新产品编号:1169607
Chemical Name: N-(4-Fluorophenyl)-N-[2-[3-(2-naphthyl)pyrrolidin-1-yl]ethyl]adamantane-1-carboxamide oxalate
项目整合开发状态: Biological Testing
项目研究机构: Merck KGaA (Originator)
合成路线:Reduction of 2,2-diphenylpropionitrile (I) with LiAlH4 in Et2O produced aldehyde (II),which was further converted to cyanohydrin (III) upon treatment with KCN and p-toluenesulfonic acid.The required alpha-hydroxy ester (V) was obtained either by sequential hydrolysis of (III) to amide (IV) and then to ester (V) under acidic conditions or by direct conversion of nitrile (III) to ester (V) with boiling hydroalcoholic HCl.Subsequent saponification of the ester group of (V) with LiOH provided hydroxy acid (VI).This was finally condensed with 4,6-dimethyl-2-chloropyrimidine (VII) in the presence of NaH to give the racemic pyrimidinyl ether.
📌 参考资料/链接：
参考文献标题:Novel alpha-hydroxylic acid derivs.,their production and use
文献作者:Klinge,D.; Amberg,W.; Baumann,E.; Kling,A.; Riechers,H.; Unger,L.; Raschack,M.; Hergenr鰀er,S.; Schult,S.(BASF AG)
参考来源:DE 19614533; EP 0892787; JP 2000508326; WO 9738981
📄 详细内容
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:A pilot plant process was further developed for the (S)-enantiomer.Darzens condensation of benzophenone (VIII) with methyl chloroacetate gave the glycidic ester (X).Epoxide opening in (X) with trimethylaluminum furnished methyl 2-hydroxy-3,3-diphenylbutyrate (XI),which was hydrolyzed to the corresponding acid (VI) by using KOH in isopropanol.Treatment of the racemic acid (VI) with (S)-1-(4-chlorophenyl)ethylamine (XII) provided the desired (S)-acid salt (XIII).This was finally condensed with 4,6-dimethyl-2-(methylsulfonyl)pyrimidine (XIV) in the presence of lithium amide to yield the title compound.
参考文献标题:Structural similarity and its suprises: Endothelin receptor antagonists - Process research and development report
文献作者:Jansen,R.; et al.
参考来源:Org Process Res Dev 2001,5(1),16