Tetrahydrofuran → HCID 57786270, compound

To a solution of 1-[1-(4-bromo-2-chlorophenyl)-9-chloro-1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazol-6-yl]propan-1-ol (300.0 mg, 0.659 mmol) in tetrahydrofuran (4.0 mL) was added n-butyllithium (1.60 M solution in n-hexane, 0.91 mL, 1.450 mmol) at −78° C., and the mixture was stirred for 30 min. Carbon dioxide gas was bubbled through the mixture for 30 min. The mixture was quenched with aqueous saturated ammonium chloride and added 1N sodium hydroxide solution and extracted with ethyl acetate (×2). The aqueous layer was acidified with 1N hydrochloric acid and extracted with ethyl acetate (×3). The combined organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The crude compound was subjected to next step without further purification. To a solution of crude material (73.2 mg) in tetrahydrofuran (2.0 mL)/pyridine (0.2 mL) was added acetic anhydride (0.1 mL) at 0° C. The reaction mixture was stirred at room temperature for 14 hrs. The mixture was neutralized with aqueous saturated sodium hydrogen carbonate and concentrated. The residue was extracted with ethyl acetate (×3). The combined organic layer was washed with brine (×1), dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The crude compound was subjected to next step without further purification. To a solution of crude material (58.9 mg) in N,N-dimethylformamide (1.3 mL) were added 1-hydroxy-1H-benzotriazole ammonium salt (25.2 mg, 0.166 mmol) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (26.8 mg, 0.140 mmol). The reaction mixture was stirred at room temperature for 16 hrs. The reaction mixture was quenched with aqueous saturated sodium hydrogen carbonate and extracted with ethyl acetate (×3). The combined organic layer was washed with water (×2), aqueous saturated sodium hydrogen carbonate (×1) and brine (×1), dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with a 0-100% ethyl acetate/n-hexane gradient mixture to give the title compound as a mixture. The residue was purified preparative HPLC to give the title compound as the trifluoroacetic acid salt. The salt was neutralized with aqueous saturated sodium hydrogen carbonate and extracted with ethyl acetate. The extract was washed with brine, dried over magnesium sulfate, filtered and concentrated in vacuo to give the title compound as an amorphous (16.5 mg, 0.0358 mmol, 5.4% (3 steps)).

1. customCarbon dioxide gas was bubbled through the mixture for 30 min
2. customThe mixture was quenched with aqueous saturated ammonium chloride
3. additionadded 1N sodium hydroxide solution
4. extractionextracted with ethyl acetate (×2)
5. extractionextracted with ethyl acetate (×3)
6. washThe combined organic layer was washed with brine
7. dry with materialdried over anhydrous magnesium sulfate
8. filtrationfiltered
9. concentrationconcentrated in vacuo
10. customThe crude compound was subjected to next step without further purification
11. additionTo a solution of crude material (73.2 mg) in tetrahydrofuran (2.0 mL)/pyridine (0.2 mL) was added acetic anhydride (0.1 mL) at 0° C
12. stirringThe reaction mixture was stirred at room temperature for 14 hrs
13. concentrationconcentrated
14. extractionThe residue was extracted with ethyl acetate (×3)
15. washThe combined organic layer was washed with brine (×1)
16. dry with materialdried over anhydrous magnesium sulfate
17. filtrationfiltered
18. concentrationconcentrated in vacuo
19. customThe crude compound was subjected to next step without further purification
20. stirringThe reaction mixture was stirred at room temperature for 16 hrs
21. customThe reaction mixture was quenched with aqueous saturated sodium hydrogen carbonate
22. extractionextracted with ethyl acetate (×3)
23. washThe combined organic layer was washed with water (×2), aqueous saturated sodium hydrogen carbonate (×1) and brine (×1)
24. dry with materialdried over anhydrous magnesium sulfate
25. filtrationfiltered
26. concentrationconcentrated in vacuo
27. customThe residue was purified by silica gel column chromatography
28. washeluting with a 0-100% ethyl acetate/n-hexane gradient mixture

ORD record

ord-c9d87acae31b4da994392f18c408262b

Source dataset

uspto-grants-2014_07

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08785460B2