CN106496089B - A method of preparing Oxiracetam - Google Patents
A method of preparing Oxiracetam Download PDFInfo
- Publication number
- CN106496089B CN106496089B CN201610081511.XA CN201610081511A CN106496089B CN 106496089 B CN106496089 B CN 106496089B CN 201610081511 A CN201610081511 A CN 201610081511A CN 106496089 B CN106496089 B CN 106496089B
- Authority
- CN
- China
- Prior art keywords
- oxiracetam
- reaction
- compound
- acid
- water
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Active
Links
Classifications
-
- 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
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention belongs to pharmaceutical technology fields, and in particular to a method of prepare Oxiracetam or its pharmaceutically acceptable solvate comprising following steps: make Oxiracetam acid and compound R-CH2- OH reaction, generates the compound with structure shown in formula (I)；Wherein, R is defined as in the description.The invention further relates to the compound with structure shown in formula (I) and its it is used to prepare the purposes of Oxiracetam or its pharmaceutically acceptable solvate.The invention further relates to R-CH2- OH is used to prepare the purposes of Oxiracetam or its pharmaceutically acceptable solvate.
Description
Technical field
The invention belongs to pharmaceutical technology fields, and in particular to a kind of to prepare Oxiracetam or its pharmaceutically acceptable solvent
The method of compound.
Background technique
Currently, China aging crowd is continuously increased, senile dementia is to sufferers themselves, patient home and periphery crowd
Life cause much to influence, so increasingly by society it is of interest.Oxiracetam (Oxiracetam) is a kind of cereboactive drug, is used for
Improve the memory and learning functionality of senile dementia and memory disorder patient.The medicine was synthesized in 1974, and in
It lists within 1984, is still clinically widely applied so far.Existing lot of documents reports the synthetic route and technique of Oxiracetam.
Starting material used by different process and reaction step difference, but be summed up, it all there is a problem that total recovery is low.It is some
In method, since intermediate needs that column chromatography purifies or finished product needs ion exchange resin to purify, so that it is cumbersome, it is produced into
This height.
Patent CN200710059625.5 proposes the route of following synthesizing oxiracetam:
This route is up to six steps, has used thionyl chloride in the first step, it is desirable that carry out under conditions of absolute, and chlorine
The high volatility for changing sulfoxide, reacts with water and generates hydrochloric acid, and irritation is strong；The reaction of 5th step removing hemiacetal protecting group, it is desirable that
Make solvent with glacial acetic acid, and needs to be passed through dry hydrogen chloride gas and be extremely saturated, thus it is high to equipment and environmental requirement；Also,
Raw material is strong to the corrosivity of equipment, and to the respiratory tract of operator and endangers extremely serious.In addition, total receipts of the method
Rate is not high, is unsuitable for industrialized production.
Patent CN200910050116.5 proposes another synthetic route:
Synthetic thread of the synthetic route of this method than patent CN200710059625.5 greatly shortens, difficult to understand in second step
Esterification occurs for La Xitan acid and ethyl alcohol, need to be with sulphur acid as catalyst, and makees 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 uniform three-phase body with hexamethylene and ethyl alcohol
System, can not separate, so the water generated can not be removed, and remain in reaction solution.Although when the esterification of second step
Between be up to more than ten a hours, but reaction cannot still push ahead, so reaction can not carry out completely.Second step reaction terminates
Afterwards, Oxiracetam acid in part still remains in reaction mixture, can not react in the third step with ammonia and generate Oxiracetam, after giving
Continuous purifying purification operations make troubles.
Patent CN201110022874.5 obtains mesh by one-step method using 4- chlorine-2-hydroxyl ethyl butyrate and glycine amide
The method for marking compound, but the one-step method in this method is the two step successive reactions for utilizing " one kettle way " in fact.Because of reaction site
More, by-product is more, and reacts under strongly alkaline conditions again, so that the Oxiracetam generated is very unstable, is easily decomposed, and then lead
Reaction solution complicated composition are caused, easy purification, reaction yield be not high；Also, since reaction is complicated, there are gaseous by-product generation, gas
The removal degree of body is different, so that the composition and yield of reaction product are also different, reaction condition is not easy to control, is not easy to form stabilization
Technique.
Summary of the invention
In the present invention, unless otherwise stated, Science and Technology noun used herein has art technology
The normally understood meaning of personnel institute.Also, laboratory operation step involved in herein is to be widely used in corresponding field
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, has
With flowering structure:
Oxiracetam of the present invention includes S-oxiracetam, R- Oxiracetam, and the composition being made of the two,
Such as the racemic modification being made of the two.
As used in this article, term " Oxiracetam acid " refers to -1 guanidine-acetic acid of 4- hydroxy-pyrrolidine -2- ketone, has
With flowering structure:
Oxiracetam acid of the present invention includes what S-oxiracetam was sour, R- Oxiracetam is sour, and was made of the two
Composition, such as the racemic modification being made of the two.
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 " outer temperature " refers to the temperature of the heat 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 " refers to shares two phases by two or more phenyl ring each other
Adjacent carbon atom is formed by aromatic cyclic group.Preferably, the condensed-nuclei aromatics base has 10-16 annular atom, such as has
There are 10,14 or 16 annular atoms.The condensed-nuclei aromatics base includes but is not limited to naphthalene, 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 tert-butyl." the C1-C2Alkyl ", " C1-C3Alkyl " and " C2-C4Alkyl " respectively refers to C1-C4Contain 1-2,1-3 in alkyl
A and 2-4 carbon atom specific example.
As used in this article, term " C1-C4Alkoxy " refers to C1-C4Alkyl is connected by oxygen atom with other structures
The group connect, including but not limited to C1-C2Alkoxy, C1-C3Alkoxy and C2-C4Alkoxy, such as methoxyl group, ethyoxyl, just
Propoxyl group, isopropoxy, n-butoxy, sec-butoxy, isobutoxy and tert-butoxy." the C1-C2Alkoxy ", " C1-C3
Alkoxy " and " C2-C4Alkoxy " respectively refers to C1-C4Specific reality in alkoxy containing 1-2,1-3 and 2-4 carbon atom
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
The complex or aggregation that a or multiple solvent molecules are formed, the solvent are pharmaceutically acceptable solvent, such as organic molten
Agent (such as methanol, ethyl alcohol, 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%)2SO4Aqueous solution.
During preparing Oxiracetam using Oxiracetam acid, the esterification of Oxiracetam acid is a reversible reaction,
Because reacting the presence of the water generated, reaction process cannot be pushed ahead, so that reaction not can be carried out completely.The prior art is usual
It is reacted with ethyl alcohol with Oxiracetam acid, and using the azeotropic principles of water and hexamethylene equal solvent, by reflux condensation mode, by water
It is separated from reaction system.But ethyl alcohol it is close with the boiling point of hexamethylene (boiling point of ethyl alcohol be 78.4 DEG C, the boiling point of hexamethylene
It is 80.7 DEG C), when being flowed back, ethyl alcohol, hexamethylene and water can be distilled simultaneously.Simultaneously as what esterification generated
Water is less, and water generated had both dissolved each other with ethyl alcohol, can also dissolve each other with hexamethylene, so shape between ethyl alcohol, hexamethylene and water
At uniform solution, clearly interface can not be formed.Therefore, after condensing, water is again for the steam containing ethyl alcohol, hexamethylene and water
It is brought back reaction system, cannot be effectively separated out, influences esterification process, and then influence the total recovery of product.
The present inventor has obtained a kind of side for preparing Oxiracetam of improvement by in-depth study and creative labor
Method, the method have that the total recovery of product is high, the reaction time is short, purifying is convenient, at low cost, stable product quality and/or examination
The advantages that agent easy recycling and reusing, thus provide following inventions:
In one aspect, the present invention provides a kind of sides for preparing Oxiracetam or its pharmaceutically acceptable solvate
Method comprising step 1: make Oxiracetam acid and compound R-CH2- OH reaction, generates the chemical combination with structure shown in formula (I)
Object；
Wherein, R is the phenyl, benzyl or condensed-nuclei aromatics base being optionally substituted with a substituent.
In a preferred embodiment, the phenyl, benzyl or condensed-nuclei aromatics base by it is one or more (such as 2,
3,4 or 5) replaced substituent group.
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 naphthalene.
In a preferred embodiment, the substituent group is selected from alkyl (such as C1-C4Alkyl), halogen (such as fluorine,
Chlorine, bromine or iodine) and alkoxy (such as C1-C4Alkoxy).
In a preferred embodiment, the alkyl is selected from methyl and ethyl.
In a preferred embodiment, the alkoxy is selected from methoxyl group and ethyoxyl.
In a preferred embodiment, R is phenyl, benzyl, naphthalene (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, the quality of the solvent is 5-10 times of Oxiracetam acid quality, 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
It carries out under the conditions；Preferably, the catalyst is acid (such as H2SO4Or 4- toluenesulfonic acid) 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 molar ratio of the catalyst and 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.
In a preferred embodiment, R-CH2The molar ratio of-OH and Oxiracetam acid is 2-5:1；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
Lower progress 4-5 hours.
In a preferred embodiment, the step 1 includes step 1a: will contain Oxiracetam acid, compound R-
CH2The mixture of-OH and solvent is heated to flowing back.
In a preferred embodiment, the step 1 further includes step 1b: in Oxiracetam acid and compound R-
CH2While-OH reacts, the water that reaction is generated is removed.
In a preferred embodiment, by the azeotropic of solvent and water, the water that reaction is generated is removed.Preferably,
Selected solvent is hexamethylene or toluene, more preferably hexamethylene.
In a preferred embodiment, it will be reacted using water segregator (or oil water separator) as shown in Fig. 1
The water of generation removes.As shown, the water segregator includes first the 1, second opening 2 of opening, accommodating space 3, pipeline 4 and piston
5.First opening 1 is located at the lower end of pipeline 4, for connecting reaction vessel.Second opening 2 is located at the upper end of accommodating space 3, is used for
Connect condensing unit.Accommodating space 3 is column, for containing condensed liquid.Pipeline 4 is bending, the upper end and accommodating
The side wall in space 3 is connected, and communicates with accommodating space 3.Piston 5 is located at the lower end of accommodating space 3, for condensed liquid to be discharged
Body.
In a preferred embodiment, the reaction vessel for being connected to the first opening 1 is heated in closure piston 5,
Enter the steam comprising solvent and water in water segregator from reaction vessel by the first opening 1, then through pipeline 4 and the second opening 2
Into condensing unit, condensation becomes liquid.Condensed liquid flows into accommodating space 3.The solvent is not soluble in water or slightly soluble
Yu Shui, and density is less than water, and therefore, in accommodating space 3, solvent and water can form two layers with clear interface,
In, the solvent builds up to certain altitude and is flowed into reaction vessel by pipeline 4 and the first opening 1 on upper layer；Water is under
Layer, operator can open piston 5, water are discharged.
In a preferred embodiment, the step 1 further includes step 1c: to the change with structure shown in formula (I)
Object is closed to be separated and/or purified；Preferably, using extraction to the compound with structure shown in formula (I) carry out separation and/or
Purifying.
In a preferred embodiment, the step 1 further includes step 1d: recycling unreacted R-CH2-OH；It is excellent
Selection of land recycles unreacted R-CH using rectifying or vacuum distillation2-OH
In the present invention, with R-CH2- OH replaces ethyl alcohol in the prior art, reacts with Oxiracetam acid.In esterification
At a temperature of, R-CH2- OH will not be distilled out of together with hexamethylene and water.Therefore, the steam containing hexamethylene and water is in condensation
Afterwards, interface can be formed in water segregator clearly two layers, so that water is easy to be removed.Since method of the invention can be held
It is continuous, remove moisture in time, the process for being conducive to esterification is pushed ahead, thus reaction can carry out completely, and can be with
Greatly shorten the reaction time.
On the other hand, in the prior art, the ethyl ester compound generated by ethyl alcohol and Oxiracetam acid, has biggish pole
Property, cause to handle after the reaction, needs to extract for more than ten a hours with tetrahydrofuran solution with continuous extraction, it could be by ethyl ester
Compound extracts.And in the method for the invention, the compound of the structure as shown in formula (I) larger, hydrophobicity with volume
Strong R group, so the polarity of the ester generated is also much smaller than Oxiracetam acetoacetic ester, in post-processing, it is easy to from aqueous solution
In be extracted out, save time and the energy.In addition, the compound with the structure as shown in formula (I) can be shown under ultraviolet light
Color, therefore in the esterification reaction, process monitoring is carried out using ultraviolet lamp with can be convenient and purity is observed.
In the present invention, it is preferred to which the method also includes steps 2: make to have 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 the following steps are included:
Step 2a: the solution containing the compound with structure shown in formula (I) is cooled to -5 DEG C -0 DEG C；Preferably, institute
Stating solution is 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)3It is reacted under warm 88-92 DEG C (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 further includes step 2d: after step 2c, recycling ammonia.Example
Such as, the step 2d includes: that reaction mixture is cooling (for example, being cooled to room temperature), is passed through air-flow (for example, air stream), blows
Unreacted ammonia out.
In a preferred embodiment, the step 2 further includes step 2e: isolating Oxiracetam.For example, described
Step 2e includes: by compound and NH with structure shown in formula (I)3Mixture after reaction is cooling (for example, being cooled to 0 DEG C -5
DEG C), stirring makes the Oxiracetam of solid that (preferably, stirring carries out one hour) be precipitated, is separated Oxiracetam by filtering.
Preferably, the step 2e is carried out after step 2d.
In a preferred embodiment, the purity for the Oxiracetam isolated 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 further includes step 2f: the R-CH that recycling reaction generates2-OH；
Preferably, the R-CH generated using rectifying or vacuum distillation recycling reaction2-OH。
In the present invention, with R-CH2- OH is reacted with Oxiracetam acid, the ester of generation with NH3Reaction in have it is very high
Reactivity.In contrast, certain alcohol compounds (such as tert-butyl alcohol) although have boiling point more higher than ethyl alcohol, its
The ester reacted with Oxiracetam acid, with NH3Reactivity it is lower, thus be unable to get target product Oxiracetam.By
It can develop the color under ultraviolet light in the compound with the structure as shown in formula (I), therefore, can use ultraviolet lamp and easily monitor instead
It answers, judges when reaction is completed.In addition, since the target compound Oxiracetam of reaction is solid, and the by-product R- generated
CH2- OH is liquid, and by-product can be separated easily with target compound.Furthermore for example, by vacuum distillation or essence
It evaporates, R-CH2- OH can be convenient from mother liquor and separates and recovers in high yield, obtains the R-CH of high-purity2- OH is used for next round
Reaction.The waste of material can be reduced in this way, and the reaction process of Creating Green chemistry reduces environmental pollution, and drop significantly
Low production cost.
In the present invention, it is preferred to which the method also includes steps 3: carrying out polishing purification to Oxiracetam.
In a preferred embodiment, the step 3 include: by Oxiracetam existing for the active carbon under the conditions of into
Row reflux.
In a preferred embodiment, the step 3 the following steps are included:
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) obtains Oxiracetam solution to assist dissolving；
Step 3b: active carbon is added into the Oxiracetam solution that step 3a is obtained, it is preferable that the quality of active 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: the solution containing Oxiracetam and active 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 active carbon is filtered while hot；With
Step 3e: being concentrated and cooled down to the obtained filtrate of step 3d, and Oxiracetam crystal is precipitated.
In the present invention, it is preferred to the described method comprises the following steps 1, step 2 and step 3:
Step 1: making Oxiracetam acid and compound R-CH2- OH reaction, generates the compound with structure shown in formula (I)；
Wherein, R is phenyl, benzyl, naphthalene (such as betanaphthyl) or 2,4- Dimethoxyphenyl；
In the reaction, R-CH2The molar ratio of-OH and Oxiracetam acid is 2-5:1；The reaction is molten with hexamethylene
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
It is at least 98% concentrated sulfuric acid) it is catalyst, H2SO4With the molar ratio of Oxiracetam acid be 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 the following steps are included:
Step 1a: Oxiracetam acid, compound R-CH will be contained2The mixture of-OH and solvent is heated to flowing back；
Step 1b: it while reacting progress, is removed using the water that water segregator generates reaction；
Step 1c: after reaction, by extraction to the compound with structure shown in formula (I) carry out separation and/or it is pure
Change；
Step 1d: unreacted R-CH is recycled using vacuum distillation2-OH。
Step 2: making the compound and NH with structure shown in formula (I)3Reaction generates Oxiracetam and R-CH2-OH；
The step 2 the following steps are included:
Step 2a: the ethanol solution of the compound with 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
It answers 7-16 hours (such as 7-10 hours, 10-13 hours or 13-16 hours)；
Step 2d: after step 2c, unreacted ammonia is recycled；
Step 2e: cooling to the mixture after reaction after step 2d, the Oxiracetam of solid is precipitated in stirring, leads to
Filtering separates Oxiracetam；
Step 2f: the R-CH generated using rectifying or vacuum distillation recycling reaction2-OH。
Step 3: polishing purification is carried out to Oxiracetam；
The step 3 the following steps are included:
Step 3a: the Oxiracetam that step 2 is obtained is soluble in water, and the mass ratio of water and Oxiracetam is 2:1-4:1 (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 Oxiracetam aqueous solution；
Step 3b: active carbon being added into the Oxiracetam aqueous solution that step 3a is obtained, and the quality of active 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: it heats, flows back containing the solution of Oxiracetam and active carbon in step 3b；
Step 3d: after reflow, the solution containing Oxiracetam and active carbon is filtered while hot；
Step 3e: being concentrated and cooled down to the obtained filtrate of step 3d, and Oxiracetam crystal is precipitated.
In a preferred embodiment, the total recovery of step 1, step 2 and step 3 is 65%-100%, such as
65%-70%, 70%-75%, 75%-80%, 80%-85%, 85%-90%, 90%-95% or 95%-100%.It is described
Total recovery is multiplied to obtain by the yield of step 1, step 2 and step 3.
In the present invention, it is preferred to which the Oxiracetam acid is to be reacted by glycine with 4- chloro-3-hydroxyl ethyl butyrate
It obtains.
In a preferred embodiment, the glycine and 4- chloro-3-hydroxyl ethyl butyrate are reacted in alkaline ring
It is carried out in border (such as under the conditions of sodium hydroxide is existing).
On the other hand, the compound the present invention provides one kind with the structure as shown in formula (I),
Wherein, R is the phenyl, benzyl or condensed-nuclei aromatics base being optionally substituted with a substituent.
In a preferred embodiment, the phenyl, benzyl or condensed-nuclei aromatics base by it is one or more (such as 2,
3,4 or 5) replaced substituent group.
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 naphthalene.
In a preferred embodiment, the substituent group is selected from alkyl (such as C1-C4Alkyl), halogen (such as fluorine,
Chlorine, bromine or iodine) and alkoxy (such as C1-C4Alkoxy).
In a preferred embodiment, the alkyl is selected from methyl and ethyl.
In a preferred embodiment, the alkoxy is selected from methoxyl group and ethyoxyl.
In a preferred embodiment, R is phenyl, benzyl, naphthalene (such as betanaphthyl) or 2,4- dimethoxy benzene
Base.
On the other hand, the present invention provides the compounds as described above with the structure as shown in formula (I) to be used to prepare
The purposes of Oxiracetam or its pharmaceutically acceptable solvate.
On the other hand, the present invention provides R-CH2- OH is used to prepare Oxiracetam or its pharmaceutically acceptable solvation
The purposes of object, wherein R is the phenyl, benzyl or condensed-nuclei aromatics base being optionally substituted with a substituent.
In a preferred embodiment, the phenyl, benzyl or condensed-nuclei aromatics base by it is one or more (such as 2,
3,4 or 5) replaced substituent group.
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 naphthalene.
In a preferred embodiment, the substituent group is selected from alkyl (such as C1-C4Alkyl), halogen (such as fluorine,
Chlorine, bromine or iodine) and alkoxy (such as C1-C4Alkoxy).
In a preferred embodiment, the alkyl is selected from methyl and ethyl.
In a preferred embodiment, the alkoxy is selected from methoxyl group and ethyoxyl.
In a preferred embodiment, R is phenyl, benzyl, naphthalene (such as betanaphthyl) or 2,4- dimethoxy benzene
Base.
Beneficial effect
The method for preparing Oxiracetam or its pharmaceutically acceptable solvate of the invention, has the advantages that
One or more of:
(1) in the method for the present invention, R-CH is utilized2- OH and Oxiracetam acid carry out esterification, can continue, in time
Except the water that dereaction generates, the process for being conducive to esterification is pushed ahead, so that reaction can carry out completely, and can be contracted significantly
Short reaction time.
(2) in method of the invention, the product generated by esterification, in post-processing, it is easy to be extracted out, save
Time and the energy are saved.
(3) in the present invention, with R-CH2- OH is reacted with Oxiracetam acid, with the structure as shown in formula (I) of generation
Compound, subsequent reactions (such as with NH3Reaction) in have very high reactivity, be conducive to improve product yield.
(4) compound with the structure as shown in formula (I) can develop the color under ultraviolet light, therefore in the reaction, can be convenient
Ground monitors reaction process, and the purity of observation product using ultraviolet lamp.
(5) with the compound and NH of the structure as shown in formula (I)3Reaction in, by-product R-CH2- OH is liquid, can be with
Easily separated with target compound.Also, unreacted R-CH either in step 12It is reacted in-OH or step 2
The by-product R-CH of generation2- OH can separate and recover conveniently and in high yield from mother liquor, obtain the R-CH of high-purity2-
OH, the reaction for next round.The waste of material can be reduced in this way, and it is dirty to reduce environment for the reaction process of Creating Green chemistry
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 those skilled in the art
Member will be understood that following drawings and embodiment are merely to illustrate the present invention, and should not be taken as limiting the scope of the invention.Attached drawing and
The person that is not specified actual conditions in embodiment, carries out according to conventional conditions or manufacturer's recommended conditions.Agents useful for same or instrument are not
Production firm person is indicated, being can be with conventional products that are commercially available.
Detailed description of the invention
Fig. 1 shows the water segregator (or oil water separator) that the present invention uses, and is used to react the water generated and removes.
As shown, the water segregator includes first the 1, second opening 2 of opening, accommodating space 3, pipeline 4 and piston 5.First opening 1
In the lower end of pipeline 4, for connecting reaction vessel.Second opening 2 is located at the upper end of accommodating space 3, for connecting condensing unit.
Accommodating space 3 is column, for containing condensed liquid.Pipeline 4 is bending, the side wall phase of the upper end and accommodating space 3
Even, it and is communicated with accommodating space 3.Piston 5 is located at the lower end of accommodating space 3, for condensed liquid to be discharged.
The method for preparing Oxiracetam of synthesis example and embodiment 1-5 is carried out according to following reaction route
Synthesis example synthesizing oxiracetam is sour (compound 1)
Glycine (50 grams) is suspended in 200 milliliters of water, is vigorously stirred, is heated to 80 DEG C, while to the sweet ammonia
The aqueous solution (10mol/L, 121 milliliters) of 4- chloro-3-hydroxyl ethyl butyrate (100 grams) and sodium hydroxide is added dropwise in sour suspension, partly
It is added dropwise in hour, later, 80 DEG C are reacted 10 hours.It is examined through thin-layer chromatography, reaction is completed, and a brown solution, ice bath are obtained
It is cooling lower be added dropwise concentrated hydrochloric acid to pH be 2, with active carbon decoloring.Filtrate is concentrated to dryness through rotary evaporation, with the mixed of ethyl alcohol and methanol
Bonding solvent (volume ratio 1:1) crystallization, obtains the product of 81 grams of White crystals, is that Oxiracetam is sour (compound 1), yield
84.6%.
Embodiment 1
Step 1 synthesizes compound 2 (R is phenyl)
By compound 1 (79.5g, 0.5mol), benzyl alcohol (162g, 1.5mol), 2.7 milliliters of mass fractions be 98% it is dense
Sulfuric acid (0.05mol H2SO4) and 780 milliliters of hexamethylene be placed in the reaction flask equipped with water segregator (as shown in Fig. 1), stir
While, heating reflux reaction 5 hours.The water separated is discarded, reaction solution is concentrated to dryness, recycles hexamethylene.It is added 300 milliliters
Water, then powdered sodium bicarbonate is added while stirring, adjusting pH value is 7~8.Twice with petroleum ether extraction, petroleum ether extraction
Layer is concentrated through vacuum distillation, and the complete benzyl alcohol of recycling unreacted, remaining water phase uses the mixing of ethyl acetate and tetrahydrofuran again
Solvent (volume ratio 1:1) extracts three times.Combining extraction liquid, it is dry with anhydrous sodium sulfate, light yellow oil, weight are obtained after concentration
116 grams.It is not purified, it is directly used in and reacts in next step.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 2 synthesizing oxiracetam
In autoclave, compound 2 (R is phenyl) is dissolved in 1000 milliliters of dehydrated alcohol, is cooled to -5 DEG C, is passed through dry
Dry ammonia is extremely saturated, re-closed to be heated to 90 DEG C, is reacted 7 hours.It is cooled to room temperature, is passed through air and blows the complete ammonia of unreacted
Out, and ammonia is recycled.It is cooled to -5 DEG C, stirring and crystallizing one hour again.Filtering, filtrate are concentrated to dryness, and water is added, is extracted with petroleum ether
It takes.Extract liquor is through drying, vacuum distillation recycling benzyl alcohol, then by the benzyl alcohol redistillation of recycling, and purity, can be with up to 98% or more
It is continued to use in the test of next group.Filter cake twice, obtains off-white color mealy crystal Oxiracetam with cold ethanol washing.
Step 3 is refined and is purified to Oxiracetam
The resulting crystal of step 2 is soluble in water, active carbon is added, is heated to 50 DEG C, decolourizes 1 hour.It filters, filters while hot
Liquid vacuum distillation concentration, crystallization obtain white powder crystal Oxiracetam, weigh 60 grams.Steps 1 and 2 and 3 total recovery be 76%.It produces
The HPLC purity of object 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 aggravating 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 synthesizes 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% it is dense
Sulfuric acid (0.05mol H2SO4) and 780 milliliters of hexamethylene be placed in the reaction flask equipped with water segregator (as shown in Fig. 1), stir
While, heating reflux reaction 4 hours.The water separated is discarded, reaction solution is concentrated to dryness, recycles hexamethylene.It is added 300 milliliters
Water, then powdered sodium bicarbonate is added while stirring, adjusting pH value is 7~8.Twice with petroleum ether extraction, petroleum ether extraction
Layer is concentrated through vacuum distillation, the complete benzyl carbinol of recycling unreacted.Remaining water phase uses the mixing of ethyl acetate and tetrahydrofuran again
Solvent (volume ratio 1:1) extracts three times.Combining extraction liquid, it is dry with anhydrous sodium sulfate, light yellow oil is obtained after concentration.Not
It is purified, it is directly used in and reacts in next step.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 2 synthesizing oxiracetam
In autoclave, compound 2 (R is benzyl) is dissolved in 1000 milliliters of dehydrated alcohol, is cooled to -5 DEG C, is passed through dry
Dry ammonia is extremely saturated, re-closed to be heated to 90 DEG C, is reacted 7 hours.It is cooled to room temperature, is passed through air and blows the complete ammonia of unreacted
Out, and ammonia is recycled.It is cooled to -5 DEG C, stirring and crystallizing one hour again.Filtering, filtrate are concentrated to dryness, and water is added, is extracted with petroleum ether
It takes.Extract liquor is through drying, vacuum distillation recycling benzyl carbinol, then by the benzyl carbinol redistillation of recycling, and purity, can be with up to 98% or more
It is continued to use in the test of next group.Filter cake twice, obtains off-white color mealy crystal Oxiracetam with cold ethanol washing.
Step 3 is refined and is purified to Oxiracetam
Step 2 gained crystal is soluble in water, active carbon is added, is heated to 50 DEG C, decolourizes 1 hour.Filtering, filtrate decompression
Distillation and concentration, crystallization, obtains white powder crystal Oxiracetam, weighs 59 grams.Steps 1 and 2 and 3 total recovery be 75%.Product
HPLC purity reaches 99.67%, and the content of Oxiracetam acid is less than 0.05%.
Embodiment 3
Step 1 synthesizes compound 2 (R is 2,4- Dimethoxyphenyl)
By compound 1 (79.5g, 0.5mol), 2,4- 3,5-dimethoxybenzoic alcohols (252g, 1.5mol), 2.7 milliliters of quality point
The concentrated sulfuric acid (the 0.05mol H that number is 98%2SO4) and 780 milliliters of hexamethylene be placed in equipped with water segregator (as shown in Fig. 1)
In reaction flask, while stirring, heating reflux reaction 4 hours.The water separated is discarded, by reaction solution concentration distillation to dry, recycling
Hexamethylene.200 milliliters of water are added, powdered sodium bicarbonate is added while stirring, adjusting pH value is 7~8.With petroleum ether extraction
Twice, petroleum ether extraction layer is concentrated through vacuum distillation, complete 2, the 4- 3,5-dimethoxybenzoic alcohol of recycling unreacted.Remaining water phase is again
It is extracted three times with the mixed solvent (volume ratio 1:1) of ethyl acetate and tetrahydrofuran.Combining extraction liquid, it is dry with anhydrous sodium sulfate
It is dry, light yellow oil is obtained after concentration.It is not purified, it is directly used in and reacts in next step.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 2 synthesizing oxiracetam
In autoclave, compound 2 (R 2,4- Dimethoxyphenyl) is dissolved in 1000 milliliters of dehydrated alcohol, it is cold
To -5 DEG C, dry ammonia is passed through to saturation, re-closed to be heated to 90 DEG C, reaction 7 hours.It is cooled to room temperature, being passed through air will not
Reacted ammonia blowout, and recycle ammonia.It is cooled to -5 DEG C, stirring and crystallizing one hour again.Filtering, filtrate are concentrated to dryness, and are added
Water, with petroleum ether extraction.Extract liquor is through drying, vacuum distillation recycling benzylalcohol, then by the benzylalcohol redistillation of recycling, and purity is up to 98%
More than, it can be continued to use in the test of next group.Filter cake twice, obtains off-white color mealy crystal Aura west with cold ethanol washing
It is smooth.
Step 3 is refined and is purified to Oxiracetam
Step 2 gained crystal is soluble in water, active carbon is added, is heated to 50 DEG C, decolourizes 1 hour.Filtering, filtrate decompression
Distillation and concentration, crystallization, obtains white powder crystal Oxiracetam, weighs 61 grams.Steps 1 and 2 and 3 total recovery be 77%.Product
HPLC purity reaches 99.72%, and the content of Oxiracetam acid is less than 0.05%.
Embodiment 4
Step 1 synthesizes compound 2 (R is betanaphthyl)
By compound 1 (79.5g, 0.5mol), β-naphthalene methanol (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 flask equipped with water segregator (as shown in Fig. 1),
While stirring, heating reflux reaction 4 hours.The water separated is discarded, reaction solution is concentrated to dryness, recycles hexamethylene.It is added 200
Milliliter water, is added powdered sodium bicarbonate while stirring, and adjusting pH value is 7~8.Twice with petroleum ether extraction, petroleum ether extracts
Layer is taken to be concentrated through vacuum distillation, the complete β-naphthalene methanol of recycling unreacted.Remaining water phase uses ethyl acetate and tetrahydrofuran again
Mixed solvent (volume ratio 1:1) extracts three times.Combining extraction liquid, it is dry with anhydrous sodium sulfate, faint yellow oily is obtained after concentration
Object.It is not purified, it is directly used in and reacts in next step.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 2 synthesizing oxiracetam
In autoclave, compound 2 (R is betanaphthyl) is dissolved in 1000 milliliters of dehydrated alcohol, is cooled to -5 DEG C, is passed through
Dry ammonia is extremely saturated, re-closed to be heated to 90 DEG C, is reacted 7 hours.It is cooled to room temperature, is passed through the air ammonia that unreacted is complete
Blowout, and recycle ammonia.It is cooled to -5 DEG C, stirring and crystallizing one hour again.Filtering, filtrate are concentrated to dryness, and water is added, is extracted with petroleum ether
It takes.Extract liquor merges β-naphthalene methanol that step 1 recycles through drying, vacuum distillation recycling β-naphthalene methanol, and rectifying obtains purity and reaches
98% or more β-naphthalene methanol can be continued to use in the test of next group.Filter cake twice, obtains off-white color with cold ethanol washing
Mealy crystal Oxiracetam.
Step 3 is refined and is purified to Oxiracetam
Step 2 gained crystal is soluble in water, active carbon is added, is heated to 50 DEG C, decolourizes 1 hour.Filtering, filtrate decompression
Distillation and concentration, crystallization, obtains white powder crystal Oxiracetam, weighs 60.3 grams.Steps 1 and 2 and 3 total recovery be 76%.Product
HPLC purity reaches 99.65%, and the content of Oxiracetam acid is less than 0.05%.
Although a specific embodiment of the invention has obtained detailed description, those skilled in the art will appreciate that root
According to all introductions having disclosed, details can be carry out various modifications and be changed, and these change in guarantor of the invention
Within the scope of shield.Full scope of the invention is given by the appended claims and any equivalents thereof.
Claims (40)
1. a kind of method for preparing Oxiracetam comprising
Step 1: making Oxiracetam acid and compound R-CH2- OH reaction, generates the compound with structure shown in formula (I)；
Step 2: making the compound and NH with structure shown in formula (I)3Reaction generates Oxiracetam and R-CH2-OH；
Wherein, R is phenyl, benzyl or the naphthalene optionally replaced by 1 or 2 substituent groups；
The substituent group is selected from C1-C4Alkyl, fluorine, chlorine, bromine, iodine and C1-C4Alkoxy.
2. method of claim 1, the C1-C4Alkyl is selected from methyl and ethyl.
3. method of claim 1, the C1-C4Alkoxy is selected from methoxyl group and ethyoxyl.
4. method of claim 1, R is phenyl, benzyl, betanaphthyl or 2,4- Dimethoxyphenyl.
5. the method for claim 1 wherein the Oxiracetam acid and compound R-CH2The reaction of-OH is with hexamethylene or toluene
For solvent.
6. method for claim 5, the quality of the solvent is 5-10 times of Oxiracetam acid quality.
7. method of claim 1, the Oxiracetam acid and compound R-CH2Under the conditions of the reaction of-OH is existing for the catalyst
It carries out.
8. method for claim 7, the catalyst is acid or storng-acid cation exchange resin.
9. method for claim 8, the catalyst is H2SO4Or 4- toluenesulfonic acid.
10. the molar ratio of method for claim 7, the catalyst and Oxiracetam acid is 1:5-1:15.
11. method of claim 1, R-CH2The molar ratio of-OH and Oxiracetam acid is 2-5:1.
12. method of claim 1, the Oxiracetam acid and compound R-CH2The outer temperature of the reaction of-OH is 88-95 DEG C.
13. method of claim 1, the Oxiracetam acid and compound R-CH2The reaction of-OH carries out 4-5 under reflux conditions
Hour.
14. the method for claim 1 wherein the step 1 includes step 1a: Oxiracetam acid, compound R-CH will be contained2-
The mixture of OH and solvent is heated to flowing back.
15. the method for claim 14, the step 1 further includes step 1b: in Oxiracetam acid and compound R-CH2- OH reaction
While, the water that reaction is generated removes.
16. the method for claim 15, by the azeotropic of solvent and water, the water that reaction is generated is removed.
17. the method for claim 16, the solvent is hexamethylene or toluene.
18. the method for claim 14, the step 1 further includes step 1c: being carried out to the compound with structure shown in formula (I)
Separation and/or purifying.
19. the method for claim 18 is separated and/or is purified to the compound with structure shown in formula (I) using extraction.
20. the method for claim 14, the step 1 further includes step 1d: recycling unreacted R-CH2-OH。
21. the method for claim 20 recycles unreacted R-CH using rectifying or vacuum distillation2-OH。
22. method of claim 1, the step 2 the following steps are included:
Step 2a: the solution containing the compound with structure shown in formula (I) is cooled to -5 DEG C -0 DEG C；
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)3Temperature is to react 7-16 hours at 88-92 DEG C outside.
23. the method for claim 22, wherein the solution containing the compound with structure shown in formula (I) is ethanol solution.
24. the method for claim 22, the step 2 further includes step 2d: after step 2c, recycling ammonia.
25. the method for claim 24, the step 2 further includes step 2e: isolating Oxiracetam.
26. the method for claim 25, the step 2e is carried out after step 2d.
27. the method for claim 25, the purity for the Oxiracetam isolated is at least 90%.
28. the method for claim 22, the step 2 further includes step 2f: the R-CH that recycling reaction generates2-OH。
29. the method for claim 28, the R-CH generated using rectifying or vacuum distillation recycling reaction2-OH。
30. method of claim 1, the method also includes steps 3: carrying out polishing purification to Oxiracetam.
31. the method for claim 30, the step 3 include: by Oxiracetam existing for the active carbon under the conditions of flow back.
32. the method for claim 30, the step 3 the following steps are included:
Step 3a: Oxiracetam is dissolved in solvent, obtains Oxiracetam solution；
Step 3b: active carbon is added into the Oxiracetam solution that step 3a is obtained；
Step 3c: the solution containing Oxiracetam and active carbon is heated, is flowed back；
Step 3d: after reflow, the solution containing Oxiracetam and active carbon is filtered while hot；With
Step 3e: being concentrated and cooled down to the obtained filtrate of step 3d, and Oxiracetam crystal is precipitated.
33. the method for claim 32, the solvent in step 3a is water.
34. the method for claim 32, in step 3a, the mass ratio of the solvent and Oxiracetam is 2:1-4:1.
35. the method for claim 32, in step 3a, the mixture containing Oxiracetam and solvent is heated molten to assist
Solution, obtains Oxiracetam solution.
36. the method for claim 32, in step 3b, the quality of active carbon is 0.15-0.5 times of Oxiracetam quality.
37. method of claim 1 the described method comprises the following steps 1, step 2 and step 3:
Step 1: making Oxiracetam acid and compound R-CH2- OH reaction, generates the compound with structure shown in formula (I)；
Wherein, R is phenyl, benzyl, naphthalene or 2,4- Dimethoxyphenyl；
In the reaction, R-CH2The molar ratio of-OH and Oxiracetam acid is 2-5:1；The reaction is using hexamethylene as solvent, hexamethylene
The quality of alkane is 5-10 times of Oxiracetam acid quality；The reaction is using the concentrated sulfuric acid as catalyst, H2SO4With Oxiracetam acid
Molar ratio is 1:5-1:15；The outer temperature of the reaction is 88-95 DEG C；The reaction carries out 4-5 hours under reflux conditions；It is described
The concentrated sulfuric acid refers to H2SO4Mass fraction be at least 90% H2SO4Aqueous solution；
The step 1 the following steps are included:
Step 1a: Oxiracetam acid, compound R-CH will be contained2The mixture of-OH and solvent is heated to flowing back；
Step 1b: it while reacting progress, is removed using the water that water segregator generates reaction；
Step 1c: after reaction, the compound with structure shown in formula (I) is separated and/or is purified by extraction；
Step 1d: unreacted R-CH is recycled using rectifying or vacuum distillation2-OH；
Step 2: making the compound and NH with structure shown in formula (I)3Reaction generates Oxiracetam and R-CH2-OH；
The step 2 the following steps are included:
Step 2a: the ethanol solution of the compound with 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 to react 7-16 hours at 88-92 DEG C outside；
Step 2d: after step 2c, unreacted ammonia is recycled；
Step 2e: cooling to the mixture after reaction after step 2d, stirring is precipitated the Oxiracetam of solid, passed through
Filter separates Oxiracetam；
Step 2f: the R-CH generated using rectifying or vacuum distillation recycling reaction2-OH；
Step 3: polishing purification is carried out to Oxiracetam；
The step 3 the following steps are included:
Step 3a: the Oxiracetam that step 2 is obtained is soluble in water, and the mass ratio of water and Oxiracetam is 4:1-2:1, by water with
The mixture of Oxiracetam is heated to 45-50 DEG C to assist dissolution, obtains Oxiracetam aqueous solution；
Step 3b: active carbon being added into the Oxiracetam aqueous solution that step 3a is obtained, and the quality of active carbon is Oxiracetam matter
0.15-0.5 times of amount；
Step 3c: it heats, flows back containing the solution of Oxiracetam and active carbon in step 3d；
Step 3d: after reflow, the solution containing Oxiracetam and active carbon is filtered while hot；
Step 3e: being concentrated and cooled down to the obtained filtrate of step 3d, and Oxiracetam crystal is precipitated.
38. the method for claim 37, the total recovery of the step 1, step 2 and step 3 is 65%-100%.
39. the method for claim 1 wherein the Oxiracetam acid is anti-by glycine and 4- chloro-3-hydroxyl ethyl butyrate
It should obtain.
40. the method for claim 39, the glycine and 4- chloro-3-hydroxyl ethyl butyrate react in alkaline environment into
Row.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201610081511.XA CN106496089B (en) | 2016-02-05 | 2016-02-05 | A method of preparing Oxiracetam |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201610081511.XA CN106496089B (en) | 2016-02-05 | 2016-02-05 | A method of preparing Oxiracetam |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN106496089A CN106496089A (en) | 2017-03-15 |
| CN106496089B true CN106496089B (en) | 2019-05-21 |
Family
ID=58287204
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201610081511.XA Active CN106496089B (en) | 2016-02-05 | 2016-02-05 | A method of preparing Oxiracetam |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN106496089B (en) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109748837B (en) * | 2018-05-14 | 2021-07-09 | 重庆医药高等专科学校 | Preparation method of 4-hydroxy-2-oxo-1-pyrrolidine acetamide |
Citations (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5276164A (en) * | 1990-06-26 | 1994-01-04 | Lonza Ltd. | Process for the production of 4-hydroxy-2-oxopyrrolidin-1-yl-acetamide |
| CN101121688A (en) * | 2007-09-14 | 2008-02-13 | 南开大学 | Improved method for synthesizing oxiracetam |
| CN101575309A (en) * | 2009-04-28 | 2009-11-11 | 中国医药集团总公司四川抗菌素工业研究所 | Method for synthesizing (S)-oxiracetam |
| CN102531990A (en) * | 2011-12-29 | 2012-07-04 | 杭州师范大学 | 2-(4- OBzl-2-oxo-2,5-pyrroline-1-yl)-acetamide and synthesis and application thereof |
| CN103058911A (en) * | 2011-10-19 | 2013-04-24 | 重庆福安药业(集团)股份有限公司 | Oxiracetam preparation technology |
| CN104230777A (en) * | 2013-06-19 | 2014-12-24 | 成都百途医药科技有限公司 | Synthetic method of oxiracetam |
| CN105330581A (en) * | 2014-08-07 | 2016-02-17 | 重庆东泽医药科技发展有限公司 | Preparation method for (S)-oxiracetam |
| CN105439936A (en) * | 2014-08-07 | 2016-03-30 | 重庆东泽医药科技发展有限公司 | Oxiracetam preparation method |
-
2016
- 2016-02-05 CN CN201610081511.XA patent/CN106496089B/en active Active
Patent Citations (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5276164A (en) * | 1990-06-26 | 1994-01-04 | Lonza Ltd. | Process for the production of 4-hydroxy-2-oxopyrrolidin-1-yl-acetamide |
| CN101121688A (en) * | 2007-09-14 | 2008-02-13 | 南开大学 | Improved method for synthesizing oxiracetam |
| CN101575309A (en) * | 2009-04-28 | 2009-11-11 | 中国医药集团总公司四川抗菌素工业研究所 | Method for synthesizing (S)-oxiracetam |
| CN103058911A (en) * | 2011-10-19 | 2013-04-24 | 重庆福安药业(集团)股份有限公司 | Oxiracetam preparation technology |
| CN102531990A (en) * | 2011-12-29 | 2012-07-04 | 杭州师范大学 | 2-(4- OBzl-2-oxo-2,5-pyrroline-1-yl)-acetamide and synthesis and application thereof |
| CN104230777A (en) * | 2013-06-19 | 2014-12-24 | 成都百途医药科技有限公司 | Synthetic method of oxiracetam |
| CN105330581A (en) * | 2014-08-07 | 2016-02-17 | 重庆东泽医药科技发展有限公司 | Preparation method for (S)-oxiracetam |
| CN105439936A (en) * | 2014-08-07 | 2016-03-30 | 重庆东泽医药科技发展有限公司 | Oxiracetam preparation method |
Non-Patent Citations (2)
| Title |
|---|
| An Efficient Synthesis of Racemic 4-Hydroxy-2-0x0-1-pyrrolidineacetamide Using Tetramic-Acid Intermediates;David D.等;《HELVETICA CHIMICA ACTA》;19921231;第75卷;第892-900页 |
| 促智药物(S)-奥拉西坦的合成;李坤等;《中国新药杂志》;20111231;第20卷(第19期);第1920-1921,1925页 |
Also Published As
| Publication number | Publication date |
|---|---|
| CN106496089A (en) | 2017-03-15 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN104447600B (en) | A kind of Preparation Method And Their Intermediate impurity of Parecoxib sodium compound, preparation method and application | |
| CN103664912B (en) | A kind of synthesis technique of prucalopride | |
| CN108947861A (en) | The synthetic method of C14H10Cl2NNaO2 | |
| CN105130926A (en) | Preparation method of methylene blue | |
| CN111807973B (en) | Preparation method of vilanterol and salt thereof | |
| CN105949118B (en) | A kind of preparation method of 2- aryl quinoline derivatives | |
| CN101993447A (en) | Method for synthesizing Prasugrel artificially | |
| CN107216298A (en) | A kind of preparation method of butylphenyl phthaleine | |
| CN106496089B (en) | A method of preparing Oxiracetam | |
| CN106279175A (en) | A kind of preparation method of Ertapenem Sodium | |
| CN101260092B (en) | Method for preparing cinepazide maleate | |
| CN103601645A (en) | Preparation method of 1-(phenethylamino) propane-2-alcoholic compounds or salts thereof | |
| CN102766088B (en) | Novel process for synchronizing 4,4'-dibromo-2,2'-bipyridyl | |
| CN107235943A (en) | A kind of preparation method of high purity butylene phthalide | |
| CN108341788A (en) | A kind of mosapride citrate intermediate and purposes | |
| JPS5973579A (en) | Benzofuran or benzothiophene derivative, diuretic agent containing said compound as active constituent and preparation thereof | |
| CN103772189B (en) | Synthesis method of diethylstilbestrol compound methyl pigeon pea ketonic acid A | |
| CN100427460C (en) | Method for synthesis of L-norvaline | |
| CN105646324A (en) | Preparation method of high-purity indole | |
| CN107936045A (en) | A kind of preparation method of high-purity Flurbiprofen known impurities | |
| CN105130972B (en) | Benzoic acid emtricitabine salt, its preparation method and the method for preparing emtricitabine with benzoic acid emtricitabine salt | |
| CN104910113B (en) | Preparation method of hydroxy benzene anhydride | |
| CN106966980A (en) | The preparation method of high-purity Eptazocine intermediate | |
| CN112194581A (en) | Preparation method of flurbiprofen axetil | |
| CN104557666B (en) | Method of synthesizing 3-phthalimide-2-oxobutryaldehyde-1, 2-bis-thiosemicarbazide |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant |