Application of Pd catalyst in hydrogenation process for producing doxycycline

Abstract

The invention discloses an application of a Pd catalyst in a hydrogenation process for producing doxycycline, belonging to the field of pharmaceutical chemistry synthesis. The method is as follows: based on polyvinyl chloride-polyethylene polyamine-loaded palladium complex (pvc-pp-Pd) used as a catalyst, and 11 alpha-chlorine-6-methylene oxytetracycline or 11 alpha-chlorine-6,12-hemiketal oxytetracycline or metacycline or salts thereof used as raw material, introducing hydrogen, stirring and reacting, filtering, adding sulfo-group salicylic acid to filtrate so as to form salt; and cooling, filtering, washing and drying so as to obtain alpha-6-deoxytetracycline sulfo-group salicylic acid salt, wherein the yield is higher than 90%, the content of the corresponding beta-6-deoxytetracycline sulfo-group salicylic acid salt isomer is less than 1%. The method has the advantages of mild reaction conditions, good reaction directionality and less side reactions; a toxic agent is not required inthe hydrogenation process, and pollutant emission is reduced, thereby being beneficial to protecting the environment; and the catalyst can be recycled, and production cost is reduced, thereby extremely being beneficial to industrial production.

Description

technical field [0001] The present invention relates to the application of Pd catalyst in the production process of hydrogenation of doxycycline, in particular to the application of loaded Pd catalyst in the production process of chiral asymmetric hydrogenation of antibiotic doxycycline intermediate α-6-deoxyoxytetracycline salt, belonging to The field of medicinal chemistry synthesis. Background technique [0002] Doxycycline, also known as doxycycline hydrochloride strong or deoxyoxytetracycline hydrochloride, is mainly used as an antibiotic drug for the treatment of fast purple stain-positive cocci and negative bacillus infections, and can also be used for typhus, scrub typhus, etc. Rickettsia infection is also effective for amoebic dysentery and atypical pneumonia. The current production process of doxycycline (1) uses oxytetracycline as a raw material, which is refined through chlorination, dehydration, hydrogenation, and transformation. Among them, the hydrogenation ...

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Problems solved by technology

Currently used hydrogenation catalysts mainly include Pd / C and triphenylphosphorous rhodium chloride [Rh(Ph 3 P) 3 Cl ] , the former is a heterogeneous catalyst with poor stereoselectivity, the yield is only 60%, and the β-body content reaches 10%, but the catalyst can be recycled and regenerated; the latter is a homogeneous catalyst, the yield can reach 90%, the β - The volume content is lower than 2%, but the catalyst cannot be separated and recovered

Hu Hanfeng et al. (Hu Hanfeng. Research on the hydrogenation synthesis of doxycycline hydrochloride [J]. Jiangsu Chemical Industry, 2003, 31 (4): 36-37) proposed to use silica gel immobilized homogeneous rhodium catalyst for hydrogenation reaction, which can not only improve hydrogenation Yield and stereoselectivity, without affecting the separation and recovery of the catalyst, but the cost is high, which is not conducive to industrial production

In 2007, Gu Minghai et al. ( Gu Minghai. A hydrogenation process iridium catalyst for the production of drug doxycycline and its application [P]. CN101352692A, 2009-01-28) published an iridium-catalyzed compound used as doxycycline before catalysis The hydrogenation production method catalyst improves the main body selectivity of the hydrogenation reaction and the amount of the available β-6 isomer is lower than 0.8%, but the preparation yield of the catalyst is low and cannot be recycled and reused

[0003] At present, the catalyst used in the production of doxycycline is still a palladium carbon catalyst. In order to realize the stereoselectivity of the hydrogenation reaction, toxic agents such as methylthiourea have been added to the reaction system, which has a certain stereoselectivity. Carcinogenicity and toxicity have brought huge environmental pressures. At present, manufacturers urgently need to improve the existing processes

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