CN105669515B - A kind of Oxiracetam Photodegradation Products and preparation method thereof and analyzing detecting method - Google Patents
A kind of Oxiracetam Photodegradation Products and preparation method thereof and analyzing detecting method Download PDFInfo
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- CN105669515B CN105669515B CN201610096799.8A CN201610096799A CN105669515B CN 105669515 B CN105669515 B CN 105669515B CN 201610096799 A CN201610096799 A CN 201610096799A CN 105669515 B CN105669515 B CN 105669515B
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- 238000001782 photodegradation Methods 0.000 title claims abstract description 39
- IHLAQQPQKRMGSS-UHFFFAOYSA-N oxiracetam Chemical compound NC(=O)CN1CC(O)CC1=O IHLAQQPQKRMGSS-UHFFFAOYSA-N 0.000 title claims abstract description 36
- 229960001227 oxiracetam Drugs 0.000 title claims abstract description 35
- 238000002360 preparation method Methods 0.000 title claims abstract description 25
- 238000000034 method Methods 0.000 title claims abstract description 10
- 239000000126 substance Substances 0.000 claims abstract description 17
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 67
- 239000000047 product Substances 0.000 claims description 38
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 29
- 239000000741 silica gel Substances 0.000 claims description 21
- 229910002027 silica gel Inorganic materials 0.000 claims description 21
- 238000005286 illumination Methods 0.000 claims description 19
- 239000012043 crude product Substances 0.000 claims description 15
- 239000003480 eluent Substances 0.000 claims description 14
- 238000000746 purification Methods 0.000 claims description 14
- 238000010829 isocratic elution Methods 0.000 claims description 13
- 239000012141 concentrate Substances 0.000 claims description 11
- 230000006378 damage Effects 0.000 claims description 9
- GBMDVOWEEQVZKZ-UHFFFAOYSA-N methanol;hydrate Chemical compound O.OC GBMDVOWEEQVZKZ-UHFFFAOYSA-N 0.000 claims description 9
- 239000012046 mixed solvent Substances 0.000 claims description 7
- 230000005526 G1 to G0 transition Effects 0.000 claims description 5
- 239000000706 filtrate Substances 0.000 claims description 5
- YTJSFYQNRXLOIC-UHFFFAOYSA-N octadecylsilane Chemical group CCCCCCCCCCCCCCCCCC[SiH3] YTJSFYQNRXLOIC-UHFFFAOYSA-N 0.000 claims description 5
- 238000003756 stirring Methods 0.000 claims description 5
- WGLUMOCWFMKWIL-UHFFFAOYSA-N dichloromethane;methanol Chemical compound OC.ClCCl WGLUMOCWFMKWIL-UHFFFAOYSA-N 0.000 claims description 4
- 238000010898 silica gel chromatography Methods 0.000 claims description 4
- 238000004458 analytical method Methods 0.000 abstract description 9
- 238000000926 separation method Methods 0.000 abstract description 9
- 238000001514 detection method Methods 0.000 abstract description 7
- 239000007791 liquid phase Substances 0.000 abstract description 7
- 238000010521 absorption reaction Methods 0.000 abstract description 4
- 239000012071 phase Substances 0.000 description 26
- 239000012535 impurity Substances 0.000 description 12
- 239000000243 solution Substances 0.000 description 12
- 239000003814 drug Substances 0.000 description 10
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 9
- 229940079593 drug Drugs 0.000 description 8
- 230000015556 catabolic process Effects 0.000 description 7
- 238000006731 degradation reaction Methods 0.000 description 7
- 239000002994 raw material Substances 0.000 description 7
- 230000007774 longterm Effects 0.000 description 6
- 238000013112 stability test Methods 0.000 description 6
- 238000004128 high performance liquid chromatography Methods 0.000 description 4
- 239000013558 reference substance Substances 0.000 description 4
- 239000012085 test solution Substances 0.000 description 4
- 239000007864 aqueous solution Substances 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 239000000843 powder Substances 0.000 description 3
- 239000000377 silicon dioxide Substances 0.000 description 3
- 239000002904 solvent Substances 0.000 description 3
- 238000003786 synthesis reaction Methods 0.000 description 3
- FTOAOBMCPZCFFF-UHFFFAOYSA-N 5,5-diethylbarbituric acid Chemical compound CCC1(CC)C(=O)NC(=O)NC1=O FTOAOBMCPZCFFF-UHFFFAOYSA-N 0.000 description 2
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- 210000004556 brain Anatomy 0.000 description 2
- 238000009658 destructive testing Methods 0.000 description 2
- 238000007689 inspection Methods 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 230000003340 mental effect Effects 0.000 description 2
- 125000000325 methylidene group Chemical group [H]C([H])=* 0.000 description 2
- 238000010606 normalization Methods 0.000 description 2
- IOQPZZOEVPZRBK-UHFFFAOYSA-N octan-1-amine Chemical compound CCCCCCCCN IOQPZZOEVPZRBK-UHFFFAOYSA-N 0.000 description 2
- 229910052698 phosphorus Inorganic materials 0.000 description 2
- 239000011574 phosphorus Substances 0.000 description 2
- 239000011550 stock solution Substances 0.000 description 2
- 0 *C(C*1=C=CCC1=O)=O Chemical compound *C(C*1=C=CCC1=O)=O 0.000 description 1
- 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 1
- MUEOQEUSJMFYHV-UHFFFAOYSA-N 4-amino-1-methylpyrrole-2-carboxylic acid Chemical compound CN1C=C(N)C=C1C(O)=O MUEOQEUSJMFYHV-UHFFFAOYSA-N 0.000 description 1
- 208000007848 Alcoholism Diseases 0.000 description 1
- 208000024827 Alzheimer disease Diseases 0.000 description 1
- 208000000044 Amnesia Diseases 0.000 description 1
- 208000002381 Brain Hypoxia Diseases 0.000 description 1
- GWBRQNQKTMXXDV-PLNGDYQASA-N CCC/C=C\N(CC(N)=O)C=O Chemical compound CCC/C=C\N(CC(N)=O)C=O GWBRQNQKTMXXDV-PLNGDYQASA-N 0.000 description 1
- UGFAIRIUMAVXCW-UHFFFAOYSA-N Carbon monoxide Chemical compound [O+]#[C-] UGFAIRIUMAVXCW-UHFFFAOYSA-N 0.000 description 1
- 208000022306 Cerebral injury Diseases 0.000 description 1
- 206010008428 Chemical poisoning Diseases 0.000 description 1
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- 208000026139 Memory disease Diseases 0.000 description 1
- 208000027382 Mental deterioration Diseases 0.000 description 1
- 206010027374 Mental impairment Diseases 0.000 description 1
- 238000005481 NMR spectroscopy Methods 0.000 description 1
- 206010039966 Senile dementia Diseases 0.000 description 1
- 230000004913 activation Effects 0.000 description 1
- 150000001343 alkyl silanes Chemical group 0.000 description 1
- 239000002249 anxiolytic agent Substances 0.000 description 1
- 230000000949 anxiolytic effect Effects 0.000 description 1
- 229960002319 barbital Drugs 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000033228 biological regulation Effects 0.000 description 1
- 210000004958 brain cell Anatomy 0.000 description 1
- 230000003925 brain function Effects 0.000 description 1
- 229910002091 carbon monoxide Inorganic materials 0.000 description 1
- 238000001460 carbon-13 nuclear magnetic resonance spectrum Methods 0.000 description 1
- 230000003915 cell function Effects 0.000 description 1
- 210000003169 central nervous system Anatomy 0.000 description 1
- 210000003710 cerebral cortex Anatomy 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 230000001684 chronic effect Effects 0.000 description 1
- 208000010877 cognitive disease Diseases 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 238000012790 confirmation Methods 0.000 description 1
- 230000000994 depressogenic effect Effects 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- 238000002330 electrospray ionisation mass spectrometry Methods 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 238000010812 external standard method Methods 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- 210000001320 hippocampus Anatomy 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 230000010354 integration Effects 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 230000006984 memory degeneration Effects 0.000 description 1
- 208000023060 memory loss Diseases 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 210000002569 neuron Anatomy 0.000 description 1
- 230000005311 nuclear magnetism Effects 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
- 230000008832 photodamage Effects 0.000 description 1
- 230000001737 promoting effect Effects 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 230000001337 psychedelic effect Effects 0.000 description 1
- 239000004089 psychotropic agent Substances 0.000 description 1
- 150000004040 pyrrolidinones Chemical class 0.000 description 1
- 238000003908 quality control method Methods 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
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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
- C07D207/30—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 two double bonds between ring members or between ring members and non-ring members
- C07D207/34—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 two double bonds between ring members or between ring members and non-ring members 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
- C07D207/36—Oxygen or sulfur atoms
- C07D207/38—2-Pyrrolones
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N30/00—Investigating or analysing materials by separation into components using adsorption, absorption or similar phenomena or using ion-exchange, e.g. chromatography or field flow fractionation
- G01N30/02—Column chromatography
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N30/00—Investigating or analysing materials by separation into components using adsorption, absorption or similar phenomena or using ion-exchange, e.g. chromatography or field flow fractionation
- G01N30/02—Column chromatography
- G01N2030/022—Column chromatography characterised by the kind of separation mechanism
- G01N2030/027—Liquid chromatography
Abstract
The invention discloses a kind of Oxiracetam Photodegradation Products and preparation method thereof and analyzing detecting methods.Present invention finds a kind of new Oxiracetam Photodegradation Products, which reports for the first time；Preparation method is simple for the Photodegradation Products provided by the invention, can largely prepare the catabolite；Liquid phase analysis method provided by the invention can quickly detect the catabolite, select the maximum absorption wavelength of the catabolite as Detection wavelength, improve the recall rate of the catabolite, as a result accurately and reliably；Photodegradation Products provided by the invention can be used for the Related substances separation of Oxiracetam and its preparation, further increase the quality standard of Oxiracetam and its preparation, improve its safety and controllability.
Description
Technical field
The present invention relates to technical field of pharmaceuticals, and in particular to a kind of Oxiracetam Photodegradation Products and the light degradation produce
The preparation method and analyzing detecting method of object.
Background technique
Cereboactive drug is a kind of novel medicine for central nervous system that can promote ability of learning and memory, with mental inhibitor, anti-
The psychotropic agents such as depressant drug, anxiolytic, psychoanaleptic and psychedelic are different, it is by bio-energy in brain cell
It is metabolized the assimilation of (such as glucose, ATP, protein, RNA, lipoid), selectively acting is protected in cerebral cortex and hippocampus
Shield, activation or the recovery for promoting nerve cell function improve Integration mechanisms of human brain related with mental act and (such as memory, study, return
Question and answer topic and problem analysis, problem-solving ability).Current most noticeable cereboactive drug is pyrrolidinone compounds, representative
Drug Oxiracetam is a kind of hydroxy-amino-butyric acid cyclic derivatives of synthesis, also known as oxiracetam, oxiracetam, trade name
There is neuromet and be good for bright magnitude, synthesized for the first time by Italian SmithKline ratio Qie Mu company in 1974, is the use of U.S. FDA approval
In one of the drug for the treatment of senile dementia.Its chemical structural formula is as follows：
Oxiracetam is clinically used for cerebral injury caused by treating various chemical factors, various cerebral anoxias and chronic brain function
It is not congruent.To dull-witted, shock, old mental deterioration syndrome, (such as memory loss, adaptability are reduced, old age is weak and spirit
Sexuality obstacle etc.), promote children's brain and intelligence development, have one to the memory of normal person, the raising of working efficiency
Constant current modulation effect.It can be used for treating carbon monoxide and chronic alcoholism, also have certain work to the rescue of barbital and pesticide poisoning
With.
Generally acknowledged drug registration will meet human drugs registration technology international coordination meeting (ICH) and EP European Pharmacopoeia in the world
In requirement, stringent regulation has been carried out to the impurity in drug.ICH requires declarer to cope with bulk pharmaceutical chemicals in synthesis, purification
Those of generate physical presence with most probable during storage and potential impurity is summarized, in description reply synthesis
Chemical reaction, the impurity as caused by raw material and possible catabolite reasonably, scientifically assess；And in declaration material
It also copes with those apparent amounts of physical presence in bulk pharmaceutical chemicals and is greater than or equal to the miscellaneous of 0.05% (daily maximum dose is greater than 2g)
Matter structure feature is described.
Possible catabolite can be assessed by destructive testing and stability test.But existing Aura west
In smooth quality standard, the liquid phase analysis method eluotropic strength in relation to substance is weaker, catabolite can not all may be separated to inspection
It measures and.The catabolite that these missing inspections go out undoubtedly reduces the quality of Oxiracetam, if not being subject to sternly to these catabolites
Lattice control may generate serious toxic side effect to human body.
Summary of the invention
In order to overcome drawbacks described above, the present invention is using the high eluant, eluent of eluotropic strength to the destructive testing sample of Oxiracetam
Product and stability test sample are analyzed, and have found that a kind of new catabolite, the catabolite exist in photo damage sample
It is not protected from light within stability test long-term 6 months and starts to detect in sample, and content increases at any time, long-term 18 months whens reach
0.05%.Therefore：
The first object of the present invention is to provide a kind of new Oxiracetam Photodegradation Products；
The second object of the present invention is to provide the preparation method of the Photodegradation Products；
The third object of the present invention is to provide the analyzing detecting method of the Photodegradation Products；
The fourth object of the present invention is that provide the Photodegradation Products examines in the related substance of Oxiracetam and its preparation
Look into the purposes in item as impurity reference substance.
Above-mentioned purpose is achieved by the following technical solution：
A kind of Oxiracetam Photodegradation Products, chemical structure is as follows,
A kind of preparation method of the Photodegradation Products, includes the following steps：
(1) illumination destroys sample preparation：Oxiracetam bulk pharmaceutical chemicals illumination is destroyed, first through cold white fluorescence light irradiation, then is passed through
Ultraluminescence light irradiation；
(2) catabolite is enriched with：It is 70%~85% that above-mentioned illumination destruction sample, which is dissolved in methanol concentration expressed in percentage by volume,
It in methanol solution, stirs, filters, collect filtrate, concentrate is concentrated under reduced pressure to obtain；
(3) catabolite crude product：Above-mentioned concentrate is separated with normal phase silica gel column chromatography, is 8 with volume ratio:1~10:1
Methylene chloride-methanol mixed solvent isocratic elution, collect 5~10 column volume eluents, be concentrated to give catabolite crude product；
(4) prepared by reverse phase silica gel column：By above-mentioned catabolite crude product reverse phase silica gel column purification, stationary phase is octadecyl
Silane group silica gel, mobile phase are the methanol-water that methanol concentration expressed in percentage by volume is 80%~90%, and isocratic elution collects 5~9
A column volume eluent, concentration are freeze-dried up to the Photodegradation Products.
Further, step (1) the illumination destruction methods are：First through 1,200,000 lux cold white fluorescence light irradiations
36~48 hours, then through 200 watts of hours/square metre Ultraluminescence light irradiation 24~36 hours.
Further, step (1) the illumination destruction methods are：First shone through 1,200,000 lux cold white fluorescence lamps
Penetrate 42 hours, then through 200 watts of hours/square metre Ultraluminescence light irradiation 30 hours.
Further, step (3) is：Step (2) concentrate is separated with normal phase silica gel column chromatography, is 9 with volume ratio:1
Methylene chloride-methanol mixed solvent isocratic elution, collect 7~8 column volume eluents, be concentrated to give catabolite crude product.
Further, step (3) the purification on normal-phase silica gel particle size is 200~300 mesh.
Further, step (4) is：By step (3) catabolite crude product reverse phase silica gel column purification, stationary phase is 18
Alkyl silane bonded silica gel, mobile phase are the methanol-water that methanol concentration expressed in percentage by volume is 85%, and isocratic elution collects 7~8
Column volume eluent, concentration are freeze-dried up to the Photodegradation Products.
A kind of liquid phase analysis method of the Photodegradation Products, HPLC chromatogram condition include：
Chromatographic column：Agilent ZORBAX XDB-C18 (4.6mm × 250mm, 5 μm)；
Mobile phase：A is acetonitrile, and B is 0.05mol/L n-octyl amine solution (phosphorus acid for adjusting pH value to 6.8)；
Gradient elution program：0~6min, A 20%；6~15min, A 20% → 75%；15~40min, A 75%；40
~50min, A 75% → 20%；50~60min, A 20%；
Flow rate of mobile phase：1.0mL·min-1；
Detection wavelength：260nm；
Column temperature：30℃；
Sample volume：10μL.
Under above-mentioned chromatographic condition, the Photodegradation Products can be opened with separated from impurities similar in polarity, and separating degree is greater than
1.5.Mobile phase ultraviolet background absorption under 260nm Detection wavelength is low, and 260nm is the maximum absorption wave of the Photodegradation Products
It is long, it ensure that the response sensitivity of the Photodegradation Products, improve detected level.
The Oxiracetam Photodegradation Products are used as impurity in the Related substances separation item of Oxiracetam and its preparation
The purposes of reference substance.The Photodegradation Products are easy to get, and purity is high (being greater than 98%), and the compound can be used as control
Product carry out quality control to it using external standard method.
Beneficial effects of the present invention：
(1) present invention finds a kind of new Oxiracetam Photodegradation Products, which reports for the first time；
(2) preparation method is simple for the Photodegradation Products provided by the invention, can largely prepare the catabolite；
(3) liquid phase analysis method provided by the invention can quickly detect the catabolite, select the catabolite
Maximum absorption wavelength improves the recall rate of the catabolite, as a result accurately and reliably as Detection wavelength；
(4) Photodegradation Products provided by the invention can be used for the Related substances separation of Oxiracetam and its preparation, into one
Step improves the quality standard of Oxiracetam and its preparation, improves its safety and controllability.
Specific embodiment
The technical solution that the present invention will be described in detail combined with specific embodiments below.
Embodiment 1：The preparation of Oxiracetam Photodegradation Products
It takes 50g Oxiracetam raw material to be uniformly spread out in culture dish, is placed in illumination 42 hours, intensity of illumination under cold white fluorescence lamp
For 1,200,000 luxs；Surface plate is taken out, then is placed under ultraviolet fluorescent lamp and irradiates 30 hours, ultraviolet fluorescent lamp exposure intensity
For 200 watts of hours/square metre, taken out after irradiation.Then illumination destruction sample is dissolved in methanol concentration expressed in percentage by volume is
It in 75% methanol-water solution, stirs 20 minutes, is filtered with suction funnel, collect filtrate, concentrate 3.5g is concentrated under reduced pressure to obtain；
Then concentrate 5ml methanol is dissolved, mixes sample with the purification on normal-phase silica gel that 4g granularity is 100~200 mesh, solvent is volatilized, with 80g
Degree is that the purification on normal-phase silica gel of 200~300 mesh carries out pillar layer separation as separation silica gel, is 9 with volume ratio:1 methylene chloride-first
Alcohol mixed solvent isocratic elution collects 7~8 column volume eluents, catabolite crude product 1.2g is concentrated under reduced pressure to obtain；It then will drop
It solves the methanol aqueous solution that product crude product methanol concentration expressed in percentage by volume is 75% to dissolve, with reverse phase silica gel column purification, stationary phase is
Octadecylsilane chemically bonded silica, mobile phase are the methanol-water that methanol concentration expressed in percentage by volume is 85%, isocratic elution, collect 7~
The eluent of 8 column volumes is concentrated under reduced pressure, is freeze-dried to obtain pale yellow powder 750mg (Photodegradation Products).HPLC normalization is pure
Degree is greater than 98%.
Photodegradation Products chemical structure confirmation：
HR-ESIMS shows [M+H]+For m/z 141.0708, [M+Na]+For m/z 163.0512.It can in conjunction with nuclear-magnetism feature
Obtaining molecular formula is C6H8N2O2, degree of unsaturation 4.Hydrogen nuclear magnetic resonance modal data δH(ppm, DMSO-d6, 500MHz)：2.87 (m,
2H), 4.35 (m, 2H), 5.24 (m, 1H), 7.28 (m, 1H), 7.32 (m, 2H)；Carbon-13 nmr spectra data δC(ppm, DMSO-
d6, 150MHz)：36.9,56.2,104.8,128.4,170.1,177.4.Determine that its chemical structural formula is as follows：
Embodiment 2：The preparation of Oxiracetam Photodegradation Products
It takes 50g Oxiracetam raw material to be uniformly spread out in culture dish, is placed in illumination 36 hours, intensity of illumination under cold white fluorescence lamp
For 1,200,000 luxs；Surface plate is taken out, then is placed under ultraviolet fluorescent lamp and irradiates 24 hours, ultraviolet fluorescent lamp exposure intensity
For 200 watts of hours/square metre, taken out after irradiation.Then illumination destruction sample is dissolved in methanol concentration expressed in percentage by volume is
It in 70% methanol-water solution, stirs 20 minutes, is filtered with suction funnel, collect filtrate, concentrate 3.5g is concentrated under reduced pressure to obtain；
Then concentrate 5ml methanol is dissolved, mixes sample with the purification on normal-phase silica gel that 4g granularity is 100~200 mesh, solvent is volatilized, with 80g
Degree is that the purification on normal-phase silica gel of 200~300 mesh carries out pillar layer separation as separation silica gel, is 10 with volume ratio:1 methylene chloride-
Methanol mixed solvent isocratic elution collects 9~10 column volume eluents, catabolite crude product 1.2g is concentrated under reduced pressure to obtain；Then
The methanol aqueous solution that catabolite crude product methanol concentration expressed in percentage by volume is 70% is dissolved, it is fixed with reverse phase silica gel column purification
It is mutually octadecylsilane chemically bonded silica, mobile phase is the methanol-water that methanol concentration expressed in percentage by volume is 80%, and isocratic elution is received
Collect the eluent of 8~9 column volumes, is concentrated under reduced pressure, is freeze-dried to obtain pale yellow powder 750mg (Photodegradation Products).HPLC returns
One, which changes purity, is greater than 98%.
Photodegradation Products chemical structure is confirmed with embodiment 1.
Embodiment 3：The preparation of Oxiracetam Photodegradation Products
It takes 50g Oxiracetam raw material to be uniformly spread out in culture dish, is placed in illumination 48 hours, intensity of illumination under cold white fluorescence lamp
For 1,200,000 luxs；Surface plate is taken out, then is placed under ultraviolet fluorescent lamp and irradiates 36 hours, ultraviolet fluorescent lamp exposure intensity
For 200 watts of hours/square metre, taken out after irradiation.Then illumination destruction sample is dissolved in methanol concentration expressed in percentage by volume is
It in 85% methanol-water solution, stirs 20 minutes, is filtered with suction funnel, collect filtrate, concentrate 3.5g is concentrated under reduced pressure to obtain；
Then concentrate 5ml methanol is dissolved, mixes sample with the purification on normal-phase silica gel that 4g granularity is 100~200 mesh, solvent is volatilized, with 80g
Degree is that the purification on normal-phase silica gel of 200~300 mesh carries out pillar layer separation as separation silica gel, is 8 with volume ratio:1 methylene chloride-first
Alcohol mixed solvent isocratic elution collects 5~6 column volume eluents, catabolite crude product 1.2g is concentrated under reduced pressure to obtain；It then will drop
It solves the methanol aqueous solution that product crude product methanol concentration expressed in percentage by volume is 85% to dissolve, with reverse phase silica gel column purification, stationary phase is
Octadecylsilane chemically bonded silica, mobile phase are the methanol-water that methanol concentration expressed in percentage by volume is 90%, isocratic elution, collect 5~
The eluent of 6 column volumes is concentrated under reduced pressure, is freeze-dried to obtain pale yellow powder 750mg (Photodegradation Products).HPLC normalization is pure
Degree is greater than 98%.
Photodegradation Products chemical structure is confirmed with embodiment 1.
Embodiment 4：It is protected from light within Oxiracetam stability test long-term 6 months and is not protected from light sample detection analysis
Reference substance solution preparation：Precision weighs 2mg light degradation impurity in 200ml volumetric flask, dissolves constant volume with acetonitrile, makees
For light degradation impurity stock solution；Precision measures light degradation impurity stock solution 1ml in 20ml volumetric flask, in liquid phase analysis method
The flowing phase dilution constant volume (about 0.5 μ g/mL) of initial proportion.
Test solution preparation：It is former that the Oxiracetam for being protected from light for 6 months and not being protected from light is taken out from stability test lighting box
Material, precision weighs 20mg in 20ml volumetric flask respectively, with the flowing phased soln constant volume of initial proportion in liquid phase analysis method, divides
It does not obtain being protected from light raw material test solution long-term June and long-term June is not protected from light raw material test solution, concentration is each about 1mg/
mL。
Liquid phase chromatogram condition：
High performance liquid chromatograph：Agilent 1260, binary pump, VWD；
Chromatographic column：Agilent ZORBAX XDB-C18 (4.6mm × 250mm, 5 μm)；
Mobile phase：A is acetonitrile, and B is 0.05mol/L n-octyl amine solution (phosphorus acid for adjusting pH value to 6.5)；
Gradient elution program：0~5min, A 20%；5~15min, A 20% → 75%；15~40min, A 75%；40
~50min, A 75% → 20%；50~60min, A 20%；
Flow rate of mobile phase：1.0mL·min-1；
Detection wavelength：260nm；
Column temperature：30℃；
Sample volume：10μL.
It is accurate respectively to measure light degradation impurity reference substance solution and 10 μ L of Oxiracetam test solution injection liquid chromatogram
Instrument analysis.As a result detection light degradation impurity, content 0.05% in raw material is not protected from light in long-term June to be protected from light in sample and do not detect
It arrives, illustrates that Oxiracetam should be kept in dark place.The light degradation impurity shows a increasing trend as time goes by stability test,
And content is higher, should be included in quality research control.
The effect of above-described embodiment indicates that essentiality content of the invention, but protection of the invention is not limited with this
Range.Those skilled in the art should understand that can with modification or equivalent replacement of the technical solution of the present invention are made,
Without departing from the essence and protection scope of technical solution of the present invention.
Claims (5)
1. a kind of Oxiracetam Photodegradation Products, it is characterised in that：Chemical structure is as follows,
2. a kind of preparation method of Photodegradation Products described in claim 1, it is characterised in that include the following steps：
(1) illumination destroys sample preparation：Oxiracetam bulk pharmaceutical chemicals illumination is destroyed, first through cold white fluorescence light irradiation, then through ultraviolet
Fluorescent lamp；
(2) catabolite is enriched with：Above-mentioned illumination destruction sample is dissolved in the methanol that methanol concentration expressed in percentage by volume is 70%~85%
It in solution, stirs, filters, collect filtrate, concentrate is concentrated under reduced pressure to obtain；
(3) catabolite crude product：Above-mentioned concentrate is separated with normal phase silica gel column chromatography, is 8 with volume ratio:1~10:The two of 1
Chloromethanes-methanol mixed solvent isocratic elution collects 5~10 column volume eluents, is concentrated to give catabolite crude product；
(4) prepared by reverse phase silica gel column：By above-mentioned catabolite crude product reverse phase silica gel column purification, stationary phase is octadecylsilane
Bonded silica gel, mobile phase are the methanol-water that methanol concentration expressed in percentage by volume is 80%~90%, and isocratic elution collects 5~9 columns
Volume eluent, concentration are freeze-dried up to the Photodegradation Products.
3. the preparation method of Photodegradation Products according to claim 2, it is characterised in that：Step (1) the illumination destruction side
Method is：First through 1,200,000 lux cold white fluorescence light irradiation 36~48 hours, then through 200 watts of hours/square metre it is ultraviolet
Fluorescent lamp 24~36 hours.
4. the preparation method of Photodegradation Products according to claim 3, it is characterised in that：Step (1) the illumination destruction side
Method is：First through 1,200,000 lux cold white fluorescence light irradiation 42 hours, then through 200 watts of hours/square metre Ultraluminescence
Light irradiation 30 hours.
5. the preparation method of Photodegradation Products according to claim 2, it is characterised in that step (3) is：Step (2) are concentrated
Object is separated with normal phase silica gel column chromatography, is 9 with volume ratio:1 methylene chloride-methanol mixed solvent isocratic elution collects 7~8
A column volume eluent, is concentrated to give catabolite crude product.
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Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4686296A (en) * | 1985-07-26 | 1987-08-11 | Denki Kagaku Kogyo Kabushiki Kaisha | Process for producing oxiracetam |
| US4868313A (en) * | 1985-06-21 | 1989-09-19 | I.S.F. Societa Per Azioni | A process for making pyrrolidone derivatives |
| CN103076409A (en) * | 2012-12-31 | 2013-05-01 | 北京元延医药科技有限公司 | Analysis and detection method for oxiracetam and impurities thereof |
| CN104672123A (en) * | 2014-12-30 | 2015-06-03 | 青岛黄海制药有限责任公司 | Oxiracetam refining and purifying method |
| CN105017243A (en) * | 2015-06-29 | 2015-11-04 | 苏州东瑞制药有限公司 | Ceftriaxone sodium photodecomposition product, and preparation method and analysis and detection method thereof |
-
2016
- 2016-02-22 CN CN201610096799.8A patent/CN105669515B/en active Active
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4868313A (en) * | 1985-06-21 | 1989-09-19 | I.S.F. Societa Per Azioni | A process for making pyrrolidone derivatives |
| US4686296A (en) * | 1985-07-26 | 1987-08-11 | Denki Kagaku Kogyo Kabushiki Kaisha | Process for producing oxiracetam |
| CN103076409A (en) * | 2012-12-31 | 2013-05-01 | 北京元延医药科技有限公司 | Analysis and detection method for oxiracetam and impurities thereof |
| CN104672123A (en) * | 2014-12-30 | 2015-06-03 | 青岛黄海制药有限责任公司 | Oxiracetam refining and purifying method |
| CN105017243A (en) * | 2015-06-29 | 2015-11-04 | 苏州东瑞制药有限公司 | Ceftriaxone sodium photodecomposition product, and preparation method and analysis and detection method thereof |
Non-Patent Citations (7)
| Title |
|---|
| HPLC法测定奥拉西坦原料及其注射剂中奥拉西坦的含量和有关物质;袁利杰,等;《中国药师》;20140731;第17卷(第7期);第1112-1116页 * |
| HPLC法测定奥拉西坦原料药中的有关物质;刘宪勇,等;《中国药房》;20140131;第25卷(第1期);第66-68页尤其是图3、表1 * |
| HPLC法测定奥拉西坦氯化钠注射液中奥拉西坦含量及其有关物质;湛建峰,等;《药物分析杂志》;20091231;第29卷(第12期);第2077-2080页 * |
| 奥拉西坦合成方法研究;李柏娜,等;《沈阳化工大学学报》;20141231;第28卷(第4期);第329-332页 * |
| 奥拉西坦的合成工艺改进;杨英梅,等;《河北工业科技》;20130531;第30卷(第3期);第212-214页 * |
| 奥拉西坦的合成工艺改进;潘冰,等;《煤炭与化工》;20150731;第38卷(第7期);第80-82页 * |
| 正交试验法优化奥拉西坦的合成工艺条件;张燕梅,等;《广东药学院学报》;20140430;第30卷(第2期);第153-155页 * |
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