Hydrochloric Acid → 2,4-Dimethylpyrimidin-5-ol

Temperature

107.5 °C

To a 22-Liter round bottomed flask was charged potassium tert-butoxide (1200 g, 11 mol, 3.5 equiv.) and 1-butanol (2700 mL). The mixture was stirred for 40 mins and then 1-decanethiol (1300 mL, 6.1 mol, 2.0 equiv.) was added. To the resulting slurry was added portionwise, 5-methoxy-2,6-dimethylpyrimidin-1-ium chloride (17, 532 g, 3.05 mol, 1.0 equiv.), using a minimal amount of 1-butanol for rinses as needed. The mixture was heated to 105-110° C. and stirred for 24 hours at this temperature. The mixture was cooled to room temperature and aqueous hydrochloric acid solution (6 N, 2000 mL) was added slowly, maintaining the internal temperature below 35° C. Heptane (2700 mL) was added and the mixture stirred for 10 mins. Stirring was halted and the phases were separated. The upper organic phase was backwashed with additional 6 N HCl solution (1000 mL). The aqueous phases were combined and neutralized by addition of aqueous sodium hydroxide solution (50% w/w, 789 mL) to pH=7-8, then extracted with 2-methyltetrahydrofuran (2×3000 mL) The 2-methyltetrahydrofuran was removed by vacuum distillation and replaced with heptane (3000 mL). The mixture was concentrated to near dryness and heptane (1300 mL was added). The resulting slurry was filtered and the wet cake was washed with heptane (3×400 mL). The cake was dried under vacuum with a nitrogen sweep to afford 2,4-dimethylpyrimidin-5-ol (18, 281 g, 74% yield) as an off-white solid.

1. additionTo the resulting slurry was added portionwise
2. stirringstirred for 24 hours at this temperature
3. temperatureThe mixture was cooled to room temperature
4. temperaturemaintaining the internal temperature below 35° C
5. stirringthe mixture stirred for 10 mins
6. stirringStirring
7. customthe phases were separated
8. additionneutralized by addition of aqueous sodium hydroxide solution (50% w/w, 789 mL) to pH=7-8
9. extractionextracted with 2-methyltetrahydrofuran (2×3000 mL) The 2-methyltetrahydrofuran
10. customwas removed by vacuum distillation
11. concentrationThe mixture was concentrated
12. filtrationThe resulting slurry was filtered
13. washthe wet cake was washed with heptane (3×400 mL)
14. customThe cake was dried under vacuum with a nitrogen sweep

ORD record

ord-37ca968d5dc3419e8e1965b1a3724c9b

Source dataset

uspto-grants-2016_08

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US09416109B2