Chloroform → 2-(4-fluoro-2-methyl-phenylamino)-1,6-dimethyl-7-[3-(4-oxo-4-phenyl-4lambda5-[1,4]azaphosphinan-1-yl)-propenyl]-1,8-dihydro-imidazo[4,5-h]isoquinolin-9-one HCl salt

To a 500 mL 3-neck round-bottom flask equipped with a magnetic stir-bar and internal thermometer was added Pd2(dba)3.HCCl3 (0.476 g, 0.46 mmole), triphenylphosphine (0.383 g, 1.5 mmol), and THF (100 mL). The resulting wine-red solution was stirred under a nitrogen atmosphere for 30 minutes. To the stirred solution was then added solid acetic acid 1-[2-(4-fluoro-2-methyl-phenylamino)-1,6-dimethyl-9-oxo-8,9-dihydro-1H-imidazo[4,5-h]isoquinolin-7-yl]-allyl ester (4.0 g, 9.2 mmole) in a single portion. An aqueous solution of 4-phenyl-[1,4]azaphosphinane 4-oxide free-base (200 mL, 0.106 M) was next added to the stirring solution over 3 minutes via an addition funnel. The temperature of the reaction immediately rose from 24° C. to 29.5° C. and maintained this temperature for about 20 minutes. After 1 hour, the reaction mixture had cooled to room temperature and a yellow precipitate had formed. The precipitate was isolated by filtration and washed with water followed by diethyl ether. The filter cake was re-dissolved in methanol (150 mL) and cooled over an ice bath. To the chilled solution with rapid stirring was added anhydrous HCl (10 mL, 1.25 M in methanol). The solution was then poured into a flask containing diethyl ether (600 mL) with stirring. Pentane (100 mL) was added, followed by additional anhydrous HCl (20 mL, 1.25 M in methanol). The resulting solution was decanted, leaving crude product as a gum on the sides of the flask. This material was re-dissolved in methanol (100 mL). Into the stirred solution was poured diethyl ether, resulting in a yellow flocculent precipitate. This was recovered by filtration and washed with diethyl ether to give 2-(4-fluoro-2-methyl-phenylamino)-1,6-dimethyl-7-[3-(4-oxo-4-phenyl-4λ5-[1,4]azaphosphinan-1-yl)-propenyl]-1,8-dihydro-imidazo[4,5-h]isoquinolin-9-one HCl salt (2.9 g, 52%). 1H NMR (400 MHz, CD3OD) δ 7.96-7.89 (m, 2H), 7.89 (d, 1H, J=9.0 Hz), 7.73 (d, 1H, J=9.0 Hz), 7.71-7.65 (m, 1H), 7.66-7.61 (m, 2H), 7.51 (dd, 1H, J1=5.5 Hz, J2=8.6 Hz), 7.32 (d, 1H, J=15.7 Hz), 7.26 (dd, 1H, J1=3.1 Hz, J2=9.4 Hz), 7.16 (td, 1H, J1=3.1 Hz, J2=8.6 Hz), 6.56-6.48 (m, 1H), 4.26 (s, 3H), 4.19 (d, 2H, J=7.0 Hz), 4.2-3.8 (br m, 2H), 3.8-3.6 (br m, 2H), 3.0-2.9 (br m, 2H), 2.47 (s, 3H), 2.37 (s, 3H), 2.5-2.3 (br m, 2H); ESMS m/z 569.7 (MH+).

1. customTo a 500 mL 3-neck round-bottom flask equipped with a magnetic stir-bar
2. customThe temperature of the reaction
3. customimmediately rose from 24° C. to 29.5° C.
4. temperaturemaintained this temperature for about 20 minutes
5. waitAfter 1 hour
6. customa yellow precipitate had formed
7. customThe precipitate was isolated by filtration
8. washwashed with water
9. dissolutionThe filter cake was re-dissolved in methanol (150 mL)
10. temperaturecooled over an ice bath
11. stirringTo the chilled solution with rapid stirring
12. additionwas added anhydrous HCl (10 mL, 1.25 M in methanol)
13. additionThe solution was then poured into a flask
14. additioncontaining diethyl ether (600 mL)
15. stirringwith stirring
16. additionPentane (100 mL) was added
17. customThe resulting solution was decanted
18. customleaving crude product as a gum on the sides of the flask
19. customresulting in a yellow flocculent precipitate
20. filtrationThis was recovered by filtration
21. washwashed with diethyl ether

ORD record

ord-7953b094404e4f34a60b62477149e433

Source dataset

uspto-grants-2011_11

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08067395B2