Preparation method of crystal form I of clopidogrel hydrogen sulfate

A technology of clopidogrel hydrogen sulfate and clopidogrel free base, which is applied in the field of preparation of clopidogrel hydrogen sulfate crystal form I, can solve the problems of high production cost, simple and reliable process, and low solvent recovery rate, and achieve The effect of small health hazards to personnel, simple and easy process, and high solvent recovery rate

Active Publication Date: 2013-02-13
ZHEJIANG HISOAR PHARMA
View PDF8 Cites 10 Cited by
  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The disadvantages of the process using a mixed solvent system are that the operation is complicated, the cost of solvent recovery is high, and it is not conducive to industrial production, and the process using a single solvent also has different defects.
The yield of this method is only 73~80%, and the production cost is higher
Tetrahydrofuran has a low boiling point, low solvent recovery rate, large waste ga

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 crystal form I of clopidogrel hydrogen sulfate
  • Preparation method of crystal form I of clopidogrel hydrogen sulfate
  • Preparation method of crystal form I of clopidogrel hydrogen sulfate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0057] Add 32.1g (0.10 mol) of clopidogrel free base and 214g of 2-methyltetrahydrofuran into a 1000mL four-neck flask, stir and dissolve at room temperature, cool the system to -10°C, add 9.5g of 98% concentrated sulfuric acid (0.095 mol) dropwise, and then The system was heated up to 10°C, kept stirring and crystallized for 20 hours, filtered under nitrogen pressure, and the filter cake was vacuum-dried at room temperature for 3 hours, then heated to 45°C and vacuum-dried for 10 hours to obtain 39.3g of clopidogrel bisulfate crystal form I , the molar yield is 93.8%, the HPLC content is 99.6%, and the HPLC content of all single heterogeneous compounds is less than 0.1%.

Embodiment 2

[0059] Add 32.1g (0.10 mol) of clopidogrel free base and 270g of 2-methyltetrahydrofuran into a 500mL four-neck flask, stir and dissolve, control the temperature of the system at -5°C, add 9.8g of 98% concentrated sulfuric acid (0.098 mol) dropwise, and the addition is complete Afterwards, the system was heated up to 20°C, kept stirring and crystallized for 12 hours, filtered under nitrogen pressure, washed the filter cake with 100mL 2-methyltetrahydrofuran, filtered under nitrogen pressure, and dried under vacuum at 40°C for 10 hours to obtain 39.9g of clopidogrel sulfate Hydrogen salt crystal form I, molar yield 95.0%, HPLC content 99.8%, all single hetero HPLC content less than 0.1%.

Embodiment 3

[0061] Add 32.1g (0.10mol) of clopidogrel free base and 321g of 2-methyltetrahydrofuran into a 500mL four-neck flask, stir and dissolve, control the temperature of the system at 0°C, add 9.8g of 98% concentrated sulfuric acid (0.098mol) dropwise, after the addition is complete The system was heated up to 25°C, kept stirring and crystallized for 10 hours, filtered under nitrogen pressure, and the filter cake was vacuum-dried at 40°C for 10 hours to obtain 40.6g of clopidogrel bisulfate crystal form I, with a molar yield of 96.7% and an HPLC content of 99.8 %, all simple HPLC content is less than 0.1%.

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 a crystal form I of clopidogrel hydrogen sulfate. The preparation method comprises the following steps of (1) dropwise adding concentrated sulfuric acid or 2-methyltetrahydrofuran solution of the concentrated sulfuric acid into 2-methyltetrahydrofuran solution of clopidogrel free base to obtain mixed solution, wherein the temperature of the mixed solution is controlled to range from -10 DEG C to 5 DEG C when the dropwise adding is performed; and (2) heating the mixed solution to the temperature of 10-35 DEG C, performing crystal precipitation with stirring, separating precipitated crystals, and drying the precipitated crystals to obtain the crystal form I of the clopidogrel hydrogen sulfate. The preparation method is simple, easy to implement, good in reproducibility and suitable for industrial production. The prepared crystal form I of the clopidogrel hydrogen sulfate has the advantages of being high in crystal form purity and high-performance liquid chromatography (HPLC) purity, low in cost, good in stability, high in solvent recovery, environment-friendly and the like.

Description

technical field [0001] The invention relates to the technical field of medicinal chemical crystallization, in particular to a preparation method of clopidogrel bisulfate crystal form I. Background technique [0002] Clopidogrel bisulfate is a platelet aggregation inhibitor developed by Sanofi, France. It is clinically used to prevent and treat heart, brain and other arterial circulation disorders caused by high platelet aggregation. It is suitable for patients with recent stroke, myocardial infarction and confirmed peripheral arterial disease, and can reduce the occurrence of atherosclerotic events. Compared with other antiplatelet drugs, clopidogrel bisulfate has the advantages of strong curative effect, good safety, and good tolerance, and has been ranked among the best-selling drugs in the world for many years. [0003] The molecular structure of clopidogrel bisulfate is as follows: [0004] [0005] EP0281459A is the first to describe clopidogrel hydrogen sulfate an...

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): C07D495/04
Inventor 唐方辉李洪明孙常磊许会凌张群辉
Owner ZHEJIANG HISOAR PHARMA
Who we serve
  • R&D Engineer
  • R&D Manager
  • IP Professional
Why Eureka
  • Industry Leading Data Capabilities
  • Powerful AI technology
  • Patent DNA Extraction
Social media
Try Eureka
PatSnap group products

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

© 2024 PatSnap. All rights reserved.Legal|Privacy policy|Modern Slavery Act Transparency Statement|Sitemap