Acetamidine monohydrochloride → 4-(3,5-ditert-butyl-4-hydroxy-phenyl)-N,2-dimethyl-pyrimidine-5-carboxamide

Temperature

75 °C

A 50-mL round bottom flask was charged with 3-(3,5-ditert-butyl-4-hydroxy-phenyl)-3-oxo-propanoic acid methyl amide (3.05 g, 10 mmol) and toluene (20 mL). The mixture was warmed to give a solution, then N,N-dimethylformamide dimethyl acetal (1.60 mL, 12 mmol) was added while the solution was still hot. The mixture was stirred for 2 h at room temperature and 30 min 75° C. To this solution was added acetamidine hydrochloride (1.8908 g, 20 mmol) and 2-propanol (50 mL), followed by potassium tert. butoxide (3.14 g, 28 mmol). The stirred mixture was immersed into a bath maintained at 74° C. and after 50 min the temperature of the heating bath was increased to 80° C. and maintained for 80 min. The mixture was allowed to cool to ambient temperature and was equilibrated with water (50 mL), a 1 M solution of potassium dihydrogen phosphate and ethyl acetate (100 mL). The aqueous layer was discarded and the organic layer was washed with water (2×25 mL), brine (25 mL), dried with sodium sulfate, concentrated to a crystalline suspension and heated again to dissolve some of the solids. The resulting suspension was further diluted with cyclohexane and allowed to crystallize. The crystals were washed with cyclohexane and pentane, and dried. The resulting material (2.94 g) was dissolved in a mixture of acetone and ethanol. The solution was filtered, the filtrate was concentrated to a crystalline suspension, then reheated and sufficient hot ethanol was added to give a solution. This solution was concentrated until turbid, and then allowed to crystallize first at room temperature then at 5° C. The solids were filtered off, washed with 1:1 ethyl acetate-hexane and hexane to afford 2.50 g of the title compound (70% yield). TLC (EtOAc) Rf 0.30; 1H-NMR (300 MHz, DMSO-d6) δ 1.39 (9H, s), 2.65 (3H, s), 2.71 (3H, d, J=4.5 Hz), 7.50 (1H, s), 7.83 (2H, s), 8.50 (1H, br s), 8.72 (1H, s).

1. temperatureThe mixture was warmed
2. customto give a solution
3. customThe stirred mixture was immersed into a bath
4. temperaturemaintained at 74° C. and after 50 min the temperature of the heating bath
5. temperaturewas increased to 80° C.
6. temperaturemaintained for 80 min
7. temperatureto cool to ambient temperature
8. washthe organic layer was washed with water (2×25 mL), brine (25 mL)
9. dry with materialdried with sodium sulfate
10. concentrationconcentrated to a crystalline suspension
11. temperatureheated again
12. dissolutionto dissolve some of the solids
13. additionThe resulting suspension was further diluted with cyclohexane
14. customto crystallize
15. washThe crystals were washed with cyclohexane and pentane
16. customdried
17. dissolutionThe resulting material (2.94 g) was dissolved in a mixture of acetone and ethanol
18. filtrationThe solution was filtered
19. concentrationthe filtrate was concentrated to a crystalline suspension
20. additionsufficient hot ethanol was added
21. customto give a solution
22. concentrationThis solution was concentrated until turbid
23. customto crystallize first at room temperature
24. customat 5° C
25. filtrationThe solids were filtered off
26. washwashed with 1:1 ethyl acetate-hexane and hexane

ORD record

ord-2c692267594b43c785fda2fef77c8de3

Source dataset

uspto-grants-2016_02

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US09249107B2