CN101898993A - Preparation method of 4-hydroxyl ketopyrrolidine-2-acetamide - Google Patents
Preparation method of 4-hydroxyl ketopyrrolidine-2-acetamide Download PDFInfo
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- CN101898993A CN101898993A CN2009100992608A CN200910099260A CN101898993A CN 101898993 A CN101898993 A CN 101898993A CN 2009100992608 A CN2009100992608 A CN 2009100992608A CN 200910099260 A CN200910099260 A CN 200910099260A CN 101898993 A CN101898993 A CN 101898993A
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Abstract
The invention provides a preparation method of 4-hydroxyl ketopyrrolidine-2-acetamide as a medicine with a cerebral metabolism improving function, comprising the following steps of: 1, reducing 4-halogenated acetylacetic ester as a raw material into 4-chloro-3hydroxybutyrate by using a reducing agent; and 2, condensing the obtained 4-chloro-3-hydroxybutyrate of the step 1 and glycine amide or glycine amide hydrochloride to obtain 4-hydroxyl ketopyrrolidine-2-acetamide and purifying the obtained 4-hydroxyl ketopyrrolidine-2-acetamide. The invention ensures that the total yield of a product is increased above 36 percent, shortens a process route and reaction time, reduces an intermediate process and is more suitable for the large-scale production of medical industry.
Description
Technical field
The invention belongs to medical field of fine chemical, relate in particular to a kind of synthetic method of 4-hydroxy pyrrolidone-2-acetamine.
Background technology
The 4-hydroxy pyrrolidone-2-acetamine, the popular name oxiracetam is people's brain metabolism improving medicine.Have the central excitation effect, can promote half senile cell vigor to strengthen, improve and promotion brain memory ability, can also resist anoxic in the brain, can promote brain function and metabolism.
Oxiracetam molecular formula: C
6H
10N
2O
3Molecular weight: 158.16
The 4-hydroxy pyrrolidone-2-acetamine, first by the exploitation of Italian ISFS.P.A company, listing in 1987.So far the synthesis technique patent that existing many companies have applied for the 4-hydroxy pyrrolidone-2-acetamine.Press the precedence of tetramethyleneimine Cheng Huan, can be divided into two big classes to synthetic route:
One class is first synthesis of pyrrolidine, and then through reduction, replaces, steps such as ammonification obtain the purpose product, as patent publications CN101121688 in the world, CN1513836, US4118396, US5276164, KR20030042883 all disclose above-mentioned technological step and technology.The problem that their manufacture craft exists is that reactions steps is many, and total recovery is low, and " Atom economy " is not high.In addition, intermediate or product are difficult for purifying, and the technology that has also uses the toxic substance of comparison danger.
Another kind of is to synthesize the hydrochlorate of G-NH2 or G-NH2 and the butyric acid alkyl ester or 3 that γ, β position replace from the basis, inexpensive industrial chemicals earlier, 4 epoxy butyric acid alkyl esters, the butyric acid alkyl ester or 3 that replaces of the hydrochlorate of described G-NH2 and γ, β position then, behind 4 one step of epoxy butyric acid alkyl ester annulations, generate the purpose product.As patent publications US4686296 in the world, JP3181458, JP63027477, JP62185069." Atom economy " of this class technology is higher, and the problem of existence is that total recovery is low, and the final product complicated component need just can obtain after process resin absorption and the desorb, and purity does not reach the requirement that medicine uses yet.In addition the reaction times very long, can not satisfy need of industrial production equally.
Be the chemical structural formula of 4-chloro-3-butyric ester and derivative thereof below:
A is halogen atom or epoxy group(ing) in the formula, and B is a hydroxyl, and when A was epoxy group(ing), A, B formed epoxy group(ing).R is straight chain, the branched paraffin of 1 to 4 carbon atom.
Chinese patent CN1948285 is the synthesizing chlorinated acetoacetyl chlorine of raw material with the ketene dimer, again with the hydrochlorate generation substitution reaction of G-NH2, through reduction, becomes the ring step to obtain the purpose product.Require low temperature, compressive reaction, thereby limited its application in suitability for industrialized production.
In addition, in these inventions, generally with organic bases, basic metal or alkaline earth metal hydroxides such as potassium hydroxide, sodium hydroxide, lime carbonate, or carbonate is acid binding agent, consider the yellow soda ash that adopt for economy more, owing to be solid-liquid phase reaction, thereby the reaction times is longer, generally needs 24-70 hour, reaction generates a large amount of solid salts, contaminate environment.
Summary of the invention:
Technical problem to be solved by this invention provides a kind of improved 4-hydroxy pyrrolidone-2-acetamine production technique, improves product yield, reduces production costs, and reduces the generation of " three wastes ".
4-hydroxy pyrrolidone-2-acetamine production technique of the present invention comprises following chemical equation:
Concrete building-up process is as follows:
1, reduction operation: 4-halo acetylacetic ester is reduced to 4-chloro-3-butyric ester;
2, condensation operation: 4-chloro-3-butyric ester and G-NH2 are condensed into 4-hydroxy pyrrolidone-2-acetamine crude product;
3, refining step: step 2 gained 4-hydroxy pyrrolidone-2-acetamine is purified.
The method for preparing the 4-hydroxy pyrrolidone-2-acetamine of the present invention, be to be raw material with market 4-halo acetylacetic ester (IV) cheap and easy to get, X is a halogen atom in the formula, R is the straight chain of 1～4 carbon atom, branched-chain alkyl, this compound can be following compound: the 4-chloro methyl acetoacetate, the 4-chloroacetyl acetacetic ester, 4-chloracetyl isopropyl acetate, 4-chloracetyl butylacetate, 4-chloracetyl tert.-butyl acetate, 4-acetobrom methyl acetate, the 4-ethyl bromoacetoacetate, 4-acetobrom isopropyl acetate, 4-acetobrom butylacetate, 4-acetobrom tert.-butyl acetate etc., wherein, be the best with 4-chloro methyl acetoacetate and 4-chloroacetyl acetacetic ester.
Among the present invention, at first above-mentioned 4-halo acetylacetic ester and reductive agent reaction are made 4-chloro-3-butyric ester (III).Described reductive agent is sodium borohydride POTASSIUM BOROHYDRIDE or lithium aluminium hydride, and described solvent is a protic solvent, as N, dinethylformamide, tetrahydrofuran (THF), methyl alcohol, ethanol, propyl alcohol, Virahol, butanols, the mixture of the trimethyl carbinol or above-mentioned solvent etc., temperature of reaction is 0-80 ℃, and preferred temperature is 10-35 ℃.
The preparation method of 4-hydroxy pyrrolidone-2-acetamine as mentioned above, the G-NH2 in the described step 2 (II) can be for its hydrochlorate, as glycyl amide hydrochloride.Described solvent is a protic solvent, methyl alcohol, ethanol, propyl alcohol, Virahol, butanols, the trimethyl carbinol, ethylene glycol, 2-methyl cellosolve or ether compound, as 1,4-dioxane, 1,2-glycol dimethyl ether, diglyme etc., or the mixture of these solvents.Preferred solvent is an ethanol.
Chemical reaction is to carry out to the solvent refluxing temperature in room temperature in the step 2 as mentioned above.Adopt strongly basic anion exchange resin in this reaction, or organic bases, basic metal or alkaline earth metal hydroxides such as potassium hydroxide, sodium hydroxide, calcium hydroxide, carbonate are acid binding agent.Anionite-exchange resin can recycled after manipulation of regeneration.Adopting quarternary ammonium salt such as Tetramethylammonium hydroxide, Tetrabutyl amonium bromide, tetrabutylammonium iodide, benzyltriethylammoinium chloride and their arbitrary composition is phase-transfer catalyst, with fast reaction speed, shortens the reaction times.
The preparation method of 4-hydroxy pyrrolidone-2-acetamine as mentioned above, refining step comprises decolorizing with activated carbon and ion exchange resin removal of impurities.The weight proportion of crude product, water and activated carbon is: 1: (6-12): (0.05-0.15), bleaching temperature is 40-100 ℃, and bleaching time is 0.5-2 hour.Use strongly-acid anionite-exchange resin (as 732 types, 001 * 7,1 * 4 then, 1 * 7,1 * 14 etc.) and/or strongly basic anion exchange resin (717 types, 201 * 7,201 * 4 etc.) handle, obtain purity and satisfy 4-hydroxy pyrrolidone-2-acetamine (I) product that medicine requires.
The present invention improves more than 36% the total recovery of product, has shortened operational path and reaction times, has reduced the intermediate treating processes, is more suitable for the medicine industry large-scale production.
Embodiment
The invention will be further described below in conjunction with embodiment, but be not limited to present embodiment.
Embodiment step 1
The preparation of 4-chloro-3-beta-hydroxymethyl butyrate
In the four-hole bottle of 2L, load onto dropping funnel, thermometer, stirring, add KBH418.5g, add industrial alcohol 1700ml, fully stir and make it the mixing suspension.The 163g4-chloro methyl acetoacetate is added drop-wise in the above-mentioned solution, after being added dropwise to complete, stirred filtration 6 hours in 32-35 ℃.Filtrate is removed solution through concentrating under reduced pressure, and gained oily matter adds 150ml saturated common salt water extraction, divides oil-yielding stratum, water layer merges organic layer with 80ml dichloromethane extraction secondary, uses the 15g anhydrous sodium sulfate drying, concentrate and reclaim methylene dichloride, get 4-chloro-3-beta-hydroxymethyl butyrate 140.8g.
Embodiment step 2
The preparation of oxiracetam
(1) add ethanol 480kg in the retort of 1000L, glycyl amide hydrochloride 66.2kg adds 4-chloro-3-beta-hydroxymethyl butyrate 70kg, adds Na then
2CO
360kg adds Tetramethylammonium hydroxide methanol solution 5kg at last.And with adding in the retort behind the ethanol 30kg washing material bucket.At this moment, open vapour and be warming up to reflux temperature, and begin to be incubated timing, kept reflux state 20 hours.
(2) after insulation reaction is finished, turn off steam, and continue crawl and open stirring, it is centrifugal that reaction solution is put into preprepared whizzer, and the solid phase in the reaction solution is discarded, and centrifugate is with in the vacuum suction concentration tank, open the steam intensification and open vacuum pump, reach ethanol receiving tank valve and carry out the ethanol recovery, the solvent reclaim under reduced pressure near doing, can be got the dark oil thing.Steam off, vacuum and ethanol receiving tank valve add the 40L dehydrated alcohol then in retort at this moment, behind the heat of solution oily matter, open refrigerated brine, static freezing and crystallizing 4～5 hours, and centrifuging is with dehydrated alcohol 10L wash crystallization.Play material and dry and to get faint yellow oxiracetam crude product 42.7kg.
Embodiment step 3
(1) after the purified water dissolving of crude product with 400L, and in treatment tank, added the 3kg decolorizing with activated carbon 1 hour, suction filtration.Add 25kg717 type strong base ion exchange resin in the filtrate again, open and stir, after about 1 hour feed liquid put into the centrifugal resin (resin is recyclable to be used again) that filters, and with in another treatment tank of filtrate usefulness vacuum suction, the 732 type strong acid ion exchange resins that add 8kg, behind the stir about 50 minutes, the centrifugal resin (resin is recyclable to be used again) that filters, filtrate is opened vacuum with in the vacuum suction concentration tank, under agitation concentrates, dewater after do, can get white crystalline solid, add dehydrated alcohol 40L after, freezing and crystallizing is the centrifugal white powder solid that gets after 2 hours.Be the oxiracetam elaboration.
(2) elaboration is put into bipyramid formula loft drier, and vacuum-drying can get finished product 25.8kg, yield 36%, 166.5～168.7 ℃ of fusing points.
Though above shown detailed embodiment of the present invention, apparent, those skilled in the art is under the prerequisite of essence of the present invention, can carry out the part modifications and changes; Description above is the illustration of property as an illustration only, is not as limitation of the present invention, has the preparation method of the 4-hydroxy pyrrolidone-2-acetamine of above-mentioned technical characterictic, all falls into protection domain of the present invention.
Claims (8)
1. the preparation method of a 4-hydroxy pyrrolidone-2-acetamine, it comprises the condensation operation: 4-chloro-3-butyric ester and G-NH2 are condensed into the 4-hydroxy pyrrolidone-2-acetamine; It is characterized in that: it is made of following steps:
1, reduction operation: 4-halo acetylacetic ester is reduced to 4-chloro-3-butyric ester through reductive agent;
2, condensation operation: 4-chloro-3-butyric ester and G-NH2 are condensed into the 4-hydroxy pyrrolidone-2-acetamine
3, refining step: step 2 gained 4-hydroxy pyrrolidone-2-acetamine is purified.
2. the preparation method of 4-hydroxy pyrrolidone-2-acetamine as claimed in claim 1, it is characterized in that: in the structural formula of the 4-halo acetylacetic ester in the described step 1, X is a halogen atom, R is the straight chain of 1～4 carbon atom, branched-chain alkyl, this compound can be following compounds: the 4-chloro methyl acetoacetate, the 4-chloroacetyl acetacetic ester, 4-chloracetyl propyl acetate, 4-chloracetyl butylacetate, 4-chloracetyl tert.-butyl acetate, 4-acetobrom methyl acetate, the 4-ethyl bromoacetoacetate, 4-acetobrom isopropyl acetate, 4-acetobrom butylacetate, 4-acetobrom tert.-butyl acetate.
3. the preparation method of 4-hydroxy pyrrolidone-2-acetamine as claimed in claim 1, it is characterized in that: the described reductive agent in the described step 1 is the mixture of sodium borohydride POTASSIUM BOROHYDRIDE or lithium aluminium hydride and described reductive agent sodium hydroxide potassium borate or lithium aluminium hydride, the solvent that adopts is a protic solvent, as N, dinethylformamide, tetrahydrofuran (THF), methyl alcohol, ethanol, propyl alcohol, Virahol, butanols, the mixture of the trimethyl carbinol or above-mentioned solvent, temperature of reaction are 0-80 ℃, and preferred temperature is 10-35 ℃.
4. the preparation method of 4-hydroxy pyrrolidone-2-acetamine as claimed in claim 1, it is characterized in that: reactant can be selected the hydrochlorate of G-NH2 or G-NH2 for use in the described step 2, the solvent that is adopted is a protic solvent, methyl alcohol, ethanol, propyl alcohol, Virahol, butanols, the trimethyl carbinol, ethylene glycol, 2-methyl cellosolve or ether compound, as 1,4-dioxane, 1,2-glycol dimethyl ether, diglyme, preferred solvent are ethanol.
5. the preparation method of 4-hydroxy pyrrolidone-2-acetamine as claimed in claim 1, it is characterized in that: chemical reaction in the described step 2 adopts strongly basic anion exchange resin, or organic bases, basic metal or alkaline earth metal hydroxides or carbonate are acid binding agent.
6. the preparation method of 4-hydroxy pyrrolidone-2-acetamine as claimed in claim 1, it is characterized in that: in the described step 2, the employing quarternary ammonium salt is a phase-transfer catalyst, as Tetramethylammonium hydroxide, Tetrabutyl amonium bromide, tetrabutylammonium iodide, benzyltriethylammoinium chloride or as described in the mixture of arbitrary combination in the Tetramethylammonium hydroxide, Tetrabutyl amonium bromide, tetrabutylammonium iodide, benzyltriethylammoinium chloride.
7. the preparation method of 4-hydroxy pyrrolidone-2-acetamine as claimed in claim 1 is characterized in that: described refining step comprises decolorizing with activated carbon and ion exchange resin adsorption-edulcoration.Crude product, H
2The weight proportion of O and activated carbon is: 1: (6-12): (0.05-0.15), bleaching temperature is 40-100 ℃, and bleaching time is 0.5-2 hour.
8. the preparation method of 4-hydroxy pyrrolidone-2-acetamine as claimed in claim 7, it is characterized in that: described ion exchange resin adsorption-edulcoration comprises with strongly-acid anionite-exchange resin as 732 types, 001 * 7,1 * 4,1 * 7,1 * 14 grade and/or strongly basic anion exchange resin be as 717 types, adsorption treatment such as 201 * 7,201 * 4.The weight ratio of crude product and resin is: 0.1～1: 1, and the adsorption treatment time is 0.5-2 hour, temperature is 20-100 ℃.
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Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102304046A (en) * | 2011-06-24 | 2012-01-04 | 南通诚信氨基酸有限公司 | Method for preparing hydroxyl ester |
| CN102603598A (en) * | 2011-01-21 | 2012-07-25 | 重庆润泽医疗器械有限公司 | Preparation method of (S)-4-hydroxy-2-oxo-1-pyrrolidineacetamide |
| CN102633705A (en) * | 2012-03-31 | 2012-08-15 | 石家庄利康医药科技有限公司 | Method for preparing oxiracetam |
| CN103342673A (en) * | 2013-07-31 | 2013-10-09 | 石药集团欧意药业有限公司 | Oxiracetam crystal form and preparation method thereof |
| CN103588695A (en) * | 2013-11-25 | 2014-02-19 | 石药集团欧意药业有限公司 | Oxiracetam compound adopting crystallization form and preparation method thereof |
| CN113292426A (en) * | 2021-06-15 | 2021-08-24 | 河北师范大学 | Method for preparing ethyl 3-hydroxy-4-chlorobutyrate |
-
2009
- 2009-05-28 CN CN2009100992608A patent/CN101898993A/en active Pending
Cited By (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102603598A (en) * | 2011-01-21 | 2012-07-25 | 重庆润泽医疗器械有限公司 | Preparation method of (S)-4-hydroxy-2-oxo-1-pyrrolidineacetamide |
| CN102603598B (en) * | 2011-01-21 | 2014-07-16 | 重庆润泽医药有限公司 | Preparation method of (S)-4-hydroxy-2-oxo-1-pyrrolidineacetamide |
| CN102304046A (en) * | 2011-06-24 | 2012-01-04 | 南通诚信氨基酸有限公司 | Method for preparing hydroxyl ester |
| CN102633705A (en) * | 2012-03-31 | 2012-08-15 | 石家庄利康医药科技有限公司 | Method for preparing oxiracetam |
| CN103342673A (en) * | 2013-07-31 | 2013-10-09 | 石药集团欧意药业有限公司 | Oxiracetam crystal form and preparation method thereof |
| CN103342673B (en) * | 2013-07-31 | 2015-11-18 | 石药集团欧意药业有限公司 | A kind of Oxiracetam crystal form and preparation method thereof |
| CN103588695A (en) * | 2013-11-25 | 2014-02-19 | 石药集团欧意药业有限公司 | Oxiracetam compound adopting crystallization form and preparation method thereof |
| CN103588695B (en) * | 2013-11-25 | 2015-08-05 | 石药集团欧意药业有限公司 | Oxiracetam compound of a kind of crystallized form and preparation method thereof |
| CN113292426A (en) * | 2021-06-15 | 2021-08-24 | 河北师范大学 | Method for preparing ethyl 3-hydroxy-4-chlorobutyrate |
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Open date: 20101201 |