METHYL 6-OXO-1,6-DIHYDRO-3-PYRIDINECARBOXYLATE

A suspension of 5-hydroxynicotinic acid (200 g, 1438 mmol) in methanol (1.0 1) was treated drop wise over 25 min with sulfuric acid (84 ml, 1505 mmol, exothermic.), heated to reflux and stirred at this temperature for 18 h. The yellow solution was cooled to ca. 30°C and the solvent evaporated under reduced pressure (ca. 50-100 mbar) until a residual volume of ca. 600 ml. The solvent of the formed suspension was exchanged by water keeping the volume of ca. 600 ml. The suspension was stirred for 1 h at room temperature. The crystals were filtered, washed with water (50 ml) and dried to isolate the product in 68percent yield.MS (GC_Split): 153 (M, 64percent), 122 (100percent), 94 (36), 66 (14).Intermediate 116Methyl 6-hydroxynicotininate 6-Hydroxy-nicotinic acid (100 g, 719 mmol) was suspended in methanol (1 L). 18M Sulfuric acid (50 rnL) was added and the reaction was heated at reflux for 16 h. The reaction mixture was then cooled, and sodium bicarbonate powder (45 g) was added slowly to neutralize some of the acid. Most of the methanol was then removed in vacuo. Water (IL) was added, and the pH adjusted to 7 with the careful addition of bicarbonate solution. The suspension was extracted with dichloromethane (4x, 200 mL), and the organic phases were combined, dried over sodium sulfate, and the solvent was removed in vacuo. The solid was dried in a vacuum oven at 5OExample 16-Hydroxy-nicotinic acid methyl esterA suspension of 5-hydroxynicotinic acid (200 g, 1438 mmol) in methanol (1.0 l) was treated drop wise over 25 min with sulfuric acid (84 ml, 1505 mmol, exothermic.), heated to reflux and stirred at this temperature for 18 h. The yellow solution was cooled to ca. 30° C. and the solvent evaporated under reduced pressure (ca. 50-100 mbar) until a residual volume of ca. 600 ml. The solvent of the formed suspension was exchanged by water keeping the volume of ca. 600 ml. The suspension was stirred for 1 h at room temperature. The crystals were filtered, washed with water (50 ml) and dried to isolate the product in 68percent yield. MS (GC_Split): 153 (M, 64percent), 122 (100percent), 94 (36), 66 (14).Reference Example 36-1 To a solution of methyl coumalate (308mg, 2.0 mmol) in MeCN (1 mL) was added hexamethyldisilazane (387 mg, 2.4 mmol) and DBU(16 mL) and the mixture was stirred for 48 h at room temperature. After the solvent was removedunder vacuuo, the residue was chromatographed on silica gel (AcOEt/hexane = 4 : 1) to give1ad (213 mg, 70percent): 1H NMR (400MHz, CD3OD): δ 8.12 (s, 1H, Ar), 7.97 (d, 1H, J = 9.7 Hz, Ar), 6.50 (d, 1H, J = 9.7 Hz, Ar), 3.82 (s, 3H, Me); 13C NMR (100.5 MHz, CD3OD): δ 165.9, 165.5, 141.8, 141.2, 120.3, 111.7, 52.4.Stage 1.-Preparation of 6-Hydroxynicotinamide Step A: 6-Hydroxy-nicotinic acid methyl esterTo the solution of 6-hydroxy nicotinic acid (1.070 g, 7.69 mmol) in benzene (45 mL) and methanol (15 mL) is added TMS diazomethane (5.00 mL, 10.00 mmol) dropwise over 5 minutes. The reaction is stirred at room temperature for 4 hours. The reaction is evaporated in vacuo to give the desired product (1 g, 84.9percent). Step 1: Reference Example 55 6-Hydroxynicotinic Acid Methyl Ester To 500 ml of methyl alcohol, cooled to 0-5 C. is added HCl gas over 30 minutes. The solution is allowed to reach room temperature and 50 g of 6-hydroxynicotinic acid added. The reaction mixture is stirred at reflux for 2 days. The methyl alcohol is removed in vacuo and the residue suspended in 200 ml of water and poured into 300 ml of saturated aqueous NaHCO3. The insoluble crystals are collected by filtration, washed with 500 ml of water and dried under vacuum at 60 C. to give 53.9 g of the desired productA suspension of 5-hydroxynicotinic acid (200 g, 1438 mmol) in methanol (1.0 1) was treated drop wise over 25 min with sulfuric acid (84 ml, 1505 mmol, exothermic.), heated to reflux and stirred at this temperature for 18 h. The yellow solution was cooled to ca. 30C and the solvent evaporated under reduced pressure (ca. 50-100 mbar) until a residual volume of ca. 600 ml. The solvent of the formed suspension was exchanged by water keeping the volume of ca. 600 ml. The suspension was stirred for 1 h at room temperature. The crystals were filtered, washed with water (50 ml) and dried to isolate the product in 68% yield.MS (GC_Split): 153 (M, 64%), 122 (100%), 94 (36), 66 (14).Intermediate 116Methyl 6-hydroxynicotininate 6-Hydroxy-nicotinic acid (100 g, 719 mmol) was suspended in methanol (1 L). 18M Sulfuric acid (50 rnL) was added and the reaction was heated at reflux for 16 h. The reaction mixture was then cooled, and sodium bicarbonate powder (45 g) was added slowly to neutralize some of the acid. Most of the methanol was then removed in vacuo. Water (IL) was added, and the pH adjusted to 7 with the careful addition of bicarbonate solution. The suspension was extracted with dichloromethane (4x, 200 mL), and the organic phases were combined, dried over sodium sulfate, and the solvent was removed in vacuo. The solid was dried in a vacuum oven at 5O0C for 1.5 h to give 83g (75%) of Example 16-Hydroxy-nicotinic acid methyl esterA suspension of 5-hydroxynicotinic acid (200 g, 1438 mmol) in methanol (1.0 l) was treated drop wise over 25 min with sulfuric acid (84 ml, 1505 mmol, exothermic.), heated to reflux and stirred at this temperature for 18 h. The yellow solution was cooled to ca. 30 C. and the solvent evaporated under reduced pressure (ca. 50-100 mbar) until a residual volume of ca. 600 ml. The solvent of the formed suspension was exchanged by water keeping the volume of ca. 600 ml. The suspension was stirred for 1 h at room temperature. The crystals were filtered, washed with water (50 ml) and dried to isolate the product in 68% yield. MS (GC_Split): 153 (M, 64%), 122 (100%), 94 (36), 66 (14).Reference Example 36-1 Methyl 6-hydroxynicotinate To a suspension of 6-hydroxynictonic acid (5.23 g, 37.6 mmol) in methanol (60 ml) was added dropwise thionyl chloride (5.0 g, 42.0 mmol) at 55C, and the reaction mixture was stirred at 55C for one hour. To the reaction mixture was further added thionyl chloride (3.3 g, 27.7 mmol), and the mixture was stirred at 55C for 3 hours, and then further stirred at room temperature overnight. The reaction solution was neutralized (around pH 7) with a saturated aqueous sodium hydrogen carbonate solution and a 1N aqueous sodium hydroxide solution, and further it was made a saturated solution with sodium chloride. The reaction mixture was extracted three times with ethyl acetate. The organic layers were combined, and washed with a saturated saline, dried over magnesium sulfate, and the solvent was evaporated under reduced pressure to give the title compound (3.15 g, 55 %). 1H-NMR (400MHz in CDCl3) delta 12.65 (1H, brs), 8.19 (1H, d, J = 2.5 Hz), 8.00 (1H, dd, J = 9.6, 2.5 Hz), 6.58 (1H, d, J = 9.6 Hz), 3.87 (3H, s).General procedure: 6-Hydroxybenzoic acid and 6-hydroxynicotinic acid were previously transformed in their corresponding methyl esters, using methanol-sulfuric acid under reflux by 5days. Methyl esters were benzylated using benzyl chloride in acetonitrile as solvent and NaHCO3, the mixture was kept under reflux for 3days. After this time, the solvent was evaporated and the benzyloxy esters were hydrolyzed in KOH by refluxing for 1h. benzyloxy acids were purified by column chromatography using Silica gel 60 and a mobile phase of CHCl3/CH3OH (90/10).

Molecular Weight:153.14
XLogP3:-0.2
Hydrogen Bond Donor Count:1
Hydrogen Bond Acceptor Count:3
Rotatable Bond Count:2
Exact Mass:153.042593085
Monoisotopic Mass:153.042593085
Topological Polar Surface Area:55.4
Heavy Atom Count:11
Complexity:252
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes