CN105272792B

CN105272792B - Compound and preparation method thereof containing difluoro methylene

Info

Publication number: CN105272792B
Application number: CN201410334117.3A
Authority: CN
Inventors: 张新刚; 肖玉兰
Original assignee: Shanghai Institute of Organic Chemistry of CAS
Current assignee: Shanghai Institute of Organic Chemistry of CAS
Priority date: 2014-07-14
Filing date: 2014-07-14
Publication date: 2019-08-16
Anticipated expiration: 2034-07-14
Also published as: CN105272792A

Abstract

The invention discloses the compounds and preparation method thereof containing difluoro methylene.The present invention provides a kind of preparation methods of compound containing difluoro methylene, it is the following steps are included: in a solvent, under the conditions of alkali, ligand and catalyst are existing, compound A and compound B is subjected to suzuki coupling reaction, obtain compound C, the catalyst is nickel salt, and the nickel salt is NiQ₂·mH₂O、NiL_nCl₂、NiL_nBr₂、NiL_nI₂Or NiL_n(OH)₂.Preparation method raw material of the invention is simple and easy to get, and reaction step is few, high conversion rate, reaction yield are high, and post-processing operation is simple, catalyst is cheap, dosage is few, functional group compatibility is good, broad spectrum activity is strong, can avoid using poisonous reagent, production cost low, has good market application prospect.

Description

Compound and preparation method thereof containing difluoro methylene

Technical field

The present invention relates to the compounds and preparation method thereof containing difluoro methylene.

Background technique

The aromatic compound that fluoroalkyl replaces suffers from important application in medicine, pesticide and materials science field.Although Recent years makes great progress to the method that aromatic ring introduces fluoroalkyl, but develops some transition metal-catalyzed honest and clean The general method of valence, wide spectrum is also very important.

In fluoroalkyl substituted arene compound, we are concerned with a kind of compound containing difluoro methylene.Due to two Fluorine methylene can be used as the bioisostere of carbonyl, along with the unique reason of fluorine atom, change, biological property, this kind ofization Close object life science have it is very important application ((a) J.O.Link, J.G.Taylor, L.Xu, M.Mitchell, H.Guo,H.Liu,D.Kato,T.Kirschberg,J.Sun,N.Squires,J.Parrish,T.Keller,Z.-Y.Yang, C.Yang,M.Matles,Y.Wang,K.Wang,G.Cheng,Y.Tian,E.Mogalian,E.Mondou, M.Cornpropst,J.Perry,M.C.Desai,J.Med.Chem.2014,57,2033；(b)JR.T.R.Burke,K.Lee, Acc.Chem.Res.2003,36,426；(c)Z.-Y.Zhang,Acc.Chem.Res.2003,36,385.).Metal is crossed at present The method of such compound of the synthesis of catalysis makes some progress, however also there was only a small amount of several ((a) K.Fujikawa,Y.Fujioka,A.Kobayashi,H.Amii,Org.Lett.2011,13,5560；(b)Z.Feng, F.Chen,X.Zhang,Org.Lett.2012,14,1938；(c)Z.Feng,Y.-L.Xiao,X.Zhang, Org.Chem.Front.2014,1,113；(d)Z.Feng,Q.-Q.Min,Y.-L.Xiao,B.Zhang,X.Zhang, Angew.Chem.2014,126,1695；Angew.Chem.,Int.Ed.2014,53,1669；(e)Q.-Q.Min,Z.Yin, Z.Feng,W.-H.Guo,X.Zhang,J.Am.Chem.Soc.2014,136,1230；(f)S.Ge,W.Chaladj, J.F.Hartwig,J.Am.Chem.Soc.2014,136,4149；(g)C.Guo,R.-W.Wang,F.-L.Qing, J.Fluorine Chem.2012,143,135.) and these methods still have some shortcomings, such as: severe reaction conditions are urged Agent is expensive, and functional group compatibility is bad, and broad spectrum activity is bad etc..Bibliography d is aryl boric acid and bromine two based on palladium chtalyst The cross-coupling reaction of ethyl fluoroacetate, the reaction either palladium catalyst or ligand xantphos are very expensive, are applicable in Substrate spectrum it is limited, reaction efficiency is to be improved.Therefore, explore that a kind of high-efficient simple, functional group compatibility is good, catalyst is honest and clean The method of valence and low, the synthesisization function dough of reaction condition mildly the compound containing difluoro methylene of dosage has extremely important Meaning.

Summary of the invention

The technical problem to be solved by the present invention is to the systems in order to overcome the compound containing difluoro methylene in the prior art The disadvantages of Preparation Method severe reaction conditions, expensive catalyst, functional group compatibility is bad, and broad spectrum activity is bad and provide one kind and contain Difluoro methylene compound and preparation method thereof.Preparation method raw material of the invention is simple and easy to get, and reaction step is few, conversion ratio High, reaction yield height, post-processing operation is simple, catalyst is cheap, dosage is few, and functional group compatibility is good, and broad spectrum activity is strong, can avoid It is low using poisonous reagent, production cost, there is good market application prospect.

The present invention provides a kind of preparation methods of compound containing difluoro methylene comprising following steps: in a solvent, Under the conditions of alkali, ligand and catalyst are existing, compound A and compound B is subjected to suzuki coupling reaction, obtains compound C , the catalyst is nickel salt, and the nickel salt is NiQ₂·mH₂O、NiL_nCl₂、NiL_nBr₂、NiL_nI₂Or NiL_n (OH)₂；

Wherein, Q is nitrate anion, acetate, trifluoracetic acid root or halogen (such as fluorine, chlorine, bromine or iodine), and 0≤m≤10 (such as 0,1,2,3,4,5,6,7,8,9 or 10)；And 0 < n < 3 (such as 0,1,2 or 3)；L is triphenylphosphine, O-methoxy triphen Base phosphine, adjacent methyl triphenyl phosphine, tri-tert-butylphosphine, tricyclohexyl phosphine, tri-adamantylphosphine, 1,2 bis- (diphenylphosphine) ethane (dppe), bis- (diphenylphosphine) propane (dppp) of 1,3-, bis- (diphenylphosphine) butane (dppb) of 1,4-, the bis- (diphenyl of 1,1'- Phosphine) ferrocene (dppf), double diphenylphosphine methane (dppm), the bis- two triphenylphosphines benzene (dppbz) of 1,2-, dimethyl second diether (DME), diethylene glycol dimethyl ether (Diglyme), " substituted or unsubstituted 1,10- ferrosin " (it is described " unsubstituted 1, 10- ferrosin " is) substituted or unsubstituted bipyridyl is (preferably ) or " substituted or unsubstituted terpyridyl "Described " replaces Or unsubstituted bipyridyl ", described in " substituted or unsubstituted 1,10- ferrosin " or " replace or replace terpyridyl " " substitution " refers in heteroatomic non-ortho by C₁~C₁₀Alkyl (preferably C₁~C₆Alkyl, " the C₁~C₆Alkane Base " such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl group or tert-butyl) and C₁~C₁₀Alkoxy (preferably C₁ ~C₆Alkoxy, " the C₁~C₆Alkoxy " such as methoxyl group, ethyoxyl, propoxyl group, isopropoxy, butoxy, different Butoxy or tert-butoxy) one or more of replaced, when there are multiple substituent groups, the substituent group can be identical Or it is different；X is halogen (such as chlorine, bromine or iodine, preferably chlorine or bromine)；

R¹For " substituted or unsubstituted C₃~C₁₅Aryl " (preferably " substituted or unsubstituted C₅~C₁₄Aryl ", institute " the substituted or unsubstituted C stated₅~C₁₄Aryl " preferably " substituted or unsubstituted phenyl ", " substituted or unsubstituted naphthalene " Or " substituted or unsubstituted phenanthryl "；" the unsubstituted naphthalene " is for example" the unsubstituted phenanthrene Base " is for example" the substituted phenyl " preferably 4- methoxyphenyl, 2- aminomethyl phenyl, 3- aminomethyl phenyl, 4- Aminomethyl phenyl,4- trifluoromethyl, N, N- diformazan Base phenyl, 3- trifluoromethyl, 4- cyano-phenyl, 4- fluorophenyl, 2,4 difluorobenzene base, 3- nitrobenzophenone, 4- bromophenyl, 3, 5- dichlorophenyl, 3,5- Dimethoxyphenyl, 4- tert-butyl-phenyl, 3- bromophenyl, 4- bromophenyl, " hetero atom is oxygen, sulphur or nitrogen-atoms, and hetero atom number is 1-3, substituted or unsubstituted C₂ ~C₁₅Heteroaryl " (preferably " hetero atom is oxygen, sulphur or nitrogen-atoms, and hetero atom number is 1 C₃~C₁₀Heteroaryl ", it is described " hetero atom is oxygen, sulphur or nitrogen-atoms, and hetero atom number is 1 C₃~C₁₀Heteroaryl " preferred " substituted or unsubstituted pyrrole Piperidinyl ", " substituted or unsubstituted thienyl ", " substituted or unsubstituted furyl ", " substituted or unsubstituted pyrrole radicals ", " substituted or unsubstituted benzofuranyl ", " substituted or unsubstituted benzothienyl ", " substituted or unsubstituted benzopyrrole Base ", " the unsubstituted pyrrole Piperidinyl " can be 2- pyridyl group, 3- pyridyl group or 4- pyridyl group；" the unsubstituted thienyl " can for 2- thienyl or 3- thienyl；" the substituted thienyl " can beDescribed is " unsubstituted Furyl " can be 2- furyl or 3- furyl；" the substituted furyl " can be" the unsubstituted pyrrole radicals " can be 2- pyrrole radicals or 3- pyrrole radicals；Institute " the substituted pyrrole radicals " stated can be " the substituted or unsubstituted C₃~C₁₅Aryl " or " hetero atom be oxygen, sulphur or nitrogen-atoms, Hetero atom number is 1-3, substituted or unsubstituted C₂~C₁₅Heteroaryl " described in " substitution " be by cyano, hydroxyl, nitre Base, halogen (such as fluorine, chlorine, bromine or iodine), C₁~C₁₀Alkyl (preferably C₁~C₆Alkyl, " the C₁~C₆Alkyl " example Such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl group or tert-butyl), C₁~C₁₀Alkoxy (preferably C₁~C₆Alcoxyl The base, " C₁~C₆Alkoxy " such as methoxyl group, ethyoxyl, propoxyl group, isopropoxy, butoxy, isobutoxy or uncle Butoxy), C₁~C₁₀Alkylthio group (preferably C₁~C₆Alkylthio group, " the C₁~C₆Alkylthio group " such as methyl mercapto, second Sulfenyl, rosickyite base, isopropyisulfanyl, butylthio, isobutylthio or tertiary butylthio), C₁~C₁₀Alkyl silyl (preferably C₁~C₆'s The alkyl silyl, " C₁~C₆Alkyl silyl " such as methylsilyl, trimethyl silicon substrate, ethyl silicon substrate, propyl silicon substrate, different Propyl silicon substrate, butyl silicon substrate, isobutyl group silicon substrate or tert-butyl silicon substrate), " halogen replace C₁~C₁₀Alkyl " (" halogen The C that element replaces₁~C₁₀Alkyl " described in the preferred fluorine of halogen, chlorine or bromine, the number of the halogen is 1-4, works as presence When multiple halogen atoms, the halogen atom can be identical or different；" the C that halogen replaces₁~C₁₀Alkyl " in " the C₁~C₁₀Alkyl " preferred C₁~C₆Alkyl, " the C₁~C₆Alkyl " can for methyl, ethyl, propyl, Isopropyl, butyl, isobutyl group or tert-butyl." the C that halogen replaces₁~C₁₀Alkyl " preferably " in fluorine, chlorine and bromine atom One or more C replaced₁~C₆Alkyl ", described " one or more C replaced in fluorine, chlorine and bromine atom₁~C₆ Alkyl " preferably " one or more methyl replaced in fluorine, chlorine and bromine atom ", " one or more in fluorine, chlorine and bromine atom A substituted ethyl ", " one or more propyl replaced in fluorine, chlorine and bromine atom ", " one in fluorine, chlorine and bromine atom Or multiple substituted isopropyls ", " one or more butyl replaced in fluorine, chlorine and bromine atom ", " in fluorine, chlorine and bromine atom One or more isobutyl groups replaced " or " one or more tert-butyls replaced in fluorine, chlorine and bromine atom "；Described " methyl that fluorine atom replaces " preferred trifluoromethyl, " methyl that bromine atom replaces " are preferred), " hydroxyl takes The C in generation₁~C₁₀Alkyl " (preferably " and hydroxyl replace C₁~C₆Alkyl ", the described " C that hydroxyl replaces₁~C₆Alkyl " Such as " methyl that hydroxyl replaces ", " ethyl that hydroxyl replaces ", " propyl that hydroxyl replaces ", " isopropyl that hydroxyl replaces ", " hydroxyl The butyl that base replaces ", " isobutyl group that hydroxyl replaces " or " tert-butyl that hydroxyl replaces "；),C₂~C₁₀Alkenyl (preferably C₂~C₆ Alkenyl, " the C₂~C₆Alkenyl " such as vinyl,)、C₂ ~C₁₀Alkynyl (preferably C₂~C₆Alkynyl, " the C₂~C₆Alkynyl " such as acetenyl, )、C₃~C₁₀Aryl (preferably C₃~C₆Aryl, " the C₃~C₆Aryl " preferred phenyl), " hetero atom be oxygen, sulphur or Nitrogen-atoms, the C that hetero atom number is 1-3₂~C₆Heterocyclylalkyl " (preferably " hetero atom is oxygen or nitrogen-atoms, hetero atom number are 1-2 C₃~C₄Heterocyclylalkyl ", the described " C that hetero atom is oxygen or nitrogen-atoms, hetero atom number are 1-2₃~C₄'s The preferred morpholinyl of Heterocyclylalkyl ", " morpholinyl " for example)、(preferably)、WithIn one A or multiple replaced, when there are multiple substituent groups, the substituent group is identical or different；Wherein, R³、R⁴And R⁵Respectively solely Vertical is hydrogen atom, amino, C₁~C₆Alkyl (such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl group or tert-butyl) Or C₃~C₆Naphthenic base (such as cyclopropyl, cyclopenta or cyclohexyl).R⁶And R⁷Independent is C₁~C₆Alkyl (such as Methyl, ethyl, propyl, isopropyl, butyl, isobutyl group or tert-butyl) or C₃~C₆Naphthenic base (such as cyclopropyl, cyclopenta or Cyclohexyl).R⁸For hydrogen atom, C₁~C₆Alkyl (such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl group or tert-butyl) Or C₃~C₆Naphthenic base (such as cyclopropyl, cyclopenta or cyclohexyl).

R²For(preferably)、(preferably) or " hetero atom is oxygen, sulphur or nitrogen-atoms, hetero atom number is 1-3 substitution or not Substituted C₂~C₁₅Heteroaryl " (preferably " substitution or do not take that hetero atom is oxygen, sulphur or nitrogen-atoms, hetero atom number is 1-2 The C in generation₃~C₈Heteroaryl ", it is described that " hetero atom is oxygen, sulphur or nitrogen-atoms, hetero atom number is 1-2 substituted or unsubstituted C₃~C₈Heteroaryl " preferably " substituted or unsubstituted benzoxazolyl ", " substituted or unsubstituted benzimidazolyl " or " substituted or unsubstituted thiazolyl "；" the unsubstituted benzoxazolyl " can beIt is described " not Substituted thiazolyl " can be" the substituted thiazolyl " can beDescribed " does not take The benzimidazolyl in generation " can be" the substituted benzimidazolyl " can be), " the substituted or unsubstituted C that hetero atom is oxygen, sulphur or nitrogen-atoms, hetero atom number is 1-3₂~C₁₅Heteroaryl " in " substitution " refers to by cyano, halogen (such as fluorine, chlorine, bromine or iodine), C₁~C₁₀Alkyl (preferably C₁~C₆Alkyl, institute " the C stated₁~C₆Alkyl " such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl group or tert-butyl), C₁~C₁₀Alcoxyl Base (preferably C₁~C₆Alkoxy, " the C₁~C₆Alkoxy " for example methoxyl group, ethyoxyl, propoxyl group, isopropoxy, Butoxy, isobutoxy or tert-butoxy), " halogen replace C₁~C₁₀Alkyl " (described " C that halogen replaces₁~C₁₀'s The preferred fluorine of halogen described in alkyl ", chlorine or bromine, the number of the halogen is 1-4, when there are multiple halogen atoms, The halogen atom can be identical or different；" the C that halogen replaces₁~C₁₀Alkyl " preferably " fluorine, chlorine and bromine atom In one or more C replaced₁~C₆Alkyl ", described " one or more C replaced in fluorine, chlorine and bromine atom₁~ C₆Alkyl " preferably " one or more methyl replaced in fluorine, chlorine and bromine atom ", " one in fluorine, chlorine and bromine atom or Multiple substituted ethyls ", " one or more propyl replaced in fluorine, chlorine and bromine atom ", " one in fluorine, chlorine and bromine atom A or multiple substituted isopropyls ", " one or more butyl replaced in fluorine, chlorine and bromine atom ", " fluorine, chlorine and bromine atom In one or more isobutyl groups replaced " or " one or more tert-butyls replaced in fluorine, chlorine and bromine atom "；Described " methyl that fluorine atom replaces " preferred trifluoromethyl, " methyl that bromine atom replaces " are preferred)、C₂~C₁₀'s Alkenyl (preferably C₂~C₆Alkenyl, " the C₂~C₆Alkenyl " such as vinyl, )、C₂~C₁₀Alkynyl (preferably C₂~C₆Alkynyl, " the C₂~C₆Alkynyl " such as second Alkynyl,) one or more of replaced, when there are multiple substituent groups, the substituent group It can be identical or different.

Wherein, R⁹For C₁~C₆Alkyl (such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl group or tert-butyl) or C₃~C₆Naphthenic base (such as cyclopropyl, cyclopenta or cyclohexyl)；

R¹⁰For substituted or unsubstituted C₁~C₁₀Alkyl (preferably substituted or unsubstituted C₁~C₆Alkyl, it is described " substituted or unsubstituted C₁~C₆Alkyl " can for " substituted or unsubstituted methyl ", " substituted or unsubstituted ethyl ", " substituted or unsubstituted propyl ", " substituted or unsubstituted isopropyl ", " replace or do not take " substituted or unsubstituted butyl " The isobutyl group in generation " or " substituted or unsubstituted tert-butyl "；" the substituted ethyl " is preferred), " miscellaneous original Son is oxygen, sulphur or nitrogen-atoms, the substituted or unsubstituted C that hetero atom number is 1-3₂~C₁₅Heterocyclylalkyl " (preferably " miscellaneous original Son is oxygen, sulphur or nitrogen-atoms, the C that hetero atom number is 1-2₂~C₆Heterocyclylalkyl ", it is described that " hetero atom is oxygen, sulphur or nitrogen Atom, the C that hetero atom number is 1-2₂~C₆Heterocyclylalkyl " preferably hetero atom be oxygen and/or nitrogen-atoms, hetero atom number be 2 C₃~C₄Heterocyclylalkyl, it is described that " hetero atom is oxygen and/or nitrogen-atoms, the C that hetero atom number is 2₃~C₄Heterocycle alkane Base " preferably substituted or unsubstituted morpholinyl, " the unsubstituted morpholinyl " is preferred), substituted or unsubstituted C₃ ~C₁₅Aryl (preferably " substituted or unsubstituted C₅~C₁₀Aryl ", " the substituted or unsubstituted C₅~C₁₀Virtue Base " preferably substituted or unsubstituted phenyl, " the substituted phenyl " preferably 4- methoxyphenyl, 2- aminomethyl phenyl, 4- tri- Trifluoromethylphenyl, 3- trifluoromethyl, 4- cyano-phenyl, 4- fluorophenyl, 4- bromophenyl, 3,5- Dimethoxyphenyl, uncle 4- Butyl phenyl, 3- bromophenyl, 4- bromophenyl, 4- aminomethyl phenyl, ) or C₃~C₁₅Fragrant amino (preferably C₅~C₁₀Fragrant amino, " the C₅~C₁₀ Fragrant amino " preferably)；The R¹⁰Described in " substituted or unsubstituted C₁~C₁₀Alkyl " described in " take In generation ", refers to by C₃~C₁₅Aryl (preferably C₅~C₁₀Aryl, " the C₅~C₁₀Aryl " preferred phenyl) it is replaced.

The R¹⁰Described in " hetero atom is oxygen, sulphur or nitrogen-atoms, and hetero atom number is the substituted or unsubstituted of 1-3 C₂~C₁₅Heterocyclylalkyl " described in " substitution " refer to by C₁~C₁₀Alkyl (preferably C₁~C₆Alkyl, " the C₁ ~C₆Alkyl " such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl group or tert-butyl) and C₃~C₆Naphthenic base Replaced one or more of (such as cyclopropyl, cyclopenta or cyclohexyl), when there are multiple substituent groups, the substitution Base can be identical or different.

The R¹⁰Described in " substituted or unsubstituted C₃~C₁₅Aryl " described in " substitution " be by cyano, halogen Plain (such as fluorine, chlorine, bromine or iodine), C₁~C₁₀Alkyl (preferably C₁~C₆Alkyl, " the C₁~C₆Alkyl " such as first Base, ethyl, propyl, isopropyl, butyl, isobutyl group or tert-butyl), C₁~C₁₀Alkoxy (preferably C₁~C₆Alkoxy, institute " the C stated₁~C₆Alkoxy " such as methoxyl group, ethyoxyl, propoxyl group, isopropoxy, butoxy, isobutoxy or tertiary fourth oxygen Base), " halogen replace C₁~C₁₀Alkyl " (described " C that halogen replaces₁~C₁₀Alkyl " described in halogen it is preferred Fluorine, chlorine or bromine, the number of the halogen are 1-4, and when there are multiple halogen atoms, the halogen atom can be identical Or it is different；" the C that halogen replaces₁~C₁₀Alkyl " preferably " one or more C replaced in fluorine, chlorine and bromine atom₁ ~C₆Alkyl ", described " one or more C replaced in fluorine, chlorine and bromine atom₁~C₆Alkyl " preferably " fluorine, chlorine and One or more methyl replaced in bromine atom ", " one or more ethyls replaced in fluorine, chlorine and bromine atom ", " fluorine, One or more propyl replaced in chlorine and bromine atom ", " one or more isopropyls replaced in fluorine, chlorine and bromine atom Base ", " one or more butyl replaced in fluorine, chlorine and bromine atom ", " one or more substitutions in fluorine, chlorine and bromine atom Isobutyl group " or " one or more tert-butyls replaced in fluorine, chlorine and bromine atom "；" methyl that fluorine atom replaces " It is preferred that trifluoromethyl, " methyl that bromine atom replaces " is preferred)、C₂~C₁₀Alkenyl (preferably C₂~C₆Alkene The base, " C₂~C₆Alkenyl " such as vinyl, )、C₂~C₁₀ Alkynyl (preferably C₂~C₆Alkynyl, " the C₂~C₆Alkynyl " such as acetenyl,)、One or more of replaced, when there are multiple substituent groups When, the substituent group is identical or different.

R¹¹For C₁~C₆Alkyl (such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl group or tert-butyl), C₃~C₆ Naphthenic base (such as cyclopropyl, cyclopenta or cyclohexyl) or " C₁~C₆Alkyl silyl " (" C₁~C₆Alkyl silicon " C described in base "₁~C₆Alkyl " preferably methyl, ethyl, propyl, isopropyl, butyl, isobutyl group or tert-butyl, it is described “C₁~C₆Alkyl silyl " such as trimethyl silicon substrate, triethyl group silicon substrate, tripropyl silicon substrate or triisopropylsilyl).

R¹²For C₁~C₆Alkyl (such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl group or tert-butyl, it is preferably different Propyl or normal-butyl).

In the present invention, the compound AFurther preferably following any compound:

In the present invention, the compound BFurther preferably following any compound:

In the present invention, the compound CFurther preferably following any compound:

In the preparation method of the compound containing difluoro methylene, the solvent can be such in this field The Conventional solvents of Suzuki coupling reaction, particularly preferably one of ether solvent and water or a variety of in the present invention, preferably ethers Solvent.The preferred tetrahydrofuran of the ether solvent, ether, glycol dimethyl ether (DME), diethylene glycol dimethyl ether, 1,4- bis- One of six ring of oxygen and methyl tertiary butyl ether(MTBE) are a variety of, further preferred Isosorbide-5-Nitrae-dioxane and/or tetrahydrofuran.

In the preparation method of the compound containing difluoro methylene, the body of the solvent and the compound B The product preferred 1mL/mmol~100mL/mmol of molar ratio, further preferred 1mL/mmol~10mL/mmol.

In the preparation method of the compound containing difluoro methylene, the alkali can be such in this field The conventional alkali of Suzuki coupling reaction, the present invention in particularly preferably alkali metal hydroxide, alkali carbonate, alkali metal carbonic acid Hydrogen salt, alkali metal phosphate, " alkali metal and C₁~C₄The salt that alcohol is formed " or C₁~C₄Alkylamine (such as triethylamine), it is described One of the preferred potassium carbonate of alkali carbonate, sodium carbonate and cesium carbonate are a variety of, further preferred potassium carbonate and/or carbonic acid Sodium, still further preferably potassium carbonate.The preferred potassium phosphate of the alkali metal phosphate." alkali metal and the C₁~C₄Alcohol is formed Salt " described in " C₁~C₄Alcohol " preferably methanol, ethyl alcohol, propyl alcohol, isopropanol or the tert-butyl alcohol；" alkali metal and the C₁~C₄ " alkali metal " preferably lithium, sodium, potassium, rubidium or caesium described in the salt that alcohol is formed "；" alkali metal and the C₁~C₄Alcohol shape At salt " preferably one of sodium methoxide, sodium ethoxide, sodium tert-butoxide and potassium tert-butoxide or a variety of.

In the preparation method of the compound containing difluoro methylene, mole of the alkali and the compound B Ratio preferably 1~5, further preferred 2~3.

In the preparation method of the compound containing difluoro methylene, the ligand can be such in this field The conventional ligands of suzuki coupling reaction, particularly preferably nitrogenous bidentate ligand or nitrogenous tridentate ligand in the present invention, described " contains (" the substituted bipyridyl " is preferred for the preferably substituted or unsubstituted bipyridyl of nitrogen bidentate ligand " ), (" the unsubstituted 1,10- ferrosin " be substituted or unsubstituted 1,10- ferrosin) or N, N, N ', N '-tetramethyl ethamine；The nitrogenous tridentate ligand preferably " substituted or unsubstituted three (" the unsubstituted terpyridyl " be bipyridyl "), described is " substituted or unsubstituted " substitution " described in pyridine ", " substituted or unsubstituted 1,10- ferrosin " or " replace or replace terpyridyl " refers to By C in heteroatomic non-ortho₁~C₁₀Alkyl (preferably C₁~C₆Alkyl, " the C₁~C₆Alkyl " such as first Base, ethyl, propyl, isopropyl, butyl, isobutyl group or tert-butyl) and C₁~C₁₀Alkoxy (preferably C₁~C₆Alkoxy, institute " the C stated₁~C₆Alkoxy " such as methoxyl group, ethyoxyl, propoxyl group, isopropoxy, butoxy, isobutoxy or tertiary fourth oxygen Base) one or more of replaced, when there are multiple substituent groups, the substituent group can be identical or different.

In the preparation method of the compound containing difluoro methylene, the ligand rubs with the compound B's That ratio preferably 0.01~0.1, further preferred 0.025~0.05.

In the preparation method of the compound containing difluoro methylene, the preferred dimethyl second diether of the nickel salt closes chlorine Change nickel (NiCl₂DME), 1,2 bis- (diphenylphosphine) ethane close nickel chloride (NiCl₂Dppe), bis- (diphenylphosphines) two of 1,1'- Luxuriant iron closes nickel chloride (NiCl₂Dppf), bis- (diphenylphosphine) propane of 1,3- close nickel chloride (NiCl₂Dppp), two thricyclohexyl Phosphine closes nickel chloride (NiCl₂·(PCy₃)₂), dimethyl second diether close nickelous bromide (NiBr₂DME), diethylene glycol dimethyl ether closes bromine Change nickel (NiBr₂Diglyme), two triphenylphosphines close nickelous bromide (NiBr₂·(PPh₃)₂), two triphenylphosphines close nickel chloride (NiCl₂·(PPh₃)₂), Nickelous nitrate hexahydrate (Ni (NO₃)₂·6H₂O) and three are hydrated nickelous bromide (NiBr₂·3H₂One of O) Or it is a variety of.

In the preparation method of the compound containing difluoro methylene, the nickel salt rubs with the compound B's That ratio preferably 0.01~0.1, further preferred 0.025~0.05.

In the preparation method of the compound containing difluoro methylene, the temperature of the Suzuki coupling reaction is preferred 20 DEG C~120 DEG C, further preferred 60 DEG C~80 DEG C.

In the preparation method of the compound containing difluoro methylene, the process of the Suzuki coupling reaction can be with It is monitored using the common detection methods (such as TLC, HPLC or NMR) in this field, is anti-when generally being disappeared with compound B Answer terminal, the reaction time preferably 1 hour~48 hours, further preferred 8 hours~24 hours.

The preparation method of the compound containing difluoro methylene carries out under the conditions of can also be existing for the co-catalyst, institute The preferred mantoquita of the co-catalyst stated.The preferred copper oxide of the mantoquita, copper acetate, copper chloride, copper bromide, cupric iodide, iodate are sub- One of copper, copper fluoride and copper carbonate are a variety of.

In the preparation method of the compound containing difluoro methylene, carried out under the conditions of existing for the co-catalyst When, the molar ratio preferably 0~4 of the co-catalyst and the compound B, but do not include 0.

In the present invention,Synthetic method bibliography D.Maximilian, et al.PCT Int.Appl., 2013092850,27Jun 2013。

Synthetic method bibliography P.Ackermann, H.R.Kaenel, B.Schaub, Eur.Pat.Appl.1989, EP 33,365,8A2 19890920.

Synthetic method bibliography S.Mao, X.Fang, L.Ba, F.Wu, J.Fluorine Chem., 2007,128,5。

Synthetic method bibliography T.Nihei, N.Twai, T.Matsuda,T.Kitazume,J.Org.Chem.,2005,70,5912。

Synthetic method bibliography Z.-M.Qiu, D.J.Burton, J.Org.Chem., 1995,60, 5570。

Synthetic method bibliography W.R.Dolbier Jr, C.R.Burkholder, M. J.Fluor.Chem.,1999,95,127。

Synthetic method bibliography C.R.Burkholder, W.R.Dolbier Jr, J.Org.Chem., 1998,63,5385。

Synthetic method bibliography R.M.Flynn, D.J.Burton, J.Fluor.Chem., 2011,132, 815。

Synthetic method bibliography B.Xu,；M.S.Mashuta,；G.B.Hammond,Angew.Chem., Int.Ed.2006,45,7265。

The present invention also provides such as formula C compound represented,

Wherein, R¹And R²Definition it is same as above, but not including that following compound:

The present invention also provides the compound C as carbonyl bioisostere preparation medicine, pesticide or Application in medical material, such as the case where following documents is reported: (a) J.O.Link, J.G.Taylor, L.Xu, M.Mitchell,H.Guo,H.Liu,D.Kato,T.Kirschberg,J.Sun,N.Squires,J.Parrish, T.Keller,Z.-Y.Yang,C.Yang,M.Matles,Y.Wang,K.Wang,G.Cheng,Y.Tian,E.Mogalian, E.Mondou,M.Cornpropst,J.Perry,M.C.Desai,J.Med.Chem.2014,57,2033；(b) JR.T.R.Burke,K.Lee,Acc.Chem.Res.2003,36,426；(c)Z.-Y.Zhang,Acc.Chem.Res.2003, 36,385。

In the present invention, when not specifying, " alkyl " is to include with specified carbon atom number purpose branch The saturated aliphatic hydrocarbons of chain or straight chain；Such as in " C₁~C₂₀Being defined as being included in straight chain or branched structure in alkyl " has 1, the group of 2,3,4,5,6,7,8,9,11,11,12,13,14,15,16,17,18,19 or 20 carbon atoms.For example, " C₁ ~C₁₀Alkyl " specifically include methyl, ethyl, n-propyl, isopropyl, normal-butyl, tert-butyl, isobutyl group, amyl, hexyl, heptyl, Octyl, nonyl and decyl etc..

In the present invention, when not specifying, " alkoxy " indicates the life after alkyl is connect with oxygen atom At group, i.e.,R is alkyl.

In the present invention, when not specifying, " alkylthio group " indicates the life after alkyl is connect with sulphur atom At group, i.e.,R is alkyl.

In the present invention, when not specifying, " fragrant amino " refers to " NH₃" in a hydrogen taken by aryl Amino after generation.

In the present invention, when not specifying, " alkyl silyl " is structureIn, R₁、R₂And R₃In At least one is alkyl, remaining is the group of hydrogen.

In the present invention, when not specifying, " naphthenic base " refers to full carbon one or more cyclic groups, wherein often A ring can be containing one or more double bonds, but none ring has the pi-electron system of total conjugated.It is preferred that 3~20 carbon It is formed by the naphthenic base of 1~3 ring, more preferable 3~10 carbon, such as: cyclopropyl, cyclobutyl, cyclopenta, cyclohexyl, ring Heptyl, cyclooctyl, cyclodecane and cyclo-dodecyl.

In the present invention, when not specifying, " Heterocyclylalkyl " is herein individually or as another group A part in use, referring to 4~12 unit monocycles comprising 1~4 hetero atom (such as one of nitrogen, oxygen and sulphur or a variety of) or more Cyclic group, wherein each ring can be containing one or more double bonds, but none ring has the pi-electron system of total conjugated. In addition, any heterocycloalkyl ring can be condensed on naphthenic base, aryl, heteroaryl or heterocycloalkyl ring.Within the range defined herein Heterocyclylalkyl include but is not limited to: oxazoline, oxygen cyclobutyl, pyranose, THP trtrahydropyranyl, azetidinyl, 1,4- bis- Oxane base, hexahydro azatropylidene base, piperazinyl, piperidyl, pyrrolidinyl, morpholinyl, thio-morpholinyl, dihydrofuryl, dihydro Imidazole radicals, indolinyl, dihydro-isoxazole base, dihydro isothiazolyl, dihydro oxadiazoles base, dihydro-oxazole base, dihydro pyrazine Base, pyrazoline base, dihydropyridine base, dihydro-pyrimidin base, pyrrolin base, dihydro tetrazole radical, thiodiazoline base, dihydro thiophene Oxazolyl, dihydrothiophene, dihydro triazolyl, dihydro azetidinyl, tetrahydrofuran base and tetrahydro-thienyl and its N- oxidation Object.Heterocyclylalkyl can be attached through carbon atom therein or hetero atom with other groups.

In the present invention, when not specifying, " alkenyl " refers to containing specifying number carbon atom and at least Straight chain, branch or the cyclic annular non-aromatic alkyl of one carbon-carbon double bond.It is preferred that there are a carbon-carbon double bonds, and there may be height Up to four non-aromatic carbon-carbon double bonds." C as a result,₂~C₁₂Alkenyl " refers to the alkenyl with 2~12 carbon atoms."C₂~C₆Alkenyl " Refer to the alkenyl with 2~6 carbon atoms, including vinyl, acrylic, cyclobutenyl, 2- methyl butene base and cyclohexenyl group.

In the present invention, when not specifying, " alkynyl " refers to containing specifying number carbon atom and at least Straight chain, branch or the cyclic hydrocarbon group of one triple carbon-carbon bonds.Wherein there may be up to three triple carbon-carbon bonds." C as a result,₂~C₁₂ Alkynyl " refers to the alkynyl with 2~12 carbon atoms."C₂~C₆Alkynyl " refers to the alkynyl with 2~6 carbon atoms, including second Alkynyl, propinyl, butynyl and 3- methylbutynyl etc..

In the present invention, when not specifying, " aryl " refers to any stable up to 7 in each ring The monocycle or bicyclic carbocyclic of a atom, wherein at least one ring are aromatic rings；The example of above-mentioned aryl unit includes phenyl, naphthalene Base, tetralyl, indanyl, xenyl, phenanthryl, anthryl or acenaphthenyl (acenaphthyl).It is appreciated that In the case where aryl substituent is two ring substituents, and one of ring is non-aromatic ring, connection is carried out by aromatic ring.

In the present invention, when not specifying, " heteroaryl " indicates to may be up to the steady of 7 atoms in each ring Order ring or two rings, wherein at least one ring are aromatic rings and are selected from the hetero atom of O, N and S containing 1-4；It defines herein Heterocyclic aryl in range includes but is not limited to: acridinyl, carbazyl, cinnoline base, quinoxalinyl, pyrazolyl, indyl, benzo Triazolyl, furyl, thienyl, benzothienyl, benzofuranyl, quinolyl, isoquinolyl, oxazolyl, isoxazolyl, Yin Diindyl base, pyrazinyl, pyridazinyl, pyridyl group, pyrimidine radicals, pyrrole radicals, tetrahydroquinoline.As the definition of following heterocycle, " heterocycle Aryl " is it should also be understood that be the N- oxide derivative for including any nitrogenous heteroaryl.Heterocyclic aryl substituent group is two wherein Ring substituents and a ring are non-aromatic rings or do not include in heteroatomic situation, it will be understood that connection passes through virtue respectively Ring is carried out by the inclusion of the hetero atom of ring.

In the present invention, when not specifying, " heterocycloalkenyl " refers to single heterocycle or more heterocyclic groups, wherein Each ring can be containing one or more double bonds, but none ring has the pi-electron system of total conjugated.Such as

In the present invention, when not specifying, " halogen " indicates fluorine, chlorine, bromine, iodine or astatine.

In the present invention, described has determined the " C of carbon number range_x1~C_y1" substituent group (x1 be with y1 integer), such as " C_x1 ~C_y1" alkyl, " C_x1~C_y1" alkoxy, " C_x1~C_y1" aryl, " C_x1~C_y1" heteroaryl or " C_x1~C_y1" alkane Epoxide carbonyl indicates carbon number not comprising substituent group, such as C₁~C₁₀Alkyl indicates C not comprising substituent group₁~C₁₀Alkyl.

Without prejudice to the field on the basis of common sense, above-mentioned each optimum condition, can any combination to get the present invention it is each preferably Example.

The reagents and materials used in the present invention are commercially available.

In the present invention, the room temperature refers to that environment temperature is 10 DEG C~35 DEG C.

The positive effect of the present invention is that: the present invention using nickel salt as catalyst, other metal salts (silver salt or mantoquita, Or zinc salt) it is co-catalyst, the short-cut method of the compound containing difluoro methylene by coupling reaction synthesis function dough.It should Method has raw material simple and easy to get, and reaction step is few, high conversion rate, reaction yield are high, and post-processing operation is simple, catalyst is honest and clean Valence, dosage are few, and functional group compatibility is good, and broad spectrum activity is strong, can avoid using poisonous reagent, production cost low, have good city Field application prospect.

Specific embodiment

The present invention is further illustrated below by the mode of embodiment, but does not therefore limit the present invention to the reality It applies among a range.In the following examples, the experimental methods for specific conditions are not specified, according to conventional methods and conditions, or according to quotient The selection of product specification.

Embodiment 1

Into the reaction tube of 25mL, 110mg (0.9mmol) phenyl boric acid is added, (2.5mol% refers to and accounts for phenyl boric acid 4.4mg The percentage of mole) Nickelous nitrate hexahydrate, 2.4mg (2.5mol% refers to the percentage for accounting for phenyl boric acid mole) bpy (2, 2 '-bipyridyls), 166mg (1.2mmol) K₂CO₃, 4mL Isosorbide-5-Nitrae-dioxane, 78 μ L (0.6mmol) Bromodifluoroacetic acid second of injection Ester, after stirring 24 hours at 60 DEG C, separation yield is that 87% (when using 0.6mmol chlorine ethyl difluoro, stirring 24 is small at 80 DEG C Shi Hou, separation yield are that 76%), purity is greater than 95% through hydrogen spectrum identification.¹H NMR(500MHz,CDCl₃) δ 7.62 (d, J= 7.0Hz, 2H), 7.53-7.41 (m, 3H), 4.30 (q, J=7.1Hz, 2H), 1.30 (t, J=7.2Hz, 3H)¹³C NMR (125.7MHz,CDCl₃) δ 164.2 (t, J=35.3Hz), 132.8 (t, J=25.5Hz), 130.9 (t, J=1.7Hz), 128.6,125.4 (t, J=6.2Hz), 113.4 (t, J=251.9Hz), 63.1,13.8.¹⁹F NMR(376MHz,CDCl₃)δ- 103.9(s,2F).

Embodiment 2

Into the reaction tube of 25mL, 137mg (0.9mmol) 4- methoxyphenylboronic acid is added, (2.5mol% refers to 4.4mg Account for the percentage of 4- methoxyphenylboronic acid mole) Nickelous nitrate hexahydrate, (2.5mol% refers to and accounts for 4- methoxybenzene boron 2.4mg The percentage of sour mole) bpy (2,2 '-bipyridyl), 166mg (1.2mmol) K₂CO₃, 4mL1,4- dioxane, 78 μ L of injection (0.6mmol) Bromodifluoroacetic acid ethyl ester, after stirring 24 hours at 60 DEG C, separation yield is 81% (to use 0.6mmol chlorine difluoroacetic acid When ethyl ester, after stirring 24 hours at 80 DEG C, separation yield is that 62%), purity is greater than 95% through hydrogen spectrum identification.¹H NMR (400MHz,CDCl₃) δ 7.53 (d, J=8.9Hz, 2H), 6.95 (d, J=8.9Hz, 2H), 4.29 (q, J=7.1Hz, 2H), 3.84 (s, 3H), 1.30 (t, J=7.1Hz, 3H)¹³C NMR(125.7MHz,CDCl₃) δ 164.4 (t, J=36.0Hz), 161.6,127.0 (t, J=6.1Hz), 124.9 (t, J=26.2Hz), 114.0,113.5 (t, J=251.5Hz), 63.0, 55.3,13.8.¹⁹F NMR(376MHz,CDCl₃)δ-102.6(s,2F).

Embodiment 3

Into the reaction tube of 25mL, 122mg (0.9mmol) 2- methylphenylboronic acid is added, (2.5mol% refers to and accounts for 4.4mg The percentage of 2- methylphenylboronic acid mole) Nickelous nitrate hexahydrate, (2.5mol% refers to and accounts for 2- methylphenylboronic acid mole 2.4mg The percentage of amount) bpy (2,2 '-bipyridyl), 166mg (1.2mmol) K₂CO₃, 4mL Isosorbide-5-Nitrae-dioxane, 78 μ L of injection (0.6mmol) Bromodifluoroacetic acid ethyl ester, after stirring 24 hours at 80 DEG C, separation yield is 87% (to use 0.6mmol chlorine difluoroacetic acid When ethyl ester, separation yield is that 65%), purity is greater than 95% through hydrogen spectrum identification.¹H NMR(400MHz,CDCl₃) δ 7.57 (d, J= 7.9Hz, 1H), 7.37 (t, J=7.5Hz, 1H), 7.27 (t, J=7.2Hz, 1H), 7.23 (d, J=7.5Hz, 1H), 4.32 (q, J=7.1Hz, 2H), 2.42 (s, 3H), 1.31 (t, J=7.1Hz, 3H)¹³C NMR(125.7MHz,CDCl₃)δ164.2(t,J =35.1Hz), 136.4 (t, J=3.2Hz), 131.8,131.1 (t, J=23.3Hz), 130.7 (t, J=1.4Hz), 126.1 (t, J=8.8Hz), 125.9,114.2 (t, J=251.6Hz), 63.0,19.6 (t, J=2.7Hz), 13.8.¹⁹F NMR (376MHz,CDCl₃) δ -101.3 (s, 2F) .IR (membrane process) ν_max 2986,1767,1462,1290,1255,1112, 1018cm^-1.MS 214 (M of (EI): m/z (%)⁺), 141 (100) .HRMS:Calculated for (theoretical value) C₁₁H₁₂F₂O₂: 214.0805；Found (measured value): 214.0804.

Embodiment 4

Into the reaction tube of 25mL, 171mg (0.9mmol) 4- trifluoromethylbenzene boronic acid is added, (2.5mol% is 4.4mg Refer to the percentage for accounting for 4- trifluoromethylbenzene boronic acid mole) Nickelous nitrate hexahydrate, (2.5mol% refers to and accounts for 4- fluoroform 2.4mg The percentage of base phenyl boric acid mole) bpy (2,2 '-bipyridyl), 166mg (1.2mmol) K₂CO₃, 4mL Isosorbide-5-Nitrae-dioxane, 78 μ L (0.6mmol) Bromodifluoroacetic acid ethyl esters are injected, after stirring 24 hours at 60 DEG C, separation yield is 74% (with 0.6mmol chlorine When ethyl difluoro, after stirring 24 hours at 80 DEG C, separation yield is that 61%), purity is greater than 95% through hydrogen spectrum identification.¹H NMR(400MHz,CDCl₃) (t, J=7.1Hz, the 3H) of δ 7.83-7.57 (m, 4H), 4.31 (q, J=7.1Hz, 2H), 1.31¹³C NMR(125.7MHz,CDCl₃) δ 163.5 (t, J=34.7Hz), 136.5 (t, J=26.4Hz), 133.1 (q, J=32.8Hz), 126.2 (t, J=6.1Hz), 125.7 (q, J=3.8Hz), 123.5 (q, J=272.5Hz), 112.7 (t, J=253.0Hz), 63.5,13.8.¹⁹F NMR(376MHz,CDCl₃)δ-63.1(s,3F),-104.6(s,2F).

Embodiment 5

Into the reaction tube of 25mL, 171mg (0.9mmol) 3- trifluoromethylbenzene boronic acid is added, (2.5mol% is 4.4mg Refer to the percentage for accounting for 3- trifluoromethylbenzene boronic acid mole) Nickelous nitrate hexahydrate, (2.5mol% refers to and accounts for 3- fluoroform 2.4mg The percentage of base phenyl boric acid mole) bpy (2,2 '-bipyridyl), 166mg (1.2mmol) K₂CO₃, 4mL Isosorbide-5-Nitrae-dioxane, 78 μ L (0.6mmol) Bromodifluoroacetic acid ethyl esters are injected, after stirring 24 hours at 60 DEG C, separation yield is 81% (with 0.6mmol chlorine When ethyl difluoro, after stirring 24 hours at 80 DEG C, separation yield is that 56%), purity is greater than 95% through hydrogen spectrum identification.¹H NMR(400MHz,CDCl₃) δ 7.89 (s, 1H), 7.82 (d, J=7.8Hz, 1H), 7.77 (d, J=7.8Hz, 1H), 7.61 (t, J =7.9Hz, 1H), 4.32 (q, J=7.2Hz, 2H), 1.31 (t, J=7.1Hz, 3H)¹³C NMR(125.7MHz,CDCl₃)δ 163.5 (t, J=34.8Hz), 133.9 (t, J=26.2Hz), 131.3 (q, J=33.0Hz), 129.4,129.0 (tq, J= 6.0Hz, 1.2Hz), 127.8 (m), 113.5 (q, J=272.5Hz), 122.6 (m), 112.6 (t, J=253.0Hz), 63.5, 13.8.¹⁹F NMR(376MHz,CDCl₃) δ -62.9 (s, 3F), -104.2 (s, 2F) .IR (membrane process) ν_max 1771,1623cm^-1.MS 268 (M of (EI): m/z (%)⁺), 195 (100) .HRMS:Calculated for (theoretical value) C₁₁H₉F₅O₂: 2268.0523；Found (measured value): 268.0522.

Embodiment 6

Into the reaction tube of 25mL, 175mg (0.9mmol) 4- carbethoxyl group phenyl boric acid is added, (2.5mol% is 4.4mg Refer to the percentage for accounting for 4- carbethoxyl group phenyl boric acid mole) Nickelous nitrate hexahydrate, (2.5mol% refers to and accounts for 4- ethoxy carbonyl 2.4mg The percentage of base phenyl boric acid mole) bpy (2,2 '-bipyridyl), 166mg (1.2mmol) K₂CO₃, 4mL Isosorbide-5-Nitrae-dioxane, 78 μ L (0.6mmol) Bromodifluoroacetic acid ethyl esters are injected, after stirring 24 hours at 60 DEG C, separation yield is 96% (with 0.6mmol chlorine When ethyl difluoro, after stirring 24 hours at 80 DEG C, separation yield is that 40%), purity is greater than 95% through hydrogen spectrum identification.¹H NMR(400MHz,CDCl₃) δ 8.12 (d, J=8.7Hz, 2H), 7.68 (d, J=8.6Hz, 2H), 4.40 (q, J=7.1Hz, 2H), 4.30 (q, J=7.1Hz, 2H), 1.40 (t, J=7.1Hz, 3H), 1.29 (t, J=7.1Hz, 3H)¹³C NMR (125.7MHz,CDCl₃) δ 165.5,163.5 (t, J=34.8Hz), 136.8 (t, J=25.5Hz), 132.9,129.7, 125.5 (t, J=6.1Hz), 112.9 (t, J=252.7Hz), 63.3,61.3,14.1,13.7.¹⁹F NMR(376MHz, CDCl₃)δ-104.5(s,2F).

Embodiment 7

Into the reaction tube of 25mL, 148mg (0.9mmol) 3- acetylbenzene boric acid is added, (2.5mol% refers to 4.4mg Account for the percentage of 3- acetylbenzene boric acid mole) Nickelous nitrate hexahydrate, (2.5mol% refers to and accounts for 3- acetylbenzene boron 2.4mg The percentage of sour mole) bpy (2,2 '-bipyridyl), 166mg (1.2mmol) K₂CO₃, 4mL1,4- dioxane, 78 μ L of injection (0.6mmol) Bromodifluoroacetic acid ethyl ester, after stirring 24 hours at 80 DEG C, separation yield is 74%, and purity is greater than through hydrogen spectrum identification 95%.¹H NMR(400MHz,CDCl₃) δ 8.19 (s, 1H), 8.09 (d, J=7.8Hz, 1H), 7.81 (d, J=7.8Hz, 1H), 7.58 (t, J=7.8Hz, 1H), 4.31 (q, J=7.1Hz, 2H), 2.64 (s, 3H), 1.31 (t, J=7.1Hz, 3H)¹³C NMR (101MHz,CDCl₃) δ 196.9,163.8 (t, J=35.0Hz), 137.5,133.5 (t, J=26.0Hz), 130.7 (t, J= 1.5Hz), 129.9 (t, J=5.9Hz), 129.1,125.4 (t, J=6.2Hz), 112.9 (t, J=252.9Hz), 63.4, 26.6,13.9.¹⁹F NMR(376MHz,CDCl₃) δ -103.9 (s, 2F) .IR (membrane process) ν_max 1767,1693,1607cm^- ¹.MS 242 (M of (EI): m/z (%)⁺), 169 (100) .HRMS:Calculated for (theoretical value) C₁₂H₁₂F₂O₃:242.0755； Found (measured value): 242.0758.

Embodiment 8

Into the reaction tube of 25mL, 132mg (0.9mmol) 4- cyanophenylboronic acid is added, (2.5mol% refers to and accounts for 4.4mg The percentage of 4- cyanophenylboronic acid mole) Nickelous nitrate hexahydrate, (2.5mol% refers to and accounts for 4- cyanophenylboronic acid mole 2.4mg The percentage of amount) bpy (2,2 '-bipyridyl), 166mg (1.2mmol) K₂CO₃, 4mL Isosorbide-5-Nitrae-dioxane, 78 μ L of injection (0.6mmol) Bromodifluoroacetic acid ethyl ester, after stirring 24 hours at 80 DEG C, separation yield is 56% (to use 0.6mmol chlorine difluoroacetic acid When ethyl ester, separation yield is that 31%), purity is greater than 95% through hydrogen spectrum identification.¹H NMR(400MHz,CDCl₃) δ 7.77 (d, J= 8.4Hz, 2H), 7.74 (d, J=8.4Hz, 2H), 4.31 (q, J=7.1Hz, 2H), 1.31 (t, J=7.1Hz, 3H)¹³C NMR (101MHz,CDCl₃) δ 163.2 (t, J=34.5Hz), 137.1 (t, J=26.0Hz), 132.5,126.4 (t, J=6.2Hz), 117.7,115.1 (t, J=1.9Hz), 112.4 (t, J=253.6Hz), 63.6,13.8.¹⁹F NMR(376MHz,CDCl₃)δ- 104.9 (s, 2F) .IR (membrane process) ν_max 2235,1768cm^-1.MS 225 (M of (EI): m/z (%)⁺),152(100).HRMS: Calculated for (theoretical value) C₁₁H₉F₂NO₂:225.0601；Found (measured value): 225.0602.

Embodiment 9

Into the reaction tube of 25mL, 180mg (0.9mmol) 3- mesyl phenyl boric acid is added, (2.5mol% is 4.4mg Refer to the percentage for accounting for 3- mesyl phenyl boric acid mole) Nickelous nitrate hexahydrate, (2.5mol% refers to and accounts for 3- methylsulfonyl 2.4mg The percentage of base phenyl boric acid mole) bpy (2,2 '-bipyridyl), 166mg (1.2mmol) K₂CO₃, 4mL Isosorbide-5-Nitrae-dioxane, 78 μ L (0.6mmol) Bromodifluoroacetic acid ethyl esters are injected, after stirring 24 hours at 80 DEG C, separation yield is 63%, and purity is composed through hydrogen Identification is greater than 95%.¹H NMR(400MHz,CDCl₃) δ 8.21 (s, 1H), 8.09 (d, J=7.9Hz, 1H), 7.91 (d, J= 7.8Hz, 1H), 7.70 (t, J=7.8Hz, 1H), 4.32 (q, J=7.1Hz, 2H), 3.09 (s, 3H), 1.32 (t, J=7.1Hz, 3H).¹³C NMR(125.7MHz,CDCl₃) δ 163.2 (t, J=34.5Hz), 141.4,134.5 (t, J=26.3Hz), 130.8 (t, J=5.8Hz), 130.0,129.9 (t, J=1.2Hz), 124.7 (t, J=6.3Hz), 112.3 (t, J=253.6Hz), 63.6,44.3,13.8.¹⁹F NMR(376MHz,CDCl₃) δ -103.7 (s, 2F) .IR (membrane process) ν_max 1767,1322, 1306,1262,1151,1090,1024cm^-1.MS 278 (M of (EI): m/z (%)⁺),126(100),205,206.HRMS: Calculated for (theoretical value) C₁₁H₁₂F₂O₄S:278.0424；Found (measured value): 278.0423.

Embodiment 10

Into the reaction tube of 25mL, 126mg (0.9mmol) 4- fluorobenzoic boric acid is added, (2.5mol% refers to and accounts for 4- 4.4mg The percentage of fluorobenzoic boric acid mole) Nickelous nitrate hexahydrate, (2.5mol% refers to and accounts for the hundred of 4- fluorobenzoic boric acid mole 2.4mg Divide ratio) bpy (2,2 '-bipyridyl), 166mg (1.2mmol) K₂CO₃, 4mL Isosorbide-5-Nitrae-dioxane, 78 μ L (0.6mmol) bromines of injection Ethyl difluoro, after stirring 24 hours at 80 DEG C, separation yield is 60%, and purity is greater than 95% through hydrogen spectrum identification.¹H NMR (400MHz,CDCl₃) δ 7.61 (dd, J=8.8Hz, 5.2Hz, 2H), 7.14 (t, J=8.8Hz, 2H), 4.30 (q, J= 7.1Hz, 2H), 1.31 (t, J=7.1Hz, 3H)¹³C NMR(125.7MHz,CDCl₃) δ 164.3 (dt, J=251.1Hz, 1.9Hz), 164.0 (t, J=35.4Hz), 128.9 (td, J=26.2Hz, 3.2Hz), 127.8 (dt, J=9.0Hz, 6.2Hz), 115.8 (d, J=22.2Hz), 113.0 (t, J=252.3Hz), 63.2,13.8.¹⁹F NMR(376MHz,CDCl₃)δ-103.1 (d, J=2.5Hz, 2F), -109.1 (m, 1F) .IR (membrane process) ν_max 1767,1609cm^-1.MS 218 (M of (EI): m/z (%)⁺), 145 (100) .HRMS:Calculated for (theoretical value) C₁₀H₉F₃O₂:218.0555；Found (measured value): 218.0554.

Embodiment 11

Into the reaction tube of 25mL, 180mg (0.9mmol) 4- bromobenzeneboronic acid is added, (2.5mol% refers to and accounts for 4- 4.4mg The percentage of bromobenzeneboronic acid mole) Nickelous nitrate hexahydrate, (2.5mol% refers to and accounts for the hundred of 4- bromobenzeneboronic acid mole 2.4mg Divide ratio) bpy (2,2 '-bipyridyl), 166mg (1.2mmol) K₂CO₃, 4mL Isosorbide-5-Nitrae-dioxane, 78 μ L (0.6mmol) bromines of injection Ethyl difluoro, after stirring 24 hours at 60 DEG C, separation yield is 95%, and purity is greater than 95% through hydrogen spectrum identification.¹H NMR (400MHz,CDCl₃) δ 7.60 (d, J=8.8Hz, 2H), 7.48 (d, J=8.7Hz, 2H), 4.30 (q, J=7.1Hz, 2H), 1.30 (t, J=7.1Hz, 3H)¹³C NMR(125.7MHz,CDCl₃) δ 163.7 (t, J=35.2Hz), 131.9,131.8 (t, J =26.0Hz), 127.1 (t, J=6.1Hz), 125.6 (t, J=2.2Hz), 113.0 (t, J=252.6Hz), 63.3, 13.8.¹⁹F NMR(376MHz,CDCl₃) δ -104.1 (s, 2F) .IR (membrane process) ν_max 1767,1597,1489cm^-1.MS (EI): 278 (M of m/z (%)⁺), 207,205 (100) .HRMS:Calculated for (theoretical value) C₁₀H₉BrF₂O₂: 277.9754；Found (measured value): 277.9750.

Embodiment 12

Into the reaction tube of 25mL, 189mg (0.9mmol) 4- bromomethyl benzene boric acid is added, (2.5mol% refers to 4.4mg Account for the percentage of 4- bromomethyl benzene boric acid mole) Nickelous nitrate hexahydrate, (2.5mol% refers to and accounts for 4- bromomethyl benzene boron 2.4mg The percentage of sour mole) bpy (2,2 '-bipyridyl), 166mg (1.2mmol) K₂CO₃, 4mL1,4- dioxane, 78 μ L of injection (0.6mmol) Bromodifluoroacetic acid ethyl ester, after stirring 24 hours at 80 DEG C, separation yield is 58%, and purity is greater than through hydrogen spectrum identification 95%.¹H NMR(400MHz,CDCl₃) δ 7.59 (d, J=8.3Hz, 2H), 7.48 (d, J=8.2Hz, 2H), 4.49 (s, 2H), 4.30 (q, J=7.1Hz, 2H), 1.31 (t, J=7.1Hz, 3H)¹³C NMR(125.7MHz,CDCl₃) δ 163.9 (t, J= 35.1Hz), 140.7,132.8 (t, J=25.7Hz), 129.3,126.0 (t, J=6.1Hz), 113.1 (t, J=252.3Hz), 63.2,32.1,13.8.¹⁹F NMR(376MHz,CDCl₃) δ -103.9 (s, 2F) .IR (membrane process) ν_max 2985,1766, 1268,1104cm^-1.MS 292 (M of (EI): m/z (%)⁺),294(M⁺),140(100),213.HRMS:Calculated for (theoretical value) C₁₁H₁₁BrF₂O₂:291.9910；Found (measured value): 291.9914.

Embodiment 13

Into the reaction tube of 25mL, 110mg (0.9mmol) phenyl boric acid is added, (2.5mol% refers to and accounts for phenyl boric acid 4.4mg The percentage of mole) Nickelous nitrate hexahydrate, 2.4mg (2.5mol% refers to the percentage for accounting for phenyl boric acid mole) bpy (2, 2 '-bipyridyls), 166mg (1.2mmol) K₂CO₃, 4mL Isosorbide-5-Nitrae-dioxane, the injection fluoro- 2- of 146mg (0.6mmol) 2,2- bis- Bromo- 1- morpholinyl ethyl ketone, after stirring 24 hours at 80 DEG C, separation yield is that 73% (when using 0.6mmol chloro thing, yield is 85%), purity is greater than 95% through hydrogen spectrum identification.Fusing point: 105 DEG C of¹H NMR(400MHz,CDCl₃)δ7.56-7.53(m,2H), 7.50-7.46(m,3H),3.70(s,4H),3.47(s,4H).¹³C NMR(125.7MHz,CDCl₃) δ 162.0 (t, J= 30.3Hz), 133.4 (t, J=24.9Hz), 130.9 (t, J=1.8Hz), 128.8,125.1 (t, J=5.7Hz), 115.5 (t, ), J=250.7Hz 66.6,66.3,46.6,43.4.¹⁹F NMR(376MHz,CDCl₃) δ -94.8 (s, 2F) .IR (KBr tabletting) ν_max 2933,2870,1656,1449,1251,1111,1045,987cm^-1.MS 241 (M of (EI): m/z (%)⁺),114(100), 127.HRMS:Calculated for (theoretical value) C₁₂H₁₃F₂NO₂:241.0914；Found (measured value): 241.0917.

Embodiment 14

Into the reaction tube of 25mL, 110mg (0.9mmol) phenyl boric acid is added, (2.5mol% refers to and accounts for phenyl boric acid 4.4mg The percentage of mole) Nickelous nitrate hexahydrate, 2.4mg (2.5mol% refers to the percentage for accounting for phenyl boric acid mole) bpy (2, 2 '-bipyridyls), 166mg (1.2mmol) K₂CO₃, 4mL Isosorbide-5-Nitrae-dioxane, the injection fluoro- 2- of 149mg (0.6mmol) 2,2- bis- Bromo- phenyl acetanilide,Phenacetylaniline, after stirring 24 hours at 80 DEG C, separation yield is 88%, and purity is greater than 95% through hydrogen spectrum identification.It is molten Point: 98 DEG C of¹H NMR(400MHz,CDCl₃) δ 8.14 (s, 1H), 7.69 (d, J=6.9Hz, 2H), 7.58 (d, J=7.7Hz, 2H), 7.54-7.43 (m, 3H), 7.36 (t, J=7.9Hz, 2H), 7.19 (t, J=7.4Hz, 1H)¹³C NMR(101MHz, CDCl₃) δ 161.8 (t, J=31.3Hz), 136.0 (s), 132.6 (t, J=25.5Hz), 131.1 (t, J=1.8Hz), 129.2 (s), 128.6 (s), 125.6 (s), 125.5 (t, J=6.1Hz), 120.17-120.14 (m), 114.7 (t, J=254.3Hz) .¹⁹F NMR(376MHz,CDCl₃) δ -102.3 (s, 2F) .IR (KBr tabletting) max 3336,1694,1600,1533,1445cm^-1.MS 247 (M of (EI): m/z (%)⁺), 127,120 (100) .HRMS:Calculated for (theoretical value) C₁₄H₁₁F₂NO: 247.0809；Found (measured value): 247.0811.

Embodiment 15

Into the reaction tube of 25mL, 110mg (0.9mmol) phenyl boric acid is added, (2.5mol% refers to and accounts for phenyl boric acid 4.4mg The percentage of mole) Nickelous nitrate hexahydrate, 2.4mg (2.5mol% refers to the percentage for accounting for phenyl boric acid mole) bpy (2, 2 '-bipyridyls), 166mg (1.2mmol) K₂CO₃, 4mL Isosorbide-5-Nitrae-dioxane, the injection fluoro- 2- of 140mg (0.6mmol) 2,2- bis- Bromoacetophenone, after stirring 24 hours at 80 DEG C, separation yield is 93% (when using 0.6mmol chloro thing, yield 65%), purity It is greater than 95% through hydrogen spectrum identification.¹H NMR(400MHz,CDCl₃) δ 8.03 (d, J=7.5Hz, 2H), 7.65-7.56 (m, 3H), 7.51–7.40(m,5H).¹³C NMR(125.7MHz,CDCl₃) δ 189.0 (t, J=31.0Hz), 134.2,133.1 (t, J= 25.0Hz), 132.2 (t, J=1.3Hz), 130.9 (t, J=1.8Hz), 130.3 (t, J=3.0Hz), 128.8,128.6, 125.6 (t, J=6.0Hz), 116.9 (t, J=253.2Hz)¹⁹F NMR(376MHz,CDCl₃)δ-97.6(s,2F).

Embodiment 16

Into the reaction tube of 25mL, 137mg (0.9mmol) 4- methoxyphenylboronic acid is added, (2.5mol% refers to and accounts for 4- The percentage of methoxyphenylboronic acid mole) NiCl₂(dppe), (2.5mol% refers to that accounting for 4- methoxyphenylboronic acid rubs to 2.4mg The percentage of your amount) bpy (2,2 '-bipyridyl), 166mg (1.2mmol) K₂CO₃, 4mL Isosorbide-5-Nitrae-dioxane, injection 140mg The bis- bromo- 1- Phenyl ethyl ketone of fluoro- 2- of (0.6mmol) 2,2-, after stirring 24 hours at 80 DEG C, separation yield is 52%, and purity is through hydrogen Spectrum identification is greater than 95%.¹H NMR(400MHz,CDCl₃) δ 8.02 (d, J=7.6Hz, 2H), 7.58 (tt, J=7.4Hz, 1.5Hz, 1H), 7.54 (d, J=8.9Hz, 2H), 7.44 (t, J=7.8Hz, 2H), 6.96 (d, J=8.9Hz, 2H), 3.83 (s, 3H).¹³C NMR(101MHz,CDCl₃) δ 189.1 (t, J=31.4Hz), 161.4 (t, J=1.7Hz), 134.1,132.1 (t, J =1.2Hz), 130.2 (t, J=2.9Hz), 128.6,127.2 (t, J=5.9Hz), 125.1 (t, J=25.7Hz), 117.0 (t, J=252.4Hz), 114.2,55.3.¹⁹F NMR(376MHz,CDCl₃)δ-96.2(s,2F).

Embodiment 17

Into the reaction tube of 25mL, 110mg (0.9mmol) phenyl boric acid is added, (2.5mol% refers to and accounts for phenyl boric acid 4.4mg The percentage of mole) Nickelous nitrate hexahydrate, 2.4mg (2.5mol% refers to the percentage for accounting for phenyl boric acid mole) bpy (2, 2 '-bipyridyls), 166mg (1.2mmol) K₂CO₃, 4mL Isosorbide-5-Nitrae-dioxane, the injection fluoro- 2- of 181mg (0.6mmol) 2,2- bis- Bromo- 1- (4- trifluoromethyl) ethyl ketone, after stirring 24 hours at 80 DEG C, separation yield is 73%, and purity is big through hydrogen spectrum identification In 95%.¹H NMR(400MHz,CDCl₃) δ 8.14 (d, J=8.2Hz, 2H), 7.72 (d, J=8.4Hz, 2H), 7.61 (d, J= 6.6Hz,2H),7.54–7.44(m,3H).¹³C NMR(125.7MHz,CDCl₃) δ 188.2 (t, J=32.1Hz), 135.3 (q, J =32.9Hz), 134.9,132.4 (t, J=24.9Hz), 131.2 (t, J=1.8Hz), 130.5 (t, J=3.0Hz), 129.0, 125.7 (q, J=3.5Hz), 125.6 (t, J=6.0Hz), 123.3 (q, J=272.9Hz), 116.8 (t, J=253.4Hz) .¹⁹F NMR(376MHz,CDCl₃) δ -63.5 (s, 3F), -98.1 (s, 2F) .IR (membrane process) ν_max 1716,1454,1412, 1328,1257,1174,1135,1069,901cm^-1.MS 300 (M of (EI): m/z (%)⁺),173(100).HRMS: Calculated for (theoretical value) C₁₅H₉F₅O:300.0574；Found (measured value): 300.0576.

Embodiment 18

Into the reaction tube of 25mL, 110mg (0.9mmol) phenyl boric acid is added, (2.5mol% refers to and accounts for phenyl boric acid 4.4mg The percentage of mole) Nickelous nitrate hexahydrate, 2.4mg (2.5mol% refers to the percentage for accounting for phenyl boric acid mole) bpy (2, 2 '-bipyridyls), 166mg (1.2mmol) K₂CO₃, 4mL Isosorbide-5-Nitrae-dioxane, the injection fluoro- 1- of 157mg (0.6mmol) 1,1- bis- Bromo- 4- phenyl butyl- 2- ketone, after stirring 24 hours at 80 DEG C, separation yield is 93%, and purity is greater than 95% through hydrogen spectrum identification.¹H NMR(400MHz,CDCl₃)δ7.53–7.46(m,3H),7.43(m,2H),7.25(m,2H),7.19(m,1H),7.12(m, 2H), 3.00 (t, J=6.9Hz, 2H), 2.90 (t, J=7.1Hz, 2H)¹³C NMR(125.7MHz,CDCl₃)δ199.0(t,J =31.9Hz), 139.9,131.8 (t, J=25.4Hz), 130.9 (t, J=1.6Hz), 128.7,128.5,128.2,126.3, 125.4 (t, J=6.3Hz), 115.9 (t, J=254.2Hz), 38.0,28.7.¹⁹F NMR(376MHz,CDCl₃)δ-106.7 (s, 2F) .IR (membrane process) ν_max3065,3030,2931,1746,1497,1453,1262,1126,1057,745,698cm^- ¹.MS 260 (M of (EI): m/z (%)⁺), 133,127,105 (100), 91.HRMS:Calculated for (theoretical value) C₁₆H₁₄F₂O:260.1013；Found (measured value): 260.1008.

Embodiment 19

Into the reaction tube of 25mL, 110mg (0.9mmol) phenyl boric acid is added, (5mol% refers to that accounting for phenyl boric acid rubs to 8.8mg The percentage of your amount) Nickelous nitrate hexahydrate, 4.8mg (5mol% refers to the percentage for accounting for phenyl boric acid mole) bpy (2,2 '-connection Pyridine), 166mg (1.2mmol) K₂CO₃, 4mL Isosorbide-5-Nitrae-dioxane, injection 148mg (0.6mmol) 2- bromine difluoro methyl benzo Oxazole, after stirring 24 hours at 80 DEG C, separation yield is that 87% (when using 0.6mmol chloro thing, separation yield is 88%) purity It is greater than 95% through hydrogen spectrum identification.¹H NMR(400MHz,CDCl₃) δ 7.84-7.80 (m, 1H), 7.73 (dd, J=5.9Hz, 2Hz, 2H),7.62–7.58(m,1H),7.56–7.47(m,3H),7.47–7.36(m,2H).¹³C NMR(125.7MHz,CDCl₃)δ 158.4 (t, J=36.8Hz), 150.7,140.0,133.5 (t, J=26.0Hz), 131.1 (t, J=1.7Hz), 128.7, 126.7,125.6 (t, J=5.9Hz), 125.2,121.3,114.4 (t, J=243.8Hz), 111.3.¹⁹F NMR(376MHz, CDCl₃)δ-95.4(s,2F).

Embodiment 20

Into the reaction tube of 25mL, 164mg (0.9mmol) 3,5- dimethoxyphenylboronic is added, (5mol% is 8.8mg Refer to the percentage for accounting for 3,5- dimethoxyphenylboronic mole) Nickelous nitrate hexahydrate, (5mol% refers to and accounts for 3,5- diformazan 4.8mg The percentage of oxygroup phenyl boric acid mole) bpy (2,2 '-bipyridyl), 166mg (1.2mmol) K₂CO₃, 4mL Isosorbide-5-Nitrae-dioxy six Ring injects 148mg (0.6mmol) 2- bromine difluoro methyl benzoxazoles, and after stirring 24 hours at 80 DEG C, separation yield is 73% (when using 0.6mmol chloro thing, separation yield is that 84%), purity is greater than 95% through hydrogen spectrum identification.Fusing point: 66 DEG C of¹H NMR (400MHz,CDCl₃) δ 7.81 (m, 1H), 7.57 (m, 1H), 7.40 (m, 1H), 6.85 (d, J=2.2Hz, 2H), 6.57 (t, J =2.1Hz, 1H), 3.80 (s, 6H)¹³C NMR(125.7MHz,CDCl₃) δ 160.9,158.3 (t, J=36.8Hz), 150.7, 140.0,135.4 (t, J=26.2Hz), 126.7,125.2,121.3,114.1 (t, J=244.6Hz), 111.3,103.7 (t, ), J=6.1Hz 103.0,55.4.19F NMR (376MHz, CDCl₃) δ -95.7 (s, 2F) .IR (KBr tabletting) ν_max 3006, 2941,2842,1601,1453,1430,1353,1335,1310,1291,1238,1207,1159,1092,1055,1014, 932,889,846cm^-1.MS 305 (M of (EI): m/z (%)⁺), 187 (100) .HRMS:Calculated for (theoretical value) C₁₆H₁₃F₂NO₃:305.0863；Found (measured value): 305.0862.

Embodiment 21

Into the reaction tube of 25mL, 160mg (0.9mmol) 4- tert-butylbenzeneboronic acid is added, (5mol% refers to and accounts for 8.8mg The percentage of 4- tert-butylbenzeneboronic acid mole) Nickelous nitrate hexahydrate, (5mol% refers to that accounting for 4- tert-butylbenzeneboronic acid rubs to 4.8mg The percentage of your amount) bpy (2,2 '-bipyridyl), 166mg (1.2mmol) K₂CO₃, 4mL1,4- dioxane, injection 148mg (0.6mmol) 2- bromine difluoro methyl benzoxazoles, after stirring 24 hours at 80 DEG C, separation yield is 83% (to use 0.6mmol chloro When object, separation yield is that 94%), purity is greater than 95% through hydrogen spectrum identification.Fusing point: 58 DEG C of¹H NMR(400MHz,CDCl₃)δ 7.82 (dd, J=6.9Hz, 1.2Hz, 1H), 7.66 (d, J=7.6Hz, 2H), 7.59 (d, J=7.5Hz, 1H), 7.52 (d, J= 8.3Hz,2H),7.46–7.36(m,2H),1.34(s,9H).¹³C NMR(101MHz,CDCl₃) δ 158.7 (t, J=37.1Hz), (154.4,150.7,140.1,130.6 t, J=26.2Hz), 126.7,125.7,125.4 (t, J=5.8Hz), 125.2, (121.3,114.6 t, J=243.4Hz), 111.3,34.9,31.1.¹⁹F NMR(376MHz,CDCl₃) δ -94.8 (d, J= 5.1Hz, 2F) .IR (KBr tabletting) ν_max 2966,1614,1454,1293,1266,1238,1112,1080,984cm^-1.MS (EI): 301 (M of m/z (%)⁺), 286 (100) .HRMS:Calculated for (theoretical value) C₁₈H₁₇F₂NO₂:301.1278； Found (measured value): 301.1277.

Embodiment 22

Into the reaction tube of 25mL, 175mg (0.9mmol) 4- carbethoxyl group phenyl boric acid is added, (5mol% refers to 8.8mg Account for the percentage of 4- carbethoxyl group phenyl boric acid mole) Nickelous nitrate hexahydrate, (5mol% refers to and accounts for 4- carbethoxyl group benzene 4.8mg The percentage of boric acid mole) bpy (2,2 '-bipyridyl), 166mg (1.2mmol) K₂CO₃, 4mL Isosorbide-5-Nitrae-dioxane, injection 148mg (0.6mmol) 2- bromine difluoro methyl benzoxazoles, after stirring 24 hours at 80 DEG C, separation yield is 62% (to use When 0.6mmol chloro thing, separation yield is that 95%), purity is greater than 95% through hydrogen spectrum identification.55 DEG C of of fusing point¹H NMR (400MHz,CDCl₃) δ 8.17 (d, J=8.2Hz, 2H), 7.80 (d, J=8.3Hz, 3H), 7.59 (d, J=7.8Hz, 1H), 7.46-7.33 (m, 2H), 4.40 (q, J=7.1Hz, 2H), 1.40 (t, J=7.1Hz, 3H)¹³C NMR(101MHz,CDCl₃)δ 165.5,157.8 (t, J=36.3Hz), 150.7,139.9,137.5 (t, J=26.0Hz), 133.0 (t, J=1.6Hz), (129.9,126.9,125.8 t, J=5.8Hz), 125.3,121.4,114.0 (t, J=244.4Hz), 111.3,61.4, 14.2.¹⁹F NMR(376MHz,CDCl₃) δ -96.0 (s, 2F) .IR (KBr tabletting) max 1715,1453,1276,1101, 1077,1003cm^-1.MS 317 (M of (EI): m/z (%)⁺), 199 (100) .HRMS:Calculated for (theoretical value) C₁₇H₁₃F₂NO₃:317.0863；Found (measured value): 317.0862.

Embodiment 23

Into the reaction tube of 25mL, 148mg (0.9mmol) 4- acetylbenzene boric acid is added, (5mol% refers to and accounts for 8.8mg The percentage of 4- acetylbenzene boric acid mole) Nickelous nitrate hexahydrate, (5mol% refers to that accounting for 4- acetylbenzene boric acid rubs to 4.8mg The percentage of your amount) bpy (2,2 '-bipyridyl), 166mg (1.2mmol) K₂CO₃, 4mL1,4- dioxane, injection 148mg (0.6mmol) 2- bromine difluoro methyl benzoxazoles, after stirring 24 hours at 80 DEG C, separation yield is 87% (to use 0.6mmol chloro When object, separation yield is that 86%), purity is greater than 95% through hydrogen spectrum identification.Fusing point: 78 DEG C of¹H NMR(400MHz,CDCl₃)δ 8.07 (d, J=7.4Hz, 2H), 7.83 (d, J=7.0Hz, 2H), 7.79 (dd, J=8.8Hz, 1.2Hz, 1H), 7.59 (dd, J =7.8Hz, 1.7Hz, 1H), 7.48-7.36 (m, 2H), 2.63 (m, 3H)¹³C NMR(125.7MHz,CDCl₃)δ197.0, 157.7 (t, J=36.2Hz), 150.7,139.9,139.1,137.6 (t, J=26.0Hz), 128.6,127.0,126.1 (t, J =5.7Hz), 125.4,121.4,113.9 (t, J=244.3Hz), 111.3,26.7.¹⁹F NMR(376MHz,CDCl₃)δ- 96.0 (d, J=10.9Hz, 2F) .IR (KBr tabletting) max 3071,1670,1610,1452,1265,1078cm^-1.MS(EI): 287 (M of m/z (%)⁺), 272 (100) .HRMS:Calculated for (theoretical value) C₁₆H₁₁F₂NO₂:287.0758；Found (measured value): 287.0754.

Embodiment 24

Into the reaction tube of 25mL, 171mg (0.9mmol) 4- trifluoromethylbenzene boronic acid is added, (5mol% refers to 8.8mg Account for the percentage of 4- trifluoromethylbenzene boronic acid mole) Nickelous nitrate hexahydrate, (5mol% refers to and accounts for 4- trifluoromethylbenzene 4.8mg The percentage of boric acid mole) bpy (2,2 '-bipyridyl), 166mg (1.2mmol) K₂CO₃, 4mL Isosorbide-5-Nitrae-dioxane, injection 148mg (0.6mmol) 2- bromine difluoro methyl benzoxazoles, after stirring 24 hours at 80 DEG C, separation yield is 93% (to use When 0.6mmol chloro thing, separation yield is that 87%), purity is greater than 95% through hydrogen spectrum identification.Fusing point: 66 DEG C of¹H NMR (400MHz,CDCl₃) δ 7.88 (d, J=8.2Hz, 2H), 7.82 (d, J=7.7Hz, 1H), 7.78 (d, J=8.0Hz, 2H), 7.61 (d, J=8.0Hz, 1H), 7.49-7.37 (m, 2H)¹³C NMR(125.7MHz,CDCl₃) δ 157.7 (t, J= 36.1Hz), 150.8,139.9,137.1 (t, J=26.3Hz), 133.2 (q, J=32.9Hz), 127.1,126.4 (t, J= 5.8Hz), 125.8 (q, J=3.7Hz), 125.4,123.5 (q, J=272.5Hz), 121.5,113.8 (t, J=244.4Hz), 111.4.¹⁹F NMR(376MHz,CDCl₃) δ -63.1 (s, 3F), -95.9 (s, 2F) .IR (KBr tabletting) max 1616,1452, 1412,1324,1254,1180,1085cm^-1.MS 313 (M of (EI): m/z (%)⁺),195(100),145.HRMS: Calculated for (theoretical value) C₁₅H₈F₅NO:313.0526；Found (measured value): 313.0529.

Embodiment 25

Into the reaction tube of 25mL, 180mg (0.9mmol) 3- bromobenzeneboronic acid phenyl boric acid is added, (5mol% refers to 8.8mg Account for the percentage of 3- bromobenzeneboronic acid mole) Nickelous nitrate hexahydrate, (5mol% refers to and accounts for 3- bromobenzeneboronic acid mole 4.8mg Percentage) bpy (2,2 '-bipyridyl), 166mg (1.2mmol) K₂CO₃, 4mL Isosorbide-5-Nitrae-dioxane, injection 148mg (0.6mmol) 2- bromine difluoro methyl benzoxazoles, after stirring 24 hours at 80 DEG C, separation yield is 68%, and purity is composed through hydrogen and reflected Surely it is greater than 95%.Fusing point: 62 DEG C of¹H NMR(400MHz,CDCl₃) δ 7.88 (s, 1H), 7.82 (dd, J=7.0Hz, 1.0Hz, 1H), 7.66 (d, J=7.9Hz, 2H), 7.61 (d, J=7.7Hz, 1H), 7.46 (td, J=7.8Hz, 1.4Hz, 1H), 7.42 (dd, J=7.7Hz, 1.3Hz, 1H), 7.38 (t, J=7.6Hz, 1H)¹³C NMR(125.7MHz,CDCl₃) δ 157.8 (t, J= 36.5Hz), 150.7,140.0,135.5 (t, J=26.4Hz), 134.3,130.3,128.9 (t, J=6.0Hz), 126.9, 125.4,124.4 (t, J=5.8Hz), 122.8,121.4,113.5 (t, J=244.8Hz), 111.4.¹⁹F NMR(376MHz, CDCl₃) δ -95.6 (s, 2F) .IR (KBr tabletting) ν_max 3072,1617,1573,1476,1449,1424,1348,1252, 1130,1108,1070,1004cm^-1.MS 323 (M of (EI): m/z (%)⁺),325(M⁺),205,207(100).HRMS: Calculated for (theoretical value) C₁₄H₈BrF₂NO:322.9757；Found (measured value): 322.9760.

Embodiment 26

Into the reaction tube of 25mL, 110mg (0.9mmol) phenyl boric acid is added, (5mol% refers to that accounting for phenyl boric acid rubs to 8.8mg The percentage of your amount) Nickelous nitrate hexahydrate, 4.8mg (5mol% refers to the percentage for accounting for phenyl boric acid mole) bpy (2,2 '-connection Pyridine), 166mg (1.2mmol) K₂CO₃, 4mL Isosorbide-5-Nitrae-dioxane, injection 145mg (0.6mmol) 2- bromine difluoro methyl -4,5- Dimethyl-benzothiazole, after stirring 24 hours at 80 DEG C, separation yield is 85%, and purity is greater than 95% through hydrogen spectrum identification.¹H NMR(400MHz,CDCl₃)δ7.64(m,2H),7.52–7.34(m,3H),2.37(s,3H),2.33(s,3H).¹³C NMR (101MHz,CDCl₃) δ 159.3 (t, J=36.1Hz), 149.7,135.5 (t, J=27.2Hz), 130.3 (t, J=1.7Hz), 129.2 (t, J=1.2Hz), 128.3,125.7 (t, J=5.7Hz), 117.1 (t, J=241.9Hz), 14.6,11.1.¹⁹F NMR(376MHz,CDCl₃) δ -85.5 (s, 2F) .IR (membrane process) max 3419,1548,1452,1273,1215,1047, 903cm^-1.MS 239 (M of (EI): m/z (%)⁺, 100), 127.HRMS:Calculated for (theoretical value) C₁₂H₁₁F₂NS: 239.0580；Found (measured value): 239.0582.

Embodiment 27

Into the reaction tube of 25mL, 110mg (0.9mmol) phenyl boric acid is added, (5mol% refers to that accounting for phenyl boric acid rubs to 8.8mg The percentage of your amount) Nickelous nitrate hexahydrate, 4.8mg (5mol% refers to the percentage for accounting for phenyl boric acid mole) bpy (2,2 '-connection Pyridine), 166mg (1.2mmol) K₂CO₃, 4mL Isosorbide-5-Nitrae-dioxane, injection 156mg (0.6mmol) 2- bromine difluoro methyl -1- first Base -1H- benzimidazole, after stirring 24 hours at 80 DEG C, separation yield is 69%, and purity is greater than 95% through hydrogen spectrum identification.It (uses When 0.6mmol chloro thing, 77%) separation yield is.¹H NMR(400MHz,CDCl₃) δ 7.86 (d, J=8.0Hz, 1H), 7.65 (d, J=6.5Hz, 2H), 7.55-7.45 (m, 3H), 7.38 (m, 2H), 7.34-7.30 (m, 1H), 3.86 (s, 3H)¹³C NMR (101MHz,CDCl₃) δ 147.2 (t, J=33.0Hz), 141.2,136.3,134.4 (t, J=25.7Hz), 130.7 (t, J= 1.9Hz), 128.5,125.9 (t, J=5.6Hz), 124.2,122.7,121.1,117.1 (t, J=240.0Hz), 109.7, 30.9.¹⁹F NMR(376MHz,CDCl₃) δ -89.0 (s, 2F) .IR (membrane process) max 3055,1474,1395,1274,1249, 1073,1016,967,761,745cm^-1.MS 258 (M of (EI): m/z (%)⁺),257(M⁺-1,100),127.HRMS: Calculated for (theoretical value) C₁₅H₁₂F₂N₂:258.0969；Found (measured value): 258.0968.

Embodiment 28

Into the reaction tube of 25mL, 107mg (0.4mmol) flavones phenyl boric acid is added, (5mol% refers to and accounts for brass boric acid The percentage of mole) Nickelous nitrate hexahydrate, (5mol% refers to the percentage for accounting for brass boric acid mole) bpy (2,2 '-connection Pyridine), 48mg (0.4mmol) K₂CO₃, 2mL Isosorbide-5-Nitrae-dioxane, 26 μ L (0.2mmol) Bromodifluoroacetic acid ethyl esters of injection, 80 DEG C After lower stirring 24 hours, separation yield is 53%, and purity is greater than 95% through hydrogen spectrum identification.¹H NMR(400MHz,CDCl₃)δ7.93 (dd, J=7.8Hz, 1.7Hz, 1H), 7.69 (d, J=8.3Hz, 2H), 7.59 (d, J=8.3Hz, 2H), 7.56-7.49 (m, 1H), 7.10-7.05 (m, 2H), 5.54 (dd, J=13.1Hz, 3.0Hz, 1H), 4.31 (q, J=7.1Hz, 2H), 3.05 (dd, J =16.9Hz, 13.1Hz, 1H), 2.91 (dd, J=16.9Hz, 3.1Hz, 1H), 1.32 (t, J=7.1Hz, 3H)¹³C NMR (101MHz,CDCl₃) δ 191.3,164.0 (t, J=35.1Hz), 161.2,141.8 (t, J=1.7Hz), 136.3,133.1 (t, J=25.8Hz), 127.1,126.3,126.1 (t, J=6.1Hz), 121.9,120.8,118.0,113.1 (t, J= 252.3Hz),78.6,63.3,44.6,13.9.¹⁹F NMR(376MHz,CDCl₃) δ -103.9 (d, J=3.0Hz) .IR (film Method) max 2985,1765,1694,1607,1465,1305cm^-1.MS 346 (M of (EI): m/z (%)⁺),120(100).HRMS: Calculated for (theoretical value) C₁₉H₁₆F₂O₄:346.1017；Found (measured value): 346.1020.

Embodiment 29

Into the reaction tube of 25mL, 107mg (0.4mmol) flavones phenyl boric acid is added, (5mol% refers to and accounts for brass boric acid The percentage of mole) Nickelous nitrate hexahydrate, (5mol% refers to the percentage for accounting for brass boric acid mole) bpy (2,2 '-connection Pyridine), 48mg (0.4mmol) K₂CO₃, 2mL Isosorbide-5-Nitrae-dioxane, injection 49mg (0.2mmol) 2- bromine difluoro methyl benzo evil Azoles, after stirring 24 hours at 80 DEG C, separation yield is 65%, and purity is greater than 95% through hydrogen spectrum identification.¹H NMR(400MHz, CDCl₃) δ 7.94 (dd, J=8.1Hz, 1.4Hz, 1H), 7.86-7.77 (m, 3H), 7.63 (d, J=8.2Hz, 2H), 7.61- 7.57 (m, 1H), 7.54-7.50 (m, 1H), 7.45 (td, J=7.6Hz, 1.2Hz, 1H), 7.40 (td, J=7.6Hz, 1.2Hz, 1H), 7.09-7.05 (m, 2H), 5.55 (dd, J=13.1Hz, 2.9Hz, 1H), 3.06 (dd, J=16.8Hz, 13.1Hz, 1H), 2.92 (dd, J=16.9Hz, 3.1Hz, 1H)¹³C NMR(125.7MHz,CDCl₃) δ 191.2,161.2,158.2 (t, J= 36.7Hz), 150.7,141.9 (t, J=1.7Hz), 140.0,136.3,133.9 (t, J=26.2Hz), 127.1,126.9, 126.4,126.3 (t, J=5.8Hz), 125.3,121.9,121.4,120.9,118.0,114.2 (t, J=244.0Hz), 111.3,78.8,44.6.¹⁹F NMR(376MHz,CDCl₃) δ -95.3 (s, 2F) .IR (membrane process) max 2926,1694, 1607,1464,1306cm^-1.MS 391 (M of (EI): m/z (%)⁺), 153,120 (100) .HRMS:Calculated for are (theoretical Value) C₂₃H₁₅F₂NO₃:391.1020；Found (measured value): 391.1022.

Embodiment 30

Into the reaction tube of 25mL, 134mg (0.45mmol) oestrone boric acid is added, (5mol% refers to and accounts for oestrone phenyl boric acid The percentage of mole) Nickelous nitrate hexahydrate, (5mol% refers to the percentage for accounting for oestrone phenyl boric acid mole) bpy (2,2 '- Bipyridyl), 83mg (0.6mmol) K₂CO₃, 2mL Isosorbide-5-Nitrae-dioxane, injection 74mg (0.3mmol) 2- bromine difluoro methyl benzo Oxazole, after stirring 24 hours at 80 DEG C, separation yield is 56%, and purity is greater than 95% through hydrogen spectrum identification.¹H NMR(400MHz, CDCl₃) δ 7.81 (d, J=7.5Hz, 1H), 7.59 (d, J=8.0Hz, 1H), 7.52-7.35 (m, 5H), 2.97 (m, 2H), 2.62–2.39(m,2H),2.33(s,1H),2.24–1.92(m,4H),1.73–1.36(m,6H),0.90(s,3H).¹³C NMR (101MHz,CDCl₃) δ 220.6,158.6 (t, J=37.1Hz), 150.6,143.0,139.9,137.2,130.8 (t, J= 26.0Hz), 126.7,126.0 (t, J=5.6Hz), 125.8,125.2,122.9 (t, J=5.7Hz), 121.3,114.4 (t, J =243.4Hz), 111.3,50.3,47.8,44.3,37.7,35.7,31.4,29.3,26.1,25.5,21.5,13.7.¹⁹F NMR(376MHz,CDCl₃) δ -94.9 (s, 2F) .IR (membrane process) max 2933,2249,1736,1453,1259cm^-1.MS (EI): 421 (M of m/z (%)⁺, 100) and .HRMS:Calculated for (theoretical value) C₂₆H₂₅F₂NO₂:421.1853；Found (measured value): 421.1857.

Embodiment 31

Into the reaction tube of 25mL, 110mg (0.9mmol) phenyl boric acid is added, (2.5mol% refers to and accounts for phenyl boric acid 4.4mg The percentage of mole) Nickelous nitrate hexahydrate, 2.4mg (2.5mol% refers to the percentage for accounting for phenyl boric acid mole) bpy (2, 2 '-bipyridyls), 166mg (1.2mmol) K₂CO₃, 4mL Isosorbide-5-Nitrae-dioxane, injection 186mg (0.6mmol) 1- triisopropyl silicon The fluoro- 3- propargyl bromide of base -3,3- bis-, after stirring 24 hours at 80 DEG C, separation yield is 77%, and purity is greater than through hydrogen spectrum identification 95%.¹H NMR(400MHz,CDCl₃) δ 7.71 (d, J=7.8Hz, 2H), 7.54-7.34 (m, 3H), 1.26-0.95 (m, 21H).¹³C NMR(125.7MHz,CDCl₃) δ 136.2 (t, J=27.9Hz), 130.6 (t, J=1.8Hz), 128.4,125.4 (t, J=4.5Hz), 111.6 (t, J=231.0Hz), 98.9 (t, J=40.0Hz), 92.5 (t, J=5.0Hz), 18.5, 11.0.¹⁹F NMR(376MHz,CDCl₃) δ -74.5 (s, 2F) .IR (membrane process) max 2946,2868,2186,1455, 1263cm^-1.MS 308 (M of (EI): m/z (%)⁺), 265,115 (100) .HRMS:Calculated for (theoretical value) C₁₈H₂₆F₂Si:308.1772；Found (measured value): 308.1777.

Embodiment 32

Into the reaction tube of 25mL, 122mg (0.9mmol) 4- methylphenylboronic acid is added, (2.5mol% refers to and accounts for 4.4mg The percentage of 4- methylphenylboronic acid mole) Nickelous nitrate hexahydrate, (2.5mol% refers to and accounts for 4- methylphenylboronic acid mole 2.4mg The percentage of amount) bpy (2,2 '-bipyridyl), 166mg (1.2mmol) K₂CO₃, 4mL Isosorbide-5-Nitrae-dioxane, injection 186mg The fluoro- 3- propargyl bromide of (0.6mmol) 1- triisopropylsilyl -3,3- bis-, after stirring 24 hours at 80 DEG C, separation yield is 60%, Purity is greater than 95% through hydrogen spectrum identification.¹H NMR(400MHz,CDCl₃) δ 7.59 (d, J=8.0Hz, 2H), 7.24 (d, J= 7.9Hz,2H),2.40(s,3H),1.19–1.04(m,21H).¹³C NMR(125.7MHz,CDCl₃) δ 140.8 (t, J= 1.9Hz), 133.4 (t, J=28.0Hz), 129.1 (s), 125.4 (t, J=4.5Hz), 111.7 (t, J=230.3Hz), 99.0 (t, J=40.1Hz), 92.1 (t, J=4.9Hz), 21.3 (s), 18.5 (s), 11.0 (s)¹⁹F NMR(376MHz,CDCl₃)δ- 73.7 (s, 2F) .IR (membrane process) max 2946,2868,2375,2292,1464,1266,1149,1003cm^-1.MS(EI):m/ 322 (M of z (%)⁺), 279,129 (100) .HRMS:Calculated for (theoretical value) C₁₉H₂₈F₂Si:322.1928；Found (measured value): 322.1933.

Embodiment 33

Into the reaction tube of 25mL, 175mg (0.9mmol) 4- carbethoxyl group phenyl boric acid is added, (2.5mol% refers to and accounts for The percentage of 4- carbethoxyl group phenyl boric acid mole) NiCl₂(dppe), (2.5mol% refers to and accounts for 4- carbethoxyl group benzene 2.4mg The percentage of boric acid mole) bpy (2,2 '-bipyridyl), 166mg (1.2mmol) K₂CO₃, 4mL1,4- dioxane, injection The fluoro- 3- propargyl bromide of 186mg (0.6mmol) 1- triisopropylsilyl -3,3- bis-, after stirring 24 hours at 80 DEG C, separation yield is 92%, purity is greater than 95% through hydrogen spectrum identification.¹H NMR(400MHz,CDCl₃) δ 8.12 (d, J=8.6Hz, 2H), 7.76 (d, J =8.6Hz, 2H), 4.40 (q, J=7.1Hz, 2H), 1.41 (t, J=7.1Hz, 3H), 1.19-0.96 (m, 21H)¹³C NMR (125.7MHz,CDCl₃) δ 165.7,140.2 (t, J=28.1Hz), 132.5,129.7,125.4 (t, J=4.4Hz), 110.9 (t, J=232.2Hz), 98.4 (t, J=39.8Hz), 93.5 (t, J=4.9Hz), 61.3,18.4,14.3,10.9.¹⁹F NMR (376MHz,CDCl₃) δ -76.1 (s, 2F) .IR (membrane process) max 2946,2868,2189,1725,1277,1153cm^-1.MS (EI): 380 (M of m/z (%)⁺), 337 (100) .HRMS:Calculated for (theoretical value) C₂₁H₃₀F₂O₂Si:380.1983； Found (measured value): 380.1986.

Embodiment 34

Into the reaction tube of 25mL, 148mg (0.9mmol) 4- acetylbenzene boric acid is added, (2.5mol% refers to and accounts for 4- The percentage of acetylbenzene boric acid mole) NiCl₂(dppe), (2.5mol% refers to that accounting for 4- acetylbenzene boric acid rubs to 2.4mg The percentage of your amount) bpy (2,2 '-bipyridyl), 166mg (1.2mmol) K₂CO₃, 4mL Isosorbide-5-Nitrae-dioxane, injection 186mg The fluoro- 3- propargyl bromide of (0.6mmol) 1- triisopropylsilyl -3,3- bis-, after stirring 24 hours at 80 DEG C, separation yield is 82%, Purity is greater than 95% through hydrogen spectrum identification.¹H NMR(400MHz,CDCl₃) δ 8.03 (d, J=8.5Hz, 2H), 7.79 (d, J= 8.5Hz,2H),2.64(s,3H),1.24–0.96(m,21H).¹³C NMR(125.7MHz,CDCl₃)δ197.2,140.3(t,J =28.2Hz), 138.7,128.4,125.7 (t, J=4.4Hz), 110.8 (t, J=232.2Hz), 98.3 (t, J= 39.7Hz), 93.6 (t, J=4.9Hz), 26.7,18.4,10.9.¹⁹F NMR(376MHz,CDCl₃)δ-76.1(s,2F).IR (membrane process) max 2946,2868,2187,1694,1464,1262,1151cm^-1.MS 350 (M of (EI): m/z (%)⁺),307, 43 (100) .HRMS:Calculated for (theoretical value) C₂₀H₂₈F₂OSi:350.1878；Found (measured value): 350.1877.

Embodiment 35

Into the reaction tube of 25mL, 181mg (0.9mmol) 4- bromobenzeneboronic acid is added, (2.5mol% refers to and accounts for 4- bromobenzene The percentage of boric acid mole) NiCl₂(dppe), 2.4mg (2.5mol% refers to the percentage for accounting for 4- bromobenzeneboronic acid mole) Bpy (2,2 '-bipyridyl), 166mg (1.2mmol) K₂CO₃, 4mL Isosorbide-5-Nitrae-dioxane, injection 186mg (0.6mmol) 1- tri- it is different The fluoro- 3- propargyl bromide of propyl silicon substrate -3,3- bis-, after stirring 24 hours at 80 DEG C, separation yield is 77%, and purity is big through hydrogen spectrum identification In 95%.¹H NMR(400MHz,CDCl₃)δ7.63–7.50(m,4H),1.23–0.99(m,21H).¹³C NMR(101MHz, CDCl₃) δ 135.2 (t, J=28.5Hz), 131.7,127.1 (t, J=4.4Hz), 125.2 (t, J=2.2Hz), 111.0 (t, J =231.6Hz), 98.3 (t, J=41.3Hz), 93.1 (t, J=4.9Hz), 18.4,10.9.¹⁹F NMR(376MHz,CDCl₃) δ -75.0 (s, 2F) .IR (membrane process) max 2945,2868,2187,1904,1597,1464,1263cm^-1.MS(EI):m/z (%) 386 (M⁺), 345,155 (100) .HRMS:Calculated for (theoretical value) C₁₈H₂₅BrF₂Si:386.0877；Found (measured value): 386.0881.

Example 36

Into the reaction tube of 25mL, 80mg (0.4mmol) flavones boric acid is added, (5mol% refers to and accounts for brass boric acid 3mg The percentage of mole) Nickelous nitrate hexahydrate, 1.6mg (2.5mol% refers to the percentage for accounting for brass boric acid mole) bpy (2,2 '-bipyridyl), 55mg (0.2mmol) K₂CO₃, 2mL Isosorbide-5-Nitrae-dioxane, injection 62mg (0.2mmol) 1- triisopropyl The fluoro- 3- propargyl bromide of silicon substrate -3,3- bis-, after stirring 24 hours at 80 DEG C, separation yield is 58%, and purity is greater than through hydrogen spectrum identification 95%.¹H NMR(400MHz,CDCl₃) δ 7.94 (dd, J=8.1Hz, 1.7Hz, 1H), 7.78 (d, J=8.3Hz, 2H), 7.58 (d, J=8.2Hz, 2H), 7.53 (ddd, J=8.9Hz, 7.3Hz, 1.7Hz, 1H), 7.10-7.06 (m, 2H), 5.54 (dd, J= 13.1Hz, 2.8Hz, 1H), 3.07 (dd, J=16.9Hz, 13.2Hz, 1H), 2.92 (dd, J=16.9Hz, 3.1Hz, 1H), 1.24–0.95(m,21H).¹³C NMR(125.7MHz,CDCl₃) δ 191.4,161.3,141.4 (t, J=1.2Hz), 136.6 (t, J=28.1Hz), 136.3,127.1,126.2,126.0 (t, J=4.4Hz), 121.9,120.9,118.1,111.2 (t, J =231.2Hz), 98.6 (t, J=39.7Hz), 92.9 (t, J=5.0Hz), 79.0,44.7,18.5,11.0.¹⁹F NMR (376MHz,CDCl₃) δ -74.4 (s, 2F) .IR (membrane process) max 2945,2867,2187,1694,1607,1464,1305cm^-1.MS 454 (M of (EI): m/z (%)⁺), 411,224,120 (100) .HRMS:Calculated for (theoretical value) C₂₇H₃₂F₂O₂Si:454.2140；Found (measured value): 454.2138.

Embodiment 37-43

Into the reaction tube of 25mL, phenyl boric acid (0.45mmol), nickel salt, ligand, alkali, solvent (2mL), injection is added 0.3mmol Bromodifluoroacetic acid ethyl ester, reaction was completed after stirring 8 hours at 80 DEG C.

The respective reaction condition of embodiment 37-43 and product fluorine spectrum yield are as shown in table 1, and obtaining target compound is nothing Color transparency liquid；It is that interior target fluorine composes yield that the fluorine spectrum yield, which refers to trifluomethoxybenzene,.

Table 1

Embodiment 44-59

The respective reaction condition of embodiment 44-59 and product yield are as shown in table 2, and it is colourless for obtaining target compound Prescribed liquid.

Table 2

Embodiment 60-64

Into the reaction tube of 25mL, phenyl boric acid (0.45mmol), nickel salt, ligand, potassium carbonate (200%), Isosorbide-5-Nitrae-two is added Six ring of oxygen (2mL) injects 0.3mmol Bromodifluoroacetic acid ethyl ester, and reaction was completed after stirring 8-24 hours at 40-70 DEG C.

The respective reaction condition of embodiment 60-64 and product yield are as shown in table 3, and it is colourless for obtaining target compound Prescribed liquid.

Table 3

Example 65-75

Into the reaction tube of 25mL, phenyl boric acid (0.45mmol), nickel salt, ligand, alkali, solvent (2mL), injection is added The fluoro- 3- propargyl bromide of 0.3mmol1- triisopropylsilyl -3,3- bis-, reaction was completed after stirring 16 hours at 80 DEG C.

The respective reaction condition of embodiment 65-75 and product yield are as shown in table 4, and it is colourless for obtaining target compound Prescribed liquid.

Table 4

Example 76-79

Into the reaction tube of 25mL, phenyl boric acid (0.45mmol), nickel salt, ligand, alkali, solvent (2mL), injection is added The fluoro- 3- propargyl bromide of 0.3mmol1- triisopropylsilyl -3,3- bis-, reaction was completed after stirring 24 hours at 80 DEG C.

The respective reaction condition of embodiment 76-79 and product yield are as shown in table 5, and it is colourless for obtaining target compound Prescribed liquid.

Table 5

Example 80-86

Into the reaction tube of 25mL, 4- carbethoxyl group phenyl boric acid (0.45mmol), nickel salt, ligand, alkali, solvent is added (2mL) injects the fluoro- 3- propargyl bromide of 0.3mmol1- triisopropylsilyl -3,3- bis-, and reaction was completed after stirring 24 hours at 80 DEG C.

The respective reaction condition of embodiment 80-86 and product yield are as shown in table 6, and it is colourless for obtaining target compound Prescribed liquid.

Table 6

Example 87-90

Into the reaction tube of 25mL, 4- acetylbenzene boric acid (0.45mmol), nickel salt, ligand, alkali, solvent (2mL) is added, The fluoro- 3- propargyl bromide of 0.3mmol1- triisopropylsilyl -3,3- bis- is injected, reaction was completed after stirring 24 hours at 80 DEG C.

The respective reaction condition of embodiment 87-90 and product yield are as shown in table 7, and it is colourless for obtaining target compound Prescribed liquid.

Table 7

Example 91-101

Into the reaction tube of 25mL, phenyl boric acid (0.45mmol), nickel salt, ligand, alkali, solvent (2mL), injection is added 0.3mmol2- bromine difluoro methyl benzoxazoles, reaction was completed after stirring 12 hours at 80 DEG C.

The respective reaction condition of embodiment 91-101 and product yield are as shown in table 8, and it is colourless for obtaining target compound Transparency liquid.

Table 8

Example 102-114

Into the reaction tube of 25mL, phenyl boric acid (0.45mmol), nickel salt, ligand, alkali, solvent (2mL), injection is added 0.3mmol bromine difluorophosphoric acid diisopropyl ester, reaction was completed after stirring 24 hours at 80 DEG C.

The respective reaction condition of embodiment 102-114 and product yield are as shown in table 9, and it is colourless for obtaining target compound Transparency liquid.

Table 9

Embodiment 115-125

Into the reaction tube of 25mL, 1 is added to 0.9mmol phenyl boric acid or substituted phenyl boric acid, catalyst, alkali, solvent (4mL) injects the humorous difluoromethyl reagent of 0.6mmol function dough, and reaction was completed after stirring 24 hours at 60-80 DEG C.

In embodiment 115-125, tried using the corresponding phenyl boric acid of respective product or substituted phenyl boric acid, humorous difluoromethyl Agent, product and its yield obtained are as shown in table 10, and obtaining target compound is colourless transparent liquid or solid.

Table 10

Embodiment 126

Into the reaction tube of 25mL, 55mg (0.45mmol) phenyl boric acid is added, (5mol% refers to that accounting for phenyl boric acid rubs to 4.4mg The percentage of your amount) Nickelous nitrate hexahydrate, 2.4mg (5mol% refers to the percentage for accounting for phenyl boric acid mole) bpy (2,2 '-connection Pyridine), 2.9mg (5mol% refers to the percentage for accounting for phenyl boric acid mole) cuprous iodide, 83mg (0.6mmol) K₂CO₃, 2mL Isosorbide-5-Nitrae-dioxane injects 38ul (0.3mmol) chlorine ethyl difluoro, and after stirring 24 hours at 80 DEG C, separation yield is 52%.

Material synthesis method:

Embodiment 127

Schlenk bottles of 250mL, addition heterocycle 4,5- dimethylthiazole (2g, 17.7mmol), anhydrous THF 100ml is done Ice ethanol bath is cooled to -78 degree, is slowly added into n-BuLi (2.5M in hexane, 7.8ml), -78 degree stirring 30min, Difluoro dibromo 10ml is rapidly joined, solution becomes orange red, continues -78 degree stirring 2h.Thin-layer chromatography detects raw material and disappears, and has product raw At still also there are a large amount of by-products to generate, stop reaction.Concentration, crosses silicagel column separation product, and pure petroleum ether elution obtains 1.4g Product 15e, yield: 33%.¹H NMR(400MHz,CDCl₃)δ2.41(s,3H),2.38(s,3H).¹⁹F NMR(376MHz, CDCl₃)δ-41.21(s,2F).

Embodiment 128

Bromodifluoroacetic acid (75mmol, 16g) is added in 20mL single port bottle, the aqueous hydrochloric acid solution 40mL of 4M, amine salt (37.5mmol, 7.3g), is heated to reflux 5h.Stopping reaction, is neutralized to neutrality with sodium hydrate aqueous solution, ethyl acetate extracts, Have it is several layers of dried, filtered with anhydrous sodium sulfate, be concentrated, cross silicagel column separation product, obtain 2.5g white solid product.Yield 25%.81 DEG C of of fusing point¹H NMR(500MHz,CDCl₃) δ 7.86 (d, J=8.0Hz, 1H), 7.41 (s, 2H), 7.36 (t, J= 5.9Hz,1H),3.95(s,3H).¹³C NMR(125.7MHz,CDCl₃) δ 144.31 (t, J=31.6Hz), 140.7,136.3, (125.2,123.6,121.5,120.8 t, J=287.5Hz), 110.0,31.1 (t, J=2.7Hz)¹⁹F NMR(376MHz, CDCl₃) δ -50.5 (s, 2F) .IR (KBr tabletting) max1588,1483,1401,1213,1076,935,745cm^-1.MS(EI): 262 (M of m/z (%)⁺), 181 (100) .HRMS:Calculated for (theoretical value) C₉H₇BrF₂N₂:259.9761；Found is (real Measured value): 259.9763.

Embodiment 129

Chlorine difluoroacetic acid (30mmol, 3.92g) is added in 20mL single port bottle, the aqueous hydrochloric acid solution 20mL of 4M, amine salt (15mmol, 2.96g), is heated to reflux 5h.Stop reaction, is neutralized to neutrality with sodium hydrate aqueous solution, ethyl acetate extraction has Several layers of to be dried, filtered with anhydrous sodium sulfate, concentration crosses silicagel column separation product, obtains 2.6g white solid product.Yield 80%.81 DEG C of of fusing point¹H NMR(400MHz,CDCl₃) δ 7.86 (dd, J=8.1Hz, 0.8Hz, 1H), 7.45-7.39 (m, 2H), 7.39–7.33(m,1H),3.95(s,3H).¹³C NMR(125.7MHz,CDCl₃)δ145.1–144.0(m),140.7,136.3, 125.2,123.6-123.5 (m), 121.6-121.4 (m), 120.9 (t, J=287.6Hz), 110.0 (s), 31.1-31.0 (m).¹⁹F NMR(376MHz,CDCl₃) δ -50.5 (s, 2F) .IR (KBr tabletting) max 1588,1483,1076,935,745cm^-1.MS 216 (M of (EI): m/z (%)⁺), 181 (100) .HRMS:Calculated for (theoretical value) C₉H₇ClF₂N₂: 216.0266；Found (measured value): 216.0267.

All references mentioned in the present invention is incorporated herein by reference, independent just as each document It is incorporated as with reference to such.In addition, it should also be understood that, after reading the above teachings of the present invention, those skilled in the art can To make various changes or modifications to the present invention, such equivalent forms equally fall within model defined by the application the appended claims It encloses.

Claims

1. a kind of preparation method of compound containing difluoro methylene, it is characterised in that the following steps are included: in a solvent, alkali is matched Under the conditions of body and catalyst is existing, compound A and compound B is subjected to suzuki coupling reaction, obtains compound C, The catalyst is nickel salt, and the nickel salt is NiQ₂·mH₂O、NiL_nCl₂Or NiL_nBr₂；

Wherein, Q is nitrate anion or halogen, 0≤m≤10,0 < n < 3；L is triphenylphosphine, tricyclohexyl phosphine, 1,2 bis- (diphenyl Phosphine) ethane, bis- (diphenylphosphine) propane of 1,3-, bis- (diphenylphosphine) ferrocene of 1,1'-, dimethyl second diether or diethylene glycol Dimethyl ether；X is halogen；

R¹For " substituted or unsubstituted C₃~C₁₅Aryl ", " hetero atom is oxygen, sulphur or nitrogen-atoms, and hetero atom number is 1-3, Substituted or unsubstituted C₂~C₁₅Heteroaryl ",It is described " to replace or not Substituted C₃~C₁₅Aryl " or " hetero atom is oxygen, sulphur or nitrogen-atoms, and hetero atom number is 1-3, substituted or unsubstituted C₂~C₁₅Heteroaryl " described in " substitution " be by cyano, hydroxyl, nitro, halogen, C₁~C₁₀Alkyl, C₁~C₁₀Alkane Oxygroup, C₁~C₁₀Alkylthio group, C₁~C₁₀Alkyl silyl, " halogen replace C₁~C₁₀Alkyl ", " hydroxyl replace C₁~ C₁₀Alkyl ", C₂~C₁₀Alkenyl, C₂~C₁₀Alkynyl, C₃~C₁₀Aryl, " hetero atom be oxygen, sulphur or nitrogen-atoms, miscellaneous original The C that subnumber is 1-3₂~C₆Heterocyclylalkyl ",One or more of replaced, When there are multiple substituent groups, the substituent group is identical or different；R³、R⁴And R⁵Independent is hydrogen atom, amino, C₁ ~C₆Alkyl or C₃~C₆Naphthenic base；R⁶And R⁷Independent is C₁~C₆Alkyl or C₃~C₆Naphthenic base；R⁸For hydrogen Atom, C₁~C₆Alkyl or C₃~C₆Naphthenic base；

R²ForOr " hetero atom is oxygen, sulphur or nitrogen-atoms, hetero atom The substituted or unsubstituted C that number is 1-3₂~C₁₅Heteroaryl ", it is described that " hetero atom is oxygen, sulphur or nitrogen-atoms, hetero atom The substituted or unsubstituted C that number is 1-3₂~C₁₅Heteroaryl " described in " substitution " refer to by cyano, halogen, C₁~C₁₀ Alkyl, C₁~C₁₀Alkoxy, " halogen replace C₁~C₁₀Alkyl ", C₂~C₁₀Alkenyl, C₂~C₁₀Alkynyl in Replaced one or more, when there are multiple substituent groups, the substituent group can be identical or different；R⁹For C₁~C₆Alkane Base or C₃~C₆Naphthenic base；

R¹⁰For substituted or unsubstituted C₁~C₁₀Alkyl, " hetero atom is oxygen, sulphur or nitrogen-atoms, and hetero atom number is taking for 1-3 Generation or unsubstituted C₂~C₁₅Heterocyclylalkyl ", substituted or unsubstituted C₃~C₁₅Aryl or C₃~C₁₅Fragrant amino；It is described R¹⁰Described in " substituted or unsubstituted C₁~C₁₀Alkyl " described in " substitution " refer to by C₃~C₁₅Aryl taken Generation；The R¹⁰Described in " hetero atom is oxygen, sulphur or nitrogen-atoms, and hetero atom number is the substituted or unsubstituted C of 1-3₂~ C₁₅Heterocyclylalkyl " described in " substitution " refer to by C₁~C₁₀Alkyl and C₃~C₆Naphthenic base in one or more institutes Replace, when there are multiple substituent groups, the substituent group can be identical or different；

The R¹⁰Described in " substituted or unsubstituted C₃~C₁₅Aryl " described in " substitution " be by cyano, halogen, C₁~C₁₀Alkyl, C₁~C₁₀Alkoxy, " halogen replace C₁~C₁₀Alkyl ", C₂~C₁₀Alkenyl, C₂~C₁₀Alkynes Base,One or more of replaced, when there are multiple substituent groups When, the substituent group is identical or different；R¹¹For C₁~C₆Alkyl, C₃~C₆Naphthenic base or " C₁~C₆Alkyl silyl "； R¹²For C₁~C₆Alkyl.

2. the preparation method of the compound containing difluoro methylene as described in claim 1, it is characterised in that: when the X is halogen When plain, the halogen is chlorine or bromine；

As the R¹Described in " substituted or unsubstituted C₃~C₁₅Aryl " or " hetero atom be oxygen, sulphur or nitrogen-atoms, it is miscellaneous Atomicity is 1-3, substituted or unsubstituted C₂~C₁₅Heteroaryl " described in " substitution " be institute when being optionally substituted by halogen " halogen " stated is fluorine, chlorine, bromine or iodine；

As the R¹Described in " substituted or unsubstituted C₃~C₁₅Aryl " or " hetero atom be oxygen, sulphur or nitrogen-atoms, it is miscellaneous Atomicity is 1-3, substituted or unsubstituted C₂~C₁₅Heteroaryl " described in " substitution " be by C₁~C₁₀Alkyl take The Dai Shi, " C₁~C₁₀Alkyl " be C₁~C₆Alkyl；

As the R¹Described in " substituted or unsubstituted C₃~C₁₅Aryl " or " hetero atom be oxygen, sulphur or nitrogen-atoms, it is miscellaneous Atomicity is 1-3, substituted or unsubstituted C₂~C₁₅Heteroaryl " described in " substitution " be by C₁~C₁₀Alkoxy When substitution, " the C₁~C₁₀Alkoxy " be C₁~C₆Alkoxy；

As the R¹Described in " substituted or unsubstituted C₃~C₁₅Aryl " or " hetero atom be oxygen, sulphur or nitrogen-atoms, it is miscellaneous Atomicity is 1-3, substituted or unsubstituted C₂~C₁₅Heteroaryl " described in " substitution " be by C₁~C₁₀Alkylthio group When replaced, " the C₁~C₁₀Alkylthio group " be C₁~C₆Alkylthio group；

As the R¹Described in " substituted or unsubstituted C₃~C₁₅Aryl " or " hetero atom be oxygen, sulphur or nitrogen-atoms, it is miscellaneous Atomicity is 1-3, substituted or unsubstituted C₂~C₁₅Heteroaryl " described in " substitution " be by " C₁~C₁₀Alkyl When replaced silicon substrate ", " C₁~C₁₀Alkyl silyl " be C₁~C₆Alkyl silyl；

As the R¹Described in " substituted or unsubstituted C₃~C₁₅Aryl " or " hetero atom be oxygen, sulphur or nitrogen-atoms, it is miscellaneous Atomicity is 1-3, substituted or unsubstituted C₂~C₁₅Heteroaryl " described in " substitution " be by " the C that halogen replaces₁ ~C₁₀Alkyl " replaced when, the described " C that halogen replaces₁~C₁₀Alkyl " described in " halogen " be fluorine, chlorine or bromine, The number of the halogen is 1-4, and when there are multiple halogen atoms, the halogen atom can be identical or different, institute " the C that halogen replaces stated₁~C₁₀Alkyl " described in " C₁~C₁₀Alkyl " be C₁~C₆Alkyl；

As the R¹Described in " substituted or unsubstituted C₃~C₁₅Aryl " or " hetero atom be oxygen, sulphur or nitrogen-atoms, it is miscellaneous Atomicity is 1-3, substituted or unsubstituted C₂~C₁₅Heteroaryl " described in " substitution " be by " the C that hydroxyl replaces₁ ~C₁₀Alkyl " replaced when, the described " C that hydroxyl replaces₁~C₁₀Alkyl " be " and hydroxyl replace C₁~C₆Alkyl "；

As the R¹Described in " substituted or unsubstituted C₃~C₁₅Aryl " or " hetero atom be oxygen, sulphur or nitrogen-atoms, it is miscellaneous Atomicity is 1-3, substituted or unsubstituted C₂~C₁₅Heteroaryl " described in " substitution " be by " C₂~C₁₀Alkenyl " When replaced, " the C₂~C₁₀Alkenyl " be C₂~C₆Alkenyl；

As the R¹Described in " substituted or unsubstituted C₃~C₁₅Aryl " or " hetero atom be oxygen, sulphur or nitrogen-atoms, it is miscellaneous Atomicity is 1-3, substituted or unsubstituted C₂~C₁₅Heteroaryl " described in " substitution " be by " C₂~C₁₀Alkynyl " When replaced, " the C₂~C₁₀Alkynyl " be C₂~C₆Alkynyl；

As the R¹Described in " substituted or unsubstituted C₃~C₁₅Aryl " or " hetero atom be oxygen, sulphur or nitrogen-atoms, it is miscellaneous Atomicity is 1-3, substituted or unsubstituted C₂~C₁₅Heteroaryl " described in " substitution " be by " C₃~C₁₀Aryl " When replaced, " the C₃~C₁₀Aryl " be C₃~C₆Aryl；

As the R¹Described in " substituted or unsubstituted C₃~C₁₅Aryl " or " hetero atom be oxygen, sulphur or nitrogen-atoms, it is miscellaneous Atomicity is 1-3, substituted or unsubstituted C₂~C₁₅Heteroaryl " described in " substitution " be by " hetero atom is oxygen, sulphur Or the C that nitrogen-atoms, hetero atom number are 1-3₂~C₆Heterocyclylalkyl " replaced when, it is described that " hetero atom is that oxygen, sulphur or nitrogen are former Son, the C that hetero atom number is 1-3₂~C₆Heterocyclylalkyl " be that " hetero atom is oxygen or nitrogen-atoms, hetero atom number are 1-2's C₃~C₄Heterocyclylalkyl "；

As the R²Described in " the substituted or unsubstituted C that hetero atom is oxygen, sulphur or nitrogen-atoms, hetero atom number is 1-3₂ ~C₁₅Heteroaryl " described in " substitution " when being by replaced " halogen ", " halogen " is fluorine, chlorine, bromine or iodine；

As the R²Described in " the substituted or unsubstituted C that hetero atom is oxygen, sulphur or nitrogen-atoms, hetero atom number is 1-3₂ ~C₁₅Heteroaryl " described in " substitution " be by " C₁~C₁₀Alkyl " replaced when, " the C₁~C₁₀Alkyl " be C₁~C₆Alkyl；

As the R²Described in " the substituted or unsubstituted C that hetero atom is oxygen, sulphur or nitrogen-atoms, hetero atom number is 1-3₂ ~C₁₅Heteroaryl " described in " substitution " be by " C₁~C₁₀Alkoxy " replaced when, " the C₁~C₁₀Alcoxyl Base " is C₁~C₆Alkoxy；

As the R²Described in " the substituted or unsubstituted C that hetero atom is oxygen, sulphur or nitrogen-atoms, hetero atom number is 1-3₂ ~C₁₅Heteroaryl " described in " substitution " be by " the C that halogen replaces₁~C₁₀Alkyl " replaced when, it is described that " halogen takes The C in generation₁~C₁₀Alkyl " described in " halogen " be fluorine, chlorine or bromine, the number of the halogen is 1-4, when there are multiple When halogen atom, the halogen atom can be identical or different, " the C that halogen replaces₁~C₁₀Alkyl " described in " C₁~C₁₀Alkyl " be C₁~C₆Alkyl；

As the R²Described in " the substituted or unsubstituted C that hetero atom is oxygen, sulphur or nitrogen-atoms, hetero atom number is 1-3₂ ~C₁₅Heteroaryl " described in " substitution " be by " C₂~C₁₀Alkenyl " replaced when, " the C₂~C₁₀Alkenyl " be C₂~C₆Alkenyl；

As the R²Described in " the substituted or unsubstituted C that hetero atom is oxygen, sulphur or nitrogen-atoms, hetero atom number is 1-3₂ ~C₁₅Heteroaryl " described in " substitution " be by " C₂~C₁₀Alkynyl " replaced when, " the C₂~C₁₀Alkynyl " be C₂~C₆Alkynyl；

As the R¹⁰Described in " substituted or unsubstituted C₁~C₁₀Alkyl " described in " substitution " refer to by " C₃~C₁₅ Aryl " replaced when, " the C₃~C₁₅Aryl " be C₅~C₁₀Aryl；

As the R¹⁰Described in " hetero atom is oxygen, sulphur or nitrogen-atoms, and hetero atom number is the substituted or unsubstituted of 1-3 C₂~C₁₅Heterocyclylalkyl " described in " substitution " refer to by " C₁~C₁₀Alkyl " replaced when, " the C₁~C₁₀Alkane Base " is C₁~C₆Alkyl；

As the R¹⁰Described in " hetero atom is oxygen, sulphur or nitrogen-atoms, and hetero atom number is the substituted or unsubstituted of 1-3 C₂~C₁₅Heterocyclylalkyl " described in " substitution " refer to by " C₃~C₆Naphthenic base " replaced when, " the C₃~C₆'s Naphthenic base " is cyclopropyl, cyclopenta or cyclohexyl；

As the R¹⁰Described in " substituted or unsubstituted C₃~C₁₅Aryl " described in " substitution " be by " halogen " institute When substitution, " halogen " is fluorine, chlorine, bromine or iodine；

As the R¹⁰Described in " substituted or unsubstituted C₃~C₁₅Aryl " described in " substitution " be by C₁~C₁₀'s When replaced alkyl, " the C₁~C₁₀Alkyl " C₁~C₆Alkyl；

As the R¹⁰Described in " substituted or unsubstituted C₃~C₁₅Aryl " described in " substitution " be by C₁~C₁₀'s When replaced alkoxy, " the C₁~C₁₀Alkoxy " be C₁~C₆Alkoxy；

As the R¹⁰Described in " substituted or unsubstituted C₃~C₁₅Aryl " described in " substitution " be by " halogen replaces C₁~C₁₀Alkyl " replaced when, the described " C that halogen replaces₁~C₁₀Alkyl " described in " halogen " be fluorine, chlorine or Bromine, the number of the halogen are 1-4, and when there are multiple halogen atoms, the halogen atom can be identical or different, " the C that halogen replaces₁~C₁₀Alkyl " described in " C₁~C₁₀Alkyl " be C₁~C₆Alkyl；

As the R¹⁰Described in " substituted or unsubstituted C₃~C₁₅Aryl " described in " substitution " be by " C₂~C₁₀'s When replaced alkenyl ", " C₂~C₁₀Alkenyl " be C₂~C₆Alkenyl；

As the R¹⁰Described in " substituted or unsubstituted C₃~C₁₅Aryl " described in " substitution " be by " C₂~C₁₀'s When replaced alkynyl ", " C₂~C₁₀Alkynyl " be C₂~C₆Alkynyl.

3. the preparation method of the compound containing difluoro methylene as claimed in claim 2, it is characterised in that:

As the R¹Described in " substituted or unsubstituted C₃~C₁₅Aryl " or " hetero atom be oxygen, sulphur or nitrogen-atoms, it is miscellaneous Atomicity is 1-3, substituted or unsubstituted C₂~C₁₅Heteroaryl " described in " substitution " be by C₁~C₆Alkyl take The Dai Shi, " C₁~C₆Alkyl " be methyl, ethyl, propyl, isopropyl, butyl, isobutyl group or tert-butyl；

As the R¹Described in " substituted or unsubstituted C₃~C₁₅Aryl " or " hetero atom be oxygen, sulphur or nitrogen-atoms, it is miscellaneous Atomicity is 1-3, substituted or unsubstituted C₂~C₁₅Heteroaryl " described in " substitution " be by C₁~C₆Alkoxy When substitution, " the C₁~C₆Alkoxy " be methoxyl group, ethyoxyl, propoxyl group, isopropoxy, butoxy, isobutoxy or Tert-butoxy；

As the R¹Described in " substituted or unsubstituted C₃~C₁₅Aryl " or " hetero atom be oxygen, sulphur or nitrogen-atoms, it is miscellaneous Atomicity is 1-3, substituted or unsubstituted C₂~C₁₅Heteroaryl " described in " substitution " be by C₁~C₆Alkylthio group When replaced, " the C₁~C₆Alkylthio group " be methyl mercapto, ethylmercapto group, rosickyite base, isopropyisulfanyl, butylthio, isobutylthio Or tertiary butylthio；

As the R¹Described in " substituted or unsubstituted C₃~C₁₅Aryl " or " hetero atom be oxygen, sulphur or nitrogen-atoms, it is miscellaneous Atomicity is 1-3, substituted or unsubstituted C₂~C₁₅Heteroaryl " described in " substitution " be by C₁~C₆Alkyl silicon When replaced base, " the C₁~C₆Alkyl silyl " be methylsilyl, trimethyl silicon substrate, ethyl silicon substrate, propyl silicon substrate, different Propyl silicon substrate, butyl silicon substrate, isobutyl group silicon substrate or tert-butyl silicon substrate；

As the R¹Described in " substituted or unsubstituted C₃~C₁₅Aryl " or " hetero atom be oxygen, sulphur or nitrogen-atoms, it is miscellaneous Atomicity is 1-3, substituted or unsubstituted C₂~C₁₅Heteroaryl " described in " substitution " be by " the C that halogen replaces₁ ~C₆Alkyl " replaced when, the described " C that halogen replaces₁~C₆Alkyl " in, " the C₁~C₆Alkyl " be first Base, ethyl, propyl, isopropyl, butyl, isobutyl group or tert-butyl；

As the R¹Described in " substituted or unsubstituted C₃~C₁₅Aryl " or " hetero atom be oxygen, sulphur or nitrogen-atoms, it is miscellaneous Atomicity is 1-3, substituted or unsubstituted C₂~C₁₅Heteroaryl " described in " substitution " be by " the C that hydroxyl replaces₁ ~C₆Alkyl " replaced when, the described " C that hydroxyl replaces₁~C₆Alkyl " be " hydroxyl replace methyl ", " hydroxyl replaces Ethyl ", " hydroxyl replace propyl ", " isopropyl that hydroxyl replaces ", " butyl that hydroxyl replaces ", " isobutyl that hydroxyl replaces Base " or " tert-butyl that hydroxyl replaces "；

As the R¹Described in " substituted or unsubstituted C₃~C₁₅Aryl " or " hetero atom be oxygen, sulphur or nitrogen-atoms, it is miscellaneous Atomicity is 1-3, substituted or unsubstituted C₂~C₁₅Heteroaryl " described in " substitution " be by " C₂~C₆Alkenyl " When replaced, " the C₂~C₆Alkenyl " be vinyl,

As the R¹Described in " substituted or unsubstituted C₃~C₁₅Aryl " or " hetero atom be oxygen, sulphur or nitrogen-atoms, it is miscellaneous Atomicity is 1-3, substituted or unsubstituted C₂~C₁₅Heteroaryl " described in " substitution " be by " C₂~C₆Alkynyl " When replaced, " the C₂~C₆Alkynyl " be acetenyl,

As the R¹Described in " substituted or unsubstituted C₃~C₁₅Aryl " or " hetero atom be oxygen, sulphur or nitrogen-atoms, it is miscellaneous Atomicity is 1-3, substituted or unsubstituted C₂~C₁₅Heteroaryl " described in " substitution " be by " C₃~C₆Aryl " When replaced, " the C₃~C₆Aryl " be phenyl；

As the R¹Described in " substituted or unsubstituted C₃~C₁₅Aryl " or " hetero atom be oxygen, sulphur or nitrogen-atoms, it is miscellaneous Atomicity is 1-3, substituted or unsubstituted C₂~C₁₅Heteroaryl " described in " substitution " be by " hetero atom be oxygen or Nitrogen-atoms, the C that hetero atom number is 1-2₃~C₄Heterocyclylalkyl " replaced when, it is described " hetero atom be oxygen or nitrogen-atoms, The C that hetero atom number is 1-2₃~C₄Heterocyclylalkyl " be morpholinyl；

As the R²Described in " the substituted or unsubstituted C that hetero atom is oxygen, sulphur or nitrogen-atoms, hetero atom number is 1-3₂ ~C₁₅Heteroaryl " described in " substitution " be by " C₁~C₆Alkyl " replaced when, " the C₁~C₆Alkyl " be first Base, ethyl, propyl, isopropyl, butyl, isobutyl group or tert-butyl；

As the R²Described in " the substituted or unsubstituted C that hetero atom is oxygen, sulphur or nitrogen-atoms, hetero atom number is 1-3₂ ~C₁₅Heteroaryl " described in " substitution " be by " C₁~C₆Alkoxy " replaced when, " the C₁~C₆Alkoxy " For methoxyl group, ethyoxyl, propoxyl group, isopropoxy, butoxy, isobutoxy or tert-butoxy；

As the R²Described in " the substituted or unsubstituted C that hetero atom is oxygen, sulphur or nitrogen-atoms, hetero atom number is 1-3₂ ~C₁₅Heteroaryl " described in " substitution " be by " the C that halogen replaces₁~C₆Alkyl " replaced when, it is described that " halogen takes The C in generation₁~C₆Alkyl " in, " the C₁~C₆Alkyl " be methyl, ethyl, propyl, isopropyl, butyl, isobutyl group or Tert-butyl；

As the R²Described in " the substituted or unsubstituted C that hetero atom is oxygen, sulphur or nitrogen-atoms, hetero atom number is 1-3₂ ~C₁₅Heteroaryl " described in " substitution " be by " C₂~C₆Alkenyl " replaced when, " the C₂~C₆Alkenyl " be second Alkenyl,

As the R²Described in " the substituted or unsubstituted C that hetero atom is oxygen, sulphur or nitrogen-atoms, hetero atom number is 1-3₂ ~C₁₅Heteroaryl " described in " substitution " be by " C₂~C₆Alkynyl " replaced when, " the C₂~C₁₆Alkynyl " be Acetenyl,

As the R¹⁰Described in " substituted or unsubstituted C₁~C₁₀Alkyl " described in " substitution " refer to by " C₅~C₁₀ Aryl " replaced when, " the C₅~C₁₀Aryl " be phenyl；

As the R¹⁰Described in " hetero atom is oxygen, sulphur or nitrogen-atoms, and hetero atom number is the substituted or unsubstituted of 1-3 C₂~C₁₅Heterocyclylalkyl " described in " substitution " refer to by " C₁~C₆Alkyl " replaced when, " the C₁~C₆Alkane Base " is methyl, ethyl, propyl, isopropyl, butyl, isobutyl group or tert-butyl；

As the R¹⁰Described in " substituted or unsubstituted C₃~C₁₅Aryl " described in " substitution " be by C₁~C₆Alkane When replaced base, " the C₁~C₆Alkyl " be methyl, ethyl, propyl, isopropyl, butyl, isobutyl group or tert-butyl；

As the R¹⁰Described in " substituted or unsubstituted C₃~C₁₅Aryl " described in " substitution " be by C₁~C₆Alkane When replaced oxygroup, " the C₁~C₆Alkoxy " be methoxyl group, ethyoxyl, propoxyl group, isopropoxy, butoxy, isobutyl Oxygroup or tert-butoxy；

As the R¹⁰Described in " substituted or unsubstituted C₃~C₁₅Aryl " described in " substitution " be by " halogen replaces C₁~C₆Alkyl " replaced when, the described " C that halogen replaces₁~C₆Alkyl " in, " the C₁~C₆Alkyl " be Methyl, ethyl, propyl, isopropyl, butyl, isobutyl group or tert-butyl；

As the R¹⁰Described in " substituted or unsubstituted C₃~C₁₅Aryl " described in " substitution " be by " C₂~C₆'s When replaced alkenyl ", " C₂~C₆Alkenyl " be vinyl,

As the R¹⁰Described in " substituted or unsubstituted C₃~C₁₅Aryl " described in " substitution " be by " C₂~C₆'s When replaced alkynyl ", " C₂~C₆Alkynyl " be acetenyl,

4. the preparation method of the compound containing difluoro methylene as claimed in claim 3, it is characterised in that:

As the R¹Described in " substituted or unsubstituted C₃~C₁₅Aryl " or " hetero atom be oxygen, sulphur or nitrogen-atoms, it is miscellaneous Atomicity is 1-3, substituted or unsubstituted C₂~C₁₅Heteroaryl " described in " substitution " be by " the C that halogen replaces₁ ~C₆Alkyl " replaced when, the described " C that halogen replaces₁~C₆Alkyl " be " one or more in fluorine, chlorine and bromine atom A substituted methyl ", " one or more ethyls replaced in fluorine, chlorine and bromine atom ", " one in fluorine, chlorine and bromine atom Or multiple substituted propyl ", " one or more isopropyls replaced in fluorine, chlorine and bromine atom ", " in fluorine, chlorine and bromine atom One or more butyl replaced ", " one or more isobutyl groups replaced in fluorine, chlorine and bromine atom " or " fluorine, chlorine and bromine One or more tert-butyls replaced in atom "；

As the R¹Described in " substituted or unsubstituted C₃~C₁₅Aryl " or " hetero atom be oxygen, sulphur or nitrogen-atoms, it is miscellaneous Atomicity is 1-3, substituted or unsubstituted C₂~C₁₅Heteroaryl " described in " substitution " be replaced morpholinyl When, " morpholinyl " is

As the R²Described in " the substituted or unsubstituted C that hetero atom is oxygen, sulphur or nitrogen-atoms, hetero atom number is 1-3₂ ~C₁₅Heteroaryl " described in " substitution " be by " the C that halogen replaces₁~C₆Alkyl " replaced when, it is described that " halogen takes The C in generation₁~C₆Alkyl " be " one or more methyl replaced in fluorine, chlorine and bromine atom ", " in fluorine, chlorine and bromine atom The ethyl that one or more replaces ", " one or more propyl replaced in fluorine, chlorine and bromine atom ", " fluorine, chlorine and bromine atom In one or more isopropyls replaced ", " one or more butyl replaced in fluorine, chlorine and bromine atom ", " fluorine, chlorine and One or more isobutyl groups replaced in bromine atom " or " one or more tert-butyls replaced in fluorine, chlorine and bromine atom "；

As the R¹⁰Described in " substituted or unsubstituted C₃~C₁₅Aryl " described in " substitution " be by " halogen replaces C₁~C₆Alkyl " replaced when, the described " C that halogen replaces₁~C₆Alkyl " be " one in fluorine, chlorine and bromine atom Or multiple substituted methyl ", " one or more ethyls replaced in fluorine, chlorine and bromine atom ", " in fluorine, chlorine and bromine atom The propyl that one or more replaces ", " one or more isopropyls replaced in fluorine, chlorine and bromine atom ", " fluorine, chlorine and bromine are former One or more butyl replaced in son ", " one or more isobutyl groups replaced in fluorine, chlorine and bromine atom " or " fluorine, chlorine With one or more tert-butyls replaced in bromine atom ".

5. the preparation method of the compound containing difluoro methylene as claimed in claim 4, it is characterised in that:

As the R¹Described in " substituted or unsubstituted C₃~C₁₅Aryl " or " hetero atom be oxygen, sulphur or nitrogen-atoms, it is miscellaneous Atomicity is 1-3, substituted or unsubstituted C₂~C₁₅Heteroaryl " described in " substitution " be by " fluorine atom replaces When replaced methyl ", " methyl that fluorine atom replaces " is trifluoromethyl；

As the R¹Described in " substituted or unsubstituted C₃~C₁₅Aryl " or " hetero atom be oxygen, sulphur or nitrogen-atoms, it is miscellaneous Atomicity is 1-3, substituted or unsubstituted C₂~C₁₅Heteroaryl " described in " substitution " be by " bromine atom replaces When replaced methyl ", " methyl that bromine atom replaces " is

As the R²Described in " the substituted or unsubstituted C that hetero atom is oxygen, sulphur or nitrogen-atoms, hetero atom number is 1-3₂ ~C₁₅Heteroaryl " described in " substitution " when being by replaced " methyl that fluorine atom replaces ", it is described " fluorine atom substitution Methyl " is trifluoromethyl；

As the R²Described in " the substituted or unsubstituted C that hetero atom is oxygen, sulphur or nitrogen-atoms, hetero atom number is 1-3₂ ~C₁₅Heteroaryl " described in " substitution " when being by replaced " methyl that bromine atom replaces ", it is described " bromine atom substitution Methyl " is

As the R¹⁰Described in " substituted or unsubstituted C₃~C₁₅Aryl " described in " substitution " be by " fluorine atom takes When replaced the methyl in generation ", " methyl that fluorine atom replaces " is trifluoromethyl；

As the R¹⁰Described in " substituted or unsubstituted C₃~C₁₅Aryl " described in " substitution " be by " bromine atom takes When replaced the methyl in generation ", " methyl that bromine atom replaces " is

6. the preparation method of the compound containing difluoro methylene as described in claim 1, it is characterised in that: as the R¹Middle institute " the substituted or unsubstituted C stated₃~C₁₅Aryl " or " hetero atom is oxygen, sulphur or nitrogen-atoms, and hetero atom number is 1-3, is taken Generation or unsubstituted C₂~C₁₅Heteroaryl " described in " substitution " be quiltIt is described when replaced For

As the R¹For " substituted or unsubstituted C₃~C₁₅Aryl " when, " the substituted or unsubstituted C₃~C₁₅Virtue Base " is " substituted or unsubstituted C₅~C₁₄Aryl "；

As the R¹For " hetero atom is oxygen, sulphur or nitrogen-atoms, and hetero atom number is 1-3, substituted or unsubstituted C₂~C₁₅ Heteroaryl " when, it is described that " hetero atom is oxygen, sulphur or nitrogen-atoms, and hetero atom number is 1-3, substituted or unsubstituted C₂~ C₁₅Heteroaryl " be that " hetero atom is oxygen, sulphur or nitrogen-atoms, and hetero atom number is 1 C₃~C₁₀Heteroaryl "；

As the R³、R⁴And R⁵Independent is " C₁~C₆Alkyl " when, " the C₁~C₆Alkyl " be methyl, second Base, propyl, isopropyl, butyl, isobutyl group or tert-butyl；

As the R³、R⁴And R⁵Independent is C₃~C₆Naphthenic base when, " the C₃~C₆Naphthenic base " be cyclopropyl Base, cyclopenta or cyclohexyl；

As the R⁶And R⁷Independent is " C₁~C₆Alkyl " when, " the C₁~C₆Alkyl " be methyl, ethyl, Propyl, isopropyl, butyl, isobutyl group or tert-butyl；

As the R⁶And R⁷Independent is C₃~C₆Naphthenic base when, " the C₃~C₆Naphthenic base " be cyclopropyl, Cyclopenta or cyclohexyl；

As the R⁸Independent is " C₁~C₆Alkyl " when, " the C₁~C₆Alkyl " be methyl, ethyl, third Base, isopropyl, butyl, isobutyl group or tert-butyl；

As the R⁸Independent is C₃~C₆Naphthenic base when, " the C₃~C₆Naphthenic base " be cyclopropyl, ring penta Base or cyclohexyl；

As the R²ForWhen, it is describedFor

As the R²For " the substituted or unsubstituted C that hetero atom is oxygen, sulphur or nitrogen-atoms, hetero atom number is 1-3₂~C₁₅'s When heteroaryl ", " the substituted or unsubstituted C that hetero atom is oxygen, sulphur or nitrogen-atoms, hetero atom number is 1-3₂~C₁₅ Heteroaryl " be " the substituted or unsubstituted C that hetero atom is oxygen, sulphur or nitrogen-atoms, hetero atom number is 1-2₃~C₈Heteroaryl Base "；

As the R⁹For C₁~C₆Alkyl when, " the C₁~C₆Alkyl " be methyl, ethyl, propyl, isopropyl, fourth Base, isobutyl group or tert-butyl；

As the R⁹For C₃~C₆Naphthenic base when, " the C₃~C₆Naphthenic base " be cyclopropyl, cyclopenta or cyclohexyl；

As the R¹⁰For " substituted or unsubstituted C₁~C₁₀Alkyl " when, " the substituted or unsubstituted C₁~C₁₀'s Alkyl " is " substituted or unsubstituted C₁~C₆Alkyl "；

As the R¹⁰For " hetero atom is oxygen, sulphur or nitrogen-atoms, the substituted or unsubstituted C that hetero atom number is 1-3₂~C₁₅ Heterocyclylalkyl " when, it is described that " hetero atom is oxygen, sulphur or nitrogen-atoms, the substituted or unsubstituted C that hetero atom number is 1-3₂ ~C₁₅Heterocyclylalkyl " be that " hetero atom is oxygen, sulphur or nitrogen-atoms, and hetero atom number is the C of 1-2₂~C₆Heterocyclylalkyl "；

As the R¹⁰For " substituted or unsubstituted C₃~C₁₅Aryl " when, " the substituted or unsubstituted C₃~C₁₅'s Aryl " is " substituted or unsubstituted C₅~C₁₀Aryl "；

As the R¹⁰For C₃~C₁₅Fragrant amino when, " the C₃~C₁₅Fragrant amino " be C₅~C₁₀Fragrant amino；

As the R¹¹For C₁~C₆Alkyl when, " the C₁~C₆Alkyl " be methyl, ethyl, propyl, isopropyl, fourth Base, isobutyl group or tert-butyl；

As the R¹¹For C₃~C₆Naphthenic base when, " the C₃~C₆Naphthenic base " be cyclopropyl, cyclopenta or hexamethylene Base；

As the R¹¹For C₁~C₆Alkyl silyl when, " the C₁~C₆Alkyl silyl " described in " C₁~C₆Alkane Base " is methyl, ethyl, propyl, isopropyl, butyl, isobutyl group or tert-butyl；

As the R¹²For C₁~C₆Alkyl when, " the C₁~C₆Alkyl " be methyl, ethyl, propyl, isopropyl, fourth Base, isobutyl group or tert-butyl.

7. the preparation method of the compound containing difluoro methylene as claimed in claim 6, it is characterised in that:

As the R¹For " substituted or unsubstituted C₅~C₁₄Aryl " when, " the substituted or unsubstituted C₅~C₁₄Virtue Base " is " substituted or unsubstituted phenyl ", " substituted or unsubstituted naphthalene " or " substituted or unsubstituted phenanthryl "；

As the R¹For " hetero atom is oxygen, sulphur or nitrogen-atoms, the C that hetero atom number is 1₃~C₁₀Heteroaryl " when, it is described " hetero atom is oxygen, sulphur or nitrogen-atoms, the C that hetero atom number is 1₃~C₁₀Heteroaryl " be " substituted or unsubstituted pyridine Base ", " substituted or unsubstituted furyl ", " substituted or unsubstituted pyrrole radicals ", " takes " substituted or unsubstituted thienyl " Generation or unsubstituted benzofuranyl ", " substituted or unsubstituted benzothienyl ", " substituted or unsubstituted benzopyrrole Base ",

As the R²For " the substituted or unsubstituted C that hetero atom is oxygen, sulphur or nitrogen-atoms, hetero atom number is 1-2₃~C₈'s When heteroaryl ", " the substituted or unsubstituted C that hetero atom is oxygen, sulphur or nitrogen-atoms, hetero atom number is 1-2₃~C₈'s Heteroaryl " is " substituted or unsubstituted benzoxazolyl ", " substituted or unsubstituted benzimidazolyl " or " substituted or unsubstituted Thiazolyl "；

As the R¹⁰For " substituted or unsubstituted C₁~C₆Alkyl " when, " the substituted or unsubstituted C₁~C₆Alkane Base " is " substituted or unsubstituted methyl ", " substituted or unsubstituted ethyl ", " substituted or unsubstituted propyl ", " is replaced or not Substituted isopropyl ", " substituted or unsubstituted butyl ", " substituted or unsubstituted isobutyl group " or " substituted or unsubstituted uncle Butyl "；

As the R¹⁰For " hetero atom is oxygen, sulphur or nitrogen-atoms, the C that hetero atom number is 1-2₂~C₆Heterocyclylalkyl " when, institute State " hetero atom is oxygen, sulphur or nitrogen-atoms, and hetero atom number is the C of 1-2₂~C₆Heterocyclylalkyl " be " and hetero atom be oxygen and/ Or nitrogen-atoms, the C that hetero atom number is 2₃~C₄Heterocyclylalkyl "；

As the R¹⁰For " substituted or unsubstituted C₅~C₁₀Aryl " when, " the substituted or unsubstituted C₅~C₁₀'s Aryl " is substituted or unsubstituted phenyl；

As the R¹⁰For C₅~C₁₀Fragrant amino when, " the C₅~C₁₀Fragrant amino " be

As the R¹¹For C₁~C₆Alkyl silyl when, " the C₁~C₆Alkyl silyl " be trimethyl silicon substrate, triethyl group Silicon substrate, tripropyl silicon substrate or triisopropylsilyl.

8. the preparation method of the compound containing difluoro methylene as claimed in claim 7, it is characterised in that:

As the R¹When for unsubstituted naphthalene, " the unsubstituted naphthalene " is

As the R¹When for unsubstituted phenanthryl, " the unsubstituted phenanthryl " is

As the R¹When for substituted phenyl, " the substituted phenyl " is 4- methoxyphenyl, 2- aminomethyl phenyl, 3- first Base phenyl, 4- aminomethyl phenyl,4- trifluoromethylbenzene Base, N, N- 3,5-dimethylphenyl, 3- trifluoromethyl, 4- cyano-phenyl, 4- fluorophenyl, 2,4 difluorobenzene base, 3- nitrobenzophenone, 4- bromophenyl, 3,5- dichlorophenyl, 3,5- Dimethoxyphenyl, 4- tert-butyl-phenyl, 3- bromophenyl, 4- bromophenyl,

As the R¹When for " unsubstituted pyridyl group ", " the unsubstituted pyridyl group " be 2- pyridyl group, 3- pyridyl group or 4- pyridyl group；

As the R¹When for " unsubstituted thienyl ", " the unsubstituted thienyl " is 2- thienyl or 3- thienyl；

As the R¹When for " substituted thienyl ", " the substituted thienyl " is

As the R¹When for " unsubstituted furyl ", " the unsubstituted furyl " is 2- furyl or 3- furyl；

As the R¹When for " substituted furyl ", " the substituted furyl " is

As the R¹When for " unsubstituted pyrrole radicals ", " the unsubstituted pyrrole radicals " is 2- pyrrole radicals or 3- pyrrole radicals；

As the R¹When for " substituted pyrrole radicals ", " the substituted pyrrole radicals " is

As the R²When for " unsubstituted benzoxazolyl ", " the unsubstituted benzoxazolyl " is

As the R²When for " unsubstituted thiazolyl ", " the unsubstituted thiazolyl " is

As the R²When for " substituted thiazolyl ", " the substituted thiazolyl " is

As the R²When for " unsubstituted benzimidazolyl ", " the unsubstituted benzimidazolyl " is

As the R²When for " substituted benzimidazolyl ", " the substituted benzimidazolyl " is

As the R¹⁰When for " substituted ethyl ", " the substituted ethyl " is

As the R¹⁰For " hetero atom is oxygen and/or nitrogen-atoms, the C that hetero atom number is 2₃~C₄Heterocyclylalkyl " when, it is described " hetero atom is oxygen and/or nitrogen-atoms, and hetero atom number is 2 C₃~C₄Heterocyclylalkyl " be substituted or unsubstituted morpholine Base；

As the R¹⁰When for " substituted phenyl ", " the substituted phenyl " is 4- methoxyphenyl, 2- aminomethyl phenyl, 4- Trifluoromethyl, 3- trifluoromethyl, 4- cyano-phenyl, 4- fluorophenyl, 4- bromophenyl, 3,5- Dimethoxyphenyl, 4- Tert-butyl-phenyl, 3- bromophenyl, 4- bromophenyl, 4- aminomethyl phenyl,

9. the preparation method of the compound containing difluoro methylene as described in claim 1, it is characterised in that: the compound A For following any compound:

The compound B is following any compound:

The compound C is following any compound:

10. the preparation method of the compound containing difluoro methylene as described in claim 1, it is characterised in that: contain two in described In the preparation method of fluorine methylene compound, the ligand is nitrogenous bidentate ligand or nitrogenous tridentate ligand.

11. the preparation method of the compound containing difluoro methylene as claimed in claim 10, it is characterised in that: contain two in described In the preparation method of fluorine methylene compound, the nitrogenous bidentate ligand is substituted or unsubstituted bipyridyl, substitution or not Substituted 1,10- ferrosin or N, N, N ', N '-tetramethyl ethamine；The nitrogenous tridentate ligand is " substituted or unsubstituted Terpyridyl "；" the substituted or unsubstituted bipyridyl ", " substituted or unsubstituted 1,10- ferrosin " " replace or take " substitution " described in the terpyridyl in generation " refers in heteroatomic non-ortho by C₁~C₁₀Alkyl and C₁~C₁₀Alcoxyl Replaced one or more of base, when there are multiple substituent groups, the substituent group can be identical or different.

12. the preparation method of the compound containing difluoro methylene as claimed in claim 11, it is characterised in that: when described " takes Described in generation or unsubstituted bipyridyl ", " substituted or unsubstituted 1,10- ferrosin " or " replace or replace terpyridyl " " substitution " refer in heteroatomic non-ortho by C₁~C₁₀Alkyl replaced when, " the C₁~C₁₀Alkyl " be C₁ ~C₆Alkyl；

When " the substituted or unsubstituted bipyridyl ", " substituted or unsubstituted 1,10- ferrosin " or " replaces or replace " substitution " described in terpyridyl " refers in heteroatomic non-ortho by C₁~C₁₀Alkoxy replaced when, it is described “C₁~C₁₀Alkoxy " be C₁~C₆Alkoxy.

13. the preparation method of the compound containing difluoro methylene as claimed in claim 12, it is characterised in that:

When " the substituted or unsubstituted bipyridyl ", " substituted or unsubstituted 1,10- ferrosin " or " replaces or replace " substitution " described in terpyridyl " refers in heteroatomic non-ortho by C₁~C₆Alkyl replaced when, " the C₁ ~C₆Alkyl " be methyl, ethyl, propyl, isopropyl, butyl, isobutyl group or tert-butyl；

When " the substituted or unsubstituted bipyridyl ", " substituted or unsubstituted 1,10- ferrosin " or " replaces or replace " substitution " described in terpyridyl " refers in heteroatomic non-ortho by C₁~C₆Alkoxy replaced when, it is described “C₁~C₆Alkoxy " be methoxyl group, ethyoxyl, propoxyl group, isopropoxy, butoxy, isobutoxy or tert-butoxy.

14. the preparation method of the compound containing difluoro methylene as claimed in claim 11, it is characterised in that: contain two in described In the preparation method of fluorine methylene compound, when the nitrogenous bidentate ligand is " substituted bipyridyl ", described " replaces Bipyridyl " be

In the preparation method of the compound containing difluoro methylene, when the nitrogenous bidentate ligand is " to replace or do not take When 1, the 10- ferrosin in generation ", " unsubstituted 1, the 10- ferrosin " is

In the preparation method of the compound containing difluoro methylene, when the nitrogenous tridentate ligand is " unsubstituted three When bipyridyl ", " the unsubstituted terpyridyl " is

15. the preparation method of the compound containing difluoro methylene as described in claim 1, it is characterised in that: contain two in described In the preparation method of fluorine methylene compound, when the Q is halogen, " halogen " is fluorine, chlorine, bromine or iodine；

In the preparation method of the compound containing difluoro methylene, the m is 0,1,2,3,4,5,6,7,8,9 or 10；

In the preparation method of the compound containing difluoro methylene, the n is 1 or 2.

16. the preparation method of the compound containing difluoro methylene as described in claim 1, it is characterised in that: contain two in described In the preparation method of fluorine methylene compound, the solvent is one of ether solvent and water or a variety of；

And/or

In the preparation method of the compound containing difluoro methylene, the volume of the solvent and the compound B is rubbed You are than being 1mL/mmol~100mL/mmol；

And/or

In the preparation method of the compound containing difluoro methylene, the alkali is alkali metal hydroxide, alkali metal carbon Hydrochlorate, alkali metal hydrogencarbonate, alkali metal phosphate, " alkali metal and C₁~C₄The salt that alcohol is formed " or C₁~C₄Alkylamine；

And/or

In the preparation method of the compound containing difluoro methylene, the molar ratio of the alkali and the compound B It is 1~5；

And/or

The molar ratio of the ligand and the compound B is 0.01~0.1；

And/or

In the preparation method of the compound containing difluoro methylene, the molar ratio of the nickel salt and the compound B Value is 0.01~0.1；

And/or

In the preparation method of the compound containing difluoro methylene, the temperature of the Suzuki coupling reaction is 20 DEG C~ 120℃。

17. the preparation method of the compound containing difluoro methylene as claimed in claim 16, it is characterised in that: contain two in described In the preparation method of fluorine methylene compound, when the solvent be ether solvent when, the ether solvent be tetrahydrofuran, One of ether, glycol dimethyl ether, diethylene glycol dimethyl ether, 1,4- dioxane and methyl tertiary butyl ether(MTBE) are a variety of；

And/or

It is described when the alkali is alkali carbonate in the preparation method of the compound containing difluoro methylene " alkali carbonate " is one of potassium carbonate, sodium carbonate and cesium carbonate or a variety of；

And/or

It is described when the alkali is alkali metal phosphate in the preparation method of the compound containing difluoro methylene " alkali metal phosphate " is potassium phosphate；

And/or

In the preparation method of the compound containing difluoro methylene, when the alkali is " alkali metal and C₁~C₄What alcohol was formed When salt ", " alkali metal and the C₁~C₄" C described in the salt that alcohol is formed "₁~C₄Alcohol " is methanol, ethyl alcohol, propyl alcohol, isopropyl Alcohol or the tert-butyl alcohol, " alkali metal and the C₁~C₄" alkali metal " described in the salt that alcohol is formed " is lithium, sodium, potassium, rubidium or caesium；

And/or

In the preparation method of the compound containing difluoro methylene, the molar ratio of the alkali and the compound B It is 2~3；

And/or

The molar ratio of the ligand and the compound B is 0.025~0.05；

In the preparation method of the compound containing difluoro methylene, the molar ratio of the nickel salt and the compound B Value is 0.025~0.05；

In the preparation method of the compound containing difluoro methylene, the temperature of the Suzuki coupling reaction is 60 DEG C~ 80℃。

18. the preparation method of the compound containing difluoro methylene as described in claim 1, it is characterised in that: described contains difluoro It is carried out under the conditions of the preparation method of methylene compound is existing for the co-catalyst, the co-catalyst is mantoquita；Described The molar ratio of co-catalyst and the compound B are 0~4, but do not include 0.

19. the preparation method of the compound containing difluoro methylene as claimed in claim 18, it is characterised in that: the mantoquita is One of copper oxide, copper acetate, copper chloride, copper bromide, cupric iodide, cuprous iodide, copper fluoride and copper carbonate are a variety of.