Background and overview of the preparation method of 4-methyl-2-(1,1,1-trifluoro-2-dimethyl-2-ethyl)pyridine
4-Methyl-2-(1,1,1-trifluoro-2-dimethyl-2-ethyl)pyridine is an organic intermediate that can be synthesized from 2-acetyl-4-methylpyridine It is prepared from raw materials through a four-step reaction.
Preparation method of 4-methyl-2-(1,1,1-trifluoro-2-dimethyl-2-ethyl)pyridine
Preparation method of 4-methyl-2-(1,1,1-trifluoro-2-dimethyl-2-ethyl)pyridine 4-methyl-2-(2,2, Preparation of 2-trifluoro-1-methyl-1-trimethylsilyloxy-ethyl)pyridine (b)
To a fine white suspension of sodium acetate (96.0g, 117mmol, 1.0eq) dissolved in 1 LDMSO was added 2-acetyl-4-methylpyridinedimethoxypyridine (158g, 117mmol, 1.0eq) . After diluting with another 0.5 L of DMSO, trimethyltrifluoromethylsilane (375 g, 264 mmol, 2.2 equiv) was added over 75 minutes. During the addition, the reaction vessel was placed in a cooling bath at 10°C to maintain an internal temperature between 20 and 25°C. The resulting black suspension was stirred at room temperature overnight and then the reaction was quenched by careful addition of 1.5 L of water over 20 minutes. During the addition of water, the reaction vessel was placed in a -5°C cooling bath to maintain an internal temperature between 10 and 25°C. After stirring at room temperature for 45 minutes, the mixture was diluted with 3 L of ethyl acetate and stirred for a further 15 minutes. The phases were separated, and the aqueous layer was extracted with 2 L of ethyl acetate. The combined organic phases were washed with 3 L of saturated aqueous NaHCO3, dried over MgSO4, filtered and concentrated in vacuo to yield 346 g (106%, 88.6 area% by HPLC) of the trifluoromethyl compound (b) as a brown, strongly smelling oil. ).
Preparation method of 4-methyl-2-(1,1,1-trifluoro-2-dimethyl-2-ethyl)pyridine 1,1,1-trifluoro-2-( Preparation of 4-methylpyridin-2-yl)propan-2-ol (c)
Add 4-methyl-2-(2,2,2-trifluoro-1-methyl-1-trimethylsilyloxy-ethyl)pyridine dissolved in 1.5L MeOH at room temperature. (b) To a solution of (b) (346g, 125mmol, 1.0eq), solid K2CO3 (344g, 249mmol, 2.0eq) was added. The resulting beige suspension was stirred at room temperature for 1 hour and then filtered through filter paper. The filtrate was concentrated in vacuo to produce a solid, strong-odorous residue. The residue was dissolved in 1 L of ethyl acetate and washed with water (2 x 1 L). Drying over MgSO4, filtration, and concentration in vacuo provided 252 g (98%) of alcohol (c) as an oil.
Preparation method of 4-methyl-2-(1,1,1-trifluoro-2-dimethyl-2-ethyl)pyridine methanesulfonic acid 1,1,1-trifluoro- Preparation of 2-(4-methylpyridin-2-yl)propan-2-ester (d)
To a suspension of NaH (60% in mineral oil, 23.4 g, 585 mmol, 1.5 equiv) in 1 L THF at 0°C, 1,1,1-trifluoro2-( A solution of 4-methylpyridin-2-yl)propan-2-ol (c) (80 g, 390 mmol, 1.0 equiv) in 200 ml THF. Gas evolution occurred and the reaction mixture turned brown. The reaction temperature was raised to 40°C and stirred at 40°C for 45 minutes, at which time gas evolution stopped. After cooling to room temperature, a solution of methanesulfonyl chloride (45.6 ml, 585 mmol, 1.5 equiv) in 50 ml THF was added dropwise over 30 minutes. The internal temperature rose to 36°C, and the reaction mixture turned into a light brown suspension. The reaction mixture was warmed to 40°C and stirred at this temperature for 15 minutes, then cooled to room temperature and further stirred overnight. While cooling in an ice bath, the reaction was stopped by carefully adding 750 ml of water. The resulting brown biphasic mixture was stirred at room temperature for 30 minutes and then the phases separated. The aqueous layer was extracted with 750 ml of ethyl acetate, and the combined organic phases were washed with saturated NaHCO3 aqueous solution. Dry over MgSO4, filter and concentrate in vacuo to give a beige solid. The residue was redissolved in 300 ml of ethyl acetate to produce a cloudy solution, which was then filtered through a pad of silica gel (120 g) and eluted with 600 ml of ethyl acetate. Concentration in vacuo gave a beige solid, which was redissolved under reflux in ml of heptane and 150 ml of ethyl acetate. After hot filtration on a sintered funnel, the product crystallized at 0°C. The crystals were collected by filtration, washed with 8:3 cold heptane/ethyl acetate (2 x 80 ml) and dried (50°C, 10 mbar) overnight, yielding 94.0 g (85%) of formazan as white crystals. Sulfonate ester (d).
Preparation method of 4-methyl-2-(1,1,1-trifluoro-2-dimethyl-2-ethyl)pyridine 4-methyl-2-(1,1, Preparation of 1-trifluoro-2-dimethyl-2-ethyl)pyridine (1)
To 1,1,1-trifluoro-2-(4-methylpyridin-2-yl)propan-2-methanesulfonate (d) dissolved in 60 ml cyclohexane at 10°C (5.68 g, 20.1 mmol, 1.0 equiv) was added dropwise to the suspension AlMe3 (2.0 M, 15.0 ml, 30 mmol, 23.0 equiv) dissolved in hexane over 15 minutes. The reaction was warmed to room temperature and stirred at room temperature for 3 hours. The mixture was quenched by careful addition of 100 ml of 0°C water and stirred at room temperature for 15 minutes. After filtration in Cellflock plugs and elution with ethyl acetate, the phases were separated. The aqueous layer was extracted with ethyl acetate, and the combined organic phases were washed with water and saturated aqueous NaCl solution. After drying over Na2SO4, filtration and concentration in vacuo yielded a light brown oil, which was purified by silica gel chromatography (hexane/TBME=9:1) yielding 1.15 g (28%) of aminochloropyridine as free The desired compound (1) for color oil.
References
[1] From PCT Int. Appl., 2012117071, 07 Sep 2012
