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【结 构 式】 
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【分子编号】20985 【品名】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 【CA登记号】 |
【 分 子 式 】C33H54O7 【 分 子 量 】562.78756 【元素组成】C 70.43% H 9.67% O 19.9% |
合成路线1
该中间体在本合成路线中的序号：(XVI)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
该中间体在本合成路线中的序号：(XVI)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 |