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Preparation method for Clarithromycin intermediate

A technology for clarithromycin and intermediates, applied in the field of preparation of clarithromycin intermediates, can solve the problems of difficult to realize industrialized production, high recovery cost, low yield and the like, and achieves low pollution, sufficient reaction and high conversion rate. Effect

Active Publication Date: 2014-08-20
ZHEJIANG BETTER PHARMA
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0006] Chinese patent CN1318548 reported the use of (2',4"-0-bistrimethylsilyl)-erythromycin A-9[0-(1-ethoxyl-1-methylethyl)oxime compound as protection The compound reacts with methyl iodide in tetrahydrofuran and dimethyl sulfoxide, reacts at room temperature for 5 minutes, and obtains compound II. This process uses tetrahydrofuran, and the recovery cost is high, and it is difficult to realize industrial production
The defect of this method is that the purity of the compound II synthesized is only about 74%, the conversion rate is about 76%, the amount of toluene and dimethyl sulfoxide solvent used is 6-10 times of the compound mass ratio, and industrial production leads to too many three wastes , low yield, high cost

Method used

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  • Preparation method for Clarithromycin intermediate

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Experimental program
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Effect test

Embodiment 1

[0028] In a 1000ml reaction flask equipped with a stirrer and a thermometer, add 20g compound I (content 96%, 0.02mol), toluene 150ml (130g), stir to dissolve, add dimethyl sulfoxide 150ml (165g), control the temperature 15~ 20°C, add 0.03mol of methylation reagent, 1.4g of potassium hydroxide (content ≥ 96%, 0.024mol), control the temperature at 15-20°C for 15min, add 150ml of water, stop the reaction, HPLC detection, the purity of compound II is 73.6%, the reaction raw material is 17.5%, and the by-product is 4.0%.

Embodiment 2

[0030] The preparation method is the same as in Example 1, the difference is that the amount of Compound I, toluene and dimethyl sulfoxide is adjusted, the reaction time is adjusted, and the conversion rate under different reaction conditions is tested, as shown in Table 1.

[0031] Table 1: Effects of different solvent ratios and reaction times on conversion.

[0032] Proportion (g:ml:ml) 20 minutes to react 30 minutes to react 40 minutes to react Compound 1: Toluene: DMSO = 1:3:3 55％ 65％ 58％ Compound 1: Toluene: DMSO = 1:5:5 48％ 64％ 63％ Compound 1: Toluene: DMSO = 1:7:7 47％ 65％ 70％

[0033] Compound 1: Toluene: DMSO = 1:10:10 43％ 70％ 72％

[0034] It can be seen from Table 1 that as the amount of solvent increases, the reaction rate slows down and the conversion rate increases, and the amount of solvent being more than 10 times that of compound 1 is of little significance.

[0035] The second group of embodiments: t...

Embodiment 3

[0037] In a 500ml reaction flask equipped with a stirrer and a thermometer, add 20g of compound I (content 96%, 0.02mol), 50g of toluene, 10g of n-hexane, stir to dissolve, add 100g of dimethyl sulfoxide, and control the temperature at 15-20°C , add 0.03 mol of methylating reagent, 1.4 g of potassium hydroxide (content ≥ 96%, 0.024 mol), control the temperature at 15-20 ° C for 50 min, add 50 ml of water, terminate the reaction, HPLC detection, compound II purity is 76.4%, The reaction raw material is 15.1%, and the by-product is 3.9%.

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Abstract

The invention discloses a preparation method for a Clarithromycin intermediate. The method is characterized in that (2',4"-O-bistrimethylsilyl)-erythromycin A-9[O-(1-ethoxy-1-methylethyl)]oxime is used as a raw material, toluene, hexane and dimethyl sulfoxide are used as solvents, bromomethane, iodomethane and methyl p-toluenesulfonate are used as methylation reagents, potassium hydroxide is used as a catalyst, and methylation is carried out so as to prepare the Clarithromycin intermediate. According to the invention, through selection of a solvent system, cooperative control of the amounts of the reaction reagent and the catalyst and synergism of temperature and time, the preparation method for the Clarithromycin intermediate has the advantages of simple process, stable operation, a high conversion rate, low cost, a small amount of waste gas, waste water and industrial residue and suitability for industrial production.

Description

Technical field: [0001] The invention relates to a preparation method of a clarithromycin intermediate, which refers to (2′,4″-O-bistrimethylsilyl)-6-O-methylerythromycin A -9[O-(1-ethoxy-1-methylethyl)]oximide. Background technique: [0002] Clarithromycin (also known as clarithromycin), whose chemical name is 6-0-methylerythromycin, is a 14-membered ring macrolide antibiotic. The synthesis of clarithromycin in the prior art includes the following steps, using erythromycin-A-9 oxime as a starting material, and successively undergoing the reaction steps of etherification, silanization of a protective group, methylation, and deprotection. obtain the target product. [0003] The methylation reaction is based on (2′,4″-O-bistrimethylsilyl)-erythromycin A-9[O-(1-ethoxy-1-methylethyl)]oxime The compound (hereinafter referred to as compound I) is a protected object, and the intermediate (2′, 4″-O-bistrimethylsilyl)-6-O-methyl red of clarithromycin is synthesized through the met...

Claims

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Application Information

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IPC IPC(8): C07F7/18
Inventor 唐小波邓佰能汪广星朱赛赛
Owner ZHEJIANG BETTER PHARMA
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