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【结 构 式】 
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【分子编号】43271 【品名】2-(cyclohexylmethoxy)-6,7,8,9-tetrahydro-5H-benzo[a]cyclohepten-5-one 【CA登记号】 |
【 分 子 式 】C18H24O2 【 分 子 量 】272.38736 【元素组成】C 79.37% H 8.88% O 11.75% |
合成路线1
该中间体在本合成路线中的序号：(IV)Treatment of 6,7,8,9-tetrahydro-5H-benzocyclohepten-2-ol (I) with (bromomethyl)cyclohexane (II) in the presence of Cs2CO3 provided the cyclohexylmethyl ether (III). Regioselective oxidation of (III) by means potassium persulfate gave ketone (IV), which was reduced to alcohol (V) with NaBH4. Azide (VI) was obtained by treatment of alcohol (V) with diphenylphosphoryl azide. Catalytic hydrogenation of azide (VI) in the presence of Boc2O furnished the tert-butyl carbamate (VII). Aromatic bromination of (VII) with N-bromosuccinimide provided bromide (VIII) which, upon lithiation and subsequent quenching with CO2, gave rise to carboxylic acid (IX). Amide (X) was prepared by treatment of acid (IX) with ammonium hydroxide in the presence of EDC and HOBt. The Boc protecting group of (X) was then removed using trifluoroacetic acid to give (XI).
| 【1】 Bohacek, R.; Sawyer, T.K.; Yang, M.G.; Eyermann, C.J.; Sundaramoorthi, R.; Shakespeare, W.C. (Ariad Pharmaceuticals Inc.); Bicyclic signal transduction inhibitors, compsns. containing them & uses thereof. WO 0027802 . |
| 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) | 43269 | 6,7,8,9-tetrahydro-5H-benzo[a]cyclohepten-2-ol | C11H14O | 详情 | 详情 | |
| (II) | 31767 | 1-(bromomethyl)cyclohexane | 2550-36-9 | C7H13Br | 详情 | 详情 |
| (III) | 43270 | 2-(cyclohexylmethoxy)-6,7,8,9-tetrahydro-5H-benzo[a]cycloheptene; cyclohexylmethyl 6,7,8,9-tetrahydro-5H-benzo[a]cyclohepten-2-yl ether | C18H26O | 详情 | 详情 | |
| (IV) | 43271 | 2-(cyclohexylmethoxy)-6,7,8,9-tetrahydro-5H-benzo[a]cyclohepten-5-one | C18H24O2 | 详情 | 详情 | |
| (V) | 43272 | 2-(cyclohexylmethoxy)-6,7,8,9-tetrahydro-5H-benzo[a]cyclohepten-5-ol | C18H26O2 | 详情 | 详情 | |
| (VI) | 43273 | 5-azido-6,7,8,9-tetrahydro-5H-benzo[a]cyclohepten-2-yl cyclohexylmethyl ether; 5-azido-2-(cyclohexylmethoxy)-6,7,8,9-tetrahydro-5H-benzo[a]cycloheptene | C18H25N3O | 详情 | 详情 | |
| (VII) | 43274 | tert-butyl 2-(cyclohexylmethoxy)-6,7,8,9-tetrahydro-5H-benzo[a]cyclohepten-5-ylcarbamate | C23H35NO3 | 详情 | 详情 | |
| (VIII) | 43275 | tert-butyl 3-bromo-2-(cyclohexylmethoxy)-6,7,8,9-tetrahydro-5H-benzo[a]cyclohepten-5-ylcarbamate | C23H34BrNO3 | 详情 | 详情 | |
| (IX) | 43276 | 9-[(tert-butoxycarbonyl)amino]-3-(cyclohexylmethoxy)-6,7,8,9-tetrahydro-5H-benzo[a]cycloheptene-2-carboxylic acid | C24H35NO5 | 详情 | 详情 | |
| (X) | 43277 | tert-butyl 3-(aminocarbonyl)-2-(cyclohexylmethoxy)-6,7,8,9-tetrahydro-5H-benzo[a]cyclohepten-5-ylcarbamate | C24H36N2O4 | 详情 | 详情 | |
| (XI) | 43278 | 9-amino-3-(cyclohexylmethoxy)-6,7,8,9-tetrahydro-5H-benzo[a]cycloheptene-2-carboxamide | C19H28N2O2 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(IX)Condensation of 6,7,8,9-tetrahydro-5H-benzocyclohepten-2-ol (VI) with (bromomethyl)cyclohexane (VII) in the presence of Cs2CO3 gave ether (VIII). Benzylic oxidation of (VIII) to provide ketone (IX) was effected by treatment with potassium persulfate in the presence of cupric sulfate. Subsequent reduction of (IX) with NaBH4 yielded alcohol (X), which was converted to azide (XI) using diphenylphosphoryl azide and DBU. Catalytic hydrogenation of the azido group of (XI) in the presence of Boc2O produced carbamate (XII). Bromination of (XII) at position 3 was carried out by means of N-bromosuccinimide in acetonitrile. The resulting aryl bromide (XIII) was lithiated with butyllithium in cold THF and subsequently converted to carboxylic acid (XIV) by quenching with CO2 gas. Coupling of acid (XIV) with ammonia by means of EDC and HOBt afforded amide (XV). The Boc group of (XV) was then removed by treatment with trifluoroacetic acid to furnish the racemic amine (XVI).
| 【1】 Bohacek, R.; Sawyer, T.K.; Yang, M.G.; Eyermann, C.J.; Sundaramoorthi, R.; Shakespeare, W.C. (Ariad Pharmaceuticals Inc.); Bicyclic signal transduction inhibitors, compsns. containing them & uses thereof. WO 0027802 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (VI) | 43269 | 6,7,8,9-tetrahydro-5H-benzo[a]cyclohepten-2-ol | C11H14O | 详情 | 详情 | |
| (VII) | 31767 | 1-(bromomethyl)cyclohexane | 2550-36-9 | C7H13Br | 详情 | 详情 |
| (VIII) | 43270 | 2-(cyclohexylmethoxy)-6,7,8,9-tetrahydro-5H-benzo[a]cycloheptene; cyclohexylmethyl 6,7,8,9-tetrahydro-5H-benzo[a]cyclohepten-2-yl ether | C18H26O | 详情 | 详情 | |
| (IX) | 43271 | 2-(cyclohexylmethoxy)-6,7,8,9-tetrahydro-5H-benzo[a]cyclohepten-5-one | C18H24O2 | 详情 | 详情 | |
| (X) | 43272 | 2-(cyclohexylmethoxy)-6,7,8,9-tetrahydro-5H-benzo[a]cyclohepten-5-ol | C18H26O2 | 详情 | 详情 | |
| (XI) | 43273 | 5-azido-6,7,8,9-tetrahydro-5H-benzo[a]cyclohepten-2-yl cyclohexylmethyl ether; 5-azido-2-(cyclohexylmethoxy)-6,7,8,9-tetrahydro-5H-benzo[a]cycloheptene | C18H25N3O | 详情 | 详情 | |
| (XII) | 43274 | tert-butyl 2-(cyclohexylmethoxy)-6,7,8,9-tetrahydro-5H-benzo[a]cyclohepten-5-ylcarbamate | C23H35NO3 | 详情 | 详情 | |
| (XIII) | 43275 | tert-butyl 3-bromo-2-(cyclohexylmethoxy)-6,7,8,9-tetrahydro-5H-benzo[a]cyclohepten-5-ylcarbamate | C23H34BrNO3 | 详情 | 详情 | |
| (XIV) | 43276 | 9-[(tert-butoxycarbonyl)amino]-3-(cyclohexylmethoxy)-6,7,8,9-tetrahydro-5H-benzo[a]cycloheptene-2-carboxylic acid | C24H35NO5 | 详情 | 详情 | |
| (XV) | 43277 | tert-butyl 3-(aminocarbonyl)-2-(cyclohexylmethoxy)-6,7,8,9-tetrahydro-5H-benzo[a]cyclohepten-5-ylcarbamate | C24H36N2O4 | 详情 | 详情 | |
| (XVI) | 43278 | 9-amino-3-(cyclohexylmethoxy)-6,7,8,9-tetrahydro-5H-benzo[a]cycloheptene-2-carboxamide | C19H28N2O2 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(IX)An alternative procedure has been reported for the synthesis of the chiral (S)-amine (XXIV). Ketone (IX) was treated with O-methyl hydroxylamine to afford a geometric mixture of O-methyl oximes, from which isomer (XVII) was isolated by silica gel chromatography. Asymmetric reduction of the O-methyl oxime (XVII) with borane in the presence of the chiral auxiliary (XVIII) furnished the desired (S)-amine (XIX), which was further protected as the tert-butyl carbamate (XX) by treatment with Boc2O. Bromide (XXI), carboxylic acid (XXII) and amide (XXIII) were obtained following the same procedures as above. Then, acid cleavage of the Boc group of (XXIII) yielded the chiral amine (XXIV).
| 【1】 Bohacek, R.; Yang, M.; Shakespeare, W.; et al.; Structure-based design of an osteoclast-selective, nonpeptide Src homology 2 inhibitor with in vivo antiresorptive activity. Proceedings of the National Academy of Sciences of the United States of America 2000, 97, 17, 9373. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (IX) | 43271 | 2-(cyclohexylmethoxy)-6,7,8,9-tetrahydro-5H-benzo[a]cyclohepten-5-one | C18H24O2 | 详情 | 详情 | |
| (XVII) | 43279 | 2-(cyclohexylmethoxy)-6,7,8,9-tetrahydro-5H-benzo[a]cyclohepten-5-one O-methyloxime | C19H27NO2 | 详情 | 详情 | |
| (XVIII) | 10103 | (2R)-2-Amino-3-methyl-1,1-diphenyl-1-butanol | 56755-20-5 (hydrochloride) | C17H21NO | 详情 | 详情 |
| (XIX) | 43281 | (5S)-2-(cyclohexylmethoxy)-6,7,8,9-tetrahydro-5H-benzo[a]cyclohepten-5-ylamine; (5S)-2-(cyclohexylmethoxy)-6,7,8,9-tetrahydro-5H-benzo[a]cyclohepten-5-amine | C18H27NO | 详情 | 详情 | |
| (XX) | 43282 | tert-butyl (5S)-2-(cyclohexylmethoxy)-6,7,8,9-tetrahydro-5H-benzo[a]cyclohepten-5-ylcarbamate | C23H35NO3 | 详情 | 详情 | |
| (XXI) | 43283 | tert-butyl (5S)-3-bromo-2-(cyclohexylmethoxy)-6,7,8,9-tetrahydro-5H-benzo[a]cyclohepten-5-ylcarbamate | C23H34BrNO3 | 详情 | 详情 | |
| (XXII) | 43284 | (9S)-9-[(tert-butoxycarbonyl)amino]-3-(cyclohexylmethoxy)-6,7,8,9-tetrahydro-5H-benzo[a]cycloheptene-2-carboxylic acid | C24H35NO5 | 详情 | 详情 | |
| (XXIII) | 43285 | tert-butyl (5S)-3-(aminocarbonyl)-2-(cyclohexylmethoxy)-6,7,8,9-tetrahydro-5H-benzo[a]cyclohepten-5-ylcarbamate | C24H36N2O4 | 详情 | 详情 | |
| (XXIV) | 43286 | (9S)-9-amino-3-(cyclohexylmethoxy)-6,7,8,9-tetrahydro-5H-benzo[a]cycloheptene-2-carboxamide | C19H28N2O2 | 详情 | 详情 |