Synthetic method of cinacalcet hydrochloride and intermediate compound of cinacalcet hydrochloride

A technology of cinacalcet hydrochloride and a synthesis method, which is applied in the field of synthesis of cinacalcet hydrochloride and its intermediate compounds, can solve the problems affecting the quality of the cinacalcet hydrochloride product, the low free base yield and purity, Product market competitiveness and other issues, to achieve the effect of reducing product cost, improving yield and purity, and improving utilization rate

Active Publication Date: 2015-07-15
CHENGDU ZIHAO PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

This shows that when the purity and the yield of intermediate trifluoromethyl phenylpropyl bromide are not ideal, the free base yield and the purity will be correspondingly low, and finally affect the product quality of cinacalcet hydrochloride, which is unfavorable for the product Cost savings affect the market competitiveness of products

Method used

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  • Synthetic method of cinacalcet hydrochloride and intermediate compound of cinacalcet hydrochloride
  • Synthetic method of cinacalcet hydrochloride and intermediate compound of cinacalcet hydrochloride
  • Synthetic method of cinacalcet hydrochloride and intermediate compound of cinacalcet hydrochloride

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0045]Synthesis of embodiment 1 m-trifluoromethyl phenylpropyl bromide (formula III compound)

[0046] Add 208.9g (1.023mol) of 3-[3-(tri-fluoromethyl)-phenyl]propanol (Formula II), 338g (2.005mol) of 48% hydrobromic acid and tetrabutylsulfuric acid into a 1000ml three-necked flask After 20g (0.0589mol) of ammonium hydrogen, stir and heat up until the temperature of the solution in the reaction bottle is stable at 82±2°C, weigh 402g (1.998mol) of 98% concentrated sulfuric acid in a 500ml constant pressure dropping funnel, and pour it slowly into the reaction bottle Slowly add concentrated sulfuric acid, control the dropping speed, keep the temperature in the reaction bottle at 82±2°C, drop it in about 3 hours, keep the temperature in the bottle, react for 22 hours, TLC (developing agent: petroleum ether / ethyl acetate =10:1) Monitor the completion of the reaction, cool down to room temperature, pour the reaction solution into a 2L separatory funnel, and after standing still, se...

Embodiment 2

[0048] The synthetic method of embodiment 2 cinacalcet hydrochloride

[0049] Step 1: Prepare the intermediate compound of formula III according to the method of Example 1 to obtain 248.6g;

[0050] Step 2: Synthetic formula V compound

[0051] Add 187.3g (1.0939mol) R-(+)-1-naphthylethylamine (Formula IV), 252g (1.832mol) anhydrous potassium carbonate, 0.36g potassium iodide, and 2.4L acetonitrile in a 3L three-necked reaction flask, and react Heat the system to an internal temperature of 60-70°C, then add 248.5g of the refined intermediate (Formula III) within 1 hour, keep the temperature in the reaction bottle at 60-70°C, react for 22 hours, and detect by TLC (developing agent: petroleum Ether / ethyl acetate=10:1) reaction solution, the intermediate (Formula III) basically reacted completely, the reaction solution was filtered and concentrated to recover acetonitrile to obtain cinacalcet free base oil; dissolve the oil in ethyl acetate , add 1mol / L hydrochloric acid soluti...

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Abstract

The invention provides a synthetic method of cinacalcet hydrochloride intermediate compound meta-trifluoro methyl phenylpropyl bromine and cinacalcet hydrochloride. According to the synthetic method, synthetic technology of intermediate compound meta-trifluoro methyl phenylpropyl bromine is optimized, so that yield and purity of meta-trifluoro methyl phenylpropyl bromine and cinacalcet hydrochloride are improved significantly, product quality is ensured, raw material utilization ratio is increased, and product cost is reduced effectively.

Description

technical field [0001] The invention relates to a synthesis method of cinacalcet hydrochloride and an intermediate compound thereof. Background technique [0002] Cinacalcet Hydrochloride (Cinacalcet Hydrochloride), its chemical name is: N-[1-R-(-)-(1-naphthyl)ethyl]-3-[3-(trifluoromethyl)benzene Base]-1-aminopropane hydrochloride, the chemical formula is C 22 h 22 f 3 N·HCl, CAS No. 364782-34-3, its structural formula is as follows: [0003] [0004] Cinacalcet hydrochloride is a calcimimetic agent developed by NPS Pharmaceuticals of the United States. On March 8, 2004, the FDA approved the marketing of cinacalcet hydrochloride produced by Amgen (the licensee of the product of NPS Pharmaceuticals). The trade name is Sensipar; in October 2007, cinacalcet hydrochloride produced by Kylin Pharmaceutical Co., Ltd. was launched in Japan, the trade name is REGPARA, and the specifications are 25mg and 75mg (based on cinacalcet). This product is not available in China. Cina...

Claims

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Application Information

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IPC IPC(8): C07C22/08C07C17/16C07C211/30C07C209/08
Inventor 余建红周武春叶兵刘忠荣
Owner CHENGDU ZIHAO PHARMA
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