Method for synthesizing doxycycline hydrochloride intermediate alpha-6-doxycycline through hydrogenation on basis of silica gel rhodium catalyst

Abstract

The invention discloses a method for synthesizing a doxycycline hydrochloride intermediate alpha-6-doxycycline through hydrogenation on the basis of a silica gel rhodium catalyst. The invention adopts the key technical scheme that the method comprises the following steps: (1), a rhodium complex is loaded on functionalization silica gel to prepare the silica gel rhodium catalyst; (2), the prepared silica gel rhodium catalyst is dispersed into an organic solvent, methacycline or the salt of the methacycline is used as a raw material, hydrogen is introduced, and the reaction lasts for 4 to 12 hours under the conditions that the pressure is 0.4 to 2.5 MPa and the reaction temperature is 40 to 120 DEG C, so that the doxycycline hydrochloride intermediate alpha-6-doxycycline is prepared. The silica gel rhodium catalyst in the invention has high catalytic activity and enantio selectivity and can be used for doxycycline hydrochloride production process, the yield can reach more than 60 percent, the content of beta-isomer is only 0.03 percent to 0.10 percent, the reaction condition is mild, the reaction directionality is excellent, side reactions are less, and the catalyst can be reduced, so that the production cost is lowered and the industrial production is facilitated.

Description

technical field [0001] The invention belongs to the technical field of pharmaceutical chemical synthesis, and in particular relates to a method for synthesizing doxycycline hydrochloride intermediate α-6-deoxyoxytetracycline based on the hydrogenation of a silica gel rhodium catalyst. Background technique [0002] Doxycycline hydrochloride is a good antibacterial drug. It is a long-acting broad-spectrum semi-synthetic tetracycline antibiotic processed by oxytetracycline. It has a broad antibacterial spectrum and strong antibacterial effect. In addition to the effect on Gram-positive bacteria and negative bacteria, it can also inhibit Rickettsia, Mycoplasma pneumoniae, Mycoplasma trachomatis and amoeba. In particular, common bacteria in the respiratory tract of patients with chronic bronchitis are more sensitive to doxycycline. And the medicine has certain antitussive, expectorant and antiasthmatic effects. In addition, the drug is also widely used in veterinary medicine to...

AI Technical Summary

Problems solved by technology

At present, the hydrogenation catalyst widely used in factories is the heterogeneous Pd / C / poison method. In this method, the Pd / C is first poisoned by quinoline compounds, and part of its activity is lost, and then used for the hydrogenation reduction of oxytetracycline , so as to achieve stereoselective control, the ratio of α / β in the product is usually 60 / 30; there are also toxic agents such as methylthiourea added to the reaction system, although there is a certain stereoselectivity, but their carcinogenic toxicity and other belts There is a huge pressure on environmental protection; and the use of homogeneous catalysts such as rhodium complex catalysts can increase the yield to about 85%, and the β-body content is lower than 0.1%, but the catalyst consumption is large and cannot be recycled and reused, and the process cost is relatively Higher; Some literature proposes to use iridium compound as catalyst for the hydrogenation production of doxycycline hydrochloride, the amount of the resulting β-isomer is lower than 0.8%, but the preparation yield of the catalyst is low and cannot be recycled; there are also literature It is proposed to use Pd / transition metal (such as Fe, Ti, Sn and other water-soluble inorganic salts) / support (activated carbon, silica gel, etc.) composite catalyst for hydrogenation reaction, the content of α-isomer is 98%, and the amount of β-isomer is less than 2%, but the catalyst cannot be reused; in addition, there are literatures that use silica gel-immobilized rhodium catalysts for hydrogenation reactions, which does not affect the separation of catalysts, but is not conducive to industrial production, and the cost is too high

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