4-Methylmorpholine → Setrobuvir

Temperature

23 °C

(7-Methanesulfonylamino-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,2,4]thiadiazin-3-yl)-acetic acid (prepared as described in Example 1g, 1.88 kg, 5.63 mol) and (1S,2R,3S,4R)-3-(4-fluoro-benzylamino)-bicyclo[2.2.1]heptane-2-carboxylic acid ethyl ester (prepared as described in Example 6l, 1.72 kg, 5.91 mol) were dissolved in acetonitrile (18.8 L) at 23° C. N-Methylmorpholine (1.25 kg, 12.4 mol) was added and the resulting suspension was stirred at 23° C. for 1 h. The suspension was cooled to 0° C. and 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (1.19 kg, 6.20 mol) was added in one portion. The mixture was stirred at 0° C. for 3 h, and was then allowed to warm to 23° C. and stirred overnight. Triethylamine (1.88 kg, 18.6 mol) was added and the mixture was then heated at 50° C. for 3 h. The mixture was partially concentrated in vacuo at 45° C., and was then diluted with ethyl acetate (22.5 L) and washed with 2.0M aqueous hydrochloric acid solution (22.6 L). The resulting aqueous fraction was extracted with ethyl acetate (2×9.4 L). The combined organic extracts were washed with 1.0M aqueous hydrochloric acid solution (10.4 L) and then with water (18.8 L). The resulting organic fraction was filtered through Celite (600 g), and the filtrate was then partially concentrated in vacuo at 45° C. Absolute ethanol (5.6 L) was added to the residue, and the mixture was then heated at 50° C. with stirring. Dichloromethane (400 mL) was added in portions until crystallization initiated. Absolute ethanol (20.7 L) was added in portions over 1 h, and the resulting mixture was stirred at 23° C. overnight. The mixture was filtered and the solid was then washed with absolute ethanol (1.9 L). The solid was further dried in vacuo at 45° C. to afford the desired product, N-{3-[(1R,2S,7R,8S)-3-(4-fluoro-benzyl)-6-hydroxy-4-oxo-3-aza-tricyclo[6.2.1.02,7]undec-5-en-5-yl]-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,2,4]thiadiazin-7-yl}-methanesulfonamide (2.46 kg, 4.39 mol, 78%), as an off-white crystalline solid.

1. temperatureThe suspension was cooled to 0° C.
2. stirringThe mixture was stirred at 0° C. for 3 h
3. temperatureto warm to 23° C.
4. stirringstirred overnight
5. temperaturethe mixture was then heated at 50° C. for 3 h
6. concentrationThe mixture was partially concentrated in vacuo at 45° C.
7. additionwas then diluted with ethyl acetate (22.5 L)
8. washwashed with 2.0M aqueous hydrochloric acid solution (22.6 L)
9. extractionThe resulting aqueous fraction was extracted with ethyl acetate (2×9.4 L)
10. washThe combined organic extracts were washed with 1.0M aqueous hydrochloric acid solution (10.4 L)
11. filtrationThe resulting organic fraction was filtered through Celite (600 g)
12. concentrationthe filtrate was then partially concentrated in vacuo at 45° C
13. additionAbsolute ethanol (5.6 L) was added to the residue
14. temperaturethe mixture was then heated at 50° C.
15. stirringwith stirring
16. additionDichloromethane (400 mL) was added in portions until crystallization
17. additionAbsolute ethanol (20.7 L) was added in portions over 1 h
18. stirringthe resulting mixture was stirred at 23° C. overnight
19. filtrationThe mixture was filtered
20. washthe solid was then washed with absolute ethanol (1.9 L)
21. customThe solid was further dried in vacuo at 45° C.

ORD record

ord-7aaaab0b9888483ebe09d34690054588

Source dataset

uspto-grants-2015_10

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US09156832B2