Sodium Hydroxide → 6-tert-Butyl-8-fluoro-2-(2-hydroxymethyl-3-{1-methyl-5-[6-(1-methyl-piperidin-4-yl)-pyridazin-3-ylamino]-6-oxo-1,6-dihydro-pyridazin-3-yl}-phenyl)-2H-phthalazin-1-one

HRID 449649

반응식

HRID 449649 반응식
Cl[C:2]1[CH:3]=[C:4]([NH:10][C:11]2[N:12]=[N:13][C:14]([CH:17]3[CH2:22][CH2:21][N:20]([CH3:23])[CH2:19][CH2:18]3)=[CH:15][CH:16]=2)[C:5](=[O:9])[N:6]([CH3:8])[N:7]=1.C([O:27][CH2:28][C:29]1[C:34]([N:35]2[N:44]=[CH:43][C:42]3[C:37](=[C:38]([F:49])[CH:39]=[C:40]([C:45]([CH3:48])([CH3:47])[CH3:46])[CH:41]=3)[C:36]2=[O:50])=[CH:33][CH:32]=[CH:31][C:30]=1[B-](F)(F)F)(=O)C.[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+].[OH-].[Na+]>O.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].CCCCO>[C:45]([C:40]1[CH:41]=[C:42]2[C:37](=[C:38]([F:49])[CH:39]=1)[C:36](=[O:50])[N:35]([C:34]1[CH:33]=[CH:32][CH:31]=[C:30]([C:2]3[CH:3]=[C:4]([NH:10][C:11]4[N:12]=[N:13][C:14]([CH:17]5[CH2:22][CH2:21][N:20]([CH3:23])[CH2:19][CH2:18]5)=[CH:15][CH:16]=4)[C:5](=[O:9])[N:6]([CH3:8])[N:7]=3)[C:29]=1[CH2:28][OH:27])[N:44]=[CH:43]2)([CH3:48])([CH3:46])[CH3:47]

참가 물질

9

반응물 5

HCID 14798Sodium HydroxideHCID 62657Potassium Phosphate, TribasicHCID 111557942-Dicyclohexylphosphino-2',4',6'-triisoprophylbiphenylHCID 667421866-chloro-2-methyl-4-(6-(1-methylpiperidin-4-yl)pyridazin-3-ylamino)pyridazin-3(2H)-oneHCID 87134390potassium (2-(acetoxymethyl)-3-(6-tert-butyl-8-fluoro-1-oxophthalazin-2(1H)-yl)phenyl)trifluoroborate

생성물 1

HCID 566560526-tert-Butyl-8-fluoro-2-(2-hydroxymethyl-3-{1-methyl-5-[6-(1-methyl-piperidin-4-yl)-pyridazin-3-ylamino]-6-oxo-1,6-dihydro-pyridazin-3-yl}-phenyl)-2H-phthalazin-1-one수율 20.4%

시약·촉매·용매 3

HCID 6505921(1E,4E)-1,5-diphenylpenta-1,4-dien-3-one; palladium촉매HCID 2631-Butanol용매HCID 962Water용매3회

반응 조건

온도
110 °C

실험 절차

In a 15 mL microwave reaction vial was added 6-chloro-2-methyl-4-(6-(1-methylpiperidin-4-yl)pyridazin-3-ylamino)pyridazin-3(2H)-one (160 mg, 478 μmol, Eq: 1.00), potassium (2-(acetoxymethyl)-3-(6-tert-butyl-8-fluoro-1-oxophthalazin-2(1H)-yl)phenyl)trifluoroborate (272 mg, 573 μmol, Eq: 1.2) with n-BuOH (7.5 ml) and water (1.5 ml). Argon was bubbled through the solution for 5 min. To the mixture was added X-PHOS (34.2 mg, 71.7 μmol, Eq: 0.15) and potassium phosphate tribasic (304 mg, 1.43 mmol, Eq: 3). Argon was bubbled through the mixture for 5 min. To this mixture was added bis(dibenzylideneacetone)palladium (20.6 mg, 35.8 μmol, Eq: 0.075). The tube was sealed under argon and heated in oil bath at 110° C. for 3 hrs. The mixture was cooled to room temperature and treated with a solution of 220 mg NaOH in 1.5 mL water dropwise. The resultant mixture was heated in an oil bath at 50° C. for 3 hrs with strong stirring. The reaction mixture was diluted with water (20 mL) and extracted with DCM (3×30 mL). The combined extracts were concentrated and purified by solid loading on a 40 g silica gel column and eluting with 5-10% (10% NH4OH in MeOH) in 1/1 EtOAc/hexane to afford 61 mg (20%) of the title compound as a yellow solid. mp: 260-265° C. 1H NMR (300 MHz, CHLOROFORM-d) 1.43 (s, 9H), 1.80-2.20 (m, 6H), 2.37 (s, 3H), 2.90-3.07 (m, 3H), 3.85 (t, J=6.2 Hz, 1H), 3.92 (s, 3H), 4.45 (d, J=6.2 Hz, 2H), 7.15 (d, J=9 Hz, 1H), 7.35 (d, J=9 Hz, 1H), 7.43-7.65 (m, 5H), 8.28 (d, J=2.5, 1H), 8.32 (s, 1H), 8.78 (s, 1H). LCMS (ES): 625 (M+H), RT=2.21 min.

후처리

  1. customIn a 15 mL microwave reaction
  2. customArgon was bubbled through the solution for 5 min
  3. customArgon was bubbled through the mixture for 5 min
  4. customThe tube was sealed under argon
  5. temperatureThe mixture was cooled to room temperature
  6. extractionextracted with DCM (3×30 mL)
  7. concentrationThe combined extracts were concentrated
  8. custompurified by solid loading on a 40 g silica gel column
  9. washeluting with 5-10% (10% NH4OH in MeOH) in 1/1 EtOAc/hexane

출처 및 근거

ORD 기록
ord-7a4197fef61946bbac7cad7632969f5c
출처 데이터셋
uspto-grants-2013_07
특허 번호
US08481540B2

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