CN105199423B - A kind of synthetic method of the violated pigment of cold labeling - Google Patents
A kind of synthetic method of the violated pigment of cold labeling Download PDFInfo
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- CN105199423B CN105199423B CN201510527201.1A CN201510527201A CN105199423B CN 105199423 B CN105199423 B CN 105199423B CN 201510527201 A CN201510527201 A CN 201510527201A CN 105199423 B CN105199423 B CN 105199423B
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Abstract
The present invention relates to a kind of synthetic method of the violated pigment of cold labeling, this method be with stable isotope D or13The bromobenzene of C flag, through ammonification, sulfonation synthesize stable isotope D or13The intermediate sodium sulfanilate of C flag, or using bromobenzene as raw material, with stable isotope15The aminating agent of N marks synthesizes stable isotope through ammonification, sulfonation15N mark intermediate sodium sulfanilate, then through diazotising, coupling, i.e., synthesis obtain stable isotope D or15N or13The violated pigment of C flag.Compared with prior art, present invention process route is simple, it is easy to synthesize, the easily separated purification of product, product chemical purity is more than 99.0%, and isotope abundance is in more than 98.0%atom, the demand of field of food safety trace detection can be fully met, with good economy and use value.
Description
Technical field
The invention belongs to isotope labelling techniques field, it is related to a kind of synthesis side of the violated pigment of cold labeling
Method.
Background technology
Acid Orange II belongs to chemical dyestuff, is typically golden yellow powder, therefore is commonly called as Acid orange Ⅱ, is dissolved in water in feux rouges yellow,
Add hydrochloric acid and produce brown color precipitation, it is in dark-brown to add sodium hydroxide solution, is dissolved in ethanol in orange, be dissolved in the concentrated sulfuric acid and be in
Magenta, produces brown color precipitation, is mainly used in wool, silk, the dyeing of polyamide fibre and its direct printing of fabric, color after dilution
Damp bright-coloured, good level-dyeing property, but fastness is poor, it can also be used to the coloring of leather, paper and biological products.Meanwhile, it is one again
Indicator is planted, is medically usually used in the dyeing of histotomy.In food industry, Acid Orange II belongs in non-food coloring, food and prohibited
Only add.If these materials are used in food processing, food poisoning, long-term consumption even meeting may be caused after people is edible
It is carcinogenic.
Lemon yellow is also known as tartrazines, and chemical name is 1- (4- sulphenyls) -4- (4- sulphenyls azo) -5- pyrazolines
Ketone -3- carboxylic acid trisodium salts, are water-soluble synthetic dyestuff, in bright-coloured bright yellow, are dissolved in water, glycerine and propane diols, are slightly soluble in second
Alcohol, insoluble in grease.It has preferable heat resistance, acid resistance, light resistance and salt tolerance, stable to citric acid and tartaric acid,
But oxidative resistance is poor, meet alkali redden, faded during reduction, once as food colour, be widely used in food, beverage, medicine,
Industries such as cosmetics, feed, but because it has carcinogenicity, through forbidding being used for meat and its processed goods, (including internal organ are processed
Product), fish and its processed goods, fruit and its product.
But at present, have the illegal manufacturer in part, will Acid Orange II, lemon yellow add food in, this seriously endanger consumer
It is healthy.Therefore, to prevent Acid Orange II, lemon yellow from being caused harm into field of food, hygienic relevant departments need one
Kind it is capable of the technology of rapid, accurate and smaller error to detect it, this has extremely important existing to the healthy of the people
Sincere justice.
Stable isotope dilution mass spectrometry IDMS (Isotope Dilution Mass Spectrometry) be use with
Measured matter has the compound of the cold labeling of identical molecular structure as internal standard substance, with high-resolution liquid phase color
Spectrum-GC-MS (LC/MS) detected, measures the ratio of the ion of respective quality number by mass spectrograph, and with standard
Ratio is compared, and then reaches the purpose of accurate quantitative analysis.Sample can effectively be eliminated in chemistry and thing using Isotopic Internal Standard
In the pre-treatment step of reason, caused rate of recovery difference, so as to avoid because the loss of sample handling processes is to testing result
The deviation caused.
This characteristic of stable isotope dilution mass spectrometry and LC/MS high sensitivity and the ability knot for handling complex sample
Altogether so that chromatogram/isotope dilution mass spectrometry technology is acknowledged as a kind of micro and trace organic substance benchmark side of measurement
Method.And target is succeeded in developing in cold labeling Acid Orange II, lemon yellow, will for more more accurate quantitative analysis Acid Orange II,
Lemon yellow provides standard reagent, improves China's food safety detection technical system, meets the demand of China's food security development.
The content of the invention
It is an object of the present invention to overcome the above-mentioned drawbacks of the prior art and provide a kind of processing step simply,
Reaction condition is gentle, it is easy to the synthetic method of the violated pigment of cold labeling of operation.
The purpose of the present invention can be achieved through the following technical solutions：
A kind of synthetic method of the violated pigment of cold labeling, this method be with stable isotope D or13C flag
Bromobenzene, through ammonification, sulfonation synthesize stable isotope D or13The intermediate sodium sulfanilate of C flag, or using bromobenzene as raw material,
With stable isotope15The aminating agent of N marks synthesizes stable isotope through ammonification, sulfonation15The intermediate p-aminophenyl of N marks
Sodium sulfonate, then through diazotising, coupling, i.e., synthesis obtain stable isotope D or15N or13The violated pigment of C flag.
A kind of synthetic method of the violated pigment of cold labeling, this method specifically includes following steps：
(1) aminating reaction：By stable isotope D or13The bromobenzene of C flag mixed with aminating agent or with bromobenzene with it is stably same
Position element15The aminating agent mixing of N marks, adds amination catalyst, and under the conditions of 30-150 DEG C, reacts 1-20h, that is, is made
Stable isotope D or15N or13The aniline of C flag；
(2) sulfonating reaction：By stable isotope D or15N or13The aniline of C flag is added in organic solvent, adds sulphur
Change reagent, and under the conditions of 30-200 DEG C, react 1-24h, that is, be made stable isotope D or15N or13The intermediate pair of C flag
Sodium p-aminobenzene sulfonat；
(3) diazo-reaction：By stable isotope D or15N or13The intermediate sodium sulfanilate of C flag is added to
In acid flux material, nitrite is added, and under the conditions of 0-15 DEG C, reacts 0.5-5h, that is, is made and contains stable isotope D
Or15N or13The diazo liquid of C flag sodium sulfanilate diazol；
(4) coupling reaction：Beta naphthal is added into the diazo liquid of step (3), and under the conditions of -30-100 DEG C, reaction
0.5-8h, that is, be made stable isotope D or15N or13The violated pigment Acid Orange II of C flag.
Described stable isotope D or15N or13The molecular structural formula of the violated pigment Acid Orange II of C flag is：
Wherein, * represents that carbon atom is at this13C atoms.
Described aminating agent is the one or more in ammoniacal liquor, liquefied ammonia, Sodamide or potassamide, described ammonification catalysis
Agent is the one or more in ferric trichloride, copper chloride, cupric oxide, iron oxide, ferric sulfate, copper sulphate, described sulfonated reagent
For the one or more in oleum, sulfuric acid or sulfur trioxide, described organic solvent is methanol, ethanol, ether, acetonitrile,
One or more in acetic anhydride, ethylene glycol, o-dichlorohenzene, described acid flux material is sulfuric acid, acetic acid, nitric acid, formic acid, hydrochloric acid
In one or more.
It is preferred that, described organic solvent is the one or more in methanol, ethanol, ethylene glycol or o-dichlorohenzene.
Described bromobenzene and the mol ratio of aminating agent are 1：1-40, preferably 1：1-15, described aniline and sulfonated reagent
Mol ratio be 1：1-6, preferably 1：2-4, described intermediate sulfanilate and the mol ratio of nitrite are 1：1-
6, preferably 1：The mol ratio of sodium sulfanilate diazol and beta naphthal is 1 in 1-3, described diazo liquid：1-6, preferably 1：
1-4。
A kind of synthetic method of the violated pigment of cold labeling, this method specifically includes following steps：
(A) aminating reaction：By stable isotope D or13The bromobenzene of C flag mixed with aminating agent or with bromobenzene with it is stably same
Position element15The aminating agent mixing of N marks, adds amination catalyst, and under the conditions of 30-150 DEG C, reacts 1-20h, that is, is made
Stable isotope D or15N or13The aniline of C flag；
(B) sulfonating reaction：By stable isotope D or15N or13The aniline of C flag is added in organic solvent, adds sulphur
Change reagent, and under the conditions of 30-200 DEG C, react 1-24h, that is, be made stable isotope D or15N or13The intermediate pair of C flag
Sodium p-aminobenzene sulfonat；
(C) diazo-reaction：By stable isotope D or15N or13The intermediate sodium sulfanilate of C flag is added to
In acid flux material, nitrite is added, and under the conditions of 0-15 DEG C, reacts 0.5-5h, that is, is made and contains stable isotope D
Or15N or13The diazo liquid of C flag sodium sulfanilate diazol；
(D) coupling reaction：Diacetyl succinic acid dimethyl ester is added into step (C) diazo liquid, regulation pH value is to 5, in 90-
Under the conditions of 150 DEG C, 2-4h is reacted, midbody solution is made, then separately take a step (C) diazo liquid, and be added dropwise to
Between in liquid solution, under the conditions of 0 DEG C, react 4-5h, that is, be made stable isotope D or15N or13The violated pigment lemon of C flag
It is yellow.
Described stable isotope D or13C or15The molecular structural formula of violated pigment lemon yellow of N marks is：
Wherein, * represents that carbon atom is 13C atoms at this.
Described aminating agent is the one or more in ammoniacal liquor, liquefied ammonia, Sodamide or potassamide, described ammonification catalysis
Agent is the one or more in ferric trichloride, copper chloride, cupric oxide, iron oxide, ferric sulfate, copper sulphate, described sulfonated reagent
For the one or more in oleum, sulfuric acid or sulfur trioxide, described organic solvent is methanol, ethanol, ether, acetonitrile,
One or more in acetic anhydride, ethylene glycol, o-dichlorohenzene, described acid flux material is sulfuric acid, acetic acid, nitric acid, formic acid, hydrochloric acid
In one or more.
It is preferred that, described organic solvent is the one or more in methanol, ethanol, ethylene glycol or o-dichlorohenzene.
Described bromobenzene and the mol ratio of aminating agent are 1：1-40, preferably 1：1-15, described aniline and sulfonated reagent
Mol ratio be 1：1-6, preferably 1：2-4, described intermediate sulfanilate and the mol ratio of nitrite are 1：1-
6, preferably 1：The mol ratio of sodium sulfanilate diazol and diacetyl succinic acid dimethyl ester is 1 in 1-3, described diazo liquid：
1-6, preferably 1：1-4.
The present invention synthesis stable isotope D or15N or13The Acid Orange II and lemon yellow of C flag can use following technique road
Line is represented：
Compared with prior art, the invention has the characteristics that：
(1) a kind of violated pigment Acid Orange II of cold labeling, the synthetic method of lemon yellow are made public for the first time；
(2) process route is simple, it is easy to synthesize；
(3) the easily separated purification of product, product chemical purity is more than 99.0%, and isotope abundance, can more than 98.0%
Fully meet the demand of field of food safety trace detection；
(4) there is good economy and use value, available for extension industrial production, before preferable promote
Scape.
Embodiment
With reference to specific embodiment, the present invention is described in detail.
Embodiment 1
A, cold labeling aniline-D5Synthesis
Bromobenzene-D is sequentially added in flask5, ammoniacal liquor, bromobenzene-D5Mol ratio with ammoniacal liquor is 1:10, it is separately added into trichlorine
(both mol ratios are 1 for change iron and iron oxide:1), and reaction volume 20% distilled water, stirring is heated to 60 DEG C, reaction
18h.After reaction terminates, extract, wash, dry.Thick yield is 68.5%, distillation, yield 42.0%, HPLC detection purity
99.4%, abundance 99.2%.
B, cold labeling sodium sulfanilate synthesis
Aniline-the D of cold labeling is added in flask5, sequentially add oleum, aniline-D5With oleum
The mol ratio of acid is 1:2, add ethylene glycol, aniline-D5Mol ratio with ethylene glycol is 1:10.React vacuum tightness, reaction
Temperature control is at 120 DEG C, and reaction 4h stops reaction.Reactant is stood, the cooling of question response thing adds sodium hydroxide, until in alkali
Property, cooling treats solid crystal, suction filtration.Yield is 85.5%, recrystallization, yield 80.0%.HPLC detects purity 99.2%, rich
Degree 99.0%.
C, cold labeling Acid Orange II synthesis
The sodium sulfanilate of stable isotope D marks is added in flask, natrium nitrosum, hydrochloric acid is sequentially added, it is right
The mol ratio of Sodium p-aminobenzene sulfonat and natrium nitrosum, hydrochloric acid is 1:1.2:4, reacted at 0 DEG C after 20min, slowly with to amino
The mol ratio of benzene sulfonic acid sodium salt diazol and beta naphthal is 1:1.1, beta naphthal is added, 1h is reacted, chlorination is added with volume ratio 10%
Sodium, suction filtration, drying, weighs.Yield is 78.2%, recrystallization, and yield is 65.2%, HPLC detection purity 99.0%, abundance
98.8%.
Embodiment 2
A, cold labeling aniline-D5Synthesis
Bromobenzene-D is sequentially added in flask5, ammoniacal liquor, bromobenzene-D5Mol ratio with ammoniacal liquor is 1:15, it is separately added into trichlorine
(both mol ratios are 1 for change iron and iron oxide:1), and the distilled water of reaction volume 20%, stirring, is heated to 60 DEG C, reacts 18h.
After reaction terminates, extract, wash, dry.Thick yield is 68.5%, distillation, yield 42.0%, HPLC detection purity 99.3%,
Abundance 99.1%.
B, cold labeling sodium sulfanilate synthesis
Aniline-the D of cold labeling is added in flask5, sequentially add oleum, aniline-D5With oleum
The mol ratio of acid is 1:2.5, add o-dichlorohenzene, aniline-D5Mol ratio with o-dichlorohenzene is 1:8.React vacuum tightness,
Reaction temperature is controlled at 140 DEG C, and reaction 5h stops reaction.Reactant is stood, the cooling of question response thing adds sodium hydroxide, until
In alkalescence, solid crystal, suction filtration are treated in cooling.Yield is 87.5%, recrystallization, yield 82.3%.HPLC detects purity
99.4%, abundance 99.0%.
C, cold labeling Acid Orange II synthesis
The sodium sulfanilate of stable isotope D marks is added in flask, natrium nitrosum, hydrochloric acid is sequentially added, it is right
The mol ratio of Sodium p-aminobenzene sulfonat and natrium nitrosum, hydrochloric acid is 1:1.5:3, reacted at 0 DEG C after 30min, slowly with to amino
The mol ratio of benzene sulfonic acid sodium salt diazol and beta naphthal is 1:1.2, beta naphthal is added, 2h is reacted, chlorination is added with volume ratio 10%
Sodium, suction filtration, drying, weighs.Yield is 79.2%, recrystallization, and yield is 66.2%, HPLC detection purity 99.0%, abundance
98.9%.
Embodiment 3
A, cold labeling aniline-13C6Synthesis
Sequentially added in flask bromobenzene-13C6, ammoniacal liquor, bromobenzene-13C6Mol ratio with ammoniacal liquor is 1:15, it is separately added into three
(both mol ratios are 1 for iron chloride and iron oxide:1.5), and the distilled water of reaction volume 20%, stirring, is heated to 100 DEG C, instead
Answer 20h.After reaction terminates, extract, wash, dry.Thick yield is 70.5%, distillation, yield 46.0%, HPLC detection purity
99.4%, abundance 99.5%.
B, cold labeling sodium sulfanilate-13C6Synthesis
In flask add cold labeling aniline-13C6, sequentially add oleum, aniline-13C6With hair
The mol ratio of cigarette sulfuric acid is 1:3, add ethylene glycol, aniline-13C6Mol ratio with ethylene glycol is 1:12.React vacuum tightness,
Reaction temperature is controlled at 160 DEG C, and reaction 4h stops reaction.Reactant is stood, the cooling of question response thing adds sodium hydroxide, until
In alkalescence, solid crystal, suction filtration are treated in cooling.Yield is 84.5%, recrystallization, yield 81.0%.HPLC detects purity
99.0%, abundance 99.3%.
C, cold labeling Acid Orange II-13C6Synthesis
Stable isotope is added in flask13The sodium sulfanilate of C flag, sequentially adds natrium nitrosum, hydrochloric acid, right
The mol ratio of Sodium p-aminobenzene sulfonat and natrium nitrosum, hydrochloric acid is 1:2:3.5, reacted at 0 DEG C after 30min, slowly with to amino
The mol ratio of benzene sulfonic acid sodium salt diazol and beta naphthal is 1:1.3, beta naphthal is added, 2h is reacted, chlorination is added with volume ratio 10%
Sodium, suction filtration, drying, weighs.Yield is 79.2%, recrystallization, and yield is 68.2%, HPLC detection purity 99.0%, abundance
99.0%.
Embodiment 4
A, cold labeling aniline-13C6Synthesis
Sequentially added in flask bromobenzene-13C6, ammoniacal liquor, bromobenzene-13C6Mol ratio with ammoniacal liquor is 1:15, it is separately added into three
(both mol ratios are 1 for iron chloride and iron oxide:1.5), and the distilled water of reaction volume 20%, stirring, is heated to 70 DEG C, reaction
24h.After reaction terminates, extract, wash, dry.Thick yield is 77.5%, distillation, yield 53.0%, HPLC detection purity
98.8%, abundance 99.7%.
B, cold labeling sodium sulfanilate-13C6Synthesis
In flask add cold labeling aniline-13C6, sequentially add oleum, aniline-13C6With hair
The mol ratio of cigarette sulfuric acid is 1:2.5, add o-dichlorohenzene, aniline-13C6Mol ratio with o-dichlorohenzene is 1:14.Reaction is true
Empty closed, reaction temperature is controlled at 165 DEG C, and reaction 4.5h stops reaction.Reactant is stood, the cooling of question response thing adds hydrogen-oxygen
Change sodium, until in alkalescence, solid crystal, suction filtration are treated in cooling.Yield is 84.5%, recrystallization, yield 78.8%.HPLC is detected
Purity 98.6%, abundance 99.5%.
C, cold labeling Acid Orange II-13C6Synthesis
Stable isotope is added in flask13The sodium sulfanilate of C flag, sequentially adds natrium nitrosum, hydrochloric acid, right
The mol ratio of Sodium p-aminobenzene sulfonat and natrium nitrosum, hydrochloric acid is 1:1.6:3.5, reacted at 0 DEG C after 40min, slowly with to ammonia
The mol ratio of base benzene sulfonic acid sodium salt diazol and beta naphthal is 1:1.2, beta naphthal is added, 3h is reacted, chlorine is added with volume ratio 10%
Change sodium, suction filtration, drying, weigh.Yield is 76.2%, recrystallization, and yield is 65.2%, HPLC detection purity 98.5%, abundance
99.2%.
Embodiment 5
A, cold labeling aniline-15N synthesis
Sequentially added in flask bromobenzene,15N- ammoniacal liquor, bromobenzene with15The mol ratio of N- ammoniacal liquor is 1:6, it is separately added into trichlorine
(both mol ratios are 1 for change iron and iron oxide:1.5), and the distilled water of reaction volume 20%, stirring, is heated to 85 DEG C, reaction
20h.After reaction terminates, extract, wash, dry.Thick yield is 60.5%, distillation, yield 40.3%, HPLC detection purity
99.2%, abundance 99.5%.
B, cold labeling sodium sulfanilate-15N synthesis
In flask add cold labeling aniline-15N, sequentially adds oleum, and aniline-15N and smoke
The mol ratio of sulfuric acid is 1:4, add ethylene glycol, aniline-15The mol ratio of N and ethylene glycol is 1:10.Vacuum tightness is reacted, instead
Temperature control is answered at 135 DEG C, reaction 3.5h stops reaction.Reactant is stood, the cooling of question response thing adds sodium hydroxide, until
In alkalescence, solid crystal, suction filtration are treated in cooling.Yield is 76.5%, recrystallization, yield 72.0%.HPLC detects purity
98.2%, abundance 99.0%.
C, cold labeling Acid Orange II-15N synthesis
Stable isotope is added in flask15The sodium sulfanilate of N marks, sequentially adds natrium nitrosum, hydrochloric acid, right
The mol ratio of Sodium p-aminobenzene sulfonat and natrium nitrosum, hydrochloric acid is 1:2:5, reacted at 0 DEG C after 35min, slowly with p-aminophenyl
The mol ratio of sodium sulfonate diazol and beta naphthal is 1:1.1, beta naphthal is added, 3h is reacted, sodium chloride is added with volume ratio 10%,
Suction filtration, drying, weigh.Yield is 76.2%, recrystallization, and yield is 63.2%, HPLC detection purity 98.5%, abundance
98.7%.
Embodiment 6
A, cold labeling aniline-15N synthesis
Sequentially added in flask bromobenzene,15N- ammoniacal liquor, bromobenzene with15The mol ratio of N- ammoniacal liquor is 1:9, it is separately added into trichlorine
(both mol ratios are 1 for change iron and iron oxide:2), and the distilled water of reaction volume 20%, stirring, is heated to 90 DEG C, reacts 20h.
After reaction terminates, extract, wash, dry.Thick yield is 68.5%, distillation, yield 43.0%, HPLC detection purity 99.2%,
Abundance 99.2%.
B, cold labeling sodium sulfanilate-15N synthesis
In flask add cold labeling aniline-15N, sequentially adds oleum, and aniline-15N and smoke
The mol ratio of sulfuric acid is 1:4.5, add o-dichlorohenzene, aniline-15The mol ratio of N and o-dichlorohenzene is 1:16.React vacuum close
Close, reaction temperature is controlled at 145 DEG C, reaction 4.5h stops reaction.Reactant is stood, the cooling of question response thing adds sodium hydroxide,
Until in alkalescence, solid crystal, suction filtration are treated in cooling.Yield is 80.5%, recrystallization, yield 78.0%.HPLC detects purity
99.0%, abundance 99.0%.
C, cold labeling Acid Orange II-15N synthesis
Stable isotope is added in flask15The sodium sulfanilate of N marks, sequentially adds natrium nitrosum, hydrochloric acid, right
The mol ratio of Sodium p-aminobenzene sulfonat and natrium nitrosum, hydrochloric acid is 1:1.3:4.5, reacted at 0 DEG C after 45min, slowly with to ammonia
The mol ratio of base benzene sulfonic acid sodium salt diazol and beta naphthal is 1:1.3, beta naphthal is added, 2h is reacted, chlorine is added with volume ratio 10%
Change sodium, suction filtration, drying, weigh.Yield is 77.2%, recrystallization, and yield is 66.2%, HPLC detection purity 98.7%, abundance
98.8%.
Embodiment 7
A, cold labeling aniline-D5Synthesis
Bromobenzene-D is sequentially added in flask5, ammoniacal liquor, bromobenzene-D5Mol ratio with ammoniacal liquor is 1:10, it is separately added into trichlorine
(both mol ratios are 1 for change iron and iron oxide:1.8), and the distilled water of reaction volume 20%, stirring, is heated to 95 DEG C, reaction
19h.After reaction terminates, extract, wash, dry.Thick yield is 67.5%, distillation, yield 41.5%, HPLC detection purity
99.3%, abundance 99.1%.
B, cold labeling sodium sulfanilate synthesis
Aniline-the D of cold labeling is added in flask5, sequentially add oleum, aniline-D5With oleum
The mol ratio of acid is 1:2.5, add ethylene glycol, aniline-D5Mol ratio with ethylene glycol is 1:14.Vacuum tightness is reacted, instead
Temperature control is answered at 120 DEG C, reaction 5h stops reaction.Reactant is stood, the cooling of question response thing adds sodium hydroxide, until being in
Alkalescence, cooling, treats solid crystal, suction filtration.Yield is 86.5%, recrystallization, yield 82.0%.HPLC detects purity 99.2%,
Abundance 98.7%.
C, cold labeling Acid Orange II synthesis
The sodium sulfanilate of stable isotope D marks is added in flask, natrium nitrosum, hydrochloric acid is sequentially added, it is right
The mol ratio of Sodium p-aminobenzene sulfonat and natrium nitrosum, hydrochloric acid is 1:1.2:4, reacted at 0 DEG C after 20min, slowly with to amino
The mol ratio of benzene sulfonic acid sodium salt diazol and beta naphthal is 1:3, beta naphthal is added, rise temperature reacts 4h, with volume ratio to 90 DEG C
10% adds sodium chloride, suction filtration, drying, weighs.Yield is 68.2%, recrystallization, and yield is 55.2%, HPLC detection purity
99.0%, abundance 98.6%.
Embodiment 8
A, cold labeling aniline-D5Synthesis
Bromobenzene-D is sequentially added in flask5, ammoniacal liquor, bromobenzene-D5Mol ratio with ammoniacal liquor is 1:13, it is separately added into trichlorine
(both mol ratios are 1 for change iron and iron oxide:2), and the distilled water of reaction volume 20%, stirring, is heated to 60 DEG C, reacts 19h.
After reaction terminates, extract, wash, dry.Thick yield is 71.5%, distillation, yield 45.3%, HPLC detection purity 99.2%,
Abundance 99.4%.
B, cold labeling sodium sulfanilate synthesis
Aniline-the D of cold labeling is added in flask5, sequentially add oleum, aniline-D5With oleum
The mol ratio of acid is 1:3, add o-dichlorohenzene, aniline-D5Mol ratio with o-dichlorohenzene is 1:10.React vacuum tightness,
Reaction temperature is controlled at 120 DEG C, and reaction 6h stops reaction.Reactant is stood, the cooling of question response thing adds sodium hydroxide, until
In alkalescence, solid crystal, suction filtration are treated in cooling.Yield is 85.5%, recrystallization, yield 80.0%.HPLC detects purity
99.2%, abundance 99.2%.
C, cold labeling lemon yellow synthesis
The sodium sulfanilate of stable isotope D marks is added in flask, natrium nitrosum, hydrochloric acid is sequentially added, it is right
The mol ratio of Sodium p-aminobenzene sulfonat and natrium nitrosum, hydrochloric acid is 1:1.4:5,40min is reacted at 0 DEG C, in addition such as above-mentioned method
A diazo liquid is prepared again, and slowly the mol ratio using sodium sulfanilate diazol and diacetyl succinic acid dimethyl ester is 1:1.5,
Diacetyl succinic acid dimethyl ester is added, pH to 5 is adjusted, rise temperature reacts 3h, prepare midbody solution to 100 DEG C.At 0 DEG C,
First part of diazo liquid is added dropwise to midbody solution, 4h is reacted, sodium chloride is added with volume ratio 10%, 5h is stood, it is suction filtration, dry
It is dry, weigh.Yield is 66.2%, recrystallization, and yield is 55.2%, HPLC detection purity 99.0%, abundance 98.9%.
Embodiment 9
A, cold labeling aniline-D5Synthesis
Bromobenzene-D is sequentially added in flask5, ammoniacal liquor, bromobenzene-D5Mol ratio with ammoniacal liquor is 1:3, it is separately added into tri-chlorination
(both mol ratios are 1 for iron and iron oxide:1.6), and the distilled water of reaction volume 20%, stirring, is heated to 95 DEG C, reacts 17h.
After reaction terminates, extract, wash, dry.Thick yield is 66.5%, distillation, yield 41.0%, HPLC detection purity 99.3%,
Abundance 99.1%.
B, cold labeling sodium sulfanilate synthesis
Aniline-the D of cold labeling is added in flask5, sequentially add oleum, aniline-D5With oleum
The mol ratio of acid is 1:4.5, add ethylene glycol, aniline-D5Mol ratio with ethylene glycol is 1:10.Vacuum tightness is reacted, instead
Temperature control is answered at 165 DEG C, reaction 4.5h stops reaction.Reactant is stood, the cooling of question response thing adds sodium hydroxide, until
In alkalescence, solid crystal, suction filtration are treated in cooling.Yield is 83.5%, recrystallization, yield 78.0%.HPLC detects purity
99.2%, abundance 99.0%.
C, cold labeling lemon yellow synthesis
Natural abundance sodium sulfanilate is added in flask, natrium nitrosum, hydrochloric acid, p-aminobenzene sulfonic acid is sequentially added
The mol ratio of sodium and natrium nitrosum, hydrochloric acid is 1:1.5:4.5,45min is reacted at 0 DEG C, slowly with sodium sulfanilate weight
The mol ratio of nitrogen salt and diacetyl succinic acid dimethyl ester is 1:1.4, diacetyl succinic acid dimethyl ester is added, pH to 5 is adjusted, temperature is raised
To 95 DEG C, 3.5h is reacted, midbody solution is prepared.In addition, as walked the stable isotope D marks of preparation in the addition of above-mentioned method
Sodium sulfanilate, then a diazo liquid is prepared, at 0 DEG C, diazo liquid is added dropwise to midbody solution, 5h is reacted, with body
Product adds sodium chloride than 10%, stands 8h, suction filtration, drying, weighs.Yield is 69.2%, recrystallization, and yield is 58.2%,
HPLC detects purity 98.6%, abundance 98.6%.
Embodiment 10
A, cold labeling aniline-D5Synthesis
Bromobenzene-D is sequentially added in flask5, ammoniacal liquor, bromobenzene-D5Mol ratio with ammoniacal liquor is 1:16, it is separately added into trichlorine
(both mol ratios are 1 for change iron and iron oxide:1.8), and the distilled water of reaction volume 20%, stirring, is heated to 60 DEG C, reaction
20h.After reaction terminates, extract, wash, dry.Thick yield is 65.5%, distillation, yield 41.0%, HPLC detection purity
99.3%, abundance 99.1%.
B, cold labeling sodium sulfanilate synthesis
Aniline-the D of cold labeling is added in flask5, sequentially add sulfuric acid, aniline-D5With mole of sulfuric acid
Than for 1:6, add o-dichlorohenzene, aniline-D5Mol ratio with o-dichlorohenzene is 1:10.React vacuum tightness, reaction temperature
Control is at 155 DEG C, and reaction 7h stops reaction.Reactant is stood, the cooling of question response thing adds sodium hydroxide, until in alkalescence, it is cold
But, solid crystal, suction filtration are treated.Yield is 87.5%, recrystallization, yield 81.0%.HPLC detects purity 99.2%, abundance
98.9%.
C, cold labeling lemon yellow synthesis
Natural abundance sodium sulfanilate is added in flask, natrium nitrosum, hydrochloric acid, p-aminobenzene sulfonic acid is sequentially added
The mol ratio of sodium and natrium nitrosum, hydrochloric acid is 1:1.5:4.5,45min is reacted at 0 DEG C, slowly with sodium sulfanilate weight
The mol ratio of nitrogen salt and diacetyl succinic acid dimethyl ester is 1:1.4, diacetyl succinic acid dimethyl ester is added, pH to 5 is adjusted, temperature is raised
To 95 DEG C, 3.5h is reacted, midbody solution is prepared.In addition, as walked the stable isotope D marks of preparation in the addition of above-mentioned method
Sodium sulfanilate, then a diazo liquid is prepared, at 0 DEG C, diazo liquid is added dropwise to midbody solution, 5h is reacted, with body
Product adds sodium chloride than 10%, stands 8h, suction filtration, drying, weighs.Yield is 69.2%, recrystallization, and yield is 58.2%,
HPLC detects purity 98.9%, abundance 98.7%.
Embodiment 11
A, cold labeling aniline-13C6Synthesis
Sequentially added in flask bromobenzene-13C6, ammoniacal liquor, bromobenzene-13C6Mol ratio with ammoniacal liquor is 1:15, it is separately added into three
(both mol ratios are 1 for iron chloride and iron oxide:2), and the distilled water of reaction volume 20%, stirring, is heated to 110 DEG C, reaction
23h.After reaction terminates, extract, wash, dry.Thick yield is 76.5%, distillation, yield 53.0%, HPLC detection purity
99.1%, abundance 99.4%.
B, cold labeling sodium sulfanilate-13C6Synthesis
In flask add cold labeling aniline-13C6, sequentially add oleum, aniline-13C6With hair
The mol ratio of cigarette sulfuric acid is 1:3.5, add ethylene glycol, aniline-13C6Mol ratio with ethylene glycol is 1:15.React vacuum close
Close, reaction temperature is controlled at 130 DEG C, reaction 5h stops reaction.Reactant is stood, the cooling of question response thing adds sodium hydroxide, directly
To in alkalescence, solid crystal, suction filtration are treated in cooling.Yield is 84.5%, recrystallization, yield 80.8%.HPLC detects purity
98.7%, abundance 99.1%.
C, cold labeling lemon yellow synthesis
Natural abundance sodium sulfanilate is added in flask, natrium nitrosum, hydrochloric acid, p-aminobenzene sulfonic acid is sequentially added
The mol ratio of sodium and natrium nitrosum, hydrochloric acid is 1:1.3:5,50min is reacted at 0 DEG C, slowly with sodium sulfanilate diazonium
The mol ratio of salt and diacetyl succinic acid dimethyl ester is 1:1.3, diacetyl succinic acid dimethyl ester is added, pH to 5 is adjusted, rise temperature is extremely
110 DEG C, 3h is reacted, midbody solution is prepared.In addition, the stable isotope as walked preparation in the addition of above-mentioned method13Pair of C flag
Sodium p-aminobenzene sulfonat, then a diazo liquid is prepared, at 0 DEG C, diazo liquid is added dropwise to midbody solution, 5h is reacted, with volume
Sodium chloride is added than 10%, 8h is stood, suction filtration, drying, weighs.Yield is 72.2%, recrystallization, and yield is 59.2%, HPLC
Detect purity 98.3%, abundance 98.5%.
Embodiment 12
A, cold labeling aniline-13C6Synthesis
Sequentially added in flask bromobenzene-13C6, ammoniacal liquor, bromobenzene-13C6Mol ratio with ammoniacal liquor is 1:13, it is separately added into three
(both mol ratios are 1 for iron chloride and iron oxide:1.2), and the distilled water of reaction volume 20%, stirring, it is heated to 80 DEG C, reaction
20h.After reaction terminates, extract, wash, dry.Thick yield is 73.5%, distillation, yield 47.0%, HPLC detection purity
99.0%, abundance 99.5%.
B, cold labeling sodium sulfanilate-13C6Synthesis
In flask add cold labeling aniline-13C6, sequentially add oleum, aniline-13C6With hair
The mol ratio of cigarette sulfuric acid is 1:4, add o-dichlorohenzene, aniline-13C6Mol ratio with o-dichlorohenzene is 1:13.React vacuum
Closed, reaction temperature is controlled at 170 DEG C, and reaction 2.5h stops reaction.Reactant is stood, the cooling of question response thing adds hydroxide
Sodium, until in alkalescence, solid crystal, suction filtration are treated in cooling.Yield is 84.5%, recrystallization, yield 80.8%.HPLC detections are pure
Degree 98.3%, abundance 99.3%.
C, cold labeling lemon yellow synthesis
Stable isotope is added in flask13The sodium sulfanilate of C flag, sequentially adds natrium nitrosum, hydrochloric acid, right
The mol ratio of Sodium p-aminobenzene sulfonat and natrium nitrosum, hydrochloric acid is 1:1.5:5.5,45min is reacted at 0 DEG C, in addition, side as described above
Method prepares a diazo liquid again, and slowly the mol ratio using sodium sulfanilate diazol and diacetyl succinic acid dimethyl ester is 1:
1.6, diacetyl succinic acid dimethyl ester is added, rise temperature reacts 2.5h, prepare midbody solution to 130 DEG C.At 0 DEG C, by
A diazo liquid is added dropwise to midbody solution, reacts 4h, and sodium chloride is added with volume ratio 10%, stands 7h, suction filtration, drying, title
Weight.Yield is 63.2%, recrystallization, and yield is 52.2%, HPLC detection purity 99.1%, abundance 98.7%.
Embodiment 13
A, cold labeling aniline-13C6Synthesis
Sequentially added in flask bromobenzene-13C6, ammoniacal liquor, bromobenzene-13C6Mol ratio with ammoniacal liquor is 1:11, it is separately added into three
(both mol ratios are 1 for iron chloride and iron oxide:1), and the distilled water of reaction volume 20%, stirring, is heated to 75 DEG C, reaction
22h.After reaction terminates, extract, wash, dry.Thick yield is 75.5%, distillation, yield 51.0%, HPLC detection purity
99.1%, abundance 99.5%.
B, cold labeling sodium sulfanilate-13C6Synthesis
In flask add cold labeling aniline-13C6, sequentially add oleum, aniline-13C6With hair
The mol ratio of cigarette sulfuric acid is 1:3, add ethylene glycol, aniline-13C6Mol ratio with ethylene glycol is 1:15.React vacuum tightness,
Reaction temperature is controlled at 150 DEG C, and reaction 4.5h stops reaction.Reactant is stood, the cooling of question response thing adds sodium hydroxide, directly
To in alkalescence, solid crystal, suction filtration are treated in cooling.Yield is 85.5%, recrystallization, yield 80.3%.HPLC detects purity
98.5%, abundance 99.2%.
C, cold labeling lemon yellow synthesis
Stable isotope is added in flask13The sodium sulfanilate of C flag, sequentially adds natrium nitrosum, hydrochloric acid, right
The mol ratio of Sodium p-aminobenzene sulfonat and natrium nitrosum, hydrochloric acid is 1:1.2:6,35min is reacted at 0 DEG C, in addition, such as above-mentioned method
A natural abundance diazo liquid is prepared again, slowly with the mol ratio of sodium sulfanilate diazol and diacetyl succinic acid dimethyl ester
For 1:1.6, diacetyl succinic acid dimethyl ester is added, rise temperature reacts 4h, prepare midbody solution to 120 DEG C., will at 0 DEG C
First part of diazo liquid is added dropwise to midbody solution, reacts 4.5h, and sodium chloride is added with volume ratio 10%, stands 4h, suction filtration, dry
It is dry, weigh.Yield is 65.2%, recrystallization, and yield is 53.2%, HPLC detection purity 98.4%, abundance 98.7%.
Embodiment 14
A, cold labeling aniline-13C6Synthesis
Sequentially added in flask bromobenzene-13C6, ammoniacal liquor, bromobenzene-13C6Mol ratio with ammoniacal liquor is 1:11, it is separately added into three
(both mol ratios are 1 for iron chloride and iron oxide:1.3), and the distilled water of reaction volume 20%, stirring, is heated to 65 DEG C, reaction
25h.After reaction terminates, extract, wash, dry.Thick yield is 71.5%, distillation, yield 45.3%, HPLC detection purity
99.2%, abundance 99.5%.
B, cold labeling sodium sulfanilate-13C6Synthesis
In flask add cold labeling aniline-13C6, sequentially add oleum, aniline-13C6With hair
The mol ratio of cigarette sulfuric acid is 1:3, add o-dichlorohenzene, aniline-13C6Mol ratio with o-dichlorohenzene is 1:12.React vacuum
Closed, reaction temperature is controlled at 120 DEG C, and reaction 4h stops reaction.Reactant is stood, the cooling of question response thing adds sodium hydroxide,
Until in alkalescence, solid crystal, suction filtration are treated in cooling.Yield is 84.5%, recrystallization, yield 81.8%.HPLC detects purity
98.9%, abundance 99.2%.
C, cold labeling lemon yellow synthesis
Stable isotope is added in flask13The sodium sulfanilate of C flag, sequentially adds natrium nitrosum, hydrochloric acid, right
The mol ratio of Sodium p-aminobenzene sulfonat and natrium nitrosum, hydrochloric acid is 1:1.8:6,55min is reacted at 0 DEG C, in addition, such as above-mentioned method
A diazo liquid is prepared again, and slowly the mol ratio using sodium sulfanilate diazol and diacetyl succinic acid dimethyl ester is 1:1.6,
Diacetyl succinic acid dimethyl ester is added, rise temperature reacts 4h, prepare midbody solution to 110 DEG C.At 0 DEG C, by first part of weight
Nitrogen drop adds midbody solution, reacts 4.5h, and sodium chloride is added with volume ratio 10%, stands 5h, suction filtration, drying, weighs.Receive
Rate is 68.2%, recrystallization, and yield is 56.2%, HPLC detection purity 98.9%, abundance 98.7%.
Embodiment 15
A, cold labeling aniline-15N synthesis
Sequentially added in flask bromobenzene,15N- ammoniacal liquor, bromobenzene with15The mol ratio of N- ammoniacal liquor is 1:8, it is separately added into trichlorine
(both mol ratios are 1 for change iron and iron oxide:2), and the distilled water of reaction volume 20%, stirring, is heated to 80 DEG C, reacts 23h.
After reaction terminates, extract, wash, dry.Thick yield is 71.5%, distillation, yield 44.0%, HPLC detection purity 99.3%,
Abundance 99.4%.
B, cold labeling sodium sulfanilate-15N synthesis
In flask add cold labeling aniline-15N, sequentially adds oleum, and aniline-15N and smoke
The mol ratio of sulfuric acid is 1:5, add ethylene glycol, aniline-15The mol ratio of N and ethylene glycol is 1:15.Vacuum tightness is reacted, instead
Temperature control is answered at 150 DEG C, reaction 4h stops reaction.Reactant is stood, the cooling of question response thing adds sodium hydroxide, until being in
Alkalescence, cooling, treats solid crystal, suction filtration.Yield is 85.5%, recrystallization, yield 80.2%.HPLC detects purity 99.3%,
Abundance 99.2%.
C, cold labeling lemon yellow synthesis
Natural abundance sodium sulfanilate is added in flask, natrium nitrosum, hydrochloric acid, p-aminobenzene sulfonic acid is sequentially added
The mol ratio of sodium and natrium nitrosum, hydrochloric acid is 1:1.4:5,55min is reacted at 0 DEG C, slowly with sodium sulfanilate diazonium
The mol ratio of salt and diacetyl succinic acid dimethyl ester is 1:1.2, diacetyl succinic acid dimethyl ester is added, pH to 5 is adjusted, rise temperature is extremely
130 DEG C, 4h is reacted, midbody solution is prepared.In addition, the stable isotope as walked preparation in the addition of above-mentioned method15Pair of N marks
Sodium p-aminobenzene sulfonat, then a diazo liquid is prepared, at 0 DEG C, diazo liquid is added dropwise to midbody solution, 4h is reacted, with volume
Sodium chloride is added than 10%, 5h is stood, suction filtration, drying, weighs.Yield is 71.2%, recrystallization, and yield is 56.2%, HPLC
Detect purity 98.8%, abundance 98.7%.
Embodiment 16
A, cold labeling aniline-15N synthesis
Sequentially added in flask bromobenzene,15N- ammoniacal liquor, bromobenzene with15The mol ratio of N- ammoniacal liquor is 1:9, it is separately added into trichlorine
(both mol ratios are 1 for change iron and iron oxide:2), and the distilled water of reaction volume 20%, stirring, is heated to 85 DEG C, reacts 23h.
After reaction terminates, extract, wash, dry.Thick yield is 72.5%, distillation, yield 43.0%, HPLC detection purity 99.2%,
Abundance 99.1%.
B, cold labeling sodium sulfanilate-15N synthesis
In flask add cold labeling aniline-15N, sequentially adds oleum, and aniline-15N and smoke
The mol ratio of sulfuric acid is 1:3.5, add o-dichlorohenzene, aniline-15The mol ratio of N and o-dichlorohenzene is 1:15.React vacuum close
Close, reaction temperature is controlled at 120 DEG C, reaction 4h stops reaction.Reactant is stood, the cooling of question response thing adds sodium hydroxide, directly
To in alkalescence, solid crystal, suction filtration are treated in cooling.Yield is 87.5%, recrystallization, yield 82.5%.HPLC detects purity
99.0%, abundance 99.0%.
C, cold labeling lemon yellow synthesis
Natural abundance sodium sulfanilate is added in flask, natrium nitrosum, hydrochloric acid, p-aminobenzene sulfonic acid is sequentially added
The mol ratio of sodium and natrium nitrosum, hydrochloric acid is 1:1.1:4,55min is reacted at 0 DEG C, slowly with sodium sulfanilate diazonium
The mol ratio of salt and diacetyl succinic acid dimethyl ester is 1:1.3, diacetyl succinic acid dimethyl ester is added, pH to 5 is adjusted, rise temperature is extremely
150 DEG C, 4h is reacted, midbody solution is prepared.In addition, the stable isotope as walked preparation in the addition of above-mentioned method15Pair of N marks
Sodium p-aminobenzene sulfonat, then a diazo liquid is prepared, at 0 DEG C, diazo liquid is added dropwise to midbody solution, 4h is reacted, with volume
Sodium chloride is added than 10%, 3h is stood, suction filtration, drying, weighs.Yield is 71.2%, recrystallization, and yield is 56.2%, HPLC
Detect purity 98.6%, abundance 98.4%.
Embodiment 17
A, cold labeling aniline-15N synthesis
Sequentially added in flask bromobenzene,15N- ammoniacal liquor, bromobenzene with15The mol ratio of N- ammoniacal liquor is 1:7, it is separately added into trichlorine
(both mol ratios are 1 for change iron and iron oxide:3), and the distilled water of reaction volume 20%, stirring, is heated to 85 DEG C, reacts 21h.
After reaction terminates, extract, wash, dry.Thick yield is 71.5%, distillation, yield 44.8%, HPLC detection purity 99.0%,
Abundance 99.2%.
B, cold labeling sodium sulfanilate-15N synthesis
In flask add cold labeling aniline-15N, sequentially adds oleum, and aniline-15N and smoke
The mol ratio of sulfuric acid is 1:4, add ethylene glycol, aniline-15The mol ratio of N and ethylene glycol is 1:14.Vacuum tightness is reacted, instead
Temperature control is answered at 140 DEG C, reaction 4h stops reaction.Reactant is stood, the cooling of question response thing adds sodium hydroxide, until being in
Alkalescence, cooling, treats solid crystal, suction filtration.Yield is 85.5%, recrystallization, yield 81.0%.HPLC detects purity 99.2%,
Abundance 99.0%.
C, cold labeling lemon yellow synthesis
Stable isotope is added in flask15The sodium sulfanilate of N marks, sequentially adds natrium nitrosum, hydrochloric acid, right
The mol ratio of Sodium p-aminobenzene sulfonat and natrium nitrosum, hydrochloric acid is 1:1.1:4,40min is reacted at 0 DEG C, in addition, such as above-mentioned method
A diazo liquid is prepared again, and slowly the mol ratio using sodium sulfanilate diazol and diacetyl succinic acid dimethyl ester is 1:1.4,
Diacetyl succinic acid dimethyl ester is added, rise temperature reacts 3h, prepare midbody solution to 110 DEG C.At 0 DEG C, by first part of weight
Nitrogen drop adds midbody solution, reacts 5h, and sodium chloride is added with volume ratio 10%, stands 5h, suction filtration, drying, weighs.Yield
For 67.2%, recrystallization, yield is 56.2%, HPLC detection purity 99.1%, abundance 98.7%.
Embodiment 18
A, cold labeling aniline-15N synthesis
Sequentially added in flask bromobenzene,15N- ammoniacal liquor, bromobenzene with15The mol ratio of N- ammoniacal liquor is 1:7, it is separately added into trichlorine
(both mol ratios are 1 for change iron and iron oxide:3), and the distilled water of reaction volume 20%, stirring, is heated to 80 DEG C, reacts 20h.
After reaction terminates, extract, wash, dry.Thick yield is 68.5%, distillation, yield 43.0%, HPLC detection purity 99.4%,
Abundance 99.2%.
B, cold labeling sodium sulfanilate-15N synthesis
In flask add cold labeling aniline-15N, sequentially adds oleum, and aniline-15N and smoke
The mol ratio of sulfuric acid is 1:3, add ethylene glycol, aniline-15The mol ratio of N and ethylene glycol is 1:12.Vacuum tightness is reacted, instead
Temperature control is answered at 120 DEG C, reaction 4h stops reaction.Reactant is stood, the cooling of question response thing adds sodium hydroxide, until being in
Alkalescence, cooling, treats solid crystal, suction filtration.Yield is 86.5%, recrystallization, yield 82.0%.HPLC detects purity 99.2%,
Abundance 99.0%.
C, cold labeling lemon yellow synthesis
Stable isotope is added in flask15The sodium sulfanilate of N marks, sequentially adds natrium nitrosum, hydrochloric acid, right
The mol ratio of Sodium p-aminobenzene sulfonat and natrium nitrosum, hydrochloric acid is 1:1.5:2,40min is reacted at 0 DEG C, in addition, such as above-mentioned method
A diazo liquid is prepared again, and slowly the mol ratio using sodium sulfanilate diazol and diacetyl succinic acid dimethyl ester is 1:1.5,
Diacetyl succinic acid dimethyl ester is added, rise temperature reacts 3h, prepare midbody solution to 110 DEG C.At 0 DEG C, by first part of weight
Nitrogen drop adds midbody solution, reacts 4h, and sodium chloride is added with volume ratio 10%, stands 5h, suction filtration, drying, weighs.Yield
For 66.2%, recrystallization, yield is 55.2%, HPLC detection purity 99.0%, abundance 98.8%.
Claims (6)
1. a kind of synthetic method of the violated pigment of cold labeling, it is characterised in that this method specifically includes following steps：
(1) aminating reaction：By stable isotope D or13The bromobenzene of C flag is mixed with aminating agent or with bromobenzene and stably same position
Element15The aminating agent mixing of N marks, adds amination catalyst, and under the conditions of 30-150 DEG C, reacts 1-20h, that is, is made steady
Determine isotope D or15N or13The aniline of C flag；
(2) sulfonating reaction：By stable isotope D or15N or13The aniline of C flag is added in organic solvent, adds sulfonation examination
Agent, and under the conditions of 30-200 DEG C, reacts 1-24h, that is, be made stable isotope D or15N or13The intermediate of C flag is to amino
Benzene sulfonic acid sodium salt；
(3) diazo-reaction：By stable isotope D or15N or13The intermediate sodium sulfanilate of C flag is added to acid molten
In agent, add nitrite, and under the conditions of 0-15 DEG C, react 0.5-5h, that is, be made containing stable isotope D or15N or13The diazo liquid of C flag sodium sulfanilate diazol；
(4) coupling reaction：Beta naphthal is added into the diazo liquid of step (3), and under the conditions of -30-100 DEG C, reacts 0.5-8h,
I.e. be made stable isotope D or15N or13The violated pigment Acid Orange II of C flag；
Described aminating agent is the one or more in ammoniacal liquor, liquefied ammonia, Sodamide or potassamide, and described amination catalyst is
One or more in ferric trichloride, copper chloride, cupric oxide, iron oxide, ferric sulfate, copper sulphate, described sulfonated reagent is hair
One or more in cigarette sulfuric acid, sulfuric acid or sulfur trioxide, described organic solvent is methanol, ethanol, ether, acetonitrile, acetic acid
One or more in acid anhydride, ethylene glycol, o-dichlorohenzene, described acid flux material is in sulfuric acid, acetic acid, nitric acid, formic acid, hydrochloric acid
It is one or more of.
2. the synthetic method of the violated pigment of a kind of cold labeling according to claim 1, it is characterised in that described
Stable isotope D or15N or13The molecular structural formula of the violated pigment Acid Orange II of C flag is：
Wherein, * represents that carbon atom is at this13C atoms.
3. the synthetic method of the violated pigment of a kind of cold labeling according to claim 1, it is characterised in that described
Bromobenzene and aminating agent mol ratio be 1：1-40, described aniline and the mol ratio of sulfonated reagent are 1：1-6, it is described in
The mol ratio of mesosome sulfanilate and nitrite is 1：Sodium sulfanilate diazonium in 1-6, described diazo liquid
The mol ratio of salt and beta naphthal is 1：1-6.
4. a kind of synthetic method of the violated pigment of cold labeling, it is characterised in that this method specifically includes following steps：
(A) aminating reaction：By stable isotope D or13The bromobenzene of C flag is mixed with aminating agent or with bromobenzene and stably same position
Element15The aminating agent mixing of N marks, adds amination catalyst, and under the conditions of 30-150 DEG C, reacts 1-20h, that is, is made steady
Determine isotope D or15N or13The aniline of C flag；
(B) sulfonating reaction：By stable isotope D or15N or13The aniline of C flag is added in organic solvent, adds sulfonation examination
Agent, and under the conditions of 30-200 DEG C, reacts 1-24h, that is, be made stable isotope D or15N or13The intermediate of C flag is to amino
Benzene sulfonic acid sodium salt；
(C) diazo-reaction：By stable isotope D or15N or13The intermediate sodium sulfanilate of C flag is added to acid molten
In agent, add nitrite, and under the conditions of 0-15 DEG C, react 0.5-5h, that is, be made containing stable isotope D or15N or13The diazo liquid of C flag sodium sulfanilate diazol；
(D) coupling reaction：Diacetyl succinic acid dimethyl ester is added into step (C) diazo liquid, regulation pH value is to 5, in 90-150
Under the conditions of DEG C, 2-4h is reacted, midbody solution is made, then separately takes a step (C) diazo liquid, and is added dropwise to intermediate
In solution, under the conditions of 0 DEG C, react 4-5h, that is, be made stable isotope D or15N or13The violated pigment lemon yellow of C flag；
Described aminating agent is the one or more in ammoniacal liquor, liquefied ammonia, Sodamide or potassamide, and described amination catalyst is
One or more in ferric trichloride, copper chloride, cupric oxide, iron oxide, ferric sulfate, copper sulphate, described sulfonated reagent is hair
One or more in cigarette sulfuric acid, sulfuric acid or sulfur trioxide, described organic solvent is methanol, ethanol, ether, acetonitrile, acetic acid
One or more in acid anhydride, ethylene glycol, o-dichlorohenzene, described acid flux material is in sulfuric acid, acetic acid, nitric acid, formic acid, hydrochloric acid
It is one or more of.
5. the synthetic method of the violated pigment of a kind of cold labeling according to claim 4, it is characterised in that described
Stable isotope D or13C or15The molecular structural formula of violated pigment lemon yellow of N marks is：
Wherein, * represents that carbon atom is 13C atoms at this.
6. the synthetic method of the violated pigment of a kind of cold labeling according to claim 4, it is characterised in that described
Bromobenzene and aminating agent mol ratio be 1：1-40, described aniline and the mol ratio of sulfonated reagent are 1：1-6, it is described in
The mol ratio of mesosome sodium sulfanilate and nitrite is 1：Sodium sulfanilate diazonium in 1-6, described diazo liquid
The mol ratio of salt and diacetyl succinic acid dimethyl ester is 1：1-6.
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