1-Dodecanethiol → 2,4-Dimethylpyrimidin-5-ol

Temperature

12.5 °C

1-Butanol (158 mL) was added into the reaction flask which was fitted with a mechanical stirrer, a temperature probe, nitrogen inlet, and distillation equipment. The solvent was cooled to 10-15° C. and potassium t-butoxide (33.7 g, 0.3 mol) was charged in 3 portions maintaining an internal temperature less than 40° C. 1-Dodecanethiol (43.2 mL, 0.18 mol) was added to the resulting suspension, and was agitated at 20-25° C. for 30 min. 1-Dodecanethiol (43.2 mL, 0.18 mol) was added to the suspension and the mixture was stirred at room temperature for an additional 30 min. Next, 5-methoxy-2,6-dimethylpyrimidin-1-ium chloride, 17, (21 g, 0.12 mol) was added in 3 portions with efficient agitation, and the inlet was rinsed with 1-butanol (10 mL). The reaction flask was degassed with vacuum and purged with nitrogen (3×) and then maintained under a nitrogen atmosphere. The reaction mixture was heated to 117˜120° C., and volatile tert-butanol (=30 mL) was collected. Then, the reaction was aged at reflux temperature (120-125° C.) for 20 h (conversion was 99.5%). The reaction mixture was cooled to 10-15° C., and 6 N HCl (90 mL) charged at 10-15° C. Deionized water was added (63 mL), and the reaction was aged for 20 min at room temperature. Heptane (126 mL) was added, agitated for 15 min, and allowed to split for 15 min. The product containing lower aqueous layer was drained to a suitable vessel. The upper organic layer was extracted with a combined solution of water (84 mL), 6 N HCl (21 mL) and MeOH (42 mL). The organic layer was back-extracted with water (42 mL). The aqueous layers were combined, and cooled to 10-15° C. The pH of the aqueous layer was adjusted to 6.8-7.2 with 50% sodium hydroxide (26 mL). Sodium chloride (37.8 g) was added, and the reaction was agitated for 30 min. 2-MeTHF (140 mL) was charged, agitated for 15 min, and allowed to split. The aqueous layer was back-extracted twice with 2-MeTHF (140 mL) with pH adjustment of the aqueous layer after each extraction (0.5 mL of 6 N HCl, desired pH in aqueous layer is 6.8˜7.2). Note: The pH of the aqueous layer went up slightly after each extraction, and it should be adjusted accordingly (with 0.25 mL of 6 N HCl). The organic layers were combined and concentrated at reduced pressure to a minimum stirrable volume maintaining the internal temperature below 40° C. The concentrated solution was dried azeotropically with 2-MeTHF (3×65 mL), and then 2-MeTHF was charged to adjust the final solvent volume to 100 mL (any product on the wall of the reactor should be dissolved). Insoluble inorganic material was filtered off using a sintered glass funnel. The reactor and filter pot were rinsed with 2-MeTHF (40 mL). The filtrate was concentrated under a reduced pressure maintaining the internal temperature below 40° C. to ca. 60 mL of total batch volume. The reaction was next chased with heptane (4×80 mL) and the final batch volume was adjusted to a total volume of 65 mL. Then, the slurry mixture was cooled to 0-5° C. over 30 min, and aged for 1 h at this temperature. The resulting slurry was filtered, and the wet cake was rinsed with pre-cooled (0-5° C.) heptane (63 mL). The wet cake was dried under vacuum with a nitrogen flush at room temperature for 24 h to afford 11.6 g of 2,4-dimethylpyrimidin-5-ol, (18, 78˜85% yield).

1. customwas fitted with a mechanical stirrer
2. distillationa temperature probe, nitrogen inlet, and distillation equipment
3. temperaturemaintaining an internal temperature less than 40° C
4. stirringthe mixture was stirred at room temperature for an additional 30 min
5. washthe inlet was rinsed with 1-butanol (10 mL)
6. customThe reaction flask was degassed with vacuum
7. custompurged with nitrogen (3×)
8. temperaturemaintained under a nitrogen atmosphere
9. temperatureThe reaction mixture was heated to 117˜120° C.
10. customvolatile tert-butanol (=30 mL) was collected
11. temperatureat reflux temperature (120-125° C.) for 20 h (conversion was 99.5%)
12. temperatureThe reaction mixture was cooled to 10-15° C.
13. addition6 N HCl (90 mL) charged at 10-15° C
14. additionDeionized water was added (63 mL)
15. waitthe reaction was aged for 20 min at room temperature
16. additionHeptane (126 mL) was added
17. stirringagitated for 15 min
18. customto split for 15 min
19. additionThe product containing lower aqueous layer
20. customwas drained to a suitable vessel
21. extractionThe upper organic layer was extracted with a combined solution of water (84 mL), 6 N HCl (21 mL) and MeOH (42 mL)
22. extractionThe organic layer was back-extracted with water (42 mL)
23. temperaturecooled to 10-15° C
24. additionSodium chloride (37.8 g) was added
25. stirringthe reaction was agitated for 30 min
26. addition2-MeTHF (140 mL) was charged
27. stirringagitated for 15 min
28. customto split
29. extractionThe aqueous layer was back-extracted twice with 2-MeTHF (140 mL) with pH adjustment of the aqueous layer
30. extractionafter each extraction (0.5 mL of 6 N HCl
31. extractionafter each extraction, and it
32. concentrationconcentrated at reduced pressure to a minimum stirrable volume
33. temperaturemaintaining the internal temperature below 40° C
34. dry with materialThe concentrated solution was dried azeotropically with 2-MeTHF (3×65 mL)
35. addition2-MeTHF was charged
36. dissolutionshould be dissolved)
37. filtrationInsoluble inorganic material was filtered off
38. filtrationThe reactor and filter pot
39. washwere rinsed with 2-MeTHF (40 mL)
40. concentrationThe filtrate was concentrated under a reduced pressure
41. temperaturemaintaining the internal temperature below 40° C. to ca. 60 mL of total batch volume
42. temperatureThen, the slurry mixture was cooled to 0-5° C. over 30 min
43. waitaged for 1 h at this temperature
44. filtrationThe resulting slurry was filtered
45. washthe wet cake was rinsed
46. temperaturewith pre-cooled (0-5° C.) heptane (63 mL)
47. customThe wet cake was dried under vacuum with a nitrogen
48. customflush at room temperature for 24 h

ORD record

ord-59587db983604edf9a99d59853505bd0

Source dataset

uspto-grants-2016_08

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US09416109B2