Sulfur-containing tryptophan cyclic peptide compound as well as synthesis method and application thereof

Abstract

The invention relates to a sulfur-containing tryptophan cyclic peptide compound as well as a synthesis method and application thereof. The synthesis method comprises the following steps: carrying out electrolytic reaction on a tryptophan peptide compound with a structure as shown in a formula I or a stereoisomer thereof and a thiosulfonate compound with a structure as shown in a formula II to obtain the sulfur-containing tryptophan cyclic peptide compound with a structure as shown in a formula III or a stereoisomer thereof. The sulfur-containing tryptophan cyclic peptide compound can be obtained by directly electrolyzing the tryptophan peptide compound by adopting an electrochemical method, so that the use of a transition metal catalyst and stoichiometric alkali is avoided, the generation of chemical wastes is avoided, and the realization of atom economy is facilitated. The method has the advantages of simple operation, high product purity, easy purification, high efficiency and yield, low production cost, mild reaction conditions, no need of inert gas protection, greener reaction system, environmental protection, safety, economy, energy saving and environmental protection, and is more conducive to realization of industrial production.

Description

Invention Field

[0001] This invention belongs to the field of pharmaceutical and organic synthesis technology, specifically relating to a sulfur-containing tryptophan cyclic peptide compound, its synthesis method, and its application. Background Technology

[0002] Sulfur-containing tryptophan cyclic peptides are widely found in bioactive molecules, especially in antibacterial and antitumor applications. They are a class of natural products that perfectly combine the stability of cyclic peptides, the diversity of tryptophan, and the rigidity of sulfur bridges.

[0003] However, the rapid and efficient synthesis of sulfur-containing tryptophan cyclic peptides remains a significant challenge. The Chen Gong research group (P. Yang, MJ Širvinskas, B. Li, NW Heller, H. Rong, G. He, AK Yudin, G. Chen) J. Am. Chem. Soc. 2023, 145 (13968-13978.) reported a copper-catalyzed method for synthesizing tryptophan peptides. However, this method requires a transition metal catalyst, copper, and 3.0 equivalents of potassium carbonate as a base, and the reaction must be carried out at 120°C. The use of a metal catalyst easily introduces trace amounts of heavy metals into the peptide drug synthesis, significantly increasing the difficulty of drug purification and causing considerable trouble for subsequent purification processes. Furthermore, the high temperature conditions are challenging for compounds with chiral structures, as they are prone to racemization, and the experimental process is relatively dangerous.

[0004] Therefore, there is an urgent need to develop novel synthetic methods for sulfur-containing tryptophan cyclic peptides to meet the needs of drug development. Summary of the Invention

[0005] Based on this, the present invention provides an electrochemical synthesis method for sulfur-containing tryptophan cyclic peptides. This method is simple to operate, low in cost, and enables the green, mild, and efficient synthesis of sulfur-containing tryptophan cyclic peptides.

[0006] The specific technical solutions include the following:

[0007] In a first aspect, the present invention provides a method for synthesizing sulfur-containing tryptophan cyclic peptides or their stereoisomers, comprising the following steps:

[0008] Electrolytic reaction is carried out between a tryptophan peptide compound having the structure shown in Formula I or its stereoisomer and a thiosulfonate compound having the structure shown in Formula II to obtain a sulfur-containing tryptophan cyclic peptide compound having the structure shown in Formula III or its stereoisomer.

[0009]

[0010]

[0011] Wherein, R is an amino acid residue with one amino hydrogen and one hydroxyl group removed, or a polypeptide group containing two or three amino acid residues.

[0012] R 1 It is an amino protecting group; R 2 It is a C1 to C6 alkyl group;

[0013] A is selected from: C6~C 10 aryl, 5-10 quinone heteroaryl, C6-C 10 Aspartic-X-C6~C 10 aryl, 5-10 nucleotide aryl-X-5-10 nucleotide aryl, where X is O or S.

[0014] Secondly, the present invention provides sulfur-containing tryptophan cyclic peptide compounds or their stereoisomers or pharmaceutically acceptable salts prepared by the preparation method described herein.

[0015] Thirdly, the present invention provides the use of the sulfur-containing tryptophan cyclic peptide compound or its stereoisomer or its pharmaceutically acceptable salt in the preparation of an antitumor drug, wherein the tumor is preferably lung cancer.

[0016] Fourthly, the present invention provides an antitumor drug prepared from an active ingredient and pharmaceutically acceptable excipients, wherein the active ingredient comprises the sulfur-containing tryptophan cyclic peptide compound or its stereoisomer or its pharmaceutically acceptable salt as described in the present invention.

[0017] The electrochemical synthesis method of the sulfur-containing tryptophan cyclic peptides of the present invention has the following beneficial effects:

[0018] (1) This invention employs an electrochemical method to directly electrolyze p-dithiosulfonate, generating p-diarylsulfonate free radicals through electrolysis. These free radicals then attack tryptophan peptides, constructing sulfur-nitrogen bonds to obtain sulfur-containing tryptophan cyclic peptides. This method has a novel reaction mechanism, significantly improving upon the shortcomings of the copper-catalyzed synthesis method previously used by Gong Chen et al. It avoids the use of transition metal catalysts and stoichiometric bases, greatly improving reaction efficiency. Electrons are used as the oxidant during the reaction, resulting in a clean and environmentally friendly reaction system that avoids the generation of chemical waste and contributes to atom economy. This method is simple to operate, produces high-purity products that are easy to purify. After electrolysis, sulfur-containing tryptophan cyclic peptides can be obtained efficiently and in high yields through simple purification steps, significantly reducing production costs. Furthermore, the reaction conditions are mild, requiring no inert gas protection, making the reaction system greener, more environmentally friendly, safer, more economical, energy-saving, and more conducive to industrial production.

[0019] (2) The method of the present invention further realizes the conversion in a single-chamber electrolytic cell. The single-chamber electrolytic cell has a small internal resistance and a small decomposition voltage during electrolysis, thus greatly reducing energy consumption. At the same time, the single-chamber electrolytic cell device is simple and can be made with an ordinary beaker. It is easy to operate and control.

[0020] (3) The method of the present invention is further preferably to use constant current for electrolysis. Constant current electrolysis requires low equipment cost and is more suitable for industrial production.

[0021] (4) The method of the present invention further prefers graphite sheets as working electrodes. Using graphite sheets as anodes can not only obtain higher product yields, but also graphite sheets are inexpensive and readily available, which greatly reduces the synthesis cost.

[0022] (5) The yield of the obtained sulfur-containing tryptophan cyclic peptide compounds can be further improved by further optimizing the specific reaction conditions (solvent, electrolyte, electrolysis time and temperature, current intensity, concentration of reactants, etc.).

[0023] (6) The sulfur-containing tryptophan cyclic peptide compounds prepared by the synthesis method of the present invention have certain anti-tumor effects and can be used to prepare anti-tumor drugs. They can also be further optimized into compounds with better activity and applied to the development of tumor drugs to develop tumor treatment drugs with higher efficacy. Detailed Implementation

[0024] To facilitate understanding of the present invention, a more complete description will be provided below. The present invention can be implemented in many different forms and is not limited to the embodiments described herein. Rather, these embodiments are provided to provide a thorough and complete understanding of the disclosure of the present invention.

[0025] Unless otherwise specified, experimental methods in the following examples are generally performed under standard conditions or as recommended by the manufacturer. All commonly used chemical reagents used in the examples are commercially available products.

[0026] Unless otherwise defined, all technical and scientific terms used in this invention have the same meaning as commonly understood by one of ordinary skill in the art to which this invention pertains. The terminology used in this specification is for the purpose of describing particular embodiments only and is not intended to limit the invention. The term "and / or" as used in this invention includes any and all combinations of one or more of the associated listed items.

[0027] Furthermore, as used herein, the term "or" is an inclusive "or" sign and is equivalent to the term "and / or" unless the context clearly specifies otherwise. The term "based on" is not exclusive and allows for basing on other factors not described unless the context clearly specifies otherwise. Additionally, throughout the specification, the meanings of "an," "a," and "the" include plural indicators. The meaning of "in" includes both "in" and "on."

[0028] Some embodiments of the present invention relate to a method for synthesizing a sulfur-containing tryptophan cyclic peptide compound or its stereoisomer, comprising the following steps:

[0029] Electrolytic reaction is carried out between a tryptophan peptide compound having the structure shown in Formula I or its stereoisomer and a thiosulfonate compound having the structure shown in Formula II to obtain a sulfur-containing tryptophan cyclic peptide compound having the structure shown in Formula III or its stereoisomer.

[0030]

[0031]

[0032] Wherein, R is an amino acid residue with one amino hydrogen and one hydroxyl group removed, or a polypeptide group containing two or three amino acid residues.

[0033] R 1 It is an amino protecting group; R 2 It is a C1 to C6 alkyl group;

[0034] A is selected from: C6~C 10 aryl, 5-10 quinone heteroaryl, C6-C 10 Aspartic-X-C6~C 10 aryl, 5-10 nucleotide aryl-X-5-10 nucleotide aryl, where X is O or S.

[0035] The amino acid refers to a carboxylic acid compound containing an amino substituted group, including natural or non-natural amino acids, wherein the side chain amino or carboxyl groups in the amino acid residues can be protected by corresponding amino protecting groups or carboxyl protecting groups.

[0036] In some embodiments of the present invention, R 1 It is tert-butyloxycarbonyl.

[0037] In some embodiments of the present invention, R 2 It can be methyl or ethyl.

[0038] In some embodiments of the present invention, A is selected from: phenylene, 5-membered heteroaryl, phenylene-S-phenylene, 5-membered heteroaryl-S-5-membered heteroaryl, 6-membered heteroaryl-S-6-membered heteroaryl, phenylene-O-phenylene, 5-membered heteroaryl-O-5-membered heteroaryl, 6-membered heteroaryl-O-6-membered heteroaryl.

[0039] In some embodiments of the present invention, R is selected from the following groups:

[0040] .

[0041] In some embodiments of the present invention, A is selected from the following groups:

[0042] .

[0043] In some embodiments of the present invention, the tryptophan peptide compounds having the structure shown in formula (I) are selected from the following compounds:

[0044] ;

[0045] Thiosulfonates having the structure shown in formula (II) are selected from the following compounds:

[0046]

[0047] The sulfur-containing tryptophan cyclic peptides having the structure shown in formula (III) are selected from the following compounds:

[0048] .

[0049] In the synthesis method of the present invention, the electrolysis reaction can be carried out in a conventional electrolytic cell. For example, in some embodiments of the present invention, the electrolysis reaction is carried out in a single-chamber electrolytic cell containing an electrolyte.

[0050] In some embodiments of the present invention, the solvent in the electrolyte is selected from at least one of acetonitrile, dichloromethane, and water.

[0051] In some embodiments of the present invention, the solvent in the electrolyte is a mixture of solvent A and solvent B, wherein solvent A is acetonitrile and solvent B is dichloromethane or water.

[0052] In some embodiments of the present invention, the volume ratio of solvent A to solvent B is 0.2 to 2:1, preferably 0.5 to 1.5:1; more preferably 0.8 to 1:1, at which a higher product yield can be obtained.

[0053] In some embodiments of the present invention, the electrolyte in the electrolyte is selected from at least one of borate and quaternary ammonium halide.

[0054] In some embodiments of the present invention, the borate is at least one of tetrabutylammonium tetrafluoroborate, tetrabutylammonium hexafluoroborate, tetraethylammonium tetrafluoroborate, and tetraethylammonium hexafluoroborate, and the quaternary ammonium halide is at least one of tetrabutylammonium iodide, tetrabutylammonium bromide, and tetraethylammonium bromide.

[0055] In some embodiments of the present invention, the electrolyte is tetrabutylammonium iodide and / or tetraethylammonium tetrafluoroborate.

[0056] In some embodiments of the present invention, the molar concentration of the electrolyte in the electrolyte solution is 0.03 mol / L to 0.15 mol / L, preferably 0.08 mol / L to 0.12 mol / L.

[0057] In some embodiments of the present invention, the reaction concentration of the tryptophan peptide compound having the structure shown in formula (I) or its stereoisomer is 0.01 mol / L to 0.3 mol / L, preferably 0.01 mol / L to 0.1 mol / L, and more preferably 0.02 mol / L to 0.03 mol / L.

[0058] In some embodiments of the present invention, the molar ratio of the electrolyte to the tryptophan peptide compound or its stereoisomer having the structure shown in formula (I) is 1.5 to 7:1, preferably 3 to 6:1, and more preferably 4 to 5:1.

[0059] In some embodiments of the present invention, the molar ratio of the thiosulfonate compound having the structure shown in formula (II) to the tryptophan peptide compound or its stereoisomer having the structure shown in formula (I) is 1 to 1.5:1.

[0060] In some embodiments of the present invention, the anode for electrolysis is a graphite sheet, a mesh glassy carbon, glassy carbon, or a platinum sheet, and the cathode is a platinum sheet, an iron sheet, a copper sheet, a nickel sheet, or a zinc sheet.

[0061] In some embodiments of the present invention, the electrolysis reaction is carried out using a constant current with an intensity of 3 mA to 10 mA, preferably 4 mA to 6 mA; the amount of charge is 3.3 F / mol to 11.3 F / mol, preferably 4.5 F / mol to 6.8 F / mol, based on the amount of substance of the tryptophan peptide compound having the structure shown in formula (I) or its stereoisomer.

[0062] In some embodiments of the present invention, the temperature of the electrolysis reaction is 15°C to 50°C, preferably 20°C to 30°C.

[0063] In some embodiments of the present invention, the application of sulfur-containing tryptophan cyclic peptides or their stereoisomers or pharmaceutically acceptable salts prepared by the method described herein in the preparation of antitumor drugs, wherein the tumor is preferably lung cancer.

[0064] Some embodiments of the present invention also relate to an antitumor drug prepared from an active ingredient and pharmaceutically acceptable excipients, said active ingredient comprising the sulfur-containing tryptophan cyclic peptide compound or its stereoisomer or its pharmaceutically acceptable salt as described in the present invention.

[0065] The present invention will be further described in detail below with reference to specific embodiments.

[0066] The starting materials and reagents used in the following examples are all commercially available conventional materials and reagents. Tryptophan peptides with the structure shown in formula (I) and thiosulfonates with the structure shown in formula (II) can be synthesized using methods reported in known literature as substrates for electrolysis.

[0067] In the following examples, room temperature refers to 23-25°C.

[0068] In the compound structure of this invention, Ts refers to p-toluenesulfonyl group (p-CH3-C6H4-SO2-).

[0069] In the compound structure of this invention, Boc refers to tert-butyloxycarbonyl.

[0070] Example 1: Electrochemical synthesis of compound 3

[0071]

[0072] In a 10 mL single-chamber electrolytic cell, starting materials 1a (0.2 mmol), 2a (0.24 mmol), and electrolyte tetra-n-butylammonium iodide (n-Bu4NI) (1.0 mmol) were added to a mixed solvent of 5 mL acetonitrile and 5 mL dichloromethane (volume ratio 1:1). Electrolysis was performed with a graphite sheet electrode as the anode and a platinum sheet as the cathode under a constant current of 5 mA. After stirring at room temperature for 6 hours, electrolysis was stopped, the reaction solution was transferred, concentrated, and purified by column chromatography to obtain compound 3 as a white solid with a yield of 59%.

[0073] The characterization data for compound 3 are as follows: 1 H NMR (400 MHz, DMSO- d 6) d 8.40 (d, J = 7.3 Hz, 1H), 7.90 (d, J = 8.4 Hz, 1H), 7.70 (s, 1H), 7.60 (d, J = 7.7 Hz, 1H), 7.48 (d, J =7.8 Hz, 1H), 7.44 (dd, J = 8.2, 4.3 Hz, 2H), 7.30 (d, J = 6.9 Hz, 2H), 7.29–7.21(m, 6H), 7.20–7.17 (m, 1H), 7.16–7.08 (m, 3H), 6.76 (d, J = 6.8 Hz, 1H), 4.57(d, J = 9.8 Hz, 1H), 4.43 (d, J = 8.6 Hz, 1H), 4.13 (s, 1H), 3.70 (s, 3H), 3.59–3.50 (m, 1H), 3.30–3.15 (m, 2H), 3.12–2.98 (m, 4H), 2.78–2.73 (m, 1H), 1.40(s, 9H);

[0074] 13 C NMR (100 MHz, DMSO- d 6) d172.6, 171.9, 171.6, 168.7, 155.4, 140.1, 139.9, 138.3, 137.7, 137.6, 133.1, 129.7, 128.6, 126.9, 125.7, 123.9, 123.5, 121.7, 121.3, 119.4, 114.7, 114.5, 111.5, 111.1, 78.8, 55.6, 53.8, 42.2, 40.7, 40.1, 28.7, 27.8, 26.5;

[0075] HRMS (ESI) m / z calcd. for C 43 H 43 N5NaO6S2 [M+Na] + 812.2547, found 812.2530.

[0076] Example 2: Electrochemical synthesis of compound 4

[0077]

[0078] In a 10 mL single-chamber electrolytic cell, starting materials 1b (0.2 mmol), 2a (0.24 mmol), and electrolyte n-Bu4NI (1.0 mmol) were added to a mixed solvent of 5 mL acetonitrile and 5 mL dichloromethane (volume ratio 1:1). Electrolysis was performed with a graphite sheet electrode as the anode and a platinum sheet as the cathode under a constant current of 5 mA. After stirring at room temperature for 6 hours, electrolysis was stopped, the reaction solution was transferred, concentrated, and purified by column chromatography to obtain compound 4 as a yellow solid with a yield of 60%.

[0079] The characterization data for compound 4 are as follows: 1 H NMR (400 MHz, DMSO- d6 ) d (400 MHz, DMSO- d 6) d 8.39 (d, J = 8.6 Hz, 1H), 7.96 (s, 1H), 7.74 (d, J = 7.5 Hz, 1H), 7.69 (d, J = 8.0Hz, 1H), 7.60 (d, J = 8.2 Hz, 1H), 7.52 (d, J= 8.4 Hz, 1H), 7.36–7.24 (m, 6H), 7.02 (s, 1H), 6.95 (d, J = 8.2 Hz, 1H), 6.84 (d, J = 8.1 Hz, 2H), 4.83 (t, J = 10.6Hz, 1H), 4.51 (s, 1H), 4.10–4.02 (m, 1H), 3.85 (d, J = 7.4 Hz, 3H), 3.11–2.75(m, 4H), 1.53 (d, J = 9.8 Hz, 9H), 1.44–1.36 (m, 2H);

[0080] 13 C NMR (100 MHz, DMSO- d 6) d 174.7, 171.6, 169.1, 156.1, 140.2, 139.6, 137.8, 133.8, 133.1, 130.1, 128.9, 125.6, 124.4, 124.0, 123.7, 121.8, 121.4, 120.5, 119.9, 119.6, 115.0, 111.3, 111.1, 78.0, 59.4, 55.1, 52.9, 51.7, 38.9, 30.2, 28.9, 27.3;

[0081] HRMS (ESI) m / z calcd. for C 36 H 37 N5NaO6S2 [M+Na] + 722.2077, found 722.2078.

[0082] Example 3: Electrochemical synthesis of compound 5

[0083]

[0084] In a 10 mL single-chamber electrolytic cell, starting materials 1c (0.2 mmol), 2a (0.24 mmol), and electrolyte n-Bu4NI (1.0 mmol) were added to a mixed solvent of 5 mL acetonitrile and 5 mL dichloromethane (volume ratio 1:1). Electrolysis was performed using a graphite sheet electrode as the anode and a platinum sheet as the cathode at a constant current of 5 mA. After stirring at room temperature for 6 hours, electrolysis was stopped, the reaction solution was transferred, concentrated, and purified by column chromatography to obtain compound 5 as a white solid with a yield of 59%.

[0085] The characterization data of compound 5 are as follows: 1 H NMR (400 MHz, CDCl3) d 7.60–7.53 (m, 2H), 7.47 (d, J = 8.1 Hz, 1H), 7.44 (d, J = 7.9 Hz, 1H), 7.24 (d, J = 9.8 Hz, 1H), 7.20 (d, J =7.5 Hz, 1H), 7.17 (d, J = 5.2 Hz, 1H), 7.13 (d, J = 7.1 Hz, 1H), 7.02 (s, 1H),7.00 (s, 1H), 6.52 (d, J = 1.8 Hz, 4H), 6.37 (d, J = 7.2 Hz, 1H), 5.29 (s, 1H), 4.98 (d, J = 5.8 Hz, 1H), 4.84–4.67 (m, 1H), 4.41 (s, 1H), 4.04 (d, J = 6.4 Hz,1H), 3.81 (s, 3H), 3.49–3.28 (m, 2H), 2.31–2.90 (m, 4H), 1.88 (s, 1H), 1.46(d, J = 3.7 Hz, 18H), 1.30–1.23 (m, 2H), 1.21–1.12 (m, 2H), 0.89 – 0.81 (m,2H);

[0086] 13 C NMR (100 MHz, DMSO- d 6) d172.8, 172.0, 170.1, 156.1, 155.9, 139.9, 139.5, 138.1, 137.7, 133.9, 133.7, 129.7, 128.8, 124.4, 124.3, 124.0, 123.7, 121.8, 121.6, 119.6, 119.3, 115.3, 114.6, 111.3, 111.1, 79.2, 77.9, 54.6, 53.0, 52.7, 52.3, 32.4, 30.2, 28.9, 28.8, 26.6, 22.0;

[0087] HRMS (ESI) m / z calcd. for C 45 H 55 N6O8S2 [M+H] + 871.3517, found 871.3515.

[0088] Example 4: Electrochemical synthesis of compound 6

[0089]

[0090] In a 10 mL single-chamber electrolytic cell, starting materials 1d (0.2 mmol), 2a (0.24 mmol), and electrolyte n-Bu4NI (1.0 mmol) were added to a mixed solvent of 5 mL acetonitrile and 5 mL dichloromethane (volume ratio 1:1). Electrolysis was performed using a graphite sheet electrode as the anode and a platinum sheet as the cathode at a constant current of 5 mA. After stirring at room temperature for 6 hours, electrolysis was stopped, the reaction solution was transferred, concentrated, and purified by column chromatography to obtain compound 6 as a white solid with a yield of 60%.

[0091] The characterization data for compound 6 are as follows: 1 H NMR (400 MHz, DMSO- d 6) d H 8.20 (d, J = 7.0 Hz, 1H), 7.64 (d, J = 7.6 Hz, 2H), 7.58 (d, J= 7.1 Hz, 1H), 7.51–7.49 (m, 3H), 7.41(s, 1H), 7.30–7.24 (m, 2H), 7.24–7.15 (m, 4H), 6.78 (s, 3H), 4.62–4.49 (m,1H), 4.38–4.32 (m, 1H), 4.11 (t, J = 6.0 Hz, 1H), 3.78 (s, 3H), 3.59–3.50 (m,2H), 3.29 (s, 3H), 3.25–2.89 (m, 4H), 1.52 (s, 9H);

[0092] 13 C NMR (100 MHz, DMSO- d 6) d C = 172.7, 170.5, 170.0, 155.7, 140.1,139.7, 138.20, 137.7, 133.8, 133.6, 129.9, 128.9, 124.5, 124.2, 124.0, 123.7,121.8, 121.6, 119.7, 119.4, 115.3, 114.7, 111.3, 111.2, 79.2, 72.4, 59.0,55.0, 53.0, 52.7, 30.4, 28.8, 28.2, 26.7;

[0093] HRMS (ESI) m / z calcd. for C 38 H 42 N5O7S2 [M+H] + 744.2520, found 744.2507.

[0094] Example 5: Electrochemical synthesis of compound 7

[0095]

[0096] In a 10 mL single-chamber electrolytic cell, starting materials 1e (0.2 mmol), 2a (0.24 mmol), and electrolyte n-Bu4NI (1.0 mmol) were added to a mixed solvent of 5 mL acetonitrile and 5 mL dichloromethane (volume ratio 1:1). Electrolysis was performed using a graphite sheet electrode as the anode and a platinum sheet as the cathode at a constant current of 5 mA. After stirring at room temperature for 6 hours, electrolysis was stopped, the reaction solution was transferred, concentrated, and purified by column chromatography to obtain compound 7 as a white solid with a yield of 39%.

[0097] The characterization data for compound 7 are as follows: 1 H NMR (400 MHz, DMSO- d 6) d 8.40 (d, J = 7.3 Hz, 1H), 7.90 (d, J = 8.4 Hz, 1H), 7.70 (s, 1H), 7.60 (d, J = 7.7 Hz, 1H), 7.48 (d, J =7.8 Hz, 1H), 7.44 (dd, J = 8.2, 4.3 Hz, 2H), 7.34–7.27 (m, 3H), 7.25 (d, J = 6.3Hz, 5H), 7.21–7.17 (m, 1H), 7.16–7.07 (m, 3H), 7.06 (d, J = 8.4 Hz, 2H), 7.03(s, 1H), 6.76 (d, J = 6.8 Hz, 1H), 4.57 (d, J = 9.7 Hz, 1H), 4.43 (d, J = 6.9 Hz,1H), 4.13 (s, 1H), 3.70 (s, 3H), 3.57–3.47 (m, 1H), 3.29–3.15 (m, 2H), 3.12–2.97 (m, 4H), 2.81–2.70 (m, 1H), 1.40 (s, 9H);

[0098] 13 C NMR (100 MHz, DMSO- d 6 ) d 172.6, 171.9, 171.6, 168.7, 155.5, 140.1, 139.9, 138.3, 137.7, 137.6, 133.1, 133.0, 130.1, 129.7, 129.4, 128.6, 126.9, 125.7, 123.9, 123.5, 121.7, 121.3, 119.4, 114.7, 114.5, 111.5, 111.1, 78.8, 55.6, 53.8, 52.7, 42.2, 40.7, 37.8, 28.7, 27.8, 26.5;

[0099] HRMS (ESI) m / z calcd. for C 45 H 47 N6O7S2 [M+H] + 847.2942, found 847.2943.

[0100] Example 6: Electrochemical synthesis of compound 8

[0101]

[0102] In a 10 mL single-chamber electrolytic cell, starting materials 1f (0.2 mmol), 2a (0.24 mmol), and electrolyte n-Bu4NI (1.0 mmol) were added to a mixed solvent of 5 mL acetonitrile and 5 mL dichloromethane (volume ratio 1:1). Electrolysis was performed with a graphite sheet electrode as the anode and a platinum sheet as the cathode under a constant current of 5 mA. After stirring at room temperature for 6 hours, electrolysis was stopped, the reaction solution was transferred, concentrated, and purified by column chromatography to obtain compound 8 as a white solid with a yield of 58%.

[0103] The characterization data for compound 8 are as follows: 1 H NMR (400 MHz, CDCl3) d 7.62 (d, J = 7.8 Hz, 1H), 7.55 (d, J = 8.1 Hz, 1H), 7.46 (d, J = 8.2 Hz, 1H), 7.39–7.31 (m, 3H), 7.27 (d, J =7.3 Hz, 1H), 7.26–7.17 (m, 5H), 6.96 (d, J = 8.1 Hz, 4H), 6.87 (d, J= 8.3 Hz, 2H), 6.78 (s, 1H), 6.53 (d, J = 6.4 Hz, 1H), 6.17 (d, J = 7.4 Hz, 1H), 5.96 (s,1H), 5.46–5.32 (m, 1H), 4.86–4.72 (m, 1H), 4.49 (q, J = 7.0 Hz, 2H), 4.07–4.00(m, 1H), 3.70 (s, 3H), 3.51–3.38 (m, 1H), 3.30–3.24 (m, 1H), 3.14–3.05 (m, 2H), 3.01 (t, J = 7.2 Hz, 2H), 2.78–2.72 (m, 1H), 1.40 (s, 9H). 0.33 (d, J = 6.9Hz, 3H);

[0104] 13 C NMR (100 MHz, CDCl3) δ 171.5, 171.4, 170.3, 169.9, 155.4, 140.8,140.1, 138.3, 137.2, 136.2, 132.8, 132.2, 129.7, 129.6, 129.2, 129.1, 127.5,125.8, 125.3, 123.8, 123.7, 121.5, 121.2, 119.3, 118.9, 114.4, 113.2, 111.7,111.3, 80.1, 55.1, 53.7, 52.6, 52.6, 48.5, 36.8, 28.6, 28.5, 27.1, 18.6;

[0105] HRMS (ESI) m / z calcd. for C 46 H 49 N6O7S2 [M+H] + 861.3099, found 861.3099.

[0106] Example 7: Electrochemical synthesis of compound 9

[0107]

[0108] In a 10 mL single-chamber electrolytic cell, 1 g (0.2 mmol) of the raw material, 2a (0.24 mmol) and electrolyte n-Bu4NI (1.0 mmol) were added to a mixed solvent of 5 mL acetonitrile and 5 mL dichloromethane (volume ratio 1:1). Electrolysis was performed with a graphite sheet electrode as the anode and a platinum sheet as the cathode under a constant current of 5 mA. After stirring at room temperature for 6 hours, electrolysis was stopped, the reaction solution was transferred, concentrated, and purified by column chromatography to obtain compound 9 as a white solid with a yield of 50%.

[0109] The characterization data for compound 9 are as follows: 1 H NMR (400 MHz, CDCl3) d H = 7.56 (d, J = 7.2 Hz,2H), 7.50–7.43 (m, 2H), 7.24 (d, J = 9.9 Hz, 1H), 7.14 (d, J = 9.1 Hz, 3H), 7.02(s, 1H), 6.93 (d, J = 7.9 Hz, 2H), 6.82 (s, 1H), 6.76 (d, J = 8.2 Hz, 2H), 6.54(s, 1H), 6.05 (s, 1H), 5.43 (d, J = 7.1 Hz, 1H), 4.73 (s, 1H), 4.36–4.11 (m,2H), 3.70 (s, 3H), 3.40–3.36 (m, 1H), 3.55–3.42 (m, 1H), 3.23–3.05 (m, 2H),2.99–2.83 (m, 2H), 2.14 (s, 1H), 1.95 (s, 1H), 1.70–1.56 (m, 2H), 1.44 (s,9H), 0.90–0.82 (m, 6H);

[0110] 13 C NMR (100 MHz, CDCl3) δ C= 172.1, 172.0, 171.8, 168.6, 155.5,140.7, 140.1, 139.0, 137.3, 132.5, 132.4, 129.5, 128.9, 126.5, 124.2, 123.8, 123.7, 121.4, 119.2, 119.0, 116.7, 116.6, 114.3, 113.7, 111.4, 80.3, 55.9,52.8, 51.9, 42.3, 40.1, 28.9, 28.5, 26.9, 24.7, 22.7, 22.4;

[0111] HRMS (ESI) m / z calcd. for C 42 H 49 N6O7S2 [M+H] + 813.3099, found 813.3095.

[0112] Example 8: Electrochemical synthesis of compound 10

[0113]

[0114] In a 10 mL single-chamber electrolytic cell, the starting materials 1h (0.2 mmol), 2a (0.24 mmol), and electrolyte n-Bu4NI (1.0 mmol) were added to a mixed solvent of 5 mL acetonitrile and 5 mL dichloromethane (volume ratio 1:1). Electrolysis was performed with a graphite sheet electrode as the anode and a platinum sheet as the cathode under a constant current of 5 mA. After stirring at room temperature for 6 hours, electrolysis was stopped, the reaction solution was transferred, concentrated, and purified by column chromatography to obtain 10 as a white solid with a yield of 49%.

[0115] The characterization data of compound 10 are as follows: 1 H NMR (400 MHz, CDCl3) d 7.63 (d, J = 7.8 Hz, 1H), 7.59 (d, J = 8.1 Hz, 1H), 7.50 (d, J = 8.1 Hz, 1H), 7.44 (d, J = 7.9 Hz, 1H),7.28 (s, 1H), 7.25 – 7.22 (m, 1H), 7.20 (d, J= 7.4 Hz, 1H), 7.17–7.08 (m, 3H), 7.10 (s, 1H), 7.03 (d, J = 2.9 Hz, 1H), 7.01 (d, J = 2.9 Hz, 2H), 6.81 (d, J = 8.0Hz, 2H), 6.50 (s, 1H), 6.21 (d, J = 8.9 Hz, 1H), 5.43–5.22 (m, 1H), 4.77 (q, J =5.8 Hz, 1H), 4.39–4.27 (m, 1H), 4.15–4.10 (m, 3H), 3.64 (s, 3H), 3.40–2.96(m, 4H), 3.30–2.98 (m, 1H), 1.65–1.56 (m, 2H), 1.47 (s, 9H), 1.29–1.23 (m, 4H), 0.86 (t, J = 6.1 Hz, 6H), 0.61 (s, 3H);

[0116] 13 C NMR (100 MHz, CDCl3) δ C = 171.8, 171.6, 170.9, 170.8, 155.2,140.8, 140.3, 138.5, 137.5, 132.3, 132.1, 129.3, 128.9, 126.6, 125.4, 123.8, 123.6, 121.49, 121.2, 119.7, 118.7, 114.8, 113.1, 111.3, 111.2, 80.3, 60.5, 52.9, 52.6, 51.7, 51.3, 40.2, 32.5, 28.4, 26.6, 24.6, 22.7, 22.4, 22.3, 14.3, 13.8;

[0117] HRMS (ESI) m / z calcd. for C 46 H 57 N6O7S2 [M+H] + 869.3725, found 869.3724.

[0118] Example 9: Electrochemical synthesis of compound 11

[0119]

[0120] In a 10 mL single-chamber electrolytic cell, starting materials 1i (0.2 mmol), 2a (0.24 mmol), and electrolyte n-Bu4NI (1.0 mmol) were added to a mixed solvent of 5 mL acetonitrile and 5 mL dichloromethane (volume ratio 1:1). Electrolysis was performed with a graphite sheet electrode as the anode and a platinum sheet as the cathode under a constant current of 5 mA. After stirring at room temperature for 6 hours, electrolysis was stopped, the reaction solution was transferred, concentrated, and purified by column chromatography to obtain compound 11 as a white solid with a yield of 51%.

[0121] The characterization data of compound 11 are as follows: 1 H NMR (400 MHz, CDCl3) d 7.59 (d, J = 7.8 Hz, 1H), 7.54 (d, J = 8.2 Hz, 1H), 7.47 (d, J = 8.0 Hz, 1H), 7.37 (d, J = 7.9 Hz, 1H), 7.27–7.22 (m, 4H), 7.18–7.14 (m, 2H), 7.09 (dd, J = 7.4, 4.0 Hz, 3H), 6.97 (s, 1H), 6.96–6.87 (m, 4H), 6.75 (s, 1H), 6.39 (s, 1H), 6.19–6.08 (m, 1H), 5.46 (s,1H), 4.88 (s, 1H), 4.62 (td, J = 7.3, 4.4 Hz, 1H), 4.36–4.26 (m, 1H), 4.22–4.14(m, 1H), 4.04 (d, J = 7.3 Hz, 1H), 3.66 (s, 3H), 3.31–3.25 (m, 2H), 3.11–2.97(m, 2H), 2.96–2.82 (m, 4H), 2.18 (d, J = 9.6 Hz, 1H), 1.46 (s, 9H), 1.44 (s, 9H), 1.24–1.01 (m, 4H), 0.93–0.80 (m, 2H);

[0122] 13 C NMR (100 MHz, CDCl3) δ 171.5, 170.9, 170.5, 170.3, 156.1, 155.1, 140.6, 140.3, 138.3, 137.3, 136.2, 132.6, 132.1, 129.5, 129.4, 128.7, 128.6, 127.1, 126.1, 124.9, 123.6, 123.5, 121.3, 121.1, 119.4, 118.7, 114.4, 113.2, 111.2, 111.1, 80.1, 79.0, 55.6, 54.0, 52.5, 52.4, 51.9, 39.8, 37.2, 32.2, 29.0, 28.5, 28.4, 26.7, 21.7, 14.1;

[0123] HRMS (ESI) m / z calcd. for C 54 H 64 N7O9S2 [M+H] + 1018.4201, found 1018.4187.

[0124] Example 10: Electrochemical synthesis of compound 12

[0125]

[0126] In a 10 mL single-chamber electrolytic cell, starting materials 1j (0.2 mmol), 2a (0.24 mmol), and electrolyte n-Bu4NI (1.0 mmol) were added to a mixed solvent of 5 mL acetonitrile and 5 mL dichloromethane (volume ratio 1:1). Electrolysis was performed using a graphite sheet electrode as the anode and a platinum sheet as the cathode at a constant current of 5 mA. After stirring at room temperature for 6 hours, electrolysis was stopped, the reaction solution was transferred, concentrated, and purified by column chromatography to obtain compound 12 as a white solid with a yield of 39%.

[0127] The characterization data of compound 12 are as follows: 1 H NMR (400 MHz, CDCl3) d 7.60–7.54 (m, 2H), 7.47 (d, J = 8.1 Hz, 1H), 7.41 (d, J = 7.8 Hz, 1H), 7.25–7.22 (m, 1H), 7.20–7.16(m, 1H), 7.13–7.07 (m, 2H), 7.03 (d, J= 8.9 Hz, 2H), 6.92 (d, J = 8.2 Hz, 2H), 6.85 (d, J = 8.4 Hz, 2H), 6.35 (d, J = 6.8 Hz, 1H), 6.24 (d, J = 8.4 Hz, 1H), 6.10(d, J = 7.9 Hz, 1H), 5.51 (d, J = 8.3 Hz, 1H), 4.82–4.74 (m, 1H), 4.27 (s, 1H), 4.05–3.90 (m, 2H), 3.67 (s, 3H), 3.29–2.99 (m, 4H), 1.97 (s, 1H), 1.60–1.55(m, 3H), 1.46 (s, 9H), 1.40–1.36 (m, 1H), 0.84 (dd, J = 6.6, 4.4 Hz, 6H), 0.57(d, J = 6.7 Hz, 3H), 0.35 (d, J = 6.4 Hz, 2H);

[0128] 13 C NMR (100 MHz, CDCl3) δ 171.9, 171.5, 171.1, 169.6, 155.2, 140.7, 140.5, 138.1, 137.6, 132.3, 132.05, 129.3, 128.7, 125.6, 125.3, 123.8, 123.6, 121.3, 121.2, 119.6, 118.8, 114.8, 113.2, 111.3, 111.1, 80.1, 57.8, 55.7, 52.6, 51.4, 51.1, 40.2, 31.6, 28.8, 28.4, 26.9, 24.6, 22.5, 18.1;

[0129] HRMS (ESI) m / z calcd. for C 45 H 55 N6O7S2 [M+H] + 855.3568, found 855.3554.

[0130] Example 11: Electrochemical synthesis of compound 13

[0131]

[0132] In a 10 mL single-chamber electrolytic cell, starting materials 1i (0.2 mmol), 2b (0.24 mmol), and electrolyte n-Bu4NI (1.0 mmol) were added to a mixed solvent of 5 mL acetonitrile and 5 mL dichloromethane (volume ratio 1:1). Electrolysis was performed using a graphite sheet electrode as the anode and a platinum sheet as the cathode at a constant current of 5 mA. After stirring at room temperature for 6 hours, electrolysis was stopped, the reaction solution was transferred, concentrated, and purified by column chromatography to obtain compound 13 as a white solid with a yield of 49%.

[0133] The characterization data of compound 13 are as follows: 1 H NMR (400 MHz, CDCl3) d 7.64 (d, J = 7.5 Hz, 1H), 7.45 (dd, J = 8.1, 4.1 Hz, 2H), 7.42 (d, J = 7.8 Hz, 1H), 7.26–7.21 (m, 3H), 7.20 (s, 1H), 7.16 (dd, J = 7.5, 5.5 Hz, 5H), 7.10 (d, J = 7.8 Hz, 2H), 7.01 (d, J = 7.6 Hz, 1H), 6.96–6.92 (m, 1H), 6.91 (s, 1H), 6.83 (s, 1H), 6.70 (d, J = 8.6Hz, 1H), 6.52 (d, J = 7.8 Hz, 1H), 6.34 (s, 1H), 5.44 (s, 1H), 4.94 (d, J = 6.5Hz, 1H), 4.73–4.67 (m, 1H), 4.49–4.40 (m, 2H), 4.29 (q, J = 6.7 Hz, 1H), 3.55(s, 3H), 3.34–4.28 (m, 1H), 3.19 (d, J= 5.6 Hz, 2H), 3.15–2.93 (m, 4H), 2.92–2-81 (m, 2H), 2.47–2.40 (m, 1H), 1.43 (s, 9H), 1.40 (s, 9H), 1.18–1.10 (m,2H), 1.07–0.96 (m, 2H);

[0134] 13 C NMR (100 MHz, CDCl3) δ 171.7, 171.4, 171.1, 170.7, 156.1, 155.6, 141.2, 140.5, 140.3, 140.0, 136.5, 132.4, 132.3, 129.6, 129.4, 129.1, 128.8, 128.6, 126.9, 123.6, 123.4, 123.0, 121.4, 121.1, 119.3, 118.8, 114.2, 113.5, 111.0, 111.0, 80.5, 78.9, 55.3, 54.7, 53.4, 52.4, 52.3, 39.8, 37.4, 32.1, 29.1, 28.4, 28.3, 27.2, 22.2, 14.1;

[0135] HRMS (ESI) m / z calcd. for C 54 H 64 N7O9S2 [M+H] + 1018.4201, found 1018.4185.

[0136] Example 12: Electrochemical synthesis of compound 14

[0137]

[0138] In a 10 mL single-chamber electrolytic cell, starting materials 1k (0.2 mmol), 2b (0.24 mmol), and electrolyte n-Bu4NI (1.0 mmol) were added to a mixed solvent of 5 mL acetonitrile and 5 mL dichloromethane (volume ratio 1:1). Electrolysis was performed using a graphite sheet electrode as the anode and a platinum sheet as the cathode at a constant current of 5 mA. After stirring at room temperature for 6 hours, electrolysis was stopped, the reaction solution was transferred, concentrated, and purified by column chromatography to obtain compound 14 as a white solid with a yield of 51%.

[0139] The characterization data of compound 14 are as follows: 1H NMR (400 MHz, CDCl3) d 7.59 (d, J = 8.1 Hz, 2H),7.47 (d, J = 8.1 Hz, 1H), 7.42 (d, J = 7.7 Hz, 1H), 7.27 (d, J = 7.9 Hz, 1H), 7.19(d, J = 7.8 Hz, 1H), 7.16–7.14 (m, 2H), 7.13–7.00 (m, 2H), 6.95 (d, J = 8.1 Hz,2H), 6.89 (d, J = 8.4 Hz, 2H), 6.40 (d, J = 8.0 Hz, 2H), 6.05 (d, J = 7.8 Hz, 1H),5.64–5.56 (m, 1H), 4.80 (td, J = 7.2, 5.1 Hz, 1H), 4.25 (t, J = 9.1 Hz, 1H), 4.05(t, J = 7.5 Hz, 1H), 3.99 (td, J = 6.7, 5.7, 2.1 Hz, 1H), 3.73 (s, 3H), 3.32–3.01(m, 4H), 2.51–2.45 (m, 2H), 2.00 (s, 3H), 1.99 (s, 2H), 1.80–1.70 (m, 1H),1.47 (s, 9H), 0.55 (d, J = 6.7 Hz, 3H), 0.46 (d, J = 6.7 Hz, 3H);

[0140] 13 C NMR (100 MHz, CDCl3) δ 172.1, 171.1, 170.8, 169.5, 155.3, 140.6, 138.3, 137.3, 132.5, 132.2, 129.4, 128.5, 125.9, 125.0, 123.9, 123.5, 121.3, 121.3, 119.5, 118.8, 114.8, 113.0, 111.4, 111.1, 57.8, 56.0, 52.7, 51.3, 31.7, 30.5, 30.0, 29.1, 28.5, 27.0, 18.4, 18.0, 15.2;

[0141] HRMS (ESI) m / z calcd. for C 44 H 53 N6O7S3 [M+H] + 873.3132, found 873.3127.

[0142] Example 13: Electrochemical synthesis of compound 15

[0143]

[0144] In a 10 mL single-chamber electrolytic cell, starting materials 1j (0.2 mmol), 2b (0.24 mmol), and electrolyte n-Bu4NI (1.0 mmol) were added to a mixed solvent of 5 mL acetonitrile and 5 mL dichloromethane (volume ratio 1:1). Electrolysis was performed using a graphite sheet electrode as the anode and a platinum sheet as the cathode at a constant current of 5 mA. After stirring at room temperature for 6 hours, electrolysis was stopped, the reaction solution was transferred, concentrated, and purified by column chromatography to obtain compound 15 as a white solid with a yield of 45%.

[0145] The characterization data of compound 15 are as follows: 1 H NMR (400 MHz, CDCl3) d 7.68–7.63 (m, 1H), 7.51 (d, J = 8.2 Hz, 1H), 7.45 (d, J = 7.6 Hz, 2H), 7.19 (d, J = 7.5 Hz, 3H), 7.16–7.13 (m, 2H), 7.13–7.10 (m, 2H), 6.99 (s, 1H), 6.88 (d, J = 7.3 Hz, 1H), 6.75(d, J= 7.5 Hz, 1H), 6.66 (d, J = 8.2 Hz, 2H), 5.64 (s, 1H), 4.78 (dt, J = 8.1, 5.2Hz, 1H), 4.41 (q, J = 6.6 Hz, 1H), 4.23–4.15 (m, 2H), 3.60 (s, 3H), 3.33–3.16(m, 4H), 2.19 (s, 1H), 2.00–1.85 (m, 1H), 1.72–1.67 (m, 1H), 1.55–1.49 (m,3H), 1.45 (s, 9H), 0.87 (dd, J = 8.4, 6.2 Hz, 6H), 0.83 (d, J = 6.7 Hz, 3H), 0.75(d, J = 6.3 Hz, 2H);

[0146] 13 C NMR (100 MHz, CDCl3) δ 171.9, 171.7, 171.5, 170.5, 155.8, 141.1,140.7, 140.4, 139.6, 133.0, 131.9, 129.5, 129.3, 129.0, 124.6, 123.7, 123.3,121.4, 121.1, 119.3, 118.9, 114.5, 113.4, 111.1, 111.1, 80.5, 59.1, 55.8,52.5, 52.1, 52.0, 40.1, 30.9, 28.4, 27.2, 24.8, 22.7, 22.2, 18.8;

[0147] HRMS (ESI) m / z calcd. for C 45 H 55 N6O7S2 [M+H] + 855.3568, found 855.3552.

[0148] Example 14: Electrochemical synthesis of compound 16

[0149]

[0150] In a 10 mL single-chamber electrolytic cell, starting materials 1j (0.2 mmol), 2c (0.24 mmol), and electrolyte n-Bu4NI (1.0 mmol) were added to a mixed solvent of 5 mL acetonitrile and 5 mL dichloromethane (volume ratio 1:1). Electrolysis was performed using a graphite sheet electrode as the anode and a platinum sheet as the cathode at a constant current of 5 mA. After stirring at room temperature for 6 hours, electrolysis was stopped, the reaction solution was transferred, concentrated, and purified by column chromatography to obtain compound 16 as a white solid with a yield of 38%.

[0151] The characterization data of compound 16 are as follows: 1 H NMR (400 MHz, CDCl3) d 7.59 (d, J = 7.7 Hz, 1H), 7.51 (dd, J = 8.2, 2.8 Hz, 3H), 7.35–7.31 (m, 1H), 7.25–7.22 (m, 3H), 7.20(d, J = 2.3 Hz, 1H), 7.15 (d, J = 7.5 Hz, 5H), 7.05 (d, J = 7.5 Hz, 1H), 6.98 (s,1H), 6.95–6.89 (m, 2H), 6.80 (d, J = 8.1 Hz, 1H), 6.69–6.65 (m, 3H), 5.33 (s,1H), 4.91 (t, J = 9.1 Hz, 1H), 4.55 (s, 1H), 4.42 (d, J = 8.2 Hz, 1H), 3.95 (s, 1H), 3.65 (s, 1H), 3.61 (s, 3H), 3.38–3.30 (m, 2H), 3.27–3.17 (m, 4H), 1.54 (s, 9H), 0.92–0.80 (m, 12H);

[0152] 13 C NMR (100 MHz, CDCl3) δ 172.9, 172.4, 172.2, 171.0, 155.4, 140.0, 133.8, 133.5, 132.5, 132.3, 131.9, 131.3, 130.1, 129.7, 129.6, 125.8, 125.6, 125.1, 124.8, 124.0, 121.3, 119.7, 116.6, 115.9, 111.2, 78.5, 56.0, 52.9, 52.3, 51.4, 50.9, 31.9, 29.5, 28.6, 28.5, 27.0, 24.6, 22.2, 19.5, 18.5;

[0153] HRMS (ESI) m / z calcd. for C 51 H 58 N6O7S3 [M+H] + 963.3602, found 963.3617.

[0154] Example 15: Electrochemical synthesis of compound 3

[0155] The only difference between this embodiment and Embodiment 1 is the electrolyte. Details are as follows:

[0156] In a 10 mL single-chamber electrolytic cell, raw materials 1a (0.2 mmol), 2a (0.24 mmol), and electrolyte tetraethylammonium tetrafluoroborate (Et4NBF4) (1.0 mmol) were added to a mixed solvent of 5 mL acetonitrile and 5 mL dichloromethane (volume ratio 1:1). Electrolysis was performed with a graphite sheet electrode as the anode and a platinum sheet as the cathode under a constant current of 5 mA. After stirring at room temperature for 6 hours, electrolysis was stopped, the reaction solution was transferred, concentrated, and purified by column chromatography to obtain compound 3 as a white solid with a yield of 50%.

[0157] Example 16: Electrochemical synthesis of compound 3

[0158] The only difference between this embodiment and Embodiment 1 is the anode material. Details are as follows:

[0159] In a 10 mL single-chamber electrolytic cell, feedstocks 1a (0.2 mmol), 2a (0.24 mmol), and electrolyte n-Bu4NI were added. 1.0 mmol was added to a mixed solvent of 5 mL acetonitrile and 5 mL dichloromethane (volume ratio 1:1). Electrolysis was performed with a platinum sheet as the anode and a platinum sheet as the cathode under a constant current of 5 mA. After stirring at room temperature for 6 hours, the electrolysis was stopped, the reaction solution was transferred, concentrated, and purified by column chromatography to obtain compound 3 as a white solid with a yield of 47%.

[0160] Example 17: Electrochemical synthesis of compound 3

[0161] The only difference between this embodiment and Example 1 is the solvent. Details are as follows:

[0162] In a 10 mL single-chamber electrolytic cell, feedstocks 1a (0.2 mmol), 2a (0.24 mmol), and electrolyte n-Bu4NI were added. 1.0 mmol was added to a mixed solvent system of 5 mL acetonitrile and 5 mL water (volume ratio 1:1). Electrolysis was performed with a graphite sheet as the anode and a platinum sheet as the cathode under a constant current of 5 mA. After stirring at room temperature for 6 hours, the electrolysis was stopped, the reaction solution was transferred, concentrated, and purified by column chromatography to obtain compound 3 as a white solid with a yield of 53%.

[0163] Example 18: Electrochemical synthesis of compound 3

[0164] The only difference between this embodiment and Example 1 is the solvent ratio. Details are as follows:

[0165] In a 10 mL single-chamber electrolytic cell, feedstocks 1a (0.2 mmol), 2a (0.24 mmol), and electrolyte n-Bu4NI were added. 1.0 mmol was added to a mixed solvent of 10 mL acetonitrile and 5 mL dichloromethane (volume ratio 2:1). Electrolysis was performed with a graphite sheet as the anode and a platinum sheet as the cathode under a constant current of 5 mA. After stirring at room temperature for 6 hours, the electrolysis was stopped, the reaction solution was transferred, concentrated, and purified by column chromatography to obtain compound 3 as a white solid with a yield of 23%.

[0166] Example 19: Electrochemical synthesis of compound 3

[0167] The only difference between this embodiment and Embodiment 1 is the current intensity. Specifically:

[0168] In a 10 mL single-chamber electrolytic cell, feedstocks 1a (0.2 mmol), 2a (0.24 mmol), and electrolyte n-Bu4NI were added. 1.0 mmol was added to a mixed solvent system of 5 mL acetonitrile and 5 mL dichloromethane (volume ratio 1:1). Electrolysis was performed with a graphite sheet as the anode and a platinum sheet as the cathode under a constant current of 4 mA. After stirring at room temperature for 6 hours, the electrolysis was stopped, the reaction solution was transferred, concentrated, and purified by column chromatography to obtain compound 3 as a white solid with a yield of 57%.

[0169] Example 20: Synthesis of Compound 3

[0170] The difference between this embodiment and Embodiment 1 is that no electricity is applied, i.e., there is no current. Specifically:

[0171] In a 10 mL single-chamber electrolytic cell, feedstocks 1a (0.2 mmol), 2a (0.24 mmol), and electrolyte n-Bu4NI were added. 1.0 mmol was added to a mixed solvent of 5 mL acetonitrile and 5 mL dichloromethane (volume ratio 1:1). The reaction was carried out with a graphite sheet as the anode and a platinum sheet as the cathode under no-electricity conditions. After stirring at room temperature for 6 hours, the reaction solution was transferred, concentrated, and purified by column chromatography. Compound 3 could not be obtained, i.e., the yield was 0%.

[0172] Example 21 Antitumor activity test

[0173] Healthy lung cancer cells H460 and A549 were seeded into 96-well plates at 5 × 10⁻⁶ wells. 3 Cells / wells: The well plates were incubated in a cell culture incubator. After cell attachment, the original culture medium was removed. A series of concentration gradients of the test compound were prepared using complete culture medium: 100, 50, 25, 12.5, 6.25, 3.125, and 1.5625 μM. These were added to each well, and an equal volume of complete culture medium was added to the control wells. The well plates were incubated in a cell culture incubator for 48 h. After 48 h of incubation, 10 μL of CCK8 working solution was added to each well, and the plates were incubated for another 2 h. The absorbance of each well at 450 nm was measured using a microplate reader, and cell viability was calculated using the following formula: Cell viability (%) = (A... 实验孔 – A 空白孔 ) / (A 对照孔 – A 空白孔 () × 100%. Based on the administered concentration and corresponding cell viability, statistical analysis was performed using GraphPad Prism software to calculate the IC50 of the test compound. 50 .

[0174] The results are shown in Table 1: The sulfur-containing tryptophan cyclic peptide compounds prepared in this invention have certain inhibitory activity against H460 and A549 tumor cells.

[0175] Table 1

[0176]

[0177] The technical features of the above embodiments can be combined in any way. For the sake of brevity, not all possible combinations of the technical features in the above embodiments are described. However, as long as there is no contradiction in the combination of these technical features, they should be considered to be within the scope of this specification.

[0178] The embodiments described above are merely illustrative of several implementations of the present invention, and while the descriptions are relatively specific and detailed, they should not be construed as limiting the scope of the invention patent. It should be noted that those skilled in the art can make various modifications and improvements without departing from the concept of the present invention, and these all fall within the protection scope of the present invention. Therefore, the protection scope of this invention patent should be determined by the appended claims.

Claims

1. A method for synthesizing a sulfur-containing tryptophan cyclic peptide compound or its stereoisomer, characterized in that, Includes the following steps: Electrolytic reaction is carried out between a tryptophan peptide compound having the structure shown in Formula I or its stereoisomer and a thiosulfonate compound having the structure shown in Formula II to obtain a sulfur-containing tryptophan cyclic peptide compound having the structure shown in Formula III or its stereoisomer. Wherein, R is an amino acid residue with one amino hydrogen and one hydroxyl group removed, or a polypeptide group containing two or three amino acid residues. R 1 It is an amino protecting group; R 2 It is a C1 to C6 alkyl group; A is selected from: C6~C 10 aryl, 5-10 quinone heteroaryl, C6-C 10 Aspartic-X-C6~C 10 aryl, 5-10 nucleotide aryl-X-5-10 nucleotide aryl, where X is O or S.

2. The method for synthesizing sulfur-containing tryptophan cyclic peptides or their stereoisomers according to claim 1, characterized in that, R 1 It is tert-butyloxycarbonyl; And / or, R 2 It is methyl or ethyl; And / or, A is selected from: phenylene, 5-membered heteroaryl, phenylene-S-phenylene, 5-membered heteroaryl-S-5-membered heteroaryl, 6-membered heteroaryl-S-6-membered heteroaryl, phenylene-O-phenylene, 5-membered heteroaryl-O-5-membered heteroaryl, 6-membered heteroaryl-O-6-membered heteroaryl.

3. The method for synthesizing sulfur-containing tryptophan cyclic peptides or their stereoisomers according to claim 1, characterized in that, R is selected from the following groups: And / or, A is selected from the following groups: 。 4. The method for synthesizing sulfur-containing tryptophan cyclic peptides or their stereoisomers according to claim 1, characterized in that, Tryptophan peptides having the structure shown in formula (I) are selected from the following compounds: Thiosulfonates having the structure shown in formula (II) are selected from the following compounds: The sulfur-containing tryptophan cyclic peptides having the structure shown in formula (III) are selected from the following compounds: #imgpt8#.

5. The method for synthesizing sulfur-containing tryptophan cyclic peptides or their stereoisomers according to any one of claims 1-4, characterized in that, The electrolysis reaction is carried out in a single-chamber electrolytic cell containing an electrolyte. Preferably, the solvent in the electrolyte is selected from at least one of acetonitrile, dichloromethane, and water; Preferably, the solvent in the electrolyte is a mixture of solvent A and solvent B, wherein solvent A is acetonitrile and solvent B is dichloromethane or water; Preferably, the volume ratio of solvent A to solvent B is 0.2 to 2:1, more preferably 0.5 to 1.5:1; and even more preferably 0.8 to 1:

1. Preferably, the electrolyte in the electrolyte solution is selected from at least one of borate and quaternary ammonium halide; Preferably, the borate is at least one of tetrabutylammonium tetrafluoroborate, tetrabutylammonium hexafluoroborate, tetraethylammonium tetrafluoroborate, and tetraethylammonium hexafluoroborate, and the quaternary ammonium halide is at least one of tetrabutylammonium iodide, tetrabutylammonium bromide, and tetraethylammonium bromide; Preferably, the electrolyte is tetrabutylammonium iodide and / or tetraethylammonium tetrafluoroborate.

6. The method for synthesizing sulfur-containing tryptophan cyclic peptides or their stereoisomers according to claim 5, characterized in that, The concentration of the electrolyte in the electrolyte solution is 0.03 mol / L to 0.15 mol / L, preferably 0.08 mol / L to 0.12 mol / L; And / or, the reaction concentration of the tryptophan peptide compound having the structure shown in formula (I) or its stereoisomer is 0.01 mol / L to 0.3 mol / L, preferably 0.01 mol / L to 0.1 mol / L, more preferably 0.02 to 0.03 mol / L; And / or, the molar ratio of the electrolyte to the tryptophan peptide compound or its stereoisomer having the structure shown in formula (I) is 1.5 to 7:1, preferably 3 to 6:1, more preferably 4 to 5:1; And / or, the molar ratio of the thiosulfonate compound having the structure shown in formula (II) to the tryptophan peptide compound having the structure shown in formula (I) or its stereoisomer is 1 to 1.5:

1.

7. The method for synthesizing sulfur-containing tryptophan cyclic peptides or their stereoisomers according to any one of claims 1-4, characterized in that, The anode used for electrolysis is a graphite sheet, a mesh glassy carbon, glassy carbon, or a platinum sheet, and the cathode is a platinum sheet, an iron sheet, a copper sheet, a nickel sheet, or a zinc sheet. And / or, the electrolysis reaction is carried out using a constant current, with a current intensity of 3 mA to 10 mA, preferably 4 mA to 6 mA; the amount of charge is 3.3 F / mol to 11.3 F / mol, preferably 4.5 F / mol to 6.8 F / mol, based on the amount of substance of the tryptophan peptide compound having the structure shown in formula (I) or its stereoisomers; And / or, the temperature of the electrolysis reaction is 15℃~50℃, preferably 20℃~30℃.

8. The sulfur-containing tryptophan cyclic peptide compound or its stereoisomer or its pharmaceutically acceptable salt as described in any one of claims 1-4.

9. The use of the sulfur-containing tryptophan cyclic peptide compound or its stereoisomer or pharmaceutically acceptable salt as described in any one of claims 1-4 in the preparation of an antitumor drug, wherein the tumor is preferably lung cancer.

10. An antitumor drug, characterized in that, It is prepared from an active ingredient and pharmaceutically acceptable excipients, wherein the active ingredient comprises a sulfur-containing tryptophan cyclic peptide compound or its stereoisomer or its pharmaceutically acceptable salt as described in any one of claims 1-4.

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