CN112979442A - Stable isotope labeled methyl vanillin and synthesis method thereof - Google Patents
Stable isotope labeled methyl vanillin and synthesis method thereof Download PDFInfo
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- CN112979442A CN112979442A CN201911274928.8A CN201911274928A CN112979442A CN 112979442 A CN112979442 A CN 112979442A CN 201911274928 A CN201911274928 A CN 201911274928A CN 112979442 A CN112979442 A CN 112979442A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
- C07C45/61—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups
- C07C45/64—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by introduction of functional groups containing oxygen only in singly bound form
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- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B59/00—Introduction of isotopes of elements into organic compounds ; Labelled organic compounds per se
- C07B59/001—Acyclic or carbocyclic compounds
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- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C47/00—Compounds having —CHO groups
- C07C47/52—Compounds having —CHO groups bound to carbon atoms of six—membered aromatic rings
- C07C47/575—Compounds having —CHO groups bound to carbon atoms of six—membered aromatic rings containing ether groups, groups, groups, or groups
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- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/05—Isotopically modified compounds, e.g. labelled
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Abstract
The invention discloses stable isotope labeled methyl vanillin and a synthesis method thereof, which comprise the following steps: s1: dissolving vanillin and stable isotope labeled methanol in tetrahydrofuran solvent, and carrying out redox coupling reaction under the action of oxidant and coupling agent; s2: and after the reaction is finished, carrying out post-treatment and purification to obtain the stable isotope labeled methyl vanillin. The stable isotope labeled methyl vanillin and the synthesis method thereof provided by the invention can fully meet the requirements of standard reagents for quantifying the methyl vanillin, and the synthesis process is simple, the product is easy to separate and purify, and the obtained product has high chemical purity and isotope abundance.
Description
Technical Field
The invention relates to an isotope labeled compound and a synthetic method thereof, in particular to stable isotope labeled methyl vanillin and a synthetic method thereof.
Background
The methyl vanillin has the special fragrance of vanilla beans, can be used as a spice for correcting smell and enhancing flavor, and is widely used in the industries of food and pharmaceutical intermediates. However, after a large amount of the infant formula is ingested, liver and kidney injury can be caused, and the requirement of the infant formula for 0-6 months cannot be detected. The stable isotope labeled methyl vanillin can be used as an isotope internal standard substance in a stable isotope dilution mass spectrometry to carry out trace and trace reference quantification on the methyl vanillin, and product support is provided for infant food quality safety monitoring and inspection.
At present, the synthesis method of the stable isotope labeled methyl vanillin is rarely reported. Patent document WO2011-US28631 discloses a preparation method of stable isotope deuterium-labeled methyl vanillin, which is prepared by reacting with methyl iodide-D3 under an alkaline condition, and has the disadvantages of long synthesis process time, low yield and limited application.
Disclosure of Invention
The technical problem to be solved by the invention is to provide a method for synthesizing stable isotope labeled methyl vanillin, which can fully meet the requirements of standard reagents for quantifying the methyl vanillin, and has the advantages of simple synthesis process, easy separation and purification of products, and high chemical purity and isotope abundance of the obtained products.
The technical scheme adopted by the invention for solving the technical problems is to provide a synthetic method of stable isotope labeled methyl vanillin, which comprises the following steps: s1: dissolving vanillin and stable isotope labeled methanol in tetrahydrofuran solvent, and carrying out redox coupling reaction under the action of oxidant and coupling agent; s2: and after the reaction is finished, carrying out post-treatment and purification to obtain the stable isotope labeled methyl vanillin.
Further, the stable isotope-labeled methanol in the step S1 is methanol-D4.
Further, the oxidant in step S1 is one or more of diisopropyl azodicarboxylate, dimethyl azodicarboxylate, and diethyl azodicarboxylate.
Further, the coupling agent in the step S1 is triphenylphosphine.
Further, the step S1 process is as follows: dissolving vanillin, stable isotope-labeled methanol and a coupling agent in a predetermined amount in a tetrahydrofuran solution, slowly dropwise adding an oxidant solution in a predetermined amount, keeping the temperature at 0-5 ℃, and stirring for 40-60 min.
Further, the step S2 process is as follows: after the reaction is finished, removing tetrahydrofuran by rotary evaporation, and carrying out column chromatography separation to obtain the stable isotope labeled methyl vanillin.
Further, the charging molar ratio of the vanillin, the stable isotope labeled methanol, the coupling agent and the oxidant is 1: (0.8-1.1): (1-1.1): (1-1.1).
The invention also provides a stable isotope labeled methyl vanillin prepared by the synthesis method, which is used for solving the technical problems and has the following molecular structure:
the invention has the following beneficial effects: the synthesis method of the stable isotope labeled methyl vanillin provided by the invention has the following advantages:
(1) the invention has the advantages of mild synthesis process conditions, short process route and high yield. methanol-D4 with isotope abundance of more than 99.8 percent is taken as an isotope labeling source, and methyl vanillin-D3 is synthesized by adopting simple one-step reaction, so that the utilization rate of stable isotope atoms is high.
(2) The product of the invention is easy to separate and purify, the chemical purity and the stable isotope abundance of the product both reach more than 99 percent, and the requirement of a standard reagent for quantifying the methyl vanillin can be fully met.
Drawings
FIG. 1 shows stable isotope-labeled methyl vanillin-D obtained in the example of the present invention3Nuclear magnetic resonance hydrogen spectrum of (a).
FIG. 2 shows stable isotope labeled methyl vanillin-D obtained in the example of the present invention3The high performance liquid chromatogram of (1).
Detailed Description
The invention is further described in connection with the following figures and examples, which should not be construed as limiting the invention.
Aiming at the defects of the existing synthetic route of the methyl vanillin-D3, the invention provides a synthetic method with simple route, mild conditions and high yield through mitsunobu reaction, and the synthesized product can be used as a standard reagent for measuring the methyl vanillin, thereby meeting the detection requirement of food safety in China. The mitsunobu reaction, which is the redox coupling reaction of an alcohol and a nucleophile precursor having an acidic property in the presence of a trihydrocarbylphosphine and an azodicarboxylate, was first reported by the japanese organic chemist mitsunobu. The reaction features mild reaction condition and high yield.
The molecular structure of the methyl vanillin-D3 prepared by the invention is as follows:
example 1
The procedure for the synthesis of stable isotope labeled methyl vanillin-D3 of this example is as follows:
dissolving 1.52g of vanillin, 360mg of methanol-D4 and 2.62g of triphenylphosphine in 10mL of tetrahydrofuran solution under the ice salt bath, slowly dropwise adding (preferably one drop per 2 s) the tetrahydrofuran solution (2.02g/5mL) of azodiisopropyl ester, keeping the temperature at 0-5 ℃, continuously stirring for 60min after dropwise adding is finished, monitoring by a TLC (thin layer chromatography) spot plate, removing the tetrahydrofuran solvent by spinning after the reaction is finished, and performing column chromatography separation to obtain the methyl vanillin-D3 with the yield of 98%, wherein the chemical purity of the obtained product reaches 99.5% and the isotopic abundance is 99.9%.
In the product obtained in the embodiment, CDCl3 is used as a solvent, and a nuclear magnetic resonance hydrogen spectrogram is obtained by a Bruke-400M nuclear magnetic resonance instrument; referring to fig. 1, the ordinate represents intensity,1h NMR (400MHz, CDCl3) δ 9.84(s,1H),7.47(dd, J ═ 8.2,1.9Hz,1H),7.42(D, J ═ 1.8Hz,1H),6.98(D, J ═ 8.2Hz,1H),3.95(s,3H), indicating the structure is methyl vanillin-D3.
Meanwhile, the product sample obtained in this example was dissolved in methanol, and the ratio of acetonitrile: a flow rate of 50mmol/L ammonium acetate aqueous solution of 50:50 mobile phase 1.0mL/min a high performance liquid chromatogram of methyl vanillin-D3 was obtained by a DAD (230nm) detector through a liquid phase column (CNW Athena C184.6 × 250mm,5um (LAEQ-462571)) at a column temperature of 30 ℃, as shown in fig. 2, the sample purity reached 99.5%.
Example 2
The procedure for the synthesis of stable isotope labeled methyl vanillin-D3 of this example is as follows:
dissolving 1.52g of vanillin, 400mg of methanol-D4 and 2.88g of triphenylphosphine in 10mL of tetrahydrofuran solution in an ice salt bath, slowly dropwise adding the tetrahydrofuran solution of azodiisopropyl ester (2.22g/5mL), keeping the temperature at 0-5 ℃, continuing stirring for 40min after dropwise adding is finished, removing the tetrahydrofuran solvent by spinning after the reaction is finished, and performing column chromatography separation to obtain the methyl vanillin-D3 with the yield of 99%. The product is obtained, the chemical purity of the obtained product reaches 99.5%, and the isotopic abundance is 99.9%.
Although the present invention has been described with respect to the preferred embodiments, it will be understood by those skilled in the art that various changes in form and details may be made therein without departing from the spirit and scope of the invention as defined by the appended claims.
Claims (8)
1. A synthetic method of stable isotope labeled methyl vanillin is characterized by comprising the following steps:
s1: dissolving vanillin and stable isotope labeled methanol in tetrahydrofuran solvent, and carrying out redox coupling reaction under the action of oxidant and coupling agent;
s2: and after the reaction is finished, carrying out post-treatment and purification to obtain the stable isotope labeled methyl vanillin.
2. The method of synthesis according to claim 1, wherein the stable isotope labeled methanol in step S1 is methanol-D4.
3. The synthesis method according to claim 1, wherein the oxidant in step S1 is one or more of diisopropyl azodicarboxylate, dimethyl azodicarboxylate and diethyl azodicarboxylate.
4. The synthesis method according to claim 1, wherein the coupling agent in step S1 is triphenylphosphine.
5. The synthesis method according to claim 1, wherein the step S1 is as follows: dissolving a predetermined amount of vanillin, stable isotope labeled methanol and a coupling agent in a tetrahydrofuran solution in a cold salt bath, slowly dropwise adding a predetermined amount of oxidant solution, keeping the temperature at 0-5 ℃, and stirring for 40-60 min.
6. The synthesis method according to claim 5, wherein the step S2 is as follows: after the reaction is finished, removing tetrahydrofuran by rotary evaporation, and carrying out column chromatography separation to obtain the stable isotope labeled methyl vanillin.
7. The synthesis method according to claim 5, wherein the charging molar ratio of the vanillin, the stable isotope labeled methanol, the coupling agent and the oxidizing agent is 1: (0.8-1.1): (1-1.1): (1-1.1).
8. A stable isotope labeled methyl vanillin produced by the synthesis method of any one of claims 1 to 7, having a molecular structure as shown below:
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20110257271A1 (en) * | 2010-03-17 | 2011-10-20 | Concert Pharmaceuticals, Inc. | Derivatives of dimethylcurcumin |
| WO2018157779A1 (en) * | 2017-02-28 | 2018-09-07 | 康朴生物医药技术（上海）有限公司 | Novel isoindoline derivative, and pharmaceutical composition and application thereof |
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Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20110257271A1 (en) * | 2010-03-17 | 2011-10-20 | Concert Pharmaceuticals, Inc. | Derivatives of dimethylcurcumin |
| WO2018157779A1 (en) * | 2017-02-28 | 2018-09-07 | 康朴生物医药技术（上海）有限公司 | Novel isoindoline derivative, and pharmaceutical composition and application thereof |
Non-Patent Citations (2)
| Title |
|---|
| GUOR-JIEN WEI 等: "Identification of Sinensetin Metabolites in Rat Urine by an Isotope-Labeling Method and Ultrahigh-Performance Liquid Chromatography-Electrospray Ionization Mass Spectrometry", 《J. AGRIC. FOOD CHEM.》 * |
| WEN-CHIEN LU 等: "Identification of 5,7,3′,4′-Tetramethoxyflavone Metabolites in Rat Urine by the Isotope-Labeling Method and Ultrahigh-Performance Liquid Chromatography-Electrospray Ionization-Mass Spectrometry", 《J. AGRIC. FOOD CHEM.》 * |
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