CN109369447A - 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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- CN109369447A CN109369447A CN201811350786.4A CN201811350786A CN109369447A CN 109369447 A CN109369447 A CN 109369447A CN 201811350786 A CN201811350786 A CN 201811350786A CN 109369447 A CN109369447 A CN 109369447A
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- ammonium
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- propionate
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- trimethyl hydrazine
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- 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
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 present invention relates to organic chemistry and drug, the present invention relates to organic chemistry and drug research field, specifically a kind of
The preparation method technology of improved 3- (2,2,2- trimethyl hydrazine) propionate dihydrate " Mildronate dihydrate " bulk pharmaceutical chemicals and
Purification technique.
Background technique
International Non-Proprietary Name is 3- (2,2, the 2- trimethyl hydrazine) propionate dihydrate of Meldonium since its heart is protected
Shield effect and it is famous.Usually the described method includes:
1,1- dimethylhydrazine reacts to form 3- (2,2- dimethyl diazanyl) methyl propionate with methyl acrylate, further uses first
Base halogen or dimethyl suflfate generate suitable 3- (2,2,2- trimethyl hydrazine) methyl propionate halide or Methylsulfate, then to it
It is hydrolyzed and deionization, is separated with the saturated solution of carbon dioxide or sulfur dioxide, this method WO2008028514 patent
It is open, although this method can to avoid using electrodialysis in the preparation of 3- (2,2,2- trimethyl hydrazine) propionate dihydrate,
But actual industrialization produces and uses in sour gas and when a large amount of reaction solution, on the one hand the precision required by production technology
The error range of pH value is difficult to control really, and K is easy to produce in neutralization reaction2CO3/KHCO3Or Na2SO3/NaHSO3Mixing
The mixed system of salt and the different double salt of 3- (2,2,2- trimethyl hydrazine) propionate dihydrate, final goal product are soluble in
Water causes separation water-soluble inorganic salt, purification of target product difficult, it is necessary to carry out complicated double salt separating step and complexity
Inorganic salts separating step；On the other hand this industrial gasses acidification technique is time-consuming, this workshop section at least needs complete for 8-10 hours,
Gas bomb is especially low in winter temperature, is acidified more time-consuming；Reaction system dragging with acidificatoin time after third aspect hydrolysis
Prolong increasingly complexization, leads to the decomposed of product.This patented method cannot reach satisfactory purifies and separates, and product is not up to
It is required to pharmacopoeial quality standard (sulfated ass < 0.1% is not achieved).
There are also known another methods to prepare 3- (2,2,2- trimethyl hydrazine) propionate dihydrate (Russ P
RU2404159C2, publication date 2010.11.20), and with the basic hydrolysis of pharmaceutical intermediate, carried out after reaction terminating
The separation of KBr, reaction mixture have been selected orthophosphoric acid and monosubstituted and two replace ammonium phosphate, have been isolated from mixed solution
K3PO4, with isopropanol, treated contains the mixed solution of 3- (2,2,2- trimethyl hydrazine) propionic acid dihydrogen orthophosphate, then is handled with NH3
The third inorganic salts (NH is separated using cooling alcohol deposition method4)2HPO4, last mother liquor add water cooling be converted into dihydrate.This side
Method has selected phosphoric acid in mixed solution, and it is weak electrolyte, a point three-level ionizes, it not only makes that phosphoric acid, which is strong acid in ternary,
Reaction system complicates, the phosphoric acid trivalent salt or a kind of emulsifier of generation, rather than demulsifier, cannot only be solved by a step
Demulsification problem obtains target compound, because the dihydrate of hydrolysis and phosphoric acid salt reaction can generate more complicated double salt,
Therefore there is the step of four separation and NH3ization step etc. in this method.The method first destroys target product, rear and logical
Overweight solution conversion obtains, but separating for several times inorganic salts, causes residual impurity type contained by bulk pharmaceutical chemicals quite a lot of, is extremely difficult to original
Expect the standard of medicine, also directly reduce the yield of product, production cost is too high, these can not produce in actual industrial metaplasia and realize.Make
With the another kind of phosphoric acid and ammonium phosphate salt the disadvantage is that substituted potassium phosphate different from the KOH of various concentration reaction generation, very
Hardly possible removal leads to process complications, therefore this method is more suited to production Meldonium phosphate rather than Mildronate dihydrate
Method.In conclusion being acidified so far without successfully realizing using other suitable inorganic compounds, therefore band in industrial production
Many difficulty are carried out.
The purpose of the present invention is finding one kind, to be suitable for 3- (2,2,2- trimethyl hydrazine) propionate dihydrate in and anti-
Generated water solubility K in answering2CO3/KHCO3Or Na2SO3/NaHSO3The 3- (2,2,2- trimethyl hydrazine) that salt-mixture is consequently formed
Simple process is used to separate our water-soluble target product in the complex compound (emulsus) or double salt mixed system of propionic acid monocalcium salt
Or it finds simple improved method in a kind of 3- (2,2,2- trimethyl hydrazine) propionate dihydrate preparation process and preferably solves
Produce the product of pharmaceutical comg purity.
Summary of the invention
For the purpose of the present invention is in order to complete and overcome disadvantages mentioned above, added in the reaction solution in alcohol a kind of mixed solution or
Person substitutes original used gas acidulant carbon dioxide, sulfur dioxide etc. using a kind of new acidizing reagent completely.Invention
People has been surprisingly found that if the solution after hydrolyzing is before being passed through inorganic acid anhydrides (such as carbon dioxide, sulfur dioxide etc.) and being acidified the solution
Or solves emulsus after a kind of a small amount of (can all add namely before acidification and after acidification) mixed liquor is added in reaction solution later
Complex compound, double salt parsing problem prevent the formation of double salt and milk, avoid electrodialysis, which forms
3- (2,2,2- trimethyl hydrazine) propionate and inorganic salts quick and complete can separate, control solution acid alkalinity very well, effectively
Inorganic salts are prevented to remain excessive problem, it should be noted that stringent experimental data determines mixed solution type be added, original
The ratio of first material and the time being most preferably added, control temperature can just obtain the above effect；The present invention is based on another unexpected hairs
Existing, the gas acidulant carbon dioxide originally used, sulfur dioxide etc. is substituted by a kind of ammonium salt that strong acid weak base combines, thus
To the method for 3- (2,2,2- trimethyl hydrazine) propionate dihydrate.
The present invention is in order to solve the above technical problems, adopt the technical scheme that from the hydrolysate alcohol of pharmaceutical intermediate
Reaction solution in add a kind of mixed solution or using a kind of new acidulant substitute it is original used in gas acidulant
Carbon dioxide (sulfur dioxide) obtains 3- (2,2,2- trimethyl hydrazine) propionate dihydrate bulk pharmaceutical chemicals method and reactivity worth, packet
It includes: reaction route
Wherein: nNH4 ++OH-→H2O+nNH3↑
1. constituent: Meldonium molecular structural formula is C6H14N2O2.2H2O；Pharmaceutical intermediate 3- (2,2,2- trimethyls
Hydrazine) methyl propionate salt (CH3)3N+NHCH2CH2COOCH3X-, wherein X indicates Cl-、Br-、I-、CH3SO4 -；The mixed solution of addition
Selection includes water and aqueous solution group, and inorganic salts contained by the solution have: halogen ion salt, including NaCl, NaI, NaBr,
KCl、KI、MgCl2、CaCl2、AlCl3Deng, sodium ion salt, including NaClO4、NaNO3、Na2CO3、NaOC2H5、NaNO2, compound
At least one of, solvent and solute ratio are 100: 1-20 (m/m), and the ratio of original solution and mixed solution additional amount is 25:
1-5(m/m)；Acidizing reagent is a kind of ammonium salt (NH4)nY, acidizing reagent are inorganic ammonium salt (NH4)nY, comprising: ammonium nitrate, carbonic acid
One or both of ammonium, ammonium hydrogen carbonate, ammonium sulfate, ammonium chloride, ammonium iodide, ammonium iodate, ammonium acetate, ammonium oxalate mixture.
2. component ratio: the main content of 3- (2,2,2- trimethyl hydrazine) propionate dihydrate medicine material is 99.0-
101%, sulfated ass < 0.1%.
Technical effect
We have found tool, there are two types of unexpected effects: 1) thus not forming 3- (2,2,2- trimethyl hydrazine) propionate
The complex compound (emulsus) or double salt of two water avoid electrodialysis purification procedures.2) step quantitatively realizes Mildronate dihydrate
Control within the scope of reaction system necessary PH, acidificatoin time and process are significantly improved, for changing for acid substitute
Develop simplest technical process on the basis of and obtains pharmaceutical grade 3- (2,2,2- trimethyl hydrazine) propionate dihydrate raw material
Medicine, the method acidification is simple, quickly, convenient post-treatment, be exactly simple filtration and crystallization obtain high yield high-purity 3- (2,
2,2- trimethyl hydrazines) propionate dihydrate, it is easy to reach pharmacopoeial quality prescribed by standard quality requirement dopant species and
The range of limitation, sulfated ass also control within the scope of less than 0.1%, are 3- (2,2, the 2- front threes for producing pharmaceutical comg purity
Base hydrazine) one simpler method of propionate dihydrate.
The method of the invention and existing be directed to prepare 3- (2,2,2- trimethyl hydrazine) propionate dihydrate known formula
There are many advantages described above for method, realize that business is mass produced, to reduce cost, equipment simple to operation etc. excellent
Point.
The detail of the method for the present invention specifically describes in the following embodiments, only provides the example of this method here
Son, but should not be construed as limiting the scope of the invention.
Specific embodiment
Embodiment 1
It takes 67g potassium hydroxide (90%) to be added in 470ml ethyl alcohol to dissolve, 121g 3- is added when dropping to 18-20 DEG C in temperature
Whether (2,2,2- trimethyl hydrazine) 18-20 DEG C of temperature control of methyl propionate bromide hydrolysis (is terminated) with TLC detection reaction, and temperature drops to 2
Precipitating is filtered when to 4 DEG C, removes inorganic sediment, and with 2*20ml ethanol washing, washing lotion and mother liquor are added a certain amount of after merging
NaOC2H5Aqueous solution leads to CO again2It is 8.2-8.5 (test of PH acidometer) that gas, which is acidified to PH, filters off the precipitating of formation, uses 2*
20ml ethanol washing merges washing lotion mother liquor and is examined or have a small amount of part double salt emulsus, therefore adds in mother liquor a certain amount of
NaOC2H5Aqueous solution stirring is quiet to put about 15 minutes clear generation granular precipitates of emulsus change, then filters out remaining inorganic salts, obtains
The clear solution that arrives is concentrated under reduced pressure, crystallisation by cooling it is dry 91g, 3- (2,2,2- trimethyl hydrazine) propionate dihydrate medicine material
Crude product about 94%, with isopropanol or ethyl alcohol recrystallization, fusing point is at 86-88 DEG C, content > 99.5%；Sulfated ass < 0.1%.
Embodiment 2
It takes 67g potassium hydroxide (90%) to be added in 470ml ethyl alcohol to dissolve, 145g 3- is added when dropping to 18-20 DEG C in temperature
Whether (2,2,2- trimethyl hydrazine) 18-20 DEG C of temperature control of methyl propionate sulfate hydrolysis (is terminated) with TLC detection reaction, temperature drop
Precipitating is filtered when to 2 to 4 DEG C, removes inorganic sediment, and with 2*20ml ethanol washing, washing lotion and mother liquor merge logical SO2Gas acidification
It is 8.2-8.5 (test of PH acidometer) to PH, filters off the precipitating of formation, with 2*20ml ethanol washing, merging washing lotion mother liquor (is
Milk filtration method is unable to get clear solution), a certain amount of CaCl is added in mother liquor2Aqueous solution stirring is quiet to put about 15 minutes emulsus
Become clear and generate granular precipitate, then filter out remaining inorganic salts, obtained clear solution is concentrated under reduced pressure, and crystallisation by cooling is dry
88g, 3- (2,2,2- trimethyl hydrazine) propionate dihydrate medicine material crude product about 95%, with isopropanol or ethyl alcohol recrystallization,
Fusing point is at 86-88 DEG C, content > 99.5%.(sulfated ass < 0.1%)
Embodiment 3
It takes 67g potassium hydroxide (90%) to be added in 470ml ethyl alcohol to dissolve, 145g 3- is added when dropping to 18-20 DEG C in temperature
Whether (2,2,2- trimethyl hydrazine) 18-20 DEG C of temperature control of methyl propionate sulfate hydrolysis (is terminated) with TLC detection reaction, temperature drop
Precipitating is filtered when to 2 to 4 DEG C, removes inorganic sediment, and with 2*20ml ethanol washing, washing lotion and mother liquor merge logical SO2Gas acidification
It is 8.2-8.5 (test of PH acidometer) to PH, filters off the precipitating of formation, with 2*20ml ethanol washing, merges washing lotion mother liquor (cream
Shape object filtration method is unable to get clear solution), it is purified eventually by electrodialysis.It is concentrated under reduced pressure, crystallisation by cooling, dry 88g, 3-
(2,2,2- trimethyl hydrazine) propionate dihydrate medicine material crude product about 97%, with isopropanol or ethyl alcohol recrystallization, fusing point exists
85-87 DEG C, content > 99.5%, sulfated ass < 0.1%.
Embodiment 4
It takes 71.5g potassium hydroxide (90%) to be added in 480ml ethyl alcohol to dissolve, 129g 3- is added when dropping to 18-20 DEG C in temperature
Whether (2,2,2- trimethyl hydrazine) 18-20 DEG C of temperature control of methyl propionate bromide hydrolysis (is terminated) with TLC detection reaction, and temperature drops to 2
Precipitating is filtered when to 4 DEG C, removes inorganic sediment, and with 2*20ml ethanol washing, washing lotion and mother liquor, which merge, is added 19g NH4NO3It is water-soluble
Liquid filters and removes inorganic sediment, with 2*20ml ethanol washing, merges washing lotion mother liquor, pressurization concentration crystallisation by cooling it is dry 96g,
3- (2,2,2- trimethyl hydrazine) propionate dihydrate medicine material crude product about 94%, with isopropanol or ethyl alcohol recrystallization, fusing point
At 85-87 DEG C, content > 99.5%, sulfated ass < 0.1%.
Embodiment 5
It takes 33g potassium hydroxide (90%) to be added in 480ml ethyl alcohol to dissolve, 145g 3- is added when dropping to 18-20 DEG C in temperature
Whether (2,2,2- trimethyl hydrazine) 18-20 DEG C of temperature control of methyl propionate bromide hydrolysis (is terminated) with TLC detection reaction, and temperature drops to 2
Precipitating is filtered when to 4 DEG C, removes inorganic sediment, and with 2*20ml ethanol washing, washing lotion and mother liquor, which merge, is added 33g NH4NO3It is water-soluble
Liquid filters and removes inorganic sediment, with 2*20ml ethanol washing, merges washing lotion mother liquor, pressurization concentration crystallisation by cooling it is dry 97g,
3- (2,2,2- trimethyl hydrazine) propionate dihydrate medicine material crude product about 93%, with isopropanol or ethyl alcohol recrystallization, fusing point
At 86-87 DEG C, content > 99.5%, sulfated ass < 0.1%.
Embodiment 6
It takes 33g potassium hydroxide (90%) to be added in 480ml ethyl alcohol to dissolve, 145g 3- is added when dropping to 18-20 DEG C in temperature
Whether (2,2,2- trimethyl hydrazine) 18-20 DEG C of temperature control of methyl propionate sulfate hydrolysis (is terminated) with TLC detection reaction, temperature drop
Precipitating is filtered when to 2 to 4 DEG C, removes inorganic sediment, and with 2*20ml ethanol washing, washing lotion and mother liquor, which merge, is added 18g (NH4)
HCO3Acidification filters and removes inorganic sediment, with 2*20ml ethanol washing, merges washing lotion mother liquor, pressurization concentration crystallisation by cooling is dry
90g is obtained, 3- (2,2,2- trimethyl hydrazine) propionate dihydrate medicine material crude product about 94% is tied again with isopropanol or ethyl alcohol
Crystalline substance, fusing point is at 87-89 DEG C, content > 99.5%, sulfated ass < 0.1%.
Embodiment 7
It takes 28g sodium hydroxide to be added in 480ml ethyl alcohol to dissolve, 96g 3- (2,2,2- tri- is added when dropping to 18-20 DEG C in temperature
Methyl hydrazine) 18-20 DEG C of temperature control of methyl propionate villaumite hydrolysis (whether being terminated with TLC detection reaction), pumping when temperature drops to 2 to 4 DEG C
Filter precipitating, removes inorganic sediment, solid 2*20ml ethanol washing, and washing lotion and mother liquor merge addition 31g NH4I acidification, filters
Except inorganic sediment, solid 2*20ml ethanol washing merges washing lotion mother liquor, pressurization concentration crystallisation by cooling it is dry 99g, 3-
(2,2,2- trimethyl hydrazine) propionate dihydrate medicine material crude product about 95%, with isopropanol or ethyl alcohol recrystallization, fusing point exists
87-88 DEG C, content > 99.5%, sulfated ass < 0.1%.
Embodiment 8
It takes 67g potassium hydroxide (90%) to be added in 470ml ethyl alcohol to dissolve, 145g 3- is added when dropping to 18-20 DEG C in temperature
Whether (2,2,2- trimethyl hydrazine) 18-20 DEG C of temperature control of methyl propionate sulfate hydrolysis (is terminated) with TLC detection reaction, temperature drop
Precipitating is filtered when to 2 to 4 DEG C, removes inorganic sediment, and with 2*20ml ethanol washing, washing lotion and mother liquor merge logical CO2Gas acidification
It is 8.2-8.5 (test of PH acidometer) to PH, filters off the precipitating of formation, with 2*20ml ethanol washing, merges washing lotion mother liquor (cream
The filtering of shape object is unable to get clear solution), lotion is by filling out CaCl2Filter layer, obtained clear solution are concentrated under reduced pressure, and crystallisation by cooling is dry
It is dry to obtain 88g, 3- (2,2,2- trimethyl hydrazine) propionate dihydrate medicine material crude product about 96%, with isopropanol or ethyl alcohol weight
Crystallization, fusing point is at 86-88 DEG C, content > 99.5%, sulfated ass < 0.1%.
Embodiment 9
It takes 67g potassium hydroxide (90%) to be added in 470ml ethyl alcohol to dissolve, 121g 3- is added when dropping to 18-20 DEG C in temperature
Whether (2,2,2- trimethyl hydrazine) 18-20 DEG C of temperature control of methyl propionate bromide hydrolysis (is terminated) with TLC detection reaction, and temperature drops to 2
Precipitating is filtered when to 4 DEG C, filters and removes inorganic sediment, and with 2*20ml ethanol washing, washing lotion and mother liquor merge logical CO2Gas acidification
It is 8.2-8.5 to PH, filters and remove inorganic sediment, with 2*20ml ethanol washing, merges washing lotion mother liquor, the cooling knot of pressurization concentration
Brilliant dry 90g, 3- (2,2,2- trimethyl hydrazine) propionate dihydrate medicine material crude product about 94%, with isopropanol or ethyl alcohol
Recrystallization, fusing point is at 85-88 DEG C, content > 99.5%, sulfated ass < 0.1%.
Claims (2)
1. a kind of improved method of the technology of preparing of 3- (2,2,2- trimethyl hydrazine) propionate dihydrate, compared with prior art
It is characterized by: being added on a small quantity (also in the reaction solution before or after the acidification such as sour gas carbon dioxide (sulfur dioxide)
It is that acidification front and back can all add) a kind of mixed solution or substitute original used gaseous acid completely using a kind of new acidizing reagent
Agent carbon dioxide, sulfur dioxide etc., 3- (2,2, the 2- trimethyl hydrazine) propionate and inorganic salts for forming acidification can divide completely
From technology, mixed solution selection used includes water and aqueous solution group, inorganic salts contained by the solution have halogen from
Alite, including NaCl, NaI, NaBr, KCl, KI, MgCl2、CaCl2、AlCl3Deng, sodium ion salt, including NaClO4、NaNO3、
Na2CO3、NaOC2H5、NaNO2, at least one of compound, solvent and solute ratio are 100: 1-20 (m/m), original solution with
The ratio of mixed solution additional amount is 25: 1-5 (m/m).
2. according to the method for claim 1 compared with prior art it is characterized by: using except monosubstituted two substitutions phosphoric acid
The ammonium salt that strong acid weak base other than class combines replaces sour gas, decomposes without double salt and obtains Meldonium with the technology of prevention, a step
The Acidizing Technology of bulk pharmaceutical chemicals 3- (2,2,2- trimethyl hydrazine) propionate dihydrate, acidizing reagent is inorganic ammonium salt (NH4)nY, packet
It is one such to include ammonium nitrate, ammonium carbonate, ammonium hydrogen carbonate, ammonium sulfate, ammonium chloride, ammonium iodide, ammonium iodate, ammonium acetate, ammonium oxalate
Or two kinds of mixtures.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111333534A (en) * | 2019-12-13 | 2020-06-26 | 东力（南通）化工有限公司 | Novel method for preparing 3- (2, 2, 2-trimethylhydrazinium) propionate dihydrate by methyl methylation of methyl halide |
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| CN101541739A (en) * | 2006-09-04 | 2009-09-23 | 乔治·席尔瓦 | Method for producing 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 | Method for improving preparation technology of 3-(2,2-dimethylhydrazino)methyl propionate and 3-(2,2,2-trimethylhydrazino)methyl propionate |
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| CN101541739A (en) * | 2006-09-04 | 2009-09-23 | 乔治·席尔瓦 | Method for producing 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 |
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| CN111333534A (en) * | 2019-12-13 | 2020-06-26 | 东力（南通）化工有限公司 | Novel method for preparing 3- (2, 2, 2-trimethylhydrazinium) propionate dihydrate by methyl methylation of methyl halide |
| CN111333534B (en) * | 2019-12-13 | 2022-06-28 | 东力（南通）化工有限公司 | Method for preparing 3- (2, 2, 2-trimethylhydrazinium) propionate dihydrate by methylating methyl halide |
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