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Preparation method of doripenem

A technology of doripenem and deprotection is applied in the field of preparation of carbapenem compound doripenem, which can solve the problems of poor purity, low product yield, difficult post-processing and the like

Inactive Publication Date: 2016-01-20
双鹤药业(海南)有限责任公司
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  • Summary
  • Abstract
  • Description
  • Claims
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Problems solved by technology

These methods have fast reaction speed, many degradation products, low product yield, poor purity, and difficult post-processing.

Method used

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Effect test

Embodiment 1

[0018] The production of doripenem requires four steps of deprotection of the side chain of doripenem, condensation, hydrogenation deprotection, and refining. The specific implementation steps are as follows:

[0019] Step 1: Side chain deprotection

[0020] raw material name molecular weight Feeding amount moles Remark doripenem side chain 532.59 8.16kg 15.32mol —— concentrated sulfuric acid 98 3.84kg 38.40mol —— Anhydrous Methanol —— 33.6kg —— —— ethyl acetate —— 54kg —— —— 5% NaCl —— 40kg×3 —— —— activated carbon —— 0.8kg —— —— Anhydrous Sodium Sulfate —— 5~6kg —— ——

[0021] In a 100L reaction kettle, add 33.6kg of anhydrous methanol under nitrogen protection, slowly add 3.84kg of concentrated sulfuric acid while stirring to make a sulfuric acid methanol solution; add 8.16kg of doripenem side chains, stir and heat to 62-65°C The reaction system was refluxed, the solid gradually dis...

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Abstract

The invention relates to a preparation method of doripenem. The method comprises the following steps: removing an acetyl group and a tert-butyloxycarbonyl group from an acetylthiopyrrolidine derivative (SM-1) used as an initial raw material to prepare a thiopyrrolidine derivative (DN-1), carrying out a nucleophilic substitution reaction on the DN-1 and a doripenem parent nucleus (SM-2, MAP) to prepare protected doripenem, carrying out catalytic hydrogenation to remove PNZ and PNB protection, and purifying to obtain final doripenem. A solvent and a catalyst used in the method can be recycled, so the production cost is greatly saved, and the method is suitable for large-scale industrial production.

Description

technical field [0001] The invention belongs to the field of synthesizing carbapenem antibacterial drugs, and in particular relates to a preparation method of carbapenem compound doripenem. Background technique [0002] Doripenem (Doripenem) is a broad-spectrum carbapenem antibacterial drug developed by Shionogi Co., Ltd. of Japan. It was first launched in Japan in September 2005 under the trade name Finibax. The injection of this product was launched in Japan in 2005, and was approved by the US FDA on October 15, 2007. This product belongs to 1β-methyl carbapenems, and the 2-position side chain is tetrahydropyrrole substituted with aminosulfonamide group. Ring, due to the sulfonylation of the side chain amino group, this product has strong antibacterial activity. This product has good antibacterial activity against most Gram-negative bacteria, Gram-positive bacteria and anaerobic bacteria. The antibacterial activity against gram-positive (G+) bacteria is better than that ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D477/20C07D477/06
CPCC07D477/20C07D477/06
Inventor 魏雪纹李强
Owner 双鹤药业(海南)有限责任公司
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