A kind of preparation method of roquinex

Abstract

A preparation method of roquinimex comprises the following steps: carrying out a reflux reaction on 1, 2-dihydro-4-hydroxy-1-methyl-2-oxoquinoline-3-methyl formate shown as a formula II, N-methylaniline shown as a formula III and a catalyst calcium chloride in a solvent, removing methanol generated by reaction and trace water in the system by adopting an A-type molecular sieve pervaporation inorganic membrane, ending the reaction, filtering a reaction solution at 60-70 DEG C after the reaction is finished, cooling and crystallizing a filtrate, and carrying out filtering and drying to obtain the N-methyl-N-phenyl-1, 2-dihydro-4-hydroxy-1-methyl-2-oxoquinoline-3-formamide (roquinimex) shown in a formula I. The yield reaches 98.5%, and the product content reaches 99.7% (liquid spectrum external standard). The preparation method has the advantages of simple process, no need of distillation, high product purity and yield and the like.

Description

technical field [0001] The invention relates to a preparation method of roquinex. More specifically, the present invention relates to an improved and simplified process for the preparation of roquinex. Background technique [0002] Roquinex (Chinese name: N-methyl-N-phenyl-1,2-dihydro-4-hydroxy-1-methyl-2-oxo-quinoline-3-carboxamide) was found to be An effective immunomodulator, it has therapeutic effects on various autoimmune diseases in animal experiments. Due to its pharmacological properties of high activity and low side effects, this compound is considered valuable in the treatment of diseases caused by pathological inflammation and autoimmune diseases, as well as various malignant tumors. N-methyl-N-phenyl-1,2-dihydro-4-hydroxy-1-methyl-2-oxoquinoline-3- Formamide. Said patent discloses four preparation methods. Compounds are prepared by reacting carboxylic acids with amines in the presence of pyridine or quinoline as an inert solvent. US5912349 discloses an impr...

AI Technical Summary

Problems solved by technology

[0008] 1. Since the main reaction is an equilibrium reaction, the methanol produced by the reaction cannot be completely separated from the system, which affects the yield

[0009] 2. Due to the unavoidable existence of trace amounts of water in the system, the raw materials and products are hydrolyzed, which affects the product content and yield

[0010] 3. Separate the methanol and water in the solvent from the system by distillation. Although the method of adding fresh solvent at the same time can be used to promote the reaction balance to move to the right to a certain extent, the operation is cumbersome and the solvent loss is large. After recovery The solvent also needs to separate the methanol separately

[0011] 4. Long reaction time

[0013] There are also reports in the literature that permeable membranes are used for the separation of methanol and other solvents, such as literature (Methanolremoval from organic mixtures by pervaporation using polypyrrole membranes, Ming Zhou et al, Journal of Membrane Science, No. 117, No. 1-2, No. 303 -309 pages, published on August 21, 1996), using a polypyrrole membrane to separate methanol from other solvents, the membrane is kept in contact with the feed liquid during the separation process, the liquid mixture swells the membrane, and the feed liquid is circulated in the pool , and then apply a vacuum on the other side of the membrane to make methanol permeate through the membrane. The membrane is separated by direct contact with the liquid. Compared with the gas permeable membrane and the solvent gas contact, the membrane is not in contact with the high temperature solvent gas, and the separation efficiency Low, the film is an organic film, its thermal stability may be poor at high temperature, and its stability and mechanical strength have not been further reported

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