Preparation method of cinacalcet intermediate

A cinacalcet, Chinese-style technology, applied in the field of preparation of cinacalcet intermediates, can solve the problems of unsuitability for industrial production, carcinogenicity of ethyl acrylate, instability, etc., and achieves low cost, easy purification, and low production cost. Effect

Active Publication Date: 2014-03-26
BEIJING WINSUNNY PHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The ethyl acrylate used in the reaction is carcinogenic, flammable and unstable, not suitable for industrial production

Method used

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  • Preparation method of cinacalcet intermediate
  • Preparation method of cinacalcet intermediate
  • Preparation method of cinacalcet intermediate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0045] Preparation of (Z)-3-chloro-3-[3-(trifluoromethyl)phenyl]-2-propenoic acid

[0046] Dissolve 8.46g of 3-(trifluoromethyl)acetophenone and 21.3g of N,N-dimethylaminoformal in 100mL of DMF, and stir the reaction mixture under reflux at 153°C. TLC monitors that the reaction is complete, and evaporates the solvent Obtained 10.28g (E)-3-(N,N-dimethylamino)-1-[3-(trifluoromethyl)phenyl]-2-propen-1-one (compound of formula I), yield 94.0 %.

[0047] Dissolve 2.67g of the compound of formula I and 3.34g of phosphorus oxychloride in 25mL of dichloromethane, stir the reaction mixture at reflux temperature, monitor the completion of the reaction by TLC, remove the solvent to obtain a crude product, dissolve it in a mixture of 50mL of water and tetrahydrofuran solution (volume ratio = 1:1), stirred at room temperature for 24 hours, added water, extracted with ethyl acetate, dried over anhydrous sodium sulfate, concentrated to give 2.52g (Z)-3-chloro-3-[3-(trifluoroform Base) ph...

Embodiment 2

[0050] Preparation of (Z)-3-chloro-3-[3-(trifluoromethyl)phenyl]-2-propenoic acid

[0051] Dissolve 8.46g of 3-(trifluoromethyl)acetophenone and 15.75g of N,N-dimethylaminopropyl acetal in 100mL of dioxane, and stir the reaction mixture under reflux at 101°C. TLC monitors that the reaction is complete. The solvent was evaporated to obtain 10.01g (E)-3-(dimethylamino)-1-[3-(trifluoromethyl)phenyl]prop-2-en-1-one (compound of formula I), yield 91.5 %.

[0052] Dissolve 2.67g of the compound of formula I and 6.86g of phosphorus pentachloride in 50mL of tetrahydrofuran, stir at 60°C, monitor the completion of the reaction by TLC, remove the solvent to obtain a crude product, and dissolve the crude product in a mixture of 50mL of water and acetone (volume ratio = 1 : 1), stirred at room temperature for 24h, added water, extracted with ethyl acetate, dried over anhydrous sodium sulfate, concentrated to give 2.38g (Z)-3-chloro-3-[3-(trifluoromethyl)phenyl]- 2-Acrolein (compound o...

Embodiment 3

[0055] Preparation of (Z)-3-chloro-3-[3-(trifluoromethyl)phenyl]-2-propenoic acid

[0056] Dissolve 8.46g of 3-(trifluoromethyl)acetophenone and 19.84g of N,N-dimethylaminoacetal in 100mL of acetonitrile, and stir the reaction mixture under reflux at 80°C. TLC monitors that the reaction is complete, and evaporates the solvent 10.09 g of (E)-3-(dimethylamino)-1-[3-(trifluoromethyl)phenyl]prop-2-en-1-one (compound of formula I) was obtained with a yield of 92.3%.

[0057] Dissolve 2.67g of the compound of formula I and 6.69g of phosphorus oxychloride in 50mL of toluene, stir at 80°C, monitor the complete reaction by TLC, remove the solvent to obtain the crude product, and dissolve the crude product in a mixture of 50mL of water and acetonitrile (volume ratio = 2 : 1), stirred at room temperature, added water, extracted with dichloromethane, dried over anhydrous sodium sulfate, concentrated to give 2.41g (Z)-3-chloro-3-[3-(trifluoromethyl)phenyl]-2 - Acrolein (compound of form...

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Abstract

The invention relates to a preparation method of a cinacalcet intermediate (Z)-3-chlorine-3-[3-(trifluoromethyl)phenyl]-2-crylic acid. The preparation method comprises the following steps: condensing 3-(trifluoromethyl) acetophenone used as a starting material; reducing and performing other reactions to obtain the intermediate. The invention also relates to two methods for preparing cinacalcet by utilizing intermediate.

Description

technical field [0001] The present invention relates to the preparation method of cinacalcet intermediate, in particular to the preparation method of (Z)-3-chloro-3-[3-(trifluoromethyl)phenyl]-2-acrylic acid and its use in the preparation of cinacalcet Nakasai's method. Background technique [0002] Secondary hyperparathyroidism (SHPT) is a common complication of chronic kidney disease. In recent years, a new understanding of the pathogenesis of SHPT has been obtained at the molecular level, and it is believed that the parathyroid calcium-sensing receptor plays an important role. SHPT is characterized by mineral metabolism disorder, increased secretion of parathyroid hormone, and parathyroid hyperplasia, which can cause a series of consequences, including renal osteodystrophy, calcification of blood vessels and heart valves, etc. [0003] Cinacalcet is a calcimimetic agent developed by NPS Pharmaceuticals in the United States. In 2004, the FDA approved the marketing of cin...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C57/60C07C51/16C07C211/30C07C209/50
CPCC07C45/65C07C51/09C07C51/16C07C209/50C07C221/00C07C231/02C07C231/12C07C57/60C07C47/24C07C225/16C07C211/30C07C233/11C07C57/58
Inventor 林国良韩杰张利华耿玉先潘海群
Owner BEIJING WINSUNNY PHARMA CO LTD
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