CN103553998A - Preparation method of (S)-oxiracetam crystal form III - Google Patents
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Abstract
The invention relates to a preparation method of a (S)-oxiracetam crystal form III, which comprises the following steps: dissolving (S)-oxiracetam in a sec-butyl alcohol solvent according to the concentration of 5-50 mg/ml, continuously stirring, heating to 40-80 DEG C for dissolution, and filtering to form a supersaturated solution; and sealing the obtained supersaturated solution in a -17-21 DEG C low-temperature environment, and cooling to crystallize to obtain a colorless massive crystal which is the (S)-oxiracetam new crystal form III. The preparation method has the advantages of cheap and accessible raw materials, high purity of the prepared (S)-oxiracetam new crystal form III, mild conditions, fewer introduced impurities, favorable reproducibility, controllable production process and high safety, and is simple to operate and suitable for industrial production.
Description
Technical field
The present invention relates to field of medicaments, definite saying relates to a kind of preparation method, relates to specifically the preparation method of levo-oxiracetam crystal form II I.
Background technology
Oxiracetam is synthetic first in 1974 by Italian SmithKline Bi Qiemu company, the nootropic agents of new generation of listing in 1987, pyrrolidinone compounds (ring GABOB) derivative, piracetam analogue, can promote Phosphorylcholine and adjacent acyl thanomin synthetic, promote brain metabolism, by hemato encephalic barrier, specificity central nervous pathway is had to hormesis, improve intelligence and memory.Cerebro-vascular diseases, brain injury, brain tumor (postoperative), intracranial infection, dementia, brain degenerative disease etc. are had to good efficacy.Be applicable to memory and disturbance of intelligence that the diseases such as light moderate vascular dementia, senile dementia and cerebral trauma cause, better than piracetam to remembering concentrating of especially thinking, and toxicity is less.Have report to show, the levo form of oxiracetam is higher than dextrorotation activity.
Patent CN102050774A has reported a kind of process for purification of oxiracetam compound; Patent CN101121688A discloses improving one's methods of a kind of oxiracetam; Patent CN101575309A, CN101367757, CN101575309 disclose respectively the synthetic method of (S)-oxiracetam.Patent CN102249975A discloses (S)-oxiracetam crystal formation I and preparation method thereof.Patent CN102351770B discloses a kind of oxiracetam two crystal types.Patent WO2013/020391A1 discloses S-oxiracetam crystal form II and preparation method.
Research staff chances on, and (S)-oxiracetam, except the crystal formation I and crystal form II that have announced, also exists another kind of new crystal.
The alleged crystal formation I of the present invention is the crystal formation in Chinese patent CN102249975A disclosed " (S)-Esomeprazole crystal formation I and its production and use ", and alleged crystal form II is disclosed crystal formation in published Chinese patent CN102558013A " (S)-Esomeprazole crystal form II and preparation method thereof ".
For the polymorphic of medicine, different polymorphics can have different characteristics, as chemical stability, fusing point, apparent solubility, dissolution rate and density etc.These character can directly affect processing and the production of bulk drug and preparation, and can affect stability, solubleness and the bioavailability of preparation.In the solid preparation of making at the polymorphic of medicine, solubleness directly affects bioavailability, conventionally, the medicine that solubleness is large, bioavailability can be higher.Therefore, the polymorphic of medicine all has great importance with quality, security and the validity of pharmaceutical preparation.
Summary of the invention
The invention provides the preparation method of (S)-oxiracetam crystal form II I, integrity property of the present invention as mentioned below, still for convenience's sake, is called " crystal form II I " by found (S)-oxiracetam new crystal.The method is simple, with low cost, and (S)-oxiracetam crystal form II I purity of making is high, foreign matter content is low.
The object of the invention is to be achieved through the following technical solutions:
(S) preparation method of-oxiracetam crystal form II I, adopts cooling down mode to prepare, and makes by the following method:
(1). (S)-oxiracetam is dissolved in sec-butyl alcohol solvent with 5mg/mL-50mg/mL, constantly stirs, 40 ℃～80 ℃ heating for dissolving, filter, and form supersaturated solution;
(2). the supersaturated solution that step (1) is obtained seals crystallisation by cooling in the low temperature environment that is placed on-17 ℃～-21 ℃, obtains colourless bulk crystals, is (S)-oxiracetam new crystal III.
In above-mentioned steps (2), crystal reached balance greatly in the time of 24 hours-36 hours, no longer separated out afterwards.Preferably 40 ℃～50 ℃ of the temperature of described heating for dissolving.Preferably-18 ℃～-20 ℃ of low temperature environments.
Described reaction raw materials and reagent are commercially available prod.
In order further to improve yield and the purity of crystal form II I, (S)-oxiracetam that the mode of being preferably as follows makes:
Intermediate II intermediate III
(S)-oxiracetam
First S-4-amino-3-hydroxybutyrate is mixed with the ethanol of 5～20 times of weight, then add sulfur oxychloride at 0～60 ℃, to react 1～5 hour, S-4-amino-3-hydroxybutyrate and sulfur oxychloride mol ratio are 1:1.5～1.65; The alcoholic solution that acquisition contains intermediate compound I is then collected intermediate compound I from the alcoholic solution that contains intermediate compound I.
The intermediate compound I that will obtain from step (1), in the tetrahydrofuran solvent of the 10-15 of S-4-amino-3-hydroxybutyrate times of weight with halogenated acetic acids ester catalyzed reaction 5～10 hours under triethylamine or lutidine alkali exist, temperature of reaction is 0～60 ℃, then collects and obtains intermediate II; The mol ratio of intermediate compound I and halogenated acetic acids ester is: 1: 1～3, and the mol ratio of intermediate compound I and described alkaline catalysts is: 1: 2～3.
The intermediate II that step (2) is obtained is carried out ring closure reaction under 50～120 ℃ of conditions in toluene solvant, and the time is 3～8 hours, obtains the solution that contains intermediate III, then from the solution that contains intermediate III, collects and obtains intermediate III.
The intermediate III that step (3) is obtained is reacted with strong aqua 4～16 hours at 20～30 ℃, then from reaction product, collects target product (S)-oxiracetam.
Specifically, the preparation method of above-mentioned (S)-oxiracetam new crystal III:
First S-4-amino-3-hydroxybutyrate is mixed with the ethanol of 5～20 times of weight, then add sulfur oxychloride at 0～60 ℃, to react 1～5 hour, S-4-amino-3-hydroxybutyrate and acylating agent or catalyzer (sulfur oxychloride) mol ratio is 1:1.5～1.65; The alcoholic solution that acquisition contains intermediate compound I is then collected intermediate compound I from the alcoholic solution that contains intermediate compound I.
The intermediate compound I that will obtain from step (1), in the tetrahydrofuran solvent of the 10-15 of S-4-amino-3-hydroxybutyrate times of weight with halogenated acetic acids ester catalyzed reaction 5～10 hours under triethylamine or lutidine alkali exist, temperature of reaction is 0～60 ℃, then collects and obtains intermediate II; The mol ratio of intermediate compound I and halogenated acetic acids ester is: 1: 1～3, and the mol ratio of intermediate compound I and described alkaline catalysts is: 1: 2～3.
The intermediate II that step (2) is obtained is carried out ring closure reaction under 50～130 ℃ of conditions in toluene solvant, and the time is 3～8 hours, obtains the solution that contains intermediate III, then from the solution that contains intermediate III, collects and obtains intermediate III.
The intermediate III that step (3) is obtained is reacted with strong aqua 4～16 hours at 20～30 ℃, then from reaction product, collects target product (S)-oxiracetam.
(the S)-oxiracetam of above-mentioned collection is dissolved in sec-butyl alcohol solvent with 10mg/mL-50mg/mL, constantly stirs, heat 40 ℃～50 ℃ dissolvings, filter, form supersaturated solution; The sealing of this solution being placed in-18 ℃～-20 ℃ environment to crystallisation by cooling 24～36 hours, obtaining colourless bulk crystals, is (S)-oxiracetam new crystal III.
Described reaction raw materials and reagent are commercially available prod.
Beneficial effect of the present invention:
(S)-oxiracetam new crystal III that preparation method of the present invention makes has equally oxiracetam and can promote Phosphorylcholine and adjacent acyl thanomin to synthesize, promote brain metabolism, by hemato encephalic barrier, specificity central nervous pathway is had to hormesis, improve intelligence and memory, the advantage to memory dysfunction successful.The fusing point peak temperature of (S)-oxiracetam new crystal III that the inventive method is prepared is 117.3 ℃, and in water, dissolution rate is fast, solubleness >=100mg/mL in water, and bioavailability is high.Preparation method of the present invention adopts raw material (S)-oxiracetam new crystal III purity cheap and easy to get, that make high, and preparation method's mild condition is easy and simple to handle, introducing impurity is few, favorable reproducibility, and production process is easy to control, safe, be applicable to suitability for industrialized production.
Accompanying drawing explanation
Fig. 1 is the crystalline structure figure of crystal type (S)-oxiracetam crystal form II I;
Fig. 2 is the structure cell accumulation graph of crystal type (S)-oxiracetam crystal form II I;
Fig. 3 is crystal type (S)-oxiracetam crystal form II I monocrystalline simulation X-ray powder diffraction figure;
Fig. 4 is crystal type (S)-oxiracetam crystal form II I Single Crystal X-ray powder diagram;
Fig. 5 is the Single Crystal X-ray powdery diffractometry comparison diagram of crystal type (S)-oxiracetam crystal form II I, (S)-oxiracetam crystal form II, (S)-oxiracetam crystal formation I.Be respectively from top to bottom: levo-oxiracetam anhydrous crystal forms (crystal form II I), anhydrous crystal forms (crystal formation I) and 0.5 crystal type (crystal form II).
Embodiment
Below by embodiment, the present invention is specifically described; be necessary to be pointed out that at this following examples are only used to further illustrate the present invention; can not be interpreted as limiting the scope of the invention, person skilled in art can make some nonessential improvement and adjustment to the present invention according to the invention described above content.
Embodiment 1
A synthetic method for (S)-oxiracetam, it carries out as follows,
(1) preparation of intermediate compound I:
Get raw material S-4-amino-3-hydroxybutyrate 50g, add in a single neck bottle, add ethanol 250ml, stir, ice-water bath is cooling, slowly splash into thionyl chloride 150ml, keep temperature to be no more than 60 ℃, solid first has a dissolution process, then separates out again, drip solid while making a concentrated effort to finish and dissolve again, finally form a faint yellow clarified liq.Continue to stir 5 hours, some plate is shown in that raw material primitive reaction is complete, and stopped reaction directly concentratedly obtains faint yellow oily matter except desolventizing, under low temperature, solidifies and obtains intermediate compound I.Through nuclear-magnetism, detect, intermediate compound I is: 1H-NMR (300MHz, D2O): δ 2.76-2.67 (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): δ 43.7 (C-2), 48.4 (C-4), 57.0 (OCH,), 68.9 (C-3), 177.5 (C-I). intermediate compound I is:
(2) preparation of intermediate II
The intermediate compound I that step (1) is obtained is dissolved in the tetrahydrofuran solution of 500ml, be cooled to 0 ℃ of outer temperature, add triethylamine (3eq), there are a large amount of solids to generate, stir five minutes, start to drip ethyl bromoacetate 90ml (2eq), dropping process has exothermic phenomenon, dropwising rear continuation stirs 2 hours, point plate is shown in that raw material reaction is complete, stopped reaction, filter, filtrate adds EA (ethyl acetate) 500ml, water 300ml, solid dissolves completely, water layer is saturated by solid sodium chloride, for going out organic layer, water layer EA200ml extracting twice, merge organic layer, organic layer is washed three times with the hydrochloric acid 200ml of 2M, merge hydrochloric acid water, organic phase discards, water continues to regulate pH to 8 with sodium bicarbonate, solid sodium chloride is saturated, EA300ml extraction three times, merge organic phase, anhydrous magnesium sulfate drying, concentrated obtain faint yellow oily matter except desolventizing, under low temperature, solidify and obtain intermediate II.Through nuclear-magnetism, detect intermediate II: 1H-NMR (300MHz, D2O): δ 1.3 (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 II is:
R1 is methyl, and R2 is ethyl.
(3) preparation of intermediate III
The intermediate II that step (2) is obtained is dissolved with 500ml toluene, is warming up to 120 ℃, refluxes 8 hours, obtains a red tan solution, and some plate is shown in that raw material reaction is complete.Stopped reaction, concentrates and removes toluene, adds EA (ethyl acetate) to dissolve, and removes by filter salt, and activated carbon decolorizing, concentrates and remove to such an extent that yellow oil obtains intermediate III.Through nuclear-magnetism, detect, intermediate III is: 1H-NMR (300MHz, CDCl3) δ 1.280 (t, 3H), 2.38 (dd, 1H), 2.69 (dd, 1H), 3.34 (dd, 1H), 3.77 (dd, 1H), 3.93 (d, 1H), 4.18 (d, 1H), 4.19 (q, 2H), 4.30 (bs, 1H), 4.50 (m, 1H). intermediate III:
r2 is ethyl.
(4) preparation of (S)-oxiracetam
The intermediate III that step (3) is obtained adds strong aqua 200ml, stirring at room 18 hours, some plate is shown in that raw material reaction is complete, stopped reaction, concentrated water and the ammonia removed, obtain yellow oil, add acetone solution oily matter, add a small amount of crystal seed to stir, separate out solid, a small amount of acetone rinsing bottle wall ,-10 ℃ of crystallizations 5 hours, filter and obtain off-white color crude product 36g.Purity 99.3%, isomer proportion 0.2%.By this dissolving crude product, in the water of 100ml, heating is dissolved it, activated carbon decolorizing half an hour, remove by filter gac, crystallisation by cooling, 5 ℃ of placements are spent the night, filter to obtain white solid 32g next day, purity 99.9%, isomer proportion 0.1%, yield is 48.2%, detects levo-oxiracetam: 1H-NMR (300MHz through nuclear-magnetism, DMS0-d6) δ 2.10 (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). optical value :-37.3.(S)-oxiracetam is that structural formula is as follows:
A synthetic method for (S)-oxiracetam, it carries out as follows,
(1) preparation of intermediate compound I:
Get raw material S-4-amino-3-hydroxybutyrate 1g, add in a single neck bottle, add ethanol 20ml, stir, ice-water bath is cooling, slowly splash into thionyl chloride 30ml, keep temperature to be no more than 60 ℃, solid first has a dissolution process, then separates out again, drip solid while making a concentrated effort to finish and dissolve again, finally form a faint yellow clarified liq.Continue to stir 5 hours, some plate is shown in that raw material primitive reaction is complete, and stopped reaction directly concentratedly obtains faint yellow oily matter except desolventizing, under low temperature, solidifies and obtains intermediate compound I.Through nuclear-magnetism, detect, intermediate compound I is: 1H-NMR (300MHz, D2O): δ 2.76-2.67 (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): δ 43.7 (C-2), 48.4 (C-4), 57.0 (OCH,), 68.9 (C-3), 177.5 (C-I). intermediate compound I is:
(2) preparation of intermediate II
The intermediate compound I that step (1) is obtained is dissolved in the tetrahydrofuran solution of 100ml, be cooled to 0 ℃ of outer temperature, add lutidine (1eq), there are a large amount of solids to generate, stir five minutes, start to drip ethyl bromoacetate (2eq), dropping process has exothermic phenomenon, dropwising rear continuation stirs 2 hours, point plate is shown in that raw material reaction is complete, stopped reaction, filter, filtrate adds EA (ethyl acetate) 100ml, water 60ml, solid dissolves completely, water layer is saturated by solid sodium chloride, separate organic layer, water layer EA60ml extracting twice, merge organic layer, organic layer is washed three times with the hydrochloric acid 60ml of 2M, merge hydrochloric acid water, organic phase discards, water continues to regulate pH to 8 with sodium bicarbonate, solid sodium chloride is saturated, EA60ml extraction three times, merge organic phase, anhydrous magnesium sulfate drying, concentrated obtain faint yellow oily matter except desolventizing, under low temperature, solidify and obtain intermediate II.Through nuclear-magnetism, detect intermediate II: 1H-NMR (300MHz, D2O): δ 1.3 (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 II is:
R1 is methyl, and R2 is ethyl.
(3) preparation of intermediate III
The intermediate II that step (2) is obtained is dissolved with 100ml toluene, is warming up to 120 ℃, refluxes 8 hours, obtains a red tan solution, and some plate is shown in that raw material reaction is complete.Stopped reaction, concentrates and removes toluene, adds EA (ethyl acetate) to dissolve, and removes by filter salt, and activated carbon decolorizing, concentrates and remove to such an extent that yellow oil obtains intermediate III.Through nuclear-magnetism, detect, intermediate III is: 1H-NMR (300MHz, CDCl3) δ 1.280 (t, 3H), 2.38 (dd, 1H), 2.69 (dd, 1H), 3.34 (dd, 1H), 3.77 (dd, 1H), 3.93 (d, 1H), 4.18 (d, 1H), 4.19 (q, 2H), 4.30 (bs, 1H), 4.50 (m, 1H). intermediate III:
(4) preparation of (S)-oxiracetam
The intermediate III that step (3) is obtained adds strong aqua 50ml, stirring at room 18 hours, some plate is shown in that raw material reaction is complete, stopped reaction, concentrated water and the ammonia removed, obtain yellow oil, add acetone solution oily matter, add a small amount of crystal seed to stir, separate out solid, a small amount of acetone rinsing bottle wall ,-10 ℃ of crystallizations 5 hours, filter and obtain off-white color crude product 36g.Purity 99.3%, isomer proportion 0.2%.By this dissolving crude product, in the water of 100ml, heating is dissolved it, activated carbon decolorizing half an hour, remove by filter gac, crystallisation by cooling, 5 ℃ of placements are spent the night, filter to obtain white solid 32g next day, purity 99.9%, isomer proportion 0.1%, yield is 48.2%, detects levo-oxiracetam: 1H-NMR (300MHz through nuclear-magnetism, DMS0-d6) δ 2.10 (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). optical value :-37.3.(S)-oxiracetam is that structural formula is as follows:
Embodiment 3
The 50mg that embodiment 1 is made (S)-oxiracetam is dissolved in 2mL sec-butyl alcohol solution, and 40 ° of C heating, filters, and obtains supersaturated solution, and this solution sealing is placed under-19 ℃ of environment to cooling crystallization 24 hours, obtains colourless bulk crystals, is crystal form II I.
Embodiment 4
The prepared crystal type of embodiment 3 (S)-oxiracetam crystal form II I crystal parameter is measured.
Single crystal structure to (S)-oxiracetam crystal form II I is resolved, and its structure cell is rhombic system, and spacer is P4
1,
α=90.00 °, β=90.00 °, γ=90.00 °, unit cell volume
its crystalline structure as shown in Figure 1, pile up as shown in Figure 2 by structure cell.
The crystallographic parameter of crystal type (S)-oxiracetam crystal form II I is as shown in the table:
aR
1＝Σ||F
o|-|F
c||/ΣF
o|.
b?wR
2＝[Σ[w(F
o 2-F
c 2)
2]/Σw(F
o 2)
2]
1/2,w＝1/[σ
2(F
o)
2+(aP)
2+bP],where?P＝[(F
o 2)+2F
c 2]/3.
Described crystal type levo-oxiracetam crystal form II I is 10.54 at angle of diffraction 2 θ, 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, 38.28, 38.96, there is diffraction peak at 40.02 degree places, its monocrystalline simulation X-ray powder diffraction figure as shown in Figure 3, wherein 2 θ are 14.44, 17.12, 18.88, 19.24, 20.66, 20.84, having located the strong peak of diffraction peak for 21.18 ° occurs.Fig. 3 is that above-mentioned crystal type (S)-oxiracetam is from the powder diagram of single crystal structure digital simulation, monocrystalline simulation be take perfect crystallization and is simulated as prerequisite, and in the middle of actual, be difficult to occur definitely perfect, may cause two close peaks just can merge becomes a peak, and causes peak width.The peak of Fig. 4 and Fig. 3 overlaps substantially, and overlap ratio, more than 99%, is said technically and can be thought that crystal type (S)-oxiracetam crystal form II I of preparation is pure single crystal form.
Crystal type of the present invention (S)-oxiracetam crystal form II I, its powder X-ray ray diagram is expressed with the per-cent I crystal formation of spacing d, Bragg angle (2 θ) and relative intensity, as follows:
Crystal type (S)-oxiracetam crystal form II I, crystal type (S)-oxiracetam crystal form II, crystal type (S)-oxiracetam crystal formation I are done to powder diffraction experiment contrast, as shown in Figure 5.
Embodiment 6
20mg (S)-oxiracetam is dissolved in 2mL sec-butyl alcohol solution, and 50 ℃ of heating, filter, supersaturated solution, the sealing of this solution is placed under-17 ℃ of environment to cooling crystallization 3 hours, obtain colourless bulk crystals, by the method for embodiment 4, identifying, is crystal form II I.
Embodiment 7
50mg (S)-oxiracetam is dissolved in 1mL sec-butyl alcohol solution, and 45 ℃ of heating, filter, supersaturated solution, the sealing of this solution is placed under-18 ℃ of environment to cooling crystallization 36 hours, obtain colourless bulk crystals, by the method for embodiment 4, identifying, is crystal form II I.
Embodiment 8
30mg (S)-oxiracetam is dissolved in 6mL sec-butyl alcohol solution, and 80 ℃ of heating, filter, obtain supersaturated solution, this solution sealing is placed on to lower 24 hours cooling crystallizations of-20 ℃ of environment, obtain colourless bulk crystals, by the method for embodiment 4, identifying, is crystal form II I.
Embodiment 9
70mg (S)-oxiracetam is dissolved in 2mL sec-butyl alcohol solution, and 60 ℃ of heating, filter, supersaturated solution, the sealing of this solution is placed under-21 ℃ of environment to cooling crystallization 36 hours, obtain colourless bulk crystals, by the method for embodiment 4, identifying, is crystal form II I.
In existing biological sample, measure on the LC-MS method basis of left oxiracetam, 6 of healthy Beagle dogs are selected in experiment, and body weight is 8～10kg, is divided into two groups, 3 every group, are used for observing the bioavailability of the left oxiracetam of different crystal forms after oral to dog.Study left oxiracetam I crystal formation and the pharmacokinetics of left oxiracetam III crystal formation in dog body, and take oxiracetam as reference preparation, whether the bioavailability of evaluating I crystal formation and III crystal formation is equivalent.And by calculating its pharmacokinetic parameter, it is carried out to evaluation of bioequivalence.Result: left oxiracetam I crystal formation and the main pharmacokinetic parameter of left oxiracetam III crystal formation in Beagle dog body are as follows: Tmax is respectively (1.561 ± 0.398), (1.498 ± 0.3988), Cmax is respectively (198.076 ± 80.462), (186.205 ± 50.321) mg/ml; T1/2 is respectively (0.915 ± 0.125), (0.909 ± 0.112) h; AUC0-∞ is respectively (456.268 ± 85.567), (436.364 ± 75.204) mg*h/ml.Left oxiracetam I crystal formation and left oxiracetam III crystal formation bioavailability are in full accord as can be seen here.
Comparative example 1
10mg (S)-oxiracetam is dissolved in 1mL ethanolic soln, 40 ℃ of heating, filter, obtain supersaturated solution, the sealing of this solution is placed under-19 ℃ of environment to cooling crystallization 24 hours, obtain colourless bulk crystals, by the method for X powder diffraction, identify, (angle of diffraction 2 θ are 12.011 to be found to be crystal formation I, 15.318, 17.407, 19.633, 21.228, 22.052, 24.577, 25.223, 27.647, 28.161, 29.109, 30.805, 31.276, 31.766, 32.77, 33.477, 35.252, 35.645, 36.236, 37.379, 39.56, 40.489, 41.256, 41.948, 43.443, there is diffraction peak at 44.628 degree places).
Comparative example 2
10mg (S)-oxiracetam is dissolved in 1mL butanol solution, 50 ℃ of heating, filter, obtain supersaturated solution, the sealing of this solution is placed under-19 ℃ of environment to cooling crystallization 36 hours, obtain colourless bulk crystals, by the method for X powder diffraction, identify, (angle of diffraction 2 θ are 12.011 to be found to be crystal formation I, 15.318, 17.407, 19.633, 21.228, 22.052, 24.577, 25.223, 27.647, 28.161, 29.109, 30.805, 31.276, 31.766, 32.77, 33.477, 35.252, 35.645, 36.236, 37.379, 39.56, 40.489, 41.256, 41.948, 43.443, there is diffraction peak at 44.628 degree places).
Comparative example 3
10mg (S)-oxiracetam is dissolved in 1mL pyridine solution, and 50 ℃ of heating, filter, and obtain supersaturated solution, and this solution sealing is placed under-17 ℃ of environment to cooling crystallization 36 hours, do not have crystal to separate out.
Comparative example 4
10mg (S)-oxiracetam is dissolved in 1mLTHF solution, 50 ℃ of heating, filter, obtain supersaturated solution, the sealing of this solution is placed under-17 ℃ of environment to cooling crystallization 36 hours, obtain colourless bulk crystals, by the method for X powder diffraction, identify, being found to be crystal form II (is 10.669 at angle of diffraction 2 θ, 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 peak at 39.721 degree places).
Claims (8)
1. the method for (S)-oxiracetam crystal form II I, is characterized in that, adopts cooling down mode to prepare, and specifically adopts following steps:
1). (S)-oxiracetam is dissolved in sec-butyl alcohol solvent, stirs, heating for dissolving, filters, and forms supersaturated solution;
2) supersaturated solution sealing step (1) being obtained is placed on crystallisation by cooling in low temperature environment, obtains colourless bulk crystals, is (S)-oxiracetam new crystal III.
2. as claimed in claim 1 the preparation method of (S)-oxiracetam crystal form II I, is characterized in that: the temperature of described heating for dissolving is 40 ℃～80 ℃.
3. as claimed in claim 2 the preparation method of (S)-oxiracetam crystal form II I, is characterized in that: the temperature of described heating for dissolving is 40 ℃～50 ℃.
4. the preparation method of (S)-oxiracetam crystal form II I as described in claim 1 or 2 or 3, is characterized in that: described low temperature environment is-17 ℃～-21 ℃.
5. as claimed in claim 4 the preparation method of (S)-oxiracetam crystal form II I, is characterized in that: described low temperature environment is-18 ℃～-20 ℃.
6. the preparation method of (S)-oxiracetam crystal form II I as described in claim 1 or 5, is characterized by: the soluble end of described (S)-oxiracetam crystal form II I in sec-butyl alcohol is 5mg/mL-50mg/mL.
7. as claimed in claim 6 the preparation method of (S)-oxiracetam crystal form II I, is characterized by: the soluble end of described (S)-oxiracetam crystal form II I in sec-butyl alcohol is 10mg/mL-50mg/mL.
8. the preparation method of (S)-oxiracetam crystal form II I as claimed in claim 1, is characterized in that:
(1) first S-4-amino-3-hydroxybutyrate is mixed with the ethanol of 5～20 times of weight, then add sulfur oxychloride at 0～60 ℃, to react 1～5 hour, S-4-amino-3-hydroxybutyrate and acylating agent or catalyzer (sulfur oxychloride) mol ratio is 1: 1.5～1.65; The alcoholic solution that acquisition contains intermediate compound I is then collected intermediate compound I from the alcoholic solution that contains intermediate compound I;
(2) intermediate compound I that will obtain from step (1), in the tetrahydrofuran solvent of the 10-15 of S-4-amino-3-hydroxybutyrate times of weight with halogenated acetic acids ester catalyzed reaction 5～10 hours under triethylamine or lutidine alkali exist, temperature of reaction is 0～60 ℃, then collects and obtains intermediate II; The mol ratio of intermediate compound I and halogenated acetic acids ester is: 1: 1～3, and the mol ratio of intermediate compound I and described alkaline catalysts is: 1: 2～3;
(3) intermediate II step (2) being obtained, in toluene solvant, under 50～130 ℃ of conditions, carry out ring closure reaction, time is 3～8 hours, obtains the solution that contains intermediate III, then from the solution that contains intermediate III, collects and obtains intermediate III;
(4) intermediate III step (3) being obtained is reacted with strong aqua 4～16 hours at 20～30 ℃, then from reaction product, collects target product (S)-oxiracetam;
(5) (the S)-oxiracetam of above-mentioned collection is dissolved in sec-butyl alcohol solvent with 10mg/mL-35mg/mL, constantly stirs, heat 40 ℃～50 ℃ dissolvings, filter, form supersaturated solution; The sealing of this solution being placed in-17 ℃～-19 ℃ environment to crystallisation by cooling 24～36 hours, obtaining colourless bulk crystals, is (S)-oxiracetam new crystal III.
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Cited By (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2015067130A1 (en) * | 2013-11-06 | 2015-05-14 | 重庆润泽医药有限公司 | (s)-oxiracetam crystal form iii, preparation method therefor, and application thereof |
| CN105330581A (en) * | 2014-08-07 | 2016-02-17 | 重庆东泽医药科技发展有限公司 | Preparation method for (S)-oxiracetam |
| CN105439936A (en) * | 2014-08-07 | 2016-03-30 | 重庆东泽医药科技发展有限公司 | Oxiracetam preparation method |
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Citations (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS6228964A (en) * | 1985-07-30 | 1987-02-06 | Matsushita Electric Ind Co Ltd | Recording disk reproducing device |
| WO1993006826A1 (en) * | 1991-10-08 | 1993-04-15 | Smithkline Beecham Farmaceutici S.P.A. | Composition comprising s-oxiracetame for use as nootropic |
| JPH06228964A (en) * | 1993-01-28 | 1994-08-16 | ▲緑▼邦實業有限公司 | Stabilizing tree-planting execution method of base rock slope |
| US20040204476A1 (en) * | 2001-08-10 | 2004-10-14 | Celal Ates | Oxopyrrolidine compounds, preparations of said compounds and their use in the manufacturing of levetiracetam and analogues |
| 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 |
| CN101575309A (en) * | 2009-04-28 | 2009-11-11 | 中国医药集团总公司四川抗菌素工业研究所 | Method for synthesizing (S)-oxiracetam |
| CN101885697A (en) * | 2009-05-15 | 2010-11-17 | 天津药物研究院 | Preparation method of Oxiracetam, product of Oxiracetam and use of product |
| CN102531989A (en) * | 2011-08-11 | 2012-07-04 | 重庆润泽医疗器械有限公司 | Purification method for (S)-oxiracetam |
-
2013
- 2013-11-06 CN CN201310544263.4A patent/CN103553998B/en active Active
Patent Citations (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS6228964A (en) * | 1985-07-30 | 1987-02-06 | Matsushita Electric Ind Co Ltd | Recording disk reproducing device |
| WO1993006826A1 (en) * | 1991-10-08 | 1993-04-15 | Smithkline Beecham Farmaceutici S.P.A. | Composition comprising s-oxiracetame for use as nootropic |
| JPH06228964A (en) * | 1993-01-28 | 1994-08-16 | ▲緑▼邦實業有限公司 | Stabilizing tree-planting execution method of base rock slope |
| US20040204476A1 (en) * | 2001-08-10 | 2004-10-14 | Celal Ates | Oxopyrrolidine compounds, preparations of said compounds and their use in the manufacturing of levetiracetam and analogues |
| 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 |
| CN101575309A (en) * | 2009-04-28 | 2009-11-11 | 中国医药集团总公司四川抗菌素工业研究所 | Method for synthesizing (S)-oxiracetam |
| CN101885697A (en) * | 2009-05-15 | 2010-11-17 | 天津药物研究院 | Preparation method of Oxiracetam, product of Oxiracetam and use of product |
| CN102531989A (en) * | 2011-08-11 | 2012-07-04 | 重庆润泽医疗器械有限公司 | Purification method for (S)-oxiracetam |
Cited By (11)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2015067130A1 (en) * | 2013-11-06 | 2015-05-14 | 重庆润泽医药有限公司 | (s)-oxiracetam crystal form iii, preparation method therefor, and application thereof |
| US9670156B2 (en) | 2013-11-06 | 2017-06-06 | Chongqing Ruzer Pharmaceutical Company Limited | Crystal form III of (S)-oxiracetam, preparation method and use thereof |
| CN105330581A (en) * | 2014-08-07 | 2016-02-17 | 重庆东泽医药科技发展有限公司 | Preparation method for (S)-oxiracetam |
| CN105439936A (en) * | 2014-08-07 | 2016-03-30 | 重庆东泽医药科技发展有限公司 | Oxiracetam preparation method |
| CN108467355A (en) * | 2014-08-07 | 2018-08-31 | 重庆润泽医药有限公司 | (R) preparation method of-Esomeprazole |
| US10556863B1 (en) | 2016-10-24 | 2020-02-11 | Chongqing Ruzer Pharmaceutical Company Limited | Crystalline form of (R)-4-hydroxy-2-oxo-1-pyrrolidineacetamide, preparation method therefor and use thereof |
| US10696629B2 (en) | 2016-10-24 | 2020-06-30 | Chongqing Runze Pharmaceutical Company Limited | Crystalline form of dextral oxiracetam, preparation method therefor and use thereof |
| US10793521B2 (en) | 2016-10-24 | 2020-10-06 | Chongqing Ruzer Pharmaceutical Company Limited | Crystalline form II of dextral oxiracetam, preparation method therefor and use thereof |
| WO2018130063A1 (en) * | 2017-01-12 | 2018-07-19 | 重庆润泽医药有限公司 | (r)-4-hydroxy-2-oxo-1-pyrrolidineacetamide crystal form, preparation method therefor, and application thereof |
| JP2020504124A (en) * | 2017-01-12 | 2020-02-06 | チョンチン ルゼル ファーマスーティカル カンパニー リミテッド | Crystalline form of (R) -4-hydroxy-2-oxo-1-pyrrolidineacetamide, its preparation and use |
| US10961192B2 (en) | 2017-01-12 | 2021-03-30 | Chongqing Ruzer Pharmaceutical Company Limited | (R)-4-hydroxy-2-oxo-1-pyrrolidineacetamide crystal form, preparation method therefor, and application thereof |
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