CN-121974867-A - Synthesis method and application of febuxostat key intermediate

CN121974867ACN 121974867 ACN121974867 ACN 121974867ACN-121974867-A

Abstract

The application provides a method for synthesizing febuxostat and a key intermediate, belonging to the technical field of medicine synthesis. 4-hydroxybenzaldehyde is used as a raw material, and reacts with hydroxylamine hydrochloride and sulfur in continuous flow equipment under the conditions of a photocatalyst, a solvent and illumination to obtain 4-hydroxybenzenesulfide, the 4-hydroxybenzenesulfide reacts with ethyl 2-chloroacetoacetate to obtain ethyl 2- (4-hydroxyphenyl) -4-methylthiazole-5-carboxylate, the ethyl 2- (4-hydroxyphenyl) -4-methylthiazole-5-carboxylate reacts with a cyano source under the conditions of illumination to obtain ethyl 2- (3-cyano-4-hydroxyphenyl) -4-methylthiazole-5-carboxylate, and the ethyl 2- (3-cyano-4-hydroxyphenyl) -4-methylthiazole-5-carboxylate reacts with bromoisobutane to obtain a key intermediate of non-b-betasol. The obtained febuxostat key intermediate does not need to be separated, and the febuxostat is synthesized by a two-step one-pot method.

Inventors

SHEN YONGMIAO
HU SHUQING
ZHENG YIYANG
TANG RENHE
XI ZIWEI

Assignees

浙江理工大学

Dates

Publication Date: 20260505
Application Date: 20260317

Claims (10)

1. The synthesis method of the febuxostat key intermediate is characterized by comprising the following steps of: step one, 4-hydroxybenzaldehyde is taken as a raw material, and reacts with hydroxylamine hydrochloride and sulfur in continuous flow equipment under the conditions of a photocatalyst, a solvent and illumination to obtain 4-hydroxybenzenesulfonamide; step two, reacting 4-hydroxybenzene sulfamide with ethyl 2-chloroacetoacetate to obtain ethyl 2- (4-hydroxyphenyl) -4-methylthiazole-5-formate; Step three, under the illumination condition, reacting the ethyl 2- (4-hydroxyphenyl) -4-methylthiazole-5-carboxylate with a cyano source to obtain ethyl 2- (3-cyano-4-hydroxyphenyl) -4-methylthiazole-5-carboxylate; And step four, carrying out etherification reaction on the ethyl 2- (3-cyano-4-hydroxyphenyl) -4-methylthiazole-5-carboxylate and bromoisobutane to obtain a febuxostat key intermediate.
2. The method for synthesizing a key intermediate of febuxostat according to claim 1, wherein in the first step, the photocatalyst is eosin Y, and the dosage of the photocatalyst is 5-20% of the molar quantity of 4-hydroxybenzaldehyde.
3. The method for synthesizing a febuxostat key intermediate according to claim 1, wherein the illumination is 400-420 nm.
4. The method for synthesizing a febuxostat key intermediate according to claim 1, wherein the continuous flow equipment is an AF multi-channel photocatalytic reactor.
5. The method for synthesizing a key intermediate of febuxostat according to claim 1, wherein in the first step, the solvent is at least one of water and acetonitrile.
6. The method for synthesizing the febuxostat key intermediate according to claim 1, wherein in the second step, at least one of water and ethanol is added as a solvent.
7. The method for synthesizing a key intermediate of febuxostat according to claim 1, wherein in the third step, the cyano source is any one of acetonitrile, potassium thiocyanate and benzoyl cyanide.
8. The method for synthesizing the febuxostat key intermediate according to claim 1, wherein DMAC is added as a solvent in the fourth step.
9. A method of performing febuxostat synthesis using the key intermediate of claim 1.
10. The method for synthesizing febuxostat according to claim 9, characterized by the following steps: step one, 4-hydroxybenzaldehyde is taken as a raw material, and reacts with hydroxylamine hydrochloride and sulfur in continuous flow equipment under the conditions of a photocatalyst, a solvent and illumination to obtain 4-hydroxybenzenesulfonamide; step two, reacting 4-hydroxybenzene sulfamide with ethyl 2-chloroacetoacetate to obtain ethyl 2- (4-hydroxyphenyl) -4-methylthiazole-5-formate; Step three, under the illumination condition, reacting the ethyl 2- (4-hydroxyphenyl) -4-methylthiazole-5-carboxylate with a cyano source to obtain ethyl 2- (3-cyano-4-hydroxyphenyl) -4-methylthiazole-5-carboxylate; And step four, after etherification reaction of the ethyl 2- (3-cyano-4-hydroxyphenyl) -4-methylthiazole-5-carboxylate and bromoisobutane, directly adding sodium hydroxide solution and ethanol into an etherification reaction product for alkalization reaction, and then acidifying to obtain febuxostat.

Description

Synthesis method and application of febuxostat key intermediate Technical Field The application relates to a synthesis method of febuxostat and a key intermediate, belonging to the technical field of medicine synthesis. Background Febuxostat is a non-purine xanthine oxidase inhibitor that can treat gout by inhibiting xanthine oxidase to reduce uric acid formation. The developed core technical logic is to carry out structural design on the active site of xanthine oxidase, and the selectivity and affinity of the medicine are improved through molecular modification, so that the method has great development value in the medicine market for treating gout. With the increasing severity of the global antibiotic resistance, the research and optimization of the synthesis process are particularly serious. Currently, the synthetic route of febuxostat mainly extends around the construction of key intermediates, and reported routes include synthetic routes using p-hydroxybenzaldehyde, p-chlorobenzaldehyde or 2-chloro-4-methylthiazole-5-carboxylic acid as starting materials, wherein the synthesis of intermediates requires multi-step reactions such as etherification, cyanidation, condensation and the like. In the etherification reaction, the nucleophilic substitution reaction of isobutanol and halogenated aromatic hydrocarbon has poor selectivity, and byproducts are easy to generate, so that the yield of the intermediate is only 50-70%, and the overall synthesis efficiency is limited. Also enzyme catalysis is too costly and the production cycle is also relatively long. Disclosure of Invention In view of the above, the application provides a method for synthesizing a key intermediate of febuxostat, which has the advantages of green and safe, low production cost, high product yield and the like. Specifically, the application is realized by the following scheme: a method for synthesizing a febuxostat key intermediate comprises the following steps: Step one, 4-hydroxybenzaldehyde is used as a raw material, and is subjected to thioamidation reaction with hydroxylamine hydrochloride and sulfur in continuous flow equipment under the conditions of a photocatalyst, a solvent and illumination to obtain 4-hydroxybenzenesulfonamide; step two, reacting 4-hydroxybenzene sulfamide with ethyl 2-chloroacetoacetate to obtain ethyl 2- (4-hydroxyphenyl) -4-methylthiazole-5-formate; Step three, under the illumination condition, reacting the ethyl 2- (4-hydroxyphenyl) -4-methylthiazole-5-carboxylate with a cyano source to obtain ethyl 2- (3-cyano-4-hydroxyphenyl) -4-methylthiazole-5-carboxylate; And step four, carrying out etherification reaction on the ethyl 2- (3-cyano-4-hydroxyphenyl) -4-methylthiazole-5-carboxylate and bromoisobutane to obtain a febuxostat key intermediate. The key intermediate of febuxostat has the structural formula:。 Further, as preferable: In the first step, the first step is to perform, The photocatalyst is an Eosin Y (Eosin Y) photocatalyst. The dosage of the photocatalyst is 5-20mol% of 4-hydroxybenzaldehyde. The illumination is 400-420 nm. The continuous flow device is an AF multi-channel photocatalytic reactor. The solvent is at least one of water and acetonitrile. In the second step, at least one of water and ethanol is added as a solvent. In the third step, the first step is performed, The cyano source is any one of acetonitrile, potassium thiocyanate and benzoyl cyanide. The illumination is 400-420 nm. In the fourth step, the first step is performed, N, N-Dimethylacetamide (DMAC) was added as a solvent. Anhydrous potassium carbonate was added as a base. The key intermediate of the febuxostat synthesized by the method is applied to the synthesis of febuxostat, and the febuxostat can be synthesized by directly adopting an etherification product without separation in the synthesis process, wherein the process comprises the steps of directly adding sodium hydroxide solution and ethanol into the etherification reaction product for alkalization reaction, and then acidifying to obtain the febuxostat. Compared with the prior art, the application has the following beneficial effects: 1) The application takes hydroxylamine hydrochloride as an initial raw material, and is matched with a photocatalysis method to carry out multi-step photocatalysis and continuous flow process, thereby realizing the synthesis of key intermediates, greatly reducing reaction conditions and having low production cost. 2) In the reaction process, acetonitrile and the like are used as cyano sources, the introduction of cyano is realized under the illumination condition, the application of traditional potassium cyanide and other highly toxic reagents is avoided, and the reaction system is pollution-free. 3) The method can obtain the key intermediate with high yield and high purity, and the key intermediate can be directly obtained by adopting a one-pot two-step method without separation, so that the method has simple process and mild condition. Dra