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A method of producing cinacalcet

A technology of cinacalcet and a catalyst, which is applied in the preparation of amino compounds, chemical instruments and methods, preparation of organic compounds, etc., can solve the problems of increasing the number of steps in the synthesis of cinacalcet, etc.

Active Publication Date: 2014-07-30
ZENTIVA AS
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, all these solutions increase the number of steps required in the synthesis of cinacalcet

Method used

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  • A method of producing cinacalcet
  • A method of producing cinacalcet
  • A method of producing cinacalcet

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0051] Weigh 6.12g (35.7mmol) of (R)-1-(1-naphthyl)-ethylamine and 8.02g (39.3mmol) of 3-[3-(trifluoromethyl)phenyl] propanol, put into the flask. The mixture was diluted with 16 ml of toluene and 0.14 g (0.5 mol %) of [IrCp*Cl 2 ] 2 . Under a nitrogen atmosphere, the mixture was heated in a bath at t = 110° C. under a reflux condenser for 6 hours. After cooling, the mixture was diluted with 80 ml ethyl acetate and a solution of hydrogen chloride in ether was added dropwise. The resulting suspension was stirred at laboratory temperature for 1 hour, then in an ice bath for 1 hour. After aspiration, washing with 10 ml of ethyl acetate, and finally drying (in a vacuum oven at 45° C. for 2.5 hours), 10.53 g (75%) of cinacalcet hydrochloride were obtained in a purity of 99.52% (HPLC) salt (corresponding to Form A). If necessary, the product was repurified by crystallization from ethyl acetate.

[0052] For HPLC determination, a column Gemini C-18 with reversed phase, 150 mm ...

Embodiment 2

[0056] 175 g (1 mmol) of (R)-1-(1-naphthyl)-ethylamine and 200 mg (1 mmol) of 3-[3-(trifluoromethyl)phenyl]propanol were weighed and put into a flask. The mixture was diluted with 2 ml of anhydrous toluene, and 28 mg (5 mol %) of catalyst [Ru(p-cymene)Cl was added 2 ] 2 and 52 mg (10 mol%) of bis[(2-diphenylphosphino)phenyl]ether. Under a nitrogen atmosphere, the mixture was heated in a bath at t = 110° C. under a reflux condenser for 18 hours. After cooling, 1 ml of concentrated hydrochloric acid was added to the reaction mixture. After evaporation in a rotary vacuum evaporator, the product was mixed with 3 ml of ethyl acetate. By aspiration, 230 mg (60%) of cinacalcet hydrochloride were obtained.

Embodiment 3

[0058] Weigh 2.51g (14.7mmol) of (R)-1-(1-naphthyl)-ethylamine and 3.01g (14.7mmol) of 3-[3-(trifluoromethyl)phenyl] propanol, put into the flask. The mixture was diluted with 6 ml of toluene and 53 mg (0.45 mol %) of [IrCp*Cl 2 ] 2 . Under a nitrogen atmosphere, the mixture was heated in a bath at t = 110° C. under a reflux condenser for 20 hours. After cooling, the reaction mixture was diluted with a mixture of hexane and ethyl acetate. Upon addition of a solution of hydrogen chloride in diethyl ether, a solid salt formed and by suctioning it off, 4.83 g (83%) of cinacalcet hydrochloride in 97.8% purity (HPLC) were obtained. HPLC assays were performed using the method described in Example 1.

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Abstract

A new efficient method of producing Cinacalcet of formula I and its pharmaceutically acceptable salts, which consists in direct alkylation of (R)-(1-naphthyl)ethylamine of formula III with 3-[3-(trifluoromethyl)phenyl]propanol of formula II in presence of a catalyst in an inert organic solvent. Use of Cinacalcet of formula I prepared by the claimed method in preparation of pharmaceutically acceptable salts of Cinacalcet.

Description

technical field [0001] The present invention relates to a preparation chemical name is N-[(1R)-1-(naphthyl)ethyl]-3-[3-(trifluoromethyl)-phenyl]propane-1-amine of formula I Cinacalcet and its pharmaceutically acceptable salts (eg hydrochloride) method. [0002] Background technique [0003] Cinacalcet in the hydrochloride form is being sold under the trademark Mimpara. It has been approved for the treatment of secondary hyperparathyroidism in dialysis patients with kidney disease and for the treatment of hypercalcemia in patients with parathyroid cancer. [0004] US Patent No. 6,011,068 discloses a group of arylalkylamines in which cinacalcet and generally its pharmaceutically acceptable salts are also included. Cinacalcet is specifically described in US Patent 6,211,244. The patent also shows that it is possible to synthesize substances similar to cinacalcet using reductive amination consisting in coupling the corresponding aromatic aldehyde or aromatic ketone with a ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C209/16
CPCC07C209/16C07C211/30
Inventor 卢泽纳·瓦拉撒科瓦约瑟夫·哈吉塞克
Owner ZENTIVA AS