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Preparation method of ambrisentan

A technology of ambrisentan and intermediates, applied in the field of compound preparation, can solve the problems of expensive resolving agent, high cost, large amount of organic solvent, etc., and achieve the effect of high resolution efficiency, low cost and low reagent toxicity

Inactive Publication Date: 2016-10-12
西安大唐制药集团有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0008] The purpose of the present invention is to provide a kind of preparation method of ambrisentan, adopt lipohydrolase as resolving agent, solve the problem of high cost caused by expensive resolving agent and large amount of organic solvent used in the existing preparation method

Method used

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  • Preparation method of ambrisentan
  • Preparation method of ambrisentan
  • Preparation method of ambrisentan

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0033] 1. Preparation of Intermediate 1

[0034] In a 500ml three-necked flask, add 240ml of N,N-dimethylformamide, 30g (0.1mol) of ethyl (R,S)-3,3-diphenyl-3-methoxy-2-hydroxypropionate, Lipase PS "Amano" SD 6g, pH7.0 phosphate buffer 90ml, phase transfer catalyst benzyltriethylammonium chloride 6g, reaction temperature 30°C, reaction time about 2h, HPLC monitoring, until S-configuration Less than 1% terminated the reaction. Add 100ml of 2N sodium carbonate solution to the reactant, stir for 30min, and separate the layers. The organic phases were combined, collected and concentrated to dry to obtain the R-configuration ester; the aqueous phase was washed once with 50ml of methyl tert-butyl ether, and then slowly added to 100ml of 3N hydrochloric acid under stirring, a large amount of white solids precipitated, stirred for 1h, filtered, and the solid The product was dried to obtain 12.5 g of S-configuration acid intermediate 1 with a yield of 41.7% and a chiral content of 97...

Embodiment 2

[0042] 1. Preparation of Intermediate 1

[0043] Into a 500ml three-necked flask, add 240ml acetone, 40g (0.13mol) of ethyl (R,S)-3,3-diphenyl-3-methoxy-2-hydroxypropionate, 5g lipase AP6, pH7 .0 Phosphate buffer 120ml, phase transfer catalyst tributylamine 5g, reaction temperature 40°C, reaction time about 2h, HPLC monitoring, S-configuration is less than 1% to terminate the reaction. Add 150ml of 2N sodium carbonate solution to the reactant, stir for 30min, and separate the layers. After the organic phase was racemized, it continued to participate in the reaction as a substrate; the aqueous phase was washed once with 60ml of methyl tert-butyl ether, and then slowly added to 150ml of 3N hydrochloric acid under stirring, a large amount of white solids precipitated, stirred for 1h, filtered, and dried 18.6 g of intermediate 1 was obtained by drying, the yield was 46.5%, and the chiral content was 98.2%.

[0044] 2. Preparation of Crude Ambrisentan

[0045] At room temperatur...

Embodiment 3

[0050] 1. Preparation of Intermediate 1

[0051] In a 500ml three-necked flask, add 320ml of ethanol, 40g (0.13mol) of ethyl (R,S)-3,3-diphenyl-3-methoxy-2-hydroxypropionate, lipohydrolase PS "Amano" IM 4g, pH 7.0 phosphate buffer 100ml, phase transfer catalyst chain polyethylene glycol 4g, reaction temperature 50°C, reaction time about 2h, HPLC monitoring, S-configuration is less than 1% to terminate the reaction. Add 150ml of 2N sodium carbonate solution to the reactant, stir for 30min, and separate the layers. The organic phases were combined, collected and concentrated to dry to obtain the R-configuration ester; the aqueous phase was washed once with 50ml of methyl tert-butyl ether, and then slowly added to 150ml of 3N hydrochloric acid under stirring, a large amount of white solids were precipitated, stirred for 1h, filtered, and dried 18.2 g of intermediate 1 was obtained, the yield was 45.5%, and the chiral content was 97.8%.

[0052] 2. Preparation of Crude Ambrisent...

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Abstract

The invention discloses a preparation method of ambrisentan. The preparation method includes the following steps that firstly, (R,S)-3,3-diphenyl-3-methoxyl-ethyl-2-hydroxypropionate, a lipolytic enzyme, a phase transfer catalyst, an organic solvent and a phosphate buffer solution are reacted till the S-configuration ester disappears, alkali liquor is added for liquid separation, a water phase is washed, a solid is separated out in acid liquor, and an intermediate 1 is obtained; secondly, the intermediate 1 and a catalyst are added into 4,6-dimethoxy-2-(methylsulfonyl)pyrimidine or N,N-dimethyl formamide for a condensation reaction to generate an intermediate 2, the reaction product is acidized and cooled, and coarse ambrisentan is obtained; thirdly, coarse ambrisentan is subjected to reflux discoloration and is filtered while being hot, filter liquor is cooled, the temperature is maintained for crystallization, reflux, filtering and drying are carried out, and refined ambrisentan is obtained. According to the method, the lipolytic enzyme is adopted as a resolving agent, and resolving efficiency is high; the use amount of the organic solvent is small, experimental conditions are mild, cost is low, and the method is suitable for industrial production.

Description

technical field [0001] The invention belongs to the technical field of compound preparation, and in particular relates to a preparation method of ambrisentan. Background technique [0002] Ambrisentan is an endothelin receptor antagonist developed by U.S.-based Myogen (Gilead Corporation acquired Myogen Corporation later), and was approved by the U.S. FDA on June 19, 2007. Its trade name is Letairis, and it is clinically applicable to the treatment of pulmonary arterial hypertension ( PAH), the chemical name is (+)-(2S)-2-[(4,6-dimethylpyrimidin-2-yl)oxy]-3-methoxy-3,3-diphenylpropanoic acid , whose structural formula is: [0003] [0004] There are three endothelin receptor antagonists currently on the market: bosentan, sitaxsentan, and ambrisentan. Compared with the other two, ambrisentan has shown more therapeutic potential for PAH in 2 completed phase III clinical trials. In addition, the use of ambrisentan is more convenient, and it only needs to be administered o...

Claims

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Application Information

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IPC IPC(8): C12P17/12C07D239/34
CPCC07B2200/07C07D239/34C12P17/12
Inventor 卫东崔平宋亚宁程捷恺张明吕卓张国跃杨晓莉
Owner 西安大唐制药集团有限公司
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