Ammonia → 2-amino-6-(Trifluoromethyl)nicotinic acid

Temperature

100 °C

2-Chloro-6-trifluoromethylnicotinic acid (3000 mg, 13.30 mmol) was added under argon to 24% aqueous ammonia solution (5 ml), and copper(I) chloride (1580 mg, 15.96 mmol) was added. The resulting reaction mixture was stirred at a temperature of 100° C. and at an elevated pressure of approx. 5 bar in a pressure vessel for 15 h. After cooling to room temperature and lowering the pressure to standard pressure, ethyl acetate and dilute hydrochloric acid (2N) were added to the reaction mixture. The aqueous phase was extracted repeatedly with ethyl acetate, and the combined organic phases were then dried over magnesium sulfate, filtered and concentrated under reduced pressure. Column chromatography purification (ethyl acetatein-heptane gradient) of the crude product gave 2-amino-6-trifluoromethylnicotinic acid (1640 mg, 58% of theory) as a colorless solid. 2-Amino-6-trifluoromethylnicotinic acid (500 mg, 2.43 mmol) was dissolved in abs. tetrahydrofuran (8 ml), and triethylamine (369 mg, 3.64 mmol) was added. Thereafter, the reaction solution was cooled under argon to 0° C., and cyclobutanecarbonyl chloride (316 mg, 2.69 mmol) was slowly added dropwise. The resulting reaction mixture was stirred at room temperature for a further 7 h, then dist. water and dichloromethane were added. The aqueous phase was extracted repeatedly with dichloromethane, and the combined organic phases were then dried over magnesium sulfate, filtered and concentrated under reduced pressure. Preparative HPLC purification (acetonitrile/water/trifluoroacetic acid gradient) of the crude product gave 2-[(cyclobutylcarbonyl)amino]-6-(trifluoro-methyl)nicotinamide (197 mg, 28% of theory) as a colorless solid. 2-[(Cyclobutyl-carbonyl)amino]-6-(trifluoromethyl)nicatinamide (197 mg, 0.68 mmol) was dissolved in acetic anhydride (5 ml) and stirred under reflux conditions under argon for 5 h. After cooling to room temperature, concentrated ammonia solution was added (10 ml) and the reaction mixture was stirred at room temperature for a further 6 h. The precipitated solid was filtered off with suction and dried. Preparative HPLC purification of the crude product gave 2-cyclobutyl-7-(trifluoromethyl)pyrido[2,3-d]pyrimidin-4(3H)-one (55 mg, 30% of theory) as a yellowish solid. 1H NMR (400 MHz, CDCl3 δ, ppm) 8.79 (d, 1H), 7.78 (d, 1H), 7.28 (br. s, 1H, NH), 3.62 (quint, 1H), 2.64 (m, 2H), 2.48 (m, 2H), 2.18 (m, 1H), 2.02 (m, 1H).

1. additionwas added
2. customThe resulting reaction mixture
3. temperatureAfter cooling to room temperature
4. additionwere added to the reaction mixture
5. extractionThe aqueous phase was extracted repeatedly with ethyl acetate
6. dry with materialthe combined organic phases were then dried over magnesium sulfate
7. filtrationfiltered
8. concentrationconcentrated under reduced pressure
9. customColumn chromatography purification (ethyl acetatein-heptane gradient) of the crude product

ORD record

ord-6da63c2f7e4a4e02875d5731ac5c7c4a

Source dataset

uspto-grants-2015_04

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US09006265B2