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

HRID 2067135Notes

Reaction equation

HRID 2067135 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[C:18]([F:19])=[CH:17][CH:16]=[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[C:18]([F:19])=[CH:17][CH:16]=[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 782782,3-DifluoroanilineHCID 5993714,6-Dichloropyrimidine-5-carbonitrileHCID 242088454-(3-(Propan-2-yl)-1,2,4-oxadiazol-5-yl)piperidine

Product 1

HCID 582165364-(2,3-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 2,3-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 completion of the reaction, 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=0.49) to afford Compound B130 (501 mg; 76.7%). 1H-NMR (DMSO-d6): 9.60 (1H, s), 8.28 (1H, s), 7.45˜7.29 (3H, m), 4.64 (2H, m), 3.59˜3.52 (4H, m), 3.41˜3.49 (2H, m), 2.29˜2.25 (2H, b), 1.96˜1.86 (2H, m), 1.39 (6H, d) ppm. LCMS: 426.43.

Workup

  1. additionwere added at 0° C
  2. temperatureThe reaction was heated to 40° C.
  3. temperaturemaintained for 1 h
  4. temperatureThe reaction was cooled to rt
  5. extractionextracted with EtOAc (50 mL, two times)
  6. dry with materialThe EtOAc was dried over MgSO2
  7. concentrationconcentrated under vacuum The crude product
  8. customwas purified over SiO2 (EtOAc:Hex=1:1, Rf=0.49)
  9. customto afford Compound B130 (501 mg; 76.7%)

Sources & evidence

ORD record
ord-6ff42a3076f54a7787b75da6691553ab
Source dataset
uspto-grants-2012_10
Patent number
US08293751B2

Reaction notes

Loading…