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Method for chemical synthesis and purification of moxidectin

A chemical synthesis and pore adsorption technology, applied in organic chemistry and other fields, can solve the problems of high impurity content related to moxictine and difficulty in controlling the maximum impurity content, and achieve the effects of improving product quality, effectively removing impurities, and reducing costs

Active Publication Date: 2015-05-20
HEBEI SHENGXUE DACHENG PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Although this method can obtain a moxictine solution with a purity of more than 93%, the content of related impurities in the obtained moxictine is relatively high, especially the maximum impurity content is not easy to control within the standard range stipulated in Pharmacopoeia EP

Method used

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Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0023] Add nimoctine (58.5g, purity 65%, 41.7mmol, 1.0eq), dichloromethane (333g) and triethylamine (21.1g, 208.3mmol, 5.0eq) in 1.0L one-necked flask, stir until dissolved Clear, add tert-butyldimethylsilyl chloride (20.5g, 100mmol, 2.4eq), control the internal temperature at 20°C-25°C. After the reaction was completed, the reaction solution was washed successively with 1% hydrochloric acid and 15% saline, the organic phase was separated and added to anhydrous magnesium sulfate for drying, filtered, and the filtrate was precipitated under negative pressure to obtain 60.8 g of the upper-protected crude product of nimoctine, which was analyzed by HPLC The method detects that the purity is 64.2%.

[0024] In a 1.0L three-necked flask equipped with electromagnetic stirring, a thermometer, and a constant-pressure dropping funnel, add the upper-protected crude product of nimoctine (19.3g, 13.9mmol, 1.0eq), dichloromethane (500mL), triethyl Amine (13.8g, 132.1mmol, 9.5eq) and dimet...

Embodiment 2

[0027] Add nimoctine (58.5g, purity 65%, 41.7mmol, 1.0eq), dichloromethane (333g) and triethylamine (21.1g, 208.3mmol, 5.0eq) in 1.0L one-necked flask, stir until dissolved Clear, add tert-butyldimethylsilyl chloride (20.5g, 100mmol, 2.4eq), control the internal temperature at 20°C-25°C. After the reaction was completed, the reaction solution was washed successively with 1% hydrochloric acid and 15% saline, the organic phase was separated and added to anhydrous magnesium sulfate for drying, filtered, and the filtrate was precipitated under negative pressure to obtain 60.8 g of the upper-protected crude product of nimoctine, which was analyzed by HPLC The method detects that the purity is 64.2%.

[0028] In a 1.0L three-necked flask equipped with electromagnetic stirring, a thermometer, and a constant-pressure dropping funnel, add the upper-protected crude product of nimoctine (19.3g, 13.9mmol, 1.0eq), dichloromethane (500mL), triethyl Amine (13.8g, 132.1mmol, 9.5eq) and dimet...

Embodiment 3

[0031] Add nimoctine (58.5g, purity 65%, 41.7mmol, 1.0eq), dichloromethane (333g) and triethylamine (21.1g, 208.3mmol, 5.0eq) in 1.0L one-necked flask, stir until dissolved Clear, add tert-butyldimethylsilyl chloride (20.5g, 100mmol, 2.4eq), control the internal temperature at 20°C-25°C. After the reaction was completed, the reaction solution was washed successively with 1% hydrochloric acid and 15% saline, the organic phase was separated and dried by adding anhydrous magnesium sulfate, filtered, and the filtrate was precipitated under negative pressure to obtain 60.8 g of the upper-protected crude product of nimoctine, which was analyzed by HPLC The method detects that the purity is 64.2%.

[0032] In a 1.0L three-necked flask equipped with electromagnetic stirring, a thermometer, and a constant-pressure dropping funnel, add the upper-protected crude product of nimoctine (19.3g, 13.9mmol, 1.0eq), dichloromethane (500mL), triethyl Amine (13.8g, 132.1mmol, 9.5eq) and dimethyls...

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Abstract

The invention discloses a method for chemical synthesis and purification of moxidectin, and relates to the technical field of synthetic medicines. The method comprises the following steps: (1) carrying out upper protective reaction on nemadectin to obtain an upper protective crude product; (2) carrying out oxidation reaction on the upper protective crude product to obtain an oxidized crude product; (3) carrying out chromatography purification of macroporous resin on the oxidized crude product, and concentrating to obtain an oxidized pure product; (4) carrying out deprotection reaction on the oxidized pure product to obtain a deprotected product; and (5) carrying out oximation reaction on the deprotected product, carrying out chromatography purification of macroporous resin, concentrating, filtering and drying in vacuum to obtain the moxidectin of which the purity is higher than 96% and the maximal single impurity content is lower than 0.3%. The upper protective crude product is subjected to chromatography purification of the macroporous resin after oxidized reaction; and the impurities introduced into the subsequent chemical reaction are reduced, so that the purity of the moxidectin is improved; the impurity content is reduced; the total yield of the moxidectin is improved; and the cost is reduced.

Description

technical field [0001] The invention relates to the technical field of synthetic medicines, in particular to a method for chemically synthesizing and purifying moxictine. Background technique [0002] Moxidectin, also known as Moxidectin (MXD), CAS No. 113507-06-5, is a broad-spectrum, high-efficiency, new type of macrolide anthelmintic antibiotic widely used in veterinary clinics. At the same time, it has long-acting, safe and other characteristics. Moxidectin is a derivative of Nemadectin, and the main way is to produce Nemadectin by fermentation of Streptomyces.cyanneogrisens noncyanogenus (see: J.Antibiot. , 1988, 41, 519-529; CN102336796, 2010), and then obtained through four-step chemical modification of upprotection, oxidation, deprotection and oximation. Wherein, the crude product and the final product after the up-protection reaction are purified by macroporous adsorption resin chromatography. Although this method can obtain a moxictine solution with a purity of m...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D493/22
CPCC07D493/22
Inventor 李爱科
Owner HEBEI SHENGXUE DACHENG PHARMA
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