CN110357832A - A kind of preparation method of aromatic amine compounds and EphB4 kinase inhibitor and its derivative - Google Patents

A kind of preparation method of aromatic amine compounds and EphB4 kinase inhibitor and its derivative Download PDF

Info

Publication number
CN110357832A
CN110357832A CN201910610239.3A CN201910610239A CN110357832A CN 110357832 A CN110357832 A CN 110357832A CN 201910610239 A CN201910610239 A CN 201910610239A CN 110357832 A CN110357832 A CN 110357832A
Authority
CN
China
Prior art keywords
aryl
cdcl
nmr
reaction
ester
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Granted
Application number
CN201910610239.3A
Other languages
Chinese (zh)
Other versions
CN110357832B (en
Inventor
周强辉
陈树清
王鹏
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Wuhan University WHU
Original Assignee
Wuhan University WHU
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Wuhan University WHU filed Critical Wuhan University WHU
Priority to CN201910610239.3A priority Critical patent/CN110357832B/en
Publication of CN110357832A publication Critical patent/CN110357832A/en
Application granted granted Critical
Publication of CN110357832B publication Critical patent/CN110357832B/en
Active legal-status Critical Current
Anticipated expiration legal-status Critical

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C209/00—Preparation of compounds containing amino groups bound to a carbon skeleton
    • C07C209/04—Preparation of compounds containing amino groups bound to a carbon skeleton by substitution of functional groups by amino groups
    • C07C209/22—Preparation of compounds containing amino groups bound to a carbon skeleton by substitution of functional groups by amino groups by substitution of other functional groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
    • C07D211/10—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with radicals containing only carbon and hydrogen atoms attached to ring carbon atoms
    • C07D211/14—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with radicals containing only carbon and hydrogen atoms attached to ring carbon atoms with hydrocarbon or substituted hydrocarbon radicals attached to the ring nitrogen atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
    • C07D211/18—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D211/20—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by singly bound oxygen or sulphur atoms
    • C07D211/22—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by singly bound oxygen or sulphur atoms by oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D211/40—Oxygen atoms
    • C07D211/44—Oxygen atoms attached in position 4
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D211/40—Oxygen atoms
    • C07D211/44—Oxygen atoms attached in position 4
    • C07D211/46—Oxygen atoms attached in position 4 having a hydrogen atom as the second substituent in position 4
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D211/60—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D211/60—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D211/62—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals attached in position 4
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/72—Nitrogen atoms
    • C07D213/73—Unsubstituted amino or imino radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D215/38—Nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/02—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms containing only hydrogen and carbon atoms in addition to the ring hetero elements
    • C07D295/027—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms containing only hydrogen and carbon atoms in addition to the ring hetero elements containing only one hetero ring
    • C07D295/033—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms containing only hydrogen and carbon atoms in addition to the ring hetero elements containing only one hetero ring with the ring nitrogen atoms directly attached to carbocyclic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/06—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by halogen atoms or nitro radicals
    • C07D295/073—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by halogen atoms or nitro radicals with the ring nitrogen atoms and the substituents separated by carbocyclic rings or by carbon chains interrupted by carbocyclic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/08—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms
    • C07D295/096—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms separated by carbocyclic rings or by carbon chains interrupted by carbocyclic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/12—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms
    • C07D295/135—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms with the ring nitrogen atoms and the substituent nitrogen atoms separated by carbocyclic rings or by carbon chains interrupted by carbocyclic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/14—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D295/155—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals with the ring nitrogen atoms and the carbon atoms with three bonds to hetero atoms separated by carbocyclic rings or by carbon chains interrupted by carbocyclic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/16—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms
    • C07D295/18—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms by radicals derived from carboxylic acids, or sulfur or nitrogen analogues thereof
    • C07D295/182—Radicals derived from carboxylic acids
    • C07D295/185—Radicals derived from carboxylic acids from aliphatic carboxylic acids
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/16—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms
    • C07D295/18—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms by radicals derived from carboxylic acids, or sulfur or nitrogen analogues thereof
    • C07D295/182—Radicals derived from carboxylic acids
    • C07D295/192—Radicals derived from carboxylic acids from aromatic carboxylic acids
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/16—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms
    • C07D295/20—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms by radicals derived from carbonic acid, or sulfur or nitrogen analogues thereof
    • C07D295/205—Radicals derived from carbonic acid
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/10—Spiro-condensed systems
    • C07D491/113—Spiro-condensed systems with two or more oxygen atoms as ring hetero atoms in the oxygen-containing ring

Abstract

The present invention provides the preparation method of a kind of aromatic amine compounds and EphB4 kinase inhibitor and its derivative.Using aryl boric acid or aryl-boric acid ester and O- benzoyl-hydroxylamine compound as starting material; under the action of palladium catalyst, norbornene derivative, alkali, air atmosphere is stirred to react in organic solvent at 30 DEG C to 100 DEG C; separating-purifying after reaction, can be obtained aromatic amine compounds.Raw material used in this method is cheap and easy to get and reaction end halogen-free ionic residual, reaction condition are mild.Simultaneously, the present invention also provides a kind of methods of synthesis EphB4 kinase inhibitor and its derivative, only need a simple step that can synthesize EphB4 kinase inhibitor and its derivative on the basis of the halogeno-benzene or class halogeno-benzene for 3,5 diamines that the present invention synthesizes.

Description

A kind of preparation of aromatic amine compounds and EphB4 kinase inhibitor and its derivative Method
Technical field
The present invention relates to the synthetic method of a kind of aromatic amine compounds and EphB4 kinase inhibitor and its derivative, Belong to organic synthesis and field of medicinal chemistry.
Background technique
Aromatic amine compounds are widely present in biologically active natural products and pharmaceutical reagent, for example, Common antipsychotics Aripiprazole, anti-type-2 diabetes mellitus Repaglinide, antibacterials Linezolid and the kinases suppression of listing Preparation EphB4 contains aromatic amine skeleton structure.Currently, the method for the building synthesis aromatic amine compound built by C-N mainly has: (1) the C-N key building of copper catalysis；(2) the C-N key building of palladium chtalyst；(3) the C-N key building of nickel catalysis；(4) C-N of cobalt catalysis Key building；(5) the C-N key building participated in without transition metal, approach described above can only obtain location-specific amination in situ Arylamine class product cannot achieve the direct aminatin of other inertia site c h bonds of aromatic ring.
3,5- bis- core fragments of (1- morpholine) aniline as EphB4 kinase inhibitor, it is main in existing report method Need 3 steps that could complete the synthesis of the intermediate using halogenated nitrobenzene costly as starting material, synthetic route compared with It is long, higher cost.
Summary of the invention
In order to solve the deficiencies in the prior art, the present invention provides one kind in aryl boric acid or borate ortho position C-H The method that key amination synthesizes aromatic amine derivant, the method achieve aryl boric acids or the amination of borate ortho position to protonate in situ, Raw material be easy to get and there is no halogen residue problem, it is easy to operate, without adding extra protons source and Phosphine ligands, reaction condition temperature With and reaction it is insensitive to water, oxygen.On the basis of synthesizing the aromatic amine compound method of ortho position amination, we have invented a kind of high The method of effect synthesis EphB4 kinase inhibitor, this method only need three steps, and the aryl boric acid that 4 halogens of initial feed replace Or aryl-boric acid ester is cheap and easy to get, greatly reduces synthesis step and cost, improves combined coefficient.
Technical solution provided by the invention is specific as follows:
A method of synthesis aromatic amine compounds, comprising the following steps: under air atmosphere, with aryl boric acid or virtue Ylboronic acid ester A is that starting material is spread out using O- formoxyl-hydroxylamine compound B as amination reagent with palladium catalyst and norbornene Biology is that the above material is placed in 30-100 DEG C of organic solvent and is stirred to react using alkali as promotor by synergistic catalyst, is reacted After separating-purifying, obtain unitary substitution aromatic amine compounds C or binary replace aromatic amine compounds D, reaction Formula are as follows:
Wherein:
R1For hydrogen, aryl, heterocyclic aryl, alkyl, ester group, aldehyde radical, carboxyl, hydroxyl, silicon substrate, amino, cyano, nitro, acyl One of amido, sulfonyl, alkoxy, halogen；
R2For aromatic ring, hetero-aromatic ring or the substituent group for replacing hydrogen on Ar ring with Ar ring and ring, substituent group is aryl, heterocycle virtue Base, alkyl, ester group, aldehyde radical, carboxyl, hydroxyl, silicon substrate, amino, cyano, nitro, amide groups, sulfonyl, alkoxy, in halogen It is one or more of；N indicates R2Number, 0≤n≤3；
R3For hydrogen, C1-20Alkyl, aryl, heterocyclic aryl；
R4For hydrogen, aryl, heterocyclic aryl, C1-20Alkyl；
R5、R6For the substituent group on the heterocycloalkane, hetero-aromatic ring or nitrogen with nitrogen cyclization, substituent group is hydrogen, aryl, heterocycle virtue Base, C1-20Alkyl, ester group, amide groups, sulfonyl, alkoxy, tertbutyloxycarbonyl, benzyloxycarbonyl group, benzyl, to methoxy-benzyl, One of alkanoyl, sulfonyl, phthalyl, nitrine；
X, Y, Z are N or CH.
Preferably, the norbornene derivative, has the following structure:
Wherein:
R7For the substituent group on five-membered ring, o represents substituent group number, 0≤o≤8；
R8For the substituent group in double bond, p represents substituent group number, 0≤p≤2；
R7、R8Carboxylate, ester group, cyano, nitro, amide groups, sulfonyl, C independently selected from metal ions M1-10Alcoxyl Base, aryl, heterocyclic aryl, C1-10One of alkyl, halogen, wherein M is Li+、Na+、K+、Rb+、Cs+、Mg2+、Ca2+、Sr2+、 Ba2+One of；When o >=2, each R7It is identical or different；When p=2, each R8It is identical or different.
Preferably, it is preferable to use palladium catalysts to promote to react for method of the invention, and adoptable palladium catalyst includes zero The palladium salt of valence or divalent, such as: Pd (PPh3)4、Pd(dba)2、Pd2(dba)3、Pd(OAc)2、Pd(O2CCF3)2、Pd (PhCN)2Cl2、Pd(MeCN)2Cl2、PdCl2、[Pd(allyl)Cl]2Deng.Useful commercial reagent is not necessarily to specially treated.
It is preferable to use alkali for method of the invention to promote to react, and sodium carbonate, potassium carbonate, cesium carbonate, sodium acetate, vinegar can be used Sour potassium, cesium acetate, tripotassium phosphate, potassium formate, sodium hydroxide, sodium tert-butoxide etc..Useful commercial reagent is not necessarily to specially treated.
Preferably, the organic solvent is methanol, ethyl alcohol, isopropanol, the tert-butyl alcohol, tetrahydrofuran, 2- methyl tetrahydro furan It mutters, ether, dimethyl second diether, methyl tertiary butyl ether(MTBE), six alkane of 1,4- epoxy, six alkane of 1,3- epoxy, methylene chloride, 1,2- dichloro Ethane, chloroform, carbon tetrachloride, C4-12Saturated alkane, C3-12Fluoro or chloralkane, benzene,toluene,xylene, front three Benzene, dimethyl sulfoxide, N,N-dimethylformamide, DMAC N,N' dimethyl acetamide, acetone, N-Methyl pyrrolidone, acetonitrile, C3-12's One or more of saturated alkyl nitrile, dimethyl sulfoxide.
Preferably, the synergistic catalyst is palladium catalyst and norbornene, and the palladium catalyst is Pd (OAc)2, The alkali is potassium carbonate, and the organic solvent is Isosorbide-5-Nitrae-dioxane and dimethyl sulfoxide.
The molar ratio of two kinds of reactants of the method for the present invention is aryl boric acid or aryl-boric acid ester: O- formoxyl-azanol Class compound=(1~10): 1, preferably 1.5:1.
The method of the present invention reaction time, reaction temperature was 30~100 DEG C within 48 hours.Oil bath can be used in heating process (such as silicone oil, paraffin oil etc.) or other heating methods.
The present invention preferably after completion of the reaction post-processes reaction product, including suction filtration, concentration and purifying.
Sand core funnel can be used to filter at reduced pressure for the suction filtration process.
The methods of air-distillation, vacuum distillation can be used in the concentration process, such as is concentrated under reduced pressure with Rotary Evaporators.
The purification process is to chromatograph to obtain pure product by column.
The present invention also provides a kind of aromatic amine compounds of ortho position amination, adopt and are prepared with the aforedescribed process.
The present invention also provides a kind of methods for preparing EphB4 kinase inhibitor and its derivative, comprising the following steps: in sky Under atmosphere is enclosed, the phenyl boric acid or borate ester E and O- formoxyl-hydroxylamine compound B for replacing 4- halogen are in palladium catalyst, alkali With reacted in organic solvent under the action of norbornene derivative, obtain intermediate F, by gained intermediate separating-purifying, with Compound EphB4 kinase inhibitor or derivatives thereof H, reaction equation is made through copper catalysis Ullmann aminating reaction in amine reagent G are as follows:
Wherein:
W is one of fluorine, chlorine, bromine, iodine and triflate；
R5、R6For the substituent group on the heterocycloalkane, hetero-aromatic ring or nitrogen with nitrogen cyclization, substituent group is hydrogen, aryl, heterocycle Aryl, C1-20Alkyl, ester group, amide groups, sulfonyl, alkoxy, tertbutyloxycarbonyl, benzyloxycarbonyl group, benzyl, to methoxybenzyl One of base, alkanoyl, sulfonyl, phthalyl, nitrine；
R9For hydrogen, C1-20Alkyl, aryl, heterocyclic aryl；
R10、R11For the substituent group on the heterocycloalkane, hetero-aromatic ring or nitrogen with nitrogen cyclization, substituent group is hydrogen, aryl, heterocycle Aryl, C1-20Alkyl, ester group, amide groups, sulfonyl, alkoxy, tertbutyloxycarbonyl, benzyloxycarbonyl group, benzyl, to methoxybenzyl One of base, alkanoyl, sulfonyl, phthalyl, nitrine.
The method and condition of the Ullmann aminating reaction is the conventional method and condition of the such reaction in this field.
The present invention also provides a kind of EphB4 kinase inhibitor and its derivatives, adopt and are prepared with the aforedescribed process.
Method of the invention can efficiently prepare aromatic amine compounds, compared to the prior art, under the present invention has Column advantage:
1, primary raw material according to the present invention be aryl boric acid or aryl-boric acid ester, this raw material useful commercial reagent, Without specially treated, and it is cheap, it is many kinds of；
2, operation involved in the method for the present invention is easy and reaction is insensitive to water oxygen, needs compared to reaction before It to carry out being an important improvement under inert gas protection；
3, reaction involved in the method for the present invention makes without adding additional ligand and proton source compared to reaction before Phosphine ligands and equivalent alcohol do proton source reaction cost and substantially reduce；
4, reaction involved in the method for the present invention has good tolerance and universality to functional group, and substituent group can be Alkyl, alkoxy, trifluoromethyl, trifluoromethoxy, cyano, ester group, nitro, halogen atom (F, Cl, Br, I) etc..
5, the method for the present invention largely (gram-grade) can prepare aromatic amine compounds, establish for industrialized production good Basis.
6, the halogeno-benzene (or class halogeno-benzene) of 3,5 diamines of the method for the present invention preparation efficiently, fast (can only need One step) be converted to EphB4 kinase inhibitor and its derivative.
Specific embodiment
The present invention is described further below by example, it is notable that the present invention is not limited only to following Embodiment.
Embodiment 1: the preparation of compound I-1
Catalyst acetic acid palladium (4.5mg, 0.02mmol), potassium carbonate are added into the reaction tube equipped with magnetic stir bar (69.0mg, 0.5mmol), norbornene (37.6mg, 0.4mmol), 1- naphthalene boronic acids pinacol ester (76.2mg, 0.3mmol), 4- Benzoic acid morpholine ester (41.4mg, 0.2mmol), dimethyl sulfoxide (0.8mL) and Isosorbide-5-Nitrae-dioxane (2.0mL), are then heated It is reacted 12 hours under air conservation atmosphere to 70 DEG C.After reaction is cooled to room temperature, mixture is filtered with diatomite, ethyl acetate Washing, filtrate successively wash primary, organic solvent through dry Na with water, saturated sodium-chloride water solution2SO4It dries, filters, depressurize and remove Solvent is removed, column Chromatographic purification obtains compound I-1 (yellow solid, yield 84%).1H NMR(400MHz,CDCl3):δ7.76– 7.70 (m, 3H), 7.42 (t, J=7.5Hz, 1H), 7.31 (t, J=7.5Hz, 1H), 7.28-7.25 (m, 1H), 7.13 (s, 1H),3.94–3.91(m,4H),3.28–3.26(m,4H)；13C NMR(100MHz,CDCl3):δ149.2,134.6,129.0, 128.8,127.6,126.9,126.5,123.7,119.1,110.2,67.1,49.9；HRMS (ESI-TOF): calculated value: C14H16NO+[M+H+] 214.1226, measured value: 214.1228.
Embodiment 2: the preparation of compound I-2
Catalyst acetic acid palladium (4.5mg, 0.02mmol), potassium carbonate are added into the reaction tube equipped with magnetic stir bar (69.0mg, 0.5mmol), norbornene (37.6mg, 0.4mmol), 4- methyl-1-naphthalene boronic acids pinacol ester (80.4mg, 0.3mmol), 4 benzoic acid morpholine ester (41.4mg, 0.2mmol), dimethyl sulfoxide (0.8mL) and 1,4- dioxane (2.0mL) is then heated to 70 DEG C and reacts 12 hours under air conservation atmosphere.After reaction is cooled to room temperature, mixture silicon Diatomaceous earth filtering, ethyl acetate washing, filtrate successively wash primary, organic solvent through dry Na with water, saturated sodium-chloride water solution2SO4 It dries, filters, solvent is removed under reduced pressure, column Chromatographic purification obtains compound I-1 (colourless oil liquid, yield 68%).1H NMR (400MHz,CDCl3): δ 7.90 (d, J=8.3Hz, 1H), 7.74 (d, J=8.1Hz, 1H), 7.45 (t, J=7.5Hz, 1H), 7.38 (t, J=7.5Hz, 1H), 7.14 (s, 1H), 7.02 (s, 1H), 3.94-3.92 (m, 4H), 3.28-3.26 (m, 4H), 2.69(s,3H)；13C NMR(100MHz,CDCl3):δ148.8,135.4,134.9,128.2,127.5,126.2,124.0, 123.5,119.8,108.7,67.1,49.9,19.8；HRMS (ESI-TOF): calculated value: C15H18NO+[M+H+] 228.1383 measured value: 228.1382.
Embodiment 3: the preparation of compound I-3
Catalyst acetic acid palladium (4.5mg, 0.02mmol), potassium carbonate are added into the reaction tube equipped with magnetic stir bar (69.0mg, 0.5mmol), norbornene (37.6mg, 0.4mmol), 4- methoxyl group -1- naphthalene boronic acids pinacol ester (85.2mg, 0.3mmol), 4 benzoic acid morpholine ester (41.4mg, 0.2mmol), dimethyl sulfoxide (0.8mL) and 1,4- dioxane (2.0mL) is then heated to 70 DEG C and reacts 12 hours under air conservation atmosphere.After reaction is cooled to room temperature, mixture silicon Diatomaceous earth filtering, ethyl acetate washing, filtrate successively wash primary, organic solvent through dry Na with water, saturated sodium-chloride water solution2SO4 It dries, filters, solvent is removed under reduced pressure, column Chromatographic purification obtains compound I-1 (brown oil liquid, yield 62%).1H NMR (400MHz,CDCl3): δ 8.13 (d, J=8.3Hz, 1H), 7.67 (d, J=8.2Hz, 1H), 7.44 (t, J=7.5Hz, 1H), 7.31 (t, J=7.5Hz, 1H), 6.75 (s, 1H), 6.60 (s, 1H), 4.00 (s, 3H), 3.94-3.92 (m, 4H), 3.27- 3.25(m,4H)；13C NMR(100MHz,CDCl3):δ156.3,149.8,135.3,127.1,126.6,123.1,121.9, 121.7,103.2,98.0,67.1,55.5,50.4；HRMS (ESI-TOF): calculated value: C15H18NO2 +[M+H+] 244.1332 measured value: 244.1334.
Embodiment 4: the preparation of compound I-4
Catalyst acetic acid palladium (4.5mg, 0.02mmol), potassium carbonate are added into the reaction tube equipped with magnetic stir bar (69.0mg, 0.5mmol), norbornene (37.6mg, 0.4mmol), the bromo- 1- naphthalene boronic acids pinacol ester of 4- (99.6mg, 0.3mmol), 4 benzoic acid morpholine ester (41.4mg, 0.2mmol), dimethyl sulfoxide (0.8mL) and 1,4- dioxane (2.0mL) is then heated to 70 DEG C and reacts 12 hours under air conservation atmosphere.After reaction is cooled to room temperature, mixture silicon Diatomaceous earth filtering, ethyl acetate washing, filtrate successively wash primary, organic solvent through dry Na with water, saturated sodium-chloride water solution2SO4 It dries, filters, solvent is removed under reduced pressure, column Chromatographic purification obtains compound I-1 (yellow oily liquid, yield 68%).1H NMR (400MHz,CDCl3): δ 8.08 (d, J=8.2Hz, 1H), 7.67 (d, J=7.5Hz, 1H), 7.58 (d, J=2.4Hz, 1H), 7.47-7.38 (m, 2H), 7.07 (d, J=2.3Hz, 1H), 3.91-3.89 (m, 4H), 3.26-3.23 (m, 4H)；13C NMR (100MHz,CDCl3):δ149.2,135.4,127.30,127.28,127.27,126.9,124.9,123.7,122.9, 110.2,66.9,49.6；HRMS (ESI-TOF): calculated value: C14H15BrNO+[M+H+] 292.0332, measured value: 292.0332。
Embodiment 5: the preparation of compound I-5
Catalyst acetic acid palladium (4.5mg, 0.02mmol), potassium carbonate are added into the reaction tube equipped with magnetic stir bar (69.0mg, 0.5mmol), norbornene (37.6mg, 0.4mmol), 1- pyrene pinacol borate (98.4mg, 0.3mmol), 4- Benzoic acid morpholine ester (41.4mg, 0.2mmol), dimethyl sulfoxide (0.8mL) and Isosorbide-5-Nitrae-dioxane (2.0mL), are then heated It is reacted 12 hours under air conservation atmosphere to 70 DEG C.After reaction is cooled to room temperature, mixture is filtered with diatomite, ethyl acetate Washing, filtrate successively wash primary, organic solvent through dry Na with water, saturated sodium-chloride water solution2SO4It dries, filters, depressurize and remove Solvent is removed, column Chromatographic purification obtains compound I-1 (yellow solid, yield 70%).1H NMR(400MHz,CDCl3):δ8.12(d,J =7.6Hz, 2H), 8.03-8.01 (m, 2H), 7.96-7.88 (m, 3H), 7.72 (s, 2H), 4.01-3.99 (m, 4H), 3.47- 3.45(m,4H)；13C NMR(100MHz,CDCl3):δ149.7,132.4,130.3,128.0,127.1,125.2,124.9, 124.8,119.9,112.7,67.2,50.1；HRMS (ESI-TOF): calculated value: C20H18NO+[M+H+] 288.1383, it is real Measured value: 288.1385.
Embodiment 6: the preparation of compound I-6
Catalyst acetic acid palladium (4.5mg, 0.02mmol), potassium carbonate are added into the reaction tube equipped with magnetic stir bar (69.0mg, 0.5mmol), norbornene (37.6mg, 0.4mmol), 2- methylphenylboronic acid pinacol ester (65.4mg, 0.3mmol), 4 benzoic acid morpholine ester (41.4mg, 0.2mmol), dimethyl sulfoxide (0.8mL) and 1,4- dioxane (2.0mL) is then heated to 70 DEG C and reacts 12 hours under air conservation atmosphere.After reaction is cooled to room temperature, mixture silicon Diatomaceous earth filtering, ethyl acetate washing, filtrate successively wash primary, organic solvent through dry Na with water, saturated sodium-chloride water solution2SO4 It dries, filters, solvent is removed under reduced pressure, column Chromatographic purification obtains compound I-1 (colourless oil liquid, yield 70%).1H NMR (400MHz,CDCl3):δ7.20–7.16(m,1H),6.75–6.71(m,3H),3.88–3.85(m,4H),3.17–3.14(m, 4H),2.34(s,3H)；13C NMR(100MHz,CDCl3):δ151.5,139.0,129.2,121.1,116.7,113.0, 67.1,49.6,21.9；HRMS (ESI-TOF): calculated value: C11H16NO+[M+H+] 178.1226, measured value: 178.1229。
Embodiment 7: the preparation of compound I-7
Catalyst acetic acid palladium (4.5mg, 0.02mmol), potassium carbonate are added into the reaction tube equipped with magnetic stir bar (69.0mg, 0.5mmol), norbornene (37.6mg, 0.4mmol), 2- ethylo benzene pinacol borate (69.6mg, 0.3mmol), 4 benzoic acid morpholine ester (41.4mg, 0.2mmol), dimethyl sulfoxide (0.8mL) and 1,4- dioxane (2.0mL) is then heated to 70 DEG C and reacts 12 hours under air conservation atmosphere.After reaction is cooled to room temperature, mixture silicon Diatomaceous earth filtering, ethyl acetate washing, filtrate successively wash primary, organic solvent through dry Na with water, saturated sodium-chloride water solution2SO4 It dries, filters, solvent is removed under reduced pressure, column Chromatographic purification obtains compound I-1 (colourless oil liquid, yield 61%).1H NMR (400MHz,CDCl3): δ 7.21 (t, J=7.8Hz, 1H), 6.78-6.75 (m, 3H), 3.89-3.86 (m, 4H), 3.18-3.16 (m, 4H), 2.63 (q, J=7.6Hz, 2H), 1.25 (t, J=7.8Hz, 3H)；13C NMR(100MHz,CDCl3):δ151.5, 145.4,129.2,119.9,115.6,113.2,67.1,49.6,29.3,15.8；HRMS (ESI-TOF): calculated value: C12H18NO+[M+H+] 192.1383, measured value: 192.1385.
Embodiment 8: the preparation of compound I-8
Catalyst acetic acid palladium (4.5mg, 0.02mmol), potassium carbonate are added into the reaction tube equipped with magnetic stir bar (69.0mg, 0.5mmol), norbornene (37.6mg, 0.4mmol), 2- isopropyl benzene boronic acid pinacol ester (69.6mg, 0.3mmol), 4 benzoic acid morpholine ester (41.4mg, 0.2mmol), dimethyl sulfoxide (0.8mL) and 1,4- dioxane (2.0mL) is then heated to 70 DEG C and reacts 12 hours under air conservation atmosphere.After reaction is cooled to room temperature, mixture silicon Diatomaceous earth filtering, ethyl acetate washing, filtrate successively wash primary, organic solvent through dry Na with water, saturated sodium-chloride water solution2SO4 It dries, filters, solvent is removed under reduced pressure, column Chromatographic purification obtains compound I-1 (colourless oil liquid, yield 44%).1H NMR (400MHz,CDCl3): δ 7.22 (t, J=7.8Hz, 1H), 6.81-6.74 (m, 3H), 3.89-3.86 (m, 4H), 3.18-3.16 (m, 4H), 2.87 (hept, J=6.9Hz, 1H), 1.26 (s, 3H), 1.25 (s, 3H)；13C NMR(100MHz,CDCl3):δ 151.5,150.1,129.2,118.5,114.4,113.3,67.1,49.7,34.6,24.2；HRMS (ESI-TOF): theory meter Calculation value: C13H20NO+[M+H+] 206.1539, measured value: 206.1543.
Embodiment 9: the preparation of compound I-9
Catalyst acetic acid palladium (4.5mg, 0.02mmol), potassium carbonate are added into the reaction tube equipped with magnetic stir bar (69.0mg, 0.5mmol), norbornene (37.6mg, 0.4mmol), 2- trifluoromethylbenzene boronic acid pinacol ester (81.6mg, 0.3mmol), 4 benzoic acid morpholine ester (41.4mg, 0.2mmol), dimethyl sulfoxide (0.8mL) and 1,4- dioxane (2.0mL) is then heated to 70 DEG C and reacts 12 hours under air conservation atmosphere.After reaction is cooled to room temperature, mixture silicon Diatomaceous earth filtering, ethyl acetate washing, filtrate successively wash primary, organic solvent through dry Na with water, saturated sodium-chloride water solution2SO4 It dries, filters, solvent is removed under reduced pressure, column Chromatographic purification obtains compound I-1 (colourless oil liquid, yield 39%).1H NMR (400MHz,CDCl3): δ 7.37 (t, J=8.2Hz, 1H), 7.12-7.05 (m, 3H), 3.88-3.86 (m, 4H), 3.21-3.19 (m,4H)；13C NMR(100MHz,CDCl3): δ 151.52,131.63 (q, J=31.8Hz), 129.76,124.40 (q, J= 272.4Hz), 118.58,118.57,116.37 (q, J=3.9Hz), 112.00 (q, J=3.9Hz), 66.86,48.97；19F NMR(376MHz,CDCl3)δ–62.7；HRMS (ESI-TOF): calculated value: C11H13F3NO+[M+H+] 232.0944, actual measurement Value: 232.0946.
Embodiment 10: the preparation of compound I-10
Catalyst acetic acid palladium (4.5mg, 0.02mmol), potassium carbonate are added into the reaction tube equipped with magnetic stir bar (69.0mg, 0.5mmol), norbornene (37.6mg, 0.4mmol), 2- methoxyphenylboronic acid pinacol ester (70.2mg, 0.3mmol), 4 benzoic acid morpholine ester (41.4mg, 0.2mmol), dimethyl sulfoxide (0.8mL) and 1,4- dioxane (2.0mL) is then heated to 70 DEG C and reacts 12 hours under air conservation atmosphere.After reaction is cooled to room temperature, mixture silicon Diatomaceous earth filtering, ethyl acetate washing, filtrate successively wash primary, organic solvent through dry Na with water, saturated sodium-chloride water solution2SO4 It dries, filters, solvent is removed under reduced pressure, column Chromatographic purification obtains compound I-10 (colourless oil liquid, yield 39%).1H NMR (400MHz,CDCl3):δ7.22–7.17(m,1H),6.55–6.52(m,1H),6.46–6.44(m,2H),3.87–3.84(m, 4H),3.80(s,3H),3.17–3.14(m,4H)；13C NMR(100MHz,CDCl3):δ160.7,152.8,123.0,108.6, 104.8,102.3,67.0,55.3,49.4；HRMS (ESI-TOF): calculated value: C11H16NO2 +[M+H+] 194.1176, it is real Measured value: 194.1177.
Embodiment 11: the preparation of compound I-11
Catalyst acetic acid palladium (4.5mg, 0.02mmol), potassium carbonate are added into the reaction tube equipped with magnetic stir bar (69.0mg, 0.5mmol), norbornene (37.6mg, 0.4mmol), 2- trifluomethoxybenzene pinacol borate (86.4mg, 0.3mmol), 4 benzoic acid morpholine ester (41.4mg, 0.2mmol), dimethyl sulfoxide (0.8mL) and 1,4- dioxane (2.0mL) is then heated to 70 DEG C and reacts 12 hours under air conservation atmosphere.After reaction is cooled to room temperature, mixture silicon Diatomaceous earth filtering, ethyl acetate washing, filtrate successively wash primary, organic solvent through dry Na with water, saturated sodium-chloride water solution2SO4 It dries, filters, solvent is removed under reduced pressure, column Chromatographic purification obtains compound I-11 (colourless oil liquid, yield 38%).1H NMR (400MHz,CDCl3):δ7.28–7.24(m,1H),6.83–6.80(m,1H),6.73–6.71(m,2H),3.87–3.85(m, 4H),3.18–3.16(m,4H)；13C NMR(100MHz,CDCl3): δ 152.7,150.4,130.2,120.6 (q, J= 255.2Hz),113.6,111.8,108.2,66.8,48.9；19F NMR(376MHz,CDCl3)δ–57.47；HRMS(ESI- TOF): calculated value: C11H13F3NO2 +[M+H+] 248.0893, measured value: 248.0895.
Embodiment 12: the preparation of compound I-12
Catalyst acetic acid palladium (4.5mg, 0.02mmol), potassium carbonate are added into the reaction tube equipped with magnetic stir bar (69.0mg, 0.5mmol), norbornene (37.6mg, 0.4mmol), 2- (4,4,5,5- tetramethyl -1,3,2- dioxane penta Borine -2- base) methyl benzoate (78.6mg, 0.3mmol), 4 benzoic acid morpholine ester (41.4mg, 0.2mmol), dimethyl Asia Sulfone (0.8mL) and Isosorbide-5-Nitrae-dioxane (2.0mL) are then heated to 70 DEG C and react 12 hours under air conservation atmosphere.Reaction After being cooled to room temperature, mixture is filtered with diatomite, and ethyl acetate washing, filtrate is successively washed with water, saturated sodium-chloride water solution Once, organic solvent is through dry Na2SO4It dries, filters, solvent is removed under reduced pressure, column Chromatographic purification obtains compound I-12 (yellow oil Shape liquid, yield 75%).1H NMR(400MHz,CDCl3): δ 7.57 (s, 1H), 7.53 (d, J=7.7Hz, 1H), 7.32 (t, J =7.9Hz, 1H), 7.10-7.07 (m, 1H), 3.89 (s, 3H), 3.87-3.85 (m, 4H), 3.20-3.18 (m, 4H)；13C NMR (100MHz,CDCl3):δ167.4,151.3,131.1,129.3,121.1,120.1,116.4,66.9,52.2,49.2；HRMS (ESI-TOF): calculated value: C12H16NO3 +[M+H+] 222.1125, measured value: 222.1125.
Embodiment 13: the preparation of compound I-13
Catalyst acetic acid palladium (4.5mg, 0.02mmol), potassium carbonate are added into the reaction tube equipped with magnetic stir bar (69.0mg, 0.5mmol), norbornene (37.6mg, 0.4mmol), 2- nitrobenzene boronic acid pinacol ester (74.7mg, 0.3mmol), 4 benzoic acid morpholine ester (41.4mg, 0.2mmol), dimethyl sulfoxide (0.8mL) and 1,4- dioxane (2.0mL) is then heated to 70 DEG C and reacts 12 hours under air conservation atmosphere.After reaction is cooled to room temperature, mixture silicon Diatomaceous earth filtering, ethyl acetate washing, filtrate successively wash primary, organic solvent through dry Na with water, saturated sodium-chloride water solution2SO4 It dries, filters, solvent is removed under reduced pressure, column Chromatographic purification obtains compound I-13 (yellow solid, yield 77%).1H NMR (400MHz,CDCl3): δ 7.73-7.66 (m, 2H), 7.40 (t, J=8.1Hz, 1H), 7.18 (dd, J=8.3,2.5Hz, 1H), 3.89–3.87(m,4H),3.26–3.24(m,4H)；13C NMR(100MHz,CDCl3):δ152.0,149.4,129.9, 121.0,114.3,109.6,66.7,48.6；HRMS (ESI-TOF): calculated value: C10H12N2NaO3 +[M+Na+] 231.0740 measured value: 231.0737.
Embodiment 14: the preparation of compound I-14
Catalyst acetic acid palladium (4.5mg, 0.02mmol), potassium carbonate are added into the reaction tube equipped with magnetic stir bar (69.0mg, 0.5mmol), norbornene (37.6mg, 0.4mmol), 2- methyl -3- fluorobenzoic boric acid pinacol ester (70.8mg, 0.3mmol), 4 benzoic acid morpholine ester (41.4mg, 0.2mmol), dimethyl sulfoxide (0.8mL) and 1,4- dioxane (2.0mL) is then heated to 70 DEG C and reacts 12 hours under air conservation atmosphere.After reaction is cooled to room temperature, mixture silicon Diatomaceous earth filtering, ethyl acetate washing, filtrate successively wash primary, organic solvent through dry Na with water, saturated sodium-chloride water solution2SO4 It dries, filters, solvent is removed under reduced pressure, column Chromatographic purification obtains compound I-14 (yellow solid, yield 77%).1H NMR (400MHz,CDCl3): δ 6.91 (t, J=9.0Hz, 1H), 6.74-6.67 (m, 2H), 3.86-3.84 (m, 4H), 3.08-3.05 (m,4H),2.25(s,3H)；13C NMR(100MHz,CDCl3): δ 156.1 (d, J=236.6Hz), 147.7 (d, J= 2.6Hz), 125.2 (d, J=17.8Hz), 119.3 (d, J=4.6Hz), 115.3 (d, J=22.9Hz), 114.9 (d, J= 7.5Hz), 67.1,50.5,15.1 (d, J=3.3Hz)；19F NMR(376MHz,CDCl3)δ–128.3；HRMS(ESI-TOF): Calculated value: C11H15FNO+[M+H+] 196.1132, measured value: 196.1133.
Embodiment 15: the preparation of compound I-15
Catalyst acetic acid palladium (4.5mg, 0.02mmol), potassium carbonate are added into the reaction tube equipped with magnetic stir bar (69.0mg, 0.5mmol), norbornene (37.6mg, 0.4mmol), 2- methyl -3- fluorobenzoic boric acid pinacol ester (70.8mg, 0.3mmol), 4 benzoic acid morpholine ester (41.4mg, 0.2mmol), dimethyl sulfoxide (0.8mL) and 1,4- dioxane (2.0mL) is then heated to 70 DEG C and reacts 12 hours under air conservation atmosphere.After reaction is cooled to room temperature, mixture silicon Diatomaceous earth filtering, ethyl acetate washing, filtrate successively wash primary, organic solvent through dry Na with water, saturated sodium-chloride water solution2SO4 It dries, filters, solvent is removed under reduced pressure, column Chromatographic purification obtains compound I-15 (yellow oily liquid, yield 56%).1H NMR (400MHz,CDCl3):δ6.49(s,1H),6.41(s,1H),6.39(s,1H),3.85–3.83(m,4H),3.15–3.13(m, 4H),2.30(s,3H)；13C NMR(100MHz,CDCl3): δ 163.9 (d, J=242.6Hz), 152.8 (d, J=10.5Hz), 140.7 (d, J=9.7Hz), 111.7 (d, J=2.2Hz), 107.3 (d, J=21.3Hz), 99.8 (d, J=25.3Hz), (66.9,49.1,21.9 d, J=2.3Hz)；19F NMR(376MHz,CDCl3)δ–113.4；HRMS (ESI-TOF): theoretical calculation Value: C11H15FNO+[M+H+] 196.1132, measured value: 196.1135.
Embodiment 16: the preparation of compound I-16
Catalyst acetic acid palladium (4.5mg, 0.02mmol), potassium carbonate are added into the reaction tube equipped with magnetic stir bar (69.0mg, 0.5mmol), norbornene (37.6mg, 0.4mmol), 2- methyl -4- chlorophenylboronic acid pinacol ester (75.6mg, 0.3mmol), 4 benzoic acid morpholine ester (41.4mg, 0.2mmol), dimethyl sulfoxide (0.8mL) and 1,4- dioxane (2.0mL) is then heated to 70 DEG C and reacts 12 hours under air conservation atmosphere.After reaction is cooled to room temperature, mixture silicon Diatomaceous earth filtering, ethyl acetate washing, filtrate successively wash primary, organic solvent through dry Na with water, saturated sodium-chloride water solution2SO4 It dries, filters, solvent is removed under reduced pressure, column Chromatographic purification obtains compound I-16 (yellow oily liquid, yield 62%).1H NMR (400MHz,CDCl3):δ6.69–6.68(m,2H),6.59(s,1H),3.85–3.83(m,4H),3.15–3.12(m,4H), 2.29(s,3H)；13C NMR(100MHz,CDCl3):δ152.3,140.4,134.8,120.7,114.6,112.9,66.9, 49.1,21.7；HRMS (ESI-TOF): calculated value: C11H15ClNO+[M+H+] 212.0837, measured value: 212.0839.
Embodiment 17: the preparation of compound I-17
Catalyst acetic acid palladium (4.5mg, 0.02mmol), potassium carbonate are added into the reaction tube equipped with magnetic stir bar (69.0mg, 0.5mmol), norbornene (37.6mg, 0.4mmol), 2,4- dimethylphenyl boronic acid pinacol ester (69.6mg, 0.3mmol), 4 benzoic acid morpholine ester (41.4mg, 0.2mmol), dimethyl sulfoxide (0.8mL) and 1,4- dioxane (2.0mL) is then heated to 70 DEG C and reacts 12 hours under air conservation atmosphere.After reaction is cooled to room temperature, mixture silicon Diatomaceous earth filtering, ethyl acetate washing, filtrate successively wash primary, organic solvent through dry Na with water, saturated sodium-chloride water solution2SO4 It dries, filters, solvent is removed under reduced pressure, column Chromatographic purification obtains compound I-17 (yellow oily liquid, yield 60%).1H NMR (400MHz,CDCl3):δ6.57(s,3H),3.87–3.85(m,4H),3.16–3.14(m,4H),2.30(s,6H)；13C NMR (100MHz,CDCl3):δ151.5,138.8,122.1,113.8,67.1,49.7,21.8；HRMS (ESI-TOF): theoretical calculation Value: C12H18NO+[M+H+] 192.1383, measured value: 192.1387.
Embodiment 18: the preparation of compound I-18
Catalyst acetic acid palladium (4.5mg, 0.02mmol), potassium carbonate are added into the reaction tube equipped with magnetic stir bar (69.0mg, 0.5mmol), norbornene (37.6mg, 0.4mmol), 3- methyl -4- (4,4,5,5- tetramethyl -1,3,2- dioxy Heterocycle pentaborane -2- base) methyl benzoate (82.8mg, 0.3mmol), 4 benzoic acid morpholine ester (41.4mg, 0.2mmol), two Methyl sulfoxide (0.8mL) and Isosorbide-5-Nitrae-dioxane (2.0mL), be then heated to 70 DEG C under air conservation atmosphere reaction it is 12 small When.After reaction is cooled to room temperature, mixture is filtered with diatomite, and ethyl acetate washing, filtrate successively uses water, saturated sodium chloride water Solution washes primary, organic solvent through dry Na2SO4It dries, filters, solvent is removed under reduced pressure, column Chromatographic purification obtains compound I-18 (colourless oil liquid, yield 74%).1H NMR(400MHz,CDCl3): δ 7.68-7.66 (m, 2H), 7.23 (d, J=7.6Hz, 1H),3.89(s,3H),3.86–3.84(m,4H),2.94–2.92(m,4H),2.36(s,3H)；13C NMR(100MHz, CDCl3):δ167.3,151.4,138.5,131.3,128.8,124.7,120.2,67.4,52.3,52.1,18.3；HRMS (ESI-TOF): calculated value: C13H18NO3 +[M+H+] 236.1281, measured value: 236.1283.
Embodiment 19: the preparation of compound I-19
Catalyst acetic acid palladium (4.5mg, 0.02mmol), potassium carbonate are added into the reaction tube equipped with magnetic stir bar (69.0mg, 0.5mmol), norbornene (37.6mg, 0.4mmol), 2,4 difluorobenzene pinacol borate (72.0mg, 0.3mmol), 4 benzoic acid morpholine ester (41.4mg, 0.2mmol), dimethyl sulfoxide (0.8mL) and 1,4- dioxane (2.0mL) is then heated to 70 DEG C and reacts 12 hours under air conservation atmosphere.After reaction is cooled to room temperature, mixture silicon Diatomaceous earth filtering, ethyl acetate washing, filtrate successively wash primary, organic solvent through dry Na with water, saturated sodium-chloride water solution2SO4 It dries, filters, solvent is removed under reduced pressure, column Chromatographic purification obtains compound I-19 (yellow oily liquid, yield 69%).1H NMR (400MHz,CDCl3): δ 6.39-6.32 (m, 2H), 6.28 (tt, J=8.8,2.2Hz, 1H), 3.84-3.82 (m, 4H), 3.15–3.13(m,4H)；13C NMR(100MHz,CDCl3): δ 164.1 (dd, J=244.3,15.8Hz), 153.4 (t, J= 12.2Hz), 98.0-97.7 (m), 94.6 (t, J=26.1Hz), 66.6,48.4；19F NMR(376MHz,CDCl3):δ-119.0 (s)；HRMS (ESI-TOF): calculated value: C10H12F2NO+[M+H+] 200.0881, measured value: 200.0877.
Embodiment 20: the preparation of compound I-20
Catalyst acetic acid palladium (4.5mg, 0.02mmol), potassium carbonate are added into the reaction tube equipped with magnetic stir bar (69.0mg, 0.5mmol), norbornene (37.6mg, 0.4mmol), 2,4- dimethoxyphenylboronic pinacol ester (79.2mg, 0.3mmol), 4 benzoic acid morpholine ester (41.4mg, 0.2mmol), dimethyl sulfoxide (0.8mL) and 1,4- dioxane (2.0mL) is then heated to 70 DEG C and reacts 12 hours under air conservation atmosphere.After reaction is cooled to room temperature, mixture silicon Diatomaceous earth filtering, ethyl acetate washing, filtrate successively wash primary, organic solvent through dry Na with water, saturated sodium-chloride water solution2SO4 It dries, filters, solvent is removed under reduced pressure, column Chromatographic purification obtains compound I-20 (colourless oil liquid, yield 52%).1H NMR (400MHz,CDCl3):δ6.084–6.079(m,2H),6.05–6.04(m,1H),3.86–3.83(m,4H),3.78(s,6H), 3.15–3.12(m,4H)；13C NMR(100MHz,CDCl3):δ161.6,153.4,94.8,91.9,67.0,55.4,49.5； HRMS (ESI-TOF): calculated value: C12H18NO3 +[M+H+] 224.1281, measured value: 224.1276.
Embodiment 21: the preparation of compound I-21
Catalyst acetic acid palladium (4.5mg, 0.02mmol), potassium carbonate are added into the reaction tube equipped with magnetic stir bar (69.0mg, 0.5mmol), norbornene (37.6mg, 0.4mmol), the fluoro- 2- of 5- (4,4,5,5- tetramethyl -1,3,2- dioxa Ring pentaborane -2- base) methyl benzoate (84.0mg, 0.3mmol), 4 benzoic acid morpholine ester (41.4mg, 0.2mmol), diformazan Base sulfoxide (0.8mL) and Isosorbide-5-Nitrae-dioxane (2.0mL) are then heated to 70 DEG C and react 12 hours under air conservation atmosphere. After reaction is cooled to room temperature, mixture is filtered with diatomite, and ethyl acetate washing, filtrate successively uses water, saturated sodium-chloride water-soluble Liquid washes primary, organic solvent through dry Na2SO4It dries, filters, solvent is removed under reduced pressure, column Chromatographic purification obtains compound I-21 (nothing Color oily liquids, yield 52%).1H NMR(400MHz,CDCl3):δ7.36(s,1H),7.20–7.17(m,1H),6.74(dt, J=11.6,2.3Hz, 1H), 3.90 (s, 3H), 3.87-3.84 (m, 4H), 3.21-3.19 (m, 4H)；13C NMR(100MHz, CDCl3): δ 166.5 (d, J=3.7Hz), 163.6 (d, J=244.1Hz), 152.8 (d, J=9.9Hz), 132.5 (d, J= 9.8Hz), 112.0 (d, J=2.3Hz), 107.2 (d, J=23.8Hz), 106.5 (d, J=25.5Hz), 66.7,52.5, 48.6；19F NMR(376MHz,CDCl3):δ–111.4；HRMS (ESI-TOF): calculated value: C12H15FNO3 +[M+H+] 240.1030 measured value: 240.1024.
Embodiment 22: the preparation of compound I-22
Catalyst acetic acid palladium (4.5mg, 0.02mmol), potassium carbonate are added into the reaction tube equipped with magnetic stir bar (69.0mg, 0.5mmol), norbornene (37.6mg, 0.4mmol), 2- (2- bromobenzene oxygroup)-methylphenylboronic acid pinacol ester (116.4mg, 0.3mmol), 4 benzoic acid morpholine ester (41.4mg, 0.2mmol), dimethyl sulfoxide (0.8mL) and 1,4- dioxy Six rings (2.0mL) are then heated to 70 DEG C and react 12 hours under air conservation atmosphere.After reaction is cooled to room temperature, mixture It is filtered with diatomite, ethyl acetate washing, filtrate successively washes primary, organic solvent through drying with water, saturated sodium-chloride water solution Na2SO4It dries, filters, solvent is removed under reduced pressure, column Chromatographic purification obtains compound I-22 (colourless oil liquid, yield 55%).1H NMR(400MHz,CDCl3): δ 7.56 (dd, J=7.9,1.6Hz, 1H), 7.31-7.21 (m, 2H), 7.09 (s, 1H), 6.97- 6.93(m,2H),6.88–6.83(m,2H),5.13(s,2H),3.88–3.86(m,4H),3.20–3.18(m,4H)；13C NMR (100MHz,CDCl3):δ155.1,151.7,137.7,133.5,129.5,128.6,122.3,118.5,115.2,114.1, 114.0,112.6,71.0,67.0,49.3；HRMS (ESI-TOF): calculated value: C17H19BrNO2 +[M+H+]348.0594, Measured value: 348.0589.
Embodiment 23: the preparation of compound I-23
Catalyst acetic acid palladium (4.5mg, 0.02mmol), potassium carbonate are added into the reaction tube equipped with magnetic stir bar (69.0mg, 0.5mmol), norbornene (37.6mg, 0.4mmol), 2- (2- iodobenzene oxygroup)-methylphenylboronic acid pinacol ester (130.8mg, 0.3mmol), 4 benzoic acid morpholine ester (41.4mg, 0.2mmol), dimethyl sulfoxide (0.8mL) and 1,4- dioxy Six rings (2.0mL) are then heated to 70 DEG C and react 12 hours under air conservation atmosphere.After reaction is cooled to room temperature, mixture It is filtered with diatomite, ethyl acetate washing, filtrate successively washes primary, organic solvent through drying with water, saturated sodium-chloride water solution Na2SO4It dries, filters, solvent is removed under reduced pressure, column Chromatographic purification obtains compound I-23 (colourless oil liquid, yield 51%).1H NMR(400MHz,CDCl3): δ 7.79 (dd, J=7.8,1.6Hz, 1H), 7.30-7.25 (m, 2H), 7.14 (t, J=1.9Hz, 1H), 7.00-6.95 (m, 1H), 6.88-6.84 (m, 2H), 6.72 (td, J=7.6,1.3Hz, 1H), 5.12 (s, 2H), 3.88- 3.86(m,4H),3.21–3.18(m,4H)；13C NMR(100MHz,CDCl3):δ157.3,151.7,139.6,137.7, 129.6,129.4,123.0,118.4,115.2,114.2,112.9,87.0,71.0,67.0,49.4；HRMS(ESI-TOF): Calculated value: C17H19INO2 +[M+H+] 396.0455, measured value: 396.0454.
Embodiment 24: the preparation of compound I-24
Catalyst acetic acid palladium (4.5mg, 0.02mmol), potassium carbonate are added into the reaction tube equipped with magnetic stir bar (69.0mg, 0.5mmol), norbornene (37.6mg, 0.4mmol), the fluoro- 6- methyl -5- pyridine boronic acid pinacol ester of 2- (71.1mg, 0.3mmol), 4 benzoic acid morpholine ester (41.4mg, 0.2mmol), dimethyl sulfoxide (0.8mL) and 1,4- dioxy six Ring (2.0mL) is then heated to 70 DEG C and reacts 12 hours under air conservation atmosphere.After reaction is cooled to room temperature, mixture is used Diatomite filtering, ethyl acetate washing, filtrate successively wash primary, organic solvent through drying with water, saturated sodium-chloride water solution Na2SO4It dries, filters, solvent is removed under reduced pressure, column Chromatographic purification obtains compound I-24 (colourless oil liquid, yield 43%).1H NMR(400MHz,CDCl3): δ 7.56 (s, 1H), 7.04 (dd, J=10.1,1.9Hz, 1H), 3.87-3.85 (m, 4H), 3.10- 3.07(m,4H),2.28(s,3H)；13C NMR(100MHz,CDCl3): δ 154.5 (d, J=236.8Hz), 138.2 (d, J= 14.3Hz), 134.5 (d, J=23.8Hz), 131.6 (d, J=4.6Hz), 128.2 (d, J=4.8Hz), 66.9,50.4 (d, J =3.7Hz), 17.8；19F NMR(376MHz,CDCl3):δ–78.1；HRMS (ESI-TOF): calculated value: C10H14FN2O+ [M+Na+] 197.1085, measured value: 197.1086.
Embodiment 25: the preparation of compound I-25
Catalyst acetic acid palladium (4.5mg, 0.02mmol), potassium carbonate are added into the reaction tube equipped with magnetic stir bar (69.0mg, 0.5mmol), norbornene (37.6mg, 0.4mmol), 2- methoxyl group -6- methyl -3- pyridine boronic acid pinacol ester (74.7mg, 0.3mmol), 4 benzoic acid morpholine ester (41.4mg, 0.2mmol), dimethyl sulfoxide (0.8mL) and 1,4- dioxy six Ring (2.0mL) is then heated to 70 DEG C and reacts 12 hours under air conservation atmosphere.After reaction is cooled to room temperature, mixture is used Diatomite filtering, ethyl acetate washing, filtrate successively wash primary, organic solvent through drying with water, saturated sodium-chloride water solution Na2SO4It dries, filters, solvent is removed under reduced pressure, column Chromatographic purification obtains compound I-25 (colourless oil liquid, yield 44%).1H NMR(400MHz,CDCl3): δ 6.25 (d, J=1.9Hz, 1H), 5.88 (d, J=2.0Hz, 1H), 3.88 (s, 3H), 3.81- 3.79(m,4H),3.23–3.21(m,4H),2.36(s,3H)；13C NMR(100MHz,CDCl3):δ165.6,158.6, 156.6,102.9,90.3,66.6,53.4,46.9,24.7；HRMS (ESI-TOF): calculated value: C11H17N2O2 +[M+H+] 209.1285 measured value: 209.1289.
Embodiment 26: the preparation of compound I-26
Catalyst acetic acid palladium (4.5mg, 0.02mmol), potassium carbonate are added into the reaction tube equipped with magnetic stir bar (69.0mg, 0.5mmol), norbornene (37.6mg, 0.4mmol), 5- quinoline boronic acid pinacol ester (76.5mg, 0.3mmol), 4 benzoic acid morpholine ester (41.4mg, 0.2mmol), dimethyl sulfoxide (0.8mL) and Isosorbide-5-Nitrae-dioxane (2.0mL), then plus Heat is reacted 12 hours under air conservation atmosphere to 70 DEG C.After reaction is cooled to room temperature, mixture is filtered with diatomite, acetic acid second Ester washing, filtrate successively wash primary, organic solvent through dry Na with water, saturated sodium-chloride water solution2SO4It dries, filters, depressurize Solvent is removed, column Chromatographic purification obtains compound I-26 (yellow solid, yield 74%).1H NMR(400MHz,CDCl3):δ6.25 (d, J=1.9Hz, 1H), 5.88 (d, J=2.0Hz, 1H), 3.88 (s, 3H), 3.81-3.79 (m, 4H), 3.23-3.21 (m, 4H),2.36(s,3H)；13C NMR(100MHz,CDCl3):δ165.6,158.6,156.6,102.9,90.3,66.6,53.4, 46.9,24.7；HRMS (ESI-TOF): calculated value: C11H17N2O2 +[M+H+] 209.1285, measured value: 209.1289.
Embodiment 27: the preparation of compound I-27
Catalyst acetic acid palladium (4.5mg, 0.02mmol), potassium carbonate are added into the reaction tube equipped with magnetic stir bar (110.4mg, 0.8mmol), norbornene (37.6mg, 0.4mmol), 4- fluorobenzoic boric acid pinacol borate (66.6mg, 0.3mmol), 4 benzoic acid morpholine ester (82.8mg, 0.4mmol), dimethyl sulfoxide (0.8mL) and 1,4- dioxane (2.0mL) is then heated to 70 DEG C and reacts 12 hours under air conservation atmosphere.After reaction is cooled to room temperature, mixture silicon Diatomaceous earth filtering, ethyl acetate washing, filtrate successively wash primary, organic solvent through dry Na with water, saturated sodium-chloride water solution2SO4 It dries, filters, solvent is removed under reduced pressure, column Chromatographic purification obtains compound I-27 (white solid, yield 42%).1H NMR (400MHz,CDCl3): δ 6.18-6.16 (m, 2H), 6.13 (d, J=2.1Hz, 1H), 3.85-3.82 (m, 8H), 3.14-3.12 (m,8H)；13C NMR(100MHz,CDCl3): δ 164.8 (d, J=240.1Hz), 153.5 (d, J=12.1Hz), 98.4 (d, J =2.0Hz), 94.9 (d, J=25.7Hz), 66.9,49.3；19F NMR(376MHz,CDCl3):δ-109.7；HRMS(ESI- TOF): calculated value: C14H20FN2O2 +[M+H+] 267.1503, measured value: 267.1502.
Embodiment 28: the preparation of compound I-28
Catalyst acetic acid palladium (4.5mg, 0.02mmol), potassium carbonate are added into the reaction tube equipped with magnetic stir bar (110.4mg, 0.8mmol), norbornene (37.6mg, 0.4mmol), 4- chlorophenylboronic acid pinacol borate (71.4mg, 0.3mmol), 4 benzoic acid morpholine ester (82.8mg, 0.4mmol), dimethyl sulfoxide (0.8mL) and 1,4- dioxane (2.0mL) is then heated to 70 DEG C and reacts 12 hours under air conservation atmosphere.After reaction is cooled to room temperature, mixture silicon Diatomaceous earth filtering, ethyl acetate washing, filtrate successively wash primary, organic solvent through dry Na with water, saturated sodium-chloride water solution2SO4 It dries, filters, solvent is removed under reduced pressure, column Chromatographic purification obtains compound I-28 (colourless oil liquid, yield 47%).1H NMR (400MHz,CDCl3): δ 6.43 (s, 1H), 6.42 (s, 1H), 6.28 (t, J=2.1Hz, 1H), 3.84-3.82 (m, 8H), 3.14–3.12(m,8H)；13C NMR(100MHz,CDCl3):δ153.1,135.8,108.0,101.5,66.9,49.3；HRMS (ESI-TOF): calculated value: C14H20ClN2O2 +[M+H+] 283.1208, measured value: 283.1207.
Embodiment 29: the preparation of compound I-29
Catalyst acetic acid palladium (4.5mg, 0.02mmol), potassium carbonate are added into the reaction tube equipped with magnetic stir bar (110.4mg, 0.8mmol), norbornene (37.6mg, 0.4mmol), 4- bromobenzeneboronic acid pinacol borate (84.6mg, 0.3mmol), 4 benzoic acid morpholine ester (82.8mg, 0.4mmol), dimethyl sulfoxide (0.8mL) and 1,4- dioxane (2.0mL) is then heated to 70 DEG C and reacts 12 hours under air conservation atmosphere.After reaction is cooled to room temperature, mixture silicon Diatomaceous earth filtering, ethyl acetate washing, filtrate successively wash primary, organic solvent through dry Na with water, saturated sodium-chloride water solution2SO4 It dries, filters, solvent is removed under reduced pressure, column Chromatographic purification obtains compound I-29 (colourless oil liquid, yield 44%).1H NMR (400MHz,CDCl3): δ 6.57 (s, 1H), 6.57 (s, 1H), 6.32 (t, J=2.1Hz, 1H), 3.84-3.81 (m, 8H), 3.14–3.11(m,8H)；13C NMR(100MHz,CDCl3):δ153.3,124.1,111.0,102.1,66.9,49.4；HRMS (ESI-TOF): calculated value: C14H20BrN2O2 +[M+H+] 327.0703, measured value: 327.0704.
Embodiment 30: the preparation of compound I-30
Methyl 2-(bis(tert-butoxycarbonyl)amino)-3-(3,5-dimorpholinophenyl) propanoate(3ad)
Catalyst acetic acid palladium (4.5mg, 0.02mmol), potassium carbonate are added into the reaction tube equipped with magnetic stir bar (110.4mg, 0.8mmol), norbornene (37.6mg, 0.4mmol), 2- (two (tertbutyloxycarbonyl) amino) -3- (4- (4,4, 5,5- tetramethyl -1,3,2- dioxaborolanes -2- base) phenyl) methyl propionate (151.5mg, 0.3mmol), 4 benzoic acid Morpholine ester (82.8mg, 0.4mmol), dimethyl sulfoxide (0.8mL) and Isosorbide-5-Nitrae-dioxane (2.0mL), are then heated to 70 DEG C It is reacted 12 hours under air conservation atmosphere.After reaction is cooled to room temperature, mixture is filtered with diatomite, ethyl acetate washing, Filtrate successively washes primary, organic solvent through dry Na with water, saturated sodium-chloride water solution2SO4Dry, filter, be removed under reduced pressure it is molten Agent, column Chromatographic purification obtain compound I-30 (colourless oil liquid, yield 26%).1H NMR(400MHz,CDCl3):δ6.30– 6.28 (m, 3H), 5.13 (dd, J=10.5,4.8Hz, 1H), 3.84-3.81 (m, 8H), 3.74 (s, 3H), 3.32 (dd, J= 14.0,4.8Hz, 1H), 3.17-3.12 (m, 1H), 3.12-3.09 (m, 8H), 1.39 (s, 18H)；13C NMR(100MHz, CDCl3):δ171.1,152.5,151.9,139.2,109.9,102.7,83.0,67.1,59.4,52.4,49.9,36.8, 28.0；HRMS (ESI-TOF): calculated value: C28H43N3NaO8 +[M+Na+] 572.2941, measured value: 572.2941.
Embodiment 31: the preparation of compound I-31
Catalyst acetic acid palladium (4.5mg, 0.02mmol), potassium carbonate are added into the reaction tube equipped with magnetic stir bar (69.0mg, 0.5mmol), norbornene (37.6mg, 0.4mmol), 1- naphthalene boronic acids pinacol ester (76.2mg, 0.3mmol), 1- Benzoate ester (41.0mg, 0.2mmol), dimethyl sulfoxide (0.8mL) and Isosorbide-5-Nitrae-dioxane (2.0mL), are then heated It is reacted 12 hours under air conservation atmosphere to 70 DEG C.After reaction is cooled to room temperature, mixture is filtered with diatomite, ethyl acetate Washing, filtrate successively wash primary, organic solvent through dry Na with water, saturated sodium-chloride water solution2SO4It dries, filters, depressurize and remove Solvent is removed, column Chromatographic purification obtains compound I-31 (white solid, yield 57%).1H NMR(400MHz,CDCl3):δ7.72– 7.64 (m, 3H), 7.39-7.35 (m, 1H), 7.30-7.23 (m, 2H), 7.12 (d, J=2.5Hz, 1H), 3.28-3.21 (m, 4H),1.79–1.73(m,4H),1.65–1.58(m,2H)；13C NMR(100MHz,CDCl3):δ150.2,134.8,128.6, 128.4,127.5,126.8,126.2,123.2,120.3,110.5,51.2,26.0,24.5；HRMS (ESI-TOF): theory meter Calculation value: C15H18N+[M+H+] 212.1434, measured value: 212.1432.
Embodiment 32: the preparation of compound I-32
Catalyst acetic acid palladium (4.5mg, 0.02mmol), potassium carbonate are added into the reaction tube equipped with magnetic stir bar (69.0mg, 0.5mmol), norbornene (37.6mg, 0.4mmol), 1- naphthalene boronic acids pinacol ester (76.2mg, 0.3mmol), 1- Benzoic acid -4- methyl piperidine ester (43.8mg, 0.2mmol), dimethyl sulfoxide (0.8mL) and Isosorbide-5-Nitrae-dioxane (2.0mL), so After be heated to 70 DEG C and reacted 12 hours under air conservation atmosphere.After reaction is cooled to room temperature, mixture is filtered with diatomite, second Acetoacetic ester washing, filtrate successively wash primary, organic solvent through dry Na with water, saturated sodium-chloride water solution2SO4Dry, filter, Solvent is removed under reduced pressure, column Chromatographic purification obtains compound I-32 (yellow solid, yield 70%).1H NMR(400MHz,CDCl3):δ 7.64–7.59(m,3H),7.33–7.29(m,1H),7.22–7.18(m,2H),7.06(s,1H),3.72–3.68(m,2H), 2.73-2.66 (m, 2H), 1.73-1.69 (m, 2H), 1.55-1.42 (m, 2H), 1.39-1.29 (m, 2H), 0.93 (d, J= 6.4Hz,3H)；13C NMR(100MHz,CDCl3):δ149.9,134.8,128.6,128.4,127.5,126.8,126.2, 123.2,120.3,110.5,50.5,34.3,30.9,22.1；HRMS (ESI-TOF): calculated value: C16H20N+[M+H+] 226.1590 measured value: 226.1592.
Embodiment 33: the preparation of compound I-33
Catalyst acetic acid palladium (4.5mg, 0.02mmol), potassium carbonate are added into the reaction tube equipped with magnetic stir bar (69.0mg, 0.5mmol), norbornene (37.6mg, 0.4mmol), 1- naphthalene boronic acids pinacol ester (76.2mg, 0.3mmol), 1- Benzoic acid -4- Phenylpiperidine ester (43.8mg, 0.2mmol), dimethyl sulfoxide (0.8mL) and Isosorbide-5-Nitrae-dioxane (2.0mL), so After be heated to 70 DEG C and reacted 12 hours under air conservation atmosphere.After reaction is cooled to room temperature, mixture is filtered with diatomite, second Acetoacetic ester washing, filtrate successively wash primary, organic solvent through dry Na with water, saturated sodium-chloride water solution2SO4Dry, filter, Solvent is removed under reduced pressure, column Chromatographic purification obtains compound I-33 (yellow solid, yield 72%).1H NMR(400MHz,CDCl3):δ 7.74–7.69(m,3H),7.42–7.37(m,1H),7.35–7.18(m,8H),3.95–3.92(m,2H),2.93–2.86(m, 2H),2.74–2.66(m,1H),2.02–1.91(m,4H)；13C NMR(100MHz,CDCl3):δ149.8,146.2,134.8, 128.8,128.7,128.5,127.5,127.01,126.8,126.5,126.3,123.4,120.3,110.7,51.0,42.7, 33.5；HRMS (ESI-TOF): calculated value: C21H22N+[M+H+] 288.1747, measured value: 288.1747.
Embodiment 34: the preparation of compound I-34
Catalyst acetic acid palladium (4.5mg, 0.02mmol), potassium carbonate are added into the reaction tube equipped with magnetic stir bar (69.0mg, 0.5mmol), norbornene (37.6mg, 0.4mmol), 1- naphthalene boronic acids pinacol ester (76.2mg, 0.3mmol), 1- Benzoic acid -4- hydroxy piperidine ester (43.8mg, 0.2mmol), dimethyl sulfoxide (0.8mL) and Isosorbide-5-Nitrae-dioxane (2.0mL), so After be heated to 70 DEG C and reacted 12 hours under air conservation atmosphere.After reaction is cooled to room temperature, mixture is filtered with diatomite, second Acetoacetic ester washing, filtrate successively wash primary, organic solvent through dry Na with water, saturated sodium-chloride water solution2SO4Dry, filter, Solvent is removed under reduced pressure, column Chromatographic purification obtains compound I-34 (white solid, yield 73%).1H NMR(400MHz,CDCl3):δ 7.72-7.66 (m, 3H), 7.41-7.37 (m, 1H), 7.30-7.24 (m, 2H), 7.13 (d, J=2.4Hz, 1H), 3.89-3.83 (m,1H),3.68–3.63(m,2H),3.02–2.95(m,2H),2.07–2.01(m,2H),1.78–1.69(m,3H)；13C NMR (100MHz,CDCl3):δ149.2,134.7,128.8,128.5,127.5,126.8,126.3,123.4,120.1,110.7, 68.0,47.8,34.3；HRMS (ESI-TOF): calculated value: C15H18NO+[M+H+] 228.1383, measured value: 228.1378。
Embodiment 35: the preparation of compound I-35
Catalyst acetic acid palladium (4.5mg, 0.02mmol), potassium carbonate are added into the reaction tube equipped with magnetic stir bar (69.0mg, 0.5mmol), norbornene (37.6mg, 0.4mmol), 1- naphthalene boronic acids pinacol ester (76.2mg, 0.3mmol), 1- Benzoic acid -4- ((tert-butyl dimethyl silyl) oxygroup) piperidine ester (67.0mg, 0.2mmol), dimethyl sulfoxide (0.8mL) and 1,4- Dioxane (2.0mL) is then heated to 70 DEG C and reacts 12 hours under air conservation atmosphere.After reaction is cooled to room temperature, mix It closes object to be filtered with diatomite, ethyl acetate washing, filtrate is successively washed primary, organic solvent with water, saturated sodium-chloride water solution and passed through Dry Na2SO4It dries, filters, solvent is removed under reduced pressure, column Chromatographic purification obtains compound I-35 (white solid, yield 45%).1H NMR(400MHz,CDCl3): δ 7.71-7.66 (m, 3H), 7.40-7.36 (m, 1H), 7.30-7.24 (m, 2H), 7.14 (d, J= 1.9Hz,1H),3.94–3.88(m,1H),3.57–3.51(m,2H),3.14–3.08(m,2H),1.96–1.90(m,2H), 1.77–1.69(m,2H),0.91(s,9H),0.09(s,6H)；13C NMR(100MHz,CDCl3):δ149.5,134.8, 128.7,128.4,127.5,126.8,126.3,123.3,120.0,110.5,67.6,47.1,34.5,26.0,18.5,- 4.5；HRMS (ESI-TOF): calculated value: C21H32NOSi+[M+H+] 342.2248, measured value: 342.2243.
Embodiment 36: the preparation of compound I-36
Catalyst acetic acid palladium (4.5mg, 0.02mmol), potassium carbonate are added into the reaction tube equipped with magnetic stir bar (69.0mg, 0.5mmol), norbornene (37.6mg, 0.4mmol), 1- naphthalene boronic acids pinacol ester (76.2mg, 0.3mmol), 1- Benzoic acid -4- hydroxymethyl piperidine ester (47.0mg, 0.2mmol), dimethyl sulfoxide (0.8mL) and Isosorbide-5-Nitrae-dioxane (2.0mL), 70 DEG C are then heated to react 12 hours under air conservation atmosphere.After reaction is cooled to room temperature, mixture is filtered with diatomite, Ethyl acetate washing, filtrate successively wash primary, organic solvent through dry Na with water, saturated sodium-chloride water solution2SO4It is dry, mistake It filters, solvent is removed under reduced pressure, column Chromatographic purification obtains compound I-36 (violet solid, yield 83%).1H NMR(400MHz, CDCl3):δ7.70–7.66(m,3H),7.40–7.36(m,1H),7.30–7.25(m,2H),7.14(s,1H),3.79–3.75 (m,1H),3.66–3.53(m,3H),2.83–2.77(m,1H),2.66–2.60(m,1H),2.01–1.90(m,1H),1.87– 1.67(m,4H),1.26–1.11(m,1H)；13C NMR(100MHz,CDCl3):δ149.9,134.7,128.7,128.5, 127.5,126.8,126.3,123.4,120.4,110.8,66.2,53.8,51.0,38.7,27.2,24.8；HRMS(ESI- TOF): calculated value: C16H20NO+[M+H+] 242.1539, measured value: 242.1547.
Embodiment 37: the preparation of compound I-37
Catalyst acetic acid palladium (4.5mg, 0.02mmol), potassium carbonate are added into the reaction tube equipped with magnetic stir bar (69.0mg, 0.5mmol), norbornene (37.6mg, 0.4mmol), 1- naphthalene boronic acids pinacol ester (76.2mg, 0.3mmol), 1- Benzoic acid -4- (hydroxyl diphenyl methyl) piperidine ester (77.4mg, 0.2mmol), dimethyl sulfoxide (0.8mL) and 1,4- dioxy six Ring (2.0mL) is then heated to 70 DEG C and reacts 12 hours under air conservation atmosphere.After reaction is cooled to room temperature, mixture is used Diatomite filtering, ethyl acetate washing, filtrate successively wash primary, organic solvent through drying with water, saturated sodium-chloride water solution Na2SO4It dries, filters, solvent is removed under reduced pressure, column Chromatographic purification obtains compound I-37 (yellow solid, yield 53%).1H NMR (400MHz,CDCl3):δ7.70–7.65(m,3H),7.53–7.51(m,4H),7.40–7.19(m,9H),7.10(s,1H), 3.86–3.81(m,2H),2.84–2.77(m,2H),2.66–2.58(m,1H),2.13(s,1H),1.69–1.60(m,4H)；13C NMR(100MHz,CDCl3):δ149.5,145.9,134.7,128.7,128.5,128.4,127.5,126.8,126.3, 125.9,123.4,120.2,110.6,79.7,50.7,44.3,26.6；HRMS (ESI-TOF): calculated value: C28H28NO+ [M+H+] 394.2165, measured value: 394.2169.
Embodiment 38: the preparation of compound I-38
Catalyst acetic acid palladium (4.5mg, 0.02mmol), potassium carbonate are added into the reaction tube equipped with magnetic stir bar (69.0mg, 0.5mmol), norbornene (37.6mg, 0.4mmol), 1- naphthalene boronic acids pinacol ester (76.2mg, 0.3mmol), 8- Benzoic acid -1,4- dioxy -8- azaspiro [4.5] last of the ten Heavenly stems ester (52.6mg, 0.2mmol), dimethyl sulfoxide (0.8mL) and 1,4- dioxy Six rings (2.0mL) are then heated to 70 DEG C and react 12 hours under air conservation atmosphere.After reaction is cooled to room temperature, mixture It is filtered with diatomite, ethyl acetate washing, filtrate successively washes primary, organic solvent through drying with water, saturated sodium-chloride water solution Na2SO4It dries, filters, solvent is removed under reduced pressure, column Chromatographic purification obtains compound I-38 (yellow solid, yield 57%).1H NMR (400MHz,CDCl3): δ 7.74-7.68 (m, 3H), 7.43-7.39 (m, 1H), 7.32-7.27 (m, 2H), 7.16 (d, J= 2.4Hz,1H),4.02(s,4H),3.47–3.42(m,4H),1.95–1.89(m,4H)；13C NMR(100MHz,CDCl3):δ 148.9,134.7,128.8,128.5,127.5,126.8,126.3,123.4,120.1,110.8,107.3,64.5,48.2, 34.7；HRMS (ESI-TOF): calculated value: C17H20NO2 +[M+H+] 270.1489, measured value: 270.1489.
Embodiment 39: the preparation of compound I-39
Catalyst acetic acid palladium (4.5mg, 0.02mmol), potassium carbonate are added into the reaction tube equipped with magnetic stir bar (69.0mg, 0.5mmol), norbornene (37.6mg, 0.4mmol), 1- naphthalene boronic acids pinacol ester (76.2mg, 0.3mmol), 1- Benzoxy phenylpiperidines -3- Ethyl formate (52.6mg, 0.2mmol), dimethyl sulfoxide (0.8mL) and 1,4- dioxane (2.0mL) is then heated to 70 DEG C and reacts 12 hours under air conservation atmosphere.After reaction is cooled to room temperature, mixture silicon Diatomaceous earth filtering, ethyl acetate washing, filtrate successively wash primary, organic solvent through dry Na with water, saturated sodium-chloride water solution2SO4 It dries, filters, solvent is removed under reduced pressure, column Chromatographic purification obtains compound I-39 (yellow oily liquid, yield 71%).1H NMR (400MHz,CDCl3):δ7.74–7.69(m,3H),7.43–7.39(m,1H),7.32–7.29(m,2H),7.17(s,1H), 4.21 (q, J=7.1Hz, 2H), 3.85-3.81 (m, 1H), 3.63-3.59 (m, 1H), 3.17-3.11 (m, 1H), 2.95-2.88 (m, 1H), 2.79-2.72 (m, 1H), 2.09-2.06 (m, 1H), 1.92-1.67 (m, 3H), 1.31 (t, J=7.1Hz, 3H)；13C NMR(100MHz,CDCl3):δ174.0,149.4,134.7,128.8,128.6,127.5,126.8,126.3,123.5, 120.4,110.9,60.7,52.6,50.3,41.6,27.1,24.4,14.4；HRMS (ESI-TOF): calculated value: C18H22NO2 +[M+H+] 284.1645, measured value: 284.1639.
Embodiment 40: the preparation of compound I-40
Catalyst acetic acid palladium (4.5mg, 0.02mmol), potassium carbonate are added into the reaction tube equipped with magnetic stir bar (69.0mg, 0.5mmol), norbornene (37.6mg, 0.4mmol), 1- naphthalene boronic acids pinacol ester (76.2mg, 0.3mmol), 1- Benzoyloxy piperidine-4-ethyl formate (52.6mg, 0.2mmol), dimethyl sulfoxide (0.8mL) and 1,4- dioxane (2.0mL) is then heated to 70 DEG C and reacts 12 hours under air conservation atmosphere.After reaction is cooled to room temperature, mixture silicon Diatomaceous earth filtering, ethyl acetate washing, filtrate successively wash primary, organic solvent through dry Na with water, saturated sodium-chloride water solution2SO4 It dries, filters, solvent is removed under reduced pressure, column Chromatographic purification obtains compound I-40 (yellow oily liquid, yield 59%).1H NMR (400MHz,CDCl3): δ 7.72-7.66 (m, 3H), 7.41-7.37 (m, 1H), 7.30-7.25 (m, 2H), 7.12 (d, J= 2.3Hz, 1H), 4.17 (q, J=7.1Hz, 2H), 3.75 (dt, J=12.4,3.2Hz, 2H), 2.86 (td, J=12.3, 2.8Hz, 2H), 2.51-2.43 (m, 1H), 2.15-1.86 (m, 4H), 1.28 (t, J=7.2Hz, 3H)；13C NMR(100MHz, CDCl3):δ175.0,149.5,134.7,128.8,128.6,127.5,126.8,126.3,123.5,120.2,110.8, 60.6,49.7,41.2,28.2,14.4；HRMS (ESI-TOF): calculated value: C18H22NO2 +[M+H+] 284.1645, actual measurement Value: 284.1639.
Embodiment 41: the preparation of compound I-41
Catalyst acetic acid palladium (4.5mg, 0.02mmol), potassium carbonate are added into the reaction tube equipped with magnetic stir bar (69.0mg, 0.5mmol), norbornene (37.6mg, 0.4mmol), 1- naphthalene boronic acids pinacol ester (76.2mg, 0.3mmol), 1- Benzoic acid -4- benzoyl-piperazine ester (61.8mg, 0.2mmol), dimethyl sulfoxide (0.8mL) and 1,4- dioxane (2.0mL) is then heated to 70 DEG C and reacts 12 hours under air conservation atmosphere.After reaction is cooled to room temperature, mixture silicon Diatomaceous earth filtering, ethyl acetate washing, filtrate successively wash primary, organic solvent through dry Na with water, saturated sodium-chloride water solution2SO4 It dries, filters, solvent is removed under reduced pressure, column Chromatographic purification obtains compound I-41 (yellow oily liquid, yield 43%).1H NMR (400MHz,CDCl3):δ7.76–7.68(m,3H),7.49–7.39(m,6H),7.35–7.29(m,1H),7.26–7.24(m, 1H),7.12(s,1H),3.99(brs,2H),3.64(brs,2H),3.35(brs,2H),3.21(brs,2H)；13C NMR (100MHz,CDCl3):δ170.5,148.8,135.7,134.5,130.0,129.1,129.0,128.7,127.6,127.2, 126.9,126.6,124.0,119.8,111.2,50.3,50.1,47.7,42.2；HRMS (ESI-TOF): calculated value: C21H21N2O+[M+H+] 317.1648, measured value: 317.1649.
Embodiment 42: the preparation of compound I-42
Catalyst acetic acid palladium (4.5mg, 0.02mmol), potassium carbonate are added into the reaction tube equipped with magnetic stir bar (69.0mg, 0.5mmol), norbornene (37.6mg, 0.4mmol), 1- naphthalene boronic acids pinacol ester (76.2mg, 0.3mmol), 4- Benzoyloxy -1- piperazinecarboxylic acid benzyl ester (67.8mg, 0.2mmol), dimethyl sulfoxide (0.8mL) and 1,4- dioxane (2.0mL) is then heated to 70 DEG C and reacts 12 hours under air conservation atmosphere.After reaction is cooled to room temperature, mixture silicon Diatomaceous earth filtering, ethyl acetate washing, filtrate successively wash primary, organic solvent through dry Na with water, saturated sodium-chloride water solution2SO4 It dries, filters, solvent is removed under reduced pressure, column Chromatographic purification obtains compound I-42 (yellow solid, yield 50%).1H NMR (400MHz,CDCl3):δ7.76–7.66(m,3H),7.44–7.28(m,7H),7.27–7.22(m,1H),7.11(s,1H), 5.18 (s, 2H), 3.71 (t, J=5.1Hz, 4H), 3.24 (s, 4H)；13C NMR(100MHz,CDCl3):δ155.4,149.0, 136.7,134.5,129.0,128.9,128.7,128.2,128.1,127.6,126.9,126.5,123.9,119.9, 111.1,67.4,49.9,43.9；HRMS (ESI-TOF): calculated value: C22H23N2O2 +[M+H+] 347.1754, measured value: 347.1751。
Embodiment 43: the preparation of compound I-43
Catalyst acetic acid palladium (4.5mg, 0.02mmol), potassium carbonate are added into the reaction tube equipped with magnetic stir bar (69.0mg, 0.5mmol), norbornene (37.6mg, 0.4mmol), 1- naphthalene boronic acids pinacol ester (76.2mg, 0.3mmol), 4- Benzoyloxy -1- piperazinecarboxylic acid the tert-butyl ester (61.2mg, 0.2mmol), dimethyl sulfoxide (0.8mL) and 1,4- dioxane (2.0mL) is then heated to 70 DEG C and reacts 12 hours under air conservation atmosphere.After reaction is cooled to room temperature, mixture silicon Diatomaceous earth filtering, ethyl acetate washing, filtrate successively wash primary, organic solvent through dry Na with water, saturated sodium-chloride water solution2SO4 It dries, filters, solvent is removed under reduced pressure, column Chromatographic purification obtains compound I-43 (white solid, yield 60%).1H NMR (400MHz,CDCl3): δ 7.76-7.67 (m, 3H), 7.41 (t, J=7.1Hz, 1H), 7.34-7.24 (m, 2H), 7.12 (d, J =2.3Hz, 1H), 3.63 (t, J=5.1Hz, 4H), 3.23 (t, J=5.2Hz, 4H), 1.50 (s, 9H)；13C NMR(100MHz, CDCl3):δ154.9,149.2,134.6,129.0,128.9,127.6,126.9,126.5,123.8,119.9,111.0, 80.1,49.9,28.6；HRMS (ESI-TOF): calculated value: C19H24N2NaO2 +[M+Na+] 335.1730, measured value: 335.1731。
Embodiment 44: the preparation of compound I-44
Catalyst acetic acid palladium (4.5mg, 0.02mmol), potassium carbonate are added into the reaction tube equipped with magnetic stir bar (69.0mg, 0.5mmol), norbornene (37.6mg, 0.4mmol), 1- naphthalene boronic acids pinacol ester (76.2mg, 0.3mmol), 1- Benzoic acid thiomorpholine ester (44.6mg, 0.2mmol), dimethyl sulfoxide (0.8mL) and Isosorbide-5-Nitrae-dioxane (2.0mL), then 70 DEG C are heated to react 12 hours under air conservation atmosphere.After reaction is cooled to room temperature, mixture is filtered with diatomite, acetic acid Ethyl ester washing, filtrate successively wash primary, organic solvent through dry Na with water, saturated sodium-chloride water solution2SO4It dries, filters, subtract Pressure removes solvent, and column Chromatographic purification obtains compound I-44 (white solid, yield 56%).1H NMR(400MHz,CDCl3):δ 7.75-7.68 (m, 3H), 7.44-7.40 (m, 1H), 7.33-7.29 (m, 1H), 7.22 (dd, J=9.0,2.5Hz, 1H), 7.13 (m,1H),3.65–3.63(m,4H),2.83–2.81(m,4H)；13C NMR(100MHz,CDCl3):δ149.2,134.7, 129.0,128.6,127.6,126.8,126.5,123.7,120.3,111.5,52.5,27.1；HRMS (ESI-TOF): theoretical Calculated value: C14H16NS+[M+H+] 230.0998, measured value: 230.0993.
Embodiment 45: the preparation of compound I-45
Catalyst acetic acid palladium (4.5mg, 0.02mmol), potassium carbonate are added into the reaction tube equipped with magnetic stir bar (69.0mg, 0.5mmol), norbornene (37.6mg, 0.4mmol), 1- naphthalene boronic acids pinacol ester (76.2mg, 0.3mmol), 1- Benzoic acid pyrrole esters (38.2mg, 0.2mmol), dimethyl sulfoxide (0.8mL) and Isosorbide-5-Nitrae-dioxane (2.0mL), are then heated It is reacted 12 hours under air conservation atmosphere to 70 DEG C.After reaction is cooled to room temperature, mixture is filtered with diatomite, ethyl acetate Washing, filtrate successively wash primary, organic solvent through dry Na with water, saturated sodium-chloride water solution2SO4It dries, filters, depressurize and remove Solvent is removed, column Chromatographic purification obtains compound I-45 (white solid, yield 42%).1H NMR(400MHz,CDCl3):δ7.70– 7.62 (m, 3H), 7.36-7.32 (m, 1H), 7.17-7.14 (m, 1H), 7.00 (dd, J=9.0,2.5Hz, 1H), 6.76 (d, J =2.4Hz, 1H), 3.43-3.40 (m, 4H), 2.08-2.04 (m, 4H)；13C NMR(100MHz,CDCl3):δ146.0, 135.4,128.9,127.7,126.4,126.3,125.9,121.3,115.8,104.8,48.0,25.7；HRMS(ESI- TOF): calculated value: C14H16N+[M+H+] 198.1277, measured value: 198.1276.
Embodiment 46: the preparation of compound I-46
Catalyst acetic acid palladium (4.5mg, 0.02mmol), potassium carbonate are added into the reaction tube equipped with magnetic stir bar (69.0mg, 0.5mmol), norbornene (37.6mg, 0.4mmol), 1- naphthalene boronic acids pinacol ester (76.2mg, 0.3mmol), 1- Benzoate imines ester (43.8mg, 0.2mmol), dimethyl sulfoxide (0.8mL) and Isosorbide-5-Nitrae-dioxane (2.0mL), then 70 DEG C are heated to react 12 hours under air conservation atmosphere.After reaction is cooled to room temperature, mixture is filtered with diatomite, acetic acid Ethyl ester washing, filtrate successively wash primary, organic solvent through dry Na with water, saturated sodium-chloride water solution2SO4It dries, filters, subtract Pressure removes solvent, and column Chromatographic purification obtains compound I-46 (yellow oily liquid, yield 33%).1H NMR(400MHz,CDCl3): δ 7.69-7.65 (m, 2H), 7.61 (d, J=8.3Hz, 1H), 7.36-7.32 (m, 1H), 7.17-7.10 (m, 2H), 6.88 (d, J =2.5Hz, 1H), 3.60-3.57 (m, 4H), 1.88-1.84 (m, 4H), 1.60-1.56 (m, 4H)；13C NMR(100MHz, CDCl3):δ146.9,135.5,129.0,127.5,126.2,126.0,121.4,115.3,104.6,49.6,28.0,27.2； HRMS (ESI-TOF): calculated value: C16H20N+[M+H+] 226.1590, measured value: 226.1591.
Embodiment 47: the preparation of compound I-47
Catalyst acetic acid palladium (4.5mg, 0.02mmol), potassium carbonate are added into the reaction tube equipped with magnetic stir bar (69.0mg, 0.5mmol), norbornene (37.6mg, 0.4mmol), 1- naphthalene boronic acids pinacol ester (76.2mg, 0.3mmol), O- Benzoyl-N-Benzyl-N-methyl azanol (48.2mg, 0.2mmol), dimethyl sulfoxide (0.8mL) and 1,4- dioxane (2.0mL) is then heated to 70 DEG C and reacts 12 hours under air conservation atmosphere.After reaction is cooled to room temperature, mixture silicon Diatomaceous earth filtering, ethyl acetate washing, filtrate successively wash primary, organic solvent through dry Na with water, saturated sodium-chloride water solution2SO4 It dries, filters, solvent is removed under reduced pressure, column Chromatographic purification obtains compound I-47 (yellow oily liquid, yield 35%).1H NMR (400MHz,CDCl3):δ7.68–7.61(m,3H),7.37–7.29(m,3H),7.26–7.24(m,3H),7.21–7.14(m, 2H), 6.95 (d, J=2.6Hz, 1H), 4.64 (s, 2H), 3.09 (s, 3H)；13C NMR(100MHz,CDCl3):δ147.8, 139.0,135.2,129.0,128.7,127.6,127.1,127.0,126.9,126.4,126.3,122.1,116.3, 106.3,56.9,38.8；HRMS (ESI-TOF): calculated value: C18H18N+[M+H+] 248.1434, measured value: 248.1427。
Embodiment 48: the preparation of compound II-1
Method one: under argon gas protection, catalyst iodate is added into dry and reaction tube equipped with magnetic stir bar Cuprous (1.0mg, 0.005mmol), ligand N1,N2- two (4- methyl -2- phenyl) oxalamides (7.98mg, 0.019mmol), phosphorus Sour potassium (44.5mg, 0.21mmol), aryl chloride I-28 (28mg, 0.1mmol), ammonium hydroxide (w/w 25%, 46 μ L, 0.3mmol) with dimethyl sulfoxide (0.2mL), then in the case where argon gas protects atmosphere, 120 DEG C of heating are reacted 48 hours.Reaction cooling To room temperature, the direct column Chromatographic purification of mixture obtains compound II-1 (white solid, yield 61%), while recycling raw material I-28 (rate of recovery 32%).
Method two: under argon gas protection, catalyst oxidation is added into dry and reaction tube equipped with magnetic stir bar Cuprous (1.2mg, 0.008mmol), ligand N1(2- methyl naphthalene), N2(2- furfuryl)-oxalamide (2.32mg, 0.008mmol), potassium hydroxide (11.8mg, 0.21mmol), aryl bromide I-29 (53mg, 0.16mmol), ammonium hydroxide (w/w 25%, 64 μ L, 0.8mmol) and ethyl alcohol (0.2mL), then in the case where argon gas protects atmosphere, 80 DEG C of heating are reacted 24 hours.React cold But to after room temperature, mixture is directly concentrated under reduced pressure then directly column Chromatographic purification and obtains compound II-1 (white solid, yield 64%).1H NMR(400MHz,CDCl3): δ 5.92 (t, J=2.1Hz, 1H), 5.84 (d, J=1.9Hz, 2H), 3.83-3.81 (m,8H),3.12–3.09(m,8H)；13C NMR(100MHz,CDCl3):δ153.5,148.1,95.8,95.3,67.1,49.7； HRMS (ESI-TOF): calculated value: C14H22N3O2 +[M+H+] 264.1706, measured value: 264.1701.

Claims (8)

1. a kind of method for synthesizing aromatic amine compounds, which comprises the following steps: with aryl boric acid or aryl boron Acid esters A is starting material, using O- formoxyl-hydroxylamine compound B as amination reagent, with the derivative of palladium catalyst and norbornene Object is synergistic catalyst, using alkali as promotor, the above material is placed in 30-100 DEG C of organic solvent and is stirred to react, reaction knot Separating-purifying after beam, the aromatic amine compounds D that the aromatic amine compounds C or binary for obtaining unitary substitution replace, reaction equation Are as follows:
Wherein:
R1For hydrogen, aryl, heterocyclic aryl, alkyl, ester group, aldehyde radical, carboxyl, hydroxyl, silicon substrate, amino, cyano, nitro, amide groups, One of sulfonyl, alkoxy, halogen；
R2For aromatic ring, hetero-aromatic ring or the substituent group for replacing hydrogen on Ar ring with Ar ring and ring, substituent group is aryl, heterocyclic aryl, alkane One of base, ester group, aldehyde radical, carboxyl, hydroxyl, silicon substrate, amino, cyano, nitro, amide groups, sulfonyl, alkoxy, halogen Or it is several；N indicates R2Number, 0≤n≤3；
R3For hydrogen, C1-20Alkyl, aryl, heterocyclic aryl；
R4For hydrogen, aryl, heterocyclic aryl, C1-20Alkyl；
R5、R6For the substituent group on the heterocycloalkane, hetero-aromatic ring or nitrogen with nitrogen cyclization, substituent group be hydrogen, aryl, heterocyclic aryl, C1-20Alkyl, ester group, amide groups, sulfonyl, alkoxy, tertbutyloxycarbonyl, benzyloxycarbonyl group, benzyl, to methoxy-benzyl, alkane acyl One of base, sulfonyl, phthalyl, nitrine；
X, Y, Z are N or CH.
2. according to the method described in claim 1, it is characterized by: the norbornene derivative, has the following structure:
Wherein:
R7For the substituent group on five-membered ring, o represents substituent group number, 0≤o≤8；
R8For the substituent group in double bond, p represents substituent group number, 0≤p≤2；
R7、R8Carboxylate, ester group, cyano, nitro, amide groups, sulfonyl, C independently selected from metal ions M1-10Alkoxy, Aryl, heterocyclic aryl, C1-10One of alkyl, halogen, wherein M is Li+、Na+、K+、Rb+、Cs+、Mg2+、Ca2+、Sr2+、Ba2+ One of.
3. according to the method described in claim 1, it is characterized by: the palladium catalyst is Pd (PPh3)4、Pd(dba)2、Pd2 (dba)3、Pd(OAc)2、Pd(O2CCF3)2、Pd(PhCN)2Cl2、Pd(MeCN)2Cl2、PdCl2Or [Pd (allyl) Cl]2In one Kind, the alkali is sodium carbonate, potassium carbonate, cesium carbonate, sodium acetate, potassium acetate, cesium acetate, tripotassium phosphate, potassium formate, bicarbonate One or more of potassium, potassium hydroxide, sodium hydroxide, sodium tert-butoxide.
4. according to the method described in claim 1, it is characterized by: the organic solvent is methanol, ethyl alcohol, isopropanol, uncle Butanol, tetrahydrofuran, 2- methyltetrahydrofuran, ether, dimethyl second diether, methyl tertiary butyl ether(MTBE), six alkane of 1,4- epoxy, 1,3- Six alkane of epoxy, methylene chloride, 1,2- dichloroethanes, chloroform, carbon tetrachloride, C4-12Saturated alkane, C3-12Fluoro or chloro Alkane, benzene,toluene,xylene, trimethylbenzene, dimethyl sulfoxide, N,N-dimethylformamide, DMAC N,N' dimethyl acetamide, acetone, N- Methyl pyrrolidone, acetonitrile, C3-12Saturated alkyl nitrile, one or more of dimethyl sulfoxide.
5. according to the method described in claim 1, it is characterized by: the synergistic catalyst is palladium catalyst and norborneol Alkene, the palladium catalyst are Pd (OAc)2, the alkali is potassium carbonate, and the organic solvent is Isosorbide-5-Nitrae-dioxane and two Methyl sulfoxide.
6. a kind of aromatic amine compounds of ortho position amination, which is characterized in that use the described in any item sides of Claims 1 to 5 Method is prepared.
7. a kind of method for preparing EphB4 kinase inhibitor and its derivative, which comprises the following steps: in air Under atmosphere, make 4- halogen replace phenyl boric acid or borate ester E and O- formoxyl-hydroxylamine compound B palladium catalyst, alkali and It is reacted in organic solvent under the action of norbornene derivative, obtains intermediate F, by gained intermediate separating-purifying, with amine Compound EphB4 kinase inhibitor or derivatives thereof H, reaction equation is made through copper catalysis Ullmann aminating reaction in reagent G are as follows:
Wherein:
W is one of fluorine, chlorine, bromine, iodine and triflate；
R5、R6For the substituent group on the heterocycloalkane, hetero-aromatic ring or nitrogen with nitrogen cyclization, substituent group be hydrogen, aryl, heterocyclic aryl, C1-20Alkyl, ester group, amide groups, sulfonyl, alkoxy, tertbutyloxycarbonyl, benzyloxycarbonyl group, benzyl, to methoxy-benzyl, alkane acyl One of base, sulfonyl, phthalyl, nitrine；
R9For hydrogen, C1-20Alkyl, aryl, heterocyclic aryl；
R10、R11For the substituent group on the heterocycloalkane, hetero-aromatic ring or nitrogen with nitrogen cyclization, substituent group be hydrogen, aryl, heterocyclic aryl, C1-20Alkyl, ester group, amide groups, sulfonyl, alkoxy, tertbutyloxycarbonyl, benzyloxycarbonyl group, benzyl, to methoxy-benzyl, alkane acyl One of base, sulfonyl, phthalyl, nitrine.
8. a kind of EphB4 kinase inhibitor and its derivative, which is characterized in that be prepared into using method of claim 7 It arrives.
CN201910610239.3A 2019-07-08 2019-07-08 Preparation method of aromatic amine compound, EphB4 kinase inhibitor and derivatives thereof Active CN110357832B (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CN201910610239.3A CN110357832B (en) 2019-07-08 2019-07-08 Preparation method of aromatic amine compound, EphB4 kinase inhibitor and derivatives thereof

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
CN201910610239.3A CN110357832B (en) 2019-07-08 2019-07-08 Preparation method of aromatic amine compound, EphB4 kinase inhibitor and derivatives thereof

Publications (2)

Publication Number Publication Date
CN110357832A true CN110357832A (en) 2019-10-22
CN110357832B CN110357832B (en) 2022-03-15

Family

ID=68218477

Family Applications (1)

Application Number Title Priority Date Filing Date
CN201910610239.3A Active CN110357832B (en) 2019-07-08 2019-07-08 Preparation method of aromatic amine compound, EphB4 kinase inhibitor and derivatives thereof

Country Status (1)

Country Link
CN (1) CN110357832B (en)

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN111039813A (en) * 2019-12-24 2020-04-21 江南大学 Synthetic method of aromatic amide compound
CN114213267A (en) * 2021-12-15 2022-03-22 江苏超跃化学有限公司 Method for preparing 2-amino-3-methylbenzoic acid by using ammonolysis method
CN115433097A (en) * 2022-08-24 2022-12-06 盐城师范学院 Method for preparing 4-butoxybenzoic acid (2-diethylaminoethyl) ester without metal

Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008132505A1 (en) * 2007-04-27 2008-11-06 Astrazeneca Ab N' - (phenyl) -n- (morpholin-4-yl-pyridin-2-yl) -pyrimidine-2, 4-diamine derivatives as ephb4 kinase inhibitors for the treatment of proliferative conditions
WO2009010794A1 (en) * 2007-07-19 2009-01-22 Astrazeneca Ab 2,4-diamino-pyrimidine derivatives
CN101668749A (en) * 2007-02-28 2010-03-10 阿斯利康(瑞典)有限公司 Novel pyrimidine derivatives 698
WO2011009695A1 (en) * 2009-07-21 2011-01-27 Universität Zürich New anti-angiogenic compounds
CN102558095A (en) * 2011-12-13 2012-07-11 大连理工大学 Method for preparing aromatic amine compound
CN104744190A (en) * 2015-03-26 2015-07-01 浙江大学 Method for preparing o-alkynyl phenylamine derivative

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101668749A (en) * 2007-02-28 2010-03-10 阿斯利康(瑞典)有限公司 Novel pyrimidine derivatives 698
WO2008132505A1 (en) * 2007-04-27 2008-11-06 Astrazeneca Ab N' - (phenyl) -n- (morpholin-4-yl-pyridin-2-yl) -pyrimidine-2, 4-diamine derivatives as ephb4 kinase inhibitors for the treatment of proliferative conditions
WO2009010794A1 (en) * 2007-07-19 2009-01-22 Astrazeneca Ab 2,4-diamino-pyrimidine derivatives
WO2011009695A1 (en) * 2009-07-21 2011-01-27 Universität Zürich New anti-angiogenic compounds
CN102558095A (en) * 2011-12-13 2012-07-11 大连理工大学 Method for preparing aromatic amine compound
CN104744190A (en) * 2015-03-26 2015-07-01 浙江大学 Method for preparing o-alkynyl phenylamine derivative

Non-Patent Citations (4)

* Cited by examiner, † Cited by third party
Title
CATHERINE BARDELLE 等: "Inhibitors of the tyrosine kinase EphB4. Part 3: Identification of non-benzodioxole-based kinase inhibitors", 《BIOORGANIC & MEDICINAL CHEMISTRY LETTERS》 *
SHUQING CHEN 等: "Redox-neutral ortho-C–H amination of pinacol arylborates via palladium(II)/norbornene catalysis for aniline synthesis", 《CHEMICAL SCIENCE》 *
SHUQING CHEN 等: "The discovery of a Palladium(Ⅱ)-initiated borono-Catellani reaction", 《ANGEW. CHEM. INT. ED.》 *
ZHE DONG 等: "Ortho vs Ipso: Site-Selective Pd and Norbornene-Catalyzed Arene C-H Amination Using Aryl Halides", 《JOURNAL OF THE AMERICAN CHEMICAL SOCIETY》 *

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN111039813A (en) * 2019-12-24 2020-04-21 江南大学 Synthetic method of aromatic amide compound
CN111039813B (en) * 2019-12-24 2022-07-01 江南大学 Synthetic method of aromatic amide compound
CN114213267A (en) * 2021-12-15 2022-03-22 江苏超跃化学有限公司 Method for preparing 2-amino-3-methylbenzoic acid by using ammonolysis method
CN114213267B (en) * 2021-12-15 2024-02-23 江苏超跃化学有限公司 Method for preparing 2-amino-3-methylbenzoic acid by using ammonolysis method
CN115433097A (en) * 2022-08-24 2022-12-06 盐城师范学院 Method for preparing 4-butoxybenzoic acid (2-diethylaminoethyl) ester without metal

Also Published As

Publication number Publication date
CN110357832B (en) 2022-03-15

Similar Documents

Publication Publication Date Title
CN110357832A (en) A kind of preparation method of aromatic amine compounds and EphB4 kinase inhibitor and its derivative
JP5560715B2 (en) Selective reduction of nitro group by metal catalyst supported carbon
CN102875601B (en) Phosphine-oxazoline ligand and ionic type metal title complex thereof and its enantiomorph or raceme preparation method and application
KR20210057032A (en) Methyl 6-(2,4-dichlorophenyl)-5-[4-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-8,9-dihydro- Salt of 7H-benzo[7]annulene-2-carboxylate and preparation method thereof
CN110437068A (en) A kind of preparation method of aromatic hydrocarbons methylation
CN108997215A (en) A kind of preparation method of 1,2,3,4- tetrahydro isoquinoline derivative
CN108658853B (en) 4-nitrogen heteroaryl alkanol compound and synthesis method thereof
CN113105357B (en) Synthesis method and application of novel p-aryl azophenol derivative
CN111517964A (en) Method for splitting chiral compound
Karjalainen et al. Scalable synthesis of (−)-trans-3-hydroxypipecolic acid via a useful chiral building block
CN108164493B (en) Aromatic polyketone compound and preparation method thereof
CN110003081A (en) A kind of synthetic method for the indoline and tetrahydroisoquinoline that Polyfluoroalkyl replaces
CN108530241A (en) A kind of preparation method of Benzocyclodirivative and Eptazocine with benzyl position quaternary carbon center
WO2011019066A1 (en) Method for producing optically active 1-amino-2-vinylcyclopropanecarboxylic acid ester
CN105985316A (en) Preparation method for trelagliptin and salt thereof
CN106831862B (en) Chiral bridged axial chiral monophosphine ligand and preparation method thereof
WO2008007670A1 (en) Fluoroboron compound, aminomethylating agent for aromatic ring comprising the compound, and process for production of compound having aminomethyl-aromatic ring using the aminomethylating agent
TW201339250A (en) Triarylmethane dye for color filter, and color filter using the same
CN114276251B (en) Method for synthesizing nitro (hetero) arene
US10221203B2 (en) Chiral dihydrobenzooxaphosphole ligands and synthesis thereof
KR20220005559A (en) Synthesis of CRAC Channel Inhibitors
CN112079865B (en) Phosphine nitrogen ligand with multiple chiral centers and synthetic method and application thereof
CN108276266B (en) Anthracycline compound and preparation method thereof
CN112624908B (en) Method for dibromo-trifluoromethoxylation of terminal alkyne
JP7164381B2 (en) Method for producing N,N'-dialkylbicyclo[2.2.2]oct-7-ene-2,3:5,6-tetracarboxydiimide

Legal Events

Date Code Title Description
PB01 Publication
PB01 Publication
SE01 Entry into force of request for substantive examination
SE01 Entry into force of request for substantive examination
GR01 Patent grant
GR01 Patent grant