Process for preparation of substituted p-aminophenol
a technology of p-aminophenol and compound, which is applied in the preparation of amino-carboxyl compound, carboxylic acid nitrile preparation, organic chemistry, etc., can solve the problems of not being suitable for large-scale manufacture, and achieve the effects of less expensive, commercially available starting materials, and convenient handling
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example 1
Preparation of 2-fluoro-3-hydroxy-4-methyl-6-nitrobenzoic acid
[0036]
[0037]To a 500 mL glass reactor equipped with mechanical stirrer, addition funnel, thermocouple, reflux condenser and nitrogen inlet is charged potassium trimethylsilanolate (TMSOK, 61.2 g, 0.48 mol, 3.2 eq) and 2-methyl tetrahydrofuran (240 mL) to form a suspension. The suspension is stirred at 20-25° C. 2,3-difluoro-4-methyl-6-nitrobenzoic acid (32.5 g, 0.15 mol, 1 eq) is dissolved in 2-MeTHF (75 mL). To the TMSOK suspension, the solution of 2,3-difluoro-4-methyl-6-nitrobenzoic acid is added. The addition is exothermic and the temperature of the reaction mixture rises to 40-50° C. during addition. After charging is complete, the jacket temperature is set at 65-70° C. The suspension is stirred for 2-3 hour, until HPLC sample shows complete conversion. The mixture is cooled down to room temp. The reaction is quenched with water (100 mL), and acidified to pH 1 with HCl aqueous solution (6M, 90 mL). The layers are sep...
example 2
Preparation of methyl 5-hydroxy-4-methoxy-2-nitrobenzoate
[0039]
[0040]5-hydroxy-4-methoxy-2-nitrobenzoic acid (31.9 g, 0.15 mol, 1.0 eq) and 2-methyltetrahydrofuran (200 mL) are charged into a glass reactor under nitrogen. The solution is stirred and jacket temp is set to 20° C. Oxalyl chloride (24 g, 0.19 mol, 1.25 eq) is added at a rate that the internal temperature is below 25° C. The reaction mixture is stirred for 1-2 hour at 20° C., and cooled to 15° C. Then, anhydrous MeOH (60 ml, 1.5 mol, 10 eq) is added over 15 min, and the reaction temperature is maintained below 25° C. during addition. The reaction mixture is stirred for 2-4 hour at 20° C. until HPLC sample shows complete conversion. Na2CO3 aqueous solution (1 M, 100 ml) is added to the reaction mixture. Layers are separated. The upper organic layer is distilled under vacuum to minimum volume. The dark brown residue is stirred in 100 mL mixed solvent of toluene / hexane (v / v, 2:1) to give a suspension. The slurry is filtered...
example 3
Preparation of methyl 2-amino-5-hydroxy-3-methylbenzoate hydrochloride
[0042]
[0043]Palladium on carbon (5 wt.%, wet, contains ˜50% water, 2.4 g, 0.56 mmol, 0.005 eq) is charged into a 300 mL Parr bomb. Then, methyl 5-hydroxy-3-methyl-2-nitrobenzoate (23.2 g, 0.11 mol, 1 eq) and MeOH (80 mL) are charged. The bomb is sealed, and pressurized / vented three times with hydrogen, and pressured with 100 psi hydrogen. The reaction mixture is stirred, until the hydrogen pressure is not dropping. The bomb is opened, and an HPLC sample shows that the reaction is complete. The mixture is diluted with 80 ml of THF and filtered through a Celite pad. The solution is concentrated under vacuum and solvent is switched to EtOAc. To the suspension in EtOAc (150 mL) at 15° C., HCl in dioxane (4M, 36 mL, 0.14 mol, 1.3 eq) is charged at a rate that the internal temperature is below 30° C. The suspension is stirred at 20° C. for 2 hour. The slurry is filtered. The solid is dried under vacuum to provide the de...
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