Synthesis method of drug Tafamidis

Abstract

The invention relates to a synthesis method of a drug Tafamidis. According to the synthesis method, 3-hydroxy-4-amidobenzoic acid is used as a raw material, and the drug Tafamidis is prepared through esterification, amidation, cyclization and hydrolysis reaction. According to the method, concentrated sulfuric acid and methanol are used for replacing expensive and dangerous trimethylsilyl diazomethane to carry out methylation reaction of carboxyl; in the cyclization reaction, the dosage of p-toluenesulfonic acid is obviously reduced; reaction post-treatment is simplified, column chromatography for product purification is not needed in each step of reaction, the total yield of the reaction is remarkably increased, and the method is more suitable for industrial production.

Description

technical field [0001] The invention belongs to the field of organic synthesis and pharmacy, in particular to a method for synthesizing the drug Tafamidis. Background technique [0002] Rare diseases, also known as "orphan diseases", refer to diseases with extremely low incidence. There are certain differences in the identification standards of rare diseases in different countries in the world according to their specific conditions. There is no official standard for rare diseases in China. One in 500,000 (0.002‰) diseases are identified as rare diseases, and they are divided into four categories and 43 types, with an estimated 10-20 million cases. Transthyretin-related familial amyloidosis polyneuropathy (TTR-FAP) is a lethal chromosomal dominant genetic rare disease with malignant progression, which was first discovered in 1952 by Portuguese physician Andrade. The pathogenesis of the disease is the abnormal deposition of transthyretin-type amyloid in tissues due to TTR ge...

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Problems solved by technology

[0004] The currently reported methods for synthesizing the drug Tafamidis mainly include (1) the original research route of the drug (KellyJ.W.; et alAngew. Chem. Int. Edit. 2003, 42 , 2758; Kelly J.W.; et al WO2004056315, etc.) as shown in the figure below, but this method has the following disadvantages: ① Trimethylsilyldiazomethane (TMSCHN 2 ), the reagent is relatively expensive and has potential safety hazards; ② the total yield of the reaction is only 10%, and the yield is low; ③ when preparing intermediate 5, the product needs to be purified by column chromatography, which limits its industrial application application

[0006] (2) Itami et al reported the use of nickel-catalyzed aryl coupling reaction as a key step to synthesize the drug Tafamidis (Itami, K.; et alChem. Eur. J. 2011, 17 , 10113) as shown in the figure below, but this method has the following disadvantages: ① need to use potentially dangerous hydrogen fluoride pyridine solution; ② use metallic nickel as a catalyst, which may cause heavy metal residues; ③ multi-step reactions in this route need to pass through the column layer Analysis and purification of the product limit its industrial application

[0008] (3) Su et al reported the use of palladium-catalyzed C-C coupling reaction as a key step to prepare the precursor of the drug Tafamidis (Su, W.; et al Chem. Commun. 2012, 48 , 8964) as shown in the figure below, but this method has the following disadvantages: ① need to use precious metal palladium; ② use metal palladium and copper as catalysts, which may cause metal residues and the yield is only 43%; ③ there is a problem of regioselectivity, And the by-product 12 is difficult to separate from the Tafamidis precursor 5; ④ The reaction needs to be separated and purified by column chromatography, which limits its industrial application

[0010] (4) Kumar et al reported the use of copper-catalyzed direct C-H bond arylation reaction as a key step to synthesize the precursor of Tafamidis (Kumar, D.; et al Org Biomol Chem. 2014, 12 , 6340) as shown in the figure below, but this method has the following disadvantages: ① the price of diaryliodonium compounds is expensive; ② using copper as a catalyst may lead to metal residues; ③ the reaction needs to be separated and purified by column chromatography, which limits its Application in industrialization

[0012] (5) The synthesis of benzoxazole ring from amidoxime under the promotion of iodine as a key step to synthesize the precursor of Tafamidis reported by Ji et al. (Ji, M.; et al Eur. J. Org. Chem. 2019, 7506.) as shown in the figure below, but this method has the following disadvantages: ① The synthesis yield of amidoxime 16 and the synthesis yield of Tafamidis precursor 17 are only 51% and 46%, respectively, and the yield is low; ② The reaction requires Separation and purification by column chromatography limits its industrial application

[0014] (5) Karumanchi et al reported the synthesis of Tafamidis from 3-hydroxy-4-nitrobenzoic acid through esterification, reduction and ring closure reactions (Karumanchi, K.; et al J. Chem. Sci. 2021, 133 , 48) as shown in the figure below, but this method has the following disadvantages: ① Using metal zinc as a reducing agent may lead to metal residues; ② The total yield of the reaction is 44%, and the yield is low; ③ It requires 7 times the equivalent of metal Zinc as a reducing agent is less economical; ④ Metal zinc and methanesulfonic acid are used as a reducing agent, and a large amount of muddy zinc salt will be generated after the reaction, which will cause serious environmental pollution, and at the same time bring difficulties and restrictions to the cleaning of instruments and pipelines. Its application in industrialization

[0016] (6) A method for synthesizing benzoxazole compounds disclosed by Tan Meimei et al. to synthesize Tafamidis (Tan Meimei et al., 2018, CN: 108484517) is shown in the figure below, but this method has the following deficiencies: ① Raw materials Compound 20 is more expensive; ② Although this patent does not disclose the yield of synthesizing Tafamidis by using this method, the yield of other analogues disclosed by it is 48%-52%. It can be inferred that the yield of synthesizing Tafamidis by this method is relatively Low; ③ It can be known from other analogue examples disclosed that this method needs to separate and purify the product by column chromatography, thus limiting its industrial application

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