SB-219994

3-[4-[2-[N-(2-苯氧基)-N-甲基氨基]苯基]-2(S)-(2,2,2-三氟乙氧基)丙酸Chemical Name: 3-[4-[2-[N-(2-Benzoxazolyl)-N-methylamino]ethoxy]phenyl]-2(S)-(2,2,2-trifluoroethoxy)propionic acid
CAS No. 177785-17-0
项目整合开发状态: Preclinical
项目研究机构: GlaxoSmithKline (Originator)
合成路线:The chiral compound was prepared by several alternative procedures.Acid hydrolysis of the known racemic ester (I) gave carboxylic acid (II),which was converted into acid chloride (III) by using oxalyl chloride in benzene.This was either condensed with (S)-2-phenylglycinol (V) or with (S)-4-benzyloxazolidine-2-one (VI) to provide the diastereomeric mixtures of amides (VI) or imides (VII),respectively.After chromatographic separation of the required (S,S)-diastereoisomers,the title compound was obtained by acid hydrolysis of the (S,S)-amide or by hydrolysis of the corresponding imide with NaOH.

合成路线:In an alternative procedure,(2,2,2-trifluoroethoxy)acetic acid (VIII) was converted into acid chloride (IX) by means of oxalyl chloride,and then coupled with (S)-4-benzyloxazolidine-2-one (V) in the presence of butyllithium to afford the chiral imide (X).The boron enolate obtained by treatment of (X) with di-n-butylboron triflate and triethylamine was then condensed with aldehyde (XI) to produce,after oxidative work-up with H2O2,a mixture of 3 diastereomeric aldol products (XII).The major [3(2S,3R),4S] isomer was isolated by column chromatography,and subsequently reduced with triethylsilane and trifluoroacetic acid to the (S,S) dehydroxylated compound (XIII).Basic hydrolysis of the imide (XIII) as above furnished the title carboxylic acid.Alternatively,treatment of the imide (XIII) with methanolic NaOMe produced the methyl ester (XIV),which was finally hydrolyzed to the target carboxylic acid employing HCl in aqueous dioxan.