Title of Invention

PROCESS FOR SALIFICATION OF CEPHALOSPORIN ANTIBIOTICS

Abstract

The present invention relates to a process for the preparation of beta-lactam antibiotics, which have wide range of anti-bacterial activity. More particularly, the present invention relates to a process for the preparation of cephalosporin antibiotics of the formula (I) Wherein Rj represents CH3, CRaRbCOORc where Ra and Rb independently represent hydrogen or methyl and Re represents hydrogen or (C1-C6) alkyl; R2 is carboxylate ion or COORd, where Rd represents a counter ion, which forms a salt; R3 represents,

Full Text

Field of the Invention The present invention relates to a process for the preparation of beta-lactam antibiotics, which have wide range of anti-bacterial activity. More particularly, the present invention relates to a process for the preparation of cephalosporin antibiotics of the formula (I) as sulphate salt. wherein R1 represents CH3, CRaRbCOORc where Ra and Rb independently represent hydrogen or methyl and R6 represents hydrogen or (C1-C6)alkyl; R2 is carboxylate ion or COOR^, where Rd represents a counter ion which forms a salt; R3 represents, Background of the Invention Cefquinome and Cefpirome are the important antibiotics and are administered as their sulphate salt. There are several literature evidence reports the preparation of the said compound. All of them involve isolation of these compounds as HC1 or HI salt followed by converting the salt into sulphate salt using Amberlite LA-2 resin. None of them provide a direct isolation of these compounds as sulphate salt. US patent Nos. 4,767,852 and 5,003,073 discloses a process for the production of cephalosporin derivatives by acylating 7-amino-3-cephem-4-carboxylic acid with 2-mercaptobenzothiazolyl-(Z)-2-(2-aminothiazol-4-yl)-2- using solvents such as chlorinated hydrocarbon, or ethers such as ethyl acetate or in a mixture of such solvent with water. US patent 5,003,073 discloses and claims the compound of formula (II) and its use in the preparation of different cephalosporin derivatives. US patent 4,845,087 discloses a process for preparing cefquinome acid addition salts after isolating the inner salt. Preparation of inner salt is carried out by condensing MAEM with different moieties in presence of DMF/water,and the obtained inner salt is further converted into its sulfate salt with Amberlite LA-2, followed by sulfuric acid. US patent number 4,667,028 discloses and claims a process for the preparation of the different cephalosporin derivatives by the condensation of 2-Mercaptobenzothiazolyl-(Z)-(2-aminothiazol-4-yl]-2-methoxyiminoacetate or its activated derivative with different cephem moieties in the presence of a base and tri-Cl-C4-alkyl-iodosilane. According to this patent the final product is isolated as iodide or hydrochloride salt which is further converted into sulfate salt. So far the reported prior art process that are widely reported for the preparation of the title compound involve preparation of intermediary salts like hydrochloride or iodide to achieve purity. These salts are further converted into sulphate salt using resins like Amberlite LA-2 (J.Antibiotics. (1988), 41(10), 1374-94). All the above procedures involve cumbersome processes like washing (several times) with resin to achieve quality. So there exists a need to develop an industrially viable process, which does not involve the use of resins and its recovery. During the course of our research, we have made a lot of efforts to develop an easily scalable and commercially viable process for the preparation of cephalosporins. Unexpectedly it was observed that, this condensation and salification could be achieved in a single step. This invention is cost effective, high yielding and easy to scale up with very less unit operations. The primary objective of the invention is to provide a process for the preparation of cephalosporin antibiotics of the general formula (I) as sulphate salt, which is simple, high yielding and cost effective. Still another objective of the present invention is to produce cephalosporin antibiotics that are highly pure industrially. Yet another objective of the present invention is to produce sulphate salt of cephalosporin antibiotics, directly without isolating any intermediary compounds like inner salt or any other acid addition salts like hydrochloride, hydroiodide etc., Yet another objective of the present invention is to replace usage of resins such as Amberlite LA-2 Yet another objective of the invention is to produce sulfate salts of cephalosporins antibiotics selected from Cefquinome, Cefpirome and Ceftazidime. Summary of the Invention Accordingly, the present invention provides a process for the preparation of cephalosporin antibiotics of the formula (I) as sulphate salt wherein R1 represents CH3, CRaRbCOORc where Ra and Rb independently represent hydrogen or methyl and Rc represents hydrogen or (C1-C6)alkyl; R2 is carboxylate ion or COORd, where Rd represents a counter ion which forms a salt and R3 represents (i) wherein R is a group which forms a basis that a compound of formula (III) is in a reactive form ; including halogen, or a group which forms together with the -C=0 group to which R is attached as an active ester, and a group which forms together with the -C=0 group to which R is attached as mixed anhydride and R1 are as defined above, with 7-amino cephem derivative of the formula (IV) wherein R2 and R3 are as defined above, and R4 represents hydrogen or trimethylsilyl, with or without base in the presence of organic solvent at a temperature in the range of-50 °C to +60 °C, (ii) quenching reaction mass into mixture of water and organic solvent, and (iii) adjusting pH in the range of 1.0 to 2.5 using aqueous sulphuric acid solution to isolate the compound as sulphate salt. The process is shown in Scheme-1 In an embodiment of the present invention the organic base is selected from triethylamine, diethyl amine, trimethylamine, dimethylamine, tributylamine, pyridine, N-alkylanilines, N-methylmorpholine, N,N-diisopropylethylamine, N,N-diisopropylamine, N-methylpiperidine, N-methylpyrrolidine, dicyclohexylamine or mixtures thereof. In another embodiment of the present invention activation of compound of formula (III) is done using the literature evidences available for such condensation. Preferably converting the compound formula (III) into its reactive derivative using halogen, or active ester using thioester like 2-Mercaptobenzothiazolyl-(Z)-(2-aminothiazol-4-yl]-2-methoxyiminoacetate derivative or condensation in the presence of CDI. Alternatively the compound of formula (IV) is employed in free or its silylated reactive derivative. The silylated derivative of formula (IV) is prepared using silylating agent like iodotrimethylsilane (TMIS), N,0-bis-(trimethylsilyl)-trifluoracetamide (BSTFA), N-methyl-N-trimethylsilyltrifluoracetamide (MSTFA); 1,1,3,3,3- hexamethyidisilazane (HMDS); bis-(trimethylsilyl)-urea (BSS), N,N'-bis-(trimethylsilyl)-urea (BSU); or a mixture of two or more of silylation agents. If necessary a base may present in the condensation. In another embodiment of the present invention the solvent used in step (i) or (ii) is selected from dimethyl acetamide, dimethyl formamide, N-methyl pyrrolidine, ethyl acetate, methylene dichloride, ethylene dichloride, acetone, toluene, tetrahydrofuran, acetonitrile, dioxane, xylene, water and alcohols like methanol, ethanol, isopropyl alcohol or mixtures thereof. In yet another embodiment of the present invention the compound of formula (I) is directly isolated as sulphate salt by from the reaction mass by the addition of sulfuric acid or dilute sulfuric acid. In yet another embodiment of the present invention the reactive derivative of compound of formula (III) includes acid halide, acid anhydride, active amide, ester and the like. To MDC, Hexamethyl Disilane (145 g) and Iodine (214 g) was added and refluxed about 45 minutes followed by 2, 3-Cyclopentanopyridine 100 g was added at 0 to -5° C charged stirred for 30 minutes (Solution A). To 7-aminocephalosporanic acid (115 g) in MDC BSA (176 g) {alternatively HMDS/TMCS also can be utilized as silylating agent} was charged and stirred (Solution B) To solution B, solution A was added and stirred at 0 to -5° C. The resultant mass was stirred at 30±5° C till completion of reaction. After completion of reaction, pre-cooled (-20° C) mixture of methanol (195 ml) & water (310 ml) were charged to reaction mass. Temperature of reaction mass was raised to 20° C and stirred layer were separated. MDC layer again extracted with methanol & water mixture. To aqueous layer was subjected to carbon treatment and excess methanol was added to filtrate. The pH of filtrate was adjusted to 3.0 using TEA. The solid obtained was filtered To the mixture of MDC and methanol the step -1 solid, MAEM (2-Mercaptobenzothiazolyl-(Z)-(2-aminothiazol-4-yl]-2-methoxyiminoacetate) and TEA were added. The resultant solution was stirred at 5° C till completion of reaction. After completion of reaction the product was extracted with water. The aqueous layer was subjected to carbon treatment and to filtrate IP A was added to isolate the product. The solid filter washed with water to yield Cefpirome HC1. To the mixture of ethyl acetate and water cefpirome HC1 was added and stirred to get clear solution. The clear solution was washed five times with 20% Amberlite LA-2 in ethyl acetate (1000 ml) solution (during washing acetic acid was added to mass). After washing the aqueous layer pH was aqueous layer was adjusted to 1.5 using 30% sulphuric acid and excess acetone was to precipitate the product. The solid was washed with acetone to yield Cefpirome sulphate. The following examples are provided by way of illustration only and should not be limited to construe the scope of the invention. To a mixture of dichloromethane (120 mL) and methanol (40 mL) containing 7-amino-3-[(2,3-cyclohexen0-l-pyridino)methyl]-ceph-3-em-4- carboxylate hydroiodide (40g) at 5°C was added 2-Mercaptobenzothiazolyl-(Z)-(2-aminothiazol-4-yl]-2-methoxyiminoacetate (33.6 g). Triethylamine (9 g) was added at 0-5°C and the mixture stirred for 2 hours. The reaction mass was added to a cold solution of dichloromethane (430 mL) and water (160 mL). The aqueous layer was separated and diluted with acetone and the pH adjusted to 1.0-2.0 at 5°C, using dil.sulphuric acid solution. Excess acetone was added while adjusting the pH to 1.0-2.0 at 0-5°C. Crystals obtained were filtered and dried to get Cefquinome sulphate (38-40g) HPLC purity (> 99%). To a mixture of dichloromethane (120 mL) and methanol (40 mL) containing 7-amino-3-[(2,3-cyclopenteno-l-pyridino)methyl]-ceph-3-em-4- carboxylate hydroiodide (39 g) at 5°C was added 2-Mercaptobenzothiazolyl-(Z)-(2-aminothiazol-4-yl]-2-methoxyiminoacetate (33.6 g). Then triethylamine (9 g) was added stirred for 2 hours. After completion of reaction, reaction mass was added to a cold solution of dichloromethane (430 mL) and water (160 mL). The aqueous layer was separated. The aqueous layer was diluted with acetone and the pH adjusted to 1.5-2.5 using dil.sulphuric acid. Excess acetone was added while adjusting pH to 1.0-2.0 at 0-5°C. Crystals obtained were filtered and dried to get Cefpirome sulphate (38-40g) in more than 99% purity. To a mixture of dichloromethane (120 mL) and methanol (40 mL) containing 7-amino-3-[(2,3-cyclohexeno-l-pyridino)methyl]-ceph-3-em-4- carboxylate hydroiodide (40g) at 5°C was added 2-Mercaptobenzothiazolyl-(Z)- (2-aminothiazol-4-yl]-2-methoxyiminoacetate (33.6 g). N-methylpiperidine (9 g) was added at 0-5°C and the mixture stirred for 2 hours. The reaction mass was added to a cold solution of dichloromethane (430 mL) and water (160 mL). The aqueous layer was separated and diluted with acetone and the pH adjusted to 1.0-2.0 at 5°C, using dil.sulphuric acid solution. Excess acetone was added while adjusting the pH to 1.5-2.0 at 0-5°C. Crystals obtained were filtered and dried to get Cefquinome sulphate (38-40g) HPLC purity (> 99%). To a mixture of dichloromethane (120 mL) and methanol (40 mL) containing 7-amino-3-[(2,3-cyclopenteno-l-pyridino)methyl]-ceph-3-em-4-carboxylate hydroiodide (39 g) at 5°C was added 2-Mercaptobenzothiazolyl-(Z)-(2-aminothiazol-4-yl]-2-methoxyiminoacetate (33.6 g). Then Dicyclohexylamine (16.3 g) was added stirred for 2 hours. After completion of reaction, reaction mass was added to a cold solution of dichloromethane (430 mL) and water (160 mL). The aqueous layer was separated. The aqueous layer was diluted with acetone and the pH adjusted to 1.5-2.5 using dil.sulphuric acid. Excess acetone was added while adjusting pH to 1.0-2.0 at 0-5°C. Crystals obtained were filtered and dried to get Cefpirome sulphate (38-40g) in more than 99% purity. Advantages: 1. In the present invention sulphate salt is obtained directly without isolating the intermediary compounds as shown in the reference example 2. Sulfate salt is prepared without using any resins like Amberlite LA-2 as shown in the reference example. 3. Ease of scale up with very less unit operations. We Claim: 1. A process for the preparation of cephalosporin antibiotics of the formula (I) as sulphate salt wherein R1 represents CH3, CRaRbCOORc where Ra and Rb independently represent hydrogen or methyl and Rc represents hydrogen or (C1-C6)alkyl;R2 is carboxylate ion or COORa, where Rd represents a counter ion, which forms a salt; wherein R is a group which forms a basis that a compound of formula (III) is in a reactive form ; including halogen, or a group which forms together with the -C=0 group to which R is attached as an active ester, and a group which forms together with the -C=0 group to which R is attached as mixed anhydride and R1 is as defined above, with wherein R2 and R3 are as defined above, and R4 represents hydrogen or trimethylsilyl, with or without base in the presence of organic solvent at a temperature in the range of-50 °C to +60 °C (ii) quenching reaction mass into mixture of water and organic solvent, and (iii) adjusting pH in the range of 1.0 to 2.5 using aqueous sulphuric acid solution to isolate the title compound as sulphate salt. 2. The process according to claim 1, wherein the base used in step (i) is is selected from triethylamine, diethylamine, trimethylamine, dimethylamine, tributylamine, pyridine, N-alkylanilines, N-methylmorpholine, N,N- diisopropylethylamine, N,N-diisopropylamine, N-methylpiperidine, N-methylpyrolidine, dicyclohexylamine or mixtures thereof. 3. The process according to claim 1, wherein the organic solvent used in step (i) and step (ii) is selected from dimethyl acetamido (DMAc), dimethyl formamide (DMF), N-methyl pyrrolidine, ethyl acetate, methylene dichloride (MDC), ethylene dichloride, acetone, toluene, tetrahydrofuran, acetonitrile, dioxane, xylene and alcohols like methanol, ethanol, isopropyl alcohol (IPA) or mixtures thereof. 4. The process according to claim 1, wherein the compound of formula (I) is a syn-isomer.

Documents:

0911-che-2005-abstract.pdf

0911-che-2005-claims.pdf

0911-che-2005-correspondnece-others.pdf

0911-che-2005-description(complete).pdf

0911-che-2005-form 1.pdf

0911-che-2005-form 5.pdf

911-CHE-2005 AMENDED CLAIMS 26-10-2012.pdf

911-CHE-2005 EXAMINATION REPORT REPLY RECEIVED 26-10-2012.pdf

911-CHE-2005 AMENDED CLAIMS 05-03-2012.pdf

911-CHE-2005 AMENDED CLAIMS 17-10-2012.pdf

911-CHE-2005 AMENDED PAGES OF SPECIFICATION 05-03-2012.pdf

911-CHE-2005 EXAMINATION REPORT REPLY RECEIVED 17-10-2012.pdf

911-CHE-2005 CORRESPONDENCE OTHERS 05-03-2012.pdf

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