JPH0328434B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention is based on the general formula The present invention relates to a novel 1-carba-2-penem-3-carboxylic acid derivative having the following, a pharmacologically acceptable salt thereof, and a method for producing the same. In the above formula, R ¹ represents a hydroxyl group-substituted alkyl group,
R ² is a saturated cyclic amino group that forms a three-membered ring and a six-membered ring as a whole through a nitrogen atom in the ring, and the nitrogen atom has the formula

[Formula] represents a group that may be substituted with a group (in the formula, R ⁴ represents a hydrogen atom or a lower alkyl group), and R ³ represents hydrogen or a protecting group for a carboxy group. Since the discovery of thienamycin, an antibiotic with extremely strong natural antibacterial activity (Japanese Patent Application Laid-open No. 51-73191)
(No.), and research on this family of compounds has been actively conducted. However, this class of compounds is known to be quite unstable (The Journal of Antibiotics, Vol. 32, 1).
Page, 1978). Therefore, the present inventors have conducted a deep search for compounds that increase the stability of thienamycins without reducing their antibacterial activity, and have completed the present invention. In the general formula (1), R ¹ is preferably, for example, hydroxymethyl, 2-hydroxyethyl, 1-
Hydroxyethyl, 3-hydroxypropyl, 1
-hydroxypropyl, 1-hydroxy-1-methylethyl, 4-hydroxybutyl, 1-hydroxybutyl, 5-hydroxypentyl, 1-hydroxypentyl, and ^R2 is preferably a hydroxyl-substituted alkyl group, such as aziridine. , azetidine, pyrrolidine, piperidine, etc. are residues of saturated cyclic amines that form a three- to six-membered ring as a whole through a nitrogen atom in the ring, and the nitrogen atom therein is represented by the formula

[Formula] A group that may be substituted with a hydrogen atom or a lower alkyl group such as methyl, ethyl, propyl, or isopropyl, and R ³ is preferably ^a hydrogen atom. ; for example, linear or branched lower alkyl groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl; for example, 2-iodoethyl, 2,2-dibromoethyl, 2 , 2,2-trichloroethyl; lower alkoxymethyl groups such as methoxymethyl, ethoxyethyl, propoxymethyl, isopropoxymethyl, butoxymethyl, isobutoxymethyl; e.g. acetoxymethyl, propionyloxymethyl ,
Lower aliphatic acyloxymethyl groups such as butyryloxymethyl, isobutyryloxymethyl, pivaloyloxymethyl; e.g. 1-methoxycarboxynyloxyethyl, 1-ethoxycarbonyloxyethyl, 1-propoxycarbonyloxyethyl, 1-isoproxycarbonyloxyethyl, 1-butoxycarbonyloxyethyl, 1
-1-lower alkoxycarbonyloxyethyl group such as isobutoxycarbonyloxyethyl;
For example, aralkyl groups such as benzyl, p-methoxybenzyl, o-nitrobenzyl, p-nitrobenzyl; benzhydryl or phthalidyl groups. Further, more preferable compounds in the general formula (1) are alkyl groups substituted with a hydroxyl group at the α position such as hydroxymethyl group, 1-hydroxyethyl, and 1-hydroxy-1-methylethyl; ² is a residue of a saturated cyclic amine, such as aziridine, azetidine, pyrrolidine, or piperidine, which forms a three- to six-membered ring as a whole through a nitrogen atom in the ring, and the nitrogen atom therein has the formula

[Formula] is a group that may be substituted with a hydrogen atom or a lower alkyl group such as methyl, ethyl, propyl, or isopropyl, and R ³ is a hydrogen atom, ² , Mention may be made of compounds which are 2-dibromoethyl, methoxymethyl, acetoxymethyl, pivaloyloxymethyl, 1-ethoxycarbonyloxyethyl, benzyl, p-nitrobenzyl, benzhydryl or phthalidyl groups. In addition, as particularly preferred compounds in the general formula (1), R ¹ is hydroxymethyl, 1-hydroxyethyl or 1-hydroxy-1-methylethyl group, and R ² is aziridine, azetidine,
It is a saturated cyclic amine residue forming a three- to six-membered ring such as pyrrolidine or piperidine, and the nitrogen atom therein is of the formula

[Formula] may be substituted with a group (in the formula, R ⁴ represents a hydrogen atom, methyl, ethyl, or propyl group),
R ³ is a hydrogen atom, pivaloyloxymethyl, 1-
Mention may be made of compounds which are ethoxycarbonyloxyethyl, p-nitrobenzyl, benzhydryl or phthalidyl groups. Furthermore, as the most preferred compound in general formula (1), R ¹ is 1-hydroxyethyl, 1-
It is a hydroxy-1-methylethyl group, R ² is a 4- to 6-membered saturated cyclic amine residue such as azetidine, pyrrolidine, or piperidine, and the nitrogen atom therein has the formula

[Formula] A group that may be substituted with a group (in the formula, R ⁴ represents a hydrogen atom, methyl or ethyl group), and R ³
can be a hydrogen atom, pivaloyloxymethyl, 1-ethoxycarbonyloxyethyl or phthalidyl group. In addition, in the compound having the above general formula (1), there are optical isomers and stereoisomers based on asymmetric carbon atoms, and all of these isomers are represented by a single formula, but this However, the scope of the present invention is not limited. However, it is preferable to select a compound in which the carbon atom at position 5 has the same coordination as that of penicillins, that is, the R coordination. Furthermore, in the general formula (1), the carboxylic acid compound in which R ³ is a hydrogen atom can be made into a pharmacologically acceptable salt form, if necessary. Such salts include lithium, sodium, potassium,
Examples include salts of inorganic metals such as calcium and magnesium, and ammonium salts such as ammonium, cyclohexylammonium, diisopropylammonium, and triethylammonium, but sodium salts and potassium salts are preferred. The compound having the general formula (1) of the present invention belongs to carbapenem derivatives in which the sulfur atom at the 1-position of the penicillin ring is substituted with methylene and a double bond is present between the 2-position and the 3-position of the ring, It is a group of novel compounds that have various substituted mercapto groups at the 2-position substituent, and these compounds exhibit excellent antibacterial activity and are useful as pharmaceuticals, or are important synthetic compounds that exhibit these activities. It is an intermediate. Examples of the compounds having the general formula (1) obtained by the present invention include the compounds shown in Table 1.

【table】

【table】

[Table] Furthermore, for all of the carboxylic acid derivatives shown in Table 1, their sodium salts, potassium salts, pivaloyloxymethyl esters, 1-ethoxycarbonyloxyethyl esters, or phthalidyl esters can be cited as exemplary compounds. can. In addition, as mentioned above, this exemplary compound has stereoisomers, and among these isomers, preferred are compounds having (5R, 6S) coordination and (5R, 6R) coordination, and When the 6-position substituent has a hydroxyl group at the α-position, its coordination is R
Examples include compounds that are coordinating. The novel compound (1) according to the present invention can be produced by the method shown below. In the above formula, R ¹ , R ² , and R ³ have the same meanings as described above, R ⁸ represents a hydroxyl group or an alkyl group substituted with a trialkylsilyloxy group, and R ⁵
is a saturated cyclic amino group that forms a three- to six-membered ring as a whole through a nitrogen atom in the ring, and the nitrogen atom therein may have a protecting group, and R ⁶ is a carboxy represents a protecting group for the group, R ⁷ represents an alkyl group such as butyl or octyl, or an aryl group such as phenyl or tolyl, R ⁹ represents a protective group for a hydrogen atom or a β-lactam nitrogen atom, and Y and Z represents a halogen atom such as chlorine, bromine or iodine. The α-halogenoketone compound having the above-mentioned general formula (2) and the epoxy compound having the above-mentioned general formula (4), which are the raw material compounds in the production of the present invention, are described in the published specification (Japanese Patent Application Laid-Open No. 122379/1989) by the applicant of the present invention. It can be synthesized by the method described. The first step (a) is a step of producing a compound having the general formula (3), in which the α-halogenoketone compound having the general formula (2) has the general formula HS-R ⁵ (11) (wherein R ⁵ is Indicates the same meaning as above.)
This is a step of reacting a thiol compound having the following in a solvent in the presence of a base. Bases used in this reaction include alkali metal lower alkoxides such as sodium methoxide, sodium ethoxide, sodium ethoxide, and sodium t-butoxide, and alkali metal carbonates such as sodium carbonate, sodium bicarbonate, and sodium carbonate. or bicarbonates, mixtures of the above-mentioned alkali metal bicarbonates and silver nitrate, triethylamine, pyridine, N-methylmorpholine, N,
Organic bases such as N-dimethylaniline may be mentioned, but a mixture of sodium bicarbonate and silver nitrate is preferred. Examples of the solvent used in the reaction include halogenated hydrocarbons such as methylene chloride and chloroform, ethers, ethers such as tetrahydrofuran, alcohols such as methanol, ethanol, and propanol, or mixtures of these organic solvents. I can give it to you. The reaction temperature is not particularly limited and is usually -10 to 100°C, and the reaction time is 30 minutes to 30 hours. After the reaction is completed, the target compound (3) of this step is collected from the reaction mixture according to a conventional method. For example, diluting the reaction mixture with a water-immiscible organic solvent such as ethyl acetate, ether, benzene, or chloroform;
If necessary, it can be obtained by neutralizing, washing with water, drying, distilling off the solvent, and purifying the residue by recrystallization, reprecipitation, or column chromatography. Note that the compound having the general formula (3) can also be produced by a separate synthesis method that involves the first step (b ₁ ) and the first step (b ₂ ) shown below. The first step (b ₁ ) is a step of producing a compound having the general formula (5), in which the epoxide compound having the general formula (4) is converted into the general formula HS-R ⁵ (11) (wherein R ⁵ is the same as the above-mentioned )
This is a step in which a nucleophilic reagent or a reactive derivative thereof is reacted in a solvent. Reactive derivatives of the nucleophile used in this reaction include alkali metal salts or alkaline earth metal salts such as salts with lithium, sodium, potassium or calcium, magnesium, and triethylamine, N-methylmorpholine, tetraethylammonium Examples include salts with organic bases such as hydroxide. Examples of the solvent used in the reaction include inert solvents such as halogenated hydrocarbons such as methylene chloride and chloroform, and ethers such as methyl ether and tetrahydrofuran.
The reaction temperature is not particularly limited and is usually -10 to 100°C.
℃, and the reaction time is 10 to 2 hours. Incidentally, this reaction also proceeds by allowing the nucleophilic reagent (11) to act in the presence of a base such as n-butyllithium or an acid such as boron trifluoride etherate. After the reaction is completed, the target compound (5) of this step is collected from the reaction mixture according to a conventional method. For example, diluting the reaction mixture with a water-immiscible organic solvent such as ethyl acetate, ether, benzene, or chloroform;
If necessary, it can be obtained by neutralizing, washing with water, drying, distilling off the solvent, and purifying the residue by recrystallization, reprecipitation, or column chromatography. The first step (b ₂ ) is a step of producing a compound having general formula (3), and is a step of oxidizing a secondary alcohol compound having general formula (5) in a solvent to form a ketone compound. The oxidizing agent used in this reaction is not particularly limited as long as it converts into a secondary alcohol compound, but chromate, manganate, hypohalite, halogen, N-haloamide, N - Examples include haloimides, oxygen, dialkyl sulfoxides and acid anhydrides. Solvents used in the reaction include halogenated hydrocarbons such as methylene chloride and chloroform, ketones such as acetone and methyl ethyl ketone, ethers such as tetrahydrofuran and dioxane, esters such as methyl acetate and ethyl acetate, or Mention may be made of various oxidizing solvents, including mixtures of these solvents. Chromic anhydride is preferably used as the oxidizing agent, especially John's reagent (from 6 to 60% of chromic anhydride).
using 10N sulfuric acid solution) or pyridinium chlorochromate at 0 to 10°C for 5 minutes to 2 hours.
React in acetone or dioxane, or
or using an oxidizing agent (Moffatt oxidation) with a combination of dimethyl sulfoxide and a carbodiimide such as dicyclohexylcarbodiimide and an acid such as phosphoric acid, acetic anhydride, trifluoroacetic acid, dichloroacetic acid at -20 to 30°C for 1 minute. This is carried out by reacting for 96 hours. After the reaction is completed, the target compound (3) of this step is collected from the reaction mixture according to a conventional method. For example, after decomposing excess oxidizing agent, the reaction mixture is diluted with a water-immiscible organic solvent such as those mentioned above, washed with water, dried, the solvent is distilled off, and the residue is subjected to recrystallization, reprecipitation, or column chromatography. It can be obtained by purification using graphite. The second step is a step of purifying the compound having the general formula (6) and, if necessary, removing the protecting group R ⁹ of the β-lactam nitrogen atom of the compound having the general formula (3). Removal of the protecting group R ⁹ is carried out according to conventional methods,
When the protecting group is a trialkylsilyl group such as tert-butyldimethylsilyl, it is treated in the presence of a hydrohalic acid such as hydrochloric acid, hydrobromic acid, or hydrofluoric acid or a salt thereof that generates a halogen anion. or with an organic quaternary ammonium base such as tetraalkylammonium fluoride, and when the protecting group is a tetrahydropyranyl group, dilute hydrochloric acid, dilute sulfuric acid, etc. It can be removed by treatment with an aqueous mineral acid solution such as Examples of the solvent used in this removal reaction include fatty acid dialkylamides such as dimethylformamide and diethylacetamide, dimethyl sulfoxide, hydrous alcohols such as hydrous methanol and hydrous ethanol, hydrous tetrahydrofuran,
Polar solvents such as hydrated ethers such as hydrated dioxane are preferred. The reaction is usually carried out at -10 to 30°C for 10 minutes to 3 hours. After the reaction is completed, the target compound of the reaction for removing the protecting group R ⁹ is collected from the reaction mixture according to a conventional method. For example, the reaction mixture is diluted with an organic solvent that is immiscible with water, neutralized, washed with water, dried, the solvent is distilled off, and the residue is purified by recrystallization, reprecipitation, or column chromatography. You can get it. The third step is a step of producing a compound having the general formula (7), in which the compound having the general formula (6) is added to the compound having the general formula OHC-COOR ⁶ (12) (wherein R ⁶ has the same meaning as above). show.)
This is a step of reacting a glyoxylic acid ester having the following or its hemiacetal derivative in a solvent. Glyoxylic acid ester (12) used in this reaction
When is a hemiacetal derivative, a hemiacetal with a lower alkanol such as methanol or ethanol is suitable. Examples of the solvent used in the reaction include fatty acid dialkylamides such as dimethylformamide and dimethylacetamide, and aromatic hydrocarbons such as benzene and xylene. The reaction temperature is not particularly limited, but it is preferably 25°C to around the reflux temperature of the solvent used, and is usually carried out in a nitrogen or argon atmosphere to avoid side reactions. The reaction time varies depending on the reaction temperature, etc., but is approximately 2 to 15 minutes.
It's time. Note that when a hydrate of glyoxylic acid ester (12) is used, water may be removed by azeotropic distillation or a dehydration method using a molecular sieve, if necessary. After the reaction is completed, the target compound (7) of this step is collected from the reaction mixture according to a conventional method. For example, it can be obtained by distilling off the organic solvent from the reaction mixture and purifying the residue by recrystallization, reprecipitation, or column chromatography. The fourth step is a step of producing a compound having the general formula (8), and is a step of halogenating the compound having the general formula (7) in a solvent. The halogenating agent used in this reaction is not particularly limited as long as it is a reagent that halogenates hydroxy compounds, but phosphorus trihalides such as phosphorus trichloride and phosphorus tribromide, phosphorus pentachloride, and Phosphorus pentahalides such as phosphorus chloride, phosphorus oxychloride, phosphorus oxyhalides such as phosphorus oxybromide, thionyl halides such as thionyl chloride, thionyl bromide, oxalyl chloride, oxalyl bromide Examples include oxalic acid halide. The reaction is preferably carried out in the presence of a strong acid mixture, and the acid mixture used is preferably an organic base such as triethylamine, pyridine, or lutidine. Examples of the solvent used in the reaction include inert solvents such as ethers, ethers such as tetrahydrofuran and dioxane, and halogenated hydrocarbons such as methylene chloride and chloroform. Reaction temperature is -40 to
The temperature is 40°C, and the reaction time varies depending on the halogenating agent, reaction temperature, etc., but is 15 minutes to 5 hours. After completion of the reaction, the target compound (8) of this step is taken from the reaction mixture according to a conventional method. For example, the reaction mixture is diluted with an inert organic solvent, the generated hydrohalide of the organic base is filtered off, the solvent is distilled off from the filtrate, and the residue is purified by recrystallization or reprecipitation. However, the halogenating agent and organic solvent may be distilled off from the reaction mixture under reduced pressure, and the residue may be used as it is in the next reaction step. The fifth step is a step of producing a compound having the general formula (9), in which the compound having the general formula (8) is converted into the compound having the general formula P(R ⁷ ) ₃ (13) (wherein R ⁷ is Indicates the same meaning as above.)
This is a step of reacting a phosphine compound having the following in a solvent. This reaction is a part of the so-called Wittig reaction and produces the phosphorus-ylide compound (9), and the most suitable phosphine (13) to be used is triphenylphosphine. The base used in the reaction is not particularly limited, but examples include organic bases such as triethylamine, pyridine, and lutidine, and alkali metal carbonates such as sodium carbonate and potassium carbonate. Examples of the solvent used in the reaction include ethers such as tetrahydrofuran and dioxane, aromatic acid hydrocarbons such as benzene, toluene, and xylene, halogenated hydrocarbons such as methylene chloride and chloroform, dimethylformamide, and dimethyl. Examples include inert solvents such as fatty acid dimethylamide such as acetamide and dimethyl sulfoxide. The reaction temperature is not particularly limited, but is from -30 to 120°C, and the reaction time varies depending on the reaction temperature, etc., but is usually 0.5 to 120°C.
It is 10 hours. In this reaction, if necessary, a catalytic amount of an antioxidant such as hydroquinone can be added to prevent the oxidation reaction. After the reaction is completed, the target compound (9) of this step is collected from the reaction mixture according to a conventional method. For example, it can be obtained by diluting the reaction mixture with an organic solvent that is immiscible with water, washing with water, drying, distilling off the solvent, and purifying the residue by recrystallization, reprecipitation, or column chromatography. can. The sixth step is a step of producing a carbapenem compound having the general formula (10), and includes a ring-closing reaction in which the compound having the general formula (9) is heated in a solvent, and if necessary,
This is a step in which the reactions of removing the protecting group contained in R ⁸ and restoring the hydroxyl group are carried out in an appropriate combination. Examples of solvents used in the ring-closing reaction include inert solvents such as ethers such as tetrahydrofuran and dioxane, halogenated hydrocarbons such as methylene chloride and chloroform, and aromatic acid hydrocarbons such as benzene, toluene, and xylene. Examples include solvents and mixed solvents of these solvents. The heating reaction temperature ranges from 30 to 200°C,
The reaction time varies depending on the reaction temperature, etc., but is usually 1 to 40 hours. In this reaction, in order to prevent side reactions due to heating, it is preferable to carry out the reaction in a stream of inert gas such as argon or nitrogen, if necessary.In addition, to prevent oxidation reactions, a catalytic amount of hydroquinone, etc. Antioxidants can also be added. The main ring-closing reaction by heating may also proceed in the phosphorus-ylide synthesis reaction of the fifth step described above to produce the target compound (10) of this step. In addition, when R ⁸ contains a protected hydroxyl group,
The phosphorus-ylide bond can be protected as necessary with a mineral acid such as hydrochloric acid, and the hydroxyl protecting group can be removed. When the protected hydroxyl group is a tri-lower alkylsilyloxy group such as tert-butyldimethylsilyloxy, the reaction can be carried out by treating the corresponding compound (9) with tetrabutylammonium fluoride. The solvent used is not particularly limited, but ethers such as tetrahydrofuran and dioxane, or a mixture of water and methanol are suitable. The reaction is suitably carried out by treating at around room temperature for 1 to 18 hours. After the reaction is completed, the target compound of this step is collected from the reaction mixture according to a conventional method. For example, it can be obtained by distilling off the solvent from the reaction mixture and purifying the residue by recrystallization, reprecipitation, or column chromatography. The seventh step is the compound of general formula (1) which is the object compound of the present invention.
In the step of producing a 1-carba-2-penem- ³ -carboxylic acid derivative having and a reaction of removing the protecting group contained in R ⁵ to restore the saturated cyclic amino group,
Furthermore, the restored in R ² groups

[Formula] The group is the formula

[Formula] This is a process in which reactions for converting into a group (in the formula, R ⁴ has the same meaning as described above) are carried out in an appropriate combination. That is, in the reaction for producing a carboxylic acid compound in which the substituent R ³ is a hydrogen atom in the compound having the general formula (1), the protecting group R ⁶ of the carboxy group of the compound having the general formula (10) is removed. This is achieved by doing. Removal of protecting group ⁶ varies depending on the type, but
It is generally removed by methods known in the art. Preferably, the reaction is carried out using a compound having the general formula (10) in which the protecting group R ⁶ is a protecting group that can be removed by reduction treatment, such as a halogenoalkyl group, an aralkyl group, or a benzhydryl group, using a reducing agent. This is accomplished by making contact. The reducing agent used in this reaction includes a carboxy group protecting group such as 2,2-dibromoethyl, 2,
Zinc and acetic acid are preferred when the protecting group is a halogenoalkyl group such as 2,2-trichloroethyl, hydrogen and acetic acid when the protecting group is an aralkyl group such as benzyl, p-nitrobenzyl, or a benzhydryl group. Catalytic reduction catalysts such as palladium-carbon or alkali metal sulfides such as sodium or potassium sulfide are preferred. The reaction is carried out in the presence of a solvent, and the solvent used is not particularly limited as long as it does not participate in this reaction, but alcohols such as methanol and ethanol, ethers such as tetrahydrofuran and dioxane, and acetic acid are used. A mixed solvent of fatty acids such as and organic solvents thereof and water or a phosphate buffer (PH7.0) is suitable. The reaction temperature is usually around 0° C. to room temperature, and the reaction time varies depending on the raw material compound and the type of reducing agent, but is usually 5 minutes to 12 hours. In addition, in the reduction reaction of this step, when the substituent R ⁵ of compound (10) has a saturated cyclic amino group protected by an aralkyloxycarbonyl group, the aralkyloxycarbonyl protecting group is Can be removed. After completion of the reaction, the target compound of the reaction for removing the carboxyl protecting group R ⁶ is collected from the reaction mixture according to a conventional method. For example, after filtering off insoluble matter precipitated from the reaction mixture, the organic solvent layer is washed with water, dried, and the solvent is distilled off. If necessary, conventional methods such as recrystallization, preparative thin layer chromatography, column chromatography It can be purified by graphite, etc. In addition, when the target compound is water-soluble, insoluble matter precipitated from the reaction mixture is filtered off, and if necessary, the filtrate is concentrated under reduced pressure, and then Diaion
It can be obtained by subjecting it to column chromatography using a porous adsorption resin such as HP20AG (manufactured by Mitsubishi Kasei Corporation), separating the portion from which the target compound is eluted, and freeze-drying it. In compound (10), substituent R ³ is an acylamino group,
When the compound has an aralkylamino group or an aralkyloxycarbonylamino group, if desired, each protecting group is removed according to a conventional method as described below to convert the compound to the corresponding amino group. The compound obtained can also be subjected to the above-mentioned reaction for removing the protecting group R ⁶ for the carboxy group. That is, the reaction for producing a compound having an amino group as the substituent R ² among the compounds having the general formula (1) is performed when R ⁵ of the compounds having the general formula (10) is produced.
is a halogenoacetylamino group, an aryl- or aryloxy-substituted acetylamino group, an aralkyloxycarbonylamino group, or a halogenoacetylamino group, an aryl- or aryloxy-substituted acetylamino group, an aralkyloxycarbonylamino group, or an aralkylamino group This is achieved by removing the halogenoacetyl, aryl or aryloxy substituted acetyl, aralkyloxycarbonyl or aralkyl protecting group of the amino group from the group. When the compound has a halogenoacetyl group such as trifluoroacetyl or trichloroacetyl, its removal reaction can be carried out by treating the corresponding compound (10) with a base in the presence of an aqueous solvent. The solvent to be used is not particularly limited as long as it is a solvent used in ordinary hydrolysis reactions, but water, water and alcohols such as methanol, ethanol, and propanol, or ethers such as tetrahydrofuran and dioxane, etc. A mixed solvent with an organic solvent is suitable. The base used is not particularly limited as long as it does not affect other parts of the compound, especially the β-lactam ring, but alkali metal carbonates such as sodium carbonate and potassium carbonate are preferably used. It is done using The reaction temperature is not particularly limited, but a temperature of about 0° C. to room temperature is suitable in order to suppress side reactions. The time required for the reaction varies depending on the type of raw material compound, reaction temperature, etc., but is usually 1 to 6 hours. When the compound has an aryl- or aryloxy-substituted acetyl group, such as phenylacetyl or phenoxyacetyl, the removal reaction can be carried out by contacting the corresponding compound (10) with acylase. This enzyme division reaction is N
-Acyl-thienamycin can be carried out according to the method disclosed in JP-A No. 54-46890, and the acylase used is preferably penicillin amidohydrolase such as Escherichia coli. It is. When an aralkyloxycarbonyl group such as benzyloxycarbonyl or p-nitrobenzyloxycarbonyl or an aralkyl group such as diphenylmethyl is present, the removal reaction can be carried out by contacting the corresponding compound (10) with a reducing agent. Implemented. The type of reducing agent and reaction conditions used in this reaction are the same as those for removing the aralkyl group, which is the carboxy-protecting group R ⁶ described above, and therefore the carboxy-protecting group R ⁶ can also be removed at the same time. can. After carrying out the above various protecting group removal reactions,
The target compound for each reaction is collected from the reaction mixture according to a conventional method, and if necessary, it can be further purified by a conventional method such as recrystallization, preparative thin layer chromatography, column chromatography, etc. . Furthermore, among the compounds having the general formula (1),
Substituent R ² has the formula

[Formula] The reaction for producing a compound containing a group (in the formula, R ⁴ has the same meaning as defined above) has the general formula (1) obtained by the removal reaction of the various protecting groups described above. Of the compounds, the formula

[Formula] The general formula for an amino compound having a group is or (In the formula, R ⁴ and Y have the same meanings as above, R ¹⁰ represents a lower alkyl group such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, and R ¹¹ represents a hydrogen atom or methyl, ethyl , n-propyl, isopropyl, etc.). The reaction is carried out by contacting the compound (1) in which the substituent included in R ² is a cyclic amino group with an imide ester compound having the general formula (14) or (15) under alkaline conditions, preferably around pH 8 to 9. It can be carried out by The alkaline reagent used in the reaction is not particularly limited, but includes alkali metal hydroxides such as sodium hydroxide and potassium hydroxide, alkaline earth metal hydroxides such as calcium hydroxide and barium hydroxide,
Alkali metal carbonates such as sodium carbonate and potassium carbonate are preferred. This reaction is carried out in the presence of an aqueous solvent, and the solvents used include water, water and alcohols such as methanol, ethanol, and n-propanol, ethers such as tetrahydrofuran and dioxane, dimethylformamide, dimethyl A mixed solvent with an organic solvent such as a fatty acid dialkylamide such as acetamide or a nitrile such as acetonitrile is suitable. The reaction temperature is preferably a relatively low temperature of about 0° C. to room temperature. The time required for the reaction varies depending on the type of raw material compound, reaction temperature, etc., but is usually 5 minutes to 1 hour. After completion of the reaction, the target compound of this reaction is collected from the reaction mixture according to a conventional method. For example, if the liquid nature of the reaction mixture is near neutral, then the diamond ion
Subjected to column chromatography using a porous adsorption resin such as HP20AG (manufactured by Mitsubishi Kasei Corporation), the portion from which the target compound is eluted is collected and freeze-dried.
If necessary, it can be obtained by further purification by conventional methods such as recrystallization and reprecipitation. Next, the obtained compound can be converted into a carboxylic acid derivative by removing the protecting group of the carboxy group according to the conventional method described above, if necessary. In addition, when carrying out the present oxidation reaction using the phosphorus-ylide compound (9), the phosphorus-ylide bond is removed in the presence of 1 mol or more of a mineral acid such as hydrochloric acid, hydrobromic acid, or trifluoroacetic acid. need to be protected by protonation. Carbapenem of the present invention having the general formula (1)
3-Carboxylic acid derivatives exhibit excellent antibacterial activity or are important intermediates in the synthesis of compounds exhibiting such antibacterial activity. Among them, the activity of compounds exhibiting antibacterial activity was measured by the agar plate dilution method, and it was found that, for example, Gram-positive bacteria such as Staphylococcus aureus and Bacillus subtilis, as well as Escherichia coli, Shigella, Klebsiella pneumoniae, M. mutiformis, and B. aeruginosa, It showed activity against a wide range of pathogenic bacteria, including Gram-negative bacteria. Such compounds are therefore useful as antibacterial agents to treat bacterial infections caused by these pathogens. Examples of dosage forms for this purpose include oral administration using tablets, capsules, granules, powders, syrups, etc., and parenteral administration via intravenous injection, intramuscular injection, etc. The dosage varies depending on age, body weight, symptoms, etc., as well as the mode of administration and frequency of administration, but the usual dose for adults is about 250 to 3000 mg per day, once or divided into several doses. Next, the present invention will be explained in more detail with reference to Examples. Example 1 1-A (3S,4R)-3-[1-(R)-t-butyldimethylsilyloxy]ethyl-4-[N-p-nitrobenzyloxycarbonyl-3-(S)-pyrrolidinyl]thiomethylcarbonyl Methyl-azetidin-2-one [N-p-nitrobenzyloxycarbonyl-
379 mg of solid sodium bicarbonate was added to a mixture of 1.27 g of 3-(S)-pyrrolidinyl]mercaptan, 5.6 ml of tetrahydrofuran, and 11.2 ml of methanol under ice cooling.
and then a solution of 765 mg of silver nitrate in 40 ml of methanol is added dropwise. To the resulting ice-cold suspension solution (3S, 4R)
-3-[1-(R)-t-butyldimethylsilyloxy]ethyl-4-iodomethylcarbonylmethyl-azetidin-2-one 922 mg methanol 10
After adding ml solution, the reaction mixture was placed in an oil bath (40℃).
Stir on top for 16 hours. After the reaction is completed, the mixture is diluted with ethyl acetate, passed through Celite to remove insoluble parts, and the resulting organic layer is washed with water and brine, and then dried over sodium sulfate. After distilling off the solvent, the resulting residue was subjected to silica gel column chromatography (cyclohexane-ethyl acetate/1:
4) to obtain the desired azetidine-2-
892 mg of ion were obtained as an oil. (Yield 70.3%) IR (CHCl ₃ ): 1760 (β-lactam), 1710 (ketone) cm ^-1 NMR δ (CDCl ₃ ): 0.07 (6H, s, Me ₂ Si), 0.87
(9H, s, But) 1.22 (3H, d, J=6Hz,
CH ₃ CH−OSi), 1.5−4.4 (14H, m), 5.20
(2H, s, COCH ₂ Ph), 6.1−6.4 (1H, bs, β
-lactam NH), 7.50 (2H, d, J = 9Hz,
PhNO ₂ ), 8.20 (2H, d, J = 9Hz, PhNO ₂ ) 1-B (3S,4R)-3-[1-(R)-t-butyldimethylsilyloxy]ethyl-1-(1-hydroxy -1-p-nitrobenzyloxycarbonyl)methyl-4-[N-p-nitrobenzyloxycarbonyl-3-(S)-pyrrolidinyl]thiomethylcarbonylmethyl-azetidine-2-
On p-nitrobenzylglyoxylate hydrate
806 mg was placed in 300 ml of benzene with a dehydration tube to remove water, then the benzene was concentrated to 200 ml, and azetidin-2-one (compound of Example 1-A) was added to this.
892 mg of benzene with 10 ml of tetrahydrofuran solution
Add 200ml and reflux for 8 hours while removing water.200ml
Concentrate to The solvent was distilled off from the reaction mixture under reduced pressure, and the resulting residue was subjected to silica gel column chromatography (first, glyoxylate was removed with isopropyl ether-ethyl acetate 2:1, then cyclohexane-ethyl acetate 1:2). The target product was eluted using a method of elution) to obtain 962 mg of the target hydroxyazetidin-2-one. (Yield 78.7%) IR (CHCl ₃ ): 1750 (β-lactam), 1700 (ester) cm ⁻¹ 1-C (3S,4R)-3-[1-(R)-t-butyldimethylsilyloxy ]Ethyl-4-[N-p-nitrobenzyloxycarbonyl-3-(S)-pyrrolidinyl]thiomethylcarbonylmethyl-1
-(1-p-Nitrobenzyloxycarbonyl-1-triphenylphosphoranylidene)methyl-azetidin-2-one Hydroxyazetidin-2-one (Example 1-
Compound B) 941 mg was added to a 25 ml solution of tetrahydrofuran at -24°C under an argon gas stream at 2,6
- Add 0.43 ml of lutidine and 0.27 ml of thionyl chloride, and stir at -24°C for 20 minutes and then at room temperature for 20 minutes. After the reaction is completed, the mixture is diluted with benzene, passed through Celite to remove insoluble parts, and the resulting organic layer is concentrated under reduced pressure. To the obtained residue, 25 ml of tetrahydrofuran, 655 mg of triphenylphosphine and 0.29 ml of 2,6-lutidine were added in a stream of argon gas.
and stir at 40°C for 4 hours. Next, the reaction mixture was diluted with 250 ml of ethyl acetate, washed with saturated brine, and dried over sodium sulfate. After distilling off the solvent under reduced pressure, the resulting residue was subjected to silica gel column chromatography (benzene-acetone/4:
1) to obtain 1071 mg of the desired phosphoranylideneazetidin-2-one as an amorphous product. (Yield 86.4%) IR (CHCl ₃ ): 1730 (β-lactam), 1700 (ester) cm ⁻¹ 1-D (3S,4R)-3-[1-(R)-hydroxyethyl]-4- [N-p-nitrobenzyloxycarbonyl-3-(S)-pyrrolidinyl]thiomethylcarbonylmethyl-1-(1-p-nitrobenzyloxycarbonyl-1-triphenylphosphoranylidene)methyl-azetidin-2-one Ylide compound (compound of Example 1-C) 1059 mg
Add 10% hydrochloric acid water to 106 ml of methanol solution under ice cooling.
Add 43ml. Then remove the ice bath and stir at room temperature for 1.5 hours to obtain a clear solution. After the reaction is completed, the reaction mixture is slowly poured into a mixed solution consisting of 21 g of sodium hydrogen carbonate, 203 ml of water, and 203 ml of ethyl acetate under ice cooling. After the mixed solution is saturated with common salt, the organic layer is separated, and the aqueous layer is extracted twice with ethyl acetate. The obtained organic layer and ethyl acetate layer are combined, washed with an aqueous sodium bicarbonate solution and saturated brine, and dried over sodium sulfate. After distilling off the solvent under reduced pressure, the resulting residue was purified by silica gel column chromatography (cyclohexane-acetone/1:1) to obtain 931 mg of the desired hydroxy compound as an amorphous substance.
(Yield 99.1%) IR (CHCl ₃ ): 1740 (β-lactam and ester)
cm ^-1 1-E p-nitrobenzyl (5R, 6S)-6-[1-
(R)-hydroxyethyl]-3-[N-p-nitrobenzyloxycarbonyl-3-(S)-pyrrolidinyl]thiomethyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2- Carboxylate: Attach 200 ml of benzene to a dehydration tube to remove water, then concentrate to 100 ml, and then add phosphoranylidene-azetidin-2-one (compound of Example 1-D).
919 mg of tetrahydrofuran in 20 ml of solution and benzene
Add 200ml and reflux for 3 hours in an argon gas stream.
Concentrate to 100ml. Next, the solvent was distilled off under reduced pressure,
The resulting residue was separated and purified using silica gel column chromatography (benzene-acetone/3:1), yielding 453 mg of the target carbapenem compound.
I got it. (Yield 71.3%) IR (CHCl ₃ ): 1780 (β-lactam) cm ⁻¹ NMR δ (CDCl ₃ ): 1.20 (3H, d, J = 6 Hz,
CH ₃ CHOSi, 1.6−4.5 (15H, m), 5.03 and
5.38 (2H, ABq, J=14Hz,

[Formula]), 5.10 (2H, S, NHCOOCH ₂ ), 7.43 and 7.52 (4H, two d,
J = 9Hz, PhNO ₂ ), 8.13 (4H, d, J = 9Hz,
PhNO ₂ ) 1-F (5R,6S)-6-[1-(R)-hydroxyethyl]-3-[3-(S)-pyrrolidinyl]thiomethyl-7-oxo-1-azabicyclo[3.2.0]
Hept-2-ene-2-carboxylic acid carbapenem compound (compound of Example 1-E)
1289 mg of 10% palladium-carbon and phosphate buffer (PH7.0) in 429 mg of tetrahydrofuran (35 ml)
Add 35 ml and perform catalytic reduction for 40 minutes at 10° C. under 40 psi hydrogen pressure. After the reaction is complete, the palladium-carbon is removed through Celite, the solution is washed three times with cold ethyl ether, and the aqueous layer is concentrated to the lower half of reduced pressure. This concentrate was applied to HP-20AG column chromatography, thoroughly washed with water, and eluted with 2% acetone water to obtain 96.7 mg of the target compound. (Yield 45.2%) IR (KBr): 1755 (β-lactam) cm ⁻¹ UV (H ₂ O): λmax = 274 nm (ε = 6270) NMR δ (D ₂ O): 1.32 (3H, d, J = 7Hz, _CH3-
CHO), 1.6-4.4 (14H, m) Example-2 (5R,6S)-3-[N-formimidoyl-3-
(S)-pyrrolidinyl]thiomethyl-6-[1-
(R)-Hydroxyethyl]-7-oxo-1-
Azabicyclo[3.2.0]hept-2-ene-2
-carboxylic acid (5R,6S)-6- obtained in Example (1-F)
[1-(R)-Hydroxyethyl]-3-[3-(S)
-pyrrolidinyl]thiomethyl-7-oxo-1-
Azabicyclo[3.2.0]hept-2-ene-2-
Carboxylic acid 185mg in phosphate buffer (PH7.0) 13
ml and pH it with 1N caustic soda aqueous solution under ice-cooling.
Set it to 8.5. Methylformimidate hydrochloride 850mg
and 1N aqueous caustic soda solution were added alternately to carry out the reaction while maintaining the reaction solution at pH 8.5. After further stirring for 20 minutes under ice cooling, the pH was adjusted to 7.0 with 1N hydrochloric acid, and the solution was concentrated to about half under reduced pressure. This concentrate was applied to HP-20AG column chromatography, thoroughly washed with water, and then eluted with 3% acetone water to obtain 125 mg of the target compound. (Yield 62.2%) IR (KBr): 1770 (β-lactam) cm ⁻¹ NMR δ (D ₂ O): 1.33 (3H, d, J = 7Hz,
CH ₃ CHO), 2.90−4.50 (14H, m), 7.94 (1H,
s, -CH=NH) Example-3 3-A (3S,4R)-3-[1-(R)-t-butyldimethylsilyloxy]ethyl-4-[N-p-nitrobenzyloxycarbonyl-3-azetidinyl]thiomethylcarbonylmethyl-azetidine- 2-one [N-p-nitrobenzyloxycarbonyl-
Add 1.69 g of 3-azetidinyl mercaptan to a mixture of 7.5 ml of tetrahydrofuran and 15 ml of methanol.
Add 531 mg of solid sodium hydrogen carbonate under ice cooling,
Next, a solution of 1.07 mg of silver nitrate in 56 ml of methanol is added dropwise. (3S,4R)-3-
[1-(R)-t-butyldimethylsilyloxy]
After adding a solution of 1.30 mg of ethyl-4-iodomethylcarbonylmethyl-azetidin-2-one in 15 ml of methanol, the reaction mixture was placed on an oil bath (40°C).
Stir for 24 hours. After the reaction is completed, the mixture is diluted with ethyl acetate, passed through Celite to remove insoluble parts, and the resulting organic layer is washed with water and brine, and then dried over sodium sulfate. After distilling off the solvent under reduced pressure, the resulting residue was subjected to silica gel column chromatography (cyclohexane-ethyl acetate/1:4).
to obtain the desired azetidin-2-one.
Obtained 1428 mg as an oil. (Yield 81.9%) IR (CHCl ₃ ): 1760 (β-lactam) cm ⁻¹ NMR δ (CDCl ₃ ): 0.07 (6H, s, Me ₂ Si), 0.83
(9H, s, ^But ), 1.20 (3H, d, J=7Hz,
CH ₃ CHOSi), 2.6−4.6 (12H, m), 5.13 (2H,
s, COCH ₂ Ph), 6.47 (1H, bs, β-lactam
NH), 7.45 (2H, d, J=10Hz, PhNO ₂ ),
8.15 (2H, d, J = 10Hz, PhNO ₂ ) 3-B (3S,4R)-3-[1-(R)-t-butyldimethylsilyloxy]ethyl-1-(1-hydroxy-1-p -nitrobenzyloxycarbonyl)methyl-4-[N-p-nitrobenzyloxycarbonyl-3-azetidinyl]thiomethylcarbonylmethyl-azetidin-2-one p-nitrobenzylglyoxylate hydrate
1175 mg was placed in 400 ml of benzene with a dehydration tube to remove water, then the benzene was concentrated to 200 ml, and to this was added 1420 mg of azetidin-2-one (compound of Example 3-A) in a 20 ml solution of tetrahydrofuran and 200 ml of benzene. and reflux for 10 hours while removing water.
Concentrate to 200ml. The solvent was distilled off from the reaction mixture under reduced pressure, and the resulting residue was subjected to silica gel column chromatography (first, glyoxylate was removed with isopropyl ether-ethyl acetate 2:1, then cyclohexane-ethyl acetate 1:2). The desired product was purified by eluting the desired product (1502 mg of the desired hydroxyazetidin-2-one). (yield
76.3%) IR (CHCl ₃ ): 1750 (β-lactam) cm ⁻¹ 3-C (3S,4R)-3-[1-(R)-t-butyldimethylsilyloxy]ethyl-4-[N- p-Nitrobenzyloxycarbonyl-3-azetidinyl]thiomethylcarbonylmethyl-1-(1
-pnitrobenzyloxycarbonyl-1-triphenylphosphoranylidene)methyl-azetidin-2-one Hydroxyazetidin-2-one (Example 3-
Compound B) 1491 mg was added to 38 ml of tetrahydrofuran solution at -24°C under an argon gas stream at 2,6
- Add 0.69 ml of lutidine and 0.43 ml of thionyl chloride, and stir at -24°C for 20 minutes and then at room temperature for 20 minutes. After the reaction is completed, the mixture is diluted with benzene, passed through Celite to remove insoluble parts, and the resulting organic layer is concentrated under reduced pressure. To the obtained residue, 38 ml of tetrahydrofuran, 1032 mg of triphenylphosphine and 0.46 ml of 2,6-lutidine were added in an argon gas stream.
and stir at 40°C for 4 hours. Next, the reaction mixture was diluted with ethyl acetate, washed with saturated brine, and dried over sodium sulfate. After distilling off the solvent under reduced pressure, the resulting residue was subjected to silica gel column chromatography (cyclohexane-ethyl acetate/
1:2) to obtain 1551 mg of the desired phosphoranylideneazetidin-2-one as an amorphous product. (Yield 78.7%) IR (CHCl ₃ ): 1735 (β-lactam) cm ⁻¹ 3-D (3S,4R)-3-[1-(R)-hydroxyethyl]-4-[N-p- nitrobenzyloxycarbonyl-3-azetidinyl]thiomethylcarbonylmethyl-1-(1-p-nitrobenzyloxycarbonyl-1-triphenylphosphoranylidene)methyl-azetidin-2-one ylide compound (Example 3-C) Compound) 1550mg
Add 10% hydrochloric acid water to 160 ml of methanol solution under ice cooling.
Add 65ml. Then remove the ice bath and stir at room temperature for 1.5 hours to obtain a clear solution. After the reaction is complete, the reaction mixture is slowly poured into a mixture of 32 g of sodium hydrogen carbonate, 305 ml of water and 305 ml of ethyl acetate under ice cooling. After the mixed solution is saturated with common salt, the organic layer is separated, and the aqueous layer is extracted twice with ethyl acetate. The obtained organic layer and ethyl acetate layer are combined, washed with an aqueous sodium bicarbonate solution and saturated brine, and dried over sodium sulfate. After distilling off the solvent under reduced pressure, the resulting residue was purified by silica gel column chromatography (cyclohexane-acetone/1:2) to obtain 1049 mg of the desired hydroxy compound as an amorphous substance. (Yield 76.3%) IR (CHCl ₃ ): 1740 (β-lactam) cm ⁻¹ 3-E p-nitrobenzyl (5R, 6S)-6-[1-
(R)-Hydroxyethyl]-3-[N-p-nitrobenzyloxycarbonyl-3-azetidinyl]thiomethyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate Benzene 400ml Attach a dehydration tube to remove water, then concentrate to 200 ml, and then add phosphoranylidene-azetidin-2-one (compound of Example 3-D).
1047mg of tetrahydrofuran 20ml solution and benzene
Add 200ml and reflux for 6 hours in an argon gas stream.
Concentrate to 200ml. Next, the solvent was distilled off under reduced pressure,
The resulting residue was separated and purified using silica gel column chromatography (benzene-acetone/2:1), yielding 619 mg of the target carbapenem compound.
I got it. (Yield 85.9%) IR (CHCl ₃ ): 1780 (β-lactam) cm ⁻¹ NMR δ (CDCl ₃ ): 1.33 (3H, d, J = 6 Hz,
CH ₃ CHOSi, 2.2−4.5 (13H, m), 5.13 and
5.47 (2H, ABq, J=14Hz,

[Formula]), 5.13 (2H, s, NHCOOCH ₂ ), 7.43 and 7.57 (4H, two d,
J = 9.5Hz, PhNO ₂ ), 8.17 (4H, d, J = 9.5
Hz, _PhNO2 ) 3-F (5R,6S)-6-[1-(R)-hydroxyethyl]-3-(3-azetidinylthiomethyl)-7
-Oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid Carbapenem compound (compound of Example 3-E)
1852 mg of 10% palladium-carbon in 15 ml of 615 mg of tetrahydrofuran and phosphate buffer (PH7.0)
Add 15 ml and perform catalytic reduction under 55 psi hydrogen pressure (10°C) for 70 minutes. After the reaction is complete, the palladium-carbon is removed through Celite, the solution is washed three times with cold ethyl ether, and the aqueous layer is concentrated to the lower half of reduced pressure. This concentrate was applied to HP-20AG column chromatography, thoroughly washed with water, and then eluted with 3% acetone water to obtain the target compound 137.
mg was obtained. (Yield 45.9%) IR (KBr): 1755 (β-lactam) cm ⁻¹ NMR δ (D ₂ O): 1.33 (3H, d, J = 6 Hz,
_CH3CHO ), 2.8-4.5 (12H, m) Example-4 (5R,6S)-3-(N-formimidoyl-3
-azetidinyl)thiomethyl-6-[1-(R)
-hydroxyethyl]-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid (5R,6S)-6- obtained in Example (3-F)
92.3 mg of [1-(R)-hydroxyethyl]-3-(3-azetidinyl)thiomethyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid was added to a phosphate buffer (PH7). .0) Dissolve in 8ml and add 1N caustic soda aqueous solution under ice cooling to PH8.5mg.
shall be. Methylformimidate hydrochloride 430mg and
The reaction is carried out while maintaining the reaction solution at pH 8.5 by alternately adding 1N aqueous caustic soda solution. Further under ice cooling
After stirring for 20 minutes, adjust the pH to 7.0 with 1N hydrochloric acid, and concentrate the solution to about half under reduced pressure. This concentrate
The mixture was subjected to HP-20AG column chromatography, thoroughly washed with water, and then eluted with 3% acetone water to obtain 46.3 mg of the target compound. (Yield 45.9%) IR (KBr): 1770 (β-lactam) cm ^-1 NMR δ (D ₂ O): 1.43 (3H, d, J = 6Hz), 3.0-
4.6 (14H, m), 7.80 (1H, s, -CH=NH). Example-5 (5R,6S)-3-[N-acetimidoyl-3
-(S)-pyrrolidinyl]thiomethyl-6-[1
-(R)-hydroxyethyl]-7-oxo-1
-Azabicyclo[3.2.0]hept-2-ene-
2-carboxylic acid (5R,6S)-6- obtained in Example (1-F)
[1-(R)-Hydroxyethyl]-3-[3-(S)
-pyrrolidinyl]thiomethyl-7-oxo-1-
Azabicyclo[3.2.0]hept-2-ene-2-
234.6mg of carboxylic acid in phosphate buffer (PH7.0)
Dissolve in 21ml and add with 1N caustic soda aqueous solution under ice cooling.
PH should be 8.5mg. Ethylacetimidate hydrochloride
1291 mg and a 1N caustic soda aqueous solution are added alternately under water cooling, and the reaction is carried out at the same temperature while maintaining the reaction solution at pH 8.5. After further stirring for 20 minutes under ice cooling,
Adjust the pH to 7.0 with 1N hydrochloric acid, and concentrate the solution to about half under reduced pressure. This concentrate was applied to HP-20AG column chromatography, thoroughly washed with water, and eluted with 5% acetone water to obtain 136 mg of the target compound. (Yield 51.0%) IR (KBr): 1770 cm ^-1 (β-lactam) NMR δ (D ₂ O): 1.32 (3H, d, J = 7 Hz,
CH ₃ CHO), 2.28 (3H, s,

【formula】), 2.90−4.50 (14H, m).

Claims (1)

[Claims] 1. General formula [In the formula, R ¹ represents a hydroxyl group-substituted alkyl group,
R ² is a saturated cyclic amino group that forms a three- to six-membered ring as a whole through a nitrogen atom in the ring, and the nitrogen atom is a group of the formula [formula] (wherein R ⁴ is a hydrogen atom or a lower alkyl R ³ represents hydrogen or a protecting group for a carboxy group. 1-carba-2-penem-3-carboxylic acid and a pharmacologically acceptable salt thereof. 2 General formula [In the formula, R ¹ represents a hydroxyl group-substituted alkyl group,
R ⁵ is a saturated cyclic amino group that forms a three- to six-membered ring as a whole through a nitrogen atom in the ring, and the nitrogen atom therein may have a protecting group, and R ⁶ represents a carboxyl group-protecting group, and R ⁷ represents an alkyl group or an aryl group. ) by heating a phosphorus-ylide compound having the general formula (In the formula, R ¹ , R ⁵ and R ⁶ have the same meanings as described above.) Then, if desired, the obtained compound is subjected to a reaction for removing the carboxyl group protecting group R ⁶ and the protecting group contained in R ⁵ is removed and subjected to a reaction to restore the saturated cyclic amino group, and the [formula] group contained in the substituent at the 2-position of the obtained compound is converted to the formula [formula] group ( In the formula, R ⁴ represents a hydrogen atom or a lower alkyl group.)
A general formula characterized by being attached in appropriate combinations to reactions that convert into [In the formula, R ¹ represents a hydroxyl group-substituted alkyl group,
R ² is a saturated cyclic amino group that forms a three- to six-membered ring as a whole through a nitrogen atom in the ring, and the nitrogen atom is a group of the formula [formula] (wherein R ⁴ is a hydrogen atom or a lower (represents an alkyl group), and R ³ represents hydrogen or a protecting group for a carboxy group. ] 1-carba-2-
A method for producing penem-3-carboxylic acid and a pharmacologically acceptable salt thereof.