CN104945277A - Stable isotope labeling alkaline bright yellow O and synthetic method thereof - Google Patents
Stable isotope labeling alkaline bright yellow O and synthetic method thereof Download PDFInfo
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Abstract
The invention relates to stable isotope labeling alkaline bright yellow O and a synthetic method thereof. When the stable isotope labeling alkaline bright yellow O is D or 15N or 13 C labeling alkaline bright yellow O, during preparing, stable isotope D or 15N or 13 C labeling methyl alcohol and aniline serve as raw materials, N and N-methyl toluidine precursor labeled by the stable isotope D or 15N or 13 C are obtained, condensation, sulfuration and ammonification are conducted, and the stable isotope D or 15N or 13 C labeling alkaline bright yellow O is obtained. Compared with the prior art, the process route is simple, compounding is easy, a product is easy to separate and purify, the chemical purity of the product is more than 99.0%, the isotope abundance is more than 98.0% atom, trace detection requirements in the food safety field can be met completely, the economical efficiency and the use value are good, and a good popularizing prospect is achieved.
Description
Technical field
The invention belongs to isotope labelling techniques field, relate to a kind of cold labeling basic flavine O and synthetic method thereof.
Background technology
Basic flavine O, yellow homogeneous powder.Be dissolved in cold water, being soluble in hot water is glassy yellow, boils and namely decomposes, be dissolved in ethanol in yellow, its dye powder in colourless, turns light yellow in the vitriol oil after dilution, in orange in concentrated nitric acid, in sodium hydroxide solution, become white precipitate, for country forbids foodstuff additive.The chemical structure of basic flavine O determines that it has carinogenicity, has obvious toxicity to human body.At present, developed country and China all forbid that basic flavine O is for food processing field.But the illegal businessman of part, is added in the edible product such as dried bean curd, and this can have a strong impact on the healthy of human consumer, great social repercussion even can be caused.Enter field of food for preventing basic flavine O to work the mischief, health relevant departments need a kind of can rapidly, accurately and the technology of less error detects it, this has extremely important realistic meaning to the healthy of the people.
Stable isotope dilution mass spectrometry IDMS (Isotope Dilution Mass Spectrometry) adopts to have the compound of the cold labeling of same molecular structure as internal standard substance matter with measured matter, detect by high resolution liquid chromatography-GC-MS (LC/MS), the ratio of the ion of respective quality number is measured by mass spectrograph, and with the odds ratio of standard comparatively, and then reach the object of accurate quantitative analysis.Adopt Isotopic Internal Standard effectively can eliminate sample rate of recovery difference caused in the pre-treatment step of chemistry and physics, thus avoid the deviation that the loss because of sample handling processes causes detected result.
This characteristic of stable isotope dilution mass spectrometry combines with the highly sensitive of LC/MS and the ability processing complex sample, makes chromatogram/isotope dilution mass spectrometry technology be acknowledged as a kind of pedestal method measuring trace and trace organic substance.And target is succeeded in developing in cold labeling basic flavine O, standard reagent will be provided for more accurate quantitative analysis basic flavine O, improve China's food safety detection technical system, meet the demand of China's food safety development.At present, there is not yet the bibliographical information of the synthetic method of cold labeling basic flavine O both at home and abroad.
Summary of the invention
Object of the present invention is exactly provide a kind of operational path simple to overcome defect that above-mentioned prior art exists, is easy to the synthetic method of the cold labeling basic flavine O prepared.
Object of the present invention can be achieved through the following technical solutions:
A kind of cold labeling basic flavine O, described cold labeling basic flavine O be D or
15n or
13the basic flavine O of C mark, wherein,
The molecular structural formula of the basic flavine O of D mark is:
or
15the molecular structural formula of the basic flavine O of N mark is:
13the molecular structural formula of the basic flavine O of C mark is:
or
wherein, * represents that this place's carbon atom is
13c atom.
A synthetic method for cold labeling basic flavine O, the method be with stable isotope D or
15n or
13it is raw material that C marks methyl alcohol, aniline, synthesis obtain stable isotope D or
15n or
13the DMA precursor of C mark, then through condensation, sulfuration, ammonification, make stable isotope D or
15n or
13c marks basic flavine O.
In the present invention, the DMA of cold labeling is DMA-D
6, DMA-D
4, DMA-
13c
6, DMA-
15n, DMA-
13c
2, synthetic method reference literature carries out (Yang Weicheng etc. the deuterium-labeled D of stable isotope
6the synthesis and characterization [J] of-Viola crystallina. applied chemistry, 2013,31 (03): 262-267.).
A synthetic method for cold labeling basic flavine O, the method specifically comprises the following steps:
(1) condensation step: with stable isotope D or
15n or
13the DMA of C mark is raw material, and after condensing agent, catalyst mix, controls temperature of reaction is 30-150 DEG C, and to control reaction pressure be 0-5MPa, reacts 1-10h, preferred 1-6h, synthesizing stable isotope D or
15n or
13the methane bass of C mark;
(2) vulcanisation step: the stable isotope D that step (1) is synthesized or
15n or
13the methane bass of C mark, mix with vulcanizing agent in liquid phase environment, control temperature of reaction is 30-200 DEG C, and to control reaction pressure be 0-5MPa, reacts 1-24h, preferred 1-20h, synthesizing stable isotope D or
15n or
13the intermediate of C mark;
(3) ammonification becomes salinization step: the stable isotope D that step (2) is synthesized or
15n or
13the intermediate of C mark, mix with ammoniation agent in liquid phase environment, control temperature of reaction is 30-200 DEG C, and to control reaction pressure be 0-5MPa, reacts 1-24h, preferred 1-20h, namely synthesizes described cold labeling basic flavine O.
Condensing agent described in step (1) is one or both in trioxymethylene, paraformaldehyde or urea, preferred trioxymethylene and urea, described catalyzer is the one in hydrochloric acid, sodium hydroxide, acetic acid or sodium carbonate, preferred sodium hydroxide, sodium carbonate or acetic acid.
Stable isotope D described in step (1) or
15n or
13dMA and the mol ratio of condensing agent of C mark are (2-6): 1, and described stable isotope D or
15n or
13the DMA of C mark and the mol ratio of catalyzer are 1:(0.1-0.3).
Vulcanizing agent described in step (2) is sulphur powder, and described stable isotope D or
15n or
13the methane bass of C mark and the mol ratio of sulphur powder are 1:(1-6).
Described stable isotope D or
15n or
13the methane bass of C mark and the mol ratio of sulphur powder are 1:(2-4).
Ammoniation agent described in step (3) is ammonium chloride, and described stable isotope D or
15n or
13the intermediate of C mark and the mol ratio of ammonium chloride are 1:(1-6).
Described stable isotope D or
15n or
13the intermediate of C mark and the mol ratio of ammonium chloride are 1:(1-3).
Described liquid phase is one or more in methyl alcohol, ethanol, ether, acetonitrile, diacetyl oxide, ethylene glycol or chloroform.
Stable isotope D of the present invention
12or
15n or
13c marks the overall synthetic method of basic flavine O compound and can summarize and be:
Wherein, * represents that this place's carbon atom is
13c atom.
Concrete, in the present invention, cold labeling basic flavine O-D
12the synthetic route of compound is: cold labeling methyl alcohol is raw material, after methylating, obtain the deuterium-labeled DMA of stable isotope, obtain cold labeling basic flavine O compound through condensation, sulfuration, ammonification salify again, concrete technology route is:
In the present invention, isotopic labeling basic flavine O-D is determined
8the synthetic route of compound is: stable isotope deuterium methyl mark aniline is raw material, the deuterium-labeled N of stable isotope is obtained after methylating, accelerine, then obtain cold labeling basic flavine O compound through condensation, sulfuration, ammonification salify, concrete technology route is:
In the present invention, cold labeling basic flavine O-
13c
12the synthetic route of compound is: stable isotope
13c phenyl ring mark aniline is raw material, after methylating, obtain stable isotope
13c marks DMA, then obtains cold labeling basic flavine O compound through condensation, sulfuration, ammonification salify, and concrete technology route is:
Wherein, * represents that this place's carbon atom is
13c.
In the present invention, cold labeling basic flavine O-
13c
4the synthetic route of compound is: stable isotope
13c methyl mark aniline is raw material, after methylating, obtain stable isotope
13c marks DMA, then obtains cold labeling basic flavine O through condensation, sulfuration, ammonification salify, and concrete technology route is:
Wherein, * represents that this place's carbon atom is
13c.
In the present invention, cold labeling basic flavine O-
15n
2the synthetic route of compound is: stable isotope
15n amino labeled aniline is raw material, after methylating, obtain stable isotope
15n marks DMA, then obtains cold labeling basic flavine O compound through condensation, sulfuration, ammonification salify, and concrete technology route is:
Compared with prior art, the present invention has following characteristics:
(1) the present invention makes public for the first time a kind of synthetic method of cold labeling basic flavine O;
(2) the present invention adopts operational path simple, is easy to synthesis;
(3) the easily separated purification of product of the present invention, product chemical purity is more than 99.0%, and isotopic abundance, at more than 98.0%atom, fully can meet the demand of field of food safety trace detection;
(4) economy of the present invention and use value well, have good promotion prospect.
Embodiment
Below in conjunction with specific embodiment, the present invention is described in detail.
Embodiment 1
A, cold labeling methane bass-D
12synthesis
In flask, by DMA-D
6be 2:1 with the mol ratio of trioxymethylene (mass concentration 37%), and with DMA-D
6be 1:1:0.1 with the mol ratio of urea, acetic acid, add urea, acetic acid successively, then add the distilled water of reaction volume 20%, stir, be heated to 60 DEG C, reaction 2h.After reaction terminates, washing, leaves standstill suction filtration, filter cake, and washing is dry.Thick yield is 98.5%, recrystallization, and yield 94.0%, HPLC detects purity 99.4%, abundance 99.2%atom.
B, cold labeling basic flavine O-D
12synthesis
In flask, add the methane bass-D of cold labeling
12, then press methane bass-D
12be 1:2 with the mol ratio of sulphur powder, add sulphur powder, reaction vacuum seal, pass into ammonia, temperature of reaction controls at 120 DEG C, after reaction 4h, adds ammonium chloride, then continues reaction 16h, stopped reaction.Standing and reacting thing, question response thing cools, crystallization, suction filtration, i.e. obtained cold labeling basic flavine O-D
12.Yield is 85.5%, recrystallization, yield 80.0%.HPLC detects purity 99.2%, abundance 99.0atom%.
Embodiment 2
A, cold labeling methane bass-D
12synthesis
In flask, by DMA-D
6be 3:1 with the mol ratio of trioxymethylene (mass concentration 37%), and with DMA-D
6be 1:1.5:0.15 with the mol ratio of urea, sodium carbonate, add urea, sodium carbonate successively, then add the distilled water of reaction volume 20%, stir, be heated to 100 DEG C, reaction 3h.After reaction terminates, washing, leaves standstill suction filtration, filter cake, and washing is dry.Thick yield is 95.5%, recrystallization, and yield 91.0%, HPLC detects purity 99.3%, abundance 98.9%atom.
B, cold labeling basic flavine O-D
12synthesis
Methane bass-the D of cold labeling is added in flask
12, then press methane bass-D
12be 1:2.5 with the mol ratio of sulphur powder, add sulphur powder, reaction vacuum seal, pass into ammonia, temperature of reaction controls at 160 DEG C, after reaction 5h, adds ammonium chloride, then continues reaction 14h, stopped reaction.Standing and reacting thing, question response thing cools, crystallization, suction filtration, i.e. obtained cold labeling basic flavine O-D
12.Yield is 86.5%, recrystallization, yield 81.4%.HPLC detects purity 99.1%, abundance 98.3%atom.
Embodiment 3
A, cold labeling methane bass-D
12synthesis
In flask, by DMA-D
6be 4:1 with the mol ratio of trioxymethylene (mass concentration 37%), and with DMA-D
6be 1:2:0.15 with the mol ratio of urea, acetic acid, add urea, acetic acid successively, then add the distilled water of reaction volume 20%, stir, be heated to 140 DEG C, reaction 5h.After reaction terminates, washing, leaves standstill suction filtration, filter cake, and washing is dry.Thick yield is 92.5%, recrystallization, and yield 89.0%, HPLC detects purity 99.6%, abundance 99.2%atom.
B, cold labeling basic flavine O-D
12synthesis
Methane bass-the D of cold labeling is added in flask
12, then press methane bass-D
12be 1:3 with the mol ratio of sulphur powder, add sulphur powder, reaction vacuum seal, pass into ammonia, temperature of reaction controls at 180 DEG C, after reaction 7h, adds ammonium chloride, then continues reaction 15h, stopped reaction.Standing and reacting thing, question response thing cools, crystallization, suction filtration, i.e. obtained cold labeling basic flavine O-D
12.Yield is 88.5%, recrystallization, yield 82.4%.HPLC detects purity 99.0%, abundance 99.0%atom.
Embodiment 4
A, cold labeling methane bass-D
8synthesis
In flask, by DMA-D
4be 3:1 with the mol ratio of trioxymethylene (mass concentration 37%), and with DMA-D
4be 1:2.5:0.15 with the mol ratio of urea, sodium hydroxide, add urea, sodium hydroxide successively, then add the distilled water of reaction volume 20%, stir, be heated to 90 DEG C, reaction 4h.After reaction terminates, washing, leaves standstill suction filtration, filter cake, and washing is dry.Thick yield is 97.5%, recrystallization, and yield 93.0%, HPLC detects purity 99.1%, abundance 99.0%atom.
B, cold labeling basic flavine O-D
8synthesis
Methane bass-the D of cold labeling is added in flask
8, then press methane bass-D
8be 1:3.5 with the mol ratio of sulphur powder, add sulphur powder, reaction vacuum seal, pass into ammonia, temperature of reaction controls at 100 DEG C, after reaction 8h, adds ammonium chloride, then continues reaction 16h, stopped reaction.Standing and reacting thing, question response thing cools, crystallization, suction filtration, i.e. obtained cold labeling basic flavine O-D
8.Yield is 82.5%, recrystallization, yield 76.2%.HPLC detects purity 99.0%, abundance 98.8%atom.
Embodiment 5
A, cold labeling methane bass-D
8synthesis
In flask, by DMA-D
4be 4:1 with the mol ratio of trioxymethylene (mass concentration 37%), and with DMA-D
4be 1:1.5:0.2 with the mol ratio of urea, acetic acid, add urea, acetic acid successively, then add the distilled water of reaction volume 20%, stir, be heated to 125 DEG C, reaction 6h.After reaction terminates, washing, leaves standstill suction filtration, filter cake, and washing is dry.Thick yield is 96.0%, recrystallization, and yield 91.8%, HPLC detects purity 99.5%, abundance 99.0%atom.
B, cold labeling basic flavine O-D
8synthesis
Methane bass-the D of cold labeling is added in flask
8, then press methane bass-D
8be 1:2.5 with the mol ratio of sulphur powder, add sulphur powder, reaction vacuum seal, pass into ammonia, temperature of reaction controls at 120 DEG C, after reaction 4h, adds ammonium chloride, then continues reaction 16h, stopped reaction.Standing and reacting thing, question response thing cools, crystallization, suction filtration, i.e. obtained cold labeling basic flavine O-D
8.Yield is 86.5%, recrystallization, yield 82.0%.HPLC detects purity 99.3%, abundance 98.8%atom.
Embodiment 6
A, cold labeling methane bass-D
8synthesis
In flask, by DMA-D
4be 2:1 with the mol ratio of trioxymethylene (mass concentration 37%), and with DMA-D
4be 1:3.5:0.2 with the mol ratio of urea, sodium carbonate, add urea, sodium carbonate successively, then add the distilled water of reaction volume 20%, stir, be heated to 120 DEG C, reaction 7h.After reaction terminates, washing, leaves standstill suction filtration, filter cake, and washing is dry.Thick yield is 96.0%, recrystallization, and yield 91.8%, HPLC detects purity 99.7%, abundance 99.0%atom.
B, cold labeling basic flavine O-D
8synthesis
Methane bass-the D of cold labeling is added in flask
8, then press methane bass-D
8be 1:1.5 with the mol ratio of sulphur powder, add sulphur powder, reaction vacuum seal, pass into ammonia, temperature of reaction controls at 145 DEG C, after reaction 4h, adds ammonium chloride, then continues reaction 16h, stopped reaction.Standing and reacting thing, question response thing cools, crystallization, suction filtration, i.e. obtained cold labeling basic flavine O-D
8.Yield is 86.5%, recrystallization, yield 82.0%.HPLC detects purity 99.3%, abundance 98.8%atom.
Embodiment 7
A, cold labeling methane bass-
13c
12synthesis
In flask, by DMA-
13c
6be 2.5:1 with the mol ratio of trioxymethylene (mass concentration 37%), and with DMA-
13c
6be 1:3:0.2 with the mol ratio of urea, acetic acid, add urea, acetic acid successively, then add the distilled water of reaction volume 20%, stir, be heated to 60 DEG C, reaction 6h.After reaction terminates, washing, leaves standstill suction filtration, filter cake, and washing is dry.Thick yield is 97.5%, recrystallization, and yield 92.0%, HPLC detects purity 99.8%, abundance 99.0%atom.
B, cold labeling basic flavine O-
13c
12synthesis
Add in flask the methane bass of cold labeling-
13c
12, then press methane bass-
13c
12be 1:3 with the mol ratio of sulphur powder, add sulphur powder, reaction vacuum seal, pass into ammonia, temperature of reaction controls at 120 DEG C, after reaction 4h, adds ammonium chloride, then continues reaction 16h, stopped reaction.Standing and reacting thing, question response thing cools, crystallization, suction filtration, i.e. obtained cold labeling basic flavine O-
13c
12.Yield is 88.5%, recrystallization, yield 85.8%.HPLC detects purity 99.5%, abundance 98.7%atom.
Embodiment 8
A, cold labeling methane bass-
13c
12synthesis
In flask, by DMA-
13c
6be 3.5:1 with the mol ratio of trioxymethylene (mass concentration 37%), and with DMA-
13c
6be 1:2.5:0.25 with the mol ratio of urea, sodium hydroxide, add urea, sodium hydroxide successively, then add the distilled water of reaction volume 20%, stir, be heated to 110 DEG C, reaction 2h.After reaction terminates, washing, leaves standstill suction filtration, filter cake, and washing is dry.Thick yield is 96.4%, recrystallization, and yield 92.2%, HPLC detects purity 99.6%, abundance 99.2%atom.
B, cold labeling basic flavine O-
13c
12synthesis
Add in flask the methane bass of cold labeling-
13c
12, then press methane bass-
13c
12be 1:3.5 with the mol ratio of sulphur powder, add sulphur powder, reaction vacuum seal, pass into ammonia, temperature of reaction controls at 120 DEG C, after reaction 4h, adds ammonium chloride, then continues reaction 16h, stopped reaction.Standing and reacting thing, question response thing cools, crystallization, suction filtration, i.e. obtained cold labeling basic flavine O-
13c
12.Yield is 87.5%, recrystallization, yield 84.8%.HPLC detects purity 99.5%, abundance 98.9%atom.
Embodiment 9
A, cold labeling methane bass-
13c
12synthesis
In flask, by DMA-
13c
6be 1:1 with the mol ratio of trioxymethylene (mass concentration 37%), and with DMA-
13c
6be 1:4:0.3 with the mol ratio of urea, acetic acid, add urea, acetic acid successively, then add the distilled water of reaction volume 20%, stir, be heated to 130 DEG C, reaction 5h.After reaction terminates, washing, leaves standstill suction filtration, filter cake, and washing is dry.Thick yield is 95.8%, recrystallization, and yield 91.2%, HPLC detects purity 99.6%, abundance 98.7%atom.
B, cold labeling basic flavine O-
13c
12synthesis
Add in flask the methane bass of cold labeling-
13c
12, then press methane bass-
13c
12be 1:3.5 with the mol ratio of sulphur powder, add sulphur powder, reaction vacuum seal, pass into ammonia, temperature of reaction controls at 150 DEG C, after reaction 3h, adds ammonium chloride, then continues reaction 18h, stopped reaction.Standing and reacting thing, question response thing cools, crystallization, suction filtration, i.e. obtained cold labeling basic flavine O-
13c
12.Yield is 88.5%, recrystallization, yield 84.8%.HPLC detects purity 99.4%, abundance 98.0%atom.
Embodiment 10
A, cold labeling methane bass-
13c
4synthesis
In flask, by DMA-
13c
2be 4:1 with the mol ratio of trioxymethylene (mass concentration 37%), and with DMA-
13c
2be 1:3.5:0.25 with the mol ratio of urea, sodium carbonate, add urea, sodium carbonate successively, then add the distilled water of reaction volume 20%, stir, be heated to 70 DEG C, reaction 3.5h.After reaction terminates, washing, leaves standstill suction filtration, filter cake, and washing is dry.Thick yield is 97.3%, recrystallization, and yield 93.0%, HPLC detects purity 99.5%, abundance 99.3%atom.
B, cold labeling basic flavine O-
13c
4synthesis
Add in flask the methane bass of cold labeling-
13c
4, then press methane bass-
13c
4be 1:2.5 with the mol ratio of sulphur powder, add sulphur powder, reaction vacuum seal, pass into ammonia, temperature of reaction controls at 120 DEG C, after reaction 4h, adds ammonium chloride, then continues reaction 16h, stopped reaction.Standing and reacting thing, question response thing cools, crystallization, suction filtration, i.e. obtained cold labeling basic flavine O-
13c
4.Yield is 86.5%, recrystallization, yield 83.0%.HPLC detects purity 99.4%, abundance 99.1%atom.
Embodiment 11
A, cold labeling methane bass-
13c
4synthesis
In flask, by DMA-
13c
2be 2.5:1 with the mol ratio of trioxymethylene (mass concentration 37%), and with DMA-
13c
2be 1:5.5:0.2 with the mol ratio of urea, acetic acid, add urea, acetic acid successively, then add the distilled water of reaction volume 20%, stir, be heated to 60 DEG C, reaction 4h.After reaction terminates, washing, leaves standstill suction filtration, filter cake, and washing is dry.Thick yield is 97.3%, recrystallization, and yield 93.0%, HPLC detects purity 99.5%, abundance 98.5%atom.
B, cold labeling basic flavine O-
13c
4synthesis
Add in flask the methane bass of cold labeling-
13c
4, then press methane bass-
13c
4be 1:2 with the mol ratio of sulphur powder, add sulphur powder, reaction vacuum seal, pass into ammonia, temperature of reaction controls at 130 DEG C, after reaction 6h, adds ammonium chloride, then continues reaction 18h, stopped reaction.Standing and reacting thing, question response thing cools, crystallization, suction filtration, i.e. obtained cold labeling basic flavine O-
13c
4.Yield is 84.5%, recrystallization, yield 81.0%.HPLC detects purity 99.4%, abundance 98.1%atom.
Embodiment 12
A, cold labeling methane bass-
13c
4synthesis
In flask, by DMA-
13c
2be 3.5:1 with the mol ratio of trioxymethylene (mass concentration 37%), and with DMA-
13c
2be 1:4.5:0.2 with the mol ratio of urea, sodium hydroxide, add urea, sodium hydroxide successively, then add the distilled water of reaction volume 20%, stir, be heated to 145 DEG C, reaction 4h.After reaction terminates, washing, leaves standstill suction filtration, filter cake, and washing is dry.Thick yield is 96.3%, recrystallization, and yield 92.0%, HPLC detects purity 99.3%, abundance 98.8%atom.
B, cold labeling basic flavine O-
13c
4synthesis
Add in flask the methane bass of cold labeling-
13c
4, then press methane bass-
13c
4be 1:2.5 with the mol ratio of sulphur powder, add sulphur powder, reaction vacuum seal, pass into ammonia, temperature of reaction controls at 130 DEG C, after reaction 6h, adds ammonium chloride, then continues reaction 18h, stopped reaction.Standing and reacting thing, question response thing cools, crystallization, suction filtration, i.e. obtained cold labeling basic flavine O-
13c
4.Yield is 87.5%, recrystallization, yield 84.0%.HPLC detects purity 99.2%, abundance 98.3%atom.
Embodiment 13
A, cold labeling methane bass-
15n
2synthesis
In flask, by DMA-
15the mol ratio of N and trioxymethylene (mass concentration 37%) is 4:1, and with DMA-
15the mol ratio of N and urea, acetic acid is 1:6:0.25, adds urea, acetic acid successively, then adds the distilled water of reaction volume 20%, stirs, is heated to 80 DEG C, reaction 5h.After reaction terminates, washing, leaves standstill suction filtration, filter cake, and washing is dry.Thick yield is 95.3%, recrystallization, and yield 93.3%, HPLC detects purity 99.5%, abundance 99.4%atom.
B, cold labeling basic flavine O-
15n
2synthesis
Add in flask the methane bass of cold labeling-
15n
2, then press methane bass-
15n
2be 1:4 with the mol ratio of sulphur powder, add sulphur powder, reaction vacuum seal, pass into ammonia, temperature of reaction controls at 100 DEG C, after reaction 4h, adds ammonium chloride, then continues reaction 16h, stopped reaction.Standing and reacting thing, question response thing cools, crystallization, suction filtration, i.e. obtained cold labeling basic flavine O-
15n
2.Yield is 85.5%, recrystallization, yield 83.3%.HPLC detects purity 99.3%, abundance 99.2%atom.
Embodiment 14
A, cold labeling methane bass-
15n
2synthesis
In flask, by DMA-
15the mol ratio of N and trioxymethylene (mass concentration 37%) is 3:1, and with DMA-
15the mol ratio of N and urea, acetic acid is 1:5.5:0.3, adds urea, acetic acid successively, then adds the distilled water of reaction volume 20%, stirs, is heated to 80 DEG C, reaction 6h.After reaction terminates, washing, leaves standstill suction filtration, filter cake, and washing is dry.Thick yield is 92.3%, recrystallization, and yield 90.3%, HPLC detects purity 99.7%, abundance 99.3%atom.
B, cold labeling basic flavine O-
15n
2synthesis
Add in flask the methane bass of cold labeling-
15n
2, then press methane bass-
15n
2be 1:2 with the mol ratio of sulphur powder, add sulphur powder, reaction vacuum seal, pass into ammonia, temperature of reaction controls at 120 DEG C, after reaction 8h, adds ammonium chloride, then continues reaction 18h, stopped reaction.Standing and reacting thing, question response thing cools, crystallization, suction filtration, i.e. obtained cold labeling basic flavine O-
15n
2.Yield is 88.5%, recrystallization, yield 85.3%.HPLC detects purity 99.2%, abundance 99.0%atom.
Embodiment 15
A, cold labeling methane bass-
15n
2synthesis
In flask, by DMA-
15the mol ratio of N and trioxymethylene (mass concentration 37%) is 2.5:1, and with DMA-
15the mol ratio of N and urea, sodium carbonate is 1:4.5:0.3, adds urea, sodium carbonate successively, then adds the distilled water of reaction volume 20%, stirs, is heated to 80 DEG C, reaction 4.5h.After reaction terminates, washing, leaves standstill suction filtration, filter cake, and washing is dry.Thick yield is 94.3%, recrystallization, and yield 92.3%, HPLC detects purity 99.4%, abundance 99.2%atom.
B, cold labeling basic flavine O-
15n
2synthesis
Add in flask the methane bass of cold labeling-
15n
2, then press methane bass-
15n
2be 1:4 with the mol ratio of sulphur powder, add sulphur powder, reaction vacuum seal, pass into ammonia, temperature of reaction controls at 120 DEG C, after reaction 6h, adds ammonium chloride, then continues reaction 17h, stopped reaction.Standing and reacting thing, question response thing cools, crystallization, suction filtration, i.e. obtained cold labeling basic flavine O-
15n
2.Yield is 83.5%, recrystallization, yield 81.3%.HPLC detects purity 99.0%, abundance 98.7%atom.
Embodiment 16
The present embodiment cold labeling basic flavine O-D
8, molecular structural formula is
Concrete preparation method is as follows:
(1) condensation step: with stable isotope D
4the DMA of mark is raw material, and after condensing agent, catalyst mix, controlling temperature of reaction is 150 DEG C, and to control reaction pressure be 5MPa, reaction 1h, synthesizing stable isotope D
4methane bass-the D of mark
8;
(2) vulcanisation step: the stable isotope D that step (1) is synthesized
4methane bass-the D of mark
8, mix with vulcanizing agent in liquid phase environment, controlling temperature of reaction is 200 DEG C, and to control reaction pressure be 5MPa, reaction 1h, synthesizing stable isotope D
8the intermediate of mark;
(3) ammonification becomes salinization step: stable isotope D step (2) synthesized
4intermediate-the D of mark
8, mix with ammoniation agent in liquid phase environment, controlling temperature of reaction is 200 DEG C, and to control reaction pressure be 5MPa, reaction 1h, i.e. synthesizing stable isotopic labeling basic flavine O-D
8.
Wherein, the condensing agent in step (1) is trioxymethylene, and catalyzer is hydrochloric acid, and stable isotope D
4dMA and the mol ratio of trioxymethylene of mark are 6:1, and the mol ratio of itself and hydrochloric acid is 1:0.3.
Vulcanizing agent in step (2) is sulphur powder, and stable isotope D
4methane bass-the D of mark
8be 1:6 with the mol ratio of sulphur powder.
Ammoniation agent in step (3) is ammonium chloride, and stable isotope D
4intermediate-the D of mark
8be 1:6 with the mol ratio of ammonium chloride.
In the present embodiment, liquid phase is ether, ethylene glycol and chloroform is the blended liquid phase of 1:1:1 in mass ratio.
Embodiment 17
The present embodiment cold labeling basic flavine O-D
12, molecular structural formula is
Concrete preparation method is as follows:
(1) condensation step: with stable isotope D
6the DMA of mark is raw material, and after condensing agent, catalyst mix, controlling temperature of reaction is 30 DEG C, and to control reaction pressure be 0MPa, reaction 10h, synthesizing stable isotope D
6methane bass-the D of mark
12;
(2) vulcanisation step: the stable isotope D that step (1) is synthesized
6methane bass-the D of mark
12, mix with vulcanizing agent in liquid phase environment, controlling temperature of reaction is 30 DEG C, and to control reaction pressure be 0MPa, reaction 24h, synthesizing stable isotope D
12the intermediate of mark;
(3) ammonification becomes salinization step: stable isotope D step (2) synthesized
6intermediate-the D of mark
12, mix with ammoniation agent in liquid phase environment, controlling temperature of reaction is 30 DEG C, and to control reaction pressure be 0MPa, reaction 24h, i.e. synthesizing stable isotopic labeling basic flavine O-D
12.
Wherein, the condensing agent in step (1) is urea, and catalyzer is sodium carbonate, and stable isotope D
6dMA and the mol ratio of urea of mark are 2:1, and the mol ratio of itself and sodium carbonate is 1:0.1.
Vulcanizing agent in step (2) is sulphur powder, and stable isotope D
6methane bass-the D of mark
12be 1:1 with the mol ratio of sulphur powder.
Ammoniation agent in step (3) is ammonium chloride, and stable isotope D
6intermediate-the D of mark
12be 1:1 with the mol ratio of ammonium chloride.
In the present embodiment, liquid phase is methyl alcohol.
Embodiment 18
The present embodiment cold labeling basic flavine O-
15n
2, molecular structural formula is
Concrete preparation method is as follows:
(1) condensation step: with stable isotope
15the DMA of N mark is raw material, and after condensing agent, catalyst mix, controlling temperature of reaction is 80 DEG C, and to control reaction pressure be 3MPa, reaction 6h, synthesizing stable isotropic substance
15the methane bass that N marks-
15n
2;
(2) vulcanisation step: the stable isotope that step (1) is synthesized
15the methane bass that N marks-
15n
2, mix with vulcanizing agent in liquid phase environment, controlling temperature of reaction is 120 DEG C, and to control reaction pressure be 3MPa, reaction 12h, synthesizing stable isotropic substance
15the intermediate that N marks-
15n
2;
(3) ammonification becomes salinization step: stable isotope step (2) synthesized
15the intermediate that N marks-
15n
2, mix with ammoniation agent in liquid phase environment, controlling temperature of reaction is 120 DEG C, and to control reaction pressure be 3MPa, reaction 12h, i.e. synthesizing stable isotopic labeling basic flavine O-
15n
2.
Wherein, the condensing agent in step (1) is paraformaldehyde, and catalyzer is sodium hydroxide, and stable isotope
15dMA and the mol ratio of paraformaldehyde of N mark are 3:1, and the mol ratio of itself and sodium hydroxide is 1:0.2.
Vulcanizing agent in step (2) is sulphur powder, and stable isotope
15the methane bass that N marks-
15n
2be 1:4 with the mol ratio of sulphur powder.
Ammoniation agent in step (3) is ammonium chloride, and stable isotope
15the intermediate that N marks-
15n
2be 1:3 with the mol ratio of ammonium chloride.
In the present embodiment, liquid phase is ethanol, acetonitrile and diacetyl oxide is the blended liquid phase of 1:1:1 in mass ratio.
Embodiment 19
The present embodiment cold labeling basic flavine O-
13c
4, molecular structural formula is
wherein, * represents that this place's carbon atom is
13c atom.
Concrete preparation method is as follows:
(1) condensation step: with stable isotope
13the DMA of C mark is raw material, and after condensing agent, catalyst mix, controlling temperature of reaction is 100 DEG C, and to control reaction pressure be 4MPa, reaction 4h, synthesizing stable isotropic substance
13the methane bass that C marks-
13c
4;
(2) vulcanisation step: the stable isotope that step (1) is synthesized
13the methane bass that C marks-
13c
4, mix with vulcanizing agent in liquid phase environment, controlling temperature of reaction is 150 DEG C, and to control reaction pressure be 4MPa, reaction 20h, synthesizing stable isotropic substance
13the intermediate that C marks-
13c
4;
(3) ammonification becomes salinization step: stable isotope step (2) synthesized
13the intermediate that C marks-
13c
4, mix with ammoniation agent in liquid phase environment, controlling temperature of reaction is 150 DEG C, and to control reaction pressure be 4MPa, reaction 20h, i.e. synthesizing stable isotopic labeling basic flavine O-
13c
4.
Wherein, the condensing agent in step (1) is trioxymethylene, and catalyzer is acetic acid, and stable isotope
13dMA and the mol ratio of trioxymethylene of C mark are 5:1, and the mol ratio of itself and acetic acid is 1:0.25.
Vulcanizing agent in step (2) is sulphur powder, and stable isotope
13the methane bass that C marks-
13c
4be 1:3 with the mol ratio of sulphur powder.
Ammoniation agent in step (3) is ammonium chloride, and stable isotope
13the intermediate that C marks-
13c
4be 1:2 with the mol ratio of ammonium chloride.
In the present embodiment, liquid phase is ether.
Claims (10)
1. a cold labeling basic flavine O, is characterized in that, described cold labeling basic flavine O be D or
15n or
13the basic flavine O of C mark, wherein,
The molecular structural formula of the basic flavine O of D mark is:
15the molecular structural formula of the basic flavine O of N mark is:
13the molecular structural formula of the basic flavine O of C mark is:
wherein, * represents that this place's carbon atom is
13c atom.
2. a synthetic method for cold labeling basic flavine O as claimed in claim 1, is characterized in that, the method be with stable isotope D or
15n or
13it is raw material that C marks methyl alcohol, aniline, synthesis obtain stable isotope D or
15n or
13the DMA precursor of C mark, then through condensation, sulfuration, ammonification, make stable isotope D or
15n or
13c marks basic flavine O.
3. the synthetic method of a kind of cold labeling basic flavine O according to claim 2, it is characterized in that, the method specifically comprises the following steps:
(1) condensation step: with stable isotope D or
15n or
13the DMA of C mark is raw material, and after condensing agent, catalyst mix, controls temperature of reaction is 30-150 DEG C, and to control reaction pressure be 0-5MPa, reacts 1-10h, synthesizing stable isotope D or
15n or
13the methane bass of C mark;
(2) vulcanisation step: the stable isotope D that step (1) is synthesized or
15n or
13the methane bass of C mark, mix with vulcanizing agent in liquid phase environment, control temperature of reaction is 30-200 DEG C, and to control reaction pressure be 0-5MPa, reacts 1-24h, synthesizing stable isotope D or
15n or
13the intermediate of C mark;
(3) ammonification becomes salinization step: the stable isotope D that step (2) is synthesized or
15n or
13the intermediate of C mark, mix with ammoniation agent in liquid phase environment, control temperature of reaction is 30-200 DEG C, and to control reaction pressure be 0-5MPa, reacts 1-24h, namely synthesizes described cold labeling basic flavine O.
4. the synthetic method of a kind of cold labeling basic flavine O according to claim 3, it is characterized in that, condensing agent described in step (1) is one or both in trioxymethylene, paraformaldehyde or urea, and described catalyzer is the one in hydrochloric acid, sodium hydroxide, acetic acid or sodium carbonate.
5. the synthetic method of a kind of cold labeling basic flavine O according to claim 3 or 4, is characterized in that, the stable isotope D described in step (1) or
15n or
13dMA and the mol ratio of condensing agent of C mark are (2-6): 1, and described stable isotope D or
15n or
13the DMA of C mark and the mol ratio of catalyzer are 1:(0.1-0.3).
6. the synthetic method of a kind of cold labeling basic flavine O according to claim 3, is characterized in that, the vulcanizing agent described in step (2) is sulphur powder, and described stable isotope D or
15n or
13the methane bass of C mark and the mol ratio of sulphur powder are 1:(1-6).
7. the synthetic method of a kind of cold labeling basic flavine O according to claim 6, is characterized in that, described stable isotope D or
15n or
13the methane bass of C mark and the mol ratio of sulphur powder are 1:(2-4).
8. the synthetic method of a kind of cold labeling basic flavine O according to claim 3, is characterized in that, the ammoniation agent described in step (3) is ammonium chloride, and described stable isotope D or
15n or
13the intermediate of C mark and the mol ratio of ammonium chloride are 1:(1-6).
9. the synthetic method of a kind of cold labeling basic flavine O according to claim 8, is characterized in that, described stable isotope D or
15n or
13the intermediate of C mark and the mol ratio of ammonium chloride are 1:(1-3).
10. the synthetic method of a kind of cold labeling basic flavine O according to claim 3, is characterized in that, described liquid phase is one or more in methyl alcohol, ethanol, ether, acetonitrile, diacetyl oxide, ethylene glycol or chloroform.
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