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Preparation methods of 6-O-methylerythromycin A derivative and clarithromycin

A technology of methylation and trimethylsilyl, which is applied in the field of preparation of 6-O-methylerythromycin A derivatives and clarithromycin, can solve the problems of difficult solvent recovery, low yield and high cost, and achieve Ease of separation, high yield, and reduced dosage

Inactive Publication Date: 2015-07-08
SHANGHAI INST OF PHARMA IND CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0011] The technical problem to be solved by the present invention is to overcome the low yield, low purity, difficult solvent recovery, heavy pollution, high cost, etc. Deficiency, provide a kind of simple, economical, environmental protection and the preparation method of the 6-O-methylerythromycin A derivative shown in formula III and the clarithromycin that are easy to industrialized production, this method can be reacted after finishing 2-Methyltetrahydrofuran is fully separated from other polar inert solvents, saving the amount of solvent, and can produce high-yield, high-purity formula III compound and clarithromycin

Method used

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  • Preparation methods of 6-O-methylerythromycin A derivative and clarithromycin
  • Preparation methods of 6-O-methylerythromycin A derivative and clarithromycin
  • Preparation methods of 6-O-methylerythromycin A derivative and clarithromycin

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Effect test

Embodiment 1

[0050] Add 10 grams of 2', 4"-O-bis(trimethylsilyl)erythromycin A9-O-(1-ethoxy-1- Methyl ethyl) oxime (compound of formula II, see Table 1), then add 100 milliliters of 2-methyltetrahydrofuran, stir to make it dissolve, then add 100 milliliters of dimethyl sulfoxide, cool to 10 ℃, add 1.4 grams Potassium hydroxide (content ≥ 82%) (2 times of the molar weight of the compound of formula II) and 2.9 grams of methyl iodide (2 times of the molar weight of the compound of formula II), after reacting for 2 hours, add aqueous dimethylamine and 200 milliliters of water, Stir for 30 minutes, separate the organic layer and wash with water, dry over anhydrous magnesium sulfate, filter, and evaporate the solvent to obtain 10 grams of 2', 4"-O-bis(trimethylsilyl)-6-O-methylerythromycin The element A9-O-(1-ethoxy-1-methylethyl)oxime (compound of formula III, see Table 1) has a purity of 85%.

Embodiment 2

[0052] Add 10 grams of 2', 4"-O-bis(trimethylsilyl)-erythromycin A9-O-(1-ethoxy-1 -cyclohexyl) oxime (compound of formula II, see Table 1), then add 100 milliliters of 2-methyltetrahydrofuran, stir to make it dissolve, then add 100 milliliters of dimethyl sulfoxide, cool to 15 ° C, add 1.3 grams of hydrogen Potassium oxide (content ≥ 82%) (2 times of the molar weight of the compound of formula II) and 2.7 grams of methyl iodide (2 times of the molar weight of the compound of formula II), after reacting for 2 hours, add aqueous dimethylamine and 200 milliliters of water, stir After 30 minutes, the organic layer was separated and washed with water, dried over anhydrous magnesium sulfate, filtered, and the solvent was evaporated to obtain 10 grams of 2', 4"-O-bis(trimethylsilyl)-6-O-methylerythromycin A9-O-(1-ethoxy-1-cyclohexyl)oxime (compound of formula III, see Table 1), the purity is 90%.

Embodiment 3

[0054] Add 10 grams of 2', 4"-O-bis(trimethylsilyl)-erythromycin A9-O-(1-isopropoxy- 1-cyclohexyl) oxime (compound of formula II, see Table 1), then add 100 milliliters of 2-methyltetrahydrofuran, stir to make it dissolve, then add 100 milliliters of dimethyl sulfoxide, cool to 10 ℃, add 1.3 grams Potassium hydroxide (content ≥ 82%) (2 times of the molar weight of the compound of formula II) and 2.7 grams of methyl iodide (2 times of the molar weight of the compound of formula II), after reacting for 2 hours, add aqueous dimethylamine and 200 milliliters of water, Stir for 30 minutes, separate the organic layer and wash with water, dry over anhydrous magnesium sulfate, filter, and evaporate the solvent to obtain 10 grams of 2', 4"-O-bis(trimethylsilyl)-6-O-methylerythromycin Element A9-O-(1-isopropoxy-1-cyclohexyl)oxime (compound of formula III, see Table 1) with a purity of 92%.

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Abstract

The invention provides a preparation method of a compound of formula III The preparation method is characterized in that: the preparation method comprises the following step: a hydroxy group at the sixth position of a compound of formula II is subjected to a methylation reaction in a mixed solvent of 2-methyltetrahydrofuran and other polar and inertia solvents under the effect of alkali and a methylating reagent to obtain the compound of the formula III; wherein R1 is an oxime hydroxy protecting group, and R2 is a hydroxy protecting group. In the invention, defects of low output, low purity, difficult recovery of solvents, large pollution, high cost and the like of present selective methylation methods of the compound of formula II are overcome, and preparation methods of the compound of the formula III and clarithromycin which are simple, economic, environment friendly, and easy to industrially produce, are provided The preparation methods of the present invention allow 2-methyltetrahydrofuran and other polar and inertia solvents to be fully separated when reactions are finished, the dosage of solvents to be saved, and the compound of the formula III and clarithromycin with high yield and high purity to be prepared.

Description

technical field [0001] The invention relates to the field of drug synthesis, in particular to a preparation method of 6-O-methylerythromycin A derivatives and clarithromycin. Background technique [0002] 6-O-methylerythromycin A (also known as clarithromycin) is a semi-synthetic new macrolide antibiotic of erythromycin A, which has strong antibacterial activity, high bioavailability, wide tissue distribution and The advantage of long half-life has a very broad prospect of clinical application. [0003] Clarithromycin was first disclosed in US Patent No. 4,331,803. Since then, various methods for preparing clarithromycin have also been reported in the literature. Among them, the most conventional method includes the following steps: (a) protecting the 9-position oxime hydroxyl group; (b) protecting the 2' and 4"-position hydroxyl groups; (c) methylating the 6-position hydroxyl groups; (d) removing 2', 4 " and 9-position protecting groups. The key step in the synthesis of...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07H17/08C07H1/00
CPCY02P20/55
Inventor 杨哲洲黄成军
Owner SHANGHAI INST OF PHARMA IND CO LTD