CN107434797B - A kind of synthetic method of deuterium-labeled zearalenone and its derivative - Google Patents
A kind of synthetic method of deuterium-labeled zearalenone and its derivative Download PDFInfo
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Abstract
The present invention relates to the synthetic methods of a kind of deuterium-labeled zearalenone and its derivative, inventor is found surprisingly that, the reactant prepared using ad hoc approach, which carries out hydrogen deuterium exchange, can synthesize the deuterium-labeled compound in formula (1)~(4) of four deuteriums substitution, synthetic method is simple, reaction condition is mild, high conversion efficiency, and the purity of product is higher, and isotope abundance is high.
Description
Technical field
The present invention relates to the synthetic methods and the deuterium-labeled jade of a kind of deuterium-labeled zearalenone and its derivative
The application of Zearlenone and its derivative as internal standard compound in the Mass Spectrometry detection method of zearalenone and its derivative,
Belong to chemical technology field.
Background technique
Zearalenone (zearalenone, ZEN) is also known as F2 toxin, is that the one kind generated by Gibberella zeae bacterium has
The secondary fungus metabolite of estrogenic effect, entitled 6- (- ten one-carbene base of -6 oxygroup of the 10- hydroxyl) β of chemistry-thunder lock
Acid lactone is primarily present in corn and corn product, also there is a degree of distribution in wheat, sorghum and rice.
Zearalenone and its derivative (such as zearalenol, zearalanol, zearelone etc.), tool
There is the bioactivity of very strong female hormone substance, there is certain genotoxicity and teratogenesis to mammal, such as
Intake can lead to the animals such as poultry, especially pig, cattle and sheep by the feed that zearalenone and its derivative pollute and generate estrogen
Excessive disease, reproductive capability are abnormal or even dead, bring biggish loss to animal husbandry.
The food-borne harm of zearalenone and its derivative receives more and more attention.2002, Chinese agriculture
In all food animals, all edible animals must not detect the bulletin clear stipulaties zearalanol disabling of portion the 193rd；2010
Clearly zearalanol is arranged in " the non-edible material from soybeans list (the 4th batch) of possible illegal addition in food " of Ministry of Public Health's publication
Enter non-edible material from soybeans.
To prevent zearalenone and its derivative from entering food chain, Governmental monitoring department need one kind can quickly,
Accurate and very sensitive technology detects them.
Detecting zearalenone and its common method of derivative now has: enzyme linked immunosorbent assay (ELISA), thin layer
Chromatography, immune affinity column-HPLC method, mass-spectrometric technique etc..However, due to residues of veterinary drug such as zearalenone and its derivatives
That there is test substance concentration in analytic process is low, sample substrate is complicated, interfering substance is more, metabolite is various or indefinite etc.
Problem, detection positive findings must carry out qualitative and quantitative analysis by specific verification method, and these inspection methods
In, only Mass Spectrometer Method can provide qualitative and quantitative information simultaneously.Therefore, developed country is for the beast in animal derived food
Medicine residue detection is required to test using isotope dilution mass spectrometry, the error that can effectively occur in bearing calibration, significantly
Improve the accuracy of detection method.
Stable isotope dilution mass spectrometry IDMS (Isotope Dilution Mass Spectrometry) be using with
Measured matter has the compound of the stable isotope labeling of identical molecular structure as internal standard substance, uses liquid chromatography-mass spectrography
Combined instrument (LC/MS) is detected, and measures the ratio of the ion of corrresponding quality number by mass spectrograph and compared with the ratio of standard
Achieve the purpose that accurate quantitative analysis.This method is acknowledged as a kind of measuring micro and trace organic substance pedestal method.
Therefore, the internal standard compound using the zearalenone and its derivative of which kind of isotope labelling as Mass Spectrometer Method
Matter, and the zearalenone and its derivative of the isotope labelling how are synthesized, to China relevant food security fields
Supervision detection work is of great significance.
Summary of the invention
In view of the above problem and/or other problems of the relevant technologies, the present invention provides a kind of deuterium-labeled Gibberella zeae alkene
The synthetic method of ketone and its derivative, the deuterium-labeled zearalenone and its derivative are selected from the deuterium-labeled corn of formula (1)
Zeranol, the deuterium-labeled zearelone of formula (2), the deuterium-labeled zearalenol of formula (3) and formula (4) deuterium-labeled corn
One of red mould alcohol,
The synthetic method includes using the process of the deuterium-labeled compound of following formula (b) compound synthesis formula (a),
In formula (a) and formula (b) structural formula, C1And C2Dotted line between two carbon atoms indicates between two carbon atoms
Chemical bond is singly-bound either double bond；
The process using formula (b) compound synthesis formula (a) compound is the following steps are included: 1) by alkali metal, alkali gold
One of or several in the deuteride of the deuteride of category, alkaline-earth metal or alkaline-earth metal is dissolved in deuterium-labeled alkylol
Prepare reactant；The deuterium-labeled alkylol has the structural formula of R-OD, and wherein R is the full deuterium substitution of C1-C5, part
The alkyl that deuterium replaces or do not replaced by deuterium；2) following formula (b) compound is placed in the reactant of step (1) acquisition and carries out hydrogen-deuterium
Displacement reaction obtains the deuterium-labeled compound with formula (a)；The step 1) and step 2) are protected in atmosphere of inert gases
Lower progress.
Preferably, the alkali metal is sodium or potassium.
Preferably, the alkaline-earth metal is magnesium or calcium.
Preferably, in the structural formula of the deuterium-labeled alkylol, R is the methyl or ethyl that full deuterium replaces.
Preferably, the step 2) carries out under conditions of temperature is 20 DEG C -80 DEG C.
Preferably, alkali metal and/alkaline-earth metal member in the step 2), in formula (b) compound and the reactant
The molar ratio of element is 1:2~1:10.
Preferably, the synthetic method further includes the purification step of the deuterium-labeled compound of the formula (a) after step 2),
Then plus water and by gained the purification step includes the pH value of step 2) acquired solution being adjusted to after 1-5 to be spin-dried for first,
Solution is adjusted to alkalinity, then the process using organic solvent extraction.
Preferably, the organic solvent is methylene chloride.
Preferably, the inert gas is nitrogen.
Preferably, the C in formula (b) compound1And C2Chemical bond between two carbon atoms is double bond, by described
The deuterium-labeled zearalenone of step 1) and step 2) production (1)；
The formula is obtained as the deuterium-labeled zearalenone of go back original reagent reduction-type (1) using sodium borohydride and methanol
(3) deuterium-labeled zearalenol, reaction temperature are 0 DEG C -30 DEG C；Alternatively,
It is obtained using aluminium isopropoxide and isopropanol as the deuterium-labeled zearalenone of go back original reagent reduction-type (1)
The deuterium-labeled zearalenol of the formula (3), reaction temperature are 55 DEG C -95 DEG C；
Under organic solvent environment, hydrogen as catalyst and is passed through come the deuterium of reduction-type (1) using Raney's nickel or Pd/C
Zearalenone is marked to obtain the deuterium-labeled zearalanol of the formula (4)；Alternatively,
Under organic solvent environment, using platinum oxide and hydrogen is passed through come the deuterium-labeled zearalenone of reduction-type (1)
The deuterium-labeled zearelone of the formula (2) is obtained, reaction temperature is 30 DEG C -60 DEG C.
The synthetic method of deuterium-labeled zearalenone and its derivative of the invention, inventor are found surprisingly that, use
The reactant that ad hoc approach is prepared, which carries out hydrogen deuterium exchange, can synthesize the deuterium-labeled compound in formula (1)~(4) of four deuteriums substitution, close
Simple at method, reaction condition is mild, high conversion efficiency, and the purity of product is higher, and isotope abundance is high.
Specific embodiment
The present invention is further illustrated by the following examples, but the present invention is not limited to these specific embodiment parties
Formula.
In one embodiment of the invention, the synthesis side of a kind of deuterium-labeled zearalenone and its derivative
Method, the deuterium-labeled zearalenone and its derivative are selected from the deuterium mark of the deuterium-labeled zearalenone of formula (1), formula (2)
Remember one of zearelone, the deuterium-labeled zearalenol of formula (3) and deuterium-labeled zearalanol of formula (4),
The synthetic method includes using the process of the deuterium-labeled compound of following formula (b) compound synthesis formula (a),
In formula (a) and formula (b) structural formula, C1And C2Dotted line between two carbon atoms indicates between two carbon atoms
Chemical bond is singly-bound either double bond；
Specifically, work as C1And C2When being double bond between two carbon atoms, formula (a) compound is the deuterium-labeled jade of formula (1)
Zearlenone；Work as C1And C2When being singly-bound between two carbon atoms, formula (a) compound is the deuterium-labeled Gibberella zeae of formula (2)
Ketone.
Using formula (b) compound synthesis formula (a) compound process the following steps are included:
It 1) will be one of or several in the deuteride of alkali metal, the deuteride of alkali metal, alkaline-earth metal or alkaline-earth metal
Kind, which is dissolved in deuterium-labeled alkylol, prepares reactant；
The deuterium-labeled alkylol has the structural formula of R-OD, and the full deuterium that wherein R is C1-C5 replaces, part deuterium replaces
Or the alkyl not replaced by deuterium；
2) following formula (b) compound is placed in the reactant of step (1) acquisition and carries out hydrogen-deuterium exchange reaction acquisition tool
There is the deuterium-labeled compound of formula (a)；
The step 1) and step 2) carry out under atmosphere of inert gases protection.
In one embodiment of the invention, alkali metal can for sodium (Na), potassium (K), lithium (Li), rubidium (Rb) or
Caesium (Cs), preferably Na.
In one embodiment of the invention, the deuteride of alkali metal can be NaD, KD or LiD etc., preferably
NaD。
In one embodiment of the invention, alkaline-earth metal can be magnesium (Mg), beryllium (Be), calcium (Ca), strontium
(Sr) or barium (Ba), preferably Mg.
In one embodiment of the invention, the deuteride of alkaline-earth metal can be MgD2、BeD2、CaD2Deng excellent
Select MgD2。
In one embodiment of the invention, in the structural formula of R-OD possessed by deuterium-labeled alkylol, R is
The alkyl of C1-C5, it is preferable that methyl or ethyl.It is further preferred that methyl or ethyl that full deuterium replaces.
In one embodiment of the invention, hydrogen-deuterium exchange reaction of step 2) is 20 DEG C -80 DEG C in temperature
Under the conditions of carry out, can be 40 DEG C, 50 DEG C, 60 DEG C, 70 DEG C etc., preferably 50 DEG C.
Alkali in one embodiment of the invention, in the step 2), in formula (b) compound and reactant
The molar ratio of metal and/alkali earth metal is 1:2~1:10.The molar ratio can be 1:3,1:4,1:5, and preferably 1:3 is left
It is right.
In one embodiment of the invention, atmosphere of inert gases is nitrogen atmosphere.
In one embodiment of the invention, the synthetic method further includes the formula (a) after step 2)
The purification step of deuterium-labeled compound, the purification step include first by the pH value of step 2) acquired solution be adjusted to 1-5 it
After be spin-dried for, then plus water and acquired solution is adjusted to alkalinity, then using the process of organic solvent extraction.At of the invention one
In specific embodiment, the pH value of step 2) acquired solution is adjusted to 3 or so using the ethanol solution of hydrochloric acid, it is molten to be spin-dried for ethyl alcohol
Agent is added after water and adjusts solution to alkalinity with ammonium hydroxide, then repeatedly extracted using methylene chloride, is merged organic obtained by extraction
Phase dries, filters back spin dry dichloromethane solvent with anhydrous sodium sulfate, obtains after recrystallization after saturated common salt water washing
Obtain the deuterium-labeled compound of formula (a) after purification.
In one embodiment of the invention, using sodium borohydride and methanol as go back original reagent reduction-type (1)
Deuterium-labeled zearalenone obtain the deuterium-labeled zearalenol of the formula (3), reaction temperature is 0 DEG C -30 DEG C.It is preferred that
, NaOH there are in the environment of carry out reduction reaction.Preferably, reaction temperature is 0 DEG C -10 DEG C.
In one embodiment of the invention, restored using aluminium isopropoxide and isopropanol as go back original reagent
The deuterium-labeled zearalenone of formula (1) obtains the deuterium-labeled zearalenol of the formula (3), and reaction temperature is 55 DEG C -95
℃.Preferably, reaction temperature is about 75 DEG C.
In one embodiment of the invention, hydrogen as catalyst and is passed through come also using Raney's nickel or Pd/C
The deuterium-labeled zearalenone of former formula (1) obtains the deuterium-labeled zearalanol of the formula (4).Preferably, using Raney's nickel
As catalyst, reaction temperature is about 70 DEG C.Preferably, using Pd/C as catalyst, reaction temperature is about 20 DEG C.
In one embodiment of the invention, using platinum oxide and hydrogen is passed through come the deuterium-labeled of reduction-type (1)
Zearalenone obtains the deuterium-labeled zearelone of the formula (2), and reaction temperature is 30 DEG C -60 DEG C.Preferably, reaction temperature
About 0 DEG C of degree.
Embodiment 1
The synthetic method of the deuterium-labeled zearalenone of formula (1)
Step 1): in the round-bottomed flask of nitrogen atmosphere protection, CD is added3OD (100mL), sodium (1.6g, 70mmol), are stirred
It mixes to sodium and obtains reactant after being completely dissolved；Step 2): being added zearalenone (7.3g, 23mmol) in reactant, and 50
DEG C reaction 3 hours.
Purification process after the reaction was completed: will step 2) products therefrom it is cooling after be added ethanol solution hydrochloride adjust pH value to
3, it is spin-dried for solvent.It is added after 50mL water and is adjusted to alkalinity with ammonium hydroxide, methylene chloride extracts three times.Combined organic phase is eaten through saturation
It is dry with anhydrous sodium sulfate after salt water washing.Solvent is spin-dried for after filtering, recrystallize formula (1) deuterium-labeled zearalenone
5.6g, yield 75%, purity 99.8% (HPLC), isotope abundance 99.5% (atom%, HRMS).
1H NMR(300MHz,CDCl3) δ 7.01 (1H, d, J=15.5Hz), 6.44 (1H, s), 6.40 (1H, s), 5.88
(1H,m),5.01(1H,m),2.31(2H,m),2.10(2H,m),1.81(2H,m),1.67(2H,m),1.36(3H,d)。
Embodiment 2
The synthetic method of the deuterium-labeled zearelone of formula (2)
Reaction condition and purification process are specifically repeated no more with embodiment 1.
Embodiment 3
The synthetic method of the deuterium-labeled zearelone of formula (2)
Using (1) compound of formula made from embodiment 1 come preparation formula (2) compound；
Platinum oxide (500mg), ethyl alcohol (20mL) are added in round-bottomed flask, liquid nitrogen frozen deaerates, and formula (1) is added at 0 DEG C
Deuterium-labeled zearalenone (515mg, 1.6mmol) ethanol solution (10mL), lead to hydrogen (0.1MPa) react 3 hours.
Solvent is spin-dried for after filtering, silica gel column purification after ethyl acetate dissolution obtains the deuterium-labeled zearelone of formula (2)
192mg, yield 37%, purity 99.7% (HPLC), isotope abundance 99.2% (atom%, HRMS).
1H NMR(300MHz,acetone-d6)δ6.70(1H,s),6.12(1H,s),5.17(1H,m),3.58(2H,d),
2.42(2H,m),2.10(2H,m),1.86(2H,m),1.66(2H,m),1.52(2H,m),1.34(3H,d)。
Embodiment 4
The synthetic method of the deuterium-labeled zearalenol of formula (3)
Using (1) compound of formula made from embodiment 1 come preparation formula (3) compound；
Sodium hydroxide (60mg, 1.5mmol) and methanol 10mL are added in 100mL flask, under ice-water bath is cooling, stirring adds
Enter the methanol solution (5mL) of sodium borohydride (130mg, 3.3mmol) and deuterium-labeled zearalenone (515mg, 1.6mmol).
Slowly restore to room temperature, sodium borohydride (210mg, 5.5mmol) is added after reacting 6h, reaction to raw material disappears.
25mL water quenching reaction is added after boiling off part methanol, ethyl acetate extracts three times.After combined organic phase washing
It is dry with anhydrous sodium sulfate.Solvent is removed after filtering, obtains deuterium-labeled zearalenol 451mg, yield 87%, purity 99.1%
(HPLC), isotope abundance 98.9% (atom%, HRMS).
1H NMR(300MHz,CDCl3) δ 7.17 (1H, d, J=15.5Hz), 6.56 (1H, s), 6.21 (1H, s), 5.89
(1H,m),5.08(1H,m),3.85(2H,m),1.95(1H,m),1.85(2H,m),1.73(2H,m),1.51(2H,m),1.34
(3H,d)。
In an alternative solution of embodiment 4, can be replaced using aluminium isopropoxide and isopropanol sodium borohydride and
Methanol becomes 75 DEG C from 20 DEG C as go back original reagent, reaction temperature, and other conditions are the same as embodiment 4.
Embodiment 5
The synthetic method of the deuterium-labeled zearalanol of formula (4)
Using (1) compound of formula made from embodiment 1 come preparation formula (4) compound；
By deuterium-labeled zearalenone (5.8g, 18mmol), dehydrated alcohol 174mL, catalyst RaneyNi (1g) investment
In stainless steel autoclave, it is passed through H2(0.4MPa).After stirring 6h at 70 DEG C, reaction solution Filtration of catalyst boils off second
Be evaporated under reduced pressure, decolourize after alcohol, recrystallizing formula (4) deuterium-labeled zearalanol 3.6g, yield 62%, purity 99.5%
(HPLC), isotope abundance 99.3% (atom%, HRMS).
1H NMR(300MHz,acetone-d6)δ6.28(1H,s),6.22(1H,s),5.17(1H,m),3.76(1H,t),
3.58(2H,d),2.42(2H,m),2.10(2H,m),1.86(2H,m),1.66(2H,m),1.52(2H,m),1.34(3H,d)。
In an alternative solution of embodiment 5, replace Raney-Ni as the catalyst of hydrogenation, reaction temperature using Pd/C
Degree becomes 20 DEG C from 70 DEG C, and Hydrogen Vapor Pressure becomes 0.1MPa from 0.4MPa, and other conditions are the same as embodiment 5.
It should be appreciated that although this specification is described in terms of embodiments, but not each embodiment only includes one
A independent technical solution, this description of the specification is merely for the sake of clarity, and those skilled in the art should will say
As a whole, the technical solution in each embodiment may also be suitably combined to form those skilled in the art can for bright book
With the other embodiments of understanding.
The series of detailed descriptions listed above only for feasible embodiment of the invention specifically
Protection scope bright, that they are not intended to limit the invention, it is all without departing from equivalent implementations made by technical spirit of the present invention
Or change should all be included in the protection scope of the present invention.
Claims (9)
1. the synthetic method of a kind of deuterium-labeled zearalenone and its derivative, the deuterium-labeled zearalenone and its spread out
Biology is red selected from the deuterium-labeled zearalenone of formula (1), the deuterium-labeled zearelone of formula (2), the deuterium-labeled corn of formula (3)
One of mould enol and the deuterium-labeled zearalanol of formula (4),
It is characterized by: the synthetic method includes the mistake using the deuterium-labeled compound of following formula (b) compound synthesis formula (a)
Journey,
In formula (a) and formula (b) structural formula, C1And C2Dotted line between two carbon atoms indicates the chemistry between two carbon atoms
Key is singly-bound either double bond；
The process using formula (b) compound synthesis formula (a) compound the following steps are included:
It 1) will be one of or several molten in the deuteride of alkali metal, the deuteride of alkali metal, alkaline-earth metal or alkaline-earth metal
Reactant is prepared in Xie Yu deuterium-labeled alkylol；
The deuterium-labeled alkylol have R-OD structural formula, wherein R be C1-C5 full deuterium replace, part deuterium replace or not
The alkyl replaced by deuterium；
2) following formula (b) compound is placed in the reactant of step 1) acquisition and carries out that there is formula described in hydrogen-deuterium exchange reaction acquisition
(a) deuterium-labeled compound；
The step 1) and step 2) carry out under atmosphere of inert gases protection；
The synthetic method further includes the purification step of the deuterium-labeled compound of the formula (a) after step 2), the purifying step
Rapid includes the pH value of step 2) acquired solution being adjusted to after 1-5 to be spin-dried for first, then plus water and is adjusted to acquired solution
Alkalinity, then the process using organic solvent extraction.
2. synthetic method as described in claim 1, it is characterised in that:
The alkali metal is sodium or potassium.
3. synthetic method as described in claim 1, it is characterised in that:
The alkaline-earth metal is magnesium or calcium.
4. synthetic method as described in claim 1, it is characterised in that:
In the structural formula of the deuterium-labeled alkylol, R is the methyl or ethyl that full deuterium replaces.
5. synthetic method as described in claim 1, it is characterised in that:
The step 2) carries out under conditions of temperature is 20 DEG C -80 DEG C.
6. synthetic method as described in claim 1, it is characterised in that:
In the step 2), the molar ratio of alkali metal and/alkali earth metal in formula (b) compound and the reactant
For 1:2~1:10.
7. synthetic method as claimed in claim 6, it is characterised in that:
The organic solvent is methylene chloride.
8. synthetic method as described in claim 1, it is characterised in that:
The inert gas is nitrogen.
9. synthetic method as claimed in any of claims 1 to 8 in one of claims, it is characterised in that:
C in formula (b) compound1And C2Chemical bond between two carbon atoms is double bond, by the step 1) and step
2) the deuterium-labeled zearalenone of production (1)；
The formula (3) is obtained as the deuterium-labeled zearalenone of go back original reagent reduction-type (1) using sodium borohydride and methanol
Deuterium-labeled zearalenol, reaction temperature be 0 DEG C -30 DEG C；Alternatively,
Using described in the deuterium-labeled zearalenone acquisition of aluminium isopropoxide and isopropanol as go back original reagent reduction-type (1)
The deuterium-labeled zearalenol of formula (3), reaction temperature are 55 DEG C -95 DEG C；
Under organic solvent environment, hydrogen as catalyst and is passed through come the deuterium-labeled of reduction-type (1) using Raney's nickel or Pd/C
Zearalenone obtains the deuterium-labeled zearalanol of the formula (4)；Alternatively,
Under organic solvent environment, using platinum oxide and hydrogen is passed through come the deuterium-labeled zearalenone acquisition of reduction-type (1)
The deuterium-labeled zearelone of the formula (2), reaction temperature are 30 DEG C -60 DEG C.
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| CN101339187A (en) * | 2008-08-15 | 2009-01-07 | 中国科学院上海有机化学研究所 | Methylsulfonyl miazines isotope labelling reagent, synthesis method and uses thereof |
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| 固相萃取-超高效液相色谱-串联质谱法检测猪肉中玉米赤霉醇类的残留量;李丽萍等;《色谱》;20130731;第31卷(第7期);第703-708页 * |
| 超高压液相色谱-串联质谱法检测猪肉中玉米赤霉醇类物质;谢继安，刘柏林;《食品安全质量检测学报》;20130228;第4卷(第1期);第150-158页 * |
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