Potassium Carbonate → 1-(2,4-Dichlorophenyl)-N,N-diethyl-3,3-difluoro-1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazol-6-amine

Temperature

0 °C

To a solution of 3-{2-[(2,4-dichlorophenyl)amino]-7-(diethylamino)-1H-benzimidazol-1-yl}-2,2-difluoropropan-1-ol (Reference example 154, 48.9 mg, 0.110 mmol) in pyridine (1.5 mL) was added methanesulfonyl chloride (25.6 μL, 0.330 mmol) at 0° C. The mixture was stirred at 0° C. for 2 hrs. The starting material wasn't consumed completely. To the mixture was added methanesulfonyl chloride (25.6 μL, 0.330 mmol) at 0° C. and the mixture was stirred at room temperature for 14 hrs. The mixture was quenched with 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 resulting mesylate was dissolved into N,N-dimethylformamide (1.5 mL) and to the solution was added potassium carbonate (30.4 mg, 0.220 mmol) at room temperature. The mixture was stirred at 40° C. for 1 hr. After cooling, the mixture was diluted with water and extracted with ethyl acetate. The combined organic layer was washed with water and brine, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with a 0-40% ethyl acetate/n-hexane gradient mixture. The resulting solid was recrystallized from hexane to give the title compound as a solid (24.0 mg, 0.0564 mmol, 51%).

1. customThe starting material wasn't consumed completely
2. stirringthe mixture was stirred at room temperature for 14 hrs
3. customThe mixture was quenched with aqueous sodium hydrogen carbonate
4. extractionextracted with ethyl acetate
5. washThe combined organic layer was washed with brine
6. dry with materialdried over anhydrous magnesium sulfate
7. filtrationfiltered
8. concentrationconcentrated in vacuo
9. dissolutionThe resulting mesylate was dissolved into N,N-dimethylformamide (1.5 mL) and to the solution
10. stirringThe mixture was stirred at 40° C. for 1 hr
11. temperatureAfter cooling
12. extractionextracted with ethyl acetate
13. washThe combined organic layer was washed with water and brine
14. dry with materialdried over anhydrous magnesium sulfate
15. filtrationfiltered
16. concentrationconcentrated in vacuo
17. customThe residue was purified by silica gel column chromatography
18. washeluting with a 0-40% ethyl acetate/n-hexane gradient mixture
19. customThe resulting solid was recrystallized from hexane

ORD record

ord-277cbc18cddf4c3292856b3957a8c6fe

Source dataset

uspto-grants-2014_12

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08901141B2