Reaction #78404

Reaction equation

3-amino-2-chloropyridine

2,2,2-trifluoroethanol

t-butyl nitrite

mesitylene

methanesulfonic acid

2,2,2-trifluoroethanol

2,2,2-trifluoroethanol

mesitylene

→

2-chloro-3-(2,2,2-trifluoroethoxy)pyridine

Yield 73.0%

Conditions

Workup

1. 1
   Temperatureafter cooling in an ice bath
2. 2
   TemperatureThe solution is cooled to the range −5° C. to 0° C.
3. 3
   Temperaturewhile maintaining the temperature in the range −5° C. to 0° C
4. 4
   Otheris transferred by Masterflex® pump to a reactor vessel
5. 5
   Temperaturemaintained at 65° C. to 70° C
6. 6
   workup.DISTILLATIONa distillation column
7. 7
   workup.DISTILLATIONImpure 2,2,2-trifluoroethanol (114 g, 90% recovery) is distilled out of the vessel
8. 8
   TemperatureAfter cooling the solution it
9. 9
   Extractionextracted with MTBE
10. 10
    OtherThe volatiles were removed by evaporation

Procedure

A reactor vessel is charged with 3-amino-2-chloropyridine (10 g, 77.8 mmol), 2,2,2-trifluoroethanol (55.6 g, 556 mmol), and after cooling in an ice bath, methanesulfonic acid (7.48 g, 77.8 mmol) is added. The solution is cooled to the range −5° C. to 0° C. and then the reagent t-butyl nitrite (2.51 g of a 96% solution, 23.4 mmol) is added drop-wise to the vessel while maintaining the temperature in the range −5° C. to 0° C. After stirring a few minutes the solution is transferred by Masterflex® pump to a reactor vessel containing 2,2,2-trifluoroethanol (74.1 g, 741 mmol) maintained at 65° C. to 70° C. The pump line is cleared into the second reactor with 2,2,2-trifluoroethanol (5 g, 50 mmol) and mesitylene (10 g). An additional 20 g mesitylene was charged to the reactor vessel and a distillation column is attached to the reactor. Impure 2,2,2-trifluoroethanol (114 g, 90% recovery) is distilled out of the vessel. After cooling the solution it is neutralized with aqueous saturated sodium bicarbonate solution and then extracted with MTBE. The volatiles were removed by evaporation to obtain 2-chloro-3-(2,2,2-trifluoroethoxy)pyridine as a crude oil (44 g) with an actual yield of 73%.

Source