C2 symmetric N-N axial chiral biindolyl diphosphine ligand as well as preparation method and application thereof

Abstract

The invention belongs to the technical field of organic synthetic chemistry, and particularly relates to a C2 symmetric N-N axial chiral biindolyl diphosphine ligand as well as a preparation method and application thereof. The preparation method comprises the following steps: reacting 2-indolyl amino aryl benzaldehyde or 2-indolyl amino aryl benzophenone with carbon tetrahalide to generate a 1, 1-dihalogenated olefin compound 3; carrying out cyclization reaction on the 1, 1-dihalogenated olefin compound 3 under the action of transition metal to obtain a biindole compound 4; reacting the biindole halide 4 with diaryl phosphorus halide in the presence of alkyl metal to generate a biindole diaryl phosphine compound 5; and reacting the biindolyl diaryl phosphine compound 5 with diaryl phosphorus halide in the presence of alkyl metal to generate the compound as shown in the general formula I. The optical pure chiral diphosphine ligand can be obtained through kinetic resolution, chiral preparative column separation and other methods. The ligand is simple in framework, convenient to synthesize and easy to transform, can be applied to asymmetric reactions catalyzed by various metals, and has very high reaction activity and stereoselectivity.

Description

Technical Field

[0001] The invention belongs to the technical field of organic synthetic chemistry, and specifically relates to a C2 symmetric NN axial chiral biindole diphosphine ligand and a preparation method and application thereof. Background Art

[0002] The information disclosed in the background of the invention is only intended to enhance the understanding of the overall background of the invention and should not be necessarily regarded as an acknowledgment or any form of suggestion that the information constitutes the prior art already known to a person skilled in the art.

[0003] Asymmetric synthesis is an important means to obtain chiral compounds. Among them, the catalytic system of transition metals and chiral ligands is a very important catalytic synthesis method in asymmetric synthesis. Designing and synthesizing chiral ligands of different types and kinds is a hot topic in current asymmetric catalysis research. Chiral bisphosphine ligands with C2 symmetry have the characteristics of high catalytic efficiency and wide application range in asymmetric catalysis. They have achieved great results in asymmetric hydrogenation and other research and have been industrialized. Although the synthesis research of chiral bisphosphine ligands has achieved certain achievements, it is still very necessary to synthesize bisphosphine ligands with novel structures and good catalytic effects.

[0004] In recent years, the asymmetric synthesis of NN axial chirality has gradually attracted the attention of chemists, and the chiral synthesis of some skeletons has been achieved. However, although some biindole monophosphine ligands have been reported, the NN biindole diphosphine ligand with C2 symmetry in structure has not been synthesized. Therefore, the synthesis of chiral ligands based on NN axial chirality, especially diphosphine ligands, is still lacking. Compared with diphosphine ligands with CC axial chirality, NN axial chiral diphosphine ligands have the following advantages: 1) The new NN axial chiral skeleton has a short bond length compared with the CC chiral axis, which is conducive to providing a torsion angle different from the previous diphosphine ligand chelation with metals; 2) The diindole skeleton is more electron-rich, which is in line with the characteristics of electron-rich diphosphine ligand skeletons being conducive to asymmetric hydrogenation; 3) The NN biindole skeleton can provide multiple structural sites that can be modified, which can further enrich its chiral phosphine ligand library.

[0005] However, current synthetic methods are unable to synthesize NN axially chiral diphosphine ligands with C2 symmetric electron-rich skeletons, and the currently reported synthetic routes for NN axially chiral ligands are long and have low yields. Summary of the invention

[0006] In response to the needs of the prior art, the purpose of the present invention is to provide a C2-symmetric NN axial chiral biindole bisphosphine ligand and a preparation method and application thereof. The present invention starts with low-cost raw materials and synthesizes the NN axial chiral bisphosphine ligand efficiently and selectively through methods such as kinetic resolution or chiral preparative column resolution in a short synthesis step. The ligand can be applied to various metal-catalyzed asymmetric reactions and has high reactivity and stereoselectivity.

[0007] Specifically, the present invention provides the following technical solutions:

[0008] In the first aspect of the present invention, there is provided a C2-symmetric NN-axial chiral biindole bisphosphine ligand compound or a pharmaceutically acceptable salt, isomer, solvate and hydrate thereof, having a structure shown in general formula I:

[0009]

[0010] Among them, R 1 is a substituent on the benzene ring of the indole part of the parent structure, and the number is one or two, R 1 is selected from hydrogen, alkyl, alkoxy, halogen, aryl, substituted aryl, heteroaryl;

[0011] R 2 is selected from aryl, substituted aryl, and heteroaryl;

[0012] R 3 Selected from hydrogen, halogen, aryl, and substituted aryl.

[0013] Preferably, the R 1 Selected from hydrogen, C1-C5 alkyl, C1-C3 alkoxy, halogen, five-membered to seven-membered nitrogen heterocyclic group, phenyl, and phenyl substituted by at least one of methyl, methoxy, and halogen;

[0014] Preferably, the R 1 is selected from the group consisting of hydrogen, methyl, methoxy, fluorine, chlorine and bromine;

[0015] Preferably, the R 1 The substitution position is selected from the group consisting of 4, 5, 6, 7 or 4', 5', 6', 7' on the indole; R 1 When the number is one, the preferred position is 5, 6 or 5', 6',; R 1 When the number is two, the two substituents are R 1 and R 1 ', the preferred positions of the two substituents are 5, 7 or 5', 7', R 1 and R 1 'It can be the same or different;

[0016] Preferably, the R2 is selected from aryl, substituted aryl, and heteroaryl;

[0017] Preferably, the R 2 A phenyl group, a phenyl group substituted by at least one of a methyl group, a methoxy group, and a halogen group, and a five-membered to seven-membered nitrogen heterocyclic group;

[0018] Preferably, the R 2 Selected from phenyl, 4-tolyl, 4-methoxyphenyl, 4-fluorophenyl, 4-chlorophenyl, 4-bromophenyl;

[0019] Preferably, the R 3 The group consisting of phenyl and phenyl substituted by at least one of methyl, methoxy and halogen.

[0020] Preferably, the pharmaceutically acceptable salt is a derivative after group modification aimed at improving the physicochemical properties of the C2 symmetric NN axial chiral biindole bisphosphine ligand, usually a salt formed by the C2 symmetric NN axial chiral biindole bisphosphine ligand and an inorganic salt such as hydrochloric acid, sulfuric acid, nitric acid or hydrobromic acid, and a salt formed by an organic acid such as methanesulfonic acid, toluenesulfonic acid, citric acid or trifluoroacetic acid.

[0021] Preferably, the isomer is an R configuration isomer; and the isomer is an S configuration isomer.

[0022] Preferably, the compound represented by general formula I comprises the following structure:

[0023]

[0024] The second aspect of the present invention provides a method for preparing the C2 symmetric NN axial chiral biindole bisphosphine ligand compound or its pharmaceutically acceptable salt, isomer, solvate and hydrate described in the first aspect, comprising the following steps:

[0025] S1. Adding compound A to an organic solution containing carbon tetrahalide, a reducing agent and triphenylphosphine, and obtaining 1,1-dihaloolefin compound 3 after reaction; wherein the structural formula of compound A is: Where R 1 Same as the definition in claim 1 or 2; the structural formula of the 1,1-dihaloolefin compound 3 is: R 1 As defined in claim 1 or 2, X is selected from halogen;

[0026] S2, mixing 1,1-dihaloolefin compound 3, transition metal compound, ligand compound and K2CO3 in an organic solvent, and performing cyclization reaction to obtain biindole compound 4; wherein the structural formula of the biindole compound 4 is: Where R1 As defined in claim 1 or 2, X is selected from halogen;

[0027] S3, the biindole halide 4 reacts with a diaryl phosphorus halide in the presence of an alkyl metal compound to generate a biindole diaryl phosphine compound 5; wherein the structural formula of the biindole diaryl phosphine compound 5 is: Where R 1 , R 2 Same as defined in claim 1 or 2;

[0028] S4, the biindole diaryl phosphine compound 5 reacts with a diaryl phosphorus halide in the presence of an alkyl metal compound to generate a compound represented by the general formula I.

[0029] Preferably, in step S1, the molar ratio of the carbon tetrahalide, the reducing agent, triphenylphosphine, and compound A is 1-10:1-20:1-10:1, preferably 2:8:2:1; the carbon tetrahalide is selected from one of carbon tetrachloride, carbon tetrabromide, and carbon tetraiodide; the reducing agent is selected from one of magnesium, iron, zinc, copper, and manganese; the compound A is selected from one of 2-indolylaminoarylbenzaldehyde and 2-indolylaminoarylbenzophenone; further preferably, the compound A is selected from 2-((1H-indolyl)amino)benzaldehyde and 5-methyl-2-((5-methyl-1H-indolyl)amino)benzaldehyde.

[0030] Preferably, in step S1, the organic solvent is selected from one or more of dichloromethane, chloroform, ethyl acetate, tetrahydrofuran, methyltetrahydrofuran, ethyl ether, dibutyl ether, methyl tert-butyl ether, ethylene glycol dimethyl ether, dioxane, toluene, xylene, benzene, and chlorobenzene.

[0031] Preferably, in step S1, the reaction temperature is -5 to 10°C and the reaction time is 1 to 48 hours.

[0032] Preferably, in step S2, the specific process of the cyclization reaction is: adding a transition metal compound, a ligand compound and K2CO3 to an organic solvent of the 1,1-dihaloolefin compound 3, and heating the mixture for reaction;

[0033] Wherein, the molar ratio of the 1,1-dihaloolefin compound 3, the transition metal compound, the ligand compound and K2CO3 is 1:0.005-2:0.01-4:1.5-2.5, preferably 1:0.2:0.4:2;

[0034] The transition metal compound is selected from one of copper compounds, palladium compounds, rhodium compounds, iridium compounds and ruthenium compounds.

[0035] The ligand compound is selected from one of 1,1'-bi-2-naphthol, 2,2'-dihydroxybiphenyl, 1,1'-bi-2-naphthylamine and 1,2-diaminocyclohexane;

[0036] The organic solvent is selected from one or more of dichloromethane, chloroform, ethyl acetate, tetrahydrofuran, methyltetrahydrofuran, ether, dibutyl ether, methyl tert-butyl ether, ethylene glycol dimethyl ether, dioxane, toluene, xylene, benzene, and chlorobenzene;

[0037] The temperature of the heating reaction is 60-120° C. and the time is 8-24 hours.

[0038] Preferably, in step S3, the specific process of the reaction is: firstly mixing the biindole halide 4 and the alkyl metal compound for low temperature reaction, then adding the diaryl phosphorus halide and stirring for reaction;

[0039] Wherein, the molar ratio of the biindole halide 4, the alkyl metal compound and the diaryl phosphorus halide is 1:1-5:1-5, preferably 1:1.4:1.5.

[0040] The alkyl metal compound is selected from one of alkyl lithium and alkyl magnesium, and is preferably n-butyl lithium.

[0041] The diaryl phosphorus halide is selected from one of diaryl phosphorus chloride, diaryl phosphorus bromide, and diaryl phosphorus iodide; further preferably, the diaryl phosphorus halide is selected from one of diphenyl phosphorus chloride and di(p-methylphenyl)phosphine chloride;

[0042] The biindole halide 4 is dissolved in an organic solvent and reacted with an alkyl metal compound at low temperature, wherein the organic solvent is selected from one or more of dichloromethane, chloroform, ethyl acetate, tetrahydrofuran, methyltetrahydrofuran, diethyl ether, dibutyl ether, methyl tert-butyl ether, ethylene glycol dimethyl ether, dioxane, toluene, xylene, benzene, and chlorobenzene;

[0043] The temperature of the low-temperature reaction is -78 to 0°C, and the time is 15 to 30 minutes; the temperature of the stirring reaction is 25 to 50°C, and the time is 6 to 24 hours.

[0044] Preferably, in step S4, the specific process of the reaction is: firstly, the biindole diaryl phosphine compound 5, the alkyl metal compound and the lithium salt are mixed to react at low temperature, and then the diaryl phosphorus halide is added to react by stirring;

[0045] The molar ratio of the biindole diaryl phosphine compound 5, the alkyl metal compound, the lithium salt and the diaryl phosphorus halide is 1:1-5:10-15:1-5, preferably 1:1.5:12:1.5.

[0046] The alkyl metal compound is selected from one of alkyl lithium and alkyl magnesium, and is preferably lithium diisopropylamide (LDA).

[0047] The lithium salt is selected from one of lithium chloride, lithium bromide and lithium iodide;

[0048] The diaryl phosphorus halide is selected from one of diaryl phosphorus chloride, diaryl phosphorus bromide, and diaryl phosphorus iodide; further preferably, the diaryl phosphorus halide is selected from one of diphenyl phosphorus chloride and di(p-methylphenyl)phosphine chloride;

[0049] The biindole diarylphosphine compound 5 is dissolved in an organic solvent and reacted with an alkyl metal compound and a lithium salt at low temperature, wherein the organic solvent is selected from one or more of dichloromethane, chloroform, ethyl acetate, tetrahydrofuran, methyltetrahydrofuran, diethyl ether, dibutyl ether, methyl tert-butyl ether, ethylene glycol dimethyl ether, dioxane, toluene, xylene, benzene, and chlorobenzene;

[0050] The temperature of the low-temperature reaction is -78 to 0°C, and the time is 1 to 2 hours; the temperature of the stirring reaction is 25 to 50°C, and the time is 6 to 24 hours.

[0051] Preferably, the preparation method further comprises splitting the product obtained in the above step S4 to obtain an R-configuration or S-configuration biindole diphosphine compound, wherein the structural formula of the R-configuration biindole diphosphine compound is: The structural formula of the S-configuration biindole diphosphine compound is: R 1 , R 2 Same as defined in claim 1 or 2;

[0052] Preferably, the resolution reaction is specifically as follows: firstly, the compound represented by the general formula I is subjected to an oxidation reaction with an oxidant to obtain a biindole diphosphine compound 6, which is reacted with a resolution agent, and the obtained R-configuration biindole diphosphine compound and S-configuration biindole diphosphine compound are washed with an alkaline solution, and then a reduction reaction is performed to obtain the R-configuration or S-configuration biindole diphosphine compound in the compound represented by the general formula I; wherein the structural formula of the biindole diphosphine compound 6 is: R 1 , R 2 Same as the definition in claim 1 or 2; the structural formula of the R-configured biindole diphosphine oxide compound is: R 1 , R 2 Same as the definition in claim 1 or 2; the structural formula of the S-configuration biindole diphosphine oxide compound is: R 1 , R 2 Same as defined in claim 1 or 2;

[0053] Further preferably, the process of the oxidation reaction is specifically as follows: mixing the compound represented by the general formula I and the oxidant, and carrying out a stirring reaction to obtain the biindole diphosphine oxide compound 6; wherein the molar ratio of the compound represented by the general formula I to the oxidant is 1:1 to 20; the oxidant is selected from one of hydrogen peroxide, m-chloroperbenzoic acid, and tert-butyl peroxide; the stirring reaction temperature is 5 to 50°C, and the time is 10 to 50 minutes.

[0054] Further preferably, the molar ratio of the biindole diphosphine oxide 6 to the resolving agent is 1:1 to 10, preferably 1:1.1; the resolving agent is (2S, 3S)-2,3-di(benzoyloxy)succinic acid or (2R, 3R)-2,3-di(benzoyloxy)succinic acid; and the alkaline solution is selected from one of an aqueous sodium hydroxide solution, an aqueous potassium hydroxide solution, an aqueous barium hydroxide solution, and an aqueous calcium hydroxide solution.

[0055] Further preferably, the reduction reaction process is specifically as follows: adding a reducing agent and triethylamine to the washed R-configuration or S-configuration biindole diphosphine oxide compound, and heating the reaction; wherein the molar ratio of the washed R-configuration or S-configuration biindole diphosphine oxide compound, the reducing agent and the triethylamine is 1:1-20:1-20, preferably 1:5:5.5; the reducing agent is selected from one of sodium borohydride, trichlorosilane, and lithium aluminum tetrahydride; the heating reaction temperature is 100-150°C, and the time is 8-48h.

[0056] Further preferably, the product obtained by the reduction reaction is further purified by silica gel column chromatography, the eluent is a petroleum ether / ethyl acetate mixture with a volume ratio of 20:1, and the elution flow rate is 0.1-5 mL / min.

[0057] Further preferably, an R-configuration or S-configuration biindole diphosphorus oxide compound, a halogen compound and an oxidant are mixed and heated to react to obtain compound 8, wherein the molar ratio of the R-configuration or S-configuration biindole diphosphorus oxide compound, the halogen compound and the oxidant is 1:2-3:1-2.5, the halogen compound is selected from one of potassium bromide, sodium bromide, calcium bromide, cesium bromide, potassium iodide, sodium iodide, potassium chloride and sodium chloride, the oxidant is potassium peroxymonosulfonate, the temperature of the heating reaction is 65-85°C, and the time is 15-30h; wherein the structural formula of compound 8 is: Where R 1 , R 2 As defined in claim 1 or 2, X is selected from halogen;

[0058] Further preferably, compound 8, phenylboronic acid, Pd(PPh3)4 and Na2CO3 are mixed in an organic solvent and heated to react to obtain compound 9, wherein the molar ratio of compound 8, phenylboronic acid, Pd(PPh3)4 and Na2CO3 is 1:1-2:0.02-0.08:0.05-1.5, the organic solvent is a mixed solvent of toluene, ethanol and water, the temperature of the heating reaction is 100-150°C, and the time is 20-36h; wherein the structural formula of compound 9 is: R 1 , R 2 , R 3 Same as defined in claim 1 or 2;

[0059] Further preferably, a reducing agent and triethylamine are added to the compound 9 for a heating reaction, wherein the molar ratio of the compound 9, the reducing agent and the triethylamine is 1:1-20:1-20; the reducing agent is selected from one of sodium borohydride, trichlorosilane and lithium aluminum tetrahydride; the heating reaction temperature is 100-150°C and the time is 8-48h.

[0060] Further preferably, the preparation method further comprises first subjecting the product obtained in the above step S4 to a complex reaction with a borane solution, and then separating the obtained biindole diphosphine borane complex by preparative chiral high performance liquid chromatography to obtain an R-configuration or S-configuration biindole diphosphine compound, wherein the structural formula of the biindole diphosphine borane complex is: R 1 , R 2 , R 3 Same as defined in claim 1 or 2.

[0061] Preferably, the process of the complex reaction is specifically as follows: adding a borane solution to an organic solvent of the compound represented by the general formula I, and stirring the reaction; wherein the borane solution is prepared by dissolving borane in tetrahydrofuran; the molar ratio of the compound represented by the general formula I to the borane solution is 1:4; the mixture after the complex reaction is further purified by silica gel column chromatography to obtain a biindole diphosphine borane complex, and the eluent is a petroleum ether / ethyl acetate mixture with a volume ratio of 20:1; the separation conditions of the high performance liquid chromatography are CHIRALPAK IG, the eluent is a hexane / dichloromethane mixture with a volume ratio of 70:30, and the elution flow rate is 0.5 to 1 mL / min; the product obtained by the high performance liquid chromatography separation is further purified by washing and silica gel column chromatography in sequence, the eluent is a petroleum ether / ethyl acetate mixture with a volume ratio of 50:1, and the elution flow rate is 0.1 to -5 mL / min.

[0062] The third aspect of the present invention provides a composition comprising the C2 symmetric NN axial chiral biindole bisphosphine ligand compound or its pharmaceutically acceptable salt, isomer, solvate and hydrate described in the first aspect.

[0063] The fourth aspect of the present invention provides the use of the C2 symmetric NN axial chiral biindole bisphosphine ligand compound or its pharmaceutically acceptable salts, isomers, solvates and hydrates as catalyst ligands in asymmetric catalytic reactions.

[0064] Preferably, the asymmetric catalytic reaction includes but is not limited to asymmetric addition reaction of pyridinium salt and quinoline salt, intramolecular asymmetric cyclization reaction of indole, asymmetric hydrogenation reaction of quinoline and asymmetric hydrogenation reaction of methyl 3-oxo-3-phenylpropanoate.

[0065] Preferably, the C2-symmetric NN-axial chiral biindole diphosphine ligand is complexed with a rhodium compound and applied to the asymmetric addition reaction of boric acid to quinoline salt to prepare a structure shown in general formula II:

[0066]

[0067] in:

[0068] R 4 is selected from alkyl, alkoxy, aryl, substituted aryl, and halogen;

[0069] R 5 is selected from hydrogen, alkyl, alkoxy, aryl, substituted aryl, and halogen;

[0070] Ar is selected from aryl, substituted aryl, heteroaryl;

[0071] Preferably, the R 4 Selected from C1-C5 alkyl;

[0072] Preferably, the R 5 Selected from phenyl, methoxyphenyl, trifluoromethylphenyl, fluorophenyl, chlorophenyl;

[0073] Preferably, the preferred substitution positions of the fluorophenyl group are the 2-position, 3-position, 4-position and 5-position; wherein, when there is one substituent, the preferred substitution positions are the 2-position and 4-position; and when there are two substituents, the preferred substitution positions are the 3-position and 5-position.

[0074] Preferably, the rhodium compound is monovalent rhodium, selected from one of [Rh(COD)Cl]2, Rh(COD)SbF6, Rh(COD)BF4, Rh(COD)NTf2, Rh(C2H4)Cl, Rh(C2H4)SbF6, Rh(C2H4)BF4, and Rh(C2H4)NTf2.

[0075] Preferably, the C2-symmetric NN-axial chiral biindole diphosphine ligand is complexed with a rhodium compound and applied to the asymmetric addition reaction of boric acid to pyridinium salt to prepare a structure shown in general formula III:

[0076]

[0077] in:

[0078] R 6 is selected from alkyl, alkoxy, aryl, substituted aryl, and halogen;

[0079] R 7 is selected from hydrogen, alkyl, alkoxy, aryl, substituted aryl, and halogen;

[0080] R 8 is selected from hydrogen, alkyl, alkoxy, aryl, substituted aryl, and halogen;

[0081] Ar is selected from aryl, including substituted aryl and heteroaryl;

[0082] Preferably, the R 6 Selected from C1-C5 alkyl, C1-C5 benzyl;

[0083] Preferably, the R 7 Selected from acyl substituents R 9 Selected from alkoxy;

[0084] Preferably, the R 8 Selected from hydrogen, C1-C5 alkyl;

[0085] Preferably, Ar is selected from phenyl and substituted phenyl; wherein the substituted phenyl is selected from C1-C3 alkyl, phenyl, methoxy, carboxyl, furyl, naphthyl, nitro, halogen; wherein the preferred substitution positions of the halogen are 2-position and 4-position.

[0086] Preferably, the rhodium compound is monovalent rhodium, selected from one of [Rh(COD)Cl]2, Rh(COD)SbF6, Rh(COD)BF4, Rh(COD)NTf2, Rh(C2H4)Cl, Rh(C2H4)SbF6, Rh(C2H4)BF4, and Rh(C2H4)NTf2.

[0087] Preferably, the C2-symmetric NN-axial chiral biindole bisphosphine ligand is complexed with a palladium compound and applied to the intramolecular asymmetric cyclization reaction of indole to prepare a structure shown in general formula IV:

[0088]

[0089] in:

[0090] R 10 is a substituent on the benzene ring of the indoline part of the parent structure, and the number is one or two, R 1 is selected from hydrogen, alkyl, alkoxy, aryl, substituted aryl, and halogen;

[0091] R 11 is selected from hydrogen, alkyl, alkoxy, aryl, substituted aryl, and halogen;

[0092] R 12 is selected from hydrogen, alkyl, alkoxy, aryl, substituted aryl, and halogen;

[0093] Preferably, the R 10 When the number of substituents is 1, they are selected from hydrogen, C1-C5 alkyl, and halogen;

[0094] Preferably, the R 10 When the number of substituents is 2, they are selected from C1 to C5 alkyl groups;

[0095] Preferably, the R 11 Selected from hydrogen, C1-C5 alkyl, halogen;

[0096] Preferably, the R 12 Selected from C1-C5 alkyl, phenyl, substituted phenyl, acyl substituent R 13 Selected from alkoxy; wherein the substituted phenyl is selected from C1-C3 alkyl, trifluoromethyl, and halogen.

[0097] Preferably, the palladium compound is divalent palladium, selected from one of Pd(OAc)2, PdCl2, PdBr2, PdI2, Pd2(dba)3, Pd(dba)2, and Pd(allyl)Cl.

[0098] Preferably, the C2-symmetric NN-axial chiral biindole diphosphine ligand is complexed with an iridium compound and applied to the asymmetric hydrogenation reaction of quinoline to prepare a structure shown in general formula V:

[0099]

[0100] Preferably, the iridium compound is monovalent iridium, selected from one of [Ir(COD)Cl]2, Ir(COD)SbF6, Ir(COD)BF4, Ir(COD)NTf2, Ir(C2H4)Cl, Ir(C2H4)SbF6, Ir(C2H4)BF4, and Ir(C2H4)NTf2.

[0101] Preferably, the C2-symmetric NN-axial chiral biindole diphosphine ligand is complexed with a ruthenium compound and applied to the asymmetric hydrogenation reaction of methyl 3-oxo-3-phenylpropionate to prepare a structure shown in general formula VI:

[0102]

[0103] Where: R 14 Selected from hydrogen, alkyl, alkoxy, aryl, substituted aryl, and halogen.

[0104] Preferably, the ruthenium compound is divalent ruthenium selected from [Ru(benzene)Cl2]2, [Ru(benzene)I2]2, [Ru(4- i Pr-tol)Cl2]2, Ru(COD)Cl2, [Ru2Cl4(4- i Pr-tol)2].

[0105] The beneficial effects achieved by one or more of the above technical solutions of the present invention are as follows:

[0106] The C2-symmetric NN-axis chiral biindole bisphosphine ligand obtained by the present invention through kinetic resolution and chiral preparative column separation has a simple skeleton, convenient synthesis, and easy modification, and can be applied to various metal-catalyzed asymmetric reactions, such as rhodium-catalyzed asymmetric dearomatization reaction of quinoline salt or pyridine salt with arylboronic acid, palladium-catalyzed asymmetric cyclization dearomatization reaction of indole, iridium-catalyzed asymmetric hydrogenation reaction, etc., and has good reaction efficiency and enantioselectivity, and has very good application prospects. DETAILED DESCRIPTION

[0107] It should be noted that the following detailed descriptions are exemplary and are intended to provide further explanation of the present invention. Unless otherwise specified, all technical and scientific terms used herein have the same meanings as those commonly understood by those skilled in the art to which the present invention belongs.

[0108] In order to enable those skilled in the art to more clearly understand the technical solution of the present invention, the technical solution of the present invention will be described in detail below in conjunction with specific embodiments.

[0109] Source of reagents: The purity and origin of the experimental reagents used in the present invention and the model and origin of the experimental instruments are shown in Table 1 and Table 2, respectively.

[0110] Table 1 Experimental instruments

[0111] name brand model High performance liquid chromatography Shimadzu LC-20AT Nuclear Magnetic Resonance Spectrometer Brooke AV 400MHz High Resolution Mass Spectrometry Waters Xevo G2-XSQT Chiral Columns Daicel OD,IG

[0112] Table 2 Experimental drugs and reagents

[0113]

[0114]

[0115] In the following examples, the abbreviations represent the following meanings: CDCl3: deuterated chloroform; 1 H NMR: hydrogen nuclear magnetic resonance; 13 C NMR: carbon nuclear magnetic resonance; 31 P NMR: phosphorus nuclear magnetic resonance; 19 F NMR: fluorine nuclear magnetic resonance; HRMS(ESI): high resolution mass spectrometry (electrospray ionization); rac-BINOL: racemic 1,1'-binaphthol; LDA: lithium diisopropylamide; [Rh(COD)Cl]2: (1,5-cyclooctadiene) rhodium(I) chloride dimer; Rh(COD)2BF4: di(1,5-cyclooctadiene) rhodium tetrafluoroborate; [Ir(COD)Cl]2: 1,5-cyclooctadiene iridium chloride dimer; [Ru(benzene)Cl2]2: dichlorophenylruthenium(II) dimer; Specific rotation values ​​measured under deuterium lamp conditions at 25°C.

[0116] Example 1 :This example provides the preparation process and verification data of 2,2'-bis(diphenylphosphino)-1,1'-diindole

[0117]

[0118] (1) Under air atmosphere, a solution of (2-nitrophenyl)methanol (3.06 g, 20 mmol), indoline (1.19 g, 10 mmol), tetrabutylammonium iodide (2.57 g, 10 mmol), and acetic acid (0.57 mL, 10 mmol) in dichloromethane (200 mL, 0.05 M) was stirred under blue light (385-405 nm) at room temperature for 24 hours. After the reaction was completed, the solvent was removed under reduced pressure, and the crude mixture was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 50:1) to obtain 2-((1H-indolyl)amino)benzaldehyde with a yield of 66%.

[0119] Then, under nitrogen atmosphere, a solution of triphenylphosphine (5.25 g, 20 mmol) in dichloromethane (20 mL) was added to a mixture of carbon tetrabromide (6.63 g, 20 mmol), zinc powder (5.20 g, 80 mmol) and anhydrous dichloromethane (80 mL). After 30 minutes, 2-((1H-indole)amino)benzaldehyde (2.36 g, 10 mmol) was added, and the reaction mixture was stirred at 0°C for 12 hours. After the reaction was completed, the mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 50:1) to obtain N-(2-(2,2-dibromovinyl)phenyl)-1H-indole-1-amine with a yield of 65%.

[0120] Verify data: 1 H NMR (400MHz, CDCl3) δ7.57(d,J=7.4Hz,1H),7.40(s,1H),7.24(d,J=7.7Hz,1H),7.16(d,J=7.2Hz,1H),7.11(s,1H) ,7.09–7.05(m,2H),7.00(t,J=7.9Hz,1H),6.83(t,J=7.5Hz,1H),6.53(s,1H),6.48(s,1H),6.00(d,J=8.2Hz,1H). 13 C NMR (100MHz, CDCl3) δ144.0,135.7,133.2,130.0,129.1,128.5,126.6,122.6,1 21.24,121.20,120.8,120.5,112.5,109.3,101.2,94.8.HRMS:(ESI)m / z:[M+H] + Calcd for C 16 H 13 N2Br2 + 390.9440; Found 390.9445.

[0121]

[0122] (2) CuI (190.5 mg, 1.0 mmol), rac-BINOL (572.6 mg, 2 mmol) and K2CO3 (1.38 g, 10 mmol) were added to a solution of N-(2-(2,2-dibromovinyl)phenyl)-1H-indole-1-amine (1.96 g, 5 mmol) in anhydrous toluene (10 mL). The mixture was stirred at 100° C. for 12 hours. After the reaction was completed, the solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 200:1) to obtain 2-bromo-1,1'-diindole with a yield of 90%.

[0123] Verify data: 1 H NMR (400MHz, CDCl3) δ7.63(d,J=7.6Hz,1H),7.53(d,J=7.8Hz,1H),7.15(t,J=5.6Hz,2H),7.10(d ,J=8.2Hz,2H),7.06(d,J=7.8Hz,1H),6.74(t,J=7.6Hz,2H),6.67(s,1H),6.63(d,J=3.4Hz,1H). 13 C NMR (100MHz, CDCl3) δ137.4,136.6,128.1,126.4,126.2,123.5,121.9,121 .5,121.4,120.2,114.4,109.1,109.0,104.9,102.8.HRMS:(ESI)m / z:[M+H] + Calcd for C 16 H 12 N2Br + 311.0178; Found 311.0177.

[0124]

[0125] (3) Under nitrogen atmosphere, to a mixture of 2-bromo-1,1'-diindole (1.55 g, 5 mmol) in anhydrous tetrahydrofuran (10 mL) was slowly added n-butyl lithium (4.4 mL, 7 mmol) at -78°C. After 20 minutes, diphenylphosphine chloride (1.35 mL, 7.5 mmol) was added and the mixture was stirred at room temperature for 12 hours. After monitoring the reaction completion, the reaction was quenched with water and extracted three times with ethyl acetate. The combined organic layer was dried over sodium sulfate and concentrated. The crude residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 200: 1) to obtain 2-(diphenylphosphino)-1,1'-diindole with a yield of 90%.

[0126] Verify data: 1H NMR (400MHz, CDCl3) δ7.51(t,J=9.6Hz,2H),7.29–7.28(m,2H),7.27–7.26(m,2H),7.25–7.23(m,2H),7.22(s,1H),7.20(d,J=4.9Hz,2H),7.16( s,1H),7.04(dd,J=12.3,7.2Hz,3H),6.94(d,J=8.1Hz,1H),6.79(s,1H) ,6.64(d,J=8.2Hz,1H),6.57(d,J=8.3Hz,1H),6.41(s,1H),6.28(s,1H). 13 C NMR (100MHz, CDCl3) δ140.03,139.95,139.6,136.6,135.0,134.9,134.6,134.5,133.89,133.87,133.69,133.66,129.2,129.1 ,128.6,128.50,128.47,128.4,128.3,126.2,126.1,123.6,122.9,121.3,121.01,120.97,120.9,110.3,109.4,109.0,102.2. 31 P NMR(162MHz,CDCl3)δ-30.66.HRMS:(ESI)m / z:[M+H] + Calcd for C 28 H 22 N2P + 417.1515; Found 417.1523.

[0127]

[0128] (4) Under nitrogen atmosphere, a mixture of LDA (3.75 ml, 7.5 mmol) and LiCl (2.54 g, 60 mmol) in anhydrous tetrahydrofuran (10 mL) was slowly added to a tetrahydrofuran solution of 2-(diphenylphosphino)-1,1'-diindole (2.08 g, 5 mmol) at -78°C. After 1.5 hours, diphenylphosphine chloride (1.35 mL, 7.5 mmol) was added and the mixture was stirred at room temperature for 24 hours. The reaction was quenched with water and the organic phase was extracted three times with ethyl acetate. The combined organic layers were dried over sodium sulfate and concentrated. The crude residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 200:1 to 100:1) to give 2,2'-bis(diphenylphosphino)-1,1'-diindole in a yield of 55%.

[0129] Verify data: 1H NMR(400MHz, CDCl3)δ7.49(d,J=7.9Hz,2H),7.32–7.27(m,4H),7.26–7.25(m,4H),7.24–7.23(m,2H),7.22–7.21(m,2H),7.20– 7.17(m,4H),7.16(d,J=7.2Hz,4H),6.99(t,J=7.6Hz,2H),6.77(t,J=7.7Hz,2H),6.44(d,J=1.7Hz,2H),6.34(d,J=8.3Hz,2H). 13 C NMR (100MHz, CDCl3) δ140.8,139.5,135.8,135.1,134.3,134.2,134.1,133.3,133.2,1 33.1,129.1,128.5,128.30,128.25,128.2,126.2,123.3,120.9,120.7,111.1,109.5. 31 P NMR(162MHz,CDCl3)δ-32.33.HRMS:(ESI)m / z:[M+H] + Calcd for C 40 H 31 N2P2 + 601.1957; Found 601.1960.

[0130] Example 2 :This example provides the preparation process and verification data of 2,2'-bis(dimethylphenylphosphino)-1,1'-diindole

[0131] The difference between this embodiment and embodiment 1 is that in step (3), the phosphorus reagent used is di(p-methylphenyl)phosphine chloride, and the other components, contents and preparation methods are consistent with those in embodiment 1. The specific reaction process of step (3) is as follows, and the yield is 63%:

[0132]

[0133] Verify data: 1H NMR (400MHz, CDCl3) δ7.59 (dd, J=12.3, 8.3Hz, 2H), 7.28 (s, 1H), 7.24–7.20 (m ,2H),7.19(s,1H),7.15–7.13(m,2H),7.12–7.10(m,2H),7.09(s,1H),7.07–7 .04(m,2H),7.02(s,1H),6.87(d,J=3.2Hz,1H),6.72(d,J=8.1Hz,1H),6.65(d ,J=8.3Hz,1H),6.49(d,J=3.2Hz,1H),6.36(s,1H),2.36(s,3H),2.31(s,3H). 13 C NMR (100MHz, CDCl3) δ140.7,140.6,139.59,139.57,139.2,139.1,136.5,133.9,133.8,133.7,133.6,131.6,131.5,131.13,131.08,129.4 ,129.3,129.2,129.1,128.5,126.2,126.1,123.4,122.8,121.2,121 .0,120.9,120.8,109.9,109.42,109.40,109.0,102.0,21.34,21.28. 31 PNMR(162MHz,CDCl3)δ-32.18.HRMS:(ESI)m / z:[M+H] + Calcd for C 30 H 26 N2P + 445.1828; Found 445.1830.

[0134] The specific reaction process of step (4) is as follows, and 2,2'-bis(dimethylphenylphosphino)-1,1'-diindole is obtained with a yield of 37%:

[0135]

[0136] Verify data: 1 H NMR (400MHz, CDCl3) δ7.43(d,J=7.9Hz,2H),7.12(s,4H),7.07–7.01(m,4H),7.00–6.96(m,4H),6.94(s,2H ),6.91–6.82(m,4H),6.75(d,J=7.9Hz,2H),6.37(s,2H),6.30(d,J=8.3Hz,2H),2.24(s,6H),2.20(s,6H).13 C NMR (100MHz, CDCl3) δ141.3,139.5,138.9,138.3,134.3,134.2,134.1,133.3,133.2,133.1,132.4,1 31.9,129.04,129.00,128.97,126.2,123.0,120.8,120.6,110.7,109.6,21.3.HRMS:(ESI)m / z:[M+H] + Calcd for C 44 H 39 N2P2 + 657.2583; Found 657.2589.

[0137] Example 3 :This example provides the preparation process and verification data of 2,2'-bis(diphenylphosphino)-5,5'-dimethyl-1,1'-diindole

[0138] The difference between this embodiment and embodiment 1 is that in step (1), the raw material used is 5-methyl-2-((5-methyl-1H-indolyl)amino)benzaldehyde, and the other components, contents and preparation methods are consistent with those in embodiment 1. The specific reaction process of step (1) is as follows to obtain N-(2-(2,2-dibromovinyl)-4-methylphenyl)-5-methyl-1H-indol-1-amine with a yield of 60%:

[0139]

[0140] Verify data: 1 H NMR (400MHz, CDCl3) δ7.37–7.34(m,2H),7.06–7.01(m,3H),6.91(d,J=8.6Hz,1H),6.79(d,J= 8.3Hz,1H),6.42(s,1H),6.37(d,J=3.0Hz,1H),5.94–5.86(m,1H),2.36(s,3H),2.18(s,3H). 13 C NMR (100MHz, CDCl3) δ141.8,134.1,133.4,130.5,130.2,129.7,129.3,128.6,126.9 ,124.1,121.2,120.8,112.8,109.0,100.4,94.4,21.4,20.4.HRMS:(ESI)m / z:[M+H] + Calcd for C 18 H 17 N2Br2 +Found 418.9753.

[0141] The specific reaction process of step (2) is as follows, and 2-bromo-5,5'-methyl-1,1'-diindole is obtained with a yield of 85%:

[0142]

[0143] Verify data: 1 H NMR (400MHz, CDCl3) δ7.52(s,1H),7.42(s,1H),7.22(d,J=1.9Hz,1H),7.03(d,J=8.4Hz,1H),6.99(d,J=8 .3Hz,1H),6.75(t,J=9.1Hz,2H),6.69(d,J=2.1Hz,1H),6.64(t,J=2.4Hz,1H),2.49(s,3H),2.47(s,3H). 13 C NMR (100MHz, CDCl3) δ135.8,135.0,131.3,130.7,128.2,126.6,126.4,124.9,124.8, 121.1,119.9,114.3,108.8,108.7,104.4,102.2,21.38,21.35.HRMS:(ESI)m / z:[M+H] + Calcd for C 18 H 16 N2Br + 339.0491; Found 339.0497.

[0144] The specific reaction process of step (3) is as follows, and 2-(diphenylphosphino)-5,5'-dimethyl-1,1'-diindole is obtained with a yield of 87%:

[0145]

[0146] Verify data: 1H NMR(400MHz, CDCl3)δ7.30(s,1H),7.27–7.26(m,2H),7.25–7.24(m,2H),7.23– 7.22(m,2H),7.21–7.20(m,2H),7.19–7.17(m,2H),7.14(d,J=11.8Hz,1H),6.8 4(d,J=8.5Hz,1H),6.77(d,J=8.5Hz,1H),6.70(d,J=2.9Hz,1H),6.54(d,J=8.4 Hz,1H),6.49(d,J=8.4Hz,1H),6.30(d,J=3.1Hz,1H),6.18(s,1H),2.32(m,6H). 13 C NMR (101MHz, CDCl3) δ140.0,139.9,138.1,135.2,135.13,135.07,134.9,134.8,133.9,133.8,133.7,133.6,130.7,130.2,129.2 ,129.0,128.6,128.52,128.45,128.38,128.3,126.5,126.4,125.2,124.5,120.8,120.5,109.7,109.0,108.7,101.6,21.4,21.3. 31 P NMR(162MHz,CDCl3)δ-30.62.HRMS:(ESI)m / z:[M+H] + Calcd for C 30 H 26 N2P + 445.1828; Found 445.1832.

[0147] The specific reaction process of step (4) is as follows, and 2,2'-bis(diphenylphosphino)-5,5'-dimethyl-1,1'-diindole is obtained with a yield of 57%:

[0148]

[0149] Verify data 1H NMR (400MHz, CDCl3) δ7.31–7.27(m,2H),7.26–7.25(m,2H),7.24–7.23(m,4H),7.22–7.21(m,4H),7.20–7.19(m,4 H),7.18–7.16(m,4H),7.15–7.10(m,2H),6.63(d,J=8.4Hz,2H),6.33(s,2H),6.27(d,J=8.4Hz,2H),2.31(s,6H). 13 C NMR (100MHz, CDCl3) δ140.6,138.1,136.0,135.5,134.2,134.1,134.0,133.3,133.2, 133.1,130.3,128.9,128.4,128.21,128.17,126.5,125.0,120.4,110.7,109.2,21.3. 31 P NMR(162MHz,CDCl3)δ-32.69.HRMS:(ESI)m / z:[M+H] + Calcd for C 42 H 35 N2P2 + 629.2270; Found 629.2277.

[0150] Example 4 :This example provides the preparation process and verification data of (S)-2,2'-bis(diphenylphosphino)-1,1'-diindole

[0151]

[0152] (1) Slowly add 30% pure H2O2 (2.1 mL, 20 mmol) to a solution of 2,2'-bis(diphenylphosphino)-1,1'-diindole (3.0 g, 5 mmol) prepared in Example 1 in 1,2-dichloroethane (20 mL). The reactants were stirred at room temperature for 10 minutes, then the solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 2:1) to obtain (1,1'-diindolyl)-2,2'-bis(diphenylphosphino) with a yield of 99%.

[0153] Verify data: 1H NMR (400MHz, CDCl3) δ7.73(t,J=10.1Hz,4H),7.62(t,J=10.0Hz,4H),7.51(d,J=7.7Hz,2H),7.48–7.39(m ,4H),7.33(d,J=8.9Hz,4H),7.02(d,J=8.5Hz,2H),6.79(d,J=8.6Hz,2H),6.60(s,2H),6.48–6.25(m,2H). 13 C NMR (100MHz, CDCl3) δ139.9,139.8,132.3,132.2,131.62,131.59,128.12 ,128.05,128.0,127.9,125.0,124.6,124.5,121.7,121.3,114.7,109.5. 31 P NMR(243MHz,CDCl3)δ16.91.HRMS:(ESI)m / z:[M+Na] + Calcd for C 40 H 30 N2O2P2Na + 655.1675; Found 655.1670.

[0154]

[0155] (2) (1,1'-diindolyl)-2,2'-bis(diphenylphosphine oxide) (550 mg, 0.87 mmol) was completely dissolved in dichloromethane (2 mL) at room temperature. A solution of (2S,3S)-2,3-di(benzoyloxy)succinic acid (342 mg, 0.96 mmol) in diethyl ether (80 mL) was added dropwise to the above solution. A precipitate was then produced, and the suspension was stirred at room temperature for 5 h. The solid was collected by filtration and washed three times with diethyl ether to obtain a (1,1'-diindolyl)-2,2'-bis(diphenylphosphine oxide) / (2S,3S)-2,3-di(benzoyloxy)succinic acid complex as white crystals. The complex was then redissolved in dichloromethane and washed with 2 M sodium hydroxide. The organic layer was separated and dried to obtain (R)-(1,1'-diindolyl)-2,2'-bis(diphenylphosphine oxide). The above steps were repeated three times to obtain (S)-(1,1'-diindolyl)-2,2'-bis(diphenylphosphine) with 99% ee in a yield of 83%. (c=0.14, CH2Cl2, 99%ee).

[0156]

[0157] (3) Under nitrogen atmosphere, trichlorosilane (0.25 mL, 2.5 mmol) was added to a solution of (S)-(1,1'-diindolyl)-2,2'-bis(diphenylphosphino) (316 mg, 0.5 mmol) and triethylamine (0.38 mL, 2.75 mmol) in anhydrous toluene (10 mL). The reactants were stirred at 120°C for 10 hours. The reaction was quenched with water and the organic phase was extracted three times with ethyl acetate. The combined organic layers were dried over sodium sulfate and concentrated. The crude residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 20:1) to obtain (S)-2,2'-bis(diphenylphosphino)-1,1'-diindole with a yield of 98%. Verification data: (c=0.14, CH2Cl2, 99%ee).

[0158] Example 5 :This example provides the preparation process and verification data of (R)-2,2'-bis(diphenylphosphino)-1,1'-diindole

[0159]

[0160] (1) (1,1'-diindolyl)-2,2'-bis(diphenylphosphine oxide) (500 mg, 0.79 mmol) was completely dissolved in dichloromethane (2 mL) at room temperature. A solution of (2R,3R)-2,3-di(benzoyloxy)succinic acid (311 mg, 0.87 mmol) in diethyl ether (80 mL) was added dropwise to the above solution. A precipitate was then produced, and the suspension was stirred at room temperature for 5 h. The solid was collected by filtration and washed three times with diethyl ether to obtain a (1,1'-diindolyl)-2,2'-bis(diphenylphosphine oxide) / (2R,3R)-2,3-di(benzoyloxy)succinic acid complex as white crystals. The complex was then redissolved in dichloromethane and washed with 2 M sodium hydroxide. The organic layer was separated and dried to obtain (R)-(1,1'-diindolyl)-2,2'-bis(diphenylphosphine oxide). The above steps were repeated three times to obtain (R)-(1,1'-diindolyl)-2,2'-bis(diphenylphosphine) with 99% ee in a yield of 80%. (c=0.12, CH2Cl2, 99%ee).

[0161]

[0162] (3) Under nitrogen atmosphere, trichlorosilane (0.25 mL, 2.5 mmol) was added to a solution of (R)-(1,1'-diindolyl)-2,2'-bis(diphenylphosphino) (316 mg, 0.5 mmol) and triethylamine (0.38 mL, 2.75 mmol) in anhydrous toluene (10 mL). The reactants were stirred at 120°C for 10 hours. The reaction was quenched with water and the organic phase was extracted three times with ethyl acetate. The combined organic layers were dried over sodium sulfate and concentrated. The crude residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 20:1) to obtain (R)-2,2'-bis(diphenylphosphino)-1,1'-diindole with a yield of 98%. Verification data: (c=0.14, CH2Cl2, 98%ee).

[0163] Example 6 :This example provides the chiral separation of compound 1a

[0164]

[0165] (1) BH3·THF (8 mL, 8 mmol) was slowly added to a tetrahydrofuran solution of compound 1a (2 mmol, 1.0 equivalent). The reactants were stirred at room temperature for 10 minutes. The solvent was then removed under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 20:1) to obtain 2,2'-bis(diphenylphosphino)-1,1'-diindolylborane complex with a yield of 99%.

[0166] (2) Separate 2,2'-bis(diphenylphosphino)-1,1'-diindolyl borane complex by preparative chiral high performance liquid chromatography to obtain (R / S)-2,2'-bis(diphenylphosphino)-1,1'-diindolyl borane complex, 99% ee. High performance liquid chromatography separation conditions: CHIRALPAK IG, eluent: hexane / dichloromethane = 70:30, flow rate: 1.0 mL / min.

[0167] Verify data 1 H NMR (400MHz, CDCl3) δ7.72(t,J=9.6Hz,4H),7.61(d,J=9.5Hz,4H),7.58(s,2H),7.49(dd,J=12.1,7.2Hz,4H),7.43(d,J=7.3Hz, 4H),7.37(d,J=8.0Hz,4H),7.03(t,J=7.8Hz,2H),6.82(s,2H),6.57(t,J=7.9Hz,2H),5.86(d,J=8.4Hz,2H),1.13–0.33(m,6H). 13C NMR (100MHz, CDCl3) δ140.10,140.06,134.3,134.2,133.0,132.9,131.51,131.49,130.94,130.92,130.7,130.2,13 0.1,129.5,128.63,128.56,128.5,128.4,127.3,126.7,125.3,125.2,124.4,121.43,121.36,116.3,116.3,109.0. 31 P NMR(162MHz,CDCl3)δ8.98,32.87.HRMS:(ESI)m / z:[M+Na] + Calcd for C 40 H 36 N2B2P2Na + 651.2432; Found 651.2439. (c=0.14, CH2Cl2, 99%ee), (S)-7a; (c=0.14, CH2Cl2, 98%ee), (R)-7a.

[0168]

[0169] (3) The ((R / S)-2,2'-bis(diphenylphosphino)-1,1'-diindole borane complex was dissolved in an appropriate amount of diethylamine and stirred at room temperature for 10 minutes. The solvent was then removed under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate=50:1) to obtain ((R / S)-2,2'-bis(diphenylphosphino)-1,1'-diindole with a yield of 99%.

[0170] Example 7 :This example provides the chiral separation of compound 1b

[0171]

[0172] The difference between this embodiment and embodiment 6 is that in step (1), the raw material used is 2,2'-bis(di-p-methylphenylphosphino)-1,1'-diindole (compound 1b), and 2,2'-bis(di-p-methylphenylphosphino)-1,1'-diindole borane complex is obtained with a yield of 99%, and the other components and preparation methods are consistent.

[0173] In step (2), 2,2'-bis(di-p-methylphenylphosphino)-1,1'-diindolyl borane complex is separated by preparative chiral high performance liquid chromatography to obtain (R / S)-2,2'-bis(di-p-methylphenylphosphino)-1,1'-diindolyl borane complex with 99% ee. The other components are consistent with the preparation method.

[0174] Verify data: 1 H NMR (400MHz, CDCl3) δ7.61–7.57(m,2H),7.56–7.50(m,4H),7.44(t,J=9.6Hz,4H),7.19(d,J=7.6Hz,4H),7.14(d,J=7.6Hz,4H),7.0 2(t,J=8.0Hz,2H),6.78(d,J=3.0Hz,2H),6.56(t,J=8.1Hz,2H),5.88(d,J=8.4Hz,2H),2.41(s,6H),2.38(s,6H),0.95–0.41(m,6H). 13 C NMR (100MHz, CDCl3) δ141.9,141.8,141.2,141.1,140.2,140.1,134.2,134.1,133.0,132.9,131.3,130.6,129.30,1 29.25,129.2,129.1,126.7,126.0,125.3,125.2,124.1,123.5,121.3,121.2,116.00,115.96,109.2,21.49,21.48. 31 P NMR(162MHz,CDCl3)δ7.79.HRMS:(ESI)m / z:[M+Na] + Calcd for C 44 H 44 N2B2P2Na + 707.3058; Found 707.3065. (c=0.07, CH2Cl2, 99%ee), (S)-7b; (c=0.07, CH2Cl2, 99%ee), (R)-7b.

[0175]

[0176] In step (3), the raw material used is (R / S)-2,2'-bis(di-p-methylphenylphosphino)-1,1'-diindole borane complex, and (R / S)-2,2'-bis(di-p-methylphenylphosphino)-1,1'-diindole is obtained. The other components are consistent with the preparation method, and the yield is 99%. Verification data: (c=0.07, CH2Cl2, 99%ee), (S)-1b; (c=0.07, CH2Cl2, 99%ee), (R)-1b.

[0177] Example 8 :This example provides the chiral separation of compound 1c

[0178]

[0179] The difference between this embodiment and embodiment 6 is that in step (1), the raw material used is 2,2'-bis(diphenylphosphino)-5,5'-dimethyl-1,1'-diindole (compound 1c), and 2,2'-bis(diphenylphosphino)-5,5'-dimethyl-1,1'-diindole borane complex is obtained with a yield of 99%, and the other components and preparation methods are consistent.

[0180] In step (2), 2,2'-bis(diphenylphosphino)-5,5'-dimethyl-1,1'-diindolyl borane complex is separated by preparative chiral high performance liquid chromatography to obtain (R / S)-2,2'-bis(diphenylphosphino)-5,5'-dimethyl-1,1'-diindolyl borane complex with 99% ee. The other components are consistent with the preparation method.

[0181] Verify data: 1 H NMR (400MHz, CDCl3) δ7.68(t,J=9.6Hz,4H),7.58(t,J=9.5Hz,4H),7.47(dd,J=14.7,7.1Hz,4H),7.40(d,J=7.2Hz,4H),7 .37(s,2H),7.35–7.29(m,4H),6.71(s,2H),6.40(d,J=8.5Hz,2H),5.75(d,J=8.5Hz,2H),2.32(s,6H),0.94–0.49(m,6H). 13CNMR (100MHz, CDCl3) δ138.7,138.64,134.3,134.2,133.0,132.9,131.43,131.41,130.88,130.85,130.8,130.4,130. 3,129.8,129.6,128.6,128.5,128.44,128.40,127.6,127.0,126.1,125.5,125.4,120.9,115.84,115.80,108.7,21.3. 31 P NMR(162MHz,CDCl3)δ8.93.HRMS:(ESI)m / z:[M+Na] + Calcd for C 42 H 40 N2B2P2Na + 679.2745; Found 679.2751. (c=0.07, CH2Cl2, 99%ee), (S)-7c; (c=0.07, CH2Cl2, 99%ee), (R)-7c.

[0182]

[0183] In step (3), the raw material used is (R / S)-2,2'-bis(diphenylphosphino)-5,5'-dimethyl-1,1'-diindole borane complex, and (R / S)-2,2'-bis(diphenylphosphino)-5,5'-dimethyl-1,1'-diindole is obtained. The other components are consistent with the preparation method, and the yield is 99%. Verification data: (c=0.07, CH2Cl2, 99%ee), (S)-1c; (c=0.07, CH2Cl2, 99%ee), (R)-1c.

[0184] Example 9 :This example provides the preparation process and verification data of (S)-2,2'-bis(diphenylphosphinoyl)-3,3'-diphenyl-1,1'-bisindole (the preparation method of (R)-2,2'-bis(diphenylphosphinoyl)-3,3'-diphenyl-1,1'-bisindole is the same as that of this example)

[0185]

[0186] (1) KBr (297 mg, 2.5 mmol) and potassium peroxymonosulfonate (1.23 g, 2 mmol) were added to a mixture of (S)-6 (1 mmol, 1.0 equivalent) in DCE (5 mL). The reaction mixture was reacted at 70° C. for 18 hours. The solvent was then removed under vacuum, and the residue was purified by silica gel chromatography (DCM:MeOH=20:1) to give (S)-8 in a yield of 86%.

[0187] Verify data: 1 H NMR(400MHz, CDCl3)δ7.89(dt,J=12.5,5.5Hz,2H),7.71(t,J=8.6Hz,2H),7.59(s,1H),7.54–7.44(m,2H), 7.42–7.36(m,2H),7.35–7.29(m,2H),7.16(t,J=7.8Hz,1H),6.91(t,J=5.8Hz,1H),6.33(t,J=5.9Hz,1H). 13 C NMR (100MHz, CDCl3) δ139.1,132.8,132.7,132.3,132.2,132.0,131.2,130.1, 129.4,128.3,128.2,128.1,126.0,125.7,125.6,122.1,120.5,109.2,102.2. 31 P NMR(162MHz,CDCl3)δ18.55.HRMS:(ESI)m / z:[M+Na] + Calcd for C 40 H 28 Br2N2NaO2P2 + 810.9885; Found 810.9883. (c=0.28, CH2Cl2, 98%ee), (S)-8.

[0188]

[0189] (2) Under nitrogen protection, phenylboronic acid (183.0 mg, 1.5 mmol), Pd(PPh3)4 (57.8 mg, 0.05 mmol) and Na2CO3 (106.0 mg, 1 mmol) were added to a solution of (S)-8 (0.5 mmol, 1.0 equivalent) in toluene:ethanol:water (4 mL, 2 mL, 0.5 mL) . The mixture was reacted at 110°C for 24 hours. The solvent was then removed under vacuum, and the residue was purified by silica gel chromatography (DCM:MeOH=20:1) to give (S)-9 in a yield of 77%.

[0190] Verify data: 1 H NMR(400MHz, CDCl3)δ7.70(s,2H),7.52(s,2H),7.37(s,2H),7.27(s,1H),7.17(s,1H),7.14–7.08 (m,2H),7.07–7.04(m,2H),7.03–7.01(m,2H),7.00–6.98(m,2H),6.97–6.74(m,2H),6.53(s,1H). 13 C NMR (100MHz, CDCl3) δ138.3,132.5,132.3,132.2,132.0,131.9,131.6,130.93,130. 85,129.9,127.60,127.59,127.4,127.3,127.1,126.9,125.6,121.7,120.9,109.7. 31 P NMR(162MHz,CDCl3)δ14.32.HRMS:(ESI)m / z:[M+Na] + Calcdfor C 52 H 38 N2NaO2P2 + 807.2301; Found 807.2298. (c=0.28, CH2Cl2, 99%ee), (S)-9.

[0191]

[0192] (3) Under nitrogen atmosphere, HSiCl3 (0.25 mL, 2.5 mmol) was added to a mixture of (S)-9 (0.5 mmol, 1.0 equiv.) and Et3N (0.38 mL, 2.75 mmol) in anhydrous toluene (10 mL). The mixture was reacted at 120°C for 10 hours. The reaction was quenched with water and the organic phase was extracted three times with ethyl acetate. The combined organic layers were dried over sodium sulfate and concentrated. The crude residue was purified by silica gel chromatography (petroleum ether: EtOAc = 50:1) to give (S)-1d.

[0193] Verify data: 1H NMR (400MHz, CDCl3) δ7.28(d,J=4.3Hz,1H),7.18(d,J=3.0Hz,1H),7.16–7.12(m,2H),7.12–7.05(m,2H),7.05–7.02(m,2 H),7.01–6.99(m,2H),6.96–6.94(m,2H),6.93–6.91(m,2H),6.90–6.87(m,2H),6.86–6.80(m,2H),6.59(d,J=5.0Hz,1H). 13 CNMR (100MHz, CDCl3) δ139.0,133.8,133.7,133.6,133.5,132.9,132.8,132.7,130.7,128.4,128.0 ,127.91,127.88,127.72,127.65,127.62,127.59,127.4,126.5,126.2,124.1,121.1,120.0,109.7. 31 P NMR(162MHz,CDCl3)δ-27.01.HRMS:(ESI)m / z:[M+H] + Calcdfor C 52 H 39 N2P2 + 753.2583; Found 753.2577.=-35.0° (c=0.14, CH2Cl2, 99%ee), (S)-1d.

[0194] Example 10 This example provides asymmetric addition reaction of boronic acid to quinoline salt catalyzed by compound (R)-1a as a chiral ligand.

[0195]

[0196] Under nitrogen atmosphere, [Rh(COD)Cl]2 (0.0025mmol), compound (R)-1a (0.007mmol), AgBF4 (2.0mg, 0.01mmol) and toluene (3mL) were added to a dry reaction tube, and the resulting mixture was stirred at room temperature for 20 minutes. Quinoline salt (0.1mmol, 1.0 equivalent), arylboronic acid (0.2mmol) and K3PO4·3H2O (40mg, 0.15mmol) were added, and the mixture was stirred at 45°C for 12 hours (or until the reaction was completed by TLC analysis). The reaction results are shown in Table 3:

[0197] Table 3

[0198]

[0199] Embodiment 11 :This example provides the asymmetric addition reaction of boric acid to pyridinium salt catalyzed by compound (R)-1a as a chiral ligand

[0200]

[0201] Under nitrogen atmosphere, Rh(COD)2BF4 (0.005 mmol), compound (R)-1a (0.005 mmol) and 1,4-dioxane (0.5 mL) were added to a dry reaction tube, and the resulting mixture was stirred at room temperature for 20 minutes. Pyridinium salt (0.1 mmol), arylboronic acid (0.25 mmol), sodium carbonate (0.25 mmol) and degassed water (0.125 mL) were added, and the mixture was stirred at 80°C for 2 hours (or until the reaction was completed by TLC analysis). The reaction results are shown in Table 4:

[0202] Table 4

[0203]

[0204]

[0205] Example 12 This example provides asymmetric cyclization of indole catalyzed by compound (R)-1a as a chiral ligand.

[0206]

[0207] Under nitrogen atmosphere, Pd(OAc)2 (0.005 mmol), compound (R)-1a (0.006 mmol) and methanol (1.0 mL) were added to a dry reaction tube, and the resulting mixture was stirred at room temperature for 1 hour. Indole compound (0.1 mmol) and sodium formate (13.6 mg, 0.2 mmol) were added, and the mixture was stirred at 100°C until the reaction was complete (monitored by TLC). The reaction results are shown in Table 5:

[0208] Table 5

[0209]

[0210] Example 13 :This embodiment provides asymmetric hydrogenation reaction catalyzed by compound (R)-1a as a chiral ligand

[0211]

[0212] In an argon-filled glove box, [Ir(COD)Cl]2 (0.0025 mmol) was added to a toluene (2.5 mL) solution of compound (R)-1a (0.005 mmol). The reaction mixture was stirred at room temperature for 30 minutes. Then I2 (0.025 mmol) and 2-methylquinoline (0.5 mmol) were added to the reaction mixture. The reaction tube was then transferred to an autoclave, 20 atm of H2 was charged into the autoclave, and the mixture was stirred at room temperature for 24 hours to give (S)-2-methyl-1,2,3,4-tetrahydroquinoline (Compound 13) with a yield of 85%, 92% ee.

[0213] Embodiment 14 This example provides compound (R)-1a as a chiral ligand to catalyze the asymmetric hydrogenation of methyl 3-oxo-3-phenylpropionate.

[0214]

[0215] Under nitrogen atmosphere, [Ru(benze)Cl2]2 (0.002mmol) and compound (R)-1a (0.0042mmol) were dissolved in degassed dimethyl sulfoxide (0.2mL), heated to 100°C and reacted for 30 minutes. After the mixture was cooled to 50°C, the solvent was removed under vacuum to obtain a reddish brown solid catalyst. In an autoclave, the catalyst was dissolved in degassed methanol (0.4mL), and 3-oxo-3-phenylpropionic acid methyl ester (0.2mmol, 1.0 equivalent) was added. 50atm of H2 was charged into the autoclave and stirred at 80°C for 12 hours. The reaction results are shown in Table 6:

[0216] Table 6

[0217] serial number <![CDATA[R 14 ]]> Yield / % Enantiomeric excess ee / % 14a F 99 95 14b Cl 99 95

[0218] The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention. For those skilled in the art, the present invention may have various modifications and variations. Any modification, equivalent replacement, improvement, etc. made within the spirit and principle of the present invention shall be included in the protection scope of the present invention.

Claims

1. A C2-symmetric NN-axial chiral biindole bisphosphine ligand compound or a pharmaceutically acceptable salt, isomer, solvate and hydrate thereof, characterized in that: It has the structure shown in general formula I: Among them, R 1 is a substituent on the benzene ring of the indole part of the parent structure, and the number is one or two, R 1 is selected from hydrogen, alkyl, alkoxy, halogen, aryl, substituted aryl, heteroaryl; R 2 is selected from aryl, substituted aryl, and heteroaryl; R 3 Selected from hydrogen, halogen, aryl, and substituted aryl.

2. The C2-symmetric NN-axial chiral biindole bisphosphine ligand compound or its pharmaceutically acceptable salt, isomer, solvate and hydrate as claimed in claim 1, characterized in that: The R 1 Selected from hydrogen, C1-C5 alkyl, C1-C3 alkoxy, halogen, five-membered to seven-membered nitrogen heterocyclic group, phenyl, and phenyl substituted by at least one of methyl, methoxy, and halogen; Preferably, the R 1 is selected from the group consisting of hydrogen, methyl, methoxy, fluorine, chlorine and bromine; Preferably, the R 1 The substitution position is selected from the group consisting of 4, 5, 6, 7 or 4', 5', 6', 7' on the indole; R 1 When the number is one, the preferred position is 5, 6 or 5', 6',; R 1 When the number is two, the two substituents are R 1 and R 1 ', the preferred positions of the two substituents are 5, 7 or 5', 7', R 1 and R 1 'It can be the same or different; Preferably, the R 2 is selected from aryl, substituted aryl, and heteroaryl; Preferably, the R 2 A phenyl group, a phenyl group substituted by at least one of a methyl group, a methoxy group, and a halogen group, and a five-membered to seven-membered nitrogen heterocyclic group; Preferably, the R 2 Selected from phenyl, 4-tolyl, 4-methoxyphenyl, 4-fluorophenyl, 4-chlorophenyl, 4-bromophenyl; Preferably, the R 3 A phenyl group and a phenyl group substituted by at least one of a methyl group, a methoxy group and a halogen group; Preferably, the pharmaceutically acceptable salt is a derivative obtained by group modification to improve the physical and chemical properties of the C2-symmetric NN-axial chiral biindole diphosphine ligand, and is generally a salt formed by the C2-symmetric NN-axial chiral biindole diphosphine ligand and an inorganic salt or an organic acid; Preferably, the isomer is an R configuration isomer; Preferably, the isomer is an S configuration isomer.

3. The C2-symmetric NN-axial chiral biindole bisphosphine ligand compound or its pharmaceutically acceptable salt, isomer, solvate and hydrate as claimed in claim 1, characterized in that: The compounds shown in general formula I include the following structures:

4. A method for preparing the C2-symmetric NN-axial chiral biindole bisphosphine ligand compound or its pharmaceutically acceptable salt, isomer, solvate and hydrate as claimed in any one of claims 1 to 3, characterized in that: The steps include: S1. Adding compound A to an organic solution containing carbon tetrahalide, a reducing agent and triphenylphosphine, and obtaining 1,1-dihaloolefin compound 3 after reaction; wherein the structural formula of compound A is: R 1 Same as the definition in claim 1 or 2; the structural formula of the 1,1-dihaloolefin compound 3 is: R 1 As defined in claim 1 or 2, X is selected from halogen; S2, mixing 1,1-dihaloolefin compound 3, transition metal compound, ligand compound and K2CO3 in an organic solvent, and performing cyclization reaction to obtain biindole compound 4; wherein the structural formula of the biindole compound 4 is: R 1 As defined in claim 1 or 2, X is selected from halogen; S3, the biindole halide 4 reacts with a diaryl phosphorus halide in the presence of an alkyl metal compound to generate a biindole diaryl phosphine compound 5; wherein the structural formula of the biindole diaryl phosphine compound 5 is: R 1 , R 2 Same as defined in claim 1 or 2; S4, the biindole diaryl phosphine compound 5 reacts with a diaryl phosphorus halide in the presence of an alkyl metal compound to generate a compound represented by the general formula I.

5. The preparation method according to claim 4, characterized in that: In step S1, the molar ratio of the carbon tetrahalide, the reducing agent, triphenylphosphine, and the compound A is 1-10:1-20:1-10:1; the carbon tetrahalide is selected from one of carbon tetrachloride, carbon tetrabromide, and carbon tetraiodide; the reducing agent is selected from one of magnesium, iron, zinc, copper, and manganese; the compound A is selected from one of 2-indolylaminoarylbenzaldehyde and 2-indolylaminoarylbenzophenone; the organic solvent is selected from one of dichloromethane, chloroform, ethyl acetate, tetrahydrofuran, methyltetrahydrofuran, ether, dibutyl ether, methyl tert-butyl ether, ethylene glycol dimethyl ether, dioxane, toluene, xylene, benzene, and chlorobenzene; the reaction temperature is -5-10°C, and the reaction time is 1-48h; Preferably, in step S2, the molar ratio of the 1,1-dihaloolefin compound 3, the transition metal compound, the ligand compound and K2CO3 is 1:0.005~2:0.01~4:1.5~2.5; the transition metal compound is selected from one of a copper compound, a palladium compound, a rhodium compound, an iridium compound, and a ruthenium compound; the ligand compound is selected from one of 1,1'-bi-2-naphthol, 2,2'-dihydroxybiphenyl, 1,1'-bi-2-naphthylamine, and 1,2-diaminocyclohexane; the organic solvent is selected from one of dichloromethane, chloroform, ethyl acetate, tetrahydrofuran, methyltetrahydrofuran, ether, dibutyl ether, methyl tert-butyl ether, ethylene glycol dimethyl ether, dioxane, toluene, xylene, benzene, and chlorobenzene; the temperature of the cyclization reaction is 60~120°C, and the time is 8~24h.

6. The preparation method according to claim 4, characterized in that: In step S3, the specific process of the reaction is: firstly mix the biindole halide 4 and the alkyl metal compound for low-temperature reaction, then add the diaryl phosphorus halide and stir to react; wherein the molar ratio of the biindole halide 4, the alkyl metal compound and the diaryl phosphorus halide is 1:1-5:1-5; the alkyl metal compound is selected from one of alkyl lithium and alkyl magnesium; the diaryl phosphorus halide is selected from one of diaryl phosphorus chloride, diaryl phosphorus bromide and diaryl phosphorus iodide; the temperature of the low-temperature reaction is -78-0°C, and the time is 15-30min; the temperature of the stirring reaction is 25-50°C, and the time is 6-24h; Preferably, in step S4, the specific process of the reaction is: first mix the biindole diaryl phosphine compound 5, the alkyl metal compound and the lithium salt for low-temperature reaction, then add the diaryl phosphorus halide and stir to react; wherein the molar ratio of the biindole diaryl phosphine compound 5, the alkyl metal compound, the lithium salt and the diaryl phosphorus halide is 1:1-5:10-15:1-5; the alkyl metal compound is selected from one of alkyl lithium and alkyl magnesium; the lithium salt is selected from one of lithium chloride, lithium bromide and lithium iodide; the diaryl phosphorus halide is selected from one of diaryl phosphorus chloride, diaryl phosphorus bromide and diaryl phosphorus iodide; the temperature of the low-temperature reaction is -78-0°C, and the time is 1-2h; the temperature of the stirring reaction is 25-50°C, and the time is 6-24h.

7. The preparation method according to claim 4, characterized in that: The preparation method further comprises splitting the product obtained in step S4 of claim 4 to obtain an R-configuration or S-configuration biindole diphosphine compound, wherein the structural formula of the R-configuration biindole diphosphine compound is: The structural formula of the S-configuration biindole diphosphine compound is: R 1 , R 2 Same as defined in claim 1 or 2; Preferably, the splitting reaction is specifically as follows: firstly, the compound represented by the general formula I is subjected to an oxidation reaction with an oxidant to obtain a biindole diphosphine oxide compound 6, which is reacted with a splitting agent, the obtained R-configuration biindole diphosphine oxide compound and S-configuration biindole diphosphine oxide compound are washed with an alkaline solution, and then a reduction reaction is performed to obtain the R-configuration or S-configuration biindole diphosphine in the compound represented by the general formula I. R 2 Same as the definition in claim 1 or 2; the structural formula of the R-configured biindole diphosphine oxide compound is: R 1 , R 2 Same as the definition in claim 1 or 2; the structural formula of the S-configuration biindole diphosphine oxide compound is: R 1 , R 2 Same as defined in claim 1 or 2; Further preferably, the oxidation reaction process is specifically as follows: mixing the compound represented by the general formula I and the oxidant, and carrying out a stirring reaction to obtain the biindole diphosphine oxide compound 6; wherein the molar ratio of the compound represented by the general formula I to the oxidant is 1:1-20; the oxidant is selected from one of hydrogen peroxide, m-chloroperbenzoic acid, and tert-butyl peroxide; the stirring reaction temperature is 5-50°C, and the time is 10-50min; Further preferably, the molar ratio of the biindole diphosphine oxide 6 to the resolving agent is 1:1-10; the resolving agent is (2S, 3S)-2,3-di(benzoyloxy)succinic acid or (2R, 3R)-2,3-di(benzoyloxy)succinic acid; the alkaline solution is selected from one of a sodium hydroxide aqueous solution, a potassium hydroxide aqueous solution, a barium hydroxide aqueous solution, and a calcium hydroxide aqueous solution; Further preferably, the reduction reaction process is specifically as follows: adding a reducing agent and triethylamine to the washed R-configuration or S-configuration biindole diphosphine oxide compound, and performing a heating reaction; wherein the molar ratio of the washed R-configuration or S-configuration biindole diphosphine oxide compound, the reducing agent and the triethylamine is 1:1-20:1-20; the reducing agent is selected from one of sodium borohydride, trichlorosilane and lithium aluminum tetrahydride; the heating reaction temperature is 100-150°C, and the time is 8-48h; Further preferably, the product obtained by the reduction reaction is further purified by silica gel column chromatography, the eluent is a petroleum ether / ethyl acetate mixture with a volume ratio of 20:1, and the elution flow rate is 0.1-5 mL / min; Further preferably, an R-configuration or S-configuration biindole diphosphorus oxide compound, a halogen compound and an oxidant are mixed and heated to react to obtain compound 8, wherein the molar ratio of the R-configuration or S-configuration biindole diphosphorus oxide compound, the halogen compound and the oxidant is 1:2-3:1-2.5, the halogen compound is selected from one of potassium bromide, sodium bromide, calcium bromide, cesium bromide, potassium iodide, sodium iodide, potassium chloride and sodium chloride, the oxidant is potassium peroxymonosulfonate, the temperature of the heating reaction is 65-85°C, and the time is 15-30h; wherein the structural formula of compound 8 is: R 1 , R 2 As defined in claim 1 or 2, X is selected from halogen; Further preferably, compound 8, phenylboronic acid, Pd(PPh3)4 and Na2CO3 are mixed in an organic solvent and heated to react to obtain compound 9, wherein the molar ratio of compound 8, phenylboronic acid, Pd(PPh3)4 and Na2CO3 is 1:1-2:0.02-0.08:0.05-1.5, the organic solvent is a mixed solvent of toluene, ethanol and water, the temperature of the heating reaction is 100-150°C, and the time is 20-36h; wherein the structural formula of compound 9 is: R 1 , R 2 , R 3 Same as defined in claim 1 or 2; Further preferably, a reducing agent and triethylamine are added to the compound 9 for a heating reaction, wherein the molar ratio of the compound 9, the reducing agent and the triethylamine is 1:1-20:1-20; the reducing agent is selected from one of sodium borohydride, trichlorosilane and lithium aluminum tetrahydride; the heating reaction temperature is 100-150°C and the time is 8-48h.

8. The preparation method according to claim 4, characterized in that: The preparation method further comprises firstly subjecting the product obtained in step S4 of claim 4 to a complex reaction with a borane solution, and then separating the obtained biindole diphosphine borane complex by preparative chiral high performance liquid chromatography to obtain an R-configuration or S-configuration biindole diphosphine compound, wherein the structural formula of the biindole diphosphine borane complex is: R 1 , R 2 , R 3 Same as defined in claim 1 or 2; Preferably, the process of the complex reaction is specifically as follows: adding a borane solution to an organic solvent of the compound represented by the general formula I, and stirring the reaction; wherein the borane solution is prepared by dissolving borane in tetrahydrofuran; the molar ratio of the compound represented by the general formula I to the borane solution is 1:4; the mixture after the complex reaction is further purified by silica gel column chromatography to obtain a biindole diphosphine borane complex, and the eluent is a petroleum ether / ethyl acetate mixture with a volume ratio of 20:1; the separation conditions of the high performance liquid chromatography are CHIRALPAK IG, the eluent is a hexane / dichloromethane mixture with a volume ratio of 70:30, and the elution flow rate is 0.5 to 1 mL / min; the product obtained by the high performance liquid chromatography separation is further purified by washing and silica gel column chromatography in sequence, the eluent is a petroleum ether / ethyl acetate mixture with a volume ratio of 50:1, and the elution flow rate is 0.1 to -5 mL / min.

9. A composition comprising the C2-symmetric NN-axial chiral biindole bisphosphine ligand compound or a pharmaceutically acceptable salt, isomer, solvate or hydrate thereof as claimed in any one of claims 1 to 3.

10. Use of the C2-symmetric NN-axial chiral biindole bisphosphine ligand compound or its pharmaceutically acceptable salts, isomers, solvates and hydrates as claimed in any one of claims 1 to 3 as a catalyst ligand in an asymmetric catalytic reaction; Preferably, the asymmetric catalytic reaction includes but is not limited to asymmetric addition reaction of pyridinium salt and quinoline salt, intramolecular asymmetric cyclization reaction of indole, asymmetric hydrogenation reaction of quinoline and asymmetric hydrogenation reaction of methyl 3-oxo-3-phenylpropionate; Preferably, the C2-symmetric NN-axial chiral biindole diphosphine ligand is complexed with a rhodium compound and applied to the asymmetric addition reaction of boric acid to quinoline salt to prepare a structure shown in general formula II: in: R 4 is selected from alkyl, alkoxy, aryl, substituted aryl, and halogen; R 5 is selected from hydrogen, alkyl, alkoxy, aryl, substituted aryl, and halogen; Ar is selected from aryl, substituted aryl, heteroaryl; Preferably, the R 4 Selected from C1-C5 alkyl; Preferably, the R 5 Selected from phenyl, methoxyphenyl, trifluoromethylphenyl, fluorophenyl, chlorophenyl; Preferably, the preferred substitution positions of the fluorophenyl group are 2, 3, 4 and 5; wherein, when there is one substituent, the preferred substitution positions are 2 and 4; when there are two substituents, the preferred substitution positions are 3 and 5; Preferably, the rhodium compound is monovalent rhodium, selected from one of [Rh(COD)Cl]2, Rh(COD)SbF6, Rh(COD)BF4, Rh(COD)NTf2, Rh(C2H4)Cl, Rh(C2H4)SbF6, Rh(C2H4)BF4, and Rh(C2H4)NTf2; Preferably, the C2-symmetric NN-axial chiral biindole diphosphine ligand is complexed with a rhodium compound and applied to the asymmetric addition reaction of boric acid to pyridinium salt to prepare a structure shown in general formula III: in: R 6 is selected from alkyl, alkoxy, aryl, substituted aryl, and halogen; R 7 is selected from hydrogen, alkyl, alkoxy, aryl, substituted aryl, and halogen; R 8 is selected from hydrogen, alkyl, alkoxy, aryl, substituted aryl, and halogen; Ar is selected from aryl, including substituted aryl and heteroaryl; Preferably, the R 6 Selected from C1-C5 alkyl, C1-C5 benzyl; Preferably, the R 7 Selected from acyl substituents R 9 Selected from alkoxy; Preferably, the R 8 Selected from hydrogen, C1-C5 alkyl; Preferably, Ar is selected from phenyl and substituted phenyl; wherein the substituted phenyl is selected from C1-C3 alkyl, phenyl, methoxy, carbomethoxy, furyl, naphthyl, nitro, halogen; wherein the preferred substitution positions of the halogen are 2 and 4; Preferably, the rhodium compound is monovalent rhodium, selected from one of [Rh(COD)Cl]2, Rh(COD)SbF6, Rh(COD)BF4, Rh(COD)NTf2, Rh(C2H4)Cl, Rh(C2H4)SbF6, Rh(C2H4)BF4, and Rh(C2H4)NTf2; Preferably, the C2-symmetric NN-axial chiral biindole bisphosphine ligand is complexed with a palladium compound and applied to the intramolecular asymmetric cyclization reaction of indole to prepare a structure shown in general formula IV: in: R 10 is a substituent on the benzene ring of the indoline part of the parent structure, and the number is one or two, R 1 is selected from hydrogen, alkyl, alkoxy, aryl, substituted aryl, and halogen; R 11 is selected from hydrogen, alkyl, alkoxy, aryl, substituted aryl, and halogen; R 12 is selected from hydrogen, alkyl, alkoxy, aryl, substituted aryl, and halogen; Preferably, the R 10 When the number of substituents is 1, they are selected from hydrogen, C1-C5 alkyl, and halogen; Preferably, the R 10 When the number of substituents is 2, they are selected from C1 to C5 alkyl groups; Preferably, the R 11 Selected from hydrogen, C1-C5 alkyl, halogen; Preferably, the R 12 Selected from C1-C5 alkyl, phenyl, substituted phenyl, acyl substituent R 13 is selected from alkoxy; wherein the substituted phenyl is selected from C1-C3 alkyl, trifluoromethyl, halogen; Preferably, the palladium compound is divalent palladium, selected from one of Pd(OAc)2, PdCl2, PdBr2, PdI2, Pd2(dba)3, Pd(dba)2, and Pd(allyl)Cl; Preferably, the C2-symmetric NN-axial chiral biindole diphosphine ligand is complexed with an iridium compound and applied to the asymmetric hydrogenation reaction of quinoline to prepare a structure shown in general formula V: Preferably, the iridium compound is monovalent iridium, selected from one of [Ir(COD)Cl]2, Ir(COD)SbF6, Ir(COD)BF4, Ir(COD)NTf2, Ir(C2H4)Cl, Ir(C2H4)SbF6, Ir(C2H4)BF4, and Ir(C2H4)NTf2; Preferably, the C2-symmetric NN-axial chiral biindole diphosphine ligand is complexed with a ruthenium compound and applied to the asymmetric hydrogenation reaction of methyl 3-oxo-3-phenylpropionate to prepare a structure shown in general formula VI: Where: R 14 is selected from hydrogen, alkyl, alkoxy, aryl, substituted aryl, and halogen; Preferably, the ruthenium compound is monovalent ruthenium selected from [Ru(benzene)Cl2]2, [Ru(benzene)I2]2, [Ru(4- i Pr-tol)Cl2]2, Ru(COD)Cl2, [Ru2Cl4(4- i Pr-tol)2].

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