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Sodium hydride → 6-(1-methyl-1H-pyrazol-4-yl)-3-((S)-1-{2-[2-(tetrahydro-pyran-2-yloxy)-ethyl]-2H-indazol-5-yl}-ethyl)imidazo[1,2-b]pyridazine

HRID 69276
Notes
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Reaction equation

HRID 69276 reaction equation
[CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[CH:8]=[CH:9][C:10]3[N:11]([C:13]([C@H:16]([C:18]4[CH:19]=[C:20]5[C:24](=[CH:25][CH:26]=4)[N:23]([CH2:27][CH2:28][O:29][CH:30]4[CH2:35][CH2:34][CH2:33][CH2:32][O:31]4)[N:22]=[CH:21]5)[CH3:17])=[CH:14][N:15]=3)[N:12]=2)[CH:4]=[N:3]1.[H-].[Na+].BrCCOC1CCCCO1>C1COCC1.C(Cl)Cl>[CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[CH:8]=[CH:9][C:10]3[N:11]([C:13]([C@H:16]([C:18]4[CH:19]=[CH:20][C:21]5[C:25](=[CH:24][N:23]([CH2:27][CH2:28][O:29][CH:30]6[CH2:35][CH2:34][CH2:33][CH2:32][O:31]6)[N:22]=5)[CH:26]=4)[CH3:17])=[CH:14][N:15]=3)[N:12]=2)[CH:4]=[N:3]1
ParticipantsProcedureWorkupSources & evidenceReaction notes

Participants

6

Reactant 3

HCID 24758Sodium hydrideHCID 866212-(2-Bromoethoxy)tetrahydro-2H-pyranHCID 686322276-(1-Methyl-1H-pyrazol-4-yl)-3-((S)-1-{1-[2-(tetrahydro-pyran-2-yloxy)-ethyl]-1H-indazol-5-yl}-ethyl)-imidazo[1,2-b]pyridazine

Product 1

HCID 686342906-(1-methyl-1H-pyrazol-4-yl)-3-((S)-1-{2-[2-(tetrahydro-pyran-2-yloxy)-ethyl]-2H-indazol-5-yl}-ethyl)imidazo[1,2-b]pyridazine

Reagents, catalysts & solvents 2

HCID 6344
Dichloromethane
Solvent
HCID 8028TetrahydrofuranSolvent

Procedure

6-(1-Methyl-1H-pyrazol-4-yl)-3-((S)-1-{1-[2-(tetrahydro-pyran-2-yloxy)-ethyl]-1H-indazol-5-yl}-ethyl)-imidazo[1,2-b]pyridazine (Example 195, 34 mg, 0.1 mmol) was added to a suspension of NaH (55%, 4.8 mg 0.11 mmol) in dry THF (0.5 mL) at 0° C. The RM was allowed to stir at rt for 15 min and 2-(2-bromo-ethoxy)-tetrahydro-pyran (0.024 mL, 0.150 mmol) was added at 0° C. It was stirred additionally 7 h at rt, then overnight at 60° C., and finally 7 h at 120° C. in a pressure safe capped vial. After cooling at rt the RM was taken-up in DCM, washed with brine, the organic phase was dried over MgSO4 and concentrated under reduced pressure. The residue was purified by flash chromatography (CombiFlash® Companion System®, with RediSep® silica gel column, EtOAc/MeOH=100:0->80:20) to afford 6-(1-methyl-1H-pyrazol-4-yl)-3-((S)-1-{2-[2-(tetrahydro-pyran-2-yloxy)-ethyl]-2H-indazol-5-yl}-ethyl)imidazo[1,2-b]pyridazine and the title compound (tR 4.05 min (conditions 2), MH+=472.3).

Workup

  1. stirringIt was stirred additionally 7 h at rt
  2. customovernight at 60° C., and finally 7 h at 120° C. in a pressure safe capped vial
  3. temperatureAfter cooling at rt the RM
  4. washwashed with brine
  5. dry with materialthe organic phase was dried over MgSO4
  6. concentrationconcentrated under reduced pressure
  7. customThe residue was purified by flash chromatography (CombiFlash® Companion System®, with RediSep® silica gel column, EtOAc/MeOH=100:0->80:20)

Sources & evidence

ORD record
ord-e9e4e70efad8413a81f98e5db3212071
Source dataset
uspto-grants-2014_09
DOI
10.6084/m9.figshare.5104873.v1
Patent number
US08822468B2

Reaction notes

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On this pageParticipantsProcedureWorkupSources & evidenceReaction notes