4-(Bromomethyl)phenylaceticacidphenacylester

To a stirred suspension of 2-(4-(bromomethyl)phenyl)acetic acid (5.00 g, 21.8 mmol, 1.0 eq.) in methanol (75 mL) was added chlorotrimethylsilane (0.64 mL, 5.02 mmol, 0.23 eq.) at room temperature. The resulting mixture was stirred at room temperature for 2 hr, at which time the reaction was a clear colorless solution. The volatile material was removed under reduced pressure, the residue dissolved in methanol (25 mL), and the volatile material was removed under reduced pressure. This process was repeated two additional times to afford methyl 2-(4-(bromomethyl)phenyl)acetate as an orange solid (5.30 g, quantitative yield). Step (ii); 4-Bromomethylphenylacetic acid methyl ester; To 4-bromomethylphenylacetic acid 25g (109mmol) in methanol (120ml) was added thionyl chloride 120μl (1.64mmol) and the mixture was stirred at room temperature for 8 hours. After removal of the solvent in vacuo, the residue was neutralized with aqueous saturated sodium bicarbonate, and the mixture was extracted with ethyl acetate (300ml). The organic layer was washed aqueous saturated sodium bicarbonate, (50ml) and saturated brine (20ml), successively and dried over magnesium sulfate. The solvent was removed in vacuo to give the subtitled compound 25g as colorless crystals. Yield 99percent [7101 Step 1: Synthesis of methyl 2-(4-(bromomethyl)phenyl)acetate[7111 2-(4-(bromomethyl)phenyl)acetic acid (3.000 g, 13.096 mmol) was dissolved in methanol (30 mL), and SOC12(1.900 mL, 26.193 mmol) was added thereto at 0 °C, followed by stirring at the same temperature for 1 hour. Then, the reaction mixture was concentrated under reduced pressure to remove the solvent. A saturated aqueous solution of sodium hydrogen carbonate was added to the concentrate, followed by extraction with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium chloride, dried with anhydrous magnesium sulfate, and then concentrated under reduced pressure to yield the desired compound (3.140 g, 98.6 percent) as a colorless oil.a) Methyl 2- r4-(bromomethyl)phenyll acetate (1-72) Thionyl chloride (48 μ; 0.65 mmol; 0.017 eq) was added to a solution of 2-[4- (bromomethyl)phenyl] acetic acid (10 g; 43.07 mmol; 1 eq) in methanol (48 mL). The reaction mixture was stirred at room temperature for 16 hours, then, concentrated to dryness. The residue was taken up in saturated sodium hydro genocarbonate (150 mL) and the resulting aqueous layer was extracted with ethyl acetate (3 x 100 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated under reduced pressure. The title compound, methyl 2-[4- (bromomethyl)phenyl] acetate was obtained in 96percent yield (10.2 g) as a white solid. 1H NMR (CDC1A mixture of 2- [4-(bromomethyl)phenyl] acetic acid (3 g, 13.10 mmol), methanol (100 mL), thionyl chloride (2.3 g, 19.33 mmol) was stirred for 3 h at 60°C. The resulting mixture was concentrated under vacuum. This resulted in the title compound (2.5 g, 79percent) as colorless oil.To a stirring solution of 14 in tetrahydrofuran (0.6 M) at 0 C. under nitrogen was added dimethylaminopyridine (0.2 eq), methanol (2.2 eq) and 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (2.2 eq). The reaction was stirred at room temperature overnight. The tetrahydrofuran was removed under reduced pressure. The resulting oil was partitioned between ethyl acetate and saturated sodium bicarbonate. The phases were separated and the organic phase was washed with saturated sodium bicarbonate (1?), 1N hydrochloric acid (1?), brine (1?), dried over sodium sulfate, filtered and concentrated in vacuo to afford the product. (58percent) 1H NMR (400 MHz, DMSO-d6) ' 7.38 (d, 2H), 7.27 (d, 2H), 4.75 (s, 2H), 3.69 (s, 2H), 3.61 (s, 3H).In a 100 mL round bottom flask, a solution of 2-(4-(bromomethyl)phenyl)acetic acid (2.5 g, 10.91 mmol) in MeOH (50 mL) was treated with TMSC1 (0.2 mL) under nitrogen atmosphere. The reaction mixture was stirred for 1 h at RT. Upon completion of reaction (TLC), the solvent was removed under reduced pressure. The residue obtained was dissolved in methanol and concentrated under reduced pressure to give the title compound. Yield: 2.5 g (94.3percent). (0727) 1H NMR (300 MHz, CDC : δ 7.36 (d, J = 8.1 Hz, 2H), 7.26 (d, J = 8.4 Hz, 2H), 4.48 (s, 2H), 3.69 (s, 3H), 3.62 (s, 2H)To a stirring solution of 15 in dioxane (0.4 M) at room temperature under nitrogen was added calcium carbonate (5.5 eq) and H2O (0.8 M). The reaction was refluxed overnight then vacuum filtered. The dioxane was removed under reduced pressure. The reaction mixture was diluted with H2O then extracted with dichloromethane (3?). The organic phases were combined, dried over sodium sulfate, filtered and concentrated in vacuo to afford the product. (77percent) 1H NMR (400 MHz, CDCl3) ' 7.33 (d, 2H), 7.27 (d, 2H), 4.67 (s, 2H), 3.69 (s, 3H), 3.63 (s, 2H), 1.78 (br s, 1H).To a stirred suspension of 2-(4-(bromomethyl)phenyl)acetic acid (5.00 g, 21.8 mmol, 1.0 eq.) in methanol (75 mL) was added chlorotrimethylsilane (0.64 mL, 5.02 mmol, 0.23 eq.) at room temperature. The resulting mixture was stirred at room temperature for 2 hr, at which time the reaction was a clear colorless solution. The volatile material was removed under reduced pressure, the residue dissolved in methanol (25 mL), and the volatile material was removed under reduced pressure. This process was repeated two additional times to afford Step (ii); 4-Bromomethylphenylacetic acid methyl ester; [Show Image] To 4-bromomethylphenylacetic acid 25g (109mmol) in methanol (120ml) was added thionyl chloride 120mul (1.64mmol) and the mixture was stirred at room temperature for 8 hours. After removal of the solvent in vacuo, the residue was neutralized with aqueous saturated sodium bicarbonate, and the mixture was extracted with ethyl acetate (300ml). The organic layer was washed aqueous saturated sodium bicarbonate, (50ml) and saturated brine (20ml), successively and dried over magnesium sulfate. The solvent was removed in vacuo to give the subtitled compound 25g as colorless crystals. Yield 99percent 1H NMR (CDCl3) delta 7.36 (2H, t, J= 8.1 Hz), 7.26 (2H, d, J= 8.1 Hz), 4.48 (2H, s), 3.69 (3H, s), 3.62 (2H, s).[7101 Step 1: Synthesis of a) Methyl 2- r4-(bromomethyl)phenyll acetate (1-72) Thionyl chloride (48 mu; 0.65 mmol; 0.017 eq) was added to a solution of 2-[4- (bromomethyl)phenyl] acetic acid (10 g; 43.07 mmol; 1 eq) in methanol (48 mL). The reaction mixture was stirred at room temperature for 16 hours, then, concentrated to dryness. The residue was taken up in saturated sodium hydro genocarbonate (150 mL) and the resulting aqueous layer was extracted with ethyl acetate (3 x 100 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated under reduced pressure. The title compound, methyl 2-[4- (bromomethyl)phenyl] acetate was obtained in 96percent yield (10.2 g) as a white solid. 1H NMR (CDC13): delta (ppm) 3.68 (s, 2H), 3.75 (s, 3H), 4.54 (s, 2H), 7.37 (m, 4H).A mixture of 2- [4-(bromomethyl)phenyl] acetic acid (3 g, 13.10 mmol), methanol (100 mL), thionyl chloride (2.3 g, 19.33 mmol) was stirred for 3 h at 60°C. The resulting mixture was concentrated under vacuum. This resulted in the title compound (2.5 g, 79percent) as colorless oil.To a stirring solution of 14 in tetrahydrofuran (0.6 M) at 0 C. under nitrogen was added dimethylaminopyridine (0.2 eq), methanol (2.2 eq) and 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (2.2 eq). The reaction was stirred at room temperature overnight. The tetrahydrofuran was removed under reduced pressure. The resulting oil was partitioned between ethyl acetate and saturated sodium bicarbonate. The phases were separated and the organic phase was washed with saturated sodium bicarbonate (1?), 1N hydrochloric acid (1?), brine (1?), dried over sodium sulfate, filtered and concentrated in vacuo to afford the product. (58percent) 1H NMR (400 MHz, DMSO-d6) ' 7.38 (d, 2H), 7.27 (d, 2H), 4.75 (s, 2H), 3.69 (s, 2H), 3.61 (s, 3H).Description 16: Methyl [4-(bromomethyl)phenyl]acetate (D16). To a solution of 4-(bromomethyl)phenylacetic acid (2Og, 87.3mmol) in MeOH (200ml) was added trimethylsilylchloride (2ml) and the reaction stirred for 2h. The solvent was removed in vacuo and the residue was twice re-dissolved in MeOH (200ml) and re-concentrated to give the title compound (21.08g). deltaH (CDCI3, 250MHz) 7.36 (2H, d), 7.26 (2H, d), 4.49 (2H, s), 3.69 (3H, s), 3.62 (2H, s).Example 3. Synthesis of Bromomethyl Phenyl Acetic Acid Methyl Ester. [Show Image] Procedure: A mixture of bromomethyl phenyl acetic acid and TsOH in methanol is stirred at room temperature overnight. Thin layer chromatography (TLC) (20percent ethyl acetate) is used to demonstrate the formation of a new spot and disappearance of the starting material. The reaction mixture is concentrated in vacuo to give the crude product 5 as a thick, colorless oil. This crude product is used in the next reaction without further purification.(i) Methyl [4-(bromomethyl)phenyl] acetateTo a mixture of /?-bromomethylphenylacetic acid (50.0g, 218mmol) in MeOH (125g) and toluene (250g), was added thionyl chloride (15.6g) dropwise at 0°C and stirred for 3 hr. Separately NaHC03 (33g, 393mmol) was dissolved in water (540g), mixed with toluene (200g) and cooled to 0°C. The reaction solution described above was added dropwise to the mixture and stirred for 1 hr. The aqueous layer was removed and the organic layer washed with water. The solution was then concentrated under reduced pressure at a temperature below 40°C to give the subtitle compound as a crude product (58.9g) used directly in the following reaction. 1H NMR (OMSO-d ) delta 7.37 (d, 2H), 7.34 (d, 2H), 4.62 (s, 2H), 3.73 (s, 2H), 3.63 (s, 3H)Under a nitrogen atmosphere, SOCl2 (0.55 mL, 7.55 mmol, 0.2 eq). was added dropwise to a stirred suspension of 2-(4-(bromomethyl)phenyl)acetic acid (8.65 g, 37.74 mmol, 1 eq) in MeOH (85.0 mL) at 0 °C. The mixture was stirred at room temperature for 2 h, then was diluted with water. The solvent was partially removed in vacuo and the resulting aqueous phase was extracted with EtOAc (x3) The combined organic layers were washed with brine (xl), dried over sodium sulfate and concentrated in vacuo, to give 8, 23 g of product as an amorphous off-white solid; yield 90percent, which was used in the next step without further purification. IR (KBr) 2998, 2951, 1736, 1435, 1160, 1012, 602; 1H- MR (300 MHz, CDC13) delta 7.35 (d, J = 8.0 Hz, 2-H), 7.25 (d, J = 8.0 Hz, 2-H), 4.48 (s, 2-H), 3.69 (s, 3-H), 3.62 (s, 2-H) ppm; 1 C- MR (75 MHz, CDC13) delta 171.7, 136.7, 134.3, 129.8, 129.3, 52.1, 40.9, 33.2 ppm.To a solution of 2 g of 4-(bromomethyl)phenyl acetic acid in 20 mL of methanol was added 0.2 mL of TMSCl and mixture was stirred for 2 hrs. The solvent was removed in vacuo and residue was twice redissolved in MeOH and reconcentrated to give desired product, which was used in the xet step without purification. Bromoester was refluxed in 50 mL of water in the presence of 2.5 g of sodium bisulfilte for 3 hs. After cooling down the precipitate was filtered off and dried on the funnel overnight. The solid was suspended in 15 mL of POCl3 and 1 g of PCl5 was slowly added to a suspension. The mixture stirred for 3 hs at RT. A mixture was concentrated and 10 mL of conc. ammonia in water was slowly added to 0° C., redissolved compound in 30 mL of acetonitrile. After stirring for 12 hs at RT, a mixture was concentrated, partitioned between ethyl acetate and saturated sodium carbonate solution. Organic layer was washed with brine, dried over MgSO4 and evaporated. The intermediate ester was dissolved in 5 mL of EtOH and 10 ml of 10M NaOH was added. The mixture was stirred for 24 hs and then concentrated. Acidification with 12M HCl resulted in precipitate. 2-(4-(sulfamoylmethyl)phenyl)acetic acid was filtered off and dried overnight. Used without purification in the next step.