1-BROMO-3-METHOXY-5-METHYLBENZENE

Colorless Oil

In a 250 ml round bottom flask, 4- bromo-2-methoxy-6-methyl-phenylamine (5.8 g, 26.84 mmol) was charged with acetic acid (49 mL) and concentrated HCl (5.6 mL). Sodium nitrite (2.19 g, 31.78 mmol) in 7 mL water was added to the mixture dropwise at 0 The reaction is performed in a water/ice bath. 500 mg (2.31 mmol, 1 eq) of 4-bromo-2-methoxy-6-methylaniline is dissolved in a mixture of 7 ml of acetic acid and 3 ml of water, followed by adding 0.8 ml of concentrated hydrochloric acid (37percent) and 207 mg (3.00 mmol, 1.5 eq) of sodium nitrite dissolved in 1 ml of water. To a mixture of 3-bromo-5-methyl-phenol (185 g; 0.940 mol) and KC. Preparation of 3-methyl-5-methoxybromobenzene In a three-necked flask, 3-methyl 5-bromophenol (10.0 g, 53.5 mmol), potassium carbonate (22.2 g, 160.4 mol) andIodomethane (7.6 g, 53.5 mol) was dissolved in acetone (50 mL) and refluxed for 3 h. After the reaction is complete, add 30 mL of water, methylene chloride(50mL × 3) extraction, dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated under reduced pressure to give 3-methyl-5-methoxybromobenzene white.Crystals 9.2 g, yield 85.8percent[0297] To the mixture of compound 29-1 (300 g, 1.6 mol) and KIn a 250 ml round bottom flask, 4- bromo-2-methoxy-6-methyl-phenylamine (5.8 g, 26.84 mmol) was charged with acetic acid (49 mL) and concentrated HCl (5.6 mL). Sodium nitrite (2.19 g, 31.78 mmol) in 7 mL water was added to the mixture dropwise at 0 0C. The reaction mixture was stirred at 0 0C for 30 minutes. 50% Hypophosphorous acid (56.5 mL) was added at 0 0C. The reaction mixture was stirred at at 0 0C, and warmed up to room, temperature overnight. Ethyl acetate was then added, followed by washing with saturated NaHCtheta3 solution. The organic layer was concentrated and purified (silica gel, 100% hexane) to give a pale liquid (5.12 g, 95%). 1H NMR (300 MHz, CDCb): delta 6.97(s, 1 H), 6.87 (s, 1 H), 6.64 (s, 1 H), 3.80 (s, 3 H), 2.36 (s, 3 H).The reaction is performed in a water/ice bath. 500 mg (2.31 mmol, 1 eq) of 4-bromo-2-methoxy-6-methylaniline is dissolved in a mixture of 7 ml of acetic acid and 3 ml of water, followed by adding 0.8 ml of concentrated hydrochloric acid (37%) and 207 mg (3.00 mmol, 1.5 eq) of sodium nitrite dissolved in 1 ml of water. The mixture is stirred for 30 min and subsequently added to 8 ml of ice-cooled 50% by weight hypophosphoric acid. The reaction is stirred at 0 C. for 8 hours and allowed to stand at RT over night. For the processing, the mixture is extracted with ethyl acetate, dried over magnesium sulfate, filtered, and the solvent is removed in vacuum on a rotary evaporator. The raw product was not further purified (yield 90%, 418 mg). C8H9BrO; MW 200/202; 1H-NMR (CDCl3): delta 6.45 (s, 1H), 6.39 (s, 1H), 6.18 (s, 1H), 3.30 (s, 3H), 1.83 (s, 3H); 13C-NMR (CDCl3): delta 160.2, 141.0, 124.5, 122.4, 114.1, 113.9, 55.4, 21.2; IR: 2925, 1599, 1569, 1464 1/cmTo a cold (0 0C) solution of 4-bromo-2-methoxy-6-methylaniline (36 g, 167 mmol) in a mixture of acetic acid (280 mL), water (120 mL) and concentrated HCl (32 mL) was added dropwise a solution OfNaNO2 (13.8 g, 200 mmol) in water (40 mL). The reaction mixture was stirred for 30 min at 0 0C and 50% aq H3PO2 (320 mL) was added. After stirring for 8 h at 0 0C, the reaction mixture was allowed to stand at rt for 48 h. The reaction mixture was extracted with EtOAc/Et2O. The crude residue was purified by flash chromatography on silica gel (ISCO Combiflash, 330 g column, 100% hexane) to afford 27.5 g of l-bromo-3-methoxy-5-methylbenzene as a colorless oil.Step 2. l-bromo-3-methoxy-5-methylbenzene: To a cold (0 0C) solution of 4- bromo-2-methoxy-6-methylaniline (36 g, 167 mmol) in a mixture of acetic acid (280 mL), water (120 mL) and concentrated HCl (32 mL) was added dropwise a solution OfNaNO2 (13.8 g, 200 mmol) in water (40 mL). The reaction mixture was stirred for 30 min at 0 0C and 50% aq H3PO2 (320 mL) was added. After stirring for 8 h at 0 0C, the reaction mixture was allowed to stand at rt for 48 h. The reaction mixture was extracted with EtOAc/Et2O. The crude residue was purified by flash chromatography on silica gel (ISCO Combiflash, 330 g column, 100% hexane) to afford 27.5 g of 1- bromo-3-methoxy-5-methylbenzene as a colorless oil.EXAMPLE 23 2-Fluoro-6-?(3[-methyl-5-methoxyphenyl)thio]benzonitrile A solution of 1 g (0.005 mol) of ). 1-Bromo-3-methoxy-5-methylbenzene (1.00 g, 5.0mmol) and pyridine/H2O (2:5, 30 mL) were added to a round-bottomflask, followed by KMnO4 (3.14 g, 20 mmol). The resulting mixturewas then heated while refluxing for 48 hr. After the removal of the precipitateby filtration, 2 M HCl was added to the reaction mixture to acidify it (pH 2).The aqueous phase was extracted with ethyl acetate. The organic phase waswashed with brine and dried over anhydrous Na2SO4. Thesolvent was removed under reduced pressure and the residue was purified usingsilica gel column chromatography. The white solid (385 mg, 34% yield) wasidentified as 3-bromo-5-methoxybenzoic acid (3a) on the basis of 1H-NMR spectra. 1H-NMR(400 MHz, CDCl3): d3.86(s, -OCH3, 3H), 7.29 (t, J=2.0Hz, Ar H, 1H), 7.54 (t, J=2.0 Hz, ArH, 1H), 7.83 (t, J=2.0 Hz, Ar H, 1H).To a vigorously stirred mixture of 1-Bromo-3-methoxy-5-methylbenzene (1 g, 4.97 mmol), Pyridine (3.22 ml_, 39.8 mmol) and Water (8 ml) was added in small portions KMnO 4 (3.14g, 19.89 mmol) at 105C. The mixture which turned to a black suspension was stirred 24 hours at 105C, then cooled down to RT and filtered over Hyflo. The black residue was washed several times with EtOAc. The filtrate was then diluted in EtAOc and washed with a 2M solution of HCI. The organic layer was dried over sodium sulfate, filtered and concentrated to afford the title compound (281 mg, 24% yield) as a white solid. MS: 229.1 [M+H]+, Rt (1 ) 1 .18 min.To a vigorously stirred mixture of 1 -Bromo-3-methoxy-5-methylbenzene (1 g, 4.97 mmol), Pyridine (3.22 mL, 39.8 mmol) and Water (8 ml) was added in small portions KMn04 (3.14g, 19.89 mmol) at 105C. The mixture which turned to a black suspension was stirred 24 hours at 105C, then cooled down to RT and filtered over Hyflo. The black residue was washed several times with EtOAc. The filtrate was then diluted in EtAOc and washed with a 2M solution of HCI. The organic layer was dried over sodium sulfate, filtered and concentrated to afford the title compound (281 mg, 24% yield) as a white solid. MS: 229.1 [M+H]+, Rt (1 ) = 1 .18 min.3-Bromo-5-methoxybenzoic acid To a vigorously stirred mixture of 1-Bromo-3-methoxy-5-methylbenzene (1 g, 4.97 mmol), Pyridine (3.22 mL, 39.8 mmol) and Water (8 ml) was added in small portions KMnO4 (3.14 g, 19.89 mmol) at 105 C. The mixture which turned to a black suspension was stirred 24 hours at 105 C., then cooled down to RT and filtered over Hyflo. The black residue was washed several times with EtOAc. The filtrate was then diluted in EtAOc and washed with a 2M solution of HCl. The organic layer was dried over sodium sulfate, filtered and concentrated to afford the title compound (281 mg, 24% yield) as a white solid. MS: 229.1 [M+H]+, Rt(1)=1.18 min.

Molecular Weight:201.06
XLogP3:2.9
Hydrogen Bond Acceptor Count:1
Rotatable Bond Count:1
Exact Mass:199.98368
Monoisotopic Mass:199.98368
Topological Polar Surface Area:9.2
Heavy Atom Count:10
Complexity:105
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes