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Cinacalcet hydrochloride preparation method

A technology of cinacalcet hydrochloride and cinnamic acid, which is applied in the preparation of organic compounds, the preparation of amino compounds, chemical instruments and methods, etc., can solve the problems of troublesome processing, high processing cost, low yield, etc., and achieves alleviation of post-processing high pressure, low product impurity content, and the effect of simplifying operation steps

Inactive Publication Date: 2015-04-01
CHENGDU QITAI PHARMA TECH
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Problems solved by technology

[0005] The patent US6211244 provides a method for preparing cinacalcet hydrochloride, using m-trifluoromethylbenzaldehyde and R-(1)naphthylethylamine as raw materials, and condensing tetraisopropoxytitanium as a catalyst to prepare (R) -N-(1-(naphthalen-1-yl)ethyl)-3-(trifluoromethyl)phenyl)propionamide; (R)-N-(1-(naphthalen-1-yl)ethyl) -3-(trifluoromethyl) phenyl) propanamide obtains cinacalcet hydrochloride through sodium nitrile borohydride reduction, hydrochloric acid salification, the preparation method yield is low, and the tetraisopropoxy used in condensation reaction It is very difficult to deal with this compound in the process of large-scale industrial production of titanium-based titanium, and the requirement for anhydrous is high, which brings a lot of trouble to the whole reaction. Troublesome and emits a large amount of toxic gas, which is not good for mass production
Patent US6011068 provides a method for preparing cinacalcet hydrochloride, using m-trifluoromethylbenzaldehyde as raw material, obtaining m-trifluoromethyl cinnamic acid through condensation reaction, and obtaining m-trifluoromethyl phenylpropanoid through palladium carbon reduction Acid, m-trifluoromethylphenylpropionic acid is activated by thionyl chloride, triethylamine is used as an acid-binding agent to form an amide with (R)-1-naphthylethylamine, the amide is reduced by sodium borohydride, and hydrochloric acid is salified to obtain the target Compound cinacalcet hydrochloride, the preparation method uses thionyl chloride to acylate m-trifluoromethylphenylpropionic acid during the preparation of amide, the reaction steps are more cumbersome, the acylation reaction is not complete, and a large amount of harmful gas is released during the reaction, which is harmful to The environment causes a lot of pollution, and the post-treatment cost of excess thionyl chloride is relatively high

Method used

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  • Cinacalcet hydrochloride preparation method

Examples

Experimental program
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Effect test

Embodiment 1

[0048] The preparation method of cinacalcet hydrochloride is as follows:

[0049] (A) Using 25 kg of trifluoromethyl cinnamic acid as a raw material, 2.5 kg of palladium carbon as a catalyst, and 150 L of methanol as a solvent, carry out hydrogenation reduction at a temperature of 0-60 ° C for 1-24 h to obtain a yellow oil Fluoromethylbenzoic acid, yield 98.0%;

[0050] (B) Condensation reaction of m-trifluoromethylbenzoic acid and R-(1)naphthylethylamine at a mass ratio of 1:4 at a temperature of 50-200°C for 1-20h to obtain an off-white solid (R )-N-(1-(naphthalene-1-yl)ethyl)-3-(trifluoromethyl)phenyl)propionamide, the yield was 92.1%;

[0051] (C) (R)-N-(1-(naphthalene-1-yl)ethyl)-3-(trifluoromethyl)phenyl)propanamide and acetic acid in a mass ratio of 10:1 at a temperature of 0- Cinacalcet was obtained as a yellow oil after being reduced by the reducing agent boron trifluoride at 10°C, the solvent used was tetrahydrofuran, and the yield was 98.2%;

[0052] (D) reacting...

Embodiment 2

[0054] The preparation method of cinacalcet hydrochloride is as follows:

[0055] (A) Add 50kg of trifluoromethyl cinnamic acid, 0.5kg of palladium carbon and 150L of N,N-dimethylformamide in the autoclave, first replace the nitrogen with nitrogen twice, then replace the nitrogen twice with hydrogen, pass Add hydrogen to keep the pressure at 0.2-0.3MPa, carry out hydrogenation and reduction at a temperature of 30°C for 4 hours, stop stirring, evacuate, discharge and filter, wash with 20L of methanol, and concentrate the filtrate to dryness under vacuum at 40°C. Obtain 49.6 kg of yellow oil m-trifluoromethylbenzoic acid, yield 98.0%;

[0056] (B) Condensate 45kg m-trifluoromethylbenzoic acid and 14kg R-(1)naphthylethylamine at a temperature of 140°C for 5h, stop heating and cool to 40-60°C and add 100L ethyl acetate , 30L of water, separated after stirring, the water phase was extracted once with 40L of ethyl acetate, the organic phase was combined, and the organic phase was w...

Embodiment 3

[0061] The preparation method of cinacalcet hydrochloride is as follows:

[0062] (A) Add 50kg of trifluoromethylcinnamic acid, 0.25kg of palladium carbon and ethanol and N,N-dimethylformamide mixture 150L in the autoclave, wherein the mass percentage of palladium in the catalyst is 5 -10%, first replace nitrogen twice with hydrogen, then replace nitrogen twice with hydrogen, feed hydrogen to maintain the pressure of 0.2-0.3MPa, carry out hydrogenation and reduction at a temperature of 40°C for 10h, stop stirring, empty and discharge Filter, wash with 20L of methanol, and concentrate the filtrate to dryness at 40°C to obtain 48.6kg of m-trifluoromethylbenzoic acid as a yellow oil, with a yield of 98.0%;

[0063] (B) Condensate 45kg m-trifluoromethylbenzoic acid and 36kg R-(1)naphthylethylamine at a temperature of 150°C for 6h, stop heating and cool to 40-60°C and add 100L ethyl acetate , 30L of water, separated after stirring, the water phase was extracted once with 40L of et...

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Abstract

The invention provides a cinacalcet hydrochloride preparation method which comprises the following steps: (A) by taking trifluoromethylcinnamic acid as a raw material and palladium on carbon as a catalyst, performing hydrogenation reduction to obtain m-trifluoromethylbenzoic acid; (B) performing condensation reaction on the m-trifluoromethylbenzoic acid and R-(1) naphthylethylamine, thus obtaining (R)-N-(1-(naphthalen-1-yl)ethyl)-3-(trifluoromethyl)phenyl)propanamide; (C) performing catalytic reduction on the (R)-N-(1-(naphthalen-1-yl)ethyl)-3-(trifluoromethyl)phenyl)propanamide to obtain cinacalcet; and (D) reacting the cinacalcet and hydrochloric acid to obtain cinacalcet hydrochloride. The method has the advantages of thorough reaction, high yield, no pollution in the reaction process and the like.

Description

technical field [0001] The invention relates to the field of pharmacy, in particular to a preparation method of cinacalcet hydrochloride. Background technique [0002] Cinacalcet hydrochloride (cinacalcet hydrochloride, (αR)-α-methyl-N-[3-[3-(trifluoromethyl)-phenyl]propyl]-1-naphthylmethylamine hydrochloride), It is a calcimimetic agent developed by NPS Pharmaceuticals of the United States, which was first launched in the United States in 2004. [0003] Cinacalcet hydrochloride is clinically used to treat hypercalcemia in patients with secondary hyperparathyroidism and parathyroid tumors caused by chronic kidney disease receiving dialysis. This product can inhibit the secretion of parathyroid hormone by activating calcium ion receptors. It is well absorbed in the body and has good bioavailability (about 80%). It reaches the maximum blood concentration within 3 hours after taking it, and it has long-term taking tolerance. [0004] Its therapeutic effects are mainly divided...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C211/30C07C209/50
Inventor 余潜李军
Owner CHENGDU QITAI PHARMA TECH
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