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【结 构 式】

【分子编号】18773

【品名】[(1R,2R,3S,6R)-6-isopropenyl-2-methoxy-3-methyl-3-[2-(trityloxy)ethyl]cyclohexyl]methyl methanesulfonate

【CA登记号】

【 分 子 式 】C34H42O5S

【 分 子 量 】562.77048

【元素组成】C 72.56% H 7.52% O 14.21% S 5.7%

与该中间体有关的原料药合成路线共 2 条

合成路线1

该中间体在本合成路线中的序号:(XVII)

Reduction of (-)-R-carvone (I) with LiAlH4 in Et2O at -78 C gave alcohol (II). Inversion of the hydroxyl group was then achieved by Mitsunobu reaction with 4-nitrobenzoic acid (III), followed by hydrolysis of the resulting 4-nitrobenzoate ester (IV) to give (V). Treatment of alcohol (V) with ethyl vinyl ether (VI) and N-bromosuccinimide produced the bromoacetal (VII). Subsequent intermolecular radical cyclization of (VII) with NaBH4 in the presence of a catalytic amount of Bu3SnCl and AIBN yielded cyclic acetal (VIII). Acidic hydrolysis of (VIII) followed by reduction of the resulting aldehyde (IX) with LiAlH4 provided diol (X). Protection of the primary alcohol group with trityl chloride in the presence of DMAP gave (XI), and subsequent oxidation of the secondary alcohol with pyridinum chlorochromate afforded ketone (XII). Further carbomethoxylation of (XII) by treatment with LDA and methyl cyanoformate yielded ketoester (XIII), which was reduced to alcohol (XIV) with NaBH4 in MeOH at 0 C. Then, alcohol (XIV) was converted to methyl ether (XV) by reaction with methyl iodide and NaH in DMF, and the ester group was reduced to alcohol (XVI) with LiAlH4 in Et2O at 0 C. Alcohol (XVI) was converted to mesylate (XVII) with methanesulfonyl chloride and Et3N.

1 Tsukuda, T.; Watanabe, M.; Ontsuka, H.; Hattori, K.; Shirai, M.; Shimma, N.; Synthesis of novel antifungal agents (2). Bioorg Med Chem Lett 1998, 8, 14, 1825.
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) 13386 (5R)-5-Isopropenyl-2-methyl-2-cyclohexen-1-one; L-(-)-Carvone 6485-40-1 C10H14O 详情 详情
(II) 18758 (1R,5R)-5-isopropenyl-2-methyl-2-cyclohexen-1-ol C10H16O 详情 详情
(III) 18119 4-nitrobenzoic acid; p-nitrobenzoic acid 62-23-7 C7H5NO4 详情 详情
(IV) 18760 (1S,5R)-5-isopropenyl-2-methyl-2-cyclohexen-1-yl 4-nitrobenzoate C17H19NO4 详情 详情
(V) 18761 (1S,5R)-5-isopropenyl-2-methyl-2-cyclohexen-1-ol C10H16O 详情 详情
(VI) 18762 1-Ethoxyethylene; Ethyl vinyl ether;Ethoxyethene 109-92-2 C4H8O 详情 详情
(VII) 18763 2-bromo-1-ethoxyethyl (1S,5R)-5-isopropenyl-2-methyl-2-cyclohexen-1-yl ether; (4R,6S)-6-(2-bromo-1-ethoxyethoxy)-4-isopropenyl-1-methyl-1-cyclohexene C14H23BrO2 详情 详情
(VIII) 18764 (3aS,6R,7aS)-2-ethoxy-6-isopropenyl-3a-methyloctahydro-1-benzofuran; (3aS,6R,7aS)-6-isopropenyl-3a-methyloctahydro-1-benzofuran-2-yl ethyl ether C14H24O2 详情 详情
(IX) 18765 2-[(1S,2S,4R)-2-hydroxy-4-isopropenyl-1-methylcyclohexyl]acetaldehyde C12H20O2 详情 详情
(X) 18766 (1S,2S,5R)-2-(2-hydroxyethyl)-5-isopropenyl-2-methylcyclohexanol C12H22O2 详情 详情
(XI) 18767 (1S,2S,5R)-5-isopropenyl-2-methyl-2-[2-(trityloxy)ethyl]cyclohexanol C31H36O2 详情 详情
(XII) 18768 (2S,5R)-5-isopropenyl-2-methyl-2-[2-(trityloxy)ethyl]cyclohexanone C31H34O2 详情 详情
(XIII) 18769 methyl (3S,6R)-6-isopropenyl-3-methyl-2-oxo-3-[2-(trityloxy)ethyl]cyclohexanecarboxylate C33H36O4 详情 详情
(XIV) 18770 methyl (1S,2R,3S,6R)-2-hydroxy-6-isopropenyl-3-methyl-3-[2-(trityloxy)ethyl]cyclohexanecarboxylate C33H38O4 详情 详情
(XV) 18771 methyl (1S,2R,3S,6R)-6-isopropenyl-2-methoxy-3-methyl-3-[2-(trityloxy)ethyl]cyclohexanecarboxylate C34H40O4 详情 详情
(XVI) 18772 [(1R,2R,3S,6R)-6-isopropenyl-2-methoxy-3-methyl-3-[2-(trityloxy)ethyl]cyclohexyl]methanol C33H40O3 详情 详情
(XVII) 18773 [(1R,2R,3S,6R)-6-isopropenyl-2-methoxy-3-methyl-3-[2-(trityloxy)ethyl]cyclohexyl]methyl methanesulfonate C34H42O5S 详情 详情

合成路线2

该中间体在本合成路线中的序号:(XVII)

Reduction of (-)-R-carvone (I) with LiAlH4 in Et2O at -78 C gave alcohol (II). Inversion of the hydroxyl group was then achieved by Mitsunobu reaction with 4-nitrobenzoic acid (III), followed by hydrolysis of the resulting 4-nitrobenzoate ester (IV) to give (V). Treatment of alcohol (V) with ethyl vinyl ether (VI) and N-bromosuccinimide produced the bromoacetal (VII). Subsequent intermolecular radical cyclization of (VII) with NaBH4 in the presence of a catalytic amount of Bu3SnCl and AIBN yielded cyclic acetal (VIII). Acidic hydrolysis of (VIII) followed by reduction of the resulting aldehyde (IX) with LiAlH4 provided diol (X). Protection of the primary alcohol group with trityl chloride in the presence of DMAP gave (XI), and subsequent oxidation of the secondary alcohol with pyridinum chlorochromate afforded ketone (XII). Further carbomethoxylation of (XII) by treatment with LDA and methyl cyanoformate yielded ketoester (XIII), which was reduced to alcohol (XIV) with NaBH4 in MeOH at 0 C. Then, alcohol (XIV) was converted to methyl ether (XV) by reaction with methyl iodide and NaH in DMF, and the ester group was reduced to alcohol (XVI) with LiAlH4 in Et2O at 0 C. Alcohol (XVI) was converted to mesylate (XVII) with methanesulfonyl chloride and Et3N.

1 Tsukuda, T.; Watanabe, M.; Ontsuka, H.; Hattori, K.; Shirai, M.; Shimma, N.; Synthesis of novel antifungal agents (2). Bioorg Med Chem Lett 1998, 8, 14, 1825.
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) 13386 (5R)-5-Isopropenyl-2-methyl-2-cyclohexen-1-one; L-(-)-Carvone 6485-40-1 C10H14O 详情 详情
(II) 18758 (1R,5R)-5-isopropenyl-2-methyl-2-cyclohexen-1-ol C10H16O 详情 详情
(III) 18119 4-nitrobenzoic acid; p-nitrobenzoic acid 62-23-7 C7H5NO4 详情 详情
(IV) 18760 (1S,5R)-5-isopropenyl-2-methyl-2-cyclohexen-1-yl 4-nitrobenzoate C17H19NO4 详情 详情
(V) 18761 (1S,5R)-5-isopropenyl-2-methyl-2-cyclohexen-1-ol C10H16O 详情 详情
(VI) 18762 1-Ethoxyethylene; Ethyl vinyl ether;Ethoxyethene 109-92-2 C4H8O 详情 详情
(VII) 18763 2-bromo-1-ethoxyethyl (1S,5R)-5-isopropenyl-2-methyl-2-cyclohexen-1-yl ether; (4R,6S)-6-(2-bromo-1-ethoxyethoxy)-4-isopropenyl-1-methyl-1-cyclohexene C14H23BrO2 详情 详情
(VIII) 18764 (3aS,6R,7aS)-2-ethoxy-6-isopropenyl-3a-methyloctahydro-1-benzofuran; (3aS,6R,7aS)-6-isopropenyl-3a-methyloctahydro-1-benzofuran-2-yl ethyl ether C14H24O2 详情 详情
(IX) 18765 2-[(1S,2S,4R)-2-hydroxy-4-isopropenyl-1-methylcyclohexyl]acetaldehyde C12H20O2 详情 详情
(X) 18766 (1S,2S,5R)-2-(2-hydroxyethyl)-5-isopropenyl-2-methylcyclohexanol C12H22O2 详情 详情
(XI) 18767 (1S,2S,5R)-5-isopropenyl-2-methyl-2-[2-(trityloxy)ethyl]cyclohexanol C31H36O2 详情 详情
(XII) 18768 (2S,5R)-5-isopropenyl-2-methyl-2-[2-(trityloxy)ethyl]cyclohexanone C31H34O2 详情 详情
(XIII) 18769 methyl (3S,6R)-6-isopropenyl-3-methyl-2-oxo-3-[2-(trityloxy)ethyl]cyclohexanecarboxylate C33H36O4 详情 详情
(XIV) 18770 methyl (1S,2R,3S,6R)-2-hydroxy-6-isopropenyl-3-methyl-3-[2-(trityloxy)ethyl]cyclohexanecarboxylate C33H38O4 详情 详情
(XV) 18771 methyl (1S,2R,3S,6R)-6-isopropenyl-2-methoxy-3-methyl-3-[2-(trityloxy)ethyl]cyclohexanecarboxylate C34H40O4 详情 详情
(XVI) 18772 [(1R,2R,3S,6R)-6-isopropenyl-2-methoxy-3-methyl-3-[2-(trityloxy)ethyl]cyclohexyl]methanol C33H40O3 详情 详情
(XVII) 18773 [(1R,2R,3S,6R)-6-isopropenyl-2-methoxy-3-methyl-3-[2-(trityloxy)ethyl]cyclohexyl]methyl methanesulfonate C34H42O5S 详情 详情
Extended Information