CN111333534B - Method for preparing 3- (2, 2, 2-trimethylhydrazinium) propionate dihydrate by methylating methyl halide - Google Patents
Method for preparing 3- (2, 2, 2-trimethylhydrazinium) propionate dihydrate by methylating methyl halide Download PDFInfo
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- CN111333534B CN111333534B CN201911333357.0A CN201911333357A CN111333534B CN 111333534 B CN111333534 B CN 111333534B CN 201911333357 A CN201911333357 A CN 201911333357A CN 111333534 B CN111333534 B CN 111333534B
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- 238000000034 method Methods 0.000 title claims abstract description 31
- 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 18
- -1 methyl halide Chemical class 0.000 title claims abstract description 15
- 230000001035 methylating effect Effects 0.000 title description 2
- 230000011987 methylation Effects 0.000 claims abstract description 7
- 238000007069 methylation reaction Methods 0.000 claims abstract description 7
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 36
- 238000001914 filtration Methods 0.000 claims description 34
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 27
- 238000001816 cooling Methods 0.000 claims description 25
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 22
- 238000003756 stirring Methods 0.000 claims description 22
- 239000000706 filtrate Substances 0.000 claims description 19
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 18
- 239000000243 solution Substances 0.000 claims description 18
- 239000000047 product Substances 0.000 claims description 17
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 16
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 claims description 12
- 238000002156 mixing Methods 0.000 claims description 12
- 239000002244 precipitate Substances 0.000 claims description 12
- 239000007864 aqueous solution Substances 0.000 claims description 11
- 229910001385 heavy metal Inorganic materials 0.000 claims description 10
- 239000011541 reaction mixture Substances 0.000 claims description 10
- 239000007787 solid Substances 0.000 claims description 10
- 238000004448 titration Methods 0.000 claims description 10
- 238000005406 washing Methods 0.000 claims description 10
- 238000010438 heat treatment Methods 0.000 claims description 9
- 239000012047 saturated solution Substances 0.000 claims description 9
- 150000003839 salts Chemical class 0.000 claims description 7
- 238000001291 vacuum drying Methods 0.000 claims description 7
- 239000001110 calcium chloride Substances 0.000 claims description 6
- 229910001628 calcium chloride Inorganic materials 0.000 claims description 6
- XFSUFSQSUUMXLB-UHFFFAOYSA-N propanoic acid;hydrobromide Chemical compound Br.CCC(O)=O XFSUFSQSUUMXLB-UHFFFAOYSA-N 0.000 claims description 6
- 239000000839 emulsion Substances 0.000 claims description 4
- 235000006408 oxalic acid Nutrition 0.000 claims description 4
- 229910001626 barium chloride Inorganic materials 0.000 claims description 3
- 230000020477 pH reduction Effects 0.000 claims description 3
- 239000003995 emulsifying agent Substances 0.000 claims description 2
- 238000000967 suction filtration Methods 0.000 claims description 2
- 238000000909 electrodialysis Methods 0.000 abstract description 5
- 238000000746 purification Methods 0.000 abstract description 5
- 229920005989 resin Polymers 0.000 abstract description 5
- 239000011347 resin Substances 0.000 abstract description 5
- 238000000926 separation method Methods 0.000 abstract description 4
- 238000003912 environmental pollution Methods 0.000 abstract description 2
- 238000011031 large-scale manufacturing process Methods 0.000 abstract description 2
- 229940017219 methyl propionate Drugs 0.000 abstract description 2
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 15
- 238000006243 chemical reaction Methods 0.000 description 6
- 239000000843 powder Substances 0.000 description 6
- PZFLIZRXZJKOLG-UHFFFAOYSA-N Br.CCC(=O)OC Chemical compound Br.CCC(=O)OC PZFLIZRXZJKOLG-UHFFFAOYSA-N 0.000 description 5
- PVBQYTCFVWZSJK-UHFFFAOYSA-N meldonium Chemical compound C[N+](C)(C)NCCC([O-])=O PVBQYTCFVWZSJK-UHFFFAOYSA-N 0.000 description 5
- 229960002937 meldonium Drugs 0.000 description 5
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 4
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 description 4
- RAHZWNYVWXNFOC-UHFFFAOYSA-N Sulphur dioxide Chemical compound O=S=O RAHZWNYVWXNFOC-UHFFFAOYSA-N 0.000 description 4
- 239000012670 alkaline solution Substances 0.000 description 4
- 229910017053 inorganic salt Inorganic materials 0.000 description 4
- 239000000203 mixture Substances 0.000 description 4
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 3
- 150000007513 acids Chemical class 0.000 description 3
- 229910002092 carbon dioxide Inorganic materials 0.000 description 3
- 239000003814 drug Substances 0.000 description 3
- 230000007062 hydrolysis Effects 0.000 description 3
- 238000006460 hydrolysis reaction Methods 0.000 description 3
- 238000004519 manufacturing process Methods 0.000 description 3
- 239000002904 solvent Substances 0.000 description 3
- NWUYHJFMYQTDRP-UHFFFAOYSA-N 1,2-bis(ethenyl)benzene;1-ethenyl-2-ethylbenzene;styrene Chemical compound C=CC1=CC=CC=C1.CCC1=CC=CC=C1C=C.C=CC1=CC=CC=C1C=C NWUYHJFMYQTDRP-UHFFFAOYSA-N 0.000 description 2
- XBDQKXXYIPTUBI-UHFFFAOYSA-N Propionic acid Chemical class CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 2
- 230000001476 alcoholic effect Effects 0.000 description 2
- WDIHJSXYQDMJHN-UHFFFAOYSA-L barium chloride Chemical group [Cl-].[Cl-].[Ba+2] WDIHJSXYQDMJHN-UHFFFAOYSA-L 0.000 description 2
- 229920001429 chelating resin Polymers 0.000 description 2
- 150000001875 compounds Chemical class 0.000 description 2
- VAYGXNSJCAHWJZ-UHFFFAOYSA-N dimethyl sulfate Chemical compound COS(=O)(=O)OC VAYGXNSJCAHWJZ-UHFFFAOYSA-N 0.000 description 2
- 238000001035 drying Methods 0.000 description 2
- 239000003456 ion exchange resin Substances 0.000 description 2
- 229920003303 ion-exchange polymer Polymers 0.000 description 2
- 239000012528 membrane Substances 0.000 description 2
- 239000011259 mixed solution Substances 0.000 description 2
- VLTRZXGMWDSKGL-UHFFFAOYSA-N perchloric acid Chemical compound OCl(=O)(=O)=O VLTRZXGMWDSKGL-UHFFFAOYSA-N 0.000 description 2
- 239000012716 precipitator Substances 0.000 description 2
- 238000002360 preparation method Methods 0.000 description 2
- 239000002994 raw material Substances 0.000 description 2
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical class [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- RJUFJBKOKNCXHH-UHFFFAOYSA-N Methyl propionate Chemical compound CCC(=O)OC RJUFJBKOKNCXHH-UHFFFAOYSA-N 0.000 description 1
- 241000219873 Vicia Species 0.000 description 1
- 208000020329 Zika virus infectious disease Diseases 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 239000008186 active pharmaceutical agent Substances 0.000 description 1
- 229910052925 anhydrite Inorganic materials 0.000 description 1
- 230000000844 anti-bacterial effect Effects 0.000 description 1
- 239000002585 base Substances 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- 230000002308 calcification Effects 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- AXCZMVOFGPJBDE-UHFFFAOYSA-L calcium dihydroxide Chemical compound [OH-].[OH-].[Ca+2] AXCZMVOFGPJBDE-UHFFFAOYSA-L 0.000 description 1
- 239000000920 calcium hydroxide Substances 0.000 description 1
- 229910001861 calcium hydroxide Inorganic materials 0.000 description 1
- 159000000007 calcium salts Chemical class 0.000 description 1
- OSGAYBCDTDRGGQ-UHFFFAOYSA-L calcium sulfate Chemical compound [Ca+2].[O-]S([O-])(=O)=O OSGAYBCDTDRGGQ-UHFFFAOYSA-L 0.000 description 1
- 239000001569 carbon dioxide Substances 0.000 description 1
- 230000003293 cardioprotective effect Effects 0.000 description 1
- 238000011109 contamination Methods 0.000 description 1
- 238000000354 decomposition reaction Methods 0.000 description 1
- 239000008367 deionised water Substances 0.000 description 1
- 229910021641 deionized water Inorganic materials 0.000 description 1
- 238000011033 desalting Methods 0.000 description 1
- 238000003795 desorption Methods 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 150000004683 dihydrates Chemical class 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 229940088679 drug related substance Drugs 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- XLYOFNOQVPJJNP-ZSJDYOACSA-N heavy water Substances [2H]O[2H] XLYOFNOQVPJJNP-ZSJDYOACSA-N 0.000 description 1
- 230000001771 impaired effect Effects 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- IMNJQLRJRBNZGF-UHFFFAOYSA-N methyl 3-(2,2-dimethylhydrazinyl)propanoate Chemical compound COC(=O)CCNN(C)C IMNJQLRJRBNZGF-UHFFFAOYSA-N 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 230000035699 permeability Effects 0.000 description 1
- 230000001376 precipitating effect Effects 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- SSNBZPCCTUTRBD-UHFFFAOYSA-N propanoic acid;sulfuric acid Chemical compound CCC(O)=O.OS(O)(=O)=O SSNBZPCCTUTRBD-UHFFFAOYSA-N 0.000 description 1
- 230000008929 regeneration Effects 0.000 description 1
- 238000011069 regeneration method Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C241/00—Preparation of compounds containing chains of nitrogen atoms singly-bound to each other, e.g. hydrazines, triazanes
- C07C241/02—Preparation of hydrazines
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention provides a novel method for preparing 3- (2, 2, 2-trimethylhydrazinium) propionate dihydrate from 3- (2, 2, 2-trimethylhydrazinium) methyl propionate halide salt obtained by methyl halide methylation, which has the main advantages of obtaining a high-purity target finished product by using the most conventional process, avoiding separation and purification processes such as macroporous resin or electrodialysis and the like, improving the yield, reducing the environmental pollution, easily realizing commercial large-scale production, reducing the cost, and having simple and easy-operating equipment.
Description
Technical Field
The invention relates to an active compound 3- (2, 2, 2-trimethylhydrazinium) propionate dihydrate in the field of medicine, in particular to a synthetic route for synthesizing a raw material of a mildronate medicine and a technology for separating the compound.
Background
The international non-patent name 3- (2, 2, 2-trimethylhydrazinium) propionate dihydrate meldonium is well known for its cardioprotective effect.
There are currently many methods for preparing 3- (2, 2, 2-trimethylhydrazinium) propionate dihydrate.
The earliest preparation of 3- (2, 2, 2-trimethylhydrazinium) propionate dihydrate was disclosed in WO 80/01068A (INST ORGANICHESKOGO SINTEZA) 1980.05.29. In the method, methyl 3- (2, 2-dimethylhydrazino) propionate is firstly treated by methyl halide or dimethyl sulfate to generate suitable methyl 3- (2, 2, 2-trimethylhydrazino) propionate, and the suitable methyl 3- (2, 2, 2-trimethylhydrazino) propionate is converted into 3- (2, 2, 2-trimethylhydrazino) propionate by using an ion exchange resin column (Amberlite IRA-400, OH type column), and then the dihydrate inner salt is obtained by washing, distilling, concentrating, ethanol recrystallizing and the like. The disadvantages of this process are that the very low productivity makes the process extremely complex, requires more large production equipment, occupies a large amount of space, and requires large amounts of solvents, acids and bases and deionized water for resin regeneration. Furthermore, the ion exchange resin Amberlite IRA-400 caused the product to be unstable and gradually degraded, resulting in oligomer contamination of the final product, and the meldonium product containing decomposition residues obtained by this method could not be used for preparing injection solutions because the bactericidal membrane permeability was impaired. The method described in SU978808(INST organichoko sinomenia) 1982.12.07 is a method of hydrolysis of methyl 3- (2, 2, 2-trimethylhydrazinium) propionate salt using an excess of standard bases, which also does not lead to the desired product of the drug substance, and its isolation and purification has not been successful because 3- (2, 2, 2-trimethylhydrazinium) propionate dihydrate and inorganic salts present from the hydrolysis form multiple double salts.
The WO 2008028514 patent discloses that the methyl 3- (2, 2, 2-trimethylhydrazinium) propionate salt is a process in which excess potassium hydroxide in an alcoholic medium is hydrolyzed and inorganic acid anhydride (e.g. carbon dioxide, sulfur dioxide, etc.) is introduced and the precipitated inorganic salt is separated, which process still has the disadvantage that it does not completely solve the problem of completely removing the inorganic salt from the product, and as a result, the product quality is unsatisfactory and does not meet pharmacopoeia quality standards. [ RU 2404159, 2010.11.20] discloses a method which does not solve the problem of purification and separation well, and it is very difficult to control the designated range of pH in the actual industrial production.
The CN 102036950a (lina zika) 2011.04.27 patent discloses that the hydrolysis method of methyl 3- (2, 2, 2-trimethylhydrazinium) propionate sulfate using basic calcium salt can avoid the use of electrodialysis in the preparation of 3- (2, 2, 2-trimethylhydrazinium) propionate dihydrate, and a product with higher purity is obtained by a conventional desalting method, but the sulfuric acid method for preparing 3- (2, 2, 2-trimethylhydrazinium) propionate dihydrate is clinically failed due to the problems of dimethyl sulfate residue and the like, and the european pharmacopoeia does not admit the method at present.
The above described process for the production of electrodialytic ionic membranes is only used as the most convenient and reliable process in the company GRINDEKS, licensed to la vicia for the production of meldonium.
The invention aims to find a conventional precipitation treatment method for avoiding separation and purification processes such as macroporous resin or electrodialysis and the like when 3- (2, 2, 2-trimethylhydrazinium) propionate dihydrate is prepared by methylation of methyl halide.
Disclosure of Invention
The main composition of the invention is that methyl 3- (2, 2, 2-trimethylhydrazinium) propionate (Cl, Br or I) halide salt is hydrolyzed in an alkaline solution to adjust pH, the mixture after filtration is treated with an alkaline inorganic salt (or two mixed salts) to obtain a mixed solution containing water-insoluble precipitate, the inorganic salt is completely removed by solvent concentration and simple filtration, and the precipitate residue can be quantified. The invention has the main advantages that the precipitate residue in the mixed solution of the 3- (2, 2, 2-trimethylhydrazinium) propionate dihydrate is separated and purified by a simple filtration method, the target product with high purity is obtained by using the most conventional process, the separation and purification processes such as macroporous resin or electrodialysis and the like are avoided, the yield is improved, the environmental pollution is reduced, the commercial large-scale production is easy to realize, the cost is reduced, the equipment is simple and easy to operate, and the like.
In order to solve the technical problems, the technical scheme is as follows: a novel method for preparing 3- (2, 2, 2-trimethylhydrazinium) propionate dihydrate by methyl methylation of methyl halide comprises the following steps:
The technical scheme includes that methyl 3- (2, 2, 2-trimethylhydrazinium) propionate halide salt is hydrolyzed in an alkaline solution, an acidic compound is used for adjusting the pH value to a proper range, a precipitator is added into a filtered mixture for treatment, and an obtained solid-liquid substance can be purified in a special solvent in a simple filtering mode to completely remove double salts to obtain a high-purity 3- (2, 2, 2-trimethylhydrazinium) propionate dihydrate raw material drug.
Comprises the following components: the molecular structural formula of the bromine salt of 3- (2, 2, 2-trimethylhydrazinium) methyl propionate is (CH)3)3N+NHCH2CH2COOCH3Br-(ii) a 3- (2, 2, 2-Trimethylhydrazinium) propionate dihydrate C6H14N2O2.2H2O; the alkaline solution is NaOH or KOH aqueous solution, KOH and CaCl2Ethanol solution of the mixture, alcoholic solution of NaOH or KOH and clear Ca (OH)2At least one of the solutions.
The acidic compound is CO2、SO2、NH4HCO3、(NH4)2CO3、(NH4)2C2O4At least one of oxalic acid, perchloric acid and an HCl compound; the pH range is 6.0-11; the precipitator is BaCl2、CaSO4、(NH4)2C2O4、Ca(OH)2、 NH4NO3、CaCl2And oxalic acid.
The component ratio is as follows: the concentration of the alkaline solution is 10-25%, and the ratio of alkaline compound NaOH (or KOH) to calcification is 1: 0-0.02 (m: m); the ratio of the precipitant to the 3- (2, 2, 2-trimethylhydrazinium) methyl propionate bromide salt is (1: 20-100 m/m).
Detailed Description
The following examples will help to understand the present invention, but they are only for illustrative purposes and the present invention is not limited to these contents.
EXAMPLE 1
65g of 3- (2, 2, 2-trimethylhydrazinium) propionic acid methyl ester bromide salt are dissolved by adding 700ml of water with stirring and a quantity of saturated NaOH solution is added. Heating the reaction mixture to 60 deg.C for 3h (detecting whether the reaction is terminated by TLC), adding a certain amount of CaCl2And continuously stirring the solution for 30min, adding 600ml of isopropanol, mixing, cooling to-2 ℃, filtering precipitates, acidifying the filtrate by oxalic acid, adding a saturated BaCl2 solution, mixing, stirring, cooling, filtering, adding 120ml of isopropanol into the filtrate, cooling to-10 ℃, standing for 1h, filtering, washing and drying in vacuum to obtain 50g of finished product (white crystalline powder). The major content of dry solids was determined quantitatively by non-aqueous titration to be 99.9%; pH: pH7.85 of 10% aqueous solution; ash content of sulfuric acid: 0.02 percent; moisture (karl fischer): 20.61 percent; heavy metals: less than 0.001%.
EXAMPLE 2
65g of 3- (2, 2, 2-trimethylhydrazinium) propionic acid methyl ester bromide salt are dissolved by adding 700ml of water with stirring and a quantity of saturated NaOH solution is added. Heating the reaction mixture to 60 deg.C, maintaining the temperature for 3h (detecting whether the reaction is terminated by TLC), adding 600ml isopropanol, mixing, cooling to-2 deg.C, filtering the precipitate with special emulsion, and filtering the filtrate with CO 2Filtering the acidified milky double salt by using an emulsifier, adding 120ml of isopropanol into the filtrate, cooling to-10 ℃, standing for 1h, filtering, washing and drying in vacuum to obtain 39g of finished product (white crystalline powder). The major content of dry solids was determined quantitatively by non-aqueous titration to be 99.0%; pH: pH 8.8 of 10% aqueous solution; ash content of sulfuric acid: 0.24 percent; water (W)Parts (karl fischer): 20.03 percent; heavy metals: less than 0.001%.
EXAMPLE 3
65g of 3- (2, 2, 2-trimethylhydrazinium) propionic acid methyl ester bromide salt are dissolved by adding 700ml of water with stirring and a quantity of saturated NaOH solution is added. Heating the reaction mixture to 60 deg.C for 3h (detecting whether the reaction is terminated by TLC), adding a certain amount of CaCl2Stirring the solution for 30min, adding 600ml isopropanol, cooling to-2 deg.C, filtering the precipitate, and adding CO into the filtrate2Acidifying, adding BaCl2Mixing and stirring the saturated solution, cooling and filtering, adding 120ml of isopropanol into the filtrate, cooling to-10 ℃, standing for 1h, filtering, washing and vacuum drying to obtain 48g of finished product (white crystalline powder). The main content of dry solids was determined quantitatively by non-aqueous titration to be 100.3%; pH: pH 7.38 for 10% aqueous solution; ash content of sulfuric acid: 0.02 percent; moisture (karl fischer): 20.11 percent; heavy metals: less than 0.001%.
EXAMPLE 4
65g of 3 methyl (2, 2, 2-trimethylhydrazinium) propionate bromide salt are dissolved by adding 700ml of water with stirring and an amount of saturated NaOH solution is added. The reaction mixture was heated to 60 ℃ for 3h (detection of reaction termination by TLC) and a defined amount of CaCl was added2Stirring the solution for 30min, adding 600ml isopropanol, cooling to-2 deg.C, filtering the precipitate, and adding CO into the filtrate2After acidification, BaCl is added2Mixing and stirring the saturated solution, cooling and filtering, adding 120ml of isopropanol into the filtrate, cooling to-10 ℃, standing for 1h, filtering, washing and vacuum drying to obtain 48g of finished product (white crystalline powder). The major content of dry solids was determined quantitatively by non-aqueous titration to be 100.3%; pH: pH 7.70 for 10% aqueous solution; ash content of sulfuric acid: 0.04 percent; moisture (karl fischer): 20.11 percent; heavy metals: less than 0.001%.
EXAMPLE 5
65g of 3- (2, 2, 2-trimethylhydrazinium) propionic acid methyl ester bromide salt are dissolved by adding 700ml of water with stirring and a quantity of saturated NaOH solution is added. Heating the reaction mixture to 60 deg.C, keeping the temperature for 3h (detecting whether the reaction is terminated by TLC), adding 600ml isopropanol, mixing, cooling to-2 deg.C, filtering and precipitating with special-purpose emulsion deviceUsing CO for the precipitate and filtrate2And (3) adsorbing the acidified filtered filtrate by using macroporous resin, then carrying out desorption treatment, concentrating, cooling to-10 ℃, standing for 1h, carrying out suction filtration, washing and vacuum drying to obtain 37g of finished product (white crystalline powder). The major content of dry solids was determined quantitatively by non-aqueous titration to be 99.6%; pH: pH8.12 of 10% aqueous solution; ash content of sulfuric acid: 0.05 percent; moisture (karl fischer): 20.00 percent; heavy metals: less than 0.001%.
EXAMPLE 6
65g of 3 methyl (2, 2, 2-trimethylhydrazinium) propionate bromide salt are dissolved by adding 700ml of water with stirring and an amount of saturated NaOH solution is added. Heating the reaction mixture to 60 deg.C, keeping the temperature for 3h (detecting whether the reaction is terminated by TLC), adding 600ml isopropanol, mixing, cooling to-2 deg.C, filtering the precipitate with special emulsion device, and filtering the filtrate with CO2After filtration after acidification, the obtained milky solution was purified by filtration through an EMOU-2-purifying electrodialysis device using meldonium (electromembrane device EMA-30/2), concentrated under vacuum, cooled, filtered under vacuum, and dried under vacuum to obtain 40g of a finished product (white crystalline powder). The main content of dry solids was determined quantitatively by non-aqueous titration to be 100.2%; pH: pH7.46 of 10% aqueous solution; ash content of sulfuric acid: 0.03 percent; moisture (karl fischer): 19.98 percent; heavy metals: less than 0.001%.
Claims (4)
1. A method for preparing 3- (2, 2, 2-trimethylhydrazinium) propionate dihydrate by methyl methylation of methyl halide is characterized in that: adding 65g of methyl 3- (2, 2, 2-trimethylhydrazinium) propionate bromide into 700ml of water under stirring, adding a certain amount of NaOH saturated solution, heating the reaction mixture to 60 ℃, keeping the temperature for 3 hours, adding a certain amount of CaCl2Stirring the solution for 30min, adding 600ml isopropanol, mixing, cooling to-2 deg.C, filtering, acidifying the filtrate with oxalic acid, and adding BaCl 2Mixing and stirring the saturated solution, cooling and filtering, adding 120ml of isopropanol into the filtrate, cooling to-10 ℃, standing for 1h, filtering, washing and vacuum drying to obtain 50g of finished product, and quantitatively determining the main content of the dried solid to be 99.9% by using a non-aqueous titration method; pH: pH7.85 of 10% aqueous solution; ash content of sulfuric acid: 0.02 percent; measuring the water content by a Karl Fischer method: 20.61 percent; heavy metals: less than 0.001％。
2. A method for preparing 3- (2, 2, 2-trimethylhydrazinium) propionate dihydrate by methyl methylation of methyl halide is characterized in that: adding 65g of methyl 3- (2, 2, 2-trimethylhydrazinium) propionate bromide into 700ml of water under stirring, adding a certain amount of NaOH saturated solution, heating the reaction mixture to 60 ℃, keeping the temperature for 3h, adding 600ml of isopropanol, mixing, cooling to-2 ℃, filtering the precipitate by using a special emulsion device, filtering the filtrate by using CO2Filtering the acidified milky double salt by using an emulsifier, adding 120ml of isopropanol into the filtrate, cooling to-10 ℃, standing for 1h, filtering, washing, vacuum-drying to obtain 39g of finished product, and quantitatively determining the main content of the dried solid to be 99.0% by using a non-aqueous titration method; pH: pH 8.8 for 10% aqueous solution; ash content of sulfuric acid: 0.24 percent; measuring the water content by a Karl Fischer method: 20.03 percent; heavy metals: less than 0.001%.
3. A method for preparing 3- (2, 2, 2-trimethylhydrazinium) propionate dihydrate by methyl methylation of methyl halide is characterized in that: adding 65g of methyl 3- (2, 2, 2-trimethylhydrazinium) propionate bromide into 700ml of water under stirring, adding a certain amount of NaOH saturated solution, heating the reaction mixture to 60 ℃, keeping the temperature for 3 hours, adding a certain amount of CaCl 2Stirring the solution for 30min, adding 600m cooling isopropanol, cooling to-2 deg.C, filtering the precipitate, and adding CO into the filtrate2After acidification, BaCl is added2Mixing and stirring the saturated solution, filtering, adding 120ml of isopropanol into the filtrate, cooling to-10 ℃, standing for 1h, carrying out suction filtration, washing and vacuum drying to obtain 48g of finished product, and quantitatively determining the main content of the dried solid to be 100.3% by using a non-aqueous titration method; pH: pH 7.38 for 10% aqueous solution; ash content of sulfuric acid: 0.02 percent; measuring the water content by a Karl Fischer method: 20.11 percent; heavy metals: less than 0.001%.
4. A method for preparing 3- (2, 2, 2-trimethylhydrazinium) propionate dihydrate by methyl methylation of methyl halide is characterized in that: adding 65g of methyl 3- (2, 2, 2-trimethylhydrazinium) propionate bromide into 700ml of water under stirring, adding a certain amount of NaOH saturated solution, heating the reaction mixture to 60 ℃, keeping the temperature for 3 hours, adding a certain amount of CaCl2Stirring the solution for 30min, adding 600ml isopropanol, cooling to-2 deg.C, filtering the precipitate, and adding CO into the filtrate2Acidifying, adding BaCl2Mixing and stirring the saturated solution, cooling and filtering, adding 120ml of isopropanol into the filtrate, cooling to-10 ℃, standing for 1h, filtering, washing and vacuum drying to obtain 48g of finished product, and quantitatively determining the main content of the dried solid to be 100.3% by using a non-aqueous titration method; pH: pH 7.70 for 10% aqueous solution; ash content of sulfuric acid: 0.04 percent; measuring the water content by a Karl Fischer method: 20.11 percent; heavy metals: less than 0.001%.
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| CN101541739A (en) * | 2006-09-04 | 2009-09-23 | 乔治·席尔瓦 | Process for the preparation of 3- (2,2, 2-trimethylhydrazinium) propionate dihydrate |
| CN102036950A (en) * | 2008-05-26 | 2011-04-27 | 格林代克斯联合股份公司 | New process for the preparation of 3-(2,2,2-trimethylhydrazinium) propionate dihydrate |
| CN102093254A (en) * | 2010-11-19 | 2011-06-15 | 绍兴文理学院 | Preparation method of 3-(2,2,2-trimethylhydrazine)propionate dihydrate |
| CN104163776A (en) * | 2014-05-28 | 2014-11-26 | 东力（南通）化工有限公司 | Improved preparation technology method of 3- (2, 2-dimethylhydrazino) methyl propionate and 3- (2,2, 2-trimethylhydrazine) methyl propionate |
| CN109369447A (en) * | 2018-11-05 | 2019-02-22 | 东力（南通）化工有限公司 | Improved method of preparation technology of 3- (2, 2, 2-trimethylhydrazinium) propionate dihydrate |
| CN109369446A (en) * | 2018-11-12 | 2019-02-22 | 东力（南通）化工有限公司 | Preparation method of high-purity 3- (2, 2, 2-trimethylhydrazinium) methyl propionate raw material medicine intermediate |
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| CN101541739A (en) * | 2006-09-04 | 2009-09-23 | 乔治·席尔瓦 | Process for the preparation of 3- (2,2, 2-trimethylhydrazinium) propionate dihydrate |
| CN102036950A (en) * | 2008-05-26 | 2011-04-27 | 格林代克斯联合股份公司 | New process for the preparation of 3-(2,2,2-trimethylhydrazinium) propionate dihydrate |
| CN102093254A (en) * | 2010-11-19 | 2011-06-15 | 绍兴文理学院 | Preparation method of 3-(2,2,2-trimethylhydrazine)propionate dihydrate |
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| CN109369447A (en) * | 2018-11-05 | 2019-02-22 | 东力（南通）化工有限公司 | Improved method of preparation technology of 3- (2, 2, 2-trimethylhydrazinium) propionate dihydrate |
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