CN107011185A - One group is used for isotope labeling reagent and its synthetic method that carboxyl is marked - Google Patents

One group is used for isotope labeling reagent and its synthetic method that carboxyl is marked Download PDF

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CN107011185A
CN107011185A CN201710191430.XA CN201710191430A CN107011185A CN 107011185 A CN107011185 A CN 107011185A CN 201710191430 A CN201710191430 A CN 201710191430A CN 107011185 A CN107011185 A CN 107011185A
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reaction
isotope
synthetic method
alkali
iodomethane
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吴明火
刘敏
周豪
胡玉峰
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Dalian University of Technology
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C211/00—Compounds containing amino groups bound to a carbon skeleton
    • C07C211/62—Quaternary ammonium compounds
    • C07C211/63—Quaternary ammonium compounds having quaternised nitrogen atoms bound to acyclic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B59/00—Introduction of isotopes of elements into organic compounds ; Labelled organic compounds per se
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B59/00—Introduction of isotopes of elements into organic compounds ; Labelled organic compounds per se
    • C07B59/001—Acyclic or carbocyclic compounds
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C209/00—Preparation of compounds containing amino groups bound to a carbon skeleton
    • C07C209/62—Preparation of compounds containing amino groups bound to a carbon skeleton by cleaving carbon-to-nitrogen, sulfur-to-nitrogen, or phosphorus-to-nitrogen bonds, e.g. hydrolysis of amides, N-dealkylation of amines or quaternary ammonium compounds
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C269/00—Preparation of derivatives of carbamic acid, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
    • C07C269/04—Preparation of derivatives of carbamic acid, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups from amines with formation of carbamate groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C269/00—Preparation of derivatives of carbamic acid, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
    • C07C269/06—Preparation of derivatives of carbamic acid, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups by reactions not involving the formation of carbamate groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/05—Isotopically modified compounds, e.g. labelled
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)

Abstract

The present invention, which provides one group, is used for isotope labeling reagent and its synthetic method that carboxyl is marked, and belongs to the field of chemical synthesis.One end of isotope labeling reagent is primary amine, and the other end is leptodactyline, is connected between primary amine and leptodactyline by multiple carbochains.Building-up process is：With N, N dimethyl-ethylenediamines and its homologue are reaction raw materials, with di-tert-butyl dicarbonate ((BOC)2O) primary amino radical is protected, then in the basic conditions with containing isotope D and13C iodomethane reagent reacting, finally sloughs blocking group in acid condition and obtains target product.The present invention has synthesized one group of new isotope labeling reagent available for highly efficient labeling carboxyl by nucleophilic substitution, and price is low, simple to operate；The isotope reagent obtained using the present invention is remarkably improved the efficiency and accuracy of analysis after being marked.

Description

One group is used for isotope labeling reagent and its synthetic method that carboxyl is marked
Technical field
The invention belongs to the field of chemical synthesis, it is related to one group of isotope labeling reagent and its synthesis side for being used to mark carboxyl Method.
Background technology
With mass spectrum (mass spectrometry) continuing to develop for technology and deepening continuously for proteomics research, Cold labeling (stable isotope labeling) technology for quantitative analysis is developed rapidly.The party Involved isotope and its labelled reagent are a kind of commodity with high technology content and high added value in method.By to target In analyte can reactive group modified and introduce isotopic label, the phase of efficiently and accurately can be realized with reference to LC-MS Pair or absolute quantitation.Since the seventies in last century, this method is widely used in agricultural, food security, life science, ring The fields such as border, clinical medicine, pharmacy.
For the target analytes containing carboxyl, it may be selected to modify carboxyl, same position will be contained by condensation reaction The labelled reagent of element is connected on object.In numerous modification reagents, the reagent with primary amino radical is repairing of being most widely used One of reagent is adornd, can be modified by being realized with the carboxyl formation amido link in object.Preparing the mistake of isotope modification reagent Cheng Zhong, the present invention has selected the iodomethane containing isotope as isotope source reagent, passes through its nucleophilic displacement of fluorine with tertiary amine groups Reaction, isotope is incorporated on final target product, i.e., the isotope labeling reagent marked for carboxyl.Enter to sample During row analysis, first reacted with the labelled reagent with the target analytes in sample, the quaternary ammonium with isotope marks is drawn Enter into former analyte, then the product after mark is analyzed with LC-MS.
The content of the invention
Main contents of the present invention are one group of new isotope labeling reagent of synthesis, with N, N- dimethyl-ethylenediamines and its same It is that thing is raw material, by nucleophilic substitution, isotope is incorporated into final target product.To obtain desired product, When carrying out nucleophilic substitution, it is necessary to which its primary amine is shielded, primary amine is prevented to be methylated；Nucleophilic substitution is completed Afterwards, then by the blocking group in original primary amine groups remove, recovery is obtained for the primary amine groups with carboxyl reaction.
The technical scheme is that：
One group be used for the isotope labeling reagent that carboxyl is marked, and described isotope labeling reagent is structurally characterized in that one end For primary amine, the other end is leptodactyline, is connected between primary amine and leptodactyline by multiple carbochains, and carbon is former in the carbochain of middle part Sub- number is 2-7, and structural formula is as follows：
The synthetic method of above-mentioned isotope labeling reagent, building-up process first uses di-tert-butyl dicarbonate ((BOC)2O) to primary Amino is protected, the reaction such as iodomethane (deuterium and carbon 13) then replaced in the basic conditions with iodomethane or isotope, most Afterwards the serial similar compound that blocking group obtains (2- amino-ethyls) trimethyl ammonium, described serial class are sloughed in acid condition It is isotope labeling reagent like compound.Specifically include following steps：
The first step：With N, N- dimethyl-ethylenediamines and its homologue (n=1-6) are reaction raw materials, using two dimethyl dicarbonates Butyl ester ((BOC)2O) primary amino radical is protected, reaction equation is as follows：
Concretely comprise the following steps：
1.1) it is 1 that mol ratio is added in reaction bulb:1‐1:After 3 water and organic solvent, reaction raw materials are sequentially added And alkali, obtain mixed solution after stirring at room temperature.Concentration of the described reaction raw materials in water is 0.5-5mmol/mL；Institute The alkali stated is sodium hydroxide, sodium carbonate, sodium acid carbonate or triethylamine, and concentration of the alkali in water is 0.75-25mmol/mL；It is described Organic solvent be tetrahydrofuran, Isosorbide-5-Nitrae-dioxane, dichloromethane in one kind.
1.2) under the conditions of 0-5 DEG C, by di-tert-butyl dicarbonate (BOC)2Step 1.1 is added dropwise in O) obtained mixing is molten In liquid, ice-water bath reaction 10-30min, then normal-temperature reaction 2-4h obtain reaction solution.Described reaction raw materials and (BOC)2O's Mol ratio is 1:1.-3.
Second step：The iodomethane of iodomethane or isotope substitution is introduced in reaction system, corresponding quaternary ammonium product is obtained；Should The mode that isotope is introduced in step is realized by the nucleophilic substitution between iodomethane and tertiary amino containing isotope. Specific steps：
Regulating step 1.2) obtained reaction solution pH is to neutral left and right, after rotation solvent evaporated, in reaction bulb successively Add the iodomethane reagent of solvent, alkali and iodomethane or isotope substitution, under the conditions of 60-80 DEG C, heating reflux reaction 2-4h After obtain reaction solution.Described alkali is one kind in sodium hydroxide, sodium carbonate, potassium carbonate；Described solvent is acetonitrile, third One kind in ketone, DMF；Described reaction raw materials, the iodomethane of iodomethane or isotope substitution, the mol ratio of alkali are 1:1.1-2: 1.5-10；The iodomethane of the isotope substitution is CH2DI、CHD2I、CD3I、13CH3I、13CH2DI、13CHD2I、13CD3I。
By taking the iodomethane without isotope as an example, reaction equation is as follows：
3rd step：Blocking group, which is sloughed, in acid condition obtains corresponding leptodactyline
The pH to 6-8 for the reaction solution that second step is obtained is adjusted with hydrochloric acid, solvent evaporated is rotated, chlorine is added in reaction bulb Change the ethyl acetate solution of hydrogen, the concentration of hydrogen chloride is 1-4mol/L, and magnetic agitation reacts 20- under the conditions of 20-40 DEG C After 60min, the hydrochloride of corresponding trimethyl ammonium is separated out, revolving just obtains target product after drying, and structural formula is：Wherein R is CH3、CH2D、CHD2、CD3、13CH3、13CH2D、13CHD2、13CD3；N=1-6, The carbon atom number of carbochain can be 2-7 i.e. in the middle of target product.
The present invention has selected the iodomethane containing isotope as isotope source reagent, with N, N- dimethyl-ethylenediamine homologys Thing (carbon number is 2-7 in middle carbochain) is raw material, passes through the nucleophilic of tertiary amine groups in iodomethane and raw material containing isotope Substitution reaction, isotope is incorporated on final target product.By this quaternary ammonium salt with isotope marks with containing The material of carboxyl carries out amidation process, carboxyl can be marked, obtain its corresponding Isotopic Internal Standard thing.
Beneficial effects of the present invention are, by with price more cheap D or13The iodomethane of C substitutions, uses efficient nucleophilic Substitution reaction has synthesized one group of new isotope labeling reagent available for highly efficient labeling carboxyl.When with MS or LC-MS to containing When the object for having carboxyl carries out quantitative analysis, without for respective Isotopic Internal Standard.Can be by sample and concentration known The standard items of object to be measured are derived with synthesized labelled reagent respectively, are translated into the target with isotope Thing.After mark, the carboxyl of object is converted into quaternary ammonium, in MS or LC-MS analysis, and its detection pattern is by commonly using Negative ion mode be changed into positive ion mode, Ionization Efficiency is uprised, and can improve sensitivity and the detectability of analysis.When right When multiple samples carry out relative quantification or absolute quantitation, while parallel to 5-8 sample be marked processing, it is anti-completing mark These samples should be mixed afterwards, analysis is once completed with MS or LC-MS, the Instrumental Analysis time is reduced to original aspect 1/5-1/8.Compared with each sample single sample introduction is analyzed, it is remarkably improved after being marked using the serial isotope reagent point The efficiency and accuracy of analysis.
Embodiment
With reference to specific embodiment, the present invention is expanded on further.
Embodiment 1：
(1) 1mL water and 1mL tetrahydrofurans are added in 25mL round-bottomed flasks, adds 1.5mmol N, N- dimethyl second Diamines and the 7.5mmol NaOH aqueous solution, it is well mixed to be placed in 0 DEG C of ice-water bath.It is slowly added dropwise in mixed solution 2.5mmol(BOC)2Reacted under O solution, magnetic agitation after 20min, then react at room temperature 2h.
(2) after reaction terminates, solvent in vacuo is dried, 3mL acetonitriles, 2mmol CH is sequentially added3I and 6mmol NaOH water Solution, magnetic agitation reacts 3h at 65 DEG C.
(3) pH that the reaction solution that second step is obtained is adjusted with hydrochloric acid is 7, and revolving is dried after solvent, is added in reaction bulb Enter the ethyl acetate solution (concentration is 1mol/L) of 3mL hydrogen chloride, magnetic agitation reacts 25min under 25 DEG C of reaction temperature.
(4) after the completion of reacting, the hydrochloride of (2- amino-ethyls) trimethyl ammonium chloride is separated out, revolving obtains target after drying Product.
Embodiment 2：
(1) 1mL water and 2mL tetrahydrofurans are taken in 25mL round-bottomed flasks, 1.5mmol N, N- dimethyl-ethylenediamines are added With 6mmol triethylamine aqueous solutions, it is well mixed, is placed in 2 DEG C of ice-water baths.3mmol is slowly added dropwise into mixed solution (BOC)2O solution, reacts 10min under magnetic stirring, after react 2h at room temperature.
(2) after reaction terminates, solvent in vacuo is dried, 3mL acetonitriles, 1.7mmol CD is sequentially added3I and 6mmol NaOH The aqueous solution, magnetic agitation reacts 4h at 70 DEG C.
(3) solution during second step is reacted adjusts pH=6 with hydrochloric acid, and rotation is evaporated, and 3ml chlorinations are added into reaction bulb The ethyl acetate solution (2mol/L) of hydrogen, 25 DEG C of reaction temperature, magnetic agitation carries out reaction 30min.
(4) after the completion of reacting, the hydrochloric acid for having (2- amino-ethyls) trimethyl ammonium chloride is salted out, and revolving is just obtained after drying Target product.
Embodiment 3：
(1) 1.5mL water and 1.5mL tetrahydrofurans are taken in 25mL round-bottomed flasks, 1.5mmolN, N- dimethyl second two is added Amine and the 6mmol NaOH aqueous solution, are well mixed, are placed in 3 DEG C of ice-water baths.3.5mmol is slowly added dropwise into mixed solution (BOC)2O solution, reacts 15min under magnetic stirring, after react 3h at room temperature.
(2) after reaction terminates, solvent in vacuo is dried, 3mL acetonitriles, 2mmol CH is sequentially added2DI and 6mmol NaOH The aqueous solution, magnetic agitation reacts 3h at 65 DEG C.
(3) solution during second step is reacted adjusts pH=6.5 with hydrochloric acid, and rotation is evaporated, and 3ml chlorine is added into reaction bulb Change the ethyl acetate solution (3mol/L) of hydrogen, 30 DEG C of reaction temperature, magnetic agitation carries out reaction 35min.
(4) after the completion of reacting, the hydrochloric acid for having (2- amino-ethyls) trimethyl ammonium chloride is salted out, and revolving is just obtained after drying Target product.
Embodiment 4：
(1) 1mL water and 1mL Isosorbide-5-Nitraes-dioxane are taken in 25mL round-bottomed flasks, 1.5mmolN, N- dimethyl second is added Diamines and the 7.5mmol NaOH aqueous solution, are well mixed, are placed in 4 DEG C of ice-water baths.3mmol is slowly added dropwise into mixed solution (BOC)2O solution, reacts 25min under magnetic stirring, after react 3h at room temperature.
(2) after reaction terminates, solvent in vacuo is dried, 3mL acetone, 2mmol CHD is sequentially added2I and 6mmol NaOH The aqueous solution, magnetic agitation reacts 4h at 75 DEG C.
(3) solution during second step is reacted adjusts pH=7.5 with hydrochloric acid, and rotation is evaporated, and 3mL chlorine is added into reaction bulb Change the ethyl acetate solution (4mol/L) of hydrogen, 40 DEG C of reaction temperature, magnetic agitation carries out reaction 30min.
(4) after the completion of reacting, the hydrochloric acid for having (2- amino-ethyls) trimethyl ammonium chloride is salted out, and revolving is just obtained after drying Target product.
Embodiment 5：
(1) 1mL water and 3mL tetrahydrofurans are taken in 25mL round-bottomed flasks, 1.5mmol 4- dimethylaminobutylamines are added With 7.5mmol triethylamine aqueous solutions, it is well mixed, is placed in 3 DEG C of ice-water baths.3mmol is slowly added dropwise into mixed solution (BOC)2O solution, reacts 20min under magnetic stirring, after react 3h at room temperature.
(2) after reaction terminates, solvent in vacuo is dried, 3mL DMF, 2mmol CH is sequentially added3I and 7mmol sodium carbonate The aqueous solution, magnetic agitation reacts 3h at 80 DEG C.
(3) solution during second step is reacted adjusts pH=6.5 with hydrochloric acid, and rotation is evaporated, and 3ml chlorine is added into reaction bulb Change the ethyl acetate solution (3mol/L) of hydrogen, 35 DEG C of reaction temperature, magnetic agitation carries out reaction 40min.
(4) after the completion of reacting, the hydrochloric acid for having corresponding trimethyl ammonium chloride is salted out, and revolving just obtains target production after drying Product.
Embodiment 6：
(1) 1mL water and 2mL Isosorbide-5-Nitraes-dioxane are taken in 25mL round-bottomed flasks, 1.5mmolN, N- dimethyl second is added Diamines and 10mmol triethylamine aqueous solutions, are well mixed, are placed in 1 DEG C of ice-water bath.4mmol is slowly added dropwise into mixed solution (BOC)2O solution, reacts 20min under magnetic stirring, after react 2h at room temperature.
(2) after reaction terminates, solvent in vacuo is dried, 3mL acetonitriles, 1.8mmol is sequentially added13CH3I and 6mmol The NaOH aqueous solution, magnetic agitation reacts 4h at 75 DEG C.
(3) solution during second step is reacted adjusts pH=7 with hydrochloric acid, and rotation is evaporated, and 3mL chlorinations are added into reaction bulb The ethyl acetate solution (3mol/L) of hydrogen, 30 DEG C of reaction temperature, magnetic agitation carries out reaction 30min.
(4) after the completion of reacting, the hydrochloric acid for having (2- amino-ethyls) trimethyl ammonium chloride is salted out, and revolving is just obtained after drying Target product.
Embodiment 7：
(1) 1mL water and 3mL tetrahydrofurans are taken in 25mL round-bottomed flasks, 1.5mmol N, N- dimethyl-ethylenediamines are added With the 5mmol NaOH aqueous solution, it is well mixed, is placed in 0 DEG C of ice-water bath.2.8mmol is slowly added dropwise into mixed solution (BOC)2O solution, reacts 20min under magnetic stirring, after react 2h at room temperature.
(2) after reaction terminates, solvent in vacuo is dried, 3mL acetone, 2mmol is sequentially added13CD3I and 6mmol NaOH The aqueous solution, magnetic agitation reacts 3h at 70 DEG C.
(3) solution during second step is reacted adjusts pH=7 with hydrochloric acid, and rotation is evaporated, and 3ml chlorinations are added into reaction bulb The ethyl acetate solution (3mol/L) of hydrogen, 25 DEG C of reaction temperature, magnetic agitation carries out reaction 50min.
(4) after the completion of reacting, the hydrochloric acid for having (2- amino-ethyls) trimethyl ammonium chloride is salted out, and revolving is just obtained after drying Target product.
Embodiment 8：
(1) 1mL water and 2mL tetrahydrofurans are added in 25mL round-bottomed flasks, add 1.5mmol6- (dimethylamino) oneself Amine and the 8mmol NaOH aqueous solution, it is well mixed to be placed in 0 DEG C of ice-water bath.2.5mmol is slowly added dropwise in mixed solution (BOC)2Reacted under O solution, magnetic agitation after 15min, then react at room temperature 2h.
(2) after reaction terminates, solvent in vacuo is dried, 3mL DMF, 2mmol CD is sequentially added3I and 7mmol NaOH water Solution, magnetic agitation reacts 4h at 70 DEG C.
(3) solution during second step is reacted adjusts pH=6 with hydrochloric acid, and rotation is evaporated, and 3ml chlorinations are added into reaction bulb The ethyl acetate solution (4mol/L) of hydrogen, 30 DEG C of reaction temperature, magnetic agitation carries out reaction 40min.
(4) after the completion of reacting, the hydrochloric acid for having corresponding trimethyl ammonium chloride is salted out, and revolving just obtains target production after drying Product.
Embodiment 9：
(1) 1mL water and 2mL Isosorbide-5-Nitraes-dioxane are added in 25mL round-bottomed flasks, adds 1.5mmol7- (diformazan ammonia Base) heptyl amice and the 7mmol NaOH aqueous solution, it is well mixed to be placed in 0 DEG C of ice-water bath.It is slowly added dropwise in mixed solution Reacted under 2.5mmol (BOC) 2O solution, magnetic agitation after 20min, then react at room temperature 4h.
(2) after reaction terminates, solvent in vacuo is dried, 3mL acetonitriles, 2mmol CH3I and 7mmol NaOH water is sequentially added Solution, magnetic agitation reacts 4h at 75 DEG C.
(3) solution during second step is reacted adjusts pH=7 with hydrochloric acid, and rotation is evaporated, and 3mL chlorinations are added into reaction bulb The ethyl acetate solution (4mol/L) of hydrogen, 30 DEG C of reaction temperature, magnetic agitation carries out reaction 50min.
(4) after the completion of reacting, the hydrochloric acid for having corresponding trimethyl ammonium chloride is salted out, and revolving just obtains target production after drying Product.

Claims (9)

1. one group is used for the isotope labeling reagent that carboxyl is marked, it is characterised in that described isotope labeling reagent one end is Primary amine, the other end is leptodactyline, is connected between primary amine and leptodactyline by carbochain, and carbon atom number is 2- in carbochain 7, the structural formula of isotope labeling reagent is as follows：
Wherein R is CH3、CH2D、CHD2、CD3、13CH3、13CH2D、13CHD2、13CD3；n =1-6.
2. the synthetic method of the isotope labeling reagent described in claim 1, it is characterised in that following steps：
The first step：With N, N- dimethyl-ethylenediamines and its homologue (n=1-6) are reaction raw materials, using di-tert-butyl dicarbonate ((BOC)2O) primary amino radical is protected, reaction equation is as follows：
Concretely comprise the following steps：
1.1) it is 1 by mol ratio:1-1:After 3 water and organic solvent mixing, reaction raw materials and alkali are sequentially added, are stirred at room temperature Uniformly obtain mixed solution；Concentration of the described reaction raw materials in water is 0.5-5mmol/mL；Concentration of the alkali in water is 0.75-25mmol/mL；
1.2) under the conditions of 0-5 DEG C, by di-tert-butyl dicarbonate (BOC)2Step 1.1 is added dropwise in O) in obtained mixed solution, Ice-water bath reacts 10-30min, then normal-temperature reaction 2-4h obtains reaction solution；Described reaction raw materials and (BOC)2O mol ratio For 1:1.5-3；
Second step：The iodomethane of iodomethane or isotope substitution is introduced in reaction system, quaternary ammonium product is obtained；
Regulating step 1.2) obtained reaction solution pH to neutral left and right, after rotation solvent evaporated, sequentially adds solvent, alkali and iodine Methane or the iodomethane reagent of isotope substitution, under the conditions of 60-80 DEG C, reaction solution is obtained after heating reflux reaction 2-4h； Described reaction raw materials, the iodomethane of iodomethane or isotope substitution, the mol ratio of alkali are 1:1.1-2:1.5-10；The same position The iodomethane of element substitution is CH2DI、CHD2I、CD3I、13CH3I、13CH2DI、13CHD2I、13CD3I；
3rd step：Blocking group, which is sloughed, in acid condition obtains corresponding leptodactyline
After the pH to 6-8 of the reaction solution obtained with acid regulation second step, solvent evaporated, the ethyl acetate for adding hydrogen chloride is molten Liquid, under the conditions of 20-40 DEG C, magnetic agitation reaction 20-60min separates out the hydrochloride of trimethyl ammonium, revolving obtains mesh after drying Mark product.
3. synthetic method according to claim 2, it is characterised in that step 1.1) described in alkali be sodium hydroxide, carbon Sour sodium, sodium acid carbonate or triethylamine；Step 1.1) described in organic solvent be tetrahydrofuran, Isosorbide-5-Nitrae-dioxane, dichloromethane One kind in alkane.
4. the synthetic method according to Claims 2 or 3, it is characterised in that in the ethyl acetate solution of described hydrogen chloride The concentration of hydrogen chloride is 1-4mol/L.
5. the synthetic method according to Claims 2 or 3, it is characterised in that the alkali described in second step is sodium hydroxide, carbon One kind in sour sodium, potassium carbonate；Alkali described in second step is one kind in sodium hydroxide, sodium carbonate, potassium carbonate.
6. synthetic method according to claim 4, it is characterised in that the alkali described in second step is sodium hydroxide, carbonic acid One kind in sodium, potassium carbonate；Alkali described in second step is one kind in sodium hydroxide, sodium carbonate, potassium carbonate.
7. the synthetic method according to Claims 2 or 3 or 6, it is characterised in that second step reaction solution is adjusted in the 3rd step PH acid is hydrochloric acid.
8. synthetic method according to claim 4, it is characterised in that second step reaction solution pH acid is adjusted in the 3rd step For hydrochloric acid.
9. synthetic method according to claim 5, it is characterised in that second step reaction solution pH acid is adjusted in the 3rd step For hydrochloric acid.
CN201710191430.XA 2017-03-29 2017-03-29 One group is used for isotope labeling reagent and its synthetic method that carboxyl is marked Withdrawn CN107011185A (en)

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2018176253A1 (en) * 2017-03-29 2018-10-04 大连理工大学 Group of isotope labelling reagents for carboxyl labelling and synthesis method therefor
WO2020102737A1 (en) * 2018-11-15 2020-05-22 Saint Louis University Isotope labeling for universal multiplexing of metabolites
CN112961060A (en) * 2021-02-09 2021-06-15 武汉大学 Isotope labeled N, N-dimethylethylenediamine, preparation method thereof and analysis method of short-chain fatty acid

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20100330680A1 (en) * 2009-04-15 2010-12-30 Frey Brian L Labeling peptides with tertiary amines and other basic functional groups for improved mass spectrometric analysis

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20100330680A1 (en) * 2009-04-15 2010-12-30 Frey Brian L Labeling peptides with tertiary amines and other basic functional groups for improved mass spectrometric analysis

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
RICHARD G. TORDE，ET AL.: ""Multiplexed Analysis of Cage and Cage Free Chicken Egg Fatty Acids Using Stable Isotope Labeling and Mass Spectrometry"", 《MOLECULES》 *

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2018176253A1 (en) * 2017-03-29 2018-10-04 大连理工大学 Group of isotope labelling reagents for carboxyl labelling and synthesis method therefor
WO2020102737A1 (en) * 2018-11-15 2020-05-22 Saint Louis University Isotope labeling for universal multiplexing of metabolites
CN112961060A (en) * 2021-02-09 2021-06-15 武汉大学 Isotope labeled N, N-dimethylethylenediamine, preparation method thereof and analysis method of short-chain fatty acid

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