反应详情

To a solution of 2-chloro-6-(trifluoromethyl)nicotinic acid (0.45 g, 2.0 mmol) and 2-chloro-6-(trifluoromethyl)isonicotinic acid (0.55 g, 2.4 mmol) (as a mixture from Step A) in tetrahydrofuran (10 mL) cooled in an ice bath was added triethylamine (0.64 mL, 4.6 mmol) followed by isobutyl chloroformate (0.60 mL, 4.6 mmol, Aldrich). The reaction was stirred for 30 minutes, then was filtered through a pad of celite into a flask containing 3.0M methylmagnesium bromide in diethyl ether (4.0 mL, 12 mmol, Aldrich) in tetrahydrofuran (5 mL) also cooled in an ice bath. The celite pad was rinsed with an additional 10 mL of THF. After warming to room temperature, an additional portion of 3.0M methylmagnesium bromide in diethyl ether (4.0 mL, 12 mmol) was added to the reaction mixture. When the reaction was determined to be complete by LCMS, saturated ammonium chloride solution was added to the reaction. After stirring for 20 minutes, the mixture was transferred to a separatory funnel and was extracted with ethyl acetate. The combined organic extracts were washed with water and brine, dried over sodium sulfate, filtered and concentrated. Flash chromatography on silica gel, eluting with a gradient from 0-30% EtOAc/Hexanes afforded product (0.28 g, 58%). 1H NMR (400 MHz, CDCl3) δ 7.70 (d, J=1.4 Hz, 1H), 7.63 (d, J=1.2 Hz, 1H), 1.60 (s, 6H); LCMS (M+H)+: 240.1, 242.1.

1. filtrationwas filtered through a pad of celite into a flask
2. temperaturealso cooled in an ice bath
3. washThe celite pad was rinsed with an additional 10 mL of THF
4. additionwas added to the reaction
5. stirringAfter stirring for 20 minutes
6. customthe mixture was transferred to a separatory funnel
7. extractionwas extracted with ethyl acetate
8. washThe combined organic extracts were washed with water and brine
9. dry with materialdried over sodium sulfate
10. filtrationfiltered
11. concentrationconcentrated
12. washFlash chromatography on silica gel, eluting with a gradient from 0-30% EtOAc/Hexanes afforded product (0.28 g, 58%)