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A kind of preparation method of clindamycin phosphate

A technology of clindamycin phosphate and clindamycin, which is applied in the field of preparation of clindamycin phosphate, can solve the problems of material transfer and dripping, hidden dangers of operation safety, and leakage of phosgene, etc., so as to improve the purity , The effect of small product damage and low cost

Active Publication Date: 2021-02-19
福安药业集团重庆博圣制药有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, the phosgene produced by solid phosgene under the decomposition of DMF is highly toxic. There have been many vicious accidents in my country where phosgene leaked from companies using solid phosgene and caused death.
The reason for the leakage lies in the process of preparing the solid phosgene solution. The process used by the manufacturer is to first dissolve the solid phosgene in chloroform in the open field, and after fully dissolving, the trichloromethane dissolved in the solid phosgene The methane solution is transferred to the solvent tank with a solvent pipe and transported to the production workshop, and then the chloroform solution dissolved in solid phosgene is vacuum filtered into the high level tank, and the chloroform solution dissolved in solid phosgene is filtered through the pipeline Add it dropwise into a DMF reactor to form a chlorinated reagent. During the whole process, there are many and frequent material transfers and drops, and the chloroform solution dissolved in solid phosgene is in the state of being heated and wet during the transfer process. It is easy to decompose and produce phosgene, which is easy to cause leakage, cause phosgene volatilization and cause poisoning incidents, and there are great safety hazards in operation

Method used

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  • A kind of preparation method of clindamycin phosphate
  • A kind of preparation method of clindamycin phosphate
  • A kind of preparation method of clindamycin phosphate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0052] 1) Preparation of Clindamycin Isopropylidene

[0053] Add 120g (0.2364mol) of clindamycin hydrochloride alcoholate, 60g (0.405mol) of triethyl orthoformate to 480g of acetone, then add 1.8g (0.01mol) of p-toluenesulfonic acid, and keep warm at 40°C for 3 Hours; after the reaction is completed by pointing the board, cool down to 0°C, grow the crystal for 2 hours, filter, wash with acetone; add the obtained wet product to 200g purified water containing 26.5g sodium carbonate (0.25mol) and 200g acetone, and stir at 50°C After 30 minutes, the temperature was lowered to 20° C. to grow crystals for 2 hours, filtered, and then dried at 70° C. to obtain 105 g of clindamycin isopropylidene, with a yield of 95.0% and a purity of ≥99.2%.

[0054] 2) Preparation of Clindamycin Phosphate

[0055] Add 32.5g (0.47mol) of 1,2,4-triazole into 520g of dichloromethane, cool down to 0°C, then slowly add dropwise a dichloromethane solution containing 30.6g (0.2mol) of phosphorus oxychlorid...

Embodiment 2

[0059] 1) Preparation of Clindamycin Isopropylidene

[0060] Add 79g (0.15mol) of clindamycin hydrochloride alcoholate and 44g (0.3mol) of triethyl orthoformate to 290.4g of acetone, then add 0.86g (0.005mol) of p-toluenesulfonic acid, and keep the reaction at 45°C 3 hours; after the reaction is completed by pointing the plate, cool down to 0°C, grow the crystal for 2 hours, filter and wash with acetone; Stir for 30 minutes, then cool down to 20°C to grow crystals for 2 hours, filter, and then dry at 70°C to obtain 69 g of clindamycin isopropylidene, with a yield of 94.3% and a purity of ≥99.0%.

[0061] 2) Preparation of Clindamycin Phosphate

[0062] Add 27.6g (0.4mol) of 1,2,4-triazole into 420g of dichloromethane, cool down to 0°C, then slowly add dropwise a solution of dichloromethane containing 15.3g (0.1mol) of phosphorus oxychloride, dropwise After adding, slowly add the dichloromethane solution containing 46.5g (0.1mol) clindamycin isopropylidene base dropwise, then...

Embodiment 3

[0066] 1) Preparation of Clindamycin Isopropylidene

[0067] Add 152g (0.3mol) of clindamycin hydrochloride alcoholate and 74g (0.5mol) of triethyl orthoformate to 580g of acetone, then add 2.6g (0.015mol) of p-toluenesulfonic acid, and keep warm at 40°C for 3 Hours; after the reaction is completed by pointing the board, cool down to 0°C, grow crystals for 2 hours, filter, and wash with acetone; the obtained wet product is added to 253g of purified water containing 41.3g of sodium carbonate (0.39mol) and 253g of acetone, and stirred at 50°C After 30 minutes, the temperature was lowered to 20° C. to grow crystals for 2 hours, filtered, and then dried at 70° C. to obtain 132 g of clindamycin isopropylidene, with a yield of 95.0% and a purity of ≥99.2%.

[0068] 2) Preparation of Clindamycin Phosphate

[0069] Add 38g (0.55mol) of 1,2,4-triazole into 600g of dichloromethane, cool down to 0°C, then slowly add dropwise a solution of dichloromethane containing 38.3g (0.25mol) of ph...

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Abstract

The invention belongs to the technical field of chemical synthesis and relates to a preparation method of clindamycin phosphate. The method of the present invention uses clindamycin hydrochloride alcoholate as a raw material to prepare clindamycin isopropylidene, and then uses phosphorus oxychloride as a phosphating agent and 1,2,4-triazole as an acid-binding agent, A phosphoesterification reaction occurs to obtain isopropylidene clindamycin phosphate, which is finally deprotected by mixed acid hydrolysis to obtain clindamycin phosphate. The method of the present invention prepares clindamycin phosphate by a one-step method of organic acid hydrolysis. The product is refined so that the molar yield of clindamycin phosphate can reach 96.15%, and the crystal form of the product is good (bulk density, fluidity), which is very conducive to aseptic packaging.

Description

technical field [0001] The invention belongs to the technical field of chemical synthesis and relates to a preparation method of clindamycin phosphate. Background technique [0002] Clindamycin Phosphate, chemical name 6(1-methyl-trans-4-propyl-L-pyrrolidinecarboxamido)-1-thio-7(s)-chloro-6 , 7,8-trideoxy-L-threo-a-D-galactopyranoside-2-phosphate, white crystalline powder, hygroscopic, easily soluble in water, slightly soluble in methanol, in ethanol, Almost insoluble in acetone. Its structural formula is: [0003] [0004] Clindamycin phosphate is widely used clinically. It is a derivative of lincomycin hydrochloride and belongs to antibiotic drugs. The mechanism of action is to inhibit bacterial protein synthesis. Its antibacterial spectrum is the same as that of lincomycin, and it is effective against Gram-positive bacteria such as Staphylococcus aureus, Staphylococcus epidermidis, Streptococcus hemolyticus, Streptococcus viridans, Pneumococcus pneumoniae, and Bacil...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07H1/00C07H15/16
CPCC07H1/00C07H15/16
Inventor 罗开伟张闯洪荣川袁明华陈伟东万军李隆骄
Owner 福安药业集团重庆博圣制药有限公司
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