CN105837490A - Oxiracetam compound and preparation method thereof - Google Patents
Oxiracetam compound and preparation method thereof Download PDFInfo
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- CN105837490A CN105837490A CN201610268923.4A CN201610268923A CN105837490A CN 105837490 A CN105837490 A CN 105837490A CN 201610268923 A CN201610268923 A CN 201610268923A CN 105837490 A CN105837490 A CN 105837490A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/18—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
- C07D207/22—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D207/24—Oxygen or sulfur atoms
- C07D207/26—2-Pyrrolidones
- C07D207/273—2-Pyrrolidones with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to other ring carbon atoms
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/13—Crystalline forms, e.g. polymorphs
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Abstract
The invention belongs to the technical field of medicines, and particularly relates to an oxiracetam compound .The X-ray diffraction pattern of the oxiracetam compound is shown in the drawing 1 .The invention further relates to a preparation method of the oxiracetam compound .An oxiracetam rough product is dissolved in N,N-dimethylformamide/water at a certain temperature, after the pH value is adjusted to be 4.5-5, activated carbon is added for decoloring and filtering, and after a super-saturated solution is obtained through decompression and concentration, cooling, oscillating and crystallizing are conducted to obtain the product .The new oxiracetam crystal type has good powder mobility, the pipeline transmission during medicine production is easy, and bioavailability is high .
Description
Technical field
The present invention relates to technical field of pharmaceuticals, specifically, relate to a kind of oxiracetam compound and preparation method thereof.
Background technology
Oxiracetam (Oxiracetam) is a kind of pyrrolidones analog derivative, chemical entitled 4-hydroxyl-2-oxo pyrroles
Alkane-N-acetamide, molecule is for C6H10N2O3, structural formula is as follows:
Researched and developed successfully and in listing in 1987 in 1974 than Qie Mu company by Italy SmithKline.This medicine have on the market many
Planting formulation, wherein parenteral solution administering mode is for being dissolved in physiological saline or other dilution iv drip, each 4g, every day one
Secondary, consumption can be increased and decreased as one sees fit.Treatment usual course for the treatment of to neurological deficit is 2 weeks, and the treatment to memory with disturbance of intelligence is led to
Often the course for the treatment of is 3 weeks.
Oxiracetam is the derivative of Piracetam, and its Main Function mechanism includes the following aspects: 1. promote phosphatide
Phatidylcholine and phosphatidyl ethanolamine synthesis, improve the ratio of ATP/ADP in brain, make the synthesis of protein and nucleic acid in brain increase
Add；2. strengthen the Changes of Plasticity of brain, the mouldability of strengthening cynapse, improve senile dementia, the memory of memory disorder patient
And learning functionality；3. reduce cerebral vascular resistance, suppress platelet aggregation, improve microcirculation and increase cerebral tissue blood flow；4. promote
Enter the neurotoxic effect of damaged nerve cell excitatory amino acid.Be applicable to brain damage and the neurological deficit caused thereof,
Memory and the treatment of disturbance of intelligence, be applicable to senile dementia, it may also be used for the brain diseases such as neurosis, encephalitis especially
Convalescence treatment etc..
The Chinese invention patent of Application No. 201410321549.0 discloses a kind of oxiracetam compound and medicine thereof
Composition.The X-ray powder diffraction that the oxiracetam compound that this invention prepares uses Cu-K alpha ray measurement to obtain at 2 θ is
12.2 °, 14.4 °, 18.1 °, 19.6 °, 20.0 °, 21.8 °, 22.7 °, 24.6 °, show characteristic peak at 25.1 °.This compound
Preparation process employs high-tension apparatus, and uses toluene disagreeableness to environment to crystallize as solvent, technics comparing
Complicated.
The Chinese invention patent of Application No. 201310328754.5 discloses a kind of Oxiracetam crystal form and preparation side thereof
Method.This invention for solvent with the aqueous solution Oxiracetam is dissolved and concentrates after decrease temperature crystalline, it is to avoid employ organic solvent.
But this invention employs the mode of stirring and crystallizing in crystallization process, owing to blade is on the impact of crystal nucleation in solution, can make
Become the defects such as too small, the structural instability of crystal grain.
In view of this, the special proposition present invention.
Summary of the invention
It is an object of the invention to overcome existing technological deficiency, it is provided that one is applicable to technique and produces, and drug effect is more excellent
Oxiracetam compound.
For realizing the purpose of the present invention, the present invention adopts the following technical scheme that
A kind of oxiracetam compound, it is characterised in that the main diffraction peak of the x-ray diffraction pattern of described compound is such as
Under:
The X-ray diffracting spectrum of above-mentioned oxiracetam compound powder substantially as shown in, is a kind of new Austria
La Xitan crystal formation.
Present invention also offers the preparation method of a kind of oxiracetam compound, this preparation method comprises the steps:
(1) Oxiracetam crude product is added dissolving in the water of 40～60 DEG C and the solution of DMF, wherein
Water is 1:3～6 with the volume ratio of DMF, and the amount ratio of Oxiracetam crude product and solvent is 1g:10～15ml；
(2), after addition vinegar acid for adjusting pH is 4.5～5.0 in the solution of step (1), adds activated carbon decolorizing and filter；
(3) solution decompression after the decarburization described in step (2) is concentrated, obtain supersaturated solution；
(4) it is sealed and placed in the supersaturated solution described in step (3) on shaking table carrying out forward and the most alternately shaking,
It is cooled to 0～10 DEG C according to the cooling rate of 2～5 DEG C/h simultaneously, isolates white crystalline powder；
(5) white crystalline powder drying under reduced pressure described in step (4) constant weight are obtained product.
In above-mentioned preparation method, described in step (2), pH value is 4.8.
Described in step (4), the shaking frequency range of shaking table is 60～100 revs/min.
The alternate run time of shaking table described in step (4) is 5～20 minutes, and the preferably alternate run time is 10 minutes.
Described in step (4), supersaturated solution is down to 5 DEG C with the cooling rate of 3 DEG C/h.
Described in step (1), solution temperature is 50 DEG C.
Water described in step (1) is 1:4 with the volume ratio of DMF, Oxiracetam crude product and the use of solvent
Amount ratio is 1g:12mL.
The generation of nucleus has three kinds of forms: i.e. primary homogeneous nucleation, primary nonhomogen-ous nucleation and secondary nucleation.Satiate at height
With under degree, solution spontaneously generates the process of nucleus, is referred to as primary homogeneous nucleation；Solution generates nucleus under the induction of exotic
Process, be referred to as primary nonhomogen-ous nucleation；And the nucleation process in the solution containing solute crystals, referred to as secondary nucleation.Two
Secondary nucleation falls within nonhomogen-ous nucleation process, produced small crystalline substance when it is between crystal or crystal collides with other solids
The lower generation of induction of grain.
The present invention utilizes shaking table granting the solution sealed on the basis of Oxiracetam supersaturated solution decrease temperature crystalline
Vibrations, are surprised to find that the Oxiracetam of vibrations induction nucleation creates a kind of new crystalline structure in the process, and by
Change in crystal structure so that it is the solid of crystallization obtains excellent effect on powder fluidity, is analyzing simultaneously
It is found that it has higher bioavilability during this crystal formation absorbability in vivo.
Compared with prior art, the oxiracetam compound of the present invention has more preferable powder fluidity and higher biology
Availability.
Accompanying drawing explanation
Fig. 1 is the X-ray diffraction spectrogram of the oxiracetam compound of the embodiment of the present invention 1 preparation.
Fig. 2 is that the oxiracetam compound of comparative example 2 of the present invention preparation is to the blood concentration-time after Oral Administration in Rats administration
Curve.
Fig. 3 is that the oxiracetam compound of the embodiment of the present invention 1 preparation is to the blood concentration-time after Oral Administration in Rats administration
Curve.
Detailed description of the invention
Be below the detailed description of the invention of the present invention, described embodiment be in order to further describe the present invention rather than
Limit the present invention.
Embodiment 1
(1) Oxiracetam crude product 50g is added dissolving in the water of 50 DEG C and the solution of DMF, Qi Zhongshui
Being 1:4 with the volume ratio of DMF, the amount ratio of Oxiracetam crude product and solvent is 1g:12ml；
(2), after addition vinegar acid for adjusting pH is 4.8 in the solution of step (1), adds activated carbon decolorizing and filter；
(3) solution decompression after the decarburization described in step (2) is concentrated, obtain supersaturated solution；
(4) it is sealed and placed on the shaking table that frequency is 90 revs/min just carrying out by the supersaturated solution described in step (3)
Shaking to reversely replacing, the alternate run time is 10 minutes, is cooled to 5 DEG C according to the cooling rate of 3 DEG C/h simultaneously, point
Separate out white crystalline powder；
(5) white crystalline powder drying under reduced pressure described in step (4) constant weight are obtained product.
Obtain 43.27g Oxiracetam powder, yield 86.54% through said method, be 99.90% through HPLC detection purity,
X-ray diffracting spectrum is as shown in Figure 1.
Embodiment 2
(1) Oxiracetam crude product 50g is added dissolving in the water of 40 DEG C and the solution of DMF, Qi Zhongshui
Being 1:3 with the volume ratio of DMF, the amount ratio of Oxiracetam crude product and solvent is 1g:15ml；
(2), after addition vinegar acid for adjusting pH is 4.5 in the solution of step (1), adds activated carbon decolorizing and filter；
(3) solution decompression after the decarburization described in step (2) is concentrated, obtain supersaturated solution；
(4) it is sealed and placed on the shaking table that frequency is 100 revs/min carrying out by the supersaturated solution described in step (3)
Forward and the most alternately shaking, the alternate run time is 5 minutes, is cooled to 10 DEG C according to the cooling rate of 2 DEG C/h simultaneously,
Isolate white crystalline powder；
(5) white crystalline powder drying under reduced pressure described in step (4) constant weight are obtained product.
Obtain 41.73g Oxiracetam powder, yield 83.46% through said method, be 99.87% through HPLC detection purity,
The spectrogram drawn through X-ray diffraction is basically identical with embodiment 1.
Embodiment 3
(1) Oxiracetam crude product 50g is added dissolving in the water of 60 DEG C and the solution of DMF, Qi Zhongshui
Being 1:6 with the volume ratio of DMF, the amount ratio of Oxiracetam crude product and solvent is 1g:10ml；
(2), after addition vinegar acid for adjusting pH is 5.0 in the solution of step (1), adds activated carbon decolorizing and filter；
(3) solution decompression after the decarburization described in step (2) is concentrated, obtain supersaturated solution；
(4) it is sealed and placed on the shaking table that frequency is 60 revs/min just carrying out by the supersaturated solution described in step (3)
Shaking to reversely replacing, the alternate run time is 20 minutes, is cooled to 0 DEG C according to the cooling rate of 5 DEG C/h simultaneously, point
Separate out white crystalline powder；
(5) white crystalline powder drying under reduced pressure described in step (4) constant weight are obtained product.
Obtain 42.15g Oxiracetam powder, yield 84.3% through said method, be 99.82% through HPLC detection purity,
The spectrogram drawn through X-ray diffraction is basically identical with embodiment 1.
Comparative example 1
Comparative example 1 be use this specification record preparation method in step (1)～(3) prepare, with embodiment 1 phase
Ratio, difference is not use shaking table to shake saturated solution, but the mode that have employed stirring carries out crystallization.
(1) Oxiracetam crude product 50g is added dissolving in the water of 50 DEG C and the solution of DMF, Qi Zhongshui
Being 1:4 with the volume ratio of DMF, the amount ratio of Oxiracetam crude product and solvent is 1g:12ml；
(2), after addition vinegar acid for adjusting pH is 4.8 in the solution of step (1), adds activated carbon decolorizing and filter；
(3) solution decompression after the decarburization described in step (2) is concentrated, obtain supersaturated solution；
(4) supersaturated solution described in step (3) is carried out the stirring of 90 revs/min, simultaneously according to 3 DEG C/h
Cooling rate is cooled to 5 DEG C, isolates white crystalline powder；
(5) white crystalline powder drying under reduced pressure described in step (4) constant weight are obtained product.
Obtain 40.98g Oxiracetam powder, yield 81.96% through said method, be 99.76% through HPLC detection purity.
Comparative example 2
Use commercially available Oxiracetam bulk drug, originate from Hubei emerging milky way chemical company.
The powder fluidity test of test example 1 Oxiracetam
The mobility of powder cannot be expressed with single characteristic value, and conventional angle of repose represents.Angle of repose refers at gravitational field
In, when particle slides on the free inclined-plane of powder accumulation horizon, between suffered gravity and particle, frictional force reaches balance and is in quiet
The maximum angular only recorded under state.Good fluidity when it is generally acknowledged angle of repose≤30 degree, can meet life during angle of repose≤40 degree
Need for liquidity during product.
Using injection method to measure angle of repose, be slowly added into by powder above funnel, the material spilt from funnel bottom exists
The inclination angle of coniform accumulation body is formed on horizontal plane.
The solubility of the oxiracetam compound embodiment of the present invention 1～3 prepared compares with comparative example 1, comparative example 2
Relatively, obtained experimental result is shown in Table 1.
The angle of repose test result of table 1 Oxiracetam sample
| Embodiment 1 | Embodiment 2 | Embodiment 3 | Comparative example 1 | Comparative example 2 | |
| Angle of repose (°) | 36.7 | 37.4 | 37.2 | 41.5 | 45.2 |
As shown in Table 1, compared with comparative example 2 commercially available product Oxiracetam, the oxiracetam compound and right that the present invention provides
Ratio 1 has less angle of repose；And embodiment 1～3 employing prepares Oxiracetam to supersaturated solution shaking mode and stops
Angle is substantially better than in comparative example 1 Oxiracetam using stirring and crystallizing to prepare.It follows that to satiety in preparation method of the present invention
Vibrations with solution serve the effect of key in the crystal formation of Oxiracetam changes, and reduce angle of repose so that it is obtain excellence
Powder fluidity.
Test example 2 bioavilability is tested
One, tested medicine:
The oxiracetam compound prepared by the embodiment of the present invention 1 and comparative example 2 commercially available product Oxiracetam bulk drug three kinds
Sample forms.
Two, zoopery:
Take the healthy male rat 20 that weight range is 100～200g, be divided into embodiment 1 group and comparative example 2 groups, often group
10 carry out test, before test only according to " chemicals Non-clinical Pharmacokinetics investigative technique guideline ([H] GPT5-1) "
Water is can't help in fasting in 12 hours, takes rat vein blood in 12 hours interior different time points after oral administration, is placed in liquaemin and processes
Centrifuge tube at a temperature of 4 DEG C, be centrifuged 10min with 4000r/min, take supernatant and be stored in-80 DEG C of refrigerators, use organic examination afterwards
Agent extracts and uses HPLC-MS to detect, and acquired results is shown in Table 2 after being computed arranging.
Table 2 is administered orally the pharmacokinetic parameter of Oxiracetam rat
| Pharmacokinetic parameter | Embodiment 1 group | Comparative example 2 groups |
| Cmax(mg/L) | 103.27±12.35 | 95.24±10.87 |
| Tmax(h) | 1.54±0.89 | 1.74±1.12 |
| AUC0-12h(mg·L-1·h-1) | 442.875±31.57 | 381.37±28.65 |
| Ke(h-1) | 0.28±0.12 | 0.40±0.08 |
| T1/2(h) | 2.48±1.06 | 1.72±0.26 |
As shown in Table 2, the relatively low (AUC of bioavilability of 2 groups of commercially available product Oxiracetams of Oral Administration in Rats comparative example0-12h=
378.37±28.65mg·L-1·h-1), the embodiment 1 group that the present invention provides has more preferable bioavilability (AUC0-12h=
442.875±31.57mg·L-1·h-1)；And compare the comparative example 2 groups of commercially available product, embodiment 1 group can be in the shorter time
Inside reach higher blood concentration (Cmax=103.27 ± 12.35mg/L, Tmax=1.54 ± 0.89h), also have longer half
Decline the phase (T1/2=2.48 ± 1.06h).It follows that to the vibrations of supersaturated solution at Oxiracetam in preparation method of the present invention
Crystal formation constitute in serve key effect, substantially increase the oral administration biaavailability of Oxiracetam.
The data of summary test example and result, it is known that the oxiracetam compound of the present invention compares existing commercially available product
Oxiracetam bulk drug has more preferable powder fluidity, can preferably improve the bioavilability of Oxiracetam.The present invention
Preparation method in supersaturated solution shaken the improvement to crystal formation serve the effect of key.
Oxiracetam compound prepared by other embodiments of the present invention is also carried out above-mentioned test, its result obtained
Similar.
Above the present invention is described in detail, its object is to allow those of ordinary skill in the art will appreciate that this
Invention content and be carried out, can not limit the scope of the invention with this, all Spirit Essence institutes according to the present invention
The equivalence change done or modification, all should contain within the scope of the present invention.
Claims (10)
1. an oxiracetam compound, it is characterised in that when the angle of diffraction of the X-ray powder diffraction of described compound is 2 θ,
Characteristic peak includes: 14.4 ± 0.1 °, 17.6 ± 0.1 °, 19.6 ± 0.1 °, 20.4 ± 0.1 °, 20.8 ± 0.1 °, 21.4 ± 0.1 °,
24.6 ± 0.1 °, 31.7 ± 0.1 °, 36.4 ± 0.1 °.
Oxiracetam compound the most according to claim 1, it is characterised in that the x-ray diffraction pattern of described compound
Diffraction maximum includes:
。
Oxiracetam compound the most according to claim 2, it is characterised in that the X-ray diffracting spectrum of described compound
As shown in Figure 1.
4. the preparation method of the oxiracetam compound described in a claims 1 to 3 any one, it is characterised in that described
Preparation method comprises the steps:
(1) will the solution of the Oxiracetam crude product water and the DMF that add 40～60 DEG C dissolve, wherein water with
The volume ratio of DMF is 1:3～6, and the amount ratio of Oxiracetam crude product and solvent is 1g:10～15ml；
(2), after addition vinegar acid for adjusting pH is 4.5～5.0 in the solution of step (1), adds activated carbon decolorizing and filter；
(3) solution decompression after the decarburization described in step (2) is concentrated, obtain supersaturated solution；
(4) supersaturated solution described in step (3) is sealed and placed on shaking table carrying out forward and the most alternately shaking, simultaneously
It is cooled to 0～10 DEG C according to the cooling rate of 2～5 DEG C/h, isolates white crystalline powder；
(5) white crystalline powder drying under reduced pressure described in step (4) constant weight are obtained product.
Preparation method the most according to claim 4, it is characterised in that described in step (2), pH value is 4.8.
Preparation method the most according to claim 4, it is characterised in that the shaking frequency range of shaking table described in step (4)
It it is 60～100 revs/min.
Preparation method the most according to claim 4, it is characterised in that the alternate run time of shaking table described in step (4)
Being 5～20 minutes, the preferably alternate run time is 10 minutes.
Preparation method the most according to claim 4, it is characterised in that the supersaturated solution described in step (4) with 3 DEG C/
Hour cooling rate be down to 5 DEG C.
Preparation method the most according to claim 4, it is characterised in that the solution temperature described in step (1) is 50 DEG C.
Preparation method the most according to claim 4, it is characterised in that water and N described in step (1), N-dimethyl formyl
The volume ratio of amine is 1:4, and the amount ratio of Oxiracetam crude product and solvent is 1g:12mL.
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