A-192558

Chemical Name: (?-4(R*)-Amino-1-(N-ethyl-N-isopropylcarbamoyl)-5(S*)-(trifluoroacetamidomethyl)pyrrolidine-3(R*)-carboxylic acid
CAS No. 341969-96-8 (enantiomer)
项目整合开发状态: Biological Testing
项目研究机构: Abbott (Originator)
合成路线:Condensation between benzyl N-Cbz-alpha-glutamate (I) and tert-butyl acrylate (II) in THF in the presence of tert-BuOK followed by treatment with ammonium acetate in refluxing methanol provides pyrroline acetic acid (III),which is converted into the corresponding benzyl ester (IV) by reaction with benzyl bromide and DIEA in refluxing CH2Cl2.Protection of (IV) with Boc2O and DMAP in CH2Cl2 yields the bis-Boc derivative (V),which is subjected to hydrogenation over Pd/C in HOAc to afford a mixture diastereomers (VI) and (VI? which are inseparable chromatographically.The mixture of (VI)/(VI? is subjected to reaction with carbamoyl chloride (VII) in CH2Cl2 in the presence of DIEA or pyridine to give the corresponding N-ethyl-N-isopropylureas from which diastereomer (2S,3R,4R)-(VIII) is chromatographically isolated.Derivative (2S,3R,4R)-(VIII) is subjected to Curtius rearrangement using diphenylphosphoryl azide (DPPA) and Et3N in toluene in the presence of benzyl alcohol to give the Cbz-protected amine (IX),which is then deprotected by hydrogenation over Pd in formic acid/MeOH to yield free amine (X).Coupling of (X) with trifluoroacetic acid (XI) by means of EDCI and HOBt in CH2Cl2 furnishes acetamide (XII),which is finally converted into the desired product by removal of the corresponding protecting groups with TFA in CH2Cl2.