Methods for preparing sulfadoxine and intermediate of sulfadoxine

Abstract

The invention relates to methods for preparing sulfadoxine and an intermediate of the sulfadoxine. The method for preparing the sulfadoxine sequentially comprises the following steps of: (1), in the presence of sodium ethylate, reacting methyl methoxyacetate with excessive diethyl oxalate to generate 3-methoxyl-2-oxo-ethyl methyl succinate, decarbonylating the 3-methoxyl-2-oxo-ethyl methyl succinate to obtain 2-methoxyl-ethyl methyl malonate; (2) reacting the 2-methoxyl-ethyl methyl malonate with formamide to generate a cyclized compound; (3) reacting the cyclized compound with phosphorus oxychloride to generate chloride; (4) performing condensation reaction; and (5) performing methyl oxidation reaction, wherein the purity of the 2-methoxyl-ethyl methyl malonate which is obtained in the step (1) is controlled to be more than or equal to 95 weight percent. By adoption of the methods, the purity of the 2-methoxyl-ethyl methyl malonate is effectively controlled to be more than 95 weight percent, the quality of the cyclized compound for cyclization reaction in next step can be improved, operation is simplified, and production cost is reduced.

Description

technical field [0001] The invention belongs to the technical field of preparation of sulfonamide drugs, in particular to a preparation method of sulfonamide and its intermediate. Background technique [0002] Sulfonamide, the chemical name is 4-(p-aminobenzenesulfonyl)-5,6-dimethoxypyrimidine, and its structural formula is as follows: [0003] [0004] Sulfonamide can be used clinically to treat general inflammation, such as upper respiratory tract infection tonsillitis, bacillary dysentery enteritis, skin infection, etc. It can also be used in combination with other medicines to treat pulmonary tuberculosis and lymphatic tuberculosis; it also has a certain effect on leprosy (madness). It can also treat malaria. In addition, sulfonamide can also be used as a preventive drug for rheumatic venereal diseases. When used for the above purposes, sulfonamide has the characteristics of long curative effect and low toxicity. [0005] Sulfonamide has gone through several generat...

AI Technical Summary

Problems solved by technology

[0017] 1, step (1) Kjeldahl reaction makes raw material carry out in sodium ethylate / ethanol solution, and after decarbonylation, removes low boiler (comprising unreacted raw material, intermediate A3 etc.) by first fractional distillation, then fractional distillation obtains intermediate 2-methoxy-methyl ethyl malonate, the purity of the method's gained 2-methoxy-methyl ethyl malonate is lower (generally lower than 92%), which is unfavorable for subsequent reactions, especially in large During the trial production, the quality and yield of Zhouxiao Sulfa products were affected

[0018] 2, step (2) ring closure reaction gained ring compound quality is poor: traditional method makes ring compound separate out under acidic condition, gained ring compound (A5 ) can exist in two forms of hydroxy substance and hydroxy sodium salt. Because the hydroxy substance has a certain solubility in water, the mother liquor of the cyclization reaction must be applied mechanically repeatedly in the traditional process, and the salt concentration in the mother liquor is equivalent due to the application of the mother liquor. large, resulting in poor quality of cyclic compounds (nearly 40% of which are salt), sticky materials, difficult to dry and other shortcomings; and the acidic environment has corrosion effects on equipment pipes, centrifuges, and drying rooms, and the production site is not easy clean

[0019] 3, the preparation of step (3) chloride (A6) must adopt N,N-dimethylaniline as catalyst, so that the recovery and mechanical application of the catalyst produce a large In addition, the quality of the chloride is dark red, which is obviously unfavorable to the next condensation reaction. The reddish color of the condensation reaction will directly affect the yellowish color of the finished product (quality)

[0020] 4, step (5) methoxide reaction adopts sodium methylate / methanol solution, in post-treatment stage, recovery methanol is not easy, and the longer heating time of recovery stage may As a result, the material at the bottom of the (product) reactor is heated unevenly, causing local overheating, resulting in decomposition, and the color of the crude product is not ideal

[0021] In summary, the total yield of the traditional method is only about 65%, the production cost is relatively high, and the quality of the product needs to be further improved

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