Dichloromethane → HCID 57929906, compound

The 1-(2,4-difluorophenyl)-2-(3-isopropyl-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)ethanone (0.250 g, 0.790 mmol, Preparation #K.1) was dissolved in THF (4 mL) then pyridinium tribromide (0.253 g, 0.790 mmol) was added in one portion. Within about 2-3 min, a solid started forming. The mixture was stirred at ambient temperature for about 1.5 h then DCM (20 mL) and water (10 mL) were added. The mixture was transferred to a separatory funnel and the layers were separated. The organic layer was dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was dissolved in DMF (4 mL) and then tert-butyl 4-carbamothioylpiperidine-1-carboxylate (0.290 g, 1.19 mmol) was added. The mixture was stirred overnight at ambient temperature, then concentrated under reduced pressure, and partitioned between EtOAc and water. The organic layer was concentrated under reduced pressure and then the residue was purified by flash chromatography with EtOAc as an eluent. Concentration of the desired fractions gave an oil which was dissolved in 1,4-dioxane (3 mL) and 6 N HCl (1 mL). The mixture was heated at about 60° C. in an oil bath for about 30 min then concentrated and purified by RP-HPLC (Table 1, Method d). Concentration of the appropriate fractions followed by basification with 1 N NaOH gave a turbid solution that was extracted with EtOAc (3×25 mL). The organic extracts were combined, dried over MgSO4, and filtered. The filtrate was concentrated under reduced pressure. The residue was then suspended in water and lyophilized to give the title compound (0.125 g, 36% yield: LC/MS (Table 1, Method a) Rt=1.54 min; MS m/z: 441.2 (M+H)+; 1H NMR (DMSO-d6) δ 1.33 (d, 6H), 1.63 (m, 2H), 2.05 (m, 2H), 2.62 (m, 2H), 3.04 (m, 2H), 3.17 (m, 1H), 3.37 (m, 1H), 7.13 (m, 1H), 7.24 (m, 1H), 7.36 (m, 1H), 7.70 (m, 1H), 8.26 (d, 1H); Anal. calcd. for C22H22F2N6S: C, 59.98; H, 5.03; N, 19.08. found C, 59.66; H, 4.72; N, 19.05.

1. customa solid started forming
2. customThe mixture was transferred to a separatory funnel
3. customthe layers were separated
4. dry with materialThe organic layer was dried over magnesium sulfate
5. filtrationfiltered
6. concentrationconcentrated under reduced pressure
7. dissolutionThe residue was dissolved in DMF (4 mL)
8. stirringThe mixture was stirred overnight at ambient temperature
9. concentrationconcentrated under reduced pressure
10. custompartitioned between EtOAc and water
11. concentrationThe organic layer was concentrated under reduced pressure
12. customthe residue was purified by flash chromatography with EtOAc as an eluent
13. customConcentration of the desired fractions gave an oil which
14. temperatureThe mixture was heated at about 60° C. in an oil bath for about 30 min
15. concentrationthen concentrated
16. custompurified by RP-HPLC (Table 1, Method d)
17. customgave a turbid solution that
18. extractionwas extracted with EtOAc (3×25 mL)
19. dry with materialdried over MgSO4
20. filtrationfiltered
21. concentrationThe filtrate was concentrated under reduced pressure

ORD record

ord-44a34e52d4cd4ee1b2b844bb097b5bac

Source dataset

uspto-grants-2012_05

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08188083B2