Selective amidation modification method of tryptophan indole C-2 site and application of selective amidation modification method

Abstract

The invention provides a selective amidation modification method of tryptophan indole C-2 site and application thereof.The method comprises the steps that a tryptophan substrate and an aryloxy amide compound are mixed and dissolved in a solvent, stirring reaction is conducted at room temperature under the action of visible light catalysis and alkali, and selective amidation modification of tryptophan indole C-2 site can be achieved; wherein the tryptophan substrate comprises tryptophan and oligopeptide containing tryptophan residues. The method disclosed by the invention is mild in reaction condition, green and environment-friendly, high in chemical selectivity and good in specificity, avoids the use of a photocatalyst, is low in economic cost, provides a simple and convenient method for selective modification of tryptophan-containing polypeptide, greatly makes up the limitation and deficiency of a tryptophan indole C-2 site modification method, and is suitable for industrial production. The method can provide a new tool for development of polypeptide drugs and research of compound structure functions, and has a wide application prospect in the fields of organic chemistry and polypeptide drug chemistry.

Description

Technical Field

[0001] The present invention belongs to the technical field of polypeptide chemical modification, and particularly relates to a method for selective amidation modification at the C-2 position of tryptophan indole and its application. Background Art

[0002] Due to the precise targeting and selectivity of polypeptides and proteins, in recent years, the focus of drug research and development has gradually shifted to the field of biomolecule modification, and such modified molecules have occupied an important position in drug research and development. Among them, the chemical modification of polypeptides is one of the most important tools in the process of polypeptide drug research and development. In the modification of polypeptides, the active groups on the amino acid side chains often interfere with the selective modification at specific sites. Therefore, some low-abundance amino acids with specific structures have become important sites for polypeptide selective modification. In the biological system, tryptophan (Trp) is the amino acid with the lowest abundance (accounting for about 1.4%), but at least one tryptophan residue is contained in about 90% of the natural protein sequences. Tryptophan not only helps to stabilize the secondary and tertiary structures of polypeptides, but also has an important impact on the biological activities of polypeptides, and has unique pharmacological activities and medicinal values. In addition, the indole heterocycle on the tryptophan side chain has unique chemical reaction activities, and excellent site-selective modification can be achieved. Given the many advantages of tryptophan, selectively modifying the tryptophan site while maintaining the structural integrity of polypeptides has become a research hotspot in the field of polypeptide chemical modification; nevertheless, due to the low natural abundance and weak nucleophilicity of tryptophan, designing effective methods to achieve its chemical modification is still a challenge. Most of the early tryptophan modification reactions required the use of oxidants and had many side reactions, and could not be effectively applied to the modification of bioactive polypeptides. With the development of C-H bond activation and radical reactions, the number of mild methods for specifically modifying polypeptides or proteins has gradually increased. In particular, visible light-mediated transformation has become a powerful strategy for achieving chemoselective modification of biomolecules. These reactions have broadened the types of tryptophan modification products. At present, various types of reactions, including arylation, alkylation, and fluoroalkylation, have been achieved for the chemical modification of the C-2 position of tryptophan indole mediated by visible light. Amidation is a very important type of functional modification, and many natural products and synthetic drugs contain amide functional groups. However, there are very limited reports on the amidation modification of the C-2 position of tryptophan indole. For example, the oxidative modification strategy reported by the Francis group requires the use of CAN as an oxidant, which has problems such as over-oxidation and many side reactions. This requires that other amino acid side chains in the polypeptide cannot contain functional groups that are easily oxidized, limiting the wide range of applications of this method; in addition, when this method is applied to tryptophan-containing polypeptides (melittin), the conversion rate is low. Another example is the light-induced electron transfer strategy developed by the Taylor group, which solves the problem of using oxidants well, but this method requires the addition of glutathione to inhibit the occurrence of double amidation, and the previous reported work requires the use of UV-B light for irradiation, which may induce unstable polypeptides to undergo photodegradation reactions. The Chiang group reported a visible light-induced late photoredox CH amidation strategy involving a free radical mechanism, but this method requires the use of eosin Y as a photocatalyst, which not only increases the experimental cost, but also makes the reaction system more complicated, which is not conducive to its potential application in biological systems. In view of the fact that there are few strategies for amidation modification of the C-2 position of tryptophan indole, the poor universality of peptides, and some problems and shortcomings in the reaction process, it is necessary to explore more efficient, mild, low-cost, and simple-to-operate methods to achieve amidation modification of the C-2 position of tryptophan indole. Summary of the invention

[0003] Technical problems to be solved: In view of the above-mentioned technical problems, the purpose of the present invention is to provide a method for selective amidation modification of the C-2 position of tryptophan indole and its application, wherein the method comprises mixing a tryptophan substrate and an aromatic oxyamide compound and dissolving them in a solvent, and stirring the reaction at room temperature under the catalysis of visible light and the action of a base, so as to achieve selective amidation modification of the C-2 position of tryptophan indole; wherein the tryptophan substrate comprises tryptophan and an oligopeptide containing a tryptophan residue. The method of the present invention has mild reaction conditions, is green and environmentally friendly, has high chemical selectivity, good specificity, avoids the use of a photocatalyst, has low economic cost, provides a simple method for selective modification of tryptophan-containing polypeptides, greatly makes up for the limitations and shortcomings of the C-2 position modification method of tryptophan indole, can provide a new tool for the development of polypeptide drugs and the study of the structure and function of compounds, and has broad application prospects in the fields of organic chemistry and polypeptide medicinal chemistry.

[0004] Technical solution: A method for selective amidation modification of the C-2 position of tryptophan indole, comprising the following steps: S1. a tryptophan substrate and an aryloxyamide compound are mixed and dissolved in a solvent; S2. Under the action of visible light catalysis and base, stirring reaction is carried out at room temperature to obtain a tryptophan indole C-2 amidation product; the specific reaction formula is as follows: Among them, R 1 is one or more of an acetyl group, a tert-butoxycarbonyl group, a 9-fluorenylmethoxycarbonyl group, and other amino protecting groups; R 2 is one or more of carboxylic acid protecting groups such as a methoxy group, an ethoxy group, and a tert-butoxy group; R 3 is one or more of an alkyl group, an alkenyl group, an aryl group, and a heteroaryl group. Preferably, R 1 is an acetyl group and a tert-butoxycarbonyl group; R 2 is a methoxy group; R 3 is a p-trifluoromethylphenyl group. The tryptophan substrate is tryptophan or a polypeptide containing tryptophan; the molecular structural formula of the tryptophan indole C-2 position amidation product is any one of the following. Further, the molar ratio of the tryptophan substrate to the aryloxyamide compound in the step S1 is (1 - 2.5):(1 - 1.5); furthermore, the molar ratio of the tryptophan substrate to the aryloxyamide compound is 2:1. Further, the solvent is acetonitrile, acetone, a mixed solvent of acetonitrile or acetone and water; furthermore, the solvent is acetonitrile. Further, the wavelength of the visible light in the step S2 is 400 - 600 nm; furthermore, the wavelength of the visible light is 400 - 500 nm. When blue light (450 - 480 nm) is used as the light source, the yield of the target product is higher. Further, the base in the step S2 is one or more of triethylamine, KHCO3, K2CO3, Cs2CO3, K2HPO4, and K3PO4; furthermore, the base is K2CO3. Use of the tryptophan indole C-2 position amidation product prepared by the method according to any one of the above in the preparation of polypeptide drugs. Beneficial effects: 1. In the present invention, tryptophan or an oligopeptide containing tryptophan is used as a substrate, and selective amidation modification of the tryptophan indole C-2 position is successfully achieved under visible light catalysis and the action of a base. This method uses an amide donor with a trifluoromethyl functional group, introducing a trifluoromethyl functional group while achieving amidation modification, and obtaining a fluorine-containing polypeptide with special properties and functions, which has great application potential in the field of polypeptide medicinal chemistry. 2. The preparation of the tryptophan-containing oligopeptide and N-aryloxyamide derivative involved in the present invention is simple, with a low synthesis cost and is easily obtainable; the reaction conditions of this method are mild, the operation is simple, and there is no need to use a photocatalyst, which conforms to the concept of green chemistry. At the same time, it has a good substrate scope and good compatibility with the active functional groups in a variety of natural amino acids. During the synthesis process, the indole NH and the OH of the amino acid side chain do not need to be pre-protected. BRIEF DESCRIPTION OF THE DRAWINGS Figure 1 1H NMR spectrum of the indole C-2 amidation product 3a in Example 1; Figure 2 13C NMR spectrum of the indole C-2 amidation product 3a in Example 1; Figure 3 19F NMR spectrum of the indole C-2 amidation product 3a in Example 1; Figure 4 1H NMR spectrum of the indole C-2 amidation product 3b in Example 2; Figure 5 13C NMR spectrum of the indole C-2 amidation product 3b in Example 2; Figure 6 19F NMR spectrum of the indole C-2 amidation product 3b in Example 2; Figure 7 1H NMR spectrum of the indole C-2 amidation product 3c in Example 3; Figure 8 13C NMR spectrum of the indole C-2 amidation product 3c in Example 3; Figure 9 19F NMR spectrum of the indole C-2 amidation product 3c in Example 3; Figure 10 1H NMR spectrum of the indole C-2 amidation product 3d in Example 4; Figure 11 13C NMR spectrum of the indole C-2 amidation product 3d in Example 4; Figure 12 19F NMR spectrum of the indole C-2 amidation product 3d in Example 4; Figure 13 1H NMR spectrum of the indole C-2 amidation product 3e in Example 5; Figure 14 13C NMR spectrum of the indole C-2 amidation product 3e in Example 5; Figure 15 19F NMR spectrum of the indole C-2 amidation product 3e in Example 5; Figure 16 1H NMR spectrum of the indole C-2 amidation product 3f in Example 6; Figure 17 13C NMR of the indole C-2 amidation product 3f in Example 6; Figure 18 19F NMR of the indole C-2 amidation product 3f in Example 6. Detailed implementation manners The present invention will be further described below in conjunction with examples. The following examples are explanations of the present invention and the present invention is not limited to the following examples: Example 1 A method for selective amidation modification of the indole C-2 position of tryptophan, comprising the following steps: S1. Add 52.1 mg of methyl acetyltryptophan 1a (0.2 mmol), 38.5 mg of N-aryloxyamide derivative 2a (0.1 mmol) and 27.6 mg of K2CO3 (0.2 mmol) to a dry 10 mL Schlenk reaction tube equipped with a magnetic stir bar in sequence, evacuate and replace with nitrogen 3 times, and add 1.0 mL of acetonitrile; S2. Then irradiate the reaction mixture in S1 with 460 nm blue light at room temperature for 12 h; after the reaction is completed, filter the reaction mixture through diatomaceous earth, wash with ethyl acetate, remove the solvent by rotary evaporation under reduced pressure, and the obtained crude product is separated and purified by column chromatography to obtain the indole C-2 amidation product 3a (white solid, 68% yield). The specific reaction formula is shown below. From Figure 1 , Figure 2 and Figure 3 it can be seen that the characterization data of product 3a: 1 H NMR (400 MHz, CD3CN) δ 9.67 (s, 1H), 7.51 (d, J = 8.1 Hz, 2H), 7.44 (d, J = 8.2 Hz, 2H), 7.39 - 7.30 (m, 2H), 7.15 (t, J = 7.5 Hz, 1H), 7.01 (t, J = 7.5 Hz, 1H), 6.85 (d, J = 7.8 Hz, 1H), 4.59 (br, 1H), 3.56 (s, 3H), 3.41 (s, 3H), 2.68 (d, J = 28.0 Hz, 2H), 1.81 (s, 3H); 13 C NMR (100 MHz, CD3CN) δ 173.0, 170.8, 170.0, 140.7, 135.6, 134.5, 131.62 (q, J C-F = 32.2 Hz), 128.8, 127.4, 125.5 (q, J C-F = 3.7 Hz), 124.7 (q, J C-F= 272.3 Hz), 123.6, 120.5, 119.9, 112.2, 105.6, 53.1, 52.7, 38.1, 27.1, 22.7; 19 19F NMR (377 MHz, CD3CN) δ -63.4; HRMS (ESI-TOF) calculated for C 23 H 22 F3N3O4, [M+Na] + 484.1455, found 484.1459. Example 2 A method for selective amidation modification at the C-2 position of tryptophan indole, comprising the following steps: S1. Add 78.3 mg of dipeptide acetyltryptophan-methionine methyl ester (Ac-Trp-Met-OMe) 1b (0.2 mmol), 38.5 mg of N-aryloxyamide derivative 2a (0.1 mmol) and 27.6 mg of K2CO3 (0.2 mmol) successively to a dry 10 mL Schlenk reaction tube equipped with a magnetic stir bar, evacuate and backfill with nitrogen 3 times, and add 1.0 mL of acetonitrile; S2. Then irradiate the reaction mixture in S1 with 460 nm blue light at room temperature for 12 h; after the reaction is completed, filter the reaction mixture through diatomaceous earth, wash with ethyl acetate, and remove the solvent by rotary evaporation under reduced pressure. The obtained crude product is separated and purified by column chromatography to obtain the indole C-2 amidation product 3b (white solid, 53% yield). The specific reaction formula is shown below. From Figure 4 , Figure 5 and Figure 6 it can be seen that the characterization data of product 3b: 11H NMR (400 MHz, CD3CN, rotamers) δ 9.80 (s, 1H), 7.50 (d, J = 8.1 Hz, 2H), 7.46 - 7.36 (m, 3H), 7.30 (d, J = 8.2 Hz, 1H), 7.18 - 7.01 (m, 3H), 6.95 (t, J = 7.5 Hz, 1H), 4.78 (q, J = 7.2 Hz, 0.18H) & 4.67 (q, J = 7.6 Hz, 0.86H), 4.58 - 4.41 (m, 1H), 3.57 (s, 3H), 3.47 (s, 1.41H) & 3.41 (s, 1.58H), 2.81 (dd, J = 14.6, 6.7 Hz, 1H), 2.59 (dd, J = 14.8, 7.6 Hz, 1H), 2.40 (br, 2H), 2.00 (s, 3H), 1.99 - 1.95 (m, 1H), 1.88 - 1.83 (m, 1H), 1.80 (s, 3H); 13 13C NMR (100 MHz, CD3CN, rotamers) δ 172.6, 172.1, 170.8, 170.1, 140.9, 135.5, 134.5, 131.5 (q, J C-F = 32.4 Hz), 128.7, 127.4, 125.5 (q, J C-F = 3.9 Hz), 124.7 (q, J C-F = 272.6 Hz), 123.4, 120.4, 120.2, 112.1, 106.0, 53.9, 52.7, 52.1, 38.3 & 37.8, 31.7, 30.3, 27.4, 23.0, 15.1; 19 19F NMR (377 MHz, CD3CN) δ -63.3; HRMS (ESI-TOF) calculated for C 28 H 31 F3N4O5S, [M+Na] + 615.1859, found 615.1850. Example 3 A method for selective amidation modification at the C-2 position of tryptophan indole, comprising the following steps: S1. Add 81.5 mg of dipeptide acetyltryptophan-phenylalanine methyl ester (Ac-Trp-Phe-OMe) 1c (0.2 mmol), 38.5 mg of N-aryloxyamide derivative 2a (0.1 mmol) and 27.6 mg of K2CO3 (0.2 mmol) successively to a dry 10 mL Schlenk reaction tube equipped with a magnetic stir bar. Flush with nitrogen three times and add 1.0 mL of acetonitrile. S2. Then irradiate the reaction mixture in S1 with 460 nm blue light at room temperature for 12 h. After the reaction is completed, filter the reaction mixture through diatomaceous earth, wash with ethyl acetate, and remove the solvent by rotary evaporation under reduced pressure. The crude product obtained is separated and purified by column chromatography to obtain the indole C-2 amidation product 3c (pale yellow solid, 56% yield). The specific reaction formula is shown below. From Figure 7 , Figure 8 and Figure 9 it can be seen that the characterization data of product 3c are as follows: 1 H NMR (400 MHz, CD3CN, rotamers) δ 9.86 (s, 1H), 7.50 (d, J = 7.9 Hz, 2H), 7.46 - 7.35 (m, 3H), 7.31 (d, J = 8.2 Hz, 1H), 7.28 - 7.07 (m, 7H), 7.02 (d, J = 8.5 Hz, 1H), 6.97 (t, J = 7.6 Hz, 1H), 4.80 - 4.51 (m, 2H), 3.55 (s, 3H), 3.43 (s, 3H), 3.16 - 2.87 (m, 2H), 2.79 (dd, J = 14.5, 6.4 Hz, 1H), 2.55 (d, J = 14.5 Hz, 1H), 1.78 (s, 3H); 13 C NMR (100 MHz, CD3CN, rotamers) δ 172.2, 171.7, 170.9, 170.1, 140.8, 137.5 135.6 & 135.4, 134.5, 131.46 (q, J C-F = 32.4 Hz), 130.1, 129.2, 128.7, 127.6, 127.3, 125.5 (q, J C-F = 3.9 Hz), 124.6 (q, J C-F = 272.8 Hz), 123.4, 120.4, 120.1, 112.1, 106.0, 54.5, 53.7, 52.6, 38.3 & 37.8, 38.0, 27.2, 22.9; 1919F NMR (377 MHz, CD3CN) δ -63.2; HRMS (ESI-TOF) calculated for C 32 H 31 F3N4O5, [M+Na] + 631.2139, found 631.2133. Example 4 A method for selective amidation modification at the C-2 position of tryptophan indole, comprising the following steps: S1. Add 72.3 mg of dipeptide acetyltryptophan-threonine methyl ester (Ac-Trp-Thr-OMe) 1d (0.2 mmol), 38.5 mg of N-aryloxyamide derivative 2a (0.1 mmol) and 27.6 mg of K2CO3 (0.2 mmol) successively to a dry 10 mL Schlenk reaction tube equipped with a magnetic stir bar, evacuate and refill with nitrogen 3 times, and add 1.0 mL of acetonitrile; S2. Then irradiate the reaction mixture in S1 with 460 nm blue light at room temperature for 12 h; after the reaction is completed, filter the reaction mixture through diatomaceous earth, wash with ethyl acetate, evaporate the solvent under reduced pressure, and purify the obtained crude product by column chromatography to obtain the indole C-2 amidation product 3d (pale yellow solid, 50% yield), and the specific reaction formula is shown as follows. From Figure 10 , Figure 11 and Figure 12 it can be seen that the characterization data of product 3d: 1 1H NMR (400 MHz, CD3CN, rotamers) δ 9.65 (s, 1H), 7.51 (d, J = 8.3 Hz, 2H), 7.46 - 7.36 (m, 3H), 7.30 (dd, J = 8.1, 5.2 Hz, 1H), 7.22 - 7.05 (m, 2H), 6.96 (t, J = 7.6 Hz, 2H), 4.84 - 4.71 (m, 0.50H) & 4.70 - 4.60 (m, 0.53H), 4.42 - 4.34 (m, 0.62H) & 4.33 - 4.22 (m, 0.42H), 4.14 (br, 1H), 3.64 (s, 1.40H) & 3.58 (s, 1.68H), 3.43 (br, 3H), 3.43 (br, 1H), 2.85 - 2.71 (m, 1H), 2.59 (dd, J = 14.4, 8.1 Hz, 1H), 1.80 (s, 1.55H) & 1.79 (s, 1.48H), 1.27 (d, J = 4.2 Hz, 1.45H) & 1.07 (d, J = 4.1 Hz, 1.65H); 13 13C NMR (100 MHz, CD3CN, rotamers) δ 171.8, 171.6, 171.1, 170.2, 140.9, 135.6, 134.6, 131.6 (q, J C-F = 32.8 Hz), 128.8 & 128.7, 127.4 & 127.3, 125.5 (q, J C-F = 3.3 Hz), 124.8 (q, J C-F = 272.4 Hz), 123.5, 120.5, 120.2 & 120.1, 112.2, 106.1, 68.2 & 67.7, 58.7 & 58.6, 54.2 & 53.9, 52.8 & 52.7, 38.0 & 37.9, 27.5 & 27.2, 22.9, 20.2 & 20.0; 19 19F NMR (377 MHz, CD3CN) δ -63.3; HRMS (ESI-TOF) calculated for C 27 H 29 F3N4O6, [M+Na] + 585.1931, found 585.1912. Example 5 A method for selective amidation modification at the C-2 position of tryptophan indole, comprising the following steps: S1. Add 122.5 mg of tripeptide Boc-Phe-Phe-Trp-OMe 1e (0.2 mmol), 38.5 mg of N-aryloxyamide derivative 2a (0.1 mmol) and 27.6 mg of K2CO3 (0.2 mmol) to a dry 10 mL Schlenk reaction tube equipped with a magnetic stir bar in sequence, evacuate and refill with nitrogen 3 times, and add 1.0 mL of acetonitrile; S2. Then irradiate the reaction mixture in S1 with 460 nm blue light at room temperature for 12 h; after the reaction is completed, filter the reaction mixture through diatomaceous earth, wash with ethyl acetate, evaporate the solvent under reduced pressure, and the obtained crude product is separated and purified by column chromatography to obtain the indole C-2 amidation product 3e (pale yellow solid, 58% yield), and the specific reaction formula is as follows. From Figure 13 , Figure 14 and Figure 15 it can be seen that the characterization data of product 3e: 11H NMR (400 MHz, CD3CN) δ 9.97 (s, 1H), 7.64 (d, J = 8.1 Hz, 1H), 7.57 (d, J = 8.1 Hz, 2H), 7.49 (br, 1H), 7.43 - 7.35 (m, 3H), 7.33 - 7.11 (m, 12H), 7.03 (t, J = 7.6 Hz, 1H), 5.97 (br, 1H), 4.92 (q, J = 7.2 Hz, 1H), 4.86 - 4.72 (m, 1H), 4.53 (br, 1H), 3.54 (s, 3H), 3.50 (s, 3H), 3.22 - 3.05 (m, 2H), 2.97 (br, 2H), 2.85 - 2.70 (m, 2H), 1.36 (s, 9H); 13 13C NMR (100 MHz, CD3CN, rotamers) δ 172.7, 172.6, 171.7, 170.2, 156.4, 140.6, 138.4, 137.7, 135.6, 134.5, 131.6 (q, J C-F = 32.4 Hz), 130.4, 130.2, 129.1, 128.8, 127.5, 127.4, 127.3, 125.5 (q, J C-F = 3.3 Hz), 124.6 (q, J C-F = 272.9 Hz), 123.6, 120.6, 119.9, 112.4, 105.3, 80.0, 56.7, 54.8, 53.6 & 53.3, 52.8339.1, 38.8, 38.4 & 38.2, 28.5, 27.8 & 27.1; 19 19F NMR (377 MHz, CD3CN) δ -63.0; HRMS (ESI-TOF) calculated for C 44 H 46 F3N5O7, [M+Na] + 836.3242, found 836.3247. Example 6 A method for selective amidation modification at the C-2 position of tryptophan indole, comprising the following steps: S1. Add 97.9 mg of tetrapeptide Boc-Gly-Gly-Gly-Trp-OMe 1f (0.2 mmol), 38.5 mg of N-aryloxyamide derivative 2a (0.1 mmol) and 27.6 mg of K2CO3 (0.1 mmol) successively to a dry 10 mL Schlenk reaction tube equipped with a magnetic stir bar. Flush with nitrogen three times and add 1.0 mL of acetonitrile. S2. Then irradiate the reaction mixture in S1 with blue light at 460 nm for 12 h at room temperature. After the reaction is completed, filter the reaction mixture through diatomaceous earth, wash with ethyl acetate, and remove the solvent by rotary evaporation under reduced pressure. The crude product obtained is separated and purified by column chromatography to obtain the indole C-2 amidation product 3f (yellow solid, 60% yield). The specific reaction formula is shown below. From Figure 16 , Figure 17 and Figure 18 it can be seen that the characterization data of product 3f are as follows: 1 H NMR (400 MHz, CD3CN) δ 9.96 (s, 1H), 7.52 (d, J = 7.8 Hz, 2H), 7.47 (s, 1H), 7.42 (d, J = 8.3 Hz, 3H), 7.37 (br, 2H), 7.33 (d, J = 8.2 Hz, 1H), 7.13 (t, J = 7.6 Hz, 1H), 6.99 (t, J = 7.5 Hz, 1H), 6.07 (t, J = 5.9 Hz, 1H), 4.63 (q, J = 7.4 Hz, 1H), 3.86 - 3.77 (m, 3H), 3.76 - 3.68 (m, 3H), 3.51 (s, 3H), 3.43 (s, 3H), 2.88 - 2.66 (m, 2H), 1.40 (s, 9H); 13 C NMR (100 MHz, CD3CN, rotamers) δ 172.8, 172.1, 170.6, 170.2, 170.1, 157.4, 140.7, 135.6, 134.4, 131.5 (q, J C-F = 32.3 Hz), 128.7, 127.2, 125.5 (q, J C-F = 3.7 Hz), 124.7 (q, J C-F = 272.8 Hz), 123.5, 120.5, 119.9 & 119.8, 112.3, 105.4, 80.3, 53.3, 52.8, 44.8, 43.5, 43.0, 38.2 & 38.1, 28.5, 27.1 & 26.8; 19 19F NMR (377 MHz, CD3CN) δ -63.2; HRMS (ESI-TOF) calculated for C 32 H 37 F3N6O8, [M+Na] + 713.2517, found 713.2515. The above are only the preferred embodiments of the present invention and do not impose any formal limitations on the present invention. Any person skilled in the art can make many possible changes and modifications to the technical solution of the present invention by using the methods and technical contents disclosed above, or modify it into equivalent embodiments with equivalent changes. Therefore, any simple modification, equivalent replacement, equivalent change and modification made to the above embodiments based on the technical essence of the present invention without departing from the technical solution of the present invention still fall within the scope of protection of the technical solution of the present invention.

Claims

1. A method for selective amidation modification at the C-2 position of tryptophan indole, characterized in that, It includes the following steps: S1. Mix the tryptophan substrate and the aryloxyamide compound and dissolve them in a solvent; S2. Under the action of visible light catalysis and a base, carry out a stirring reaction at room temperature to obtain the tryptophan indole C-2 amide product; the molecular structural formula of the tryptophan indole C-2 amide product is any one of the following.

2. The selective amidation modification method of tryptophan indole at C-2 position according to claim 1, characterized in that, In the step S1, the tryptophan substrate is tryptophan or a polypeptide containing tryptophan.

3. A method for selective amidation modification at the C-2 position of tryptophan indole, according to claim 1, wherein The molecular structural formula of the aryloxyamide compound in the step S1 is as follows: wherein R 3 is one or more of alkyl, alkenyl, aryl and heteroaryl.

4. A method for selective amidation modification at the C-2 position of tryptophan indole according to claim 1, characterized in that, In the step S1, the molar ratio of the tryptophan substrate to the aryloxyamide compound is (1 - 2.5):(1 - 1.5).

5. A method for selective amidation modification at the C-2 position of tryptophan indole, as claimed in claim 1, wherein In the S1, the solvent is acetonitrile, acetone, acetonitrile or a mixed solvent of acetone and water.

6. The selective amidation modification method of tryptophan indole C-2 position according to claim 1, wherein In the step S2, the wavelength of the visible light is 400 - 600 nm.

7. A method for selective amidation modification at the C-2 position of tryptophan indole, according to claim 1, characterized in that, In the step S2, the base is one or more of triethylamine, KHCO3, K2CO3, Cs2CO3, K2HPO4, K3PO4.

8. The tryptophan indole C-2 amide product prepared by the method according to any one of claims 1 - 7.

9. Use of the tryptophan indole C-2 amide product according to claim 8 in the preparation of polypeptide drugs.

Images