Antitumor active molecule benz[b]azepine derivatives and synthesis method and application thereof

Abstract

This invention belongs to the field of synthesis of benzo[b]azapyrrolizidine derivatives, specifically disclosing an antitumor active molecule, a benzo[b]azapyrrolizidine derivative, its synthesis method, and its application. This invention uses a transition metal Pd catalyst to generate a benzo[b]azapyrrolizidine derivative active molecule, as shown in general formula (2), from an acetylacetamide of general formula (1) in the presence of a ligand, a basic substance, and a solvent, under a nitrogen atmosphere and irradiation with light at a wavelength of 420–500 nm. This invention achieves the synthesis of structures containing benzo[b]azapyrrolizidine molecular fragments through a free radical relay tandem cyclization reaction from aryl to alkyl to vinyl groups catalyzed by transition metal Pd, realizing the synthesis of such molecules. Furthermore, a series of synthesized benzo[b]azapyrrolizidine molecules and their derivative active molecules have been tested and found to possess antitumor activity.

Description

Technical Field

[0001] This invention pertains to the synthesis of benzo[b]azapyrrolizidine derivatives, specifically relating to a method for synthesizing an antitumor active molecule, a benzo[b]azapyrrolizidine derivative. Background Technology

[0002] Benzoazapyrrolidone fragments play a crucial role as fundamental structural elements in a range of biologically and pharmacologically important compounds (Le Diguarher, T.; Ortuno, J.-C.; Shanks, D.; Guilbaud, N.; Pierré, A.; Raimbaud, E.; Fauchère, J.-L.; Bioorg*. Med. Chem. Lett. 2004, 14, 767-771; Kondo, K.; Ogawa, H.; Shinohara, T.; Kurimura, M.; Tanada, Y.; Kan, K.; Yamashita, H.; Nakamura, S.; Hira). no, T.; Yamamura, Y.; Mori, T.; Tominaga, M.; Itai, A*.J.Med.Chem.2000,43,4388-4397; Failli, AA; lliams, DK; Trybulski, EJ; Ning,It is worth noting that benzo[b]azazepine is a core component of various antidepressants, such as benazepril, mozaptan, etanerpine, dalrenzepine, and dibenzo[b]azazepine (Hou, FF; Zhang, X.; Zhang, GH; Xie, D.; Chen, PY; Zhang, WR; Jiang, JP; Liang, M.; Wang, GB; Liu, ZR; Geng, RWN; Nengl. J. Med. 2006, 354, 131-140; Decaux, G.; Soupart, A.; Vassart, G. The Lancet 2008, 371, 1624-1632; Groth, C.; Alvord, WG; Quinones, OA; Fortini, ME; Mol. Pharmaco l. 2010, 77, 567-574; CM; Allan, CE; Ashworth, DM; Barne, J.; Baxter, AJ; Broadbridge, JD; Franklin, RJ; Hampton, SL; Hudson, P.; Horton, JA; Jenkins, PD; Penson, AM; Pitt, GRW; Riviere, P.; Robson, PA; Rooker, DP; Semile, G.; Sheppard, A.; Haigh, RM; Roe, MBJ Med. Chem. 2008, 51, 8124-8134.). Current methods mainly suffer from cumbersome synthetic steps, demanding reaction conditions, and limitations on substrate structures. Summary of the Invention

[0003] Due to the limitations and harsh reaction conditions of the known methods, there is an urgent need to develop a simple, efficient, and mild practical method. To address the shortcomings of existing technologies, this invention provides a universal, simple, and efficient one-step synthetic method for the active molecules of benzo[b]azapine and its derivatives. This method synthesizes a series of active molecules of benzo[b]azapine and its derivatives under mild conditions through an intramolecular radical relay cascade cyclization reaction combining single-electron transfer and hydrogen atom transfer. This method follows the single-electron transfer process with a hydrogen atom transfer step to generate new radical intermediates, and ultimately synthesizes structures containing benzo[b]azapine molecular fragments through a relay process of radicals from aryl to alkyl to vinyl groups. This specific reaction mode is extremely rare.

[0004] The technical solution adopted in this invention is as follows:

[0005] A method for synthesizing an antitumor benzo[b]azapyrrol derivative active molecule, the specific steps are as follows: using a transition metal Pd catalyst, acetylacetamide compound (1) is used to generate a benzo[b]azapyrrol derivative active molecule in the presence of ligands, alkaline substances and solvents, under a nitrogen atmosphere and under visible light irradiation with a wavelength of 420-500 nm, as shown in general formula (2);

[0006]

[0007] R 1 It is one of hydrogen, alkyl groups with up to 20 carbon atoms, alkoxy groups, halogens, ester groups, trifluoromethyl groups, and cyano groups;

[0008] R 2 It is one of hydrogen, alkyl with 20 or fewer carbon atoms, phenyl, phenyl with alkoxy substituent, phenyl with halogen substituent, phenyl with nitro substituent, phenyl with cyano substituent, naphthyl, thiophene, pyridyl, monosubstituted or polysubstituted phenyl;

[0009] R 3 The substituents are one of alkyl, benzyl, or phenyl groups with up to 20 carbon atoms;

[0010] X is an oxygen atom, a nitrogen atom, or a carbon atom with a substituent;

[0011] Y is an oxygen atom, a nitrogen atom, or a carbon atom with a substituent;

[0012] Furthermore, the transition metal Pd catalyst is one or more combinations of palladium acetate, bis(dibenzylacetone)palladium, palladium trifluoroacetate, bis(2-diphenylphosphine) ether palladium dichloride, bis(triphenylphosphine) dichloride palladium, bis(triphenylphosphine) acetate palladium, tetra(triphenylphosphine)palladium, and bis(1,2-bis(diphenylphosphine)ethane)palladium, wherein tetra(triphenylphosphine)palladium and / or bis(1,2-bis(diphenylphosphine)ethane)palladium are preferred.

[0013] Furthermore, the ligand is 1,1'-binaphthyl-2,2'-bis(diphenylphosphine), bis(2-diphenylphosphine) ether, 4,5-bis(diphenylphosphine)-9,9-dimethyloxanthracene, 1,3-bis(diphenylphosphine)propane, 1,2-bis(diphenylphosphine)ethane, 1,1'-bis(diphenylphosphine)ferrocene, triphenylphosphine, 2,2'-bipyridine, wherein bis(2-diphenylphosphine) ether is preferred.

[0014] Furthermore, the alkaline substance is potassium phosphate, potassium carbonate, cesium carbonate, silver oxide, sodium acetate, potassium phosphate, sodium tert-butoxide, sodium ethoxide, sodium methoxide, N,N-dihexylmethylamine, with sodium methoxide being preferred.

[0015] Furthermore, the solvent is benzene, trifluorotoluene, tetrahydrofuran, or 1,4-dioxane, with benzene being preferred.

[0016] Furthermore, the reaction temperature is 0℃~100℃, preferably 25℃.

[0017] Furthermore, the reaction time is 2 to 48 hours, with 12 hours being preferred.

[0018] Furthermore, the molar ratio of the acetylamid to the palladium catalyst is 1:0.01 to 1:0.2, preferably 1:0.1.

[0019] Furthermore, the molar ratio of the palladium catalyst to the ligand is 1:0 to 1:4, preferably 1:1.

[0020] Furthermore, the molar ratio of the acetylene amide to the base is 1:0 to 1:5, preferably 1:2.

[0021] Furthermore, the concentration of compound 1 in the solvent is 0.01–0.2 M, preferably 0.05 M.

[0022] Furthermore, the process includes a purification step: after the reaction is complete, the mixture is washed with water and extracted with the organic phase, the organic phases are combined, dried over anhydrous sodium sulfate and concentrated under reduced pressure, and then purified by column chromatography.

[0023] Preferably, the material addition method includes: first adding the acetylacetamide, ligand, and alkaline substance of general formula (1) to the reaction flask; then adding the metal catalytic palladium catalyst and solvent in a nitrogen atmosphere.

[0024] Preferably, vigorous stirring is used during the reaction process.

[0025] Compounds of general formula (2), preferably the following specific compounds of general formula (2):

[0026]

[0027] Application of the prepared antitumor active molecule benzo[b]azapyrrol derivative in the preparation of antitumor drugs.

[0028] Compared with the prior art, the beneficial effects of the present invention are as follows: (1) The synthesis of a structure containing a benzo[b]azapyrrolidone molecular fragment by a radical relay cascade cyclization reaction from aryl to alkyl to vinyl via transition metal Pd catalysis is extremely rare. There are currently no reports of synthesizing such molecules using this method.

[0029] (2) The method of the present invention is simple to operate and has excellent substrate universality. The series of benzo[b]azapyrrolizidine molecules and their derivative active molecules synthesized have been tested and found to have antitumor activity. Attached Figure Description

[0030] Figure 1 This is a screening diagram of the antiproliferative phenotype of benzo[b]azapyridine derivatives in different tumor cell lines.

[0031] Figure 2 Linear regression analysis plot for benzo[b]azapyrrolizidine derivative 2u.

[0032] Figure 3 Linear regression analysis plot for benzo[b]azapyrrolizidine derivative 2n. Detailed Implementation

[0033] The specific embodiments of the present invention will be described in further detail below with reference to examples.

[0034] Example 1

[0035]

[0036] In a glove box, 23.1 mg (0.02 mmol) of tetra(triphenylphosphine)palladium, 10.8 mg (0.02 mmol) of bis(2-diphenylphosphine) ether, 21.6 mg (0.40 mmol) of sodium methoxide, and 83.4 mg (0.20 mmol) of compound 1a were added to an 8 mL vial, followed by 4 mL of benzene. The mixture was stirred at room temperature for 12 hours under 24 W blue LED light. After the reaction was complete, the mixture was washed with water and extracted with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was separated by column chromatography to give the target compound 2a (50.6 mg of product, 87% yield).

[0037] The target product 2a obtained by the above synthesis method was subjected to proton and carbon NMR spectra, and the test results are as follows: 1 H NMR (400MHz, CDCl3) δ7.28-7.16(m,5H),7.11(d,J=6.8Hz,2H),6.92(dd,J=6.4,2.0Hz,2H),3.38(s,3 H),2.78(d,J=7.6Hz,1H),2.64-2.52(m,2H),2.34-2.28(m,1H),1.85-1.78(m,2H),1.74-1.65(m,1H). 13 C NMR (101MHz, CDCl3) δ172.4,146.5,141.3,140.8,136.3,130.8,129.8,129.6,128.0,127.1,126.8,123.8,122.5,47.7,36.7,32.9,27.9,26.2.

[0038] The study investigated the effect of changing reaction conditions (a single variable) on the yield, as follows:

[0039]

[0040]

[0041]

[0042]

[0043]

[0044]

[0045]

[0046]

[0047] Example 2

[0048]

[0049] In a glove box, 23.1 mg (0.02 mmol) of tetra(triphenylphosphine)palladium, 10.8 mg (0.02 mmol) of bis(2-diphenylphosphine) ether, 21.6 mg (0.40 mmol) of sodium methoxide, and 89.5 mg (0.20 mmol) of compound 1b were added to an 8 mL vial, followed by 4 mL of benzene. The mixture was stirred at room temperature for 12 hours under 24 W blue LED light. After the reaction was complete, the mixture was washed with water and extracted with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was separated by column chromatography to give the target compound 2b (42.3 mg product, 66% yield).

[0050] The target product 2b obtained by the above synthesis method was subjected to proton and carbon NMR spectra, and the test results are as follows: 1 H NMR (400MHz, CDCl3) δ7.28-7.23(m,2H),7.20-7.10(m,4H),6.76(dd,J=9.2,3.2Hz,1H),6.38(d,J=3.2Hz,1H),3.55(s ,3H),3.33(s,3H),2.81(d,J=7.6Hz,1H),2.62-2.51(m,2H),2.32-2.25(m,1H),1.84-1.76(m,2H),1.73-1.64(m,1H). 13C NMR (101MHz, CDCl3) δ172.2,155.3,146.8,140.6,137.5,135.1,130.7,129 .8,128.0,126.9,123.7,113.7,113.5,55.3,47.7,36.8,32.9,27.9,26.1.

[0051] Example 3

[0052]

[0053] In a glove box, 23.1 mg (0.02 mmol) of tetra(triphenylphosphine)palladium, 10.8 mg (0.02 mmol) of bis(2-diphenylphosphine) ether, 21.6 mg (0.40 mmol) of sodium methoxide, and 86.2 mg (0.20 mmol) of compound 1c were added to an 8 mL vial, followed by 4 mL of benzene. The mixture was stirred at room temperature for 12 hours under 24 W blue LED light. After the reaction was complete, the mixture was washed with water and extracted with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was separated by column chromatography to give the target compound 2c (37.6 mg of product, 62% yield).

[0054] The target product 2c obtained by the above synthesis method was subjected to proton and carbon NMR spectra, and the test results are as follows: 1 H NMR (400MHz, CDCl3) δ7.37-7.33(m,2H),7.30-7.27(m,1H),7.21-7.18(m,3H),7.09-7.07(m,1H),6.77(d,J=2.0Hz,1H),3. 43(s,3H),2.86(d,J=7.6Hz,1H),2.71-2.58(m,2H),2.40-2.33(m,1H),2.20(s,3H),1.92-1.84(m,2H),1.81-1.73(m,1H). 13 C NMR (101MHz, CDCl3) δ172.4,146.4,140.9,139.1,136.2,133.4,130.8,129 .8,129.6,128.1,128.0,126.8,122.4,47.7,36.7,32.9,27.9,26.2,20.7.

[0055] Example 4

[0056]

[0057] In a glove box, 23.1 mg (0.02 mmol) of tetra(triphenylphosphine)palladium, 10.8 mg (0.02 mmol) of bis(2-diphenylphosphine) ether, 21.6 mg (0.40 mmol) of sodium methoxide, and 87.1 mg (0.20 mmol) of compound 1d were added to an 8 mL vial, followed by 4 mL of benzene. The mixture was stirred at room temperature for 12 hours under 24 W blue LED light. After the reaction was complete, the mixture was washed with water and extracted with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was separated by column chromatography to give the target compound 2d (46.0 mg product, 75% yield).

[0058] The target product 2d obtained by the above synthesis method was subjected to proton, carbon, and fluorine NMR spectra. The test results are as follows: 1 H NMR (400MHz, CDCl3) δ7.29-7.25(m,2H),7.22-7.15(m,2H),7.11-7.08(m,2H),6.89(ddd,J=9.2,7.6,3.2Hz,1H),6.58(dd,J=10 .0,3.2Hz,1H),3.34(s,3H),2.77(d,J=7.6Hz,1H),2.62-2.52(m,2H),2.33-2.25(m,1H),1.84-1.76(m,2H),1.75-1.65(m,1H). 13 C NMR (101MHz, CDCl3) δ 172.1, 158.4 (d, J = 244.6Hz), 147.6, 140.1, 138.2 (d, J = 7.8Hz), 137.6 (d, J = 2.7Hz), 130.2 (d, J = 1. 9Hz), 129.7, 128.2, 127.1, 124.2 (d, J = 8.6Hz), 115.3 (d, J = 22.6Hz), 114.5 (d, J = 23.2Hz), 47.7, 36.9, 33.0, 27.9, 26.1. 19 F NMR (376MHz, CDCl3) δ-117.8.

[0059] Example 5

[0060]

[0061] In a glove box, 23.1 mg (0.02 mmol) of tetra(triphenylphosphine)palladium, 10.8 mg (0.02 mmol) of bis(2-diphenylphosphine) ether, 21.6 mg (0.40 mmol) of sodium methoxide, and 90.3 mg (0.20 mmol) of compound 1e were added to an 8 mL vial, followed by 4 mL of benzene. The mixture was stirred at room temperature for 12 hours under 24 W blue LED light. After the reaction was complete, the mixture was washed with water and extracted with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was separated by column chromatography to give the target compound 2e (46.9 mg product, 73% yield).

[0062] The target product 2e obtained by the above synthesis method was subjected to proton, carbon, and fluorine NMR spectra. The test results are as follows: 1 H NMR (400MHz, CDCl3) 1 H NMR (400MHz, CDCl3) δ7.30-7.26(m,2H),7.24-7.19(m,1H),7.15(d,J=1.6Hz,2H),7.10-7.08(m,2H),6.87(t ,J=1.6Hz,1H),3.35(s,3H),2.76(d,J=7.2Hz,1H),2.63-2.52(m,2H),2.33-2.26(m,1H),1.84-1.67(m,3H). 13 CNMR (101MHz, CDCl3) δ172.1,147.7,140.0,139.8,137.9,130.0,129.7,129.2,129.1,128.2,127.3,127.2,123.9,47.8,36.8,33.03,27.9,26.1.

[0063] Example 6

[0064]

[0065] In a glove box, 23.1 mg (0.02 mmol) of tetratetraphenylphosphine palladium, 10.8 mg (0.02 mmol) of bis(2-diphenylphosphine) ether, 21.6 mg (0.40 mmol) of sodium methoxide, and 97.1 mg (0.20 mmol) of compound 1f were added to an 8 mL vial, followed by 4 mL of benzene. The mixture was stirred at room temperature for 12 hours under 24 W blue LED light. After the reaction was complete, the mixture was washed with water and extracted with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was separated by column chromatography to give the target compound 2f (42.0 mg product, 55% yield).

[0066] The target product 2f obtained by the above synthesis method was subjected to proton, carbon, and fluorine NMR spectra. The test results are as follows: 1 H NMR (400MHz, CDCl3) δ7.43(dd,J=8.4,2.0Hz,1H),7.33-7.26(m,3H),7.24-7.17(m,2H),7.10(dd,J=6.8,1.6Hz,2H ),3.40(s,3H),2.74(d,J=7.2Hz,1H),2.66-2.54(m,2H),2.37-2.30(m,1H),1.85-1.79(m,2H),1.77-1.67(m,1H). 13 C NMR (101MHz, CDCl3) δ172.2,148.0,143.8,139.9,136.6,130.2,129.7,128.3,127.3,126.9(q,J=4.0Hz ),125.8(q,J=32.6Hz),123.8(q,J=3.5Hz),123.7(q,J=272.7Hz),122.9,47.9,36.7,33.1,28.0,26.0. 19 F NMR (376MHz, CDCl3) δ-62.3.

[0067] Example 7

[0068]

[0069] In a glove box, 23.1 mg (0.02 mmol) of tetra(triphenylphosphine)palladium, 10.8 mg (0.02 mmol) of bis(2-diphenylphosphine) ether, 21.6 mg (0.40 mmol) of sodium methoxide, 1 g (95.0 mg) of the compound (0.20 mmol) were added to an 8 mL vial, followed by 4 mL of benzene. The mixture was stirred at room temperature for 12 hours under 24 W blue LED light. After the reaction was complete, the mixture was washed with water and extracted with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was separated by column chromatography to give 2 g of the target compound (34.0 mg of product, yield 49%).

[0070] The target product (2g) obtained by the above synthesis method was subjected to proton and carbon NMR spectra. The test results are as follows: 1H NMR (400MHz, CDCl3) δ7.92(dd,J=8.8,2.0Hz,1H),7.68(d,J=2.0Hz,1H),7.38-7.29(m,4H),7.19-7.16(m,2H),3.81(s ,3H),3.48(s,3H),2.82(d,J=7.2Hz,1H),2.74-2.61(m,2H),2.45-2.38(m,1H),1.93-1.85(m,2H),1.84-1.74(m,1H). 13 C NMR (101MHz, CDCl3) δ172.3,166.3,147.2,144.8,140.2,136.2,131.5,130.5, 129.8,128.2,128.1,127.2,125.5,122.4,52.1,47.9,36.7,33.1,28.0,26.1.

[0071] Example 8

[0072]

[0073] In a glove box, 23.1 mg (0.02 mmol) of tetra(triphenylphosphine)palladium, 10.8 mg (0.02 mmol) of bis(2-diphenylphosphine) ether, 21.6 mg (0.40 mmol) of sodium methoxide, and 90.3 mg (0.20 mmol) of compound 2h were added to an 8 mL vial, followed by 4 mL of benzene. The mixture was stirred at room temperature for 12 hours under 24 W blue LED light. After the reaction was complete, the mixture was washed with water and extracted with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was separated by column chromatography to give the target compound 2h (34.0 mg product, 53% yield).

[0074] The target product obtained by the above synthesis method was subjected to 1H and 1C NMR spectra 2h, and the test results are as follows: 1 H NMR (400MHz, CDCl3) δ7.37-7.33(m,2H),7.30-7.26(m,2H),7.17(dd,J=7.2,1.6Hz,2H),6.97(dd,J=8.4,2.0Hz,1H),6.91 (d,J=8.4Hz,1H),3.44(s,3H),2.84(d,J=7.2Hz,1H),2.72-2.60(m,2H),2.38(dt,J=17.6,4.8Hz,1H),1.92-1.76(m,3H). 13C NMR (101MHz, CDCl3) δ172.1,146.7,142.1,140.4,134.9,132.4,130.9,130.2,129.8,128.2,127.1,124.0,122.4,47.8,36.7,32.9,28.0,26.1.

[0075] Example 9

[0076]

[0077] In a glove box, 23.1 mg (0.02 mmol) of tetratetraphenylphosphine palladium, 10.8 mg (0.02 mmol) of bis(2-diphenylphosphine) ether, 21.6 mg (0.40 mmol) of sodium methoxide, and 94.7 mg (0.20 mmol) of compound 1i were added to an 8 mL vial, followed by 4 mL of benzene. The mixture was stirred at room temperature for 12 hours under 24 W blue LED light. After the reaction was complete, the mixture was washed with water and extracted with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was separated by column chromatography to give the target compound 2i (60.0 mg product, 88% yield).

[0078] The target product 2i obtained by the above synthesis method was subjected to proton and carbon NMR spectra. The test results are as follows: δ 7.34 (d, J = 8.0 Hz, 2H), 7.29-7.23 (m, 2H), 7.12 (d, J = 8.0 Hz, 2H), 7.04-6.98 (m, 2H), 3.44 (s, 3H), 2.84 (d, J = 7.6 Hz, 1H), 2.74-2.59 (m, 2H), 2.46-2.40 (m, 1H), 1.93-1.85 (m, 2H), 1.82-1.72 (m, 1H), 1.33 (s, 9H). 13 C NMR (101MHz, CDCl3) δ172.5,149.6,146.1,141.4,137.8,136.6,130.6,129.8 ,129.4,127.0,124.8,123.7,122.4,47.7,36.7,34.5,33.0,31.3,28.0,26.2.

[0079] Example 10

[0080]

[0081] In a glove box, 23.1 mg (0.02 mmol) of tetra(triphenylphosphine)palladium, 10.8 mg (0.02 mmol) of bis(2-diphenylphosphine) ether, 21.6 mg (0.40 mmol) of sodium methoxide, and 89.5 mg (0.20 mmol) of compound 1j were added to an 8 mL vial, followed by 4 mL of benzene. The mixture was stirred at room temperature for 12 hours under 24 W blue LED light. After the reaction was complete, the mixture was washed with water and extracted with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was separated by column chromatography to give the target compound 2j (39.0 mg product, 61% yield).

[0082] The target product 2j obtained by the above synthesis method was subjected to proton and carbon NMR spectra, and the test results are as follows: 1 H NMR (400MHz, CDCl3) δ7.30-7.24(m,2H),7.14-7.10(m,2H),7.01-7.00(m,2H),6.89-6.86(m,2H),3.83(s,3H), 3.45(s,3H),2.83(d,J=7.6Hz,1H),2.71-2.59(m,2H),2.44-2.36(m,1H),1.93-1.85(m,2H),1.82-1.74(m,1H). 13 C NMR (101MHz, CDCl3) δ172.6,158.4,145.9,141.4,136.7,133.3,131.0,130 .3,129.7,127.1,123.7,122.5,113.4,55.2,47.7,36.7,32.9,28.0,26.2.

[0083] Example 11

[0084]

[0085] In a glove box, 23.1 mg (0.02 mmol) of tetratetraphenylphosphine palladium, 10.8 mg (0.02 mmol) of bis(2-diphenylphosphine) ether, 21.6 mg (0.40 mmol) of sodium methoxide, and 87.1 mg (0.20 mmol) of compound 2h were added to an 8 mL vial, followed by 4 mL of benzene. The mixture was stirred at room temperature for 12 hours under 24 W blue LED light. After the reaction was complete, the mixture was washed with water and extracted with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was separated by column chromatography to give the target compound 2h (54.5 mg product, 89% yield).

[0086] The target product obtained by the above synthesis method was subjected to 1H, 1C, and fluorine NMR spectra 2h, and the test results are as follows: 1 H NMR (400MHz, CDCl3) δ7.32-7.25(m,2H),7.19-7.14(m,2H),7.06-7.00(m,3H),6.97-6.94(m,1H),3.45(s ,3H),2.85(d,J=7.6Hz,1H),2.69-2.60(m,2H),2.41-2.33(m,1H),1.94-1.86(m,2H),1.82-1.74(m,1H). 13 C NMR (101MHz, CDCl3) δ172.3,161.6(d,J=246.3Hz),146.7,141.3,136.8(d,J=3.5Hz),136.2,131.4( d,J=7.9Hz),129.8,129.5,127.3,123.8,122.5,115.0(d,J=21.3Hz),47.7,36.7,32.9,28.0,26.2. 19 F NMR (376MHz, CDCl3) δ-115.1.

[0087] Example 12

[0088]

[0089] In a glove box, 23.1 mg (0.02 mmol) of tetratetraphenylphosphine palladium, 10.8 mg (0.02 mmol) of bis(2-diphenylphosphine) ether, 21.6 mg (0.40 mmol) of sodium methoxide, 90.3 mg (0.20 mmol) of compound 1l, and finally 4 mL of benzene were added to an 8 mL vial. The mixture was stirred at room temperature for 12 hours under 24 W blue LED light. After the reaction was complete, the mixture was washed with water and extracted with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was separated by column chromatography to give target compound 2l (50.0 mg product, 77% yield).

[0090] The target product 2l obtained by the above synthesis method was subjected to proton and carbon NMR spectra, and the test results are as follows: 1H NMR (400MHz, CDCl3) δ7.32-7.25(m,4H),7.15-7.12(m,2H),7.03-6.98(m,1H),7.96-6.93(m,1H),3.45(s ,3H),2.84(d,J=7.6Hz,1H),2.69-2.60(m,2H),2.41-2.33(m,1H),1.94-1.86(m,2H),1.81-1.71(m,1H). 13 C NMR (101MHz, CDCl3) δ172.1,146.9,141.3,139.1,135.8,132.6,131.1,129.6,129.4,128.2,127.3,123.8,122.5,47.7,36.6,32.8,27.9,26.1.

[0091] Example 13

[0092]

[0093] In a glove box, 18.1 mg (0.02 mmol) of bis(1,2-bis(diphenylphosphine)ethane)palladium, 10.8 mg (0.02 mmol) of bis(2-diphenylphosphine) ether, 21.6 mg (0.40 mmol) of sodium methoxide, and 99.2 mg (0.20 mmol) of compound 1m were added to an 8 mL vial, followed by 4 mL of benzene. The mixture was stirred at room temperature for 12 hours under 24 W blue LED light. After the reaction was complete, the mixture was washed with water and extracted with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was separated by column chromatography to give the target compound 2m (36.1 mg product, 49% yield).

[0094] The target product 2m obtained by the above synthesis method was subjected to proton and carbon NMR spectra, and the test results are as follows: 1 H NMR (400MHz, CDCl3) δ7.47(d,J=8.0Hz,2H),7.30-7.26(m,2H),7.08(d,J=8.0Hz,2H),7.04-7.00(m,1H),6.95(d,J=8.0Hz,1H ),3.45(s,3H),2.85(d,J=7.6Hz,1H),2.69-2.60(m,2H),2.38(dt,J=17.6,4.4Hz,1H),1.93-1.87(m,2H),1.82-1.72(m,1H). 13CNMR(101MHz, CDCl3)δ172.3,147.1,141.4,139.7,135.9,131.6,131.3,129.7,129.5,127.4,123.9,122.6,120.9,47.9,36.8,32.9,28.0,26.2.

[0095] Example 14

[0096]

[0097] In a glove box, 23.1 mg (0.02 mmol) of tetratetraphenylphosphine palladium, 10.8 mg (0.02 mmol) of bis(2-diphenylphosphine) ether, 21.6 mg (0.40 mmol) of sodium methoxide, and 97.1 mg (0.20 mmol) of compound 1n were added to an 8 mL vial, followed by 4 mL of benzene. The mixture was stirred at room temperature for 12 hours under 24 W blue LED light. After the reaction was complete, the mixture was washed with water and extracted with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was separated by column chromatography to give the target compound 2n (54.1 mg product, 76% yield).

[0098] The target product 2n obtained by the above synthesis method was subjected to proton, carbon, and fluorine NMR spectra. The test results are as follows: 1 H NMR (400MHz, CDCl3) δ7.61 (d, J = 8.0Hz, 2H), 7.34-7.28 (m, 4H), 7.05-7.01 (m, 1H), 6.93-6.91 (m, 1H), 3.47 (s,3H),2.89(d,J=7.6Hz,1H),2.73-2.62(m,2H),2.42-2.34(m,1H),1.95-1.88(m,2H),1.85-1.74(m,1H). 13 C NMR (101MHz, CDCl3) δ172.1,147.9,144.5(q,J=1.4Hz),141.5,135.6,130.2,129.7,129.4,129.0(q,J= 32.4Hz), 127.5, 125.0 (q, J = 3.8Hz), 124.2 (q, J = 272.7Hz), 124.0, 122.6, 48.0, 36.8, 32.9, 27.9, 26.2. 19 F NMR (376MHz, CDCl3) δ-62.4.

[0099] Example 15

[0100]

[0101] In a glove box, 23.1 mg (0.02 mmol) of tetra(triphenylphosphine)palladium, 10.8 mg (0.02 mmol) of bis(2-diphenylphosphine) ether, 21.6 mg (0.40 mmol) of sodium methoxide, and 88.5 mg (0.20 mmol) of compound 1o were added to an 8 mL vial, followed by 4 mL of benzene. The mixture was stirred at room temperature for 12 hours under 24 W blue LED light. After the reaction was complete, the mixture was washed with water and extracted with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was separated by column chromatography to give the target compound 2o (45.0 mg product, 72% yield).

[0102] The target product 2o obtained by the above synthesis method was subjected to proton and carbon NMR spectra, and the test results are as follows: 1 H NMR (400MHz, CDCl3) δ7.66-7.64(m,2H),7.35-7.31(m,4H),7.06-7.02(m,1H),6.90-6.88(m,1H),3.46(s ,3H),2.90(d,J=7.6Hz,1H),2.73-2.62(m,2H),2.41-2.34(m,1H),1.96-1.88(m,2H),1.83-1.74(m,1H). 13 C NMR (101MHz, CDCl3) δ171.9,148.6,145.5,141.5,135.1,131.9,130.5,129 .4,129.3,127.7,124.0,122.6,118.7,110.5,48.1,36.7,32.9,27.8,26.2.

[0103] Example 16

[0104]

[0105] In a glove box, 23.1 mg (0.02 mmol) of tetra(triphenylphosphine)palladium, 10.8 mg (0.02 mmol) of bis(2-diphenylphosphine) ether, 21.6 mg (0.40 mmol) of sodium methoxide, and 95.1 mg (0.20 mmol) of compound 1p were added to an 8 mL vial, followed by 4 mL of benzene. The mixture was stirred at room temperature for 12 hours under 24 W blue LED light. After the reaction was complete, the mixture was washed with water and extracted with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was separated by column chromatography to give the target compound 2p (45.2 mg product, 65% yield).

[0106] The target product 2p obtained by the above synthesis method was subjected to proton and carbon NMR spectra, and the test results are as follows: 1 H NMR (400MHz, CDCl3) δ8.03-8.01(m,2H),7.31-7.27(m,4H),7.03-6.99(m,1H),6.93-6.91(m,1H),3.93(s,3H), 3.47(s,3H),2.89(d,J=7.6Hz,1H),2.74-2.61(m,2H),2.42-2.35(m,1H),1.95-1.87(m,2H),1.83-1.75(m,1H). 13 C NMR (101MHz, CDCl3) δ172.1,166.8,147.8,145.6,141.4,135.7,130.0,129.9, 129.5,129.4,128.5,127.5,123.9,122.6,52.1,48.0,36.8,32.9,27.9,26.2.

[0107] Example 17

[0108]

[0109] In a glove box, 23.1 mg (0.02 mmol) of tetra(triphenylphosphine)palladium, 10.8 mg (0.02 mmol) of bis(2-diphenylphosphine) ether, 21.6 mg (0.40 mmol) of sodium methoxide, and 89.1 mg (0.20 mmol) of compound 1q were added to an 8 mL vial, followed by 4 mL of benzene. The mixture was stirred at room temperature for 12 hours under 24 W blue LED light. After the reaction was complete, the mixture was washed with water and extracted with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was separated by column chromatography to give the target compound 2q (41.0 mg product, 65% yield).

[0110] The target product 2q obtained by the above synthesis method was subjected to proton and carbon NMR spectra, and the test results are as follows: 1 H NMR (400MHz, CDCl3) δ7.34-7.17(m,6H),7.02-6.78(m,2H),3.46(d,J=8.8Hz,3H),2.91(d,J=6.8Hz, 1H),2.67-2.62(m,1H),2.49-2.40(m,1H),2.19-2.00(m,3H),1.95-1.75(m,3H),1.34-0.76(m,3H). 13C NMR (101MHz, CDCl3) δ172.4,147.4,142.4,140.6,139.1,136.0,130.4,130.2,129.0 ,127.8,127.7,127.0,125.6,123.9,122.8,47.1,36.6,32.3,27.5,26.3,25.9,14.4.

[0111] Example 18

[0112]

[0113] In a glove box, 18.1 mg (0.02 mmol) of bis(1,2-bis(diphenylphosphine)ethane)palladium, 10.8 mg (0.02 mmol) of bis(2-diphenylphosphine) ether, 21.6 mg (0.40 mmol) of sodium methoxide, and 89.5 mg (0.20 mmol) of compound 1r were added to an 8 mL vial, followed by 4 mL of benzene. The mixture was stirred at room temperature for 12 hours under 24 W blue LED light. After the reaction was complete, the mixture was washed with water and extracted with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was separated by column chromatography to give the target compound 2r (33.2 mg product, 52% yield).

[0114] The target product 2r obtained by the above synthesis method was subjected to proton and carbon NMR spectra, and the test results are as follows: 1 H NMR (400MHz, CDCl3) δ7.36-7.21(m,4H),7.04-6.80(m,4H),3.89-3.45(m,6H),2.90(d,J =7.6Hz,1H),2.64-2.60(m,1H),2.57-2.34(m,1H),2.28-2.08(m,1H),1.93-1.75(m,3H). 13 C NMR (101MHz, CDCl3) δ172.4,156.9,148.3,140.8,136.7,131.4,129.1,128.8,127 .2,126.6,123.8,122.8,120.3,111.8,110.7,55.5,47.4,37.0,32.3,27.7,26.0.

[0115] Example 19

[0116]

[0117] In a glove box, 23.1 mg (0.02 mmol) of tetratetraphenylphosphine palladium, 10.8 mg (0.02 mmol) of bis(2-diphenylphosphine) ether, 21.6 mg (0.40 mmol) of sodium methoxide, 95.5 mg (0.20 mmol) of compound 2S were added to an 8 mL vial, followed by 4 mL of benzene. The mixture was stirred at room temperature for 12 hours under 24 W blue LED light. After the reaction was complete, the mixture was washed with water and extracted with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was separated by column chromatography to give the target compound 2S (52.2 mg product, 75% yield).

[0118] The target product 2s obtained by the above synthesis method was subjected to proton, carbon, and fluorine NMR spectra. The test results are as follows: 1 H NMR (400MHz, CDCl3) δ7.30-7.24(m,2H),7.06-6.99(m,2H),6.41(t,J=2.4Hz,1H),6.33(d,J=2.4Hz,2H),3.77(s,6 H),3.46(s,3H),2.84(d,J=7.6Hz,1H),2.70-2.59(m,2H),2.46-2.38(m,1H),1.91-1.85(m,2H),1.81-1.72(m,1H). 13 C NMR (101MHz, CDCl3) δ172.3,160.4,146.5,142.7,141.1,135.9,130.7,12 9.5,127.1,123.8,122.4,108.1,98.8,55.3,47.6,36.7,32.9,27.8,26.1.

[0119] Example 20

[0120]

[0121] In a glove box, 18.1 mg (0.02 mmol) of bis(1,2-bis(diphenylphosphine)ethane)palladium, 10.8 mg (0.02 mmol) of bis(2-diphenylphosphine) ether, 21.6 mg (0.40 mmol) of sodium methoxide, and 95.3 mg (0.20 mmol) of compound 1t were added to an 8 mL vial, followed by 4 mL of benzene. The mixture was stirred at room temperature for 24 hours under 24 W blue LED light. After the reaction was complete, the mixture was washed with water and extracted with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was separated by column chromatography to give compound 2t (43.2 mg product, 62% yield).

[0122] The target product 2t obtained by the above synthesis method was subjected to proton, carbon, and fluorine NMR spectra. The test results are as follows: 1 H NMR (400MHz, CDCl3) δ7.84 (d, J = 1.6Hz, 1H), 7.36-7.29 (m, 4H), 7.05-7.01 (m, 1H), 6.94-6.92 (m, 1H), 3.47 (s, 3H) ,2.88(d,J=7.6Hz,1H),2.75-2.65(m,2H),2.62(s,3H),2.43-2.35(m,1H),1.96-1.88(m,2H),1.84-1.76(m,1H). 13 C NMR (101MHz, CDCl3) δ172.1,149.0,148.2,141.5,139.9,135.2,134.4,132.5,132 .1,129.3,128.6,127.7,125.7,124.1,122.7,48.0,36.8,32.9,27.9,26.2,20.2.

[0123] Example 21

[0124]

[0125] In a glove box, 23.1 mg (0.02 mmol) of tetra(triphenylphosphine)palladium, 10.8 mg (0.02 mmol) of bis(2-diphenylphosphine) ether, 21.6 mg (0.40 mmol) of sodium methoxide, 93.5 mg (0.20 mmol) of compound 1u were added to an 8 mL vial, followed by 4 mL of benzene. The mixture was stirred at room temperature for 12 hours under 24 W blue LED light. After the reaction was complete, the mixture was washed with water and extracted with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was separated by column chromatography to give the target compound 2u (53.1 mg product, 78% yield).

[0126] The target product 2u obtained by the above synthesis method was subjected to proton and carbon NMR spectra, and the test results are as follows: 1 H NMR (400MHz, CDCl3) δ7.95-7.80(m,2H),7.55-7.51(m,2H),7.45-7.32(m,2H),7.24-7.18(m,2H),7.09-6.80(m,3 H),3.56(d,J=34.0Hz,3H),3.04(dd,J=18.0,6.4Hz,1H),2.73-2.45(m,2H),2.16-2.04(m,1H),1.89-1.73(m,3H).13 C NMR (101MHz, CDCl3) δ172.9,148.9,140.5,137.3,136.0,134.0,133.6,131.6,128.7,128.1, 127.8,127.7,127.7,127.2,125.7,125.3,125.2,124.0,122.9,47.4,36.7,32.4,27.7,25.9.

[0127] Example 22

[0128]

[0129] In a glove box, 23.1 mg (0.02 mmol) of tetratetraphenylphosphine palladium, 10.8 mg (0.02 mmol) of bis(2-diphenylphosphine) ether, 21.6 mg (0.40 mmol) of sodium methoxide, and 93.5 mg (0.20 mmol) of compound 1v were added to an 8 mL vial, followed by 4 mL of benzene. The mixture was stirred at room temperature for 12 hours under 24 W blue LED light. After the reaction was complete, the mixture was washed with water and extracted with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was separated by column chromatography to give the target compound 2v (47.0 mg product, 81% yield).

[0130] The target product 2v obtained by the above synthesis method was subjected to proton and carbon NMR spectra, and the test results are as follows: 1 H NMR (400MHz, CDCl3) δ8.53 (s, 2H), 7.25-7.23 (m, 2H), 7.07 (d, J = 4.8Hz, 2H), 6.96 (ddd, J = 8.0, 4.8, 3.6Hz, 1H), 6.84 (dt, J = 8. 0,1.1Hz,1H),3.38(s,3H),2.82(d,J=7.6Hz,1H),2.68-2.54(m,2H),2.38-2.30(m,1H),1.88-1.80(m,2H),1.75-1.68(m,1H). 13 CNMR (101MHz, CDCl3) δ171.8,149.5,149.0,148.6,141.5,134.7,129.3,128.4,127.7,124.7,124.0,122.6,48.2,36.7,32.9,27.8,26.2.

[0131] Example 23

[0132]

[0133] In a glove box, 23.1 mg (0.02 mmol) of tetra(triphenylphosphine)palladium, 10.8 mg (0.02 mmol) of bis(2-diphenylphosphine) ether, 21.6 mg (0.40 mmol) of sodium methoxide, 84.7 mg (0.20 mmol) of compound 1w were added to an 8 mL vial, followed by 4 mL of benzene. The mixture was stirred at room temperature for 12 hours under 24 W blue LED light. After the reaction was complete, the mixture was washed with water and extracted with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was separated by column chromatography to give compound 2w (44.3 mg product, 70% yield).

[0134] The target product 2w obtained by the above synthesis method was subjected to proton and carbon NMR spectra, and the test results are as follows: 1 H NMR (400MHz, CDCl3) δ7.32-7.26(m,4H),7.09-7.05(m,1H),7.03-7.01(m,1H),6.94(d,J=3.6Hz,1H),3.43(s,3H) ,2.85(d,J=7.6Hz,1H),2.70(t,J=7.6Hz,2H),2.60(dt,J=12.4,4.0Hz,1H),2.00-1.92(m,2H),1.83-1.72(m,1H). 13 C NMR (101MHz, CDCl3) δ172.4,147.8,142.7,141.1,136.0,129.7,127.7,127.6,126.5,125.2,124.0,123.7,122.4,48.2,36.5,33.5,27.9,26.1.

[0135] Example 24

[0136]

[0137] In a glove box, 23.1 mg (0.02 mmol) of tetra(triphenylphosphine)palladium, 10.8 mg (0.02 mmol) of bis(2-diphenylphosphine) ether, 21.6 mg (0.40 mmol) of sodium methoxide, and 79.5 mg (0.20 mmol) of compound 1x were added to an 8 mL vial, followed by 4 mL of benzene. The mixture was stirred at room temperature for 12 hours under 24 W blue LED light. After the reaction was complete, the mixture was washed with water and extracted with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was separated by column chromatography to give the target compound 2x (39.3 mg product, 73% yield).

[0138] The target product 2x obtained by the above synthesis method was subjected to proton and carbon NMR spectra, and the test results are as follows: 1 H NMR (400MHz, CDCl3) δ7.44(d,J=8.0Hz,1H),7.26(d,J=4.0Hz,2H),7.15(dt,J=8.4,4.0Hz,1H),3.35(s,3H),2.66-2.61(m,2H),2.58 -2.37(m,4H),2.00-1.92(m,1H),1.89-1.80(m,1H),1.72-1.63(m,1H),1.39-1.31(m,1H),1.29-1.15(m,3H),0.82(t,J=7.2Hz,3H). 13 C NMR (101MHz, CDCl3) δ173.0,144.9,141.3,135.7,128.8,126.6,126.1,124.0,123.0,46.9,36.4,31.7,30.8,30.7,27.1,25.7,22.2,13.9.

[0139] Example 25

[0140]

[0141] In a glove box, 23.1 mg (0.02 mmol) of tetra(triphenylphosphine)palladium, 10.8 mg (0.02 mmol) of bis(2-diphenylphosphine) ether, 21.6 mg (0.40 mmol) of sodium methoxide, and 68.2 mg (0.20 mmol) of compound 1y were added to an 8 mL vial, followed by 4 mL of benzene. The mixture was stirred at room temperature for 12 hours under 24 W blue LED light. After the reaction was complete, the mixture was washed with water and extracted with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was separated by column chromatography to give the target compound 2y (29.9 mg product, 70% yield).

[0142] The target product 2y obtained by the above synthesis method was subjected to proton and carbon NMR spectra, and the test results are as follows: 1 H NMR (400MHz, CDCl3) δ7.21-7.18(m,2H),7.16-7.14(m,1H),7.08-7.02(m,1H),6.49(q,J=2.0Hz,1H),3.3 1(s,3H),2.65-2.62(m,1H),2.59-2.52(m,1H),2.46-2.42(m,2H),1.90-1.81(m,1H),1.77-1.67(m,2H). 13C NMR (101MHz, CDCl3) δ171.6,150.6,140.8,133.0,128.4,126.8,123.9,123.0,119.2,47.1,37.3,33.1,27.1,26.1.

[0143] Example 26

[0144]

[0145] In a glove box, 23.1 mg (0.02 mmol) of tetra(triphenylphosphine)palladium, 10.8 mg (0.02 mmol) of bis(2-diphenylphosphine) ether, 21.6 mg (0.40 mmol) of sodium methoxide, and 98.7 mg (0.20 mmol) of compound 1z were added to an 8 mL vial. Finally, 4 mL of 1,4-dioxane was added. The mixture was stirred at room temperature for 12 hours under 24 W blue LED illumination. After the reaction was complete, the mixture was washed with water and extracted with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was separated by column chromatography to give the target compound 2z (40.2 mg product, 55% yield).

[0146] The target product 2z obtained by the above synthesis method was subjected to proton and carbon NMR spectra, and the test results are as follows: 1 H NMR (400MHz, CDCl3) δ7.28-7.16(m,5H),7.11(d,J=6.8Hz,2H),6.92(dd,J=6.4,2.0Hz,2H),3.38(s,3 H),2.78(d,J=7.6Hz,1H),2.64-2.52(m,2H),2.34-2.28(m,1H),1.85-1.78(m,2H),1.74-1.65(m,1H). 13 C NMR (101MHz, CDCl3) δ172.4,146.5,141.3,140.8,136.3,130.8,129.8,129.6,128.0,127.1,126.8,123.8,122.5,47.7,36.7,32.9,27.9,26.2.

[0147] Example 27

[0148]

[0149] In a glove box, 23.1 mg (0.02 mmol) of tetra(triphenylphosphine)palladium, 10.8 mg (0.02 mmol) of bis(2-diphenylphosphine) ether, 21.6 mg (0.40 mmol) of sodium methoxide, and 112.3 mg (0.20 mmol) of compound 1aa were added to an 8 mL vial, followed by 4 mL of benzene. The mixture was stirred at room temperature for 12 hours under 24 W blue LED light. After the reaction was complete, the mixture was washed with water and extracted with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was separated by column chromatography to give the target compound 2aa (46.0 mg product, 53% yield).

[0150] The target product 2aa obtained by the above synthesis method was subjected to proton and carbon NMR spectra, and the test results are as follows: 1 H NMR (400MHz, CDCl3) δ7.35-7.26(m,5H),7.18-7.15(m,2H),7.06-6.99(m,2H),4.31-4.14(m,4H ),3.71(s,1H),3.42(s,3H),2.82-2.68(m,2H),2.51-2.41(m,2H),1.26(dt,J=11.2,7.2Hz,6H). 13 C NMR (101MHz, CDCl3) δ170.8,169.7,169.1,142.4,141.0,140.0,135.9,131.5,130.0,129. 9,128.1,127.5,127.2,124.3,122.8,62.7,61.8,61.1,54.2,36.7,32.3,29.8,14.0,14.0.

[0151] Example 28

[0152]

[0153] In a glove box, 18.1 mg (0.02 mmol) of bis(1,2-bis(diphenylphosphine)ethane)palladium, 10.8 mg (0.02 mmol) of bis(2-diphenylphosphine) ether, 21.6 mg (0.40 mmol) of sodium methoxide, and 84.0 mg (0.20 mmol) of compound 1ab were added to an 8 mL vial, followed by 4 mL of benzene. The mixture was stirred at room temperature for 12 hours under 24 W blue LED light. After the reaction was complete, the mixture was washed with water and extracted with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was separated by column chromatography to give the target compound 2ab (47.2 mg product, 81% yield).

[0154] The target product 2ab obtained by the above synthesis method was subjected to proton and carbon NMR spectra, and the test results are as follows: 1 H NMR(400MHz, CDCl3)δ7.40-7.30(m,5H),7.25-7.21(m,2H),7.08-6.99(m,2H),4.51(s,1H),4.3 4(td,J=8.4,2.4Hz,1H),4.28-4.21(m,1H),3.48(s,3H),3.12-3.03(m,1H),2.61-2.55(m,1H). 13 C NMR (101MHz, CDCl3) δ170.2,141.9,140.3,139.8,135.4,129.7,129.5,129.4,128.3,128.0,127.4,124.3,122.9,78.9,69.4,36.8,31.6.

[0155] Example 29

[0156]

[0157] In a glove box, 23.1 mg (0.02 mmol) of tetra(triphenylphosphine)palladium, 10.8 mg (0.02 mmol) of bis(2-diphenylphosphine) ether, 21.6 mg (0.40 mmol) of sodium methoxide, and 99.3 mg (0.20 mmol) of compound 1ac were added to an 8 mL vial. Finally, 4 mL of 1,4-dioxane was added. The mixture was stirred at room temperature for 36 hours under a 24 W blue LED lamp. After the reaction was complete, the mixture was washed with water and extracted with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was separated by column chromatography to give the target compound 2ac (62.2 mg product, 70% yield).

[0158] The target product 2ac obtained by the above synthesis method was subjected to proton and carbon NMR spectra, and the test results are as follows: 1H NMR (400MHz, CDCl3) δ7.78-7.76(m,2H),7.40-7.29(m,8H),7.13-7.10(m,2H),7.04(ddd,J=8.4,6.0,2.4Hz,1H),6.97-6.95(m,1H),4.36(dd,J=9 .6,2.8Hz,1H),4.15(d,J=14.8Hz,1H),3.77(dd,J=14.8,2.0Hz,1H),3.4 5(s,3H),3.37(dd,J=9.6,7.6Hz,1H),3.04(d,J=6.8Hz,1H),2.43(s,3H). 13 C NMR (101MHz, CDCl3) δ169.5,143.8,140.9,139.0,136.4,134.5,132.6,132.6,129.7, 129.5,129.2,128.7,128.3,128.1,127.9,124.4,122.8,50.9,48.2,46.3,37.2,21.5.

[0159] Antitumor activity assays of benzo[b]azapyridine derivatives against various cancer cell lines:

[0160] 1. Cell Culture

[0161] Gastric cancer cell line SGC-7901, melanoma cell line B16F10, liver cancer cell line HEPG2, colorectal cancer cell line HCT116 and SW480 were cultured in RPMI-1640 (SGC-7901, B16F10), DMEM (HEPG2, HCT116) and L15 (SW480) medium containing 10% fetal bovine serum (FBS) and incubated at 37°C in a 5% CO2 incubator.

[0162] 2. Cytotoxicity analysis

[0163] Cytotoxicity was detected using the 3-(4,5-dimethylthiazol-2-yl)-2,tetramethylazazole salt method (MTT). 5000 SGC-7901, B16F10, HEPG2, HCT116, and SW480 cells were seeded in 96-well plates containing 100 μL of culture medium. When the cell density reached approximately 70%, different concentrations of the compound (5, 10, 20, 40, 60, and 80 μM) were added to the cells. Dimethyl sulfoxide (DMSO) served as a control. After 24 h, cell viability was analyzed using MTT assay (20 μL per well) at a concentration of 5 mg / mL, and measured using iMark. TM The absorbance was measured at 450 nm using an ELISA reader.

[0164] Based on the best straight line fit and regression line obtained from linear regression analysis, IC is calculated using their respective regression equations. 50 value( Figure 2 , Figure 3 SGC-7901, B16F10, HEPG2, HCT116, and SW480 cells were treated with different concentrations of benzo[b]azapyridine derivatives (1, 5, 10, 20, 30, 40, 50, 60, 80, and 100 μM) for 24 h. Cell growth inhibition rate was determined by the MTT assay. Data were processed using GraphPad Prism 8 Software and are presented as the average of three independent experiments (Table 1).

[0165] Table 1. IC50 of benzo[b]azapyridine derivatives 50 Value (μM)

[0166]

[0167] 3. Western blot experiment

[0168] Protein samples were extracted from HCT116 and SGC-7901, separated by 10% SDS-polyacrylamide gel electrophoresis, and transferred to polyvinylidene fluoride membranes. ASP330, c-myc, CDK4, BCL-2, and BCL-XL proteins were detected using rabbit polyclonal antibodies (1:1000) against ASP330, c-myc, CDK4, BCL-2, and BCL-XL. Mouse GAPDH monoclonal antibody (1:2000) was used as an internal control. HRP-labeled secondary antibody (1:10000) was also used. The bound proteins were visualized using persistent chemiluminescent substrates.

[0169] 4. Apoptosis experiment

[0170] Flow cytometry was used to detect HCT116 and SGC-7901 cells at different concentrations according to their respective IC50 values. 50 Apoptosis rate after treatment. HCT116 and SGC-7901 cells were seeded at a density of 3.5 × 10⁵ cells / well in six-well plates and cultured at 37°C until 70% or 80% confluence. Then, the apoptosis rate was determined according to their respective IC⁻¹ values. 50 Cells were treated with different concentrations of [agent name missing]. After 24 hours, cells were collected, double-stained, and the percentage of apoptotic cells was calculated. The results were analyzed using FlowJo software version 10.

[0171] Activity data analysis:

[0172] Phenotypic screening for antiproliferative activity was performed in vitro using the MTT assay. The results showed that compounds 2n ​​and 2u exhibited significant, dose-dependent anticancer activity in five different cancer cell lines (SGC-7901 gastric cancer cells, B16F10 melanoma cells, HEPG2 hepatocellular carcinoma cells, HCT116, and SW480 colorectal cancer cells). Specifically, compounds 2n ​​and 2u showed significant inhibitory effects on the IC50 values ​​of HCT116 and SGC-7901 cells. 50 The values ​​were 44.1 and 33.3 μM, respectively. Specifically, compounds 2n ​​and 2u showed significant inhibitory effects on the growth of HCT116 and SGC-7901 cell lines, with IC50 values ​​of 44.1 and 33.3 μM, respectively. 50 The half-maximum inhibition concentrations (WMCs) were 44.1 and 33.3 μM, respectively. Notably, the observed biological effects exhibited high specificity for both steric and electrophilic factors. Compounds 2d, 2l, 2y, and 2w (see...) Figure 1 The significant reduction in the activities of a and Table 1) demonstrates this specificity. Furthermore, a comprehensive analysis of the effects of 2n and 2u on apoptosis and related molecular pathways was performed using flow cytometry and Western blotting. The results showed that compounds 2n ​​and 2u significantly induced apoptosis in HCT116 and SGC-7901 cells (e.g., ...). Figure 1 (As shown in b and c). Furthermore, a slight increase in ASP330 expression was observed in SGC-7901 cells, while significant decreases in CKD4 and BCL-2 expression were observed in both HCT116 and SGC-7901 cells. Figure 1 (As shown in d and e). In summary, our preliminary findings strongly suggest that benzozazepine derivatives 2n and 2u possess good antiproliferative activity, attributed to their ability to induce apoptosis in cancer cells. Utilizing these analyses to design enhanced inhibitors is a focus of ongoing research.

Claims

1. A benzo[a] antitumor active molecule b The method for synthesizing azapyrrolizidine derivatives is characterized by: The acetylamide compound (1) was irradiated with light at a wavelength of 420-500 nm in the presence of a transition metal Pd catalyst, ligand, alkaline substance and solvent to generate a benzo[b]azapyridine derivative active molecule (2). ； The transition metal Pd catalyst is tetra(triphenylphosphine)palladium, bis(1,2-bis(diphenylphosphine)ethane)palladium, palladium trifluoroacetate, bis(2-diphenylphosphine) ether palladium dichloride, palladium acetate, or bis(triphenylphosphine)acetate palladium; the ligand is bis(2-diphenylphosphine) ether, 4,5-bisdiphenylphosphine-9,9-dimethyloxanthracene, 1,1'-bis(diphenylphosphine)ferrocene, or 1,1'-binaphthyl-2,2'-bisdiphenylphosphine; the alkaline substance is sodium methoxide, sodium tert-butoxide, sodium ethoxide, cesium carbonate, potassium phosphate, N,N-dihexylmethylamine, or potassium carbonate; the solvent is benzene, trifluorotoluene, tetrahydrofuran, or 1,4-dioxane. The specific structure of the benzo[b]azapyrrolizidine derivative active molecule (2) is selected from one of the following compounds: 。 2. The antitumor active molecule benzo[a] according to claim 1 b The method for synthesizing azapyrrolizidine derivatives is characterized by: The reaction temperature is 0 ℃~100 ℃, and the reaction time is 2~48 h.

3. The antitumor active molecule benzo[a] according to claim 1 b The method for synthesizing azapyrrolizidine derivatives is characterized by: The molar ratio of acetylamide compound (1) to palladium catalyst is 1:0.01~1:0.2; the molar ratio of palladium catalyst to ligand is 1:0~1:4; and the molar ratio of acetylamide compound (1) to alkaline substance is 1:0~1:

5.

4. The antitumor active molecule benzo[a] according to claim 1 b The method for synthesizing azapyrrolizidine derivatives is characterized by: Acrylamide compound (1) in a solvent concentration of 0.01~0.2M.

5. The antitumor active molecule benzo[a] prepared by the method according to any one of claims 1-4 b The application of azaphene derivatives in the preparation of antitumor drugs is characterized by: The molecule benzo[ b The specific structures of the azaporide derivatives are shown below: or The tumor is selected from gastric cancer, melanoma, liver cancer, or colorectal cancer.

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