A kind of preparation method of tazarotene without using cuprous iodide

Abstract

The invention provides a method for preparing tazarotene without the participation of cuprous iodide. First, a palladium catalyst and triphenylphosphine are added to a specific organic solvent, stirred, replaced by nitrogen, and then added 4,4-dimethyl Benzothiopyran-6-yl-acetylene, ethyl 6-chloronicotinate and acid-binding agent are reacted. The method is environmentally friendly, the catalyst is easy to recycle, no waste water containing heavy metals is produced, and the reaction time is shorter and the reaction temperature is lower than the prior art. The product obtained by the method has high yield, high purity and stable quality.

Description

Technical field: [0001] The invention relates to a drug synthesis method, in particular to a preparation method of tazarotene without using cuprous iodide. Background technique: [0002] Tazarotene (I) is the first receptor-selective, third-generation aromatic retinoid drug that selectively binds to two retinoic acid receptors (RAR-β; RAR-γ), but not Binds to retinoic acid X receptor (RXR). It is clinically safe and effective for the treatment of psoriasis, acne, abnormal keratosis, pilosebaceous gland disease, and precancerous lesions of the skin. [0003] [0004] There are many reports on the synthesis methods of tazarotene, but each has some disadvantages and is not suitable for industrial production. [0005] For example, US Patent No. 5,089,509 in 1992 and US No. 5,602,130 in 1997 all disclose different synthesis methods of tazarotene. The last step synthesis of above-mentioned two kinds of methods all is to use 4,4-dimethylbenzothiopyran-6-yl-acetylene and ethyl...

AI Technical Summary

Problems solved by technology

Because both methods use palladium complexes as catalysts, not only the price is expensive, but also the recovery of heavy metals is very cumbersome and the recovery cost is high

In addition, due to the use of n-butyllithium in the reaction system, anhydrous reaction is required, and the reaction conditions are relatively harsh.

[0006] In the synthesis of tazarotene reported in US Patent No. 7,273,937 in 2006, the operation method of the last step of synthesis requires low temperature and column passage. These complicated means are not conducive to industrial scale production

[0017] Cuprous iodide is easy to form a complex with the product, and it is difficult to remove in the product, resulting in excessive heavy metal content in the product, which cannot meet the quality standard of the drug

[0018] In addition, the wastewater generated during the synthesis process contains heavy metals, which will also have an impact on the environment;

[0019] 2. The reaction is carried out under high temperature conditions for a long time (105~115°C for 10 hours), which not only consumes a lot of energy, but more importantly, it is very easy to increase the impurity content in the product, affecting the subsequent processing of the product, and causing Product Yield Reduction

Images