Preparation method of cinacalcet

A technology of cinacalcet and solvent, which is applied in the field of cinacalcet preparation, can solve problems such as inconvenience, and achieve the effects of low preparation cost, high yield and simple operation

Inactive Publication Date: 2013-09-04
SHANGHAI INST OF PHARMA IND +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The reducing agent red aluminum is relatively economical and has good stability. It is usually formulated into a solution for easy storage and transportation. It needs to be transported through pipelines in industrial production, which brings inconvenience to large-scale industrial production.

Method used

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  • Preparation method of cinacalcet
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  • Preparation method of cinacalcet

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0040] Synthesis of N-[1-(R)-(1-naphthyl)ethyl]-3-[3-(trifluoromethyl)phenyl]-1-propionamide (4)

[0041] Add 250ml THF, ZnCl 2 (108.7g, 0.8mol), KBH 4 (86.4g, 1.6mol), stirred at 25°C for 3 hours. Add compound (3) (74.2 g, 0.2 mol) and 100 ml of toluene to the reaction liquid, heat, evaporate part of the solvent until the internal temperature rises to 95 ° C, and stir for 5 h. The reaction solution was cooled to room temperature 25°C, poured into 250ml of hydrochloric acid with a volume ratio of 1%, and filtered to remove solid salts. The mother liquor was extracted with ethyl acetate (100ml×3), separated, and the water phase was treated with 20% sodium hydroxide by weight. The aqueous solution was basified to PH=11~12, then extracted with ethyl acetate, the organic phase extracts were combined, and washed with anhydrous Na 2 SO 4 Dry, filter, concentrate the mother liquor, obtain off-white solid target compound (4), dry weighing 67.8g, yield 95%

Embodiment 2

[0043] Synthesis of N-[1-(R)-(1-naphthyl)ethyl]-3-[3-(trifluoromethyl)phenyl]-1-propionamide (4)

[0044] Add 250ml THF, ZnCl 2 (108.7g, 0.8mol), NaBH 4 (60.8g, 1.6mol), stirred at 25°C for 3 hours. Compound (3) (74.2g, 0.2mol) and 50ml of toluene were added to the reaction liquid, heated slowly, part of the solvent was evaporated to raise the internal temperature to 98°C, and the reaction was stirred for 5h. The reaction solution was cooled to room temperature 25°C, poured into 250ml of hydrochloric acid with a volume ratio of 1%, and filtered to remove solid salts. The mother liquor was extracted with ethyl acetate (100ml×3), separated, and the water phase was treated with 20% sodium hydroxide by weight. The aqueous solution was basified to PH=11~12, then extracted with ethyl acetate, the organic phase extracts were combined, and washed with anhydrous Na 2 SO 4 After drying, filtering, and concentrating the mother liquor, the target compound (4) was obtained as an off-wh...

Embodiment 3

[0046] Synthesis of N-[1-(R)-(1-naphthyl)ethyl]-3-[3-(trifluoromethyl)phenyl]-1-propionamide (4)

[0047] Add 250ml THF, MgCl 2 (75.1g, 0.8mol), KBH 4(86.4g, 1.6mol), stirred at 25°C for 3 hours. Compound (3) (74.2g, 0.2mol) and 50ml of toluene were added to the reaction liquid, heated slowly, part of the solvent was evaporated to raise the internal temperature to 100°C, and the reaction was stirred for 5h. The reaction solution was cooled to room temperature 25°C, poured into 250ml of hydrochloric acid with a volume ratio of 1%, and filtered to remove solid salts. The mother liquor was extracted with ethyl acetate (100ml×3), separated, and the water phase was treated with 20% sodium hydroxide by weight. The aqueous solution was basified to PH=11~12, then extracted with ethyl acetate, the organic phase extracts were combined, and washed with anhydrous Na 2 SO 4 After drying, filtering, and concentrating the mother liquor, the target compound (4) was obtained as an off-whit...

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Abstract

The invention provides a preparation method of cinacalcet, which comprises the following steps of: 1) mixing an alkali metal hydroboron, Lewis acid and a solvent (1); 2) mixing a compound shown in the formula (3) and a solvent (2), adding the mixture into a reaction product of the step 1), and partially steaming out the mixture until the internal temperature of the reaction liquid is 90-110 DEG C for reaction; and 3) collecting a compound shown in the formula (4) from the reaction product to obtain the target product: N-[1-(R)-(1-naphthyl ethyl)-N-[3-[3-(trifluoromethyl)phenyl]propyl]amine. Without a reagent with fairly great toxicity in the original document and through process improvement, the method provided by the invention has the advantages of low preparation cost, simplicity in operation and high yield, is suitable for industrial production and has substantial positive effects and application values. The reaction formula is shown in the specification.

Description

technical field [0001] The present invention relates to a kind of preparation method of cinacalcet, and the chemical name of cinacalcet is N-[1-(R)-(1-naphthylethyl)-N-[3-[3-(trifluoromethyl ) phenyl] propyl] amine, the compound is used to prepare cinacalcet hydrochloride, which is a therapeutic drug for secondary hyperparathyroidism (SHPT). Background technique [0002] Cinacalcet Hydrochloride (CinacalcetHydrochlorid), the chemical name is N-[1-(R)-(1-naphthylethyl)-N-[3-[3-(trifluoromethyl)phenyl]propyl]amine Hydrochloride, researched and developed by Amgen, is a second-generation calcium receptor (CaR) modulator, which directly inhibits the secretion of parathyroid hormone (PTH) by activating calcium receptors on parathyroid cells, and It has application value in the treatment of primary and secondary hyperparathyroidism, and has exact curative effect on patients with secondary hyperparathyroidism (SHPT) receiving dialysis due to chronic kidney disease, and has good saf...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C211/30C07C209/50
Inventor 李建其王冠张莉黄雷
Owner SHANGHAI INST OF PHARMA IND
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