反应详情

温度

-5 °C

Charge a nitrogen-flushed 3 L reactor that equipped with an overhead stirrer, condenser, nitrogen inlet/outlet and rubber septum with 112.14 g (0.63 mol) of N-bromosuccinimide (NBS) and 645 g (725 mL) of tetrahydrofuran. Stir and cool the slurry to −5±3° C. Charge a nitrogen-flushed 1 L round bottom 4-neck flask that equipped with a thermocouple, mechanical stirrer and nitrogen inlet/outlet with 97.26 g (0.6 mol) of 2-amino-4-(trifluoromethyl)pyridine, 4b and 511 g (575 mL) of tetrahydrofuran. Stir to dissolve the 4b. Transfer the 4b solution to the addition funnel on the reactor and add the solution to the NBS slurry over 2 h maintaining an internal temperature of 0±3° C. throughout the addition. Rinse the 1 L flask and addition funnel with 44 g (50 mL) of tetrahydrofuran and add the wash to the reaction mixture. Warm the solution to 20±3° C. over 30 minutes. Check for completeness of the reaction. Quench by charging a solution of 24.6 g of sodium thiosulfate pentahydrate dissolved in 475 mL of water over 10 minutes, maintaining a batch temperature of 20±3° C. throughout the addition. Stir for 1 h after the quench. Concentrate (internal temp=25° C., 50 mbar) to remove tetrahydrofuran. Add 379 g (500 mL) of tert-butyl methyl ether. Stir and warm the resulting solution/suspension to 30±3° C. and stir for 15 minutes. Separate the phases. Wash the extract four times with a solution of 32 g of sodium chloride dissolved in 768 g (768 mL) of water (4×200 mL per wash), separating the phases after each wash. Finally, wash the extract with 150 g (150 mL) of water. Separate the phases. Charge 152 g (200 mL) of tert-butyl methyl ether. Partially concentrate (57±3° C.) to a volume of 350 mL. Cool to 50° C. and add 265 g (350 mL) of tert-butyl methyl ether. Resume the concentration (57±3° C.) until a batch volume of 350 mL is reached. Cool to 50° C. and add 265 g (350 mL) of tert-butyl methyl ether. Again, resume the concentration (57±3° C.) until a batch volume of 350 mL is reached. Cool to 50° C. and add 103 g (150 mL) of tert-butyl methyl ether to raise the batch volume to 500 mL. Charge 1026 g (1500 mL) of heptane over 15 minutes maintaining 45±3° C. throughout the addition. Slowly increase the vacuum and concentrate (internal temp=40° C. to 50° C.) to a batch volume of 1000 mL. Release the vacuum and seed the batch. Resume the distillation, further increase the vacuum (slowly) and concentrate (internal temp=25° C. to 40° C.) to a batch volume of 500 mL. Stir the resulting suspension at 0° C. for 30 min. Filter the solids. Wash the filter cake with 68 g (100 mL) of cold (0° C.) heptane (containing 30 ppm Octastat). Dry the solids (40° C., 50 mbar) for 16 h to afford 109.8 g (78.0% yield) 4a as an orange solid.

1. additionCharge a nitrogen-
2. customflushed 3 L reactor
3. customthat equipped with an overhead stirrer, condenser, nitrogen inlet/outlet
4. additionCharge a nitrogen-
5. customflushed 1 L round bottom 4-neck flask
6. stirringStir
7. temperaturemaintaining an internal temperature of 0±3° C.
8. additionthroughout the addition
9. washRinse
10. additionthe 1 L flask and addition funnel with 44 g (50 mL) of tetrahydrofuran
11. additionadd the
12. washwash to the reaction mixture
13. temperatureWarm the solution to 20±3° C. over 30 minutes
14. customCheck for completeness of the reaction
15. customQuench
16. dissolutiondissolved in 475 mL of water over 10 minutes
17. temperaturemaintaining a batch temperature of 20±3° C.
18. additionthroughout the addition
19. stirringStir for 1 h after the quench
20. concentrationConcentrate (internal temp=25° C., 50 mbar)
21. customto remove tetrahydrofuran
22. additionAdd 379 g (500 mL) of tert-butyl methyl ether
23. stirringStir
24. temperaturewarm the resulting solution/suspension to 30±3° C.
25. stirringstir for 15 minutes
26. customSeparate the phases
27. washWash the
28. extractionextract four times with a solution of 32 g of sodium chloride
29. dissolutiondissolved in 768 g (768 mL) of water (4×200 mL per wash)
30. customseparating the phases after each wash
31. washFinally, wash the
32. extractionextract with 150 g (150 mL) of water
33. customSeparate the phases
34. additionCharge 152 g (200 mL) of tert-butyl methyl ether
35. concentrationPartially concentrate (57±3° C.) to a volume of 350 mL
36. temperatureCool to 50° C.
37. additionadd 265 g (350 mL) of tert-butyl methyl ether
38. concentrationthe concentration (57±3° C.) until a batch volume of 350 mL
39. temperatureCool to 50° C.
40. additionadd 265 g (350 mL) of tert-butyl methyl ether
41. concentrationthe concentration (57±3° C.) until a batch volume of 350 mL
42. temperatureCool to 50° C.
43. additionadd 103 g (150 mL) of tert-butyl methyl ether
44. temperatureto raise the batch volume to 500 mL
45. additionCharge 1026 g (1500 mL) of heptane over 15 minutes
46. temperaturemaintaining 45±3° C. throughout the addition
47. temperatureSlowly increase the vacuum
48. concentrationconcentrate (internal temp=40° C. to 50° C.) to a batch volume of 1000 mL
49. distillationthe distillation
50. temperaturefurther increase the vacuum (slowly) and
51. concentrationconcentrate (internal temp=25° C. to 40° C.) to a batch volume of 500 mL
52. stirringStir the resulting suspension at 0° C. for 30 min
53. filtrationFilter the solids
54. washWash the filter cake with 68 g (100 mL) of cold (0° C.) heptane (containing 30 ppm Octastat)
55. customDry the solids (40° C., 50 mbar) for 16 h