新产品编号:2060273

Chemical Name: 6-[5-Imino-3(R)-(trifluoromethyl)pyrrolidin-2(R)-yl]-L-norleucine
项目整合开发状态: Preclinical
项目研究机构: Pfizer (Originator)
合成路线:Michael addition of ethyl trifluorocrotonate (I) to 3-nitropropionaldehyde dimethyl acetal (II) gave adduct (III).Reductive cyclization of nitro ester (III) furnished a mixture of cis- (IV) and trans- (V) pyrrolidinones.The desired cis-isomer (IV) was protected by N-alkylation with p-methoxybenzyl chloride,yielding (VI).After acid hydrolysis of the acetal function of (VI),the resulting aldehyde (VII) was subjected to a Wittig reaction with ethoxycarbonylmethylene triphenylphosphorane to afford the unsaturated ester (VIII),which was further hydrogenated over of Pd/C to the saturated ester (IX).The ester function of (IX) was then converted to aldehyde (X) by either reduction with DIBAL or by reduction to alcohol,followed by Swern oxidation.

合成路线:Horner-Emmons condensation of aldehyde (X) with Z-alpha-phosphonoglycine trimethyl ester (XI) furnished the unsaturated amino ester (XII).The required saturated compound (XIII) was then prepared by asymmetric hydrogenation of (XII) in the presence of a rhodium chiral catalyst.Removal of the p-methoxybenzyl protecting group of (XIII) was achieved by treatment with cerium ammonium nitrate yielding pyrrolidinone (XIV).Treatment of (XIV) with triethyloxonium tetrafluoroborate produced the cyclic imidate (XV),which was converted to amidine (XVI) by reaction with ammonium chloride.Finally,acid hydrolysis of the ester and carbamate groups of (XVI) provided the title compound.