3-Hydroxybenzaldehyde → 1-(3-(Cyclopropylmethoxy)phenyl)ethanamine

Temperature

90 °C

3-Hydroxybenzaldehyde (692 mg) was dissolved in DMF (25 mL). To the solution, potassium carbonate (1.56 g), potassium iodide (95 mg), and (chloromethyl)cyclopropane (578 μL) were added, and the mixture was stirred at 90° C. for 4 hours. To the reaction mixture, water (20 mL) was added, and the resultant mixture was then extracted with toluene (20 mL). The organic layer was washed with brine (20 mL), dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The residue was dissolved in THF (2.5 mL). To the mixture, a solution of methylmagnesium bromide in THF (1.0 M, 6.5 mL) was added dropwise at 0° C., and the mixture was stirred at room temperature for 2 hours. To the reaction mixture, an aqueous saturated ammonium chloride solution (10 mL) was added at 0° C., and the resultant mixture was then extracted with ethyl acetate (20 mL×2). The organic layer was washed with brine (20 mL), dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (40% ethyl acetate/hexane). The obtained compound was dissolved in THF (5.0 mL). To the solution, diphenylphosphoryl azide (875 μL) and DBU (592 μL) were added dropwise at room temperature, and the mixture was stirred for 1 hour. To the reaction mixture, brine (10 mL) was added, and the resultant mixture was then extracted with ethyl acetate (20 mL×2). The organic layer was washed with brine (10 mL), dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (20% ethyl acetate/hexane). The obtained compound was dissolved in methanol (7.5 mL). To the solution, 10% palladium-carbon (180 mg) was added, and the reaction mixture was stirred at room temperature for 2 hours under a hydrogen atmosphere. The precipitate was removed by filtration through a pad of Celite and washed with methanol (100 mL). Then, the combined filtrate was concentrated under reduced pressure to obtain the title compound (740 mg) as a crude product.

1. extractionthe resultant mixture was then extracted with toluene (20 mL)
2. washThe organic layer was washed with brine (20 mL)
3. dry with materialdried over anhydrous sodium sulfate
4. concentrationconcentrated under reduced pressure
5. dissolutionThe residue was dissolved in THF (2.5 mL)
6. additionTo the mixture, a solution of methylmagnesium bromide in THF (1.0 M, 6.5 mL) was added dropwise at 0° C.
7. stirringthe mixture was stirred at room temperature for 2 hours
8. additionTo the reaction mixture, an aqueous saturated ammonium chloride solution (10 mL) was added at 0° C.
9. extractionthe resultant mixture was then extracted with ethyl acetate (20 mL×2)
10. washThe organic layer was washed with brine (20 mL)
11. dry with materialdried over anhydrous sodium sulfate
12. concentrationconcentrated under reduced pressure
13. customThe residue was purified by silica gel column chromatography (40% ethyl acetate/hexane)
14. dissolutionThe obtained compound was dissolved in THF (5.0 mL)
15. additionTo the solution, diphenylphosphoryl azide (875 μL) and DBU (592 μL) were added dropwise at room temperature
16. stirringthe mixture was stirred for 1 hour
17. additionTo the reaction mixture, brine (10 mL) was added
18. extractionthe resultant mixture was then extracted with ethyl acetate (20 mL×2)
19. washThe organic layer was washed with brine (10 mL)
20. dry with materialdried over anhydrous sodium sulfate
21. concentrationconcentrated under reduced pressure
22. customThe residue was purified by silica gel column chromatography (20% ethyl acetate/hexane)
23. dissolutionThe obtained compound was dissolved in methanol (7.5 mL)
24. additionTo the solution, 10% palladium-carbon (180 mg) was added
25. stirringthe reaction mixture was stirred at room temperature for 2 hours under a hydrogen atmosphere
26. customThe precipitate was removed by filtration through a pad of Celite
27. washwashed with methanol (100 mL)
28. concentrationThen, the combined filtrate was concentrated under reduced pressure

ORD record

ord-cdb2e2ea909b42e6b62c5b87c66064a9

Source dataset

uspto-grants-2014_11

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08883759B2