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

Preparation method of mildronate

A technology of meldonium and methylation, which is applied in the field of preparation of meldonium, can solve the problems of unsuitability for industrial production, difficulty in removal, difficulty in product quality meeting the requirements of raw materials, etc., and avoid inorganic bases and anion exchange resins. , the effect of high purity

Inactive Publication Date: 2011-02-16
SHAOXING UNIVERSITY
View PDF6 Cites 3 Cited by
  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Alkaline hydrolysis will bring a large amount of alkali metal ions, which is difficult to remove and the quality of the product is difficult to meet the requirements of raw materials
The method disclosed in WO2008028514A1 uses a molar ratio of more than twice the inorganic strong base for hydrolysis, and then neutralizes it with carbon dioxide or sulfur dioxide and other acidic gases. Although most of the alkali metal ions can be removed, the gas charging process is long and produces a large amount of inorganic salts. Low production efficiency
The method disclosed in US4481218 adopts anion exchange resin to carry out hydrolysis, and the amount of solvent is large, and the same efficiency is low, so it is not suitable for industrial production

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 mildronate
  • Preparation method of mildronate
  • Preparation method of mildronate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0026] Add 162g (1mol) of benzyl acrylate into a three-necked flask with mechanical stirring and dropping funnel, cool to 10°C, add 63g (1.05mol) of unsymmetrical dimethylhydrazine dropwise, and continue to stir at the same temperature after 2 hours. After 2 hours, 199.4 g of benzyl 3-(2,2-dimethylhydrazine)propionate was distilled under reduced pressure, with a yield of 89.8% and a content of 98.3%;

[0027] Dissolve the above distilled product in 200ml of ethanol, cool to 10°C, pass through 90.4g of methyl bromide within 1 hour, continue to stir at the same temperature for 1 hour, filter, wash with cold ethanol, and dry to obtain 3-(2,2,2-trimethyl hydrazine) benzyl propionate bromide 256.5g, yield 90.1%, content 98.5%;

[0028] Dissolve the above benzyl ester bromide in 150ml of water, add 5g of 5% Pd / C, heat to 50°C, feed hydrogen and keep the pressure at 0.3MPa, react for 2 hours, filter the catalyst, remove the solvent water under reduced pressure, and the residue Add 3...

Embodiment 2

[0030] The preparation of 3-(2,2,2-trimethylhydrazine) benzyl propionate bromide is the same as in Example 1;

[0031] Dissolve the above-mentioned benzyl ester bromide in 150ml of water, add 10g of Raney-Ni, heat to 60°C, pass in hydrogen and keep the pressure at 0.5MPa, react for 3 hours, filter the catalyst, remove the solvent water under reduced pressure, add ethyl acetate to the residue 300ml of ester, adjust the pH to 7-8 with triethylamine, stir for 10 minutes, filter, wash twice with ethyl acetate, and recrystallize the solid with 95% ethanol to obtain 106.6g of the target product, with a yield of 90.3% and a content of 99.6% .

Embodiment 3

[0033] The preparation of 3-(2,2-dimethylhydrazine) benzyl propionate is with embodiment 1;

[0034] Dissolve the above distillation product in 200ml of ethanol, cool to 10°C, add 134.5g of iodomethane dropwise for 1 hour, continue stirring at the same temperature for 1 hour, filter, wash with cold ethanol, and dry to obtain 3-(2,2,2- Trimethylhydrazine) benzyl propionate iodide 300.7g, yield 92%, content 99.1%;

[0035] Dissolve the above-mentioned benzyl ester iodide in 150ml of water, add 5g of 5% Pt / C, feed hydrogen at room temperature and keep the pressure at 0.2MPa, react for 2 hours, filter the catalyst, remove the solvent water under reduced pressure, and add dichloromethane to the residue 300ml, adjusted the pH to 7-8 with triethylamine, stirred for 10 minutes, filtered, washed twice with dichloromethane, and the solid was recrystallized with 95% ethanol to obtain 109.1g of the target product with a yield of 90.5% and a content of 99.5%.

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 discloses a preparation method of mildronate, belonging to the technical field of chemical synthesis. The preparation method is characterized by comprising the following steps: adding benzyl acrylate in a flask, cooling to 0-20 DEG C; dropping excessive 5-50% of unsymmetrical dimethyl hydrazine, performing reduced pressure distillation to obtain 3-(2,2-dimethylhydrazine)benzylpropionate; dissolving the product of distillation with ethanol; passing through or dropping excessive 5-30% of methylating agent, washing with cold ethanol to obtain 3-(2,2,2-trimethylhydrazine)benzylpropionate; dissolving the benzyl ester salt in water, pouring the solution in an autoclave, adding hydrogenation catalyst to stand for 2-5 hours; filtering the catalyst, reducing pressure to remove the solvent water; adding solvent and organic amine in the residue, filtering, and recrystallizing the solid with 95% ethanol to obtain the target product. The preparation method of the invention adopt the hydrogenolysis to replace the alkaline hydrolysis in the prior art so that alkali is not needed to use and the method does not have residual metal ions; and a small amount of alkali is used for neutralization and the solvent is easy to remove after neutralization, thus the obtained product has high purity.

Description

Technical field: [0001] The invention relates to a preparation method of Meldonium, which belongs to the technical field of chemical synthesis. Background technique: [0002] Meldonium is a new type of cardioprotective drug, its chemical name is 3-(2,2,2-trimethylhydrazine) propionate dihydrate, it is a structural analogue of carnitine, and it can competitively inhibit butyrobetaine Hydroxylase, thereby inhibiting the biosynthesis of carnitine, directly inhibits the transport of carnitine-dependent fatty acids in mitochondria, reduces the concentration of free carnitine in cells, and prevents the accumulation of acylcarnitines induced by isoproterenol. Therefore, the drug has a significant protective effect on the myocardium, can promote the redistribution of blood in the heart and brain ischemic areas, and is used for the treatment of various acute and chronic cerebral blood supply disorders; it can improve the symptoms of myocardial ischemia and hypoxia, and can be used fo...

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): C07C243/40C07C241/02
Inventor 姚献东胡六江梁洪祥蒋杭平刘健
Owner SHAOXING UNIVERSITY
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