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【结 构 式】 
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【分子编号】57089 【品名】2-[3,5-bis(trifluoromethyl)phenyl]-N-(4-oxo-1-phenylcyclohexyl)propanamide 【CA登记号】 |
【 分 子 式 】C23H21F6NO2 【 分 子 量 】457.4156992 【元素组成】C 60.39% H 4.63% F 24.92% N 3.06% O 7% |
合成路线1
该中间体在本合成路线中的序号：(XIII)Michael addition of methyl acrylate (VIII) to methyl phenylacetate (VII) in the presence of NaH produces the intermediate triester (IX) which, under the reaction conditions, undergoes Dieckmann cyclization to the cyclohexanone diester (X). Hydrolysis and decarboxylation of keto diester (X) leads to keto acid (XI). This is then subjected to Curtius rearrangement in the presence of diphenylphosphoryl azide (DPPA) to yield, after acidic hydrolysis of the intermediate isocyanate, the amino cyclohexanone (XII). Acylation of amine (XII) by acid chloride (VI) then gives amide (XIII).
| 【1】 Elliott, J.M.; Castro Pineiro, J.L.; Swain, C.J.; Hollingworth, G.J.; Dinnell, K.; Shaw, D.E. (Merck Sharp & Dohme Ltd.); Cyclohexane derivs. and their use as therapeutic agents. WO 0187838 . |
| 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) | 57084 | 2-[3,5-bis(trifluoromethyl)phenyl]propanoyl chloride | C11H7ClF6O | 详情 | 详情 | |
| (VII) | 32831 | methyl 2-phenylacetate | 101-41-7 | C9H10O2 | 详情 | 详情 |
| (VIII) | 14156 | methyl acrylate | 96-33-3 | C4H6O2 | 详情 | 详情 |
| (IX) | 57085 | trimethyl 3-phenyl-1,3,5-pentanetricarboxylate | C17H22O6 | 详情 | 详情 | |
| (X) | 57086 | dimethyl 4-oxo-1-phenyl-1,3-cyclohexanedicarboxylate | C16H18O5 | 详情 | 详情 | |
| (XI) | 57087 | 4-oxo-1-phenylcyclohexanecarboxylic acid | C13H14O3 | 详情 | 详情 | |
| (XII) | 57088 | 4-amino-4-phenylcyclohexanone | C12H15NO | 详情 | 详情 | |
| (XIII) | 57089 | 2-[3,5-bis(trifluoromethyl)phenyl]-N-(4-oxo-1-phenylcyclohexyl)propanamide | C23H21F6NO2 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(XIII)Alkylation of the enolate derived from N-Boc ethyl isonipecotate (XIV) with allyl bromide (XV) gives the alpha-allyl ester (XVI). Double bond ozonolysis in (XIV) with reductive work-up in the presence of NaBH4 leads to lactone (XVII). Reductive ring-opening of lactone (XVII) by means of DIBAL affords diol (XVIII). This is then cyclized under Mitsunobu conditions to the spirocyclic amine (XIX). Acidic Boc group cleavage in (XIX) provides 2-oxa-8-azaspiro[4.5]decane (XX). Finally, reductive amination of cyclohexanone (XIII) with the bicyclic amine (XX) gives rise to a cis/trans mixture of diamino cyclohexanes, from which the desired trans isomer is isolated by chromatography.
| 【1】 Cooper, L.C.; et al.; 4,4-Disubstituted cyclohexylamine NK1 receptor antagonists II. Bioorg Med Chem Lett 2002, 12, 13, 1759. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XIII) | 57089 | 2-[3,5-bis(trifluoromethyl)phenyl]-N-(4-oxo-1-phenylcyclohexyl)propanamide | C23H21F6NO2 | 详情 | 详情 | |
| (XIV) | 49847 | 1-(tert-butyl) 4-ethyl-1,4-piperidinedicarboxylate; N-Boc-4-Carbethoxypiperidine | 142851-03-4 | C13H23NO4 | 详情 | 详情 |
| (XV) | 11463 | 3-Bromo-1-propene; 3-Bromopropene；allyl bromide | 106-95-6 | C3H5Br | 详情 | 详情 |
| (XVI) | 57090 | 1-(tert-butyl) 4-ethyl 4-allyl-1,4-piperidinedicarboxylate | C16H27NO4 | 详情 | 详情 | |
| (XVII) | 57091 | tert-butyl 1-oxo-2-oxa-8-azaspiro[4.5]decane-8-carboxylate | C13H21NO4 | 详情 | 详情 | |
| (XVIII) | 57092 | tert-butyl 4-(2-hydroxyethyl)-4-(hydroxymethyl)-1-piperidinecarboxylate | C13H25NO4 | 详情 | 详情 | |
| (XIX) | 57093 | tert-butyl 2-oxa-8-azaspiro[4.5]decane-8-carboxylate | C13H23NO3 | 详情 | 详情 | |
| (XX) | 57094 | 2-oxa-8-azaspiro[4.5]decane | C8H15NO | 详情 | 详情 |