5-Bromo-2-fluoro-α-methylbenzenemethanol

J. 1-(5-bromo-2-fluorophenyl)ethan-1-ol. To a solution of 5-Bromo-2-fluorobenzaldehyde (10.0 g., 49.26 mmol) in anhydrous ether (60 mL) at 0° C. was added 1.4M methyl magnesium bromide (THF/Tol. solution) (36.9 mL) dropwise. The solution stirred for 30 minutes and quenched with water (50 mL) followed by 1N HCl (10 mL). The organics were separated and dried over magnesium sulfate, filtered and solvent removed under reduced pressure to afford the title compound (10.8 g., 100percent). MS (ESI) m/z 218 [M+1][00199] 5-Bromo-2-fluro-phenyl-methanol: 5-Bromo-2-fluorobenzaldehyde(commercially available from Aldrich)( 150.0 g, 739 mmol) was charged into a 2 liter round bottom flask. The reaction mixture in the flask was immersed in an ice-water bath. Methylmagnesium bromide (270 mL, 812 mmol) was added dropwise via an addition funnel. The reaction mixture was stirred for one hour following completion of the addition. After the reaction was completed, the mixture was slowly poured into 500 mL ice water and 250 mL saturated ammonium chloride. The resulting aqueous solution was extracted with ether (800 mL x2) in a separation funnel. The combined ether layer was washed with brine and dried over sodium sulfate. Removal of the solvent gave the product (150 g, yield = 93percent). The product was used directly in the next step without further purification.Commercially available 4a (150.0 g, Methylmagnesium bromide (3M solution in tetrahydrofuran, 18 ml, 54.2 mmol) was added to a solution of 5-bromo-2-fluorobenzaldehyde (10.0 g, 49.3 mmol) under nitrogen at 0° C. over 30 min. The resulting solution was allowed to warm to room temperature over 14 h, upon which TLC analysis showed no remaining starting material, and two new products. The mixture was quenched with water, diluted with ethyl acetate and the organic phase removed and dried over sodium sulfate. This was then concentrated and purified by column chromatography (120 g ISCO column eluting with hexanes and ethyl acetate; gradient 100percent hexanes to 50percent hexanes). The second fraction was collected as the product, providing the alcohol (5.8 g, 53percent) as an oil; A solution of 5-bromo-2-fluoro-benzaldehyde (55.0 g, 270.9 mmol) in THF (500.0 mL) was cooled to 0°C. Then MeMgBr (3 M, 94.8 mL) was added. The mixture was stirred at 0°C for 0.5 h, quenched with HAcid Preparation 5; 3-Methyl-1 H-indazole-5-carboxvlic acid; To a cooled solution of 3-bromobenzaldehyde (42.5 g, 209 mmol) in THF (300 ml_) at 0 Step 1 [0200] 5-Bromo-2-fluorobenzaldehyde (1) (12.98 g) was dissolved in tetrahydrofuran (60 ml) under nitrogen atmosphere, and the solution was cooled in a dry ice-acetone bath. To the solution was added dropwise methylmagnesium chloride (3M in THF, 25.6 ml) at a temperature between −78° C. and −30° C. After completion of addition, the mixture was stirred at a temperature between −10° C. and −5° C. for 1 hour. To the reaction solution were added an aqueous saturated ammonium chloride solution and water, extracted with ethyl acetate and washed subsequently with water and brine. The organic layer was dried over anhydrous magnesium sulfate and the solvent was evaporated under reduced pressure to afford Compound 2 (14.51 g). [0201]

Molecular Weight:219.05
XLogP3:2.2
Hydrogen Bond Donor Count:1
Hydrogen Bond Acceptor Count:2
Rotatable Bond Count:1
Exact Mass:217.97426
Monoisotopic Mass:217.97426
Topological Polar Surface Area:20.2
Heavy Atom Count:11
Complexity:131
Undefined Atom Stereocenter Count:1
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes