A method for photocatalytic preparation of N-dimercaptobenzamide and its derivatives

Abstract

The present invention belongs to the technical field of organic synthesis, and particularly relates to a method for photocatalytic preparation of N-dimercaptobenzamide and its derivatives. The method comprises the following steps: using a compound of formula 1 as a raw material and a compound of formula 2 as a disulfur source, and carrying out a reaction through a photocatalytic system to prepare a compound of formula 3, wherein R<supgt;1< / supgt> and R<supgt;2< / supgt> are each independently selected from an aryl group, an alkyl group or an electron-withdrawing group. The synthesis method of the present invention has simple operation, does not involve metals, has a wide range of applicable reaction substrates, good regioselectivity, high yield, and can greenly and efficiently synthesize a series of novel N-dimercaptobenzamide derivatives, and has broad application prospects in agrochemicals, drug preparation and fluorescent materials.

Description

Technical Field

[0001] The present invention belongs to the technical field of organic synthesis, and particularly relates to a method for photocatalytic preparation of N-dimercaptobenzamide and its derivatives. Background Art

[0002] Polysulfides are present in a variety of therapeutic drugs and play unique roles. Disulfide bonds enhance the stability of higher-order structures and usually appear in three forms: natural products, food chemistry, and medicinal chemistry. For example, the disulfide bridge in insulin, allicin which is the main component in garlic, and the anticancer drug romidepsin, etc. These higher-order structures are also indispensable for the efficiency and specificity of biological actions. In recent decades, the synthetic community has been vigorously pursuing the development of efficient synthetic methods for extracting sulfur-sulfur bonds. Marzo (L. Marzo, S. K. Pagire, O. Reiser, B. Angew.Chem, Int.Ed.2018, 57, 10034 - 10072) et al. reported that photocatalytic transformation is considered an attractive synthetic scheme for constructing disulfide compounds due to its sustainable and green nature. The traditional method for constructing asymmetric disulfides is to gradually introduce sulfur atoms, that is, to construct an S-S bond to achieve the synthesis of asymmetric disulfides. However, these methods still have certain limitations, such as thiols having a strong pungent odor and the need to use transition metals, among which there are noble metals used; the substrate scope is not wide and other defects, which are not conducive to the application of products and their industrial synthesis.

[0003] Chinese Patent CN108191651A provides a preparation method for synthesizing phenolic esters by thio-carboxylic acid-mediated visible-light photocatalytic phenolic acylation reaction. Thio-carboxylic acid compounds react with phenolic compounds site-specifically under certain conditions to prepare phenolic ester compounds. The certain conditions are: under normal temperature, normal pressure and visible light conditions, using K2CO3 as the base catalyst, tris(2,2'-bipyridine)ruthenium(II) dichloride hexahydrate as the photosensitizer, and acetonitrile as the reaction solvent; this invention efficiently realizes site-specific phenolic esterification reaction under mild conditions of normal temperature, normal pressure and visible light irradiation.

[0004] As a cheap and easily available renewable energy source, photoreaction fully meets the requirements of sustainable development in today's era. Photocatalytic transformation is considered a promising alternative method for organic synthesis under mild conditions. They provide a unique direct way to synthesize molecular structures that are usually difficult to synthesize using other reaction types. The development of photocatalytic reactions is an attractive synthetic strategy in synthetic chemistry. Compared with transition metal catalysts, photocatalysis has the advantages of low cost, strong synthetic versatility, non-toxic and environmental protection.

[0005] Therefore, it is of great significance to develop a simple, green and efficient method for photocatalytic synthesis of N-dimercaptobenzamide and its derivatives. Summary of the Invention

[0006] Terms:

[0007] 1. N-dimercaptobenzamide: It is a very important polysulfur compound with benzamide, and it is a nucleophilic disulfide reagent.

[0008] 2. Photosensitizer: Also known as sensitizer, sensitizing agent, photo-crosslinking agent. In a photochemical reaction, a substance that transfers light energy to some reactants that are insensitive to visible light to improve or expand their photosensitive properties.

[0009] 3. Solvent: It is a liquid that can dissolve solid, liquid or gaseous solutes to form a solution. Solvents usually have relatively low boiling points and are easy to volatilize, or can be removed by distillation, leaving the solute behind. Therefore, solvents cannot react chemically with solutes.

[0010] 4. Rose bengal: Purple to reddish-brown granules or powder, soluble in water (30 g / 100 mL) and ethanol, and insoluble in hard water.

[0011] 5. Eosin Y: Eosin Y, also known as tetrabromofluorescein, is a dye and pigment with the molecular formula C 20 H6Br4Na3O5.

[0012] 6. Tris(2-phenylpyridine)iridium: It is a yellow solid under normal temperature and pressure. It is a transition metal complex and is often used as a catalyst in organic chemical reactions. Due to its unique optoelectronic properties, this compound can also be used as an initiator in photochemical reactions.

[0013] The present invention provides a method for photocatalytic preparation of N-dimercaptobenzamide and its derivatives in view of the problems existing in the prior art.

[0014] To achieve the above object, the technical solution adopted by the present invention is as follows:

[0015] A method for preparing N-dimercaptobenzamide and its derivatives, comprising the following steps: using a compound of formula 1 as a raw material and a compound of formula 2 as a disulfur source, and preparing a compound of formula 3 through a reaction in a photocatalytic system,

[0016]

[0017] Wherein, the R 1 , R 2 are each independently selected from aryl, alkyl or electron-withdrawing groups.

[0018] Preferably, the R 1 and R 2 are each independently selected from aryl, C1-C5 alkyl or halogen.

[0019] More preferably, the R 1 is selected from any one of H, methyl, methoxy, halogen, nitro and naphthyl, and the R 2 is selected from any one of methyl, propyl, isopropyl, tert-butyl and tert-octyl. Most preferably, the R 2 is selected from tert-butyl.

[0020] Preferably, the photocatalytic system includes a light source, a photosensitizer, a base and a solvent, and the molar ratio of the base, the photosensitizer, the compound of formula 1 to the compound of formula 2 is 1-3:0.02-0.03:2-2.2:1.

[0021] Preferably, the light source is blue LED, and the photosensitizer is selected from one or more of Rose Bengal, Eosin Y, tris(2-phenylpyridine)iridium and fluorescein.

[0022] More preferably, the light source is 25-35W blue LED, and the photosensitizer is selected from one or more of Rose Bengal, tris(2-phenylpyridine)iridium and Eosin Y. Even more preferably, the photosensitizer is selected from one or two of Rose Bengal and Eosin Y. Most preferably, the light source is 30W blue LED, and the photosensitizer is Rose Bengal.

[0023] Preferably, the base is selected from one or more of tripotassium phosphate, cesium carbonate, 1,8-diazabicyclo[5.4.0]undec-7-ene, triethylamine and potassium tert-butoxide, and the solvent is selected from one or more of 1,2-dichloroethane, dimethyl sulfoxide, dichloromethane, acetonitrile and toluene.

[0024] More preferably, the base is selected from one or more of cesium carbonate, 1,8-diazabicyclo[5.4.0]undec-7-ene, triethylamine and potassium tert-butoxide. Even more preferably, the base is selected from one or more of cesium carbonate, triethylamine and potassium tert-butoxide. Most preferably, the base is potassium tert-butoxide.

[0025] Even more preferably, the solvent is selected from one or more of 1,2-dichloroethane, dichloromethane, acetonitrile and toluene. Even more preferably, the solvent is selected from one or two of dichloromethane and toluene. Most preferably, the solvent is dichloromethane.

[0026] Preferably, the reaction is stirred, the reaction temperature is 20-25°C, the reaction time is 10-14h, and after the reaction by the photocatalytic system, rotary evaporation and purification are also carried out.

[0027] Preferably, the purification is column chromatography purification. The eluent for the column chromatography purification is a mixture of petroleum ether and ethyl acetate with a volume ratio of 6 - 60:1, and the column packing is silica gel with a mesh size of 100 - 200.

[0028] The present invention also provides a synthetic route for the above - mentioned synthesis method:

[0029]

[0030] Compared with the prior art, the present invention has the following beneficial effects:

[0031] (1) By directly synthesizing N - dimercaptobenzamide and its derivatives through photocatalysis, the N - dimercaptobenzamide and its derivatives prepared by the present invention have good yields in gram - scale reactions and are suitable for industrial production.

[0032] (2) The synthesis method of the present invention is simple to operate, does not involve metals, has a wide range of applicable reaction substrates, good regioselectivity, high yields, and can synthesize a series of novel N - dimercaptobenzamide and its derivatives greenly and efficiently, and has broad application prospects in agrochemicals, drug preparation, and fluorescent materials. BRIEF DESCRIPTION OF THE DRAWINGS

[0033] Figure 1 is the 1H NMR spectrum of the target product prepared in Example 1 of the present invention;

[0034] Figure 2 is the 13C NMR spectrum of the target product prepared in Example 1 of the present invention;

[0035] Figure 3 is the 1H NMR spectrum of the target product prepared in Example 2 of the present invention;

[0036] Figure 4 is the 13C NMR spectrum of the target product prepared in Example 2 of the present invention;

[0037] Figure 5 is the 1H NMR spectrum of the target product prepared in Example 3 of the present invention;

[0038] Figure 6 is the 13C NMR spectrum of the target product prepared in Example 3 of the present invention;

[0039] Figure 7 is the 1H NMR spectrum of the target product prepared in Example 4 of the present invention;

[0040] Figure 8 is the 13C NMR spectrum of the target product prepared in Example 4 of the present invention;

[0041] Figure 9 is the 1H NMR spectrum of the target product prepared in Example 5 of the present invention;

[0042] Figure 10 13C NMR spectrum of the target product prepared in Example 5 of the present invention;

[0043] Figure 11 1H NMR spectrum of the target product prepared in Example 6 of the present invention;

[0044] Figure 12 13C NMR spectrum of the target product prepared in Example 6 of the present invention;

[0045] Figure 13 1H NMR spectrum of the target product prepared in Example 7 of the present invention;

[0046] Figure 14 13C NMR spectrum of the target product prepared in Example 7 of the present invention;

[0047] Figure 15 1H NMR spectrum of the target product prepared in Example 8 of the present invention;

[0048] Figure 16 13C NMR spectrum of the target product prepared in Example 8 of the present invention;

[0049] Figure 17 1H NMR spectrum of the target product prepared in Example 9 of the present invention;

[0050] Figure 18 13C NMR spectrum of the target product prepared in Example 9 of the present invention;

[0051] Figure 19 1H NMR spectrum of the target product prepared in Example 10 of the present invention;

[0052] Figure 20 13C NMR spectrum of the target product prepared in Example 10 of the present invention;

[0053] Figure 21 1H NMR spectrum of the target product prepared in Example 11 of the present invention;

[0054] Figure 22 13C NMR spectrum of the target product prepared in Example 11 of the present invention. Detailed Description of the Invention

[0055] It should be noted that the raw materials used in the present invention are all ordinary commercially available products.

[0056] Example 1

[0057] 27.6 mg (0.1 mmol) of trisulfide dioxide, 2.1 mg - 3.1 mg (0.002 mmol - 0.003 mmol) of rose bengal, 24.2 mg - 26.6 mg (0.2 mmol - 0.22 mmol) of benzamide, and 11.2 mg - 33.7 mg (0.1 mmol - 0.3 mmol) of potassium tert-butoxide were placed in a 25 mL test tube with a magnetic stir bar. After adding 1 mL of dichloromethane solution at room temperature, the mixture was stirred for 12 hours under 30 W LED blue light illumination. After evaporation, flash column chromatography (column packing: silica gel 100 - 200 mesh, eluent: petroleum ether / ethyl acetate volume ratio = 10:1) was performed to obtain the target product with a 73% yield.

[0058]

[0059] 1 H NMR (400 MHz, CDCl3) δ ppm 7.75 (d, J = 7.7 Hz, 2H), 7.54 (t, J = 7.3 Hz, 1H), 7.45 (t, J = 7.5 Hz, 2H), 7.20 (s, 1H), 1.42 (s, 9H). As Figure 1 shown.

[0060] 13 C NMR (101 MHz, CDCl3) δ ppm 168.94, 133.72, 132.40, 128.84, 127.58, 49.12, 30.23. As Figure 2 shown.

[0061] HR-ESI-MS m / z calcd. for C 11 H 16 NOS2 [M + H]+: 242.0673, found: 242.0677.

[0062] Example 2

[0063] 27.6 mg (0.1 mmol) of trisulfide dioxide, 2.1 mg - 3.1 mg (0.002 mmol - 0.003 mmol) of rose bengal, 39.7 mg - 43.8 mg (0.2 mmol - 0.22 mmol) of 2-bromobenzamide, and 11.2 mg - 33.7 mg (0.1 mmol - 0.3 mmol) of potassium tert-butoxide were placed in a 25 mL test tube with a magnetic stir bar. After adding 1 mL of dichloromethane solution at room temperature, the mixture was stirred for 12 hours under 30 W LED blue light illumination. After evaporation, flash column chromatography (column packing: silica gel 100 - 200 mesh, eluent: petroleum ether / ethyl acetate volume ratio = 60:1) was performed to obtain the target product with a 71% yield.

[0064]

[0065] 1 1H NMR (400 MHz, CDCl3) δ ppm 7.69 - 7.45 (m, 2H), 7.42 - 7.19 (m, 3H), 1.42 (s, 9H). As Figure 3 shown.

[0066] 13 13C NMR (101 MHz, CDCl3) δ ppm 168.99, 136.55, 133.38, 131.72, 129.35, 127.47, 119.25, 48.89, 30.14. As Figure 4 shown.

[0067] HR-ESI-MS m / z calcd. for C 11 H 14 BrNOS2 [M]+: 318.9700, found: 318.9697.

[0068] Example 3

[0069] 27.6 mg (0.1 mmol) of trisulfide dioxide, 2.1 mg - 3.1 mg (0.002 mmol - 0.003 mmol) of Rose Bengal, 30.2 mg - 33.2 mg (0.2 mmol - 0.22 mmol) of 3-methoxybenzamide, and 11.2 mg - 33.7 mg (0.1 mmol - 0.3 mmol) of potassium tert-butoxide were placed in a 25 mL test tube with a magnetic stir bar. After adding 1 mL of dichloromethane solution at room temperature, the mixture was stirred for 12 hours under 30 W LED blue light irradiation. After rotary evaporation, flash column chromatography (column packing: silica gel 100 - 200 mesh, eluent: petroleum ether / ethyl acetate volume ratio = 6:1) was performed to obtain the target product with a 65% yield.

[0070]

[0071] 1 1H NMR (400 MHz, CDCl3) δ ppm 7.67 (s, 1H), 7.38 - 7.28 (m, 3H), 7.05 (s, 1H), 3.82 (s, 3H), 1.41 (s, 9H). As Figure 5 shown.

[0072] 1313C NMR (101 MHz, CDCl3) δ ppm 168.99, 159.80, 135.01, 129.75, 119.41, 118.61, 112.79, 55.51, 49.01, 30.16. As Figure 6 shown.

[0073] HR-ESI-MS m / z calcd. for C 12 H 17 NO2S2 [M]+: 271.0701, found: 271.0707.

[0074] Example 4

[0075] 27.6 mg (0.1 mmol) of trisulfide dioxide, 2.1 mg - 3.1 mg (0.002 mmol - 0.003 mmol) of rose bengal, 27.8 mg - 30.6 mg (0.2 mmol - 0.22 mmol) of 3-fluorobenzamide, and 11.2 mg - 33.7 mg (0.1 mmol - 0.3 mmol) of potassium tert-butoxide were placed in a 25 mL test tube with a magnetic stir bar. After adding 1 mL of dichloromethane solution at room temperature, the mixture was stirred for 12 hours under 30 W LED blue light irradiation. After evaporation, flash column chromatography (column packing: silica gel 100 - 200 mesh, eluent: petroleum ether / ethyl acetate volume ratio = 30:1) was performed to obtain the target product with a yield of 73%.

[0076]

[0077] 1 1H NMR (400 MHz, CDCl3) δ ppm 7.86 (s, 1H), 7.61 - 7.47 (m, 2H), 7.41 - 7.36 (m, 1H), 7.24 - 7.14 (m, 1H), 1.38 (s, 9H). As Figure 7 shown.

[0078] 13 13C NMR (101 MHz, CDCl3) δ ppm 168.09, 162.67 (d, J = 248.3 Hz), 135.78 (d, J = 6.9 Hz), 130.48 (d, J = 7.7 Hz), 123.17 (d, J = 3.1 Hz), 119.38 (d, J = 21.2 Hz), 115.06 (d, J = 23.1 Hz), 49.12, 30.14. As Figure 8 shown.

[0079] 19 19F NMR (376 MHz, CDCl3) δ ppm -111.33.

[0080] HR-ESI-MS m / z calculated for C 11 H 14 FNOS2[M]+: 259.0501, found: 259.0496。

[0081] Example 5

[0082] 27.6 mg (0.1 mmol) of trisulfide, 2.1 mg - 3.1 mg (0.002 mmol - 0.003 mmol) of Rose Bengal, 27.0 mg - 29.7 mg (0.2 mmol - 0.22 mmol) of 4-methylbenzamide, and 11.2 mg - 33.7 mg (0.1 mmol - 0.3 mmol) of potassium tert-butoxide were placed in a 25 mL test tube with a stir bar. After adding 1 mL of dichloromethane solution at room temperature, the mixture was stirred for 12 hours under 30 W LED blue light irradiation. After evaporation, flash column chromatography (column packing: silica gel 100 - 200 mesh, eluent: petroleum ether / ethyl acetate volume ratio = 6:1) was used to obtain the target product with a yield of 76%.

[0083]

[0084] 1 H NMR (400 MHz, CDCl3) δ ppm 7.67 (d, J = 7.9 Hz, 2H), 7.43 (s, 1H), 7.22 (d, J = 7.9 Hz, 2H), 2.38 (s, 3H), 1.40 (s, 9H). As Figure 9 shown.

[0085] 13 C NMR (101 MHz, CDCl3) δ ppm 168.86, 143.03, 130.82, 129.46, 127.63, 49.04, 30.21, 21.63, 1.12. As Figure 10 shown.

[0086] HR-ESI-MS m / z calculated for C 12 H 17 NOS2[M]+: 255.0752, found: 255.0744。

[0087] Example 6

[0088] 27.6 mg (0.1 mmol) of trisulfide dioxide, 2.1 mg - 3.1 mg (0.002 mmol - 0.003 mmol) of rose bengal, 30.2 mg - 33.2 mg (0.2 mmol - 0.22 mmol) of 4 - methoxybenzamide, and 11.2 mg - 33.7 mg (0.1 mmol - 0.3 mmol) of potassium tert - butoxide were placed in a 25 mL test tube with a magnetic stirrer. After adding 1 mL of dichloromethane solution at room temperature, the mixture was stirred for 12 hours under 30 W LED blue light illumination. After evaporation, flash column chromatography (column packing: silica gel 100 - 200 mesh, eluent: petroleum ether / ethyl acetate volume ratio = 10:1) was carried out to obtain the target product with an 83% yield.

[0089]

[0090] 1 1H NMR (400 MHz, CDCl3) δ ppm 7.73 (d, J = 9.0 Hz, 2H), 7.11 (s, 1H), 6.93 (d, J = 9.1 Hz, 2H), 3.85 (s, 3H), 1.42 (s, 9H). As Figure 11 shown.

[0091] 13 13C NMR (101 MHz, CDCl3) δ ppm 168.24, 162.95, 129.58, 125.90, 114.05, 55.60, 49.08, 30.26. As Figure 12 shown.

[0092] HR - ESI - MS m / z calcd. for C 12 H 17 NO2S2[M]+: 271.0701, found: 271.0693.

[0093] Example 7

[0094] 27.6 mg (0.1 mmol) of trisulfide dioxide, 2.1 mg - 3.1 mg (0.002 mmol - 0.003 mmol) of rose bengal, 27.8 mg - 30.6 mg (0.2 mmol - 0.22 mmol) of 4 - fluorobenzamide, and 11.2 mg - 33.7 mg (0.1 mmol - 0.3 mmol) of potassium tert - butoxide were placed in a 25 mL test tube with a magnetic stirrer. After adding 1 mL of dichloromethane solution at room temperature, the mixture was stirred for 12 hours under 30 W LED blue light illumination. After evaporation, flash column chromatography (column packing: silica gel 100 - 200 mesh, eluent: petroleum ether / ethyl acetate volume ratio = 10:1) was carried out to obtain the target product with a 77% yield.

[0095]

[0096] 1 1H NMR (400 MHz, CDCl3) δ ppm 7.81 - 7.78 (m, 2H), 7.31 (s, 1H), 7.12 (t, J = 8.7 Hz, 2H), 1.41 (s, 9H). As Figure 13 shown.

[0097] 13 13C NMR (101 MHz, CDCl3) δ ppm 167.93, 165.29 (d, J = 253.6 Hz), 130.08 (d, J = 9.2 Hz), 129.88 (d, J = 3.1 Hz), 116.01 (d, J = 22.0 Hz), 49.22, 30.23. As Figure 14 shown.

[0098] 19 19F NMR (376 MHz, CDCl3) δ ppm -106.35.

[0099] HR-ESI-MS m / z calcd. for C 11 H 14 FNOS2 [M]+: 259.0501, found: 259.0499.

[0100] Example 8

[0101] 27.6 mg (0.1 mmol) of trisulfide dioxide, 2.1 mg - 3.1 mg (0.002 mmol - 0.003 mmol) of Rose Bengal, 39.8 mg - 43.8 mg (0.2 mmol - 0.22 mmol) of 4-bromobenzamide, and 11.2 mg - 33.7 mg (0.1 mmol - 0.3 mmol) of potassium tert-butoxide were placed in a 25 mL test tube with a magnetic stir bar. After adding 1 mL of dichloromethane solution at room temperature, the mixture was stirred for 12 hours under 30 W LED blue light irradiation. After evaporation, flash column chromatography (column packing: silica gel 100 - 200 mesh, eluent: petroleum ether / ethyl acetate volume ratio = 10:1) was performed to obtain the target product with a 76% yield.

[0102]

[0103] 1 1H NMR (400 MHz, CDCl3) δ ppm 7.68 - 7.61 (m, 2H), 7.60 - 7.52 (m, 3H), 1.39 (s, 9H). As Figure 15 shown.

[0104] 13 13C NMR (101 MHz, CDCl3) δ ppm 168.28, 132.46, 132.06, 129.23, 127.28, 49.20, 30.20. As Figure 16 shown.

[0105] HR-ESI-MS m / z calcd. for C 11 H 14 BrNOS2 [M]+: 318.9700, found: 318.9692.

[0106] Example 9

[0107] 27.6 mg of thiosulfate trioxide, 2.1 mg - 3.1 mg (0.002 mmol - 0.003 mmol) of Rose Bengal, 33.2 mg - 36.5 mg (0.2 mmol - 0.22 mmol) of 4-nitrobenzamide, and 11.2 mg - 33.7 mg (0.1 mmol - 0.3 mmol) of potassium tert-butoxide were placed in a 25 mL test tube with a magnetic stir bar. After adding 1 mL of dichloromethane solution at room temperature, the mixture was stirred for 12 hours under 30 W LED blue light illumination. After evaporation, flash column chromatography (column packing: silica gel 100 - 200 mesh, eluent: petroleum ether / ethyl acetate volume ratio = 6:1) was performed to obtain the target product with an 82% yield.

[0108]

[0109] 1 1H NMR (400 MHz, CDCl3) δ ppm 8.29 (d, J = 8.4 Hz, 3H), 8.04 (d, J = 8.7 Hz, 2H), 1.41 (s, 9H). As Figure 17 shown.

[0110] 13 13C NMR (101 MHz, CDCl3) δ ppm 167.73, 149.91, 139.08, 129.01, 123.92, 49.33, 30.09. As Figure 18 shown.

[0111] HR-ESI-MS m / z calcd. for C 11 H 14 N2O3S2 [M]+: 286.0446, found: 286.0450.

[0112] Example 10

[0113] Place 27.6 mg (0.1 mmol) of trisulfide dioxide, 2.1 mg - 3.1 mg (0.002 mmol - 0.003 mmol) of rose bengal, 42.6 mg - 46.9 mg (0.2 mmol - 0.22 mmol) of 4-bromo-3-methylbenzamide, and 11.2 mg - 33.7 mg (0.1 mmol - 0.3 mmol) of potassium tert-butoxide in a 25 mL test tube with a magnetic stir bar. After adding 1 mL of dichloromethane solution at room temperature, stir for 12 hours under 30 W LED blue light illumination. After rotary evaporation, perform flash column chromatography (the column packing is silica gel with a mesh size of 100 - 200, and the eluent is a mixture of petroleum ether and ethyl acetate with a volume ratio of 30:1) to obtain the target product with a yield of 78%.

[0114]

[0115] 1 1H NMR (400 MHz, CDCl3) δ ppm 7.64 (s, 1H), 7.57 (d, J = 8.2 Hz, 1H), 7.47 (s, 1H), 7.41 (d, J = 8.3 Hz, 1H), 2.41 (s, 3H), 1.40 (s, 9H). As Figure 19 shown.

[0116] 13 13C NMR (101 MHz, CDCl3) δ ppm 168.41, 138.83, 132.79, 132.69, 129.97, 129.68, 126.14, 49.17, 30.21, 23.08. As Figure 20 shown.

[0117] HR-ESI-MS m / z calcd. for C 12 H 16 BrNOS2 [M]+: 332.9857, found: 332.9851.

[0118] Example 11

[0119] 27.6 mg (0.1 mmol) of trisulfide, 2.1 mg - 3.1 mg (0.002 mmol - 0.003 mmol) of rose bengal, 27.0 mg - 29.7 mg (0.2 mmol - 0.22 mmol) of 2-phenylacetamide, and 11.2 mg - 33.7 mg (0.1 mmol - 0.3 mmol) of potassium tert-butoxide were placed in a 25 mL test tube with a magnetic stir bar. After adding 1 mL of dichloromethane solution at room temperature, the mixture was stirred for 12 hours under 30 W LED blue light illumination. After evaporation, flash column chromatography (the column packing was silica gel of 100 - 200 mesh, and the eluent was petroleum ether and ethyl acetate with a volume ratio of 10:1) was carried out to obtain the target product with a yield of 81%.

[0120]

[0121] 1 H NMR (400 MHz, CDCl3) δ ppm 7.33 - 7.27 (m, 3H), 7.22 (d, J = 7.4 Hz, 2H), 7.05 (d, J =

[0122] 14.7 Hz, 1H), 3.61 (s, 2H), 1.28 (s, 9H). As Figure 21 shown.

[0123] 13 C NMR (101 MHz, CDCl3) δ ppm 172.52, 134.02, 129.38, 129.03, 127.53, 48.87, 44.12, 30.04. As Figure 22 shown.

[0124] HR-ESI-MS m / z calcd. for C 12 H 17 NOS2[M]+: 255.0752, found: 255.0742.

[0125] Comparative Example 1

[0126] Place 27.6 mg (0.1 mmol) of trisulfide dioxide, 2.1 mg - 3.1 mg (0.002 mmol - 0.003 mmol) of rose bengal, 24.2 mg - 26.6 mg (0.2 mmol - 0.22 mmol) of benzamide, and 11.2 mg - 33.7 mg (0.1 mmol - 0.3 mmol) of potassium tert-butoxide in a 25 mL test tube with a stir bar. After adding 1 mL of dichloromethane solution at room temperature, stir for 12 hours under sunlight lamp illumination. After rotary evaporation, perform flash column chromatography (the column packing is silica gel with a mesh size of 100 - 200, and the eluent is a mixture of petroleum ether and ethyl acetate with a volume ratio of 10:1) to obtain the target product with a yield of 42%.

[0127] Comparative Example 2

[0128] Place 27.6 mg (0.1 mmol) of trisulfide dioxide, 2.1 mg - 3.1 mg (0.002 mmol - 0.003 mmol) of rhodamine 6G, 24.2 mg - 26.6 mg (0.2 mmol - 0.22 mmol) of benzamide, and 11.2 mg - 33.7 mg (0.1 mmol - 0.3 mmol) of potassium tert-butoxide in a 25 mL test tube with a stir bar. After adding 1 mL of dichloromethane solution at room temperature, stir for 12 hours under 30W LED blue light illumination. After rotary evaporation, perform flash column chromatography (the column packing is silica gel with a mesh size of 100 - 200, and the eluent is a mixture of petroleum ether and ethyl acetate with a volume ratio of 10:1) to obtain the target product with a yield of 37%.

[0129] Comparative Example 3

[0130] Place 27.6 mg (0.1 mmol) of trisulfide dioxide, 2.1 mg - 3.1 mg (0.002 mmol - 0.003 mmol) of rose bengal, 24.2 mg - 26.6 mg (0.2 mmol - 0.22 mmol) of benzamide, and 11.2 mg - 33.7 mg (0.1 mmol - 0.3 mmol) of potassium carbonate in a 25 mL test tube with a stir bar. After adding 1 mL of dichloromethane solution at room temperature, stir for 12 hours under 30W LED blue light illumination. After rotary evaporation, perform flash column chromatography (the column packing is silica gel with a mesh size of 100 - 200, and the eluent is a mixture of petroleum ether and ethyl acetate with a volume ratio of 10:1) to obtain the target product with a yield of 52%.

[0131] Comparative Example 4

[0132] 27.6 mg (0.1 mmol) of trisulfide ether dioxide, 2.1 mg - 3.1 mg (0.002 mmol - 0.003 mmol) of rose bengal, 24.2 mg - 26.6 mg (0.2 mmol - 0.22 mmol) of benzamide, and 11.2 mg - 33.7 mg (0.1 mmol - 0.3 mmol) of potassium tert-butoxide were placed in a 25 mL test tube with a stir bar. After adding 1 mL of tetrahydrofuran solution at room temperature, the mixture was stirred for 12 hours under 30 W LED blue light illumination. After rotary evaporation, flash column chromatography (column packing: silica gel 100 - 200 mesh, eluent: petroleum ether / ethyl acetate volume ratio = 10:1) was performed to obtain the target product with a 29% yield.

[0133] Effect Example

[0134] The target products prepared in Examples 4, 8, and 11 were selected for MTT tests. The cells selected were HepG2 (human hepatocellular carcinoma cells), HeLa (cervical cancer cells), and LO2 (human normal hepatocytes), and the IC 50 value of the products was analyzed.

[0135] The specific process was as follows:

[0136] (1) Cell resuscitation, culture, and passage

[0137] After taking out the cryopreserved cells from the refrigerator, they were quickly placed in a 37.5 °C constant temperature water bath for thawing. Subsequently, in a laminar flow hood, the thawed cells were added to an ep tube containing 1 mL of DMEM, placed in a centrifuge, and centrifuged at 1000 rpm for 3 minutes. After completion, the supernatant was discarded, complete medium was added, and after pipetting evenly, it was transferred to a culture flask. When the color of the medium changed, the medium was replaced. When the cells grew to 90% of the culture flask, passage was performed. First, the old medium was poured out, 2 mL of PBS was slowly added to wash the culture flask, then 0.5 mL of trypsin was added for digestion. When it was observed that the cells began to detach, medium was added and gently pipetted until the cells were completely detached. Then, the cell suspension was collected and centrifuged at 1000 rpm for 3 minutes. The supernatant was discarded, complete medium was added, and after pipetting evenly, it was aliquoted into two culture flasks.

[0138] (2) MTT method

[0139] For logarithmically growing cells, digest and pipette them to evenly distribute the cells, then perform cell counting. Subsequently, dilute them to 6×103 (cell / mL), and evenly add 100 μL of the cell suspension to the 96-well plate (do not add to the 36 wells at the edge). Place it in the incubator. After the cells adhere to the wall for 12 hours, administer the drug. Set 5 concentrations (90 μM, 30 μM, 10 μM, 3.3 μM, 1.1 μM) for the target products prepared in Examples 4, 8, and 11, and set 3 replicates. After administering the drug, continue to incubate in the incubator for 48 hours. After incubation is completed, discard the original solution, add 10 μL of MTT solution (5 mg / mL) and 90 μL of blank medium, and continue to culture for 4 hours. Subsequently, discard the original solution, add 100 μL of DMSO solution to dissolve, shake on a shaker for 15 minutes, and measure the absorbance value of each well at a wavelength of 490 nm using an enzyme-linked immunosorbent assay (ELISA) reader.

[0140] Finally, calculate the cell survival rate using the following formula:

[0141]

[0142] In the formula: OD value is the absorbance.

[0143] As can be seen from Table 1, this series of compounds has certain inhibitory activity against the above cell lines.

[0144] Table 1

[0145]

[0146] Finally, it should be noted that the above content is only used to illustrate the technical solution of the present invention, rather than a limitation on the protection scope of the present invention. Any simple modification or equivalent replacement of the technical solution of the present invention by those of ordinary skill in the art shall not depart from the essence and scope of the technical solution of the present invention.

Claims

1. A method for preparing N- dithiobenzamide and its derivatives, characterized in that It includes the following steps: Using the compound of Formula 1 as a raw material and the compound of Formula 2 as a disulfur source, through a photocatalytic system reaction, the compound of Formula 3 is prepared. ， ， ， Among them, the R 1 is an aryl group, and R 2 is an aryl group or an alkyl group; the photocatalytic system includes a light source, a photosensitizer, a base and a solvent, and the photosensitizer is selected from one or more of rose bengal, eosin Y, tris(2-phenylpyridine)iridium and fluorescein.

2. The method according to claim 1, wherein The alkyl group is a C1-C5 alkyl group.

3. The method according to claim 1, wherein The molar ratio of the base, photosensitizer, compound of Formula 1 to the compound of Formula 2 is 1-3:0.02-0.03:2-2.2:

1.

4. The method according to claim 3, wherein The light source is LED blue light.

5. The method according to claim 4, wherein The light source is 25-35 W LED blue light, and the photosensitizer is Rose Bengal.

6. The method according to claim 3, characterized in that The base is selected from one or more of tripotassium phosphate, cesium carbonate, 1,8-diazabicycloundec-7-ene, triethylamine, and potassium tert-butoxide, and the solvent is selected from one or more of 1,2-dichloroethane, dimethyl sulfoxide, dichloromethane, acetonitrile, and toluene.

7. The method according to claim 6, wherein The base is potassium tert-butoxide, and the solvent is dichloromethane.

8. The method according to claim 1, characterized in that, During the reaction, stirring is carried out. The temperature of the reaction is 20-25 °C, and the reaction time is 10-14 h. After the reaction through the photocatalytic system, rotary evaporation and purification are also carried out.

9. The method according to claim 8, characterized in that, The purification is column chromatography purification. The eluent for the column chromatography purification is a mixture of petroleum ether and ethyl acetate with a volume ratio of 6-60:1, and the column packing is silica gel with a mesh size of 100-200.

10. Prepared by the method according to any one of claims 1-9 N- Use of dimercaptobenzamide and its derivatives in the preparation of anti-hepatocellular carcinoma or anti-cervical cancer drugs, wherein N- the chemical structural formula of dimercaptobenzamide and its derivatives is or .

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