Process for synthesizing clindamycin hydrochloride

A technology of clindamycin hydrochloride and lincomycin hydrochloride, which is applied in the field of clindamycin hydrochloride synthesis technology, can solve the problems of many steps, high impurities, large impurities, etc., and achieve the effect of increased yield and high yield

Inactive Publication Date: 2010-11-24
ZHANGJIAGANG XINYI CHEM
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Like other semi-synthetic antibiotics, clindamycin is the fundamental factor affecting product quality, yield and cost due to many steps and complicated process. The current popular preparation method is basically to prepare gram hydrochloride in the following way: Lincomycin: 1. Using lincomycin hydrochloride as the basic raw material, in the solvent system of dichloroethane / chloroform, complete the Vilsmeier reaction, and then undergo alkaline hydrolysis to obtain clindamycin free base (excessive state); 2. Clindamycin free base (excessive state), in absolute ethanol, forms a complex with hydrochloric acid / ethanol: clindamycin hydrochloride alcoholate, separated by centrifugation; 3. Clindamycin hydrochloride compound, in the water phase, and then under relatively strong conditions, the ethanol in the molecule is removed to obtain the target compound-clindamycin hydrochloride. This process system has the following disadvantages: ① due to the chlorination activity of phosphorus oxychloride If the temperature is low, the reaction must be completed at a higher temperature; ②The increase of the reaction temperature leads to a large amount of impurities in the reaction, especially the main impurity, Epiclinoid, is maintained at 1.3-1.5%; The salt of free base and hydrochloric acid cannot be directly crystallized, and must be passed through the intermediate clindamycin hydrochloride alcoholate; ④ the intermediate clindamycin hydrochloride alcoholate must be dealcoholized and transformed under severe conditions

Method used

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Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0017] (1) Chlorination reaction: get lincomycin hydrochloride 80 billion, methylene chloride 800Kg, solid phosgene [two (trichloromethyl) carbonate] 100Kg, DMF150Kg, antioxidant i.e. four [β-(3 , 2Kg of 5-di-tert-butyl-4-hydroxyphenyl) propionate] pentaerythritol ester, mix the above-mentioned five substances, keep the reaction at 30-50°C for 24 hours, and then lower the temperature to 0-10°C;

[0018] (2) Hydrolysis reaction: Take 100Kg of sodium hydroxide and 1200Kg of water, stir and dissolve, then add to the product of step (1), and heat-preserve and hydrolyze for 6 hours at 20-40°C;

[0019] (3) Salt-forming reaction: layering, washing the clindamycin free base obtained in step (2), concentrating dichloromethane, adding 750Kg of acetone, 15Kg of water, and 18Kg of hydrochloric acid, stirring and crystallizing at 0-20°C, Get clindamycin hydrochloride wet product;

[0020] (4) drying to obtain 80Kg of dry product clindamycin hydrochloride, the weight yield is 100%, and th...

Embodiment 2

[0022] (1) Chlorination reaction: get lincomycin hydrochloride 160 billion, dichloromethane 1500Kg, solid phosgene 230Kg, DMF250Kg, antioxidant tetrakis [β-(3,5-di-tert-butyl-4-hydroxybenzene base) propionic acid] pentaerythritol ester 3.5Kg, the above five substances are mixed, at 30 ~ 50 ° C, heat preservation reaction for 36 hours, and then cooled to 0 ~ 10 ° C;

[0023] (2) Hydrolysis reaction: Take 200Kg of sodium hydroxide and 1500Kg of water, stir and dissolve, then add to the product of step (1), at 20-40°C, heat-preserve and hydrolyze for 5 hours;

[0024] (3) Salt-forming reaction: layering, washing the clindamycin free base obtained in step (2), concentrating dichloromethane, adding 1500Kg of acetone, 35Kg of water, and 40Kg of hydrochloric acid, stirring and crystallizing at 0-20°C, Get clindamycin hydrochloride wet product;

[0025] (4) drying to obtain dry product clindamycin hydrochloride 163Kg, weight yield 101.88%, impurity content epicrine≤0.2%.

Embodiment 3

[0027] (1) Chlorination reaction: get lincomycin hydrochloride 240 billion, chloroform 2000Kg, solid phosgene 340Kg, DMF400Kg, antioxidant tetrakis [β-(3,5-di-tert-butyl-4-hydroxybenzene base) propionic acid] pentaerythritol ester 4.5Kg, the above five substances are mixed, at 30 ~ 50 ° C, heat preservation reaction for 48 hours, and then cooled to 0 ~ 10 ° C;

[0028] (2) Hydrolysis reaction: Take 300Kg of sodium hydroxide and 2500Kg of water, stir and dissolve, then add to the product of step (1), at 20-40°C, heat-preserve and hydrolyze for 6 hours;

[0029] (3) Salt-forming reaction: layering, washing the clindamycin free base obtained in step (2), concentrating chloroform, adding 2800Kg of acetone, 50Kg of water, and 60Kg of hydrochloric acid, stirring and crystallizing at 0-20°C, Get clindamycin hydrochloride wet product;

[0030] (4) drying to obtain dry product clindamycin hydrochloride 243Kg, weight yield 101.25%, impurity content epicrine≤0.2%.

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Abstract

The invention relates to a process for synthesizing new clindamycin hydrochloride. The process comprises the following steps of: 1) finishing chlorination reaction by using lincomycin hydrochloride as a basic raw material and using low-C halogenated hydrocarbon as a solvent; 2) finishing hydrolysis reaction of sodium hydroxide in an aqueous phase by using a product obtained in the step 1), and demixing the solution to obtain clindamycin free alkali; and 3) in a solvent system of acetone, performing salt forming reaction on the clindamycin free alkali obtained in the step 2) and hydrochloric acid, and crystallizing the reaction product to obtain the clindamycin hydrochloride. The invention has the advantages that: 1, the process is simple; 2, the process reduces one-step chemical reaction on chemical unit reaction; 3, the process reduces one raw material and one intermediate on materials and intermediate links; and 4, the yield of the product is greatly improved, the epimer clint content of impurities is reduced by 80 percent, the process has high yield, and the yield is improved by over 5 percent compared with a four-step method.

Description

technical field [0001] The invention relates to a new synthesis process of clindamycin hydrochloride. Background technique [0002] Clindamycin hydrochloride is a lincomycin antibiotic, a semi-synthetic derivative obtained by replacing the 7th hydroxyl in the lincomycin molecule with chloride ions by Magerlein et al. Its antibacterial effect is stronger than that of lincomycin4 ~8 times, it has gradually replaced the position of lincomycin in clinical practice. Like other semi-synthetic antibiotics, clindamycin is the fundamental factor affecting product quality, yield and cost due to many steps and complicated process. The current popular preparation method is basically to prepare gram hydrochloride in the following way: Lincomycin: 1. Using lincomycin hydrochloride as the basic raw material, in the solvent system of dichloroethane / chloroform, complete the Vilsmeier reaction, and then undergo alkaline hydrolysis to obtain clindamycin free base (excessive state); 2. Clinda...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07H15/16C07H1/00
Inventor 楼新灿陈立坤
Owner ZHANGJIAGANG XINYI CHEM
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