AP-1903

利米多赛Chemical Name: Bis[1-[2(S)-(3,4,5-Trimethoxypheny)butyryl]piperidine-2(S)-carboxylic acid] ester with 1,2-ethanediylbis[imino(2-oxo-2,1-ethanediyl)oxy-3,1-phenylene[(1R)-3-(3,4-dimethoxyphenyl)propylidene]] ester
CAS No. 195514-63-7
项目整合开发状态: Phase II
项目研究机构: Ariad Pharmaceuticals (Originator)
合成路线:The intermediate alcohol (VIII) was prepared as shown in Scheme 27060901a:Aldol condensation of 3,4-dimethoxybenzaldehyde (I) with 3-hydroxyacetophenone (II) in the presence of KOH provided chalcone (III),which was hydrogenated over Pd/C to yield the corresponding diarylpropanone (IV).Subsequent alkylation of the phenolic hydroxyl group of (IV) with tert-butyl bromoacetate (V) using NaH in DMF gave ether (VI).Then,enantioselective reduction of ketone by means of (+)-beta-chlorodiisopinocampheylborane (VII) at -20 C furnished the (R)-alcohol (VIII).

合成路线:3,4,5-Trimethoxyphenylacetic acid (IX) was alkylated with ethyl iodide in the presence of two equivalents of sodium bis(trimethylsilyl)amide to afford racemic trimethoxyphenylbutyric acid (X).After conversion to the corresponding acid chloride with SOCl2,condensation with (R)-4-benzyl-2-oxazolidinone (XI) in the presence of n-butyllithium gave N-acyloxazolidinone (XII) as a diastereomeric mixture that was separated by column chromatography.The required diastereoisomer was then hydrolyzed with lithium peroxide to provide (S)-2-(3,4,5-trimethoxyphenyl)butyric acid (XIII).Subsequent coupling of (XIII) with methyl (S)-pipecolate (XIV) employing 2-chloro-1-methylpyridinium iodide,followed by ester hydrolysis with LiOH,provided amide (XV).Further DCC-promoted coupling of (XV) to alcohol (VIII) provided (XVI).After acid cleavage of the tert-butyl ester,the resulting carboxylic acid was finally coupled to etylenediamine (XVII) in the presence of 1-benzotriazolyloxy tris(dimethylamino)phosphonium hexafluorophosphate to yield the title compound.