FI68238B - FOERFARANDE FOER FRAMSTAELLNING AV CEFALEXIN - Google Patents

Description

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C Patent granted 12 08 1985 'Patent oeddelat (51) Kv.lk. * / Lnt.CI. * C 07 D 501/0 ^, 501/12, 501/22 FINLAND —FINLAND (21) Patent application - Patenuntiknlng 731195 (22 ) Date of application - Ansökningsdag 1 1. 0 k. 79 (23) Start date - Giltighetsdag 20.01.72 (41) Become Public - Blivit offend ig 1 ^ .0 ^ .79 "e 'f44 \ Date of entry and date of publication— in ry /, Or:, ·', ; .ent- rc.h registerstyrelsen '' Ansökan utlagd och utl.skriften publlcerad (32) (33) (31) Privilege requested — Begird priority 20.0 1 .71 USA (US) 108216 (71) Eli Lilly and Company, 307 East McCarty Street, Indianapolis, Indiana, USA (72) William Lee Garbrecht, Indianapolis, Indiana, USA (71 *) Oy Kolster Ab (54) Method for the preparation of cefalexin - Förfarande för framstallnin av Cefalexin (62) application 11 * 5/72 (patent 6 patent565) -Avdelad frln trap 1 ^ 5/72 (patent 60565)

The invention relates to the release of cefalexin from a cephalexin bis- (Ν, Ν-dimethylformamide) solvate.

Cefalexin is prepared primarily by acylation of p-nitrobenzyl ester of 7-amino-deacetoxycephalosporanic acid (7-ADCA ester) in acetonitrile with a C 1 -C 4 alkyl mixed anhydride of phenylglycine. In this glycine derivative, the amino nitrogen as enamine is protected with methylacetone. The p-nitrobenzyl ester group is then removed by treating the acetonitrile mixture of cefalexin ester with a reducing agent, e.g., metallic zinc dust and acid. This acid reduction step. which also removes the enamine, is then followed by a base treatment to raise the pH of the mixture to about 4.5 to 5.0, whereupon the crude cefalexin zwitterion precipitates.

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Although this acid reduction effectively degrades the p-nitrobenzyl ester group, certain impurities are also generated that are difficult to remove from the cefalexin zwitterionic product. Such impurities are likely to include small amounts of 7-ADCA, phenylglycine, and p-nitrobenzyl ester, an impurity whose structure has not yet been determined with certainty. Whatever the chemical structure, any of the latter impurities contain diazotizable nitrogen as measured by the Bratton-Marshall method described below. Those skilled in the art of cephalosporin antibiotics recommend the complete removal of the diazotizable nitrogen impurity or a reduction in its amount to a negligible amount in the cefalexin product.

It is an object of the invention to provide a process for the preparation of cefalexin which does not form the above impurities and in particular does not form a diazotizable nitrogen-containing compound. The invention is characterized in that the cefalexin bis- (N, N-dimethylforamide) solvate is dissolved in acidified water having a pH of less than 2, the solution is heated to 40-70 ° C, the pH of the solution is adjusted to about 4.5 to 5 and the precipitated cefalexin is separated.

The cefalexin bis- (N, N-dimethylformamide solvate) used according to the invention is prepared by mixing paranitrobenzyl cephalexin ester with N, N-dimethylformamide, treating the mixture in an acidic medium with reducing agents, for example zinc and acid, decomposing the ester group , the pH of the solution is adjusted so that the solvate separates.

To prepare cefalexin, the cefalexin bis- (N, N-dialkylacylamide) solvate is placed in water, acid is added to lower the pH to 1-2, the mixture is heated to 40-70 ° C, preferably 50-60 ° C to form the monohydrate, and then a base such as ammonium hydroxide or triethyl-3,68238 amine is added to raise the pH to the required value. This pH is about 4.5 to 5.0 but depends on the solvent system used. If unsolvated cefalexin is desired, the complex can be dissolved in and recovered from the aqueous acetonitrile mixture. The cefalexin zwitterion can be recovered from the reaction mixture by conventional methods, washed with acetonitrile, dried and formulated into pharmaceutical preparations for use in antibiotic therapy in the treatment of various inflammatory diseases. Special preparations, capsules or tablets sizes and uses for the use of cephalosporin antibiotics such as cefalexin, cephaloglycine, etc. are known in the art.

The present invention provides improvements in the process for the preparation of cefalexin which allow the acylation step and the ester group removal step to be separated from each other and both to be optimized independently. The new process yields a cefalexin product that is significantly purer in terms of zinc, phenylglycine, and 7-ADCA compared to previous intermediates. The absence of these impurities is advantageous because the yield and reliability of the final crystallization of cefalexin hydrate from water are improved. In addition, the improvement of the present invention allows complete recovery of cefalexin. The yield based on DMF is of the order of 95-98% per difference.

The invention is further described in the following detailed example.

Example To a 284 liter open glass lined vessel with a strong stirrer was added 92 liters of distilled water, 6 kg of reagent grade hydrochloric acid, 23 kg of Keeieksin-bis (DMF) complex. This mixture was rinsed in with 11.5 liters of deionized water and then 0.640 kg of sodium ethylenediamine tetraacetate in 5.5 liters of distilled water and 1.67 kg of carbon (Darco G 60) were added and stirred for 1 hour. The solution was then filtered through a glass filter with a plate and frame press and washed with 15.3 liters of distilled water. The filtrate and washings were transferred to a 284 liter distillation vessel and heated to 55 ° C. The pH was adjusted to 4.5 with triethylamine.

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Some excess triethylaraine accumulated around the mixer. This accumulation of excess amine was neutralized with 3.0 liters of hydrochloric acid. A maximum pH of 5.6 was reached in less than 5 minutes. The mixture was filtered through a Buchner funnel, washed with 5 liters of water and two 15 liter portions of deionized water. The filtrate (180 liters) was cooled and transferred to a 284 liter distillation vessel. 90 liters of acetonitrile were then added to precipitate a second crop. Both products were air dried at 32 ° C to constant weight. 12.5 kg of cefalexin monohydrate product (93% based on cefalexin) were measured as measured by ultraviolet analysis (pm 264). The concentration of diazotizable nitrogen was less than 50 ppm. The DMF content was 0.0602%. The water content as determined by Karl Fischer's analytical method was 6.25%.