3-BROMO-2-METHYL-BENZOIC ACID METHYL ESTER

White Solid

Methyl 3-bromo-2-methylbenzoate A solution of 3-bromo-2-methylbenzoic acid (2.98 g, 13.9 mmol) in DMF (20 mL) was treated with cesium carbonate (4.56 g, 13.9 mmol) and iodomethane (0.900 mL, 14.4 mmol). To a mixture of 3-bromo-2-methylbenzoic acid (5.0 g, 23 mmol) in MeOH (80 mL) was added 50C12 (11.0 g, 93 mmol) at 20°C. The mixture was stirred for 1.5h at 70°C. Thevolatiles were removed and the residue was taken up by EtOAc (100 mL), which was washed sequentially with saturated NaHCO3 and brine (each 100 mL). The EtOAc layer was dried over Na2504, concentrated and the residue was purified by flash column chromatography to give methyl 3-bromo-2-methylbenzoate (5.3g, 99percent yield) as a red solid.3-bromo-2-methylbenzoic acid (6.13 g, 28.5 mmol) was suspended in MeOH (52 ml) and concentrated H2-methyl-3-bromobenzoic acid (10 g, 46.7 mmol) was added to 150 mL of methanol, Stir, 0.5 mL of concentrated sulfuric acid was added dropwise at room temperature, Heated to reflux overnight.TLC shows the reaction is complete, cooled, The reaction solution PH to neutral, The methanol was removed by concentration under reduced pressure, To the residue was added 100 mL of ethyl acetate, Washed with water, concentrated under reduced pressure, organic, dried, 2-methyl-3-bromobenzoic acid methyl ester 10.2 g (yield: 96percent);Step 1: To a solution of 3-bromo-2-methylbenzoic acid II-l (10 g, 47 mmol) in 150 mL of MeOH was added concentrated H2SO4 (10 mL) dropwise. The mixture was stirred at 70C overnight. The solvent was evaporated and the remaining mixture was adjusted to pH 9 by adding saturated NaHC0 solution. The mixture was extracted with ethyl acetate. The organic layers were dried over Na2S04, filtered and concentrated. The residue was purified by column chromatography (petroleum ether : ethyl acetate = 150 : 1) to give the product as a yellow oil (10.1 g, 94percent). 1H NMR (400 MHz, CDC1 ) _ 7.72 (d, J= 8.0 Hz, 1H), 7.69 (d, J = 8.0 Hz, 1H), 7.09 (t, J= 8.0 Hz, 7.6Hz, 1H), 3.90 (s, 3H), 2.63 (s, 3H).Synthesis of 5-methyldibenzo[crf(1) Synthesis of methyl 3-bromo-2-methylbenzoate [104-1] (hereinafter referred to as a compound [104-1]) 3-Bromo-2-methylbenzoic acid (1.08 g) was dissolved in methanol (16 mL), and to the solution was added concentrated sulfuric acid (1.6 mL) at room temperature, and the mixture was subjected to microwave irradiation at 110°C for 10 minutes. The reaction mixture was cooled by ice, added an aqueous solution of 5N-sodium hydroxide, and the mixture was extracted with ethyl acetate. The obtained organic layer was sequentially washed with water and brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give the titled compound (1.10 g) as a yellow oil. Step 1: Preparation of methyl 3-bromo-2-methylbenzoate (2) To a solution of 3-bromo-2-methylbenzoic acid 1 (10.8 g, 0.05 mol) in MeOH (92 mL) was added conc. HTo an ice-cooled solution of Compound I (1.0 g) in methylene chloride (9.0mL) were added dropwise DMF (20 μL) and thionyl chloride (480 μL), and then the mixture was stirred at room temperature for 3 hours, and the reaction mixture was concentrated under reduced pressure. The resulting residue was dissolved in methylene chloride (9.3 mL), and the mixture was ice-cooled, and then thereto were added dropwise triethylamine (1.3 mL) and methanol (4.6 mL). The mixture was stirred at room temperature overnight, and then the reaction mixture was concentrated under reduced pressure. To the residue was added water, and then the mixture was extracted with ethyl acetate. The organic layer was washed with brine, and then dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate = 100/0 to 85/15) to give Compound II (957 mg).A 60: 40 mixture of 5-bromo-2-methyl benzoic acid and 3-bromo-2-methyl benzoic acid (8.0 g, 0.037 mol) was dissolved in N, N'-dimethylformamide (130 mL). Methyl iodide (2.28 mL, 2.3 mol) and potassium carbonate (5.11 g, 0.037 mol) were added in sequence at room temperature. The mixture was stirred at room temperature for 2 hours at which point the reaction was determined to be complete by HPLC. The solvent was removed under high vacuum and the resulting residue was passed through a silica gel column using 5percent ethyl acetate in hexanes as the eluent. The mixture of isomers was obtained as an oil and then separated by preparative normal phase HPLC using 0.5percent isopropyl alcohol in hexanes as the eluent. The title compound was obtained as a white solid (1.38 g, 29percent).

Molecular Weight:229.07
XLogP3:2.8
Hydrogen Bond Acceptor Count:2
Rotatable Bond Count:2
Exact Mass:227.97859
Monoisotopic Mass:227.97859
Topological Polar Surface Area:26.3
Heavy Atom Count:12
Complexity:170
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes