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A kind of tafamidis derivative and its synthetic method

A synthesis method and derivative technology, applied in the direction of organic chemistry, can solve the problems of limiting the research on the biological activity of Tafamidis derivatives and the improvement of drug performance, cost increase, environmental pressure, etc., to improve atom economy, reduce reaction steps, The effect of reducing pollution

Active Publication Date: 2022-05-24
HUNAN FIRST NORMAL UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

The complex raw materials required for this process lead to almost no reports on the synthesis of Tafamidis derivatives with different substituents on the benzoxazole skeleton, which limits the biological activity research and drug performance improvement of Tafamidis derivatives to a certain extent.
In addition, the traditional synthesis method requires strong acid, strong base and additives, which greatly increases the cost of the method and puts great pressure on the environment.

Method used

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  • A kind of tafamidis derivative and its synthetic method
  • A kind of tafamidis derivative and its synthetic method
  • A kind of tafamidis derivative and its synthetic method

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preparation example Construction

[0040] In one embodiment, a kind of synthetic method of Tafamidis derivative, the preparation raw material of described Tafamidis derivative comprises: catechol compound, ammonium acetate, aldehyde compound, sodium periodate (NaIO 4 ),potassium permanganate.

[0041] In one embodiment, the catechol compound is selected from the group consisting of 4-tert-butyl-5-methylcatechol, 4-tert-amyl-5-methylcatechol, 4-tert-octyl- One of 5-methylcatechol.

[0042] In one embodiment, the aldehyde compound is selected from benzaldehyde, p-tert-butylbenzaldehyde, p-methoxybenzaldehyde, p-fluorobenzaldehyde, p-chlorobenzaldehyde, p-bromobenzaldehyde, p-iodine One of benzaldehyde, 3,5-dichlorobenzaldehyde, p-trifluoromethylbenzaldehyde, p-nitrobenzaldehyde.

[0043]In one embodiment, preferably, a kind of synthetic method of Tafamidis derivative, comprises the following steps:

[0044] (1) get catechol compound 1, ammonium acetate, aldehyde compound, sodium periodate and solvent and place...

Synthetic example 1

[0064] like figure 1 shown,

[0065] Synthesis of 5-tert-butyl-2-(3,5-dichlorophenyl)benzo[d]oxazole-6-carboxylic acid

[0066] (1) Preparation of 5-tert-butyl-2-(3,5-dichlorophenyl)-6-methylbenzo[d]oxazole: add 1 mmol of 4-tert-butyl-5-methyl to the reactor catechol, 2 mmol 3,5-dichlorobenzaldehyde, 2 mmol ammonium acetate (NH 4 OAc), 2mmolNaIO 4 , 10mL EA. Under a nitrogen atmosphere, continue stirring at 100 °C for 3 hours, stop the reaction, cool to room temperature, wash with saturated NaCl, then extract with ethyl acetate, concentrate under reduced pressure to remove the solvent, dry, and the crude product is separated by column chromatography to obtain The target product in 81% yield.

[0067] (2) Synthesis of Tafamidis derivative 5-tert-butyl-2-(3,5-dichlorophenyl)benzo[d]oxazole-6-carboxylic acid: 0.4 mmol of 5-tert-butyl-2-( 3,5-Dichlorophenyl)-6-methylbenzo[d]oxazole and 6eq KMnO 4 It was added to a mixed solution of pyridine (0.9 mL) and water (0.6 mL). The...

Synthetic example 2

[0069] Synthesis of 5-tert-butyl-2-phenylbenzo[d]oxazole-6-carboxylic acid

[0070] (1) Preparation of 5-tert-butyl-2-phenyl-6-methylbenzo[d]oxazole: add 1 mmol of 4-tert-butyl-5-methylcatechol, 2 mmol of p-trioxazole to the reactor Fluoromethylbenzaldehyde, 2mmol ammonium acetate (NH 4 OAc), 2mmol NaIO 4 , 10mLEA. Under a nitrogen atmosphere, continue stirring at 100 °C for 3 hours, stop the reaction, cool to room temperature, wash with saturated NaCl, then extract with ethyl acetate, concentrate under reduced pressure to remove the solvent, dry, and the crude product is separated by column chromatography to obtain The target product, the yield is 85%.

[0071] (2) Synthesis of Tafamidis derivative 5-tert-butyl-2-phenylbenzo[d]oxazole-6-carboxylic acid: 0.4 mmol of 5-tert-butyl-2-phenyl-6-methylbenzo [d]oxazole and 6eq KMnO 4 It was added to a mixed solution of pyridine (0.9 mL) and water (0.6 mL). The resulting solution was stirred at room temperature for 30 minutes an...

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Abstract

The invention provides a novel Tafamidis derivative and a synthesis method for preparing the Tafamidis derivative from catechol compounds, ammonium acetate and aldehyde compounds using sodium periodate as an oxidant. This method reaction condition is simple, and raw material synthesis cost is lower, has improved the atom economy of reaction, has reduced reaction steps, has avoided acylating reagent dichlorobenzoyl chloride and esterifying reagent (trimethylsilyl) diazonium The use of methane solves the environmental hazards of acid chlorides, diazonium reagents, and strong acid and strong base additives. The reaction uses sodium periodate as an oxidant, and the iodate generated after the reaction is insoluble in the reaction solution and can be well recycled, greatly reducing the pollution caused by the reaction system. It provides a more economical and environmentally friendly path and has great application value.

Description

【Technical field】 [0001] The invention relates to the field of organic synthesis, in particular to a Tafamidis derivative and a synthesis method thereof. 【Background technique】 [0002] Tafamidis is the first FDA-approved drug for cardiomyopathy caused by transthyretin-mediated amyloidosis (ATTR-CM). The drug was applied for by Pfizer and approved for use in the United States in 2019. The drug reduced the risk of death by 30 percent and reduced hospitalizations for cardiovascular-related diseases by 32 percent, according to clinical trials. Associated pharmacodynamics suggest that Tafamidis can bind to the thyroxine-binding site of the thyroxine transporter (TTR) tetramer and inhibit its dissociation into monomers, thereby preventing the TTR amyloidogenic cascade. [0003] A representative synthesis for Tafamidis is the acylation of aminohydroxybenzoic acid with dichlorobenzoyl chloride, the resulting product is treated with p-toluenesulfonic acid monohydrate, and the resu...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D263/57
CPCC07D263/57
Inventor 董建玉武少峰刘锋
Owner HUNAN FIRST NORMAL UNIV
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