2-Amino-4,6-dichloropyrimidine → 6-chloro-N4-(4-{[2-(trifluoromethyl)pyridin-4-yl]oxy}phenyl)pyrimidine-2,4-diamine

HRID 729924Notes

Reaction equation

HRID 729924 reaction equation
[NH2:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[C:4]([Cl:9])[N:3]=1.[F:10][C:11]([F:27])([F:26])[C:12]1[CH:17]=[C:16]([O:18][C:19]2[CH:24]=[CH:23][C:22]([NH2:25])=[CH:21][CH:20]=2)[CH:15]=[CH:14][N:13]=1>O.C(O)(C)C.Cl>[Cl:9][C:4]1[N:3]=[C:2]([NH2:1])[N:7]=[C:6]([NH:25][C:22]2[CH:23]=[CH:24][C:19]([O:18][C:16]3[CH:15]=[CH:14][N:13]=[C:12]([C:11]([F:27])([F:10])[F:26])[CH:17]=3)=[CH:20][CH:21]=2)[CH:5]=1

Participants

6

Reactant 2

HCID 655222-Amino-4,6-dichloropyrimidineHCID 591345604-{[2-(Trifluoromethyl)pyridin-4-yl]oxy}aniline2×

Product 1

HCID 578333536-chloro-N4-(4-{[2-(trifluoromethyl)pyridin-4-yl]oxy}phenyl)pyrimidine-2,4-diamine

Reagents, catalysts & solvents 3

HCID 313Hydrochloric AcidSolventHCID 962WaterSolventHCID 3776IsopropanolSolvent

Conditions

Temperature
65 °C

Procedure

A stirred solution containing 2-amino-4,6-dichloropyrimidine (17.74 g, 0.11 mol) and 4-{[2-(trifluoromethyl)pyridin-4-yl]oxy}aniline (Intermediate 2U) in water (400 mL), isopropanol (100 mL) and concentrated hydrochloric acid (5 mL) was heated at 65° C. for 18 h. The reaction was cooled to 0° C. and the yellow-tan solid was collected by suction filtration and washed with water. The filtered product was dissolved in hot N,N-dimethylformamide (90° C.) and triethylamine was slowly added until the solution was slightly basic (pH˜8). The solution was then cooled to rt, added to vigorously stirred ice water (1.2 L), and stirring was continued for 1 h. The tan solids were collected by suction filtration and washed sequentially with water, isopropanol, diethyl ether and finally hexane. The material was dried by air suction to afford a light tan solid, 28.8 g (77%). 1H NMR (DMSO-d6) δ ppm 9.46 (s, 1H), 8.59 (d, 1H, J=5.6 Hz), 7.81 (d, 2H, J=9.0), 7.37 (d, 1H, J=2.4 Hz), 7.17 (d, 2H, J=9.0 Hz), 7.11 (dd, 1H, J=2.6, 5.6 Hz), 6.78 (s, 2H), 6.00 (s, 1H).

Workup

  1. temperatureThe reaction was cooled to 0° C.
  2. filtrationthe yellow-tan solid was collected by suction filtration
  3. washwashed with water
  4. dissolutionThe filtered product was dissolved in hot N,N-dimethylformamide (90° C.)
  5. additiontriethylamine was slowly added until the solution
  6. temperatureThe solution was then cooled to rt
  7. additionadded to vigorously stirred ice water (1.2 L)
  8. filtrationThe tan solids were collected by suction filtration
  9. washwashed sequentially with water, isopropanol, diethyl ether and finally hexane
  10. customThe material was dried by air suction
  11. customto afford a light tan solid, 28.8 g (77%)

Sources & evidence

ORD record
ord-e12642cf67f341b38bd331d5685ed3a9
Source dataset
uspto-grants-2009_09
Patent number
US07582645B2

Reaction notes

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