Sodium hydride → (3R)-tert-butyl 3-(6-(5-bromo-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-3-yl)pyrazin-2-yloxy)piperidine-1-carboxylate

HRID 1529268Notes

Reaction equation

HRID 1529268 reaction equation
[H-].[Na+].[OH:3][C@@H:4]1[CH2:9][CH2:8][CH2:7][N:6]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:5]1.[Br:17][C:18]1[CH:19]=[C:20]2[C:24](=[CH:25][CH:26]=1)[N:23]([CH:27]1[CH2:32][CH2:31][CH2:30][CH2:29][O:28]1)[N:22]=[C:21]2[C:33]1[CH:38]=[N:37][CH:36]=[C:35](Cl)[N:34]=1>CN(C=O)C>[Br:17][C:18]1[CH:19]=[C:20]2[C:24](=[CH:25][CH:26]=1)[N:23]([CH:27]1[CH2:32][CH2:31][CH2:30][CH2:29][O:28]1)[N:22]=[C:21]2[C:33]1[N:34]=[C:35]([O:3][C@@H:4]2[CH2:9][CH2:8][CH2:7][N:6]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:5]2)[CH:36]=[N:37][CH:38]=1

Participants

5

Reactant 3

HCID 24758Sodium hydrideHCID 1514398(R)-1-Boc-3-hydroxypiperidineHCID 86709758HCID 86709758, compound

Product 1

HCID 67960228(3R)-tert-butyl 3-(6-(5-bromo-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-3-yl)pyrazin-2-yloxy)piperidine-1-carboxylateYield 99%

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent

Procedure

NaH (60% in mineral oil, 0.081 g, 2.032 mmol) was added to a solution of (R)-tert-butyl 3-hydroxypiperidine-1-carboxylate (0.245 g, 1.219 mmol, Astatech, Inc.) in DMF (2.50 mL) at 0° C. The mixture was stirred for 15 min then 5-bromo-3-(6-chloropyrazin-2-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole 1c (0.400 g, 1.016 mmol, Pharmacore) was added and the heterogenous mixture was warmed to RT. After 60 min at RT, ice was added and the mixture was extracted with EtOAc (3×). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated. The crude material was absorbed onto a plug of silica gel and purified by chromatography through a Redi-Sep pre-packed silica gel column (12 g), eluting with a gradient of 0% to 50% EtOAc in hexane, to provide tert-butyl (3R)-3-((6-(5-bromo-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-3-yl)-2-pyrazinyl)oxy)-1-piperidinecarboxylate (0.562 g, 1.006 mmol, 99% yield) as a light-yellow foam. MS (ESI, pos. ion) m/z: 558.0, 560.0 (M+1).

Workup

  1. waitAfter 60 min at RT
  2. additionice was added
  3. extractionthe mixture was extracted with EtOAc (3×)
  4. dry with materialThe combined organic layers were dried over anhydrous Na2SO4
  5. filtrationfiltered
  6. concentrationconcentrated
  7. customThe crude material was absorbed onto a plug of silica gel
  8. custompurified by chromatography through a Redi-Sep pre-packed silica gel column (12 g)
  9. washeluting with a gradient of 0% to 50% EtOAc in hexane

Sources & evidence

ORD record
ord-7bf7961db35a46cf8814d7138582318f
Source dataset
uspto-grants-2015_07
Patent number
US09090593B2

Reaction notes

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