Water → 5-(Difluoromethoxy)thiazolo[5,4-b]pyridin-2-amine

HRID 250030Notes

Reaction equation

HRID 250030 reaction equation
[S-:1][C:2]#[N:3].[K+].[F:5][CH:6]([F:15])[O:7][C:8]1[N:13]=[CH:12][C:11]([NH2:14])=[CH:10][CH:9]=1.BrBr.O>C(O)(=O)C>[F:15][CH:6]([F:5])[O:7][C:8]1[N:13]=[C:12]2[S:1][C:2]([NH2:3])=[N:14][C:11]2=[CH:10][CH:9]=1

Participants

6

Reactant 4

HCID 962WaterHCID 24408BromineHCID 516872Potassium thiocyanateHCID 450909846-(Difluoromethoxy)pyridin-3-amine

Product 1

HCID 574765555-(Difluoromethoxy)thiazolo[5,4-b]pyridin-2-amineYield 36.1%

Reagents, catalysts & solvents 1

HCID 176Acetic AcidSolvent2×

Procedure

To acetic acid (10 mL) cooled in an ice bath was added potassium thiocyanate (3.18 g, 32.8 mmol) and 6-(difluoromethoxy)pyridin-3-amine (1 g, 4.1 mmol). The reaction was cooled in an ice-salt bath until the reaction temperature reached <0° C. A solution of bromine (0.65 mL, 12.7 mmol) in acetic acid (3 mL) was added dropwise over 2 hours at a rate that maintained the reaction temperature <0° C. This gave a very thick mixture. After the addition was complete, the mixture was left to stir and allowed to slowly warm to room temperature overnight. After stirring overnight, water (5 mL) was added and the mixture was heated to 85° C. in an oil bath. This mixture was then filtered while still hot. The yellow filter cake was returned to the reaction flask, and an additional 5 mL acetic acid was added. The mixture was heated again to 85° C., and then filtered while still hot. The combined filtrates were cooled in an ice bath and neutralized to pH 8 with concentrated ammonium hydroxide. A yellow precipitate formed which was then collected by filtration. This crude material was purified by column chromatography (12-100% ethyl acetate/hexanes) to afford 5-(difluoromethoxy)thiazolo[5,4-b]pyridin-2-amine (321 mg, 1.48 mmol, 36.1% yield) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 7.64-7.81 (m, 2 H), 6.92 (d, J=8.53 Hz, 1 H). MS (LC/MS) R.T.=1.66; [M+H]+=218.10.

Workup

  1. temperatureThe reaction was cooled in an ice-salt bath until the reaction temperature
  2. customreached <0° C
  3. temperaturemaintained the reaction temperature <0° C
  4. customThis gave a very thick mixture
  5. additionAfter the addition
  6. waitthe mixture was left
  7. stirringAfter stirring overnight
  8. temperaturethe mixture was heated to 85° C. in an oil bath
  9. filtrationThis mixture was then filtered while still hot
  10. additionan additional 5 mL acetic acid was added
  11. temperatureThe mixture was heated again to 85° C.
  12. filtrationfiltered while still hot
  13. temperatureThe combined filtrates were cooled in an ice bath
  14. customA yellow precipitate formed which
  15. filtrationwas then collected by filtration
  16. customThis crude material was purified by column chromatography (12-100% ethyl acetate/hexanes)

Sources & evidence

ORD record
ord-cec2410f62ad47f8882e21aa4d284e56
Source dataset
uspto-grants-2011_01
Patent number
US07863291B2

Reaction notes

Loading…