Preparation method of beta, gamma-unsaturated nitrile compound

Abstract

The invention discloses a preparation method of a beta, gamma-unsaturated nitrile compound, and the preparation method comprises the following steps: dissolving an N-(quinoline-8-yl)-3-butylene amide derivative, azodiisobutyronitrile and a copper salt catalyst in an organic solvent, and reacting at 80-110 DEG C to obtain the beta, gamma-unsaturated nitrile compound. The invention provides a brand new system, azodiisobutyronitrile is used as a free radical source, the source is rich, the price is low, and synthesis of beta, gamma-unsaturated nitrile compounds with high regioselectivity and stereoselectivity is realized. The products obtained by using the method provided by the invention have various types, can be directly used, and can also be used for other further reactions. The method is novel in reaction, simple in reaction operation and post-treatment process, excellent in yield and suitable for large-scale production.

Description

Technical Field

[0001] This invention relates to the field of organic synthesis technology, and specifically to a method for preparing β,γ-unsaturated nitrile compounds. Background Technology

[0002] Cyano groups, as common organic functional groups and excellent hydrogen bond acceptors, are widely found in various bioactive natural products, drug molecules, and functional materials. They readily undergo subsequent reactions to transform into other functional groups such as aldehydes, ketones, carboxylic acids, and amides, and can also be converted into pyrazole heterocyclic derivatives through cycloaddition reactions. Heck coupling is a powerful tool for achieving carbon-carbon coupling. Traditional Heck-type coupling reactions of inactive olefins usually involve the use of the noble metal palladium. At the same time, controlling the regioselectivity and stereoselectivity of the olefin products has always been a challenge. Therefore, designing copper-catalyzed Heck-type coupling reactions of inactive olefins to prepare β,γ-unsaturated nitrile compounds with good regioselectivity and stereoselectivity is of great significance.

[0003] To date, the main methods for introducing cyano functional groups intramolecularly and achieving Heck-type coupling reactions include the following: organic synthesis methods for introducing cyano functional groups intramolecularly have been published in publications such as Chem. Commun. 2017, 53, 11544., J. Org. Chem. 2018, 83, 4239–4249., and Adv. Synth. Catal. 2019, 361, 3787–3799. However, the free radicals introduced in these molecules usually have special structures, making it impossible to achieve efficient coupling of large-volume straight-chain hydrocarbon groups. Furthermore, the pre-preparation and addition of additional oxidants and the generation of free radical donor byproducts do not meet the requirements of high efficiency, atom economy, and environmental friendliness.

[0004] Methods for achieving Heck-type coupling reactions have been disclosed in publications such as Nat. Commun. 2022, 13, 6297., Org. Lett. 2020, 22, 3524–3530., and Org. Lett. 2022, 24, 2738–2743. However, these methods typically involve the use of alkyl halides, leading to the generation of haloalkanes as byproducts, which does not meet the requirements of being green, atom-economical, and environmentally friendly. Summary of the Invention

[0005] To address the above technical problems, this invention provides a method for preparing β,γ-unsaturated nitrile compounds, which belongs to the double bond radical addition reaction initiated by azobisisobutyronitrile and promoted by free radicals. The conditions are relatively mild and meet the requirements of green chemistry.

[0006] The above-mentioned objective of this invention is achieved through the following technical solution:

[0007] A method for preparing a β,γ-unsaturated nitrile compound includes the following steps:

[0008] The N-(quinolin-8-yl)-3-butenamide derivative of formula (1), azobisisobutyronitrile and copper salt catalyst were dissolved in an organic solvent and reacted at 80-110 °C to obtain the β,γ-unsaturated nitrile compound of formula (2).

[0009] Equations (1) and (2) are shown below:

[0010]

[0011] R1 is selected from one of hydrogen, C1-C6 saturated or unsaturated alkyl groups, substituted or unsubstituted benzyl groups and substituted or unsubstituted methylene groups; R2 is selected from one of hydrogen and C1-C6 saturated or unsaturated alkyl groups; and R3 is selected from one of hydrogen and C1-C6 saturated or unsaturated alkyl groups.

[0012] The reaction route is as follows:

[0013]

[0014] To introduce cyano functional groups into the molecule to achieve highly regioselective and stereoselective synthesis of β,γ-unsaturated nitrile compounds, while avoiding the use of alkyl electrophilic halogenated hydrocarbons and solving problems such as low atom utilization and environmental unfriendliness, this invention provides a method for preparing β,γ-unsaturated nitrile compounds using azobisisobutyronitrile as the free radical source. This method uses readily available raw materials, is highly efficient, has high atom utilization, good versatility, is environmentally friendly, and exhibits excellent chemical selectivity.

[0015] In one embodiment of the present invention, R1 is selected from hydrogen, C1-C6 saturated or unsaturated alkyl groups, substituted or unsubstituted benzyl groups and substituted or unsubstituted methylene groups, R2 is selected from hydrogen, and R3 is selected from hydrogen.

[0016] In one embodiment of the present invention, R1 is selected from hydrogen, R2 is selected from hydrogen, and R3 is selected from one of hydrogen C1-C6 saturated or unsaturated alkyl groups.

[0017] In one embodiment of the present invention, R1 is selected from hydrogen, R2 is selected from hydrogen, and R3 is selected from methyl or ethyl.

[0018] Furthermore, the copper salt catalyst is selected from one or more of cuprous chloride, cuprous iodide, copper tetraacetonitrile hexafluorophosphate, cuprous trifluoromethanesulfonate, copper trifluoromethanesulfonate, copper acetate, copper bromide, and copper acetate monohydrate, preferably copper acetate monohydrate.

[0019] Furthermore, the organic solvent is selected from one or more of acetonitrile, 1,2-dichloroethane, toluene, dimethyl sulfoxide, tetrahydrofuran, methanol, ethanol and 2-butanol, preferably 2-butanol.

[0020] Furthermore, the molar ratio of the N-(quinolin-8-yl)-3-butenamide derivative to azobisisobutyronitrile is 1:(2-6), preferably 1:(2-4).

[0021] Furthermore, the molar ratio of the N-(quinolin-8-yl)-3-butenamide derivative to the copper salt catalyst is 1:(0.1 to 0.3), preferably 1:(0.1 to 0.5).

[0022] Further, the N-(quinoline-8-yl)-3-butenamide derivatives are N-(quinoline-8-yl)-3-butenamide, 2-methyl-N-(quinoline-8-yl)but-3-enamide, 2-ethyl-N-(quinoline-8-yl)but-3-enamide, N-(quinoline-8-yl)-2-vinylhexamide, 2-(cyclopropylmethyl)-N-(quinoline-8-yl)but-3-enamide, etc. Amines, 2-(cyclobutylmethyl)-N-(quinoline-8-yl)but-3-enamide, 2-isopropyl-N-(quinoline-8-yl)but-3-enamide, 2-cyclopentyl-N-(quinoline-8-yl)but-3-enamide, 2-cyclohexyl-N-(quinoline-8-yl)but-3-enamide, 2-benzyl-N-(quinoline-8-yl)but-3-enamide, 2-(2-methylbenzyl)-N-( Quinoline-8-yl)but-3-enamide, 2-(3-methylbenzyl)-N-(quinoline-8-yl)but-3-enamide, 2-(4-methylbenzyl)-N-(quinoline-8-yl)but-3-enamide, 2-(4-fluorobenzyl)-N-(quinoline-8-yl)but-3-enamide, 2-(4-chlorobenzyl)-N-(quinoline-8-yl)but-3-enamide, 2-(4-bromobenzyl)- N-(quinoline-8-yl)but-3-enamide, N-(quinoline-8-yl)-2-vinylpentan-4-enamide, 2-(methoxymethyl)-N-(quinoline-8-yl)but-3-enamide, 5-chloro-N-(quinoline-8-yl)-2-vinylpentanamide, 3-methyl-N-(quinoline-8-yl)but-3-enamide or (Z)-N-(quinoline-8-yl)hexyl-3-enamide.

[0023] Furthermore, the reaction temperature is 80–100°C, preferably 90°C.

[0024] Further, R1 is hydrogen, methyl, ethyl, n-butyl, hexyl, cyclopropylmethyl, cyclobutylmethyl, methoxymethyl, cyclopropylmethylene, cyclobutylmethylene, isopropyl, cyclopentyl, cyclohexyl, benzyl, 2-methylbenzyl, 3-methylbenzyl, 4-methylbenzyl, 4-fluorobenzyl, 4-chlorobenzyl, 4-bromobenzyl, vinyl, vinylpentyl, allyl, methyl ether methylene, or methylene-3-chloropropyl.

[0025] Furthermore, the preparation method of the N-(quinolin-8-yl)-3-butenamide derivative of formula (1) is as follows:

[0026] The 8-aminoquinoline of formula (3) and the 3-butenoic acid derivative of formula (4) were reacted at 20–40 °C in the presence of pyridine, 2-(7-azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (HATU), and dichloromethane to obtain the N-(quinoline-8-yl)-3-butenamide derivative of formula (1); the reaction route is as follows:

[0027]

[0028] R1 is selected from one of hydrogen, C1-C6 saturated or unsaturated alkyl groups, substituted or unsubstituted benzyl groups and substituted or unsubstituted methylene groups; R2 is selected from one of hydrogen and C1-C6 saturated or unsaturated alkyl groups; and R3 is selected from one of hydrogen and C1-C6 saturated or unsaturated alkyl groups.

[0029] Further, R1 is hydrogen, methyl, ethyl, n-butyl, methylenecyclopropane, methylenecyclobutane, isopropyl, cyclopentane, cyclohexane, benzyl, 2-methylbenzyl, 3-methylbenzyl, 4-methylbenzyl, 4-fluorobenzyl, 4-chlorobenzyl, 4-bromobenzyl, allyl, methylene methyl ether, or methylene-3-chloropropane.

[0030] The above-described technical solution of the present invention has the following beneficial effects:

[0031] 1. This invention provides a novel system that utilizes azobisisobutyronitrile as a free radical source, which is abundant and inexpensive, to achieve the synthesis of β,γ-unsaturated nitrile compounds with high regioselectivity and stereoselectivity.

[0032] 2. This invention uses substituted N-(quinoline-8-yl)-3-butenamide derivatives and azobisisobutyronitrile as starting materials, which are readily available and diverse. The products obtained by the method of this invention are of various types and can be used directly or in other further reactions.

[0033] 3. The present invention has a novel reaction, simple reaction operation and post-processing, excellent yield, and is suitable for large-scale production. Detailed Implementation

[0034] The present invention will be further described below with reference to specific embodiments, so that those skilled in the art can better understand and implement the present invention, but the embodiments are not intended to limit the present invention.

[0035] Unless otherwise specified, the experimental methods used in the following examples are conventional methods, and the materials and reagents used are commercially available.

[0036] Example 1

[0037] The preparation method of (E)-5-cyano-5-methyl-N-(quinolin-8-yl)hexyl-3-enamide (2a) includes the following steps:

[0038]

[0039] 1.4 g (10 mmol, 1 equiv) of 8-aminoquinoline 3a, 1.03 g (12 mmol, 1.2 equiv) of 3-butenoic acid 4a, and 4.94 g (13 mmol, 1.3 equiv) of HATU were weighed and dissolved in 30 mL of dichloromethane. After stirring at room temperature for 3–5 min, pyridine (1.6 g, 20 mmol, 2 equiv) was added and the reaction was continued for 24 h. After the reaction was completed, dichloromethane was added for dilution. The reaction system was washed with saturated sodium bicarbonate solution, and the organic phase was collected and dried over anhydrous sodium sulfate. The solvent was concentrated under reduced pressure, and the compound 1a (1.89 g) was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 10:1) to obtain compound 1a (1.89 g) in a fraction of 89%.

[0040] The above compound 1a was characterized by NMR and mass spectrometry, and the results are as follows:

[0041] 1 H NMR(400MHz,Chloroform-d)δ9.97(s,1H),8.78(ddt,J=10.3,7.2,1.7Hz,2H),8.15(ddd,J=8.3,4.4,1.9Hz,1H),7.58–7.47(m,2 H),7.45(ddd,J=9.8,4.8,3.1Hz,1H),6.15(ddtd,J=17.1,10.1,7.1,0.9Hz,1H),5.49–5.27(m,2H),3.36(dq,J=7.1,1.5Hz,2H).

[0042] 13C NMR (101MHz, Chloroform-d) δ169.42,148.30,138.52,136.56,134.46,131.10,128.07,127.54,121.75,121.70,120.19,116.69,43.30.

[0043] HRMS (ESI-TOF): m / z Calcd for C 13 H 13 N2O + [M+H + ]:213.1022;found:213.1029.

[0044]

[0045] (1) Weigh N-(quinolin-8-yl)-3-butenamide 1a (0.042 g, 0.2 mmol, 1 equiv), azobisisobutyronitrile 5 (0.098 g, 0.6 mmol, 3 equiv), and Cu(OAc)₂·H₂O (0.016 g, 0.08 mmol, 0.4 equiv) and dissolve them in 1 mL of 2-butanol. The mixture was heated to 90 °C under a nitrogen atmosphere, and the reaction was monitored by TLC until complete. After the reaction, the crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 10:1) to obtain compound 2a (42 mg). The yield was 75%.

[0046] (2) Weigh N-(quinolin-8-yl)-3-butenamide 1a (0.042 g, 0.2 mmol, 1 equiv), azobisisobutyronitrile 5 (0.098 g, 0.6 mmol, 3 equiv), and Cu(OAc)₂·H₂O (0.016 g, 0.08 mmol, 0.4 equiv) and dissolve them in 1 mL of 2-butanol. The mixture was heated to 80 °C under a nitrogen atmosphere, and the reaction was monitored by TLC until complete. After the reaction, the crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 10:1) to obtain compound 2a (37 mg). The yield was 66%.

[0047] (3) Weigh N-(quinolin-8-yl)-3-butenamide 1a (0.042 g, 0.2 mmol, 1 equiv), azobisisobutyronitrile 5 (0.098 g, 0.6 mmol, 3 equiv), and Cu(OAc)₂·H₂O (0.016 g, 0.08 mmol, 0.4 equiv) and dissolve them in 1 mL of 2-butanol. Heat the mixture to 100 °C under a nitrogen atmosphere and monitor the reaction by TLC until complete. After the reaction, the crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 10:1) to obtain compound 2a (40 mg). The yield was 71%.

[0048] (4) Weigh N-(quinolin-8-yl)-3-butenamide 1a (0.042 g, 0.2 mmol, 1 equiv), azobisisobutyronitrile 5 (0.098 g, 0.6 mmol, 3 equiv), and CuCl (0.008 g, 0.08 mmol, 0.4 equiv) and dissolve them in 1 mL of 2-butanol. Heat the mixture to 90 °C under a nitrogen atmosphere and monitor the reaction by TLC until complete. After the reaction, the crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 10:1) to obtain compound 2a (20 mg). The yield was 35%.

[0049] (5) Weigh N-(quinolin-8-yl)-3-butenamide 1a (0.042 g, 0.2 mmol, 1 equiv), azobisisobutyronitrile 5 (0.098 g, 0.6 mmol, 3 equiv), and CuI (0.015 g, 0.08 mmol, 0.4 equiv) and dissolve them in 1 mL of 2-butanol. Heat the mixture to 90 °C under a nitrogen atmosphere and monitor the reaction by TLC until complete. After the reaction, the crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 10:1) to obtain compound 2a (17 mg). The yield was 30%.

[0050] (6) Weigh N-(quinolin-8-yl)-3-butenamide 1a (0.042 g, 0.2 mmol, 1 equiv), azobisisobutyronitrile 5 (0.098 g, 0.6 mmol, 3 equiv), and Cu(OAc)2 (0.015 g, 0.08 mmol, 0.4 equiv) and dissolve them in 1 mL of 2-butanol. Heat the mixture to 90 °C under a nitrogen atmosphere and monitor the reaction by TLC until complete. After the reaction, the crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 10:1) to obtain compound 2a (35 mg). The yield was 62%.

[0051] (7) Weigh N-(quinolin-8-yl)-3-butenamide 1a (0.042 g, 0.2 mmol, 1 equiv), azobisisobutyronitrile 5 (0.098 g, 0.6 mmol, 3 equiv), and CuBr2 (0.018 g, 0.08 mmol, 0.4 equiv) and dissolve them in 1 mL of 2-butanol. Heat the mixture to 90 °C under a nitrogen atmosphere and monitor the reaction by TLC until complete. After the reaction, the crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 10:1) to obtain compound 2a (33 mg). The yield was 59%.

[0052] (8) Weigh out N-(quinolin-8-yl)-3-butenamide 1a (0.042 g, 0.2 mmol, 1 equiv), azobisisobutyronitrile 5 (0.098 g, 0.6 mmol, 3 equiv), and Cu(OAc)₂·H₂O (0.016 g, 0.08 mmol, 0.4 equiv) and dissolve them in 1 mL of acetonitrile. Heat the mixture to 90 °C under a nitrogen atmosphere and monitor the reaction by TLC until complete. After the reaction, the crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 10:1) to obtain compound 2a (36 mg). The yield was 65%.

[0053] (9) Weigh N-(quinolin-8-yl)-3-butenamide 1a (0.042 g, 0.2 mmol, 1 equiv), azobisisobutyronitrile 5 (0.098 g, 0.6 mmol, 3 equiv), and Cu(OAc)₂·H₂O (0.016 g, 0.08 mmol, 0.4 equiv) and dissolve them in 1 mL of 1,2-dichloroethane. Heat the mixture to 90 °C under a nitrogen atmosphere and monitor the reaction by TLC until complete. After the reaction, the crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 10:1) to obtain compound 2a (16 mg). The yield was 28%.

[0054] (10) Weigh N-(quinolin-8-yl)-3-butenamide 1a (0.042 g, 0.2 mmol, 1 equiv), azobisisobutyronitrile 5 (0.098 g, 0.6 mmol, 3 equiv), and Cu(OAc)₂·H₂O (0.016 g, 0.08 mmol, 0.4 equiv) and dissolve them in 1 mL of methanol. Heat the mixture to 90 °C under a nitrogen atmosphere and monitor the reaction by TLC until complete. After the reaction, the crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 10:1) to obtain compound 2a (38 mg), with a yield of 67%.

[0055] The above compound 2a was characterized by NMR and mass spectrometry, and the results are as follows:

[0056] 1 H NMR(400MHz,Chloroform-d)δ10.00(s,1H),8.78–8.68(m,2H),8.12(dd,J=8.3,1.7Hz,1H),7.53–7.45(m,2H),7.42(dd, J=8.3,4.2Hz,1H),6.15(dt,J=15.5,7.2Hz,1H),5.73(dt,J=15.5,1.3Hz,1H),3.32(dd,J=7.2,1.3Hz,2H),1.54(s,6H).

[0057] 13 C NMR(101MHz,Chloroform-d)δ168.44,148.20,138.39,136.85,136.42,134.15, 127.93,127.35,123.39,123.33,121.80,121.71,116.39,41.19,34.74,27.37.

[0058] HRMS (ESI-TOF): m / z Calcd for C 17 H 18 N3O + [M+H + ]:280.1444; found:280.1447.

[0059] Example 2

[0060] The preparation method of (E)-5-cyano-2,5-dimethyl-N-(quinolin-8-yl)hexyl-3-enamide (2b) includes the following steps:

[0061]

[0062] 8-Aminoquinoline 3a (1.4 g, 10 mmol, 1 equiv), 2-methyl-3-butenoic acid 4b (1.20 g, 12 mmol, 1.2 equiv), and HATU (4.94 g, 13 mmol, 1.3 equiv) were weighed and dissolved in 30 mL of dichloromethane. After stirring at room temperature for 3–5 min, pyridine (1.6 g, 20 mmol, 2 equiv) was added, and the reaction was continued for 24 h. After the reaction was completed, dichloromethane was added for dilution. The reaction system was washed with saturated sodium bicarbonate solution, and the organic phase was collected and dried over anhydrous sodium sulfate. The solvent was concentrated under reduced pressure, and the mixture was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 10:1) to give compound 1b (0.32 g), with a yield of 14%.

[0063] The above compound 1b was characterized by NMR and mass spectrometry, and the results are as follows:

[0064] 1 H NMR(400MHz,Chloroform-d)δ10.02(s,1H),8.80–8.73(m,2H),8.10(dd,J=8.3,1.7Hz,1H),7.53–7.43(m,2H),7.40(dd,J=8.2,4.2Hz,1H) ,6.10(ddd,J=17.1,10.2,7.8Hz,1H),5.38(dt,J=17.1,1.3Hz,1H),5.29(dt,J=10.2,1.1Hz,1H),3.43–3.27(m,1H),1.44(d,J=7.0Hz,3H).

[0065] 13 C NMR (101MHz, Chloroform-d) δ172.57,148.26,138.58,138.03,136.35,134.53,127.96,127.39,121.60,121.55,117.33,116.42,47.03,17.01.

[0066] HRMS (ESI-TOF): m / z Calcd for C 14 H 15 N2O + [M+H + ]:227.1179; found:227.1177.

[0067]

[0068] 2-Methyl-N-(quinolin-8-yl)but-3-enamide 1b (0.045 g, 0.2 mmol, 1 equiv), azobisisobutyronitrile 5 (0.098 g, 0.6 mmol, 3 equiv), and Cu(OAc)₂·H₂O (0.016 g, 0.08 mmol, 0.4 equiv) were dissolved in 1 mL of 2-butanol. The mixture was heated to 90 °C under a nitrogen atmosphere, and the reaction was monitored by TLC until complete. After the reaction, the crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 10:1) to give compound 2b (49 mg), with a yield of 78%.

[0069] The above compound 2b was characterized by NMR and mass spectrometry, and the results are as follows:

[0070] 1 H NMR(400MHz,Chloroform-d)δ10.08(s,1H),8.78–8.71(m,2H),8.14(dd,J=8.3,1.7Hz,1H),7.55–7.46(m,2H),7.43(dd,J=8.3,4.2Hz,1 H),6.11(dd,J=15.6,8.2Hz,1H),5.74(dd,J=15.5,1.0Hz,1H),3.36(tt,J=8.1,6.5Hz,1H),1.54(d,J=9.9Hz,6H),1.46(d,J=7.0Hz,3H).

[0071] 13 C NMR(101MHz,Chloroform-d)δ171.74,148.20,138.54,136.46,134.42,134.33,13 0.32,127.99,127.43,123.42,121.72,116.38,45.37,34.72,27.48,27.40,17.10.

[0072] HRMS (ESI-TOF): m / z Calcd for C 18 H 20 N3O + [M+H + ]:294.1601; found:294.1607.

[0073] Example 3

[0074] The preparation method of (E)-5-cyano-2-ethyl-5-methyl-N-(quinolin-8-yl)hexyl-3-enamide includes the following steps:

[0075]

[0076] 8-Aminoquinoline 3a (1.4 g, 10 mmol, 1 equiv), 2-ethyl-3-butenoic acid 4c (1.37 g, 12 mmol, 1.2 equiv), and HATU (4.94 g, 13 mmol, 1.3 equiv) were weighed and dissolved in 30 mL of dichloromethane. After stirring at room temperature for 3–5 min, pyridine (1.6 g, 20 mmol, 2 equiv) was added, and the reaction was continued for 24 h. After the reaction was completed, dichloromethane was added for dilution. The reaction system was washed with saturated sodium bicarbonate solution, and the organic phase was collected and dried over anhydrous sodium sulfate. The solvent was concentrated under reduced pressure, and the compound 1c (0.83 g) was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 10:1) to obtain compound 1c (0.83 g), with a yield of 35%.

[0077] The above compound 1c was characterized by NMR and mass spectrometry, and the results are as follows:

[0078] 1 H NMR(400MHz,Chloroform-d)δ9.97(s,1H),8.83–8.71(m,2H),8.08(dt,J=8.3,1.6Hz,1H),7.52–7.41(m,2H),7.39(ddd,J=8.3,4.2,1.5Hz,1H),6.01(ddd ,J=17.1,10.2,8.7Hz,1H),5.41–5.21(m,2H),3.15–3.01(m,1H),2.03(ddd, J=14.0,7.5,6.6Hz,1H),1.72(dt,J=13.6,7.4Hz,1H),1.00(t,J=7.5Hz,3H).

[0079] 13 C NMR(101MHz,Chloroform-d)δ172.12,148.21,138.50,136.82,136.28,134.49,127.91,127.33,121.56,121.50,118.15,116.39,55.09,25.12,11.82.

[0080] HRMS (ESI-TOF): m / z Calcd for C 15 H 16 N2NaO + [M+Na + ]:263.1155; found:263.1162.

[0081]

[0082] 2-Ethyl-N-(quinolin-8-yl)but-3-enamide 1c (0.048 g, 0.2 mmol, 1 equiv), azobisisobutyronitrile 5 (0.098 g, 0.6 mmol, 3 equiv), and Cu(OAc)₂·H₂O (0.016 g, 0.08 mmol, 0.4 equiv) were weighed and dissolved in 1 mL of 2-butanol. The mixture was heated to 90 °C under a nitrogen atmosphere, and the reaction was monitored by TLC until complete. After the reaction, the crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 10:1) to give compound 2c (49 mg), with a yield of 78%.

[0083] The above compound 2c was characterized by NMR and mass spectrometry, and the results are as follows:

[0084] 1 H NMR(400MHz,Chloroform-d)δ10.02(s,1H),8.81–8.69(m,2H),8.13(dt,J=8.3 ,1.5Hz,1H),7.54–7.46(m,2H),7.43(ddd,J=8.3,4.2,1.2Hz,1H),6.04(dd,J= 15.5,8.8Hz,1H),5.71(dd,J=15.5,0.9Hz,1H),3.19–3.00(m,1H),2.06(ddd,J =13.8,7.6,6.4Hz,1H),1.81–1.67(m,1H),1.51(s,6H),1.00(t,J=7.4Hz,3H).

[0085] 13 C NMR(101MHz,Chloroform-d)δ171.34,148.23,138.52,136.42,135.21,134.32,129.0 3,127.97,127.40,123.43,121.71,116.41,53.09,34.72,27.56,27.38,25.11,11.85.

[0086] HRMS (ESI-TOF): m / z Calcd for C 19 H 21 N3NaO + [M+Na + ]:330.1577; found:330.1557.

[0087] Example 4

[0088] The method for synthesizing (E)-2-butyl-5-cyano-5-methyl-N-(quinolin-8-yl)hexyl-3-enamide (2d) includes the following steps:

[0089]

[0090] 8-Aminoquinoline 3a (1.4 g, 10 mmol, 1 equiv), 2-n-butyl-3-butenoic acid 4d (1.71 g, 12 mmol, 1.2 equiv), and HATU (4.94 g, 13 mmol, 1.3 equiv) were weighed and dissolved in 30 mL of dichloromethane. After stirring at room temperature for 3–5 min, pyridine (1.6 g, 20 mmol, 2 equiv) was added, and the reaction was continued for 24 h. After the reaction was completed, dichloromethane was added for dilution. The reaction system was washed with saturated sodium bicarbonate solution, and the organic phase was collected and dried over anhydrous sodium sulfate. The solvent was concentrated under reduced pressure, and the compound 1d (0.72 g) was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 10:1) to obtain compound 1d (0.72 g), with a yield of 27%.

[0091] The above compound 1d was characterized by NMR and mass spectrometry, and the results are as follows:

[0092] 1 H NMR(400MHz,Chloroform-d)δ9.97(s,1H),8.83–8.74(m,2H),8.10(dd,J=8.3,1.7Hz,1H),7.54–7.43(m,2H),7.40(dd,J=8.3,4.2Hz,1H),6.02(dd d,J=17.2,10.1,8.6Hz,1H),5.41–5.21(m,2H),3.17(q,J=7.7Hz,1H),2. 05–1.93(m,1H),1.76–1.61(m,1H),1.46–1.27(m,4H),0.94–0.85(m,3H).

[0093] 13 C NMR(101MHz,Chloroform-d)δ172.26,148.25,138.56,137.17,136.32,134.56,12 7.95,127.39,121.59,121.51,117.95,116.43,53.55,31.71,29.47,22.64,14.03.

[0094] HRMS (ESI-TOF): m / z Calcd for C 17 H 20 N2NaO + [M+Na+ ]:291.1468; found:291.1470.

[0095]

[0096] N-(quinolin-8-yl)-2-vinylhexamide 1d (0.054 g, 0.2 mmol, 1 equiv), azobisisobutyronitrile 5 (0.098 g, 0.6 mmol, 3 equiv), and Cu(OAc)₂·H₂O (0.016 g, 0.08 mmol, 0.4 equiv) were weighed and dissolved in 1 mL of 2-butanol. The mixture was heated to 90 °C under a nitrogen atmosphere, and the reaction was monitored by TLC until complete. After the reaction, the crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 10:1) to give compound 2d (46 mg), with a yield of 68%.

[0097] The above compound 2d was characterized by NMR and mass spectrometry, and the results are as follows:

[0098] 1 H NMR(400MHz,Chloroform-d)δ10.02(s,1H),8.85–8.68(m,2H),8.15(dd,J=8.3, 1.7Hz,1H),7.56–7.47(m,2H),7.44(dd,J=8.3,4.2Hz,1H),6.05(dd,J=15.5,8. 8Hz,1H),5.71(dd,J=15.5,0.9Hz,1H),3.28–3.08(m,1H),2.09–1.97(m,1H),1. 74–1.63(m,1H),1.52(d,J=9.4Hz,6H),1.42–1.30(m,4H),0.91(t,J=6.9Hz,3H).

[0099] 13 C NMR(101MHz,Chloroform-d)δ171.50,148.25,138.56,136.49,134.95,134.38,129.40,128. 03,127.47,123.47,121.73,116.49,51.61,34.75,31.71,29.52,27.60,27.41,22.64,14.04.

[0100] HRMS (ESI-TOF): m / z Calcd for C 21 H 25 N3NaO + [M+Na +]:358.1890; found:358.1893.

[0101] Example 5

[0102] The preparation method of (E)-5-cyano-2-(cyclopropylmethyl)-5-methyl-N-(quinolin-8-yl)hexyl-3-enamide includes the following steps:

[0103]

[0104]

[0105] 8-Aminoquinoline 3a (1.4 g, 10 mmol, 1 equiv), 2-cyclopropylmethyl-3-butenoic acid 4e (1.68 g, 12 mmol, 1.2 equiv), and HATU (4.94 g, 13 mmol, 1.3 equiv) were weighed and dissolved in 30 mL of dichloromethane. After stirring at room temperature for 3–5 min, pyridine (1.6 g, 20 mmol, 2 equiv) was added, and the reaction was continued for 24 h. After the reaction was completed, dichloromethane was added for dilution. The reaction system was washed with saturated sodium bicarbonate solution, and the organic phase was collected and dried over anhydrous sodium sulfate. The solvent was concentrated under reduced pressure, and the compound 1e (0.95 g) was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 10:1) to obtain compound 1e (0.95 g), with a fraction and yield of 36%.

[0106] The above compound 1e was characterized by NMR and mass spectrometry, and the results are as follows:

[0107] 1 H NMR(400MHz,Chloroform-d)δ9.98(s,1H),8.81–8.76(m,1H),8.74(td,J=4.2,2.1Hz,1H),8.02(td,J=8.5,1.8Hz,1H),7. 48–7.42(m,1H),7.39(dd,J=7.8,6.4Hz,1H),7.33(td,J=8.1,4.3Hz,1H),6.06(dddd,J=17.1,10.2,9.2,2.6Hz,1H),5.34 (ddd,J=17.1,3.1,1.6Hz,1H),5.25(dq,J=10.2,1.5Hz,1H),3.29(qd,J=7.3,2.6Hz,1H),1.81(dtd,J=14.3,7.3,2.5Hz,1 H),1.65(dtd,J=13.8,6.9,3.0Hz,1H),0.77(qdt,J=11.3,7.8,4.0Hz,1H),0.49–0.34(m,2H),0.10(dq,J=5.1,3.7Hz,2H).

[0108] 13 C NMR(101MHz,Chloroform-d)δ171.98,148.10,138.37,137.00,136.14,134.41,1 27.78,127.20,121.44,121.39,117.65,116.26,53.81,37.22,8.97,4.68,4.57.

[0109] HRMS (ESI-TOF): m / z Calcd for C 17 H 18 N2NaO + [M+Na + ]:289.1311; found:289.1316.

[0110]

[0111] Weigh 0.053 g (0.2 mmol, 1 equiv) of 2-(cyclopropylmethyl)-N-(quinolin-8-yl)but-3-enamide 1e, 0.098 g (0.6 mmol, 3 equiv) of azobisisobutyronitrile 5, and 0.016 g (0.08 mmol, 0.4 equiv) of Cu(OAc)₂·H₂O, and dissolve them in 1 mL of 2-butanol. The mixture was heated to 90 °C under a nitrogen atmosphere, and the reaction was monitored by TLC until complete. After the reaction, the crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 10:1) to give compound 2e (48 mg), with a yield of 72%.

[0112] The above compound 2e was characterized by NMR and mass spectrometry, and the results are as follows:

[0113] 1H NMR (400MHz, Chloroform-d) δ10.05 (s, 1H), 8.76 (ddd, J=9.0, 5.7, 1.9Hz, 2H), 8.13 (dd, J=8. 3,1.7Hz,1H),7.54–7.46(m,2H),7.43(dd,J=8.3,4.2Hz,1H),6.12(dd,J=15.5,8.8Hz,1H),5 .74(dd,J=15.5,0.8Hz,1H),3.38–3.27(m,1H),1.89–1.82(m,1H),1.73–1.65(m,1H),1.53(s ,3H),1.50(s,3H),0.76(ddt,J=10.3,7.6,3.8Hz,1H),0.53–0.38(m,2H),0.19–0.07(m,2H).

[0114] 13 C NMR(101MHz,Chloroform-d)δ171.34,148.23,138.52,136.41,134.72,134.34,129.35,127 .97,127.40,123.44,121.70,116.39,52.06,37.21,34.67,27.49,27.32,9.04,4.98,4.59.

[0115] HRMS (ESI-TOF): m / z Calcd for C 21 H 23 N3NaO + [M+Na + ]:356.1733; found:356.1734.

[0116] Example 6

[0117] The preparation method of (E)-5-cyano-2-(cyclobutylmethyl)-5-methyl-N-(quinolin-8-yl)hexyl-3-enamide (2f) includes the following steps:

[0118]

[0119] 8-Aminoquinoline 3a (1.4 g, 10 mmol, 1 equiv), 2-cyclobutylmethyl-3-butenoic acid 4f (1.85 g, 12 mmol, 1.2 equiv), and HATU (4.94 g, 13 mmol, 1.3 equiv) were weighed and dissolved in 30 mL of dichloromethane. After stirring at room temperature for 3–5 min, pyridine (1.6 g, 20 mmol, 2 equiv) was added, and the reaction was continued for 24 h. After the reaction was completed, dichloromethane was added for dilution. The reaction system was washed with saturated sodium bicarbonate solution, and the organic phase was collected and dried over anhydrous sodium sulfate. The solvent was concentrated under reduced pressure, and the compound 1f (1.05 g) was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 10:1) to obtain compound 1f (1.05 g), with a yield of 38%.

[0120] The above compound 1f was characterized by NMR and mass spectrometry, and the results are as follows:

[0121] 1 H NMR(400MHz,Chloroform-d)δ9.94(s,1H),8.82–8.75(m,2H),8.11(dd,J=8.3,1.7Hz,1H), 7.54–7.44(m,2H),7.41(dd,J=8.3,4.2Hz,1H),6.01(ddd,J=17.1,10.1,8.6Hz,1H),5.38–5 .19(m,2H),3.12(q,J=7.7Hz,1H),2.41(hept,J=7.9Hz,1H),2.09(ddd,J=15.2,10.3,6.6H z,2H),2.02(ddd,J=11.5,7.4,3.8Hz,1H),1.89–1.75(m,3H),1.69(tt,J=10.9,8.4Hz,2H).

[0122] 13 C NMR(101MHz,Chloroform-d)δ172.21,148.26,138.56,137.17,136.37,134.57,127.9 9,127.43,121.61,121.53,117.72,116.48,51.77,39.29,34.00,28.59,28.32,18.55.

[0123] HRMS (ESI-TOF): m / z Calcd for C 18 H 20 N2NaO + [M+Na + ]:303.1468; found:303.1474.

[0124]

[0125] 2-(cyclobutylmethyl)-N-(quinolin-8-yl)but-3-enamide 1f (0.056 g, 0.2 mmol, 1 equiv), azobisisobutyronitrile 5 (0.098 g, 0.6 mmol, 3 equiv), and Cu(OAc)₂·H₂O (0.016 g, 0.08 mmol, 0.4 equiv) were dissolved in 1 mL of 2-butanol. The mixture was heated to 90 °C under a nitrogen atmosphere, and the reaction was monitored by TLC until complete. After the reaction, the crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 10:1) to give compound 2f (45 mg), with a yield of 65%.

[0126] The above compound 2f was characterized by NMR and mass spectrometry, and the results are as follows:

[0127] 1 H NMR(400MHz,Chloroform-d)δ9.99(s,1H),8.80–8.72(m,2H),8.14(dd,J=8.3,1.7Hz,1H),7.55 –7.46(m,2H),7.43(dd,J=8.3,4.2Hz,1H),6.03(dd,J=15.5,8.8Hz,1H),5.68(dd,J=15.5,0.8H z,1H),3.13(td,J=8.3,6.2Hz,1H),2.38(hept,J=7.9Hz,1H),2.17–2.06(m,2H),2.02(ddt,J=1 1.5,7.7,3.6Hz,1H),1.89–1.77(m,3H),1.69(dq,J=10.3,8.7Hz,2H),1.53(s,3H),1.50(s,3H).

[0128] 13 C NMR(101MHz,Chloroform-d)δ171.36,148.22,138.51,136.44,134.59,134.34,129.41,127.99, 127.42,123.41,121.70,116.43,49.98,39.14,34.66,34.08,28.73,28.26,27.48,27.31,18.55.

[0129] HRMS (ESI-TOF): m / z Calcd for C 22 H 25 N3NaO + [M+Na+ ]:370.1890; found:370.1889.

[0130] Example 7

[0131] The preparation method of (E)-5-cyano-2-isopropyl-5-methyl-N-(quinolin-8-yl)hexyl-3-enamide (2g) includes the following steps:

[0132]

[0133] 1.4 g (10 mmol, 1 equiv) of 8-aminoquinoline 3a, 4 g (1.54 g, 12 mmol, 1.2 equiv) of 2-isopropyl-3-butenoic acid, and 4.94 g (13 mmol, 1.3 equiv) of HATU were weighed and dissolved in 30 mL of dichloromethane. After stirring at room temperature for 3–5 min, pyridine (1.6 g, 20 mmol, 2 equiv) was added and the reaction was continued for 24 h. After the reaction was completed, dichloromethane was added for dilution. The reaction system was washed with saturated sodium bicarbonate solution, and the organic phase was collected and dried over anhydrous sodium sulfate. The solvent was concentrated under reduced pressure, and the compound was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 10:1) to give 1 g (0.82 g) of the compound, with a yield of 32%.

[0134] The above compound was characterized by NMR and mass spectrometry, and the results are as follows:

[0135] 1 H NMR (400MHz, Chloroform-d) δ9.91 (s, 1H), 8.80 (dd, J = 7.5, 1.5Hz, 1H), 8.76 (d d,J=4.2,1.7Hz,1H),8.06(dt,J=8.3,1.5Hz,1H),7.51–7.40(m,2H),7.37(dd, J=8.3,4.2Hz,1H),6.03(ddd,J=17.0,10.2,9.4Hz,1H),5.35–5.23(m,2H),2.9 2–2.78(m,1H),2.32–2.22(m,1H),1.03(d,J=6.7Hz,3H),0.98(d,J=6.7Hz,3H).

[0136] 13 C NMR(101MHz,Chloroform-d)δ172.06,148.17,138.44,136.25,135.75,134.45 ,127.88,127.31,121.54,121.47,118.73,116.39,61.37,30.30,21.02,19.71.

[0137] HRMS (ESI-TOF): m / z Calcd for C 16 H 18 N2NaO + [M+Na + ]:277.1311; found:277.1317.

[0138]

[0139] 1 g (0.051 g, 0.2 mmol, 1 equiv) of 2-isopropyl-N-(quinoline-8-yl)but-3-enamide, 5 g (0.098 g, 0.6 mmol, 3 equiv) of azobisisobutyronitrile, and 0.016 g (0.08 mmol, 0.4 equiv) of Cu(OAc)₂·H₂O were dissolved in 1 mL of 2-butanol. The mixture was heated to 90 °C under a nitrogen atmosphere, and the reaction was monitored by TLC until complete. After the reaction, the crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 10:1) to give 2 g (44 mg) of the compound, with a yield of 69%.

[0140] The above compound 2g was characterized by NMR and mass spectrometry, and the results are as follows:

[0141] 1 H NMR(400MHz,Chloroform-d)δ9.95(s,1H),8.82–8.71(m,2H),8.13(dd,J=8.2,1 .7Hz,1H),7.54–7.46(m,2H),7.43(dd,J=8.3,4.2Hz,1H),6.08(dd,J=15.5,9.5 Hz,1H),5.67(d,J=15.5Hz,1H),2.89(dd,J=9.5,7.6Hz,1H),2.40–2.26(m,J=6. 8Hz,1H),1.51(s,3H),1.49(s,3H),1.03(d,J=6.7Hz,3H),0.98(d,J=6.8Hz,3H).

[0142] 13 C NMR(101MHz,Chloroform-d)δ171.31,148.24,138.47,136.44,135.67,134.29,127.98,1 27.76,127.40,123.46,121.71,116.48,59.06,34.69,30.45,27.60,27.35,21.08,19.58.

[0143] HRMS (ESI-TOF): m / z Calcd for C 20 H 24 N3O + [M+H + ]:322.1914; found:322.1919.

[0144] Example 8

[0145] The preparation method of (E)-5-cyano-2-cyclopentyl-5-methyl-N-(quinolin-8-yl)hexyl-3-enamide (2h) includes the following steps:

[0146]

[0147] 1.4 g (10 mmol, 1 equiv) of 8-aminoquinoline 3a, 1.85 g (12 mmol, 1.2 equiv) of 2-cyclopentyl-3-butenoic acid 4h, and 4.94 g (13 mmol, 1.3 equiv) of HATU were weighed and dissolved in 30 mL of dichloromethane. After stirring at room temperature for 3–5 min, pyridine (1.6 g, 20 mmol, 2 equiv) was added and the reaction was continued for 24 h. After the reaction was completed, dichloromethane was added for dilution. The reaction system was washed with saturated sodium bicarbonate solution, and the organic phase was collected and dried over anhydrous sodium sulfate. The solvent was concentrated under reduced pressure, and the compound 1h (0.48 g) was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 10:1) to obtain compound 1h (0.48 g), with a yield of 17%.

[0148] The above compounds were characterized by NMR and mass spectrometry after 1 hour, and the results are as follows:

[0149] 1 H NMR(400MHz,Chloroform-d)δ9.90(s,1H),8.86–8.75(m,2H),8.14(dd,J=8.2,1.7Hz,1 H),7.55–7.46(m,2H),7.44(dd,J=8.3,4.2Hz,1H),6.05(ddd,J=17.1,10.2,9.0Hz,1H) ,5.31(ddd,J=17.1,1.6,0.8Hz,1H),5.22(dd,J=10.1,1.6Hz,1H),2.97(t,J=9.2Hz,1H ), 2.42(qt,J=9.0,7.4Hz,1H),1.92–1.78(m,2H),1.70–1.51(m,4H),1.39–1.22(m,2H).

[0150] 13C NMR(101MHz,Chloroform-d)δ172.36,148.29,138.58,136.76,136.47,134.63,128.0 5,127.53,121.67,121.54,117.77,116.58,59.74,42.11,31.11,30.50,25.32,25.12.

[0151] HRMS (ESI-TOF): m / z Calcd for C 18 H 21 N2O + [M+H + ]:281.1648; found:281.1652.

[0152]

[0153] 2-Cyclopentyl-N-(quinolin-8-yl)but-3-enamide 1h (0.056 g, 0.2 mmol, 1 equiv), azobisisobutyronitrile 5 (0.098 g, 0.6 mmol, 3 equiv), and Cu(OAc)₂·H₂O (0.016 g, 0.08 mmol, 0.4 equiv) were dissolved in 1 mL of 2-butanol. The mixture was heated to 90 °C under a nitrogen atmosphere, and the reaction was monitored by TLC until complete. After the reaction, the crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 10:1) to give compound 2h (42 mg), with a yield of 61%.

[0154] The above compounds were characterized by NMR and mass spectrometry after 2 hours, and the results are as follows:

[0155] 1H NMR(400MHz,Chloroform-d)δ9.93(s,1H),8.79(dd,J=4.3,1.7Hz,1H),8.76(dd,J=7.0,2.0Hz,1H),8.15(dd,J=8.3, 1.7Hz,1H),7.56–7.47(m,2H),7.44(dd,J=8.3,4.2Hz,1H),6.08(dd,J=15.5,9.1Hz,1H),5.67(dd,J=15.5,0.7Hz,1H) ,2.98(t,J=9.1Hz,1H),2.42(qt,J=9.1,7.4Hz,1H),1.90–1.78(m,2H),1.64(tdd,J=7.5,3.5,1.9Hz,2H),1.57(dddd ,J=12.0,8.0,5.2,3.4Hz,2H),1.49(s,3H),1.48(s,3H),1.38–1.29(m,1H),1.25(dddd,J=13.7,7.7,3.3,1.6Hz,1H).

[0156] 13 C NMR(101MHz,Chloroform-d)δ171.54,148.26,138.50,136.50,134.46,134.39,128.87,128.03,127. 46,123.51,121.72,121.70,116.57,57.51,42.26,34.64,31.09,30.43,27.61,27.37,25.22,25.04.

[0157] HRMS (ESI-TOF): m / z Calcd for C 22 H 25 N3NaO + [M+Na + ]:370.1890; found:370.1896.

[0158] Example 9

[0159] The preparation method of (E)-5-cyano-2-cyclohexyl-5-methyl-N-(quinolin-8-yl)hexyl-3-enamide (2i) includes the following steps:

[0160]

[0161] 8-Aminoquinoline 3a (1.4 g, 10 mmol, 1 equiv), 2-cyclohexyl-3-butenoic acid 4i (2.02 g, 12 mmol, 1.2 equiv), and HATU (4.94 g, 13 mmol, 1.3 equiv) were weighed and dissolved in 30 mL of dichloromethane. After stirring at room temperature for 3–5 min, pyridine (1.6 g, 20 mmol, 2 equiv) was added, and the reaction was continued for 24 h. After the reaction was completed, dichloromethane was added for dilution. The reaction system was washed with saturated sodium bicarbonate solution, and the organic phase was collected and dried over anhydrous sodium sulfate. The solvent was concentrated under reduced pressure, and the compound 1i (0.35 g) was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 10:1) in a fractional yield of 12%.

[0162] The above compound 1i was characterized by NMR and mass spectrometry, and the results are as follows:

[0163] 1 H NMR(400MHz,Chloroform-d)δ9.89(s,1H),8.84–8.76(m,2H),8.13(dd,J=8.3,1.7Hz,1H), 7.54–7.45(m,2H),7.43(dd,J=8.2,4.2Hz,1H),6.03(ddd,J=17.0,10.2,9.4Hz,1H),5.32–5 .21(m,2H),2.89(t,J=8.9Hz,1H),1.94(tdd,J=11.0,5.6,2.4Hz,1H),1.89–1.78(m,2H),1. 77–1.60(m,3H),1.36–1.22(m,2H),1.21–1.05(m,2H),0.97(tdd,J=12.6,11.4,3.5Hz,1H).

[0164] 13 C NMR(101MHz,Chloroform-d)δ172.19,148.28,138.56,136.41,136.03,134.54,128.0 2,127.48,121.65,121.56,118.50,116.52,60.82,39.81,31.56,30.33,26.45,26.29.

[0165] HRMS (ESI-TOF): m / z Calcd for C 19 H 23 N2O + [M+H + ]:295.1805;found:295.1812

[0166]

[0167] 0.059 g (0.2 mmol, 1 equiv) of 2-cyclohexyl-N-(quinolin-8-yl)but-3-enamide 1i, 0.098 g (0.6 mmol, 3 equiv) of azobisisobutyronitrile 5, and 0.016 g (0.08 mmol, 0.4 equiv) of Cu(OAc)₂·H₂O were dissolved in 1 mL of 2-butanol. The mixture was heated to 90 °C under a nitrogen atmosphere, and the reaction was monitored by TLC until complete. After the reaction, the crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 10:1) to give compound 2i (39 mg), with a yield of 54%.

[0168] The above compound 2i was characterized by NMR and mass spectrometry, and the results are as follows:

[0169] 1 H NMR(400MHz,Chloroform-d)δ9.93(s,1H),8.82–8.75(m,2H),8.15(dd,J=8.3,1.7Hz,1H),7.56 –7.48(m,2H),7.45(dd,J=8.3,4.2Hz,1H),6.07(dd,J=15.5,9.5Hz,1H),5.64(dd,J=15.5,0.6Hz ,1H),2.91(dd,J=9.5,8.0Hz,1H),1.97(tdt,J=11.5,7.9,3.3Hz,1H),1.85–1.74(m,3H),1.73– 1.62(m,2H),1.50(s,3H),1.49(s,3H),1.36–1.22(m,2H),1.21–1.06(m,2H),1.06–0.92(m,1H).

[0170] 13 C NMR(101MHz,Chloroform-d)δ171.40,148.27,138.51,136.52,135.25,134.33,128.13,128.05, 127.49,123.57,121.74,116.57,58.60,40.01,34.67,31.62,30.22,27.68,27.37,26.35,26.27.

[0171] HRMS (ESI-TOF): m / z Calcd for C 23 H 28 N3O + [M+H +]:362.2227;found:362.2229.

[0172] Example 10

[0173] The preparation method of (E)-2-benzyl-5-cyano-5-methyl-N-(quinolin-8-yl)hexyl-3-enamide (2j) includes the following steps:

[0174]

[0175] 8-Aminoquinoline 3a (1.4 g, 10 mmol, 1 equiv), 2-benzyl-3-butenoic acid 4j (2.11 g, 12 mmol, 1.2 equiv), and HATU (4.94 g, 13 mmol, 1.3 equiv) were weighed and dissolved in 30 mL of dichloromethane. After stirring at room temperature for 3–5 min, pyridine (1.6 g, 20 mmol, 2 equiv) was added, and the reaction was continued for 24 h. After the reaction was completed, dichloromethane was added for dilution. The reaction system was washed with saturated sodium bicarbonate solution, and the organic phase was collected and dried over anhydrous sodium sulfate. The solvent was concentrated under reduced pressure, and the compound 1j (0.62 g) was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 10:1) to obtain compound 1j (0.62 g), with a yield of 21%.

[0176] The above compound 1j was characterized by NMR and mass spectrometry, and the results are as follows:

[0177] 1 H NMR(400MHz,Chloroform-d)δ9.81(s,1H),8.68(dd,J=7.6,1.5Hz,1H),8.61(dd,J=4.3,1.7 Hz,1H),7.95(dd,J=8.3,1.7Hz,1H),7.42–7.30(m,2H),7.24(dd,J=8.3,4.3Hz,1H),7.18–7 .09(m,4H),7.04(ddt,J=8.6,5.5,2.7Hz,1H),5.94(ddd,J=17.2,10.2,8.5Hz,1H),5.24–5. 07(m,2H),3.38(q,J=7.8Hz,1H),3.27(dd,J=13.7,6.9Hz,1H),2.87(dd,J=13.7,7.6Hz,1H).

[0178] 13C NMR(101MHz,Chloroform-d)δ171.26,148.19,139.19,138.48,136.35,136.28,134.42, 129.26,128.38,127.91,127.35,126.33,121.62,121.57,118.71,116.47,55.14,38.16.

[0179] HRMS (ESI-TOF): m / z Calcd for C 20 H 18 N2NaO + [M+Na + ]:325.1311; found:325.1307.

[0180]

[0181] 2-Benzyl-N-(quinolin-8-yl)but-3-enamide 1j (0.060 g, 0.2 mmol, 1 equiv), azobisisobutyronitrile 5 (0.098 g, 0.6 mmol, 3 equiv), and Cu(OAc)₂·H₂O (0.016 g, 0.08 mmol, 0.4 equiv) were dissolved in 1 mL of 2-butanol. The mixture was heated to 90 °C under a nitrogen atmosphere, and the reaction was monitored by TLC until complete. After the reaction, the crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 10:1) to give compound 2j (50 mg), with a yield of 68%.

[0182] The above compound 2j was characterized by NMR and mass spectrometry, and the results are as follows:

[0183] 1 H NMR(400MHz,Chloroform-d)δ9.92(s,1H),8.74–8.59(m,2H),8.04(dd,J=8.3,1.7Hz,1H),7.48–7.38(m,2H),7.33(dd,J=8.3,4.2Hz,1H),7. 20–7.05(m,5H),6.02–5.92(m,1H),5.41(dd,J=15.5,0.7Hz,1H),3.41–3.28(m,2H),2.88(tt,J=10.5,3.5Hz,1H),1.35(s,3H),1.27(s,3H).

[0184] 13C NMR(101MHz,Chloroform-d)δ170.54,148.22,138.81,138.47,136.41,135.77,134.22,129.39,128.43 ,128.31,127.96,127.39,126.48,123.25,121.82,121.71,116.48,53.43,38.11,34.65,27.35,27.25.

[0185] HRMS (ESI-TOF): m / z Calcd for C 24 H 23 N3NaO + [M+Na + ]:392.1733; found:392.1731.

[0186] Example 11

[0187] The preparation method of (E)-5-cyano-5-methyl-2-(2-methylbenzyl)-N-(quinolin-8-yl)hexyl-3-enamide (2k) includes the following steps:

[0188]

[0189] 8-Aminoquinoline 3a (1.4 g, 10 mmol, 1 equiv), 2-(2-methylbenzyl)-3-butenoic acid 4k (2.28 g, 12 mmol, 1.2 equiv), and HATU (4.94 g, 13 mmol, 1.3 equiv) were weighed and dissolved in 30 mL of dichloromethane. After stirring at room temperature for 3–5 min, pyridine (1.6 g, 20 mmol, 2 equiv) was added, and the reaction was continued for 24 h. After the reaction was completed, dichloromethane was added for dilution. The reaction system was washed with saturated sodium bicarbonate solution, and the organic phase was collected and dried over anhydrous sodium sulfate. The solvent was concentrated under reduced pressure, and the compound 1k (0.95 g) was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 10:1) to obtain compound 1k (0.95 g) in a yield of 30%.

[0190] The above compound 1k was characterized by NMR and mass spectrometry, and the results are as follows:

[0191] 1H NMR(400MHz,Chloroform-d)δ9.94(s,1H),8.81(dd,J=7.4,1.6Hz,1H),8.77(dd,J=4.2 ,1.7Hz,1H),8.13(dd,J=8.3,1.7Hz,1H),7.57–7.46(m,2H),7.42(dd,J=8.3,4.2Hz,1H) ,7.25–7.19(m,1H),7.17–7.12(m,1H),7.12–7.05(m,2H),6.11(ddd,J=17.3,9.9,8.4H z,1H),5.34–5.19(m,2H),3.55–3.36(m,2H),2.99(dd,J=13.7,7.4Hz,1H),2.40(s,3H).

[0192] 13 C NMR(101MHz,Chloroform-d)δ171.49,148.27,138.57,137.49,136.49,136.38,134.51,130.39, 129.94,128.00,127.45,126.50,125.93,121.67,121.65,118.66,116.55,54.06,35.32,19.78.

[0193] HRMS (ESI-TOF): m / z Calcd for C 21 H 20 N2NaO + [M+Na + ]:339.1468; found:339.1475.

[0194]

[0195]

[0196] Weigh out 0.063 g (0.2 mmol, 1 equiv) of 2-(2-methylbenzyl)-N-(quinolin-8-yl)but-3-enamide 1k, 0.098 g (0.6 mmol, 3 equiv) of azobisisobutyronitrile 5, and 0.016 g (0.08 mmol, 0.4 equiv) of Cu(OAc)2·H2O, and dissolve them in 1 mL of 2-butanol. Heat the mixture to 90 °C under a nitrogen atmosphere and monitor the reaction by TLC until complete. After the reaction, purify the crude product by silica gel column chromatography (petroleum ether: ethyl acetate = 10:1) to obtain compound 2k (47 mg), with a yield of 61%.

[0197] The above compound 2k was characterized by NMR and mass spectrometry, and the results are as follows:

[0198] 1 H NMR (400MHz, Chloroform-d) δ10.03 (s, 1H), 8.78 (dd, J=7.3, 1.8Hz, 1H), 8.75 (dd, J= 4.2,1.7Hz,1H),8.13(dd,J=8.3,1.7Hz,1H),7.57–7.47(m,2H),7.43(dd,J=8.3,4.2H z,1H),7.18–7.12(m,2H),7.11–7.05(m,2H),6.16–6.03(m,1H),5.45(dd,J=15.4,0.7 Hz,1H),3.52–3.39(m,2H),3.04–2.89(m,1H),2.39(s,3H),1.45(s,3H),1.36(s,3H).

[0199] 13 C NMR(101MHz,Chloroform-d)δ170.68,148.22,138.46,137.06,136.40,136.24,135.59,134.22,130.40,130.13,12 8.24,127.95,127.38,126.60,125.88,123.21,121.80,121.71,116.44,52.30,35.14,34.64,27.35,27.18,19.70.

[0200] HRMS (ESI-TOF): m / z Calcd for C 25 H 25 N3NaO + [M+Na + ]:406.1890; found:406.1894.

[0201] Example 12

[0202] The preparation method of (E)-5-cyano-5-methyl-2-(3-methylbenzyl)-N-(quinolin-8-yl)hexyl-3-enamide (2l) includes the following steps:

[0203]

[0204] 8-Aminoquinoline 3a (1.4 g, 10 mmol, 1 equiv), 2-(3-methylbenzyl)-3-butenoic acid 4l (2.28 g, 12 mmol, 1.2 equiv), and HATU (4.94 g, 13 mmol, 1.3 equiv) were weighed and dissolved in 30 mL of dichloromethane. After stirring at room temperature for 3–5 min, pyridine (1.6 g, 20 mmol, 2 equiv) was added, and the reaction was continued for 24 h. After the reaction was completed, dichloromethane was added for dilution. The reaction system was washed with saturated sodium bicarbonate solution, and the organic phase was collected and dried over anhydrous sodium sulfate. The solvent was concentrated under reduced pressure, and the compound was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 10:1) to give compound 1l (0.53 g), with a yield of 17%.

[0205] The above compound 1l was characterized by NMR and mass spectrometry, and the results are as follows:

[0206] 1 H NMR(400MHz,Chloroform-d)δ9.95(s,1H),8.83(dd,J=7.6,1.4Hz,1H),8.75(dd,J=4.3,1.7Hz,1H ),8.09(dd,J=8.2,1.8Hz,1H),7.57–7.43(m,2H),7.39(dd,J=8.2,4.2Hz,1H),7.17(t,J=7.4Hz,1 H),7.13–7.06(m,2H),6.99(d,J=7.4Hz,1H),6.10(ddd,J=17.2,10.2,8.5Hz,1H),5.39–5.24(m,2 H),3.54(q,J=7.6Hz,1H),3.39(dd,J=13.7,6.9Hz,1H),2.99(dd,J=13.7,7.6Hz,1H),2.30(s,3H).

[0207] 13 C NMR(101MHz,Chloroform-d)δ171.35,148.14,139.06,138.44,137.85,136.43,136.24,134.40,130 .01,128.25,127.87,127.31,127.07,126.23,121.58,121.54,118.57,116.45,55.11,38.14,21.40.

[0208] HRMS (ESI-TOF): m / z Calcd for C 21 H 20 N2NaO + [M+Na+ ]:339.1468; found:339.1472.

[0209]

[0210] 1 L (0.063 g, 0.2 mmol, 1 equiv) of 2-(3-methylbenzyl)-N-(quinolin-8-yl)but-3-enamide, 5 L (0.098 g, 0.6 mmol, 3 equiv) of azobisisobutyronitrile, and 0.016 g (0.08 mmol, 0.4 equiv) of Cu(OAc)₂·H₂O were dissolved in 1 mL of 2-butanol. The mixture was heated to 90 °C under a nitrogen atmosphere, and the reaction was monitored by TLC until complete. After the reaction, the crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 10:1) to give compound 2 L (41 mg), with a yield of 54%.

[0211] The above compound 2l was characterized by NMR and mass spectrometry, and the results are as follows:

[0212] 1 H NMR(400MHz,Chloroform-d)δ10.00(s,1H),8.78(dd,J=7.3,1.7Hz,1H),8.75(dd,J=4.3,1. 7Hz,1H),8.13(dd,J=8.3,1.7Hz,1H),7.57–7.46(m,2H),7.42(dd,J=8.3,4.2Hz,1H),7.16( t,J=7.5Hz,1H),7.07–6.94(m,3H),6.07(dd,J=15.5,8.7Hz,1H),5.51(dd,J=15.5,0.7Hz,1 H),3.54–3.29(m,2H),2.94(dd,J=13.2,8.2Hz,1H),2.29(s,3H),1.46(s,3H),1.39(s,3H).

[0213] 13 C NMR(101MHz,Chloroform-d)δ170.63,148.20,138.70,138.49,137.91,136.37,135.62,134.25,130.20,128.45,12 8.31,127.95,127.38,127.19,126.37,123.28,121.77,121.69,116.46,53.44,38.11,34.64,27.35,27.29,21.40.

[0214] HRMS (ESI-TOF): m / z Calcd for C 25 H 25 N3NaO + [M+Na + ]:406.1890; found:406.1892.

[0215] Example 13

[0216] The preparation method of (E)-5-cyano-5-methyl-2-(4-methylbenzyl)-N-(quinolin-8-yl)hexyl-3-enamide (2m) includes the following steps:

[0217]

[0218] 8-Aminoquinoline 3a (1.4 g, 10 mmol, 1 equiv), 2-(4-methylbenzyl)-3-butenoic acid 4m (2.28 g, 12 mmol, 1.2 equiv), and HATU (4.94 g, 13 mmol, 1.3 equiv) were weighed and dissolved in 30 mL of dichloromethane. After stirring at room temperature for 3–5 min, pyridine (1.6 g, 20 mmol, 2 equiv) was added, and the reaction was continued for 24 h. After the reaction was completed, dichloromethane was added for dilution. The reaction system was washed with saturated sodium bicarbonate solution, and the organic phase was collected and dried over anhydrous sodium sulfate. The solvent was concentrated under reduced pressure, and the compound 1m (0.97 g) was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 10:1) with a fraction and yield of 31%.

[0219] The above compound 1m was characterized by NMR and mass spectrometry, and the results are as follows:

[0220] 1 H NMR(400MHz,Chloroform-d)δ9.96(s,1H),8.83(dd,J=7.5,1.5Hz,1H),8.75(dd,J=4.2,1.7 Hz,1H),8.09(dd,J=8.2,1.7Hz,1H),7.57–7.43(m,2H),7.39(dd,J=8.3,4.2Hz,1H),7.19(d, J=8.1Hz,2H),7.08(d,J=7.8Hz,2H),6.09(ddd,J=17.2,10.2,8.5Hz,1H),5.39–5.23(m,2H) ,3.56–3.46(m,1H),3.38(dd,J=13.8,6.9Hz,1H),2.99(dd,J=13.8,7.6Hz,1H),2.29(s,3H).

[0221] 13C NMR(101MHz,Chloroform-d)δ171.35,148.15,138.46,136.44,136.24,136.03,135.72,134 .43,129.10,129.07,127.88,127.32,121.57,121.54,118.60,116.44,55.21,37.75,21.05.

[0222] HRMS (ESI-TOF): m / z Calcd for C 21 H 20 N2NaO + [M+Na + ]:339.1468; found:339.1473.

[0223]

[0224] Weigh 1m of 2-(4-methylbenzyl)-N-(quinolin-8-yl)but-3-enamide (0.063 g, 0.2 mmol, 1 equiv), 5m of azobisisobutyronitrile (0.098 g, 0.6 mmol, 3 equiv), and 0.016 g of Cu(OAc)₂·H₂O (0.08 mmol, 0.4 equiv) and dissolve them in 1 mL of 2-butanol. The mixture was heated to 90 °C under a nitrogen atmosphere, and the reaction was monitored by TLC until complete. After the reaction, the crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 10:1) to give compound 2m (46 mg), with a yield of 60%.

[0225] The above compound 2m was characterized by NMR and mass spectrometry, and the results are as follows:

[0226] 1 H NMR(400MHz,Chloroform-d)δ9.99(s,1H),8.80–8.72(m,2H),8.14(dd,J=8.2,1.7 Hz,1H),7.58–7.47(m,2H),7.43(dd,J=8.3,4.2Hz,1H),7.11(d,J=8.1Hz,2H),7.07 (d,J=8.0Hz,2H),6.06(dd,J=15.5,8.7Hz,1H),5.53(dd,J=15.6,0.7Hz,1H),3.50 –3.30(m,2H),2.94(dd,J=13.4,8.1Hz,1H),2.28(s,3H),1.46(s,3H),1.39(s,3H).

[0227] 13C NMR(101MHz,Chloroform-d)δ170.70,148.24,138.54,136.45,135.98,135.70,135.59,134.31,129.29,12 9.15,128.53,128.01,127.46,123.35,121.81,121.73,116.54,53.56,37.80,34.70,27.40,27.33,21.10.

[0228] HRMS (ESI-TOF): m / z Calcd for C 25 H 26 N3O + [M+H + ]:384.2070; found:384.2074.

[0229] Example 14

[0230] The preparation method of (E)-5-cyano-2-(4-fluorobenzyl)-5-methyl-N-(quinolin-8-yl)hex-3-enamide (2n) includes the following steps:

[0231]

[0232] 8-Aminoquinoline 3a (1.4 g, 10 mmol, 1 equiv), 2-(4-fluorobenzyl)-3-butenoic acid 4n (2.33 g, 12 mmol, 1.2 equiv), and HATU (4.94 g, 13 mmol, 1.3 equiv) were weighed and dissolved in 30 mL of dichloromethane. After stirring at room temperature for 3–5 min, pyridine (1.6 g, 20 mmol, 2 equiv) was added, and the reaction was continued for 24 h. After the reaction was completed, dichloromethane was added for dilution. The reaction system was washed with saturated sodium bicarbonate solution, and the organic phase was collected and dried over anhydrous sodium sulfate. The solvent was concentrated under reduced pressure, and the compound 1n (1.0 g) was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 10:1) to obtain compound 1n (1.0 g), with a yield of 31%.

[0233] The above compound 1n was characterized by NMR and mass spectrometry, and the results are as follows:

[0234] 1H NMR(400MHz,Chloroform-d)δ9.92(s,1H),8.79(dd,J=7.5,1.5Hz,1H),8.74(dd,J=4.3,1.7Hz,1H),8.09(dt,J=8.3,1.3Hz,1H),7.55–7.43(m,2H),7.38(dd,J=8.4,4.1Hz,1H),7.25–7.16(m,2H),6.99–6.87(m,2H),6.13–5.96(m,1H),5.39–5.18(m,2H),3.46(q,J=7.5Hz,1H),3.34(dd,J=13.8,7.0Hz,1H),2.96(dd,J=13.8,7.4Hz,1H).

[0235] 13 C NMR(101MHz,Chloroform-d)δ171.04,162.78,160.35,148.22,138.46,136.30,136.17,134.85,134.82,134.34,130.73,130.65,127.92,127.32,121.70,121.61,118.85,116.48,115.25,115.04,55.25,37.35.

[0236] 19 F NMR(376MHz,Chloroform-d)δ-116.92.

[0237] HRMS(ESI-TOF):m / z Calcd for C 20 H 17 FN2NaO + [M+Na + ]:343.1217;found:343.1223.

[0238]

[0239] Weigh 0.064 g (0.2 mmol, 1 equiv) of 2-(4-fluorobenzyl)-N-(quinolin-8-yl)but-3-enamide 1n, 0.098 g (0.6 mmol, 3 equiv) of azobisisobutyronitrile 5, and 0.016 g (0.08 mmol, 0.4 equiv) of Cu(OAc)2·H2O and dissolve them in 1 mL of 2-butanol. The mixture was heated to 90 °C under a nitrogen atmosphere, and the reaction was monitored by TLC until complete. After the reaction, the crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 10:1) to give compound 2n (40 mg), with a yield of 52%.

[0240] The above compound 2n was characterized by NMR and mass spectrometry, and the results are as follows:

[0241] 1 H NMR(400MHz,Chloroform-d)δ9.98(s,1H),8.80–8.69(m,2H),8.13(dd,J=8.3,1.7Hz,1H),7.57–7.46(m,2H),7.42(dd,J=8.3,4.2Hz,1H),7.22–7.13(m, 2H),6.99–6.90(m,2H),6.05(dd,J=15.5,8.7Hz,1H),5.52(d,J=15.5Hz,1H) ,3.48–3.31(m,2H),2.95(dt,J=13.0,6.7Hz,1H),1.46(s,3H),1.38(s,3H).

[0242] 13 C NMR(101MHz,Chloroform-d)δ170.30,162.84,160.41,148.23,138.44,136.43,135.95,134.51,134.48,134.13,130.86 ,130.78,128.20,127.96,127.36,123.19,121.89,121.74,116.48,115.32,115.10,53.45,37.27,34.69,27.33,27.30.

[0243] HRMS (ESI-TOF): m / z Calcd for C 24 H 23 FN3O + [M+H + ]:388.1820; found:388.1823.

[0244] Example 15

[0245] The preparation method of (E)-2-(4-chlorobenzyl)-5-cyano-5-methyl-N-(quinolin-8-yl)hexyl-3-enamide (2o) includes the following steps:

[0246]

[0247] 8-Aminoquinoline 3a (1.4 g, 10 mmol, 1 equiv), 2-(4-chlorobenzyl)-3-butenoic acid 4o (2.52 g, 12 mmol, 1.2 equiv), and HATU (4.94 g, 13 mmol, 1.3 equiv) were weighed and dissolved in 30 mL of dichloromethane. After stirring at room temperature for 3–5 min, pyridine (1.6 g, 20 mmol, 2 equiv) was added, and the reaction was continued for 24 h. After the reaction was completed, dichloromethane was added for dilution. The reaction system was washed with saturated sodium bicarbonate solution, and the organic phase was collected and dried over anhydrous sodium sulfate. The solvent was concentrated under reduced pressure, and the compound 1o (0.52 g) was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 10:1) to obtain compound 1o (0.52 g), with a yield of 15%.

[0248] The above compound 1o was characterized by NMR and mass spectrometry, and the results are as follows:

[0249] 1 H NMR(400MHz,Chloroform-d)δ9.92(s,1H),8.82–8.69(m,2H),8.11(dd,J=8.3,1.7Hz,1H),7.56–7.44(m,2H),7.41(dd,J=8.3,4.2Hz,1H), 7.24–7.14(m,4H),6.14–5.93(m,1H),5.36–5.22(m,2H),3.46(q,J=7.6Hz,1H),3.34(dd,J=13.8,7.0Hz,1H),2.95(dd,J=13.7,7.4Hz,1H).

[0250] 13 C NMR(101MHz,Chloroform-d)δ170.94,148.28,138.49,137.69,136.36,136.06,134.33, 132.14,130.67,128.53,127.96,127.37,121.77,121.66,119.05,116.54,55.05,37.48.

[0251] HRMS (ESI-TOF): m / z Calcd for C 20 H 17ClN2NaO + [M+Na + ]:359.0922; found:359.0928.

[0252]

[0253] Weigh out 2-(4-chlorobenzyl)-N-(quinolin-8-yl)but-3-enamide 1o (0.067 g, 0.2 mmol, 1 equiv), azobisisobutyronitrile 5 (0.098 g, 0.6 mmol, 3 equiv), and Cu(OAc)₂·H₂O (0.016 g, 0.08 mmol, 0.4 equiv) and dissolve them in 1 mL of 2-butanol. Heat the mixture to 90 °C under a nitrogen atmosphere and monitor the reaction by TLC until complete. After the reaction, purify the crude product by silica gel column chromatography (petroleum ether: ethyl acetate = 10:1) to obtain compound 2o (55 mg), with a yield of 68%.

[0254] The above compound 2o was characterized by NMR and mass spectrometry, and the results are as follows:

[0255] 1 H NMR(400MHz,Chloroform-d)δ9.98(s,1H),8.80–8.68(m,2H),8.15(dd,J=8.3 ,1.7Hz,1H),7.58–7.48(m,2H),7.44(dd,J=8.3,4.2Hz,1H),7.25–7.20(m,2H ),7.18–7.12(m,2H),6.05(dd,J=15.4,8.7Hz,1H),5.55(dd,J=15.6,0.7Hz,1 H),3.48–3.29(m,2H),2.94(dd,J=13.1,7.6Hz,1H),1.47(s,3H),1.40(s,3H).

[0256] 13 C NMR(101MHz,Chloroform-d)δ170.20,148.29,138.51,137.37,136.51,136.08,134.16,132.37,130.78 ,128.61,128.21,128.03,127.44,123.21,121.97,121.79,116.59,53.29,37.48,34.77,27.41,27.38.

[0257] HRMS (ESI-TOF): m / z Calcd for C 24 H23 ClN3O + [M+H + ]:404.1524; found:404.1521.

[0258] Example 16

[0259] The preparation method of (E)-2-(4-bromobenzyl)-5-cyano-5-methyl-N-(quinolin-8-yl)hexyl-3-enamide (2p) includes the following steps:

[0260]

[0261] 8-Aminoquinoline 3a (1.4 g, 10 mmol, 1 equiv), 2-(4-bromobenzyl)-3-butenoic acid 4p (3.05 g, 12 mmol, 1.2 equiv), and HATU (4.94 g, 13 mmol, 1.3 equiv) were weighed and dissolved in 30 mL of dichloromethane. After stirring at room temperature for 3–5 min, pyridine (1.6 g, 20 mmol, 2 equiv) was added, and the reaction was continued for 24 h. After the reaction was completed, dichloromethane was added for dilution. The reaction system was washed with saturated sodium bicarbonate solution, and the organic phase was collected and dried over anhydrous sodium sulfate. The solvent was concentrated under reduced pressure, and the compound 1p (0.36 g) was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 10:1) in a fractional yield of 10%.

[0262] The above compound 1p was characterized by NMR and mass spectrometry, and the results are as follows:

[0263] 1 H NMR(400MHz,Chloroform-d)δ9.91(s,1H),8.81–8.70(m,2H),8.13(dd,J=8.3,1.7Hz,1H),7.56–7.46(m,2H),7.42(dd,J=8.3,4.2Hz,1H),7.39–7.3 1(m,2H),7.17–7.08(m,2H),6.11–5.94(m,1H),5.36–5.22(m,2H),3.46(q ,J=7.6Hz,1H),3.32(dd,J=13.8,7.0Hz,1H),2.93(dd,J=13.8,7.4Hz,1H).

[0264] 13C NMR(101MHz,Chloroform-d)δ170.96,148.33,138.54,138.26,136.43,136.08,134.37, 131.52,131.11,128.02,127.44,121.81,121.70,120.30,119.11,116.61,55.02,37.59.

[0265] HRMS (ESI-TOF): m / z Calcd for C 20 H 18 BrN2O + [M+H + ]:381.0597;found:381.0592

[0266]

[0267] Weigh out 1p of 2-(4-bromobenzyl)-N-(quinolin-8-yl)but-3-enamide (0.076 g, 0.2 mmol, 1 equiv), 5 of azobisisobutyronitrile (0.098 g, 0.6 mmol, 3 equiv), and 0.016 g of Cu(OAc)₂·H₂O (0.08 mmol, 0.4 equiv) and dissolve them in 1 mL of 2-butanol. The mixture was heated to 90 °C under a nitrogen atmosphere, and the reaction was monitored by TLC until complete. After the reaction, the crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 10:1) to give compound 2p (52 mg), with a yield of 58%.

[0268] The above compound 2p was characterized by NMR and mass spectrometry, and the results are as follows:

[0269] 1 H NMR(400MHz,Chloroform-d)δ9.98(s,1H),8.78–8.71(m,2H),8.15(dd,J=8.3 ,1.7Hz,1H),7.58–7.48(m,2H),7.44(dd,J=8.3,4.3Hz,1H),7.41–7.34(m,2H ),7.14–7.07(m,2H),6.05(dd,J=15.5,8.8Hz,1H),5.55(dd,J=15.5,0.8Hz,1 H),3.52–3.25(m,2H),2.93(dd,J=13.4,7.9Hz,1H),1.47(s,3H),1.40(s,3H).

[0270] 13C NMR(101MHz,Chloroform-d)δ170.18,148.29,138.49,137.90,136.54,136.10,134.14,131.57,131.18 ,128.19,128.04,127.45,123.22,121.98,121.80,120.44,116.61,53.23,37.54,34.78,27.42,27.39.

[0271] HRMS (ESI-TOF): m / z Calcd for C 24 H 23 BrN3O + [M+H + ]:448.1019; found:448.1027.

[0272] Example 17

[0273] The preparation method of (E)-2-allyl-5-cyano-5-methyl-N-(quinolin-8-yl)hexyl-3-enamide (2q) includes the following steps:

[0274]

[0275] 1.4 g (10 mmol, 1 equiv) of 8-aminoquinoline 3a, 1.51 g (12 mmol, 1.2 equiv) of 2-vinyl-3-butenoic acid 4q, and 4.94 g (13 mmol, 1.3 equiv) of HATU were weighed and dissolved in 30 mL of dichloromethane. After stirring at room temperature for 3–5 min, pyridine (1.6 g, 20 mmol, 2 equiv) was added and the reaction was continued for 24 h. After the reaction was completed, dichloromethane was added for dilution. The reaction system was washed with saturated sodium bicarbonate solution, and the organic phase was collected and dried over anhydrous sodium sulfate. The solvent was concentrated under reduced pressure, and the compound 1q (0.55 g) was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 10:1) to obtain compound 1q (0.55 g) in a fraction of 22%.

[0276] The above compound 1q was characterized by NMR and mass spectrometry, and the results are as follows:

[0277] 1H NMR(400MHz,Chloroform-d)δ10.00(s,1H),8.84–8.72(m,2H),8.11(dd,J=8.3,1.7Hz,1H),7.54 –7.44(m,2H),7.41(dd,J=8.3,4.3Hz,1H),6.03(ddd,J=17.2,10.2,8.6Hz,1H),5.86(ddt,J=17. 1,10.2,7.0Hz,1H),5.43–5.28(m,2H),5.15(dq,J=17.1,1.6Hz,1H),5.06(ddt,J=10.1,2.0,1.1 Hz,1H),3.29(ddd,J=8.5,7.6,6.7Hz,1H),2.76(dtt,J=13.8,6.8,1.3Hz,1H),2.56–2.43(m,1H).

[0278] 13 C NMR(101MHz,Chloroform-d)δ171.32,148.25,138.51,136.38,136.33,135.38, 134.41,127.93,127.36,121.62,121.60,118.51,117.12,116.47,53.02,36.16.

[0279] HRMS (ESI-TOF): m / z Calcd for C 16 H 17 N2O + [M+H + ]:253.1335; found:253.1334.

[0280]

[0281] Weigh out N-(quinolin-8-yl)-2-vinylpentan-4-enamide 1q (0.050 g, 0.2 mmol, 1 equiv), azobisisobutyronitrile 5 (0.098 g, 0.6 mmol, 3 equiv), and Cu(OAc)₂·H₂O (0.016 g, 0.08 mmol, 0.4 equiv) and dissolve them in 1 mL of 2-butanol. Heat the mixture to 90 °C under a nitrogen atmosphere and monitor the reaction by TLC until complete. After the reaction, purify the crude product by silica gel column chromatography (petroleum ether: ethyl acetate = 10:1) to give compound 2q (51 mg), with a yield of 80%.

[0282] The above compound 2q was characterized by NMR and mass spectrometry, and the results are as follows:

[0283] 1 H NMR(400MHz,Chloroform-d)δ10.06(s,1H),8.77(ddd,J=9.0,5.5,2.0Hz,2H),8.16(dd,J=8.2,1.7Hz,1H),7.5 7–7.48(m,2H),7.45(dd,J=8.3,4.3Hz,1H),6.06(dd,J=15.6,8.8Hz,1H),5.82(ddt,J=17.1,10.1,7.0Hz,1H), 5.74(dd,J=15.5,0.9Hz,1H),5.15(dq,J=17.1,1.6Hz,1H),5.08(ddt,J=10.1,1.9,1.1Hz,1H),3.30(dddd,J=8 .7,7.3,6.2,0.8Hz,1H),2.78(dddt,J=14.4,7.4,6.2,1.3Hz,1H),2.61–2.38(m,1H),1.55(s,3H),1.52(s,3H).

[0284] 13 C NMR(101MHz,Chloroform-d)δ170.64,148.27,138.56,136.55,135.62,135.03,134.29,128.66 ,128.06,127.50,123.41,121.86,121.78,117.66,116.58,51.08,36.18,34.81,27.59,27.44.

[0285] HRMS (ESI-TOF): m / z Calcd for C 20 H 21 N3NaO + [M+Na + ]:342.1577; found:342.1579.

[0286] Example 18

[0287] The preparation method of (E)-5-cyano-2-(methoxymethyl)-5-methyl-N-(quinolin-8-yl)hex-3-enamide (3r) includes the following steps:

[0288]

[0289] 8-Aminoquinoline 3a (1.4 g, 10 mmol, 1 equiv), 2-methoxymethyl-3-butenoic acid 4r (1.56 g, 12 mmol, 1.2 equiv), and HATU (4.94 g, 13 mmol, 1.3 equiv) were weighed and dissolved in 30 mL of dichloromethane. After stirring at room temperature for 3–5 min, pyridine (1.6 g, 20 mmol, 2 equiv) was added, and the reaction was continued for 24 h. After the reaction was completed, dichloromethane was added for dilution. The reaction system was washed with saturated sodium bicarbonate solution, and the organic phase was collected and dried over anhydrous sodium sulfate. The solvent was concentrated under reduced pressure, and the compound 1r (0.21 g) was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 10:1) to obtain compound 1r (0.21 g) in a fraction of 8%.

[0290] The above compound 1r was characterized by NMR and mass spectrometry, and the results are as follows:

[0291] 1 H NMR(400MHz,Chloroform-d)δ10.35(s,1H),8.84–8.73(m,2H),8.13(dd,J=8.3,1.7Hz,1H),7.55–7.46(m,2H),7.42(dd,J=8.3,4.2Hz,1H),6. 09(ddd,J=17.2,10.3,8.3Hz,1H),5.47–5.32(m,2H),3.86(dd,J=9.2,7.2Hz,1H),3.72(dd,J=9.2,5.2Hz,1H),3.55–3.47(m,1H),3.45(s,3H).

[0292] 13 C NMR(101MHz,Chloroform-d)δ170.46,148.30,138.67,136.40,134.67,133.75,128.03,127.45,121.72,121.63,119.49,116.79,73.24,59.29,53.29.

[0293] HRMS (ESI-TOF): m / z Calcd for C 15 H 16 N2NaO2 + [M+Na + ]:279.1104; found:279.1107.

[0294]

[0295] 2-(methoxymethyl)-N-(quinolin-8-yl)but-3-enamide 1r (0.051 g, 0.2 mmol, 1 equiv), azobisisobutyronitrile 5 (0.098 g, 0.6 mmol, 3 equiv), and Cu(OAc)₂·H₂O (0.016 g, 0.08 mmol, 0.4 equiv) were dissolved in 1 mL of 2-butanol. The mixture was heated to 90 °C under a nitrogen atmosphere, and the reaction was monitored by TLC until complete. After the reaction, the crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 10:1) to give compound 2r (43 mg), with a yield of 66%.

[0296] The above compound 2r was characterized by NMR and mass spectrometry, and the results are as follows:

[0297] 1 H NMR(400MHz,Chloroform-d)δ10.36(s,1H),8.81–8.70(m,2H),8.11(dd,J=8.3,1.7 Hz,1H),7.53–7.45(m,2H),7.41(dd,J=8.3,4.2Hz,1H),6.13(dd,J=15.6,8.5Hz,1H) ,5.77(dd,J=15.7,0.9Hz,1H),3.81(dd,J=9.2,6.6Hz,1H),3.75(dd,J=9.3,5.0Hz, 1H),3.47(dddd,J=8.7,6.3,5.0,1.0Hz,1H),3.42(s,3H),1.52(s,3H),1.50(s,3H).

[0298] 13 C NMR(101MHz,Chloroform-d)δ169.67,148.23,138.57,136.34,136.13,134.40,127.95,12 7.32,126.08,123.32,121.81,121.66,116.61,72.88,59.25,51.45,34.77,27.45,27.28.

[0299] HRMS (ESI-TOF): m / z Calcd for C 19 H 22 N3O2 + [M+H + ]:324.1707; found:324.1701.

[0300] Example 19

[0301] The preparation method of (E)-2-(3-chloropropyl)-5-cyano-5-methyl-N-(quinolin-8-yl)hexyl-3-enamide (2s) includes the following steps:

[0302]

[0303] 8-Aminoquinoline 3a (1.4 g, 10 mmol, 1 equiv), 5-chloro-2-vinylpentanoic acid 4s (1.94 g, 12 mmol, 1.2 equiv), and HATU (4.94 g, 13 mmol, 1.3 equiv) were weighed and dissolved in 30 mL of dichloromethane. After stirring at room temperature for 3–5 min, pyridine (1.6 g, 20 mmol, 2 equiv) was added, and the reaction was continued for 24 h. After the reaction was completed, dichloromethane was added for dilution. The reaction system was washed with saturated sodium bicarbonate solution, and the organic phase was collected and dried over anhydrous sodium sulfate. The solvent was concentrated under reduced pressure, and the compound 1s (0.28 g) was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 10:1) in a fractional yield of 10%.

[0304] The above compound 1s was characterized by NMR and mass spectrometry, and the results are as follows:

[0305] 1 H NMR (400MHz, Chloroform-d) δ10.00 (s, 1H), 8.85–8.72 (m, 2H), 8.14 (dd, J = 8. 3,1.7Hz,1H),7.56–7.46(m,2H),7.43(dd,J=8.3,4.2Hz,1H),6.01(ddd,J=17. 1,10.1,8.6Hz,1H),5.39(dt,J=17.2,1.1Hz,1H),5.33(dd,J=10.1,1.3Hz,1H ),3.65–3.50(m,2H),3.28–3.14(m,1H),2.23–2.07(m,1H),1.96–1.80(m,3H).

[0306] 13 C NMR(101MHz,Chloroform-d)δ171.50,148.35,138.58,136.51,136.45,134.44 ,128.03,127.44,121.75,121.70,118.83,116.57,52.73,44.82,30.38,29.16.

[0307] HRMS (ESI-TOF): m / z Calcd for C 16 H 18 ClN2O+ [M+H + ]:289.1102;found:289.1108.

[0308]

[0309] Weigh out 0.058 g (0.2 mmol, 1 equiv) of 5-chloro-N-(quinolin-8-yl)-2-vinylpentanamide 1S, 0.098 g (0.6 mmol, 3 equiv) of azobisisobutyronitrile 5, and 0.016 g (0.08 mmol, 0.4 equiv) of Cu(OAc)₂·H₂O, and dissolve them in 1 mL of 2-butanol. Heat the mixture to 90 °C under a nitrogen atmosphere and monitor the reaction by TLC until complete. After the reaction, purify the crude product by silica gel column chromatography (petroleum ether: ethyl acetate = 10:1) to give compound 2S (42 mg), with a yield of 59%.

[0310] The above compound 2s was characterized by NMR and mass spectrometry, and the results are as follows:

[0311] 1 H NMR(400MHz,Chloroform-d)δ10.06(s,1H),8.78(dd,J=4.2,1.7Hz,1H),8.74(dd,J=6.4,2.6 Hz,1H),8.16(dd,J=8.3,1.7Hz,1H),7.57–7.48(m,2H),7.45(dd,J=8.3,4.2Hz,1H),6.06(dd, J=15.5,8.8Hz,1H),5.77(dd,J=15.5,0.8Hz,1H),3.58(tt,J=7.4,3.6Hz,2H),3.23(dt,J=8.8 ,6.7Hz,1H),2.18(ddt,J=13.7,7.8,4.4Hz,1H),1.94–1.82(m,3H),1.55(s,3H),1.53(s,3H).

[0312] 13 C NMR(101MHz,Chloroform-d)δ170.69,148.33,138.56,136.54,135.72,134.23,128.79,128.0 5,127.47,123.32,121.93,121.82,116.56,50.82,44.73,34.83,30.41,29.23,27.57,27.42.

[0313] HRMS (ESI-TOF): m / z Calcd for C 20 H 22 ClN3NaO + [M+Na + ]:378.1344; found:378.1338.

[0314] Example 20

[0315] The preparation method of (E)-5-cyano-3,5-dimethyl-N-(quinolin-8-yl)hexyl-3-enamide (2t) includes the following steps:

[0316]

[0317] 1.4 g (10 mmol, 1 equiv) of 8-aminoquinoline 3a, 1.2 g (12 mmol, 1.2 equiv) of 3-methyl-3-butenoic acid 4t, and 4.94 g (13 mmol, 1.3 equiv) of HATU were weighed and dissolved in 30 mL of dichloromethane. After stirring at room temperature for 3–5 min, pyridine (1.6 g, 20 mmol, 2 equiv) was added and the reaction was continued for 24 h. After the reaction was completed, dichloromethane was added for dilution. The reaction system was washed with saturated sodium bicarbonate solution, and the organic phase was collected and dried over anhydrous sodium sulfate. The solvent was concentrated under reduced pressure, and the compound was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 10:1) to give compound 1t (0.42 g), with a yield of 19%.

[0318] The above compound 1t was characterized by NMR and mass spectrometry, and the results are as follows:

[0319] 1 H NMR(400MHz,Chloroform-d)δ10.05(s,1H),8.85–8.68(m,2H),8.10(dd,J=8.3,1.7Hz,1H),7.53–7.4 3(m,2H),7.40(dd,J=8.3,4.2Hz,1H),5.15–5.05(m,2H),3.28(d,J=1.1Hz,2H),1.91(t,J=1.2Hz,3H).

[0320] 13 C NMR (101MHz, Chloroform-d) δ169.19,148.31,139.86,138.56,136.29,134.45,127.94,127.35,121.59,116.41,115.96,47.91,22.58.

[0321] HRMS (ESI-TOF): m / z Calcd for C 14 H 14 N2NaO + [M+Na + ]:249.0998; found:249.0997.

[0322]

[0323] Weigh 1 t (0.045 g, 0.2 mmol, 1 equiv) of 3-methyl-N-(quinoline-8-yl)but-3-enamide, 5 t (0.098 g, 0.6 mmol, 3 equiv) of azobisisobutyronitrile, and 0.016 g (0.08 mmol, 0.4 equiv) of Cu(OAc)₂·H₂O and dissolve them in 1 mL of 2-butanol. The mixture was heated to 90 °C under a nitrogen atmosphere, and the reaction was monitored by TLC until complete. After the reaction, the crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 10:1) to give 2 t (40 mg) of compound, with a yield of 68%.

[0324] The above compound 2t was characterized by NMR and mass spectrometry, and the results are as follows:

[0325] 1 H NMR(400MHz,Chloroform-d)δ10.04(s,1H),8.79(dd,J=4.2,1.7Hz,1H),8.76(dd,J=6.8,2.2Hz,1H),8.15(dd,J=8.3,1.7Hz,1H ),7.57–7.48(m,2H),7.44(dd,J=8.3,4.2Hz,1H),5.47–5.29(m,1H),3.71(d,J=0.8Hz,2H),1.93(d,J=1.5Hz,3H),1.58(s,6H).

[0326] 13 C NMR(101MHz,Chloroform-d)δ168.02,148.35,138.58,136.42,134.47,134.10,130 .26,128.04,127.46,124.69,121.78,121.74,116.62,41.28,31.00,29.41,25.14.

[0327] HRMS (ESI-TOF): m / z Calcd for C 18 H 20 N3O + [M+H+ ]:294.1601; found:294.1607.

[0328] Example 21

[0329] The preparation method of (E)-5-cyano-4-ethyl-5-methyl-N-(quinolin-8-yl)hexyl-3-enamide includes the following steps:

[0330]

[0331] 1.4 g (10 mmol, 1 equiv) of 8-aminoquinoline 3a, 1.37 g (12 mmol, 1.2 equiv) of (Z)-hexyl-3-enoic acid 4u, and HATU (4.94 g, 13 mmol, 1.3 equiv) were weighed and dissolved in 30 mL of dichloromethane. After stirring at room temperature for 3–5 min, pyridine (1.6 g, 20 mmol, 2 equiv) was added and the reaction was continued for 24 h. After the reaction was completed, dichloromethane was added for dilution. The reaction system was washed with saturated sodium bicarbonate solution, and the organic phase was collected and dried over anhydrous sodium sulfate. The solvent was concentrated under reduced pressure, and the compound 1u (0.52 g) was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 10:1) to obtain compound 1u (0.52 g), with a yield of 22%.

[0332] The above compound 1u was characterized by NMR and mass spectrometry, and the results are as follows:

[0333] 1 H NMR(400MHz,Chloroform-d)δ10.03(s,1H),8.82–8.67(m,2H),8.07(dd,J=8.3,1.7Hz,1H),7.51–7.40(m,2H),7.37(dd,J=8.3,4 .2Hz,1H),5.85–5.77(m,1H),5.76–5.68(m,1H),3.32(dd,J=7.3,1.1Hz,2H),2.18(pd,J=7.5,1.4Hz,2H),1.05(t,J=7.5Hz,3H).

[0334] 13 C NMR(101MHz,Chloroform-d)δ169.63,148.17,138.48,137.11,136.22,134.45,127.88,127.30,121.53,121.50,120.68,116.36,36.77,20.84,13.95.

[0335] HRMS (ESI-TOF): m / z Calcd for C15 H 17 N2O + [M+H + ]:241.1335; found:241.1337.

[0336]

[0337] Weigh out 1 unit (0.048 g, 0.2 mmol, 1 equiv) of (Z)-N-(quinolin-8-yl)hexyl-3-enamide, 5 unit (0.098 g, 0.6 mmol, 3 equiv) of azobisisobutyronitrile, and 0.016 g (0.08 mmol, 0.4 equiv) of Cu(OAc)₂·H₂O, and dissolve them in 1 mL of 2-butanol. The mixture was heated to 90 °C under a nitrogen atmosphere, and the reaction was monitored by TLC until complete. After the reaction, the crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 10:1) to give compound 2 unit (38 mg), with a yield of 62%.

[0338] The above compound 2u was characterized by NMR and mass spectrometry, and the results are as follows:

[0339] 1 H NMR(400MHz,Chloroform-d)δ10.06(s,1H),8.79–8.70(m,2H),8.14(dd,J=8.3,1.7Hz,1H),7.56–7.46(m,2H),7.43(dd,J =8.3,4.2Hz,1H),5.97(t,J=7.6Hz,1H),3.37(d,J=7.6Hz,2H),2.34(q,J=7.6Hz,2H),1.63(s,6H),1.18(t,J=7.6Hz,3H).

[0340] 13 C NMR(101MHz,Chloroform-d)δ168.86,148.24,145.87,138.48,136.46,134.23,127.99,12 7.43,124.20,121.79,121.75,118.63,116.45,77.36,38.94,37.27,27.06,21.93,14.79.

[0341] HRMS (ESI-TOF): m / z Calcd for C 19 H 21 N3NaO + [M+Na +]:330.1577; found:330.1571.

[0342] In summary, this invention discloses a method for preparing β,γ-unsaturated nitrile derivatives using azobisisobutyronitrile as the free radical source. Using N-(quinolin-8-yl)-3-butenamide derivatives as substrates and azobisisobutyronitrile as the free radical source, the reaction is carried out at 90°C in 2-butanol under the action of a copper salt catalyst, yielding β,γ-unsaturated nitrile compounds with high regioselectivity and stereoselectivity in good to high yields.

[0343] Obviously, the above embodiments of the present invention are merely examples for clearly illustrating the present invention, and are not intended to limit the implementation of the present invention. Those skilled in the art should understand that other variations or modifications can be made based on the above description. It is neither necessary nor possible to exhaustively describe all embodiments here. Any modifications, equivalent substitutions, and improvements made within the spirit and principles of the present invention should be included within the scope of protection of the claims of the present invention.

Claims

1. A method for preparing a β,γ-unsaturated nitrile compound, characterized in that: The following steps are involved: The N-(quinoline-8-yl)-3-buteneamide derivative of formula (1), azobisisobutyronitrile and a copper salt catalyst are dissolved in an organic solvent and reacted at 80 to 110° C. to obtain the β,γ-unsaturated nitrile compound of formula (2); Formula (1) and formula (2) are shown as follows: Wherein, R1 is selected from one of hydrogen, C1-C6 saturated or unsaturated alkyl, substituted or unsubstituted benzyl and substituted or unsubstituted methylene, R2 is selected from one of hydrogen and C1-C6 saturated or unsaturated alkyl, and R3 is selected from one of hydrogen and C1-C6 saturated or unsaturated alkyl.

2. The preparation method according to claim 1, characterized in that: The copper salt catalyst is selected from one or more of cuprous chloride, cuprous iodide, copper tetraacetonitrile hexafluorophosphate, cuprous trifluoromethanesulfonate, copper trifluoromethanesulfonate, copper acetate, copper bromide and copper acetate monohydrate.

3. The preparation method according to claim 1, characterized in that: The organic solvent is selected from one or more of acetonitrile, 1,2-dichloroethane, toluene, dimethyl sulfoxide, tetrahydrofuran, methanol, ethanol and 2-butanol.

4. The preparation method according to claim 1, characterized in that: The molar ratio of the N-(quinoline-8-yl)-3-buteneamide derivative to azobisisobutyronitrile is 1:(2-6).

5. The preparation method according to claim 1, characterized in that: The molar ratio of the N-(quinoline-8-yl)-3-buteneamide derivative and the copper salt catalyst is 1:(0.1-1).

6. The preparation method according to claim 1, characterized in that: The reaction temperature is 80-100°C.

7. The preparation method according to claim 1, characterized in that: The R1 is hydrogen, methyl, ethyl, n-butyl, hexyl, cyclopropylmethyl, cyclobutylmethyl, methoxymethyl, cyclopropylmethylene, cyclobutylmethylene, isopropyl, cyclopentyl, cyclohexyl, benzyl, 2-methylbenzyl, 3-methylbenzyl, 4-methylbenzyl, 4-fluorobenzyl, 4-chlorobenzyl, 4-bromobenzyl, vinyl, vinylpentyl, allyl, methyl ether methylene or methylene-3-chloropropyl.

8. The preparation method according to claim 1, characterized in that: The N-(quinolin-8-yl)-3-butenamide derivatives are N-(quinolin-8-yl)-3-butenamide, 2-methyl-N-(quinolin-8-yl)but-3-enamide, 2-ethyl-N-(quinolin-8-yl)but-3-enamide, N-(quinolin-8-yl)-2-vinylhexanamide, 2-(cyclopropylmethyl)-N-(quinolin-8-yl)but-3-enamide, 2- (Cyclobutylmethyl)-N-(quinolin-8-yl)but-3-enamide, 2-isopropyl-N-(quinolin-8-yl)but-3-enamide, 2-cyclopentyl-N-(quinolin-8-yl)but-3-enamide, 2-cyclohexyl-N-(quinolin-8-yl)but-3-enamide, 2-benzyl-N-(quinolin-8-yl)but-3-enamide, 2-(2-methylbenzyl)-N-(quinolin-8-yl)but-3-enamide 8-yl) but-3-enamide, 2-(3-methylbenzyl)-N-(quinolin-8-yl) but-3-enamide, 2-(4-methylbenzyl)-N-(quinolin-8-yl) but-3-enamide, 2-(4-fluorobenzyl)-N-(quinolin-8-yl) but-3-enamide, 2-(4-chlorobenzyl)-N-(quinolin-8-yl) but-3-enamide, 2-(4-bromobenzyl)-N- (Z)-N-(quinolin-8-yl)but-3-enamide, N-(quinolin-8-yl)-2-vinylpent-4-enamide, 2-(methoxymethyl)-N-(quinolin-8-yl)but-3-enamide, 5-chloro-N-(quinolin-8-yl)-2-vinylpentanamide, 3-methyl-N-(quinolin-8-yl)but-3-enamide or (Z)-N-(quinolin-8-yl)hexyl-3-enamide.

9. The preparation method according to claim 1, characterized in that: The preparation method of the N-(quinoline-8-yl)-3-buteneamide derivative of formula (1) is as follows: The 8-aminoquinoline of formula (3) and the 3-butenoic acid derivative of formula (4) are reacted at 20-40° C. in the presence of pyridine, 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate and dichloromethane to obtain the N-(quinolin-8-yl)-3-butenoic acid derivative of formula (1); the reaction scheme is as follows: Wherein, R1 is selected from one of hydrogen, C1-C6 saturated or unsaturated alkyl, substituted or unsubstituted benzyl and substituted or unsubstituted methylene, R2 is selected from one of hydrogen and C1-C6 saturated or unsaturated alkyl, and R3 is selected from one of hydrogen and C1-C6 saturated or unsaturated alkyl.

10. The preparation method according to claim 9, characterized in that: The R1 is hydrogen, methyl, ethyl, n-butyl, methylenecyclopropane, methylenecyclobutane, isopropyl, cyclopentane, cyclohexane, benzyl, 2-methylbenzyl, 3-methylbenzyl, 4-methylbenzyl, 4-fluorobenzyl, 4-chlorobenzyl, 4-bromobenzyl, allyl, methylene methyl ether or methylene-3-chloropropane.

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