Trimoprostil, Ro-216937, Ro-216937/000, Ulstar

曲莫前列素Chemical Name: (5Z,11alpha,13E,15R)-15-Hydroxy-11,16,16-trimethyl-9-oxoprosta-5,13-dien-1-oic acid
CAS No. 69900-72-7
项目整合开发状态: Phase III
项目研究机构: Alcon (Originator), Roche (Originator)
合成路线:The resolution of racemic 3,3alpha-beta,4,5,6,6alpha-beta-hexahydro-4beta-nitromethyl-5alpha-carboxy-2H-cyclopenta[b]furan-2-one (I),with R(+)-alpha-methyl-p-nitrobenzylamine gives optical active 3,3aR,4,5,6,6aS-hexahydro-4R-nitromethyl-5R-carboxy-2H-cyclopenta[b]furan-2-one (I),which is reduced with borane-methyl sulfide complex in ethyl acetate yielding the corresponding hydroxymethyl compound (II).The reaction of (II) with I2 and triphenylphosphine in HMPT affords the iodomethyl derivative (III),which is finally reduced with sodium cyanoborohydride in the same solvent to give 3,3aR,4,5,6,6aS-hexahydro-4S-nitromethyl-5R-methyl-2H-cyclopenta[b]furan-2-one (IV).The treatment of (IV) with sodium methoxide in methanol and with H2SO4-methanol yields the 4S-dimethoxymethyl derivative (V),which is hydrolyzed with trifluoro acetic acid in water-CHCl3 to afford the corresponding 4S-formyl compound (VI).The Wittig reaction of (VI) with dimethyl (3,3-dimethyl-2-oxoheptyl)phosphonate (VII) in 1,2-dimethoxyethane affords 3,3aR,4,5,6,6aS-hexahydro-4R-(4,4-dimethyl-3-oxo-1-trans-octenyl)-5R-methyl-2H-cyclopenta[b]furan-2-one (VIII),which is reduced with NaBH4 in methanol to yield the corresponding 3S-hydroxy compound (IX).The protection of the hydroxy group of (IX) with dihydropyran/p-toluenesulfonic acid in CH2Cl2 affords the 3S-tetrahydropyranyloxy compound (X),which is reduced again with diisobutyl aluminum hydride in toluene to afford 3,3aR,4,5,6,6-hexahydro-4R-(4,4-dimethyl-3R-tetrahydropyranyloxy-1-trans-octenyl)-5R-methyl-2H-cyclopenta[b]furan-2-ol (XI).

合成路线:The Wittig reaction of (XI) with (4-carboxybutyl)triphenylphosphonium bromide (XII) in HMPT gives nat-11R,16,16-trimethyl-15R-(2-tetrahydropyranyloxy)-9S-hydroxyprosta-cis-5-trans-13-dienoic acid (XIII),which is oxidized with Jones reagent (CrO3-H2SO4) affording the corresponding 9-oxo compound (XIV).Finally,this compound is hydrolyzed with acetic acid in a mixture THF-water.