反应详情

A suspension of 5-methoxypyrazine-2-carboxylic acid (4.01 g, 0.026 mol, 1.10 equiv.) in N,N′-dimethylimidazoline-2-one (22.5 mL) was stirred at ambient temperature for 15 min, then cooled to 0° C. Thionyl chloride (2.24 mL, 0.031 mol, 1.3 equiv.) was added while maintaining temperature under 10° C. The resulting suspension was stirred at 0-10° C. for 2 h while it transitioned to a clear solution. In another vessel, (4aS,5S,7aS)-7a-(5-amino-2,3-difluorophenyl)-5-(fluoromethyl)-4a,5,7,7a-tetrahydro-4H-furo[3,4-d][1,3]thiazin-2-amine (7.60 g, 0.024 mol, 1.0 equiv.) was dissolved into N,N′-dimethylimidazoline-2-one (22.5 mL). The resolution solution was added to the solution of acyl chloride while maintaining temperature below 10° C. The reaction mixture was stirred for 30 min. Water (112 mL) was charged while maintaining temperature below 30° C. The resolution mixture was stirred for 30 min., and then EtOAc (112 mL) was added. To this mixture was added, 50% aq. NaOH (10.0 g) until the pH of the aqueous layer reached 11. The aq. layer was extracted with EtOAc (75 mL). The organics were combined, washed with sat. aq. NaCl (38 mL) and water (38 mL). The organics were filtered over a pad of silica gel (15 g) and rinsed with EtOAc (37.5 mL). The organics were concentrated under vacuum to afford a solid. To the solid was added 1-propanol (112 mL), and the suspension was heated to 100° C. The mixture was cooled to −10° C. and held for 1 h. The solid was filtered, rinsed with cold 1-propanol (15 mL) and dried under vacuum (35° C.) until constant weight to afford the title compound (8.18 g). 1H NMR (500 MHz, DMSO) δ ppm 10.73 (s, 1H), 8.88 (d, =0.8 Hz, 1H), 8.39 (d, J=0.9 Hz, 1H), 8.11-7.87 (m, 1H), 7.73 (d, J=5.0 Hz, 1H), 6.07 (s, 2H), 4.68-4.44 (m, 2H), 4.41-4.28 (m, 1H), 4.23 (d, J=8.3 Hz, 1H), 4.01 (s, 3H), 3.82 (dd, J=8.1, 2.4 Hz, 1H), 3.18 (dd, J=13.5, 3.5 Hz, 1H), 3.01 (dd, J=13.5, 3.8 Hz, 1H), 2.77-2.69 (m, 1H); 13C NMR (125 MHz, DMSO) δ ppm 162.24, 162.20, 150.05 (dd, JCF=242.1, 14.4 Hz), 149.37, 144.42 (dd, JCF=245.5, 13.7 Hz), 142.18, 138.09, 134.73 (dd, JCF=10.3, 2.7 Hz), 134.03, 133.22 (d, JCF=9.1 Hz), 116.6, 108.42 (d, JCF=22.4 Hz), 83.98 (d, JCF=169.9 Hz), 79.21 (d, JCF=18.2 Hz), 77.96 (d, JCF=5.2 Hz), 66.26, 54.78, 36.23, 23.64.

1. temperaturecooled to 0° C
2. temperaturewhile maintaining temperature under 10° C
3. stirringThe resulting suspension was stirred at 0-10° C. for 2 h while it
4. temperaturewhile maintaining temperature below 10° C
5. stirringThe reaction mixture was stirred for 30 min
6. temperaturewhile maintaining temperature below 30° C
7. stirringThe resolution mixture was stirred for 30 min.
8. additionTo this mixture was added
9. extractionThe aq. layer was extracted with EtOAc (75 mL)
10. washwashed with sat. aq. NaCl (38 mL) and water (38 mL)
11. filtrationThe organics were filtered over a pad of silica gel (15 g)
12. washrinsed with EtOAc (37.5 mL)
13. concentrationThe organics were concentrated under vacuum
14. customto afford a solid
15. temperaturethe suspension was heated to 100° C
16. temperatureThe mixture was cooled to −10° C.
17. waitheld for 1 h
18. filtrationThe solid was filtered
19. washrinsed with cold 1-propanol (15 mL)
20. customdried under vacuum (35° C.) until constant weight