Synthesis method of tamibarotene

Abstract

The invention relates to a synthesis method of tamibarotene, which comprises the steps of: 1)taking aniline and monomethyl ester terephthalate as raw materials, and synthesizing p-carbaniloyl methyl benzoate (III); 2) under the protection of nitrogen in an anhydrous condition, carrying out cyclization on the intermediate III and 2, 5-dimethyl-2, 5-hexanediol at a low temperature, to obtain an intermediate II; and 3) hydrolyzing the intermediate II to obtain the tamibarotene (I), wherein dicyclohexyl carbodiimide (DCC) / hydroxyl benzotriazole (HOBt), diisopropylcarbodiimide (DIC) / HOBt, HATU or HBTU taken as a condensing agent as well as triethylamine and diisopropylethylamine (DIEA) taken as acid-binding agents can be added into the step 1); halogen acid taken as a catalyst is added into the step 2); and the reaction solvent is halogenated alkanes. The synthesis method of the tamibarotene avoids the link with high pollution, thus reducing the environmental cost.

Description

technical field [0001] The invention relates to a method for synthesizing tamibarotene. Background technique [0002] According to statistics, acute promyelocytic autovascular disease (APL) accounts for 6.5% to 32.4% of acute myeloid autovascular disease in China, and is classified as M3 in the FAB classification. In 1986, the first all trans retinoic acid (ATRA) induction differentiation therapy in China can make the complete remission rate (CR) of APL reach more than 85%. With further clinical application, it is found that it can form drug resistance and cause recurrence It is difficult for patients to regain remission. At present, most APL patients are treated with ATRA or with arsenic trioxide (ie, arsenic) or combined chemotherapy. ATRA treatment can activate RAR and induce the differentiation and maturation of promyelocytes, prevent their proliferation, and alleviate the disease. Retinoic acid-based therapy makes APL patients relapse after complete remission, can us...

AI Technical Summary

Problems solved by technology

The disadvantages of this route are: the synthetic route is long; the halogenation reaction involving the participation of concentrated hydrochloric acid, the nitration of mixed acid, and the catalytic reduction reaction of heavy metals are not only low in yield, but also cause serious environmental pollution.

However, there are still the following disadvantages: nitrogen protection is required in the transesterification reaction, and low temperature reaction, cumbersome operation and high cost; the steps are still cumbersome

The post-treatment of a large amount of concentrated hydrochloric acid waste liquid is too costly to the environment

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