JPH0797381A - New production method of azetidinone compound and new raw material compound therefor - Google Patents

Abstract

PURPOSE:To sterically selectively obtain the subject compound useful as a synthetic intermediate for a 1beta-methylcar bapenem derivative as an antimicrobial agent without using a Lewis acid by a new method using a specific alkanoic acid amide compound as a raw material. CONSTITUTION:An alkanoic acid amide compound of formula I (R<1> is H a or lower alkyl; R<2> and R<3> together with an adjoining nitrogen atom form a heterocyclic ring) is reacted with an azetidinone compound of formula III (R<4> is a hydroxy-substituted lower alkyl; L<1> is an eliminable group) in the presence of a base [preferably lithium bis(trimethylsilyl)amide] preferably at -60 to -30 deg.C to give the objective compound. A compound of formula IV (ring B is benzene; X is O or S; Y is O, imino, etc.; Z<1> and Z<2> are H, an aryl, etc.) among the compound of formula I is a new substance and to be concrete, 2,2-di- n-butyl-3-propionyl-2,3-dihydro-4H-1,3-benzoxazin-4-one may be cited as the compound.

Description

Detailed Description of the Invention

[0001]

The present invention relates to 1β having an antibacterial action.
TECHNICAL FIELD The present invention relates to a novel method for producing an azetidinone compound useful as a synthetic intermediate for a methylcarbapenem derivative and a novel raw material compound thereof.

[0002]

BACKGROUND OF THE INVENTION 1.beta.-Methylcarbapenem derivatives show excellent antibacterial activity against a wide range of pathogens including Gram-positive and Gram-negative bacteria, and also show strong antibacterial activity against cephem-resistant bacteria, and in vivo. It is attracting attention as an antibacterial agent because it is also excellent in stability.

Various methods are known as methods for synthesizing the 1β-methylcarbapenem derivative.

[Chemical 21] The azetidinone compound having a β-methyl group at the 1′-position of the 4-position side chain represented by the formula (wherein R represents an optionally protected hydroxy-substituted lower alkyl group) is a particularly important synthetic intermediate. It was synthesized by a method in which the hydrogen atom at the 1'position present in the acetic acid residue at the 4-position was extracted with a strong base and then a methyl group was introduced [Heterocycles (Heterocyc
les) 21, 29 (1984)]. However, with this method, it is difficult to stereoselectively produce a compound having a β-coordinate at the 1′-position of the 4-position side chain, and therefore various methods have been proposed.

For example, Feentes et al. Combine 4-acetoxyazetidinone compounds and certain propionimides with complex reagents of certain bases and Lewis acids, such as tin triflate-ethylpiperidine-zinc bromide, diethylborane. A method of reacting in the presence of triflate-diisopropylethylamine-zinc bromide and the like is proposed [L.
M. Fuentes et al., J. Am. Chem. Soc., 108 , 46
75 (1986)]. A similar method has been proposed by Nagao et al. [Y. Nagao et al., J. Am. Chem. Soc., 1
08 , 4673 (1986)]. Also proposed is a method of reacting a 4-acetoxyazetidinone compound with a propionic acid thiol ester or a propionic acid ester in the presence of a complex reagent of a base and a Lewis acid [C.U.
Kim et al., Tetrahedron Lett., 28 , 507 (197)
8), A. Martel et al., Can. J. Chem., 66 , 153.
7 (1988), and M. Endo, Can. J. Chem., 65 ,
2140 (1987)].

[0005]

However, in all of these methods, it is essential to use a complex reagent of a base and a Lewis acid, and a compound having an undesired 1'-position is α-coordinated, It is hard to say that the desired purity of the 1'-β form is still sufficient. The present inventors have conducted various studies to solve the above-mentioned drawbacks of the present invention and to find a method for selectively obtaining a synthetic intermediate of a carbapenem antibacterial agent having a desired 1'-β coordination. As a result, the inventors have found a method for selectively producing a desired 1'-β coordination compound by reacting it in the presence of a constant base without using a Lewis acid as in the above known method.

[0006]

The present invention provides a desired 1'-β coordinated azetidinone by reacting an azetidinone compound with a specific alkanoic acid amide compound in the presence of a base without using a Lewis acid. It is intended to provide a novel method for producing a compound stereoselectively.

That is, the present invention has the general formula [I]

[Chemical formula 22] (In the formula, R ¹ is a hydrogen atom or a lower alkyl group, and R ² and R ³ form a heterocyclic group with the adjacent nitrogen atom.)
An alkanoic acid amide compound represented by the general formula [II]

[Chemical formula 23] (Wherein R ⁴ represents an optionally protected hydroxy-substituted lower alkyl group, and L ¹ represents a leaving group) in the presence of a base.
II]

[Chemical formula 24] (Wherein each symbol is the same as the above), a method for producing an azetidinone compound is provided.

The present invention has the general formula [IA]

[Chemical 25] (In the formula, ring B is a benzene ring which may have a substituent,
X is an oxygen atom or a sulfur atom, Y is an oxygen atom, a sulfur atom, an optionally protected imino group or a methylene group,
Z ¹ and Z ² are the same or different and each represent a hydrogen atom, an alkyl group which may have a substituent, a cycloalkyl group which may have a substituent, an aryl group or an aralkyl group, or they are mutually terminal. To form an alkylene group having 4 to 7 carbon atoms which may have a substituent, and R ¹
Are also the same as the above).

In the alkanoic acid amide compound represented by the general formula [I] used in the present invention, the formula --N (R ² ) (R
The heterocyclic group of the group represented by ³ ) includes a nitrogen atom alone or a 5- or 6-membered heterocyclic group containing an oxygen atom or a sulfur atom in addition to the nitrogen atom, and examples thereof include JP-A-63-10765. JP-A-62-252786, JP-A-63-284176, JP-A-2-292269.
No. 2, JP-A-2-788, JP-A-61-275267.
JP-A-62-169781, JP-A-62-773
84, JP-A-63-170377, JP-A-62-2.
Groups described in JP-A-46550 and JP-A-6-65195, that is, the general formula

[Chemical formula 26] (In the formula, X ¹ represents an oxygen atom or a sulfur atom, Y ¹ represents an oxygen atom, a sulfur atom, a methylene group or an imino group substituted with an alkyl group or an aryl group, and R ¹¹ , R
¹² , R ¹³ and R ^{14, which} may be the same or different, each represents a hydrogen atom, a C _{1 to} C ₅ lower alkyl group, a cyano group, an alkoxycarbonyl group, an aralkyl group or an aryl group, or R ¹¹ and R ^{14 12} together represent a C ₂ -C ₆ alkylene chain, or simultaneously or separately R ¹³ and R ¹⁴ together represent a C ₂ -C ₆ alkylene chain, or R ¹¹ , R ¹² , R ¹³ and R ¹⁴ together with two adjacent carbon atoms form an aromatic cyclic group which may have a substituent).

As another example of the heterocyclic group, Japanese Patent Application No. 4-
No. 303662, Japanese Patent Application No. 5-111460, Japanese Patent Application No. 5
Groups described in -283148, that is, the general formula

[Chemical 27] (In the formula, X, Y, Z ¹ and Z ² are the same as above, ring A represents a benzene ring which may have the same substituent as ring B, or an oxygen atom, a sulfur atom and a nitrogen atom. Represents a substituted or unsubstituted heterocycle having 1 to 4 heteroatoms selected from

General formula

[Chemical 28] (In the formula, X, Y and ring A are the same as above).

Among the above heterocycles, preferred examples of the case where ring A represents a heterocycle include the following formulas

[Chemical 29] (In the formula, Y is the same as the above).

In the present invention, the substituent on ring A or ring B is, for example, a halogen atom, a lower alkyl group,
A lower alkoxy group and an aryl group are preferred, and these substituents are the same or different and are 1 to 4 rings A or ring B.
The above may be substituted. Further, the group represented by R ⁴ is preferably an optionally protected 1-hydroxyethyl group, and as the hydroxyl group-protecting group, any group which can be easily removed by a conventional method is used. You can Specific examples of the hydroxyl-protecting group include, for example, a lower alkoxycarbonyl group, a halogeno lower alkoxycarbonyl group, a substituted or unsubstituted phenyl lower alkyl group (for example, benzyl which may be substituted with a nitro group or a lower alkoxy group). Group), a tri-lower alkylsilyl group, a substituted or unsubstituted phenyl lower alkoxycarbonyl group (for example, a benzyloxycarbonyl group which may be substituted with a nitro group or a lower alkoxy group), and the like.

Examples of the alkyl group for Z ¹ , Z ² , R ¹¹ , R ¹² , R ¹³ and R ¹⁴ include those having 1 to 20 carbon atoms, preferably those having 1 to 15 carbon atoms, and cycloalkyl. Examples of the group include those having 4 to 7 carbon atoms,
The aryl group includes a substituted or unsubstituted phenyl group, and the aralkyl group includes a lower alkyl group substituted with a substituted or unsubstituted phenyl group. Examples of the substituent on the alkyl group and cycloalkyl group and the substituent on the phenyl group of the aryl group and aralkyl group include a lower alkoxy group, a halogen atom,
The amino group which may be protected may be preferably mentioned. The amino-protecting group and the imino-protecting group in Y include those usually used as amino-protecting groups in peptide chemistry and the like, for example, lower alkyl groups, acyl groups (eg lower alkanoyl groups, lower alkoxycarbonyl groups). , A substituted or unsubstituted phenylcarbonyl group or a substituted or unsubstituted phenyl lower alkoxycarbonyl group) can be preferably used.

Among the starting compound [I], the compound of the general formula [I-
The compound represented by [A] is a novel compound, and its amide moiety (hereinafter referred to as a supporting group) is a 6-membered heterocyclic group in which a benzene ring is condensed, whereas the conventionally known supporting group is a thiazolidine or oxazolidine. It is a structurally completely different from the known one in that it is a 5-membered heterocyclic group such as. The compound of the present invention [I-
In A], this supporting group is

[Chemical 30] (However, the symbols are the same as the above), and therefore, when the ring B and / or Y has a substituent, the substituent is any if it does not participate in the reaction. Can also be used. However, the compound [I
-A], ring B is an unsubstituted benzene ring, both X and Y are oxygen atoms, Z ¹ and Z ² are an alkyl group which may have a substituent, or they are bonded to each other at the ends. Particularly preferred are compounds which form an unsubstituted alkylene group having 4 to 7 carbon atoms.

Compounds of the present invention with alkanoic amides [I]
The base used in the reaction of reacting with [II] to give compound [III] includes a usual organic or inorganic base, but a strong base is preferable. In addition, as a preferable strong base, a base having a basicity sufficient to withdraw a hydrogen atom from the α-position of alkanoic acid amide [I] to form an enolate, and as a more preferable strong base, pKb <−
There are 10 bases. Examples of preferable strong bases include alkali metal salts or alkaline earth metal salts of amines (for example, alkali metal bis (tri-lower alkylsilyl) amide), or alkali metal salts or alkaline earth metal salts of alcohols. , More specifically, lithium bis (trimethylsilyl) amide, sodium bis
Examples include (trimethylsilyl) amide, potassium bis (trimethylsilyl) amide, lithium diisopropylamide, sodium amide, sodium methylate, sodium ethylate, potassium tertiary butyrate, and the like.

The alkanoic acid amide compound [I] and the compound
The reaction with [II] is preferably carried out in a suitable inert solvent such as ethers such as tetrahydrofuran, diethyl ether, dioxane, dimethoxyethane and diisopropyl ether, and aromatic hydrocarbons such as toluene and xylene. It is particularly preferred to carry out in tetrahydrofuran. Further, as the leaving group L ¹ in the compound [II], any conventional leaving group which can be easily removed by the reaction with the alkanoic acid amide compound [I] can be used,
Examples thereof include an acyloxy group, a lower alkylsulfonyloxy group, an arylsulfonyloxy group, a lower alkylsulfonyl group, an arylsulfonyl group, an arylthio group, and a halogen atom, and an acyloxy group is particularly preferable.

The amount of the alkanoic acid amide compound [I] used is
It is preferably 1 to 1.5 mol, especially 1.1 to 1.3 mol, relative to 1 mol of the compound [II], and the amount of the base used is relative to 1 mol of the compound [II]. 1-2 moles,
It is particularly preferably 1.2 to 1.5 mol. This reaction is generally -80 to 10 ° C, preferably -60 to -30 ° C.
To implement.

The alkanoic acid amide compound [I] containing the novel raw material compound [IA] has the general formula [IV]

[Chemical 31] (Provided that R ² and R ³ are the same as above) and the compound of the general formula [V]

[Chemical 32] (Provided that R ¹ is the same as above) or a reactive derivative thereof. When the novel compound [IA] is produced by this reaction, the compound [IV] is represented by the general formula [IV-
1]

[Chemical 33] (In the formula, each symbol is the same as the above), a benzene compound is used.

The reaction between the compound [IV] and the compound [V] can be carried out in a suitable solvent in the presence of a dehydrating agent.
Examples of the dehydrating agent include carbonyldiimidazole,
Dicyclohexylcarbodiimide, N-hydroxysuccinimide, 1-hydroxybenzotriazole, etc.,
As the solvent, ether, methylene chloride, tetrahydrofuran, acetonitrile and the like can be preferably used.
The present reaction suitably proceeds at -30 to 70 ° C, especially at 0 to 30 ° C.

The reaction of the compound [IV] with the reactive derivative of the compound [V] can be carried out in a suitable solvent in the presence or absence of a deoxidizing agent. As the reactive derivative,
Acid halides and acid anhydrides can be preferably used, and as the deoxidizing agent, organic bases such as alkali metal hydrides, alkali metals, lower alkyl and aryl lithium compounds, pyridine, di-lower alkylaniline, and tri-lower alkylamines can be used. Can be used. As the solvent, tetrahydrofuran, diethyl ether, benzene, toluene,
Dichloromethane, chloroform and the like can be preferably used. This reaction is generally carried out at -80 ° C to 50 ° C, preferably -20 to 30 ° C.

The azetidinone compound [III] obtained by the above-mentioned method of the present invention is hydrolyzed to give a general formula useful as a synthetic intermediate for carbapenem compounds.

[Chemical 34] (In the formula, symbols are the same as the above), and the compound can be converted to an azetidinone alkanoic acid compound [VI].

This hydrolysis reaction can be carried out by a conventional method, but is preferably carried out in the presence of hydrogen peroxide and alkali metal hydroxide in a suitable solvent. Examples of the solvent include dioxane, tetrahydrofuran, dimethylformamide, a mixed solvent of water with an organic solvent such as methanol, and particularly preferably a mixed solvent of tetrahydrofuran and water, and as the alkali metal hydroxide, lithium hydroxide, Examples thereof include sodium hydroxide and potassium hydroxide, and lithium hydroxide is particularly preferable. Also,
The amount of hydrogen peroxide used is preferably 1 to 10 mol, especially 6 to 8 mol per 1 mol of the azetidinone compound [III], and the amount of alkali metal hydroxide used is 1 mol of the azetidinone compound [III]. It is preferably 1 to 5 mol, especially 2 to 3 mol. This reaction is -10
C. to 30.degree. C., especially -5.degree. C. to 5.degree. C., are preferred.

The azetidinone compound [III] can be appropriately converted into a desired 1β-methylcarbapenem antibacterial agent as follows. That is, the azetidinone compound [III] and the general formula [VII]

[Chemical 35] (Wherein R ⁵ represents a hydrogen atom or an ester residue, and L ² represents a leaving group), and the resulting compound of the general formula [VIII]

[Chemical 36] (Wherein the symbols are the same as those described above), the N-substituted azetidinone compound or a salt thereof is intramolecularly ring-closed, and the obtained intramolecular ring-closed compound is esterified to give a compound represented by the general formula [IX]

[Chemical 37] (In the formula, —OA represents an esterified hydroxyl group, and other symbols are the same as the above), and a 1β-methyl-2-oxycarbapenem derivative represented by the formula [X] is obtained.

[Chemical 38] (Wherein R ⁶ represents an organic group) is reacted with a thiol compound or a salt thereof, and R ⁴ is a protected hydroxy-substituted lower alkyl group, and / or R
^{When 5} is an ester residue, if desired, the protecting group of the hydroxy-substituted lower alkyl group and / or the ester residue is removed to give a compound of the general formula [XI]

[Chemical Formula 39] (Wherein R ⁴¹ is a hydroxy-substituted lower alkyl group which may be protected, R ⁵¹ is a hydrogen atom or an ester residue, and other symbols are the same as the above), and is converted to a 1β-methylcarbapenem derivative. can do.

Of the ester residue of R ⁵ in the acetic acid compound [VII], the N-substituted azetidinone compound [VIII] and the 1β-methyl-2-oxycarbapenem derivative [IX] and the R ⁵¹ of the 1β-methylcarbapenem derivative [XI]. Examples thereof include an ester residue that is metabolized and hydrolyzed in vivo, or an ester residue that can serve as a protective group for a carboxyl group.

Examples of the ester residue which is metabolized and hydrolyzed in the living body include, for example, formulas -Q-OCOR ⁷ and -Q-.
OCO ₂ R ⁷ or -Q-O-R ⁷ (wherein Q represents a lower alkylene group, R ⁷ represents a lower alkyl group, a cycloalkyl group, a lower alkenoyl group, a lower alkoxy lower alkyl group, a lower alkanoyloxy lower alkyl group) And a group represented by).

Specific examples of such a group include, for example, lower alkanoyloxy lower alkyl group, cycloalkylcarbonyloxy lower alkyl group, lower alkenoyloxy lower alkyl group, lower alkoxy lower alkanoyloxy lower alkyl group, lower alkanoyloxy lower alkoxy group. Examples thereof include a lower alkyl group, a lower alkoxy lower alkyl group, a lower alkoxy lower alkoxy lower alkyl group, a lower alkoxycarbonyloxy lower alkyl group, and a lower alkoxy lower alkoxycarbonyloxy lower alkyl group.

On the other hand, as the ester residue which can be a protective group for the carboxyl group, any group which can be easily removed by a conventional method can be used. Specific examples of the ester residue that can be a protective group for the carboxyl group include lower alkyl group, lower alkenyl group, halogeno lower alkyl group, nitrobenzyl group, lower alkoxybenzyl group, and benzhydryl group.

The esterified hydroxyl group represented by -OA is, for example, represented by the formula: -OP (O) (OR ⁰ ) ₂ [wherein R ⁰ represents an aryl group or a lower alkyl group]. Diarylphosphoryloxy group (for example, diphenylphosphoryloxy group etc.) or di-lower alkylphosphoryloxy group, unsubstituted or substituted lower alkylsulfonyloxy group such as methanesulfonyloxy group, ethanesulfonyloxy group, trifluoromethanesulfonyloxy group, benzenesulfonyl Examples thereof include an unsubstituted or substituted arylsulfonyloxy group such as an oxy group and a toluenesulfonyloxy group, a lower alkanoyloxy group such as an acetoxy group, and an arylcarbonyloxy group such as a benzoyloxy group. Of these groups, active esterified hydroxyl groups such as a diarylphosphoryloxy group, a di-lower alkylphosphoryloxy group, an unsubstituted or substituted lower alkylsulfonyloxy group, and an unsubstituted or substituted arylsulfonyloxy group are particularly preferable.

In the thiol compound [X] and the 1β-methylcarbapenem derivative [XI], as the organic group represented by R ⁶ , any group used in known carbapenem antibacterial agents can be used. JP 61
-18779, JP-A-60-202886, JP-A-61-5081, JP-A-2-49783, U.S. Pat. No. 4,194,047, JP-A-4-279588 and the like known carbapenem antibacterial agents Any of the groups mentioned can be used. Examples of such a group include a lower alkyl group, a cycloalkyl group, a 6-8 membered aryl group, a 4-8 membered aliphatic heterocyclic group, a 4-8 membered aromatic heterocyclic group and the like. Further, these groups may have one or more substituents, and examples of such a substituent include a lower alkyl group, a hydroxyl group, a lower alkoxy group, a lower alkylamino group, a mercapto group, a lower alkylthio group, Amidino group, guanidino group, carbamoyl group, thiocarbamoyl group, sulfamoyl group, cyano group, carboxyl group, lower alkoxycarbonyl group, aralkyloxycarbonyl group, oxo group, halogeno group,
Examples thereof include a cycloalkyl group, a 6 to 8 membered aryl group, a 4 to 8 membered aliphatic heterocyclic group and a 4 to 8 membered aromatic heterocyclic group.

Azetidinone compound [III] and acetic acid compound
The reaction with [VII] can be carried out in the presence of a base in a suitable solvent. Examples of the leaving group (L ² ) include a halogen atom and an acyloxy group, and examples of the base include an organic base such as 1,8-diazabicyclo [5.4.0] undec-7-ene and hydrogen. Examples thereof include alkali metal compounds such as alkali metal halides, alkali metal hydroxides and alkali metal carbonates, and metal salts of amines such as sodium amide, lithium diisopropylamide and sodium bis (trimethylsilyl) amide. As a solvent,
Inert solvents such as tetrahydrofuran, benzene, dichloromethane and the like can be used. This reaction is
It can be suitably carried out at 50 to -20 ° C.

The intramolecular ring closure reaction of the N-substituted azetidinone compound [VIII] can be carried out in the presence of a base. Examples of the base include metal salts of amines such as sodium bis (trimethylsilyl) amide and lithium bis (trimethylsilyl) amide, metal salts of alcohols such as tertiary butoxy potassium, and alkali metal hydrides such as sodium hydride. To be Also, the amount used is
The amount is preferably 1.0 to 3.0 mol, and more preferably 2.0 to 2.5 mol per 1 mol of [VIII]. Examples of the solvent include tetrahydrofuran, ethylene glycol dimethyl ether, dioxane, toluene, diethyl ether, benzene and the like. This reaction is carried out under cooling to room temperature, for example, -78 ° C to 50 ° C, especially -60.
It can be suitably carried out at 10 to 10 ° C.

By the intramolecular ring-closing reaction, the compound of the general formula [XI
I]

[Chemical 40] It is presumed that an intramolecular closed ring having a structure represented by (in the formula, symbols are the same as above) is produced. The thus-obtained intramolecular ring-closure product may be isolated or may be directly subjected to an esterification reaction without isolation, but particularly, the esterification reaction is continuously performed in the same solvent without isolation. Preferably.

The esterification reaction of the intramolecular ring-closed product can be carried out by reacting the intramolecular ring-closed product with an esterifying agent for the hydroxyl group. Examples of the esterifying agent for the hydroxyl group include diaryl phosphates such as diphenyl phosphate, di-lower alkyl phosphates such as diethyl phosphate,
Of phosphoric acid or sulfonic acid compounds such as unsubstituted or substituted lower alkane sulfonic acids such as methane sulfonic acid, ethane sulfonic acid, trifluoromethane sulfonic acid etc., unsubstituted or substituted aryl sulfonic acids such as benzene sulfonic acid, toluene sulfonic acid etc. Reactive derivative (for example, corresponding acid halide, corresponding acid anhydride, etc.) or reactive derivative of lower alkanoic acid such as acetic acid (for example, corresponding acid halide, corresponding acid anhydride, etc.), arylcarboxylic acid such as benzoic acid And the like (eg, corresponding acid halide, corresponding acid anhydride, etc.). Further, the amount thereof used is preferably 1.0 to 4.0 mol, and particularly preferably 2.0 to 3.0 mol, relative to 1 mol of the compound [VIII].

Among these esterifying agents for hydroxyl groups, among phosphoric acid or sulfonic acid compounds such as diaryl phosphate, di-lower alkyl phosphate, unsubstituted or substituted lower alkane sulfonic acid, unsubstituted or substituted aryl sulfonic acid, etc. Active esterifying agents for hydroxyl groups such as reactive derivatives (eg corresponding acid halides, corresponding acid anhydrides) are preferable. In addition, this reaction is performed under cooling to room temperature, for example, -7.
It suitably proceeds at 5 ° C to 40 ° C, especially at -60 ° C to 10 ° C.

The intramolecular ring-closing reaction and the subsequent esterification reaction of the N-substituted azetidinone compound [VIII] can be carried out in the presence or absence of an acid, but it is particularly preferably carried out in the presence of an acid.

As the acid, both a Lewis acid and a protic acid can be used, but it is particularly preferable to carry out in the presence of a Lewis acid. Examples of the Lewis acid include cupric chloride, cuprous iodide, zinc chloride, zinc iodide, zinc fluoride, iron halide, stannous chloride, stannic chloride, and other metal halides, trimethyl borate. And a silylating agent such as tetrahalogenosilane such as trimethylchlorosilane and t-butyldimethylchlorosilane, and tetrahalogenosilane such as tetrachlorosilane. In addition, the amount used thereof is preferably 0.1 to 2.0 mol, and more preferably 1.0 to 1.5 mol, relative to 1 mol of the compound [VIII].

On the other hand, examples of the protic acid include sulfuric acid, paratoluenesulfonic acid, acetic acid, citric acid, hydrochloric acid, phosphoric acid and boric acid. The amount of the compound used is [V
III] It is preferably 0.1 to 1.0 mol per 1 mol. When the esterification reaction is carried out in the presence of an acid, the amount of the esterifying agent used is the compound [VIII].
It is particularly preferably 1.2 to 1.5 mol per mol.

The reaction between the 1β-methyl-2-oxycarbapenem derivative [IX] and the thiol compound [X] is described in JP-A No. 4/1999.
Can be carried out according to the method described in JP-A-279588, and further, when R ⁴ is a protected hydroxy-substituted lower alkyl group, and / or R ⁵ is an ester residue, the protecting group or The ester residue can be removed by a conventional method such as hydrolysis and reduction.

In each of the above reactions, compound [VIII],
[IX] and [X] can also be used in the reaction in the form of their salts. These compounds [VIII], [IX] and
Examples of the salt of [X] include alkali metal salts, tri-lower alkylammonium salts and the like. Since the method of the present invention proceeds while maintaining the three-dimensional structure of the azetidinone compound [III], 1β-
Methyl-2-oxycarbapenem derivative [IX] and 1
It can be converted into a β-methylcarbapenem derivative [XI].

The compound [IV] can be produced according to a known method. For example, the compound [IV-1] in which Y is an oxygen atom, a sulfur atom, or an imino group which may have a substituent is a compound of the Journal of the American Chemical Society.
It can be produced according to the method described in Chemical Society) 72, 721 (1950). That is, the general formula [XII
I]

[Chemical 41] (In the formula, Y ² represents an oxygen atom, a sulfur atom or an imino group which may have a substituent, and other symbols are the same as the above), and a compound represented by the general formula [XIV]

[Chemical 42] (In the formula, symbols are the same as above) and can be produced by condensation in the presence of an acid (eg, paratoluenesulfonic acid, sulfuric acid, hydrochloric acid, etc.).

Further, the compound [XIII] in which X is an oxygen atom and Y ² is a sulfur atom is represented by the general formula [XV]

[Chemical 43] (Wherein the symbols are the same as above) are halogenated to give a compound of the general formula [XVI]

[Chemical 44] (Wherein, X ² represents a halogen atom, and other symbols are the same as the above), and then amidated to give a compound of the general formula
[XVII]

[Chemical formula 45] (Where the symbols are the same as above),
Further reduction can be performed.

The compound [XIII] in which X is an oxygen atom and Y ² is an optionally substituted imino group can be prepared by the general formula [XVIII].

[Chemical formula 46] (In the formula, Y ³ represents an imino group which may have a substituent, and other symbols are the same as the above), and the compound can be produced by reacting with ammonia.

A compound wherein X is a sulfur atom and Y ² is a sulfur atom or an imino group which may have a substituent [X
[III] is a compound [XI wherein X is an oxygen atom and Y ² is a sulfur atom or an imino group which may have a substituent.
II] can be produced by thiocarbonylation.

Further, among the benzene compounds [IV-1], compounds in which Y is a methylene group are represented by the general formula

[Chemical 47] (In the formula, L ³ represents a halogen atom, and other symbols are the same as the above), and a compound represented by the general formula

[Chemical 48] (Wherein the symbols are the same as above), the compound represented by the general formula

[Chemical 49] (Wherein the symbols are the same as above), and the compound of the general formula

[Chemical 50] (Wherein the symbols are the same as the above), and then the compound represented by the general formula

[Chemical 51] It can be obtained by reacting with a compound represented by the formula (in the formula, symbols are the same as above) and then ring-closing the compound.

In the present invention, preferred examples of the lower alkyl group, the lower alkylene group and the lower alkoxy group include linear or branched ones having 1 to 6 carbon atoms, particularly 1 to 4 carbon atoms. Examples of the alkanoyl group and the lower alkenyl group include those having 2 to 8 carbon atoms, especially those having 2 to 6 carbon atoms, and the lower alkenoyl group and the cycloalkyl group have 3 to 8 carbon atoms, and particularly 3 to 6 carbon atoms. I can give you one.

[0047]

【Example】

Example 1 2,2-di-n-butyl-2,3-dihydro-4H-1,
3-benzoxazin-4-one 13.5 g (51.7 m
mol) in methylene chloride 30 ml, propionyl bromide 6.05 ml (67.2 mmol) in methylene chloride 15 ml and pyridine 5.02 ml (62.0 mmol).
With 15 ml of methylene chloride solution of
Add dropwise over 30 minutes at ° C. After the dropping is completed, the temperature is gradually raised and the mixture is stirred overnight at room temperature. 50m water in this reaction liquid
l is added and the layers are separated. The aqueous layer is re-extracted with 50 ml of methylene chloride, the organic layers are combined, washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (hexane: ethyl acetate = 19:
Purification in 1) yields 14.8 g (90%) of 2,2-di-n-butyl-3-propionyl-2,3-dihydro-4H-1,3-benzoxazin-4-one. mp 52-
54 ° C NMR δ (CDCl ₃ ): 0.65 (6H, t, J = 5.0H
z), 1.03 to 1.62 (11H, m), 1.94 to 2.44
(4H, m), 2.91 (2H, q, J = 7.2Hz), 6.91
(1H, d, J = 8.0Hz), 7.07 (1H, dd, J = 7.0)
8,7.8 Hz), 7.50 (1H, ddd, J = 1.6, 8.0,
8.0Hz), 7.94 (1H, dd, J = 1.6,8.0Hz) IR (KBr) cm ^-1 : 1718,1682,1610,1
469,1174

Example 2 30.0 g of spiro [2,3-dihydro-4H-1,3-benzoxazin-2,1'-cyclohexane] -4-one
A solution of (138 mmol) in 60 ml of methylene chloride, a solution of 16.1 ml (179 mmol) of propionyl bromide in 30 ml of methylene chloride and 13.4 ml of pyridine (166 ml).
mmol) in 30 ml of methylene chloride and in the same manner as in Example 1, 3-propionyl-spiro [2,3-dihydro-4H-1,3-benzoxazin-2,1′-cyclohexane] -4-one. 34.7 g (92%) are obtained.
Mp 58-60 ° C NMR δ (CDCl ₃ ): 1.20 (3H, t, J = 7.4H
z), 1.16 to 1.43 (2H, m), 1.55 to 1.81 (4
H, m), 1.98 to 2.40 (4H, m), 2.84 (2H, q,
J = 7.4 Hz), 6.98 (1H, d, J = 8.2 Hz), 7.
10 (1H, dd, J = 7.6, 7.6Hz), 7.52 (1H,
ddd, J = 1.6,7.6,7.6 Hz), 7.95 (1H, d
d, J = 1.6,8.2 Hz) IR (KBr) cm ⁻¹ : 1724,1687,1611,1
467, 1320, 1159

Example 3 2,2-di-n-butyl-3-propionyl-2,3-dihydro-4H-1,3-benzoxazin-4-one 1
90 mg (0.6 mmol) of tetrahydrofuran 3 ml
0.7 ml of a tetrahydrofuran solution of 1M sodium bis (trimethylsilyl) amide was added dropwise to the solution at −60 ° C. under a nitrogen stream, and the mixture was stirred at the same temperature for 1 hour. (3R, 4R) -4-acetoxy-3-[(1R)-
A solution of 143 mg (0.5 mmol) of 1-t-butyldimethylsilyloxyethyl] -2-azetidinone in 1 ml of tetrahydrofuran was added dropwise at -50 ° C, and the mixture was stirred for 10 minutes. 0.1M phosphate buffer (pH 7.
0, 10 ml) is added, and the mixture is extracted with 10 ml of ethyl acetate. The buffer layer is re-extracted with 5 ml of ethyl acetate, the organic layers are combined, washed with water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 20: 1 to 4: 1) to give 3-{(2R) -2-[(3S, 4R) -3-[(1R)).
-1-tert-Butyldimethylsilyloxyethyl] -2-
Oxoazetidin-4-yl] propionyl} -2,2-
237 mg (87%) of di-n-butyl-2,3-dihydro-4H-1,3-benzoxazin-4-one are obtained.
m.p. 100-102 ° C β: α = 100: 0 (HPLC) NMR δ (CDCl ₃ ): 0.07 (9H, s), 0.78-1.
02 (12H, m), 1.10 to 1.58 (11H, m), 1.9
2 to 2.44 (4H, m), 3.13 to 3.20 (1H, m), 3.
70-3.82 (1H, m), 4.07-4.24 (2H, m),
5.97 (1H, s), 6.92 (1H, d, J = 8.1Hz),
7.09 (1H, dd, J = 7.4, 7.4Hz), 7.53 (1
H, ddd, J = 1.6, 8.1, 8.1 Hz), 7.93 (1H,
dd, J = 1.6,7.4Hz)

Example 4 In the same manner as in Example 3, 3-propionyl-spiro [2,
3-dihydro-4H-1,3-benzoxazine-2,
1'-Cyclohexane] -4-one 164 mg (0.6 mm
ol) and (3R, 4R) -4-acetoxy-3-[(1R)-
1-t-butyldimethylsilyloxyethyl] -2-azetidinone was reacted with 143 mg (0.5 mmol) to give 3-{(2R) -2-[(3S, 4R) -3-[(1R) -1.
-T-Butyldimethylsilyloxyethyl] -2-oxoazetidin-4-yl] propionyl} -spiro [2,3
-Dihydro-4H-1,3-benzoxazine-2,1 '
205 mg (82%) of -cyclohexane] -4-one are obtained. mp 149-151 ° C. β: α = 100: 0 (HPLC) NMR δ (CDCl ₃ ): 0.07 (9H, s), 0.85 (6
H, s), 1.16 to 1.40 (5H, m), 1.50 to 2.40
(8H, m), 3.16-3.24 (1H, m), 3.48-3.6
3 (1H, m), 4.00 ~ 4.30 (2H, m), 5.95 (1
H, s), 7.00 (1 H, d, J = 8.2 Hz), 7.11 (1
H, dd, J = 7.5,7.5 Hz), 7.54 (1H, ddd,
J = 1.6, 7.5, 7.5 Hz), 7.93 (1H, dd, J =
1.6, 8.2Hz)

Example 5 Lithium bis (trimethylsilyl) amide was used as a base and treated in the same manner as in Example 3 to give 3-{(2R) -2-
[(3S, 4R) -3-[(1R) -1-t-butyldimethylsilyloxyethyl] -2-oxoazetidin-4-yl] propionyl} -2,2-di-n-butyl-2,3- Dihydro-4H-1,3-benzoxazin-4-one is obtained. β: α = 100: 0 (HPLC)

Example 6 Lithium bis (trimethylsilyl) amide was used as the base and treated in the same manner as in Example 4 to give 3-{(2R) -2-
[(3S, 4R) -3-[(1R) -1-t-butyldimethylsilyloxyethyl] -2-oxoazetidin-4-yl] propionyl} -spiro [2,3-dihydro-4H-
1,3-benzoxazine-2,1'-cyclohexane]-
Get 4-on. β: α = 100: 0 (HPLC)

Examples 7 to 18 The corresponding starting compounds and propionyl chloride were treated in the same manner as in Example 1 to obtain the compounds shown in Table 1 below.

[0054]

[Table 1]

Examples 19 to 46 The corresponding starting compounds and propionyl bromide were treated in the same manner as in Example 1 to obtain the compounds shown in Tables 2 to 4 below.

[0056]

[Table 2]

[0057]

[Table 3]

[0058]

[Table 4]

Examples 47-66 Corresponding starting compounds and (3R, 4R) -4-acetoxy-3-
[(1R) -1-t-butyldimethylsilyloxyethyl]
2-Azetidinone is treated in the same manner as in Example 3 to obtain the compounds shown in Tables 5 to 7 below.

[0060]

[Table 5]

[0061]

[Table 6]

[0062]

[Table 7]

Examples 67-80 Corresponding starting compounds and (3R, 4R) -4-acetoxy-3-
[(1R) -1-t-butyldimethylsilyloxyethyl]
2-Azetidinone is treated in the same manner as in Example 3 to obtain the compounds shown in Tables 8 to 9 below.

[0064]

[Table 8]

[0065]

[Table 9]

Example 81 Using sodium methylate as a base and treating in the same manner as in Example 3, 3-{(2R) -2-[(3S, 4R) -3 was treated.
-[(1R) -1-t-butyldimethylsilyloxyethyl] -2-oxoazetidin-4-yl] propionyl}
-2,2-di-n-butyl-2,3-dihydro-4H-
1,3-benzoxazin-4-one is obtained.

Example 82 (A) 3-{(2R) -2-[(3S, 4R) -3-[(1R) -1
-T-Butyldimethylsilyloxyethyl] -2-oxoazetidin-4-yl] propionyl} -spiro [2,3
-Dihydro-4H-1,3-benzoxazine-2,1 '
-Cyclohexane] -4-one (7 g) and bromoacetic acid allyl ester (2.89 g) in tetrahydrofuran (35 ml)
Add 1M sodium bis (trimethylsilyl) amide to the solution.
16.2 ml of a tetrahydrofuran solution is added at -60 ° C, and the temperature is raised to -30 ° C over 1 hour. The reaction solution is water
It is poured into a mixed solution of ethyl acetate, the ethyl acetate layer is washed and dried, and then the solvent is distilled off. The residue was subjected to silica gel column chromatography (solvent; hexane: ethyl acetate = 20: 1 to 1).
5: 1) to give 3-{(2R) -2-[(3S, 4R)-
1-allyloxycarbonylmethyl-3-[(1R) -1
-T-Butyldimethylsilyloxyethyl] -2-oxoazetidin-4-yl] propionyl} -spiro [2,3
-Dihydro-4H-1,3-benzoxazine-2,1 '
8.03 g of -cyclohexane] -4-one are obtained as a syrup.

(B) 3-{(2R) -2-[(3S, 4R) -1
-Allyloxycarbonylmethyl-3-[(1R) -1-
t-Butyldimethylsilyloxyethyl] -2-oxoazetidin-4-yl] propionyl} -spiro [2,3-
Dihydro-4H-1,3-benzoxazine-2,1'-
A solution of 1.2 g of cyclohexane] -4-one in 6 ml of tetrahydrofuran was added to 1M sodium bis (trimethylsilyl).
Amide-tetrahydrofuran solution 4.4 ml, -30
Add dropwise at -20 ° C over 1 minute. Trimethylsilyl chloride (261 mg) was added at -50 ° C, and the mixture was stirred for 2 minutes.
Add 645 mg of diphenylphosphoryl chloride at -50 ° C and stir at 0 ° C for 2 hours. The reaction mixture is poured into 50 ml of 0.2M phosphate buffer (pH 7.0) and extracted with ethyl acetate. The extract is washed and dried, and the solvent is distilled off. Isopropyl ether was added to the residue, and 355 mg of spiro [2,3-dihydro-4H-1,3-benzoxazin-2,1'-cyclohexane] -4-one was separated by filtration as a precipitated crystal. The filtrate was concentrated to (1R, 5R, 6S) -6-[(1R)-
1-t-butyldimethylsilyloxyethyl] -1-methyl-2-diphenylphosphoryloxy-carbapene-
2-M-3-carboxylic acid / allyl ester 1.04 g
As a syrup.

Example 83 3-{(2R) -2-[(3S, 4R) -3-[(1R) -1-t
-Butyldimethylsilyloxyethyl] -2-oxoazetidin-4-yl] propionyl} -spiro [2,3-dihydro-4H-1,3-benzoxazine-2,1'-cyclohexane] -4-one 500 mg of tetrahydrofuran -To a solution of 20 ml of water, 0.9 ml of 30% hydrogen peroxide and 84 mg of lithium hydroxide are sequentially added at 0 ° C, and the mixture is stirred at the same temperature for 1 hour. Next, at the same temperature, 5 ml of a 1.5 N sodium sulfite aqueous solution was added dropwise to adjust the pH to about 10, and then tetrahydrofuran was concentrated under reduced pressure. The precipitated crystals were filtered, the aqueous layer of the filtrate was washed with 20 ml of chloroform, and then 1
Add 10 ml of 0% hydrochloric acid to bring the pH to about 1. This aqueous layer was extracted with 30 ml of ethyl acetate, the organic layer was dried, and the crystals obtained by vacuum drying were recrystallized from a mixed solution of ethyl acetate-hexane to give (2R) -2-[(3S, 4R) -3- [(1R) -1-
216 mg of t-butyldimethylsilyloxyethyl] -2-oxoazetidin-4-yl] propionic acid are obtained. mp 146-147 ° C

Reference Example 1 20 g of dibutyl ketone, 19.3 g of salicylamide and 2.7 g of p-toluenesulfonic acid hydrate were added to 3 parts of toluene.
In addition to 00 ml, heat and reflux overnight with a Dean Stark dehydrator. After cooling, the reaction solution was washed and dried, the solvent was distilled off, and the residue was purified by silica gel column chromatography (solvent; hexane: ethyl acetate = 95: 5) to give 2,
2-dibutyl-4-oxo-2,3-dihydro-4H-
34 g of 1,3-benzoxazine are obtained as a yellow oil.

Reference Example 2 (1) 2,2'-dithiodibenzoic acid 25.0 g of toluene 1
After adding 12.5 ml of thionyl chloride at room temperature to a 0.5 ml mixture of 20 ml-dimethylformamide, 70-
Warm to 80 ° C. and stir overnight. After 20 hours, the crystals are collected by filtration to obtain 14.9 g of 2,2'-dithiodibenzoic acid chloride as colorless crystals. mp 140-14
1 ° C

(2) To a suspension of 7.03 g of 2,2'-dithiodibenzoic acid chloride in 20 ml of dioxane was added 20 ml of aqueous ammonia at room temperature, and then the temperature was raised to 80 to 90 ° C. After stirring at the same temperature for 5 hours, the temperature was returned to room temperature to obtain 4.8 g of 2,2'-dithiodibenzoic acid amide as colorless crystals. m.
p.249-250 ° C

(3) 2,2'-dithiodibenzoic acid amide 4.
To a suspension of 14 g and 2.5 g of zinc dust in 70 ml of dioxane, 41 ml of 2N hydrochloric acid was added dropwise at room temperature, and then 60 to 70 ° C.
The temperature rises to. After stirring at the same temperature for 4 hours, the reaction solution was mixed with water 50
The mixture is dropped to ml, extracted with ethyl acetate, washed, dried, and dried under reduced pressure. Toluene solution of the obtained residue was added with cyclohexanone (5.64 ml) and paratoluenesulfonic acid.
Add 1.03 g of the hydrate and heat to reflux for 40 minutes while dehydrating with a Dean-Stark dehydrator. After returning to room temperature and concentrating the reaction solution under reduced pressure, methanol was added to the residue to give spiro [2,3-dihydro-4H-1,3-benzothiazin-2,1'-cyclohexane] -4-one 3.0.
5 g are obtained as colorless crystals. mp 193 ~ 195 ℃

Reference Example 3 (1) 140 ml of water at room temperature in N-methyl isatinic acid 10.
0 g is added little by little, and then 9.6 g of aqueous ammonia is added dropwise. The reaction solution is heated to 80 ° C. over 45 minutes, and then ethanol is added until the reaction solution becomes transparent. Then, the reaction solution was cooled to room temperature, and the precipitated crystals were collected by filtration,
7.11 g of 2-carbamoyl-N-methylaniline are obtained as colorless crystals. mp.155-156 ℃

(2) To a solution of 5.00 g of this product in toluene was added 6.9 ml of cyclohexanone and 633 mg of paratoluenesulfonic acid monohydrate, and the mixture was heated under reflux for 1 hour while dehydrating with a Dean-Stark dehydrator. After cooling to room temperature, the precipitated crystals were collected by filtration and washed with methanol to prepare spiro [1-methyl-1,2,3,4-tetrahydroquinazoline-2,1'-cyclohexane] -4-one 6.
32 g are obtained as colorless crystals. mp 183-185 ° C

Reference Example 4 (1) A solution of 9.6 ml of ethyl chloroformate in 25 ml of ether was added dropwise to a solution of 30 g of 1- (2-amino-2-methylpropyl) -4-methoxybenzene in 300 ml of ether under ice cooling. Then, a solution of 9.6 ml of ethyl chloroformate in 25 ml of ethyl and 8 g of sodium hydroxide in 50 parts of water.
ml solution is added dropwise at the same time. After the addition is complete, the mixture is stirred for 1 hour and water is added. The ether layer is separated and the aqueous layer is extracted twice with ether. The ether layer and the ether extract are combined and dried, and then the solvent is distilled off. The residue was purified by silica gel column chromatography to give 1- [2- (N-
Ethoxycarbonyl) amino-2-methylpropyl] -4
-29.1 g of methoxybenzene are obtained as an oil. NMR δ (CDCl ₃ ): 1.02 (6H, s), 1.32 (3
H, t, J = 7.5 Hz), 3.12 (2H, s), 3.72 (3
H, s), 4.17 (2H, q, J = 7.5 Hz), 6.70 to 7.
10 (4H, m)

(2) 10 g of this product is added to 100 ml of polyphosphoric acid and stirred at room temperature for 30 minutes. Then, the reaction solution is gradually heated to 100 ° C. and stirred for 2 hours. After cooling to room temperature, add 300 ml of water and extract with chloroform. After the extract was dried, the solvent was evaporated and the residue was purified by column chromatography to give 1-oxo-3,3-dimethyl-
5.43 g of 7-methoxy-1,2,3,4-tetrahydroisoquinoline are obtained as an oil. NMR δ (CDCl ₃ ): 1.02 (6H, s), 3.10 (2
H, s), 3.72 (3H, s), 6.90 (1H, d, J = 9H
z), 7.45 (1H, d, J = 9Hz), 7.85 (1H, d, J
= 3Hz)

Reference Examples 5 to 14 The corresponding starting material compound [XIII] and the corresponding starting material compound [XIV] are treated in the same manner as in Reference Example 1 to obtain the compounds shown in Table 10 below.

[0079]

[Table 10]

[0080]

INDUSTRIAL APPLICABILITY According to the present invention, by reacting an alkanoic imide compound [I] and a compound [II] in the presence of a base without using a Lewis acid, an azetidinone compound [a carbapenem synthesis intermediate] can be obtained. III] can be produced. In particular, a group represented by the formula -N (R ² ) (R ³ ) is a group represented by the formula

[Chemical 52] (Wherein the symbols are the same as above)
When using the [I], by using a lower alkyl group, particularly a methyl group as R ^1, compounds the group R ¹ is stereoselectively β-position [III-A]

[Chemical 53] (Wherein R ¹⁵ represents a lower alkyl group, and other symbols are the same as described above). Therefore, the present invention is
A useful synthetic intermediate of a 1β-methylcarbapenem derivative having an antibacterial action can be provided.

Further, the compound [III-A] was used as it is without being activated by chemically modifying the 4-position side chain.
It can lead to [XII] and [IX]. Compound
In the reaction from [III-A] to compound [XII] and compound [IX], a compound of formula

[Chemical 54] The group represented by the formula (where the symbols are the same as above) can be eliminated very easily, and this group can be recovered as the compound [IV]. Therefore, the production method of the compound [IX] using the compound [III-A] is It is excellent both in terms of operation and economically.

Further, a novel alkanoic imide compound
[IA] is easy to synthesize, and in particular, a compound in which X and Y are oxygen atoms and ring B is an unsubstituted benzene ring can be synthesized from commercially available salicylamide in two steps, which is industrially excellent. It is a reactive agent. Therefore, according to the present invention, without using an alkylation method which is industrially difficult to perform, without performing optical resolution, without using an expensive Lewis acid, and further performing a special waste liquid treatment. Without this, the azetidinone compound [III], the azetidinone propionic acid compound [VI] and the 1β-methylcarbapenem derivative [XI] can be industrially advantageously produced easily and inexpensively.

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁶ Identification code Internal reference number FI Technical indication C07D 239/88 239/90 265/20 265/22 279/08 401/06 205 403/06 205 205 413 / 06 205 417/06 205 // (C07D 401/06 205: 00 217: 00) (C07D 403/06 205: 00 239: 00) (C07D 403/06 205: 00 233: 00) (C07D 413/06 205: 00 265: 00) (C07D 413/06 205: 00 263: 00) (C07D 417/06 205: 00 279: 00) (C07D 417/06 205: 00 277: 00)

Claims (9)

[Claims] 1. A compound represented by the general formula [I]: (In the formula, R ¹ is a hydrogen atom or a lower alkyl group, and R ² and R ³ form a heterocyclic group together with the adjacent nitrogen atom.)
And an alkanoic acid amide compound represented by the general formula [II] (Wherein R ⁴ represents an optionally protected hydroxy-substituted lower alkyl group, and L ¹ represents a leaving group) in the presence of a base.
II] (Wherein each symbol is the same as the above), a process for producing an azetidinone compound. 2. A compound represented by the general formula [IA]: (In the formula, R ¹ is a hydrogen atom or a lower alkyl group, Ring B is a benzene ring which may have a substituent, X is an oxygen atom or a sulfur atom, Y is an oxygen atom, a sulfur atom, or may be protected. Good imino group or methylene group, Z ¹ and Z ² are the same or different and each is a hydrogen atom, an alkyl group which may have a substituent, a cycloalkyl group which may have a substituent, an aryl group or an aralkyl group. Or an alkylene group having 4 to 7 carbon atoms which may have a substituent by being bonded to each other at the terminals). 3. A compound represented by the general formula [IV-1]: (In the formula, ring B is a benzene ring which may have a substituent,
X is an oxygen atom or a sulfur atom, Y is an oxygen atom, a sulfur atom, an optionally protected imino group or a methylene group,
Z ¹ and Z ² are the same or different and each represent a hydrogen atom, an alkyl group which may have a substituent, a cycloalkyl group which may have a substituent, an aryl group or an aralkyl group, or they are mutually terminal. To form an alkylene group having 4 to 7 carbon atoms which may be substituted with a substituent) and a compound represented by the general formula [V]: (Wherein R ¹ represents a hydrogen atom or a lower alkyl group) or a reactive derivative thereof is reacted with the compound of the general formula [IA] (In the formula, symbols are the same as the above), and a method for producing an alkanoic acid amide compound. 4. A compound represented by the general formula [III]: (In the formula, R ¹ is a hydrogen atom or a lower alkyl group, R ² and R ³ form a heterocyclic group together with the adjacent nitrogen atom,
R ⁴ represents an optionally protected hydroxy-substituted lower alkyl group), which is characterized by hydrolyzing an azetidinone compound represented by the formula [VI] (Wherein the symbols are the same as the above), a process for producing an azetidinone alkanoic acid compound. 5. A compound represented by the general formula [I]: (In the formula, R ¹ is a hydrogen atom or a lower alkyl group, and R ² and R ³ form a heterocyclic group together with the adjacent nitrogen atom.)
And an alkanoic acid amide compound represented by the general formula [II] (Wherein R ⁴ represents an optionally protected hydroxy-substituted lower alkyl group, L ¹ represents a leaving group) in the presence of a base, and the compound of the general formula [III] Chemical 12] Wherein the azetidinone compound represented by the formula (wherein the symbols are the same as above) or a salt thereof is hydrolyzed. (In the formula, symbols are the same as the above), and a method for producing an azetidinone alkanoic acid compound. 6. A general formula [II] obtained by the method according to claim 1.
I] (Wherein R ¹ is a hydrogen atom or a lower alkyl group, R ⁴ is an optionally protected hydroxy-substituted lower alkyl group, R 4
² and R ³ form a heterocyclic group together with the adjacent nitrogen atom) and a azetidinone compound represented by the general formula [VII] (In the formula, R ⁵ represents a hydrogen atom or an ester residue, and L ² represents a leaving group), and the resulting compound is reacted with an acetic acid compound represented by the general formula [VIII] (Wherein the symbols are the same as above), the N-substituted azetidinone compound or a salt thereof is intramolecularly ring-closed, and then the obtained intramolecular ring-closed compound is subjected to an esterification reaction. [Chemical 17] (In the formula, —OA represents an esterified hydroxyl group, and other symbols are the same as the above), and a method for producing a 2-oxycarbapenem derivative. 7. The method according to claim 6, wherein either one or both of the intramolecular ring-closing reaction of the N-substituted azetidinone compound or a salt thereof and the esterification reaction of the obtained intramolecular ring-closed compound is conducted with a Lewis acid. 2-oxycarbapenem derivative [I] characterized by being carried out in the presence of
X] manufacturing method. 8. A compound represented by the general formula [IX] obtained by the process according to claim 6. (Wherein R ¹ is a hydrogen atom or a lower alkyl group, R ⁴ is an optionally protected hydroxy-substituted lower alkyl group, R 4
⁵ is a hydrogen atom or an ester residue, and -OA represents an esterified hydroxyl group), a 2-oxycarbapenem derivative represented by the general formula [X] (Wherein R ⁶ represents an organic group) is reacted with a thiol compound or a salt thereof, and R ⁴ is a protected hydroxy-substituted lower alkyl group, and / or R
^{When 5} is an ester residue, the protecting group and / or ester residue of the hydroxy-substituted lower alkyl group is optionally removed, and if necessary, the product is converted to a salt thereof in the general formula [ XI] (Wherein R ⁴¹ is an optionally protected hydroxy-substituted lower alkyl group, R ⁵¹ is a hydrogen atom or an ester residue, and other symbols are the same as the above), and a process for producing a carbapenem derivative or a salt thereof. 9. R ¹ is a methyl group, R ⁴ is an optionally protected 1-hydroxyethyl group, and R ⁶ is 2.
9. The method according to claim 8, which is a -thioxopyrrolidin-4-yl group.