Methyl2-bromomethylbenzoate

(2) Add 1.50 g (10 mmol) of compound 2 into a 250 ml round bottom flask, dissolve it in 80 ml of CCl50 g of methyl 2-methylbenzoate (0.33 M), 60.4 g of N-bromosuccinimide (0.340 M) and 4 g of benzoyl peroxide are added to a 2000 ml reactor containing 1500 ml of carbon tetrachloride. The reaction mixture is refluxed for 2 hours. After cooling to room temperature, the reaction medium is concentrated under vacuum. The oil obtained is purified by chromatography on silica (eluent: ChbCb). 74.5 g of a colourless oil are obtained (98percent yield).TLC: diisopropyl ether/petroleum ether (50/50).NMR (5 in ppm, DMSO, 200 MHz): 4.12 (s, 3H); 5.27 (s, 2H); 7.39 (d, 3H); 7.70 (d, 1H).IR (cm2-Methyl-benzoic acid methyl ester (1.50 g 10 mmol), N-bromo-succinimide (1.96 g, 11 mmol) and 2, 2'-azobis(2-methyl-propionitrile) (AIBN) (25 mg, 0.15 mmol) were dissolved in chloroform (3 ml). The solution was heated at reflux for 16 hours cooled and the solvent evaporated in vacuo. The residue was purified by silica gel chromatography using a gradient of ethyl acetate/hexane (1-2 percent) as eluent. Pure fractions were collected and the solvent evaporated in vacuo affording 2.05 g (89 percent) of 2-bromomethyl-benzoic acid methyl ester as a solid. Example 53 2-(Oxalyl-amino)-5-(1-oxo-1, 3-dihydro-isoindol-2-ylmethyl)-4, 5, 6, 7-tetrahydro-thieno[2, 3-c]pyridine-3-carboxylic acid; 2-Methyl-benzoic acid methyl ester (1.50 g 10 mmol), N-bromosuccinimide (1.96 g, 11 mmol) and 2, 2'-azobis(2-methylpropionitrile) (AIBN) (25 mg, 0.15 mmol) were dissolved in chloroform (3 ml). The solution was heated at reflux for 16 h. cooled and the solvent evaporated in vacuo. The residue was purified by silica gel chromatography using a gradient of ethyl acetate/hexane (1-2percent) as eluant. Pure fractions were collected and the solvent evaporated in vacuo affording 2.05 g (89percent) of 2-bromomethyl-benzoic acid methyl ester as a solid.A solution of compound 18b (4.5 g, 30 mmol), NBS (5.9 g, 33 mmol) and AIBN (0.5 g, 3 mmol) in CCITo a solution of methyl 2-methylbenzoate (5g, 0. 033mol) in carbon tetrachloride (85ml) was added n-bromosuccinimide (5.93g, 0. 033mol) and benzoyl peroxide (0.22g, 0. 9mol). The reaction was refluxed for 4 hr. The reaction was cooled to room temperature. The white precipitate was filtered and the solvent removed. The oil was dissolved in ET2O and cooled to-78°C The product precipitated and collected yielding v (5. 86G, 77percent).A mixture of Methyl 2-methylbenzoate (1.00 mL, 7.20 mmol)and NBS (1.40 g, 7.90 mmol) in CCl4 (28 mL) was degassed. AIBN(24.0 mg, 0.140 mmol) was added and the mixture was heatedto 85 C for 16 h. Further NBS (0.130 g, 0.710 mmol) was addedand the whole was refluxed for 1 more hour. The mixture wasdiluted with CH2Cl2 and washed with sat. aq NaHCO3 solutionand water. The organic layer was dried (Na2SO4), filtered and concentratedin vacuo. Purification of the residue by flash chromatography(hexane/EtOAc 100:0'95:5) gave the title compound as anorange to pink liquid that solidifies on standing (68percent). 1H NMR(300 MHz, CDCl3) d ppm 3.92 (s, 3H), 4.95 (s, 2H), 7.30–7.39 (m, 1H), 7.41–7.53 (m, 2H), 7.89–8.01 (m, 1H). 13C NMR (75 MHz, CDCl3) d ppm 31.7, 52.4, 128.7, 129.2, 131.4, 131.8, 132.7, 139.4, 167.2.A mixture of Methyl 2-methylbenzoate (1 mL, 7.2 mmol) and NBS (1.4 g, 7.9 mmol) in 0014 (28 mL) was degassed. AIBN (24 mg, 0.14 mmol) was added and the mixture was heated to 85 00 overnight. Eurther NBS (0.13 g, 0.71 mmol) was added and the whole was refluxed for 1 more hour. The mixture was diluted with 0H2012 and washed with sat. aq. NaHOO3 solution andwater. The organic layer was dried (Na2SO4), filtered and concentrated in vacuo. Purification of the residue by flash chromatography (hexane/EtOAc 100:0 —* 95:5) gave the title compound as an orange to pink liquid that solidifies on standing (67.6percent). 1H NMR (300 MHz, ODd3) 6 ppm 3.92 (s, 3 H) 4.95 (s, 2 H) 7.30 - 7.39 (m, 1 H) 7.41 - 7.53 (m, 2 H) 7.89 - 8.01 (m, 1 H). 130 NMR (75 MHz, 0D013)6 ppm 31.7, 52.4, 128.7, 129.2, 131.4, 131.8, 132.7, 139.4, 167.2.To a stirred solution of methyl 2-methylbenzoate 6- 1 A (5 g, 33.3 mmol) in ACN (200 mL) was added NBS (5.3 g, 30 mmol) and AIBN (547 mg, 3.33 mmol) at RT. The reaction mixture was warmed to 90 °C for 6 hr under nitrogen atmosphere. The reaction mixture solvent was evaporated under reduced pressure and the crude residue washed with toluene (500 mL) and filtered the precipitate (NBS). Filtrate evaporated under reduced pressure and the crude residue was purified by flash column chromatography (100-200 silica) using 2percent EtOAc/pet. ether to afford 6-2A (5 g, 22.1 mmol, 65.7 percent yield) as a yellow thick liquid.To a solution of methyl 2-(methyl)benzoate 3a (9.46 g, 6.3 mmol) in chloroform (200 mL) were added NBS (13.8 g, 7.6 mmol) and benzoyl peroxide (760 mg, 0.32 mmol). The reaction mixture was stirred at reflux overnight. When the mixture was cooled to rt, filtered and concentrated. The residue was purified by CC, eluted with PE to give 3b as a colorless oil (9 g, 62percent yield).To a solution of compound 3a (9.46 g, 6.3 mmol) in chloroform (200 mL) were added NBS (13.8 g, 7.6 mmol) and benzoyl peroxide (760 mg, 0.32 mmol). A mixture of methyl o-toluate (13.5 g, 89.9 mmol), NBS (17.6 g, 98.9 mmol), and benzoyl peroxide (50 mg, 0.2 mmol) in carbon tetrachloride (250 mL) was heated at reflux over the weekend. The reaction mixture was allowed to cool, and it was then filtered. The solvents were evaporated under reduced pressure and the residue was purified by chromatography, eluting with 3percent ethyl acetate/hexanes to give 2-bromomethyl-benzoic acid methyl ester (7.7 g, 37percent) as a white solid. 1HNMR (CDCl3): δ 7.97 (dd, J=1.5 Hz, 8.0 Hz, 1H), 7.49 (m, 2H), 7.38 (dt, J=1.5 Hz, 8.0 Hz, 1H), 4.96 (s, 2H), 3.94 (s, 3H). MS (APCI+): 231 (100), 229 (93).The o-methylbenzoate (6 g, 39.95 mmol) was weighed into 60 mL of carbon tetrachloride and NBS(2.73 g, 47.94 mmol) and benzoyl peroxide (484 mg, 2 mmol) and refluxed for 2 h. TLC detectionAfter completion of the reaction, the reaction solution was cooled, filtered and the filtrate was dried to give intermediate o-bromomethylbenzoic acid methyl ester (7 g).Synthesis of 2-(Bromomethyl)benzoic acid methyl ester EXAMPLE 33

Molecular Weight:229.07
XLogP3:2.9
Hydrogen Bond Acceptor Count:2
Rotatable Bond Count:3
Exact Mass:227.97859
Monoisotopic Mass:227.97859
Topological Polar Surface Area:26.3
Heavy Atom Count:12
Complexity:159
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes