CN107021899A - 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
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- CN107021899A CN107021899A CN201610064208.9A CN201610064208A CN107021899A CN 107021899 A CN107021899 A CN 107021899A CN 201610064208 A CN201610064208 A CN 201610064208A CN 107021899 A CN107021899 A CN 107021899A
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- 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
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- 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, the high-purity levo-oxiracetam prepared using S-4- chloro-3-hydroxybutanoic acid esters and sodium azide as initiation material, then levo-oxiracetam crystal formation II is prepared by pH methods with formic acid/potassium hydroxide, chemical purity is high, does not contain；And optical purity is more than 99.9%, levo-oxiracetam crystal formation II product quality is greatly improved.
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, prepare levo-oxiracetam II according to the patented method, react
Time is 1~3 day, and is handled comparatively laborious., it is necessary to develop a kind of technique simply the need in order to meet medical industry, institute
Take time short, the method for post-processing easy levo-oxiracetam II.
The content of the invention
It is an object of the invention to provide a kind of levo-oxiracetam crystal formation II preparation method, this method preparation technology letter
Single, required time is short, and obtained product chiral purity is high.
Technical scheme involved in the present invention is as follows：
A kind of levo-oxiracetam crystal formation II preparation method, it is characterised in that use following steps：
Levo-oxiracetam is configured to the 80~150mg/mL aqueous solution with deionized water, added equivalent to left-handed Aura
The formic acid solution of the amount of western smooth 2~3 times of materials, is warming up to 80~90 DEG C of 2~3h of insulation, then adds activated carbon decolorizing, filter,
Filtrate mass concentration adjusts pH to 6~7 for 10~20% potassium hydroxide solution, and suction filtration is dried and both obtained；The formic acid solution
Mass concentration is 88~95%.
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 the left-handed Aura of certain concentration
Levo-oxiracetam crystal formation II has been made by adjusting pH value, successfully for the formic acid of western smooth process certain concentration, promotes significantly
The scientific research of levo-oxiracetam crystal formation and industrialized production.The present invention process time is short, and whole crystal formation culture is small no more than 4
When, for CN102558013A, preparation efficiency is greatly improved.
Above-mentioned activated carbon dosage is 0.01~0.02 times of levo-oxiracetam weight.
Found in R＆D process, obtained levo-oxiracetam is relatively low to crystal formation II purity, or even sometimes measures
It is micro- but be difficult to the impurity that separates, such as
In order to ensure the purity of raw material, high-purity levo-oxiracetam can be first made, then makes under given conditions
Obtain levo-oxiracetam crystal formation II.
A kind of levo-oxiracetam crystal formation II preparation method, is first made levo-oxiracetam, then brilliant with the culture of pH methods
Type II, it is characterised in that the route for preparing levo-oxiracetam is：
；Operating procedure is：
1), first S-4- chloro-3-hydroxyls isopropyl isobutyrate is dissolved with isopropanol, then Azide is added at 80~90 DEG C
Sodium reaction obtains intermediate compound I for 3~4 hours, and wherein S-4- chloro-3-hydroxyls isopropyl isobutyrate and sodium azide mol ratio are 1：2~
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 toluene, ring closure reaction is carried out under the conditions of 110~120 DEG C and obtains intermediate compound IV, instead
It is 6~7 hours between seasonable；
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) levo-oxiracetam is configured to the 100~150mg/mL aqueous solution with deionized water, added equivalent to left-handed
The formic acid solution of the amount of 2~3 times of materials of Oxiracetam, is warming up to 80~90 DEG C of 2~3h of insulation, then adds activated carbon decolorizing,
Filtering, filtrate mass concentration adjusts pH to 6~7 for 10~20% potassium hydroxide solution, and suction filtration is dried and both obtained；The formic acid
The mass concentration of solution is 88~95%；The activated carbon dosage is 0.01~0.02 times of levo-oxiracetam weight.
Left-handed Austria of high-purity that the present invention is prepared using S-4- chloro-3-hydroxybutanoic acid esters and sodium azide as initiation material
La Xitan, intermediate and product do not need the impurity for not produced in column chromatography, preparation process and being difficult to removeProduct purity reaches more than 99.5% through efficient liquid phase detection；Obtained levo-oxiracetam
Levo-oxiracetam crystal formation II is prepared by pH methods with formic acid/potassium hydroxide, optical purity is more than 99.9%, greatly
Improve levo-oxiracetam crystal formation II product quality；For CN102558013A, reaction efficiency is high, and the time is obvious
(crystal formation culture of the present invention is no more than 4 hours, and CN102558013A is 1~3 day for shortening.
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 structure cell accumulation graph of levo-oxiracetam hydrate crystal forms II；
Fig. 4 is the Raman spectrogram of levo-oxiracetam hydrate crystal forms II；
Fig. 5 is thermogravimetric analysis (TG) figure of levo-oxiracetam hydrate crystal forms II；
Fig. 6 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.
Embodiment 1
1g levo-oxiracetams are dissolved with 10mL deionized waters, the formic acid solution that mass concentration is 90%, formic acid is added
The amount of solution is the amount of 2 times of materials of levo-oxiracetam, is warming up to 85 DEG C or so insulation 2.5h, then adds 15mg activated carbons
Decolouring, filtering, filtrate mass concentration adjusts pH to 6.5 for 10% potassium hydroxide solution, and suction filtration is dried and both obtained.
Obtained levo-oxiracetam crystal formation is subjected to Structural Identification, Fig. 1 is levo-oxiracetam hydrate crystal forms II
Powder diagram；Fig. 2 is the mono-crystalline structures figure of levo-oxiracetam hydrate crystal forms II；Fig. 3 is levo-oxiracetam hydrate
The structure cell accumulation graph of crystal formation II；Fig. 4 is the Raman spectrogram of levo-oxiracetam hydrate crystal forms II；Fig. 5 is left-handed Aura west
Thermogravimetric analysis (TG) figure of smooth hydrate crystal forms II；Fig. 6 is infrared spectrum (IR) figure of levo-oxiracetam hydrate crystal forms II.
Wherein tested by X-ray powder diffraction, diffraction maximum parsing 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 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 99.92%.
For the crystal formation culture of levo-oxiracetam is carried out using pH methods, the concentration of the levo-oxiracetam aqueous solution,
The concentration of formic acid and the pH scopes of consumption, the concentration of alkali lye and adjustment, possible different degrees of influence crystal formation cultivation results.It is left
Revolve Oxiracetam concentration of aqueous solution too low, then can not obtain levo-oxiracetam powder or monocrystalline, excessive concentration then easily occurs
The mixture of crystal formation parcel and crystal formation I and crystal formation II.The concentration of formic acid is too low, and levo-oxiracetam crystal formation, first can not be made
The consumption of acid is excessive, then can cannot get levo-oxiracetam powder or crystal formation, or even cause levo-oxiracetam medicine to decompose.
Comparative example 1
5g levo-oxiracetams are dissolved with 10mL deionized waters, the formic acid solution that mass concentration is 90%, formic acid is added
The amount of solution is the amount of 2 times of materials of levo-oxiracetam, is warming up to 85 DEG C or so insulation 2.5h, then adds 15mg activated carbons
Decolouring, filtering, filtrate mass concentration adjusts pH to 6.5 for 10% potassium hydroxide solution, and suction filtration is dried and both obtained, by X powder
Diffraction is detected, is found to be crystal formation I and crystal formation II mixture.Crystal formation I design parameters are referring to CN102249975A.
Comparative example 2
1g levo-oxiracetams are dissolved with 10mL deionized waters, the formic acid solution that mass concentration is 90%, formic acid is added
The amount of solution is the amount of 2 times of materials of levo-oxiracetam, is warming up to 85 DEG C or so insulation 2.5h, then adds 15mg activated carbons
Decolourize, filtering, filtrate mass concentration for 10% potassium hydroxide solution adjust pH to 4, suction filtration, as a result both do not obtained powder or
Single crystal form material is not obtained.
Tested with reference to comparative example 2, when pH is 1, medicine is decomposed；When pH is 2-4, powder was not as a result both obtained or had not had
Obtain single crystal form material；When pH is 9-13, both powder was not obtained or had not obtained single crystal form material；When pH is 14
When, medicine is decomposed.
Embodiment 2
1.2g levo-oxiracetams are dissolved with 10mL deionized waters, the formic acid solution that mass concentration is 90%, first is added
The amount of acid solution is the amount of 2 times of materials of levo-oxiracetam, is warming up to 90 DEG C or so insulation 3h, then adds 15mg activated carbons
Decolouring, filtering, filtrate mass concentration adjusts pH to 6 for 15% potassium hydroxide solution, and suction filtration is dried and both obtained；Use X powder diffraction
Method verifies that obtained crystal formation is identical with the crystal formation II of embodiment 1, and optical purity is 99.92%.
Embodiment 3
1g levo-oxiracetams are dissolved with 10mL deionized waters, the formic acid solution that mass concentration is 92%, formic acid is added
The amount of solution is the amount of 2 times of materials of levo-oxiracetam, is warming up to 85 DEG C or so insulation 2h, then adds 12mg activated carbons and takes off
Color, filtering, filtrate mass concentration adjusts pH to 6.5 for 15% potassium hydroxide solution, and suction filtration is dried and both obtained；Use X powder diffraction
Method verifies that obtained crystal formation is identical with the crystal formation II of embodiment 1, and optical purity is 99.90%.
Embodiment 4
1.3g levo-oxiracetams are dissolved with 10mL deionized waters, the formic acid solution that mass concentration is 88%, first is added
The amount of acid solution is the amount of 2 times of materials of levo-oxiracetam, is warming up to 95 DEG C or so insulation 3h, then adds 18mg activated carbons
Decolouring, filtering, filtrate mass concentration adjusts pH to 6.8 for 18% potassium hydroxide solution, and suction filtration is dried and both obtained；Spread out with X powder
Method checking is penetrated, obtained crystal formation is identical with the crystal formation II of embodiment 1, and optical purity is 99.90%.
Embodiment 5
(l) preparation of intermediate compound I：
Raw material S-4- chloro-3-hydroxyl isopropyl isobutyrate 5g are taken, is added in a single neck bottle, is added isopropanol 10ml, stir, plus
Enter sodium azide 5g, reacted 3 hours at 85 DEG C or so after adding, yellow solution is reacted to obtain in stopping.Water 20ml is added, acetic acid second is used
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):1.35-1.73(m,8H)2.76-2.67(AB system,m,2H,),3.31-3.23(AB system,
M, 2H), 4.31 (m, 1H), 4.40 (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：1.35 (m, 6H), 2.76-2.67 (AB system, m,
2H), 3.31-3.23 (AB system, m, 2H), 4.31 (m, 1H), 4.40 (m, 1H), 4.70 (bs, 3H) intermediate IIs are
(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):1.35
(m,6H),2.28-2.53(m,2H),2.58-2.83(m,2H)3.51(s,2H),4.09-4.22(m,2H),5.34(m,2H)
7.05-7.23(m,5H).
Intermediate III is
(4) preparation of intermediate compound IV
The intermediate III that step (2) is obtained 50ml toluene dissolves, and is warming up to 115 DEG C or so and reacts 5 hours, obtains one
Red tan solution, point plate is shown in that raw material reaction is complete.Stop reaction, concentration removes toluene, 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)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
22.5g, chemical purity 98.7%.
(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 20.2g, chemical purity 99.6%, end-product
HaveDetected 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) levo-oxiracetam crystal formation II preparation：
0.8g levo-oxiracetams are dissolved with 10mL deionized waters, the formic acid solution that mass concentration is 90%, first is added
The amount of acid solution is the amount of 3 times of materials of levo-oxiracetam, is warming up to 80 DEG C or so insulation 2h, then adds 20mg activated carbons
Decolouring, filtering, filtrate mass concentration adjusts pH to 6.5 for 18% potassium hydroxide solution, and suction filtration is dried and both obtained；By X powder
Diffraction is verified, identical with crystal formation II made from embodiment 1, and optical purity is 99.90%.
Embodiment 6-8 is made with reference to embodiment 1, partial parameters are according to following operation：
(S)-Oxiracetam chemical purity made from embodiment 6-8 is high, wherein not containing
Chemical purity more than 99.5% can be achieved in general purification (being handled without column chromatography), as crystalline substance of the raw material with reference to embodiment 1
Type culture, is successfully made (S)-Oxiracetam crystal form II, and its optical purity is more than 99.90%.
Claims (3)
1. a kind of levo-oxiracetam crystal formation II preparation method, it is characterised in that use following steps：
Levo-oxiracetam is configured to the 80~150mg/mL aqueous solution with deionized water, added equivalent to levo-oxiracetam
The formic acid solution of the amount of 2~3 times of materials, is warming up to 80~90 DEG C of 2~3h of insulation, then adds activated carbon decolorizing, filter, filtrate
PH to 6~7 is adjusted for 10~20% potassium hydroxide solution with mass concentration, suction filtration is dried and both obtained；The quality of the formic acid solution
Concentration is 88~95%；The levo-oxiracetam 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、27.901、28.621、28.925、29.449、29.484、31.702、36.516、
37.685th, there is diffraction maximum at 39.721 degree.
2. the method as described in claim 1, it is characterised in that：The activated carbon dosage is the 0.01 of levo-oxiracetam weight
~0.02 times.
3. a kind of levo-oxiracetam crystal formation II preparation method, is first made levo-oxiracetam, then with pH method culture crystal formations
II, it is characterised in that the route for preparing levo-oxiracetam is：
；
Operating procedure is：
1), first S-4- chloro-3-hydroxyls isopropyl isobutyrate is dissolved with isopropanol, sodium azide is then added at 80~90 DEG C anti-
Answer and obtain within 3~4 hours intermediate compound I, wherein S-4- chloro-3-hydroxyls isopropyl isobutyrate and sodium azide mol ratio are 1：2~3；
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 toluene, ring closure reaction is carried out under the conditions of 110~120 DEG C and obtains intermediate compound IV, during reaction
Between be 6~7 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), levo-oxiracetam is configured to the 100~150mg/mL aqueous solution with deionized water, is added equivalent to left-handed Aura
The formic acid solution of the amount of western smooth 2~3 times of materials, is warming up to 80~90 DEG C of 2~3h of insulation, then adds activated carbon decolorizing, filter,
Filtrate mass concentration adjusts pH to 6~7 for 10~20% potassium hydroxide solution, and suction filtration is dried and both obtained；The formic acid solution
Mass concentration is 88~95%；The activated carbon dosage is 0.01~0.02 times of levo-oxiracetam weight.
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| Publication number | Priority date | Publication date | Assignee | Title |
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| 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 |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| 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.》 * |
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