Novel preparation method of cinacalcet hydrochloride

Abstract

The invention discloses a novel preparation method of cinacalcet hydrochloride, belonging to the technical filed of preparation of cinacalcet hydrochloride and comprising the steps of: firstly, with 1-acetonaphthone (II) as a raw material, introducing a chiral reagent, and reducing with sodium borohydride to obtain a compound (III); secondly, dissolving the compound (III) into a proper solvent, and reacting with 3-propiolic halide to obtain a compound (IV); thirdly, adding a proper catalyst into the obtained compound (IV) in a solvent at a certain temperature, and carrying out a coupling reaction with meta-chlorobenzotrifluoride to generate a compound (V); and fourthly, reducing the obtained compound (V) with a proper reducing agent and acidizing with hydrochloric acid to obtain the cinacalcet hydrochloride (I). The cinacalcet hydrochloride is synthesized chirally, and has the advantages of special reaction course, good selectivity, high yield, less reaction steps, safe and simple operation and little environment pollution. The raw material used in the reaction course is easy to obtain, has lower production cost and high optical purity, and is suitable for industrialized production.

Description

Technical field: [0001] The invention relates to a new preparation method of cinacalcet hydrochloride used for treating hyperparathyroidism. It belongs to the technical field of preparation of cinacalcet hydrochloride. Background technique: [0002] In 2004, the US Food and Drug Administration approved a new drug, cinacalcet, produced by Amgen, which can not only treat secondary hyperparathyroidism in patients with chronic kidney disease on dialysis, but also treat hypercalcemia in patients with parathyroid cancer. Cinacalcet hydrochloride is the international common product of N-[1-(R)-(-)-naphthyl]ethyl]-3-[3-(trifluoromethyl)phenyl]-1-propanamine hydrochloride Nomenclature, CAS number is 364782-34-3, chemical formula is C 22 h 22 f 3 N HCl, its structural formula is as follows: [0003] [0004] Cinacalcet hydrochloride, an oral calcimimetic, was the first drug of its kind to be approved by the FDA. In the United States it goes by the name sold; in Europe it is...

AI Technical Summary

Problems solved by technology

[0008] The disadvantages of this process are: ① serious side reactions and low yield; ② expensive and highly toxic sodium cyanoborohydride is used as a reducing agent, which is not conducive to industrial production

[0014] Although the synthesis steps given in the WO2008 / 058235 A2 patent are relatively comprehensive, there are still many disadvantages: ① serious by-products are formed, and the process of obtaining naphthylethylamine needs to be split, and the yield is low; And toxic reagents, such as HOBt (benzotriazole), DCC (dicyclohexylcarbodiimide) etc.; 3. the product will be separated and purified through many times, and the steps are numerous, which is not conducive to industrialized production

[0015] Although there are many reports on the synthesis of cinacalcet, all of them have their limitations, such as low yield, many steps, and the reagents used are toxic or harmful to the environment, etc.

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