Put 100g of methanol, 10g of oxytetracycline base and 0.1g of methanolic ammonia in the reaction flask in turn, stir at 20~30°C for 30min, then start cooling to -10~-15°C, add 5g of dry and crushed NBS at one time, stir for 15min, TLC monitored the complete reaction of the raw materials, and a large amount of solids precipitated out in the reaction bottle, which was filtered through a filter rejection machine, and the filter cake was washed with cold methanol to obtain oxytetracycline 11α-bromo-6,12-hemiketal, with a yield of 95%. Dry at low temperature until the dry content is about 90%. After fractional distillation of the mother liquor, the resulting methanol is used mechanically.
Add 500mL of anhydrous treated benzene into a reaction kettle with a dehydration device, blow nitrogen into the reaction kettle, slowly add 11α-bromo-6,12-hemiketal oxytetracycline 100g under stirring, and then add HZSM-5 20g, first stirred at room temperature for 2 hours, then slowly raised the temperature to reflux reaction and discharged the water generated by the reaction in time, after TLC monitored the complete reaction of the raw materials, slowly lowered the temperature to 50°C, filtered the reaction solution while it was hot, and filtered out Solid hydroxyl dehydrating agent, distill the filtrate to remove the reaction solvent benzene, dilute the raffinate with double the amount of ethanol, slowly add ammonia ethanol solution (7%), neutralize the reaction solution to pH 1~2, cool to 0 ℃, shake filter, wash with cold ethanol 50mL, add 50g p-toluenesulfonic acid to the filtrate, and add a small amount of seed crystals to precipitate crystals, cool to 0°C shake filter, wash with cold ethanol to obtain 11α-bromo-6-methine Oxytetracycline p-toluenesulfonic acid 105g, yield 100% (by weight). After the mother liquor is neutralized to neutral with alkali, the benzene and ethanol obtained by distillation can be used mechanically.
Add 400mL of DMF and 200mL of water into the reaction bottle, then add 100g of 11α-bromo-6-methine oxytetracycline p-toluenesulfonic acid and 12g of palladium carbon (5wt%), and finally add the chiral catalyst tetraisopropyl oxide Titanium 4g and S-biphenol 5g, stir for 10min, add p-toluenesulfonate, stir evenly, suck into the hydrogenation tank, close the valve, use a vacuum pump to 40mm Hg, maintain for 15min, and inject hydrogen at 30~35℃, keep The internal pressure is 1.5~2 kg/cm2, and the hydrogen gas is passed through for 2 hours under stirring until the hydrogen absorption is slow, and the sample is taken for TLC. When the internal pressure is zero, feed nitrogen to drive away the remaining hydrogen, add nitrogen to 50°C, pass nitrogen, filter through a filter press, and fully press filter with DMF solution (heated to 50°C) with a content of 10wt%~50wt% Washing, then washing the palladium carbon with an appropriate amount of distilled water, combining the filtrate and the washing liquid into the reaction kettle, so that the DMF content in the solution is 40wt%~42wt%, cooling to 5 ° C, centrifugal filtration, the filter cake is washed once with a small amount of cold ethanol, After drying, α-6-debromooxytetracycline p-toluenesulfonate (Doxymycin p-toluenesulfonate) was obtained with a yield of 45% (by weight).
