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

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.

1. customA 22 L round bottom flask equipped with an air stirrer
2. temperatureheating mantle
3. temperaturethermometer, and reflux condenser
4. temperatureThe reaction mixture was heated
5. temperatureto reflux for 3.5 hours
6. concentrationthe red solution was concentrated under reduced pressure
7. customto remove toluene, methanol
8. additionThe residue was then treated with ethyl acetate (2 L), water (2 L), and enough 10% (w/v) aqueous sodium bisulfate solution
9. additionAfter mixing
10. extractionthe aqueous layer was extracted with additional ethyl acetate (2×2 L)
11. dry with materialdried over sodium sulfate
12. concentrationconcentrated under reduced pressure

ORD record

ord-00fdc7451a7341299f677beb99af8ad6

Source dataset

uspto-grants-2009_03

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US07504501B2