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Method for preparing ambrisentan

An ambrisentan and salt-forming technology, which is applied in the field of chemistry, can solve the problems of potential safety hazards in the use of lithium amide, unsuitable for industrial production, expensive resolving agents, etc., and achieves good separation efficiency, easy recovery, and improved safety. Effect

Active Publication Date: 2015-04-29
JIANGSU KANION PHARMA CO LTD +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0009] The reported synthetic methods of ambrisentan are relatively cumbersome in operation, all of which are to construct chirality by resolving 2-hydroxy-3-methoxyl-3,3-diphenylpropionic acid. More expensive, the use of lithium amide in the condensation step also brings hidden dangers to production safety, and is not suitable for industrial production

Method used

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  • Method for preparing ambrisentan
  • Method for preparing ambrisentan
  • Method for preparing ambrisentan

Examples

Experimental program
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Effect test

Embodiment 1

[0025] In order to enable those skilled in the art to better understand the technical solutions of the present invention, the present invention will be further described below in conjunction with examples, but these examples do not constitute any limitation to the present invention. 1 HNMR was recorded by AM 400 nuclear magnetic resonance instrument, and chemical shifts were expressed in δ (ppm). The mass spectrum was measured with a Shimadzu LCMS-2010 mass spectrometer, and the optical rotation was measured with a Perkin-Elmer 341 polarimeter. Embodiment 1: the preparation of ambrisentan

[0026] Take a 50ml one-mouth bottle, add 3.04g (8mmol) 2-[(4,6-dimethylpyrimidin-2-yl)oxy]-3-methoxy-3,3-diphenylpropionic acid, 0.97g (8mmol) (S)-phenethylamine, 30ml methanol. After reflux reaction for 2 hours, it was lowered to room temperature, methanol was distilled off, 20 ml of isopropanol was added for recrystallization, cooled to room temperature naturally, and 1.40 g of solid wa...

Embodiment 2

[0035] Embodiment 2: the preparation of ambrisentan

[0036] Take a 50ml one-mouth bottle, add 3.04g (8mmol) 2-[(4,6-dimethylpyrimidin-2-yl)oxy]-3-methoxy-3,3-diphenylpropionic acid, 0.97g (8mmol) (S)-phenethylamine, 30ml methanol. After reflux reaction for 2 hours, it was lowered to room temperature, methanol was distilled off, 15 ml of ethyl acetate was added for recrystallization, cooled to room temperature naturally, and 1.28 g of solid was obtained by filtration.

[0037] The solid was added with 30ml of water, 30ml of ethyl acetate, dilute hydrochloric acid to adjust the pH to acidic, and the organic layer was separated. The organic layer was washed with water, dried, and concentrated to obtain 0.8g of a white solid, with a yield of 26%.

[0038] [a] D 20 =+180.3° (C=0.5, MeOH)

Embodiment 3

[0039] Embodiment 3: the preparation of ambrisentan

[0040] Take a 50ml one-mouth bottle, add 3.04g (8mmol) 2-[(4,6-dimethylpyrimidin-2-yl)oxy]-3-methoxy-3,3-diphenylpropionic acid, 1.46g (12mmol) (S)-phenethylamine, 30ml ethanol. After reflux reaction for 2 hours, it was cooled to room temperature, ethanol was distilled off, 15ml of isopropanol was added for recrystallization, cooled to 0°C, and 1.45g of solid was obtained by filtration.

[0041] The solid was added with 30ml of water, 30ml of ethyl acetate, dilute hydrochloric acid to adjust the pH to acidic, and the organic layer was separated. The organic layer was washed with water, dried and concentrated to give 1.0g of white solid with a yield of 33%.

[0042] [a] D 20 =+100.3° (C=0.5, MeOH)

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Abstract

The invention relates to the field of chemical synthesis, and discloses a preparation method of ambrisentan. According to the invention, (S)-phenethylamine is adopted as a resolving agent, and forms two diastereomers with 2-[(4,6-dimethyl pyrimidine-2-yl)oxy]-3-methoxy-3,3-diphenyl propionic acid in a specific solvent; diastereomers with lower solubility are obtained through re-crystallization; and ambrisentan is prepared through acid ionization. The yield of the method is approximately 30%. The adopted resolving agent is cheap and is easy to recover. The method is suitable for industrialized productions.

Description

technical field [0001] The invention relates to the field of chemistry, in particular to a method for preparing ambrisentan. Background technique [0002] Ambrisentan (Ambrisentan) is an endothelin receptor antagonist developed by Myogen (Gilead later acquired Myogen) in the United States. It was approved by the US FDA on June 19, 2007. Its trade name is Letairis, and it is clinically applicable to the treatment of Pulmonary arterial hypertension (PAH), with the chemical name (+)-(2S)-2-[(4,6-dimethylpyrimidin-2-yl)oxy]-3-methoxy-3,3-diphenyl Propionic acid, its structure is as shown in formula I: [0003] [0004] Formula I [0005] There are three endothelin receptor antagonists currently on the market: bosentan, sitaxsentan, and ambrisentan. Compared with bosentan and sitaxsentan, 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 administ...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D239/34C07B57/00
Inventor 张福利金林勇萧伟吴泰志王振中郭庆明张军章晨峰李丹凤
Owner JIANGSU KANION PHARMA CO LTD
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