CN109369447B - Improved method of preparation technology of 3- (2, 2, 2-trimethylhydrazinium) propionate dihydrate - Google Patents
Improved method of preparation technology of 3- (2, 2, 2-trimethylhydrazinium) propionate dihydrate Download PDFInfo
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- CN109369447B CN109369447B CN201811350786.4A CN201811350786A CN109369447B CN 109369447 B CN109369447 B CN 109369447B CN 201811350786 A CN201811350786 A CN 201811350786A CN 109369447 B CN109369447 B CN 109369447B
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- 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 45
- 238000000034 method Methods 0.000 title claims abstract description 35
- 238000002360 preparation method Methods 0.000 title description 4
- 239000000243 solution Substances 0.000 claims abstract description 39
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims abstract description 18
- 150000003839 salts Chemical class 0.000 claims abstract description 13
- 239000000839 emulsion Substances 0.000 claims abstract description 10
- 230000007062 hydrolysis Effects 0.000 claims abstract description 4
- 238000006460 hydrolysis reaction Methods 0.000 claims abstract description 4
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 137
- 238000005406 washing Methods 0.000 claims description 65
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 48
- 238000001816 cooling Methods 0.000 claims description 47
- 239000002244 precipitate Substances 0.000 claims description 40
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 36
- 238000001914 filtration Methods 0.000 claims description 35
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 30
- 239000003814 drug Substances 0.000 claims description 27
- 229940079593 drug Drugs 0.000 claims description 21
- 239000002994 raw material Substances 0.000 claims description 21
- 239000012452 mother liquor Substances 0.000 claims description 20
- 238000002156 mixing Methods 0.000 claims description 18
- 238000001035 drying Methods 0.000 claims description 17
- 238000002844 melting Methods 0.000 claims description 17
- 230000008018 melting Effects 0.000 claims description 17
- 230000003301 hydrolyzing effect Effects 0.000 claims description 15
- 239000010413 mother solution Substances 0.000 claims description 12
- 239000007864 aqueous solution Substances 0.000 claims description 11
- 229910017053 inorganic salt Inorganic materials 0.000 claims description 10
- SSNBZPCCTUTRBD-UHFFFAOYSA-N propanoic acid;sulfuric acid Chemical compound CCC(O)=O.OS(O)(=O)=O SSNBZPCCTUTRBD-UHFFFAOYSA-N 0.000 claims description 7
- 238000000967 suction filtration Methods 0.000 claims description 7
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 7
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 6
- XFSUFSQSUUMXLB-UHFFFAOYSA-N propanoic acid;hydrobromide Chemical compound Br.CCC(O)=O XFSUFSQSUUMXLB-UHFFFAOYSA-N 0.000 claims description 5
- 239000007787 solid Substances 0.000 claims description 4
- 238000003756 stirring Methods 0.000 claims description 4
- 230000001376 precipitating effect Effects 0.000 claims description 3
- UKFWSNCTAHXBQN-UHFFFAOYSA-N ammonium iodide Chemical compound [NH4+].[I-] UKFWSNCTAHXBQN-UHFFFAOYSA-N 0.000 claims description 2
- 239000001110 calcium chloride Substances 0.000 claims description 2
- 229910001628 calcium chloride Inorganic materials 0.000 claims description 2
- 239000007788 liquid Substances 0.000 claims description 2
- YYFIGOPUHPDIBO-UHFFFAOYSA-N propanoic acid;hydrochloride Chemical compound Cl.CCC(O)=O YYFIGOPUHPDIBO-UHFFFAOYSA-N 0.000 claims description 2
- PZFLIZRXZJKOLG-UHFFFAOYSA-N Br.CCC(=O)OC Chemical compound Br.CCC(=O)OC PZFLIZRXZJKOLG-UHFFFAOYSA-N 0.000 claims 2
- 230000020477 pH reduction Effects 0.000 abstract description 15
- 239000011259 mixed solution Substances 0.000 abstract description 10
- 238000000926 separation method Methods 0.000 abstract description 7
- 238000004519 manufacturing process Methods 0.000 abstract description 6
- 238000000746 purification Methods 0.000 abstract description 6
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 abstract description 4
- 239000002253 acid Substances 0.000 abstract description 4
- 238000000909 electrodialysis Methods 0.000 abstract description 4
- JZMJDSHXVKJFKW-UHFFFAOYSA-M methyl sulfate(1-) Chemical compound COS([O-])(=O)=O JZMJDSHXVKJFKW-UHFFFAOYSA-M 0.000 abstract description 3
- 238000005904 alkaline hydrolysis reaction Methods 0.000 abstract description 2
- 208000024172 Cardiovascular disease Diseases 0.000 abstract 1
- 239000003795 chemical substances by application Substances 0.000 abstract 1
- 238000006243 chemical reaction Methods 0.000 description 23
- RAHZWNYVWXNFOC-UHFFFAOYSA-N Sulphur dioxide Chemical compound O=S=O RAHZWNYVWXNFOC-UHFFFAOYSA-N 0.000 description 12
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 10
- 239000000047 product Substances 0.000 description 9
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 8
- 229910002092 carbon dioxide Inorganic materials 0.000 description 7
- 150000003863 ammonium salts Chemical class 0.000 description 5
- 239000001569 carbon dioxide Substances 0.000 description 5
- 239000002535 acidifier Substances 0.000 description 4
- 235000011007 phosphoric acid Nutrition 0.000 description 4
- -1 propionate halide Chemical class 0.000 description 4
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 3
- 150000004683 dihydrates Chemical class 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 238000009776 industrial production Methods 0.000 description 3
- 239000000463 material Substances 0.000 description 3
- FVAUCKIRQBBSSJ-UHFFFAOYSA-M sodium iodide Chemical compound [Na+].[I-] FVAUCKIRQBBSSJ-UHFFFAOYSA-M 0.000 description 3
- RHUYHJGZWVXEHW-UHFFFAOYSA-N 1,1-Dimethyhydrazine Chemical compound CN(C)N RHUYHJGZWVXEHW-UHFFFAOYSA-N 0.000 description 2
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 2
- ATRRKUHOCOJYRX-UHFFFAOYSA-N Ammonium bicarbonate Chemical compound [NH4+].OC([O-])=O ATRRKUHOCOJYRX-UHFFFAOYSA-N 0.000 description 2
- TWRXJAOTZQYOKJ-UHFFFAOYSA-L Magnesium chloride Chemical compound [Mg+2].[Cl-].[Cl-] TWRXJAOTZQYOKJ-UHFFFAOYSA-L 0.000 description 2
- BAPJBEWLBFYGME-UHFFFAOYSA-N Methyl acrylate Chemical compound COC(=O)C=C BAPJBEWLBFYGME-UHFFFAOYSA-N 0.000 description 2
- 229910002651 NO3 Inorganic materials 0.000 description 2
- 229910019142 PO4 Inorganic materials 0.000 description 2
- WCUXLLCKKVVCTQ-UHFFFAOYSA-M Potassium chloride Chemical compound [Cl-].[K+] WCUXLLCKKVVCTQ-UHFFFAOYSA-M 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- 239000001099 ammonium carbonate Substances 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 150000001875 compounds Chemical class 0.000 description 2
- 239000012043 crude product Substances 0.000 description 2
- 238000002425 crystallisation Methods 0.000 description 2
- 230000008025 crystallization Effects 0.000 description 2
- 239000012535 impurity Substances 0.000 description 2
- PVBQYTCFVWZSJK-UHFFFAOYSA-N meldonium Chemical compound C[N+](C)(C)NCCC([O-])=O PVBQYTCFVWZSJK-UHFFFAOYSA-N 0.000 description 2
- 229960002937 meldonium Drugs 0.000 description 2
- 238000006386 neutralization reaction Methods 0.000 description 2
- 239000012450 pharmaceutical intermediate Substances 0.000 description 2
- 239000011736 potassium bicarbonate Substances 0.000 description 2
- 229910000028 potassium bicarbonate Inorganic materials 0.000 description 2
- PPQFUDZMTNGHBJ-UHFFFAOYSA-N propanoic acid;dihydrate Chemical compound O.O.CCC(O)=O PPQFUDZMTNGHBJ-UHFFFAOYSA-N 0.000 description 2
- JHJLBTNAGRQEKS-UHFFFAOYSA-M sodium bromide Chemical compound [Na+].[Br-] JHJLBTNAGRQEKS-UHFFFAOYSA-M 0.000 description 2
- VWDWKYIASSYTQR-UHFFFAOYSA-N sodium nitrate Chemical compound [Na+].[O-][N+]([O-])=O VWDWKYIASSYTQR-UHFFFAOYSA-N 0.000 description 2
- GEHJYWRUCIMESM-UHFFFAOYSA-L sodium sulfite Chemical compound [Na+].[Na+].[O-]S([O-])=O GEHJYWRUCIMESM-UHFFFAOYSA-L 0.000 description 2
- JMGQRZWIKKHUNB-UHFFFAOYSA-N (2-carboxyethylamino)-trimethylazanium;dihydrogen phosphate Chemical compound OP(O)([O-])=O.C[N+](C)(C)NCCC(O)=O JMGQRZWIKKHUNB-UHFFFAOYSA-N 0.000 description 1
- PAWQVTBBRAZDMG-UHFFFAOYSA-N 2-(3-bromo-2-fluorophenyl)acetic acid Chemical compound OC(=O)CC1=CC=CC(Br)=C1F PAWQVTBBRAZDMG-UHFFFAOYSA-N 0.000 description 1
- XZXYQEHISUMZAT-UHFFFAOYSA-N 2-[(2-hydroxy-5-methylphenyl)methyl]-4-methylphenol Chemical compound CC1=CC=C(O)C(CC=2C(=CC=C(C)C=2)O)=C1 XZXYQEHISUMZAT-UHFFFAOYSA-N 0.000 description 1
- USFZMSVCRYTOJT-UHFFFAOYSA-N Ammonium acetate Chemical compound N.CC(O)=O USFZMSVCRYTOJT-UHFFFAOYSA-N 0.000 description 1
- 239000005695 Ammonium acetate Substances 0.000 description 1
- 229910000013 Ammonium bicarbonate Inorganic materials 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical class [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- UXVMQQNJUSDDNG-UHFFFAOYSA-L Calcium chloride Chemical compound [Cl-].[Cl-].[Ca+2] UXVMQQNJUSDDNG-UHFFFAOYSA-L 0.000 description 1
- VXLCNTLWWUDBSO-UHFFFAOYSA-N Ethiazide Chemical compound ClC1=C(S(N)(=O)=O)C=C2S(=O)(=O)NC(CC)NC2=C1 VXLCNTLWWUDBSO-UHFFFAOYSA-N 0.000 description 1
- 241001275899 Salta Species 0.000 description 1
- FKNQFGJONOIPTF-UHFFFAOYSA-N Sodium cation Chemical class [Na+] FKNQFGJONOIPTF-UHFFFAOYSA-N 0.000 description 1
- 229910000831 Steel Inorganic materials 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- VSCWAEJMTAWNJL-UHFFFAOYSA-K aluminium chloride Substances Cl[Al](Cl)Cl VSCWAEJMTAWNJL-UHFFFAOYSA-K 0.000 description 1
- 235000019257 ammonium acetate Nutrition 0.000 description 1
- 229940043376 ammonium acetate Drugs 0.000 description 1
- 235000012538 ammonium bicarbonate Nutrition 0.000 description 1
- 235000012501 ammonium carbonate Nutrition 0.000 description 1
- 235000019270 ammonium chloride Nutrition 0.000 description 1
- 229940107816 ammonium iodide Drugs 0.000 description 1
- VBIXEXWLHSRNKB-UHFFFAOYSA-N ammonium oxalate Chemical compound [NH4+].[NH4+].[O-]C(=O)C([O-])=O VBIXEXWLHSRNKB-UHFFFAOYSA-N 0.000 description 1
- ZRIUUUJAJJNDSS-UHFFFAOYSA-N ammonium phosphates Chemical class [NH4+].[NH4+].[NH4+].[O-]P([O-])([O-])=O ZRIUUUJAJJNDSS-UHFFFAOYSA-N 0.000 description 1
- BFNBIHQBYMNNAN-UHFFFAOYSA-N ammonium sulfate Chemical compound N.N.OS(O)(=O)=O BFNBIHQBYMNNAN-UHFFFAOYSA-N 0.000 description 1
- 229910052921 ammonium sulfate Inorganic materials 0.000 description 1
- 235000011130 ammonium sulphate Nutrition 0.000 description 1
- 150000008064 anhydrides Chemical class 0.000 description 1
- ZRDJERPXCFOFCP-UHFFFAOYSA-N azane;iodic acid Chemical compound [NH4+].[O-]I(=O)=O ZRDJERPXCFOFCP-UHFFFAOYSA-N 0.000 description 1
- 230000003293 cardioprotective effect Effects 0.000 description 1
- 238000000354 decomposition reaction Methods 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 239000003792 electrolyte Substances 0.000 description 1
- 239000003995 emulsifying agent Substances 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- XLYOFNOQVPJJNP-ZSJDYOACSA-N heavy water Substances [2H]O[2H] XLYOFNOQVPJJNP-ZSJDYOACSA-N 0.000 description 1
- 239000000413 hydrolysate Substances 0.000 description 1
- 150000002484 inorganic compounds Chemical class 0.000 description 1
- 229910010272 inorganic material Inorganic materials 0.000 description 1
- 239000000543 intermediate Substances 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- 238000011031 large-scale manufacturing process Methods 0.000 description 1
- 229910001629 magnesium chloride Inorganic materials 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
- 239000000203 mixture Substances 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- 235000021317 phosphate Nutrition 0.000 description 1
- 150000003013 phosphoric acid derivatives Chemical class 0.000 description 1
- KSHRIBUREVIIFI-UHFFFAOYSA-N phosphoric acid;propanoic acid Chemical compound CCC(O)=O.OP(O)(O)=O KSHRIBUREVIIFI-UHFFFAOYSA-N 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 239000012047 saturated solution Substances 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 description 1
- LPXPTNMVRIOKMN-UHFFFAOYSA-M sodium nitrite Substances [Na+].[O-]N=O LPXPTNMVRIOKMN-UHFFFAOYSA-M 0.000 description 1
- BAZAXWOYCMUHIX-UHFFFAOYSA-M sodium perchlorate Chemical compound [Na+].[O-]Cl(=O)(=O)=O BAZAXWOYCMUHIX-UHFFFAOYSA-M 0.000 description 1
- 229910001488 sodium perchlorate Inorganic materials 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 239000010959 steel Substances 0.000 description 1
- LWIHDJKSTIGBAC-UHFFFAOYSA-K tripotassium phosphate Chemical class [K+].[K+].[K+].[O-]P([O-])([O-])=O LWIHDJKSTIGBAC-UHFFFAOYSA-K 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
An improved process for preparing 3- (2, 2, 2-trimethylhydrazinium) propionate dihydrate used for treating cardiovascular diseases is disclosed, which is prepared from the intermediate methyl 3- (2, 2, 2-trimethylhydrazinium) propionate (CH)3)3N+NHCH2CH2COOCH3X‑(wherein X represents Cl)‑、Br‑、I‑、CH3SO4 ‑) The alkaline hydrolysis and acidification products have no better process solution so far because the acidification purification process adopted after the hydrolysis is relatively complex. The acidification method is characterized in that a mixed solution is added before and after acidification, so that a complex (emulsion) or double salt of 3- (2, 2, 2-trimethylhydrazinium) propionate dihydrate is not formed, and an electrodialysis separation and purification step is avoided. In addition, the invention adds another novel acid agent to obtain a high-purity product in one step, thereby realizing the advantages of commercial scale production, cost reduction, simple equipment and the like.
Description
Technical Field
The invention relates to organic chemistry and medicine, in particular to a preparation method technology and a purification technology of an improved 3- (2, 2, 2-trimethylhydrazinium) propionate dihydrate mirtahydrazine dihydrate raw material medicine, belonging to the field of organic chemistry and medicine research.
Background
The international non-patent name 3- (2, 2, 2-trimethylhydrazinium) propionate dihydrate meldonium is well known for its cardioprotective effect. Generally, the method comprises:
1, 1-dimethylhydrazine is reacted with methyl acrylate to form methyl 3- (2, 2-dimethylhydrazino) propionate which is further hydrolyzed and deionized to form the appropriate methyl 3- (2, 2, 2-trimethylhydrazino) propionate halide or methyl sulfate, which is then separated with a saturated solution of carbon dioxide or sulfur dioxide, as disclosed in the WO2008028514 patent, although this process can be avoided in the 3- (2, 2-dimethylhydrazino) propionateElectrodialysis is used for preparing 2,2, 2-trimethylhydrazinium) propionate dihydrate, but in the case of using acidic gas to neutralize a large amount of reaction solution in actual industrial production, on the one hand, the error range of precise pH value required by the production process is difficult to control, and K is easily generated in the neutralization reaction2CO3/KHCO3Or Na2SO3/NaHSO3The final target product is easy to dissolve in water due to a mixed system of different double salts of the mixed salt and 3- (2, 2, 2-trimethylhydrazinium) propionate dihydrate, so that the separation of water-soluble inorganic salt and the purification of the target product are difficult to treat, and a complex double salt separation step and a complex inorganic salt separation step are required; on the other hand, the industrial gas acidification process is time-consuming, the working section needs at least 8-10 hours to complete, and the gas steel cylinder is low in temperature especially in winter, so that the acidification is more time-consuming; the reaction system after hydrolysis of the third aspect is further complicated by the delay of the acidification time, resulting in partial decomposition of the product. The method of the patent can not achieve satisfactory purification and separation, and the product can not meet the requirements of pharmacopeia quality standard (the sulfated ash content is less than 0.1 percent).
There is also known another method for preparing 3- (2, 2, 2-trimethylhydrazinium) propionate dihydrate (Russian patent RU2404159C2, published as 2010.11.20) by alkaline hydrolysis of a pharmaceutical intermediate, followed by isolation of KBr after the reaction is terminated, the reaction mixture being selected from orthophosphoric acid and mono-and di-substituted ammonium phosphates, and K is isolated from the mixture3PO4Treating the mixed solution containing 3- (2, 2, 2-trimethylhydrazinium) propionic acid dihydrogen phosphate treated with isopropanol with NH3, and separating the third inorganic salt (NH) by cooling and alcohol precipitation4)2HPO4Finally, the mother liquor is cooled by adding water and converted into dihydrate. The method selects phosphoric acid for acidification in a mixed solution, the phosphoric acid is a ternary medium-strong acid and a weak electrolyte, three-stage ionization is adopted, the method not only complicates a reaction system, and the generated trivalent phosphate is also an emulsifier instead of a demulsifier, but also solves the demulsification problem only by one step to obtain a target compound, and because the reaction of the dihydrate and the phosphate salt generated by hydrolysis can generate more complex double salt, the method has the appearance of tetra-complex saltA secondary separation step and an NH3 conversion step, etc. The method firstly destroys the target product and then obtains the target product through recalcitrance and conversion, but the inorganic salt is separated for multiple times, so that the types of residual impurities contained in the raw material medicine are quite large, the standard of the raw material medicine is difficult to achieve, the yield of the product is directly reduced, the production cost is too high, and the method cannot be realized in the actual industrial production. Another disadvantage of using phosphoric acid and ammonium phosphate salts is that the reaction with KOH of different concentrations to form different substituted potassium phosphate salts is difficult to remove, resulting in a complicated process, and thus the process is more suitable for the production of meldonium phosphate rather than meldonium dihydrate. In view of the above, acidification with other suitable inorganic compounds has not been successfully achieved so far, and therefore presents many difficulties in industrial production.
The object of the present invention was to find a water-soluble K suitable for the neutralization of 3- (2, 2, 2-trimethylhydrazinium) propionate dihydrate2CO3/KHCO3Or Na2SO3/NaHSO3The mixed salt is formed into a 3- (2, 2, 2-trimethylhydrazinium) propionate dihydrate complex (milky) or a double salt mixed system, a water-soluble target product is separated by using a simple process, or a simple improved method for preparing the 3- (2, 2, 2-trimethylhydrazinium) propionate dihydrate is found, so that the problem of producing a product with pharmaceutical-grade purity is better solved.
Disclosure of Invention
In order to achieve and overcome the above-mentioned disadvantages, the present invention is to add a mixed solution to the reaction solution in alcohol or to use a new acidifying agent to completely replace the previously used gaseous acidifying agents carbon dioxide, sulfur dioxide, etc. The inventor unexpectedly finds that if a small amount of mixed solution (namely, a mixed solution can be added before acidification and after acidification) is added into a reaction solution before or after inorganic anhydride (such as carbon dioxide, sulfur dioxide and the like) is introduced into the hydrolyzed solution to acidify the solution, the problems of emulsion complex and double salt resolution are solved or the formation of double salt and emulsion is completely prevented, and electrodialysis is avoided, 3- (2, 2, 2-trimethylhydrazinium) propionate and inorganic salt formed by the acidification method can be quickly and completely separated, so that the pH value of the solution is well controlled, and the problem of excessive inorganic salt residue is effectively prevented, and it should be pointed out that the above effects can be obtained only by determining the type of the added mixed solution, the proportion of the original materials, the optimal adding time and the temperature through strict experimental data; the present invention is based on the further unexpected discovery that the previously used gaseous acidulants carbon dioxide, sulfur dioxide, etc. are replaced by an ammonium salt in combination with a strong acid and a weak base to provide 3- (2, 2, 2-trimethylhydrazinium) propionate dihydrate.
In order to solve the technical problems, the invention adopts the technical scheme that a mixed solution is added into a reaction solution in a hydrolysate alcohol of a drug intermediate or a new acidulant is used for replacing carbon dioxide (sulfur dioxide) which is a gas acidulant used originally to obtain the 3- (2, 2, 2-trimethylhydrazinium) propionate dihydrate bulk drug and the reaction performance, and the method comprises the following steps: reaction scheme
Wherein: nNH4 ++OH-→H2O+nNH3↑
1. Comprises the following components: the molecular structural formula of the mildronate is C6H14N2O2.2H2O; pharmaceutical intermediate methyl 3- (2, 2, 2-trimethylhydrazinium) propionate (CH)3)3N+NHCH2CH2COOCH3X-Wherein X represents Cl-、Br-、I-、CH3SO4 -(ii) a The added mixed solution is selected from a group consisting of water and aqueous solutions containing inorganic salts of: halide ion salts including NaCl, NaI, NaBr, KCl, KI, MgCl2、CaCl2、AlCl3Etc. sodium ion salts, including NaClO4、NaNO3、Na2CO3、NaOC2H5、NaNO2At least one compound, wherein the ratio of the solvent to the solute is 100: 1-20(m/m), and the ratio of the addition amount of the original solution to the mixed solution is 25: 1-5 (m/m); acidifying agent being an ammonium salt (NH)4)nY, acidifying agent is inorganic ammonium salt (NH)4)nY, comprising: ammonium nitrate, ammonium carbonate, ammonium bicarbonate, ammonium sulfate, ammonium chloride, ammonium iodide, ammonium iodate, ammonium acetate, and ammonium oxalate.
2. The component ratio is as follows: the main content of the raw material of the 3- (2, 2, 2-trimethylhydrazinium) propionate dihydrate medicine is 99.0-101%, and the ash content of the sulfuric acid is less than 0.1%.
Technical effects
We have found that there are two unexpected effects: 1) thus, no formation of a complex (milky) or double salt of 3- (2, 2, 2-trimethylhydrazinium) propionate dihydrate avoids the electrodialysis separation purification step. 2) The method has the advantages that the mildronate dihydrate is quantitatively controlled within the necessary PH range of a reaction system in one step, the acidification time and the acidification process are obviously improved, the simplest technological process is developed on the basis of the improvement of an acid substitute to obtain the pharmaceutical grade 3- (2, 2, 2-trimethylhydrazinium) propionate dihydrate raw material drug, the acidification is simple and rapid, the post-treatment is convenient, namely the 3- (2, 2, 2-trimethylhydrazinium) propionate dihydrate with high yield and high purity is obtained by simple filtration and crystallization, the quality requirement impurity types and the limitation range specified by pharmacopoeia quality standards are easily reached, the ash content of sulfuric acid is controlled within the range of less than 0.1%, and the method is a simpler method for producing the pharmaceutical grade 3- (2, 2, 2-trimethylhydrazinium) propionate dihydrate.
The process of the present invention and the known processes for the preparation of 3- (2, 2, 2-trimethylhydrazinium) propionate dihydrate have many of the advantages described above, enabling commercial large-scale production, reducing costs, simple equipment and ease of operation.
Specific details of the process of the present invention are set forth in the following examples, which are provided as examples and should not be construed as limiting the scope of the invention.
Detailed Description
Example 1
67g of potassium hydroxide (90%) are dissolved in 470ml of ethanol, 121g of methyl 3- (2, 2, 2-trimethylhydrazinium) propionate are added when the temperature is reduced to 18-20 DEG CHydrolyzing bromine salt at 18-20 deg.C (detecting whether reaction is terminated by TLC), filtering precipitate when temperature is reduced to 2-4 deg.C, removing inorganic precipitate, washing with 2 × 20ml ethanol, mixing washing solution and mother liquor, and adding a certain amount of NaOC2H5CO passing through the aqueous solution2Acidifying the gas to pH 8.2-8.5(pH acidometer test), filtering off the precipitate formed, washing with 2 x 20ml ethanol, combining the mother liquors of the washings, and checking whether there is a small amount of partially double-salt emulsion, whereby the mother liquor is supplemented with a certain amount of NaOC2H5Stirring the aqueous solution, standing for about 15 minutes, allowing the aqueous solution to emulsify and become clear to generate granular precipitates, performing suction filtration to obtain the rest inorganic salt, performing reduced pressure concentration on the obtained clear solution, cooling, crystallizing and drying to obtain 91g of crude 3- (2, 2, 2-trimethylhydrazinium) propionate dihydrate drug raw material of about 94 percent, performing recrystallization by using isopropanol or ethanol, wherein the melting point is 86-88 ℃, and the content is more than 99.5 percent; the ash content of the sulfuric acid is less than 0.1 percent.
Example 2
Dissolving 67g potassium hydroxide (90%) in 470ml ethanol, cooling to 18-20 deg.C, adding 145g methyl 3- (2, 2, 2-trimethylhydrazinium) propionate sulfate, hydrolyzing at 18-20 deg.C (detecting whether the reaction is terminated by TLC), cooling to 2-4 deg.C, filtering to remove inorganic precipitate, washing with 2 x 20ml ethanol, mixing the washing solution and mother solution, and introducing SO2Acidifying the gas to pH 8.2-8.5(pH acidity meter test), filtering off precipitate, washing with 2 x 20ml ethanol, combining the mother liquors of the washings (clear solution not obtained by emulsion filtration), adding a certain amount of CaCl to the mother liquor2Stirring the aqueous solution, standing for about 15 minutes, allowing the aqueous solution to emulsify and become clear to generate granular precipitates, performing suction filtration to obtain the rest inorganic salt, performing reduced pressure concentration on the obtained clear solution, cooling, crystallizing and drying to obtain 88g of crude 3- (2, 2, 2-trimethylhydrazinium) propionate dihydrate drug raw material of about 95 percent, and recrystallizing with isopropanol or ethanol, wherein the melting point is 86-88 ℃, and the content is more than 99.5 percent. (sulfated Ash < 0.1%)
Example 3
Dissolving 67g potassium hydroxide (90%) in 470ml ethanol, cooling to 18-20 deg.C, adding 145g methyl 3- (2, 2, 2-trimethylhydrazinium) propionate sulfate, hydrolyzing at 18-20 deg.C (detecting whether reaction is terminated by TLC), cooling to 2-4 deg.C, filtering, precipitating, and removingWashing inorganic precipitate with 2 × 20ml ethanol, combining the washing solution and mother liquor, and introducing SO2The gas was acidified to PH 8.2-8.5(PH acidimeter test), the precipitate formed was filtered off, washed with 2 x 20ml ethanol, the mother liquors of the washings were combined (emulsion filtration did not give a clear solution), and finally purified by electrodialysis. Vacuum concentrating, cooling for crystallization, drying to obtain 88g crude product of 3- (2, 2, 2-trimethylhydrazinium) propionate dihydrate drug raw material 97%, recrystallizing with isopropanol or ethanol, melting point 85-87 deg.C, content > 99.5%, and sulfated ash content < 0.1%.
Example 4
Dissolving 71.5g potassium hydroxide (90%) in 480ml ethanol, cooling to 18-20 deg.C, adding 129g methyl 3- (2, 2, 2-trimethylhydrazinium) propionate bromide, controlling temperature, hydrolyzing at 18-20 deg.C (detecting whether reaction is terminated by TLC), filtering to remove inorganic precipitate, washing with 2 x 20ml ethanol, mixing washing solution and mother solution, adding 19g NH4NO3Filtering the water solution to remove inorganic precipitate, washing with 2 x 20ml ethanol, combining washing mother liquor, pressurizing, concentrating, cooling, crystallizing and drying to obtain 96g of crude 3- (2, 2, 2-trimethylhydrazinium) propionate dihydrate drug raw material of about 94%, recrystallizing with isopropanol or ethanol, wherein the melting point is 85-87 ℃, the content is more than 99.5%, and the ash content of sulfuric acid is less than 0.1%.
Example 5
Dissolving 33g potassium hydroxide (90%) in 480ml ethanol, cooling to 18-20 deg.C, adding 145g methyl 3- (2, 2, 2-trimethylhydrazinium) propionate bromide, controlling temperature, hydrolyzing at 18-20 deg.C (detecting whether reaction is terminated by TLC), filtering to remove inorganic precipitate when temperature is reduced to 2-4 deg.C, washing with 2 x 20ml ethanol, mixing washing solution and mother solution, adding 33g NH4NO3Filtering the water solution to remove inorganic precipitate, washing with 2 x 20ml ethanol, combining washing mother liquor, pressurizing, concentrating, cooling, crystallizing and drying to obtain 97g of crude 3- (2, 2, 2-trimethylhydrazinium) propionate dihydrate drug raw material (about 93%), recrystallizing with isopropanol or ethanol, wherein the melting point is 86-87 ℃, the content is more than 99.5%, and the ash content of sulfuric acid is less than 0.1%.
Example 6
33g of potassium hydroxide (90%) is added into 480ml of ethanol for dissolution,cooling to 18-20 deg.C, adding 145g methyl 3- (2, 2, 2-trimethylhydrazinium) propionate sulfate, controlling temperature, hydrolyzing at 18-20 deg.C (detecting whether reaction is terminated by TLC), cooling to 2-4 deg.C, filtering, removing inorganic precipitate, washing with 2 × 20ml ethanol, mixing the washing solution and mother solution, and adding 18g (NH)4)HCO3Acidifying, filtering to remove inorganic precipitate, washing with 2 × 20ml ethanol, mixing mother liquor of washing solution, pressurizing, concentrating, cooling, crystallizing, and drying to obtain 90g crude product of 3- (2, 2, 2-trimethylhydrazinium) propionate dihydrate drug raw material (about 94%), recrystallizing with isopropanol or ethanol, melting point is 87-89 deg.C, content is more than 99.5%, and ash content of sulfuric acid is less than 0.1%.
Example 7
Dissolving 28g sodium hydroxide in 480ml ethanol, cooling to 18-20 deg.C, adding 96g methyl 3- (2, 2, 2-trimethylhydrazinium) propionate chloride salt, controlling temperature, hydrolyzing at 18-20 deg.C (detecting whether reaction is terminated by TLC), cooling to 2-4 deg.C, filtering, precipitating, removing inorganic precipitate, washing solid with 2 x 20ml ethanol, mixing washing solution and mother solution, adding 31g NH4I, acidifying, filtering to remove inorganic precipitate, washing the solid with 2 x 20ml ethanol, merging washing liquid mother liquor, pressurizing, concentrating, cooling, crystallizing and drying to obtain 99g of crude 3- (2, 2, 2-trimethylhydrazinium) propionate dihydrate drug raw material of about 95%, recrystallizing with isopropanol or ethanol, wherein the melting point is 87-88 ℃, the content is more than 99.5%, and the ash content of sulfuric acid is less than 0.1%.
Example 8
Dissolving 67g potassium hydroxide (90%) in 470ml ethanol, cooling to 18-20 deg.C, adding 145g methyl 3- (2, 2, 2-trimethylhydrazinium) propionate sulfate, hydrolyzing at 18-20 deg.C (detecting whether the reaction is terminated by TLC), cooling to 2-4 deg.C, filtering to remove inorganic precipitate, washing with 2 x 20ml ethanol, mixing the washing solution and mother liquor, introducing CO2Acidifying the gas to pH 8.2-8.5(pH acidity meter test), filtering off the precipitate formed, washing with 2 x 20ml ethanol, combining the mother liquors of the washings (milky filtrate does not give a clear solution), passing the emulsion through a CaCl-packed filter2Filtering, concentrating the obtained clear solution under reduced pressure, cooling, crystallizing, drying to obtain crude drug material (about 96% crude drug material) of 3- (2, 2, 2-trimethylhydrazinium) propionate dihydrate 88g, recrystallizing with isopropanol or ethanol, and melting point 86-88The content is more than 99.5 percent, and the ash content of the sulfuric acid is less than 0.1 percent.
Example 9
Dissolving 67g potassium hydroxide (90%) in 470ml ethanol, cooling to 18-20 deg.C, adding 121g methyl 3- (2, 2, 2-trimethylhydrazinium) propionate bromide salt, hydrolyzing at 18-20 deg.C (detecting whether reaction is terminated by TLC), cooling to 2-4 deg.C, vacuum filtering to remove inorganic precipitate, washing with 2 x 20ml ethanol, mixing the washing solution and mother liquor, introducing CO2Acidifying the gas until the pH value is 8.2-8.5, removing inorganic precipitates by suction filtration, washing with 2 x 20ml of ethanol, combining washing liquor mother liquor, pressurizing, concentrating, cooling, crystallizing and drying to obtain 90g of crude 3- (2, 2, 2-trimethylhydrazinium) propionate dihydrate drug raw material of about 94%, recrystallizing with isopropanol or ethanol, wherein the melting point is 85-88 ℃, the content is more than 99.5%, and the sulfated ash content is less than 0.1%.
Claims (8)
1. An improved method for preparing 3- (2, 2, 2-trimethylhydrazinium) propionate dihydrate is characterized in that: dissolving 67g potassium hydroxide 90% in 470ml ethanol, cooling to 18-20 deg.C, adding 121g 3- (2, 2, 2-trimethylhydrazinium) methyl propionate bromide salt, hydrolyzing at 18-20 deg.C, cooling to 2-4 deg.C, vacuum filtering to remove inorganic precipitate, washing with 2 x 20ml ethanol, mixing the washing solution and mother solution, adding a certain amount of NaOC2H5CO passing through the aqueous solution2Acidifying the gas to pH 8.2-8.5, filtering off the precipitate, washing with 2 x 20ml ethanol, combining the mother liquors of the washings, and checking that there is still a small amount of partial double salt emulsion, thereby adding a certain amount of NaOC in the mother liquor2H5Stirring and standing the aqueous solution for about 15 minutes, allowing the aqueous solution to emulsify and become clear to generate granular precipitates, then performing suction filtration to obtain the rest inorganic salt, performing reduced pressure concentration on the obtained clear solution, cooling, crystallizing and drying to obtain 91g of crude drug raw material 94% of 3- (2, 2, 2-trimethylhydrazinium) propionate dihydrate, and recrystallizing with isopropanol or ethanol, wherein the melting point is 86-88 ℃, and the content is more than 99.5%; the ash content of the sulfuric acid is less than 0.1 percent.
2. An improved method for preparing 3- (2, 2, 2-trimethylhydrazinium) propionate dihydrate is characterized in that: 67g of potassium hydroxide 90% are addedDissolving in 470ml ethanol, cooling to 18-20 deg.C, adding 145g methyl 3- (2, 2, 2-trimethylhydrazinium) propionate sulfate, hydrolyzing at 18-20 deg.C, cooling to 2-4 deg.C, vacuum filtering to remove inorganic precipitate, washing with 2 x 20ml ethanol, mixing the washing solution and mother solution, and introducing SO2Acidifying the gas to pH 8.2-8.5, filtering to remove precipitate, washing with 2 × 20ml ethanol, mixing the mother solutions, adding a certain amount of CaCl2Stirring the aqueous solution, standing for about 15 minutes, allowing clear emulsion to generate granular precipitates, performing suction filtration to obtain the rest inorganic salt, performing reduced pressure concentration on the obtained clear solution, cooling, crystallizing and drying to obtain 88g of crude 3- (2, 2, 2-trimethylhydrazinium) propionate dihydrate drug raw material 95%, recrystallizing with isopropanol or ethanol, wherein the melting point is 86-88 ℃, the content is more than 99.5%, and the ash content of sulfuric acid is less than 0.1%.
3. An improved method for preparing 3- (2, 2, 2-trimethylhydrazinium) propionate dihydrate is characterized in that: dissolving 71.5g potassium hydroxide 90% in 480ml ethanol, cooling to 18-20 deg.C, adding 129g methyl 3- (2, 2, 2-trimethylhydrazinium) propionate bromide, hydrolyzing at 18-20 deg.C, cooling to 2-4 deg.C, filtering, removing inorganic precipitate, washing with 2 x 20ml ethanol, mixing the washing solution and mother solution, adding 19g NH4NO3Filtering the water solution to remove inorganic precipitate, washing with 2 x 20ml ethanol, combining washing mother liquor, pressurizing, concentrating, cooling, crystallizing and drying to obtain 96g of crude drug raw material of 3- (2, 2, 2-trimethylhydrazinium) propionate dihydrate 94%, recrystallizing with isopropanol or ethanol, wherein the melting point is 85-87 ℃, the content is more than 99.5%, and the ash content of sulfuric acid is less than 0.1%.
4. An improved method for preparing 3- (2, 2, 2-trimethylhydrazinium) propionate dihydrate is characterized in that: dissolving 33g potassium hydroxide 90% in 480ml ethanol, cooling to 18-20 deg.C, adding 145g 3- (2, 2, 2-trimethylhydrazinium) methyl propionate bromide, hydrolyzing at 18-20 deg.C, cooling to 2-4 deg.C, filtering, removing inorganic precipitate, washing with 2 x 20ml ethanol, mixing the washing solution and mother solution, adding 33g NH4NO3Filtering the aqueous solution to remove inorganic precipitate, washing with 2 × 20ml ethanolWashing, combining washing mother liquor, pressurizing, concentrating, cooling, crystallizing and drying to obtain 97g of crude drug raw material 93% of 3- (2, 2, 2-trimethylhydrazinium) propionate dihydrate, recrystallizing with isopropanol or ethanol, wherein the melting point is 86-87 ℃, the content is more than 99.5%, and the ash content of sulfuric acid is less than 0.1%.
5. An improved method for preparing 3- (2, 2, 2-trimethylhydrazinium) propionate dihydrate is characterized in that: dissolving 33g potassium hydroxide 90% in 480ml ethanol, cooling to 18-20 deg.C, adding 145g methyl 3- (2, 2, 2-trimethylhydrazinium) propionate sulfate, hydrolyzing at 18-20 deg.C, cooling to 2-4 deg.C, filtering to remove inorganic precipitate, washing with 2 x 20ml ethanol, mixing the washing solution and mother solution, and adding 18g (NH)4)HCO3Acidifying, filtering to remove inorganic precipitate, washing with 2 × 20ml ethanol, mixing mother liquor of washing solution, pressurizing, concentrating, cooling, crystallizing and drying to obtain 90g crude drug raw material of 3- (2, 2, 2-trimethylhydrazinium) propionate dihydrate 94%, recrystallizing with isopropanol or ethanol, melting point is 87-89 deg.C, content is more than 99.5%, and ash content of sulfuric acid is less than 0.1%.
6. An improved method for preparing 3- (2, 2, 2-trimethylhydrazinium) propionate dihydrate is characterized in that: dissolving 28g sodium hydroxide in 480ml ethanol, cooling to 18-20 deg.C, adding 96g methyl 3- (2, 2, 2-trimethylhydrazinium) propionate chloride salt, controlling temperature, hydrolyzing at 18-20 deg.C, cooling to 2-4 deg.C, filtering, precipitating, removing inorganic precipitate, washing solid with 2 x 20ml ethanol, mixing the washing solution and mother solution, adding 31g NH4I, acidifying, filtering to remove inorganic precipitates, washing solids with 2 x 20ml of ethanol, combining washing liquor mother liquor, pressurizing, concentrating, cooling, crystallizing and drying to obtain 99g of crude drug raw material of 3- (2, 2, 2-trimethylhydrazinium) propionate dihydrate 95%, recrystallizing with isopropanol or ethanol, wherein the melting point is 87-88 ℃, the content is more than 99.5%, and the ash content of sulfuric acid is less than 0.1%.
7. An improved method for preparing 3- (2, 2, 2-trimethylhydrazinium) propionate dihydrate is characterized in that: adding 90% of 67g potassium hydroxide into 470ml ethanol, dissolving, cooling to 18-20 deg.CAdding 145g of methyl 3- (2, 2, 2-trimethylhydrazinium) propionate sulfate, controlling the temperature to 18-20 ℃ for hydrolysis, performing suction filtration on the precipitate when the temperature is reduced to 2-4 ℃, removing inorganic precipitate, washing with 2 x 20ml of ethanol, combining washing liquid and mother liquor, introducing CO2Acidifying the gas to pH 8.2-8.5, filtering off the precipitate formed, washing with 2 x 20ml ethanol, combining the washing liquors, passing the emulsion through a CaCl-packed column2Filtering the layer, concentrating the obtained clear solution under reduced pressure, cooling, crystallizing and drying to obtain 88g of crude drug raw material of 3- (2, 2, 2-trimethylhydrazinium) propionate dihydrate 96%, recrystallizing with isopropanol or ethanol, wherein the melting point is 86-88 ℃, the content is more than 99.5%, and the sulfated ash content is less than 0.1%.
8. An improved method for preparing 3- (2, 2, 2-trimethylhydrazinium) propionate dihydrate is characterized in that: dissolving 67g potassium hydroxide 90% in 470ml ethanol, cooling to 18-20 deg.C, adding 121g methyl 3- (2, 2, 2-trimethylhydrazinium) propionate bromide salt, hydrolyzing at 18-20 deg.C, cooling to 2-4 deg.C, vacuum filtering to remove inorganic precipitate, washing with 2 x 20ml ethanol, mixing the washing solution and mother liquor, introducing CO2Acidifying the gas until the pH value is 8.2-8.5, removing inorganic precipitates by suction filtration, washing with 2 x 20ml of ethanol, combining washing liquor mother liquor, pressurizing, concentrating, cooling, crystallizing and drying to obtain 90g of crude drug raw material 94% of 3- (2, 2, 2-trimethylhydrazinium) propionate dihydrate, recrystallizing with isopropanol or ethanol, wherein the melting point is 85-88 ℃, the content is more than 99.5%, and the ash content of sulfuric acid is less than 0.1%.
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Citations (4)
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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 |
| CN101952245A (en) * | 2008-02-19 | 2011-01-19 | 格林代克斯联合股份公司 | Carbonic and sulphuric acid salts of 3-(2,2,2-trimethylhydrazinium)propionate esters and their use for 3-(2,2,2-trimethylhydrazinium)propionate dihydrate preparation |
| 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 | An improved method for the preparation of methyl 3-(2,2,-dimethylhydrazino)propionate and methyl 3-(2,2,2-trimethylhydrazino)propionate |
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Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
| CN101952245A (en) * | 2008-02-19 | 2011-01-19 | 格林代克斯联合股份公司 | Carbonic and sulphuric acid salts of 3-(2,2,2-trimethylhydrazinium)propionate esters and their use for 3-(2,2,2-trimethylhydrazinium)propionate dihydrate preparation |
| 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 | An improved method for the preparation of methyl 3-(2,2,-dimethylhydrazino)propionate and methyl 3-(2,2,2-trimethylhydrazino)propionate |
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