CN115353443A - Synthesis method of deuterium-labeled diethylstilbestrol - Google Patents
Synthesis 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 isotopic abundance of the compound with the structure shown in the formula I are over 99 percent, and the compound can be used as an internal standard substance for detecting diethylstilbestrol veterinary drug residues; the method has the advantages of easily obtained 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 deuterium-hydrogen exchange reaction.
Background
Diethylstilbestrol (DES) is a synthetic orally available non-steroidal 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 hypoestrogenic symptoms and hormonal imbalance disorders in clinic. Meanwhile, the diethylstilbestrol can also promote the accumulation of calcium, phosphorus and the like, promote protein synthesis, increase the weight of young livestock, reduce fat production and the like. Therefore, the additive is widely added into feed in the animal husbandry breeding process so as to improve the feed utilization rate and the product yield. However, the drug has potential carcinogenicity and genetic toxicity in subsequent studies, and is therefore prohibited from being used in clinical drug therapy. In 2017, the world health organization international agency for research on cancer has also listed diethylstilbestrol as a carcinogen. In 2019, diethylstilbestrol is listed as a prohibited drug for food and animals. There are also a number of announcements by the ministry of agriculture in our country, such as 176, 193, 235, etc., and the use of diethylstilbestrol in breeding animals is definitely prohibited. Therefore, effective detection means for detecting diethylstilbestrol in drugs and animal foods are required.
At present, liquid chromatography-mass spectrometry (LC-MSMS) and gas chromatography-mass spectrometry (GC-MS) are mainly used for detecting diethylstilbestrol in animal foods. In the international food safety standard GB 31658.9-2021 for measuring the residue of estrogen drug in animal food and urine, which is newly issued in 2021, the detection of diethylstilbestrol adopts the method of liquid chromatography tandem mass spectrometry. The method adopts the principle of isotope dilution mass spectrometry for detection, and deuterium-labeled Diethylstilbestrol (Diethylstilbestrol-D8, CAS: 91318-10-4) is used as an internal standard substance. However, no patent is published on the synthesis method of deuterium-labeled diethylstilbestrol at present, and related research documents are few.
The literature reports that the synthesis of deuterium-labeled diethylstilbestrol has the problems of complicated steps, long reaction time, low yield, and incapability of meeting the use requirement of using the deuterium-labeled diethylstilbestrol as an internal standard (LIEHR J G, BALLATORE A M. Deuterium labeling of diethyl tilbatrol and analytes [ J/OL ]].Steroids,1982,40(6):713-722.https://doi.org/10.1016/0039-128X(82)90012-5)。
The stable isotope is used as an internal standard, which has high requirements on chemical purity and isotopic abundance of the compound, the chemical purity is usually more than 98%, and the isotopic abundance also needs to reach more than 98%. At present, the deuterium-labeled diethylstilbestrol is completely dependent on import and is expensive. Therefore, there is an urgent need in the art to provide a method for synthesizing deuterium-labeled diethylstilbestrol with high purity and isotopic abundance, low cost and simple steps.
Disclosure of Invention
The invention aims to provide a synthesis method of deuterium-labeled diethylstilbestrol, which is characterized in that (E) -diethylstilbestrol-d 8 is prepared through deuterium-hydrogen exchange reaction, the purity and isotopic abundance of the obtained target compound are both more than 99%, and the use requirement of the target compound as an analysis internal standard substance is met.
The technical scheme adopted by the invention for solving the technical problems is to provide a method for synthesizing deuterium-labeled diethylstilbestrol, 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) Carrying out hydrogen and deuterium exchange reaction at a certain reaction temperature and pressure;
(4) Purifying to obtain the target compound.
The invention has the advantages that: the synthesis method of 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 deuterium-hydrogen 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, and the purity and the abundance are both more than 99 percent, so that the deuterium-labeled diethylstilbestrol can be used as an internal standard substance for detecting diethylstilbestrol residue.
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 water to the organic solvent is 0.5 to 2.
In a preferred embodiment of the present invention, in the step (1), the molar ratio of the deuterium oxide to the diethylstilbestrol is 50 to 300.
In a preferred embodiment of the present invention, in the step (1), the organic solvent is tetrahydrofuran, dioxolane, dioxane or diglyme.
In a preferred mode of the present invention, in the step (2), the mixed metal catalyst is composed of metal palladium, metal platinum and metal ruthenium.
In a preferred embodiment of the present invention, the palladium metal is 10% palladium on carbon, palladium acetate or tetrakis (triphenylphosphine) palladium.
In a preferred embodiment of the present invention, the platinum metal is 10% platinum carbon, platinum octaethylporphyrin, or tetrakis (triphenylphosphine) platinum.
In a preferred embodiment of the present invention, the ruthenium metal is ruthenium acetate, anhydrous ruthenium chloride or ruthenium acetylacetonate.
In a preferred embodiment of the present invention, the molar ratio of the metal palladium, the metal platinum and the metal ruthenium is 0.5 to 2.
In a preferred embodiment of the present invention, the molar ratio of the mixed metal catalyst to diethylstilbestrol is 0.05 to 0.15.
As a preferred mode of the present invention, the strong base catalyst is cesium carbonate or cesium hydroxide.
In a preferred embodiment of the present invention, the molar ratio of the strong base catalyst to diethylstilbestrol is 0.1 to 0.3.
In a preferred embodiment of the present invention, in the step (3), the reaction temperature is 60 to 100 ℃; preferably, the temperature of 60-100 deg.C includes 60-70 deg.C, 70-80 deg.C, 80-90 deg.C, and 90-100 deg.C.
In a preferred embodiment of the present invention, 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 synthetic method of deuterium-labeled diethylstilbestrol, which has the advantages of low cost, simple steps and high purity and isotopic 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 understand the features and effects of the present invention, the terms used in the following description and claims are generally described and defined. Unless defined otherwise, 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 case of conflict, the definitions in this specification shall control.
All features defined herein as numerical ranges or percentage ranges, such as values, amounts, levels and concentrations, are provided for brevity and convenience only. Accordingly, the description of numerical ranges or percentage ranges should be considered to cover and specifically disclose all possible subranges and individual numerical values (including integers and fractions) within the range.
The features mentioned above with reference to the invention, or the features mentioned with reference to the embodiments, can be combined arbitrarily. All features disclosed in this specification may be combined in any combination, provided that there is no conflict between such features and the combination, and all possible combinations are to be considered within the scope of the present specification. Each feature disclosed in this specification may be replaced by an alternative feature serving the same, equivalent, or similar purpose. Thus, unless expressly stated otherwise, the features disclosed are merely generic 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 described in detail below with reference to specific embodiments of the present invention and accompanying drawings. It is to be understood that the described embodiments are merely a few embodiments of the invention, and not all embodiments. All other embodiments, which can be obtained by a person skilled in the art without making any creative effort based on the embodiments in the present invention, belong to the protection scope of the present invention.
The main compounds to which the present invention relates are shown in the following table:
as used herein, the terms "compound having the structure shown in formula I" and "compound of formula I" refer to the compound numbered I in the above table. And so on to compounds of other structures.
The invention provides a synthesis preparation method of deuterium-labeled diethylstilbestrol, which comprises the steps of 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, and obtaining a target compound with a structure shown in a formula I, namely deuterium-labeled diethylstilbestrol, by conventional purification means such as extraction, chromatography and the like after the reaction is finished.
The synthetic route of the invention is as follows:
specifically, the synthesis preparation method of the compound with the structure shown in the formula I 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) Carrying out hydrogen and deuterium exchange reaction at a certain reaction temperature and pressure;
(4) And carrying out aftertreatment to obtain deuterium-labeled diethylstilbestrol.
In one embodiment of the present invention, the mixed solvent in step (1) is deuterium oxide 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 atmospheric pressures and 1 hour of reaction time; the post-treatment in the step (4) comprises purification, chromatography and the like.
In one embodiment of the present invention, the mixed solvent in step (1) is deuterium water and dioxane; the mixed metal catalyst in the step (2) is palladium acetate, platinum octaethylporphyrin and ruthenium acetate; the strong base catalyst in the step (2) is cesium hydroxide; the reaction conditions in the step (3) are 80 ℃, 3 atmospheric pressures and 2 hours of reaction time; the post-treatment in the step (4) comprises purification, chromatography and the like.
In one embodiment of the present invention, the mixed solvent in step (1) is deuterium oxide and diglyme; the mixed metal catalyst in the step (2) is tetrakis (triphenylphosphine) palladium, tetrakis (triphenylphosphine) platinum and ruthenium acetylacetonate, and the strong base catalyst is cesium carbonate; the reaction conditions in the step (3) are 100 ℃,4 atmospheric pressures and 3 hours of reaction time; the post-treatment in the step (4) comprises purification, chromatography and the like.
The purity and isotopic abundance measurements used in the following examples are as follows:
purity detection method
(1) The target product was dissolved in methanol to prepare a 1mg/mL solution, which was then detected by high performance liquid chromatography. The chromatographic conditions were as follows:
a chromatographic column: athena C18-WP,4.6X 250mm,5um;
mobile phase: acetonitrile (a): 0.2% phosphoric acid aqueous solution (B) (volume ratio) = 60;
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) Dissolving the obtained target product in methanol to prepare a solution of 0.1mg/mL, and injecting the solution into a mass spectrometer for detection by adopting a flow injection mode. Wherein, the mobile phase is: acetonitrile: water (with 0.1% formic acid) =84:16 (volume ratio); mass spectrometry conditions are positive ion mode (ESI +); the ion source temperature is 400 ℃, the dissociation temperature is 250 ℃, the spray voltage is-3.5 kV, the back-blowing gas is 100, and the atomization gas is 250; drying gas: nitrogen gas; collision gas: argon gas; the three parameters of the inlet voltage, the collision cell inlet voltage and the collision voltage are shown in the following table:
| inlet voltage | Inlet voltage of collision cell | Collision voltage |
| -11 | 25 | 18 |
(2) And carrying out normalization calculation on the peak area according to corresponding ions to obtain the isotopic abundance.
Example 1 Synthesis method 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 comprises 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 specifically 20g of deuterium oxide and 20g of tetrahydrofuran;
(3) After nitrogen bubbling is used for removing oxygen, adding a mixed metal catalyst and a strong base catalyst, wherein the mixed metal catalyst is specifically as follows: 1.06g 10% palladium on carbon, 1.95g 10% platinum on carbon and 0.104g anhydrous ruthenium chloride; specifically, the strong base catalyst is 0.325g cesium carbonate;
(4) Stirring and mixing evenly, and then placing at 60 ℃ and 2 atmospheric pressures for reaction for 1 hour;
(5) And (3) post-treatment: after cooling to room temperature, the solution pH was adjusted to 6-7 by addition of hydrochloric acid, filtered through celite, extracted 3 times with 50mL dichloromethane, the organic phases were combined, washed 1 time with saturated brine, then dried over anhydrous sodium sulfate overnight, filtered, concentrated, passed through a chromatographic column with the eluting solvent being n-hexane: ethyl acetate 4:1,
finally, 2.21g of a target product with the structure shown in the formula (I) is obtained, and the yield is 82.5%. The analysis of the purity and isotopic abundance detection method shows that the chromatographic purity of the product is 99.3 percent, and the isotopic abundance is 99.1 percent. The invention has obvious effect.
Fig. 1 is a mass spectrum of (E) -diethylstilbestrol-d 8, the abscissa in fig. 1 is the mass-to-charge ratio, the ordinate is the ion intensity, and it can be seen from the figure that a peak of 275.2 appears in the mass spectrum of (E) -diethylstilbestrol-d 8, which is consistent with the theoretical calculation value of 275.3, and is the mass of the target compound after binding one hydrogen ion, and a fragment ion peak of 259.1 appears, which is consistent with the standard spectrum of the substance, and the isotopic abundance is 99.1% by the liquid mass spectrometry.
FIG. 2 is a high performance liquid chromatogram of (E) -diethylstilbestrol-d 8, and the purity was determined to be 99.3% by area normalization.
FIG. 3 is the 1H NMR spectrum of (E) -diethylstilbestrol-d 8 in deuterated dimethyl sulfoxide on the abscissa, and the chemical shift is shown. 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 the allylic position on the benzene ring have successfully exchanged with the deuterium atom in the deuterium water to obtain the desired target compound.
Example 2
The synthetic route of this example is the same as 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 comprises the following steps:
(1) 2.68g of diethylstilbestrol is put in a high-pressure reaction kettle;
(2) Adding a mixed solvent, and dissolving the mixed solvent by ultrasonic waves, wherein the mixed solvent is 40g of deuterium water and 20g of dioxane;
(3) After nitrogen bubbling is used for removing oxygen, 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 caesium hydroxide;
(4) Stirring and mixing evenly, and then placing at 80 ℃ and 3 atmospheric pressures for reaction for 2 hours;
(5) The post-treatment was the same as in step (5) in example 1.
Finally, 2.14g of a target product with a structure shown in a formula (I) is obtained, and the yield is 80.5%. The detection method of this example is the same as example 1. The chromatographic purity of the target product is 99.1 percent and the isotopic abundance is 99.4 percent.
Example 3
The synthetic route is the same as in example 1, specifically, the mixed metal catalyst is tetrakis (triphenylphosphine) palladium, tetrakis (triphenylphosphine) platinum and ruthenium acetylacetonate, and the strong base catalyst is cesium carbonate;
a method for synthesizing deuterium-labeled diethylstilbestrol comprises the following steps:
(1) 2.68g of diethylstilbestrol is put into a high-pressure reaction kettle,
(2) Adding a mixed solvent, and dissolving the mixed solvent by ultrasonic waves, wherein the mixed solvent is 60g of deuterium oxide and 40g of diglyme;
(3) After nitrogen bubbling is used for removing oxygen, adding a mixed metal catalyst and a strong base catalyst, wherein the mixed metal catalyst is specifically as follows: 1.25g tetrakis (triphenylphosphine) palladium, 1.24g tetrakis (triphenylphosphine) platinum and 0.4g ruthenium acetylacetonate; the strong base catalyst was 0.65g cesium carbonate;
(4) Stirring and mixing evenly, and then placing at 100 ℃ and 4 atmospheric pressures for reaction for 3 hours;
(5) The post-treatment was the same as in step (5) in example 1.
Finally, 2.04g of the target compound with the structure shown in the formula (I) is obtained, and the yield is 76.1%. The detection method of this example is the same as example 1. The chromatographic purity of the target compound is 99.6 percent and the isotopic abundance is 99.2 percent.
Claims (10)
1. A method for synthesizing deuterium-labeled diethylstilbestrol is characterized by comprising the following steps: dissolving diethylstilbestrol in deuterium water and an organic solvent, and carrying out hydrogen-deuterium exchange reaction in the presence of a mixed metal catalyst and a strong base catalyst to obtain deuterium-labeled diethylstilbestrol; wherein the mixed metal catalyst consists of metallic palladium, metallic platinum and metallic ruthenium.
2. The method of synthesis of claim 1, wherein the metallic palladium is 10% palladium on carbon, palladium acetate or tetrakis (triphenylphosphine) palladium.
3. The method of synthesis of claim 1, wherein the platinum metal is 10% platinum carbon, platinum octaethylporphyrin, or tetrakis (triphenylphosphine) platinum.
4. The method of claim 1, wherein the ruthenium metal is ruthenium acetate, anhydrous ruthenium chloride, or ruthenium acetylacetonate.
5. The synthesis method according to any one of claims 1 to 4, wherein the molar ratio of the metal palladium, the metal platinum and the metal ruthenium in the mixed metal catalyst is 0.5 to 2; the molar ratio of the mixed metal catalyst to the diethylstilbestrol is 0.05-0.15.
6. The synthesis method of claim 1, wherein the strong base catalyst is cesium carbonate or cesium hydroxide.
7. The synthesis method according to claim 1 or 6, wherein the molar ratio of the strong base catalyst to diethylstilbestrol is 0.1-0.3.
8. The method of claim 1, wherein the organic solvent is tetrahydrofuran, dioxolane, dioxane, or diglyme.
9. The synthesis method according to claim 1 or 8, wherein the mass ratio of the deuterium water to the organic solvent is 0.5 to 2; the molar ratio of the deuterium water to the diethylstilbestrol is 50-300.
10. The synthesis method of claim 1, wherein the reaction temperature of the deuterium-hydrogen reaction is 60-100 ℃, the reaction pressure is 2-4 atmospheres, and the reaction time is 1-3 hours.
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Citations (4)
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|---|---|---|---|---|
| US20080234488A1 (en) * | 2004-01-23 | 2008-09-25 | Wako Pure Chemical Industries, Ltd. | Method of Deuteration Using Mixed Catalyst |
| US20160130194A1 (en) * | 2014-11-06 | 2016-05-12 | E I Du Pont De Nemours And Company | Method for preparing deuterated aromatic compounds |
| 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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|---|---|---|---|---|
| US20080234488A1 (en) * | 2004-01-23 | 2008-09-25 | Wako Pure Chemical Industries, Ltd. | Method of Deuteration Using Mixed Catalyst |
| US20160130194A1 (en) * | 2014-11-06 | 2016-05-12 | E I Du Pont De Nemours And Company | Method for preparing deuterated aromatic compounds |
| 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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| JOACHIM G. LIEHR, ET AL.: "Deuterium Labeling Of Diethylstilbestrol And Analogues", 《STEROIDS》 * |
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