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Processes for preparing cinacalcet hydrochloride and polymorphic forms thereof

A technology of cinacalcet hydrochloride and cinacalcet, which is applied in the field of cinacalcet hydrochloride, can solve the problems such as no specific examples of preparation of cinacalcet hydrochloride reported

Inactive Publication Date: 2009-09-02
MEDICHEM
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0013] In addition to the synthetic route shown in Scheme 1 above, there are no specific examples of the preparation of cinacalcet hydrochloride reported in the literature

Method used

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  • Processes for preparing cinacalcet hydrochloride and polymorphic forms thereof
  • Processes for preparing cinacalcet hydrochloride and polymorphic forms thereof
  • Processes for preparing cinacalcet hydrochloride and polymorphic forms thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0204] Example 1: Preparation of Cinacalcet Hydrochloride

[0205] In an argon atmosphere, 1.69 g (9.89 mmol, 1.1 equiv) of (R)-1-naphthylethylamine was added to 2.0 g (8.93 mmol, GC purity: 90.3%) of 3-(3-trifluoromethane) phenyl)propanal in 40 mL of tetrahydrofuran. The resulting clear solution was stirred for 15 minutes, 2 mL of acetic acid and 3.18 g (15.0 mmol) of sodium triacetoxyborohydride were added. The reaction mixture was stirred for 2 hours and the solvent was evaporated in vacuo. The resulting residue was dissolved in 30 mL of dichloromethane, and the resulting solution was washed with 30 mL of 10% sodium carbonate solution. The inorganic layer was extracted with 20 mL of dichloromethane and the solvent of the collected organic phase was evaporated in vacuo. The resulting crude base (3.17 g, 89%) was then dissolved in 5 mL of ethyl acetate and acidified with hydrochloric acid in diethyl ether. The evaporated crude salt was then treated with 2-3 mL of ethyl ac...

Embodiment 2

[0207] Example 2: Preparation of Cinacalcet Hydrochloride

[0208] To a cold (10°C) solution of 19.25 g (112 mmol) of (R)-1-naphthylethylamine was alternately added 4.5 mL of acetic acid and 500 mL of isobutyl acetate, 150 mL of freshly prepared 8 portions over 4 hours of sodium triacetoxyborohydride and 25.0 g (124.0 mmol, 96.7%) of 3-(3-trifluoromethylphenyl)propanal in 100 mL of isobutyl acetate, starting from the reducing agent. An aliquot of the borohydride was added simultaneously, while an aliquot of the aldehyde was added dropwise over 10 minutes. After the addition was complete, the resulting white suspension was stirred for 20 minutes, and then 300 mL of distilled water was added. Next, 100 mL of a 10% aqueous sodium carbonate solution was added dropwise. The organic layer was separated and concentrated to about 250 mL. To the concentrated solution was added 75 mL of 2M aqueous hydrochloric acid followed by 150 mL of heptane with stirring. The precipitated crude ...

Embodiment 3

[0210] Example 3: General procedure for the preparation of Cinacalcet hydrochloride salt form I by evaporation

[0211] Solutions of cinacalcet hydrochloride were obtained in appropriate solvents at the concentrations shown in Table 1. This solution was slowly evaporated at room temperature and the resulting solid was ground smoothly for XRD analysis. The results are summarized in Table 1.

[0212] solvent Concentration (Volume) XRD acetone 25 Form 1 Ethanol 5 Form 1 2-Propanol 35 Form 1 methyl ethyl ketone 25 Form 1 Dichloromethane 3 Form 1 Ethyl acetate 80 Form 1 2-Butanol 60 Form 1 2-Methyltetrahydrofuran 50 Form 1 dimethylformamide 5 Form 1 dimethylacetamide 5 Form 1 dimethyl sulfoxide 5 Form 1 1,4-Dioxane 23 Form 1

[0213] Table 1

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Abstract

The invention relates to cinacalcet hydrochloride, new polymorphic crystalline forms of cinacalcet hydrochloride, amorphous cinacalcet hydrochloride and synthetic processes for their preparation.

Description

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS [0002] This application claims priority to US Provisional Application No. 60 / 811,782, filed June 8, 2006, which is incorporated herein by reference in its entirety. technical field [0003] The present invention relates to cinacalcet hydrochloride, new polymorphic crystal forms of cinacalcet hydrochloride, amorphous cinacalcet hydrochloride and synthetic methods for their preparation. Background technique [0004] Cinacalcet hydrochloride is a commercially available pharmaceutically active substance known to be useful in the treatment of hyperparathyroidism and in the maintenance of bone density in patients suffering from renal failure or hypercalcemia due to cancer. Cinacalcet hydrochloride is N-[1-(R)-(-)-1-naphthyl)ethyl]-3-[3-(trifluoromethyl)phenyl]-1-propanamine hydrochloride International common name for salts having formula (I) as shown below: [0005] [0006] Formula I [0007] Cinacalcet hydrochloride is an o...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C209/28C07C209/84C07C211/30
CPCC07B2200/13C07C209/28C07C209/84A61P13/12A61P19/10A61P3/14A61P35/00A61P5/18C07C211/30
Inventor T·塞凯赖什J·雷帕希A·绍博M·贝尼托韦莱兹B·马吉隆
Owner MEDICHEM
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