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Method for synthesizing cinacalcet intermediate

A technology of cinacalcet and an intermediate is applied in the field of preparation of cinacalcet hydrochloride intermediate-N-ethyl-3-phenyl) propionamide, and can solve the problems of difficult to scale up production, high cost, difficult separation and the like, To achieve the effect of mild reaction temperature, low equipment requirements and high economic value

Inactive Publication Date: 2020-03-24
JIANGSU QINGJIANG PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Among them, m-trifluoromethylpropenone is complicated to synthesize, and cannot be supplied in large quantities on the market, and cannot be mass-produced
[0009] In patent CN104926665A, 3-(3-trifluoromethylphenyl)propionic acid of formula (II) is coupled with (R)-1-(1-naphthyl)ethylamine of formula (I) in one pot to obtain carbamide Nacalcet product uses expensive catalyst tris(pentafluorophenyl)borane, and there are many impurities in one-pot method, and chromatographic column is used for post-treatment, which makes separation difficult, low yield, and difficult to scale up production

Method used

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  • Method for synthesizing cinacalcet intermediate
  • Method for synthesizing cinacalcet intermediate
  • Method for synthesizing cinacalcet intermediate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0035] Add 10g of "3-(3-trifluoromethylphenyl)propionic acid" to a 250ml three-necked flask, add 60ml of toluene, protect with nitrogen, add 6g of thionyl chloride dropwise, and add 50mg of DMF as a catalyst. After the addition, The temperature was raised to 47±3°C for 2 hours, and the reaction system was decompressed and rotated to remove toluene and excess thionyl chloride to obtain 11 g of "3-(3-trifluoromethylphenyl)propionyl chloride". The obtained "3-( 3-Trifluoromethylphenyl) propionyl chloride" was dissolved in 45ml of acetonitrile in a 250ml three-necked flask, and 7.8g of "(R)-1-(1-naphthyl)ethylamine" and 6.4g of anhydrous potassium carbonate were added, and the addition was completed After that, the temperature was raised to reflux for 22 hours, the reaction system was filtered, and the filtrate was distilled to dryness under reduced pressure to obtain 18 g of solid. The solid was dissolved in 130ml of toluene, and 37ml of 32% hydrochloric acid was added to adjust ...

Embodiment 2

[0038] Add 10g of "3-(3-trifluoromethylphenyl)propionic acid" to a 250ml three-necked flask, add 60ml of toluene, protect with nitrogen, add 6g of thionyl chloride dropwise, and add 50mg of DMF as a catalyst. After the addition, The temperature was raised to 48±3°C for 2 hours, and the reaction system was decompressed and rotated to remove toluene and excess thionyl chloride to obtain 11 g of "3-(3-trifluoromethylphenyl)propionyl chloride". The obtained "3-( 3-Trifluoromethylphenyl) propionyl chloride" was dissolved in 45ml of acetonitrile in a 250ml three-necked flask, and 7.8g of "(R)-1-(1-naphthyl)ethylamine" and 6.4g of anhydrous potassium carbonate were added, and the addition was completed After that, the temperature was raised to reflux for 22 hours, the reaction system was filtered, and the filtrate was distilled to dryness under reduced pressure to obtain 18 g of solid. The solid was dissolved in 130ml of toluene, and 37ml of 32% hydrochloric acid was added to adjust ...

Embodiment 3

[0041] Add 10g of "3-(3-trifluoromethylphenyl)propionic acid" to a 250ml three-necked flask, add 60ml of toluene, protect with nitrogen, add 6g of thionyl chloride dropwise, and add 50mg of DMF as a catalyst. After the addition, Raise the temperature to 46±3°C and react for 2 hours. The reaction system was decompressed and rotated to remove toluene and excess thionyl chloride to obtain 11 g of "3-(3-trifluoromethylphenyl)propionyl chloride". The obtained "3-( 3-Trifluoromethylphenyl) propionyl chloride" was dissolved in 45ml of acetonitrile in a 250ml three-necked flask, and 7.8g of "(R)-1-(1-naphthyl)ethylamine" and 6.4g of anhydrous potassium carbonate were added, and the addition was completed After that, the temperature was raised to reflux for 22 hours, the reaction system was filtered, and the filtrate was distilled to dryness under reduced pressure to obtain 18 g of solid. The solid was dissolved in 130ml of toluene, and 37ml of 32% hydrochloric acid was added to adjust...

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Abstract

The invention particularly discloses a method for preparing a cinacalcet hydrochloride intermediate (R)-N-(1-(naphthalen-1-yl)ethyl-3-(trifluoromethyl)phenyl)propanamide. The method comprises the following steps: 3-(3-trifluoromethylphenyl)propionic acid used as a raw material is condensed with N,N-carbonyldimidazole (CDI) to obtain an intermediatet, and the intermediate is condensed with (R)-1-(1-naphthyl)ethylamine to obtain the final product cinacalcet intermediate. The method has the advantages of avoiding of the use of an acyl halide reagent, no generation of acidic gas, environmental protection, low device requirements, mild reaction temperature, realization of high yield, few impurities and high purity of the product, and suitableness for large-scale production.

Description

technical field [0001] The invention belongs to the technical field of medicine and chemical industry, in particular to a cinacalcet hydrochloride intermediate (R)-N-(1-(naphthalene-1-yl)ethyl-3-(trifluoromethyl)phenyl)propane Amide preparation method. Background technique [0002] The chemical name of cinacalcet hydrochloride is: N-((1R)-1-(1-naphthyl)ethyl)-3-(3-(trifluoromethyl)phenyl)propyl-1-amine salt acid salt, its structure is represented by the following formula (IV): [0003] [0004] (Ⅳ) [0005] Cinacalcet hydrochloride is a calcimimetic agent developed by NPS Pharmaceuticals in the United States [0006] (calcimimetics). It activates the calcium receptors in the parathyroid glands, thereby reducing the secretion of parathyroid hormone (PTH), regulates the behavior of the calcium receptors in the parathyroid glands, and reduces the Levels of paraglandular hormones, calcium, phosphorus, and calcium-phosphorus complexes. It is mainly used for the treatment...

Claims

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Application Information

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IPC IPC(8): C07C231/02C07C233/11
CPCC07C231/02C07B2200/07C07C233/11
Inventor 郝忠言周海权陆俊王崇益王栋冯玲玲谢福佳钟健
Owner JIANGSU QINGJIANG PHARMA
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