Methylation reaction in clarithromycin synthesis process and recycling method of methylation reagent

A synthesis process and technology of clarithromycin, applied in chemical recovery, organic chemistry, sugar derivatives, etc., can solve the problems of reports that do not introduce the recovery and utilization of alkylating reagents, achieve strong methylation selectivity, avoid double Effects of methyl impurities

Active Publication Date: 2012-10-10
ZHEJIANG GUOBANG PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0009] Judging from the reported papers and patents, there is no report on the recycling of alkylating reagents

Method used

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Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0025] Put 20g (0.02mol) of compound 2 into 120g of methyl tert-butyl ether to dissolve, then add 120g of DMSO, cool to 15°C, add 7.6g (0.04mol) of methyl p-toluenesulfonate, stir for 5 minutes, and then add 2.3g (0.04mol) of potassium hydroxide powder, keep the reaction temperature at 15°C, react for 25 minutes, add 50ml of water to terminate the reaction, let it stand for stratification, directly recover the methyl tert-butyl ether liquid, and dry it to get 19.9 g solid compound 1, with a purity of 85.2%, including 6.4% of unreacted compound 2 and 2.2% of disubstituted impurities. The DMSO layer and the water layer were directly recovered and dried to obtain 9.0 g of solid potassium p-toluenesulfonate.

Embodiment 2

[0027] 20g (0.02mol) of compound 2 was dissolved in 120g of methyl tert-butyl ether, then 120g of DMSO was added, cooled to 15°C, 5.58g (0.03mol) of methyl p-toluenesulfonate was added, stirred for 5 minutes, and then 1.68 g (0.03mol) potassium hydroxide powder, keep the reaction temperature at 30°C, react for 20 minutes, add 50ml of water to terminate the reaction, let stand and separate, directly recover the methyl tert-butyl ether material liquid, and dry it to get 19.5g Solid compound 1 has a purity of 85.8%, of which 6.5% is unreacted compound 2 and 1.5% is a disubstituted impurity. The DMSO layer and the water layer were directly recovered and dried to obtain 11.3 g of solid potassium p-toluenesulfonate.

Embodiment 3

[0029] Put 20g (0.02mol) of compound 2 into 120g of methyl tert-butyl ether to dissolve, then add 120g of DMSO, cool to 0-5°C, add 13.0g (0.07mol) of methyl p-toluenesulfonate, stir for 5 minutes, then Put in 3.9g (0.07mol) of potassium hydroxide powder, keep the reaction temperature at 0-5°C, react for 60 minutes, add 50ml of water to terminate the reaction, let it stand for stratification, directly recover the methyl tert-butyl ether material liquid, and dry it 19.8g of solid compound 1 can be obtained with a purity of 86.7%, of which 5.4% is unreacted compound 2 and 2.2% is a disubstituted impurity. The DMSO layer and the water layer were directly recovered and dried to obtain 9.1 g of solid potassium p-toluenesulfonate.

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Abstract

The invention mainly discloses methylation reaction in a clarithromycin synthesis process and a recycling method of a methylation reagent. In the methylation reaction, methyl benzenesulfonate is used as the methylation reagent, potassium hydroxide is used as a catalyst, and methyl tertbutyl ether and dimethyl sulfoxide are used as solvents. After the methylation reaction, water is added for stratification, the dimethylsulfoxide (DMSO) layer is recycled and dried to obtain P-methyl benzene potassium sulfonate, dimethylsulfoxide is added for reaction to obtain P-methyl benzene sulfonyl chloride, and P-methyl benzene methyl sulfonate is regenerated via reaction with methanol. The generation of bismethyl impurities can be avoided effectively. Meanwhile, P-methyl benzene methyl sulfonate is regenerated via reaction of the dimethylsulfoxide and the methanol, and thus the recycling of the methylation reagent is realized.

Description

technical field [0001] The invention relates to the methylation reaction in the synthesis process of clarithromycin and the recovery and utilization of methylation reagents, and belongs to the technical field of preparation of macrolide drug intermediates and other compounds. Background technique [0002] (2', 4")-Obistrimethylsilyl-6-O-methylerythromycin A-9[O-(1-ethoxy-1-methylethyl)]oxime (Formula 1) is It is an intermediate in the process of synthesizing clarithromycin, which is generally composed of (2', 4")-Obistrimethylsilyl erythromycin A-9[O-(1-ethoxy-1-methylethyl )] Oxime (Formula 2) is obtained through methylation of the 6-hydroxyl group. Its reaction formula is as follows: [0003] [0004] Formula 2 Formula 1 [0005] 1. The patent US4331803 introduced the method of 6-hydroxymethylation of erythromycin derivatives for the first time, and studied its antibacterial activity and acid stability. It uses methyl iodide as the methylation reagent and alkali as ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07H17/08
CPCY02P20/582
Inventor 金勇魏常喜徐斌龚书华王兆刚侯仲轲邱家军
Owner ZHEJIANG GUOBANG PHARMA
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