6-HYDROXYNICOTINIC ACID ETHYL ESTER

Preparation of 5-(fro[2, 3-b]pyridin-5-yl)-3-((4-(4-(1, 1, 1, 3, 3, 3-hexafluoro-2-hydroxypropan-2-yl)-2-propylphenoxy) pyridin-2-yl)methyl)-5-methylimidazolidine-2, 4-dione; 148-a-1) Preparation of ethyl 6-hydroxynicotinate; To a solution of 6-hydroxynicotinic acid (5.0 g, 35.9 mmol) in ethanol (180 mL), sulfuric acid (1.0 mL) was added. The resultant mixture was stirred at 60° C. for 20 minutes, then added with surfuric acid (33.0 mL), and stirred for 6.5 hours while heated to reflux. The reaction solution was then added with a saturated aqueous solution of sodium hydrogen carbonate under ice-cold conditions and ethanol was concentrated in vacuo. After extracted with ethyl acetate, the organic layer was washed with brine, dried over sodium sulfate, and concentrated in vacuo. Ethyl 6-hydroxynicotinate (5.33 g, yield 89percent) was obtained as a white crystal.To a stirred solution of 6-hydroxynicotinic acid (10 g, 72 mmol) in absolute ethanol (500 mL) was added sulfuric acid (4 mL) at room temperature. The mixture was heated to reflux for 48 h. After cooling down to room temperature, water (50 mL) was added and the reaction mixture was neutralised to pH= 6-7 by portionwise addition of sodiumhydrogen carbonate (caution: gas evolution). The mixture was evaporated under reduced pressure (most of ethanol was removed), and the residue was extracted with ethyl acetate (3 × 50 mL). The combined organic extracts were washed with brine, dried over Na2SO4 and evaporated under reduced pressure leading to the pure ethyl 6-hydroxynicotinate[30] (10 g, 86percent). 1H NMR (400 MHz, CDCl3): δ 13.07 (s, 1H), 8.14 (s, 1H), 7.94 (d, 1H, J = 9.9 Hz), 6.51 (d, 1H, J = 9.4 Hz), 4.25 (q, 2H, J =7.1 Hz), 1.29 ppm.To a stirred solution of lithium aluminium hydride (1.4 g, 37 mmol, 1.2 equiv.) in anhydrous THF (20 mL) at room temperature was added dropwise over 1 h a solution of ethyl 6-hydroxynicotinate (5.1 g, 31 mmol) in anhydrous THF (150 mL) at the same temperature. The mixture was stirred at room temperature for 2 h and then heated toreflux for 30 min. The reaction mixture was cooled down to 0 °C andquenched with ethyl acetate (12 mL) and water (6 mL). The solventswere removed and the residue was taken up in refluxing ethanol(200 mL). The solution was filtered through Celite® and ethanol was evaporated under reduced pressure. The crude material was purified bycolumn chromatography on silica gel with ethyl acetate/methanol(75:25) as eluent to afford the pure title compound 12 (2.3 g, 60percent).31.1 6-hydroxy-nicotinic acid ethyl ester Example 148; Preparation of 5-(fro[2, 3-b]pyridin-5-yl)-3-((4-(4-(1, 1, 1, 3, 3, 3-hexafluoro-2-hydroxypropan-2-yl)-2-propylphenoxy) pyridin-2-yl)methyl)-5-methylimidazolidine-2, 4-dione; 148-a-1) Preparation of To a stirred solution of 6-hydroxynicotinic acid (10 g, 72 mmol) in absolute ethanol (500 mL) was added sulfuric acid (4 mL) at room temperature. The mixture was heated to reflux for 48 h. After cooling down to room temperature, water (50 mL) was added and the reaction mixture was neutralised to pH= 6-7 by portionwise addition of sodiumhydrogen carbonate (caution: gas evolution). The mixture was evaporated under reduced pressure (most of ethanol was removed), and the residue was extracted with ethyl acetate (3 × 50 mL). The combined organic extracts were washed with brine, dried over Na2SO4 and evaporated under reduced pressure leading to the pure 31.1 To a stirred solution of 6-hydroxynicotinic acid (10 g, 72 mmol) in absolute ethanol (500 mL) was added sulfuric acid (4 mL) at room temperature. The mixture was heated to reflux for 48 h. After cooling down to room temperature, water (50 mL) was added and the reaction mixture was neutralised to pH= 6-7 by portionwise addition of sodiumhydrogen carbonate (caution: gas evolution). The mixture was evaporated under reduced pressure (most of ethanol was removed), and the residue was extracted with ethyl acetate (3 × 50 mL). The combined organic extracts were washed with brine, dried over Na2SO4 and evaporated under reduced pressure leading to the pure

Molecular Weight:167.16
XLogP3:0.1
Hydrogen Bond Donor Count:1
Hydrogen Bond Acceptor Count:3
Rotatable Bond Count:3
Exact Mass:167.058243149
Monoisotopic Mass:167.058243149
Topological Polar Surface Area:55.4
Heavy Atom Count:12
Complexity:266
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes