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Method of chemically synthesizing moxidectin

A technology for chemical synthesis and nimoctin, applied in organic chemistry and other directions, can solve the problems of potential safety hazards, toxic nitrobenzene compounds, poor thermal stability, etc. Effect

Active Publication Date: 2014-09-03
DALIAN JOIN KING FINE CHEM CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, it must be pointed out that nitrobenzene compounds are toxic and have poor thermal stability, and there are potential safety hazards in large-scale applications.

Method used

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  • Method of chemically synthesizing moxidectin
  • Method of chemically synthesizing moxidectin

Examples

Experimental program
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Effect test

Embodiment 1

[0022] Example 1 Preparation of 5-oxo(4-chlorophenoxyacetyl)nimoctin

[0023] The 1.0L three-necked bottle is equipped with a mechanical stirrer, a thermometer and a constant pressure dropping funnel. Put in nimoctine (58.5g, purity 65%, 41.7mmol, 1.0eq), dichloromethane (333 g) and triethylamine (21.1 g, 208.3mmol, 5.0eq), and stir until dissolved. A solution of 4-chlorophenoxyacetyl chloride (20.5 g, 100 mmol, 2.4 eq) in dichloromethane (222 g) was added dropwise, and the internal temperature was controlled at 20°C-25°C. After the reaction is completed, the reaction solution is washed with 1% hydrochloric acid and 15% saline in sequence, the organic phase is separated and dried by adding anhydrous magnesium sulfate, filtered, and the filtrate is precipitated under negative pressure to obtain 5-oxo(4-chlorophenoxyacetyl)nemo Crude cretin was 60.8g (HPLC purity 56.9%).

[0024] Get the crude product of 5-oxo(4-chlorophenoxyacetyl)nemoctine and recrystallize it with methanol...

Embodiment 2

[0026] Example 2 Preparation of 5-oxo(4-chlorophenoxyacetyl)nimoctin

[0027] The 0.1L three-necked bottle is equipped with mechanical stirring, thermometer and constant pressure dropping funnel. Put in nimoctine (5.9g, purity 65%, 4.1mmol, 1.0eq), dichloromethane (30g) and pyridine (1.6g, 20.5mmol, 5.0eq), and stir until it dissolves. A solution of 4-chlorophenoxyacetyl chloride (5.5 g, 16.6 mmol, 4 eq) in dichloromethane (20 g) was added dropwise, and the internal temperature was controlled at 25°C-30°C. After the reaction is completed, the reaction solution is washed with 1% hydrochloric acid and 15% saline in sequence, the organic phase is separated and dried by adding anhydrous magnesium sulfate, filtered, and the filtrate is precipitated under negative pressure to obtain 5-oxo(4-chlorophenoxyacetyl)nemo Crude cretin 5.8g (HPLC purity 52.4%).

Embodiment 3

[0028] Example 3 Preparation of 5-oxo(4-chlorophenoxyacetyl)nimoctin

[0029] The 0.1L three-necked bottle is equipped with mechanical stirring, thermometer and constant pressure dropping funnel. Put in nimoctine (5.0g, purity 90%, 6.9mmol, 1.0eq), dichloromethane (30g) and triethylamine (2.1g, 20.7mmol, 3.0eq), and stir until dissolved. A solution of 4-chlorophenoxyacetyl chloride (2.8 g, 13.8 mmol, 2 eq) in dichloromethane (10 g) was added dropwise, and the internal temperature was controlled at 20°C-25°C. After the reaction is completed, the reaction solution is washed with 1% hydrochloric acid and 15% saline in sequence, the organic phase is separated and dried by adding anhydrous magnesium sulfate, filtered, and the filtrate is precipitated under negative pressure to obtain 5-oxo(4-chlorophenoxyacetyl)nemo 6.1 g of crude cretin (HPLC purity: 88.9%).

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Abstract

The invention relates to a method of chemically synthesizing moxidectin and belongs to the field of medicinal chemistry. The method comprises the following step: carrying out a reaction on nemadectin as a raw material and 4-chlorophenoxyacetyl chloride as an upper protective agent, and preparing moxidectin through a reaction of four steps: upper protection, oxidization, oximation and deprotection, wherein the reaction sequence of oximation and deprotection can be interchanged without affecting the final reaction product. In the reaction process, the products in upper protection, oxidization and oximation can be recrystallized and extracted through methanol and the like, so that the requirements on the purity of the raw material is reduced, the operating flow is simplified and the reaction cost is lowered.

Description

technical field [0001] The invention relates to a method for chemically synthesizing moxictine, which belongs to the field of medicinal chemistry. Background technique [0002] Moxictine is a single-component semi-synthetic macrolide drug produced by Streptomyces fermentation. It has good anthelmintic activity, long-acting, and safety characteristics. It is currently widely used in veterinary clinics. Broad-spectrum, high-efficiency, new macrolide anthelmintic antibiotic. The main way to obtain moxictine is to produce nemoxictine through streptomycin fermentation (see: J. Antibiot., 1988, 41, 519-529; CN102336796, 2010), and then through up-protection, oxidation, oximation and Deprotection was modified by four-step chemical reaction. [0003] [0004] [0005] At present, the main protecting reagents are chlorosilanes and aryl formyl chlorides. For example, nimoctine is protected by tert-butyldimethylsilyl chloride (see: US4916154, 1990), followed by oxidation, acid d...

Claims

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Application Information

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IPC IPC(8): C07D493/22
CPCC07D493/22
Inventor 戴耀杜志博王荣良
Owner DALIAN JOIN KING FINE CHEM CO LTD
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