Title of Invention

A PROCESS FOR THE PREPARATION OF CEPHALOSPORINS

Abstract

Abstract A process for the preparation of cephalosporins of the formula (I) which comprises: (i) condensing the activated derivative of the formula (III) where X represents halogen atom such as chlorine or bromine, with silylated derivative of 7-amino cephalosporin of the formula (XIII) wherein R represents lower alkyl, p-methoxybenzyl, p-nitrobenzyl or diphenylmethyl group in the presence of a solvent at a temperature in the range of -50 °C to 0 °C to produce a compound of formula (XIV), where R is as defined earlier. (ii) cyclising the compound of formula (XIV) with thiourea in the presence of solvent and sodium acetate at room temperature to produce cephalosporin compounds of the formula (XV) wherein R is as defined earlier, (iii) deesterifying the compound of formula (XV) using anisole/trifluoroacetic acid, phenol/ trifluoroacetic acid, formic acid in the presence or absence of a solvent at a temperature in the range of 0 °C to 10 °C to produce a compound of formula (I) and (iv) converting the compound of formula (I), to its pharmaceutically acceptable salt.

Full Text

Field of the Invention The present invention relates to a process for the preparation of cephalosporin antibiotic of the formula (I) wherein R1 represents hydrogen, trityl, CH3, CRaRbCOORc where Ra and Rb independently represent hydrogen or methyl and Re represents hydrogen or (Cr C6)alkyl; R3 is carboxylate ion or COORd, where Rd represents hydrogen, esters which form a prodrug or a counter ion which forms a salt; R4 represents H, OCH3, Background of the Invention EP 0030294 discloses a process for the preparation of compound of cephalosporin antibiotic as given in scheme 1 : Scheme 1 wherein R represents hydrogen atom or a readily hydrolysable ester group and X represents one of the groups EP patent 0 842 937 discloses a process for the preparation of compound of cephalosporin antibiotic as given in scheme 2 : wo 00/63214 discloses a process for the preparation of cephalosporins by condensation of carboxy ester intermediate with silylated thiourea. wherein X and Ri are substituents useful in cephalosporin chemistry and RE is hydrogen, a negative charge or together with the COO- group to which RE is attached is an ester, Y is halogen; R' is hydrogen or silyl and R" is silyl; RE is silyl or together with the COO- group to which RE is attached is an ester. This patent publication discloses an alternate process, which involves the desilylation of compound of formula (II) and then condensation of desilylated compound with thiourea. wo 02/083634 discloses a process for the preparation of cefpodoxime of formula (I), as shown in scheme 3 below : wherein R is hydrogen or silyl group and R' is silyl group or COOR' is a carboxylic acid salt; X is halogen. The process comprises reacting the compound of formula (IX) with compound of formula (III) and desilyating the compound of formula (X) and cyclizing the desilylated compound with thiourea to produce cefpodoxime acid of formula (XII). Objectives of the Invention The primary objective of the invention is to provide a new method for the preparation of cefpodoxime acid of the formula (I), which would be easy to implement in commercial scales. Summary of the Invention Accordingly, the present invention provides a process for the preparation of cephalosporins of the formula (I) wherein R1 represents hydrogen, trityl, CH3, CRaRbCOORc where Ra and Rb independently represent hydrogen or methyl and Rc represents hydrogen or (Cp C6)alkyl; R3 is carboxylate ion or COORd, where Rd represents hydrogen, esters which form a prodrug or a counter ion which forms a salt; R4 represents H, OCH3, OCOCH3, =CH2,OCONH2, which comprises: (i) condensing the activated derivative of the formula (III) where X represents halogen atom such as chlorine or bromine, with silylated derivative of 7-amino cephalosporin of the formula (XIII) wherein R represents lower alkyl, p-methoxybenzyl, p-nitrobenzyl or diphenylmethyl group in the presence of a solvent at a temperature in the range of -50°C to 0 °C to produce a compound of formula (XIV), where R is as defined earlier. (ii) cyclising the compound of formula (XIV) with thiourea in the presence of solvent and sodium acetate at room temperature to produce cephalosporin compounds of the formula (XV) wherein R is as defined earlier , (iii) deesterifying the compound of formula (XV) using anisole/trifluoroacetic acid, phenol/ trifluoroacetic acid, formic acid in the presence or absence of a solvent at a temperature in the range of 0 °C to 10 °C to produce a compound of formula (I) and (iv) converting the compound of formula (I), to its pharmaceutically acceptable salt. The process is shown in Scheme-4 below Scheme-4 In yet another embodiment of the present invention, there is provided a process for the preparation of compound of formula (XIII) which comprises ; (i) reacting the 7-aminocephalosporin derivative of the formula (XVI) wherein R1 represents hydrogen, (C1-C4)alkyl, substituted or unsubstituted phenyl or substituted or unsubstituted phenoxy with R4- - X wherein X represents halogen atom and R4 is as defined earlier in the presence in an organic solvent and a base at a temperature in the range of 0 °C to 30 °C to produce 7-aminocephalosporin derivative of the formula (XVII), (ii) deacylating the compound formula (XVII) using PCls/POCls/pyridine, PCl5/pyridine, triphenyl phosphite/Cl2 complexes in the presence of an alcohol, at a temperature in the range of -40 °C to 0 °C to produce a compound of the formula (XIII) and (iii) isolating the compound of formula (XIII). The process is shown in Scheme-5 below Scheme-5 In yet another embodiment of the present invention, there is provided a process for the preparation of compound of formula (XIII) which comprises ; (i) acylating the 7-aminocephalosporin derivative of the formula (XVIII) wherein to produce compound of formula (XIX) in the presence of an organic solvent and a base at a temperature in the range of 0 °C to 30 °C, (ii) esterifying the compound of formula (XIX) using an esterifying agent in the presence of a solvent and a base at a temperature in the range of 25 °C to 50 °C followed by oxidation using an oxidizing agent in the presence of a solvent at a temperature in the range of -10 °C to 10 °C to produce a compound of formula (XX) (iii) deacylating the compound of formula (XX) using PCl5/POCl3/pyridine, PCls/pyridine, triphenyl phosphite/Cl2 complexes in the presence of an alcohol, at a temperature in the range of -40 °C to 0 °C to produce a compound of the formula (XIII) and (iii) isolating the compound of formula (XIII). The process is shown in Scheme-6 below In still another embodiment of the present invention the compound of formula (XIII), can be prepared by a process, which comprises protecting the compound of the formula (XVIII) using p-methoxybenzyl halide, p-nitrobenzyl halide, or diphenylmethane halide or diphenyldiazomethane, in the presence of a solvent and base. The process is as shown in Scheme-7 below In another embodiment of the present invention, there is provided a new intermediate of the formula (XIV) wherein X represents halogen atom such as chlorine or bromine; R represents p-methoxybenzyl, p-nitrobenzyl or diphenylmethyl group; R4 represents H, OCH3, In yet another embodiment of the present invention there is provided a new intermediate of the formula (VI) wherein R represents p-methoxybenzyl, p-nitrobenzyl or diphenylmethyl group. Detailed Description of the Invention In yet another embodiment of the present invention, the condensation of compound of formula (III) with (XIII) is performed by using the activated derivative of formula (III) in the presence of a solvent selected from dichloromethane, ethyl acetate, tetrahydrofuran, aromatic hydrocarbon, acetone, dioxane, acetonitrile, DMAc, N,N-dimethylformamide, dialkylethers, water or mixtures thereof. The compound of formula (III) is activated as acid halides, mixed anhydrides, active esters, active amides. The acid halides are acid chlorides or acid bromides. The mixed anhydrides are anhydrides of the compounds of formula (III) with pivaloyl chloride, ethyl chloroformate, benzyl chloroformate. In yet another embodiment of the present invention the cyclisation of compound of (XIV) is carried out using solvents selected from water, tetrahydrofuran, acetone, acetonitrile, N,N-dimethylformamide, N,N-dimethylacetamide, dioxane, (C1-C3)alcohol and the like or mixtures thereof In still another embodiment of the present invention the deesterification of compound of formula (XV) is using anisole/trifluoroacetic acid, phenol/ trifluoroacetic acid, formic acid in the absence or presence of dichloromethane, dichloroethane as a solvent. In another embodiment of the present invention, the pharmaceutically acceptable salt is sodium or hydrochloride. In another embodiment of the present invention, the solvent used for reacting the compound of formula (XVI) in step (i) of scheme-5 is selected from tetrahydrofuran, acetone, acetonitrile, N,N-dimethyIformamide, N,N-dimethylacetamide, dioxane, (C1-C3)alcohol or mixtures thereof, in the presence of a base selected from sodium acetate, potassium carbonate, triethylamine, 1,4-diazabicyclo-[2,2,2]-octane (DABCO), l,5-diazabicyclo[4,3,0]-non-5-ene (DBN), l,8-diaza-bicyclo[5,4,0]-undec-7-ene(DBU), pyridine or sodium carbonate. In another embodiment of the present invention, the acylation of compound of formula (XVIII) in step (i) of scheme-6 is carried out in the presence of solvent selected from toluene, xylene, benzene, methylene dichloride, chloroform, ethyl acetate and the like. The esterification of compound of formula (XIX) in step (ii) of scheme -6 is carried out using esterifying agents such as diphenyl diazomethane, alkyl halide, p-methoxybenzyl chloride, p-nitrobenzyl chloride and a solvent selected from methylene dichloride, chloroform, ethyl acetate, toluene, water, tetrahydrofuran, acetone, acetonitrile, N,N-dimethylformamide, N,N-dimethylacetamide, dioxane, (Ci-C3)alcohol or mixtures thereof, in the presence of catalytic quantities of iodine. In another embodiment of the present invention, the solvent used for reaction in scheme-7 is selected from tetrahydrofuran, acetone, acetonitrile, N,N-dimethylformamide, N,N-dimethylacetamide, dioxane, (C1-C3)alcohol or mixtures thereof, in the presence of a base selected from sodium acetate, potassium carbonate, triethylamine, l,4-diazabicyclo-[2,2,2]-octane (DABCO), 1,5-diazabicyclo[4,3,0]-non-5-ene (DBN), l,8-diaza-bicyclo[5,4,0]-undec-7-ene(DBU), pyridine or sodium carbonate. The substituents on R1 in Scheme-3 are selected from methyl, methoxy, nitro or halogen atom. The present invention is provided by the examples below, which are provided by way of illustration only and should not be considered to limit the scope of the invention. EXAMPLE-1 Preparation of 7-phenylacetamido-3-[(fur-2-ylcarbonyl)thiomethyl] - 3- cepheiii-4-carboxylic acid p-methoxybenzylester Flask A : Acetone was charged and cooled to 10 °C, 7-phenylacetamido-3-chloromethyl - 3-cephem-4-carboxylic acid p-methoxybenzylester (100 g) was added. Sodium iodide (34.0 g) was added to it and mixture was stirred for 1-2 hr while temperature of the reaction mixture was maintained between 10-15 °C Flask B : Water(200 ml) was taken and cooled to 20 °C and sodium sulphide(35.0 g) was added at 20 °C. 2-Furoyl chloride (29.4 g) was added slowly drop wise into aqueous solution of sodium sulphide at 20 °C in 30 minutes. The reaction mixture was stirred at 20 °C for 1 hour added. Ethyl acetate(300 ml) was added and pH adjusted to 2-3 using 1:1 HCl [~50-60 ml] slowly. The organic layer was separated and dried over MgSO4 (10 g). The solution from flask A was transferred to flask B slowly at 10 °C. Sodium carbonate anhydrous (23.0 g) was added and mixture was stirred at 10 °C for 30 minutes. The reaction was monitored by HPLC. After completion of reaction, the inorganic salts were filtered. To the clear filtrate, excess of water (~1500 ml) was added and stirred at 10-15 °C. The solid separated out was filtered, washed with water and IPE. Yield = 110 g Purity(By HPLC) = 98% •H NMR - (DMSO-d6) 5 : 3.6(s, 2H, 2-CH2S), 3.7(s, 2H, PhCHj), 3.8(s, 3H, - OMe), 4.2(dd, 2H, -CH2), 5.1(d, IH, C6-H), 5.2(s, 2H, O-CH2-CO), 5.7(dd, IH, C7- H), 6.8(d,lH,H-4 furan), 7.2-7.4(m , 4H, Ar), 7.3(d, IH, H-3 furan), 8.0(d, IH, H-5 fiiran), 9.1(d, IH,-CONH). EXAMPLE-2 Preparation of 7-amino-3-[(fur-2-ylcarbonyl)thiomethyl]-3-cephein-4- carboxylic acid p-methoxy benzyl ester Flask - A : Dichloromethane(60 ml) was charged and cooled to -20°C. Phosphorous penta chloride(7.2 g) was added followed by POCl3(1.3 g) and the suspension was stirred for 15 minutes. Pyridine(7.0 g) was charged slowly at -30 to -40 °C. The solution of 7-phenylacetamido-3-[(fur-2-ylcarbonyl)thiomethyl]-3-cephem-4-carboxylic acid p-methoxy benzyl ester(10.0 g) in 40 ml of dichloromethane was slowly added to this mixture. The reaction mixture was stirred for 1.0 hour at -30 °C. Flask - B: In an another flask, methanol (200 ml) was taken and cooled to -40 °C and to this cooled methanol, solution from flask A was added in 1.0 hour by maintaining temperature at -10 to -15 °C. Solution becomes dark brown in color. Temperature was brought up to 0-10 °C. The reaction was monitored by HPLC for complete disappearance of starting material. After completion of reaction, dichloromethane and methanol were removed under reduced pressure. To the residue was added a mixture of water (70 ml) and ethyl acetate (70 ml). Organic layer was separated and washed with water (3 x 50 ml) and with brine solution (50 ml). The org. layer was dried with Na2SO4 and evaporated to yield the title compound. EXAMPLE-3 Preparation of 7-[(2-(syn)methoxyimino-3-oxo-4-chlorobutyrylaminol-3-[(fur- 2-ylcarbonyl)thiomethyI] - 3-cephem-4-carboxylic acid p-methoxy benzyl ester Flask - A: Dichloromethane(75 ml) was charged at room temperature, followed by 7-amino-3-[(fur-2-ylcarbonyl)thiomethyl]-3-cephem-4-carboxylic acid p-methoxy benzyl ester (15.0 g) and N,0- bis-(trimethylsilyl)acetamide (BSA) (100 g) drop wise at room temperature. The mixture was stirred at room temperature for 1 hour to get clear solution. Flask - B: 4-Chloro-3-oxo-methoxyimino-butyric acid(6.4 g) was dissolved in dichloromethane (75 ml) at room temperature The solution was cooled to -30 °C, PCI5 (7.4 g) was added portion wise at -30 °C and stirred at -30 °C for 30 minutes. The reaction mass in flask B at -30 °C was transferred into pre cooled silylated mixture in flask A. Mixture was stirred at -30 °C for 15-20 minutes and progress of the reaction was monitored by HPLC. After completion of reaction, water (75 ml) was added slowly at 10 °C. Organic layer was separated and washed again with water. IPE (200 ml) was added into organic layer at 10-20 °C to precipitate out the product. The solid was stirred at 20 °C, filtered, washed with excess of water and IPE. Yield = 12.0 g EXAMPLE-4 Preparation of 7-[(2-(syn)methoxyimino-3-oxo-4-bromobutyrylamino]-3-[(fur- 2-yIcarbonyI)thiomethyI] - 3-cephem-4-carboxyIic acid p-methoxybenzylester Flask - A: Dichloromethane(75 ml) was charged at room temperature, followed by the addition of 7-amino-3-[(fur-2-ylcarbonyl)thiomethyl]-3-cephem-4-carboxylic acid p-methoxy benzyl ester(15.0 g) and N,0-bis-(trimethylsilyl)acetamide (BSA) (100 g) drop wise at room temperature. The mixture was stirred at room temperature for 1 hour to get clear solution. Flask - B: 4-Bromo-3-oxo-methoxyimino-butyric acid (9.3 g) was dissolved in dichloromethane (75 ml) at room temperature The solution was cooled to -30 °C and PCI5 (7.4 g) was added portion wise at -30 °C. The mixture was stirred at -30 °C for 30 minutes. The reaction mass in flask B at -30 °C was transferred into pre cooled silylated mixture in flask A. The reaction mixture was stirred at -30 °C for 15-20 minutes and progress of the reaction was monitored by HPLC. After completion of reaction, water (75 ml) was added slowly at 10 °C. Organic layer was separated and washed again with water. IPE (200 ml) was added into organic layer at 10-20 °C to precipitate out the product. The solid was stirred at 20 °C, filtered, washed with excess of water and IPE. Yield = 12.0 g Purity = 98% EXAMPLE-5 Preparation of 7-[2-(2-aminothiazoI-4-yI)-2-methoxyiminoacetamdo]-3-[(fur- 2-ylcarbonyl)thiomethyl] - 3-cephem-4-carboxylic acid p-methoxy benzyl ester Tetrahydrofuran(50 ml) and water (50 ml) was charged into the reaction flask and to this 7-[(2-(syn)methoxyimino-3-oxo-4-chlorobutyrylamino]-3-[(fur-2- ylcarbonyl) thiomethyl]-3-cephem-4-carboxylic acid p-methoxybenzylester (10.0 g) was added at room temperature. Thiourea (2.0g) and sodium acetate (1.6 g) were added at room temperature. The reaction was monitored by HPLC and after completion of reaction, water (50 ml) and MDC (100 ml) were added to reaction mass. Organic layer was separated and washed with water (100 ml). Organic layer was added into IPE solvent (200 ml) at room temperature in 30 minutes, cooled to 10-20°C, filtered and washed with water (100 ml) and IPE (50 ml). Yield = 7.0 g Purity - 96% EXAMPLE-6 Preparation of Ceftiofur Sodium Dichloromethane(20 ml) was charged and cooled to 0-5 °C, 7-[2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamido]-3-[(fur-2-ylcarbonyl)thiomethyl]-3-cephem-4-carboxylic acid p-methoxy benzyl ester (6.5 g) was added followed by trifluoroacetic acid (20 ml) at 0-5 °C. The reaction mixture was stirred for 30-40 min. Anisole(12 ml) was also added at 5 °C and reaction was stirred at 5 °C for 1 hour, the reaction was checked by HPLC and after completion of reaction, water (100 ml) was added with stirring . The product was filtered and washed with water (100 ml) followed by dichloromethane (100 ml). The filtered solid was taken in tetrahydrofuran (100 ml) and dried over MgSO4. To the dried THF layer was added a solution of 5 g of 2-ethyl sodium hexanoate in THF(20 ml). The precipitated ceftiofur sodium was stirred for 30 minutes at 20°C filtered and washed with acetone(l00ml). Yield - 5.0g Purity - 99%. We claim: 1. A process for the preparation of cephalosporins of the formula (I) wherein R1 represents hydrogen, trityl, CH3, CRaRbCOORc where Ra and Rb independently represent hydrogen or methyl and Re represents hydrogen or (Cp C6)alkyl; R3 is carboxylate ion or COORd, where Rd represents hydrogen, esters which form a prodrug or a counter ion which forms a salt; R4 represents H, OCH3, which comprises: (i) condensing the activated derivative of the formula (III) where X represents halogen atom such as chlorine or bromine, with silylated derivative of 7-amino cephalosporin of the formula (XIII) wherein R represents lower alkyl, p-methoxybenzyl, p-nitrobenzyl or diphenylmethyl group in the presence of a solvent at a temperature in the range of -50 °C to 0 °C to produce a compound of formula (XIV), where R is as defined earlier, (ii) cyclising the compound of formula (XIV) with thiourea in the presence of solvent and sodium acetate at room temperature to produce cephalosporin compounds of the formula (XV) wherein R is as defined earlier , (iii) deesterifying the compound of formula (XV) using anisole/trifluoroacetic acid, phenol/ trifluoroacetic acid, formic acid in the presence or absence of a solvent at a temperature in the range of 0 °C to 10 °C to produce a compound of formula (I) and (iv) converting the compound of formula (I), to its pharmaceutically acceptable salt. 2. The process as claimed in claim 1, wherein said compound of formula (I) is a syn isomer. 3. The process as claimed in claim 1, wherein the condensation in step (i) is performed by using the activated compound of formula (III) in the presence of a solvent selected from dichloromethane, ethyl acetate, tetrahydrofuran, aromatic hydrocarbon, acetone, dioxane, acetonitrile, N,N-dimethylformamide, dialkylethers or mixtures thereof. 4. The process as claimed in claim 3, wherein the compound of formula (III) is activated as acid halides, mixed anhydrides, active esters or active amides. 5. The process of claim 4, wherein the acid halides used is acid chlorides or acid bromides. 6. The process as claimed in claim 4, wherein the mixed anhydrides used are anhydrides of the compounds of formula (III) with pivaloyl chloride, ethyl chloroformate or benzyl chloro formate. 7. The process as claimed in claim 1, wherein the cyclisation in step (ii) is carried out using a mixture of water and organic solvent selected from tetrahydrofuran, acetone, acetonitrile, N,N-dimethylformamide, N,N-dimethylacetamide, dioxane, (C1-C3)alcohol or mixtures thereof 8. The process as claimed in claim 1, wherein the deesterification in step (iii) is carried out in the absence or presence of dichloromethane or dichloroethane as a solvent.

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