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Method for preparing clindamycin hydrochloride

A technology of clindamycin hydrochloride and lincomycin hydrochloride, applied in the field of medicinal chemistry, can solve the problems of high content of related substances, long reaction time, inability to meet the requirements of high-end customers, etc., to reduce the content of impurities and avoid easy absorption The effect of tide and process optimization

Active Publication Date: 2013-06-26
ZHEJIANG HISOAR PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The 7-epiclindamycin content of this process≤0.2%, but the reaction time is long, and the consumption of solid phosgene is large, the inventor repeats experiment and records the HPLC purity of clindamycin hydrochloride finished product 2%
[0017] Generally speaking, the existing preparation method of clindamycin hydrochloride still has deficiencies, the product purity needs to be further improved, and the content of related substances is relatively high, which cannot meet the requirements of high-end customers

Method used

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  • Method for preparing clindamycin hydrochloride
  • Method for preparing clindamycin hydrochloride
  • Method for preparing clindamycin hydrochloride

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0070] Example 1 Preparation of clindamycin hydrochloride

[0071] Add 90kg of chloroform, 16kg of DMF and 10kg of lincomycin hydrochloride (HPLC purity 99.6%) into the reaction kettle in turn, cool to 0°C, add 10kg of solid phosgene in batches, control the temperature in the kettle not to exceed 15°C when adding, and then Raise the temperature to 40°C for 15 hours, and then react at 65°C for 3 hours. HPLC detects that the content of lincomycin hydrochloride in the reaction system is less than 1.0%, and the reaction is complete.

[0072] Cool the above reaction solution to 20°C, add 10% sodium hydroxide aqueous solution dropwise, adjust the pH to 9, control the temperature of the system not to exceed 30°C, keep it warm for 2 hours, let it stand for layers, extract the water phase once with 70kg of chloroform, and combine The organic phase was washed once with 20 L of water, and the organic phase was concentrated in vacuum below 80° C. until no liquid droplets appeared to ob...

Embodiment 2

[0076] Example 2 Preparation of clindamycin hydrochloride

[0077] Add 120kg of chloroform, 20kg of DMF and 10kg of lincomycin hydrochloride (HPLC purity 99.6%) into the reaction kettle in turn, cool to 0°C, add 13kg of solid phosgene in batches, control the temperature in the kettle not to exceed 15°C when adding, and then The temperature was raised to 50°C for 15 hours, and then at 55°C for 5 hours. HPLC detects that the content of lincomycin hydrochloride in the reaction system is less than 1.0%, and the reaction is complete.

[0078] Cool the above reaction solution to 20°C, add 10% sodium hydroxide aqueous solution dropwise, adjust the pH to 12, control the temperature of the system not to exceed 30°C, keep it warm for 2 hours, let it stand for stratification, extract the water phase once with 70kg of chloroform, and combine The organic phase was washed once with 20 L of water, and the organic phase was concentrated in vacuum below 80° C. until no liquid droplets appe...

Embodiment 3

[0082] Example 3 Preparation of clindamycin hydrochloride

[0083] Add 55kg of chloroform, 16kg of DMF and 10kg of lincomycin hydrochloride (HPLC purity 99.5%) into the reaction kettle in sequence, cool to 0°C, add dropwise a solution of 11kg of solid phosgene dissolved in 25kg of chloroform, and finish adding in 3 hours. The temperature in the kettle does not exceed 10°C, and then the temperature is raised to 45°C for 10 hours, and then reacted at 60°C for 4 hours. When the content of lincomycin hydrochloride in the reaction system detected by HPLC is less than 1.0%, the reaction is complete.

[0084] Cool the above reaction solution to 20°C, add 10% sodium hydroxide aqueous solution dropwise, adjust the pH to 10, control the temperature of the system not to exceed 30°C, keep it warm for 2 hours, let it stand for stratification, extract the water phase once with 70kg of chloroform, and combine The organic phase was washed once with 20 L of water, and the organic phase was...

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Abstract

The invention provides a method for preparing clindamycin hydrochloride. The method for preparing clindamycin hydrochloride comprises the following steps that: (1) performing chlorination reaction of clindamycin hydrochloride and a Vilsmeiser reagent, so as to obtain a reaction liquid containing clindamycin hydrochloride crude product; (2) performing hydrolysis, extraction and concentration on the reaction liquid so as to obtain clindamycin free alkali and then insulating for 20-120 minutes at 90-120 DEG C; (3) performing the salt forming reaction of clindamycin hydrochloride alcoholate in an ethanol water solution with the volume percentage concentration of 90-95 percent so as to obtain clindamycin hydrochloride alcoholate; and (4) dealcoholating the clindamycin hydrochloride alcoholate to obtain clindamycin hydrochloride. Based on the method for preparing clindamycin hydrochloride, the content of impurities is effectively controlled and remarkably reduced through technological optimization and high-quality clindamycin hydrochloride with the purity of more than 99.5 percent is obtained, especially the content of 7-epiclindamycin is less than 0.1 percent, and 4-chloroclindamycin is not detected. The method provided by the invention is suitable for industrial production.

Description

technical field [0001] The invention belongs to the field of medicinal chemistry, and relates to a preparation method of a crude drug, in particular to a preparation method of clindamycin hydrochloride. Background technique [0002] Clindamycin is a semi-synthetic derivative obtained by replacing the 7-hydroxyl of lincomycin with a chlorine atom, and is a lincosamide antibiotic. Its antibacterial spectrum is the same as that of lincomycin, its antibacterial activity is 4-8 times stronger than that of lincomycin, and its absorption is fast and complete. It is suitable for lower respiratory tract infection and skin and soft tissue infection caused by anaerobic bacteria, Streptococcus pneumoniae, other Streptococcus (except Enterococcus) and sensitive Staphylococcus aureus; it is often used in combination with other antibacterial drugs for abdominal infection and pelvic infection Treatment. Clindamycin has a definite curative effect and has been included in the pharmacopoeias...

Claims

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Application Information

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IPC IPC(8): C07H15/16C07H1/00
Inventor 唐方辉许会凌李洪明张群辉孙常磊
Owner ZHEJIANG HISOAR PHARMA
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