Indian Patents. 226007:A PROCESS FOR THE PREPARATION OF CEPHALOSPORIN ANTIBIOTIC

Title of Invention	A PROCESS FOR THE PREPARATION OF CEPHALOSPORIN ANTIBIOTIC
Abstract	The present invention relates to process for the preparation of Cephalosporing antibiotic of the formula (I).

Full Text	Field of the Invention The present invention relates to a novel amorphous hydrate of a cephalosporin antibiotic. More particularly, the present invention relates to novel amorphous monohydrate of cefdinir of the formula (I). The present invention also provides a process for the preparation of the novel amorphous monohydrate of cefdinir of formula (I). The present invention also provides new salts of compound of formula (XIV) and a process for the preparation of cefdinir using the new salts. Background of tlie Invention Cefdinir is a third generation cephalosporin antibiotic for oral administration and has a broader antibacterial spectrum over the general gram positive and gram negative bacteria, especially against StreptococcU than oth^r antibiotics for oral administration. In view of the vital antibiotic activities of cefdinir of the formula (I), various methods of preparation were reported. Cefdinir is for the first claimed in US patent No. 4,559,334 and the nature of the product that is disclosed in this patent is described as crystalline like amorphous in subsequent US patent (US 4,935,507). This patent also discloses a process for the preparation of cefcjinir as depicted in the i Scheme I. In the disclosed process, 7-amino-3-vinyl-3-cephem-4-carboxylic acid ester where R represents a conventional carboxy protecting group, is acylated with the reactive ester of haloacylacetic acid, which was converted to its oxirae, followed by cyclization with thiourea and deprotection of the ester group to afford cefdinir. The product obtained by the process described in examples 14 and 16 is approximately 80-85 % pure. The cyclization step suffers from poor yield and affords brownish color of the thiazole derivative, which subsequently affords cefdinir, but quality and yield were inferior. Further, owing to the fact that the expensive 7-amino-3"Vinyl-3-cephem-4-carboxylic acid is carried through four steps, cost of producing cefdinir is high. US patent number 4,935,507 claims the novel crystalline form of the cefdinir syn-isomer and a process for prepjiring the same. The X-ray crystallography data given in this is as given in the following table: The crystalline form (Crystal A) of US 4,935,507 is prepared from the syn-isomer prepared according to the procedures described in Examples 14 and 16 of US 4,559,334. In our US patent No. 6,388,070, we disclosed a process for preparing a compound of formula (VIII), wherein, Ri represents H, trityl, etc., R2 represents H, phenyl, etc., R3 represents CH3, CH=CH, etc., R4 is H or a salt or a carboxylic protecting group; R5 is H or trimethylsilyl; comprising acylating the compound of formula (VI) with compound of formula (VII) in the presence of an organic solvent, organic base and a silylating agent at a temperature in the range of -10 "^C to +30 °C. The reaction is shown in scheme II below : US patent No. 6,093,814 discloses a process for the preparation of cefdinir and its intermediate as represented in the Scheme III: In this process p-methoxybenzyl 7-amino-3-vinyl"3-cephem-4-carboxylate is condensed with 2-mercaptobenzothiazolyl (Z)-(2-aminO"4-thiazolyl)"2- (trityloxyimino)acetate in N,N-dimethyl acetamide, and the product obtained was treated with p-toluenesulfonic acid in the presence of a mixture of diethyl ether and methanol to get crystalline 7-[(2-amino-4-thiazoIyl)-"2-(Z)- (trityloxyimino)acetamido]-3-vinyl-3-cephem-4-carboxylic acid.pTSA.2DMAc solvate. This process utilizes highly volatile, low-boiling and therefore industrially-not-preferred solvent, diethyl ether, for crystallizing out the above solvate. In addition, the quantity of the low-boiling solvent used is also very high ranging from 60-100 volumes, thereby adding "hazard to the operations. Added to this is the fact that the recovery of these solvents from their mixture is not Istraight-forward. US patent No. 6,350,869 discloses the purihcapon of impure cefdinir through the preparation of N,N-dicyclohexylamine salt of 7-[2-amino-4-thiazolyl-2-(z)-hydroxyimino acetamido]-3-vinyl-3-cephem-4-carboxylic acid and subsequent hydrolysis to get pure cefdinir. This process requires jhe preparation of crude i . ifdinir, conversion to N,N-dicyclohexylamine salt and then hydrolysis of the salt to get pure cefdinir, and therefore the overall yield is not attractive. US patent No. 6,350,869 also emphasizes that cefdinir is unstable in the presence of other amines, with which, it gets heavily degraded. In addition, Yoshihiko Okamoto et al. (J. Pharm. Sci. Vol. 8S(9), 976, 1996) report that cefdinir may be unstable under basic environment. Crystalline cefdinir has limitations in formulation development as it cannot be developed into tablets. Considering the foregoing limitations, we undertook an investigation in our lab to develop a product which is easy to handle and convenient to develop a dosage which is easily absorbable. We also parellely undertook an investigation to identify a process, which involves (i) less number of steps, (ii) the direct isolation of cefdinir, with out the need to prepare crude cefdinir in an additional step. This would permit commercializing the production of high-pure cefdinir with industrial-friendly solvent, which can further be recovered for recycling. Objectives of the Invention The main objective of the present invention is to provide a novel amorphous monohydrate of cefdinir which has very good bioavailability and useful in developing different dosage forms. Another objective of the present invention is to pr9vide a commercially viable process for the preparation novel amorphous monohydjrate of cefdinir of the i formula (I), which would be easy to implement on manufacturing scale. Yet another objective of the present invention is to provide new salts of formula (XIV), which are insoluble and stable throughout thej process of producing I the cefdinir and a process for the preparation of cefdinir using these new salts. Summary of the Invention Accordingly, the present invention provides a novel amorphous monohydrate of cefdinir of the formula (I) The present invention also provides a process for the preparation of novel amorphous monohydrate of cefdinir of the formula (I), which comprises the steps of: i) condensing 7-amino-3-cephem-4-carboxylic acid of the formula (XII) with compound of the formula (XIII) wherein X represents an activating group in the presence of a tertiary amine and an organic solvent, followed by treatment with a base to produce a salt of compound formula (XIV), wherein M^ is a counter ion, ii) deprotecting the compound of formula (XIV) to produce compound of formula (XV) wherein M^ is a counter ion in the presence of an organic solvent and a base at a temperature in the range of room temperature to 80 °C and iii) hydrolyzing the compound of the formula (XV) using an acid at low temperatures in the range of -^0 to 0 ^C in the presence of an organic solvent to produce novel amorphous monohydrate of cefdinir of the formula (I). The reaction is shown in scheme-IV below : Description of Figures Figure 1 : Comparison of powder XRD pattern of the sample prepared according to US 4,935,507 and the sample prepared according to example 1 and example 2, Detailed description of the invention In an embodiment of the present invention, the activation group represented by X is selected from ester, thioester, halogen atom such as chlorine, bromine, propyl, iso-propyl, n-butyl or iso-butyl or a phenyl group; Alki group represents (Cp C4)alkyl group such as methyl, ethyl, n-propyl, iso-propyl, n-butyl or iso-butyl. i In an embodiment of the present invention, the counter ion represented by M is selected from sodium, potassium, lithium, magnesium, ammonium, dicyclohexylamine, N,N'-dibenzylethylenediamine, l,8-diazabicyclo(5.4.0)undec-7-ene (DBU), 1,5-diazabicyclo(4.3.0)non-5-ene, N,N'-diphenylethylenediamine, l,4-dizabicyclo(2.2.2)octane, N,N-diisopropylethylamine, N,N-diisopropylamine and the like. In an another embodiment of the present invention, the tertiary amine used in step (i) is selected from triethylamine, N-methylpiperidine, N,N-diisopropylethylamine, trimethylamine and the like. In yet another embodiment of the present invention, the organic solvent used in step (i) is selected from ethanol, methanol, isopropanol, THF, cyclohexanol, acetone, butan-2-one, acetonitrile, DMAc, water or a mixture thereof. In yet another embodiment of the present invention, the base used in step (i) and step (ii) is selected from sodium hydroxide, sodium acetate, sodium 2-ethyl hexanoate, potassium hydroxide, ammonium hydroxide^ ammonium acetate, calcium hydroxide, dicyclohexyl amine, N,N'-dibenzylethylenediamine diacetate, l,8-diazabicyclo(5.4.0)undec-7-ene (DBU), l,5-diazabicyclo(4.3.0)non-5-ene, N,N'-diphenylethylenediamine, l,4-dizabicyclo(2.2.^)octane, N,N- diisopropylethylamine, N,N-diisopropylamine, and the like. In yet another embodiment of the present invention, the organic solvent used in step (ii) is selected from acetone, 2-butanone, methanoj, isopropanol, ethanol, THF, acetonitrile, DMAc, water and the like or mixtures thereof. In another embodiment of the present invention, the acid employed in step (iii) is selected from HCl, sulfuric acid, formic acid, acetic acid, aromatic/aliphatic sulfonic acids such as benzenesulfonic acid, p-toluenesulfonic acid, naphthalenesulfonic acid, methanesulfonic acid, triflic acid, and the like. In yet another embodiment of the present invention, the organic solvent used in step (iii) is selected from acetone, 2-butanone, methanol, isopropanol, ethanol, THF, acetonitrile, DMAc, water and the like or mixtures thereof. In yet another embodiment of the present invention, the compound of formula (I) obtained is a syn isomer. The present invention is based on the observation that rapid cooling of the aqueous solvent solution of cefdinir to low temperatures and adding the acid rapidly produces amorphous cefdinir. The technique can be achieved either by cooling the aqueous solvent solution to low temperatures and adding the acid rapidly to adjust the pH to precipitate the amorphous product or adding the acid to adjust the pH and rapidly cooling the resultant solution to precipitate the amorphous product. In yet another embodiment of the present invention, the hydrolysis in step (iii) is carried out by cooling the aqueous solvent solution to low temperatures and adding the acid rapidly to adjust the pH to precipitate the amorphous cefdinir. In yet another embodiment of the present invention, the hydrolysis in step (iii) is carried out by adding the acid to adjust the pH and rapidly cooling the resultant solution to precipitate the amorphous cefdinir. The foregoing technique has been found to be markedly attractive, both from commercial point of view, as well as from manufacturing viewpoint and affords good quality of amorphous cefdinir of the formula (I). Many other beneficial results can be obtained by applying disclosed invention in a different manner or by modifying the invention with the scope of disclosure. The present invention is illustrated with the following examples, which should not be construed as limiting to the scope of the invention. Example 1 Step (n Preparation of (2-mercapto-5-phenyH,3,4-oxadiazolyl)-(Z)-2-(2-amino-4-thiazolyl)-2-(trityloxyimino)acetate To an ice-cold suspension of (Z)-(2-amino-4-thiazolyl)-2-(trityloxyimino)acetic acid (25 gm) in tetrahydrofuran (200 ml), triethylamine (10 gm) was added dropwise over 10 minutes at 0-5 °C. Bis-(2-oxo-oxazolidinyl)phosphinic chloride (15.4 gm) was added and stirred for one hour at 0-5 °C. To the reaction mixture 2-mercapto-5-phenyl-l,3,4-oxadiazole (9.8 gm) and triethylamine (5.0 gm) was added dropwise over 15 minutes and stirred at 0-5 °C for 6-7 hours. After completion of reaction, chilled water (500 ml) was added at 10-20 °C in 30 - 40 minutes and stirred at 20 °C for 2 hours. Then the slurry was cooled to 5-10 ^C and stirred at this temperature for 45 minutes. The product thus obtained was filtered washed with water (100 ml) and dried at 30-35 °C for 4-5 hours to yield the title compound (50 gm, water content is 40%). Step (in Preparation of potassium (Z)-7p-[2-(2-amiiio-4-tliiazolyl)-2-(trity!oxyimino) acetamidol-3-viiiyl-3-cepliem-4-carboxylate To a chilled suspension of 7-amino-3-vinyl-3-cephem-4-carboxylic acid (25 gm) and (2-mercapto-5-phenyl-1,3,4-oxadiazolyl)-(Z)-(2-amino-4-thiazolyl)-2- (trityloxyimino)acetate (155 gm, water content is 40 %) in N,]K-dimethylacetamide (150 ml), triethylamine (23 gm) was added drop-wise at 10±2 °C over 30-45 minutes and the resulting mixture was stirred at 20±2 °C for 6-8 hours. The reaction was monitored by HPLC. After completion of the reaction, tetrahydrofuran (125 ml), 10% sodium chloride solution (250 ml) and ethyl acetate ,(250 ml) were added at 25 °C and stirred for 20 min. The aqueous layer was separated and washed with ethyl acetate (250 ml). To the aqueous layer, ethyl acetate (500 ml) was added, cooled to 10 - 15 °C, and the pH was adjusted to 2.8-3.0 by 1:1 HCl in 30 min. The layers were separated and to the ethylacetate layer, 12 % (w/v) methanolic potassium hydroxide solution (60 ml) was added dropwise in 30 min at 25 °C, and stirred for 45 min. The resulting slurry was filtered, washed with ethyl acetate (150 ml) followed by acetone (150 ml) and dried at 30-35 °C under vacuum to obtain the title compound (45 gm, HPLC Purity >99.0%). Step (iii) Preparation of ammonium (Z)-7P-[2-(2-amino-4-tliiazolyl)-2-( hydroxyimino)acetamido]-3-vinyl-3-cepliem-4-carboxylate To a clear solution of potassium (Z)-7P-[2-(2-amino-4-thiazolyl)-2-(trityloxyimino)acetamido]-3-vinyl-3-cephem-4-carboxylate (250 gm) in aqueous acetonitrile (625 ml, 2:3), a solution of trimethylchlorosilane (94 gm) in acetonitrile (125 ml) was added drop wise at 60-65 °C and the temperature was maintained at 65-68 °C for 33 minutes. Chilled acetone (2000 ml) having temperature -10 °C was added to the reaction mixture to reduce the temperature to 30 - 35 ^C. A methanoHc solution of ammonium acetate (93 gm, 100 ml) was added drop wise while cooling. The resulting mixture was diluted with acetone (3000 ml), cooled to 10 °C and stirred for 30 minutes at 10 ± 2 ^C. The crystals thus obtained were filtered, washed with acetone and dried at 40-45 °C under vacuum to get anunonium (Z)-7p-[2-(2-amino-4-thiazolyl)-2-(hydroxyimino)acetamido]-3-vinyl-3-cephem-4-carboxylate (207 gm, HPLC quality 94.9 %). i Step (iv) i Preparation of (Z)-7p-[2-(2-araino-4-tliiazolyl)-2-(hydroxyimino)acetamidol-3- vinyl-3-cephem-4-carboxylic acid in amorphous hydrate form Ammonium (Z)-7p-[2-(2-amino-4-thiazolyl)-2-(hydroxyimino)acetamido]-3-vinyl-3-cephem-4-carboxylate (20 gm) was added to a mixture o:' water (250 ml) and acetone (80 ml) and warmed to 33-35 ^C. This aqueous solution was treated with activated charcoal and EDTA at 35 'C for 40 minutes. The carbon was filtered and the carbon bed was washed with water (70 ml) This aqueous acetone solution was cooled to -30 °C and a (10 %) solution of aqueous sulphuric acid was added rapidly, stirred for 30 minutes and warmed to 0-2 °C. The product thus obtained was filtered at 0-2 °C, washed with cold-water (100 ml) and dried at 40-45 "^C under vacuum for 5-6 hours to get (Z)-7p-[2-(2-amino-4-thia2olyl)-2-(hydrox)dmino)acetamido]-3-vinyl-3-cephem-4-carboxylic acid (6.0 gm, HPLC quality 89.0 %, water content 4-5 %). Example 2 Step (i) Preparation of potassium (Z)-7p-[2-(2-amino-4-thiazolyI)-2-(trityloxyimino) acetamido]-3-viny!-3-cephem-4-carboxylate To a chilled suspension of 7-amino-3-vinyl-3-cephem-4-carbQxylic acid (5 gm) and (2-mercapto-5-phenyl-l,3,4-oxadiazolyl)-(Z)-(2-ainino-4-thia:?olyl)-2-(trityloxyimino)acetate (24.2 gm) prepared according to the procedure given in example (1) step (i) in tetrahydrofuran (40 ml) and water (5 ml), triethylamine (4.6 gm) was added drop-wise at 20±2 °C over 10-15 minutes and the resulting mixture was stirred at 30±2 °C for 6-8 hours. The progress of the reaction was monitored by HPLC. After completion of reaction, ethylacetate (100 ml) and water (75 ml) were added at 30±2 °C and stirred for 20 min. The aqueous layer was separated and washed with ethyl acetate (75 ml). To the aqueous layer, ethylacetate (150 ml) was added, cooled to 10 - 15 ^C, and the pH was adjusted to 2.8-3.0 by 1:1 HCl solution in 25-30 min. To the separated ethylacetate layer, acetone (5C ml) and a methanolic potassium hydroxide solution (7.5 % w/v, 20 ml) were added dropwise in 25-30 min at 25 -27 "^C and stirred for further 45 min. The resulting slurry was filtered, washed with acetone (2 X 25 ml) and dried at 30-35 "^C under vacuum to obtain the title compound (5.0 gm, HPLC Purity >99.0 %). Step (ii) Preparation of ammonium (Z)-7P-[2-(2-amino-4-tiiiazolyl)-2- (liydroxyimino)acetamido]-3-vinyl-3-cephem-4-carboxylate To a clear solution of potassium (Z)-7P-[2-(2-amino-4-thiazolyl)-2-(trityloxyimino)acetamido]-3-vinyl-3-cephem-4-carboxylate (250 gm) in aqueous acetonitrile (625 ml, 2:3), a solution of trimethylchlorosilane (94 gm) in acetonitrile (125 ml) was added drop wise at 60-65 ^C. and the temperature was maintained at 65-68 °C for 33 minutes. Chilled acetone (2000 ml) having temperature -10 ^C was added to the reaction mixture to reduce the temperature to 30 - 35 °C. A methanolic solution of ammonium acetate (93 gm, 100 ml) was added drop wise while cooling. The resulting mixture was diluted with acetone (3000 ml), cooled to 10 °C and stirred for 30 minutes at 10 ± 2 °C. The crystals thus obtained were filtered, washed with acetone and dried at 40-45 °C under vacuum to get ammonium (Z)-7p-[2-(2-amino-4-thiazolyl)-2-(hydroxyimino)acetamido]-3-vinyl-3-cephem-4-carboxylate (207 gm, HPLC quality 94.9 %). Step (iii) Preparation of (Z)-7P-[2-(2-amino-4-thiazolyl)-2-(liydroxyimino)acetamido]-3- vinyl-3"Cepliem-4-carboxylic acid in amorplious hydrate forpi Ammonium (Z)-7P-[2-(2-amino-4-thiazolyl)-2-(hydroxyimino)acetamido]-3-vinyl-3-cephem-4-carboxylate (20 gm) was added to a mixture of water (250 ml) and acetone (80 ml) and warmed to 33-35 ^C. This aqueous solution was treated with activated charcoal and EDTA at 35 °C for 40 minutes. The carbon was filtered and the carbon bed was washed with water (70 ml). The pH of tlpis aqueous acetone solution was adjusted to 0.6 at 33-35 °C using a (10 %) solution of aqueous sulphuric acid. This solution was cooled rapidly to -10 °C and stirred for 30 minutes. The product thus obtained was filtered at -10 °C, washed with cold-water (100 ml) and dried at 40-45 'C under vacuum for 5-6 hours to get (Z)-7p-[2-(2-amino-4-thiazolyl)-2-(hydroxyimino)acetamido]-3-vinyl-3-cephem-4-carboxylic acid (6.0 gm, HPLC quality 93.0 %, water content 4-5 %). Example 3 Step (i) Preparation of potassium (Z)-7P-[2-(2-amino-4-thiazolyl)-2-(trityloxyimino) acetaraido]-3-vinyl-3-cephem-4-carboxylate To a well stirred suspension of 7-amino-3-vinyl-3-cephem-4-carboxylic acid (50 gm) and (2-mercaptobenzothiazolyl)-(Z)-2-(2-amino-4-thiazolyl)-2- (trityloxyimino)acetate (130 gm) in aqueous tetrahydrofuran solution (450 ml, 1:8), triethylamine (45 gm) was added drop wise at 25-30 °C and the resultant reaction mixture was stirred at 25-30 ^C for 4-5 hours. After completion of reaction, water (1200 ml) and ethylacetate (1000 ml) were added, cooled to 20-25 °C and pH was adjusted to 2.0 to 2.3 by dilute hydrochloric acid (1:1, « 82 ml) over 20 minutes. Ethylacetate layer was separated and the aqueous layer was extracted twice with ethylacetate (2 x 200 ml). The coipbined ethylacetate layer was treated with 15% brine solution. A methanolic potassium hydroxide solution (15 gm in 60 ml) was added dropwise to the clear ethylacetate solution at 25 to ^0 °C, To the reaction i mass, isopropyl ether (1000 ml) was added dropwise and stinted for 30 minutes. The product thus obtained was filtered, washed with isopropyl et\|ier (200 ml) and dried i at 45 "^C under vacuum to get potassium (Z)-7p-[2-(2-amino-4-thiazolyl)-2-(trityloxyimino)acetamido]-3-vinyl-3-cephem-4-carboxylate (167.5 gm, HPLC quality 93.6 % water content 8.1 % and assay 88-89 %). step (in Preparation of ammonium (Z)-7P-[2-(2-amino-4-thiazolyl)-2- (hydroxyimino)acetamido]-3-vinyl-3-cephem-4-carboxylate To a clear solution of potassium (Z)-7P-[2-(2-amino-4-thiazolyl)-2-(trityloxyimino)acetamido]-3-vinyl-3-cephem-4-carboxylate (250 gm) in aqueous acetonitrile (625 ml, 2:3), a solution of trimethylchlorosilane (94 gm) in acetonitrile (125 ml) was added drop wise at 60-65 °C, and the temperature was maintained at 65-68 'C for 33 minutes. Chilled acetone (2000 ml) having temperature -10 ""C was added to the reaction mixture to reduce the temperature to 30 - 35 °C. A methanolic solution of ammonium acetate (93 gm, 100 ml) was added drop wise while cooling. The resulting mixture was diluted with acetone (3000 ml), cooled to 10 °C and stirred for 30 minutes at 10 ± 2 °C. The crystals thus obtained were filtered, washed with acetone and dried at 40-45 °C under vacuum to get ammonium (Z)-7p-[2-(2-amino-4-thiazolyl)-2-(hydroxyimino)acetamido]-3-vinyl-3-cephem-4-carboxylate (207 gm, HPLC quality 94.9 %). Step (iii) Preparation of (Z)-7P-[2-(2-amino-4-tliiazolyI)-2-(hydroxyimino)acetamido]-3- vinyl-3-cephem-4-carboxylic acid ^ in amorplious hydrate form Anmionium (Z)-7P-[2-(2-amino-4-thiazolyl)-2-(hydroxyimiiio)acetamido]-3-vinyl-3-cephem-4-carboxylate (20 gm) was added to a mixture of water (250 ml) and acetone (80 ml) and warmed to 33-35 "^C. This aqueous solfition was treated with activated charcoal and EDTA at 35 °C for 40 minutes. The cjarbon was filtered and the carbon bed was washed with water (70 ml). The pH oi' this aqueous acetone solution was adjusted to 0.6 at 33-35 °C using a (10 %) solution of aqueous sulphuric acid. This solution was cooled rapidly to -10 ^C and stirred for 30 minutes. The product thus obtained was filtered at -10 °C, washed with cold-water (100 ml) and dried at 40-45 °C under vacuum for 5-6 hours to get (Z)-7p-[2-(2-amino-4-thiazolyl)-2-(hydroxyimino)acetamido]-3-vinyl-3-cephem'4-carboxylic acid (6.0 gm, HPLC quality 93.0 %, water content 4-5 %). Example 4 Step (i) Preparation of potassium (Z)-7P-[2-(2-amino-44hiazolyl)-2-(trityloxyimino) acetamido]-3-vinyl-3-cephem-4-carboxylate To a well stirred suspension of 7-amino-3-vinyl-3-cephem-4-carboxylic acid (50 gm) and (2-mercaptobenzothiazolyl)-(Z)-2-(2-amino-4-thiazolyl)-2- (trityloxyimino)acetate (130 gm) in aqueous tetrahydrofuran solution (450 ml, 1:8), triethylamine (45 gm) was added drop wise at 25-30 °C and the resultant reaction mixture was stirred at 25-30 °C for 4-5 hours. After completion of reaction, water (1200 ml) and ethylacetate (1000 ml) were added, cooled to 20-25 °C and pH was adjusted to 2.0 to 2.3 by dilute hydrochloric acid (1:1, « 82 ml) over 20 minutes. Ethylacetate layer was separated and the aqueous layer was extracted twice with ethylacetate (2 x 200 ml). The combined ethylacetate layer was treated with 15% brine solution, A methanolic potassium hydroxide solution (15 gm in 60 ml) was added dropwise to the clear ethylacetate solution at 25 to 30 °C. To the reaction Li I mass, isopropyl ether (1000 ml) was added dropwise and stirre i product thus obtained was filtered, washed with isopropyl ether (200 ml) and dried at 45 °C under vacuum to get potassium (Z)-7p-[2-(2-^mino-4-thiazolyl)-2-(trityloxyimino)acetamido]-3-vinyl-3-cephem-4-carboxylate j (167.5 gm, HPLC quality 93.6 % water content 8.1 % and assay 88-89 %). i step (in Preparation of ammonium (Z)-'7P-[2-(2-amino-4-ttiiazolyl)-2- (Iiy(iroxyimino)acetamido]-3-vinyl-3-cepbem-4-carboxylate To a clear solution of potassium (Z)-7p-[2-(2-amino-4-thiazolyl)-2"(trityloxyimino) acetamido]-3-vinyl-3-cephem-4-carboxyIate (100.0 gm) in an aqueous acetonitrile (240 ml, 1:5), aqueous solution of hydrochloric acid (62 gm) was added dropwise at 60-65 °C and the temperature was maintained at 65-68 °C for 33 minutes. Chilled acetone (800 ml) having temperature -10 °C was added to the reaction mixture to reduce the temperature to 30 - 35 °C. A solution of ammonium acetate (37.2 gm) in methanol (40 ml) was added dropwise. The resulting mixture was diluted with acetone (1200 ml), cooled to 10 °C and stirred for 30 minutes at 10 ± 2 °C. The product thus obtained was filtered, washed with acetone and dried at 40-45 °C under vacuum to get ammonium (Z)-7p-[2-(2-amino-4-thiazolyl)-2-(hydroxyimino)acetamido]-3-vinyl-3-cephem-4-carboxylate [80.5 gm, HPLC quality 95.45%], Step (iii) Preparation of (Z)-7p-[2-(2-amino-4-thiazolyl)-'2-(hydroxyimino)acetamido]-3- vinyl-3-cepliera-4-carboxylic acid in amorphous hydrate form Ammonium (Z)-7(3-[2-(2-amino-4-thia2olyl)-2-(hydroxyimino)acetamido]-3-vinyl-3-cephem-4-carboxylate (20 gm) was added to a mixture of water (250 ml) and acetone (80 ml) and warmed to 33-35 °C. This aqueous soliftion was treated with activated charcoal and EDTA at 35 ^C for 40 minutes. The cpbon was filtered and ! [ the carbon bed was washed with water (70 ml). The pH ofj this aqueous acetone solution was adjusted to 0.6 at 33-35 "^C using a (10 %j solution of aqueous sulphuric acid. This solution was cooled rapidly to -10 "^C and stirred for 30 minutes. The product thus obtained was filtered at -10 ^C, washed with cold-water (100 ml) and dried at 40-45 °C under vacuum for 5-6 hours to get (Z)-7p-[2-(2-amino-4-thiazolyl)-2-(hydroxyimino)acetamido]-3-vinyl-3~cephem-4-carboxylic acid (6.0 gm, HPLC quality 93.0 %, water content 4-5 %). We claim: 1. Novel amorphous monohydrate of cefdinir of the foraiula (I). 2. A process for the preparation of novel amorphous monohydrate of cefdinir of the formula (I) which comprises the steps of: i) condensing 7-amino-3-cephem-4-carboxylic acid of the formula (XII) with compound of the formula (XIII) wherein X represents an activating group in the presence of a tertiary amine and an organic solvent, followed by treatment with a base to produce a salt of compound i formula (XIV), : wherein M"" is a counter ion, ii) deprotecting the compound of formula (XIV) to produce compound of formula (XV) wherein M"^ is a counter ion in the presence of an organic solvent and a base at a temperature in the range of room temperature to 80 ^C and iii) hydrolyzing the compound of the formula (XV) using an acid at low temperatures in the range of -40 to 0 'C in the presence of an organic solvent to produce novel amorphous monohydrate of cefdinir of the formula (I). 3. The process as claimed in claim 2, wherein the activation group represented by X is selected from ester, thioester, halogen atom such as chlorine, bromine, ^^^ , where R^ represents (CrC4)alkyl group [such as methyl, ethyl, n- propyl, iso-propyl, n-butyl or iso-butyl or a phenyl group; ^Ik group represents (Cp C4)alkyl group such as methyl, ethyl, n-propyl, iso-propyl, ji-butyl or iso-butyl. 4. The process as claimed in claim 2, wherein the counter ion represented by M is selected from sodium, potassium, lithium, magnesium, ammonium, dicyclohexylamine, N,N'-dibenzylethylenediamine, l,8-diazabicyclo(5.4.0)undec-7-ene (DBU), l,5-diazabicyclo(4.3.0)non-5-ene, N,N*-diphenylethylenediamine, l,4-dizabicyclo(2.2.2)octane, N,N-diisopropylethylamine or N,N-diisopropylamine. 5. The process as claimed in claim 2, wherein the tertiary amine used in step (i) is selected from triethylamine, N-methylpiperidine, N,N-diisopropylethylamine or trimethylamine. 6. The process as claimed in claim 2, wherein the organic solvent used in step (i) is selected from ethanol, methanol, isopropanol, THF, cyclohexanol, acetone, butan-2-one, acetonitrile, DMAc, water or a mixture thereof. 7. The process as claimed in claim 2, wherein the base used in step (i) is selected from sodium hydroxide, sodium acet&te, sodium 2-ethyl hexanoate, potassium hydroxide, ammonium hydroxide, ammonium acetate, calcium hydroxide, dicyclohexyl amine, N,N'-dibenzylethylenediamine diacetate, 1,8-diazabicyclo(5.4.0)undec-7-ene (DBU), l,5-diazabicyclo(4.3.0)non-5-ene, N,N'-diphenylethylenediamine, 1,4-dizabicyclo(2.2.2)octane, N,N-diisopropylethylamine or N,N-diisopropylamine. 8. The process as claimed in claim 2, wherein the base employed in step (ii) is selected from sodium hydroxide, sodium acetate, sodium 2-ethyl hexanoate, potassium hydroxide, ammonium 'hydroxide, ammonium\ acetate, calcium hydroxide, dicyclohexyl amine, N,N'-dibenzylethylenediamine diacetate, 1,8-diazabicyclo(5.4.0)undec-7-ene (DBU), l,5-diazabicyclo(4.3.())non-5-ene, N,N'- ! diphenylethylenediamine, 1,4-dizabicyclo(2,2.2)octane, N,N-diisopropylethylamine or N,N-diisopropylamine. 9. The process as claimed in claim 2, wherein the organic solvent used in step (ii) is selected from acetone, 2-butanone, methanol, isopropanol, ethanol, THF, acetonitrile, DMAc, water or mixtures thereof. 10. The process as claimed in claim 2, wherein the hydrolysis in step (iii) is carried out by cooling the aqueous solvent solution to low temperatures and adding the acid rapidly to adjust the pH to precipitate the amorphous cefdinir. 11. The process as claimed in claim 2, wherein the hydrolysis in step (iii) is carried out by adding the acid to adjust the pH and rapidly cooling the resultant solution to precipitate the amorphous cefdinir. 12. The process as claimed in claim 2, wherein the acid employed in step (iii) is selected from HCl, sulfuric acid, formic acid, acetic acid, benzenesulfonic acid, p- toluenesulfonic acid, naphthalenesulfonic acid, methanesulfonic acid or triflic acid. 13. The process as claimed in claim 2, wherein the organic solvent used in step (iii) is selected from acetone, 2-butanone, methanol, isopropanol, ethanol, THF, acetonitrile, DMAc, water or mixtures thereof. 14. The process as claimed in claim 2, wherein the compound of formula (I) obtained is a syn isomer.

Full Text

Field of the Invention
The present invention relates to a novel amorphous hydrate of a cephalosporin antibiotic. More particularly, the present invention relates to novel amorphous monohydrate of cefdinir of the formula (I).

The present invention also provides a process for the preparation of the novel amorphous monohydrate of cefdinir of formula (I).
The present invention also provides new salts of compound of formula (XIV) and a process for the preparation of cefdinir using the new salts.
Background of tlie Invention
Cefdinir is a third generation cephalosporin antibiotic for oral administration and has a broader antibacterial spectrum over the general gram positive and gram negative bacteria, especially against StreptococcU than oth^r antibiotics for oral administration.
In view of the vital antibiotic activities of cefdinir of the formula (I), various
methods of preparation were reported. Cefdinir is for the first claimed in US patent
No. 4,559,334 and the nature of the product that is disclosed in this patent is
described as crystalline like amorphous in subsequent US patent (US 4,935,507).
This patent also discloses a process for the preparation of cefcjinir as depicted in the
i Scheme I.

In the disclosed process, 7-amino-3-vinyl-3-cephem-4-carboxylic acid ester where R represents a conventional carboxy protecting group, is acylated with the reactive ester of haloacylacetic acid, which was converted to its oxirae, followed by cyclization with thiourea and deprotection of the ester group to afford cefdinir. The product obtained by the process described in examples 14 and 16 is approximately 80-85 % pure. The cyclization step suffers from poor yield and affords brownish color of the thiazole derivative, which subsequently affords cefdinir, but quality and yield were inferior. Further, owing to the fact that the expensive 7-amino-3"Vinyl-3-cephem-4-carboxylic acid is carried through four steps, cost of producing cefdinir is high.
US patent number 4,935,507 claims the novel crystalline form of the cefdinir syn-isomer and a process for prepjiring the same. The X-ray crystallography data given in this is as given in the following table:

The crystalline form (Crystal A) of US 4,935,507 is prepared from the syn-isomer prepared according to the procedures described in Examples 14 and 16 of US 4,559,334.
In our US patent No. 6,388,070, we disclosed a process for preparing a compound of formula (VIII), wherein, Ri represents H, trityl, etc., R2 represents H, phenyl, etc., R3 represents CH3, CH=CH, etc., R4 is H or a salt or a carboxylic protecting group; R5 is H or trimethylsilyl; comprising acylating the compound of formula (VI) with compound of formula (VII) in the presence of an organic solvent, organic base and a silylating agent at a temperature in the range of -10 "^C to +30 °C. The reaction is shown in scheme II below :

US patent No. 6,093,814 discloses a process for the preparation of cefdinir and its intermediate as represented in the Scheme III:

In this process p-methoxybenzyl 7-amino-3-vinyl"3-cephem-4-carboxylate is
condensed with 2-mercaptobenzothiazolyl (Z)-(2-aminO"4-thiazolyl)"2-
(trityloxyimino)acetate in N,N-dimethyl acetamide, and the product obtained was
treated with p-toluenesulfonic acid in the presence of a mixture of diethyl ether and
methanol to get crystalline 7-[(2-amino-4-thiazoIyl)-"2-(Z)-
(trityloxyimino)acetamido]-3-vinyl-3-cephem-4-carboxylic acid.pTSA.2DMAc
solvate. This process utilizes highly volatile, low-boiling and therefore industrially-not-preferred solvent, diethyl ether, for crystallizing out the above solvate. In addition, the quantity of the low-boiling solvent used is also very high ranging from 60-100 volumes, thereby adding "hazard to the operations. Added to this is the fact that the recovery of these solvents from their mixture is not Istraight-forward.
US patent No. 6,350,869 discloses the purihcapon of impure cefdinir through the preparation of N,N-dicyclohexylamine salt of 7-[2-amino-4-thiazolyl-2-(z)-hydroxyimino acetamido]-3-vinyl-3-cephem-4-carboxylic acid and subsequent
hydrolysis to get pure cefdinir. This process requires jhe preparation of crude
i

. ifdinir, conversion to N,N-dicyclohexylamine salt and then hydrolysis of the salt to get pure cefdinir, and therefore the overall yield is not attractive.
US patent No. 6,350,869 also emphasizes that cefdinir is unstable in the presence of other amines, with which, it gets heavily degraded. In addition, Yoshihiko Okamoto et al. (J. Pharm. Sci. Vol. 8S(9), 976, 1996) report that cefdinir may be unstable under basic environment.
Crystalline cefdinir has limitations in formulation development as it cannot be developed into tablets.
Considering the foregoing limitations, we undertook an investigation in our lab to develop a product which is easy to handle and convenient to develop a dosage which is easily absorbable. We also parellely undertook an investigation to identify a process, which involves (i) less number of steps, (ii) the direct isolation of cefdinir, with out the need to prepare crude cefdinir in an additional step. This would permit commercializing the production of high-pure cefdinir with industrial-friendly solvent, which can further be recovered for recycling.
Objectives of the Invention
The main objective of the present invention is to provide a novel amorphous monohydrate of cefdinir which has very good bioavailability and useful in developing different dosage forms.
Another objective of the present invention is to pr9vide a commercially
viable process for the preparation novel amorphous monohydjrate of cefdinir of the
i formula (I), which would be easy to implement on manufacturing scale.
Yet another objective of the present invention is to provide new salts of
formula (XIV), which are insoluble and stable throughout thej process of producing
I
the cefdinir and a process for the preparation of cefdinir using these new salts.

Summary of the Invention
Accordingly, the present invention provides a novel amorphous monohydrate of cefdinir of the formula (I)

The present invention also provides a process for the preparation of novel amorphous monohydrate of cefdinir of the formula (I), which comprises the steps of:
i) condensing 7-amino-3-cephem-4-carboxylic acid of the formula (XII) with compound of the formula (XIII) wherein X represents an activating group in the presence of a tertiary amine and an organic solvent, followed by treatment with a base to produce a salt of compound formula (XIV), wherein M^ is a counter ion, ii) deprotecting the compound of formula (XIV) to produce compound of formula (XV) wherein M^ is a counter ion in the presence of an organic solvent and
a base at a temperature in the range of room temperature to 80 °C and iii) hydrolyzing the compound of the formula (XV) using an acid at low temperatures in the range of -^0 to 0 ^C in the presence of an organic solvent to produce novel amorphous monohydrate of cefdinir of the formula (I).
The reaction is shown in scheme-IV below :

Description of Figures
Figure 1 : Comparison of powder XRD pattern of the sample prepared according to US 4,935,507 and the sample prepared according to example 1 and example 2,
Detailed description of the invention
In an embodiment of the present invention, the activation group represented by X is selected from ester, thioester, halogen atom such as chlorine, bromine,

propyl, iso-propyl, n-butyl or iso-butyl or a phenyl group; Alki group represents (Cp
C4)alkyl group such as methyl, ethyl, n-propyl, iso-propyl, n-butyl or iso-butyl.
i

In an embodiment of the present invention, the counter ion represented by M is selected from sodium, potassium, lithium, magnesium, ammonium, dicyclohexylamine, N,N'-dibenzylethylenediamine, l,8-diazabicyclo(5.4.0)undec-7-ene (DBU), 1,5-diazabicyclo(4.3.0)non-5-ene, N,N'-diphenylethylenediamine, l,4-dizabicyclo(2.2.2)octane, N,N-diisopropylethylamine, N,N-diisopropylamine and the like.
In an another embodiment of the present invention, the tertiary amine used in step (i) is selected from triethylamine, N-methylpiperidine, N,N-diisopropylethylamine, trimethylamine and the like.
In yet another embodiment of the present invention, the organic solvent used in step (i) is selected from ethanol, methanol, isopropanol, THF, cyclohexanol, acetone, butan-2-one, acetonitrile, DMAc, water or a mixture thereof.
In yet another embodiment of the present invention, the base used in step (i)
and step (ii) is selected from sodium hydroxide, sodium acetate, sodium 2-ethyl
hexanoate, potassium hydroxide, ammonium hydroxide^ ammonium acetate,
calcium hydroxide, dicyclohexyl amine, N,N'-dibenzylethylenediamine diacetate,
l,8-diazabicyclo(5.4.0)undec-7-ene (DBU), l,5-diazabicyclo(4.3.0)non-5-ene,
N,N'-diphenylethylenediamine, l,4-dizabicyclo(2.2.^)octane, N,N-
diisopropylethylamine, N,N-diisopropylamine, and the like.
In yet another embodiment of the present invention, the organic solvent used in step (ii) is selected from acetone, 2-butanone, methanoj, isopropanol, ethanol, THF, acetonitrile, DMAc, water and the like or mixtures thereof.
In another embodiment of the present invention, the acid employed in step (iii) is selected from HCl, sulfuric acid, formic acid, acetic acid, aromatic/aliphatic sulfonic acids such as benzenesulfonic acid, p-toluenesulfonic acid, naphthalenesulfonic acid, methanesulfonic acid, triflic acid, and the like.

In yet another embodiment of the present invention, the organic solvent used in step (iii) is selected from acetone, 2-butanone, methanol, isopropanol, ethanol, THF, acetonitrile, DMAc, water and the like or mixtures thereof.
In yet another embodiment of the present invention, the compound of formula (I) obtained is a syn isomer.
The present invention is based on the observation that rapid cooling of the aqueous solvent solution of cefdinir to low temperatures and adding the acid rapidly produces amorphous cefdinir. The technique can be achieved either by cooling the aqueous solvent solution to low temperatures and adding the acid rapidly to adjust the pH to precipitate the amorphous product or adding the acid to adjust the pH and rapidly cooling the resultant solution to precipitate the amorphous product.
In yet another embodiment of the present invention, the hydrolysis in step (iii) is carried out by cooling the aqueous solvent solution to low temperatures and adding the acid rapidly to adjust the pH to precipitate the amorphous cefdinir.
In yet another embodiment of the present invention, the hydrolysis in step (iii) is carried out by adding the acid to adjust the pH and rapidly cooling the resultant solution to precipitate the amorphous cefdinir.
The foregoing technique has been found to be markedly attractive, both from commercial point of view, as well as from manufacturing viewpoint and affords good quality of amorphous cefdinir of the formula (I).
Many other beneficial results can be obtained by applying disclosed invention in a different manner or by modifying the invention with the scope of disclosure.
The present invention is illustrated with the following examples, which should not be construed as limiting to the scope of the invention.
Example 1 Step (n

Preparation of (2-mercapto-5-phenyH,3,4-oxadiazolyl)-(Z)-2-(2-amino-4-thiazolyl)-2-(trityloxyimino)acetate
To an ice-cold suspension of (Z)-(2-amino-4-thiazolyl)-2-(trityloxyimino)acetic acid (25 gm) in tetrahydrofuran (200 ml), triethylamine (10 gm) was added dropwise over 10 minutes at 0-5 °C. Bis-(2-oxo-oxazolidinyl)phosphinic chloride (15.4 gm) was added and stirred for one hour at 0-5 °C. To the reaction mixture 2-mercapto-5-phenyl-l,3,4-oxadiazole (9.8 gm) and triethylamine (5.0 gm) was added dropwise over 15 minutes and stirred at 0-5 °C for 6-7 hours. After completion of reaction, chilled water (500 ml) was added at 10-20 °C in 30 - 40 minutes and
stirred at 20 °C for 2 hours. Then the slurry was cooled to 5-10 ^C and stirred at this temperature for 45 minutes. The product thus obtained was filtered washed with water (100 ml) and dried at 30-35 °C for 4-5 hours to yield the title compound (50 gm, water content is 40%).
Step (in
Preparation of potassium (Z)-7p-[2-(2-amiiio-4-tliiazolyl)-2-(trity!oxyimino)
acetamidol-3-viiiyl-3-cepliem-4-carboxylate
To a chilled suspension of 7-amino-3-vinyl-3-cephem-4-carboxylic acid (25 gm)
and (2-mercapto-5-phenyl-1,3,4-oxadiazolyl)-(Z)-(2-amino-4-thiazolyl)-2-
(trityloxyimino)acetate (155 gm, water content is 40 %) in N,]K-dimethylacetamide (150 ml), triethylamine (23 gm) was added drop-wise at 10±2 °C over 30-45 minutes and the resulting mixture was stirred at 20±2 °C for 6-8 hours. The reaction was monitored by HPLC. After completion of the reaction, tetrahydrofuran (125 ml), 10% sodium chloride solution (250 ml) and ethyl acetate ,(250 ml) were added
at 25 °C and stirred for 20 min. The aqueous layer was separated and washed with ethyl acetate (250 ml). To the aqueous layer, ethyl acetate (500 ml) was added, cooled to 10 - 15 °C, and the pH was adjusted to 2.8-3.0 by 1:1 HCl in 30 min. The

layers were separated and to the ethylacetate layer, 12 % (w/v) methanolic potassium hydroxide solution (60 ml) was added dropwise in 30 min at 25 °C, and stirred for 45 min. The resulting slurry was filtered, washed with ethyl acetate (150 ml) followed by acetone (150 ml) and dried at 30-35 °C under vacuum to obtain the title compound (45 gm, HPLC Purity >99.0%).
Step (iii)
Preparation of ammonium (Z)-7P-[2-(2-amino-4-tliiazolyl)-2-(
hydroxyimino)acetamido]-3-vinyl-3-cepliem-4-carboxylate
To a clear solution of potassium (Z)-7P-[2-(2-amino-4-thiazolyl)-2-(trityloxyimino)acetamido]-3-vinyl-3-cephem-4-carboxylate (250 gm) in aqueous acetonitrile (625 ml, 2:3), a solution of trimethylchlorosilane (94 gm) in acetonitrile (125 ml) was added drop wise at 60-65 °C and the temperature was maintained at 65-68 °C for 33 minutes. Chilled acetone (2000 ml) having temperature -10 °C was added to the reaction mixture to reduce the temperature to 30 - 35 ^C. A methanoHc solution of ammonium acetate (93 gm, 100 ml) was added drop wise while cooling. The resulting mixture was diluted with acetone (3000 ml), cooled to 10 °C and stirred for 30 minutes at 10 ± 2 *^C. The crystals thus obtained were filtered, washed with acetone and dried at 40-45 °C under vacuum to get anunonium (Z)-7p-[2-(2-amino-4-thiazolyl)-2-(hydroxyimino)acetamido]-3-vinyl-3-cephem-4-carboxylate
(207 gm, HPLC quality 94.9 %).
i
Step (iv) i
Preparation of (Z)-7p-[2-(2-araino-4-tliiazolyl)-2-(hydroxyimino)acetamidol-3-
vinyl-3-cephem-4-carboxylic acid in amorphous hydrate form
Ammonium (Z)-7p-[2-(2-amino-4-thiazolyl)-2-(hydroxyimino)acetamido]-3-vinyl-3-cephem-4-carboxylate (20 gm) was added to a mixture o:' water (250 ml) and

acetone (80 ml) and warmed to 33-35 *^C. This aqueous solution was treated with activated charcoal and EDTA at 35 'C for 40 minutes. The carbon was filtered and the carbon bed was washed with water (70 ml) This aqueous acetone solution was cooled to -30 °C and a (10 %) solution of aqueous sulphuric acid was added rapidly, stirred for 30 minutes and warmed to 0-2 °C. The product thus obtained was filtered at 0-2 °C, washed with cold-water (100 ml) and dried at 40-45 "^C under vacuum for 5-6 hours to get (Z)-7p-[2-(2-amino-4-thia2olyl)-2-(hydrox)dmino)acetamido]-3-vinyl-3-cephem-4-carboxylic acid (6.0 gm, HPLC quality 89.0 %, water content 4-5 %).
Example 2
Step (i)
Preparation of potassium (Z)-7p-[2-(2-amino-4-thiazolyI)-2-(trityloxyimino)
acetamido]-3-viny!-3-cephem-4-carboxylate
To a chilled suspension of 7-amino-3-vinyl-3-cephem-4-carbQxylic acid (5 gm) and (2-mercapto-5-phenyl-l,3,4-oxadiazolyl)-(Z)-(2-ainino-4-thia:?olyl)-2-(trityloxyimino)acetate (24.2 gm) prepared according to the procedure given in example (1) step (i) in tetrahydrofuran (40 ml) and water (5 ml), triethylamine (4.6 gm) was added drop-wise at 20±2 °C over 10-15 minutes and the resulting mixture was stirred at 30±2 °C for 6-8 hours. The progress of the reaction was monitored by HPLC. After completion of reaction, ethylacetate (100 ml) and water (75 ml) were added at 30±2 °C and stirred for 20 min. The aqueous layer was separated and washed with ethyl acetate (75 ml). To the aqueous layer, ethylacetate (150 ml) was added, cooled to 10 - 15 ^C, and the pH was adjusted to 2.8-3.0 by 1:1 HCl solution in 25-30 min. To the separated ethylacetate layer, acetone (5C ml) and a methanolic potassium hydroxide solution (7.5 % w/v, 20 ml) were added dropwise in 25-30 min at 25 -27 "^C and stirred for further 45 min. The resulting slurry was filtered,

washed with acetone (2 X 25 ml) and dried at 30-35 "^C under vacuum to obtain the title compound (5.0 gm, HPLC Purity >99.0 %).
Step (ii)
Preparation of ammonium (Z)-7P-[2-(2-amino-4-tiiiazolyl)-2-
(liydroxyimino)acetamido]-3-vinyl-3-cephem-4-carboxylate
To a clear solution of potassium (Z)-7P-[2-(2-amino-4-thiazolyl)-2-(trityloxyimino)acetamido]-3-vinyl-3-cephem-4-carboxylate (250 gm) in aqueous acetonitrile (625 ml, 2:3), a solution of trimethylchlorosilane (94 gm) in acetonitrile
(125 ml) was added drop wise at 60-65 *^C. and the temperature was maintained at 65-68 °C for 33 minutes. Chilled acetone (2000 ml) having temperature -10 *^C was added to the reaction mixture to reduce the temperature to 30 - 35 °C. A methanolic solution of ammonium acetate (93 gm, 100 ml) was added drop wise while cooling. The resulting mixture was diluted with acetone (3000 ml), cooled to 10 °C and stirred for 30 minutes at 10 ± 2 °C. The crystals thus obtained were filtered, washed with acetone and dried at 40-45 °C under vacuum to get ammonium (Z)-7p-[2-(2-amino-4-thiazolyl)-2-(hydroxyimino)acetamido]-3-vinyl-3-cephem-4-carboxylate (207 gm, HPLC quality 94.9 %).
Step (iii)
Preparation of (Z)-7P-[2-(2-amino-4-thiazolyl)-2-(liydroxyimino)acetamido]-3-
vinyl-3"Cepliem-4-carboxylic acid in amorplious hydrate forpi
Ammonium (Z)-7P-[2-(2-amino-4-thiazolyl)-2-(hydroxyimino)acetamido]-3-vinyl-3-cephem-4-carboxylate (20 gm) was added to a mixture of water (250 ml) and acetone (80 ml) and warmed to 33-35 ^C. This aqueous solution was treated with activated charcoal and EDTA at 35 °C for 40 minutes. The carbon was filtered and the carbon bed was washed with water (70 ml). The pH of tlpis aqueous acetone

solution was adjusted to 0.6 at 33-35 °C using a (10 %) solution of aqueous sulphuric acid. This solution was cooled rapidly to -10 °C and stirred for 30 minutes. The product thus obtained was filtered at -10 °C, washed with cold-water (100 ml) and dried at 40-45 'C under vacuum for 5-6 hours to get (Z)-7p-[2-(2-amino-4-thiazolyl)-2-(hydroxyimino)acetamido]-3-vinyl-3-cephem-4-carboxylic acid (6.0 gm, HPLC quality 93.0 %, water content 4-5 %).
Example 3
Step (i)
Preparation of potassium (Z)-7P-[2-(2-amino-4-thiazolyl)-2-(trityloxyimino)
acetaraido]-3-vinyl-3-cephem-4-carboxylate
To a well stirred suspension of 7-amino-3-vinyl-3-cephem-4-carboxylic acid (50
gm) and (2-mercaptobenzothiazolyl)-(Z)-2-(2-amino-4-thiazolyl)-2-
(trityloxyimino)acetate (130 gm) in aqueous tetrahydrofuran solution (450 ml, 1:8), triethylamine (45 gm) was added drop wise at 25-30 °C and the resultant reaction mixture was stirred at 25-30 *^C for 4-5 hours. After completion of reaction, water (1200 ml) and ethylacetate (1000 ml) were added, cooled to 20-25 °C and pH was adjusted to 2.0 to 2.3 by dilute hydrochloric acid (1:1, « 82 ml) over 20 minutes. Ethylacetate layer was separated and the aqueous layer was extracted twice with ethylacetate (2 x 200 ml). The coipbined ethylacetate layer was treated with 15% brine solution. A methanolic potassium hydroxide solution (15 gm in 60 ml) was
added dropwise to the clear ethylacetate solution at 25 to ^0 °C, To the reaction
i
mass, isopropyl ether (1000 ml) was added dropwise and stinted for 30 minutes. The product thus obtained was filtered, washed with isopropyl et|ier (200 ml) and dried
i
at 45 "^C under vacuum to get potassium (Z)-7p-[2-(2-amino-4-thiazolyl)-2-(trityloxyimino)acetamido]-3-vinyl-3-cephem-4-carboxylate (167.5 gm, HPLC quality 93.6 % water content 8.1 % and assay 88-89 %).

step (in
Preparation of ammonium (Z)-7P-[2-(2-amino-4-thiazolyl)-2-
(hydroxyimino)acetamido]-3-vinyl-3-cephem-4-carboxylate
To a clear solution of potassium (Z)-7P-[2-(2-amino-4-thiazolyl)-2-(trityloxyimino)acetamido]-3-vinyl-3-cephem-4-carboxylate (250 gm) in aqueous acetonitrile (625 ml, 2:3), a solution of trimethylchlorosilane (94 gm) in acetonitrile (125 ml) was added drop wise at 60-65 °C, and the temperature was maintained at 65-68 'C for 33 minutes. Chilled acetone (2000 ml) having temperature -10 ""C was added to the reaction mixture to reduce the temperature to 30 - 35 °C. A methanolic solution of ammonium acetate (93 gm, 100 ml) was added drop wise while cooling. The resulting mixture was diluted with acetone (3000 ml), cooled to 10 °C and stirred for 30 minutes at 10 ± 2 °C. The crystals thus obtained were filtered, washed with acetone and dried at 40-45 °C under vacuum to get ammonium (Z)-7p-[2-(2-amino-4-thiazolyl)-2-(hydroxyimino)acetamido]-3-vinyl-3-cephem-4-carboxylate (207 gm, HPLC quality 94.9 %).
Step (iii)
Preparation of (Z)-7P-[2-(2-amino-4-tliiazolyI)-2-(hydroxyimino)acetamido]-3-
vinyl-3-cephem-4-carboxylic acid ^ in amorplious hydrate form
Anmionium (Z)-7P-[2-(2-amino-4-thiazolyl)-2-(hydroxyimiiio)acetamido]-3-vinyl-3-cephem-4-carboxylate (20 gm) was added to a mixture of water (250 ml) and acetone (80 ml) and warmed to 33-35 "^C. This aqueous solfition was treated with activated charcoal and EDTA at 35 °C for 40 minutes. The cjarbon was filtered and the carbon bed was washed with water (70 ml). The pH oi' this aqueous acetone solution was adjusted to 0.6 at 33-35 °C using a (10 %) solution of aqueous sulphuric acid. This solution was cooled rapidly to -10 *^C and stirred for 30

minutes. The product thus obtained was filtered at -10 °C, washed with cold-water (100 ml) and dried at 40-45 °C under vacuum for 5-6 hours to get (Z)-7p-[2-(2-amino-4-thiazolyl)-2-(hydroxyimino)acetamido]-3-vinyl-3-cephem'4-carboxylic acid (6.0 gm, HPLC quality 93.0 %, water content 4-5 %).
Example 4
Step (i)
Preparation of potassium (Z)-7P-[2-(2-amino-44hiazolyl)-2-(trityloxyimino)
acetamido]-3-vinyl-3-cephem-4-carboxylate
To a well stirred suspension of 7-amino-3-vinyl-3-cephem-4-carboxylic acid (50
gm) and (2-mercaptobenzothiazolyl)-(Z)-2-(2-amino-4-thiazolyl)-2-
(trityloxyimino)acetate (130 gm) in aqueous tetrahydrofuran solution (450 ml, 1:8), triethylamine (45 gm) was added drop wise at 25-30 °C and the resultant reaction mixture was stirred at 25-30 °C for 4-5 hours. After completion of reaction, water (1200 ml) and ethylacetate (1000 ml) were added, cooled to 20-25 °C and pH was adjusted to 2.0 to 2.3 by dilute hydrochloric acid (1:1, « 82 ml) over 20 minutes. Ethylacetate layer was separated and the aqueous layer was extracted twice with ethylacetate (2 x 200 ml). The combined ethylacetate layer was treated with 15% brine solution, A methanolic potassium hydroxide solution (15 gm in 60 ml) was added dropwise to the clear ethylacetate solution at 25 to 30 °C. To the reaction
Li I
mass, isopropyl ether (1000 ml) was added dropwise and stirre

i
product thus obtained was filtered, washed with isopropyl ether (200 ml) and dried at 45 °C under vacuum to get potassium (Z)-7p-[2-(2-^mino-4-thiazolyl)-2-(trityloxyimino)acetamido]-3-vinyl-3-cephem-4-carboxylate j (167.5 gm, HPLC
quality 93.6 % water content 8.1 % and assay 88-89 %). i
step (in

Preparation of ammonium (Z)-'7P-[2-(2-amino-4-ttiiazolyl)-2-
(Iiy(iroxyimino)acetamido]-3-*vinyl-3*-cepbem-4-carboxylate
To a clear solution of potassium (Z)-7p-[2-(2-amino-4-thiazolyl)-2"(trityloxyimino) acetamido]-3-vinyl-3-cephem-4-carboxyIate (100.0 gm) in an aqueous acetonitrile (240 ml, 1:5), aqueous solution of hydrochloric acid (62 gm) was added dropwise at 60-65 °C and the temperature was maintained at 65-68 °C for 33 minutes. Chilled acetone (800 ml) having temperature -10 °C was added to the reaction mixture to
reduce the temperature to 30 - 35 °C. A solution of ammonium acetate (37.2 gm) in methanol (40 ml) was added dropwise. The resulting mixture was diluted with acetone (1200 ml), cooled to 10 °C and stirred for 30 minutes at 10 ± 2 °C. The product thus obtained was filtered, washed with acetone and dried at 40-45 °C under vacuum to get ammonium (Z)-7p-[2-(2-amino-4-thiazolyl)-2-(hydroxyimino)acetamido]-3-vinyl-3-cephem-4-carboxylate [80.5 gm, HPLC quality 95.45%],
Step (iii)
Preparation of (Z)-7p-[2-(2-amino-4-thiazolyl)-'2-(hydroxyimino)acetamido]-3-
vinyl-3-cepliera-4-carboxylic acid in amorphous hydrate form
Ammonium (Z)-7(3-[2-(2-amino-4-thia2olyl)-2-(hydroxyimino)acetamido]-3-vinyl-3-cephem-4-carboxylate (20 gm) was added to a mixture of water (250 ml) and acetone (80 ml) and warmed to 33-35 °C. This aqueous soliftion was treated with activated charcoal and EDTA at 35 ^C for 40 minutes. The cpbon was filtered and
! [
the carbon bed was washed with water (70 ml). The pH ofj this aqueous acetone solution was adjusted to 0.6 at 33-35 "^C using a (10 %j solution of aqueous sulphuric acid. This solution was cooled rapidly to -10 "^C and stirred for 30 minutes. The product thus obtained was filtered at -10 ^C, washed with cold-water

(100 ml) and dried at 40-45 °C under vacuum for 5-6 hours to get (Z)-7p-[2-(2-amino-4-thiazolyl)-2-(hydroxyimino)acetamido]-3-vinyl-3~cephem-4-carboxylic acid (6.0 gm, HPLC quality 93.0 %, water content 4-5 %).

We claim:
1. Novel amorphous monohydrate of cefdinir of the foraiula (I).

2. A process for the preparation of novel amorphous monohydrate of cefdinir of
the formula (I)

which comprises the steps of:
i) condensing 7-amino-3-cephem-4-carboxylic acid of the formula (XII)

with compound of the formula (XIII)

wherein X represents an activating group in the presence of a tertiary amine and an
organic solvent, followed by treatment with a base to produce a salt of compound
i
formula (XIV), :

wherein M"*" is a counter ion,
ii) deprotecting the compound of formula (XIV) to produce compound of
formula (XV)

wherein M"^ is a counter ion in the presence of an organic solvent and a base at a
temperature in the range of room temperature to 80 *^C and
iii) hydrolyzing the compound of the formula (XV) using an acid at low
temperatures in the range of -40 to 0 'C in the presence of an organic solvent to
produce novel amorphous monohydrate of cefdinir of the formula (I).
3. The process as claimed in claim 2, wherein the activation group represented
by X is selected from ester, thioester, halogen atom such as chlorine, bromine,

^^^ , where R^ represents (CrC4)alkyl group [such as methyl, ethyl, n-
propyl, iso-propyl, n-butyl or iso-butyl or a phenyl group; ^Ik group represents (Cp C4)alkyl group such as methyl, ethyl, n-propyl, iso-propyl, ji-butyl or iso-butyl.

4. The process as claimed in claim 2, wherein the counter ion represented by M is selected from sodium, potassium, lithium, magnesium, ammonium, dicyclohexylamine, N,N'-dibenzylethylenediamine, l,8-diazabicyclo(5.4.0)undec-7-ene (DBU), l,5-diazabicyclo(4.3.0)non-5-ene, N,N*-diphenylethylenediamine, l,4-dizabicyclo(2.2.2)octane, N,N-diisopropylethylamine or N,N-diisopropylamine.
5. The process as claimed in claim 2, wherein the tertiary amine used in step (i) is selected from triethylamine, N-methylpiperidine, N,N-diisopropylethylamine or trimethylamine.
6. The process as claimed in claim 2, wherein the organic solvent used in step (i) is selected from ethanol, methanol, isopropanol, THF, cyclohexanol, acetone, butan-2-one, acetonitrile, DMAc, water or a mixture thereof.
7. The process as claimed in claim 2, wherein the base used in step (i) is selected from sodium hydroxide, sodium acet&te, sodium 2-ethyl hexanoate, potassium hydroxide, ammonium hydroxide, ammonium acetate, calcium hydroxide, dicyclohexyl amine, N,N'-dibenzylethylenediamine diacetate, 1,8-diazabicyclo(5.4.0)undec-7-ene (DBU), l,5-diazabicyclo(4.3.0)non-5-ene, N,N'-diphenylethylenediamine, 1,4-dizabicyclo(2.2.2)octane, N,N-diisopropylethylamine or N,N-diisopropylamine.
8. The process as claimed in claim 2, wherein the base employed in step (ii) is selected from sodium hydroxide, sodium acetate, sodium 2-ethyl hexanoate, potassium hydroxide, ammonium 'hydroxide, ammonium\ acetate, calcium hydroxide, dicyclohexyl amine, N,N'-dibenzylethylenediamine diacetate, 1,8-diazabicyclo(5.4.0)undec-7-ene (DBU), l,5-diazabicyclo(4.3.())non-5-ene, N,N'-
!
diphenylethylenediamine, 1,4-dizabicyclo(2,2.2)octane, N,N-diisopropylethylamine or N,N-diisopropylamine.
9. The process as claimed in claim 2, wherein the organic solvent used in step
(ii) is selected from acetone, 2-butanone, methanol, isopropanol, ethanol, THF,
acetonitrile, DMAc, water or mixtures thereof.

10. The process as claimed in claim 2, wherein the hydrolysis in step (iii) is
carried out by cooling the aqueous solvent solution to low temperatures and adding
the acid rapidly to adjust the pH to precipitate the amorphous cefdinir.
11. The process as claimed in claim 2, wherein the hydrolysis in step (iii) is
carried out by adding the acid to adjust the pH and rapidly cooling the resultant
solution to precipitate the amorphous cefdinir.
12. The process as claimed in claim 2, wherein the acid employed in step (iii) is
selected from HCl, sulfuric acid, formic acid, acetic acid, benzenesulfonic acid, p-
toluenesulfonic acid, naphthalenesulfonic acid, methanesulfonic acid or triflic acid.
13. The process as claimed in claim 2, wherein the organic solvent used in step
(iii) is selected from acetone, 2-butanone, methanol, isopropanol, ethanol, THF,
acetonitrile, DMAc, water or mixtures thereof.
14. The process as claimed in claim 2, wherein the compound of formula (I)
obtained is a syn isomer.

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Patent Number

226007

Indian Patent Application Number

152/CHE/2003

PG Journal Number

02/2009

Publication Date

09-Jan-2009

Grant Date

04-Dec-2008

Date of Filing

26-Feb-2003

Name of Patentee

ORCHID CHEMICALS & PHARMACEUTICALS LTD.

Applicant Address

ORCHID TOWERS, 313, VALLUVAR KOTTAM HIGH ROAD, NUNGAMBAKKAM, CHENNAI 600 034,

Inventors:

#	Inventor's Name	Inventor's Address
1	PANDURANG BALWANT DESHPANDE	F-3, SAND STONE APARTMENT, FIRST AVENUE, INDIRA NAGAR, CHENNAI - 600 020,
2	BHAUSAHEB PANDHARINATH KHANDANHALE	SHANTHI AVENUE, NO. 7, DR. RADHAKRISHNAN ROAD, THIRUVANMIYUR, CHENNI - 600 041,
3	CHANDRASEKARAN RAMASUBBU	NO.3 (NEW NO 7) B1, RAMMIYAM FOUNDATION, 7TH MAIN ROAD, DHANADEESHWAR NAGAR, VELACHERY, CHENNAI - 600 042,

PCT International Classification Number

C07D501/06

PCT International Application Number

N/A

PCT International Filing date

PCT Conventions:

#	PCT Application Number	Date of Convention	Priority Country
1			NA