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Preparation method of Mildronate intermediate

The technology of an intermediate, Meldonium, is applied in the field of preparation of Meldonium intermediate, that is, 3-methyl propionate salt, which can solve the problems of flammability, high volatility, and potential safety hazards, and reduce energy consumption and reduce Effects of investment in equipment and improvement in safety

Inactive Publication Date: 2010-12-22
SHAOXING UNIVERSITY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0006] The main problem of this process is that unsymmetrical dimethylhydrazine is expensive; its boiling point is low (63°C), its volatility is high, it is flammable, explosive, highly toxic and has strong carcinogenicity, so in the use of products, there are serious safety hazards

Method used

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  • Preparation method of Mildronate intermediate
  • Preparation method of Mildronate intermediate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0032] In the there-necked flask with mechanical stirring and dropping funnel, add methyl acrylate 86g (1mol), 95% ethanol 60ml, control temperature at 20-30 ℃, add dropwise the hydrazine hydrate of 80% 68.8g (1.1mol), After 1.5 hours of dripping, continue to stir at the same temperature for 1 hour, first distill ethanol under normal pressure, and then distill 93.8 g of methyl 3-hydrazinopropionate under reduced pressure, with a yield of 79.5% and a content of 98.8% (GC);

[0033] Dissolve the above distillation product in 150ml of ethanol, control the temperature at 20-30°C, pass in 237.9g ​​of methyl bromide, and at the same time pass in ammonia gas as an acid-binding agent for 1 hour, continue stirring at the same temperature for 1 hour, filter, and wash with cold ethanol , and dried to obtain 174.3 g of methyl 3-(2,2,2-trimethylhydrazine)propionate bromide, with a yield of 91.0% and a content of 99.1% (HPLC).

Embodiment 2

[0035] Add 86g (1mol) of methyl acrylate and 60ml of methanol in a three-necked flask with mechanical stirring and dropping funnel, control the temperature at 30-40°C, add 80% of 65.6g (1.05mol) of hydrazine hydrate dropwise, time 1 After hours of dripping, continue to stir at the same temperature for 1 hour, first distill methanol at normal pressure, and then distill 92.5 g of methyl 3-hydrazinopropionate under reduced pressure, with a yield of 78.4% and a content of 99.0% (GC);

[0036] Dissolve the above-mentioned distillation product in 150ml of ethanol, control the temperature at 30-40°C, pass in 245.8g of methyl bromide, and at the same time pass in ammonia gas as an acid-binding agent for 1.5 hours, continue to stir at the same temperature for 1.5 hours, filter, and wash with cold ethanol , and dried to obtain 172.5 g of methyl 3-(2,2,2-trimethylhydrazine) propionate bromide, with a yield of 91.3% and a content of 99.1% (HPLC).

Embodiment 3

[0038] In the there-necked flask with mechanical stirring and dropping funnel, add methyl acrylate 86g (1mol), isopropanol 60ml, control the temperature at 40-50°C, add dropwise 80% of 68.8g (1.1mol) of hydrazine hydrate, After 2 hours of dripping, continue to stir at the same temperature for 2 hours, first distill isopropanol under normal pressure, and then distill 93.2g of methyl 3-hydrazinopropionate under reduced pressure, with a yield of 79.0% and a content of 98.7% (GC) ;

[0039] Dissolve the above-mentioned distillation product in 150ml of ethanol, control the temperature at 40-50°C, add 313.6g of dimethyl sulfate dropwise, and at the same time pass through ammonia gas as an acid-binding agent for 3 hours, continue to stir at the same temperature for 1 hour, filter, and use Wash with cold 50% ethanol and dry to obtain 181.8 g of methyl sulfate of methyl 3-(2,2,2-trimethylhydrazine)propionate, with a yield of 84.6% and a content of 98.5% (HPLC).

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Abstract

The invention discloses a preparation method of a Mildronate intermediate, namely a preparation method of 3-(2,2,2-Trimethylhydrazine)methyl propionate, belonging to the technical field of chemical synthesis and comprising the following steps: 1, adding methyl acrylate and an alcohol solvent in a three-neck flask with mechanical agitation and a dropping funnel, and controlling the temperature at 0-50 DEG C; dropwise adding excessive hydrazine hydrate with a mole ratio of 5-50% for 1-3h; continuously stirring for 1-3h at the same temperature; evaporating the solvent at normal pressure, and evaporating 3-hydrazine methyl propionate by reduced pressure distillation; and 2, dissolving a distillation product in the step 2 by ethanol, controlling the temperature at 0-50 DEG C, introducing or dropwise adding an excessive methylating agent with the mole ratio of 5-30%, simultaneously introducing an acid catcher for 0.5-3h, continuously stirring for 0.5-2h at the same temperature, filtering, washing by ethanol and drying to obtain the product. The invention adopts the hydrazine hydrate as a starting material, thus having low cost, high safety and good environmental conservation.

Description

Technical field: [0001] The invention relates to a method for preparing a meldonium intermediate, that is, methyl 3-(2,2,2-trimethylhydrazine) propionate, and belongs to the technical field of chemical synthesis. Background technique: [0002] Meldonium is a new cardioprotective drug. The chemical name is 3-(2,2,2-trimethylhydrazine) propionate dihydrate, which is a structural analogue of carnitine, which can competitively inhibit butyrate betaine hydroxylase, thereby inhibiting the activity of carnitine Biosynthesis, direct inhibition of carnitine-dependent transport of fatty acids in mitochondria. Inhibition of carnitine biosynthesis reduces the intracellular concentration of free carnitine and prevents isoproterenol-induced accumulation of acylcarnitines. 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 cereb...

Claims

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Application Information

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IPC IPC(8): C07C243/40C07C241/02
Inventor 姚献东胡六江董华平胡仁国刘健
Owner SHAOXING UNIVERSITY
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