Title of Invention	PROCESS FOR PRODUCING A BASIC ANTIBIOTIC-INORGANIC ACID SALT, AND OXALATE INTERMEDIATE
Abstract	process for producing a basic antibiotic inorganic acid salt (I), which comprises subjecting a basic antibiotic oxalate (II) to salt-exchange with an alkali earth metal salt (III) of an inorganic acid. wherein the ring A represents the basic antibiotic; R10 represents a protected functional group used in organic synthesis; Ak-E represents the alkali earth metal; and B represents the inorganic acid and wherein the basic antibiotic inorganic acid salt (I) is any one selected from the following: (1) cefotiam hydrochloride; (2) cefmenoxime hydrochloride; (3) cefozopran hydrochloride; (4) cefpirome sulfate; (5) cefepime hydrochloride; (6) cefoselis sulfate; (7) cefotiam hexetil hydrochloride; (8) cefetamet pivoxil hydrochloride; (9) cefcapene pivoxil hydrochloride; (10) talampicillin hydrochloride; (11) bacampicillin hydrochloride; (12) lenampicillin hydrochloride; (13) pivmecillinam hydrochloride; and (14) (1R, 5S, 6S)-6-[(R)-l-hydroxyethyl]-l-methyl-2-{(2S,4S)-2-[(3R)-pyrrolidine-3-yl-(R)-hydroxy]methyl}pyrrolidine-4-ylthio]-l-carbapen-2-em-3-carboxylic acid hydrochloride.

Title of Invention

PROCESS FOR PRODUCING A BASIC ANTIBIOTIC-INORGANIC ACID SALT, AND OXALATE INTERMEDIATE

Abstract

process for producing a basic antibiotic inorganic acid salt (I), which comprises subjecting a basic antibiotic oxalate (II) to salt-exchange with an alkali earth metal salt (III) of an inorganic acid. wherein the ring A represents the basic antibiotic; R10 represents a protected functional group used in organic synthesis; Ak-E represents the alkali earth metal; and B represents the inorganic acid and wherein the basic antibiotic inorganic acid salt (I) is any one selected from the following: (1) cefotiam hydrochloride; (2) cefmenoxime hydrochloride; (3) cefozopran hydrochloride; (4) cefpirome sulfate; (5) cefepime hydrochloride; (6) cefoselis sulfate; (7) cefotiam hexetil hydrochloride; (8) cefetamet pivoxil hydrochloride; (9) cefcapene pivoxil hydrochloride; (10) talampicillin hydrochloride; (11) bacampicillin hydrochloride; (12) lenampicillin hydrochloride; (13) pivmecillinam hydrochloride; and (14) (1R, 5S, 6S)-6-[(R)-l-hydroxyethyl]-l-methyl-2-{(2S,4S)-2-[(3R)-pyrrolidine-3-yl-(R)-hydroxy]methyl}pyrrolidine-4-ylthio]-l-carbapen-2-em-3-carboxylic acid hydrochloride.

Full Text	FORM 2 THE PATENTS ACT, 1970 [39 OF 1970] COMPLETE SPECIFICATION [See Section 10; Rule 13] "PROCESS FOR PRODUCING A BASIC ANTIBIOTIC-INORGANIC ACID SALT, AND OXALATE INTERMEDIATE" EISAI R&D MANAGEMENT CO., LTD., of 6-10, Koishikawa 4-chome, Bunkyo-ku, Tokyo, Japan. The following specification particularly describes the nature of the invention and the manner in which it is to be performed:- Description Field of the Invention The present invention relates to a novel and industrially-excellent process for producing a basic antibiotic inorganic acid salt, for example, an industrially-excellent production process for producing an inorganic acid salt of an excellent antimicrobial agent having strong antimicrobial action on gram-positive bacteria and gram-negative bacteria, disclosed in JP-A 8-73462. More specifically, it relates to industrially-excellent production process for producing, for example, (1R,5S,6S) - 6 - [(R) -1 - hydroxyethyl]-1-methyl-2-{(2S,4S)-2-[(3R)-pyrrolidine-3-yl- (R)-hydroxy]methyl}pyrrolidine-4-ylthio]-1-carbapen-2-em-3 - carboxylic acid'hydrochloride, a novel oxalate useful as a production intermediate, and a process for producing it. Prior Art In order to produce a basic antibioticinorganic acid salt, it is general to produce a free form, purify by column chromatography etc., and react the product with an inorganic acid. For example, in the process disclosed in JP-A 8-73462, WO96/01261 or Example 9 of EP-A 773222 as a process for producing (1R, 5S, 6S) -6- [ (R) -1-hydroxyethyl] -l-methyl-2- { (2S,"4S) -2-[ (3R)-pyrrolidine-3-yl - (R)-hydroxy]methyl}pyrrolidine-4 - ylthio] -1- carbapen- 2 - em- 3 - carboxylic acid "hydrochloride etc . , the objective product is obtained by subjecting a p-nitrobenzyl ester compound to catalytic reduction, purifying by reversed-phase silica gel_chromatography, conversing the product to a hydrochloride, and subjecting it to freeze-drying. In the above-mentioned process in the prior art, the purification by chromatography is performed. Thus, a solvent is used in a large amount. Therefore, costs for the production rise to a considerable degree. Additionally, many problems as follows arise: difficulty in industrial processing in large amount, the possibility of the generation of thermal cruelty (thermal decomposition) at the time of concentrating fractions, a problem of the remaining of the solvent in the final product, a problem about disposal of waste liquid and environment pollution by transpiration of the solvent. Thus, it cannot be said that the process is a process suitable for industry. Moreover, it is necessary to perform subtle adjustment of pH when the free form is produced (neutralized) or converted to the hydrochloride. Thus, the process requires much labor and cost in industrial production. Moreover, freeze-drying is required in the last step, and results additional problems as follows: a further rise in the production costs, unsuitability thereof for processing in large amount and necessity of much time. Disclosure of the Invention Thus, the present inventors made eager investigations to pursue a novel production process excellent in viewpoints such as production costs, operability (workability, safety and non- toxicity) , the purity of final products, and the protection of the environment. As a result, they have found out that the above-mentioned problems can be overcome at a stroke by using a novel oxalate which will be in detail described below as a production intermediate and subjecting the oxalate to salt-exchange with an alkali earth metal salt of an inorganic acid. Thus, they have accomplished the present invention. Therefore, an object of the present invention is to provide a novel production process useful for producing a basic antibiotic'inorganic acid salt industrially, and a novel production intermediate useful for producing antimicrobial agents, and a process for producing it. The present invention is a process for producing a basic antibioticinorganic acid salt (I) , which comprises subjecting a basic antibiotic'oxalate (II) to salt-exchange with an alkali earth metal salt (III) of an inorganic acid. wherein the ring A means the basic antibiotic; R10 means a protected functional group used in organic synthesis; Ak-E means the alkali earth metal; and B means the inorganic acid. The present invention is a process for producing a basic antibiotic "inorganic acid salt (I) , which comprises subjecting a basic antibiotic protector"oxalate (VI) to deprotection reaction; and then subjecting to salt-exchange with an alkali earth metal salt (III) of an inorganic acid. The present invention is also a process for producing a basic antibiotic inorganic acid salt (I), which comprises subjecting a basic antibiotic protector oxalate (VI) to deprotection reaction; then subjecting to salt-exchange with an alkali earth metal salt (III) of an inorganic acid; and then crystallizing the resultant by adding a poor solvent thereto. The present invention is a process for producing (lR,5S,6S)-6-[(R) -1-hydroxyethyl] -1-methyl-2- { (2S,4S) -2-[ (3R) -pyrrolidine-3-yl- (R) -hydroxy]methyl}pyrrolidine-4 -ylthio] -1-carbapen-2 - em-3-carboxylic acid'hydrochloride (VIII) represented by the following formula which comprises subjecting p-nitrobenzyl (1R,5S,6S) - 6 - [ (R) -1-hydroxyethyl] -l-methyl-2-{(2S,4S)-2-[(3R)-pyrrolidine-3 -yl - (R)-hydroxy]methyl}pyrrolidine-4-ylthio] -1-carbapen-2- em-3-carboxylate'oxalate (VII) represented by the following formula: (wherein PNB represents p-nitrobenzyl group) to deprotection reaction; then subjecting to salt-exchange with calcium chloride; and then crystallizing the resultant by adding methanol and/or isopropanol thereto. The present invention is a process for producing a basic antibioticinorganic acid salt (I), in which the oxalate (II-I) of a carbapenem compound represented by the following formula is a basic antibiotic'oxalate (II), and which comprises subjecting the basic antibiotic'oxalate (II) to salt-exchange with an alkali earth metal salt (III) of an inorganic acid. Wherein the ring A represents a 3 - to 7-membered ring having at least one nitrogen atom, and the ring A may be substituted with other than R5; R1 represents hydrogen or methyl group; R2 and Rs are the same as or different from each other and each represents hydrogen or a hydroxyl-protecting group; R3 represents a carboxyl -protecting group; R4 represents hydrogen, a lower alkyl group or an amino-protecting group; R6 represents (1) hydrogen, (2) an optionally protected hydroxyl group, carbamoyl, formimidoyl, acetoimidoyl or a lower alkyl group which may be substituted with a substituent represented by the formula: (wherein R7 and R8 are the same as or different from each other and each represents hydrogen, a lower alkyl group or an amino-protecting group) or (3) an amino-protecting group or an imino-protecting group; and m is 0 or 1. The present invention is an oxalate (II-I) of a carbapenem compound represented by the following formula: wherein the ring A represents a 3 - to 7-membered ring having at least one nitrogen atom, and the ring A may be substituted with other than R6; R1 represents hydrogen or methyl group; R2 and R5 are the same as or different from each other and each represents hydrogen or a hydroxyl-protecting group; R3 represents a carboxyl -protecting group; R4 represents hydrogen, a lower alkyl group or an amino-protecting group; R6 represents (1) hydrogen, (2) an optionally protected hydroxyl group, carbamoyl, formimidoyl, acetoimidoyl or a lower alkyl group which may be substituted with a substituent represented by the formula: (wherein R7 and R8 are the same as or different from each other and each represents hydrogen, a lower alkyl group or an amino-protecting group) or (3) an amino-protecting group or an imino-protecting group; and m is 0 or 1. Further, the present invention is a process for producing p-nitrobenzyl (lR,5S,6S)-6-[(R)-l-hydroxyethyl] -1-methyl-2 -{(2S,4S)-2-[(3R)-pyrrolidine-3-yl-(R)- hydroxy]methyl}pyrrolidine-4-ylthio] -1-carbapen-2 - em-3 - carboxylate'oxalate (II-III), which comprises reacting p-nitrobenzyl (lR,5S,6S)-6-[(R)-1-hydroxyethyl]-1-methyl-1 carbapen-2 - em-3 -carboxylate-2-active compound (XIV) represented by the following formula: (wherein PNB has the same meaning as described above; and L means a leaving group) with (2S,4S)-2-{[(3R)-pyrrolidine-3-yl-(R)-hydroxy]methyl}-4-mercaptopyrrolidine"dihydrochloride (XV) represented by the following formula: and then converting the resultant into to an oxalate. Herein, the basic antibiotic'inorganic acid salt (I) according to the present invention is an antibiotic having a basic salt in the molecule thereof, and is not limited so long as the antibiotic is combined with an inorganic acid to form a salt. Preferred examples thereof include the following: (1) cefotiam (CAS Res.No.: 66309-69-1) hydrochloride; (2) cefmenoxime (CAS Res.No.: 75738-58-8) hydrochloride; (3) cefozopran(CAS Res.No.: 113981-44-5) hydrochloride; (4) cefpirome(CAS Res.No.: 98753-19-6) sulfate; (5) cefepime (CAS Res.No.: 123171-59-5) hydrochloride; (6) cefoselis (CAS Res.No.: 122841-10-5) sulfate; (7) cefotiam hexetil (CAS Res.No.: 95789-30-3) hydrochloride; (8) cefetametpivoxil (CASRes:No.: 65052-63-3) hydrochloride; (9) cefcapene pivoxil (CAS Res.No.: 135889-00-8) hydrochloride; (10) talampicillin (CAS Res.No.: 39878-70-1) hydrochloride; (11) bacampicillin (CAS Res.No.: 37661-08-8) hydrochloride (12) lenampicillin (CAS Res.No.: 80734-02-7) hydrochloride; (13) pivmecillinam (CAS Res.No.: 32886-97-8) hydrochloride; and (14) (1R,5S,6S)-6- [(R) -1-hydroxyethyl] -l-methyl-2-{ (2S,4S) -2 - [ (3R) -pyrrolidine-3-yl- (R) -hydroxy]methyl}pyrrolidine-4 -ylthio]-l-carbapen-2-em-3-carboxylic acid*hydrochloride (JP-A 8-73462, Example 9). Next, the basic antibiotic"oxalate (II) according to the present invention is a starting material for producing the above-mentioned basic antibiotic•inorganic acid salt (I) by salt-exchange, and specific examples thereof include an oxalate of the above-mentioned basic antibiotic. Next, the alkali earth metal salt (III) of the inorganic acid according to the present invention is not limited so long as it is an adduct salt made from the inorganic acid and an alkali earth metal such as beryllium, magnesium, calcium, strontium and barium. Preferred are alkali earth metal halide (IV) and alkali earth metal sulfides (V). More specific examples of the alkali earth metal halides (IV) include beryllium fluoride, magnesium fluoride, calcium fluoride, strontium fluoride, barium fluoride, beryllium chloride, magnesium chloride, calcium chloride, strontium chloride, barium chloride, beryllium bromide, magnesium bromide, calcium bromide, strontium bromide, barium bromide, beryllium iodide, magnesium iodide, calcium iodide, strontium iodide, barium iodide etc. Among these, magnesium chloride, calcium chloride, magnesium bromide, calcium bromide etc. are more preferred. Examples of the alkali earth metal sulfates (V) include beryllium sulfate, magnesium sulfate and calcium sulfate. The following will describe the process for producing the compound of the present invention in more detail. (See the following chemical reaction formula, wherein the ring A means a basic antibiotic; R1C means a protected functional group used in organic synthesis; Ak-E means an alkali earth metal; and B means an inorganic acid.) The present step is a step of conducting deprotection reaction in the case that a basic antibiotic'oxalate has a protected functional group in the molecule thereof. The protected function group herein means a group obtained by protecting a functional group such as a hydroxyl group, an amino group or a carboxyl group and used in organic synthesis. The deprotection reaction can be conducted in an ordinary manner such as hydrolysis or reduction. (2) Step 2 The present step is a step of subjecting the basic antibiotic'oxalate (II) to salt-exchange with an alkali earth metal salt (III) of an inorganic acid, to give the target basic antibiotic'inorganic acid salt (I). Herein, the amount of the alkali earth metal salt (III) of the inorganic acid used is not limited and is usually from 0.7 to 2.0 equivalents, preferably from 0.8 to 1.5 equivalent, and more preferably from 0.9 to 1.3 equivalent. Herein, the solvent used is not limited. Specific examples thereof include water, lower alcohols, ketone solvents, ester solvents, ether solvents, formamide solvents and dimethylsulfoxide. These may be used alone or in the form of a mixture thereof. Among these, water and lower alcohols are preferred. The manner of carrying out (operating) the salt-exchange is not limited. Usually, a solution wherein a necessary amount of the alkali earth metal salt (III) of the inorganic acid is dissolved is dropwise added to a solution of the basic antibioticoxalate (II). Herein, a solvent wherein an alkali earth metal'oxalate which is by-produced by the salt-exchange is insoluble is selected at this time, the alkali earth metal"oxalate is precipitated and can easily be by filtration. Therefore, this case is more suitable for industry. The target basic antibiotic•inorganic acid salt (I) is in a solution state at this stage. Accordingly, extracting operation is necessary. However, by concentration of the solvent or addition of a poor solvent (solvent having low solubility), it can easily be precipitated as crystal. In the case of concentrating the solvent, it may be completely dried. It is however allowable to concentrate it partially into a small-amount solution, cool the resultant solution or cause the resultant solution to stand still, thereby precipitating the target crystals. In the case of using the poor solvent, the kind thereof is not limited. In general, methanol, n-propanol, isopropanol etc. are preferred. In the present invention, the step 2 may be performed after the step 1 is performed to isolate and/or purify the basic antibiotic'oxalate (II) . However, the steps 1 and 2 may be continuously performed by the so-called one-spot reaction. In this case, the deprotection reaction solution can be used, as it is, for the salt-exchange. As a result, column chromatography, pH adjustment and freeze-drying become unnecessary. Therefore, this case is excellent in industrial operability, reduction in production costs, processing in large amount and environment protection. (1R,5S,6S)-6-[(R)-1-hydroxyethyl]-l-methyl-2-{(2S,4S) -2 - [ (3R) -pyrrolidine-3-yl- (R) -hydroxy]methyl}pyrrolidine-4 -ylthio]-1-carbapen-2-em-3-carboxylic acid'oxalate (II-IX) according to the present invention, which is represented by the following formula: is a novel compound and is useful for a production intermediate. Herein, the oxalate (II-I) of the carbapenem compound according to the present invention is represented by the following formula. Wherein the ring A represents a 3 - to 7 -membered ring having at least one nitrogen atom, and the ring A may be substituted with other than R6; R1 represents hydrogen or methyl group; R2 and R5 are the same as or different from each other and each represents hydrogen or a hydroxyl-protecting group; R3 represents a carboxyl-protecting group; R4 represents hydrogen, a lower alkyl group or an amino-protecting group; R6 represents (1) hydrogen, (2) an optionally protected hydroxyl group, carbamoyl, formimidoyl, acetoimidoyl or a lower alkyl group which may be substituted with a substituent represented by the formula: (wherein R7 and R8 are the same as or different from each other and each represents hydrogen, a lower alkyl group or an amino-protecting group) or (3) an amino-protecting group or an imono-protecting group; and m is 0 or 1. In the above-mentioned definition, the hydroxyl-protecting group, the carboxyl-protecting group, the lower alkyl group, the amino-protecting group, the optionally protected hydroxyl, the imino-protecting group etc. are not limited so long as they are groups which are usually used in organic synthesis. More specific examples thereof include the same groups as described in JP-A 8-73462. The oxalate (II-I) of the carbapenem compound according to the present invention has an asymmetric carbon atom or a double bond in the molecule thereof, and is in the form of an optically active substance, a diastereomer, or a racemic body. In the present invention, it is not limited and may be any one. About geometrical isomers thereof, the same matter is true. More specific examples of the oxalate (II-I) of the carbapenem compound according to the present invention include the following compounds, though it is not limited thereto. (1) p-Nitrobenzyl 6 -(1-hydroxyethyl) -1-methyl-2-{[2 - (azetidin-3-yl)hydroxymethylpyrrolidine-4-yl]thio}-1 - carbapen-2-em-3 -carboxylate'oxalate; (2) p-nitrobenzyl 6 - (1-hydroxyethyl) -1-methyl - 2-{ [2 - (pyrrolidine-3-yl)hydroxymethylpyrrolidine-4-yl]thio}-1- carbapen-2-em-3-carboxylate"oxalate; (3) p-nitrobenzyl 6 - (1-hydroxyethyl) -1-methyl - 2-{ [2 - (piperidine-3-yl) hydroxymethylpyrrolidine-4-yl]thio} -1- carbapen-2- em-3-carboxylate'oxalate,- (4) p-nitrobenzyl 6 - (1-hydroxyethyl) -1-methyl - 2-{ [2 -(piperidine-4-yl)hydroxymethylpyrrolidine-4-yl]thio}-1 -carbapen-2 - em-3-carboxylate'oxalate; and (5) p-nitrobenzyl 6 - (1-hydroxyethyl) -1-methyl - 2-{ [2 -(azepin-3-yl)hydroxymethylpyrrolidine-4-yl]thio}-1- carbapen-2-em-3 -carboxylate"oxalate. Next, 6 - (1-hydroxyethyl) -1-methyl - 2 -{ [2 - (pyrrolidine -3 -yl)hydroxymethylpyrrolidine- 4 -yl]thio}-1-carbapen- 2 - em-3 -carboxylate"oxalate (II-II) according to the present invention is represented by the following formula: wherein R3 represents a carboxyl-protecting group. Lastly, p-nitrobenzyl (1R, 5S, 6S) - 6 - [(R) -1 -hydroxyethyl]-1-methyl-2-{(2S,4S)-2-[(3R)-pyrrolidine-3-yl (R) -hydroxy]methyljpyrrolidine-4-ylthio] -1-carbapen-2 - em-3 carboxylate'oxalate (II-II1) according to the present invention is represented by the following formula: wherein PNB represents p-nitrobenzyl group. Sequentially, p-nitrobenzyl (1R,5S,6S) - 6 - [(R) -1 -hydroxyethyl] -1-methyl -1-carbapen-2-em-3 -carboxylate-2 -active compound (XIV) which is a starting material for p-nitrobenzyl (lR,5S,6S)-6-[(R) -1-hydroxyethyl] -1-methyl-2-{(2S,4S) -2- [ (3R) -pyrrolidine-3-yl- (R) - hydroxy]methyl}pyrrolidine-4-ylthio] -l-carbapen-2-em-3 -carboxylate'oxalate (II-III) according to the present invention, is represented by the following formula: (wherein PNB has the same meaning as described above; L represents a leaving group which is usually used in organic synthesis, and specific examples thereof include trifluoroacethoxy, methanesulfonyloxy, trifluoromethanesulfonyloxy, p-toluenesulfonyloxy and diphenoxyphosphoryloxy), and can be produced by the process ( [0069] - [0076] ) described in JP-A 8-73462. Furthermore, (2S,4S)-2-[[(3R)-pyrrolidine-3-yl-(R)-hydroxy]methyl]-4-mercaptopyrrolidine"dihydrochloride (XV), which is a reaction reagent, is represented by the following formula, and can be produced by the process described in Example 3 of JP-A 8-73462 etc. The following will describe the process for producing the compound of the present invention in more detail. (See the following chemical reaction formula, wherein PNB and L have the same meanings as described above.) (1) Step 1 The present step is a step of reacting p-nitrobenzyl (lR,5S,6S)-6-[(R) -1-hydroxyethyl] -1-methyl -1 -carbapen-2 -em-3 -carboxylate-2-active compound (XIV) with (2S,4S)-2-[[(3R)-pyrrolidine-3-yl- (R) -hydroxy]methyl] -4 - mercaptopyrrolidine "dihydrochloride (XV), to give a free compound or p-nitrobenzyl (1R,5S,6S) - 6 - [(R) -1 -hydroxyethyl] -1-methyl - 2 -{(2S,4S)-2-[(3R) -pyrrolidine-3-yl-(R) -hydroxy]methyl}pyrrolidine-4-ylthio] -1-carbapen-2 - em-3 -carboxylate. The present reaction is not limited so long as it is a thioether-synthesizing process which is usually conducted in organic synthesis. The process can easily be conducted in the presence of a base so as to give a high yield. The kind of the base used herein is not limited. Specific examples thereof include alkali metal hydroxides such as sodium hydroxide and potassium hydroxide; alkali earth metal hydroxides such as barium hydroxide and calcium hydroxide; alkali metal carbonates such as sodium carbonate and potassium carbonate; alkali metal hydrogencarbonates such as sodium hydrogencarbonate and potassium hydrogencarbonate; inorganic bases such as alkali metal hydrides, for example, sodium hydride; primary to tertiary organic amines such as triethylamine, diethylamine, N,N-diisopropylamine and ethylamine; aromatic amines such as pyridine; and aniline derivatives such as N,N-dimethylaniline. Among these, N,N-diisopropylamine is more preferred. (2) Stesp 2 The present step is a step of converting the free compound of p-nitrobenzyl (1R,5S,6S) - 6 - [ (R) -1-hydroxyethyl] -1 -methyl-2-{(2S,4S) -2 - [(3R) -pyrrolidine - 3-yl- (R) -hydroxy]methyl]pyrrolidine-4-ylthio] -1-carbapen-2-em-3 -carboxylate into an oxalate thereof, to give the target p-nitrobenzyl (1R,5S,6S) - 6 - [(R)-1-hydroxyethyl] -1-methyl-2-{ (2S,4S) -2- t OR) -pyrrolidine-3-yl- (R) - hydroxy]methyl]pyrrolidine-4-ylthio] -1-carbapen-2 - em-3 -carboxylate-oxalate (II-III). The present step can be conducted in a conventional way for conversion to oxalates. Usually, 0.7 to 2.0 equivalents of oxalic acid, preferably 0.8 to 1. 5 equivalent of oxalic acid, and more preferably 0.9 to 1.2 equivalent of oxalic acid is dissolved into a solvent such as dimethylsulf oxide (DMSO) , and then the resulting crystals were collected by filtration. Though the resulting crystals have sufficient purity by only air-drying, a higher-purity product can be obtained by solvent-washing, recrystallization etc. Now, Examples are shown below to describe the present invention specifically. However, it is needless to say that the present invention is not limited thereto. Example 1; Production of (1R, 5Sf 6S) -6- [ (R) -1 -hydroxypfhyl ] - 1 -methyl -2- ( (2S. 4S) -7- ( 3R) -pyrrolidine-3-yl-(R)-hydroxy] methyl pyrrolidine - 4 -yl ) thio-1 -carbapen -2- em-3-carboxylic acid "hydrochloride (calcium chloride .- 1 equivalent) 1 -1 ) Deprotection (reduction) Into a reaction vessel having a pH-stat were charged p-nitrobenzyl (lR,5S,6S)-6-[(R) -1-hydroxyethyl] -1-methyl-2 - {(2S,4S)-2-[(3R)-pyrrolidine-3-yl-(R)- hydroxy]methylpyrrolidine-4-yl}thio-l-carbapen-2 - em-3 -carboxylate'l oxalate (26.0 g, 38.3 mmol), 20% palladium hydroxide-carbon (5.24 g, a 50% wet body) and water (598 ml), and then the mixture was suspended and stirred under cooling in an ice bath. The pH of the suspension was 3.81. After purge with nitrogen was performed 5 times, a 1 N sodium hydroxide solution was dropwise added thereto from a constant rate pump connected to a pH-stat under the atmosphere of hydrogen (normal pressure, supply of hydrogen from a balloon). The reaction solution was vigorously stirred for 3.5 hours while the pH thereof was adjusted to 5.5. The advance of the reaction was confirmed by HPLC. When the consumption (about 124 mL) of the 1 N sodium hydroxide stopped, purge with nitrogen was performed . Celite (26 g) was charged therein under stirring. The reaction solution was stirred for 7 minutes. The reaction solution was subjected to filtration under reduced pressure through Buchner funnel, on the bottom of which celite (78 g) was laid. The cake was washed with water (169 mL) , to give an aqueous solution (790.7 g) of (1R,5S,6S) -6- [(R) -1-hydroxyethyl] -1-methyl - 2 -{ (2S,4S) -2- [ (3R) -pyrrolidine-3-yl- (R) - hydroxy]methylpyrrolidine-4-yl}thio-1 -carbapen-2 - em-3 -carboxylic acid'oxalate. The quantitative analysis by HPLC demonstrated that the resultant aqueous solution contained 13.08 g of the free form of the title compound (yield: 82.9%) . 1-2) Salt-exchange To a part (28 g, containing 0.421 g of (1R,5S,6S) - 6 -[(R) -1-hydroxyethyl] -1-methyl-2-{(2S,4S) -2 - [(3R) -pyrrolidine-3-yl- (R) -hydroxy]methylpyrrolidine-4-yl)thio-1 -carbapen-2 - em-3-carboxylic acid'oxalate) of this aqueous solution was dropwise added 1.6 g (about 1 equivalent) of 7.5% (w/w) calcium chloride solution (solution wherein 7.5 g of calcium chloride was dissolved in 100 g of ion-exchanged water) . The reaction solution immediately became whitely turbid. The precipitation was filtered off, to give a clear solution. Isopropanol (IPA, 120 mL) was added thereto so as to yield crystals. The precipitated crystals were collected by filtration and dried in a nitrogen stream for about 1 hour, to give the title compound as crystals (0.30 g, 0.248 g in terms of the free form). 1H-NMR(400MHz,D2O) ; 5 (ppm) 1.18(3H,d,J=7Hz). 1.24(3H,d,J=6Hz), 1.73(lH,td,J=9,13Hz), 1.84(lH,ddd,J=7,10,12Hz). 2.07-2.18(lH,m), 2.44(lH,qd,J=9,18Hz), 2.58(lH,td,J=8,14Hz), 3.15(lH,dd,J=10,12Hz). 3.21-3.37(3H,m). 3.39-3.47(2H,m). 3.51(lH,dd,J=8,12Hz), 3.64(lH,dd,J=7,12Hz), 3.83(lH,ddd,J=3,8,llHz), 3.92-4.01(2H,m), 4.15-4.23(2H,m). 2-1) Deprotection (reduction) Into a reaction vessel having a pH-stat were charged p-nitrobenzyl (1R,5S,6S) -6- [(R)-1-hydroxyethyl] -1-methyl-2-{(2S,4S)-2-[(3R)-pyrrolidine-3-yl-(R)- hydroxy]methylpyrrolidine-4-yl}thio-1 -carbapen-2-em-3 -carboxylate'l oxalate (4.0 g, 6.02 mmol), 20% palladium hydroxide-carbon (0.82 g, a 50% wet body) and water (92 ml), and then the mixture was suspended and stirred, under cooling in an ice bath. The pH of the suspension was 3 .77 . After purge with nitrogen was performed 5 times, a IN sodium hydroxide solution was dropwise added thereto from a constant rate pump connected to a pH-stat under the atmosphere of hydrogen-(normal pressure, supply of hydrogen from a balloon). The reaction solution was vigorously stirred for 3 hours while the pH thereof was adjusted to 5.5. The advance of the reaction was confirmed by HPLC. When the consumption (about 8.6 mL) of the 1 N sodium hydroxide stopped, purge with nitrogen was performed. Celite (4 g) was charged therein under stirring . The reaction solution was stirred for 7 minutes. The reaction solution was subjected to filtration under reduced pressure through Buchner funnel, on the bottom of which Celite (12 g) was laid. The cake was washed with water (26 mL) to give an aqueous solution (109.9 g) of (1R,5S,6S)-6-[(R)-1-hydroxyethyl]-1-methyl-2-{(2S,4S)-2-[(3R) -pyrrolidine-3-yl- (R) - hydroxy]methylpyrrolidine-4-yl]thio-1 -carbapen-2 - em-3 -carboxylic acid-oxalate. The quantitative analysis by HPLC demonstrated that the resultant aqueous solution contained 1. 88 g of the free form of the title compound (yield: 75.7%). 2.-2) Salt -exchange To a part (75 g, containing 1.193 g of (1R,5S,6S) - 6 -[ (R) -1-hydroxyethyl] -1-methyl-2-{(2S,4S)-2-[(3R)-pyrrolidine-3-yl- (R) -hydroxy]methylpyrrolidine- 4-yl}thio-1 -carbapen-2-em-3 -carboxylic acid'oxalate) of this solution was dropwise added 5.287 g (about 1.15 equivalent) of 7.5% (w/w) calcium chloride solution (solution wherein 7.5 g of calcium chloride was dissolved in 100 g of ion-exchanged water) . The reaction solution became whitely turbid rapidly. The resulting precipitates were filtered off, to give a clear solution. The solution was concentrated into about 1/2 of the original volume thereof . Isopropanol (88 mL) was added thereto so as to give crystals. The precipitated crystals were collected by filtration and dried in a nitrogen stream for about 1 hour, to give the title compound as crystals (1.222 g, 1.0416 g in terms of the free form). T -1) Deprotection (reduction) Into a reaction vessel having a pH-stat were charged p-nitrobenzyl (lR,5S,6S)-6-[(R) -1-hydroxyethyl] -l-methyl-2- {(2S,4S)-2-[(3R)-pyrrolidine-3-yl-(R)- hydroxy]methylpyrrolidine-4-yl}thio-1-carbapen-2-em-3 -carboxylate'oxalate (5.0 g, 7.31 mmol), 20% palladium hydroxide-carbon (0.99 g, a 50% wet body) and water (115 ml), and then the mixture was suspended and stirred, under cooling in an ice bath. The pH of the suspension was 3.75. After purge with nitrogen was performed 5 times, an 1 N sodium hydroxide solution was dropwise added thereto from a constant rate pump connected to a pH-stat under the atmosphere of hydrogen (normal pressure, supply of hydrogen from a balloon). The reaction solution was vigorously stirred for 2.5 hours while the pH thereof was adjusted to 5.5. The advance of the reaction was confirmed by HPLC. When the consumption (about 8.3 mL) of the IN sodium hydroxide stopped, purge with nitrogen was performed. Celite (5 g) was charged therein under stirring. The reaction solution was stirred for 7 minutes, and then subjected to filtration under reduced pressure through Buchner funnel, on the bottom of which Celite (15 g) was laid. The cake was washed with water (32.5 mL) , to give an aqueous solution (147 . 8 g) of (1R.5S, 6S) -6- [ (R) -1-hydroxyethyl] -1-methyl-2-{(2S.4S) -2-[ (3R) -pyrrolidine-3-yl- (R) -hydroxy]methylpyrrolidine-4-yl}thio-1-carbapen-2 - em-3 -carboxylic acid/oxalate. The quantitative analysis by HPLC demonstrated that the resultant aqueous solution contained 2.36 g of the free form of the title compound (yield: 78.4%). 3-2) Salt-exchange To a part (112.9 g, containing 1.73 g of (1R,5S,6S) - 6 -[ (R)-1-hydroxyethyl] -1-methyl-2-{(2S,4S) -2- [(3R) -pyrrolidine-3-yl- (R) -hydroxy]methylpyrrolidine-4-yl}thio-1 -carbapen-2-em-3-carboxylic acid'oxalate) of this solution was dropwise added 7.78 g (about 1.25 equivalent) of 7.5% (w/w) calcium chloride solution (solution wherein 7.5 g of calcium chloride was dissolved in 100 g of ion-exchanged water) . The reaction solution became whitely turbid rapidly. The precipitation was filtered off to give a clear solution. This solution was concentrated into about 1/2 of the original volume thereof. Isopropanol (75.3 mL) was added thereto so as to give crystals. The precipitated crystals were collected by filtration, and dried in a nitrogen stream for about 1 hour, to give the title compound as crystals (1.925 g, 1. 562 g in terms of the free form). 4-1 ) Deprotection (reduction) Into a reaction vessel having a pH-stat were charged p-nitrobenzyl (lR,5S,6S)-6-[(R) -1-hydroxyethyl] -1-methyl-2- {(2S,4S)-2-[(3R)-pyrrolidine-3-yl-(R) - hydroxy]methylpyrrolidine-4-yl}thio-l-carbapen-2-em-3 - carboxylate'oxalate (5.0 g, 7.12 mmol), 20% palladium hydroxide-carbon (0.97 g, a 50% wet body) and water (115 ml) . Then the mixture was suspended and stirred under cooling in an ice bath. The pH of the suspension was 3.7. After purge with nitrogen was performed 5 times, an 1 N sodium hydroxide solution was dropwise added thereto from a constant rate pump connected to a pH-stat under the atmosphere of hydrogen (normal pressure, supply of hydrogen from a balloon). The reaction solution was vigorously stirred for 2 hours while the pH thereof was adjusted to 5.5. The advance of the reaction was confirmed by HPLC. When the consumption (about 8.3 mL) of the 1 N sodium hydroxide stopped, purge with nitrogen was performed. Celite (5 g) was charged therein under stirring. The reaction solution was stirred for 7 minutes. The reaction solution was subjected to filtration under reduced pressure with a Buchner funnel, on the bottom of which celite (15 g) was laid. The cake was washed with water (32.5 mL) , to give an aqueous solution (154.7 g) of the title compound. The quantitative analysis by HPLC demonstrated that the resulting aqueous solution contained the title compound in a free form (2.43g, yield: 82.9%). 4-2) C rystallization To a part (25 g) of this solution were dropwise added methanol (200 mL) and isopropanol (30 mL) under stirring. The reaction solution was stirred under ice-cooling for 3 hours. The precipitated solid was filtered under reduced pressure, washed with methanol (10 mL) and dried under reduced pressure, to give the title compound as a slightly-yellowish white powder (the free form content: 67.9%, gradient HPLC purity: 98.9%). 1H-NMR(400MHz,D2O) ; 6 (ppm) 1.10(d,3H,J=7.3 Hz), 1.17(d,3H,J=6.4 Hz), 1.58-1.73(m,lH), 1.72-L85(m,lH), 1.98-2.14(m,lH). 2.36(q-like,lH,J^8.3 Hz), 2.51(dt,lHIJ=7.8,6.8 Hz), 3.09(dd,lH,J=9.0,12 Hz), 3.14-3.25(m,3H). 3.25- 3.40(m,2H), 3.43(dd,lH)J=8.0,12 Hz), 3.55-3.65(m,lH), 3.72-3.83(m,2H), 4.08- 4.17(m,2H). Kyample S: n-Ni trnhenzyl MR . 5fi . fiSl - 6 - [ (R)- 1 -hydrnvypfhyl ] - 1 -methyl -P- {(2S.4S) -2- {(3R) - pyrrolidine-3-yl-(R)- hydroxylmethyl )pyrrol i d i no - 4 -yl rh i n] -1 -rarhappn -2-pm-V carboxviate'monooxalate Wherein PNB represents p-nitrobenzyl group. p-Nitrobenzyl (1R,5S,6S) -2-dipnenoxyphosphoryloxy-6 -[ (R) -1-hydroxyethyl] -1-methyl -1-carbapen-2 - em-3-carboxylate (50.0 g, 84 .1 mmol) was dissolved in N, N-dimethylf ormamide (150 mL) and dimethylsulfoxide (300 mL) in a nitrogen stream, under stirring. After cooling to 10'C, N,N-diisopropylamine (36.6 mL, 210.3 mmol) was added thereto. Further, (2S,4S)-2-{ [ (3R) -pyrrolidine-3-yl- (R) -hydroxy]methyl}- 4 - mercaptopyrrolidine'dihydrochloride (25.46 g, 92.5 mmol) was added thereto, followed by stirring for 2 hours. A solution of oxalic acid (7.8 g, 86.6 mmol) in dimethylsulf oxide (30 mL) was added to the reaction solution, so that a solid was precipitated. Furthermore, 2-propanol (1750 mL) was added thereto, followed by stirring at the same temperature for 4 hours. The reaction solution in a slurry form was subjected to filtration under reduced pressure through Buchner funnel. and air-dried in a nitrogen stream for 1 hour, to give 117.4 g of a wet product. This product was suspended into methanol (333 mL) and ethanol (667 mL) under stirring at 14 ' C for 15 hours . The solid was collected by filtration and dried under reduced pressure for 20hr, to give the title compound (52.3 g, yield: 92%) . 1H-NMR(400MHz,DMSO-d6) ; 6 (ppm) 1.15(d, 1H, J=6.3Hz), 1.46(d, 1H,J=7.6Hz), 1.52(dt,lH,J=13,8.8Hz)> 1.64(dq,lH,J=12,9Hz). 1.87-1.98(m,lH). 2.23-2.40(m,2H), 2.80(dd,lH)J=6,12Hz)l 2.92-3.10(m,2H), 3.12-3.30(1X1,311), 3.30-3.56(m,3H). 3.73(quintet-like>lH,J=6.6Hz),3.97(quintet-Uke,lH,J=6.3Hz)l 4.22(dd,lH)J=5.4,9.5Hz)15.36(ABq,2H,J=14Hz)l7.71(d)2H,J=8.5Hz)1 8.23(d,2H,J=8.5Hz). WE CLAIM: 1. A process for producing a basic antibiotic inorganic acid salt (I), which comprises subjecting a basic antibiotic oxalate (II) to salt-exchange with an alkali earth metal salt (III) of an inorganic acid. wherein the ring A represents the basic antibiotic; R10 represents a protected functional group used in organic synthesis; Ak-E represents the alkali earth metal; and B represents the inorganic acid and wherein the basic antibiotic inorganic acid salt (I) is any one selected from the following: (1) cefotiam hydrochloride; (2) cefmenoxime hydrochloride; (3) cefozopran hydrochloride; (4) cefpirome sulfate; (5) cefepime hydrochloride; (6) cefoselis sulfate; (7) cefotiam hexetil hydrochloride; (8) cefetamet pivoxil hydrochloride; (9) cefcapene pivoxil hydrochloride; (10) talampicillin hydrochloride; (11) bacampicillin hydrochloride; (12) lenampicillin hydrochloride; (13) pivmecillinam hydrochloride; and (14) (1R, 5S, 6S)-6-[(R)-l-hydroxyethyl]-l-methyl-2-{(2S,4S)-2-[(3R)-pyrrolidine-3-yl-(R)-hydroxy]methyl}pyrrolidine-4-ylthio]-l-carbapen-2-em-3-carboxylic acid hydrochloride. 2. The process for producing the basic antibiotic inorganic acid salt (I) as claimed in claim 1, wherein the alkali earth metal salt (III) of the inorganic acid is an alkali earth metal halide (IV) or an alkali earth metal sulfate (V) 3. The process for producing the basic antibiotic inorganic acid salt (I) as claimed in claim 1 or 2, wherein the alkali earth metal halide (IV) is any one selected from beryllium fluoride, magnesium fluoride, calcium fluoride, strontium fluoride, barium fluoride, beryllium chloride, magnesium chloride, calcium chloride, strontium chloride, barium chloride, beryllium bromide, magnesium bromide, calcium bromide, strontium bromide, barium bromide, beryllium iodide, magnesium iodide, calcium iodide, strontium iodide and barium iodide. 4. The process for producing the basic antibiotic inorganic acid salt (I) as claimed in claim 1 or 2, wherein the alkali earth metal sulfate (v) is one selected from beryllium sulfate, magnesium sulfate and calcium sulfate. 5. The process for producing the basic antibiotic inorganic acid salt (I) as claimed in claims 1 to 4, wherein the use amount of the alkali earth metal salt (III) of the inorganic acid is from 0.9 to 1.3 equivalents. 6. The process for producing the basic antibiotic inorganic acid salt (I) as claimed in claims 1 to 5, wherein water is used as a solvent. 7. The process as claimed in claim 1, wherein the process comprises producing (1R,58, 6S)-6-[(R)-l-hydroxyethyll-l-methyl-2-{ (2S,4S) -2- [(3R) -pyrrolidine-3-yl- (R) - hydroxy]methyl}pyrrolidine-4-ylthio] -1-carbapen-2-em-3-carboxylic acid hydrochloride (VIII) represented by the following formula: which comprises subjecting p-nitrobenzyl (1R,5S,68) -6- [(R) -1- hydroxyethylj-l-methyl-2-{(2S,4S)-2-[(3R)-pyrrolidine-3-yl- (R) hydroxy] methyl} pyrrolidine-4-ylthio] -l-carbapen-2-em-3-carboxylate oxalate (VII) represented by the following formula: (wherein PNB represents p-nitrobenzyl group) to deprotection reaction; then subjecting to salt-exchange with calcium chloride; and then crystallizing the resultant by adding methanol and/or isopropanol thereto. 8. The process as claimed in claim 1, in which an oxalate (II-I) of a carbapenem compound, represented by the following formula: (wherein the ring A means a 3- to 7-membered ring having at least one nitrogen atom, and the ring A may be substituted with other than R6; R' represents hydrogen or methyl group; R2 and R5 are the same as or different from each other and each represents hydrogen or a hydroxyl-protecting group; R3 represents a carboxyl-protecting group; R4 represents hydrogen, a lower alkyl group or an amino-protecting group; R6 represents (1) hydrogen, (2) an optionally protected hydroxyl group, carbamoyl, formimidoyl, acetoimidoyl or a lower alkyl group which may be substituted with a substituent represented by the formula: (wherein R7 and R8 are the same as or different from each other and each represents hydrogen, a lower alkyl groups or an amino-protecting group) or (3) an amino-protecting group or an imino-protecting group; and m is 0 or 1) is the basic antibiotic oxalate (II). 9. A process for producing p-nitrobenzyl (1R, 5S, 6S)-6-[(R)-l- hydroxyethyll-l-methyl-2-{(2S,4S)-2-[(3R)-pyrrolidine-3-yl- (R) hydroxy]methyl}pyrrolidine-4-ylthio] -l-carbapen-2-em-3 carboxylateoxalate (11-111) , which comprises reacting p-nitrobenzyl (lR,5S,6S)-6-[(R)-l-hydroxyethyl] -l-methyl-l-carbapen-2-em-3- carboxylate-2-active compound (XIV) represented by the following formula: (wherein PNB has the same meaning as described above; and L represents a leaving group) with (2S,4S) -2- ([(3R) -pyrrolidine-3-yl- (R) -hydroxy] methyl) -4-mercaptopyrrolidine~ dihydrochloride (XV) represented by the following formula: and then converting the resultant into an oxalate. Dated this 4th day of January, 2002. [JAYANTA PAL] OF REMFRY & SAGAR ATTORNEY FOR THE APPLICANTS

Full Text

FORM 2
THE PATENTS ACT, 1970
[39 OF 1970]
COMPLETE SPECIFICATION [See Section 10; Rule 13]
"PROCESS FOR PRODUCING A BASIC ANTIBIOTIC-INORGANIC ACID SALT,
AND OXALATE INTERMEDIATE"
EISAI R&D MANAGEMENT CO., LTD., of 6-10, Koishikawa 4-chome, Bunkyo-ku, Tokyo, Japan.
The following specification particularly describes the nature of the invention and the manner in which it is to be performed:-

Description Field of the Invention
The present invention relates to a novel and
industrially-excellent process for producing a basic
antibiotic inorganic acid salt, for example, an
industrially-excellent production process for producing an
inorganic acid salt of an excellent antimicrobial agent having
strong antimicrobial action on gram-positive bacteria and
gram-negative bacteria, disclosed in JP-A 8-73462. More
specifically, it relates to industrially-excellent production
process for producing, for example, (1R,5S,6S) - 6 - [(R) -1 -
hydroxyethyl]-1-methyl-2-{(2S,4S)-2-[(3R)-pyrrolidine-3-yl-
(R)-hydroxy]methyl}pyrrolidine-4-ylthio]-1-carbapen-2-em-3 -
carboxylic acid'hydrochloride, a novel oxalate useful as a production intermediate, and a process for producing it.
Prior Art
In order to produce a basic antibioticinorganic acid salt, it is general to produce a free form, purify by column chromatography etc., and react the product with an inorganic acid.
For example, in the process disclosed in JP-A 8-73462,

WO96/01261 or Example 9 of EP-A 773222 as a process for producing (1R, 5S, 6S) -6- [ (R) -1-hydroxyethyl] -l-methyl-2- { (2S,"4S) -2-[ (3R)-pyrrolidine-3-yl - (R)-hydroxy]methyl}pyrrolidine-4 -
ylthio] -1- carbapen- 2 - em- 3 - carboxylic acid "hydrochloride etc . , the objective product is obtained by subjecting a p-nitrobenzyl ester compound to catalytic reduction, purifying by reversed-phase silica gel_chromatography, conversing the product to a hydrochloride, and subjecting it to freeze-drying.
In the above-mentioned process in the prior art, the purification by chromatography is performed. Thus, a solvent is used in a large amount. Therefore, costs for the production rise to a considerable degree. Additionally, many problems as follows arise: difficulty in industrial processing in large amount, the possibility of the generation of thermal cruelty (thermal decomposition) at the time of concentrating fractions, a problem of the remaining of the solvent in the final product, a problem about disposal of waste liquid and environment pollution by transpiration of the solvent. Thus, it cannot be said that the process is a process suitable for industry.
Moreover, it is necessary to perform subtle adjustment of pH when the free form is produced (neutralized) or converted to the hydrochloride. Thus, the process requires much labor and cost in industrial production. Moreover, freeze-drying is required in the last step, and results additional problems as follows: a further rise in the production costs, unsuitability thereof for processing in large amount and necessity of much

time.
Disclosure of the Invention
Thus, the present inventors made eager investigations to pursue a novel production process excellent in viewpoints such as production costs, operability (workability, safety and non- toxicity) , the purity of final products, and the protection of the environment.
As a result, they have found out that the above-mentioned problems can be overcome at a stroke by using a novel oxalate which will be in detail described below as a production intermediate and subjecting the oxalate to salt-exchange with an alkali earth metal salt of an inorganic acid. Thus, they have accomplished the present invention.
Therefore, an object of the present invention is to provide a novel production process useful for producing a basic antibiotic'inorganic acid salt industrially, and a novel production intermediate useful for producing antimicrobial agents, and a process for producing it.
The present invention is a process for producing a basic antibioticinorganic acid salt (I) , which comprises subjecting a basic antibiotic'oxalate (II) to salt-exchange with an alkali earth metal salt (III) of an inorganic acid.

wherein the ring A means the basic antibiotic; R10 means a protected functional group used in organic synthesis; Ak-E means the alkali earth metal; and B means the inorganic acid. The present invention is a process for producing a basic antibiotic "inorganic acid salt (I) , which comprises subjecting a basic antibiotic protector"oxalate (VI) to deprotection reaction; and then subjecting to salt-exchange with an alkali earth metal salt (III) of an inorganic acid. The present
invention is also a process for producing a basic antibiotic inorganic acid salt (I), which comprises subjecting a basic
antibiotic protector oxalate (VI) to deprotection reaction; then subjecting to salt-exchange with an alkali earth metal salt (III) of an inorganic acid; and then crystallizing the resultant by adding a poor solvent thereto.
The present invention is a process for producing (lR,5S,6S)-6-[(R) -1-hydroxyethyl] -1-methyl-2- { (2S,4S) -2-[ (3R) -pyrrolidine-3-yl- (R) -hydroxy]methyl}pyrrolidine-4 -ylthio] -1-carbapen-2 - em-3-carboxylic acid'hydrochloride

(VIII) represented by the following formula

which comprises subjecting p-nitrobenzyl (1R,5S,6S) - 6 - [ (R) -1-hydroxyethyl] -l-methyl-2-{(2S,4S)-2-[(3R)-pyrrolidine-3 -yl - (R)-hydroxy]methyl}pyrrolidine-4-ylthio] -1-carbapen-2-
em-3-carboxylate'oxalate (VII) represented by the following formula:

(wherein PNB represents p-nitrobenzyl group) to deprotection reaction; then subjecting to salt-exchange with calcium chloride; and then crystallizing the resultant by adding methanol and/or isopropanol thereto.
The present invention is a process for producing a basic antibioticinorganic acid salt (I), in which the oxalate (II-I) of a carbapenem compound represented by the following formula is a basic antibiotic'oxalate (II), and which comprises subjecting the basic antibiotic'oxalate (II) to salt-exchange with an alkali earth metal salt (III) of an inorganic acid.

Wherein the ring A represents a 3 - to 7-membered ring having at least one nitrogen atom, and the ring A may be substituted with other than R5; R1 represents hydrogen or methyl group; R2 and Rs are the same as or different from each other and each represents hydrogen or a hydroxyl-protecting group; R3 represents a carboxyl -protecting group; R4 represents hydrogen, a lower alkyl group or an amino-protecting group; R6 represents (1) hydrogen, (2) an optionally protected hydroxyl group, carbamoyl, formimidoyl, acetoimidoyl or a lower alkyl group which may be substituted with a substituent represented by the formula:

(wherein R7 and R8 are the same as or different from each other and each represents hydrogen, a lower alkyl group or an amino-protecting group) or (3) an amino-protecting group or an imino-protecting group; and m is 0 or 1.
The present invention is an oxalate (II-I) of a carbapenem compound represented by the following formula:

wherein the ring A represents a 3 - to 7-membered ring having at least one nitrogen atom, and the ring A may be substituted with other than R6; R1 represents hydrogen or methyl group; R2 and R5 are the same as or different from each other and each represents hydrogen or a hydroxyl-protecting group; R3 represents a carboxyl -protecting group; R4 represents hydrogen, a lower alkyl group or an amino-protecting group; R6 represents (1) hydrogen, (2) an optionally protected hydroxyl group, carbamoyl, formimidoyl, acetoimidoyl or a lower alkyl group which may be substituted with a substituent represented by the formula:

(wherein R7 and R8 are the same as or different from each other and each represents hydrogen, a lower alkyl group or an amino-protecting group) or (3) an amino-protecting group or an imino-protecting group; and m is 0 or 1.
Further, the present invention is a process for producing p-nitrobenzyl (lR,5S,6S)-6-[(R)-l-hydroxyethyl] -1-methyl-2 -{(2S,4S)-2-[(3R)-pyrrolidine-3-yl-(R)-

hydroxy]methyl}pyrrolidine-4-ylthio] -1-carbapen-2 - em-3 -
carboxylate'oxalate (II-III), which comprises reacting p-nitrobenzyl (lR,5S,6S)-6-[(R)-1-hydroxyethyl]-1-methyl-1 carbapen-2 - em-3 -carboxylate-2-active compound (XIV) represented by the following formula:

(wherein PNB has the same meaning as described above; and L means a leaving group) with (2S,4S)-2-{[(3R)-pyrrolidine-3-yl-(R)-hydroxy]methyl}-4-mercaptopyrrolidine"dihydrochloride (XV) represented by the following formula:

and then converting the resultant into to an oxalate.
Herein, the basic antibiotic'inorganic acid salt (I) according to the present invention is an antibiotic having a basic salt in the molecule thereof, and is not limited so long as the antibiotic is combined with an inorganic acid to form a salt. Preferred examples thereof include the following:
(1) cefotiam (CAS Res.No.: 66309-69-1) hydrochloride;
(2) cefmenoxime (CAS Res.No.: 75738-58-8) hydrochloride;
(3) cefozopran(CAS Res.No.: 113981-44-5) hydrochloride;
(4) cefpirome(CAS Res.No.: 98753-19-6) sulfate;

(5) cefepime (CAS Res.No.: 123171-59-5) hydrochloride;
(6) cefoselis (CAS Res.No.: 122841-10-5) sulfate;
(7) cefotiam hexetil (CAS Res.No.: 95789-30-3) hydrochloride;
(8) cefetametpivoxil (CASRes:No.: 65052-63-3) hydrochloride;
(9) cefcapene pivoxil (CAS Res.No.: 135889-00-8)
hydrochloride;
(10) talampicillin (CAS Res.No.: 39878-70-1) hydrochloride;
(11) bacampicillin (CAS Res.No.: 37661-08-8) hydrochloride
(12) lenampicillin (CAS Res.No.: 80734-02-7) hydrochloride;
(13) pivmecillinam (CAS Res.No.: 32886-97-8) hydrochloride; and
(14) (1R,5S,6S)-6- [(R) -1-hydroxyethyl] -l-methyl-2-{ (2S,4S) -2 - [ (3R) -pyrrolidine-3-yl- (R) -hydroxy]methyl}pyrrolidine-4 -ylthio]-l-carbapen-2-em-3-carboxylic acid*hydrochloride
(JP-A 8-73462, Example 9).
Next, the basic antibiotic"oxalate (II) according to the present invention is a starting material for producing the
above-mentioned basic antibiotic•inorganic acid salt (I) by salt-exchange, and specific examples thereof include an oxalate of the above-mentioned basic antibiotic.
Next, the alkali earth metal salt (III) of the inorganic acid according to the present invention is not limited so long as it is an adduct salt made from the inorganic acid and an alkali earth metal such as beryllium, magnesium, calcium, strontium and barium. Preferred are alkali earth metal halide (IV) and alkali earth metal sulfides (V).

More specific examples of the alkali earth metal halides (IV) include beryllium fluoride, magnesium fluoride, calcium fluoride, strontium fluoride, barium fluoride, beryllium chloride, magnesium chloride, calcium chloride, strontium chloride, barium chloride, beryllium bromide, magnesium bromide, calcium bromide, strontium bromide, barium bromide, beryllium iodide, magnesium iodide, calcium iodide, strontium iodide, barium iodide etc.
Among these, magnesium chloride, calcium chloride, magnesium bromide, calcium bromide etc. are more preferred.
Examples of the alkali earth metal sulfates (V) include beryllium sulfate, magnesium sulfate and calcium sulfate.
The following will describe the process for producing the compound of the present invention in more detail. (See the following chemical reaction formula, wherein the ring A means a basic antibiotic; R1C means a protected functional group used in organic synthesis; Ak-E means an alkali earth metal; and B means an inorganic acid.)

The present step is a step of conducting deprotection
reaction in the case that a basic antibiotic'oxalate has a protected functional group in the molecule thereof.
The protected function group herein means a group obtained by protecting a functional group such as a hydroxyl group, an amino group or a carboxyl group and used in organic synthesis. The deprotection reaction can be conducted in an ordinary manner such as hydrolysis or reduction. (2) Step 2
The present step is a step of subjecting the basic antibiotic'oxalate (II) to salt-exchange with an alkali earth metal salt (III) of an inorganic acid, to give the target basic antibiotic'inorganic acid salt (I).
Herein, the amount of the alkali earth metal salt (III) of the inorganic acid used is not limited and is usually from 0.7 to 2.0 equivalents, preferably from 0.8 to 1.5 equivalent, and more preferably from 0.9 to 1.3 equivalent.
Herein, the solvent used is not limited. Specific examples thereof include water, lower alcohols, ketone solvents, ester solvents, ether solvents, formamide solvents and dimethylsulfoxide. These may be used alone or in the form of a mixture thereof. Among these, water and lower alcohols are preferred.
The manner of carrying out (operating) the salt-exchange is not limited. Usually, a solution wherein a necessary amount

of the alkali earth metal salt (III) of the inorganic acid is dissolved is dropwise added to a solution of the basic antibioticoxalate (II).
Herein, a solvent wherein an alkali earth metal'oxalate which is by-produced by the salt-exchange is insoluble is selected at this time, the alkali earth metal"oxalate is precipitated and can easily be by filtration. Therefore, this case is more suitable for industry.
The target basic antibiotic•inorganic acid salt (I) is in a solution state at this stage. Accordingly, extracting operation is necessary. However, by concentration of the solvent or addition of a poor solvent (solvent having low solubility), it can easily be precipitated as crystal.
In the case of concentrating the solvent, it may be completely dried. It is however allowable to concentrate it partially into a small-amount solution, cool the resultant solution or cause the resultant solution to stand still, thereby precipitating the target crystals.
In the case of using the poor solvent, the kind thereof is not limited. In general, methanol, n-propanol, isopropanol etc. are preferred.
In the present invention, the step 2 may be performed after the step 1 is performed to isolate and/or purify the basic antibiotic'oxalate (II) . However, the steps 1 and 2 may be continuously performed by the so-called one-spot reaction. In this case, the deprotection reaction solution can be

used, as it is, for the salt-exchange. As a result, column chromatography, pH adjustment and freeze-drying become unnecessary. Therefore, this case is excellent in industrial operability, reduction in production costs, processing in large amount and environment protection.
(1R,5S,6S)-6-[(R)-1-hydroxyethyl]-l-methyl-2-{(2S,4S) -2 - [ (3R) -pyrrolidine-3-yl- (R) -hydroxy]methyl}pyrrolidine-4 -ylthio]-1-carbapen-2-em-3-carboxylic acid'oxalate (II-IX) according to the present invention, which is represented by the following formula:

is a novel compound and is useful for a production intermediate.
Herein, the oxalate (II-I) of the carbapenem compound according to the present invention is represented by the following formula.

Wherein the ring A represents a 3 - to 7 -membered ring having at least one nitrogen atom, and the ring A may be substituted

with other than R6; R1 represents hydrogen or methyl group; R2 and R5 are the same as or different from each other and each represents hydrogen or a hydroxyl-protecting group; R3 represents a carboxyl-protecting group; R4 represents hydrogen, a lower alkyl group or an amino-protecting group; R6 represents (1) hydrogen, (2) an optionally protected hydroxyl group, carbamoyl, formimidoyl, acetoimidoyl or a lower alkyl group which may be substituted with a substituent represented by the formula:
(wherein R7 and R8 are the same as or different from each other and each represents hydrogen, a lower alkyl group or an amino-protecting group) or (3) an amino-protecting group or an imono-protecting group; and m is 0 or 1.
In the above-mentioned definition, the hydroxyl-protecting group, the carboxyl-protecting group, the lower alkyl group, the amino-protecting group, the optionally protected hydroxyl, the imino-protecting group etc. are not limited so long as they are groups which are usually used in organic synthesis. More specific examples thereof include the same groups as described in JP-A 8-73462.
The oxalate (II-I) of the carbapenem compound according to the present invention has an asymmetric carbon atom or a double bond in the molecule thereof, and is in the form of an

optically active substance, a diastereomer, or a racemic body. In the present invention, it is not limited and may be any one. About geometrical isomers thereof, the same matter is true.
More specific examples of the oxalate (II-I) of the carbapenem compound according to the present invention include the following compounds, though it is not limited thereto.
(1) p-Nitrobenzyl 6 -(1-hydroxyethyl) -1-methyl-2-{[2 -
(azetidin-3-yl)hydroxymethylpyrrolidine-4-yl]thio}-1 -
carbapen-2-em-3 -carboxylate'oxalate;
(2) p-nitrobenzyl 6 - (1-hydroxyethyl) -1-methyl - 2-{ [2 -
(pyrrolidine-3-yl)hydroxymethylpyrrolidine-4-yl]thio}-1-
carbapen-2-em-3-carboxylate"oxalate;
(3) p-nitrobenzyl 6 - (1-hydroxyethyl) -1-methyl - 2-{ [2 -
(piperidine-3-yl) hydroxymethylpyrrolidine-4-yl]thio} -1-
carbapen-2- em-3-carboxylate'oxalate,-
(4) p-nitrobenzyl 6 - (1-hydroxyethyl) -1-methyl - 2-{ [2 -(piperidine-4-yl)hydroxymethylpyrrolidine-4-yl]thio}-1 -carbapen-2 - em-3-carboxylate'oxalate; and
(5) p-nitrobenzyl 6 - (1-hydroxyethyl) -1-methyl - 2-{ [2 -(azepin-3-yl)hydroxymethylpyrrolidine-4-yl]thio}-1-
carbapen-2-em-3 -carboxylate"oxalate.
Next, 6 - (1-hydroxyethyl) -1-methyl - 2 -{ [2 - (pyrrolidine -3 -yl)hydroxymethylpyrrolidine- 4 -yl]thio}-1-carbapen- 2 - em-3 -carboxylate"oxalate (II-II) according to the present invention is represented by the following formula:

wherein R3 represents a carboxyl-protecting group.
Lastly, p-nitrobenzyl (1R, 5S, 6S) - 6 - [(R) -1 -hydroxyethyl]-1-methyl-2-{(2S,4S)-2-[(3R)-pyrrolidine-3-yl (R) -hydroxy]methyljpyrrolidine-4-ylthio] -1-carbapen-2 - em-3 carboxylate'oxalate (II-II1) according to the present invention is represented by the following formula:

wherein PNB represents p-nitrobenzyl group.
Sequentially, p-nitrobenzyl (1R,5S,6S) - 6 - [(R) -1 -hydroxyethyl] -1-methyl -1-carbapen-2-em-3 -carboxylate-2 -active compound (XIV) which is a starting material for p-nitrobenzyl (lR,5S,6S)-6-[(R) -1-hydroxyethyl] -1-methyl-2-{(2S,4S) -2- [ (3R) -pyrrolidine-3-yl- (R) -
hydroxy]methyl}pyrrolidine-4-ylthio] -l-carbapen-2-em-3 -carboxylate'oxalate (II-III) according to the present invention, is represented by the following formula:

(wherein PNB has the same meaning as described above; L represents a leaving group which is usually used in organic synthesis, and specific examples thereof include trifluoroacethoxy, methanesulfonyloxy,
trifluoromethanesulfonyloxy, p-toluenesulfonyloxy and diphenoxyphosphoryloxy), and can be produced by the process ( [0069] - [0076] ) described in JP-A 8-73462.
Furthermore, (2S,4S)-2-[[(3R)-pyrrolidine-3-yl-(R)-hydroxy]methyl]-4-mercaptopyrrolidine"dihydrochloride (XV), which is a reaction reagent, is represented by the following formula, and can be produced by the process described in Example 3 of JP-A 8-73462 etc.

The following will describe the process for producing the compound of the present invention in more detail. (See the following chemical reaction formula, wherein PNB and L have the same meanings as described above.)

(1) Step 1
The present step is a step of reacting p-nitrobenzyl (lR,5S,6S)-6-[(R) -1-hydroxyethyl] -1-methyl -1 -carbapen-2 -em-3 -carboxylate-2-active compound (XIV) with (2S,4S)-2-[[(3R)-pyrrolidine-3-yl- (R) -hydroxy]methyl] -4 -
mercaptopyrrolidine "dihydrochloride (XV), to give a free compound or p-nitrobenzyl (1R,5S,6S) - 6 - [(R) -1 -hydroxyethyl] -1-methyl - 2 -{(2S,4S)-2-[(3R) -pyrrolidine-3-yl-(R) -hydroxy]methyl}pyrrolidine-4-ylthio] -1-carbapen-2 - em-3 -carboxylate.
The present reaction is not limited so long as it is a thioether-synthesizing process which is usually conducted in organic synthesis. The process can easily be conducted in the

presence of a base so as to give a high yield.
The kind of the base used herein is not limited. Specific examples thereof include alkali metal hydroxides such as sodium hydroxide and potassium hydroxide; alkali earth metal hydroxides such as barium hydroxide and calcium hydroxide; alkali metal carbonates such as sodium carbonate and potassium carbonate; alkali metal hydrogencarbonates such as sodium hydrogencarbonate and potassium hydrogencarbonate; inorganic bases such as alkali metal hydrides, for example, sodium hydride; primary to tertiary organic amines such as triethylamine, diethylamine, N,N-diisopropylamine and ethylamine; aromatic amines such as pyridine; and aniline derivatives such as N,N-dimethylaniline. Among these, N,N-diisopropylamine is more preferred. (2) Stesp 2
The present step is a step of converting the free compound of p-nitrobenzyl (1R,5S,6S) - 6 - [ (R) -1-hydroxyethyl] -1 -methyl-2-{(2S,4S) -2 - [(3R) -pyrrolidine - 3-yl- (R) -hydroxy]methyl]pyrrolidine-4-ylthio] -1-carbapen-2-em-3 -carboxylate into an oxalate thereof, to give the target p-nitrobenzyl (1R,5S,6S) - 6 - [(R)-1-hydroxyethyl] -1-methyl-2-{ (2S,4S) -2- t OR) -pyrrolidine-3-yl- (R) -
hydroxy]methyl]pyrrolidine-4-ylthio] -1-carbapen-2 - em-3 -carboxylate-oxalate (II-III).
The present step can be conducted in a conventional way for conversion to oxalates. Usually, 0.7 to 2.0 equivalents

of oxalic acid, preferably 0.8 to 1. 5 equivalent of oxalic acid, and more preferably 0.9 to 1.2 equivalent of oxalic acid is dissolved into a solvent such as dimethylsulf oxide (DMSO) , and then the resulting crystals were collected by filtration. Though the resulting crystals have sufficient purity by only air-drying, a higher-purity product can be obtained by solvent-washing, recrystallization etc.
Now, Examples are shown below to describe the present invention specifically. However, it is needless to say that the present invention is not limited thereto.
Example 1; Production of (1R, 5Sf 6S) -6- [ (R) -1 -hydroxypfhyl ] -
1 -methyl -2- ( (2S. 4S) -7- ( 3R) -pyrrolidine-3-yl-(R)-hydroxy] methyl pyrrolidine - 4 -yl ) thio-1 -carbapen -2- em-3-carboxylic acid "hydrochloride (calcium chloride .- 1 equivalent)

1 -1 ) Deprotection (reduction)
Into a reaction vessel having a pH-stat were charged p-nitrobenzyl (lR,5S,6S)-6-[(R) -1-hydroxyethyl] -1-methyl-2 -
{(2S,4S)-2-[(3R)-pyrrolidine-3-yl-(R)-
hydroxy]methylpyrrolidine-4-yl}thio-l-carbapen-2 - em-3 -carboxylate'l oxalate (26.0 g, 38.3 mmol), 20% palladium hydroxide-carbon (5.24 g, a 50% wet body) and water (598 ml), and then the mixture was suspended and stirred under cooling

in an ice bath. The pH of the suspension was 3.81. After purge with nitrogen was performed 5 times, a 1 N sodium hydroxide solution was dropwise added thereto from a constant rate pump connected to a pH-stat under the atmosphere of hydrogen (normal pressure, supply of hydrogen from a balloon). The reaction solution was vigorously stirred for 3.5 hours while the pH thereof was adjusted to 5.5. The advance of the reaction was confirmed by HPLC. When the consumption (about 124 mL) of the 1 N sodium hydroxide stopped, purge with nitrogen was performed . Celite (26 g) was charged therein under stirring. The reaction solution was stirred for 7 minutes. The reaction solution was subjected to filtration under reduced pressure through Buchner funnel, on the bottom of which celite (78 g) was laid. The cake was washed with water (169 mL) , to give an aqueous solution (790.7 g) of (1R,5S,6S) -6- [(R) -1-hydroxyethyl] -1-methyl - 2 -{ (2S,4S) -2- [ (3R) -pyrrolidine-3-yl- (R) -
hydroxy]methylpyrrolidine-4-yl}thio-1 -carbapen-2 - em-3 -carboxylic acid'oxalate. The quantitative analysis by HPLC demonstrated that the resultant aqueous solution contained 13.08 g of the free form of the title compound (yield: 82.9%) . 1-2) Salt-exchange
To a part (28 g, containing 0.421 g of (1R,5S,6S) - 6 -[(R) -1-hydroxyethyl] -1-methyl-2-{(2S,4S) -2 - [(3R) -pyrrolidine-3-yl- (R) -hydroxy]methylpyrrolidine-4-yl)thio-1 -carbapen-2 - em-3-carboxylic acid'oxalate) of this aqueous solution was dropwise added 1.6 g (about 1 equivalent) of 7.5%

(w/w) calcium chloride solution (solution wherein 7.5 g of calcium chloride was dissolved in 100 g of ion-exchanged water) . The reaction solution immediately became whitely turbid. The precipitation was filtered off, to give a clear solution. Isopropanol (IPA, 120 mL) was added thereto so as to yield crystals. The precipitated crystals were collected by filtration and dried in a nitrogen stream for about 1 hour, to give the title compound as crystals (0.30 g, 0.248 g in terms of the free form).
1H-NMR(400MHz,D2O) ; 5 (ppm) 1.18(3H,d,J=7Hz). 1.24(3H,d,J=6Hz), 1.73(lH,td,J=9,13Hz), 1.84(lH,ddd,J=7,10,12Hz). 2.07-2.18(lH,m), 2.44(lH,qd,J=9,18Hz), 2.58(lH,td,J=8,14Hz), 3.15(lH,dd,J=10,12Hz). 3.21-3.37(3H,m). 3.39-3.47(2H,m). 3.51(lH,dd,J=8,12Hz), 3.64(lH,dd,J=7,12Hz), 3.83(lH,ddd,J=3,8,llHz), 3.92-4.01(2H,m), 4.15-4.23(2H,m).

2-1) Deprotection (reduction)
Into a reaction vessel having a pH-stat were charged p-nitrobenzyl (1R,5S,6S) -6- [(R)-1-hydroxyethyl] -1-methyl-2-{(2S,4S)-2-[(3R)-pyrrolidine-3-yl-(R)-
hydroxy]methylpyrrolidine-4-yl}thio-1 -carbapen-2-em-3 -carboxylate'l oxalate (4.0 g, 6.02 mmol), 20% palladium hydroxide-carbon (0.82 g, a 50% wet body) and water (92 ml),

and then the mixture was suspended and stirred, under cooling in an ice bath. The pH of the suspension was 3 .77 . After purge with nitrogen was performed 5 times, a IN sodium hydroxide solution was dropwise added thereto from a constant rate pump connected to a pH-stat under the atmosphere of hydrogen-(normal pressure, supply of hydrogen from a balloon). The reaction solution was vigorously stirred for 3 hours while the pH thereof was adjusted to 5.5. The advance of the reaction was confirmed by HPLC. When the consumption (about 8.6 mL) of the 1 N sodium hydroxide stopped, purge with nitrogen was performed. Celite (4 g) was charged therein under stirring . The reaction solution was stirred for 7 minutes. The reaction solution was subjected to filtration under reduced pressure through Buchner funnel, on the bottom of which Celite (12 g) was laid. The cake was washed with water (26 mL) to give an aqueous solution (109.9 g) of (1R,5S,6S)-6-[(R)-1-hydroxyethyl]-1-methyl-2-{(2S,4S)-2-[(3R) -pyrrolidine-3-yl- (R) -
hydroxy]methylpyrrolidine-4-yl]thio-1 -carbapen-2 - em-3 -carboxylic acid-oxalate. The quantitative analysis by HPLC demonstrated that the resultant aqueous solution contained 1. 88 g of the free form of the title compound (yield: 75.7%). 2.-2) Salt -exchange
To a part (75 g, containing 1.193 g of (1R,5S,6S) - 6 -[ (R) -1-hydroxyethyl] -1-methyl-2-{(2S,4S)-2-[(3R)-pyrrolidine-3-yl- (R) -hydroxy]methylpyrrolidine- 4-yl}thio-1 -carbapen-2-em-3 -carboxylic acid'oxalate) of this solution was

dropwise added 5.287 g (about 1.15 equivalent) of 7.5% (w/w) calcium chloride solution (solution wherein 7.5 g of calcium chloride was dissolved in 100 g of ion-exchanged water) . The reaction solution became whitely turbid rapidly. The resulting precipitates were filtered off, to give a clear solution. The solution was concentrated into about 1/2 of the original volume thereof . Isopropanol (88 mL) was added thereto so as to give crystals. The precipitated crystals were collected by filtration and dried in a nitrogen stream for about 1 hour, to give the title compound as crystals (1.222 g, 1.0416 g in terms of the free form).

T -1) Deprotection (reduction)
Into a reaction vessel having a pH-stat were charged p-nitrobenzyl (lR,5S,6S)-6-[(R) -1-hydroxyethyl] -l-methyl-2-
{(2S,4S)-2-[(3R)-pyrrolidine-3-yl-(R)-
hydroxy]methylpyrrolidine-4-yl}thio-1-carbapen-2-em-3 -carboxylate'oxalate (5.0 g, 7.31 mmol), 20% palladium hydroxide-carbon (0.99 g, a 50% wet body) and water (115 ml), and then the mixture was suspended and stirred, under cooling in an ice bath. The pH of the suspension was 3.75. After purge with nitrogen was performed 5 times, an 1 N sodium hydroxide

solution was dropwise added thereto from a constant rate pump connected to a pH-stat under the atmosphere of hydrogen (normal pressure, supply of hydrogen from a balloon). The reaction solution was vigorously stirred for 2.5 hours while the pH thereof was adjusted to 5.5. The advance of the reaction was confirmed by HPLC. When the consumption (about 8.3 mL) of the IN sodium hydroxide stopped, purge with nitrogen was performed. Celite (5 g) was charged therein under stirring. The reaction solution was stirred for 7 minutes, and then subjected to filtration under reduced pressure through Buchner funnel, on the bottom of which Celite (15 g) was laid. The cake was washed with water (32.5 mL) , to give an aqueous solution (147 . 8 g) of (1R.5S, 6S) -6- [ (R) -1-hydroxyethyl] -1-methyl-2-{(2S.4S) -2-[ (3R) -pyrrolidine-3-yl- (R) -hydroxy]methylpyrrolidine-4-yl}thio-1-carbapen-2 - em-3 -carboxylic acid/oxalate. The quantitative analysis by HPLC demonstrated that the resultant aqueous solution contained 2.36 g of the free form of the title compound (yield: 78.4%). 3-2) Salt-exchange
To a part (112.9 g, containing 1.73 g of (1R,5S,6S) - 6 -[ (R)-1-hydroxyethyl] -1-methyl-2-{(2S,4S) -2- [(3R) -pyrrolidine-3-yl- (R) -hydroxy]methylpyrrolidine-4-yl}thio-1 -carbapen-2-em-3-carboxylic acid'oxalate) of this solution was dropwise added 7.78 g (about 1.25 equivalent) of 7.5% (w/w) calcium chloride solution (solution wherein 7.5 g of calcium chloride was dissolved in 100 g of ion-exchanged water) . The

reaction solution became whitely turbid rapidly. The precipitation was filtered off to give a clear solution. This solution was concentrated into about 1/2 of the original volume thereof. Isopropanol (75.3 mL) was added thereto so as to give crystals. The precipitated crystals were collected by filtration, and dried in a nitrogen stream for about 1 hour, to give the title compound as crystals (1.925 g, 1. 562 g in terms of the free form).

4-1 ) Deprotection (reduction)
Into a reaction vessel having a pH-stat were charged p-nitrobenzyl (lR,5S,6S)-6-[(R) -1-hydroxyethyl] -1-methyl-2-
{(2S,4S)-2-[(3R)-pyrrolidine-3-yl-(R) -
hydroxy]methylpyrrolidine-4-yl}thio-l-carbapen-2-em-3 -
carboxylate'oxalate (5.0 g, 7.12 mmol), 20% palladium hydroxide-carbon (0.97 g, a 50% wet body) and water (115 ml) . Then the mixture was suspended and stirred under cooling in an ice bath. The pH of the suspension was 3.7. After purge with nitrogen was performed 5 times, an 1 N sodium hydroxide solution

was dropwise added thereto from a constant rate pump connected to a pH-stat under the atmosphere of hydrogen (normal pressure, supply of hydrogen from a balloon). The reaction solution was vigorously stirred for 2 hours while the pH thereof was adjusted to 5.5. The advance of the reaction was confirmed by HPLC. When the consumption (about 8.3 mL) of the 1 N sodium hydroxide stopped, purge with nitrogen was performed. Celite (5 g) was charged therein under stirring. The reaction solution was stirred for 7 minutes. The reaction solution was subjected to filtration under reduced pressure with a Buchner funnel, on the bottom of which celite (15 g) was laid. The cake was washed with water (32.5 mL) , to give an aqueous solution (154.7 g) of the title compound. The quantitative analysis by HPLC demonstrated that the resulting aqueous solution contained the title compound in a free form (2.43g, yield: 82.9%). 4-2) C rystallization
To a part (25 g) of this solution were dropwise added methanol (200 mL) and isopropanol (30 mL) under stirring. The reaction solution was stirred under ice-cooling for 3 hours. The precipitated solid was filtered under reduced pressure, washed with methanol (10 mL) and dried under reduced pressure, to give the title compound as a slightly-yellowish white powder (the free form content: 67.9%, gradient HPLC purity: 98.9%). 1H-NMR(400MHz,D2O) ; 6 (ppm) 1.10(d,3H,J=7.3 Hz), 1.17(d,3H,J=6.4 Hz), 1.58-1.73(m,lH), 1.72-L85(m,lH), 1.98-2.14(m,lH). 2.36(q-like,lH,J^8.3 Hz), 2.51(dt,lHIJ=7.8,6.8 Hz), 3.09(dd,lH,J=9.0,12 Hz), 3.14-3.25(m,3H). 3.25-

3.40(m,2H), 3.43(dd,lH)J=8.0,12 Hz), 3.55-3.65(m,lH), 3.72-3.83(m,2H), 4.08-
4.17(m,2H).
Kyample S: n-Ni trnhenzyl MR . 5fi . fiSl - 6 - [ (R)- 1 -hydrnvypfhyl ] -
1 -methyl -P- {(2S.4S) -2- {(3R) - pyrrolidine-3-yl-(R)-
hydroxylmethyl )pyrrol i d i no - 4 -yl rh i n] -1 -rarhappn -2-pm-V
carboxviate'monooxalate

Wherein PNB represents p-nitrobenzyl group.
p-Nitrobenzyl (1R,5S,6S) -2-dipnenoxyphosphoryloxy-6 -[ (R) -1-hydroxyethyl] -1-methyl -1-carbapen-2 - em-3-carboxylate (50.0 g, 84 .1 mmol) was dissolved in N, N-dimethylf ormamide (150 mL) and dimethylsulfoxide (300 mL) in a nitrogen stream, under stirring. After cooling to 10'C, N,N-diisopropylamine (36.6 mL, 210.3 mmol) was added thereto. Further, (2S,4S)-2-{ [ (3R) -pyrrolidine-3-yl- (R) -hydroxy]methyl}- 4 -
mercaptopyrrolidine'dihydrochloride (25.46 g, 92.5 mmol) was added thereto, followed by stirring for 2 hours. A solution of oxalic acid (7.8 g, 86.6 mmol) in dimethylsulf oxide (30 mL) was added to the reaction solution, so that a solid was precipitated. Furthermore, 2-propanol (1750 mL) was added thereto, followed by stirring at the same temperature for 4 hours. The reaction solution in a slurry form was subjected to filtration under reduced pressure through Buchner funnel.

and air-dried in a nitrogen stream for 1 hour, to give 117.4 g of a wet product. This product was suspended into methanol (333 mL) and ethanol (667 mL) under stirring at 14 ' C for 15 hours . The solid was collected by filtration and dried under reduced pressure for 20hr, to give the title compound (52.3 g, yield: 92%) .
1H-NMR(400MHz,DMSO-d6) ; 6 (ppm) 1.15(d, 1H, J=6.3Hz), 1.46(d, 1H,J=7.6Hz), 1.52(dt,lH,J=13,8.8Hz)> 1.64(dq,lH,J=12,9Hz). 1.87-1.98(m,lH). 2.23-2.40(m,2H), 2.80(dd,lH)J=6,12Hz)l 2.92-3.10(m,2H), 3.12-3.30(1X1,311), 3.30-3.56(m,3H). 3.73(quintet-like>lH,J=6.6Hz),3.97(quintet-Uke,lH,J=6.3Hz)l 4.22(dd,lH)J=5.4,9.5Hz)15.36(ABq,2H,J=14Hz)l7.71(d)2H,J=8.5Hz)1 8.23(d,2H,J=8.5Hz).

WE CLAIM:

1. A process for producing a basic antibiotic inorganic acid salt (I), which comprises subjecting a basic antibiotic oxalate (II) to salt-exchange with an alkali earth metal salt (III) of an inorganic acid.
wherein the ring A represents the basic antibiotic; R10 represents a protected functional group used in organic synthesis; Ak-E represents the alkali earth metal; and B represents the inorganic acid and wherein the basic antibiotic inorganic acid salt (I) is any one selected from the following:
(1) cefotiam hydrochloride;
(2) cefmenoxime hydrochloride;
(3) cefozopran hydrochloride;
(4) cefpirome sulfate;
(5) cefepime hydrochloride;
(6) cefoselis sulfate;
(7) cefotiam hexetil hydrochloride;

(8) cefetamet pivoxil hydrochloride;
(9) cefcapene pivoxil hydrochloride;

(10) talampicillin hydrochloride;
(11) bacampicillin hydrochloride;
(12) lenampicillin hydrochloride;

(13) pivmecillinam hydrochloride; and
(14) (1R, 5S, 6S)-6-[(R)-l-hydroxyethyl]-l-methyl-2-{(2S,4S)-2-[(3R)-pyrrolidine-3-yl-(R)-hydroxy]methyl}pyrrolidine-4-ylthio]-l-carbapen-2-em-3-carboxylic acid hydrochloride.

2. The process for producing the basic antibiotic inorganic acid salt (I) as claimed in claim 1, wherein the alkali earth metal salt (III) of the inorganic acid is an alkali earth metal halide (IV) or an alkali earth metal sulfate (V)
3. The process for producing the basic antibiotic inorganic acid salt (I) as claimed in claim 1 or 2, wherein the alkali earth metal halide (IV) is any one selected from beryllium fluoride, magnesium fluoride, calcium fluoride, strontium fluoride, barium fluoride, beryllium chloride, magnesium chloride, calcium chloride, strontium chloride, barium chloride, beryllium bromide, magnesium bromide, calcium bromide, strontium bromide, barium bromide, beryllium iodide, magnesium iodide, calcium iodide, strontium iodide and barium iodide.
4. The process for producing the basic antibiotic inorganic acid salt (I) as claimed in claim 1 or 2, wherein the alkali earth metal sulfate (v)

is one selected from beryllium sulfate, magnesium sulfate and calcium sulfate.
5. The process for producing the basic antibiotic inorganic acid salt (I) as claimed in claims 1 to 4, wherein the use amount of the alkali earth metal salt (III) of the inorganic acid is from 0.9 to 1.3 equivalents.
6. The process for producing the basic antibiotic inorganic acid salt (I) as claimed in claims 1 to 5, wherein water is used as a solvent.
7. The process as claimed in claim 1, wherein the process comprises producing (1R,58, 6S)-6-[(R)-l-hydroxyethyll-l-methyl-2-{ (2S,4S) -2- [(3R) -pyrrolidine-3-yl- (R) - hydroxy]methyl}pyrrolidine-4-ylthio] -1-carbapen-2-em-3-carboxylic acid hydrochloride (VIII) represented by the following formula:

which comprises subjecting p-nitrobenzyl (1R,5S,68) -6- [(R) -1-
hydroxyethylj-l-methyl-2-{(2S,4S)-2-[(3R)-pyrrolidine-3-yl- (R)
hydroxy] methyl} pyrrolidine-4-ylthio] -l-carbapen-2-em-3-carboxylate oxalate (VII) represented by the following formula:

(wherein PNB represents p-nitrobenzyl group) to deprotection reaction; then subjecting to salt-exchange with calcium chloride; and then crystallizing the resultant by adding methanol and/or isopropanol thereto.
8. The process as claimed in claim 1, in which an oxalate (II-I) of a carbapenem compound, represented by the following formula:

(wherein the ring A means a 3- to 7-membered ring having at least one nitrogen atom, and the ring A may be substituted with other than R6; R' represents hydrogen or methyl group; R2 and R5 are the same as or different from each other and each represents hydrogen or a hydroxyl-protecting group; R3 represents a carboxyl-protecting group; R4 represents hydrogen, a lower alkyl group or an amino-protecting group; R6 represents (1) hydrogen, (2) an optionally protected hydroxyl group, carbamoyl, formimidoyl, acetoimidoyl or a lower alkyl group which may

be substituted with a substituent represented by the formula:

(wherein R7 and R8 are the same as or different from each other and each represents hydrogen, a lower alkyl groups or an amino-protecting group) or (3) an amino-protecting group or an imino-protecting group; and m is 0 or 1) is the basic antibiotic oxalate (II).
9. A process for producing p-nitrobenzyl (1R, 5S, 6S)-6-[(R)-l-
hydroxyethyll-l-methyl-2-{(2S,4S)-2-[(3R)-pyrrolidine-3-yl- (R)
hydroxy]methyl}pyrrolidine-4-ylthio] -l-carbapen-2-em-3
carboxylateoxalate (11-111) , which comprises reacting p-nitrobenzyl
(lR,5S,6S)-6-[(R)-l-hydroxyethyl] -l-methyl-l-carbapen-2-em-3-
carboxylate-2-active compound (XIV) represented by the following formula:

(wherein PNB has the same meaning as described above; and L represents a leaving group) with (2S,4S) -2- ([(3R) -pyrrolidine-3-yl- (R) -hydroxy] methyl) -4-mercaptopyrrolidine~ dihydrochloride (XV) represented by the following formula:

and then converting the resultant into an oxalate.
Dated this 4th day of January, 2002.
[JAYANTA PAL]
OF REMFRY & SAGAR
ATTORNEY FOR THE APPLICANTS

Documents:

in-pct-2002-00013-mum-assignment(13-12-2006).pdf

in-pct-2002-00013-mum-cancelled pages(13-12-2006).pdf

in-pct-2002-00013-mum-claims(granted)-(13-12-2006).doc

in-pct-2002-00013-mum-claims(granted)-(13-12-2006).pdf

in-pct-2002-00013-mum-correspondence(13-12-2006).pdf

in-pct-2002-00013-mum-correspondence(ipo)-(20-10-2004).pdf

in-pct-2002-00013-mum-form 19(08-07-2004).pdf

in-pct-2002-00013-mum-form 1a(04-01-2002).pdf

in-pct-2002-00013-mum-form 1a(13-12-2006).pdf

in-pct-2002-00013-mum-form 1a(29-08-2005).pdf

in-pct-2002-00013-mum-form 2(granted)-(13-12-2006).doc

in-pct-2002-00013-mum-form 2(granted)-(13-12-2006).pdf

in-pct-2002-00013-mum-form 3(05-09-2005).pdf

in-pct-2002-00013-mum-form 3(06-09-2005).pdf

in-pct-2002-00013-mum-form 3(11-01-2002).pdf

in-pct-2002-00013-mum-form 5(04-01-2002).pdf

in-pct-2002-00013-mum-form 6(13-12-2006).pdf

in-pct-2002-00013-mum-form-pct-isa-210(13-12-2006).pdf

in-pct-2002-00013-mum-petition under rule 137(08-09-2005).pdf

in-pct-2002-00013-mum-power of authority(11-01-2002).pdf

in-pct-2002-00013-mum-power of authority(13-12-2006).pdf

in-pct-2002-00013-mum-power of authority(29-08-2005).pdf

« Previous Patent

Next Patent »

Patent Number

208436

Indian Patent Application Number

IN/PCT/2002/00013/MUM

PG Journal Number

35/2007

Publication Date

31-Aug-2007

Grant Date

27-Jul-2007

Date of Filing

04-Jan-2002

Name of Patentee

EISAI R&D MANAGEMENT CO., LTD.

Applicant Address

6-10, KOISHIKAWA 4-CHOME, BUNKYO-KU, TOKYO, JAPAN.

Inventors:

#	Inventor's Name	Inventor's Address
1	AKIO KAYANO	CENTURY MURAMATSU 203, 2-7-31, KAMISU, KAMISUMACHI, KASHIMA-GUN, IBARAKI, JAPAN.
2	HIROYUKI CHIBA	KURESUTO SHIHO 102, 2727-9 AZA, KUBOYAMA, HIRAIZUMI, KAMISUMACHI, IBARAKI, JAPAN.
3	TAIJU NAKAMURA	GURANSHARIONIBANKAN 204, 1-10-5, OHNOHARA, KAMISUMACHI, KASHIMA-GUN, IBARAKI, JAPAN.
4	HIROYUKI ISHIZUKA	177-35, MIYATSUDAI, KASHIMA-SHI, IBARAKI, JAPAN.
5	YUUKI KOMATSU	4-5-62, NINOMIYA, TSUKUBA-SHI, IBARAKI, JAPAN.
6	NOBUAKI SATO	1032-19, OTTA, TSUCHIURA-SHI, IBARAKI, JAPAN.
7	SHIGETON NEGI	2-8-15, HIGASHI, TSUKUBA-SHI, IBARAKI, JAPAN.
8	SHIN SAKURAI	3061-6, KASUGACHO, CHOSHI-SHI, CHIBA, JAPAN.
9	HIROYUKI SAITO	GONOIKEOHKARYA 125, 6-16-27, SHITTECHOU, KAMISUMACHI, KASHIMA-GUN, IBARAKI, JAPAN.
10	MANABU SASHO	4-22-2-506, MATSUSHIRO, TSUKUBA-SHI, IBARAKI, JAPAN.

PCT International Classification Number

C07D 477/02

PCT International Application Number

N/A

PCT International Filing date

2000-07-27

PCT Conventions:

#	PCT Application Number	Date of Convention	Priority Country
1	11/216806	1999-07-30	Japan
2	11/216807	1999-07-30	Japan