2,4-Dichloropyridine → 1-Amino-2,4-dichloropyridinium 2,4,6-trimethylbenzenesulfonate

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To a cooled solution (0° C., ice bath) containing 2,4-dichloropyridine (4.0 g, 27.0 mmol) and dichloromethane (60 mL) was added O-(mesitylsulfonyl)hydroxylamine (10.2 g, 27.0 mmol) in dichloromethane (75 mL) quickly, dropwise. The solution was maintained at 0° C. for 15 min, removed from the cooling bath and maintained at ambient temperature for 20 h. The solution was concentrated to afford 1-amino-2,4-dichloropyridinium 2,4,6-trimethylbenzenesulfonate as a light yellow foam (165 MH+). The product thus obtained was combined with tert-butyl 3-(4-fluorophenyl)propioloyl(methyl)carbamate (6.6 g, 24.0 mmol) and THF (100 mL). The resultant solution was cooled to −78° C. (dry ice, acetone bath) and DBU (7.2 mL, 48.0 mmol) was added dropwise over 10 min with rapid stirring. The mixture was kept in the cooling bath with stirring and allowed to proceed for 15 h at ambient temperature. The mixture was then filtered and concentrated. Purification on silica gel (0-80% ethyl acetate/hexanes, 60 min gradient) afforded an off white residue. The residue thus obtained was further purified using preparative HPLC (Phenomonex-Luna, 50×100 mm, 5 micron, C18 column; 0.1M TFA, 0-100% B (B=10% H2O/CH3OH)/A (A=90% H2O/CH3OH), 15 min. gradient) to afford tert-butyl 5,7-dichloro-2-(4-fluorophenyl)pyrazolo[1,5-a]pyridine-3-carbonyl(methyl)carbamate as a white solid. Preparative HPLC retention time: 14.0 min. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.81 (d, J=2.26 Hz, 1H), 7.71 (dd, J=8.91, 5.40 Hz, 2H), 7.16 (t, J=8.66 Hz, 2H), 7.03 (d, J=2.26 Hz, 1H), 3.26 (s, 3H), 1.12 (s, 9H). LCMS retention time: 2.810 min. LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Phenomenex-Luna, 10 micron, C18, 3.0×50 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 4 mL/min, a gradient of 100% solvent A/0% solvent B to 0% solvent A/100% solvent B, a gradient time of 3 min, a hold time of 1 min, and an analysis time of 4 min where solvent A was 10% CH3OH/90% H2O/10 mM TFA and solvent B was 10% H2O/90% CH3OH/10 mM TFA. MS data was determined using a Micromass Platform for LC in electrospray mode. m/z 460 (MNa+).

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