CN101284776A - Method for preparing dimecrotic acid and magnesium salt thereof - Google Patents
Method for preparing dimecrotic acid and magnesium salt thereof Download PDFInfo
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- CN101284776A CN101284776A CNA2007100971782A CN200710097178A CN101284776A CN 101284776 A CN101284776 A CN 101284776A CN A2007100971782 A CNA2007100971782 A CN A2007100971782A CN 200710097178 A CN200710097178 A CN 200710097178A CN 101284776 A CN101284776 A CN 101284776A
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Abstract
The invention provides a method for manufacturing dimecrotic acid magnesium by adding magnesium ethylate into enthanol after dimecrotic acid is dissolved in enthanol. The invention further provides a novel method for manufacturing dimecrotic acid which is used as the starting material of the invention. According to the method, white dimecrotic acid with high purity and yield rate and the salt permitted in pharmacy can be provided. Therefore, the method has the effect of reducing the manufacture cost.
Description
Technical field
The present invention relates to the new manufacture method of Dimecrotic Acid (Dimecrotic acid) and magnesium salts thereof.
Background technology
Dimecrotic Acid is that (popular name of 3-(2,4-dimethoxy-phenyl)-2-butenoic acid), its magnesium salts is used for the prevention and treatment of diseases of abnormal bile secretion in 3-(2, the 4-Dimethoxyphenyl)-2-butylene acid.
The manufacture method of Dimecrotic Acid and the salt that pharmaceutically allows thereof is disclosed in No. the 1915023rd, German publication, and particular content is as follows.
Will be as the compound 4-methyl-umbelliferone of the chemical formula (IV) of the material that sets out, with 0.4 normal sodium hydroxide and 1 normal methyl-sulfate reaction, the compound that produces chemical formula (III) is 4-methyl-ayapanin, with the compound dissolution of described chemical formula (III) behind methyl alcohol, with sodium hydroxide and methyl-sulfate reaction, and the compound that produces chemical formula (II) is a Dimecrotic Acid, makes the reaction of Dimecrotic Acid and carbonate or amino acid salts then and produces its inorganic metal salt or organic salt (with reference to reaction formula 1).
[reaction formula 1]
But, the manufacturing yield rate of the Dimecrotic Acid that obtains according to the reaction formula 1 of above-mentioned patent disclosure be 56.8% (72% * 79%=56.8%), very low.
In addition, in No. the 2403752nd, German publication, put down in writing the manufacture method of the isomer and the salt thereof of Dimecrotic Acid.In above-mentioned patent, will be as the compound 4-methyl-ayapanin of the chemical formula (III) of the material that sets out with sodium hydroxide and methyl-sulfate reaction, the compound that obtains chemical formula (II) is the cis Dimecrotic Acid, the acid that manufacturing is obtained produces the salt (with reference to reaction formula 2) as the Dimecrotic Acid isomer of desired substance with oxyhydroxide or carbonate reaction.
[reaction formula 2]
The manufacturing yield rate of the Dimecrotic Acid of above-mentioned patent disclosure is 70% only, and does not put down in writing the manufacture method of its salt.
Summary of the invention
Therefore, the purpose of this invention is to provide a kind of method of making the Dimecrotic Acid and the magnesium salts thereof of high purity and high yield rate.
The invention provides the Dimecrotic Acid shown in the Formulae II is dissolved in ethanol after, add the method that magnesium ethylate is made the Fisiobil (S.A.L.V.A.T.) shown in the following Formula I (Magnesium Dimecrotate).
[Formula I]
[Formulae II]
Especially, when using dehydrated alcohol, can suppress side reaction, produce the Fisiobil (S.A.L.V.A.T.) of high purity and high yield rate.
The material that the material Dimecrotic Acid that sets out of the present invention can use commercially available commodity or make according to method well known in the art.
Perhaps, also can use the Dimecrotic Acid that produces according to the method that comprises the steps:
A) compound for the following Formula I V in the solvent is 4-methyl-umbelliferone and sodium hydroxide, cutting apart dropping is 2～5 normal methyl-sulfates with respect to the compound of Formula I V, under the pH of reaction soln value is condition more than 10, react, thereby produce the step of 4-methyl-ayapanin of Formulae II I;
B) compound that dissolving is obtained by a) step manufacturing in ethanol and the step of sodium hydroxide;
C) by b) drip methyl-sulfate in the solution that obtains of step manufacturing and react, and the step of synthetic thick Dimecrotic Acid; And
D) make at c with strong acid) thick Dimecrotic Acid recrystallize in ethanol of generating of step, and produce the step of Dimecrotic Acid.
[Formulae II]
[Formulae II I]
[Formula I V]
In the manufacture method of the present invention, preferably, drop into 1 sulfoxylic acid dimethyl ester in a) step, reaction solution is heated to 40～45 ℃ after, drop into remaining methyl-sulfate.
In the manufacture method of the present invention, a) pH value in reaction of step is preferably 10.0～12.0, and especially preferred pH value is 10.0～11.0.This pH value is regulated by the sodium hydroxide that adds as reactive material.
In the manufacture method of the present invention, at c) step, to by b) in the ethanol of the compound that is dissolved with sodium hydroxide and Formulae II I that obtains of step manufacturing, slowly drip methyl-sulfate slightly at every turn.At this moment, the dropping temperature of methyl-sulfate is preferably below 40 ℃.The dropping of methyl-sulfate preferably is heated to reaction soln 40 ℃～80 ℃ after finishing.More preferably be heated to 60 ℃.
Finish c with strong acid solution) reaction of step, also may further include the operation of utilizing organic solvent and water to extract, to remove unreacted reactant and by product.And, at d) and step uses strong acid to make the Dimecrotic Acid recrystallize.
Strong acid used in the present invention is meant the acid that is known as strong acid in the art, and just the dissociation degree in the aqueous solution approaches 1 acid.Nitric acid, sulfuric acid, hydrochloric acid etc. are for example arranged.Organic solvent can use water-fast all organic solvents that often use in the art, and ethyl acetate, methylene dichloride, diethyl ether etc. are for example arranged.
Embodiment
Below, further describe the present invention according to embodiment, but the present invention is not limited to these embodiment.
The manufacturing of embodiment 1:4-methyl-ayapanin (MMC)
Sodium hydroxide 31.2g is dissolved in water 1, among the 500ml, be cooled to 20～25 ℃ after, add 4-methyl-umbelliferone (MHC) 120g, under the condition of holding temperature below 30 ℃, drip methyl-sulfate 90g.
Under violent stirring, drip continuously in the early stage total methyl-sulfate amount 1/4～1/5 after, stirred 15 minutes, fully separate out crystal after, continuation under agitation drips remaining methyl-sulfate.Maintain 10.0～11.0 with sodium hydroxide solution with the pH value of reaction solution this moment, after the dropping end of methyl-sulfate, temperature risen to 40～45 ℃ and stir.
Under the condition of 40～45 ℃ of holding temperatures, in reaction solution, drip methyl-sulfate 90g again, with sodium hydroxide solution the pH value of reaction solution is maintained 10.0～11.0, react constant until the pH value always.
After reaction finishes, cool off reaction solution on one side, be below 2.0 on one side with hydrochloric acid (concentrated hydrochloric acid of 1 volume is diluted with water to 5 times of volumes to be used) solution adjusting pH value, stirring 120 minutes below 10 ℃, filter, the washing back is 35 ℃ of drying under reduced pressure 8 hours, produces the 4-methyl-ayapanin of highly purified 128g (yield rate 98%).
Embodiment 2: the manufacturing of Dimecrotic Acid
(1) synthesis procedure
After sodium hydroxide 282g is dissolved in water 660ml, before cooling, add ethanol 400mL.Under the state of 55 ℃ of solution temperatures, add 4-methyl-ayapanin 125g, after stirring is dissolved it fully, be cooled to reacting liquid temperature and reach 25 ℃.
Keeping under the condition of reacting liquid temperature below 40 ℃, continuing slowly to drip methyl-sulfate 698.25g, stirring and after 90 minutes reacting liquid temperature is risen to 60 ℃, further stirring 90 minutes, finishing reaction through 4 hours.
Reaction solution is cooled to below 20 ℃, and slowly dripping hydrochloric acid (get 1 volume concentrated hydrochloric acid be diluted with water to 3 times of volumes use) solution is adjusted to the pH value below 1.0 then, separates out crystal.Then, be cooled to the temperature of reaction solution below 5 ℃ after, agitation crystal made its slaking in 120 minutes, filtering reacting liquid washs 2 times then.
(2) operation of removal unreacted reactant and by product
Crystal after filtering and washing is put among the aqueous solution 625ml that is dissolved with sodium hydroxide 28.75g, added methylene dichloride 250ml and stirred 20 minutes.Mixed solution is carried out layer separate, behind the removal dichloromethane layer, in water layer, add methylene dichloride 125ml once more, stirred 10 minutes, remove dichloromethane layer.
Take out water layer and filter, after ethanol 150ml washing, add ethanol 350ml once more in filtrate and washings, slowly dripping hydrochloric acid (dilute with water 1 volume concentrated hydrochloric acid is made 3 times of volumes and used) solution is adjusted to the pH value below 1.0, separates out crystal.
After being cooled to the temperature of reaction solution below 5 ℃, agitation crystal made the crystal slaking in 120 minutes, filtering reacting liquid then, wash with water 2 times, once more with after the washing of the ethanol 100ml below 5 ℃, 35 ℃ of drying under reduced pressure 8 hours, produce the Dimecrotic Acid of the highly purified 132g (yield rate 90%) of white.
Embodiment 3: the manufacturing of Fisiobil (S.A.L.V.A.T.)
In dehydrated alcohol 1200ml, add Dimecrotic Acid 122g, heat make its dissolving to 55 ℃ after, be added in the magnesium ethylate 32.4g that following Production Example 1 obtains, reflux cooling finished reaction after 12 hours.
After reaction finishes, add gac 3g, reaction solution is cooled to about 30 ℃ and filtration, with dehydrated alcohol 100ml washing.Merging filtrate and washings carry out complete concentrating under reduced pressure, add dehydrated alcohol 250ml therein, heat after the dissolving, are cooled to below 5 ℃, stir slaking 240 minutes.
Filter crystalloid fluid, after a small amount of dehydrated alcohol 50ml washing that is cooled to below 5 ℃,, obtain highly purified Fisiobil (S.A.L.V.A.T.) 122g (yield rate 95%) 30 ℃ of drying under reduced pressure 6 hours.
Production Example 1: the manufacturing of magnesium ethylate
In the groove that possesses condenser and gas barrier, after dehydrated alcohol 400ml under the adding room temperature and tetracol phenixin 16ml mix, add magnesium powder 16g, at room temperature stirring reaction liquid is 120 minutes, continues to improve the temperature of reaction solution, reflux cooling 6 hours.
After reaction finishes, solution was stirred 30 minutes below 10 ℃ in temperature, filter after making the crystal slaking, behind a spot of cooling absolute ethanol washing, 30 ℃ of drying under reduced pressure 4 hours, thus acquisition magnesium ethylate 71g.
Manufacture method of the present invention is compared with manufacture method in the past, and high-purity and high the receipts can be provided The dimecrotic acid of rate and Fisiobil (S.A.L.V.A.T.), thus the effect that reduces manufacturing cost had.
Claims (8)
1. the manufacture method of the Fisiobil (S.A.L.V.A.T.) shown in the Formula I is characterized in that, comprise the Dimecrotic Acid shown in the Formulae II is dissolved in ethanol after, add the operation that magnesium ethylate reacts,
[Formula I]
[Formulae II]
2. the manufacture method of Fisiobil (S.A.L.V.A.T.) according to claim 1 is characterized in that, described ethanol is dehydrated alcohol.
3. the manufacture method of the Dimecrotic Acid that uses when the described Fisiobil (S.A.L.V.A.T.) of preparation claim 1 is characterized in that the manufacturing of the Dimecrotic Acid shown in the Formulae II of claim 1 comprises the steps:
A) compound for the following Formula I V in the solvent is 4-methyl-umbelliferone and sodium hydroxide, cutting apart dropping is 2～5 normal methyl-sulfates with respect to the compound of Formula I V, under the pH of reaction soln value is condition more than 10, react, thereby produce the step of 4-methyl-ayapanin of Formulae II I;
B) compound that dissolving is obtained by a) step manufacturing in ethanol and the step of sodium hydroxide;
C) by b) drip methyl-sulfate in the solution that obtains of step manufacturing and react the step of synthetic thick Dimecrotic Acid; And
D) making at c with strong acid) the thick Dimecrotic Acid that generates of step carries out recrystallize in ethanol, produce the step of Dimecrotic Acid.
[Formulae II]
[Formulae II I]
[Formula I V]
4. the manufacture method of Dimecrotic Acid according to claim 3 is characterized in that, in a) step, drops into 1 sulfoxylic acid dimethyl ester, reaction solution is heated to 40～45 ℃ after, drop into remaining methyl-sulfate.
5. the manufacture method of Dimecrotic Acid according to claim 3 is characterized in that, at c) step, slowly drip methyl-sulfate slightly at every turn after, be heated to 40 ℃～80 ℃ and react.
6. the manufacture method of Dimecrotic Acid according to claim 3 is characterized in that, also comprises: at c) after the reaction of step finishes, with organic solvent and water extraction resultant, to remove the step of unreacted reactant and by product.
7. the manufacture method of Dimecrotic Acid according to claim 6 is characterized in that, described organic solvent is a methylene dichloride.
8. the manufacture method of Dimecrotic Acid according to claim 3 is characterized in that, at d) step, described strong acid is hydrochloric acid.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNA2007100971782A CN101284776A (en) | 2007-04-11 | 2007-04-11 | Method for preparing dimecrotic acid and magnesium salt thereof |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNA2007100971782A CN101284776A (en) | 2007-04-11 | 2007-04-11 | Method for preparing dimecrotic acid and magnesium salt thereof |
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| Publication Number | Publication Date |
|---|---|
| CN101284776A true CN101284776A (en) | 2008-10-15 |
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CNA2007100971782A Pending CN101284776A (en) | 2007-04-11 | 2007-04-11 | Method for preparing dimecrotic acid and magnesium salt thereof |
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- 2007-04-11 CN CNA2007100971782A patent/CN101284776A/en active Pending
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