Acetic Acid → HCID 86724158, compound

Participants

Reaction Conditions

Reaction Steps

A flask fitted with a Dean-Stark apparatus containing dry molecular sieves was charged with a solution of methyl 4-(1-(5-(2-ethoxy-2-oxoethyl)-1-methyl-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-4-methoxy-4-oxobutyl)-3-methylbenzoate (0.590 g, 1.20 mmol) in toluene (120 mL). The mixture was heated to reflux for about 16 h. The Dean-Stark apparatus was removed and the mixture was cooled to about 0° C. 1 M lithium bis(trimethylsilyl)amide in toluene (1.20 mL, 1.20 mmol) was added in dropwise manner. The mixture was allowed to slowly warm to rt in the cold bath. After about 2 h, 1 M lithium bis(trimethylsilyl)amide in toluene (0.60 mL, 0.60 mmol) was added dropwise. After about 4 h, 1 M lithium bis(trimethylsilyl)amide in toluene (0.30 mL, 0.30 mmol) was added dropwise and the reaction was stirred at rt for about 16 h. The mixture was cooled to about 0° C. then HOAc (10 mL) was added. The mixture was partitioned between EtOAc (100 mL) and brine (100 mL). The organic layer was washed with brine (100 mL), dried over Na2SO4, filtered and concentrated in vacuo. The residue was dissolved in 1,4-dioxane (4 mL) and 6 N aqueous HCl (8.0 mL, 48.0 mmol). The mixture was heated at about 100° C. for about 16 h then cooled to rt and concentrated in vacuo to remove the dioxane. The mixture was neutralized with saturated NaHCO3 then adjusted to pH 5 with HOAc. The mixture was extracted with EtOAc (2×100 mL). The combined organic solutions were dried with Na2SO4, filtered and concentrated in vacuo. The residue was purified by column chromatography (SiO2, O-5% MeOH/DCM) to give 3-methyl-4-(1-methyl-7-oxo-3-(pyridin-2-yl)-1,4,5,6,7,8-hexahydrocyclohepta[c]pyrazol-4-yl)benzoic acid (0.277 g, 58%): LC-MS (Table 1, Method g) Rt=1.66 min, m/z 376 (M+H)+; 1H-NMR (DMSO, Bruker 400 MHz) δ 12.57 (s, 1H), 8.32-8.25 (m, 1H), 7.72-7.57 (m, 3H), 7.43-7.39 (m, 1H), 7.07-7.03 (m, 1H), 6.68 (d, J=8.0 Hz, 1H), 5.32-5.27 (m, 1H), 4.23 (d, J=15.6 Hz, 1H), 3.97 (d, J=15.6 Hz, 1H), 3.89 (s, 3H), 2.64-2.55 (m, 4H), 2.40-2.27 (m, 2H), 2.18-2.05 (m, 1H).

Provenance & Evidence