2,2,2-Trifluoroethanol → HCID 59126919, compound

HRID 1969361Notes

Reaction equation

HRID 1969361 reaction equation
[NH2:1][C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[C:10]([O:15][CH3:16])[C:9]=2[F:17])[N:5]=[C:4]([C:18]([OH:20])=[O:19])[C:3]=1Br.[F:22][C:23]([F:27])([F:26])[CH2:24][OH:25].[C:28](=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.O>[CH3:28][O:20][C:18]([C:4]1[C:3]([O:25][CH2:24][C:23]([F:27])([F:26])[F:22])=[C:2]([NH2:1])[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[C:10]([O:15][CH3:16])[C:9]=2[F:17])[N:5]=1)=[O:19]

Participants

6

Reactant 3

HCID 64092,2,2-TrifluoroethanolHCID 10796Cesium carbonateHCID 66953945HCID 66953945, compound

Product 1

HCID 59126919HCID 59126919, compoundYield 12.2%

Reagents, catalysts & solvents 2

HCID 962WaterSolventHCID 6228DimethylformamideSolvent

Conditions

Temperature
80 °C

Procedure

6-Amino-5-bromo-2-(4-chloro-2-fluoro-3-methoxyphenyl)-pyrimidine-4-carboxylic acid (240 mg, 0.64 mmol), 2,2,2-trifluoroethanol (1.4 mL, 1.9 g, 1.9 mmol), cesium carbonate (1.0 g, 3.2 mmol) and cuprous bromide (92 mg, 0.64 mmol) were combined in 7 mL dry DMF and heated to 80° C. for 3 h. After cooling, the mixture was diluted with water and extracted twice with ethyl acetate. The combined extracts were washed twice with water, dried and evaporated. The residue was purified by flash chromatography on silica gel (5 to 20% ethyl acetate in hexane) and then repurified by preparative HPLC (55% acetonitrile buffered with 0.1% v/v acetic acid). The purified acid was taken up in 5 mL methanol, treated with a 2 M solution of (trimethylsilyl)diazomethane in hexanes (1 mL) and stirred for 30 m at 25° C. The excess reagent was destroyed by addition of 0.5 mL acetic acid and the volatiles were removed by evaporation. The residue was taken up in ethyl acetate, washed with saturated sodium bicarbonate, washed with brine, dried and evaporated. The residue was taken up in a small amount of dichloromethane and the product was precipitated as a solid by slow addition of hexane to give 32 mg of the title compound as a white solid: mp 123-125° C.: 1H NMR (CDCl3) δ 7.61 (dd, 1H), 7.20 (dd, 1H), 5.51 (br s, 2H), 4.51 (q, 1H), 4.01 (s, 3H), 3.99 (s, 3H).

Workup

  1. temperatureAfter cooling
  2. extractionextracted twice with ethyl acetate
  3. washThe combined extracts were washed twice with water
  4. customdried
  5. customevaporated
  6. customThe residue was purified by flash chromatography on silica gel (5 to 20% ethyl acetate in hexane)
  7. customrepurified by preparative HPLC (55% acetonitrile
  8. additiontreated with a 2 M solution of (trimethylsilyl)diazomethane in hexanes (1 mL)
  9. customThe excess reagent was destroyed by addition of 0.5 mL acetic acid
  10. customthe volatiles were removed by evaporation
  11. washwashed with saturated sodium bicarbonate
  12. washwashed with brine
  13. customdried
  14. customevaporated
  15. customthe product was precipitated as a solid by slow addition of hexane

Sources & evidence

ORD record
ord-6169ea6a81b74dd0934744eb3555c7e5
Source dataset
uspto-grants-2013_04
Patent number
US08426591B2

Reaction notes

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