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【结 构 式】 
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【分子编号】53298 【品名】(2R)-4-benzyl-2-({(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethyl}oxy)-3-(4-fluorophenyl)-3-morpholinol 【CA登记号】n/a |
【 分 子 式 】C27H24F7NO3 【 分 子 量 】543.4813224 【元素组成】C 59.67% H 4.45% F 24.47% N 2.58% O 8.83% |
合成路线1
该中间体在本合成路线中的序号：(XXX)In an alternative route to morpholine (XVIII), bromination of 1,3-bis(trifluoromethyl)benzene (XX) by means of 1,3-dibromo-5,5-dimethylhydantoin (XXI) yielded bromide (XXII). The Grignard reagent prepared from aryl bromide (XXII) was acylated with acetic anhydride at -15 C to produce acetophenone (XXIII). Enantioselective reduction of ketone (XXIII) with ruthenium(II) chloride in the presence of (1S,2R)-cis-1-amino-2-indanol furnished the (R)-alcohol (XXIV). N-Benzyl ethanolamine (XXV) was condensed with glyoxylic acid (XXVI) to give the hydroxy oxazinone (XXVII). This was coupled with the chiral alcohol (XXIV) using trifluoroacetic anhydride and boron trifluoride etherate to afford the target (R,R)-adduct (XXVIII) as the main diastereoisomer. Addition of 4-fluorophenylmagnesium bromide (XXIX) to the lactam function of (XXVIII), followed by catalytic hydrogenation of the intermediate (XXX), provided the required disubstituted morpholine (XVIII).
| 【1】 Wang, J.; Crocker, L.; Cai, D. (Merck & Co., Inc.); Polymorphic form of a tachykinin receptor antagonist. WO 0132656 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XVIII) | 18293 | (1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethyl (2R,3S)-3-(4-fluorophenyl)morpholinyl ether; (2R,3S)-2-([(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethyl]oxy)-3-(4-fluorophenyl)morpholine | 171482-05-6 | C20H18F7NO2 | 详情 | 详情 |
| (XX) | 53293 | 1,3-Bis(trifluoromethyl)benzene; 1,3-Di(trifluoromethyl)benzene; alpha,alpha,alpha,alpha',alpha',alpha'-Hexafluoro-m-xylene; m-Xylene hexafluoride | 402-31-3 | C8H4F6 | 详情 | 详情 |
| (XXI) | 31277 | 1,3-dibromo-5,5-dimethyl-2,4-imidazolidinedione | 77-48-5 | C5H6Br2N2O2 | 详情 | 详情 |
| (XXII) | 53294 | 1,3-Bis(trifluoromethyl)-5-bromobenzene; 1-Bromo-3,5-bis(trifluoromethyl)benzene; 3,5-Bis(trifluoromethyl)bromobenzene | 328-70-1 | C8H3BrF6 | 详情 | 详情 |
| (XXIII) | 40778 | 1-[3,5-bis(trifluoromethyl)phenyl]-1-ethanone | 30071-93-3 | C10H6F6O | 详情 | 详情 |
| (XXIV) | 53295 | (1R)-1-[3,5-bis(trifluoromethyl)phenyl]-1-ethanol | n/a | C10H8F6O | 详情 | 详情 |
| (XXV) | 53296 | 4-benzyl-2-hydroxy-3-morpholinone | 287930-73-8 | C11H13NO3 | 详情 | 详情 |
| (XXVI) | 15618 | 2-Oxoacetic acid; Glyoxylic Acid | 298-12-4 | C2H2O3 | 详情 | 详情 |
| (XXVII) | 25630 | 2-(benzylamino)-1-ethanol | 104-63-2 | C9H13NO | 详情 | 详情 |
| (XXVIII) | 53297 | (2R)-4-benzyl-2-({(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethyl}oxy)-3-morpholinone | n/a | C21H19F6NO3 | 详情 | 详情 |
| (XXIX) | 13643 | 4-fluorophenyl magnesium bromide;Bromo(4-fluorophenyl)magnesium;bromo(p-fluorophenyl)Magnesium;p-Fluorophenylmagnesium bromide | 352-13-6 | C6H4BrFMg | 详情 | 详情 |
| (XXX) | 53298 | (2R)-4-benzyl-2-({(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethyl}oxy)-3-(4-fluorophenyl)-3-morpholinol | n/a | C27H24F7NO3 | 详情 | 详情 |