CN115353443B - Synthetic method of deuterium-labeled diethylstilbestrol - Google Patents
Synthetic method of deuterium-labeled diethylstilbestrol Download PDFInfo
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Abstract
The invention discloses a synthesis method of deuterium-labeled diethylstilbestrol, which comprises the following steps: dissolving diethylstilbestrol in a mixed solvent of deuterium water and an organic solvent; adding a mixed metal catalyst and a strong base catalyst to perform hydrogen-deuterium exchange reaction; the target compound is obtained by conventional purification means such as extraction, chromatography and the like. The purity and the isotopic abundance of the compound with the structure shown in the formula I are both over 99 percent, and the compound can be used as an internal standard for detecting diethylstilbestrol veterinary drug residues; the method has the advantages of easily available and cheap raw materials, low synthesis cost, few steps, simple and quick operation and greatly reduced detection cost.
Description
Technical Field
The invention relates to the field of production of stable isotope labeled compounds, in particular to a method for preparing stable isotope labeled diethylstilbestrol by hydrogen-deuterium exchange reaction.
Background
Diethylstilbestrol (DES) is an artificially synthesized and orally administered nonsteroidal estrogen that produces the same pharmacological and therapeutic effects as natural estradiol. Therefore, it is mainly used for functional bleeding, amenorrhea and the like caused by hypoestrogenism and hormone balance disorder in clinic. Meanwhile, diethylstilbestrol can promote accumulation of calcium, phosphorus and the like, promote protein synthesis, increase weight of young livestock, reduce fat production and the like. Therefore, the feed additive is widely added into feed in the livestock breeding process, so that the feed utilization rate and the product yield are improved. However, this drug was found to be potentially oncogenic and genotoxic in subsequent studies and was therefore prohibited from being used in clinical drug therapy. In 2017, the world health organization international cancer research institute also classified diethylstilbestrol as a class of carcinogens. In 2019, diethylstilbestrol was included in foods and medicines prohibited from being used in animals. There are also a number of announcements in the agricultural sector of China, such as 176, 193, 235, etc., which clearly prohibit the use of diethylstilbestrol for the cultivation of animals. Therefore, effective detection means are needed for detecting diethylstilbestrol in medicines and animal foods.
At present, a detection method for diethylstilbestrol in animal foods is mainly liquid chromatography mass spectrometry (LC-MSMS) and gas chromatography mass spectrometry (GC-MS). In the recently issued international standard for food safety of GB 31658.9-2021 animal food and determination of multi-residue of estrogen and drug in urine in 2021, a liquid chromatography-tandem mass spectrometry method is adopted for detecting diethylstilbestrol. The method adopts the principle of isotope dilution mass spectrometry to detect, and uses deuterium-labeled Diethylstilbestrol (Diethyltistrarol-D8, CAS: 91318-10-4) as an internal standard. However, the current synthesis method of the deuterium-labeled diethylstilbestrol has no patent disclosure and has few related research documents.
The literature reports that the synthesis of deuterium-labeled diethylstilbestrol has the problems of complex steps, long reaction time, low yield, inability of achieving the use requirements of the standard substances (LIEHR J G, BALLATORE A M.Deuterium labeling of diethylstilbestrol and analogues [ J/OL)].Steroids,1982,40(6):713-722.https://doi.org/10.1016/0039-128X(82)90012-5)。
Stable isotopes are used as internal standards and have high requirements on chemical purity and isotope abundance of the compounds, the chemical purity is usually more than 98%, and the isotope abundance is also required to reach more than 98%. At present, the deuterium-marked diethylstilbestrol is completely dependent on import and is high in price. Therefore, there is an urgent need in the art to provide a synthesis method of deuterium-labeled diethylstilbestrol with high purity and isotopic abundance, and with low cost and simple steps.
Disclosure of Invention
The invention aims to provide a synthesis method of deuterium-labeled diethylstilbestrol, which prepares (E) -diethylstilbestrol-d 8 through hydrogen-deuterium exchange reaction, and the purity and the isotopic abundance of the obtained target compound are both over 99 percent, so that the use requirement of the target compound as an analysis internal standard is met.
The technical scheme adopted by the invention for solving the technical problems is to provide a synthesis method of the diethylstilbestrol marked by deuterium, which comprises the following steps:
(1) Dissolving diethylstilbestrol in a mixed solvent, wherein the mixed solvent is deuterium water and an organic solvent;
(2) Adding a catalyst, wherein the catalyst is a mixed metal catalyst and a strong base catalyst;
(3) Hydrogen-deuterium exchange reaction is carried out under certain reaction temperature and pressure;
(4) Purifying to obtain the target compound.
The invention has the advantages that: the synthesis method of the deuterium-labeled diethylstilbestrol is provided, raw materials of deuterium water and diethylstilbestrol are easy to obtain and cheap, the synthesis cost is low, only one-step hydrogen-deuterium exchange reaction is needed, and the operation steps are few and simple; the prepared deuterium-labeled diethylstilbestrol with the structure shown in the formula I has high yield, purity and abundance of more than 99%, and can be used as an internal standard for detecting diethylstilbestrol residues.
In the invention, the diethylstilbestrol is (E) -diethylstilbestrol with a structure shown in a formula II, and the target compound and the product are (E) -diethylstilbestrol-d 8 with a structure shown in a formula I.
In a preferred embodiment of the present invention, in the step (1), the mass ratio of the deuterium oxide to the organic solvent is 0.5 to 2:1.
In a preferred mode of the present invention, in the step (1), the molar ratio of deuterium water to diethylstilbestrol is 50-300:1.
In a preferred embodiment of the present invention, in the step (1), the organic solvent is tetrahydrofuran, dioxolane, dioxane or diglyme.
As a preferred mode of the present invention, in the step (2), the mixed metal catalyst is composed of metallic palladium, metallic platinum and metallic ruthenium.
As a preferred mode of the present invention, the metallic palladium is 10% palladium carbon, palladium acetate or tetrakis (triphenylphosphine) palladium.
As a preferred mode of the present invention, the metal platinum is 10% platinum carbon, octaethylporphyrin platinum or tetrakis (triphenylphosphine) platinum.
As a preferred embodiment of the present invention, the metallic ruthenium is ruthenium acetate, anhydrous ruthenium chloride, or ruthenium acetylacetonate.
As a preferable mode of the invention, the molar ratio of the metal palladium to the metal platinum to the metal ruthenium is 0.5-2:0.5-2:1.
As a preferable mode of the invention, the molar ratio of the mixed metal catalyst to diethylstilbestrol is 0.05-0.15:1.
As a preferred mode of the present invention, the strong base catalyst is cesium carbonate or cesium hydroxide.
As a preferable mode of the invention, the molar ratio of the strong alkali catalyst to diethylstilbestrol is 0.1-0.3:1.
In the step (3), the reaction temperature is 60-100 ℃; preferably, the 60-100deg.C comprises 60-70deg.C, 70-80deg.C, 80-90deg.C, and 90-100deg.C.
In the step (3), the reaction pressure is 2 to 4 atmospheres; preferably, the 2 to 4 atmospheres include 2 to 3 atmospheres, 3 to 4 atmospheres, and the like.
In a preferred embodiment of the present invention, the reaction time in step (3) is 1 to 3 hours.
Accordingly, the invention provides a synthesis method of deuterium-labeled diethylstilbestrol with low cost, simple steps and higher purity and isotope abundance
Drawings
FIG. 1 is a mass spectrum of (E) -diethylstilbestrol-d 8 in example 1.
FIG. 2 is a high performance liquid chromatogram of (E) -diethylstilbestrol-d 8 in example 1.
FIG. 3 is a 1H NMR spectrum of (E) -diethylstilbestrol-d 8 in example 1.
Detailed Description
To enable those skilled in the art to make and use the invention, reference is made to the following terms and definitions for general description and use. Unless otherwise defined, technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs, and in the event of a conflict, the present specification shall control.
In this document, all features, such as values, amounts, and concentrations, are for brevity and convenience only, as defined in the numerical or percent range. Accordingly, the description of a numerical range or percentage range should be considered to cover and specifically disclose all possible sub-ranges and individual values (including integers and fractions) within the range.
The above-mentioned features of the invention, or of the embodiments, may be combined in any desired manner. All of the features disclosed in this specification may be used in combination with any combination of features, provided that the combination of features is not inconsistent and all such combinations are contemplated as falling within the scope of the present specification. The various features disclosed in the specification may be replaced by alternative features serving the same, equivalent or similar purpose. Thus, unless expressly stated otherwise, the disclosed features are merely general examples of equivalent or similar features.
In order to make the objects, technical solutions and advantages of the present invention more apparent, the technical solutions of the present invention will be clearly described below with reference to specific embodiments of the present invention and corresponding drawings. It will be apparent that the described embodiments are only some, but not all, embodiments of the invention. All other embodiments, which can be made by those skilled in the art based on the embodiments of the invention without making any inventive effort, are intended to be within the scope of the invention.
The main compounds to which the present invention relates are shown in the following table:
as used herein, both "compounds of formula I" and "compounds of formula I" refer to compounds numbered I in the above table. And the like, to other structures.
The invention provides a synthetic preparation method of deuterium-marked diethylstilbestrol, which comprises the steps of firstly dissolving diethylstilbestrol in a mixed solvent of deuterium water and an organic solvent, then adding a mixed metal catalyst and a strong base catalyst to carry out hydrogen-deuterium exchange reaction, and obtaining a target compound with a structure shown as formula I, namely deuterium-marked diethylstilbestrol through conventional purification means such as extraction, chromatography columns and the like after the reaction is finished.
The synthetic route of the invention is as follows:
specifically, the synthetic preparation method of the compound with the structure shown as the formula I provided by the invention comprises the following steps:
(1) Dissolving diethylstilbestrol in a mixed solvent, wherein the mixed solvent is deuterium water and an organic solvent;
(2) Adding a catalyst, wherein the catalyst is a mixed metal catalyst and a strong base catalyst;
(3) Hydrogen-deuterium exchange reaction is carried out under certain reaction temperature and pressure;
(4) Post-treatment to obtain the deuterium-labeled diethylstilbestrol.
In one embodiment of the present invention, the mixed solvent in the step (1) is deuterium water and tetrahydrofuran; the mixed metal catalyst in the step (2) is 10% of palladium carbon, 10% of platinum carbon and anhydrous ruthenium chloride; the strong base catalyst in the step (2) is cesium carbonate, and the reaction conditions in the step (3) are 60 ℃, 2 atmospheres and 1 hour of reaction time; the post-treatment in the step (4) includes purification, chromatography and the like.
In one embodiment of the present invention, the mixed solvent in the step (1) is deuterium water and dioxane; the mixed metal catalyst in the step (2) is palladium acetate, octaethylporphyrin platinum and ruthenium acetate; the strong base catalyst in the step (2) is cesium hydroxide; the reaction condition in the step (3) is 80 ℃, 3 atmospheres and 2 hours of reaction time; the post-treatment in the step (4) includes purification, chromatography and the like.
In one embodiment of the present invention, the mixed solvent in the step (1) is deuterium water and diglyme; the mixed metal catalyst in the step (2) is tetra (triphenylphosphine) palladium, tetra (triphenylphosphine) platinum and ruthenium acetylacetonate, and the strong base catalyst is cesium carbonate; the reaction condition in the step (3) is 100 ℃, the reaction time is 3 hours under 4 atmospheric pressure; the post-treatment in the step (4) includes purification, chromatography and the like.
The purity and isotopic abundance detection methods used in the examples below were as follows:
purity detection method
(1) The target product was dissolved in methanol to prepare a 1mg/mL solution, and the solution was detected by high performance liquid chromatography. The chromatographic conditions were as follows:
chromatographic column: athena C18-WP, 4.6X250 mm,5um;
mobile phase: acetonitrile (a): 0.2% phosphoric acid aqueous solution (B) (volume ratio) =60:40;
a detector: DAD;
flow rate: 1.0ml/min;
(2) And calculating to obtain the chromatographic purity by adopting a high performance liquid chromatography area normalization method.
Isotope abundance detection method
(1) And dissolving the obtained target product in methanol to prepare 0.1mg/mL solution, and adopting a flow injection mode to sample to a mass spectrometer for detection. Wherein, the mobile phase is: acetonitrile: water (0.1% formic acid) =84: 16 (volume ratio); the mass spectrometry conditions were positive ion mode (esi+); ion source temperature 400 ℃, dissociation temperature 250 ℃, spray voltage-3.5 kV, back blowing gas 100 and atomizing gas 250; drying gas: nitrogen gas; collision gas: argon gas; the three parameters of inlet voltage, collision cell inlet voltage and collision voltage are shown in the following table:
| inlet voltage | Collision cell inlet voltage | Collision voltage |
| -11 | 25 | 18 |
(2) And carrying out normalization calculation on the peak area according to the corresponding ions to obtain the isotope abundance.
Example 1 Synthesis of deuterium-labeled diethylstilbestrol
The synthetic route is as follows:
wherein the mixed metal catalyst is 10% palladium carbon, 10% platinum carbon and anhydrous ruthenium chloride; the strong base catalyst is cesium carbonate.
A method for synthesizing deuterium-labeled diethylstilbestrol, comprising the following steps:
(1) 2.68g of diethylstilbestrol is placed in a high-pressure reaction kettle;
(2) Adding a mixed solvent, and dissolving the mixed solvent by ultrasonic waves, wherein the mixed solvent is specifically 20g of deuterium water and 20g of tetrahydrofuran;
(3) After nitrogen bubbling deoxidization, adding a mixed metal catalyst and a strong base catalyst, wherein the mixed metal catalyst is as follows: 1.06g of 10% palladium on carbon, 1.95g of 10% platinum on carbon and 0.104g of anhydrous ruthenium chloride; specifically, the strong base catalyst is 0.325g cesium carbonate;
(4) Stirring and mixing uniformly, and then placing the mixture at 60 ℃ and 2 atmospheres for reaction for 1 hour;
(5) Post-treatment: after cooling to room temperature, the pH of the solution was adjusted to 6-7 by adding hydrochloric acid, filtering through celite, extracting 3 times with 50mL of dichloromethane, combining the organic phases, washing 1 time with saturated brine, drying overnight over anhydrous sodium sulfate, suction filtration, concentration, passage through a chromatographic column, eluting with n-hexane: ethyl acetate 4:1,
the final product of the structure shown in formula (I) was 2.21g, with a yield of 82.5%. Analysis by the purity and isotope abundance detection method shows that the chromatographic purity of the product is 99.3 percent and the isotope abundance is 99.1 percent. The invention has obvious effect.
FIG. 1 shows a mass spectrum of (E) -diethylstilbestrol-d 8, the abscissa in FIG. 1 shows the mass-to-charge ratio, and the ordinate shows the ionic strength, and it can be seen from the graph that a peak of 275.2 appears in the mass spectrum of (E) -diethylstilbestrol-d 8, which is consistent with the theoretical calculation 275.3, is the mass after one hydrogen ion is combined with the target compound, and a peak of 259.1 fragment ion appears, which is consistent with the standard spectrum of the substance, and the isotopic abundance is 99.1% as determined by liquid phase mass spectrometry.
FIG. 2 is a high performance liquid chromatogram of (E) -diethylstilbestrol-d 8, with an area normalization method, to determine a purity of 99.3%.
FIG. 3 is a 1H NMR spectrum of (E) -diethylstilbestrol-d 8 with deuterated dimethyl sulfoxide as solution and chemical shift on the abscissa. As can be seen from the 1H NMR spectrum, a single hydrogen peak at the meta position on the benzene ring appears at 7.0ppm, no hydrogen peak at the ortho position on the benzene ring appears, and no hydrogen peak at the allylic position appears at 2.0ppm, which indicates that the hydrogen atoms at the ortho position and allylic position on the benzene ring have been successfully exchanged with deuterium atoms in deuterium water, thus obtaining the desired target compound.
Example 2
The synthetic route of this example is the same as that of example 1, specifically, the mixed metal catalyst is palladium acetate, platinum octaethylporphyrin and ruthenium acetate, and the strong base catalyst is cesium hydroxide.
A method for synthesizing deuterium-labeled diethylstilbestrol, comprising the following steps:
(1) 2.68g of diethylstilbestrol is placed in a high-pressure reaction kettle;
(2) Adding a mixed solvent, and dissolving the mixed solvent by ultrasonic, wherein the mixed solvent is 40g of deuterium water and 20g of dioxane;
(3) After nitrogen bubbling deoxidization, adding a mixed metal catalyst and a strong base catalyst, wherein the mixed metal catalyst is as follows: 0.224g palladium acetate, 0.727g platinum octaethylporphyrin and 0.732g ruthenium acetate, the strong base catalyst being 0.5g cesium hydroxide;
(4) Stirring and mixing uniformly, and then placing the mixture at 80 ℃ and 3 atmospheric pressure for reaction for 2 hours;
(5) The post-treatment was the same as in step (5) of example 1.
Finally, 2.14g of the target product with the structure shown in the formula (I) is obtained, and the yield is 80.5%. The detection method of this embodiment is the same as that of embodiment 1. Finally, the chromatographic purity of the target product is 99.1 percent, and the isotope abundance is 99.4 percent.
Example 3
The synthetic route is the same as in example 1, specifically, the mixed metal catalyst is tetra (triphenylphosphine) palladium, tetra (triphenylphosphine) platinum and ruthenium acetylacetonate, and the strong base catalyst is cesium carbonate;
a method for synthesizing deuterium-labeled diethylstilbestrol, comprising the following steps:
(1) 2.68g of diethylstilbestrol is placed in a high-pressure reaction kettle,
(2) Adding a mixed solvent, and dissolving the mixed solvent by ultrasonic, wherein the mixed solvent is prepared from 60g of deuterium water and 40g of diglyme;
(3) After nitrogen bubbling deoxidization, adding a mixed metal catalyst and a strong base catalyst, wherein the mixed metal catalyst is as follows: 1.25g of tetrakis (triphenylphosphine) palladium, 1.24g of tetrakis (triphenylphosphine) platinum and 0.4g of ruthenium acetylacetonate; the strong base catalyst is 0.65g cesium carbonate;
(4) Stirring and mixing uniformly, and then placing the mixture at 100 ℃ and 4 atmospheres for reaction for 3 hours;
(5) The post-treatment was the same as in step (5) of example 1.
The final yield of the target compound of formula (I) was 2.04g, 76.1%. The detection method of this embodiment is the same as that of embodiment 1. Finally, the target compound is obtained with the chromatographic purity of 99.6 percent and the isotope abundance of 99.2 percent.
Claims (3)
1. A method for synthesizing deuterium-labeled diethylstilbestrol, comprising the steps of: dissolving diethylstilbestrol in deuterium water and an organic solvent, and carrying out hydrogen-deuterium exchange reaction under the participation of a mixed metal catalyst and a strong base catalyst to obtain deuterium-labeled diethylstilbestrol;
the mixed metal catalyst consists of metal palladium, metal platinum and metal ruthenium, wherein the metal palladium is 10% palladium carbon, palladium acetate or tetrakis (triphenylphosphine) palladium, the metal platinum is 10% platinum carbon, octaethylporphyrin platinum or tetrakis (triphenylphosphine) platinum, the metal ruthenium is ruthenium acetate, anhydrous ruthenium chloride or ruthenium acetylacetonate, and the molar ratio of the metal palladium to the metal platinum to the metal ruthenium is 0.5-2:0.5-2:1; the mol ratio of the mixed metal catalyst to diethylstilbestrol is 0.05-0.15:1;
the strong base catalyst is cesium carbonate or cesium hydroxide; the mol ratio of the strong base catalyst to diethylstilbestrol is 0.1-0.3:1;
the reaction temperature of the hydrogen deuterium reaction is 60-100 ℃, the reaction pressure is 2-4 atmospheres, and the reaction time is 1-3 hours.
2. The synthetic method according to claim 1, wherein the organic solvent is tetrahydrofuran, dioxolane, dioxane or diglyme.
3. The synthesis method according to claim 1 or 2, wherein the mass ratio of deuterium water to organic solvent is 0.5-2:1; the mol ratio of the deuterium water to the diethylstilbestrol is 50-300:1.
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| CN106542982A (en) * | 2016-10-31 | 2017-03-29 | 上海化工研究院 | A kind of preparation method of the deuterium-labeled acetone of stable isotope |
| CN115028603A (en) * | 2022-06-17 | 2022-09-09 | 安庆朗坤药业有限公司 | Preparation method of N-methyl-D3-piperazine hydrochloride |
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| US9505667B2 (en) * | 2014-11-06 | 2016-11-29 | E I Du Pont De Nemours And Company | Method for preparing deuterated aromatic compounds |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN106542982A (en) * | 2016-10-31 | 2017-03-29 | 上海化工研究院 | A kind of preparation method of the deuterium-labeled acetone of stable isotope |
| CN115028603A (en) * | 2022-06-17 | 2022-09-09 | 安庆朗坤药业有限公司 | Preparation method of N-methyl-D3-piperazine hydrochloride |
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| Title |
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| Deuterium Labeling Of Diethylstilbestrol And Analogues;Joachim G. Liehr, et al.;《Steroids》;第40卷(第6期);713-722 * |
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