CN106496089A - A kind of method for preparing Oxiracetam - Google Patents
A kind of method for preparing Oxiracetam Download PDFInfo
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- CN106496089A CN106496089A CN201610081511.XA CN201610081511A CN106496089A CN 106496089 A CN106496089 A CN 106496089A CN 201610081511 A CN201610081511 A CN 201610081511A CN 106496089 A CN106496089 A CN 106496089A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- 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
- C07D207/24—Oxygen or sulfur atoms
- C07D207/26—2-Pyrrolidones
- C07D207/273—2-Pyrrolidones 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 other ring carbon atoms
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Abstract
The invention belongs to pharmaceutical technology field, and in particular to a kind of method for preparing Oxiracetam or its pharmaceutically acceptable solvate, which comprises the following steps：Make Oxiracetam acid and compound R-CH2- OH reacts, and generates the compound with structure shown in formula (I)；Wherein, R is defined as in the description.The invention further relates to having the compound of structure shown in formula (I) and its purposes for preparing Oxiracetam or its pharmaceutically acceptable solvate.The invention further relates to R-CH2- OH is used for the purposes for preparing Oxiracetam or its pharmaceutically acceptable solvate.
Description
Technical field
The invention belongs to pharmaceutical technology field, and in particular to one kind prepares Oxiracetam or its pharmaceutically acceptable solvent
The method of compound.
Background technology
At present, China's aging crowd is continuously increased, and senile dementia is to sufferers themselves, patient home and periphery crowd
Life cause a lot of impacts, so increasingly of interest by society.Oxiracetam (Oxiracetam) is a kind of cereboactive drug, is used for
Improve memory and the learning functionality of senile dementia and memory disorder patient.The medicine was synthesized in 1974, and in
List within 1984, still clinically extensively apply so far.Existing lot of documents reports the synthetic route and technique of Oxiracetam.
The initiation material adopted by different process is different with reactions steps, but is summed up, and all there is a problem that total recovery is low.Some
In method, as intermediate needs column chromatography to purify, or finished product needs ion exchange resin to purify so that cumbersome, produces into
This height.
Patent CN200710059625.5 proposes the route of following synthesizing oxiracetam：
This route has used thionyl chloride in the first step, it is desirable to carry out under conditions of absolute up to six steps, and chlorine
Changing the high volatility of sulfoxide, hydrochloric acid being produced with water reaction, excitant is strong；5th step removes the reaction of hemiacetal protection group, it is desirable to
Solvent is made with glacial acetic acid, and needs to be passed through dry hydrogen chloride gas to saturation, thus high to equipment and environmental requirement；Also,
Raw material is strong to the corrosivity of equipment, and the respiratory tract to operating personnel and harm are extremely serious.In addition, total receipts of the method
Rate is not high, is unsuitable for industrialized production.
Patent CN200910050116.5, it is proposed that another kind of synthetic route：
Synthetic thread of the synthetic route of the method than patent CN200710059625.5 is greatly shortened, in second step, difficult to understand
There is esterification with ethanol in La Xitan acid, with sulphur acid as catalyst, and need to make azeotropic solvent with hexamethylene, anti-to be separated off
The water that should be generated.But, the amount of the water generated in this step is less, and water easily forms homogeneous three-phase body with hexamethylene and ethanol
System, it is impossible to separate, so the water for generating cannot be removed, and remains in reactant liquor.Although during the esterification of second step
Between be up to more than ten hour, but reaction can not still push ahead, so reaction cannot carry out completely.Second step reaction terminates
Afterwards, Oxiracetam acid in part is still remained in reactant mixture, it is impossible to generate Oxiracetam with ammonia reaction in the third step, after giving
Continuous purifying purification operations make troubles.
Patent CN201110022874.5 obtains mesh using 4- chlorine-2-hydroxyls ethyl butyrate and glycine amide by one-step method
The method of mark compound, but the one-step method in the method is the two step successive reactions for utilizing " one kettle way " in fact.Because of reaction site
Many, accessory substance is more, and reacts under strongly alkaline conditions again so that the Oxiracetam of generation is very unstable, is easily decomposed, and then leads
Cause reactant liquor composition complicated, not easy purification, reaction yield is not high；Also, as reaction is complicated, there is gaseous by-product to generate, gas
Body to remove degree different so that the composition and yield of product is also different, and reaction condition is wayward, is difficult to be formed stable
Technique.
Content of the invention
In the present invention, unless otherwise stated, Science and Technology noun used herein has art technology
The implication are generally understood that by personnel.Also, involved laboratory operation step is in corresponding field and widely uses herein
Conventional steps.Meanwhile, for a better understanding of the present invention, the definition and explanation of relational language is provided below.
As used in this article, term " Oxiracetam " refers to -1 yl acetamide of 4- hydroxy-pyrrolidine -2- ketone, and which has
Following structure：
Oxiracetam of the present invention includes S-oxiracetam, R- Oxiracetams, and the composition being made up of both,
The racemic modification being for example made up of both.
As used in this article, term " Oxiracetam acid " refers to -1 guanidine-acetic acid of 4- hydroxy-pyrrolidine -2- ketone, and which has
Following structure：
Oxiracetam acid of the present invention includes that S-oxiracetam acid, R- Oxiracetams are sour, and be made up of both
Composition, the racemic modification being for example made up of both.
As used in this article, term " R-CH2- OH " refers to that structural formula is R-CH2The compound of-OH, wherein, R such as explanation
Defined in book.
As used in this article, term " temperature outward " refers to the temperature of the heating medium of reaction system.
As used in this article, term " room temperature " refers to 25 ± 5 DEG C.
As used in this article, term " condensed-nuclei aromatics base " is referred to and shares two phases each other by two or more phenyl ring
The aromatic cyclic group formed by adjacent carbon atom.Preferably, the condensed-nuclei aromatics base has 10-16 annular atom, for example, have
There are 10,14 or 16 annular atoms.The condensed-nuclei aromatics base includes but is not limited to naphthyl, anthryl and phenanthryl.
As used in this article, term " C1-C4Alkyl " refers to the alkyl with 1-4 carbon atom, including but not limited to
C1-C2Alkyl, C1-C3Alkyl and C2-C4Alkyl, such as methyl, ethyl, n-propyl, isopropyl, normal-butyl, sec-butyl, isobutyl group
And the tert-butyl group." the C1-C2Alkyl ", " C1-C3Alkyl " and " C2-C4Alkyl " refers to C respectively1-C4Containing 1-2,1-3 in alkyl
The instantiation of individual and 2-4 carbon atom.
As used in this article, term " C1-C4Alkoxyl " refers to C1-C4Alkyl is connected with other structures by oxygen atom
The group for connecing, including but not limited to C1-C2Alkoxyl, C1-C3Alkoxyl and C2-C4Alkoxyl, such as methoxyl group, ethyoxyl, just
Propoxyl group, isopropoxy, n-butoxy, sec-butoxy, isobutoxy and tert-butoxy." the C1-C2Alkoxyl ", " C1-C3
Alkoxyl " and " C2-C4Alkoxyl " refers to C respectively1-C4Concrete reality containing 1-2,1-3 and 2-4 carbon atom in alkoxyl
Example.
As used in this article, term " halogen " includes fluorine, chlorine, bromine and iodine.
As used in this article, term " pharmaceutically acceptable solvate " refers to one or more solute molecules and one
Complex or aggregation that individual or multiple solvent molecules are formed, the solvent is pharmaceutically acceptable solvent, for example organic molten
Agent (such as methyl alcohol, ethanol, propyl alcohol or acetic acid etc.) or water.When solvent is water, the solvate of formation is hydrate (such as half
Hydrate, monohydrate, dihydrate or trihydrate etc.).
As used in this article, term " concentrated sulfuric acid " refers to H2SO4Mass fraction be at least 90% (for example, at least 92%,
At least 95% or H at least 98%)2SO4The aqueous solution.
During Oxiracetam is prepared using Oxiracetam acid, the esterification of Oxiracetam acid is a reversible reaction,
Because the presence of the water that reaction is generated, reaction process can not be pushed ahead so that reaction can not be carried out completely.Prior art is usual
Reacted with Oxiracetam acid with ethanol, and using water and the azeotropic principles of hexamethylene equal solvent, by reflux condensation mode, by water
Separate from reaction system.But, ethanol is close with the boiling point of hexamethylene, and (boiling point of ethanol is 78.4 DEG C, the boiling point of hexamethylene
For 80.7 DEG C), when being flowed back, ethanol, hexamethylene and water can be distilled simultaneously.Simultaneously as what esterification was produced
The water yield is less, and the water for being generated both had been dissolved each other with ethanol, also can dissolve each other with hexamethylene, so shape between ethanol, hexamethylene and water
Into homogeneous solution, it is impossible to form clearly interface.Therefore, after condensing, water is again for the steam containing ethanol, hexamethylene and water
It is brought back reaction system, it is impossible to be effectively separated out, affects esterification process, and then affect the total recovery of product.
The present inventor has obtained a kind of side for preparing Oxiracetam of improvement by in-depth study and performing creative labour
Method, methods described has the total recovery height of product, the reaction time is short, purifying is convenient, low cost, product quality stable and/or tries
The advantages of agent easy recycling, thus provide following inventions：
In one aspect, the invention provides a kind of side for preparing Oxiracetam or its pharmaceutically acceptable solvate
Method, it include step 1：Make Oxiracetam acid and compound R-CH2- OH reacts, and generates the chemical combination with structure shown in formula (I)
Thing；
Wherein, R is phenyl, benzyl or the condensed-nuclei aromatics base being optionally substituted with a substituent.
In a preferred embodiment, the phenyl, benzyl or condensed-nuclei aromatics base by one or more (such as 2,
3,4 or 5) substituent replaced.
In a preferred embodiment, the condensed-nuclei aromatics base has 10-16 (such as 10,14 or 16)
Annular atom.
In a preferred embodiment, the condensed-nuclei aromatics base is naphthyl.
In a preferred embodiment, the substituent is selected from alkyl (such as C1-C4Alkyl), halogen (such as fluorine,
Chlorine, bromine or iodine) and alkoxyl (such as C1-C4Alkoxyl).
In a preferred embodiment, the alkyl is selected from methyl and ethyl.
In a preferred embodiment, the alkoxyl is selected from methoxyl group and ethyoxyl.
In a preferred embodiment, R is phenyl, benzyl, naphthyl (such as betanaphthyl) or 2,4- dimethoxy benzene
Base.
In a preferred embodiment, the Oxiracetam acid and compound R-CH2The reaction of-OH with hexamethylene or
Toluene is solvent；Preferably, 5-10 times for Oxiracetam acid quality of the quality of the solvent, such as 5-7 times, 6-8 times or 8-
10 times.
In a preferred embodiment, the Oxiracetam acid and compound R-CH2The reaction of-OH is deposited in catalyst
Carry out under the conditions；Preferably, the catalyst is acid (such as H2SO4Or 4- toluene sulfonic acides) or highly acidic cation friendship
Resin is changed, it is highly preferred that the catalyst is H2SO4.
In a preferred embodiment, the catalyst is the concentrated sulfuric acid；Preferably, in the concentrated sulfuric acid, H2SO4's
Mass fraction is at least 98%；
In a preferred embodiment, the catalyst is 1 with the mol ratio of Oxiracetam acid:5-1:15, for example
1:5-1:10、1:10-1:15, such as 1:5、1:7、1:9、1:10、1:12 or 1:15.
In a preferred embodiment, R-CH2- OH is 2-5 with the mol ratio of Oxiracetam acid:1；Such as 2:1、
2.5:1、3:1、4:1、4.5:1 or 5:1.
In a preferred embodiment, the Oxiracetam acid and compound R-CH2The outer temperature of the reaction of-OH is
88-95℃；Such as 88 DEG C, 89 DEG C, 90 DEG C, 91 DEG C, 92 DEG C or 95 DEG C.
In a preferred embodiment, the Oxiracetam acid and compound R-CH2The reaction of-OH is in counterflow condition
Under carry out 4-5 hours.
In a preferred embodiment, the step 1 includes step 1a：Will containing Oxiracetam acid, compound R-
CH2The mixture of-OH and solvent is heated to flowing back.
In a preferred embodiment, the step 1 also includes step 1b：Oxiracetam acid with compound R-
CH2While-OH reacts, the water that reaction is generated is removed.
In a preferred embodiment, by solvent and the azeotropic of water, the water of reaction generation is removed.Preferably,
Selected solvent is hexamethylene or toluene, more preferably hexamethylene.
In a preferred embodiment, will reaction using water knockout drum (or claiming oil water separator) as shown in Figure 1
The water of generation is removed.As illustrated, the water knockout drum includes first the 1, second opening 2, accommodation space 3 of opening, pipeline 4 and piston
5.First opening 1 is located at the lower end of pipeline 4, for coupled reaction container.Second opening 2 is located at the upper end of accommodation space 3, is used for
Connection condensing unit.Accommodation space 3 is column, for containing condensed liquid.Pipeline 4 is bending, its upper end with accommodating
The side wall in space 3 is connected, and communicates with accommodation space 3.Piston 5 is located at the lower end of accommodation space 3, for discharging condensed liquid
Body.
In a preferred embodiment, closure piston 5, heat to the reaction vessel for being connected to the first opening 1,
The steam comprising solvent and water is made to enter in water knockout drum from reaction vessel by the first opening 1, then through pipeline 4 and the second opening 2
Condensing unit is entered, condensation becomes liquid.Condensed liquid is flowed in accommodation space 3.The solvent is water insoluble or slightly soluble
Yu Shui, and density is less than water, and therefore, in accommodation space 3, solvent and water can form the two-layer with clear interface, its
In, the solvent is built up to certain altitude and is flowed in reaction vessel by pipeline 4 and the first opening 1 on upper strata；Water is under
Layer, operator can be opened piston 5, water is discharged.
In a preferred embodiment, the step 1 also includes step 1c：To the change with structure shown in formula (I)
Compound is separated and/or is purified；Preferably, using extraction to the compound with structure shown in formula (I) carry out separate and/or
Purifying.
In a preferred embodiment, the step 1 also includes step 1d：Reclaim unreacted R-CH2-OH；Excellent
Selection of land, reclaims unreacted R-CH using rectifying or vacuum distillation2-OH
In the present invention, with R-CH2- OH replaces ethanol of the prior art, with Oxiracetam acid reaction.In esterification
At a temperature of, R-CH2- OH will not be together distilled out of with hexamethylene and water.Therefore, the steam containing hexamethylene and water is in condensation
Afterwards, the two-layer of interface is clear can be formed in water knockout drum so that water is easy to be removed.As the method for the present invention can be held
Continuous, remove moisture in time, be conducive to the process of esterification to push ahead, thus reaction can be carried out completely, and can be with
Greatly shorten the reaction time.
On the other hand, in prior art, by the sour ethyl ester compound for generating of ethanol and Oxiracetam, with larger pole
Property, in causing to process after the reaction, need to extract more than ten hour with tetrahydrofuran solution with continuous extraction, could be by ethyl ester
Compound is extracted.And in the method for the invention, the compound of structure as shown in formula (I) has that volume is larger, hydrophobicity
Strong R group, so the polarity of the ester for generating is also much smaller than Oxiracetam acetoacetic ester, in post processing, it is easy to from the aqueous solution
In be extracted out, save time and the energy.In addition, having the compound of structure as shown in formula (I) show under ultraviolet light
Color, therefore in the esterification reaction, easily can carry out process monitoring and purity observation using uviol lamp.
In the present invention, it is preferred to, methods described also includes step 2：Make with the compound of structure shown in formula (I) with
NH3Reaction, generates Oxiracetam and R-CH2- OH, the R are as defined above.
In a preferred embodiment, the step 2 is comprised the following steps：
Step 2a：- 5 DEG C -0 DEG C will be cooled to containing with the solution of the compound of structure shown in formula (I)；Preferably, institute
Solution is stated for ethanol solution；
Step 2b：Ammonia is passed through in the cold solution of step 2a, until saturation；With
Step 2c：Make the compound and NH with structure shown in formula (I)3React under 88-92 DEG C of temperature (preferably 90 DEG C) outside
7-16 hours (such as 7-10 hours, 10-13 hours or 13-16 hours).
In a preferred embodiment, the step 2 also includes step 2d：After step 2c, ammonia is reclaimed.Example
Such as, step 2d includes：Reactant mixture is cooled down (for example, being cooled to room temperature), air-flow (for example, air stream) is passed through, is blown
Go out unreacted ammonia.
In a preferred embodiment, the step 2 also includes step 2e：Isolate Oxiracetam.For example, described
Step 2e includes：Will be with the compound and NH of structure shown in formula (I)3Reacted mixture cooling (for example, is cooled to 0 DEG C -5
DEG C), stirring makes the Oxiracetam of solid separate out (preferably, stirring carries out one hour), separates Oxiracetam by filtering.
Preferably, step 2e is carried out after step 2d.
In a preferred embodiment, the purity of the Oxiracetam that isolates is at least 90%, for example, at least 91%,
At least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99%.
In a preferred embodiment, the step 2 also includes step 2f：Reclaim the R-CH that reaction is generated2-OH；
Preferably, the R-CH that reaction is generated is reclaimed using rectifying or vacuum distillation2-OH.
In the present invention, with R-CH2- OH and Oxiracetam acid reaction, the ester of generation with NH3Reaction in have very high
Reactivity.By contrast, some alcohol compounds (the such as tert-butyl alcohol) although with the boiling point higher than ethanol, its
The ester obtained with Oxiracetam acid reaction, with NH3Reactivity relatively low, thus target product Oxiracetam cannot be obtained.By
In having the compound of structure as shown in formula (I) develop the color under ultraviolet light, therefore, it can easily monitor instead using uviol lamp
Should, judge when reaction completes.Further, since the target compound Oxiracetam of reaction is solid, and the accessory substance R- for generating
CH2- OH is liquid, and accessory substance easily can be separated with target compound.Furthermore, by such as vacuum distillation or essence
Evaporate, R-CH2- OH can be convenient from mother liquor and separates and recovers in high yield, obtains highly purified R-CH2- OH, for next round
Reaction.The waste of material can be so reduced, the reaction process of Creating Green chemistry reduces environmental pollution, and drops significantly
Low production cost.
In the present invention, it is preferred to, methods described also includes step 3：Polishing purification is carried out to Oxiracetam.
In a preferred embodiment, the step 3 includes：Oxiracetam is entered under conditions of activated carbon presence
Row backflow.
In a preferred embodiment, the step 3 is comprised the following steps：
Step 3a：Oxiracetam is dissolved in solvent (for example, water), it is preferable that the quality of the solvent and Oxiracetam
Than for 2：1-4：1 (such as 2:1-3:1 or 3:1-4:1)；Preferably, the mixture containing Oxiracetam and solvent is heated
(for example, being heated to 45-50 DEG C, such as 45-47 DEG C, 47-49 DEG C or 49-50 DEG C), to aid in dissolving, obtains Oxiracetam solution；
Step 3b：Activated carbon is added in the Oxiracetam solution obtained to step 3a, it is preferable that the quality of activated carbon is Austria
0.15-0.5 times of La Xitan mass, such as 0.15-0.2 times, 0.2-0.4 times or 0.4-0.5 times；With
Step 3c：Solution containing Oxiracetam and activated carbon is heated, is flowed back.
In a preferred embodiment, the step 3 is further comprising the steps of：
Step 3d：After reflow, the solution containing Oxiracetam and activated carbon is filtered while hot；With
Step 3e：The filtrate that step 3d is obtained is concentrated and is cooled down, separated out Oxiracetam crystal.
In the present invention, it is preferred to, the method comprising the steps of 1, step 2 and step 3：
Step 1：Make Oxiracetam acid and compound R-CH2- OH reacts, and generates the compound with structure shown in formula (I)；
Wherein, R is phenyl, benzyl, naphthyl (such as betanaphthyl) or 2,4- Dimethoxyphenyl；
In the reaction, R-CH2- OH is 2-5 with the mol ratio of Oxiracetam acid:1；The reaction is with hexamethylene as molten
Agent, the quality of hexamethylene are 5-10 times of Oxiracetam acid quality；The reaction is with the concentrated sulfuric acid (for example, H2SO4Mass fraction
Be at least 98% concentrated sulfuric acid) be catalyst, H2SO4Mol ratio with Oxiracetam acid is 1:5-1:15 (such as 1:5-1:10、
1:10-1:15, such as 1:5、1:7、1:9、1:10、1:12 or 1:15)；The outer temperature of the reaction be 88-95 DEG C (such as 88 DEG C,
89 DEG C, 90 DEG C, 91 DEG C, 92 DEG C or 95 DEG C)；The reaction carries out 4-5 hours under reflux conditions.
The step 1 is comprised the following steps：
Step 1a：Will be containing Oxiracetam acid, compound R-CH2The mixture of-OH and solvent is heated to flowing back；
Step 1b：While reaction is carried out, the water removing for generating will be reacted using water knockout drum；
Step 1c：After reaction terminates, the compound with structure shown in formula (I) is carried out separating and/or pure by extraction
Change；
Step 1d：Unreacted R-CH is reclaimed using vacuum distillation2-OH.
Step 2：Make the compound and NH with structure shown in formula (I)3Reaction, generates Oxiracetam and R-CH2-OH；
The step 2 is comprised the following steps：
Step 2a：Ethanol solution with the compound of structure shown in formula (I) is cooled to -5 DEG C -0 DEG C；
Step 2b：Ammonia is passed through in the cold ethanol solution, until saturation；
Step 2c：Make the compound and NH with structure shown in formula (I)3Temperature is anti-under 88-92 DEG C (preferably 90 DEG C) outside
Answer 7-16 hours (such as 7-10 hours, 10-13 hours or 13-16 hours)；
Step 2d：After step 2c, unreacted ammonia is reclaimed；
Step 2e：After step 2d, reacted mixture is cooled down, stirring separates out the Oxiracetam of solid, leads to
Filter and Oxiracetam is separated；
Step 2f：The R-CH that reaction is generated is reclaimed using rectifying or vacuum distillation2-OH.
Step 3：Polishing purification is carried out to Oxiracetam；
The step 3 is comprised the following steps：
Step 3a：The Oxiracetam that step 2 is obtained is soluble in water, and water is 2 with the mass ratio of Oxiracetam：1-4：1 (example
Such as 2:1-3:1 or 3:1-4:1)；By the mixture of water and Oxiracetam be heated to 45-50 DEG C (such as 45-47 DEG C, 47-49 DEG C or
49-50 DEG C) to promote to dissolve, obtain the Oxiracetam aqueous solution；
Step 3b：Activated carbon is added in the Oxiracetam aqueous solution obtained to step 3a, and the quality of activated carbon is Aura west
0.15-0.5 times (such as 0.15-0.2 times, 0.2-0.4 times or 0.4-0.5 times) of smooth quality；
Step 3c：To the heating of the solution containing Oxiracetam and activated carbon in step 3b, flowed back；
Step 3d：After reflow, the solution containing Oxiracetam and activated carbon is filtered while hot；
Step 3e：The filtrate that step 3d is obtained is concentrated and is cooled down, separated out Oxiracetam crystal.
In a preferred embodiment, the total recovery of step 1, step 2 and step 3 is 65%-100%, for example
65%-70%, 70%-75%, 75%-80%, 80%-85%, 85%-90%, 90%-95% or 95%-100%.Described
Total recovery is multiplied by the yield of step 1, step 2 and step 3 and is obtained.
In the present invention, it is preferred to, the Oxiracetam acid is reacted with 4- chloro-3-hydroxyls ethyl butyrate by glycine
Obtain.
In a preferred embodiment, the reaction of the glycine and 4- chloro-3-hydroxyl ethyl butyrates is in alkaline ring
In border, (under conditions of for example NaOH is present) is carried out.
On the other hand, the invention provides one kind has the compound of structure as shown in formula (I),
Wherein, R is phenyl, benzyl or the condensed-nuclei aromatics base being optionally substituted with a substituent.
In a preferred embodiment, the phenyl, benzyl or condensed-nuclei aromatics base by one or more (such as 2,
3,4 or 5) substituent replaced.
In a preferred embodiment, the condensed-nuclei aromatics base has 10-16 (such as 10,14 or 16)
Annular atom.
In a preferred embodiment, the condensed-nuclei aromatics base is naphthyl.
In a preferred embodiment, the substituent is selected from alkyl (such as C1-C4Alkyl), halogen (such as fluorine,
Chlorine, bromine or iodine) and alkoxyl (such as C1-C4Alkoxyl).
In a preferred embodiment, the alkyl is selected from methyl and ethyl.
In a preferred embodiment, the alkoxyl is selected from methoxyl group and ethyoxyl.
In a preferred embodiment, R is phenyl, benzyl, naphthyl (such as betanaphthyl) or 2,4- dimethoxy benzene
Base.
On the other hand, the invention provides the compound with structure as shown in formula (I) as above is used for preparing
Oxiracetam or the purposes of its pharmaceutically acceptable solvate.
On the other hand, the invention provides R-CH2- OH is used for preparing Oxiracetam or its pharmaceutically acceptable solvation
The purposes of thing, wherein, R is phenyl, benzyl or the condensed-nuclei aromatics base being optionally substituted with a substituent.
In a preferred embodiment, the phenyl, benzyl or condensed-nuclei aromatics base by one or more (such as 2,
3,4 or 5) substituent replaced.
In a preferred embodiment, the condensed-nuclei aromatics base has 10-16 (such as 10,14 or 16)
Annular atom.
In a preferred embodiment, the condensed-nuclei aromatics base is naphthyl.
In a preferred embodiment, the substituent is selected from alkyl (such as C1-C4Alkyl), halogen (such as fluorine,
Chlorine, bromine or iodine) and alkoxyl (such as C1-C4Alkoxyl).
In a preferred embodiment, the alkyl is selected from methyl and ethyl.
In a preferred embodiment, the alkoxyl is selected from methoxyl group and ethyoxyl.
In a preferred embodiment, R is phenyl, benzyl, naphthyl (such as betanaphthyl) or 2,4- dimethoxy benzene
Base.
Beneficial effect
The method for preparing Oxiracetam or its pharmaceutically acceptable solvate of the present invention, has the advantages that
In one or more：
(1) in the inventive method, using R-CH2- OH and Oxiracetam acid carry out esterification, can continue, in time
Except the water that dereaction is generated, the process of esterification is conducive to push ahead so that reaction can be carried out completely, and can contract significantly
Short reaction time.
(2), in the method for the present invention, the product that generated by esterification, in post processing, it is easy to be extracted out, is saved
Time and the energy are saved.
(3) in the present invention, with R-CH2- OH and Oxiracetam acid reaction, generation with structure as shown in formula (I)
Compound, in subsequent reactions (for example with NH3Reaction) in have very high reactivity, be conducive to improve product yield.
(4) there is the compound of structure as shown in formula (I) can develop the color under ultraviolet light, therefore in the reaction, can facilitates
Ground monitors reaction process, and the purity of observation product using uviol lamp.
(5) there is the compound and NH of structure as shown in formula (I)3Reaction in, accessory substance R-CH2- OH is liquid, can be with
Easily separate with target compound.Also, either unreacted R-CH in step 12React in-OH, or step 2
The accessory substance R-CH of generation2- OH, can separate and recover conveniently and in high yield from mother liquor, obtain highly purified R-CH2-
OH, for the reaction of next round.The waste of material can be so reduced, the reaction process of Creating Green chemistry reduces environment dirty
Dye, and substantially reduce production cost.
Specific embodiment
Embodiment of the present invention is described in detail below in conjunction with drawings and Examples, but people in the art
Member will be understood that drawings below and embodiment are merely to illustrate the present invention, and should not be taken as limiting the scope of the invention.Accompanying drawing and
Unreceipted actual conditions person in embodiment, the condition that advises according to normal condition or manufacturer are carried out.Agents useful for same or instrument are not
Dated production firm person, be can pass through city available from conventional products.
Description of the drawings
Fig. 1 shows that the water knockout drum (or claiming oil water separator) that the present invention is used, its water for being used for generating reaction are removed.
As illustrated, the water knockout drum includes first the 1, second opening 2, accommodation space 3 of opening, pipeline 4 and piston 5.First opening 1
In the lower end of pipeline 4, for coupled reaction container.Second opening 2 is located at the upper end of accommodation space 3, for connecting condensing unit.
Accommodation space 3 is column, for containing condensed liquid.Pipeline 4 is bending, the side wall phase of its upper end and accommodation space 3
Even, and communicate with accommodation space 3.Piston 5 is located at the lower end of accommodation space 3, for discharging condensed liquid.
Synthesis example and the method for preparing Oxiracetam of embodiment 1-5, are carried out according to following reaction scheme
Synthesis example synthesizing oxiracetam acid (compound 1)
Glycine (50 grams) is suspended in 200 milliliters of water, is stirred vigorously, is heated to 80 DEG C, while to the sweet ammonia
Sour suspension is added dropwise the aqueous solution (10mol/L, 121 milliliters) of 4- chloro-3-hydroxyl ethyl butyrates (100 grams) and NaOH, and half
Completion of dropping in hour, afterwards, 80 DEG C are reacted 10 hours.Check through thin-layer chromatography, reaction is completed, and obtains a brown solution, ice bath
The lower dropwise addition concentrated hydrochloric acid of cooling is 2 to pH, with activated carbon decolorizing.Filtrate is rotated to be concentrated by evaporation to dry, with the mixed of ethanol and methyl alcohol
(volume ratio is 1 to bonding solvent:1) crystallize, obtain the product of 81 grams of White crystals, be that Oxiracetam is sour (compound 1), yield
84.6%.
Embodiment 1
Step 1 synthesis compound 2 (R is phenyl)
By compound 1 (79.5g, 0.5mol), phenmethylol (162g, 1.5mol), 2.7 milliliters of mass fractions be 98% dense
Sulfuric acid (0.05mol H2SO4) and 780 milliliters of hexamethylene be placed in the reaction bulb for being provided with water knockout drum (as shown in Figure 1), stir
While, heating reflux reaction 5 hours.The water for separating is discarded, reactant liquor is concentrated to dryness, reclaim hexamethylene.Add 300 milliliters
Water, then add the sodium acid carbonate of powder while stirring, it is 7～8 to adjust pH value.With petroleum ether extraction twice, petroleum ether extraction
Layer is concentrated through vacuum distillation, reclaims the complete phenmethylol of unreacted, and remaining water is mutually again with the mixing of ethyl acetate and tetrahydrofuran
(volume ratio is 1 to solvent：1) extract three times.Combining extraction liquid, with anhydrous sodium sulfate drying, obtains pale yellow oil, weight after concentration
116 grams.Not purified, it is directly used in next step reaction.Purification part sample is used column chromatography, for analyzing.1HNMR
(CDCl3):7.24 (m, 5H), 5.32 (s, 2H), 4.48 (m, 1H), 4.23 (br, s, 1H), 4.18 (d, J=17.4,1H),
3.95 (d, J=17.4,1H), 3.77 (dd, J=10.5,5.4,1H), 3.35 (dd, J=10.5,1.5,1H), 2.68 (dd, J
=17.4,6.3,1H), 2.39 (dd, J=17.4,1.5,1H)；ESI-MS:231.1[M-18]+.
Step is 2-in-1 into Oxiracetam
In autoclave, compound 2 (R is phenyl) is dissolved in 1000 milliliters of absolute ethyl alcohol, is cooled to -5 DEG C, is passed through dry
Dry ammonia to saturation, re-closed be heated to 90 DEG C, react 7 hours.It is cooled to room temperature, is passed through air and ammonia complete for unreacted is blown
Go out, and reclaim ammonia.It is cooled to -5 DEG C again, stirring and crystallizing one hour.Filter, filtrate is concentrated to dryness, add water, extracted with petroleum ether
Take.Extract drying, vacuum distillation reclaim phenmethylol, then the phenmethylol redistillation that will be reclaimed, and purity, can be with up to more than 98%
It is continuing with the test of next group.Filter cake is washed twice with cold ethanol, obtains off-white color mealy crystal Oxiracetam.
Step 3 is refined to Oxiracetam and purifies
Will be soluble in water for the crystal of step 2 gained, activated carbon is added, 50 DEG C are heated to, is decolourized 1 hour.Filter while hot, filter
Liquid vacuum distillation is concentrated, crystallization, is obtained white powder crystal Oxiracetam, is weighed 60 grams.The total recovery of step 1,2 and 3 is 76%.Produce
The HPLC purity of thing reaches 99.75%, and the content of Oxiracetam acid is less than 0.05%.
1H-NMR(400MHz,DMSO)δ(ppm)：7.30 (s, 1H), 7.10 (s, 1H), 5.20 (d, 1H) (disappear after increasing water
Lose), 4.30 (m, 1H), 3.82-3.90 (d, 1H), 3.62-3.68 (d, 1H), 3.59-3.60 (dd, 1H), 3.13-3.15 (d,
1H), 2.56-2.57 (dd, 1H), 2.03-2.10 (d, 1H)；13C-NMR(200MHz,DMSO)δ(ppm)：172.99,169.91,
63.45,56.86,44.91,39.70；MS m/z；159.0765[M+H]+.
Embodiment 2
Step 1 synthesis compound 2 (R is benzyl)
By compound 1 (79.5g, 0.5mol), benzyl carbinol (183g, 1.5mol), 2.7 milliliters of mass fractions be 98% dense
Sulfuric acid (0.05mol H2SO4) and 780 milliliters of hexamethylene be placed in the reaction bulb for being provided with water knockout drum (as shown in Figure 1), stir
While, heating reflux reaction 4 hours.The water for separating is discarded, reactant liquor is concentrated to dryness, reclaim hexamethylene.Add 300 milliliters
Water, then add the sodium acid carbonate of powder while stirring, it is 7～8 to adjust pH value.With petroleum ether extraction twice, petroleum ether extraction
Layer is concentrated through vacuum distillation, reclaims the complete benzyl carbinol of unreacted.Remaining water is mutually again with the mixing of ethyl acetate and tetrahydrofuran
(volume ratio is 1 to solvent：1) extract three times.Combining extraction liquid, with anhydrous sodium sulfate drying, obtains pale yellow oil after concentration.Not
Purified, it is directly used in next step reaction.Purification part sample is used column chromatography, for analyzing.1HNMR(CDCl3):7.22
(m, 5H), 5.32 (s, 2H), 4.48 (m, 1H), 4.43 (t, J=7.2,2H), 4.23 (br, s, 1H), 4.18 (d, J=17.4,
1H), 3.95 (d, J=17.4,1H), 3.77 (dd, J=10.5,5.4,1H), 3.35 (dd, J=10.5,1.5,1H), 2.87
(t, J=7.2,2H), 2.69 (dd, J=17.4,6.3,1H), 2.39 (dd, J=17.4,1.5,1H)；ESI-MS:245.2[M-
18]+.
Step is 2-in-1 into Oxiracetam
In autoclave, compound 2 (R is benzyl) is dissolved in 1000 milliliters of absolute ethyl alcohol, is cooled to -5 DEG C, is passed through dry
Dry ammonia to saturation, re-closed be heated to 90 DEG C, react 7 hours.It is cooled to room temperature, is passed through air and ammonia complete for unreacted is blown
Go out, and reclaim ammonia.It is cooled to -5 DEG C again, stirring and crystallizing one hour.Filter, filtrate is concentrated to dryness, add water, extracted with petroleum ether
Take.Extract drying, vacuum distillation reclaim benzyl carbinol, then the benzyl carbinol redistillation that will be reclaimed, and purity, can be with up to more than 98%
It is continuing with the test of next group.Filter cake is washed twice with cold ethanol, obtains off-white color mealy crystal Oxiracetam.
Step 3 is refined to Oxiracetam and purifies
Will be soluble in water for step 2 gained crystal, activated carbon is added, 50 DEG C are heated to, is decolourized 1 hour.Filter, filtrate decompression
Distillation and concentration, crystallization, obtains white powder crystal Oxiracetam, weighs 59 grams.The total recovery of step 1,2 and 3 is 75%.Product
HPLC purity reaches 99.67%, and the content of Oxiracetam acid is less than 0.05%.
Embodiment 3
Step 1 synthesis compound 2 (R is 2,4- Dimethoxyphenyls)
By compound 1 (79.5g, 0.5mol), 2,4- 3,5-dimethoxybenzoic alcohols (252g, 1.5mol), 2.7 milliliters of quality point
Number is 98% concentrated sulfuric acid (0.05mol H2SO4) and 780 milliliters of hexamethylene be placed in and be provided with water knockout drum (as shown in Figure 1)
In reaction bulb, while stirring, heating reflux reaction 4 hours.The water for separating is discarded, by reactant liquor concentration distillation to dry, is reclaimed
Hexamethylene.200 milliliters of water are added, the sodium acid carbonate of powder is added while stirring, it is 7～8 to adjust pH value.With petroleum ether extraction
Twice, petroleum ether extraction layer is concentrated through vacuum distillation, reclaims complete 2, the 4- 3,5-dimethoxybenzoic alcohols of unreacted.Remaining water is mutually again
With the mixed solvent of ethyl acetate and tetrahydrofuran, (volume ratio is 1：1) extract three times.Combining extraction liquid, dry with anhydrous sodium sulfate
Dry, pale yellow oil is obtained after concentration.Not purified, it is directly used in next step reaction.Purification part sample is used column chromatography,
For analyzing.1HNMR(CDCl3):7.05 (d, J=3.6,1H), 6.43 (d, J=3.6,1H), 6.38 (s, 1H), 5.34 (s,
2H), 4.48 (m, 1H), 4.23 (br, s, 1H), 4.18 (d, J=17.4,1H), 3.95 (d, J=17.4,1H), 3.81 (s,
6H), 3.77 (dd, J=10.5,5.4,1H), 3.35 (dd, J=10.5,1.5,1H), 2.68 (dd, J=17.4,6.3,1H),
2.39 (dd, J=17.4,1.5,1H)；ESI-MS:291.1[M-18]+.
Step is 2-in-1 into Oxiracetam
In autoclave, compound 2 (R is 2,4- Dimethoxyphenyls) is dissolved in 1000 milliliters of absolute ethyl alcohol, cold
To -5 DEG C, be passed through dry ammonia to saturation, re-closed be heated to 90 DEG C, react 7 hours.It is cooled to room temperature, being passed through air will not
The ammonia blowout that has reacted, and reclaim ammonia.It is cooled to -5 DEG C again, stirring and crystallizing one hour.Filter, filtrate is concentrated to dryness, add
Water, with petroleum ether extraction.Extract drying, vacuum distillation reclaim benzylalcohol, then the benzylalcohol redistillation that will be reclaimed, and purity is up to 98%
More than, can be continuing with the test of next group.Filter cake is washed twice with cold ethanol, obtains off-white color mealy crystal Aura west
Smooth.
Step 3 is refined to Oxiracetam and purifies
Will be soluble in water for step 2 gained crystal, activated carbon is added, 50 DEG C are heated to, is decolourized 1 hour.Filter, filtrate decompression
Distillation and concentration, crystallization, obtains white powder crystal Oxiracetam, weighs 61 grams.The total recovery of step 1,2 and 3 is 77%.Product
HPLC purity reaches 99.72%, and the content of Oxiracetam acid is less than 0.05%.
Embodiment 4
Step 1 synthesis compound 2 (R is betanaphthyl)
By compound 1 (79.5g, 0.5mol), β-naphthalene methyl alcohol (237.3g, 1.5mol), 2.7 milliliters of mass fractions are 98%
The concentrated sulfuric acid (0.05mol H2SO4) and 780 milliliters of hexamethylene be placed in the reaction bulb for being provided with water knockout drum (as shown in Figure 1),
While stirring, heating reflux reaction 4 hours.The water for separating is discarded, reactant liquor is concentrated to dryness, reclaim hexamethylene.Add 200
Milliliter water, adds the sodium acid carbonate of powder while stirring, and it is 7～8 to adjust pH value.With petroleum ether extraction twice, petroleum ether extraction
Take layer to concentrate through vacuum distillation, reclaim the complete β-naphthalene methyl alcohol of unreacted.Remaining water is mutually again with ethyl acetate and tetrahydrofuran
(volume ratio is 1 to mixed solvent：1) extract three times.Combining extraction liquid, with anhydrous sodium sulfate drying, obtains faint yellow oily after concentration
Thing.Not purified, it is directly used in next step reaction.Purification part sample is used column chromatography, for analyzing.1HNMR(CDCl3):
7.6～7.8 (m, 3H), 7.48 (s, 1H), 7.31 (m, 2H), 7.19 (m, 1H), 5.35 (s, 2H), 4.48 (m, 1H), 4.24
(br, s, 1H), 4.17 (d, J=17.4,1H), 3.96 (d, J=17.4,1H), 3.81 (s, 6H), 3.77 (dd, J=10.5,
5.4,1H), 3.35 (dd, J=10.5,1.5,1H), 2.68 (dd, J=17.4,6.3,1H), 2.39 (dd, J=17.4,1.5,
1H)；ESI-MS:281.3[M-18]+.
Step is 2-in-1 into Oxiracetam
In autoclave, compound 2 (R is betanaphthyl) is dissolved in 1000 milliliters of absolute ethyl alcohol, is cooled to -5 DEG C, is passed through
Dry ammonia to saturation, re-closed be heated to 90 DEG C, react 7 hours.Be cooled to room temperature, air is passed through by ammonia complete for unreacted
Blowout, and reclaim ammonia.It is cooled to -5 DEG C again, stirring and crystallizing one hour.Filter, filtrate is concentrated to dryness, add water, extracted with petroleum ether
Take.Extract drying, vacuum distillation reclaim β-naphthalene methyl alcohol, and β-naphthalene methyl alcohol that combining step 1 is reclaimed, rectifying obtain purity and reaches
More than 98% β-naphthalene methyl alcohol, can be continuing with the test of next group.Filter cake is washed twice with cold ethanol, obtains off-white color
Mealy crystal Oxiracetam.
Step 3 is refined to Oxiracetam and purifies
Will be soluble in water for step 2 gained crystal, activated carbon is added, 50 DEG C are heated to, is decolourized 1 hour.Filter, filtrate decompression
Distillation and concentration, crystallization, obtains white powder crystal Oxiracetam, weighs 60.3 grams.The total recovery of step 1,2 and 3 is 76%.Product
HPLC purity reaches 99.65%, and the content of Oxiracetam acid is less than 0.05%.
Although the specific embodiment of the present invention has obtained detailed description, it will be appreciated by those skilled in the art that：Root
According to disclosed all teachings, various modifications and changes can be carried out to details, and these changes are in the guarantor of the present invention
Within the scope of shield.The four corner of the present invention is given by claims and its any equivalent.
Claims (10)
1. a kind of method for preparing Oxiracetam or its pharmaceutically acceptable solvate, which includes step 1：Make Oxiracetam
Acid and compound R-CH2- OH reacts, and generates the compound with structure shown in formula (I)；
Wherein, R is phenyl, benzyl or the condensed-nuclei aromatics base being optionally substituted with a substituent；
Preferably, the phenyl, benzyl or condensed-nuclei aromatics base are by one or more (such as 2,3,4 or 5) substituents
Replaced；
Preferably, the condensed-nuclei aromatics base has 10-16 (such as 10,14 or 16) annular atom；
Preferably, the condensed-nuclei aromatics base is naphthyl；
Preferably, the substituent is selected from alkyl (such as C1-C4Alkyl), halogen (such as fluorine, chlorine, bromine or iodine) and alkoxyl (example
Such as C1-C4Alkoxyl)；
Preferably, the alkyl is selected from methyl and ethyl；
Preferably, the alkoxyl is selected from methoxyl group and ethyoxyl；
Preferably, R is phenyl, benzyl, naphthyl (such as betanaphthyl) or 2,4- Dimethoxyphenyl.
2. the method for claim 1 wherein, Oxiracetam acid and compound R-CH2The reaction of-OH is with hexamethylene or toluene
For solvent；
Preferably, the quality of the solvent is 5-10 times (such as 5-7 times, 6-8 times or 8-10 times) of Oxiracetam acid quality；
Preferably, the Oxiracetam acid and compound R-CH2The reaction of-OH is carried out under conditions of catalyst presence；
Preferably, the catalyst is acid (such as H2SO4Or 4- toluene sulfonic acides) or storng-acid cation exchange resin, more excellent
Selection of land, the catalyst are the concentrated sulfuric acid (such as mass fraction is at least 98% concentrated sulfuric acid)；
Preferably, the catalyst is 1 with the mol ratio of Oxiracetam acid:5-1:15 (such as 1:5-1:10、1:10-1:15, example
Such as 1:5、1:7、1:9、1:10、1:12 or 1:15)；
Preferably, R-CH2- OH is 2-5 with the mol ratio of Oxiracetam acid:1 (such as 2:1、2.5:1、3:1、4:1、4.5:1 or 5:
1)；
Preferably, the Oxiracetam acid and compound R-CH2The outer temperature of the reaction of-OH be 88-95 DEG C (such as 88 DEG C, 89 DEG C,
90 DEG C, 91 DEG C, 92 DEG C or 95 DEG C)；
Preferably, the Oxiracetam acid and compound R-CH2The reaction of-OH carries out 4-5 hours under reflux conditions.
3. the method for claim 1 or 2, wherein, the step 1 includes step 1a：Will containing Oxiracetam acid, compound R-
CH2The mixture of-OH and solvent is heated to flowing back；
Preferably, the step 1 also includes step 1b：In Oxiracetam acid and compound R-CH2While-OH reacts, will reaction
The water of generation is removed；
Preferably, by solvent and the azeotropic of water, the water of reaction generation is removed；
Preferably, selected solvent is hexamethylene or toluene, more preferably hexamethylene；
Preferably, the step 1 also includes step 1c：Compound with structure shown in formula (I) is carried out separating and/or pure
Change；Preferably, the compound with structure shown in formula (I) is separated using extraction and/or is purified；
Preferably, the step 1 also includes step 1d：Reclaim unreacted R-CH2-OH；Preferably, steamed using rectifying or decompression
Evaporate the unreacted R-CH of recovery2-OH.
4. the method for any one of claim 1-3, methods described also include step 2：Make the compound with structure shown in formula (I)
With NH3Reaction, generates Oxiracetam and R-CH2- OH, the R such as any one of claim 1-3 is defined；
Preferably, the step 2 is comprised the following steps：
Step 2a：- 5 DEG C -0 DEG C will be cooled to containing with the solution of the compound of structure shown in formula (I)；Preferably, described molten
Liquid is ethanol solution；
Step 2b：Ammonia is passed through in the cold solution of step 2a, until saturation；With
Step 2c：Step 2c：Make the compound and NH with structure shown in formula (I)3Temperature is under 88-92 DEG C (preferably 90 DEG C) outside
Reaction 7-16 hours (such as 7-10 hours, 10-13 hours or 13-16 hours)；
Preferably, the step 2 also includes step 2d：After step 2c, ammonia is reclaimed；
Preferably, the step 2 also includes step 2e：Isolate Oxiracetam；
Preferably, step 2e is carried out after step 2d；
Preferably, the purity of the Oxiracetam that isolates is at least 90%, for example, at least 91%, at least 92%, at least 93%, extremely
Few 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99%；
Preferably, the step 2 also includes step 2f：Reclaim the R-CH that reaction is generated2-OH；Preferably, using rectifying or decompression
The R-CH that Distillation recovery reaction is generated2-OH.
5. the method for any one of claim 1-4, methods described also include step 3：Polishing purification is carried out to Oxiracetam；
Preferably, the step 3 includes：Oxiracetam is flowed back under conditions of activated carbon presence；
Preferably, the step 3 is comprised the following steps：
Step 3a：Oxiracetam is dissolved in solvent (for example, water)；
Preferably, the solvent is 2 with the mass ratio of Oxiracetam：1-4：1；
Preferably, it is molten to aid in that (for example, being heated to 45-50 DEG C) is heated to the mixture containing Oxiracetam and solvent
Solution, obtains Oxiracetam solution；
Step 3b：Activated carbon is added in the Oxiracetam solution obtained to step 3a；
Preferably, the quality of activated carbon for Oxiracetam quality 0.15-0.5 times (such as 0.15-0.2 times, 0.2-0.4 times or
0.4-0.5 times)；With
Step 3c：Solution containing Oxiracetam and activated carbon is heated, is flowed back；
Preferably, the step 3 is further comprising the steps of：
Step 3d：After reflow, the solution containing Oxiracetam and activated carbon is filtered while hot；With
Step 3e：The filtrate that step 3d is obtained is concentrated and is cooled down, separated out Oxiracetam crystal.
6. the method for any one of claim 1-5, the method comprising the steps of 1, step 2 and step 3：
Step 1：Make Oxiracetam acid and compound R-CH2- OH reacts, and generates the compound with structure shown in formula (I)；
Wherein, R is phenyl, benzyl, naphthyl (such as betanaphthyl) or 2,4- Dimethoxyphenyl；
In the reaction, R-CH2- OH is 2-5 with the mol ratio of Oxiracetam acid:1；Described reaction with hexamethylene as solvent, hexamethylene
The quality of alkane is 5-10 times of Oxiracetam acid quality；The reaction is with the concentrated sulfuric acid (for example, H2SO4Mass fraction be at least
98% concentrated sulfuric acid) be catalyst, H2SO4Mol ratio with Oxiracetam acid is 1:5-1:15；The outer temperature of the reaction is 88-
95℃；The reaction carries out 4-5 hours under reflux conditions；
The step 1 is comprised the following steps：
Step 1a：Will be containing Oxiracetam acid, compound R-CH2The mixture of-OH and solvent is heated to flowing back；
Step 1b：While reaction is carried out, the water removing for generating will be reacted using water knockout drum；
Step 1c：After reaction terminates, the compound with structure shown in formula (I) is separated by extraction and/or purified；
Step 1d：Unreacted R-CH is reclaimed using rectifying or vacuum distillation2-OH；
Step 2：Make the compound and NH with structure shown in formula (I)3Reaction, generates Oxiracetam and R-CH2-OH；
The step 2 is comprised the following steps：
Step 2a：Ethanol solution with the compound of structure shown in formula (I) is cooled to -5 DEG C -0 DEG C；
Step 2b：Ammonia is passed through in the cold ethanol solution, until saturation；
Step 2c：Make the compound and NH with structure shown in formula (I)3Temperature is reaction 7-16 hours at 88-92 DEG C outside；
Step 2d：After step 2c, unreacted ammonia is reclaimed；
Step 2e：After step 2d, reacted mixture is cooled down, stirring separates out the Oxiracetam of solid, by mistake
Oxiracetam is separated by filter；
Step 2f：The R-CH that reaction is generated is reclaimed using rectifying or vacuum distillation2-OH；
Step 3：Polishing purification is carried out to Oxiracetam；
The step 3 is comprised the following steps：
Step 3a：The Oxiracetam that step 2 is obtained is soluble in water, and water is 4 with the mass ratio of Oxiracetam：1-2：1, by water with
The mixture of Oxiracetam is heated to 45-50 DEG C to aid in dissolving, obtains the Oxiracetam aqueous solution；
Step 3b：Activated carbon is added in the Oxiracetam aqueous solution obtained to step 3a, and the quality of activated carbon is Oxiracetam matter
0.15-0.5 times of amount；
Step 3c：To the heating of the solution containing Oxiracetam and activated carbon in step 3d, flowed back；
Step 3d：After reflow, the solution containing Oxiracetam and activated carbon is filtered while hot；
Step 3e：The filtrate that step 3d is obtained is concentrated and is cooled down, separated out Oxiracetam crystal；
Preferably, the total recovery of the step 1, step 2 and step 3 be 65%-100%, such as 65%-70%, 70%-
75%th, 75%-80%, 80%-85%, 85%-90%, 90%-95% or 95%-100%.
7. the method for any one of claim 1-6, wherein, the Oxiracetam acid is by glycine and 4- chloro-3-hydroxyl fourths
Acetoacetic ester reaction is obtained；
Preferably, in alkaline environment, (for example NaOH exists the glycine with the reaction of 4- chloro-3-hydroxyl ethyl butyrates
Under conditions of) carry out.
8. one kind has the compound of structure as shown in formula (I),
Wherein, R is phenyl, benzyl or the condensed-nuclei aromatics base being optionally substituted with a substituent；
Preferably, the phenyl, benzyl or condensed-nuclei aromatics base are by one or more (such as 2,3,4 or 5) substituents
Replaced；
Preferably, the condensed-nuclei aromatics base has 10-16 (such as 10,14 or 16) annular atom；
Preferably, the condensed-nuclei aromatics base is naphthyl；
Preferably, the substituent is selected from alkyl (such as C1-C4Alkyl), halogen (such as fluorine, chlorine, bromine or iodine) and alkoxyl (example
Such as C1-C4Alkoxyl)；
Preferably, the alkyl is selected from methyl and ethyl；
Preferably, the alkoxyl is selected from methoxyl group and ethyoxyl；
Preferably, R is phenyl, benzyl, naphthyl (such as betanaphthyl) or 2,4- Dimethoxyphenyl.
9. the compound of claim 8 is used for the purposes for preparing Oxiracetam or its pharmaceutically acceptable solvate.
10.R-CH2- OH is used for the purposes for preparing Oxiracetam or its pharmaceutically acceptable solvate, and wherein, R is optionally quilt
Phenyl, benzyl or condensed-nuclei aromatics base that substituent replaces；
Preferably, the phenyl, benzyl or condensed-nuclei aromatics base are by one or more (such as 2,3,4 or 5) substituents
Replaced；
Preferably, the condensed-nuclei aromatics base has 10-16 (such as 10,14 or 16) annular atom；
Preferably, the condensed-nuclei aromatics base is naphthyl；
Preferably, the substituent is selected from alkyl (such as C1-C4Alkyl), halogen (such as fluorine, chlorine, bromine or iodine) and alkoxyl (example
Such as C1-C4Alkoxyl)；
Preferably, the alkyl is selected from methyl and ethyl；
Preferably, the alkoxyl is selected from methoxyl group and ethyoxyl；
Preferably, R is phenyl, benzyl, naphthyl (such as betanaphthyl) or 2,4- Dimethoxyphenyl.
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