Ataprost, OP-41483, Ono-41483

阿前列素Chemical Name: [3aS-[2E,3aalpha,4alpha(1E,3R*),5beta,6aalpha]]-5-[4-(3-Cyclopentyl-3-hydroxy-1-propenyl)hexahydro-5-hydroxy-2(1H)-pentalenylidene]pentanoic acid; (9alpha,11alpha,15alpha)-6,9-Methano-11,15-dihydroxy-15-cyclopentyl-16,17,18,19,20-pentanorprosta-5,13-dienoic acid; 15-Cyclopentyl-omega-pentanor-5(E)-carbacyclin
CAS No. 83997-19-7
项目整合开发状态: Phase III
项目研究机构: Ono (Originator), Dainippon Pharmaceutical (Licensee)
合成路线:The esterification of 4alpha-carboxymethyl-5beta-benzyloxymethyl-cyclopent-2-en-1alpha-ol (I) with methyl iodide and K2CO3 in acetone gives the corresponding methyl ester (II),which by reaction with triethyl - orthoacetate (III) at 145 C is converted into 3-ethoxycarbonylmethyl-4-methoxycarbonylmethyl-5-benzyloxymethyl-1-cyclopentene (IV).The cyclization of (IV) with potassium tert-butoxide in benzene yields 6-benzyloxymethyl-cis-bicyclo[3.3.0]oct-7-ene-3-one (V),which by reaction with N-bromosuccinimide in DMSO - water affords 6-benzyloxymethyl-7-hydroxy-8-bromo-cis-bicyclo[3.3.0]octan-3-one (VI).Debromination of (VI) with tributyltin hydride and azobisisobutyronitrile in benzene irradiated with UV light gives 6-benzyloxymethyl-7-hydroxy-cis-bicyclo[3.3.0]octan-3-one (VII),which is treated with dihydropyran and p-toluenesulfonic acid in methylene chloride yielding the corresponding protected compound (VIII).Elimination of the benzyl group of (VIII) with H2 over Pd/C in acetic acid affords 6-hydroxymethyl-7-(tetrahydropyranyloxy)-cis-bicyclo[3.3.0]octan-3-one (IX),which is submitted to a Wittig condensation with (4-carboxybutyl) triphenylphosphonium bromide (X) and the sodium salt of DMSO in this solvent,followed by a methylation with diazomethane,affording 3-(4-methoxycarbonylbutylidene)-6-hydroxymethyl-7-tetrahydropyranyloxy)-cis-bicyclo[3.3.0]octane (XI).Oxidation of (XI) with CrO3 in methylene chloride gives the corresponding 6-formyl derivative (XII),which is submitted to a new Wittig condensation with dimethyl 2-oxo-2-cyclopentylethylphosphonate (XIII) and NaH in THF yielding methyl 6,9-methano-11-(tetrahydropyranyloxy)-15-oxo-15-cyclopentyl-16,17,18,19,20-pentanorprosta-3,5-dienoate (XIV).Deprotection of (XIV) with acetic acid in THF - water gives the corresponding 11-hydroxy compound (XVI),which is reduced with NaBH4 in methanol affording the 11,15-dihydroxy ester (XVI).Finally,this compound is hydrolyzed with NaOH in methanol - water.

合成路线:The protection of bromoketol (VI) with dihydropyran and p-toluene sulfonic acid in methylene chloride gives the corresponding tetrahydropyranyl derivative (XVII),which is debrominated with tributyltin hydride as usual yielding (VIII),already obtained.

合成路线:The protection of hydroxyester (II) with dihydropyran dihydropyran and p-toluene sulfonic acid in methylene chloride gives 1-(tetrahydropyranyloxy)-4-methoxycarbonylmethyl-6-benzyloxymethylcyclopent-2-ene (XVIII),which is condensed with ethyl acetate by means of butyllithium and diisopropyl amine in THF yielding 1-(tetrahydropyranyloxy)-4-(2-oxo-3-ethoxycarbonylpropyl)-5-benzyloxymethylcyclopent-2-ene (XIX).The reaction of (XIX) with p-toluenesulfonyl azide and triethylamine in acetonitrile affords 1-(tetrahydropyranyloxy)-4-(2-oxo-3-diazo-3-ethoxycarbonylpropyl)-5-benzyloxymethylcyclopent-2-ene (XX),which is cyclized by means of CuSO4 in refluxing benzene to 2-ethoxycarbonyl-6-benzyloxymethyl-7-(tetrahydropyranyloxy)-cis-tricyclo[3.3.0.0(2,8)]octan-3-one (XXI).Ring opening of (XXI) with tributyltin hydride and azobisisobutyronitrile in benzene irradiated with UV light affords 2-ethoxycarbonyl-6-benzyloxymethyl-7-(tetrahydropyranyloxy)-cis-bicyclo[3.3.0]octan-3-one (XXII),which is hydrolyzed and decarboxylated in HMPT - water at 160 C giving (VIII),already obtained.

合成路线:The oxidative ring opening of 2-oxa-6-benzyloxymethyl-7-(tetrahydropyranyloxy)-cis-bicyclo[3.3.0]octan-3-one (XXIII) with NaOH in methanol,followed by a treatment with CrO2Cl2 in CCl4 gives 2-methoxycarbonylmethyl-3-benzyloxymethyl-4-(tetrahydropyranyloxy)-1-cyclopentanone (XXIV),which by reaction with methyl trimethylsilylacetate (XXV) by means of butyllithium and diisopropylamine in THF is converted into 1-(methoxycarbonylmethylidene)-2-methoxycarbonylmethyl-3-benzyloxymethyl-4-(tetrahydropyranyloxy)cyclopentane (XXVI).The hydrogenation of (XXVI) with H2 over Pd/C in ethanol affords 1,2-bis(methoxycarbonylmethyl)-3-benzyloxymethyl-4-(tetrahydropyranyloxy)cyclopentane (XXVII),which is cyclized by means of potassium tert-butoxide in refluxing benzene to 2 (or 4)-methoxycarbonyl-6-benzyloxymethyl-7-(tetrahydropyranyloxy)-cis-bicyclo[3.3.0]octan-3-one (XXVIII).Finally,this compound is hydrolyzed and decarboxylated in HMPT - water at 160 C giving the ketone (VIII),already obtained.