Title of Invention	"A PROCESS FOR THE PREPARATION OF CEFPODOXIME ACID"
Abstract	The present invention relates to a cost effective and commercially viable process for the preparation of cefpodoxime acid at an industrial scale.

Full Text

The present invention relates to a cost effective and commercially viable process for the preparation of cefpodoxime acid at an industrial scale. Chemically, cefpodoxime acid is [(6R-[6α,7β(Z)]]-7-[2-(2-aminothiazol-4-yl)-2-. methoxyimino) acetamido]-3-cephem-4-carboxylic acid having Formula I, as shown in the accompanied drawings and is known from the US Patent No. 4,409,215. Although cefpodoxime acid is not suitable for oral administration, its ester derivatives, especially 1-(isoproxycarbonyloxyl)ethyl ester i.e. cefpodoxime proxetil of Formula II, as shown in the accompanied drawings, are valuable orally administered antibiotics characterized by high broad spectrum activity against gram positive and gram negative microorganisms. Cefpodoxime proxetil is an effective alternative to currently used β-lactams for emperical therapy in a wide range of community acquired infections in both adult and paediatric patients. Several general processes are known for the preparation of cephalosporin antibiotics viz., US 4,4409,215, US 5,109,131, GB 2012276 and WO 00/63214. However, attempts for extending these processes for preparing cefpodoxime acid at an industrial scale did not give desired results with respect to yield and quality. More particularly, the synthetic process comprising coupling of reactive acid derivative of compound of Formula III, as shown in the accompanied drawings, with reactive derivative of an open chain compound of Formula IV, as shown in the accompanied drawings, wherein X is a halogen selected from chloro, bromo and iodo, to get a compound of Formula V, as shown in the accompanied drawings, and its subsequent cyclization with thiourea to obtain cefpodoxime acid of Formula I was found to be unsatisfactory at a commercial scale. Processes cited in US 4,409,215-and GB 2012276 require protection at the carboxylic position of the compound of Formula III followed by the steps of coupling and cyclization as described above. The product obtained is then subjected to hydrolysis to get cefpodoxime acid. The additional steps of protection and deprotection result in low yields and cost escalation. The processes cited in WO 00/63214 and US 5,109,131 require formation of compound of Formula V as above and its subsequent cyclization with thiourea in a mixture of organic solvent and water to afford cefpodoxime acid. Cefpodoxime acid thus obtained is of poor quality and contains anti isomer of cepodoxime acid as a major impurity. Hence, none of the processes heretofore described are completely satisfactory for various reasons. The present invention provides a process for the preparation of cefpodoxime acid of Formula I, which process involves simple operations and gives good yields and high purity (99%) by HPLC. Cefpodoxime acid thus obtained gives cefpodoxime proxetil of very high purity and in high yield. In particular, the present invention provides A process for the preparation of cefpodoxime acid of Formula I as shown in the accompanied drawings, comprising (i) reacting a compound of Formula VI, as shown in the accompanied drawings, wherein R is hydrogen or a silyl group and R' is a silyl group or COOR1 is a carboxylic acid salt, with a compound of Formula IV, as shown in the accompanied drawings, or its acid halide, acid anhydride, mixed acid anhydride, reactive ester, reactive amide and the acid azide derivatives wherein X is a halogen, to obtain a compound of Formula VII as shown in the accompanied drawings, wherein X and R' are as defined above, desilylating or acidifying the compound of Formula VII to isolate the compound of formula V, as shown in the accompanied drawings, and reacting the compound of Formula V, with thiourea in aqueous medium in the presence of a weak base as described herein to obtain cefpodoxime acid of Formula I, as shown in the accompanied drawings. Cefpodoxime acid, so obtained may be converted into its ester such as cefpodoxime proxetil by the methods known in the art. According to another aspect of the present invention there is provided a process for the preparation of the intermediates of Formula V, wherein X is a halogen. The compounds of Formula V are not in the literature. Carboxylic acid salts of compound of Formula VI include salt with a metal such as sodium or potassium, or salt with an organic amine such as triethylamine, pyridine, diclyclohexylamine or N, N-dimethylaniline. R and R' in the compound of Formula VI may be silyl groups which may be the same or different. Suitable silyl groups are trialkyl silyl groups wherein the alkyl substitutents may be the same or different. Preferred alkyl substituents are methyl, ethyl, isopropyl and tert-butyl. Preferred silyl groups are trimethylsilyl and tert-butyldimethylsilyl. X in the compounds of Formula IV, V and VIII is a halogen selected from chloro, bromo and iodo. X is preferably bromo. Reactive acid derivatives of the compound of Formula IV include the acid halides, the acid anhydride, mixed acid anhydrides, reactive esters, reactive amides and the acid azide. Preferred mixed acid anhydrides include anhydrides with lower alkanoic acids such as pivalic acid, trichloroacetic acid or anhydride with a carbonic acid such as monomethylcarbonate. Preferred reactive esters include p-nitrophenylester, N-hydroxysuccinimido ester, N-hydroxyphthalimido ester, 2-mercaptobenzothioazolyl ester and 2-mercapto-5-methyl-1,3,4-thiadiazolyl ester. Among the reactive acid derivatives of Formula IV, acid halides are preferred. When the compound of Formula IV is employed in the form of a free acid, the reaction step (i) is carried out in the presence of a condensing agent such as dicylohexylcarbodiimide or a Vilsmier reagent which may be prepared for example from dimethylformamide and phosphorous oxychloride. Where a reactive derivative of the acid of Formula IV is employed, the use of such a condensing agent is not required, however, it may be desirable to carry out the reaction in the presence of a base which may be an alkali metal compound such as sodium bicarbonate, sodium carbonate and potassium carbonate or an organic amine such as triethylamine, lutidine and pyridine. The reaction of step (i) is usually conducted in a suitable solvent. When R, R' or both are silyl in the compound of Formula VI, suitable solvents for the reaction include halogenated hydrocarbons such as methylene chloride, hydrocarbons such as toluene, ethers such as tetrahydrofuran or polar solvents such as dimethylformamide, or a mixture thereof. When R is hydrogen and COOR1 is a carboxylic acid salt in the compound of Formula VI, suitable solvents for the reaction include methanol, ethanol, acetonitrile, dimethylformamide, water, or a mixture thereof. The starting compounds of Formula VI wherein R, R' or both are silyl may be obtained by silylating the corresponding 7-amino-3-methoxymethyl 3-cephem-4-' carboxylic acid of Formula III with a suitable silylating agent. Appropriate silylating agents include halosilanes such as trimethylsilylchloride (TMCS), dimethyldichlorosilane (DMDCS), silylated amides such as N, 0-bistrimethylsilyl acetamide (BSA), silazanes such as 1,1,1,3,3,3-hexamethyldisilazane (HMDS), silylated ureas such as N, N'-bis-(trimethylsilyl) urea (BSU), or a mixture thereof Where COOR' is a carboxylic acid salt in the compound of Formula VI, it may be obtained in a conventional manner, for example by treatment of compound of Formula III with a base such as sodium bicarbonate, triethylamine etc. Compounds of Formula III and IV may be obtained by methods known in the art. Desilylation (Step ii) of a compound of Formula VII (wherein R1 is a silyl group) may be carried out according to conventional methods such as treatment with methanol / water to isolate compound of Formula V. Isolation of the compound of Formula V is an important aspect of the process of our invention and instrumental in obtaining the compound of Formula I in high yields and good quality. The reactions of steps (i) and (ii) result in the formation of impurities alongwith the desired product which are automatically removed during the isolation of compound of Formula V. The reaction of a compound of Formula V with thiourea is carried out in the presence of a weak base such as sodium acetate and sodium bicarbonate in an aqueous medium comprising water and a water miscible organic solvent such as ethanol, methanol, isopropanol, acetone, tetrahydrofuran, acetonitrile, N, N-dimethylformamide or a mixture thereof. Compound of Formula V is added to aqueous solution of the weak base at a temperature of about 0 to 5°C. Thereafter, an aqueous solution of thiourea is added to the above mixture at a temperature of about 0 to 10°C. The reaction may then be carried out a temperature of about 0 to 60°C, preferably at 0-25°C, more preferably at 10-20°C. Cefpodoxime acid of purity 99% is obtained by washing the reaction mixture with ethyl acetate and acidifying the aqueous layer to a pH of about 2.5 to 3. However, the reaction of compound of Formula IV with thiourea is best carried out in water since a mixture of solvent and water may carryover impurities to the aqueous layer which may then precipitate along with the desired product. Also, lower yields are obtained as cefpodoxime acid is soluble in the water miscible solvents mentioned above. Cefpodoxime acid so obtained may be converted to cefpodoxime proxetil by methods known in the art such as reaction with 1-iodoethylisopropyl carbonate in the presence of 1,8-diazabicyclo [5.4.0] undec-7-ene (DBU) in N, N-dimethylformamide. In the following section a preferred embodiment is described by way of example to' illustrate the process of this invention. However, it is not intended in any way to limit the scope of the present invention. EXAMPLE Preparation of cefpodoxime acid (i) 7-[4-bromo-3-oxo-(Z)-2-methoxyiminobutyrylamino]-3-methoxymethyl-3-cephem-4-carboxylic acid Solution A Hexamethyldisilazane (73.9g) and acetamide (54.2g) were refluxed in dichloromethane (560ml) in the presence of a catalytic amount of imidazole. 7- amino-3-methoxymethyl-3-cephem-4-carboxylic acid (80.Og) was added to the resulting solution and refluxed for 1 hour to obtain almost a clear solution. Solution B Phosphorous pentachloride (66.2g) was added to a solution of 4-bromo-2-methoxyimino-3-oxobutyric acid (69.8g) in dichloromethane at about -20 to -10°C and stirred for about one hour. Solution A was added to solution B at about -70 to -50°C and further stirred at about -30 to -10°C for two hours. The reaction mixture was then poured into a mixture of water and methanol. The organic layer was separated, concentrated to about 240ml and toluene (800ml) was added to the concentrated mass to obtain the title compound (110g) after filtration and drying at 30°C. (ii) 7-[2-(aminothiazol-4-yl)-2-(Z)-methoxyiminoacetamido]-3-methoxymethyl-3-cephem-4-carboxylic acid 7-[4-bromo-3-oxo-(Z)-2-methoxyiminobutyrylamino]-3-methoxymethyl-3-cephem-4-carboxylic acid (90g)obtained from step (i) was added to a cold (2-5°C) solution of' sodium acetate (163.2g) in water (720ml). Thereafter, a solution of thiourea (18.3g) in water was added to it at 0-10°C. The mixture was stirred at 15-20°C for about two hours. Reaction mixture was then washed with ethyl acetate and pH of the aqueous layer was adjusted to about 2.5 - 3 to obtain cefpodoxime acid (70g; purity by HPLC = 99%) after filtration and drying at 45-50°C. Preparation of cefpodoxime proxetil 1-isopropoxycarbonyloxyethyl-7-[2-(2-aminothiazol-4-yl)-2-(Z)-methoxyiminoacetamido]-3-methoxymethyl-3-cephem-4-carboxylate 7-[2-(2-aminothiazol-4-yl)-2-(Z)-methoxyiminoacetamido]-3-methoxymethyl-3-cephem-4-carboxylic acid (50g) was dissolved in N, N-dimethylacetamide (300ml) and to this solution was added DBU (17.11g) at -10 to 0°C. lodoethylisopropyl carbonate (30.19g) was then added to the resulting mixture at the same temperature. The reaction was worked up after stirring for two hours at -10 to -5°C by addition of ethyl acetate and water. The organic layer was separated and successively washed with 0.2% aqueous hydrochloric acid solution, 1% aqueous sodium bicarbonate solution and finally 1% aqueous sodium thiosulfate solution. The organic layer was concentrated to about 200ml and the product precipiated with cyclohexane (1500ml). The product so obtained was purified by reprecipitation with methanol/water to obtain pure cefpodoxime proxetil (48g; purity by HPLC = 98%). WE CLAIM: 1. A process for the preparation of cefpodoxime acid of Formula I as shown in the accompanied drawings, comprising (i) reacting a compound of Formula VI, as shown in the accompanied drawings, wherein R is hydrogen or a silyl group and R' is a silyl group or COOR' is a carboxylic acid salt, with a compound of Formula IV, as shown in the accompanied drawings, or its acid halide, acid anhydride, mixed acid anhydride, reactive ester, reactive amide and the acid azide derivatives wherein X is a halogen, to obtain a compound of Formula VII as shown in the accompanied drawings, wherein X and R' are as defined above, desilylating or acidifying the compound of Formula VII to isolate the compound of formula V, as shown in the accompanied drawings, and reacting the compound of Formula V, with thiourea in aqueous medium in the presence of a weak base as described herein to obtain cefpodoxime acid of Formula I, as shown in the accompanied drawings. 2. The process of claim 1 wherein both R and R' are trimethylsilyl in the compound of Formula VI, as shown in the accompanied drawings. 3. The process of claim 1 wherein X is chloro or bromo in the compound of Formula IV. 4. The process of claim 1 wherein the reactive derivative of Formula IV is the acid chloride. 5. The process of claim 1 wherein the reaction of step (iii) is carried out in water alone. 6. The process of claim 1 wherein the reaction of step (iii) is carried out in the presence of sodium acetate or sodium bicarbonate as the weak base. 7. The process of claim 1 wherein in step (iii), compound of Formula V is added to an aqueous solution of sodium acetate or sodium bicarbonate at a temperature of about 0 to 5°C. 8. The process of claim 1 wherein in Step (iii) thiourea is added at a temperature of about 0 to 10°C. 9. The process of claim 1 wherein the reaction of step (iii) is performed at a temperature of about 10 to 20°C. 10.The process of claim 1 wherein cefpodoxime acid is isolated at a pH of about 2.5 to 3.0. 11. A process for preparation of cefpodoxime acid of Formula I as shown in the accompanied drawings as claimed in claim 1 for preparation of cefpodoxime proxetil of Formula II as shown in the accompanied drawing. 12.The process for the preparation of cefpodoxime acid of Formula I, as shown in the accompanied drawings, as herein described and exemplified by the example.

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