Hydrochloric Acid → HCID 86724153, compound

Participants

Reaction Conditions

Reaction Steps

A microwave vial was charged with 4-(5-chloro-1-methyl-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-4-(4-chloro-2-methylphenyl)butanoic acid (2.00 g, 4.94 mmol), potassium ferrocyanide trihydrate (3.14 g, 7.42 mmol), diacetoxypalladium (0.112 g, 0.494 mmol), dicyclohexyl(2′,4′,6′-triisopropyl-[1,1′-biphenyl]-2-yl)phosphine (0.472 g, 0.990 mmol) and potassium carbonate (1.71 g, 12.36 mmol). The vial was evacuated and backfilled with argon. 1,4-Dioxane (10 mL) and H2O (10 mL) were added then argon was bubbled through the mixture for about 15 min. The mixture was heated at about 120° C. for about 40 h then cooled to rt and partitioned between EtOAc (600 mL) and 20% citric acid (400 mL). The insoluble material was removed by filtration then the filtrate layers were separated. The collected solids were triturated with EtOAc (200 mL) and 20% citric acid (200 mL). The insoluble material was removed by filtration then the filtrate layers were separated. The combined organic layers were washed with H2O (600 mL) and brine (600 mL), dried over Na2SO4, filtered and concentrated in vacuo. The residue was treated with potassium ferrocyanide trihydrate (1.31 g, 3.09 mmol), diacetoxypalladium (0.056 g, 0.247 mmol), dicyclohexyl(2′,4′,6′-triisopropyl-[1,1′-biphenyl]-2-yl)phosphine (0.236 g, 0.495 mmol) and potassium carbonate (0.769 g, 5.57 mmol). The flask was evacuated and backfilled with argon. 1,4-Dioxane (5 mL) and H2O (5 mL) were added and argon was bubbled through the reaction for about 15 min. The mixture was heated at about 120° C. for about 8 h then cooled to rt and partitioned between EtOAc (300 mL) and 20% citric acid (200 mL). The insoluble material was removed by filtration then the filtrate layers were separated. The collected solids were triturated with EtOAc (100 mL) and 20% citric acid (100 mL), filtered then the filtrate layers were separated. The combined organic layers were washed with H2O (300 mL) and brine (300 mL), dried over Na2SO4, filtered and concentrated u in vacuo. The residue was semi-purified by column chromatography (SiO2, 0-2% MeOH/DCM) and the product-containing fractions were concentrated in vacuo. The residue was dissolved in dioxane (30 mL) then 4 N aqueous NaOH (40 mL, 160 mmol) was added. The mixture was heated at about 100° C. for about 16 h then allowed to cool to rt. The mixture was neutralized by the dropwise addition of concentrated hydrochloric acid (4.85 mL, 160 mmol). The layers were separated and the organic layer was washed with 20% citric acid (300 mL), H2O (2×300 mL) and brine (300 mL) dried with Na2SO4, filtered and concentrated in vacuo. The residue was purified by column chromatography (SiO2, 0-5% MeOH/DCM) and the product containing fractions were concentrated in vacuo. The residue was dissolved in 2-Me THF (300 mL) and washed with H2O (3×400 mL) and brine (300 mL), dried with Na2SO4, filtered and concentrated in vacuo to give 4-(3-carboxy-1-(5-chloro-1-methyl-3-(pyridin-2-yl)-1H-pyrazol-4-yl)propyl)-3-methylbenzoic acid (1.11 g, 2.68 mmol, 54%): LC-MS (Table 1, Method g) Rt=1.64 min, m/z 404/414 (M+H)+; 1H-NMR (DMSO, Bruker 400 MHz) δ 12.31 (s, 1H), 8.60-8.57 (m, 1H), 7.87-7.79 (m, 2H), 7.72-7.67 (m, 1H), 7.65-7.62 (m, 1H), 7.50 (d, J=8.1 Hz, 1H), 7.36-7.28 (m, 1H), 5.39-5.33 (m, 1H), 3.84 (s, 3H), 2.46-2.18 (m, 4H), 2.12 (s, 3H).

Provenance & Evidence