Morpholine → 3-{[(5-Bromo-pyridin-2-yl)-(5'-isopropyl-2'-methoxy-4-trifluoromethyl-biphenyl-2-ylmethyl)-amino]-methyl}-5-trifluoromethyl-benzonitrile

HRID 604186노트

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HRID 604186 반응식
[Br:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][CH2:9][C:10]2[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[CH:12][C:11]=2[C:20]2[CH:25]=[C:24]([CH:26]([CH3:28])[CH3:27])[CH:23]=[CH:22][C:21]=2[O:29][CH3:30])=[N:6][CH:7]=1.[H-].[Na+].Br[CH2:34][C:35]1[CH:36]=[C:37]([CH:40]=[C:41]([C:43]([F:46])([F:45])[F:44])[CH:42]=1)[C:38]#[N:39].N1CCOCC1>CN(C)C=O.O1CCCC1.O.C(OCC)(=O)C.C(N(CC)CC)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]([CH2:34][C:35]2[CH:36]=[C:37]([CH:40]=[C:41]([C:43]([F:44])([F:45])[F:46])[CH:42]=2)[C:38]#[N:39])[CH2:9][C:10]2[CH:15]=[C:14]([C:16]([F:18])([F:19])[F:17])[CH:13]=[CH:12][C:11]=2[C:20]2[CH:25]=[C:24]([CH:26]([CH3:28])[CH3:27])[CH:23]=[CH:22][C:21]=2[O:29][CH3:30])=[N:6][CH:7]=1

참가 물질

10

반응물 4

HCID 8083MorpholineHCID 24758Sodium hydrideHCID 116013693-(Bromomethyl)-5-(trifluoromethyl)benzonitrileHCID 66602862(5-Bromo-pyridin-2-yl)-(5'-isopropyl-2'-methoxy-4-trifluoromethyl-biphenyl-2-ylmethyl)-amine

생성물 1

HCID 866269163-{[(5-Bromo-pyridin-2-yl)-(5'-isopropyl-2'-methoxy-4-trifluoromethyl-biphenyl-2-ylmethyl)-amino]-methyl}-5-trifluoromethyl-benzonitrile수율 45.5%

시약·촉매·용매 5

HCID 962Water용매HCID 6228Dimethylformamide용매HCID 8028Tetrahydrofuran용매HCID 8471Triethylamine용매HCID 8857Ethyl Acetate용매2회

실험 절차

(5-Bromo-pyridin-2-yl)-(5′-isopropyl-2′-methoxy-4-trifluoromethyl-biphenyl-2-ylmethyl)-amine (700 mg) is dissolved in N,N-dimethylformamide (5 ml), and thereto is added sodium hydride (60%) (88 mg) under nitrogen atmosphere at −10° C., and the mixture is stirred at the same temperature for 5 minutes, and thereto is added 3-bromomethyl-5-trifluoromethyl-benzonitrile (771 mg), and the mixture is stirred under ice-cooling for 1 hour and 40 minutes. To the reaction solution are added ethyl acetate and a saturated aqueous citric acid solution, and the mixture is separated, and the organic layer is washed twice with a saturated brine, and the mixture is dried over magnesium sulfate and is concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography (hexane:ethyl acetate=19:1→17:3) and (hexane:ethyl acetate=49:1→9:1). The residue is dissolved in diethyl ether, and filtered. The filtrate is concentrated under reduced pressure, and the residue obtained above (630 mg) is dissolved in tetrahydrofuran (3 ml), and thereto are added morpholine (119 μl) and triethylamine (190 μl), and the mixture is stirred at 50° C. for 4 hours, and the reaction solution is cooled to room temperature, and stirred at same temperature overnight. To the reaction solution are added ethyl acetate and water, and the mixture is separated, and the organic layer is washed with water and a saturated brine, and the mixture is dried over magnesium sulfate and is concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography (hexane:ethyl acetate=19:1→17:3) to give 3-{[(5-bromo-pyridin-2-yl)-(5′-isopropyl-2′-methoxy-4-trifluoromethyl-biphenyl-2-ylmethyl)-amino]-methyl}-5-trifluoromethyl-benzonitrile (440 mg). MS (m/z): 662/664 [M+H]+

후처리

  1. stirringthe mixture is stirred under ice-
  2. temperaturecooling for 1 hour and 40 minutes
  3. customa saturated aqueous citric acid solution, and the mixture is separated
  4. washthe organic layer is washed twice with a saturated brine
  5. dry with materialthe mixture is dried over magnesium sulfate
  6. concentrationis concentrated under reduced pressure
  7. customThe resulting residue is purified by silica gel column chromatography (hexane:ethyl acetate=19:1→17:3) and (hexane:ethyl acetate=49:1→9:1)
  8. dissolutionThe residue is dissolved in diethyl ether
  9. filtrationfiltered
  10. concentrationThe filtrate is concentrated under reduced pressure
  11. customthe residue obtained above (630 mg)
  12. stirringthe mixture is stirred at 50° C. for 4 hours
  13. stirringstirred at same temperature overnight
  14. customthe mixture is separated
  15. washthe organic layer is washed with water
  16. dry with materiala saturated brine, and the mixture is dried over magnesium sulfate
  17. concentrationis concentrated under reduced pressure
  18. customThe resulting residue is purified by silica gel column chromatography (hexane:ethyl acetate=19:1→17:3)

출처 및 근거

ORD 기록
ord-b83ba46dfa6545a2a76ac5675e4fb2f5
출처 데이터셋
uspto-grants-2011_03
특허 번호
US07906517B2

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