CN109336887A

CN109336887A - A kind of benzimidazole and chiral heterocycle class compound and its preparation method and application

Info

Publication number: CN109336887A
Application number: CN201811045641.3A
Authority: CN
Inventors: 邱立勤; 蒋晓丁
Original assignee: National Sun Yat Sen University
Current assignee: Sun Yat Sen University; National Sun Yat Sen University
Priority date: 2018-09-07
Filing date: 2018-09-07
Publication date: 2019-02-15
Anticipated expiration: 2038-09-07
Also published as: CN109336887B

Abstract

The invention discloses a kind of benzimidazole and chiral heterocycle class compounds and its preparation method and application.The structural formula of benzimidazole provided by the invention and chiral heterocycle class compound is Formulas I, Formula II or formula III,The benzimidazole and chiral heterocycle class compound are that the allyl aminating reaction of intramolecular is carried out by allylic substrate using the iridium complex that metal iridium compound and phosphoramidite ligand are formed as catalyst, and the synthesis of high efficiency, high enantioselectivity obtains.This method is high with catalytic reaction activity, reaction condition is mild, enantioselectivity is good, wide application range of substrates, advantages of environment protection.Initial in vitro enzyme inhibition activity experiments have shown that, compound of the present invention has preferable alpha-glucosaccharase enzyme inhibition activity, it can be used as alpha-glucosidase restrainer, it can also be used as the pharmaceutical intermediate further modified simultaneously, there is the potential using value of preparation prevention or treatment II- patients with type Ⅰ DM, obesity and its complication medicine and its lead compound.

Description

A kind of benzimidazole and chiral heterocycle class compound and its preparation method and application

Technical field

The invention belongs to chipal compounds to synthesize field, be related to a kind of benzimidazole and chiral heterocycle class compound and its system Preparation Method and application.

Background technique

Compound with preferable alpha-glucosaccharase enzyme inhibition activity is to preparation prevention or treatment anti-diabetic and its simultaneously The drug for sending out disease has very important value, and existing alpha-glucosidase restrainer type is limited, it is difficult to meet people's Demand, so, it is badly in need of developing more compounds with alpha-glucosaccharase enzyme inhibition activity.

In addition, the synthetic method about compound, prior art discloses following contents.

Carbon-hetero atom binding reaction and its molecular skeleton construction strategy be Synthetic Organic Chemistry Major research field it One, it is played a crucial role to fast and efficiently synthesizing complicated natural products molecule or preparing bioactive compound library [(a)Ruiz-Castillo,P.；Buchwald,S.L.Chem.Rev.2016,116,12564.(b) Dunbar,K.L.； Scharf,D.H.；Litomska,A.；Hertweck,C.Chem.Rev.2017,117,5521.(c) Petkowski,J.J.； Bains,W.；Seager,S.J.Nat.Prod.2018,81,423.].Wherein, quantum Chemical Study on Asymmetric Allylation is in recent years Being even more to achieve rapid development, the ligands such as various chiral monophosphorus, double phosphines, phosphine nitrogen, phosphine oxygen, dinitrogen and nitrogen sulphur are applied to [(a) Korkis, S.E. in such reaction；Burns,D. J.；Lam,H.W.J.Am.Chem.Soc.2016,138,12252. (b)Feng,J.；Holmes,M.；Krische, M.J.Chem.Rev.2017,117,12564.(c)Hamilton,J.Y.； Rossler,S.L.；Carreira,E.M. J.Am.Chem.Soc.2017,139,8082.(d)Jiang,X.；Boehm,P.； Hartwig,J.F.J.Am. Chem.Soc.2018,140,1239.].Meanwhile research finds transition metal-catalyzed allyl Substitution reaction has itself unique property, such as can generate to high regioselectivity to the allyl substrate containing terminal olefin Branched product [(a) Zhang, Z.Q.；Zhang,B.；Lu X.；Liu,J.-H.；Lu,X.-Y.；Xiao,B.；Fu,Y. Org.Lett.2016,18,952.(b)Su,Y.-L.；Han,Z.-Y.；Li,Y.-H.；Gong,L.-Z.ACS Catal.2017, 7,7917.(c)Wang,H.；Lorion,M.M.；Ackermann,L.ACS Catal.2017,7, 3430.(d)Meza, A.T.；Wurm,T.；Smith,L.；Kim,S.W.；Zbieg,J.R.；Stivala,C.E.； Krische, M.J.J.Am.Chem.Soc.2018,140,1275].Wherein, John F.Hartwig seminar is to Asymmetric allylic alkylation Reaction mechanism compares systematic research [(a) Chen, M.；Hartwig,J.F. Angew.Chem.Int.Ed.2014, 53,1.(b)Madrahimov,S.T.；Li,Q.；Sharma,A.；Hartwig, J.F.J.Am.Chem.Soc.2015,137, 14968.(c)Jiang,X.；Chen,W.；Hartwig,J.F.Angew. Chem.Int.Ed.2016,55,5819.(d) Jiang,X.；Beiger,J.J.；Hartwig, J.F.J.Am.Chem. Soc.2017,139,87.], and You Shu power seminar It is dedicated to metal complex catalyzed allyl substitution reaction research, expands in nucleopilic reagent type, new ligand design and anti- Good result [(a) Xu, Q.-L. are obtained in terms of answering mechanism；Zhuo,C.-X.；Dai,L.-X.；You,S.- L.Org.Lett.2013,15,5909；(b)Hang,X.； Liu,W.-B.；Cheng,Q.；You,S.- L.Organomet.2016,35,2467.(c)Yang,Z.-P.；Jiang, R.；Zheng,C.；You,S.- L.J.Am.Chem.Soc.2018,140,3114.].With going deep into for research, chemists have found chiral phosphoramidite class ligand It is the relatively good ligand of asymmetric allylation, forms catalyst with central active metal Ir, can effectively be catalyzed such React [(a) Qu, J.；Roβbergand,L.； Helmchen,G.J.Am.Chem.Soc.2014,136,1272.(b) Bhaskararao,B.；Sunoj,R.B.J. Am.Chem.Soc.2015,137,15712.(c)S.L.； Krautwald,S.；Carreira,E.M.J. Am.Chem.Soc.,2017,139,3603.].Even to this day, transition metal is urged The allylation reaction of change include aminating reaction, etherification reaction, remove aromatization etc. and can be effectively constructed C-X (X=S, O, The hetero atoms such as N) key, it is extensive in natural products and pharmaceutical activity molecule to synthesize to high regioselectivity, enantioselectivity many Existing Chiral polycyclic compound [(a) Yang, Z.-P.；Zheng,C.；Huang,L.；Qian,C.You, S.- L.Angew.Chem.Int.Ed.2017,56,1.(b)Wei,L.；Zhu,Q.；Xu,S.-M.；Chang,X.； Wang,C.- J.J.Am.Chem.Soc.2018,140,1508.].Catalysis asymmetric allylation is a kind of environmental protection risen, original Construct to subeconomy the synthetic strategy of noval chemical compound, but effective chiral ligand and catalyst type still compare and have at present Limit, catalytic activity need to be further increased, path and the successful examples more right and wrong for being used to construct chiral heterocycle compound of report Often limited, the synthesis of the substrate type and novel chiral compound of reaction needs further to expand.Therefore, based on this reaction building The further investigation of chiral heterocycle compound has important theory significance and wide application value.

Benzimidazole is the important structural unit of drug molecule and natural products, the electronics as biomolecule such as guanines Isostere is an important pharmacophore in medicament research and development.Drug containing the class formation shows multiple combinations bioactivity And antibacterial, anti parasitic, anticancer, antiviral, anti-inflammatory, anti-hypertension and in terms of have important medical valence It is worth [(a) Chikkula, K.V.；Sundararajan,R.Med Chem Res. 2017,26,3026.(b)Farahat, A.A.；Ismail,M.A.；Kumar,A.；Wenzler,T.；Brun,R.； Paul,A.；Wilson,W.D.；Boykin, D.W.Eur.J.Med.Chem.2018,143,1590.(c) Monforte,A.M.；De Luca,L.；Buemi,M.R.； Agharbaoui,F.E.；Pannecouque,C.； Ferro,S.Bioorg.Med.Chem.2018,26,661.].In addition, benzene And glyoxaline compound also has potential application in fields such as dyestuff, chemical sensor, fluorescent material and etch chemistries [(a)Yadav,M.； Kumar,S.；Purkait,T.；Olasunkanmi,L.O.；Bahadur,I.；Ebenso, E.E.J.Mol.Liq. 2016,213,122.(b)Cao,W.；Sletten,E.M.J.Am.Chem.Soc.2018,140, 2727.(c) Horak,E.；Kassal,P.；Murkovic Steinberg,I.Supramol.Chem.2017,123,42. (d) Suresh,S.；Jayamoorthy,K.；Karthikeyan,S.J.Lumin.2018,198,28.].In view of benzimidazole Class compound its unique architectural characteristic, pharmacological activity and its wide application value synthesize it and its in chemistry and medicine The application study in field field more and more attention has been paid to.But up to the present, it is effectively synthesized benzimidazoles compound Report mainly still concentrate on constructing using raw material by the synthetic method of metering its basic framework [(a) Rasheed, S.k., Rao,D.N.；Das,P.J.Org.Chem.2015,80,9321.(b) Abou-Elkhair,R.A.I.；Hassan,A.E.A.； Boykin,D.W.；W.Wilson,D.Org.Lett.2016, 18,4714.(c)Daw,P.；Ben-David,Y.； Milstein,D.；ACS Catal.2017,7,7456.(d) Liang,T.；Tan,Z.；Zhao,H.；Chen,X.；Jiang, H.；Zhang,M.ACS Catal.2018,8, 2242.].And carry out synthesis of chiral benzimidazole using the method for asymmetry catalysis The report of compound is simultaneously few, and asymmetry catalysis is converted, only direct using chiral benzimidazole substrate of diving at present It is functionalized report [(a) Stanley, L.M. of the compound of reaction synthesis chain containing additional chiral；Hartwig, J.F.J.Am.Chem. Soc.2009,131,8971.(b)Zhang,D.；He,Y.；Tang,J.Dalton Trans.2016, 45,11699.(c) Xia,Y.；Lin,L.；Chang,F.；Liao,Y.；Liu,X.Feng, X.Angew.Chem.Int.Ed.2016,55,12228.], there is no and synthesizing benzimidazole is reacted simultaneously by Direct Asymmetric Catalytic The precedent of chiral heterocycle introducing chiral centre.

Summary of the invention

The object of the present invention is to provide a kind of benzimidazole and chiral heterocycle class compound or its pharmaceutically acceptable salts. The benzimidazole and chiral heterocycle class compound are levo form, d-isomer or raceme.The levo form is left-handed sterling, or Left-handed excessive mixture of enantiomers.The d-isomer is dextrorotation sterling or the excessive mixture of enantiomers of dextrorotation.The racemization Body is mixture of enantiomers, and its ee value is 0.

It is a further object of the present invention to provide a kind of methods for preparing the benzimidazole and chiral heterocycle class compound, mention Synthesizing optical is active containing chiral centre with can be realized high efficiency, high enantioselectivity and ring benzimidazole for the method for confession Compound.

Method of the invention be it is a kind of effectively by allylic compound as substrate through intramolecular allyl catalytic amine Change reaction synthesis of chiral benzimidazole and tetrahydro pyrazine compounds, benzimidazole and dihydro pyrazine ketone compounds and three azepines The method of benzo dihydro azulene ketones compound and its enantiomer or raceme.

Method of the invention is one kind using iridium-phosphoramidite ligand complex compound as catalyst, especially with iridium-chirality bridging It, can be by specially designed allyl compound as substrate, through intramolecular allyl when phosphoramide ligand complex is catalyst Base aminating reaction high efficiency, high enantioselectivity ground synthesizing benzimidazole and chiral heterocycle class compound；Its enantiomer is by opposite The ligand of configuration prepares corresponding catalyst, carries out similar intramolecular allyl amination catalysis reaction and obtains；Its raceme is then Corresponding catalyst is prepared by the ligand of racemization, similar intramolecular allyl amination catalysis reaction is carried out and obtains.

Application of the invention is to provide above-mentioned benzimidazole and chiral heterocycle class compound or its pharmaceutically acceptable salt In preparation for preventing or treating drug or guideization with alpha-glucosidase activity unconventionality expression related mammalian disease Close the application in object.It is described include: with alpha-glucosidase activity unconventionality expression related mammalian disease type-2 diabetes mellitus, Obesity and its complication, viral infection, cancer, hyperinsulinemia, hepatitis, insulin resistance.The benzimidazole And chiral heterocycle class compound is levo form, d-isomer or raceme.

Above-mentioned purpose of the invention is achieved by the following technical programs:

A kind of benzimidazole and chiral heterocycle class compound or its pharmaceutically acceptable salt, which is characterized in that its structure Formula is Formulas I, Formula II or formula III；Wherein, it is asymmetric carbon atom with the carbon atom that * is marked, is configured as R, S or R/S, the benzene And imidazo chiral heterocycle class compound is levo form, d-isomer or raceme；

Wherein, R¹、R²、R³、R⁴It is respectively and independently selected from hydrogen, halogen atom, hydroxyl, carboxyl, cyano, nitro, C₁-C₂₀Alkane Base, C₁-C₂₀Fluoro-alkyl, C₁-C₂₀Oxyl, C₃-C₂₀Naphthenic base, C₁-C₂₀Amide groups, C₂-C₂₀Alkenyl, C₂- C₂₀Alkynyl, C₃-C₂₀Cycloalkenyl, C₃-C₂₀Cycloalkynyl radical, C₂-C₂₀Ketone carbonyl, C₁-C₂₀Sulfonyl, trimethyl silicon substrate, Triethyl group silicon substrate, triphenyl silicon substrate, C_3-C₂₀The heterocycle or heterocyclic aryl, amino, C containing one or more of N, O or S₁- C₂₀N- alkyl substituted amido, C₁-C₂₀N, N- dialkyl group substituted amido, aryl methylene or substituted aryl methylene, virtue Base or substituted aryl；Wherein, the substituent group in the substituted aryl methylene and substituted aryl be respectively and independently selected from hydrogen, C₁-C₂₀Alkyl, C₁-C₂₀Fluoro-alkyl, halogen, nitro, C₁-C₂₀Oxyl, hydroxyl, cyano, amino, C₁-C₂₀N- Alkyl substituted amido or C₁-C₂₀N, one of N- dialkyl group substituted amido or multiple combinations；

R⁵For hydrogen, C₁-C₂₀Linear or branched alkyl group, C₃-C₂₀Naphthenic base, C₃-C₂₀Cycloalkylmethylene, C_3-C₂₀'s Heterocycle methylene or heterocyclic aryl methylene, allyl, propargyl, C containing one or more of N, O or S₁-C₂₀Acyl Base or C₁-C₂₀Sulfonyl, C₁-C₂₀Hydrocarbon carbonyl oxygen, substituted C₁-C₂₀Hydrocarbon carbonyl oxygen, substituted aryl-acyl or substitution Aryl sulfonyl, aryl methylene or substituted aryl methylene；Wherein, the substituted C₁-C₂₀Hydrocarbon carbonyl oxygen, replace Aryl-acyl, substituted aryl sulfonyl and substituted aryl methylene substituent group be respectively and independently selected from hydrogen, C₁-C₂₀Alkane Base, C₁-C₂₀Fluoro-alkyl, halogen, nitro, C₁-C₂₀Oxyl, hydroxyl, cyano, amino, C₁-C₂₀N- alkyl replace Amido or C₁-C₂₀N, one of N- dialkyl group substituted amido or multiple combinations；

R⁶And R⁷It is respectively and independently selected from hydrogen, halogen atom, C₁-C₂₀Linear or branched alkyl group, aryl methylene or substituted Aryl methylene, C₃-C₂₀Naphthenic base, aryl or substituted aryl；Wherein, the substituted aryl methylene and substituted virtue Substituent group in base is respectively and independently selected from hydrogen, halogen atom, C₁-C₂₀Alkyl, C₁-C₂₀Fluoro-alkyl, cyano, hydroxyl, three Methylsilyl, triethyl group silicon substrate, triphenyl silicon substrate, nitro, C₁-C₂₀Oxyl, C₂-C₂₀Alkenyl, C₂-C₂₀Alkynyl, C₁-C₂₀Acyl group or C₆-C₂₀One of aryl or multiple combinations；

R⁸For hydrogen, halogen atom, C₁-C₂₀Linear or branched alkyl group, C₁-C₂₀Fluoro-alkyl, C₁-C₂₀Oxyl, Aryl methylene or substituted aryl methylene, C₃-C₂₀Naphthenic base, C_3-C₂₀Containing the miscellaneous of one or more of N, O or S Ring group or heterocyclic aryl, aryl or substituted aryl；Wherein, the substitution in the substituted aryl methylene and substituted aryl Base is respectively and independently selected from hydrogen, halogen atom, C₁-C₂₀Alkyl, C₁-C₂₀Fluoro-alkyl, cyano, hydroxyl, trimethyl silicon substrate, three Ethyl silicon substrate, triphenyl silicon substrate, nitro, C₁-C₂₀Oxyl, C₂-C₂₀Alkenyl, C₂-C₂₀Alkynyl, C₁-C₂₀Acyl group or C₆-C₂₀One of aryl or multiple combinations；

The aryl is C₆-C₂₀Aryl.

Preferably, the structural formula of the benzimidazole and chiral heterocycle class compound is with benzimidazole and tetrahydro pyrazine The Formulas I of skeleton structure；

Wherein, R¹、R²、R³、R⁴It is respectively and independently selected from hydrogen, fluorine, chlorine, bromine, iodine, hydroxyl, carboxyl, cyano, trifluoromethyl, nitre Base, methyl, ethyl, n-propyl, isopropyl, normal-butyl, isobutyl group, tert-butyl, benzyl, methoxyl group, ethyoxyl, positive propoxy, Isopropoxy, n-butoxy, isobutoxy, tert-butoxy, benzyloxy, amino, C₁-C₂₀N- alkyl substituted amido, C₁-C₂₀'s Amide groups, C₁-C₂₀N, N- dialkyl group substituted amido, C₁-C₂₀Acyl group, C₁-C₂₀Sulfonyl, C₃-C₂₀Contain N, O or S One or more of heterocycle or heterocyclic aryl, trimethyl silicon substrate, triethyl group silicon substrate, triphenyl silicon substrate, aryl or substitution Aryl；Substituent group in the substituted aryl is C₁-C₂₀Alkyl, halogen or C₁-C₂₀One of oxyl or more Kind combination；

R⁵For hydrogen, acetyl group, tertbutyloxycarbonyl, fluorenylmethyloxycarbonyl, benzoyl, 2,2,2- trichloro-ethoxycarbonyl, C₁-C₂₀ Linear or branched alkyl group, C₃-C₂₀Naphthenic base, C₃-C₂₀Cycloalkylmethylene, allyl, C₁-C₂₀Sulfonyl, C_3-C₂₀ The heterocycle methylene or heterocyclic aryl methylene, aryl methylene or substituted aryl containing one or more of N, O or S Methylene, substituted benzenesulfonyl；Wherein the substituent group of the substituted aryl methylene and substituted benzenesulfonyl difference is only It is vertical to be selected from hydrogen, C₁-C₂₀Alkyl, C₁-C₂₀Fluoro-alkyl, nitro, halogen or C₁-C₂₀One of oxyl or a variety of Combination；

R⁶And R⁷It is respectively and independently selected from hydrogen, halogen atom, C₁-C₄Linear or branched alkyl group, aryl or substituted aryl, The structural formula of the aryl or substituted aryl isWherein, R⁹、R¹⁰、 R¹¹、R¹²And R¹³Independently select From hydrogen, halogen atom, C₁-C₂₀Alkyl, C₁-C₂₀Fluoro-alkyl, halogen, cyano, hydroxyl, trimethyl silicon substrate, triethyl group silicon Base, triphenyl silicon substrate, nitro, trifluoromethyl, C₁-C₂₀Oxyl, amino, C₁-C₂₀N- alkyl substituted amido or C₁-C₂₀ N, N- dialkyl group substituted amido.

Wherein, R¹、R²、R³、R⁴It is respectively and independently selected from hydrogen, fluorine, chlorine, bromine, iodine, hydroxyl, carboxyl, cyano, trifluoromethyl, nitre Base, methyl, ethyl, n-propyl, isopropyl, normal-butyl, isobutyl group, tert-butyl, benzyl, methoxyl group, ethyoxyl, positive propoxy, Isopropoxy, n-butoxy, isobutoxy, tert-butoxy, benzyloxy, amino, tert-butoxycarbonylamino, acetyl group, acetamido, Morpholinyl, piperidyl, piperazinyl, pyrrole radicals, nafoxidine base, trimethyl silicon substrate, triethyl group silicon substrate, triphenyl silicon substrate or virtue Base.

Wherein, R⁵For hydrogen, acetyl group, tertbutyloxycarbonyl, fluorenylmethyloxycarbonyl, benzoyl, 2,2,2- trichloro-ethoxycarbonyl, Ethyl, isopropyl, hexamethylene, benzyl, 4- methylbenzyl, 4- luorobenzyl or p-toluenesulfonyl, 2- thiazole methylene, 2- thiophene Methylene, 2- fural, 2- pyridine methylene.

Wherein, R⁶And R⁷It is respectively and independently selected from hydrogen, C₁-C₂₀Alkyl, chlorine atom or phenyl.

Preferably, the structural formula of the benzimidazole and chiral heterocycle class compound is with benzimidazole and dihydro pyrazine The Formula II of ketone skeleton structure；

Wherein, R¹、R²、R³And R⁴It is respectively and independently selected from hydrogen, fluorine, chlorine, bromine, iodine, hydroxyl, cyano, trifluoromethyl, nitro, first Base, ethyl, n-propyl, isopropyl, normal-butyl, isobutyl group, tert-butyl, benzyl methoxyl group, ethyoxyl, positive propoxy, isopropyl oxygen Base, n-butoxy, isobutoxy, tert-butoxy, benzyloxy, amino, C₁-C₂₀N- alkyl substituted amido, C₁-C₂₀N, N- bis- Alkyl substituted amido, C₁-C₂₀Acyl group, C₁-C₂₀Sulfonyl, C₁-C₂₀Amide groups, C₃-C₂₀One of containing N, O or S Or several heterocycle or heterocyclic aryl, trimethyl silicon substrate, triethyl group silicon substrate, triphenyl silicon substrate, aryl or substituted aryl；Institute The substituent group for stating substituted aryl is C₁-C₂₀Alkyl, halogen atom or C₁-C₂₀One of oxyl or multiple combinations；

Wherein, R⁵For hydrogen, acetyl group, tertbutyloxycarbonyl, fluorenylmethyloxycarbonyl, benzoyl, 2,2,2- trichloro-ethoxycarbonyl, C₁-C₂₀Linear or branched alkyl group, C₃-C₂₀Naphthenic base, C₃-C₂₀Cycloalkylmethylene, C_3-C₂₀Containing in N, O or S One or more of heterocycle methylenes or heterocyclic aryl methylene, allyl, C₁-C₂₀Sulfonyl, substituted aryl methylene Base or substituted benzenesulfonyl；Wherein, the substituent group of the substituted aryl methylene and substituted benzenesulfonyl is independently Selected from hydrogen, C₁-C₂₀Alkyl, C₁-C₂₀Fluoro-alkyl, nitro, halogen or C₁-C₂₀One of oxyl or a variety of groups It closes.

Wherein, R¹、R²、R³、R⁴It is respectively and independently selected from hydrogen, fluorine, chlorine, bromine, iodine, hydroxyl, cyano, trifluoromethyl, nitro, first Base, ethyl, n-propyl, isopropyl, normal-butyl, isobutyl group, tert-butyl, benzyl, methoxyl group, ethyoxyl, positive propoxy, isopropyl oxygen Base, n-butoxy, isobutoxy, tert-butoxy, benzyloxy, amino, N- methylamino, acetyl group, acetylamino, morpholinyl, Piperidyl, piperazinyl, pyrrole radicals, nafoxidine base, trimethyl silicon substrate, triethyl group silicon substrate, triphenyl silicon substrate or phenyl.

Wherein, R⁵For hydrogen, acetyl group, tertbutyloxycarbonyl, fluorenylmethyloxycarbonyl, benzoyl, 2,2,2- trichloro-ethoxycarbonyl, Propyl, cyclohexyl, allyl, benzyl, 4- luorobenzyl, 4- methoxy-benzyl, 2,4- difluorobenzyl, 2- thiazole methylene, 2- thiophene Pheno methylene, 2- fural, 2- pyridine methylene.

Preferably, the structural formula of the benzimidazole and chiral heterocycle class compound is with triazine and dihydro Azulene ketone The formula III of skeleton structure；

Wherein, R¹、R²、R³Be respectively and independently selected from hydrogen, fluorine, chlorine, bromine, iodine, hydroxyl, cyano, trifluoromethyl, nitro, methyl, Ethyl, n-propyl, isopropyl, normal-butyl, isobutyl group, tert-butyl, methoxyl group, ethyoxyl, positive propoxy, isopropoxy, positive fourth Oxygroup, isobutoxy, tert-butoxy, benzyloxy, amino, C₁-C₂₀N- alkyl substituted amido, C₁-C₂₀N, N- dialkyl group takes For amido, C₁-C₂₀Amide groups, C₁-C₂₀Acyl group, C₁-C₂₀Sulfonyl, C₃-C₂₀One or more of containing N, O or S Heterocycle or heterocyclic aryl, trimethyl silicon substrate, triethyl group silicon substrate, triphenyl silicon substrate, oxazolyl, aryl or substituted aryl in One or more combinations；The substituent group of the substituted aryl is C₁-C₂₀Alkyl, halogen or C₁-C₂₀Oxyl in one Kind or multiple combinations；

R⁵For hydrogen, acetyl group, tertbutyloxycarbonyl, fluorenylmethyloxycarbonyl, benzoyl, 2,2,2- trichloro-ethoxycarbonyl, C₁-C₂₀ Linear or branched alkyl group, C₃-C₂₀Naphthenic base, C₃-C₂₀Cycloalkylmethylene, C_3-C₂₀Containing one of N, O or S or Several heterocycle methylenes or heterocyclic aryl methylene, allyl, C₁-C₂₀Sulfonyl, substituted aryl methylene or take The benzenesulfonyl in generation；Wherein, the substituent group of the substituted aryl methylene and substituted benzenesulfonyl be respectively and independently selected from hydrogen, C₁-C₂₀Alkyl, C₁-C₂₀Fluoro-alkyl, nitro, halogen or C₁-C₂₀One of oxyl or multiple combinations；

R⁸For hydrogen, halogen atom, C₁-C₂₀Linear or branched alkyl group, C₁-C₂₀Fluoro-alkyl, C₁-C₂₀Oxyl, Aryl methylene or substituted aryl methylene, C₃-C₂₀Naphthenic base, C_3-20Containing the miscellaneous of one or more of N, O or S Ring group or heterocyclic aryl, aryl or substituted aryl, condensed-nuclei aromatics；Wherein, the substituted aryl methylene and substituted virtue Substituent group in base is respectively and independently selected from hydrogen, halogen atom, C₁-C₂₀Alkyl, C₁-C₂₀Fluoro-alkyl, cyano, hydroxyl, three Methylsilyl, triethyl group silicon substrate, triphenyl silicon substrate, nitro, C₁-C₂₀Oxyl, C₂-C₂₀Alkenyl, C₂-C₂₀Alkynyl, C₁- C₂₀Acyl group or C₆-C₂₀One of aryl or multiple combinations.

Wherein, R¹、R²、R³Be respectively and independently selected from hydrogen, fluorine, chlorine, bromine, iodine, hydroxyl, cyano, trifluoromethyl, nitro, methyl, Ethyl, n-propyl, isopropyl, normal-butyl, isobutyl group, tert-butyl, methoxyl group, ethyoxyl, positive propoxy, isopropoxy, positive fourth Oxygroup, isobutoxy, tert-butoxy, benzyloxy, amino, acetyl group, acetylamino, morpholinyl, piperidyl, piperazinyl, pyrroles Base, nafoxidine base, trimethyl silicon substrate, triethyl group silicon substrate, triphenyl silicon substrate, oxazolyl, phenyl or 4- methoxyphenyl aryl.

Wherein, R⁵For hydrogen, acetyl group, tertbutyloxycarbonyl, fluorenylmethyloxycarbonyl, benzoyl, 2,2,2- trichloro-ethoxycarbonyl, 2- methyl-propyl, cyclopropylmethylene, allyl, benzyl or 4- tosyl, 2- thiazole methylene, 2- thenylidene, 2- fural, 2- pyridine methylene.

Wherein, R⁸For hydrogen, methyl, isopropyl, trifluoromethyl, trichloromethyl, ethyoxyl, benzyl, cyclopropyl, cyclohexyl, 2- thienyl, 2- furyl, 2- pyridyl group, phenyl, 4- aminomethyl phenyl, 4- bromophenyl, 3- bromophenyl, 4- trifluoromethyl, 4- chlorphenyl, 4- fluorophenyl, 4- isopropyl phenyl, 4- nitrobenzophenone, 4- methoxyphenyl, 2- cyano-phenyl, 3,5- dichloro-benzenes Base or 2- naphthalene.

The present invention protects the method for preparing above-mentioned benzimidazole and chiral heterocycle class compound simultaneously, and the method is as follows: In a solvent, at 0 DEG C~120 DEG C, using allylic compound intermediate as raw material, made with iridic compound and phosphoramide ligand It uses the iridium complex of generation as catalyst, in the presence of alkali, generates the benzimidazole and chiral heterocycle class compound；

The structural formula of the allylic compound intermediate is formula S_a, formula S_bOr formula S_c；

The allylic compound intermediate, the iridium atom of iridic compound, ligand, alkali molar ratio be 1:(0.005 ~0.1): (0.005~0.2): (0.05~3)；

Wherein, LG is leaving group, be hydroxyl, chlorine, bromine,OrWherein, M is NH or O；

R¹⁴For C₁-C₂₀Alkyl, C₁-C₂₀Oxyl, halogen replace C₁-C₂₀Alkyl or halogen replace C₁-C₂₀ Oxyl；

R¹⁵For C₁-C₂₀Alkyl, aryl or substituted aryl；The substituent group of the substituted aryl is C₁-C₂₀Alkyl, Halogen or C₁-C₂₀Oxyl in one or more combinations；

The phosphoramidite ligand is the optically pure ligand and its enantiomer or raceme for the formula that has the following structure:

Wherein, R¹⁶For dimethylamino, diethylin, diisopropylamino, N- methylethylamine, N-methylisopropylamine base, N- methylbenzylamine base, N- aminomethyl phenyl amido, hexichol amido, N- methyl -3- pyridine amido, N- methyl -2- naphthalene amido, two Benzamido group, N-methylcyclohexylamine base, dicyclohexyl amido, pyrroles's amido, 4- methyl piperidine base, thio-morpholinyl, morpholinyl, Azetidinone base, butyrolactam base, valerolactamyl, caprolactam base, 2,2 ', 6,6 '-tetramethyl-piperidyls, N- phenyl hexichol Methylamino, 1,2,3,4- tetrahydro isoquinolyl, indyl, N- methyl -2- pyridine amido, 1- methyl piperazine base, imidazole radicals, army Stilbenes imido grpup, N- diisopropyl-benzcyclohexyl amido, N- methyl-1-phenylethyl amido (R) or (S), N- Methyl-1-naphtylethyl group amido (R) or (S), 3,4- Diphenyl Pyrrole alkyl (R, R) or (S, S), 2,5- Diphenyl Pyrrole alkyl (R, R) or (S, S), double-(1- phenylethyl) amido (R, R) or (S, S), double-(1- naphtylethyl group) amido (R, R) or (S, S), N-1- phenylethyl -1- (2- methoxybenzene) amido (R, R) or (S, S), 2,5- dinaphthyl pyrrolidinyl (R, R) or (S, S), 2- phenyl -5- naphthylpyrrole alkyl (R, R) or (S, S), N- benzyl-alpha-methylbenzylamine base (R) or (S), 2- methoxyl group-first Base pyrrolidinyl (R) or (S), 2,4- azepine cyclobutyl (R, R) or (S, S), 2- methoxycarbonyl group pyrrolidinyl (R) or (S), 2- ethoxy-methyl pyrrolidinyl (R) or (S), N- isopropyl -1- phenylethyl amido (R) or (S), 2,6- dimethyl Piperidyl (R, R) or (S, S), double-(1- (4- methoxyphenyl) ethyl) amido (R, R) or (S, S), double-(1- cyclohexyl second Base) amido (R, R) or (S, S), N- cyclohexyl -1- phenylethyl amido (R) or (S), N- naphthalene -1- phenylethyl amido (R) Or (S), N- cyclooctyl -1- phenylethyl amido (R) or (S), N- ring certain herbaceous plants with big flowers base -1- phenylethyl amido (R) or (S), N- ring ten Dialkyl group -1- naphtylethyl group amido (R) or (S), N- cyclo-dodecyl -1- (2,4- phenyl) ethyl amido (R) or (S), N-1- Phenylethyl-(1- (2- methoxyphenyl)) ethyl amido (R, R) or (S, S), N-1- menaphthyl-(1- phenyl) ethyl amido (R) or (S), N-1- phenylethyl-(2- phenylphenylmethyl) amido (R) or (S), N, N- dimethyl-ethylenediamine base, N, N- bis- are different Propyl ethylenediamine base, N, N- bis- (1- phenethyl) ethylenediamine base, 1,3- high piperazine base, N, N '-dimethyl -1,2- cyclohexanediamine Base (R, R) or (S, S), 2,3- diphenyl ethylene diamine base (R, R) or (S, S), benzyl-(2- pyrrole radicals -2- methyl) amido (R, R) or (S, S), N-1- phenylethyl-(2- methoxyphenyl) ethyl amido, double-(4- methoxyphenethyl) amido (R, R) or (S, S), N-1- methylphenethyl benzylamino (R) or (S), double-(2- methoxyphenethyl) amido (R, R) or (S, S), 1- Methylphenethyl amido (R) or (S), N- methyl-1-methyl-(2- diphenylphosphoryl group phenyl) amido (R) or (S), R or S configuration Tetrahydro chinolines amido, R or S configuration tetrahydro indole quinoline class amido；Wherein, the tetrahydro chinolines amido and tetrahydro Yin The structural formula of diindyl quinoline class amido isThe value of n is 1 or 2；

R¹⁷And R¹⁸It is respectively and independently selected from H, halogen atom, C₁-C₂₀Alkyl, C₃-C₂₀Naphthenic base, C₁-C₂₀Hydrocarbon oxygen Base, C_3-C₂₀Heterocycle containing N, O, S or one of heterocyclic aryl, aryl or substituted aryl or multiple combinations；Replace Substituent group on aryl is H, halogen, nitro, C₁-C₂₀Fluoro-alkyl, C₁-C₂₀Alkyl, C₁-C₂₀Oxyl, amino, C₁-C₂₀N- alkyl substituted amido or C₁-C₂₀N, one or more combinations in N- dialkyl group substituted amido；

R¹⁹、R^19’、R²⁰、R^20’、R²¹、R^21’、R²²、R^22’、R²³、R^23’、R²⁴、R^24’、R²⁵、 R^25’、R²⁶、R^26’、R²⁷、R^27’、 R²⁸、R^28’、R²⁹、R^29’、R³⁰、R^30’、R³¹、R^31’、R³²、R^32’、R³³、R^33’、R³⁴、R^34’Arbitrarily it is selected from H, C₁-C₂₀Alkyl or C₃- C₂₀Naphthenic base, C₃-C₂₀The heterocycle or heterocyclic aryl, substituted silicon substrate, aryl or substituted aryl containing N, O, S；It is described Substituted silicon substrate or substituted aryl on substituent group be H, halogen, nitro, C₁-C₂₀Fluoro-alkyl, C₁-C₂₀Alkyl, C₁-C₂₀Oxyl, amino, C₁-C₂₀N- alkyl substituted amido or C₁-C₂₀N, it is a kind of or more in N- dialkyl group substituted amido Kind combination；The substituent group can be one, or multiple, when substituent group is multiple, the substituent group can be with It is identical or different；The aryl is C₆-C₂₀Aryl；

For the C containing chiral centre for controlling dihedral angle size₃-C₂₀Chiral side chain,ByIt sloughs It is obtained after leaving group Lg, the Lg is hydroxyl, carboxyl, halogen, methanesulfonate ester, p-methyl benzenesulfonic acid ester or trifluoromethyl sulphur Acid esters；

For the C for controlling dihedral angle size₁-C₂₀Achiral side chain,BySlough leaving group It is obtained after Lg, the Lg is hydroxyl, carboxyl, halogen, methanesulfonate ester, p-methyl benzenesulfonic acid ester or trifluoromethane sulfonic acid ester.

Preferably,For (2R)-propylene glycol, (2S)-propylene glycol, (2R, 3R) -2,3- butanediol, (2S, 3S) -2, 3- butanediol, (1S, 2S) -1,2- hydrobenzoin, (1R, 2R) -1,2- hydrobenzoin, (2R, 3R) -1,4- benzyloxy Butanediol, (2S, 3S) -1,4- benzyloxy butanediol, (2R, 4R) -2,4-PD, (2S, 4S) -2,4-PD, (2R, 5R) -2,5-HD, (2S, 5S) -2,5-HD, (3R, 4R) -3,4- hexylene glycol, (3S, 4S) -3,4- hexylene glycol, (3S) -1,3 butylene glycol, (3R) -1,3 butylene glycol, (R)-(-) -1- vinylbenzene -1,2- glycol, vinylbenzene -1 (S)-(+) -1-, 2- glycol, (R)-Decane-1,2-diol, (S)-Decane-1,2-diol, (2S, 9S) -2,9- decanediol, (2R, 9R) -2,9- decanediol, (3S, 8S) -3,8- decanediol, (3R, 8R) -3,8- decanediol, (4S, 7S) -4,7- decanediol, (5R, 6R) -5,6- decanediol, (5S, 6S) -4,6- decanediol, cis- -1,2- cyclohexanediol, (1R, 2R)-trans- 1,2- cyclohexanediol, (1S, 2S)-trans- 1,2- Cyclohexanediol, (1R, 2R)-trans- 1,2- cyclopentadienyl alcohol, (1S, 2S)-trans- 1,2- cyclopentadienyl alcohol, cis- -1,2- cyclopentadienyl alcohol, (1S, 2S, 3R, 5S)-(+) -2,3- pinane diol, (3S, 5S)-(+) -3,5- heptane glycol, (3R, 5R)-(-) -3,5- heptane Glycol, (2S, 6S) -2,6- heptane glycol, (2R, 6R) -2,6 heptane glycol, cis-3,4- erythritan (3R, 6R) -3, 6- ethohexadiol, (3S, 6S) -3,6- ethohexadiol, (2R, 7R) -2,7- ethohexadiol, (2S, 7S) -2,7- ethohexadiol, (2R, 8R) -2, 8- nonanediol, (2S, 8S) -2,8- nonanediol, (3R, 7R) -3,7- nonanediol, (3S, 7S) -3,7- nonanediol, (4R, 6R) -4, 6- nonanediol, (4S, 6S) -4,6- nonanediol, cis- 1,2- cyclohexanedimethanol, trans- 1,2- cyclohexanedimethanol, (+) -2,3-O- are different Propylidene-L- threitol, (-) -2,3-O- isopropylidene-D- threitol, (R) -2,2 '-dinaphthol or (S) -2,2 '-dinaphthalene Phenol；Or (R) -2,2 '-dinaphthalene dicarboxylic acids, (S) -2,2 '-dinaphthalene dicarboxylic acids, L-TARTARIC ACID, D- tartaric acid, (2R, 3R) -2, 3- dibromosuccinic acid, (2S, 3S) -2,3- dibromosuccinic acid, (2R, 3R) -2,3- Succimer, two mercapto of (2S, 3S) -2,3- Succinic acid, (+)-two-are to anisoyl--D- tartaric acid, (-)-two-to anisoyl--L-TARTARIC ACID, (1R, 2R) -1,2- ring Hexane dicarboxylic acid, (1S, 2S) -1,2- cyclohexane cyclohexanedimethanodibasic, (R)-(-)-citramalic acid, (S)-(+)-citramalic acid, L MALIC ACID, D- Malic acid, (R)-(+)-methylsuccinic acid, (S)-(-)-methylsuccinic acid；Or aforementioned chiral diol methanesulfonates, to first Base benzene sulfonate or trifluoromethane sulfonic acid ester.

Preferably,For 1,1- methylene bromide, glycol dibromide, 1,3- dibromopropane, 1,4- dibromobutane, 1, Pentamethylene bromide, 1,6- dibromo-hexane, 1,7- dibromo-heptane, bis- bromooctane of 1,8-, 1,9- dibromo nonane, the 1,10- dibromo last of the ten Heavenly stems After alkane, ethylene glycol condensationThe halogenated compound of end group or its methanesulfonate ester or its p-methyl benzenesulfonic acid Ester, 1,3- dibromobenzene, 1,4- dibromobenzene, α, α-dibromo ortho-xylene, α, α-two bromo-m-xylene or α, α-dibromo paraxylene； Wherein, n is 1~10.

Preferably, the alkali is triethylamine, 4-dimethylaminopyridine, 1,8- diazabicylo [5,4,0], 11 carbon -7- Alkene, 1,5- diazabicylo [4,3,0] nonyl- 5- alkene, triethylene diamine, N, bis- (trimethyl silicon substrate) acetamides of O-, cesium carbonate, carbon Sour potassium, lithium carbonate, potassium fluoride, sodium hydride, cesium fluoride, potassium phosphate, potassium acetate, sodium phosphate, sodium acetate, lithium acetate, n-BuLi, Two (trimethyl silicon substrate) Sodamides, two (trimethyl silicon substrate) lithium amides, two (trimethyl silicon substrate) potassamides, sodium methoxide, sodium ethoxide, Sodium isopropylate, proton sponge, tert-butyl alcohol lithium, potassium tert-butoxide, sodium tert-butoxide or diisopropyl ethyl amine.

Preferably, alkali and three fluosulfonic acid silver, lithium chloride or molecular sieve additive are added in combination in reaction system.

Preferably, R¹⁴Or R¹⁵In, the C₁-C₂₀Alkyl be preferably methyl, ethyl, n-propyl, isopropyl, normal-butyl, Isobutyl group or tert-butyl.

Preferably, R¹⁴In, the C of the halogen substitution₁-C₂₀Alkyl in halogen be fluorine, chlorine, bromine or iodine.

Preferably, R¹⁴In, the C of the halogen substitution₁-C₂₀Alkyl be trichloromethyl.

Preferably, R¹⁵In, the C₁-C₂₀Oxyl be methoxyl group, ethyoxyl, positive propoxy, isopropoxy, positive fourth oxygen Base, isobutoxy, tert-butoxy or benzyloxy.

The method of benzimidazole of the present invention and chiral heterocycle class compound, it is characterized in that in organic solvent, 0 At DEG C -120 DEG C, respectively with allylic compound intermediate S_a、S_b、S_cFor raw material, made with iridic compound and phosphoramide ligand Use the iridium complex of generation as catalyst, after reacting 20min-hour for 24 hours in the presence of alkali, after purification through short column of silica gel Benzimidazole and chiral heterocycle class compound I, II, III and its enantiomer or raceme are prepared respectively；

Wherein, the allylic compound, iridic compound, ligand, alkali molar ratio be 1:(0.005~0.1): (0.005~0.2): (0.05~3)；The metal iridium source is [Ir (COD) Cl]₂、[Ir(dncot)Cl]₂、 [Ir(OMe) (COD)]₂、[Ir(COD)₂]BAr^F ₄、Ir(COD)₂BF₄、[Ir(OH)(COD)]₂、Ir(ppy)₃、 [Ir(COD)₂]SbF₆In It is a kind of；

According to specific structure, can be indicated respectively with following reaction formula:

Wherein, L is chiral or achiral ligand, and Base is the combination of various alkali and alkali and additive, and T is reaction temperature, Solvent is various organic solvents.

Heretofore described allylic compound intermediate S_a、S_b、S_cStructural formula difference it is as follows:

Wherein, R¹、R²、R³、R⁴、R⁵、R⁶、R⁷、R⁸As described in claim 1-4；LG is leaving group, be hydroxyl, chlorine, bromine,OrWherein, M is NH or O； R¹⁴For C₁-C₂₀Alkyl, the C that is replaced by one or more halogens₁- C₂₀Alkyl or C₁-C₂₀Oxyl； R¹⁵For C₁-C₂₀Alkyl, aryl or substituted aryl；R¹⁴Or R¹⁵In, the C₁- C₂₀Alkyl be preferably methyl, ethyl, n-propyl, isopropyl, normal-butyl, isobutyl group or tert-butyl；R¹⁴In, it is described by one The C that a or multiple halogens replace₁-C₂₀Alkyl described in halogen be preferably fluorine, chlorine, bromine or iodine； R¹⁴In, it is described by one The C that a or multiple halogens replace₁-C₂₀Alkyl be preferably trichloromethyl；R¹⁴In, the C₁-C₂₀Oxyl be preferably first Oxygroup, ethyoxyl, positive propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy or benzyloxy；R¹⁵In, it is described to take Substituent group in the aryl in generation is C₁-C₂₀Alkyl, halogen or C₁-C₂₀Oxyl in one or more combinations；Described takes Dai Jike is one, or multiple, when substituent group is multiple, the substituent group can be identical or different；It is described Aryl be C₆-C₂₀Aryl；

Heretofore described phosphoramidite ligand be the formula that has the following structure optically pure ligand and its enantiomer or Raceme:

Wherein, R¹⁶Optionally from dimethylamino, diethylin, diisopropylamino, N- methylethylamine, N- methyl isopropyl Amido, N- methylbenzylamine base, N- aminomethyl phenyl amido, hexichol amido, N- methyl -3- pyridine amido, N- methyl -2- naphthylamine Base, dibenzyl amido, N-methylcyclohexylamine base, dicyclohexyl amido, pyrroles's amido, 4- methyl piperidine base, thio-morpholinyl, morpholine Base, azetidinone base, butyrolactam base, valerolactamyl, caprolactam base, 2,2 ', 6,6 '-tetramethyl-piperidyls, N- phenyl Benzhydryl amido, 1,2,3,4- tetrahydro isoquinolyl, indyl, N- methyl -2- pyridine amido, 1- methyl piperazine base, imidazoles Base, army's stilbenes imido grpup, N- diisopropyl-benzcyclohexyl amido, N- methyl-1-phenylethyl amido (R) or (S), N- methyl-1-naphtylethyl group amido (R) or (S), 3,4- Diphenyl Pyrrole alkyl (R, R) or (S, S), 2,5- diphenyl Pyrrolidinyl (R, R) or (S, S), double-(1- phenylethyl) amido (R, R) or (S, S), double-(1- naphtylethyl group) amido (R, R) or (S, S), N-1- phenylethyl -1- (2- methoxybenzene) amido (R, R) or (S, S), 2,5- dinaphthyl pyrrolidinyl (R, ) or (S, S), 2- phenyl -5- naphthylpyrrole alkyl (R, R) or (S, S), N- benzyl-alpha-methylbenzylamine base (R) or (S), 2- first R Oxygroup-methylpyrrole alkyl (R) or (S), 2,4- azepine cyclobutyl (R, R) or (S, S), 2- methoxycarbonyl group pyrrolidinyl (R) or (S), 2- ethoxy-methyl pyrrolidinyl (R) or (S), N- isopropyl -1- phenylethyl amido (R) or (S), 2,6- Lupetidine base (R, R) or (S, S), double-(1- (4- methoxyphenyl) ethyl) amido (R, R) or (S, S), double-(1- ring Hexyl ethyl) amido (R, R) or (S, S), N- cyclohexyl -1- phenylethyl amido (R) or (S), N- naphthalene -1- phenyl ethyl amine Base (R) or (S), N- cyclooctyl -1- phenylethyl amido (R) or (S), N- ring certain herbaceous plants with big flowers base -1- phenylethyl amido (R) or (S), N- Cyclo-dodecyl -1- naphtylethyl group amido (R) or (S), N- cyclo-dodecyl -1- (2,4- phenyl) ethyl amido (R) or (S), N-1- phenylethyl-(1- (2- methoxyphenyl)) ethyl amido (R, R) or (S, S), N-1- menaphthyl-(1- phenyl) ethyl Amido (R) or (S), N-1- phenylethyl-(2- phenylphenylmethyl) amido (R) or (S), N, N- dimethyl-ethylenediamine base, N, N- Diisopropyl ethylenediamine base, N, N- bis- (1- phenethyl) ethylenediamine base, 1,3- high piperazine base, N, N '-dimethyl -1,2- hexamethylene Two amidos (R, R) or (S, S), 2,3- diphenyl ethylene diamine base (R, R) or (S, S), benzyl-(2- pyrrole radicals -2- methyl) amido (R, R) or (S, S), N-1- phenylethyl-(2- methoxyphenyl) ethyl amido, double-(4- methoxyphenethyl) amido (R, R) or (S, S), N-1- methylphenethyl benzylamino (R) or (S), double-(2- methoxyphenethyl) amido (R, R) or (S, S), 1- methylphenethyl amido (R) or (S), N- methyl-1-methyl-(2- diphenylphosphoryl group phenyl) amido (R) or (S), R or S The tetrahydro chinolines amido of configuration and the tetrahydro indole quinoline class amido of R or S configuration:Wherein, the value of n is 1 or 2；R¹⁷、R¹⁸Arbitrarily it is selected from H, halogen atom, C₁-C₂₀Alkyl, C₃-C₂₀Naphthenic base, C_3-20The heterocycle containing N, O, S Or one of heterocyclic aryl, aryl or substituted aryl or multiple combinations；Substituent group on substituted aryl be arbitrarily selected from H, Halogen, nitro, C₁-C₂₀Fluoro-alkyl, C₁-C₂₀Alkyl, C₁-C₂₀Oxyl, amino, C₁-C₂₀N- alkyl replace amine Base or C₁-C₂₀N, one or more combinations in N- dialkyl group substituted amido；The substituent group can be one, or Multiple, when substituent group is multiple, the substituent group can be identical or different；The aryl is C₆-C₂₀Aryl；

R¹⁹、R^19’、R²⁰、R^20’、R²¹、R^21’、R²²、R^22’、R²³、R^23’、R²⁴、R^24’、R²⁵、 R^25’、R²⁶、R^26’、R²⁷、R^27’、 R²⁸、R^28’、R²⁹、R^29’、R³⁰、R^30’、R³¹、R^31’、R³²、 R^32’、R³³、R^33’、R³⁴、R^34’Optionally from H, C₁-C₂₀Alkyl or C₃-C₂₀ Naphthenic base, C_4-20The heterocycle or heterocyclic aryl, substituted silicon substrate, aryl or substituted aryl containing N, O, S；Described Substituent group in substituted silicon substrate or substituted aryl is H, halogen, nitro, C₁-C₂₀Fluoro-alkyl, C₁-C₂₀Alkyl, C₁-C₂₀Oxyl, amino, C₁-C₂₀N- alkyl substituted amido or C₁-C₂₀N, it is a kind of or more in N- dialkyl group substituted amido Kind combination；The substituent group can be one, or multiple, when substituent group is multiple, the substituent group can be with It is identical or different；The aryl is C₆-C₂₀Aryl；

For the C containing chiral centre for controlling dihedral angle size₃-C₂₀Chiral side chain,ByIt sloughs Obtained after leaving group Lg, the Lg be hydroxyl, carboxyl, halogen, methanesulfonate ester,

P-methyl benzenesulfonic acid ester or trifluoromethane sulfonic acid ester；It is wherein chiral carbon or achirality carbon with the carbon that * is marked,

When for chiral carbon, the chiral carbon is S configuration or R configuration；

For the C for controlling dihedral angle size₁-C₂₀Achiral side chain,BySlough leaving group It is obtained after Lg, the Lg is hydroxyl, carboxyl, halogen, methanesulfonate ester, p-methyl benzenesulfonic acid ester or trifluoromethane sulfonic acid ester；

Preferably (2R)-propylene glycol, (2S)-propylene glycol, (2R, 3R) -2,3- butanediol, (2S, 3S) -2,3- fourth Glycol, (1S, 2S) -1,2- hydrobenzoin, (1R, 2R) -1,2- hydrobenzoin, (2R, 3R) -1,4- benzyloxy fourth two Alcohol, (2S, 3S) -1,4- benzyloxy butanediol, (2R, 4R) -2,4-PD, (2S, 4S) -2,4-PD, (2R, 5R) - 2,5-HD, (2S, 5S) -2,5-HD, (3R, 4R) -3,4- hexylene glycol, (3S, 4S) -3,4- hexylene glycol, (3S) -1, 3- butanediol, (3R) -1,3 butylene glycol, (R)-(-) -1- vinylbenzene -1,2- glycol, (S)-(+) -1- vinylbenzene -1,2- two Alcohol, (R)-Decane-1,2-diol, (S)-Decane-1,2-diol, (2S, 9S) -2,9- decanediol, (2R, 9R) -2,9- decanediol, (3S, 8S) -3,8- decanediol, (3R, 8R) -3,8- decanediol, (4S, 7S) -4,7- decanediol, (5R, 6R) -5,6- decanediol, (5S, 6S) -4,6- decanediol, cis- -1,2- cyclohexanediol, (1R, 2R)-trans- 1,2- cyclohexanediol, (1S, 2S)-trans- 1,2- hexamethylene Glycol, (1R, 2R)-trans- 1,2- cyclopentadienyl alcohol, (1S, 2S)-trans- 1,2- cyclopentadienyl alcohol, cis- -1,2- cyclopentadienyl alcohol, (1S, 2S, 3R, 5S)-(+) -2,3- pinane diol, (3S, 5S)-(+) -3,5- heptane glycol, (3R, 5R)-(-) -3,5- heptane two Alcohol, (2S, 6S) -2,6- heptane glycol, (2R, 6R) -2,6 heptane glycol, cis-3,4- erythritan (3R, 6R) -3,6- Ethohexadiol, (3S, 6S) -3,6- ethohexadiol, (2R, 7R) -2,7- ethohexadiol, (2S, 7S) -2,7- ethohexadiol, (2R, 8R) -2,8- Nonanediol, (2S, 8S) -2,8- nonanediol, (3R, 7R) -3,7- nonanediol, (3S, 7S) -3,7- nonanediol, (4R, 6R) -4,6- Nonanediol, (4S, 6S) -4,6- nonanediol, cis- 1,2- cyclohexanedimethanol, trans- 1,2- cyclohexanedimethanol, the different Asia (+) -2,3-O- Propyl-L- threitol, (-) -2,3-O- isopropylidene-D- threitol, (R) -2,2 '-dinaphthol or (S) -2,2 '-dinaphthol； Or (R) -2,2 '-dinaphthalene dicarboxylic acids, (S) -2,2 '-dinaphthalene dicarboxylic acids, L-TARTARIC ACID, D- tartaric acid, (2R, 3R) -2,3- two Dibromo-succinic acid, (2S, 3S) -2,3- dibromosuccinic acid, (2R, 3R) -2,3- Succimer, two mercapto fourth two of (2S, 3S) -2,3- Acid, (+)-two-are to anisoyl--D- tartaric acid, (-)-two-to anisoyl--L-TARTARIC ACID, (1R, 2R) -1,2- hexamethylene Dioctyl phthalate, (1S, 2S) -1,2- cyclohexane cyclohexanedimethanodibasic, (R)-(-)-citramalic acid, (S)-(+)-citramalic acid, L MALIC ACID, D- apple Acid, (R)-(+)-methylsuccinic acid, (S)-(-)-methylsuccinic acid；Or aforementioned chiral diol methanesulfonates, to methylbenzene Sulphonic acid ester or trifluoromethane sulfonic acid ester；

Preferably 1,1- methylene bromide, glycol dibromide, 1,3- dibromopropane, 1,4- dibromobutane, 1,5- Dibromo pentane, 1,6- dibromo-hexane, 1,7- dibromo-heptane, bis- bromooctane of 1,8-, 1,9- dibromo nonane, 1,10- dibromo-decane, second After glycol condensationThe halogenated compound of end group or its methanesulfonate ester or its p-methyl benzenesulfonic acid ester, 1,3- Dibromobenzene, 1,4- dibromobenzene, α, α-dibromo ortho-xylene, α, α-two bromo-m-xylene or α, α-dibromo paraxylene；Wherein, n It is 1~10；

Heretofore described alkali can be organic base, be also possible to inorganic base, such as: triethylamine, 4-dimethylaminopyridine, The 11 carbon -7- alkene of 1,8- diazabicylo [5,4,0], 1,5- diazabicylo [4,3,0] nonyl- 5- alkene, triethylene diamine, N, O- Bis- (trimethyl silicon substrate) acetamides, cesium carbonate, potassium carbonate, lithium carbonate, potassium fluoride, sodium hydride, cesium fluoride, potassium phosphate, potassium acetate, Sodium phosphate, sodium acetate, lithium acetate, n-BuLi, two (trimethyl silicon substrate) Sodamides, two (trimethyl silicon substrate) lithium amides, two (three Methylsilyl) potassamide, sodium methoxide, sodium ethoxide, sodium isopropylate, proton sponge, tert-butyl alcohol lithium, potassium tert-butoxide, sodium tert-butoxide or Person's diisopropyl ethyl amine；Or the combination of alkali and three fluosulfonic acid silver, lithium chloride or molecular sieve additive；

In allyl substitution reaction of the present invention, the organic solvent can be polar solvent or nonpolar solvent. The organic solvent is aromatic hydrocarbon solvent or substituted arene class solvent, halogenated hydrocarbon solvent, ether solvent, amide solvent, alkane One of hydrocarbon solvent, cycloalkane solvent, nitrile solvents, dimethyl sulfoxide and alcohols solvent or multiple combinations；The virtue Hydrocarbon or substituted arene class solvent are preferably toluene, dimethylbenzene, ethylbenzene, isopropylbenzene, chlorobenzene, nitrobenzene；The halogenated hydrocarbon is molten Agent is preferably methylene chloride, 1,2- dichloroethanes and/or chloroform；The ether solvent be preferably tetrahydrofuran, ether, One of glycol dimethyl ether, methyl tertiary butyl ether(MTBE), 1,4- dioxane or multiple combinations；The amide solvent is preferred For N,N-dimethylformamide, DMAC N,N' dimethyl acetamide, N, N- dimethylpropionamide；The alkane solvents are preferably positive Hexane, pentane, normal heptane；The cycloalkane solvent is preferably pentamethylene, hexamethylene, cycloheptane；The nitrile is molten Agent is preferably acetonitrile；The alcohols solvent is preferably one of methanol, ethyl alcohol, isopropanol, normal propyl alcohol, the tert-butyl alcohol or a variety of Combination.

Preferably, formula S_aCompound the preparation method is as follows: o-phenylenediamine class compound and Chlorinated Acetic Acidss generate Benzimidazoles compound, the benzimidazoles compound withReaction obtains formula S_aCompound.

The preparation method of the method for the present invention compounds of formula I comprises the following specific steps that:

(1) it is starting material with o-phenylenediamine class compound 1 and Chlorinated Acetic Acidss 2, is 1mol/L-in concentration In the presence of the inorganic acid of 6mol/L, cyclization obtains compound 3；The molar ratio of compound 1 and compound 2 is 1:1-1:5；Instead - 120 DEG C of temperature 60 C are answered, reaction time 1h -10h；

(2) compound 3 in organic solvent, in the presence of organic base or inorganic base and phase transfer catalyst, with chemical combination Intermolecular nucleophilic substitution occurs for object 4, obtains wherein mesosome allylic compound S_a, as next step allyl amine Change the substrate of catalysis reaction；Compound 3, compound 4, alkali, phase transfer catalyst molar ratio be 1:1:1-6:0.2-3；Reaction Temperature is 20 DEG C -110 DEG C, reaction time 30min -2h；

(3) existing for the organic base or inorganic base under the conditions of, the metal iridium network that iridic compound and phosphoramidite ligand are formed Object is closed, in organic solvent catalysis substrate S_aThe allyl aminating reaction that intramolecular occurs obtains Formulas I compound represented；S_a、 Iridium, ligand, alkali molar ratio be 1:(0.005~0.1): (0.005~0.2): (0.05~3)；Reaction temperature is 20-50 DEG C； Reaction time be 30min-for 24 hours.

Preferably, formula S_bCompound the preparation method is as follows: o-phenylenediamine class compound and glycolic acid generate hydroxyl-methylene The benzimidazoles compound that base replaces, the hydroxy methylene of the benzimidazoles compound is aoxidized to obtain what carboxyl replaced Benzimidazoles compound, carboxyl replace benzimidazoles compound withReaction obtains formula S_bCompound.

The preparation method of the method for the present invention compound of formula H comprises the following specific steps that:

It (1) is the inorganic of 1mol/L -6mol/L in concentration using o-phenylenediamine class compound 1 and glycolic acid as starting material In the presence of acid, cyclization obtains compound 5；The molar ratio of compound 1 and glycolic acid is 1:1.2-1:4；30 DEG C of reaction temperature- 110 DEG C, reaction time 2h -8h；

(2) compound 5 in water, in the presence of strong oxidizer, occurs oxidation reaction and obtains compound 6；Compound 5 and strong The molar ratio of oxidant is 1:2-1:6；Reaction temperature is -20 DEG C -110 DEG C, 30 min -5h of reaction time；

(3) compound 6 is in I-hydroxybenzotriazole (HOBt) and 1- ethyl-(3- Dimethylaminopropyl) carbodiimide salt Under hydrochlorate (EDCI) effect, it is condensed with compound 4, obtains the allyl intermediate S of amide containing structure_b, as next step allyl The substrate of base amination catalysis reaction；Solvent for use be methylene chloride, tetrahydrofuran, dioxane, N,N-dimethylformamide, N, N- dimethyl acetamide or dimethyl sulfoxide；Compound 6, compound 4, HOBt, EDCI molar ratio be 1:1:1-2:1-2；Instead Answering temperature is 0-80 DEG C；Reaction time is 1h -12h；

(4) existing for the organic base or inorganic base under the conditions of, the metal iridium network that iridic compound and phosphoramidite ligand are formed Object is closed, in organic solvent catalysis substrate S_bThe allyl aminating reaction that intramolecular occurs obtains Formula II compound represented；S_b、 Iridium, ligand, alkali molar ratio be 1:(0.005~0.1): (0.005~0.2): (0.05~3)；Reaction temperature is 20-50 DEG C； Reaction time is 20min -12h.

Preferably, formula S_cCompound the preparation method is as follows: with vicinal carboxylic acid's structure o-phenylenediamine class compound and Aldehyde compound generate benzimidazoles compound, the benzimidazoles compound withReaction obtains formula S_cCompound.

The preparation method of the method for the present invention compound of formula III comprises the following specific steps that:

(1) with vicinal carboxylic acid's structure o-phenylenediamine class compound 1 and aldehyde compound 7 be starting material, having In the presence of solvent and oxidant, cyclization obtains compound 8；Oxidant is 1,4-benzoquinone；The molar ratio of compound 1 and compound 7 For 1:1-1:4；50 DEG C -100 DEG C of reaction temperature, reaction time 4h -12h；

(2) compound 8 is in I-hydroxybenzotriazole (HOBt) and 1- ethyl-(3- Dimethylaminopropyl) carbodiimide salt Under hydrochlorate (EDCI) effect, it is condensed with compound 4, obtains the allyl compound S of amide containing structure_c, as next step allyl The substrate of base amination catalysis reaction；Solvent for use be methylene chloride, tetrahydrofuran, dioxane, N,N-dimethylformamide, N, N- dimethyl acetamide or dimethyl sulfoxide；Compound 8, compound 4, HOBt, EDCI molar ratio be 1:1:1-2:1-2；Instead Answering temperature is 0-80 DEG C；Reaction time is 1h -12h；

(3) existing for the organic base or inorganic base under the conditions of, the metal iridium network that iridic compound and phosphoramidite ligand are formed Object is closed, in organic solvent catalysis substrate S_cThe allyl aminating reaction that intramolecular occurs obtains formula III compound represented；S_c、 Iridium, ligand, alkali molar ratio be 1:(0.005~0.1): (0.005~0.2): (0.05~3)；Reaction temperature is 20-50 DEG C； Reaction time is 40min -18h.

Simultaneously chiral heterocycle class compound or its pharmaceutically acceptable salt are being prepared for preventing or controlling above-mentioned benzimidazole The application with the drug of alpha-glucosidase activity unconventionality expression related mammalian disease or in lead compound is treated also at this Within the protection scope of invention.

Described and alpha-glucosidase activity unconventionality expression related mammalian disease includes: type-2 diabetes mellitus, obesity And its complication, viral infection, cancer, hyperinsulinemia, hepatitis, insulin resistance.

Compared with prior art, the invention has the following beneficial effects:

The present invention provides one kind effectively using iridium-phosphoramidite ligand complex compound as catalyst, is closed by being specifically designed At allylic substrate through intramolecular allyl Study on Catalytic Amination of Alcohols react, high efficiency, high regioselectivity and high enantioselectivity The strategy and method of ground synthesizing new benzimidazole and chiral heterocycle class compound can be used for preparing a variety of benzimidazoles and chirality Heterocycle compound.

Meanwhile also to the benzimidazole of building, simultaneously chiral heterocycle class compound has carried out initial in vitro α-grape to the present invention Glucoside inhibiting activity evaluation.Majority of compounds alpha-glucosaccharase enzyme inhibition activity of the present invention has reached and potent phlorose The comparable activity level of glycosides enzyme inhibitor 1-DNJ, and α-glucosidase inhibitory active of part of compounds It is 4 times or so of the activity level of positive control drug 1-DNJ.

Compared with the conventional method, this method is applicable to a variety of different types of benzimidazole allylic compounds, Catalytic activity is high, reaction condition is mild, wide application range of substrates, easy to operate, and the yield reacted also preferably (generally 76% ~be greater than 99%), enantioselectivity is high (generally 88%ee~be greater than 99%ee).It is this to use alkene in catalysis asymmetric molecult Propyl aminating reaction, efficiently building benzimidazole and chiral heterocycle class compound method and thus synthesize it is corresponding this Class compound at present both at home and abroad there is no literature reported on.

The present invention had both enriched the application of bridging phosphoramidite ligand and other type phosphoramide ligands, while also widening The scope of application of allylation reaction substrate provides novel heterocycle structure and efficiently building chiral heterocycle for new drug development The new method of molecule.

Detailed description of the invention

Attached drawing 1 is the mono-crystalline structures figure of the compound II-1 prepared in embodiment 13；

Attached drawing 2 is the mono-crystalline structures figure of the compound III-5 prepared in embodiment 18.

Specific embodiment

It will be helpful to understand the present invention by following embodiments, but be not intended to limit the contents of the present invention.In lower example embodiment Test method without specific conditions is selected according to conventional method in that art and condition, or according to product manual.

Embodiment 1.O, O '-[(R)-(1,1 '-dinaphthalenes -2,2 '-diphenylol)]-N- [(R) -2- methyl-1,2,3,4- tetrahydro Quinolyl] phosphoramidite (L5) preparation:

Under nitrogen protection, in a dry 250mL three-necked bottle, be added 50mL toluene and phosphorus trichloride (0.67mL, 7.7mmol), it is cooled to 0 DEG C；In the 50mL eggplant type bottle of another drying, (R) -2- methyl-1,2,3,4- tetrahydro quinolines are added Quinoline (1.13g, 7.7mmol), toluene (8mL) and triethylamine (1.8mL, 12.9 mmol), are then gradually added drop-wise to above-mentioned 250mL Three-necked bottle in.After being added dropwise, it is warming up to 80 DEG C and reacts 6 hours, be then gradually cooling to -78 DEG C.Delay again into the system The slow toluene (30mL) and tetrahydrofuran that (R)-Binaphthol (7.7 mmol) and triethylamine (3.5mL, 25.2mmol) is added (6mL) solution.The system is stirred overnight at room temperature, and solvent is removed under reduced pressure, and crude product passes through column chromatography for separation in diatomite filtering Purifying, obtains target product.

O,O’-[(R)-1,1’-Dinaphthyl-2,2’-diyl]-N-[(R)-2-methyl-1,2,3,4- tetrahydroquinoline ]phosphoramidite(L5)

White solid, yield: 92%；Fusing point: 210.4-211.5 DEG C；[α]_D ²⁰=-255.2 ° of (c=1.0, CHCl₃).¹H NMR(300MHz,CDCl₃) δ=8.01 (d, J=9.0Hz, 1H), 7.94-7.89 (m, 3H), 7.60 (d, J=8.7Hz, 1H), 7.55 (dd, J=8.1,3.6Hz, 1H), 7.42 (dd, J=8.1,3.6Hz, 4H), 7.31-7.21 (m, 3H), 7.11-7.06 (m, 2H), 6.93 (t, J=7.2Hz, 1H), 3.71 (m, 1H), 2.78 (t, J=4.5 Hz, 2H), 2.04-1.92 (m, 1H), 1.45-1.38 (m, 1H), 0.94 (d, J=6.6Hz, 3H)¹³C NMR(75MHz,CDCl₃) δ=150.00,149.90, 149.42,139.87,139.55,132.75,132.73, 132.67,131.50,131.48,130.61,130.55, 129.92,129.80,128.35,128.25,127.17, 127.07,126.38,126.35,126.26,126.06, 126.20,126.15,124.96,124.60,124.11, 124.03,122.12,122.09,121.77,121.66, 121.63,121.31,121.28,119.77,119.30, 45.74,27.88,22.81,18.99.³¹P NMR(121MHz, CDCl₃) δ=141.99.HRMS (ESI) calcd for C₃₀H₂₄NO₂P[M+H]⁺:461.1545,Found:461.1548.

Embodiment 2. (S)-[6,6 '-((R, R) -2,4-PD oxygen)] -2,2 '-N, N- bis- [(1R) -1- phenylethyls] The preparation of phosphoramidite (L12):

Under nitrogen protection, phosphorus trichloride (32.30 μ L, 0.37mmol), triethylamine are separately added into 100mL round-bottomed flask (257.90 μ L, 1.85mmol), bis- [(1R) -1- phenylethyl] amine (83.70 μ L, 0.37mmol), dry toluene (20mL), so 4h is stirred to react at 50 DEG C afterwards.It is cooled to room temperature, (S)-[6,6 '-((2R, 4R) -2,4- pentanediol oxygen)] -2,2 '-two is added The tetrahydrofuran solution (20mL) of xenol (105.86mg, 0.37mmol), continues to be stirred to react 16h at room temperature.It is thick to produce Object obtains target compound after column chromatographic purifying.

(S)-[6,6-(2R,4R-Pentadioxy)]-(1,1’)-biphenyl-(3,5-dioxa-4- phosphacyclohepta[e,g] [1,4])-bis((R)-1-phenylethyl)amine(L12)

White solid, yield: 84%；Fusing point: 109.6-110.3 DEG C；[α]_D ²⁷=+59 (c=0.1, CHCl₃).¹H NMR (400MHz,CDCl₃) δ 7.31-7.25 (m, 2H), 7.16-7.10 (m, 2H), 6.98 (dd, J=13.6,8.2 Hz, 2H), 6.89 (t, J=7.5Hz, 2H), 4.77-4.68 (m, 2H), 4.63-4.52 (m, 2H), 2.08-1.89 (m, 2H), 1.44 (dd, J=6.4,3.6Hz, 6H)¹³C NMR(100MHz,CDCl₃)δ158.13, 157.94,152.61,152.52,151.86, 143.00,128.92,128.50,128.19,128.00,127.74, 127.66,126.52,120.79,118.75, 116.21,116.18,115.61,113.25,111.79,74.75,74.47, 52.15,52.03,41.65,22.60, 22.31.³¹P NMR(162MHz,CDCl₃)δ143.28.HRMS(ESI) calcd for C₃₃H₃₅NO₄P[M+H]⁺: 540.2298,found:540.2299.

Embodiment 3. (R)-[6,6 '-((S, S) -2,3- butanediol oxygen)] -2,2 '-N- [(R) -2- methyl-1,2,3,4- tetra- Hydrogen quinolyl] phosphoramidite (L13) preparation:

In the three-necked bottle of a dry 250mL, (R)-[6,6 '-((S, S) -2,3-butanediol oxygen)] -2,2 '-is added Dihydroxybiphenyl (2.00g, 7.3mmol) and toluene (50mL), be separately added under nitrogen protection phosphorus trichloride (9.60mL, 110.00mmol) liquid cooling then will be reacted in 50 DEG C of reaction 30min with N-Methyl pyrrolidone (21.00 μ L, 0.22mmol) But to room temperature, then it is evaporated under reduced pressure removing phosphorus trichloride, then the phosphorous acyl chlorides solid that will be obtained after concentration with the tetrahydrofuran of 50mL Dissolution；In the 250mL round-bottomed flask of another drying, (R) -2- methyl-1,2,3,4- tetrahydroquinoline hydrochlorides are added The tetrahydrofuran of (1.20g, 6.60mmol) and 30 mL are cooled to -78 DEG C, and n-BuLi is slowly then added dropwise under nitrogen protection (2.5mol/L, 5.30mL) continues to be stirred to react 1h after dripping；Finally the phosphorous solution of acid chloride of above-mentioned preparation is slowly dripped It is added in -78 DEG C of reaction solution, is reacted at room temperature after adding overnight, TLC tracks fully reacting, and vacuum distillation removes solvent, slightly Product is obtained by column chromatography for separation.

(R)-[6,6’-(2S,3S-Butadioxy)]-(1,1’)-biphenyl-(3,5-dioxa-4- phosphacyclohepta[e,g] [1,4])-(R)-2-methyl-1,2,3,4-tetrahydroquinoline(L13)

White solid, yield: 87%；Fusing point: 120.0-120.4 DEG C；[α]_D ²⁰=-78.6 (c=1.0, CHCl₃).¹H NMR(400MHz,CDCl₃) δ 7.53 (dd, J=7.8,3.2Hz, 1H), 7.40 (t, J=8.1Hz, 1H), 7.31 (t, J= 8.1Hz, 1H), 7.19-7.08 (m, 3H), 7.04 (d, J=8.1Hz, 1H), 6.98 (m, 2H), 6.95-6.89 (m, 1H), 4.02-3.89 (m, 3H), 2.88-2.73 (m, 2H), 2.02-1.92 (m, 1H), 1.44 (m, 7H), 1.00 (d, J=6.6Hz, 3H).¹³C NMR(100MHz,CDCl₃)δ159.30,159.09, 152.34,151.34,139.65,129.95,129.89, 129.50,126.37,126.25,121.24,120.30, 119.69,119.34,118.87,118.06,117.36, 116.99,85.41,85.41,45.56,27.94,22.89, 19.01,18.88,18.84.³¹P NMR(162MHz,CDCl₃)δ 139.62.HRMS(ESI)calcd for C₂₆H₂₆NO₄P[M+H]⁺:448.1672,found:448.1655.

Embodiment 1, embodiment 2 can be used in embodiment 4. phosphoramidite ligand L1-L4, L6-L8, L10-L11, L13-L21 Or the identical method of embodiment 3 or be prepared according to the method for this field routine, for details, reference can be made to documents: (a) J.Am.Chem.Soc.2011,133,4785.(b)J.Am.Chem.Soc.2012,134,4812.(c)J. Am.Chem.Soc.2012,134,15022.(d)J.Org.Chem.2015,80,6968.(e)J.Am.Chem. Soc.2015, 137,553.(f)Organometallics 2016,35,2467.(g)ACS Catal.2017,7,2397. (h) J.Am.Chem.Soc.2017,139,15022.

5. allylic substrate S of embodiment_a-1a、S_a-1b、S_a-1c、S_a-2a、S_a-3a、S_aThe preparation of -4a:

With o-phenylenediamine class compound (1.0equiv) and monoxone (1.2equiv) for starting material, it is in concentration In the presence of the dilute hydrochloric acid of 4.0mol/L, 1h is first stirred at room temperature, is again heated to 110 DEG C of back flow reactions, TLC tracks to raw material reaction Completely, reaction solution is cooled to room temperature, then with sodium carbonate liquor tune pH to neutrality, filters and obtain solid chemical compound 3.With carbonic acid Potassium (2.0equiv) is alkali, potassium iodide (1.2equiv) is catalyst, compound 3 (1.0equiv) and corresponding compound 4 Reaction is stirred at room temperature in (1.0equiv) in tetrahydrofuran solvent, and raw material fully reacting back spin removes THF, and ethyl acetate extracts, Organic phase is washed with saturation NaCl aqueous solution, and anhydrous sodium sulfate is dry.Solvent is removed under reduced pressure, crude by column chromatography purifying obtains To target compound S_a(S_a-1a、S_a-1b、S_a-1c、S_a-2a、S_a-3a、S_a-4a)。

(E) -4- ((1H- benzo [d] imidazoles methylene) benzamido group) -2- butylene methyl carbonate (S_a-1a)

(E)-4-(((1H-benzo[d]imidazol-2-yl)methyl)(benzyl)amino)but-2-en-1-yl methyl carbonate(S_a-1a)

Light brown viscous liquid, yield: 92%.¹H NMR(400MHz,CDCl₃)δ7.62–7.58(m,2H), 7.34– 7.27 (m, 4H), 7.26-7.21 (m, 3H), 5.86 (dt, J=15.4,6.0Hz, 1H), 5.77 (dt, J=15.6,5.7Hz, 1H), 4.54 (d, J=5.5Hz, 2H), 3.89 (s, 2H), 3.78 (s, 3H), 3.66 (s, 2H), 3.16 (d, J=5.9Hz, 2H).¹³C NMR(100MHz,CDCl₃)δ155.59,152.91,137.92, 137.92,132.13,132.13,128.92, 128.92,128.92,128.45,128.45,128.45,127.38, 127.22,122.38,122.38,67.68,58.57, 55.57,54.85,51.84.HRMS(ESI)calcd for C₂₁H₂₃N₃O₃[M+H]⁺:367.1851,found:367.1846.

(E) -4- ((1H- benzo [d] imidazoles methylene) benzamido group) -2- butene acetic acid ester (S_a-1b)

(E)-4-(((1H-benzo[d]imidazol-2-yl)methyl)(benzyl)amino)but-2-en-1-yl acetate (S_a-1b)

Light brown viscous liquid, yield: 76%.¹H NMR(400MHz,CDCl₃)δ7.65–7.55(m,2H), 7.37– 7.28 (m, 4H), 7.26-7.20 (m, 3H), 5.86-5.78 (m, 1H), 5.76-5.69 (m, 1H), 4.50 (d, J=5.4Hz, 2H), 3.91 (s, 2H), 3.67 (s, 2H), 3.16 (d, J=5.6Hz, 2H), 2.04 (s, 3H)¹³C NMR(100MHz, CDCl₃)δ170.86,153.05,138.00,131.38,131.38,128.94, 128.94,128.94,128.44, 128.44,128.44,127.93,127.37,127.37,122.36,122.36, 64.40,58.63,55.68,51.88, 21.00.HRMS(ESI)calcd for C₂₁H₂₃N₃O₂ [M+H]⁺:350.1824,found:350.1816.

(E) -4- ((1H- benzo [d] imidazoles methylene) benzamido group) -2- butylene t-butyl carbonate (S_a-1c)

(E)-4-(((1H-benzo[d]imidazol-2-yl)methyl)(benzyl)amino)but-2-en-1-yl tert-butyl carbonate(S_a-1c)

Light brown viscous liquid, yield: 80%.¹H NMR(400MHz,CDCl₃)δ7.82–7.40(m,2H),7.38 – 7.30 (m, 4H), 7.30-7.22 (m, 3H), 5.90 (dt, J=15.6,5.9Hz, 1H), 5.86 (dt, J=15.6,5.6Hz, 1H), 4.55 (d, J=5.5Hz, 2H), 3.91 (s, 2H), 3.73 (s, 2H), 3.16 (d, J=5.8Hz, 2H), 1.49 (s, 9H).¹³C NMR(100MHz,CDCl₃)δ152.96,137.93,131.71,131.71, 128.92,128.92,128.92, 128.50,128.50,128.50,127.77,127.77,127.43,127.43, 124.74,123.74,122.55, 119.36,82.34,66.79,58.61,55.65,51.79,27.83.HRMS(ESI) calcd for C₂₄H₂₉N₃O₃[M+H ]⁺:408.2242,found:408.2235.

(E) -4- ((1H- benzo [d] imidazoles methylene) (4- methoxy-benzyl) amido) -2- butylene methyl carbonate (S_a- 2a)

(E)-4-(((1H-benzo[d]imidazol-2-yl)methyl)(4-methoxybenzyl)amino)but- 2-en-1-yl methyl carbonate(S_a-2a)

Light brown viscous liquid, yield: 88%.¹H NMR(400MHz,CDCl₃)δ7.61(s,2H),7.25–7.19 (m, 2H), 7.18-7.14 (m, 2H), 6.75-6.69 (m, 2H), 5.79 (dt, J=15.5,5.9Hz, 1H), 5.70 (dt, J= 15.6,5.6Hz, 1H), 4.48 (d, J=5.5Hz, 2H), 3.90 (s, 2H), 3.73 (s, 3H), 3.69 (s, 3H), 3.56 (s, 2H), 3.11 (d, J=5.7Hz, 2H)¹³C NMR(100MHz,CDCl₃)δ 158.84,153.28,132.28,132.28, 130.17,130.17,130.17,130.17,129.80,127.02, 127.02,122.30,113.71,113.71, 113.71,113.71,67.70,57.75,55.31,55.14,54.77, 51.70.HRMS(ESI)calcd for C₂₂H₂₅N₃O₄[M+H]⁺:396.1879,found:396.1867.

(E) -4- ((5,6- dimethyl -1H- benzo [d] imidazoles methylene) (4- methylbenzyl) amido) -2- butylene carbonic acid Methyl esters (S_a-3a)

(E)-4-(((5,6-dimethyl-1H-benzo[d]imidazol-2-yl)methyl)(4- methylbenzyl)amino)b ut-2-en-1-yl methyl carbonate(S_a-3a)

Light brown viscous liquid, yield: 94%.¹H NMR(400MHz,CDCl₃)δ9.51(s,1H),7.45–7.33 (m, 2H), 7.22 (d, J=8.0Hz, 2H), 7.14 (d, J=7.9Hz, 2H), 5.89 (dt, J=15.5,6.1Hz, 1H), 5.79 (dt, J=15.6,5.8Hz, 1H), 4.60 (d, J=5.8Hz, 2H), 3.85 (s, 2H), 3.79 (s, 3H), 3.63 (s, 2H), 3.16 (d, J=6.0Hz, 2H), 2.38 (s, 6H), 2.34 (s, 3H)¹³C NMR(100MHz, CDCl₃)δ155.60, 152.17,136.92,134.91,132.41,132.41,129.10,129.10, 129.10,129.10,128.94, 128.94,128.94,128.94,127.02,127.02,67.75,58.20,55.40, 54.81,51.79,21.09, 20.32,20.32.HRMS(ESI)calcd for C₂₄H₂₉N₃O₃ [M+H]⁺:408.2242,found:408.2234.

(E) -4- ((5,6- dimethyl -1H- benzo [d] imidazoles methylene) (4- luorobenzyl) amido) -2- butylene carbonic acid first Ester (S_a-4a)

(E)-4-(((5,6-dimethyl-1H-benzo[d]imidazol-2-yl)methyl)(4- fluorobenzyl)amino)b ut-2-en-1-yl methyl carbonate(S_a-4a)

Light tan solid, yield: 86%, fusing point: 89.2-90.4.¹H NMR(400MHz,CDCl₃)δ9.32(s, 1H), 7.39-7.33 (m, 2H), 7.32-7.26 (m, 2H), 7.09-6.92 (m, 2H), 5.89 (dt, J=15.5,6.1Hz, 1H), 5.80 (dt, J=15.6,5.8Hz, 1H), 4.66-4.56 (m, 2H), 3.89-3.82 (m, 2H), 3.82-3.76 (m, 3H), 3.63 (d, J=11.1Hz, 2H), 3.15 (d, J=5.9Hz, 2H), 2.39 (d, J=9.3Hz, 6H)¹³C NMR(100MHz, CDCl₃) δ 162.10 (d, J=245.5Hz), 155.61,151.73,133.90,133.63,132.08,131.36, 130.52,130.52,130.44,130.44,129.71 (d, J=8.0 Hz), 127.32,125.25,115.37,115.13, 67.66,57.67,55.38,54.86,51.73,20.32, 20.32.HRMS(ESI)calcd for C₂₃H₂₆FN₃O₃[M+H ]⁺:412.1992,found:412.1985.

6. allylic substrate S of embodiment_b-1a、S_b-2a、S_b-3a、S_bThe preparation of -4a:

With o-phenylenediamine class compound (1.0equiv) and glycolic acid (2.0equiv) for starting material, it is in concentration In the presence of the aqueous hydrochloric acid solution of 4.0mol/L, back flow reaction, TLC tracks to raw material fully reacting, and reaction solution is cooled to room temperature, With 20% NaOH tune pH to 7, stands and solid is precipitated, filter, be dried to obtain compound 5；Compound 5 is transferred to round-bottomed flask In, NaOH aqueous solution is added, KMnO is added portionwise while stirring in 80 DEG C₄(2.5equiv), the reaction was continued after adding, to raw material Total overall reaction is complete, and reaction solution is cooled to room temperature, and filters to obtain filtrate, with 20% HCL aqueous solution tune pH to neutrality, is precipitated solid Body, suction filtration are dried to obtain compound 6；Compound 6 (1.0equiv) is dissolved with DMF, is then respectively adding 1- hydroxy benzo three Azoles (HOBt, 1.1equiv) and 1- ethyl-(3- Dimethylaminopropyl) carbodiimide hydrochloride (EDCI, 1.1equiv), in Reaction 30min is stirred at room temperature, then reaction solution is added in compound 4 (1.1equiv), continues to be stirred to react, TLC tracks to raw material Fully reacting pours into reaction solution in ice water, is then extracted with ethyl acetate, and organic layer is concentrated under reduced pressure, and crude product chromatographs pure through column Change obtains allylic intermediate S_b。

(E) -4- (N- benzyl -1H- benzo [d] imidazoles 2- formamido) -2- butylene methyl carbonate (S_b-1a)

(E)-4-(N-benzyl-1H-benzo[d]imidazole-2-carboxamido)but-2-en-1-yl methyl carbonate(S_b-1a)

White solid, yield: 94%；Fusing point: 127.1-128.0 DEG C of¹H NMR(400MHz,CDCl₃)δ12.01 (s, 1H),7.87–7.75(m,1H),7.48–7.43(m,1H),7.43–7.29(m,7H),6.13–5.91(m, 1H),5.90– 5.77 (m, 2H), 5.14 (d, J=5.7Hz, 1H), 4.93 (s, 1H), 4.67 (t, J=5.6Hz, 2H), 4.24 (d, J= 5.4Hz,1H),3.81(s,3H).¹³C NMR(100MHz,CDCl₃)δ160.27, 155.56,144.97,143.36, 136.38,133.21,131.04,128.83,128.71,128.11,128.01, 127.68,127.17,125.08, 123.01,121.18,111.99,67.55,54.89,51.46, 49.37.HRMS(ESI)calcd for C₂₁H₂₁N₃O₄[M+ H]⁺:380.1605,found:380.1603.

(E) -4- (N- (4- methoxy-benzyl) -1H- benzo [d] imidazoles -2- formamido) -2- butylene methyl carbonate (S_b- 2a)

(E)-4-(N-(4-methoxybenzyl)-1H-benzo[d]imidazole-2-carboxamido)but-2- en-1-yl methyl carbonate(S_b-2a)

White solid, yield: 91%；Fusing point: 125.3-126.0 DEG C of¹H NMR(400MHz,CDCl₃)δ12.00 (s, 1H),7.87–7.79(m,1H),7.54–7.45(m,1H),7.39–7.25(m,4H),6.94–6.85(m, 2H),6.17– 5.78 (m, 2H), 5.75 (s, 1H), 5.10 (d, J=4.8Hz, 1H), 4.85 (s, 1H), 4.73-4.56 (m, 2H), 4.33- 4.12(m,1H),3.81(s,6H).¹³C NMR(100MHz,CDCl₃)δ159.23, 155.57,145.11,143.36, 133.10,131.20,129.55,129.17,128.86,128.45,127.07, 125.08,123.03,121.22, 114.08,114.08,111.91,67.58,54.89,50.77,48.71, 46.91.HRMS(ESI)calcd for C₂₂H₂₃N₃O₅[M+H]⁺:410.1710,found:410.1697.

(E) -4- (fluoro- 1H- benzo [d] imidazoles -2- formamido of N- benzyl -5,6- two) -2- butylene methyl carbonate (S_b- 3a)

(E)-4-(N-benzyl-5,6-difluoro-1H-benzo[d]imidazole-2-carboxamido)but- 2-en-1-yl methyl carbonate(S_b-3a)

White solid, yield: 90%；Fusing point: 101.2-101.8 DEG C of¹H NMR(400MHz,CDCl₃)δ11.34 (s, 1H),7.65–7.52(m,1H),7.45–7.29(m,5H),7.27–7.18(m,1H),6.10–5.76(m, 2H),5.75(s, 1H), 5.02 (d, J=8.3Hz, 1H), 4.85 (s, 1H), 4.66 (d, J=6.5Hz, 2H), 4.15 (d, J=6.1Hz, 1H), 3.82(s,3H).¹³C NMR(100MHz,CDCl₃) δ 159.92,155.77,151.02,149.12 (d, J=112.1Hz), 146.79 (d, J=93.2Hz), 136.59,136.04,130.66,128.94,128.78,128.63,128.01,127.86, 127.65,127.34,107.95,99.32,67.45,54.92, 49.65,47.36.HRMS(ESI)calcd for C₂₁H₁₉F₂N₃O₄[M+H]⁺:416.1416,found:416.1415.

(E) -4- (N- benzyl -5- nitro -1H- benzo [d] imidazoles -2- formamido) -2- butylene methyl carbonate (S_b-4a)

(E)-4-(N-benzyl-5-nitro-1H-benzo[d]imidazole-2-carboxamido)but-2-en- 1-yl methyl carbonate(S_b-4a)

Light yellow solid, yield: 86%；Fusing point: 143.6-143.8 DEG C of¹H NMR(400MHz,CDCl₃)δ 12.47(s, 1H), 8.77 (d, J=2.0Hz, 1H), 8.33-8.16 (m, 1H), 7.90 (d, J=9.0Hz, 1H), 7.45-7.34 (m, 5H), 6.21-5.81 (m, 2H), 5.80 (s, 1H), 5.08 (d, J=5.8Hz, 1H), 4.95 (s, 1H), 4.68 (d, 5.8Hz, 2H), 4.22(s,1H),3.82(s,3H).¹³C NMR(100MHz,CDCl₃) δ159.25,155.47,147.95,144.17, 142.57,135.74,130.10,129.01,129.01,127.99, 127.99,127.77,127.77,120.59, 118.17,112.18,109.05,67.36,54.95,51.67, 49.93.HRMS(ESI)calcd for C₂₁H₂₀N₄O₆[M+ H]⁺:425.1456,found:425.1444.

7. allylic substrate S of embodiment_c-1a、S_c-2a、S_c-3a、S_cThe preparation of -4a:

With 2,3- diaminobenzoic acid (1.0equiv) and the aldehyde compound 7 (1.5equiv) replaced for starting material, It in the presence of dioxane and 1,4-benzoquinone (0.2equiv), is stirred to react in 80 DEG C, TLC tracks to raw material fully reacting, will be anti- It answers liquid to be cooled to room temperature, filters, washed respectively with ethyl alcohol, ether, be dried to obtain compound 8；With DMF by compound 8 (1.0equiv) dissolution, is then respectively adding I-hydroxybenzotriazole (HOBt, 1.1 equiv) and 1- ethyl-(3- dimethyl amine Base propyl) carbodiimide hydrochloride (EDCI, 1.1equiv), reaction 30min is stirred at room temperature, then by trans- 4- benzamido group -2- Reaction solution is added in butylene methyl carbonate (1.1equiv), continues reaction is stirred at room temperature and pours into reaction solution after raw material fully reacting It in ice water, is then extracted with ethyl acetate, organic layer is concentrated under reduced pressure, and crude product obtains allylic intermediate through column chromatographic purifying S_c。

(E) -4- (N- benzyl -2- cyclopropyl -1H- benzo [d] imidazoles -7- formamido) -2- butylene methyl carbonate (S_c- 1a)

(E)-4-(N-benzyl-2-cyclopropyl-1H-benzo[d]imidazole-7-carboxamido)but- 2-en-1- yl methyl carbonate(S_c-1a)

Pale yellow viscous liquid, yield: 90%.¹H NMR(400MHz,DMSO-d₆)δ12.52(s,1H),7.53(s, 1H),7.52–7.46(m,1H),7.43–7.35(m,1H),7.33–7.12(m,5H),6.22–5.47(m, 2H),4.76– 4.68(m,2H),4.48–4.40(m,2H),4.42–4.21(m,1H),4.27–4.20(m, 1H),3.71(s,3H),2.30– 2.08(m,1H),1.21–1.10(m,4H).¹³C NMR(100MHz, DMSO-d₆)δ169.61,158.71,155.40, 142.45,138.16,137.75,137.71,130.69,129.96, 128.80,128.80,127.78,127.78, 127.34,127.00,121.37,119.70,67.28,55.07, 49.84,47.05,9.68,9.52,9.52.HRMS(ESI) calcd for C₂₄H₂₅N₃O₄[M+H]⁺:420.1918, found:420.1901.

(E) -4- (N- benzyl -2- (2- thienyl) -1H- benzo [d] imidazoles -7- formamido) -2- butylene methyl carbonate (S_c-2a)

(E)-4-(N-benzyl-2-(thiophen-2-yl)-1H-benzo[d]imidazole-7-carboxamido) but-2-e n-1-yl methyl carbonate(S_c-2a)

Light yellow solid, yield: 93%；Fusing point: 139.4-140.5 DEG C of¹H NMR(400MHz,DMSO-d₆)δ 13.21 (s, 1H), 7.90 (d, J=3.1Hz, 1H), 7.80 (dd, J=10.6,4.9Hz, 1H), 7.64 (d, J=7.5Hz, 1H), 7.58 (dd, J=11.7,8.1Hz, 1H), 7.46 (t, J=7.5Hz, 1H), 7.27-7.23 (m, 6H), 6.25-5.43 (m, 2H), 4.98-4.66 (m, 2H), 4.48 (d, J=5.6Hz, 1H), 4.34 (s, 1H), 3.99 (s, 1H), 3.73 (m, 1H), 3.68(s,3H).¹³C NMR(100MHz,DMSO-d₆)δ169.58, 155.32,148.34,140.32,137.72,135.11, 133.84,130.85,129.94,129.69,128.96, 128.88,127.93,127.80,127.67,127.30, 127.03,125.46,123.12,120.50,112.57, 67.35,55.12,51.91,49.89.HRMS(ESI)calcd for C₂₅H₂₃N₃O₄S[M+H]⁺:462.1482, found:462.1462.

(E) -4- (N- benzyl -2- (4- methoxyphenyl) -1H- benzo [d] imidazoles -7- formamido) -2- butylene carbonic acid Methyl esters (S_c-3a)

(E)-4-(N-benzyl-2-(4-methoxyphenyl)-1H-benzo[d]imidazole-7- carboxamido)but- 2-en-1-yl methyl carbonate(S_c-3a)

White solid, yield: 90%；Fusing point: 87.3-88.4 DEG C of¹H NMR (400MHz, DMSO-d₆) δ 13.03 (s, 1H), 8.24 (d, J=6.7Hz, 2H), 7.65-7.58 (m, 2H), 7.49-7.40 (m, 1H), 7.36- 7.29 (m, 1H), 7.30-7.06 (m, 6H), 5.80-5.73 (m, 2H), 4.79-4.70 (m, 2H), 4.46- 4.41 (m, 2H), 3.91 (s, 1H), 3.86 (s, 3H), 3.72 (s, 3H), 3.50 (s, 1H)¹³C NMR (100 MHz, DMSO-d₆) δ 169.67,161.37, 155.33,152.78,140.46,137.93,137.46,135.44,130.54,130.18,128.88,128.88, 128.70,127.78,127.78,127.42,127.02,125.26,122.79,122.52,120.31,114.81, 112.43,67.30,55.80,55.08,51.97,49.92.HRMS (ESI) calcd for C₂₈H₂₇N₃O₅[M+H]⁺: 486.2023, found:486.2003.

(E) -4- (N- benzyl -2- (1- naphthalene) -1H- benzo [d] imidazoles -7- formamido) -2- butylene methyl carbonate (S_c-4a)

(E)-4-(N-benzyl-2-(naphthalen-1-yl)-1H-benzo[d]imidazole-7- carboxamido)but-2 -en-1-yl methyl carbonate(Sc-4a)

White solid, yield: 92%；Fusing point: 139.6-141.0 DEG C of¹H NMR (400MHz, DMSO-d₆) δ 13.35 (s, 1H), 8.78 (s, 1H), 8.47-8.34 (m, 1H), 8.19-8.12 (m, 1H), 8.09-7.96 (m, 2H), 7.70-7.67 (m, 1H), 7.66-7.62 (m, 3H), 7.49 (t, J=7.6Hz, 1H), 7.43-7.16 (m, 5H), 5.98-5.91 (m, 2H), 5.56-5.50 (m, 1H), 4.73 (d, J=5.5Hz, 1H), 4.48 (d, J=5.7Hz, 1H), 4.41 (s, 1H), 4.23-3.98 (s, 1H), 3.81-3.75 (m, 1H), 3.69 (s, 3H)¹³C NMR (100MHz, DMSO-d₆) δ 169.59,155.31, 152.55,140.61,137.85,137.46,135.59,134.08,133.23,130.76,130.16,129.15, 129.07,128.89,128.89,128.32,127.86,127.76,127.56,127.47,127.03,126.43, 125.34,124.37,123.20,120.51,112.85,67.31,55.08,49.88,47.05.HRMS (ESI) calcd for C₃₁H₂₇N₃O₄ [M+H]⁺: 506.2074, found:506.2055.

8. allylic intermediate S of embodiment_a- 1 is used as substrate to issue raw intramolecular in iridium-phosphoramidite complex catalysis The research of the ligand and leaving group of allyl aminating reaction:

Wherein, THF is tetrahydrofuran, and Bn is benzyl, and LG is leaving group, and Ac is acetyl group, and Boc is tertbutyloxycarbonyl, Troc is 2,2,2- trichloro-ethoxycarbonyls, and n.r. is not react, and trace is trace product.

9. allylic intermediate S of embodiment_a- 1a issues son estranged in iridium-phosphoramidite complex catalysis as substrate The research of the alkali and solvent of interior allyl aminating reaction:

Wherein, Bn is benzyl, and DMAP is 4- dimethylamino pyridine, and DABCO is triethylene diamine, and DBU is 1,8- diaza Two rings, 11 carbon -7- alkene, DCM is methylene chloride, Et₂O is ether, and DME is glycol dimethyl ether, and toluene is toluene, Dioxane is dioxane, and MTBE is methyl tertiary butyl ether(MTBE).

10. allylic intermediate S of embodiment_aRaw intramolecular is issued in iridium-phosphoramidite complex catalysis as substrate Allyl aminating reaction prepares tetrahydro benzo [4,5] imidazoles [1,2-a] pyrazine compound I:

Under argon gas protection, iridic compound (0.004mmol), chiral phosphoramide are sequentially added in a dry reaction tube Ligand (0.008mmol), n-propylamine (0.5mL) and tetrahydrofuran (0.5mL) react 30 minutes at 50 DEG C, are then cooled to naturally Decompressing and extracting solvent after room temperature.Substrate S is successively added into reaction tube again_a(0.2mmol), alkali (0.6mmol), organic solvent (3mL) is reacted in 20-80 DEG C.TLC is tracked after reaction, solvent is removed under reduced pressure, the crude product obtained after concentration passes through column Chromatography obtains product I (petroleum ether: ethyl acetate=1:1-6:1, v/v).The preparation method of compound I-1 to I-8 and specific Reaction condition is referring to embodiment 10 and table 1, wherein the molar ratio in table 1 refers to substrate S_a: iridium: ligand: the molar ratio of alkali.

The reaction condition of compound I-1 to I-8 is synthesized in 1. embodiment 10 of table

Wherein, Bn is benzyl, and DBU is 1,8- diazabicylo, 11 carbon -7- alkene, and DBN is 1,5- diazabicyclo nonyl- 5- Alkene, DMAP are 4- dimethylamino pyridines, and DABCO is triethylene diamine, and DIPEA is N, N- diisopropyl ethyl amine, Cs₂CO₃It is carbon Sour caesium, K₃PO₄It is potassium phosphate, KF is potassium fluoride, and DCE is 1,2- dichloroethanes, Et₂O is ether, and DME is glycol dimethyl ether, MTBE is methyl tertiary butyl ether(MTBE), and Ac is acetyl group, and Troc is 2,2,2- trichloro-ethoxycarbonyls.

I-1:(R) -2- benzyl -4- vinyl -1,2,3,4- tetrahydro benzo [4,5] imidazoles [1,2-a] pyrazine

I-1:(R)-2-Benzyl-4-vinyl-1,2,3,4-tetrahydrobenzo[4,5]imidazo[1,2-a] pyrazine

R_f=0.20 (petroleum ether: ethyl acetate=3:1, v/v)；Yellow solid；Fusing point: 100.4-101.0 DEG C of .98% Yield, 90%ee [Daicel Chiralcel OD-H (0.46cm x 25cm), n-hexane/2-propanol=85/ 15, v=1.0mLmin^-1, λ=254nm, t_R(major)=13.34min, t_R(minor)=15.11min] [α]_D ²⁵=+ 87.0 (c=1.0, CHCl₃).¹H NMR(400MHz,CDCl₃) δ 7.69 (d, J=7.8Hz, 1H), 7.42-7.26 (m, 6H), 7.26-7.16 (m, 2H), 6.07-5.89 (m, 1H), 5.31 (dd, J=13.7,3.7Hz, 2H), 4.83-4.73 (m, 1H), 4.00 (d, J=15.6Hz, 1H), 3.84 (d, J=15.6Hz, 1H), 3.78 (d, J=13.1Hz, 1H), 3.70 (d, J= 13.1Hz, 1H), 3.00 (dd, J=12.2,4.5Hz, 1H), 2.87 (dd, J=12.1,5.2Hz, 1H)¹³C NMR (100MHz,CDCl₃)δ149.38,143.12,137.02, 135.70,133.90,128.93,128.93,128.52, 128.52,127.62,122.22,121.90,119.23, 118.60,110.72,77.40,77.08,76.77,61.81, 56.68,55.64,52.37,29.72.HRMS(ESI) calcd for C₁₉H₁₉N₃[M+H]⁺:290.1613.Found: 290.1602.

I-2:(R) fluoro- 4- vinyl -1,2,3,4- tetrahydro benzo [4,5] imidazoles [1,2-a] pyrazine of -2- benzyl -7,8- two

I-2:(R)-2-Benzyl-7,8-difluoro-4-vinyl-1,2,3,4-tetrahydrobenzo[4,5] imidazo[1,2- a]pyrazine

R_f=0.25 (petroleum ether: ethyl acetate=4:1, v/v)；White solid；Fusing point: 155.0-156.4 DEG C of .95% Yield, 92%ee [Daicel Chiralcel AS-H (0.46cm x 25cm), n-hexane/2-propanol=80/ 20, v=1.0mLmin^-1, λ=254nm, t_R(minor)=10.41min, t_R(major)=12.70min] [α]_D ²⁵ =+108.0 (c=0.8, CHCl₃).¹H NMR(400MHz,CDCl₃) δ 7.47 (dd, J=10.6,7.3Hz, 1H), 7.44- 7.29 (m, 5H), 7.15 (dd, J=10.0,7.0Hz, 1H), 6.11-5.87 (m, 1H), 5.40 (dd, J=13.7,10.4Hz, 2H), 4.76 (dd, J=12.9,5.3Hz, 1H), 3.95 (d, J=15.7Hz, 1H), 3.87 (d, J=15.7Hz, 1H), 3.81 (d, J=13.1Hz, 1H), 3.75 (d, J=13.1Hz, 1H), 3.07 (dd, J=12.2,4.7Hz, 1H), 2.87 (dd, J= 12.2,5.8Hz,1H).¹³C NMR(100MHz, CDCl₃) δ 150.95,148.75 (dd, J=34.1,15.1Hz), 146.36 (dd, J=35.4,15.1Hz), 138.43,138.32,136.78,135.02,128.93,128.93,128.56,128.56, (127.71,119.37,106.56 d, J=19.8Hz), 98.87 (d, J=23.2Hz), 98.76,61.77,57.14, 55.58, 52.27.HRMS(ESI)calcd for C₁₉H₁₇F₂N₃[M+H]⁺:325.1463.Found:325.1458.

I-3:(S) chloro- 4- vinyl -1,2,3,4- tetrahydro benzo [4,5] imidazoles [1,2-a] pyrazine of -2- benzyl -7,8- two

I-3:(S)-2-benzyl-7,8-dichloro-4-vinyl-1,2,3,4-tetrahydrobenzo[4,5] imidazo[1,2- a]-pyrazine

R_f=0.30 (petroleum ether: ethyl acetate=4:1, v/v)；White solid；Fusing point: 171.0-171.8 DEG C of .93% Yield, 90%ee [Daicel Chiralcel AD-H (0.46cm x 25cm), n-hexane/2-propanol=80/ 20, v=1.0mLmin^-1, λ=254nm, t_R(major)=19.44min, t_R(minor)=20.91min] [α]_D ²⁵=- 204.0 (c=1.0, CHCl₃).¹H NMR(400MHz,CDCl₃)δ7.78(s,1H),7.45(s, 1H),7.44–7.28(m, 5H), 6.08-5.87 (m, 1H), 5.43-5.39 (m, 2H), 4.78 (dd, J=12.8,5.2Hz, 1H), 3.98 (d, J= 15.9Hz, 1H), 3.88 (d, J=15.9Hz, 1H), 3.82 (d, J=13.0Hz, 1H), 3.75 (d, J=13.0Hz, 1H), 3.07 (dd, J=12.3,4.7Hz, 1H), 2.89 (dd, J=12.3,5.6 Hz, 1H)¹³C NMR(100MHz,CDCl₃)δ 151.51,142.61,136.67,134.88,133.15, 128.95,128.95,128.58,128.58,127.75, 126.26,125.82,120.41,119.52,112.09, 61.78,57.09,55.50,52.20.HRMS(ESI)calcd for C₁₉H₁₇Cl₂N₃[M+H]⁺:358.0872. Found:358.0867.

I-4:(R) -2- benzyl -7,8- dimethyl -4- vinyl -1,2,3,4- tetrahydro benzo [4,5] imidazoles [1,2-a] pyrrole Piperazine

I-4:(R)-2-benzyl-7,8-dimethyl-4-vinyl-1,2,3,4-tetrahydrobenzo[4,5] imidazo[1,2- a]-pyrazine

R_f=0.15 (petroleum ether: ethyl acetate=3:1, v/v)；White solid；Fusing point: 131.4-132.2 DEG C of .90% Yield, 88%ee [Daicel Chiralcel OD-H (0.46cm x 25cm), n-hexane/2-propanol=85/ 15, v=1.0mLmin^-1, λ=254nm, t_R(minor)=7.91min, t_R(major)=9.58min] [α]_D ²⁵=+ 64.0 (c=1.0, CHCl₃).¹H NMR(400MHz,CDCl₃)δ7.48(s,1H),7.44– 7.27(m,5H),7.11(s, 1H), 6.00 (ddd, J=17.7,10.3,7.6Hz, 1H), 5.33 (dd, J=13.7,8.0Hz, 2H), 4.79-4.72 (m, 1H), 4.01 (d, J=15.5Hz, 1H), 3.84 (d, J=15.3Hz, 1H), 3.80 (d, J=13.0Hz, 1H), 3.71 (d, J =13.1Hz, 1H), 3.00 (dd, J=12.1,4.5Hz, 1H), 2.88 (dd, J=12.1,5.2Hz, 1H), 2.38 (d, J= 1.1Hz,6H).¹³C NMR(100MHz,CDCl₃) δ148.48,141.80,137.13,135.93,132.44,130.86, 130.81,128.95,128.95,128.50, 128.50,127.57,119.40,118.34,110.90,61.82,56.48, 55.67,52.45,20.56, 20.30.HRMS(ESI)calcd for C₂₁H₂₃N₃[M+H]⁺:318.1958.Found: 318.1965.

I-5:(S) -2- (4- luorobenzyl) -7,8- dimethyl -4- vinyl -1,2,3,4- tetrahydro benzo [4,5] imidazoles [1, 2-a] pyrazine

I-5:(S)-2-(4-fluorobenzyl)-7,8-dimethyl-4-vinyl-1,2,3,4- tetrahydrobenzo[4,5]im- idazo[1,2-a]pyrazine

R_f=0.20 (petroleum ether: ethyl acetate=3:1, v/v)；White solid；Fusing point: 139.1-139.6 DEG C of .94% Yield, 93%ee [Daicel Chiralcel OD-H (0.46cm x 25cm), n-hexane/2-propanol=85/ 15, v=1.0mLmin^-1, λ=254nm, t_R(minor)=8.49min, t_R(major)=10.62min] [α]_D ²⁵ =-146.0 (c=1.0, CHCl₃).¹H NMR(400MHz,CDCl₃)δ7.47(s,1H),7.41– 7.29(m,2H),7.09 (s, 1H), 7.10-6.89 (m, 2H), 6.08-5.91 (m, 1H), 5.33 (dd, J=13.7,9.5Hz, 2H), 4.84-4.71 (m, 1H), 4.00 (d, J=15.5Hz, 1H), 3.82 (d, J=15.5Hz, 1H), 3.77 (d, J=13.1Hz, 1H), 3.68 (d, J=13.1Hz, 1H), 3.00 (dd, J=12.1,4.6Hz, 1H), 2.88 (dd, J=12.1,5.2Hz, 1H), 2.37 (s, 3H),2.37(s,3H).¹³C NMR(100MHz, CDCl₃) δ 162.28 (d, J=245.5Hz), 148.31,141.76, 135.86,135.86,132.90 (d, J=3.0 Hz), 132.41,130.92 (d, J=4.0Hz), 130.48,130.40, 119.40,118.39,115.44,115.23, 110.88,60.98,56.42,55.60,52.37,20.53,20.27.HRMS (ESI)calcd for C₂₁H₂₂FN₃ [M+H]⁺:336.1871.Found:336.1852.

I-6:(S) -7,8- dimethyl -2- (4- methylbenzyl) -4- vinyl -1,2,3,4- tetrahydro benzo [4,5] imidazoles [1,2-a] pyrazine

I-6:(S)-7,8-dimethyl-2-(4-methylbenzyl)-4-vinyl-1,2,3,4- tetrahydrobenzo[4,5]im- idazo[1,2-a]pyrazine

R_f=0.20 (petroleum ether: ethyl acetate=3:1, v/v)；White solid；Fusing point: 116.1-117.2 DEG C of .91% Yield, 89%ee [Daicel Chiralcel OD-H (0.46cm x 25cm), n-hexane/2-propanol=90/ 10, v=1.0mLmin^-1, λ=254nm, t_R(minor)=9.29min, t_R(major)=10.99min] [α]_D ²⁵ =-132.0 (c=1.0, CHCl₃).¹H NMR(400MHz,CDCl₃) δ 7.47 (s, 1H), 7.26 (d, J=7.9Hz, 2H), 7.17 (d, J=7.9Hz, 2H), 7.11 (s, 1H), 6.11-5.89 (m, 1H), 5.33 (dd, J=13.6,6.4Hz, 2H), 4.76 (dd, J=12.3,5.1Hz, 1H), 3.99 (d, J=15.5Hz, 1H), 3.84 (d, J=15.5Hz, 1H), 3.77 (d, J =13.0Hz, 1H), 3.68 (d, J=13.0Hz, 1H), 3.00 (dd, J=12.1,4.6Hz, 1H), 2.87 (dd, J=12.1, 5.3Hz, 1H), 2.37 (d, J=2.9Hz, 9H)¹³C NMR (100MHz,CDCl₃)δ148.56,141.77,137.19, 135.95,133.99,132.43,130.84,130.78, 129.16,129.16,128.91,128.91,119.36, 118.32,110.90,77.38,77.26,77.06,76.74, 61.53,56.50,55.56,52.42,21.14,20.53, 20.27.HRMS(ESI)calcd for C₂₂H₂₅N₃[M+H]⁺:332.2082.Found:332.2075.

I-7:(R) -2- (2,4- difluorobenzyl) -4- vinyl -1,2,3,4- tetrahydro benzo [4,5] imidazoles [1,2-a] pyrrole Piperazine

I-7:(R)-2-(2,4-difluorobenzyl)-4-vinyl-1,2,3,4-tetrahydrobenzo[4,5] imidazo[1,2- a]pyrazine

R_f=0.20 (petroleum ether: ethyl acetate=3:1, v/v)；Yellow viscous liquid .90%yield, 92%ee [Daicel Chiralcel OD-H (0.46cm x 25cm), n-hexane/2-propanol=88/12, v=1.0mL min^-1, λ=254nm, t_R(major)=10.82min, t_R(minor)=14.14min] [α]_D ²⁵=+73.0 (c=1.0, CHCl₃).¹H NMR(400MHz,CDCl₃) δ 7.71 (dd, J=7.3,0.7Hz, 1H), 7.45-7.40 (m, 1H), 7.38- 7.31 (m, 1H), 7.25-7.21 (m, 2H), 7.04-6.63 (m, 2H), 6.00 (ddd, J=17.6,10.1,7.7Hz, 1H), 5.36 (dd, J=14.0,3.1Hz, 2H), 4.83 (dt, J=7.7,5.0Hz, 1H), 4.03 (d, J=15.5Hz, 1H), 3.89 (d, J=15.5Hz, 1H), 3.80 (s, 2H), 3.08 (dd, J=12.2,4.6Hz, 1H), 2.92 (dd, J=12.1,5.3Hz, 1H).¹³C NMR(100MHz,CDCl₃) δ 163.15 (dd, J=112.0,12.0Hz), 160.67 (dd, J=112.6, 11.9Hz), 149.04,143.09,135.59,133.86,132.03 (dd, J=9.6,5.8Hz), 122.29,121.99, 119.65 (dd, J=14.6,3.7Hz), 119.27,118.77,111.40 (dd, J=21.1,3.8Hz), 110.71, 103.89 (t, J=25.6Hz), 56.63,55.68,53.75,51.95.HRMS (ESI) calcd for C₁₉H₁₇F₂N₃[M+H ]⁺:326.1463.Found:326.1447.

I-8:(R) -2- (4- trifluoromethyl benzyl) -4- vinyl -1,2,3,4- tetrahydro benzo [4,5] imidazoles [1,2-a] Pyrazine

I-8:(R)-2-(4-(trifluoromethyl)benzyl)-4-vinyl-1,2,3,4-tetrahydrobenzo [4,5]imida- zo[1,2-a]pyrazine

R_f=0.30 (petroleum ether: ethyl acetate=2:1, v/v)；White solid；Fusing point: 138.0-138.5 DEG C of .96% Yield, 92%ee [Daicel Chiralcel OD-H (0.46cm x 25cm), n-hexane/2-propanol=88/ 12, v=1.0mLmin^-1, λ=254nm, t_R(major)=13.34min, t_R(minor)=15.11min] [α]_D ²⁵=+ 55.0 (c=1.0, CHCl₃).¹H NMR(400MHz,CDCl₃) δ 7.72 (d, J=7.9Hz, 1H), 7.63 (d, J=8.1Hz, 2H), 7.52 (d, J=8.0Hz, 2H), 7.36 (d, J=7.6Hz, 1H), 7.28 (d, J=4.8Hz, 1H), 7.26-7.20 (m, 1H), 6.02 (ddd, J=17.6,10.2,7.6Hz, 1H), 5.36 (dd, J=13.1,12.1Hz, 2H), 4.91-4.76 (m, 1H), 4.06 (d, J=15.5Hz, 1H), 3.90 (d, J=15.5Hz, 1H), 3.86 (d, J=13.6Hz, 1H), 3.79 (d, J =13.6Hz, 1H), 3.05 (dd, J=12.1,4.6Hz, 1H), 2.92 (dd, J=12.1,5.1Hz, 1H)¹³C NMR (100MHz,CDCl₃) δ 148.95,143.11,141.34,135.49,133.86,129.95 (q, J=32.3Hz), (129.03,129.03,129.03,125.51 q, J=3.7Hz), 122.79,122.34,122.04,119.32,118.79, 110.70,61.19, 56.56,55.70,52.46.HRMS(ESI)calcd for C₂₀H₁₈F₃N₃[M+H]⁺: 358.1526.Found: 358.1511.

The specific chemical combination of 11. reference implementation example 10 of embodiment and the reaction condition preparation of compounds of formula I of synthesis compound I-1 Object I-9-I-20 is as shown in table 2:

The yield of prepare compound I-9 to I-20 and enantiomeric excess value (ee value) in 2. embodiment 11 of table

12. allylic intermediate S of embodiment_b- 1 occurs under iridium-phosphoramidite ligand complex catalysis as substrate The catalyst amount of intramolecular allyl aminating reaction and the research of base amount:

13. allylic substrate S of embodiment_bRaw intramolecular allyl is issued in iridium-phosphoramidite ligand complex catalysis Aminating reaction prepares benzimidazole and chiral Pyrazinones compound II:

Under argon gas protection, iridic compound (0.004mmol), chiral phosphoramidite are sequentially added in a dry reaction tube Ligand (0.008mmol), n-propylamine (0.5mL) and tetrahydrofuran (0.5mL) react 30min at 50 DEG C, are then cooled to room naturally Decompressing and extracting solvent after temperature.Substrate S is successively added into reaction tube again_b(0.2mmol), alkali (0.4mmol), solvent (3mL), in It is stirred to react at 20-80 DEG C.TLC is tracked after reaction, and after solvent is removed under reduced pressure, the crude product obtained after concentration passes through column Chromatography obtains product II (petroleum ether: ethyl acetate=1:2-4:1, v/v).The preparation method of compound II-1 to II-6 and Specific reaction condition is referring to embodiment 13 and table 3, wherein the molar ratio in table 3 refers to substrate S_b: iridium: ligand: mole of alkali Than.

The reaction condition of compound II-1 to II-6 is synthesized in 3. embodiment 13 of table

Wherein, DMAP is 4-dimethylaminopyridine, and BSA is N, bis- (trimethyl silicon substrate) acetamides of O-, Li₂CO₃It is carbonic acid Lithium, DMA are dimethyl acetamides, and DME is glycol dimethyl ether

II-1:(R) -2- benzyl -4- vinyl -3,4- dihydrobenzo [4,5] imidazoles [1,2-a] pyrazine -1 (2H) -one

II-1:(R)-2-benzyl-4-vinyl-3,4-dihydrobenzo[4,5]imidazo[1,2-a]pyrazin- 1(2H)-one

R_f=0.15 (petroleum ether: ethyl acetate=2:1, v/v)；White solid；Fusing point: 138.8-139.1 DEG C of .98% Yield, 95%ee [Daicel Chiralcel AD-H (0.46cm x 25cm), n-hexane/2-propanol=75/ 25, v=1.0mLmin^-1, λ=254nm, t_R(minor)=12.22min, t_R(major)=14.19min] [α]_D ²⁵=+ 124.0 (c=1.0, CHCl₃).¹H NMR(400MHz,CDCl₃) δ 7.95 (d, J=7.1Hz, 1H), 7.38-7.32 (m, 6H), 7.26 (s, 2H), 5.90-5.70 (m, 1H), 5.24 (d, J=10.3Hz, 1H), 5.04-4.96 (m, 2H), 4.89 (d, J= 17.0Hz, 1H), 4.69 (d, J=14.7Hz, 1H), 3.97 (dd, J=13.0,4.4Hz, 1H), 3.55 (d, J=13.1Hz, 1H).¹³C NMR(100MHz,CDCl₃)δ157.15, 143.35,141.66,135.66,133.33,132.68,128.81, 128.81,128.71,127.71,128.08, 125.28,123.73,122.17,119.61,110.42,53.87,49.93, 49.53.HRMS(ESI)calcd for C₁₉H₁₇N₃O[M+H]⁺:304.1444.Found:304.1440.

II-2:(R) fluoro- 4- vinyl -3,4- dihydrobenzo [4,5] imidazoles [1,2-a] pyrazine -1 of -2- benzyl -7,8- two (2H) -one

II-2:(R)-2-benzyl-7,8-difluoro-4-vinyl-3,4-dihydrobenzo[4,5]imidazo [1,2-a]pyra- zin-1(2H)-one

R_f=0.10 (petroleum ether: ethyl acetate=2:1, v/v)；White solid；Fusing point: 160.7-161.2 DEG C of .90% Yield, 94%ee [Daicel Chiralcel AD-H (0.46cm x 25cm), n-hexane/2-propanol=80/ 20, v=1.0mLmin^-1, λ=254nm, t_R(minor)=14.06min, t_R(major)=20.32min] [α]_D ²⁵=+ 86.0 (c=1.0, CHCl₃).¹H NMR(400MHz,CDCl₃) δ 7.68 (dd, J=10.0,7.4 Hz, 1H), 7.44-7.28 (m, 5H), 7.17 (dd, J=9.3,7.0Hz, 1H), 5.81 (ddd, J=16.7,10.3,6.2Hz, 1H), 5.32 (d, J= 10.2Hz, 1H), 5.02-4.95 (m, 3H), 4.69 (d, J=14.7Hz, 1H), 3.97 (dd, J=13.2,4.7Hz, 1H), 3.58 (dd, J=13.2,3.8Hz, 1H)¹³C NMR(100MHz, CDCl₃) δ 156.48,150.60 (dd, J=107.3, 15.8Hz), 148.15 (dd, J=104.0,15.7Hz), 143.19,138.75,138.66,135.47,132.13, (128.85,128.85,128.68,128.68,128.18,120.32,109.06 d, J=19.7Hz), 98.41 (d, J= 23.2Hz),54.51, 49.96,49.49.HRMS(ESI)calcd for C₁₉H₁₅F₂N₃O[M+H]⁺:340.1256.Found: 340.1244.

II-3:(S) chloro- 4- vinyl -3,4- dihydrobenzo [4,5] imidazoles [1,2-a] pyrazine -1 of -2- benzyl -7,8- two (2H) -one

II-3:(S)-2-benzyl-7,8-dichloro-4-vinyl-3,4-dihydrobenzo[4,5]imidazo [1,2-a]pyra- zin-1(2H)-one

R_f=0.10 (petroleum ether: ethyl acetate=2:1, v/v)；White solid；Fusing point: 179.8-180.4 DEG C of .89% Yield, 96%ee [Daicel Chiralcel AD-H (0.46cm x 25cm), n-hexane/2-propanol=80/ 208, v=1.0mLmin^-1, λ=254nm, t_R(major)=16.41min, t_R(minor)=18.83 min] [α]_D ²⁵ =-153.0 (c=1.0, CHCl₃).¹H NMR(400MHz,CDCl₃)δ7.92–7.86(m, 1H),7.48–7.43(m,1H), 7.41-7.20 (m, 5H), 5.77 (ddd, J=16.6,10.2,6.1Hz, 1H), 5.28 (d, J=10.3Hz, 1H), 5.12- 4.97 (m, 2H), 4.90 (d, J=17.0Hz, 1H), 4.58 (d, J=14.7Hz, 1H), 4.03 (dd, J=13.3,4.8Hz, 1H), 3.56 (dd, J=13.2,3.8Hz, 1H)¹³C NMR(100MHz,CDCl₃)δ156.44,143.29,142.28, 135.34,132.38,132.12,129.50, 128.84,128.84,128.67,128.67,128.18,128.05, 122.71,120.23,112.03,54.28,49.92, 49.34.HRMS(ESI)calcd for C₁₉H₁₅Cl₂N₃O[M+H]⁺: 372.0670.Found:372.0659.

II-4:(S) -2- (2,4- difluorobenzyl) -4- vinyl -3,4- dihydrobenzo [4,5] imidazoles [1,2-a] pyrazine -1 (2H) -one

II-4:(S)-2-(2,4-difluorobenzyl)-4-vinyl-3,4-dihydrobenzo[4,5]imidazo [1,2-a]pyr- azin-1(2H)-one

R_f=0.10 (petroleum ether: ethyl acetate=2:1, v/v)；White solid；Fusing point: 140.8-141.4 DEG C of .93% Yield, 91%ee [Daicel Chiralcel AD-H (0.46cm x 25cm), n-hexane/2-propanol=78/22, V=1.0mLmin^-1, λ=254nm, t_R(major)=14.78min, t_R(minor)=16.97min] [α]_D ²⁵=- 96.0 (c=1.0, CHCl₃).¹H NMR(400MHz,CDCl₃)δ7.97–7.91(m,1H), 7.56–7.50(m,1H),7.44– 7.30 (m, 3H), 7.08-6.63 (m, 2H), 5.96-5.75 (m, 1H), 5.27 (dd, J=10.3,0.9Hz, 1H), 5.08 (m, 1H), 5.02-4.83 (m, 2H), 4.76 (d, J=14.7 Hz, 1H), 4.11 (dd, J=13.1,4.8Hz, 1H), 3.67 (dd, J =13.1,3.1Hz, 1H)¹³C NMR (100MHz,CDCl₃) δ 163.15 (dd, J=151.3,12.0Hz), 160.67 (dd, J =149.8,12.0Hz), 161.47,161.36,159.98,159.87,157.21,143.32,141.47,133.29, 132.71 (dd, J=9.7,5.4Hz), 132.53,125.35,123.76,122.09,119.64,118.93 (d, J= 11.2Hz), 112.08,112.04,111.95 (dd, J=21.1,3.6Hz), 110.47,103.79 (t, J=25.6Hz), 77.40,77.08, 76.76,53.82,50.23,43.03,43.01.HRMS(ESI)calcd for C₁₉H₁₅F₂N₃O[M+H ]⁺: 340.1256.Found:340.1240.

II-5:(S) -2- (4- luorobenzyl) -4- vinyl -3,4- dihydrobenzo [4,5] imidazoles [1,2-a] pyrazine -1 (2H) -one

II-5:(S)-2-(4-fluorobenzyl)-4-vinyl-3,4-dihydrobenzo[4,5]imidazo[1,2- a]pyra- in-1(2H)-one

R_f=0.10 (petroleum ether: ethyl acetate=2:1, v/v)；White solid；Fusing point: 183.6-183.9 DEG C of .95% Yield, 94%ee [Daicel Chiralcel AD-H (0.46cm x 25cm), n-hexane/2-propanol=75/ 25, v=1.0mLmin^-1, λ=254nm, t_R(major)=11.35min, t_R(minor)=13.73min] [α]_D ²⁵=- 112.0 (c=1.0, CHCl₃).¹H NMR(400MHz,CDCl₃)δ8.03-7.86(m,1H), 7.53–7.29(m,5H), 7.16-6.87 (m, 2H), 5.82 (ddd, J=16.9,10.3,5.9Hz, 1H), 5.27 (dd, J=10.3,1.1Hz, 1H), 5.12-5.03 (m, 1H), 5.03-4.82 (m, 2H), 4.65 (d, J=14.7 Hz, 1H), 4.01 (dd, J=13.0,4.8Hz, 1H), 3.56 (dd, J=13.1,3.3Hz, 1H)¹³C NMR (100MHz,CDCl₃) δ 162.51 (d, J=246.8Hz), 157.11,143.30,141.53,133.31, 132.66,131.55,130.47,130.39,125.33,123.76, 122.06,119.59,115.81,115.60, 110.49,53.77,49.55,49.18.HRMS(ESI)calcd for C₁₉H₁₆FN₃O[M+H]⁺:322.1350. Found:322.1345.

II-6:(R) -2- (4- methoxy-benzyl) -4- vinyl -3,4- dihydrobenzo [4,5] imidazoles [1,2-a] pyrazine -1 (2H) -one

II-6:(R)-2-(4-methoxybenzyl)-4-vinyl-3,4-dihydrobenzo[4,5]imidazo[1, 2-a]pyra- zin-1(2H)-one

R_f=0.10 (petroleum ether: ethyl acetate=2:1, v/v)；White solid；Fusing point: 163.6-164.0 DEG C of .88% Yield, 92%ee [Daicel Chiralcel AD-H (0.46cm x 25cm), n-hexane/2-propanol=75/ 25, v=1.0mLmin^-1, λ=254nm, t_R(minor)=15.18min, t_R(major)=22.69min] [α]_D ²⁵=+ 138.0 (c=1.0, CHCl₃).¹H NMR(400MHz,CDCl₃)δ8.03–7.86(m,1H), 7.43–7.32(m,3H), 7.32-7.23 (m, 2H), 6.92-6.87 (m, 2H), 5.92-5.72 (m, 1H), 5.25 (d, J=10.3Hz, 1H), 5.08- 5.00 (m, 1H), 4.99-4.80 (m, 2H), 4.63 (d, J=14.5 Hz, 1H), 3.96 (dd, J=13.1,4.8Hz, 1H), 3.82 (s, 3H), 3.55 (dd, J=13.1,3.3Hz, 1H)¹³C NMR(100MHz,CDCl₃)δ159.41,157.06, 143.33,141.75,133.32,132.75, 130.09,130.09,127.70,125.20,123.65,122.05, 119.49,114.13,114.13,110.47,55.31, 53.83,49.27,49.25.HRMS(ESI)calcd for C₂₀H₁₉N₃O₂[M+H]⁺:334.1523. Found:334.1516.

The materialization of the reaction condition preparation formula II compound of 14. reference implementation example 13 of embodiment and synthesis compound II-5 It is as shown in table 4 to close object II-7-II-16:

The yield of prepare compound II-7 to II-16 and enantiomeric excess value (ee value) in 4. embodiment 14 of table

15. allylic intermediate S of embodiment_c- 1 occurs under iridium-phosphoramidite ligand complex catalysis as substrate The research of the alkali and solvent of intramolecular allyl aminating reaction:

Wherein, DIPEA is diisopropyl ethyl amine, and DMAP is 4- dimethylamino pyridine, Et₃N is triethylamine, ProtonSponge is proton sponge, and DABCO is triethylene diamine, and DBU is 1,8- diazabicylo, 11 carbon -7- alkene, BSA It is N, the bis- trimethylsilyl acetamides of O-, DBN is 1,5-- diazabicyclo [4.3.0] nonyl- 5- alkene, and KF is potassium fluoride, O- Xylene is ortho-xylene.

16. allylic intermediate S of embodiment_c- 1 occurs under iridium-phosphoramidite ligand complex catalysis as substrate The research of the temperature of intramolecular allyl aminating reaction:

17. allylic intermediate S of embodiment_c- 1 occurs under iridium-phosphoramidite ligand complex catalysis as substrate The research of the ligand of intramolecular allyl aminating reaction:

18. allylic substrate S of embodiment_cRaw intramolecular allyl is issued in iridium-phosphoramidite ligand complex catalysis Aminating reaction prepares benzimidazole and chiral heterocycle class compound III:

Under argon gas protection, iridic compound (0.004mmol), chiral phosphoramide are sequentially added in a dry reaction tube Ligand (0.008mmol), n-propylamine (0.5mL) and tetrahydrofuran (0.5mL) react 30min at 50 DEG C, are then cooled to room naturally Decompressing and extracting solvent after temperature.Substrate S is successively added into reaction tube again_c(0.2mmol), alkali (0.6mmol), organic solvent (3mL) is reacted in 20-80 DEG C.TLC is tracked after reaction, solvent is removed under reduced pressure, the crude product obtained after concentration passes through column Chromatography obtains product III (petroleum ether: ethyl acetate=1:2-4:1, v/v).Compound III-1 is to the preparation side of III-22 Method and specific reaction condition are referring to embodiment 18 and table 5, wherein the molar ratio in table 5 refers to substrate S_c: iridium: ligand: alkali rubs That ratio.

The reaction condition of compound III-1 to III-22 is synthesized in 5. embodiment 18 of table

Wherein, LG is leaving group, and Bn is benzyl, and DIPEA is diisopropyl ethyl amine, and DMAP is 4- dimethylamino pyrrole Pyridine, DIPEA are diisopropyl ethyl amines, and DABCO is triethylene diamine, and DBU is 1,8- diazabicylo, 11 carbon -7- alkene, BSA It is N, the bis- trimethylsilyl acetamides of O-, DBN is 1,5- diazabicyclo [4.3.0] nonyl- 5- alkene, and CsF is cesium fluoride, and KF is fluorine Change potassium, LiO^tBu is tert-butyl alcohol lithium, NaO^tBu is sodium tert-butoxide, and Ac represents acetyl group, Boc represents tertbutyloxycarbonyl, Piv is represented 2,2- Dimethylpropanoyl, Bz represent benzoyl, Troc represents 2,2,2- trichloro-ethoxycarbonyl.

III-1:(S) -7- benzyl -9- vinyl -8,9- dihydro -2,7,9a- triazine simultaneously [cd] Azulene -6 (7H) -one

III-1:(S)-7-benzyl-9-vinyl-8,9-dihydro-2,7,9a-triazabenzo[cd]azulen-6 (7H)-one

R_f=0.10 (petroleum ether: ethyl acetate=1:1, v/v)；White viscous liquid .97%yield, 95%ee [Daicel Chiralcel OD-H (0.46cm x 25cm), n-hexane/2-propanol=80/20, v=1.0mL min^-1, λ=254nm, t_R(minor)=6.06min, t_R(major)=22.57min] [α]_D ²⁵=-113.0 (c=1.0, CHCl₃).¹H NMR(400MHz,DMSO-d₆) δ 8.34 (s, 1H), 7.96 (dd, J=21.4,7.8Hz, 2H), 7.40-7.34 (m, 5H), 7.32-7.26 (m, 1H), 6.25-6.08 (m, 1H), 5.55-5.17 (m, 3H), 4.54 (d, J=15.9Hz, 1H), 4.25 (d, J=14.1Hz, 1H), 4.10-3.88 (m, 2H)¹³C NMR(100MHz,DMSO-d₆)δ166.54,145.07, 144.22,138.24,135.33,130.69, 128.94,128.94,128.32,128.32,127.65,126.94, 123.98,122.05,117.75,117.14, 58.96,53.34,50.55.HRMS(ESI)calcd for C₁₉H₁₇N₃O[M+ H]⁺:304.1444.Found: 304.1430.

III-2:(S) -7- benzyl -1- (o-tolyl) -9- vinyl -8,9- dihydro -2,7,9a- triazine is simultaneously [cd] Azulene -6 (7H)-ketone

III-2:(S)-7-benzyl-1-(o-tolyl)-9-vinyl-8,9-dihydro-2,7,9a-triazabenzo [cd]azulen- 6(7H)-one

R_f=0.15 (petroleum ether: ethyl acetate=4:1, v/v)；White solid；Fusing point: 159.9-160.7 DEG C of .98% Yield, 99%ee [Daicel Chiralcel AD-H (0.46cm x 25cm), n-hexane/2-propanol=65/ 35, v=1.0mLmin^-1, t=25 DEG C, λ=254nm, t_R(minor)=6.06min, t_R(major)=19.75min] [α]_D ²⁵=-128.0 (c=1.0, CHCl₃).¹H NMR(400MHz,CDCl₃) δ 8.30 (dd, J=7.8,1.0Hz, 1H), 8.03 (dd, J=8.0,1.0Hz, 1H), 7.48 (t, J=7.9Hz, 1H), 7.45-7.38 (m, 1H), 7.36-7.22 (m, 8H), 5.81-5.64 (m, 1H), 5.53 (d, J=14.8Hz, 1H), 5.18 (d, J=10.4Hz, 1H), 4.81 (t, J= 4.8Hz, 1H), 4.68 (d, J=17.1Hz, 1H), 4.23 (d, J=14.8Hz, 1H), 3.92 (d, J=15.4Hz, 1H), 3.79 (dd, J=15.5,5.0Hz, 1H), 2.17 (s, 3H)¹³C NMR(100MHz,CDCl₃)δ167.03,153.07, 143.32,138.03,137.00,132.47, 130.90,130.51,130.25,129.88,129.05,128.72, 128.72,128.45,128.45,127.74, 127.64,125.55,124.08,122.40,118.98,117.17,58.81, 53.66,50.80,19.82.HRMS (ESI)calcd for C₂₆H₂₃N₃O[M+H]⁺:394.1914.Found:394.1899.

III-3:(R) -7- benzyl -1- (tolyl) -9- vinyl -8,9- dihydro -2,7,9a- triazine is simultaneously [cd] Azulene -6 (7H) -one

III-3:(R)-7-benzyl-1-(m-tolyl)-9-vinyl-8,9-dihydro-2,7,9a-triazabenzo [cd]azulen- 6(7H)-one

R_f=0.15 (petroleum ether: ethyl acetate=4:1, v/v)；White solid；Fusing point: 126.3-127.2 DEG C of .92% Yield, 92%ee [Daicel Chiralcel AD-H (0.46cm x 25cm), n-hexane/2-propanol=70/ 30, v=1.0mLmin^-1, t=25 DEG C, λ=254nm, t_R(major)=7.30min, t_R(minor)= 10.08min].[α]_D ²⁵=+59.0 (c=1.0, CHCl₃).¹H NMR(400MHz,CDCl₃) δ 8.25 (dd, J=7.7, 0.9Hz, 1H), 8.04 (dd, J=8.0,0.9Hz, 1H), 7.69 (s, 1H), 7.61 (d, J=7.3Hz, 1H), 7.48 (t, J= 7.9Hz, 1H), 7.41-7.26 (m, 7H), 5.97 (ddd, J=17.1,10.5,4.5Hz, 1H), 5.52 (d, J=14.9Hz, 1H), 5.44 (dd, J=10.6,0.8Hz, 1H), 5.23-5.17 (m, 1H), 4.99 (dd, J=17.2,1.3Hz, 1H), 4.29 (d, J=14.9Hz, 1H), 3.87-3.74 (m, 2H), 2.43 (s, 3H)¹³C NMR(100MHz,CDCl₃)δ166.95, 153.99,143.41,138.64,136.98,133.63, 131.90,131.11,130.30,129.23,128.74, 128.74,128.45,128.42,128.42,127.75, 127.56,126.17,123.89,122.63,119.54, 117.51,59.63,53.61,50.88,21.37.HRMS (ESI)calcd for C₂₆H₂₃N₃O[M+H]⁺: 394.1914.Found:394.1906.

III-4:(R) -7- benzyl -1- (p-methylphenyl) -9- vinyl -8,9- dihydro -2,7,9a- triazine is simultaneously [cd] Azulene -6 (7H) -one

III-4:(R)-7-Benzyl-1-(p-tolyl)-9-vinyl-8,9-dihydro-2,7,9a-triazabenzo [cd]azulen- 6(7H)-one

R_f=0.15 (petroleum ether: ethyl acetate=4:1, v/v)；White solid；Fusing point: 121.0-121.3 DEG C of .96% Yield, 94%ee [Daicel Chiralcel AD-H (0.46cm x 25cm), n-hexane/2-propanol=70/ 30, v=1.0mLmin^-1, t=25 DEG C, λ=254nm, t_R(major)=8.89min, t_R(minor)=16.60min] [α]_D ²⁵=+61.0 (c=1.0, CHCl₃).¹H NMR(400MHz,CDCl₃) δ 8.24 (d, J=7.7Hz, 1H), 8.03 (d, J =8.0Hz, 1H), 7.72 (d, J=8.1Hz, 2H), 7.47 (t, J=7.9Hz, 1H), 7.41-7.23 (m, 7H), 6.08- 5.86 (m, 1H), 5.52 (d, J=14.9Hz, 1H), 5.43 (d, J=10.6Hz, 1H), 5.21-5.17 (m, 1H), 4.98 (d, J=17.2Hz, 1H), 4.29 (d, J=14.9Hz, 1H), 3.83-3.79 (m, 2H), 2.44 (s, 3H)¹³C NMR(100MHz, CDCl₃)δ166.99,153.96, 143.37,140.64,136.96,133.58,131.90,129.38,129.38, 129.31,129.31,128.74, 128.74,128.41,128.41,127.75,127.46,126.38,123.78, 122.61,119.57,117.45, 59.62,53.61,50.84,21.46.HRMS(ESI)calcd for C₂₆H₂₃N₃O[M+H ]⁺:394.1914. Found:394.1902.

III-5:(R) -7- benzyl -1- phenyl -9- vinyl -8,9- dihydro -2,7,9a- triazine simultaneously [cd] Azulene -6 (7H) -one

III-5:(R)-7-benzyl-1-phenyl-9-vinyl-8,9-dihydro-2,7,9a-triazabenzo [cd]azulen- 6(7H)-one

R_f=0.10 (petroleum ether: ethyl acetate=4:1, v/v)；White solid；Fusing point: 141.0-141.5 DEG C of .91% Yield, 96%ee [Daicel Chiralcel IA-3 (0.46cm x 25cm), n-hexane/2-propanol=82/18, V=1.0mLmin^-1, λ=254nm, t_R(major)=16.90min, t_R(minor)=17.38min] [α]_D ²⁵=+ 99.0 (c=1.0, CHCl₃).¹H NMR(400MHz,CDCl₃) δ 8.24 (dd, J=7.7,0.9 Hz, 1H), 8.03 (dd, J= 8.0,0.8Hz, 1H), 7.82 (dd, J=7.8,1.5Hz, 2H), 7.55-7.43 (m, 4H), 7.39-7.20 (m, 5H), 5.95 (ddd, J=17.0,10.5,4.4Hz, 1H), 5.48 (d, J=14.9Hz, 1H), 5.41 (d, J=10.5Hz, 1H), 5.20- 5.16 (m, 1H), 4.96 (dd, J=17.2,1.1Hz, 1H), 4.28 (d, J=14.9Hz, 1H), 3.82-3.75 (m, 2H)¹³C NMR(100MHz,CDCl₃)δ166.90, 153.76,143.38,136.94,133.56,131.90,130.35,129.39, 129.39,129.32,128.73, 128.73,128.67,128.67,128.41,128.41,127.74,127.60, 123.89,122.66,119.53, 117.54,59.60,53.59,50.81.HRMS(ESI)calcd for C₂₅H₂₁N₃O[M+ H]⁺:380.1757. Found:380.1742.

III-6:(S) -7- benzyl -1- (2- naphthalene) -9- vinyl -8,9- dihydro -2,7,9a- triazine is simultaneously [cd] Azulene -6 (7H)-ketone

III-6:(S)-7-Benzyl-1-(naphthalen-2-yl)-9-vinyl-8,9-dihydro-2,7,9a- triazabenzo- [cd]azulen-6(7H)-one

R_f=0.15 (petroleum ether: ethyl acetate=3:1, v/v)；White solid；Fusing point: 120.4-121.2 DEG C of .99% Yield, 97%ee [Daicel Chiralcel AD-H (0.46cm x 25cm), n-hexane/2-propanol=65/ 35, v=1.0mLmin^-1, t=25 DEG C, λ=254nm, t_R(minor)=10.26min, t_R(major)=25.67min] [α]_D ²⁵=-123.0 (c=1.0, CHCl₃).¹H NMR(400MHz,CDCl₃) δ 8.36 (s, 1H), 8.28 (dd, J=7.7, 0.9Hz, 1H), 8.09 (dd, J=8.0,0.9Hz, 1H), 8.02-7.94 (m, 2H), 7.92 (dt, J=8.0,2.5Hz, 2H), 7.71-7.55 (m, 2H), 7.52 (t, J=7.9Hz, 1H), 7.40-7.28 (m, 5H), 6.04 (ddd, J=17.1,10.5, 4.5Hz, 1H), 5.58-5.54 (m, 1H), 5.55-5.50 (m, 1H), 5.34-5.25 (m, 1H), 5.10 (dd, J=17.2, 1.2Hz, 1H), 4.32 (d, J=14.9Hz, 1H), 3.91-3.74 (m, 2H)¹³C NMR(100MHz,CDCl₃)δ166.95, 153.83,143.54, 136.95,133.86,133.75,132.75,132.04,129.42,128.75,128.75, 128.59,128.53, 128.43,128.43,127.84,127.77,127.70,127.53,126.89,126.63, 126.23,123.95, 122.77,119.76,117.60,59.88,53.61,50.92.HRMS(ESI)calcd for C₂₉H₂₃N₃O [M+H]⁺:430.1914.Found:430.1899.

III-7:(S) -7- benzyl -1- (4- bromophenyl) -9- vinyl -8,9- dihydro -2,7,9a- triazine is simultaneously [cd] Azulene -6 (7H)-ketone

III-7:(S)-7-benzyl-1-(4-bromophenyl)-9-vinyl-8,9-dihydro-2,7,9a- triazabenzo- [cd]azulen-6(7H)-one

R_f=0.10 (petroleum ether: ethyl acetate=5:1, v/v)；White solid；Fusing point: 195.2-196.1 DEG C of .95% Yield, 97%ee [Daicel Chiralcel IA-3 (0.46cm x 25cm), n-hexane/2-propanol=70/30, V=1.0mLmin^-1, t=25 DEG C, λ=254nm, t_R(major)=11.53min, t_R(minor)=14.54 min] [α]_D ²⁵=-143.0 (c=1.0, CHCl₃).¹H NMR(400MHz,CDCl₃) δ 8.27 (dd, J=7.7,1.0Hz, 1H), 8.04 (dd, J=8.0,1.0Hz, 1H), 7.80-7.70 (m, 2H), 7.70-7.55 (m, 2H), 7.50 (t, J=7.9Hz, 1H), 7.41-7.26 (m, 5H), 5.96 (ddd, J=17.1,10.5,4.4Hz, 1H), 5.51 (d, J=14.9Hz, 1H), 5.46 (dd, J=10.6,1.0Hz, 1H), 5.19-5.10 (m, 1H), 4.99 (dd, J=17.2,1.5Hz, 1H), 4.31 (d, J =14.9Hz, 1H), 3.85-3.80 (m, 2H)¹³C NMR (100MHz,CDCl₃)δ166.80,152.66,143.32, 136.87,133.53,131.97,131.97,131.92, 130.89,130.89,128.77,128.77,128.45, 128.45,128.26,127.91,127.81,125.07, 124.01,122.90,119.81,117.63,59.74,53.58, 50.76.HRMS(ESI)calcd for C₂₅H₂₀BrN₃O[M+H]⁺:458.0862.Found:458.0843.

III-8:(R) -7- benzyl -1- (3- bromophenyl) -9- vinyl -8,9- dihydro -2,7,9a- triazine is simultaneously [cd] Azulene -6 (7H)-ketone

III-8:(R)-7-Benzyl-1-(3-bromophenyl)-9-vinyl-8,9-dihydro-2,7,9a- triazabenzo- [cd]azulen-6(7H)-one

R_f=0.15 (petroleum ether: ethyl acetate=4:1, v/v)；White solid；Fusing point: 154.2-154.6 DEG C of .90% Yield, 96%ee [Daicel Chiralcel OD-H (0.46cm x 25cm), n-hexane/2-propanol=80/ 20, v=1.0mLmin^-1, λ=254nm, t_R(major)=15.84min, t_R(minor)=18.71min] [α]_D ²⁵=+ 104.0 (c=1.0, CHCl₃).¹H NMR(400MHz,CDCl₃) δ 8.28 (d, J=7.7Hz, 1H), 8.05 (d, J=7.5Hz, 2H), 7.79 (d, J=7.7Hz, 1H), 7.66 (d, J=8.0Hz, 1H), 7.50 (t, J=7.9Hz, 1H), 7.43-7.25 (m, 6H), 6.05-5.90 (m, 1H), 5.55-5.49 (m, 2H), 5.21-5.14 (m, 1H), 5.01 (d, J=17.2Hz, 1H), 4.31 (d, J=14.9Hz, 1H), 3.86-3.80 (m, 2H)¹³C NMR(100MHz,CDCl₃)δ166.79,152.12, 143.28,136.88,133.50,133.35, 132.37,131.91,131.32,130.20,128.78,128.78, 128.45,128.45,128.02,127.87, 127.82,124.12,122.94,122.79,119.89,117.68,59.79, 53.58,50.81.HRMS(ESI) calcd for C₂₅H₂₀BrN₃O[M+H]⁺:458.0862.Found:458.0840.

III-9:(R) -7- benzyl -1- (4- trifluoromethyl) -9- vinyl -8,9- dihydro -2,7,9a- triazine And [cd] Azulene -6 (7H) -one

III-9:(R)-7-Benzyl-1-(4-(trifluoromethyl)phenyl)-9-vinyl-8,9-dihydro- 2,7,9a-tria- zabenzo[cd]azulen-6(7H)-one

R_f=0.30 (petroleum ether: ethyl acetate=4:1, v/v)；White solid；Fusing point: 190.7-192.3 DEG C of .94% Yield, 95%ee [Daicel Chiralcel IA-3 (0.46cm x 25cm), n-hexane/2-propanol=80/20, V=1.0mLmin^-1, λ=254nm, t_R(minor)=13.53min, t_R(major)=21.59min] [α]_D ²⁵=+ 59.0 (c=1.0, CHCl₃).¹H NMR(400MHz,CDCl₃) δ 8.27 (dd, J=7.7,1.0Hz, 1H), 8.04 (dd, J= 8.0,1.0Hz, 1H), 7.98 (d, J=8.1Hz, 2H), 7.75 (d, J=8.2Hz, 2H), 7.50 (t, J=7.9Hz, 1H), 7.38-.23 (m, 5H), 5.95 (ddd, J=17.0,10.5,4.4Hz, 1H), 5.49-5.43 (m, 2H), 5.16-5.12 (m, 1H), 4.99 (dd, J=17.2,1.3Hz, 1H), 4.30 (d, J=14.9 Hz, 1H), 3.82 (d, J=3.1Hz, 2H)¹³C NMR(100MHz,CDCl₃)δ166.73,152.11, 143.32,136.82,133.47,132.91,132.33,131.95, 129.81,129.81,128.79,128.79,128.48,128.48,128.24,127.85 125.70-125.60 (q, J= 3.5Hz),125.09,124.24, 123.07,122.39,119.91,117.75,59.80,53.58,50.74.HRMS(ESI) calcd for C₂₆H₂₀F₃N₃O[M+H]⁺:448.1631.Found:448.1609.

III-10:(R) -7- benzyl -1- (4- chlorphenyl) -9- vinyl -8,9- dihydro -2,7,9a- triazine is simultaneously [cd] Azulene -6 (7H) -one

III-10:(R)-7-Benzyl-1-(4-chlorophenyl)-9-vinyl-8,9-dihydro-2,7,9a- triazabenzo- [cd]azulen-6(7H)-one

R_f=0.20 (petroleum ether: ethyl acetate=3:1, v/v)；White solid；Fusing point: 161.5-161.8 DEG C of .95% Yield, 97%ee [Daicel Chiralcel IA-3 (0.46cm x 25cm), n-hexane/2-propanol=70/30, V=1.0mLmin^-1, t=25 DEG C, λ=254nm, t_R(minor)=10.70min, t_R(major)=12.78 min] [α]_D ²⁵=+78.0 (c=1.0, CHCl₃).¹H NMR(400MHz,CDCl₃) δ 8.26 (d, J=7.7 Hz, 1H), 8.04 (d, J =8.0Hz, 1H), 7.80 (d, J=8.5Hz, 2H), 7.49 (dd, J=12.2,5.3Hz, 3H), 7.43-7.21 (m, 5H), 5.96 (ddd, J=17.0,10.5,4.3Hz, 1H), 5.53-5.45 (m, 2H), 5.19-5.12 (m, 1H), 4.99 (d, J= 17.2Hz, 1H), 4.31 (d, J=14.9Hz, 1H), 3.89-3.75 (m, 2H)¹³C NMR(100MHz,CDCl₃)δ166.82, 152.62,143.31,136.87,136.72, 133.52,131.92,130.69,130.69,129.01,129.01, 128.77,128.77,128.45,128.45, 127.89,127.81,127.81,124.01,122.89,119.82, 117.61,59.74,53.58,50.76.HRMS (ESI)calcd for C₂₅H₂₀ClN₃O[M+H]⁺:414.1368.Found: 414.1354.

III-11:(R) -7- benzyl -1- (4- fluorophenyl) -9- vinyl -8,9- dihydro -2,7,9a- triazine is simultaneously [cd] Azulene -6 (7H) -one

III-11:(R)-7-Benzyl-1-(4-fluorophenyl)-9-vinyl-8,9-dihydro-2,7,9a- triazabenzo- [cd]azulen-6(7H)-one

R_f=0.15 (petroleum ether: ethyl acetate=3:1, v/v)；White solid；Fusing point: 156.5-157.3 DEG C of .89% Yield, 92%ee [Daicel Chiralcel IA-3 (0.46cm x 25cm), n-hexane/2-propanol=70/30, V=1.0mLmin^-1, t=25 DEG C, λ=254nm, t_R(minor)=10.89min, t_R(major)=14.65 min] [α]_D ²⁵=+64.0 (c=1.0, CHCl₃).¹H NMR(400MHz,CDCl₃) δ 8.25 (d, J=7.7 Hz, 1H), 8.03 (d, J =7.9Hz, 1H), 7.84 (dd, J=8.1,5.6Hz, 2H), 7.49 (t, J=7.9Hz, 1H), 7.39-7.25 (m, 5H), 7.19 (t, J=8.5Hz, 2H), 6.01-5.91 (m, 1H), 5.47 (dd, J=22.8,12.7Hz, 2H), 5.19-5.12 (m, 1H), 4.98 (d, J=17.2Hz, 1H), 4.30 (d, J=14.9 Hz, 1H), 3.85-3.80 (m, 2H)¹³C NMR(100MHz, CDCl₃)δ166.86,165.23,162.73, 152.80,143.27,136.89,133.56,131.87,131.54, 131.46,128.76,128.76,128.45, 128.45,127.80,127.74,125.52,125.49,123.91, 122.81,119.75,117.57,116.01, 115.80,59.70,53.57,50.76.HRMS(ESI)calcd for C₂₅H₂₀FN₃O[M+H]⁺:398.1663. Found:398.1647.

III-12:(R) -7- benzyl -1- (4- isopropyl phenyl) -9- vinyl -8,9- dihydro -2,7,9a- triazine And [cd] Azulene -6 (7H) -one

III-12:(R)-7-Benzyl-1-(4-isopropylphenyl)-9-vinyl-8,9-dihydro-2,7,9a- triazaben- zo[cd]azulen-6(7H)-one

R_f=0.25 (petroleum ether: ethyl acetate=3:1, v/v)；White solid；Fusing point: 156.8-156.9 DEG C of .88% Yield, 89%ee [Daicel Chiralcel IC-3 (0.46cm x 25cm), n-hexane/2-propanol=70/30, V=1.0mLmin^-1, t=25 DEG C, λ=254nm, t_R(major)=12.22min, t_R(minor)=14.19 min] [α]_D ²⁵=+121.0 (c=1.0, CHCl₃).¹H NMR(400MHz,CDCl₃) δ 8.24 (d, J=7.7 Hz, 1H), 8.04 (d, J =8.0Hz, 1H), 7.78 (d, J=7.9Hz, 2H), 7.47 (t, J=7.8Hz, 1H), 7.41-7.25 (m, 7H), 6.09- 5.83 (m, 1H), 5.48 (dd, J=28.3,12.7Hz, 2H), 5.25-5.20 (m, 1H), 4.99 (d, J=17.2Hz, 1H), 4.31 (d, J=14.9Hz, 1H), 3.84-3.79 (m, 2H), 3.08-2.89 (m, 1H), 1.30 (d, J=6.9Hz, 6H)¹³C NMR(100MHz,CDCl₃)δ166.97, 153.96,151.45,143.48,137.00,133.63,131.95,129.41, 129.41,128.74,128.74, 128.44,128.44,127.74,127.43,126.78,126.78,126.75, 123.79,122.57,119.54, 117.47,59.60,53.60,50.82,34.08,23.82,23.82.HRMS(ESI) calcd for C₂₈H₂₇N₃O [M+H]⁺:422.2232.Found:422.2218.

III-13:(S) -7- benzyl -1- (4- nitrobenzophenone) -9- vinyl -8,9- dihydro -2,7,9a- triazine is simultaneously [cd] Azulene -6 (7H) -one

III-13:(S)-7-Benzyl-1-(4-nitrophenyl)-9-vinyl-8,9-dihydro-2,7,9a- triazabenzo- [cd]azulen-6(7H)-one

R_f=0.15 (petroleum ether: ethyl acetate=3:1, v/v)；White solid；Fusing point: 239.0-240.2 DEG C of .92% Yield, 91%ee [Daicel Chiralcel AS-H (0.46cm x 25cm), n-hexane/2-propanol=65/ 35, v=1.0mLmin^-1, t=25 DEG C, λ=254nm, t_R(minor)=15.10min, t_R(major)=22.14min] [α]_D ²⁵=-97.0 (c=1.0, CHCl₃).¹H NMR(400MHz,CDCl₃) δ 8.35 (d, J=8.7Hz, 2H), 8.31 (d, J =7.6Hz, 1H), 8.12-8.04 (m, 3H), 7.53 (t, J=7.9Hz, 1H), 7.42-7.26 (m, 5H), 6.08-5.90 (m, 1H), 5.48-5.40 (m, 2H), 5.20-5.15 (m, 1H), 5.02 (d, J=17.2Hz, 1H), 4.33 (d, J=14.9Hz, 1H),3.89–3.83(m,2H).¹³C NMR (100MHz,CDCl₃)δ166.60,151.15,148.70,143.33,136.73, 135.50,133.39,132.06, 130.36,130.36,128.82,128.82,128.68,128.49,128.49, 127.90,124.44,123.85, 123.85,123.35,120.17,117.90,59.99,53.57,50.71.HRMS(ESI) calcd for C₂₅H₂₀N₄O₃[M+H]⁺:425.1568.Found:425.1562.

III-14:(S) -7- benzyl -1- (4- methoxyphenyl) -9- vinyl -8,9- dihydro -2,7,9a- triazine And [cd] Azulene -6 (7H) -one

III-14:(S)-7-Benzyl-1-(4-methoxyphenyl)-9-vinyl-8,9-dihydro-2,7,9a- triazaben- zo[cd]azulen-6(7H)-one

R_f=0.35 (petroleum ether: ethyl acetate=2:1, v/v)；White solid；Fusing point: 189.8-190.7 DEG C of .96% Yield, 92%ee [Daicel Chiralcel AD-H (0.46cm x 25cm), n-hexane/2-propanol=70/ 30, v=1.0mLmin^-1, t=25 DEG C, λ=254nm, t_R(minor)=11.23min, t_R(major)=16.26min] [α]_D ²⁵=-95.0 (c=1.0, CHCl₃).¹H NMR(400MHz,CDCl₃) δ 8.20 (d, J=7.7,1H), 7.99 (d, J= 7.9,1H),7.82–7.74(m,2H),7.69–7.65(m,1H),7.60–7.48 (m,1H),7.46–7.42(m,2H), 7.33-7.28 (m, 2H), 6.97 (d, J=8.7Hz, 2H), 5.95 (ddd, J=17.1,10.5,4.2Hz, 1H), 5.48- 5.40 (m, 2H), 5.19-5.12 (m, 1H), 4.96 (d, J=17.2,1H), 4.26 (d, J=14.6,1H), 3.83 (s, 3H), 3.80–3.69(m,2H).¹³C NMR(100MHz, CDCl₃)δ166.95,161.22,153.81,143.44,136.99, 133.72,132.01,130.88,130.88, 128.71,128.71,128.37,128.37,127.70,127.20, 123.57,122.49,121.56,119.50, 117.43,114.10,114.10,59.67,55.40,53.55, 50.80.HRMS(ESI)calcd for C₂₆H₂₃N₃O₂ [M+H]⁺:410.1863.Found:410.1844.

III-15:(S) -7- benzyl -1- (2- thienyl) -9- vinyl -8,9- dihydro -2,7,9a- triazine is simultaneously [cd] Azulene -6 (7H) -one

III-15:(S)-7-Benzyl-1-(thiophen-2-yl)-9-vinyl-8,9-dihydro-2,7,9a- triazabenzo- [cd]azulen-6(7H)-one

R_f=0.40 (petroleum ether: ethyl acetate=2:1, v/v)；White solid；Fusing point: 216.8-217.7 DEG C of .98% Yield, 95%ee [Daicel Chiralcel AD-H (0.46cm x 25cm), n-hexane/2-propanol=80/ 20, v=1.0mLmin^-1, t=25 DEG C, λ=254nm, t_R(minor)=11.97min, t_R(major)=14.55min] [α]_D ²⁵=-134.0 (c=1.0, CHCl₃).¹H NMR(400MHz,CDCl₃) δ 8.22 (d, J=7.7Hz, 1H), 8.02 (d, J =8.0Hz, 1H), 7.66-7.49 (m, 2H), 7.50-7.43 (m, 1H), 7.40-7.25 (m, 5H), 7.20-7.10 (m, 1H), 6.00 (ddd, J=14.7,10.5,3.6Hz, 1H), 5.56-5.29 (m, 3H), 4.98 (d, J=17.1Hz, 1H), 4.31 (d, J=14.9Hz, 1H), 3.91-3.85 (m, 2H)¹³C NMR(100MHz,CDCl₃)δ166.93,148.04,143.32, 136.92,132.80,132.15, 131.43,129.56,128.78,128.78,128.45,128.45,128.40, 127.95,127.80,127.68, 123.77,122.93,119.90,117.44,59.91,53.49,50.41.HRMS(ESI) calcd for C₂₃H₁₉N₃OS[M+H]⁺:386.1322.Found:386.1316.

III-16:(S) -7- benzyl -1- (2- furyl) -9- vinyl -8,9- dihydro -2,7,9a- triazine is simultaneously [cd] Azulene -6 (7H) -one

III-16:(S)-7-Benzyl-1-(furan-2-yl)-9-vinyl-8,9-dihydro-2,7,9a- triazabenzo[cd]az- ulen-6(7H)-one

R_f=0.10 (petroleum ether: ethyl acetate=3:1, v/v)；White solid；Fusing point: 189.7-190.2 DEG C of .99% Yield, 96%ee [Daicel Chiralcel AD-H (0.46cm x 25cm), n-hexane/2-propanol=80/ 20, v=1.0mLmin^-1, t=25 DEG C, λ=254nm, t_R(minor)=11.46min, t_R(major)=12.77min] [α]_D ²⁵=-115.0 (c=1.0, CHCl₃).¹H NMR(400MHz,CDCl₃)δ8.33– 8.15(m,1H),8.09–7.92(m, 1H),7.71–7.65(m,2H),7.59–7.52(m,1H),7.50–7/47(m,2H),7.41–7.36(m,2H),7.16(d,J =3.5Hz, 1H), 6.61 (dd, J=3.3,1.7Hz, 1H), 5.97 (ddd, J=17.0,10.5,4.5Hz, 1H), 5.69- 5.63 (m, 1H), 5.55 (d, J=14.9Hz, 1H), 5.34 (d, J=10.7Hz, 1H), 4.94 (d, J=17.1Hz, 1H), 4.30 (d, J=14.9Hz, 1H), 4.04-3.77 (m, 2H)¹³C NMR(100MHz,CDCl₃)δ166.92,144.57, 144.23,143.40, 136.94,133.06,132.03,131.65,128.76,128.76,128.56,128.44, 128.44,127.77, 123.90,122.96,119.08,117.49,113.43,112.05,59.77,53.49, 50.42.HRMS(ESI) calcd for C₂₃H₁₉N₃O₂[M+H]⁺:370.1550.Found:370.1529.

III-17:(R) -7- benzyl -1- methyl -9- vinyl -8,9- dihydro -2,7,9a- triazine simultaneously [cd] Azulene -6 (7H) -one

III-17:(R)-7-Benzyl-1-methyl-9-vinyl-8,9-dihydro-2,7,9a-triazabenzo [cd]azulen- 6(7H)-one

R_f=0.20 (petroleum ether: ethyl acetate=2:1, v/v)；White viscous liquid .96%yield, 89%ee [Daicel Chiralcel OD-H (0.46cm x 25cm), n-hexane/2-propanol=80/20, v=1.0mL min^-1, t=25 DEG C, λ=254nm, t_R(major)=12.18min, t_R(minor)=16.47min] [α]_D ²⁵=+ 84.0 (c=1.0, CHCl₃).¹H NMR(400MHz,CDCl₃) δ 8.18 (dd, J=7.8,0.9Hz, 1H), 7.95-7.85 (m, 1H),7.72–7.67(m,1H),7.61–7.45(m,2H),7.38–7.32(m,3H),5.96– 5.82(m,1H),5.53(d,J =14.9Hz, 1H), 5.32 (d, J=10.4Hz, 1H), 5.07-4.96 (m, 1H), 4.93 (dd, J=17.0,1.0Hz, 1H), 4.27 (d, J=14.9Hz, 1H), 3.92-3.84 (m, 2H), 2.55 (s, 3H)¹³C NMR(100MHz,CDCl₃)δ167.39, 151.79,142.94,136.99,132.08, 128.77,128.77,128.56,128.43,128.43,127.76, 126.90,123.25,122.10,119.15, 116.59,58.96,53.46,50.22,13.68.HRMS(ESI)calcd for C₂₀H₁₉N₃O [M+H]⁺:318.1601.Found:318.1590.

III-18:(R) -7- benzyl -1- trifluoromethyl -9- vinyl -8,9- dihydro -2,7,9a- triazine is simultaneously [cd] Azulene -6 (7H)-ketone

III-18:(R)-7-Benzyl-1-(trifluoromethyl)-9-vinyl-8,9-dihydro-2,7,9a- triazabenzo- [cd]azulen-6(7H)-one

R_f=0.25 (petroleum ether: ethyl acetate=1:1, v/v)；White viscous liquid .95%yield, 90%ee [Daicel Chiralcel IA-3 (0.46cm x 25cm), n-hexane/2-propanol=90/10, v=1.0mL min^-1, 30 DEG C of t=, λ=254nm, t_R(major)=11.18min, t_R(minor)=13.09min] [α]_D ²⁵=+ 123.0 (c=1.0, CHCl₃).¹H NMR(400MHz,CDCl₃) δ 8.43 (dd, J=7.7,0.8Hz, 1H), 8.12 (dd, J =8.1,0.9Hz, 1H), 7.57 (t, J=7.9Hz, 1H), 7.46-7.29 (m, 5H), 5.88 (ddd, J=17.0,10.5, 5.4Hz, 1H), 5.54 (d, J=14.8Hz, 1H), 5.43-5.38 (m, 1H), 5.32 (dd, J=10.5,1.2Hz, 1H), 4.91 (dd, J=17.1,1.2Hz, 1H), 4.30 (d, J=14.8Hz, 1H), 3.97-3.90 (m, 2H)¹³C NMR (100MHz,CDCl₃)δ166.12,141.27,136.58,131.38,130.71, 128.85,128.85,128.49, 128.49,127.96,125.93,125.93,123.96,119.39,118.37, 118.37,59.42,53.69, 50.56.HRMS(ESI)calcd for C₂₀H₁₆F₃N₃O[M+H]⁺:372.1296. Found:372.1287.

III-19:(S) -7- benzyl -1- (2- cyano-phenyl) -9- vinyl -8,9- dihydro -2,7,9a- triazine is simultaneously [cd] Azulene -6 (7H) -one

III-19:(S)-2-(7-Benzyl-6-oxo-9-vinyl-6,7,8,9-tetrahydro-2,7,9a- triazabenzo[cd]a- zulen-1-yl)benzonitrile

R_f=0.10 (petroleum ether: ethyl acetate=2:1, v/v)；White solid；Fusing point: 136.5-137.2 DEG C of .90% Yield, 93%ee [Daicel Chiralcel IA-3 (0.46cm x 25cm), n-hexane/2-propanol=70/30, V=1.0mLmin^-1, t=25 DEG C, λ=254nm, t_R(minor)=14.82min, t_R(major)=17.89 min] [α]_D ²⁵=+89.0 (c=1.0, CHCl₃).¹H NMR(400MHz,CDCl₃) δ 8.34 (d, J=7.7 Hz, 1H), 8.07 (d, J =8.0Hz, 1H), 7.83 (d, J=7.6Hz, 1H), 7.74-7.63 (m, 3H), 7.52 (t, J=7.9Hz, 1H), 7.38- 7.26 (m, 5H), 5.85-5.62 (m, 1H), 5.43 (d, J=14.8Hz, 1H), 5.21 (d, J=10.3Hz, 1H), 5.06- 4.97 (m, 1H), 4.70 (dd, J=17.1,0.8Hz, 1H), 4.34 (d, J=14.8Hz, 1H), 4.06-3.82 (m, 2H)¹³C NMR(100MHz,CDCl₃)δ166.72,149.31, 143.19,136.80,133.59,133.19,132.66,132.03, 131.30,130.97,130.63,128.77,128.77,128.67,128.49,128.49,127.82,124.70, 123.06,119.13,117.60,117.09, 113.70,59.17,53.66,50.60.HRMS(ESI)calcd for C₂₆H₂₀N₄O[M+H]⁺:405.1710. Found:405.1693.

III-20:(R) -7- benzyl -1- cyclopropyl -9- vinyl -8,9- dihydro -2,7,9a- triazine simultaneously [cd] Azulene - 6 (7H) -one

III-20:(R)-7-Benzyl-1-cyclopropyl-9-vinyl-8,9-dihydro-2,7,9a- triazabenzo[cd]az- ulen-6(7H)-one

R_f=0.30 (petroleum ether: ethyl acetate=2:1, v/v)；White solid；Fusing point: 204.2-205.1 DEG C of .88% Yield, 92%ee [Daicel Chiralcel IC-3 (0.46cm x 25cm), n-hexane/2-propanol=70/30, V=1.0mLmin^-1, t=30 DEG C, λ=254nm, t_R(major)=20.66min, t_R(minor)=22.41 min] [α]_D ²⁵=+78.0 (c=1.0, CHCl₃).¹H NMR(400MHz,CDCl₃) δ 8.13 (dd, J=7.8,1.1Hz, 1H), 7.85 (dd, J=7.9,1.1Hz, 1H), 7.43-7.23 (m, 6H), 5.94 (ddd, J=17.0,10.4,5.1Hz, 1H), 5.53 (d, J=14.9Hz, 1H), 5.32 (dd, J=10.4,1.0Hz, 1H), 5.30-5.25 (m, 1H), 4.98 (dd, J=17.0, 1.2Hz, 1H), 4.25 (d, J=14.9Hz, 1H), 3.91-3.85 (m, 2H), 1.89-1.82 (m, 1H), 1.44-1.39 (m, 1H),1.14-–1.02(m,3H).¹³C NMR (100MHz,CDCl₃)δ167.47,156.93,142.81,137.05, 132.53,131.81,128.75,128.75, 128.39,128.39,127.72,126.45,123.03,122.02, 119.10,116.42,58.65,53.41,50.26, 9.22,7.77,7.34.HRMS(ESI)calcd for C₂₂H₂₁N₃O[M+ H]⁺:344.1757.Found: 344.1737.

III-21:(S) -7- benzyl -1- cyclopropyl -9- vinyl -8,9- dihydro -2,7,9a- triazine simultaneously [cd] Azulene - 6 (7H) -one

III-21:(S)-7-Benzyl-1-cyclohexyl-9-vinyl-8,9-dihydro-2,7,9a- triazabenzo[cd]azul- en-6(7H)-one

R_f=0.25 (petroleum ether: ethyl acetate=2:1, v/v)；White solid；Fusing point: 140.2-140.8 DEG C of .93% Yield, 94%ee [Daicel Chiralcel IC-3 (0.46cm x 25cm), n-hexane/2-propanol=70/30, V=1.0mLmin^-1, t=30 DEG C, λ=254nm, t_R(minor)=13.18min, t_R(major)=16.00 min] [α]_D ²⁵=-82.0 (c=1.0, CHCl₃).¹H NMR(400MHz,CDCl₃) δ 8.18 (d, J=7.2 Hz, 1H), 7.94 (d, J =7.9Hz, 1H), 7.47-7.28 (m, 6H), 5.90 (ddd, J=16.9,10.4,5.0 Hz, 1H), 5.51 (d, J= 14.8Hz, 1H), 5.29 (d, J=10.3Hz, 1H), 5.16-5.10 (m, 1H), 4.87 (d, J=17.1Hz, 1H), 4.29 (d, J=14.9Hz, 1H), 3.89 (dt, J=15.5,10.1Hz, 2H), 2.69-2.61 (m, 1H), 1.95-1.71 (m, 7H), 1.42–1.28(m,3H).¹³C NMR(100MHz, CDCl₃)δ167.31,159.23,143.10,137.03,132.85, 131.02,128.73,128.73,128.42, 128.42,127.73,126.82,123.37,121.93,118.86, 116.78,58.19,53.45,50.36,36.20, 32.22,31.75,26.29,26.21,25.63.HRMS(ESI)calcd for C₂₅H₂₇N₃O[M+H]⁺: 386.2227.Found:386.2211.

III-22:(R) -7- benzyl -1- (3,5- dichlorophenyl) -9- vinyl -8,9- dihydro -2,7,9a- triazine And [cd] Azulene -6 (7H) -one

III-22:(R)-7-Benzyl-1-(3,5-dichlorophenyl)-9-vinyl-8,9-dihydro-2,7, 9a-triazaben- zo[cd]azulen-6(7H)-one

R_f=0.35 (petroleum ether: ethyl acetate=4:1, v/v)；White solid；Fusing point: 191.4-192.0 DEG C of .92% Yield, 91%ee [Daicel Chiralcel IC-3 (0.46cm x 25cm), n-hexane/2-propanol=75/25, V=1.0mLmin^-1, t=25 DEG C, λ=254nm, t_R(major)=22.56min, t_R(minor)=26.72 min] [α]_D ²⁵=+131.0 (c=1.0, CHCl₃).¹H NMR(400MHz,CDCl₃) δ 8.28 (dd, J=7.7,0.9Hz, 1H), 8.04 (dd, J=8.0,0.9Hz, 1H), 7.79 (d, J=1.8Hz, 2H), 7.58-7.45 (m, 2H), 7.41-7.25 (m, 5H), 6.11-5.89 (m, 1H), 5.57-5.41 (m, 2H), 5.19-5.12 (m, 1H), 5.02 (dd, J=17.2,1.1Hz, 1H), 4.31 (d, J=14.9Hz, 1H), 3.89-3.77 (m, 2H)¹³C NMR(100MHz,CDCl₃)δ166.66,150.85, 143.15,136.78,135.50,135.50, 133.39,132.16,131.90,130.27,128.80,128.80, 128.47,128.47,128.39,127.86, 127.71,127.71,124.29,123.16,120.17,117.79,59.92, 53.57,50.77.HRMS(ESI) calcd for C₂₅H₁₉C_l2N₃O[M+H]⁺:448.1214.Found:448.1208.

19. reference implementation example 18 of embodiment and synthesize compound III-2 reaction condition preparation formula III compound it is specific Compound III-23-III-32 is as shown in table 6:

The yield of prepare compound III-23 to III-32 and enantiomeric excess value (ee value) in 6. embodiment 19 of table

The activity test (In vitro) of 20. target compound of embodiment inhibition alpha-glucosidase

1. test principle:

Alpha-glucosidase and substrate p-nitrophenyl-alpha-D-glucose glycosides (pNPG) interact, and release in 400nm There is the p-nitrophenol of absorption at place, and the concentration of p-nitrophenol and the size of enzymatic activity are positively correlated.By detecting 400nm The absorbance at place determines the content of p-nitrophenol, so that it is determined that the activity of alpha-glucosidase, reflects inhibitor pair indirectly The size of inhibition of enzyme activity degree.

2. the configuration of experimental material and solution:

Test material:

Alpha-glucosidase and substrate p-nitrophenyl-alpha-D-glucose glycosides (pNPG) are purchased from Sigma company, and 1- is de- Oxygen nojirimycin (1-deoxynojirimycin) is purchased from Selleck company.Dimethyl sulfoxide (DMSO) be purchased from Aladdin, 12 The reagents such as water sodium dihydrogen phosphate, phosphate dihydrate disodium hydrogen, sodium carbonate are that analysis is pure.The configuration of testing liquid:

(1) ten sodium dihydrogen phosphate dihydrate 3.978g, phosphate dihydrate 0.05mol/L phosphate buffer (pH=6.8): are weighed Disodium hydrogen 8.771g is settled to 1000mL with distilled water dissolution；

(2) alpha-glucosidase (α-Glucosidase) solution: making solvent with 0.05mol/L phosphate buffer, configuration The solution for being 0.004U/mL at concentration；

(3) p-nitrophenyl of 0.5mmol/L-alpha-D-glucose glycosides enzyme solutions (substrate, pNPG): with 0.05 mol/L phosphorus Phthalate buffer makees solvent, is configured to the pNPG solution that concentration is 0.5mmol/L；

(4) reaction terminating liquid: precision weighs Na₂CO₃Solid 1.06g dissolves with appropriate distilled water and is settled to 100mL, It is configured to the Na that concentration is 0.1mol/L₂CO₃Solution is as reaction terminating liquid；

(5) testing compound solution: precision weighs untested compound, the mother liquor of 50mmol/L is configured to DMSO, later It is successively diluted to each experimental concentration, the concentration for controlling DMSO is no more than 5%.

3. the measuring method of alpha-glucosaccharase enzyme inhibition activity

Using alpha-glucosidase as target protein, using pNPG as substrate, using 1-DNJ as positive control Medicine.Alpha-glucosaccharase enzyme solutions, pNPG solution and sample solution use micro-pore-film filtration in advance, spare.This test enzymatic reaction tool Gymnastics make steps are as follows: alpha-glucosidase (20 μ L, 0.04U/mL) respectively with the testing sample solution (10 of various concentration gradients μ L) mixing, in 37 DEG C of constant incubator culture 15min after sufficiently shaking up.Then pNPG solution (30 μ are separately added into system L, 0.5mmol/L) starting reaction, 37 DEG C of incubation 30min are continued at after sufficiently shaking up, finally, the Na of 0.1mol/L is added₂CO₃It is molten Liquid terminates reaction, measures the absorbance value (OD value) under 400nm wavelength using microplate reader.It is replaced with the phosphate buffer of equivalent Alpha-glucosidase replaces sample liquid as positive control as negative control group, using 1-deoxynojirimycin solution, sets simultaneously Determine blank control.Each concentration gradient does 3 groups of parallel laboratory tests, calculates separately inhibition of each compound to alpha-glucosidase activity Rate (I), inhibition of enzyme activity rate (I) calculation formula are as follows:

Note: absorbance when A sample sets are both enzyme or inhibiting；A sample blank is when inhibiting is not enzyme Absorbance；Absorbance when A control group is enzyme without inhibitor；A compare blank be neither enzyme also without inhibitor when Absorbance.

Each compound is to the inhibitory activity of alpha-glucosidase with half-inhibitory concentration (IC₅₀) value measures, IC₅₀I.e. For when 50% alpha-glucosidase activity can be inhibited, the concentration of corresponding compound.With the concentration of compound for horizontal seat Mark, inhibiting rate is ordinate, is fitted beneficial effect curve using Microcal Origin Profeessional software, is calculated IC of each compound to alpha-glucosidase₅₀Value.

4. inhibiting alpha-glucosidase activity test result in vitro

Half-inhibitory concentration (IC of the part of compounds to alpha-glucosidase activity₅₀Value) it see the table below 7.

7. part of compounds of table inhibits alpha-glucosidase activity test result in vitro

^aIC₅₀Value is the average value of independent experiment three times, and experiment does two groups of data and takes mean value every time；^bAlpha-glucosaccharase enzyme activity The positive control drug of property inhibiting effect.

Preliminary experimental results show: the surveyed majority of compounds alpha-glucosaccharase enzyme inhibition activity of embodiment has reached the positive The same activity level of comparison medicine 1-DNJ, wherein suppression level of the S- configuration of compound to alpha-glucosidase Generally it is better than the compound and its corresponding racemic modification of R- configuration, and α-glucosidase inhibitory active of part of compounds It is 4 times or so of the activity level of positive control drug 1-DNJ.Thus, the present invention is the new anti-glycosuria of research and development Medicine and its lead compound provide new skeleton structure.

Claims

1. a kind of benzimidazole and chiral heterocycle class compound or its pharmaceutically acceptable salt, which is characterized in that its structural formula For Formulas I, Formula II or formula III；Wherein, it is asymmetric carbon atom with the carbon atom that * is marked, is configured as R, S or R/S, the benzo Imidazo chiral heterocycle class compound is levo form, d-isomer or raceme；

Wherein, R¹、R²、R³、R⁴It is respectively and independently selected from hydrogen, halogen atom, hydroxyl, carboxyl, cyano, nitro, C₁-C₂₀Alkyl, C₁- C₂₀Fluoro-alkyl, C₁-C₂₀Oxyl, C₃-C₂₀Naphthenic base, C₁-C₂₀Amide groups, C₂-C₂₀Alkenyl, C₂-C₂₀Alkynes Base, C₃-C₂₀Cycloalkenyl, C₃-C₂₀Cycloalkynyl radical, C₂-C₂₀Ketone carbonyl, C₁-C₂₀Sulfonyl, trimethyl silicon substrate, triethyl group Silicon substrate, triphenyl silicon substrate, C_3-C₂₀The heterocycle or heterocyclic aryl, amino, C containing one or more of N, O or S₁-C₂₀'s N- alkyl substituted amido, C₁-C₂₀N, N- dialkyl group substituted amido, aryl methylene or substituted aryl methylene, aryl or Substituted aryl；Wherein, the substituent group in the substituted aryl methylene and substituted aryl is respectively and independently selected from hydrogen, C₁- C₂₀Alkyl, C₁-C₂₀Fluoro-alkyl, halogen, nitro, C₁-C₂₀Oxyl, hydroxyl, cyano, amino, C₁-C₂₀N- alkyl Substituted amido or C₁-C₂₀N, one of N- dialkyl group substituted amido or multiple combinations；

R⁵For hydrogen, C₁-C₂₀Linear or branched alkyl group, C₃-C₂₀Naphthenic base, C₃-C₂₀Cycloalkylmethylene, C_3-C₂₀Containing N, The heterocycle methylene or heterocyclic aryl methylene, allyl, propargyl, C of one or more of O or S₁-C₂₀Acyl group or C₁-C₂₀Sulfonyl, C₁-C₂₀Hydrocarbon carbonyl oxygen, substituted C₁-C₂₀Hydrocarbon carbonyl oxygen, substituted aryl-acyl or substituted virtue Base sulfonyl, aryl methylene or substituted aryl methylene；Wherein, the substituted C₁-C₂₀Hydrocarbon carbonyl oxygen, substituted virtue The substituent group of base acyl group, substituted aryl sulfonyl and substituted aryl methylene is respectively and independently selected from hydrogen, C₁-C₂₀Alkyl, C₁-C₂₀Fluoro-alkyl, halogen, nitro, C₁-C₂₀Oxyl, hydroxyl, cyano, amino, C₁-C₂₀N- alkyl substituted amido Or C₁-C₂₀N, one of N- dialkyl group substituted amido or multiple combinations；

R⁶And R⁷It is respectively and independently selected from hydrogen, halogen atom, C₁-C₂₀Linear or branched alkyl group, aryl methylene or substituted aryl Methylene, C₃-C₂₀Naphthenic base, aryl or substituted aryl；Wherein, in the substituted aryl methylene and substituted aryl Substituent group be respectively and independently selected from hydrogen, halogen atom, C₁-C₂₀Alkyl, C₁-C₂₀Fluoro-alkyl, cyano, hydroxyl, trimethyl Silicon substrate, triethyl group silicon substrate, triphenyl silicon substrate, nitro, C₁-C₂₀Oxyl, C₂-C₂₀Alkenyl, C₂-C₂₀Alkynyl, C₁-C₂₀'s Acyl group or C₆-C₂₀One of aryl or multiple combinations；

R⁸For hydrogen, halogen atom, C₁-C₂₀Linear or branched alkyl group, C₁-C₂₀Fluoro-alkyl, C₁-C₂₀Oxyl, aryl it is sub- Methyl or substituted aryl methylene, C₃-C₂₀Naphthenic base, C_3-C₂₀Heterocycle containing one or more of N, O or S or Heterocyclic aryl, aryl or substituted aryl；Wherein, the substituent group difference in the substituted aryl methylene and substituted aryl It is independently selected from hydrogen, halogen atom, C₁-C₂₀Alkyl, C₁-C₂₀Fluoro-alkyl, cyano, hydroxyl, trimethyl silicon substrate, triethyl group silicon Base, triphenyl silicon substrate, nitro, C₁-C₂₀Oxyl, C₂-C₂₀Alkenyl, C₂-C₂₀Alkynyl, C₁-C₂₀Acyl group or C₆-C₂₀'s One of aryl or multiple combinations；

The aryl is C₆-C₂₀Aryl.

2. benzimidazole according to claim 1 and chiral heterocycle class compound or its pharmaceutically acceptable salt, special Sign is that structural formula is the Formulas I with benzimidazole and tetrahydro pyrazine skeleton structure；

Wherein, R¹、R²、R³、R⁴It is respectively and independently selected from hydrogen, fluorine, chlorine, bromine, iodine, hydroxyl, carboxyl, cyano, trifluoromethyl, nitro, first Base, ethyl, n-propyl, isopropyl, normal-butyl, isobutyl group, tert-butyl, benzyl, methoxyl group, ethyoxyl, positive propoxy, isopropyl oxygen Base, n-butoxy, isobutoxy, tert-butoxy, benzyloxy, amino, C₁-C₂₀N- alkyl substituted amido, C₁-C₂₀Amide Base, C₁-C₂₀N, N- dialkyl group substituted amido, C₁-C₂₀Acyl group, C₁-C₂₀Sulfonyl, C_3-C₂₀Containing one in N, O or S Kind or several heterocycles or heterocyclic aryl, trimethyl silicon substrate, triethyl group silicon substrate, triphenyl silicon substrate, aryl or substituted aryl； Substituent group in the substituted aryl is C₁-C₂₀Alkyl, halogen or C₁-C₂₀One of oxyl or multiple combinations；

R⁵For hydrogen, acetyl group, tertbutyloxycarbonyl, fluorenylmethyloxycarbonyl, benzoyl, 2,2,2- trichloro-ethoxycarbonyl, C₁-C₂₀It is straight Chain or branched alkyl, C₃-C₂₀Naphthenic base, C₃-C₂₀Cycloalkylmethylene, allyl, C₁-C₂₀Sulfonyl, C_3-C₂₀Contain N, the heterocycle methylene of one or more of O or S or heterocyclic aryl methylene, aryl methylene or substituted aryl methylene Base；Wherein the substituent group of the substituted aryl methylene and substituted benzenesulfonyl is respectively and independently selected from hydrogen, C₁-C₂₀Alkane Base, C₁-C₂₀Fluoro-alkyl, nitro, halogen or C₁-C₂₀One of oxyl or multiple combinations；

R⁶And R⁷It is respectively and independently selected from hydrogen, halogen atom, C₁-C₄Linear or branched alkyl group, aryl or substituted aryl, the virtue The structural formula of base or substituted aryl isWherein, R⁹、R¹⁰、R¹¹、R¹²And R¹³It is respectively and independently selected from hydrogen, halogen Atom, C₁-C₂₀Alkyl, C₁-C₂₀Fluoro-alkyl, halogen, cyano, hydroxyl, trimethyl silicon substrate, triethyl group silicon substrate, triphenyl Silicon substrate, nitro, trifluoromethyl, C₁-C₂₀Oxyl, amino, C₁-C₂₀N- alkyl substituted amido or C₁-C₂₀N, N- dioxane Base substituted amido.

3. benzimidazole according to claim 1 and chiral heterocycle class compound or its pharmaceutically acceptable salt, special Sign is that structural formula is the Formula II with benzimidazole and dihydro pyrazine ketone skeleton structure；

Wherein, R¹、R²、R³And R⁴It is respectively and independently selected from hydrogen, fluorine, chlorine, bromine, iodine, hydroxyl, cyano, trifluoromethyl, nitro, methyl, second Base, n-propyl, isopropyl, normal-butyl, isobutyl group, tert-butyl, benzyl methoxyl group, ethyoxyl, positive propoxy, isopropoxy, just Butoxy, isobutoxy, tert-butoxy, benzyloxy, amino, C₁-C₂₀N- alkyl substituted amido, C₁-C₂₀N, N- dialkyl group Substituted amido, C₁-C₂₀Acyl group, C₁-C₂₀Sulfonyl, C₁-C₂₀Amide groups, C_3-C₂₀Containing one of N, O or S or several The heterocycle or heterocyclic aryl, trimethyl silicon substrate, triethyl group silicon substrate, triphenyl silicon substrate, aryl or substituted aryl of kind；It is described to take The substituent group of the aryl in generation is C₁-C₂₀Alkyl, halogen atom or C₁-C₂₀One of oxyl or multiple combinations；

Wherein, R⁵For hydrogen, acetyl group, tertbutyloxycarbonyl, fluorenylmethyloxycarbonyl, benzoyl, 2,2,2- trichloro-ethoxycarbonyl, C₁-C₂₀ Linear or branched alkyl group, C₃-C₂₀Naphthenic base, C₃-C₂₀Cycloalkylmethylene, C_3-C₂₀Containing one of N, O or S or Several heterocycle methylenes or heterocyclic aryl methylene, allyl, C₁-C₂₀Sulfonyl, substituted aryl methylene or take The benzenesulfonyl in generation；Wherein, the substituent group of the substituted aryl methylene and substituted benzenesulfonyl be respectively and independently selected from hydrogen, C₁-C₂₀Alkyl, C₁-C₂₀Fluoro-alkyl, nitro, halogen or C₁-C₂₀One of oxyl or multiple combinations.

4. benzimidazole according to claim 1 and chiral heterocycle class compound or its pharmaceutically acceptable salt, special Sign is that structural formula is the formula III with triazine and dihydro Azulene ketone skeleton structure；

Wherein, R¹、R²、R³Be respectively and independently selected from hydrogen, fluorine, chlorine, bromine, iodine, hydroxyl, cyano, trifluoromethyl, nitro, methyl, ethyl, N-propyl, isopropyl, normal-butyl, isobutyl group, tert-butyl, methoxyl group, ethyoxyl, positive propoxy, isopropoxy, n-butoxy, Isobutoxy, tert-butoxy, benzyloxy, amino, C₁-C₂₀N- alkyl substituted amido, C₁-C₂₀N, N- dialkyl group replace amine Base, C₁-C₂₀Acyl group, C₁-C₂₀Sulfonyl, C₁-C₂₀Amide groups, C_3-C₂₀Containing the miscellaneous of one or more of N, O or S One in ring group or heterocyclic aryl, trimethyl silicon substrate, triethyl group silicon substrate, triphenyl silicon substrate, oxazolyl, aryl or substituted aryl Kind or multiple combinations；The substituent group of the substituted aryl is C₁-C₂₀Alkyl, halogen or C₁-C₂₀Oxyl in it is a kind of or Multiple combinations；

R⁵For hydrogen, acetyl group, tertbutyloxycarbonyl, fluorenylmethyloxycarbonyl, benzoyl, 2,2,2- trichloro-ethoxycarbonyl, C₁-C₂₀It is straight Chain or branched alkyl, C₃-C₂₀Naphthenic base, C₃-C₂₀Cycloalkylmethylene, C_3-C₂₀One or more of containing N, O or S Heterocycle methylene or heterocyclic aryl methylene, allyl, C₁-C₂₀Sulfonyl, substituted aryl methylene or substituted Benzenesulfonyl；Wherein, the substituent group of the substituted aryl methylene and substituted benzenesulfonyl is respectively and independently selected from hydrogen, C₁- C₂₀Alkyl, C₁-C₂₀Fluoro-alkyl, nitro, halogen or C₁-C₂₀One of oxyl or multiple combinations；

R⁸For hydrogen, halogen atom, C₁-C₂₀Linear or branched alkyl group, C₁-C₂₀Fluoro-alkyl, C₁-C₂₀Oxyl, aryl it is sub- Methyl or substituted aryl methylene, C₃-C₂₀Naphthenic base, C_3-C₂₀Heterocycle containing one or more of N, O or S or Heterocyclic aryl, aryl or substituted aryl；Wherein, the substituent group difference in the substituted aryl methylene and substituted aryl It is independently selected from hydrogen, halogen atom, C₁-C₂₀Alkyl, C₁-C₂₀Fluoro-alkyl, cyano, hydroxyl, trimethyl silicon substrate, triethyl group silicon Base, triphenyl silicon substrate, nitro, C₁-C₂₀Oxyl, C₂-C₂₀Alkenyl, C₂-C₂₀Alkynyl, C₁-C₂₀Acyl group or C₆-C₂₀'s One of aryl or multiple combinations.

5. a kind of method for preparing benzimidazole and chiral heterocycle class compound as described in any one of Claims 1 to 4, feature It is, in a solvent, at 0 DEG C~120 DEG C, using allylic compound intermediate as raw material, with iridic compound and phosphoramide The iridium complex that ligand effect generates is as catalyst, in the presence of alkali, generates the benzimidazole and chiral heterocycle class Close object；

The allylic compound intermediate, the iridium atom of iridic compound, ligand, alkali molar ratio be 1:(0.005~ 0.1): (0.005~0.2): (0.05~3)；

Wherein, LG is leaving group, be hydroxyl, chlorine, bromine,Wherein, M is NH or O；

R¹⁴For C₁-C₂₀Alkyl, C₁-C₂₀Oxyl, halogen replace C₁-C₂₀Alkyl or halogen replace C₁-C₂₀Hydrocarbon Oxygroup；

Wherein, R¹⁶For dimethylamino, diethylin, diisopropylamino, N- methylethylamine, N-methylisopropylamine base, N- first Base benzamido group, N- aminomethyl phenyl amido, hexichol amido, N- methyl -3- pyridine amido, N- methyl -2- naphthalene amido, dibenzylamine Base, N-methylcyclohexylamine base, dicyclohexyl amido, pyrroles's amido, 4- methyl piperidine base, thio-morpholinyl, morpholinyl, acyl in third Amido, butyrolactam base, valerolactamyl, caprolactam base, 2,2 ', 6,6 '-tetramethyl-piperidyls, N- phenyl benzhydryl amine Base, 1,2,3,4- tetrahydro isoquinolyl, indyl, N- methyl -2- pyridine amido, 1- methyl piperazine base, imidazole radicals, army's hexichol generation Aziridine base, N- diisopropyl-benzcyclohexyl amido, N- methyl-1-phenylethyl amido (R) or (S), N- methyl-1- Naphtylethyl group amido (R) or (S), 3,4- Diphenyl Pyrrole alkyl (R, R) or (S, S), 2,5- Diphenyl Pyrrole alkyl (R, R) or (S, S), double-(1- phenylethyl) amido (R, R) or (S, S), double-(1- naphtylethyl group) amido (R, R) or (S, S), N-1- benzene Base ethyl -1- (2- methoxybenzene) amido (R, R) or (S, S), 2,5- dinaphthyl pyrrolidinyl (R, R) or (S, S), 2- phenyl - 5- naphthylpyrrole alkyl (R, R) or (S, S), N- benzyl-alpha-methylbenzylamine base (R) or (S), 2- methoxymethyl pyrrolidinyl (R) or (S), 2,4- azepine cyclobutyl (R, R) or (S, S), 2- methoxycarbonyl group pyrrolidinyl (R) or (S), 2- ethoxy Base-methylpyrrole alkyl (R) or (S), N- isopropyl -1- phenylethyl amido (R) or (S), lupetidine base (R, R) Or (S, S), double-(1- (4- methoxyphenyl) ethyl) amido (R, R) or (S, S), double-(1- cyclohexyl-ethyl) amido (R, R) Or (S, S), N- cyclohexyl -1- phenylethyl amido (R) or (S), N- naphthalene -1- phenylethyl amido (R) or (S), N- ring are pungent Base -1- phenylethyl amido (R) or (S), N- ring certain herbaceous plants with big flowers base -1- phenylethyl amido (R) or (S), N- cyclo-dodecyl -1- naphthalene Ethyl amido (R) or (S), N- cyclo-dodecyl -1- (2,4- phenyl) ethyl amido (R) or (S), N-1- phenylethyl-(1- (2- methoxyphenyl)) ethyl amido (R, R) or (S, S), N-1- menaphthyl-(1- phenyl) ethyl amido (R) or (S), N-1- Phenylethyl-(2- phenylphenylmethyl) amido (R) or (S), N, N- dimethyl-ethylenediamine base, N, N- diisopropyl ethylenediamine base, N, N- bis- (1- phenethyl) ethylenediamine base, 1,3- high piperazine base, N, N '-dimethyl -1,2- cyclohexanediamine base (R, R) or (S, S), 2,3- diphenyl ethylene diamine base (R, R) or (S, S), benzyl-(2- pyrrole radicals -2- methyl) amido (R, R) or (S, S), N-1- benzene Base ethyl-(2- methoxyphenyl) ethyl amido, double-(4- methoxyphenethyl) amido (R, R) or (S, S), N-1- methylbenzene Ethylbenzyl amido (R) or (S), double-(2- methoxyphenethyl) amido (R, R) or (S, S), 1- methylphenethyl amido (R) Or tetrahydro chinolines amido, the R of (S), N- methyl-1-methyl-(2- diphenylphosphoryl group phenyl) amido (R) or (S), R or S configuration Or the tetrahydro indole quinoline class amido of S configuration；Wherein, the structural formula of the tetrahydro chinolines amido and tetrahydro indole quinoline class amido isThe value of n is 1 or 2；

R¹⁷And R¹⁸It is respectively and independently selected from H, halogen atom, C₁-C₂₀Alkyl, C₃-C₂₀Naphthenic base, C₁-C₂₀Oxyl, C_3- C₂₀Heterocycle containing N, O, S or one of heterocyclic aryl, aryl or substituted aryl or multiple combinations；On substituted aryl Substituent group be H, halogen, nitro, C₁-C₂₀Fluoro-alkyl, C₁-C₂₀Alkyl, C₁-C₂₀Oxyl, amino, C₁-C₂₀'s N- alkyl substituted amido or C₁-C₂₀N, one or more combinations in N- dialkyl group substituted amido；

R¹⁹、R^19’、R²⁰、R^20’、R²¹、R^21’、R²²、R^22’、R²³、R^23’、R²⁴、R^24’、R²⁵、R^25’、R²⁶、R^26’、R²⁷、R^27’、R²⁸、R^28’、 R²⁹、R^29’、R³⁰、R^30’、R³¹、R^31’、R³²、R^32’、R³³、R^33’、R³⁴、R^34’Arbitrarily it is selected from H, C₁-C₂₀Alkyl or C₃-C₂₀Cycloalkanes Base, C_3-C₂₀The heterocycle or heterocyclic aryl, substituted silicon substrate, aryl or substituted aryl containing N, O, S；Described is substituted Substituent group in silicon substrate or substituted aryl is H, halogen, nitro, C₁-C₂₀Fluoro-alkyl, C₁-C₂₀Alkyl, C₁-C₂₀Hydrocarbon Oxygroup, amino, C₁-C₂₀N- alkyl substituted amido or C₁-C₂₀N, N- dialkyl group substituted amido, C₆-C₂₀Aryl in it is a kind of Or multiple combinations；The substituent group can be one, or it is multiple, when substituent group is multiple, and the substituent group It can be identical or different；The aryl is C₆-C₂₀Aryl；

For the C containing chiral centre for controlling dihedral angle size₃-C₂₀Chiral side chain,ByIt sloughs and leaves away It is obtained after group Lg, the Lg is hydroxyl, carboxyl, halogen, methanesulfonate ester, p-methyl benzenesulfonic acid ester or trifluoromethane sulfonic acid Ester；

For the C for controlling dihedral angle size₁-C₂₀Achiral side chain,ByAfter sloughing leaving group Lg It obtains, the Lg is hydroxyl, carboxyl, halogen, methanesulfonate ester, p-methyl benzenesulfonic acid ester or trifluoromethane sulfonic acid ester.

6. according to the method described in claim 5, it is characterized in that,For (2R)-propylene glycol, (2S)-propylene glycol, (2R, 3R) -2,3- butanediol, (2S, 3S) -2,3- butanediol, (1S, 2S) -1,2- hydrobenzoin, (1R, 2R) -1,2- hexichol second two Alcohol, (2R, 3R) -1,4- benzyloxy butanediol, (2S, 3S) -1,4- benzyloxy butanediol, (2R, 4R) -2,4-PD, (2S, 4S) -2,4-PD, (2R, 5R) -2,5-HD, (2S, 5S) -2,5-HD, (3R, 4R) -3,4- hexylene glycol, (3S, 4S) -3,4- hexylene glycol, (3S) -1,3 butylene glycol, (3R) -1,3 butylene glycol, (R)-(-) -1- vinylbenzene -1,2- glycol, (S)-(+) -1- vinylbenzene -1,2- glycol, (R)-Decane-1,2-diol, (S)-Decane-1,2-diol, (2S, 9S) -2,9- decanediol, (2R, 9R) -2,9- decanediol, (3S, 8S) -3,8- decanediol, (3R, 8R) -3,8- decanediol, (4S, 7S) -4,7- decanediol, (5R, 6R) -5,6- decanediol, (5S, 6S) -4,6- decanediol, cis- -1,2- cyclohexanediol, (1R, 2R)-trans- 1,2- hexamethylene two It is alcohol, (1S, 2S)-trans- 1,2- cyclohexanediol, (1R, 2R)-trans- 1,2- cyclopentadienyl alcohol, (1S, 2S)-trans- 1,2- cyclopentadienyl alcohol, suitable Formula -1,2- cyclopentadienyl alcohol, (1S, 2S, 3R, 5S)-(+) -2,3- pinane diol, (3S, 5S)-(+) -3,5- heptane glycol, (3R, 5R)-(-) -3,5- heptane glycol, (2S, 6S) -2,6- heptane glycol, (2R, 6R) -2,6 heptane glycol, cis-3,4- tetrahydro furan Mutter glycol (3R, 6R) -3,6- ethohexadiol, (3S, 6S) -3,6- ethohexadiol, (2R, 7R) -2,7- ethohexadiol, (2S, 7S) -2,7- is pungent Glycol, (2R, 8R) -2,8- nonanediol, (2S, 8S) -2,8- nonanediol, (3R, 7R) -3,7- nonanediol, (3S, 7S) -3,7- nonyl Glycol, (4R, 6R) -4,6- nonanediol, (4S, 6S) -4,6- nonanediol, cis- 1,2- cyclohexanedimethanol, trans- 1,2- hexamethylene diformazan Alcohol, (+) -2,3-O- isopropylidene-L- threitol, (-) -2,3-O- isopropylidene-D- threitol, (R) -2,2 '-dinaphthol or (S) -2,2 '-dinaphthol；Or (R) -2,2 '-dinaphthalene dicarboxylic acids, (S) -2,2 '-dinaphthalene dicarboxylic acids, L-TARTARIC ACID, D- winestone Acid, (2R, 3R) -2,3- dibromosuccinic acid, (2S, 3S) -2,3- dibromosuccinic acid, (2R, 3R) -2,3- Succimer, (2S, 3S) -2,3- Succimer, (+)-two-to anisoyl--D- tartaric acid, (-)-two-to anisoyl--L-TARTARIC ACID, (1R, 2R) -1,2- cyclohexane cyclohexanedimethanodibasic, (1S, 2S) -1,2- cyclohexane cyclohexanedimethanodibasic, (R)-(-)-citramalic acid, (S)-(+)-citramalic acid, L MALIC ACID, D-malic acid, (R)-(+)-methylsuccinic acid, (S)-(-)-methylsuccinic acid；Or the first of aforementioned chiral diol Sulphonic acid ester, p-methyl benzenesulfonic acid ester or trifluoromethane sulfonic acid ester.

7. according to the method described in claim 5, it is characterized in that, formula S_aCompound the preparation method is as follows: o-phenylenediamine class Close object and Chlorinated Acetic Acidss and generate benzimidazoles compound, the benzimidazoles compound with Reaction obtains formula S_aCompound.

8. according to the method described in claim 5, it is characterized in that, formula S_bCompound the preparation method is as follows: o-phenylenediamine class It closes object and glycolic acid generates the benzimidazoles compound that hydroxy methylene replaces, by the hydroxyl of the benzimidazoles compound Methylene aoxidizes to obtain the benzimidazoles compound of carboxyl substitution, the benzimidazoles compound that carboxyl replaces withReaction obtains formula S_bCompound.

9. according to the method described in claim 5, it is characterized in that, formula S_cCompound the preparation method is as follows: have vicinal carboxylic acid The o-phenylenediamine class compound and aldehyde compound of structure generate benzimidazoles compound, the benzimidazoles compound withReaction obtains formula S_cCompound.

10. simultaneously chiral heterocycle class compound or its pharmaceutically acceptable salt exist any one of Claims 1 to 4 benzimidazole Preparation is for preventing or treating and answering in the drug or lead compound of alpha-glucosidase activity unconventionality expression related disease With.