CN106749622A - A kind of 4 methyl methcathinone antigen and preparation method and its application in collaurum detection - Google Patents
A kind of 4 methyl methcathinone antigen and preparation method and its application in collaurum detection Download PDFInfo
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- CN106749622A CN106749622A CN201611113663.XA CN201611113663A CN106749622A CN 106749622 A CN106749622 A CN 106749622A CN 201611113663 A CN201611113663 A CN 201611113663A CN 106749622 A CN106749622 A CN 106749622A
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- 239000000427 antigen Substances 0.000 title claims abstract description 38
- 102000036639 antigens Human genes 0.000 title claims abstract description 38
- 108091007433 antigens Proteins 0.000 title claims abstract description 38
- YELGFTGWJGBAQU-UHFFFAOYSA-N mephedrone Chemical compound CNC(C)C(=O)C1=CC=C(C)C=C1 YELGFTGWJGBAQU-UHFFFAOYSA-N 0.000 title claims abstract description 37
- 238000001514 detection method Methods 0.000 title claims description 17
- 238000002360 preparation method Methods 0.000 title abstract description 10
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 105
- 239000000047 product Substances 0.000 claims description 49
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 42
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 36
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 23
- PCHJSUWPFVWCPO-UHFFFAOYSA-N gold Chemical compound [Au] PCHJSUWPFVWCPO-UHFFFAOYSA-N 0.000 claims description 23
- 238000006243 chemical reaction Methods 0.000 claims description 21
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 claims description 20
- 238000003756 stirring Methods 0.000 claims description 17
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 15
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 15
- VSCWAEJMTAWNJL-UHFFFAOYSA-K aluminium trichloride Chemical compound Cl[Al](Cl)Cl VSCWAEJMTAWNJL-UHFFFAOYSA-K 0.000 claims description 14
- 239000007788 liquid Substances 0.000 claims description 14
- 239000000243 solution Substances 0.000 claims description 14
- 102000004169 proteins and genes Human genes 0.000 claims description 12
- 108090000623 proteins and genes Proteins 0.000 claims description 12
- 239000000126 substance Substances 0.000 claims description 12
- OZGMODDEIHYPRY-UHFFFAOYSA-N 2-bromopropanoyl chloride Chemical compound CC(Br)C(Cl)=O OZGMODDEIHYPRY-UHFFFAOYSA-N 0.000 claims description 11
- 238000001035 drying Methods 0.000 claims description 11
- 238000012360 testing method Methods 0.000 claims description 11
- 239000000020 Nitrocellulose Substances 0.000 claims description 10
- 229910052786 argon Inorganic materials 0.000 claims description 10
- 239000012528 membrane Substances 0.000 claims description 10
- 229920001220 nitrocellulos Polymers 0.000 claims description 10
- NQMRYBIKMRVZLB-UHFFFAOYSA-N methylamine hydrochloride Chemical compound [Cl-].[NH3+]C NQMRYBIKMRVZLB-UHFFFAOYSA-N 0.000 claims description 9
- 239000000203 mixture Substances 0.000 claims description 9
- 238000002390 rotary evaporation Methods 0.000 claims description 9
- 238000000034 method Methods 0.000 claims description 8
- MONMFXREYOKQTI-UHFFFAOYSA-N 2-bromopropanoic acid Chemical compound CC(Br)C(O)=O MONMFXREYOKQTI-UHFFFAOYSA-N 0.000 claims description 7
- ZCWRQEBZHFKYJH-UHFFFAOYSA-N CC1(C)C2=C1CC(C)=C(C)C2=O Chemical compound CC1(C)C2=C1CC(C)=C(C)C2=O ZCWRQEBZHFKYJH-UHFFFAOYSA-N 0.000 claims description 7
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 7
- 238000004132 cross linking Methods 0.000 claims description 7
- 239000002904 solvent Substances 0.000 claims description 7
- LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide Substances CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 claims description 5
- FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 claims description 5
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 claims description 5
- 241001465754 Metazoa Species 0.000 claims description 5
- NQTADLQHYWFPDB-UHFFFAOYSA-N N-Hydroxysuccinimide Chemical compound ON1C(=O)CCC1=O NQTADLQHYWFPDB-UHFFFAOYSA-N 0.000 claims description 5
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 5
- 239000012295 chemical reaction liquid Substances 0.000 claims description 5
- 239000013078 crystal Substances 0.000 claims description 5
- 238000000605 extraction Methods 0.000 claims description 5
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 claims description 5
- 229910000041 hydrogen chloride Inorganic materials 0.000 claims description 5
- 239000005457 ice water Substances 0.000 claims description 5
- 239000003208 petroleum Substances 0.000 claims description 5
- 239000012460 protein solution Substances 0.000 claims description 5
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- 229910002027 silica gel Inorganic materials 0.000 claims description 5
- 239000007787 solid Substances 0.000 claims description 5
- 108091003079 Bovine Serum Albumin Proteins 0.000 claims description 4
- BAVYZALUXZFZLV-UHFFFAOYSA-N Methylamine Chemical compound NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 claims description 4
- 239000002250 absorbent Substances 0.000 claims description 4
- 230000002745 absorbent Effects 0.000 claims description 4
- -1 and simultaneously Substances 0.000 claims description 4
- 229940098773 bovine serum albumin Drugs 0.000 claims description 4
- 238000002425 crystallisation Methods 0.000 claims description 4
- 230000008025 crystallization Effects 0.000 claims description 4
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 claims description 4
- 238000001914 filtration Methods 0.000 claims description 4
- 230000003053 immunization Effects 0.000 claims description 4
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- 238000005406 washing Methods 0.000 claims description 4
- CQVDKGFMVXRRAI-UHFFFAOYSA-J Cl[Au](Cl)(Cl)Cl Chemical compound Cl[Au](Cl)(Cl)Cl CQVDKGFMVXRRAI-UHFFFAOYSA-J 0.000 claims description 3
- 230000008878 coupling Effects 0.000 claims description 3
- 238000010168 coupling process Methods 0.000 claims description 3
- 238000005859 coupling reaction Methods 0.000 claims description 3
- 239000001509 sodium citrate Substances 0.000 claims description 3
- NLJMYIDDQXHKNR-UHFFFAOYSA-K sodium citrate Chemical compound O.O.[Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O NLJMYIDDQXHKNR-UHFFFAOYSA-K 0.000 claims description 3
- 238000005507 spraying Methods 0.000 claims description 3
- DHXNZYCXMFBMHE-UHFFFAOYSA-N 3-bromopropanoic acid Chemical compound OC(=O)CCBr DHXNZYCXMFBMHE-UHFFFAOYSA-N 0.000 claims description 2
- 241000283690 Bos taurus Species 0.000 claims description 2
- 101000609762 Gallus gallus Ovalbumin Proteins 0.000 claims description 2
- 108010058846 Ovalbumin Proteins 0.000 claims description 2
- 239000007864 aqueous solution Substances 0.000 claims description 2
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 2
- 150000001875 compounds Chemical class 0.000 claims description 2
- 108010074605 gamma-Globulins Proteins 0.000 claims description 2
- BTCSSZJGUNDROE-UHFFFAOYSA-N gamma-aminobutyric acid Chemical compound NCCCC(O)=O BTCSSZJGUNDROE-UHFFFAOYSA-N 0.000 claims description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 2
- 229940092253 ovalbumin Drugs 0.000 claims description 2
- 125000001037 p-tolyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)C([H])([H])[H] 0.000 claims description 2
- 239000008055 phosphate buffer solution Substances 0.000 claims description 2
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 2
- 235000019260 propionic acid Nutrition 0.000 claims description 2
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 claims description 2
- 230000002194 synthesizing effect Effects 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 claims 1
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 abstract description 4
- 239000000463 material Substances 0.000 abstract description 3
- 238000003786 synthesis reaction Methods 0.000 abstract description 3
- 230000015572 biosynthetic process Effects 0.000 abstract description 2
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- 230000001988 toxicity Effects 0.000 abstract description 2
- 239000012071 phase Substances 0.000 description 7
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 6
- 239000008346 aqueous phase Substances 0.000 description 6
- 230000000694 effects Effects 0.000 description 5
- 239000003814 drug Substances 0.000 description 4
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- 150000003384 small molecules Chemical class 0.000 description 4
- 229940079593 drug Drugs 0.000 description 3
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- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 2
- 208000005374 Poisoning Diseases 0.000 description 2
- 125000004429 atom Chemical group 0.000 description 2
- ZPUCINDJVBIVPJ-LJISPDSOSA-N cocaine Chemical compound O([C@H]1C[C@@H]2CC[C@@H](N2C)[C@H]1C(=O)OC)C(=O)C1=CC=CC=C1 ZPUCINDJVBIVPJ-LJISPDSOSA-N 0.000 description 2
- 239000003431 cross linking reagent Substances 0.000 description 2
- KOUAQOCYMAENKN-UHFFFAOYSA-N ethyl 2-bromohexanoate Chemical compound CCCCC(Br)C(=O)OCC KOUAQOCYMAENKN-UHFFFAOYSA-N 0.000 description 2
- 150000002430 hydrocarbons Chemical group 0.000 description 2
- 230000005847 immunogenicity Effects 0.000 description 2
- 231100000572 poisoning Toxicity 0.000 description 2
- 230000000607 poisoning effect Effects 0.000 description 2
- 230000001105 regulatory effect Effects 0.000 description 2
- 238000000926 separation method Methods 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- PRGXFAWAMOFULD-UHFFFAOYSA-N 2-(methylamino)-1-(2-methylphenyl)propan-1-one Chemical compound CNC(C)C(=O)C1=CC=CC=C1C PRGXFAWAMOFULD-UHFFFAOYSA-N 0.000 description 1
- SHXWCVYOXRDMCX-UHFFFAOYSA-N 3,4-methylenedioxymethamphetamine Chemical compound CNC(C)CC1=CC=C2OCOC2=C1 SHXWCVYOXRDMCX-UHFFFAOYSA-N 0.000 description 1
- ZAIANDVQAMEDFL-UHFFFAOYSA-N 3-methoxy-2-phenylchromen-4-one Chemical compound O1C2=CC=CC=C2C(=O)C(OC)=C1C1=CC=CC=C1 ZAIANDVQAMEDFL-UHFFFAOYSA-N 0.000 description 1
- SVDVJBWDBYSQLO-UHFFFAOYSA-N 5-(4-hydroxy-3-methoxyphenyl)-5-phenylimidazolidine-2,4-dione Chemical compound C1=C(O)C(OC)=CC(C2(C(NC(=O)N2)=O)C=2C=CC=CC=2)=C1 SVDVJBWDBYSQLO-UHFFFAOYSA-N 0.000 description 1
- 208000000044 Amnesia Diseases 0.000 description 1
- 208000019901 Anxiety disease Diseases 0.000 description 1
- 206010012239 Delusion Diseases 0.000 description 1
- 206010013496 Disturbance in attention Diseases 0.000 description 1
- 206010013654 Drug abuse Diseases 0.000 description 1
- 208000000059 Dyspnea Diseases 0.000 description 1
- 206010013975 Dyspnoeas Diseases 0.000 description 1
- 238000005727 Friedel-Crafts reaction Methods 0.000 description 1
- 208000004547 Hallucinations Diseases 0.000 description 1
- 101000937642 Homo sapiens Malonyl-CoA-acyl carrier protein transacylase, mitochondrial Proteins 0.000 description 1
- 206010020400 Hostility Diseases 0.000 description 1
- 102100027329 Malonyl-CoA-acyl carrier protein transacylase, mitochondrial Human genes 0.000 description 1
- 241000699666 Mus <mouse, genus> Species 0.000 description 1
- 241000699670 Mus sp. Species 0.000 description 1
- 206010033864 Paranoia Diseases 0.000 description 1
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- 241001122767 Theaceae Species 0.000 description 1
- 238000002835 absorbance Methods 0.000 description 1
- 231100000570 acute poisoning Toxicity 0.000 description 1
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 description 1
- 229910052782 aluminium Inorganic materials 0.000 description 1
- 125000003277 amino group Chemical group 0.000 description 1
- 230000036506 anxiety Effects 0.000 description 1
- 230000004596 appetite loss Effects 0.000 description 1
- 230000003542 behavioural effect Effects 0.000 description 1
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- 239000007853 buffer solution Substances 0.000 description 1
- 210000005252 bulbus oculi Anatomy 0.000 description 1
- PUAQLLVFLMYYJJ-ZETCQYMHSA-N cathinone Chemical compound C[C@H](N)C(=O)C1=CC=CC=C1 PUAQLLVFLMYYJJ-ZETCQYMHSA-N 0.000 description 1
- 229950002698 cathinone Drugs 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 229960003920 cocaine Drugs 0.000 description 1
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- 231100000868 delusion Toxicity 0.000 description 1
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- 208000029436 dilated pupil Diseases 0.000 description 1
- 238000007865 diluting Methods 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- XIMFCGSNSKXPBO-UHFFFAOYSA-N ethyl 2-bromobutanoate Chemical compound CCOC(=O)C(Br)CC XIMFCGSNSKXPBO-UHFFFAOYSA-N 0.000 description 1
- PQJJJMRNHATNKG-UHFFFAOYSA-N ethyl bromoacetate Chemical compound CCOC(=O)CBr PQJJJMRNHATNKG-UHFFFAOYSA-N 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 239000011888 foil Substances 0.000 description 1
- 239000003517 fume Substances 0.000 description 1
- 239000003365 glass fiber Substances 0.000 description 1
- 239000010931 gold Substances 0.000 description 1
- 229910052737 gold Inorganic materials 0.000 description 1
- 208000022119 inability to concentrate Diseases 0.000 description 1
- 238000011068 loading method Methods 0.000 description 1
- 235000021266 loss of appetite Nutrition 0.000 description 1
- 208000019017 loss of appetite Diseases 0.000 description 1
- YEHDMSUNJUONMW-UHFFFAOYSA-N methoxyflavone Natural products COC1=CC=CC=C1C1=CC(=O)C2=CC=CC=C2O1 YEHDMSUNJUONMW-UHFFFAOYSA-N 0.000 description 1
- 230000036651 mood Effects 0.000 description 1
- 206010029410 night sweats Diseases 0.000 description 1
- 230000036565 night sweats Effects 0.000 description 1
- 125000004433 nitrogen atom Chemical group N* 0.000 description 1
- 229920006267 polyester film Polymers 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 102000012498 secondary active transmembrane transporter activity proteins Human genes 0.000 description 1
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- 238000006467 substitution reaction Methods 0.000 description 1
- 230000009747 swallowing Effects 0.000 description 1
- 210000002700 urine Anatomy 0.000 description 1
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- C07K14/76—Albumins
- C07K14/765—Serum albumin, e.g. HSA
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- C07K14/76—Albumins
- C07K14/77—Ovalbumin
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
- C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
- G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
- G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
- G01N33/53—Immunoassay; Biospecific binding assay; Materials therefor
- G01N33/558—Immunoassay; Biospecific binding assay; Materials therefor using diffusion or migration of antigen or antibody
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N2430/00—Assays, e.g. immunoassays or enzyme assays, involving synthetic organic compounds as analytes
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- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Organic Chemistry (AREA)
- Immunology (AREA)
- Molecular Biology (AREA)
- Medicinal Chemistry (AREA)
- Biochemistry (AREA)
- General Health & Medical Sciences (AREA)
- Biophysics (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Engineering & Computer Science (AREA)
- Genetics & Genomics (AREA)
- Hematology (AREA)
- Gastroenterology & Hepatology (AREA)
- Zoology (AREA)
- Toxicology (AREA)
- Biomedical Technology (AREA)
- Urology & Nephrology (AREA)
- Cell Biology (AREA)
- Microbiology (AREA)
- Biotechnology (AREA)
- Food Science & Technology (AREA)
- Physics & Mathematics (AREA)
- Analytical Chemistry (AREA)
- General Physics & Mathematics (AREA)
- Pathology (AREA)
- Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
Abstract
The present invention relates to a kind of 4 methyl methcathinone antigen, it is characterised in that its general structure is as follows：Wherein, X=CH2, C2H4, C3H6, C4H8, C5H10.The invention further relates to the preparation method of 4 methyl methcathinone antigens and its application.Material and catalyst used in synthesis and preparation process of the invention are mill run, therefore more practicality, are suitable to industrial production and can produce economic worth；The present invention does not use chloroform, and toxicity is relatively low, with more security.
Description
Technical Field
The invention relates to the technical field of immunodetection; in particular to a method for synthesizing a 4-methyl methcathinone derivative by a chemical synthesis method, and coupling the derivative with macromolecular protein to be applied to a colloidal gold detection card.
Background
The following background is provided to aid the reader in understanding the present invention and is not admitted to be prior art.
4-Methacaracin (4-MMC), also known as Methoxyflavone (Mephedrone), other designations include, vine [1], MCAT [2], magic white (white magic) or meow. 4-MMC is an artificially synthesized analog of cathinone found in Allah beat tea. The main suction modes include swallowing, sucking, injecting and the like.
The earliest 4-MMC was synthesized in 1929. But until 2003, most countries of the world have no clear understanding of 4-MMC. 4-MMC was reconsidered in 2003 when an anonymous chemist on a shared web site, called "Kinetic", mentioned that he attempted to synthesize 2-methyl-methcathinone and 4-methyl-methcathinone, and described later as having a strong sense of well-being, and that no drug could bring this before. At that time, 4-MMC could also be legally sold and purchased over the internet. Until 2008, law enforcement agencies did not recognize 4-MMC as a drug. First in 2008 israel indicates that the transaction of 4-MMC is illegal, and later sweden also indicates that 4-MMC is regulated. But by 2010, most of europe, especially the uk, had a 4-MMC prevalence in particular. In 12 months in 2010, 4-MMC violation was declared by the European Union; the united states announced that it was regulated the next 9 months. Month 7 2012, the united states officially added it to the prevention of synthetic drug abuse act (SDAPA). It has now proven to have little medicinal value and is included in the line of products of management in various countries of the world.
After taking 4-MMC, the drug addict will generate: exciting, stimulating, increasing music appreciation, improving mood, reducing hostility and appropriate amount of sexual stimulation. These effects are similar to cocaine, amphetamines and ecstasy, etc. There were 70 netherlands who were investigating the intake of 4-MMC, of which 58 described it as a pleasant experience and 12 described as unpleasant. The side effects of sucking 4-MMC also include the following: dilated pupil, poor concentration, bruxism, inability to concentrate the eyeball focus, short-term memory loss, hallucinations, delusions and behavioral instability. Also, the sucking person shows: temperature changes, increased heart rate, dyspnea, loss of appetite, night sweats, anxiety, paranoia, depression and other side effects.
According to the current research, the poisoning phenomenon is expected to occur in 50-100 mug/L, more than 100 mug/L and less than 500 mug/L of human blood and plasma which are generally sucked by 4-MMC, and the acute poisoning phenomenon occurs in more than 500 mug/L. There are several cases of death caused by poisoning of 4-MMC in Sweden, the United kingdom and the United states, etc.
Therefore, development of reagents and products related to 4-methylcarbcinone abuse detection is required.
Disclosure of Invention
The invention uses toluene as raw material to directly synthesize hapten with cross-linking arm on N atom through Friedel-crafts reaction and affinity substitution, and then the hapten is coupled with protein with immunogenicity through the cross-linking arm, so as to obtain complete antigen with reactionogenicity and immunogenicity. To obtain specific antibodies against haptens, the cross-linking arms generally follow two principles: firstly, a complex structure is not required as much as possible, and a hydrocarbon chain is generally used as an optimal structure, so that the generation of antibodies of an anti-crosslinking arm can be avoided as much as possible; ② it should have a certain length, generally 1-10 atoms, preferably 1-6, so that the hapten can be exposed on the surface of the protein, rather than being masked by the protein. Therefore, the cross-linking agent selected by the synthesized immune antigen is generally ethyl bromoacetate, ethyl bromobutyrate or ethyl bromohexanoate and the like, and then reacts with amino groups on protein through ethyl removal, and the cross-linking arm of the cross-linking agent is a hydrocarbon chain with a simple structure and is 4-8 atoms in length.
Specifically, the invention provides a 4-methyl-methcathinone antigen, which has the following structural general formula:
wherein X is CH2，C2H4，C3H6，C4H8，C5H10。
On the other hand, the invention also provides a method for preparing 4-methyl-methcathinone antigen, wherein 2-bromopropionyl chloride and toluene are used as raw materials, a derivative of 4-methyl-methcathinone is firstly synthesized, and then the 4-methyl-methcathinone antigen is prepared by covalent coupling of carboxyl on a cross-linking arm and macromolecular protein, and the reaction formula is as follows:
the reaction formula is as follows:
the reaction formula II:
wherein,
1: 2-Bromopropionyl chloride
2: toluene
3: 2-bromo-4-methylpropiophenone
4: methyl amine
5: 3-Bromopropionic acid
6: 3-Aminomethylpropanoic acid
7: 3- (methyl (1-keto-1- (p-tolyl) -2-) amino) propionic acid
8: 4-methylcardienone antigens
In addition, the method for preparing the 4-methylcarbekinone antigen comprises the following specific preparation steps:
(1) under the protection of argon, dissolving anhydrous aluminum chloride in anhydrous dichloromethane, adding 2-bromopropionyl chloride, and stirring for dissolving; adding toluene, and finishing dropping within 30 min; the solution is refluxed for 2 hours and then cooled to room temperature; pouring the room-temperature solution into ice water, adding dichloromethane and hydrochloric acid, violently shaking, standing and layering; leaving a lower dichloromethane phase after layering, washing the dichloromethane phase for 2 times by using hydrogen chloride, drying by using anhydrous magnesium sulfate, filtering, and performing rotary evaporation to obtain a transparent oily substance; adding ether into the transparent substance for dissolving, then slowly dripping petroleum ether until the transparent substance is slightly turbid, standing for crystallization to obtain a transparent crystal product 3; wherein the mol ratio of the 2-bromopropionyl chloride to the toluene to the aluminum trichloride is 1: 1: 3-6; adding 5-20 ml of dichloromethane into every 10mmol of aluminum trichloride for dissolving;
(2) under the protection of argon, uniformly stirring dichloromethane, methylamine hydrochloride and triethylamine, slowly dropwise adding bromopropionic acid, and completing dropwise adding within 2 hours; stirring for 8-16 hours at room temperature; extracting with 0.5M NaOH aqueous solution for 3 times; after extraction, the solvent is removed by rotary evaporation to obtain light yellow liquid, namely a product 6; wherein the molar ratio of methylamine hydrochloride to bromopropionic acid is 1-1.2: 1; the proportion of dichloromethane, triethylamine and methylamine hydrochloride is 30-80 ml: 0.5-1.5 ml: 1mmol of the active component;
(3) dissolving all products 3 obtained in the step (1) and all products 6 obtained in the step (2) in dichloromethane, adding triethylamine, and stirring at room temperature for 8-16 hours; TLC detection reaction; after the reaction is finished, carrying out spin drying on the reaction liquid by using a rotary evaporator to obtain yellow liquid; passing the yellow liquid through a silica gel column to obtain a light yellow solid which is a product 7; wherein the ratio of the product 6 to the product 3 is 1 mmol: 1-6mmol, and the proportion of dichloromethane, triethylamine and product 6 is 75-125 ml: 2-4 ml: 1g of a compound;
(4) the product, 7, 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride (EDC), N-hydroxysuccinimide (NHS) was dissolved in N-Dimethylformamide (DMF) and stirred at room temperature for 8H. Then dripping the mixture into a protein solution, and stirring the mixture overnight to obtain a product 8; wherein the ratio of the product 7 to the DEC to the NHS is 1: 1.2-1.5; the DMF solution of the product 7 was 50 gm/ml; the protein solution is 5mg/ml, and the solvent is phosphate buffer solution with pH 7.410 mM; the mass ratio of the product 7 to the protein is 1g:2-10 g.
In some preferred embodiments. The macromolecular protein is Bovine Serum Albumin (BSA), bovine gamma-globulin (BGG) or chicken Ovalbumin (OVA).
The invention also provides a method for detecting the 4-methyl-methcathinone colloidal gold, which comprises the following steps:
s1, immunizing an animal by using a 4-methyl-methcathinone antigen to prepare an antibody;
s2, reducing gold tetrachloride by using sodium citrate to prepare colloidal gold, and then marking the colloidal gold on an antibody resisting 4-methylcardienone to form a gold-labeled antibody;
s3, uniformly spraying the gold-labeled antibody on the labeling pad;
s4.4-methyl-methcathinone antigen is sprayed on a detection line on the nitrocellulose membrane, and simultaneously, antigens of corresponding immune animals are sprayed on a control line on the nitrocellulose membrane;
s5, assembling the sample pad, the marking pad, the nitrocellulose membrane and the absorbent paper into a test strip;
and S6, detecting.
Advantageous effects
The invention has the following beneficial effects:
1. the materials and the catalyst used in the synthesis preparation process of the 4-methyl-methcathinone antigen are common products, so the method has higher practicability, is suitable for industrial production and can generate economic value.
2. The invention does not use chloroform, has lower toxicity and higher safety.
3. The 4-methyl methcathinone antigen is applied to test strip detection, and the reading is accurate, convenient and quick.
Drawings
FIG. 1 is a general structural formula of 4-methylcardienone antigen;
FIG. 2 is a schematic view of a colloidal gold test card;
FIG. 3 is a schematic view of a color chip;
FIG. 4 is a graph showing the results of detection of 4-methylcarbekinone antigen for small molecules;
FIG. 5 is a graph of the results of accelerated stability of the antigen;
reference numerals:
a sample pad 201, a gold-labeled pad 202, a nitrocellulose membrane 203, absorbent paper 204, a big card 205, a test strip 200, a test line (T line) 206 and a control line (C line) 207
Detailed Description
The present invention will be described in detail with reference to the accompanying drawings.
Example 1: preparation of 4-methylcarbekinone antigen (FIG. 1)
Preparation of 1.4-methylcarbekinone hapten
(1) Under the protection of argon, anhydrous aluminum chloride (4g, 30mmol) was added to the reaction flask, followed by addition of 20ml of anhydrous dichloromethane, and the mixture was stirred to dissolve. After dissolution, (1.7g, 10mmol) 2-bromopropionyl chloride was added and stirring continued for 20 min. Toluene (0.92g,10mmol) was then added and the dropwise addition was complete within 30 min. After completion of the dropwise addition, 2H was refluxed, and after completion of the refluxing, it was cooled to room temperature. After cooling, the solution was poured into 40ml of ice-water and 20ml of dichloromethane and 20ml of 6N hydrochloric acid were added, shaken vigorously and then allowed to stand for separation. The lower dichloromethane phase remained after separation, washed 2 times with 1N HCl, dried over anhydrous magnesium sulfate, filtered and rotary evaporated to give a clear oil. The clear material was placed in a crystallization dish and dissolved with diethyl ether, then petroleum ether was slowly added dropwise until slightly cloudy, capped and left to crystallize with a piece of paper in a fume hood to give 1.37g of product 3 as clear crystals. The yield is 60.6 percent
13CNMR(DMSO):192.562,144.674,134.845,129.242,129.025,41.009,22.502,20.963
ESI m/z＝227(M+1)
(2) Under the protection of argon, 60ml of dichloromethane is added into a 250ml flask, then (1.3g, 2mmol) of methylamine hydrochloride and 1ml of triethylamine are added, and the mixture is stirred uniformly. After stirring was complete bromopropionic acid (3g,2mmol) was slowly added dropwise over 2 hours. After the addition was complete, the mixture was stirred at room temperature overnight (i.e., 8-16 hours). The aqueous phase was then extracted 3 times with 0.5M aqueous NaOH, each time removing the upper aqueous phase. After extraction, solvent was removed by rotary evaporation to give product 6 (73.3% yield) which was used directly in the next reaction without purification.
(3) The product 3(103mg, 1mmol) and the product 6(227mg, 1mmol) obtained in the first two steps were dissolved in 17ml of dichloromethane, and then 0.46ml of triethylamine was added thereto, followed by stirring at room temperature for 8 to 16 hours. And (3) detecting the reaction by TLC, and after the reaction is finished, spin-drying the reaction liquid by using a rotary evaporator to obtain yellow liquid. The yellow liquid was passed through a silica gel column to obtain 163mg of a pale yellow solid as the final product 7. The yield is 65.5%
13CNMR(DMSO):195.564，176.029，143.454，133.809，129.075，77.657，52.699，42.876，36.885，22.102，14.967
ESI m/z＝249(M+1)
2. Product 7 (4-methyl-methcathinone hapten) coupled carrier protein
1.60 mg of product 7 were dissolved in 2ml of DMF at a concentration of 30 mg/ml. 10mg/ml PBS-BSA protein was prepared.
2. To 2ml X30 mg/ml of product 7 were added 40mg EDC, 25mg NHS and stirred at room temperature for 8H.
3. 30ml of the PBS-BAS protein solution obtained in step 1 was added dropwise to the activated product 7, and the reaction was carried out overnight at room temperature to obtain the final product 8. The solution was dialyzed against PBS for 3 days, and the concentration was found to be 6.62 mg/ml.
Example 2: preparation of 4-Methylcarbekinone hapten (product 7) using different starting materials
Compared with example 1, the amount of the raw materials used was different in part, and the rest of the steps were the same.
(1) Under the protection of argon, dissolving anhydrous aluminum chloride (6g,45mmol) in anhydrous dichloromethane (55ml), adding 2-bromopropionyl chloride (1.72g,10mmol), and stirring for dissolving; then adding toluene (0.92g,10mmol), and finishing dropping within 30 min; the solution is refluxed for 2 hours and then cooled to room temperature; pouring the room-temperature solution into ice water, adding dichloromethane and hydrochloric acid, violently shaking, standing and layering; leaving a lower dichloromethane phase after layering, washing the dichloromethane phase for 2 times by using hydrogen chloride, drying by using anhydrous magnesium sulfate, filtering, and performing rotary evaporation to obtain a transparent oily substance; dissolving the transparent substance with diethyl ether, slowly adding petroleum ether dropwise until the transparent substance is slightly turbid, standing and crystallizing to obtain 1.50g of a transparent crystal product 3 (yield 64.5%);
(2) under the protection of argon, dichloromethane (115ml), methylamine hydrochloride (1.5g,2.3mmol) and triethylamine (2.8ml) are stirred uniformly, then bromopropionic acid (3g,2mmol) is slowly added dropwise, and the dropwise addition is completed within 2 hours; stirring for 8-16 hours at room temperature; the aqueous phase was then extracted 3 times with 0.5M aqueous NaOH, each time removing the upper aqueous phase. After extraction, solvent was removed by rotary evaporation to give 1.60g of a pale yellow liquid, i.e., product 6 (yield 77.7%) which was used directly in the next reaction without purification.
(3) After dissolving the resulting product 3(412mg, 4mmol) and product 6(227mg, 1mmol) in dichloromethane (22.7ml), triethylamine (0.68ml) was added and the mixture was stirred at room temperature for 8 to 16 hours; TLC detection reaction; after the reaction is finished, carrying out spin drying on the reaction liquid by using a rotary evaporator to obtain yellow liquid; passing the yellow liquid through a silica gel column to obtain 152mg of a light yellow solid, namely a final product 7 (the yield is 61.1%);
example 3: preparation of 4-methylcarbekinone hapten (product 7) from a different starting material
Compared with example 1, the amount of the raw materials used was different in part, and the rest of the steps were the same.
(1) Under the protection of argon, dissolving anhydrous aluminum chloride (8g,60mmol) in anhydrous dichloromethane (120ml), adding 2-bromopropionyl chloride (1.72g,10mmol), and stirring for dissolving; then adding toluene (0.92g,10mmol), and finishing dropping within 30 min; the solution is refluxed for 2 hours and then cooled to room temperature; pouring the room-temperature solution into ice water, adding dichloromethane and hydrochloric acid, violently shaking, standing and layering; leaving a lower dichloromethane phase after layering, washing the dichloromethane phase for 2 times by using hydrogen chloride, drying by using anhydrous magnesium sulfate, filtering, and performing rotary evaporation to obtain a transparent oily substance; dissolving the transparent substance with diethyl ether, slowly adding petroleum ether dropwise until the transparent substance is slightly turbid, standing for crystallization to obtain 1.2g of transparent crystal product 3 (yield 53.1%)
(2) Under the protection of argon, dichloromethane (190ml), methylamine hydrochloride (1.6g,2.4mmol) and triethylamine (3.6ml) are stirred uniformly, then bromopropionic acid (3g,2mmol) is slowly added dropwise, and the dropwise addition is completed within 2 hours; stirring for 8-16 hours at room temperature; the aqueous phase was then extracted 3 times with 0.5M aqueous NaOH, each time removing the upper aqueous phase. After extraction, solvent was removed by rotary evaporation to give 1.49g of a pale yellow liquid, i.e., product 6 (yield 72.4%) which was used directly in the next reaction without purification.
(3) The resulting product 3(620mg, 6mmol) and product 6(227mg, 1mmol) were dissolved in methylene chloride (28ml), triethylamine (0.9ml) was added, and the mixture was stirred at room temperature for 8 to 16 hours; TLC detection reaction; after the reaction is finished, carrying out spin drying on the reaction liquid by using a rotary evaporator to obtain yellow liquid; passing the yellow liquid through a silica gel column to obtain 140mg of light yellow solid, namely a final product 7 (the yield is 56.3%);
example 4: application of antigen in colloidal gold detection test strip
The 4-methyl-methcathinone antigen is used for immunizing animals to prepare antibodies, and in the experiment, the 4-methyl-methcathinone antigen is used for immunizing mice to prepare the antibodies.
Reducing gold tetrachloride with sodium citrate to prepare colloidal gold with the diameter of 20-40nm, then labeling the colloidal gold on an antibody of anti-4-methylcardienone, and expressing the concentration of the gold-labeled antibody by using the absorbance (OD) of lambda max;
loading the gold-labeled antibody onto a gold-labeling machine, uniformly spraying the gold-labeled antibody with a certain OD value onto a polyester film (gold-labeled pad 202), and drying in a 37-degree oven for 8 h; cutting into proper size, placing into aluminum foil bag equipped with dryer, and storing at room temperature;
diluting 4-methylcarbeketone antigen to a proper concentration, spotting the diluted antigen to a corresponding T line position 206 on a nitrocellulose membrane 203 by using a film spotting machine, adding a corresponding mouse antigen (for detecting whether the detection card is effective) to a corresponding C line position 207 on the nitrocellulose membrane 203, and drying for 12h at 37 ℃;
sample pad 201-glass fiber is treated by buffer solution and surface activity, and dried for 10h at 37 ℃ for standby;
assembling a colloidal gold detection test paper card 200 according to a sample pad 201, a gold label pad 202, a nitrocellulose membrane 203, absorbent paper 204 and a big card 205, and referring to fig. 2;
preparing a small molecule solution with corresponding concentration, adding the small molecule solution to the sample pad 201, and reading the result after 5 min;
the Cutoff value of the product for 4-methylcarbekinone is 300ng/ml, i.e. -50% is 150ng/ml and + 50% is 450 ng/ml.
Remarks 1: all the small molecules to be detected are dissolved in the negative urine;
remarks 2: and (3) standard color cards, wherein the colorimetric range of the standard color cards is between 0 and 10, namely G1 and G10, and the color depth is increased from the absence to the presence in sequence, as shown in figure 3.
Remarks 3: detection standard: comparing the test T-line 206 of the test strip to a standard color chip:
a negative is indicated when the line depth is greater than G8;
the line depth more than G4 is qualified under the condition of-50% cutoff;
the line depth < G3.5 is qualified under the condition of + 50% cutoff
Table one: the detection sensitivity results of the three antigens on the 4-methylcarbekinone micromolecule are shown in figure 4, and are negative from left to right, namely-50 percent and +50 percent
TABLE II accelerated stability of antigen (55 ℃ C. for 72 hours with assembled test cards) results, see FIG. 5, negative from left to right, -50%, + 50%
From the table one and table two, it can be seen that: the product meets QC standard, and the heat stability is good, and the detected antigen is qualified.
Claims (5)
1. A4-methyl-methcathinone antigen, which is characterized in that the structural general formula is as follows:
wherein X is CH2，C2H4，C3H6，C4H8，C5H10。
2. A process for preparing the 4-methylcarbeketone antigen of claim 1, which comprises synthesizing a derivative of 4-methylcarbeketone from 2-bromopropionyl chloride and toluene, and then covalently coupling the carboxyl group of the crosslinking arm with a macromolecular protein to prepare the 4-methylcarbeketone antigen, wherein the reaction formula is as follows:
the reaction formula is as follows:
the reaction formula II:
wherein,
1: 2-Bromopropionyl chloride
2: toluene
3: 2-bromo-4-methylpropiophenone
4: methyl amine
5: 3-Bromopropionic acid
6: 3-Aminomethylpropanoic acid
7: 3- (methyl (1-keto-1- (p-tolyl) -2-) amino) propionic acid
8: 4-methylcardienone antigen.
3. A method for preparing the 4-methylcardienone antigen according to claim 1, which comprises the following steps:
(1) under the protection of argon, dissolving anhydrous aluminum chloride in anhydrous dichloromethane, adding 2-bromopropionyl chloride, and stirring for dissolving; adding toluene, and finishing dropping within 30 min; the solution is refluxed for 2 hours and then cooled to room temperature; pouring the room-temperature solution into ice water, adding dichloromethane and hydrochloric acid, violently shaking, standing and layering; leaving a lower dichloromethane phase after layering, washing the dichloromethane phase for 2 times by using hydrogen chloride, drying by using anhydrous magnesium sulfate, filtering, and performing rotary evaporation to obtain a transparent oily substance; adding ether into the transparent substance for dissolving, then slowly dripping petroleum ether until the transparent substance is slightly turbid, standing for crystallization to obtain a transparent crystal product 3; wherein the mol ratio of the 2-bromopropionyl chloride to the toluene to the aluminum trichloride is 1: 1: 3-6; adding 5-20 ml of dichloromethane into every 10mmol of aluminum trichloride for dissolving;
(2) under the protection of argon, uniformly stirring dichloromethane, methylamine hydrochloride and triethylamine, slowly dropwise adding bromopropionic acid, and completing dropwise adding within 2 hours; stirring for 8-16 hours at room temperature; extracting with 0.5M NaOH aqueous solution for 3 times; after extraction, the solvent is removed by rotary evaporation to obtain light yellow liquid, namely a product 6; wherein the molar ratio of methylamine hydrochloride to bromopropionic acid is 1-1.2: 1; the proportion of dichloromethane, triethylamine and methylamine hydrochloride is 30-80 ml: 0.5-1.5 ml: 1mmol of the active component;
(3) dissolving all products 3 obtained in the step (1) and all products 6 obtained in the step (2) in dichloromethane, adding triethylamine, and stirring at room temperature for 8-16 hours; TLC detection reaction; after the reaction is finished, carrying out spin drying on the reaction liquid by using a rotary evaporator to obtain yellow liquid; passing the yellow liquid through a silica gel column to obtain a light yellow solid which is a product 7; wherein the ratio of the product 6 to the product 3 is 1 mmol: 1-6mmol, and the proportion of dichloromethane, triethylamine and product 6 is 75-125 ml: 2-4 ml: 1g of a compound;
(4) the product, 7, 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride (EDC), N-hydroxysuccinimide (NHS) was dissolved in N-Dimethylformamide (DMF) and stirred at room temperature for 8H. Then dripping the mixture into a protein solution, and stirring the mixture overnight to obtain a product 8; wherein the ratio of the product 7 to the DEC to the NHS is 1: 1.2-1.5; the DMF solution of the product 7 was 50 gm/ml; the protein solution is 5mg/ml, and the solvent is phosphate buffer solution with pH 7.410 mM; the mass ratio of the product 7 to the protein is 1g:2-10 g.
4. 4-methylcardienone antigen according to any one of claims 1 to 3, wherein the macromolecular protein is Bovine Serum Albumin (BSA), Bovine Gamma Globulin (BGG) or chicken Ovalbumin (OVA).
5. A method for detecting 4-methyl methcathinone colloidal gold is characterized by comprising the following steps:
s1, immunizing an animal by using a 4-methyl-methcathinone antigen to prepare an antibody;
s2, reducing gold tetrachloride by using sodium citrate to prepare colloidal gold, and then marking the colloidal gold on an antibody resisting 4-methylcardienone to form a gold-labeled antibody;
s3, uniformly spraying the gold-labeled antibody on the labeling pad;
s4.4-methyl-methcathinone antigen is sprayed on a detection line on the nitrocellulose membrane, and simultaneously, antigens of corresponding immune animals are sprayed on a control line on the nitrocellulose membrane;
s5, assembling the sample pad, the marking pad, the nitrocellulose membrane and the absorbent paper into a test strip;
and S6, detecting.
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