反应详情

温度

55 °C

A jacketed reactor was charged with (1S,2S,4R)-4-(4-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-(hydroxymethyl)cyclopentanol (30.8 Kg, 115.05 mol), 2-butanol (198.5 Kg), (S)-(+)-1-aminoindane (16.95 Kg, 127.26 mol) and diisopropylethylamine (19.45 Kg, 150.50 mol). The mixture was heated to 55±5° C. and then moved to a mobile vessel. The reactor was then rinsed with 2-butanol (15.6 Kg) at 55±5° C. which was moved to the mobile vessel. The mobile vessel contents were then transferred to a pressure reactor and 2-butanol (51 L) was used to rinse the mobile vessel. The reaction mixture was then heated to 135±5° C. and adjusted to a pressure of 8 bar. The mixture was then stirred until reaction was complete by HPLC analysis. The mixture was cooled to 30±10° C. and transferred to a mobile vessel via a plate filter. The pressure reactor was rinsed with 2-butanol (43.1 L). The contents of the mobile vessel were then charged to a jacketed reactor via an in-line filter and the vessel rinsed with 2-butanol (39.2 Kg). The mixture was heated to 50±5° C. and concentrated under reduced pressure to about 50 L. The mixture was cooled to 20±5° C. and then dichloromethane (256 Kg) added over a period of about 3 hours. The mixture was stirred for a further 9.5 hours and then further cooled to 0±5° C. and stirred for about 4 hours. The solid product was isolated by filtration and washed with dichloromethane (82 Kg) at 0±5° C. The solids were then dried under reduced pressure at 40±5° C. to constant weight. A reactor was charged with water (371 Kg) and the dried solids and the mixture stirred at 20±5° C. for about 14.5 hours. The solid product was isolated by filtration and washed with water (371 Kg). The solids were then dried under reduced pressure at 50±5° C. to afford the title compound (32.4 Kg) as a white solid. 1H NMR (300 MHz, DMSO, 6): 8.15 (s, 1H), 7.71 (d, 1H), 7.07-7.29 (m, 5H), 6.61 (d, 1H), 5.88 (dd, 1H), 5.24-5.38 (m, 1H), 4.60 (d, 1H), 4.26-4.37 (m, 2H), 3.53-3.65 (m, 1H), 3.35-3.46 (m, 1H), 2.90-3.04 (m, 1H), 2.75-2.90 (m, 1H), 2.33-2.56 (m, 2H), 2.04-2.14 (m, 2H), 1.88-2.03 (m, 2H), 1.74-1.87 (m, 1H).

1. custommoved to a mobile vessel
2. washThe reactor was then rinsed with 2-butanol (15.6 Kg) at 55±5° C. which
3. customThe mobile vessel contents were then transferred to a pressure reactor
4. washto rinse the mobile vessel
5. temperatureThe reaction mixture was then heated to 135±5° C.
6. temperatureThe mixture was cooled to 30±10° C.
7. customtransferred to a mobile vessel via a plate
8. filtrationfilter
9. washThe pressure reactor was rinsed with 2-butanol (43.1 L)
10. additionThe contents of the mobile vessel were then charged to a jacketed reactor via
11. filtrationan in-line filter
12. washthe vessel rinsed with 2-butanol (39.2 Kg)
13. temperatureThe mixture was heated to 50±5° C.
14. concentrationconcentrated under reduced pressure to about 50 L
15. temperatureThe mixture was cooled to 20±5° C.
16. additiondichloromethane (256 Kg) added over a period of about 3 hours
17. stirringThe mixture was stirred for a further 9.5 hours
18. temperaturefurther cooled to 0±5° C.
19. stirringstirred for about 4 hours
20. customThe solid product was isolated by filtration
21. washwashed with dichloromethane (82 Kg) at 0±5° C
22. customThe solids were then dried under reduced pressure at 40±5° C. to constant weight
23. additionA reactor was charged with water (371 Kg)
24. stirringthe dried solids and the mixture stirred at 20±5° C. for about 14.5 hours
25. customThe solid product was isolated by filtration
26. washwashed with water (371 Kg)
27. customThe solids were then dried under reduced pressure at 50±5° C.