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【结 构 式】 
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【分子编号】53292 【品名】(1S)-1-[3,5-bis(trifluoromethyl)phenyl]ethyl (2R,3S)-3-(4-fluorophenyl)morpholinyl ether; (2R,3S)-2-({(1S)-1-[3,5-bis(trifluoromethyl)phenyl]ethyl}oxy)-3-(4-fluorophenyl)morpholine 【CA登记号】n/a |
【 分 子 式 】C20H18F7NO2 【 分 子 量 】437.3572824 【元素组成】C 54.93% H 4.15% F 30.41% N 3.2% O 7.32% |
合成路线1
该中间体在本合成路线中的序号：(XIX)Reductive alkylation of (S)-(4-fluorophenyl)glycine (VI) with benzaldehyde and NaBH4 generated the N-benzyl amino acid (XI). This was cyclized with 1,2-dibromoethane (XII) to yield the morpholinone (XIII). Reduction of the lactone function of (XIII) with L-Selectride at -70 C, followed by acylation of the intermediate lactol (XIV) with 3,5-bis(trifluoromethyl)benzoyl chloride (XV), furnished the aroyloxy morpholine (XVI) as the main isomer. Ester (XVI) was converted to the enol ether (XVII) upon treatment with dimethyltitanocene, generated from titanocene dichloride and methyllithium. Catalytic hydrogenation of the enol ether double bond of (XVII) with simultaneous benzyl group hydrogenolysis generated the desired morpholine (XVIII) along with its diastereoisomer (XIX); these were separated by flash chromatography.
| 【1】 Baker, R.; Harrison, T.; Mcleod, A.M.; Owens, A.P.; Seward, E.M.; Swain, C.J.; Teall, M.R. (Merck Sharp & Dohme Ltd.); Substd. morpholine derivs. and their use as therapeutic agents. EP 0737192; EP 1099702; JP 1997507484; JP 2000219629; US 5612337; WO 9518124 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (VI) | 43098 | (2R)-2-amino-2-(4-fluorophenyl)ethanoic acid | 7292-73-1 | C8H8FNO2 | 详情 | 详情 |
| (XI) | 44190 | (2S)-2-(benzylamino)-2-(4-fluorophenyl)ethanoic acid | C15H14FNO2 | 详情 | 详情 | |
| (XII) | 10252 | 1,2-Dibromoethane; Ethylene dibromide | 106-93-4 | C2H4Br2 | 详情 | 详情 |
| (XIII) | 18288 | (3S)-4-benzyl-3-(4-fluorophenyl)-2-morpholinone | C17H16FNO2 | 详情 | 详情 | |
| (XIV) | 18289 | (2S,3S)-4-benzyl-3-(4-fluorophenyl)-2-morpholinol | C17H18FNO2 | 详情 | 详情 | |
| (XV) | 18290 | 3,5-Bis(trifluoromethyl)benzoyl chloride | 785-56-8 | C9H3ClF6O | 详情 | 详情 |
| (XVI) | 18291 | (2R,3S)-4-benzyl-3-(4-fluorophenyl)morpholinyl 3,5-bis(trifluoromethyl)benzoate | C26H20F7NO3 | 详情 | 详情 | |
| (XVII) | 18292 | (2R,3S)-4-benzyl-2-([1-[3,5-bis(trifluoromethyl)phenyl]vinyl]oxy)-3-(4-fluorophenyl)morpholine; (2R,3S)-4-benzyl-3-(4-fluorophenyl)morpholinyl 1-[3,5-bis(trifluoromethyl)phenyl]vinyl ether | C27H22F7NO2 | 详情 | 详情 | |
| (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 |
| (XIX) | 53292 | (1S)-1-[3,5-bis(trifluoromethyl)phenyl]ethyl (2R,3S)-3-(4-fluorophenyl)morpholinyl ether; (2R,3S)-2-({(1S)-1-[3,5-bis(trifluoromethyl)phenyl]ethyl}oxy)-3-(4-fluorophenyl)morpholine | n/a | C20H18F7NO2 | 详情 | 详情 |