Acetic Acid → HCID 86724158, compound

HRID 1748835Notes

Reaction equation

C([O:3][C:4](=O)[CH2:5][C:6]1[N:10]([CH3:11])[N:9]=[C:8]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=2)[C:7]=1[CH:18]([C:25]1[CH:34]=[CH:33][C:28]([C:29]([O:31]C)=[O:30])=[CH:27][C:26]=1[CH3:35])[CH2:19][CH2:20]C(OC)=O)C.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].CC(O)=O.Cl>C1(C)C=CC=CC=1>[CH3:35][C:26]1[CH:27]=[C:28]([CH:33]=[CH:34][C:25]=1[CH:18]1[C:7]2[C:8]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=3)=[N:9][N:10]([CH3:11])[C:6]=2[CH2:5][C:4](=[O:3])[CH2:20][CH2:19]1)[C:29]([OH:31])=[O:30]

Participants

Conditions

Temperature: 0 °C

Procedure

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).

Workup

customA flask fitted with a Dean-Stark apparatus
additioncontaining
customdry molecular sieves
temperatureThe mixture was heated
temperatureto reflux for about 16 h
customThe Dean-Stark apparatus was removed
temperatureto slowly warm to rt in the cold bath
waitAfter about 4 h
temperatureThe mixture was cooled to about 0° C.
customThe mixture was partitioned between EtOAc (100 mL) and brine (100 mL)
washThe organic layer was washed with brine (100 mL)
dry with materialdried over Na2SO4
filtrationfiltered
concentrationconcentrated in vacuo
dissolutionThe residue was dissolved in 1,4-dioxane (4 mL)
temperatureThe mixture was heated at about 100° C. for about 16 h
temperaturethen cooled to rt
concentrationconcentrated in vacuo
customto remove the dioxane
extractionThe mixture was extracted with EtOAc (2×100 mL)
dry with materialThe combined organic solutions were dried with Na2SO4
filtrationfiltered
concentrationconcentrated in vacuo
customThe residue was purified by column chromatography (SiO2

Sources & evidence

ORD record: ord-f425bd37c2884fe29216e570951d272b
Source dataset: uspto-grants-2015_10
DOI: 10.6084/m9.figshare.5104873.v1
Patent number: US09150592B2

Reaction notes

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