反应详情

温度

10 °C

Thiol 9a (10.5 kg, 54.6 mol) was added to a vessel and suspended in DCM (141 kg). Oxalyl chloride (10.4 kg, 82.3 mol) was added (slightly endothermic) followed by DMF (40.0 kg, 547 mol) over 1.25 h, such that the batch temperature was ≦25° C. The batch was aged at 20° C. for approximately 30 min, HPLC analysis showed reaction to be complete. The batch was cooled to 10° C. then triethylamine (16.64 kg, 164.4 mol) was added via a sub-surface sample line at such a rate as to maintain a batch temperature of ≦10° C. A sub-surface addition protocol was required to prevent build up of triethylamine hydrochloride solid on the walls of the vessel. The batch was cooled to 0° C., then a solution of N-Boc-ethylenediamine (10.5 kg, 61.2 mol) in DCM (10 kg) was added such that the batch temperature was ≦10° C. The reaction was warmed to 20° C. and stirred for 2.5 h, HPLC analysis showed the reaction to be complete. Water (63.6 kg) was charged to the batch and the mixture stirred for 5 min. The layers were separated and the aqueous phase re-extracted with DCM (42.2 kg). The organic solutions were then combined and approximately half of the total DCM volume was distilled from the batch under vacuum whilst maintaining a temperature of ≦40° C. MeCN (83.3 kg) was then added and the remaining DCM removed by distillation (0.5 mol % DCM left by 1H NMR wrt MeCN). MVK (4.61 kg, 65.8 mol) was added to the batch followed by DBU (4.17 kg, 27.4 mol) such that the temperature was ≦20° C. The batch was aged for 10 h at 20° C. then analyzed by HPLC. The reaction was then diluted with water (42.4 kg) and aged for a further 30 min. The mixture was filtered and the slurry washed with MeCN (33.3 kg). The solid was washed with MeCN (˜10 L) then dried in a vacuum oven (T=60° C.) for 22 h. MVK adduct 10 (15.5 kg) was isolated as an off-white solid. mp 145-148° C. 1H NMR (400 MHz, CDCl3): δ 7.24 (d, 1H, J=2.3 Hz), 7.09 (d, 1H, J=8.5 Hz), 6.91 (dd, 1H, J=8.5, 2.3 Hz), 5.06 (s, 1H, br), 3.73 (t, 2H, J=6.7 Hz), 3.63 (t, 2H, J=6.1 Hz), 3.37 (d, 2H, br), 2.89 (t, 2H, J=6.7 Hz), 2.14 (s, 3H), 1.33 (s, 9H). 13C NMR (100.6 MHz, CDCl3): δ 206.7, 163.0, 156.0, 147.4, 144.6, 129.2, 120.3, 116.6, 109.2, 79.4, 49.3, 44.3, 41.9, 39.1, 30.2, 28.3. HRMS (ESI): m/z [M++H] calcd for C18H24ClN3O4: 382.1534; found: 382.1544.

1. customwas ≦25° C
2. customreaction
3. temperatureto maintain a batch temperature of ≦10° C
4. additionA sub-surface addition protocol
5. temperatureThe batch was cooled to 0° C.
6. customwas ≦10° C
7. temperatureThe reaction was warmed to 20° C.
8. customthe reaction
9. stirringthe mixture stirred for 5 min
10. customThe layers were separated
11. extractionthe aqueous phase re-extracted with DCM (42.2 kg)
12. distillationapproximately half of the total DCM volume was distilled from the batch under vacuum whilst
13. temperaturemaintaining a temperature of ≦40° C
14. additionMeCN (83.3 kg) was then added
15. customthe remaining DCM removed by distillation (0.5 mol % DCM left by 1H NMR wrt MeCN)
16. additionMVK (4.61 kg, 65.8 mol) was added to the batch
17. customwas ≦20° C
18. waitThe batch was aged for 10 h at 20° C.
19. waitaged for a further 30 min
20. filtrationThe mixture was filtered
21. washthe slurry washed with MeCN (33.3 kg)
22. washThe solid was washed with MeCN (˜10 L)
23. customthen dried in a vacuum oven (T=60° C.) for 22 h