2-Methyltetrahydrofuran → Azd-1656

Temperature

5 °C

To a flask fitted with overhead stirrer, thermometer, condenser, and nitrogen line was added 3-{[5-(azetidin-1-ylcarbonyl)pyrazin-2-yl]oxy}-5-[(1S)-2-methoxy-1-methylethoxy]benzoic acid (1.0 eq), 5-methylpyrazin-2-amine (1.12 eq) and 2-methyltetrahydrofuran (4.4 vols) under a nitrogen atmosphere. The mixture was cooled to 5° C., and then N-methylmorpholine (5.0 eq) added drop-wise over at least 15 minutes maintaining the temperature at 5±5° C. 1-Propanephosphonic acid cyclic anhydride (T3P) (as 50% w/w solution in ethyl acetate) (2.5 eq) was added drop-wise over at least 15 minutes maintaining the temperature at 5±5° C. The mixture was heated to reflux for at least 16 hours then cooled to 22±5° C. Water (4.0 vols) was added to the reaction mixture, followed by 2-methyltetrahydrofuran (4.0 vols). After agitating for 30 minutes, the mixture was separated. The upper organic layer was retained and the aqueous layer treated with 2-methyltetrahydrofuran (4.0 vols). After agitating for 30 minutes, this mixture was separated. The organic layers were combined and further 2-methyltetrahydrofuran (6.0 vols) was then added. The mixture was agitated, and 1.0N hydrochloric acid (4.0 vols) was added. The mixture was agitated for at least 30 minutes at 22±5° C., and the layers were then separated. The organic layer was treated with 1.0N hydrochloric acid (4.0 vols) then the mixture was agitated for at least 30 minutes at 22±5° C., then the layers were separated. The organic layer was treated with 5% w/w sodium hydrogen carbonate (4.0 vols). The mixture was agitated for at least 30 minutes at 22±5° C., the layers were separated. The organic layer was treated again with 5% w/w sodium hydrogen carbonate (4.0 vols) following the same procedure, and then with water (4.0 vols) following the same procedure. The organic layer was then distilled at atmospheric pressure to a pot volume of 4.7 vols. Methyl iso-butylketone (10 vols) was added, and the batch distilled at atmospheric pressure to a pot volume of 4.68 vols. Methyl iso-butylketone (10 vols) was added, and the batch distilled at atmospheric pressure to a pot volume of 4.68 vols. The batch was cooled to 70° C., heptane (2.02 vols) was added slowly drop-wise over at least 30 minutes maintaining the reaction temperature at 70±5° C. The mixture was cooled to 60° C., and seeded with 3-{[5-(azetidin-1-ylcarbonyl)pyrazin-2-yl]oxy}-5-[(1S)-2-methoxy-1-methylethoxy]-N-(5-methylpyrazin-2-yl)benzamide Form 1, agitated at 60° C. for 1 hour, cooled to 50° C. at 0.1° C., agitated at 50° C. for 140 minutes, then cooled to 22° C. at 0.1° C./minute. The mixture was held at 22° C. for at least 12 hours. Heptane (5.06 vols) was then added—drop-wise over at least 120 minutes maintaining the batch temperature at a temperature at 22±5° C. The mixture was cooled to 0° C. at 0.1° C./minute then held at 0° C. for at least 12 hours and then filtered. The isolated solid was washed with a mixture of methyl iso-butylketone (1.0 vols) and heptane (3.0 vols) pre-chilled to 0° C. The solid was dried at 40° C. After drying in the vacuum oven at 40° C. overnight, the desired product was obtained as a solid (corrected yield 85%. 1H NMR δ (400 MHz DMSO) 11.04 (s, 1H), 9.26 (s, 1H), 8.68 (s, 1H), 8.57 (s, 1H), 8.36 (s, 1H), 7.56 (s, 1H), 7.46 (s, 1H), 7.12 (s, 1H), 4.81-4.77 (m, 1H), 4.58-4.54 (t, 2H), 4.11-4.07 (t, 2H), 3.55-3.47 (m, 2H), 3.3 (s, 3H), 2.48 (s. 3H), 2.34-2.26 (m, 2H), 1.26-1.25 (d, 3H)

1. customTo a flask fitted with overhead stirrer
2. temperaturemaintaining the temperature at 5±5° C
3. temperaturemaintaining the temperature at 5±5° C
4. temperatureThe mixture was heated
5. temperatureto reflux for at least 16 hours
6. temperaturethen cooled to 22±5° C
7. customthe mixture was separated
8. additionthe aqueous layer treated with 2-methyltetrahydrofuran (4.0 vols)
9. stirringAfter agitating for 30 minutes
10. customthis mixture was separated
11. additionfurther 2-methyltetrahydrofuran (6.0 vols) was then added
12. stirringThe mixture was agitated
13. addition1.0N hydrochloric acid (4.0 vols) was added
14. stirringThe mixture was agitated for at least 30 minutes at 22±5° C.
15. customthe layers were then separated
16. additionThe organic layer was treated with 1.0N hydrochloric acid (4.0 vols)
17. stirringthe mixture was agitated for at least 30 minutes at 22±5° C.
18. customthe layers were separated
19. additionThe organic layer was treated with 5% w/w sodium hydrogen carbonate (4.0 vols)
20. stirringThe mixture was agitated for at least 30 minutes at 22±5° C.
21. customthe layers were separated
22. additionThe organic layer was treated again with 5% w/w sodium hydrogen carbonate (4.0 vols)
23. distillationThe organic layer was then distilled at atmospheric pressure to a pot volume of 4.7 vols
24. additionMethyl iso-butylketone (10 vols) was added
25. distillationthe batch distilled at atmospheric pressure to a pot volume of 4.68 vols
26. additionMethyl iso-butylketone (10 vols) was added
27. distillationthe batch distilled at atmospheric pressure to a pot volume of 4.68 vols
28. temperatureThe batch was cooled to 70° C.
29. additionheptane (2.02 vols) was added slowly drop-wise over at least 30 minutes
30. temperaturemaintaining the reaction temperature at 70±5° C
31. temperatureThe mixture was cooled to 60° C.
32. stirringagitated at 60° C. for 1 hour
33. temperaturecooled to 50° C. at 0.1° C.
34. stirringagitated at 50° C. for 140 minutes
35. temperaturecooled to 22° C. at 0.1° C./minute
36. waitThe mixture was held at 22° C. for at least 12 hours
37. additionHeptane (5.06 vols) was then added—drop-wise over at least 120 minutes
38. temperaturemaintaining the batch temperature at a temperature at 22±5° C
39. temperatureThe mixture was cooled to 0° C. at 0.1° C./minute
40. waitthen held at 0° C. for at least 12 hours
41. filtrationfiltered
42. washThe isolated solid was washed with a mixture of methyl iso-butylketone (1.0 vols) and heptane (3.0 vols)
43. temperaturepre-chilled to 0° C
44. customThe solid was dried at 40° C
45. customAfter drying in the vacuum oven at 40° C. overnight

ORD record

ord-91e50f9ec1224ffc9af7d9dd2b6192f7

Source dataset

uspto-grants-2012_01

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08093252B2