Method for synthesizing bromodifluoromethyl selenide compounds under metal-free condition

文档序号：101779 发布日期：2021-10-15 浏览：60次中文

阅读说明：本技术 一种在无金属条件下合成溴二氟甲基硒醚类化合物的方法 (Method for synthesizing bromodifluoromethyl selenide compounds under metal-free condition ) 是由方毅李欣刘春仪唐婕陈正平于 2021-07-16 设计创作，主要内容包括：本发明涉及一种在无金属条件下合成溴二氟甲基硒醚类化合物的方法,属于化学合成技术领域。本发明提供了一种合成溴二氟甲基硒醚类化合物的方法,所述方法以硒代苯磺酸酯类底物作为亲电性硒试剂,利用二氟卡宾反应策略,在无金属条件下实现了溴二氟甲基硒醚化合物的合成；所述方法使用的硒代苯磺酸酯类底物毒性较低,易于制备和保存,且具有优秀的反应活性,与现有技术相比,所述方法无需使用性质不稳定且毒性较大的含硒化合物(例如,苯硒酚和硒氰酸钾等有毒硒源),显著提高了化学合成溴二氟甲基硒醚类化合物的安全性。(The invention relates to a method for synthesizing a bromodifluoromethylseleno ether compound under a metal-free condition, belonging to the technical field of chemical synthesis. The invention provides a method for synthesizing a bromodifluoro methyl selenium ether compound, which takes selenobenzenesulfonate substrates as electrophilic selenium reagents and utilizes a difluoro carbene reaction strategy to realize the synthesis of the bromodifluoro methyl selenium ether compound under the metal-free condition; compared with the prior art, the method does not need to use selenium-containing compounds (such as phenylselenol, potassium selenocyanate and other toxic selenium sources) with unstable properties and high toxicity, and obviously improves the safety of chemically synthesizing the bromodifluoro methyl selenide compounds.)

1. A method for synthesizing a bromodifluoromethylseleno compound is characterized in that seleno-benzene sulfonate, tetrabutylammonium bromide and (bromodifluoromethyl) trimethylsilane are mixed and then react to obtain the bromodifluoromethylseleno compound.

2. The method of claim 1, wherein the selenobenzenesulfonate is Se- (2-phenoxyethyl) selenobenzenesulfonate, Se- (2- (4-methoxyphenoxy) ethyl) selenobenzenesulfonate, Se- (2- (4-trifluoromethylphenoxy) ethyl) selenobenzenesulfonate, Se- (2- (4-isopropylphenylsulfanyl) ethyl) selenobenzenesulfonate, 6- ((phenylsulfonyl) seleno) ethyl hexanoate, 3- ((phenylsulfonyl) seleno) propylthiophene-2-carboxylate, Se- (4- (benzothiazol-2-mercapto) butyl) selenobenzenesulfonate, Se- (1-p-toluenesulfonylpiperidin-4-yl) selenobenzenesulfonate, Se- (4- (benzyloxy) -2-butyl) selenobenzenesulfonate, or Se - [1,1' -biphenyl ] -4-ylselenophenylsulfonate.

3. The method of claim 2, wherein when the selenobenzenesulfonate is Se- (2-phenoxyethyl) selenobenzenesulfonate, the bromodifluoromethyl selenide-based compound is (bromodifluoromethyl) (2-phenoxyethyl) selenide;

when the selenobenzenesulfonate is Se- (2- (4-methoxyphenoxy) ethyl) selenobenzenesulfonate, the bromodifluoromethyl selenide compound is (bromodifluoromethyl) (2- (4-methoxyphenoxy) ethyl) selenide;

when the selenobenzenesulfonate is Se- (2- (4-trifluoromethylphenoxy) ethyl) selenobenzenesulfonate, the bromodifluoromethylseleno ether compound is (bromodifluoromethyl) (2- (4-trifluoromethylphenoxy) ethyl) selenoether;

when the selenobenzenesulfonate is Se- (2- (4-isopropylbenzene sulfur) ethyl) selenobenzenesulfonate, the bromodifluoromethyl selenide compound is (bromodifluoromethyl) (2- (4-isopropylbenzene sulfur) ethyl) selenide;

when the seleno-benzene sulfonate is 6- ((benzenesulfonyl) seleno) ethyl hexanoate, the bromodifluoro-methyl-seleno ether compound is 6- ((bromodifluoro-methyl) seleno) ethyl hexanoate;

when the selenobenzenesulfonate is 3- ((benzenesulfonyl) seleno) propyl thiophene-2-formate, the bromodifluoromethyl seleno ether compound is 3- ((bromodifluoromethyl) seleno) propyl thiophene-2-formate;

when the selenobenzenesulfonate is Se- (4- (benzothiazole-2-sulfydryl) butyl) selenobenzenesulfonate, the bromodifluoromethylseleno ether compound is 2- ((4- ((bromodifluoromethyl) seleno) butyl) sulfydryl) benzothiazole;

when the selenobenzenesulfonate is Se- (1-p-toluenesulfonylpiperidin-4-yl) selenobenzenesulfonate, the bromodifluoromethylseleno ether compound is 4- ((bromodifluoromethyl) seleno) -1-p-toluenesulfonylpiperidine;

when the selenobenzenesulfonate is Se- (4- (benzyloxy) -2-butyl) selenobenzenesulfonate, the bromodifluoromethyl selenide compound is (4- (benzyloxy) -2-butyl) (bromodifluoromethyl) selenide;

when the selenobenzenesulfonate is Se- [1,1 '-biphenyl ] -4-yl selenobenzenesulfonate, the bromodifluoromethyl selenide compound is [1,1' -biphenyl ] -4-yl (bromodifluoromethyl) selenide.

4. The method according to any one of claims 1 to 3, wherein the method comprises mixing selenobenzenesulfonate, tetrabutylammonium bromide and (bromodifluoromethyl) trimethylsilane in an organic solvent, and stirring at 20-40 ℃ for 0.5-2.5 h to react to obtain a reaction solution; and separating and purifying the reaction liquid to obtain the bromodifluoromethyl selenide compound.

5. The method of claim 4, wherein the organic solvent is at least one of acetonitrile, tetrahydrofuran, toluene, and ethylene glycol dimethyl ether.

6. The method of claim 4 or 5, wherein the organic solvent comprises selenobenzenesulfonate, tetrabutylammonium bromide and (bromodifluoromethyl) trimethylsilane in a molar ratio of 1: 0.1-2.0: 1.2-2.0.

7. The method of any one of claims 4 to 6, wherein the concentration of selenophenesulfonate in the organic solvent is 0.1 to 0.4 mmol/mL.

8. Use of the method of any one of claims 1 to 7 in the preparation of bromodifluoromethylseleno ethers.

9. A bromodifluoromethylseleno-ether compound, characterized in that it is prepared by the method of any one of claims 1 to 7.

10. Use of a bromodifluoromethylseleno ether of claim 9 in crystal preparation, gem-difluoromethyl compound synthesis, drug preparation or radionuclide labeling synthesis.

Technical Field

The invention relates to a method for synthesizing a bromodifluoromethylseleno ether compound under a metal-free condition, belonging to the technical field of chemical synthesis.

Background

The organic fluorine-containing compound realizes the regulation of properties such as chemical reactivity, solubility, lipophilicity, metabolic stability and the like of organic molecules by introducing fluorine atoms into a molecular structure. At present, the gem-difluoromethylene compound in the organic fluorine-containing compound shows important application value in the research of pharmaceutical chemistry (the gem-difluoromethyl compound with biological pharmaceutical activity can be shown in figure 1 specifically), and the bromine difluoromethyl selenide compound (R-SeCF) is used as the organic fluorine-containing compound₂Br) has received the most attention.

As a good halogen bond donor, the bromodifluoromethyl selenide compound has wide application prospect in the field of crystal engineering. And the C-Br bond in the bromodifluoromethyl functional group has excellent chemical activity, and can perform conversion reaction of various functional groups, thereby realizing the diversity synthesis of gem-difluoromethyl compounds, which has important significance for organic chemistry methodology research and new drug synthesis. In addition, selenium is a necessary trace element for life systems, and has important biological functions such as anti-inflammation, anti-oxidation, anti-tumor and the like.

However, the existing methods for synthesizing the bromodifluoromethylselenide compounds have limited number and serious defects. For example, Qing et al utilize phenylselenophenol with CF₂Br₂The (bromodifluoromethyl) phenylselene compound (PhSeCF) is successfully prepared by reaction₂Br) (J.org.chem.2005,70, 9040-; in situ generated bromodifluoromethylselenium chloride (BrCF) by Billard et al₂SeCl) is a selenizing reagent, realizes electrophilic bromodifluoromethyl selenization reaction of (hetero) aromatic compounds, and constructs a series of (hetero) aromatic ring substituted bromodifluoromethyl selenide compounds (J.Org.chem.2016,81, 8268-8275). All of the above methods require the use of toxic selenium sources (phenylselenophenol and potassium selenocyanate), complicated operations (Schlenk technique and low temperature conditions) and substrate modelsThe environment is relatively narrow (the systematic synthesis of alkyl substituted substrates is lacked), and the large-scale popularization and application are very unfavorable.

Therefore, a method for synthesizing the bromodifluoromethylseleno compounds without using toxic selenium sources, which is simple to operate and has a wide substrate range is urgently needed to be found, so that the large-scale popularization and application of the bromodifluoromethylseleno compounds are facilitated.

Disclosure of Invention

In order to solve the problems, the invention provides a method for synthesizing a bromodifluoromethylseleno compound, which comprises the steps of mixing selenobenzenesulfonate, tetrabutylammonium bromide and (bromodifluoromethyl) trimethylsilane and then reacting to obtain the bromodifluoromethylseleno compound.

In one embodiment of the invention, the selenobenzenesulfonate is Se- (2-phenoxyethyl) selenobenzenesulfonate, Se- (2- (4-methoxyphenoxy) ethyl) selenobenzenesulfonate, Se- (2- (4-trifluoromethylphenoxy) ethyl) selenobenzenesulfonate, Se- (2- (4-isopropylphenylsulfanyl) ethyl) selenobenzenesulfonate, 6- ((phenylsulfonyl) seleno) ethyl hexanoate, 3- ((phenylsulfonyl) seleno) propylthiophene-2-carboxylate, Se- (4- (benzothiazol-2-mercapto) butyl) selenobenzenesulfonate, Se- (1-p-toluenesulfonylpiperidin-4-yl) selenobenzenesulfonate, Se- (4- (benzyloxy) -2-butyl) selenobenzenesulfonate or Se- [1,1' -biphenyl ] -4-yl selenophenesulfonate.

In one embodiment of the present invention, when the selenobenzenesulfonate is Se- (2-phenoxyethyl) selenobenzenesulfonate, the bromodifluoromethyl selenide-based compound is (bromodifluoromethyl) (2-phenoxyethyl) selenide;

when the selenobenzenesulfonate is Se- (2- (4-methoxyphenoxy) ethyl) selenobenzenesulfonate, the bromodifluoromethyl selenide compound is (bromodifluoromethyl) (2- (4-methoxyphenoxy) ethyl) selenide;

when the seleno-benzene sulfonate is 6- ((benzenesulfonyl) seleno) ethyl hexanoate, the bromodifluoro-methyl-seleno ether compound is 6- ((bromodifluoro-methyl) seleno) ethyl hexanoate;

when the selenobenzenesulfonate is Se- (4- (benzyloxy) -2-butyl) selenobenzenesulfonate, the bromodifluoromethyl selenide compound is (4- (benzyloxy) -2-butyl) (bromodifluoromethyl) selenide;

when the selenobenzenesulfonate is Se- [1,1 '-biphenyl ] -4-yl selenobenzenesulfonate, the bromodifluoromethyl selenide compound is [1,1' -biphenyl ] -4-yl (bromodifluoromethyl) selenide.

In one embodiment of the invention, the method comprises the steps of mixing selenobenzenesulfonate, tetrabutylammonium bromide and (bromodifluoromethyl) trimethylsilane in an organic solvent, and stirring at 20-40 ℃ for 0.5-2.5 h to react to obtain a reaction solution; and separating and purifying the reaction liquid to obtain the bromodifluoromethyl selenide compound.

In one embodiment of the invention, the method comprises the steps of mixing selenobenzenesulfonate, tetrabutylammonium bromide and (bromodifluoromethyl) trimethylsilane in an organic solvent, and stirring at 30 ℃ for 0.5-2.5 hours to react to obtain a reaction solution; and separating and purifying the reaction liquid to obtain the bromodifluoromethyl selenide compound.

In one embodiment of the present invention, the organic solvent is at least one of acetonitrile, tetrahydrofuran, toluene, and ethylene glycol dimethyl ether.

In one embodiment of the invention, the organic solvent is acetonitrile.

In one embodiment of the present invention, the organic solvent contains selenobenzenesulfonate, tetrabutylammonium bromide and (bromodifluoromethyl) trimethylsilane in a molar ratio of 1: 0.1-2.0: 1.2-2.0.

In one embodiment of the invention, the organic solvent is a 2:1:3 molar ratio of selenobenzenesulfonate, tetrabutylammonium bromide and (bromodifluoromethyl) trimethylsilane.

In one embodiment of the present invention, the concentration of the selenobenzenesulfonate in the organic solvent is 0.1 to 0.4 mmol/mL.

In one embodiment of the invention, the concentration of selenobenzenesulfonate in the organic solvent is 0.2 mmol/mL.

The invention also provides application of the method in preparation of the bromodifluoromethyl selenide compound.

The invention also provides a bromine difluoro methyl selenide compound, which is prepared by the method.

The invention also provides application of the bromine difluoro methyl selenide compounds in crystal preparation, gem-difluoro methyl compound synthesis, medicine preparation or radionuclide labeling synthesis.

In one embodiment of the invention, the drug is an anti-inflammatory drug, an anti-oxidant drug or an anti-tumor drug.

The technical scheme of the invention has the following advantages:

the invention provides a method for synthesizing a bromodifluoro methyl selenium ether compound, which takes selenobenzenesulfonate substrates as electrophilic selenium reagents and utilizes a difluoro carbene reaction strategy to realize the synthesis of the bromodifluoro methyl selenium ether compound under the metal-free condition; compared with the prior art, the method does not need to use selenium-containing compounds (such as phenylselenol, potassium selenocyanate and other toxic selenium sources) with unstable properties and high toxicity, and obviously improves the safety of chemically synthesizing the bromodifluoro methyl selenide compounds.

The method can be smoothly carried out at room temperature, the yield is up to 79-97%, and compared with the prior art, the method has the advantage of high yield on the premise of no need of anhydrous and anaerobic conditions, no need of Schlenk technology and low-temperature conditions, the operation difficulty of chemical synthesis of the bromodifluoro methyl selenide compounds is greatly reduced, and the simple, convenient and efficient synthesis of the bromodifluoro methyl selenide compounds is realized.

The method has wide substrate universality, can realize the synthesis of alkyl and (hetero) aryl substituted bromodifluoromethyl selenide compounds, can realize large-scale synthesis, and is expected to realize large-scale production and application of the bromodifluoromethyl selenide compounds.

Drawings

FIG. 1: a gem-difluoromethyl compound with biological pharmaceutical activity.

FIG. 2: a synthetic route of (bromodifluoromethyl) (2-phenoxyethyl) selenide.

FIG. 3: nuclear magnetic hydrogen spectrum diagram of (bromodifluoromethyl) (2-phenoxyethyl) selenide.

FIG. 4: a synthetic route of (bromodifluoromethyl) (2- (4-methoxyphenoxy) ethyl) selenide.

FIG. 5: nuclear magnetic hydrogen spectrum of (bromodifluoromethyl) (2- (4-methoxyphenoxy) ethyl) selenide.

FIG. 6: a synthetic route of (bromodifluoromethyl) (2- (4-trifluoromethyl phenoxy) ethyl) selenide.

FIG. 7: nuclear magnetic hydrogen spectrum of (bromodifluoromethyl) (2- (4-trifluoromethylphenoxy) ethyl) selenide.

FIG. 8: a synthetic route of (bromodifluoromethyl) (2- (4-isopropylphenyl sulfide) ethyl) selenide.

FIG. 9: nuclear magnetic hydrogen spectrum of (bromodifluoromethyl) (2- (4-isopropylphenyl thio) ethyl) selenide.

FIG. 10: a synthetic route of 6- ((bromodifluoromethyl) seleno) ethyl hexanoate.

FIG. 11: nuclear magnetic hydrogen spectrum of 6- ((bromodifluoro methyl) seleno) ethyl caproate.

FIG. 12: a synthetic route of 3- ((bromodifluoromethyl) selenyl) propylthiophene-2-formate.

FIG. 13: nuclear magnetic hydrogen spectrum of 3- ((bromodifluoro methyl) seleno) propyl thiophene-2-formic ether.

FIG. 14: a synthetic route of 2- ((4- ((bromodifluoromethyl) seleno) butyl) sulfydryl) benzothiazole.

FIG. 15: nuclear magnetic hydrogen spectrum of 2- ((4- ((bromodifluoromethyl) seleno) butyl) mercapto) benzothiazole.

FIG. 16: a synthetic route of 4- ((bromodifluoromethyl) seleno) -1-p-toluenesulfonylpiperidine.

FIG. 17: nuclear magnetic hydrogen spectrum of 4- ((bromodifluoro methyl) seleno) -1-p-toluenesulfonyl piperidine.

FIG. 18: a synthetic route of (4- (benzyloxy) -2-butyl) (bromodifluoromethyl) selenide.

FIG. 19: nuclear magnetic hydrogen spectrum of (4- (benzyloxy) -2-butyl) (bromodifluoromethyl) selenide.

FIG. 20: a synthetic route of [1,1' -biphenyl ] -4-yl (bromodifluoromethyl) selenide.

FIG. 21: nuclear magnetic hydrogen spectrum of [1,1' -biphenyl ] -4-yl (bromodifluoromethyl) selenide.

Detailed Description

The following examples are provided to further understand the present invention, not to limit the scope of the present invention, but to provide the best mode, not to limit the content and the protection scope of the present invention, and any product similar or similar to the present invention, which is obtained by combining the present invention with other prior art features, falls within the protection scope of the present invention.

The following examples do not show specific experimental procedures or conditions, and can be performed according to the procedures or conditions of the conventional experimental procedures described in the literature in the field. The reagents or instruments used are not indicated by manufacturers, and are all conventional reagent products which can be obtained commercially.

Selenobenzenesulfonate compounds used in the following examples were prepared and synthesized according to the references "Rong Zhang, Pei Xu, Shun-Yi Wang, and Shun-Jun Ji, j.org.chem.2019,84, 12324-one 12333".

Example 1: preparation of (bromodifluoromethyl) (2-phenoxyethyl) selenide

The embodiment provides a preparation method of (bromodifluoromethyl) (2-phenoxyethyl) selenide, which comprises the following specific synthetic steps:

a clean 8mL screw reaction flask was charged with a 5X 10mm magnetic stirrer, and Se- (2-phenoxyethyl) selenobenzenesulfonate (1a, 136.5mg, 0.4mmol) and tetrabutylammonium bromide (64.5mg, 0.2mmol) were dissolved in 2mL acetonitrile. (bromodifluoromethyl) trimethylsilane (2, 98. mu.L, 0.60mmol) was then added and the flask was capped and stirred in an oil bath at 30 ℃ for 30 minutes (500 rpm). After the reaction is finished, transferring the reaction system to an eggplant type flask, adding 800mg of column chromatography silica gel powder, removing the solvent by rotary evaporation, and then carrying out column chromatography separation by taking petroleum ether as an eluent to obtain a target product (bromodifluoromethyl) (2-phenoxyethyl) selenide 3 a. The target product was a colorless oily liquid, yield: 93 percent. The synthetic route of the target product is shown in figure 2.

The target product is characterized by electrospray ionization mass spectrometry (ESI-MS) and nuclear magnetic resonance, and the characterization data is as follows (the nuclear magnetic hydrogen spectrum of the target product is shown in figure 3):

¹H NMR(400MHz,CDCl₃)δ7.33–7.23(m,2H),7.01–6.92(m,1H),6.92–6.84(m,2H),4.33(t,J＝6.6Hz,2H),3.34(t,J＝6.6Hz,2H).

¹³C NMR(100MHz,CDCl₃)δ158.2,129.7,121.6,114.8,107.5(t,J_C-F＝352Hz),66.9,27.7.

¹⁹F NMR(376MHz,CDCl₃)δ-16.1.

HRMS(EI)m/z[M]⁺calcd for C₉H₉BrF₂OSe⁺:329.8970,found:329.8968.

example 2: scale-up synthesis of (bromodifluoromethyl) (2-phenoxyethyl) selenoether

The embodiment provides an amplification synthesis method of (bromodifluoromethyl) (2-phenoxyethyl) selenide, which comprises the following specific synthesis steps:

a clean 50mL round bottom reaction flask was charged with 20X 10mm magnetic stirrer and Se- (2-phenoxyethyl) selenobenzenesulfonate (1a, 1.365g, 4.0mmol) and tetrabutylammonium bromide (0.645g, 2.0mmol) were dissolved in 20mL acetonitrile. (bromodifluoromethyl) trimethylsilane (2, 0.98mL, 6.0mmol) was then added and the cap capped and stirred in an oil bath at 30 deg.C (500 rpm) for 60 minutes. After the reaction is finished, transferring the reaction system to an eggplant type flask, adding 2.0g of column chromatography silica gel powder, removing the solvent by rotary evaporation, and then carrying out column chromatography separation by using petroleum ether as an eluent to obtain a target product (bromodifluoromethyl) (2-phenoxyethyl) selenide 3a which is colorless oily liquid. Yield: 92 percent.

It can be seen that the preparation method of (bromodifluoromethyl) (2-phenoxyethyl) selenide in example 1 can achieve an enlarged scale synthesis.

Example 3: preparation of (bromodifluoromethyl) (2- (4-methoxyphenoxy) ethyl) selenide

The embodiment provides a preparation method of (bromodifluoromethyl) (2- (4-methoxyphenoxy) ethyl) selenide, which comprises the following specific synthetic steps:

a clean 8mL screw reaction flask was charged with a 5 x 10mm magnetic stirrer, and Se- (2- (4-methoxyphenoxy) ethyl) selenobenzenesulfonate (1b, 148.5mg, 0.4mmol) and tetrabutylammonium bromide (64.5mg, 0.2mmol) were dissolved in 2mL acetonitrile. (bromodifluoromethyl) trimethylsilane (2, 98. mu.L, 0.60mmol) was then added and the flask was capped and stirred in an oil bath at 30 ℃ for 30 minutes (500 rpm). After the reaction is finished, transferring the reaction system to an eggplant-shaped flask, adding 800mg of column chromatography silica gel powder, removing the solvent by rotary evaporation, and then performing column chromatography separation by using a mixture of ethyl acetate and petroleum ether (ethyl acetate: petroleum ether ═ 1: 100, v/v) as an eluent to obtain a target product (bromodifluoromethyl) (2- (4-methoxyphenoxy) ethyl) selenide 3 b. The target product was a white solid, yield: 84 percent. The synthetic route of the target product is shown in figure 4.

¹H NMR(400MHz,CDCl₃)δ6.83(s,4H),4.29(t,J＝6.6Hz,2H),3.76(s,3H),3.34(t,J＝6.5Hz,2H).

¹³C NMR(100MHz,CDCl₃)δ154.5,152.3,116.0,114.9,107.5(t,J_C-F＝352Hz),67.8,55.8,27.8.

¹⁹F NMR(376MHz,CDCl₃)δ-16.1.

HRMS(EI)m/z[M]⁺calcd for C₁₀H₁₁BrF₂O₂Se⁺:359.9076,found:359.9071.

example 4: preparation of (bromodifluoromethyl) (2- (4-trifluoromethylphenoxy) ethyl) selenide

The embodiment provides a preparation method of (bromodifluoromethyl) (2- (4-trifluoromethylphenoxy) ethyl) selenide, which comprises the following specific synthetic steps:

a clean 8mL screw reaction flask was charged with a 5 x 10mm magnetic stirrer and Se- (2- (4-trifluoromethylphenoxy) ethyl) selenobenzenesulfonate (1c, 163.7mg, 0.4mmol) and tetrabutylammonium bromide (64.5mg, 0.2mmol) were dissolved in 2mL acetonitrile. (bromodifluoromethyl) trimethylsilane (2, 98. mu.L, 0.60mmol) was then added and the flask was capped and stirred in an oil bath at 30 ℃ for 30 minutes (500 rpm). After the reaction is finished, transferring the reaction system to an eggplant-shaped flask, adding 800mg of column chromatography silica gel powder, removing the solvent by rotary evaporation, and then carrying out column chromatography separation by taking petroleum ether as an eluent to obtain a target product (bromodifluoromethyl) (2- (4-trifluoromethylphenoxy) ethyl) selenide 3 c. The target product was a light yellow oily liquid, yield: 84 percent. The synthetic route of the target product is shown in figure 6.

¹H NMR(400MHz,CDCl₃)δ7.56(d,J＝8.6Hz,2H),6.96(d,J＝8.7Hz,2H),4.40(t,J＝6.6Hz,2H),3.39(t,J＝6.6Hz,2H).

¹³C NMR(100MHz,CDCl₃)δ160.5,127.1(q,J_C-F＝4Hz),124.3(q,J_C-F＝270Hz),123.6(q,J_C-F＝33Hz),114.6,107.3(t,J_C-F＝352Hz),67.0,27.2.

¹⁹F NMR(376MHz,CDCl₃)δ-16.3,-61.6.

HRMS(EI)m/z[M]⁺calcd for C₁₀H₈BrF₅OSe⁺:397.8844,found:397.8837.

example 5: preparation of (bromodifluoromethyl) (2- (4-isopropylphenyl thio) ethyl) selenide

The embodiment provides a preparation method of (bromodifluoromethyl) (2- (4-isopropylphenyl sulfide) ethyl) selenide, which comprises the following specific synthetic steps:

a clean 8mL screw-top reaction flask was charged with a 5X 10mm magnetic stirrer, and Se- (2- (4-isopropylphenylsulfanyl) ethyl) selenophenylsulfonate (1d, 159.8mg, 0.4mmol) and tetrabutylammonium bromide (64.5mg, 0.2mmol) were dissolved in 2mL acetonitrile. (bromodifluoromethyl) trimethylsilane (2, 98. mu.L, 0.60mmol) was then added and after capping the bottle, the reaction was stirred in an oil bath at 30 ℃ for 90 minutes (500 rpm). After the reaction is finished, transferring the reaction system to an eggplant type flask, adding 800mg of column chromatography silica gel powder, removing the solvent by rotary evaporation, and then carrying out column chromatography separation by taking petroleum ether as an eluent to obtain a target product (bromodifluoromethyl) (2- (4-isopropylbenzenesulfonyl) ethyl) selenide 3 d. The target product was a colorless oily liquid, yield: 88 percent. The synthetic route of the target product is shown in figure 8.

¹H NMR(400MHz,CDCl₃)δ7.41–7.31(m,2H),7.24–7.16(m,2H),3.37–3.26(m,2H),3.26–3.15(m,2H),2.91(hept,J＝6.9Hz,1H),1.26(d,J＝7.1Hz,6H).

¹³C NMR(100MHz,CDCl₃)δ148.5,131.6,130.6,127.5,107.7(t,J_C-F＝352Hz),35.2,33.9,28.4,24.0.

¹⁹F NMR(376MHz,CDCl₃)δ-15.4.

HRMS(EI)m/z[M]⁺calcd for C₁₂H₁₅BrF₂SSe⁺:387.9211,found:387.9202.

example 6: preparation of ethyl 6- ((bromodifluoromethyl) seleno) hexanoate

The embodiment provides a preparation method of ethyl 6- ((bromodifluoromethyl) seleno) hexanoate, which comprises the following specific synthetic steps:

a clean 8mL screw reaction flask was charged with a 5X 10mm magnetic stirrer, and ethyl 6- ((phenylsulfonyl) seleno) hexanoate (1e, 159.8mg, 0.4mmol) and tetrabutylammonium bromide (64.5mg, 0.2mmol) were dissolved in 2mL acetonitrile. (bromodifluoromethyl) trimethylsilane (2, 98. mu.L, 0.60mmol) was then added and, after capping, stirred in an oil bath at 30 ℃ for 2.5 hours (500 rpm). After the reaction is finished, transferring the reaction system to an eggplant-shaped flask, adding 800mg of column chromatography silica gel powder, removing the solvent by rotary evaporation, and then performing column chromatography separation by using a mixture of ethyl acetate and petroleum ether (ethyl acetate: petroleum ether ═ 1: 30, v/v) as an eluent to obtain a target product, namely 6- ((bromodifluoromethyl) seleno) ethyl hexanoate 3 e. The target product was a brown-yellow oily liquid, yield: 81 percent. The synthetic route of the target product is shown in figure 10.

¹H NMR(400MHz,CDCl₃)δ4.08(q,J＝7.1Hz,2H),3.00(t,J＝7.5Hz,2H),2.27(t,J＝7.4Hz,2H),1.80(p,J＝7.5Hz,2H),1.62(dt,J＝15.2,7.4Hz,2H),1.47–1.34(m,2H),1.21(t,J＝7.2Hz,3H).

¹³C NMR(100MHz,CDCl₃)δ173.4,107.6(t,J_C-F＝352Hz),60.3,34.0,29.5,29.1,29.1,24.3,14.3.

¹⁹F NMR(376MHz,CDCl₃)δ-15.6.

HRMS(EI)m/z[M]⁺calcd for C₉H₁₅BrF₂O₂Se⁺:351.9389,found:351.9393.

example 7: preparation of 3- ((bromodifluoromethyl) selenyl) propylthiophene-2-formate

The embodiment provides a preparation method of 3- ((bromodifluoromethyl) seleno) propyl thiophene-2-formate, which comprises the following specific synthetic steps:

a clean 8mL screw reaction flask was charged with a 5 x 10mm magnetic stirrer, and 3- ((phenylsulfonyl) seleno) propylthiophene-2-carboxylate (1f, 159.8mg, 0.4mmol) and tetrabutylammonium bromide (64.5mg, 0.2mmol) were dissolved in 2mL acetonitrile. (bromodifluoromethyl) trimethylsilane (2, 98. mu.L, 0.60mmol) was then added and after capping the bottle, the reaction was stirred in an oil bath at 30 ℃ for 90 minutes (500 rpm). After the reaction is finished, transferring the reaction system to an eggplant-shaped flask, adding 800mg of column chromatography silica gel powder, removing the solvent by rotary evaporation, and then performing column chromatography separation by using a mixture of ethyl acetate and petroleum ether (ethyl acetate: petroleum ether ═ 1: 20, v/v) as an eluent to obtain a target product 3- ((bromodifluoromethyl) seleno) propylthiophene-2-formic ester 3 f. The target product was a light yellow oily liquid, yield: 94 percent. The synthetic route of the target product is shown in figure 12.

¹H NMR(400MHz,CDCl₃)δ7.81(dd,J＝3.8,1.3Hz,1H),7.57(dd,J＝5.0,1.3Hz,1H),7.11(dd,J＝5.0,3.7Hz,1H),4.40(t,J＝6.0Hz,2H),3.16(t,J＝7.2Hz,2H),2.35–2.23(m,2H).

¹³C NMR(100MHz,CDCl₃)δ162.0,133.7,133.4,132.7,127.9,107.6(t,J_C-F＝352Hz),63.9,29.3,25.6.

¹⁹F NMR(376MHz,CDCl₃)δ-16.0.

HRMS(EI)m/z[M]⁺calcd for C₉H₉BrF₂O₂SSe⁺:377.8640,found:377.8637.

example 8: preparation of 2- ((4- ((bromodifluoromethyl) seleno) butyl) mercapto) benzothiazole

The embodiment provides a preparation method of 2- ((4- ((bromodifluoromethyl) seleno) butyl) sulfydryl) benzothiazole, which comprises the following specific synthetic steps:

a clean 8mL screw reaction flask was charged with a 5X 10mm magnetic stirrer and Se- (4- (benzothiazole-2-mercapto) butyl) selenobenzenesulfonate (1g, 88.5mg, 0.2mmol) and tetrabutylammonium bromide (32.2mg, 0.1mmol) were dissolved in 1mL acetonitrile. (bromodifluoromethyl) trimethylsilane (2, 49. mu.L, 0.30mmol) was then added and, after capping, stirred in an oil bath at 30 ℃ for 2 hours (500 rpm). After the reaction is finished, transferring the reaction system to an eggplant type flask, adding 800mg of column chromatography silica gel powder, removing the solvent by rotary evaporation, and then performing column chromatography separation by using a mixture of ethyl acetate and petroleum ether (ethyl acetate: petroleum ether ═ 1: 10, v/v) as an eluent to obtain 3g of the target product 2- ((4- ((bromodifluoromethyl) seleno) butyl) mercapto) benzothiazole. The target product was a light brown oily liquid, yield: 93 percent. The synthetic route of the target product is shown in figure 14.

¹H NMR(400MHz,CDCl₃)δ7.91–7.84(m,1H),7.78–7.71(m,1H),7.41(ddd,J＝8.3,7.2,1.3Hz,1H),7.29(ddd,J＝8.3,7.4,1.2Hz,1H),3.38(t,J＝6.8Hz,2H),3.08(t,J＝7.0Hz,2H),2.05–1.91(m,4H).

¹³C NMR(100MHz,CDCl₃)δ166.8,153.1,135.2,126.2,124.4,121.6,121.1,107.6(t,J_C-F＝352Hz),32.7,29.4,28.9,28.7.

¹⁹F NMR(376MHz,CDCl₃)δ-15.6.

HRMS(EI)m/z[M]⁺calcd for C₁₂H₁₂BrF₂NS₂Se⁺:430.8728,found:430.8727.

example 9: preparation of 4- ((bromodifluoromethyl) seleno) -1-p-toluenesulfonylpiperidine

The embodiment provides a preparation method of 4- ((bromodifluoromethyl) seleno) -1-p-toluenesulfonyl piperidine, which comprises the following specific synthetic steps:

a clean 8mL screw-top reaction flask was charged with a 5X 10mm magnetic stirrer, and Se- (1-p-toluenesulfonylpiperidin-4-yl) selenobenzenesulfonate (1h, 91.7mg, 0.2mmol) and tetrabutylammonium bromide (32.2mg, 0.1mmol) were dissolved in 1mL tetrahydrofuran. (bromodifluoromethyl) trimethylsilane (2, 98. mu.L, 0.60mmol) was then added and, after capping, stirred in an oil bath at 30 ℃ for 50 minutes (500 rpm). After the reaction is finished, transferring the reaction system to an eggplant type flask, adding 800mg of column chromatography silica gel powder, removing the solvent by rotary evaporation, and then performing column chromatography separation by using a mixture of ethyl acetate and petroleum ether (ethyl acetate: petroleum ether ═ 1: 5, v/v) as an eluent to obtain a target product, namely 4- ((bromodifluoromethyl) seleno) -1-p-toluenesulfonylpiperidine for 3 hours. The target product was a white solid, yield: 97 percent. The synthetic route of the target product is shown in figure 16.

¹H NMR(400MHz,CDCl₃)δ7.67–7.60(m,2H),7.34(d,J＝8.1Hz,2H),3.50–3.42(m,3H),2.69(ddd,J＝12.4,9.7,3.0Hz,2H),2.44(s,3H),2.23(dq,J＝12.7,4.0Hz,2H),1.97(dtd,J＝13.7,9.9,3.8Hz,2H).

¹³C NMR(100MHz,CDCl₃)δ144.0,133.0,129.9,127.8,107.6(t,J_C-F＝352Hz),46.2,41.5,32.5,21.7.

¹⁹F NMR(376MHz,CDCl₃)δ-14.8.

HRMS(EI)m/z[M]⁺calcd for C₁₃H₁₆BrF₂NO₂SSe⁺:446.9218,found:446.9221.

example 10: preparation of (4- (benzyloxy) -2-butyl) (bromodifluoromethyl) selenide

The embodiment provides a preparation method of (4- (benzyloxy) -2-butyl) (bromodifluoromethyl) selenide, which comprises the following specific synthetic steps:

a clean 8mL screw-top reaction flask was charged with a 5X 10mm magnetic stirrer and Se- (4- (benzyloxy) -2-butyl) selenophenesulfonate (1i, 153.4mg, 0.4mmol) and tetrabutylammonium bromide (64.5mg, 0.2mmol) were dissolved in 2mL tetrahydrofuran. (bromodifluoromethyl) trimethylsilane (2, 196. mu.L, 1.20mmol) was then added and after capping the flask, the reaction was stirred in an oil bath at 30 ℃ for 40 minutes (500 rpm). After the reaction is finished, transferring the reaction system to an eggplant type flask, adding 800mg of column chromatography silica gel powder, removing the solvent by rotary evaporation, and then carrying out column chromatography separation by taking petroleum ether as an eluent to obtain the target product (4- (benzyloxy) -2-butyl) (bromodifluoromethyl) selenide 3 i. The target product was a light yellow oily liquid, yield: 79 percent. The synthetic route of the target product is shown in FIG. 18.

¹H NMR(400MHz,CDCl₃)δ7.39–7.22(m,5H),4.49(d,J＝2.1Hz,2H),3.74(dt,J＝14.1,6.9Hz,1H),3.65–3.52(m,2H),2.13–1.94(m,2H),1.62(d,J＝7.1Hz,3H).

¹³C NMR(100MHz,CDCl₃)δ138.2,128.5,127.8,127.8,108.6(t,J_C-F＝352Hz),73.2,67.5,40.1,37.1,23.0.

¹⁹F NMR(376MHz,CDCl₃)δ-14.5(d,J＝131.5Hz),-15.0(d,J＝131.5Hz).

HRMS(EI)m/z[M]⁺calcd for C₁₂H₁₅BrF₂OSe⁺:371.9440,found:371.9444.

example 11: preparation of [1,1' -biphenyl ] -4-yl (bromodifluoromethyl) selenide

The embodiment provides a preparation method of [1,1' -biphenyl ] -4-yl (bromodifluoromethyl) selenide, which comprises the following specific synthetic steps:

a clean 8mL screw-top reaction flask was charged with a 5X 10mm magnetic stirrer and Se- [1,1' -biphenyl ] -4-ylselenophenylsulfonate (1j, 149.3mg, 0.4mmol) and tetrabutylammonium bromide (64.5mg, 0.2mmol) were dissolved in 2mL tetrahydrofuran. (bromodifluoromethyl) trimethylsilane (2, 196. mu.L, 1.20mmol) was then added and, after capping, stirred in an oil bath at 30 ℃ for 2 hours (500 rpm). After the reaction is finished, transferring the reaction system to an eggplant type flask, adding 800mg of column chromatography silica gel powder, removing the solvent by rotary evaporation, and then carrying out column chromatography separation by taking petroleum ether as an eluent to obtain a target product [1,1' -biphenyl ] -4-yl (bromodifluoromethyl) selenide 3 j. The target product was a white solid, yield: 89 percent. The synthetic route of the target product is shown in figure 20.

¹H NMR(400MHz,CDCl₃)δ7.84–7.76(m,2H),7.64–7.55(m,4H),7.50–7.41(m,2H),7.41–7.33(m,1H).

¹³C NMR(100MHz,CDCl₃)δ143.6,140.0,137.6,129.1,128.4,128.2,127.4,125.0,108.7(t,J_C-F＝355Hz).

¹⁹F NMR(376MHz,CDCl₃)δ-18.1.

HRMS(EI)m/z[M]⁺calcd for C₁₃H₉BrF₂Se⁺:361.9021,found:361.9020.

it should be understood that the above examples are only for clarity of illustration and are not intended to limit the embodiments. Other variations and modifications will be apparent to persons skilled in the art in light of the above description. And are neither required nor exhaustive of all embodiments. And obvious variations or modifications therefrom are within the scope of the invention.

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Method for synthesizing bromodifluoromethyl selenide compounds under metal-free condition

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