Potassium Phosphate, Tribasic → [3-(3,5-Difluoro-pyridin-2-yl)-4-methyl-phenyl]-[2-(1,1-dioxo-tetrahydro-thiophen-3-yl)-1,2,3,4-tetrahydro-isoquinolin-5-yl]-amine

HRID 1890753

반응식

HRID 1890753 반응식
Br[C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][N:6]([CH:12]1[CH2:16][CH2:15][S:14](=[O:18])(=[O:17])[CH2:13]1)[CH2:7]2.[F:19][C:20]1[C:21]([C:27]2[CH:28]=[C:29]([CH:31]=[CH:32][C:33]=2[CH3:34])[NH2:30])=[N:22][CH:23]=[C:24]([F:26])[CH:25]=1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O1CCOCC1>[F:19][C:20]1[C:21]([C:27]2[CH:28]=[C:29]([NH:30][C:2]3[CH:11]=[CH:10][CH:9]=[C:8]4[C:3]=3[CH2:4][CH2:5][N:6]([CH:12]3[CH2:16][CH2:15][S:14](=[O:18])(=[O:17])[CH2:13]3)[CH2:7]4)[CH:31]=[CH:32][C:33]=2[CH3:34])=[N:22][CH:23]=[C:24]([F:26])[CH:25]=1

참가 물질

7

반응물 4

HCID 62657Potassium Phosphate, TribasicHCID 6360441,1'-(9,9-Dimethyl-9H-xanthene-4,5-diyl)bis(1,1-diphenylphosphine)HCID 583178905-Bromo-2-(1,1-dioxo-tetrahydro-thiophen-3-yl)-1,2,3,4-tetrahydro-isoquinolineHCID 583179983-(3,5-Difluoropyridin-2-yl)-4-methylaniline

생성물 1

HCID 57493333[3-(3,5-Difluoro-pyridin-2-yl)-4-methyl-phenyl]-[2-(1,1-dioxo-tetrahydro-thiophen-3-yl)-1,2,3,4-tetrahydro-isoquinolin-5-yl]-amine수율 65%

시약·촉매·용매 2

HCID 9811564Bis(dibenzylideneacetone)palladium촉매HCID 312751,4-Dioxane용매

반응 조건

온도
100 °C

실험 절차

To the reaction vessel containing 5-bromo-2-(1,1-dioxo-tetrahydro-thiophen-3-yl)-1,2,3,4-tetrahydro-isoquinoline (50 mg, 0.15 mmol), 3-(3,5-difluoropyridin-2-yl)-4-methylaniline (33 mg, 0.15 mmol), Pd2(dba)3 (13 mg, 0.014 mmol), Xantphos (16 mg, 0.028 mmol) and K3PO4 (74 mg, 0.35 mmol) is added anhydrous dioxane (1 mL). The vessel is flushed with nitrogen, sealed and heated to 100° C. for 15 hours. The reaction is then cooled to ambient temperature, filtered through a celite pad to remove salt. The filtrate is concentrated and purified by silica gel flash chromatography to afford [3-(3,5-difluoro-pyridin-2-yl)-4-methyl-phenyl]-[2-(1,1-dioxo-tetrahydro-thiophen-3-yl)-1,2,3,4-tetrahydro-isoquinolin-5-yl]-amine as an off-white solid (45 mg, 65%). MS m/z 470.2 (M+1); 1H NMR 400 MHz (DMSO-d6) δ8.67 (d, 1H, J=2.4 Hz), 7.39 (s, 1H), 7.22 (d, 1H, J=8.4 Hz), 7.12 (m, 2H), 7.00 (dd, 1H, J1=8.0 Hz, J2=2.4 Hz), 6.91 (d, 1H, J=2.4 Hz), 6.75 (d, 1H, J=7.2 Hz), 3.79 (d, 1H, J=19.2 Hz), 3.71 (d, 1H, J=19.2 Hz), 3.47 (m, 2H), 3.34 (m, 1H), 3.18 (m, 2H), 2.82 (m, 2H), 2.72 (m, 2H), 2.47 (m, 1H), 2.17 (m, 1H), 2.11 (s, 3H).

후처리

  1. customThe vessel is flushed with nitrogen
  2. customsealed
  3. temperatureThe reaction is then cooled to ambient temperature
  4. filtrationfiltered through a celite pad
  5. customto remove salt
  6. concentrationThe filtrate is concentrated
  7. custompurified by silica gel flash chromatography

출처 및 근거

ORD 기록
ord-9981a6cc80d0421fbd5260c88e7097a6
출처 데이터셋
uspto-grants-2013_08
특허 번호
US08507491B2

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