反应详情

温度

40 °C

To a 200 L Hastelloy reactor heated to 40° C. was added sulfolane (22.4 L) and N-((3R,4R)-4-fluoropyrrolidin-3-yl)-3-(methylsulfonyl)propanamide (4.03 kg, 16.9 mol, 1.05 eq) and stirred the resulting mixture until all solids were dissolved. To this solution was added 2-fluoro-N-(3-methoxy-1-methyl-1H-pyrazol-4-yl)-9-methyl-9H-purin-6-amine (4.47 kg, 16.1 mol, 1.00 eq) and N,N-diisopropylethylamine (8.50 L, 48.7 mol, 3.0 eq) and the mixture heated at 115° C. for 16 hr. The reaction mixture was cooled to 30° C., and a solution of potassium hydroxide (2.26 kg, 40.3 mol, 2.5 eq) in water (44.7 L) was added. After stirring for 4 hr, the reaction mixture was cooled to 20° C., water (44.7 L) was added and the resulting mixture granulated for 12 hr. The crude product was isolated on a Nutsche filter and washed with water (27 L) and then dried under nitrogen on the filter. The reactor was cleaned and then charged with water (35.8 L) and acetone (53.6 L). The crude product cake was charged back into the reactor and heated to 60° C. until all of the solids had dissolved. The batch was then cooled to 40° C. and then transferred into a speck free 100 L reactor via an in-line 10 μm filter. The 200 L reactor, line and filter were rinsed with acetone (5 L) and sent into the 100 L reactor. The batch was concentrated with the jacket temperature set at 70° C. under partial vacuum until the acetone content reduced to 5 wt %, as determined by gas chromatography head space. The batch was then cooled to 20° C. and granulated for 4 hr. The product was filtered, washed with water (18 L) and dried in a vacuum oven at 55° C. for 8 hr. The title compound (3.942 kg, 9.49 mol, 59%) was isolated as a white crystalline solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.44 (d, J=6.5 Hz, 1 H) 7.97 (s, 1 H) 7.82 (s, 1 H) 7.78 (s, 1 H) 6.23 (dd, J=10.0, 17.0 Hz, 1 H) 6.14 (dd, J=2.8, 17.0 Hz, 1 H) 5.62 (dd, J=2.8, 10.0 Hz, 1 H) 5.12 (d, J=51.0 Hz, 1 H) 4.46 (td, J=6.0, 11.9 Hz, 1 H) 3.88-3.6 (m, 4 H) 3.82 (s, 3 H) 3.71 (s, 3 H) 3.62 (s, 3 H). m/z (APCI+) for C18H23FN9O2 416.3 (M+H)+.

1. dissolutionwere dissolved
2. temperaturethe mixture heated at 115° C. for 16 hr
3. temperatureThe reaction mixture was cooled to 30° C.
4. stirringAfter stirring for 4 hr
5. temperaturethe reaction mixture was cooled to 20° C.
6. customThe crude product was isolated on a Nutsche
7. filtrationfilter
8. washwashed with water (27 L)
9. customdried under nitrogen on the filter
10. additioncharged with water (35.8 L) and acetone (53.6 L)
11. additionThe crude product cake was charged back into the reactor
12. temperatureheated to 60° C. until all of the solids
13. dissolutionhad dissolved
14. temperatureThe batch was then cooled to 40° C.
15. customtransferred into a speck free 100 L reactor
16. filtrationvia an in-line 10 μm filter
17. filtrationThe 200 L reactor, line and filter
18. washwere rinsed with acetone (5 L)
19. concentrationThe batch was concentrated with the jacket temperature
20. customset at 70° C. under partial vacuum until the acetone content
21. temperatureThe batch was then cooled to 20° C.
22. waitgranulated for 4 hr
23. filtrationThe product was filtered
24. washwashed with water (18 L)
25. customdried in a vacuum oven at 55° C. for 8 hr