JPS6129357B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention is based on the general formula The present invention relates to a novel carbapenem-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 is a CH ₃ CH(OR ⁴ )- group (R ⁴
represents a hydrogen atom or a protecting group for a hydroxyl group. ),
R ² is an aliphatic amine residue forming a 4- to 8-membered ring, and its nitrogen atom is -CR ⁵ =NR ⁶ group (in the formula
R ⁵ and R ⁶ represent the same or different hydrogen atoms or lower alkyl groups. ), R ³ represents a hydrogen atom or a protecting group for a carboxy group. In the general formula (1), R ¹ is preferably CH ₃ CH
(OR ⁴ )-group [In the formula, R ⁴ is a hydrogen atom or a hydroxyl group protecting group such as an alkyl group (e.g. methyl,
Indicates an ethyl, propyl, or isopropyl group. ), an acyl group (e.g., acetyl, propionyl, butyryl, or isobutyryl), an acyloxy group (e.g., benzyloxycarbonyl, or 4-nitrobenzyloxycarbonyl), or a trialkylsilyl group (e.g., trimethylsilyl). group or t
- indicates a butyldimethylsilyl group. ) is shown. ],
R ² is preferably 2-azetidinyl, 3-azetidinyl, 2-pyrrolidinyl, 3-pyrrolidinyl, 2
-piperidyl, 3-piperidyl, or 4-piperidyl, in which the nitrogen atom of these cyclic amines is a -CR ⁵ =NR ⁶ group (wherein R ⁵ and R ⁶ are the same or different hydrogen atoms or, for example, methyl, ethyl, (represents a lower alkyl group). R ³ is preferably a hydrogen atom or a carboxyl protecting group such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl,
Straight-chain or branched lower alkyl groups such as tert-butyl; e.g. 2-iodoethyl, 2.
Halogeno lower alkyl groups such as 2-dibromoethyl, 2,2,2-trichloroethyl; lower alkoxy groups such as methoxymethyl, ethoxymethyl, n-propoxymethyl, isopropoxymethyl, n-butoxymethyl, isobutoxymethyl Methyl group; for example, acetoxymethyl, propionyloxymethyl, n-butyryloxymethyl,
Lower aliphatic acyloxymethyl groups such as isobutyryloxymethyl and pivaloyloxymethyl;
For example, 1-methoxycarbonyloxyethyl, 1
-1-lower alkoxycarbonyloxyethyl groups such as ethoxycarbonyloxyethyl, 1-n-propoxycarbonyloxyethyl, 1-isopropoxycarbonyloxyethyl, 1-n-butoxycarbonyloxyethyl, 1-isobutoxycarbonyloxyethyl ; For example, benzyl,
p-methoxybenzyl, o-nitrobenzyl, p
- an aralkyl group such as nitrobenzyl; a benzhydryl group or a phthalidyl group. Particularly preferred compounds in the general formula (1) include R ¹ in which the α-position is a hydroxyl group, such as α-hydroxyethyl, α-acetoxyethyl, α-propionyloxyethyl, or α-butyryloxyethyl, or a lower Ethyl substituted with an aliphatic acyloxy group, R ² is 3-azetidinyl,
3-pyrrolidinyl, 3-piperidyl, or 4
-piperidyl, in which the nitrogen atom of these cyclic amine residues is substituted with a -CR ⁵ =NR ⁶ group (wherein R ⁵ and R ⁶ are the same or different and represent a hydrogen atom or a methyl group), Examples include compounds in which R ³ is a hydrogen atom or a pivaloyloxymethyl group. The compound having the general formula (1) according to the present invention is a new compound, and is a broad-spectrum antibiotic having extremely remarkable effects on the treatment of infections caused by Gram-positive bacteria and Gram-negative bacteria. Thienamycin is an antibiotic that not only shows strong antibacterial activity against Gram-positive bacteria, but also strong activity against a wide range of Gram-negative bacteria, including Pseudomonas aeruginosa. In recent years, a method for synthesizing thienamycin and its derivatives has been established at Merck & Co., making it possible to synthesize new compounds, and many thienamycin derivatives have been synthesized since then (Japanese Patent Laid-Open No. 55-27169).
No.; Japanese Patent Publication No. 56-5478, etc.). On the other hand,
There are also many reports on the synthesis of penem compounds, which are analogs of thienamycin, in which the methylene group at the 1-position of thienamycin is replaced with a sulfur atom. However, in any case, there are almost no compounds known in the literature that surpass thienamycin in antibacterial activity. As a result of many years of research into the synthesis of thienamycin-related compounds, the present inventors discovered that carbapenem derivatives having a cycloaliphatic amine substitution at the 2-position of the carbapenem skeleton have strong antibacterial activity. We were able to demonstrate that it has an even stronger antibacterial effect than thienamycin, which is said to be the most powerful antibacterial agent. 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, preferably a compound can be selected in which the carbon atom at position 5 has the same configuration as thienamycin, that is, the R configuration. 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 compounds having the general formula (1) of the present invention are thienamycin derivatives, and are a group of novel compounds having a mercapto group substituted with a cycloaliphatic amine at the 2-position, and these compounds have excellent antibacterial properties. They are compounds that exhibit activities and are useful as pharmaceuticals, or are important intermediates in the synthesis of compounds that exhibit these activities. Examples of the compound having the general formula (1) obtained by the present invention include the compounds described below. (1) 2-(1-formimidoylazetidine-3
-ylthio)-6-(1-hydroxyethyl)-
2-Carbapenem-3-carboxylic acid (2) 2-(1-formimidoylpyrrolidine-3
-ylthio)-6-(1-hydroxyethyl)-
2-Carbapenem-3-carboxylic acid (3) 2-(1-formimidoylpiperidine-4
-ylthio)-6-(1-hydroxyethyl)-
2-Carbapenem-3-carboxylic acid (4) 2-(1-acetimidoylazetidine-3
-ylthio)-6-(1-hydroxyethyl)-
2-Carbapenem-3-carboxylic acid (5) 2-(1-acetimidoylpyrrolidine-3
-ylthio)-6-(1-hydroxyethyl)-
2-Carbapenem-3-carboxylic acid (6) 2-(1-acetimidoylpiperidine-3
-ylthio)-6-(1-hydroxyethyl)-
2-Carbapenem-3-carboxylic acid (7) 2-[1-(N-methylformimidoyl)azetidin-3-ylthio]-6-(1-hydroxyethyl)-2-carbapenem-3-carboxylic acid (8 ) 2-[1-(N-methylacetimidoyl)azetidin-3-ylthio]-6-(1-hydroxyethyl)-2-carbapenem-3-carboxylic acid (9) 2-[1-(N-methyl Formimidoyl)pyrrolidin-3-ylthio]-6-(1-hydroxyethyl)-2-carbapenem-3-carboxylic acid (10) 2-[1-(N-methylacetimidoyl)pyrrolidin-3-ylthio] -6-(1-hydroxyethyl)-2-carbapenem-3-carboxylic acid (11) 2-(1-formimidoylpiperidine-3
-ylthio)-6-(1-hydroxyethyl)-
2-Carbapenem-3-carboxylic acid (12) 2-(1-acetimidoylpiperidine-4
-ylthio)-6-(1-hydroxyethyl)-
2-Carbapenem-3-carboxylic acid (13) 2-[1-(N-methylformimidoyl)
piperidine]-6-(1-hydroxyethyl)-
2-Carbapenem-3-carboxylic acid (14) 2-[1-(N-methylacetimidoyl)
piperidine]-6-(1-hydroxyethyl)-
2-Carbapenem-3-carboxylic acid (15) 2-(1-formimidoylpiperidine-
4-ylthio)-6-(1-hydroxyethyl)
-2-Carbapenem-3-carboxylic acid As mentioned above, stereoisomers exist in this exemplary compound, and the preferred isomers include (5R・6S) coordination and (5R・6R) coordination. Compounds having coordination and compounds in which the α-position hydroxyl group or acetoxy group of the 6-position substituent have R coordination can be mentioned. 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, and R ¹ represents a CH ₃ CH (OR ⁴ ) group (in the formula, R ⁴ represents a hydrogen atom or a protecting group for a hydroxyl group). R ³ ' represents a carboxyl group-protecting group, R ⁷ represents an alkanesulfonyl group, arylsulfonyl group, dialkylphosphoryl group, or diarylphosphoryl group, and R ⁸ represents a 4- to 8-membered ring with a protected nitrogen atom. Indicates a cycloaliphatic amine residue forming a ring. This synthesis method involves reacting a compound having the general formula (2) with alkanesulfonic anhydride, arylsulfonic anhydride, dialkylphosphoryl halide, or diarylphosphoryl halide in the presence of a base.
producing a compound having general formula (3), and reacting a mercaptan having general formula (4) in the presence of a base without isolating the obtained compound (3) to produce a compound having general formula (5); Then, as desired, the obtained compound is subjected to a reaction for removing the protecting group R ³ ' of the carboxyl group and R ¹
The corresponding protecting groups contained in and R ⁸ are removed and subjected to a reaction to restore the hydroxyl group, amino group, cyclic amino group and mercapto group, and further contained in the 2-position substituent of the obtained compound.

【formula】 group to formula

[Formula] (In the formula, R ⁵ and R ⁶ have the same meanings as described above.) In appropriate combinations, the target compound of the present invention having the general formula (1) is produced. It is a reaction. In carrying out the method of the present invention, the general formula
(2) is reacted with an alkanesulfonic anhydride, an arylsulfonic anhydride, a dialkylphosphoryl halide, or a diarylphosphoryl halide to produce a compound having the general formula (3);
Next, the reaction of reacting the obtained compound (3) with the mercaptan compound having the general formula (4) to produce the compound having the general formula (5) is preferably carried out in the presence of a base in an inert solvent. . Examples of the alkanesulfonic anhydride used in the reaction to obtain the compound (3) from the compound (2) include methanesulfonic anhydride, ethanesulfonic anhydride, and arylsulfonic anhydride such as benzenesulfonic anhydride and p-anhydride. Examples of toluenesulfonic acid and dialkylphosphoryl halides include dimethylphosphoryl chloride, diethylphosphoryl chloride, and examples of diarylphosphoryl halides include diphenylphosphoryl chloride and diphenylphosphoryl bromide. Among these reagents, especially anhydrous toluene Sulfonic acids or diphenylphosphoryl chloride are preferred. The solvent to be used is not particularly limited as long as it does not participate in this reaction, and includes, for example, methylene chloride, 1,2-dichloroethane, halogenated carbons such as chloroform, nitriles such as acetonitrile, or N/N-dimethylformamide. , and amides such as N·N-dimethylacetamide. The base to be used is not particularly limited as long as it does not affect other parts of the compound, especially the β-lactam ring, but preferably organic bases such as triethylamine, diisopropylethylamine, and 4-dimethylaminopyridine are used. Examples include bases. There is no particular limitation on the reaction temperature, but in order to suppress side reactions, it is desirable to carry out the reaction at a relatively low temperature, and it is usually carried out at about -20°C to 40°C. The reaction time mainly depends on the reaction temperature and the type of reaction reagent.
The duration ranges from 10 minutes to 5 hours. The thus obtained compound (3) can be treated without isolation by treating the reaction mixture with the mercaptan having the general formula (4) in the presence of a base. Examples of the base used in this step include organic bases such as triethylamine and diisopropylethylamine, and inorganic bases such as potassium carbonate and sodium carbonate. There is no particular restriction on the reaction temperature, but it is usually -20℃
It is carried out at room temperature. Reaction time is 30 minutes to 8 hours. After completion of the reaction, the target compound (5) of this reaction is collected from the reaction mixture according to a conventional method. For example, it can be obtained by adding a water-immiscible organic solvent to the reaction mixture or a residue obtained by distilling off the solvent of the reaction mixture, washing with water, and then distilling off the solvent. The obtained target compound can be further purified, if necessary, by conventional methods such as recrystallization, reprecipitation, or chromatography. Next, the obtained compound (5) can be converted into a carboxylic acid derivative by carrying out a treatment for removing the carboxyl group protecting group R ³ ' according to a conventional method, if necessary. Removal of the protecting group varies depending on the type of protecting group, but is generally removed by methods known in the art. Preferably, the reaction is performed according to the above general formula (5)
This can be achieved by contacting a compound having the following in which the substituent R ³ ' is a protective group that can be removed by reduction treatment, such as a halogenoalkyl group, an aralkyl group, or a benzhydryl group, with a reducing agent. As the reducing agent used in this reaction, zinc and acetic acid are preferred when the protecting group for the carboxyl group is a halogenoalkyl group such as 2,2-dibromoethyl or 2,2,2-trichloroethyl. , hydrogen and palladium when the protecting group is, for example, an aralkyl group such as benzyl, p-nitrobenzyl, or a benzhydryl group.
Catalytic reduction catalysts such as 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. Fatty acids such as and mixed solvents of these organic solvents and water are 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 minutes.
It's time. After the reaction is completed, the target compound of the carboxyl protecting group removal reaction is collected from the reaction mixture according to a conventional method. For example, it can be obtained by removing insoluble matter precipitated from the reaction mixture, washing the organic solvent layer with water, drying, and distilling off the solvent. The target compound thus obtained can be purified, if necessary, by conventional methods such as recrystallization, preparative thin layer chromatography, column chromatography, etc. In addition, when the substituent R ¹ in compound (5) has an acyloxy group or a trialkylsilyloxy group, or when the nitrogen atom contained in the substituent R ⁸ has a protecting group such as an acyl group or an aralkyloxycarbonyl group, the desired As described below, each protecting group is removed according to a conventional method to convert the compound to the corresponding hydroxyl group or amino group, and the compound thus obtained is converted to the compound having the carboxyl group described above. can be subjected to a reaction for removing the protecting group R ³ '. That is, the general formula
The reaction for producing a compound having a hydroxyl group as the substituent R ¹ of the compound having the general formula (1) from a compound having the general formula (5) is a reaction in which R ¹ of the compound having the general formula (5) is an acyloxy group or a trioxy group. This is achieved by removing the acyl or trialkylsilyl protecting group of the hydroxyl group from a compound having an alkylsilyloxy group. When R ¹ has a lower aliphatic acyloxy group such as acetoxy, the reaction can be carried out by treating the corresponding compound (5) 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 in order to suppress side reactions, the reaction temperature is 0.
℃ to around room temperature is suitable. 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. Furthermore, when the above substituent R ¹ has an aralkyloxycarbonyloxy group such as benzyloxycarbonyloxy or p-nitrobenzyloxycarbonyloxy, by contacting the corresponding compound (5) with a reducing agent. It can be 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 protecting group R ³ ′ for the carboxyl group, as described above, and therefore the protecting group R ³ ′ for the carboxyl group is also removed at the same time. You can also. In addition, by this reduction reaction, among the compounds having the general formula (5), R ⁸
is a protecting group for an amino group, such as aralkyloxycarbonyl group such as benzyloxycarbonyl or p-nitrobenzyloxycarbonyl, or an aralkyl group such as diphenylmethyl, by removing these protecting groups and converting the compound into the corresponding amino compound. can do. In addition, when the above substituent R ¹ has a tri-lower alkylsilyloxy group such as tert-butyldimethylsilyloxy, the reaction can be carried out using the corresponding compound.
This can be carried out by treating (5) with tetrabutylammonium fluoride. The solvent used is not particularly limited, but ethers such as tetrahydrofuran and dioxane are suitable. The reaction is suitably carried out by treating at around room temperature for 10 to 18 hours. Furthermore, in the case where the substituent R ⁸ of the compound having the general formula (5) has a halogenoacetyl group such as trifluoroacetyl or trichloroacetyl, which is a protecting group for an amino group, the removal reaction is performed using the corresponding compound. (5) can be carried out by treating with a base in the presence of an aqueous solvent. The type of base and reaction conditions used in this reaction are the same as those for removing the lower aliphatic acyl protecting group of the hydroxyl group in substituent R ¹ described above. The compound having the general formula ( ¹ ) is an iminoether R ⁹ OCR ⁵ =NR ⁶ (in the formula R ⁵ and R ⁶ have the same meanings as defined above, and R ⁹ represents, for example, a lower alkyl group such as methyl, ethyl, propyl, or isopropyl group. Although there are no particular limitations on the solvent used in the reaction, it is preferable to use a phosphate buffer maintained at a pH of around 8. The reaction temperature is preferably a relatively low temperature of about 0° C. to room temperature, and the reaction time is usually 10 minutes to 2 hours. After carrying out the above various reactions, the target compound for each reaction is collected from the reaction mixture according to a conventional method,
If necessary, it can be further purified by conventional methods such as recrystallization, preparative thin layer chromatography, column chromatography, etc. Carbapenem of the present invention having the general formula (1)
3-Carboxylic acid derivatives exhibit excellent antibacterial activity or are important synthetic intermediates for compounds exhibiting such antibacterial activity. Among them, the activity of compounds that exhibit antibacterial activity was measured by the agar plate dilution method, and it was found that, for example, grape-like antibacterial, Gram-positive bacteria such as Bacillus subtilis, Escherichia coli,
It showed potent activity against a wide range of pathogenic bacteria, including Gram-negative bacteria such as Shigella, Klebsiella pneumoniae, P. aeruginosa, Serratia, Enterobacter, and Pseudomonas aeruginosa. The test results are shown in the following table in comparison with thienamycin.

[Table] 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 in the form of tablets, capsules, granules, powders, syrups, etc., and parenteral administration in the form of intravenous injections, intramuscular injections, 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 200 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 p-nitrobenzyl (5R・6S・8R)-6-(1-hydroxyethyl)-2-(N-p-nitrobenzyloxycarbonylpyrrolidin-3-ylthio)-2-carbapenem-3-carboxylate ester (5R・6S・8R)-6-(1-Hydroxyethyl)-2-oxocarbapenam-3-carboxylic acid p-nitrobenzyl ester (150 mg) in acetonitrile solution (7 ml) under ice-cooled nitrogen flow, diisopropyl Add ethylamine (82μ) and diphenylphosphoryl chloride (96μ). At the same temperature
After stirring for 30 minutes, diisopropylethylamine (82 μ) and N-p-nitrilobenzyloxycarbonyl-3-mercaptopyrrolidine (132 mg) were added.
and stir for an additional hour. The reaction solution was diluted with ethyl acetate, washed successively with saturated brine, 5% sodium bicarbonate solution, and saturated brine, and dried over magnesium sulfate. A small amount of ethyl acetate was added to the residue after the solvent was distilled off, and the precipitated crystals were collected to obtain 161 mg of the target compound. The mother liquor was concentrated and purified using silica gel column chromatography to obtain an additional 31 mg of the target compound from the portion eluted with ethyl acetate. (Yield 73%) Infrared absorption spectrum ν ^KBr _nax cm ^-1 : 3560, 1780
,
1705 Nuclear magnetic resonance spectrum ( _CDCl3 ) δppm: 1.35
(3H, d, J=6.0Hz), 1.8~2.9 (3H, m),
3.1~4.6 (10H, m), 5.23 (2H, s), 5.23,
5.50 (2H, AB-q, J=14.0Hz), 7.53, 8.20
(4H, A ₂ B ₂ , J = 9.0Hz), 7.65, 8.20 (4H,
_A2B2 , _J =9.0Hz) Example 2 (5R・6S・8R)-6-(1-hydroxyethyl)-2-(pyrrolidin-3-ylthio)-2-
Carbapenem-3-carboxylic acid (5R・6S・8R)-6-(1-hydroxyethyl)-2-(N-p-nitrobenzyloxycarbonylpyrrolidin-3-ylthio)-2-carbapenem-3-carboxylic acid p-nitrobenzyl ester (190 mg ) in tetrahydrofuran (20 ml) and diluted with morpholinopropanesulfonic acid buffer (PH
7.0, 20ml) and platinum oxide catalyst (35mg),
Hydrogenation is carried out in a pearl shaker under 40 psi hydrogen pressure for 1 hour. After removing the catalyst, tetrahydrofuran is distilled off under reduced pressure, and the precipitated insoluble matter is removed again and washed with ethyl acetate. The aqueous layer was concentrated under reduced pressure and subjected to column chromatography using Diaion HP-20AG (manufactured by Mitsubishi Chemical Industries, Ltd.) to obtain 46 mg of the target compound from the portion eluted with 5% acetone water. Infrared absorption spectrum ν ^KBr _nax cm ^-1 : 3400, 1770
,
1590 Ultraviolet absorption spectrum λ ^H2O _nax nm (ε): 298
(7290) Nuclear magnetic resonance spectrum (D ₂ O) δppm: 1.27
(3H, d, J=6.5Hz), 1.8~2.2 (1H, m),
2.3-2.7 (1H, m), 3.19 (2H, d, J = 9.5
Hz), 3.3-3.8 (5H, m), 3.9-4.4 (3H, m) Example 3 (5R・6S・8R)-2-(1-formimidoylpyrrolidin-3-ylthio)-6-(1 -hydroxyethyl)-2-carbapenem-3-carboxylic acid (5R・6S・8R)-6-(1-hydroxyethyl)-2-(pyrrolidin-3-ylthio)-2-carbapenem-3-carboxylic acid (80 mg) in phosphate buffer (PH=7.1, 12 ml) Dissolve and adjust the pH to 8.5 with 1N caustic soda aqueous solution under ice cooling. Add methylformimidate hydrochloride (129 mg) and adjust the pH to 8.5 with an aqueous caustic soda solution. After stirring for 10 minutes under ice-cooling, the pH was adjusted to 7.0 with 1N hydrochloric acid, and the mixture was applied to a Diaion (HP20AG) column, and 64 mg of the target compound was obtained from the portion eluted with 5% acetone water. Ultraviolet absorption spectrum λ ^H2O _nax nm (ε): 297
(7920) Infrared absorption spectrum ν ^KBr _nax cm ^-1 : 3400, 1765
,
1710, 1590 Nuclear magnetic resonance spectrum (D ₂ O) δppm: 1.30
(3H, d, J=6.0Hz), 1.8~2.8 (2H, m),
3.21 (2H, d-like, J=9.0Hz), 3.45 (1H,
dd, J=3.0, 6.0Hz), 3.3~4.4 (7H,
m), 8.00 (1H, s) Example 4 (5R・6S・8R)-2-(1-acetimidoylpyrrolidin-3-ylthio)-6-(1-hydroxyethyl)-2-carbapenem-3- carboxylic acid (5R・6S・8R)-6-(1-hydroxyethyl)-2-(pyrrolidin-3-ylthio)-2-carbapenem-3-carboxylic acid (63 mg) in phosphate buffer (PH=7.1, 9 ml) Dissolve and adjust the pH to 8.5 with 1N caustic soda aqueous solution under ice cooling. Add ethyl acetimidate hydrochloride (121 mg), and adjust the pH to 8.5 again with 1N aqueous caustic soda solution. After stirring for 10 minutes under ice-cooling, the pH was adjusted to 7.0 with 1N hydrochloric acid, purified using a Diaion (HP20AG) column, and the portion eluted with 5% acetone water was lyophilized to yield 42 mg.
The desired compound was obtained. This was performed using high-performance liquid chromatography (Waters Microbonta Pack).
C ₁₈ , tetrahydrofuran:water=1:10) to obtain 38 mg of the further purified target compound. Ultraviolet absorption spectrum λ ^H2O _nax nm (ε): 298
(8960) Infrared absorption spectrum ν ^KBr _nax cm ^-1 : 3400, 1760
,
1675 Nuclear magnetic resonance spectrum (D ₂ O) δppm: 1.29
(3H, d, J=6.5Hz), 1.8~2.7 (2H, m),
2.29 (3H, s), 3.23 (2H, d-like, J=9.5
Hz), 3.44 (1H, dd, J=3.0, 6.0Hz),
3.3-4.4 (7H, m) Example 5 (5R・6S・8R)-2-[1-(N-methylformimidoyl)pyrrolidin-3-ylthio]-6
-(1-hydroxyethyl)-2-carbapenem-3-carboxylic acid (5R・6S・8R)-6-(1-hydroxyethyl)-2-(pyrrolidin-3-ylthio)-2-carbapenem-3-carboxylic acid (300 mg) and methyl-N-methylformimidate tetrafluoroborum The acid salt (735 mg) was subjected to the same reaction treatment as in Example 3 to obtain 230 mg of the target compound as a colorless powder. Ultraviolet absorption spectrum λ ^H2O _nax nm (ε): 297
(8600) Infrared absorption spectrum ν ^KBr _nax cm ^-1 : 3400, 1760 Nuclear magnetic resonance spectrum (D ₂ O) δppm: 1.30
(3H, d, J=6.0Hz), 1.8~2.8 (2H, m),
3.20 (2H, d-like, J=9.0Hz), 3.45 (1H,
dd, J=3.0, 6.0Hz), 3.12 (3H, s) 3.3
~4.4 (7H, m), 8.00 (1H, s) Example 6 (5R・6S・8R)-2-[1-(N-methylacetimidoyl)pyrrolidin-3-ylthio]-6
-(1-hydroxyethyl)-2-carbapenem-3-carboxylic acid (5R・6S・8R)-6-(1-hydroxyethyl)-2-(pyrrolidin-3-ylthio)-2-carbapenem-3-carboxylic acid (300 mg) and methyl-N-methylacetimidate tetrafluoroborum The acid salt (800 mg) was subjected to the same reaction treatment as in Example 3 to obtain 280 mg of the target compound as a colorless powder. Ultraviolet absorption spectrum λ ^H2O _nax nm (ε): 298
(8700) Infrared absorption spectrum ν ^KBr _nax cm ^-1 : 3400, 1760 Nuclear magnetic resonance spectrum (D ₂ O) δppm: 1.29
(3H, d, J=6.5Hz), 1.8~2.7 (2H, m),
2.28 (3H, s), 3.22 (2H, d-like, J=9.5
Hz), 3.44 (1H, dd, J=3.0, 6.0Hz),
3.05 (3H, s), 3.3-4.4 (7H, m) Example 7 (5R・6S・8R)-6-(1-hydroxyethyl)-2-(N-p-nitrobenzyloxycarbonylazetidine-3 -ylthio)-2-carbapenem-3-carboxylic acid p-nitrobenzyl ester In the same manner as in Example 1, (5R・6S・8R)-6-
(1-Hydroxyethyl)-2-oxocarbapenam-3-carboxylic acid p-nitrobenzyl ester (60mg), diisopropylethylamine (66μ
), diphenylphosphoryl chloride (38μ
), N-p-nitrobenzyloxycarbonyl-3-methylcaptoazetidine (51 mg) to approx.
mg of target compound was obtained. Infrared absorption spectrum ν ^KBr _nax cm ^-1 : 3450, 1780
,
1730 Nuclear magnetic resonance spectrum (DMF- _d7 ) δppm: 1.22
(3H, d, J=6Hz), 3.0~4.8 (11H, m),
5.28 (2H.s), 5.35, 5.58 (2H, AB−q, J=
14.5Hz), 7.68, 8.27 (4H, A ₂ B ₂ , J = 8.5
Hz), 7.81, 8.27 (4H, _A2B2 , J=8.5Hz) Example 8 (5R・_6S・8R)-2-(azetidin-3-ylthio)-6-(1-hydroxyethyl)-2 -carbapenem-3-carboxylic acid (5R・6S・8R)-6-(1-hydroxyethyl)-2-(N-p-nitrobenzyloxycarbonylazetidin-3-ylthio)-2-carbapenem-3-carboxylic acid p-nitrobenzyl ester ( 81mg), 0.1M phosphate buffer (PH=7.0, 4
ml), water (6 ml), and tetrahydrofuran (10 ml), the reaction and treatment were carried out in the same manner as in Example 2, and 17 mg
The desired compound was obtained. Infrared absorption spectrum ν ^KBr _nax cm ^-1 : 3400, 1760
,
1605 Ultraviolet absorption spectrum λ ^H2O _nax nm (ε): 299
(5970) Nuclear magnetic resonance spectrum (D ₂ O) δppm: 1.27
(3H, d, J = 6.5Hz), 3.04 (2H, d, J = 10
Hz), 3.38 (1H, dd, J=3.0, 6.0Hz),
3.7-5.1 (7H, m) The compound thus obtained can be imidoylated in the same manner as in Examples 3-6. Example 9 p-nitrobenzyl (5R・6S・8R)-6-(1-hydroxyethyl)-2-(N-p-nitrobenzyloxycarbonylpiperidin-4-ylthio)-2-carbapenem-3-carboxylate ester In the same manner as in Example 1, (5R・6S・8R)-6-
(1-Hydroxyethyl)-2-oxocarbapenam-3-carboxylic acid p-nitrobenzyl ester (30mg), diisopropylethylamine (34μ
), diphenylphosphoryl chloride (19μ
), 45 mg of the target compound was obtained from N-p-nitrobenzyloxycarbonyl-4-mercaptopiperidine (84 mg). Infrared absorption spectrum ν ^KBr _nax cm ^-1 : 3450, 1780
,
1710 Nuclear magnetic resonance spectrum (DMF- _d7 ) δppm: 1.23
(3H, d, J=6.5Hz), 1.5~4.5 (15H, m),
5.25 (2H, s), 5.26, 5.51 (2H, AB-q, J
= 14.5Hz), 7.63, 8.22 (4H, A ₂ B ₂ , J = 8.5
Hz), 7.76, 8.22 (4H, _A2B2 , J=8.5Hz) Example 10 (5R・_6S・8R)-6-(1-hydroxyethyl)-2-piperidin-4-ylthio)-2- Carbapenem-3-carboxylic acid In the same manner as in Example 2, (5R・6S・8R)-6-
(1-Hydroxyethyl)-2-(N-p-nitrobenzyloxycarbonylpiperidin-4-ylthio)-2-carbapenem-3-carboxylic acid p-
9 mg of the target compound was obtained from nitrobenzyl ester (42 mg). Infrared absorption spectrum ν ^KBr _nax cm ^-1 : 3430, 1765
,
1595 Ultraviolet absorption spectrum λ ^H2O _nax nm (ε): 299
(7450) Nuclear magnetic resonance spectrum (D ₂ O) δppm: 1.29
(3H, d, J=6.0Hz), 1.7~2.4 (4H, m),
2.9-3.6 (7H, m), 4.0-4.4 (3H, m) The compounds obtained here can be imidoylated in the same manner as in Examples 3-6.

Claims (1)

[Claims] 1. General formula [In the formula, R ¹ is a CH ₃ CH (OR ⁴ )- group (in the formula, R ⁴ represents a hydrogen atom or a hydroxyl group protecting group), R ² is a
It is an aliphatic amine residue forming a 4-membered ring to an 8-membered ring, and its nitrogen atom is a −CR ⁵ =NR ⁶ group (in the formula, R ⁵ , R ⁶
represent the same or different hydrogen atoms or lower alkyl groups. ), and R ³ represents a hydrogen atom or a protecting group for a carboxy group. ]
A carbapenem-3-carboxylic acid derivative and a pharmacologically acceptable salt thereof. 2 General formula [In the formula, R ¹ is a CH ₃ CH (OR ⁴ )- group (in the formula, R ⁴ represents a hydrogen atom or a hydroxyl group protecting group), R ³ ' is a
In the presence of a base, an alkanesulfonic anhydride, an arylsulfonic anhydride, a dialkylphosphoryl halide, or a diarylphosphoryl halide is reacted with a compound having the following formula: [In the formula, R ¹ and R ³ ′ have the same meanings as above, R ⁷
represents an alkanesulfonyl group, an arylsulfonyl group, a dialkylphosphoryl group, or a diarylphosphoryl group. ] and none,
Next, the general formula R ⁸ SH (4) [wherein R ⁸ represents a cycloaliphatic amine residue forming a 4- to 8-membered ring with a protected nitrogen atom. ] in the presence of a base to form the general formula [In the formula, R ¹ , R ³ ′, and R ⁸ have the same meanings as described above. ], and after removing the protecting group of the obtained compound (5) as desired, the resulting compound has the general formula (R ⁹ O)CR ⁵ =NR ⁶ (6) [in the formula, R ⁵ , R ⁶ has the same meaning as described above, and R ⁹ represents a lower alkyl group. ] A general formula characterized by reacting [In the formula, R ¹ is a CH ₃ CH (OR ⁴ )- group (in the formula, R ⁴ represents a hydrogen atom or a hydroxyl group protecting group), R ²
is an aliphatic amine residue forming a 4-membered ring to an 8-membered ring, and its nitrogen atom is a −CR ⁵ =NR ⁶ group (in the formula, R ⁵ ,
R ⁶ represents the same or different hydrogen atom or lower alkyl group. ) having a substituent, R ³
represents a hydrogen atom or a protecting group for a carboxy group. ] A method for producing a compound having the following.