Dichloromethane → N-(6-(Difluoro(6-(1-methyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[4,3-a]pyridin-3-yl)methyl)imidazo[1,2-b]pyridazin-2-yl)cyclopropanecarboxamide

HRID 1925148노트

반응식

HRID 1925148 반응식
Br[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:11]([F:28])([F:27])[C:12]3[CH:13]=[CH:14][C:15]4[N:16]([CH:18]=[C:19]([NH:21][C:22]([CH:24]5[CH2:26][CH2:25]5)=[O:23])[N:20]=4)[N:17]=3)=[N:9][N:10]=2)[CH:7]=1.[CH3:29][N:30]1[CH:34]=[C:33](B2OC(C)(C)C(C)(C)O2)[CH:32]=[N:31]1.C(Cl)Cl.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[F:27][C:11]([F:28])([C:8]1[N:6]2[CH:7]=[C:2]([C:33]3[CH:32]=[N:31][N:30]([CH3:29])[CH:34]=3)[CH:3]=[CH:4][C:5]2=[N:10][N:9]=1)[C:12]1[CH:13]=[CH:14][C:15]2[N:16]([CH:18]=[C:19]([NH:21][C:22]([CH:24]3[CH2:26][CH2:25]3)=[O:23])[N:20]=2)[N:17]=1

참가 물질

7

반응물 4

HCID 6344DichloromethaneHCID 10340Sodium CarbonateHCID 27739871-Methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazoleHCID 59233213N-(6-((6-bromo-[1,2,4]triazolo[4,3-a]pyridin-3-yl)difluoromethyl)imidazo[1,2-b]pyridazin-2-yl)cyclopropanecarboxamide

생성물 1

HCID 56593558N-(6-(Difluoro(6-(1-methyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[4,3-a]pyridin-3-yl)methyl)imidazo[1,2-b]pyridazin-2-yl)cyclopropanecarboxamide수율 71.1%

시약·촉매·용매 2

HCID 44119782Bis(cyclopenta-1,4-dien-1-yl(diphenyl)phosphane);dichloropalladium;iron(2+)촉매HCID 312751,4-Dioxane용매

실험 절차

A mixture of N-(6-((6-bromo-[1,2,4]triazolo[4,3-a]pyridin-3-yl)difluoromethyl)imidazo[1,2-b]pyridazin-2-yl)cyclopropanecarboxamide (7.2 g, 16.06 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (5.01 g, 24.10 mmol) and PdCl2(dppf):CH2Cl2 (0.655 g, 0.803 mmol) in 1,4-Dioxane:1M Na2CO3 (Ratio: 2.1, Volume: 100 ml) was heated at 95° C. for 4 h. The reaction mixture cooled and concentrated to dryness via rotary evaporation, diluted with EtOAc and water. The resulting solid was collected by filtration, rinsed with H2O followed by EtOAc. The grey color solid dissolved in 20% MeOH in chloroform and treated with activated charcoal for overnight, filtered through a pad of celite and the celite pad rinsed with 20% MeOH in chloroform until no compound detected by HPLC. This solution passed through a silica gel column. The solvent evaporated and the resulting solid rinsed with EtOAc, MeOH, followed by EtOAc and then Et2O, dried under vacuum to provide N-(6-(difluoro(6-(1-methyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[4,3-a]pyridin-3-yl)methyl)imidazo[1,2-b]pyridazin-2-yl)cyclopropanecarboxamide (5.13 g, 11.41 mmol, 71.1% yield) as white solid. 1H NMR (400 MHz, DMSO-d6) δ 11.35 (s, 1H), 8.71 (s, 1H), 8.41 (s, 1H), 8.19-8.34 (m, 2H), 8.00-8.12 (m, 2H), 7.91 (dd, J=1.64, 9.47 Hz, 1H), 7.71 (d, J=9.35 Hz, 1H), 3.88 (s, 3H), 1.88-2.02 (m, 1H), 0.83 (d, J=6.32 Hz, 4H). ESI-MS:m/z 450.1 (M+H)+. MP: 274.9° C.

후처리

  1. temperatureThe reaction mixture cooled
  2. concentrationconcentrated to dryness via rotary evaporation
  3. additiondiluted with EtOAc and water
  4. filtrationThe resulting solid was collected by filtration
  5. washrinsed with H2O
  6. dissolutionThe grey color solid dissolved in 20% MeOH in chloroform
  7. additiontreated with activated charcoal for overnight
  8. filtrationfiltered through a pad of celite
  9. washthe celite pad rinsed with 20% MeOH in chloroform until no compound
  10. customThe solvent evaporated
  11. washthe resulting solid rinsed with EtOAc, MeOH
  12. dry with materialEt2O, dried under vacuum

출처 및 근거

ORD 기록
ord-317c70a53a4a48b6849d80177795450b
출처 데이터셋
uspto-grants-2012_05
특허 번호
US08178534B2

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