Method for adapting to industrially producing tebipenem
A technology of tipipenem and compounds, applied in the field of medicinal chemistry, can solve problems such as unsuitable for industrial production, unfavorable esterification reaction, large consumption of acetone, etc., achieve simple and easy-to-operate purification method, reduce environmental pollution, and use less Effect
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Embodiment 1
[0022] 500g of compound II, 2L of tetrahydrofuran, 4L of water, 60g of 2,6-lutidine, 100g of 10% palladium carbon (wet weight) were catalytically hydrogenated at 20-30°C and 4MPa pressure for 1 hour, and the reaction was completed and removed by filtration. For insoluble matter, adjust the pH of the filtrate to 5.6 with 1N HCl solution, add 12 L of tetrahydrofuran, stir and crystallize at 20°C, filter, and dry to obtain 218 g of off-white crude tipipenem, with a purity of 99.81% by HPLC.
[0023] Dissolve the crude product in 1.2L of pure water at 80°C, filter while hot after dissolving, cool the filtrate to 0-5°C, stir and crystallize for 3 hours, filter with suction, and dry to obtain 190g of white crystals with a yield of 87.2%. Karl Fischer Moisture Titrator measured water content: 15.7% (tetrahydrate), HPLC detection purity 99.95%, maximum simple impurity content 0.08%.
Embodiment 2
[0025] Compound II 500g, tetrahydrofuran 1L, water 5L, potassium bicarbonate 20g, 10% palladium carbon 25g (wet weight), catalytic hydrogenation at 20 ~ 30 ℃, under normal pressure for 5 hours, after the reaction was completed, remove the insoluble matter by filtration, and use 1N HCl solution adjusted the pH of the filtrate to 5.6, added 25 L of tetrahydrofuran, stirred and crystallized at 0-5°C, filtered, and dried to obtain 222 g of off-white crude tipipenem, the purity of which was 99.83% by HPLC.
[0026] Dissolve the crude product in 4L of pure water at 40°C, filter while hot after dissolving, cool the filtrate to -5-0°C, add seed crystals, stir and crystallize for 10 hours, filter with suction, and dry to obtain 190g of white crystals, yield 85.6%, using the Karl Fischer moisture titrator to measure the water content: 15.7% (tetrahydrate), HPLC detection purity 99.94%, maximum simple impurity content 0.05%.
Embodiment 3
[0028] Compound II 500g, tetrahydrofuran 4L, water 4L, sodium bicarbonate 20g, 10% palladium charcoal 50g (wet weight), catalytic hydrogenation at 30 ~ 40 ℃, 2MPa pressure for 3 hours, after the reaction is complete, remove insoluble matter by filtration, and use 1N HCl solution adjusted the pH of the filtrate to 5.6, added 8 L of tetrahydrofuran, stirred and crystallized at 0-5°C, filtered, and dried to obtain 225 g of off-white crude tipipenem, with a purity of 99.85% by HPLC.
[0029] Dissolve the crude product in 2L of pure water at 70°C, filter while hot after dissolving, cool the filtrate to -5-0°C, stir and crystallize for 8 hours, filter with suction, and dry to obtain 198g of white crystals with a yield of 88.0%. The water content measured by the Karl Fischer moisture titrator is: 15.7% (tetrahydrate), the HPLC detection purity is 99.97%, and the maximum simple impurity content is 0.03%.
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