INTERMEDIATES FOR THE PREPARATION OF CEFTAZIDINE, AND PROCESS FOR THEIR PREPARATION

Abstract: (6R, 7R)-7-[(Z)-2-(2-triphenylmethylaminothiazol-4-yl)-2-­ (2-tert.-butoxycarbonylprop-2-oxyimino)acetamido]-3-(1-­ pyridiniummethyl)ceph-3-em-4-carboxylate is isolated and purified by formation of a N,N-dimethylacetamide solvate.

Description: IMPROVEMENTS IN OR RELATING TO NOVEL CEPHALOSPORIN INTERMEDIATES This invention relates to a novel process and intermediate for the preparation of ceftazidime. There is a continual need to develop new antibiotics because of the constant threat that antibiotic-specific resistant strains of pathogenic microorganisms will emerge. Because of high development and production costs, particularly in the area of cephalosporin antibiotics, researchers are searching constantly for new and efficient means for producing these antibiotics. In this regard, U.S. Patent No. 4,258,041 describes the synthesis of (6R,7R)-7-f(Z)-2-(2-amino- thiazol-4-yl) -2- (2-carboxyprop-2-oxyimino) acetamidc) - 3- (l-pyridiniummethyl)ceph-3-em-4-carboxylate, a cephalosporin antibiotic now generically known as ceftazidime. The reported synthesis of ceftazidime comprises reacting (Z)-2-(2-tert.-butoxycarbonylprop2-oxyimino)-2-(2-triphenylmethylaminothiazol-4-yl)acetyl chloride with (6R,7R) -7-amino-3-(l-pyridinium- methyl)ceph-3-em-4-carboxylic acid in a mixture of N,N-dimethylacetamide and acetonitrile to provide the ceftazidime intermediate, (6R,7R)-7-[(Z)-2-(2-tri phenylmethylaminothiazol-4-yl)-2-(2-tert.-butoxyCar- bonEtlprop-2-oxyimino)acetamido]-3-(l-pyridiniummethyl)- ceph-3-em-4-carboxylate. This ceftazidime intermediate then was recovered from the reaction mixture as an amorphous solid and subsequently purified by crystal lization as an N,N-dimethylformamide solvate (2 1/2 moles of DMF per mole of intermediate) from N,N-di methylformamile. The ceftazidime intermediate then was reacted with formic acid to effect removal of the protecting groups and to provide ceftazidime. The present invention provides an improved process for preparing the ceftazidime intermediate, in which the intermediate is crystallized directly out of the reaction mixture as an N,N-dimethylacetamide solvate. This invention, therefore, obviates the need for subsequent purification and provides improved yields and reduced costs in the production of ceftazidime In accordance with the invention, a compound of Formula (I): EMI2.1 in which DMAC is N,N-dimethylacetamide and x is a number from 0.5 to 3.0, is a useful intermediate in the synthesis of ceftazidime. Also, there is provided a process for preparing a compound of Formula (I), as defined above, which comprises reacting in N,N-dimethylacetamide a ((Z)-2-(2-tert.-butoxycarbonylprop-2-oxyimino)-2 (2-triphenylmethylamino-thiazol-4-yl)acetyl halide with a (6R,7R)-7-amino-3-(1-pyridiniummethyl)ceph- 3-em-4-carboxylic acid salt. The resulting dimethylacetamide solvate can be isolated as a crystalline solid directly from the reaction mixture. The process of this invention allows one to isolate, in good yield, substantially pure ceftazidime intermediate N, N-dimethylacetamide solvate. As used throughout this description, "ceftazidime intermediate" means (6R,7R)-7-[ (Z)-2- (2-triphenylmethylaminothiazol-4-yl) -2- (2-tert.-butoxy- carbonylprop-2-oxyimino) acetamido] -3- (1-pyridinium- methyl)ceph-3-em-4-carboxylate. The process by which this ceftazidime intermediate is prepared involves a typical acylation reaction comprising reacting a cephalosporin nucleus (i.e. a 7-amino-3-cephem derivative) with an acid halide, typically an acid chloride The acid halide typically employed in the synthesis of the ceftazidime intermediate is a (Z)-2-(2-tert.-butoxy carbonylprop-2-oxyimino) -2- (2-triphenylmethylamino- thiazol-4-yl)acetic acid halide. The acylation reaction generally is accomplished by reacting the acid halide with about an equimolar quantity of the 7amino-3-cephem nucleus in an unreactive solvent such as dichloromethane, acetone, or a mixture of N,N-dimethyl acetamide and acetonitrile, and in the presence of a base such as triethylamine or pyridine. The present process is improved by employing N,N-dimethylacetamide as the reaction solvent thereby producing the ceftazidime intermediate directly from the acylation reaction mixture as a crystalline N,N-dimethylacetamide solvate. This improved process eliminates the separate purification step in which ceftazidime intermediate is converted to a solvate such as the N,N-dimethylformamide solvate. In carrying out the process of this invention, the acid halide, for instance (Z)-2-(2-tert. butoxycarbonylprop-2-oxyimino) -2- (2-triphenylmethyl- aminothiazol-4-yl)acetyl chloride, may be prepared by reaction of the free acid with a halogenating agent such as phosphorus pentachloride in a suitable solvent such as dichloromethane or diethyl ether. Once the acid halide is formed, it normally is not isolated but rather is added to a suspension of about an equimolor quantity of the cephalosporin nucleus in N,N-dimethylacetamide. A suitable base such as triethylamine is added to the reaction mixture to serve as scavenger for any free acid that might be present. The acylation reaction typically is complete within about fifteen to ninety minutes when carried out at a temperature of about -20 to about 400C. The ceftazidime intermediate that is thus produced is an N,N-dimethylacetamide solvate of Formula (I): EMI5.1 in which DMAC is N,N-dimethyiacetamide and x is a number from 0.5 to 3.0 and denotes the number of moles of DMAC per mole of ceftazidime intermediate. Preferred solvates are those in which x is about 0.5 to about 1.5, and especially in which x is 1.0. The ceftazidime intermediate solvate can be isolated readily if desired, by washing the reaction mixture with water and then adding a suitable counter solvent, i.e. a solvent in which the intermediate is substantially insoluble. Typical counter solvents include ethers, such as diethyl ether, methyl ethyl ether, diglyme, or tetrahydrofuran; and esters such as ethyl acetate, or methyl acetate. The counter solvent of choice is diethyl ether, or a combination of diethyl ether and ethyl acetate. When the counter solvent is added to the N,N-dimethylacetamide reaction mixture, the ceftazidime intermediate N,N-dimethylacetamide solvate starts to precipitate within about thirty to about ninety minutes as the solution is stirred at about -10 to about +100C. The crystalline solvate is isolated by simply filtering themixture, and generally, washing the solvate with fresh N,N-dimethylacetamide or diethyl ether is desirable. The product can be air dried at room temperature or dried in vacuum to remove any excess solvent. The product produced is an N,N-dimethylacetamide solvate of ceftazidime intermediate having a purity generally greater than about ninety percent. The ceftazidime intermediate solvate provided by this invention may be employed directly to produce ceftazidime. For example, the crystalline solvate may be dissolved in an acid solution, such as 98% formic acid, to cleave the triphenylmethyl protecting group on the amino group attached to the thiazolylacetamido side chain, and also to cleave the tert.-butoxy protecting group on the oxime portion of the side chain. If desired, hydrochloric acid can be added so as to form the dihydrochloride salt of ceftazidime, thereby facilitating isolation of the final product as a crystalline precipitate. The ceftazidime dihydrochloride produced can be employed as an antibiotic. To further illustrate the invention the following non-limiting examples are provided. Example 1 (6R,7R)-7-[ (Z)-2-(2-triphenylmethylamino- thiazol-4-yl) -2- (2-tert.-butoxycarbonylprop-2-oxy- imino) acetamido] -3- (1-pyridiniummethyl) ceph-3-em-4- carboxylate. To a cold (-100C) stirred solution of 8.70 g (41.8 mM) of phosphorus pentachloride in 150 ml of dichloromethane were added in one portion 21.72 g (38 mM) of (Z)-2-(2-tert.-butoxyzarbonylprop-2- oxyimino)-2-(2-triphenylmethylaminothiazol-4-yl)acetic acid. The reaction mixture was stirred for thirty minutes at -100C, and then diluted with a cold solution of 100 ml of water containing 11.66 ml (83.6 mM) of triethylamine. The two-phase reaction mixture was stirred vigorously for about three minutes, and then the organic layer was removed and added to a stirred cold (-100C) suspension of 16.89 g (38.0 mM) of (6R,7R) 7-amino-3-(l-pyridiniummethyl)ceph-3-em- acid dihydrochloride in 195 ml of N,N-dimethylacetamide containing 26.5 ml (190 mM) of triethylamine. The reaction mixture was stirred at O to -50C for thirty minutes, and then was diluted by the addition in one portion of 300 ml of water. The aqueous reaction mixture was stirred for ten minutes, and then the organic layer was separated and further diluted by the addition of 150 ml of fresh N,N-dimethylacetamide and 300 ml of diethyl ether. The organic solution was stirred at O to 50C for one hour, and the crystalline precipitate that ha & formed was collected by filtration, washed with fresh N,N-dimethylacetamide and then with fresh diethyl ether, and was dried at ambient temperature in vacuum for sixteen hours to produce 20.96 g (65.2% yield) of (6R,7R)-7-[(Z)-2-(2-triphenyl- methylaminothiazol-4-yl) -2- (2-tert. -butoxycarbonyl- prop-2-oxyimino)acetamido]-3-(1-pyridiniummethyl)ceph3-em-4-carboxylate N, N-dimethylacetamide solvate (1 mole of N,N-dimethylacetamide), m.p. 1500C (dec). Purity as determined by high performance liquid chromatography was 95.56%. Example 2 The process of Example 1 was repeated as follows: To a cold (-150C) stirred solution of 7.73 g of phosphorus pentachloride in 120 ml of dichloro- methane were added in one portion 17.32 g of (Z)-2 (2-tert.-butoxycarbonylprop-2-oxyimino)-2-(2-triphenylmethylaminothiazol-4-yl)acetic acid. The reaction mixture was stirred for thirty minutes while maintaining the temperature at about -10 to -150C,. The reaction mixture was then diluted by the addition of 80 ml of water containing 10.5 ml of triethylamine. After stirring the reaction mixture for three minutes, the organic layer was separated and the aqueous layer was discarded. The organic layer was then added dropwise over ten minutes to a cold (-100C) stirred suspension of 11.13 g of (6R,7R)-7-amino-3-(1-pyridiniummethyl)- ceph-3-em-4-carboxylic acid dihydrochloride in 88 ml of N,N-dimethylacetamide containing 17.5 ml of triethylamine. The reaction mixture was stirred for thirty minutes at about -5 to OOC, and then was allowed to warm to about +50C and was diluted by the addition of 200 ml of water. After stirring the aqueous mixture for two minutes, the organic layer was separated and the aqueous layer was discarded. The organic layer was further diluted with 200 ml of ethyl acetate and 100 ml of diethyl ether, and the mixture was vigorously stirred at about 20 to 250C, The mixture was seeded with ceftazidime intermediate N,N-dimethylacetamide solvate to initiate crystallization. After stirring the mixture for thirty minutes at 20 to 250C, the temperature was lowered to OOC and stirring was continued for about two hours. Filtration of the mixture and washing of the filter cake with a mixture of 10 ml of N,N-dimethylacetamide and 10 ml of diethyl ether and finally with 40 ml of diethyl ether provided, following drying at 350C under vacuum for about sixteen hours, about 78 percent yield of ceftazidime intermediate N,N-dimethylacetamide solvate (1.5 mole of N,N-di- methylacetamide). Example 3 Ceftazidime Dihydrochloride To a 250 ml, 3-necked, round-bottom flask purged with nitrogen are added 62.2 ml (75.9 g) of formic acid which is cooled to about 150C. To the stirring cooled formic acid is added 32.0 g (37.9 mM) of the ceftazidime intermediate from Example 1 or 2. The solution is stirred for 30 minutes after which 13.3 ml (15.8 g) of hydrochloric acid are added while maintaining the temperature below 200C. The mixture is stirred for about 3 hours and the triphenylmethanol produced is filtered and washed with formic acid and water. The filtrate is cooled and added to about 850 ml of acetone after which the cooled slurry is stirred for about 2 hours. The product is filtered and washed with acetone to produce the title product in about a 628 yield. NMR (DMSO-d6): 6 1.58 (s, 2 -CP.3), 6 5.33 (d, J = 5 Hz, 6-H), 6 6.01 (dd, J = 9.5 Hz, 7-H), 6 7.00 (s, aminothiazole), 6 8.30, 8.75 (t, J = 6 Hz), 6 8.75 (t, J = 6 Hz), 6 9.23 (d, J = 6 Hz, pyridinium protons), 6 9.72 (d, J = 9, acetamido proton).

Claims: CLAIMS 1. A compound of Formula (I): EMI11.1 in which DMAC is N,N-dimethylacetamide and x is a number from 0.5 to 3.0. 2. A compound of Formula (I) as claimed in claim 1 in which x is 0.5. 3. A compound of Formula (I) as claimed in claim 1 in which x is 1.0, 4. A compound of Formula (I) as claimed in claim 1 in which x is 1.5. 5. A compound of Formula (I) as claimed in claim 1 in which x is 2.0. 6. A compound of Formula (I) as claimed in claim 1 in which x is 2.5. 7. A process for preparing a compound of Formula (I) as claimed in any one of claims 1 to 6 which comprises reacting in N,N-dimethylacetamide a ((Z)-2-(2-tert.-butoxycarbonylprop-2-oxyimino)-2 (2-triphenylmethylamino-thiazol-4-yl))acetyl halide with a (6R,7R)-7-amino-3-(1-pyridiniummethyl)ceph- 3-em-4-carboxylic acid salt. 8. A process for preparing ceftazidime or a pharmaceutically acceptable salt thereof, which comprises removing the protecting groups from a compound of Formula (I) as claimed in any one of claims 1 to 6. 9. A process as claimed in claim 8 in which the protecting groups are removed by treating with acid the compound of Formula (1). 10. A compound of Formula (I) as claimed in any one of claims 1 to 6 for use as an intermediate in the preparation of ceftazidime.

Inventors: CHOU, TA-SEN, HEATH, PERRY CLARK
Applicants: ELI LILLY AND COMPANY
Application year: 1983
Main classification: C07D501
IPC codes: C07D501, A61K31