Stereoselectivity preparation method for Letairis

A basic and selected technology, which is applied in the field of stereoselective preparation of ambrisentan, can solve the problems of increased production cost, failure to meet the requirements of environmentally friendly green technology, low utilization rate of chiral drug raw materials, etc., and achieve cost reduction , the effect of increasing the yield

Inactive Publication Date: 2014-04-09
SHIJIAZHUANG BOCE BIO TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The use of chiral resolution to prepare chiral drugs has low raw material utilization, resulting in increased production costs, which has great restrictions on industrial production, and does not meet the requirements of environmentally friendly green technology.

Method used

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  • Stereoselectivity preparation method for Letairis
  • Stereoselectivity preparation method for Letairis
  • Stereoselectivity preparation method for Letairis

Examples

Experimental program
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Embodiment 1

[0032] Preparation of Ambrisentan【(+)-(S)-2-[(4,6-dimethylpyrimidine)-2-oxyl]-3-methoxy-3,3-diphenylpropionic acid】

[0033] (1) Preparation of ethyl (2S)-3,3-diphenyl-2,3-epoxypropionate

[0034]

[0035] Add benzophenone (45.56g, 0.25mol), dichloromethane (75ml), PTC and lithium hydroxide to a 500ml three-necked reaction flask with stirring, and slowly add ethyl chloroacetate (46.12g, 0.42mol), after dropping, keep stirring for 24h. Add 125ml of water, separate, extract the aqueous layer with dichloromethane (50ml×2), combine the organic layers, wash with saturated brine until neutral, anhydrous Na 2 SO 4 After drying, filtering, and evaporating the solvent to dryness, 59.75 g of light yellow liquid (IV) was obtained, with a yield of 89.2%. It was directly used in the next reaction without further treatment.

[0036] (2) Preparation of ethyl (2S)-2-hydroxy-3-methoxy-3,3-diphenylpropionate

[0037]

[0038] The oily compound (50.0 g, 0.186 mol) obtained above ...

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Abstract

The invention discloses a stereoselectivity preparation method for a compound shown in the formula (I). First, chiral phase-transfer catalysts of quaternary ammonium salts are employed to catalyze a stereoselective Darzen reaction of diphenyl ketone and alpha-halogenated acetic ester, and optically pure epoxides are obtained. Then ring opening, nucleophilic substitution and ester group hydrolysis reaction are carried out in order and optically pure Letairis is obtained. The method is aimed to achieve industrial preparation of optically pure Letairis. By utilization of the stereoselectivity preparation method, generation of another isomer is avoided, the yield of the target compound is increased, and the method accords with requirements of green synthesis.

Description

technical field [0001] The invention relates to a method for stereoselectively preparing ambrisentan. technical background [0002] Ambrisentan, the chemical name is (+)-(S)-2-[(4,6-dimethylpyrimidine)-2-oxyl]-3-methoxy-3,3-diphenylpropionic acid , is a highly selective endothelin A receptor antagonist, which can potently inhibit endothelin-induced vasoconstriction, with high bioavailability and long half-life. Developed by the American Myogen Biopharmaceutical Company, it was approved by the US FDA on June 15, 2007. The trade name is Letairis, and it is used orally for the treatment of pulmonary hypertension. [0003] The existing preparation technology of ambrisentan includes the Darzens reaction of ethyl benzophenone free chloroformate to generate racemic epoxide, which is catalyzed with methanol in boron trifluoride ether solution. Under the action, the ring is opened to obtain the alcohol of the racemate, and then the optically pure ambrisentan is obtained throug...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D239/34
CPCC07D239/34
Inventor 杜玉民方瑜
Owner SHIJIAZHUANG BOCE BIO TECH
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