Citric Acid → N-methoxy-2-(4-methoxy-1H-pyrazolo[3,4-b]pyridin-1-yl)-N-methyl-3-(tetrahydro-2H-pyran-4-yl)propanamide

Temperature

100 °C

A mixture of ethyl 2-(4-iodo-1H-pyrazolo[3,4-b]pyridin-1-yl)-3-(tetrahydro-2H-pyran-4-yl)propanoate (1.69 g), sodium cyclopropanesulfinate (1.5 g), copper (I) iodide (0.22 g), N,N′-dimethylethylenediamine (0.13 mL), potassium carbonate (1.6 g) and dimethyl sulfoxide (25 mL) was stirred overnight at 100° C. To the reaction mixture was added aqueous citric acid solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4), and concentrated. The obtained residue was dissolved in a mixed solvent of tetrahydrofuran (10 mL) and methanol (10 mL). To this solution was added an aqueous solution of potassium hydroxide (0.65 g) in water (5 mL), and the mixture was stirred overnight at room temperature. To the reaction mixture was added aqueous citric acid solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4), and concentrated. A mixture of the obtained residue, N,O-dimethylhydroxylamine hydrochloride (0.38 g), triethylamine (0.54 mL) and N,N-dimethylformamide (20 mL) was ice-cooled, 1H-1,2,3-benzotriazol-1-ol (0.45 g) and N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride (0.64 g) were added thereto, and the mixture was stirred overnight under ice-cooling to at room temperature. To the reaction mixture was added aqueous sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed successively with aqueous sodium hydrogen carbonate solution and saturated brine, dried (MgSO4), and concentrated. The obtained residue was subjected to silica gel column chromatography to give the title compound (0.37 g, yield 27%) as a colorless oil from the fraction eluted with ethyl acetate-hexane (65:35, volume ratio). MS: 349 (MH+).

1. extractionthe mixture was extracted with ethyl acetate
2. washThe ethyl acetate layer was washed with saturated brine
3. dry with materialdried (MgSO4)
4. concentrationconcentrated
5. dissolutionThe obtained residue was dissolved in a mixed solvent of tetrahydrofuran (10 mL) and methanol (10 mL)
6. additionTo this solution was added an aqueous solution of potassium hydroxide (0.65 g) in water (5 mL)
7. stirringthe mixture was stirred overnight at room temperature
8. additionTo the reaction mixture was added aqueous citric acid solution
9. extractionthe mixture was extracted with ethyl acetate
10. washThe ethyl acetate layer was washed with saturated brine
11. dry with materialdried (MgSO4)
12. concentrationconcentrated
13. additionA mixture of the obtained residue, N,O-dimethylhydroxylamine hydrochloride (0.38 g), triethylamine (0.54 mL) and N,N-dimethylformamide (20 mL)
14. temperaturecooled
15. addition1H-1,2,3-benzotriazol-1-ol (0.45 g) and N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride (0.64 g) were added
16. stirringthe mixture was stirred overnight under ice-
17. temperaturecooling to at room temperature
18. additionTo the reaction mixture was added aqueous sodium hydrogen carbonate solution
19. extractionthe mixture was extracted with ethyl acetate
20. washThe ethyl acetate layer was washed successively with aqueous sodium hydrogen carbonate solution and saturated brine
21. dry with materialdried (MgSO4)
22. concentrationconcentrated

ORD record

ord-ea04252d1ba542b9a60d300fcd2f0165

Source dataset

uspto-grants-2013_01

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08349886B2