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Preparation method of cinacalcet hydrochloride

A technology of cinacalcet hydrochloride and cinacalcet, which is applied in the field of drug synthesis, can solve the problems of large investment and high equipment requirements, achieve low production costs, meet medicinal requirements, and avoid hydrogenation reaction steps.

Pending Publication Date: 2020-09-25
NORTH CHINA UNIV OF WATER RESOURCES & ELECTRIC POWER
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

These methods need to use palladium carbon to carry out steps such as hydrogenation reduction, need to use noble metal catalyst palladium carbon, hydrogenation reaction requires higher equipment, and invests more

Method used

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  • Preparation method of cinacalcet hydrochloride
  • Preparation method of cinacalcet hydrochloride
  • Preparation method of cinacalcet hydrochloride

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0037] Example 1 Preparation of compound 5-(3-trifluoromethylbenzylidene) imidazoline-2,4-dione

[0038]Add 21.0g hydantoin, 34.8g m-trifluoromethylbenzaldehyde, 200mL water, 20mL absolute ethanol to a 500mL reaction bottle, heat and reflux at 100°C for 6h, and detect by TLC, after m-trifluoromethylbenzaldehyde basically disappears , stop heating, stir at room temperature for 10h, filter, wash the filter cake with a small amount of absolute ethanol, and dry under vacuum at 50°C (vacuum degree is -0.09MPa) to obtain compound 5-(3-trifluoromethylbenzylidene)imidazoline 43.5 g of -2,4-dione light yellow solid, yield 85.0% (yield calculated as m-trifluoromethylbenzaldehyde).

Embodiment 2

[0039] Example 2 Preparation of compound 2-oxo-trifluoromethylphenylpropionic acid

[0040] In the 500mL reaction bottle, add 5-(3-trifluoromethylbenzylidene) imidazoline-2,4-dione light yellow solid 43g, the mass percent concentration is 5% sodium hydroxide solution 200mL, in 105 Heat at reflux for 2 hours at ℃, after the reaction is complete, stop heating, cool down to room temperature, adjust the pH of the solution to 3 with hydrochloric acid with a mass percent concentration of 10% under ice bath conditions, stir and crystallize for 9 hours; filter with suction, wash the filter cake with a small amount of ethanol, 50 After vacuum drying at °C, 30.8 g of the compound 2-oxo-trifluoromethylphenylpropionic acid was obtained, with a yield of 75.1%.

Embodiment 3

[0041] Example 3 Preparation of compound (R)-3-(1-(naphthalene-1-yl)ethylamino)-1-(3-(trifluoromethyl)phenyl)propan-2,3-dione

[0042] Into a 500mL reaction flask, add 29.5g of 2-oxo-trifluoromethylphenylpropionic acid and 150mL of anhydrous tetrahydrofuran, stir for 30min, cool down to -10°C, add 22.1g / 14.7mL of oxalyl chloride dropwise, after addition, add N,N-Dimethylformamide 10mL, slowly warm up to 20°C, stir for 1h, then cool down to below 0°C, add (R)-1-(1-naphthyl)ethylamine solution in N-methylpyrrolidone dropwise Dissolve 82.2g [(R)-1-(1-naphthyl)ethylamine 21.0g in 100mL N-methylpyrrolidone, the mass percentage concentration is 17.0%], after dropping, keep stirring for 1h, add the reaction solution into 300mL purified water , add 200mL toluene, stir for 15min, then transfer to a 1000mL separatory funnel, let stand, separate the liquids, dry the organic phase with anhydrous sodium sulfate overnight, filter with suction, concentrate to get the compound (R)-3-(1-( Nap...

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Abstract

The invention relates to a preparation method of cinacalcet hydrochloride. The preparation method comprises the following steps: taking m-trifluoromethyl benzaldehyde, hydantoin and (R)-1-(1-naphthyl)ethylamine as raw materials, performing condensation, hydrolysis, amidation and reduction reaction to prepare cinacalcet, and reacting cinacalcet with hydrochloric acid to prepare cinacalcet hydrochloride. Compared with an existing synthesis method of cinacalcet hydrochloride, the preparation method is short in route and low in raw material cost, the adopted condensing agent is oxalyl chloride and thionyl chloride, which are low in price, the adopted reducing agent is sodium borohydride, which is low in price, a precious metal catalyst (palladium on carbon) is not used, the hydrogenation reaction step is avoided, the requirement for equipment is low, normal-pressure reaction operation can be adopted, and the method is suitable for large-scale industrial production.

Description

technical field [0001] The invention relates to a preparation method of cinacalcet hydrochloride, belonging to the field of drug synthesis. Background technique [0002] Cinacalcet hydrochloride, a calcimimetic agent developed by U.S. NPS Pharmaceuticals, has a chemical name of N-((1R)-1-(1-naphthyl)ethyl)-3-(3-(trifluoromethyl) Phenyl)propan-1-amine hydrochloride is clinically used to treat secondary hyperparathyroidism caused by chronic kidney disease receiving dialysis and hypercalcemia in patients with parathyroid tumors. [0003] Using m-trifluoromethylbenzaldehyde as a raw material is an important method for preparing cinacalcet hydrochloride. Route (1), represented by the patent US6011068, provides a preparation method of cinacalcet hydrochloride, using m-trifluoromethyl benzaldehyde as raw material, obtaining m-trifluoromethyl cinnamic acid through condensation reaction, and obtaining m-trifluoromethyl cinnamic acid through palladium carbon reduction. Trifluorometh...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D233/76C07C231/02C07C235/78C07C51/00C07C59/88C07C209/50C07C209/00C07C211/30
CPCC07D233/76C07C231/02C07C51/00C07C209/50C07C209/00C07B2200/07C07C235/78C07C59/88C07C211/30
Inventor 杨光瑞秦德志张丽刘辉徐迪李闻天陈孟达胡永安雷佳岩崔爱超李奎新
Owner NORTH CHINA UNIV OF WATER RESOURCES & ELECTRIC POWER
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