Hydrochloric Acid → HCID 59126910, compound

HRID 1969360Notes

Reaction equation

HRID 1969360 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(C(O)=O)[C:3]=1Br.[CH3:22][S-:23].[Na+].[C:25]([O:28][CH2:29]C)(=[O:27])[CH3:26].Cl>CN(C=O)C.O>[CH3:29][O:28][C:25]([C:26]1[C:3]([S:23][CH3:22])=[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:27]

Participants

7

Reactant 4

HCID 313Hydrochloric AcidHCID 8857Ethyl AcetateHCID 4378561Sodium methanethiolateHCID 66953945HCID 66953945, compound

Product 1

HCID 59126910HCID 59126910, compoundYield 12.7%

Reagents, catalysts & solvents 2

HCID 962WaterSolventHCID 6228DimethylformamideSolvent

Conditions

Temperature
50 °C

Procedure

6-Amino-5-bromo-2-(4-chloro-2-fluoro-3-methoxyphenyl)-pyrimidine-4-carboxylic acid (830 mg, 2.2 mmol; see WO 2007/082076 A1 for preparation) was combined with sodium methanthiolate (470 mg, 6.7 mmol) and cuprous iodide (1.6 g, 8.3 mmol) in 12 mL dry DMF and heated to 50° C. After heating for 4 h, the mixture was cooled, taken up in water and ethyl acetate and acidified with 2M HCl. A small amount of solid was removed by filtration and the separated aqueous phase was extracted again with ethyl acetate. The combined organic phases were washed twice with water, washed once with brine, dried and evaporated. The crude product was dissolved in 7 mL THF and 5 L methanol and treated with 1.5 mL of 2.0M (trimethylsilyl)diazomethane and stirred at room temperature for 30 min A few drops of acetic acid were added to destroy excess reagent. The reaction solution was heated briefly to reflux and then concentrated. The product was purified by flash chromatography on silica gel (ethyl acetate/hexane gradient with 2% acetic acid) to yield the title compound (100 mg, 12.7% yield): 1H NMR (CDCl3): δ 7.65 (m, 1H), 7.23 (m, 1H), 5.98 (br s, 2H), 4.00 (s, 3H), 3.99 (d, 3H), 2.35 (s, 3H).

Workup

  1. temperatureAfter heating for 4 h
  2. temperaturethe mixture was cooled
  3. customA small amount of solid was removed by filtration
  4. extractionthe separated aqueous phase was extracted again with ethyl acetate
  5. washThe combined organic phases were washed twice with water
  6. washwashed once with brine
  7. customdried
  8. customevaporated
  9. dissolutionThe crude product was dissolved in 7 mL THF
  10. addition5 L methanol and treated with 1.5 mL of 2.0M (trimethylsilyl)diazomethane
  11. additionwere added
  12. customto destroy excess reagent
  13. temperatureThe reaction solution was heated briefly
  14. temperatureto reflux
  15. concentrationconcentrated
  16. customThe product was purified by flash chromatography on silica gel (ethyl acetate/hexane gradient with 2% acetic acid)

Sources & evidence

ORD record
ord-d715f2834ca54123a5b0521a9312d9d6
Source dataset
uspto-grants-2013_04
Patent number
US08426591B2

Reaction notes

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