CN107011232A - The method that ball milling prepares levo-oxiracetam crystal formation II - Google Patents
The method that ball milling prepares levo-oxiracetam crystal formation II Download PDFInfo
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- CN107011232A CN107011232A CN201610064016.8A CN201610064016A CN107011232A CN 107011232 A CN107011232 A CN 107011232A CN 201610064016 A CN201610064016 A CN 201610064016A CN 107011232 A CN107011232 A CN 107011232A
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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
A kind of levo-oxiracetam crystal formation II preparation method, S-4- chloro-3-hydroxyls butyric acid ring pentyl ester and sodium azide is used to prepare the levo-oxiracetam of high-purity for initiation material, then obtained levo-oxiracetam is used as cooperation of the raw material by isopropanol, grinding frequency and milling time in this way, prepare levo-oxiracetam crystal formation II, optical purity greatly improves levo-oxiracetam crystal formation II product quality more than 99.9%.
Description
Technical field
The present invention relates to levo-oxiracetam, and in particular to a kind of ball-milling method prepares levo-oxiracetam crystal formation II side
Method.
Background technology
Oxiracetam (Oxiracetam) is pyrrolidinone compounds (ring GABOB) derivative, and Piracetam analog is big by meaning
Sharp SmithKline was synthesized first than Qie Mu company in 1974, the nootropic agents of new generation of listing in 1987, can promote phosphinylidyne courage
Alkali and adjacent acyl monoethanolamine synthesis, promote brain metabolism, have stimulation to specific central nervous pathway by blood-brain barrier, improve
Intelligence and memory.There is good treatment to cerebrovascular disease, brain damage, brain tumor (postoperative), intracranial infection, dementia, brain degenerative disease etc.
Effect.Research shows the better efficacy of its levo form, and levo-oxiracetam structure is 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 that ball-milling method prepares levo-oxiracetam crystal formation II, this method prepares work
Skill is simple, and obtained product chiral purity is high.
Technical scheme involved in the present invention is as follows：
A kind of method that ball-milling method prepares levo-oxiracetam crystal formation II, using following steps：
Levo-oxiracetam is placed in ball grinder, the ratio for adding 15~20 μ L according to 100mg levo-oxiracetams adds
Enter isopropanol, 40min~90min is then ground with 5~10HZ frequency, levo-oxiracetam crystal formation II is made.
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 selects the cooperation of specific solvent, grinding frequency and milling time by polishing, is successfully made left-handed
Oxiracetam crystal form II, has greatly promoted scientific research and the industrialized production of levo-oxiracetam crystal formation.
In order to improve levo-oxiracetam crystal formation II yield and purity, it is 5~6HZ, milling time preferably to grind frequency
For 60min~80min.
In order to further improve levo-oxiracetam crystal formation II yield and purity, preferred feedstock levo-oxiracetam purity
More than 99.5%.
In order to improve levo-oxiracetam crystal formation II yield and purity, the difficulty of post processing is reduced, preferably by with lower section
Levo-oxiracetam made from method, is then made levo-oxiracetam crystal formation II by above-mentioned polishing.
Specifically, a kind of method that polishing prepares levo-oxiracetam crystal formation II, it is characterised in that using following anti-
Answer route that levo-oxiracetam is made：
；Operating procedure is：
1), first S-4- chloro-3-hydroxyl butyric acid rings pentyl ester is dissolved with cyclohexanol, sodium azide is then added 150~170
Reaction obtains intermediate compound I for 1~2 hour at DEG C, and wherein S-4- chloro-3-hydroxyls butyric acid ring pentyl ester and sodium azide mol ratio are 1：
1.5~3；
2) intermediate compound I is dissolved with methanol, carrying out reduction reaction with hydrogen by catalyst of Metal Palladium obtains intermediate II,
Reaction temperature is 0~20 DEG C, and the reaction time is 10~12 hours；
3) intermediate II is dissolved with methanol, potassium carbonate is catalyst, reacted 5~6 hours with benzyl acetate bromide, reaction temperature
40~60 DEG C of degree；The intermediate II and the mol ratio of benzyl acetate bromide are：1:1.5~2.5, intermediate II and the potassium carbonate
Mol ratio be：1:2~3；
4) intermediate III is dissolved with dimethylbenzene, ring closure reaction is carried out under the conditions of 140~150 DEG C and obtains intermediate compound IV,
Reaction time is 5~7 hours；
5) intermediate compound IV and ammoniacal liquor are reacted 11~15 hours at 20~30 DEG C, obtains levo-oxiracetam crude product, institute
State 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 be 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) by step 6) made from levo-oxiracetam be placed in ball grinder, according to 100mg levo-oxiracetams add 15
~20 μ L ratio adds isopropanol, then grinds 60~80min in ball grinder with 5HZ~6HZ frequency, and left-handed Austria is made
La Xitan crystal formations II.
The present invention uses S-4- chloro-3-hydroxyls butyric acid ring pentyl ester and sodium azide to prepare left-handed Aura for initiation material
Western smooth, circuit is simple, and intermediate and product do not need the impurity for not produced in column chromatography, preparation process and being difficult to removeObtained levo-oxiracetam product purity reaches more than 99.5% through efficient liquid phase detection, should
Levo-oxiracetam made from method is prepared as cooperation of the raw material by specific solvent, grinding frequency and milling time
Levo-oxiracetam crystal formation II optical purities greatly improve levo-oxiracetam crystal formation II product matter more than 99.9%
Amount.
Brief description of the drawings
Fig. 1 is the powder diagram of levo-oxiracetam hydrate crystal forms II；
Fig. 2 is the mono-crystalline structures figure of levo-oxiracetam hydrate crystal forms II；
Fig. 3 is the Raman spectrogram of levo-oxiracetam hydrate crystal forms II；
Fig. 4 is thermogravimetric analysis (TG) figure of levo-oxiracetam hydrate crystal forms II；
Fig. 5 is infrared spectrum (IR) figure of levo-oxiracetam hydrate crystal forms II.
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.The raw materials used present invention is commercially available
Product.
Embodiment 1
(l) preparation of intermediate compound I：
Raw material S-4- chloro-3-hydroxyl butyric acid ring pentyl ester 5g are taken, is added in a single neck bottle, is added cyclohexanol 10ml, stir, plus
Enter sodium azide 5g, reacted 1 hour at 160 DEG C or so after adding, yellow solution is reacted to obtain in stopping.Water 20ml is added, acetic acid is used
Ethyl ester 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):1.46-1.88(m,10H)2.76-2.67(AB system,m,3H,),3.31-3.23(AB
System, m, 2H), 3.98 (m, 1H), 3.70 (s, 1H) intermediate compound Is are：
(2) preparation of intermediate II
The intermediate compound I that step (1) is obtained is dissolved in 50ml methanol, is cooled to outer 5 DEG C or so of temperature, adds 10% palladium
C catalyst 1.3g, is passed through stirring under hydrogen 12 hours, and point plate is shown in that raw material reaction is complete, stops reaction, and concentration removes solvent and obtained
To pale yellow oil intermediate II.Detected through nuclear-magnetism, intermediate II：1.46-1.88 (m, 8H), 2.76-2.67 (AB
system,m,2H,),3.31-3.23(AB system,m,2H),3.98(m,1H),4.40(m,1H),4.70(bs,3H)
Intermediate II is
(3) preparation of intermediate III
The intermediate II that step (2) is obtained is dissolved in 50ml methanol, and potassium carbonate (3eq) is added at 40 DEG C or so,
There are a large amount of solids to generate, stir five minutes, start that benzyl acetate bromide (2eq) is added dropwise, dropwise addition process has exothermic phenomenon, completion of dropping
Continue to stir 6 hours or so afterwards, 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):
1.41-1.90(m,8H),2.28-2.53(m,2H),2.58-2.83(m,2H)3.51(s,2H),4.09-4.12(m,3H),
5.30-5.32(m,2H),7.08-7.25(m,5H)
Intermediate III is
(4) preparation of intermediate compound IV
The 50ml xylene solubles of intermediate III that step (2) is obtained, are warming up to 145 DEG C or so and react 5 hours, obtain
One red tan solution, point plate is shown in that raw material reaction is complete.Stop reaction, concentration removes removal xylene, add EA (ethyl acetate) dissolvings,
Be filtered to remove salt, activated carbon decolorizing, concentration remove yellow oil obtains intermediate compound IV.Detected through nuclear-magnetism, intermediate compound IV is：
1H-NMR(300MHz,CDCl3)2.38(dd,1H),2.69(dd,1H),3.34(dd,1H),3.77(dd,lH),3.93(d,
LH), 4.18 (d, 1H), 4.30 (bs, 1H), 4.50 (m, 1H), 5.34 (s, 2H), 7.05-7.26 (m, 5H)
Intermediate compound IV：
(5) preparation of (S)-Oxiracetam
The intermediate compound IV that step (4) is obtained adds concentrated ammonia liquor (concentration is 25%) 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
22.3g, chemical purity 98.7%.(6) by the dissolving crude product in 100ml water, heating dissolves it, and activated carbon decolorizing half is small
When, it is filtered to remove activated carbon, crystallisation by cooling, 5 DEG C stand overnight, and next day filters to obtain white solid 20.5g, chemical purity
99.5%, wherein not containingDetected through nuclear-magnetism, (S)-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)。
(S)-Oxiracetam structural formula is as follows：
(7) by step 6) made from levo-oxiracetam 200mg be placed in ball grinder, add 30 μ L isopropanols, Ran Hou
60min is ground with 5HZ frequency in ball grinder, levo-oxiracetam crystal formation is obtained.
By obtained levo-oxiracetam crystal formation carry out powder diffraction discovery, 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、
36.516th, 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 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 R- isomers Oxiracetams.
Through three measurements, average, the optical purity for obtaining the levo-oxiracetam crystal formation II of embodiment 1 is 99.91%.
For the crystal formation culture of levo-oxiracetam is carried out using polishing, the selection of solvent and consumption, Yi Jiyan
Frequency and the influence of time are ground, entirely different result is all likely to be obtained.Comparative testing below uses the step 6 of embodiment 1) system
The levo-oxiracetam obtained is raw material.
Comparative example 1
Levo-oxiracetam 800mg is placed in ball grinder, 40 μ L tetrahydrofurans are added, then with 20HZ in ball grinder
Frequency be ground to dry, obtain levo-oxiracetam crystal formation；After testing, the levo-oxiracetam crystal formation obtained 12.500,
13.940,15.000,16.540,17.400,19.320,20.520,20.840,21.980,23.340,25.120,25.840,
26.240,27.660,28.100,30.040,30.660,31.040,31.780,34.300,35.180,37.060,38.020
There is characteristic peak with 42.240 degree of 2 θ angles, it is identical with the levo-oxiracetam crystal formation I that CN102249975A is disclosed.
Comparative example 2
Levo-oxiracetam 200mg is placed in ball grinder, 30 μ L isopropanols are added, then with 5HZ's in ball grinder
Frequency grinds 10min, obtains levo-oxiracetam crystal formation, is levo-oxiracetam crystal formation I and crystal formation II mixing after testing
Thing.
Comparative example 3
Levo-oxiracetam 200mg is placed in ball grinder, 40 μ L acetonitriles are added, then with 20HZ frequency in ball grinder
Rate grinding ester do, obtain levo-oxiracetam crystal formation, after testing, the θ of angle of diffraction 2 be 10.54,13.70,14.44,15.60,
17.12、18.88、19.24、20.66、20.84、21.18、21.82、22.94、23.24、24.88、27.20、27.48、
28.24、30.46、30.80、31.52、32.00、32.34、32.90、33.20、34.40、34.62、37.30、37.50、
38.28th, 38.96, there is diffraction maximum at 40.02 degree, it is identical with the crystal formation III that CN103553998A is disclosed.
Comparative example 4
Levo-oxiracetam 200mg is placed in ball grinder, 40 μ L acetic acid are added, then with 20HZ frequency in ball grinder
Rate grinds 30min, obtains levo-oxiracetam grease.
Comparative example 5
Levo-oxiracetam 200mg is placed in ball grinder, 40 μ L normal propyl alcohols are added, then with 6HZ's in ball grinder
Frequency grinds 10min, obtains levo-oxiracetam crystal formation, is levo-oxiracetam crystal formation I and crystal formation II mixing after testing
Thing.
Experiment shows that levo-oxiracetam crystal formation I can be made in some solvents, and left-handed Aura west can be made in some solvents
Levo-oxiracetam crystal formation can not be made in smooth crystal formation I and levo-oxiracetam crystal formation II mixture, some solvents；To sum up, lead to
Polishing culture levo-oxiracetam crystal formation II is crossed, with certain contingency, it is difficult to use similar compatibility, similar polarity solvent institute
Scheduling theory is substituted to derive.
Embodiment 2
Purity is placed in ball grinder for 99.5% levo-oxiracetam 200mg, 30 μ L isopropanols are added, then in ball
40min is ground with 10HZ frequency in grinding jar, levo-oxiracetam crystal formation is obtained, after testing, with crystal formation II made from embodiment 1
It is identical.
Embodiment 3
Purity is placed in ball grinder for 99.5% levo-oxiracetam 200mg, 35 μ L isopropanols are added, then in ball
90min is ground with 5HZ frequency in grinding jar, levo-oxiracetam crystal formation is obtained, after testing, with crystal formation II made from embodiment 1
It is identical.
Embodiment 4-6 is made with reference to embodiment 1, partial parameters are according to following operation：Levo-oxiracetam during crystal formation culture
Consumption is 200mg.
(S)-Oxiracetam chemical purity made from embodiment 4-6 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 that ball-milling method prepares levo-oxiracetam crystal formation II, using following steps：
Levo-oxiracetam is placed in ball grinder, the ratio for adding 15~20 μ L according to 100mg levo-oxiracetams adds different
Propyl alcohol, then grinds 40min~90min with 5~10HZ frequency, and levo-oxiracetam crystal formation II is made；The left-handed Aura
Western smooth crystal formation II 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、
27.901st, 28.621,28.925,29.449,29.484,31.702,36.516,37.685, there is diffraction maximum at 39.721 degree.
2. method as claimed in claim 2, it is characterised in that：It is described grinding frequency be 5~6HZ, milling time be 60min~
80min。
3. method as claimed in claim 2, it is characterised in that：The levo-oxiracetam purity is more than 99.5%.
4. the method as described in claim 1 or 3, it is characterised in that levo-oxiracetam is made using following reaction scheme, so
Levo-oxiracetam crystal formation II is prepared with ball-milling method afterwards；Route is：
；Operating procedure is：
1), first S-4- chloro-3-hydroxyl butyric acid rings pentyl ester is dissolved with cyclohexanol, sodium azide is then added at 150~170 DEG C
Reaction obtains intermediate compound I for 1~2 hour, and wherein S-4- chloro-3-hydroxyls butyric acid ring pentyl ester and sodium azide mol ratio are 1：1.5~
3；
2), intermediate compound I is dissolved with methanol, carrying out reduction reaction with hydrogen by catalyst of Metal Palladium obtains intermediate II, instead
It is 0~20 DEG C to answer temperature, and the reaction time is 10~12 hours；
3), intermediate II is dissolved with methanol, potassium carbonate is catalyst, reacted 5~6 hours with benzyl acetate bromide, reaction temperature
40~60 DEG C；The intermediate II and the mol ratio of benzyl acetate bromide are：1:1.5~2.5, intermediate II and the potassium carbonate
Mol ratio is：1:2~3；
4), intermediate III is dissolved with dimethylbenzene, ring closure reaction is carried out under the conditions of 140~150 DEG C and obtains intermediate compound IV, is reacted
Time is 5~7 hours；
5), intermediate compound IV and ammoniacal liquor are reacted 11~15 hours at 20~30 DEG C, levo-oxiracetam crude product is obtained, it is described in
Mesosome 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 it is dense
Spend 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), by step 6) made from levo-oxiracetam be placed in ball grinder, according to 100mg levo-oxiracetams add 15~20
μ L ratio adds isopropanol, then grinds 60~80min in ball grinder with 5HZ~6HZ frequency, and left-handed Aura west is made
Smooth crystal formation II.
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Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1513836A (en) * | 2002-06-22 | 2004-07-21 | 张家港浩波化学品有限公司 | Method of preparing 4-hydroxy pyrrolidone-2-acetamine |
| CN102249975A (en) * | 2010-05-21 | 2011-11-23 | 重庆润泽医疗器械有限公司 | (S)-4-hydroxy-2-oxo-1-pyrrolidineacetamide crystal form I and preparation method and application thereof |
| 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 |
| CN103553999A (en) * | 2013-11-06 | 2014-02-05 | 重庆润泽医药有限公司 | Preparation method of (S)-oxiracetam crystal form III |
-
2016
- 2016-01-29 CN CN201610064016.8A patent/CN107011232A/en active Pending
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1513836A (en) * | 2002-06-22 | 2004-07-21 | 张家港浩波化学品有限公司 | Method of preparing 4-hydroxy pyrrolidone-2-acetamine |
| CN102249975A (en) * | 2010-05-21 | 2011-11-23 | 重庆润泽医疗器械有限公司 | (S)-4-hydroxy-2-oxo-1-pyrrolidineacetamide crystal form I and preparation method and application thereof |
| 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 |
| CN103553999A (en) * | 2013-11-06 | 2014-02-05 | 重庆润泽医药有限公司 | Preparation method of (S)-oxiracetam crystal form III |
Non-Patent Citations (7)
| Title |
|---|
| 周年琛、李新主编: "《有机化学》", 28 February 2007, 苏州大学出版社 * |
| 张招贵编著: "《精细有机合成与设计》", 30 June 2003, 化学工业出版社 * |
| 汪焱钢主编: "《现代有机合成导论》", 31 August 1999, 华中师范大学出版社 * |
| 罗明生、高天惠主编: "《药剂辅料大全》", 31 January 2006, 四川出版集团·四川科学技术出版社 * |
| 苏德森、王思玲: "《物理药剂学》", 31 July 2004 * |
| 荣国斌主编: "《大学有机化学基础（第二版）下册》", 31 August 2006, 华东理工大学出版社 * |
| 迟延青等主编: "《最新临床用药必备》", 31 January 2011, 北京大学医学出版社 * |
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