Dimethylacetamide → 10-bromo-3-(2-chlorobenzyl)-6,7-dihydro-5H-5,7-methanobenzo[c]imidazo[1,2-a]azepine-2-carboxamide

Temperature

50 °C

A solution of methyl 10-bromo-3-iodo-6,7-dihydro-5H-5,7-methanobenzo[c]imidazo[1,2-a]azepine-2-carboxylate (150 mg, 0.33 mmol) in dry dimethylacetamide (DMA, 1.0 mL) was sparged with nitrogen gas and treated with PdCl2-[P(o-Tol)3]2 (27 mg, 0.033 mmol). A degassed solution of 2-chlorobenzylzinc bromide (0.61 M, 0.96 mL, 0.59 mmol) was added over 5 min dropwise. The flask was sealed under nitrogen and heated at 50° C. An additional 0.5 mL, of the zinc reagent was added under nitrogen sparge. After 30 min, LCMS indicated complete consumption. The mixture was diluted with ammonium chloride and extracted with ethyl acetate. The combined organics were washed with brine, dried over sodium sulfate and concentrated by rotoevaporation. The crude residue was dissolved in DMF (2 mL) and treated with formamide (1 mL) then sodium methoxide (0.5 mL, 25 wt % in methanol). After 20 min at 50° C., complete conversion to the amide was evident by LCMS. The mixture was diluted with water and extracted with ethyl acetate. The combined organics were washed with brine, dried over sodium sulfate and concentrated by rotoevaporation. The amide was used in subsequent steps without further purification.

1. customThe flask was sealed under nitrogen
2. customsparge
3. customconsumption
4. additionThe mixture was diluted with ammonium chloride
5. extractionextracted with ethyl acetate
6. washThe combined organics were washed with brine
7. dry with materialdried over sodium sulfate
8. concentrationconcentrated by rotoevaporation
9. dissolutionThe crude residue was dissolved in DMF (2 mL)
10. additiontreated with formamide (1 mL)
11. waitAfter 20 min at 50° C.
12. additionThe mixture was diluted with water
13. extractionextracted with ethyl acetate
14. washThe combined organics were washed with brine
15. dry with materialdried over sodium sulfate
16. concentrationconcentrated by rotoevaporation
17. customThe amide was used in subsequent steps without further purification

ORD record

ord-d5de18719a03437aab172cfaaa81a7a3

Source dataset

uspto-grants-2015_05

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US09034866B2