【结 构 式】 |
【分子编号】65140 【品名】tert-butyl 4-[(E)-3,3-difluoro-3-(4-fluorophenyl)-1-propenyl]-1-piperidinecarboxylate 【CA登记号】 |
【 分 子 式 】C19H24F3NO2 【 分 子 量 】355.4003096 【元素组成】C 64.21% H 6.81% F 16.04% N 3.94% O 9% |
合成路线1
该中间体在本合成路线中的序号:(XXVII)Addition of 4-fluorophenylmagnesium bromide (XXII) to dimethyl oxalate (XXIII) leads to methyl 4-fluorobenzoylformate (XXIV). Subsequent fluorination of (XXIV) employing diethylaminosulfur trifluoride affords the gem-difluoro ester (XXV). Reduction of ester (XXV) with NaBH4 in cold MeOH gives rise to the aldehyde hemiacetal (XXVI). Then, Wittig condensation of hemiacetal (XXVI) with the ylide generated from phosphonium salt (XXI) provides olefin (XXVII). This is partly reduced to the saturated compound (XXVIII) by treatment with in situ generated diimide, and completely reduced to (XXVIII) by catalytic hydrogenation over iridium black. Cleavage of the N-Boc protecting group of (XXVIII) to furnish piperidine (XXIX) is accomplished by means of iodotrimethylsilane in CHCl3.
【1】 Mills, S.G.; Kim, D.; Hale, J.; MacCoss, M.; Berk, S.; Chapman, K.; Lynch, C.; Caldwell, C.; Willoughby, C.; Rosauer, K. (Merck & Co., Inc.); Pyrrolidine modulators of chemokine receptor activity. US 6265434; WO 0059503 . |
中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
---|---|---|---|---|---|---|
(XXI) | 65138 | {[1-(tert-butoxycarbonyl)-4-piperidinyl]methyl}(triphenyl)phosphonium iodide | C29H35INO2P | 详情 | 详情 | |
(XXII) | 13643 | 4-fluorophenyl magnesium bromide;Bromo(4-fluorophenyl)magnesium;bromo(p-fluorophenyl)Magnesium;p-Fluorophenylmagnesium bromide | 352-13-6 | C6H4BrFMg | 详情 | 详情 |
(XXIII) | 37412 | methyl 2-methoxy-2-oxoacetate;dimethyl oxalate;Methyl oxalate | 553-90-2 | C4H6O4 | 详情 | 详情 |
(XXIV) | 65143 | methyl 2-(4-fluorophenyl)-2-oxoacetate | C9H7FO3 | 详情 | 详情 | |
(XXV) | 65141 | methyl 2,2-difluoro-2-(4-fluorophenyl)acetate | C9H7F3O2 | 详情 | 详情 | |
(XXVI) | 65142 | 2,2-difluoro-2-(4-fluorophenyl)-1-methoxy-1-ethanol | C9H9F3O2 | 详情 | 详情 | |
(XXVII) | 65140 | tert-butyl 4-[(E)-3,3-difluoro-3-(4-fluorophenyl)-1-propenyl]-1-piperidinecarboxylate | C19H24F3NO2 | 详情 | 详情 | |
(XXVIII) | 65139 | tert-butyl 4-[3,3-difluoro-3-(4-fluorophenyl)propyl]-1-piperidinecarboxylate | C19H26F3NO2 | 详情 | 详情 | |
(XXIX) | 65144 | 4-[3,3-difluoro-3-(4-fluorophenyl)propyl]piperidine | C14H18F3N | 详情 | 详情 |