JPH07316160A - Production of carbapenem compound - Google Patents

Abstract

PURPOSE:To effectively obtain the compound useful as an intermediate for an antibacterial agent by a new method in which ring-closure reaction of beta- lactam compound and a phosphate reaction are performed in one-pot reaction. CONSTITUTION:The compound of formula III (L is an arylsulfonyloxy, a lower- alkanesulfonyloxy, etc.) is obtained by reacting a beta-lactam compound of formula I (R1, R2 are each H or a lower alkyl; R3 is a lower alkyl; X is H or a protected hydroxyl; COZ is an active ester of a carboxyl group, an arylthiocarbonyl, etc.) {e.g. (3S,4S)-3-[(1R)-1-t-butyldimethylsilyloxyethyl]-4-[(1R)-1- imidazolylcarbonylethyl]-2-azetidinone} with an acetic acid ester derivative of formula II (R4 is a carboxyl-protecting group; Y is an active ester of a hydroxyl group or a halogen) (e.g. methyl bromoacetate) in the presence of a base (preferably, sodium hydroxide) followed by the treatment of the reaction product with an active esterification reagent for a hydroxyl group (e.g. methanesulfonic anhydride).

Description

Detailed Description of the Invention

[0001]

FIELD OF THE INVENTION The present invention relates to a novel method for producing a carbapenem compound.

[0002]

2. Description of the Related Art Thienamycin [J. Am. Chem. Soc. , 100 , 313
(1978)] has been reported to have a broad antibacterial spectrum and a strong antibacterial activity, and various carbapenem compounds useful as antibacterial agents have been reported. Position 1 of the carbapenem skeleton (conventional numbering (see formula A below))
According to the present invention, it corresponds to the 4th position in the numbering. ) A compound in which a methylene group is substituted with an alkyl group,
In particular, 1β-methylcarbapenem compound [Hetero
cycles. , 21 , 29 (1984)] is excellent in stability against the enzyme of the kidney, dehydropeptidase-I, and is reported to be extremely useful as an antibacterial agent. Accordingly, effective production of 1β-alkylcarbapenem compounds is reported. There has been much interest in developing methods. The carbapenem compound represented by the general formula (III) described below is an important intermediate in the production of the 1β-alkylcarbapenem compound, and many studies have been made on the production method thereof. Particularly, as an efficient method not accompanied by isomerization of 1β-alkyl group, the method of carrying out the ring-closing reaction and the phosphate-forming reaction in one pot is simple in operation and excellent as an industrial synthetic method. (JP-A-6
2-103084).

[Chemical 4]

[0003]

[Problems to be Solved] Under such circumstances, a method more suitable for large-scale synthesis has been desired.

[0004]

The present inventors have found that a method of carrying out a ring closure reaction and a phosphate reaction in one pot is a method suitable for large-scale synthesis. For the purpose of finding out, we conducted an intensive study. As a result, the general formula (I)

[Chemical 5] [Wherein R 1 and R 2 may be the same or different and each represents a hydrogen atom or a lower alkyl group, R 3 represents a lower alkyl group, X represents a hydrogen atom or a protected hydroxyl group, and COZ represents An active ester of a carboxyl group, a substituted or unsubstituted arylthiocarbonyl group, a substituted or unsubstituted heteroarylthiocarbonyl group, a substituted or unsubstituted aralkylthiocarbonyl group, a substituted aryloxycarbonyl group, or a heteroaryloxycarbonyl group Show. ] In the presence of a base, a β-lactam compound represented by the general formula (II)

[Chemical 6] [In the formula, R4 represents a protecting group for a carboxyl group, and Y represents an active ester of a hydroxyl group or a halogen atom. ] The compound represented by the general formula (III), which is an intermediate for producing a 1β-alkylcarbapenem compound useful as an antibacterial agent, is obtained by reacting with an acetic acid ester derivative represented by

[Chemical 7] [Wherein R 1, R 2, R 3, R 4 and X have the same meanings as described above, and L is a substituted or unsubstituted arylsulfonyloxy group, lower alkanesulfonyloxy group, halogeno lower alkanesulfonyloxy group, di-lower alkylphosphoryl. An oxy group, a di (halogeno lower alkyl) phosphoryloxy group or a di (substituted or unsubstituted aryl) phosphoryloxy group is shown. ] The present invention has been completed by finding an efficient method for producing a carbapenem compound represented by

Here, the substituents in the above formula will be mentioned. As the lower alkyl group in the present invention,
For example, a lower alkyl group having 1 to 4 carbon atoms such as methyl group, ethyl group, n-propyl group and n-butyl group can be mentioned. The protective group for the hydroxyl group in X is not particularly limited as long as it is a commonly used protective group, and examples thereof include (lower alkoxy having 1 to 4 carbon atoms) carbonyl group such as t-butyloxycarbonyl group; (Halogenated alkyloxy having 1 to 4 carbon atoms) carbonyl group such as ethyloxycarbonyl group and 2,2,2-trichloroethyloxycarbonyl group; for example, allyloxycarbonyl group (having 3 to 5 carbon atoms) Alkenyloxy) carbonyl group; for example, substituted or unsubstituted aralkyloxycarbonyl group such as benzyloxycarbonyl group, o-nitrobenzyloxycarbonyl group, p-nitrobenzyloxycarbonyl group, p-methoxybenzyloxycarbonyl group; for example, trimethylsilyl group , Triethylsilyl group, t-butyldi Birds such as Chirushiriru based on -
(C1-4 alkyl) silyl group; Diarylalkylsilyl group such as t-butyldiphenylsilyl group; Substituted methyl group such as methoxymethyl group, 2-methoxyethoxymethyl group and methylthiomethyl group;
A tetrahydropyranyl group etc. can be mentioned. Preferred are tri- (C1-4 alkyl) silyl group, diarylalkylsilyl group, substituted methyl group,
A tetrahydropyranyl group etc. can be mentioned.

When COZ is an active ester of a carboxyl group, the Z group is a heteroaryl group such as an imidazole group or a triazole group, for example, an N-succinimidooxy group, an N-phthalimidooxy group or a benztriazolyl group. Cyclic imidooxy group such as luoxy group,
For example, a heterocycloalkyl group such as a 3- (2-thioxo) thiazolidinyl group can be exemplified. Examples of the substituted or unsubstituted aryl group in the case of a substituted or unsubstituted arylthiocarbonyl group include a phenyl group, a halogenophenyl group substituted with 1 to 3 halogen atoms such as chlorine, bromine and iodine, p- Alternatively, o-nitrophenyl, p-methoxyphenyl group and the like can be mentioned.
Examples of the substituted or unsubstituted heteroaryl group in the case of a substituted or unsubstituted heteroarylthiocarbonyl group include 2-, 3- or 4-pyridyl group, 2-pyrimidyl group, 2- (4,6-dimethyl) Examples thereof include a pyrimidyl group.

In the case of a substituted or unsubstituted aralkylthiocarbonyl group, examples of the substituted or unsubstituted aralkyl group include benzyl group, p-methoxybenzyl group,
Mention may be made of a substituted or unsubstituted monoarylalkyl group such as a 2,4-dimethoxybenzyl group, a p- or o-nitrobenzyl group, a p-chlorobenzyl group. Examples of the substituted aryloxy group in the case of the substituted aryloxycarbonyl group include p- or o-nitrophenyloxy group, 2,4-dinitrophenyloxy group, 1 to 3 halogen atoms such as chlorine, bromine and iodine. Examples thereof include a substituted halogenophenyloxy group and the like.
When the heteroaryloxycarbonyl group is a heteroaryloxy group, for example, 2-, 3- or 4-
Examples thereof include a pyridyloxy group. Preferable examples thereof include active ester of carboxyl group, substituted or unsubstituted arylthiocarbonyl group and heteroarylthiocarbonyl group.

The protecting group for the carboxyl group at R4 of the acetic acid ester derivative represented by the general formula (II) may be one commonly used, but preferably, for example, methyl group, ethyl group, isopropyl group, t-butyl group. A lower alkyl group having 1 to 4 carbon atoms such as a group; a halogeno lower alkyl group having a carbon number of 1 to 4 such as a 2-ethyl iodide group and a 2,2,2-trichloroethyl group; a methoxymethyl group, an ethoxymethyl group Group, (lower alkoxy having 1 to 4 carbon atoms) such as isobutoxymethyl group; for example, acetoxymethyl group, propionyloxymethyl group, butyryloxymethyl group, pivaloyloxymethyl group (having 1 to 4 carbon atoms 5 lower aliphatic acyl) oxymethyl group; for example, allyl group, 2-methylallyl group, 3-methylallyl group, 3-phenoxy group. Carbon atoms such as Ruariru based on 3-10
A substituted or unsubstituted lower alkenyl group; and a substituted or unsubstituted monoarylalkyl group such as a benzyl group, a p- or o-nitrobenzyl group, a p-chlorobenzyl group and the like.

The active ester of the hydroxyl group of Y is, for example, benzenesulfonyloxy group, p-toluenesulfonyloxy group, p-nitrobenzenesulfonyloxy group,
a substituted or unsubstituted arylsulfonyloxy group such as p-bromobenzenesulfonyloxy group, a lower alkanesulfonyloxy group having 1 to 4 carbon atoms such as methanesulfonyloxy group and ethanesulfonyloxy group, for example, a carbon such as trifluoromethanesulfonyloxy group Number 1-4
The halogeno lower alkanesulfonyloxy group and the like can be mentioned, and as the halogen atom, chlorine, bromine,
Iodine etc. can be mentioned. A halogen atom can be mentioned as a suitable thing. The production method of the present invention will be described in more detail according to the following reaction formula.

[Chemical 8] [Wherein R 1, R 2, R 3, R 4, X, Y, Z and L
Represents the same meaning as described above, and B represents an alkali metal atom. ] The compound represented by the general formula (I) in an inert solvent,
A carbapenem compound represented by the general formula (III) can be obtained by reacting the acetic ester derivative (II) in the presence of a base and subsequently treating with an active esterifying agent for a hydroxyl group. In the present invention, "continuing" means subjecting to the next reaction without taking out the reaction product.

Here, L is an ester group derived from the reaction of a hydroxyl group with an active esterifying agent, and the substituted or unsubstituted aryl sulfonic acid ester (substituted or unsubstituted arylsulfonyloxy group) in L is Examples of the lower alkane sulfonic acid ester (lower alkane sulfonyloxy group) include benzene sulfonic acid ester, p-toluene sulfonic acid ester, p-nitrobenzene sulfonic acid ester, p-bromobenzene sulfonic acid ester, and the like. As the halogeno lower alkane sulfonic acid ester (halogeno lower alkane sulfonyloxy group), for example, trifluoromethane sulfonic acid ester and the like are di-lower alkylphosphoric acid esters. Examples of the ester (di-lower alkylphosphoryloxy group) include dimethylphosphoric acid ester and diethylphosphoric acid ester, and examples of the di-halogeno-lower alkylphosphoric acid ester (di (halogeno-lower alkyl) phosphoryloxy group) include For example, di (trichloroethyl)
Examples of the phosphoric acid ester and the like include di (substituted or unsubstituted aryl) phosphoric acid ester (di (substituted or unsubstituted aryl) phosphoryloxy group), for example, diphenylphosphoric acid ester, di-p-chlorophenylphosphoric acid. Examples thereof include esters and ditolylphosphoric acid esters.

Among these active esters of alcohols, p-toluenesulfonic acid ester, methanesulfonic acid ester and diphenylphosphoric acid ester can be mentioned. Therefore, the active esterifying agent for the hydroxyl group is a reagent that reacts with the compound (IV) to produce the active ester as described above. Specific examples of the active esterification agent that can be used include benzenesulfonyl chloride, p-toluenesulfonyl chloride, anhydrous p-toluenesulfonic acid, p-nitrobenzenesulfonyl chloride, p-bromobenzenesulfonyl chloride, methanesulfonyl chloride, ethanesulfonyl chloride. , Trifluoromethanesulfonyl chloride, anhydrous methanesulfonic acid, anhydrous trifluoromethanesulfonic acid,
Examples thereof include dimethylchlorophosphate, diethylchlorophosphate, di (trichloroethyl) chlorophosphate, diphenylchlorophosphate, di-p-chlorophenylchlorophosphate, ditolylchlorophosphate and the like.

Examples of the alkali metal atom include lithium, sodium and potassium. The inert solvent is not particularly limited as long as it is inert, but suitable examples include ether solvents such as diethyl ether, tetrahydrofuran, dioxane and ethylene glycol dimethyl ether, aromatic hydrocarbon solvents such as benzene and toluene. Examples thereof include a solvent, acetonitrile, dimethylformamide, dimethylsulfoxide, hexamethylphosphoric triamide (HMPT), t-butanol and a mixed solvent thereof.

The acetic acid ester derivative (II) is required in an amount sufficient for the reaction to proceed sufficiently, and can be used in an amount of 2 to 4 equivalents based on the compound represented by the general formula (I). Examples of the base that can be used in the reaction of the compound (I) with the acetic acid ester derivative (II) include amines such as lithium diisopropylamide, lithium bis (trimethylsilyl) amide, sodium bis (trimethylsilyl) amide, potassium (trimethylsilyl) amide and sodium amide. Alkali metal salts, alcohols such as potassium t-butoxide, alkali metal hydrides such as sodium hydride and potassium hydride, n-
Examples thereof include butyl lithium and sodium methylsulfinylmethide. Among these bases, sodium hydride can be mentioned as a suitable one.

In this case, it is desirable to use an amount of the base sufficient for the reaction to proceed sufficiently, and an appropriate amount can be 2 to 5 equivalents. The reaction can be suppressed or promoted by appropriately cooling or heating, but a suitable reaction temperature can be -78 ° C to 10 ° C. Further, if necessary, a catalytic amount of water, alcohols or the like can be added for the purpose of activating the reaction.

The active esterifying agent in the active esterification reaction of the hydroxyl group is required in an amount sufficient for the reaction to proceed sufficiently, and is 1 to 1 with respect to the compound represented by the general formula (I).
It can be carried out using 2.5 equivalents. The reaction can be suppressed or promoted by appropriately cooling or heating. Usually, the reaction temperature is −78 ° C. to 60 ° C., but -40 ° C. to 10 ° C. is preferable. After the completion of the reaction, the product can be taken out by usual organic chemical means. An enolate salt (IV) obtained by reacting a compound represented by the general formula (I) with an acetic ester derivative (II) in the presence of a base in an inert solvent.
Retains the steric structure based on the asymmetric carbon (C5 position) of the starting compound (I) under the producing condition, that is, the basic condition, and the alkyl group of R3 of the starting compound after the compound (III) is derived. The thing which keeps the solid of is obtained. That is, the carbapenem compound (III) can be obtained by this reaction without epimerization.

In this case, the enolate (IV) produced in the reaction system is represented by the following formula

[Chemical 9] It may have a chelate structure as shown in.
Further, in the production method of the present invention, the residue represented by Z is released into the reaction system by the first reaction with the acetic ester derivative (II). When the resulting Z residue exists in the reaction system as it is, it may affect the reaction of the next hydroxyl group with the active esterifying agent. However, even in such a case, the acetic ester derivative (II) used in the present method
Can trap the generated Z residue, so that the influence on the next reaction can be eliminated.

The compound represented by the general formula (I) can be synthesized, for example, by the method described in JP-A-62-103084. Here, if the β-lactam compound represented by the general formula (I) is shown more concretely,
(1) (3S, 4S) -3-[(1R) -1-t-butyldimethylsilyloxyethyl] -4-[(1R) -1-
Imidazolylcarbonylethyl] -2-azetidinone,
(2) (3S, 4S) -3-[(1R) -1-t-butyldimethylsilyloxyethyl] -4-[(1R) -1-
Triazolylcarbonylethyl] -2-azetidinone,
(3) (3S, 4S) -3-[(1R) -1-t-butyldimethylsilyloxyethyl] -4-[(1R) -1-
(N-succinimidooxy) carbonylethyl] -2-
Azetidinone,

(4) (3S, 4S) -3-[(1R) -1
-T-Butyldimethylsilyloxyethyl] -4-
[(1R) -1- (N-phthalimidooxy) carbonylethyl] -2-azetidinone, (5) (3S, 4S)-
3-[(1R) -1-t-butyldimethylsilyloxyethyl] -4-[(1R) -1- (1-benztriazolyloxy) carbonylethyl] -2-azetidinone,
(6) (3S, 4S) -3-[(1R) -1-t-butyldimethylsilyloxyethyl] -4-[(1R) -1-
(3- (2-thioxo) thiazolidinyl) carbonylethyl] -2-azetidinone,

(7) (3S, 4S) -3-[(1R) -1
-T-Butyldimethylsilyloxyethyl] -4-
[(1R) -1-phenylthiocarbonylethyl] -2
-Azetidinone, (8) (3S, 4S) -3-[(1R)
-1-tert-Butyldimethylsilyloxyethyl] -4-
[(1R) -1-p-chlorophenylthiocarbonylethyl] -2-azetidinone, (9) (3S, 4S) -3-
[(1R) -1-t-butyldiphenylsilyloxyethyl] -4-[(1R) -1-p-nitrophenylthiocarbonylethyl] -2-azetidinone, (10) (3S,
4S) -3-[(1R) -1-t-butyldiphenylsilyloxyethyl] -4-[(1R) -1-p-methoxyphenylthiocarbonylethyl] -2-azetidinone,

(11) (3S, 4S) -3-[(1R) -1
-Trimethylsilyloxyethyl] -4-[(1R)-
1-phenylthiocarbonylethyl] -2-azetidinone, (12) (3S, 4S) -3-[(1R) -1-trimethylsilyloxyethyl] -4-[(1R) -1-p-
Chlorophenylthiocarbonylethyl] -2-azetidinone, (13) (3S, 4S) -3-[(1R) -1-triethylsilyloxyethyl] -4-[(1R) -1-phenylthiocarbonylethyl] -2 -Azetidinone, (1
4) (3S, 4S) -3-[(1R) -1-triethylsilyloxyethyl] -4-[(1R) -1-p-chlorophenylthiocarbonylethyl] -2-azetidinone,
(15) (3S, 4S) -3-[(1R) -1-t-butyldimethylsilyloxyethyl] -4-[(1R) -1-
(2-pyridyl) thiocarbonylethyl] -2-azetidinone,

(16) (3S, 4S) -3-[(1R) -1
-T-Butyldimethylsilyloxyethyl] -4-
[(1R) -1- (3-pyridyl) thiocarbonylethyl] -2-azetidinone, (17) (3S, 4S) -3-
[(1R) -1-t-butyldimethylsilyloxyethyl] -4-[(1R) -1- (4-pyridyl) thiocarbonylethyl] -2-azetidinone, (18) (3S, 4
S) -3-[(1R) -1-t-butyldimethylsilyloxyethyl] -4-[(1R) -1- (2-pyrimidyl) thiocarbonylethyl] -2-azetidinone, (19)
(3S, 4S) -3-[(1R) -1-t-butyldimethylsilyloxyethyl] -4-[(1R) -1- [2
-(4,6-Dimethyl) pyrimidyl] thiocarbonylethyl] -2-azetidinone, (20) (3S, 4S) -3-
[(1R) -1-t-butyldimethylsilyloxyethyl] -4-[(1R) -1- (benzyl) thiocarbonylethyl] -2-azetidinone,

(21) (3S, 4S) -3-[(1R) -1
-T-Butyldimethylsilyloxyethyl] -4-
[(1R) -1- (p-methoxybenzyl) thiocarbonylethyl] -2-azetidinone, (22) (3S, 4S)
-3-[(1R) -1-t-butyldimethylsilyloxyethyl] -4-[(1R) -1- (2,4-dimethoxybenzyl) thiocarbonylethyl] -2-azetidinone, (23) (3S , 4S) -3-[(1R) -1-t-butyldimethylsilyloxyethyl] -4-[(1R)-
1- (p-nitrobenzyl) thiocarbonylethyl]-
2-azetidinone, (24) (3S, 4S) -3-[(1
R) -1-t-Butyldimethylsilyloxyethyl]-
4-[(1R) -1- (o-nitrobenzyl) thiocarbonylethyl] -2-azetidinone, (25) (3S, 4
S) -3-[(1R) -1-t-butyldimethylsilyloxyethyl] -4-[(1R) -1- (p-chlorobenzyl) thiocarbonylethyl] -2-azetidinone,

(26) (3S, 4S) -3-[(1R) -1
-T-Butyldimethylsilyloxyethyl] -4-
[(1R) -1- (p-chlorophenyloxy) carbonylethyl] -2-azetidinone, (27) (3S, 4S)
-3-[(1R) -1-t-butyldimethylsilyloxyethyl] -4-[(1R) -1- (2,4-dichlorophenyloxy) carbonylethyl] -2-azetidinone, (28) (3S, 4S) -3-[(1R) -1-t-butyldimethylsilyloxyethyl] -4-[(1R)-
1- (2,4,5-trichlorophenyloxy) carbonylethyl] -2-azetidinone, (29) (3S, 4S)
-3-[(1R) -1-t-butyldimethylsilyloxyethyl] -4-[(1R) -1- (p-nitrophenyloxy) carbonylethyl] -2-azetidinone,

(30) (3S, 4S) -3-[(1R) -1
-T-Butyldimethylsilyloxyethyl] -4-
[(1R) -1- (o-nitrophenyloxy) carbonylethyl] -2-azetidinone, (31) (3S, 4S)
-3-[(1R) -1-t-butyldimethylsilyloxyethyl] -4-[(1R) -1- (2,4-dinitrophenyloxy) carbonylethyl] -2-azetidinone, (32) (3S , 4S) -3-[(1R) -1-t-butyldimethylsilyloxyethyl] -4-[(1R)-
1- (2-pyridyloxy) carbonylethyl] -2-
Azetidinone, (33) (3S, 4S) -3-[(1R)-
1-t-butyldimethylsilyloxyethyl] -4-
[(1R) -1- (3-Pyridyloxy) carbonylethyl] -2-azetidinone, (34) (3S, 4S) -3-
Examples include [(1R) -1-t-butyldimethylsilyloxyethyl] -4-[(1R) -1- (4-pyridyloxy) carbonylethyl] -2-azetidinone.

Here, more specific examples of the acetic acid ester derivative represented by the general formula (II) will be described. Methyl chloroacetate, ethyl chloroacetate, isopropyl chloroacetate, t-butyl chloroacetate, chloroacetic acid. Allyl, methyl bromoacetate, ethyl bromoacetate, isopropyl bromoacetate, t-butyl bromoacetate, 2,2,2-trichloroethyl bromoacetate, allyl bromoacetate, 2-methylallyl bromoacetate, benzyl bromoacetate, p-chlorobromoacetate Benzyl, p-nitrobenzyl bromoacetate, o-nitrobenzyl bromoacetate, bromoacetate 2,
4-dinitrobenzyl, p-methoxybenzyl bromoacetate, 2,4-dimethoxybenzyl bromoacetate, methyl iodoacetate, t-butyl iodoacetate, benzyl iodoacetate, p-nitrobenzyl iodoacetate, p-methoxybenzyl iodoacetate, benzene Benzyl sulfonyloxyacetate, p-toluene Benzylsulfonyloxyacetate, p-
Examples include nitrobenzenesulfonyloxyacetate, p-bromobenzenesulfonyloxyacetate, methanesulfonyloxyacetate, ethanesulfonyloxyacetate, and trifluoromethanesulfonyloxyacetate.

Further, when it is desired to directly obtain the carbapenem compound (V) from the compound represented by the general formula (I), after the compound (I) is derived to the carbapenem compound (III) by the above-mentioned method, Compound (II
Without taking out I), the mercaptan compound (X) R ₀ -SH (X) is continued, wherein R ₀ represents an organic group. ] And a base are added and treated to give a carbapenem compound represented by the general formula (V). This is shown in the following reaction formula.

[0027]

[Chemical 10] [Wherein R ₁ , R 2, R 3, R 4, R ₀ , B, X, Y and Z have the same meanings as described above. ]

This reaction is described, for example, in JP-A-62-10308.
It can be carried out by a known method described in Japanese Patent Laid-Open No.

When the carbapenem compound represented by the general formula (III) is isolated, the derivative is reacted with the mercaptan compound (X) in the same manner as in the above-mentioned method to give the general formula (V). A carbapenem compound represented by can be produced.

As described above, the carbapenem compound represented by the general formula (III) or the carbapenem compound represented by the general formula (V) can be produced from the β-lactam compound (I).

The carbapenem compound (V) thus obtained can be easily prepared, for example, by the method described in JP-A-62-103084.

[Chemical 11] [In the formula, R 1, R 2, R 3 and R ₀ have the same meanings as described above, and X ⁰ represents a hydrogen atom or a hydroxyl group. ] You can lead to.

That is, the general formula (V)

[Chemical 12] [Wherein R ₁ , R 2, R 3, R 4, R ₀ and X have the same meanings as described above. ] The compound represented by the formula [VI] having antibacterial activity can be obtained by appropriately combining a reaction for removing a protective group for a hydroxyl group, a reaction for removing a protective group for a carboxyl group or a reaction for removing a protective group for an amino group.
A carbapenem compound represented by can be obtained.

R ₀ of the 3-position substituent SR _{0 in} the carbapenem compound (V) may be any as long as it is used in the carbapenem compound, and examples thereof include the following. That is, a substituted or unsubstituted alkyl group or alkenyl group having 1 to 10 carbon atoms; a cycloalkyl group having 3 to 6 carbon atoms in the ring, an alkylcycloalkyl group, a cycloalkyl-alkyl group; an aryl such as phenyl A group, an aryl part is phenyl, and an alkyl is an arylalkyl group having 1 to 6 carbon atoms; a heteroaryl group, a heteroarylalkyl group,
A heterocycloalkyl group; the above-mentioned group is an amino group,
Mono-, di- and trialkylamino groups, hydroxyl groups, alkoxy groups, mercapto groups, alkylthio groups, arylthio groups such as phenylthio, sulfamoyl groups, amidine groups, guanidino groups, nitro groups, substituted or unsubstituted carbamoyl groups, sulfamoyl Amino group, chloro,
It may have at least one substituent selected from the group consisting of a halogeno group such as bromo and fluoro, a cyano group, and a carboxyl group; the heteroatom of the above-mentioned heterocyclic moiety is 1 to 4 oxygen and nitrogen. Or selected from the group consisting of sulfur atoms; the alkyl portion of the above substituents has 1 to 6 carbon atoms.

Although not necessarily limited to those shown below, the production method of the present invention is shown below by taking the production method of the 1β-methylcarbapenem compound as an example.

[0035]

[Chemical 13] [Wherein R 4, Y, Z, B, L and R ₀ have the same meanings as described above, and R 10 represents a hydroxyl-protecting group. ]

The β-lactam compound represented by the general formula (I ^* ) is treated in the following order: 1) in the presence of an acetic ester derivative (II) and a base in an inert solvent. 2) Treat with a hydroxyl group active esterifying agent. Further, if necessary, 3) mercaptan derivative (X) R ₀ -SH (X) [In the formula, R ₀ has the same meaning as described above. ] In the presence of a base or by reacting a salt of the mercaptan derivative (X) with a base; and sequentially reacting in the same container, and represented by the general formula (III ^* ) or (V ^* ) Carbapenem compounds can be prepared.

In this case, in the reaction of 1), the bond of the acetic acid ester residue to the nitrogen atom of the β-lactam compound (I) (N-alkylation reaction), the methylene part of the acetic acid ester residue and the carbonyl part of the COZ group. The bond with (ring-closing reaction) proceeds in parallel, or sequentially proceeds to produce enolate (IV ^* ). Furthermore, in some cases, the capture of the released Z group by the acetic ester derivative (II) simultaneously proceeds.

The above-mentioned reactions 1) and 2) are not carried out in the same vessel, but the compound (I ^* ) is subjected to the reaction shown in 1) and then the reaction post-treatment is carried out to obtain the compound of the general formula (IV-2). ^* )

[Chemical 14] [Wherein R 4 and R 10 have the same meanings as described above. ]
The compound represented by the formula (1) has a β-position at the 1-position under various conditions, for example, after-reaction treatment in the presence of a base, storage in a highly concentrated solution, and presence in a solution using a polar solvent such as acetonitrile.
-The epimerization of the methyl group is likely to proceed. From this, after taking out the compound represented by the general formula (IV-2 ^* ),
I suspect a problem in the case of compound (IV-2 ^*) to produce a large amount stereoselectively the compound represented from the general formula (III ^*). In contrast, the compound (IV
-(2 ^* ) instead of compound (IV ^* )
Method of inducing the I ^*) is advantageous because it can lead 1 of β- epimerization carbapenem compounds without causing the methyl group (III ^*) or the (V ^*).

R 1 of the compound represented by the general formula (I)
, R2, X are different from each other, for example, R1 = methyl,
In the case of R2 = hydrogen atom and X = protected hydroxyl group, the carbon atom bonded to the 3-position of the β-lactam ring also becomes an asymmetric carbon.
Therefore, the compound represented by the general formula (I) has stereoisomers based on an asymmetric carbon other than those shown in the formulas, and all of these isomers are represented by a single formula. The scope of the description of the invention is not limited.

[0040]

EXAMPLES The present invention will be described in more detail with reference to examples and reference examples, but the present invention is not limited to these examples. The abbreviations have the following meanings. TBDMS: t-butyldimethylsilyl group TMS: trimethylsilyl group Me: methyl group Ph: phenyl group PNB: p-nitrobenzyl group PNZ: p-nitrobenzyloxycarbonyl group TES: triethylsilyl group

Example 1

[Chemical 15]

(3S, 4S) -3-[(1R) -1-t
-Butyldimethylsilyloxyethyl] -4-[(1
R) -1-p-Chlorophenylthiocarbonylethyl]
-2-azetidinone (316mg, 0.737mmo
l), allyl bromoacetate (315 mg, 1.76 mmo
l) was dissolved in tetrahydrofuran (4 ml) and sodium hydride (60% oily) (114 mg, 2.85 m) was added.
mol) and tetrahydrofuran (2 ml) in suspension-
The mixture was added dropwise at 35 ° C and stirred for 30 minutes. Then diphenylchlorophosphate (213 mg, 0.793 mmol)
Was dissolved in 2 ml of tetrahydrofuran and added dropwise, and the mixture was stirred for 1 hour. The reaction mixture was diluted with 20 ml of ethyl acetate, washed several times with brine, dried with a mixed desiccant of magnesium sulfate-potassium carbonate (10: 1), and the solvent was evaporated. The residue was purified by silica gel thin layer chromatography (4R, 5R, 6S, 8R) -3-diphenylphosphoryloxy-4-methyl-6- (1-t-butyldimethylsilyloxyethyl) -1-azabicyclo [3. 1.2.
0] hept-2-en-7-one-2-carboxylic acid allyl ester (334 mg) was obtained.

IR ^neat (cm ^-1 ): 1782, 1731, 1490, 12
94, 1189, 970, 837, 777; NMR δ (CDCl ₃ ): 0.06 (3Hx2, s), 0.87 (3Hx3, s), 1.
18 (3H, d, J = 7.3Hz), 1.23 (3H, d, J = 6.0Hz), 3.24 (1H, dd, J
= 3.0 and 6.3Hz), 3.42 (1H, m), 4.14 (1H, dd, J = 2.8 and 10.4H
z), 4.20 (1H, m), 4.65 (2H, d, J = 5.6Hz), 5.40 (2H, m),
5.86 (1H, m), 7.19 to 7.38 (10H).

Example 2

[Chemical 16]

(3S, 4S) -3-[(1R) -1-t
-Butyldimethylsilyloxyethyl] -4-[(1
R) -1-p-Chlorophenylthiocarbonylethyl]
-2-azetidinone (467mg, 1.09mmo
l), benzyl bromoacetate (549 mg, 2.4 mmo
l) was dissolved in tetrahydrofuran (4 ml) and sodium hydride (60% oily) (157 mg, 3.92 m) was added.
mol) and tetrahydrofuran (3 ml) in suspension-
The mixture was added dropwise at 35 ° C and stirred for 30 minutes. Then diphenylchlorophosphate (307 mg, 1.145 mmol)
Was dissolved in 2 ml of tetrahydrofuran and added dropwise, and the mixture was stirred for 1 hour. The reaction mixture was diluted with 20 ml of ethyl acetate, washed several times with brine, dried with a mixed desiccant of magnesium sulfate-potassium carbonate (10: 1), and the solvent was evaporated. The residue was purified by silica gel thin layer chromatography (4R, 5R, 6S, 8R) -3-diphenylphosphoryloxy-4-methyl-6- (1-t-butyldimethylsilyloxyethyl) -1-azabicyclo [3. 1.2.
0] hept-2-en-7-one-2-carboxylic acid benzyl ester (410 mg) was obtained.

IR ^neat (cm ^-1 ): 1784, 1729, 1590, 14
89, 1189, 970, 834, 778; NMRδ (CDCl ₃ ): 0.05 (3H, s), 0.06 (3H, s), 0.85 (3
Hx3, s), 1.18 (3H, d, J = 7.3Hz), 1.22 (3H, d, J = 6.3Hz), 3.
24 (1H, dd, J = 3.0 and 5.9Hz), 3.44 (1H, m), 4.14 (1H, dd, J =
2.8 and 10.4Hz), 4.21 (1H, m), 5.21 (2H, AB), 7.15 to 7.3
8 (15H).

Example 3

[Chemical 17]

(3S, 4S) -3-[(1R) -1-t
-Butyldimethylsilyloxyethyl] -4-[(1
R) -1-p-Chlorophenylthiocarbonylethyl]
-2-azetidinone (389mg, 0.907mmo
l), methyl bromoacetate (303 mg, 1.98 mmo
l), sodium hydride (60% oily) (130 mg,
3.25 mmol), and further diphenylchlorophosphate (254 mg, 0.945 mmol) were used to prepare (4R, 5R, 6S,
8R) -3-Diphenylphosphoryloxy-4-methyl-6- (1-t-butyldimethylsilyloxyethyl)
-1-Azabicyclo [3.2.0] hept-2-ene-
7-one-2-carboxylic acid methyl ester (207m
g) was obtained.

IR ^neat (cm ^-1 ): 1785, 1732, 1489, 12
90, 1187, 969, 836, 778; NMR δ (CDCl ₃ ): 0.06 (3Hx2, s), 0.87 (3Hx3, s), 1.
18 (3H, d, J = 7.3Hz), 1.23 (3H, d, J = 6.3Hz), 3.24 (1H, dd, J
= 3.0 and 6.6Hz), 3.41 (1H, m), 3.69 (3H, s), 4.13 (1H, dd, J
= 3.0 and 10.2Hz), 4.20 (1H, m), 7.22 to 7.38 (10H).

Example 4

[Chemical 18]

(3S, 4S) -3-[(1R) -1-t
-Butyldimethylsilyloxyethyl] -4-[(1
R) -1-p-Chlorophenylthiocarbonylethyl]
-2-azetidinone (343 mg, 0.8 mmol),
P-Nitrobenzyl bromoacetate (482 mg, 1.76
mmol), sodium hydride (60% oily) (114
mg, 2.85 mmol), and further diphenylchlorophosphate (236 mg, 0.88 mmol),
In the same manner as in Examples 1 and 2, (4R, 5R, 6
S, 8R) -3-Diphenylphosphoryloxy-4-methyl-6- (1-t-butyldimethylsilyloxyethyl) -1-azabicyclo [3.2.0] hept-2-en-7-one-2 -Carboxylic acid p-nitrobenzyl ester (206 mg) was obtained.

IR ^neat (cm ^-1 ): 1775, 1725, 1630, 15
85, 1518, 1482, 1340, 1285, 1185, 1160, 938, 82
5,770; NMR δ (CDCl ₃ ): 0.06 (3H, s), 0.07 (3H, s), 0.86 (9
H, s), 1.20 (3H, d, J = 7.9Hz), 1.23 (3H, d, J = 6.3Hz), 3.29
(1H, dd, J = 3.0 and 6.0Hz), 3.43 (1H, m), 4.22 (2H, m), 5.28
(2H, ABq, J = 13.5Hz), 7.56 (2H, d, J = 8.9Hz), 8.14 (2H, d,
J = 8.9Hz).

Example 5

[Chemical 19]

(3S, 4S) -3-[(1R) -1-t
-Butyldimethylsilyloxyethyl] -4-[(1
R) -1-p-Chlorophenylthiocarbonylethyl]
-2-azetidinone (343 mg, 0.8 mmol),
Allyl bromoacetate (304 mg, 1.7 mmol) was mixed with tetrahydrofuran and toluene at a ratio of 1: 1 (4 m
l) dissolved in sodium hydride (60% oily) (1
00 mg, 2.5 mmol) and a suspension of tetrahydrofuran and toluene in a 1: 1 mixed solution (2 ml) at -35 ° C.
And then stirred for 30 minutes. Then add diphenylchlorophosphate (215 mg, 0.8 mmol) and add 1
Stir for hours. The reaction mixture was treated in the same manner as in Examples 1 and 2 with (4R, 5R, 6S, 8R) -3-diphenylphosphoryloxy-4-methyl-6- (1-t-butyldimethylsilyloxyethyl) -1-azabicyclo. [3.2.0] Hept-2-en-7-one-2-carboxylic acid allyl ester (344 mg) was obtained.

The IR and NMR spectra of the compound obtained here were the same as the data of the compound obtained in Example 1.

Example 6

[Chemical 20]

(3S, 4S) -3-[(1R) -1-t
-Butyldimethylsilyloxyethyl] -4-[(1
R) -1-p-Chlorophenylthiocarbonylethyl]
-2-azetidinone (345 mg, 0.8 mmol),
Allyl bromoacetate (286 mg, 1.6 mmol), sodium hydride (60% oily) (104 mg, 2.6 m
mol), and further diphenylchlorophosphate (21
(4R, 5R, 6S, 8R) -3-diphenylphosphoryloxy-4-methyl-6- (1-t-butyldimethylsilyloxyethyl) in the same manner as in Example 5 using 5 mg, 0.8 mmol). After derivatization to -1-azabicyclo [3.2.0] hept-2-en-7-one-2-carboxylic acid allyl ester, [2] was carried out at -20 ° C.
S, 4S] -1-p-Nitrobenzyloxycarbonyl-2-dimethylaminocarbonyl-4-mercaptopyrrolidine (282 mg, 0.8 mmol) in acetonitrile (3 ml), diisopropylethylamine (11
0 mg, 0.85 mmol) was added, dimethylformamide (3 ml) was further added, and the mixture was stirred at -10 to 0 ° C for 12 hours. Dilute the reaction mixture with 50 ml of ethyl acetate,
The extract was washed with brine several times, dried over magnesium sulfate, and the solvent was evaporated. The residue was purified by silica gel chromatography to give (4R, 5S, 6S, 8R, 3 ′S, 5 ′
S) -3- [4- (1-p-nitrobenzyloxycarbonyl-2-dimethylaminocarbonylpyrrolidinyl)
Thio] -4-methyl-6- (1-t-butyldimethylsilyloxyethyl) -1-azabicyclo [3.2.0]
Hept-2-en-7-one-2-carboxylic acid allyl ester (95 mg) was obtained.

IR ^neat (cm ^-1 ): 1775, 1710, 1657, 15
23, 1345, 1209, 1141, 1110, 983, 836; NMR δ (CDCl ₃ ): 0.07-0.08 (3Hx2, s), 0.88 (3Hx3,
s), 1.24 (3H, d, J = 7.3Hz), 1.25 (3H, d, J = 5.9Hz), 1.91 (1
H, m), 2.72 (1H, m), 2.94 (3Hx2 / 5, s), 2.98 (3Hx2 / 5, s),
3.00 (3Hx3 / 5, s), 3.10 (3Hx3 / 5, s), 3.20-3.30 (1H, m),
3.31-3.54 (1H, m), 3.70 (1H, m), 4.00-4.26 (3H, m), 4.59
-4.81 (3H, m), 5.19 (2Hx2 / 5, ABq, J = 13.5Hz), 5.22 (2Hx3 /
5, s), 5.44 (1H, d, J = 17.5Hz), 5.94 (1H, m), 7.44 (1H, d, J
= 8.6Hz), 7.52 (1H, d, J = 8.6Hz), 8.20 (1H, d, J = 8.6Hz),
8.23 (1H, d, J = 8.6Hz).

Reference Example 1

[Chemical 21]

(3S, 4S) -3-[(1R) -1-t
-Butyldimethylsilyloxyethyl] -4-[(1
R) -1-p-Chlorophenylthiocarbonylethyl]
2-Azetidinone (1.29 g, 3.0 mmol) is dissolved in toluene (10 ml) and methanol (2 ml)
And chlorotrimethylsilane (0.1 ml) were added, and the mixture was stirred at room temperature overnight. The reaction mixture was diluted with 50 ml of ethyl acetate, washed several times with brine, dried over magnesium sulfate, and the solvent was evaporated, (3S, 4S) -3-[(1R)-
1-Hydroxyethyl] -4-[(1R) -1-p-chlorophenylthiocarbonylethyl] -2-azetidinone (627 mg) was obtained.

IR ^KBr (cm ^-1 ): 3329, 1728, 1702, 14
76, 1357, 1091, 970, 818. NMR δ (CDCl ₃ ): 1.30 (3H, d, J = 6.3Hz), 1.35 (3H, d,
J = 6.9Hz), 2.09 (1H, d, J = 4.3Hz), 2.98 (1H, m), 3.09 (1H,
dd, J = 1.7 and 6.3Hz), 3.86 (1H, dd, J = 2.3 and 6.6), 4.16 (1H,
m), 6.07 (1H, br.s), 7.32 (2H, d, J = 8.6Hz), 7.40 (2H, d,
J = 8.6Hz).

Reference Example 2

[Chemical formula 22]

(3S, 4S) -3-[(1R) -1-hydroxyethyl] -4-[(1R) -1-p-chlorophenylthiocarbonylethyl] -2-azetidinone (4
77 mg, 1.51 mmol) was dissolved in dry N, N-dimethylformamide (3 ml) and imidazole (26
0 mg, 3.79 mmol) and triethylchlorosilane (456 mg, 3.0 mmol) were added, and the mixture was stirred at room temperature for 5 hours. The reaction solution was diluted with ethyl acetate (30 ml),
Wash with water. The aqueous layer was extracted with 20 ml of ethyl acetate, the organic layers were combined and washed twice with brine. After drying with sodium sulfate, the solvent was distilled off, and the oily residue was subjected to silica gel chromatography to obtain (3S, 4S) -3-[(1R) -1-triethylsilyloxyethyl] -4-[(1R) -1-. p-Chlorophenylthiocarbonylethyl] -2-azetidinone (342 mg) was obtained.

IR ^neat (cm ^-1 ): 1760, 1708, 1478, 13
76, 1240, 1145, 1096, 970; NMR δ (CDCl ₃ ): 0.60 (2Hx3, q, J = 7.9Hz), 0.95 (3Hx
3, t, J = 7.6Hz), 1.21 (3H, d, J = 6.3Hz), 1.32 (3H, d, J = 6.9H)
z), 2.99 (1H, m), 3.03 (1H, dd, J = 2.1 and 5.0Hz), 3.92 (1H,
dd, J = 2.1 and 5.5), 4.20 (1H, m), 5.99 (1H, br.s), 7.31 (2
H, d, J = 8.6Hz), 7.40 (2H, d, J = 8.9Hz).

Example 7

[Chemical formula 23]

(3S, 4S) -3-[(1R) -1-Triethylsilyloxyethyl] -4-[(1R) -1-
p-Chlorophenylthiocarbonylethyl] -2-azetidinone (170 mg, 0.4 mmol), allyl bromoacetate (152 mg, 0.85 mmol), sodium hydride (60% oily) (50 mg, 1.25 mmol).
In the same manner as in Examples 1 and 2 (4R,
5R, 6S, 8R) -3-Diphenylphosphoryloxy-4-methyl-6- (1-triethylsilyloxyethyl) -1-azabicyclo [3.2.0] hept-2-en-7-one-2- Carboxylic acid allyl ester (60 m
g) was obtained.

IR ^neat (cm ^-1 ): 1770, 1746, 1490, 12
98, 1189, 970, 747; NMRδ (CDCl ₃ ): 0.61 (2Hx3, q, J = 7.9Hz), 0.96 (3Hx
3, t, J = 7.6Hz), 1.19 (3H, d, J = 7.3Hz), 1.25 (3H, d, J = 6.3H)
z), 3.24 (1H, dd, J = 3.0 and 6.6Hz), 3.42 (1H, m), 4.14 (1H,
dd, J = 3.0 and 10.2Hz), 4.20 (1H, m), 4.66 (2H, d, J = 5.6H
z), 5.40 (2H, m), 5.86 (1H, m), 7.21 to 7.37 (10H).

Reference Example 3

[Chemical formula 24]

(3S, 4S) -3-[(1R) -1-t
-Butyldimethylsilyloxyethyl] -4-[(1
R) -1-Carboxyethyl] -2-azetidinone (1.05 g, 3.5 mmol), 2-mercapto-2
-Thiazoline (417 mg, 3.5 mmol), 2-chloro-1,3-dimethylimidazolinium chloride (5
92 mg, 3.5 mmol) with methylene chloride (3 ml)
And pyridine (550 mg, 7.0 mm) under ice cooling.
ol) was added and the mixture was stirred at room temperature for 10 hours. The reaction mixture was diluted with methylene chloride (5 ml), water was added, the organic layer was washed successively with 0.5N hydrochloric acid, aqueous sodium hydrogen carbonate and water, dried over magnesium sulfate, and the solvent was evaporated. The residue was subjected to silica gel chromatography, (3S, 4S) -3-
[(1R) -1-t-Butyldimethylsilyloxyethyl] -4-[(1R) -1- [3- (2-thioxo) thiazolino] carbonylethyl] -2-azetidinone (1.07 g) was obtained. .

IR ^KBr (cm ^-1 ): 1763, 1704, 1369, 12
80, 1258, 1152, 1058, 835; NMR δ (CDCl ₃ ): 0.07 (3Hx2, s), 0.87 (3Hx3, s), 1.
21 (3H, d, J = 6.3Hz), 1.26 (3H, d, J = 6.9Hz), 3.04 (1H, dd, J
= 2.6 and 4.6Hz), 3.29 (2H, dt, J = 2.0 and 7.6Hz), 3.96 (1H, d
d, J = 2.0 and 4.0), 4.19 (1H, m), 4.56 (2H, dt, J = 1.0 and 7.6Hz
s), 4.96 (1H, m), 5.99 (1H, br.s).

Example 8

[Chemical 25]

(3S, 4S) -3-[(1R) -1-t
-Butyldimethylsilyloxyethyl] -4-[(1
R) -1- [3- (2-Thioxo) thiazolino] carbonylethyl] -2-azetidinone (219 mg, 0.5
mmol), benzyl bromoacetate (137 mg, 0.6
mmol), sodium hydride (60% oily) (44m
g, 1.1 mmol) and further diphenylchlorophosphate (135 mg, 0.5 mmol) by the same method as in Example 2 (4R, 5R, 6S, 8R) -3.
-Diphenylphosphoryloxy-4-methyl-6- (1
-T-Butyldimethylsilyloxyethyl) -1-azabicyclo [3.2.0] hept-2-en-7-one-
2-Carboxylic acid benzyl ester (55 mg) was obtained.

The IR and NMR spectra of the compound obtained here were the same as the data of the carbapenem compound obtained in Example 2.

Reference Example 4

[Chemical formula 26]

(3S, 4S) -3-[(1R) -1-t
-Butyldimethylsilyloxyethyl] -4-[(1
R) -1-carboxyethyl] -2-azetidinone (9
95 mg, 3.3 mmol), benzyl mercaptan (409 mg, 3.5 mmol), 2-chloro-1,3
-Dimethylimidazolinium chloride (592 mg,
3.5 mmol) in methylene chloride (3 ml),
Pyridine (550 mg, 7.0 mmol) was added under ice cooling, and the mixture was stirred at room temperature for 10 hours. By the same treatment as in Reference Example 3, (3S, 4S) -3-[(1R) -1-t-butyldimethylsilyloxyethyl] -4-[(1R) -1.
-(Benzylthiocarbonyl) ethyl] -2-azetidinone (868 mg) was obtained.

IR ^neat (cm ^-1 ): 1764, 1687, 1374, 12
55, 1140, 980, 961; NMR δ (CDCl ₃ ): 0.06 (3Hx2, s), 0.87 (3Hx3, s), 1.
08 (3H, d, J = 6.3Hz), 1.26 (3H, d, J = 6.9Hz), 2.86 (1H, m),
2.98 (1H, dd, J = 2.3 and 4.3Hz), 3.88 (1H, dd, J = 2.2 and 5.7),
4.11 (2H, s), 4.17 (1H, m), 5.84 (1H, br.s), 7.19-7.33
(5H).

Example 9

[Chemical 27]

(3S, 4S) -3-[(1R) -1-t
-Butyldimethylsilyloxyethyl] -4-[(1
R) -1- (Benzylthiocarbonyl) ethyl] -2-
Azetidinone (180 mg, 0.406 mmol), benzyl bromoacetate (152 mg, 0.82 mmol),
Sodium hydride (60% oily) (52 mg, 1.3 m
mol), and further diphenylchlorophosphate (11
(4R, 5R, 6S, 8R) -3-diphenylphosphoryloxy-4-methyl-6- (1-t-butyldimethylsilyloxyethyl) in the same manner as in Example 2 using 8 mg, 0.44 mmol). -1-Azabicyclo [3.2.0] hept-2-en-7-one-2-carboxylic acid benzyl ester (6.5 mg) was obtained.

The IR and NMR spectra of the compound obtained here were the same as the data of the carbapenem compound obtained in Example 2.

Example 10

[Chemical 28]

(3S, 4S) -3-[(1R) -1-t
-Butyldimethylsilyloxyethyl] -4-[(1
R) -1-p-Chlorophenylthiocarbonylethyl]
-2-azetidinone (214 mg, 0.5 mmol),
Allyl bromoacetate (197 mg, 0.55 mmol) was mixed with toluene and tetrahydrofuran in a ratio of 8: 2 (1.
5 ml), sodium hydride (60% oily)
(66 mg, 1.65 mmol) in a suspension of an 8: 2 mixed solution of toluene and tetrahydrofuran (4.3 g)-
The mixture was added dropwise at 35 to -40 ° C and stirred for 1.5 hours. Further diphenyl chlorophosphate (148 mg, 0.55 m
mol) and stirred for 2 hours to give (4R,
5R, 6S, 8R) -3-Diphenylphosphoryloxy-4-methyl-6- (1-t-butyldimethylsilyloxyethyl) -1-azabicyclo [3.2.0] hept-2-en-7-one After induction with 2-carboxylic acid allyl ester, [2S, 4S] -1-allyloxycarbonyl-2-dimethylaminocarbonyl-4 at -35 ° C.
-Mercaptopyrrolidine (129 mg, 0.55 mmo
1) in acetonitrile (0.4 ml) and 1,8-diazabicyclo [5.4.0] undec-7-ene (DB
U) (76 mg, 0.5 mmol) was added to -20 to 30
The mixture was stirred at 0 ° C for 1 hour. 50 ml of ethyl acetate in the reaction mixture
Was diluted with, washed several times with brine, dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue is purified by silica gel chromatography, (4R, 5S, 6S, 8
R, 3 ′S, 5 ′S) -3- [4- (1-allyloxycarbonyl-2-dimethylaminocarbonylpyrrolidinyl) thio] -4-methyl-6- (1-t-butyldimethylsilyloxy Ethyl) -1-azabicyclo [3.2.
0] Hept-2-en-7-one-2-carboxylic acid allyl ester (115 mg) was obtained.

IR ^KBr (cm ^-1 ): 1788, 1704, 1694, 166
0, 1553, 1410, 1338, 1209, 1146, 982, 838 NMR δ (CDCl ₃ : 0.08 (3H × 2, s), 0.88 (3H × 3, s),
1.23 (3H, d, J = 7.3Hz), 1.24 (3H, d, J = 6.3Hz), 1.96 (1H,
m), 2.65 (1H, m), 2.98 (3H, s), 3.10 (3H, s), 3.21 (1H,
m), 3.27 (1H, m), 3.45 (1H, t, J = 10.2Hz), 3.61 (1H, m), 4.
01 (1H, dd, J = 6.9 and 10.2Hz), 4.21 (2H, m), 4.54-4.81 (4H + 1
H, m), 5.16-5.47 (4H, m), 5.85-6.01 (2H, m)

Claims (3)

[Claims] 1. A compound represented by the general formula (I): [Wherein R 1 and R 2 may be the same or different and each represents a hydrogen atom or a lower alkyl group, R 3 represents a lower alkyl group, X represents a hydrogen atom or a protected hydroxyl group, and COZ represents An active ester of a carboxyl group, a substituted or unsubstituted arylthiocarbonyl group, a substituted or unsubstituted heteroarylthiocarbonyl group, a substituted or unsubstituted aralkylthiocarbonyl group, a substituted aryloxycarbonyl group, or a heteroaryloxycarbonyl group Show. ] In the presence of a base, a β-lactam compound represented by the general formula (II) [In the formula, R4 represents a protecting group for a carboxyl group, and Y represents an active ester of a hydroxyl group or a halogen atom. ] The compound represented by the general formula (III) is characterized by reacting with an acetic ester derivative represented by [Wherein R 1, R 2, R 3, R 4 and X have the same meanings as described above, and L is a substituted or unsubstituted arylsulfonyloxy group, lower alkanesulfonyloxy group, halogeno lower alkanesulfonyloxy group, di-lower alkylphosphoryl. An oxy group, a di (halogeno lower alkyl) phosphoryloxy group or a di (substituted or unsubstituted aryl) phosphoryloxy group is shown. ] The manufacturing method of the carbapenem compound represented by these. 2. The production method according to claim 1, wherein R3 is a methyl group. 3. The production method according to claim 1, wherein R1 is a hydrogen atom, R2 is a methyl group, R3 is a methyl group, and X is a protected hydroxyl group.