Ambrisentan, BSF-208075, LU-208075

安倍生坦Chemical Name: (+)-2(S)-(4,6-Dimethylpyrimidin-2-yloxy)-3-methoxy-3,3-diphenylpropionic acid
CAS No. 177036-94-1
项目整合开发状态: Phase III
项目研究机构: Myogen (Orphan Drug), Abbott (Originator), Myogen (Licensee)
合成路线:The condensation of benzophenone (I) with chloroacetic acid methyl ester (II) by means of sodium methoxide in THF gives the epoxide (III),which is treated with methanol/BF3.Et2O,yielding 2-hydroxy-3-methoxy-3,3-diphenylpropionic acid methyl ester (IV).The condensation of (IV) with 4,6-dimethoxy-2-(methylsulfonyl)pyrimidine (V) by means of K2CO3 in DMF affords 2-(4,6-dimethoxypyrimidin-2-yloxy)-3-methoxy-3,3-diphenylpropionic acid methyl ester (VI),which is hydrolyzed with NaOH in hot dioxane/water to give the corresponding free acid (VII).Finally,this compound is submitted to optical resolution,affording LU-135252.Optical resolution of (VIII),the free acid derivative of (IV),with (R)-phenylethylamine,L-proline methyl ester,(S)-1-(4-nitrophenyl)ethylamine or (S)-1-(4--chlorophenyl)ethylamine leads to the enantiomerically pure (S)-enatiomer (IX),which by reaction with 4,6-dimethoxy-2-(methylsulfonyl)pyrimidine (V) directly affords LU-135252.

合成路线:The condensation of benzophenone (I) with methyl 2-chloroacetate (II) by means of NaOMe in THF gives 3,3-diphenyloxirane-2-carboxylic acid methyl ester (III),which by treatment with BF3/Et2O and methanol,followed by optical resolution,yielded the pure enantiomer 2(S)-hydroxy-3-methoxy-3,3-diphenylpropionic acid methyl ester (IV).The condensation of (IV) with 4,6-dimethyl-2-(methylsulfonyl)pyrimidine (V) by means of K2CO3 in DMF affords 2-(4,6-dimethylpyrimidin-2-yloxy)-3-methoxy-3,3-diphenylpropionic acid methyl ester (VI),which is finally hydrolyzed with KOH in hot dioxane to afford the target propionic acid as a racemic mixture.