Dimethylformamide dimethyl acetal → 4-(3,5-ditert-butyl-4-hydroxy-phenyl)-2-dimethylamino-N-methyl-pyrimidine-5-carboxamide

Temperature

80 °C

A 50-mL round bottom flask was charged with 3-(3,5-di-tert-butyl-4-hydroxy-phenyl)-3-oxo-propanoic acid methyl ester (2.69 g, 8.8 .mmol) and toluene (18 mL). The mixture was warmed to give a solution, then N,N-dimethylformamide dimethyl acetal (1.46 mL, 11 mmol) was added while the solution was still hot. The mixture was stirred for 2.5 h then evaporated. The residue was taken up in 2-propanol (28 mL) and 1,1-dimethylguanidine sulfate (1.80 g, 6.6 mmol) was added. The mixture was stirred at room temperature and a 1 M solution of potassium tert. butoxide in tert. butanol (21 mL) was added and the mixture was immersed into a bath maintained at 80° C. and stirred for 4 hours then at 50° C. overnight. The mixture was allowed to cool to room temperature, and was equilibrated with ethyl acetate (80 mL) and water (60 mL). The organic layer was washed with water (2×25 mL), once with brine (20 mL) then dried with sodium sulfate and evaporated to a brown solid. This material was boiled in dichloromethane (200 mL) without dissolving all solids. The mixture was allowed to cool and was filtered. The brown filtrate was charged to a column of silica gel G (70-230 mesh) in dichloromethane and using 1:4, 1:2, 1:1 ethyl acetate-hexane and ethyl acetate as mobile phases. The product was eluted with ethyl acetate and crystallized partly in the receptacles. The appropriate fractions were evaporated and the residue dissolved in a boiling ethanol-acetone mixture. The solution was concentrated, the resulting suspension diluted with cyclohexane and refrigerated. The solids were washed with 1:2 ethyl acetate-hexane to leave the title compound as a white powder, 1.52 g, 45% yield. TLC (ethyl acetate) Rf 0.73, TLC (1:1 ethyl acetate-hexane) Rf 0.20; 1H-NMR (300 MHz, DMSO-d6) δ 1.38 (9H, s), 2.64 (3H, d, J=4.5 Hz), 3.15 (6H, s), 7.60 (2H, s), 8.15 (1H, br s), 8.22 (1H, s).

1. temperatureThe mixture was warmed
2. customto give a solution
3. customthen evaporated
4. stirringThe mixture was stirred at room temperature
5. customthe mixture was immersed into a bath
6. stirringstirred for 4 hours
7. customat 50° C.
8. customovernight
9. temperatureto cool to room temperature
10. washThe organic layer was washed with water (2×25 mL), once with brine (20 mL)
11. dry with materialthen dried with sodium sulfate
12. customevaporated to a brown solid
13. dissolutionwithout dissolving all solids
14. temperatureto cool
15. filtrationwas filtered
16. additionThe brown filtrate was charged to a column of silica gel G (70-230 mesh) in dichloromethane
17. washThe product was eluted with ethyl acetate
18. customcrystallized partly in the receptacles
19. customThe appropriate fractions were evaporated
20. dissolutionthe residue dissolved in a boiling ethanol-acetone mixture
21. concentrationThe solution was concentrated
22. additionthe resulting suspension diluted with cyclohexane
23. washThe solids were washed with 1:2 ethyl acetate-hexane

ORD record

ord-7ded1fb3e00545b781d402981fd63fab

Source dataset

uspto-grants-2013_11

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08580805B2