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Preparation method of high-purity cinacalcet hydrochloride

A technology of cinacalcet hydrochloride and vacuum degree, which is applied in the preparation of amino-substituted functional groups, purification/separation of amino compounds, organic chemistry, etc. Low cost, high purity effect

Inactive Publication Date: 2013-04-17
CHINA RESOURCES SAIKE PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

In the process of using this route to develop cinacalcet hydrochloride, we found that the product quality of cinacalcet hydrochloride produced according to this process is difficult to meet the requirements of the ICH guidelines, and there are many impurities in the product that are difficult to be purified and removed
These impurities are still difficult to remove through known solvents and repeated recrystallization

Method used

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  • Preparation method of high-purity cinacalcet hydrochloride
  • Preparation method of high-purity cinacalcet hydrochloride
  • Preparation method of high-purity cinacalcet hydrochloride

Examples

Experimental program
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Effect test

Embodiment 1

[0041] Embodiment 1: the preparation of m-trifluoromethylphenylpropyl bromide crude product

[0042] Under stirring at room temperature, 3-trifluoromethylphenylpropanol (150g, 734.6mmol) was added to the mixed solution of water: concentrated sulfuric acid (5:7, 360ml), and lithium bromide monohydrate (210g, 2002.67mmol) was slowly added, Heat to reflux at 90°C for about 4 hours, TCL detection (PE: EA = 20: 1), after the reaction is complete, cool down to room temperature, filter out the solid with suction (210ml of ethyl acetate rinse), separate the obtained liquid, wash with water (300ml× 2), washed with saturated sodium bicarbonate (300ml×2), washed with water (300ml×1), dried over anhydrous sodium sulfate, and spin-dried in the organic phase to obtain 225g of crude product.

[0043] The crude yield of this step reaction is 95%-100%.

Embodiment 2

[0044] Embodiment 2: the preparation of m-trifluoromethyl phenylpropyl bromide fine work

[0045] 225g of m-trifluoromethylphenylpropyl bromide crude product was subjected to oil pump rectification, vacuum: 133-266 Pa, external temperature 85-90 degrees, headspace 58-60 degrees, collected fractions, and obtained 466g of colorless oily product, collected Rate: 87%.

Embodiment 3

[0046] Embodiment 3: the preparation of cinacalcet hydrochloride crude product

[0047] Add 275g of (R)-α-naphthylethylamine and 1580g of acetonitrile into a 5L reactor, add 450g of m-trifluoromethylphenylpropyl bromide, 222kg of anhydrous potassium carbonate under stirring, heat and reflux at 81°C for 20h-22h, TLC Detecting the reaction, m-trifluoromethylphenylpropyl bromide is basically completely consumed, and the reaction is terminated, and the reaction drops to 25-30 degrees.

[0048] Post-processing: filter to remove the solid in the reaction solution, rinse with 158g of acetonitrile, add the filtrate to 8.2kg of water, add 317g of concentrated hydrochloric acid dropwise, adjust the pH<2, stir and precipitate the solid, continue to stir for 2 hours, and filter with suction to get a earthy color Solid, the obtained crude product was placed in a 10L reaction kettle, 8kg of purified water was added, stirred and washed at room temperature for 3 hours, and the earth-colored s...

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Abstract

The invention relates to a preparation method of high-purity cinacalcet hydrochloride. The method comprises the following steps: using R(+)-1-naphthylethanamine and (3-(3-trifluoromethyl) phenyl)-1-bromopropane as starting materials, taking acetonitrile as a solvent, reacting under the action of alkali to get cinacalcet, acidifying a reaction solution in water with hydrochloric acid to get a cinacalcet hydrochloride crude product, and recrystallizing the crude product with ethyl acetate to get the high-purity cinacalcet hydrochloride. The method is simple to operate and suitable for industrialization.

Description

Technical field: [0001] The invention relates to an industrial synthesis method of high-purity cinacalcet, a chiral drug for treating secondary hyperparathyroidism. Background technique: [0002] Cinacalcet hydrochloride, the first drug in a new class of compounds known as calcimimetics, activates calcium receptors in the parathyroid glands, thereby lowering parathyroid hormone (PTH) secretion. It modulates the behavior of the parathyroid calcium receptor and reduces the levels of parathyroid hormone, calcium, phosphorus, and calcium-phosphorus complexes by increasing the sensitivity of the receptor to calcium levels in the bloodstream, FDA approved March 8, 2004 Cinacalcet hydrochloride produced by Amgen (the licensee of the product from NPS Pharmaceuticals) is marketed under the trade name Sensipar. [0003] Cinacalcet hydrochloride, chemical name: N-((1R)-1-(1-naphthyl)ethyl)-3-(3-(trifluoromethyl)phenyl)propan-1-amine hydrochloride , Molecular formula: C22H22F3N HCl, ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C211/30C07C209/08C07C209/84
Inventor 吕会超白雪松邹江杨琰
Owner CHINA RESOURCES SAIKE PHARMA
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