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

HRID 449708

반응식

HRID 449708 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]([CH3:23])[CH2:19][CH2:18]3)=[CH:13][N:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[N:7]=1.[C:24]([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:26])[CH3:25].[K+].CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>C(O)CCC.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.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:24]([O:27][CH2:28][C:29]1[C:30]([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]([CH3:23])[CH2:19][CH2:18]4)=[CH:13][N:12]=3)[C:5](=[O:9])[N:6]([CH3:8])[N:7]=2)=[CH:31][CH:32]=[CH:33][C:34]=1[N:35]1[N:44]=[CH:43][C:42]2[C:37](=[C:38]([F:49])[CH:39]=[C:40]([C:45]([CH3:47])([CH3:46])[CH3:48])[CH:41]=2)[C:36]1=[O:50])(=[O:26])[CH3:25]

참가 물질

7

반응물 4

HCID 62657Potassium Phosphate, TribasicHCID 111557942-Dicyclohexylphosphino-2',4',6'-triisoprophylbiphenylHCID 667423806-Chloro-2-methyl-4-(5-(1-methylpiperidin-4-yl)pyridin-2-ylamino)pyridazin-3(2H)-oneHCID 87134390potassium (2-(acetoxymethyl)-3-(6-tert-butyl-8-fluoro-1-oxophthalazin-2(1H)-yl)phenyl)trifluoroborate

생성물 1

HCID 667426042-(6-tert-butyl-8-fluoro-1-oxophthalazin-2(1H)-yl)-6-(1-methyl-5-(5-(1-methylpiperidin-4-yl)pyridin-2-ylamino)-6-oxo-1,6-dihydropyridazin-3-yl)benzyl acetate수율 75.6%

시약·촉매·용매 2

HCID 9811564Bis(dibenzylideneacetone)palladium촉매HCID 22253497Water butanol용매

반응 조건

온도
110 °C

실험 절차

A mixture of 6-chloro-2-methyl-4-(5-(1-methylpiperidin-4-yl)pyridin-2-ylamino)pyridazin-3(2H)-one (1.06 g, 3.18 mmol), potassium (2-(acetoxymethyl)-3-(6-tert-butyl-8-fluoro-1-oxophthalazin-2(1H)-yl)phenyl)trifluoroborate (1.51 g, 3.18 mmol), xPhos (227 mg, 476 μmol) and potassium phosphate (1.48 g, 6.99 mmol) in 60 ml of butanol/water (5:1) was degassed with nitrogen for 10 minutes and bis(dibenzylideneacetone)palladium (0) (137 mg, 238 mmol) was added. The reaction mixture was heated to 110° C. for 3 hr. The crude reaction mixture was extracted with DCM, washed with water, dried over Na2SO4, filtered and concentrated to form a solid during concentration. This solid was triturated with ether to afford 1.67 g of crude product. Combined with 300 mg of crude material from a previous batch and purified by silica chromatography to afford 2-(6-tert-butyl-8-fluoro-1-oxophthalazin-2(1H)-yl)-6-(1-methyl-5-(5-(1-methylpiperidin-4-yl)pyridin-2-ylamino)-6-oxo-1,6-dihydropyridazin-3-yl)benzyl acetate (1.6 g) as a white solid.

후처리

  1. customwas degassed with nitrogen for 10 minutes
  2. customThe crude reaction mixture
  3. extractionwas extracted with DCM
  4. washwashed with water
  5. dry with materialdried over Na2SO4
  6. filtrationfiltered
  7. concentrationconcentrated
  8. customto form a solid
  9. concentrationduring concentration
  10. customThis solid was triturated with ether
  11. customto afford 1.67 g of crude product
  12. custompurified by silica chromatography

출처 및 근거

ORD 기록
ord-c26d48dfcfca48a1aebaf48f2d03bf83
출처 데이터셋
uspto-grants-2013_07
특허 번호
US08481540B2

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