Preparation method of 3-(2,2,2-trimethylhydrazine)propionate dihydrate

A technology of trimethylhydrazine and dihydration, applied in the field of preparation of dihydrate 3-propionate, can solve the problems of long filling process, difficult removal, low efficiency, etc., and achieve the effect of less dosage and high purity

Inactive Publication Date: 2013-08-14
SHAOXING UNIVERSITY
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  • 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 with carbon dioxide or sulfur dioxide and other acid 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

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  • Preparation method of 3-(2,2,2-trimethylhydrazine)propionate dihydrate
  • Preparation method of 3-(2,2,2-trimethylhydrazine)propionate dihydrate
  • Preparation method of 3-(2,2,2-trimethylhydrazine)propionate dihydrate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0029] Add 128 g (1 mol) of tert-butyl acrylate into a three-necked flask with mechanical stirring and dropping funnel, cool to 0°C, add 63 g (1.05 mol) of unsymmetrical dimethylhydrazine dropwise, drop it in 1.5 hours, and continue at the same temperature After stirring for 1 hour, 171.1 g of tert-butyl 3-(2,2-dimethylhydrazine)propionate was distilled under reduced pressure, with a yield of 91% and a content of 98.8%;

[0030] Dissolve the above distillation product in 200ml of ethanol, cool to 0°C, pass through 90.8g of methyl chloride 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) tert-butyl propionate chloride 234.3g, yield 91.0%, content 99.1%;

[0031] Dissolve the above-mentioned tert-butyl ester chloride in 100ml of water, add 10ml of 50% hydrochloric acid, heat and reflux for 2 hours, remove water and acid under reduced pressure, add 300ml of chloroform to the residue, ...

Embodiment 2

[0033] Add 128 g (1 mol) of tert-butyl acrylate into a three-necked flask with mechanical stirring and dropping funnel, cool to 0°C, add 66 g (1.1 mol) of unsymmetrical dimethylhydrazine dropwise for 1.5 hours, and continue at the same temperature After stirring for 1 hour, 172 g of tert-butyl 3-(2,2-dimethylhydrazine) propionate was distilled under reduced pressure, with a yield of 91.5% and a content of 98.7%;

[0034] Dissolve the above distillation product in 200ml of ethanol, cool to 0°C, pass through 96g of methyl bromide 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-trimethyl hydrazine) tert-butyl propionate bromide 236.3g, yield 91.3%, content 99.1%;

[0035] Dissolve the above-mentioned tert-butyl ester bromide in 100ml of water, add 10ml of 50% hydrobromic acid, heat to reflux for 3 hours, remove water and acid under reduced pressure, add 300ml of ethyl acetate to the residue, and adjust w...

Embodiment 3

[0037] The preparation of 3-(2,2-dimethylhydrazine) tert-butyl propionate is the same as in Example 1, except for step 2 and step 3;

[0038] Dissolve the above distillation product in 200ml of ethanol, cool to 10°C, pass through 135.7g of iodomethane 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) tert-butyl propionate iodide 275.7g, yield 91.8%, content 99.0%;

[0039] Dissolve the above-mentioned tert-butyl ester iodide in 100ml of water, add 10ml of 50% hydroiodic acid, heat to reflux for 3 hours, remove water and acid under reduced pressure, add 300ml of dichloromethane to the residue, adjust the pH to 7-8 with trimethylamine, Stir for 10 minutes, filter, wash twice with dichloromethane, and recrystallize the solid with 95% ethanol to obtain 108.2 g of the target product, with a yield of 88.7% and a content of 99.6%.

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Abstract

The invention discloses a preparation method of 3-(2,2,2-trimethylhydrazine)propionate dihydrate, belonging to the technical field of chemical synthesis. The method comprises the following steps: adding tert-butyl acrylate into a three-neck flask with a mechanical stirring and dropping funnel, dropwisely adding excessive 5-50% unsymmetrical dimethylhydrazine, and distilling out 3-(2,2-dimethylhydrazine)tert-butyl propionate while depressurizing; dissolving the distillation product in ethanol, introducing or dropwisely adding excessive 5-30% methylation reagent, and washing with cold ethanol to obtain 3-(2,2,2-trimethylhydrazine)tert-butyl propionate; dissolving the 3-(2,2,2-trimethylhydrazine)tert-butyl propionate in water, adding a small amount of acid, and heating under reflux for 1-3 hours; depressurizing to remove water and acid; and adding solvent and organic amines into the remainder, filtering, and recrystallizing the solid with 95% ethanol to obtain the target product. The invention converts the alkaline hydrolysis in the prior art into acidic hydrolysis and consumes less acid, and the acid can be removed by depressurized distillation; and the neutralization only needs a small amount of alkali, and the salt generated after neutralization can be dissolved in the solvent so as to be removed, so that the purity of the obtained product is high.

Description

Technical field: [0001] The invention relates to a preparation method of 3-(2,2,2-trimethylhydrazine) propionate dihydrate, 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 ...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07C243/40C07C241/02
Inventor 姚献东胡六江梁洪祥李虎刘健
Owner SHAOXING UNIVERSITY
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