Styrene → 4-(1-methyl-piperidin-4-yloxy)-8-phenethyl-2-phenyl-9,10-dihydro-4H-3,10a-diaza-benzo[f]azulene

HRID 1773923

반응식

HRID 1773923 반응식
Br[C:2]1[C:15]2[CH2:14][CH2:13][N:12]3[C:8](=[N:9][C:10]([C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=4)=[CH:11]3)[CH:7]([O:22][CH:23]3[CH2:28][CH2:27][N:26]([CH3:29])[CH2:25][CH2:24]3)[C:6]=2[CH:5]=[CH:4][CH:3]=1.[Cl-].[Li+].[CH2:32]=[CH:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:29][N:26]1[CH2:27][CH2:28][CH:23]([O:22][CH:7]2[C:6]3[CH:5]=[CH:4][CH:3]=[C:2]([CH2:32][CH2:33][C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)[C:15]=3[CH2:14][CH2:13][N:12]3[C:8]2=[N:9][C:10]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)=[CH:11]3)[CH2:24][CH2:25]1

참가 물질

7

반응물 4

HCID 7501StyreneHCID 11430Potassium CarbonateHCID 433294Lithium ChlorideHCID 867040028-bromo-4-(1-methyl-piperidin-4-yloxy)-2-phenyl-9,10-dihydro-4H-3,10a-diaza-benzo[f]azulene

생성물 1

HCID 867040084-(1-methyl-piperidin-4-yloxy)-8-phenethyl-2-phenyl-9,10-dihydro-4H-3,10a-diaza-benzo[f]azulene

시약·촉매·용매 2

HCID 167845palladium(II) acetate촉매HCID 6228Dimethylformamide용매

반응 조건

온도
95 °C

실험 절차

To a solution of 8-bromo-4-(1-methyl-piperidin-4-yloxy)-2-phenyl-9,10-dihydro-4H-3,10a-diaza-benzo[f]azulene (example 231) (276 mg, 0, 61 mmole) in anhydrous dimethylformamide (5 mL) in a screw-capped vial are added n-tetrabutylammonium bromide (196 mg, 0, 61 mmole), lithium chloride (26 mg, 0, 61 mmole), palladium(II) acetate (27 mg, 0, 12 mmole), styrene (174 μL, 1, 5 mmole) and potassium carbonate (420 mg, 3, 0 mmoles). The vial is evacuated and filled with argon. The reaction mixture is stirred at 95° C. for 20 hours. Water and diethyl ether are added to the reaction mixture. The organic phase is washed with water, dried over magnesium sulphate, filtered and concentrated under reduced pressure. To the residue are added methanol (10 mL), 10% Pd/C (150 mg) and ammonium formate (3 g). After reflux for 1.5 hours the mixture is filtered on a celite pad, concentrated under reduced pressure, diluted with ethyl acetate, washed with water, dried over magnesium sulphate and the solvent was removed under reduced pressure. The residue is purified by preparative HPLC-MS (Waters AutoPurification HPLC/MS System, Sunfire Prep C18 5 μm OBD 30×150 mm column, eluents: water/0.1% formic acid (A) and acetonitrile/0.1% formic acid (B), focus gradient from 23% (B) to 33% (B) in 10 minutes) to afford 4-(1-methyl-piperidin-4-yloxy)-8-phenethyl-2-phenyl-9,10-dihydro-4H-3,10a-diaza-benzo[f]azulene melting at 67° C.

후처리

  1. customThe vial is evacuated
  2. additionfilled with argon
  3. additionWater and diethyl ether are added to the reaction mixture
  4. washThe organic phase is washed with water
  5. dry with materialdried over magnesium sulphate
  6. filtrationfiltered
  7. concentrationconcentrated under reduced pressure
  8. additionTo the residue are added methanol (10 mL), 10% Pd/C (150 mg) and ammonium formate (3 g)
  9. temperatureAfter reflux for 1.5 hours the mixture
  10. filtrationis filtered on a celite pad
  11. concentrationconcentrated under reduced pressure
  12. additiondiluted with ethyl acetate
  13. washwashed with water
  14. dry with materialdried over magnesium sulphate
  15. customthe solvent was removed under reduced pressure
  16. customThe residue is purified by preparative HPLC-MS (Waters AutoPurification HPLC/MS System, Sunfire Prep C18 5 μm OBD 30×150 mm column, eluents: water/0.1% formic acid (A) and acetonitrile/0.1% formic acid (B), focus gradient from 23% (B) to 33% (B) in 10 minutes)

출처 및 근거

ORD 기록
ord-c1b5d70bc5ac45e98af0ea5693792169
출처 데이터셋
uspto-grants-2016_02
특허 번호
US09255101B2

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