CN101012294A - Method of preparing benzodiazepines pharmaceutical molecular engram solid phase extractant - Google Patents
Method of preparing benzodiazepines pharmaceutical molecular engram solid phase extractant Download PDFInfo
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- ZESXUEKAXSBANL-UHFFFAOYSA-N trifluoromethyl prop-2-enoate Chemical compound FC(F)(F)OC(=O)C=C ZESXUEKAXSBANL-UHFFFAOYSA-N 0.000 claims description 5
- SMZOUWXMTYCWNB-UHFFFAOYSA-N 2-(2-methoxy-5-methylphenyl)ethanamine Chemical compound COC1=CC=C(C)C=C1CCN SMZOUWXMTYCWNB-UHFFFAOYSA-N 0.000 claims description 4
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- 238000010438 heat treatment Methods 0.000 claims description 4
- 238000001291 vacuum drying Methods 0.000 claims description 4
- OZAIFHULBGXAKX-UHFFFAOYSA-N 2-(2-cyanopropan-2-yldiazenyl)-2-methylpropanenitrile Chemical compound N#CC(C)(C)N=NC(C)(C)C#N OZAIFHULBGXAKX-UHFFFAOYSA-N 0.000 claims description 3
- OZAIFHULBGXAKX-VAWYXSNFSA-N AIBN Substances N#CC(C)(C)\N=N\C(C)(C)C#N OZAIFHULBGXAKX-VAWYXSNFSA-N 0.000 claims description 3
- GTTSNKDQDACYLV-UHFFFAOYSA-N Trihydroxybutane Chemical compound CCCC(O)(O)O GTTSNKDQDACYLV-UHFFFAOYSA-N 0.000 claims description 3
- -1 acrylic ester Chemical class 0.000 claims description 3
- 238000006392 deoxygenation reaction Methods 0.000 claims description 3
- 229960002336 estazolam Drugs 0.000 claims description 3
- CDCHDCWJMGXXRH-UHFFFAOYSA-N estazolam Chemical compound C=1C(Cl)=CC=C(N2C=NN=C2CN=2)C=1C=2C1=CC=CC=C1 CDCHDCWJMGXXRH-UHFFFAOYSA-N 0.000 claims description 3
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- KJONHKAYOJNZEC-UHFFFAOYSA-N nitrazepam Chemical compound C12=CC([N+](=O)[O-])=CC=C2NC(=O)CN=C1C1=CC=CC=C1 KJONHKAYOJNZEC-UHFFFAOYSA-N 0.000 claims description 3
- VVWRJUBEIPHGQF-UHFFFAOYSA-N propan-2-yl n-propan-2-yloxycarbonyliminocarbamate Chemical compound CC(C)OC(=O)N=NC(=O)OC(C)C VVWRJUBEIPHGQF-UHFFFAOYSA-N 0.000 claims description 3
- 238000007789 sealing Methods 0.000 claims description 3
- 229960003386 triazolam Drugs 0.000 claims description 3
- JOFWLTCLBGQGBO-UHFFFAOYSA-N triazolam Chemical compound C12=CC(Cl)=CC=C2N2C(C)=NN=C2CN=C1C1=CC=CC=C1Cl JOFWLTCLBGQGBO-UHFFFAOYSA-N 0.000 claims description 3
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Abstract
The invention discloses a making method of benzene-dinitrogen molecular printing solid-phase extract, which comprises the following steps: adopting functional monomer of acroleic acid, benzene-dinitrogen and drug mould molecule in the poring agent; vibrating; adding crosslinking agent and initiator in the solution; aerating nitrogen to exhaust oxygen; extracting into vacuum; initiating through light or heat; obtaining rough product; eluting; washing; drying; obtaining the product.
Description
One, technical field
The present invention relates to a kind of preparation method of molecule blotting solid phase extracter of benzene phenodiazine class medicine, more particularly, relate to a kind of benzene phenodiazine class medicine to be had the preparation method of the solid extracting agent of singleness identity.
Two, background technology
Benzene phenodiazine class medicine has calmness, hypnosis, lax maincenter skeletal muscle effect.The clinical manifestation of this medicine acute poisoning is mainly aspect muscle and central nervous system, occur that myasthenia, muscular tension are low, coordinate movement imbalance, dysphonia, symptom such as drowsiness, show as stupor, platycoria, respiration inhibition, shock during serious the poisoning, even cause death.To stabilize is example, and haemoconcentration just shows toxicity symptom at 1-30 μ g/mL, and concentration surpasses 50 μ g/mL will cause death.Therefore accurately quick diagnosis is to formulate the key of effective emergency measures.
At present, method for separating and concentrating commonly used both at home and abroad, mostly be with the medicine in the liquid-liquid extraction extraction body fluid, measure after the drying, this method need consume relatively large organic solvent again, and the sample of acute poisoning censorship generally is blood, gastric juice, vomitus or urine etc., complicated component, the selectivity of liquid-liquid extraction method is not high, and impurity serious interference during mensuration can't be accurately qualitative, quantitative.In addition, the method for body fluid being carried out pre-treatment with solid phase extraction techniques is also arranged, but common sorbing material, as C18 etc., selectivity ratios is relatively poor, equally can't be qualitative accurately, quantitative.
The relevant document of molecularly imprinted polymer is increasing in recent years, but is template and with the correlation technique of precipitator method preparation with benzene phenodiazine class medicine at present not.Existing technology is generally with the mass polymerization Synthesis of Molecular Imprinting Polymers, the product that obtains is column or bulk, must be through steps such as grinding, screenings, on productive rate, bring bigger loss, and its particle diameter is very inhomogeneous often at tens more than the micron, template molecule is embedded in polymkeric substance inside, be difficult to complete wash-out when wash-out, seepage can not take place in the template molecule of wash-out in the later actual use of product, makes accurately quantitative assay of actual sample.
Three, summary of the invention
The object of the present invention is to provide a kind of preparation method of molecule blotting solid phase extracter of benzene phenodiazine class medicine, it compares the embedding that can reduce preparation process, raising productive rate, reduce template molecule with bulk polymerization commonly used now, the extraction agent that is obtained all has specific recognition to such medicine, when practical application, can overcome the shortcoming of impurity serious interference in the present universal method, quick, qualitative, detect this type of medicine quantitatively.
Concretely, the present invention includes following steps:
(1) the molecule blotting solid phase extracter crude product is synthetic: with a kind of acrylic acid or the like function monomer, a kind of benzene phenodiazine class drug template molecule is dissolved in the pore-creating agent, vibration preact 20～40min, in gained solution, add linking agent, initiator, logical nitrogen deoxygenation 10～30min, vacuumize tube sealing, light-initiated or thermal booster reaction obtains the molecule blotting solid phase extracter crude product, wherein the consumption of each reactant (mol ratio) is: template molecule: function monomer: linking agent=1: 2～6: 10～40, the quality of initiator is 1～2% of a linking agent quality, and the volume of pore-creating agent accounts for 90～99% of cumulative volume;
(2) purifying crude: add the organic solvent elution after the crude product drying that step (1) is obtained, eluant is the methanol (mixed solution of expression first alcohol and water, the back content is in like manner), acetonitrile/water, acetate/acetonitrile or acetate/methyl alcohol etc., reflux, the wash-out template molecule obtains the extraction agent behind the preliminary purification;
(3) washing: will use residual organic solvent in organic solvent methyl alcohol or the acetonitrile flush away step (2) after the extraction agent drying behind the preliminary purification again;
(4) drying: step (3) products obtained therefrom drying can be obtained the pure product of solid extracting agent that will prepare.
In step (1), described acrylic acid or the like function monomer adopts vinylformic acid (AA), methacrylic acid (MAA) or trifluoromethyl acrylate (TFMAA).Template molecule is a kind of of benzene phenodiazine class medicine, as stable (diazepam, Diazepam), clonazepam (Clonazepam), nitrazepam (Nitrazepam), estazolam (Estazolam), alprazolam (Alprazolam) or triazolam (Triazolam).Pore-creating agent is one or both strong polarity or weak polar solvents, as methylene dichloride, chloroform, toluene, acetonitrile, toluene/chloroform or acetonitrile/chloroform etc., preferably toluene/chloroform (3: 1, V/V) or acetonitrile/chloroform (3: 1, V/V).Linking agent adopts linking agent ethylene glycol dimethacrylate (EGDMA) commonly used or trihydroxy methyl propane trimethyl acrylic ester (TRIM).Initiator adopts Diisopropyl azodicarboxylate (AIBN).Reaction conditions is that 50～70 ℃ of heating in water bath cause or 0-10 ℃ of ice-water bath UV-light causes, and the reaction times is 16～72h.
In step (2), described volume of organic solvent is 50 of pore-creating agent volume～1 50 times, the volume ratio of two kinds of components is in the solvent: last component: back one component=1～3: 9～7, and adopt vacuum drying oven to vacuumize for 50～70 ℃ when dry and be dried to constant weight.
In step (3), the same step of the consumption of described organic solvent and drying means (2), reflux, to template molecule, then repeating step (2), (3) are detected less than till the template molecule in solvent if can detect (adopting efficient liquid-phase chromatography method commonly used) in solvent.
In step (4), the same step of described drying means (2).
Principle of the present invention is as follows: template molecule and function monomer form reversible mixture under certain condition, add linking agent, under action of evocating, monomeric pair of key copolymerization of congenerous forms high crosslinked polymkeric substance, the fixed die plate molecule, with eluant template molecule is extracted, obtain having and the particular space of template molecule coupling or the hole of size.Its ultimate principle as shown in Figure 1.
Compared with prior art, advantage of the present invention or effect are:
1. adopt precipitation polymerization on synthetic method, increased the amount of solvent, the molecularly imprinted polymer that obtains is Powdered precipitation, particle diameter 0.3～4 μ m, and big or small homogeneous need not grind screening during use, and productive rate is higher;
2. owing to adopted the method for precipitation polymerization, reduced template molecule and be embedded in the shortcoming that polymkeric substance inside is difficult to wash-out, later actual use has not been had the influence of seepage;
The present invention only with a kind of (as stable) of benzene phenodiazine class medicine as template molecule, but the benzene phenodiazine class medicine of synthetic product pair and its structural similitude all has specific adsorption;
4. in practical application, compare with methods such as common Solid-Phase Extraction, liquid-liquid extraction, molecularly imprinted polymer is to template molecule and analogue thereof, and promptly all benzene phenodiazine class medicines all have specific adsorption, have very high selectivity and sensitivity, thoroughly got rid of the interference of impurity in the body fluid.
Four, description of drawings
Fig. 1 is the composition principle synoptic diagram of the inventive method.
Fig. 2 is the aspect graph of embodiment 1 synthetic molecule blotting solid phase extracter.
Fig. 3 is the aspect graph of embodiment 2 synthetic molecule blotting solid phase extracters.
Fig. 4 is the aspect graph of embodiment 3 synthetic molecule blotting solid phase extracters.
Fig. 5 is high performance liquid chromatography (HPLC) figure of embodiment 1 products obtained therefrom effect of extracting.
Fig. 6 is high performance liquid chromatography (HPLC) figure of embodiment 2 products obtained therefrom effect of extracting.
Fig. 7 is high performance liquid chromatography (HPLC) figure of embodiment 3 products obtained therefrom effect of extracting.
Five, embodiment
Fig. 1 is the composition principle synoptic diagram of the inventive method, and wherein a is a function monomer, and b is a linking agent, and c is a template molecule, and 1 expression template molecule and function monomer form mixture; 2 expression linking agent and the crosslinked fixed die plate molecules of function monomer, 3 expression extracting flush away template molecules, 4 expressions are to the identification of template molecule.
Take by weighing template molecule stable (Diazepam, Dz) 0.25mmol, function monomer methacrylic acid (MAA) 1.5mmol in erlenmeyer flask, add 20mL toluene/chloroform (3: 1, V/V) in, vibration preact 40min.Add linking agent ethylene glycol dimethacrylate (EGDMA) 5mmol, initiator Diisopropyl azodicarboxylate (AIBN) 10mg, logical nitrogen deoxygenation 20min shifts solution in the ampere bottle, vacuumizes tube sealing, 50～70 ℃ of heating in water bath for reaction 16h; Add behind the product drying 75 times of pore-creating agent volumes methyl alcohol/acetate (8: 2, V/V) 1 50mL eluant, reflux; Change organic solvent, select the methyl alcohol reflux for use, the residual acetate of flush away, 60～70 ℃ vacuumize and are dried to constant weight, weighing, calculating its productive rate is 92.4%.In this experiment, the mol ratio of template molecule, function monomer and linking agent is 1: 6: 20, and the volume of pore-creating agent accounts for 95% of cumulative volume, and the initiator quality is 1% of a linking agent quality, and polymer morphology as shown in Figure 2.
Other is with embodiment 1, different is: function monomer is trifluoromethyl acrylate (TFMAA), be clonazepam (Clonazepam), function monomer and template molecule preact time are 20min, linking agent is trihydroxy methyl propane trimethyl acrylic ester (TRIM), the mol ratio of template molecule, function monomer and linking agent is :=1: 2: 10, pore-creating agent is acetonitrile/chloroform (3: 1, V/V), account for 99% of cumulative volume, the initiator quality is 2% of a linking agent quality, and reaction conditions is 0～10 ℃ of ice-water bath UV-light initiation reaction 72h; The preliminary purification eluant be acetonitrile/water (3: 7, V/V), volume is 50 times of pore-creating agent volume, selects the acetonitrile reflux for use, the water that flush away is residual, 50～60 ℃ are dried to constant weight, weighing, calculating its productive rate is 91.0%.Polymer morphology figure as shown in Figure 3.
Other is with embodiment 1, different is: the mol ratio of template molecule, function monomer and linking agent is 1: 4: 40, function monomer and template molecule preact time are 30min, pore-creating agent is a chloroform, volume accounts for 90% of cumulative volume, and reaction conditions is 50～70 ℃ of heating in water bath initiation reaction 48h; The preliminary purification eluant be methyl alcohol/acetate (9: 1, V/V), volume is 100 times of pore-creating agent volume, calculating its productive rate is 95.7%.Polymer morphology figure as shown in Figure 4.
By Fig. 2,3 and 4 as can be known, synthetic polymeric articles particle is less, and particle diameter is even, need not grind, sieve, and avoids unnecessary loss, so its productive rate is higher, has reduced the embedding of template molecule in polymkeric substance inside.
The effect of extracting of synthetic product in order to verify, it is as follows that the spy does experiment:
Experiment 1: take by weighing the product of 100mg embodiment 1, make carrier with methyl alcohol, install in the solid-phase extraction column of a sky (SUPELCO, internal diameter 0.4cm), obtain solid-phase extraction column (MISPE post), (expression is used 1mL to the activation of 10 * 1mL methyl alcohol at every turn, operates 10 times.The back is in like manner), 1: 9 (V/V) balance of 10 * 1mL acetonitrile/water.1: 9 (V/V) solution of clonazepam, alprazolam, stabile acetonitrile/water that 1mL concentration is 1 μ g/mL loads 1: 9 (V/V) solution washing of 3mL acetonitrile/water, 4: 6 (V/V) wash-outs of 2 * 1mL acetonitrile/water, N2 dries up elutriant, residue 1mL dissolve with methanol, 20 μ L sample introductions, HPLC.Color atlas as shown in Figure 5.
In Fig. 5,1 is clonazepam, and 2 is alprazolam, and 3 for stable; The chromatographic curve of " A " expression after MISPE handles; The chromatographic curve of " B " expression 1 μ g/mL methyl alcohol standardized solution, clonazepam, alprazolam, the stabile rate of recovery are respectively 89.6%, 93.8%, 94.9%.This product is except having a specific adsorption to template molecule is stable, to the also selective absorption of clonazepam, alprazolam of its structural similitude.
Experiment 2: other is with experiment 1, and different is loads liquid and be the blood sample after handling, and the blood sample treatment step is as follows: draw serum 1mL, add clonazepam, alprazolam, stable to make its concentration be 10 μ g/mL, adds 1.5mL acetonitrile precipitation albumen, leaves standstill centrifugal.Draw supernatant liquid in the 10mL volumetric flask, the water constant volume must be handled back blood sample (wherein the concentration of three kinds of solutes is 1 μ g/mL, and solvent is the acetonitrile/water that volume ratio was about 15: 85).As solid extracting agent is product prepared among the embodiment 2.Elutriant does not directly dry up, but places 5mL volumetric flask constant volume.Color atlas as shown in Figure 6.
In Fig. 6,1 is clonazepam, and 2 is alprazolam, and 3 for stable, the chromatographic curve of " A " expression after MISPE handles, the chromatographic curve of " B " expression 1 μ g/mL methyl alcohol standardized solution.Clonazepam, alprazolam, stabile average recovery rate are respectively 93.8%, 94.0%, 101.0%.More as can be known, when doing the actual sample experiment, impurity a, b, c all there is not adsorption with serum.
Experiment 3: other is experiment 2 together, with the more complicated whole blood of composition, only adds and stabilizes when different is the blood sample processing, adds 1mL acetonitrile precipitation albumen.As solid extracting agent is product prepared among the embodiment 3.The wash-out solvent is 3 * 1mL methyl alcohol/acetate 6: 4 (V/V).Color atlas as shown in Figure 7.
In Fig. 7, the chromatographic curve of " A " expression after MISPE handles; The chromatographic curve of direct injection behind " B " expression acetonitrile precipitation albumen, three times are measured stabile average recovery rate is 100.3%.More as can be known, when doing the actual sample experiment with whole blood, the blood sample after MIP-SPE handles, impurity significantly reduces, and particularly the noisy impurity a of stabile mensuration is not had absorption fully, makes to stabilize to reach baseline separation, can carry out detection by quantitative.
In sum, the present invention has prepared a kind of molecule blotting solid phase extracter that benzene phenodiazine class medicine is had specific recognition, this method is compared the embedding that can reduce preparation process, raising productive rate, reduce template molecule with existing bulk polymerization, prepared extraction agent all has specific recognition to such medicine, when practical application, can overcome the shortcoming of impurity serious interference in the present universal method, when utilizing high performance liquid chromatography to detect, can reach baseline separation, quick, qualitative, detect this type of medicine quantitatively.
Claims (7)
1, a kind of preparation method of benzene phenodiazine class pharmaceutical molecular engram solid phase extractant is characterized in that comprising the steps:
(1) the molecule blotting solid phase extracter crude product is synthetic: with a kind of acrylic acid or the like function monomer, a kind of benzene phenodiazine class drug template molecule is dissolved in the pore-creating agent, vibration preact 20～40min, in gained solution, add linking agent, initiator, logical nitrogen deoxygenation 10～30min, vacuumize tube sealing, light-initiated or thermal booster reaction obtains the molecule blotting solid phase extracter crude product, wherein the mol ratio of each reactant is: template molecule: function monomer: linking agent=1: 2～6: 10～40, the quality of initiator is 1～2% of a linking agent quality, and the volume of pore-creating agent accounts for 90～99% of cumulative volume;
(2) purifying crude: add elution in the organic solvent after the crude product drying that step (1) is obtained, eluant is methanol, acetonitrile/water, acetate/acetonitrile or acetate/methyl alcohol, reflux, and the wash-out template molecule obtains the extraction agent of preliminary purification;
(3) washing: use residual organic solvent in organic solvent methyl alcohol or the acetonitrile flush away step (2) after the extraction agent drying with preliminary purification again;
(4) drying: step (3) products obtained therefrom drying can be obtained the pure product of solid extracting agent that will prepare.
2, the method for claim 1 is characterized in that: in step (1), described acrylic acid or the like function monomer adopts vinylformic acid, methacrylic acid or trifluoromethyl acrylate; Template molecule is stable, clonazepam, nitrazepam, estazolam, alprazolam or triazolam; Pore-creating agent is methylene dichloride, chloroform, toluene, acetonitrile, toluene/chloroform or acetonitrile/chloroform; Linking agent adopts ethylene glycol dimethacrylate or trihydroxy methyl propane trimethyl acrylic ester; Initiator adopts Diisopropyl azodicarboxylate (AIBN); Reaction conditions is that 50～70 ℃ of heating in water bath cause or 0-10 ℃ of ice-water bath UV-light causes, and the reaction times is 16～72h.
3, method as claimed in claim 2 is characterized in that: described pore-creating agent is toluene/chloroform, and volume ratio is a toluene: chloroform=3: 1; Or acetonitrile/chloroform, volume ratio is an acetonitrile: chloroform=3: 1.
4, the method for claim 1 is characterized in that: in step (2), described volume of organic solvent is 50～150 times of pore-creating agent volume, and the volume ratio of two kinds of components is in the solvent: last component: back one component=1～3: 9～7; Adopt vacuum drying oven to vacuumize for 50～70 ℃ when dry and be dried to constant weight.
5, the method for claim 1 is characterized in that: in step (3), described volume of organic solvent is 50～150 times of pore-creating agent volume; Adopt vacuum drying oven to vacuumize for 50～70 ℃ when dry and be dried to constant weight.
6, the method for claim 1, it is characterized in that: in step (3), after the reflux, adopt efficient liquid-phase chromatography method to detect in the solvent whether contain template molecule, if have then repeating step (2) and step (3), in solvent, detect less than till the template molecule.
7, as the described method of the arbitrary claim of claim 1～6, it is characterized in that: in step (4), adopt vacuum drying oven to vacuumize for 50～70 ℃ when dry and be dried to constant weight.
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Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN101962420A (en) * | 2010-09-10 | 2011-02-02 | 中国检验检疫科学研究院 | Salbutamol molecularly imprinted polymer and preparation method thereof |
| CN102174138A (en) * | 2011-01-25 | 2011-09-07 | 尹小英 | Preparation method and application of codonopsis lactone molecularly imprinted solid phase extraction column |
| CN104546698A (en) * | 2014-12-17 | 2015-04-29 | 华润双鹤药业股份有限公司 | Busulfan injection and preparation method thereof |
| CN105688857A (en) * | 2016-01-22 | 2016-06-22 | 南京医科大学 | Preparation method of clonazepam molecular imprinting stirring rod coating |
| CN116297781A (en) * | 2023-03-03 | 2023-06-23 | 正大制药（青岛）有限公司 | Quality detection method of topiroxostat tablet |
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- 2007-02-09 CN CN200710026856A patent/CN100586965C/en not_active Expired - Fee Related
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101962420A (en) * | 2010-09-10 | 2011-02-02 | 中国检验检疫科学研究院 | Salbutamol molecularly imprinted polymer and preparation method thereof |
| CN101962420B (en) * | 2010-09-10 | 2014-04-16 | 中国检验检疫科学研究院 | Salbutamol molecularly imprinted polymer and preparation method thereof |
| CN102174138A (en) * | 2011-01-25 | 2011-09-07 | 尹小英 | Preparation method and application of codonopsis lactone molecularly imprinted solid phase extraction column |
| CN102174138B (en) * | 2011-01-25 | 2013-01-16 | 江西中医学院 | Preparation method and application of codonopsis lactone molecularly imprinted solid phase extraction column |
| CN104546698A (en) * | 2014-12-17 | 2015-04-29 | 华润双鹤药业股份有限公司 | Busulfan injection and preparation method thereof |
| CN104546698B (en) * | 2014-12-17 | 2017-06-20 | 华润双鹤药业股份有限公司 | Busulfan parenteral solution and preparation method |
| CN105688857A (en) * | 2016-01-22 | 2016-06-22 | 南京医科大学 | Preparation method of clonazepam molecular imprinting stirring rod coating |
| CN105688857B (en) * | 2016-01-22 | 2018-10-26 | 南京医科大学 | The preparation method of Clonazepam molecular imprinting stirring rod coating |
| CN116297781A (en) * | 2023-03-03 | 2023-06-23 | 正大制药（青岛）有限公司 | Quality detection method of topiroxostat tablet |
| CN116297781B (en) * | 2023-03-03 | 2023-10-03 | 正大制药（青岛）有限公司 | Quality detection method of topiroxostat tablet |
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