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Improved method used for preparing ambrisentan

A technology of ambrisentan and metal carbonate, which is applied in the field of chemistry, can solve the problems of cumbersome operation, unsuitability for industrial production, and expensive resolution reagents, and achieve simplified reaction and processing steps, cheap and easy-to-obtain resolution reagents, and The effect of high yield

Active Publication Date: 2015-05-06
山东瑞银生物工程有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0008] The reported synthetic methods of ambrisentan are relatively cumbersome in operation, all of which are through (S)-2-hydroxyl-3-methoxyl-3,3-diphenylpropionic acid or its ester and 4,6-diphenyl Methyl-2-methylsulfonylpyrimidine is condensed under the action of base, and after purification, (S)-2-[(4,6-dimethylpyrimidin-2-yl)oxy]-3-methoxy-3 , Methyl 3-diphenylpropionate, then hydrolyzed and purified to obtain ambrisentan, that is, (S)-2-hydroxy-3-methoxy-3,3-diphenylpropionic acid or its ester through Two-step reaction of condensation and hydrolysis to obtain ambrisentan
In addition, the reported synthetic methods of ambrisentan all construct chirality by resolving 2-hydroxy-3-methoxy-3,3-diphenylpropionic acid. Suitable for industrial production

Method used

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  • Improved method used for preparing ambrisentan
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  • Improved method used for preparing ambrisentan

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0031] Preparation of methyl 3,3-diphenyl-2,3-epoxypropionate

[0032] Chemical reaction formula:

[0033]

[0034] Add tetrahydrofuran (16 L), benzophenone (4 kg) and sodium methoxide (2.96 kg) into the reaction kettle, stir well, continue to add methyl chloroacetate (5.96 kg), after the reaction is completed, add methyl Methyl tert-butyl ether (MTBE) (8 L) and water (10 L), the organic layer was washed with saturated brine and dried with a desiccant, and the organic solvent was concentrated to give the oil 3,3-diphenyl-2,3- Methyl glycidate (5.54 kg).

[0035] Mass Spectrum (ESI): m / z 255.1 (M+H) + .

[0036] 1 H NMR (400 MHz, CDCl 3 ) δ: 7.48~7.45 (m, 2H), 7.40~7.32 (m, 8H), 4.02 (s, 1H), 3.54 (s, 3H).

Embodiment 2

[0038] Preparation of methyl 2-hydroxy-3-methoxy-3,3-diphenylpropionate

[0039] chemical reaction formula

[0040]

[0041] The oily product 3,3-diphenyl-2,3-epoxypropionate methyl ester (5.54kg) and methanol (15 L) in Example 1 were put into the reaction kettle, and boron trifluoride ether was added dropwise (BF 3 -ether) (148 ml), after the reaction was completed, water (15L) was added to the reaction system to quench the reaction, the reaction solution was extracted three times with ether (7L) and the organic layer was combined, the organic layer was cooled to 0°C, filtered, and the solid was collected. Dry to obtain 5.33 kg of methyl 2-hydroxy-3-methoxy-3,3-diphenylpropionate, and the two-step yield is 85%.

[0042] Mass spectrum (ESI): m / z 255.1 (M-MeO) + .

[0043] 1 H NMR (400 MHz, DMSO- d 6) δ: 7.38 ~7.35 (m, 4H), 7.31 ~ 7.22 (m, 6H), 5.80 (d, J = 4 Hz, 1H), 5.24 (d, J = 4 Hz, 1H), 3.41 (s, 3H), 3.22 (s, 3H).

Embodiment 3

[0045] Preparation of Ambrisentan Racemate

[0046] Chemical reaction formula:

[0047]

[0048] Add tetrahydrofuran (19.4 L), 3,3-diphenyl-2,3-epoxypropionic acid methyl ester (4.64 kg), 4,6-dimethyl-2-methylsulfonyl pyrimidine (3.32 kg) and potassium carbonate (3.36 kg), stir evenly, and heat to reflux. After completion of the reaction, add water (13.7 kg) to the reaction system, stir and separate the liquid, and remove the water layer; then add 2.5mol / L potassium hydroxide solution (18.1L) to the reaction system, and heat to reflux. Remove tetrahydrofuran, then add water (29 L) and dichloromethane (11.7 L), stir and separate, remove the dichloromethane layer, neutralize the water layer with hydrochloric acid to pH 1~5, filter, collect the solid, and dry to obtain Ambrisentan racemate (5.9 kg), the yield was 96%, and the purity was 99%.

[0049] Mass Spectrum (ESI): m / z 377.0 (M-H) - .

[0050] 1 H NMR (400 MHz, DMSO- d 6 ) δ: 12.56 (s, 1H), 7.35 ~ 7.19 (m, 10H)...

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Abstract

The invention belongs to the field of chemical synthesis, and discloses an improved method used for preparing ambrisentan. According to the improved method, 2-hydroxy-3-methoxy-3,3-diphenylpropionic ester and 4,6-dimethyl-2-methylsulfonylpyrimidine are subjected to condensation, and one-pot hydrolysis in tetrahydrofuran solvent so as to obtain ambrisentan racemate; and ambrisentan is obtained via resolution with (S)-1-phenylethylamine. The improved method is simple in operation, and high in yield, and is suitable for industrial production.

Description

technical field [0001] The invention relates to the field of chemistry, in particular to an improved method for preparing ambrisentan. Background technique [0002] Ambrisentan is an endothelin receptor antagonist (ERA) originally developed by Abbott of the United States, and Myogen Corporation of the United States has acquired its global development and marketing rights. Subsequently, GlaxoSmithKline (Glaxosmithkline) of the United States signed an agreement with Myogen to obtain the production rights of this product outside the United States. On November 17, 2006, Gilead Science of the United States acquired Myogen as a subsidiary company and obtained the ownership of Ambrisentan. The drug was approved by the US FDA on June 15, 2007. The trade name is Letairis. It is used orally for the treatment of pulmonary arterial hypertension (PAH). The chemical name is (+)-(2S)-2-[(4,6-two Methylpyrimidin-2-yl)oxy]-3-methoxy-3,3-diphenylpropionic acid, the structure of which is sho...

Claims

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Application Information

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IPC IPC(8): C07D239/34
CPCC07D239/34
Inventor 朱高军袁洪顺刘勇潘新王朝东
Owner 山东瑞银生物工程有限公司
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