Triethylamine → Pyrrolo[1,2-b]pyridazine-3-carboxylic acid, 4-chloro-, ethyl ester

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Reaction Conditions

Reaction Steps

To POCl3 (225 mL, 2.42 mmol) at 0° C. was added ethyl 4-hydroxypyrrolo[1,2-b]pyridazine-3-carboxylate (50 g, 0.242 mmol) and the mixture was stirred until complete dissolution. At this time, triethylamine (36.8 mL, 0.266 mmol) was added dropwise and the resulting mixture was heated to 110° C. and allowed to stir for ˜16 h. The resulting mixture was allowed to cool and the POCl3 was removed in vacuo to afford a dark brown residue. This material was dissolved in dichloromethane and was cooled to 0° C. and diluted with 375 mL of ethanol. The resulting mixture was stirred at 0° C. for 30 min and then at rt for 1 h. The ethanol was removed under vacuum and the resulting semi-solid was dissolved in dichloromethane and stirred with 10% aqueous NaHCO3 for 1 h. The mixture was filtered through celite and the phases were separated. The aqueous portion was extracted with additional dichloromethane and the combined organic layers were washed with brine, dried over Na2SO4, decanted and the solvent was removed under vacuum to give the crude product. The crude material was purified by flash silica gel column chromatography to yield 47 g (86%) of a solid as the title compound. 1H NMR (400 MHz, CDCl3) δ ppm: 1.43 (t, J=7.2, 6.8 Hz, 3 H), 4.43 (q, J=7.2, 6.8 Hz, 2 H), 6.940-6.99 (m, 2H), 7.84 (q, J=0.8, 1.6 Hz, 1 H), 8.51 (s, 1H)). 13C-NMR (400 MHz, DMS-d6) ppm: 163.30, 141.89, 138.16, 124.86, 120.69, 114.99, 109.90, 105.22, 61.55, 14.21. LCMS (conditions A): m/z 225. HPLC (condition B): Retention time=3.47 min.

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