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 1529290Notizen

Reaktionsgleichung

Reaktionsgleichung von HRID 1529290
[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

Komponenten

5

Edukt 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

Produkt 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-carboxylateAusbeute 28,9 %

Reagenzien, Katalysatoren, Lösungsmittel 1

HCID 6228DimethylformamideLösungsmittel

Reaktionsbedingungen

Temperatur
0 °C

Versuchsvorschrift

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).

Aufarbeitung

  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

Quellen und Nachweise

ORD-Eintrag
ord-0cffe056ed5c47889b59aec3b2437a7d
Quelldatensatz
uspto-grants-2015_07
Patentnummer
US09090593B2

Notizen zur Reaktion

Wird geladen…