Citric Acid → 2-[4-(cyclopropylsulfonyl)-1H-indazol-1-yl]-N-methoxy-N-methyl-3-(tetrahydro-2H-pyran-4-yl)propanamide

Temperature

100 °C

A mixture of ethyl 2-(4-bromo-1H-indazol-1-yl)-3-(tetrahydro-2H-pyran-4-yl)propanoate (3.10 g), copper(I) iodide (0.46 g), N,N′-dimethylethylenediamine (0.26 mL), potassium carbonate (3.37 g), sodium cyclopropanesulfinate (3.1 g) and dimethyl sulfoxide (30 mL) was stirred overnight at 100° C. To the reaction mixture was added 10% 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. To a mixture of the obtained residue, tetrahydrofuran (10 mL) and methanol (10 ml) was added 2M aqueous sodium hydroxide solution (8.0 mL), and the mixture was stirred at 50° C. for 4 hr. To the reaction mixture was added 10% 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. To a mixture of the obtained residue, N,O-dimethylhydroxylamine hydrochloride (1.60 g), triethylamine (2.3 mL), 1H-1,2,3-benzotriazol-1-ol (1.84 g) and N,N-dimethylformamide (25 mL) was added N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride (0.88 g), and the mixture was stirred overnight at room temperature. To the reaction mixture was added 10% aqueous citric acid solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed successively with saturated brine, saturated aqueous sodium hydrogen carbonate and saturated brine, dried (MgSO4), and concentrated. The obtained residue was subjected to silica gel column chromatography to give the title compound (2.30 g, yield 67%) as a yellow oil from the fraction eluted with ethyl acetate. MS: 422 (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. additionTo a mixture of the obtained residue, tetrahydrofuran (10 mL) and methanol (10 ml)
6. additionwas added 2M aqueous sodium hydroxide solution (8.0 mL)
7. stirringthe mixture was stirred at 50° C. for 4 hr
8. additionTo the reaction mixture was added 10% 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. additionTo a mixture of the obtained residue, N,O-dimethylhydroxylamine hydrochloride (1.60 g), triethylamine (2.3 mL), 1H-1,2,3-benzotriazol-1-ol (1.84 g) and N,N-dimethylformamide (25 mL)
14. additionwas added N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride (0.88 g)
15. stirringthe mixture was stirred overnight at room temperature
16. additionTo the reaction mixture was added 10% aqueous citric acid solution
17. extractionthe mixture was extracted with ethyl acetate
18. washThe ethyl acetate layer was washed successively with saturated brine, saturated aqueous sodium hydrogen carbonate and saturated brine
19. dry with materialdried (MgSO4)
20. concentrationconcentrated

ORD record

ord-8682aa133005458aa25342ee3bbc9049

Source dataset

uspto-grants-2013_01

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08349886B2