Tetrahydrofuran → 1-[1-(2,4-Dichlorophenyl)-1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazol-6-yl]-N,N-dimethylpropan-1-amine

Temperature

50 °C

Ethylmagnesium bromide (3.0 M solution in diethyl ether, 3.19 mL, 9.57 mmol) was added to a stirred solution of 1-(2,4-dichlorophenyl)-1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazole-6-carbonitrile (1.64 g, 4.78 mmol) in tetrahydrofuran (15 mL) at 0° C., and the mixture was stirred at 50° C. for 2 hr. The reaction was quenched by water, and the mixture was extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. Sodium borohydride (361 mg, 9.54 mmol) was added to a stirred solution of the resulting imine, and the mixture was stirred at room temperature for 2 hr. The reaction was quenched by aqueous saturated ammonium chloride and the mixture was extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. Formaldehyde (36-38% solution in water, 678 mg) was added to a solution of the resulting benzylamine (510 mg) in acetonitrile (4.0 mL). After 5 min sodium cyanoborohydride (510 mg, 8.14 mmol) was added to the mixture, and the mixture was stirred at room temperature for 3 hr. The mixture was diluted with saturated aqueous sodium hydrogen carbonate and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel eluting with a 5-50% ethyl acetate/n-hexane gradient mixture. The filtrate was concentrated in vacuo to give the solid, which was recrystallized from ethyl acetate/diisopropyl ether to give the title compound as a colorless crystal (100 mg, 0.248 mmol, 18% in 3 steps).

1. customThe reaction was quenched by water
2. extractionthe mixture was extracted with ethyl acetate
3. washThe combined organic layer was washed with brine
4. dry with materialdried over anhydrous magnesium sulfate
5. filtrationfiltered
6. concentrationconcentrated in vacuo
7. stirringthe mixture was stirred at room temperature for 2 hr
8. customThe reaction was quenched by aqueous saturated ammonium chloride
9. extractionthe mixture was extracted with ethyl acetate
10. washThe combined organic layer was washed with brine
11. dry with materialdried over anhydrous magnesium sulfate
12. filtrationfiltered
13. concentrationconcentrated in vacuo
14. additionFormaldehyde (36-38% solution in water, 678 mg) was added to a solution of the resulting benzylamine (510 mg) in acetonitrile (4.0 mL)
15. stirringthe mixture was stirred at room temperature for 3 hr
16. extractionextracted with ethyl acetate
17. washThe combined organic layer was washed with brine
18. dry with materialdried over anhydrous magnesium sulfate
19. filtrationfiltered
20. concentrationconcentrated in vacuo
21. customThe residue was purified by flash column chromatography on silica gel eluting with a 5-50% ethyl acetate/n-hexane gradient mixture
22. concentrationThe filtrate was concentrated in vacuo
23. customto give the solid, which
24. customwas recrystallized from ethyl acetate/diisopropyl ether

ORD record

ord-1bb59111e3874b8b91543824d0c232dc

Source dataset

uspto-grants-2014_12

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08901141B2