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With lithium aluminium tetrahydride; In tetrahydrofuran; for 4.0h;Cooling with ice;
General procedure: Step A: Preparation of 2,6-Dimethylbenzyl Alcohol To a solution of 2,6-dimethylbenzoic acid (10 g, 66.5 mmol) and potassium carbonate (9.18 g, 66.5 mmol) in dimethylformamide (67 ml), was added methyl iodide (8.28 ml, 133.16 mmol) in an ice bath, and the mixture was stirred for 16 hours. To the reaction mixture was added toluene and water, and the organic layer was washed with 3% K2CO3, 1N HCl, and brine. The organic layer was dried over Na2SO4, filtered and concentrated. The oily residue was redissolved in dry THF (135 ml), added to LiAlH4 (3.79 g, 99.8 mmol), and stirred for 4 hours in an ice bath. To the reaction mixture was added 1N HCl slowly followed by ethyl acetate, and the organic layer was washed with brine, dried over Na2SO4, filtered and concentrated. The oily residue was used without further purification. 1H NMR (270 MHz, CDCl3): 2.4 (s, 6H); 4.7 (s, 2H); 7.0-7.15 (m, 3H).
Step B Preparation of 2-Fluoro-6-methylbenzyl Alcohol: Using the method of Example 35, Step A, the title compound was obtained. 1H NMR (270 MHz, CDCl3): 2.4 (s, 3H); 4.7 (s, 2H); 6.85 (t, 1H); 6.95 (d, 1H); 7.15 (m, 1H).
2
[ 478163-35-8 ]
[ 886502-18-7 ]
Yield
Reaction Conditions
Operation in experiment
85%
With carbon tetrabromide; 1,3-bis-(diphenylphosphino)propane; In dichloromethane; at 0 - 20℃;
To a solution of the benzyl alcohol from Step 5 (2.65 g, 18.9 mmol) in CH2CI2 (15 mL) was added 1 ,3-bis(diphenylphosphino)propane (4.7 g, 11 mmol). The mixture was EPO <DP n="54"/>cooled to 0 0C and CBr4 (7.4 g, 22 mmol) was added slowly. The mixture was stirred overnight at room temperature. The mixture was diluted with CH2CI2 (50 ml_) and poured into Et2O (75 mL). The mixture was filtered and the solution phase was concentrated. The resulting product was again dissolved in CH2CI2 (75 mL) and poured into Et2O (100 mL). Filtration and concentration afforded 3.27 g (85%) of the bromide, an orange oil. 1H NMR (400 MHz, CDCI3) delta 2.42 (s, 3 H), 4.56 (d, J=1.5 Hz, 2 H), 6.91 (t, J=9.1 Hz, 1 H), 6.97 (d, J=7.6 Hz1 1 H), 7.08 - 7.24 (m, 1 H).
To a solution of the acid from Step 4 (3.60 g, 23.4 mmol) in thionyl chloride (40 mL) was added DMF (0.42 mL) and the mixture was heated to reflux for 5.5 h. The mixture was cooled to room temperature and concentrated. The residue was taken up in THF (40 mL) and added over 20 min to a 0 0C slurry of NaBH4 (3.53 g, 93.4 mmol) in THF (40 mL). The mixture was stirred at room temperature for 2 h and then quenched by the addition of H2O and 4 M HCI and extracted with EtOAc. The combined organic phase was washed with sat. NaHCO3 and brine, dried (MgSO4) and concentrated to afford 2.67 g (~ 75%) of the benzyl alcohol, a pale yellow solid. 1H NMR (400 MHz, CDCI3) delta 2.42 (s, 3 H), 4.72 (s, 2 H), 6.88 (t, J=9.0 Hz, 1 H), 6.96 (d, J=7.6 Hz, 1 H), 7.07 - 7.20 (m, 1 H).
With thionyl chloride;N,N-dimethyl-formamide; In toluene; at 20℃;Cooling with ice;
After dissolving <strong>[478163-35-8](2-fluoro-6-methylphenyl)methanol</strong> (CAS 478163-35-8) (2.35 g) in toluene (20 ml), thionyl chloride (3.68 ml) was added dropwise while stirring on ice. A catalytic amount of N,N-dimethylformamide was added, and the mixture was stirred at room temperature for 25 hours and 30 minutes. The reaction mixture was concentrated under reduced pressure, a saturated aqueous solution of sodium hydrogencarbonate was added to the residue, and extraction was performed with n-heptane. The organic layer was washed with water and brine in that order and then dried over anhydrous magnesium sulfate. After filtration with NH silica gel, the filtrate was concentrated under reduced pressure. The title compound (2.04 g) was thus obtained.1H-NMR (400 MHz, CDCl3); delta 2.45 (s, 3H), 4.68 (d, J=1.6 Hz, 2H), 6.89-7.01 (m, 2H), 7.17-7.24 (m, 1H).