Hydrogen Peroxide → Trifluoroacetic acid

To 6-[2-amino-6-(methylthio)-4-pyrimidinyl]-1H-indazol-3-amine (0.25 g, 0.92 mmol) in TFA (8.74 mL) at 0° C. was added aqueous H2O2 (0.375 mL, 3.67 mmol, 30% (w/w)) dropwise over 2 minutes. Upon completion of the addition, the reaction was allowed to warm to room temperature. After 2 hours, the reaction mixture was cooled back to 0° C. and quenched with dimethyl sulfide (0.54 mL, 7.34 mmol, dropwise addition). The reaction was allowed to warm to room temperature and stirred for 1 hour. The mixture was cooled to 0° C. and diluted with Et2O (5 mL) Et2O and hexane (15 mL). The resulting orange precipitate was filtered and transferred to a 25 mL sealable tube under nitrogen. 1,4-Dioxane (5.83 mL), 2-(1-methylethyl)pyrrolidine hydrochloride (0.275 g, 1.84 mmol), and triethylamine (0.51 mL, 3.67 mmol) were added, the tube was sealed, and the reaction mixture was stirred overnight at 95° C. Since LCMS showed a minimal amount of product, additional triethylamine (1 mL) was added, and the reaction mixture was stirred overnight at 95° C. The reaction was cooled to room temperature and decanted. The solution was concentrated, and the resulting oil was dissolved in a mixture of 50/50 CH3CN/H2O w/0.1 mL TFA. The resulting mixture was filtered through a 0.45μ frit and purified on a Gilson RPHPLC (CH3CN/H2O w/0.1% TFA) to afford a TFA salt of the title compound (12 mg) as a yellow solid as a mixture of rotamers. LC-MS (ES) m/z=338 [M+H]+. 1H NMR (400 MHz, DMSO-d6): δ 0.75-0.99 (m, 6H), 1.79-2.04 (m, 4H), 3.58-3.88 (m, 3H), 4.26 (m, 1H), 4-5 (bs), [6.59 (s) and 6.65 (s)] (1H), [7.33 (d, J=8.6 Hz) and 7.37 (d, J=8.6 Hz)] (1H), [7.69 (s) and 7.73 (s)] (1H), 7.91 (d, J=8.6 Hz, 1H), 12.04 (bs, 1H).

1. additionUpon completion of the addition
2. temperaturethe reaction mixture was cooled back to 0° C.
3. customquenched with dimethyl sulfide (
4. addition0.54 mL, 7.34 mmol, dropwise addition)
5. temperatureto warm to room temperature
6. temperatureThe mixture was cooled to 0° C.
7. additiondiluted with Et2O (5 mL) Et2O and hexane (15 mL)
8. filtrationThe resulting orange precipitate was filtered
9. customtransferred to a 25 mL sealable tube under nitrogen
10. customthe tube was sealed
11. stirringthe reaction mixture was stirred overnight at 95° C
12. additionwas added
13. stirringthe reaction mixture was stirred overnight at 95° C
14. temperatureThe reaction was cooled to room temperature
15. customdecanted
16. concentrationThe solution was concentrated
17. dissolutionthe resulting oil was dissolved in a mixture of 50/50 CH3CN/H2O
18. filtrationThe resulting mixture was filtered through a 0.45μ frit
19. custompurified on a Gilson RPHPLC (CH3CN/H2O w/0.1% TFA)

ORD record

ord-44be99ff72b448109f262e66bdba2a9f

Source dataset

uspto-grants-2014_04

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08697685B2