Dimethylformamide dimethyl acetal → 4-Methyl-2-(methylsulfanyl)pyrimidine

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Reaction Steps

A 22 L round bottom flask equipped with an air stirrer, heating mantle, thermometer, and reflux condenser was charged with toluene (12 L), 2-mercapto-4-methylpyrimidine hydrochloride (1) (900 g, 5.53 mol), diisopropylethylamine (1.07 kg, 8.30 mol), and N,N-dimethylformamide dimethyl acetal (1.61 kg, 12.7 mol). The reaction mixture was heated to reflux for 3.5 hours, and then the red solution was concentrated under reduced pressure to remove toluene, methanol, and some N,N-dimethylformamide. The residue was then treated with ethyl acetate (2 L), water (2 L), and enough 10% (w/v) aqueous sodium bisulfate solution to reach a pH of 4.5. After mixing, the organic layer was siphoned into a separate container, and the aqueous layer was extracted with additional ethyl acetate (2×2 L). All organic extracts were combined, dried over sodium sulfate, and concentrated under reduced pressure to yield ˜1 L of a red oil, which was then purified by vacuum distillation at <1 mm Hg. Fractions that distilled off are as follows: T=30°-50° C.: ˜100 mL ethyl acetate and N,N-dimethylformamide; T=60°-70° C.: 436.8 g product +14.5 g N,N-dimethylformamide; T=68°-72° C.: 267.4 g of pure product. Identity and purity of each fraction was determined by 1H NMR. Fractions 2 and 3 were combined and used in the next step without further purification. Yield of 2: 704.2 g (91%). 1H NMR (400 MHz, CDCl3) δ 2.38 (s, 3H), 2.49 (s, 3H), 6.75 (d, J=5.2 Hz, 1H), 8.29 (d, J=5.2 Hz, 1H). MS (ESI+) 141.1.

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