Preparation method of antibacterial agent

Abstract

The invention discloses a preparation method of an antibacterial medicament tebipenem pivoxil. (4R,5R,6S)-3-((diphenyl-phosphoroso-carbonyl)oxyl)-6-((R)-1-ethoxyl)-4-methyl-7-carbonyl-1-azabicyclo[3.2.0]heptane-2-alkenyl-2-carboxylic acid p-nitro ester(6-MAP(I)) serving as a raw material reacts with 1-(4,5-dihydro-2-thiazolinyl)-3-sulfydryl azetidine hydrochloride (II) in the presence of alkali to obtain (4R,5S,6S)-3-((1-(4,5-dihydro-2-thiazolinyl)-3-azetidine) sulfenyl)-6-((R)-1-ethoxy)-4-methyl-7-oxygen-1-azabicyclo[3.2.0]heptane-2-alkenyl-2-carboxylic acid p-nitro ester (III); the protecting group of the compound (III) is removed under the catalytic hydrogenation condition to obtain (4R,5S,6S)-3-((1-(4,50dihydro-2-thiazolinyl)-3-azetidine)sulfenyl)-6-((R)-1-ethoxy)-4-methyl-7-oxygen-1-azabicyclo[3.2.0]heptane-2-alkenyl-2-carboxylic acid (IV); and the compound (IV) reacts with chloromethyl pivalate and sodium iodide or potassium iodide in the presence of alkali to obtain tebipenem pivoxil (V). According to the preparation method, the selected initial raw materials are low in price and easily available, so that the synthesizing route is simplified, the raw material utilization and total yield can be improved; and the intermediate substance obtained in the reaction is purified by using a re-crystallization method with high yield, less three wastes are generated in the reacting process, and the low cost is advantageous to industrial production.

Description

technical field [0001] The invention belongs to the field of medicinal chemistry, and in particular relates to a new preparation method of tipipenem ester, a novel oral antibacterial drug. Background technique [0002] The present invention relates to the synthesis of a novel oral antimicrobial drug tipipenem ester (V), the structural formula of which is as follows: [0003] [0004] Tebipenem pivoxil (Tebipenem pivoxil) is a new type of broad-spectrum antibiotic (V) for oral administration. It was originally developed by Wyeth Rieter Co., Ltd. in Japan, and was transferred to Meiji Seika Pharmaceutical Co., Ltd. in March 2002. It was released in April 2009 It was approved by the Ministry of Health and Welfare in Japan, and was first listed in Japan on August 26, 2009. Tipipenem axetil has a broad antibacterial spectrum. For most clinically isolated strains, tipipenem axetil has shown stronger antibacterial activity than penicillin series and cephalosporin series. Compar...

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Problems solved by technology

[0006] (1) In the patents EP0632039 and US5534510 applied by Wyeth Rieter Corporation of Japan, Abe, T. et al. disclose a synthetic route of tipipenem ester, which uses a silica gel chromatographic column or a large column for each step of the reaction. Pore ​​resin purification, low yield, difficult to achieve in large-scale production

[0007] (2) Yasuda, S. et al. of Meiji Pharmaceutical Co., Ltd. disclosed a new synthesis route of tipipenem ester in patent WO2004 / 035539 in 2004. The starting material price of this route is relatively low, but in the synthesis process Two special metal-organic reagents are used, which increases the production cost. At the same time, there are several steps in this route that require silica gel chromatography to purify the intermediates, which also increases the difficulty of large-scale production.

[0008] (3) In 2009, Kaneka Chemical Co., Ltd. of Japan disclosed another synthesis process of tipipenem ester in the patent US7524952. This route is similar to the synthesis route of Japan Meiji Pharmaceutical Co., Ltd., and this route uses protection and deprotection The process increases the steps of the synthetic route, which reduces the total yield. In addition, the silica gel chromatography column is used to purify the intermediate many times during the synthetic process, resulting in high production cost and low yield of this route, which is not suitable for large-scale industrial production. requirements

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