Diisopropylethylamine → 3-{1-[2-(5-Methyl-3-trifluoromethyl-pyrazol-1-yl)-acetyl]-piperidin-4-yl}-benzoic acid ethyl ester

Participants

Reaction Steps

To a solution of (5-methyl-3-trifluoromethyl-pyrazol-1-yl)-acetic acid (5.23 g, 20.75 mmol) in DMF (50 mL) was added diisopropylethylamine (43 mL, 207.58 mmol), followed by 2-(1H-7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyl uronium hexafluorophosphate methanaminium (10.52 g, 22.83 mmol) at RT. After stirring 15 min. at RT, 3-piperidin-4-yl-benzoic acid ethyl ester hydrochloride salt (5.6 g, 20.75 mmol) was added to the reaction mixture. After stirring overnight at RT, solvent was evaporated and the resulting brown oil was dissolved in ethylacetate (200 mL), washed with aq. sat. sodium bicarbonate solution (100 mL) and the aqueous phase was re-extracted with ethylacetate (200 mL). The combined organic layers were washed with 1M HCl solution (400 mL) and brine (400 mL), dried over sodium sulfate, filtered, and evaporated under reduce pressure. The crude mixture was purified by column chromatography on silica gel (ethylacetate/cyclohexane 0:1 to 1:1) to give 3-{1-[2-(5-methyl-3-trifluoromethyl-pyrazol-1-yl)-acetyl]-piperidin-4-yl}-benzoic acid ethyl ester (4.35 g, 49.5%). 1H-NMR (400 MHz, d6-DMSO): δ=1.28-1.39 (t, 3H), 1.45-1.55 (m, 1H), 1.65-1.1.79 (m, 1H), 1.80-1.91 (m, 2H), 2.22 (s, 3H), 2.68-2.73 (m, 1H), 2.89-2.95 (m, 1H), 3.99-4.04 (m, 1H), 4.29-4.33 (q, 2H), 4.46-4.52 (m, 1H), 5.21-5.38 (dd, 2H, diastereotopic), 6.50 (s, 1H), 7.47 (t, 1H), 7.55 (d, 1H), 7.80 (s, 1H), 7.81 (d, 1H). MS: m/z=424 (M+1).

Provenance & Evidence