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 hydrochloride

HRID 1925144ノート

反応式

HRID 1925144 の反応式
Br[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:11]([F:33])([F:32])[C:12]3[CH:13]=[CH:14][C:15]4[N:16]([CH:18]=[C:19]([N:21]([C:27]([CH:29]5[CH2:31][CH2:30]5)=[O:28])[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.[CH3:34][N:35]1[CH:39]=[C:38](B2OC(C)(C)C(C)(C)O2)[CH:37]=[N:36]1.C([O-])([O-])=O.[Na+].[Na+].C(Cl)[Cl:56]>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:33][C:11]([F:32])([C:8]1[N:6]2[CH:7]=[C:2]([C:38]3[CH:37]=[N:36][N:35]([CH3:34])[CH:39]=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:27]([CH:29]3[CH2:31][CH2:30]3)=[O:28])[N:20]=2)[N:17]=1.[ClH:56].[F:33][C:11]([F:32])([C:8]1[N:6]2[CH:7]=[C:2]([C:38]3[CH:37]=[N:36][N:35]([CH3:34])[CH:39]=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

参加物

8

反応物 4

HCID 6344Dichloromethane2 回HCID 10340Sodium CarbonateHCID 27739871-Methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazoleHCID 59233175N-(6-((6-bromo-[1,2,4]triazolo[4,3-a]pyridin-3-yl)difluoromethyl)imidazo[1,2-b]pyridazin-2-yl)-N-(cyclopropanecarbonyl)cyclopropanecarboxamide

生成物 2

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)cyclopropanecarboxamideHCID 66633890N-(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 hydrochloride収率 38%

試薬・触媒・溶媒 2

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

実験手順

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)-N-(cyclopropanecarbonyl)cyclopropanecarboxamide (0.6 g, 1.16 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (0.242 g, 1.162 mmol), and PdCl2(dppf):CH2Cl2 (0.048 g, 0.058 mmol) in dioxane (10 mL)/2N Na2CO3 (5 mL) was heated in a microwave at 110° C. for 30 min. This reaction was repeated 4 times and reaction mixtures were combined. The reaction was diluted with CH2Cl2 (500 mL) and washed with H2O (3×200 mL). The organic phase was separated and concentrated to dryness via rotary evaporation. The resulting residue was suspended in EtOAc and sonicated. The resulting solid was collected by filtration and rinsed with EtOAc. The solid was the dissolved in MeOH/CH2Cl2 (5:95, 300 mL) and filtered through a silica plug and rinsed with MeOH/CH2Cl2 (5:95). Concentrated HCl (0.5 mL) was added to the collected eluent followed by active charcoal. The solution was stirred at ambient temperature for 1 hour and filtered through celite. The solvent was evaporated and the resulting residue was then triturated in EtOAc. The solid was collected by filtration, rinsed with EtOAc and dried in vacuum to provide the title compound, 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 hydrochloride (0.92 g, 1.78 mmol, 38%). 1H NMR (400 MHz, DMSO-d6) δ ppm 0.82 (d, J=6.32 Hz, 4 H) 1.91-2.01 (m, 1 H) 3.87 (s, 3 H) 7.70 (d, J=9.35 Hz, 1 H) 7.90 (dd, J=9.60, 1.52 Hz, 1 H) 7.98-8.11 (m, 2 H) 8.19-8.32 (m, 2 H) 8.40 (s, 1 H) 8.70 (s, 1 H) 11.35 (s, 1 H). ESI-MS:m/z 516.1 (M+H)+. MP: 195° C. dec.

後処理

  1. custom4 times and reaction mixtures
  2. washwashed with H2O (3×200 mL)
  3. customThe organic phase was separated
  4. concentrationconcentrated to dryness via rotary evaporation
  5. customsonicated
  6. filtrationThe resulting solid was collected by filtration
  7. washrinsed with EtOAc
  8. dissolutiondissolved in MeOH/CH2Cl2 (5:95, 300 mL)
  9. filtrationfiltered through a silica plug
  10. washrinsed with MeOH/CH2Cl2 (5:95)
  11. additionConcentrated HCl (0.5 mL) was added to the collected eluent
  12. filtrationfiltered through celite
  13. customThe solvent was evaporated
  14. customthe resulting residue was then triturated in EtOAc
  15. filtrationThe solid was collected by filtration
  16. washrinsed with EtOAc
  17. customdried in vacuum

出典と根拠

ORDレコード
ord-287fc7b34f024bdea3e95a3f54102879
出典データセット
uspto-grants-2012_05
特許番号
US08178534B2

反応ノート

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