CN104230777A - Synthetic method of oxiracetam - Google Patents
Synthetic method of oxiracetam Download PDFInfo
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- CN104230777A CN104230777A CN201310243165.7A CN201310243165A CN104230777A CN 104230777 A CN104230777 A CN 104230777A CN 201310243165 A CN201310243165 A CN 201310243165A CN 104230777 A CN104230777 A CN 104230777A
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- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/18—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
- C07D207/22—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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- C07C229/04—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated
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Abstract
The invention discloses a synthetic method of (S)-oxiracetam. The synthetic method comprises the following steps: (1) by adopting S-4-amino-3-hydroxybutyric acid as a starting material, performing esterification reaction with alcohol to obtain an intermediate I; (2) performing condensation reaction between the intermediate I and halogenated acetic ester to obtain an intermediate II; (3) performing ring closing reaction on the intermediate II to obtain an intermediate III; and (4) performing ammonolysis reaction on the intermediate III to obtain a target product namely (S)-oxiracetam. By adopting a synthetic route of oxiracetam disclosed by the invention, at least more than 20% of an (S)-oxiracetam product with relatively ideal yield can be obtained, and a new oxiracetam synthetic route can be created.
Description
Technical field
The present invention relates to a kind of synthetic method of oxiracetam, particularly relate to the synthetic method of one (S)-oxiracetam.
Background technology
Oxiracetam is the nootropics synthesized first in 1974 than Qie Mu company by Italian SmithKline, the raceme be made up of two kinds of isomer (S)-oxiracetams ((S)-oxiracetam) and (R)-oxiracetam ((R)-oxiracetam).(S)-oxiracetam is a single enantiomer of oxiracetam, and chemistry is by name: (S)-4-hydroxyl-2 oxo-1-pyrrolidine ethanamide.Nootropics oxiracetam is a kind of hydroxy-amino-butyric acid (GABOB) derivative of synthesis, and it is that a kind of can promotion learns, memory, the medicine for central nervous system of protection damaged nerve cell.
At present, the method for synthesis (the S)-oxiracetam of bibliographical information has four kinds:
US Patent No. 4173569 has addressed a kind of synthetic method of (S)-oxiracetam: (S)-4-amino-3-hydroxybutyrate is starting raw material; through sillylation reagent protection hydroxyl; product after cyclization and halogenated acetic acids ethyl ester react; reaction product is through Deprotection; ammonia solution, finally obtains target compound.This kind of preparation method is not suitable for commercial scale production, because it has a lot of shortcoming, carrying out protection and can increase reactions steps, wasting raw material as used protecting group to hydroxyl, consuming time longer, increases cost, total recovery is reduced.In addition, in this reaction process, need to carry out column chromatography purification to intermediate, just can carry out next step reaction.These shortcomings are all very disadvantageous for commercial scale production.
Document: Tetrahedron:Asymmetry1992,3 (11) report a kind of method of synthesizing this compound; With oxysuccinic acid and glycine methyl ester for starting raw material, Acetyl Chloride 98Min. protection hydroxyl, through selective reduction, remove hydroxyl, Deprotection, ammonia solution, obtains target compound.In this approach, need to carry out a selective reduction and cause the multiple by product of generation, and each intermediate needs column chromatography purification, just can carry out next step reaction.Such technique can not meet the requirement of industrially scalable equally.
Technology disclosed in patent W02005/115978, wherein (S)-4-chloro-3-hydroxyl ethyl butyrate and G-NH2 are obtained by reacting target compound, or react with glycine ethyl ester, then obtain target compound through ammonia solution.Wherein (S)-4-chloro-3-hydroxybutanoic acid ester and sweet amine amide are obtained by reacting the finished product oxiracetam is in the basic conditions add by disposable the alkalescence that alkali controls reaction solution, but because oxiracetam is easily destroyed in strong base solution, directly affects purity and the yield of oxiracetam like this; In purifying the finished product oxiracetam, adopt silica gel column chromatography method in addition, the elutriant of use is organic mixed solvent, and quantity of solvent is large, and not easily reclaim, cost is high, and silica gel column chromatography method is also not suitable for industrial amplification production.
Chinese patent CN10575309A report a kind of with glycine and S-4-halogen-3-hydroxybutyrate ester for raw material carries out condensation, carry out the synthetic route of esterification ammonia solution again, but the method drips highly basic mode under adopting hot conditions equally carries out condensation, can with multiple side reactions such as S-4-halogen-3-hydroxybutyrate Ester hydrolysis while condensation, cause condensation yield lower, by product is more, obtain end product S-oxiracetam cannot to separate out by direct crystallization under this purity, need the chromatography removal of impurities of ion exchange resin, cost is high, purity is low, is difficult to industrialization.
Summary of the invention
The object of the present invention is to provide a kind of synthetic method of oxiracetam, the inventive method is simple to operate, purity is high, yield is high.
The object of the invention is achieved through the following technical solutions:
A kind of synthetic method of (S)-oxiracetam, comprises the steps:
(1) with S-4-amino-3-hydroxybutyrate for starting raw material, carry out esterification with alcohol, obtain intermediate compound I;
(2) intermediate compound I and halogenated acetic acids ester are carried out condensation reaction, obtain intermediate II;
(3) intermediate II is carried out ring closure reaction and obtain intermediate III;
(4) intermediate III is carried out ammonolysis reaction, obtain target product (S)-oxiracetam.
Reaction expression is as follows:
Contriver studies through long-term experiment, attempt a lot of new synthesis route to be all difficult to obtain (S)-oxiracetam, final by above synthetic route, obtain (S)-oxiracetam product of more than 20% more satisfactory yield by the cooperation of above each reaction type and sequencing, open a new oxiracetam synthetic route.
In order to make, impurity is more easily separated, operation steps is simple, thus obtain the industrialization of high-purity product, promotion pharmaceutical production, also ensure reaction yield, the halogenated acetic acids ester in above-mentioned steps (2) preferably adopts the positive butyl ester of ethyl bromoacetate, ethyl chloroacetate, bromoacetic acid, bromide isobutyl acetate, bromo-acetic acid tert-butyl or benzyl acetate bromide simultaneously.
In order to improve reactive behavior further thus improve reaction yield further, above-mentioned (1) step is preferably:
S-4-amino-3-hydroxybutyrate is added in alcohol, also under the condition instilling acylating agent or catalyzer, carries out esterification and obtain intermediate compound I; The optional methyl alcohol of described alcohol, ethanol, n-propyl alcohol, Virahol, propyl carbinol, the trimethyl carbinol, hexalin or cyclopentanol, preferably adopt methyl alcohol, ethanol, n-propyl alcohol or cyclopentanol; Described acylating agent is concentrated hydrochloric acid, the vitriol oil, sulfur oxychloride, phosphorus oxychloride, phosphorus pentachloride or oxalyl chloride; Described catalyzer is the vitriol oil, methanesulfonic, tosic acid or trifluoroacetic acid.
Intermediate compound I general formula is as follows:
R1 is methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, the tertiary butyl, isobutyl-, cyclopentyl or cyclohexyl etc.
In order to further improve reactive behavior, improve reaction yield, the mol ratio of above-mentioned acylating agent or catalyzer and S-4-amino-3-hydroxybutyrate is: S-4-amino-3-hydroxybutyrate: acylating agent or catalyzer=1:1 ~ 2.5.
More particularly, above-mentioned (1) step is:
First mixed with the above-mentioned alcohol of 5 ~ 20 times of weight by S-4-amino-3-hydroxybutyrate, then add above-mentioned acylating agent or catalyzer reacts 1 ~ 5 hour at 0 ~ 60 DEG C, S-4-amino-3-hydroxybutyrate and acylating agent or catalyst molar ratio are 1:1.5 ~ 1.65; Obtain the alcoholic solution containing intermediate compound I, then collect intermediate compound I from containing the alcoholic solution of intermediate compound I.
Above-mentioned S-4-amino-3-hydroxybutyrate, alcohol and acylating reagent are commercially available prod.
Above-mentioned (2) step, specifically, be the intermediate compound I will obtained from step (1), react 5 ~ 10 hours in a solvent with halogenated acetic acids ester under alkaline catalysts exists, temperature of reaction is 0 ~ 60 DEG C, then collects and obtains intermediate II; Described solvent is without particular requirement, and one or more in prioritizing selection methyl alcohol, ethanol, Virahol, tetrahydrofuran (THF), DMF, DMSO combine; Said alkaline catalysts is preferably pyridine, triethylamine, lutidine, salt of wormwood or sodium bicarbonate.
In order to further improve reaction purity and yield, the mol ratio of intermediate compound I and halogenated acetic acids ester is: 1:1 ~ 3, and the mol ratio of intermediate compound I and described alkaline catalysts is: 1:2 ~ 3.
The most specifically, above-mentioned (2) step, it is the intermediate compound I that will obtain from step (1), under alkaline catalysts exists, 5 ~ 10 hours are reacted with halogenated acetic acids ester in the solvent of the 10-15 times of weight of S-4-amino-3-hydroxybutyrate, temperature of reaction is 0 ~ 60 DEG C, then collects and obtains intermediate II; Described solvent is without particular requirement, and one or more in prioritizing selection methyl alcohol, ethanol, Virahol, tetrahydrofuran (THF), DMF, DMSO combine; Said alkaline catalysts is preferably pyridine, triethylamine, lutidine, salt of wormwood or sodium bicarbonate; The mol ratio of intermediate compound I and halogenated acetic acids ester is: 1:1 ~ 3, and the mol ratio of intermediate compound I and described alkaline catalysts is: 1:2 ~ 3.
Intermediate II general formula is as follows:
R1 is methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, the tertiary butyl, isobutyl-, cyclopentyl or cyclohexyl etc.; R2 is ethyl, n-propyl, sec.-propyl, normal-butyl, the tertiary butyl, isobutyl-, benzyl or cyclopentyl etc.
Above-mentioned steps (3), specifically, by the intermediate II that step (2) obtains, ring closure reaction is carried out in a solvent under 50 ~ 130 DEG C of conditions, time is 3 ~ 8 hours, obtain the solution containing intermediate III, then collect from the solution containing intermediate III and obtain intermediate III; Described solvent can be selected: ethanol, the trimethyl carbinol, toluene, dimethylbenzene, water, ethyl acetate, butylacetate or ethyl butyrate, preferably adopts ethanol, toluene or dimethylbenzene.
Intermediate III general formula is as follows:
R2 is ethyl, n-propyl, sec.-propyl, normal-butyl, the tertiary butyl, isobutyl-, benzyl or methoxybenzyl etc.
In order to further improve reaction purity and yield, the mol ratio of intermediate II and solvent is 1:10 ~ 30.
Above-mentioned steps (4), specifically, by the intermediate III that step (3) obtains, reacts 4 ~ 16 hours with strong aqua, from reaction product, then collects target product (S)-oxiracetam at 20 ~ 30 DEG C.
In order to improve reactive behavior further thus improve overall yield of reaction, above-mentioned intermediate III: the mol ratio of ammonia is intermediate III: ammonia=1:12 ~ 15, in the ammonia in ammonia methanol solution; Described strong aqua is well known in the art, and the concentrations by weight of its solution is about 25 ~ 28%.
The method of target product (S)-oxiracetam is collected from the reaction product of above-mentioned steps (4), preferably as follows: reaction product is dissolved in the water, heating for dissolving, activated carbon decolorizing, cross and filter gac, concentrating under reduced pressure dewaters, when surplus water is concentrated for stopping when adding products weight 2 ~ 3 times, 0 ~ 5 DEG C of subcooling crystallization, obtains to obtain product (S)-oxiracetam.
A synthetic method for DL body oxiracetam, is characterized in that, comprise the steps:
(1) with 4-amino-3-hydroxybutyrate for starting raw material, carry out esterification with alcohol, obtain intermediate compound I;
(2) intermediate compound I and halogenated acetic acids ester are carried out condensation reaction, obtain intermediate II;
(3) intermediate II is carried out ring closure reaction and obtain intermediate III;
(4) intermediate III is carried out ammonolysis reaction, obtain target product oxiracetam.
Contriver has attempted a lot of new synthesis route and has all been difficult to obtain oxiracetam, final by above synthetic route, obtain the oxiracetam product of more than 20% more satisfactory yield by the cooperation of above each reaction type and sequencing, open a new oxiracetam synthetic route.
Preferably, the halogenated acetic acids ester in above-mentioned steps (2) preferably adopts the positive butyl ester of ethyl bromoacetate, ethyl chloroacetate, bromoacetic acid, bromide isobutyl acetate, bromo-acetic acid tert-butyl or benzyl acetate bromide.
Further preferably say, above-mentioned (1) step is: first mixed with the alcohol of 5 ~ 20 times of weight by 4-amino-3-hydroxybutyrate, then add acylating agent or catalyzer reacts 1 ~ 5 hour at 0 ~ 60 DEG C, 4-amino-3-hydroxybutyrate and acylating agent or catalyst molar ratio are 1:1.5 ~ 1.65; Obtain the alcoholic solution containing intermediate compound I, then collect intermediate compound I from containing the alcoholic solution of intermediate compound I; Described alcohol is methyl alcohol, ethanol, n-propyl alcohol, Virahol, propyl carbinol, the trimethyl carbinol, hexalin or cyclopentanol; Described acylating agent is concentrated hydrochloric acid, the vitriol oil, sulfur oxychloride, phosphorus oxychloride, phosphorus pentachloride or oxalyl chloride; Described catalyzer is the vitriol oil, methanesulfonic, tosic acid or trifluoroacetic acid.
Specifically, above-mentioned (2) step: be the intermediate compound I will obtained from step (1), under alkaline catalysts exists, 5 ~ 10 hours are reacted with halogenated acetic acids ester in the solvent of the 10-15 times of weight of 4-amino-3-hydroxybutyrate, temperature of reaction is 0 ~ 60 DEG C, then collects and obtains intermediate II; One or more combinations in methyl alcohol, ethanol, Virahol, tetrahydrofuran (THF), DMF, DMSO selected by described solvent; Said alkaline catalysts is preferably pyridine, triethylamine, lutidine, salt of wormwood or sodium bicarbonate; The mol ratio of intermediate compound I and halogenated acetic acids ester is: 1:1 ~ 3, and the mol ratio of intermediate compound I and described alkaline catalysts is: 1:2 ~ 3.
The present invention has following beneficial effect:
Oxiracetam synthetic route of the present invention is one and is suitable for the synthetic route of suitability for industrialized production, is beneficial to very much the separation and purification of product, synthetic route of the present invention at least can obtain (S)-oxiracetam or the DL body oxiracetam product of more than 20% more satisfactory yield, opens a new oxiracetam synthetic route.Meanwhile, purity and the optical purity of final (S)-oxiracetam that synthetic route of the present invention is obtained by further optimal control condition or DL body oxiracetam product all can reach more than 99.9%, and total recovery reaches 48.2%.Meanwhile, adopt the synthetic method of the present invention (S)-oxiracetam or DL body oxiracetam compared with prior art, raw material is cheap and easy to get, and purifying is low, easy and simple to handle without the need to column chromatography, cost, better quality.The present invention opens a new oxiracetam synthetic route.
Embodiment
Below by embodiment, the present invention is specifically described; what be necessary to herein means out is; following examples are only for being further detailed the present invention; can not be interpreted as limiting the scope of the invention, the person skilled in the art in this field can make some nonessential improvement and adjustment according to foregoing invention content to the present invention.
Embodiment 1
A kind of synthetic method of (S)-oxiracetam, it carries out as follows,
The preparation of (l) intermediate compound I:
Get raw material S-4-amino-3-hydroxybutyrate 50g, add in a single neck bottle, add methyl alcohol 50ml, stir, ice-water bath cools, slow instillation concentrated hydrochloric acid 150ml, keep temperature to be no more than 40 DEG C, solid first has a dissolution process, then separates out again, drip solid when making a concentrated effort to finish to dissolve again, finally form a faint yellow clarified liq.Continue stirring 3 hours, some plate is shown in that raw material primitive reaction is complete, stopped reaction, and directly concentrate except desolventizing obtains pale yellow oil, curing at low temperatures obtains intermediate compound I.Detect through nuclear-magnetism, intermediate compound I is: 1H-NMR (300MHz, D2O): δ 2.76-2.67 (AB system, m, 2H), 3.31-3.23 (AB system, m, 2H), 3.75 (s, 3H), 4.40 (m, 1H), 4.70 (bs, 3H) .13C-NMR (50MHz, D2O): δ 43.7 (C-2), 48.4 (C-4), 57.0 (OCH), 68.9 (C-3), 177.5 (C-I). intermediate compound I is:
r1 is methyl.
(2) preparation of intermediate II
The intermediate compound I that step (1) obtains is dissolved in the methyl alcohol of 500ml, be cooled to outer temperature 0 DEG C, add salt of wormwood 173g (3eq), a large amount of solid is had to generate, stir five minutes, start to drip ethyl bromoacetate 90ml (2eq), dropping process has exothermic phenomenon, dropwise rear continuation stirring 2 hours, point plate is shown in that raw material reaction is complete, stopped reaction, add EA(ethyl acetate) 500ml, water 300ml, solid dissolves completely, by saturated for water layer solid sodium chloride, separate organic layer, water layer EA200ml extracting twice, merge organic layer, the hydrochloric acid 200ml of organic layer 2M washes three times, merge hydrochloric acid aqueous phase, organic phase discards, aqueous phase continuation sodium bicarbonate regulates pH to 8, solid sodium chloride is saturated, EA300ml extracts three times, merge organic phase, anhydrous magnesium sulfate drying, concentrate except desolventizing obtains pale yellow oil, curing at low temperatures obtains intermediate II.Detect through nuclear-magnetism, intermediate II: 1H-NMR (300MHz, D2O): δ 1.3 (t, 3H), 2.28-2.53 (m, 2H), 2.58-2.83 (m, 2H) 3.51 (s, 2H), 3.67 (s, 3H), 4.09-4.12 (m, 3H). intermediate II is:
R1 is methyl, and R2 is ethyl.
(3) preparation of intermediate III
By the intermediate II 500ml dissolve with ethanol that step (2) obtains, be warming up to 75 DEG C, reflux 8 hours, obtain a red tan solution, some plate is shown in that raw material reaction is complete.Stopped reaction, concentrated removing ethanol, adds EA(ethyl acetate) dissolve, cross and filter salt, activated carbon decolorizing, concentrate and remove yellow oil obtains intermediate III.Detect through nuclear-magnetism, intermediate III is: 1H-NMR (300MHz, CDCl3) δ 1.280(t, 3H), 2.38 (dd, 1H), 2.69 (dd, 1H), 3.34 (dd, 1H), 3.77 (dd, lH), 3.93 (d, lH), 4.18 (d, 1H), 4.19 (q, 2H), 4.30 (bs, 1H), 4.50 (m, 1H). intermediate III:
r2 is ethyl.
(4) preparation of (S)-oxiracetam
The intermediate III that step (3) obtains is added strong aqua 200ml, stirring at room temperature 18 hours, some plate is shown in that raw material reaction is complete, stopped reaction, concentrated removal water and ammonia, obtain yellow oil, add acetone solution oily matter, add a small amount of crystal seed and stir, separate out solid, a small amount of acetone rinsing bottle wall ,-10 DEG C of crystallizations 5 hours, filter and obtain off-white color crude product 36g.Purity 99.3%, isomer proportion 0.2%.By this dissolving crude product in the water of 100ml, heating makes it dissolve, activated carbon decolorizing half an hour, cross and filter gac, crystallisation by cooling, 5 DEG C of placements are spent the night, filter to obtain white solid 32g next day, purity 99.9%, isomer proportion 0.1%, yield is 48.2%, detect through nuclear-magnetism, levo-oxiracetam: 1H-NMR (300MHz, DMSO-d6) δ 2.10 (d, 1H), 2.57 (dd, 1H), 3.69 (d, 1H), 3.88 (d, 1H), 4.10 (d, 1H), 4.31 (m, 1H), 5.25 (s, 1H), 7.13 (s, 1H), 7.33 (s, 1H). optical value :-37.3.(S)-oxiracetam is that structural formula is as follows:
Embodiment 2
1, a kind of synthetic method of (S)-oxiracetam, as follows:
(1) by S-4-amino-3-hydroxybutyrate and the ethanol accounting for its 18 times of weight, stir, at 60 DEG C of reaction esterification 5 hours, raw material primitive reaction is complete, stopped reaction, and directly concentrated except desolventizing, curing at low temperatures obtains intermediate compound I; Simultaneously above solvent additionally uses methyl alcohol, n-propyl alcohol, Virahol, propyl carbinol, the trimethyl carbinol, hexalin or cyclopentanol etc. and prepares intermediate compound I, detect finally by nuclear-magnetism, obtained intermediate compound I is: 1H-NMR (300MHz, D2O): δ 1.30 (m, 3H), 2.76-2.67 (AB system, m, 2H), 3.31-3.23 (AB system, m, 2H), 4.12 (m, 2H), 4.40 (m, 1H), 4.70 (bs, 3H)..
(2) intermediate compound I that will obtain from step (1), in the ethanol of 15 times of weight of S-4-amino-3-hydroxybutyrate, stir cooling, drip the positive butyl ester of bromoacetic acid 60 DEG C of condensation reactions 10 hours, the mol ratio of described intermediate compound I and halogenated acetic acids ester is 1:1.5, then collect and obtain intermediate II, above solvent additionally uses methyl alcohol simultaneously, Virahol, tetrahydrofuran (THF), DMF or DMSO etc. prepare intermediate II, detect finally by nuclear-magnetism, obtained intermediate II is: 1H-NMR (300MHz, D2O): δ 0.96 (t, 3H), 1.30-1.33 (m, 5H), 1.57 (m, 2H), 2.28-2.53 (m, 2H), 2.58-2.83 (m, 2H) 3.51 (s, 2H), 4.08-4.12 (m, 5H)..
(3) by intermediate II that step (2) obtains, be dissolved in ethyl acetate, the mol ratio of described intermediate II and ethyl acetate is 1:12, ring closure reaction is carried out 6.5 hours at being warming up to 85 DEG C, obtain the solution containing intermediate III, then collect from the solution containing intermediate III and obtain intermediate III, described solvent additionally uses as ethanol, the trimethyl carbinol, toluene, dimethylbenzene, water, butylacetate or ethyl butyrate, detect finally by nuclear-magnetism, obtained intermediate III is: 1H-NMR (300MHz, CDCl3) δ 0.96 (t, 3H) 1.33(m, 2H), 1.57 (m, 2H) 2.38 (dd, 1H), 2.69 (dd, 1H), 3.34 (dd, 1H), 3.77 (dd, lH), 3.93 (d, lH), 4.18 (d, 1H), 4.19 (q, 2H), 4.30 (bs, 1H), 4.50 (m, 1H)..
(4) add in strong aqua by the intermediate III that step (3) obtains, stirring at room temperature carries out ammonolysis reaction 15 hours, described intermediate III: the mol ratio of ammonia is intermediate III: ammonia=1:13, in the ammonia in ammonia methanol solution; React completely concentrated removal water and ammonia, and adopt acetone purifying, crystallization obtains product (S)-oxiracetam crude product.By dissolving crude product in water, heating for dissolving, activated carbon decolorizing, cross and filter gac, concentrating under reduced pressure dewaters, and when surplus water is concentrated for stopping when adding products weight 2 ~ 3 times, 0 ~ 5 DEG C of subcooling crystallization, obtains product (S)-oxiracetam.It is 80.4% that HPLC measures its purity, calculates yield is 20%, and detect through nuclear-magnetism, gained levo-oxiracetam is: 1H-NMR (300MHz, DMSO-d6) δ 2.10 (d, 1H), 2.57 (dd, 1H), 3.69 (d, 1H), 3.88 (d, 1H), 4.10 (d, 1H), 4.31 (m, 1H), 5.25 (s, 1H), 7.13 (s, 1H), 7.33 (s, 1H). optical value :-37.2.
Embodiment 3--12: the embodiment optimized further for the present invention relative to embodiment 2, is undertaken by with the step of following table 1 and parameter, other identical with embodiment 1.
Table 1
Through nuclear-magnetism detect, intermediate prepared by embodiment 3-12 and levo-oxiracetam as shown in table 2:
The levo-oxiracetam obtained by above embodiment 3-12 measures its purity at 99.5-99.9% through HPLC, calculate yield at 35-45%.
Embodiment 13
1, a synthetic method for DL body oxiracetam, as follows:
(1) by 4-amino-3-hydroxybutyrate and the ethanol accounting for its 18 times of weight, stir, at 60 DEG C of reaction esterification 5 hours, raw material primitive reaction is complete, stopped reaction, and directly concentrated except desolventizing, curing at low temperatures obtains intermediate compound I; Simultaneously above solvent additionally uses methyl alcohol, n-propyl alcohol, Virahol, propyl carbinol, the trimethyl carbinol, hexalin or cyclopentanol etc. and prepares intermediate compound I, detect finally by nuclear-magnetism, obtained intermediate compound I is: 1H-NMR (300MHz, D2O): δ 1.28 (m, 3H), 2.75-2.66 (AB system, m, 2H), 3.30-3.22 (AB system, m, 2H), 4.09 (m, 2H), 4.39 (m, 1H), 4.72 (bs, 3H)..
(2) intermediate compound I that will obtain from step (1), in the ethanol of 15 times of weight of 4-amino-3-hydroxybutyrate, stir cooling, drip the positive butyl ester of bromoacetic acid 60 DEG C of condensation reactions 10 hours, the mol ratio of described intermediate compound I and halogenated acetic acids ester is 1:1.5, then collect and obtain intermediate II, above solvent additionally uses methyl alcohol simultaneously, Virahol, tetrahydrofuran (THF), DMF or DMSO etc. prepare intermediate II, detect finally by nuclear-magnetism, obtained intermediate II is: 1H-NMR (300MHz, D2O): δ 0.95 (t, 3H), 1.31-1.34 (m, 5H), 1.55 (m, 2H), 2.29-2.54 (m, 2H), 2.56-2.81 (m, 2H) 3.50 (s, 2H), 4.05-4.10 (m, 5H)..
(3) by intermediate II that step (2) obtains, be dissolved in ethyl acetate, the mol ratio of described intermediate II and ethyl acetate is 1:12, ring closure reaction is carried out 6.5 hours at being warming up to 85 DEG C, obtain the solution containing intermediate III, then collect from the solution containing intermediate III and obtain intermediate III, described solvent additionally uses as ethanol, the trimethyl carbinol, toluene, dimethylbenzene, water, butylacetate or ethyl butyrate, detect finally by nuclear-magnetism, obtained intermediate III is: 1H-NMR (300MHz, CDCl3) δ 0.94 (t, 3H) 1.32 (m, 2H), 1.55 (m, 2H) 2.37 (dd, 1H), 2.68 (dd, 1H), 3.33 (dd, 1H), 3.77 (dd, lH), 3.92 (d, lH), 4.16 (d, 1H), 4.18 (q, 2H), 4.31 (bs, 1H), 4.50 (m, 1H)..
(4) add in strong aqua by the intermediate III that step (3) obtains, stirring at room temperature carries out ammonolysis reaction 15 hours, described intermediate III: the mol ratio of ammonia is intermediate III: ammonia=1:13, in the ammonia in ammonia methanol solution; React completely concentrated removal water and ammonia, and adopt acetone purifying, crystallization obtains product (S)-oxiracetam crude product.By dissolving crude product in water, heating for dissolving, activated carbon decolorizing, cross and filter gac, concentrating under reduced pressure dewaters, and when surplus water is concentrated for stopping when adding products weight 2 ~ 3 times, 0 ~ 5 DEG C of subcooling crystallization, obtains product DL body oxiracetam.It is 82.1% that HPLC measures its purity, calculates yield is 19.5%, and detect through nuclear-magnetism, gained DL body oxiracetam is: 1H-NMR (300MHz, DMSO-d6) δ 2.05 (d, 1H), 2.43 (dd, 1H), 3.57 (d, 1H), 3.78 (d, 1H), 4.10 (d, 1H), 4.35 (m, 1H), 5.31 (s, 1H), 7.23 (s, 1H), 7.43 (s, 1H).
Claims (16)
1. a synthetic method for (S)-oxiracetam, is characterized in that, comprises the steps:
(1) with S-4-amino-3-hydroxybutyrate for starting raw material, carry out esterification with alcohol, obtain intermediate compound I;
(2) intermediate compound I and halogenated acetic acids ester are carried out condensation reaction, obtain intermediate II;
(3) intermediate II is carried out ring closure reaction and obtain intermediate III;
(4) intermediate III is carried out ammonolysis reaction, obtain target product (S)-oxiracetam.
2. the synthetic method of (S)-oxiracetam as claimed in claim 1, is characterized in that: the halogenated acetic acids ester in described step (2) preferably adopts the positive butyl ester of ethyl bromoacetate, ethyl chloroacetate, bromoacetic acid, bromide isobutyl acetate, bromo-acetic acid tert-butyl or benzyl acetate bromide.
3. as claimed in claim 1 or 2 the synthetic method of (S)-oxiracetam, is characterized in that, described (1) step is:
S-4-amino-3-hydroxybutyrate is added in alcohol, also under the condition instilling acylating agent or catalyzer, carries out esterification and obtain intermediate compound I; Described alcohol is methyl alcohol, ethanol, n-propyl alcohol, Virahol, propyl carbinol, the trimethyl carbinol, hexalin or cyclopentanol; Described acylating agent is concentrated hydrochloric acid, the vitriol oil, sulfur oxychloride, phosphorus oxychloride, phosphorus pentachloride or oxalyl chloride; Described catalyzer is the vitriol oil, methanesulfonic, tosic acid or trifluoroacetic acid.
4. the synthetic method of (S)-oxiracetam as claimed in claim 3, is characterized in that: the mol ratio of described acylating agent or catalyzer and S-4-amino-3-hydroxybutyrate is: S-4-amino-3-hydroxybutyrate: acylating agent or catalyzer=1:1 ~ 2.5.
5. the synthetic method of (S)-oxiracetam as described in any one of Claims 1 to 4, it is characterized in that, described (1) step is:
First mixed with the alcohol of 5 ~ 20 times of weight by S-4-amino-3-hydroxybutyrate, then add acylating agent or catalyzer reacts 1 ~ 5 hour at 0 ~ 60 DEG C, S-4-amino-3-hydroxybutyrate and acylating agent or catalyst molar ratio are 1:1.5 ~ 1.65; Obtain the alcoholic solution containing intermediate compound I, then collect intermediate compound I from containing the alcoholic solution of intermediate compound I.
6. the synthetic method of (S)-oxiracetam as described in any one of Claims 1 to 5, is characterized in that, described (2) step:
Be the intermediate compound I that will obtain from step (1), react 5 ~ 10 hours in a solvent with halogenated acetic acids ester under alkaline catalysts exists, temperature of reaction is 0 ~ 60 DEG C, then collects and obtains intermediate II; Described solvent can select one or more combinations in methyl alcohol, ethanol, Virahol, tetrahydrofuran (THF), DMF, DMSO; Said alkaline catalysts is pyridine, triethylamine, lutidine, salt of wormwood or sodium bicarbonate.
7. the synthetic method of (S)-oxiracetam as claimed in claim 6, it is characterized in that, in order to further improve reaction purity and yield, the mol ratio of intermediate compound I and halogenated acetic acids ester is: 1:1 ~ 3, and the mol ratio of intermediate compound I and described alkaline catalysts is: 1:2 ~ 3.
8. the synthetic method of (S)-oxiracetam as described in any one of Claims 1 to 5, it is characterized in that, described (2) step: be the intermediate compound I will obtained from step (1), under alkaline catalysts exists, 5 ~ 10 hours are reacted with halogenated acetic acids ester in the solvent of the 10-15 times of weight of S-4-amino-3-hydroxybutyrate, temperature of reaction is 0 ~ 60 DEG C, then collects and obtains intermediate II; One or more combinations in methyl alcohol, ethanol, Virahol, tetrahydrofuran (THF), DMF, DMSO selected by described solvent; Said alkaline catalysts is preferably pyridine, triethylamine, lutidine, salt of wormwood or sodium bicarbonate; The mol ratio of intermediate compound I and halogenated acetic acids ester is: 1:1 ~ 3, and the mol ratio of intermediate compound I and described alkaline catalysts is: 1:2 ~ 3.
9. the synthetic method of (S)-oxiracetam as described in any one of claim 1 ~ 8, it is characterized in that, described step (3): be the intermediate II that step (2) is obtained, ring closure reaction is carried out in a solvent under 50 ~ 130 DEG C of conditions, time is 3 ~ 8 hours, obtain the solution containing intermediate III, then collect from the solution containing intermediate III and obtain intermediate III; Described solvent can be selected: ethanol, the trimethyl carbinol, toluene, dimethylbenzene, water, ethyl acetate, butylacetate or ethyl butyrate.
10. the synthetic method of (S)-oxiracetam as claimed in claim 9, is characterized in that: the mol ratio of described intermediate II and solvent is 1:10 ~ 30.
The synthetic method of 11. (S)-oxiracetams as claimed in claim 10, it is characterized in that, described step (4): be the intermediate III that step (3) is obtained, at 20 ~ 30 DEG C, react 4 ~ 16 hours with strong aqua, from reaction product, then collect target product (S)-oxiracetam; Described intermediate III: the mol ratio of ammonia is intermediate III: ammonia=1:12 ~ 15, in the ammonia in ammonia methanol solution.
The synthetic method of 12. 1 kinds of (S)-oxiracetams, is characterized in that, mainly carries out as follows:
(1), first S-4-amino-3-hydroxybutyrate is mixed with the alcohol of 5 ~ 20 times of weight, then acylating agent is added or catalyzer reacts 1 ~ 5 hour at 0 ~ 60 DEG C, S-4-amino-3-hydroxybutyrate and acylating agent or catalyst molar ratio are 1:1.5 ~ 1.65, obtain the alcoholic solution containing intermediate compound I, then collect intermediate compound I from containing the alcoholic solution of intermediate compound I; Described alcohol is methyl alcohol, ethanol, n-propyl alcohol, Virahol, propyl carbinol, the trimethyl carbinol, hexalin or cyclopentanol, described acylating agent is concentrated hydrochloric acid, the vitriol oil, sulfur oxychloride, phosphorus oxychloride, phosphorus pentachloride or oxalyl chloride, and described catalyzer is the vitriol oil, methanesulfonic, tosic acid or trifluoroacetic acid;
(2) intermediate compound I that, will obtain from step (1), under alkaline catalysts exists, 5 ~ 10 hours are reacted with halogenated acetic acids ester in the solvent of the 10-15 times of weight of S-4-amino-3-hydroxybutyrate, temperature of reaction is 0 ~ 60 DEG C, then collects and obtains intermediate II; One or more combinations in methyl alcohol, ethanol, Virahol, tetrahydrofuran (THF), DMF, DMSO selected by described solvent, described alkaline catalysts is pyridine, triethylamine, lutidine, salt of wormwood or sodium bicarbonate, and described halogenated acetic acids ester is ethyl bromoacetate, ethyl chloroacetate, the positive butyl ester of bromoacetic acid, bromide isobutyl acetate, bromo-acetic acid tert-butyl or benzyl acetate bromide; The mol ratio of described intermediate compound I and halogenated acetic acids ester is: 1:1 ~ 3, and the mol ratio of intermediate compound I and described alkaline catalysts is: 1:2 ~ 3;
(3), be intermediate II step (2) obtained, ring closure reaction is carried out in a solvent under 50 ~ 130 DEG C of conditions, time is 3 ~ 8 hours, obtains the solution containing intermediate III, then collects from the solution containing intermediate III and obtains intermediate III; Described solvent is ethanol, the trimethyl carbinol, toluene, dimethylbenzene, water, ethyl acetate, butylacetate or ethyl butyrate, and the mol ratio of described intermediate II and solvent is 1:10 ~ 30;
(4) intermediate III, by step (3) obtained, reacts 4 ~ 16 hours with strong aqua at 20 ~ 30 DEG C, obtains reaction product (S)-oxiracetam crude product; Described intermediate III: the mol ratio of ammonia is intermediate III: ammonia=1:12 ~ 15, in the ammonia in ammonia methanol solution;
(5), (4) step gained reaction product is dissolved in the water, heating for dissolving, activated carbon decolorizing, cross and filter gac, concentrating under reduced pressure dewaters, when surplus water is concentrated for stopping when adding products weight 2 ~ 3 times, 0 ~ 5 DEG C of subcooling crystallization, obtains product (S)-oxiracetam.
The synthetic method of 13. 1 kinds of oxiracetams, is characterized in that, comprises the steps:
(1) with 4-amino-3-hydroxybutyrate for starting raw material, carry out esterification with alcohol, obtain intermediate compound I;
(2) intermediate compound I and halogenated acetic acids ester are carried out condensation reaction, obtain intermediate II;
(3) intermediate II is carried out ring closure reaction and obtain intermediate III;
(4) intermediate III is carried out ammonolysis reaction, obtain target product oxiracetam.
The synthetic method of 14. oxiracetams as claimed in claim 13, is characterized in that: the halogenated acetic acids ester in described step (2) preferably adopts the positive butyl ester of ethyl bromoacetate, ethyl chloroacetate, bromoacetic acid, bromide isobutyl acetate, bromo-acetic acid tert-butyl or benzyl acetate bromide.
15. as described in claim 13 or 14 synthetic method of oxiracetam, it is characterized in that, described (1) step is:
First mixed with the alcohol of 5 ~ 20 times of weight by 4-amino-3-hydroxybutyrate, then add acylating agent or catalyzer reacts 1 ~ 5 hour at 0 ~ 60 DEG C, 4-amino-3-hydroxybutyrate and acylating agent or catalyst molar ratio are 1:1.5 ~ 1.65; Obtain the alcoholic solution containing intermediate compound I, then collect intermediate compound I from containing the alcoholic solution of intermediate compound I; Described alcohol is methyl alcohol, ethanol, n-propyl alcohol, Virahol, propyl carbinol, the trimethyl carbinol, hexalin or cyclopentanol; Described acylating agent is concentrated hydrochloric acid, the vitriol oil, sulfur oxychloride, phosphorus oxychloride, phosphorus pentachloride or oxalyl chloride; Described catalyzer is the vitriol oil, methanesulfonic, tosic acid or trifluoroacetic acid.
16. as described in any one of claim 13 ~ 15 synthetic method of oxiracetam, it is characterized in that, described (2) step: be the intermediate compound I will obtained from step (1), under alkaline catalysts exists, 5 ~ 10 hours are reacted with halogenated acetic acids ester in the solvent of the 10-15 times of weight of 4-amino-3-hydroxybutyrate, temperature of reaction is 0 ~ 60 DEG C, then collects and obtains intermediate II; One or more combinations in methyl alcohol, ethanol, Virahol, tetrahydrofuran (THF), DMF, DMSO selected by described solvent; Said alkaline catalysts is preferably pyridine, triethylamine, lutidine, salt of wormwood or sodium bicarbonate; The mol ratio of intermediate compound I and halogenated acetic acids ester is: 1:1 ~ 3, and the mol ratio of intermediate compound I and described alkaline catalysts is: 1:2 ~ 3.
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106496089A (en) * | 2016-02-05 | 2017-03-15 | 华润双鹤药业股份有限公司 | A kind of method for preparing Oxiracetam |
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Families Citing this family (2)
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Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20040204476A1 (en) * | 2001-08-10 | 2004-10-14 | Celal Ates | Oxopyrrolidine compounds, preparations of said compounds and their use in the manufacturing of levetiracetam and analogues |
| CN1869008A (en) * | 2006-06-19 | 2006-11-29 | 张文 | Preparation method of chiral non alpha amino acid derivative of simultaneously protected by hydroxyl group and amino group |
| CN1956953A (en) * | 2004-05-25 | 2007-05-02 | 安国药品株式会社 | Process for the preparation of optically pure 4-hydroxy-2-oxo-1-pyrrolidine acetamide |
| EP1806339A1 (en) * | 2005-12-21 | 2007-07-11 | Ucb, S.A. | Process for the preparation of 2-oxo-1-pyrrolidine derivatives |
| CN101704778A (en) * | 2009-09-30 | 2010-05-12 | 厦门市华兴化工有限公司 | Method for preparing 4-hydroxyl yrrolidone-2-acetamide |
| CN102603597A (en) * | 2011-01-21 | 2012-07-25 | 重庆润泽医疗器械有限公司 | Preparation method of (S)-oxiracetam |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| AU581887B2 (en) * | 1984-04-17 | 1989-03-09 | Glaxo Group Limited | Ethanolamine compounds |
| JP3184758B2 (en) * | 1996-02-02 | 2001-07-09 | 高砂香料工業株式会社 | Method for producing optically active 4-hydroxy-2-pyrrolidone |
-
2013
- 2013-06-19 CN CN201610754462.1A patent/CN106349143A/en active Pending
- 2013-06-19 CN CN201610881945.8A patent/CN106478482A/en active Pending
- 2013-06-19 CN CN201610560685.4A patent/CN106146379B/en active Active
- 2013-06-19 CN CN201610560643.0A patent/CN105968024A/en active Pending
- 2013-06-19 CN CN201610882486.5A patent/CN106631963A/en active Pending
- 2013-06-19 CN CN201610854853.0A patent/CN106631961A/en active Pending
- 2013-06-19 CN CN201610750215.4A patent/CN106349142A/en active Pending
- 2013-06-19 CN CN201310243165.7A patent/CN104230777B/en active Active
- 2013-06-19 CN CN201610854647.XA patent/CN106631960A/en active Pending
Patent Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20040204476A1 (en) * | 2001-08-10 | 2004-10-14 | Celal Ates | Oxopyrrolidine compounds, preparations of said compounds and their use in the manufacturing of levetiracetam and analogues |
| CN1956953A (en) * | 2004-05-25 | 2007-05-02 | 安国药品株式会社 | Process for the preparation of optically pure 4-hydroxy-2-oxo-1-pyrrolidine acetamide |
| EP1806339A1 (en) * | 2005-12-21 | 2007-07-11 | Ucb, S.A. | Process for the preparation of 2-oxo-1-pyrrolidine derivatives |
| CN1869008A (en) * | 2006-06-19 | 2006-11-29 | 张文 | Preparation method of chiral non alpha amino acid derivative of simultaneously protected by hydroxyl group and amino group |
| CN101704778A (en) * | 2009-09-30 | 2010-05-12 | 厦门市华兴化工有限公司 | Method for preparing 4-hydroxyl yrrolidone-2-acetamide |
| CN102603597A (en) * | 2011-01-21 | 2012-07-25 | 重庆润泽医疗器械有限公司 | Preparation method of (S)-oxiracetam |
Non-Patent Citations (3)
| Title |
|---|
| JESUS F. ALMEIDA，等: "New enantioselective synthesis of 4-hydroxy-2-oxopyrrolidine-N-acetamide(Oxiracetam) from malic acid", 《TETRAHEDRON: ASYMMETRY》 * |
| 李坤，等: "促智药物(S)-奥拉西坦的合成", 《中国新药杂志》 * |
| 杨英梅，等: "奥拉西坦的合成工艺改进", 《河北工业科技》 * |
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| CN105968024A (en) | 2016-09-28 |
| CN106349143A (en) | 2017-01-25 |
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| CN106631960A (en) | 2017-05-10 |
| CN106631963A (en) | 2017-05-10 |
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| CN106146379A (en) | 2016-11-23 |
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| CN106478482A (en) | 2017-03-08 |
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