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Freshly prepared sodium methoxide (from 1.5 g sodium in 15 mL dry methanol) was added dropwise to a solution of Example 16 (5.0 g, 26 mmol) in dry methanol (25 mL). The reaction mixture was refluxed for 24 h, allowed to cool to RT and poured in aqueous HCl (10%, 100 mL). A pinkish solid separated and was collected on a filter, washed with water and air-dried (4.0 g, 82%). IH NMR (400 MHz, DMSO-d6) 5 3.89 (s, 3H) 7.17 (s, 1H) 7.39 (s, 1H) 13.96 (br s, OH).
81%
In methanol; for 24h;Reflux;
200 mL of a25% solution of sodium methoxide in methanol was added on a solution of 10.3 g (53.6 mmol) of 2,6-dichloropyridine-4-carboxylic acid (1) in100 mL of methanol and refluxed for 24 h. The mixture was cooled toroom temperature, filtered off and evaporated. The solid was dissolvedin water, acidified with 2 N HCl and extracted with ethyl acetate. Theorganic phase was dried over anhydrous Na2SO4, filtered andevaporated, to obtain 8.1 g (43.2 mmol, 81%) of 2-chloro-6-methoxypyridine-4-carboxylic acid (2) as a brown amorphous solid.1H NMR (200 MHz, CD3OD): 3.87 (3H, s), 7.15 (1H, s), 7.36 (1H, s). 13CNMR (50 MHz, CD3OD): 54.5 (CH3), 109.4 (CH), 115.5 (CH), 144.3 (C),148.1 (C), 164.1 (C), 164.6 (C).
2-(1 -Ethyl -propyl)-6-methoxy-isonicotinic acid; a) To a solution of 2,6-dichloroisonicotinic acid (200 g, 1.04 mol) in methanol (3 L), 32% aq. NaOH (770 mL) is added. The stirred mixture becomes warm (34C) and is then heated to 700C for 4 h before it is cooled to rt. The mixture is neutralised by adding 32% aq. HCI (100 mL) and 25% aq. HCI (700 mL). The mixture is stirred at rt overnight. The white precipitate that forms is collected, washed with methanol and dried. The filtrate is evaporated and the residue is suspended in water (200 mL). The resulting mixture is heated to 600C. Solid material is collected, washed with water and dried. The combined crops give 2-chloro-6- methoxy-isonicotinic acid (183 g) as a white solid; LC-MS: tR = 0.80 min, [M+1]+ = 187.93.
a) To a solution of 2,6-dichloroisonicotinic acid (200 g, 1.04 mol) in methanol (3 L), 32% aq. NaOH (770 mL) is added. The stirred mixture becomes warm (34 C.) and is then heated to 70 C. for 4 h before it is cooled to rt. The mixture is neutralised by adding 32% aq. HCl (100 mL) and 25% aq. HCl (700 mL). The mixture is stirred at rt overnight. The white precipitate that forms is collected, washed with methanol and dried. The filtrate is evaporated and the residue is suspended in water (200 mL). The resulting mixture is heated to 60 C. Solid material is collected, washed with water and dried. The combined crops give 2-chloro-6-methoxy-isonicotinic acid (183 g) as a white solid; LC-MS: tR=0.80 min, [M+1]+=187.93.
183 g
With sodium hydroxide; In water; at 70℃; for 4h;
a) To a solution of 2,6-dichloroisonicotinic acid (200 g, 1.04 mol) in methanol (3 L), 32% aq. NaOH (770 mL) is added. The stirred mixture becomes warm (34 C.) and is then heated to 70 C. for 4 h before it is cooled to rt. The mixture is neutralised by adding 32% aq. HCl (100 mL) and 25% aq. HCl (700 mL). The mixture is stirred at rt overnight. The white precipitate that forms is collected, washed with methanol and dried. The filtrate is evaporated and the residue is suspended in water (200 mL). The resulting mixture is heated to 60 C. Solid material is collected, washed with water and dried. The combined crops give 2-chloro-6-methoxy-isonicotinic acid (183 g) as a white solid; LC-MS: tR=0.80 min, [M+1]+=187.93.
Example 32; Synthesis of 2-chloro-6-methoxyisonicotinic; [0131] 2-Chloro-6-methoxyisonicotinic acid was synthesized by a known literature procedure [Tetrahedron 58 (2002) 6951] in 33 % yield from 2, 6-dichloroisonicotinic acid.
2-Cyclopentyl-6-methoxy-isonicotinic acida) To a solution of 2,6-dichloroisonicotinic acid (200 g, 1.04 mol) in methanol (3 L), 32% aq. NaOH (770 mL) is added. The stirred mixture becomes warm (34C) and is then heated to 70C for 4 h before it is cooled to rt. The mixture is neutralised by adding 32% aq. HCI (100 mL) and 25% aq. HCI (700 mL). The mixture is stirred at rt overnight. The white precipitate that forms is collected, washed with methanol and dried. The filtrate is evaporated and the residue is suspended in water (200 mL). The resulting mixture is heated to 60C. Solid material is collected, washed with water and dried. The combined crops give 2-chloro-6- methoxy-isonicotinic acid (183 g) as a white solid; LC-MS: tR = 0.80 min, [M+1]+ = 187.93
To a solution of 13.6 g (102 mmol, 2 eq) sodium hydroxide in 50 ml MeOH 10.0 g (51 mmol, 1 eq) 2,6-dichloro-isonicotinic acid are added. The reaction mixture is heated at reflux temperature for 30 min. After cooling to rt the mixture is diluted with water and acidified to pH 5-6 with 4 N HCl. Extraction with EtOAc, drying over sodium sulfate and evaporation of the solvent gives a first amount of the product. The water layers are evaporated to about 250 ml, acidified with 4 N HCl to pH 4-5 and again extracted with EtOAc. The extracts are dried over sodium sulfate and evaporated to give a further amount of the product. The product contains traces of 2,6-dimethoxy-isonicotinic acid.MS (LC/MS): 188/190=[M+H]+ 1H-NMR (400 MHz, d6-DMSO): 7.38 (s, 1H), 7.16 (s, 1H), 3.90 (s, 3H).
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