Cesium carbonate → N4-methyl-N2-(1-methyl-2,3-dihydro-1H-imidazo[1,2-b]pyrazol-7-yl)-5-(trifluoromethyl)pyrimidine-2,4-diamine

HRID 1503480Notes

Reaction equation

HRID 1503480 reaction equation
[CH3:1][N:2]1[CH2:6][CH2:5][N:4]2[N:7]=[CH:8][C:9]([NH2:10])=[C:3]12.Cl[C:12]1[N:17]=[C:16]([NH:18][CH3:19])[C:15]([C:20]([F:23])([F:22])[F:21])=[CH:14][N:13]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CC(C1C=C(C(C)C)C(C2C(P(C3CCCCC3)C3CCCCC3)=C(OC)C=CC=2OC)=C(C(C)C)C=1)C>O1CCOCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:19][NH:18][C:16]1[C:15]([C:20]([F:22])([F:21])[F:23])=[CH:14][N:13]=[C:12]([NH:10][C:9]2[CH:8]=[N:7][N:4]3[CH2:5][CH2:6][N:2]([CH3:1])[C:3]=23)[N:17]=1

Participants

7

Reactant 4

HCID 10796Cesium carbonateHCID 210775872-Chloro-N-methyl-5-(trifluoromethyl)pyrimidin-4-amineHCID 25112535BrettphosHCID 838151031-methyl-2,3-dihydro-1H-pyrazolo[1,5-a]imidazol-7-amine

Product 1

HCID 72201491N4-methyl-N2-(1-methyl-2,3-dihydro-1H-imidazo[1,2-b]pyrazol-7-yl)-5-(trifluoromethyl)pyrimidine-2,4-diamineYield 14%

Reagents, catalysts & solvents 2

HCID 167845palladium(II) acetateCatalystHCID 312751,4-DioxaneSolvent

Conditions

Temperature
100 °C

Procedure

A mixture of 1-methyl-2,3-dihydro-1H-pyrazolo[1,5-a]imidazol-7-amine (91 mg, 0.66 mmol), 2-chloro-N-methyl-5-(trifluoromethyl)pyrimidin-4-amine (90 mg, 0.44 mmol), cesium carbonate (287 mg, 0.88 mmol), palladium acetate (2 mg, 0.009) and Brettphos (7 mg, 0.013 mmol) in 1,4-dioxane (1.5 mL) was degassed by bubbling nitrogen through the mixture for 5 min. The reaction tube was sealed and the mixture was heated to 100° C. for 18 h. The mixture was cooled, diluted with ethyl acetate (5 mL) and washed with water (2×5 mL). The aqueous washes were combined and extracted with EtOAc (5 mL). The organic extracts were combined and filtered through a hydrophobic frit. The solvent was removed in vacuo and the residue was purified by preparative HPLC to give the title compound (19 mg, 14%). 1H NMR (400 MHz, DMSO) δ 8.64† (br s, 1H), 8.32* (br s, 1H), 8.05 (s, 1H), 7.30† (br s, 1H), 7.11* (br s, 1H), 6.91 (s, 1H), 4.06 (t, J=7.6 Hz, 2H), 3.65 (t, J=7.6 Hz, 2H), 2.86 (d, J=4.4 Hz, 3H), 2.69 (s, 3H)†and * refer to different rotamers (arbitrarily assigned). LC-MS (Method C): m/z=314 (M+H)+, 2.78 min, 98.7% purity.

Workup

  1. customwas degassed
  2. customby bubbling nitrogen through the mixture for 5 min
  3. customThe reaction tube was sealed
  4. temperatureThe mixture was cooled
  5. additiondiluted with ethyl acetate (5 mL)
  6. washwashed with water (2×5 mL)
  7. extractionextracted with EtOAc (5 mL)
  8. filtrationfiltered through a hydrophobic frit
  9. customThe solvent was removed in vacuo
  10. customthe residue was purified by preparative HPLC

Sources & evidence

ORD record
ord-2b9add3581a349e6bf94d3869c2600c1
Source dataset
uspto-grants-2015_12
Patent number
US09212186B2

Reaction notes

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