Erythromycin A oxime clean synthetic method and specially-combined reaction equipment for same

Abstract

The invention belongs to the technical field of medicine intermediate synthesis and discloses an erythromycin A oxime clean synthetic method and specially-combined reaction equipment for the same. The method includes: using polar solvent to dissolve erythromycin thiocyanate, inorganic acid salt of hydroxylamine and water-soluble alkali, adding dehydrating agent, controlling certain outlet pressure through the specially-combined reaction equipment, constantly boiling for dehydration, completely performing oximation of erythromycin A after a certain time, cooling to enable complete precipitation of oximate, filtering, alkalizing the oximate conventionally, continuing oximation synthesis of oximate mother liquor after a certain quantity of raw materials are supplemented, and cycling so to enable the erythromycin thiocyanate and auxiliary materials to be fully used to improve overall yield. The specially-combined reaction equipment mainly comprises a water bath 1, a reaction vessel 2, a dephlegmator 3, a separator 4, a condenser 5, a stirring motor 6, a buffering bottle 7, a vacuum meter 8, a regulating valve 9, a vacuum pump 10 and a thermometer 11.

Description

technical field [0001] The invention belongs to the technical field of pharmaceutical intermediate synthesis. In particular, it is a clean synthetic method of erythromycin A oxime, an intermediate of pharmaceutical raw materials, and its specially combined reaction equipment. Background technique [0002] Erythromycin A oxime is a key intermediate for the synthesis of some second-generation macrolide antibiotics --- azithromycin, clarithromycin and roxithromycin, using erythromycin thiocyanate as raw material. [0003] Erythromycin is the most typical and one of the most important drugs among macrolide antibiotics, and it has various superior properties of macrolide antibiotics. Erythromycin, as a cheap and effective drug, has been widely used clinically, and erythromycin has become the drug of choice for most respiratory patients. [0004] However, erythromycin also has many inherent disadvantages: for example, it has a weak effect on Gram-negative bacteria, which makes t...

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Problems solved by technology

[0004] However, erythromycin also has many inherent disadvantages: for example, it has a weak effect on Gram-negative bacteria, which makes these bacteria resistant; it is not stable enough in acidic conditions, and its oral bioavailability is low; it has adverse irritating effects on the gastrointestinal tract, etc.

[0009] In this synthesis reaction, it is generally a reversible exothermic reaction requiring weak acid catalysis with water removal. Reducing the water in the system, causing the product to form thiocyanate to precipitate out and lowering the reaction temperature can make the reaction proceed in the positive direction. In terms of catalysis, there are those that actively add weak acid catalysis and control the pH value of the system. The existing synthesis process is an anhydrous system with one-time dosing, low-temperature stirring or high-temperature reflux reaction. After the reaction is completed, the red mold is one-time Element A oxime proposes, except that the solvent can be recycled and dehydrated and used mechanically, most raw materials such as: hydroxylamine hydrochloride, triethylamine and sodium acetate cannot be recycled in the case of excessive excess. In the patent CN 101077882A, free hydroxylamine with inorganic ammonia , the author clarifies that the mother liquor can be applied continuously, but the water generated by the reaction will definitely affect the number of times the mother liquor is applied mechanically

In a word, the original production method of erythromycin A oxime has relatively high cost and high degree of environmental pollution, which is not conducive to the popularization and application of this drug

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