Method for preparing biapenem with high purity

Abstract

The invention relates to a method for preparing biapenem with high purity, which takes low-cost Raney N1 as catalyst, and comprises the steps of: leading the catalyst and H2 to have hydrogenation reaction in buffer solution or the mixed solution of the buffer solution and organic solvent, removing protecting group, and then collecting biapenem from the reaction product. The method has mild reaction condition, simple operation, no need of resin purification, high purity of the obtained product and low production cost, and is suitable for industrialized production.

Description

technical field [0001] The invention relates to a preparation method of high-purity biapenem. technical background [0002] Biapenem is a new type of 1β-methyl carbapenem antibiotics, which has a broad antibacterial spectrum and is effective against Gram-positive bacteria, Gram-negative bacteria (including drug-resistant Pseudomonas aeruginosa), anaerobic bacteria, etc. Strong antibacterial activity; stable to β-lactamase, no enzyme inhibitor needed. Biapenem has almost zero nephrotoxicity, no central nervous system toxicity, no seizures, and can be used for the treatment of bacterial meningitis. [0003] Biapenem is an injectable carbapenem antibiotic variety developed by Japan Lederle Company and American Cyamide Company, and was approved for marketing in Japan in March 2002. [0004] At present, the preparation method of biapenem is obtained by removing the protecting group from the compound with the general formula I as the raw material. There are mainly four methods: ...

AI Technical Summary

Problems solved by technology

[0005] 1. The patent CN101121716 and the document Toshio Kumagai, J.O.C., 1998, 63:8145-8149 reported that zinc powder was used as a catalyst to remove the protective group in a phosphate buffer solution with a pH of 5.6, and the post-treatment was purified by an adsorption resin to obtain Products, in which a large amount of eluent needs to be concentrated and freeze-dried, and carbapenems are easy to degrade in solution, making it difficult to produce in large quantities

[0006] 2. Literature Kenneth J. Wildonger, Journal of antibiotics, 1993, 46(12): 1866-1882 reported that Pd(OH)2 was used as a catalyst to remove the protective group in phosphate buffer solution, and the ion exchange resin Dowex 50 -X4 is purified, concentrated, and freeze-dried to obtain the product, and the yield is lower than 30% (it is 2 steps in the literature, and the total yield is 24%)

[0007] 3. Patent EP0480100; CN1927867 reported that in a buffer solution or a mixture of a buffer solution and an organic solvent, an expensive compound containing palladium or platinum was used as a catalyst to carry out a hydrogenation reaction with hydrogen to remove the protecting group, and then remove the protective group from the reaction solution Collect biapenem, the yield is not higher than 60%, and the use of expensive catalysts leads to higher costs

[0008] 4. Patent CN1995040 reported that in a two-phase system, expensive palladium was used as a catalyst to remove the protective group by hydrogenation, and then the biapenem was collected from the water phase, and the yield was only 60%.

[0009] The above patents and documents mainly have the following disadvantages: 1. Use expensive palladium-containing or platinum-containing catalysts, and the yield is not high, resulting in higher cost of finished products; 2. The product after deprotection needs to be treated by resin purification. Not conducive to scale-up production

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