CN107935850A - A kind of synthetic method of the nipagin esters of stable isotope 18O marks - Google Patents

A kind of synthetic method of the nipagin esters of stable isotope 18O marks Download PDF

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CN107935850A
CN107935850A CN201711259562.8A CN201711259562A CN107935850A CN 107935850 A CN107935850 A CN 107935850A CN 201711259562 A CN201711259562 A CN 201711259562A CN 107935850 A CN107935850 A CN 107935850A
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nipalgin
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nipagin esters
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CN107935850B (en
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邱俊
王帅
肖斌
李虎林
姜永悦
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Shanghai Research Institute of Chemical Industry SRICI
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Abstract

The present invention relates to a kind of synthetic method of the nipagin esters of stable isotope 18O marks, stable isotope is utilized18O water is raw material, is utilized18O water difference inventorys, and 4 diazonium sulfuric acid reactant salt of benzoic acid, and respectively obtain intermediate products nipalgin acid through column chromatography silica gel18O or nipalgin acid18O2.Then it is finally separating purifying with hydroxy compounds condensation reaction under conditions of catalyst and organic solvent and obtains target product nipagin esters18O or nipagin esters18O2.Prepared by the present invention18The nipagin esters series of products of O marks, chemical purity are above 98%, and stable isotope abundance is above 95%atom18O, can fully meet the Mass Spectrometer Method internal standard substance for the content detection of parabens preservative in food, cosmetics.

Description

A kind of synthetic method of the nipagin esters of stable isotope 18O marks
Technical field
The invention belongs to stable isotope labelled compound synthesis technical field, more particularly, to a kind of same position of stability Element18The synthetic method of the nipagin esters of O marks.
Background technology
Nipagin esters in 1932 formally go through to be applied in food as mould inhibitor and fungicide, are applied to change later again Cosmetic, medicine and other fields.Wherein in food service industry, parabens is prevented as the broad spectrum activity efficient food generally acknowledged in the world Rotten agent, ratifies to apply in food successively by states such as the U.S., Europe, Japan, Canada, China, Russia, at present main application In fields such as the flavouring such as soy sauce, vinegar, curing food, bakery, jam product, beverage, yellow rice wine and preserving fruit and vegetable utilizings.Chinese food Additive use sanitary standard (GB2760-2007) in also provide ethylparaben, propylben and soluble metyl hydroxybenzoate, Nipagin A sodium, propylben sodium salt can be used as food preservative, and specified volume is between 0.012-0.5g/kg (in terms of P-hydroxybenzoic acid).Provide that parabens preservative exists in cosmetic industry, in China cosmetic hygienic practice The highest limitation of single ester is 0.4% in cosmetics, mixed ester 0.8%.Parabens preservative mechanism of action is mainly The cell membrane of microorganism is destroyed, makes intracellular protein denaturation, and can inhibit the breathing enzyme system and electronics biography of microbial cell Pass the activity of enzyme system.The bacteriostatic activity of nipagin esters is mainly that molecular state works, and the carboxyl of its intramolecular has been esterified, no Ionize again, so it has good fungistatic effect in the range of pH3~8.
The harm of parabens preservative is gradually reported at present, and some researches show that nipalgin is excessively used in cosmetics Esters preservative can cause contact dermatitis.Also studies have reported that nipagin esters can be accumulated in human body, increase women suffers from mammary gland The risk of cancer and uterine cancer, finds the residual for having a large amount of nipagin esters in the pathological section of a large amount of patient with breast cancers.It is more serious Be that pregnant woman can cause neonate's genital malformation using excessive parabens preservative.
Stable isotope dilution mass spectrometry IDMS (Isotope Dilution Mass Spectrometry) is will be known The enriched stable isotopic of quality and abundance is added in sample as internal standard compound and mixed, by measuring corrresponding quality number ionic ratios And compared with typical ratio, so as to determine the content of the material in the sample.Liquid chromatogram and high resolution mass spec combined instrument Have the characteristics that accurate, efficient, sensitive, be widely used in food, cosmetics additive level and detect.Using stablizing same position Element mark nipagin esters series of products, can be more accurately quantitatively to detect parabens antiseptic content in food, cosmetics Standard reagent is provided.
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 stable isotope is former Sub- utilization rate is high, is adapted to the stable isotope of the special synthetic technology of stable isotope labeling18The conjunction of the nipagin esters of O marks Into method.
The purpose of the present invention can be achieved through the following technical solutions：
A kind of stable isotope18The synthetic method of the nipagin esters of O marks, using following steps：
(1) dry organic solvent is added in the reactor, and controlling reaction temperature is -10~10 DEG C, adds benzoic acid -4- Diazonium sulfate, then be slowly added dropwise18O- water, low-temp reaction 2h~12h, then raise reaction temperature to 60~100 DEG C reaction 1h~ 12h, is then stirred at room temperature 4h~24h, and rotary evaporation is concentrated to dryness, and then utilizes the isolated intermediate products Buddhist nun of silica gel column chromatography Pool auric acid-18O or nipalgin acid-18O2；
(2) under conditions of catalyst and organic reaction solvent, nipalgin acid-18O or nipalgin acid-18O2With hydroxy compound Thing condensation reaction, under reflux state, using fraction water device water-dividing, reacts 2~12h, after reaction, evaporated under reduced pressure solvent, and then Frozen water is added, sodium hydroxide solution tune pH to 9~11 is recycled, is then extracted using organic solvent, organic phase anhydrous sodium sulfate It is dry, boil off organic solvent, then using eluent carry out the isolated purified product nipagin esters of silica gel column chromatography-18O or Buddhist nun Pool auric acid-18O2。
Organic solvent described in step (1) is mainly acetone, tetrahydrofuran, 2- methyltetrahydrofurans, 1,4- dioxies six One or more in alkane, 1-methyl-2-pyrrolidinone, dimethyl sulfoxide (DMSO) or N,N-dimethylformamide.Nipalgin is prepared Acid-18Added during O18O- water is 1 with benzoic acid -4- diazonium sulfate molar ratio:10~1:1；Be prepared nipalgin acid-18O2When add18O- water is 3 with benzoic acid -4- diazonium sulfate sulfatase salt molar ratio:1~10:1.
Organic reaction solvent described in step (2) is one in benzene, toluene, hexamethylene, paraxylene or ortho-xylene Kind is several, can not also add organic reaction solvent.The hydroxy compounds for methanol, ethanol, propyl alcohol, isopropanol, butanol, It is a kind of several in isobutanol, amylalcohol, 2-Ethylhexyl Alcohol, enanthol or octanol；When organic solvent is added in preparation, nipalgin acid-18O or nipalgin acid-18O2Molar ratio with hydroxy compounds is 1：1~10：1；If be added without organic solvent, hydroxy compound Thing is as reaction dissolvent；The catalyst for the concentrated sulfuric acid, methanesulfonic acid, NSC 209983, p-methyl benzenesulfonic acid, ferric sulfate hydrate, It is a kind of several in Iron(III) chloride hexahydrate, six trichloride hydrate aluminium, rare earth compound, solid super-strong acid or heteropoly acid.For The organic solvent of extraction is a kind of several in dichloromethane, ethyl acetate, ether, chloroform, toluene or benzene.The eluent To be a kind of several in dichloromethane, ethyl acetate, ether, petroleum ether, hexamethylene or n-hexane.
Preferably, eluent uses petroleum ether and ethyl acetate mixture, both volume ratios are 2:1~15:1.Profit Silica gel column chromatography separation is carried out with mixing elution solution, product purity is high, and impurity is few.
The product nipagin esters-18The synthesis route of O, it is as follows：
The product nipagin esters-18O2Synthesis route, it is as follows：
Compared with prior art, the present invention has the following advantages：
(1) present invention develop with simplest18O mark water is starting radioisotope starting material, is utilized18O water differences feed intake Amount, can introduce 1 or 2 isotopes respectively in product molecule18O atom, obtain nipagin esters-18O and nipagin esters-18O2Two class products, synthetic method is novel, and operating technology handy and safe, possesses the potentiality of large-scale production.
(2) two classes that the present invention develops18The nipagin esters product of O marks, stable isotope atom utilization is high, isotope Dilution is smaller, and abundance is above 95%atom18O；In addition being separated by column chromatography silica gel, product chemical purity is above 98%, It can fully meet the Mass Spectrometer Method internal standard substance for the content detection of parabens preservative in food, cosmetics.
(3) present invention has good economy and use value, has in the detection fields such as food, cosmetics, medicine There is good application prospect.
Embodiment
With reference to specific embodiment, the present invention is described in detail.Following embodiments will be helpful to the technology of this area Personnel further understand the present invention, but the invention is not limited in any way.It should be pointed out that the ordinary skill to this area For personnel, without departing from the inventive concept of the premise, various modifications and improvements can be made.These belong to the present invention Protection domain.
Embodiment 1
A kind of stable isotope18The synthetic method of the methyl hydroxybenzoate of O marks, using following steps：
(1) in 100ml glass there-necked flasks, benzoic acid -4- diazonium sulfate 18.45g (0.075mol), anhydrous four are added Hydrogen furans 50mL, controlling reaction temperature are 0 DEG C, stir lower be added dropwise slowly18O marks water 0.9g (0.05mol), is reacted under low temperature 4h, then oil bath heating to 60 DEG C of reaction 2h, is then stirred at room temperature 4h, direct evaporated under reduced pressure solvent, then silica gel column chromatography separation Obtain 6.3g intermediate products nipalgin acid-18O。
(2) in 100ml glass there-necked flasks, add above-mentioned nipalgin acid-18O and 25mL methanol, in whipping process, delays The slow 4.4g concentrated sulfuric acids that add are used as catalyst, and then oil bath is warming up to reflux, are down to room temperature after reaction 8h, evaporated under reduced pressure solvent, 25mL frozen water is then slowly added into, it is 9 then to add sodium hydroxide solution tune pH, recycles 100mL dichloromethane to extract 3 times, Organic phase anhydrous sodium sulfate is dried, and boils off solvent, then with eluent petroleum ether：Ethyl acetate=8：1, carry out silica gel column chromatography and obtain To purified product methyl hydroxybenzoate-18O 5.8g, overall yield of reaction 75.0%, chemical purity reach 99.2%, and isotope abundance reaches To 98.5atom%18O is correct using infrared spectrum and nmr analysis, its chemical constitution.
Embodiment 2
A kind of stable isotope18The synthetic method of the propylben of O marks, using following steps：
(1) in 100ml glass there-necked flasks, benzoic acid -4- diazonium sulfate 24.6g (0.1mol), anhydrous 2- first are added Base tetrahydrofuran 50mL, controlling reaction temperature are 5 DEG C, stir lower be added dropwise slowly18O mark water 0.9g (0.05mol) are anti-under low temperature 6h is answered, then then to 80 DEG C of reaction 4h 8h, direct evaporated under reduced pressure solvent is stirred at room temperature, then carry out silica gel column layer in oil bath heating Analyse isolated 6.1g intermediate products nipalgin acid-18O。
(2) in 100ml glass there-necked flasks, add above-mentioned nipalgin acid-18O and 25mL propyl alcohol, in whipping process, delays The slow 7.5g p-methyl benzenesulfonic acid that adds is warming up to reflux, is down to room temperature after reacting 6h, evaporated under reduced pressure is molten as catalyst, then oil bath Agent, is then slowly added into 25mL frozen water, and it is 10 then to add sodium hydroxide solution tune pH, recycles 100mL benzene to extract 3 times, has Machine phase anhydrous sodium sulfate is dried, and boils off solvent, then with eluent petroleum ether：Ethyl acetate=6：1, carry out silica gel column chromatography separation Obtain purified product propylben-18O 6.6g, overall yield of reaction 72.6%, chemical purity reach 99.5%, isotope abundance Reach 98.7atom%18O is correct using infrared spectrum and nmr analysis, its chemical constitution.
Embodiment 3
A kind of stable isotope18The synthetic method of the nipalgin monooctyl ester of O marks, using following steps：
(1) in 100ml glass there-necked flasks, addition benzoic acid -4- diazonium sulfate 36.9g (0.15mol), anhydrous Isosorbide-5-Nitrae - Six alkane 50mL of dioxy, controlling reaction temperature are 5 DEG C, stir lower be added dropwise slowly18O marks water 0.9g (0.05mol), is reacted under low temperature 8h, then oil bath heating to 80 DEG C reaction 6h, 6h, direct evaporated under reduced pressure solvent is then stirred at room temperature, then carry out silica gel column chromatography Isolated 6.0g intermediate products nipalgin acid-18O。
(2) in 100ml glass there-necked flasks, add above-mentioned nipalgin acid-18O, add octanol 24.7g (0.21mol) and 25mL toluene, in whipping process, is slowly added to the 4.1g concentrated sulfuric acids as catalyst, then oil bath is warming up to reflux, and utilizes Fraction water device water-dividing, room temperature is down to after reacting 12h, and evaporated under reduced pressure solvent, is then slowly added into 25mL frozen water, and it is molten then to add NaOH Liquid tune pH is 10, recycles 100mL ethyl acetate to extract 3 times, and the drying of organic phase anhydrous sodium sulfate, boils off solvent, then with elution Liquid petroleum ether：Ethyl acetate=8：1, carry out silica gel column chromatography obtain purified product nipalgin monooctyl ester-18O 7.4g, react total and receive Rate 58.5%, chemical purity reach 99.6%, and isotope abundance reaches 98.3atom%18O, utilizes infrared spectrum and nuclear-magnetism point Analysis, its chemical constitution are correct.
Embodiment 4
A kind of stable isotope18The synthetic method of the methyl hydroxybenzoate of O marks, using following steps：
(1) in 100ml glass there-necked flasks, benzoic acid -4- diazonium sulfate 12.3g (0.05mol), anhydrous tetrahydrochysene are added Furans 50mL, controlling reaction temperature are 0 DEG C, stir lower be added dropwise slowly18O marks water 2.7g (0.15mol), reacts 8h under low temperature, Then then to 60 DEG C of reaction 10h 12h, direct evaporated under reduced pressure solvent is stirred at room temperature, then carry out silica gel column chromatography point in oil bath heating From obtain 5.42g intermediate products nipalgin acid-18O2。
(2) in 100ml glass there-necked flasks, add above-mentioned nipalgin acid-18O and 25mL methanol, in whipping process, delays The slow 3.8g concentrated sulfuric acids that add are used as catalyst, and then oil bath is warming up to reflux, are down to room temperature after reaction 6h, evaporated under reduced pressure solvent, 25mL frozen water is then slowly added into, it is 11 then to add sodium hydroxide solution tune pH, recycles 100mL dichloromethane to extract 3 times, Organic phase anhydrous sodium sulfate is dried, and boils off solvent, then with eluent petroleum ether：Ethyl acetate=12：1, carry out silica gel column chromatography Obtain purified product methyl hydroxybenzoate-18O25.08g, overall yield of reaction 66.0%, chemical purity reach 99.0%, and isotope is rich Degree reaches 95.7atom%18O is correct using infrared spectrum and nmr analysis, its chemical constitution.
Embodiment 5
A kind of stable isotope18The synthetic method of the ethylparaben of O marks, using following steps：
(1) in 100ml glass there-necked flasks, benzoic acid -4- diazonium sulfate 12.3g (0.05mol), anhydrous 2- first are added Base tetrahydrofuran 50mL, controlling reaction temperature are -10 DEG C, stir lower be added dropwise slowly18O mark water 3.6g (0.2mol), under low temperature 10h is reacted, then then to 80 DEG C of reaction 8h 16h, direct evaporated under reduced pressure solvent is stirred at room temperature, then carry out silica gel in oil bath heating Column chromatography for separation obtain 5.72g intermediate products nipalgin acid-18O2。
(2) in 100ml glass there-necked flasks, add above-mentioned nipalgin acid-18O and 25mL ethanol, in whipping process, delays The slow 4.0g concentrated sulfuric acids that add are used as catalyst, and then oil bath is warming up to reflux, are down to room temperature after reaction 8h, evaporated under reduced pressure solvent, 25mL frozen water is then slowly added into, it is 10 then to add sodium hydroxide solution tune pH, recycles 100mL ether to extract 3 times, organic Phase anhydrous sodium sulfate is dried, and boils off solvent, then with eluent petroleum ether：Ethyl acetate=6：1, carry out silica gel column chromatography and obtain essence Product ethylparaben processed-18O25.76g, overall yield of reaction 68.5%, chemical purity reach 99.1%, and isotope abundance reaches 96.3atom%18O is correct using infrared spectrum and nmr analysis, its chemical constitution.
Embodiment 6
A kind of stable isotope18The synthetic method of the butyl hydroxybenzoate of O marks, using following steps：
(1) in 100ml glass there-necked flasks, addition benzoic acid -4- diazonium sulfate 12.3g (0.05mol), anhydrous Isosorbide-5-Nitrae - Six alkane 50mL of dioxy, controlling reaction temperature are 10 DEG C, stir lower be added dropwise slowly18O mark water 4.5g (0.25mol) are anti-under low temperature 12h is answered, then then to 100 DEG C of reaction 2h 8h, direct evaporated under reduced pressure solvent is stirred at room temperature, then carry out silicagel column in oil bath heating Chromatography obtain 6.14g intermediate products nipalgin acid-18O2。
(2) in 100ml glass there-necked flasks, add above-mentioned nipalgin acid-18O2, add butanol 16.2g (0.22mol) With 25mL toluene, in whipping process, it is slowly added to 4.2g methanesulfonic acids and is warming up to reflux, and profit as catalyst, then oil bath With fraction water device water-dividing, room temperature is down to after reacting 6h, evaporated under reduced pressure solvent, is then slowly added into 25mL frozen water, then adds NaOH Solution tune pH is 10, recycles 100mL ethyl acetate to extract 3 times, and the drying of organic phase anhydrous sodium sulfate, boils off solvent, then to wash De- liquid petroleum ether：Ethyl acetate=6：1, the isolated purified product butyl hydroxybenzoate of progress silica gel column chromatography-18O25.46g Overall yield of reaction 55.7%, chemical purity reach 99.3%, and isotope abundance reaches 97.1atom%18O, using infrared spectrum and Nmr analysis, its chemical constitution are correct.
Embodiment 7
A kind of stable isotope18The synthetic method of the methyl hydroxybenzoate of O marks, using following steps：
(1) dry organic solvent-acetone is added in the reactor, and controlling reaction temperature is -20 DEG C, adds benzoic acid -4- Diazonium sulfate, then be slowly added dropwise18O- water,18O- water is 1 with benzoic acid -4- diazonium sulfate molar ratio:10, low-temp reaction 4h, then reaction temperature is raised to 60 DEG C of reaction 12h, 6h is then stirred at room temperature, rotary evaporation is concentrated to dryness, and then utilizes silicagel column Chromatography obtain intermediate products nipalgin acid-18O；
(2) under conditions of the catalyst concentrated sulfuric acid and organic reaction solvent benzol, nipalgin acid-18O is in molar ratio with methanol 1：1 carries out condensation reaction, under reflux state, using fraction water device water-dividing, reacts 4h, after reaction, evaporated under reduced pressure solvent, and then Frozen water is added, sodium hydroxide solution tune pH to 9 is recycled, is then extracted using organic solvents, chloroform, organic phase anhydrous sodium sulfate It is dry, organic solvent is boiled off, then with eluent hexamethylene：Ether=10：1, carry out the isolated purified product of silica gel column chromatography Methyl hydroxybenzoate-18O。
Embodiment 8
A kind of stable isotope18The synthetic method of the nipalgin isopropyl ester of O marks, using following steps：
(1) dry organic solvent tetrahydrofuran is added in the reactor, and controlling reaction temperature is -15 DEG C, adds benzene first Acid -4- diazonium sulfate, then be slowly added dropwise18O- water, addition18O- water is 1 with benzoic acid -4- diazonium sulfate molar ratio:1, Low-temp reaction 12h, then reaction temperature is raised to 120 DEG C of reaction 2h, 18h is then stirred at room temperature, rotary evaporation is concentrated to dryness, then Using silica gel column chromatography isolated intermediate products nipalgin acid-18O,
(2) under conditions of catalyst methanesulfonic acid, nipalgin acid-18O is 5 in molar ratio with isopropanol：1 condensation reaction, is returned Under stream mode, using fraction water device water-dividing, 6h is reacted, after reaction, evaporated under reduced pressure solvent, then adds frozen water, recycles hydrogen Sodium hydroxide solution tune pH to 10, is then extracted using organic solvent ethyl acetate, and the drying of organic phase anhydrous sodium sulfate, boils off organic Solvent, then with eluent n-hexane：Ethyl acetate=6：1, carry out the isolated purified product nipalgin isopropyl of silica gel column chromatography Ester-18O。
Embodiment 9
A kind of stable isotope18The synthetic method of the nipalgin -2- ethylhexyls of O marks, using following steps：
(1) dry organic solvent 2- methyltetrahydrofurans are added in the reactor, and controlling reaction temperature is 0 DEG C, is added Benzoic acid -4- diazonium sulfate, then be slowly added dropwise18O- water, addition18O- water and benzoic acid -4- diazonium sulfate sulfatase salt mole Than for 3:1, low-temp reaction 2h, then reaction temperature is raised to 60 DEG C of reaction 12h, 24h is then stirred at room temperature, rotary evaporation is concentrated into It is dry, then using the isolated intermediate products nipalgin acid of silica gel column chromatography-18O2；
(2) under conditions of catalyst NSC 209983 and organic reaction solvent hexamethylene, nipalgin acid-18O2With 2- second Base hexanol is 6 in molar ratio：1 carries out condensation reaction, under reflux state, using fraction water device water-dividing, reacts 6h, after reaction, Evaporated under reduced pressure solvent, then adds frozen water, recycles sodium hydroxide solution tune pH to 10, is then extracted using organic solvents, chloroform Taking, the drying of organic phase anhydrous sodium sulfate, boils off organic solvent, then with eluent hexamethylene：Chloroform=15：1, carry out silica gel column layer Analyse isolated purified product nipalgin -2- ethylhexyls -18O2。
Embodiment 10
A kind of stable isotope18The synthetic method of the nipalgin monooctyl ester of O marks, using following steps：
(1) dry organic solvent dimethyl sulfoxide (DMSO) is added in the reactor, and controlling reaction temperature is 10 DEG C, adds benzene first Acid -4- diazonium sulfate, then be slowly added dropwise18O- water,18O- water is 10 with benzoic acid -4- diazonium sulfate sulfatase salt molar ratio:1, Low-temp reaction 12h, then raise reaction temperature to 100 DEG C reaction 4h, then room 8h is then stirred at room temperature, rotary evaporation is concentrated into It is dry, then using the isolated intermediate products nipalgin acid of silica gel column chromatography-18O2；
(2) under conditions of catalyst Iron(III) chloride hexahydrate and organic reaction solvent paraxylene, nipalgin acid-18O2 It is 8 in molar ratio with octanol：1 carries out condensation reaction, under reflux state, using fraction water device water-dividing, reacts 12h, after reaction, Evaporated under reduced pressure solvent, then adds frozen water, recycles sodium hydroxide solution tune pH to 11, then utilizes organic solvent ethyl acetate Extraction, organic phase anhydrous sodium sulfate drying, boils off organic solvent, then with eluent petroleum ether：Chloroform=15：1, carry out silicagel column Chromatography obtain purified product nipalgin monooctyl ester-18O2。
Embodiment 11
A kind of stable isotope18The synthetic method of the nipalgin monooctyl ester of O marks, using following steps：
(1) dry organic solvent n,N-Dimethylformamide is added in the reactor, and controlling reaction temperature is 15 DEG C, is added Enter benzoic acid -4- diazonium sulfate, then be slowly added dropwise18O- water,18O- water is with benzoic acid -4- diazonium sulfate sulfatase salt molar ratios 1:5, low-temp reaction 10h, then reaction temperature is raised to 80 DEG C of reaction 2h, 4h is then stirred at room temperature, rotary evaporation is concentrated to dryness, so Afterwards using silica gel column chromatography isolated intermediate products nipalgin acid-18O；
(2) under conditions of catalyst solid super acids and organic reaction solvent ortho-xylene, nipalgin acid-18O and octanol It is 5 in molar ratio：1 carries out condensation reaction, under reflux state, using fraction water device water-dividing, reacts 8h, after reaction, decompression is steamed Dry solvent, then adds frozen water, recycles sodium hydroxide solution tune pH to 10, is then extracted using organic solvent ethyl acetate, Organic phase anhydrous sodium sulfate is dried, and boils off organic solvent, then with eluent petroleum ether：Dichloromethane=12：1, carry out silicagel column Chromatography obtain purified product nipalgin monooctyl ester-18O。
Embodiment 12
A kind of stable isotope18The synthetic method of the nipalgin monooctyl ester of O marks, using following steps：
(1) dry organic solvent Isosorbide-5-Nitrae-six alkane of dioxy is added in the reactor, and controlling reaction temperature is 20 DEG C, adds benzene Formic acid -4- diazonium sulfate, then be slowly added dropwise18O- water,18O- water is 8 with benzoic acid -4- diazonium sulfate sulfatase salt molar ratio:1, Low-temp reaction 12h, then reaction temperature is raised to 100 DEG C of reaction 6h, 24h is then stirred at room temperature, rotary evaporation is concentrated to dryness, then Using silica gel column chromatography isolated intermediate products nipalgin acid-18O2；
(2) under conditions of catalyst Iron(III) chloride hexahydrate and organic reaction solvent paraxylene, nipalgin acid-18O2 It is 10 in molar ratio with octanol：1 carries out condensation reaction, under reflux state, using fraction water device water-dividing, reacts 12h, reaction terminates Afterwards, evaporated under reduced pressure solvent, then adds frozen water, recycles sodium hydroxide solution tune pH to 11, then utilizes organic solvent acetic acid Ethyl ester extracts, and the drying of organic phase anhydrous sodium sulfate, boils off organic solvent, then with eluent n-hexane：Dichloromethane=20：1, into The isolated purified product nipalgin monooctyl ester of row silica gel column chromatography-18O2。
The specific embodiment of the present invention is described above.It is to be appreciated that the invention is not limited in above-mentioned Particular implementation, those skilled in the art can make various deformations or amendments within the scope of the claims, this not shadow Ring the substantive content of the present invention.

Claims (10)

1. a kind of synthetic method of the nipagin esters of stable isotope 18O marks, it is characterised in that this method uses following step Suddenly：
(1) dry organic solvent is added in the reactor, and controlling reaction temperature is -20~20 DEG C, adds benzoic acid -4- diazonium Sulfate, then be slowly added dropwise18O- water, low-temp reaction 2h~12h, then raise reaction temperature to 60~100 DEG C reaction 1h~12h, Then 4h~24h is stirred at room temperature, rotary evaporation is concentrated to dryness, and then carries out the isolated intermediate products nipalgin of silica gel column chromatography Acid-18O or nipalgin acid-18O2；
(2) under conditions of catalyst and organic reaction solvent, nipalgin acid-18O or nipalgin acid-18O2Contract with hydroxy compounds Close and react, under reflux state, using fraction water device water-dividing, react 4~12h, after reaction, evaporated under reduced pressure solvent, then adds Frozen water, is adjusted pH to 9~11, is then extracted using organic solvent, and the drying of organic phase anhydrous sodium sulfate, boils off organic solvent, so Afterwards using eluent carry out silica gel column chromatography isolated purified product nipagin esters-18O or nipalgin acid-18O2。
2. a kind of synthetic method of the nipagin esters of stable isotope 18O marks according to claim 1, its feature exist In the organic solvent described in step (1) is mainly acetone, tetrahydrofuran, 2- methyltetrahydrofurans, six alkane of Isosorbide-5-Nitrae-dioxy, N- One or more in methyl pyrrolidone, dimethyl sulfoxide (DMSO) or N,N-dimethylformamide.
3. a kind of synthetic method of the nipagin esters of stable isotope 18O marks according to claim 1, its feature exist In, step (1) be prepared nipalgin acid-18Added during O18O- water is 1 with benzoic acid -4- diazonium sulfate molar ratio:10 ~1:1；Be prepared nipalgin acid-18O2When add18O- water is 3 with benzoic acid -4- diazonium sulfate sulfatase salt molar ratio:1~ 10:1。
4. a kind of synthetic method of the nipagin esters of stable isotope 18O marks according to claim 1, its feature exist In the organic reaction solvent described in step (2) is one kind or several in benzene, toluene, hexamethylene, paraxylene or ortho-xylene Kind.
5. a kind of synthetic method of the nipagin esters of stable isotope 18O marks according to claim 1, its feature exist In step can also be added without organic reaction solvent in (2).
6. a kind of synthetic method of the nipagin esters of stable isotope 18O marks according to claim 1, its feature exist In the hydroxy compounds described in step (2) is methanol, ethanol, propyl alcohol, isopropanol, butanol, isobutanol, amylalcohol, 2- ethyl hexyls It is a kind of several in alcohol, enanthol, octanol；When organic solvent is added in preparation, nipalgin acid-18O or nipalgin acid-18O2With hydroxyl The molar ratio of compound is 1：1~10：1；When being added without organic solvent, the hydroxy compounds is as reaction dissolvent.
7. a kind of synthetic method of the nipagin esters of stable isotope 18O marks according to claim 1, its feature exist In the catalyst described in step (2) is the concentrated sulfuric acid, methanesulfonic acid, NSC 209983, p-methyl benzenesulfonic acid, ferric sulfate hydrate, six water Close a kind of several in ferric trichloride, six trichloride hydrate aluminium, rare earth compound, solid super-strong acid or heteropoly acid.
8. a kind of synthetic method of the nipagin esters of stable isotope 18O marks according to claim 1, its feature exist In the organic solvent for being used to extract in step (2) is one kind in dichloromethane, ethyl acetate, ether, chloroform, toluene or benzene It is several.
9. a kind of synthetic method of the nipagin esters of stable isotope 18O marks according to claim 1, its feature exist In the eluent described in step (2) is one in dichloromethane, ethyl acetate, ether, petroleum ether, hexamethylene or n-hexane Kind is several.
10. a kind of synthetic method of the nipagin esters of stable isotope 18O marks according to claim 1 or 9, it is special Sign is that the preferable eluent described in step (2) uses petroleum ether and ethyl acetate mixture, both volume ratios are 2:1~15:1.
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CN113880704A (en) * 2021-10-18 2022-01-04 西北师范大学 Rapid synthesis18Method for marking aldehyde compound by O
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