[3+2] cycloaddition method of amino acid active ester and diazo compound and its application in synthetic chemistry

Abstract

This invention belongs to the field of organic synthesis and relates to a [3+2] orthogonal cycloaddition method for the reaction of an active amino acid ester with a diazo compound and its application in synthetic chemistry. The method comprises: under inert gas protection and in the presence of a base and solvent, contacting the active amino acid ester with a diazo compound to undergo a [3+2] orthogonal cycloaddition reaction to obtain the 1,2,4-triazole compound represented by Formula I. The method of this invention uses readily available active amino acids and diazo compounds as starting materials, enabling the efficient and selective synthesis of highly functionalized, fully substituted 1,2,4-triazoles, and achieving a rapid and efficient orthogonal connection between two molecules linked to the diazo compound and the active ester.

Description

Technical Field

[0001] This invention belongs to the field of organic synthesis, specifically relating to a [3+2] orthogonal cycloaddition method of amino acid active esters and diazo compounds and its application in synthetic chemistry. Background Technology

[0002] In chemical science, orthogonal reactions are considered reactions that selectively transform one functional group under specific conditions without affecting other functional groups. They are characterized by specificity and high selectivity in complex systems. Therefore, developing efficient synthetic systems to enrich the existing orthogonal reaction library is an important task in contemporary chemical synthesis. The term "orthogonal" in protecting groups was first proposed by Merrifield in 1977 for the protection of amino groups in peptide synthesis. Carbohydrates naturally contain a large number of hydroxyl groups, making this concept of orthogonal protection particularly important in carbohydrate chemistry. In the following decades, orthogonal chemistry has developed and is widely used in protecting group chemistry, the construction of supramolecular complexes through self-assembly, bioorthogonalization, material surface modification, and the synthesis of complex molecules. However, the orthogonal method utilizing free radical attack on diazo compounds to carry out [3+2] cycloaddition reactions has not yet been reported in the literature. Summary of the Invention

[0003] The purpose of this invention is to develop a [3+2] orthogonal cycloaddition reaction of N-α radical with diazo compounds, starting from readily available amino acid active esters and diazo compounds.

[0004] To achieve the above objectives, the present invention provides a method for the [3+2] orthogonal cycloaddition of an amino acid active ester with a diazo compound, the method comprising:

[0005] Under inert gas protection and in the presence of alkali and solvent, the active ester of amino acid is contacted with a diazo compound to carry out a [3+2] orthogonal cycloaddition reaction to obtain the 1,2,4-triazole compound shown in Formula I.

[0006]

[0007] The diazo compound is at least one of the compounds shown in Formula II or Formula III;

[0008] The amino acid active ester is at least one of the compounds shown in Formula IV;

[0009]

[0010] Among them, R 1 R 2 R 3 R 4 Each can be an independent arbitrary group, and R 1R 2 Optional ring formation;

[0011] It is a benzene ring or a heteroaromatic ring.

[0012] The equation for the [3+2] cycloaddition reaction between the active ester of amino acids and a diazo compound in this invention is shown below:

[0013]

[0014] This invention verifies R 1 R 2 R 3 R 4 Various compounds with different substituents can be prepared simply and efficiently using the synthetic route designed in this invention, including compounds with different substituent types, chain lengths, and steric hindrances. Therefore, the method of this invention has virtually no limitations on the substituents.

[0015] According to a specific embodiment of the present invention, R 1 R is hydrogen, alkyl, alkenyl, acyl or aryl. 2 It is an ester group, acyl group, phosphonoyl group, sulfonyl group or aryl group, and R 1 R 2 Choose any ring. Specifically, R 1 It is hydrogen, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 acyl or C6-C 12 Aryl, R 2 For C1-C 30 Ester group, C1-C 30 Acyl group, C1-C 16 Phosphonyl, C1-C 16 sulfonyl or C6-C 12 Aryl, and R 1 R 2 Choose any ring to form a ring.

[0016] According to a specific embodiment of the present invention, R 3 It can be hydrogen, alkyl, alkoxy, fluorine, chlorine, or bromine. Specifically, R 3 It can be hydrogen, C1-C8 alkyl, C1-C8 alkoxy, fluorine, chlorine, or bromine.

[0017] According to a specific embodiment of the present invention, R 4 It can be alkyl, halogen-substituted alkyl, benzyl, aryl, alkylaryl, or heteroaryl. R 4 For C1-C 16 Alkyl, halogen-substituted C1-C8 alkyl, C7-C 12 Benzyl, C6-C 12 Aryl, C7-C 12Alkyl or C5-C 20 Mixed aromatic compounds.

[0018] It can be a benzene ring, pyridine ring, furan ring, thiophene ring, pyrrole ring, pyrazine ring, oxazole ring, thiazole ring, imidazole ring, indole ring, or quinoline ring.

[0019] To verify the applicability of the method of the present invention, various compounds were synthesized in the embodiments of the present invention. Some of these compounds have complex structures. Therefore, the group types mentioned above in the present invention refer to the group types that are directly connected to the carbon atoms in the group, for example, R. 2 An ester group refers to at least one of the ester groups shown in Formula V.

[0020]

[0021] Among them, R 5 It can be further classified as other types of groups, specifically alkyl, substituted alkyl, alkenyl, alkynyl, aryl, aralkyl, alkylaryl, cycloalkyl, heterocyclic, bridged cyclic, or fused cyclic; the substituent is selected from alkyl (e.g., C1-C1). 12 Alkyl), azide, amino, nitro, cyano; preferably, R 5 C1-C8 alkyl, C1-C 20 Substituted alkyl, C1-C8 alkenyl, C1-C8 ynyl, C6-C 16 Aryl, C7-C 16 Aryl group, C7-C 16 Alkyl, C5-C 12 cycloalkyl, C4-C 12 Heterocyclic group, C6-C 16 Bridge ring base or C8-C 16 Fused ring group.

[0022] The alkali mentioned in this invention can be at least one of organic alkali and inorganic alkali; preferably, the alkali is selected from at least one of diisopropylethylamine, triethylamine, 1,8-diazabicyclo[5.4.0]undec-7-ene, triethylenediamine, tetramethylguanidine, diethylamine, dicyclohexylamine, sodium carbonate, sodium bicarbonate, potassium carbonate, cesium carbonate, potassium phosphate, potassium dihydrogen phosphate, sodium phosphate, sodium dihydrogen phosphate, and sodium acetate.

[0023] The amount of alkali used can be 0.1 to 15 times the molar equivalent of the compound shown in Formula I.

[0024] The solvent used in this invention can be at least one of nitrile solvents, haloalkane solvents, amide solvents, sulfoxide solvents, and water; preferably, the solvent is selected from at least one of acetonitrile, water, dichloromethane, trichloromethane, 1,2-dichloroethane, N,N-dimethylformamide, N,N-dimethylacetamide, and dimethyl sulfoxide. The amount used is not specifically limited, as long as it does not affect the reaction.

[0025] The reaction described in this invention can be carried out under natural light at room temperature, making it simple, convenient, and energy-efficient. Alternatively, it can be carried out under external light.

[0026] The present invention also provides 1,2,4-triazole compounds prepared by the above method, namely the compounds shown in Formula I.

[0027] This invention provides a [3+2] orthogonal cycloaddition reaction method under room temperature and natural light conditions. This method uses readily available amino acid actives and diazo compounds as starting materials, and can efficiently and selectively synthesize highly functionalized fully substituted 1,2,4-triazoles. It also enables rapid and efficient orthogonal connection of two molecules linked to diazo and active esters. This method can play an important role in synthetic chemistry.

[0028] Other features and advantages of the present invention will be described in detail in the following detailed description section. Detailed Implementation

[0029] Preferred embodiments of the invention will now be described in more detail. While preferred embodiments of the invention are described below, it should be understood that the invention can be implemented in various forms and should not be limited to the embodiments set forth herein.

[0030] Example 1: Preparation of Compound I-1

[0031]

[0032] In an argon-filled glove box, diazo compound II-1 (11.4 mg, 0.1 mmol), active ester IV-1 (50.7 mg, 0.15 mmol), and DIPEA (38.7 mg, 0.15 mmol) were sequentially introduced into a 10 mL vial equipped with a magnetic stir bar, followed by the addition of MeCN (1.0 mL). The mixture was stirred at room temperature for 30 min, and the reaction was monitored by TLC. The concentrated reaction residue was purified by flash column chromatography on silica gel to give 21.8 mg of product I-1, in 89% yield.

[0033] 1H NMR (400MHz, Chloroform-d) δ7.63–7.56(m,2H),7.51–7.46(m,3H),4.88(d,J=1.3Hz,2H),4.26(q,J=7.2Hz,2H),2.45(s,3H),1.28(t,J=7.2,1.3Hz,3H). 13 C NMR (101MHz, Chloroform-d) δ167.3,160.6,156.3,130.3,129.0,128.5,127.6,62.2,50.3,14.0,13.9.

[0034] High resolution: Calculated value: [M+H] + 246.1237, Measured value: 246.1234.

[0035] Example 2 Preparation of compound I-2

[0036]

[0037] In an argon-filled glove box, diazo compound II-2 (13.8 mg, 0.1 mmol), active ester IV-1 (50.7 mg, 0.15 mmol), and DIPEA (38.7 mg, 0.3 mmol) were sequentially introduced into a 10 mL vial equipped with a magnetic stir bar, followed by the addition of MeCN (1.0 mL). The mixture was stirred at room temperature for 30 min, and the reaction was monitored by TLC. The concentrated reaction residue was purified by flash column chromatography on silica gel to give 17.2 mg of product I-2, in 64% yield.

[0038] 1 H NMR(400MHz,Chloroform-d)δ7.61(dd,J=7.4,2.3Hz,2H),7.54–7.44(m,3H),4.93(s,2H) ),4.31(t,J=6.7Hz,2H),2.55(td,J=6.7,2.6Hz,2H),2.45(s,3H),2.00(t,J=2.7Hz,1H). 13 C NMR (101MHz, Chloroform-d) δ167.2,160.9,156.5,130.5,129.1,128.7,127.7,70.5,63.7,50.3,19.0,14.0.

[0039] High resolution: Calculated value: [M+H] + 270.1237, Measured value: 270.1231.

[0040] Example 3 Preparation of compound I-3

[0041]

[0042] In an argon-filled glove box, a 10 mL vial equipped with a magnetic stir bar was sequentially charged with diazo compound II-3 (16.9 mg, 0.1 mmol), active ester IV-1 (50.7 mg, 0.15 mmol), and DIPEA (38.7 mg, 0.3 mmol), followed by the addition of MeCN (1.0 mL). The mixture was stirred at room temperature for 30 min, and the reaction was monitored by TLC. The concentrated reaction residue was purified by flash column chromatography on silica gel to give 19.4 mg of product I-3, in 72% yield.

[0043] 1 H NMR(400MHz,Chloroform-d)δ7.62–7.56(m,2H),7.52–7.47(m,3H),4.92(s,2H), 4.29(t,J=6.2Hz,2H), 3.34(t,J=6.6Hz,2H), 2.45(s,3H), 1.89(q,J=6.4Hz,2H). 13 CNMR(101MHz,Chloroform-d)δ167.2,160.8,156.4,130.5,129.1,128.6,63.1,50.4,48.0,28.0,14.0

[0044] High resolution: Calculated value: [M+H] + 301.1408, Measured value: 301.1402.

[0045] Example 4 Preparation of compound I-4

[0046]

[0047] In an argon-filled glove box, diazo compound II-4 (26.6 mg, 0.1 mmol), active ester IV-1 (50.7 mg, 0.15 mmol), and DIPEA (38.7 mg, 0.3 mmol) were sequentially introduced into a 10 mL vial equipped with a magnetic stir bar, followed by the addition of MeCN (1.0 mL). The mixture was stirred at room temperature for 30 min, and the reaction was monitored by TLC. The concentrated reaction residue was purified by flash column chromatography on silica gel to give 34.5 mg of product I-4, in 87% yield.

[0048] 1H NMR (400MHz, Chloroform-d) δ9.01(t,J=2.1Hz,1H),8.51(d,J=2.1Hz,2H),7.58–7.53(m,2H),7.50–7.43(m,3H),5.41(s,2H),5.05(s,2H),2.46(s,3H). 13 C NMR (101MHz, Chloroform-d) δ166.8,161.1,156.5,148.8,139.3,134.1,130.8,129.2,128.5,127.9,127.2,123.2,118.9,65.2,50.2,13.9.

[0049] High resolution: Calculated value: [M+H] + 398.1095, Measured value: 398.1097.

[0050] Example 5 Preparation of compound I-5

[0051]

[0052] In an argon-filled glove box, a 10 mL vial equipped with a magnetic stir bar was sequentially charged with diazo compound II-5 (22.6 mg, 0.1 mmol), active ester IV-1 (50.7 mg, 0.15 mmol), and DIPEA (38.7 mg, 0.3 mmol), followed by the addition of MeCN (1.0 mL). The mixture was stirred at room temperature for 30 min, and the reaction was monitored by TLC. The concentrated reaction residue was purified by flash column chromatography on silica gel to give 30.3 mg of product I-5, in 85% yield.

[0053] 1 H NMR (400MHz, Chloroform-d) δ7.80-7.73(m,3H),7.71(s,1H),7.48-7.40(m,4H),7.38-7.26(m,4H),5.30(s,2H),4.87(s,2H),2.37(s,3H). 13 C NMR(101MHz,Chloroform-d)δ167.3,160.8,156.5,133.3,133.2,132.2,130.4,129. 0,128.7,128.6,128.1,128.0,127.8,127.6,126.7,126.6,125.9,68.1,50.5,14.1.

[0054] High resolution: Calculated value: [M+H] +358.1550, Measured value: 358.1550.

[0055] Example 6 Preparation of compound I-6

[0056]

[0057] In an argon-filled glove box, diazo compound II-6 (16.2 mg, 0.1 mmol), active ester IV-1 (50.7 mg, 0.15 mmol), and DIPEA (38.7 mg, 0.3 mmol) were sequentially introduced into a 10 mL vial equipped with a magnetic stir bar, followed by the addition of MeCN (1.0 mL). The mixture was stirred at room temperature for 30 min, and the reaction was monitored by TLC. The concentrated reaction residue was purified by flash column chromatography on silica gel to yield 24.3 mg of product I-6, in 83% yield.

[0058] 1 H NMR(400MHz,Chloroform-d)δ7.67–7.61(m,2H),7.55–7.49(m,3H),7.41–7.35(m,2H),7.26–7.23(m,1H),7.12–7.05(m,2H),5.15(s,2H),2.47(s,3H). 13 C NMR (101MHz, Chloroform-d) δ165.9,161.0,156.6,150.2,130.7,129.7,129.2,128.7,127.7,126.6,121.2,50.7,14.1.

[0059] High resolution: Calculated value: [M+H] + :294.1237, Measured value: 294.1231.

[0060] Example 7 Preparation of Compound I-7

[0061]

[0062] In an argon-filled glove box, diazo compound II-7 (14.6 mg, 0.1 mmol), active ester IV-1 (50.7 mg, 0.15 mmol), and DIPEA (38.7 mg, 0.3 mmol) were sequentially introduced into a 10 mL vial equipped with a magnetic stir bar, followed by the addition of MeCN (1.0 mL). The mixture was stirred at room temperature for 30 min, and the reaction was monitored by TLC. The concentrated reaction residue was purified by flash column chromatography on silica gel to yield 19.1 mg of product I-7, in 69% yield.

[0063] 1H NMR(400MHz,Chloroform-d)δ7.97–7.92(m,2H),7.64(t,J=7.5Hz,1H),7.59–7 .54(m,2H),7.51(t,J=7.7Hz,2H),7.47–7.39(m,3H),5.59(s,2H),2.47(s,3H). 13 C NMR(101MHz,Chloroform-d)δ191.8,160.8,156.8,134.5,134.3,130.4,129.2,129.0,128.5,128.2,127.9,55.0,14.1

[0064] High resolution: Calculated value: [M+H] + 278.1288, Measured value: 278.1289.

[0065] Example 8 Preparation of Compound I-8

[0066]

[0067] In an argon-filled glove box, a 10 mL vial equipped with a magnetic stir bar was sequentially charged with diazo compound II-8 (24.2 mg, 0.1 mmol), active ester IV-1 (50.7 mg, 0.15 mmol), and DIPEA (38.7 mg, 0.3 mmol), followed by the addition of MeCN (1.0 mL). The mixture was stirred at room temperature for 30 min, and the reaction was monitored by TLC. The concentrated reaction residue was purified by flash column chromatography on silica gel to give 19.4 mg of product I-8, in 52% yield.

[0068] 1 H NMR (400MHz, Chloroform-d) δ7.76–7.69(m,4H),7.60–7.54(m,2H),7.50–7.39(m,9H),5.06(d,J=7.0Hz,2H),2.31(s,3H). 13 C NMR(101MHz,Chloroform-d)δ160.5,156.7,156.65,132.7,132.69,131.7,131 .6,130.6,130.3,129.5,129.0,128.9,128.9,128.7,127.5,49.7,49.0,13.9.

[0069] 31 P NMR(162MHz,Chloroform-d)δ27.6.

[0070] High resolution: Calculated value: [M+H] + 374.1417, Measured value: 374.1413.

[0071] Example 9 Preparation of Compound I-9

[0072]

[0073] In an argon-filled glove box, a 10 mL vial equipped with a magnetic stir bar was sequentially charged with diazo compound II-9 (19.6 mg, 0.1 mmol), active ester IV-1 (50.7 mg, 0.15 mmol), and DIPEA (38.7 mg, 0.3 mmol), followed by the addition of MeCN (1.0 mL). The mixture was stirred at room temperature for 30 min, and the reaction was monitored by TLC. The concentrated reaction residue was purified by flash column chromatography on silica gel to give 19.6 mg of product I-9, in 60% yield.

[0074] 1 H NMR (400MHz, Chloroform-d) δ7.61–7.53(m,4H),7.51–7.42(m,3H),7.29(d,J=8.0Hz,2H),5.41(s,2H),2.46(s,3H),2.37(s,3H). 13 C NMR (101MHz, Chloroform-d) δ161.4,157.6,146.1,133.8,130.8,130.1,129.2,129.1,128.9,126.9,67.7,21.9,14.0.

[0075] High resolution: Calculated value: [M+H] + 328.1114, Measured value: 328.1112.

[0076] Example 10 Preparation of compound I-10

[0077]

[0078] In an argon-filled glove box, diazo compound II-10 (24.0 mg, 0.1 mmol), active ester IV-1 (50.7 mg, 0.15 mmol), and DIPEA (38.7 mg, 0.3 mmol) were sequentially introduced into a 10 mL vial equipped with a magnetic stir bar, followed by the addition of MeCN (1.0 mL). The mixture was stirred at room temperature for 30 min, and the reaction was monitored by TLC. The concentrated reaction residue was purified by flash column chromatography on silica gel to yield 26.7 mg of product I-10, in 72% yield.

[0079] 1H NMR(400MHz,Chloroform-d)δ7.86-7.79(m,3H),7.71(s,1H),7.53-7.48(m,4H),7.46-7.36(m,3H),7.34 (dd,J=8.5,1.7Hz,1H),5.34(d,J=1.9Hz,2H),5.13(q,J=7.1Hz,1H),2.45(s,3H),1.82(d,J=7.2Hz,3H). 13 C NMR(101MHz,Chloroform-d)δ169.4,160.6,156.0,133.3,133.2,132.5,130.3,129.0, 128.9,128.5,128.1,127.9,127.8,127.5,126.6,126.5,125.6,67.8,56.4,17.2,14.2.

[0080] High resolution: Calculated value: [M+H] + 372.1707, Measured value: 372.1705.

[0081] Example 11 Preparation of compound I-11

[0082]

[0083] In an argon-filled glove box, a 10 mL vial equipped with a magnetic stir bar was sequentially charged with diazo compound II-11 (21.0 mg, 0.1 mmol), active ester IV-1 (50.7 mg, 0.15 mmol), and DIPEA (38.7 mg, 0.3 mmol), followed by the addition of MeCN (1.0 mL). The mixture was stirred at room temperature for 30 min, and the reaction was monitored by TLC. The concentrated reaction residue was purified by flash column chromatography on silica gel to give 24.2 mg of product I-11, in 71% yield.

[0084] 1 H NMR(400MHz,Chloroform-d)δ7.61–7.56(m,2H),7.54(dd,J=5.0,1.2Hz,1H),7.40–7.30( m,3H),7.20(dd,J=3.9,1.2Hz,1H),7.03(dd,J=5.0,4.0Hz,1H),3.72(s,3H),2.54(s,3H). 13C NMR (101MHz, Chloroform-d) δ170.6,166.2,162.0,157.1,133.9,133.8,132.8,130.4,128.8,128.2,127.9,127.4,123.0,101.8,52.9,14.2.

[0085] High resolution: Calculated value: [M+H] + 342.0907, Measured value: 342.0904.

[0086] Example 12 Preparation of compound I-12

[0087]

[0088] In an argon-filled glove box, a 10 mL vial equipped with a magnetic stir bar was sequentially charged with diazo compound II-12 (14.0 mg, 0.1 mmol), active ester IV-1 (50.7 mg, 0.15 mmol), and DIPEA (129.2 mg, 1 mmol), followed by the addition of MeCN (1.0 mL). The mixture was stirred at room temperature for 30 min, and the reaction was monitored by TLC. The concentrated reaction residue was purified by flash column chromatography on silica gel to give 24.4 mg of product I-12, in 90% yield.

[0089] 1 H NMR(400MHz,Chloroform-d)δ7.67–7.63(m,2H),7.44–7.40(m,3H),7.28(q,1H), 4.12(q,J=7.1Hz,2H),2.49(s,3H),1.73(d,J=7.2Hz,3H),1.09(t,J=7.1Hz,3H). 13 CNMR(101MHz,Chloroform-d)δ162.6,161.3,156.2,141.7,131.1,130.3,128.9,128.0,127.8,61.9,14.2,14.1,14.0.

[0090] High resolution: Calculated value: [M+H] + 272.1394, Measured value: 272.1388.

[0091] Example 13 Preparation of compound I-13

[0092]

[0093] In an argon-filled glove box, a 10 mL vial equipped with a magnetic stir bar was sequentially charged with diazo compound II-13 (13.5 mg, 0.1 mmol), active ester IV-1 (50.7 mg, 0.15 mmol), and DIPEA (38.7 mg, 0.3 mmol), followed by the addition of MeCN (1.0 mL). The mixture was stirred at room temperature for 30 min, and the reaction was monitored by TLC. The concentrated reaction residue was purified by flash column chromatography on silica gel to give 23.3 mg of product I-13, in 88% yield.

[0094] 1 H NMR(400MHz,Chloroform-d)δ8.59(s,1H),7.52–7.48(m,2H),7.43–7.37(m,1H),7.36–7.30 (m,2H),6.93(s,1H),6.74(d,J=8.1Hz,1H),6.54(d,J=8.1Hz,1H),2.50(s,3H),2.31(s,3H). 13 C NMR (101MHz, Chloroform-d) δ161.2,154.8,150.3,140.6,130.4,129.0,128.8,127.8,124.9,121.9,120.9,119.1,21.4,14.0.

[0095] High resolution: Calculated value: [M+H] + 266.1288, Measured value: 266.1286.

[0096] Example 14 Preparation of compound I-14

[0097]

[0098] In an argon-filled glove box, a 10 mL vial equipped with a magnetic stir bar was sequentially charged with diazo compound II-14 (22.5 mg, 0.1 mmol), active ester IV-1 (50.7 mg, 0.15 mmol), and DIPEA (38.7 mg, 0.3 mmol), followed by the addition of MeCN (1.0 mL). The mixture was stirred at room temperature for 30 min, and the reaction was monitored by TLC. The concentrated reaction residue was purified by flash column chromatography on silica gel to give 22.4 mg of product I-14, in 88% yield.

[0099] 1H NMR(400MHz,Chloroform-d)δ7.63–7.56(m,2H),7.52–7.42(m,3H),4.88(s,2H),4 .78(td,J=10.8,4.2Hz,1H),2.45(s,3H),1.97(dd,J=13.0,3.5Hz,1H),1.78–1.62 (m,3H),1.53–1.41(m,1H),1.39–1.29(m,1H),1.11–1.00(m,1H),0.99–0.94(m,1H ),0.90(d,3H),0.87(d,J=7.0Hz,3H),0.84(d,J=3.2Hz,1H),0.73(d,J=7.2Hz,3H). 13 C NMR (101MHz, Chloroform-d) δ167.0,160.6,156.3,130.4,129.0,128.6,127.9,50.7,47.0,40.7,34.1,31.5,26.3,23.3,22.0,20.8,16.2,14.0.

[0100] High resolution: Calculated value: [M+H] + 256.2333, Measured value: 256.2328.

[0101] Example 15 Preparation of compound I-15

[0102]

[0103] In an argon-filled glove box, a 10 mL vial equipped with a magnetic stir bar was sequentially charged with diazo compound II-15 (23.5 mg, 0.1 mmol), active ester IV-1 (50.7 mg, 0.15 mmol), and DIPEA (38.7 mg, 0.3 mmol), followed by the addition of MeCN (1.0 mL). The mixture was stirred at room temperature for 30 min, and the reaction was monitored by TLC. The concentrated reaction residue was purified by flash column chromatography on silica gel to give 32.8 mg of product I-15, in 90% yield.

[0104] 1H NMR(400MHz,Chloroform-d)δ7.65–7.54(m,2H),7.54–7.44(m,3H),5.25(s,1H),4.87(s,2H),4.31–4.08(m,2H),2.44(s,3H),2.38–2.31(m ,1H),2.31–2.24(m,2H),2.23–2.11(m,2H),2.10–2.03(m,1H),2.00(t d,J=5.6,1.5Hz,1H),1.25(s,3H),1.09(d,J=8.6Hz,1H),0.77(s,3H). 13 C NMR(101MHz,Chloroform-d)δ167.4,160.7,156.3,143.5,130.4,129.1,128.6, 127.7,119.4,64.3,50.4,45.6,40.7,38.1,35.8,31.7,31.4,26.3,21.2,14.0.

[0105] High resolution: Calculated value: [M+H] + 366.2176, Measured value: 366.2172.

[0106] Example 16 Preparation of compound I-16

[0107]

[0108] In an argon-filled glove box, diazo compound II-16 (33.8 mg, 0.1 mmol), active ester IV-1 (50.7 mg, 0.15 mmol), and DIPEA (38.7 mg, 0.3 mmol) were sequentially introduced into a 10 mL vial equipped with a magnetic stir bar, followed by the addition of MeCN (1.0 mL). The mixture was stirred at room temperature for 30 min, and the reaction was monitored by TLC. The concentrated reaction residue was purified by flash column chromatography on silica gel to give 36.9 mg of product I-16, with a yield of 79%.

[0109] 1H NMR(400MHz,Chloroform-d)δ7.67–7.60(m,2H),7.57–7.48(m,3H),7.29(s,1H ),6.84(dd,J=8.5,2.6Hz,1H),6.80(dd,J=2.5Hz,1H),5.13(s,2H),2.90(dd,J =9.0,4.2Hz,2H),2.47(s,3H),2.44–2.34(m,1H),2.33–2.23(m,1H),2.20–2.1 1(m,1H),2.09–1.92(m,4H),1.67–1.57(m,2H),1.55–1.40(m,4H),0.91(s,3H). 13 C NMR(101MHz,Chloroform-d)δ166.1,160.9,156.6,148.1,138.4,138.2,130.6,129.3,129.2,128.7,127.7 ,127.6,126.7,121.2,118.3,50.6,50.5,48.0,44.2,38.1,36.0,31.6,29.5,26.4,25.9,21.7,14.1,13.9.

[0110] High resolution: Calculated value: [M+H] + 470.2438, Measured value: 470.2438.

[0111] Example 17 Preparation of compound I-17

[0112]

[0113] In an argon-filled glove box, a 10 mL vial equipped with a magnetic stir bar was sequentially charged with diazo compound II-7 (47.0 mg, 0.1 mmol), active ester IV-1 (50.7 mg, 0.15 mmol), and DIPEA (38.7 mg, 0.3 mmol), followed by the addition of MeCN (1.0 mL). The mixture was stirred at room temperature for 30 min, and the reaction was monitored by TLC. The concentrated reaction residue was purified by flash column chromatography on silica gel to give 39.1 mg of product I-17, in 65% yield.

[0114] 1H NMR(400MHz,Chloroform-d)δ7.66–7.62(m,2H),7.53–7.49(m,3H),6.65–6.59(m,2H),5.09 (s,2H),2.74–2.68(m,2H),2.46(s,3H),2.13(s,3H),2.12–2.03(m,1H),1.84–1.68(m,4H),1 .59–1.47(m,4H),1.43–1.34(m,4H),1.33–1.27(m,4H),1.25(s,3H),1.24–1.15(m,4H),1.1 4–1.11(m,2H),1.10–1.01(m,4H),0.87(s,3H),0.85(d,J=2.2Hz,6H),0.84(d,J=4.4Hz,3H). 13 C NMR(101MHz,Chloroform-d)δ166.5,160.9,156.5,150.3,142.0,130.6,129.2,128.7,127.8,127.7,121.2,120.7,118.7,5 0.6,40.2,39.5,37.6,37.5,37.4,32.9,32.8,31.0,28.1,24.9,24.6,24.3,22.9,22.8,22.6,21.1,19.9,19.8,16.2,14.0.

[0115] High resolution: Calculated value: [M+H] + 602.4316, Measured value: 602.4314

[0116] Example 18 Preparation of compound I-18

[0117]

[0118] In an argon-filled glove box, a 10 mL vial equipped with a magnetic stir bar was sequentially charged with diazo compound II-18 (39.4 mg, 0.1 mmol), active ester IV-1 (50.7 mg, 0.15 mmol), and DIPEA (38.7 mg, 0.3 mmol), followed by the addition of MeCN (1.0 mL). The mixture was stirred at room temperature for 30 min, and the reaction was monitored by TLC. The concentrated reaction residue was purified by flash column chromatography on silica gel to give 50.1 mg of product I-18, in 86% yield.

[0119] 1H NMR(400MHz,Chloroform-d)δ8.68(d,J=4.6Hz,1H),8.03(d,J=9.2Hz,1H),7.49–7.42(m,3H),7.4 1–7.35(m,2H),7.35–7.32(m,2H),7.17(d,J=4.6Hz,1H),6.59(d,J=6.9Hz,1H),5.84–5.73(m,1H) ,5.04–4.98(m,3H),4.97(s,1H),3.91(s,3H),3.32(q,J=8.0Hz,1H),3.07–2.95(m,2H),2.69–2.5 8(m,2H),2.44(s,3H),2.33–2.23(m,2H),1.87–1.74(m,2H),1.55–1.48(m,1H),1.45–1.37(m,1H). 13 C NMR(101MHz,Chloroform-d)δ166.7,160.9,158.4,156.3,147.4,144.9,142.5,141.5,132.0,130.6,129.1, 128.5,127.4,126.9,122.3,118.8,114.9,101.1,58.9,56.6,55.8,50.7,42.6,39.6,27.6,27.5,24.2,14.0.

[0120] High resolution: Calculated value: [M+H] + 524.2656, Measured value: 524.2644

[0121] Example 19 Preparation of compound I-19

[0122]

[0123] In an argon-filled glove box, diazo compound III-1 (35.2 mg, 0.1 mmol), active ester IV-1 (50.7 mg, 0.15 mmol), and tetramethylguanidine (57.5 mg, 0.5 mmol) were sequentially introduced into a 10 mL vial equipped with a magnetic stir bar, followed by the addition of MeCN (1.0 mL). The mixture was stirred at room temperature for 30 min, and the reaction was monitored by TLC. The concentrated reaction residue was purified by flash column chromatography on silica gel to give 21.2 mg of product I-19, in 71% yield.

[0124] 1H NMR(400MHz,Chloroform-d)δ7.80–7.73(m,2H),7.73–7.66(m,1H),7.55–7.48( m,3H),7.44–7.33(m,5H),7.23(dd,J=8.5,1.8Hz,1H),5.45(s,2H),2.42(s,3H). 13 C NMR(101MHz,Chloroform-d)δ160.7,155.9,133.7,133.5,133.0,130.3,129.0,128.8,128.1,128.1,127.9,126.6,126.4,125.8,124.6,52.7,

[0125] High resolution: Calculated value: [M+H] + 300.1495, Measured value: 300.1492.

[0126] Example 20 Preparation of compound I-20

[0127]

[0128] In an argon-filled glove box, diazo compound III-2 (42.8 mg, 0.1 mmol), active ester IV-1 (50.7 mg, 0.15 mmol), and tetramethylguanidine (57.5 mg, 0.50 mmol) were sequentially introduced into a 10 mL vial equipped with a magnetic stir bar, followed by the addition of MeCN (1.0 mL). The mixture was stirred at room temperature for 30 min, and the reaction was monitored by TLC. The concentrated reaction residue was purified by flash column chromatography on silica gel to give 15.4 mg of product I-20, in 41% yield.

[0129] 1 H NMR (400MHz, Chloroform-d) δ7.67(d,J=8.4Hz,4H),7.58–7.44(m,5H),7.32(d,J=8.2Hz,4H),6.69(s,1H),2.43(s,3H). 13 C NMR (101MHz, Chloroform-d) δ161.4,156.7,143.0,132.8,130.9,129.4,129.2,128.8,127.6,118.3,112.9,64.6,14.3.

[0130] High resolution: Calculated value: [M+H] + 376.1557, Measured value: 376.1553.

[0131] Example 21 Preparation of compound I-21

[0132]

[0133] In an argon-filled glove box, diazo compound II-1 (11.4 mg, 0.1 mmol), active ester IV-2 (52.8 mg, 0.15 mmol), and DIPEA (38.7 mg, 0.3 mmol) were sequentially introduced into a 10 mL vial equipped with a magnetic stir bar, followed by the addition of MeCN (1.0 mL). The mixture was stirred at room temperature for 30 min, and the reaction was monitored by TLC. The concentrated reaction residue was purified by flash column chromatography on silica gel to give 24.6 mg of product I-21, with a yield of 95%.

[0134] 1 H NMR (400MHz, Chloroform-d) δ7.51–7.45(m,2H),7.32–7.27(m,2H),4.87(d,J=1. 5Hz, 2H), 4.26 (q, J = 7.1Hz, 2H), 2.44 (s, 3H), 2.41 (s, 3H), 1.28 (t, J = 7.1Hz, 3H). 13 CNMR(101MHz,Chloroform-d)δ167.5,160.7,156.5,140.7,129.8,128.5,124.8,62.3,50.5,21.6,14.19,14.0.

[0135] High resolution: Calculated value: [M+H] + 260.1394, Measured value: 260.1390.

[0136] Example 22 Preparation of compound I-22

[0137]

[0138] In an argon-filled glove box, diazo compound II-1 (11.4 mg, 0.1 mmol), active ester IV-3 (55.2 mg, 0.15 mmol), and DIPEA (38.7 mg, 0.3 mmol) were sequentially introduced into a 10 mL vial equipped with a magnetic stir bar, followed by the addition of MeCN (1.0 mL). The mixture was stirred at room temperature for 30 min, and the reaction was monitored by TLC. The concentrated reaction residue was purified by flash column chromatography on silica gel to give 23.4 mg of product I-22, in 86% yield.

[0139] 1H NMR (400MHz, Chloroform-d) δ7.56–7.52(m,2H),7.01–6.97(m,2H),4.87(s,2H),4.26(q,J=7.1Hz,2H),3.86(s,3H),2.44(s,3H),1.28(t,J=7.2Hz,3H). 13 C NMR (101MHz, Chloroform-d) δ167.6,161.3,160.6,156.4,130.1,120.0,114.5,62.3,55.5,50.5,14.2,14.1.

[0140] High resolution: Calculated value: [M+H] + 276.1343, Measured value: 276.1337.

[0141] Example 23 Compound I-23

[0142] Preparation

[0143] In an argon-filled glove box, a 10 mL vial equipped with a magnetic stir bar was sequentially charged with diazo compound II-1 (11.4 mg, 0.1 mmol), active ester IV-4 (53.4 mg, 0.15 mmol), and DIPEA (38.7 mg, 0.3 mmol), followed by the addition of MeCN (1.0 mL). The mixture was stirred at room temperature for 30 min, and the reaction was monitored by TLC. The concentrated reaction residue was purified by flash column chromatography on silica gel to give 23.4 mg of product I-23, in 89% yield.

[0144] 1 H NMR (400MHz, Chloroform-d) δ7.66–7.56(m,2H),7.23–7.14(m,2H),4.86(s,2H),4.27(q,J=7.1Hz,2H),2.44(s,3H),1.29(t,J=7.2Hz,3H). 13 C NMR (101MHz, Chloroform-d) δ167.3,165.3,162.8,160.8,155.6,130.8,130.7,124.0,123.95,116.5,116.2,62.5,50.4,14.2,14.0.

[0145] 9 F NMR(377MHz,Chloroform-d)δ-109.4.

[0146] High resolution: Calculated value: [M+H]+ 264.1143, Measured value: 264.1139.

[0147] Example 24 Preparation of compound I-24

[0148]

[0149] In an argon-filled glove box, diazo compound II-1 (11.4 mg, 0.1 mmol), active ester IV-5 (62.6 mg, 0.15 mmol), and DIPEA (38.7 mg, 0.3 mmol) were sequentially introduced into a 10 mL vial equipped with a magnetic stir bar, followed by the addition of MeCN (1.0 mL). The mixture was stirred at room temperature for 30 min, and the reaction was monitored by TLC. The concentrated reaction residue was purified by flash column chromatography on silica gel to give 20.7 mg of product I-24, in 64% yield.

[0150] 1 H NMR (400MHz, Chloroform-d) δ7.65–7.58(m,2H),7.23–7.16(m,2H),4.87(s,2H),4.28(q,J=7.1Hz,2H),2.45(s,3H),1.30(t,J=7.2Hz,3H). 13 C NMR (101MHz, Chloroform-d) δ167.2,160.9,155.4,132.4,130.2,126.6,125.1,62.5,50.5,14.2,14.0.

[0151] High resolution: Calculated value: [M+H] + 324.0342, Measured value: 324.0343.

[0152] Example 25 Preparation of compound I-25

[0153]

[0154] In an argon-filled glove box, a 10 mL vial equipped with a magnetic stir bar was sequentially charged with diazo compound II-1 (11.4 mg, 0.1 mmol), active ester IV-6 (56.0 mg, 0.15 mmol), and DIPEA (38.7 mg, 0.3 mmol), followed by the addition of MeCN (1.0 mL). The mixture was stirred at room temperature for 30 min, and the reaction was monitored by TLC. The concentrated reaction residue was purified by flash column chromatography on silica gel to give 25.1 mg of product I-25, in 90% yield.

[0155] 1H NMR (400MHz, Chloroform-d) δ7.59–7.52(m,1H),7.51–7.43(m,1H),4.86(s,1H),4.26(q,J=7.1Hz,1H),2.44(s,1H),1.28(t,J=7.2Hz,2H). 13 C NMR (101MHz, Chloroform-d) δ167.3,160.9,155.4,136.8,130.0,129.4,62.5,50.5,14.2,14.0.

[0156] High resolution: Calculated value: [M+H] + 280.0848, Measured value: 280.0842.

[0157] Example 26 Preparation of compound I-26

[0158]

[0159] In an argon-filled glove box, diazo compound II-1 (11.4 mg, 0.1 mmol), active ester IV-7 (56.0 mg, 0.15 mmol), and DIPEA (38.7 mg, 0.3 mmol) were sequentially introduced into a 10 mL vial equipped with a magnetic stir bar, followed by the addition of MeCN (1.0 mL). The mixture was stirred at room temperature for 30 min, and the reaction was monitored by TLC. The concentrated reaction residue was purified by flash column chromatography on silica gel to give 24.3 mg of product I-26, in 87% yield.

[0160] 1 H NMR (400MHz, Chloroform-d) δ7.65–7.58(m,2H),7.23–7.16(m,2H),4.87(s,2H),4.28(q,J=7.1Hz,2H),2.45(s,3H),1.30(t,J=7.2Hz,3H). 13 C NMR (101MHz, Chloroform-d) δ167.3,165.3,162.8,155.6,130.8,130.7,124.0,123.9,116.5,116.2,62.4,50.4,14.2,14.0.

[0161] High resolution: Calculated value: [M+H] + 280.0848, Measured value: 280.0842.

[0162] Example 27 Preparation of compound I-27

[0163]

[0164] In an argon-filled glove box, a 10 mL vial equipped with a magnetic stir bar was sequentially charged with diazo compound II-1 (11.4 mg, 0.1 mmol), active ester IV-8 (56.0 mg, 0.15 mmol), and DIPEA (38.7 mg, 0.3 mmol), followed by the addition of MeCN (1.0 mL). The mixture was stirred at room temperature for 30 min, and the reaction was monitored by TLC. The concentrated reaction residue was purified by flash column chromatography on silica gel to give 8.4 mg of product I-27, in 30% yield.

[0165] 1 H NMR (400MHz, Chloroform-d) δ7.55-7.43(m,1H),7.41-7.35(m,1H),4.75(s,1H),4.16(q,J=7.2Hz,1H),2.48(s,1H),1.22(t,J=7.1Hz,1H). 13 C NMR (101MHz, Chloroform-d) δ166.7,161.0,153.8,133.5,132.2,131.8,123.0,127.4,127.2,62.1,49.9,14.05,14.0.

[0166] High resolution: Calculated value: [M+H] + 280.0848, Measured value: 280.0846.

[0167] Example 28 Preparation of compound I-28

[0168]

[0169] In an argon-filled glove box, diazo compound II-1 (11.4 mg, 0.1 mmol), active ester IV-9 (58.8 mg, 0.15 mmol), and DIPEA (38.7 mg, 0.3 mmol) were sequentially introduced into a 10 mL vial equipped with a magnetic stir bar, followed by the addition of MeCN (1.0 mL). The mixture was stirred at room temperature for 30 min, and the reaction was monitored by TLC. The concentrated reaction residue was purified by flash column chromatography on silica gel to give 25.1 mg of product I-28, in 84% yield.

[0170] 1 H NMR (400MHz, Chloroform-d) δ7.46-7.22(m,1H),4.88(s,1H),4.29(q,J=7.1Hz,1H),2.43(s,1H),1.31(t,J=7.1Hz,1H).13 C NMR (101MHz, Chloroform-d) δ166.7,161.0,153.8,133.5,132.2,131.8,123.0,127.4,127.2,62.1,49.9,14.05,14.0.

[0171] 19 F NMR (377MHz, CDCl3) δ-131.7 (dd, J=20.6, 7.6Hz), -156.3 (tt, J=20.7, 6.5Hz).

[0172] High resolution: Calculated value: [M+H] + 300.0955, Measured value: 300.0951.

[0173] Example 29 Preparation of compound I-29

[0174]

[0175] In an argon-filled glove box, a 10 mL vial equipped with a magnetic stir bar was sequentially charged with diazo compound II-1 (11.4 mg, 0.1 mmol), active ester IV-10 (51.6 mg, 0.15 mmol), and DIPEA (38.7 mg, 0.3 mmol), followed by the addition of MeCN (1.0 mL). The mixture was stirred at room temperature for 30 min, and the reaction was monitored by TLC. The concentrated reaction residue was purified by flash column chromatography on silica gel to give 20.8 mg of product I-29, in 83% yield.

[0176] 1 H NMR(400MHz,Chloroform-d)δ7.67(dd,J=2.9,1.3Hz,1H),7.46(dd,J=5.0,3.0Hz,1H),7.39( dd,J=5.1,1.3Hz,1H),4.94(s,2H),4.27(q,J=7.2Hz,2H),2.43(s,3H),1.28(t,J=7.2Hz,3H). 13 C NMR (101MHz, Chloroform-d) δ167.3,160.6,152.0,128.3,127.4,127.2,126.6,624,50.6,14.2,14.0.

[0177] High resolution: Calculated value: [M+H] + 252.0801, Measured value: 252.0798.

[0178] Example 30 Preparation of compound I-30

[0179]

[0180] In an argon-filled glove box, diazo compound II-1 (11.4 mg, 0.1 mmol), active ester IV-11 (52.9 mg, 0.15 mmol), and DIPEA (38.7 mg, 0.3 mmol) were sequentially introduced into a 10 mL vial equipped with a magnetic stir bar, followed by the addition of MeCN (1.0 mL). The mixture was stirred at room temperature for 30 min, and the reaction was monitored by TLC. The concentrated reaction residue was purified by flash column chromatography on silica gel to give 24.2 mg of product I-30, in 92% yield.

[0181] 1 H NMR(400MHz,Chloroform-d)δ7.63–7.57(m,2H),7.52–7.45(m,3H),4.89(s,2H),4.25 (q,J=7.1Hz,2H),2.81(q,J=7.6Hz,2H),1.37(t,J=7.6Hz,3H),1.27(t,J=7.1Hz,3H). 13 C NMR (101MHz, Chloroform-d) δ167.4,165.6,156.4,130.4,129.1,128.7,127.9,62.3,50.5,21.9,14.2,12.7.

[0182] High resolution: Calculated value: [M+H] + 260.1394, Measured value: 264.1384.

[0183] Example 31 Preparation of compound I-31

[0184]

[0185] In an argon-filled glove box, a 10 mL vial equipped with a magnetic stir bar was sequentially charged with diazo compound II-1 (11.4 mg, 0.1 mmol), active ester IV-12 (55.0 mg, 0.15 mmol), and DIPEA (38.7 mg, 0.3 mmol), followed by the addition of MeCN (1.0 mL). The mixture was stirred at room temperature for 30 min, and the reaction was monitored by TLC. The concentrated reaction residue was purified by flash column chromatography on silica gel to give 27.3 mg of product I-31, in 92% yield.

[0186] 1H NMR(400MHz,Chloroform-d)δ7.60(q,J=3.1Hz,2H),7.53–7.43(m,3H),4.89(s,2H),4.25(q,J=7 .3Hz,2H),2.75(t,J=6.9Hz,2H),1.90–1.77(m,2H),1.26(t,J=6.4Hz,3H),1.01(t,J=6.8Hz,3H). 13 C NMR (101MHz, Chloroform-d) δ167.3,164.4,156.2,130.3,128.9,128.6,127.8,62.1,50.4,30.3,21.7,14.1,13.9.

[0187] High resolution: Calculated value: [M+H] + 274.1550, Measured value: 274.1547.

[0188] Example 32 Preparation of compound I-32

[0189]

[0190] In an argon-filled glove box, a 10 mL vial equipped with a magnetic stir bar was sequentially charged with diazo compound II-1 (11.4 mg, 0.1 mmol), active ester IV-13 (57.0 mg, 0.15 mmol), and DIPEA (38.7 mg, 0.30 mmol), followed by the addition of MeCN (1.0 mL). The mixture was stirred at room temperature for 30 min, and the reaction was monitored by TLC. The concentrated reaction residue was purified by flash column chromatography on silica gel to give 13.2 mg of product I-32, in 46% yield.

[0191] 1 H NMR (400MHz, Chloroform-d) δ7.63–7.55(m,2H),7.50–7.43(m,3H),4.88(s,2H),4.23(q,J=7.2,2.4Hz,2H),1.43(s,9H),1.27(t,J=7.1Hz,3H). 13 CNMR(101MHz,Chloroform-d)δ171.8,167.5,156.2,130.3,129.0,128.9,128.2,62.1,50.4,32.9,29.7,14.2.

[0192] High resolution: Calculated value: [M+H] + 288.1707, Measured value: 288.1706.

[0193] Example 33 Preparation of compound I-33

[0194]

[0195] In an argon-filled glove box, diazo compound II-1 (11.4 mg, 0.1 mmol), active ester IV-14 (58.8 mg, 0.15 mmol), and DIPEA (38.7 mg, 0.30 mmol) were sequentially introduced into a 10 mL vial equipped with a magnetic stir bar, followed by the addition of MeCN (1.0 mL). The mixture was stirred at room temperature for 30 min, and the reaction was monitored by TLC. The concentrated reaction residue was purified by flash column chromatography on silica gel to give 25.7 mg of product I-33, in 86% yield.

[0196] 1 H NMR (400MHz, Chloroform-d) δ7.69–7.60(m,2H),7.60–7.48(m,3H),5.02(s,2H),4.27(q,J=7.1Hz,2H),1.28(t,J=7.1Hz,3H). 13 C NMR (101MHz, Chloroform-d) δ166.3,157.9,153.9,153.5,131.4,129.4,128.9,126.3,120.6,117.9,62.8,51.3,14.1.

[0197] 19 F NMR(377MHz,Chloroform-d)δ-65.4.

[0198] High resolution: Calculated value: [M+H] + 300.0955, Measured value: 300.0956.

[0199] Example 34 Preparation of compound I-34

[0200]

[0201] In an argon-filled glove box, diazo compound II-1 (11.4 mg, 0.1 mmol), active ester IV-15 (62.2 mg, 0.15 mmol), and DIPEA (38.7 mg, 0.30 mmol) were sequentially introduced into a 10 mL vial equipped with a magnetic stir bar, followed by the addition of MeCN (1.0 mL). The mixture was stirred at room temperature for 30 min, and the reaction was monitored by TLC. The concentrated reaction residue was purified by flash column chromatography on silica gel to give 29.8 mg of product I-34, in 93% yield.

[0202] 1 H NMR(400MHz,Chloroform-d)δ7.62–7.55(m,2H),7.47(dd,J=5.7,1.8Hz,3H),7.42–7.35(m,2H),7.30(dd,J =8.3,6.8Hz,2H),7.26–7.17(m,1H),4.90(s,2H),4.24(q,J=7.1Hz,2H),4.13(s,2H),1.25(t,J=7.1Hz,4H). 13 C NMR (101MHz, Chloroform-d) δ167.3,163.1,156.7,138.1,130.5,129.0,129.0,128.8,128.6,127.7,126.6,62.3,50.6,34.9,14.2.

[0203] High resolution: Calculated value: [M+H] + 322.1550, Measured value: 322.1539.

[0204] Example 35 Preparation of compound I-35

[0205]

[0206] In an argon-filled glove box, a 10 mL vial equipped with a magnetic stir bar was sequentially charged with diazo compound II-1 (11.4 mg, 0.1 mmol), active ester IV-16 (60.0 mg, 0.15 mmol), and DIPEA (38.7 mg, 0.3 mmol), followed by the addition of MeCN (1.0 mL). The mixture was stirred at room temperature for 30 min, and the reaction was monitored by TLC. The concentrated reaction residue was purified by flash column chromatography on silica gel to give 22.2 mg of product I-35, in 72% yield.

[0207] 1 H NMR(400MHz,Chloroform-d)δ8.16(d,J=6.9Hz,1H),7.68(dd,J=6.4,2.7Hz,1H),7.56-7 .50(m,1H),7.47-7.37(m,1H),4.99(s,1H),4.26(q,J=7.1Hz,1H),1.27(t,J=7.1Hz,1H). 13 C NMR (101MHz, CDCl3) δ167.1,161.7,156.8,130.7,130.4,129.3,129.0,128.6,128.5,127.7,126.5,62.2,50.7,14.0.

[0208] High resolution: Calculated value: [M+H] + 308.1394, Measured value: 308.1391.

[0209] Example 36 Preparation of compound I-36

[0210]

[0211] In an argon-filled glove box, a 10 mL vial equipped with a magnetic stir bar was sequentially charged with diazo compound II-1 (11.4 mg, 0.1 mmol), active ester IV-17 (59.0 mg, 0.15 mmol), and DIPEA (38.7 mg, 0.3 mmol), followed by the addition of MeCN (1.0 mL). The mixture was stirred at room temperature for 30 min, and the reaction was monitored by TLC. The concentrated reaction residue was purified by flash column chromatography on silica gel to give 16.9 mg of product I-36, in 57% yield.

[0212] 1 H NMR(400MHz,Chloroform-d)δ7.69–7.65(m,2H),7.55–7.49(m,4H),7.05(d,J=3.3H z,1H),6.53(dd,J=3.4,1.8Hz,1H),4.99(s,2H),4.26(q,J=7.2Hz,2H),1.27(q,3H). 13 C NMR (101MHz, Chloroform-d) δ167.0,157.0,155.1,146.3,143.5,130.8,129.2,128.8,127.3,111.6,109.9,62.4,50.9,14.2.

[0213] High resolution: Calculated value: [M+H] + 298.1186, Measured value: 298.1191.

[0214] Example 37 Preparation of compound I-37

[0215]

[0216] In an argon-filled glove box, a 10 mL vial equipped with a magnetic stir bar was sequentially charged with diazo compound II-1 (11.4 mg, 0.1 mmol), active ester IV-18 (60.9 mg, 0.15 mmol), and DIPEA (38.7 mg, 0.3 mmol), followed by the addition of MeCN (1.0 mL). The mixture was stirred at room temperature for 30 min, and the reaction was monitored by TLC. The concentrated reaction residue was purified by flash column chromatography on silica gel to give 16.4 mg of product I-37, in 53% yield.

[0217] 1 H NMR(400MHz,Chloroform-d)δ7.75(dd,J=3.6,1.2Hz,1H),7.69–7.63(m,2H),7.55–7.48(m,3H),7.36(dd, J=5.0,1.2Hz,1H),7.11(dd,J=5.0,3.6Hz,1H),4.96(s,2H),4.26(q,J=7.1Hz,2H),1.28(t,J=7.1Hz,3H). 13 C NMR (101MHz, Chloroform-d) δ167.1,158.2,156.9,133.7,130.7,129.2,128.9,127.8,127.5,126.7,62.4,50.8,14.2.

[0218] High resolution: Calculated value: [M+H] + 314.0958, Measured value: 314.0959.

[0219] Example 38 Preparation of compound I-38

[0220]

[0221] In an argon-filled glove box, diazo compound II-1 (11.4 mg, 0.1 mmol), active ester IV-19 (72.6 mg, 0.15 mmol), and DIPEA (38.7 mg, 0.30 mmol) were sequentially introduced into a 10 mL vial equipped with a magnetic stir bar, followed by the addition of MeCN (1.0 mL). The mixture was stirred at room temperature for 12 h, and the reaction was monitored by TLC. The concentrated reaction residue was purified by flash column chromatography on silica gel to give 22.7 mg of product I-38, in 58% yield.

[0222] 1H NMR (400MHz, Chloroform-d) δ7.61–7.55(m,2H),7.49–7.43(m,3H),7.30(d,J=8.1Hz,2H),7.07(d,J=8.1Hz,2H),4.89(s,2H),4.29(q,J= 7.2Hz,1H),4.22(q,2H),2.43(d,J=7.2Hz,2H),1.89–1.77(m,1H),1.73(d,J=7.3Hz,3H),1.24(t,J=7.1Hz,3H),0.89(s,3H),0.88(s,3H). 13 C NMR(101MHz,Chloroform-d)δ167.4,167.2,156.4,141.6,139.8,130.4,129.3,1 29.0,128.9,128.0,127.4,62.2,50.6,45.2,39.3,30.3,22.6,22.6,21.3,14.2.

[0223] High resolution: Calculated value: [M+H] + 392.2333, Measured value: 392.2327.

[0224] Example 39 Preparation of compound I-39

[0225]

[0226] In an argon-filled glove box, a 10 mL vial equipped with a magnetic stir bar was sequentially charged with diazo compound II-1 (11.4 mg, 0.1 mmol), active ester IV-20 (84.0 mg, 0.15 mmol), and DIPEA (38.7 mg, 0.3 mmol), followed by the addition of MeCN (1.0 mL). The mixture was stirred at room temperature for 12 h, and the reaction was monitored by TLC. The concentrated reaction residue was purified by flash column chromatography on silica gel to give 24.1 mg of product I-38, in 50% yield.

[0227] 1H NMR(400MHz,Chloroform-d)δ8.19(dd,J=8.0,1.6Hz,1H),7.60–7.54(m,4H),7.50–7.44(m,4H),7.41(td,J=7.5,1.7Hz,1H),7.30(td,J=7.6,1.3Hz, 1H),7.24(dd,J=8.0,2.0Hz,1H),4.89(s,2H),4.35(s,2H),4.30(q,J=7.4H z, 1H), 4.24 (q, J = 7.1Hz, 2H), 1.71 (d, J = 7.2Hz, 3H), 1.25 (t, J = 7.1Hz, 3H). 13 C NMR(101MHz,Chloroform-d)δ167.4,167.2,156.4,141.6,139.8,130.4,129.3,1 29.0,128.9,128.0,127.3,62.2,50.6,45.2,39.3,30.3,22.6,22.6,21.3,14.2.

[0228] High resolution: Calculated value: [M+H] + 484.1690, Measured value: 484.1683.

[0229] Example 40 Preparation of compound I-40

[0230]

[0231] In an argon-filled glove box, diazo compound II-1 (11.4 mg, 0.1 mmol), active ester IV-21 (76.8 mg, 0.15 mmol), and DIPEA (38.7 mg, 0.30 mmol) were sequentially introduced into a 10 mL vial equipped with a magnetic stir bar, followed by the addition of MeCN (1.0 mL). The mixture was stirred at room temperature for 12 h, and the reaction was monitored by TLC. The concentrated reaction residue was purified by flash column chromatography on silica gel to give 28.7 mg of product I-40, in 66% yield.

[0232] 1H NMR (400MHz, Chloroform-d) δ7.60–7.54(m,2H),7.50–7.44(m,3H),6.98(d,J=7.4Hz,1H),6.63(d,J=7.5Hz,1H),6.59(s,1H),4.88(s,2H),4. 21(q,J=7.1Hz,2H),3.89(t,J=6.5Hz,2H),2.28(s,3H),2.16(s,3H),1. 94–1.88(m,2H),1.78–1.71(m,2H),1.44(s,6H),1.23(t,J=7.1Hz,3H). 13 C NMR(101MHz,Chloroform-d)δ170.5,167.4,157.2,156.3,136.5,130.3,130.3,129.0,128 .9,128.2,123.7,120.6,112.1,68.4,62.1,50.5,39.0,35.9,27.3,25.2,21.5,15.9,14.2.

[0233] High resolution: Calculated value: [M+H] + :436.2595, Measured value: 436.2592.

[0234] Example 41 Preparation of compound I-41

[0235]

[0236] In an argon-filled glove box, diazo compound II-18 (39.4 mg, 0.1 mmol), active ester IV-19 (72.6 mg, 0.15 mmol), and DIPEA (38.7 mg, 0.30 mmol) were sequentially introduced into a 10 mL vial equipped with a magnetic stir bar, followed by the addition of MeCN (1.0 mL). The mixture was stirred at room temperature for 30 min, and the reaction was monitored by TLC. The concentrated reaction residue was purified by flash column chromatography on silica gel to give 44.8 mg of product I-41, in 67% yield.

[0237] 1H NMR(400MHz,Chloroform-d)δ8.66(t,J=4.2Hz,1H),8.02(dt,J=9.1,1.6Hz,1H),7.48–7.38(m,4H),7.36(dt,J=4.7,1.5Hz,1H),7.33–7. 26(m,4H),7.14(dd,J=7.6,4.6Hz,1H),7.09–7.05(m,2H),6.55(dd,J=14.6,6.9Hz,1H),5.86–5.72(m,1H),5.02–4.94(m,4H),4.28(q,1H ),3.95(s,1H),3.88(s,3H),3.53(q,J=7.3Hz,1H),3.35–3.20(m,1H),3.07–2.99(m,1H),2.65(q,J=7.2Hz,2H),2.41(d,J=7.1Hz,2H),1. 87–1.76(m,2H),1.72(dd,J=7.3,1.4Hz,3H),1.40(t,J=7.3Hz,1H),1.34–1.29(m,1H),1.10(t,J=7.2Hz,2H),0.87(d,J=6.7,1.4Hz,6H). 13 C NMR(101MHz,Chloroform-d)δ167.4,167.36,166.6,166.58,158.2,158.1,156.1,147.5,147.5, 144.8,142.5,141.8,141.6,141.3,141.28,139.9,132.0,130.5,129.3,129.0,128.6,128.6,12 7.3,122.1,114.7,114.6,101.5,101.1,59.2,59.0,58.9,56.7,56.7,55.8,55.7,53.0,50.8,46.1,45.2,42.7,42.6,39.6,39.3,30.3,27.7,27.6,27.5,24.0,22.5,22.5,21.3,21.2,10.9,8.1.

[0238] High resolution: Calculated value: [M+H] + 670.3752, Measured value: 670.3752.

[0239] Example 42 Preparation of compound I-42

[0240]

[0241] In an argon-filled glove box, diazo compound II-18 (39.4 mg, 0.1 mmol), active ester IV-21 (76.8 mg, 0.15 mmol), and DIPEA (38.7 mg, 0.30 mmol) were sequentially introduced into a 10 mL vial equipped with a magnetic stir bar, followed by the addition of MeCN (1.0 mL). The mixture was stirred at room temperature for 30 min, and the reaction was monitored by TLC. The concentrated reaction residue was purified by flash column chromatography on silica gel to give 28.7 mg of product I-42, in 66% yield.

[0242] 1 H NMR (400MHz, Chloroform-d) δ7.60–7.54(m,2H),7.50–7.44(m,3H),6.98(d,J=7.4Hz,1H),6.63(d,J=7.5Hz,1H),6.59(s,1H),4.88(s,2H),4. 21(q,J=7.1Hz,2H),3.89(t,J=6.5Hz,2H),2.28(s,3H),2.16(s,3H),1. 94–1.88(m,2H),1.78–1.71(m,2H),1.44(s,6H),1.23(t,J=7.1Hz,3H). 13 C NMR(101MHz,Chloroform-d)δ170.5,167.4,157.2,156.3,136.5,130.3,130.3,129.0,128 .9,128.2,123.7,120.6,112.1,68.4,62.1,50.5,39.0,35.9,27.3,25.2,21.5,15.9,14.2.

[0243] High resolution: Calculated value: [M+H] + 714.4014, Measured value: 714.3997.

[0244] The raw material structure used in each embodiment:

[0245]

[0246]

[0247]

[0248] The various embodiments of the present invention have been described above. These descriptions are exemplary and not exhaustive, nor are they limited to the disclosed embodiments. Many modifications and variations will be apparent to those skilled in the art without departing from the scope and spirit of the described embodiments.

Claims

1. A method for the [3+2] orthogonal cycloaddition of an amino acid active ester with a diazo compound, characterized in that, The method includes: Under inert gas protection and in the presence of alkali and solvent, the active ester of amino acid is contacted with a diazo compound to carry out a [3+2] orthogonal cycloaddition reaction to obtain the 1,2,4-triazole compound shown in Formula I. The diazo compound is at least one of the compounds shown in Formula II or Formula III; The amino acid active ester is at least one of the compounds shown in Formula IV; Among them, R 1 It is hydrogen, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 acyl or C6-C 12 Aryl, R 2 The ester group shown in Formula V, C1-C 30 Acyl group, C1-C 16 Phosphonyl, C1-C 16 sulfonyl or C6-C 12 Aryl; Among them, R 5 C1-C8 alkyl, C1-C 20 Substituted alkyl, C1-C8 alkenyl, C1-C8 ynyl, C6-C 16 Aryl, C7-C 16 Aryl group, C7-C 16 Alkyl, C5-C 12 cycloalkyl, C4-C 12 Heterocyclic group, C6-C 16 Bridge ring base or C8-C 16 Fused ring groups; R 3 It can be hydrogen, C1-C8 alkyl, C1-C8 alkoxy, fluorine, chlorine, or bromine; R 4 For C1-C 16 Alkyl, halogen-substituted C1-C8 alkyl, C7-C 12 Benzyl, C6-C 12 Aryl, C7-C 12 Alkyl or C5-C 20 Mixed aromatics; It is a benzene ring or a heteroaromatic ring; The base is diisopropylethylamine; The solvent is acetonitrile.

2. The method according to claim 1, wherein, It can be a benzene ring, pyridine ring, furan ring, thiophene ring, pyrrole ring, pyrazine ring, oxazole ring, thiazole ring, imidazole ring, indole ring, or quinoline ring.

3. The method according to claim 1, wherein, The reaction was carried out under ambient light at room temperature or under external light source illumination.

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