Methyl 2-(3-bromophenyl)acetate

To dichloromethane (580 ml) solution of 25 g (116 mmol) of 3-bromophenylacetic acid were added 9.4 ml (232 mmol) of methanol and 0.15 g (1.2 mmol) of 4-(dimethylamino)pyridine. After cooling with ice, 26.8 g (140 mmol) of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride was added thereto, and the resulting mixture was stirred overnight with gradually warming up to room temperature. The reaction mixture was washed with hydrochloric acid, saturated sodium bicarbonate solution and brine, and then dried over anhydrous magnesium sulfate. After filtrating and concentrating under reduced pressure, 27.3 g (quantitative) of the entitled compound was obtained as a pale yellow oil.1H-NMR(CDCl3)δ: 3.60(2H, s), 3.70(3H, s), 7.16-7.23(2H, m), 7.39-7.45(2H, m).A mixture of 3-bromophenylacetic acid (5.29 g, 24.6 mmol) and concentrated sulfuric acid (100 μL) in anhydrous methanol (40 mL) was refluxed overnight and then concentrated in vacuo. The residue was partitioned between ethyl acetate and saturated sodium bicarbonate solution. The organic layer was washed with saturated sodium bicarbonate solution, saturated sodium chloride solution, dried (MgSOINTERMEDIATE 6(3-BromophenyDacetic acid methyl ester Acetyl chloride (0.5 niL) was added to MeOH (100 mL). 3-Bromophenylacetic acid (15 g, 69.8 mmol) was added, and the mixture refluxed for 2 h. The solvent was removed in vacuo and the residue partitioned between DCM and water (50 mL each). The aqueous phase was extracted with DCM (20 mL) and the combined organic phases were dried (MgSOTo a solution of 3-bromophenylacetic acid (1 g, 4.65 mmol) in 20 mL MeOH at 0° C. was added thionyl chloride (0.51 mL, 1.5 eq.) dropwise. The resulting solution was then refluxed overnight under N2. The reaction was cooled to rt and the solvent was removed in vacuo. The residue was taken up in EtOAc, washed with sat'd. NaHCO3 and brine, then dried over Na2SO4, filtered and evaporated to provide the methyl ester in 98percent yield. 1HNMR (300 MHz, CDCl3) δ 7.57 (d, 1H, J=12 Hz); 7.29 (2H, dd, J=2.5, 0.8 Hz); 7.16 (m, 1H); 3.81 (s, 2H); 3.72 (s, 3H).Acetyl chloride (0.08 mL, 1.2 mmol, 0.5 equiv), and 2-(3-bromophenyl)acetic acid (0.5 g, 2.3 mmol, 1.0 equiv) were added to MeOH (10 mL) and the reaction mixture was refluxed for 2 h. After consumption of starting material, the reaction mixture was concentrated and extracted with DCM. The organics were combined and washed with brine and dried over Naa) Synthesis of methyl(3-bromophenyl)acetate25.00 g of (3-bromophenyl)acetic acid are dissolved in 80 ml of methanol in a 100 ml flask provided with magnetic stirrer, condenser, thermometer, dropping funnel and gas-discharge tube, 13.22 ml of thionyl chloride are added dropwise at max. 10° C. with cooling and stirring, and the mixture is subsequently stirred at RT for a further 2 h. The reaction mixture is poured onto ice, rendered alkaline using conc. sodium hydroxide solution and extracted with MTB ether. The combined MTB ether phases are dried and filtered. The solvent is subsequently removed.Yield: 25.44 g=0.111 mol=97percent of methyl(3-bromophenyl)acetate; TLC: CHa)3-BROMOPHENYLACETIC acid (10000 mg, 46. 50MMOL) was dissolved in methanol (200 mL) at room temperature and concentrated hydrochloric acid (4 mL) was added. The resulting solution was heated at 58°C for 2h then cooled to room temperature at which time the volatiles were removed in vacuo. The crude material was dissolved in ethyl acetate and the solution was carefully poured into a saturated aqueous sodium bicarbonate solution. The phases were separated and the combined organic extracts were dried over magnesium sulfate and concentrated under reduced pressure. The crude product was purified by MPLC (Biotage) with a gradient of 4 to 35percent ACOET/HEXANES to give (3-bromo-phenyl)-acetic acid methyl ester as a colorless oil (10250 mg, 96percent). GC- MS (MH+ 230 RT = 9.34 min).Acetyl chloride (0 7ml, 9 3mmol) was added dropwise to a solution of (3-bromo-phenyl)-acetic acid (20 Og, 93mmol) in methanol (500ml) at 0°C The reaction was stirred for 5 hours, allowing the temperature to warm gradually to 25°C The solvent was removed in vacuo and the residual oil was re-dissolved in dichloromethane, dried over sodium sulfate and concentrated in vacuo to afford the title compound as a colourless oil in 96percent yield, 20 6gIntermediate 2. (3-Bromo-phenyl)-acetic acid methyl ester. 3-Bromophenylacetic acid (100 g, 0.47 mol) was dissolved in methanol (1000 ml) and concentrated sulfuric acid (1 ml) added and the mixture heated at reflux overnight. 2- (3-bromophenyl) acetic acid (1.00 g, 4.65 mmol) was dissolved in freshly distilled methanol (50 ml.) . Added cone. H[0180] To a solution of 2-(3-bromophenyl)acetic acid (5.0 g, 23.3 mmol) in CHExample 18; Preparation of Methyl (3-Bromophenyl)acetateA stirred solution of (3-bromophenyl)acetic acid (10.0 g, 0.0465 mol) and concentrated sulfuric acid (4.5 mL) in MeOH (230 mL) was heated at 40 Step 1 : [00152] To a solution of (3-bromophenyl)acetic acid (12.2 g, 56.8 mmol) in methanol (150 ml_) was added p-toluenesulfonic acid (5.4 g, 28.4 mmol). The reaction mixture was stirred at reflux for 3 hours. The solvent was evaporated and the residue was dissolved in a mixture of ethyl acetate/water (3:2). The organic layer was dried over sodium sulfate and concentrated. The residue was purified using a silica pad eluting with a mixture of hexanes/ethyl acetate (9:1). This gave (3-bromophenyl)acetic acid methyl ester as a colorless oil (11.7 g, 90percent). [0095] Step 1 : To a solution of (3-bromophenyl)acetic acid (12.2 g, 56.8 mmol) in methanol(150 mL) was added p-toluenesulfonic acid (5.4 g, 28.4 mmol). The reaction mixture was stirred at reflux for 3 h. The solvent was evaporated and the residue was dissolved in a mixture of ethyl acetate/water (3:2). The organic layer was dried over sodium sulfate and concentrated. The residue was purified using a silica pad eluting with a mixture of hexanes/ethyl acetate (9:1 ). This gave (3- bromophenyl)acetic acid methyl ester as a colorless oil (1 1.7 g, 90percent). Methyl 2-(3-bromophenyl) acetateBrTo the solution of the starting material (12.0 g, 55.8 mmol) in MeOH (200 mL) wasadded SOCI2(2 mL). The reaction solution was stirred and heated to reflux overnight.After the reaction was completed, 200mL of water and 30 mL of NaHCO3 aq. were added. The mixture was extracted with EA (150 mL x 3). The combined organic layers were washed with brine and dried over Na2504. After filtration and evaporation of the solvent, the product (11 .Og, 86.1 percent) was obtained.To the solution of the starting material (12.0 g, 55.8 mmol) in MeOH (200 mL) was added SOCI2 (2 mL). The reaction solution was stirred and heated to reflux overnight. After the reaction was completed, 200mL of water and 30 mL of NaHCOs aq. were added. The mixture was extracted with EA (150 mL x 3). The combined organic layers were washed with brine and dried over Na2SO(3-Bromophenyl)acetic acid 11 (5.0 g, 23.3 mmol) and methanol (50 mL) were refluxed for 3 h in the presence of 0.2 mL of concentrated hydrochloric acid (HCl) to give the methyl (3-bromophenyl)acetate. After neutralization with saturated NaHCOExample 5A: Methyl 2-(3 -bromophenyl)acetate j00225j 3-Bromophenylacetic acid (2.0 g, 9.30 mmol) was dissolved in MeOH (46.5mL) and cooled to 0 °C. SOC12 (3.39 mL, 46.5 mmol) was added carefully dropwise.The reaction was then heated to reflux at for 2 h. The reaction was cooled to ambient temperature and concentrated in vacuo. The crude material was purified by silica gel chromatography (0 to 100percent EtOAc in hexanes to yield Example 5A (1 .97g, 8.60 mmol). 1H NMR (400 MHz, CHLOROFORM-cl) ö ppm 7.44 (1 H, s), 7.36 - 7.43 (1 H, m), 7.15 -7.24 (2 H, m), 3.70 (3 H, s), 3.60 (2 H, s).Step (v); Methyl 3-bromophenylacetate;To 3-bromophenylacetic acid 10.0g (46.5mmol) were added methanol 150ml and sulfuric acid 5ml and the mixture was refluxed for 3 hours. After neutralization with aqueous ammonia and removal of the solvent by distillation, to the residue was added water and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, concentrated and the residue was purified by column chromatography (SiOPart A General procedure: A stirred solution of the appropriate bromophenyl alkanoic acid(1 eq) in MeOH (25 mL)was treated with H2SO4 (0.1 eq of a conc. aq.solution) and heated at reflux for 18 h. The resultant solution wascooled to room temperature and concentrated under reducedpressure. The resultant oil was diluted with NaHCO3 (50 mL of a sat.aq. solution) and subsequently extracted with diethyl ether(3 25 mL). The combined organics were washed with brine(1 100 mL), dried (MgSO4), filtered and concentrated underreduced pressure to give the desired methyl ester:

Molecular Weight:229.07
XLogP3:2.7
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