Cesium carbonate → 6-chloro-N-(4-(difluoromethyl)pyridin-2-yl)-4-(1-(oxetan-3-yl)piperidin-4-yl)pyridin-2-amine

HRID 1057037Notes

Reaction equation

HRID 1057037 reaction equation
Cl[C:2]1[CH:7]=[C:6]([CH:8]2[CH2:13][CH2:12][N:11]([CH:14]3[CH2:17][O:16][CH2:15]3)[CH2:10][CH2:9]2)[CH:5]=[C:4]([Cl:18])[N:3]=1.[F:19][CH:20]([F:28])[C:21]1[CH:26]=[CH:25][N:24]=[C:23]([NH2:27])[CH:22]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1>[Cl:18][C:4]1[N:3]=[C:2]([NH:27][C:23]2[CH:22]=[C:21]([CH:20]([F:28])[F:19])[CH:26]=[CH:25][N:24]=2)[CH:7]=[C:6]([CH:8]2[CH2:13][CH2:12][N:11]([CH:14]3[CH2:17][O:16][CH2:15]3)[CH2:10][CH2:9]2)[CH:5]=1

Participants

6

Reactant 3

HCID 10796Cesium carbonateHCID 672825704-(Difluoromethyl)pyridin-2-amineHCID 900154092,6-Dichloro-4-(1-(oxetan-3-yl)piperidin-4-yl)pyridine

Product 1

HCID 900671026-chloro-N-(4-(difluoromethyl)pyridin-2-yl)-4-(1-(oxetan-3-yl)piperidin-4-yl)pyridin-2-amineYield 77.1%

Reagents, catalysts & solvents 2

HCID 6360441,1'-(9,9-Dimethyl-9H-xanthene-4,5-diyl)bis(1,1-diphenylphosphine)CatalystHCID 9811564Bis(dibenzylideneacetone)palladiumCatalyst

Conditions

Temperature
80 °C

Procedure

A round-bottomed flask was charged with 2,6-dichloro-4-[1-(oxetan-3-yl)-4-piperidyl]pyridine (1.00 g, 3.48 mmol), 4-(difluoromethyl)pyridin-2-amine (502 mg, 3.48 mmol), tris(dibenzylideneacetone)dipalladium(0) (82.2 mg, 2.5 mol %), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (125 mg, 6 mol %) and cesium carbonate (1.59 g, 4.87 mmol). The flask was sealed with a septum and purged with nitrogen gas before injecting anhydrous 1,4-dioxane (14 mL, 0.25 M). The reaction mixture was stirred at 80° C. for 22 hr before cooling to rt and filtering through Celite, rinsing with CH2Cl2. After concentration, flash column chromatography (100:0-95:5 CH2Cl2/MeOH) afforded 6-chloro-N-(4-(difluoromethyl)pyridin-2-yl)-4-(1-(oxetan-3-yl)piperidin-4-yl)pyridin-2-amine as a colorless solid (1.06 g, 77%); 1H NMR (400 MHz, CDCl3) δ 8.38 (d, J=5.1 Hz, 1H), 7.53 (s, 1H), 7.46 (s, 1H), 7.34 (br s, 1H), 7.00 (d, J=5.1 Hz, 1H), 6.80 (s, 1H), 6.61 (t, J=55.8 Hz, 1H), 4.72-4.60 (m, 4H), 3.57-3.46 (m, 1H), 2.94-2.81 (m, 2H), 2.58-2.41 (m, 1H), 2.00-1.75 (m, 6H); ESI-LRMS m/z [M+1]+=395.

Workup

  1. customThe flask was sealed with a septum
  2. custompurged with nitrogen gas
  3. temperaturebefore cooling to rt
  4. filtrationfiltering through Celite
  5. washrinsing with CH2Cl2
  6. concentrationAfter concentration, flash column chromatography (100:0-95:5 CH2Cl2/MeOH)

Sources & evidence

ORD record
ord-3ab95470a5db447e944d6fde2667c92f
Source dataset
uspto-grants-2016_07
Patent number
US09399636B2

Reaction notes

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