CN107021901A - (S)-oxiracetam crystal form II preparation method - Google Patents
(S)-oxiracetam crystal form II preparation method Download PDFInfo
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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
- 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 (S)-Oxiracetam crystal form II preparation method, the oxo-1-pyrrolidine ethanamide crystal formation II of (S) -4- hydroxyls -2 is prepared by the way of good solvent/poor solvent, preparation process does not need large industry equipment, processing step is simple, product can be easily separated, and be adapted to industrialized production.
Description
Technical field
The present invention relates to a kind of (S)-Oxiracetam crystal form II preparation method.
Background technology
(S)-Oxiracetam, (No. CAS is 62613-82- to the entitled oxo-1-pyrrolidine ethanamide of (S) -4- hydroxyls -2 of chemistry
5) synthesis of Phosphorylcholine and phosphatidyl ethanolamine, can be promoted, promote brain metabolism, by blood-brain barrier to special nervous centralis road
There is stimulation, improve the ratio of ATP/ADP in brain, making the synthesis of protein and nucleic acid in brain increases, and can improve intelligence
The memory of energy impaired patients and learning functionality, and medicine is also acted in itself without direct vasoactive without central excitation, it is right
The influence of ability of learning and memory is a kind of lasting facilitation.
For the oxo-1-pyrrolidine ethanamide of (S) -4- hydroxyls -2 effectively is developed into medicine, it is necessary to which one kind, which has, is easy to system
Make and acceptable chemically and physically stability solid-state form, with promote its processing with circulation store.For enhancing chemical combination
For the purity and stability of thing, crystalline solid form generally to be preferred over armorphous form.The presently disclosed oxygen of (S) -4- hydroxyls -2
In generation, -1- pyrrolidine acetamide crystal formations had tri- kinds of crystal formations of I, II, III, and wherein crystal formation II has preferable stability.
CN102558013A discloses oxo-1-pyrrolidine ethanamide crystal formation II of one kind (S) -4- hydroxyls -2 and preparation method thereof, and (S) -
The crystallization after frozen water top is washed of the oxo-1-pyrrolidine ethanamide of 4- hydroxyls -2 obtains crystal formation II, and the crystal formation is in the θ of angle of diffraction 2
For 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、
29.449th, 29.484,31.702,36.516,37.685, there is diffraction maximum at 39.721 degree, the preparation method according to the patent is obtained
The oxo-1-pyrrolidine ethanamide II chiral purities of (S) -4- hydroxyls -2 arrived are in 98-99% or so, and wherein R content of isomer connects
Nearly 1%., it is necessary to which developing one kind prepares the oxo -1- pyrroles of higher purity (S) -4- hydroxyls -2 the need in order to meet medical industry
Alkyl acetamide II method.
The content of the invention
It is an object of the invention to provide the oxo-1-pyrrolidine ethanamide crystal formation II of one kind (S) -4- hydroxyls -2 preparation side
Method, this method preparation technology is simple, is adapted to industrialized production.
Technical scheme involved in the present invention is as follows：
The oxo-1-pyrrolidine ethanamide crystal formation II of one kind (S) -4- hydroxyls -2 preparation method, is dissolved using good solvent
(S) oxo-1-pyrrolidine ethanamide of -4- hydroxyls -2, then adds poor solvent and is mixed to prepare the oxo -1- pyrroles of (S) -4- hydroxyls -2
Cough up alkyl acetamide crystal formation II, it is characterised in that：
The good solvent is dimethyl acetamide or isopropanol, and poor solvent is tetrahydrofuran, dichloromethane, acetone, second
Acetoacetic ester, ether, n-hexane or petroleum ether；Wherein when good solvent is dimethyl acetamide, poor solvent is tetrahydrofuran, two
Chloromethanes, acetone or ethyl acetate；When good solvent is isopropanol, poor solvent is n-hexane or petroleum ether.
In order to improve the oxo-1-pyrrolidine ethanamide crystal formation II of (S) -4- hydroxyls -2 yield and purity, preferably good solvent
During for dimethyl acetamide, poor solvent is acetone, dichloromethane or ethyl acetate；It is bad molten when good solvent is isopropanol
Agent is n-hexane or petroleum ether.
The oxo-1-pyrrolidine ethanamide crystal formation II of (S) -4- hydroxyls -2 that the present invention is prepared is in the θ of angle of diffraction 2
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、
29.484th, 31.702,36.516,37.685, 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 good solvent and poor solvent by anti-solvent dripping method, be successfully made (S)-
The oxo-1-pyrrolidine ethanamide crystal formation II of 4- hydroxyls -2, has greatly promoted the oxo-1-pyrrolidine ethanamide of (S) -4- hydroxyls -2
The scientific research of crystal formation and industrialized production.
Found in preparation process, the sometimes obtained oxo-1-pyrrolidine ethanamide crystal formation II of (S) -4- hydroxyls -2 is difficult to
Separation, further study show that, the tittle of certain in raw material it is micro- it can be difficult to separation material such as
The separation of product after crystal formation culture can be influenceed.
In order to improve the oxo-1-pyrrolidine ethanamide crystal formation II of (S) -4- hydroxyls -2 yield and purity, reduction post processing
Difficulty, preferably as made from following methods the oxo-1-pyrrolidine ethanamide of (S) -4- hydroxyls -2 be raw material, then by above-mentioned
The oxo-1-pyrrolidine ethanamide crystal formation II of (S) -4- hydroxyls -2 is made in anti-solvent method.
Specifically, the oxo-1-pyrrolidine ethanamide crystal formation II of one kind (S) -4- hydroxyls -2 preparation method, its feature exists
In using the obtained oxo-1-pyrrolidine ethanamide of (S) -4- hydroxyls -2 of following reaction scheme：
Operating procedure is：
1), first S-4- chloro-3-hydroxyls ethyl butyrate is dissolved with cyclopentanol, sodium azide is then added at 120~130 DEG C
Lower reaction obtains intermediate compound I for 2~3 hours, and wherein S-4- chloro-3-hydroxyls ethyl butyrate and sodium azide mol ratio are 1：2~3；
2) intermediate compound I is dissolved with DMSO, carrying out reduction reaction with hydrogen by catalyst of Metal Palladium obtains intermediate II,
Reaction temperature is 10~40 DEG C, and the reaction time is 5~8 hours；
3) intermediate II is dissolved with tetrahydrofuran, potassium carbonate is catalyst, reacted 7~8 hours with bromoacetic acid N-butyl,
Reaction temperature is 50~60 DEG C；The mol ratio of the intermediate II and bromoacetic acid N-butyl is：1:1~2, intermediate II with it is described
The mol ratio of potassium carbonate is：1:2~3；
4) intermediate III is dissolved with ethanol, ring closure reaction is carried out under the conditions of 70~80 DEG C and obtains intermediate compound IV, is reacted
Time is 8~10 hours；
5) intermediate compound IV and ammoniacal liquor are reacted 13~18 hours at 20~30 DEG C, obtains the oxo -1- of (S) -4- hydroxyls -2
Pyrrolidine acetamide crude product, the intermediate compound IV：The mol ratio of ammonia is intermediate compound IV：Ammonia=1：12~15, it is molten with ammonia methanol
Ammonia meter in liquid, the concentration of the ammoniacal liquor is 25-28%；
6) the oxo-1-pyrrolidine ethanamide crude product of (S) -4- hydroxyls -2 is dissolved by heating in water, activated carbon decolorizing, filtered
Activated carbon is removed, be concentrated under reduced pressure water removal, stop concentrating when surplus water is adds 2~3 times of products weight, 0~5 DEG C of low temperature cold
But crystallize, obtain the oxo-1-pyrrolidine ethanamide of (S) -4- hydroxyls -2；
7) by step 6) the obtained oxo-1-pyrrolidine ethanamide dimethylacetamide amine solvent of (S) -4- hydroxyls -2, so
Solution is added drop-wise in acetone, dichloromethane or ethyl acetate afterwards, is stirred continuously 3~5h, after the precipitation of precipitation is filtered, vacuum is done
It is dry both to obtain.
Above-mentioned steps 7) it can also be dissolved for the oxo-1-pyrrolidine ethanamide isopropanol of (S) -4- hydroxyls -2, Ran Hourong
Drop is added in n-hexane or petroleum ether, is stirred continuously after 4~6h and is filtered the precipitation of precipitation, vacuum drying was both obtained.
The present invention uses S-4- chloro-3-hydroxyls methyl butyrate and sodium azide to prepare the oxygen of (S) -4- hydroxyls -2 for initiation material
Generation -1- pyrrolidine acetamides, circuit is simple, and intermediate and product are not needed not produce in column chromatography, preparation process and be difficult to
The impurity removedThe obtained oxo-1-pyrrolidine ethanamide product purity of (S) -4- hydroxyls -2 warp
Efficient liquid phase detection reaches more than 99.5%, and the oxo-1-pyrrolidine ethanamide of (S) -4- hydroxyls -2 is used as original made from this method
Material prepares the oxo-1-pyrrolidine ethanamide crystal formation II of (S) -4- hydroxyls -2, optical purity exists by the cooperation of specific solvent
More than 99.9%, greatly improve the oxo-1-pyrrolidine ethanamide crystal formation II of (S) -4- hydroxyls -2 product quality.
Brief description of the drawings
Fig. 1 is the powder diagram of the oxo-1-pyrrolidine ethanamide hydrate crystal forms II of (S) -4- hydroxyls -2；
Fig. 2 is the mono-crystalline structures figure of the oxo-1-pyrrolidine ethanamide hydrate crystal forms II of (S) -4- hydroxyls -2；
Fig. 3 is the structure cell accumulation graph of the oxo-1-pyrrolidine ethanamide hydrate crystal forms II of (S) -4- hydroxyls -2；
Fig. 4 is the Raman spectrogram of the oxo-1-pyrrolidine ethanamide hydrate crystal forms II of (S) -4- hydroxyls -2；
Fig. 5 is thermogravimetric analysis (TG) figure of the oxo-1-pyrrolidine ethanamide hydrate crystal forms II of (S) -4- hydroxyls -2；
Fig. 6 is infrared spectrum (IR) figure of the oxo-1-pyrrolidine ethanamide hydrate crystal forms II of (S) -4- hydroxyls -2.
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 present invention is raw materials used equal with reagent
For commercially available prod.
Embodiment 1
(l) preparation of intermediate compound I：
Raw material S-4- chloro-3-hydroxyl methyl butyrate 5g are taken, is added in a single neck bottle, is added cyclopentanol 10ml, stir, add
Sodium azide 5g, 120~130 DEG C of keeping temperature is reacted 2 hours, and 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):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 DMSO, is added 10% palladium-carbon catalyst 1g, is passed through hydrogen
In 10~30 DEG C of stirring reactions 5 hours under gas, point plate is shown in that raw material reaction is complete, stops reaction, and concentration removes solvent and obtains yellowish
Color grease 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 tetrahydrofuran, at 30 DEG C or so, adds potassium carbonate
17.3g (3eq), has a large amount of solids to generate, and stirs five minutes, starts that bromoacetic acid N-butyl 9ml (2eq) is added dropwise, dropwise addition process has
Continue to stir 7 hours after exothermic phenomenon, completion of dropping, 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 with EA 20ml
Twice, merge organic layer, organic layer is washed three times with 2M hydrochloric acid 20ml, merge hydrochloric acid aqueous phase, organic phase is discarded, aqueous phase carbonic acid
Hydrogen sodium adjusts pH to 8, and solid sodium chloride saturation, EA 30ml are extracted three times, merges organic phase, and anhydrous magnesium sulfate is dried, and concentration is removed
Solvent is gone to obtain pale yellow oil, curing at low temperatures obtains intermediate III.Detected through nuclear-magnetism, intermediate III：1H-NMR
(300MHz,D2O):0.96-1.62(m,7H),2.28-2.53(m,2H),2.58-2.83(m,2H)3.51(s,2H),3.67
(s,3H),4.08-4.11(m,3H)
Intermediate III is
(4) preparation of intermediate compound IV
The intermediate III that step (2) is obtained 50ml ethanol dissolves, and is warming up to 75 DEG C and reacts 8 hours, obtains one reddish brown
Color solution, point plate is shown in that raw material reaction is complete.Stop reaction, concentration removes ethanol, 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)0.96(t,3H)1.33(m,2H),1.57(m,2H)2.38(dd,1H),2.69(dd,1H),3.34(dd,
1H), (m, the 1H) intermediate of 3.77 (dd, lH), 3.93 (d, lH), 4.18 (d, 1H), 4.19 (q, 2H), 4.30 (bs, 1H), 4.50
IV：
(5) preparation of the oxo-1-pyrrolidine ethanamide of (S) -4- hydroxyls -2
The intermediate compound IV that step (4) is obtained adds concentrated ammonia liquor (concentration is 25%) 20ml, is stirred at room temperature 15 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
24g, chemical purity 99.0%.(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 22g, chemical purity 99.5%.
Detected through nuclear-magnetism, the oxo-1-pyrrolidine ethanamide of (S) -4- hydroxyls -2：1H-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) the oxo-1-pyrrolidine ethanamide structural formula of -4- hydroxyls -2 is as follows：
7) the oxo-1-pyrrolidine ethanamide crystal formation II of (S) -4- hydroxyls -2 preparation：
With 10mL dimethyl acetamide dissolving step 6) the obtained oxo-1-pyrrolidine ethanamide of (S) -4- hydroxyls -2
Settled solution, is then added drop-wise in ethyl acetate by 1g, is stirred continuously after 5h and filters the precipitation of precipitation, vacuum drying was both obtained
(S) the oxo-1-pyrrolidine ethanamide crystal formation of -4- hydroxyls -2.
The obtained oxo-1-pyrrolidine ethanamide crystal formation of (S) -4- hydroxyls -2 is subjected to powder diffraction discovery, in the angle of diffraction
Spend 2 θ for 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、
29.449th, 29.484,31.702,36.516,37.685, there is diffraction maximum at 39.721 degree, the crystalline substance disclosed with CN102558013A
Type II is consistent.
The infrared spectrum that the obtained oxo-1-pyrrolidine ethanamide crystal formation II of (S) -4- hydroxyls -2 is produced is aobvious in following wave number
Absworption peak is shown：
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)。
The oxo-1-pyrrolidine ethanamide crystal formation II of (S)-4- hydroxyls made from embodiment 1-2 is subjected to optical purity measure：
The oxo-1-pyrrolidine ethanamide crystal formation II of (S) -4- hydroxyls -2 is taken, precision weighs quantity (equivalent to containing (S) -4- hydroxyls
The oxo-1-pyrrolidine ethanamide 120mg of base -2) put 100ml measuring bottles, plus mobile phase ultrasonic dissolution and constant volume are made in every 1ml and contained
(S) the oxo-1-pyrrolidine ethanamide 1.2mg of -4- hydroxyls -2 solution, 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 the oxo-1-pyrrolidine ethanamide of main ingredient active component (S) -4- hydroxyls -2；
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, obtain the oxo-1-pyrrolidine ethanamide crystal formation II of (S) -4- hydroxyls -2 of embodiment 1
Optical purity be 99.92%.
For the crystal formation culture of the oxo-1-pyrrolidine ethanamide of (S) -4- hydroxyls -2 is carried out using anti-solvent method, no
Same good solvent and the proportioning of poor solvent, it would be possible to obtain entirely different result.Comparative testing below uses embodiment 1
Step 6) the obtained oxo-1-pyrrolidine ethanamide of (S) -4- hydroxyls -2 is raw material.
Comparative example 1
With the 10mL oxo-1-pyrrolidine ethanamide 1g of dimethylacetamide amine solvent (S) -4- hydroxyls -2, then it will clarify
Solution is added drop-wise in petroleum ether, is stirred continuously 5h, it is impossible to form precipitation；Continue to stir 14 hours, still can not form precipitation.
Comparative example 2
With the 10mL oxo-1-pyrrolidine ethanamide 1g of dimethylacetamide amine solvent (S) -4- hydroxyls -2, then it will clarify
Solution is added drop-wise in n-hexane, is stirred continuously 5 hours, it is impossible to form precipitation；Continue to stir 12 hours, it is heavy still can not to be formed
Form sediment.
Comparative example 3
With the 10mL oxo-1-pyrrolidine ethanamide 1g of isopropanol dissolving (S) -4- hydroxyls -2, then settled solution is dripped
Be added in ether, be stirred continuously 5 hours, formed precipitation, after filtering be dried in vacuo, by detection, 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,
26.240,27.660,28.100,30.040,30.660,31.040,31.780,34.300,35.180,37.060,38.020
There is characteristic peak with 42.240 degree of 2 θ angles, the OXo-1-pyrrolidine acetyl of (S) -4- hydroxyls -2 disclosed with CN102249975A
Amine crystal formation I is identical.
Comparative example 4
With the 10mL oxo-1-pyrrolidine ethanamide 1g of isopropanol dissolving (S) -4- hydroxyls -2, then settled solution is dripped
It is added in tetrahydrofuran, is stirred continuously 5h, it is impossible to forms precipitation；Continue to stir 14 hours, still can not form precipitation.
Change the tetrahydrofuran in comparative example 4 into dichloromethane, acetone or ethyl acetate, can not form precipitation.
Comparative example 5
With the 10mL oxo-1-pyrrolidine ethanamide 1g of isopropanol dissolving (S) -4- hydroxyls -2, then settled solution is dripped
It is added in ether, is stirred continuously 5 hours, form precipitation, is dried in vacuo after filtering, is what CN102249975A was disclosed after testing
(S) the oxo-1-pyrrolidine ethanamide crystal formation I of -4- hydroxyls -2.
Comparative example 6
With the 10mL oxo-1-pyrrolidine ethanamide 1g of methanol dissolving (S) -4- hydroxyls -2, then settled solution is added dropwise
Into tetrahydrofuran, it is stirred continuously 5 hours, it is impossible to form precipitation；Continue to stir 14 hours, still can not form precipitation.
Change the tetrahydrofuran in comparative example 6 into n-hexane, petroleum ether, can not form precipitation.
Comparative example 7
With the 10mL oxo-1-pyrrolidine ethanamide 1g of acetate dissolution (S) -4- hydroxyls -2, then settled solution is added dropwise
Into acetone, it is stirred continuously 5 hours, it is impossible to form precipitation；Continue to stir 14 hours, still can not form precipitation.
Change the acetic acid in comparative example 7 into normal propyl alcohol, isopropanol or n-butanol, can not form precipitation.
Comparative example 8
Levo-oxiracetam 1g is dissolved with 10mL ethanol, then settled solution is added drop-wise in n-hexane, is stirred continuously
5 hours, precipitation is formed, is dried in vacuo after filtering, is S-oxiracetam crystal formation I and S-oxiracetam crystal formation II by detection
Mixture.
Experiment shows that the oxo-1-pyrrolidine ethanamide crystal formation I of (S) -4- hydroxyls -2 can be made in some solvent combinations, have
Solvent combination the oxo-1-pyrrolidine ethanamide crystal formation I of (S) -4- hydroxyls -2 and the oxo -1- pyrroles of (S) -4- hydroxyls -2 can be made
Alkyl acetamide crystal formation II mixture is coughed up, the oxo-1-pyrrolidine ethanamide of (S) -4- hydroxyls -2 can not be made in some solvent combinations
Crystal formation；To sum up, the oxo-1-pyrrolidine ethanamide crystal formation II of culture (S) -4- hydroxyls -2 by way of good solvent/poor solvent,
With certain contingency, it is difficult to use similar compatibility, similar polarity solvent substitutes scheduling theory derivation.
Embodiment 2
The oxo-1-pyrrolidine ethanamide 1g of (S) -4- hydroxyls -2 that purity is 99.5% is dissolved with dimethyl acetamide 8mL,
Then settled solution is added drop-wise in tetrahydrofuran, is stirred continuously after 3h and filters the precipitation of precipitation, vacuum drying both (S)-
The oxo-1-pyrrolidine ethanamide crystal formation of 4- hydroxyls-2, after testing, with the oxo-1- pyrroles of (S)-4- hydroxyls made from embodiment 1-2
Alkyl acetamide crystal formation II is identical.
Embodiment 3
The oxo-1-pyrrolidine ethanamide of (S) -4- hydroxyls -2 that purity is 99.5% is dissolved with dimethyl acetamide 10mL
Settled solution, is then added drop-wise in acetone by 1g, is stirred continuously after 5h and filters the precipitation of precipitation, vacuum drying both obtains (S) -4-
The oxo-1-pyrrolidine ethanamide crystal formation of hydroxyl -2, after testing, with the OXo-1-pyrrolidine of (S) -4- hydroxyls -2 made from embodiment 1
Acetamide crystal formation II is identical.
Embodiment 4
The oxo-1-pyrrolidine ethanamide 1g of (S) -4- hydroxyls -2 that purity is 99.5% is dissolved with isopropanol 10mL, then
Settled solution is added drop-wise in petroleum ether, is stirred continuously after 4h and filters the precipitation of precipitation, vacuum drying both (S) -4- hydroxyls -
2 oxo-1-pyrrolidine ethanamide crystal formations, after testing, with the OXo-1-pyrrolidine acetyl of (S) -4- hydroxyls -2 made from embodiment 1
Amine crystal formation II is identical.
Embodiment 5
The oxo-1-pyrrolidine ethanamide of (S) -4- hydroxyls -2 that purity is 99.5% is dissolved with dimethyl acetamide 10mL
Settled solution, is then added drop-wise in dichloromethane by 1g, is stirred continuously after 3h and filters the precipitation of precipitation, vacuum drying was both obtained
(S) the oxo-1-pyrrolidine ethanamide crystal formation of -4- hydroxyls -2, after testing, with the oxo -1- of (S) -4- hydroxyls -2 made from embodiment 1
Pyrrolidine acetamide crystal formation II is identical.
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. the oxo-1-pyrrolidine ethanamide crystal formation II of one kind (S) -4- hydroxyls -2 preparation method, using good solvent dissolve (S) -
The oxo-1-pyrrolidine ethanamide of 4- hydroxyls -2, then adds poor solvent and is mixed to prepare the OXo-1-pyrrolidine of (S) -4- hydroxyls -2
Acetamide crystal formation II, it is characterised in that：
The good solvent is dimethyl acetamide or isopropanol, and poor solvent is tetrahydrofuran, dichloromethane, acetone, acetic acid second
Ester, ether, n-hexane or petroleum ether；Wherein when good solvent is dimethyl acetamide, poor solvent is tetrahydrofuran, dichloromethane
Alkane, acetone or ethyl acetate；When good solvent is isopropanol, poor solvent is n-hexane or petroleum ether；(the S) -4- hydroxyls -
2 oxo-1-pyrrolidine ethanamide 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、37.685、39.721
There is diffraction maximum at degree.
2. method as claimed in claim 1, it is characterised in that：When good solvent be dimethyl acetamide when, poor solvent be acetone,
Dichloromethane or ethyl acetate；When good solvent is isopropanol, poor solvent is n-hexane or petroleum ether.
3. the method as described in claim 1, it is characterised in that：The oxygen of (S) -4- hydroxyls -2 is first made using following reaction scheme
Generation -1- pyrrolidine acetamides, then obtain crystal formation II with anti-solvent legal system again；Reaction scheme is：
Operating procedure is：
1), first S-4- chloro-3-hydroxyls ethyl butyrate is dissolved with cyclopentanol, sodium azide is then added anti-at 120~130 DEG C
Answer and obtain within 2~3 hours intermediate compound I, wherein S-4- chloro-3-hydroxyls ethyl butyrate and sodium azide mol ratio are 1：2~3；
2), intermediate compound I is dissolved with DMSO, carrying out reduction reaction with hydrogen by catalyst of Metal Palladium obtains intermediate II, instead
It is 10~40 DEG C to answer temperature, and the reaction time is 5~8 hours；
3), intermediate II is dissolved with tetrahydrofuran, potassium carbonate is catalyst, with bromoacetic acid N-butyl react 7~8 hours, instead
It is 50~60 DEG C to answer temperature；The mol ratio of the intermediate II and bromoacetic acid N-butyl is：1:1~2, intermediate II and the carbon
The mol ratio of sour potassium is：1:2~3；
4), intermediate III is dissolved with ethanol, ring closure reaction is carried out under the conditions of 70~80 DEG C and obtains intermediate compound IV, reaction time
For 8~10 hours；
5), intermediate compound IV and ammoniacal liquor are reacted 13~18 hours at 20~30 DEG C, the oxo -1- pyrroles of (S) -4- hydroxyls -2 is obtained
Alkyl acetamide crude product, the intermediate compound IV：The mol ratio of ammonia is intermediate compound IV：Ammonia=1：12~15, with ammonia methanol solution
Ammonia meter, the concentration of the ammoniacal liquor is 25-28%；
6), the oxo-1-pyrrolidine ethanamide crude product of (S) -4- hydroxyls -2 is dissolved by heating in water, activated carbon decolorizing, crosses and filter out
Deactivation charcoal, be concentrated under reduced pressure water removal, and concentration, 0~5 DEG C of sub-cooled are stopped when surplus water is adds 2~3 times of products weight
Crystallization, obtains the oxo-1-pyrrolidine ethanamide of (S) -4- hydroxyls -2；
7), by step 6) the obtained oxo-1-pyrrolidine ethanamide dimethylacetamide amine solvent of (S) -4- hydroxyls -2, Ran Hourong
Drop is added in acetone, dichloromethane or ethyl acetate, is stirred continuously 3~5h, after the precipitation of precipitation is filtered, vacuum drying was both
.
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN101367757A (en) * | 2008-10-13 | 2009-02-18 | 重庆润泽医疗器械有限公司 | Preparation method for (S)-4-hydroxyl-2-oxo-1-pyrrolidine ethanamide |
| 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 |
| CN102603596A (en) * | 2011-01-21 | 2012-07-25 | 重庆润泽医疗器械有限公司 | Preparation method of (S)-4-hydroxy-2-oxo-1-pyrrolidine acetamide |
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| CN101367757A (en) * | 2008-10-13 | 2009-02-18 | 重庆润泽医疗器械有限公司 | Preparation method for (S)-4-hydroxyl-2-oxo-1-pyrrolidine ethanamide |
| CN102603596A (en) * | 2011-01-21 | 2012-07-25 | 重庆润泽医疗器械有限公司 | Preparation method of (S)-4-hydroxy-2-oxo-1-pyrrolidine acetamide |
| 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 |
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