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【结 构 式】 
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【分子编号】40675 【品名】2,2,2-trifluoroethyl trifluoromethanesulfonate 【CA登记号】6226-25-1 |
【 分 子 式 】C3H2F6O3S 【 分 子 量 】232.1034992 【元素组成】C 15.52% H 0.87% F 49.11% O 20.68% S 13.82% |
合成路线1
该中间体在本合成路线中的序号：(II)The etherification of hydroquinone (I) with 2,2,2-trifluoroethyl trifluoromethanesulfonate (II) by means of K2CO3 in refluxing acetone gives the corresponding diether (III), which is submitted to a Friedel-Crafts condensation with Ac-Cl or Ac2O and AlCl3 in dichloromethane yielding the acetophenone (IV). The chlorination of (IV) with Cl2 in acetic acid at 55 C gives the alpha, alpha-dichloroacetophenone (V), which is further chlorinated with Cl2 and NaOAc in acetic acid at 100 C affording the corresponding trichloro derivative (VI). The reaction of (VI) with 2-(aminomethyl)pyridine (VII) in cyclohexane/toluene or isopropanol furnishes the benzamide (VIII), which is finally hydrogenated with H2 over Pt/C in isopropanol/acetic acid to give the target piperidine derivative.
| 【1】 Leir, C.M. (3M Pharmaceuticals); Process for the preparation of derivs. of pyrrolidine and piperidine. US 4642384 . |
| 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) | 13163 | p-Dihydrobenzene; Hydroquinone | 123-31-9 | C6H6O2 | 详情 | 详情 |
| (II) | 40675 | 2,2,2-trifluoroethyl trifluoromethanesulfonate | 6226-25-1 | C3H2F6O3S | 详情 | 详情 |
| (III) | 40737 | 1,4-bis(2,2,2-trifluoroethoxy)benzene; 4-(2,2,2-trifluoroethoxy)phenyl 2,2,2-trifluoroethyl ether | 66300-61-6 | C10H8F6O2 | 详情 | 详情 |
| (IV) | 40738 | 1-[2,5-bis(2,2,2-trifluoroethoxy)phenyl]-1-ethanone | 76784-40-2 | C12H10F6O3 | 详情 | 详情 |
| (V) | 40739 | 1-[2,5-bis(2,2,2-trifluoroethoxy)phenyl]-2,2-dichloro-1-ethanone | C12H8Cl2F6O3 | 详情 | 详情 | |
| (VI) | 40740 | 1-[2,5-bis(2,2,2-trifluoroethoxy)phenyl]-2,2,2-trichloro-1-ethanone | 76784-42-4 | C12H7Cl3F6O3 | 详情 | 详情 |
| (VII) | 13582 | 2-Pyridinylmethanamine; 2-Pyridinylmethylamine; 2-(Aminomethyl)pyridine | 3731-51-9 | C6H8N2 | 详情 | 详情 |
| (VIII) | 33970 | N-(2-pyridinylmethyl)-2,5-bis(2,2,2-trifluoroethoxy)benzamide | C17H14F6N2O3 | 详情 | 详情 | |
| (IX) | 18983 | 1,4-dibromobenzene | 106-37-6 | C6H4Br2 | 详情 | 详情 |
| (X) | 19483 | 2,2,2-trifluoro-1-ethanol | 75-89-8 | C2H3F3O | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：Regioselective Mitsunobu condensation of 2',4'-dihydroxyacetophenone (VII) with N-Boc-4-piperidinol (VIII) afforded ether (IX). The 2'-hydroxyl group of (IX) was then alkylated with 2,2,2-trifluoroethyl trifluoromethanesulfonate in the presence of Cs2CO3 to give (X). Oxidative rearrangement of the acetophenone (X) employing thallium trinitrate and trimethyl orthoformate generated the phenylacetic ester (XI), which was hydrolyzed to acid (XII) with NaOH in aqueous MeOH. Subsequent EDC-mediated coupling of (XII) with piperidine intermediate (VI) yielded amide (XIII). The N-Boc group of (XIII) was cleaved using HCl in EtOAc, and the secondary amine (XIV) was acylated with acetic anhydride in the presence of diisopropyl ethylamine to afford the target acetamide.
| 【1】 Bock, M.G.; Evans, B.E.; Williams, P.D.; et al.; Nonpeptide oxytocin antagonists: Analogs of L-371,257 with improved potency. Bioorg Med Chem Lett 1999, 9, 9, 1311. |
| 【2】 Freidinger, R.M.; Stauffer, K.; Perlow, D.S.; Sparks, M.A.; Williams, P.D.; Bell, I.M. (Merck & Co., Inc.); Tocolytic oxytocin receptor antagonists. GB 2326410; US 6090805 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 40675 | 2,2,2-trifluoroethyl trifluoromethanesulfonate | 6226-25-1 | C3H2F6O3S | 详情 | 详情 | |
| (VI) | 19420 | 1-(4-piperidinyl)-1,4-dihydro-2H-3,1-benzoxazin-2-one | C13H16N2O2 | 详情 | 详情 | |
| (VII) | 13961 | Resacetophenone; 1-(2,4-Dihydroxyphenyl)-1-ethanone | 89-84-9 | C8H8O3 | 详情 | 详情 |
| (VIII) | 18625 | tert-butyl 4-hydroxy-1-piperidinecarboxylate | C10H19NO3 | 详情 | 详情 | |
| (X) | 27110 | tert-butyl 4-[4-acetyl-3-(2,2,2-trifluoroethoxy)phenoxy]-1-piperidinecarboxylate | C20H26F3NO5 | 详情 | 详情 | |
| (XI) | 27111 | tert-butyl 4-[4-(2-methoxy-2-oxoethyl)-3-(2,2,2-trifluoroethoxy)phenoxy]-1-piperidinecarboxylate | C21H28F3NO6 | 详情 | 详情 | |
| (XII) | 27112 | 2-[4-[[1-(tert-butoxycarbonyl)-4-piperidinyl]oxy]-2-(2,2,2-trifluoroethoxy)phenyl]acetic acid | C20H26F3NO6 | 详情 | 详情 | |
| (XIII) | 27113 | tert-butyl 4-[4-(2-oxo-2-[4-[2-oxo-2H-3,1-benzoxazin-1(4H)-yl]-1-piperidinyl]ethyl)-3-(2,2,2-trifluoroethoxy)phenoxy]-1-piperidinecarboxylate | C33H40F3N3O7 | 详情 | 详情 | |
| (XIV) | 27114 | phenyl(1-[2-[4-(4-piperidinyloxy)-2-(2,2,2-trifluoroethoxy)phenyl]acetyl]-4-piperidinyl)formamide | C27H32F3N3O4 | 详情 | 详情 |