Methanol → Benzoic acid, 3-methoxy-2-nitro-, methyl ester

To a stirred solution of 3-methoxy-2-nitro-benzoic acid (11.50 g) in DMF (100 ml) was added N,N′-carbonyldiimidazole (11.35 g) and the reaction mixture was stirred at room temperature for 45 minutes. Methanol (18.6 ml) was added and the mixture was stirred at room temperature for 60 minutes. The mixture was poured into water (800 ml) containing some ice and the precipitated material was isolated by filtration and crystallised from hot ethanol and gave 3-Methoxy-2-nitro-benzoic acid methyl ester. Step 2: The above obtained methyl ester (11.81 g) was suspended in water (45 ml) and ethanol (60 ml). Ammonium chloride (12.26 g) was added followed by addition of iron powder (11.86 g). The reaction mixture was heated to reflux and stirred for 1 hour. The mixture was cooled on an ice bath and was then filtrated though a pad of Celite. The filtrate was evaporated under reduced pressure. The residue was re-dissolved in a minimum amount of EtOAc and was filtrated through a pad of silica gel, washing with EtOAc. The combined filtrates were evaporated under reduced pressure. The remaining oil was dissolved in EtOAc (40 ml) and hexane was added until a precipitate formed. The solid material was isolated by filtration and dried under high vacuum and gave 2-amino-3-methoxy-benzoic acid methyl ester. Step 3: The above obtained amine (7.5 g) was dissolved in 1,2-dichloroethane (125 ml) and pyridine-4-carbaldehyde (6.65 g) was added followed by addition of sodium triacetoxy-borohydride (17.5 g). The reaction mixture was heated to 50° C. and stirred for 2.5 hours. More and pyridine-4-carbaldehyde (1.5 ml) and sodium triacetoxy-borohydride (5.0 g) was added and stirring was continued at 50° C. for 15 hours. Saturated aqueous sodium bicarbonate was carefully added and the mixture was extracted with dichloromethane. The organic layer washed with saturated aqueous sodium bicarbonate, water and brine, dried (MgSO4) and evaporated under reduced pressure. The residue was subjected to column chromatography on silica gel (elution with 0 to 50% EtOAc in dichloromethane) and gave 3-methoxy-2-[(pyridin-4-ylmethyl)-amino]-benzoic acid methyl ester as a pale yellow oil. Step 4: The compound obtained in step 3 (8 g) was dissolved in methanol (100 ml) and 2M sodium hydroxide (50 ml) was added. The reaction mixture was heated to 45° C. and stirred for 1 hour. The mixture was cooled to room temperature and stirring continued for 18 hours. The mixture was concentrated to ca. 50 ml under reduced pressure. Water (200 ml) was added and the pH of the mixture was adjusted to 6 with 4M HCl. The precipitated material was isolated by filtration and dried in vacuo and gave the title compound. 13C-NMR (DMSO-d6) δ 170.1, 150.3, 149.8, 149.3, 141.8, 123.4, 122.0, 117.0, 116.4, 114.8, 55.6, 48.4.