Methanol → HCID 135936827, compound

Temperature

60 °C

A mixture of N-(3-methyl-4-(6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentyl)cyclopropanesulfonamide (7.1 g, 13.9 mmol), 1,4-dioxane (139 mL) and aqueous 1 N NaOH (30.0 mL, 30.0 mmol) was heated at about 60° C. for about 2 h. The reaction was cooled to ambient temperature, diluted with water (150 mL), and extracted with EtOAc (3×150 mL). The combined organic layers were washed with brine (200 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude mixture was triturated with EtOAc (50 mL) and filtered to give a tan solid, which was purified by chiral preparative HPLC (Table 3, Method 3, Rt=18 min, or =negative). The product containing fractions were combined and concentrated to give a pale yellow solid. The solid was dissolved in a 1:1 mixture of DCM:MeOH (about 100 mL), 10 g of silica gel was added, and the mixture was concentrated. The resulting mixture was purified by silica gel chromatography using a gradient of 0-100% DCM/MeOH/Et2NH (990:9:1) to DCM/MeOH/Et2NH (970:27:3). The product-containing fractions were combined and concentrated to give a white solid. The solid was dissolved in boiling EtOH (150 mL) and sonicated for about 1 h. The solvent was removed under reduced pressure and the solid was dried in a vacuum oven at about 70° C. for about 72 h. Water (12 mL) and EtOH (3 mL) were added, and the resulting slurry was refluxed for 2 h. The slurry was cooled to ambient temperature, followed by further cooling at about 0° C. in an ice bath. The solids were filtered while rinsing with ice-cooled water (about 3 mL) and dried in a vacuum oven to give N-((1S,3R,4S)-3-methyl-4-(6H-pyrrolo[2,3-e][1, 2, 4]triazolo[4,3-a]pyrazin-1-yl)cyclopentyl)cyclopropanesulfonamide (0.5 g, 10.4%) as a white solid with 0.5% EtOH: LC/MS (Table 2, Method a) Rt=1.61 min; MS m/z: 361 (M+H)+.

1. temperatureThe reaction was cooled to ambient temperature
2. extractionextracted with EtOAc (3×150 mL)
3. washThe combined organic layers were washed with brine (200 mL)
4. dry with materialdried over anhydrous Na2SO4
5. filtrationfiltered
6. concentrationconcentrated under reduced pressure
7. customThe crude mixture was triturated with EtOAc (50 mL)
8. filtrationfiltered
9. customto give a tan solid, which
10. customwas purified by chiral preparative HPLC (Table 3, Method 3, Rt=18 min, or =negative)
11. additionThe product containing fractions
12. concentrationconcentrated
13. customto give a pale yellow solid
14. concentrationthe mixture was concentrated
15. customThe resulting mixture was purified by silica gel chromatography
16. concentrationconcentrated
17. customto give a white solid
18. dissolutionThe solid was dissolved
19. customsonicated for about 1 h
20. customThe solvent was removed under reduced pressure
21. customthe solid was dried in a vacuum oven at about 70° C. for about 72 h
22. additionWater (12 mL) and EtOH (3 mL) were added
23. temperaturethe resulting slurry was refluxed for 2 h
24. temperatureThe slurry was cooled to ambient temperature
25. temperatureby further cooling at about 0° C. in an ice bath
26. filtrationThe solids were filtered
27. washwhile rinsing with ice-
28. temperaturecooled water (about 3 mL)
29. customdried in a vacuum oven

ORD record

ord-c4eda6df09ae47deac203985b12a6fd1

Source dataset

uspto-grants-2015_02

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08962629B2