Sodium Hydroxide → 5,11-Dihydro-11-ethyl-5-methyl-8-{2-(4-quinolinyloxy)ethyl}-6H-dipyrido[3,2-b:2',3'-e][1,4]diazepin-6-one

3.47 g NaOH and 40 ml toluene were charged into a three-neck flask equipped with temperature couple and addition funnel. The mixture was brought to 20° C. Next, 10.02 g of N-(2-chloro(3-pyridyl))[2-(ethylamino)-5-(2-(4-quinolyloxy)ethyl)(3-pyridyl)]-N-methylcarboxamide and 0.7 g tetrabutylammonium bromide were dissolved in 50 ml of toluene at 60-70° C. and allowed to cool to room temperature. The solution of N-(2-chloro(3-pyridyl))[2-(ethylamino)-5-(2-(4-quinolyloxy)ethyl)(3-pyridyl)]-N-methylcarboxamide and TBAB was charged to the addition funnel and slowly added to the slurry from NaOH in Toluene. The reaction mixture was kept at 20-30° C. and stirred overnight. Reaction monitoring was performed with HPLC. During the reaction the product crystallized from the reaction mixture. In the event that the reaction had not completed after 16 h the reaction mixture was heated up to 30° C. and kept there until the reaction was complete. The reaction mixture was quenched with 25 ml saturated NH4Cl solution. A temperature increase from 20.8° C. to 25.5° C. was observed. The reaction mixture was heated to 85-90° C. The precipitate dissolved upon heating and a slow release of a gas (Ammonia) was observed. Phase separation at 85-90° C. was performed. The lower aqueous layer was analyzed for product and pH (target: pH=6) and then discarded. 41 ml of toluene/water (about 40 ml toluene, 1 ml water) was azeotropically distilled off the solution under reduced pressure. The solution was slowly cooled to room temp., then to 0° C. and stirred for at least 30 min at 0° C. to complete crystallization. The crystals were collected by filtration and washed twice with 10 ml of cooled toluene at 0° C. Crude Yield: 8.436 g; yellowish to off-white crystals. The off-white to yellow product was dried at 50° C. under vacuum over night.

1. customequipped with temperature couple and addition funnel
2. customwas brought to 20° C
3. customwas kept at 20-30° C.
4. customReaction monitoring
5. customDuring the reaction the product
6. customcrystallized from the reaction mixture
7. waitIn the event that the reaction had not completed after 16 h
8. temperaturethe reaction mixture was heated up to 30° C.
9. customThe reaction mixture was quenched with 25 ml saturated NH4Cl solution
10. temperatureA temperature increase from 20.8° C. to 25.5° C.
11. temperatureThe reaction mixture was heated to 85-90° C
12. dissolutionThe precipitate dissolved
13. temperatureupon heating
14. customPhase separation at 85-90° C.
15. distillation41 ml of toluene/water (about 40 ml toluene, 1 ml water) was azeotropically distilled off the solution under reduced pressure
16. temperatureThe solution was slowly cooled to room temp.
17. stirringto 0° C. and stirred for at least 30 min at 0° C.
18. customcrystallization
19. filtrationThe crystals were collected by filtration
20. washwashed twice with 10 ml of cooled toluene at 0° C
21. customThe off-white to yellow product was dried at 50° C. under vacuum over night

ORD record

ord-81e9e0609a0c457e9488066a7641f788

Source dataset

uspto-grants-2007_10

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US07282583B2