Potassium Phosphate, Tribasic → 2-(6-tert-butyl-8-fluoro-1-oxophthalazin-2(1H)-yl)-6-(5-(5-(1-ethylpiperidin-4-yl)pyridin-2-ylamino)-1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)benzyl acetate

HRID 449624

반응식

HRID 449624 반응식
Cl[C:2]1[CH:3]=[C:4]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([CH:17]3[CH2:22][CH2:21][N:20]([CH2:23][CH3:24])[CH2:19][CH2:18]3)=[CH:13][N:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[N:7]=1.[C:25]([O:28][CH2:29][C:30]1[C:35]([N:36]2[N:45]=[CH:44][C:43]3[C:38](=[C:39]([F:50])[CH:40]=[C:41]([C:46]([CH3:49])([CH3:48])[CH3:47])[CH:42]=3)[C:37]2=[O:51])=[CH:34][CH:33]=[CH:32][C:31]=1[B-](F)(F)F)(=[O:27])[CH3:26].[K+].CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.[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.[Pd].O.C(O)CCC>[C:25]([O:28][CH2:29][C:30]1[C:31]([C:2]2[CH:3]=[C:4]([NH:10][C:11]3[CH:16]=[CH:15][C:14]([CH:17]4[CH2:22][CH2:21][N:20]([CH2:23][CH3:24])[CH2:19][CH2:18]4)=[CH:13][N:12]=3)[C:5](=[O:9])[N:6]([CH3:8])[N:7]=2)=[CH:32][CH:33]=[CH:34][C:35]=1[N:36]1[N:45]=[CH:44][C:43]2[C:38](=[C:39]([F:50])[CH:40]=[C:41]([C:46]([CH3:48])([CH3:47])[CH3:49])[CH:42]=2)[C:37]1=[O:51])(=[O:27])[CH3:26]

참가 물질

8

반응물 4

HCID 62657Potassium Phosphate, TribasicHCID 111557942-Dicyclohexylphosphino-2',4',6'-triisoprophylbiphenylHCID 667427666-chloro-4-(5-(1-ethylpiperidin-4-yl)pyridin-2-ylamino)-2-methylpyridazin-3(2H)-oneHCID 87134390potassium (2-(acetoxymethyl)-3-(6-tert-butyl-8-fluoro-1-oxophthalazin-2(1H)-yl)phenyl)trifluoroborate

생성물 1

HCID 667432512-(6-tert-butyl-8-fluoro-1-oxophthalazin-2(1H)-yl)-6-(5-(5-(1-ethylpiperidin-4-yl)pyridin-2-ylamino)-1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)benzyl acetate수율 62.1%

시약·촉매·용매 3

HCID 6505921(1E,4E)-1,5-diphenylpenta-1,4-dien-3-one; palladium촉매HCID 2631-Butanol용매HCID 962Water용매

반응 조건

온도
100 °C

실험 절차

In a 50 mL test tube, 6-chloro-4-(5-(1-ethylpiperidin-4-yl)pyridin-2-ylamino)-2-methylpyridazin-3(2H)-one (121 mg, 348 μmol, Eq: 1.00) and potassium (2-(acetoxymethyl)-3-(6-tert-butyl-8-fluoro-1-oxophthalazin-2(1H)-yl)phenyl)trifluoroborate (165 mg, 348 μmol, Eq: 1.00) were combined with BuOH (4 ml) to give a orange solution. Water (1.00 ml) was added. X-PHOS (16.6 mg, 34.8 μmol, Eq: 0.1) and potassium phosphate tribasic (148 mg, 696 μmol, Eq: 2) were added. Bis(dibenzylideneacetone)palladium (10.0 mg, 17.4 μmol, Eq: 0.05) was added. The reaction mixture was purged with argon. The mixture was heated in a oil bath at 100° C. for 1.5 hours, then cooled to room temperature. The reaction mixture was poured into 75 mL H2O and extracted with twice with EtOAc. The organic layers were combined and dried over Na2SO4. Concentrated in vacuo. The crude material was purified by flash chromatography (silica gel, 12 g, 50% to 100% (60:10:1 DCM:MeOH:NH4OH)/DCM gradient) to give a solid. The solid was triturated with Et2O to give 2-(6-tert-butyl-8-fluoro-1-oxophthalazin-2(1H)-yl)-6-(5-(5-(1-ethylpiperidin-4-yl)pyridin-2-ylamino)-1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)benzyl acetate (147 mg, 62%). LC/MS-ESI observed [M+H]+ 680.

후처리

  1. customto give a orange solution
  2. customThe reaction mixture was purged with argon
  3. temperaturecooled to room temperature
  4. additionThe reaction mixture was poured into 75 mL H2O
  5. extractionextracted with twice with EtOAc
  6. dry with materialdried over Na2SO4
  7. concentrationConcentrated in vacuo
  8. customThe crude material was purified by flash chromatography (silica gel, 12 g, 50% to 100% (60:10:1 DCM:MeOH:NH4OH)/DCM gradient)
  9. customto give a solid
  10. customThe solid was triturated with Et2O

출처 및 근거

ORD 기록
ord-db409b78d06040b9badeeb1f6235d652
출처 데이터셋
uspto-grants-2013_07
특허 번호
US08481540B2

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