CN102796025B - Synthesis method for stable isotope labeled malachite green - Google Patents

Synthesis method for stable isotope labeled malachite green Download PDF

Info

Publication number
CN102796025B
CN102796025B CN201210313832.XA CN201210313832A CN102796025B CN 102796025 B CN102796025 B CN 102796025B CN 201210313832 A CN201210313832 A CN 201210313832A CN 102796025 B CN102796025 B CN 102796025B
Authority
CN
China
Prior art keywords
dma
malachite green
reaction
cold labeling
coupler
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Active
Application number
CN201210313832.XA
Other languages
Chinese (zh)
Other versions
CN102796025A (en
Inventor
杨超
杨维成
罗勇
李美华
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Shanghai Research Institute of Chemical Industry SRICI
Original Assignee
Shanghai Research Institute of Chemical Industry SRICI
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Shanghai Research Institute of Chemical Industry SRICI filed Critical Shanghai Research Institute of Chemical Industry SRICI
Priority to CN201210313832.XA priority Critical patent/CN102796025B/en
Publication of CN102796025A publication Critical patent/CN102796025A/en
Application granted granted Critical
Publication of CN102796025B publication Critical patent/CN102796025B/en
Active legal-status Critical Current
Anticipated expiration legal-status Critical

Links

Landscapes

  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

The invention relates to a synthesis method for stable isotope labeled malachite green. The stable isotope labeled malachite green is obtained by the steps of reacting stable isotope labeled N, N-dimethylaniline with a coupling agent and benzaldehyde, introducing mixed gas of NO and NO2, and separating and purifying after the reaction is finished. Compared with the prior art, after the stable isotope labeled malachite green prepared by the method is separated and purified, the chemical purity reaches over 99 percent and the isotope abundance is over 98 percent atom.

Description

A kind of synthetic method of cold labeling malachite green
Technical field
The present invention relates to isotopic labeling field, especially relate to a kind of synthetic method of Isotopic Internal Standard detection reagent cold labeling malachite green.
Background technology
Malachite green was once widely used in fish farming industry as sterilant.Chemical functional group tritane in malachite green can be carcinogenic, and a lot of countries forbid, but still have fisherman to use in the time of control infection of marine fishes fungi, also has forwarding agent to be used as sterilizing agent, to extend the survival time of fish in long-distance traffic.For preventing the residual food chain that enters of the Synthesis of diaminodiphenyl such as malachite green, culturist and Governmental monitoring department need a kind of can be fast, accurately also very sensitive technology detects it.
The main detection technique that is used for detecting this class Synthesis of diaminodiphenyl has high performance liquid chromatography, tlc, spectrophotometry and using high performance liquid chromatography tandem mass spectrum method.High performance liquid chromatography highly sensitive, but the method is loaded down with trivial details, therefore the method is seldom used.Tlc is simple and efficient to handle, but can not detect malachite green and procrypsis malachite green simultaneously.The detectability of spectrophotometry is very high, but the sensitivity detecting is lower, and accuracy is very poor.And mass spectrum is as current detection technique with fastest developing speed, in all kinds of residue detection, apply and popularize gradually, become the detecting instrument of analysis and confirmatory test chamber indispensability.Because mass spectrum can provide quantitative and qualitative analysis information simultaneously, therefore developed country is detected by mass spectroscopy for residual all requirement the in food, feed, and relevant criterion has been carried out to detailed regulation as the 2002/657/EC instruction of European Union.
Stable isotope dilution mass spectrometry IDMS (Isotope Dilution Mass Spectrometry) adopts the compound of cold labeling that has same molecular structure with measured matter as internal standard substance matter, detect by high resolution liquid chromatography one GC-MS (LC/MS), measure by mass spectrograph respective quality number ion ratio and reach the object of accurate quantitative analysis with the odds ratio of standard.Adopt Isotopic Internal Standard can effectively eliminate sample caused rate of recovery difference in the pre-treatment step of chemistry and physics, thereby avoid because the deviation that the loss of sample preparation process causes detected result.
In stable isotope, the ability of the highly sensitive of this specific character of target and LC/MS and processing complex sample combines, and makes chromatogram/isotopic dilution mass-spectrometric technique be acknowledged as a kind of pedestal method of measuring trace and trace organic substance.And the succeeding in developing of triphenylmethane compounds marked with stable isotopes cold labeling procrypsis malachite green, malachite green, to provide standard reagent for detection by quantitative procrypsis malachite green, malachite green more accurately, thereby be effectively the detection of veterinary drugs in food service of China's food safety field.
Summary of the invention
Object of the present invention is exactly to provide in order to overcome the defect that above-mentioned prior art exists the synthetic method that a kind of process is simple, separating-purifying is easy to cold labeling malachite green.
Object of the present invention can be achieved through the following technical solutions:
The synthetic method of cold labeling malachite green, utilizes the DMA of cold labeling to react with coupler, phenyl aldehyde, after pass into NO and NO 2mixed gas, after reaction finishes, through separating, purifying, obtain the malachite green of cold labeling.
The DMA of described cold labeling be DMA- 15n, DMA- 13c 2or DMA-D 6.
DMA- 15the malachite green of N mark- 15n 2molecular structure be:
DMA- 13c 2the malachite green of mark- 13c 4molecular structure be:
DMA-D 6malachite green-the D of mark 12molecular structure be:
The synthetic of malachite green specifically comprises the following steps: by the N of cold labeling, accelerine mixes by certain mol proportion example with coupler, phenyl aldehyde, be placed in liquid phase environment, under catalyst action, under certain pressure, control temperature of reaction reaction certain hour, after pass into again NO and NO 2mixed gas, reaction solution obtains the malachite green of cold labeling after separating-purifying.
The DMA of described cold labeling and the mol ratio of coupler are 2: 1～4: 1; The DMA of described cold labeling and phenyl aldehyde are 1: 1～3: 1 in molar ratio; Described coupler comprises urea, paraformaldehyde or FORMAMIDINE ACETATE; Described liquid phase environment is one or more in hydrochloric acid, acetic acid, diacetyl oxide, acetone, acetonitrile or dioxane; Described catalyzer is selected from one or more in tri-n-octyl methyl ammonium chloride, Dodecyl trimethyl ammonium chloride, benzyltriethylammoinium chloride, Tetrabutyl amonium bromide, tetrabutylammonium chloride or 4-butyl ammonium hydrogen sulfate; The weight ratio of the DMA of catalyzer and cold labeling is 0.01: 1～0.2: 1; Reaction pressure is 0～5MPa; Temperature of reaction is 10～190 DEG C; Reaction times is 2～16h.
The preferably one in 2: 1,3: 1 or 4: 1 of the DMA of described cold labeling and the mol ratio of coupler; The DMA of described cold labeling and the phenyl aldehyde preferred one in 1: 1,2: 1 or 3: 1 in molar ratio; The preferred urea of described coupler or paraformaldehyde; One or more in the preferred hydrochloric acid of described liquid phase environment, acetic acid, diacetyl oxide, acetone or acetonitrile; The preferred Dodecyl trimethyl ammonium chloride of described catalyzer, benzyltriethylammoinium chloride, Tetrabutyl amonium bromide or tetrabutylammonium chloride; The weight ratio of the DMA of catalyzer and cold labeling preferably 0.04: 1～0.1: 1; Preferably 30～160 DEG C of temperature of reaction; Reaction times is 4～12h preferably.
Compared with prior art, the present invention has the following advantages:
(1) the present invention adopts procedure simple, and stable isotope atom utilization is high;
(2) the easily separated purification of product of the present invention, product chemical purity is more than 99%, and isotopic abundance, more than 98%atom, can fully meet the demand of food safety field detection of veterinary drugs in food;
(3) the present invention has good economy and use value.
Embodiment
Below in conjunction with specific embodiment, the present invention is described in detail.
Embodiment 1
A kind of isotropic substance 13the synthetic method of C mark malachite green, the method specifically comprises the following steps:
By isotropic substance 13the DMA of C mark- 13c 2be 1: 1 in molar ratio, within 2: 1 in molar ratio, mix in the mixing solutions that is placed on acetic acid and diacetyl oxide with urea with phenyl aldehyde, add Dodecyl trimethyl ammonium chloride, Dodecyl trimethyl ammonium chloride with 13the weight ratio of the procrypsis malachite green of C mark is 0.04: 1, control temperature of reaction be 120 DEG C, stirring reaction 4h, after pass into again NO and NO 2mixed gas, stirring reaction 8h, obtains 13the malachite green of C mark, is product, and products obtained therefrom chemical purity reaches 99.0%, and isotopic abundance is 99.0%atom.
Embodiment 2
A kind of isotropic substance 13the synthetic method of C mark malachite green, the method specifically comprises the following steps:
By isotropic substance 13the DMA of C mark- 13c 2be 3: 1 in molar ratio, within 4: 1 in molar ratio, mix and be placed in hydrochloric acid soln with urea with phenyl aldehyde, add tetrabutylammonium chloride, tetrabutylammonium chloride with 13the weight ratio of the procrypsis malachite green of C mark is 0.1: 1, control temperature of reaction be 160 DEG C, stirring reaction 2h, after pass into again NO and NO 2mixed gas, stirring reaction 4h, obtains 13the malachite green of C mark, is product, and products obtained therefrom chemical purity reaches 99.1%, and isotopic abundance is 99.4%atom.
Embodiment 3
A kind of isotropic substance 15the synthetic method of N mark malachite green, the method specifically comprises the following steps:
By isotropic substance 15the DMA of N mark- 15n is 2: 1 in molar ratio, within 3: 1 in molar ratio, mixes and be placed in acetonitrile solution with urea with phenyl aldehyde, adds Tetrabutyl amonium bromide, Tetrabutyl amonium bromide with 15the weight ratio of the procrypsis malachite green of N mark is 0.06: 1, control temperature of reaction be 90 DEG C, stirring reaction 4h, after pass into again NO and NO 2mixed gas, stirring reaction 6h, obtains 15the malachite green of N mark, is product, and products obtained therefrom chemical purity reaches 99.2%, and isotopic abundance is 99.2%atom.
Embodiment 4
A kind of isotropic substance 15the synthetic method of N mark malachite green, the method specifically comprises the following steps:
By isotropic substance 15the DMA of N mark- 15n is 1: 1 in molar ratio, within 2: 1 in molar ratio, mixes and be placed in acetone soln with urea with phenyl aldehyde, adds benzyltriethylammoinium chloride, tetrabenzyl triethyl ammonium chloride with 15the weight ratio of the procrypsis malachite green of N mark is 0.08: 1, control temperature of reaction be 60 DEG C, stirring reaction 6h, after pass into again NO and NO 2mixed gas, stirring reaction 6h, obtains 15the malachite green of N mark, is product, and products obtained therefrom chemical purity reaches 99.1%, and isotopic abundance is 99.2%atom.
Embodiment 5
A synthetic method for isotope D mark malachite green, the method specifically comprises the following steps:
By the DMA-D of isotope D mark 6be 3: 1 in molar ratio, within 2: 1 in molar ratio, mix and be placed in dioxane solution with urea with phenyl aldehyde, add tetrabutylammonium chloride, the weight ratio of the procrypsis malachite green of tetrabutylammonium chloride and D mark is 0.1: 1, and controlling temperature of reaction is 30 DEG C, stirring reaction 8h, after pass into again NO and NO 2mixed gas, stirring reaction 4h, obtains the malachite green of D mark, is product, products obtained therefrom chemical purity reaches 99.5%, isotopic abundance is 99.0%atom.
Embodiment 6
A synthetic method for isotope D mark malachite green, the method specifically comprises the following steps:
By the DMA-D of isotope D mark 6be 2: 1 in molar ratio, within 4: 1 in molar ratio, mix and be placed in acetonitrile solution with urea with phenyl aldehyde, add Tetrabutyl amonium bromide, the weight ratio of the procrypsis malachite green of Tetrabutyl amonium bromide and D mark is 0.04: 1, and controlling temperature of reaction is 100 DEG C, stirring reaction 4h, after pass into again NO and NO 2mixed gas, stirring reaction 6h, obtains the malachite green of D mark, is product, products obtained therefrom chemical purity reaches 99.4%, isotopic abundance is 99.2%atom.
Embodiment 7
By isotropic substance 13the DMA of C mark- 13c 2mix and be placed in liquid phase environment acetic acid with coupler paraformaldehyde, phenyl aldehyde, wherein, DMA- 13c 2with the mol ratio of coupler be 2: 1, DMA- 13c 2with phenyl aldehyde be 1: 1 in molar ratio, add tri-n-octyl methyl ammonium chloride and Dodecyl trimethyl ammonium chloride as catalyzer, catalyzer and DMA- 13c 2weight ratio be 0.01: 1, control reaction pressure is 0MPa, controlling temperature of reaction is 10 DEG C of reaction 16h, then passes into NO and NO in reaction system 2mixed gas, reaction solution after separating-purifying, obtain DMA- 13c 2the malachite green of mark- 13c 4, its molecular structure is:
Embodiment 8
By isotropic substance 15the DMA of N mark- 15n mixes and is placed in liquid phase environment acetone with coupler urea, phenyl aldehyde, wherein, and DMA- 15the mol ratio of N and coupler is 2: 1, DMA- 15n and phenyl aldehyde are 2: 1 in molar ratio, add Tetrabutyl amonium bromide as catalyzer, catalyzer and DMA- 15the weight ratio of N is 0.04: 1, and control reaction pressure is 2MPa, and controlling temperature of reaction is 30 DEG C of reaction 12h, then passes into NO and NO in reaction system 2mixed gas, reaction solution after separating-purifying, obtain DMA- 15the malachite green of N mark- 15n 2, molecular structure is:
Embodiment 9
By the DMA-D of isotope D mark 6mix and be placed in liquid phase environment dioxane with coupler FORMAMIDINE ACETATE, phenyl aldehyde, wherein, DMA-D 6with the mol ratio of coupler be 4: 1, DMA-D 6with phenyl aldehyde be 3: 1 in molar ratio, add 4-butyl ammonium hydrogen sulfate as catalyzer, catalyzer and DMA-D 6weight ratio be 0.2: 1, control reaction pressure is 5MPa, controlling temperature of reaction is 190 DEG C of reaction 2h, then passes into NO and NO in reaction system 2mixed gas,, reaction solution obtains DMA-D after separating-purifying 6malachite green-the D of mark 12, molecular structure is:

Claims (2)

1. the synthetic method of cold labeling malachite green, is characterized in that, the method utilizes the DMA of cold labeling to mix with coupler, phenyl aldehyde, adds catalyzer, reaction for some time, passes into NO and NO 2mixed gas, after reaction finishes, through separating, purifying, obtain the malachite green of cold labeling, be product;
The DMA of described cold labeling be DMA- 15n, DMA- 13c 2or DMA-D 6,
DMA- 15the malachite green of N mark- 15n 2molecular structure be:
DMA- 13c 2the malachite green of mark- 13c 4molecular structure be:
DMA-D 6malachite green-the D of mark 12molecular structure be:
The synthetic of malachite green specifically comprises the following steps: by the N of cold labeling, accelerine mixes by certain mol proportion example with coupler, phenyl aldehyde, be placed in liquid phase environment, under catalyst action, under certain pressure, control temperature of reaction reaction certain hour, after pass into again NO and NO 2mixed gas, reaction solution obtains the malachite green of cold labeling after separating-purifying,
The DMA of described cold labeling and the mol ratio of coupler are 2:1～4:1; The DMA of described cold labeling and phenyl aldehyde are 1 ︰ 1～3 ︰ 1 in molar ratio; Described coupler is urea, paraformaldehyde or FORMAMIDINE ACETATE; Described liquid phase environment is one or more in hydrochloric acid, acetic acid, diacetyl oxide, acetone, acetonitrile or dioxane; Described catalyzer is selected from one or more in tri-n-octyl methyl ammonium chloride, Dodecyl trimethyl ammonium chloride, benzyltriethylammoinium chloride, Tetrabutyl amonium bromide, tetrabutylammonium chloride or 4-butyl ammonium hydrogen sulfate; The weight ratio of the DMA of catalyzer and cold labeling is 0.01 ︰ 1～0.2 ︰ 1; Reaction pressure is 0～5MPa; Temperature of reaction is 10～190 DEG C; Reaction times is 2～16h.
2. the synthetic method of a kind of cold labeling malachite green according to claim 1, is characterized in that, the one in the DMA of described cold labeling and the preferred 2:1 of the mol ratio of coupler, 3:1 or 4:1; The DMA of described cold labeling and the phenyl aldehyde preferred one in 1:1,2:1 or 3:1 in molar ratio; The preferred urea of described coupler or paraformaldehyde; One or more in the preferred hydrochloric acid of described liquid phase environment, acetic acid, diacetyl oxide, acetone or acetonitrile; The preferred Dodecyl trimethyl ammonium chloride of described catalyzer, benzyltriethylammoinium chloride, Tetrabutyl amonium bromide or tetrabutylammonium chloride; Preferred 0.04:1～the 0.1:1 of weight ratio of the DMA of catalyzer and cold labeling; Preferably 30～160 DEG C of temperature of reaction; Reaction times is 4～12h preferably.
CN201210313832.XA 2012-08-29 2012-08-29 Synthesis method for stable isotope labeled malachite green Active CN102796025B (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CN201210313832.XA CN102796025B (en) 2012-08-29 2012-08-29 Synthesis method for stable isotope labeled malachite green

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
CN201210313832.XA CN102796025B (en) 2012-08-29 2012-08-29 Synthesis method for stable isotope labeled malachite green

Publications (2)

Publication Number Publication Date
CN102796025A CN102796025A (en) 2012-11-28
CN102796025B true CN102796025B (en) 2014-11-26

Family

ID=47195365

Family Applications (1)

Application Number Title Priority Date Filing Date
CN201210313832.XA Active CN102796025B (en) 2012-08-29 2012-08-29 Synthesis method for stable isotope labeled malachite green

Country Status (1)

Country Link
CN (1) CN102796025B (en)

Families Citing this family (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN104945277B (en) * 2015-06-23 2017-07-07 上海化工研究院有限公司 A kind of cold labeling basic flavine O and its synthetic method
CN105199423B (en) * 2015-08-25 2017-09-26 上海化工研究院有限公司 A kind of synthetic method of the violated pigment of cold labeling
CN108623477A (en) * 2017-03-21 2018-10-09 上海安谱实验科技股份有限公司 A kind of leucogentian violet and its synthetic method of stable isotope labeling
CN113512304B (en) * 2021-06-16 2023-04-11 丰城三友制笔科技有限公司 Preparation process of environment-friendly alkaline green dye

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101973910A (en) * 2010-10-14 2011-02-16 上海化工研究院 Method for synthesizing triphenylmethane compounds marked with stable isotopes

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4394314A (en) * 1981-04-23 1983-07-19 E. I. Du Pont De Nemours And Company Process of preparing aromatic aldehydes by reacting selected aromatic compounds with formamidine acetate and an organic acid anhydride

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101973910A (en) * 2010-10-14 2011-02-16 上海化工研究院 Method for synthesizing triphenylmethane compounds marked with stable isotopes

Non-Patent Citations (5)

* Cited by examiner, † Cited by third party
Title
Naghi Saadatjou.Synthesis and Electronic Absorption Spectra of Some Novel Methoxy.《Fibers and Polymers》.2008,第9卷(第3期),第281-285页. *
Steven C. DeFina，Thorsten Dieckmann.Synthesis of selectively 15N- or 13C-labelled.《JOURNAL OF LABELLED COMPOUNDS AND RADIOPHARMACEUTICALS》.2002,第45卷第241–248页. *
Synthesis and Electronic Absorption Spectra of Some Novel Methoxy;Naghi Saadatjou;《Fibers and Polymers》;20081231;第9卷(第3期);第281-285页 *
罗勇等.稳定同位素标记13 C6 -结晶紫和13 C6 -隐色.《精细化工》.2011,第28卷(第10期),第950-953页. *
罗勇等.稳定同位素标记13 C6-结晶紫和13 C6-隐色.《精细化工》.2011,第28卷(第10期),第950-953页. *

Also Published As

Publication number Publication date
CN102796025A (en) 2012-11-28

Similar Documents

Publication Publication Date Title
CN102796025B (en) Synthesis method for stable isotope labeled malachite green
CN102796009A (en) Synthesis method for stable isotope labeled leucomalachite green
CN103497121A (en) Preparation method of trimesoyl hydrazone series derivatives and application of trimesoyl hydrazone series derivatives as probe molecules for identifying fluorine ions
CN102621297A (en) Fluorescence polarization immunoassay detection method for sarafloxacin
CN105842235A (en) High-sensitivity fluorescent test paper capable of realizing naked-eye detection of volatile organic amine and preparation thereof
CN101973910B (en) Method for synthesizing triphenylmethane compounds marked with stable isotopes
CN104502477B (en) Organic analytical approach in a kind of trichloroacetaldehyde Waste Sulfuric Acid
CN102253142A (en) Method for determining coexisting impurities and trace arenes in methanol simultaneously
CN103254096B (en) A kind of synthetic method of cold labeling basic orange II
CN112326847B (en) Method for detecting impurities in isophthalonitrile
CN106053634A (en) Method for detecting N-dimethyl nitrosamine in cooked meat products
CN102798688B (en) Method for determining contents of methyl propionate, methyl methacrylate and propionic acid by gas chromatography internal standard method
CN102424656A (en) Stable isotope labeled Sudan red I and synthetic method thereof
CN103048407A (en) Content detection method for lysine of compound ketoacid tablet
CN104165935B (en) The analyzing monitoring method of 1,2-ethylene dichloride production cycle mother liquor
CN103592377A (en) Method for determining dimethyl sulfate and diethyl sulfate in electronic and electric products
CN116626087A (en) Method for quantitatively analyzing allyl sucrose ether content through nuclear magnetic resonance hydrogen spectrum
CN109912512B (en) New telmisartan impurity compound and preparation method and application thereof
CN104502473A (en) Quantitative method of detecting cyanamide by utilizing HPLC method
CN102338779A (en) Method for detecting sorbic acid content in cheese
CN103776935A (en) Method for determining content of major components in mother liquor produced by progestin
CN113884584B (en) Method for detecting content of flurbiprofen and/or flurbiprofen axetil
CN102954961B (en) Method for rapidly detecting content of numb-taste components
CN116087375A (en) Guanidine nitrate quantitative analysis method
CN112461957B (en) Method for detecting impurity content in ulipristal acetate intermediate II

Legal Events

Date Code Title Description
C06 Publication
PB01 Publication
C10 Entry into substantive examination
SE01 Entry into force of request for substantive examination
C14 Grant of patent or utility model
GR01 Patent grant
CP01 Change in the name or title of a patent holder

Address after: 200062 Shanghai city Putuo District Yunling Road No. 345

Patentee after: Shanghai Chemical Research Institute Co., Ltd.

Address before: 200062 Shanghai city Putuo District Yunling Road No. 345

Patentee before: Shanghai Research Institute of Chemical Industry

CP01 Change in the name or title of a patent holder