Sodium hydride → (3R)-tert-butyl 3-(4-(5-(2,6-difluorophenyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-3-yl)pyrimidin-2-ylamino)piperidine-1-carboxylate

HRID 1529290Notes

Reaction equation

HRID 1529290 reaction equation
[NH2:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][N:4]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:3]1.[H-].[Na+].Cl[C:18]1[N:23]=[C:22]([C:24]2[C:32]3[C:27](=[CH:28][CH:29]=[C:30]([C:33]4[C:38]([F:39])=[CH:37][CH:36]=[CH:35][C:34]=4[F:40])[CH:31]=3)[N:26]([CH:41]3[CH2:46][CH2:45][CH2:44][CH2:43][O:42]3)[N:25]=2)[CH:21]=[CH:20][N:19]=1>CN(C=O)C>[F:39][C:38]1[CH:37]=[CH:36][CH:35]=[C:34]([F:40])[C:33]=1[C:30]1[CH:31]=[C:32]2[C:27](=[CH:28][CH:29]=1)[N:26]([CH:41]1[CH2:46][CH2:45][CH2:44][CH2:43][O:42]1)[N:25]=[C:24]2[C:22]1[CH:21]=[CH:20][N:19]=[C:18]([NH:1][C@@H:2]2[CH2:7][CH2:6][CH2:5][N:4]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:3]2)[N:23]=1

Participants

5

Reactant 3

HCID 24758Sodium hydrideHCID 1501974tert-butyl (3R)-3-aminopiperidine-1-carboxylateHCID 867097653-(2-chloropyrimidin-4-yl)-5-(2,6-difluorophenyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole

Product 1

HCID 67960035(3R)-tert-butyl 3-(4-(5-(2,6-difluorophenyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-3-yl)pyrimidin-2-ylamino)piperidine-1-carboxylateYield 28.9%

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent

Conditions

Temperature
0 °C

Procedure

To a solution of (R)-tert-butyl 3-aminopiperidine-1-carboxylate (0.28 g, 1.32 mmol) in DMF (10 mL) was treated with NaH (0.056 g, 2.34 mmol) and stirred for 15 min. The reaction mixture was cooled to 0° C. and 3-(2-chloropyrimidin-4-yl)-5-(2,6-difluorophenyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole (0.5 g, 1.17 mmol) was added. The resulting mixture was stirred at RT for 2 h. The reaction mixture was quenched with ice cold water and extracted with EtOAc. The organic layer was dried over Na2SO4, filtered and concentrated to yield crude compound. Purification by silica gel column chromatography, eluting with 5-15% EtOAc and hexanes to obtain (3R)-tert-butyl 3-(4-(5-(2,6-difluorophenyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-3-yl)pyrimidin-2-ylamino)piperidine-1-carboxylate (0.2 g, 18%). MS (ESI, pos. ion) m/z: 591.1 (M+1). To a solution of (3R)-tert-butyl 3-(4-(5-(2,6-difluorophenyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-3-yl)pyrimidin-2-ylamino)piperidine-1-carboxylate (0.3 g, 0.5 mmol) in EtOAc (10 mL) was added EtOAc-HCl (10 mL) and stirred at RT for 16 h. The reaction mixture was quenched with saturated NaHCO3 solution and extracted with EtOAc. The organic layer was washed with water and brine, dried over Na2SO4 and concentrated. The crude product was purified by reverse-phase preparative HPLC (using a AG/PP/C18-15/021 column, eluting with gradient, A: 5% TFE+0.01% TFA in Water; B: ACN). The title compound was obtained. MS (ESI, pos. ion) m/z: 407.2 (M+1).

Workup

  1. stirringThe resulting mixture was stirred at RT for 2 h
  2. customThe reaction mixture was quenched with ice cold water
  3. extractionextracted with EtOAc
  4. dry with materialThe organic layer was dried over Na2SO4
  5. filtrationfiltered
  6. concentrationconcentrated
  7. customto yield crude compound
  8. customPurification by silica gel column chromatography
  9. washeluting with 5-15% EtOAc and hexanes

Sources & evidence

ORD record
ord-0cffe056ed5c47889b59aec3b2437a7d
Source dataset
uspto-grants-2015_07
Patent number
US09090593B2

Reaction notes

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