Tigecycline impurity stereoselective preparation method

A technology of stereoselectivity and tigecycline, which is applied in the field of preparation of tigecycline impurity E, can solve problems such as no literature reports in the preparation, and achieve the effects of good stereoselectivity, improved quality and high yield

Active Publication Date: 2014-11-19
福安药业集团重庆博圣制药有限公司 +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0005] According to the Pharmacopoeia standard, there are no less than 7 kinds of impurities in the finished product of tigecycline, among which, the preparation of impurity E (structural formula as shown below) has not been reported in the literature

Method used

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  • Tigecycline impurity stereoselective preparation method
  • Tigecycline impurity stereoselective preparation method

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0022] Add 500 ml of methanol and 40 ml of acetic acid into a 1 L reaction bottle, and add 40 g of minocycline hydrochloride (source: North China Pharmaceutical Co., Ltd., the same below) under stirring. Raise the temperature to 40°C, hold the reaction for 3 hours, stop heating, lower the temperature to -5-5°C, control the temperature and add triethylamine dropwise, adjust the pH value to 7.5-8.0, precipitate a light yellow solid, control the temperature at 0-5°C and stir for 2 hours, The pH value did not change again, filtered, washed the filter cake with methanol, and dried under reduced pressure at room temperature for 4 hours to obtain 19.4 g of tigecycline impurity E with a purity of 98.2% and a yield of 52.5%.

[0023] The condition and the method (the same below) that HPLC method detects tigecycline impurity E purity are:

[0024] Chromatographic column: ODS-BP C18 (4.6×250mm 5μm);

[0025] Mobile phase: acetonitrile—0.05mol / L ammonium dihydrogen phosphate solution (ad...

Embodiment 2

[0036] Add 500ml of methanol and 38ml of formic acid into a 1L reaction flask, and add 40g of minocycline hydrochloride under stirring. Raise the temperature to 40°C, keep it warm for 3 hours, stop heating, lower the temperature to -5-5°C, control the temperature and add methylamine dropwise, adjust the pH value to 7.5-8.0, precipitate a light yellow solid, control the temperature at 0-5°C and stir for 2 hours, repeat There was no change in the pH value, filtered, washed the filter cake with methanol, and dried under reduced pressure at room temperature for 4 hours to obtain 20 g of tigecycline impurity E with a purity of 98.5% and a yield of 54.2%.

Embodiment 3

[0038] Add 500ml of ethanol and 40ml of formic acid into a 1L reaction flask, and add 40g of minocycline hydrochloride under stirring. Raise the temperature to 40°C, hold the reaction for 3 hours, stop heating, lower the temperature to -5-5°C, control the temperature and add sodium carbonate, adjust the pH value to 7.6-8.0, precipitate a light yellow solid, control the temperature at 0-5°C and stir for 2 hours, retest The pH value remained unchanged, filtered, washed the filter cake with ethanol, and dried under reduced pressure at room temperature for 4 hours to obtain 19.6 g of tigecycline impurity E with a purity of 98.2% and a yield of 53%.

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Abstract

The invention discloses a tigecycline impurity stereoselective preparation method. According to the invention, minocycline hydrochloride is adopted as a raw material, and is stirred in lower alkanol and liquid acid; the temperature is increased to 35-45 DEG C; the temperature is maintained and a reaction is allowed for 2-5h; the temperature is reduced, and the pH value of the mixed liquid is regulated to 6.5-8.5, such that solid is precipitated; a reaction is carried out for 2h under controlled temperature; the pH value is retested and the pH value is not changed; the material is filtered; a lower alkanol solvent is used for washing a filter cake; and drying is carried out, such that tigecycline impurity E is obtained. The purity can be higher than 98.0%, and a yield is higher than 50%.

Description

technical field [0001] The invention belongs to the technical field of medicine, and in particular relates to a preparation method of tigecycline impurity E. Background technique [0002] Tigecycline (Tigecycline), the chemical name is (4S,4aS,5aR,12aS)-4,7-bis(dimethylamino)-9-[(tert-butylamino)acetamido]-3,10, 12,12a-tetrahydroxy-1,11-dioxo-1,4,4a,5,5a,6,11,12a-octahydrotetracene-2-carboxamide, the structural formula is as follows: [0003] [0004] Tigecycline was developed by Wyeth, and it was first approved for marketing in the United States in July 2005 in the form of lyophilized powder for injection. It is mainly used for the treatment of gram-negative and positive pathogenic bacteria, anaerobic bacteria, Complicated intra-abdominal infection, skin and skin tissue infection, pneumococcal infection, etc. [0005] According to the Pharmacopoeia standard, there are no less than 7 kinds of impurities in the finished product of tigecycline, and the preparation of impu...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C237/26C07C231/08
Inventor 唐劲包丹谭超张军
Owner 福安药业集团重庆博圣制药有限公司
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