Synthetic process of c-fos/ap-1 inhibitor

Abstract

The invention belongs to the technical field of pharmaceutical synthesis and especially relates to a synthesis technology of a C-Fos / AP-1 inhibitor. Starting from cheap raw materials 2,4-dimethoxybenzoic acid and 2-methoxyphenylpropionic acid, acid chloride is prepared by using thionyl chloride, and a Friedel-Crafts acylation reaction is carried out under the catalysis of aluminium trichloride soas to obtain a coupled product; then, pyridine hydrobromide and sodium chloride are used to react at 160 DEG C for 30 minutes to complete the demethylation for synthesis of lactonic ring by one step,and the product can be directly used in the next reaction without purification; the cyclopentyl group is introduced by nucleophilic substitution; the lactone ring is opened to form methyl ester; afterpurification, a benzoisoxazolyl group is introduced by nucleophilic substitution, and a protecting group is taken off to prepare the final product T5224. The route of the invention is short, and onlythe Friedel-Crafts acylation, lactone ring opening and introduction of the benzoisoxazolyl group require the step of purification. The cost of the raw materials is low, and the reaction time of the process route is short. The synthesis technology is suitable for industrial production.

Description

technical field [0001] The invention belongs to the technical field of drug synthesis, and in particular relates to a synthesis process of a C-Fos / AP-1 inhibitor. Background technique [0002] T5224 is a selective inhibitor of c-Fos / AP-1, which regulates and controls the expression of inflammatory cytokines and matrix metalloproteinases, which are involved in the pathogenesis of rheumatoid arthritis have a vital role. [0003] The structural formula of T5224 is as follows: [0004] [0005] T5224 refers to 3-{[2-[3-oxo-(1,2-benzisoxazol-6-yl)methoxy-5-(2-hydroxy-4-cyclopentyloxybenzoyl) ] phenyl} propionic acid; in the prior art, the synthetic route of T5224 mainly contains four: 1) with 6-methyl coumarin described in US2009099369A1 as raw material, generate coumarin-6-carboxylic acid through oxidation , and then prepared into acid chloride and m-phenylenedimethyl ether through Friedel-Crafts acylation coupling to remove the methyl protecting group on the phenolic hydr...

AI Technical Summary

Problems solved by technology

[0006] Among the four routes, the starting materials of route 1-3 are relatively expensive, and the route is relatively long. In particular, route 3 also uses Grignard reaction, and it is not easy to operate without water and oxygen.

The used raw material price of No. 4 route is cheap, and route is moderate, but the aluminum trichloride and the ethyl acetate condition productive rate that adopts when taking off the methyl protecting group step on the phenol methyl ether are 53%, and the total productive rate of first three steps is 17% significantly lower

And before introducing the cyclopentyl group, it is necessary to catalyze the formation of the lactone ring by p-toluenesulfonic acid, and then use the Mitsunobu reaction to introduce the cyclopentyl group, which increases the number of steps and increases the cost of raw materials

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