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Synthesis method of Tafamidis and derivative thereof

A synthesis method and technology of derivatives, applied in the direction of organic chemistry, etc., can solve the problems of many reaction steps, increased cost, low total yield, etc., and achieve the effects of fewer reaction steps, high total yield, and reduced pollution.

Active Publication Date: 2021-08-20
HUNAN FIRST NORMAL UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

There are many reaction steps in this process, the total yield is low, and the required raw materials, strong acid and strong alkali and additives etc. greatly increase the cost of the method and cause great pressure on the environment.

Method used

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  • Synthesis method of Tafamidis and derivative thereof
  • Synthesis method of Tafamidis and derivative thereof
  • Synthesis method of Tafamidis and derivative thereof

Examples

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preparation example Construction

[0034] A kind of synthetic method of Tafamidis and derivative thereof, the preparation raw material of described Tafamidis derivative comprises: 6-amino m-cresol, aldehyde compound, sodium periodate (NaIO 4 ),potassium permanganate.

[0035] In one embodiment, the Tafamidis derivative has the following structural formula (I):

[0036]

[0037] In one embodiment, in the structural formula, R is a substituent at any one or more positions on the benzene ring, and each R is independently selected from H, tert-butyl, methoxy, F, Cl, Br, I, trifluoromethyl, nitro, methyl formate.

[0038] In one embodiment, the aldehyde compound is selected from benzaldehyde, p-methoxybenzaldehyde, p-tert-butylbenzaldehyde, p-fluorobenzaldehyde, p-chlorobenzaldehyde, p-bromobenzaldehyde, p-iodine One of benzaldehyde, 3,5-dichlorobenzaldehyde, p-trifluoromethylbenzaldehyde, p-nitrobenzaldehyde, and methyl p-formylbenzoate.

[0039] In one embodiment, preferably, a kind of synthetic method of Ta...

Synthetic example 1

[0061] Synthesis of Tafamidis

[0062] (1) Preparation of 2-(3,5-dichlorophenyl)-6-methylbenzo[d]oxazole: add 1mmol 6-amino-m-cresol, 2mmol 3,5-dichlorobenzaldehyde in the reactor , 2 mmol NaIO 4 , 10 mL EA. Under nitrogen atmosphere, keep stirring at 100°C for 5h, stop the reaction, cool to room temperature, wash with saturated NaCl, then extract with ethyl acetate, distill and concentrate under reduced pressure to remove the solvent, dry, and the crude product is separated by column chromatography to obtain Target product, yield 91%.

[0063] (2) Synthesis of Tafamidis: Then 0.4mmol 2-(3,5-dichlorophenyl)-6-methylbenzo[d]oxazole and 6eq KMnO 4 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 and heated to boiling (about 100°C). After the reaction was completed, the pH was adjusted to pH=2-3 using 1M HCl solution, and then the product was extracted twice with ethyl acetate and water. ...

Synthetic example 2

[0065] Synthesis of 2-(4-methoxyphenyl)benzo[d]oxazole-6-carboxylic acid

[0066] (1) Preparation of 6-methyl-2-(4-methoxyphenyl)benzo[d]oxazole: add 1mmol6-amino-m-cresol, 2mmol 4-methoxybenzaldehyde, 2mmol NaIO 4 , 10 mL EA. Under nitrogen atmosphere, keep stirring at 100°C for 5h, stop the reaction, cool to room temperature, wash with saturated NaCl, then extract with ethyl acetate, distill and concentrate under reduced pressure to remove the solvent, dry, and the crude product is separated by column chromatography to obtain Target product, yield 87%.

[0067] (2) Synthesis of 2-(4-methoxyphenyl)benzo[d]oxazole-6-carboxylic acid: Then 0.4mmol 6-methyl-2-(4-methoxyphenyl)benzo [d] Oxazole and 6eq KMnO 4 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 and heated to boiling (about 100°C). After the reaction was completed, the pH was adjusted to pH=2-3 using 1M HCl solution, and then ...

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Abstract

The invention provides a synthesis method for preparing Tafamidis and a derivative thereof from 6-amino-m-cresol and an aldehyde compound under the action of sodium periodate and potassium permanganate. In the method, the use of an acylation reagent dichlorobenzoyl chloride and an esterification reagent (trimethylsilyl) diazomethane is avoided, and the problem that acyl chloride, a diazonium reagent, a strong acid and strong alkali additive and the like are harmful to the environment is solved; the reaction steps are few, and the total yield is high; methoxy, halogen, trifluoromethyl and the like can be well tolerated; and the iodate and the manganese dioxide after the reaction are insoluble in the reaction solution and can be well recycled, so that the pollution caused by the reaction system is greatly reduced, a more economical and environment-friendly path is provided for synthesis of Tafamidis and the derivative thereof, and the method has a huge application value.

Description

【Technical field】 [0001] The invention relates to the field of organic synthesis, in particular to a method for synthesizing Tafamidis and derivatives thereof. 【Background technique】 [0002] Tafamidis is the first FDA-approved drug for the treatment of 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 in patients by 30 percent and reduced hospitalizations for cardiovascular-related diseases by 32 percent in drug users, as assessed by clinical trials. Related pharmacodynamics showed that Tafamidis can bind to the thyroxine-binding site of the transthyretin (TTR) tetramer and inhibit its dissociation into monomers, thereby preventing the TTR amyloidogenic cascade. [0003] A representative synthetic method for Tafamidis is to acylate 4-amino-3-hydroxybenzoic acid with dichlorobenzoyl chloride, treat the resulting product with p-toluen...

Claims

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Application Information

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IPC IPC(8): C07D263/57
CPCC07D263/57
Inventor 董建玉武少峰耿富荣
Owner HUNAN FIRST NORMAL UNIV
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