CN117700335A - Method for preparing pharmaceutical agent mildronate dihydrate by hydrolysis acidification improvement technology - Google Patents
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- 238000006460 hydrolysis reaction Methods 0.000 title claims abstract description 12
- 230000007062 hydrolysis Effects 0.000 title claims abstract description 11
- JFWLFLLRLZSBRA-UHFFFAOYSA-N 3-[(trimethylazaniumyl)amino]propanoate;dihydrate Chemical compound O.O.C[N+](C)(C)NCCC([O-])=O JFWLFLLRLZSBRA-UHFFFAOYSA-N 0.000 title claims abstract description 7
- 238000005516 engineering process Methods 0.000 title claims abstract description 6
- 230000006872 improvement Effects 0.000 title claims abstract description 6
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- 238000001816 cooling Methods 0.000 claims abstract description 34
- PPQFUDZMTNGHBJ-UHFFFAOYSA-N propanoic acid;dihydrate Chemical compound O.O.CCC(O)=O PPQFUDZMTNGHBJ-UHFFFAOYSA-N 0.000 claims abstract description 25
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- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
A method for preparing a pharmaceutical agent mildronate dihydrate by hydrolysis acidification improvement technology, namely, a mildronate intermediate 3- (2, 2-trimethylhydrazinium) methyl propionate halide or methyl sulfate is subjected to alkaline hydrolysis, and bicarbonate or bisulfate and carbonate or sulfate ions generated during neutralization of carbon dioxide or sulfur dioxide acid gas are hydrolyzed to a degree different, so that a colloidal double salt mixed system formed with a target product is not better solved for separation and purification of the product. The improvement of the control technology of the acidification buffer steady reaction by the inventor completely prevents the formation of double salts and emulsions, and according to the method, the pharmaceutical grade 3- (2, 2-trimethylhydrazinium) propionate dihydrate serving as the raw material of the mildronate can be obtained through conventional working sections of cooling crystallization, centrifugal separation, drying and the like.
Description
Technical Field
The invention relates to the field of organic chemistry and medicine research, in particular to a technical method for preparing a medicine agent mildronate dihydrate '3- (2, 2-trimethylhydrazinium) propionate dihydrate' by hydrolysis acidification improvement technology.
Background
Mildronate (Mildronate) was created by Lativalia organic synthesis studies and belongs to the class of partial inhibitors of fatty acid beta-oxidation, which are well known to clinicians for their cytoprotective properties in the pathology of ischemia occurrence. Hundreds of different levels of research are devoted to researching the clinical effects of mildronate, namely 3- (2, 2-trimethylhydrazinium) propionate dihydrate, which is used as a novel heart protecting medicine, can effectively regulate the energy metabolism of the heart to improve the heart function in the onset process of ischemic heart diseases, and can regulate the balance between the oxygen amount in heart tissues required by the normal operation of cardiac muscles and the oxygen amount actually available for metabolism. Thus, the difference between oxygen delivery and oxygen consumption is effectively reduced, and at the same time, the oxygen consumption, the coronary blood flow rate, and the blood oxygen amount are increased. The mechanism of action of mildronate is based on that it is a structural analogue of carnitine, which can compete for inhibition of betaine hydroxylase butyrate, thus inhibiting the biosynthesis of carnitine and directly inhibiting the transport of carnitine-dependent fatty acids in mitochondria. Inhibition of carnitine biosynthesis reduces the intracellular concentration of free carnitine, prevents the accumulation of acyl carnitine induced by isoproterenol, thus regulating the concentration of carnitine, and in ischemic state mildronate improves the energy metabolism of the heart, which allows the oxidative energy supply of fatty acids, and turns into more beneficial oxidative energy supply of glucose, so mildronate is used not only for the treatment of ischemic heart diseases, coronary heart diseases (angina pectoris, myocardial infarction, congestive heart failure, arterial hypertension of heart rhythm disorders, etc.), but also for the comprehensive treatment of various diseases, which increases the motility of sperm for impotence patients, european patent EP 1039894B (SIGMA-TAU HEALTHSCIENCE SPA) 01.12.1997 discloses a pharmaceutical composition for increasing the concentration and/or motility of human sperm, L-carnitine and/or acetyl-L-carnitine, including compositions for treating impaired sperm function in persons suffering from idiopathic effects, namely sexual impotence; the composition can restore activity balance of sympathetic nervous system and parasympathetic nervous system for patients with mental fatigue and physical weakness, including athlete acceleration, infectious and allergic bronchial asthma and chronic bronchitis, which are immunomodulators in comprehensive treatment, abstinence syndrome alcoholism, which can be combined with specific treatment of alcoholism, acute diseases of retina in blood circulation, acute and chronic circulatory diseases of brain, and can treat cerebral apoplexy and cerebral vascular insufficiency; mildronate can effectively reduce the accumulation of fat in the liver and accelerate the liver to remove fat; treating arterial hypertension, secondary diabetes and neurologic diseases.
Mildronate has been increasingly used in the medical field as an over-the-counter drug due to its low toxicity, with an average daily dose of 1.0-g-2.0 g. The prior art for preparing mildronate is complex in process and inconvenient for large-scale production (U.S. patent 8,153,842), and the preparation is used as an over-the-counter drug, so that the production cost of the raw material drug is far from meeting the current market demand. The international market demand increases every year (500-700 tons/year of mildronate). In order to meet the market demand, an inexpensive large-scale manufacturing process is required, and therefore, the object of the present invention is to improve the heretofore known manufacturing method of mildronate, realizing lower production costs and application of the large-scale manufacturing process.
Various methods are known for preparing the 3- (2, 2-trimethylhydrazinium) propionate dihydrate as a drug substance, generally comprising: the 1, 1-dimethylhydrazine reacts with methyl acrylate to generate 3- (2, 2-dimethylhydrazino) methyl propionate, methyl halide or dimethyl sulfate is further used for methylation to generate corresponding 3- (2, 2-trimethylhydrazino) methyl propionate halide or methyl sulfate, and the obtained intermediate 3- (2, 2-trimethylhydrazino) alkyl propionate halide or methyl sulfate is further hydrolyzed and deionized to obtain mildronate.
The known processes for the preparation of mildronate differ in the hydrolysis and/or deionization process of the corresponding 3- (2, 2-trimethylhydrazinium) propionate. One known method is disclosed in U.S. patent No. 4,481,218, in which a solution of a halide or methylsulfonate of alkyl-3- (2, 2-trimethylhydrazinium) propionic acid is treated with a strongly basic ion exchange resin to exchange the acid anion for a hydroxyl anion, according to which a solution of a halide or methyl sulfate of an alkyl 3- (2, 2-trimethylhydrazinium) propionate is treated with a strongly basic ion exchange resin to exchange the acid anion for a hydroxyl anion. This method has a number of disadvantages: the strong alkaline ion exchanger is unstable and can be decomposed and oxidized in the processing process; they can only withstand a limited regeneration period; the regenerated resin requires a large amount of solvent, acid and alkali and deionized water; the ion exchange capacity is low, so that the production cost of mildronate dihydrate by the method is high, and the process is inconvenient for large-scale production.
Vasiloev V., kavins I.et al published in Russian J.App. (1992,. 12, vol. 65, pp. 2823-2825) a paper published in methods for electrolytic synthesis of 3- (2, 2-trimethylhydrazinium) propionic acid dihydrate. If the alkyl 3- (2, 2-trimethylhydrazinium) propionate salt is deionized by electrodialysis, some of the above disadvantages can be avoided. The disadvantage of this process is the need for highly specialized equipment, with increased demands on the corrosion resistance of the materials used (platinized titanium electrodes, porous membranes of controlled pore size, mechanical and chemical stability of the membrane material, ceramic-coated construction elements in electrodialysis plants). The main parameters of the electrodialysis process must be experimentally adjusted-current, flow rate, solution concentration, distance between electrodes, etc. The parameters initially set are constantly changed because the membrane is subject to contamination during the production process. The membrane also degrades during operation and must be replaced periodically. Therefore, such equipment is costly to maintain and the process is more complicated in mass production. Unsafe explosive gases are easily generated during electrodialysis and electrolysis. Thus, the use of electrodialysis to produce mildronate dihydrate is also a relatively costly process.
Another method for the production of mildronate is known, according to which, in a first step, condensation of 1, 1-dimethylhydrazine with trimethylsilyl methacrylate and subsequent spontaneous hydrolysis of the resulting product with trimethylsilyl propionate, an alkylated product of haloalkyl 3- (2, 2-trimethylhydrazine), takes place in water, even without basic catalysis, to give the desired product (RU 95118258.04). The main disadvantage of this process is the relatively high cost of trimethylsilyl acrylate compared to methyl acrylate.
International patent WO2008028514 discloses a process wherein the alkyl ester salt of the intermediate 3- (2, 2-trimethylhydrazinium) propionate of meldonium is neutralised by carbon dioxide or sulphur dioxide acid gas after alkaline hydrolysis to a pH of the solution of 8.2-8.5. The treated desalted solution is subjected to multiple dissolution, crystallization, separation and other working sections under the laboratory condition, and the electrodialysis and macroporous resin methods are not used to obtain the finished product of the bulk drug of the pharmaceutical drug. But single direct use of dioxygenWhen a large amount of reaction liquid is neutralized by the method for introducing acid gas of carbon dioxide or sulfur dioxide, the pH of the solution is 8.2-8.5 near the neutralization point, so that the solution is extremely high in sensitivity, and is difficult to control in actual industrial production, and the neutralization reaction has typical nonlinear characteristics and is the reverse reaction of hydrolysis reaction. In order to avoid the formation of complex colloidal salts in practical production processes, a nonlinear control neutralization technique or a nonlinear control agent should be considered to ensure the smooth progress of the neutralization reaction. The difference in the degree of hydrolysis of bicarbonate or (bisulfate) and carbonate (or sulfate) ions produced during the neutralization of carbon dioxide or sulfur dioxide results in the easy production of K 2 CO 3 /KHCO 3 Or K 2 SO 3 /KHSO 3 And the target product 3- (2, 2-trimethylhydrazinium) propionate, which is a gelatinous complex mixed system, is a difficult operation and control point of the process and is a main reason for generating gelatinous double salt, so that the separation and purification in the actual mass production of the process do not obtain good effects and fail.
The object of the present invention is to find an improved method for the production of 3- (2, 2-trimethylhydrazinium) propionate dihydrate, suitable for the use of the acidizing and acidifying technique in the neutralization reaction, avoiding the water-soluble K 2 CO 3 /KHCO 3 Or K 2 SO 3 /KHSO 3 Formation of double salt complex of by-product and target product 3- (2, 2-trimethylhydrazinium) propionate dihydrate, the product of mildronate pharmaceutical grade purity is obtained using conventional industrial purification isolation methods.
Disclosure of Invention
In order to accomplish and overcome the above-mentioned drawbacks, the inventors have unexpectedly found that if an acidulant (such as carbon dioxide, sulfur dioxide, etc.) is introduced into a solution obtained by alkaline hydrolysis treatment of methyl 3- (2, 2-trimethylhydrazinium) propionate as an intermediate of mildronate for neutralization or a certain amount of buffering agent (also referred to as an acid-base stabilizer) is added at the critical point of the PH jump range, the neutralization reaction is ensured to be stably carried out stepwise. Surprisingly, we found that the method uses one or two acidulants to neutralize step by step, and simultaneously the hybrid complex system of byproduct inorganic salt is effectively controlled, thus completely preventing the formation of double salt and emulsion, avoiding electrodialysis and macroporous resin, and obtaining the medical grade mildronate raw material 3- (2, 2-trimethylhydrazinium) propionate dihydrate through conventional cooling crystallization, centrifugal separation, drying and other working sections according to the method.
The technical scheme adopted by the invention is that one or two acidulants are respectively selected for stepwise acidulation operation, and a certain amount of acid-base buffer is added to effectively control neutralization, and finally the crude product is subjected to conventional cooling crystallization, centrifugal separation, drying and other working procedures to obtain the high-purity mildronate 3- (2, 2-trimethylhydrazinium) propionate dihydrate bulk drug, and the method comprises the following steps: 1. the composition is Midrozide with a molecular structure of C 6 H 14 N 2 O 2 .2H 2 O; pharmaceutical intermediate methyl 3- (2, 2-trimethylhydrazinium) propionate (CH) 3 ) 3 N + NHCH 2 CH 2 COOCH 3 X - Wherein X represents Cl - 、Br - 、I - 、CH 3 SO 4 - The method comprises the steps of carrying out a first treatment on the surface of the The buffering agent is as follows: CH (CH) 3 COONa、NH 4 HCO 3 、 KHCO 3 、Na 2 B 4 O 7 、（NH 4 ） 2 CO 3 、K 2 CO 3 、KH 2 PO 4 -K 2 HPO 4 At least one of the compounds; the buffer is generally used in an amount of 4.0 to 25% by weight, preferably 4.0 to 10% by weight, based on the weight of the basic hydrolysis compound to be added. The acidulant comprises the following components: carbon dioxide (CO) 2 ) Sulfur dioxide (SO) 2 ）、NH 4 Cl, nitrogen dioxide (NO) 2 ) At least one of them. 2. The component proportions are as follows: 3- (2, 2-trimethylhydrazinium) propionate dihydrate (C) 6 H 14 N 2 O 2 .2H 2 The main content of the O) medicine raw material is 99.0-101%, the ash content of sulfuric acid is less than 0.1%, and the melting point is 85-90 ℃ (by capillary measurement).
Detailed Description
The following examples will aid in the understanding of the present invention, but are merely illustrative of the invention and the invention is not limited thereto.
Example 1
Dissolving 34g of 90% potassium hydroxide in 240ml of ethanol, adding 61g of methyl 3- (2, 2-trimethylhydrazinium) propionate bromide, hydrolyzing at 18-20deg.C (detecting termination of reaction by TLC or HPLC), cooling to room temperature, vacuum filtering to remove inorganic precipitate, washing with 2X 20ml of ethanol, mixing the washing solution with mother liquor, and introducing CO 2 Acidifying with gas to pH 8.2-8.5 (pH acidimeter test), filtering to remove precipitate, washing with 2×20ml ethanol, mixing the washing liquor mother liquor, directly filtering to obtain clear solution, cooling and standing for about 10 min to make the emulsion become clear, pumping and filtering out the rest inorganic salt, concentrating the obtained filtrate under reduced pressure, cooling and crystallizing to obtain 48g 3- (2, 2-trimethylhydrazinium) propionate dihydrate crude drug raw material, recrystallizing with isopropanol or ethanol, melting point 85-87 deg.C (detection by capillary method), main content > 99.0%, and sulfated ash content 0.21%.
Example 2
Dissolving 34g of 90% potassium hydroxide in 240ml of ethanol, adding 61g of methyl 3- (2, 2-trimethylhydrazinium) propionate bromide, hydrolyzing at 18-20deg.C (detecting termination of reaction by TLC or HPLC), cooling to room temperature, vacuum filtering to remove inorganic precipitate, washing with 2×20ml of ethanol, mixing the washing solution with mother liquor, and introducing SO 2 Acidifying with gas to pH 8.2-8.5 (pH acidimeter test), filtering to remove precipitate, washing with 2×20ml ethanol, mixing the washing liquor mother liquor, directly filtering to obtain clear solution, cooling and standing for about 10 min to make the emulsion become clear, pumping and filtering out the rest inorganic salt, concentrating the obtained filtrate under reduced pressure, cooling, crystallizing, drying to obtain 44g 3- (2, 2-trimethylhydrazinium) propionate dihydrate crude drug raw material, recrystallizing with isopropanol or ethanol, melting point 85-88deg.C, main content > 99.0%, and sulfated ash content 0.35%.
Example 3
34g of 90% potassium hydroxide is added into 240ml of ethanol for dissolution, 61g of methyl 3- (2, 2-trimethylhydrazinium) propionate bromide is added for hydrolysis at 18-20 ℃ under temperature control (TLC or HPLC is used for detecting whether the reaction is stopped) and the temperature isFiltering to remove inorganic precipitate, washing with 2×20ml ethanol, mixing the washing solution and mother liquor, and introducing CO 2 Acidifying the gas, filtering the precipitate, and adding 2g Na into the filtrate 2 B 4 O 7 Is uniformly mixed with the aqueous solution of (C) and then is reused with SO 2 Acidifying and saturating the gas to pH 8.2-8.5 (pH acidimeter test), filtering to remove the precipitate, washing with 2X 20ml ethanol, mixing the washing solution and the mother liquor, concentrating under reduced pressure, cooling, crystallizing, drying to obtain 43g of crude 3- (2, 2-trimethylhydrazinium) propionate dihydrate medicine raw material, recrystallizing with isopropanol or ethanol, melting point 87-88 ℃, main content > 99.0%, and sulfated ash content 0.07%.
Example 4
Dissolving 34g of 90% potassium hydroxide in 240ml of ethanol, adding 61g of methyl 3- (2, 2-trimethylhydrazinium) propionate bromide, hydrolyzing at 18-20deg.C (detecting whether the reaction is terminated by TLC or HPLC), cooling to room temperature, vacuum filtering to precipitate, removing inorganic precipitate, washing with 2X 20ml of ethanol, mixing the washing solution and mother liquor, and introducing SO 2 Acidifying the gas, filtering the precipitate, and adding 3g NH into the filtrate 4 HCO 3 Is uniformly mixed with the aqueous solution of (C) and then is reused with SO 2 Acidifying and saturating the gas to pH 8.2-8.5 (pH acidimeter test), filtering to remove the precipitate, washing with 2X 20ml ethanol, mixing the washing solution and the mother liquor, concentrating under reduced pressure, cooling, crystallizing, drying to obtain 44g of crude 3- (2, 2-trimethylhydrazinium) propionate dihydrate medicine raw material, recrystallizing with isopropanol or ethanol, melting point 87-88 ℃, main content > 99.0%, and sulfated ash content 0.05%.
Example 5
Dissolving 34g of 90% potassium hydroxide in 240ml of ethanol, adding 61g of methyl 3- (2, 2-trimethylhydrazinium) propionate bromide, hydrolyzing at 18-20deg.C (detecting termination of reaction by TLC or HPLC), cooling to room temperature, vacuum filtering to remove inorganic precipitate, washing with 2X 20ml of ethanol, mixing the washing solution and mother liquor, adding solution containing 2g of NH 4 HCO 3 Uniformly mixing the aqueous solution of (C) and then introducing SO 2 Gas acidification to remove inorganic precipitate, washing with 2×20ml ethanol, adding solution containing 1.5. 1.5g K 2 CO 3 Is reused with CO 2 Gas acidification saturation to pH 8.2-8.5 (pH acidometer test)Filtering to remove precipitate, washing with 2×20ml ethanol, mixing the washing solution and mother liquor, concentrating under reduced pressure, cooling, crystallizing, and drying to obtain 46g 3- (2, 2-trimethylhydrazinium) propionate dihydrate crude drug raw material, recrystallizing with isopropanol or ethanol, melting point 88-89 deg.C, main content > 99.0%, and sulfated ash content 0.02%.
Example 6
Dissolving 34g of 90% potassium hydroxide in 240ml of ethanol, adding 61g of methyl 3- (2, 2-trimethylhydrazinium) propionate bromide, hydrolyzing at 18-20deg.C (detecting whether the reaction is terminated by TLC or HPLC), cooling to room temperature, vacuum filtering to precipitate, removing inorganic precipitate, washing with 2X 20ml of ethanol, mixing the washing solution and mother liquor, and introducing CO 2 Acidifying and filtering the gas, washing the filtrate with 2X 20ml ethanol, adding a liquid containing 2. 2g K 2 CO 3 Filtering to remove precipitate, washing with 2 x 20ml ethanol, mixing the washing solution and the mother liquor, concentrating under reduced pressure, cooling, crystallizing, and drying to obtain 45g crude 3- (2, 2-trimethylhydrazinium) propionate dihydrate medicine raw material, recrystallizing with isopropanol or ethanol, melting point at 89-90deg.C, main content > 99.0%, and sulfated ash content 0.01%.
Example 7
Dissolving 34g of 90% potassium hydroxide in 240ml of ethanol, adding 61g of methyl 3- (2, 2-trimethylhydrazinium) propionate bromide, hydrolyzing at 18-20deg.C (detecting termination of reaction by TLC or HPLC), cooling to room temperature, vacuum filtering to remove inorganic precipitate, washing with 2X 20ml of ethanol, mixing the washing solution and mother liquor, adding solution containing 2g of CH 3 Removing inorganic precipitate by COONa aqueous solution, washing with 2 x 20ml ethanol, mixing the washing solution and mother liquor, and introducing NO 2 Acidifying with gas to pH 8.2-8.5 (pH acidimeter test), filtering to remove precipitate, washing with 2×20ml ethanol, mixing the washing liquor mother liquor, directly filtering to obtain clear solution, cooling and standing for about 10 min to make the emulsion become clear, pumping and filtering out the rest inorganic salt, concentrating the obtained filtrate under reduced pressure, cooling, crystallizing, drying to obtain 49g 3- (2, 2-trimethylhydrazinium) propionate dihydrate crude drug raw material, recrystallizing with isopropanol or ethanol, melting point 85-86 deg.C, main content > 99.0%, and sulfated ash content 0.49%.
Example 8
Dissolving 34g of 90% potassium hydroxide in 240ml of ethanol, adding 61g of methyl 3- (2, 2-trimethylhydrazinium) propionate bromide, hydrolyzing at 18-20deg.C (TLC or HPLC to detect termination of reaction), cooling to room temperature, vacuum filtering to remove inorganic precipitate, washing with 2X 20ml of ethanol, mixing the washing solution and mother liquor, adding solution containing 1g K 2 CO 3 Uniformly mixing the aqueous solution of (C) and then introducing SO 2 Gas acidification and suction filtration, washing the solid with 2X 20ml ethanol, combining the washing liquid and the mother liquor, adding a solution containing 1.5g KHCO 3 Is mixed with the aqueous solution of (C) 2 Acidifying with gas to pH 8.2-8.5 (pH acidimeter test), filtering to remove precipitate, washing solid compound with 2 x 20ml ethanol, mixing the washing liquid and mother liquor, concentrating under reduced pressure, cooling, crystallizing, drying to obtain 45g crude 3- (2, 2-trimethylhydrazinium) propionate dihydrate medicine raw material, recrystallizing with isopropanol or ethanol, melting point 89-90deg.C, main content > 99.0%, and sulfated ash content 0.02%.
Example 9
Dissolving 34g of 90% potassium hydroxide in 240ml of ethanol, adding 61g of methyl 3- (2, 2-trimethylhydrazinium) propionate bromide, hydrolyzing at 18-20deg.C (detecting termination of reaction by TLC or HPLC), cooling to room temperature, vacuum filtering to remove inorganic precipitate, washing with 2X 20ml of ethanol, mixing the washing solution and mother liquor, adding solution containing 1g (NH) 4 ） 2 CO 3 Is introduced into CO after being uniformly mixed 2 Gas acidification and suction filtration, washing the solid with 2X 20ml ethanol, combining the washing liquid and the mother liquor, adding 6.5g NH 4 Cl and stirring for 10-15min, filtering to remove precipitate, washing solid compound with 2X 20ml ethanol, mixing the washing liquid and mother liquor, concentrating under reduced pressure, cooling, crystallizing, drying to obtain 46g crude 3- (2, 2-trimethylhydrazinium) propionate dihydrate medicine raw material, recrystallizing with isopropanol or ethanol, melting point 87-89 deg.C, main content > 99.0%, and sulfated ash content 0.08%.
Claims (7)
1. A method for preparing a pharmaceutical agent mildronate dihydrate by hydrolysis acidification improvement technology, which is characterized by comprising the following steps of: 34g of 90% potassium hydroxide is added into 240ml of ethanol for dissolution, 61g of 3- (2, 2-trimethylhydrazine is added) Hydrolyzing methyl propionate bromide at 18-20deg.C (TLC or HPLC to detect termination of reaction), filtering to remove inorganic precipitate, washing with 2×20ml ethanol, mixing the washing solution and mother liquor, and introducing CO 2 Filtering the precipitate by gas, adding 2g Na into the filtrate 2 B 4 O 7 Is uniformly mixed with the aqueous solution of (C) and then is reused with SO 2 Acidifying and saturating the gas to pH 8.2-8.5 (pH acidimeter test), filtering to remove the precipitate, washing with 2X 20ml ethanol, mixing the washing solution and the mother liquor, concentrating under reduced pressure, cooling, crystallizing, drying to obtain 43g of crude 3- (2, 2-trimethylhydrazinium) propionate dihydrate medicine raw material, recrystallizing with isopropanol or ethanol, melting point 87-88 ℃, main content > 99.0%, and sulfated ash content 0.07%.
2. The method according to claim 1, characterized in that: dissolving 34g of 90% potassium hydroxide in 240ml of ethanol, adding 61g of methyl 3- (2, 2-trimethylhydrazinium) propionate bromide, hydrolyzing at 18-20deg.C (detecting whether the reaction is terminated by TLC or HPLC), cooling to room temperature, vacuum filtering to precipitate, removing inorganic precipitate, washing with 2X 20ml of ethanol, mixing the washing solution and mother liquor, and introducing SO 2 Filtering the precipitate by gas, adding 3g NH into the filtrate 4 HCO 3 Is uniformly mixed with the aqueous solution of (C) and then is reused with SO 2 Acidifying and saturating the gas to pH 8.2-8.5 (pH acidimeter test), filtering to remove the precipitate, washing with 2X 20ml ethanol, mixing the washing solution and the mother liquor, concentrating under reduced pressure, cooling, crystallizing, drying to obtain 44g of crude 3- (2, 2-trimethylhydrazinium) propionate dihydrate medicine raw material, recrystallizing with isopropanol or ethanol, melting point 87-88 ℃, main content > 99.0%, and sulfated ash content 0.05%.
3. The method according to claim 1, characterized in that: dissolving 34g of 90% potassium hydroxide in 240ml of ethanol, adding 61g of methyl 3- (2, 2-trimethylhydrazinium) propionate bromide, hydrolyzing at 18-20deg.C (detecting termination of reaction by TLC or HPLC), cooling to room temperature, vacuum filtering to remove inorganic precipitate, washing with 2X 20ml of ethanol, mixing the washing solution and mother liquor, adding solution containing 2g of NH 4 HCO 3 Uniformly mixing the aqueous solution of (C) and then introducing SO 2 Gas acidification to remove inorganic precipitate, washing with 2×20ml ethanol, adding solution containing 1.5. 1.5g K 2 CO 3 Is reused with CO 2 The gas is acidified and saturated to pH 8.2-8.5 (pH acidimeter test), the formed precipitate is filtered, washed by 2.20 ml of ethanol, the washing liquor and the mother liquor are combined and then concentrated under reduced pressure, 46g of crude 3- (2, 2-trimethylhydrazinium) propionate dihydrate medicine raw material is obtained after cooling crystallization and drying, isopropanol or ethanol is used for recrystallization, the melting point is 88-89 ℃, the main content is more than 99.0%, and the sulfated ash content is 0.02%.
4. The method according to claim 1, characterized in that: dissolving 34g of 90% potassium hydroxide in 240ml of ethanol, adding 61g of methyl 3- (2, 2-trimethylhydrazinium) propionate bromide, hydrolyzing at 18-20deg.C (detecting whether the reaction is terminated by TLC or HPLC), cooling to room temperature, vacuum filtering to precipitate, removing inorganic precipitate, washing with 2X 20ml of ethanol, mixing the washing solution and mother liquor, and introducing CO 2 Acidifying and filtering the gas, washing the filtrate with 2X 20ml ethanol, adding a liquid containing 2. 2g K 2 CO 3 Filtering to remove precipitate, washing with 2 x 20ml ethanol, mixing the washing solution and the mother liquor, concentrating under reduced pressure, cooling, crystallizing, and drying to obtain 45g crude 3- (2, 2-trimethylhydrazinium) propionate dihydrate medicine raw material, recrystallizing with isopropanol or ethanol, melting point 89-90deg.C, main content > 99.0%, and sulfated ash content 0.01%.
5. The method according to claim 1, characterized in that: dissolving 34g of 90% potassium hydroxide in 240ml of ethanol, adding 61g of methyl 3- (2, 2-trimethylhydrazinium) propionate bromide, hydrolyzing at 18-20deg.C (TLC or HPLC to detect termination of reaction), cooling to room temperature, vacuum filtering to remove inorganic precipitate, washing with 2X 20ml of ethanol, mixing the washing solution and mother liquor, adding solution containing 1g K 2 CO 3 Uniformly mixing the aqueous solution of (C) and then introducing SO 2 Gas acidification and suction filtration, washing the solid with 2X 20ml ethanol, combining the washing liquid and the mother liquor, adding a solution containing 1.5g KHCO 3 Is mixed with the aqueous solution of (C) 2 Acidifying the gas to pH 8.2-8.5 (pH acidometer test), filtering to remove precipitateWashing the solid compound with 2 x 20ml ethanol, merging the washing liquid and the mother liquid, concentrating under reduced pressure, cooling, crystallizing and drying to obtain 45g of crude 3- (2, 2-trimethylhydrazinium) propionate dihydrate medicine raw material, recrystallizing with isopropanol or ethanol, melting point 89-90 ℃, main content > 99.0% and sulfated ash content 0.02%.
6. The method according to claim 1, characterized in that: dissolving 34g of 90% potassium hydroxide in 240ml of ethanol, adding 61g of methyl 3- (2, 2-trimethylhydrazinium) propionate bromide, hydrolyzing at 18-20deg.C (detecting termination of reaction by TLC or HPLC), cooling to room temperature, vacuum filtering to remove inorganic precipitate, washing with 2X 20ml of ethanol, mixing the washing solution and mother liquor, adding solution containing 1g (NH) 4 ） 2 CO 3 Is introduced into CO after being uniformly mixed 2 Gas acidification and suction filtration, washing the solid with 2X 20ml ethanol, combining the washing liquid and the mother liquor, adding 6.5g NH 4 Cl and stirring for 10-15min, filtering to remove precipitate, washing solid compound with 2X 20ml ethanol, mixing the washing liquid and mother liquor, concentrating under reduced pressure, cooling, crystallizing, drying to obtain 46g crude 3- (2, 2-trimethylhydrazinium) propionate dihydrate medicine raw material, recrystallizing with isopropanol or ethanol, melting point 87-89 deg.C, main content > 99.0%, and sulfated ash content 0.08%.
7. The method of claim 1, wherein the buffer is CH 3 COONa、NH 4 HCO 3 、 KHCO 3 、Na 2 B 4 O 7 、（NH 4 ） 2 CO 3 、K 2 CO 3 、KH 2 PO 4 -K 2 HPO 4 The buffer is generally used in an amount of 4.0 to 25% by weight, preferably 4.0 to 10% by weight, based on the weight of the basic hydrolysis compound to be added.
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