A Study On Synthesis Of Minocycline Hydrochloride

Minocycline is a 2nd generation of tetracycline antibiotics and also an important intermediate for the manufacture of Tigecycline,a family member of Tetracycline,which is an efficient,rapid-acting and long-lasting semi-synthesized tetracycline agent.Minocycline has shown to be effective in clinical application and also with valuable market prospect.The domestic research on the synthesis of minocycline has shown to be insufficient,however,the need for the development of highly efficient and low contaminate minocycline synthesis process can not be neglected.This article has proposed a way to manufacture minocycline hydrochloride from demeclocycline hydrochloride by dechlorination,dehydroxylation,chlorination,azo,methylation,adsorption&purification,crystallation and recrystallization.This novel process was structured by summarizing the advantages of domestic and international researches and articles.The total mole yield of the process is approximately 31.5%.In alkaline,55?,8 kg/cm2,demeclocycline hydrochloride was catalyzed by 5%Pd/C to generate 6-demethyltetracycline.In acidic,40?-50?,8 kg/cm2,6-demethyltetracycline was further catalyzed by 5%Rh/C to generate 6-demethyl-6-deoxytetracycline.The kinetics data at different temperatures were fitted by the first-order equation,and the apparent activation energy of the reaction obtained by Arrhenius plot was 41 kJ/mol.6-demethyl-6-deoxytetracyclin was chlorinated by N-Chlorosuccinimide in 20?-25? to generate 11a-chloro-6-demethyl-6-deoxytetracycline.In 0-5?,pH 7.0-8.0,11a-chloro-6-demethyl-6-deoxytetracycline was further reacted by diazol,and then reduce the pH to 2.0-2.5 to generate 7-(toluenesulfonic)azo-lla-chloro-6-demethyl-6-deoxytetracycline crystal in 5?-15?.In acidic,20-25?,7-9 kg/cm2,7-(toluenesulfonic)azo-lla-chloro-6-demethyl-6-deoxytetracycline was catalyzed by 5%Pd/C to generate 7-amino-6-demethyl-6-deoxytetracycline.7-amino-6-demethyl-6-deoxytetracycline was methylated by dosing HCHO to generate minocycline.The methylation solution was future purified through H-60 macroporous adsorbent resin to generate minocycline hydrochloride solution.Minocycline hydrochloride was concentrated to certain volume,and then crystallized and recrystallized in 0-10? and pH 3.8-4.2.The crystal was vacuum dried with temperature below 40? to get the dry product.The final mole yield was 31.5%.Control the hydrogenation pressure to 8 kg/cm2 to reduce the loading of the equipment and the consumption of the hydrogen.Using water as the solvent during the chlorination,azo and crystallization instead of organic solvent,which can avoid the contamination by the organic solvent,and reduce the cost.Using macroporous adsorbent resin H-60 to do the absorption and purification to reduce the consumption of the organic solvent,which is better for the environmental protection and the cost control.