Diisopropylethylamine → 6-(6,6-Difluorohexahydro-1H-1,4-diazepin-1-yl)-3-(trifluoromethyl)-1,2,4-triazolo[4,3-b]pyridazine

Temperature

135 °C

A mixture of 6-chloro-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine (1 g, 4.49 mmol), tert-butyl 6,6-difluoro-1,4-diazepane-1-carboxylate (1.06 g, 4.49 mmol) and DIPEA (1.56 ml, 8.99 mmol) in DMA (15 mL) was stirred at 135° C. for 6 hours. The reaction mixture was concentrated to dryness and DCM (30 mL) was added. The solution was cooled in an ice bath and TFA (15 mL) was added. The resulting mixture was stirred at room temperature for 4 hours. The reaction mixture was concentrated to dryness, diluted with water, basified with 6M aqueous sodium hydroxide and extracted with DCM. The organic phase was washed with water and brine, dried over magnesium sulfate and concentrated. The residue was purified by flash chromatography on silica gel eluting with 0 to 4% methanol in DCM to give 6-(6,6-difluoro-1,4-diazepan-1-yl)-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine (0.820 g, 56.6%) as a beige solid.

1. concentrationThe reaction mixture was concentrated to dryness and DCM (30 mL)
2. additionwas added
3. temperatureThe solution was cooled in an ice bath
4. additionTFA (15 mL) was added
5. stirringThe resulting mixture was stirred at room temperature for 4 hours
6. concentrationThe reaction mixture was concentrated to dryness
7. additiondiluted with water
8. extractionextracted with DCM
9. washThe organic phase was washed with water and brine
10. dry with materialdried over magnesium sulfate
11. concentrationconcentrated
12. customThe residue was purified by flash chromatography on silica gel eluting with 0 to 4% methanol in DCM

ORD record

ord-60791e5f542c4fb09e2aa1d5845daa0a

Source dataset

uspto-grants-2011_08

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08003649B2