Vapiprost hydrochloride, SN-309, GR-32191B

盐酸伐普前列素 伐哌前列素 Chemical Name: [1R-[1alpha(Z),2beta,3beta,5alpha]]-(+)-7-[5-[(1,1'-Biphenyl)-4-ylmethoxy]-3-hydroxy-2-(1-piperidinyl)cyclopentyl]-4-heptenoic acid hydrochloride; (Z)-(1R,2R,3S,5S)-7-[5-(Biphenyl-4-ylmethoxy)-3-hydroxy-2-piperidinocyclopentyl]hept-4-enoic acid hydrochloride; (Z)-(9S,11S,12R)-9-(Biphenyl-4-ylmethoxy)-11-hydroxy-12-piperidino(13-20)octanorprost-4-enoic acid hydrochloride
CAS No. 87248-13-3, 85505-64-2 (free base)
项目整合开发状态: Phase III
项目研究机构: GlaxoSmithKline (Originator)
合成路线:Resolution of bicyclo[3.2.0]hept-2-en-6-one (I) via the R-(+)-alpha-methylbenzylamine-bisulfite (A) addition complex provides the 1S-(-)-enantiomer (II),which affords the 3-endo-acetoxy-2-exo-bromobicyclo[3.2.0]heptan-6-one (III) on treatment with 1,3-dibromo-5,5-dimethylhydantoin (DBDMH).Reaction with piperidine followed by hydrolysis gives the hydroxynorbornanone (IV),which is alkylated with biphenylmethylbromide (B) under phase-transfer catalysis to yield the norbornanone (V).Baeyer-Villiger oxidation followed by partial reduction with diisobutylaluminum hydride (Dibal) gives the aldehyde (VII),which is then homologated to the aldehyde (VIII) using methoxymethylene-phosphorane and subsequent treatment with 2N HCl.Condensation of (VIII) with carboxypropyltriphenylphosphorane in tetrahydrofuran followed by esterification with tritylchloride gives the ester (IX).The alcohol stereochemistry in (IX) is inverted via oxidation with pyridine-sulfur trioxide complex in dimethylsulfoxide followed by reduction with Dibal in the presence of 2,6-di-tert-butyl-4-methylphenol.Finally,the ester is hydrolyzed with hydrochloric acid to give the required acid.