CN108484470B - A kind of preparation method of Oxiracetam - Google Patents
A kind of preparation method of Oxiracetam Download PDFInfo
- Publication number
- CN108484470B CN108484470B CN201810279999.6A CN201810279999A CN108484470B CN 108484470 B CN108484470 B CN 108484470B CN 201810279999 A CN201810279999 A CN 201810279999A CN 108484470 B CN108484470 B CN 108484470B
- Authority
- CN
- China
- Prior art keywords
- oxiracetam
- added
- minutes
- cooled
- preparation
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Active
Links
- 229960001227 oxiracetam Drugs 0.000 title claims abstract description 93
- IHLAQQPQKRMGSS-UHFFFAOYSA-N oxiracetam Chemical compound NC(=O)CN1CC(O)CC1=O IHLAQQPQKRMGSS-UHFFFAOYSA-N 0.000 title claims abstract description 89
- 238000002360 preparation method Methods 0.000 title claims abstract description 23
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims abstract description 26
- 238000001914 filtration Methods 0.000 claims abstract description 23
- 239000012043 crude product Substances 0.000 claims abstract description 22
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 20
- 239000003960 organic solvent Substances 0.000 claims abstract description 19
- 239000007787 solid Substances 0.000 claims abstract description 14
- 229910052757 nitrogen Inorganic materials 0.000 claims abstract description 13
- YMWUJEATGCHHMB-UHFFFAOYSA-N dichloromethane Natural products ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 37
- 239000000243 solution Substances 0.000 claims description 30
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 29
- 238000000034 method Methods 0.000 claims description 17
- 239000008215 water for injection Substances 0.000 claims description 13
- ODHCTXKNWHHXJC-VKHMYHEASA-N 5-oxo-L-proline Chemical compound OC(=O)[C@@H]1CCC(=O)N1 ODHCTXKNWHHXJC-VKHMYHEASA-N 0.000 claims description 12
- 239000000725 suspension Substances 0.000 claims description 12
- -1 dichloromethane Alkane Chemical class 0.000 claims description 6
- 239000002904 solvent Substances 0.000 claims description 3
- NEHMKBQYUWJMIP-UHFFFAOYSA-N chloromethane Chemical class ClC NEHMKBQYUWJMIP-UHFFFAOYSA-N 0.000 claims 1
- 238000004090 dissolution Methods 0.000 abstract description 7
- 238000001816 cooling Methods 0.000 abstract description 4
- 239000000706 filtrate Substances 0.000 abstract description 2
- 238000004811 liquid chromatography Methods 0.000 abstract description 2
- 238000004064 recycling Methods 0.000 abstract description 2
- 238000012360 testing method Methods 0.000 description 18
- 230000000052 comparative effect Effects 0.000 description 8
- 239000000843 powder Substances 0.000 description 7
- 239000007788 liquid Substances 0.000 description 6
- 239000000203 mixture Substances 0.000 description 6
- 238000000634 powder X-ray diffraction Methods 0.000 description 6
- 239000000126 substance Substances 0.000 description 6
- KRQUFUKTQHISJB-YYADALCUSA-N 2-[(E)-N-[2-(4-chlorophenoxy)propoxy]-C-propylcarbonimidoyl]-3-hydroxy-5-(thian-3-yl)cyclohex-2-en-1-one Chemical compound CCC\C(=N/OCC(C)OC1=CC=C(Cl)C=C1)C1=C(O)CC(CC1=O)C1CCCSC1 KRQUFUKTQHISJB-YYADALCUSA-N 0.000 description 5
- 239000012535 impurity Substances 0.000 description 5
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 4
- 239000013078 crystal Substances 0.000 description 4
- 235000013922 glutamic acid Nutrition 0.000 description 4
- 239000004220 glutamic acid Substances 0.000 description 4
- 230000008569 process Effects 0.000 description 4
- WHUUTDBJXJRKMK-UHFFFAOYSA-N Glutamic acid Natural products OC(=O)C(N)CCC(O)=O WHUUTDBJXJRKMK-UHFFFAOYSA-N 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- 239000000356 contaminant Substances 0.000 description 3
- 238000002347 injection Methods 0.000 description 3
- 239000007924 injection Substances 0.000 description 3
- 230000007774 longterm Effects 0.000 description 3
- 238000004519 manufacturing process Methods 0.000 description 3
- 238000005259 measurement Methods 0.000 description 3
- 239000002245 particle Substances 0.000 description 3
- 239000012085 test solution Substances 0.000 description 3
- 238000005382 thermal cycling Methods 0.000 description 3
- 229910017488 Cu K Inorganic materials 0.000 description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- 230000008901 benefit Effects 0.000 description 2
- 150000001875 compounds Chemical class 0.000 description 2
- 239000008367 deionised water Substances 0.000 description 2
- 229910021641 deionized water Inorganic materials 0.000 description 2
- 238000001514 detection method Methods 0.000 description 2
- 238000009826 distribution Methods 0.000 description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 2
- 239000000825 pharmaceutical preparation Substances 0.000 description 2
- 239000002994 raw material Substances 0.000 description 2
- 238000012216 screening Methods 0.000 description 2
- 238000013112 stability test Methods 0.000 description 2
- 238000003860 storage Methods 0.000 description 2
- 238000010998 test method Methods 0.000 description 2
- 208000024827 Alzheimer disease Diseases 0.000 description 1
- 208000000044 Amnesia Diseases 0.000 description 1
- 208000031091 Amnestic disease Diseases 0.000 description 1
- 229910017541 Cu-K Inorganic materials 0.000 description 1
- JZNWSCPGTDBMEW-UHFFFAOYSA-N Glycerophosphorylethanolamin Natural products NCCOP(O)(=O)OCC(O)CO JZNWSCPGTDBMEW-UHFFFAOYSA-N 0.000 description 1
- 241000721701 Lynx Species 0.000 description 1
- 206010039966 Senile dementia Diseases 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- XUIMIQQOPSSXEZ-UHFFFAOYSA-N Silicon Chemical compound [Si] XUIMIQQOPSSXEZ-UHFFFAOYSA-N 0.000 description 1
- 201000004810 Vascular dementia Diseases 0.000 description 1
- 238000009825 accumulation Methods 0.000 description 1
- 230000005260 alpha ray Effects 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 229940124277 aminobutyric acid Drugs 0.000 description 1
- 229960002298 aminohydroxybutyric acid Drugs 0.000 description 1
- 230000006986 amnesia Effects 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 238000003556 assay Methods 0.000 description 1
- 230000008499 blood brain barrier function Effects 0.000 description 1
- 210000001218 blood-brain barrier Anatomy 0.000 description 1
- 210000004556 brain Anatomy 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 238000003889 chemical engineering Methods 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 125000004093 cyano group Chemical group *C#N 0.000 description 1
- 125000004122 cyclic group Chemical group 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 238000002242 deionisation method Methods 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- SUBDBMMJDZJVOS-DEOSSOPVSA-N esomeprazole Chemical compound C([S@](=O)C1=NC2=CC=C(C=C2N1)OC)C1=NC=C(C)C(OC)=C1C SUBDBMMJDZJVOS-DEOSSOPVSA-N 0.000 description 1
- 229960004770 esomeprazole Drugs 0.000 description 1
- 235000019441 ethanol Nutrition 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 239000000945 filler Substances 0.000 description 1
- YQGDEPYYFWUPGO-UHFFFAOYSA-N gamma-amino-beta-hydroxybutyric acid Chemical compound [NH3+]CC(O)CC([O-])=O YQGDEPYYFWUPGO-UHFFFAOYSA-N 0.000 description 1
- 238000007429 general method Methods 0.000 description 1
- 125000000291 glutamic acid group Chemical group N[C@@H](CCC(O)=O)C(=O)* 0.000 description 1
- 150000002307 glutamic acids Chemical class 0.000 description 1
- 230000005484 gravity Effects 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 238000005286 illumination Methods 0.000 description 1
- 230000008676 import Effects 0.000 description 1
- 238000007689 inspection Methods 0.000 description 1
- 238000011835 investigation Methods 0.000 description 1
- 230000000622 irritating effect Effects 0.000 description 1
- 230000014759 maintenance of location Effects 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- GBMDVOWEEQVZKZ-UHFFFAOYSA-N methanol;hydrate Chemical compound O.OC GBMDVOWEEQVZKZ-UHFFFAOYSA-N 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 229910000402 monopotassium phosphate Inorganic materials 0.000 description 1
- 235000019796 monopotassium phosphate Nutrition 0.000 description 1
- 229910000403 monosodium phosphate Inorganic materials 0.000 description 1
- 235000019799 monosodium phosphate Nutrition 0.000 description 1
- 239000002664 nootropic agent Substances 0.000 description 1
- 238000010899 nucleation Methods 0.000 description 1
- 230000006911 nucleation Effects 0.000 description 1
- 150000008104 phosphatidylethanolamines Chemical class 0.000 description 1
- YHHSONZFOIEMCP-UHFFFAOYSA-O phosphocholine Chemical compound C[N+](C)(C)CCOP(O)(O)=O YHHSONZFOIEMCP-UHFFFAOYSA-O 0.000 description 1
- PJNZPQUBCPKICU-UHFFFAOYSA-N phosphoric acid;potassium Chemical compound [K].OP(O)(O)=O PJNZPQUBCPKICU-UHFFFAOYSA-N 0.000 description 1
- 229950004354 phosphorylcholine Drugs 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 238000012545 processing Methods 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 230000005855 radiation Effects 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 230000035945 sensitivity Effects 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 229910052710 silicon Inorganic materials 0.000 description 1
- 239000010703 silicon Substances 0.000 description 1
- AJPJDKMHJJGVTQ-UHFFFAOYSA-M sodium dihydrogen phosphate Chemical compound [Na+].OP(O)([O-])=O AJPJDKMHJJGVTQ-UHFFFAOYSA-M 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
Classifications
-
- 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
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention belongs to field of pharmaceutical chemistry technology.More particularly to a kind of preparation method of Oxiracetam, by Oxiracetam crude product, in the water of inflated with nitrogen, after being heated to dissolution, by gradient cooling, organic solvent, filtering is added in obtained solid, and filtrate is concentrated after recycling organic solvent, obtains Oxiracetam.Oxiracetam purity is high prepared in accordance with the present invention, when by high effective liquid chromatography for measuring Oxiracetam purity, the purity of Oxiracetam is not less than 99.6%.
Description
Technical field
The invention belongs to biomedicine technical fields.More particularly to a kind of preparation method of Oxiracetam.
Background technique
Oxiracetam (Oxiracetam), the entitled Esomeprazole of chemistry, is a kind of hydroxyl
The cyclic derivatives of aminobutyric acid (GABOB) can promote Phosphorylcholine and phosphatidyl ethanolamine close for nootropic agents of new generation
At, promote brain metabolism, through blood-brain barrier to the specific irritating effect of nervous centralis road, improves intelligence and memory, it is clinical
On be primarily adapted for use in treatment amnesia, senile dementia, vascular dementia etc..Its structural formula is as follows:
Oxiracetam is cut nurse by Italian SmithKline ratio and is synthesized in 1974, and takes notice of that people's benefit listed in 1987.Domestic Aura
It is western it is smooth from 1998 listing since be widely used, the kinds such as capsule, injection (small water needle).Published preparation
Method is more, for example, US4824861, JP62026267, US5276164, US4118396, chemical engineering and equipment, 2010,
(12): 71；Sichuan physiological science magazine, 2010,32 (3): 108 etc..
Application No. is 201410321549.0 Chinese invention patents to disclose a kind of oxiracetam compound and its drug
Composition.The X-ray powder diffraction that oxiracetam compound made from the invention is obtained using Cu-K alpha ray measurement is in 2 θ
Characteristic peak is shown at 12.2 °, 14.4 °, 18.1 °, 19.6 °, 20.0 °, 21.8 °, 22.7 °, 24.6 °, 25.1 °.The compound
High-tension apparatus has been used in preparation process, and uses and the disagreeableness toluene of environment is crystallized as solvent, technics comparing
It is complicated.Application No. is 201310328754.5 Chinese invention patents to disclose a kind of Oxiracetam crystal form and preparation method thereof.
Decrease temperature crystalline after the invention is dissolved and is concentrated to Oxiracetam as solvent using aqueous solution avoids having used organic solvent.But
The invention has used the mode of stirring and crystallizing in crystallization process, and the influence due to blade to crystal nucleation in solution will cause
The defects of crystal grain is too small, structural instability.
Therefore, the preparation method for researching and developing new Oxiracetam, is of great significance.
Summary of the invention
For these reasons, applicant obtains a kind of preparation method of new Oxiracetam by repeatedly creative test,
This method, using gradient cooling method and the preparation method of addition Pidolidone, obtains Austria using Oxiracetam crude product as raw material
La Xitan, the Oxiracetam impurity and changes of contents that the present invention obtains are small, and stability is high, have good mobility, Ke Yizuo
For the use of injection raw material.
The targeted Oxiracetam crude product of preparation method provided by the invention is obtained by the synthetic method that is currently known
Oxiracetam crude product or commercially available or import Oxiracetam crude product, hereafter referred to collectively as Oxiracetam crude product, it is however generally that,
The purity of Oxiracetam crude product is lower than 98%, even lower than 92%.
The present inventor, by a large amount of creative screening experiments, has found above-mentioned text on the basis of carefully analyzing the prior art
It offers and general method for purifying and separating is difficult to the Oxiracetam that high productivity obtains high-purity, and other various sides of isolating and purifying
There may be diversified associativity and unpredictabilities again for method and a variety of conditional parameters.The present inventor is by long-term conscientious
Research had been surprisingly found that a kind of Austria including following processing step by the specific method of combined application and after Optimal Parameters
The method of La Xitan.
Specifically, the present invention provides:
A kind of preparation method of Oxiracetam: Oxiracetam crude product after being heated to dissolution, passes through in the water of inflated with nitrogen
Organic solvent, filtering is added in gradient cooling, obtained solid, and filtrate is concentrated after recycling organic solvent, obtains Oxiracetam.
The organic solvent is selected from: methylene chloride, chloroform, chloroform, isopropanol, acetone.
The organic solvent is methylene chloride and acetone.
The organic solvent is methylene chloride and acetone weight ratio are as follows: 1-5:1.
The organic solvent is methylene chloride and acetone weight ratio are as follows: 1-3:1.
The preparation method of the Oxiracetam: taking Oxiracetam crude product, and water for injection is added, after being passed through nitrogen, heating
To 68-75 DEG C, Oxiracetam is completely dissolved, and solution is cooled to 35-50 DEG C, Pidolidone is added, keeps solution temperature 35-50
DEG C, 80-120 minutes are stood, the temperature of the suspension is cooled to 15-25 DEG C, after standing 50-100 minutes, by the suspension liquid cooling
But to 5-10 DEG C, 50-100 minutes is stood, is then filtered, solid is added in organic solvent after filtering, filtering, filter vacuum concentration
It is dry, obtain Oxiracetam.
A kind of preparation method of Oxiracetam: taking Oxiracetam crude product, and water for injection is added, after being passed through nitrogen, is heated to
70 DEG C, Oxiracetam is completely dissolved, and solution is cooled to 45 DEG C, Pidolidone is added, is kept for 45 DEG C of solution temperature, stands 100
Minute, the temperature of the suspension is cooled to 20 DEG C, after standing 75 minutes, which is cooled to 5-10 DEG C, stands 75 points
Then clock filters, solid is added in organic solvent after filtering, and filtering, filter vacuum is concentrated and dried, and obtains Oxiracetam.
The weight of the Pidolidone is 0.01-0.03 times of Oxiracetam weight.
The weight of the organic solvent is 1.5-3.5 times of Oxiracetam weight.
Preparation method of the present invention obtains having following characteristics peak in the powder x-ray diffraction of Oxiracetam process are as follows: 9.2 °
± 0.1 °, 16.24 ° ± 0.1 °, 16.63 ° ± 0.1 °, 16.55 ° ± 0.1 ° and 18.20 ° ± 0.1 °.
Compared with the prior art, the present invention has the following advantages and good effect:
The Oxiracetam purity is high that the method for the present invention obtains, when by high effective liquid chromatography for measuring Oxiracetam purity, hair
Now substantially only one chromatographic peak, the purity of Oxiracetam are not less than 99.6%.Compared with prior art, Aura of the invention
Western smooth compound has better stability, has better powder fluidity.
Specific embodiment
The following describes the present invention further through the description of specific embodiments, but it is to limit of the invention that this, which is not,
System, those skilled in the art's basic thought according to the present invention can make various modifications or improvements, but without departing from this
The basic thought of invention, is all within the scope of the present invention.
Oxiracetam crude product used in the present invention is purchased from Ou Yi Shi Pharmaceutical Group Pharmaceutical Co, and the purchase date is 2017
On October 11, in, the content of Oxiracetam crude product of the present invention are 96.3%, single maximum contaminant 0.29, total impurities 1.20%.
Test example 1
Craft screening studies thermal cycling test
Test method: taking each 1g of Oxiracetam made from comparative example 1~4 and embodiment 2, and water for injection 10mL is added, adds
Enter sodium dihydrogen phosphate 0.2g, 1~10 DEG C is placed 2 days, places two days then at 40 DEG C as 1 circulation, circulation three times, is measured with HPLC
Content results are as shown in table 1.
Comparative example 1: taking Oxiracetam crude product 20g, is added in 50ml water for injection, is heated to 70 DEG C, dissolution completely, cools down
To being cooled to 8 DEG C, 75 minutes are stood, is then filtered, solid is added in organic solvent after filtering, filtering, and filter vacuum concentration is dry
It is dry, obtain Oxiracetam.
Comparative example 2: taking Oxiracetam crude product 20g, and water for injection 50ml is added, after being passed through nitrogen, is heated to 68 DEG C, Aura
It is western it is smooth be completely dissolved, solution is cooled to 35 DEG C, is kept for 35 DEG C of solution temperature, stands 80 minutes, the temperature of the suspension is cold
But to 15 DEG C, after standing 50 minutes, which is cooled to 5 DEG C, 50 minutes is stood, then filters, solid is added after filtering
In acetone 30g, filtering, filter vacuum is concentrated and dried, and obtains Oxiracetam.
Comparative example 3: taking Oxiracetam crude product 20g, and water for injection 50ml is added, after being passed through nitrogen, is heated to 68 DEG C, Aura
It is western it is smooth be completely dissolved, solution is cooled to 35 DEG C, is kept for 35 DEG C of solution temperature, stands 80 minutes, the temperature of the suspension is cold
But to 15 DEG C, after standing 50 minutes, which is cooled to 5 DEG C, 50 minutes is stood, then filters, solid is added after filtering
In methylene chloride 30g, filtering, filter vacuum is concentrated and dried, and obtains Oxiracetam.
Comparative example 4: taking Oxiracetam crude product 20g, and water for injection 50ml is added, after being passed through nitrogen, is heated to 68 DEG C, Aura
It is western it is smooth be completely dissolved, solution is cooled to 35 DEG C, is kept for 35 DEG C of solution temperature, stands 80 minutes, the temperature of the suspension is cold
But to 15 DEG C, after standing 50 minutes, which is cooled to 5 DEG C, 50 minutes is stood, then filters, solid is added after filtering
In the mixture (30g, mass ratio 5:1) of methylene chloride and acetone, filtering, filter vacuum is concentrated and dried, and obtains Oxiracetam.
[assay] is measured according to high performance liquid chromatography (two annex V D of Chinese Pharmacopoeia version in 2015).
Chromatographic condition and system suitability are filler with cyano bonded silica gel；With methanol-water solution (40:60)
For mobile phase；Detection wavelength is 210nm.；Precision weighs Oxiracetam bulk pharmaceutical chemicals about 40mg, sets in 10ml measuring bottle, adds deionization
Water dissolves and is diluted to scale, shakes up, as test solution.Precision measures 1.0ml, sets in 100ml measuring bottle, adds deionized water
It is diluted to scale, is shaken up, precision measures 1.0ml, sets in 10ml measuring bottle, deionized water is added to be diluted to scale, shake up, as control
Solution.20 μ l of contrast solution is taken, liquid chromatograph is injected, detector sensitivity is adjusted, makes principal component peak height full scale
10%, then it is accurate measure test solution and each 20 μ l of contrast solution, inject high performance liquid chromatograph, record chromatogram to it is main at
3 times or more of swarming retention time.
[related substance] weighs that Oxiracetam is appropriate, and (0.01mol/L potassium dihydrogen phosphate is (with phosphoric acid tune with mobile phase
3.0) section pH is to being made the solution of about 1.0mg/ml as test solution；Precision measurement test sample is appropriate, gradually with mobile phase
It is diluted to the solution of 0.01mg/ml, as contrast solution.Under the chromatographic condition of above-mentioned determination, accurate measurement is above-mentioned molten respectively
Each 20 μ l of liquid, injecting chromatograph record chromatogram, measure impurity content with principal component Self-control method.
1 thermal cycling test result of table
Conclusion (of pressure testing): as shown above, relative to the method for comparative example, the Oxiracetam prepared using method of the invention
After thermal cycling test, content, single maximum contaminant and total impurities variation range are small, and Austria that comparative example method obtains
La Xitan content significantly reduces, single maximum contaminant and total impurities dramatically increase, and absolutely proves Austria that the present invention is prepared
La Xitan has better stability, is suitble to the manufacture and long term storage of pharmaceutical preparation.
Prepare embodiment
Embodiment 1
Oxiracetam crude product 20g is taken, water for injection 50ml is added, after being passed through nitrogen, is heated to 68 DEG C, Oxiracetam is complete
Solution is cooled to 35 DEG C, Pidolidone 0.2g is added, kept for 35 DEG C of solution temperature, 80 minutes stood, by the suspension by dissolution
Temperature be cooled to 15 DEG C, after standing 50 minutes, which is cooled to 5 DEG C, 50 minutes is stood, then filters, after filtering
Solid is added in the mixture (30g, mass ratio 5:1) of methylene chloride and acetone, and filtering, filter vacuum is concentrated and dried, and obtains Austria
La Xitan 19.22g.
Embodiment 2
Oxiracetam crude product 20g is taken, water for injection 50ml is added, after being passed through nitrogen, is heated to 70 DEG C, Oxiracetam is complete
Solution is cooled to 45 DEG C, Pidolidone 0.4g is added, kept for 45 DEG C of solution temperature, 100 minutes stood, by the suspension by dissolution
The temperature of liquid is cooled to 20 DEG C, after standing 75 minutes, which is cooled to 5-10 DEG C, 75 minutes is stood, then filters, mistake
Solid is added in the mixture (60g, mass ratio 3:1) of methylene chloride and acetone after filter, and filtering, filter vacuum is concentrated and dried, and obtains
To Oxiracetam 19.27g.
Embodiment 3
Oxiracetam crude product 20g is taken, water for injection 50ml is added, after being passed through nitrogen, is heated to 72 DEG C, Oxiracetam is complete
Solution is cooled to 40 DEG C, Pidolidone 0.5g is added, kept for 45 DEG C of solution temperature, 90 minutes stood, by the suspension by dissolution
Temperature be cooled to 23 DEG C, after standing 90 minutes, which is cooled to 8 DEG C, 75 minutes is stood, then filters, after filtering
Solid is added in the mixture (50g, mass ratio 1:1) of methylene chloride and acetone, and filtering, filter vacuum is concentrated and dried, and obtains Austria
La Xitan 19.21g.
Embodiment 4
Oxiracetam crude product 20g is taken, water for injection 50ml is added, after being passed through nitrogen, is heated to 75 DEG C, Oxiracetam is complete
Solution is cooled to 50 DEG C, Pidolidone 0.6g is added, kept for 50 DEG C of solution temperature, 120 minutes stood, by the suspension by dissolution
The temperature of liquid is cooled to 25 DEG C, after standing 100 minutes, which is cooled to 10 DEG C, 100 minutes is stood, then filters, mistake
Solid is added in the mixture (70g, weight ratio 2:1) of methylene chloride and acetone after filter, and filtering, filter vacuum is concentrated and dried, and obtains
To Oxiracetam 19.22g.
The Oxiracetam that above-described embodiment preparation method is obtained contains according to Chinese Pharmacopoeia two Glutamic Acids of version in 2015
Quantity measuring method is not detected in Oxiracetam and contains glutamic acid.
In above-mentioned preparation method, even if there is glutamic acid to be swept along in Oxiracetam precipitation process, (glutamic acid is soluble in
Water), but it does not dissolve in the organic solvents such as methylene chloride, acetone, ethyl alcohol, therefore, the Oxiracetam that preparation method of the present invention obtains
In do not contain Pidolidone.
Test case 1
Powder x-ray diffraction
2 sample of Example carries out powder x-ray diffraction
Test method: using Bruker D8Advance Powder X-ray Diffractometer, is irradiated with Cu K α with Bragg-
Brentano reflection geometry carries out.In general, the 2 θ value is accurate in ± 0.1-0.2 ° error range.Due to crystal
The relative peak intensities of different preferred orientations, the different samples of same crystalline form can be dramatically different.In addition to using slight pressure
For power to obtain other than smooth surface, the preparation of the sample does not need any specially treated.Using 0.5mm or 0.1mm depth and
The monocrystal silicon sample cup of 12mm bore dia.Tube voltage and electric current are respectively 40kV and 40mA.The x-ray diffractometer is equipped with
Lynx Eye detector.Variable scattering light is used with 3 ° of detection window.Step-length is 0.02 ° of 2 θ, and stepping time is 37 seconds.It is examining
During survey, sample is rotated with 0.5rps.
Test result: the X-ray powder diffraction figure for the Oxiracetam that the radiation of CuK α 1 obtains is used.In 5-40 ° of 2 θ ranges
It is interior, diffraction pattern is measured in reflection.It is characterized in that at 9.2,16.24,16.55,16.63 and 18.20 ° (2 θ ± 0.1 °)
XRPD reflection.
Test case 2
The powder fluidity of embodiment Oxiracetam is tested
The mobility of powder can not be expressed with single characteristic value, and commonly using angle of repose indicates.Angle of repose refers in gravitational field
In, when sliding on the free inclined-plane of powder stack layer, frictional force reaches balance and is in quiet particle between suffered gravity and particle
The maximum angular only measured under state.It is generally acknowledged that good fluidity when angle of repose≤30 °, whens angle of repose≤40 °, can satisfy production
Need for liquidity in the process.
Angle of repose is measured using injection method, powder is slowly added into above funnel, the material leaked out from funnel bottom exists
The inclination angle of coniform accumulation body is formed on horizontal plane.
The mobility of oxiracetam compound made from the embodiment of the present invention 1~4 is compared with commercially available Oxiracetam,
Obtained experimental result is shown in Table 2.
The angle of repose test result of 2 Oxiracetam sample of table
| Group | Angle of repose (°) |
| Embodiment 1 | 29.7 |
| Embodiment 2 | 28.7 |
| Embodiment 3 | 31.3 |
| Embodiment 4 | 30.4 |
| Comparative example | 41.3 |
Conclusion (of pressure testing): as shown in Table 2, compared with commercially available product Oxiracetam, oxiracetam compound tool provided by the invention
There is smaller angle of repose, there is better powder fluidity.
Test case 3
Particle size distribution test
Using Malvern Mastersizer S instrument, pass through the granularity for the Oxiracetam that determination of laser diffraction obtains.Table
Size distribution is provided in 3:
The testing graininess result of 3 Oxiracetam sample of table
| Group | D10 | D50 | D90 |
| Embodiment 1 | 14μm | 122μm | 287μm |
| Embodiment 2 | 13μm | 124μm | 286μm |
| Embodiment 3 | 13μm | 123μm | 289μm |
| Embodiment 4 | 14μm | 122μm | 287μm |
Test case 4
Stability test
The chemical stability of the Oxiracetam of the embodiment of the present invention 2 is studied, investigation condition be high temperature (60 DEG C ±
2 DEG C), strong illumination (4500Lx ± 500lx), high humidity (92.5%, RH) inspection target be content and related substance.
The stability test test result of 4 Oxiracetam sample of table
Conclusion (of pressure testing): from 0,5 day, 10 days under strong light, high temperature, super-humid conditions, related substance, content do not change, say
Bright chemical stability is good, is suitble to the manufacture and long term storage of pharmaceutical preparation.
Claims (3)
1. a kind of preparation method of Oxiracetam, it is characterised in that this method are as follows: Oxiracetam crude product is taken, water for injection is added,
After being passed through nitrogen, it is heated to 68-75 DEG C, Oxiracetam is completely dissolved, and solution is cooled to 35-50 DEG C, Pidolidone is added, is protected
35-50 DEG C of solution temperature is held, stands 80-120 minutes, the temperature of the suspension is cooled to 15-25 DEG C, stands 50-100 minutes
Afterwards, which is cooled to 5-10 DEG C, stands 50-100 minutes, then filters, solid is added in organic solvent after filtering, mistake
Filter, filter vacuum are concentrated and dried, and obtain Oxiracetam；
Wherein the weight of the Pidolidone is 0.01-0.03 times of Oxiracetam weight；The organic solvent is dichloromethane
Alkane and acetone；The weight of the organic solvent is 1.5-3.5 times of Oxiracetam weight；The organic solvent is dichloromethane
Alkane and acetone weight ratio are as follows: 1-5:1.
2. a kind of preparation method of Oxiracetam according to claim 1, it is characterised in that: the organic solvent is two
Chloromethanes and acetone weight ratio are as follows: 1-3:1.
3. a kind of preparation method of Oxiracetam according to claim 1 or 2, should the preparation method comprises the following steps:
Oxiracetam crude product is taken, water for injection is added, after being passed through nitrogen, is heated to 70 DEG C, Oxiracetam is completely dissolved, by solution
45 DEG C are cooled to, Pidolidone is added, is kept for 45 DEG C of solution temperature, 100 minutes is stood, the temperature of the suspension is cooled to 20
DEG C, after standing 75 minutes, which is cooled to 5-10 DEG C, 75 minutes is stood, then filters, solid is added organic after filtering
In solvent, filtering, filter vacuum is concentrated and dried, and obtains Oxiracetam.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201810279999.6A CN108484470B (en) | 2018-04-03 | 2018-04-03 | A kind of preparation method of Oxiracetam |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201810279999.6A CN108484470B (en) | 2018-04-03 | 2018-04-03 | A kind of preparation method of Oxiracetam |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN108484470A CN108484470A (en) | 2018-09-04 |
| CN108484470B true CN108484470B (en) | 2019-08-27 |
Family
ID=63317779
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201810279999.6A Active CN108484470B (en) | 2018-04-03 | 2018-04-03 | A kind of preparation method of Oxiracetam |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN108484470B (en) |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
| CN105348167A (en) * | 2015-11-11 | 2016-02-24 | 北京万全德众医药生物技术有限公司 | Refining method for oxiracetam |
-
2018
- 2018-04-03 CN CN201810279999.6A patent/CN108484470B/en active Active
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
| CN105348167A (en) * | 2015-11-11 | 2016-02-24 | 北京万全德众医药生物技术有限公司 | Refining method for oxiracetam |
Also Published As
| Publication number | Publication date |
|---|---|
| CN108484470A (en) | 2018-09-04 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| US10280173B2 (en) | Ibrutinib solid forms and production process therefor | |
| CN101291911B (en) | Crystals of laquinimod sodium, and process for the manufacture thereof | |
| CN103550159B (en) | Bendamustine hydrochloride solid form | |
| US4894459A (en) | Process for the preparation of morphologically homogeneous forms of thiazole derivatives | |
| CN102281877B (en) | Novel forms of bendamustine free base | |
| EP3141540B1 (en) | Preparation of a crystalline form of chlorogenic acid | |
| JP2013529641A (en) | Polymorph of OSI-906 | |
| US20160176847A1 (en) | Sovaprevir polymorphs and methods of manufacture thereof | |
| WO1999048876A1 (en) | Crystalline sodium phenytoin monohydrate | |
| CN108484470B (en) | A kind of preparation method of Oxiracetam | |
| JP2022525125A (en) | E crystal form of braiaconitine A and its manufacturing method and application | |
| CN110903239A (en) | Novel crystal form of lenvatinib mesylate and preparation method thereof | |
| EP3190115A1 (en) | Salt of cephalosporin derivative, crystalline solid form of same and method for producing same | |
| UA125938C2 (en) | Crystalline form of n-butyldeoxygalactonojirimycin | |
| CN102531936B (en) | Lysine hydrochloride trihydrate and preparation method thereof | |
| US8729130B2 (en) | Methods of using novel solid forms of tacedinaline | |
| WO2021084260A1 (en) | Crystalline entrectinib anhydrate and monohydrate forms; crystalline entrectinib thf, nitromethane, isopropyl acetate and methanol solvate forms; processes for preparing a crystalline entrectinib anhydrate form | |
| CN105859748B (en) | Polycyclic compound sodium salt and its polymorphic, preparation method and application | |
| CN109942487A (en) | A kind of pyridine compounds and their and preparation method thereof, purposes | |
| CN115521205B (en) | Crystal form of diacerein sodium salt and preparation method thereof | |
| CN105012310A (en) | Angiectasis medicine fasudil hydrochloride composition | |
| US20230088511A1 (en) | Polymorphic Form of (-)-Cibenzoline Succinate | |
| CN106459064A (en) | Polymorphic forms and co-crystals of a C-MET inhibitor | |
| CN105055337A (en) | Medicament namely fasudil hydrochloride composite granules for treating cerebral ischemia | |
| CN110437234A (en) | Tofacitinib citrate crystal form compound and preparation method and application thereof |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| TA01 | Transfer of patent application right |
Effective date of registration: 20190228 Address after: 101400 Beijing Huairou Quanhe Garden Area II No.3 Applicant after: Beijing Jinyang United Technology Development Co.,Ltd. Address before: 100070 Building 1203, No. 128 South Fourth Ring West Road, Fengtai District, Beijing Applicant before: Luo Man |
|
| TA01 | Transfer of patent application right | ||
| TA01 | Transfer of patent application right |
Effective date of registration: 20190301 Address after: 101400 Beijing Huairou Quanhe Garden Area II No.3 Applicant after: Beijing Jinyang United Technology Development Co.,Ltd. Address before: 100070 Building 1203, No. 128 South Fourth Ring West Road, Fengtai District, Beijing Applicant before: Luo Man |
|
| TA01 | Transfer of patent application right | ||
| TA01 | Transfer of patent application right |
Effective date of registration: 20190719 Address after: 100070 Beijing Fengtai District South Fourth Ring West Road 128 Building 1202 (Park) Applicant after: BEIJING LIUSHENGHE MEDICAL TECHNOLOGY Co.,Ltd. Address before: 101400 Beijing Huairou Quanhe Garden Area II No.3 Applicant before: Beijing Jinyang United Technology Development Co.,Ltd. |
|
| TA01 | Transfer of patent application right | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant | ||
| TR01 | Transfer of patent right |
Effective date of registration: 20190829 Address after: No. 120 Daquan Road, Xialian District, Huangshi City, Hubei Province Patentee after: LANGTIAN PHARMACEUTICAL (HUBEI) CO.,LTD. Address before: 100070 Beijing Fengtai District South Fourth Ring West Road 128 Building 1202 (Park) Patentee before: Beijing Liushenghe Medical Technology Co.,Ltd. |
|
| TR01 | Transfer of patent right | ||
| PE01 | Entry into force of the registration of the contract for pledge of patent right |
Denomination of invention: A kind of preparation method of oxiracetam Effective date of registration: 20220916 Granted publication date: 20190827 Pledgee: China Minsheng Banking Corp Wuhan branch Pledgor: LANGTIAN PHARMACEUTICAL (HUBEI) CO.,LTD. Registration number: Y2022420000295 |
|
| PE01 | Entry into force of the registration of the contract for pledge of patent right | ||
| PC01 | Cancellation of the registration of the contract for pledge of patent right |
Date of cancellation: 20231114 Granted publication date: 20190827 Pledgee: China Minsheng Banking Corp Wuhan branch Pledgor: LANGTIAN PHARMACEUTICAL (HUBEI) CO.,LTD. Registration number: Y2022420000295 |
|
| PC01 | Cancellation of the registration of the contract for pledge of patent right | ||
| PE01 | Entry into force of the registration of the contract for pledge of patent right |
Denomination of invention: A Preparation Method of Olaxitam Effective date of registration: 20231206 Granted publication date: 20190827 Pledgee: China Minsheng Banking Corp Wuhan branch Pledgor: LANGTIAN PHARMACEUTICAL (HUBEI) CO.,LTD. Registration number: Y2023980069646 |
|
| PE01 | Entry into force of the registration of the contract for pledge of patent right |