyldimethylsilyloxy)ethyl]
-4-[[2-(4-nitrobenzyloxycarbonylamino)ethylthio]carbonylmethyl]-
1-(4-nitrobenzyloxyoxalyl)-2
- Dissolve 560 mg (0.76 mmole) of azetidinone in 12 ml of acetonitrile and add 280 mg (1.97 mmole) of boron trifluoride ether complex while stirring at 0°C.
After 15 minutes, dilute the reaction solution with 0.1M phosphate buffer (PH7.1) at 50%
Pour into stirring medium and 20 ml of ethyl acetate and separate the ethyl acetate layer. After drying, the solvent was distilled off to obtain 478 mg (yield 100%) of the title compound as an oil. IR spectrum ν ^CHCl3 _nax cm ^-1 : 3400, 1805,
1750, 1720 (sh.), 1700 NMR spectrum (CDCl ₃ ) δppm: 1.26 (3H,
d, J=6Hz), 2.7~3.7 (8H, m), 3.9~
4.7 (2H, m), 5.13 (2H, s), 5.35 (2H,
s), 5.47 (1H, br), 7.44 (2H, d), 7.51
(2H, d), 8.15 (4H, d) Reference example 16 (3S, 4R)-4-[[2-(4-nitrobenzyloxycarbonylamino)ethylthio]carbonylmethyl]-1-(4-nitrobenzyloxy oxalyl)-3-[(R)-1-(trimethylsilyloxy)ethyl]-2-azetidinone (3S,4R)-3-[(R)-1-hydroxyethyl]-4-[[2-(4-nitrobenzyloxycarbonylamino)ethylthio]carbonylmethyl]
-1-(4-nitrobenzyloxyoxalyl)-
Dissolve 112 mg (0.18 mmole) of 2-azetidinone in 2 ml of tetrahydrofuran and add 95 mg of bis(trimethylsilyl)trifluoroacetamide.
(0.37 mmole), 4-dimethylaminopyridine 1 mg
Add and leave at room temperature for 45 minutes. After the reaction is completed, the solvent is distilled off under reduced pressure, and the residue is subjected to column chromatography using 1 g of silica gel. Elute with benzene-ethyl acetate (2:1) mixed solvent to obtain the title compound.
115 mg (92% yield) was obtained as an oil. NMR spectrum (CDCl ₃ ) δppm: −0.01, 0.03
(1:1, 9H, s), 1.17, 1.22 (1:1,
3H, d, J = 6Hz), 2.6-3.7 (7H, m),
3.9-4.7 (2H, m), 5.14 (2H, s), 5.35
(2H, s), ~5.3 (1H, br), 7.45 (2H,
d), 7.52 (2H, d), 8.18 (4H, d) Reference example 17 (3S, 4R)-4-[[2-(4-nitrobenzyloxycarbonylamino)ethylthio]carbonylmethyl]-3-[( R)-1-(4-nitrobenzyloxycarbonyloxy)ethyl]-2-
Azetidinone (3S,4R)-4-acetoxy-3-[(R)-1
-(4-nitrobenzyloxycarbonyloxy)ethyl]-1-(trimethylsilyl)-2-azetidinone 30 mg (0.051 mmole) and S-[2-[N
-(4-nitrobenzyloxycarbonyl)-N-
(trimethylsilyl)amino]ethyl](trimethylsilyl)ethanethioate 47mg
(0.106 mmole) in 0.5 ml of methylene chloride,
Add 3 mg (0.014 mmole) of trifluoromethanesulfonic acid trimethylsilyl ester under a nitrogen stream. After standing at room temperature for 24 hours, the reaction solution was cooled and stirred in 5% sodium bicarbonate solution, and stirred 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: benzyl-ethyl acetate (1:2)] to obtain 29 mg (yield 69%) of the title compound as an oil. IR spectrum ν ^CHCl3 _nax cm ^-1 : 3460, 3420,
1763, 1750 (sh.), 1730 (sh.), 1685 NMR spectrum (CDCl ₃ ) δppm: 1.40 (3H,
d, J=6Hz), 2.6-3.6 (7H, m), 3.91
(1H, m), 5.13 (2H, s), 5.19 (2H,
s), 4.9-5.5 (2H, m), 6.67 (1H, br.
s), 7.45 (2H, d), 7.48 (2H, d), 8.16
(2H, d), 8.19 (2H, d) Reference example 18 (3S, 4R)-4-[[2-(4-nitrobenzyloxycarbonylamino)ethylthio]carbonylmethyl]-3-[(R)-1 -(4-nitrobenzyloxycarbonyloxy)ethyl]-1-
(4-nitrobenzyloxyoxalyl)-2-
Azetidinone (3S,4R)-4-[[2-(4-nitrobenzyloxycarbonylamino)ethylthio]carbonylmethyl]-3-[(R)-1-(4-nitrobenzyloxycarbonyloxy)ethyl]-2- 358mg (0.449mmole) of azetidinone to 88% of methylene chloride
184 mg (1.82 mmole) of triethylamine and then 443 mg of 4-nitrobenzyloxyoxalyl chloride while stirring at 0°C.
(1.82 mmole). After stirring at the same temperature for 1 hour, add 20ml of 0.1M phosphate buffer (PH7.2) to the reaction solution.
The organic layer is separated and the aqueous layer is 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 5 g of silica gel and eluted with a hexane-ethyl acetate (1:1) mixed solvent to obtain 351 mg (yield 73%) of the title compound as an oil. Hexane-ethyl acetate (1:3)
Further elution with mixed solvent yields 75 mg (21%) of starting material
was recovered. IR spectrum ν ^CHCl3 _nax cm ^-1 : 1808, 1749,
1718
(br.), 1700 (Sh.), 1682 (Sh.) NMR spectrum (CDCl ₃ ) δppm: 1.40 (3H,
d, J=6.5Hz), 2.7-3.7 (7H, m), 4.5
(1H, 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 (2H, d), 7.50
(2H, d), 8.15 (2H, d), 8.17 (4H, d) Reference example 19 (3S, 4R)-3-[(R)-1-(4-nitrobenzyloxycarbonyloxy)ethyl]-4 −
[[(S)-1-(4-nitrobenzyloxycarbonyl)pyrrolidin-3-ylthio]carbonylmethyl]-2-azetidinone (3S,4R)-4-acetoxy-3-[(R)-1
-(4-Nitrobenzyloxycarbonyloxy)ethyl]-1-(trimethylsilyl)-2-azetidinone 53 mg (0.125 mmole) and (S)-1-
(4-nitrobenzyloxycarbonyl)-3-
(trimethylsilylacetylthio)pyrrolidine 103
Dissolve mg (0.25 mmole) in 1 ml of methylene chloride,
Add 5 mg (0.023 mmole) of trifluoromethanesulfonic acid trimethylsilyl ester to this solution, and let stand at room temperature under a nitrogen atmosphere for 28 hours. The reaction solution was diluted with chloroform and washed 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), 3 mg of pyridine-p-toluenesulfonate was added, and the mixture was allowed to stand at room temperature for 30 minutes. Add ethyl acetate, wash with water, dry, and distill off the solvent. The residue obtained is purified by preparative thin layer chromatography on silica gel [developing solvent: benzene-ethyl acetate (2:1)] and labeled. 67 mg (87% yield) of the compound was obtained as a solid. Recrystallization from benzene gave platelet crystals with a melting point of 54-56°C. Elemental analysis value as C ₂₇ H ₂₈ O ₄ S Calculated value: C, 52.59; H, 4.58; N, 9.09
; S, 5.20 Actual value: C, 52.88; H, 4.54; N, 8.93
;S, 5.47 IR spectrum ν ^CHCl3 _nax cm ^-1 : 3410, 1760,
1688 Specific rotation [α] ²⁵ _D +53° (C=0.55, CHCl ₃ ) NMR spectrum (CDCl ₃ ) δppm: 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 (1H, br.), 7.47 (2H,
d), 7.51 (2H, d), 8.20 (4H, d) Reference example 20 (3S, 4R)-4-[[(S)-1-[N-(4-nitrobenzyloxycarbonyl)acetimidoyl] pyrrolidin-3-ylthio]carbonylmethyl]-3-[(R)-1-(4-nitrobenzyloxycarbonyloxy)ethyl]-2-azetidinone (3S,4R)-4-acetoxy-3-[(R)-1
-(4-nitrobenzyloxycarbonyloxy)ethyl]-1-(trimethylsilyl)-2-azetidinone 50 mg (0.118 mmole) and (S)-1-
Dissolve 103 mg (0.24 mmole) of [N-(4-nitrobenzyloxycarbonyl)acetimidoyl]-3-(trimethylsilylacetylthio)pyrrolidine in 0.8 ml of methylene chloride, and add 63 mg of trifluoromethanesulfonic acid trimethylsilyl ester to this solution.
(0.28 mmole) was added for 14 hours at room temperature under a nitrogen atmosphere.
Let stand for a while. Cool the reaction solution on ice and add 5 ml of 5% sodium bicarbonate solution.
Add and stir 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)] and labeled. 45 mg (58% yield) of the compound was obtained as an oil. IR spectrum ν ^CHCl3 _nax cm ^-1 : 3380, 1740,
1680 NMR spectrum (CDCl ₃ ) δppm: 1.41 (3H,
d, J=6.5Hz), 1.7-2.5 (2H, m), 2.27
(3H, s), 2.84 (2H, d, J=7Hz), 3.01
(1H, dd, J=8, 2.5Hz), 3.3~4.2 (5H,
m), 5.1 (1H, m), 5.17 (2H, s), 5.20
(2H, s), 6.32 (1H, br.), 7.51 (4H,
d), 8.17 (2H, d), 8.20 (2H, d) Reference example 21 (3S, 4R)-4-[[(S)-1-[N-(4-nitrobenzyloxycarbonyl)acetimidoyl] pyrrolidin-3-ylthio]carbonylmethyl]-3-[(R)-1-(4-nitrobenzyloxycarbonyloxy)ethyl]-1-[[4
-nitrobenzyloxy)oxalyl]-2-
Azetidinone (3S,4R)-4-[[(S)-1-[N-(4-nitrobenzyloxycarbonyl)acetimidoyl]pyrrolidin-3-ylthio]carbonylmethyl]-3-[(R)-1- (4-Nitrobenzyloxycarbonyloxy)ethyl]-2-azetidinone 150 mg (0.23 mmole) was added to 50 mg of tetrahydrofuran.
ml of 15% butyllithium hexane solution while stirring at -78℃ under a nitrogen stream.
(0.24 mmole) dropwise. After stirring for 2 minutes,
4-Nitrobenzyloxyoxalyl chloride 84
Add mg (0.34 mmole). After stirring for 4 minutes,
Add 7 ml of 0.1M phosphate buffer (PH7.1) to the reaction mixture, and extract with ethyl acetate. After drying, the solvent is distilled off, and the residue is subjected to column chromatography using 4 g of silica gel. Elute with benzene-ethyl acetate (1:5) mixed solvent to obtain 61 mg of the title compound.
(yield 31%) was obtained as an oil. IR spectrum ν ^CHCl3 _nax cm ^-1 : 1810, 1753,
1682
(br.) NMR spectrum (CDCl ₃ ) 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
(1H, m), 5.17 (2H, s), 5.21 (2H,
s), 5.37 (2H, s), ~5.2 (1H, m), 7.52
(6H, br.d), 8.15 (2H, d), 8.19 (4H,
d) Reference example 22 (3S,4R)-3-[(R)-1-(t-butyldimethylsilyloxy)ethyl]-4-[1-[(phenylthio)carbonyl]ethyl]-2-azetidinone (3S,4R)-4-acetoxy-3-[(R)-1
-(t-butyldimethylsilyloxy)ethyl]-
1-trimethylsilyl-2-azetidinone 1.50g
and 1.00 g of 1-phenylthio-1-(trimethylsilyloxy)propene were dissolved in 10 ml of methylene chloride, 50 μl of trifluoromethanesulfonic acid trimethylsilyl ester was added, and the mixture was stirred overnight at room temperature under a nitrogen atmosphere. After washing the reaction solution with water, the solvent was distilled off, and the residue was dissolved in 10 ml of ethanol and dissolved in potassium fluoride.
140 mg was added and stirred at room temperature for 1 hour. Purification on a silica gel column [eluted with cyclohexane-ethyl acetate (4:1)] yielded the title compound [isomer A870].
mg, isomer B 340 mg, approximately 1:1 mixture of A and B 120
mg: total of 1330 mg (yield 81%)]. Isomer A; IR spectrum ν ^CHCl3 _nax cm ^-1 : 3430, 1765,
1695 NMR spectrum ( _CDCl3 ) δppm: 0.08 (6H,
s), 0.87 (9H, s), 1.20 (3H, d, J=
6Hz), 1.32 (3H, d, J=6Hz), 2.7~3.2
(2H, m), 3.94 (1H, dd, J=6,2Hz),
4.20 (1H, dq, J=6.5Hz), 5.90 (1H,
br.s), 7.41 (5H, s) Isomer B; IR spectrum ν ^CHCl3 _nax cm ^-1 : 3430, 1765,
1695 NMR spectrum ( _CDCl3 ) 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 (1H, dd, J=8,2Hz),
4.18 (1H, quint.J=6Hz), 6.05 (1H, br.
s), 7.41 (5H, s) Reference example 23 (3S,4R)-3-[(R)-1-(tert-butyldimethylsilyloxy)ethyl]-4-[(R)-1
-[(phenylthio)carbonyl]ethyl]-1
-(4-nitrobenzyloxyoxalyl)-2
-Azetidinone (3S,4R)-3-[(R)-1-(tert-butyldimethylsilyloxy)ethyl]-4-[(R)-1-
Dissolve 240 mg (0.61 mmole) of [(phenylthio)carbonyl]ethyl]-2-azetidinone in 4 ml of methylene chloride, and add 125 mg of triethylamino under ice cooling.
(1.24 mmole) Then, 300 mg (1.23 mmole) of 4-nitrobenzyloxyoxalyl chloride was added and stirred for 1 hour. Add 0.1M phosphate buffer (PH7.2) to the reaction solution, separate the organic layer, and wash with water.
After drying, the solvent is distilled off and the resulting residue is subjected to column chromatography using 10 g of silica gel. Elution with a hexane-ethyl acetate (4:1) mixed solvent gave 343 mg (yield 92%) of the title compound as an oil. IR spectrum ν ^CHCl3 _nax cm ^-1 : 1805, 1757,
1699 Reference example 24 (3S,4R)-3-[(R)-1-(4-nitrobenzyloxycarbonyloxy)ethyl]-4-
[(phenylthio)carbonylmethyl]-2-azetidinone (3R,4R)-4-acetoxy-3-[(R)-1
-(4-nitrobenzyloxycarbonyloxy)ethyl]-1-trimethylsilyl-2-azetidinone 650 mg (1.53 mmole) and 1-phenylthio-1-(trimethylsilyloxy)ethylene 514
mg (2.29 mmole) is dissolved in 17 ml of dry methylene chloride, 75 mg (0.34 mmole) of trifluoromethanesulfonic acid trimethylsilyl ester is added, and the mixture is left at room temperature for 25 hours under a nitrogen stream. After the reaction is completed, the reaction solution is poured into diluted sodium bicarbonate solution and extracted with chloroform. The residue obtained by distilling off the chromium form was dissolved in a mixture of tetrahydrofuran and water (4:1), and p-
Add 20 mg of toluenesulfonic acid pyridine salt and leave at room temperature for 30 minutes. Add ethyl acetate, wash with saturated brine, dry, and then evaporate the solvent. The residual oil was subjected to column chromatography using 10 g of silica gel and eluted with a mixed solvent of benzene-ethyl acetate (5:1) to obtain 631 mg (yield 93%) of the desired product as an oil. IR spectrum ν ^CHCl3 _nax cm ^-1 : 3410, 1762,
1750
(sh.), 1690 NMR spectrum (CDCl ₃ ) δppm: 1.47 (3H,
d, J=6Hz), ~3.0 (2H, d-like),
3.13 (1H, dd, J=7,2Hz), 4.02 (1H,
ddd, J = 8, 6, 2Hz), ~5.1 (1H,
m), 5.19 (2H, s), 6.32 (1H, br.s),
7.35 (5H, s), 7.43 (2H, d), 8.15
(2H, d) Reference example 25 (3S, 4R)-3-[(R)-1-(4-nitrobenzyloxycarbonyloxy)ethyl]-1-
(4-nitrobenzyloxyoxalyl)-4-
[(phenylthio)carbonylmethyl]-2-azetidinone (3S,4R)-3-[(R)-1-(4-nitrobenzyloxycarbonyloxy)ethyl]-4-
1.00 g (2.25 mmole) of [(phenylthio)carbonylmethyl]-2-azetidinone was dissolved in methylene chloride 20
ml of diisopropylethylamine and 350 mg (2.71 mmole) of diisopropylethylamine with stirring at 0℃.
Nitrobenzyloxyoxalyl chloride 660mg
(2.71 mmole). After 15 minutes, add 230 mg (1.78 mmole) of diisopropylethylamine and 4-
Nitrobenzyloxyoxalyl chloride 433mg
(1.78 mmole) and stir at the same temperature for 15 minutes. After the reaction is complete, add 0.1M phosphate buffer (PH7.1)
Add 30 ml, separate the organic layer, and further extract the aqueous layer with chloroform. Combine the organic layers and evaporate the solvent. The residue was dissolved in benzene-ethyl acetate (1:
1) Dissolve in 50ml of mixed solvent 0.02N-hydrochloric acid, water, 5
% sodium bicarbonate solution and then saturated saline solution. After drying,
After distilling off the solvent, 1.47 g of crystalline target product (yield 100
%) was obtained. A pure product with a melting point of 129-130°C was obtained by recrystallization from a benzene-ethyl acetate mixed solvent. Reference example 26 (5R,6S)-2-[(S)-1-(acetimidoyl)pyrrolidin-3-ylthio]-6-[(R)-
1-Hydroxyethyl]carbapen-2-em-3-carboxylic acid (5R,6S)-2-[(S)-1-[N-(4-nitrobenzyloxycarbonyl)acetimidoyl]pyrrolidin-3-ylthio]-6-[(R)-1
Dissolve 485 mg of -(4-nitrobenzyloxycarbonyloxy)ethyl]carbapen-2-em-3-carboxylic acid 4-nitrobenzyl ester in a mixed solution of 25 ml of tetrahydrofuran and 25 ml of 0.1M phosphate buffer (PH7.1). , 1.4 g of 10% palladium-carbon was added, and the mixture was stirred for 70 minutes under normal pressure of hydrogen. After the reaction is complete, remove the catalyst by filtration, add 15 ml of the above buffer solution, and wash with ethyl acetate.
After concentrating the aqueous layer to about 1/2 at room temperature under reduced pressure,
The fractions eluted with 3% acetone-water were collected by column chromatography using 15 ml of HP20AG (manufactured by Mitsubishi Kasei Corporation), and lyophilized to obtain 115 mg (yield 58%) of the title compound as a white powder. Obtained. IR spectrum ν ^KBr _nax cm ^-1 : 3400, 1760, 1675 NMR spectrum (D ₂ O) δppm: 1.29 (3H,
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)

Claims (1)

[Claims] 1 formula characterized by heating a compound having the formula A method for producing a carbapenem derivative having In the above formula, R ¹ represents a hydrogen atom or a hydroxyl group protecting group, R ² and R ³ are the same or different and represent a hydrogen atom, an alkyl group or a phenyl group,
R ⁴ is an alkyl group that may have a substituent, an aralkyl group that may have a substituent, an aryl group that may have a substituent, or an alicyclic heterocyclic group that may have a substituent , represents an alicyclic heterocyclic substituted alkyl group which may have a substituent or an aromatic heterocyclic group which may have a substituent, R ⁵ represents a hydrogen atom or a protecting group for a carboxy group, R ⁶ represents an alkoxy group, an aryloxy group or a dialkylamino group. 2 formulas A compound having the formula P(R ^{6 ) 3 is reacted with a compound having the formula P(R 6} ) ₃ , and the formula and then heating this compound. A method for producing a carbapenem derivative having In the above formula, R ¹ represents a hydrogen atom or a hydroxyl group protecting group, R ² and R ³ are the same or different and represent a hydrogen atom, an alkyl group or a phenyl group,
R ⁴ is an alkyl group that may have a substituent, an aralkyl group that may have a substituent, an aryl group that may have a substituent, or an alicyclic heterocyclic group that may have a substituent , represents an alicyclic heterocyclic substituted alkyl group which may have a substituent or an aromatic heterocyclic group which may have a substituent, R ⁵ represents a hydrogen atom or a protecting group for a carboxy group, R ⁶ represents an alkoxy group, an aryloxy group or a dialkylamino group.