CN107021897A - A kind of method for preparing levo-oxiracetam crystal formation II - Google Patents
A kind of method for preparing levo-oxiracetam crystal formation II Download PDFInfo
- Publication number
- CN107021897A CN107021897A CN201610063991.7A CN201610063991A CN107021897A CN 107021897 A CN107021897 A CN 107021897A CN 201610063991 A CN201610063991 A CN 201610063991A CN 107021897 A CN107021897 A CN 107021897A
- Authority
- CN
- China
- Prior art keywords
- oxiracetam
- levo
- crystal formation
- dissolved
- capillary
- 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.)
- Withdrawn
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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/13—Crystalline forms, e.g. polymorphs
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Epoxy Compounds (AREA)
Abstract
A kind of levo-oxiracetam crystal formation II preparation method, it is specific to be dissolved levo-oxiracetam using organic solvent, then sucked by siphon among capillary, with the one end for capillary of sealing with wax, it is 40~60 DEG C to be positioned over temperature, and humidity is that RH (%) is made to carry out volatilization in 70%~80% air；The present invention opens the route of a brand-new culture levo-oxiracetam monocrystalline, with capillary tube method under the combination of specific solvent and humiture, so that levo-oxiracetam crystal formation II has successfully been made, has greatly promoted the crystal formation of levo-oxiracetam to study.
Description
Technical field
The present invention relates to levo-oxiracetam, and in particular to a kind of method for preparing levo-oxiracetam crystal formation II.
Background technology
Oxiracetam (Oxiracetam) is nootropic agents of new generation, pyrrolidinone compounds (ring GABOB) derivative, pyrrole
La Xitan analogs, can promote Phosphorylcholine and adjacent acyl monoethanolamine synthesis, promote brain metabolism, by blood-brain barrier in specificity
Pivot nerve pathway has stimulation, improves intelligence and memory.To cerebrovascular disease, brain damage, brain tumor (postoperative), intracranial infection, silly
Slow-witted, brain degenerative disease etc. has good efficacy.Draw suitable for diseases such as light moderate vascular dementia, senile dementia and brain traumas
The memory risen and disturbance of intelligence.Oxiracetam was synthesized first by Italian SmithKline than Qie Mu company in 1974, was listed within 1987,
Concentration to memory especially thinking is more preferable than Piracetam, and toxicity is smaller, and research shows the better efficacy of its levo form, left
Revolve Oxiracetam structure as follows：
For levo-oxiracetam is effectively developed into medicine, it is necessary to it is a kind of have easily fabricated and acceptable chemistry and
The solid-state form of physical stability, to promote its processing and circulation to store.For the purity and stability that strengthen compound,
Crystalline solid form generally to be preferred over armorphous form.Presently disclosed levo-oxiracetam crystal formation has tri- kinds of crystal formations of I, II, III,
Wherein crystal formation II has preferable stability.CN102558013A discloses a kind of levo-oxiracetam crystal formation II and its preparation side
Method, levo-oxiracetam by frozen water top wash after crystallization obtain crystal formation II, the crystal formation the θ of angle of diffraction 2 be 10.669,
13.25、13.847、14.198、16.729、17.934、18.746、18.816、20.273、20.413、21.431、21.617、
21.663、23.38、24.324、24.415、26.069、26.107、27.901、28.621、28.925、29.449、29.484、
31.702nd, 36.516,37.685, there is diffraction maximum at 39.721 degree, the left-handed Aura west that the preparation method according to the patent is obtained
Smooth II chiral purities are in 98-99% or so, and wherein R content of isomer is close to 1%.The need in order to meet medical industry, it is necessary to
A kind of method for preparing higher purity levo-oxiracetam II of exploitation.
The content of the invention
It is an object of the invention to provide a kind of method for preparing levo-oxiracetam crystal formation II, this method preparation technology letter
Single, obtained product chiral purity is high.
Technical scheme involved in the present invention is as follows：
A kind of method for preparing levo-oxiracetam crystal formation II, it is characterised in that use following steps：
Levo-oxiracetam is dissolved with organic solvent, then sucked by siphon among capillary, with capillary of sealing with wax
One end of pipe, is positioned over temperature for 40~60 DEG C, and humidity be to be volatilized in the air that RH (%) is 70%~80%, obtained left
Revolve Oxiracetam crystal form II；The organic solvent is tetrahydrofuran, dioxane, n-butanol or propane diols.
The levo-oxiracetam crystal formation II that the present invention is prepared the θ of angle of diffraction 2 be 10.669,13.25,13.847,
14.198、16.729、17.934、18.746、18.816、20.273、20.413、21.431、21.617、21.663、23.38、
24.324、24.415、26.069、26.107、27.901、28.621、28.925、29.449、29.484、31.702、36.516、
37.685th, there is diffraction maximum at 39.721 degree, it is consistent with the crystal formation that CN102558013A is disclosed.
The present invention opens the route of a brand-new culture levo-oxiracetam monocrystalline, with capillary tube method specific molten
Under agent and the cooperation of humiture, so that levo-oxiracetam crystal formation II has successfully been made, levo-oxiracetam has been promoted significantly
The scientific research of crystal formation and industrialized production.
In order to further improve the yield and purity of the present invention, the temperature preferably volatilized in air is 40~50 DEG C, humidity
It is 70%~75% for RH (%).
In order to further improve the purity of the present invention, the purity of raw material levo-oxiracetam of the present invention is more than 99.5%.
In order to ensure the purity of raw material, levo-oxiracetam can first be made by the following method, then pass through capillary
Levo-oxiracetam crystal formation II is made in method under given conditions, is specially：
A kind of method for preparing levo-oxiracetam crystal formation II, it is characterised in that levo-oxiracetam, Ran Houyong is first made
Capillary tube method culture levo-oxiracetam crystal formation II, wherein reaction scheme is：
；Using following steps：
1), first S-4- chloro-3-hydroxyls methyl butyrate is dissolved with ethanol, sodium azide is then added at 70~80 DEG C anti-
Answer and obtain within 2~4 hours intermediate compound I, wherein S-4- chloro-3-hydroxyls methyl butyrate and sodium azide mol ratio are 1：1~2；
2) intermediate compound I is dissolved with DMF, carrying out reduction reaction with hydrogen by catalyst of Metal Palladium obtains intermediate II,
Reaction temperature is 10~25 DEG C, and the reaction time is 6~8 hours；
3) intermediate II is dissolved with DMF, triethylamine is catalyst, reacted 9~12 hours with ethyl chloroacetate, reaction temperature
Spend for 70~80 DEG C；The intermediate II and the mol ratio of ethyl chloroacetate are：1:1~2, intermediate II and the triethylamine
Mol ratio is：1:2~3；
4) intermediate III is dissolved with the tert-butyl alcohol, ring closure reaction is carried out under the conditions of 80~100 DEG C and obtains intermediate compound IV, instead
It is 7~9 hours between seasonable；
5) intermediate compound IV and ammoniacal liquor are reacted 8~14 hours at 20~30 DEG C, obtains levo-oxiracetam crude product, it is described
Intermediate compound IV：The mol ratio of ammonia is intermediate compound IV：Ammonia=1：12~15, in terms of the ammonia in ammonia methanol solution, the ammoniacal liquor
Concentration is 25-28%；
6) levo-oxiracetam crude product is dissolved by heating in water, activated carbon decolorizing is filtered to remove activated carbon, is concentrated under reduced pressure
Water removal, stops concentration when surplus water is adds 2~3 times of products weight, and 0~5 DEG C of sub-cooled crystallization obtains left-handed Aura
It is western smooth；
7) levo-oxiracetam is dissolved with organic solvent, then sucked by siphon among capillary, with hair of sealing with wax
One end of tubule, is positioned over temperature for 40~50 DEG C, and humidity be to be volatilized in the air that RH (%) is 70%~75%, obtained
Levo-oxiracetam crystal formation II；The organic solvent is tetrahydrofuran, dioxane, n-butanol or propane diols.
The concentration of above-mentioned concentrated ammonia liquor is 25-28%.
The present invention uses S-4- chloro-3-hydroxybutanoic acid esters and sodium azide to prepare levo-oxiracetam, line for initiation material
Road is simple, and intermediate and product do not need the impurity for not produced in column chromatography, preparation process and being difficult to removeIn the case where not needing column chromatography, obtained levo-oxiracetam product chemistry purity is through efficient
Liquid phase detection reaches more than 99.5%, then under the cooperation of specific solvent, temperature and humidity, is prepared by capillary tube method
Levo-oxiracetam crystal formation II, optical purity greatly improves levo-oxiracetam crystal formation II product more than 99.9%
Quality.
Brief description of the drawings
Fig. 1 is levo-oxiracetam crystal formation II powder diagram；
Fig. 2 is levo-oxiracetam crystal formation I and crystal formation II differential scanning calorimeter figure (DSC)；
Fig. 3 is levo-oxiracetam crystal formation II infrared spectrum (IR) figure.
Embodiment
The present invention is specifically described below by embodiment, it is necessary to it is pointed out here that be that following examples are only used
It is further described in the present invention, it is impossible to be interpreted as limiting the scope of the invention, person skilled in art can
To make some nonessential modifications and adaptations to the present invention according to the invention described above content.
Embodiment 1
The levo-oxiracetam (20mg) that purity is more than 99.5% is dissolved with tetrahydrofuran (2mL), then passes through siphon
Suck among capillary, with the one end for capillary of sealing with wax, it is 50 DEG C to be positioned over temperature, humidity is the air that RH (%) is 70%
It is middle to be volatilized, levo-oxiracetam crystal formation is made.
Obtained levo-oxiracetam crystal formation is tested by X-ray powder diffraction, as a result such as Fig. 1, diffraction maximum is parsed such as
Following table：
Obtained levo-oxiracetam crystal formation the θ of angle of diffraction 2 be 10.669,13.25,13.847,14.198,
16.729、17.934、18.746、18.816、20.273、20.413、21.431、21.617、21.663、23.38、24.324、
24.415、26.069、26.107、27.901、28.621、28.925、29.449、29.484、31.702、36.516、37.685、
There is diffraction maximum at 39.721 degree, it is consistent with the crystal formation II that CN102558013A is disclosed.
The infrared spectrum (see Fig. 3) that obtained levo-oxiracetam crystal formation II is produced shows absworption peak in following wave number：
3318(cm-1)、3223(cm-1)、2929(cm-1)、2875(cm-1)、1680(cm-1)、1487(cm-1)、1402
(cm-1)、1276(cm-1)、1220(cm-1)、1078(cm-1)、968(cm-1)、943(cm-1)、694(cm-1)、611(cm-1)。
Levo-oxiracetam crystal formation II made from embodiment 1 is subjected to optical purity measure：
Levo-oxiracetam crystal formation II is taken, precision weighs quantity (equivalent to containing levo-oxiracetam 120mg) and puts 100ml amounts
The solution of the 1.2mg containing levo-oxiracetam in every 1ml is made in bottle, plus mobile phase ultrasonic dissolution and constant volume, is used as need testing solution.
Precision measures solution 20ul, injects liquid chromatograph, records chromatogram, calculates unknown miscellaneous by area normalization method
The content of matter.
Determining chromatographic condition used is：
Instrument：Shimadzu LC-2010AHT high performance liquid chromatographs；
Work station title：LC-Solutio；
Chromatographic column：AGOP (4.6 × 100mm, 5 μm)；
Mobile phase:Acetonitrile：Phosphate buffer (pH6.0)=15:85；
Detection wavelength：210nm；
Flow velocity：1ml/min；
35 DEG C of column temperature；
Calculation formula is as follows：
In formula, Ai is the peak area of main ingredient active component levo-oxiracetam；
Σ A are the peak area sum of S- configurations and the oxo-1-pyrrolidine ethanamide of R- isomers 4- hydroxyls -2.
Through three measurements, average, the optical purity for obtaining the levo-oxiracetam crystal formation II of embodiment 1 is 99.93%.
For using capillary tube method carry out levo-oxiracetam crystal formation culture for, different solvents, volatilization temperature with
And the condition such as the humidity of air may cause different results.Such as following comparative example 1-3, air humidity is excessive, can not obtain
To single crystal form, it is levo-oxiracetam crystal formation I that humidity is smaller, volatilization temperature mismatched with humidity may obtain crystal formation I and
Crystal formation II mixture.
Comparative example 1
The levo-oxiracetam (20mg) that purity is more than 99.5% is dissolved with tetrahydrofuran (2mL), then passes through siphon
Suck among capillary, with the one end for capillary of sealing with wax, it is 50 DEG C to be positioned over temperature, humidity is the air that RH (%) is 30%
It is middle to be volatilized, levo-oxiracetam crystal formation is made, the crystal formation 12.500,13.940,15.000,16.540,17.400,
19.320,20.520,20.840,21.980,23.340,25.120,25.840,26.240,27.660,28.100,30.040,
There is characteristic peak under 30.660,31.040,31.780,34.300,35.180,37.060,38.020 and 42.240 degree of 2 θ angles, with
The levo-oxiracetam crystal formation I that CN102249975A is disclosed is identical.
Comparative example 2
The levo-oxiracetam (20mg) that purity is more than 99.5% is dissolved with tetrahydrofuran (2mL), then passes through siphon
Suck among capillary, with the one end for capillary of sealing with wax, it is 50 DEG C to be positioned over temperature, humidity is the air that RH (%) is 90%
It is middle to be volatilized, levo-oxiracetam single crystal form as a result can not be made.
Comparative example 3
The levo-oxiracetam (20mg) that purity is more than 99.5% is dissolved with tetrahydrofuran (2mL), then passes through siphon
Suck among capillary, with the one end for capillary of sealing with wax, it is 80 DEG C to be positioned over temperature, humidity is the air that RH (%) is 70%
It is middle to be volatilized, levo-oxiracetam crystal formation is made, is the mixed of levo-oxiracetam crystal formation I and crystal formation II by Structural Identification
Compound.
Embodiment 2
The levo-oxiracetam (100mg) that purity is more than 99.5% is dissolved with dioxane (5mL), then passes through siphon
Suck among capillary, with the one end for capillary of sealing with wax, it is 40 DEG C to be positioned over temperature, humidity is the air that RH (%) is 75%
It is middle to be volatilized, levo-oxiracetam crystal formation is made, is verified with X powder diffraction method, obtained crystal formation and the crystal formation II of embodiment 1
It is identical, and optical purity is 99.92%.
Embodiment 3
99.5% levo-oxiracetam (80mg) is dissolved with propane diols (10mL), capillary is then sucked by siphon
Central, with the one end for capillary of sealing with wax, it is 60 DEG C to be positioned over temperature, and humidity be RH (%) to be waved in 80% air
Hair, is made levo-oxiracetam crystal formation, is verified with X powder diffraction method, and obtained crystal formation is identical with the crystal formation II of embodiment 1, and
Optical purity is 99.90%.
Embodiment 4
Purity is dissolved by heating for 99.5% levo-oxiracetam (300mg) with n-butanol (10mL), then passes through rainbow
Among suction capillary, with the one end for capillary of sealing with wax, it is 40 DEG C to be positioned over temperature, and humidity is the sky that RH (%) is 70%
Volatilized in gas, levo-oxiracetam crystal formation is made, verified with X powder diffraction method, obtained crystal formation and the crystal formation of embodiment 1
II is identical, and optical purity is 99.93%.
Embodiment 5
(l) preparation of intermediate compound I：
Raw material S-4- chloro-3-hydroxyl methyl butyrate 5g are taken, are added in a single neck bottle, ethanol 10ml is added, stirring is added folded
Sodium nitride 5g, 70~80 DEG C of keeping temperature is reacted 2 hours, and yellow solution is reacted to obtain in stopping.Water 20ml is added, ethyl acetate is used
20ml is extracted, and concentration removes ethyl acetate, obtains yellow oil intermediate compound I.Detected through nuclear-magnetism, intermediate compound I is：1H-NMR
(300MHz,CDCl3):δ1.42-1.73(m,2H)2.76-2.67(AB system,m,2H,),3.31-3.23(AB
system,m,2H),3.75(s,3H),4.40(m,1H),3.70(s,1H).
Intermediate compound I is：
(2) preparation of intermediate II
The intermediate compound I that step (1) is obtained is dissolved in 50ml DMF, is added 10% palladium-carbon catalyst 1g, is passed through hydrogen
Reacted 8 hours at 10 DEG C or so, point plate is shown in that raw material reaction is complete, stops reaction, and concentration removes solvent and obtains pale yellow oil
Intermediate II.Detected through nuclear-magnetism, intermediate II：1H-NMR(300MHz,D2O):δ2.76-2.67(AB system,m,2H,),
3.31-3.23(AB system,m,2H),3.75(s,3H),4.40(m,1H),4.70(bs,3H).13C-NMR(50MHz,
D2O):δ43.7(C-2),48.4(C-4),57.0(OCH,),68.9(C-3),177.5(C-I).
Intermediate II is
(3) preparation of intermediate III
The intermediate II that step (2) is obtained is dissolved in 50ml DMF, at 75 DEG C or so, adds triethylamine (3eq),
There are a large amount of solids to generate, stir five minutes, start that ethyl chloroacetate 9ml (2eq) is added dropwise, dropwise addition process has exothermic phenomenon, be added dropwise
Continue to stir 9 hours after finishing, point plate is shown in that raw material reaction is complete, stops reaction, adds EA (ethyl acetate) 50ml, water 30ml,
Solid is completely dissolved, by water layer solid sodium chloride saturation, separates organic layer, and water layer is extracted twice with EA 20ml, is merged organic
Layer, organic layer washed three times with 2M hydrochloric acid 20ml, merges hydrochloric acid aqueous phase, and organic phase is discarded, aqueous phase with sodium acid carbonate adjust pH to
8, solid sodium chloride saturation, EA 30ml are extracted three times, merge organic phase, and anhydrous magnesium sulfate is dried, and concentration removes solvent and obtains light
Yellow oil, curing at low temperatures obtains intermediate III.Detected through nuclear-magnetism, intermediate III：1H-NMR(300MHz,D2O):δ1.3
(t,3H),2.28-2.53(m,2H),2.58-2.83(m,2H)3.51(s,2H),3.67(s,3H),4.09-4.12(m,3H).
Intermediate III is
(4) preparation of intermediate compound IV
The intermediate III that step (2) the is obtained 50ml tert-butyl alcohols dissolve, and are warming up to 85 DEG C and react 8 hours, obtain one red
Brown solution, point plate is shown in that raw material reaction is complete.Stop reaction, concentration removes the tert-butyl alcohol, add EA (ethyl acetate) dissolvings, filtering
Except desalting, activated carbon decolorizing, concentration remove yellow oil obtains intermediate compound IV.Detected through nuclear-magnetism, intermediate compound IV is：1H-
NMR(300MHz,CDCl3)δ1.280(t,3H),2.38(dd,1H),2.69(dd,1H),3.34(dd,1H),3.77(dd,
lH),3.93(d,lH),4.18(d,1H),4.19(q,2H),4.30(bs,1H),4.50(m,1H).
Intermediate compound IV：
(5) preparation of levo-oxiracetam
The intermediate compound IV that step (4) is obtained adds concentrated ammonia liquor (concentration is 27%) 20ml, is stirred at room temperature 13 hours, puts plate
See that raw material reaction is complete, stop reaction, water removal and ammonia are removed in concentration, obtain yellow oil, add acetone solution grease, plus
Enter a small amount of crystal seed to stir, precipitation solid, a small amount of acetone rinsing bottle wall, -10 DEG C crystallize 5 hours, are filtrated to get off-white color crude product
23.2g, chemical purity 99.0%.
(6) by the dissolving crude product in 100ml water, heating dissolves it, activated carbon decolorizing half an hour, is filtered to remove work
Property charcoal, crystallisation by cooling, 5 DEG C are stood overnight, and next day filters to obtain to be free of in white solid 21.5g, chemical purity 99.5%, end-product
HaveDetected through nuclear-magnetism, levo-oxiracetam：1H-NMR(300MHz,DMSO-d6)δ2.10(d,
1H),2.57(dd,1H),3.69(d,1H),3.88(d,1H),4.10(d,1H),4.31(m,1H),5.25(s,1H),7.13
(s,1H),7.33(s,1H)。
Levo-oxiracetam structural formula is as follows：
(7) levo-oxiracetam crystal formation II preparation：
Levo-oxiracetam (70mg) made from step (5) is dissolved with n-butanol (5mL), hair is then sucked by siphon
Among tubule, with the one end for capillary of sealing with wax, it is 40 DEG C to be positioned over temperature, and humidity is progress in the air that RH (%) is 70%
Volatilization, is made levo-oxiracetam crystal formation, is verified by X powder diffraction, identical with crystal formation II made from embodiment 1, and optics
Purity is 99.92%.
Embodiment 6-8 is made with reference to embodiment 5, partial parameters are according to following operation：
(S)-Oxiracetam chemical purity made from embodiment 6-8 is high, wherein not containingOften
Chemical purity more than 99.5% can be achieved in rule purifying (being handled without column chromatography), as crystal formation of the raw material with reference to embodiment 1
Culture, is successfully made (S)-Oxiracetam crystal form II, and its optical purity is more than 99.90%.
Claims (4)
1. a kind of method for preparing levo-oxiracetam crystal formation II, it is characterised in that use following steps：
Levo-oxiracetam is dissolved with organic solvent, then sucked by siphon among capillary, with capillary of sealing with wax
One end, is positioned over temperature for 40~60 DEG C, and humidity be to be volatilized in the air that RH (%) is 70%~80%, obtained left-handed Austria
La Xitan crystal formations II；The organic solvent is tetrahydrofuran, dioxane, n-butanol or propane diols.
2. the method as described in claim 1, it is characterised in that：The temperature volatilized in the air is 40~50 DEG C, and humidity is
RH (%) is 70%~75%.
3. method as claimed in claim 1 or 2, it is characterised in that：The purity of raw material levo-oxiracetam is more than 99.5%.
4. a kind of method for preparing levo-oxiracetam crystal formation II, it is characterised in that first pass through following route prepare it is left-handed
Oxiracetam, then prepares levo-oxiracetam crystal formation II with capillary tube method；Route is：
；
Using following steps：
1), first S-4- chloro-3-hydroxyls methyl butyrate is dissolved with ethanol, reaction of sodium azide 2 is then added at 70~80 DEG C
Intermediate compound I is obtained within~4 hours, wherein S-4- chloro-3-hydroxyls methyl butyrate and sodium azide mol ratio are 1：1~2；
2) intermediate compound I is dissolved with DMF, carrying out reduction reaction with hydrogen by catalyst of Metal Palladium obtains intermediate II, reacts
Temperature is 10~25 DEG C, and the reaction time is 6~8 hours；
3) intermediate II is dissolved with DMF, triethylamine is catalyst, reacted 9~12 hours with ethyl chloroacetate, reaction temperature is
70~80 DEG C；The intermediate II and the mol ratio of ethyl chloroacetate are：1:1~2, mole of intermediate II and the triethylamine
Than for：1:2~3；
4) intermediate III is dissolved with the tert-butyl alcohol, ring closure reaction is carried out under the conditions of 80~100 DEG C and obtains intermediate compound IV, during reaction
Between be 7~9 hours；
5) intermediate compound IV and ammoniacal liquor are reacted 8~14 hours at 20~30 DEG C, obtains levo-oxiracetam crude product, the centre
Body IV：The mol ratio of ammonia is intermediate compound IV：Ammonia=1：12~15, in terms of the ammonia in ammonia methanol solution, the concentration of the ammoniacal liquor
For 25-28%；
6) levo-oxiracetam crude product is dissolved by heating in water, activated carbon decolorizing is filtered to remove activated carbon, is concentrated under reduced pressure and removes
Water, stops concentration when surplus water is adds 2~3 times of products weight, and 0~5 DEG C of sub-cooled crystallization obtains left-handed Aura west
It is smooth；
7) levo-oxiracetam is dissolved with organic solvent, then sucked by siphon among capillary, with capillary of sealing with wax
One end, be positioned over temperature for 40~50 DEG C, humidity be to be volatilized in the air that RH (%) is 70%~75%, obtained left-handed
Oxiracetam crystal form II；The organic solvent is tetrahydrofuran, dioxane, n-butanol or propane diols.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201610063991.7A CN107021897A (en) | 2016-01-29 | 2016-01-29 | A kind of method for preparing levo-oxiracetam crystal formation II |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201610063991.7A CN107021897A (en) | 2016-01-29 | 2016-01-29 | A kind of method for preparing levo-oxiracetam crystal formation II |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN107021897A true CN107021897A (en) | 2017-08-08 |
Family
ID=59524442
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201610063991.7A Withdrawn CN107021897A (en) | 2016-01-29 | 2016-01-29 | A kind of method for preparing levo-oxiracetam crystal formation II |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN107021897A (en) |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102558013A (en) * | 2011-08-11 | 2012-07-11 | 重庆润泽医疗器械有限公司 | (S)-4-hydroxy-2-oxo-1-pyrrolidine acetamide crystal form II and preparation method 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 |
-
2016
- 2016-01-29 CN CN201610063991.7A patent/CN107021897A/en not_active Withdrawn
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102558013A (en) * | 2011-08-11 | 2012-07-11 | 重庆润泽医疗器械有限公司 | (S)-4-hydroxy-2-oxo-1-pyrrolidine acetamide crystal form II and preparation method 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 |
Non-Patent Citations (1)
| Title |
|---|
| ENGIN SAHIN, ET AL.: "AN EFFICIENT SYNTHESIS OF (R)-GABOB AND OF (±)-GABOB", 《ORGANIC PREPARATIONS AND PROCEDURES INT.》 * |
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 | |
| KR101333620B1 (en) | Crystals of morphinan derivative and process for producing the same | |
| CN103664912B (en) | A kind of synthesis technique of prucalopride | |
| CN102351847B (en) | Industrial method for refining esomeprazole sodium salt | |
| CN107021897A (en) | A kind of method for preparing levo-oxiracetam crystal formation II | |
| JP5460209B2 (en) | Method for purifying 4-amino-5-chloro-2-ethoxy-N-[[4- (4-fluorobenzyl) -2-morpholinyl] methyl] benzamide | |
| CN107021907A (en) | Levo-oxiracetam crystal formation II preparation method | |
| CN107698596A (en) | A kind of synthetic method of Allopurinol | |
| CN107021902A (en) | A kind of levo-oxiracetam crystal formation I preparation method | |
| JP4892821B2 (en) | Epalrestat manufacturing method | |
| CN107021908A (en) | The method for preparing levo-oxiracetam crystal formation II | |
| CN107021913A (en) | A kind of method for preparing levo-oxiracetam crystal formation I | |
| CN107011233A (en) | The method that capillary tube method prepares levo-oxiracetam crystal formation I | |
| CN107021901A (en) | (S)-oxiracetam crystal form II preparation method | |
| CN107021904A (en) | The method for preparing levo-oxiracetam crystal formation II | |
| CN107021911A (en) | A kind of method for preparing levo-oxiracetam crystal formation II | |
| CN107021899A (en) | A kind of method for preparing levo-oxiracetam crystal formation II | |
| CN107021910A (en) | The method for preparing S-oxiracetam crystal formation II | |
| CN107021914A (en) | Levo-oxiracetam crystal formation II preparation method | |
| CN107021900A (en) | A kind of (S)-Oxiracetam crystal form II preparation method | |
| CN109516973A (en) | Substituted uracil compound, preparation method and the usage | |
| CN107011234A (en) | The method that fusion method prepares levo-oxiracetam crystal formation II | |
| CN107021896A (en) | A kind of levo-oxiracetam crystal formation II preparation method | |
| CN107021906A (en) | The method for preparing levo-oxiracetam crystal formation II | |
| CN107021898A (en) | A kind of method that ball-milling method prepares levo-oxiracetam crystal formation II |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| WW01 | Invention patent application withdrawn after publication | ||
| WW01 | Invention patent application withdrawn after publication |
Application publication date: 20170808 |