Sulfuric Acid → 5,7-Dihydropyrido[2,3-d][3]benzazepin-6-one

Temperature

88 °C

Add potassium carbonate (235.7 g, 1.71 mol) to a solution of 2-amino-3-bromopyridine (88.5 g, 511.7 mmol) in 1,4-dioxane (550 mL) and water (550 mL). Degas the mixture with three cycles of vacuum/nitrogen, add palladium (II) acetate (6.4 g, 28.4 mmol) and tri-t-butylphosphonium tetrafluoroborate (16.5 g, 56.9 mmol) and stir under nitrogen at 88° C. Add a solution of methyl 2-[2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]acetate (157.0 g, 568.5 mmol) in 1,4-dioxane (550 mL) dropwise over three minutes and stir the mixture at 88° C. for 20 minutes. Cool mixture to 50° C., add water (100 mL), and separate layers. Extract from aqueous with ethyl acetate (2×100 mL), dry combined organics over sodium sulfate and concentrate. Dissolve the concentrated material in N-methylpyrrolidone (314 mL), cool in ice bath and add sulfuric acid (314 mL, 5.9 mol) dropwise to maintain a temperature of approximately 45° C. Stir mixture at 140° C. for 90 minutes. Cool to ambient temperature, add ice (4 kg) and basify with portion wise addition of 50% aqueous NaOH solution until solution is pH 7-8. Cool suspension to 10-15° C., filter out solids and wash with water (2 L), hexanes (1 L) and methyl tertiary butyl ether (1 L). Dry under vacuum at 40° C. Treat material with refluxing mixture of 10% methanol/dichloromethane solution and filter hot (×4). Concentrate combined filtrates to afford the title compound as a light brown solid (85 g, 404.3 mmol, 71%). MS (m/z): 211 (M+1).

1. customDegas the mixture with three cycles of vacuum/nitrogen
2. stirringstir the mixture at 88° C. for 20 minutes
3. temperatureCool mixture to 50° C.
4. customseparate layers
5. extractionExtract from aqueous with ethyl acetate (2×100 mL)
6. dry with materialdry combined organics over sodium sulfate
7. concentrationconcentrate
8. dissolutionDissolve the concentrated material in N-methylpyrrolidone (314 mL)
9. temperaturecool in ice bath
10. temperatureto maintain a temperature of approximately 45° C
11. stirringStir mixture at 140° C. for 90 minutes
12. temperatureCool to ambient temperature
13. temperatureCool suspension to 10-15° C.
14. filtrationfilter out solids
15. washwash with water (2 L), hexanes (1 L) and methyl tertiary butyl ether (1 L)
16. customDry under vacuum at 40° C
17. temperatureTreat material with refluxing
18. additionmixture of 10% methanol/dichloromethane solution
19. filtrationfilter hot (×4)
20. concentrationConcentrate

ORD record

ord-a751bdc4723c4a23a80cdf108794901e

Source dataset

uspto-grants-2013_10

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08569286B2