5-BROMO-2-METHYL-3-NITROBENZOIC ACID

Step 1:[01 123] Step 1 : 5-bromo-2-methyl-3-nitrobenzoic acid[01 124] To stirred solution of 2-methyl-3-nitrobenzoic acid (50 g, 276.2 mmol) in cone.H2SO4 (200 mL), l , 3-dibromo-5, 5-dimethyl-2, 4-imidazolidinedione (43.4 g, 151.8 mmol) was added portion wise at room temperature and reaction mass was stirred at room temperature for 5 h. On completion, reaction mass was poured on ice cold water, solid precipitated was filtered, resulting residue was washed with water and dried under vacuum giving the desired compound (71 .7 g, 100percent)To a stirred solution of 2-methyl-3-nitrobenzoic acid (5.00 g, 27.6 mmol) in HA 5000 mL three neck RBF equipped with an overhead stirrer was charged with 2-methyl-3-nitro benzoic acid (150.0 g, 0.82 mol) and concentrated HTo a mixture of 2-methyl-3-nitrobenzoic acid (150 g, 820 mmol) in concentrate sulphuric acid (600 ml.) was added 1 , 3-dibromo-5, 5-dimethyl-2, 4-imidazolidinedione (130.7 g, 457 mmol). The reaction mixture was stirred at room temperature for 5 hrs and then the reaction mixture was carefully added to 4L of ice-water. The solid precipitated out, which was washed with 1.5 L water. The solid was filtered off and dried in a heated desiccator at 30-40[01036] Step 2: 5-bromo-2-methyl-3-nitrobenzoic acid[01037] l, 3-dibromo-5, 5-dimethyl-2, 4-imidazolidinedione (13.0 g, 45.7 mmol) was added to a mixture of 2-methyl-3-nitrobenzoic acid (15 g, 82.8 mmol) in cone. H5-bromo-2-methyl-3-nitrobenzoic acid stirred solution of 2-methyl-3-nitrobenzoic acid (100 g, 552 mmol) in cone. H0323] Step 1: Synthesis of 5-brom -2-methyl-3-nitrobenzoic acid [0324] To stirred solution of 2-methyl-3-nitrobenzoic acid (100 g, 552 mmol) in cone. H[00182] Preparation of5-bromo-2-methyl-3-nitrobenzoic acid C2-l. To a mixture of compound C2-O (15 g, 82.8 mmol) in cone. H2S04 (60 mL) in an ice-water bath was added 1, 3-dibromo-5, 5-dimethylhydantoin (DBDMH) (13.4 g, 46.8 mmol) portionwise over 30 mins. After the mixture was stirred at room temperature overnight, the reactionmixture was added slowly to ice-water (400 mL). The precipitation was collected and dried to yield compound C2-1 as a white solid ((21.2 g, yield: 98percent), which was used directly in the next step without further purification. MS (ESfl: m/z 257.9 and 259.9 (M1).5-bromo-2-methyl-3-nitrobenzoic acidThe N-bromo succinimide (15g, 84.3mmol) is added to the 2-methyl-3-nitro-benzoic acid (15g, 82.8mmol) in the strong sulphuric acid solution (60 ml), then the reaction solution stirring the mixture at room temperature for overnight. After, when the reaction is complete, the reaction solution slowly into ice water (400 ml). The precipitate filtered, and drying in vacuum, to obtain it is expected the product 2-methyl-3-nitro-5-bromobenzoic acid 21g, the yield is 98percent.a) S-BromG-2-roeth I-3-idtrii-ber.zoic acidTo a stirred solution of 2-methyl-3-nitro benzoic acid (300 g, 1647 mmol) in cone. HTo a stirred solution of 2-methyl-3-nitro benzoic acid (300 g, 1647 mmol) in conc. HIn a 500-ml four-necked flask, 2-methyl-3-nitrobenzoic acid (20 g, 110 mmol) was charged. Thereto, tetrahydrofuran (200 ml) and 64percent sulfuric acid (100 ml) were added sequentially. The mixture was heated and stirred at an external temperature of 8Oc) 2-methyl-3-nitrobenzoic acid (50g, 276mmol) was dissolved in 200mL of concentrated sulfuric acid, then under ice bath was added 1, 3-dibromo-5, 5-dimethylhydantoin (47.3g, 166mmol), stirred for 2 hours at room temperature. The reaction solution was slowly poured into a large amount of ice water to precipitate a large number of off-white solid, filtered and the solid washed with 1L of water, washed with 1L petroleum ether, and dried to give Compound E 64g, yield 90percent.To a stirred solution of 2-methyl-3-nitrobenzoic acid (10 g, 55 mmol) in conc. HTo stirred solution of 2-methyl-3-nitrobenzoic acid (25 g, 138.1 mmol) in cone. H2-Methyl-3-nitrobenzoic acid (5 g) was dissolved in conc. H2S04 (20 mL) at 0°C. To this solution, NBS (6.2 g) was added gradually. The resulting mixture was stirred at 0°C for 2 hours, and then warmed to 40°C. After stirring at 40°C for 3 hours, the mixture was poured into ice/water. The white solid precipitate was filtered and dried to afford the title compound (7 g) as off-white solid. MS (ESI): C8H6BrNO4 requires 259; found no mass.Description 137 5-Bromo-2-methyl-3-nitrobenzoic acid (P137)2-Methyl-3-nitrobenzoic acid (5.0 g) was dissolved in conc. H2S04 (20 mL) at 0°C. To this solution, NBS (6.2 g) was added gradually. The resulting mixture was stirred at 0°C for 2 hours, and thenwarmed to 40°C. After stirring at 40°C for 3 hours, the mixture was poured into ice water. Thewhite solid precipitate was filtered and dried to give the title compound (7.0 g) as off-white solid.MS (ESI): C8H6BrNO4 requires 259; found no mass.Step 1:To stirred solution of 2-methyl-3-nitrobenzoic acid(10 g, 55 mmol) in conc. H2504 (40 mE), 1, 3-dibromo-5, 5-dimethyl-2, 4-imidazolidinedione (9 g, 32 mmol) wasadded portion wise at room temperature and reaction wasstirred at room temperature for 5 hours. Then the reactionmass was poured on an ice cold watet Solid was filtered, andthe resulting residue was washed with water and dried undervacuum to afford 5-Bromo-2-methyl-3-nitrobenzoic acid(12 g, 84percent) as a light yellow solid. 1H NMR: (400 MHz, DMSO-d6): δ 8.28 (d, J=2.0Hz, 1H), 8.13(d, J=2.0 Hz, 1H), 2.51(s, 3H). Chemical Formula: C8H613rNO4; MolecularWeight: 260.04. Total H count from ‘HNMR data: 5.To the solution of compound K501-A (14.0 g, 51.1 mmol) in THF (90 mL) was added LiOH (6.4g, 153 mmol)and H2O (30 mL). The reaction mixture was stirred at 25°C overnight and then concentrated. The remaining liquid wasdiluted with Et2O (60 mL) and water (100 mL). The organic layer was separated. The water layer was adjusted with 2NHCl to pH = 2, extracted with EtOAc (150 mL). The organic layers were washed with sat. brine (200 mL), dried, filteredand concentrated to afford K501-B (12.9 g) as yellow solid.1H NMR (400 MHz, DMSO-d6): δ 8.30 (d, J = 2.0 Hz, 1 H), 8.14 (d, J = 2.0 Hz, 1 H), 2.45 (s, 3H)