|
【结 构 式】 
|
【分子编号】45687 【品名】N-(3-phenoxyphenyl)-N-[3-(1,1,2,2-tetrafluoroethoxy)benzyl]amine; 3-phenoxy-N-[3-(1,1,2,2-tetrafluoroethoxy)benzyl]aniline 【CA登记号】 |
【 分 子 式 】C21H17F4NO2 【 分 子 量 】391.3651328 【元素组成】C 64.45% H 4.38% F 19.42% N 3.58% O 8.18% |
合成路线1
该中间体在本合成路线中的序号：(IV)Radical bromination of 3-(1,1,2,2-tetrafluoroethoxy)toluene (I) by means of N-bromosuccinimide in the presence of AIBN provided benzyl bromide (II), which was then condensed with 3-phenoxyaniline (III) in refluxing cyclohexane to afford (IV). Alternatively, (IV) was obtained by reductive condensation of 3-(1,1,2,2-tetrafluoroethoxy)benzaldehyde (A) with 3-phenoxyaniline (III) in the presence of sodium triacetoxyborohydride. The condensation of the secondary amine (IV) with commercially available trifluoromethyloxirane (V) of unspecified enantiomeric composition in the presence of ytterbium triflate furnished a 1:7 mixture of enantiomeric amino alcohols (VI). The title compound was then isolated from (VI) as the minor enantiomer by means of preparative chiral HPLC.
| 【1】 Durley, R.C.; et al.; Discovery of chiral N,N-disubstituted trifluoro-3-amino-2-propanols as potent inhibitors of cholesteryl ester transfer protein. J Med Chem 2000, 43, 24, 4575. |
| 【2】 Vernier, W.F.; Wang, L.; Mischke, D.A.; Hamme, A.T.; Promo, M.A.; Sikorski, J.A.; Spangler, D.P.; Grapperhaus, M.L.; Massa, M.A.; Durley, R.C.; Reinhard, E.J.; Fobian, Y.M.; Hickory, B.S.; Tollefson, M.B.; Norton, M.B.; Rueppel, M.L. (Pharmacia Corp.); (R)-Chiral halogenated 1-substd.amino-(n+1)-alkanols useful for inhibiting cholesteryl ester transfer protein activity. WO 0018721; WO 0018724 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (A) | 45688 | 3-(1,1,2,2-tetrafluoroethoxy)benzaldehyde | 35295-35-3 | C9H6F4O2 | 详情 | 详情 |
| (Va) | 45689 | (2R)-2-(trifluoromethyl)oxirane | C3H3F3O | 详情 | 详情 | |
| (VIa) | 45690 | (2R)-1,1,1-trifluoro-3-[3-phenoxy[3-(1,1,2,2-tetrafluoroethoxy)benzyl]anilino]-2-propanol | C24H20F7NO3 | 详情 | 详情 | |
| (Vb) | 45691 | (2S)-2-(trifluoromethyl)oxirane | C3H3F3O | 详情 | 详情 | |
| (VIb) | 45692 | (2S)-1,1,1-trifluoro-3-[3-phenoxy[3-(1,1,2,2-tetrafluoroethoxy)benzyl]anilino]-2-propanol | C24H20F7NO3 | 详情 | 详情 | |
| (I) | 45684 | 3-methylphenyl 1,1,2,2-tetrafluoroethyl ether; 1-methyl-3-(1,1,2,2-tetrafluoroethoxy)benzene | 1737-10-6 | C9H8F4O | 详情 | 详情 |
| (II) | 45685 | 3-(bromomethyl)phenyl 1,1,2,2-tetrafluoroethyl ether; 1-(bromomethyl)-3-(1,1,2,2-tetrafluoroethoxy)benzene | C9H7BrF4O | 详情 | 详情 | |
| (III) | 45686 | 3-phenoxyphenylamine; 3-phenoxyaniline | 3586-12-7 | C12H11NO | 详情 | 详情 |
| (IV) | 45687 | N-(3-phenoxyphenyl)-N-[3-(1,1,2,2-tetrafluoroethoxy)benzyl]amine; 3-phenoxy-N-[3-(1,1,2,2-tetrafluoroethoxy)benzyl]aniline | C21H17F4NO2 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(IV)The chiral (R)-(+)-epoxide (X) was synthesized by asymmetric reduction of 3-bromotrifluoroacetone (VII) using (+)-B-chlorodiisopinocampheylborane (VIII), followed by intramolecular cyclization of the resulting (R)-bromohydrin (VIII) in aqueous NaOH. Finally, reaction of amine (IV) with the chiral epoxide (X) furnished the desired enantiomer.
| 【1】 Durley, R.C.; et al.; Chiral N,N-disubstituted trifluoro-3-amino-2-propanols are potent inhibitors of cholesteryl ester transfer protein. J Med Chem 2002, 45, 18, 3891. |
| 【2】 Grapperhaus, M.L.; Hickory, B.S.; Sikorski, J.A.; Wang, L.J.; Massa, M.A.; Mischke, D.A.; Honda, D.D.; New simple class of potent cholesteryl ester transfer protein inhibitors. 220th ACS Natl Meet (Aug 20 2000, Washington DC) 2000, Abst MEDI 283. |
| 【3】 Durley, R.C.; et al.; Discovery of chiral N,N-disubstituted trifluoro-3-amino-2-propanols as potent inhibitors of cholesteryl ester transfer protein. J Med Chem 2000, 43, 24, 4575. |
| 【4】 Vernier, W.F.; Wang, L.; Mischke, D.A.; Hamme, A.T.; Promo, M.A.; Sikorski, J.A.; Spangler, D.P.; Grapperhaus, M.L.; Massa, M.A.; Durley, R.C.; Reinhard, E.J.; Fobian, Y.M.; Hickory, B.S.; Tollefson, M.B.; Norton, M.B.; Rueppel, M.L. (Pharmacia Corp.); (R)-Chiral halogenated 1-substd.amino-(n+1)-alkanols useful for inhibiting cholesteryl ester transfer protein activity. WO 0018721; WO 0018724 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (IV) | 45687 | N-(3-phenoxyphenyl)-N-[3-(1,1,2,2-tetrafluoroethoxy)benzyl]amine; 3-phenoxy-N-[3-(1,1,2,2-tetrafluoroethoxy)benzyl]aniline | C21H17F4NO2 | 详情 | 详情 | |
| (VII) | 39909 | 3-bromo-1,1,1-trifluoroacetone | 431-35-6 | C3H2BrF3O | 详情 | 详情 |
| (VIII) | 45693 | chloro[(1R,2R,3S,5R)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl][(1S,2S,3R,5S)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]borane | C20H34BCl | 详情 | 详情 | |
| (IX) | 45694 | (2S)-3-bromo-1,1,1-trifluoro-2-propanol | 88378-50-1 | C3H4BrF3O | 详情 | 详情 |
| (X) | 45689 | (2R)-2-(trifluoromethyl)oxirane | C3H3F3O | 详情 | 详情 |