CN104016889A - Isotope labeled sodium cyclamate and preparation method thereof - Google Patents
Isotope labeled sodium cyclamate and preparation method thereof Download PDFInfo
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Abstract
The invention discloses isotope labeled sodium cyclamate and a preparation method thereof. The sodium cyclamate is sodium cyclamate labeled by isotopic deuterium. The chemical structural formula is as follows, wherein X is H or D. The preparation method of the sodium cyclamate comprises the following steps: by taking cyclohexanone as a raw material, firstly, carrying out H-D exchange on heavy water and cyclohexanone to obtain tetradeuterated cyclohexanone; then, reducing and ammoniating to obtain tetradeuterated cyclohexylamine or pentadeuterated cyclohexylamine; and then sulfonating and alkalizing to obtain sodium cyclamate. The isotope abundance of the isotope labeled sodium cyclamate reaches over 99% which fully meets the demands of detection reagents. The method is simple in synthetic process and cheap in price of raw material and the synthesized product has the advantages of high product purity, low production cost and the like, and is easy to separate and purify. The isotope labeled sodium cyclamate has good economical efficiency and using value.
Description
Technical field
The present invention relates to a kind of isotope-labeled Sodium Cyclamate and preparation method thereof, belong to chemical analysis technology field.
Background technology
Sodium Cyclamate is a kind of sweeting agent of synthetic, and chemistry is by name: Sugaron or calcium cyclamate.The sweet taste of Sodium Cyclamate is pure, sugariness is sucrose 40～50 times, for without nutritive sweetener.Sodium Cyclamate can be decomposed into the hexahydroaniline that may have chronic toxicity under the effect of intestines bacterium, although used decades in China, its security is under suspicion always.In " national food safety standard foodstuff additive use standard " (GB2760-2011) of issuing in Ministry of Health of the People's Republic of China, the scope of application to people's Sodium Cyclamate and usage quantity have clearly regulation.But, ordered about by interests, Sodium Cyclamate, usually by excess and Use overrun, particularly infant foods, is easy to the absorption a large amount of by child on long-term.Children especially infant's immunity system also do not reach maturity, the detoxification ability of liver a little less than, after taking in, easily cause the harm more serious than adult.
At present, in national standard, be all chromatography about the mensuration of sweeting agent.Import and export industry standard SN/T3538-2013 and specified the detection method of six kinds of synthetic sweeteners in export food, wherein, chromatograph-mass spectrometer coupling technology has highly sensitive, and the advantage such as is quick and precisely more and more concerned in the application in food safety field in recent years.But the method is analyzed sweeting agent, a large problem that need to overcome is the matrix effect of complicated food samples, therefore, often needs comparatively loaded down with trivial details long sample preparation process.For preventing the abuse of Sodium Cyclamate, foodstuff production processing enterprise and government regulator all need one fast and accurately technology detect it.
Summary of the invention
For the existing the problems referred to above of prior art, the object of this invention is to provide a kind of isotope-labeled Sodium Cyclamate and preparation method thereof, with realize to Sodium Cyclamate fast, accurately detect.
For achieving the above object, the present invention adopts following technical scheme:
A kind of isotope-labeled Sodium Cyclamate, is the deuterium-labelled Sodium Cyclamate of isotropic substance, and its chemical structural formula is:
wherein: X is H or D.
Preparing a method for isotope-labeled Sodium Cyclamate of the present invention, is taking pimelinketone as raw material, first uses heavy water (D
2o) carry out H-D exchange with pimelinketone and obtain four deuterated pimelinketone, then obtain four deuterated hexahydroaniline or five deuterated hexahydroaniline through reduction amination, then obtain described isotope-labeled Sodium Cyclamate through oversulfonate, alkalization, its synthetic route is as follows:
wherein: X is H or D.
As a kind of preferred version, method of the present invention comprises following concrete steps:
A) pimelinketone is added in the heavy aqueous solution of deuterium sodium oxide or deuterium potassium oxide, stirring reaction, obtains the mixed solution of four deuterated pimelinketone and heavy water;
B) sodium acetate and azanol or oxammonium hydrochloride are added in the mixed solution that step a) obtains, stirring reaction at 20～100 DEG C, has reacted rear crystallisation by cooling, filters, and obtains four deuterated cyclohexanone-oximes;
C) the four deuterated cyclohexanone-oximes and the reductive agent that step b) are obtained carry out reduction amination, obtain four deuterated hexahydroaniline or five deuterated hexahydroaniline;
D) the four deuterated hexahydroaniline that step c) obtained or five deuterated hexahydroaniline and sulfonated reagent carry out sulfonation reaction, obtain four deuterated cyclohexyl thionamic acids or five deuterated cyclohexyl thionamic acids;
E) by steps d) the four deuterated cyclohexyl thionamic acids that obtain or five deuterated cyclohexyl thionamic acid sodium hydroxide or calcium hydroxide alkalizes, and obtains described isotope-labeled Sodium Cyclamate.
The heavy aqueous solution of the deuterium sodium oxide of step described in a) can be by adding at least one preparation in deuterium sodium oxide, sodium hydroxide, sodium Metal 99.5 to obtain in heavy water; The heavy aqueous solution of described deuterium potassium oxide can be by adding at least one preparation in deuterium potassium oxide, potassium hydroxide, potassium metal to obtain in heavy water; The concentration of described heavy aqueous solution can be 0.001～4.0mol/L.
The mol ratio of the pimelinketone of step described in a) and heavy water is for can be 1:(5～100).
The azanol of step described in b) or the mol ratio of oxammonium hydrochloride and four deuterated pimelinketone can be (1.0～4.0): 1.
The four deuterated cyclohexanone-oximes of step described in c) and the mol ratio of reductive agent can be 1:(0.5～5).
In the time of preparation four deuterated hexahydroaniline, described reductive agent is preferably lithium aluminum hydride, diisobutyl aluminium hydride, borine, sodium borohydride, POTASSIUM BOROHYDRIDE, lithium borohydride or hydrogen; In the time of preparation five deuterated hexahydroaniline, described reductive agent is preferably deuterate aluminium lithium, deuterated borine, boron deuterate sodium, boron deuterate potassium, boron lithium deuteride LiD or deuterium gas.
Described sulfonated reagent is preferably chlorsulfonic acid, thionamic acid, thionamic acid sodium or sulphur trioxide.
Adopt sample preparation step when summarized chromatogram-mass spectroscopy to a great extent of mark in stable isotope, can improve speed and the sensitivity of food analysis, matrix be can offset well and the error that detects the response signal variation of thing and cause, the error that while eliminating sample pre-treatments, the rate of recovery causes caused.The successful exploitation of cold labeling Sodium Cyclamate, will greatly simplify the testing process of Sodium Cyclamate, for food analysis provides a kind of easy, accurate, reliable analysis and detection technology, thereby is effectively the foodstuff additive detection service in China's food safety field.
It is starting raw material that the present invention adopts pimelinketone cheap and easy to get and heavy water, through the deuterated four deuterated pimelinketone that obtain, restore ammonification and obtain four deuterated hexahydroaniline or five deuterated hexahydroaniline, after oversulfonate, alkalization, obtain four deuterated or five deuterated Sodium Cyclamates again, isotopic abundance reaches more than 99%, meets detection reagent requirement completely.Described method has that building-up process is simple, raw material is cheap, the easily separated purification of synthetic product and product purity high (can reach more than 98%), and the advantage such as production cost is low, has good economy and use value.
Brief description of the drawings
Fig. 1 for embodiment 4 obtain 2,2,6, the mass spectrum of 6-tetra-deuterated Sodium Cyclamates;
Fig. 2 for embodiment 4 obtain 2,2,6,6-tetra-deuterated Sodium Cyclamates
1hNMR spectrogram.
Embodiment
Below in conjunction with specific embodiment, further set forth the present invention.Should be understood that these embodiment are only not used in and limit the scope of the invention for the present invention is described.
Embodiment 1
In the eggplant-shape bottle of 50mL, add 20mL heavy water, 100mg sodium Metal 99.5, after dissolving, add again 4mL pimelinketone, load onto reflux condensing tube, after 90 DEG C of stirring reactions make to carry out H-D permutoid reaction for 3 hours, be cooling, separate organic phase, obtain the deuterated pimelinketone in ortho position; Deuterated the ortho position obtaining pimelinketone is carried out to H-D permutoid reaction again twice, finally obtain the mixed solution of four deuterated pimelinketone and heavy water; In the mixed solution of the four deuterated pimelinketone that obtain and heavy water, add 6g oxammonium hydrochloride, 9g sodium acetate, in 70 DEG C of stirring reactions 10 minutes, cooling, separate out the deuterated cyclohexanone-oxime 3.5g of 2,2,6,6-tetra-, molar yield is 76%.
By 3g2,2,6, the deuterated cyclohexanone-oxime of 6-tetra-is dissolved in 100mL ether, adds 5g lithium aluminum hydride, back flow reaction 30 minutes, after cooling, add saturated metabisulfite solution, make unreacted lithium aluminum hydride just till quencher, filter, filter cake washs with ether, and filtrate anhydrous sodium sulfate drying is concentrated, obtain 2,2,6, the deuterated hexahydroaniline 2.2g of 6-tetra-, molar yield is 81%.
Embodiment 2
In the eggplant-shape bottle of 50mL, add 20mL heavy water, 180mg potassium metal, after dissolving, add again 4mL pimelinketone, load onto reflux condensing tube, after 90 DEG C of stirring reactions make to carry out H-D permutoid reaction for 3 hours, be cooling, separate organic phase and obtain the deuterated pimelinketone in ortho position.Deuterated the ortho position obtaining pimelinketone is carried out to H-D permutoid reaction again twice, finally obtain the mixed solution of four deuterated pimelinketone and heavy water; In the mixed solution of the four deuterated pimelinketone that obtain and heavy water, add 6g oxammonium hydrochloride, 9g sodium acetate, in 70 DEG C of stirring reactions 10 minutes, cooling, separate out the deuterated cyclohexanone-oxime 3.4g of 2,2,6,6-tetra-, molar yield is 73%.
By 3g2,2,6, the deuterated cyclohexanone-oxime of 6-tetra-is dissolved in 100mL ether, adds 5g lithium aluminum hydride, back flow reaction 30 minutes, after cooling, add saturated metabisulfite solution, make unreacted lithium aluminum hydride just till quencher, filter, filter cake washs with ether, and filtrate anhydrous sodium sulfate drying is concentrated, obtain 2,2,6, the deuterated hexahydroaniline 2.3g of 6-tetra-, molar yield is 85%.
Embodiment 3
By 3g2,2,6, the deuterated cyclohexanone-oxime of 6-tetra-is dissolved in 80mL ether, adds 3g deuterate aluminium lithium, back flow reaction 30 minutes, after cooling, add saturated metabisulfite solution, make unreacted deuterate aluminium lithium just till quencher, filter, filter cake washs with ether, and filtrate anhydrous sodium sulfate drying is concentrated, obtain 1,2,2, the deuterated hexahydroaniline 2.3g of 6,6-five, molar yield is 83%.
Embodiment 4
In the eggplant-shape bottle of 25mL, add 1g thionamic acid, 2g2,2,6, the deuterated hexahydroaniline of 6-tetra-, 4mL orthodichlorobenzene, in 200 DEG C of reacting by heating 4 hours, add sodium hydroxide solution and the 10mL sherwood oil of 10mL10% after cooling, divide and go organic phase, water to be concentrated to 2mL left and right, be placed in frozen water crystallisation by cooling, filter, obtain 2,2,6, the deuterated Sodium Cyclamate 1.9g of 6-tetra-, molar yield is 92%.
LC-MS detects and adopts ESI negative ion mode, its result as shown in Figure 1, purity > 98%; Mass spectrometric detection, abundance>=99atom%D; Its
1hNMR (400MHz, DMSO) detects as shown in Figure 2, δ 3.79 (d, J=5.8Hz, 1H), 2.84 (d, J=5.6Hz, 1H), 1.59 (m, 2H), 1.48 (m, 1H), 1.12 (m, 3H).
Embodiment 5
In the eggplant-shape bottle of 25mL, add 1g thionamic acid, 2g1,2,2, the deuterated hexahydroaniline of 6,6-five, 4mL orthodichlorobenzene, in 200 DEG C of reacting by heating 4 hours, after cooling, add sodium hydroxide solution and the 10mL sherwood oil of 10mL10wt%, divide and go organic phase, water to be concentrated to 2mL left and right, be placed in frozen water crystallisation by cooling, filter, obtain 1,2,2,6, the deuterated Sodium Cyclamate 2.0g of 6-five, molar yield is 94%.
LC-MS detects, purity > 98%; Mass spectrometric detection, abundance >=99atom%D.
Embodiment 6
In the eggplant-shape bottle of 25mL, add 1g thionamic acid, 2g2,2,6, the deuterated hexahydroaniline of 6-tetra-, 4mL orthodichlorobenzene, in 200 DEG C of reacting by heating 4 hours, add 1g calcium hydroxide, 10mL water and 10mL sherwood oil after cooling, the unreacted calcium hydroxide of elimination, point goes organic phase, water to be concentrated to 2mL left and right and is placed in frozen water crystallisation by cooling, filter, obtain 2,2,6, the deuterated Cyclan 1.8g of 6-tetra-, molar yield is 88%.
LC-MS detects, purity > 98%; Mass spectrometric detection, abundance >=99atom%D.
Embodiment 7
In the eggplant-shape bottle of 25mL, add 1g thionamic acid, 2g1,2,2, the deuterated hexahydroaniline of 6,6-five, 4mL orthodichlorobenzene, in 200 DEG C of reacting by heating 4 hours, after cooling, add 1g calcium hydroxide, 10mL water and 10mL sherwood oil, the unreacted calcium hydroxide of elimination, divides and goes organic phase, water is concentrated to 2mL left and right, is placed in frozen water crystallisation by cooling, filters, obtain 1,2,2, the deuterated Cyclan 1.9g of 6,6-five, molar yield is 90%.
LC-MS detects, purity > 98%; Mass spectrometric detection, abundance >=99atom%D.
Embodiment 8
In the eggplant-shape bottle of 50mL, add 2g2,2,6, the deuterated hexahydroaniline of 6-tetra-, 10mL tetracol phenixin, slowly drip the chlorsulfonic acid of 0.53mL stirring reaction 2 hours under condition of ice bath, add sodium hydroxide solution and the 10mL sherwood oil of 10mL10wt% after cooling, divide and go organic phase, water is concentrated to 2mL left and right and is placed in frozen water crystallisation by cooling, filters, and obtains 2,2, the deuterated Sodium Cyclamate 1.8g of 6,6-tetra-, molar yield is 90%.
LC-MS detects, purity > 98%; Mass spectrometric detection, abundance >=99atom%D.
Embodiment 9
In the eggplant-shape bottle of 50mL, add 2g2,2,6, the deuterated hexahydroaniline of 6-tetra-, 10mL tetracol phenixin, slowly drip the chlorsulfonic acid of 0.53mL stirring reaction 2 hours under condition of ice bath, add 1g calcium hydroxide, 10mL water and 10mL sherwood oil after cooling, divide and go organic phase, water is concentrated to 2mL left and right and is placed in frozen water crystallisation by cooling, filters, and obtains 2,2, the deuterated Cyclan 1.7g of 6,6-tetra-, molar yield is 87%.
LC-MS detects, purity > 98%; Mass spectrometric detection, abundance >=99atom%D.
Embodiment 10
In the eggplant-shape bottle of 50mL, add 2g1,2,2, the deuterated hexahydroaniline of 6,6-tetra-, 10mL tetracol phenixin, slowly drip the chlorsulfonic acid of 0.53mL stirring reaction 2 hours under condition of ice bath, after cooling, add sodium hydroxide solution and the 10mL sherwood oil of 10mL10wt%, point go organic phase, water to be concentrated to 2mL left and right and be placed in frozen water crystallisation by cooling, filter, obtain 1,2,2, the deuterated Sodium Cyclamate 1.8g of 6,6-five, molar yield is 90%.
LC-MS detects, purity > 98%; Mass spectrometric detection, abundance >=99atom%D.
Embodiment 11
In the eggplant-shape bottle of 50mL, add 2g1,2,2, the deuterated hexahydroaniline of 6,6-five, 10mL tetracol phenixin, slowly drip the chlorsulfonic acid of 0.53mL stirring reaction 2 hours under condition of ice bath, after cooling, add 1g calcium hydroxide, 10mL water and 10mL sherwood oil, point go organic phase, water to be concentrated to 2mL left and right and be placed in frozen water crystallisation by cooling, filter, obtain 1,2,2, the deuterated Cyclan 1.7g of 6,6-five, molar yield is 87%.
LC-MS detects, purity > 98%; Mass spectrometric detection, abundance >=99atom%D.
Finally be necessary described herein: above embodiment is only for being described in more detail technical scheme of the present invention; can not be interpreted as limiting the scope of the invention, some nonessential improvement that those skilled in the art's foregoing according to the present invention is made and adjustment all belong to protection scope of the present invention.
Claims (10)
1. an isotope-labeled Sodium Cyclamate, is characterized in that, is the deuterium-labelled Sodium Cyclamate of isotropic substance, and its chemical structural formula is:
wherein: X is H or D.
2. prepare the method for isotope-labeled Sodium Cyclamate claimed in claim 1 for one kind, it is characterized in that, taking pimelinketone as raw material, first use heavy water and pimelinketone to carry out H-D exchange and obtain four deuterated pimelinketone, then obtain four deuterated hexahydroaniline or five deuterated hexahydroaniline through reduction amination, obtain described isotope-labeled Sodium Cyclamate through oversulfonate, alkalization again, its synthetic route is as follows:
wherein: X is H or D.
3. method as claimed in claim 2, is characterized in that, described method comprises following concrete steps:
A) pimelinketone is added in the heavy aqueous solution of deuterium sodium oxide or deuterium potassium oxide, stirring reaction, obtains the mixed solution of four deuterated pimelinketone and heavy water;
B) sodium acetate and azanol or oxammonium hydrochloride are added in the mixed solution that step a) obtains, stirring reaction at 20～100 DEG C, has reacted rear crystallisation by cooling, filters, and obtains four deuterated cyclohexanone-oximes;
C) the four deuterated cyclohexanone-oximes and the reductive agent that step b) are obtained carry out reduction amination, obtain four deuterated hexahydroaniline or five deuterated hexahydroaniline;
D) the four deuterated hexahydroaniline that step c) obtained or five deuterated hexahydroaniline and sulfonated reagent carry out sulfonation reaction, obtain four deuterated cyclohexyl thionamic acids or five deuterated cyclohexyl thionamic acids;
E) by steps d) the four deuterated cyclohexyl thionamic acids that obtain or five deuterated cyclohexyl thionamic acid sodium hydroxide or calcium hydroxide alkalizes, and obtains described isotope-labeled Sodium Cyclamate.
4. method as claimed in claim 3, is characterized in that: the concentration of the heavy aqueous solution of the deuterium sodium oxide of step described in a) or deuterium potassium oxide is 0.001～4.0mol/L.
5. method as claimed in claim 3, is characterized in that: the mol ratio of the pimelinketone of step described in a) and heavy water is for being 1:(5～100).
6. method as claimed in claim 3, is characterized in that: the azanol of step described in b) or the mol ratio of oxammonium hydrochloride and four deuterated pimelinketone are (1.0～4.0): 1.
7. method as claimed in claim 3, is characterized in that: the four deuterated cyclohexanone-oximes of step described in c) and the mol ratio of reductive agent are 1:(0.5～5).
8. method as claimed in claim 3, is characterized in that: in the time of preparation four deuterated hexahydroaniline, described reductive agent is selected lithium aluminum hydride, diisobutyl aluminium hydride, borine, sodium borohydride, POTASSIUM BOROHYDRIDE, lithium borohydride or hydrogen.
9. method as claimed in claim 3, is characterized in that: in the time of preparation five deuterated hexahydroaniline, described reductive agent is selected deuterate aluminium lithium, deuterated borine, boron deuterate sodium, boron deuterate potassium, boron lithium deuteride LiD or deuterium gas.
10. method as claimed in claim 3, is characterized in that: described sulfonated reagent is selected chlorsulfonic acid, thionamic acid, thionamic acid sodium or sulphur trioxide.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN106083661A (en) * | 2016-06-06 | 2016-11-09 | 江苏联威生化实业有限公司 | A kind of preparation method of calcium cyclamate |
| CN114773174A (en) * | 2022-04-29 | 2022-07-22 | 常州大学 | Synthetic method of alpha-deuterated carbonyl compound |
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106083661A (en) * | 2016-06-06 | 2016-11-09 | 江苏联威生化实业有限公司 | A kind of preparation method of calcium cyclamate |
| CN114773174A (en) * | 2022-04-29 | 2022-07-22 | 常州大学 | Synthetic method of alpha-deuterated carbonyl compound |
| CN114773174B (en) * | 2022-04-29 | 2024-05-28 | 常州大学 | Synthesis method of alpha-deuterated carbonyl compound |
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