N-methyl-2-pyrrolidone → 4-(Methoxymethyl)-6-(trifluoromethyl)pyridine-2-carbonitrile

Temperatur

140 °C

A solution of 2-chloro-4-(methoxymethyl)-6-(trifluoromethyl)pyridine (0.5 g, 2 mmol, from Step B) and zinc cyanide (1.56 g, 13.3 mmol) in N-methylpyrrolidinone (8 mL) was degassed by bubbling a stream of nitrogen through the solution for 10 minutes. Tetrakis(triphenylphosphine)palladium(0) (0.51 g, 0.44 mmol) was added and the mixture was degassed similarly for 5 minutes. The reaction vial was sealed and heated in the microwave to 140° C. for 10 minutes. The reaction mixture was partitioned between water and ethyl acetate, and the aqueous portion was extracted with two further portions of ethyl acetate. The combined organic extracts were washed with water, followed by brine, dried over sodium sulfate, filtered and concentrated. Flash chromatography on silica gel, eluting with a gradient from 0-30% EtOAc/Hexanes afforded purified product (0.36 g, 80%). 1H NMR (400 MHz, CDCl3) δ 7.87-7.83 (m, 2H), 4.60 (dd, J=0.9 Hz, 2H), 3.51 (s, 3H); 19F NMR (376 MHz, CDCl3) 5-68.55 (s); LCMS (M+H)+: 217.1.

1. customby bubbling a stream of nitrogen through the solution for 10 minutes
2. customthe mixture was degassed similarly for 5 minutes
3. customThe reaction
4. customvial was sealed
5. customThe reaction mixture was partitioned between water and ethyl acetate
6. extractionthe aqueous portion was extracted with two further portions of ethyl acetate
7. washThe combined organic extracts were washed with water
8. dry with materialdried over sodium sulfate
9. filtrationfiltered
10. concentrationconcentrated
11. washFlash chromatography on silica gel, eluting with a gradient from 0-30% EtOAc/Hexanes
12. customafforded
13. custompurified product (0.36 g, 80%)

ORD-Eintrag

ord-0112f9b9e7764b05a9ebf466293568f9

Quelldatensatz

uspto-grants-2015_01

DOI

10.6084/m9.figshare.5104873.v1

Patentnummer

US08933085B2