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With potassium carbonate In N,N-dimethyl-formamide at 20℃;
Intermediate 1 : lsoxazolo[5,4-cipyridin-3-ylamine.; To a solution of 3-chloro-isonicotinitrile (1.13 g, 8.36 mmol) in DMF (6.0 mL) were added potassium carbonate (1.69 g, 12.2 mmol) and acetohydroxamic acid (0.91 g, 12.2 mmol). The reaction mixture was stirred at rt overnight, diluted with EtOAc (200 mL) and extracted with saturated aqueous NaHCO3 (200 mL) then saturated aqueous NaCI (100 mL). The aqueous layers were back extracted with EtOAc (200 mL) and the combined organic layers were dried (MgSO4) and concentrated. The crude residue was purified (FCC, 2 N NH3 in MeOH/DCM) to give isoxazolo[5,4-c]pyhdin-3-ylamine (0.447 g, 41 percent). MS (ESI+): calcd for C6H5N3O m/z 135.04, found 136.2 (M+H)+. 1H NMR (d6-DMSO): 8.93 (d, J = 0.8, 1 H), 8.45 (d, J = 5.2, 1 H), 7.88-7.86 (dd, J = 5.2, 1.2, 1 H), 6.72 (br s, 2H).
Reference：
[1] Patent: WO2010/68452, 2010, A1, . Location in patent: Page/Page column 26
[2] Bioorganic and Medicinal Chemistry Letters, 2012, vol. 22, # 24, p. 7357 - 7362
Synthesis of intermediate VX001: Isoxazolo[5,4-b]pyridin-3-amine 909 mg (8.1 mmol) of KO-t-Bu were added, with vigorous stirring, to a suspension of 668 mg (8.9 mmol) of acethydroxamic acid in DMF (20 ml), and the mixture was stirred for 30 min at RT. 990 mg (8.1 mmol) of 2-fluoro-nicotinonitrile were then added, and stirring was carried out for a further 5 h at 50 C. The mixture was then extracted with EA and the organic phase was dried over Na2SO4, filtered and concentrated in vacuo. CC (hexane/EA 7:3) of the residue yielded 305 mg (2.3 mmol, 28%) of isoxazolo[5,4-b]pyridin-3-amine.
b) 4-Ethoxybenzo[d]isoxazol-3-amine I53 To a solution of acetohydroxamic acid (2.18 g, 29 mmol) in DMF (40 ml.) at 0 C under N2was added t-BuOK (3.26 g, 29 mmol) and the mixture was stirred at RT for 1 h. 2-Ethoxy-6-fluorobenzonitrile I52 (1.6 g, 9.7 mmol) was then added and the mixture was stirred at RT overnight. The mixture was diluted with DCM (80 ml_), washed with water (60 ml. x 4), dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (Pet.ether/EtOAc = 5/1) to give the title compound (240 mg, 15%) as a white solid. LCMS- E: Rt5.05 min; m/z 179.0 [M+H]+.
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