反应详情

温度

60 °C

On a larger scale, 6-bromo-4-(oxan-4-ylamino)quinoline-3-carboxylic acid (2011 g, (2005 g active), 5.71 mol) was added to the vessel with DMF (18.2 L). Triethylamine (4.7 L, 33.72 mol) was added with an endotherm observed from 21-18° C. Diphenyl phosphorazidate (1600 mL, 7.42 mol) was added over 10 minutes with an observed exotherm from 21° C. to 23° C. over the addition. The exotherm continued with the batch reaching 55° C. after 1 h (jacket held at 30° C.) with gas evolution. The reaction initially went into solution with a precipitate then forming after ˜30 minutes. Once the temperature had stabilised the batch was analysed by HPLC showing consumption of starting material and 99% product. The batch was heated to 60° C. for h with HPLC again indicating consumption of starting material and 98% product. The batch was concentrated in vacuo to a minimum volume (˜3 volumes) and the residue added to water (17 L) rinsing in with a further portion of water (10 L). The mixture was slurried for 1 h and filtered, washing with water (2×17 L). The solid was then returned to the vessel and slurried in sat. NaHCO3 solution (10 L) and MeOH (495 ml) for 1 h. The solid was collected by filtration, washing with water (2×3.5 L) and then oven dried in vacuo at 40° C. for 116 h to obtain 2023 g of desired material. Analytical data was consistent with that obtained from previous batches.

1. customobserved from 21-18° C
2. custom(jacket held at 30° C.)
3. customThe reaction
4. customthen forming after ˜30 minutes
5. customconsumption of starting material and 99% product
6. customconsumption of starting material and 98% product
7. concentrationThe batch was concentrated in vacuo to a minimum volume (˜3 volumes)
8. additionthe residue added to water (17 L)
9. washrinsing in with a further portion of water (10 L)
10. waitThe mixture was slurried for 1 h
11. filtrationfiltered
12. washwashing with water (2×17 L)
13. waitMeOH (495 ml) for 1 h
14. filtrationThe solid was collected by filtration
15. washwashing with water (2×3.5 L)
16. customoven dried in vacuo at 40° C. for 116 h