Potassium Carbonate → 4-(2,5-Difluoro-phenylamino)-6-[4-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-1-yl]-pyrimidine-5-carbonitrile

HRID 1426075Notes

Reaction equation

HRID 1426075 reaction equation
Cl[C:2]1[C:7]([C:8]#[N:9])=[C:6](Cl)[N:5]=[CH:4][N:3]=1.[F:11][C:12]1[CH:18]=[CH:17][C:16]([F:19])=[CH:15][C:13]=1[NH2:14].C([O-])([O-])=O.[K+].[K+].[CH:26]([C:29]1[N:33]=[C:32]([CH:34]2[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]2)[O:31][N:30]=1)([CH3:28])[CH3:27]>CN(C=O)C.O.CCOC(C)=O>[F:11][C:12]1[CH:18]=[CH:17][C:16]([F:19])=[CH:15][C:13]=1[NH:14][C:2]1[C:7]([C:8]#[N:9])=[C:6]([N:37]2[CH2:36][CH2:35][CH:34]([C:32]3[O:31][N:30]=[C:29]([CH:26]([CH3:28])[CH3:27])[N:33]=3)[CH2:39][CH2:38]2)[N:5]=[CH:4][N:3]=1

Participants

8

Reactant 4

HCID 11430Potassium Carbonate2×HCID 677752,5-DifluoroanilineHCID 5993714,6-Dichloropyrimidine-5-carbonitrileHCID 242088454-(3-(Propan-2-yl)-1,2,4-oxadiazol-5-yl)piperidine

Product 1

HCID 582164154-(2,5-Difluoro-phenylamino)-6-[4-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-1-yl]-pyrimidine-5-carbonitrile

Reagents, catalysts & solvents 3

HCID 962WaterSolventHCID 6228DimethylformamideSolventHCID 8857Ethyl AcetateSolvent

Procedure

To a solution of 4,6-Dichloro-pyrimidine-5-carbonitrile (254 mg, 1.47 mmol) and 2,5-difluoroaniline (190 mg, 1.47 mmol) in DMF (3 mL) at 0° C. was added K2CO3 (203 mg, 1.47 mmol) The completion of the reaction was monitored by TLC (EtOAc:Hex=1:1, Rf=0.90). After the reaction was complete, 4-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-piperidine (340 mg, 1.47 mmol) and K2CO3 (406 mg, 2.94 mmol) were added at 0° C. The reaction was warmed to rt and stirred for 30 min. The reaction was heated to 40° C. and maintained for 1 h. The reaction was cooled to rt, poured in to H2O (50 mL) and extracted with EtOAc (50 mL, two times). The EtOAc was dried over MgSO2 and concentrated under vacuum. The crude product was purified over SiO2 (EtOAc:Hex=1:1, Rf=0.44) to afford the desired Compound B131 (465 mg; 71.1%). 1H-NMR (DMSO-d6): 9.32 (1H, s), 8.19 (1H, s), 7.40-7.08 (3H, m), 4.54 (2H, m), 3.48-3.32 (4H, m), 3.07-3.01 (2H, m), 2.18-2.14 (2H, b), 1.96-1.86 (2H, m), 1.27 (6H, d) ppm. LCMS: 426.43.

Workup

  1. temperatureThe reaction was heated to 40° C.
  2. temperaturemaintained for 1 h
  3. temperatureThe reaction was cooled to rt
  4. extractionextracted with EtOAc (50 mL, two times)
  5. dry with materialThe EtOAc was dried over MgSO2
  6. concentrationconcentrated under vacuum
  7. customThe crude product was purified over SiO2 (EtOAc:Hex=1:1, Rf=0.44)

Sources & evidence

ORD record
ord-f6e45539f951422580dcd89bc009d832
Source dataset
uspto-grants-2015_01
Patent number
US08933083B2

Reaction notes

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