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To a solution of 2-amino-4-methylphenol (2-amino-p-cresol, Mol. Wt.: 123.15, 157.6 g, 1.28 mol) in 1500 ml of EtOH at room temperature, under stirred condition, was added bromocyanogen (Mol. Wt.: 105.92, 135.00 g, 1.28 mol) in about 30 mins. During the addition, the reaction mixture became to warm and water bath was used to cool the reaction to room temperature. The reaction color became to a dark color. After 5-6 hours, the reaction solvent was evaporated under reduced pressure. The residue was dissolved in about 1500 ml of EtOAc and washed with the saturated 1500 ml NaHCO3, the gas of CO2 was generated, and water phase was separated and washed again by 400 ml of EtOAc. The organic layer was combined and dried over anhydrous MgSO4. Removal of solvent and dried by high vacuum yielded about 150 g of product 2 as pale brown color, which can be used in next step. The TLC RF value of the product is about 0.35 in solution of acetone and hexane by the ratio of 1 to 2. MS(ESI): m/e 149 (M+H), 1H NMR (CDC13) (ppm) : 2.21(s, 3H); 5.30(bs, 2H); 6.99(d, 1H); 7.10(s, 1H); 7.22(d, 2H).
In ethanol; at 20℃; for 5.5 - 5.6h;
Example 1; To a solution of 2-amino-4-methylphenol (157.6 g, 1.28 mol) in 1500 ml of EtOH at room temperature, under stirred condition, was added bromocyanogen (135.00 g, 1.28 mol) in about 30 minutes. During the addition, the reaction mixture became warm and water bath was used to cool the reaction to room temperature. After 5-6 hours, the reaction solvent was evaporated under reduced pressure. The residue was dissolved in about 1500 ml of EtOAc and washed with the saturated NaHCO3 (1.5 L). The organic layer was separated and dried over anhydrous MgSO4. Removal of solvent and dried by high vacuum gave about 150 g of the title compound as pale brown color, which can be used in next step. ESI MS m/e: 149 (M+H)+.
In ethanol; at 20℃; for 5.5 - 6.5h;
To a solution of 2-amino-4-methylphenol (157.6 g, 1.28 mol) in 1500 ml of EtOH at room temperature, under stirred condition, was added bromocyanogen (135.00 g, 1.28 mol) in about 30 minutes. During the addition, the reaction mixture became warm and water bath was used to cool the reaction to room temperature. After 5-6 hours, the reaction solvent was evaporated under reduced pressure. The residue was dissolved in about 1500 ml of EtOAc and washed with the saturated NaHCO3 (1.5 L). The organic layer was separated and dried over anhydrous MgSO4. Removal of solvent and dried by high vacuum gave about 150 g of the title compound as pale brown color, which can be used in next step.
In 2500 ml of anhydrous toluene, succinic anhydride (Mol. Wt.: 100.07, 141.1 g, 1.41 mol) and 70 g (about 0.47 mol) of compound from Step 9a were added under stirred condition, and then the mixture was refluxed for overnight. After that, 100 g (0.26 mol) of HATU and 41.36 ml (0.376 mol) of 4-methylpholine were added and then the resulting mixture was refluxed for 2-3 hours. TLC showed that the major spot was product and its TLC RF value is about 0.45 in solution of acetone and hexane by the ratio of 1 to 2. After reaction was completed, the solvent was evaporated and the residues was dissolved in about 2000 ml of CH2Cl2, the solution was treated with aqueous NaHCO3 and CO2 was generated during stirring. After pH was adjusted to be about 7-8 and washed with brine, organic phase was separated and dried over MgSO4. Filtration and removal of solvent gave about 98 g of crude desired product as fine white needle crystalline. MS(ESI): m/e (M+H) 231.
A solution of succinic anhydride (141.1 g, 1.41 mol) and 70 g (about 0.47 mol) of compound of step 1a (70 g, 0.47 mol) in 2500 ml of anhydrous toluene was refluxed for overnight. After that, HATU (10 g, 0.26 mol) and 4-methylmorpholine (41.36 ml, 0.376 mol) were added and the resulting mixture was refluxed for 2-3 hours. TLC showed that the major spot was product (Rf=0.35, acetone:hexane=1:2). After reaction was completed, the solvent was evaporated and the residue was dissolved in about 2000 ml of CH2Cl2. The solution was washed with aqueous NaHCO3. After pH was adjusted to 7-8 and washed with brine, organic phase was separated and dried over MgSO4. Filtration and removal of solvent gave the title compound (98 g) as fine white needle crystalline ESI MS m/e: 231 (M+H)+.
A solution of succinic anhydride (141.1 g, 1.41 mol) and 70 g (about 0.47 mol) of compound of step 1a (70 g, 0.47 mol) in 2500 ml of anhydrous toluene was refluxed for overnight. After that, HATU (100 g, 0.26 mol) and 4-methylmorpholine (41.36 ml, 0.376 mol) were added and the resulting mixture was refluxed for 2-3 hours. TLC showed that the major spot was product (Rf=0.35, acetone:hexane=1:2). After reaction was completed, the solvent was evaporated and the residue was dissolved in about 2000 ml of CH2Cl2. The solution was washed with aqueous NaHCO3. After pH was adjusted to 7-8 and washed with brine, organic phase was separated and dried over MgSO4. Filtration and removal of solvent gave the title compound (98 g) as fine white needle crystalline
With triethylamine; In tetrahydrofuran; at -5 - 20℃; for 4h;
To a 50 ml three-necked flask was added <strong>[64037-15-6]5-methylbenzoxazol-2-amine</strong>, 10 ml of tetrahydrofuran, 5 ml of triethylamine. The acid chloride was then dissolved in 10 ml of dry tetrahydrofuran, Below 5 deg C under the conditions of slow drop, The reaction was stirred at room temperature for 4 h. 40 ml of saturated aqueous sodium chloride solution was added,The aqueous phase was extracted three times with 25 ml of dichloromethane, Combine the organic phase. Column separation, Dichloromethane: methanol 60: 1 to give 1.39 g of a white solid, M.p. 174 to 176 C, yield: 70.6%.
Synthesis of 5-methylbenzoxazol-2-amine: 40 ml of 1.5 mol / L HCl was placed in a 250 ml round bottom flask, (0.04 mol) of 4-methyl-2-aminophenol, 4.57 g (0.06 mol) of ammonium thiocyanate, The reaction was carried out in a water bath at 100 C for 6 hours.Let cool, Precipitation of solids, Eluting with ethyl acetate, The solvent is distilled off, To give a pale yellow solid .Ethyl acetate to recrystallize, To give 1.23 g of white crystals, M.p. 149 to 151 C, Yield 17.5%. Taking the above solid 1.23 g (0.007 mol) Was dissolved in 50 ml of a round bottom flask with 20 ml of methanol, 1.57 g (0.007 mol) of lead oxide was added, Reflux 8h. Hot filter, Get a black liquid. Recovery solvent, Column separation, Dichloromethane: methanol = 30: 1, Yellow soil solid 0.69g, M.p. 140 to 141 C, Yield 66.3%.