Methanol → 4-Amino-8-bromo-N-propylcinnoline-3-carboxamide

Temperature

90 °C

A 22 L, 3-necked flask equipped with a mechanical stirrer, thermometer, nitrogen inlet, reflux condenser, and addition funnel was charged with N-propyl-2-cyano-2-[(2-bromophenyl)hydrazono]acetamide (195.4 g, 0.632 mol) in toluene (4 L). Aluminum chloride (295 g, 2.21 mol) was added in three portions. The mixture was heated with a mantle to 90° C. in approximately 30 minutes. After 2.5 hours, the heat was removed and the reaction mixture was allowed to cool to room temperature overnight. The reaction mixture was cooled in an ice bath to ≦10° C. and celite was added. Water (680 mL) was added dropwise over 1 hr at ≦10° C. After stirring for 30 minutes, methylene chloride was added (8 L). The reaction mixture was cooled to ≦10° C. and 10% sodium hydroxide (5.8 L) was added dropwise over 45 minutes at ≦10° C. After stirring for 30 minutes, tetrahydrofuran (2 L) was added and the phases were allowed to separate. The aqueous layer was removed, filtered through celite, and the filter cake washed with 2:1 methylene chloride:tetrahydrofuran (4 L). Note: Addition of fresh portions of methylene chloride helped expediate the rather tedious filtration. The phases of the filtrate were separated and the organic phase was transferred to a separatory funnel. Separation of the organic phase from the aqueous base as quickly as possible helped avoid undue hydrolysis of the propyl amide in the product. The solids remaining in the reaction flask were dissolved with 2:1 tetrahydrofuran:methanol (4 L) and then 10% methanol in chloroform (4 L). The layers were separated and the organic layer was washed with brine (500 mL), dried over magnesium sulfate, filtered, and concentrated under reduced pressure to a dark brown solid. The solid was slurried in diethyl ether, collected by filtration and dried. The crude solid (188 g) was then dissolved in hot methanol (6 L), treated with activated charcoal (19 g), stirred 15 minutes at reflux, filtered through celite while hot, concentrated to approximately 3 L, and allowed to crystallize overnight. The solids were collected, washed with diethyl ether (400 mL) and dried in a vacuum oven at 50° C. to give a white crystalline solid. The filtrate was concentrated to approximately 1 L and a second crop obtained. The mother liquors were stripped and a third and fourth crop were obtained from additional recrystallizations to afford a total of 164.6 g of the desired compound as a white crystalline solid (84%). 1H NMR (300.132 MHz, CDCl3) δ 8.57 (bs, 1H), 8.12 (dd, J=7.6, 1.1 Hz, 1H), 7.83 (dd, J=8.4, 1.0 Hz, 1H), 7.50 (dd, J=8.4, 7.5 Hz, 1H), 3.48 (q, J=6.7 Hz, 2H), 1.69 (sextet, J=7.3 Hz, 2H), 1.03 (t, J=7.4 Hz, 3H). MS APCI, m/z=309/311 (M+H). HPLC 1.66 min.

1. customA 22 L, 3-necked flask equipped with a mechanical stirrer
2. temperaturethermometer, nitrogen inlet, reflux
3. additioncondenser, and addition funnel
4. customthe heat was removed
5. temperatureto cool to room temperature overnight
6. temperatureThe reaction mixture was cooled in an ice bath to ≦10° C.
7. additioncelite was added
8. additionWater (680 mL) was added dropwise over 1 hr at ≦10° C
9. additionmethylene chloride was added (8 L)
10. temperatureThe reaction mixture was cooled to ≦10° C.
11. addition10% sodium hydroxide (5.8 L) was added dropwise over 45 minutes at ≦10° C
12. stirringAfter stirring for 30 minutes
13. additiontetrahydrofuran (2 L) was added
14. customto separate
15. customThe aqueous layer was removed
16. filtrationfiltered through celite
17. washthe filter cake washed with 2:1 methylene chloride
18. additionNote: Addition of fresh portions of methylene chloride
19. filtrationthe rather tedious filtration
20. customThe phases of the filtrate were separated
21. customthe organic phase was transferred to a separatory funnel
22. customSeparation of the organic phase from the aqueous base as quickly
23. customhydrolysis of the propyl amide in the product
24. customThe layers were separated
25. washthe organic layer was washed with brine (500 mL)
26. dry with materialdried over magnesium sulfate
27. filtrationfiltered
28. concentrationconcentrated under reduced pressure to a dark brown solid
29. filtrationcollected by filtration
30. customdried
31. dissolutionThe crude solid (188 g) was then dissolved in hot methanol (6 L)
32. additiontreated with activated charcoal (19 g)
33. stirringstirred 15 minutes
34. temperatureat reflux
35. filtrationfiltered through celite while hot,
36. concentrationconcentrated to approximately 3 L
37. customto crystallize overnight
38. customThe solids were collected
39. washwashed with diethyl ether (400 mL)
40. customdried in a vacuum oven at 50° C.
41. customto give a white crystalline solid
42. concentrationThe filtrate was concentrated to approximately 1 L
43. customa second crop obtained
44. customa third and fourth crop were obtained from additional recrystallizations

ORD record

ord-b0325476e9fa42cd9731164edf694e85

Source dataset

uspto-grants-2008_12

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US07465795B2