4-(4-Aminophenyl)-3-methyl-4-oxobutanoic acid

5 kg of nitrobenzoic acid (I), 28 kg of dichloromethane, 4.34 kg propylidene malonate, 5.4 kg of N, N-dimethyl-4-aminopyridine, 13.2 kg of dicyclohexylcarbodiimide were successively added and reacted at 26 °C for 34 hours, solids were filtered, 1N hydrochloric acid 43 liter was added to the organic phase, stirred, the organic phase was separated, dried using sodium sulfate for 6 hours, filtered and the organic solvent were evaporated to obtain 8.5 kg intermediate (II). 8.5 kg intermediate (II), was charged with 21 kg DMF and the bath temperature is controlled to 8 °C, further 2.3 kg sodium ethoxide was then added to the mixed solution, then the temperature of the reaction liquid was controlled to -5 °C, 4.4 kg of methyl iodide was added dropwise. After dripping was completed for about 1.5 hours, the reaction temperature is controlled to 0 °C for 14 hours, DMF is distilled off under reduced pressure, then methyl tert-butyl ether was added; The temperature of the liquid in ice water bath is controlled, neutralized with dilute hydrochloric acid, pH is adjusted to 6-8, organic phase is separated and washed with purified water, washed twice with saturated sodium chloride, the organic phase is separated, the organic phase is dried over sodium sulfate, after drying organic phase the sodium sulfate was filtered off, methyl tert-butyl ether was concentrated under reduced pressure to give 8.33 kg intermediate (III). 8.33 kg intermediate (III) is added to 21 kg of ethanol, the reaction temperature was controlled to 52 °C, reacted for 16 hours later, and ethanol is concentrated to give 3.89 kg of the intermediate (IV). 3.89 kg of intermediate (IV) is dissolved in 22 kg of DMF, the temperature of the solution was controlled to 18 °C, 2.0 kg of sodium ethoxide and 5.6 kg of ethyl bromoacetate were added, the reacted at 16 °C for 14 hours, DMF was distilled off under reduced pressure, recycled, methyl tert-butyl ether was added, the temperature of the solution in ice bath was controlled, neutralized with dilute hydrochloric acid, pH was adjusted to 6-8, the organic phase was separated and washed with purified water, again washed twice with saturated sodium chloride, the organic phase was separated, the organic phase was dried using sodium sulfate, the sodium sulfate was filtered off, methyl tert-butyl ether was concentrated under reduced pressure to obtain 8.1 kg intermediate (V). 8. 1 kg of the intermediate (V) is dissolved in 17 kg ethanol, 22 liters of 5N sodium hydroxide solution was added, the reacted at 67 °C for 28 hours, ethanol was distilled off under reduced pressure, 34 L of methyl tert-butyl ether was added, the temperature of the solution was controlled by placing in ice water bath, pH is adjusted to 2-3 using 1N hydrochloric acid; the organic phase was separated, washed twice with saturated sodium chloride, dried using sodium sulfate; after drying, the sodium sulfate was filtered off, methyl tert-butyl ether was concentrated under reduced pressure, the obtained solution of methyl tert-butyl ether intermediate was concentrated to supersaturation, crystallized slowly at room temperature, and then cooled to -10-5°C, filtered, methyl tert-butyl ether was washed in ice, vacuum-dried at 30-50 °C for 9 hours to obtain 4.9 kg pale yellow solid intermediate (VI). 4.9 kg of the intermediate (VI) is dissolved in 36 kg ethanol, 500 g Raney Ni was added, hydrogen was replaced three times, in hydrogen, pressure 2 atm, the mixture is reacted at 58 °C for 22 hours, Raney Ni is filtered off, the ethanol solution of final product (VII) is concentrated to supersaturation, crystallized slowly at room temperature, and then the temperature was cooled to -10-0°C, filtered, washed with ice in ethanol, vacuum-dried at 50-70 °C for 18 hours to obtain 3.9 kg light yellow final product 3-methyl-4-oxo-4-(p-amino) phenylbutyric acid (VII).a.

Is an intermediate of the drug levosimantan