Reaction #87457

Reaction equation

2-Chloro-4-(cyclopropylmethoxy)-6-[(2,2,2-trifluoroethoxy)methyl]pyrimidine

3-methoxy-4-(4-methyl-1H-imidazol-1-yl)aniline

cesium carbonate

2-(dicyclohexylphosphino)biphenyl

→

title compound

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

Solvents

dioxane

ethylacetate

Conditions

Workup

1. 1
   Othersealed
2. 2
   Washwashed with water, brine
3. 3
   Dryingdried over Mg2SO4
4. 4
   Otherthe solvent was removed under reduced pressure
5. 5
   OtherThe residue was purified by chromatography on silica gel
6. 6
   Washeluting with mixtures of 0% to 5% methanol in ethyl acetate
7. 7
   OtherThe product was further purified by chromatography on a reverse phase column
8. 8
   Washeluting with mixtures of 0% to 100% methanol in water containing 5% trifluoroacetic acid

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).

Source