CN104163776A - An improved method for the preparation of methyl 3-(2,2,-dimethylhydrazino)propionate and methyl 3-(2,2,2-trimethylhydrazino)propionate - Google Patents

Abstract

An improved process for preparing 3- (2, 2-dimethylhydrazino) methyl propionate and 3- (2,2, 2-trimethylhydrazine) methyl propionate is a mildronate C₆H₁₄N₂O₂.2H₂The conventional method for synthesizing the intermediate is to react 1, 1-dimethylhydrazine with methyl acrylate and then react with methylation to obtain a target product, and the product obtained by the continuous reaction has poor quality and stability, so that the final production process of the mildronate bulk drug is complicated, and the synthesis cost is increased. The synthesis route of the predecessor is changed to separate two reactions, each reaction realizes the automatic control of exothermic reaction feeding under mild conditions, and the adopted first-step cooling precipitation and second-step special purification technical method ensures that the final product can not be subjected to complex processes such as recrystallization, washing and the like, not only can directly obtain a high-purity product, but also improves the stability and yield of the product, shortens the time, prolongs the quality guarantee period of the product to four years according to two years of a conventional method, and realizes commercial large-scale production.

Description

An improved method for the preparation of methyl 3-(2,2,-dimethylhydrazino)propionate and methyl 3-(2,2,2-trimethylhydrazino)propionate

technical field

The invention relates to an improved method for the preparation of methyl 3-(2,2,-dimethylhydrazino)propionate and methyl 3-(2,2,2-trimethylhydrazino)propionate, belonging to The field of chemical synthesis technology. the

Background technique

The international nonproprietary name is Meldonium, and the chemical name is 3-(2,2,2-trimethylhydrazine) propionate dihydrate, which is famous for its cardioprotective effect. the

A variety of methods are known to prepare 3-(2,2,2-trimethylhydrazine) propionate dihydrate, generally including:

1,1-Dimethylhydrazine reacts with methyl acrylate to form 3-(2,2-dimethylhydrazino)propionic acid methyl ester, further generates corresponding 3-(2, 2,2-Trimethylhydrazine) methyl propionate halide or methyl sulfate, which is then hydrolyzed and deionized, separated with a saturated solution of carbon dioxide or sulfur dioxide, and crystallized in ethanol to obtain the dihydrate internal Salt. This conventional method avoids the use of electrodialysis and has many disadvantages: strong base ion exchange resins are unstable and decomposed or oxidized during processing; strong base ion exchange resins can only withstand a limited number of regeneration cycles; resin regeneration A large amount of solvent, acid and base, and deionized water are required; and the ion exchange capacity is low, so the production cost of 3-(2,2,2-trimethylhydrazine)propionate dihydrate using this method is generally high. the

However, at the same time, it is also very important to obtain high-quality intermediates of meldonium bulk drug for the production of 3-(2,2,2-trimethylhydrazine)propionate dihydrate. Methyl 3-(2,2,2-trimethylhydrazine)propionate is one such intermediate. The conventional method for producing this intermediate is to make 1,1-dimethylhydrazine react with methyl acrylate and then react with methylating reagent halide to obtain the target product. This conventional continuous reaction method has many disadvantages: 1) The by-products and oxide impurities generated in the first step reaction are directly brought into the second step reaction. On the one hand, many by-products are also methylated by methylating reagents to form secondary, tertiary or quaternary ammonium salts, resulting in the target crude product Impurity content and kind complicate, and the color of the 3-(2,2,2-trimethylhydrazine) methyl propionate salt that finally obtains is very dark, causes certain difficulty to aftertreatment purification, increases production cost, more importantly It directly affects the yield and the quality and stability of the product, such as the current international quality standard for 3-(2,2,2-trimethylhydrazine) methyl propionate bromide: the appearance is white, light yellow or pink crystal It is a non-toxic powder with a melting point of 118-135°C, a main content of 99.5-105%, and a validity period of up to two years. 2) This continuous reaction is difficult to predict the correct reaction ratio relationship of each reactant and intermediate, so that product quality, output and production process cannot be stabilized. 3) The raw materials used in the reaction are easy to polymerize or oxidize at a certain temperature. Although the method of insulating the air with nitrogen is used to prevent the oxidation of raw materials and intermediates according to conventional methods, the reaction temperature and pressure involved can accelerate the alkylation reaction. , will still lead to the generation of a large number of by-products. 4) The patent application publication number CN102036949A invented by Daina Chicane and Maris Tilkes has publicly mentioned the method of adding antioxidants to the reactants. Although this method suppresses the production of some by-products, it has not yet Thoroughly solve the complete optimization and stability of the final product process, the added antioxidant residue has a certain impact on the raw material drug, so this method has not yet been approved by the Pharmacopoeia in industrial production. the

Invention content:

In the conventional synthesis method, 1,1-dimethylhydrazine reacts with methyl acrylate under the conditions of higher temperature and higher reaction pressure set for the reaction to generate several by-products. In addition, 1,1-dimethylhydrazine itself is easily oxidized and may form oxides 1-18, as shown in Figure 1. Some of these oxides react with methyl acrylate to form different types of by-products. For example, in the oxidation of 1,1-dimethylhydrazine, the formation of dimethylamine reacts with methyl acrylate to form the by-product 3-(dimethylamino)propionic acid methyl ester, and other oxides can also interact to form different high-boiling point compounds. A complex reaction system. Similarly, methyl acrylate polymerizes under these reaction conditions or the product 3-(2,2-dimethylhydrazino)methyl propionate is sensitive to air and slowly oxidizes to 2-(2,2-dimethyl Hydrazone) methyl acetate, etc. All in all, the by-products of the first step reaction are more complex and diverse. If we carry out the methylation reaction in this reaction system, the by-products will double, making it difficult to purify the target product of meldonium intermediate, which will directly affect the production of meldonium. The quality of hydrazine API. the

The technical problem to be solved in the present invention is to overcome the problems of the above-mentioned prior art, and to invent a kind of 3-(2,2,-dimethylhydrazino) methyl propionate and 3-(2,2,2-trimethylhydrazine) The preparation technology improvement method of methyl hydrazine) methyl propionate halide, the characteristics of this method are: take 1,1-dimethyl hydrazine and methyl acrylate as starting raw materials, adopt different synthetic routes from the predecessors, The addition reaction and the methylation reaction are carried out as two separate synthetic reaction steps, and the specific steps are as follows: 1) the first step reaction is an exothermic reaction, therefore, in order to make the reaction temperature rise steadily to better control the reaction temperature For the content of by-products, in the synthesis process, an optimal curve diagram of feed amount, temperature, pressure and reaction time is set as a standard, and the automatic control of the whole set of reactions is realized. 2) After the reaction, use a precision filter to filter and purify the cooled intermediate. 3) After passing the test, the intermediate is used as the starting material of the methylation reaction to accurately measure and feed again. 4) The methylation reaction is also an exothermic reaction. In order to make the reaction temperature rise steadily and better control the content of by-products in the reaction, an optimum method of feeding amount, temperature, pressure and reaction time is also set in the synthesis process. Graphs are used as standard, enabling automated control of the entire set of reactions. 5) A special method of purification technology is adopted, which allows the crude product after the methylation reaction to be purified directly without undergoing complicated purification processes such as recrystallization and washing after conventional filtration. The main advantage of the present invention is that 3-(2,2,-dimethylhydrazino) methyl propionate intermediate can be produced and stored in large quantities as the starting raw material for the second step reaction, which greatly reduces the time used for the whole set of reactions, More importantly, the stability and product quality of the production process are guaranteed, and it can be converted into the target product in high yield. The second advantage is that the final product does not go through complex processes such as recrystallization and washing, not only the high-purity product can be directly obtained, but also the product stability and yield are improved. The shelf life of the product is extended from two years to four years according to the conventional method. Commercial large-scale production, cost reduction, simple and easy operation of equipment and other advantages. the

The chemical reaction formula is as follows:

1) CH ₂ ＝CH-COOCH ₃ +(CH ₃ ) ₂ N-NH ₂ →(CH ₃ ) ₂ N-NH-CH ₂ -CH ₂ -COOCH ₃

side effects:

2)(CH ₃ ) ₂ N-NH-CH ₂ -CH ₂ -COOCH ₃ +CH ₃ X→(CH ₃ ) ₃ N ⁺ -NH-CH ₂ -CH ₂ -COOCH ₃

X ^-

side effects:

1. Composition: The molecular formula of the intermediate 3-(2,2,2-trimethylhydrazine) propionate methyl halide of Meldonium is: (CH ₃ ) ₃ N ⁺ NHCH ₂ CH ₂ COOCH ₃ X ^- , where X represents Cl ^- , Br ^- , I ^- , CH ₃ SO ₄ ^-- ; the molecular formula of the intermediate product 3-(2,2,-dimethylhydrazino) propionate methyl ester is: (CH ₃ ) ₂ N-NH-CH ₂ -CH ₂ -COOCH ₃ ; the methylating agent is one of methyl chloride, methyl bromide, methyl iodide, dimethyl sulfate or dimethyl carbonate.

2. Ingredients ratio:

In step 1:

The dropwise addition of methyl acrylate with an excess molar ratio of 1-50% refers to the dropwise addition of methyl acrylate to excess, and the molar ratio of excess methyl acrylate to 1,1-dimethylhydrazine is 1-50%. the

In step 2:

The methylation reagent with an excess molar ratio of 1-20% is added dropwise to an excess, and the excess methylation reagent and 3-(2,2,-dimethylhydrazino) The molar ratio of methyl propionate is 5-30%. the

The methylating agent is selected from one of halogenated alkanes, dimethyl sulfate or dimethyl carbonate; the alcohol solvent is selected from lower alcohol ethanol, methanol, ethylene glycol, propylene glycol or other alcohol compounds One of. the

3. Process:

A; The synthetic technique of 3-(2,2,-dimethylhydrazino) methyl propionate

1) Addition reaction: add 1,1-dimethylhydrazine dropwise to methyl acrylate and keep stirring;

2) Sampling and testing to determine whether the addition reaction is terminated;

3) vacuum distillation;

4) cooling precipitation;

5) precision filtration;

6) Packaging: isolated from air, always stored under nitrogen protection. the

B; Synthetic process of 3-(2,2,2-trimethylhydrazine) methyl propionate salt

1) Methylation: the alcohol solution of methyl 3-(2,2,-dimethylhydrazino)propionate is methylated by excess methylating reagent;

2) Purification

3) Suction filtration

4) Vacuum drying: crystalline white powder, vacuum drying at 20-110°C;

5) Packaging: HDPE (low-pressure high-density polyethylene) material for API packaging, two-layer bag ( 60*80cm), each layer of bags must be sealed separately, and the outer packaging is a special cardboard barrel for raw materials, sealed with wax. The net weight of each barrel is 25kg (standard). Packing Specifications: 36*40cm; transportation: according to OST64-034-87; storage: dark, dry place; after long-term stability test, the shelf life is 4 years.

Process A is: addition reaction-vacuum distillation-cooling precipitation-precision filtration-packaging. the

Process B is: methylation-purification-suction filtration-vacuum distillation-vacuum drying-packaging. the

technical effect

The technical effect of the present invention is that the 3-(2,2,-dimethylhydrazino) methyl propionate intermediate obtained by the above process is a colorless transparent liquid with a product content ≥ 98.5%; The main content of the 3-(2,2,2-trimethylhydrazine) methyl propionate halide product is controlled between 100.0-102.0%. It is a white crystalline powder, 3-(2,2,2- The melting point range of trimethylhydrazine) methyl propionate bromide is: 126-132°C, and the product is valid for 4 years. Adopting this process not only guarantees the quality of the product and improves its stability, it is a white crystalline powder, but also extends the validity period of the product from the original 2 years to 4 years, realizing commercial mass production, reducing costs, and improving the technology Simple, high yield, high-purity API intermediates can be directly obtained without complicated processes such as recrystallization and washing, and more importantly, it solves the problem of preparing Meldonium 3-(2,2,2-trimethylhydrazine) Difficult reprocessing of propionate dihydrate also reduces costs. the

Description of drawings

Figure 1 shows the oxides that may be formed by easy oxidation of 1,1-dimethylhydrazine itself. the

Detailed ways

The present invention will be described in more detail below with reference to following non-limiting examples, and first three kinds of embodiments are the result comparison after the original process and three kinds of embodiments after the improved process. the

Example 1

Add methyl acrylate 172g (2mol) in the three-neck round-bottomed flask with mechanical stirrer, dropping funnel and reflux condenser, under cooling, dropwise the 1,1-dimethylhydrazine of 132g (2.2mol), After 2 hours the dropwise was completed, then the reaction mixture was heated at the same temperature until methyl 3-(2,2-dimethylhydrazino)propionate was formed (monitored by GM-MS). the

Dissolve the above-mentioned 3-(2,2-dimethylhydrazino)propionate methyl ester product in 40% ethanol (350ml), cool to 0°C, pass through methyl bromide (189g, 1.99mol) for 1 hour, and continue at the same temperature Stir for 0 to 5 hours, cool and filter the yellowish or brown precipitate, and wash the crude product with acetone (1000ml). Dry to obtain yellow 3-(2,2,2-trimethylhydrazine) methyl propionate bromide crude product 265.7g, yield 91.0%,; Crude product is recrystallized with ethanol, dry to obtain light yellow crystalline powder 219.8g, product The yield is 75.3%, the melting point is 130-132°C, and the main content is 103.3% (verified by the stability experiment, the stability is poor, and the color gradually becomes darker. Because the contained trace impurities have a greater impact on the product, it is found that the molecular formula decays and various indicators change. larger, the product is valid for a maximum of two years). the

Example 2

Repeat the method in the above-mentioned Example 1 and dry to obtain brown yellow 3-(2,2,2-trimethylhydrazine) methyl propionate bromide crude product 261.3g, yield 89.5%; Crude product is recrystallized with ethanol, dried to obtain White crystalline powder 214.2g, yield 73.4%, melting point 133-135 ° C, main content 102.5% (verified by stability experiments, the stability is poor, and the color gradually becomes darker, because the contained trace impurities have a greater impact on the product, It was found that the molecular formula decayed, and various indicators changed greatly, and the product was valid for a maximum of two years). the

Example 3

Repeat the method in the above-mentioned Example 1 and dry to obtain light yellow 3-(2,2,2-trimethylhydrazine) methyl propionate bromide crude product 271.5g, yield 89.5%; The crude product is recrystallized with ethanol, dried to obtain White crystalline powder 225.3g, yield 77.2%, melting point 132-134 ℃, main content 103.0% (verified by the stability experiment, the stability is poor, the color gradually becomes darker, because the contained trace impurities have a greater impact on the product, It was found that the molecular formula decayed, and various indicators changed greatly, and the product was valid for a maximum of two years). the

Example 4

Add methyl acrylate 258g (3mol) in the three-neck round-bottomed flask with mechanical stirrer, dropping funnel and reflux condenser, under cooling, dropwise the 1,1-dimethylhydrazine of 192g (3.2mol), After 2 hours of dripping, the reaction mixture was heated at the same temperature until forming 3-(2,2-dimethylhydrazino)propionate methyl ester (monitored by GM-MS), nitrogen protection, pressurized cooling and static overnight found that some The sticky thing precipitates, and filters out the sticky precipitate with precision filtration to obtain 3-(2,2-dimethylhydrazino) methyl propionate colorless transparent liquid (417g, productive rate 95.2%, content is 99.2%) ( Store in a dark place in an air-isolated container, and divide into three reactions for later use). the

The above-mentioned 3-(2,2-dimethylhydrazino)propionate methyl ester (139g, 0.95mol) was dissolved in 40% ethanol (350ml), cooled to 0°C, and bromomethane (123g, 1.30mol) was introduced into the mixture for a period of time 1 hour, continue stirring at the same temperature for 0, 5 hours, cooling and filtering the white precipitate, washing and washing on the filter with a small amount of cold ethanol solvent, and drying the mother liquor to obtain a white crystalline powder 3-(2,2,2 _trimethylhydrazine) methyl propionate bromide pure product 212,4g, main content is 100.4%, productive rate is 94.4%, fusing point is 129-130 ℃ (verified by stability experiment, stability is better, product color It has not changed, and the type of trace impurities contained has little effect on the product. Through four years of stability tests, it is found that the molecular formula has a small decay, and the properties, melting point, content and other indicators of the sample conform to the relevant regulations of the Pharmacopoeia. The performance is stable and does not deteriorate after long-term storage. In full compliance with the standard, the product validity period can be extended to four years). the

Example 5

Repeat method in above-mentioned embodiment 4 and can directly cool and filter after synthesis, dry to obtain white crystalline powder 3-(2,2,2-trimethylhydrazine) methyl propionate bromide pure product 211.5g, main content is 100.8% , the productive rate is 94.0%, and the melting point is 130-131°C (verified by the stability experiment, the stability is better, the color of the product does not change, and the type of trace impurities contained has little influence on the product, and it is found by the stability test of four years Molecular formula decay is small, the properties of the sample, melting point, content and other indicators meet the relevant provisions of the Pharmacopoeia, stable performance, no deterioration in long-term storage, quality fully meets the standards, and the product validity period can be extended to four years). the

Example 6

Repeat method in above-mentioned embodiment 4 and can directly cool and filter after synthesis, dry to obtain white crystalline powder 3-(2,2,2-trimethylhydrazine) methyl propionate bromide pure product 214.0g, main content is 100.3% , the productive rate is 95.1%, and the fusing point is 129-130°C (verified by the stability experiment, the stability is better, the color of the product does not change, and the type of trace impurities contained has little influence on the product, and it is found that it has The decay of the molecular formula is small, the properties, melting point, content and other indicators of the sample conform to the relevant regulations of the Pharmacopoeia, the performance is stable, the long-term storage does not deteriorate, the quality fully meets the standards, and the product validity period can be extended to four years). the

Claims (3)

1. a kind of preparation technology improvement method of 3-(2,2,-dimethylhydrazino) methyl propionate and 3-(2,2,2-trimethylhydrazine) propionate salt, its feature Because: the molecular formula of the intermediate 3-(2,2,2-trimethylhydrazine) propionate methyl ester salt of Meldonium raw material is: (CH ₃ ) ₃ N ⁺ NHCH ₂ CH ₂ COOCH ₃ X ^- , wherein, X represents Cl ^- , Br ^- , I ^- , CH ₃ SO ₄ ^-- ; the molecular formula of the intermediate product 3-(2,2,-dimethylhydrazino) propionate methyl ester is: (CH ₃ ) ₂ N-NH -CH ₂ -CH ₂ -COOCH ₃ ; the methylating agent is one of methyl chloride, methyl bromide, methyl iodide, dimethyl sulfate or dimethyl carbonate. Processes include: A; The synthetic technique of 3-(2,2,-dimethylhydrazino) methyl propionate B; Synthetic process of methyl 3-(2,2,2-trimethylhydrazine) propionate. the 2. a kind of 3-(2,2,-dimethylhydrazino) methyl propionate and 3-(2,2,2-trimethylhydrazine) methyl propionate salt according to claim 1 The preparation technology improvement method is characterized in that: we change the synthetic route of the predecessors, that is, the addition reaction and the methylation reaction are carried out as two separate synthetic reaction steps, and the specific steps are as follows: 1) The first step reaction is an exothermic reaction , therefore, in order to make the reaction temperature rise steadily and better control the content of by-products in the reaction, in the synthesis process, an optimal curve diagram based on the amount of feed, temperature, pressure and reaction time was set as a standard to realize a complete set of Automated control of reactions. 2) After the reaction, use a precision filter to filter and purify the cooled intermediate. 3) After passing the test, the intermediate is used as the starting material of the methylation reaction to accurately measure and feed again. 4) The methylation reaction is also an exothermic reaction. In order to make the reaction temperature rise steadily and better control the content of by-products in the reaction, an optimum method of feeding amount, temperature, pressure and reaction time is also set in the synthesis process. Graphs are used as standard, enabling automated control of the entire set of reactions. 5) A special method of purification technology is adopted, which allows the crude product after the methylation reaction to be purified directly without undergoing complicated purification processes such as recrystallization and washing after conventional filtration. The desalination technology after carbon dioxide or carbon dioxide sulfation, or the synthesis technology plan for the synthesis of meldonium raw material drug by using related ammonium hydrochloride for the first time. the 3. a kind of 3-(2,2,-dimethylhydrazino) methyl propionate and 3-(2,2,2-trimethylhydrazine) methyl propionate salt according to claim 1 The preparation technology improvement method is characterized in that the intermediate of 3-(2,2,-dimethylhydrazino)methyl propionate is a colorless transparent liquid, and the product content is ≥98.5%; the intermediate of meldonium raw material medicine 3 -(2,2,2-Trimethylhydrazine) methyl propionate salt product main content between 100.0-102.0%, is a kind of white crystalline powder, 3-(2,2,2-trimethylhydrazine ) Methyl propionate bromide has a melting point range of 126-132°C and a shelf life of 4 years. the