Hydrochloric Acid → Ethyl 2-cyano-2-[4-methyl-6-(trifluoromethyl)pyrimidin-2-yl]acetate hydrochloride salt

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Reaction Steps

A solution of 1,1,1-trifluoro-2,4-pentanedione (5.00 g; 32.4 mmol) and S-methylisothiourea hemisulfate (4.06 g; 29.2 mmol) in pyridine (3.75 mL) and water (62 mL) was heated at reflux for 1 day. The mixture was cooled to room temperature, extracted with chloroform, and the chloroform extract washed with water to give 4-methyl-2-(methylthio)-6-(trifluoromethyl)pyrimidine as an off-white solid (4.60 g, 22.1 mmol). This was dissolved in MeOH (60 mL), and a solution of OXONE® (27.1 g, 44.2 mmol) in water (100 mL) was added over 10 min. The mixture was stirred at room temperature for 4 hr and then extracted with EA. The EA was washed with water, dried, and concentrated to give 4-methyl-2-(methylsulfonyl)-6-(trifluoromethyl)pyrimidine (4.8 g) as a white solid. Sodium hydride (0.16 g of a 60% dispersion in mineral oil; 4.0 mmol) was added to a stirred solution of ethyl cyanoacetate (0.21 mL; 2.0 mmol) in THF (8 mL), and the resulting suspension stirred at room temperature for 15 min. 4-Methyl-2-(methylsulfonyl)-6-(trifluoromethyl)pyrimidine (0.48 g; 2.0 mmol) was then added, and the mixture stirred overnight. Water was added, followed by 1M hydrochloric acid to adjust to pH 3-4. The solid that formed solid was filtered, washed with water, and dried under high vacuum to give ethyl 2-cyano-2-[4-methyl-6-(trifluoromethyl)pyrimidin-2-yl]acetate hydrochloride salt (0.43 g) as a pale yellow solid.

Provenance & Evidence