Hydrochloric Acid → 6-Acetyl-3-tert-butoxycarbonylamino-pyrazine-2-carboxylic acid methyl ester

Temperature

0 °C

To a stirred solution of an 1:4 mixture of methyl 3-(bis(tert-butoxycarbonyl)amino)-6-bromopyrazine-2-carboxylate and methyl 6-bromo-3-(tert-butoxycarbonylamino)pyrazine-2-carboxylate (ca. 4.1 g, 11.6 mmol) at rt in toluene (55 ml) under an argon atmosphere were added bis(triphenylpohsphine)palladium(II) chloride (81.1 mg, 0.12 mmol) and 1-ethoxyvinyl tri-N-butyltin (3.0 g, 2.8 ml, 12.7 mmol). The clear yellow solution was heated to reflux and stirring was continued for 18 h. The mixture was cooled to 0° C. 1 N HCl (55 ml) was added dropwise within 15 min. The biphasic mixture was stirred vigourously for 22 h, slowly warming up to rt. The layers were separated. The organic layer was diluted with 150 ml EtOAc (150 ml). Then, a 10% aqueous ammonium fluoride solution (150 ml) was added. The biphasic mixture was then stirred at rt for 5 h and then filtered. The organic phase of the filtrate was washed with 50 ml brine, dried (MgSO4), filtered and concentrated. The product was purified by silica gel chromatography using a n-heptane/ethyl acetate gradient. The product-containing fractions were concentrated. The residue was triturated with n-heptane/cyclohexane 9:1 (20 ml). The suspension was stirred for 2 hrs. The solid was filtrated, washed with n-heptane and dried to give the title compound (1.54 g, 45%) as off-white solid.

1. temperatureThe clear yellow solution was heated
2. temperatureto reflux
3. stirringThe biphasic mixture was stirred vigourously for 22 h
4. temperatureslowly warming up to rt
5. customThe layers were separated
6. additionThe organic layer was diluted with 150 ml EtOAc (150 ml)
7. additionThen, a 10% aqueous ammonium fluoride solution (150 ml) was added
8. stirringThe biphasic mixture was then stirred at rt for 5 h
9. filtrationfiltered
10. washThe organic phase of the filtrate was washed with 50 ml brine
11. dry with materialdried (MgSO4)
12. filtrationfiltered
13. concentrationconcentrated
14. customThe product was purified by silica gel chromatography
15. concentrationThe product-containing fractions were concentrated
16. customThe residue was triturated with n-heptane/cyclohexane 9:1 (20 ml)
17. stirringThe suspension was stirred for 2 hrs
18. filtrationThe solid was filtrated
19. washwashed with n-heptane
20. customdried

ORD record

ord-4e8b83c721404ea88fc5e0d1979e912b

Source dataset

uspto-grants-2014_01

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08623866B2