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【结 构 式】 
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【分子编号】20984 【品名】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 【CA登记号】 |
【 分 子 式 】C33H52O7 【 分 子 量 】560.77168 【元素组成】C 70.68% H 9.35% O 19.97% |
合成路线1
该中间体在本合成路线中的序号：(XV)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：(I)Reaction of 1-O-acetyl-2,3,5-tri-O-benzoyl-beta-D-ribofuranose (I) with trimethylsilyl cyanide in the presence of boron trifluoride gave nitrile (II), which was treated with liquid hydrogen sulfide and DMAP to yield thioamide (III). Condensation of this thioamide with bromoketone (IV) in acetonitrile afforded the thiazole derivative (V). Hydrolysis of the benzoate esters of (V) using sodium methoxide in methanol, followed by protection of the resulting 2,3-diol with acetone and triethyl orthoformate produced the corresponding isopropylidene ketal (VI). Treatment of the primary alcohol group of (VI) with sulfamoyl chloride gave rise to the sulfamate ester (VII). Further condensation of (VII) with N-Boc-L-leucine furnished (IX). The Boc and isopropylidene groups of (IX) were finally eliminated with trifluoroacetic acid to provide the title compound.
| 【1】 Wang, W.; Gallant, P.; Hill, J.M.; Yu, G.; Wendler, P.; Kluge, A.F.; Yu, X.Y.; Synthesis and structure-activity relationships of a series of novel thiazoles as inhibitors of aminoacyl-tRNA synthetases. Bioorg Med Chem Lett 1999, 9, 3, 375. |
| 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) | 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 | |
| (II) | 29143 | (2S,3S,4R,5R)-4-(benzoyloxy)-5-[(benzoyloxy)methyl]-2-cyanotetrahydro-3-furanyl benzoate | C27H21NO7 | 详情 | 详情 | |
| (III) | 29144 | (2R,3S,4R,5R)-2-(aminocarbothioyl)-4-(benzoyloxy)-5-[(benzoyloxy)methyl]tetrahydro-3-furanyl benzoate | C27H23NO7S | 详情 | 详情 | |
| (IV) | 29211 | 1-bromo-4-phenyl-2-butanone | C10H11BrO | 详情 | 详情 | |
| (V) | 29212 | [(2R,3R,4S,5R)-3,4-bis(benzoyloxy)-5-(4-phenethyl-1,3-thiazol-2-yl)tetrahydro-2-furanyl]methyl benzoate | C37H31NO7S | 详情 | 详情 | |
| (VI) | 29213 | [(3aR,4R,6R,6aS)-2,2-dimethyl-6-(4-phenethyl-1,3-thiazol-2-yl)tetrahydrofuro[3,4-d][1,3]dioxol-4-yl]methanol | C19H23NO4S | 详情 | 详情 | |
| (VII) | 29214 | [(3aR,4R,6R,6aS)-2,2-dimethyl-6-(4-phenethyl-1,3-thiazol-2-yl)tetrahydrofuro[3,4-d][1,3]dioxol-4-yl]methylsulfamate | C19H24N2O6S2 | 详情 | 详情 | |
| (VIII) | 23663 | (2S)-2-[(tert-butoxycarbonyl)amino]-4-methylpentanoic acid；N-Boc-L-leucine | C11H21NO4 | 详情 | 详情 | |
| (IX) | 29215 | tert-butyl (1S)-1-[[([[(3aR,4R,6R,6aS)-2,2-dimethyl-6-(4-phenethyl-1,3-thiazol-2-yl)tetrahydrofuro[3,4-d][1,3]dioxol-4-yl]methoxy]sulfonyl)amino]carbonyl]-3-methylbutylcarbamate | C30H43N3O9S2 | 详情 | 详情 |