Racemization recovery method of dextromethorphan hydrobromide intermediate byproducts

Abstract

A racemization recovery method of dextromethorphan hydrobromide intermediate byproducts comprises the following steps: 1) performing mother liquor treatment: under a stirring condition, carrying out reduced pressure distillation until methanol is basically evaporated completely, when the temperature of the concentrated mother liquor is lower than 40 DEG C, adding a sodium hydroxide solution, stirring, standing, detecting that the pH value is greater than 12, layering, recovering mandelic acid by using the obtained water phase, concentrating the obtained oil phase under reduced pressure until toluene is completely evaporated, and cooling to 65-80 DEG C; 2) performing N-chlorination: adding isopropanol, and dropwise adding a sodium hypochlorite solution; 3) performing racemization: adding liquid caustic soda into the reaction system, and stirring for reaction; 4) reducing: dropwise adding a sodium borohydride solution, and reacting completely; 5) performing chiral resolution: adding methanol and D-mandelic acid into the toluene solution of a compound (I), and carrying out chiral resolution; and (6) refining the mother liquor: treating the mother liquor obtained in step (5) as a raw material according to the treatment methods in steps (1)-(4) to obtain a mother liquor prepared compound (I) methylbenzene solution, and adding oxalic acid for refining.

Description

technical field [0001] The present invention relates to a method for producing isoquinoline heterocyclic compounds, in particular to a method for racemization and chiral resolution thereof. Background technique [0002] Dextromethorphan is the dextromeric isomer of morphine levomorphine and exerts a central antitussive effect by inhibiting the medulla oblongata cough center. Its antitussive strength is comparable to or slightly stronger than codeine. No analgesic effect, no tolerance and addiction in long-term application. Therapeutic doses do not inhibit breathing. The hydrobromide salt of dextromethorphan is currently clinically used, namely dextromethorphan hydrobromide. Important intermediates that dextromethorphan needs to pass through in the synthetic route: 1, 2, 3, 4, 5, 6, 7, 8-Octahydro-1-[(4-methoxyphenyl)methyl]isoquinoline (I), (the molecular formula is CAS No.: 51072-36-7), the intermediate is a racemic mixture, which requires chiral resolution to enter th...

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Problems solved by technology

However, when compound (II) redox reaction is carried out, it needs to be purified from the crystalline mother liquor after the resolution reaction before it can be put into the reduction reaction as a raw material. Not Applicable to Industry Actually In Existing Industrial Production

The crystallization mother liquor after the chiral resolution of compound (I) is mainly the methanol solution of compound (II), and the toluene added when washing the crystallization. Since the mother liquor is mixed with a variety of solvents, it is recrystallized in a conventional way to obtain Compound (II) will cause the loss of raw materials and produce a large amount of waste liquid, which not only increases the production cost, but also pollutes the environment

The oxidation reaction must be carried out in a toluene solvent, which will also produce a large amount of waste liquid, which further increases the cost. Therefore, on the basis of the existing compound (II) racemization recovery, the reaction route is improved so that it can simplify the operation and increase the production capacity. Efficiency, adapting to the needs of industrialized production, has become an urgent problem to be solved in the prior art

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