CN114920684B - Selenium-containing benzamide compounds and their synthesis methods and applications - Google Patents

Abstract

The invention discloses a selenium-containing benzamide compound and a green synthesis method and application thereof, wherein the method comprises the following steps: dissolving indole compounds, benzisoselenazolone compounds and monovalent copper catalysts in a solvent, heating for reaction, and purifying the reaction system by column chromatography after the reaction is finished to obtain selenium-containing benzamide compounds. The compounds have potential application in preparing medicines for treating various malignant tumors. The compound has good inhibitory activity on human breast cancer MCF-7 cells and human ovarian cancer SKOV-3 cells. The method has the advantages of high atom economy, low cost and easy acquisition of raw materials and catalysts, simple and convenient operation, good tolerance of functional groups and higher application value.

Description

Selenium-containing benzamide compounds and their synthesis method and application

Technical Field

The invention belongs to the technical field of pharmaceutical chemical intermediate synthesis, relates to a green synthesis method of selenium-containing benzamide compounds, and specifically relates to a method for preparing selenium-containing benzamide compounds through monovalent copper catalysis.

Background Art

3-Arylselenoindole is an important parent nucleus of selenium-containing compounds, which has broad application prospects in the field of pharmaceuticals and chemicals. 3-Arylselenoindole derivatives have strong biological activity, for example, compound 1 has good anti-inflammatory activity (FreeRadic Biol Med. 2017; 113: 395); compound 2 has IC ₅₀ of 9.5nM and 2.4nM for human gastric cancer SGC7901 cells and human fibrosarcoma HT1080 cells, respectively (Eur J Med Chem. 2015; 90: 184); compound 3 has anti-tumor activity with IC ₅₀ of 98nM, 150nM and 130nM for human gastric cancer SGC7901 cells, human lung cancer A549 cells and human fibrosarcoma HT1080 cells, respectively (Eur J Med Chem. 2014; 87: 306).

Due to the important pharmacological activities of 3-arylselenyl indole compounds, many researchers have focused on the research of new synthetic methods for this class of compounds. The synthetic methods reported so far mainly use four types of compounds as selenium sources: diaryl diselenide compounds (Chem. Eur. J. 2018, 24, 4173; Org. Biomol. Chem. 2018, 16, 4958; Angew. Chem. Int. Ed. 2015, 54, 5772), aryl selenyl chloride (J. Org. Chem. 2009, 74, 6802), aryl selenonitrile (J. Org. Chem. 2021, 86, 9317) and N-aryl selenyl phthalimide (Org. Lett. 2007, 9, 5263). However, these selenium sources all contain a part of leaving groups, and by-products will be generated after the reaction, which not only affects the atom economy of the reaction and the separation and purification of the product, but is also environmentally unfriendly. In addition, the reported methods have one or more of the following disadvantages: long reaction time, use of equivalent oxidants or bases, generation of toxic cyanide ions, poor functional group tolerance, etc.

Therefore, it is very necessary to develop a method for synthesizing 3-arylselenyl indole compounds with a simple reaction system, high atom economy, rapid reaction, and environmental friendliness.

Summary of the invention

In view of the above problems existing in the prior art, the purpose of the present invention is to provide a green synthesis method for selenium-containing benzamide compounds, which adopts 100% atomic benzisoselenoazolone compounds as selenium sources and cheap monovalent copper reagents as catalysts, and can efficiently synthesize selenium-containing benzamide compounds without any other additives.

In order to achieve the above object, the technical solution of the present invention is as follows:

In a first aspect, the present invention provides a selenium-containing benzamide compound represented by Formula III or Formula 6,

In formula III, R ¹ is selected from one of hydrogen, C ₁ -C ₄ alkyl, C ₁ -C ₄ haloalkyl, halogen, C ₁ -C ₄ alkoxy, C ₁ -C ₄ haloalkoxy, nitro, carboxyl, and C ₁ -C ₄ alkoxycarbonylmethyl;

^R2 is selected from hydrogen, _C1 - _C4 alkyl, unsubstituted or halogen, C1 _{- C4} alkyl, _C1 - _C4 haloalkyl, C1- _C4 alkoxy, C1 _{- C4} haloalkoxy, phenyl substituted with _{nitro, unsubstituted or halogen, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy , C1 - C4 haloalkoxy , benzyl} substituted with nitro, _C1 - _C4 alkanoyl;

R ³ is selected from one of hydrogen, halogen, C ₁ -C ₄ alkoxy, C ₁ -C ₄ haloalkoxy, C ₁ -C ₄ alkyl, and C ₁ -C ₄ haloalkyl;

^R4 is selected from hydrogen, _C3 - _C8 cycloalkyl, _C1 - _C4 alkyl, C1- _C4 haloalkyl, _C1 - _C4 alkoxy, C1-C4 haloalkoxy, C6-C10 aryl substituted with nitro, C3-C8 cycloalkyl, C1- _C4 alkyl, C1 _- C4 haloalkyl, C1 _- C4 alkoxy, C1 _{- C4} haloalkoxy, C6- _C10 aryl substituted with nitro, C3-C8 cycloalkyl, _C1 -C4 alkyl, C1- _C4 haloalkyl, C1- _C4 alkoxy, C1-C4 haloalkoxy, C6-C10 aryl substituted with nitro, C3-C8 cycloalkyl, _C1 - _C4 alkyl, C1-C4 haloalkyl, C1 _{- C4} alkoxy, C1-C4 haloalkoxy, C6-C10 aryl substituted with nitro, One of them.

Furthermore, the selenium-containing benzamide compound represented by formula III is one of the following:

In a second aspect, the present invention provides an application of the selenium-containing benzamide compound in the preparation of anti-tumor drugs, especially in the preparation of drugs for treating human breast cancer MCF-7 cells or human ovarian cancer SKOV-3 cells.

In a third aspect, the present invention provides a green synthesis method of selenium-containing benzamide compounds represented by formula III, wherein the method is:

The indole compound represented by formula I, the benzisoselenozolide compound represented by formula II and the monovalent copper catalyst are dissolved in an organic solvent and placed in a protective atmosphere (such as N ₂ or Ar) at 60-150° C. (preferably 80-100° C., particularly preferably 100° C.) for 1-6 hours (preferably 2-4 hours), and the obtained reaction solution is post-treated to obtain the selenium-containing benzamide compound shown in formula III; the monovalent copper catalyst is cuprous iodide, cuprous oxide, copper thiophene-2-carboxylate, cuprous bromide or cuprous acetate (preferably cuprous iodide and cuprous oxide); the molar ratio of the monovalent copper catalyst to the theoretical reaction amount of the raw material is 1-50:100 (preferably 5-10:100), and the theoretical reaction amount of the raw material is calculated based on the compound with the smaller amount of the input substance among the indole compound shown in formula I and the benzisoselenozolane compound shown in formula II; (when the molar ratio of the indole compound shown in formula I to the benzisoselenozolane compound shown in formula II is 1:1, it is calculated based on any raw material)

The molar ratio of the indole compound of formula I to the benzisoselenozolide compound of formula II is 1:0.5-4 (preferably 1:0.5-2);

The general reaction formula is as follows:

In formula I, II and III,

^R1 is selected from the group consisting of hydrogen, _C1 - _C4 alkyl, _C1 - _C4 haloalkyl, halogen, _C1 - _C4 alkoxy, _C1 - _C4 haloalkoxy, nitro, carboxyl, and _C1 - _C4 alkoxycarbonylmethyl;

^R2 is selected from hydrogen, _C1 - _C4 alkyl, unsubstituted or halogen, C1 _{- C4} alkyl, _C1 - _C4 haloalkyl, C1- _C4 alkoxy, C1 _{- C4} haloalkoxy, phenyl substituted with _{nitro, unsubstituted or halogen, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy , C1 - C4 haloalkoxy , benzyl} substituted with nitro, _C1 - _C4 alkanoyl;

R ³ is selected from one of hydrogen, halogen, C ₁ -C ₄ alkoxy, C ₁ -C ₄ haloalkoxy, C ₁ -C ₄ alkyl, and C ₁ -C ₄ haloalkyl;

^R4 is selected from hydrogen, _C3 - _C8 cycloalkyl, _C1 - _C4 alkyl, C1-C4 haloalkyl, _C1 - _C4 alkoxy, C1-C4 haloalkoxy, C6-C10 aryl substituted with nitro, C3-C8 cycloalkyl, C1- _C4 alkyl, C1 _- C4 haloalkyl, C1 _- C4 alkoxy, C1 _{- C4} haloalkoxy, C6- _C10 aryl substituted with nitro, C3-C8 cycloalkyl, _C1 -C4 alkyl, C1- _C4 haloalkyl, C1- _C4 alkoxy, C1-C4 haloalkoxy, C6- _C10 aryl substituted with nitro, C3-C8 cycloalkyl, _C1 - _C4 alkyl, C1-C4 haloalkyl, C1 _{- C4} alkoxy, C1-C4 haloalkoxy, C6-C10 aryl substituted with nitro, One of them.

Preferably, ^R4 is selected from hydrogen, cyclohexyl, phenyl, pyridyl, pyrazolyl, One of them.

Furthermore, the organic solvent is selected from one or a mixed solvent of two or more of N,N-dimethylformamide, dioxane, 1,2-dichloroethane, 1,4-dichlorobutane, hexafluoroisopropanol, acetonitrile and trifluorotoluene.

Furthermore, the amount of the organic solvent is a conventional amount in the art, and does not affect the reaction. For example, the volume of the organic solvent is 5-100 L/mol based on the amount of the benzisoselenazolone compound represented by formula II.

Furthermore, the post-treatment is: subjecting the reaction solution to silica gel column chromatography with an eluent, collecting the eluent containing the target compound, and performing reduced pressure rotary evaporation to obtain the selenium-containing benzamide compound represented by formula III; the eluent is a mixed solvent of dichloromethane and methanol in a volume ratio of 40-100:1 or a mixed solvent of petroleum ether and ethyl acetate in a volume ratio of 1-5:1.

In a fourth aspect, the present invention provides a green synthesis method of selenium-containing benzamide compounds shown in Formula 6, wherein the method is:

3-methylindole, 1,2-benzisoselenazole-3-one and a monovalent copper catalyst are dissolved in an organic solvent, and reacted at 60-150°C (preferably 80-100°C, particularly preferably 100°C) in a protective atmosphere (such as _N2 or Ar) for 1-6 hours (preferably 2-4 hours), and the obtained reaction solution is purified to obtain a selenium-containing benzamide compound shown in Formula 6; the monovalent copper catalyst is cuprous iodide, cuprous oxide, thiophene-2-carboxylate copper, cuprous bromide or cuprous acetate (preferably cuprous iodide and cuprous oxide); the molar ratio of the monovalent copper catalyst to the theoretical reaction amount of the raw material is 1-50:100 (preferably 5-10:100), and the theoretical reaction amount of the raw material is calculated based on the compound with a smaller amount of the input substance in the 3-methylindole and 1,2-benzisoselenazole-3-one;

The molar ratio of the substance of the formula 3-methylindole to 1,2-benzisoselenazol-3-one is 1:0.5-4 (preferably 1:0.5-2);

Furthermore, the organic solvent is selected from one or a mixed solvent of two or more of N,N-dimethylformamide, dioxane, 1,2-dichloroethane, 1,4-dichlorobutane, hexafluoroisopropanol, acetonitrile and trifluorotoluene.

Furthermore, the amount of the organic solvent used is a conventional amount in the art, and does not affect the reaction. For example, the volume of the organic solvent is 5-100 L/mol based on the amount of the 1,2-benzisoselenazol-3-one.

Furthermore, the refining treatment is: subjecting the reaction solution to silica gel column chromatography with an eluent, collecting the eluent containing the target compound, and performing reduced pressure rotary evaporation to obtain the selenium-containing benzamide compound represented by Formula 6; the eluent is a mixed solvent of dichloromethane and methanol in a volume ratio of 40-100:1.

Compared with the prior art, the beneficial effects of the present invention are mainly reflected in: benzisoselenazolone is selected as a selenization reagent, with high atom economy and an atom conversion rate of up to 100%; in addition to two raw materials, the reaction system only needs to add a catalytic amount of a monovalent copper catalyst, the catalyst is cheap and easy to obtain, and the reaction system is simple; the reaction is tolerant to both air and water, no inert gas protection is required, the reaction solvent does not need to be dehydrated, and the operation is simple; the reaction yield is high and has excellent functional group tolerance, especially aromatic groups, heteroaromatic groups, aliphatic groups, highly functionalized amino acid side chains and adenosine side chains can be introduced through the ^R4 group.

DETAILED DESCRIPTION

The present invention is described in detail below through specific embodiments, but the protection scope of the present invention is not limited thereto.

Example 1

Indole (35 mg, 0.3 mmol), 1,2-benzisoselenazol-3-one (40 mg, 0.2 mmol), cuprous iodide (3.8 mg, 0.02 mmol) and 2 mL of 1,2-dichloroethane were added to the reaction tube in succession. After nitrogen was replaced, the reaction system was reacted at 100°C for 3 hours. Silica gel was added to mix the sample and purified by silica gel column chromatography (the volume ratio of dichloromethane: methanol was 50:1). The eluate containing the target compound was collected and evaporated under reduced pressure to obtain a white solid product 1 (61 mg, yield 97%, liquid phase purity 99%). ¹ HNMR (500MHz, DMSO-d ₆ ) δ11.64(s,1H),8.04(s,1H),7.76(d,J＝7.6Hz,1H),7.65(d,J＝2.0Hz,1H),7.48(d,J＝7.9Hz,2H),7.33(d,J＝7.9Hz,1H),7.18(t,J =7.6Hz,1H),7.15(t,J＝7.6Hz,1H),7.07(t,J＝7.6Hz,1H),7.05(t,J＝7.6Hz,1H),6.78(d,J＝7.9Hz,1H). ¹³ CNMR(125MHz,DMSO-d ₆ )δ169.4,137.3,136.9,132.9,132.1,130.6,129.9,128.2,128.1,124.4,121.8,119.8,119.1,112.0,97.5.LRMS(ESI)calcd for[M+H] ⁺ [C ₁₅ H ₁₃ N ₂ OSe] ⁺ 317.0,found 317.0.

Example 2

Indole (35 mg, 0.3 mmol), 1,2-benzisoselenazol-3-one (40 mg, 0.2 mmol), cuprous iodide (3.8 mg, 0.02 mmol) and 2 mL of 1,2-dichloroethane were successively added into the reaction tube. After nitrogen was replaced, the reaction system was reacted at 80° C. for 3 hours. The white solid product 1 (55 mg, yield 88%, liquid phase purity 99%) was separated and purified according to the post-treatment method described in Example 1.

Example 3

Indole (35 mg, 0.3 mmol), 1,2-benzisoselenazol-3-one (40 mg, 0.2 mmol), cuprous iodide (3.8 mg, 0.02 mmol) and 2 mL of 1,2-dichloroethane were successively added into the reaction tube. After nitrogen was replaced, the reaction system was reacted at 60° C. for 3 hours. The white solid product 1 (35 mg, yield 55%, liquid phase purity 99%) was separated and purified according to the post-treatment method described in Example 1.

Example 4

Indole (35 mg, 0.3 mmol), 1,2-benzisoselenazol-3-one (40 mg, 0.2 mmol), cuprous iodide (3.8 mg, 0.02 mmol) and 2 mL of 1,2-dichloroethane were added to the reaction tube successively. After nitrogen was replaced, the reaction system was reacted at 40°C for 3 hours, and then the white solid product 1 (14 mg, yield 22%, liquid phase purity 99%) was separated and purified according to the post-treatment method described in Example 1. The reaction yield decreased as the temperature decreased.

Example 5

Indole (35 mg, 0.3 mmol), 1,2-benzisoselenazol-3-one (40 mg, 0.2 mmol), cuprous oxide (3.0 mg, 0.02 mmol) and 2 mL of 1,2-dichloroethane were successively added into the reaction tube. After nitrogen was replaced, the reaction system was reacted at 100 ° C. for 3 hours. The white solid product 1 (60 mg, yield 95%, liquid phase purity 99%) was separated and purified according to the post-treatment method described in Example 1.

Example 6

Indole (35 mg, 0.3 mmol), 1,2-benzisoselenazol-3-one (40 mg, 0.2 mmol), cuprous acetate (2.5 mg, 0.02 mmol) and 2 mL of 1,2-dichloroethane were added successively into the reaction tube. After nitrogen was replaced, the reaction system was reacted at 100 °C for 3 hours and purified by silica gel column chromatography to obtain a white solid product 1 (54 mg, yield 85%, liquid phase purity 99%).

Example 7

Indole (35 mg, 0.3 mmol), 1,2-benzisoselenazol-3-one (40 mg, 0.2 mmol), cuprous iodide (2.5 mg, 0.02 mmol) and 2 mL of 1,4-dichlorobutane were added successively into the reaction tube. After nitrogen was replaced, the reaction system was reacted at 100 °C for 3 hours and purified by silica gel column chromatography to obtain a white solid product 1 (60 mg, yield 95%, liquid phase purity 99%).

Example 8

Indole (35 mg, 0.3 mmol), 1,2-benzisoselenazol-3-one (40 mg, 0.2 mmol), cuprous iodide (2.5 mg, 0.02 mmol) and 2 mL of hexafluoroisopropanol were successively added to the reaction tube. After nitrogen was replaced, the reaction system was reacted at 100 ° C for 3 hours and purified by silica gel column chromatography to obtain a white solid product 1 (57 mg, yield 90%, liquid phase purity 99%).

Embodiment 9

The method described in Example 1 was followed, except that indole was replaced with N-phenylindole (58 mg, 0.3 mmol) and a silica gel column was passed with an eluent having a volume ratio of dichloromethane:methanol of 100:1 to obtain a white solid product 2 (60 mg, yield 77%, liquid phase purity 99%). ¹ H NMR (500MHz, DMSO-d ₆ ) δ8.14(s,1H),7.99(s,1H),7.79(dd,J＝7.6,1.9Hz,1H),7.70–7.66(m,2H),7.66–7.55(m,4H),7.48–7.44(m,1H),7.40(dt,J＝ 7.6, 1.0Hz, 1H), 7.28 (m, J＝8.2, 1H), 7.23–7.11 (m, 3H), 6.96 (dd, J＝8.2, 1.5Hz, 1H). ¹³ C NMR (125MHz, DMSO-d ₆ )δ169.4,138.4,136.7,136.2,135.4,132.0,131.1,131.0,129.9,128.4,128.4,127.0,124.7,124.1,123.3,121.2,120.2,111.0,100.6.LRMS(ESI) calcd for[M+H] ⁺ [C ₂₁ H ₁₇ N ₂ OSe] ⁺ 393.0,found 393.0.

Example 10

The method described in Example 1 was followed, except that indole was replaced with N-methylindole (39 mg, 0.3 mmol) and a dichloromethane:methanol volume ratio of 80:1 was used as an eluent for passing through a silica gel column to obtain a light yellow solid product 3 (42 mg, yield 64%, liquid phase purity 99%). ¹ H NMR (500MHz, DMSO-d ₆ ) δ8.12–8.05(m,1H),7.75(dd,J＝7.5,1.5Hz,1H),7.64(s,1H),7.57–7.52(m,2H),7.31(dt,J＝8.1,1.0Hz,1H),7.24(m,1H),7.1 4(td,J＝7.5,1.5Hz,1H),7.09–7.06(m,2H),6.80(dd,J＝8.1,1.5Hz,1H),3.88(s,3H). ¹³ CNMR(125MHz,DMSO-d ₆ )δ169.5,137.5,137.4,136.9,132.0,130.7,130.4,128.3,128.2,124.5,122.0,120.0,119.4,110.4,96.5,32.7.LRMS(ESI)calcd for[M+H] ⁺ [C ₁₆ H ₁₅ N ₂ OSe] ⁺ 331.0, found 331.0.

Embodiment 11

The method described in Example 1 was followed, except that indole was replaced by 2-methylindole (39 mg, 0.3 mmol), to obtain a yellow solid product 4 (49 mg, yield 74%, liquid phase purity 99%). ¹ H NMR (500MHz, DMSO-d ₆ ) δ11.55(s,1H),8.06(s,1H),7.72(dd,J＝7.6,1.5Hz,1H),7.51(s,1H),7.35(d,J＝7.9Hz,1H),7.21(dd,J＝7.6,1H),7.13(td,J＝7 .1,1.5Hz,1H),7.07(td,J＝7.6,1.5Hz,2H),6.96(td,J＝7.9,1.0Hz,1H),6.68(dd,J＝8.1,1.5Hz,1H),2.43(s,3H). ¹³ C NMR (125MHz, DMSO-d ₆ )δ169.5,142.0,136.9,136.2,132.3,131.0,130.7,128.4,127.7,124.4,121.2,119.6,118.6,111.1,95.7,12.7.LRMS(ESI)calcd for[M+H] ⁺ [C ₁₆ H ₁₅ N ₂ OSe] ⁺ 331.0, found 331.0.

Example 12

The method described in Example 1 was followed, except that indole was replaced with indole-2-acetic acid methyl ester (61 mg, 0.3 mmol) and a dichloromethane:methanol volume ratio of 60:1 was used as an eluent when passing through a silica gel column to obtain a yellow oily product 5 (13 mg, yield 11%, liquid phase purity 99%). ¹ H NMR (500MHz, DMSO-d ₆ ) δ 11.70 (s, 1H), 8.08 (s, 1H), 7.73 (d, J = 7.6Hz, 1H), 7.54 (s, 1H), 7.45 (d, J = 8.6Hz, 1H), 7.25 (d, J = 8.0Hz, 1H), 7.12 (d, J = 6.9Hz, 2H), 7.03 (dt, J＝28.0, 8.1Hz, 2H), 6.72 (d, J＝8.1Hz, 1H), 4.01 (d, J＝7.6Hz, 2H), 3.93 (s, 2H), 1.09 (t, J＝7.5Hz, 3H). ¹³ C NMR (151MHz, DMSO-d ₆ )δ169.4,169.4,138.1,136.6,136.5,132.1,130.6,130.3,128.3,128.2,124.5,121.9,119.8,119.1,111.6,97.8,60.6,32.9,13.9.LRMS(ESI)calcd for[M +H] ⁺ [C ₁₉ H ₁₉ N ₂ O ₃ Se] ⁺ 403.0,found403.0.

Example 13

The method described in Example 1 was followed, except that indole was replaced with 3-methylindole (39 mg, 0.3 mmol), to obtain a yellow solid product 6 (34 mg, yield 52%, liquid phase purity 99%). It is worth noting that when there is no substituent at the C-3 position of indole, the selenization reaction occurs selectively at the C-3 position; when there is a substituent at the C-3 position of indole, the selenization reaction occurs at the C-2 position, as shown in this example. ¹ H NMR (500MHz, DMSO-d ₆ ) δ11.21(s,1H),8.15(s,1H),7.84(dd,J＝6.1,3.6Hz,1H),7.62(s,1H),7.55(d,J＝7.6Hz,1H),7.33(d,J＝8.0Hz,1H),7.22–7.18( m,2H),7.12(td,J＝7.0,1.5Hz,1H),7.05(t,J＝8.1Hz,1H),6.62(m,1H),2.27(s,3H). ¹³ C NMR (125MHz, DMSO-d ₆ )δ169.2,137.9,136.4,131.4,131.4,128.6,128.2,127.7,125.0,122.2,120.7,118.8,118.6,118.2,111.1,10.1.LRMS(ESI)calcd for[M+H] ⁺ [C ₁₆ H ₁₅ N ₂ OSe] ⁺ 331.0, found 331.0.

Embodiment 14

The method described in Example 1 was followed, except that indole was replaced by 4-methylindole (39 mg, 0.3 mmol), to obtain a white-grey solid product 7 (42 mg, yield 64%, liquid phase purity 99%). ¹ H NMR (500MHz, DMSO-d ₆ ) δ 11.54 (s, 1H), 8.05 (s, 1H), 7.76 (dd, J = 6.1, 3.5Hz, 1H), 7.54 (d, J = 2.5Hz, 1H), 7.47 (s, 1H), 7.32 (d, J = 7.9Hz, 1H), 7.13 (dd, J = 6. 1,3.5Hz,2H),7.03(t,J＝7.5Hz,1H),6.88(dd,J＝6.1,3.5Hz,1H),6.74(d,J＝7.0Hz,1H),2.47(d,J＝12.0Hz,3H). ¹³ C NMR (125MHz, DMSO-d ₆ )δ169.3,139.9,137.3,133.7,131.5,130.8,130.4,128.4,128.2,127.4,124.3,121.8,121.2,110.0,96.8,18.3.LRMS(ESI)calcd for[M+H] ⁺ [C ₁₆ H ₁₅ N ₂ OSe] ⁺ 331.0, found 331.0.

Embodiment 15

2-Chloroselenobenzoyl chloride (200 mg, 0.79 mmol) was dissolved in 10 mL of acetonitrile, and then added dropwise into 15 mL of acetonitrile solution containing 3-amino-5-methylpyrazole (83 mg, 0.86 mmol) and triethylamine (28 mg, 1.18 mmol). After reacting at room temperature overnight, the mixture was purified by silica gel column chromatography (the volume ratio of petroleum ether: ethyl acetate was 3:2). The eluate containing the target compound was collected and evaporated under reduced pressure to obtain a white solid raw material 8 (55 mg, yield 25%, liquid phase purity 99%). ¹ H NMR (500MHz, DMSO-d ₆ ) δ12.26(s,1H),8.05(d,J＝8.1Hz,1H),7.87(d,J＝7.4Hz,1H),7.64(t,J＝7.4Hz,1H),7.45(t,J＝7.4Hz,1H),6.64(s,1H),2.26(s,3H ). ¹³ C NMR (125MHz, DMSO-d ₆ ) δ164.0,148.4,139.8,139.1,132.2,128.9,127.3,126.0,125.9,95.2,10.9.LRMS(ESI)calcd for[M+H] ⁺ [C ₁₁ H ₁₀ N ₃ OSe] ⁺ 280.0, found 280.0.

The method described in Example 1 was followed, except that indole was replaced by 6-ethoxyindole (48 mg, 0.3 mmol), 1,2-benzisoselenazol-3-one was replaced by raw material 8 (56 mg, 0.2 mmol), and a dichloromethane:methanol volume ratio of 40:1 was used as an eluent when passing through a silica gel column to obtain a yellow solid product 8 (62 mg, yield 71%, liquid phase purity 99%). ¹ H NMR (500MHz, DMSO-d ₆ ) δ11.46(s,1H),11.16(s,1H),7.85(d,J＝6.8Hz,1H),7.52(d,J＝2.0Hz,1H),7.23–7.11(m,3H),6.97(d,J＝2.4Hz,1H),6.86(dd,J＝ 8.1,1.0Hz,1H),6.68(dd,J＝8.5,2.0Hz,1H),6.43(s,1H),4.04(q,J＝6.8Hz,2H),2.29(s,3H),1.35(t,J＝6.8Hz,3H). ¹³ CNMR(125MHz,DMSO-d ₆ )δ165.7,155.4,145.5,140.5,137.7,137.6,131.9,131.3,128.8,128.5,124.7,123.8,119.8,110.7,96.7,96.3,95.8,63.2,14.8,10.9.LRMS(ESI) calcdfor[M+H] ⁺ [C ₂₁ H ₂₁ N ₄ O ₂ Se] ⁺ 441.1, found 441.1.

Example 16

The method described in Example 1 was followed, except that indole was replaced by 7-methoxyindole (44 mg, 0.3 mmol), 1,2-benzisoselenazol-3-one was replaced by raw material 8 (56 mg, 0.2 mmol), and a dichloromethane:methanol volume ratio of 40:1 was used as an eluent when passing through a silica gel column to obtain a yellow solid product 9 (58 mg, yield 68%, liquid phase purity 99%). ¹ H NMR (500MHz, DMSO-d ₆ ) δ11.81(s,1H),11.21–11.07(m,1H),7.85(d,J＝6.9Hz,1H),7.55(d,J＝2.5Hz,1H),7.23–7.08(m,2H),6.97(t,J＝8.1Hz,1H),6. 91(d,J＝8.1Hz,1H),6.82(d,J＝7.8Hz,1H),6.73(d,J＝7.6Hz,1H),6.42(s,1H),3.93(s,3H),2.28(s,3H). ¹³ C NMR (125MHz, DMSO-d ₆ )δ165.7,146.5,145.6,140.4,137.5,132.7,131.8,131.4,131.3,128.8,128.4,127.0,124.7,120.6,111.8,102.5,97.3,96.3,55.3,10.8.LRMS(ES I)calcd for[M+H] ⁺ [C ₂₀ H ₁₉ N ₄ O ₂ Se] ⁺ 427.1,found 427.1.

Embodiment 17

The method described in Example 1 was followed, except that indole was replaced with 5-fluoroindole (40 mg, 0.3 mmol), to obtain a white solid product 10 (56 mg, yield 84%, liquid phase purity 99%). ¹ H NMR(500MHz,DMSO-d ₆ )δ11.75(s,1H),8.09(s,1H),7.74(dd,J＝7.4,2.0Hz,1H),7.71(d,J＝2.4Hz,1H),7.53(s,1H),7.51(dd,J＝9.1,4.4Hz,1H),7.14(td,J＝7.4,1.5Hz,1H),7.10(td,J＝7.4,2.0Hz,1H),7.01(td,J＝9.1,2.5Hz,1H),6.95(dd,J＝9.5,2.0Hz,1H),6.74(dd,J＝7.9,1.5Hz,1H). ¹³ C NMR(125MHz,DMSO-d ₆ )δ169.4,158.5(d,J＝233.1Hz),137.0,135.1,133.5,132.1,130.8,130.7(d,J＝9.9Hz),128.4,128.0,124.6,113.3(d,J＝9.8Hz),110.1(d,J＝26.3Hz) ,103.6(d,J＝23.3Hz),97.6(d,J＝4.8Hz).LRMS(ESI)calcd for[M+H] ⁺ [C ₁₅ H ₁₂ FN ₂ OSe] ⁺ 335.0,found 335.0.

Embodiment 18

The method described in Example 1 was followed, except that indole was replaced with 5-chloroindole (45 mg, 0.3 mmol), to obtain a yellow solid product 11 (64 mg, yield 92%, liquid phase purity 99%). ¹ H NMR (500MHz, DMSO-d ₆ ) δ11.85(s,1H),8.09(s,1H),7.81–7.70(m,2H),7.57–7.53(m,2H),7.23(s,1H),7.20–7.09(m,2H),6.74(dd,J＝8.1,1.5Hz,1H). ¹³ C NMR (125MHz, DMSO-d ₆ ) δ169.4,136.9,135.4,134.9,132.1,131.3,130.9,128.4,128.0,124.7,124.6,122.0,118.2,113.8,97.3.LRMS(ESI)calcd for[M+H] ⁺ [C ₁₅ H ₁₂ ClN ₂ OSe] ⁺ 351.0,found 351.0.

Embodiment 19

The method described in Example 1 was followed, except that indole was replaced with 5-bromoindole (59 mg, 0.3 mmol) and a silica gel column was passed with an eluent having a volume ratio of dichloromethane:methanol of 60:1 to obtain a yellow solid product 12 (55 mg, yield 70%, liquid phase purity 99%). ¹ H NMR (500MHz, DMSO-d ₆ ) δ11.87(s,1H),8.07(s,1H),7.78(dd,J＝7.6,1.5Hz,1H),7.75(d,J＝2.5Hz,1H),7.56(s,1H),7.49(d,J＝8.4Hz,1H),7.39(d,J＝1 .8Hz, 1H), 7.29 (dd, J＝9.0, 1.8Hz, 1H), 7.14 (m, 2H), 6.74 (dd, J＝7.6, 1.5Hz, 1H). ¹³ C NMR (125MHz, DMSO-d ₆ )δ169.4,136.9,135.7,134.7,132.0,132.0,130.9,128.4,128.0,124.6,124.5,121.2,114.2,112.6,97.2.LRMS(ESI)calcd for[M+H] ⁺ [C ₁₅ H ₁₂ BrN ₂ OSe] ⁺ 394.9, found 394.9.

Embodiment 20

The method described in Example 1 was followed, except that indole was replaced with 5-iodoindole (73 mg, 0.3 mmol) and a silica gel column was passed with an eluent having a volume ratio of dichloromethane:methanol of 60:1 to obtain a yellow solid product 13 (69 mg, yield 78%, liquid phase purity 99%). ¹ H NMR (500MHz, DMSO-d ₆ ) δ11.85(s,1H),8.11(s,1H),7.78(dd,J＝6.9,1.4Hz,1H),7.67(d,J＝2.5Hz,1H),7.61(d,J＝1.4Hz,1H),7.56(s,1H),7.42(dd,J＝8 .4,1.4Hz,1H),7.37(d,J＝8.4Hz,1H),7.20–7.10(m,2H),6.74(dd,J＝7.5,1.4Hz,1H). ¹³ CNMR(151MHz,DMSO-d ₆ )δ169.4,137.0,136.1,134.2,132.7,132.0,130.9,129.9,128.4,127.9,127.4,124.6,114.6,96.8,83.9,39.5.LRMS(ESI)calcd for[M+H] ⁺ [C ₁₅ H ₁₂ IN ₂ OS e] ⁺ 442.9,found 442.9.

Embodiment 21

The method described in Example 1 was followed, except that indole was replaced with 5-methoxyindole (44 mg, 0.3 mmol), to obtain a yellow solid product 14 (38 mg, yield 55%, liquid phase purity 99%). ¹ H NMR (500MHz, DMSO-d ₆ ) δ11.60(s,1H),8.08(s,1H),7.76(dd,J＝7.4,1.8Hz,1H),7.57(d,J＝3.0Hz,1H),7.50(s,1H),7.40(d,J＝8.4Hz,1H),7.11(m,2H) ,6.82(d,J＝1.8Hz,1H),6.81(d,J＝1.8Hz,1H),6.80(d,J＝1.8Hz,1H),3.66(s,3H). ¹³ C NMR (125MHz, DMSO-d ₆ )δ169.5,154.1,137.5,133.5,132.0,131.8,130.7,130.7,128.3,128.0,124.4,112.9,112.0,100.6,97.0,55.2.LRMS(ESI)calcd for[M+H] ⁺ [C ₁₆ H ₁₅ N ₂ O ₂ Se] ⁺ 347.0,found 347.0.

Example 22

The method described in Example 1 was followed, except that indole was replaced with 5-nitroindole (49 mg, 0.3 mmol), to obtain a yellow solid product 15 (45 mg, yield 63%, liquid phase purity 99%). ¹ H NMR (500MHz, DMSO-d ₆ ) δ12.36 (s, 1H), 8.19 (d, J = 2.4Hz, 1H), 8.17 (s, 1H), 8.09 (dd, J = 9.0, 2.4Hz, 1H), 7.97 (d, J = 2.0Hz, 1H), 7.81 (dd, J = 8.1, 1.5Hz, 1H) ,7.72(d,J＝9.0Hz,1H),7.61(s,1H),7.18(td,J＝6.8,1.0Hz,1H),7.12(td,J＝8.1,1.5Hz,1H),6.74(dd,J＝8.1,1.0Hz,1H). ¹³ C NMR (125MHz, DMSO-d ₆ )δ169.4,141.4,140.4,137.2,136.6,131.9,131.1,129.6,128.6,128.0,124.9,117.4,115.8,112.9,100.7.LRMS(ESI)calcd for[M+H] ⁺ [C ₁₅ H ₁₂ N ₃ O ₃ Se ] ⁺ 362.0,found 362.0.

Embodiment 23

The method described in Example 1 was followed, except that indole was replaced with 7-methylindole (39 mg, 0.3 mmol), to obtain a brown solid product 16 (21 mg, yield 32%, liquid phase purity 99%). ¹ H NMR (500 MHz, DMSO-d ₆ ) δ 11.60 (s, 1H), 8.05 (s, 1H), 7.74 (d, J = 7.6 Hz, 1H), 7.63 (t, J = 2.5 Hz, 1H), 7.50 (s, 1H), 7.17-7.04 (m, 3H), 6.99-6.92 (m, 2H), 6.79 (d, J = 7.8 Hz, 1H), 2.51 (s, 3H). ¹³ C NMR (125 MHz, DMSO-d ₆ )δ169.4,137.4,136.3,132.6,132.1,130.6,129.6,128.2,128.2,124.3,122.4,121.2,120.0,116.8,97.9,16.6.LRMS(ESI)calcd for[M+H] ⁺ [C ₁₆ H ₁₅ N ₂ OSe] ⁺ 331.0, found 331.0.

Embodiment 24

The method described in Example 1 was followed, except that 1,2-benzisoselenazole-3-one was replaced with 2-cyclohexyl-1,2-benzisoselenazole-3-one (56 mg, 0.2 mmol), and a volume ratio of petroleum ether to ethyl acetate of 5:1 was used as an eluent for silica gel column to obtain a yellow solid product 17 (44 mg, yield 55%, liquid phase purity 99%). ¹ H NMR (500 MHz, DMSO-d ₆ ) δ 11.65 (s, 1H), 8.32 (d, J = 7.4 Hz, 1H), 7.66 (d, J = 2.5 Hz, 1H), 7.64 (d, J = 6.6 Hz, 1H), 7.48 (d, J = 8.1 Hz, 1H), 7.33 (d, J = 8.1 Hz, 1H), 7.15 (t, J = 7.4 Hz, 1H), 7.13 (t, J = 7. 4Hz,1H),7.08–7.01(m,2H),6.77(d,J＝8.1Hz,1H),3.82–3.72(m,1H),1.93–1.85(m,2H),1.78–1.74(m,2H),1.65–1.57(m,1H),1.41–1.25(m,4H),1 .22–1.10(m,1H). ¹³ C NMR (125MHz, DMSO-d ₆ ) δ167.2,137.3,136.9,133.9,133.5,130.8,130.4,128.6,128.4,124.9,122.4,120.4,119.6,112.5,97.6,48.9,32.9,25.8 ,25.4.LRMS(ESI)calcd for[M+H] ⁺ [C ₂₁ H ₂₃ N ₂ OSe] ⁺ 399.1,found 399.1.

Embodiment 25

The method described in Example 1 was followed, except that 1,2-benzisoselenazol-3-one was replaced with raw material 18 (75 mg, 0.2 mmol), and a volume ratio of petroleum ether to ethyl acetate of 3:1 was used as an eluent for silica gel column to obtain a gray solid product 18 (84 mg, yield 85%, liquid phase purity 99%). ¹ H NMR (500 MHz, CDCl ₃ ) δ8.57 (s, 1H), 7.55 (d, J＝7.4 Hz, 1H), 7.47–7.43 (m, 2H), 7.41 (dd, J＝8.1, 2.0 Hz, 1H), 7.25 (d, J＝7.4 Hz, 1H), 7.15 (t, J＝7.4 Hz, 1H), 7.09–7.01 (m, 4H), 6.95 (dd, J＝7.4, 1 .5Hz,1H),6.78(d,J＝8.1Hz,2H),6.65(d,J＝6.9Hz,1H),5.19(s,1H),5.13(m,1H),3.81(s,3H),3.33(dd,J＝14.0,6.0Hz,1H),3.22(dd,J＝14.0,5.0Hz,1H ),1.61(s,1H). ¹³ C NMR (151MHz, CDCl ₃ ) δ172.2,168.0,155.1,137.4,136.7,132.1,131.9,131.3,130.5,130.1,129.5,127.4,127.1,124.9,122.8,120.7,120.3,1 15.6,111.5,98.8,53.9,52.6,37.0.LRMS(ESI)calcd for[M+H] ⁺ [C ₂₅ H ₂₃ N ₂ O ₄ Se] ⁺ 495.1, found 495.1.

Embodiment 26

The method described in Example 1 was followed, except that indole was replaced by N-methylindole, 1,2-benzisoselenazol-3-one was replaced by raw material 19 (80 mg, 0.2 mmol), and the eluent was petroleum ether:ethyl acetate in a volume ratio of 3:1 when passing through a silica gel column, to obtain a yellow solid product 19 (50 mg, yield 64%, liquid phase purity 99%). ¹ H NMR (500 MHz, CDCl ₃ )δ8.21(s,1H),7.62(d,J＝8.1Hz,1H),7.57(d,J＝7.4Hz,1H),7.41(d,J＝8.4Hz,1H),7.35(d,J＝8.4Hz,1H),7.31(m,3H),7.18(m,2H),7.11(d,J＝7.4Hz,1 H),7.09(d,J＝2.5Hz,1H),6.98(m,3H),6.73(d,J＝7.4Hz,1H),5.25–5.20(m,1H),3.85(s,3H),3.74(s,3H),3.56(dd,J＝15.2,5.5Hz,1H),3.48(dd,J＝1 5.2,5.0Hz,1H). ¹³ C NMR (125MHz, CDCl ₃ ) δ172.3,167.8,138.0,137.8,136.2,136.1,131.8,131.1,131.0,129.5,127.8,127.2,124.6,123.0,122.4,122.2,120.6,120.4 ,119.7,118.8,111.2,110.1,109.5,97.3,53.6,52.5,33.0,27.7.LRMS(ESI)calcd for[M+H] ⁺ [C ₂₈ H ₂₆ N ₃ O ₃ Se] ⁺ 532.1,found 532.1.

Embodiment 27

A solution of o-chloroselenobenzoyl chloride (200 mg, 0.79 mmol) in acetonitrile was added dropwise to an acetonitrile solution containing serine methyl ester hydrochloride (134 mg, 0.86 mmol) and potassium carbonate (162 mg, 1.17 mmol). The mixture was then reacted overnight at room temperature, extracted with water and ethyl acetate, and the organic phase was separated, dried over anhydrous magnesium sulfate, filtered, concentrated, and purified by silica gel column chromatography (volume ratio of petroleum ether: ethyl acetate was 1:1). The eluate containing the target compound was collected and vacuum rotary evaporated to obtain a white solid raw material 20 (83 mg, yield 35%, liquid phase purity 99%). ¹ H NMR (400MHz, DMSO-d ₆ ) δ8.12(d,J＝8.1Hz,1H),7.83(d,J＝7.5Hz,1H),7.65–7.53(m,1H),7.47–7.35(m,1H),5.71(t,J＝4.7Hz,1H),5.17(t,J＝3.5Hz,1H ), 4.09 (dt, J＝11.2, 4.0Hz, 1H), 3.82–3.73 (m, 1H), 3.67 (s, 3H). ¹³ C NMR (125MHz, CDCl ₃ )δ170.0,167.3,141.5,131.4,127.0,126.9,125.7,125.4,61.8,57.4,52.1.LRMS(ESI)calcd for[M+H] ⁺ [C ₁₁ H ₁₂ NO ₄ Se] ⁺ 302.0,found 302.0.

The method described in Example 1 was followed, except that 1,2-benzisoselenazol-3-one was replaced with raw material 20 (60 mg, 0.2 mmol), to obtain white solid product 20 (55 mg, yield 66%, liquid phase purity 99%). ¹ H NMR (400MHz, CDCl ₃ ) δ8.78(s,1H),7.60(dd,J＝7.5,1.5Hz,1H),7.56(d,J＝8.0Hz,1H),7.48(s,1H),7.45(d,1.5Hz,1H),7.29–7.19(m,2H),7.14(t,J＝7 .5Hz,1H),7.07(td,J＝7.2,1.5Hz 1H),7.08–6.92(m,2H),4.96(t,J＝3.6Hz,1H),4.15(d,J＝3.2Hz,2H),3.84(s,3H),2.84(s,1H). ¹³ CNMR(125MHz, CDCl ₃ )δ171.0,168.6,137.5,136.7,132.0,131.6,131.4,130.1,129.6,127.5,124.9,122.9,120.8,120.4,111.5,98.9,63.4,55.2,52.9.LRMS(ESI)calcd for[M +H] ⁺ [C ₁₉ H ₁₉ N ₂ O ₄ Se] ⁺ 419.0, found 419.0.

Embodiment 28

The method described in Example 27 for the raw material 20 was followed, except that the substrate used was dimethyl glutamate hydrochloride (182 mg, 0.86 mmol), to obtain a yellow solid raw material 21 (90 mg, 32%, liquid phase purity 99%). ¹ H NMR (500 MHz, CDCl ₃ ) δ8.04 (d, J=7.4 Hz, 1H), 7.66 (d, J=7.9 Hz, 1H), 7.58 (td, J=7.0, 1.5 Hz, 1H), 7.43-7.35 (m, 1H), 5.41 (dd, J=9.5, 4.5 Hz, 1H), 3.75 (s, 3H), 3.65 (s, 3H), 2.47-2.28 (m, 3H), 2.17-2.08 (m, 1H). ¹³ C NMR (151 MHz, CDCl ₃ )δ172.5,171.2,167.8,139.1,132.4,128.9,126.4,126.2,123.8,55.0,52.7,51.8,30.2,28.1.LRMS(ESI)calcd for[M+H] ⁺ [C ₁₄ H ₁₆ NO ₅ Se] ⁺ 358.0, found 358 .0.

The method described in Example 1 was followed, except that 1,2-benzisoselenazol-3-one was replaced with raw material 21 (71 mg, 0.2 mmol), and a silica gel column was passed with an eluent having a volume ratio of petroleum ether:ethyl acetate of 1:1 to obtain a yellow solid product 21 (30 mg, yield 32%, liquid phase purity 99%). ¹ H NMR (500MHz, CDCl ₃ ) δ8.76(s,1H),7.57(dd,J＝7.6,1.5Hz,2H),7.47(s,1H),7.45(d,J＝5.6Hz,1H),7.26(t,J＝7.5,1H),7.15(m,2H),7.05(m,2H),6.99 (d,J＝8.1Hz,1H),4.93(m,1H),3.82(s,3H),3.67(s,3H),2.68–2.49(m,2H),2.45–2.32(m,1H),2.23(m,1H). ¹³ C NMR (125MHz, CDCl ₃ )δ173.6,172.4,168.1,137.8,136.7,132.0,131.5,131.3,130.2,129.5,127.3,124.8,122.8,120.8,120.4,111.4,99.1,52.7,52.3,51.9,30.2 ,27.4.LRMS(ESI)calcd for[M+H] ⁺ [C ₂₃ H ₂₅ N ₂ O ₅ Se] ⁺ 489.1,found489.1.

Embodiment 29

According to the method described in Example 27, starting material 20, except that the substrate used was 2,3,5-triacetyladenosine (338 mg, 0.86 mmol), a yellow solid starting material 22 (153 mg, 34%, liquid phase purity 99%) was obtained. ¹ H NMR (400MHz, CDCl ₃ ) δ 8.74 (s, 1H), 8.31 (s, 1H), 8.17 (d, J = 7.8Hz, 1H), 7.67 (m, 2H), 7.43 (m, 1H), 6.33 (d, J = 5.6Hz, 1H), 5.98 (t, J = 5.6Hz, 1H), 5.67 (t ,J＝4.0Hz,1H),4.47(t,J＝4.0Hz,1H),4.45–4.39(m,2H),2.14(s,3H),2.13(s,3H),2.08(s,3H). ¹³ C NMR (125MHz, CDCl ₃ )δ170.3,169.5,169.2,164.4,153.0,151.8,149.1,141.2,139.5,133.5,129.6,128.7,126.4,124.7,123.9,86.2,80.5,72.9,70.7,63.1,20.7, 20.5,20.3.LRMS(ESI)calcd for[M+H] ⁺ [C ₂₃ H ₂₂ N ₅ O ₈ Se] ⁺ 576.1,found 576.1.

The method described in Example 1 was followed, except that 1,2-benzisoselenazol-3-one was replaced with raw material 22 (115 mg, 0.2 mmol), and a dichloromethane:methanol volume ratio of 60:1 was used as an eluent when passing through a silica gel column to obtain a yellow solid product 22 (32 mg, yield 24%, liquid phase purity 99%). ¹ H NMR (400 MHz, CDCl ₃ )δ9.29(s,1H),8.95(s,1H),8.85(s,1H),8.23(s,1H),7.81(d,J＝7.6Hz,1H),7.55(m,2H),7.44(d,J＝7.8Hz,1H),7.26(d,J＝7.8Hz,1H),7.17–7.05(m, 4H),6.27(d,J＝5.6Hz,1H),5.98(t,J＝5.6Hz,1H),5.68(t,J＝4.8Hz,1H),4.47(t,J＝3.6Hz,1H),4.44–4.36(m,2H),2.18(s,3H),2.14(s,3H),2.08(s,3H ). ¹³ C NMR (125MHz, CDCl ₃ ) δ170.3,169.6,169.4,141.3,139.8,136.7,132.2,132.1,130.2,130.1,124.9,122.8,120.7,120.4,111.4,86.3,80.5,73.1,70.7,63.0,20 .7,20.5,20.3.LRMS(ESI)calcd for[M+H] ⁺ [C ₃₁ H ₂₉ N ₆ O ₈ Se] ⁺ 693.1,found 693.1.

Embodiment 30

The method described in Example 27 for the raw material 20 was followed, except that the substrate used was cysteine methyl ester hydrochloride (160 mg, 0.86 mmol), and the eluent was petroleum ether:ethyl acetate in a volume ratio of 2:1 when passing through a silica gel column, to obtain a yellow solid raw material 23 (89 mg, 34%, liquid phase purity 99%). ¹ H NMR (500 MHz, CDCl ₃ ) δ8.05 (d, J＝8.1 Hz, 1H), 7.64 (d, J＝7.6 Hz, 1H), 7.62 (td, J＝7.6, 1.5 Hz, 1H), 7.43-7.37 (m, 1H), 5.61 (dd, J＝7.6, 5.9 Hz, 1H), 3.81 (s, 3H), 3.07-2.95 (m, 2H), 2.16 (s, 3H). ¹³ C NMR (125 MHz, CDCl ₃ )δ170.6,167.9,139.7,132.3,128.9,126.3,126.1,123.8,54.9,52.8,37.0,16.1.LRMS(ESI)calcdfor[M+H] ⁺ [C ₁₂ H ₁₄ NO ₃ SSe] ⁺ 332.0,found 332.0.

The method described in Example 1 was followed, except that 1,2-benzisoselenazole-3-one was replaced with raw material 23 (66 mg, 0.2 mmol), and a dichloromethane:methanol volume ratio of 60:1 was used as an eluent when passing through a silica gel column to obtain a yellow oily product 23 (63 mg, yield 70%, liquid phase purity 99%). ¹ H NMR (500MHz, CDCl ₃ ) δ8.89(s,1H),7.63(d,J＝8.1Hz,1H),7.56(d,J＝8.1Hz,1H),7.49(dd,J＝5.5,3.0Hz,2H),7.29–7.25(m,1H),7.12(m,3H),7.05(t,J＝8 .1Hz,1H),6.97(d,J＝7.9Hz,1H),5.11(q,J＝5.2Hz,1H),3.85(s,3H),3.25(dd,J＝14.0,5.0Hz,1H),3.16(dd,J＝14.1,5.1Hz,1H),2.17(s,3H). ¹³ C NMR(125 MHz, CDCl ₃ )δ171.4,168.0,137.7,136.7,132.1,131.6,131.4,130.1,129.5,127.3,124.8,122.8,120.7,120.3,111.5,98.8,52.7,52.3,36.5,16.4.LRMS(ESI )calcd for[M+H] ⁺ [C ₂₀ H ₂₁ N ₂ O ₃ SSe] ⁺ 449.0,found 449.0.

In vitro antitumor activity assay

The CCK-8 method was used to select human breast cancer MCF-7 cells for in vitro antitumor activity evaluation (triptolide was used as a positive control), and the operation was as follows:

1. Inoculate 100 μL of MCF-7 cell suspension in a 96-well plate, with a cell density of 1×10 ⁴ cells per well. Set up a blank control without cells. Pre-culture the 96-well plate in an incubator for 24 hours (37°C, 5% CO ₂ ) to allow the cells to adhere to the wall.

2. Add 10 μL of the test compound at a concentration of 50 μM to the culture wells, and set up 3 parallel wells for each concentration (set up a control group without drug). After incubation in the incubator for 72 hours, add 10 μL of CCK-8 solution to each well, and incubate the 96-well plate in the incubator for 1-4 hours;

3. Measure the absorbance at 450nM using an ELISA reader:

Cell viability (%) = (A _drug -A _blank ) / (A _{0 drug} -A _blank ) × 100%

A _: Absorbance of the wells containing cell suspension, CCK-8 solution and test compound solution

A _Blank : The absorbance of the wells containing no cell suspension, culture medium solution, CCK-8 solution and test compound solution

A _{0 drug addition} : absorbance of the wells containing no test compound solution, cell suspension, CCK-8 solution and culture medium solution

Cell inhibition rate (%) = (A _{0 drug addition} - _{A drug addition} ) / (A _{0 drug addition} - _{A blank} ) × 100%

Table 1. Inhibitory effect of some compounds on MCF-7 cells at a concentration of 50 μM

The results in Table 1 show that 7 out of the 14 compounds tested have an inhibition rate of more than 30% on MCF-7 cells at 50 μM, and 2 compounds have an inhibition rate of more than 60%. It can be seen that this class of selenium-containing benzamide compounds has good anti-tumor activity.

The most active compounds, product 8 and product 9, were further selected to test their half-maximal inhibitory concentration IC ₅₀ against human breast cancer MCF-7 cells and human ovarian cancer SKOV-3 cells. The results are shown in Table 2: the IC ₅₀ of product 8 against MCF-7 and SKOV-3 cells were 0.82 and 0.95 μM, respectively; the IC ₅₀ of product 9 against MCF-7 and SKOV-3 cells were 1.92 and 5.26 μM, respectively. These good results further indicate that this class of compounds has significant anti-tumor activity.

Table 2. Inhibitory activity of product 8 and product 9 on MCF-7 and SKOV-3 cells

^Each experiment used 9 concentrations and was repeated at least three times.

The above examples are only for illustrating the technical concept and features of the present invention, and their purpose is to enable people familiar with the technology to understand the content of the present invention and implement it accordingly, and they cannot be used to limit the protection scope of the present invention. Any equivalent transformation or modification made according to the spirit of the present invention should be included in the protection scope of the present invention.

Claims (8)

1. The synthesis method of the selenium-containing benzamide compound shown in the formula III is characterized by comprising the following steps:

dissolving an indole compound shown in a formula I, a benzisoselenazolone compound shown in a formula II and a monovalent copper catalyst in an organic solvent, reacting for 1-6 hours at 60-150 ℃ in a protective atmosphere, and performing aftertreatment on the obtained reaction solution to obtain a selenium-containing benzamide compound shown in a formula III; the cuprous catalyst is cuprous iodide, cuprous oxide, cuprous bromide or cuprous acetate; the ratio of the monovalent copper catalyst to the theoretical reaction amount of the raw material is 1-50: 100, the theoretical reaction amount of the raw materials is calculated by the compound with smaller amount of input substances in the indole compound shown in the formula I and the benzisoselenazolone compound shown in the formula II;

the ratio of the mass of the indole compound shown in the formula I to the mass of the benzisoselenazolone compound shown in the formula II is 1:0.5-4; the organic solvent is one or more than two solvents selected from dioxane, 1, 2-dichloroethane, 1, 4-dichlorobutane and hexafluoroisopropanol;

in the formulas I, II and III,

R ¹ selected from hydrogen, C ₁ -C ₄ Alkyl, C ₁ -C ₄ Haloalkyl, halogen, C ₁ -C ₄ Alkoxy, C ₁ -C ₄ Haloalkoxy, nitro, carboxyl, C ₁ -C ₄ One of alkoxycarbonylmethyl groups;

R ² selected from hydrogen, C ₁ -C ₄ Alkyl, unsubstituted or substituted by halogen, C ₁ -C ₄ Alkyl, C ₁ -C ₄ Haloalkyl, C ₁ -C ₄ Alkoxy, C ₁ -C ₄ One of haloalkoxy, nitro substituted phenyl;

R ³ selected from hydrogen, halogen, C ₁ -C ₄ Alkoxy, C ₁ -C ₄ Haloalkoxy, C ₁ -C ₄ Alkyl, C ₁ -C ₄ One of the haloalkyl groups;

R ⁴ selected from hydrogen, C ₃ -C ₈ Cycloalkyl, unsubstituted or substituted by halogen, C ₁ -C ₄ Alkyl, C ₁ -C ₄ Haloalkyl, C ₁ -C ₄ Alkoxy, C ₁ -C ₄ Haloalkoxy, nitro substituted five-or six-membered heteroaryl,

One of them.

2. The method for synthesizing the selenium-containing benzamide compound shown in the formula III in claim 1, which is characterized in that: the volume of the organic solvent is 5-100L/mol based on the amount of the benzisoselenazolone compound shown in the formula II.

3. The method for synthesizing the selenium-containing benzamide compound shown in the formula III in claim 1, which is characterized in that: the protective atmosphere is nitrogen or argon.

4. The method for synthesizing the selenium-containing benzamide compound shown in the formula III in claim 1, wherein the post-treatment is as follows: performing silica gel column chromatography on the reaction solution by using an eluent, collecting eluent containing a target compound, and performing rotary evaporation under reduced pressure to obtain a selenium-containing benzamide compound shown in the formula III; the eluent is a mixed solvent of dichloromethane and methanol with the volume ratio of 40-100:1 or a mixed solvent of petroleum ether and ethyl acetate with the volume ratio of 1-5:1.

5. The synthesis method of the selenium-containing benzamide compound shown in the formula 6 is characterized by comprising the following steps:

dissolving 3-methylindole, 1, 2-benzisoselenazol-3-one and a monovalent copper catalyst in an organic solvent, reacting for 1-6 hours at 60-150 ℃ in a protective atmosphere, and refining the obtained reaction solution to obtain a selenium-containing benzamide compound shown in a formula 6; the cuprous catalyst is cuprous iodide, cuprous oxide, cuprous bromide or cuprous acetate; the ratio of the monovalent copper catalyst to the theoretical reaction amount of the raw material is 1-50: 100, the theoretical reaction amount of the raw materials is calculated by the compound with smaller amount of substances added into the 3-methylindole and the 1, 2-benzisoselenazol-3-one;

the ratio of the 3-methylindole to the 1, 2-benzisoselenazol-3-one is 1:0.5-4; the organic solvent is one or more than two solvents selected from dioxane, 1, 2-dichloroethane, 1, 4-dichlorobutane and hexafluoroisopropanol;

6. the method for synthesizing the selenium-containing benzamide compound shown in the formula 6 in claim 5, which is characterized in that: the protective atmosphere is nitrogen or argon.

7. The method for synthesizing the selenium-containing benzamide compound shown in the formula 6 in claim 5, which is characterized in that: the volume of the organic solvent is 5-100L/mol based on the amount of the 1, 2-benzisoselenazol-3-one substance.

8. The method for synthesizing the selenium-containing benzamide compound represented by the formula 6 in claim 5, wherein the refining treatment is as follows: performing silica gel column chromatography on the reaction solution by using an eluent, collecting eluent containing a target compound, and performing rotary evaporation under reduced pressure to obtain a selenium-containing benzamide compound shown in the formula 6; the eluent is a mixed solvent of dichloromethane and methanol with the volume ratio of 40-100:1.