CN102746207A - Synthesis method of oxiracetam - Google Patents
Synthesis method of oxiracetam Download PDFInfo
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- CN102746207A CN102746207A CN2012102551705A CN201210255170A CN102746207A CN 102746207 A CN102746207 A CN 102746207A CN 2012102551705 A CN2012102551705 A CN 2012102551705A CN 201210255170 A CN201210255170 A CN 201210255170A CN 102746207 A CN102746207 A CN 102746207A
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- oxiracetam
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- tertiary butyl
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
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- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
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Abstract
The invention provides a method for preparing oxiracetam, which comprises the steps of: reacting 2-(4-tertiary butyl disilyloxy-2-oxo pyrrolidine-1-yl) ethyl acetate or 2-(4-tertiary butyl diphenylsilyl-2-oxo pyrrolidine-1-yl) ethyl acetate as raw materials with low-molecular-weight halogenated acetic acid ester in a non-protonated solvent under basic condition, and respectively removing protecting groups to prepare oxiracetam. By adopting the method, the problems of the prior art that reaction conditions are rigor, byproducts are many, and the product purity and yield are low in the oxiracetam synthesis process are solved. The method is simple to operate, low in equipment requirements, and high in product purity and yield, and is particularly suitable for industrial production.
Description
Technical field
The present invention relates to the pharmaceutical chemistry field, relate in particular to a kind of compound method of oxiracetam.
Background technology
Oxiracetam (oxiracetam), chemical name 2-(4-hydroxyl-2-oxo-pyrrolidine ketone-1-yl) ethanamide, molecular formula C
6H
10N
2O
3, molecular weight 158.16.Oxiracetam is a kind ofly can promote the metabolic compound of Phosphorylcholine, phosphatidyl ethanolamine and brain, and the elderly takes the medicine that contains this compound for a long time, can obviously improve and organize function, and memory disorder is particularly to preventing and treating the evident in efficacy of senile dementia.The medicine that contains this compounds also is used to treat senile brain insufficiency property psychosyndrome and mental act is disorderly.
Mainly be divided into dual mode in the synthetic technology of the oxiracetam of having reported at present, the one, preparation pyrrolidone line again with acid amides or amide salt or the synthetic oxiracetam for preparing of halogenated acetic acids ethyl ester; The 2nd, directly will have hydroxyl pyrrolidone or hydroxyl butyric ester and acid amides or amide salt or the synthetic oxiracetam for preparing of halogenated acetic acids ethyl ester.But disclosed these two kinds of route modes all have very big drawback in the prior art:
U.S. Pat 4173569A discloses a kind of compound method of oxiracetam; This route is to be starting raw material with 4-amino-3 hydroxyls-butyric acid; Prepare the trimethyl silicon based oxygen base of 4--2-oxo-pyrrolidine with trimethyl silicon based as blocking group; Obtaining 2-(4-trimethylsiloxy group-2-oxo-pyrrolidine-1-yl) ETHYLE ACETATE with the METHYL BROMOACETATE condensation; Slough trimethyl silicon based blocking group and obtain 2-(4-hydroxyl-2-oxo-pyrrolidine-1-yl) ETHYLE ACETATE, last aminolysis obtains oxiracetam, and concrete route is following:
Related midbody X, the VI of this synthetic route all is liquid, separation difficulty, and these two midbodys are all water-soluble, are difficult for purifying, need remove a large amount of moisture content under reduced pressure during aftertreatment, and the difficulty of reaction is increased, and high to the requirement of equipment, complicated operating process.In the reaction with trimethyl silicon based as blocking group earlier at acidic conditions deprotection aminolysis again; Cause product meeting hydrolytic reactions when aminolysis like this, produce a large amount of acid and be difficult to separation and purification, can only lean on and cross resin column repeatedly; This process need concentrate big water gaging; Heated time length will inevitably hydrolytic reactions in water for oxiracetam, causes the finished product purity difference, can not satisfy the requirement that medicine uses.
Patent WO2005115978 discloses the method for a kind of Synthetic 2-(4-hydroxyl-2-oxo-pyrrolidine ketone-1-yl) ethanamide; Obtain oxiracetam with 4-chloro-3-hydroxyl-ethyl n-butyrate and glycyl amide hydrochloride in the reflux in ethanol prepared in reaction in this route, concrete route is following:
This reaction scheme is simple, but side reaction is many especially, and yield is low, has many bibliographical informations to go to control side reaction through different means, does not all have the ideal method, and ultimate yield is only about 30%.And the finished product that obtains must be gone up zwitterion resin desalination and the charged impurity of part repeatedly through behind the activated carbon decolorizing; After condensed water is extremely done; Again in organic solvent such as methyl alcohol repeatedly recrystallization be met the finished product of the drug standard; Post-reaction treatment is complicated, is not suitable for producing under the GMP condition as medicament preparation technology.
Patent CN101885697B discloses a kind of method for preparing oxiracetam, and this method is carried out prepared in reaction with 4-hydroxyl-2-Pyrrolidone and 2-Haloacetamide and obtained 2-(4-hydroxyl-2-oxo-pyrrolidine ketone-1-yl) ethanamide, and concrete route is following:
This reaction scheme is simple; But severe reaction conditions; Need before the preparation 4-hydroxyl-2-Pyrrolidone is carried out alkaline purification, handling for said needs in anhydrous system, to carry out, because the existence of water can cause side reaction; Not and the consumption of alkali also need strict control, excessive alkali can cause a large amount of production of by-products.Reaction is not protected the hydroxyl in 4-hydroxyl-2-Pyrrolidone, causes that product purity is poor, quality is low, and productive rate is not high, and about about 58%.
The present invention provides a kind of preparation method of oxiracetam, and present method operation is simple, and equipment requirements is low, and product purity and yield are high, are particularly suitable for suitability for industrialized production.
Summary of the invention
The object of the invention is to provide a kind of method of new synthesizing oxiracetam, solves severe reaction conditions in the synthesizing oxiracetam process, and by product is more, the problem that product and productive rate are low.
In order to address the above problem, to the invention provides following synthetic route and prepare oxiracetam:
Concrete steps are following:
1) with the compound shown in compound shown in the formula (I) and the formula (II) in the non-protonated solvent, reaction 1-3 hour down of-5-10 ℃ of alkaline condition makes the compound shown in the formula (III);
R wherein
1Silica-based or tert-butyl diphenyl is silica-based for tertiary butyl dimethyl-.R
1 It is silica-based to be preferably tertiary butyl dimethyl-.
R wherein
2Be C
1-C
6Alkyl or benzyl.R
2Be preferably methyl, ethyl, propyl group, sec.-propyl.R
2Ethyl more preferably.
Wherein X is a halogen.X is fluorine, chlorine, bromine or iodine.X is bromine more preferably.
Non-protonated solvent described in the above-mentioned reaction includes but not limited to N, dinethylformamide, DMAC N,N, acetonitrile, THF, methyl-sulphoxide or heptane etc.; Described alkali includes but not limited to sodium hydrogen, n-Butyl Lithium, two trimethyl silicon based amido sodium or lithium hexamethyldisilazide etc.
Low molecule halogenated acetic acids ester shown in its Chinese style (II) is commercially available usual vehicle, can think biochemical technology ltd etc. available from the Tianjin Skien like the 2-METHYL BROMOACETATE; The 2-isopropyl acetate bromide can be available from Shanghai Mai Ruier chemical technology ltd etc.
2) slough the R in formula (III) compound that step 1) prepares through aminolysis reaction
2The protection base prepares the compound shown in the formula (IV);
Step 2) method that the aminolysis reaction in adopts those skilled in the art to be familiar with, said aminolysis reagent is preferably ammoniacal liquor, and formula (IV) compound reacts down at 20-30 ℃ and made through concentrating in 10-15 hour again.
3) under acidic conditions, in the alcoholic solvent, slough step 2) R in formula (IV) compound for preparing
1The protection base prepares oxiracetam;
Described acidic conditions is a hydrochloric acid, formula (IV)) compound 20-30 ℃ down reaction 1-3 hour again through filter, the wash-out drying makes title product.
Described pure lower alcohol includes but not limited to methyl alcohol, ethanol, Virahol, the trimethyl carbinol etc.; Particular methanol or ethanol.
The method that the invention provides a kind of brand-new synthesizing oxiracetam has solved the severe reaction conditions difficulty high to equipment requirements, has also avoided a large amount of production of by-products, has improved product gas purity and productive rate greatly, is more suitable for suitability for industrialized production.
The technology of existing synthesizing oxiracetam when in the end making with extra care oxiracetam, has all been used ion exchange resin desalination and impurity; Owing to use the mode of resin purification need concentrate a large amount of water to obtain the oxiracetam of solid form; Complicated operation not only, and in concentration process, oxiracetam is hydrolyzed into carboxylic acid easily; Bring impurity in the purge process again into, cause product purifying fully.
The contriver finds unexpectedly, works as R
1The protection base is that the silica-based or tert-butyl diphenyl of tertiary butyl dimethyl-is when silica-based; Use reactions step of the present invention; In reactions step 2) in earlier formula (III) compound is carried out aminolysis after; The formula IV compound that obtains is directly separated out with solid form from reaction solution, and most of impurity that reaction produces can both be removed through filtering directly, through detecting formula IV compound purity greater than 99%.The contriver is also unexpected to be found; Because step 3) deprotection process has used alcohol to be solvent; In the reaction process of dehydroxylation protection, step 2) for a small amount of carboxylic acid byproduct of removing becomes ester with pure, this esterification material can not be separated out from alcoholic solution in; And the title product oxiracetam can directly be separated out with solid form from pure reaction solution, and title product purity is through detecting greater than 99%.Whole technology has effectively been avoided the complex operations of resin purification, the more important thing is, has avoided oxiracetam that the situation that hydrolysis produces by product takes place in last handling process.
Embodiment
Only if definition is arranged in addition, all technology that the present invention uses and the implication of scientific terminology are identical with the implication of the affiliated technical field those of ordinary skill common sense of the present invention.Usually, the name and the following experimental technique of the present invention's use all are well known in the art or commonly used.
Clearer for technical problem, technical scheme and beneficial effect that the present invention is solved, below in conjunction with specific embodiment, the present invention is further described.
Embodiment 1
R
1For tertiary butyl dimethyl-silica-based
The preparation of the 4-tertiary butyl two silyloxies-2-oxo-pyrrolidine ketone
4-hydroxyl-2-oxo-pyrrolidine ketone 101.1g (1.0mol) is added the DMF500ml dissolving, add TBDMSCl 165.8g (1.1mol), imidazoles 102.1g (1.5mol), reacted 18 hours.Reaction solution adds in the 1500.0g water, MTBE (1000ml * 3) extraction, 1000ml washing 1 time; Anhydrous sodium sulfate drying; Filtration back mother liquor is concentrated into dried, the crystallization of resistates normal heptane, filtration, the dry 4-tertiary butyl two silyloxies-2-oxo-pyrrolidine ketone that gets.
Embodiment 2
R
1For tert-butyl diphenyl silica-based
The 4-tert-butyl diphenyl is silica-based-preparation of 2-oxo-pyrrolidine ketone
4-hydroxyl-2-oxo-pyrrolidine ketone 200g (1.0mol) is added the DMF500ml dissolving, adds tert-butyl diphenyl chlorosilane 300g (1.1mol), imidazoles 190.5g (1.5mol), keep 40 ℃ under, reacted 10 hours.Reaction solution adds in the 2000.0g water, MTBE (1500ml * 3) extraction, 1000ml washing 1 time; Anhydrous sodium sulfate drying; Filter the back mother liquor and be concentrated into driedly, the crystallization of resistates normal heptane is filtered, dry 4-tert-butyl diphenyl is silica-based-2-oxo-pyrrolidine ketone.
Embodiment 3
The preparation of oxiracetam
The product 4-tertiary butyl two silyloxies-2-oxo-pyrrolidine ketone 215.36g, the 2-METHYL BROMOACETATE 200.4g that get among the embodiment 1 are dissolved among the 800ml THF; 5 ℃ of HMDSLi tetrahydrofuran solution 750ml that slowly drip 1.6M down drip off the maintenance temperature and stirred 1 hour.TLC detects (developping agent methylene dichloride: methyl alcohol=30:1, phospho-molybdic acid colour developing) reaction and finishes, and adds 900ml water, branch vibration layer, and organic layer is concentrated into dried, and resistates adds 900ml ETHYLE ACETATE, washes 1 time.Ethyl acetate layer is concentrated into dried, adds normal heptane 600ml crystallization, normal heptane 100ml washing, and dry 2-(the 4-tertiary butyl two silyloxies-2-oxo-pyrrolidine-1-yl) ETHYLE ACETATE that gets, yield 85%, performance liquid detect and show that purity is greater than 98%.
Get above-mentioned product 2-(the 4-tertiary butyl two silyloxies-2-oxo-pyrrolidine-1-yl) ETHYLE ACETATE 301.45g, 25 ℃ slowly add in the 1500ml strong aqua while stirring, react 10 hours.The TLC detection reaction finishes; ETHYLE ACETATE (600ml * 2) extraction; The combined ethyl acetate layer, 600ml saturated aqueous common salt washing 1 time, ETHYLE ACETATE is concentrated into dried 2-(the 4-tertiary butyl two silyloxies-2-oxo-pyrrolidine-1-yl) ethanamide solid; Yield 92%, performance liquid detect and show that purity is greater than 99%.
Get above-mentioned product 2-(the 4-tertiary butyl two silyloxies-2-oxo-pyrrolidine-1-yl) ethanamide 270.45 g and add in the 900ml methanol solution and dissolve, add 4mol/L hydrochloric acid methanol 50ml again, 25 ℃ of stirring reactions 2 hours; Separate out a large amount of white solids; Filter, 200ml methyl alcohol is washed, dry 2-(4-hydroxyl-2-oxo-pyrrolidine ketone-1-yl) ethanamide that gets; Yield 96%, performance liquid detect and show that purity is greater than 99%.
Embodiment 4
The preparation of oxiracetam
Get product 4-tert-butyl diphenyl among the embodiment 2 silica-based-2-oxo-pyrrolidine ketone 205.47g, 2-isopropyl acetate bromide 179.98g be dissolved among the 800ml THF ,-5 ℃ of HMDSLi tetrahydrofuran solution 750ml that slowly drip 1.6M down keep temperature to stir 3 hours.TLC detects (developping agent methylene dichloride: methyl alcohol=30:1, phospho-molybdic acid colour developing) reaction and finishes, and adds 900ml water, concentrates to remove and desolvates, and resistates adds 900ml ETHYLE ACETATE, wash 2 times, the sodium pyrosulfate aqueous solution wash 1 time, wash 1 time.Ethyl acetate layer is concentrated into dried, adds normal heptane 600ml crystallization, normal heptane 100ml washing, and dry 2-(4-tert-butyl diphenyl silica-based-2-oxo-pyrrolidine-1-yl) isopropyl acetate, yield 83%, performance liquid detect demonstration purity greater than 98%.
Get above-mentioned product 2-(4-tert-butyl diphenyl silica-based-2-oxo-pyrrolidine-1-yl) isopropyl acetate 258.45g, 20 ℃ slowly add in the 1230ml strong aqua while stirring, react 15 hours.The TLC detection reaction finishes; ETHYLE ACETATE (450ml * 2) extraction; Combined ethyl acetate layer, saturated aqueous common salt 450ml are washed 1 time, and ETHYLE ACETATE is concentrated into dried 2-(4-tert-butyl diphenyl silica-based-2-oxo-pyrrolidine-1-yl) ethanamide solid; Yield 90%, performance liquid detect and show that purity is greater than 99%.
Get above-mentioned product 2-(4-tert-butyl diphenyl silica-based-2-oxo-pyrrolidine-1-yl) ethanamide 260.37 g and add in the 850ml methanol solution and dissolve, add 4mol/L hydrochloric acid methanol 50ml again, 30 ℃ of stirring reactions 1 hour; Separate out a large amount of white solids; Filter, 200ml methyl alcohol is washed, dry 2-(4-hydroxyl-2-oxo-pyrrolidine ketone-1-yl) ethanamide that gets; Yield 95%, performance liquid detect and show that purity is greater than 99%.
Embodiment 5
The preparation of oxiracetam
The product 4-tertiary butyl two silyloxies-2-oxo-pyrrolidine ketone 232.15g, the 2-benzyl acetate bromide 213.96g that get among the embodiment 1 are dissolved among the 800ml THF, and 10 ℃ of HMDSLi tetrahydrofuran solution 750ml that slowly drip 1.6M down keep temperature to stir 2 hours.TLC detects (developping agent methylene dichloride: methyl alcohol=20:1, phospho-molybdic acid colour developing) reaction and finishes, and adds 900ml water, concentrates to remove and desolvates, and resistates adds 900ml ETHYLE ACETATE, wash 2 times, the sodium pyrosulfate aqueous solution wash 1 time, wash 1 time.Ethyl acetate layer is concentrated into dried, adds normal heptane 600ml crystallization, normal heptane 100ml washing, and dry 2-(the 4-tertiary butyl two silyloxies-2-oxo-pyrrolidine-1-yl) jasmal that gets, yield 84%, performance liquid detect and show that purity is greater than 98%.
Get above-mentioned product 2-(the 4-tertiary butyl two silyloxies-2-oxo-pyrrolidine-1-yl) jasmal 285.46g, be added dropwise in the 1200ml strong aqua under 30 ℃ of stirrings, reacted 12 hours.The TLC detection reaction finishes; ETHYLE ACETATE (450ml * 2) extraction; Combined ethyl acetate layer, saturated aqueous common salt 450ml are washed 1 time, and ETHYLE ACETATE is concentrated into dried 2-(the 4-tertiary butyl two silyloxies-2-oxo-pyrrolidine-1-yl) ethanamide solid; Yield 90%, performance liquid detect and show that purity is greater than 99%.
Get above-mentioned product 2-(the 4-tertiary butyl two silyloxies-2-oxo-pyrrolidine-1-yl) ethanamide 265.32g and add in the 900ml methanol solution and dissolve, add 4mol/L hydrochloric acid methanol 50ml again, 20 ℃ of stirring reactions 3 hours; Separate out a large amount of white solids; Filter, 200ml methyl alcohol is washed, dry 2-(4-hydroxyl-2-oxo-pyrrolidine ketone-1-yl) ethanamide that gets; Yield 95%, performance liquid detect and show that purity is greater than 99%.
Should be noted that the above is merely preferred embodiment of the present invention,, all any modifications of within spirit of the present invention and principle, being done, be equal to and replace and improvement etc., all should be included within protection scope of the present invention not in order to restriction the present invention.
Claims (8)
1. the compound method of an oxiracetam comprises the steps:
1) compound shown in compound shown in the formula (I) and the formula (II) is reacted under non-protonated solvent neutral and alkali condition makes the compound shown in the formula (III)
2); Slough the R in formula (III) compound that step 1) prepares through aminolysis reaction
2The protection base prepares the compound shown in the formula (IV)
；
3) under acidic conditions, slough step 2 in the alcoholic solvent) R in formula (IV) compound for preparing
1The protection base prepares oxiracetam
R wherein
1Silica-based or tert-butyl diphenyl is silica-based for tertiary butyl dimethyl-; R
2Be C
1-C
6Alkyl or benzyl, X is a halogen.
2. the method for claim 1 is characterized in that described R
2Be methyl, ethyl, propyl group or sec.-propyl; X is fluorine, chlorine, bromine or iodine.
3. the method for claim 1 is characterized in that described R
1For tertiary butyl dimethyl-silica-based.
4. method as claimed in claim 2 is characterized in that described R
2Be ethyl; X is a bromine.
5. the method for claim 1 is characterized in that, the non-protonated solvent is N in the described step 1), dinethylformamide, DMAC N,N, acetonitrile, THF, methyl-sulphoxide or heptane; Described alkali is sodium hydrogen, n-Butyl Lithium, two trimethyl silicon based amido sodium or lithium hexamethyldisilazide.
6. the method for claim 1 is characterized in that, described step 2) in aminolysis reagent be ammoniacal liquor.
7. the method for claim 1 is characterized in that, acidic conditions is a hydrochloric acid in the described step 3).
8. the method for claim 1 is characterized in that, the alcoholic solvent in the described step 3) is methyl alcohol or ethanol.
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104557655A (en) * | 2013-10-10 | 2015-04-29 | 重庆医药工业研究院有限责任公司 | Oxiracetam purifying method |
| CN106397294A (en) * | 2016-08-30 | 2017-02-15 | 山东默得森生物制药有限公司 | Preparation method of nootropic of (S)-oxiracetam |
| CN112876397A (en) * | 2021-01-19 | 2021-06-01 | 江苏诚信药业有限公司 | Preparation method of 2, 5-dihydro-2-oxo-1H-pyrrole-1-acetamide |
| CN114621128A (en) * | 2022-03-10 | 2022-06-14 | 成都百途医药科技有限公司 | Preparation method of (S) -oxiracetam |
-
2012
- 2012-07-23 CN CN2012102551705A patent/CN102746207B/en active Active
Non-Patent Citations (1)
| Title |
|---|
| MARIO ORENA ET AL: "A new synthesis of (R)-GABOB and (R)-oxiracetam", 《J. CHEM. RESEARCH (S)》 * |
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104557655A (en) * | 2013-10-10 | 2015-04-29 | 重庆医药工业研究院有限责任公司 | Oxiracetam purifying method |
| CN106397294A (en) * | 2016-08-30 | 2017-02-15 | 山东默得森生物制药有限公司 | Preparation method of nootropic of (S)-oxiracetam |
| CN112876397A (en) * | 2021-01-19 | 2021-06-01 | 江苏诚信药业有限公司 | Preparation method of 2, 5-dihydro-2-oxo-1H-pyrrole-1-acetamide |
| CN112876397B (en) * | 2021-01-19 | 2022-03-18 | 江苏诚信药业有限公司 | Preparation method of 2, 5-dihydro-2-oxo-1H-pyrrole-1-acetamide |
| CN114621128A (en) * | 2022-03-10 | 2022-06-14 | 成都百途医药科技有限公司 | Preparation method of (S) -oxiracetam |
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