Triethylamine → 5-(5-bromo-1-methyl-1H-pyrazol-4-yl)-4-chloro-7-methylimidazo[5,1-f][1,2,4]triazine

Temperature

105 °C

A mixture of 5-(5-bromo-1-methyl-1H-pyrazol-4-yl)-7-methylimidazo[5,1-f][1,2,4]triazin-4(3H)-one (10.00 g, 32.35 mmol) in toluene (100 mL) was treated with phosphorus oxychloride (9.05 mL, 97.1 mmol). After drop-wise addition of N,N-diisopropylethylamine (28.2 mL, 162 mmol), the mixture was heated at 105° C. for 24 hours. The reaction was allowed to cool to room temperature, and then was diluted with dichloromethane (20 mL) and added over 10 minutes to a solution comprised of triethylamine (30 mL), toluene (50 mL) and water (80 mL), while keeping the internal temperature below 36° C. After an additional 20 minutes of stirring, the phases were separated, and the aqueous layer (pH ˜7) was extracted with toluene (100 mL). The combined organic layers were washed with aqueous citric acid solution (1 M, 150 mL), then washed with saturated aqueous sodium chloride solution, dried over magnesium sulfate and filtered. The filtrate was concentrated in vacuo to provide the product as a solid. Yield: 9.80 g, 29.9 mmol, 92%. LCMS m/z 328.9 (M+1). 1H NMR (400 MHz, CDCl3) δ 2.78 (s, 3H), 3.97 (s, 3H), 7.75 (s, 1H), 8.18 (s, 1H).

1. temperatureto cool to room temperature
2. additionadded over 10 minutes to a solution
3. customthe internal temperature below 36° C
4. customthe phases were separated
5. extractionthe aqueous layer (pH ˜7) was extracted with toluene (100 mL)
6. washThe combined organic layers were washed with aqueous citric acid solution (1 M, 150 mL)
7. washwashed with saturated aqueous sodium chloride solution
8. dry with materialdried over magnesium sulfate
9. filtrationfiltered
10. concentrationThe filtrate was concentrated in vacuo

ORD record

ord-331e8b4d045143e99d7ebe1ce0bc368a

Source dataset

uspto-grants-2015_12

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US09200000B2