反应详情

温度

30.5 °C

Into a reactor was added 3 (15.0 kg, 38.4 mol), 7 (7.2 kg, 46.4 mol) and cyclohexane (230 L). The suspension was degassed three times for at least 3 min each time using a vacuum-nitrogen cycle. Diethylamine (8.6 kg, 119 mol) was added and the reaction mixture was heated to 28 to 33° C. Dichlorobis(triphenylphosphine)palladium (II) (0.134 kg, 0.192 mol) and copper (II) iodide (0.037 kg, 0.192 mol) were added and the mixture was stirred at 28 to 33° C. for at least 15 h until ≧99.0% conversion was obtained by HPLC analysis. Water (68 L) followed by MTBE (92 L) were added. The reaction mixture was heated to 45 to 50° C. and stirred for a minimum of 30 min and until all solids fully dissolved. The phases were separated at 45 to 50° C. and the organic phase was washed with water (2×68 L) at 45 to 50° C. The resulting organic phase was filtered and the reactor was rinsed with MTBE (32 L) at 45 to 50° C. The rinse was then transferred to the second reactor containing the filtrate via the filter membrane. The combined filtrate was concentrated under vacuum using a jacket temperature of 45 to 50° C. until 225 kg remained in the reactor. The mixture was cooled to 35 to 40° C. and a slurry of seed crystals (10 g of 8 in 500 mL cyclohexane) was added. The reaction mixture was stirred for 60 min at 35 to 40° C. and concentrated under vacuum using a jacket temperature of 45 to 50° C. until 144 kg remained in the reactor. The mixture was cooled to 18 to 23° C. over a minimum of 2 h and stirred for an additional 2 h at 18 to 23° C. The resulting suspension was filtered and washed with cyclohexane (2×53 L). The wet cake was dried under vacuum at 40 to 45° C. to provide 16.0 kg (80% yield) of 8. 1H NMR (300 MHz, CDCl3) δ 7.72 (s, 1H), 7.41 (m, 3H), 6.77 (m, 2H), 4.43 (s, 1H), 3.88 (d, J=5.3 Hz, 2H), 3.74 (s, 3H), 1.46 (s, 9H); MS (ESI) m/z 318.4 (M+H+-Boc, 23%), 362.4 (M+H+-t-butyl cation, 20%).

1. customThe suspension was degassed three times for at least 3 min each time
2. customwas obtained by HPLC analysis
3. additionwere added
4. temperatureThe reaction mixture was heated to 45 to 50° C.
5. stirringstirred for a minimum of 30 min and until all solids
6. dissolutionfully dissolved
7. customThe phases were separated at 45 to 50° C.
8. washthe organic phase was washed with water (2×68 L) at 45 to 50° C
9. filtrationThe resulting organic phase was filtered
10. washthe reactor was rinsed with MTBE (32 L) at 45 to 50° C
11. additioncontaining the filtrate via the filter membrane
12. concentrationThe combined filtrate was concentrated under vacuum
13. customa jacket temperature of 45 to 50° C.
14. temperatureThe mixture was cooled to 35 to 40° C.
15. additiona slurry of seed crystals (10 g of 8 in 500 mL cyclohexane) was added
16. stirringThe reaction mixture was stirred for 60 min at 35 to 40° C.
17. concentrationconcentrated under vacuum
18. customa jacket temperature of 45 to 50° C.
19. temperatureThe mixture was cooled to 18 to 23° C. over a minimum of 2 h
20. stirringstirred for an additional 2 h at 18 to 23° C
21. filtrationThe resulting suspension was filtered
22. washwashed with cyclohexane (2×53 L)
23. customThe wet cake was dried under vacuum at 40 to 45° C.