Cesium fluoride → 2,3-Difluoro-5-(trifluoromethyl)pyridine

Temperature

75 °C

A 500 ml 4-neck round bottom flask, equipped with an air-driven mechanical stirrer and fitted with a thermometer, a distillation condenser and a stopper, was charged with 500 ml of DMSO, 1 g anhydrous K2CO3 and 25 g (0.165 mole) of CsF (one third of total CsF). The flask was heated with a heating mantle and about 100 ml of DMSO was distilled at ~110° C./~40 mm Hg to dry the reaction mixture. The reaction mixture was cooled to about 75° C. and N2 was reintroduced into the flask. The distillation condenser was replaced by a reflux condenser which was vented to a dry ice trap with a N2 atmosphere. To the reaction mixture was added 65.7 g of 3-chloro-2-fluoro-5-(trifluoromethyl)pyridine (0.329 mole) in one portion, with constant agitation, and the temperature of the reaction mixture was increased to between 120°-125° C. with the aid of a thermowatch® temperature controller. In 2.5 hours and 21.5 hours after the addition of the 3-chloro-2-fluoro-5-(trifluoromethyl)pyridine, additional 25 g portions of CsF were added to the reaction mixture for a total of 75 g of CsF in the reaction mixture. The reaction was allowed to run 69 hours at which time the reaction mixture appeared black with dark solids on the walls of the flask. A distillation condenser was attached to the flask and the reflux condenser was removed to allow the removal of the crude product by distillation (pressure=210 mm Hg; temperature (overhead)=90°-130° C.; temperature (pot)=~160° C.). To prevent the volatile product from being lost, the receiver was cooled in a dry ice/acetone bath. The distillation was continued until the head temperature stopped increasing at which time the vacuum was released, the receivers changed and the distillation resumed. An additional 10 ml was distilled over at a temperature of 130° C. and the distillation was stopped. The crude material was extracted with 100 ml of water and dried over 0.5 g of 4Å molecular sieves to give 35.1 g of 2,3-difluoro-5-(trifluoromethyl)pyridine. Elemental analysis results of the product were:

1. customA 500 ml 4-neck round bottom flask, equipped with an air-driven mechanical stirrer
2. customfitted with a thermometer, a distillation condenser
3. distillationwas distilled at ~110° C./~40 mm Hg
4. customto dry the reaction mixture
5. additionN2 was reintroduced into the flask
6. customThe distillation condenser was replaced by a reflux condenser
7. customwhich was vented to a dry ice trap with a N2 atmosphere
8. temperaturewith constant agitation, and the temperature of the reaction mixture was increased to between 120°-125° C. with the aid of a thermowatch® temperature controller
9. waitto run 69 hours at which time
10. customA distillation condenser was attached to the flask
11. customthe reflux condenser was removed
12. customthe removal of the crude product
13. distillationby distillation (pressure=210 mm Hg; temperature (overhead)=90°-130° C.; temperature (pot)=~160° C.)
14. temperaturethe receiver was cooled in a dry ice/acetone bath
15. distillationThe distillation
16. temperaturestopped increasing at which time the vacuum
17. distillationthe distillation
18. distillationAn additional 10 ml was distilled over at a temperature of 130° C.
19. distillationthe distillation
20. extractionThe crude material was extracted with 100 ml of water
21. customdried over 0.5 g of 4Å molecular sieves

ORD record

ord-1fa9200d384d449f80497d61533f2ee2

Source dataset

uspto-grants-1984_10

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US04480102