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

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).

1. stirringAfter stirring overnight at RT
2. customsolvent was evaporated
3. dissolutionthe resulting brown oil was dissolved in ethylacetate (200 mL)
4. washwashed with aq. sat. sodium bicarbonate solution (100 mL)
5. extractionthe aqueous phase was re-extracted with ethylacetate (200 mL)
6. washThe combined organic layers were washed with 1M HCl solution (400 mL) and brine (400 mL)
7. dry with materialdried over sodium sulfate
8. filtrationfiltered
9. customevaporated
10. customThe crude mixture was purified by column chromatography on silica gel (ethylacetate/cyclohexane 0:1 to 1:1)

ORDレコード

ord-c0e554e0f79946b3994a23893ca4f742

出典データセット

uspto-grants-2013_02

DOI

10.6084/m9.figshare.5104873.v1

特許番号

US08367844B2