2-HYDROXY-6-(TRIFLUOROMETHYL)PYRIDINE

(3), 1500 g of t-butanol, 140 g of potassium hydroxide and 2-chloro-6-trifluoromethylpyridine prepared in step (2) were added to a 3 L reaction flask, and the temperature was raised to 70 ° C, Insulation reaction 8 hours, After completion of the reaction, tert-butanol was removed under reduced pressure, 550 g of ethyl acetate and 550 g of water were added and stirred, The organic layer was washed with 370 g of saturated brine, dried over 100 g of anhydrous sodium sulfate, and the ethyl acetate was removed by steaming To give crude 172.4 g;(4), the crude product prepared in step (3) was added to 150 g of ethyl acetate, heated to 70 ° C, stirred and dissolved, and 1200 g of petroleum ether was added dropwise, After the addition of petroleum ether, the mixture was cooled to 2 ° C, solid crystals were precipitated, and the solid was filtered. The solid was washed with 50 g of petroleum ether and dried at 70 ° C, To obtain 131.2 g of 2-hydroxy-6-trifluoromethylpyridine as a pale yellow solid powder in a yield of 80.8percent.EXAMPLE 8 EXAMPLE 5 This Example illustrates the preparation of 2-hydroxy-6-trifluoromethylpyridine by reacting a 50:50 mixture of 2-fluoro-6-trifluoromethylpyridine and 2-chloro-6-trifluoromethylpyridine with aqueous potassium hydroxide at 100-105°C. Potassium hydroxide flake (95percent, 13.0 g, 2.22 mole equivalents), and water (113.9 g) were charged to a 250 ml round bottomed flask fitted with a condenser, agitator and contents thermometer. The contents were stirred to give a solution. 2-Fluoro-6-trifluoromethylpyridine (99.7percent, 8.27 g, 0.5 mole equivalents) and 2-chloro-6-trifluoromethylpyridine (99.0percent, 9.17 g, 0.5 mole equivalents) were added and the reaction mixture heated to 100° C. During the reaction the temperature rose to 105° C. The reaction mixture was sampled and analyzed and found to contain 0.9percent 2-fluoro-6-trifluoromethylpyridine and 98.4 percent 2-hydroxy-6-trifluoromethylpyridine. No 2-chloro-6-trifluoromethylpyridine was present. The reaction mixture was cooled to 5° C. Concentrated hydrochloric acid (36.0percent, 14.2 g) was added dropwise over 40 minutes and the temperature maintained below 5° C. The product slurry was stirred for a further 60 minutes at less than 5° C. The product was filtered and displacement washed with water (18.5 g). The title product was then dried under vacuum at 40° C.: isolated dry weight 12.9 g, strength 99.0percent; isolated yield 78.3percent.EXAMPLE 7 This Example illustrates the preparation of 2-hydroxy-6-trifluoromethylpyridine by reacting a 50:50 mixture of 2-fluoro-6-trifluoromethylpyridine and 2-chloro-6-trifluoromethylpyridine with solid potassium hydroxide and t-amyl alcohol at 105-108° C. Potassium hydroxide flake (95percent, 13.0 g, 2.22 mole equivalents) and t-amyl alcohol (99percent, 73.9 g, 8.32 mole equivalents) were charged to a 250 ml round bottomed flask fitted with a condenser, agitator and contents thermometer. The contents were stirred to give a slurry. 2-Fluoro-6-trifluoromethylpyridine (99.7percent, 8.27 g, 0.5 mole equivalents) and 2-chloro-6-trifluoromethylpyridine (99.0percent, 9.17 g, 0.5 mole equivalents) were added and the reaction mixture heated to 105° C. (slight reflux). During the reaction the temperature rose to 108° C. The reaction mixture was sampled after 4 hours and found to contain 0.2percent 2-fluoro-6-trifluoromethylpyridine and 93.6percent 2-hydroxy-6-trifluoromethylpyridine. No 2-chloro-6-trifluoromethylpyridine was present. The reaction mixture was cooled to 80° C. t-Amyl alcohol was distilled off to 108° C. and the reaction mixture was cooled to 40° C. Water (4.6 g) was added. Water and t-amyl alcohol were distilled off to a temperature of 110° C. The reaction mixture was cooled to 50° C. and water (79.6 g) was added. The reaction was cooled to 5° C. and concentrated hydrochloric acid (36.0percent, 14.2 g) added dropwise over 40 minutes while the temperature was maintained below 5° C. The product slurry was stirred for a further 60 minutes at less than 5° C. The product was filtered off and displacement washed with water (18.5 g). The title product was then dried under vacuum at 40° C.: isolated dry, weight 8.2 g, strength 97.5percent; isolated yield 49.0percent (residual t-amyl alcohol left after distillation led to yield losses).The methoxy acrylate compound 3o (1.0 mmol), A mixture of 2, 4-difluoro-6-methoxybenzonitrile(0.200g, 1.183mmol), 2-hydroxy-6- trifluoromethylpyridine(0.231g, 1.419mmol), potassium carbonate(0.196g, 1.419mmol), and NMP(2mL), were heated via microwave for 10minutes at 130C. LCMS shows the desired product. The crude reaction was used in the next step without purification.

Molecular Weight:163.10
XLogP3:1.1
Hydrogen Bond Donor Count:1
Hydrogen Bond Acceptor Count:4
Exact Mass:163.02449824
Monoisotopic Mass:163.02449824
Topological Polar Surface Area:29.1
Heavy Atom Count:11
Complexity:239
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes