Réaction #155562

Équation de réaction

Pyrimidin-5-ylboronic acid

cesium carbonate

DCM

tert-Butyl ((4aS,5S,7aS)-7a-(5-bromo-2,4-difluorophenyl)-5-(fluoromethyl)-4a,5,7,7a-tetrahydro-4H-furo[3,4-d][1,3]thiazin-2-yl)carbamate

TFA

→

title compound

(4aS,5S,7aS)-7a-(2,4-difluoro-5-(pyrimidin-5-yl)phenyl)-5-(fluoromethyl)-4a,5,7,7a-tetrahydro-4H-furo[3,4-d][1,3]thiazin-2-amine

Solvants

water

EtOH

DME

Conditions de réaction

Traitement

1. 1
   TempératureThe reaction was cooled to room temperature
2. 2
   Autrepartitioned between DCM and saturated aqueous NaHCO3
3. 3
   AutreThe layers were separated
4. 4
   Extractionthe aqueous layer was extracted with DCM (×2)
5. 5
   Séchagedried (MgSO4)
6. 6
   Concentrationconcentrated in vacuo
7. 7
   AutreThe residue was purified by column chromatography (Biotage SNAP 10 g, 12 mL/min eluting with 20-80% EtOAc in n-hexane)
8. 8
   AutreThe solvents were removed in vacuo
9. 9
   Lavagewashing with MeOH
10. 10
    ConcentrationThe basic fractions were concentrated in vacuo
11. 11
    Autrethe residue was purified by column chromatography (Biotage SNAP 10 g, 12 mL/min gradient 0-20% MeOH in EtOAc)

Mode opératoire

tert-Butyl ((4aS,5S,7aS)-7a-(5-bromo-2,4-difluorophenyl)-5-(fluoromethyl)-4a,5,7,7a-tetrahydro-4H-furo[3,4-d][1,3]thiazin-2-yl)carbamate (100 mg, 0.21 mmol) was dissolved in DME (1.5 mL), EtOH (0.7 mL) and water (0.5 mL). The solution was heated to 100° C. Pyrimidin-5-ylboronic acid (51.5 mg, 0.416 mmol), bis(triphenylphosphine)palladium (II) chloride (29.2 mg, 0.042 mmol) and cesium carbonate (406 mg, 1.25 mmol) were added and the reaction was stirred at 100° C. for 45 minutes. The reaction was cooled to room temperature and partitioned between DCM and saturated aqueous NaHCO3. The layers were separated and the aqueous layer was extracted with DCM (×2). The organic layers were combined, dried (MgSO4) and concentrated in vacuo. The residue was purified by column chromatography (Biotage SNAP 10 g, 12 mL/min eluting with 20-80% EtOAc in n-hexane). The material was stirred in DCM (2 mL, 31.08 mmol) and TFA (2 mL) for 1 hour at room temperature. The solvents were removed in vacuo. The residue was passed over a 5 g SCX cartridge, washing with MeOH then 2N NH3/MeOH. The basic fractions were concentrated in vacuo and the residue was purified by column chromatography (Biotage SNAP 10 g, 12 mL/min gradient 0-20% MeOH in EtOAc) to leave the title compound as a white solid.

Source