Preparation method of 4-(2, 2-dimethyl-2-cyanoethyl)-beta-lactam derivative

Abstract

The invention discloses a preparation method of a 4-(2, 2-dimethyl-2-cyanoethyl)-beta-lactam derivative, which comprises the following steps: by taking a substituted N-(5-iodoquinoline-8-yl)-3-butene amide derivative as a substrate and azodiisobutyronitrile as a free radical source, reacting in an organic solvent at 80-110 DEG C under the action of a copper salt catalyst to obtain the 4-(2, 2-dimethyl-2-cyanoethyl)-beta-lactam derivative. The invention relates to a 2, 2-dimethyl-2-cyanoethyl)-beta-lactam derivative. The preparation method provided by the invention has the advantages of easily available raw materials, mild reaction conditions, simple reaction operation and post-treatment process, high yield, good universality, greenness and environmental protection, and is suitable for large-scale production.

Description

Technical Field

[0001] The invention relates to the technical field of organic synthesis, and in particular to a method for preparing a 4-(2,2-dimethyl-2-cyanoethyl)-β-lactam derivative. Background Art

[0002] β-lactam is an important component of N-heterocycles. Some natural products and drug molecules have this core skeleton. In particular, β-lactam derivatives have significant biological and pharmacological activities, such as antiviral and anti-Gram-negative bacteria.

[0003] So far, the synthesis methods of lauryl-β-lactam derivatives are mainly the following:

[0004] The synthesis method of β-lactam derivatives is disclosed in J.Am.Chem.Soc, 1982, 104, 3233, which is a method of oxidative ring closure. J.Org.Chem. 1995, 60, 1276 discloses a method of preparing β-lactam derivatives by ring closure reaction using a reduction method. Methods for synthesizing β-lactams using CH bond activation and metal catalysis are disclosed in Angewandte Chemie, 2013, 52, 13588, Angewandte Chemie 2014, 53, 3496 and Chem.Eur.J, 2014, 20, 9530, respectively. However, the above methods have harsh reaction conditions, require the use of noble metal catalysts, are costly, and reactions using activation groups or positioning groups do not meet the requirements of atom economy and environmental friendliness.

[0005] The literature Chem. Commun. 2019, 55, 10523-10526, Org. Lett. 2022, 24, 2738-2743 and J. Am. Chem. Soc. 2021, 143, 1195-1202 reported a series of methods for synthesizing β-lactams using metal copper catalysis. The literature Org. Lett. 2021, 23, 3620-3625 also reported the synthesis of β-lactam derivatives containing cyano groups. However, the above methods have low yields and high costs. Summary of the invention

[0006] In order to overcome the shortcomings of the prior art for preparing β-lactam derivatives, such as low yield, expensive raw materials, harsh reaction conditions and unfriendly environment, the present invention provides a method for preparing β-lactam derivatives containing cyano group by using azobisisobutyronitrile as a free radical source. The method has easy-to-obtain raw materials, high yield, mild reaction conditions, good universality and is green and environmentally friendly.

[0007] The above-mentioned purpose of the present invention is achieved through the following technical solutions:

[0008] A method for preparing a 4-(2,2-dimethyl-2-cyanoethyl)-β-lactam derivative comprises the following steps:

[0009] The substituted N-(5-iodoquinoline)-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 4-(2,2-dimethyl-2-cyanoethyl)-β-lactam derivative of formula (2);

[0010] Formula (1) and formula (2) are shown as follows:

[0011]

[0012] Wherein, R is selected from one of hydrogen, C1-C6 saturated or unsaturated alkyl, substituted or unsubstituted benzyl, and substituted or unsubstituted phenethyl.

[0013] The present invention uses a substituted N-(5-iodoquinoline-8-yl)-3-buteneamide derivative as a substrate, azobisisobutyronitrile as a free radical source, and reacts in an organic solvent under the action of a copper salt catalyst to obtain multiple 4-(2,2-dimethyl-2-cyanoethyl)-β-lactam derivatives in high yield. The reaction in the preparation method belongs to a double-bond free radical addition ring-forming reaction promoted by free radicals initiated by azobisisobutyronitrile. The preparation method provided by the present invention has easy-to-obtain raw materials, mild reaction conditions, simple reaction operation and post-processing process, good universality, and is green and environmentally friendly, and is suitable for large-scale production.

[0014] Furthermore, the copper salt catalyst is selected from one or more of cuprous iodide, copper tetraacetonitrile hexafluorophosphate (Cu(CH3CN)4PF6) and copper trifluoromethanesulfonate, preferably copper tetraacetonitrile hexafluorophosphate.

[0015] Furthermore, the organic solvent is selected from one or more of acetonitrile, dioxane and dichloromethane, preferably acetonitrile.

[0016] Furthermore, the molar ratio of the substituted N-(5-iodoquinoline)-3-buteneamide derivative to azobisisobutyronitrile is 1:(2-6), preferably 1:(4-5).

[0017] Furthermore, the molar ratio of the substituted N-(5-iodoquinoline)-3-buteneamide derivative to the copper salt catalyst is 1:(0.1-0.3), preferably 1:0.2.

[0018] Furthermore, the molar ratio of the substituted N-(5-iodoquinoline)-3-buteneamide derivative to the organic solvent is 1:(20-30), preferably 1:(16-26).

[0019] Furthermore, the molar ratio of the substituted N-(5-iodoquinoline)-3-buteneamide derivative, azobisisobutyronitrile, copper salt catalyst and organic solvent is 1:(2-6):(0.1-0.3):(10-30), preferably 1:(4-5):(0.1-0.3):(16-26).

[0020] Furthermore, the reaction temperature is 90-100°C.

[0021] Furthermore, R is hydrogen, methyl, ethyl, isopropyl, allyl, cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, benzyl, phenethyl, o-methylbenzyl or p-o-methylbenzyl.

[0022] Furthermore, the preparation method of the substituted N-(5-iodoquinoline)-3-buteneamide derivative of formula (1) is as follows:

[0023] The 5-iodo-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 (HATU) and dichloromethane to obtain the substituted N-(5-iodoquinoline)-3-butenoic acid derivative of formula (1); the reaction scheme is as follows:

[0024]

[0025] Wherein, R is selected from one of hydrogen, C1-C6 saturated or unsaturated alkyl, substituted or unsubstituted benzyl, and substituted or unsubstituted phenethyl.

[0026] Furthermore, R is hydrogen, methyl, ethyl, isopropyl, allyl, cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, benzyl, phenethyl, o-methylbenzyl or p-o-methylbenzyl.

[0027] The above technical solution of the present invention has the following beneficial effects:

[0028] 1. The present invention provides a completely new system, using azobisisobutyronitrile as a free radical source to achieve the synthesis of 4-(2,2-dimethyl-2-cyanoethyl)-β-lactam derivatives and introduce a cyano group into the molecule.

[0029] 2. The present invention uses substituted N-(5-iodoquinoline)-3-buteneamide derivatives and azobisisobutyronitrile as starting materials, and the raw materials are easily available and of many types. The products obtained by the method of the present invention are of various types and have good universality, and can be used directly or in other further reactions.

[0030] 3. The reaction of the present invention is novel, the reaction conditions are relatively mild, the reaction operation and post-treatment process are simple, the yield is very high, and it is green and environmentally friendly, and is suitable for large-scale production. DETAILED DESCRIPTION

[0031] The present invention is further described below in conjunction with specific embodiments so that those skilled in the art can better understand the present invention and implement it, but the embodiments are not intended to limit the present invention.

[0032] Unless otherwise specified, the experimental methods used in the following examples are all conventional methods, and the materials, reagents, etc. used are all available from commercial sources unless otherwise specified.

[0033] Example 1

[0034] The preparation method of 3-(1-(5-iodoquinolin-8-yl)-4-oxoazetidine-2-yl))-2,2-dimethylpropionitrile (2a) comprises the following steps:

[0035]

[0036] 5-iodo-8-aminoquinoline (3) (2.7 g, 10 mmol, 1 equiv), 3-butenoic acid (4a) (1.03 g, 12 mmol, 1.2 equiv), 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, and the reaction system was washed with saturated sodium bicarbonate solution. The organic phase was collected and dried over anhydrous sodium sulfate, and the solvent was concentrated under reduced pressure. Compound 1a was obtained after purification by silica gel column chromatography (petroleum ether: ethyl acetate = 10: 1) with a fraction yield of 85%.

[0037] 1a: 1 H NMR(400MHz,Chloroform-d)δ9.97(s,1H),8.77(dd,J=4.2,1.6Hz,1H),8.54(d,J=8.3Hz,1H),8.36(dd,J=8.5,1.6Hz,1H),8.07( d,J=8.3Hz,1H),7.53(dd,J=8.5,4.2Hz,1H),6.13(ddt,J=16.6,10.4,7.1Hz,1H),5.44–5.34(m,2H),3.35(dt,J=7.1,1.3Hz,2H). 13C NMR(101MHz,Chloroform-d)δ169.46,148.95,140.85,139.21,138.38,135.41,130.87,129.72,123.28,120.45,117.96,89.55,43.32.HRMS(ESI-TOF):m / z Calcdfor C 13 H 12 IN2O + [M+H + ]:338.9989;found:338.9989.

[0038]

[0039] (1) Weigh N-(5-iodoquinolin-8-yl)but-3-enamide (1a) (0.034 g, 0.1 mmol), azobisisobutyronitrile (5) (0.066 g, 0.4 mmol), and Cu(CH3CN)4PF6 (0.008 g, 0.02 mmol) and dissolve them in 1 mL of acetonitrile. Heat the mixture to 90°C for reaction, and monitor the reaction by TLC until the reaction is completely completed. After the reaction is completed, the crude product is purified by silica gel column chromatography (petroleum ether: ethyl acetate = 8:1) to obtain compound 2a. The isolated yield is 89%.

[0040] (2) Weigh N-(5-iodoquinolin-8-yl)but-3-enamide (1a) (0.034 g, 0.1 mmol), azobisisobutyronitrile (5) (0.066 g, 0.4 mmol), and Cu(CH3CN)4PF6 (0.008 g, 0.02 mmol) and dissolve them in 1 mL of acetonitrile. Heat the mixture to 110°C for reaction, and monitor the reaction by TLC until the reaction is completely completed. After the reaction is completed, the crude product is purified by silica gel column chromatography (petroleum ether: ethyl acetate = 8:1) to obtain compound 2a. The isolated yield is 60%.

[0041] (3) Weigh N-(5-iodoquinolin-8-yl)but-3-enamide (1a) (0.034 g, 0.1 mmol), azobisisobutyronitrile (5) (0.066 g, 0.4 mmol), and Cu(CH3CN)4PF6 (0.008 g, 0.02 mmol) and dissolve them in 1 mL of acetonitrile. Heat the mixture to 80°C for reaction, and monitor the reaction by TLC until the reaction is completely completed. After the reaction is completed, the crude product is purified by silica gel column chromatography (petroleum ether: ethyl acetate = 8:1) to obtain compound 2a. The isolated yield is 75%.

[0042] (4) Weigh N-(5-iodoquinolin-8-yl)but-3-enamide (1a) (0.034 g, 0.1 mmol), azobisisobutyronitrile (5) (0.033 g, 0.2 mmol), and Cu(CH3CN)4PF6 (0.008 g, 0.02 mmol) and dissolve them in 1 mL of acetonitrile. Heat the mixture to 90°C for reaction, and monitor the reaction by TLC until the reaction is completely completed. After the reaction is completed, the crude product is purified by silica gel column chromatography (petroleum ether: ethyl acetate = 8:1) to obtain compound 2a. The isolated yield is 52%.

[0043] (5) Weigh N-(5-iodoquinolin-8-yl)but-3-enamide (1a) (0.034 g, 0.1 mmol), azobisisobutyronitrile (5) (0.049 g, 0.3 mmol), and Cu(CH3CN)4PF6 (0.008 g, 0.02 mmol) and dissolve them in 1 mL of acetonitrile. Heat the mixture to 90°C for reaction, and monitor the reaction by TLC until the reaction is completely completed. After the reaction is completed, the crude product is purified by silica gel column chromatography (petroleum ether: ethyl acetate = 8:1) to obtain compound 2a. The isolated yield is 60%.

[0044] (6) Weigh N-(5-iodoquinolin-8-yl)but-3-enamide (1a) (0.034 g, 0.1 mmol), azobisisobutyronitrile (5) (0.058 g, 0.35 mmol), and Cu(CH3CN)4PF6 (0.008 g, 0.02 mmol) and dissolve them in 1 mL of acetonitrile. Heat the mixture to 90°C for reaction, and monitor the reaction by TLC until the reaction is completely completed. After the reaction is completed, the crude product is purified by silica gel column chromatography (petroleum ether: ethyl acetate = 8:1) to obtain compound 2a. The isolated yield is 71%.

[0045] 1a: 1 H NMR(400MHz,Chloroform-d)δ8.85(dt,J=3.6,1.7Hz,1H),8.35(ddd,J=8.6,2.9,1.5Hz,1H),8 .11(dd,J=8.2,1.5Hz,1H),8.04(dd,J=8.3,2.3Hz,1H),7.49(ddd,J=8.6,4.1,1.7Hz,1H),5.46 (ddt,J=12.9,4.6,2.2Hz,1H),3.52(dd,J=15.3,5.2Hz,1H),3.02(ddd,J=15.4,2.6,1.0Hz,1H) ,2.39(dt,J=13.6,1.5Hz,1H),1.71–1.65(m,1H),1.45(d,J=1.0Hz,3H),1.38(d,J=1.0Hz,3H).13 C NMR(101MHz,Chloroform-d)δ165.77,149.79,140.64,140.56,137.86,134.03,130.59,124 .28,123.23,122.14,92.04,54.20,45.58,44.16,30.82,27.33,27.14.HRMS(ESI-TOF):m / z Calcd for C 17 H 16 IN3NaO + [M+Na + ]:428.0230;found:428.0237.

[0046] Example 2

[0047] The preparation method of 3-(1-(5-iodoquinolin-8-yl)-3-methyl-4-oxoazetidine-2-yl)-2,2-dimethylpropionitrile (2b) comprises the following steps:

[0048]

[0049] 5-iodo-8-aminoquinoline (3) (2.7 g, 10 mmol, 1 equiv), 2-methyl-3-butenoic acid (4b) (1.20 g, 12 mmol, 1.2 equiv), 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, and the reaction system was washed with saturated sodium bicarbonate solution. The organic phase was collected and dried over anhydrous sodium sulfate, and the solvent was concentrated under reduced pressure. Compound 1b was obtained after purification by silica gel column chromatography (petroleum ether: ethyl acetate = 10: 1) with a fraction yield of 25%.

[0050] 1b: 1 H NMR(400MHz,Chloroform-d)δ9.98(s,1H),8.71(dd,J=4.2,1.6Hz,1H),8.51(d,J=8.3Hz,1H),8.27(dd,J=8.5,1.6Hz,1H),8.00(d,J=8. 3Hz,1H),7.45(dd,J=8.5,4.2Hz,1H),6.08(ddd,J=17.3,10.2,7.9Hz,1H),5.43–5.26(m,2H),3.41–3.27(m,1H),1.43(d,J=7.0Hz,3H). 13C NMR(101MHz,Chloroform-d)δ172.55,148.80,140.60,139.09,138.20,137.83,1 35.39,129.50,123.12,117.72,117.59,89.35,47.05,16.94.HRMS(ESI-TOF):m / z Calcd for C 14 H 13 IN2NaO + [M+Na + ]:374.9965; found:374.9968.

[0051]

[0052] Weigh N-(5-iodoquinolin-8-yl)-2-methylbut-3-enamide (1b) (0.035 g, 0.1 mmol), azobisisobutyronitrile (5) (0.066 g, 0.4 mmol), and Cu(CH3CN)4PF6 (0.008 g, 0.02 mmol) and dissolve them in 1 mL of acetonitrile. Heat the mixture to 90°C for reaction, and track the reaction by TLC until the reaction is completely completed. After the reaction is completed, the crude product is purified by silica gel column chromatography (petroleum ether: ethyl acetate = 8:1) to obtain compound 2b. The isolated yield is 81%.

[0053] 2b: 1 H NMR (400MHz, Chloroform-d) δ8.84 (dd, J=4.1, 1.7Hz, 1H), 8.36 (dd, J=8.6, 1.6Hz, 1H),8.12(d,J=8.2Hz,1H),8.05(d,J=8.2Hz,1H),7.49(dd,J=8.6,4.1Hz,1H),5.0 7(dt,J=10.8,2.0Hz,1H),3.18(qd,J=7.3,2.2Hz,1H),2.33(dd,J=13.6,1.7Hz,1H ),1.74(dd,J=13.6,10.7Hz,1H),1.58(d,J=7.3Hz,3H),1.48(s,3H),1.39(s,3H). 13CNMR(101MHz,Chloroform-d)δ169.59,149.73,140.72,140.64,137.89,134.00,130.64,124.3 9,123.19,122.51,91.94,62.41,53.15,44.23,30.57,27.58,27.18,13.97.HRMS(ESI-TOF):m / z Calcd for C 18 H 18 IN3NaO + [M+Na + ]:442.0387;found:442.0381.

[0054] Example 3

[0055] The preparation method of 3-(3-ethyl-1-(5-iodoquinolin-8-yl)-4-oxoazetidine-2-yl)-2,2-dimethylpropionitrile (2c) comprises the following steps:

[0056]

[0057]

[0058] 5-iodo-8-aminoquinoline (3) (2.7 g, 10 mmol, 1 equiv), 2-ethyl-3-butenoic acid (4c) (1.37 g, 12 mmol, 1.2 equiv), 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, and the reaction system was washed with saturated sodium bicarbonate solution. The organic phase was collected and dried over anhydrous sodium sulfate, and the solvent was concentrated under reduced pressure. Compound 2c was obtained after purification by silica gel column chromatography (petroleum ether: ethyl acetate = 10: 1) with a fraction yield of 30%.

[0059] 2c: 1H NMR(400MHz,Chloroform-d)δ9.98(s,1H),8.77(dd,J=4.3,1.6Hz,1H),8.57(d,J=8 .3Hz,1H),8.36(dd,J=8.5,1.6Hz,1H),8.07(d,J=8.3Hz,1H),7.53(dd,J=8.5,4.2H z,1H),6.00(ddd,J=17.1,10.2,8.6Hz,1H),5.44–5.23(m,2H),3.09(q,J=7.5Hz,1H ), 2.03(tt,J=13.8,7.3Hz,1H), 1.72(dp,J=13.6,7.5Hz,1H), 1.01(t,J=7.4Hz,3H). 13 C NMR(101MHz,Chloroform-d)δ172.34,148.91,140.86,139.26,138.40,136.73,135. 54,129.72,123.25,118.55,117.95,89.36,55.23,25.13,11.92.HRMS(ESI-TOF):m / z Calcd for C 15 H 15 IN2NaO + [M+Na + ]:389.0121; found:389.0118.

[0060]

[0061] Weigh 2-ethyl-N-(5-iodoquinolin-8-yl)but-3-enamide (1c) (0.037 g, 0.1 mmol), azobisisobutyronitrile (5) (0.066 g, 0.4 mmol), and Cu(CH3CN)4PF6 (0.008 g, 0.02 mmol) and dissolve them in 1 mL of acetonitrile. Heat the mixture to 90°C for reaction, and track the reaction by TLC until the reaction is completely completed. After the reaction is completed, the crude product is purified by silica gel column chromatography (petroleum ether: ethyl acetate = 8:1) to obtain compound 2c. The isolated yield is 78%.

[0062] 2c: 1H NMR(400MHz,Chloroform-d)δ8.84(dd,J=4.1,1.6Hz,1H),8.36(dd,J=8.6,1.6Hz,1H),8 .14(d,J=8.2Hz,1H),8.05(d,J=8.2Hz,1H),7.49(dd,J=8.6,4.1Hz,1H),5.15(dt,J=10. 6,2.0Hz,1H),3.18(ddd,J=7.7,5.4,2.2Hz,1H),2.31(dd,J=13.6,1.9Hz,1H),2.11–1.9 5(m,2H),1.75(dd,J=13.6,10.7Hz,1H),1.46(s,3H),1.38(s,3H),1.19(t,J=7.5Hz,3H). 13 C NMR(101MHz,Chloroform-d)δ169.17,149.72,140.78,140.64,137.92,134.01,130.64,124.40,12 3.17,122.43,91.89,59.61,59.27,44.17,30.56,27.74,27.14,22.36,11.24.HRMS(ESI-TOF):m / z Calcd for C 19 H 21 IN3O + [M+H + ]:434.0724; found:434.0725.

[0063] Example 4

[0064] The preparation method of 3-(1-(5-iodoquinolin-8-yl)-3-isopropyl-4-oxoazetidine-2-yl)-2,2-dimethylpropionitrile (2d) comprises the following steps:

[0065]

[0066] 5-iodo-8-aminoquinoline (3) (2.7 g, 10 mmol, 1 equiv), 2-isopropyl-3-butenoic acid (4d) (1.54 g, 12 mmol, 1.2 equiv), 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, and the reaction system was washed with saturated sodium bicarbonate solution. The organic phase was collected and dried over anhydrous sodium sulfate, and the solvent was concentrated under reduced pressure. Compound 1d was obtained after purification by silica gel column chromatography (petroleum ether: ethyl acetate = 10: 1) with a fraction yield of 32%.

[0067] 1d: 1 H NMR(400MHz,Chloroform-d)δ9.91(s,1H),8.76(dd,J=4.2,1.6Hz,1H),8.57(d,J=8.3Hz,1H),8.34(dd,J=8.5,1.6Hz,1H),8.05(d,J=8.3Hz,1H),7.51(dd,J= 8.5,4.2Hz,1H),6.08–5.96(m,1H),5.35–5.26(m,2H),2.86(dd,J=9.4,8.0Hz, 1H), 2.27(dp,J=8.0,6.6Hz,1H), 1.03(d,J=6.7Hz,3H), 0.99(d,J=6.7Hz,3H). 13 C NMR(101MHz,Chloroform-d)δ172.28,148.87,140.80,139.18,138.35,135.58,135.46, 129.66,123.22,119.14,117.93,89.36,61.46,30.38,21.14,19.79.HRMS(ESI-TOF):m / z Calcd forC 16 H 18 IN2O + [M+H + ]:381.0458;found:381.0465.

[0068]

[0069] Weigh N-(5-iodoquinolin-8-yl)-2-isopropylbut-3-enamide (1d) (0.038 g, 0.1 mmol), azobisisobutyronitrile (5) (0.066 g, 0.4 mmol), and Cu(CH3CN)4PF6 (0.008 g, 0.02 mmol) and dissolve them in 1 mL of acetonitrile. Heat the mixture to 90°C for reaction, and track the reaction by TLC until the reaction is completely completed. After the reaction is completed, the crude product is purified by silica gel column chromatography (petroleum ether: ethyl acetate = 8:1) to obtain compound 2d. The isolated yield is 86%.

[0070] 2d: 1 H NMR(400MHz,Chloroform-d)δ8.84(dd,J=4.1,1.7Hz,1H),8.36(dd,J=8.6,1.6Hz,1H ),8.15(d,J=8.2Hz,1H),8.05(d,J=8.2Hz,1H),7.49(dd,J=8.6,4.1Hz,1H),5.20(dt, J=10.4,2.1Hz,1H),3.16(dd,J=5.3,2.1Hz,1H),2.35–2.22(m,2H),1.76(dd,J=13.7 ,10.5Hz,1H),1.45(s,3H),1.37(s,3H),1.23(d,J=6.9Hz,3H),1.18(d,J=6.7Hz,3H). 13 C NMR(101MHz,Chloroform-d)δ168.46,149.71,140.87,140.64,137.93,133.93,130.63,124.42,123.1 6,122.44,91.92,64.16,58.27,44.17,30.48,28.39,28.01,27.03,21.67,18.70.HRMS(ESI-TOF):m / z Calcd for C 20 H 22 IN3NaO + [M+Na + ]:470.0700;found:470.0708.

[0071] Example 5

[0072] The preparation method of 3-(3-allyl-1-(5-iodoquinolin-8-yl)-4-oxoazetidine-2-yl)-2,2-dimethylpropionitrile (2e) comprises the following steps:

[0073]

[0074]

[0075] 5-iodo-8-aminoquinoline (3) (2.7 g, 10 mmol, 1 equiv), 2-vinyl-3-butenoic acid (4e) (1.51 g, 12 mmol, 1.2 equiv), 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, and the reaction system was washed with saturated sodium bicarbonate solution. The organic phase was collected and dried over anhydrous sodium sulfate, and the solvent was concentrated under reduced pressure. Compound 1e was obtained after purification by silica gel column chromatography (petroleum ether: ethyl acetate = 10: 1) with a fraction yield of 22%.

[0076] 1e: 1 H NMR(400MHz,Chloroform-d)δ10.01(s,1H),8.77(dd,J=4.2,1.6Hz,1H),8.56(d,J=8.3 Hz,1H),8.37(dd,J=8.5,1.6Hz,1H),8.07(d,J=8.3Hz,1H),7.53(dd,J=8.5,4.2Hz,1H) ,6.02(ddd,J=17.2,10.2,8.6Hz,1H),5.84(ddt,J=17.1,10.2,7.0Hz,1H),5.42–5.31( m,2H),5.19–5.02(m,2H),3.28(q,J=7.6Hz,1H),2.80–2.69(m,1H),2.54–2.42(m,1H). 13 C NMR(101MHz,Chloroform-d)δ171.45,148.86,140.80,139.14,138.32,136.25,135.36,1 35.33,129.65,123.20,118.82,117.96,117.29,89.48,53.09,36.14.HRMS(ESI-TOF):m / z Calcd for C 16 H 16 IN2O + [M+H + ]:379.0302; found:379.0309.

[0077]

[0078] Weigh N-(5-iodoquinolin-8-yl)-2-vinylpentyl-4-enamide (1e) (0.038 g, 0.1 mmol), azobisisobutyronitrile (5) (0.066 g, 0.4 mmol), and Cu(CH3CN)4PF6 (0.008 g, 0.02 mmol) and dissolve them in 1 mL of acetonitrile. Heat the mixture to 90°C for reaction, and track the reaction by TLC until the reaction is completely completed. After the reaction is completed, the crude product is purified by silica gel column chromatography (petroleum ether: ethyl acetate = 8:1) to obtain compound 2e. The isolated yield is 75%.

[0079] 2e: 1 H NMR (400MHz, Chloroform-d) δ8.83 (dd, J=4.1, 1.7Hz, 1H), 8.36 (dd, J=8.6, 1.7Hz, 1H), 8.14 (d, J=8. 3Hz,1H),8.06(d,J=8.2Hz,1H),7.49(dd,J=8.6,4.2Hz,1H),6.00(ddt,J=17.1,10.1,7.1Hz,1H),5.2 8(dq,J=17.0,1.5Hz,1H),5.22–5.12(m,2H),3.31(ddd,J=6.8,6.0,2.2Hz,1H),2.75(dtt,J=7.0,5. 5,1.3Hz,2H),2.31(dd,J=13.7,1.9Hz,1H),1.77(dd,J=13.6,10.7Hz,1H),1.47(s,3H),1.39(s,3H). 13 C NMR(101MHz,Chloroform-d)δ168.40,149.72,140.73,140.65,137.91,134.15,133.94,130.65,124.44 ,123.19,122.46,118.39,92.01,59.31,57.38,44.09,33.31,30.51,27.91,26.97.HRMS(ESI-TOF):m / z Calcd for C 20 H 20 IN3NaO + [M+Na + ]:468.0543;found:468.0548.

[0080] Example 6

[0081] The preparation method of 3-(3-(cyclopropylmethyl)-1-(5-iodoquinolin-8-yl)-4-oxoazetidine-2-yl)-2,2-dimethylpropionitrile (2f) comprises the following steps:

[0082]

[0083] 5-iodo-8-aminoquinoline (3) (2.7 g, 10 mmol, 1 equiv), 2-cyclopropylmethyl-3-butenoic acid (4f) (1.68 g, 12 mmol, 1.2 equiv), 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, and the reaction system was washed with saturated sodium bicarbonate solution. The organic phase was collected and dried over anhydrous sodium sulfate, and the solvent was concentrated under reduced pressure. After purification by silica gel column chromatography (petroleum ether: ethyl acetate = 10: 1), compound 1f was obtained with a fraction yield of 26%.

[0084] 1f: 1 H NMR(400MHz,Chloroform-d)δ10.01(s,1H),8.77(dd,J=4.2,1.6Hz,1H),8.56(d,J=8.3Hz,1 H),8.36(dd,J=8.5,1.6Hz,1H),8.06(d,J=8.3Hz,1H),7.52(dd,J=8.5,4.2Hz,1H),6.07(ddd ,J=17.1,10.2,8.6Hz,1H),5.42–5.26(m,2H),3.31(q,J=7.5Hz,1H),1.82(dt,J=14.4,7.3Hz ,1H),1.68(dt,J=13.9,6.9Hz,1H),0.85–0.74(m,1H),0.54–0.37(m,2H),0.20–0.06(m,2H). 13 CNMR(101MHz,Chloroform-d)δ172.34,148.91,140.84,139.26,138.41,136.99,135.56,1 29.71,123.24,118.13,117.93,89.35,54.07,37.33,9.14,4.85,4.74.HRMS(ESI-TOF):m / z Calcd for C 17 H 18 IN2O + [M+H + ]:393.0458; found:393.0462.

[0085]

[0086] Weigh 2-(cyclopropylmethyl)-N-(5-iodoquinolin-8-yl)but-3-enamide (1f) (0.039 g, 0.1 mmol), azobisisobutyronitrile (5) (0.066 g, 0.4 mmol), and Cu(CH3CN)4PF6 (0.008 g, 0.02 mmol) and dissolve them in 1 mL of acetonitrile. Heat the mixture to 90°C for reaction, and track the reaction by TLC until the reaction is completely completed. After the reaction is completed, the crude product is purified by silica gel column chromatography (petroleum ether: ethyl acetate = 8:1) to obtain compound 2f. The isolated yield is 84%.

[0087] 2f: 1 H NMR(400MHz,Chloroform-d)δ8.83(dd,J=4.1,1.6Hz,1H),8.35(dd,J=8.6,1.7Hz,1H),8.15(d,J=8.2Hz,1H) ,8.05(d,J=8.2Hz,1H),7.48(dd,J=8.6,4.1Hz,1H),5.30(dt,J=10.7,2.0Hz,1H),3.30(ddd,J=7.6,5.5,2.2H z,1H),2.32(dd,J=13.6,1.9Hz,1H),2.00(ddd,J=14.2,7.6,6.4Hz,1H),1.85–1.78(m,1H),1.77–1.69(m,1H) ,1.46(s,3H),1.39(s,3H),1.03(qdt,J=7.9,6.5,4.9Hz,1H),0.61–0.45(m,2H),0.20(dq,J=4.8,1.7Hz,2H). 13 C NMR(101MHz,Chloroform-d)δ169.20,149.67,140.74,140.59,137.89,134.03,130.60,124.38,123.15 ,122.37,91.84,59.63,58.31,44.28,34.13,30.55,27.68,27.16,8.51,5.29,4.74.HRMS(ESI-TOF):m / z Calcd for C 21 H 23 IN3O + [M+H + ]:460.0880;found:460.0883.

[0088] Example 7

[0089] The preparation method of 3-(3-(cyclobutylmethyl)-1-(5-iodoquinolin-8-yl)-4-oxoazetidine-2-yl)-2,2-dimethylpropionitrile (2g) comprises the following steps:

[0090]

[0091] 5-iodo-8-aminoquinoline (3) (2.7 g, 10 mmol, 1 equiv), 2-cyclobutylmethyl-3-butenoic acid (4 g) (1.85 g, 12 mmol, 1.2 equiv), 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, and the reaction system was washed with saturated sodium bicarbonate solution. The organic phase was collected and dried over anhydrous sodium sulfate, and the solvent was concentrated under reduced pressure. After purification by silica gel column chromatography (petroleum ether: ethyl acetate = 10: 1), 1 g of compound was obtained with a fraction yield of 27%.

[0092] 1g: 1 H NMR (400MHz, Chloroform-d) δ9.94 (s, 1H), 8.76 (dd, J=4.2, 1.6Hz, 1H), 8.55 (d, J= 8.3Hz,1H),8.34(dd,J=8.5,1.6Hz,1H),8.05(d,J=8.3Hz,1H),7.51(dd,J=8.5,4.2 Hz,1H),5.99(ddd,J=17.1,10.1,8.6Hz,1H),5.37–5.23(m,2H),3.17–3.05(m,1H), 2.40(hept,J=7.9Hz,1H),2.15–1.97(m,3H),1.89–1.74(m,3H),1.71–1.60(m,2H). 13 CNMR(101MHz,Chloroform-d)δ172.33,148.90,140.80,139.22,138.37,136.99,135.51,129.68 ,123.22,118.05,117.90,89.35,51.83,39.21,34.02,28.63,28.35,18.60.HRMS(ESI-TOF):m / z Calcd for C 18 H 19 IN2NaO + [M+Na + ]:429.0434; found:429.0436.

[0093]

[0094] Weigh 2-(cyclobutylmethyl)-N-(5-iodoquinolin-8-yl)but-3-enamide (1g) (0.041g, 0.1mmol), azobisisobutyronitrile (5) (0.066g, 0.4mmol), Cu(CH3CN)4PF6 (0.008g, 0.02mmol) and dissolve them in 1mL acetonitrile. Heat the mixture to 90℃ for reaction, and track the reaction by TLC until the reaction is completely completed. After the reaction is completed, the crude product is purified by silica gel column chromatography (petroleum ether: ethyl acetate = 8:1) to obtain compound 2g. The isolation yield is 85%.

[0095] 2g: 1 H NMR(400MHz,Chloroform-d)δ8.84(dd,J=4.1,1.7Hz,1H),8.36(dd,J=8.6,1.6Hz,1H),8. 13(d,J=8.3Hz,1H),8.05(d,J=8.3Hz,1H),7.49(dd,J=8.6,4.1Hz,1H),5.14(dt,J=10.6,2 .0Hz,1H),3.13(ddd,J=7.9,5.5,2.2Hz,1H),2.70(p,J=7.8Hz,1H),2.29(dd,J=13.6,1.9H z,1H),2.21–2.04(m,4H),1.92–1.79(m,2H),1.78–1.68(m,3H),1.46(s,3H),1.38(s,3H). 13 C NMR(101MHz,Chloroform-d)δ169.25,149.70,140.74,140.69,137.95,134.02,130.65,123.18,122.42, 91.87,59.90,56.66,44.36,36.42,33.64,30.59,29.26,28.48,27.66,27.22,18.61.HRMS(ESI-TOF):m / z Calcd forC 22 H 25 IN3O + [M+H + ]:474.1037; found:474.1037.

[0096] Example 8

[0097] The preparation method of 3-(3-(cyclopentylmethyl)-1-(5-iodoquinolin-8-yl)-4-oxoazetidine-2-yl)-2,2-dimethylpropionitrile (2h) comprises the following steps:

[0098]

[0099] 5-iodo-8-aminoquinoline (3) (2.7 g, 10 mmol, 1 equiv), 2-cyclopentylmethyl-3-butenoic acid (4h) (1.85 g, 12 mmol, 1.2 equiv), 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, and the reaction system was washed with saturated sodium bicarbonate solution. The organic phase was collected and dried over anhydrous sodium sulfate, and the solvent was concentrated under reduced pressure. After purification by silica gel column chromatography (petroleum ether: ethyl acetate = 10: 1), compound 1h was obtained with a fraction yield of 32%.

[0100] 1h: 1 H NMR(400MHz,Chloroform-d)δ9.98(s,1H),8.78(dd,J=4.3,1.6Hz,1H),8.56(d,J=8.3Hz,1H),8.3 6(dd,J=8.5,1.6Hz,1H),8.06(d,J=8.3Hz,1H),7.53(dd,J=8.5,4.2Hz,1H),6.00(ddd,J=17.1,10. 1,8.7Hz,1H),5.40–5.24(m,2H),3.22(q,J=7.8Hz,1H),2.00(dt,J=13.2,7.1Hz,1H),1.94–1.76(m ,3H),1.72(ddd,J=13.2,8.0,6.1Hz,1H),1.63–1.58(m,2H),1.55–1.45(m,2H),1.24–1.07(m,2H). 13 C NMR(101MHz,Chloroform-d)δ172.53,148.93,140.85,139.27,138.40,137.24,135.56,129.72,12 3.25,118.09,117.95,89.34,53.00,38.39,37.79,33.05,32.48,25.32,25.26.HRMS(ESI-TOF):m / z Calcd for C 19 H 22 IN2O +[M+H + ]:421.0771; found:421.0768.

[0101]

[0102] Weigh 2-(cyclopentylmethyl)-N-(5-iodoquinolin-8-yl)but-3-enamide (1h) (0.042g, 0.1mmol), azobisisobutyronitrile (5) (0.066g, 0.4mmol), Cu(CH3CN)4PF6 (0.008g, 0.02mmol) and dissolve in 1mL acetonitrile. Heat the mixture to 90℃ for reaction, and track the reaction by TLC until the reaction is completely completed. After the reaction is completed, the crude product is purified by silica gel column chromatography (petroleum ether: ethyl acetate = 8:1) to obtain compound 2h. The isolated yield is 85%.

[0103] 2h: 1 H NMR(400MHz,Chloroform-d)δ8.83(dd,J=4.1,1.7Hz,1H),8.36(dd,J=8.6,1.7Hz,1H),8.15(d,J=8.2 Hz,1H),8.06(d,J=8.2Hz,1H),7.48(dd,J=8.6,4.1Hz,1H),5.12(dt,J=10.6,2.0Hz,1H),3.22(ddd,J =10.1,4.8,2.1Hz,1H),2.35–2.19(m,2H),2.10(ddd,J=13.4,10.2,5.4Hz,1H),2.01–1.84(m,3H),1. 74(dd,J=13.7,10.6Hz,1H),1.68–1.51(m,5H),1.46(s,3H),1.39(s,3H),1.21(q,J=11.3,9.4Hz,2H). 13 C NMR(101MHz,Chloroform-d)δ169.45,149.69,140.77,140.62,137.93,134.12,130.62,124.43,123.16,122.39, 91.82,60.72,57.58,44.32,37.92,36.21,33.65,32.48,30.57,27.70,27.20,25.27,25.23.HRMS(ESI-TOF):m / z Calcd for C 23 H 26 IN3NaO + [M+Na + ]:510.1013;found:510.1011.

[0104] Example 9

[0105] The preparation method of 3-(3-benzyl-1-(5-iodoquinolin-8-yl)-4-oxoazetidine-2-yl)-2,2-dimethylpropionitrile (2i) comprises the following steps:

[0106]

[0107] 5-iodo-8-aminoquinoline (3) (2.7 g, 10 mmol, 1 equiv), 2-benzyl-3-butenoic acid (4i) (2.11 g, 12 mmol, 1.2 equiv), 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, and the reaction system was washed with saturated sodium bicarbonate solution. The organic phase was collected and dried over anhydrous sodium sulfate, and the solvent was concentrated under reduced pressure. Compound 1i was obtained after purification by silica gel column chromatography (petroleum ether: ethyl acetate = 10: 1) with a fraction yield of 31%.

[0108] 1i: 1 H NMR(400MHz,Chloroform-d)δ9.93(s,1H),8.73(dd,J=4.3,1.6Hz,1H),8.57(d,J=8.3Hz, 1H),8.35(dd,J=8.5,1.6Hz,1H),8.07(d,J=8.3Hz,1H),7.51(dd,J=8.5,4.2Hz,1H),7.27 (d,J=1.6Hz,4H),7.18(ddd,J=8.7,5.0,3.7Hz,1H),6.12–5.99(m,1H),5.36–5.23(m,2H) ,3.50(dt,J=8.5,7.1Hz,1H),3.38(dd,J=13.7,6.9Hz,1H),2.99(dd,J=13.7,7.5Hz,1H). 13 C NMR(101MHz,Chloroform-d)δ171.44,148.87,140.77,139.18,139.13,138.33,136.23,135.39,1 29.66,129.32,128.50,126.47,123.23,119.01,117.93,89.50,55.27,38.20.HRMS(ESI-TOF):m / z Calcd for C 20 H 17IN2NaO + [M+Na + ]:451.0278;found:451.0277.

[0109]

[0110] 2-Benzyl-N-(5-iodoquinolin-8-yl)but-3-enamide (1i) (0.043 g, 0.1 mmol), azobisisobutyronitrile (5) (0.066 g, 0.4 mmol), Cu(CH3CN)4PF6 (0.008 g, 0.02 mmol) were weighed and dissolved in 1 mL of acetonitrile. The mixture was heated to 90°C for reaction, and the reaction was monitored by TLC until the reaction was completely completed. After the reaction was completed, the crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 8:1) to obtain compound 2i. The isolated yield was 66%.

[0111] 2i: 1 H NMR (400MHz, Chloroform-d) δ8.80 (dd, J=4.1, 1.7Hz, 1H), 8.34 (dd, J=8.6, 1.7Hz, 1H), 8.11 (d, J= 8.2Hz,1H),8.04(d,J=8.2Hz,1H),7.47(dd,J=8.6,4.1Hz,1H),7.42–7.35(m,2H),7.34–7.27(m,2 H),7.24–7.16(m,1H),5.20(dt,J=10.6,2.0Hz,1H),3.43(ddd,J=7.2,6.2,2.1Hz,1H),3.31(d,J= 6.7Hz, 2H), 2.27 (dd, J=13.7, 1.9Hz, 1H), 1.72 (dd, J=13.7, 10.6Hz, 1H), 1.34 (s, 3H), 1.16 (s, 3H). 13 C NMR(101MHz,Chloroform-d)δ168.42,149.71,140.71,140.57,138.07,137.85,133.83,130.60,129.56,128.77 ,126.86,124.41,123.17,122.48,92.13,59.70,59.33,44.11,35.42,30.55,27.25,27.11.HRMS(ESI-TOF):m / z Calcd for C 24 H 22 IN3NaO + [M+Na + ]:518.0700;found:518.0702.

[0112] Example 10

[0113] The preparation method of 3-(1-(5-iodoquinolin-8-yl)-4-oxo-3-phenylethylazetidin-2-yl)-2,2-dimethylpropionitrile (2j) comprises the following steps:

[0114]

[0115] 5-iodo-8-aminoquinoline (3) (2.7 g, 10 mmol, 1 equiv), 2-phenylethyl-3-butenoic acid (4j) (2.11 g, 12 mmol, 1.2 equiv), 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, and the reaction system was washed with saturated sodium bicarbonate solution. The organic phase was collected and dried over anhydrous sodium sulfate, and the solvent was concentrated under reduced pressure. Compound 1j was obtained after purification by silica gel column chromatography (petroleum ether: ethyl acetate = 10: 1) with a fraction yield of 24%.

[0116] 1j: 1 H NMR(400MHz,Chloroform-d)δ9.98(s,1H),8.77(dd,J=4.2,1.6Hz,1H),8.57(d,J=8.3Hz,1H),8 .36(dd,J=8.5,1.5Hz,1H),8.07(d,J=8.3Hz,1H),7.53(dd,J=8.5,4.2Hz,1H),7.32–7.26(m,2H) ,7.25–7.16(m,3H),6.04(ddd,J=17.2,10.2,8.7Hz,1H),5.43–5.31(m,2H),3.24–3.14(m,1H), 2.82–2.65(m,2H),2.37(ddt,J=13.6,9.2,6.7Hz,1H),2.00(dddd,J=13.8,9.0,7.7,6.4Hz,1H). 13C NMR(101MHz,Chloroform-d)δ171.94,148.93,141.55,140.84,139.26,138.38,136.69,135.48,129. 72,128.70,128.57,126.12,123.27,118.93,117.96,89.46,52.67,33.34,33.28.HRMS(ESI-TOF):m / z Calcdfor C 21 H 19 IN2NaO + [M+Na + ]:465.0434; found:465.0435.

[0117]

[0118] Weigh N-(5-iodoquinolin-8-yl)-2-phenylethylbut-3-enamide (1j) (0.044 g, 0.1 mmol), azobisisobutyronitrile (5) (0.066 g, 0.4 mmol), and Cu(CH3CN)4PF6 (0.008 g, 0.02 mmol) and dissolve them in 1 mL of acetonitrile. Heat the mixture to 90°C for reaction, and track the reaction by TLC until the reaction is completely completed. After the reaction is completed, the crude product is purified by silica gel column chromatography (petroleum ether: ethyl acetate = 8:1) to obtain compound 2j. The isolated yield is 83%.

[0119] 2j: 1 H NMR (400MHz, Chloroform-d) δ8.83 (dd, J=4.2, 1.7Hz, 1H), 8.37 (dd, J=8.6, 1.6Hz, 1H), 8.15 (d, J=8. 2Hz,1H),8.07(d,J=8.2Hz,1H),7.49(dd,J=8.6,4.1Hz,1H),7.27(d,J=4.4Hz,4H),7.19(h,J=4.0Hz ,1H),5.16(dt,J=10.7,2.0Hz,1H),3.23(ddd,J=9.3,5.1,2.2Hz,1H),3.13–3.02(m,1H),2.88(ddd, J=13.8,9.9,6.9Hz,1H),2.45–2.23(m,3H),1.72(dd,J=13.6,10.7Hz,1H),1.42(s,3H),1.32(s,3H). 13C NMR(101MHz,Chloroform-d)δ168.91,149.72,141.45,140.75,140.62,137.89,133.92,130.63,128.67,128.51,12 6.11,124.33,123.19,122.44,92.02,60.15,57.46,44.16,33.00,31.20,30.50,27.58,27.09.HRMS(ESI-TOF):m / z Calcd for C 25 H 24 IN3NaO + [M+Na + ]:532.0856;found:532.0863.

[0120] Embodiment 11

[0121] The preparation method of 3-(1-(5-iodoquinolin-8-yl)-3-(2-methylbenzyl)-4-oxoazetidine-2-yl)-2,2-dimethylpropionitrile (2k) comprises the following steps:

[0122]

[0123] 5-iodo-8-aminoquinoline (3) (2.7 g, 10 mmol, 1 equiv), 2-(2-methylbenzyl)-3-butenoic acid (4k) (2.28 g, 12 mmol, 1.2 equiv), 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, and the reaction system was washed with saturated sodium bicarbonate solution. The organic phase was collected and dried over anhydrous sodium sulfate, and the solvent was concentrated under reduced pressure. Compound 1k was obtained after purification by silica gel column chromatography (petroleum ether: ethyl acetate = 10: 1) with a fraction yield of 28%.

[0124] 1k: 1H NMR(400MHz,Chloroform-d)δ9.92(s,1H),8.72(dd,J=4.2,1.5Hz,1H),8.56(d,J=8.2Hz,1 H),8.36(dd,J=8.5,1.5Hz,1H),8.07(d,J=8.3Hz,1H),7.51(dd,J=8.5,4.2Hz,1H),7.21–7. 15(m,1H),7.15–7.11(m,1H),7.10–7.02(m,2H),6.14–6.02(m,1H),5.32–5.20(m,2H),3.4 8(q,J=7.6Hz,1H),3.39(dd,J=13.9,6.7Hz,1H),2.96(dd,J=13.9,7.5Hz,1H),2.38(s,3H). 13 CNMR(101MHz,Chloroform-d)δ171.63,148.76,140.97,139.03,138.41,137.37,136.41,136.31,135.34,130. 45,129.94,129.69,126.58,125.98,123.21,118.87,118.09,89.51,54.08,35.32,19.80.HRMS(ESI-TOF):m / z Calcd forC 21 H 19 IN2NaO + [M+Na + ]:465.0434; found:465.0438.

[0125]

[0126] Weigh N-(5-iodoquinolin-8-yl)-2-(2-methylbenzyl)but-3-enamide (1k) (0.044 g, 0.1 mmol), azobisisobutyronitrile (5) (0.066 g, 0.4 mmol), Cu(CH3CN)4PF6 (0.008 g, 0.02 mmol) and dissolve them in 1 mL of acetonitrile. Heat the mixture to 90°C for reaction, and track the reaction by TLC until the reaction is completely completed. After the reaction is completed, the crude product is purified by silica gel column chromatography (petroleum ether: ethyl acetate = 8:1) to obtain compound 2k. The isolated yield is 71%.

[0127] 2k: 1H NMR(400MHz,Chloroform-d)δ8.88(dd,J=4.1,1.7Hz,1H),8.37(dd,J=8.6,1.7Hz,1H),8.15(d ,J=8.2Hz,1H),8.06(d,J=8.2Hz,1H),7.50(dd,J=8.6,4.1Hz,1H),7.39(dd,J=7.0,1.6Hz,1H) ,7.22–7.10(m,3H),5.33–5.26(m,1H),3.45–3.33(m,2H),3.26(tt,J=11.1,5.7Hz,1H),2.42( s,3H),2.30(dd,J=13.8,1.8Hz,1H),1.67(dd,J=13.8,10.5Hz,1H),1.25(s,3H),1.04(s,3H). 13 CNMR(101MHz,Chloroform-d)δ168.46,149.89,140.74,140.61,137.87,136.43,136.41,133.91,130.66,130.64,130.42,1 27.13,126.40,124.28,123.24,122.50,92.18,60.57,58.16,44.13,33.23,30.58,27.42,26.43,19.77.HRMS(ESI-TOF):m / z Calcd for C 25 H 24 IN3NaO + [M+Na + ]:532.0856;found:532.0855.

[0128] Example 12

[0129] The preparation method of 2,2-dichloro-3-(1-(5-iodoquinolin-8-yl)-3-(4-methylbenzyl)-4-oxoazetidin-2-yl)propionitrile (21) comprises the following steps:

[0130]

[0131] 5-iodo-8-aminoquinoline (3) (2.7 g, 10 mmol, 1 equiv), 2-(4-methylbenzyl)-3-butenoic acid (4l) (2.28 g, 12 mmol, 1.2 equiv), 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, and the reaction system was washed with saturated sodium bicarbonate solution. The organic phase was collected and dried over anhydrous sodium sulfate, and the solvent was concentrated under reduced pressure. Compound 1l was obtained after purification by silica gel column chromatography (petroleum ether: ethyl acetate = 10: 1) with a fraction yield of 26%.

[0132] 1l: 1 H NMR(400MHz,Chloroform-d)δ9.92(s,1H),8.72(dd,J=4.2,1.5Hz,1H),8.55(d,J=8.3Hz,1H ),8.34(dd,J=8.5,1.6Hz,1H),8.06(d,J=8.3Hz,1H),7.50(dd,J=8.5,4.2Hz,1H),7.16–7.1 1(m,2H),7.05(d,J=8.0Hz,2H),6.04(ddd,J=17.0,10.2,8.5Hz,1H),5.33–5.23(m,2H),3.4 8(q,J=7.6Hz,1H),3.32(dd,J=13.8,6.9Hz,1H),2.95(dd,J=13.8,7.6Hz,1H),2.26(s,3H). 13 CNMR(101MHz,Chloroform-d)δ171.57,148.76,140.88,139.08,138.38,136.32,135.98,135.91,135. 37,129.66,129.19,129.17,123.18,118.89,118.05,89.46,55.31,37.79,21.15.HRMS(ESI-TOF):m / z Calcd for C 21 H 19 IN2NaO + [M+Na + ]:465.0434; found:465.0434.

[0133]

[0134] Weigh N-(5-iodoquinolin-8-yl)-2-(4-methylbenzyl)but-3-enamide (11) (0.045 g, 0.1 mmol), azobisisobutyronitrile (5) (0.066 g, 0.4 mmol), Cu(CH3CN)4PF6 (0.008 g, 0.02 mmol) and dissolve them in 1 mL of acetonitrile. Heat the mixture to 90°C for reaction, and track the reaction by TLC until the reaction is completely completed. After the reaction is completed, the crude product is purified by silica gel column chromatography (petroleum ether: ethyl acetate = 8:1) to obtain compound 21. The isolated yield is 62%.

[0135] 2l: 1 H NMR (400MHz, Chloroform-d) δ8.83 (dd, J=4.2, 1.7Hz, 1H), 8.35 (dd, J=8.6, 1.6Hz, 1H), 8. 13(d,J=8.2Hz,1H),8.05(d,J=8.2Hz,1H),7.49(dd,J=8.6,4.1Hz,1H),7.25–7.19(m,2H), 7.09(d,J=7.7Hz,2H),5.31(dt,J=10.2,2.0Hz,1H),3.60(ddd,J=7.6,5.6,2.3Hz,1H),3. 44(dd,J=14.3,1.7Hz,1H),3.30–3.18(m,2H),2.74(dd,J=14.3,10.2Hz,1H),2.27(s,3H). 13 C NMR(101MHz,Chloroform-d)δ167.91,150.03,140.73,140.30,137.87,136.46,134.29,133.56,130.63,129 .43,129.39,123.30,122.09,115.23,92.31,65.94,59.56,58.94,50.63,34.42,21.18.HRMS(ESI-TOF):m / z Calcd forC 23 H 19 Cl2IN3O + [M+H + ]:548.9872; found:548.9877.

[0136] In summary, the present invention discloses a method for preparing a 4-(2,2-dimethyl-2-cyanoethyl)-β-lactam derivative, which uses a substituted N-(5-iodoquinolin-8-yl)-3-buteneamide derivative as a substrate, azobisisobutyronitrile as a free radical source, and copper salts such as tetraacetonitrile hexafluorophosphate as a catalyst, and reacts in an organic solvent such as acetonitrile at 80-110° C. to prepare a 4-(2,2-dimethyl-2-cyanoethyl)-β-lactam derivative.

[0137] Obviously, the above embodiments of the present invention are only examples for clearly illustrating the present invention, and are not intended to limit the embodiments of the present invention. Those skilled in the art should understand that other different forms of changes or modifications can be made based on the above description. It is not necessary and impossible to list all the embodiments here. Any modifications, equivalent substitutions and improvements made within the spirit and principles of the present invention should be included in the protection scope of the claims of the present invention.

Claims

1. A method for preparing a 4-(2,2-dimethyl-2-cyanoethyl)-β-lactam derivative, characterized in that: The following steps are involved: The substituted N-(5-iodoquinoline)-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 4-(2,2-dimethyl-2-cyanoethyl)-β-lactam derivative of formula (2); Formula (1) and formula (2) are shown as follows: Wherein, R is selected from one of hydrogen, C1-C6 saturated or unsaturated alkyl, substituted or unsubstituted benzyl, and substituted or unsubstituted phenethyl.

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

3. The preparation method according to claim 1, characterized in that: The organic solvent is selected from one or more of acetonitrile, dioxane and dichloromethane.

4. The preparation method according to claim 1, characterized in that: The molar ratio of the substituted N-(5-iodoquinoline)-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 substituted N-(5-iodoquinoline)-3-buteneamide derivative to the copper salt catalyst is 1:(0.1-0.3).

6. The preparation method according to claim 1, characterized in that: The molar ratio of the substituted N-(5-iodoquinoline)-3-buteneamide derivative to the organic solvent is 1:(20-30).

7. The preparation method according to claim 1, characterized in that: The reaction temperature is 90-100°C.

8. The preparation method according to claim 1, characterized in that: The R is hydrogen, methyl, ethyl, isopropyl, allyl, cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, benzyl, phenethyl, o-methylbenzyl or p-o-methylbenzyl.

9. The preparation method according to claim 1, characterized in that: The preparation method of the substituted N-(5-iodoquinoline)-3-buteneamide derivative of formula (1) is as follows: The 5-iodo-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-(5-iodoquinoline)-3-butenoic acid derivative of formula (1); the reaction scheme is as follows: Wherein, R is selected from one of hydrogen, C1-C6 saturated or unsaturated alkyl, substituted or unsubstituted benzyl, and substituted or unsubstituted phenethyl.

10. The preparation method according to claim 9, characterized in that: The R is hydrogen, methyl, ethyl, isopropyl, allyl, cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, benzyl, phenethyl, o-methylbenzyl or p-o-methylbenzyl.

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