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CN-117263861-B - Anti-tumor active molecule benzo [ b ] azepine derivative and synthetic method and application thereof

CN117263861BCN 117263861 BCN117263861 BCN 117263861BCN-117263861-B

Abstract

The invention belongs to the field of synthesis of benzo [ b ] azepine derivatives, and particularly discloses an antitumor active molecule benzo [ b ] azepine derivative, and a synthesis method and application thereof. According to the invention, alkynylamide shown in the general formula (1) uses a transition metal Pd catalyst, and under the existence of a ligand, an alkaline substance and a solvent, under the irradiation of light with the wavelength of 420-500 nm, a benzo [ b ] azepine derivative active molecule is generated, wherein the benzo [ b ] azepine derivative active molecule is shown in the general formula (2). According to the invention, the structure of the benzob azepine molecule fragment is synthesized by performing free radical relay tandem cyclization reaction from aryl to alkyl to vinyl through catalysis of transition metal Pd, the synthesis of the molecules is realized, and a series of synthesized benzob azepine molecules and derivative active molecules thereof have antitumor activity through test.

Inventors

  • CHEN MING
  • DU YUJIA
  • Sheng Xiaxin

Assignees

  • 常州大学

Dates

Publication Date
20260505
Application Date
20230905

Claims (5)

  1. 1. A synthesis method of an antitumor active molecule benzo [ b ] azepine derivative is characterized in that an alkynylamide compound (1) is subjected to light irradiation with the wavelength of 420-500 nm in the presence of a transition metal Pd catalyst, a ligand, an alkaline substance and a solvent in a nitrogen atmosphere to generate the benzo [ b ] azepine derivative active molecule (2); ; The transition metal Pd catalyst is tetrakis (triphenylphosphine) palladium, bis (1, 2-bis (diphenylphosphine) ethane) palladium, palladium trifluoroacetate, bis (2-diphenylphosphine phenyl) ether palladium dichloride, palladium acetate or bis (triphenylphosphine) palladium acetate, the ligand is bis (2-diphenylphosphine phenyl) ether, 4, 5-bis (diphenylphosphine) 9, 9-dimethylxanthene, 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-dihexylmethylamine or potassium carbonate, and the solvent is benzene, benzotrifluoride, tetrahydrofuran or 1, 4-dioxane; The specific structure of the benzo [ b ] azepine derivative active molecule (2) is selected from one of the following compounds: 。
  2. 2. The method for synthesizing the anti-tumor active molecule benzo [ b ] azepine derivative according to claim 1, wherein the reaction temperature is 0-100 ℃ and the reaction time is 2-48 h.
  3. 3. The method for synthesizing the antitumor active molecule benzo [ b ] azepine derivative, which is characterized by comprising the steps of enabling a molar ratio of an alkynylamide compound (1) to a metal palladium catalyst to be 1:0.01-1:0.2, enabling a molar ratio of the metal palladium catalyst to a ligand to be 1:0-1:4, and enabling a molar ratio of the alkynylamide compound (1) to an alkaline substance to be 1:0-1:5.
  4. 4. The method for synthesizing the anti-tumor active molecule benzo [ b ] azepine derivative according to claim 1, wherein the concentration of the alkynylamide compound (1) in the solvent is 0.01-0.2M.
  5. 5. The application of the anti-tumor active molecule benzo [ b ] azepine derivative prepared by the method according to any one of claims 1-4 in preparing an anti-tumor drug is characterized in that the specific structure of the molecule benzo [ b ] azepine derivative is as follows: Or (b) The tumor is selected from gastric cancer, melanoma, liver cancer or colorectal cancer.

Description

Anti-tumor active molecule benzo [ b ] azepine derivative and synthetic method and application thereof Technical Field The invention belongs to synthesis of benzo [ b ] azepine derivatives, and particularly relates to a synthesis method of an antitumor active molecule benzo [ b ] azepine derivative. Background The benzoazepine molecular fragment plays a vital role (Le Diguarher,T.;Ortuno,J.-C.;Sh anks,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,A.A.;Shumsky,J.S.;Steffan,R.J.;Caggiano,T.J.;Wi lliams,D.K.;Trybulski,E.J.;Ning,X.;Lock,Y.;Tanikella,T.;Hartmann,D.;Chan,P.S.;Park,C.H.Bioorg.Med.Chem.Lett.2006,16,954-959.). as a basic structural element in a series of biologically and pharmacologically important compounds, and it is worth noting that the benzoazepine molecular fragment is a core component of various antidepressants, such as benazepril, mo Zapu, etanercept, daruns and dibenzoazepine (Hou,F.F.;Zhang,X.;Zhang,G.H.;Xie,D.;Chen,P.Y.;Zhang,W.R.;Jiang,J.P.;Liang,M.;Wang,G.B.;Liu,Z.R.;Geng,R.W.N.Engl.J.Med.2006,354,131-140;Decaux,G.;Soupart,A.;Vassart,G.The Lancet 2008,371,1624-1632;Groth,C.;Alvord,W.G.;Quinones,O.A.;Fortini,M.E.;Mol.Pharmaco l.2010,77,567-574;C.M.;Allan,C.E.;Ashworth,D.M.;Barne,J.;Bax ter,A.J.;Broadbridge,J.D.;Franklin,R.J.;Hampton,S.L.;Hudson,P.;Horton,J.A.;Jenkins,P.D.;Penson,A.M.;Pitt,G.R.W.;Riviere,P.;Ro bson,P.A.;Rooker,D.P.;Semple,G.;Sheppard,A.;Haigh,R.M.;Roe,M.B.J.Med.Chem.2008,51,8124-8134.)., and the currently developed methods mainly have the problems of complex synthesis steps, harsh reaction conditions, limited substrate structure and the like. Disclosure of Invention Because of the limitations of the known methods and the harsh reaction conditions, there is a need to develop a practical method that is simple and efficient and has mild reaction conditions. Aiming at the defects of the prior art, the invention provides a general, simple and efficient synthesis method for synthesizing active molecules of benzo [ b ] azepine and derivatives thereof in one step. The method synthesizes a series of active molecules of benzo [ b ] azepine and derivatives thereof under mild conditions through intramolecular free radical relay tandem cyclization reaction combining single electron transfer and hydrogen atom transfer. This method is followed by a hydrogen atom transfer step following the single electron transfer process to generate new radical intermediates and finally synthesize the structure containing the benzo [ b ] azepine molecule fragments by the relay process of the radicals from aryl to alkyl to vinyl, this particular reaction mode being extremely rare. The invention adopts the technical scheme that: the synthesis process of active benzodiazepine molecule with antitumor activity includes the steps of preparing active benzodiazepine molecule with the general expression as shown in the general expression (2) with acetylenic amide compound (1), transition metal Pd catalyst, ligand, alkaline matter and solvent in the presence of nitrogen and under the irradiation of visible light of 420-500 nm wavelength; R 1 is one of hydrogen, alkyl, alkoxy, halogen, ester group, trifluoromethyl and cyano with less than 20 carbons; R 2 is one of hydrogen, alkyl with less than 20 carbons, phenyl with substituent being alkoxy, phenyl with substituent being halogen, phenyl with substituent being nitro, phenyl with substituent being cyano, naphthyl, thienyl, pyridyl, monosubstituted or polysubstituted phenyl; The substituent of R 3 is one of alkyl, benzyl and phenyl with less than 20 carbons; x is an oxygen atom, a nitrogen atom or a carbon atom with a substituent; Y is an oxygen atom, a nitrogen atom or a carbon atom with a substituent; Further, the transition metal Pd catalyst is one or more of palladium acetate, bis (dibenzylideneacetone) palladium, trifluoroacetate palladium, bis (2-diphenylphosphinophenyl) ether palladium dichloride, bis triphenylphosphine palladium acetate, tetrakis (triphenylphosphine) palladium, bis (1, 2-bis (diphenylphosphine) ethane) palladium, wherein tetrakis (triphenylphosphine) palladium or/and bis (1, 2-bis (diphenylphosphine) ethane) palladium is/are preferable. Further, the ligand is 1,1 '-binaphthyl-2, 2' -bisdiphenylphosphine, bis (2-diphenylphosphinophenyl) ether, 4, 5-bisdiphenylphosphine-9, 9-dimethylxanthene, 1, 3-bis (diphenylphosphine) propane, 1, 2-bis (diphenylphosphine) ethane, 1 '-bis (diphenylphosphine) ferrocene, triphenylphosphine, 2' -bipyridine, of which bis (2-diphenylphosphinophenyl) ether is preferred. Further, the alkaline substance is potassium phosphate, potassium carbonate, cesium carbonate, silver oxide, sodium acetate, potassium phosphate, sodium t-butoxide, sodium ethoxide, sodium methoxide, N-dihexylmethylamine, among which