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【结 构 式】 
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【药物名称】AP-22161 【化学名称】4-[2(S)-Acetamido-3-[3-carbamoyl-2-(cyclohexylmethoxy)-6,7,8,9-tetrahydro-5H-benzo[a]cyclohepten-5(S)-ylamino]-3-oxopropyl]-2-formylbenzoic acid 【CA登记号】268741-42-0 【 分 子 式 】C32H39N3O7 【 分 子 量 】577.68353 |
【开发单位】Ariad Pharmaceuticals (Originator) 【药理作用】Bone Diseases, Treatment of, Bone Resorption Inhibitors, METABOLIC DRUGS, Treatment of Osteoporosis, Src Kinase Inhibitors |
合成路线1
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
L-3-Formyl-N-acetyltyrosine methyl ester (XII) was protected as the dithioacetal (XIII) using ethanedithiol and boron trifluoride etherate. After conversion of the phenol group of (XIII) into aryl triflate (XIV) upon treatment with N-phenyltrifluoromethanesulfonimide, its carboxylation with carbon monoxide in MeOH-DMSO in the presence of palladium catalyst generated the methyl ester (XV). Selective hydrolysis of the aliphatic ester of (XV) with LiOH at low temperature provided carboxylic acid (XVI), which was then coupled with the racemic amine (XI) to afford amide (XVII) as a diastereomeric mixture. Hydrolysis of the thioketal group of (XVII) to give aldehyde (XVIII) was achieved by treatment with mercuric perchlorate. The remaining methyl ester of (XVIII) was hydrolyzed with LiOH, and the desired diastereoisomer was finally isolated by RP-HPLC.
| 【1】 Bohacek, R.S.; Rickles, R.J.; Barlet, C.; Holt, D.A.; Guan, W.; Smith, J.A.; Baron, R.; Sawyer, T.K.; Violette, S.M.; Shakespeare, W.C.; A Src SH2 selective binding compound inhibits osteoclast-mediated resorption. Chem Biol 2000, 7, 3, 225. |
| 【2】 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 |
|---|---|---|---|---|---|---|
| (XI) | 43278 | 9-amino-3-(cyclohexylmethoxy)-6,7,8,9-tetrahydro-5H-benzo[a]cycloheptene-2-carboxamide | C19H28N2O2 | 详情 | 详情 | |
| (XII) | 44905 | methyl (2S)-2-(acetamido)-3-(3-formyl-4-hydroxyphenyl)propanoate | C13H15NO5 | 详情 | 详情 | |
| (XIII) | 44906 | methyl (2S)-2-(acetamido)-3-[3-(1,3-dithiolan-2-yl)-4-hydroxyphenyl]propanoate | C15H19NO4S2 | 详情 | 详情 | |
| (XIV) | 44907 | methyl (2S)-2-(acetamido)-3-(3-(1,3-dithiolan-2-yl)-4-[[(trifluoromethyl)sulfonyl]oxy]phenyl)propanoate | C16H18F3NO6S3 | 详情 | 详情 | |
| (XV) | 44908 | methyl 4-[(2S)-2-(acetamido)-3-methoxy-3-oxopropyl]-2-(1,3-dithiolan-2-yl)benzoate | C17H21NO5S2 | 详情 | 详情 | |
| (XVI) | 44909 | (2S)-2-(acetamido)-3-[3-(1,3-dithiolan-2-yl)-4-(methoxycarbonyl)phenyl]propionic acid | C16H19NO5S2 | 详情 | 详情 | |
| (XVII) | 44910 | methyl 4-((2S)-2-(acetamido)-3-[[3-(aminocarbonyl)-2-(cyclohexylmethoxy)-6,7,8,9-tetrahydro-5H-benzo[a]cyclohepten-5-yl]amino]-3-oxopropyl)-2-(1,3-dithiolan-2-yl)benzoate | C35H45N3O6S2 | 详情 | 详情 | |
| (XVIII) | 44911 | methyl 4-((2S)-2-(acetamido)-3-[[3-(aminocarbonyl)-2-(cyclohexylmethoxy)-6,7,8,9-tetrahydro-5H-benzo[a]cyclohepten-5-yl]amino]-3-oxopropyl)-2-formylbenzoate | C33H41N3O7 | 详情 | 详情 |