Potassium Carbonate → {8-Methyl-3-[1-(4-pyrimidin-4-ylphenyl)cyclopropyl]-5,6,8,9-tetrahydro[1,2,4]triazolo[4,3-d][1,4]thiazepin-8-yl}methanol

Temperature

130 °C

A reaction mixture of the compound (555 mg, 1.0 mmol) obtained in Example 16-5), 4-bromopyrimidine hydrochloride (234 mg, 1.5 mmol), tetrakis(triphenylphosphine)palladium(0) (231 mg, 0.2 mmol), potassium carbonate (276 mg, 2 mmol), dimethoxyethane (4 mL), and water (1 mL) was stirred at 130° C. for 1.5 h under microwave irradiation. The reaction mixture was cooled to room temperature, saturated aqueous sodium hydrogencarbonate was added to the reaction mixture, the mixture was extracted with dichloromethane, and the organic layer was washed with saturated sodium chloride solution and dried with anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the residue was partially purified by silica gel chromatography (Isco Combiflash, 40 g, methanol:ethyl acetate=0:100 to 20:80, gradient). This partially purified product was dissolved in a 4 M solution (1 mL) of hydrochloric acid in 1,4-dioxane and methanol (4 mL), and the mixture was stirred at room temperature for 15 h. The reaction mixture was concentrated under reduced pressure, saturated aqueous sodium hydrogencarbonate was added to the residue, the mixture was extracted with dichloromethane, and the organic layer was washed with saturated sodium chloride solution and dried with anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (Isco Combiflash, 12 g, methanol:ethyl acetate=0:100 to 40:60, gradient) to obtain the title compound (67 mg, 17%) as a colorless solid.

1. temperatureThe reaction mixture was cooled to room temperature
2. extractionthe mixture was extracted with dichloromethane
3. washthe organic layer was washed with saturated sodium chloride solution
4. dry with materialdried with anhydrous sodium sulfate
5. filtrationAfter filtration
6. concentrationthe filtrate was concentrated under reduced pressure
7. customthe residue was partially purified by silica gel chromatography (Isco Combiflash, 40 g, methanol:ethyl acetate=0:100 to 20:80, gradient)
8. dissolutionThis partially purified product was dissolved in a 4 M solution (1 mL) of hydrochloric acid in 1,4-dioxane and methanol (4 mL)
9. stirringthe mixture was stirred at room temperature for 15 h
10. concentrationThe reaction mixture was concentrated under reduced pressure, saturated aqueous sodium hydrogencarbonate
11. additionwas added to the residue
12. extractionthe mixture was extracted with dichloromethane
13. washthe organic layer was washed with saturated sodium chloride solution
14. dry with materialdried with anhydrous sodium sulfate
15. filtrationAfter filtration
16. concentrationthe filtrate was concentrated under reduced pressure
17. customthe residue was purified by silica gel chromatography (Isco Combiflash, 12 g, methanol:ethyl acetate=0:100 to 40:60, gradient)

ORD record

ord-be825155b0524940bd78fe2f7dbabab8

Source dataset

uspto-grants-2015_01

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08927536B2