A kind of synthetic method of clindamycin phosphate

A clindamycin phosphate and synthesis method technology, applied in chemical instruments and methods, preparation of sugar derivatives, sugar derivatives, etc., can solve problems such as material transfer and dripping, hidden dangers in operation safety, phosgene leakage, etc. , to achieve the effect of increasing conversion rate, reducing impurities and easy handling

Active Publication Date: 2016-04-20
TOPFOND PHARMA CO LTD
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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 synthetic method of clindamycin phosphate
  • A kind of synthetic method of clindamycin phosphate
  • A kind of synthetic method of clindamycin phosphate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0033] (1) Chlorination reaction Put 287kg of solid phosgene into 1250kg of chloroform, stir and dissolve, add 225kg of DMF back dropwise at below 10°C, stir for 4 hours below 10°C after dropping, and then add Linco hydrochloride in batches Clindamycin 205kg, heated up to 68°C by slow heating method (5°C / h) reflux, heat preservation reaction for 8h, then cooled down to below 10°C, added alkali hydrolysis, concentrated by distillation to remove most of the chloroform, and obtained clindamycin free base Solution (contains about 200kg clindamycin free base);

[0034] (2) Ketonization reaction Add the clindamycin free base solution obtained in step (1), 1640kg of acetone, 615kg of triethyl orthoformate, and 5kg of p-toluenesulfonic acid into a reaction tank and react at 20°C for 10 hours to obtain propylidene Acetone solution of free base (contains about 210kg of propylidene free base);

[0035] (3) Phosphorylation reaction Add 225 kg of triethylamine, 123 kg of phosphorus oxychl...

Embodiment 2

[0038] (1) Chlorination reaction: put 62kg of solid phosgene into 250kg of chloroform, stir and dissolve, then add 57kg of DMF back dropwise at below 10°C, stir for 4 hours below 10°C after dropping, add Linco hydrochloride in batches Clindamycin 41kg, heated up to 65°C by slow heating method (4°C / h) reflux, kept for 10 hours, then cooled to below 10°C and hydrolyzed with alkali, distilled and concentrated to remove most of the chloroform to obtain clindamycin free base Solution (contains about 42kg clindamycin free base);

[0039] (2) Ketonization reaction Add the clindamycin free base solution obtained in step (1), 328kg of acetone, 123g of triethyl orthoformate, and 1kg of p-toluenesulfonic acid into a reaction tank and react at 50°C for 3 hours to obtain propylidene Acetone solution of free base (containing about 44kg propylidene free base);

[0040] (3) Phosphorylation reaction Add 45 kg of triethylamine, 25 kg of phosphorus oxychloride, and 41 kg of imidazole to the ace...

Embodiment 3

[0043] (1) Chlorination reaction: put 370kg of solid phosgene into 1750kg of chloroform, stir to dissolve, add 345kg of DMF back dropwise at 5°C, stir at 5°C for 4h, add lincomycin hydrochloride in batches 287kg, the temperature was raised to 71°C by slow heating method (6°C / hour) reflux, and the temperature was kept for 2 hours, then the temperature was lowered to below 10°C, hydrolyzed with alkali, most of the chloroform was removed by distillation and concentration, and clindamycin free alkali solution was obtained (contains about 290kg clindamycin free base);

[0044] (2) Ketonization reaction Add the clindamycin free base solution obtained in step (1), 1150kg acetone, 560kg triethyl orthoformate, and 5.7kg p-toluenesulfonic acid into a reaction tank and react at 35°C for 6h to obtain acetone Acetone solution of propylidene free base (containing about 300kg propylidene free base);

[0045] (3) Phosphorylation reaction Add 315 kg of triethylamine, 175 kg of phosphorus oxyc...

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Abstract

The invention belongs to the technical field of chemical synthesis and specifically relates to a synthetic method of clindamycin phosphate. The method comprises the following steps of synthesis of clindamycin free alkali, ketonization reaction, phosphorylation reaction and aftertreatment. According to the invention, the weight yield of the clindamycin phosphate can reach over 80% by changing a charging sequence, steps and a catalyst.

Description

technical field [0001] The invention belongs to the technical field of chemical synthesis, and in particular relates to a synthesis method of clindamycin phosphate. Background technique [0002] Clindamycin phosphate is a broad-spectrum antibiotic and is widely used clinically. It is a semi-synthetic derivative of lincomycin hydrochloride, and its 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 Bacillus diphtheria, as well as Peptococcus, Peptostreptococcus, Anaerobic bacteria such as Bacteroides fragilis, Fusobacterium, Eubacterium, and Propionibacterium have antibacterial effects. Clindamycin phosphate has good water solubility and is widely used at home and abroad for its antibacterial properties of high eff...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07H15/16C07H1/00
Inventor 房凤香吕和平刘晓光祝力新孟利沙王玉梅刘新凯王勤波牛景丽王丽孔卫红李翠萍王媛张明明张垒
Owner TOPFOND PHARMA CO LTD
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