Methyl 6-formylpyridine-3-carboxylate → Methyl 6-(1-(2,6-dimethyl-4'-(trifluoromethyl)biphenyl-4-ylamino)-3-methylbutyl)nicotinate

Temperature

90 °C

To a solution of methyl 6-formylnicotinate (200 mg, 1.21 mmol) in toluene (8 mL) containing activated molecular sieves was added 2,6-dimethyl-4′-(trifluoromethyl)biphenyl-4-amine (316 mg, 1.33 mmol). The reaction mixture was heated to 90° C. and stirred overnight. The reaction mixture was concentrated and the residue dissolved in tetrahydrofuran (8 mL). The solution was cooled to 0° C. Zinc chloride (3.64 mL of a 1.0M solution in diethyl ether, 3.64 mmol) was added, followed by isobutylmagnesium bromide (1.82 mL of a 2.0M solution in THF, 3.64 mmol). The reaction mixture was stirred at 0° C. for 2 h. The reaction was quenched with saturated aqueous ammonium chloride (5 mL). The mixture was diluted with dichloromethane (30 mL) and water (30 mL). The layers were separated and the aqueous layer was extracted with dichloromethane (30 mL) two more times. The combined organic layers were dried over sodium sulfate, filtered, and concentrated. Purification by column chromatography gave methyl 6-(1-(2,6-dimethyl-4′-(trifluoromethyl)biphenyl-4-ylamino)-3-methylbutyl)nicotinate (290 mg, 51%). 1H NMR (400 MHz, CDCl3, δ): 9.20 (s, 1H), 8.25 (d, 1H), 7.62 (d, 4H), 7.50 (d, 2H), 7.45 (d, 1H), 7.20 (d, 2H), 6.30 (s, 2H), 4.62 (m, 1H), 3.95 (s, 3H), 3.5 (s, 3H), 1.87 (s, 6H), 1.73 (d, 3H), 1.26 (m, 3H), 1.10 (m, 6H).

1. concentrationThe reaction mixture was concentrated
2. dissolutionthe residue dissolved in tetrahydrofuran (8 mL)
3. temperatureThe solution was cooled to 0° C
4. additionZinc chloride (3.64 mL of a 1.0M solution in diethyl ether, 3.64 mmol) was added
5. stirringThe reaction mixture was stirred at 0° C. for 2 h
6. customThe reaction was quenched with saturated aqueous ammonium chloride (5 mL)
7. additionThe mixture was diluted with dichloromethane (30 mL) and water (30 mL)
8. customThe layers were separated
9. extractionthe aqueous layer was extracted with dichloromethane (30 mL) two more times
10. dry with materialThe combined organic layers were dried over sodium sulfate
11. filtrationfiltered
12. concentrationconcentrated
13. customPurification by column chromatography

ORD record

ord-a6a9ff54380146b98983387a7aec96bc

Source dataset

uspto-grants-2015_01

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08933104B2