Reaction #78409

Reaction equation

NaOH

t-butylnitrite

3-amino-2-chloropyridine

2,2,2-trifluoroethanol

methanesulfonic acid

→

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

Yield 65.8%

Solvents

ethylene glycol

Conditions

Workup

1. 1
   TemperatureThe solution is heated to the range 50° C. to 60° C.
2. 2
   Temperaturewhile maintaining the temperature at 50° C. to 60° C
3. 3
   TemperatureAfter nitrogen evolution ceases, the solution is cooled
4. 4
   workup.DISTILLATIONthe solvent and other volatiles are distilled off
5. 5
   Extractionextracted with MTBE
6. 6
   OtherThe solvent is removed
7. 7
   Otherto leave an oil which
8. 8
   Extractionfollowed by extraction with MTBE
9. 9
   OtherMTBE is removed under vacuum

Procedure

A reactor vessel is charged with 3-amino-2-chloropyridine (15.0 g, 117 mmol), 2,2,2-trifluoroethanol (21 g, 210 mmol), and methanesulfonic acid (11.2 g, 117 mmol). The solution is heated to the range 50° C. to 60° C. and then t-butylnitrite (14.7 g of a 90% solution, 128 mmol) is added drop-wise to the vessel while maintaining the temperature at 50° C. to 60° C. After nitrogen evolution ceases, the solution is cooled and ethylene glycol is charged to the reactor. The vessel is put under vacuum and the solvent and other volatiles are distilled off. The reaction mass is then neutralized with aqueous saturated sodium bicarbonate solution and extracted with MTBE. The solvent is removed to leave an oil which is stirred several hours with 10% aqueous NaOH (23 g) followed by extraction with MTBE. MTBE is removed under vacuum to obtain 2-chloro-3-(2,2,2-trifluoroethoxy)pyridine as a crude oil (16.83 g) with an actual yield of 65.8%. Analysis by GC indicates the purity of the 2-chloro-3-(2,2,2-trifluoroethoxy)pyridine to be 91.4%. Recovery of the 2,2,2-trifluoroethanol solvent is 88.9% by weight.

Source