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Method for preparing cinacalcet hydrochloride

A technology for cinacalcet hydrochloride and hydrochloride, which is applied in the direction of reductive alkylation preparation and organic chemistry, can solve the problems of high price, high production cost, and environmental pollution, and achieve simple operation, low cost, and good purity Effect

Inactive Publication Date: 2012-10-10
HANGZHOU XINBOSI BIOMEDICAL CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0012] In the above-mentioned method, route one has the following disadvantages: 1. The key raw material 3-trifluoromethylphenylpropionaldehyde is difficult to purchase, expensive, and the production cost is high
2. Ti(Oi-Pr) used in condensation reaction 4 , has high requirements for anhydrous, and post-processing is very difficult, which is not conducive to industrialized large-scale production
3. Reduction of NaBH used 3 CN is a highly toxic drug that pollutes the environment
Compared with other technologies, this process has easy-to-obtain raw materials, simple operation, and mild reaction conditions. It is a preferable synthetic method, but there are still some defects in the existing process, such as: many reaction steps, polluting the environment

Method used

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  • Method for preparing cinacalcet hydrochloride
  • Method for preparing cinacalcet hydrochloride
  • Method for preparing cinacalcet hydrochloride

Examples

Experimental program
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Effect test

Embodiment 1

[0041] The synthesis of embodiment 1 cinacalcet hydrochloride:

[0042] Add 50g (0.231mol) of 3-(trifluoromethyl)cinnamic acid, 250mL of methanol, 30g (0.095mol) of bismuth trichloride, and 29g (0.767mol) of sodium borohydride into the reaction flask, and stir at 20-35°C React for 24 hours, take a sample for thin-layer chromatography analysis, after the reaction is complete, add dichloromethane and wash with a large amount of water, dichloromethane is concentrated and dried to obtain 48g of oily 3-(3-trifluoromethylphenyl)-propionic acid, which is directly used in the following step.

[0043] Add 50g (0.229mol) of 3-(3-trifluoromethylphenyl)-propionic acid, 250mL of dichloromethane and 40g of carbonyldiimidazole into the reaction flask, and add R-1-naphthyl ethyl Amine 29.43g (0.172mol) dichloromethane 250mL solution, after adding 20~35 ℃ stirring reaction for 5 hours, add 250mL water, separate the water layer, wash the organic layer twice with 250mL water, concentrate and dr...

Embodiment 2

[0046] When 3-(trifluoromethyl)cinnamic acid is reduced by sodium borohydride to prepare 3-(3-trifluoromethylphenyl)-propionic acid, 3-(trifluoromethyl)cinnamic acid and bismuth trichloride The molar ratio of sodium borohydride and sodium borohydride is 1.00:0.41~0.50:3.32~4.00 (eg 1.00:0.44:3.40, 1.00:0.45:3.45, 1.00:0.48:3.60), and the temperature is 25~30°C; 3-( When the condensation reaction of 3-(3-trifluoromethylphenyl)-propionic acid and R-1-naphthylethylamine occurs, the moles of 3-(3-trifluoromethylphenyl)-propionic acid and R-1-naphthylethylamine The ratio is 1.00:0.75~1.00 (for example 1.00:0.80, 1.00:0.85, 1.00:0.90, 1.00:1.00), the temperature is 25~30℃; the compound The compound The molar ratio to sodium borohydride is 1.00:4.00~4.92 (for example: 1.00:4.00, 1.00:4.20, 1.00:4.50, 1.00:4.80), and the reaction temperature is 65°C; Sodium oxide adjusts the pH to 6-10. All the other are with embodiment 1.

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Abstract

The invention discloses a preparation method of cinacalcet hydrochloride as Formula (I) shown. The preparation method comprises the following steps: 3-(trifluoromethyl) cinnamic acid as shown in Formula (I) serving as a raw material has reduction reaction with sodium borohydride under the catalysis of bismuth trichloride so as to obtain 3-(3-trifluoromethyl benzene)-propionic acid as shown in Formula (III); 3-(3-trifluoromethyl benzene)-propionic acid directly has condensation reaction with R-1-naphthylethylamine (compound V) to obtain a compound (VI); and the compound (VI) has reduction reaction with sodium borohydride in the presence of tetrahydrofuran solution of iodine so as to obtain a hydrochloride used for preparing cinacalcet hydrochloride. Compared with conventional technique, the method disclosed by the invention is safe, environment-friendly, convenient to operate, low in cost, and high in yield of the product, and is suitable for industrial production; and the method has high practical production value.

Description

technical field [0001] The invention relates to the technical field of a preparation method of cinacalcet hydrochloride. Background technique [0002] Cinacalcet hydrochloride, the chemical name is N-[(1R)-1-(1-naphthyl)ethyl]-3-[3-(trifluoromethyl)phenyl]-1-propanamine hydrochloride, It is the first FDA-approved calcimimetic drug, which has been marketed in the United States and Europe. It is clinically used to treat secondary hyperparathyroidism in patients with chronic kidney disease on dialysis, and to reduce the increase in the blood of patients with parathyroid cancer. blood calcium levels. A number of large-scale randomized double-blind studies have confirmed that this product has definite curative effect on secondary hyperparathyroidism (SHTP) patients with chronic kidney disease receiving dialysis, and has good safety, tolerance and convenient administration. Good utilization and so on. There are many methods for preparing cinacalcet hydrochloride reported in the...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C211/30C07C209/28
Inventor 杜焕达
Owner HANGZHOU XINBOSI BIOMEDICAL CO LTD
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