Electrocatalytic oxidation modification method of indole skeleton-containing compound

Abstract

The invention discloses an electrocatalytic oxidation modification method of an indole skeleton-containing compound, which specifically comprises the following steps: adding tryptophan-containing polypeptide as shown in a formula I or an indole-containing derivative as shown in a formula III into a reaction bottle, adding a metal catalyst, a ligand, an electrolyte and a reaction solvent, introducing oxygen, and reacting at the temperature of 60-80 DEG C to obtain the indole skeleton-containing compound. Carrying out electrooxidation reduction reaction at room temperature under the condition that the electrodes are electrified; after the reaction is finished, carrying out reduced pressure distillation through a rotary evaporator to remove the solvent to obtain a crude product; further performing column chromatography separation on the crude product to obtain a pure product polypeptide compound containing a 3-hydroxy-2-indolone skeleton as shown in a formula II or a small molecule compound containing a 3-hydroxy-2-indolone skeleton as shown in a formula IV; according to the method, green and cheap oxygen is used as an oxygen source, an electrochemical technology which is environmentally friendly and high in atom economy is applied, use of an oxidizing agent and an expensive catalyst is avoided, and the catalytic efficiency is high.

Description

Technical Field

[0001] The invention belongs to the field of late modification of polypeptides or small molecules, and specifically relates to an electrocatalytic oxidation modification method of an indole skeleton-containing compound. Background Art

[0002] Among the 20 common amino acids, tryptophan has the lowest abundance, but is present in 90% of natural proteins. Tryptophan is a precursor of the human neurotransmitter serotonin and a chemical precursor of serotonin. It is involved in the synthesis of melatonin and serotonin in animals and has the functions of regulating mood, sleep and behavior (Enzyme Microb.Tech.2023,165,110198-110204). With the development of peptide drugs, tryptophan has become a key part of modification in peptide drugs and biological activities (Nature.2019,576,459-464). Based on the special skeleton of the relatively complex indole ring in the tryptophan side chain and its low abundance, tryptophan is a very promising target for peptide modification.

[0003] The functional groups contained in the drug will affect the physicochemical properties of the entire drug molecule, affect the physicochemical properties of the drug such as fat solubility and solubility, and also affect the charge density of the drug. When the functional group changes, the binding effect between the drug and the receptor will change accordingly, thereby changing the absorption and transport of the drug in the body. Natural drugs are limited by their original chemical structure and show disadvantages such as poor selectivity, unstable structure, poor solubility, strong toxic side effects, low bioavailability, poor membrane permeability, and short half-life (Nat.Chem.2018,10,383-394). Therefore, in order to improve the unfavorable factors of these drugs, scientists will structurally modify the structure of natural drugs (Front.Cell Dev.Biol.2021,9,694363-694378). The 3-hydroxy-2-indolone skeleton is a key structural feature of many alkaloid natural products and important compounds with pharmacological and biological activities. It has strong antioxidant, anti-cancer, anti-HIV, neuroprotective and other biological activities (Synthesis. 2009, 18, 3003-3025). For example, in 1995, Kamano's research group first isolated the natural alkaloid Convolutamydine A containing a 3-hydroxy-indolone skeleton from bryozoans in the Florida Ocean. The study found that the alkaloid had a strong inhibitory activity on the differentiation of HL-60 human promyelocytic leukemia cells in the concentration range of 0.1 to 25 mg / mL, and showed efficient anticancer activity (Org. Let. 2022, 24, 791-796). In addition, TMC-95A, which was isolated for the first time in the fermentation broth of Pseudomonas montagnaensis Sacc.TC 109, is a cyclic tripeptide compound containing a 3-hydroxy-2-indolone skeleton obtained by coupling the tyrosine side chain and the highly oxidized tryptophan side chain. Through research, it was found that this compound is a highly selective and competitive proteasome inhibitor that can bind to the enzyme in a non-covalent manner. Its IC 50 The values ​​are in the low nanomolar level (Org. Let, 2003, 5, 3435-3437).

[0004] Electrochemistry is a powerful sustainable tool with the advantages of mild and green conditions, low energy consumption, high efficiency, convenience, high selectivity, and no need for additional oxidants. The current electrochemical modification of tryptophan is still in the development stage, and the modification sites are mostly concentrated in the C-2 position of the indole skeleton of the tryptophan side chain. Combining electrochemistry with peptide modification, breaking through the limitations of existing peptide synthesis and modification methods, creating a milder, highly selective, cheap and sustainable method, undoubtedly opens up a milder path for tryptophan modification and peptide modification. In summary, this greatly encouraged us to use the tandem electrochemical hydroxylation reaction to modify the C-2 and C-3 positions of the indole skeleton of the tryptophan side chain, introduce hydroxyl functional groups, and construct peptide compounds and small molecule compounds containing 3-hydroxy-2-indolone skeletons. Summary of the invention

[0005] In view of the above technical problems existing in the prior art, the object of the present invention is to provide an electrocatalytic oxidation modification method for compounds containing an indole skeleton. The present invention is designed to use a tryptophan-containing polypeptide compound or an indole skeleton-containing small molecule compound as a substrate, and to modify the C-2 and C-3 positions of the tryptophan chain residues through a one-pot tandem electrochemical hydroxylation reaction, introduce a hydroxyl functional group, and successfully construct a polypeptide compound and a small molecule compound containing a 3-hydroxy-2-indolone skeleton. The present invention uses green and cheap oxygen as an oxygen source, applies an environmentally friendly, green, and highly atom-economic electrochemical technology, avoids the use of oxidants and expensive catalysts, and has high catalytic efficiency.

[0006] The technical solution adopted by the present invention is as follows:

[0007] The electrocatalytic oxidation modification method of an indole skeleton-containing compound comprises the following steps: adding a tryptophan-containing polypeptide shown in formula I or an indole-containing derivative shown in formula III to a reaction bottle, adding a metal catalyst, a ligand, an electrolyte and a reaction solvent, introducing oxygen, and performing an electro-oxidation-reduction reaction at room temperature when the electrodes are energized; after the reaction is completed, the solvent is removed by vacuum distillation using a rotary evaporator to obtain a crude product. The crude product is further separated by column chromatography to obtain a pure product, a polypeptide compound containing a 3-hydroxy-2-indole skeleton shown in formula II or a small molecule compound containing a 3-hydroxy-2-indole skeleton shown in formula IV; the reaction formula is as follows:

[0008]

[0009] In formula I and II, (AA) nrepresents a plurality of identical or different amino acids, n represents the number of amino acids, and n is an integer of 0 to 30; AA represents glycine, alanine, serine, cysteine, threonine, valine, leucine, isoleucine, proline, methionine, phenylalanine, tyrosine, aspartic acid, asparagine, glutamic acid, pyroglutamic acid, pyroglutamine, glutamine, lysine, arginine or histidine; R 1 An amino terminal protecting group selected from hydrogen, phthaloyl, allyloxycarbonyl, trimethylsilylethoxycarbonyl, methyl (or ethyl)oxycarbonyl, p-toluenesulfonyl, trifluoroacetyl, trityl, 2,4-dimethoxybenzyl, p-methoxybenzyl, benzyl, tert-butyloxycarbonyl, acetyl, benzyloxycarbonyl or 9-fluorenylmethoxycarbonyl; R 2 is selected from hydrogen, methoxy, ethoxy, benzyl or tert-butyl ester and other carboxyl terminal protecting groups; in formula III and IV, R 3 is selected from C1-15 alkyl, wherein any -CH2- is substituted by -O-, -S-, -NH-, -CO-, -CN-, -CO-O- or -O-CO-, or is substituted by alkyl, amide carboxyl, alcohol hydroxyl, ester, cyano, amino, aryl or halogen with 1 to 15 carbon atoms; R 4 Selected from halogen, carboxyl, amide, C1-C4 alkyl, phenolic hydroxyl, ester, cyano or amino.

[0010] In the present invention, the tryptophan-containing polypeptide in the compound of formula I comprises a short peptide composed of amino acids and a dipeptide R protected at the N-terminus and the C-terminus. 1 -Trp-AA-R 2 , R 1 -AA-Trp-R 2 , tripeptide R 1 -Trp-AA-AA-R 2 , R 1 -AA-Trp-AA-R 2 , R 1 -AA-AA-Trp-R 2 , tetrapeptide R 1 -Trp-AA-AA-AA-R 2 , R 1 -AA-Trp-AA-AA-R 2 , R 1 -AA-AA-Trp-AA-R 2 , R 1 -AA-AA-AA-Trp-R 2 and pentapeptide R 1 -Trp-AA-AA-AA-AA-R 2 , R 1 -AA-Trp-AA-AA-AA-R 2 , R1 -AA-AA-Trp-AA-AA-R 2 , R 1 -AA-AA-AA-Trp-AA-R 2 , R 1 -AA-AA-AA-AA-Trp-R 2 As substrate. 1 An amino terminal protecting group selected from hydrogen, phthaloyl, allyloxycarbonyl, trimethylsilylethoxycarbonyl, methyl (or ethyl)oxycarbonyl, p-toluenesulfonyl, trifluoroacetyl, trityl, 2,4-dimethoxybenzyl, p-methoxybenzyl, benzyl, tert-butyloxycarbonyl, acetyl, benzyloxycarbonyl or 9-fluorenylmethoxycarbonyl; R 2 is selected from hydrogen, methoxy, ethoxy, benzyl or tert-butyl ester and other carboxyl terminal protecting groups; in formula III and IV, R 3 is selected from C1-15 alkyl, wherein any -CH2- is substituted by -O-, -S-, -NH-, -CO-, -CN-, -CO-O- or -O-CO-, or is substituted by alkyl, amide carboxyl, alcohol hydroxyl, ester, cyano, amino, aryl or halogen with 1 to 15 carbon atoms; R 4 Selected from halogen, carboxyl, amide, C1-C4 alkyl, phenolic hydroxyl, ester, cyano or amino.

[0011] In the present invention, the active peptide in the compound of formula I may be the following compound:

[0012]

[0013] The electrocatalytic oxidation modification method of an indole skeleton-containing compound is characterized in that the metal catalyst is selected from the following: palladium, manganese, iron, copper, cobalt, titanium, aluminum, lithium, cobalt or nickel compounds. The molar amount of the metal catalyst is 1-50% of the molar amount of the tryptophan-containing polypeptide shown in formula I or the indole-containing derivative shown in formula III, preferably 5-8%.

[0014] Furthermore, the manganese compound is preferably a monovalent manganese catalyst Mn(CO)5Br, a divalent manganese catalyst MnF2, MnCl2, MnBr2, MnBr2·4H2O, MnI2, Mn(OAc)2, Mn(OAc)2·4H2O, MnSO4, MnO, Mn(OH)2, Mn(o-phen)2I2 (structure and high-resolution data characterization such as Figure 1 As shown), trivalent manganese catalyst Mn(acac)3, Mn(OAc)3·2H2O, Mn III (salen)(Cl), [Mn III (TPP)Cl]、[Mn IIIT4(-OMe)PPCl] or at least one of the tetravalent manganese catalyst MnO2.

[0015] Mn(o-phen)2I2(structure and high resolution data characterization such as Figure 1 (shown in Figure 2) Synthesis steps: dissolve the ligand 1,10-phenanthroline and MnI2 in CH3CN, reflux and stir at 75°C under nitrogen, and monitor the reaction system by TLC. After the raw materials react completely, filter and collect the precipitate, which is the corresponding metal catalyst.

[0016] The electrocatalytic oxidation modification method of an indole skeleton-containing compound is characterized in that the metal complex is any one of the substituted or unsubstituted phthalocyanine, porphyrin, oxazole, pyridine, salen and other ligands shown in the following structural formula:

[0017]

[0018] Wherein, R represents a single substitution or a multiple substitution; when there are multiple R in any structure, the R may be the same or different; R is independently selected from the group consisting of: hydrogen, deuterium, halogen, substituted or unsubstituted alkyl having 1-20 carbon atoms, substituted or unsubstituted cycloalkyl having 3-20 ring carbon atoms, substituted or unsubstituted heteroalkyl having 1-20 carbon atoms, substituted or unsubstituted aralkyl having 7-30 carbon atoms, substituted or unsubstituted alkoxy having 1-20 carbon atoms, acyl, carbonyl, carboxylic acid, nitro, ester, cyano, isocyano, sulfanyl, sulfinyl, sulfonyl, phosphino and combinations thereof; two adjacent substituents can be optionally connected to form a ring; the molar amount of the ligand is 2 to 100% of the molar amount of the tryptophan-containing polypeptide shown in formula I or the indole-containing derivative shown in formula III, preferably 10%.

[0019] The electrocatalytic oxidation modification method of the indole skeleton-containing compound is characterized in that the electrolyte is selected from one of the following: NH4I, NH4PF6, Me4NI, Et4NI, LiNO3, LiClO4, nMe4NBF4, Et4NBF4, nBu4NBF4, Me4NBF6, Et4NBF6, nBu4NPF6, nBu4NClO4, Me4NClO4, nBu4NI, nBu4NBr, nBu4NCl, nBu4NOAc, nBu4NHSO4, Et4NClO4, Me4NI, Et4NBF4, Et4NPF6; the molar amount of the electrolyte is 100-300% of the molar amount of the tryptophan-containing polypeptide shown in formula I or the indole-containing derivative shown in formula III, preferably 100%.

[0020] The electrocatalytic oxidation modification method of an indole skeleton-containing compound is characterized in that the reaction solvent includes an organic solvent and a buffer-acid system; the buffer is a buffer (Tricine) composed of tris(hydroxymethyl)aminomethyl)ethanesulfonic acid and (tris(hydroxymethyl)aminomethane) at pH=6-8, a mannitol buffer (MB) at pH=6-8, a sulfonic acid buffer (HEPES) at pH=6-8, a phosphate buffer (PB) at pH=6-8, a phosphate buffer (PBS) at pH=6-8, tris(hydroxymethyl)aminomethane (Tris) at pH=6-8, or Tris-HCl; the buffer-acid system is a mixed liquid system formed by adjusting the pH of the buffer to 5-8 with an acid, and the acid is selected from at least one of formic acid, acetic acid, trifluoroacetic acid, hydrochloric acid, sulfuric acid, phosphoric acid, nitric acid, isooctanoic acid, 2-dimethylbutyric acid, n-hexanoic acid, n-butyric acid, n-pentanoic acid, n-octanoic acid, 3-cyclohexylpropionic acid, 3-cyclopentylpropionic acid, 3-cyclooctylpropionic acid, 4-methylpentanoic acid, 3-methylpentanoic acid, 2-methylpentanoic acid, cyclohexanoic acid, cyclooctanoic acid, cyclopentanoic acid, 1-phenylcyclopentanecarboxylic acid, 1-methylcyclohexanecarboxylic acid, and 1-phenyl-1-cyclohexanecarboxylic acid;

[0021] The organic solvent is selected from at least one of methanol, ethanol, isopropanol, hexafluoroisopropanol, propylene glycol, glycerol, tert-butyl alcohol, tert-amyl alcohol, benzene, toluene, xylene, methyl acetate, ethyl acetate, dichloromethane, 1,2-dichloroethane, chloroform, tetrahydrofuran, N,N-dimethylformamide (DMF), dimethyl sulfoxide (DMSO), acetonitrile and 1,4-dioxane, preferably acetonitrile;

[0022] The volume ratio of the organic solvent to the buffer-acid system is 1:0.5-2, preferably 0.8-1.5:1, more preferably 0.8-1:1;

[0023] The electrocatalytic oxidation modification method of an indole skeleton-containing compound is characterized in that the reaction temperature is 15-45°C and the reaction time is 1-10 hours; the reaction temperature is preferably 25-30°C and the reaction time is preferably 2-8 hours.

[0024] The electrocatalytic oxidation modification method of an indole skeleton-containing compound is characterized in that the electrode used in the reaction is one of the following: the anode is at least one of GF, Ni, Sn, Al, Zn, Carbon rod, Pt, RVC, Carbon cloth, GC, etc.; the cathode is at least one of GF, Ni, Sn, Al, Zn, Carbon rod, Pt, RVC, Carbon cloth, GC, etc., and the electrode combination of the anode and the cathode is preferably GF-Pt.

[0025] The electrocatalytic oxidation modification method of the indole skeleton-containing compound is characterized in that the reaction voltage is 1 to 6V; the preferred reaction voltage is 1.5-4.5V.

[0026] The present invention has the following advantages:

[0027] (1) For the first time, green and cheap oxygen was used as an oxygen source for direct hydroxylation of tryptophan under metal catalysis. The reaction system has high catalytic efficiency and mild reaction conditions.

[0028] (2) This method has excellent functional group compatibility and chemical and site selectivity;

[0029] (3) Environmentally friendly and highly atom-economical electrochemical technology is used, using only catalytic amounts of locally abundant manganese metal, thus avoiding the use of oxidants and expensive catalysts;

[0030] (4) The reaction conditions are mild and can be carried out at room temperature and buffer conditions;

[0031] (5) Gram-scale reactions can be carried out, which makes industrial production possible.

[0032] In summary, the present invention uses environmentally friendly, green, and highly atom-economic electrochemical technology to replace the traditional reaction mode, avoiding the use of oxidants and expensive catalysts, and has high catalytic efficiency. The one-pot method realizes the hydroxylation modification of indole skeleton compounds, has excellent atom economy, high reaction efficiency, good site selectivity, excellent functional group compatibility, and a wide range of applications. It is a very promising polypeptide modification method. BRIEF DESCRIPTION OF THE DRAWINGS

[0033] Figure 1 It is the structural formula and high-resolution data characterization results of Mn(o-phen)2I2;

[0034] Figure 2 The full liquid phase diagram and the enlarged liquid phase diagram of the modified leuprorelin (i.e., product 7) in Example 18;

[0035] Figure 3 This is the high-resolution mass spectrum of leuprorelin after modification in Example 18. DETAILED DESCRIPTION

[0036] The technical solution of the present invention is described below with specific embodiments (Examples 1-19), but the protection scope of the present invention is not limited thereto.

[0037] In the embodiment of the present invention, the tryptophan-containing polypeptide shown in Formula I is reacted under electrochemical conditions to prepare a polypeptide compound containing a 3-hydroxy-2-indolone skeleton shown in Formula II, and the reaction formula is as follows:

[0038]

[0039] The substituent R in formula II 1 , R 2 The substituents at the corresponding positions are the same as those in formula I.

[0040] Similarly, the indole-containing derivative shown in formula III is reacted under electrochemical conditions to prepare a small molecule compound containing a 3-hydroxy-2-indolone skeleton shown in formula IV, and the reaction formula is as follows:

[0041]

[0042] The substituent R in formula IV 3 , R 4 The substituents at the corresponding positions are the same as those in formula III.

[0043] Example 1: Compound I Tryptophan-containing polypeptide raw material using dipeptide substrate Ac-Trp-Val-OMe, added to a clean and dry 10mL reaction bottle Compound I (Ac-Trp-Val-OMe) (90mg, 0.25mmol), catalyst manganese diiodide (3.85mg, 5mol%), ligand 1,10-phenanthroline (4.5mg, 10mol%), electrolyte tetrabutylammonium perchlorate (85.3mg, 0.25mmol), acetonitrile (1.5mL), buffer-acid system (acetic acid (0.25mL) was added to Tris (1.5mL) at pH = 6 to 8 and mixed to form a buffer-acid system at pH = 5 to 6). Conductive electrodes were installed in the reaction bottle, using GF as the anode and Pt as the cathode. Stirring and electrolysis at a constant voltage of 2V for 4.0 hours in an oxygen atmosphere at 30°C. After completion, the reaction system was decompressed to remove the solvent, and the product was purified and separated by silica gel column chromatography (volume ratio of dichloromethane / methanol = 25:1) to obtain a pair of diastereoisomer products 1a and 1b. The total yield of the reaction was 82%.

[0044] Example 1 Compound II Data Characterization:

[0045]

[0046] 1a, 1H NMR(600 MHz,DMSO-d6)(600 MHz,DMSO-d6)δ10.25(s,1H),7.88(d,J=8.4Hz,1H),7.50(d,J=8.4 Hz,1H),7.22–7.17(m,2H),6.95(td,J=7.8,1.2 Hz,1H),6.76(d,J=7.8 Hz,1H),6.07(s,1H),4.23–4.19(m,1H),4.13(dd,J=8.4,6.0 Hz,1H),3.61(s,3H),2.30(dd,J=13.8,3.0 Hz,1H),2.06–1.98(m,2H),1.75(s,3H),0.83(d,J=7.2Hz,6H).

[0047] 13 C NMR(100 MHz,DMSO-d6)δ179.1,171.7,171.6,169.2,141.8,130.9,129.1,124.2,121.4,109.7,74.2,57.1,51.8,48.9,38.8,30.2,22.4,18.9,17.9.

[0048] HR-MS(ESI)m / z calcd.for C 19 H 26 N3O6[M+H] + :392.1822;found:392.1816.

[0049]

[0050] 1b, 1 H NMR(600 MHz,DMSO-d6)7.70(d,J=8.4 Hz,1H),7.66(d,J=8.4 Hz,1H),7.27(dd,J=7.2,1.2 Hz,1H),7.18(td,J=7.2,1.2Hz,1H),6.96(t,J=7.8 Hz,1H),6.77(d,J=7.8 Hz,1H),6.04(s,1H),4.31–4.27(m,1H),4.13(dd,J=8.4,6.0 Hz,1H),3.62(s,3H),2.19(dd,J=14.4,3.6 Hz,1H),2.09(dd,J=14.4,10.2 Hz,1H),2.05–1.97(m,1H),1.52(s,3H),0.82(d,J=6.6 Hz,6H).

[0051] 13 C NMR(100MHz,DMSO-d6)δ178.7,171.8,171.7,169.1,141.6,131.5,129.0, 124.7,121.6,109.8,74.7,57.2,51.9,49.2,38.1,30.2,22.3,19.0,18.0.

[0052] HR-MS(ESI)m / z calcd.for C 19 H 26 N3O6[M+H] + :392.1822; found:392.1816.

[0053] Example 2: The steps and materials added in Example 2 are exactly the same as those in Example 1, except that the metal catalyst MnF2 is replaced by the same molar amount of Mn(o-phen)2I2 (structure and high-resolution data characterization as shown in Figure 1 49 mg of product was obtained, and the total yield of the reaction was 50%.

[0054] Mn(o-phen)2I2(structure and high resolution data characterization such as Figure 1 The synthesis steps are as shown: 1,10-phenanthroline (2.00 mmol) and MnI2 (1.00 mmol) were dissolved in 5 mL CH3CN, refluxed and stirred at 75 °C under nitrogen, and the reaction system was monitored by TLC. After the raw materials reacted completely, the precipitate was collected by filtration to obtain the corresponding metal catalyst, with a total of 602.00 mg and a yield of 90%.

[0055] Example 3: The steps and added materials of Example 3 are exactly the same as those of Example 1, except that the ligand 1,10-phenanthroline is replaced by the same molar amount of 4,4'-di-tert-butyl-2,2'-bipyridine to obtain 39 mg of product with a total reaction yield of 40%.

[0056] Example 4: The steps and added materials of Example 4 are exactly the same as those of Example 1, except that the ligand 1,10-phenanthroline is replaced by the same molar amount of 4,4'-diamino-2,2'-bipyridine to obtain 20 mg of product with a total reaction yield of 21%.

[0057] Example 5: The steps and added materials of Example 5 are exactly the same as those of Example 1, except that the ligand 1,10-phenanthroline is replaced by the same molar amount of 5-nitro-1,10-phenanthroline to obtain 12 mg of product with a total reaction yield of 13%.

[0058] Example 6: The steps and added materials of Example 6 are exactly the same as those of Example 1, except that the reaction electrolyte is adjusted to the same molar amount of lithium perchlorate, and 76 mg of product is obtained, with a total reaction yield of 78%.

[0059] Example 7: The steps and added materials of Example 7 are exactly the same as those of Example 1, except that the reaction electrolyte is adjusted to the same molar amount of tetrabutylammonium tetrafluoroborate, and 54 mg of product is obtained, with a total reaction yield of 56%.

[0060] Example 8: The steps and added materials of Example 8 are exactly the same as those of Example 1, except that the reaction electrolyte is adjusted to the same molar amount of tetrabutylammonium hexafluorophosphate, and 41 mg of product is obtained, with a total reaction yield of 43%.

[0061] Example 9: The steps and added materials of Example 9 are exactly the same as those of Example 1, except that the reaction solvent MeCN (1.5 mL) is replaced by DMF (1.5 mL). 27 mg of product is obtained, and the total yield of the reaction is 28%.

[0062] Example 10: The steps and added materials of Example 10 are exactly the same as those of Example 1, the only difference is that the constant voltage of 2V is adjusted to 3V, and 62mg of product is obtained, and the total yield of the reaction is 64%.

[0063] Example 11: The steps and added materials of Example 11 are exactly the same as those of Example 1, the only difference is that the reaction constant voltage of 2V is adjusted to a constant current of 4mA, and 56mg of product is obtained, and the total yield of the reaction is 58%.

[0064] Example 12: The steps and added materials of Example 12 are exactly the same as those of Example 1, the only difference is that the reaction constant voltage of 2V is adjusted to a constant current of 6mA, and 69mg of product is obtained, and the total yield of the reaction is 71%.

[0065] Example 13: Compound I (Ac-Trp-Tyr-OMe) (106 mg, 0.25 mmol), catalyst manganese diiodide (3.85 mg, 5 mol%), ligand 1,10-phenanthroline (4.5 mg, 10 mol%), electrolyte tetrabutylammonium perchlorate (85.3 mg, 0.25 mmol), acetonitrile (1.5 mL), buffer-acid system (acetic acid (0.25 mL) was added to Tris (1.5 mL) at pH = 6 to 8 and mixed to form a buffer-acid system at pH = 5 to 6). Conductive electrodes were installed in the reaction bottle, using GF as the anode and Pt as the cathode. Stir and electrolyze at a constant voltage of 2 V for 4.0 hours in an oxygen atmosphere at 30°C. After completion, the reaction system was decompressed to remove the solvent, and the product was purified and separated by silica gel column chromatography (volume ratio of dichloromethane / methanol = 25:1) to obtain a pair of diastereoisomer products 2a and 2b. The total yield of the reaction was 60%.

[0066] Example 13 Compound II Data Characterization:

[0067]

[0068] 2a, 1 H NMR (400MHz, DMSO-d6): δ10.20(s,1H),9.25(s,1H),7.74(d,J=8.8Hz,1H),7.57(d,J=7.2Hz,1H),7.21–7.16(m,2H),6.95–6.90(m, 3H),6.75(d,J=7.6Hz,1H),6.66–6.62(m,2H),6.01(s,1H),4.35–4.30(m,1H),4.19–4.13(m,1H),3.57(s,3H),2.87(dd,J=13.6,5.6 Hz,1H),2.79(dd,J=14.0,7.6 Hz, 1H), 2.30 (dd, J=14.0, 3.2Hz, 1H), 1,98 (dd, J=14.0, 9.6 Hz, 1H), 1.73 (s, 3H).

[0069] 13 C NMR(100 MHz, DMSO-d6)δ179.0,171.6,171.3,169.0,156.0,141.9,130.9,130.0,129.1 ,126.6,124.2,121.4,115.1,109.6,74.2,53.7,51.8,48.6,35.9,31.0,22.4.

[0070] HR-MS(ESI)m / z calcd.for C 23 H 26 N3O7[M+H] + :456.1771;found:456.1767.

[0071]

[0072] 2b, 1 H NMR(400 MHz,DMSO-d6):δ10.24(s,1H),9.26(s,1H),7.69(d,J=7.6 Hz,1H),7.58(d,J=8.0 Hz,1H),7.26(d,J=7.6 Hz,1H),7.17(t,J=7.6 Hz,1H),6.96–6.90(m,3H),6.76(d,J=7.6 Hz,1H),6.63(d,J=8.0 Hz,2H),5.97(s,1H),4.36–4.31(m,1H),4.28–4.22(m,1H),3.58(s,3H),2.89–2.76(m,2H),2.18(dd,J=14.4,3.2 Hz,1H),2.05(dd,J=14.0,10.0 Hz,1H),1.49(s,3H).

[0073] 13 C NMR(100 MHz,DMSO-d6)δ178.6,171.6,171.3,168.7,156.0,141.6,131.4,130.0,128.8,126.7,124.6,121.4,115.0,109.6,74.6,53.7,51.8,48.8,37.9,35.8,22.2.

[0074] HR-MS(ESI)m / z calcd.for C 23 H 26 N3O7[M+H] + :456.1771;found:456.1758.

[0075] Example 14: Compound I (Ac-Trp-Val-Thr-OMe) (115.1 mg, 0.25 mmol), catalyst manganese diiodide (3.85 mg, 5 mol%), ligand 1,10-phenanthroline (4.5 mg, 10 mol%), electrolyte tetrabutylammonium perchlorate (85.3 mg, 0.25 mmol), acetonitrile (1.5 mL), buffer-acid system (acetic acid (0.25 mL) was added to Tris (1.5 mL) at pH = 6 to 8 and mixed to form a buffer-acid system at pH = 5 to 6). Conductive electrodes were installed in the reaction bottle, using GF as the anode and Pt as the cathode. Stir and electrolyze at a constant voltage of 2 V for 4.0 hours in an oxygen atmosphere at 30°C. After completion, the reaction system was decompressed to remove the solvent, and the product was purified and separated by silica gel column chromatography (volume ratio of dichloromethane / methanol = 20:1) to obtain a pair of diastereoisomers 3a and 3b. The total yield of the reaction was 61%.

[0076] Example 14 Compound II Data Characterization:

[0077]

[0078] 3a, 1 H NMR (400MHz, DMSO-d6) δ10.28(s,1H),8.15(d,J=8.0Hz,1H),7.77(d,J=8.0Hz,1H),7.33(d,J=8.8Hz,1H),7.27( d,J=7.2Hz,1H),7.17(t,J=7.6Hz,1H),6.95(t,J=7.2Hz,1H),6.76(d,J=7.6Hz,1H),6.01(s,1H),4.32(dd,J=9. 2,6.4Hz,1H),4.27-4.22(m,2H),4.11–4.06(m,1H),3.60(s,3H),2.23(dd,J=14.4,3.2Hz,1H),2.11(dd,J=14.0 ,10.0,1H),2.03–1.94(m,1H),1.49(s,3H),1.05(d,J=6.0Hz,3H),0.83(d,J=6.8Hz,3H),0.78(d,J=6.8Hz,3H).

[0079] 13C NMR(100MHz,DMSO-d6)δ178.7,171.3,171.1,171.0,168.8,141.6,131.5,128.9,124.7,121.5,109.7,74.7,66.2,58.1,56.8,51.8,49.4,38.2,31.1,22.2,20.1,19.1,17.5.

[0080] HR-MS(ESI)m / z calcd for C 23 H 31 N4O8[M-H] - :491.2142;found:491.2142.

[0081]

[0082] . 3b, 1 H NMR(400MHz,DMSO-d6)δ10.22(s,1H),8.12(d,J=8.0Hz,1H),7.95(d,J=8.4Hz,1H),7.24–7.16(m,3H),6.94(t,J=7.6Hz,1H),6.76(d,J=7.6Hz,1H),4.32(dd,J=9.2,6.4Hz,1H),4.21(dd,J=8.0,3.6Hz,1H),4.17–4.11(m,1H),4.09–4.05(m,1H),3.60(s,3H),2.33(d,J=14.4,2.8Hz,1H),2.05(d,J=14.0,9.6Hz,1H),2.00–1.94(m,1H),1.74(s,3H),1.04(d,J=6.0Hz,3H),0.83(d,J=6.8Hz,3H),0.81(d,J=6.8Hz,3H).

[0083] 13 C NMR(100MHz,DMSO-d6)δ179.1,171.2,171.1,170.9,169.2,141.9,131.0,129.1,124.2,121.4,109.7,74.3,66.1,58.1,56.7,51.8,49.1,39.0,31.1,22.4,20.1,19.1,17.5.

[0084] HR-MS(ESI)m / z calcd for C 23 H 31 N4O8[M-H] -:491.2142; found:491.2141.

[0085] Example 15: Compound I (Ac-Trp-Ala-Val-Phe-OMe) (144.3 mg, 0.25 mmol), catalyst manganese diiodide (3.85 mg, 5 mol%), ligand 1,10-phenanthroline (4.5 mg, 10 mol%), electrolyte tetrabutylammonium perchlorate (85.3 mg, 0.25 mmol), acetonitrile (1.5 mL), buffer-acid system (acetic acid (0.25 mL) was added to Tris (1.5 mL) at pH = 6 to 8 and mixed to form a buffer-acid system at pH = 5 to 6). A conductive electrode was installed in the reaction bottle, using GF as the anode and Pt as the cathode. Stir and electrolyze at a constant voltage of 2 V for 4.0 hours under an oxygen atmosphere at 30°C. After completion, the reaction system was decompressed to remove the solvent, and a pair of diastereoisomer products 4a and 4b were purified and separated by silica gel column chromatography, and the total reaction yield was 50%.

[0086] Example 15 Compound II Data Characterization:

[0087]

[0088] 4a, 1 H NMR (400MHz, DMSO-d6) δ10.28(s,1H),8.38(d,J=7.2Hz,1H),7.73(d,J=8.8Hz,1H),7.70–7.65(m,2H),7.28–7.23(m,3 H),7.21–7.15(m,4H),6.94(t,J=7.2Hz,1H),6.76(d,J=7.6Hz,1H),6.01(s,1H),4.48–4.43(m,1H),4.29–4.21(m,2H) ,4.12(dd,J=8.8,6.8Hz,1H),3.55(s,3H),3.01(dd,J=13.6,5.6Hz,1H),2.91(dd,J=14.0,8.8Hz,1H),2.21(dd,J=14. 0,3.2Hz,1H),2.06(dd,J=14.0,10.0Hz,1H),1.94–1.86(m,1H),1.52(s,3H),1.10(d,J=7.2Hz,3H),0.79–0.76(m,6H).

[0089] 13C NMR(100MHz,DMSO-d6)δ178.7,171.8,171.7,171.0,168.8,141.6,137.1,131.5,129.0,128.9,128.2,126.5,124.6,121.4,109.6,74.7,57.4,53.5,51.7,49.2,48.0,38.3,36.5,30.7,22.3,19.0,18.1,18.0.

[0090] HR-MS(ESI)m / z calcd for C 31 H 38 N5O8[M-H] - :608.2720;found:608.2715.

[0091]

[0092] 4b,(400MHz,DMSO-d6)δ10.23(s,1H),8.39(d,J=7.2Hz,1H),7.81(d,J=8.4Hz,1H),7.74(d,J=9.2Hz,1H),7.60(d,J=7.2Hz,1H),7.27–7.15(m,7H),6.93(t,J=7.2Hz,1H),6.75(d,J=7.6Hz,1H),4.49–4.43(m,1H),4.26–4.21(m,1H),4.19–4.09(m,2H),3.55(s,3H),3.01(dd,J=13.6,5.6Hz,1H),2.92(dd,J=13.6,8.8Hz,1H),2.32(dd,J=14.0,3.2Hz,1H),2.00(dd,J=14.4,10.0Hz,1H),1.94–1.85(m,1H),1.74(s,3H),1.11(d,J=6.8Hz,3H),0.79–0.75(m,6H).

[0093] 13 C NMR(100MHz,DMSO-d6)δ179.1171.8,171.6,171.0,171.0,169.0,141.9,137.1,131.0,129.1,129.0,128.2,126.5,124.3,121.4,109.6,74.3,57.4,53.5,51.7,48.9,48.0,39.0,36.5,30.6,22.5,19.1,18.1,18.0.

[0094] HR-MS(ESI)m / z calcd for C 31 H 38 N5O8[MH] - :608.2720; found:608.2716.

[0095] Example 16: Compound I (Ac-Gly-Phe-Ala-Val-Trp-OH) (173.1 mg, 0.25 mmol), catalyst manganese diiodide (3.85 mg, 5 mol%), ligand 1,10-phenanthroline (4.5 mg, 10 mol%), electrolyte tetrabutylammonium perchlorate (85.3 mg, 0.25 mmol), acetonitrile (1.5 mL), buffer-acid system (acetic acid (0.25 mL) was added to Tris (1.5 mL) at pH = 6 to 8 and mixed to form a buffer-acid system at pH = 5 to 6). Conductive electrodes were installed in the reaction bottle, using GF as the anode and Pt as the cathode. Stir and electrolyze at a constant voltage of 2 V for 4.0 hours in an oxygen atmosphere at 30°C. After completion, the reaction system was decompressed to remove the solvent, and a pair of diastereoisomers 5a and 5b were obtained by purification and separation by silica gel column chromatography. The total yield of the reaction was 45%.

[0096] Example 16 Compound II Data Characterization:

[0097]

[0098] 5a, 1 H NMR (400MHz, DMSO-d6) δ10.18(s,1H),8.30(d,J=7.2Hz,1H),8.06–8.01(m,3H),7.62(d,J=9.2Hz,1H),7.26–7.21(m,5H),7.2 0–7.15(m,2H),6.92(t,J=7.6Hz,1H),6.77(d,J=8.0Hz,1H),4.57–4.51(m,1H),4.42–4.34(m,2H),4.10(dd,J=8.8,6.0Hz,1H ),3.68(dd,J=16.4,5.6Hz,1H),3.52(dd,J=16.8,5.6Hz,1H),3.01(dd,J=13.6,3.6Hz,1H),2.75(dd,J=13.6,9.6Hz,1H),2.2 9(dd,J=14.0,4.8Hz,1H),2.01–1.90(m,2H),1.81(s,3H),1.26(d,J=7.2Hz,3H),0.82(d,J=6.8Hz,3H),0.78(d,J=6.4Hz,3H).

[0099] 13 C NMR(100MHz,DMSO-d6)δ179.1,173.2,171.8,170.8,170.3,169.6,168.8,141.5,137.8,129.3,129.01,128.96,128.0,126.3,124.7,121.5,109.6,74.1,57.1,53.6,48.3,47.9,41.9,38.7,37.6,31.0,22.4,19.2,17.9,17.7.

[0100] HR-MS(ESI)m / z calcd for C 32 H 41 N6O9[M+H] + :653.2935;found:653.2933.

[0101]

[0102] 5b,1H NMR(400MHz,DMSO-d6)δ10.14(s,1H),8.25(d,J=7.6Hz,1H),8.06–8.01(m,2H),7.75–7.67(m,J=9.2Hz,1H),7.24–

[0103] 7.12(m,8H),6.89(t,J=7.2Hz,1H),6.75(d,J=8.0Hz,1H),4.55–

[0104] 4.50(m,1H),4.40–4.32(m,2H),4.02(dd,J=9.2,5.6Hz,1H),3.67(dd,J=16.4,5.6Hz,1H),3.52(dd,J=16.8,5.6Hz,1H),2.99(dd,J=13.6,4.0Hz,1H),2.74(dd,J=13.6,9.6Hz,1H),2.07–1.92(m,3H),1.81(s,3H),1.26–1.23(m,3H),0.80(d,J=6.8Hz,3H),0.76(d,J=6.8Hz,3H).

[0105] 13C NMR (100MHz, DMSO-d6) δ179.0,173.2,171.8,170.8,170.2,169.5,168.8,141.5,137.8,129.2,128.9,128. 0,126.2,124.6,121.5,109.6,74.0,57.0,53.6,48.3,41.9,40.1,38.7,37.6,30.9,22.4,19.1,17.9,17.6.

[0106] HR-MS(ESI)m / z calcd for C 32 H 41 N6O9[M+H] + :653.2935; found:653.2933.

[0107] Example 17: Compound I (endorphin) (30.1 mg, 0.05 mmol), catalyst manganese diiodide (3.85 mg, 5 mol%), ligand 1,10-phenanthroline (4.5 mg, 10 mol%), electrolyte tetrabutylammonium perchlorate (85.3 mg, 0.25 mmol), buffer-acid system (acetic acid (0.25 mL) was added to Tris (1.5 mL) at pH = 6 to 8 and mixed to form a buffer-acid system at pH = 5 to 6), acetonitrile (1.5 mL). Conductive electrodes were installed in the reaction bottle, using GF as the anode and Pt as the cathode. Stir and electrolyze at a constant voltage of 2 V for 15 minutes under an oxygen atmosphere at 30°C. After completion, product 6 was obtained by preparative liquid phase separation and purification, and the reaction yield was 30%.

[0108]

[0109] High-resolution data characterization of product 6:

[0110] HR-MS(ESI)m / z calcd.for C 34 H 39 N6O7[M+H] + :643.2802; found:643.2800.

[0111] Example 18: Compound I (leuprorelin) (24.8 mg, 0.02 mmol), catalyst manganese diiodide (3.85 mg, 5 mol%), ligand 1,10-phenanthroline (4.5 mg, 10 mol%), electrolyte tetrabutylammonium perchlorate (85.3 mg, 0.25 mmol), acetonitrile (1.5 mL), buffer-acid system (acetic acid (0.25 mL) was added to Tris (1.5 mL) at pH = 6 to 8 and mixed to form a buffer-acid system at pH = 5 to 6). Conductive electrodes were installed in the reaction flask, using GF as the anode and Pt as the cathode. Stir and electrolyze at a constant voltage of 2 V for 20 minutes under an oxygen atmosphere at 30°C. After completion, the reaction system was decompressed to remove the solvent, and product 7 was obtained by preparative liquid phase purification, with a reaction yield of 24%.

[0112] High-resolution data characterization of product 7:

[0113] HR-MS(ESI)m / z calcd.for C 59 H 84 N 16 O 14 [M+H] + :1241.6426; found:1241.6392.

[0114] Example 18 The full liquid phase diagram and enlarged liquid phase diagram of modified leuprorelin (i.e., product 7) are as follows Figure 2 As shown, it can be seen that after modification, a hydroxyl group was introduced at the indole C3 position of leuprorelin, and the retention time was 10.326 min.

[0115] Example 18 The high-resolution mass spectrum of modified leuprorelin is as follows Figure 3 As shown, it can be seen that after modification, a hydroxyl group is introduced into the indole C3 position of leuprorelin, and the retention time is 10.326min. The retention time is 10.326min, which is the product obtained after modification, and the mass is: [M+H] + :1241.6426.

[0116] Example 19: Compound III (3-indoleacetone) (43 mg, 0.25 mmol), catalyst manganese diiodide (3.85 mg, 5 mol%), ligand 1,10-phenanthroline (4.5 mg, 10 mol%), electrolyte tetrabutylammonium perchlorate (85.3 mg, 0.25 mmol), acetonitrile (1.5 mL), buffer-acid system (acetic acid (0.25 mL) was added to Tris (1.5 mL) at pH = 6 to 8 and mixed to form a buffer-acid system at pH = 5 to 6). A conductive electrode was installed in the reaction bottle, using GF as the anode and Pt as the cathode. Stir and electrolyze at a constant voltage of 2 V for 4 hours under an oxygen atmosphere at 30°C. After completion, the reaction system was decompressed to remove the solvent, and the product 8 was separated by column chromatography, with a reaction yield of 67%.

[0117] Example 19 Compound IV Product data characterization:

[0118]

[0119] 1 H NMR (400 MHz, DMSO-d6) δ10.21 (s, 1H), 7.24 (dd, J=7.2Hz, 1.2 Hz, 1H), 7.17 (td, J=7.6 Hz, 1.6 Hz, 1H), 6.90 (td, J=7.2, 0.8Hz, 1H), 6.77 (d, J=7.6 Hz,1H),5.97(s,1H),3.27(d,J=16.8 Hz,1H),3.00(d,J=16.4 Hz,1H),2.00(s,3H).

[0120] 13 C NMR (100 MHz, DMSO-d6) δ205.2,178.2,142.5,131.5,129.0,123.7,121.2,109.4,72.7,50.3,30.6.

[0121] HR-MS(ESI): m / z calcd.for C 11 H 11 NNaO3[M+Na] + :228.0637; found:228.0633.

Claims

1. A method for electrocatalytic oxidation modification of an indole skeleton-containing compound, characterized in that The method comprises the following steps: adding a tryptophan-containing polypeptide shown in formula I or an indole-containing derivative shown in formula III into a reaction bottle, adding a metal catalyst, a ligand, an electrolyte and a reaction solvent, introducing oxygen, and performing an electric redox reaction at room temperature when the electrodes are energized; after the reaction is completed, performing reduced pressure distillation by a rotary evaporator to remove the solvent to obtain a crude product; the crude product is further separated by column chromatography to obtain a pure product, a 3-hydroxy-2-indolone-containing skeleton polypeptide compound shown in formula II or a small molecule compound containing a 3-hydroxy-2-indolone skeleton shown in formula IV; the reaction formula is as follows: In formula I and II, (AA) n represents a plurality of identical or different amino acids, n represents the number of amino acids, and n is an integer of 0 to 30; AA represents glycine, alanine, serine, cysteine, threonine, valine, leucine, isoleucine, proline, methionine, phenylalanine, tyrosine, aspartic acid, asparagine, glutamic acid, pyroglutamic acid, pyroglutamine, glutamine, lysine, arginine or histidine; R 1 An amino terminal protecting group selected from hydrogen, phthaloyl, allyloxycarbonyl, trimethylsilylethoxycarbonyl, methoxycarbonyl, ethoxycarbonyl, p-toluenesulfonyl, trifluoroacetyl, trityl, 2,4-dimethoxybenzyl, p-methoxybenzyl, benzyl, tert-butyloxycarbonyl, acetyl, benzyloxycarbonyl or 9-fluorenylmethoxycarbonyl; R 2 is selected from hydrogen, methoxy, ethoxy, benzyl or tert-butyl ester carboxyl terminal protecting group; wherein R 1 , R 2 When H is selected, it means that no protecting group is used; In formula III and IV, R 3 is selected from C1-15 alkyl, wherein any -CH2- is substituted by -O-, -S-, -NH-, -CO-, -CN-, -CO-O- or -O-CO-, or is substituted by alkyl, amide carboxyl, alcohol hydroxyl, ester, cyano, amino, aryl or halogen with 1 to 15 carbon atoms; R 4 Selected from halogen, carboxyl, amide, C1-C4 alkyl, phenolic hydroxyl, ester, cyano or amino.

2. The electrocatalytic oxidation modification method of an indole skeleton-containing compound according to claim 1, characterized in that The metal catalyst is selected from the following: palladium, manganese, iron, copper, titanium, aluminum, lithium, cobalt or nickel compounds; the molar amount of the metal catalyst is 1-50% of the molar amount of the tryptophan-containing polypeptide shown in formula I or the indole-containing derivative shown in formula III, preferably 5-8%; The manganese compound is preferably a monovalent manganese catalyst Mn(CO)5Br, a divalent manganese catalyst MnF2, MnCl2, MnBr2, MnBr2·4H2O, MnI2, Mn(OAc)2, Mn(OAc)2·4H2O, MnSO4, MnO, Mn(OH)2, Mn(o-phen)2I2, a trivalent manganese catalyst Mn(acac)3, Mn(OAc3·2H2O, Mn III (salen)(Cl), [Mn III (TPP)Cl]、[Mn III T4(-OMe)PPCl] or at least one of the tetravalent manganese catalyst MnO2.

3. The electrocatalytic oxidation modification method of an indole skeleton-containing compound according to claim 1, characterized in that The metal complex is any one of substituted or unsubstituted phthalocyanine, porphyrin, oxazole, pyridine, and salen ligands: Wherein, R represents a single substitution or a multiple substitution; when there are multiple R in any structure, the R may be the same or different; R is independently selected from the group consisting of: hydrogen, deuterium, halogen, substituted or unsubstituted alkyl having 1-20 carbon atoms, substituted or unsubstituted cycloalkyl having 3-20 ring carbon atoms, substituted or unsubstituted heteroalkyl having 1-20 carbon atoms, substituted or unsubstituted aralkyl having 7-30 carbon atoms, substituted or unsubstituted alkoxy having 1-20 carbon atoms, acyl, carbonyl, carboxylic acid, ester, nitro, cyano, isocyano, sulfanyl, sulfinyl, sulfonyl, phosphino and combinations thereof; two adjacent substituents can be optionally connected to form a ring; the molar amount of the ligand is 2 to 100% of the molar amount of the tryptophan-containing polypeptide shown in formula I or the indole-containing derivative shown in formula III, preferably 10%.

4. The electrocatalytic oxidation modification method of an indole skeleton-containing compound according to claim 1, characterized in that The electrolyte is selected from one of the following: NH4I, NH4PF6, Me4NI, Et4NI, LiNO3, LiClO4, nMe4NBF4, Et4NBF4, nBu4NBF4, Me4NBF6, Et4NBF6, nBu4NPF6, nBu4NClO4, Me4NClO4, nBu4NI, nBu4NBr, nBu4NCl, nBu4NOAc, nBu4NHSO4, Et4NClO4, Me4NI, Et4NBF4, Et4NPF6; the molar amount of the electrolyte is 100-300% of the molar amount of the tryptophan-containing polypeptide shown in formula I or the indole-containing derivative shown in formula III, preferably 100%.

5. The electrocatalytic oxidation modification method of an indole skeleton-containing compound according to claim 1, characterized in that The reaction solvent comprises an organic solvent and a buffer-acid system; the buffer is a buffer (Tricine) composed of tris(hydroxymethyl)aminomethyl)ethanesulfonic acid and (tris(hydroxymethyl)aminomethane) with a pH of 6 to 8, a mannitol buffer (MB) with a pH of 6 to 8, a sulfonic acid buffer (HEPES) with a pH of 6 to 8, a phosphate buffer (PB) with a pH of 6 to 8, a phosphate buffer (PBS) with a pH of 6 to 8, tris(hydroxymethyl)aminomethane (Tris) with a pH of 6 to 8, and tris(hydroxymethyl)aminomethane hydrochloride (Tris) with a pH of 6 to 8. -HCl); the buffer-acid system is a mixed liquid system formed by adjusting the pH of the buffer to 5-8 with an acid, and the acid is selected from at least one of formic acid, acetic acid, trifluoroacetic acid, hydrochloric acid, sulfuric acid, phosphoric acid, nitric acid, isooctanoic acid, 2,2-dimethylbutyric acid, n-hexanoic acid, n-butyric acid, n-pentanoic acid, n-octanoic acid, 3-cyclohexylpropionic acid, 3-cyclopentylpropionic acid, 3-cyclooctylpropionic acid, 4-methylpentanoic acid, 3-methylpentanoic acid, 2-methylpentanoic acid, cyclohexanoic acid, cyclooctanoic acid, cyclopentanoic acid, 1-phenylcyclopentanecarboxylic acid, 1-methylcyclohexanecarboxylic acid, and 1-phenyl-1-cyclohexanecarboxylic acid; The organic solvent is selected from at least one of methanol, ethanol, isopropanol, hexafluoroisopropanol, propylene glycol, glycerol, tert-butyl alcohol, tert-amyl alcohol, benzene, toluene, xylene, methyl acetate, ethyl acetate, dichloromethane, 1,2-dichloroethane, chloroform, tetrahydrofuran, N,N-dimethylformamide (DMF), dimethyl sulfoxide (DMSO), acetonitrile and 1,4-dioxane, preferably acetonitrile; The volume ratio of the organic solvent to the buffer-acid system is 1:0.5-2, preferably 0.8-1.5:1, and more preferably 0.8-1:

1.

6. The electrocatalytic oxidation modification method of an indole skeleton-containing compound according to claim 1, characterized in that The reaction temperature is between 15 and 45° C., and the reaction time is between 1 and 10 hours; the reaction temperature is preferably between 25 and 30° C., and the reaction time is preferably between 2 and 8 hours.

7. The electrocatalytic oxidation modification method of an indole skeleton-containing compound according to claim 1, characterized in that The electrodes used in the reaction are one of the following: the anode is at least one of GF, Ni, Sn, Al, Zn, Carbon rod, Pt, RVC, Carbon cloth, and GC; the cathode is at least one of GF, Ni, Sn, Al, Zn, Carbon rod, Pt, RVC, Carbon cloth, and GC, and the electrode combination of the anode and the cathode is preferably GF-Pt.

8. The electrocatalytic oxidation modification method of an indole skeleton-containing compound according to claim 1, characterized in that The voltage of the reaction is 1-6V; the voltage of the reaction is preferably 1.5-4.5V.

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