Ammonium Chloride → (RS)-5-(3-bromo-phenyl)-5-(4-difluoromethoxy-3-methyl-phenyl)-5,6-dihydro-2H-[1,4]oxazin-3-ylamine

In a vacuum dried flask under an argon atmosphere, a solution of (RS)-5-(3-bromo-phenyl)-5-(4-difluoromethoxy-3-methyl-phenyl)-morpholin-3-one (2.5 g, 1 eq) in dichloromethane (80 ml) was treated with trimethyloxonium tetrafluoroborate (2.7 g, 3 eq). The reaction mixture was stirred at room temperature overnight. The incomplete reaction was then washed with a saturated solution of sodium hydrogen carbonate (50 ml). The organic layer was dried over sodium sulfate and evaporated. The crude was dissolved in methanol (15 ml) and the solution transferred under an nitrogen atmosphere into a dried pressure tube. After the addition of ammonium chloride (0.182 g, 3.4 mmol) the sealed pressure tube was heated at 100° C. for 16 hours. After cooling, the reaction mixture was filtered and evaporated to dryness, taken up with dichloromethane (30 ml) and filtered again. The solvent was removed and the residue was passed through a SCX (50 g) cartridge, washing with a mixture of dichloromethane and methanol. The product was recovered eluting with a solution of ammonia (2M) in methanol. 1.45 g of the (RS)-5-(3-bromo-phenyl)-5-(4-difluoromethoxy-3-methyl-phenyl)-5,6-dihydro-2H-[1,4]oxazin-3-ylamine were obtained as a white solid (58% of theory). MS (ISP): m/z=412.9 [M+H]+.

1. customIn a vacuum dried flask under an argon atmosphere
2. customThe incomplete reaction
3. washwas then washed with a saturated solution of sodium hydrogen carbonate (50 ml)
4. dry with materialThe organic layer was dried over sodium sulfate
5. customevaporated
6. dissolutionThe crude was dissolved in methanol (15 ml)
7. customthe solution transferred under an nitrogen atmosphere into a dried pressure tube
8. temperaturewas heated at 100° C. for 16 hours
9. temperatureAfter cooling
10. filtrationthe reaction mixture was filtered
11. customevaporated to dryness
12. filtrationfiltered again
13. customThe solvent was removed
14. washwashing with a mixture of dichloromethane and methanol
15. customThe product was recovered
16. washeluting with a solution of ammonia (2M) in methanol

ORD record

ord-b93c2cb4d7c446d0a94378115f3f5d96

Source dataset

uspto-grants-2013_03

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08399459B2