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【结 构 式】 
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【分子编号】40779 【品名】1-[3,5-bis(trifluoromethyl)phenyl]-1-ethanol 【CA登记号】368-63-8 |
【 分 子 式 】C10H8F6O 【 分 子 量 】258.1633392 【元素组成】C 46.52% H 3.12% F 44.15% O 6.2% |
合成路线1
该中间体在本合成路线中的序号：(XII)Reduction of 3',5'-bis(trifluoromethyl)acetophenone (XI) with NaBH4 gave alcohol (XII). This was either converted to imidate (XIII) by addition of trichloroacetonitrile, or to bromide (XIV) upon treatment with triphenylphosphine dibromide. Condensation of the chiral hydroxy ester (-)-(X) with imidate (XIII) in the presence of triflic acid provided ether (XVa-b) as a diastereomeric mixture. Alternatively, (XV) was obtained by alkylation of alcohol (-)-(X) with bromide (XIV). Cromatographic separation of the diastereomeric mixture (XVa-b), followed by basic hydrolysis of the desired isomer yielded carboxylic acid (XVI). Activation of the carboxyl group of (XVI) as the corresponding acid chloride by means of oxalyl chloride, and subsequent treatment with NaN3 generated the acyl azide (XVII). Curtius rearrangement ot the acyl azide (XVII) in hot toluene provided isocyanate.
| 【1】 MacCoss, M.; Meurer, L.C.; Finke, P.E.; et al.; Discovery of potent human NK1 antagonists having a cyclopentane-based core structure. 219th ACS Natl Meet (March 26 2000, San Francisco) 2000, Abst MEDI 98. |
| 【2】 Caldwell, C.G.; Chen, P.; Durette, P.L.; Finke, P.; Hale, J.; Holson, E.; Kopka, I.; Maccoss, M.; Meurer, L.; Mills, S.G.; Robichaud, A. (Merck & Co., Inc.); Cycloalkyl tachykinin receptor antagonists. US 5750549 . |
| 【3】 Finke, P.E.; Maccoss, M.; Meurer, L.C.; Mills, S.G.; Caldwell, C.G.; Chen, P.; Durette, P.L.; Hale, J.; Holson, E.; Kopka, I.; Robichaud, A. (Merck & Co., Inc.); Cyclopentyl tachykinin receptor antagonists. EP 0858444; WO 9714671 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (-)-(X) | 40777 | (-)-methyl (1R,2R,3S)-2-(4-fluorophenyl)-3-hydroxycyclopentanecarboxylate | C13H15FO3 | 详情 | 详情 | |
| (XVa) | 40782 | methyl (1R,2R,3S)-3-([(1S)-1-[3,5-bis(trifluoromethyl)phenyl]ethyl]oxy)-2-(4-fluorophenyl)cyclopentanecarboxylate | C23H21F7O3 | 详情 | 详情 | |
| (XVb) | 40783 | methyl (1R,2R,3S)-3-([(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethyl]oxy)-2-(4-fluorophenyl)cyclopentanecarboxylate | C23H21F7O3 | 详情 | 详情 | |
| (XI) | 40778 | 1-[3,5-bis(trifluoromethyl)phenyl]-1-ethanone | 30071-93-3 | C10H6F6O | 详情 | 详情 |
| (XII) | 40779 | 1-[3,5-bis(trifluoromethyl)phenyl]-1-ethanol | 368-63-8 | C10H8F6O | 详情 | 详情 |
| (XIII) | 40780 | 1-[3,5-bis(trifluoromethyl)phenyl]ethyl 2,2,2-trichloroethanimidoate | C12H8Cl3F6NO | 详情 | 详情 | |
| (XIV) | 40781 | 1-(1-bromoethyl)-3,5-bis(trifluoromethyl)benzene | C10H7BrF6 | 详情 | 详情 | |
| (XVI) | 40784 | (1R,2R,3S)-3-([(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethyl]oxy)-2-(4-fluorophenyl)cyclopentanecarboxylic acid | C22H19F7O3 | 详情 | 详情 | |
| (XVII) | 40785 | (1R,2R,3S)-3-([(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethyl]oxy)-2-(4-fluorophenyl)cyclopentanecarbonyl azide | C22H18F7N3O2 | 详情 | 详情 | |
| (XVIII) | 40786 | (1R,2S,3S)-3-([(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethyl]oxy)-2-(4-fluorophenyl)cyclopentyl isocyanate; 1-((1R)-1-[[(1S,2S,3R)-2-(4-fluorophenyl)-3-isocyanatocyclopentyl]oxy]ethyl)-3,5-bis(trifluoromethyl)benzene | C22H18F7NO2 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(XXXVI)
| 【1】 Brands KMJ, Payack JF, Rosen JD, et aL 2007. Efficient synthesis of NKl receptor antagonist aprepitant usinga crlrstallization-induced diastereoselective tnnsfonnationJ Am Chem Soc, 125 (8):2129~2135 |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XXXXVII) | 66099 | bis(trifluoromethyl) carbonate | C3F6O3 | 详情 | 详情 | |
| (XXXIV) | 66097 | 4-benzylmorpholine-2,3-dione | C11H11NO3 | 详情 | 详情 | |
| (XXXV) | 66098 | 4-benzyl-2-hydroxydihydro-2H-pyran-3(4H)-one | C12H14O3 | 详情 | 详情 | |
| (XXXVI) | 40779 | 1-[3,5-bis(trifluoromethyl)phenyl]-1-ethanol | 368-63-8 | C10H8F6O | 详情 | 详情 |
| (XXXVIII) | 66100 | (R)-4-benzyl-2-((S)-1-(3,5-bis(trifluoromethyl)phenyl)ethoxy)morpholin-3-one | C21H19F6NO3 | 详情 | 详情 | |
| (XXXIX) | 53297 | (2R)-4-benzyl-2-({(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethyl}oxy)-3-morpholinone | n/a | C21H19F6NO3 | 详情 | 详情 |
| (XL) | 13643 | 4-fluorophenyl magnesium bromide;Bromo(4-fluorophenyl)magnesium;bromo(p-fluorophenyl)Magnesium;p-Fluorophenylmagnesium bromide | 352-13-6 | C6H4BrFMg | 详情 | 详情 |
| (XLI) | 66101 | (2R)-2-(1-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(4-fluorophenyl)morpholine | C20H18F7NO2 | 详情 | 详情 | |
| (XLII) | 66102 | methyl 2-(2-chloro-1-iminoethyl)hydrazinecarboxylate | 155742-64-6 | C4H8ClN3O2 | 详情 | 详情 |