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

Abstract

The invention belongs to the field of organic synthesis, and relates to a [3 + 2] orthogonal cycloaddition method of amino acid active ester and a diazo compound and application of the [3 + 2] orthogonal cycloaddition method in synthetic chemistry. The method comprises the following steps: under the protection of inert gas, in the presence of alkali and a solvent, enabling amino acid active ester to be in contact with a diazo compound to carry out [3 + 2] orthogonal cycloaddition reaction, so as to obtain the 1, 2, 4-triazole compound as shown in the formula I. The invention further discloses a preparation method of the 1, 2, 4-triazole compound. According to the method, the amino acid active and diazo compounds which are simple and easy to obtain are used as starting raw materials, highly-functionalized fully-substituted 1, 2, 4-triazole can be efficiently synthesized in a high-selectivity mode, and rapid and efficient orthogonal connection of two molecules connected to diazo and active ester is achieved. # imgabs0 #

Description

Technical Field

[0001] The invention belongs to the field of organic synthesis, and in particular relates to a [3+2] orthogonal cycloaddition method of an amino acid active ester and a diazo compound and an application thereof in synthetic chemistry. Background Art

[0002] In chemical science, orthogonal reactions are considered to be reactions that selectively chemically transform a functional group under a set of specific conditions without touching other functional groups. They are characterized by specificity and high selectivity in complex systems. Therefore, developing effective synthetic systems to enrich the existing orthogonal reaction library is an important task in contemporary chemical synthesis. The term "orthogonal" in protecting groups was proposed by Merrifield as early as 1977 for amino protection in peptide synthesis. There are many hydroxyl groups naturally present in carbohydrates, so the concept of orthogonal protection is particularly important in the field of carbohydrate chemistry. In the following decades, orthogonal chemistry has been developed and widely used in protecting group chemistry, construction of supramolecular complexes by self-assembly, bioorthogonality, material surface modification, and synthesis of complex molecules. Among them, the orthogonal method of using free radicals to attack diazo compounds for [3+2] cycloaddition reaction has not been reported in the literature. Summary of the invention

[0003] The present invention aims to develop a [3+2] orthogonal cycloaddition reaction of N-α free radical and diazo from amino acid active esters and diazo compounds which are easily available.

[0004] In order to achieve the above object, the present invention provides a [3+2] orthogonal cycloaddition method of an amino acid active ester and a diazo compound, the method comprising:

[0005] Under the protection of an inert gas and in the presence of a base and a solvent, an amino acid active ester is contacted with a diazo compound to carry out a [3+2] orthogonal cycloaddition reaction to obtain a 1,2,4-triazole compound represented by formula I;

[0006]

[0007] The diazo compound is at least one of the compounds represented by formula II or formula III;

[0008] The amino acid active ester is at least one of the compounds represented by formula IV;

[0009]

[0010] Among them, R 1 , R 2 , R 3 , R 4 are each independently any group, and R 1, R 2 Optional ringing;

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

[0012] The present invention utilizes the amino acid active ester and the diazo compound to carry out the [3+2] cycloaddition reaction equation as shown below:

[0013]

[0014] The present invention verifies that R 1 , R 2 , R 3 , R 4 Various compounds with different substituents can be prepared simply and efficiently through the synthetic route designed by the present invention, including different substituent types, different chain lengths, different steric hindrances, etc. Therefore, the method of the present invention has basically no restrictions on the substituents.

[0015] According to a specific embodiment of the present invention, R 1 is hydrogen, alkyl, alkenyl, acyl or aryl, R 2 is an ester group, an acyl group, a phosphonyl group, a sulfonyl group or an aryl group, and R 1 , R 2 Optionally, R 1 is hydrogen, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 acyl or C6-C 12 Aryl, R 2 C1-C 30 Ester group, C1-C 30 Acyl, C1-C 16 Phosphonyl, C1-C 16 Sulfonyl or C6-C 12 Aryl, and R 1 , R 2 Optional ring formation.

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

[0017] According to a specific embodiment of the present invention, R 4 R is alkyl, halogen-substituted alkyl, benzyl, aryl, alkaryl or heteroaryl. 4 C1-C 16 Alkyl, halogen-substituted C1-C8 alkyl, C7-C 12 Benzyl, C6-C 12 Aryl, C7-C 12Alkyl or C5-C 20 Heteroaryl.

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

[0019] In order to verify the applicability of the method of the present invention, a variety of compounds were synthesized in the examples of the present invention, some of which have complex structures. Therefore, the above-mentioned group type of the present invention refers to the group type directly connected to the carbon atom connected to the group, for example, R 2 The ester group refers to at least one of the ester groups shown in Formula V,

[0020]

[0021] Among them, R 5 It may further be other types of groups, specifically alkyl, substituted alkyl, alkenyl, alkynyl, aryl, aralkyl, alkaryl, cycloalkyl, heterocyclic, bridged ring or condensed ring; the substituent is selected from alkyl (e.g. C1-C 12 alkyl), azido, amine, nitro, cyano; preferably, R 5 C1-C8 alkyl, C1-C 20 Substituted alkyl, C1-C8 alkenyl, C1-C8 alkynyl, C6-C 16 Aryl, C7-C 16 Aralkyl, C7-C 16 Alkyl, C5-C 12 Cycloalkyl, C4-C 12 Heterocyclic group, C6-C 16 Bridged ring or C8-C 16 Condensed ring group.

[0022] The base in the present invention can be at least one of an organic base and an inorganic base; preferably, the base 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 the base used can be 0.1 to 15 times the molar equivalent of the compound represented by formula I.

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

[0025] The reaction of the present invention can be carried out under natural light at room temperature, so it is simple, convenient and energy-saving. Alternatively, it can also be carried out under illumination of an external light source.

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

[0027] The present invention provides a [3+2] orthogonal cycloaddition reaction method under room temperature and natural light conditions. The method uses easily available amino acid activity and diazo compounds as starting materials, can efficiently and highly selectively synthesize highly functionalized fully substituted 1,2,4-triazoles, and can achieve rapid and efficient orthogonal connection of two molecules connected to diazo and active esters. The 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. DETAILED DESCRIPTION

[0029] The preferred embodiments of the present invention will be described in more detail below. Although the preferred embodiments of the present invention are described below, it should be understood that the present 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 a glove box filled with argon, a 10 mL vial equipped with a magnetic stirring bar was charged with 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) in sequence, and then MeCN (1.0 mL) was added. Stir at room temperature for 30 min and monitor by TLC analysis. The concentrated reaction residue was purified by flash column chromatography on silica gel to obtain 21.8 mg of the product of formula I-1 with a yield of 89%.

[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 a glove box filled with argon, a 10 mL vial equipped with a magnetic stirring bar was charged with 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) in sequence, and then MeCN (1.0 mL) was added. Stir at room temperature for 30 min and monitor by TLC analysis. The concentrated reaction residue was purified by flash column chromatography on silica gel to obtain 17.2 mg of the product of formula I-2 with a yield of 64%.

[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 a glove box filled with argon, a 10 mL vial equipped with a magnetic stirring bar was 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) in sequence, and then MeCN (1.0 mL) was added. Stir at room temperature for 30 min and monitor by TLC analysis. The concentrated reaction residue was purified by flash column chromatography on silica gel to obtain 19.4 mg of the product of formula I-3 with a yield of 72%.

[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 a glove box filled with argon, a 10 mL vial equipped with a magnetic stirring bar was charged with 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) in sequence, and then MeCN (1.0 mL) was added. Stir at room temperature for 30 min and monitor by TLC analysis. The concentrated reaction residue was purified by flash column chromatography on silica gel to obtain 34.5 mg of the product of formula I-4 with a yield of 87%.

[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 a glove box filled with argon, a 10 mL vial equipped with a magnetic stirring bar was 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) in sequence, and then MeCN (1.0 mL) was added. Stir at room temperature for 30 min and monitor by TLC analysis. The concentrated reaction residue was purified by flash column chromatography on silica gel to obtain 30.3 mg of the product of formula I-5 with a yield of 85%.

[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 a glove box filled with argon, a 10 mL vial equipped with a magnetic stirring bar was charged with 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) in sequence, and then MeCN (1.0 mL) was added. Stir at room temperature for 30 min and monitor by TLC analysis. The concentrated reaction residue was purified by flash column chromatography on silica gel to obtain 24.3 mg of the product of formula I-6 with a yield of 83%.

[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 a glove box filled with argon, a 10 mL vial equipped with a magnetic stirring bar was charged with 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) in sequence, and then MeCN (1.0 mL) was added. Stir at room temperature for 30 min and monitor by TLC analysis. The concentrated reaction residue was purified by flash column chromatography on silica gel to obtain 19.1 mg of the product of formula I-7 with a yield of 69%.

[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 a glove box filled with argon, a 10 mL vial equipped with a magnetic stirring bar was 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) in sequence, and then MeCN (1.0 mL) was added. Stir at room temperature for 30 min and monitor by TLC analysis. The concentrated reaction residue was purified by flash column chromatography on silica gel to obtain 19.4 mg of the product of formula I-8 with a yield of 52%.

[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 a glove box filled with argon, a 10 mL vial equipped with a magnetic stirring bar was 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) in sequence, and then MeCN (1.0 mL) was added. Stir at room temperature for 30 min and monitor by TLC analysis. The concentrated reaction residue was purified by flash column chromatography on silica gel to obtain 19.6 mg of the product of formula I-9 with a yield of 60%.

[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 a glove box filled with argon, a 10 mL vial equipped with a magnetic stirring bar was charged with 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) in sequence, and then MeCN (1.0 mL) was added. Stir at room temperature for 30 min and monitor by TLC analysis. The concentrated reaction residue was purified by flash column chromatography on silica gel to obtain 26.7 mg of the product of formula I-10 with a yield of 72%.

[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 a glove box filled with argon, a 10 mL vial equipped with a magnetic stirring bar was 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) in sequence, and then MeCN (1.0 mL) was added. Stir at room temperature for 30 min and monitor by TLC analysis. The concentrated reaction residue was purified by flash column chromatography on silica gel to obtain 24.2 mg of the product of formula I-11 with a yield of 71%.

[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 a glove box filled with argon, a 10 mL vial equipped with a magnetic stirring bar was 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) in sequence, and then MeCN (1.0 mL) was added. Stir at room temperature for 30 min and monitor by TLC analysis. The concentrated reaction residue was purified by flash column chromatography on silica gel to obtain 24.4 mg of the product of formula I-12 with a yield of 90%.

[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 a glove box filled with argon, a 10 mL vial equipped with a magnetic stirring bar was 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) in sequence, and then MeCN (1.0 mL) was added. Stir at room temperature for 30 min and monitor by TLC analysis. The concentrated reaction residue was purified by flash column chromatography on silica gel to obtain 23.3 mg of the product of formula I-13 with a yield of 88%.

[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 a glove box filled with argon, a 10 mL vial equipped with a magnetic stirring bar was 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) in sequence, and then MeCN (1.0 mL) was added. Stir at room temperature for 30 min and monitor by TLC analysis. The concentrated reaction residue was purified by flash column chromatography on silica gel to obtain 22.4 mg of the product of formula I-14 with a yield of 88%.

[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 a glove box filled with argon, a 10 mL vial equipped with a magnetic stirring bar was 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) in sequence, and then MeCN (1.0 mL) was added. Stir at room temperature for 30 min and monitor by TLC analysis. The concentrated reaction residue was purified by flash column chromatography on silica gel to obtain 32.8 mg of the product of formula I-15 with a yield of 90%.

[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 a glove box filled with argon, a 10 mL vial equipped with a magnetic stirring bar was charged with 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) in sequence, and then MeCN (1.0 mL) was added. Stir at room temperature for 30 min and monitor by TLC analysis. The concentrated reaction residue was purified by flash column chromatography on silica gel to obtain 36.9 mg of the product of formula 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 a glove box filled with argon, a 10 mL vial equipped with a magnetic stirring bar was 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) in sequence, and then MeCN (1.0 mL) was added. Stir at room temperature for 30 min and monitor by TLC analysis. The concentrated reaction residue was purified by flash column chromatography on silica gel to obtain 39.1 mg of the product of formula I-17 with a yield of 65%.

[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 a glove box filled with argon, a 10 mL vial equipped with a magnetic stirring bar was 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) in sequence, and then MeCN (1.0 mL) was added. Stir at room temperature for 30 min and monitor by TLC analysis. The concentrated reaction residue was purified by flash column chromatography on silica gel to obtain 50.1 mg of the product of formula I-18 with a yield of 86%.

[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 a glove box filled with argon, a 10 mL vial equipped with a magnetic stirring bar was charged with 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) in sequence, and then MeCN (1.0 mL) was added. Stir at room temperature for 30 min and monitor by TLC analysis. The concentrated reaction residue was purified by flash column chromatography on silica gel to obtain 21.2 mg of the product of formula I-19 with a yield of 71%.

[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 a glove box filled with argon, a 10 mL vial equipped with a magnetic stirring bar was charged with 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) in sequence, and then MeCN (1.0 mL) was added. Stir at room temperature for 30 min and monitor by TLC analysis. The concentrated reaction residue was purified by flash column chromatography on silica gel to obtain 15.4 mg of the product of formula I-20 with a yield of 41%.

[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 a glove box filled with argon, a 10 mL vial equipped with a magnetic stirring bar was charged with 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) in sequence, and then MeCN (1.0 mL) was added. Stir at room temperature for 30 min and monitor by TLC analysis. The concentrated reaction residue was purified by flash column chromatography on silica gel to obtain 24.6 mg of the product of formula 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 a glove box filled with argon, a 10 mL vial equipped with a magnetic stirring bar was charged with 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) in sequence, and then MeCN (1.0 mL) was added. Stir at room temperature for 30 min and monitor by TLC analysis. The concentrated reaction residue was purified by flash column chromatography on silica gel to obtain 23.4 mg of the product of formula I-22 with a yield of 86%.

[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 Preparation of Compound I-23

[0142]

[0143] In a glove box filled with argon, a 10 mL vial equipped with a magnetic stirring bar was 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) in sequence, and then MeCN (1.0 mL) was added. Stir at room temperature for 30 min and monitor by TLC analysis. The concentrated reaction residue was purified by flash column chromatography on silica gel to obtain 23.4 mg of the product of formula I-23 with a yield of 89%.

[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 a glove box filled with argon, a 10 mL vial equipped with a magnetic stirring bar was charged with 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) in sequence, and then MeCN (1.0 mL) was added. Stir at room temperature for 30 min and monitor by TLC analysis. The concentrated reaction residue was purified by flash column chromatography on silica gel to obtain 20.7 mg of the product of formula I-24 with a yield of 64%.

[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 a glove box filled with argon, a 10 mL vial equipped with a magnetic stirring bar was 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) in sequence, and then MeCN (1.0 mL) was added. Stir at room temperature for 30 min and monitor by TLC analysis. The concentrated reaction residue was purified by flash column chromatography on silica gel to obtain 25.1 mg of the product of formula I-25 with a yield of 90%.

[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 a glove box filled with argon, a 10 mL vial equipped with a magnetic stirring bar was charged with 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) in sequence, and then MeCN (1.0 mL) was added. Stir at room temperature for 30 min and monitor by TLC analysis. The concentrated reaction residue was purified by flash column chromatography on silica gel to obtain 24.3 mg of the product of formula I-26 with a yield of 87%.

[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 a glove box filled with argon, a 10 mL vial equipped with a magnetic stirring bar was 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) in sequence, and then MeCN (1.0 mL) was added. Stir at room temperature for 30 min and monitor by TLC analysis. The concentrated reaction residue was purified by flash column chromatography on silica gel to obtain 8.4 mg of the product of formula I-27 with a yield of 30%.

[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 a glove box filled with argon, a 10 mL vial equipped with a magnetic stirring bar was charged with 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) in sequence, and then MeCN (1.0 mL) was added. Stir at room temperature for 30 min and monitor by TLC analysis. The concentrated reaction residue was purified by flash column chromatography on silica gel to obtain 25.1 mg of the product of formula I-28 with a yield of 84%.

[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 a glove box filled with argon, a 10 mL vial equipped with a magnetic stirring bar was 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) in sequence, and then MeCN (1.0 mL) was added. Stir at room temperature for 30 min and monitor by TLC analysis. The concentrated reaction residue was purified by flash column chromatography on silica gel to obtain 20.8 mg of the product of formula I-29 with a yield of 83%.

[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 a glove box filled with argon, a 10 mL vial equipped with a magnetic stirring bar was charged with 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) in sequence, and then MeCN (1.0 mL) was added. Stir at room temperature for 30 min and monitor by TLC analysis. The concentrated reaction residue was purified by flash column chromatography on silica gel to obtain 24.2 mg of the product of formula I-30 with a yield of 92%.

[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 a glove box filled with argon, a 10 mL vial equipped with a magnetic stirring bar was 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) in sequence, and then MeCN (1.0 mL) was added. Stir at room temperature for 30 min and monitor by TLC analysis. The concentrated reaction residue was purified by flash column chromatography on silica gel to obtain 27.3 mg of the product of formula I-31 with a yield of 92%.

[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 a glove box filled with argon, a 10 mL vial equipped with a magnetic stirring bar was 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) in sequence, and then MeCN (1.0 mL) was added. Stir at room temperature for 30 min and monitor by TLC analysis. The concentrated reaction residue was purified by flash column chromatography on silica gel to obtain 13.2 mg of the product of formula I-32 with a yield of 46%.

[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 a glove box filled with argon, a 10 mL vial equipped with a magnetic stirring bar was charged with 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) in sequence, and then MeCN (1.0 mL) was added. Stir at room temperature for 30 min and monitor by TLC analysis. The concentrated reaction residue was purified by flash column chromatography on silica gel to obtain 25.7 mg of the product of formula I-33 with a yield of 86%.

[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 a glove box filled with argon, a 10 mL vial equipped with a magnetic stirring bar was charged with 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) in sequence, and then MeCN (1.0 mL) was added. Stir at room temperature for 30 min and monitor by TLC analysis. The concentrated reaction residue was purified by flash column chromatography on silica gel to obtain 29.8 mg of the product of formula I-34 with a yield of 93%.

[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 a glove box filled with argon, a 10 mL vial equipped with a magnetic stirring bar was 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) in sequence, and then MeCN (1.0 mL) was added. Stir at room temperature for 30 min and monitor by TLC analysis. The concentrated reaction residue was purified by flash column chromatography on silica gel to obtain 22.2 mg of the product of formula I-35 with a yield of 72%.

[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 a glove box filled with argon, a 10 mL vial equipped with a magnetic stirring bar was 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) in sequence, and then MeCN (1.0 mL) was added. Stir at room temperature for 30 min and monitor by TLC analysis. The concentrated reaction residue was purified by flash column chromatography on silica gel to obtain 16.9 mg of the product of formula I-36 with a yield of 57%.

[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 a glove box filled with argon, a 10 mL vial equipped with a magnetic stirring bar was 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) in sequence, and then MeCN (1.0 mL) was added. Stir at room temperature for 30 min and monitor by TLC analysis. The concentrated reaction residue was purified by flash column chromatography on silica gel to obtain 16.4 mg of the product of formula I-37 with a yield of 53%.

[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 a glove box filled with argon, a 10 mL vial equipped with a magnetic stirring bar was charged with 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) in sequence, and then MeCN (1.0 mL) was added. Then stirred at room temperature for 12 h and monitored by TLC analysis. The concentrated reaction residue was purified by flash column chromatography on silica gel to obtain 22.7 mg of the product of formula I-38 with a yield of 58%.

[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 a glove box filled with argon, a 10 mL vial equipped with a magnetic stirring bar was 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) in sequence, and then MeCN (1.0 mL) was added. Stir at room temperature for 12 h and monitor by TLC analysis. The concentrated reaction residue was purified by flash column chromatography on silica gel to obtain 24.1 mg of the product of formula I-38 with a yield of 50%.

[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 a glove box filled with argon, a 10 mL vial equipped with a magnetic stirring bar was charged with 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) in sequence, and then MeCN (1.0 mL) was added. Stir at room temperature for 12 h and monitor by TLC analysis. The concentrated reaction residue was purified by flash column chromatography on silica gel to obtain 28.7 mg of the product of formula I-40 with a yield of 66%.

[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 a glove box filled with argon, a 10 mL vial equipped with a magnetic stirring bar was charged with 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) in sequence, and then MeCN (1.0 mL) was added. Stir at room temperature for 30 min and monitor by TLC analysis. The concentrated reaction residue was purified by flash column chromatography on silica gel to obtain 44.8 mg of the product of formula I-41 with a yield of 67%.

[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 a glove box filled with argon, a 10 mL vial equipped with a magnetic stirring bar was charged with 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) in sequence, and then MeCN (1.0 mL) was added. Stir at room temperature for 30 min and monitor by TLC analysis. The concentrated reaction residue was purified by flash column chromatography on silica gel to obtain 28.7 mg of the product of formula I-42 with a yield of 66%.

[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 embodiments of the present invention have been described above, and the above description is exemplary, not exhaustive, and is not limited to the disclosed embodiments. Many modifications and changes will be apparent to those skilled in the art without departing from the scope and spirit of the described embodiments.

Claims

1. A [3+2] orthogonal cycloaddition method of an amino acid active ester and a diazo compound, characterized in that: The method comprises: Under the protection of an inert gas and in the presence of a base and a solvent, an amino acid active ester is contacted with a diazo compound to carry out a [3+2] orthogonal cycloaddition reaction to obtain a 1,2,4-triazole compound represented by formula I; The diazo compound is at least one of the compounds represented by formula II or formula III; The amino acid active ester is at least one of the compounds represented by formula IV; Among them, R 1 , R 2 , R 3 , R 4 are each independently any group, and R 1 , R 2 Optional ringing; It is a benzene ring or a heteroaromatic ring.

2. The method according to claim 1, wherein: R 1 is hydrogen, alkyl, alkenyl, acyl or aryl, R 2 is an ester group, an acyl group, a phosphonyl group, a sulfonyl group or an aryl group, and R 1 , R 2 Optional ringing; R 3 is hydrogen, alkyl, alkoxy, fluorine, chlorine or bromine; R 4 is alkyl, halogen-substituted alkyl, benzyl, aryl, alkaryl or heteroaryl; It is a benzene ring, a pyridine ring, a furan ring, a thiophene ring, a pyrrole ring, a pyrazine ring, an oxazole ring, a thiazole ring, an imidazole ring, an indole ring or a quinoline ring.

3. The method according to claim 2, wherein: R 1 is hydrogen, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 acyl or C6-C 12 Aryl, R 2 C1-C 30 Ester group, C1-C 30 Acyl, C1-C 16 Phosphonyl, C1-C 16 Sulfonyl or C6-C 12 Aryl, and R 1 , R 2 Optional ringing; R 3 is hydrogen, C1-C8 alkyl, C1-C8 alkoxy, fluorine, chlorine or bromine; R 4 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 Heteroaryl.

4. The method according to claim 3, wherein: R 2 is at least one of the ester groups shown in Formula V, Among them, R 5 is an alkyl group, a substituted alkyl group, an alkenyl group, an alkynyl group, an aryl group, an aralkyl group, an alkaryl group, a cycloalkyl group, a heterocyclic group, a bridged ring group or a condensed ring group; the substituent is selected from an alkyl group, an azido group, an amine group, a nitro group, and a cyano group; preferably, R 5 C1-C8 alkyl, C1-C 20 Substituted alkyl, C1-C8 alkenyl, C1-C8 alkynyl, C6-C 16 Aryl, C7-C 16 Aralkyl, C7-C 16 Alkyl, C5-C 12 Cycloalkyl, C4-C 12 Heterocyclic group, C6-C 16 Bridged ring or C8-C 16 Condensed ring group.

5. The method according to claim 1, wherein: The base is at least one of an organic base and an inorganic base; the amount of the base used is 0.1 to 15 times the molar equivalent of the compound represented by formula I.

6. The method according to claim 5, wherein: The base 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.

7. The method according to claim 1, wherein: The solvent is at least one of a nitrile solvent, a halogenated alkane solvent, an amide solvent, a sulfoxide solvent and water; preferably, the solvent is selected from at least one of acetonitrile, water, dichloromethane, chloroform, 1,2-dichloroethane, N,N-dimethylformamide, N,N-dimethylacetamide and dimethyl sulfoxide.

8. The method according to claim 1, wherein: The reaction is carried out at room temperature under natural light or external light source.

9. A 1,2,4-triazole compound obtained by the method according to any one of claims 1 to 8.

10. Use of the method according to any one of claims 1 to 8 in synthetic chemistry.

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