Synthesis
Step Ia: 5-(Trifluoromethyl)-2-chloro-3-nitropyridine (0.850 g, 3.75 mmol) was dissolved in methanol (17 mL), and palladium carbon (800 mg, 10% wetted, 0.375 mmol) was added. The reaction mixture was hydrogenated for 16 h at 60 psi hydrogen pressure and 20 °C. The progress of the reaction was monitored by LCMS to confirm that the starting material (M + H 213/215, 3:1) and hydroxylamine intermediate were completely consumed and a mixture of partially reduced product (M + H 163; UVmax 214, 258, 332 nm) and completely reduced product (M + H 169; no UV absorption) was detected. After completion of the reaction, the reaction mixture was filtered and the filter cake was washed well with methanol. The filtrate was concentrated in vacuum to give 0.74 g of product in the form of HCl salt. Subsequently, the product was purified by preparative HPLC/MS using a 30 mm × 100 mm C18 column; the mobile phase was 20% acetonitrile-water (containing 0.1% NH4OH), with an initial hold of 1 min and a gradient up to 40% over 6 min; the flow rate was 60 mL/min; the detector was set at m/z 163; and the product retention time was 4.4 min. Fractions containing the pure product were collected, combined and concentrated to give 52 mg of the product as an oil in 8% yield.1H NMR (CDCl3) δ 8.26 (s, 1H); 8.24 (d, 1H); 7.15 (t, 1H); 4.00 (s, 2H).
References
[1] Patent: WO2008/79965, 2008, A1. Location in patent: Page/Page column 72-73
[2] Patent: US2006/4018, 2006, A1. Location in patent: Page/Page column 14; 35-36
