BENZOIC ACID,4-BROMO-2-METHYL-,METHYL ESTER

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STEP 1 : To a cooled (0Step 1: : Example 1A: Part A:To a solution of 4-bromI'2~meihylbenzoic acid (1 ) (430 mg, 2 mmoi) in MeCN (5 ml) and MeOH (5 ml) was added trimethylsIydiazomethaI.euro.e (2Af, 3 mt, 6 mmoi). The Step 1: 5.76 l-(3-CHIX)RO-4-METHYIStep 1. A mechanically stirred mixture of 4-bromo-2-methyl-benzoic acid (100 g, 465 mmol), iodomethane (95 g, 670 mmol) and sodium bicarbonate (112 g, 1340 mmol) in DMF (325 mL) was heated at 80 C overnight. The reaction mixture was cooled to room temperature and partitioned between water (1500 mL) and 4:1 hexanes:ethyl acetate (1500 mL). The organic layer was washed with water and dried (Na[00407j Step 1: A mechanically stirred mixture of 4-bromo-2-methyl-benzoic acid (100 g, 465 mmol), iodomethane (95 g, 670 mmol) and sodium bicarbonate (112 g, 1340 mmol) in DMF (325 mL) was heated at 80 °C overnight. The reaction mixture was cooled to room temperature and partitioned between water (1500 mL) and 4:1 hexanes : ethyl acetate (1500 mL). The organic layer was washed with water and dried (Na2SO4). The solvent was removed under vacuum to give 110 g of 4-bromo-2-methyl-benzoic acid methyl ester as an oil, in 100percent yield; 1H NMR (DMSO-d6) ö 2.51 (s, 3H), 3.84 (s, 3H), 7.40-7.78 (m, 3H).A mechanically stirred mixture of 4-bromo-2-methyl-benzoic acid (100 g, 465 mmol), iodomethane (95 g, 670 mmol) and sodium bicarbonate (112 g, 1340 mmol) in DMF (325 mL) was heated at 80 °C overnight. The reaction mixture was cooled to room temperature and partitioned between water (1500 mL) and 4: 1 hexanes:ethyl acetate (1500 mL). The organic layer was washed with water and dried (NaTo a 100 mL rbf was added 4-bromo-2-methyl-benzoic acid(2.0 g, 9.300 mmol), potassium carbonate (3.856 g, 27.90 mmol), and DMF (20.00mL). Iodomethane (1.452 g, 636.8 µL, 10.23 mmol) was added dropwise and thereaction was allowed to stir at rt for 1h. By lcms analysis, the reaction wascomplete. The reaction was quenched with brine and extracted with EtOAc 3times. The organic layer was dried over sodium sulfate and evaporated. Methyl4-bromo-2-methyl-benzoate (2.0 g, 8.731 mmol, 93.9percent) was used in the next stepwithout further purification. ESI-MS m/z calc. 227.97859, found 229.3 (M+1) To a stirred solution of 4-bromo-2-methyl benzoic acid (10 g, 46.511 mmol) in DMF (50 ml) at 0°C, was added KStep 1. To 27 (3.0 g, 14.0 mmol) and CH3I (3.96 g, 27.9 mmol) in DMF (30 mL) was added K2C03 (2.89 g, 20.9 mmol). The reaction mixture was stirred at 25°C for 12 h and then quenched with H20 (20 mL). The solution was extracted with ethyl acetate (3 x 100 mL) and the organic layer was washed with H20 (3 x 100 mL) and concentrated to afford 28 (2.9 g, 82percent).Example 33A Example 263A 4-Bromo-2-methyl-benzoic acid (4.6 g, 21.39 mmol) is dissolved in 2M HCl inMeOH and refluxed for 3 hours. The solvent is evaporated to give the 4-bromo-2-methyl-benzoic acid methyl ester (4.24 g, 86 percent). This intermediate (18.51 mmol) is dissolved in carbon tetrachloride (100 mL) and N-bromosuccinimide (NBS) (5.57 g, 24.06 mmol) is added. AIBN (122 mg, 740 μmol) is then added and the mixture purged with nitrogen for 5 min. The reaction mixture is then refluxed for 4 hours. After cooling to room temperature the reaction mixture is filtered and the filtrate is evaporated. The residue is purified by flash chromatography (silica gel, 2:1 petroleum ether/ethyl acetate) to give the title compound (3.42g, 60 percent).A. Example 33A To a solution of compound 1 (79.45 g, 369.5 mmol) in methanol (450 ml) was added thionyl chloride (53.6 ml, 739 mmol), and the mixture was stirred at 70 °C for 6 hs. The reaction mixture was concentrated to afford methyl 4-bromo-2-methylbenzoate (86.37 g, yield 100percent).REFERENCE Methyl 4-bromo-2-methylbenzoate; To a solution of 4-bromo-2-methylbenzoic acid (6.17 g, 0.29 mol) in MeOH (170 mL), HReference Methyl 4-bromo-2-methylbenzoateTo a solution of 4-bromo-2-methylbenzoic acid (6.17 g, 0.29 mol) in MeOH (170 mL), HREFERENCE Methyl 4-bromo-2-methylbenzoate; To a solution of 4-bromo-2-methylbenzoic acid (6.17 g, 0.29 mol) in MeOH (170 mL), HCompound 6.1. Methyl 4-bromo-2-methylbenzoate. To a solution of 4-bromo-2- methylbenzoic acid (5.1 1 g, 23.8 mmol, 1.0 equiv) in methanol (25 mL) was added dropwise ulfuric acid (2.0 mL) over about 3 minutes (mildly exothermic). The resulting mixture was refluxed for 4 hours. After cooling to room temperature, the reaction mixture was carefully quenched into saturated aqueous NaHC0Compound 6.1. Methyl 4-bromo-2-methylbenzoate. 2-methyl-4-bromobenzoic acid 1, 5 g dissolved in 30 ml methanol, To this was added 2 ml of thionyl chloride, The reaction was refluxed at 70 ° C for 6 hours, The solution was cooled to room temperature, Add 30 ml of saturated sodium carbonate solution, Fully agitated, Extracted with ethyl acetate 15 ml twice, The organic layer was washed twice with 10 ml of water, And saturated saline 10 ml washing, Dried over anhydrous magnesium sulfate, filter, Concentrated under reduced pressure, Get brownish red2-methyl-4-bromobenzoic acid methyl ester 2, 5.17 g, Yield 97percent.Stepl. Preparation of methyl 4-bromo-2-methylbenzoate - A IL 3 neck flask with mechanical stirrer, reflux condenser, internal temperature probe and a nitrogen bubbler was charged with 4- bromo-2-methylbenzoic acid (50.35 g, leq., Hongda) and methanol (350 mL). and the reactor contents were cooled to 0 C. Acetyl chloride (27.6g, leq.) was slowly added at a rate which maintained an internal temperature of less than 30 C. The reaction mixture was heated to reflux for 16 hours, until starting material was no longer detected by LC. Once reaction was complete, the reactor contents were cooled to room temperature and the reaction mixture was concentrated to an oil via rotary evaporator. The oil was then diluted with dichloromethane (100 mL) and washed with saturated sodium bicarbonate solution (100 mL). The organic layer was concentrated via rotary evaporator to afford methyl 4-bromo-2-methylbenzoate (51.22g, 95.5 percent) as a yellow oil.Reference Example 9C077C.H4-Bromo-2-methylbenzoic acid (100 g, 465.02 mmol), concentrated sulfuric acid (52 mL) in methanol (1L) were combined and heated to 65 °C for 18 h. The reaction was concentrated and the residue diluted with ethyl acetate (500 mL), washed with saturated sodium bicarbonate solution (150 mL), water (200 mL), brine (250 mL) and dried over sodium sulfate. The organic phase was concentrated under reduced pressure and further dried under high vacuum to give methyl 4-bromo-2-methylbenzoate (102 g, 445.27 mmol, 95percent yield) as a red liquid. 1H NIVIR (400 MHz, Chloroform-di) 7.78 (d, J 8.3 Hz, 1H), 7.45 — 7.30 (m, 2H), 3.88 (s, 3H), 2.57 (s, 3H).4-Bromo-2-methylbenzoic acid(100 g, 465.02 mmol), concentrated sulfuric acid (52 mL) in methanol (1L) werecombined and heated to 65 °C for 18 hours. The reaction was concentrated and the residue diluted with ethyl acetate (500 mL), washed with saturated sodium bicarbonate solution (150 mL), water (200 mL), and brine (250 mL) and dried over sodium sulfate. The organic phase was concentrated under reduced pressure and further dried under highvacuum to give methyl 4-bromo-2-methylbenzoate (102 g, 445.27 mmol, 95percent yield) asa red liquid. 1H NMR (400 IVIFIz, Chloroform-dl) 7.78 (d, J= 8.3 Hz, 1H), 7.45 —7.30 (m, 2H), 3.88 (s, 3H), 2.57 (s, 3H).The 2-methyl-4-bromobenzoic acid (3g, 13.4 mm, 1.0equiv) suspended in methanol (30 ml) in, cooling to 0 °C, drips thionylchloride (2.4 ml, 33.5 mm, 2.5equiv), stirring 15 min after in transferred to the oil bath boiler, heating to reflux, monitoring reaction is complete by TLC, cooling to room temperature, the solvent is concentrated under reduced pressure. Column chromatography (petroleum ether: ethyl acetate = 5:1) treatment to obtain pale brown oily liquid (2.995g, yield 94percent).To a solution of 4-bromo-2-methyl-benzoic acid (30.0 g, 0.14mol) in 115 mL of methanol was added thionyl chloride (20.25 mL, 0.28 mol) slowly and the reaction mixture was stirred at 70 °C for 2 hours before it was concentrated to afford a crude product which was then purified by column chromatography to give the title compound (30.03 g, 93.6percent) as a solid4-Bromo-2-methylbenzoic acid (20.0 g, 93.1 mmol) was suspended in dry MeOH (200 mL), to which was added c.H2S04 (1 mL).This mixture was heated at reflux for 72 h. Upon cooling, all solvent was removed under reduced pressure and the resulting oil dissolved in EtOAc (500 mL) then washed with sat. NaI-1C03 (3x100 mL), brine (100 mL) and dried (Na2SO4). The solution was filtered and the solvent removed under reduced pressure to afford the title compound as a pale yellowoil (19.92 g, 93percent). ‘H NMR [400 MHz, (CD3)2S0] 6 7.77(d, J 8.4 Hz, 1 H), 7.40-7.42 (m, I H), 7.35-7.39 (m, 1 H), 3.88 (s, 3 H), 2.57 (s, 3 H).To a solution of 4-bromo-2-methyl-benzoic acid (30.0 g, 0.14 mol) in 115 mL of methanol was added thionyl chloride (20.25 mL, 0.28 mol) slowly and the reaction mixture was stilTed at 70 °C for 2 hours before it was concentrated to afford a crude product which was then purified by column chromatography to give the title compound (30.03 g, 93.6percent) as asolid.To a solution of 4-bromo-2-methyl-benzoic acid (30.0 g, 0.l4mol) in 115 mL of methanolwas added thionyl chloride (20.25 mL, 0.28 mol) slowly and the reaction mixture wasstilTed at 70 °C for 2 hours before it was concentrated to afford a crude product which was then purified by column chromatography to give the title compound (30.03 g, 93.6percent) assolid.To a solution of 4-bromo-2-methyl-benzoic acid (30.0 g, 0.14 mol) in 115 mL of methanol was added thionyl chloride (20.25 mL, 0.28 mol) slowly and the reaction mixture was stilTed at 70 °C for 2 hours before it was concentrated to afford a crude product which wasthen purified by column chromatography to give the title compound (30.03 g, 93.6percent) assolid.ΓΑ1 4-Bromo-2-methyl-benzoic acid methyl ester To a solution of 4-bromo-2-methyl-benzoic acid (30.0 g, 0.14mol) in 115 mL of methanol was added thionyl chloride (20.25 mL, 0.28 mol) slowly and the reaction mixture was stirred at 70 °C for 2 hours before it was concentrated to afford a crude product which was then purified by silica gel flash chromatography to give the title compound (30.03 g, 93.6percent) as a solid.4-Bromo-2-rnethylbenzoic acid (2.00 g, 9.30 mmol) was added to a solution of acetyl chloride (1.70 mL, 23.9 mmol) in methanol (30 mL). The mixture was allowed to stir at rt for 3 days and was then concentrated in vacuo. This gave 1.96 g (92percent) of the title compound as a light brown oil. Intermediate 14: methyl 4-bromo-2-methylbenzoate; To a solution of commercially available 4-bromo-2-methylbenzoic acid (200 g, 0.87 mol) in methanol (500 ml.) was added sulphuric acid (98percent, 10 ml_). The reaction mixture was heated to reflux overnight. After cooling, the reaction mixture was concentrated, and then water and ethyl acetate were added. The organic layers were separated, dried over sodium sulfate and concentrated in vacuo to give the title compound, methyl 4-bromo-2-methylbenzoate as red oil (190 g, 90percent), which was used for next step without purification and characterization.PREPARATION 46; 4-Bromo-2-bromomethyl-benzoic acid methyl ester.; 4-Bromo-2-methyl-benzoic acid (20.35 g, 94.6 mmol) in MeOH (200 mL) was saturated with HCI gas, cooled to rt, resaturated with HCI gas and stirred overnight. The reaction was concentrated and dissolved in EtOAc, washed with sat. NaHCO[00260] To a round bottomed flask was added MeOH (25 mL) and commercially available 4-bromo-2-methyl benzoic acid (7.0 g, 32.8 mmol). Then 4N HCL/ dioxanes (25 mL) was added to the insoluble mixture and stirred under reflux for 3 h. The reaction was concentrated. EtOAc and HMethyl 4-bromo-2-methylbenzoateStep 1: In a round bottomed flask into ice-bath, were added methanol (15 mL), acetyl chloride (8.72 g, 111 mmol) and 4-bromo-2-methylbenzoic acid (1.0 g, 4.65 mmol). The reaction mixture was stirred at room temperature for 24 h, and then concentrated under reduced pressure. The resulting residue was extracted with CH2Cl2. The organic layer was washed with 10percent sodium carbonate solution, dried over anhydrous Na2SO4, filtered and evaporated, giving the methyl 4-bromo-2-methylbenzoate 10 as a colorless oil in 86percent, which was directly used in cross coupling reaction. The compound 10 (0.30 g, 1.31 mmol) was transferred to a round bottomed flask with a mixture of toluene-methanol (9:1, 4.5–0.5 mL), followed by addition of phenylboronic acid (0.192 g, 1.57 mmol), PdCl2(PPh3)2 (0.037 g, 4 mol percent) and potassium carbonate (0.543 g, 3.93 mmol). The reaction mixture was stirred at 60 °C for3 h, and after cooling to room temperature, was filtered over Celite. The resulting oil was purified bysilica gel column chromatography (n-hexane-EtOAc 0percent–1percent), affording the title compound as a white crystalline solid in 91percent yield, after evaporation under vacuum.Step 1 Ice bath, A solution of dichlorosulfoxide (5.50 mL, 70.00 mmol)Was added dropwise to a solution of 4-bromo-2-methylbenzoic acid (5.00 g, 23.2 mmol) in methanol (60 mL). After completion of the dropwise addition, the reaction was stirred at reflux for 5 hours.The mixture was cooled to room temperature and the reaction solution was concentrated under reduced pressure.The concentrate was adjusted to neutral with saturated sodium bicarbonate solution, Extracted with ethyl acetate, and the organic layer was washed with saturated brine, Dried over anhydrous sodium sulfate and concentrated under reduced pressure to give 4.3 g of a pale yellow oil in 81percent yield.To a solution of compound 1 (208.8 g, 0.97 mol) in MeOH (1200 ml_) was added dropwise SOCIMethyl 4-bromo-2-methylbenzoate. To 4-bromo-2-methylbenzoic acid (1 g, 4.7 mol), thionyl cloride (40 mL) was added. The mixture was stirred at 80°C for 2 hours. After cooling the reaction mixture to room temperature, the mixture was concentrated to dryness. Methanol (40 mL) was added and then the mixture was concentrated in vacuo to give methyl 4-bromo-2- methylbenzoate as a yellow oil (800 mg, 78percent).To 4-bromo-2-methylbenzoic acid (1 g, 4.7 mol), thionyl chloride (40 mL) was added. The mixture was stirred at 80° C. for 2 hours. After cooling the reaction mixture to room temperature, the mixture was concentrated to dryness. Methanol (40 mL) was added and then the mixture was concentrated in vacuo to give methyl 4-bromo-2-methylbenzoate as a yellow oil (800 mg, 78percent).To a stirring solution of 4-bromo-2-methylbenzoic acid (3 g) in methanol (70 mL) was added concentrated hydrochloric acid (5 mL) and the reaction mixture was heated to 60 °C for 16 h. The reaction mixture was concentrated under reduced pressure, the residue was basified with sodium bicarbonate solution and extracted with dichloromethane (3 x). The combined dichloromethane layers were washed with brine, dried over sodium sulphate and concentrated under reduced pressure to afford Methyl 4-bromo-2- methylbenzoate as a solid (2 g , 62percent)Step 1: Synthesis of methyl 4-bromo-2-methyl-benzoate To a stirred solution of 4-bromo-2-methyl-benzoic acid (15 g, 65 mmol) in methanol (50 mL) was added sulfuric acid (2 mL). The mixture was stirred and refluxed for 15 hours. After the completion of the reaction, the mixture was quenched by water (20 mL) and then basified to pH 8. After most of the methanol was evaporated, the mixture was extracted with ethyl acetate (50mL x 3). The organic layer was washed by brine (20 mL), and then dried over sodium sulfate and then concentrated to give 15.3 g of methyl 4-bromo-2-methyl-benzoate as a white solid.10222] To a stirred solution of 4-bromo-2-methyl-benzoic acid (15 g, 65 mmol) in methanol (50 mE) was added sulthric acid (2 mE). The mixture was stirred and refluxed for 15 hours. Afier the completion of the reaction, the mixture was quenched by water (20 mE) and then basified to pH 8. Afier most of the methanol was evaporated, the mixture was extracted with ethyl acetate (50 mEx3). The organic layer was washed by brine (20 mE), and then dried over sodium sulfate and then concentrated to give 15.3 g of methyl 4-bromo-2-methyl-benzoate as a white solid.To a mixture of 4-bromo-2-methylbenzoic acid (25.0 g) and MeOH (200 mL) was added sulfuric acid (12.4 mL) at room temperature, and the mixture was stirred overnight at 60° C. The reaction mixture was neutralized with 1N aqueous sodium hydroxide solution at 0° C., and extracted with ethyl acetate. The extract was washed with water and saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to give the title compound (26.6 g). (1063)

Molecular Weight:229.07
XLogP3:3.4
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