CN106883135A - A kind of method for preparing MAH bulk drug - Google Patents
A kind of method for preparing MAH bulk drug Download PDFInfo
- Publication number
- CN106883135A CN106883135A CN201510936357.5A CN201510936357A CN106883135A CN 106883135 A CN106883135 A CN 106883135A CN 201510936357 A CN201510936357 A CN 201510936357A CN 106883135 A CN106883135 A CN 106883135A
- Authority
- CN
- China
- Prior art keywords
- magnesium
- mah
- preparation
- aminosuccinate
- reaction
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C227/00—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton
- C07C227/14—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton from compounds containing already amino and carboxyl groups or derivatives thereof
- C07C227/18—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton from compounds containing already amino and carboxyl groups or derivatives thereof by reactions involving amino or carboxyl groups, e.g. hydrolysis of esters or amides, by formation of halides, salts or esters
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C227/00—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton
- C07C227/38—Separation; Purification; Stabilisation; Use of additives
- C07C227/40—Separation; Purification
- C07C227/42—Crystallisation
Abstract
The invention belongs to medicinal chemistry art, it is related to a kind of preparation method of MAH bulk drug, it is characterised in that L-aminobutanedioic acid and magnesia are pressed 1：1 feeds intake obtains Magnesium Aminosuccinate, and the Magnesium Aminosuccinate for obtaining is with L-aminobutanedioic acid, magnesium chloride by 1：1：1 rate of charge reaction, reaction solution is spray-dried to obtain MAH solid powder.
Description
Technical field
The invention belongs to medicinal chemistry art, and in particular to a kind of method for preparing MAH bulk drug.
Background technology
MAH is a kind of new benefit magnesium medicine.With its good absorbing, Small side effects, it is widely used in magnesium shortage
In the various diseases for causing.
The benefit magnesium medicine of chloride ion-containing（Magnesium chloride, MAH）Inhaled than the benefit magnesium medicine containing L-aminobutanedioic acid and sulfate radical
Fruit of producing effects is good, although magnesium chloride is faster than the absorption of MAH, has substantial amounts of calcium through pairs such as urine ejection and acid poisonings
Effect occurs.Other 13 kinds including chloride Mg salt in, be also susceptible to compensatory extracellular low chlor-alkali poisoning, its
Middle citrate is more easy to be occurred.General benefit magnesium medicine easily causes alkalosis due to providing a large amount of alkali and alkaline earth metal ions；And mend
Acid poisoning is easily caused again containing a large amount of salt acid groups not being metabolized, sulfate radical, phosphate radical in magnesium medicine, contain in MAH etc.
The magnesium and chlorine of molal quantity, into human body after do not influence acid-base balance, while not influenceing the absorption of Fe, Ca, Zn, K again.
MAH is developed at first by German VERLA-PHARM companies, and with 1978 with trade name
" Magnesiocard " is listed, and the structure that it is announced is as follows：
Its synthetic route announced has two：First route is raw material with two Magnesium Aminosuccinates, is rapidly joined equimolar dense
Hydrochloric acid, is filtered to remove the L-aminobutanedioic acid solid of precipitation afterwards, and MAH solid is separated out after filtrate concentration；Article 2 road
It is raw material with two Magnesium Aminosuccinates that line is same, and obtaining MAH through spray drying after the equimolar magnesium chloride of addition consolidates
Body.
Our company grinds route and has carried out the experiment of some synthetic hydrochloric acid Magnesium Aminosuccinates with reference to original, in test unexpected hair
It is existing, during two Magnesium Aminosuccinates are prepared, the rate of charge reduction of magnesia, reaction solution is cooled can separate out solid.Analysis is separated out
The composition of solid, it is found that it is Magnesium Aminosuccinate solid, and according to theoretical proportions, L-aminobutanedioic acid and magnesia ingredient proportion are 1：1
When, Magnesium Aminosuccinate solid can be obtained.In experiment, some inorganic impurities are contained in magnesia, oxidation cannot be ensured after reaction
The inventory of magnesium reaches theoretical value.So, reaction solution is the mixed solution of Magnesium Aminosuccinate and two Magnesium Aminosuccinates composition.Two
Winter propylhomoserin magnesium is water-soluble good, it is impossible to separated out from solution, and Magnesium Aminosuccinate can be separated out from solution.Have benefited from this hair
Existing, our selections prepare the raw material that Magnesium Aminosuccinate is synthetic hydrochloric acid Magnesium Aminosuccinate.The route has no document report, for I am public
Department is pioneering.
Still there are the two lines can to select as raw material prepares MAH with Magnesium Aminosuccinate.We select with
Magnesium chloride is raw material, main to consider the amount that hydrochloric acid be accurately controlled addition.What the present invention was provided prepares hydrochloric acid L-aminobutanedioic acid
The method of magnesium solid, simple to operate, content precise control, product assay is homogeneous.
The content of the invention
A kind of method for preparing MAH, it is characterised in that operating process is as follows：
L-aminobutanedioic acid and magnesia are pressed 1：1 rate of charge feeds intake, and after reaction a period of time, reaction solution is concentrated, and cools naturally
To room temperature crystallization.The Magnesium Aminosuccinate of precipitation presses 1 with L-aminobutanedioic acid, magnesium chloride：1：1 rate of charge reaction, reaction solution after reaction
Spray drying obtains MAH solid powder.
The solvent of selection is water, and such salt can form solution in water；Reaction temperature is 60 ± 5 DEG C, reaction temperature
Slowly not exclusively, reaction temperature L-aminobutanedioic acid structure high is more easily damaged low reaction.
Reaction solution obtains solid powder, the method efficiency high, the product structure stabilization for obtaining, and document by spray drying
The structure of report is consistent.
The present invention ensure that the purity of Magnesium Aminosuccinate by the recrystallization of the first step so that the hydrochloric acid L-aminobutanedioic acid of preparation
Magnesium solution purity is high, meanwhile, institute's spent material is all solid, is easy to dosing operation, and whole process route is simple to operate, and product is pure
Degree is high.
Specific embodiment
Following instance is simply to illustrate that the present invention, should not serve to the limitation to this patent.
Embodiment 1：The preparation of Magnesium Aminosuccinate
In 3000 mL there-necked flasks, the g of L-aminobutanedioic acid 665.5 is added, add 2000 mL water, stirring is insoluble.Under stirring, in batches
The g of magnesia 201.5, control reacting liquid temperature is added to be less than 60 DEG C.Finish, be warmed up to 60 ± 5 DEG C, react 5 h.Reaction solution is taken advantage of
Hot suction filtration, filtrate decompression concentration removes 1000 mL water, and raffinate is cooled to room temperature naturally, separates out a large amount of white solids.Suction filtration, obtains
The h of solid forced air drying 4 for arriving（60℃）, weigh, obtain the g of Magnesium Aminosuccinate solid 841.5.
Embodiment 2：The preparation of Magnesium Aminosuccinate
In 20 L reactors, the g of L-aminobutanedioic acid 6655 is added, add 15 L water, stirring is insoluble.Under stirring, oxygen is dividedly in some parts
Change the g of magnesium 2015, control reacting liquid temperature is less than 60 DEG C.Finish, be warmed up to 60 ± 5 DEG C, react 5 h.Reacting liquor while hot suction filtration,
Filtrate decompression concentration removes 5 L water, and raffinate is cooled to room temperature naturally, separates out a large amount of white solids.Centrifugation, the solid air blast for obtaining
Dry 4 h（60℃）, weigh, obtain the g of Magnesium Aminosuccinate solid 8514.
Embodiment 3：The preparation of Magnesium Aminosuccinate
In 100 L reactors, the kg of L-aminobutanedioic acid 26.62 is added, add 60 L water, stirring is insoluble.Under stirring, it is dividedly in some parts
The kg of magnesia 8.06, control reacting liquid temperature is less than 60 DEG C.Finish, be warmed up to 60 ± 5 DEG C, react 5 h.Reacting liquor while hot is taken out
Filter, filtrate decompression concentration removes 20 L water, and raffinate is cooled to room temperature naturally, separates out a large amount of white solids.Centrifugation, the solid for obtaining
The h of forced air drying 4（60℃）, weigh, obtain the kg of Magnesium Aminosuccinate solid 30.8.
Embodiment 4：The preparation of MAH
In 3000 mL there-necked flasks, 628.2 g Magnesium Aminosuccinates solids and 2000 mL water are added, stirring is insoluble.Add
399.3 g L-aminobutanedioic acids, finish, and are warmed up to 60 DEG C, react 1 h, are completely dissolved.Afterwards, 609.9 g magnesium chlorides are added, 60
3 h are reacted under the conditions of ± 5 DEG C.The g of activated carbon 150 is added, is decolourized, while hot suction filtration, filtrate spray drying（180 DEG C of EAT）
Obtain the g of white solid powder 1058（Yield 71.7%）.
Embodiment 5：The preparation of MAH
In 20 L reactors, 6282 g Magnesium Aminosuccinates solids and 20 L water are added, stirring is insoluble.Add 3993 g winter
Propylhomoserin, finishes, and is warmed up to 60 DEG C, reacts 1 h, is completely dissolved.Afterwards, 6099 g magnesium chlorides are added, under the conditions of 60 ± 5 DEG C
React 3 h.The g of activated carbon 1500 is added, is decolourized, while hot suction filtration, filtrate spray drying（180 DEG C of EAT）Obtain white solid
The kg of body powder 11.2（Yield 75.9%）.
Embodiment 6：The preparation of MAH
In 100 L reactors, 25.13 kg Magnesium Aminosuccinates solids and 80 L water are added, stirring is insoluble.Add 15.97 kg
L-aminobutanedioic acid, finishes, and is warmed up to 60 DEG C, reacts 1 h, is completely dissolved.Afterwards, 24.40 kg magnesium chlorides are added, at 60 ± 5 DEG C
Under the conditions of react 3 h.The kg of activated carbon 6 is added, is decolourized, while hot suction filtration, filtrate spray drying（180 DEG C of EAT）Obtain white
Color solid powder 46.3kg（Yield 78.5%）.
Claims (4)
1. a kind of method for preparing MAH bulk drug, it is characterised in that L-aminobutanedioic acid and magnesia are pressed 1：1 throws
Material obtains Magnesium Aminosuccinate, and the Magnesium Aminosuccinate for obtaining is with L-aminobutanedioic acid, magnesium chloride by 1：1：1 rate of charge reaction, reaction solution
It is spray-dried to obtain MAH solid powder.
2. preparation method according to claim 1, it is characterised in that the preparation of Magnesium Aminosuccinate need to be obtained by crystallization precipitation, instead
Magnesium Aminosuccinate is separated out by being cooled naturally after solution concentration after answering.
3. preparation method according to claim 1, it is characterised in that reaction dissolvent is water, reaction temperature is 60 ± 5 DEG C.
4. preparation method according to claim 1, it is characterised in that reacted reaction solution directly obtains salt by spray drying
Sour Magnesium Aminosuccinate solid powder.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201510936357.5A CN106883135A (en) | 2015-12-16 | 2015-12-16 | A kind of method for preparing MAH bulk drug |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201510936357.5A CN106883135A (en) | 2015-12-16 | 2015-12-16 | A kind of method for preparing MAH bulk drug |
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| Publication Number | Publication Date |
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| CN106883135A true CN106883135A (en) | 2017-06-23 |
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| CN201510936357.5A Pending CN106883135A (en) | 2015-12-16 | 2015-12-16 | A kind of method for preparing MAH bulk drug |
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Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE1809119A1 (en) * | 1968-11-15 | 1970-06-11 | Verla Pharm | Magnesium aspartate prepn for the treatment - of infarction conditions |
| US4137326A (en) * | 1975-04-11 | 1979-01-30 | Verla-Pharm Arzneimittelfabrik, Apotheker H.J.V. Ehrlich | Use of magnesium monospartate hydrochloride complex |
| US4546195A (en) * | 1982-10-14 | 1985-10-08 | Verla-Pharm, Arzneimittelfabrik, Apotheker H.J.V. Ehrlich Gmbh & Co. Kg | Process for the production of amino-dicarboxylic acid-bivalent metal-halogen complexes and such complexes |
| CA2516147A1 (en) * | 2004-08-20 | 2006-02-20 | Verla-Pharm Arzneimittelfabrik Apotheker H.J.V. Ehrlich Gmbh | Process for preparing certain hydrohalide metal complex compounds having a specific coarse structure |
| CN101239925A (en) * | 2008-03-10 | 2008-08-13 | 北京京卫信康医药科技发展有限公司 | Method for preparing magnesium aspartate |
| CN104262187A (en) * | 2014-10-09 | 2015-01-07 | 中国食品发酵工业研究院 | Method for solid-phase synthesis of magnesium aspartate at room temperature |
-
2015
- 2015-12-16 CN CN201510936357.5A patent/CN106883135A/en active Pending
Patent Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE1809119A1 (en) * | 1968-11-15 | 1970-06-11 | Verla Pharm | Magnesium aspartate prepn for the treatment - of infarction conditions |
| US4137326A (en) * | 1975-04-11 | 1979-01-30 | Verla-Pharm Arzneimittelfabrik, Apotheker H.J.V. Ehrlich | Use of magnesium monospartate hydrochloride complex |
| US4546195A (en) * | 1982-10-14 | 1985-10-08 | Verla-Pharm, Arzneimittelfabrik, Apotheker H.J.V. Ehrlich Gmbh & Co. Kg | Process for the production of amino-dicarboxylic acid-bivalent metal-halogen complexes and such complexes |
| CA2516147A1 (en) * | 2004-08-20 | 2006-02-20 | Verla-Pharm Arzneimittelfabrik Apotheker H.J.V. Ehrlich Gmbh | Process for preparing certain hydrohalide metal complex compounds having a specific coarse structure |
| CN101239925A (en) * | 2008-03-10 | 2008-08-13 | 北京京卫信康医药科技发展有限公司 | Method for preparing magnesium aspartate |
| CN104262187A (en) * | 2014-10-09 | 2015-01-07 | 中国食品发酵工业研究院 | Method for solid-phase synthesis of magnesium aspartate at room temperature |
Non-Patent Citations (3)
| Title |
|---|
| SCHMIDBAUR, HUBERT等: "Elucidation of the Structure of pharmacologically active magnesium L-aspartate complexes", 《ANGEWANDTE CHEMIE》 * |
| 李绍钰 等: "饲料添加剂天门冬氨酸镁合成研究", 《河南农业科学》 * |
| 王永秋 等: "L-天门冬氨酸镁的制备研究", 《化学工程师》 * |
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