Synthetic technique for tamibarotene

Abstract

The invention discloses a synthesis method for the (I) Linarotene (I), a leukemia treatment drug. The invention mainly proposes a novel synthetic route with the steps as follows: the aniline, and p-chlorocarbonyl benzoic methyl ester are used as the raw materials; the intermediate is the p-chlorocarbonyl benzoic methyl ester and can do the cyclization with the 2,5 - dichloro-2 ,5 - dimethyl hexaneunder the anhydrous condition to get the intermediate 4-[(5,6,7,8-tetrahydrocannabinol-5,5,8,8- tetramethyl-2-naphthalene) carbamoyl] methyl benzoate. After the hydrolysis, the 4-[(5,6,7,8-tetrahydrocannabinol-5,5,8,8- tetramethyl-2-naphthalene) carbamoyl] benzoate (I) can be made, that is, the Linarotene. The synthetic route is simple; the operation is convenient and conducive to the environmental protection; the invention is suitable for the industrial production.

Description

technical field [0001] The invention relates to a new synthesis process of tamibarotene. Background technique [0002] Tamibarotene (I) is a RARα agonist designed specifically for acute promyelocytic leukemia (APL) patients who are resistant to all-trans retinoic acid (ATRA) or intolerance to drug toxicity. It is suitable for the treatment of relapsed or refractory cases of APL. Clinical studies have shown that it has the effect of relieving the symptoms of APL patients with ATRA-induced recurrence. Compared with the previous ATRA combined with chemotherapy, it has less side effects and is a promising drug for the treatment of APL. Tamibarotene was developed by Nippon Shinyaku Co., Ltd. and was first listed in Japan on June 13, 2005. [0003] [0004] Existing foreign literature tamibarotene has two synthetic routes: [0005] (1) J.Med.Chem.1988, 31(11): 2182-2191, published synthesis method: [0006] Using 2,5-dimethyl-2,5-hexanediol as raw material, through chlorina...

AI Technical Summary

Problems solved by technology

[0009] 1) The synthetic route is long;

[0010] 2) The use of toxic reagent benzene will cause great harm to labor protection and the environment;

[0011] 3) Use mixed acid (nitric acid / sulfuric acid) for nitration, and then use Pd / C for reductive hydrogenation, resulting in serious environmental pollution, dangerous operation, high cost and low yield

[0016] 1) When the Fu Ke reaction product (2-acetylamino-5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalene) is recrystallized with ethanol / water mixed solvent, an oily substance will appear, Mixed with the product crystals, it is difficult to separate and affect the yield;

[0017] 2) Nitrogen protection is required in the acyl exchange reaction, and the reaction temperature requires low temperature (-25°C)-room temperature-low temperature (-20°C~-30°C) conversion, and the operation is cumbersome;

[0018] 3) When compound (III) is hydrolyzed into compound (I) in the patent literature, excessive sodium hydroxide is used, and the reaction temperature is too high, so that not only the ester bond is hydrolyzed, but the amide bond is also hydrolyzed, resulting in by-products, low yield, and even Compound (I) could not be obtained

[0019] Therefore above-mentioned two synthetic routes are all unsuitable for industrialized production

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