Cesium carbonate → 4-(Cyclopropylmethoxy)-N-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]-6-[(2,2,2-trifluoroethoxy)methyl]pyrimidin-2-amine

HRID 59179Notes

Reaction equation

HRID 59179 reaction equation
Cl[C:2]1[N:7]=[C:6]([O:8][CH2:9][CH:10]2[CH2:12][CH2:11]2)[CH:5]=[C:4]([CH2:13][O:14][CH2:15][C:16]([F:19])([F:18])[F:17])[N:3]=1.[CH3:20][O:21][C:22]1[CH:23]=[C:24]([CH:26]=[CH:27][C:28]=1[N:29]1[CH:33]=[C:32]([CH3:34])[N:31]=[CH:30]1)[NH2:25].C(=O)([O-])[O-].[Cs+].[Cs+].C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2)CCCCC1>C(OC(=O)C)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O1CCOCC1>[CH:10]1([CH2:9][O:8][C:6]2[CH:5]=[C:4]([CH2:13][O:14][CH2:15][C:16]([F:19])([F:18])[F:17])[N:3]=[C:2]([NH:25][C:24]3[CH:26]=[CH:27][C:28]([N:29]4[CH:33]=[C:32]([CH3:34])[N:31]=[CH:30]4)=[C:22]([O:21][CH3:20])[CH:23]=3)[N:7]=2)[CH2:12][CH2:11]1

Participants

8

Reactant 4

HCID 10796Cesium carbonateHCID 27342162-(Dicyclohexylphosphino)biphenylHCID 454801813-methoxy-4-(4-methyl-1H-imidazol-1-yl)anilineHCID 1178211602-Chloro-4-(cyclopropylmethoxy)-6-[(2,2,2-trifluoroethoxy)methyl]pyrimidine

Product 1

HCID 863449804-(Cyclopropylmethoxy)-N-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]-6-[(2,2,2-trifluoroethoxy)methyl]pyrimidin-2-amine

Reagents, catalysts & solvents 3

HCID 167845palladium(II) acetateCatalystHCID 8857Ethyl AcetateSolventHCID 312751,4-DioxaneSolvent

Conditions

Temperature
100 °C

Procedure

2-Chloro-4-(cyclopropylmethoxy)-6-[(2,2,2-trifluoroethoxy)methyl]pyrimidine (55 mg, 0.19 mmol), 3-methoxy-4-(4-methyl-1H-imidazol-1-yl)aniline (45 mg, 0.22 mmol, cesium carbonate (124 mg, 0.38 mmol) and 2-(dicyclohexylphosphino)biphenyl (10 mg, 0.029 mmol) were added to dioxane (3 mL) in a microwave tube. Palladium (II) acetate (6.4 mg, 0.029 mmol) was added. The tube was vacuum-backfilled with nitrogen and sealed. The mixture was heated in a microwave reactor at 100° C. for 2 hours and then diluted with ethylacetate, washed with water, brine, dried over Mg2SO4 and the solvent was removed under reduced pressure. The residue was purified by chromatography on silica gel, eluting with mixtures of 0% to 5% methanol in ethyl acetate. The product was further purified by chromatography on a reverse phase column, eluting with mixtures of 0% to 100% methanol in water containing 5% trifluoroacetic acid to afford the title compound as a solid, 40 mg (45%). MS (ESI+) m/z 464 [M+H]+. 1H NMR (300 MHz, CDCl3) δ ppm 0.34-0.37 (m, 2H), 0.64-0.70 (m, 2H), 1.20-1.40 (m, 1H), 2.30 (s, 3H), 3.86 (s, 3H), 3.97 (q, 2H), 4.20 (d, 2H), 4.59 (s, 2H), 6.41 (s, 1H), 6.87 (s, 1H), 7.00 (d, 1H), 7.08 (s, 1H), 7.16 (d, 1H), 7.64 (s, 1H), 7.74 (s, 1H).

Workup

  1. customsealed
  2. washwashed with water, brine
  3. dry with materialdried over Mg2SO4
  4. customthe solvent was removed under reduced pressure
  5. customThe residue was purified by chromatography on silica gel
  6. washeluting with mixtures of 0% to 5% methanol in ethyl acetate
  7. customThe product was further purified by chromatography on a reverse phase column
  8. washeluting with mixtures of 0% to 100% methanol in water containing 5% trifluoroacetic acid

Sources & evidence

ORD record
ord-91e23dec1331410c89a3c3217cbaf9c3
Source dataset
uspto-grants-2016_09
Patent number
US09439904B2

Reaction notes

Loading…