Process for preparing carbapenem derivatives

Abstract: Process for preparing carbapenem derivative of the formula [I], which comprises subjecting azetidinone compound of the formula [II] to intramolecular cyclization reaction together with elimination reaction of the group of -SR⁴, followed by re-adding said group of -SR⁴ to the 2-position of the carbapenem skeleton of the intramolecularly cyclized compound, which is industrially useful as process for preparing carbapenem antimicrobials or synthetic intermediate therefor. wherein R¹ is protected or unprotected hydroxy-substituted lower alkyl group, R² is hydrogen atom or ester residue, R³ is hydrogen atom or lower alkyl group, and the group of -SR⁴ is group which can be used as substituent at 2-position of the carbapenem antimicrobials.

Description: The present invention relates to a novel process for preparing a carbapenem derivative having antimicrobial activity and a synthetic intermediate therefor. Prior Art There have been known several processes for preparing the carbapenem derivatives which show excellent antimicrobial activities against a wide variety of pathogenic bacteria including Gram-positive and Gram-negative bacteria, especially against Cephem-resistant bacteria and are stable in the living body. For example, Japanese Patent First Publication (Kokai) No. 103084/1987 discloses a process for preparing a carbapenem antimicrobial which comprises treating a 4-(phenylthiocarbonylethyl)-2-azetidinone derivative with sodium hydride, trapping a by-product; thiol with an alkylating agent (e.g. iodomethane), further reacting the product with diphenyl chlorophosphate to give a 2-oxycarbapenem derivative, followed by reacting the product with a thiol compound. EP-A-0 186 525, EP-A-0 008 497 and EP-A-0 057 565 disclose processes for preparing a carbapenem derivative by ring closing elimination of an azetidinone having a -C(=PR 3 )COOR 2 substituent at the 1-position. EP-A-0 256 377 discloses forming a carbapenem derivative by ring closure of an azetidinone having a -CH 2 COOR 2 substituent at the 1-position, and a CMeHCOY substituent at the 2-position wherein -COY is a reactive residue. Brief Description of the Invention An object of the present invention is to provide a novel and industrially useful process for preparing a carbapenem antimicrobial and a synthetic intermediate therefor. Detailed Description of the Invention According to the present invention, a process is provided for preparing a carbapenem derivative of the formula (I): wherein R 1 is a protected or unprotected hydroxy-substituted C 1-6 alkyl group; R 2 is a hydrogen atom or an ester residue; R 3 is a hydrogen atom or a C 1-6 alkyl group; and R 4 is selected from an optionally substituted C 1-6 alkyl group, an optionally substituted C 3-8 cycloalkyl group, an optionally substituted 6- to 8-membered aryl group, an optionally substituted 4- to 8-membered alicyclic heterocyclic group containing a nitrogen atom, an oxygen atom and/or a sulfur atom, or a condensed ring group thereof, or an optionally substituted 4- to 8-membered aromatic heterocyclic group containing a nitrogen atom, an oxygen atom and/or an sulfur atom, or a condensed ring group thereof, the optional substituent in the above groups for R 4 being a C 1-6 alkyl group, a hydroxy group, a C 1-6 alkoxy group, a mono- or di-C 1-6 alkylamino group, a C 3-8 alkenoyloxycarbonylamino group, a mercapto group, a C 1-6 alkylthio groups, an imino-C 1-6 alkylamino group, an amidino group, a guanidino group, a carbamoyl group, a thiocarbamoyl group, a sulfamoyl group, a cyano group, a carboxyl group, a C 1-6 alkoxycarbonyl group, an aralkyloxycarbonyl group, an oxo group, a thioxo group, a halogeno group, a C 3-8 cycloalkyl group, a 6- to 8-membered aryl group, a 4- to 8-membered alicyclic heterocyclic group containing a nitrogen atom, an oxygen atom and/or a sulfur atom, or a condensed ring group thereof, or a 4- to 8-membered aromatic heterocyclic group containing a nitrogen atom, an oxygen atom and/or an sulfur atom, or a condensed ring group thereof; the process comprising the steps of: (i) treating an azetidinone compound of the formula [II]: wherein R 1 , R 2 , R 3 and R 4 are the same as defined above, or a salt thereof, with a base and a silylating agent, (ii) without isolating the product of step (i), treating it with an active-esterification agent for a hydroxy group, and (iii) if R 1 is a protected hydroxy-substituted C 1-6 alkyl group and/or R 2 is an ester residue, optionally removing the protecting group from the hydroxy-substituted C 1-6 alkyl group and/or the ester residue. In the present invention, the group represented by R 1 is preferably a protected or unprotected 1-hydroxyethyl group, and a protecting group for hydroxy group may be any one which can easily be removed by a conventional removing method, for example, a (C 1-6 alkoxy)carbonyl group, a halogeno-(C 1-6 alkoxy)carbonyl group, a substituted or unsubstituted phenyl-C 1-6 alkyl group (e.g. a benzyl which may optionally be substituted by nitro or a C 1-6 alkoxy), a tri-C 1-6 alkylsilyl group, and a substituted or unsubstituted phenyl-(C 1-6 alkoxy)carbonyl group (e.g. a benzyloxycarbonyl which may optionally be substituted by nitro or a C 1-6 alkoxy group). The ester residue represented by R 2 is an ester residue which can be metabolized in the living body by hydrolysis, or an ester residue which can be a protecting group for carboxyl group. The ester residue which can be metabolized in the living body by hydrolysis includes groups of the formulae: -X-OCOR 5 , -X-OCO 2 R 5 and -X-O-R 5 wherein X is a C 1-6 alkylene group, R 5 is a C 1-6 alkyl group, a C 3-8 cycloalkyl group, a C 3-8 alkenoyl group, a C 1-6 alkoxy-C 1-6 alkyl group or a C 2-8 alkanoyloxy-C 1-6 alkyl group, for example, a C 2-8 alkanoyloxy-C 1-6 alkyl group, a C 4-9 cycloalkanoyloxy-C 1-6 alkyl group, a C 3-8 alkenoyloxy-C 1-6 alkyl group, a C 1-6 alkoxy-C 2-8 alkanoyloxy-C 1-6 alkyl group, a C 2-8 alkanoyloxy-C 1-6 alkoxy-C 1-6 alkyl group, a C 1-6 alkoxy-C 1-6 alkyl group, a C 1-6 alkoxy-C 1-6 alkoxy-C 1-6 alkyl group, a (C 1-6 alkoxy)carbonyloxy-C 1-6 alkyl group and a C 1-6 alkoxy-(C 1-6 alkoxy)carbonyloxy-C 1-6 alkyl group. The ester residue which can be a protecting group for carboxyl group includes, for example, a C 1-6 alkyl group, a C 2-8 alkenyl group, a halogeno-C 1-6 alkyl group, nitrobenzyl group and a C 1-6 alkoxy-benzhydryl group. The group represented by R 3 is hydrogen atom or a C 1-6 alkyl group such as methyl. The group of the formula -SR 4 is one as described above. These groups are ones which can be a substituent at 2-position of a carbapenem antimicrobial. Specific examples of the group represented by R 4 are a 2-(N-allyloxycarbonylamino)ethyl group, a 1,3-thiazol-4-ylmethyl group, thioxopyrrolidinyl group, and a pyridyl group. In the process of the present invention, the intramolecular cyclization reaction of the compound of the formula [II] and the elimination reaction of the group of the formula: -SR 4 are carried out by treating the compound [II] with a base and a silylating agent in a suitable solvent. The base includes, for example, a metal salt of an amine [e.g. sodium bis(trimethylsilyl)amide, lithium bis(trimethylsilyl)amide, etc.]; a metal salt of an alcohol (e.g. potassium t-butoxide, etc.); or an alkali metal hydride (e.g. sodium hydride, etc.). The base is usually used in an amount of 1 to 4 equivalents, preferably 2 to 3 equivalents to the starting compound. The silylating agent includes, for example, a tri-C 1-6 alkyl-halogeno-silane (e.g. trimethylchlorosilane, t-butyldimethylchlorosilane, etc.), or a tetrahalogenosilane (e.g. tetrachlorosilane, etc.). The silylating agent is usually used in an amount of 0.1 to 3 equivalents, preferably 1 to 2 equivalents to the starting compound. The treatment by these bases and silylating agents can preferably be carried out either by treating first the compound [II] with a base, and then with a silylating agent, or vice versa. The solvent includes, for example, tetrahydrofuran, ethylene glycol dimethyl ether, dioxane, toluene, diethyl ether, or benzene. The reaction is carried out under cooling or at room temperature, for example, at a temperature from -75°C to 30°C, preferably at a temperature from -60°C to 5°C. The subsequent re-addition reaction of the eliminated group of the formula: -SR 4 to the 2-position of the carbapenem skeleton of the intramolecularly cyclized product can preferably be carried out by treating the above obtained reaction solution with an active-esterification agent for hydroxy group. The active-esterification agent for hydroxy group includes a reactive derivative (e.g. a corresponding acid halide, a corresponding acid anhydride, etc.) of phosphoric acid compound or sulfonic acid compound such as a diaryl phosphate (e.g. diphenyl phosphate, etc.), a di-C 1-6 alkyl phosphate (e.g. diethyl phosphate, etc.), a substituted or unsubstituted C 1-6 alkane-sulfonic acid (e.g. methanesulfonic acid, trifluoromethanesulfonic acid, etc.), or a substituted or unsubstituted benzenesulfonic acid (e.g. benzene-sulfonic acid, p-methoxybenzenesulfonic acid, etc.). The active-esterification agent for hydroxy group is usually used in an amount of 1 to 3 equivalents, preferably 1 to 1.5 equivalent, to the starting compound. The re-addition reaction is carried out at the same temperature as defined for the intramolecular cyclization reaction of the compound [II] and the elimination reaction of the group of the formula: -SR 4 as mentioned above. In the step of the re-addition reaction of the eliminated group of the formula: -SR 4 , if necessary, the reaction solution obtained by treating with an active-esterification agent for hydroxy group may be treated with a fluoride. The yield of the desired compound [I] can be increased by the fluoride-treatment. The fluoride includes, for example, an alkali metal fluoride (e.g. potassium fluoride, sodium fluoride, cesium fluoride, etc.); an alkaline earth metal fluoride (e.g. calcium fluoride, etc.), or a hydrogenfluoride of inorganic or organic amines (e.g. ammonium fluoride, a tri-C 1-6 alkylammonium fluoride, a benzyl-di-C 1-6 alkylammonium fluoride, pyridinium fluoride, etc.). The fluoride is usually used in an amount of 0.1 to 3 equivalents, preferably 0.5 to 1.5 equivalent, to the starting compound. The starting compound [II] of the present invention can be used in the process of the present invention either in the free form or in the form of a salt thereof. The salt of the compound [II] is, for example, hydrochloride, sulfate, acetate, methanesulfonate or p-toluenesulfonate. In the process of the present invention, the starting compound [II] exists in the form of optical isomer owing to the asymmetric carbon thereof. However, when an optically active compound [II] is used in the present process, the compound [II] reacts with maintaining the stereostructure thereof to be converted without epimerization into the desired compound [I]. The resulting carbapenem derivative [I] wherein R 1 is the protected hydroxy-substituted C 1-6 alkyl group and/or R 2 is the ester residue, may be converted to the corresponding carbapenem derivative [I] wherein R 1 is the hydroxy-substituted C 1-6 alkyl group and/or R 2 is hydrogen atom by the removal of the protecting group for the hydroxy-substituted C 1-6 alkyl group and/or the ester residue. The starting compound [II] of the present invention can easily be prepared by a conventional method, for example, by reacting a compound of the formula [III]: wherein R 1 and R 3 are the same as defined above, with a compound of the formula [IV]: Y-CH 2 -COOR 2 wherein Y is a halogen atom, and R 2 is the same as defined above, in the presence of an acid acceptor, followed by reacting the product with a compound of the formula [V]: H-SR 4 wherein R 4 is the same as defined above, in the presence of a dehydrating agent. Examples The present invention is illustrated in more detail by the following Examples and Reference Example, but should not be construed to be limited thereto. Example 1 A solution of (3S,4S)-3-[(1R)-1-t-butyldimethylsilyloxyethyl]-4-{[(1R)-1-[((4R)pyrrolidine-2-thion-4-ylthio)carbonyl]ethyl}-1-(allyloxycarbonylmethyl)-2-azetidinone (1.028 g) in tetrahydrofuran (6 ml) is added dropwise to 1M solution (6.6 ml) of sodium bis(trimethylsilyl)amide in tetrahydrofuran at -60°C to -50°C over a period of 5 minutes. The mixture is stirred at -50°C for 10 minutes, and thereto is added trimethylchlorosilane (0.58 ml) at -60°C. The mixture is stirred at the same temperature for 15 minutes, and thereto is added diphenyl chlorophosphate (0.44 ml) at -60°C. The mixture is stirred at 0°C for 1.5 hour, and to the reaction mixture is added dimethylformamide (10 ml) at 0°C, and further thereto is added dropwise 1M solution (1.6 ml) of tetra-n-butylammonium fluoride in tetrahydrofuran at -60°C. The mixture is stirred at -50°C for 30 minutes, and warmed to -20°C over a period of one hour. After the reaction is complete, the reaction solution is poured into a phosphate buffer (pH 7.0, 20 ml), and the mixture is extracted with ethyl acetate. The aqueous layer is extracted with ethyl acetate, and the ethyl acetate layers are combined, washed twice with water, dried over magnesium sulfate, and concentrated under reduced pressure. The residue is purified by silica gel column chromatography (solvent; n-hexane : chloroform : ethyl acetate = 5 : 5 : 4) to give (1R,5S,6S)-2-[(4R)-pyrrolidine-2-thion-4-ylthio]-6-[(1R)-1-t-butyldimethylsilyoxyethyl]-1-methylcarbapen-2-em-3-carboxylic acid allyl ester (575 mg). M.p. 130 - 133°C Examples 2 - 4 The starting compounds [II-a] listed in Table 1 are treated in the same manner as in Example 1 to give the corresponding desired compounds [I-a]. Example 5 A mixture of (1R,5S,6S)-2-[(4R)-pyrrolidine-2-thion-4-ylthio]-6-[(1R)-1-t-butyldimethylsilyloxyethyl]-1-methylcarbapen-2-em-3-carboxylic acid ally ester (1.00 g), dimethylformamide (10 ml) and ammonium hydrogenfluoride (459 mg) is stirred at room temperature for three days. To the reaction solution is added a phosphate buffer (pH 7.0), and the mixture is extracted with ethyl acetate. The organic layer is washed with a phosphate buffer, and the both of the phosphate buffer layers are combined, and extracted with ethyl acetate. The organic layers are combined, washed, dried and concentrated under reduced pressure. The resulting residue is crystallized from a mixture of ethyl acetate and n-hexane (2:1) to give (1R,5S,6S)-2-[(4R)-pyrrolidine-2-thion-4-ylthio]-6-[(1R)-1-hydroxyethyl]-1-methylcarbapen-2-em-3-carboxylic acid allyl ester (657 mg). The filtrate of the above crystallization is concentrated under reduced pressure, and the residue is purified by silica gel flash column chromatography (solvent; chloroform : ethanol = 30 : 1), and further crystallized from a mixture of ethyl acetate and n-hexane (2:1) to give (1R,5S,6S)-2-[(4R)-pyrrolidine-2-thion-4-ylthio]-6-[(1R)-1-hydroxyethyl]-1-methylcarbapen-2-em-3-carboxylic acid allyl ester (24 mg). Yield: 88.4% M.p. 144-145°C Example 6 A mixture of sodium hydrogen carbonate (0.84 g) in water (10 ml), dimedone (0.84 g) and tetrahydrofuran (80 ml) is treated with ultrasonics, and thereto is added palladium diacetate (0.11 g) and triethyl phosphite (0.58 g) under nitrogen atmosphere, and the mixture is stirred for three minutes. To the mixture is added (1R,5S,6S)-2-[(4R)-pyrrolidine-2-thion-4-ylthio]-6-[(1R)-1-hydroxyethyl]-1-methylcarbapen-2-em-3-carboxylic acid allyl ester (3.83 g), and the mixture is stirred at 35-37°C for 45 minutes. The mixture is stirred at 5°C for 30 minutes, and the precipitated crystals are collected by filtration, washed with tetrahydrofuran, and dried under reduced pressure to give (1R,5S,6S)-2-[(4R)-pyrrolidine-2-thion-4-ylthio]-6-[(1R)-1-hydroxyethyl]-1-methyl carbapen-2-em-3-carboxylic acid sodium salt (3.28 g). Yield: 90% NMR (D 2 O) δ: 1.22 (3H, d, J=7 Hz), 1.31 (3H, d, J=6 Hz), 2.87-3.07 (1H, m), 3.20-3.60 (3H, m), 3.55-3.72 (1H, m), 4.05-4.35 (4H, m) Reference Example 1 (1) (3S,4S)3-[(1R)-1-t-Butyldimethylsilyloxyethyl]-4-[(1R)-1-carboxyethyl]-2-azetidinone (6 g) is dissolved in tetrahydrofuran (250 ml), and thereto is added 60 % sodium hydride (0.796 g) at 10°C, and the mixture is stirred at 20°C for 20 minutes. To the mixture is added t-butyldimethylsilyl chloride (3 g) at 10°C, and the mixture is stirred for 10 minutes, and concentrated under reduced pressure to the quarter volume thereof. The concentrated mixture is stirred at 20°C for 20 minutes, and thereto is added a mixture of bromoacetic acid ally ester (3.56 g) and tetrahydrofuran (190 ml), and further added thereto dropwise 1M solution (20 ml) of sodium bis(trimethylsilyl)amide in tetrahydrofuran at -50°C. The mixture is warmed to 20°C over a period of 30 minutes, and concentrated under reduced pressure to a quarter volume thereof. The concentrated mixture is stirred at 20°C for 2 hours, and thereto is added tetrahydrofuran (190 ml), and further added dropwise a solution of potassium carbonate (2.8 g) in water (40 ml) at 10°C. The mixture is stirred at 20°C for 15 minutes. To the mixture is added diluted hydrochloric acid [hydrochloric acid (4.2 g) in water (8 ml)] at 10°C, and thereto is added 1N hydrochloric acid (18 ml) under ice-cooling. The mixture is allowed to stand, and the organic layer is collected. The aqueous layer is extracted with chloroform, and the organic layers are combined, dried over magnesium sulfate, and concentrated under reduced pressure. The residue is purified by silica gel column chromatography (solvent; chloroform → chloroform : methanol = 98 : 2) to give (3S,4S)-3-[(1R)-1-t-butyldimethylsilyloxyethyl]-4-[(1R)-1-carboxyethyl]-1-(allyloxycarbonylmethyl)-2-azetidinone (5.7 g) as oil. NMR (CDCl 3 ) δ : 0.0 - 0.05 (6H, m), 0.78 (9H, s), 1.1 - 1.25 (6H, m), 2.75 - 2.90 (1H, m), 2.95 - 3.02 (1H, m), 4.0 - 4.12 (2H, m), 3.83, 4.14 (2H, ABq, J=18 Hz), 4.52 - 4.58 (2H, m), 5.15 - 5.85 (2H, m), 5.70 - 5.93 (1H, m) (2) To a solution of the above product (1 g) in acetonitrile (5 ml) is added a mixture of 4-dimethylaminopyridine (30 mg), (4R)-4-mercaptopyrrolidine-2-thione (336 mg) and dicyclohexylcarbodiimide (632 mg) at 10°C, and the mixture is stirred at the same temperature for 20 hours. The insoluble materials are removed by filtration, and the filtrate is concentrated under reduced pressure. The residue is purified by silica gel column chromatography (solvent; n-hexane : chloroform : ethyl acetate = 5 : 5 : 4) to give (3S,4S)-3-[(1R)-1-t-butyldimethylsilyloxyethyl]-4-{(1R)-1-[((4R)-pyrrolidine-2-thion-4-ylthio)carbonyl]ethyl}-1-(allyloxycarbonylmethyl)-2-azetidinone (1.073 g) as oil. NMR (CDCl 3 ) δ : 0.0 - 0.05 (6H, m), 0.79 (9H, s), 1.1 - 1.25 (6H, m), 2.7 - 2.85 (1H, m), 2.90 - 3.05 (2H, m), 3.15 - 3.35 (1H, m), 3.40 - 3.50 (1H, m), 3.96 - 4.20 (4H, m), 4.18, 3.76 (2H, ABq, J=18 Hz), 4.5 - 4.6 (2H, m), 5.15 - 5.35 (2H, m), 5.75 - 5.95 (1H, m), 8.0 - 8.12 (1H, br) Effects of the Invention According to the present invention, the carbapenem derivative [I], which is useful as a carbapenem antimicrobial and a synthetic intermediate therefor, can industrially advantageously be prepared. More particularly, hitherto, the carbapenem derivatives have been prepared by employing a conventional leaving group instead of the group of the formula: -SR 4 in the compound [II], subjecting the said compound to cyclization reaction, trapping the leaving group, reacting with a group which is a conventional substituent at 2-position of the carbapenem antimicrobials, and removing a trapped leaving group. On the other hand, in the process of the present invention, the leaving group (-SR 4 ) and the introduced 2-substituent are the same, and hence, the desired compound is obtained without trapping and removing the leaving group. Accordingly, the carbapenem antimicrobials can be obtained more easily by the present process than by the conventional methods.

Claims: A process for preparing a carbapenem derivative of the formula (I): wherein R 1 is a protected or unprotected hydroxy-substituted C 1-6 alkyl group; R 2 is a hydrogen atom or an ester residue; R 3 is a hydrogen atom or a C 1-6 alkyl group; and R 4 is selected from an optionally substituted C 1-6 alkyl group, an optionally substituted C 3-8 cycloalkyl group, an optionally substituted 6- to 8-membered aryl group, an optionally substituted 4- to 8-membered alicyclic heterocyclic group containing a nitrogen atom, an oxygen atom and/or a sulfur atom, or a condensed ring group thereof, or an optionally substituted 4- to 8-membered aromatic heterocyclic group containing a nitrogen atom, an oxygen atom and/or an sulfur atom, or a condensed ring group thereof, the optional substituent in the above groups for R 4 being a C 1-6 alkyl group, a hydroxy group, a C 1-6 alkoxy group, a mono- or di-C 1-6 alkylamino group, a C 3-8 alkenoyloxycarbonylamino group, a mercapto group, a C 1-6 alkylthio groups, an imino-C 1-6 alkylamino group, an amidino group, a guanidino group, a carbamoyl group, a thiocarbamoyl group, a sulfamoyl group, a cyano group, a carboxyl group, a C 1-6 alkoxycarbonyl group, an aralkyloxycarbonyl group, an oxo group, a thioxo group, a halogeno group, a C 3-8 cycloalkyl group, a 6- to 8-membered aryl group, a 4- to 8-membered alicyclic heterocyclic group containing a nitrogen atom, an oxygen atom and/or a sulfur atom, or a condensed ring group thereof, or a 4- to 8-membered aromatic heterocyclic group containing a nitrogen atom, an oxygen atom and/or an sulfur atom, or a condensed ring group thereof; the process comprising the steps of: (i) treating an azetidinone compound of the formula [II]: wherein R 1 , R 2 , R 3 and R 4 are the same as defined above, or a salt thereof, with a base and a silylating agent, (ii) without isolating the product of step (i), treating it with an active-esterification agent for a hydroxy group, and (iii) if R 1 is a protected hydroxy-substituted C 1-6 alkyl group and/or R 2 is an ester residue, optionally removing the protecting group from the hydroxy-substituted C 1-6 alkyl group and/or the ester residue. A process according to Claim 1, further comprising the step of treating the product of step (ii) with a fluoride. A process according to Claim 1 or Claim 2, wherein R 1 is a protected or unprotected 1-hydroxyethyl group, R 3 is a methyl group, and R 4 is a 2-thioxopyrrolidin-4-yl group.

Inventors: HORIKAWA HIROSHI, IWASAKI TAMEO, KONDO KAZUHIKO, HORIKAWA, HIROSHI, IWASAKI, TAMEO, KONDO, KAZUHIKO
Applicants: TANABE SEIYAKU CO, TANABE SEIYAKU CO., LTD.
Application year: 1993
Main classification: C07D477
IPC codes: C07D477