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【结 构 式】 
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【药物名称】OP-2507 【化学名称】15-cis-(4-n-Propylcyclohexyl)-16,17,18,19,20-pentanor-9-deoxy-6,9alpha-nitrilo PGF1 methyl ester 【CA登记号】101758-79-6 【 分 子 式 】C25H41NO4 【 分 子 量 】419.60982 |
【开发单位】Dainippon Pharmaceutical (Originator), Ono (Originator) 【药理作用】Cerebrovascular Diseases, Treatment of, Cognition Disorders, Treatment of, GASTROINTESTINAL DRUGS, Hepatoprotectants, Ischemic Stroke, Treatment of, Liver and Biliary Tract Disorders, Treatment of, NEUROLOGIC DRUGS, Stroke, Treatment of |
合成路线1
The partial protection of cyclohexane-1,4-diol (I) with dihydropyran (DHP) and p-toluenesulfonic acid in dichloromethane gives the monotetrahydropyranyloxy derivative (II), which is oxidized with oxalyl chloride in DMSO - dichloromethane to 4-(tetrahydropyranyloxy)cyclohexanone (III). The condensation of (III) with propyldiphenylphosphonium bromide by means of n-butyllithium in THF affords the 4-propenyl derivative (V), which is deprotected with p-toluenesulfonic acid in methanol giving 4-propenylcyclohexanol (VI). The hydrogenation of (VI) with H2 over Pd/C in methanol, followed by column chromatography over Lobar (trademark of Merck & Co., Inc.) affords trans-4-propylcyclohexanol (VII), which is mesylated with mesyl chloride and triethylamine in dichloromethane to the corresponding mesylate (VIII). The reaction of (VIII) with NaCN in hot DMSO gives cis-4-propylcyclohexanecarbonitrile (IX), which is hydrolyzed with H2SO4 - water at 130 C yielding cis-4-propylcyclohexanecarboxylic acid (X). Esterification of (X) with diazomethane in ether affords the corresponding methyl ester (XI), which is condensed with dimethyl methylphosphonate (XII) by means of n-butyllithium in THF to give the phosphonate (XIII). The Wittig condensation of (XIII) with 1alpha-acetoxy-2alpha-[6-(methoxycarbonyl)hex-2(Z)-enyl]-3beta-formyl-4alpha-(tetrahydropyran-2-yloxy)cyclopentane (XIV) by means of NaH in THF yields the protected 15-oxo-prostaglandin (XV), which is reduced with LiAlH4 and S-2,2'-dihydroxy-1,1'-binaphthyl (SBN) affording the 15alpha-hydroxy compound (XVI). The methyl cis-4-propylcyclohexanecarboxylate (XI) can also be obtained by a cis-selective hydrogenation of methyl 4-propylbenzoate (XXIV) with hydrogen in hexane as organic phase and a buffer solution at pH 7.6 containing a quaternary salt as phase-transfer catalyst, and the dimer chloro(1,5-cyclooctadiene)rhodium [RhCl(COD)]2 as hydrogenation catalyst.
| 【1】 Masuda, Y. (Ono Pharmaceutical Co., Ltd.); New method of treatment using prostaglandin analogues. EP 0169725; JP 1986030519 . |
| 【2】 Prous, J.; Castaner, J.; OP-2507. Drugs Fut 1989, 14, 6, 525. |
| 【3】 Iguchi, S.; et al.; T. Synthesis of 15-cis-(4-n-propylcyclohexyl)-16,17,18,19, 20-pentanor-9-deoxy-6,9-alpha-nitriloprostaglandin F2 methyl ester (OP-2507), a novel anti-cerebral ischemic agent. Chem Pharm Bull 1988, 36, 3, 1128. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (I) | 20970 | 1,4-cyclohexanediol | 556-48-9 | C6H12O2 | 详情 | 详情 |
| (II) | 20971 | 4-[(tetrahydro-2H-pyran-2-yloxy)methyl]cyclohexanol | C12H22O3 | 详情 | 详情 | |
| (III) | 20972 | 4-[(tetrahydro-2H-pyran-2-yloxy)methyl]cyclohexanone | C12H20O3 | 详情 | 详情 | |
| (IV) | 20973 | trimethyl(propyl)phosphonium bromide | C21H22BrP | 详情 | 详情 | |
| (V) | 20974 | 2-([4-[(E)-1-propenyl]cyclohexyl]methoxy)tetrahydro-2H-pyran; [4-[(E)-1-propenyl]cyclohexyl]methyl tetrahydro-2H-pyran-2-yl ether | C15H26O2 | 详情 | 详情 | |
| (VI) | 20975 | 4-[(E)-1-propenyl]cyclohexanol | C9H16O | 详情 | 详情 | |
| (VII) | 20976 | 4-propylcyclohexanol | C9H18O | 详情 | 详情 | |
| (VIII) | 20977 | methyl(dimethylene)[(4-propylcyclohexyl)oxy]-lambda(6)-sulfane | C12H24OS | 详情 | 详情 | |
| (IX) | 20978 | 4-propylcyclohexanecarbonitrile | C10H17N | 详情 | 详情 | |
| (X) | 20979 | 4-propylcyclohexanecarboxylic acid | 38289-27-9 | C10H18O2 | 详情 | 详情 |
| (XI) | 20980 | methyl 4-propylcyclohexanecarboxylate | C11H20O2 | 详情 | 详情 | |
| (XII) | 13607 | dimethyl methylphosphonate | 756-79-6 | C3H9O3P | 详情 | 详情 |
| (XIII) | 20982 | dimethyl 2-oxo-2-(4-propylcyclohexyl)ethylphosphonate | C13H25O4P | 详情 | 详情 | |
| (XIV) | 20983 | methyl (Z)-7-[(1R,2S,3R,5S)-5-(acetoxy)-2-formyl-3-[(tetrahydro-2H-pyran-2-yloxy)methyl]cyclopentyl]-5-heptenoate | C22H34O7 | 详情 | 详情 | |
| (XV) | 20984 | methyl (Z)-7-[(1R,2S,3R,5S)-5-(acetoxy)-2-[(E)-3-oxo-3-(4-propylcyclohexyl)-1-propenyl]-3-[(tetrahydro-2H-pyran-2-yloxy)methyl]cyclopentyl]-5-heptenoate | C33H52O7 | 详情 | 详情 | |
| (XVI) | 20985 | methyl (Z)-7-[(1R,2S,3R,5S)-5-(acetoxy)-2-[(E,3S)-3-hydroxy-3-(4-propylcyclohexyl)-1-propenyl]-3-[(tetrahydro-2H-pyran-2-yloxy)methyl]cyclopentyl]-5-heptenoate | C33H54O7 | 详情 | 详情 | |
| (XXIV) | 63097 | methyl 4-propylcyclohexanecarboxylate | C11H20O2 | 详情 | 详情 |
合成路线2
The protection of (XVI) with dihydropyran as usual gives the fully protected compound (XVII), which is deacetylated with K2CO3 in methanol to the 9alpha-hydroxy derivative (XVIII). The formylation of (XVIII) with diethyl azodiformate (XIX) and triphenylphosphine - formic acid in THF gives the 9beta-formyloxy compound (XX), which is hydrolyzed with K2CO3 as before to the 9beta-hydroxy compound (XXI). The tosylation of (XXI) with tosyl chloride in pyridine yields the tosylate (XXII), which is deprotected with p-toluenesulfonic acid affording the 9beta-tosyloxy-11alpha,15alpha-dihydroxyprostaglandin (XXIII). Finally, this compound is cyclized with sodium azide in hot DMSO.
| 【1】 Masuda, Y. (Ono Pharmaceutical Co., Ltd.); New method of treatment using prostaglandin analogues. EP 0169725; JP 1986030519 . |
| 【2】 Prous, J.; Castaner, J.; OP-2507. Drugs Fut 1989, 14, 6, 525. |
| 【3】 Iguchi, S.; et al.; T. Synthesis of 15-cis-(4-n-propylcyclohexyl)-16,17,18,19, 20-pentanor-9-deoxy-6,9-alpha-nitriloprostaglandin F2 methyl ester (OP-2507), a novel anti-cerebral ischemic agent. Chem Pharm Bull 1988, 36, 3, 1128. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XVI) | 20985 | methyl (Z)-7-[(1R,2S,3R,5S)-5-(acetoxy)-2-[(E,3S)-3-hydroxy-3-(4-propylcyclohexyl)-1-propenyl]-3-[(tetrahydro-2H-pyran-2-yloxy)methyl]cyclopentyl]-5-heptenoate | C33H54O7 | 详情 | 详情 | |
| (XVII) | 20987 | methyl (Z)-7-[(1R,2S,3R,5S)-5-(acetoxy)-2-[(E,3S)-3-(4-propylcyclohexyl)-4-(tetrahydro-2H-pyran-2-yloxy)-1-butenyl]-3-[(tetrahydro-2H-pyran-2-yloxy)methyl]cyclopentyl]-5-heptenoate | C39H64O8 | 详情 | 详情 | |
| (XVIII) | 20988 | methyl (Z)-7-[(1R,2S,3R,5S)-5-hydroxy-2-[(E,3S)-3-(4-propylcyclohexyl)-4-(tetrahydro-2H-pyran-2-yloxy)-1-butenyl]-3-[(tetrahydro-2H-pyran-2-yloxy)methyl]cyclopentyl]-5-heptenoate | C37H62O7 | 详情 | 详情 | |
| (XIX) | 20989 | Diethylazadicarboxylate; Diethyl Azodiformate; Azodiformic Acid Diethyl Ester; Diethyl Azodicarboxylate; Azodicarboxylic Acid Diethyl Ester; Diethyl 1,2-diazenedicarboxylate | 1972-28-7 | C6H10N2O4 | 详情 | 详情 |
| (XX) | 20990 | methyl (Z)-7-[(1R,2S,3R,5R)-5-(formyloxy)-2-[(E,3S)-3-(4-propylcyclohexyl)-4-(tetrahydro-2H-pyran-2-yloxy)-1-butenyl]-3-[(tetrahydro-2H-pyran-2-yloxy)methyl]cyclopentyl]-5-heptenoate | C38H62O8 | 详情 | 详情 | |
| (XXI) | 20991 | methyl (Z)-7-[(1R,2S,3R,5R)-5-hydroxy-2-[(E,3S)-3-(4-propylcyclohexyl)-4-(tetrahydro-2H-pyran-2-yloxy)-1-butenyl]-3-[(tetrahydro-2H-pyran-2-yloxy)methyl]cyclopentyl]-5-heptenoate | C37H62O7 | 详情 | 详情 | |
| (XXII) | 20992 | methyl (Z)-7-[(1R,2S,3R,5R)-5-[[(4-methylphenyl)sulfonyl]oxy]-2-[(E,3S)-3-(4-propylcyclohexyl)-4-(tetrahydro-2H-pyran-2-yloxy)-1-butenyl]-3-[(tetrahydro-2H-pyran-2-yloxy)methyl]cyclopentyl]-5-heptenoate | C44H68O9S | 详情 | 详情 | |
| (XXIII) | 20993 | methyl (Z)-7-((1R,2R,3R,5R)-3-hydroxy-2-[(E,3S)-3-hydroxy-3-(4-propylcyclohexyl)-1-propenyl]-5-[[(4-methylphenyl)sulfonyl]oxy]cyclopentyl)-5-heptenoate | C32H48O7S | 详情 | 详情 |