A 3-arylbenzisindole compound, its preparation method and application

Abstract

This application discloses a 3-arylbenzisisoindole compound, its preparation method, and its applications. The compound has the structural formula shown in Formula I, where X is selected from nitrogen, phosphorus, arsenic, tellurium, and boron atoms. The 3-arylbenzisisoindole compound provided in this application can play an important role in pharmaceuticals or fluorescent materials. The preparation method provided in this application has the advantages of being simple, having mild conditions, and using readily available raw materials, and can simultaneously construct multiple chemical bonds in a single reaction.

Description

Technical Field

[0001] This application relates to a 3-arylbenzisindole compound, its preparation method, and its application, belonging to the field of organic synthesis. Background Technology

[0002] Isoindole-based skeletons and their derivatives are widely found in biological and pharmaceutical active molecules, serving as important intermediates in the synthesis of alkaloids. They also have broad applications in industries such as organic pigments, luminescent materials, coatings, and plastics, making their synthesis a long-standing focus for chemists. While numerous synthetic methods have been developed in recent years, these methods typically suffer from drawbacks such as demanding reaction conditions, difficult substrate preparation, lengthy synthetic steps, and the need for expensive metal catalysts. Therefore, developing methods that are simple to operate, have mild reaction conditions, fast reaction rates, simple post-processing, readily available substrates, and short synthetic steps is of great significance. Summary of the Invention

[0003] According to one aspect of this application, a 3-arylbenzisindo compound is provided.

[0004] A 3-arylbenzisindol compound and its tautomers, polymorphs, solvates, or salts thereof, said compound having the structural formula described in Formula I:

[0005]

[0006] Wherein, X is selected from one of nitrogen atom, phosphorus atom, arsenic atom, tellurium atom, and boron atom;

[0007] R 1b Selected from hydrogen atoms, C1 to C 30 Alkyl, substituted C1-C 30 Alkyl, C6-C 30 Aryl, substituted C6-C 30 Aryl, C3~C 30 heteroaryl, substituted C3-C 30 Heteroaryl, phosphinyl, substituted phosphinyl, boronyl, substituted boronyl, silyl, substituted silyl, halogen, amino, substituted amino, heteroatom group.

[0008] Optionally, R 1b Selected from C1 to C 15 alkyl.

[0009] Optionally, R 1b Selected from the substituted C1 to C 15 alkyl.

[0010] Optionally, R 1b Selected from C6~C 15 Aryl.

[0011] Optionally, R 1b Selected from the substituted C6~C 15 Aryl.

[0012] Optionally, R 1b Selected from C3~C 15 Mixed aromatic compounds.

[0013] Optionally, R 1b Selected from the substituted C3~C 15 Mixed aromatic compounds.

[0014] R 2b Selected from C6~C 30 Aryl, substituted C6-C 30 Aryl, C3~C 30 heteroaryl, substituted C3-C 30 Mixed aromatic compounds.

[0015] Optionally, R 2b Selected from C6~C 15 Aryl.

[0016] Optionally, R 2b Selected from the substituted C6~C 15 Aryl.

[0017] Optionally, R 2b Selected from C3~C 15 Mixed aromatic compounds.

[0018] Optionally, R 2b Selected from the substituted C3~C 15 Mixed aromatic compounds.

[0019] R 3b Selected from hydrogen atoms, C1 to C 30 Alkyl, substituted C1-C 30 Alkyl, C2-C 30 Alkenyl, substituted C2-C 30 alkenyl, C2-C 30 Alkyne group, substituted C2-C 30 alkynyl group, C6-C 30 Aryl, substituted C6-C 30 Aryl, C3~C 30 heteroaryl, substituted C3-C 30 heteroaryl, C3~C 30 Cycloalkyl, substituted C3-C 30 cycloalkyl, C3-C 30 Heterocyclic alkyl groups, substituted C3-C 30 Heterocyclic alkyl groups, heteroatomic groups, phosphine groups, halogens, silicon groups, boron groups, germanium atoms, arsenic atoms, and selenium atoms.

[0020] Optionally, R 3b Selected from C1 to C 15 alkyl.

[0021] Optionally, R 3b Selected from the substituted C1 to C 15 alkyl.

[0022] Optionally, R 3b Selected from C2 to C 15 Alkenyl group.

[0023] Optionally, R 3b Selected from the substituted C2~C 15 Alkenyl group.

[0024] Optionally, R 3b Selected from C2 to C 15 Alkyne group.

[0025] Optionally, R 3b Selected from the substituted C2~C 15 Alkyne group.

[0026] Optionally, R 3b Selected from C6~C 15 Aryl.

[0027] Optionally, R 3b Selected from the substituted C6~C 15 Aryl.

[0028] Optionally, R 3b Selected from C3~C 15 Mixed aromatic compounds.

[0029] Optionally, R 3b Selected from the substituted C3~C 15 Mixed aromatic compounds.

[0030] Optionally, R 3b Selected from C3~C 15 Cycloalkyl.

[0031] Optionally, R 3b Selected from the substituted C3~C 15 Cycloalkyl.

[0032] Optionally, R 3b Selected from C3~C 15 Heterocyclic alkyl groups.

[0033] Optionally, R 3b Selected from the substituted C3~C 15 Heterocyclic alkyl groups.

[0034] R 4b Selected from hydrogen atoms, C1 to C30 Alkyl, substituted C1-C 30 Alkyl, C2-C 30 Alkenyl, substituted C2-C 30 alkenyl, C2-C 30 Alkyne group, substituted C2-C 30 alkynyl group, C6-C 30 Aryl, substituted C6-C 30 Aryl, C3~C 30 heteroaryl, substituted C3-C 30 heteroaryl, C3~C 30 Cycloalkyl, substituted C3-C 30 cycloalkyl, C3-C 30 Heterocyclic alkyl groups, substituted C3-C 30 Heterocyclic alkyl groups, heteroatomic groups, phosphine groups, halogens, silicon groups, boron groups, germanium atoms, arsenic atoms, and selenium atoms.

[0035] Optionally, R 4b Selected from C1 to C 15 alkyl.

[0036] Optionally, R 4b Selected from the substituted C1 to C 15 alkyl.

[0037] Optionally, R 4b Selected from C2 to C 15 Alkenyl group.

[0038] Optionally, R 4b Selected from the substituted C2~C 15 Alkenyl group.

[0039] Optionally, R 4b Selected from C2 to C 15 Alkyne group.

[0040] Optionally, R 4b Selected from the substituted C2~C 15 Alkyne group.

[0041] Optionally, R 4b Selected from C6~C 15 Aryl.

[0042] Optionally, R 4b Selected from the substituted C6~C 15 Aryl.

[0043] Optionally, R 4b Selected from C3~C 15 Mixed aromatic compounds.

[0044] Optionally, R 4b Selected from the substituted C3~C15 Mixed aromatic compounds.

[0045] Optionally, R 4b Selected from C3~C 15 Cycloalkyl.

[0046] Optionally, R 4b Selected from the substituted C3~C 15 Cycloalkyl.

[0047] Optionally, R 4b Selected from C3~C 15 Heterocyclic alkyl groups.

[0048] Optionally, R 4b Selected from the substituted C3~C 15 Heterocyclic alkyl groups.

[0049] R 5b Selected from hydrogen atoms, deuterium atoms, C1 to C 30 Alkyl, substituted C1-C 30 Alkyl, C2-C 30 Alkenyl, substituted C2-C 30 alkenyl, C2-C 30 Alkyne group, substituted C2-C 30 alkynyl group, C6-C 30 Aryl, substituted C6-C 30 Aryl, C3~C 30 heteroaryl, substituted C3-C 30 heteroaryl, C3~C 30 Cycloalkyl, substituted C3-C 30 cycloalkyl, C3-C 30 Heterocyclic alkyl groups, substituted C3-C 30 Heterocyclic alkyl groups, heteroatomic groups, phosphine groups, halogens, silicon groups, boron groups, germanium atoms, arsenic atoms, and selenium atoms.

[0050] Optionally, R 5b Selected from C1 to C 15 alkyl.

[0051] Optionally, R 5b Selected from the substituted C1 to C 15 alkyl.

[0052] Optionally, R 5b Selected from C2 to C 15 Alkenyl group.

[0053] Optionally, R 5b Selected from the substituted C2~C 15 Alkenyl group.

[0054] Optionally, R 5b Selected from C2 to C15 Alkyne group.

[0055] Optionally, R 5b Selected from the substituted C2~C 15 Alkyne group.

[0056] Optionally, R 5b Selected from C6~C 15 Aryl.

[0057] Optionally, R 5b Selected from the substituted C6~C 15 Aryl.

[0058] Optionally, R 5b Selected from C3~C 15 Mixed aromatic compounds.

[0059] Optionally, R 5b Selected from the substituted C3~C 15 Mixed aromatic compounds.

[0060] Optionally, R 5b Selected from C3~C 15 Cycloalkyl.

[0061] Optionally, R 5b Selected from the substituted C3~C 15 Cycloalkyl.

[0062] Optionally, R 5b Selected from C3~C 15 Heterocyclic alkyl groups.

[0063] Optionally, R 5b Selected from the substituted C3~C 15 Heterocyclic alkyl groups.

[0064] Optionally, in R 1b middle:

[0065] The heteroatomic groups are selected from CO, O, S, SO, SO2, -NR, -N=, =N-.

[0066] Alternatively, C1 to C can be replaced. 30 The substituents in the alkyl group are independently selected from R a .

[0067] Alternatively, C6 to C can be replaced. 30 Aryl, substituted C3-C 30 The substituents of the heteroaryl group are independently selected from R a1 .

[0068] Optionally, the substituents in the substituted phosphine group, substituted boron group, substituted silicon group, and substituted amino group are independently selected from R a2 .

[0069] Optionally, the R a Selected from halogens, alkenyl groups, alkynyl groups, cycloalkyl groups, aryl groups, heteroaryl groups, heterocyclic groups, -CN, -NO2, oxo, -CO-R, -COO-R, -NH-CO-R, -NH-COO-R, -NR, -OR, -SO2-R, -SR, boronyl, and silyl groups.

[0070] Optionally, the R a1 Selected from halogens, alkenyl groups, alkynyl groups, cycloalkyl groups, heterocyclic groups, -CN, -NO2, oxo, -CO-R, -COO-R, -NH-CO-R, -NH-COO-R, -NR, -OR, -SO2-R, -SR, boronyl, and silyl.

[0071] Optionally, the R a2 Selected from halogens, alkenyl groups, alkynyl groups, cycloalkyl groups, aryl groups, heteroaryl groups, heterocyclic groups, -CN, -NO2, oxo, -CO-R, -COO-R, -NH-CO-R, -NH-COO-R, -NR, -OR, -SO2-R, -SR, boronyl, and silyl groups.

[0072] Optionally, the R mentioned above is independently selected from hydrogen, alkyl, and aryl.

[0073] Optionally, in R 2b middle:

[0074] Replacement of C6~C 30 Aryl, substituted C3-C 30 The substituents in heteroaryl groups are independently selected from R a1 .

[0075] Optionally, the R a1 Selected from halogens, alkenyl groups, alkynyl groups, cycloalkyl groups, heterocyclic groups, -CN, -NO2, oxo, -CO-R, -COO-R, -NH-CO-R, -NH-COO-R, -NR, -OR, -SO2-R, -SR, boronyl, and silyl.

[0076] Optionally, in R 3b middle:

[0077] The heteroatomic groups are selected from CO, O, S, SO, SO2, -NR, -N=, =N-.

[0078] Alternatively, C1 to C can be replaced. 30 The substituents in the alkyl group are independently selected from R a .

[0079] Alternatively, C6 to C can be replaced. 30 Aryl, substituted C3-C30 The substituents of the heteroaryl group are independently selected from R a1 .

[0080] Optionally, the substituents in the substituted phosphine group, substituted boron group, substituted silicon group, and substituted amino group are independently selected from R a2 .

[0081] Optionally, the R a Selected from halogens, alkenyl groups, alkynyl groups, cycloalkyl groups, aryl groups, heteroaryl groups, heterocyclic groups, -CN, -NO2, oxo, -CO-R, -COO-R, -NH-CO-R, -NH-COO-R, -NR, -OR, -SO2-R, -SR, boronyl, and silyl groups.

[0082] Optionally, the R a1 Selected from halogens, alkenyl groups, alkynyl groups, cycloalkyl groups, heterocyclic groups, -CN, -NO2, oxo, -CO-R, -COO-R, -NH-CO-R, -NH-COO-R, -NR, -OR, -SO2-R, -SR, boronyl, and silyl.

[0083] Optionally, the R a2 Selected from halogens, alkenyl groups, alkynyl groups, cycloalkyl groups, aryl groups, heteroaryl groups, heterocyclic groups, -CN, -NO2, oxo, -CO-R, -COO-R, -NH-CO-R, -NH-COO-R, -NR, -OR, -SO2-R, -SR, boronyl, and silyl groups.

[0084] Optionally, the R mentioned above is independently selected from hydrogen, alkyl, and aryl.

[0085] Optionally, in R 4b middle:

[0086] The heteroatomic groups are selected from CO, O, S, SO, SO2, -NR, -N=, =N-.

[0087] Alternatively, C1 to C can be replaced. 30 The substituents in the alkyl group are independently selected from R a ;

[0088] Alternatively, C6 to C can be replaced. 30 Aryl, substituted C3-C 30 The substituents of the heteroaryl group are independently selected from R a1 .

[0089] Optionally, the substituents in the substituted phosphine group, substituted boron group, substituted silicon group, and substituted amino group are independently selected from R a2 .

[0090] Optionally, the R aSelected from halogens, alkenyl groups, alkynyl groups, cycloalkyl groups, aryl groups, heteroaryl groups, heterocyclic groups, -CN, -NO2, oxo, -CO-R, -COO-R, -NH-CO-R, -NH-COO-R, -NR, -OR, -SO2-R, -SR, boronyl, and silyl groups.

[0091] Optionally, the R a1 Selected from halogens, alkenyl groups, alkynyl groups, cycloalkyl groups, heterocyclic groups, -CN, -NO2, oxo, -CO-R, -COO-R, -NH-CO-R, -NH-COO-R, -NR, -OR, -SO2-R, -SR, boronyl, and silyl.

[0092] Optionally, the R a2 Selected from halogens, alkenyl groups, alkynyl groups, cycloalkyl groups, aryl groups, heteroaryl groups, heterocyclic groups, -CN, -NO2, oxo, -CO-R, -COO-R, -NH-CO-R, -NH-COO-R, -NR, -OR, -SO2-R, -SR, boronyl, and silyl groups.

[0093] Optionally, the R mentioned above is independently selected from hydrogen, alkyl, and aryl.

[0094] Optionally, in R 5b middle:

[0095] The heteroatomic groups are selected from CO, O, S, SO, SO2, -NR, -N=, =N-.

[0096] Alternatively, C1 to C can be replaced. 30 The substituents in the alkyl group are independently selected from R a .

[0097] Alternatively, C6 to C can be replaced. 30 Aryl, substituted C3-C 30 The substituents of the heteroaryl group are independently selected from R a1 .

[0098] Optionally, the substituents in the substituted phosphine group, substituted boron group, substituted silicon group, and substituted amino group are independently selected from R a2 .

[0099] Optionally, the R a Selected from halogens, alkenyl groups, alkynyl groups, cycloalkyl groups, aryl groups, heteroaryl groups, heterocyclic groups, -CN, -NO2, oxo, -CO-R, -COO-R, -NH-CO-R, -NH-COO-R, -NR, -OR, -SO2-R, -SR, boronyl, and silyl groups.

[0100] Optionally, the R a1Selected from halogens, alkenyl groups, alkynyl groups, cycloalkyl groups, heterocyclic groups, -CN, -NO2, oxo, -CO-R, -COO-R, -NH-CO-R, -NH-COO-R, -NR, -OR, -SO2-R, -SR, boronyl, and silyl.

[0101] Optionally, the R a2 Selected from halogens, alkenyl groups, alkynyl groups, cycloalkyl groups, aryl groups, heteroaryl groups, heterocyclic groups, -CN, -NO2, oxo, -CO-R, -COO-R, -NH-CO-R, -NH-COO-R, -NR, -OR, -SO2-R, -SR, boronyl, and silyl groups.

[0102] Optionally, the R mentioned above is independently selected from hydrogen, alkyl, and aryl.

[0103] Alternatively, the structural formula of the compound shown in Formula I is selected from the following compounds:

[0104]

[0105] The numbers are IM-1, IM-2, IM-3, IM-4, IM-5, IM-6, IM-7, IM-8, and IM-9, from left to right and from top to bottom.

[0106] According to another aspect of this application, a method for preparing 3-arylbenzisidine indole compounds is provided.

[0107] A method for preparing a 3-arylbenzisindol compound includes the following steps:

[0108] (S1) 1,6-diyne compounds were obtained;

[0109] The preparation of 1,6-diyne compounds includes the following steps:

[0110] Reacting a starting material containing compounds of formulas IV and V with reaction I yields 1,6-diyne compounds.

[0111]

[0112] (S2) A mixture containing 1,6-diyne compounds, a base, and organic solvent I is reacted with reaction III to obtain 3-arylbenzisindo compounds;

[0113] The 1,6-diyne compounds are selected from those having the structural formula described in Formula II:

[0114]

[0115] Optionally, in step (S1), the molar ratio of the compounds represented by formula IV and formula V is 1:1 to 5.

[0116] Optionally, reaction I is carried out in the presence of an acid reagent.

[0117] Optionally, the acid reagent includes p-toluenesulfonic acid, phenylsulfonic acid, p-nitrobenzenesulfonic acid, methanesulfonic acid, ferric chloride, and aluminum chloride;

[0118] Optionally, the temperature of reaction I is 25℃~100℃;

[0119] The reaction time for reaction I is 0.1 h to 48 h.

[0120] Optionally, the method for preparing the compound represented by Formula IV includes the following steps:

[0121] A starting material containing compounds of formulas VI and VII is reacted with reaction IV to obtain the compound of formula IV.

[0122]

[0123] Optionally, the molar ratio of the compounds shown in Formula VI and Formula VII is 1:1 to 5.

[0124] Optionally, reaction IV is carried out in the presence of a nucleophilic substitution reagent, which includes n-butyllithium, sec-butyllithium, tert-butyllithium, methyllithium, diisopropylaminolithium, and bis(trimethylsilylaminolithium).

[0125] Optionally, the temperature of reaction IV is -78℃ to 50℃; the reaction time is 0.1h to 24h.

[0126] Optionally, in step (S2), the alkali is selected from at least one of cesium carbonate, potassium carbonate, and sodium carbonate.

[0127] Optionally, the organic solvent I is selected from at least one of methanol, ethanol, isopropanol, p-xylene, n-butanol, ethyl acetate, acetonitrile, N,N-dimethylformamide, and dimethyl sulfoxide.

[0128] Optionally, the molar ratio of the 1,6-diyne compound to the base is 1:0.1 to 1:10.

[0129] Optionally, the concentration of the 1,6-diyne compound is 20 mM to 1 M.

[0130] Preferably, the molar ratio of the 1,6-diyne compound to the base is 1:1 to 1:10.

[0131] Optionally, the conditions for reaction III in step (S2) are as follows:

[0132] The temperature ranges from 25℃ to 150℃.

[0133] The time ranges from 0.5 hours to 72 hours.

[0134] Optionally, the reaction atmosphere is a non-reactive gas.

[0135] Optionally, the following steps are included:

[0136] A mixture containing 3-arylbenzisinoindole compounds, an oxidizing agent, and organic solvent II is reacted to yield benzisoindole dimer compounds.

[0137] The benzo[i]isoindole dimer compound is selected from those having the structural formula described in Formula III:

[0138]

[0139] The 3-arylbenzisindo compounds described above are selected from at least one of the 3-arylbenzisindo compounds described above and / or the 3-arylbenzisindo compounds obtained by the preparation method described above.

[0140] Optionally, R in Formula III 1 R 4 In the same formula I, R 1b ;

[0141] In Formula III, R 7 R 8 In the same formula I, R 4b ;

[0142] In Formula III, R 3 R 6 In the same formula I, R 3b ;

[0143] In Formula III, R 1 R 2 R 3 R 4 R 5 R 6 R 7 R 8 Meet one or more of the following conditions:

[0144] (i)R 1 R 4 same;

[0145] (ii)R 2 R 5 same;

[0146] (iii)R 3 R 6 same;

[0147] (iv)R 7 R 8 same.

[0148] Optionally, the oxidant is selected from at least one of 2,2,6,6-tetramethylpiperidine nitrogen oxides, oxygen, sodium hypochlorite, aqueous hydrogen peroxide solution, tert-butanol peroxide, lauroyl peroxide, benzoyl peroxide, tert-butyl peroxybenzoate, m-chloroperoxybenzoic acid, peracetic acid, and di-tert-butyl peroxide.

[0149] Optionally, the organic solvent II is selected from at least one of methanol, ethanol, isopropanol, p-xylene, n-butanol, ethyl acetate, acetonitrile, N,N-dimethylformamide, and dimethyl sulfoxide.

[0150] Alternatively, the conditions for reaction II are as follows:

[0151] The temperature ranges from 25℃ to 150℃.

[0152] The time ranges from 0.5 hours to 72 hours.

[0153] According to a third aspect of this application, an application of 3-arylbenzisindole compounds is provided in lysosomal fluorescent probes, synthesis of benzisoindole dimers, optical super-resolution microscopy, confocal microscopy, wide-field microscopy, fluorescence lifetime imaging microscopy, fluorescence resonance energy transfer microscopy, super-resolution optical wave imaging, fluorescence activation localization microscopy, and light-emitting devices.

[0154] The above-described 3-arylbenzisindole compounds and / or the 3-arylbenzisindole compounds obtained by the above-described preparation methods are used in lysosomal fluorescent probes, autophagic lysosomal fluorescent probes, synthesis of benzisoindole dimers, optical super-resolution microscopy, confocal microscopy, wide field-of-view microscopy, fluorescence lifetime imaging microscopy, fluorescence resonance energy transfer microscopy, super-resolution optical wave imaging, fluorescence activation localization microscopy, and light-emitting devices.

[0155] In this application, C1 to C 30 C6~C 30 "etc." refers to the number of carbon atoms contained in the group.

[0156] In this application, the term "alkyl" refers to a group formed by the loss of any one hydrogen atom from an alkane molecule.

[0157] In this application, the term "alkene" refers to a group formed by the loss of any one hydrogen atom from an alkene compound molecule.

[0158] In this application, the term "alkynyl" refers to a group formed by the loss of any one hydrogen atom from a molecule of an alkyne compound.

[0159] In this application, the term "aryl" refers to a group formed by the loss of a hydrogen atom from an aromatic ring in an aromatic compound molecule; for example, p-tolyl formed by the loss of a hydrogen atom at the para-position of the methyl group on the benzene ring of toluene.

[0160] In this application, the term "heteroaryl" refers to a group formed by the loss of a hydrogen atom from a heterocyclic ring in an aromatic heterocyclic compound molecule.

[0161] In this application, the term "cycloalkyl" refers to a group formed by the loss of any one hydrogen atom from a cycloalkane molecule.

[0162] In this application, the term "heterocyclic alkyl" refers to a group formed by the loss of any hydrogen atom from a heterocyclic alkane molecule.

[0163] In this application, the term "heterocyclic group" refers to a group formed when a heterocyclic compound molecule loses any one of the hydrogen atoms from the heterocycle.

[0164] In this application, the term "silyl group" refers to a group formed by the loss of any one hydrogen atom from a silane compound molecule.

[0165] In this application, the term "halogen" refers to at least one of fluorine, chlorine, bromine, and iodine.

[0166] In this application, the term "heteroatomic group" refers to a group formed by the loss of any one hydrogen atom from a compound containing elements other than H and C (e.g., halogens, S, O, P, N, etc.).

[0167] In this application, the terms "phosphine-based, boron-based, silicon-based" refer to groups formed by the loss of any one hydrogen atom from the molecule of the compound.

[0168] The structural formulas described in this application are intended to include all isomers (such as enantiomers, diastereomers, and geometric isomers (or conformational isomers)): for example, R-S configurations containing an asymmetric center, (Z) and (E) isomers with double bonds, etc. Therefore, any single stereochemical isomer of the compound of this application, or a mixture of its enantiomers, diastereomers, or geometric isomers (or conformational isomers), is within the scope of this application.

[0169] "Tautomerism" refers to structural isomers with different energies that can cross a low energy barrier and thus interconvert. For example, proton tautomerism (i.e., proton shift) involves interconversion via proton migration. Valence tautomerism involves interconversion via the recombination of some bonding electrons.

[0170] "Solvate" refers to a complex formed by the compound of this invention coordinating with solvent molecules in a specific ratio.

[0171] The beneficial effects that this application can produce include:

[0172] 1) The 3-arylbenzisindo compounds provided in this application can play an important role in pharmaceuticals or fluorescent materials.

[0173] 2) The preparation method provided in this application has the advantages of being simple, having mild conditions, and having readily available raw materials, and can simultaneously construct multiple chemical bonds in one reaction. Detailed Implementation

[0174] The present application is described in detail below with reference to the embodiments, but the present application is not limited to these embodiments.

[0175] Unless otherwise specified, the raw materials and catalysts used in the embodiments of this application were all purchased commercially.

[0176] IPA is isopropanol;

[0177] n BuOH is n-butanol;

[0178] p-xylene is p-xylene.

[0179] The analysis method in the embodiments of this application is as follows:

[0180] Nuclear magnetic resonance analysis was performed using a Bruker-BioSpin AVANCE III HD and a JEOL ECZ600S instrument.

[0181] Mass spectrometry analysis was performed using a Thermo Fisher Scientific LTQ FTICR-MS instrument.

[0182] Cell fluorescence labeling analysis was performed using a Zeiss LSM 880 instrument via confocal fluorescence microscopy.

[0183] The yields of compounds IM-(1-9) and dimer compounds FL-(1-9) in the embodiments of this application are calculated using the following formulas:

[0184] The yield of compound IM-(1~9) = molar mass of product / molar mass of starting material * 100%.

[0185] Yield of dimer FL-(1~9) = molar mass of product / molar mass of starting material * 2 * 100%.

[0186] Example 1

[0187] Synthesis of IM-1

[0188]

[0189] Compound PA-1 (0.5 mmol) and potassium carbonate (1.5 mmol) were added to a reaction tube, and 2 mL of isopropanol was added as a solvent. The reaction was carried out under nitrogen atmosphere and at 80 °C for 24 hours. The reaction solution was then evaporated to dryness and purified by column chromatography to obtain compound IM-1. The entire reaction and post-processing must be carried out under an anaerobic environment (yield 70%).

[0190] The NMR detection data of the product are as follows:

[0191] 1 H NMR (600MHz, CDCl3) δ8.29 (s, 1H), 8.10–8.01 (m, 3H), 7.99 (d, J = 8.2Hz, 1H) ,7.94(d,J=8.2Hz,1H),7.61–7.57(m,4H),7.55–7.52(m,1H),5.14(s,2H). 13 C NMR (151MHz, CDCl3) δ172.35,146.57,137.23,134.91,133.21,132.73,130. 25,129.37,128.88,128.33,128.11,127.26,125.98,121.98,120.83,63.91.

[0192] The high-resolution mass spectrometry data of the product are as follows:

[0193] HRMS m / z(ESI)calcd for [C 18 H 13 NH]([M+H] + ):244.1121,found:244.1121.

[0194] Example 2

[0195] Synthesis of IM-2

[0196]

[0197] Compound PA-2 (0.5 mmol) and potassium carbonate (1.5 mmol) were added to a reaction tube, and 2 mL of isopropanol was added as a solvent. The reaction was carried out under argon atmosphere at 80 °C for 24 hours. The reaction solution was then evaporated to dryness and purified by column chromatography to obtain compound IM-2. The entire reaction and post-processing must be carried out under an anaerobic environment (yield 48%).

[0198] The NMR detection data of the product are as follows:

[0199] 1H NMR(600MHz,Chloroform-d)δ8.27(s,1H),8.04(s,1H),7.98(d,J=8.4Hz,3H),7.93(d ,J=8.2Hz,1H),7.59–7.56(m,1H),7.54–7.51(m,1H),7.44–7.42(m,2H),2.57(s,3H).

[0200] Example 3

[0201] Synthesis of IM-1

[0202]

[0203] Compound PA-1 (0.5 mmol) and cesium carbonate (1.5 mmol) were added to a reaction tube, and 2 mL of isopropanol was added as a solvent. The reaction was carried out under nitrogen atmosphere and at 80 °C for 24 hours. The reaction solution was then evaporated to dryness and purified by column chromatography to obtain compound IM-1. The entire reaction and post-processing must be carried out under an anaerobic environment (yield 62%).

[0204] The NMR detection data of the product are as follows:

[0205] 1 H NMR (600MHz, CDCl3) δ8.29 (s, 1H), 8.10–8.01 (m, 3H), 7.99 (d, J = 8.2Hz, 1H) ,7.94(d,J=8.2Hz,1H),7.61–7.57(m,4H),7.55–7.52(m,1H),5.14(s,2H). 13 C NMR (151MHz, CDCl3) δ172.35,146.57,137.23,134.91,133.21,132.73,130. 25,129.37,128.88,128.33,128.11,127.26,125.98,121.98,120.83,63.91.

[0206] The high-resolution mass spectrometry data of the product are as follows:

[0207] HRMS m / z(ESI)calcd for [C 18 H 13 NH]([M+H] + ):244.1121,found:244.1121.

[0208] Example 4

[0209] Synthesis of IM-1

[0210]

[0211] Compound PA-1 (0.5 mmol) and potassium carbonate (1.5 mmol) were added to a reaction tube, along with 2 mL of n-butanol as a solvent. The reaction was carried out under nitrogen atmosphere at 120 °C for 24 hours. The reaction solution was then evaporated to dryness and purified by column chromatography to obtain compound IM-1. The entire reaction and post-processing must be carried out under an anaerobic environment (yield 82%).

[0212] The NMR detection data of the product are as follows:

[0213] 1 H NMR (600MHz, CDCl3) δ8.29 (s, 1H), 8.10–8.01 (m, 3H), 7.99 (d, J = 8.2Hz, 1H) ,7.94(d,J=8.2Hz,1H),7.61–7.57(m,4H),7.55–7.52(m,1H),5.14(s,2H). 13 C NMR (151MHz, CDCl3) δ172.35,146.57,137.23,134.91,133.21,132.73,130. 25,129.37,128.88,128.33,128.11,127.26,125.98,121.98,120.83,63.91.

[0214] The high-resolution mass spectrometry data of the product are as follows:

[0215] HRMS m / z(ESI)calcd for [C 18 H 13 NH]([M+H] + ):244.1121,found:244.1121.

[0216] Example 5

[0217] Synthesis of IM-2

[0218]

[0219] Compound PA-2 (0.5 mmol) and potassium carbonate (1.5 mmol) were added to a reaction tube, and 2 mL of isopropanol was added as a solvent. The reaction was carried out under nitrogen atmosphere and at 80 °C for 24 hours. The reaction solution was then evaporated to dryness and purified by column chromatography to obtain compound IM-2. The entire reaction and post-processing must be carried out under an anaerobic environment (yield 78%).

[0220] The NMR detection data of the product are as follows:

[0221] 1H NMR(600MHz,Chloroform-d)δ8.27(s,1H),8.04(s,1H),7.98(d,J=8.4Hz,3H),7.93(d ,J=8.2Hz,1H),7.59–7.56(m,1H),7.54–7.51(m,1H),7.44–7.42(m,2H),2.57(s,3H).

[0222] Example 6

[0223] Preparation of IM-1 converted into dimer compounds

[0224]

[0225] Compound IM-1 (0.2 mmol) was dissolved in 1 mL of isopropanol, with oxygen in the air as the oxidant, and the reaction was carried out at 80 °C for 24 hours. After the reaction was completed, the reaction solution was evaporated to dryness and purified by column chromatography to give the dimer compound FL-1 (yield 38%).

[0226] The NMR detection data of product FL-1 are as follows:

[0227] 1H NMR(400MHz, CDCl3)δ9.49(s,2H),8.45–8.40(m,4H),8.36(s,2H),8.12(d, J=7.8Hz,2H),7.99(d,J=7.8Hz,2H),7.73–7.65(m,6H),7.62–7.55(m,4H).

[0228] 13 C NMR (150MHz, CDCl3) δ170.75,148.39,137.13,135.36,134.99,133.73,133.1 6,131.12,130.06,129.90,129.26,129.06,127.86,127.49,126.96,122.98.

[0229] The high-resolution mass spectrometry data of the product are as follows:

[0230] HRMS m / z(ESI)calcd for [C 36 H 22 [N2H]([M+H] + ):483.1856,found:483.1855.

[0231] Example 7

[0232] Preparation of IM-2 converted into dimer compounds

[0233]

[0234] Compound IM-2 (0.2 mmol) was dissolved in 1 mL of isopropanol, and 2,2,6,6-tetramethylpiperidine nitride (TEMPO, 2 equiv.) was added. The mixture was reacted at 80 °C for 24 hours. After the reaction was complete, the reaction solution was evaporated to dryness and purified by column chromatography to give the dimer compound FL-2 (yield 18%).

[0235] The NMR detection data of product FL-2 are as follows:

[0236] 1 H NMR(400MHz, CDCl3 / CF3COOD,5:1)δ9.54(s,2H),9.07(s,2H),8.31(d,J=8.3Hz,4H),8.26(d,J =8.2Hz,4H),8.02(t,J=7.5Hz,2H),7.95(t,J=7.5Hz,2H),7.64(d,J=8.1Hz,4H),2.71(s,6H).

[0237] 13 C NMR(150MHz,CDCl3 / CF3COOD,5:1)δ166.84,156.87,136.41,134.55,134.14,133.21,13 1.97,131.70,131.49,131.12,130.76,128.61,128.23,128.01,126.65,120.88,14.57.

[0238] The high-resolution mass spectrometry data of product FL-2 are as follows:

[0239] HRMS m / z(ESI)calcd for [C 38 H 26 [N2S2Na]([M+Na] + ):597.1430,found:597.1427.

[0240] Example 8

[0241] Preparation of IM-3 converted into dimer compounds

[0242]

[0243] Compound IM-3 (0.2 mmol) was dissolved in 1 mL of isopropanol, and 2 equiv. of 8% sodium hypochlorite aqueous solution was added. The reaction was carried out at 80 °C for 24 hours. After the reaction was completed, the reaction solution was evaporated to dryness and column chromatography was performed to obtain the dimer compound FL-3 (yield 68%).

[0244] The NMR detection data of product FL-3 are as follows:

[0245] 1 H NMR(600MHz, CDCl3 / CF3COOD,5:1)δ9.50(s,2H),9.00(s,2H),8.43(d,J=8.8Hz,4H),8.26(d,J =8.3Hz, 4H), 7.96 (t, J = 7.6Hz, 2H), 7.90 (t, J = 7.5Hz, 2H), 7.59 (d, J = 8.8Hz, 4H), 3.48 (s, 12H).

[0246] 13 C NMR(150MHz, CDCl3 / CF3COOD,5:1)δ159.69,152.52,136.01,134.37,134.23,133.89,132.4 7,132.32,131.42,131.21,131.01,130.24,128.93,128.18,127.01,119.17,44.11.IR(thin film)ν1433,1455,1598,2850,2919cm -1 .

[0247] The high-resolution mass spectrometry data of product FL-3 are as follows:

[0248] HRMS m / z(ESI)calcd for [C 40 H 32 N4H]([M+H] + ):569.2700,found:569.2708.

[0249] Example 9

[0250] Preparation of IM-4 converted into dimer compounds

[0251]

[0252] Compound IM-4 (0.2 mmol) was dissolved in 1 mL of isopropanol, and 2 equiv. of 30% aqueous hydrogen peroxide solution was added. The reaction was carried out at 80 °C for 24 hours. After the reaction was completed, the reaction solution was evaporated to dryness and column chromatography was performed to give the dimer compound FL-4 (yield 22%).

[0253] The NMR detection data of product FL-4 are as follows:

[0254] 11H NMR (600MHz, CDCl3) δ9.47(s,2H),8.41(d,J=8.2Hz,4H),8.37(s,2H),8.11(d,J=8.0Hz,2H),7.98(d,J=7.9Hz,2H),7.71(d,J=8.1H z,4H),7.59(t,J=7.2Hz,2H),7.55(t,J=7.9Hz,2H),6.88(dd,J=17.6,10.8Hz,2H),5.97(d,J=17.6Hz,2H),5.43(d,J=10.9Hz,2H).

[0255] 13 C NMR (150MHz, CDCl3) δ169.99,148.39,140.24,137.18,136.51,135.35,134.35,133.69,1 33.13,130.03,129.89,129.48,127.78,127.49,126.96,126.85,122.95,115.76.IR(thin film)ν1474,1500,1603,1623,2849,2918cm -1 .

[0256] The high-resolution mass spectrometry data of product FL-4 are as follows:

[0257] HRMS m / z(ESI)calcd for [C 40 H 26 [N2H]([M+H] + ):535.2169,found:535.2169.

[0258] Example 10

[0259] Preparation of IM-5 converted into dimer compounds

[0260]

[0261] Compound IM-5 (0.2 mmol) was dissolved in 1 mL of isopropanol and reacted in an atmosphere with oxygen in the air as the oxidant at 80 °C for 24 hours. After the reaction was completed, the reaction solution was evaporated to dryness and purified by column chromatography to give the dimer compound FL-5 (yield 22%).

[0262] The NMR detection data of product FL-5 are as follows:

[0263] 1H NMR (400MHz, CDCl3) δ9.37(s,2H),8.39(d,J=7.6Hz,4H),8.18(s,2H),7.94(s,2H),7.88(d,J=8.5Hz, 2H),7.71–7.66(m,8H),6.94(dd,J=17.6,10.9Hz,2H),5.96(d,J=17.6Hz,2H),5.43(d,J=10.8Hz,2H).

[0264] 13 C NMR (150MHz, CDCl3) δ170.61,148.42,137.55,136.89,136.59,135.29,134.97,133.83,1 32.74,131.07,130.07,129.27,129.02,128.49,127.96,124.17,122.64,115.04.IR(thin film)ν1445,1473,2980,3006,3050cm -1 .

[0265] The high-resolution mass spectrometry data of product FL-5 are as follows:

[0266] HRMS m / z(ESI)calcd for[C40H26N2H]([M+H]+):535.2169,found:535.2169.

[0267] Example 11

[0268] Preparation of IM-6 converted into dimer compounds

[0269]

[0270] Compound IM-6 (0.2 mmol) was dissolved in 1 mL of isopropanol and reacted under an oxygen atmosphere at 120 °C for 24 hours. After the reaction was complete, the reaction solution was evaporated to dryness and purified by column chromatography to give the dimer compound FL-6 (yield 42%).

[0271] The NMR detection data of product FL-6 are as follows:

[0272] 1H NMR (400MHz, CDCl3) δ9.42 (s, 2H), 8.43 (d, J = 7.2Hz, 4H), 8.31 (s, 2H), 7.95–7.86 (m, 4H), 7.73–7. 62(m,6H),7.41(d,J=8.2Hz,2H),2.83(t,J=7.6Hz,4H),1.87–1.73(m,4H),1.03(t,J=7.3Hz,6H).

[0273] 13 C NMR (150MHz, CDCl3) δ170.79,148.44,142.25,137.30,135.13,134.78,134.00,131.63, 131.00,129.71,129.24,129.03,128.69,128.66,127.47,122.77,38.40,24.54,14.00.

[0274] The high-resolution mass spectrometry data of product FL-6 are as follows:

[0275] HRMS m / z(ESI)calcd for [C 42 H 34 [N2H]([M+H] + ):567.2795,found:567.2795.

[0276] Example 12

[0277] Preparation of IM-7 converted into dimer compounds

[0278]

[0279] Compound IM-7 (0.2 mmol) was dissolved in 1 mL of p-xylene and reacted under an oxygen atmosphere at 80 °C for 24 hours. After the reaction was complete, the reaction solution was evaporated to dryness and purified by column chromatography to give the dimer compound FL-7 (yield 33%).

[0280] The NMR detection data of product FL-7 are as follows:

[0281] 1H NMR(400MHz, CDCl3 / CF3COOD,5:1)δ10.30(s,2H),8.86(d,J=8.1Hz,2H),8.73(s,2H),8.71–8.65(m,4H),8.54(d,J =8.1Hz,2H),7.80–7.71(m,6H),7.68(t,J=7.5Hz,2H),7.58(t,J=7.7Hz,2H),7.42(d,J=7.7Hz,4H),2.45(s,12H).

[0282] 13 C NMR(100MHz, CDCl3 / CF3COOD,5:1)δ177.99,137.03,134.76,134.18,133.70,132.22,131.19,130.97,129.5 5,129.19,129.10,129.03,128.53,128.34,127.87,125.06,124.86,123.84,123.71,123.47,121.42,20.55.

[0283] The high-resolution mass spectrometry data of product FL-7 are as follows:

[0284] HRMS m / z(ESI)calcd for [C 56 H 38 [N2H]([M+H] + ):739.3108,found:739.3108.

[0285] Example 13

[0286] Preparation of IM-1 and IM-8 converted into heterodimer compounds

[0287]

[0288] Compounds IM-8 (0.1 mmol) and IM-1 (0.1 mmol) were dissolved in 1 mL of isopropanol and reacted under an oxygen atmosphere at 80 °C for 24 hours. After the reaction was complete, the reaction solution was evaporated to dryness and purified by column chromatography to give the heterodimer compound FL-8 (yield 21%).

[0289] The NMR detection data of product FL-8 are as follows:

[0290] 1H NMR(600MHz, CDCl3)δ9.46(s,1H),9.42(s,1H),8.43–8.41(m,2H),8.37–8.33(m,4H), 8.09(d,J=7.3Hz,1H),7.97(d,J=8.3Hz,1H),7.88–7.84(m,2H),7.70–7.67(m,2H),7.6 5–7.61(m,1H),7.57–7.51(m,2H),7.40–7.35(m,5H),7.29–7.25(m,6H),7.18–7.14(m ,2H),2.84–2.80(m,2H),1.77–1.72(m,2H),1.40–1.27(m,10H),0.87(t,J=7.1Hz,3H).

[0291] 13 C NMR (150MHz, CDCl3) δ169.83,169.57,150.80,149.01,147.19,147.05,142.45,137.52,137 .30,135.31,135.22,134.86,133.93,133.65,133.01,131.60,130.82,130.46,130.00,129. 83,129.68,129.20,129.01,128.59,128.57,127.88,127.44,127.36,127.27,126.71,125.78,124.31,122.87,122.68,121.69,36.38,32.00,31.50,29.65,29.52,29.40,22.78,14.23.

[0292] The high-resolution mass spectrometry data of product FL-8 are as follows:

[0293] HRMS m / z(ESI)calcd for [C 56 H 47 N3H]([M+H] + ):762.3843,found:762.3846.

[0294] Example 14

[0295] Preparation of IM-9 converted into dimer compounds

[0296]

[0297] Compound IM-9 (0.2 mmol) was dissolved in 1 mL of p-xylene and reacted under an oxygen atmosphere at 80 °C for 24 hours. After the reaction was complete, the reaction solution was evaporated to dryness and purified by column chromatography to give the dimer compound FL-9 (yield 52%).

[0298] The NMR detection data of product FL-9 are as follows:

[0299] 1 H NMR (600MHz, CDCl3) δ8.16(s,2H),8.01(s,2H),7.86(d,J=8.7Hz,2H),7.78(d,J=8.8Hz,4H),7.67–7.62(m,4H),7.47–7.42(m,6H),7.27(t, J=8.2Hz,2H),6.99(d,J=8.8Hz,4H),4.06(t,J=6.6Hz,4H),1.87–1.82(m,4H),1.52–1.48(m,4H),1.39–1.29(m,24H),0.89(t,J=7.0Hz,6H).

[0300] 13 C NMR (151MHz, CDCl3) δ164.46,161.29,150.00,139.80,138.12,136.77,136.04,133.64,133.34,131.79,131.31,131.02,130.94, 128.60,127.54,127.21,126.85,126.47,122.70,114.33,68.30,32.01,29.70,29.68,29.52,29.44,29.33,26.15,22.79,14.24.

[0301] The high-resolution mass spectrometry data of product FL-9 are as follows:

[0302] HRMS m / z(ESI)calcd for [C 68 H 68 Cl2N2O2Na]([M+Na] + ):1037.4550,found:1037.4550.

[0303] Example 15

[0304] Fluorescent labeling experiment of IM-1 compound on L292 cells

[0305] Cell line: L929 cells (mouse fibroblasts).

[0306] Cell culture: Cells were cultured in a CO2 incubator (37℃, 5% CO2) in DMEM medium (penicillin (100U / mL) and streptomycin (100μg / mL)).

[0307] Cell imaging experiments: Cells were cultured in 15mm bottom-mounted cell culture dishes. Before labeling cells with the probe, the culture medium was removed, and the cells were washed twice with Hank's buffer to remove residual culture medium. 200 μL of probe IM-1 (10 μM) was added to the culture dish, and the cells were incubated in the dark for 30 minutes. The cells were washed twice with Hank's buffer to remove residual probe, and 1 mL of Hank's solution was added to the culture dish. Cells were observed under a 100x objective lens using a laser confocal microscope. The excitation wavelength was 543 nm, and the emission wavelength was 550-600 nm. It was found that the probe labeled lysosomes and lysophosphatases, indicating that this compound can fluorescently label intracellular lysosomes and lysophosphatases.

[0308] Example 16

[0309] Fluorescent labeling experiment of IM-2 compound on L292 cells

[0310] Cell line: L929 cells (mouse fibroblasts).

[0311] Cell culture: Cells were cultured in a CO2 incubator (37°C, 5% CO2) in DMEM medium (penicillin (100 U / mL) and streptomycin (100 μg / mL)).

[0312] Cell imaging experiments: Cells were cultured in 15mm bottom-mounted cell culture dishes. Before labeling cells with the probe, the culture medium was removed, and the cells were washed twice with Hank's buffer to remove residual culture medium. 200 μL of probe IM-2 (5 μM) was added to the culture dish, and the cells were incubated in the dark for 30 minutes. The cells were washed twice with Hank's buffer to remove residual probe, and 1 mL of Hank's solution was added to the culture dish. Cells were observed under a 100x objective lens using a laser confocal microscope. The excitation wavelength was 543 nm, and the emission wavelength was 550-600 nm. It was found that the probe labeled lysosomes and lysophosphatases, indicating that this compound can fluorescently label intracellular lysosomes and lysophosphatases.

[0313] Example 17

[0314] Fluorescent labeling experiment of IM-3 compound on L292 cells

[0315] Cell line: L929 cells (mouse fibroblasts).

[0316] Cell culture: Cells were cultured in a CO2 incubator (37°C, 5% CO2) in DMEM medium (penicillin (100 U / mL) and streptomycin (100 μg / mL)).

[0317] Cell imaging experiments: Cells were cultured in 15mm bottom-mounted cell culture dishes. Before labeling cells with the probe, the culture medium was removed, and the cells were washed twice with Hank's buffer to remove residual medium. 200 μL of probe IM-3 (2 μM) was added to the culture dish, and the cells were incubated in the dark for 30 minutes. The cells were washed twice with Hank's buffer to remove residual probe, and 1 mL of Hank's solution was added to the culture dish. Cells were observed under a 100x objective lens using a laser confocal microscope. The excitation wavelength was 488 nm, and the emission wavelength was 600-650 nm. It was found that the probe labeled lysosomes and lysophosphatases, indicating that this compound can fluorescently label intracellular lysosomes and lysophosphatases.

[0318] The above description is merely a few embodiments of this application and is not intended to limit this application in any way. Although this application discloses preferred embodiments as described above, it is not intended to limit this application. Any changes or modifications made by those skilled in the art without departing from the scope of the technical solution of this application using the disclosed technical content are equivalent to equivalent implementation cases and fall within the scope of the technical solution.

Claims

1. A 3-arylbenzisindol compound and its salt, characterized in that, The structural formulas of the 3-arylbenzisindo compounds are selected from the following compounds: ； From left to right, they are numbered IM-2 and IM-3.

2. A method for preparing a benzisoindole dimer compound, characterized in that, Includes the following steps: A mixture containing 3-arylbenzisinoindole compounds, an oxidizing agent, and organic solvent II is reacted to yield benzisoindole dimers. The benzo[i]isoindole dimer compound is selected from those having the structural formula described in Formula III: Formula III; The specific structural formula of formula III is as follows: , ; The 3-arylbenzisindol compounds described above are selected from the 3-arylbenzisindol compounds of claim 1; The reaction conditions are as follows: The temperature ranges from 25 ℃ to 150 ℃; The time ranges from 0.5 h to 72 h; The oxidant is selected from at least one of 2,2,6,6-tetramethylpiperidine nitrogen oxides, oxygen, sodium hypochlorite, aqueous hydrogen peroxide solution, tert-butanol peroxide, lauroyl peroxide, benzoyl peroxide, tert-butyl peroxybenzoate, m-chloroperoxybenzoic acid, peracetic acid, and di-tert-butyl peroxide.

3. The preparation method according to claim 2, characterized in that, The organic solvent II is selected from at least one of methanol, ethanol, isopropanol, p-xylene, n-butanol, ethyl acetate, acetonitrile, N,N-dimethylformamide, and dimethyl sulfoxide.

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