反应详情

A suspension of 5-methoxypyrazine-2-carboxylic acid (26.29 g, 0.17 mol) in N,N′-dimethylimidazoline-2-one (160 mL) was stirred at ambient temperature for 15 min, then cooled to 2.2° C. Thionyl chloride (14.7 mL, 0.202 mol) was added while maintaining temperature under 5° 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-fluorophenyl)-5-(trifluoromethyl)-4a,5,7,7a-tetrahydro-4H-furo[3,4-d][1,3]thiazin-2-amine (52.0 g, 0.155 mol) was dissolved into N,N′-dimethylimidazoline-2-one (160 mL). The resulting solution was added to the solution of acyl chloride while maintaining temperature below 10° C. The reaction mixture was stirred for 30 min. Water (780 mL) was charged while maintaining temperature below 30° C. The resulting mixture was stirred for 30 min, and then EtOAc (780 mL) was added. To this mixture was added, 50% aq. NaOH (84.8 g) until the pH of the aqueous layer reached 11. The aq. layer was extracted with EtOAc (260 mL). The organics were combined, washed with sat. aq. NaCl (260 mL) and water (260 mL). The organics were filtered over Celite pad (26 g) and rinsed with EtOAc (260 mL). The organics were concentrated under vacuum to afford a solid. To the solid was added 1-propanol (728 mL), and the suspension was heated to 75° C. until a clear solution formed. The solution was cooled to −10° C. and held for 1 h. The solid was filtered, rinsed with cold 1-propanol (104 mL) and dried under vacuum (35° C.) until constant weight to afford the title compound (62.1 g, 84.9%). 1H NMR (500 MHz, DMSO) δ ppm 10.56 (s, 2H), 8.88 (d, J=1.2 Hz, 1H), 8.39 (d, J=1.2 Hz, 1H), 7.95-7.83 (m, 2H), 7.18 (dd, J=12.0, 8.8 Hz, 1H), 6.25 (s, 2H), 4.76-4.60 (m, 1H), 4.36 (d, J=8.1 Hz, 1H), 4.01 (s, 3H), 3.88 (dd, J=7.9, 2.3 Hz, 1H), 3.23-3.11 (m, 2H), 2.91 (dd, J=13.8, 3.6 Hz, 1H); 13C NMR (125 MHz, DMSO) δ ppm 162.11, 161.93, 156.13 (d, JCF=242.9 Hz), 149.38, 142.01, 138.35, 135.09, 133.98, 128.53 (d, JCF=11.6 Hz), 126.06 (q, JCF=282.0 Hz), 123.32, 121.93 (d, JCF=8.6 Hz), 116.76 (d, JCF=25.1 Hz), 78.86 (d, JCF=6.9 Hz), 76.94 (q, JCF=30.5 Hz), 66.37, 54.75, 36.44, 23.53.

1. temperaturecooled to 2.2° C
2. temperaturewhile maintaining temperature under 5° 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 resulting mixture was stirred for 30 min
8. additionTo this mixture was added
9. extractionThe aq. layer was extracted with EtOAc (260 mL)
10. washwashed with sat. aq. NaCl (260 mL) and water (260 mL)
11. filtrationThe organics were filtered over Celite pad (26 g)
12. washrinsed with EtOAc (260 mL)
13. concentrationThe organics were concentrated under vacuum
14. customto afford a solid
15. temperaturethe suspension was heated to 75° C. until a clear solution
16. customformed
17. temperatureThe solution was cooled to −10° C.
18. waitheld for 1 h
19. filtrationThe solid was filtered
20. washrinsed with cold 1-propanol (104 mL)
21. customdried under vacuum (35° C.) until constant weight