CN114085175A - Deuterated difluoromethyl substituted selenophenyl sulfonate and preparation method and application thereof - Google Patents
Deuterated difluoromethyl substituted selenophenyl sulfonate and preparation method and application thereof Download PDFInfo
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Abstract
The invention discloses deuterated difluoromethyl substituted selenophenyl sulfonate and a preparation method and application thereof, belonging to the technical field of organic synthesis. The preparation method comprises the following steps: preparation of intermediate product BnSeCF2D: adding sodium hydride and benselenol into an organic solvent for reaction; adding alkaline heavy water solution into the reaction solution, adding difluorocarbene reagent for reaction to obtain an intermediate product BnSeCF2D; preparing a deuterated difluoromethylseleno-based reagent: the BnSeCF obtained in the step one2D and Cl2The chloroform solution is reacted, then sodium benzene sulfinate is added into the reaction solution for continuous reaction, and PhSO is obtained2SeCF2D. The invention synthesizes SeCF with extremely high deuteration level for the first time by matching sodium hydride with heavy water2D' reagent, the deuteration rate reaches 96%; the deuterated difluoromethyl substituted selenophenyl sulfonate can be used for synthesizingForming different kinds of deuterated difluoromethylseleno-based drugs.
Description
Technical Field
The invention belongs to the technical field of organic synthesis, and particularly relates to deuterated difluoromethyl substituted selenophenyl sulfonate, and a preparation method and application thereof.
Background
Organic selenium drugs are a new class of compounds, and have been the focus of drug research due to their antiviral, antitumor and nervous system disease treatment effects. Research shows that the organic selenium compound also has the pharmacological effects of resisting inflammation, resisting senility, preventing and treating cardiovascular diseases, preventing liver diseases and the like. Because selenium has unique biochemical property and pharmacological action, the development of selenium-containing medicaments is very significant. The atomic mass of the C-D bond is larger than that of H, and the C-D bond is more stable (6-9 times) than the C-H bond, so that the deuteration of the C-H bond can greatly change the metabolism and pharmacokinetic properties of the candidate drug. The deuteration technology is widely applied to various fields of organic synthesis, drug metabolism, nuclear magnetic resonance analysis, drug development and the like. In recent years, researchers have conducted intensive research on deuterated drugs, and in 2017, the FDA approved the first deuterated drug, deutetrabenazine (Austedo), and has greatly promoted the development of deuterated synthetic methods. The fluorine-containing CH has stronger lipophilicity, unique medicament and biological activity and important value in medicament synthesis application. Given the importance of organoselenium, deuteration and difluoromethyl in drug candidates, "SeCF" was constructed2The use of D "substituted molecules for the research exploration of drugs is highly desirable.
The literature Conditions-drive Selective Synthesis of derivatives and monomers from elementary Selenium. Synlett 2004, number 10, 1751-1754 reports the Synthesis of benzylselenol, and in reference to this method we have synthesized the starting materials required for the reaction.
The document Metal-Free Difluoromethyl selection of arylamides Underer VisibleLight photocatalysis. J. org. chem. 2020, 85, 1224-1231 discloses the preparation of TsSO2SeCF2The operating method of H has the yield of 70 percent, but the technical method can not realize that the deuterium generation product with high deuterium generation purity can be obtained by replacing hydrogen by deuterium, and the reaction temperature is as low as-78oC, is not beneficial to production operation.
The document Metal-Free Difluoromethyl selection of Arylamines Under VisibleLight photocatalysis. J. org. chem. 2020, 85, 1224-1231 discloses the use of TsSeCF2H photocatalytically reacting' SeCF2H' introduction of aniline substrate, but the corresponding deuterated drug substrate cannot be synthesized.
The document hopper-catalyzed direct fluorogenic separation of aryl boronic acids with Se- (fluorogenic) 4-methylbenezene sulfoselenate Tetrahedron Letters 68 (2021) 152897 discloses the report of TsSeCF2H will be "SeCF2H' introduction of boronic acid substrates, but deuteration of such substrates is not achievable.
The literature Synthesis of fluoromonomers from inorganic acids a chemical process, chem. Commun, 2020, 56, 8976-8979 discloses reports of PhSO2SeCF2H will be "SeCF2H "method for introducing benzaldehyde substrates, but this method also does not allow deuteration of aldehyde substrates.
Therefore, the research on deuterated difluoromethyl substituted selenophenyl sulfonate is very important.
Disclosure of Invention
The invention aims to solve the defects of the prior art and provides deuterated difluoromethyl-substituted selenophenyl sulfonate, a preparation method and application thereof.
In order to achieve the purpose, the technical scheme adopted by the invention is as follows:
the invention provides deuterated difluoromethyl substituted selenophenyl sulfonate, which has the following structural formula:
the invention also provides a preparation method of the deuterated difluoromethyl substituted selenophenyl sulfonate, which comprises the following steps
The method comprises the following steps:
the method comprises the following steps: preparation of BnSeCF2D；
Step two: preparation of deuterated difluoromethylseleno-based reagent PhSO2SeCF2D。
Further, the preparation method of the deuterated difluoromethyl substituted selenophenyl sulfonate comprises the following steps:
the method comprises the following steps: adding sodium hydride and benselenol into an organic solvent for reaction; adding alkaline heavy water solution into the reaction solution, adding difluorocarbene reagent for reaction to obtain an intermediate product BnSeCF2D；
Step two: the BnSeCF obtained in the step one2D and Cl2The chloroform solution is reacted, then sodium benzene sulfinate is added into the reaction solution for continuous reaction, and PhSO is obtained2SeCF2D。
Further, the preparation method of the deuterated difluoromethyl substituted selenophenyl sulfonate is characterized in that the step one is carried out under the protection of inert gas;
in the step one, the organic solvent is anhydrous ether;
in the step one, the difluorocarbene reagent is BrCF2P(O)(EtO)2、TMSCF2 Br、TMSCF2 Cl、BrCF2CO2Na、BrCF2CO2K or Ph3P+CF2CO2 -；
In the step one, the alkaline heavy water solution is NaOH or KOH heavy water solution.
Further, in the preparation method of the deuterated difluoromethyl substituted selenophenyl sulfonate, the molar ratio of the benzylselenol to the sodium hydride in the first step is 1: 1-1: 1.2; in the step one, the difluorocarbene reagent is BrCF2P(O)(EtO)2And said benselenol and BrCF2P(O)(EtO)2In a molar ratio of 1: 1-1: 1.5, the mass concentration of the alkaline heavy water solution is 5-15%, and the volume ratio of the alkaline heavy water solution to the anhydrous ether is 1: 0.5-1: 3.
furthermore, in the first step, the molar ratio of the benselenol to the sodium hydride is 1: 1.1, said benzylisoninol with BrCF2P(O)(EtO)2In a molar ratio of 1: 1.15, the mass concentration of the alkaline heavy water solution is 10%, and the volume ratio of the alkaline heavy water solution to the anhydrous ether is 1: 1.2.
further, the preparation method of the deuterated difluoromethyl substituted selenophenyl sulfonate is characterized in that Cl is adopted in the second step2The concentration of the chloroform solution is 0.2-1.2 mol/L; the BnSeCF in the second step2D and Cl2In a molar ratio of 1: 1-1: 1.5 sodium benzenesulfonate with Cl2In a molar ratio of 1: 0.5-1: 1; BnSeCF2D and Cl2The reaction time of the chloroform solution is 2-6 h; and adding sodium benzene sulfinate to continue the reaction for 8-15 h.
Further, the preparation method of deuterated difluoromethyl substituted selenophenyl sulfonate, the Cl in the second step2The concentration of the chloroform solution is 0.4 mol/L-0.7mol/L; the BnSeCF in the second step2D and Cl2In a molar ratio of 1: 1.3, BnSeCF2D and Cl2The reaction time of the chloroform solution is 5 hours; sodium benzene sulfinate and Cl in the second step2In a molar ratio of 1.6: 1, adding sodium benzene sulfinate to continue the reaction for 12 hours.
Further, in the first step, after the reaction is finished, standing, extracting and separating upper-layer oily liquid by using ethyl acetate, and separating by using column chromatography, wherein the eluent is a mixed solution of petroleum ether and ethyl acetate, and the mixed solution is prepared by mixing the following components in percentage by volume: preparing ethyl acetate at a ratio of 30: 1; in the second step, after the reaction is finished, the eluent is separated by column chromatography, the eluent is a mixed solution of petroleum ether and ethyl acetate, and the mixed solution is prepared from the following components in percentage by volume: ethyl acetate 15: 1.
The invention also provides application of the deuterated difluoromethyl substituted selenophenyl sulfonate in preparation of drug molecules.
Compared with the prior art, the invention has the beneficial effects that:
(1) the invention synthesizes SeCF with extremely high deuteration level for the first time by matching sodium hydride with heavy water2D' reagent, the deuteration rate reaches 96%;
(2) the synthesized reagent can be applied to various drug substrates, so that drug molecules can have biological and pharmaceutical activities specific to selenium, fluorine and deuterium at the same time, and the reagent has extremely important research and application values;
(3) the preparation and application methods of the synthesized reagent are simple and convenient, the operation is easy, and the mass production can be realized.
Drawings
FIG. 1 is a scheme showing the preparation of benzyl (difluoromethyl-d) selenane according to the present invention1H NMR spectrum;
FIG. 2 is a diagram of benzyl (difluoromethyl-d) selenane of the present invention13C NMR spectrum;
FIG. 3 is a scheme showing the preparation of benzyl (difluoromethyl-d) selenane according to the present invention19F NMR spectrum;
FIG. 4 shows Se- (difluoromethyl-d) benzene sulfonate of the present invention1H NMR spectrum;
FIG. 5 shows Se- (difluoromethyl-d) benzene sulfonate of the present invention13C NMR spectrum;
FIG. 6 shows Se- (difluoromethyl-d) benzene sulfonate of the present invention19F NMR spectrum.
Detailed Description
The present invention will be described in further detail with reference to examples.
It will be appreciated by those skilled in the art that the following examples are illustrative of the invention only and should not be taken as limiting the scope of the invention. The examples do not specify particular techniques or conditions, and are performed according to the techniques or conditions described in the literature in the art or according to the product specifications. The reagents or instruments used are not indicated by the manufacturer, and are all conventional products available by purchase.
PhSO of the invention2SeCF2The synthesis process is shown as the following figure:
synthesis of deuterated difluoromethylseleno-based reagent (PhSO)2SeCF2D) Examples of the embodiments
Example 1
Under the condition of nitrogen protection and room temperature, 20mL of anhydrous ether is added into a 100mL reaction bottle to serve as a solvent, 1.3g of sodium hydride (with the mass purity of 60%) is added, and the mixture is stirred uniformly; the temperature of the mixed solution is kept between 0 and 5 through ice bathoC, slowly adding 5.1g of benselenol, raising the temperature to normal temperature after the addition is finished, and continuously reacting for 3 hours; cooling the reaction solution to 0-5 deg.c in ice bathoC, slowly adding 20mL of 10% NaOH heavy water solution by mass concentration, uniformly stirring, adding 9.2 g of diethyl bromodifluoromethyl phosphate after 5min, continuing to react for 5h, standing, extracting and separating an upper-layer oily liquid by 50mL of ethyl acetate, and separating by column chromatography (eluent is petroleum ether, ethyl acetate is 30:1) to obtain 5.7g of BnSeCF2D, yield 87%.
Ice bath (0-5) oC) Under the condition, the volume of the solution is increased to 100mL35mL of 0.7mol/L Cl was added to the reaction flask2And 4.1g of BnSeCF2D, raising the temperature to the normal temperature, continuing the reaction for 5 hours, and then placing the reaction bottle in an ice bath (0-5) oC) Under the condition, 6.3g of sodium benzene sulfinate is added into the solution, the solution is heated to normal temperature and continuously reacted for 12 hours, and finally, the mixture is separated by column chromatography (eluent is petroleum ether: ethyl acetate 15:1) to yield 3.87g of PhSO as a colorless liquid2SeCF2D, yield 77%.
Example 2
Under the condition of nitrogen protection and room temperature, 50mL of anhydrous ether is added into a 200mL reaction bottle to serve as a solvent, 2.6g of sodium hydride (with the mass purity of 60%) is added, and the mixture is stirred uniformly; the temperature of the mixed solution is kept between 0 and 5 through ice bathoC, slowly adding 10.2g of benselenol, raising the temperature to normal temperature after the addition is finished, and continuously reacting for 3 hours; cooling the reaction solution to 0-5 deg.c in ice bathoC, slowly adding 40mL of 10% NaOH heavy water solution in mass concentration, uniformly stirring, adding 18.4g of bromodifluoromethyl diethyl phosphate after 5min, and continuing to react for 5h; standing, extracting with 100mL ethyl acetate to separate the upper oily liquid, and separating by column chromatography (eluent: petroleum ether: ethyl acetate: 30:1) to obtain 11.4g BnSeCF2D, yield 87%.
Ice bath (0-5) oC) Under the conditions, 80mL of Cl with a concentration of 0.6mol/L was added to a 200mL reaction flask2And 8.2g of BnSeCF, and2d, raising the temperature to the normal temperature, continuing the reaction for 5 hours, and then placing the reaction bottle in an ice bath (0-5) oC) Under the condition, 12.6g of sodium benzene sulfinate is added into the solution, the solution is heated to normal temperature to continue to react for 12 hours, and finally, the solution is separated by column chromatography (eluent is petroleum ether: ethyl acetate 15:1) to yield 7.74g of a colorless liquid, i.e. PhSO2SeCF2D, yield 77%.
Example 3
Under the condition of nitrogen protection and room temperature, 125 mL of anhydrous ether is added into a 500mL reaction bottle to serve as a solvent, 6.5 g of sodium hydride (with the mass purity of 60%) is added, and the mixture is stirred uniformly; the temperature of the mixed solution is kept between 0 and 5 through ice bathoC, slowly adding 25.5 g of benselenol, raising the temperature to normal temperature after the addition is finished, and continuously reacting for 3 hours; cooling the reaction solution to 0-5 deg.c in ice bathoC, and slowly addingAdding 100mL of NaOH heavy water solution with the mass concentration of 10%, uniformly stirring, adding 46 g of bromodifluoromethyl diethyl phosphate after 5min, and continuing to react for 5h; standing, extracting with 250 mL ethyl acetate to separate the upper oily liquid, and separating by column chromatography (eluent: petroleum ether: ethyl acetate: 30:1) to obtain 28.5g BnSeCF2D, yield 87%.
Ice bath (0-5) oC) Under the conditions, 240mL of Cl with a concentration of 0.5mol/L was added to a 500mL reaction flask2And 20.5 g of BnSeCF2D, raising the temperature to the normal temperature, continuing the reaction for 5 hours, and then placing the reaction bottle in an ice bath (0-5) oC) Under the condition, 31.5 g of sodium benzene sulfinate is added into the solution, the solution is heated to normal temperature and continuously reacted for 12 hours, and finally, the mixture is separated by column chromatography (eluent is petroleum ether: ethyl acetate 15:1) to yield 19.1g of a colorless liquid, i.e. PhSO2SeCF2D, yield 76%.
The nuclear magnetic data of the present invention are as follows:
benzyl (difluoromethyl-d) selenane
Benzyl(difluoromethyl-d)selane
Colourless oil, yield 87%. Eluent: ethyl acetate/ petroleum ether (1:30). 1H NMR (500 MHz, CDCl3) δ 7.40-7.31 (m, 4H), 7.27 (ddd, J = 8.5, 5.6, 2.2 Hz, 1H), 4.11 (s, 2H); 13C NMR (126 MHz, Chloroform-d) δ 137.42 (s), 129.05 (s), 128.90 (s), 127.48 (s), 115.48 (tt, J = 286.0, 31.5 Hz), 26.33 (t, J = 3.2); 19F NMR (470 MHz, CDCl3) δ -93.86 (t, J = 9.4 Hz, 2F); HR-MS (EI) Calcd. For 216.9876, C8H7DF2 74Se, found 216.9882.
Se- (difluoromethyl-d) phenylsulfonic acid salt
Se-(difluoromethyl-d) benzenesulfonoselenoate
Colourless oil, yield 76%. Eluent: ethyl acetate/ petroleum ether (1:15). 1H NMR (500 MHz, CDCl3) δ 7.93-7.87 (m, 2H), 7.70-7.65 (m, 1H), 7.58 (dd, J = 8.5, 7.2 Hz, 2H); 13C NMR (126 MHz, CDCl3) δ 147.90 (s), 134.59 (s), 129.69 (s), 126.58 (s), 120.31 (tt, J = 293.6, 33.4 Hz); 19F NMR (470 MHz, CDCl3) δ -91.40 (t, J = 9.4 Hz, 2F).
For reagent PhSO2SeCF2D is applied to the three substrates to obtain the corresponding SeCF2The D' chemical product has the physical and chemical characteristics of selenium, fluorine and deuterium, and has important potential value in medicine application.
The embodiments of the present invention have been described in detail with reference to the above examples, but the present invention is not limited to the above embodiments, and various changes can be made without departing from the spirit of the present invention within the knowledge of those skilled in the art. The above description is only for the purpose of illustrating preferred embodiments of the present invention and is not intended to limit the scope of the present invention, which is defined by the appended claims.
Claims (10)
1. A deuterated difluoromethyl-substituted selenophenyl sulfonate, characterized by the following structural formula:
2. the method of preparing deuterated difluoromethyl-substituted selenophenyl sulfonate as recited in claim 1, comprising the steps of:
the method comprises the following steps: preparation of BnSeCF2D；
Step two: preparation of deuterated difluoromethylseleno-based reagent PhSO2SeCF2D。
3. The method of claim 2, comprising the steps of:
the method comprises the following steps: adding sodium hydride and benselenol into an organic solvent for reaction; adding alkaline heavy water solution into the reaction solution, adding difluorocarbene reagent for reaction to obtain an intermediate product BnSeCF2D；
Step two: the BnSeCF obtained in the step one2D and Cl2The chloroform solution is reacted, then sodium benzene sulfinate is added into the reaction solution for continuous reaction, and PhSO is obtained2SeCF2D。
4. The method of claim 3, wherein step one is performed under an inert gas atmosphere;
in the step one, the organic solvent is anhydrous ether;
in the step one, the difluorocarbene reagent is BrCF2P(O)(EtO)2、TMSCF2 Br、TMSCF2 Cl、BrCF2CO2Na、BrCF2CO2K or Ph3P+CF2CO2 -；
In the step one, the alkaline heavy water solution is NaOH or KOH heavy water solution.
5. The method of claim 4, wherein the molar ratio of benzylselenol to sodium hydride in step one is 1: 1-1: 1.2; in the step one, the difluorocarbene reagent is BrCF2P(O)(EtO)2And said benzylselenol andBrCF2P(O)(EtO)2in a molar ratio of 1: 1-1: 1.5, the mass concentration of the alkaline heavy water solution is 5-15%, and the volume ratio of the alkaline heavy water solution to the anhydrous ether is 1: 0.5-1: 3.
6. the method of claim 5, wherein in step one, the molar ratio of benzylselenol to sodium hydride is 1: 1.1, said benzylisoninol with BrCF2P(O)(EtO)2In a molar ratio of 1: 1.15, the mass concentration of the alkaline heavy water solution is 10%, and the volume ratio of the alkaline heavy water solution to the anhydrous ether is 1: 1.2.
7. the method of claim 3, wherein the Cl in step two is replaced by deuterium-difluoromethyl-substituted selenophenyl sulfonate2The concentration of the chloroform solution is 0.2-1.2 mol/L;
the BnSeCF in the second step2D and Cl2In a molar ratio of 1: 1-1: 1.5 sodium benzenesulfonate with Cl2In a molar ratio of 1: 0.5-1: 1; BnSeCF2D and Cl2The reaction time of the chloroform solution is 2-6 h; and adding sodium benzene sulfinate to continue the reaction for 8-15 h.
8. The method of claim 7, wherein the Cl in step two is replaced by deuterium-difluoromethyl-substituted selenophenyl sulfonate2The concentration of the chloroform solution is 0.4-0.7 mol/L; the BnSeCF in the second step2D and Cl2In a molar ratio of 1: 1.3, BnSeCF2D and Cl2The reaction time of the chloroform solution is 5 hours; sodium benzene sulfinate and Cl in the second step2In a molar ratio of 1.6: 1, adding sodium benzene sulfinate to continue the reaction for 12 hours.
9. The method of claim 3, wherein in the first step, after the reaction is completed, the mixture is left to stand, the upper oily liquid is extracted and separated by ethyl acetate, and the upper oily liquid is separated by column chromatography, the eluent is a mixture of petroleum ether and ethyl acetate, and the volume ratio of the mixture is petroleum ether: preparing ethyl acetate at a ratio of 30: 1; in the second step, after the reaction is finished, the eluent is separated by column chromatography, the eluent is a mixed solution of petroleum ether and ethyl acetate, and the mixed solution is prepared from the following components in percentage by volume: ethyl acetate 15: 1.
10. Use of deuterated difluoromethyl-substituted selenophenylsulfonate as recited in claim 1 for the preparation of a pharmaceutical molecule.
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Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS6124563A (en) * | 1984-07-13 | 1986-02-03 | Daikin Ind Ltd | Aromatic difluoromethyl chalcogenide |
| CN107226769A (en) * | 2017-06-19 | 2017-10-03 | 郑州泰基鸿诺医药股份有限公司 | A kind of deuterated methoxy containing difluoro（Sulphur）The synthetic method of the aromatic compounds of base functional group |
| CN107540586A (en) * | 2016-06-23 | 2018-01-05 | 中国科学院上海有机化学研究所 | A kind of preparation method of the thioaryl sulphonic acid ester of difluoromethyl substitution |
| CN112279796A (en) * | 2020-06-19 | 2021-01-29 | 西北大学 | Difluoromethyl selenium ester compound and synthetic method thereof |
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2021
- 2021-12-10 CN CN202111505868.3A patent/CN114085175A/en active Pending
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS6124563A (en) * | 1984-07-13 | 1986-02-03 | Daikin Ind Ltd | Aromatic difluoromethyl chalcogenide |
| CN107540586A (en) * | 2016-06-23 | 2018-01-05 | 中国科学院上海有机化学研究所 | A kind of preparation method of the thioaryl sulphonic acid ester of difluoromethyl substitution |
| CN107226769A (en) * | 2017-06-19 | 2017-10-03 | 郑州泰基鸿诺医药股份有限公司 | A kind of deuterated methoxy containing difluoro（Sulphur）The synthetic method of the aromatic compounds of base functional group |
| CN112279796A (en) * | 2020-06-19 | 2021-01-29 | 西北大学 | Difluoromethyl selenium ester compound and synthetic method thereof |
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