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An improved method for the preparation of 3-(2,2,2-trimethylhydrazine) propionate dihydrate

A technology of trimethylhydrazine and dihydrate, which is applied in the preparation of hydrazine, organic chemistry and other directions, can solve the problems of difficulty in meeting the standards of raw materials, many types of residual impurities, and reduced product yield, etc., and achieves commercial large-scale production. , The equipment is simple and easy to operate, and the effect of acidification time and process is improved

Active Publication Date: 2022-05-13
DONGLI NANTONG CHEM +1
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

This method first destroys the target product, and then obtains it through re-decomposition conversion. However, the separation of inorganic salts many times leads to a considerable number of residual impurities contained in the raw material drug, which is difficult to meet the standard of the raw material drug, and directly reduces the yield of the product. , the production cost is too high, these cannot be realized in actual industrial production
Another disadvantage of using phosphoric acid and ammonium phosphate salts is that they react with different concentrations of KOH to generate differently substituted potassium phosphate salts, which are difficult to remove and complicate the process. Therefore, this method is more suitable for the production of meldonium phosphate instead of Meldonium Dihydrate Method
To sum up, acidification using other suitable inorganic compounds has not been successfully realized so far, so many difficulties have been brought about in industrial production.

Method used

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  • An improved method for the preparation of 3-(2,2,2-trimethylhydrazine) propionate dihydrate

Examples

Experimental program
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Effect test

Embodiment 1

[0017] Take 67g of potassium hydroxide (90%) and add it into 470ml of ethanol to dissolve it. When the temperature drops to 18-20°C, add 121g of 3-(2,2,2-trimethylhydrazine) methyl propionate bromide. Temperature control 18-20 Hydrolyze at ℃ (use TLC to detect whether the reaction is terminated), filter the precipitate when the temperature drops to 2 to 4 ℃, remove the inorganic precipitate, wash with 2*20ml ethanol, add a certain amount of NaOC after the washing liquid and the mother liquor are combined 2 h 5 Aqueous solution repassed CO 2 Acidify the gas to a pH of 8.2-8.5 (tested by a pH meter), filter off the formed precipitate, wash with 2*20ml ethanol, and combine the washing liquid. After inspection, the mother liquor still has a small amount of double salt milky, so add a certain amount to the mother liquor NaOC 2 h 5 The aqueous solution was stirred and left for about 15 minutes, and the milky state became clear to produce granular precipitates, and then the remain...

Embodiment 2

[0019]Take 67g of potassium hydroxide (90%) and add it into 470ml of ethanol to dissolve it. When the temperature drops to 18-20°C, add 145g of 3-(2,2,2-trimethylhydrazine) methyl propionate sulfate. Temperature control 18-20 Hydrolyze at ℃ (use TLC to detect whether the reaction is terminated), filter the precipitate when the temperature drops to 2 to 4°C, remove the inorganic precipitate, wash with 2*20ml ethanol, combine the washing liquid and the mother liquor and pass through SO 2 Acidify the gas to PH of 8.2-8.5 (PH acidity meter test), filter off the formed precipitate, wash with 2*20ml ethanol, combine the mother liquor of the washing liquid (the clear solution cannot be obtained by milk filtration method), and add a certain amount of CaCl 2 The aqueous solution was stirred and left to stand for about 15 minutes, and the milky state became clear to produce granular precipitates, and then the remaining inorganic salts were filtered out, and the obtained clear solution w...

Embodiment 3

[0021] Take 67g of potassium hydroxide (90%) and add it into 470ml of ethanol to dissolve it. When the temperature drops to 18-20°C, add 145g of 3-(2,2,2-trimethylhydrazine) methyl propionate sulfate. Temperature control 18-20 Hydrolyze at ℃ (use TLC to detect whether the reaction is terminated), filter the precipitate when the temperature drops to 2 to 4°C, remove the inorganic precipitate, wash with 2*20ml ethanol, combine the washing liquid and the mother liquor and pass through SO 2 The gas is acidified to a pH of 8.2-8.5 (tested by a pH meter), and the formed precipitate is filtered off, washed with 2*20ml of ethanol, combined with the mother liquor of the wash (milk filtration method cannot obtain a clear solution), and finally purified by electrodialysis. Concentrate under reduced pressure, cool and crystallize, dry to obtain 88g, 3-(2,2,2-trimethylhydrazine) propionate dihydrate crude drug raw material about 97%, recrystallize with isopropanol or ethanol, melting point ...

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Abstract

A kind of preparation technology improvement method of 3-(2,2,2-trimethylhydrazine) propionate dihydrate, it is a kind of medicine for cardiovascular disease, it is made from intermediate 3-(2, 2,2-trimethylhydrazine) methyl propionate salt (CH 3 ) 3 N + NHCH 2 CH 2 COOCH 3 x ‑ (wherein, X represents Cl ‑ 、Br ‑ , I ‑ 、CH 3 SO 4 ‑ ) products after alkaline hydrolysis and acidification, because the acidification purification process adopted after this hydrolysis is more complicated, and there is no better process solution so far. A method of adding a mixed solution for acidification before and after acidification does not form a complex (emulsion) or double salt of 3-(2,2,2-trimethylhydrazine) propionate dihydrate, avoiding electrodialysis separation and purification step. In addition, the addition of another new type of acid agent was invented to obtain high-purity products in one step, realizing commercial-scale production, reducing costs, and simple equipment.

Description

technical field [0001] The present invention relates to organic chemistry and medicine The present invention relates to the field of organic chemistry and medicine research, specifically a kind of improved 3-(2,2,2-trimethylhydrazine) propionate dihydrate "meldonium dihydrate The preparation method technology and purification technology of "substance" API. Background technique [0002] 3-(2,2,2-Trimethylhydrazine) propionate dihydrate with the International Nonproprietary Name Meldonium is known for its cardioprotective effects. Typically the methods include: [0003] 1,1-Dimethylhydrazine reacts with methyl acrylate to form 3-(2,2-dimethylhydrazino)propionic acid methyl ester, further generates the appropriate 3-(2, 2,2-trimethylhydrazine) methyl propionate halide or methyl sulfate, then hydrolyze and deionize it, and separate it with a saturated solution of carbon dioxide or sulfur dioxide. This method is disclosed in WO2008028514 patent, although this method can avoid ...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07C243/40C07C241/02
CPCC07C241/02C07C243/40
Inventor 阿依别克·马力克衣伟男周建阿拉法特·阿依别克乌拉阔夫·巴洛特
Owner DONGLI NANTONG CHEM
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