First, take 200 kg of crude Azithromycin Bnf (preserve the chromatogram) and dissolve it in 600 liters of dichloromethane. Follow the steps below:
The first step: separation of easily water-soluble impurities
1. Add 40 liters of pure water, add 5 liters of 10% hydrochloric acid aqueous solution dropwise at 0-5 °C, stir for 1 hour, let stand for 1 hour, separate the upper water phase to the water phase tank, add 10 liters of pure water to the reactor to rinse Clean into the water phase tank.
2. Return the dichloromethane phase from the oil phase tank to the reaction kettle, add 40 liters of pure water, dropwise add 5 liters of 10% hydrochloric acid aqueous solution at 0-5 °C, stir for 1 hour, leave standstill for 1 hour, and separate the upper water phase to Water phase tank, add 10 liters of pure water to the reaction kettle and rinse it to the water phase tank.
3. Return the dichloromethane phase from the oil phase tank to the reaction kettle, add 40 liters of pure water, dropwise add 5 liters of 10% hydrochloric acid aqueous solution at 0-5 °C, stir for 1 hour, leave standstill for 1 hour, and separate the upper water phase to Water phase tank, add 10 liters of pure water to the reaction kettle and rinse it to the water phase tank.
④, the methylene chloride layer is washed once with 40 liters of pure water, and the separated water phase is merged into the water phase tank, which is the water phase containing easily water-soluble impurities.
The second step: separation of the dichloromethane phase containing oil-soluble impurities
①, return the dichloromethane phase from the oil phase tank to the reaction kettle, add 10 liters of dichloromethane rinsing oil phase tank to the reaction kettle, add 240 liters of pure water to the dichloromethane phase, add dropwise at 0-5 °C 117 kg of 10% hydrochloric acid aqueous solution, sampled to detect the dichloromethane phase containing 5.8% (weight ratio). Stir for 1 hour, let stand for 1 hour, and separate the lower layer of dichloromethane to the oil phase tank.
2. Add 40 liters of dichloromethane to the water phase, add 2.6 kg of 20% aqueous sodium hydroxide solution dropwise below 10°C, stir for 1 hour, let stand for 1 hour, and separate the dichloromethane phase to the oil phase tank.
3. The water layer was stirred with 40 liters of dichloromethane for 1 hour, and allowed to stand for 1 hour. The separated dichloromethane phase was merged into the oil phase tank, which was the dichloromethane phase containing oil-soluble impurities. The aqueous phase was sampled and chromatographed to make it qualified.
The third step: extraction and crystallization:
①. The water layer in the reaction kettle is heated to 30 degrees Celsius, and the vacuum (-0.8MP) is pulled for 1 hour to remove clean methylene chloride, then 240 liters of acetone are added, and activated carbon is added and stirred for 2 hours. Add 20% aqueous sodium hydroxide solution dropwise at 45°C, stop adding alkali when crystals are precipitated, add 0.1 kg of seed crystals, and stir for 0.5 hours.
2. Continue to add 20% aqueous sodium hydroxide solution dropwise until the pH value is 9.5, continue to add 120 kg of purified water dropwise, and maintain stirring for 1 hour.
③. Cool down to 20°C, keep stirring for 1 hour, and centrifuge. Dry at 60°C and weigh.
