Method for catalytically synthesizing tamibarotene through acenaphthene imidazole n-heterocyclic carbine allyl palladium chloride compound

Abstract

The invention belongs to the technical field of medicine pharmaceutical synthesis, and particularly relates to a method for catalytically synthesizing tamibarotene through an acenaphthene imidazole n-heterocyclic carbine allyl palladium chloride compound, aiming at providing a novel synthesis method of tamibarotene. The method comprises the following steps of: by taking a novel acenaphthene imidazole n-heterocyclic carbine allyl palladium chloride compound with high catalytic activity as a catalyst; performing amide carbonylation coupled reaction under carbon monoxide in order to directly synthesize a key precursor of tamibarotene by such one step; and then simply hydrolyzing to obtain the target compound, namely, tamibarotene. According to the method, the catalyst adopted has high catalytic performance, so that the catalytic coupling reaction brings high yield; and the catalyst is naturally easily synthesized, the raw materials adopted in the synthetic line are easily available, so that such synthetic line has high competitive advantages and high utility value in industrial production.

Description

technical field [0001] The invention belongs to the technical field of medicine synthesis, and specifically relates to a new method for catalyzing the synthesis of tamibarotene by using a novel acenaphthoimidazole nitrogen heterocyclic carbene allylpalladium chloride compound as a catalyst. Background technique [0002] Tamibarotene, English name: tamibarotene, (structural formula 1), chemical name 4-[(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl ) carbamoyl] benzoic acid, a new retinoic acid receptor α (retinoic acid receptor α, RAR α) agonist, developed by Nippon Shinyaku as a treatment for relapsed or refractory acute early childhood A new drug for myeloid leukemia (APL) with some potential anticancer activity. It was first launched in Japan in June 2005 under the product name Amnolake. This product has been shown to be significantly effective against relapsed APL after ATRA remission. The drug has the advantages of good curative effect, less drug resistance, and l...

AI Technical Summary

Problems solved by technology

[0015] 1) The synthetic route is relatively long, and generally requires four to five steps of reaction to obtain the final target compound;

[0016] 2) The strategy of protection and deprotection needs to be used multiple times in the synthesis, and the atom economy is poor;

[0017] 3) The low temperature and other operations used in the synthesis complicate the synthesis steps, which is not conducive to industrial production;

[0018] 4) Concentrated hydrochloric acid, phosphine pentachloride and other reagents are used many times in the synthesis, resulting in more by-products and greater pollution to the environment, which does not conform to the concept of green environmental protection;

[0019] 5) The yield of some reactions is low, and the raw materials (such as methyl p-chloroformylbenzoate) are relatively expensive and difficult to synthesize, which increases the economic cost of the synthetic route

[0020] These disadvantages all limit the application of existing synthetic routes in industry to a certain extent.

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