Looking for breakthrough ideas for innovation challenges? Try Patsnap Eureka!

Preparation method of high-purity nitrendipine

A technology for purity of nitren and dipine, which is applied in the field of preparation of high-purity nitrendipine, can solve problems such as non-conformance, difficult to control impurity content, and increased impurity content, and achieves the effect of solving the continuous increase

Inactive Publication Date: 2019-12-10
SHANDONG XINHUA PHARMA CO LTD
View PDF0 Cites 3 Cited by
  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0003] "Synthesis of Nitrendipine", Liu Xiaoping, Natural Science Journal of XiangtanUniversity, the preparation method provided by Jun.1998, 3-nitrobenzylidene ethyl acetoacetate (II), 3-aminocrotonate methyl ester (III) , and solvent reflux reaction, as the reaction proceeds, the impurity content continues to increase, the impurity content is difficult to control, the impurity B content is 0.5-1.0%, and does not meet the requirements of the European Pharmacopoeia (EP8.0 standard: impurity B≤0.4%)

Method used

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
View more

Image

Smart Image Click on the blue labels to locate them in the text.
Viewing Examples
Smart Image
  • Preparation method of high-purity nitrendipine
  • Preparation method of high-purity nitrendipine

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0032] Add 2.63g (10mmol) of ethyl 3-nitrobenzylidene acetoacetate, 1.15g (10.0mmol) of methyl 3-aminocrotonate, and 2ml of methanol, and heat up to 40°C for 10min. Evaporate the solvent under reduced pressure, and control the heating rate of 0.5°C / min to raise the temperature. When the temperature rises to 90°C, the reaction solution solidifies; react at 90°C for 10 minutes, and immediately lower the temperature; the yellow solid in the reaction bottle is the crude product of nitrendipine, with a weight of 3.61g. 98.41%, yield 98.68%; add 8ml of ethanol, heat up to dissolve, cool down to crystallize, filter at room temperature, 3.05g of nitrendipine fine product, total yield 84.72%, HPLC content 99.71%, impurity B0.18%, impurity A0. 042%, impurity C0.031%.

Embodiment 2

[0034] Add 2.63g (10mmol) ethyl 3-nitrobenzylidene acetoacetate, 1.27g (11.0mmol) methyl 3-aminocrotonate, 8ml ethanol, raise the temperature to 60°C and react for 120min; evaporate the solvent under reduced pressure, and control the temperature rise The temperature was raised at a speed of 2°C / min, and the reaction liquid solidified when the temperature was raised to 110°C; the reaction was carried out at 110°C for 60 minutes, and the temperature was immediately lowered. The yellow solid in the reaction bottle is the crude product of nitrendipine, with a weight of 3.65g, a content of 98.33%, and a yield of 99.69%; 40ml of isopropanol is added, dissolved by heating, cooled to crystallize, and filtered at room temperature to obtain 3.03g of the refined product of nitrendipine. The total yield is 84.16%, the HPLC content is 99.70%, the impurity B is 0.19%, the impurity A is 0.045%, and the impurity C is 0.028%.

Embodiment 3

[0036] Add 2.63g (10mmol) ethyl 3-nitrobenzylidene acetoacetate, 1.21g (10.5mmol) methyl 3-aminocrotonate, 5ml acetonitrile, heat up to 50°C and react for 60min; evaporate the solvent under reduced pressure, and control the temperature rise Heat up at a rate of 1°C / min, and the reaction solution solidifies when the temperature rises to 100°C; react at 100°C for 40 minutes, and immediately cool down; the yellow solid in the reaction bottle is the crude product of nitrendipine, with a weight of 3.58g, a content of 98.49%, and a yield of 97.93%; Add 24ml of acetonitrile, heat up to dissolve, cool down to crystallize, filter at room temperature, and get 3.08g of Nitrendipine fine product, the total yield is 85.55%, the HPLC content is 99.74%, the impurity B is 0.16%, the impurity A is 0.049%, and the impurity C is 0.033%. .

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
Login to View More

PUM

No PUM Login to View More

Abstract

The invention provides a preparation method of high-purity nitrendipine. The preparation method is characterized by comprising the following steps that (1) ethyl 2-(m-nitrobenzylidene)-acetoacetate, methyl 3-aminocrotonate and a solvent are added into a reaction flask, and temperature increasing for a reaction is conducted; (2) the solvent is evaporated to dryness in a pressure reduction mode, andgradual temperature increasing for a reaction is conducted till reaction liquid is solidified; (3) after the reaction liquid is solidified, the temperature and the reaction time are controlled, and thus a nitrendipine crude product is obtained; and (4) a solvent is added for backflow, the temperature is decreased to be the room temperature, and staying overnight, filtering, washing and drying areconducted to obtain a nitrendipine refined product. According to the preparation method, the reactions are conducted in segments, the problem that impurities are continuously increased along with thereactions is solved, all the impurities contained in the nitrendipine meet pharmacopoeia standard requirements, and the impurity level is significantly lower than that of other factories in China.

Description

technical field [0001] The invention belongs to the technical field of medicinal chemistry, and in particular relates to a preparation method of high-purity nitrendipine. Background technique [0002] Nitrendipine is the second-generation calcium ion antagonist developed by Bayer Company in Germany. It was launched in 1985 and has significant and lasting antihypertensive and vasoconstrictive effects. It is an ideal drug for treating hypertension. [0003] "Synthesis of Nitrendipine", Liu Xiaoping, Natural Science Journal of XiangtanUniversity, the preparation method provided by Jun.1998, 3-nitrobenzylidene ethyl acetoacetate (II), 3-aminocrotonate methyl ester (III) , and solvent reflux reaction, along with the carrying out of reaction, impurity content constantly raises, and impurity content is difficult to control, and impurity B content 0.5~1.0%, does not meet European Pharmacopoeia requirement (EP8.0 standard: ask impurity B≤0.4%). Contents of the invention [0004] I...

Claims

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
Login to View More

Application Information

Patent Timeline
no application Login to View More
IPC IPC(8): C07D211/90
CPCC07D211/90
Inventor 翟吉胜赵春燕
Owner SHANDONG XINHUA PHARMA CO LTD
Who we serve
  • R&D Engineer
  • R&D Manager
  • IP Professional
Why Patsnap Eureka
  • Industry Leading Data Capabilities
  • Powerful AI technology
  • Patent DNA Extraction
Social media
Patsnap Eureka Blog
Learn More
PatSnap group products

Browse by: Latest US Patents, China's latest patents, Technical Efficacy Thesaurus, Application Domain, Technology Topic, Popular Technical Reports.

© 2024 PatSnap. All rights reserved.Legal|Privacy policy|Modern Slavery Act Transparency Statement|Sitemap|About US| Contact US: help@patsnap.com