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Method for synthetizing clarithromycin intermediate

A technology of clarithromycin and its synthesis method, which is applied in the field of synthesis of clarithromycin intermediates, can solve the problems of pyridine corrosive equipment, safety and environmental hazards, pyridine explosion, etc., and achieve the elimination of major safety hazards, safe and reliable production, Environmentally friendly effect

Inactive Publication Date: 2012-08-15
ZHEJIANG UNIV OF TECH +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0007] However, pyridine hydrochloride is easy to corrode equipment, pyridine is explosive, has strong irritation and neurotoxicity, and brings great safety and environmental protection risks to production.

Method used

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  • Method for synthetizing clarithromycin intermediate
  • Method for synthetizing clarithromycin intermediate
  • Method for synthetizing clarithromycin intermediate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0035] According to the amount of substance, lactam: concentrated hydrochloric acid is 1.0: 1.0 feeding, wherein N-methyl-pyrrolidone (9.9g, 0.1mol), concentrated hydrochloric acid (10g, 0.1mol), organic solvent absolute ethanol is 40mL, stir at room temperature After 4 hours, the solvent was removed by rotary evaporation, and then 20 mL of absolute ethanol was added, and then rotary evaporation was repeated, the above operation was repeated 3 times, and the filter cake was filtered with suction. The resulting filter cake was a white solid, which was dried to obtain 12.5 g of N-methyl-pyrrolidone hydrochloride The yield was 92%.

[0036] According to the amount of substance, lactam: concentrated hydrochloric acid is 1.0: 1.0 feeding, wherein N-ethyl-pyrrolidone (11.3g, 0.1mol), concentrated hydrochloric acid (10g, 0.1mol), organic solvent absolute ethanol is 40mL, stir at room temperature After 6 hours, the solvent was removed by rotary evaporation, then 20 mL of absolute etha...

Embodiment 2

[0043] According to the amount of substance ratio erythromycin A-9-oxime, lactam salt and etherifying agent are 1.0: 1.5: 3.0 feed intake, wherein erythromycin A-9-oxime is 10g (0.0137mol, purity is 94.5%), 2.78 g (0.0205 mol) of N-methyl-pyrrolidone hydrochloride, 5.3 g (0.041 mol) of 2-ethoxypropene, 120 mL of organic solvent dichloromethane, 3.15 g of imidazole, and 4 mL of trimethylchlorosilane.

[0044] First, add erythromycin A-9-oxime and 120 mL of dichloromethane into the reaction flask, turn on the mechanical stirring, heat to 40 ° C, cool to room temperature, add N-methyl-pyrrolidone hydrochloride, and then drop 2 -Ethoxypropene, after the dropwise addition, control the temperature between 20-25 degrees Celsius, after 2 hours of reaction, add imidazole and trimethylchlorosilane, control the temperature at 25-30 degrees Celsius, after 1 hour of reaction, add 40mL of water to stop reaction. The system is layered, take the dichloromethane layer, add 50mL saturated brin...

Embodiment 3

[0046] Ratio erythromycin A-9-oxime by substance amount, lactam salt and etherifying agent are 1.0: 2.0: 3.0 feeding intake, wherein erythromycin A-9-oxime is 10g (0.0137mol, purity is 94.5%), 3.71g (0.0274mol) of N-methyl-pyrrolidone hydrochloride, 4.76g (0.041mol) of 2-methoxypropene, 80mL of organic solvent N, N-dimethylformamide, 3.15g of imidazole, trimethyl Chlorosilane was 4 mL.

[0047] Add N-methyl-pyrrolidone hydrochloride to the solution of erythromycin A-9-oxime in N,N-dimethylformamide, then add 2-methoxypropene dropwise, after the dropwise addition, control the temperature Between 10 and 15 degrees Celsius, after reacting for 3 hours, add imidazole and trimethylchlorosilane, control the temperature between 20 and 25 degrees Celsius, and after reacting for 2 hours, add 30 mL of water to stop the reaction. The reaction solution was not separated after standing, adding 30mL of ethyl acetate to extract, repeating the operation 3 times, combining the ethyl acetate la...

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Abstract

The invention discloses a method for synthetizing clarithromycin intermediate, which includes: dissolving erythrocin A-9-oxime shown as the formula II in organic solvent, adding lactam salt shown as the formula IV and etherifying agent shown as the formula III, reacting for 1-4 hours at the temperature of 10-60 DEG C, adding imidazole and trimethylchlorosilane, reacting 1-3 hours at the temperature of 20-60 DEG C, adding water to stop reaction, separating and purifying reaction liquid to prepare clarithromycin intermediate shown as the formula I. Compared with the prior art, the method for synthetizing clarithromycin intermediate has the advantages that environment-friendly lacetam salt prepared by the method is used for substituting pyridine hydrochloride used in the prior art, problems of potential safety hazards and serious waste pollution and the like of the pyridine hydrochloride are eliminated, and the method is safe, low in waste discharge, high in product yield, fine in purity and the like and is applicable to industrialized production.

Description

(1) Technical field [0001] The invention discloses a synthesis method of a clarithromycin intermediate. (2) Background technology [0002] As the second generation of macrolide antibiotics, clarithromycin, also known as clarithromycin, its chemical name is 6-O-methyl erythromycin, a macrolide antibiotic, and its activity in the body is significantly higher than that of erythromycin. Mycin, resistant to acid and enzyme, has good pharmacokinetic properties, and is one of the first-choice drugs for oral antibiotics. In recent years, the market prospect of clarithromycin has become increasingly optimistic, especially in the aspect of children's medicine, it has obviously become a rising variety. [0003] Most of clarithromycin chemical synthesis methods in the prior art use erythromycin A-9-oxime as the starting material through etherification reaction, silanization reaction to add protective group, methylation and deprotection reaction steps. [0004] For example, the clarith...

Claims

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Application Information

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IPC IPC(8): C07H23/00C07H1/00
Inventor 李坚军苏为科戴佳佳侯仲轲朱兴一孟仲健邱家军
Owner ZHEJIANG UNIV OF TECH
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