Suzuki coupling method of B (9, 10)-site o-dibromo substituted m-carborane and application

Abstract

The invention discloses a synthesis method of aryl / heteroaryl / alkenyl substituted m-carborane, which comprises the following steps: taking m-carborane as a raw material, carrying out electrophilic substitution reaction in a first solvent in the presence of a first catalyst and a bromine elementary substance to generate B (9, 10)-bit dibromo-m-carborane in one step, then taking the B (9, 10)-bit dibromo-m-carborane as a raw material, and carrying out electrophilic substitution reaction on the B (9, 10)-bit dibromo-m-carborane in a second solvent to generate aryl / heteroaryl / alkenyl substituted m-carborane. The preparation method comprises the following steps: by taking m-carborane as a raw material, carrying out palladium-catalyzed Suzuki coupling reaction in a second solvent under the action of a second catalyst, a first ligand, alkali and an additive to realize selective mono-aryl / heteroaryl / alkenylation reaction of m-carborane B (9, 10), and then carrying out palladium-catalyzed Suzuki coupling reaction in a corresponding solvent under the action of a catalyst by taking mono-aryl / heteroaryl / alkenylation B (9, 10) m-carborane as a raw material to realize selective mono-aryl / heteroaryl / alkenylation reaction of the m-carborane B (9, 10). The invention relates to a carborane derivative substituted by diaryl / heteroaryl / alkenyl at a (1, 10) site. The invention provides a series of m-carborane substituted by monoaryl / heteroaryl / alkenyl and m-carborane substituted by diaryl / heteroaryl / alkenyl. The method has a wide application prospect.

Description

Technical Field

[0001] The invention belongs to the technical field of chemical synthesis, and specifically relates to a synthesis method and application of aryl / heteroaryl / alkenyl substituted meta-carborane, and specifically relates to a Suzuki coupling method and application of B (9,10) position ortho-dibromo substituted meta-carborane. Background Art

[0002] Carborane is a type of boron cluster compound composed of three elements: carbon, boron and hydrogen. Among them, the neutral icosahedral closed carborane (C2B 10 H 12 ) is the most common type of carbon-boron cluster structure. 10 H 12 The twelve vertices (two carbon vertices and ten boron vertices) all form bonds using sp hybridization.

[0003] There is a unique non-covalent bond inside the carborane molecule, which makes the way that carborane binds to biological targets different from conventional molecules; the rigid polyhedral structure of carborane can enhance its interaction with lipophilic enzyme pockets, providing a platform for constructing three-dimensional pharmacophores; carborane has a BH bond with low polarity, and the negative hydrogen characteristics of the H atom in the BH bond make the overall carborane more lipophilic, but on the other hand, by changing the substituents on the carborane and using different carborane isomers, the overall hydrophilicity and lipophilicity of the carborane molecule can be adjusted, which makes it play an important role in regulating pharmacokinetics and bioavailability; for biological organisms, carborane is an exogenous substance, and there are no specific enzymes in the body that can degrade the carborane structure, which enhances its metabolic stability.

[0004] Combretastatin A-4 (CA-4) is a natural cis-stilbene compound isolated from the South African shrub Combretum caffrum. Studies have shown that it can bind to tubulin and depolymerize tubulin. So far, various derivatives of CA-4 have been reported, and CA-4P is a water-soluble CA-4 prodrug that is undergoing Phase II clinical trials for cancer treatment.

[0005] Scientists envision replacing the cis-olefin structure in CA-4 with the adjacent CC bond of ortho-carborane to enhance the drug's ability to bind to the target and thus better exert its efficacy. Using functionalized benzyne as the starting substrate, the internal alkyne product is obtained through the Sonogashira coupling reaction, and then it is reacted with B 10 H 14The corresponding CA-4 analogs were obtained by reaction under microwave conditions. Then the scientists tested the inhibitory effects of these carborane derivatives on HIF-1α and found that all synthesized carborane derivatives showed significant inhibitory effects on HIF-1α. Some of the products showed stronger inhibitory effects than the currently commonly used HIF inhibitor YC1.

[0006] In the prior art, the dibromination reaction of the 9,10 positions of m-carborane is carried out in two steps. At the same time, the diaryl / heteroaryl / olefination of the 9,10 positions of m-carborane is difficult, and the 9,10 positions of m-carborane cannot be modified in a directional manner. In the prior art, the Suzuki coupling of the boron position of m-carborane also has problems such as large steric hindrance and difficult modification. In CA-4, the two aromatic groups are linked by cis-olefins, and there are cis-trans isomers. Summary of the invention

[0007] In order to solve the above problems existing in the prior art, the present invention designs a dibromine substitution reaction at the B(9,10) position of the meta-carborane in advance, and then uses Suzuki coupling to conveniently and efficiently realize the monoaryl / heteroaryl / alkenyl functionalization of the B(9) position of the meta-carborane and the diaryl / heteroaryl / alkenyl functionalization of the B(9,10) position of the meta-carborane, thereby obtaining a series of aryl / heteroaryl / alkenyl substituted meta-carborane derivatives.

[0008] The present invention innovatively proposes a method for synthesizing an aryl / heteroaryl / alkenyl substituted meta-carborane derivative, the method comprising the following steps:

[0009] Step 1: using m-carborane as a raw material, an electrophilic substitution reaction occurs in a first solvent in the presence of a first catalyst and a bromine element to generate B(9,10)-position dibromom-carborane;

[0010] Step 2: Using the B(9,10)-dibromocarborane prepared in step 1 and an aryl / heteroaryl / alkenyl boronic acid reagent as raw materials, a palladium-catalyzed Suzuki coupling reaction is carried out in a second solvent under the action of a second catalyst, a first ligand, a base and an additive to achieve a selective monoaryl / heteroaryl / alkenylation reaction of the B(9,10)-dibromocarborane to generate a monoaryl / heteroaryl / alkenyl brominated B(9,10)-carborane;

[0011] The monoaryl / heteroaryl / alkenylated brominated B(9,10)carborane includes monoarylized brominated B(9,10)carborane, monopyridylated brominated B(9,10)carborane, and monoalkenylated brominated B(9,10)carborane;

[0012] Step 3: using the monoarylated brominated B(9,10)-carborane and an aryl / heteroaryl / alkenyl boronic acid reagent as raw materials, in the presence of a third catalyst, a second ligand, and a base, a palladium-catalyzed Suzuki coupling reaction is carried out in a third solvent to achieve a biaryl / heteroaryl / alkenyl-substituted carborane at the B(9,10) position; and / or,

[0013] The monopyridyl brominated B(9,10) meta-carborane and an aryl / heteroaryl boronic acid reagent are used as raw materials, and a palladium-catalyzed Suzuki coupling reaction is carried out in a fourth solvent in the presence of a fourth catalyst, a third ligand and a base to generate a B(9,10) disubstituted meta-carborane.

[0014] The present invention innovatively proposes a Suzuki coupling method for bromocarborane, and synthesizes a series of mono / diaryl / heteroaryl / alkenyl substituted bromocarborane derivatives. The method includes but is not limited to: a one-pot synthesis of dibromocarborane at position B(9,10), such as step one; a Suzuki coupling method for bromocarborane substituted with monoaryl / heteroaryl / alkenyl at position B(9), such as step two; a Suzuki coupling method for monoarylated bromocarborane B(9,10), and / or a Suzuki coupling method for monopyridylated bromocarborane B(9,10), such as step three.

[0015] The present invention proposes a series of mono-aryl / heteroaryl / alkenyl substituted meta-carborane derivatives, including but not limited to:

[0016]

[0017] The present invention proposes a series of biaryl / heteroaryl / alkenyl substituted meta-carborane derivatives, including but not limited to:

[0018]

[0019] The present invention also provides a medicine or a pharmaceutical composition, which comprises the aryl / heteroaryl / alkenyl substituted meta-carborane. The medicine or pharmaceutical composition may also comprise other pharmaceutically applicable carriers, components, excipients, etc.; the pharmaceutically applicable carriers, components or excipients refer to diluents, adjuvants or carriers used in the pharmaceutical field.

[0020] In a specific embodiment, the pharmaceutical composition includes but is not limited to the HIF-1α analogs containing a meta-carborane structure as shown below:

[0021]

[0022] In a specific embodiment, the aforementioned drugs or drug compositions of the present invention were subjected to a cell activity test, and the experimental results showed that after four independent repeated experiments, it was found that the two drug analogs 4b and 4c containing a carborane structure had a significant effect on Hela cell apoptosis at 4uM (p value <0.05), and the effect was not obvious at 2uM.

[0023] In the synthesis method of the present invention, in step 1, a carborane and a bromine reagent are used as raw materials, and an electrophilic substitution reaction occurs in a first solvent in the presence of a first catalyst to generate a B (9, 10) position dibromocarborane; as shown in reaction formula (A):

[0024]

[0025] Wherein, the first catalyst is anhydrous aluminum chloride; the first solvent is one or both of dichloromethane and 1,2-dichloroethane.

[0026] In a specific implementation scheme, the method comprises the following steps: weighing meta-carborane and adding it to a three-necked flask, stirring, and replacing nitrogen three times; adding redistilled dichloromethane to dissolve, and the solution becomes colorless and clear; weighing bromine element in a 10 mL glass bottle by incremental method; adding 1,2-dichloroethane to dilute the bromine element under a nitrogen atmosphere; rapidly adding the above solution to the three-necked flask, at which time the solution turns dark brown; transferring the flask to a cold bath at -78°C (dry ice / acetone); weighing anhydrous aluminum trichloride by incremental method and rapidly adding it to the flask; removing the cold bath after reacting for 30 minutes and returning to room temperature; rapidly setting up a condenser under a nitrogen atmosphere, heating to 55°C and reflux for 2 hours; after the reaction is completed, adding a saturated sodium thiosulfate aqueous solution to quench; after the solution is allowed to stand and separate, the aqueous layer is extracted three times with dichloromethane, and the organic layers are combined; adding magnesium sulfate to dry, then filtering and concentrating with a rotary evaporator; the obtained crude product is separated by column chromatography (petroleum ether / ethyl acetate, petroleum ether / dichloromethane).

[0027] Specifically, the one-pot method for synthesizing B(9,10) dibrominated m-carborane proposed in the present invention is a one-pot method for directly dibrominating m-carborane, and the specific steps are as follows:

[0028] 1) Weigh m-carborane into a three-necked flask, start stirring, and replace nitrogen three times;

[0029] 2) Add redistilled dichloromethane to dissolve, and the solution becomes colorless and clear;

[0030] 3) Weigh bromine into a 10 mL glass bottle using the incremental method;

[0031] 4) Add 1,2-dichloroethane to dilute the bromine under a nitrogen atmosphere;

[0032] 5) The solution in step 4) was quickly added to the three-necked flask, and the solution turned into dark brown;

[0033] 6) Transfer the flask in step 5) to a cold bath at -78°C (dry ice / acetone);

[0034] 7) Weigh anhydrous aluminum chloride using the incremental method and quickly add it to the flask;

[0035] 8) After reacting for 30 min, remove the cold bath and return to room temperature;

[0036] 9) Rapidly set up the condenser under nitrogen atmosphere and heat to 55°C for reflux reaction;

[0037] 10) After the reaction is completed, saturated sodium thiosulfate aqueous solution is added to quench;

[0038] 11) After the solution was allowed to stand for stratification, the aqueous layer was extracted three times with dichloromethane, and the organic layers were combined;

[0039] 12) adding magnesium sulfate to dry, then filtering and concentrating using a rotary evaporator;

[0040] 13) The obtained crude product was separated by column chromatography (petroleum ether / ethyl acetate, petroleum ether / dichloromethane).

[0041] The amount of the meta-carborane is 2.0-5.0 mmol, preferably 5 mmol; the amount of the bromine element is 2.0-2.5 eq, preferably 2.2 eq.

[0042] Wherein, the volume ratio of dichloromethane / 1,2-dichloroethane is 1:1-2:1, preferably, 2:1.

[0043] The reaction time at -78°C is 30-40 min, preferably 30 min.

[0044] Wherein, the reflux temperature is 50-55°C, preferably 55°C; the reflux time is 1.5-2.0h, preferably 2h.

[0045] Wherein, the amount of aluminum chloride is 15-20 mol%, preferably, 20 mol%;

[0046] The column chromatography separation eluent ratio is 20:1-10:1 (petroleum ether / ethyl acetate), preferably 20:1.

[0047] The second step is a Suzuki coupling method for a brominated meta-carborane substituted with a single aromatic / heteroaromatic / alkenyl group at position B(9): using the dibrominated meta-carborane at position B(9,10) and the aromatic / heteroaromatic / alkenyl boronic acid reagent as raw materials, and carrying out a Suzuki coupling reaction in the second solvent in the presence of the second catalyst, the first ligand, a base and an additive to generate an aromatic / heteroaromatic / alkenyl brominated B(9,10) meta-carborane; the method is shown in reaction formula (B):

[0048]

[0049] Wherein, the R group includes but is not limited to the following:

[0050]

[0051] Wherein, the second solvent is toluene;

[0052] Wherein, the aryl / heteroaryl / alkenyl boronic acid reagent includes but is not limited to phenylboronic acid, 4-methoxyphenylboronic acid, 3-methoxyphenylboronic acid, 3,4-dimethoxyphenylboronic acid, 2,4-dimethoxyphenylboronic acid, 3,4,5-trimethoxyphenylboronic acid, 3,5-dimethylphenylboronic acid, 4-methyl-3-fluorophenylboric acid, 3,4-(methylenedioxy)phenylboronic acid, 2-benzyloxyphenylboronic acid, 4-thiomethylphenylboronic acid, 4-hydroxyphenylboronic acid, 2,6-dimethoxypyridine-3-boric acid, 2-methoxy-5-pyridineboric acid, 3-thiopheneboric acid, 1-naphthaleneboric acid, 6-methoxynaphthalene-2-boric acid, 9-phenanthreneboric acid, dibenzothiophene-2-boric acid, 4-(carbazole-9-yl)phenylboric acid, 9-phenylcarbazole-3-boric acid, 4-boric acid triphenylamine, cyclohexene-1-ylboric acid;

[0053] Wherein, the molar amount of the dibromocarborane at position B (9,10) is 0.1-0.2 mmol, preferably 0.2 mmol.

[0054] The first ligand includes XPhos, SPhos, DavePhos, RuPhos, BrettPhos, 2-dicyclohexylphosphino-2'-methylbiphenyl, 1-dimethylamino-2-(diadamantylphosphine)benzene, tri-tert-butylphosphine tetrafluoroborate, tricyclohexylphosphine tetrafluoroborate, tricyclohexylphosphine, tricyclopentylphosphine tetrafluoroborate, tert-butyldicyclohexylphosphine tetrafluoroborate, bis(dicyclohexylphosphinophenyl)ether, 9,9-dimethyl-4,5-bis(dicyclohexylphosphino)-9H-xanthene, bis(cyclohexylphosphino)ferrocene, 1,3-bis(dicyclohexylphosphino)propane bis(tetrafluoroborate), preferably, tricyclohexylphosphine tetrafluoroborate;

[0055] The second catalyst is a palladium catalyst, including Pd(dba)2, Pd2(dba)3, Pd(acac)2, Pd(OTFA)2, Pd(OAc)2, Pd(OPiv)2, Pd(MeCN)2Cl2, PdCl2, preferably Pd(OAc)2;

[0056] The base includes K2CO3, KOAc, K3PO4, Na2CO3, Cs2CO3, CsF, TMSOK, preferably K3PO4;

[0057] The additives include TBAI, TMAI, TMAPF6, TMABF4, TEAPF6, preferably TMAPF6.

[0058] Among them, the amount of the aromatic / heteroaromatic / alkenyl boronic acid is 1.5-2.0eq, preferably 1.5eq; the amount of the first ligand is 10mol%-20mol%, preferably 10mol%; the amount of the second catalyst is 5mol%-10mol%, preferably 5mol%; the amount of the base is 2.0-3.0eq, preferably 3.0eq; the total concentration of the reaction solution containing all reaction substrates is 0.1M, 0.2M, 0.05M, preferably 0.1M.

[0059] The reaction temperature is 80° C., 90° C., 100° C., 110° C., 120° C., preferably 100° C. The reaction time is 12 h, 18 h, 24 h, preferably 24 h.

[0060] In a specific embodiment, the method includes the following steps: placing a stirring bar of appropriate size into a Schlenk tube and drying it for later use; weighing 9,12-dibromocarborane, aryl / heteroaryl / alkenyl boronic acid, tricyclohexylphosphine tetrafluoroborate, palladium acetate, and potassium phosphate in sequence and adding them to the Schlenk tube after drying; replacing nitrogen three times; adding toluene and tightening the stopcock to seal; placing it in a 100°C oil bath and reacting for 24 hours; after the reaction is completed, adding saturated sodium chloride aqueous solution, layering, and extracting the water layer three times with ethyl acetate; after the organic layers are combined, adding anhydrous magnesium sulfate and drying; filtering and rotary evaporating to obtain a crude product (or directly filtering with a syringe filled with cotton and diatomaceous earth and then rotary evaporating to obtain a crude product); separating with a chromatographic column (petroleum ether / ethyl acetate, petroleum ether / dichloromethane).

[0061] Specifically, the present invention proposes a Suzuki coupling method for a brominated meta-carborane substituted with a single aromatic / heteroaromatic / alkenyl group at position B(9), and the specific steps are as follows:

[0062] 1) Place a stirring bar of appropriate size into a Schlenk tube and dry it for later use;

[0063] 2) Weigh 9,12-dibromocarborane, aryl / heteroaryl / alkenyl boronic acid, tricyclohexylphosphine tetrafluoroborate, palladium acetate, and potassium phosphate in sequence and add them into the dried Schlenk tube;

[0064] 3) Replace nitrogen three times;

[0065] 4) After adding toluene, tighten the stopcock to seal;

[0066] 5) Place in a 100°C oil bath and react for 24 hours;

[0067] 6) After the reaction was completed, a saturated sodium chloride aqueous solution was added, the layers were separated, and the aqueous layer was extracted three times with ethyl acetate.

[0068] 7) After the organic layers are combined, anhydrous magnesium sulfate is added to dry;

[0069] 8) filtering and rotary evaporating to obtain a crude product (or directly filtering through a syringe filled with cotton and diatomaceous earth and then rotary evaporating to obtain a crude product);

[0070] 9) Separate using a chromatography column (petroleum ether / ethyl acetate, petroleum ether / dichloromethane).

[0071] Wherein, the molar amount of the 9,12-dibromocarborane is 0.1-0.2 mmol, preferably 0.2 mmol.

[0072] The aromatic / heteroaromatic / alkenyl boronic acid includes, but is not limited to, phenylboronic acid, 4-methoxyphenylboronic acid, 3-methoxyphenylboronic acid, 3,4-dimethoxyphenylboronic acid, 2,4-dimethoxyphenylboronic acid, 3,4,5-trimethoxyphenylboronic acid, 3,5-dimethylphenylboronic acid, 4-methyl-3-fluorophenylboronic acid, 3,4-(methylenedioxy)phenylboronic acid, 2-benzyloxyphenylboronic acid, 4-thiomethylphenylboronic acid. , 4-hydroxyphenylboric acid, 2,6-dimethoxypyridine-3-boric acid, 2-methoxy-5-pyridineboric acid, 3-thiopheneboric acid, 1-naphthaleneboric acid, 6-methoxynaphthalene-2-boric acid, 9-phenanthreneboric acid, dibenzothiophene-2-boric acid, 4-(carbazole-9-yl)phenylboric acid, 9-phenylcarbazole-3-boric acid, 4-boric acid triphenylamine, cyclohexene-1-ylboric acid; preferably, 4-methoxyphenylboric acid;

[0073] Among them, the amount of the aryl / heteroaryl / alkenyl boronic acid is 1.5-2.0eq, preferably 1.5eq; the amount of the tricyclohexylphosphine tetrafluoroborate is 10mol%-20mol%, preferably 10mol%; the amount of palladium acetate is 5mol%-10mol%, preferably 5mol%; the amount of potassium phosphate is 2.0-3.0eq, preferably 3.0eq; the total concentration of the reaction solution containing all reaction substrates is 0.1M, 0.2M, 0.05M, preferably 0.1M.

[0074] The reaction temperature is 80° C., 90° C., 100° C., 110° C., 120° C., preferably 100° C. The reaction time is 12 h, 18 h, 24 h, preferably 24 h.

[0075] Wherein, the column chromatography separation eluent ratio is 40:1-20:1, preferably, 40:1 (petroleum ether / ethyl acetate).

[0076] The step 3 is a method for Suzuki coupling of monoarylated brominated B(9,10)-carborane: monoarylated brominated B(9,10)-carborane and aryl / heteroaryl / alkenyl boronic acid reagent are used as raw materials, and a palladium-catalyzed Suzuki coupling reaction is carried out in the third solvent in the presence of the third catalyst, the second ligand, and the base to generate a biaryl / heteroaryl / alkenyl substituted carborane at the B(9,10) position. The synthesis method is shown in reaction formula (C):

[0077]

[0078] Among them, the R group includes the following:

[0079]

[0080] The monoarylated brominated B(9,10)carborane is present in an amount of 0.1-0.2 mmol, preferably 0.2 mmol.

[0081] The aryl / heteroaryl / alkenyl boronic acid includes 4-methoxyphenylboronic acid, 3,4-dimethoxyphenylboronic acid, 2,4-dimethoxyphenylboronic acid, 3,4,5-trimethoxyphenylboronic acid, 3,4-(methylenedioxy)phenylboronic acid, 6-methoxynaphthalene-2-boric acid, 4-thiomethylphenylboronic acid, 2,6-dimethoxypyridine-3-boric acid, 2-methoxy-5-pyridineboric acid, 1-cyclohexenylboronic acid, 1-methylindole-5-boric acid; preferably, 2,4-dimethoxyphenylboronic acid;

[0082] The second ligand includes tricyclohexylphosphine tetrafluoroborate, 1,3-bis(dicyclohexylphosphine)propane bis(tetrafluoroborate), dicyclohexyl(2-methylphenyl)phosphine, phenyldicyclohexylphosphine, triphenylphosphine, [(4-(N,N-dimethylamino)phenyl]dicyclohexylphosphine, tri(2-methoxyphenyl)phosphine, p-anisyldiphenylphosphine, tri(2,4,6-trimethoxyphenyl)phosphine, tri(2,4-dimethoxyphenyl)phosphine, bis(dicyclohexylphosphine)methane bis(tetrafluoroborate), 1,3-bis(1-adamantyl)imidazole tetrafluoroborate, 1,4-bis(dicyclohexylphosphine)butane bis(tetrafluoroborate), preferably 1,4-bis(dicyclohexylphosphine)butane bis(tetrafluoroborate);

[0083] The third catalyst is a palladium catalyst, including Pd(dba)2, Pd2(dba)3, Pd(acac)2, Pd(OTFA)2, Pd(OAc)2, Pd(OPiv)2, preferably Pd(OTFA)2;

[0084] The base comprises K3PO4;

[0085] The third solvent is toluene.

[0086] In the present invention, the amount of the aryl / heteroaryl / alkenyl boronic acid is 1.5-2.0 eq, preferably 1.5 eq; the amount of the second ligand is 10 mol%-20 mol%, preferably 10 mol%; the amount of the third catalyst is 5 mol%-10 mol%, preferably 5 mol%; the amount of the base is 2.0-3.0 eq, preferably 3.0 eq; the total concentration of the reaction solution containing all reaction substrates is 0.1 M;

[0087] In the present invention, the reaction temperature is 90°C, 100°C, 110°C, preferably 100°C; the reaction time is 12h, 18h, 24h, preferably 24h.

[0088] In a specific embodiment, the method includes the following steps: placing a stirring bar of appropriate size into a Schlenk tube and drying it for later use; weighing monoaryl-substituted brominated B(9,10)carborane, aryl / heteroaryl / alkenyl boronic acid, 1,4-bis(dicyclohexylphosphino)butane bis(tetrafluoroborate), palladium trifluoroacetate, and potassium phosphate in sequence and adding them to the dried Schlenk tube; replacing nitrogen three times; adding toluene and tightening the stopcock to seal; placing in a 100°C oil bath and reacting for 24 hours; after the reaction is completed, filtering with a syringe filled with cotton and diatomaceous earth and rotary evaporating to obtain a crude product; separating with a chromatographic column (petroleum ether / ethyl acetate, petroleum ether / dichloromethane).

[0089] Specifically, the present invention provides a method for Suzuki coupling of monoarylated brominated B(9,10)-carborane, the specific steps of which are as follows:

[0090] 1) Place a stirring bar of appropriate size into a Schlenk tube and dry it for later use;

[0091] 2) Weigh monoarylated brominated B(9,10)-carborane, aryl / heteroaryl / alkenyl boronic acid, 1,4-bis(dicyclohexylphosphino)butane bis(tetrafluoroborate), palladium trifluoroacetate, and potassium phosphate in sequence and add them into a dried Schlenk tube;

[0092] 3) Replace nitrogen three times;

[0093] 4) After adding toluene, tighten the stopcock to seal;

[0094] 5) Place in a 100°C oil bath and react for 24 hours;

[0095] 6) After the reaction is completed, filter with a needle tube filled with cotton and diatomaceous earth and then rotary evaporate to obtain a crude product;

[0096] 7) Separate using a chromatography column (petroleum ether / ethyl acetate, petroleum ether / dichloromethane).

[0097] In the present invention, the mono-aryl-substituted brominated B(9,10)carborane is 0.1-0.2 mmol, preferably 0.2 mmol.

[0098] In the present invention, the aryl / heteroaryl / alkenyl boronic acid includes 4-methoxyphenylboronic acid, 3,4-dimethoxyphenylboronic acid, 2,4-dimethoxyphenylboronic acid, 3,4,5-trimethoxyphenylboronic acid, 3,4-(methylenedioxy)phenylboronic acid, 6-methoxynaphthalene-2-boric acid, 4-thiomethylphenylboronic acid, 2,6-dimethoxypyridine-3-boric acid, 2-methoxy-5-pyridineboric acid, 1-cyclohexenylboric acid, 1-methylindole-5-boric acid; preferably, 2,4-dimethoxyphenylboronic acid;

[0099] In the present invention, the amount of the aryl / heteroaryl / alkenyl boronic acid is 1.5-2.0 eq, preferably 1.5 eq; the amount of the 1,4-bis(dicyclohexylphosphino)butane bis(tetrafluoroborate) is 10 mol%-20 mol%, preferably 10 mol%; the amount of the palladium trifluoroacetate (Pd(OTFA)2) is 5 mol%-10 mol%, preferably 5 mol%; the amount of the potassium phosphate is 2.0-3.0 eq, preferably 3.0 eq; the total concentration of the reaction solution containing all reaction substrates is 0.1 M

[0100] In the present invention, the reaction temperature is 90°C, 100°C, 110°C, preferably 100°C; the reaction time is 12h, 18h, 24h, preferably 24h.

[0101] In the present invention, the volume of toluene is 2 ml.

[0102] In the present invention, the column chromatography separation eluent ratio is 40:1-20:1, preferably, 40:1 (petroleum ether / ethyl acetate).

[0103] The step 3 is a method for Suzuki coupling of monopyridyl brominated B(9,10)-carborane: monopyridyl brominated B(9,10)-carborane and an aryl / heteroaryl boronic acid reagent are used as raw materials, and a palladium-catalyzed Suzuki coupling reaction is carried out in a fourth solvent in the presence of a fourth catalyst, a third ligand, and a base to generate a B(9,10) disubstituted-carborane. The synthesis method is shown in reaction formula (D):

[0104]

[0105] Among them, the R group includes the following:

[0106]

[0107] Wherein, the fourth catalyst is palladium trifluoroacetate; the fourth solvent is toluene;

[0108] Wherein, the B(9,10) pyridine-substituted brominated meta-carborane is 0.1-0.2 mmol, preferably 0.2 mmol.

[0109] Wherein, the aryl / heteroaryl boronic acid includes 2,4-dimethoxyphenylboronic acid, 3,4,5-trimethoxyphenylboronic acid, 6-methoxynaphthalene-2-boric acid, 2,6-dimethoxypyridine-3-boric acid, 2-methoxy-5-pyridineboric acid, 1-methylindole-5-boric acid, preferably 3,4,5-trimethoxyphenylboric acid;

[0110] The third ligand includes 1,4-bis(dicyclohexylphosphino)butane bis(tetrafluoroborate);

[0111] The base comprises potassium phosphate;

[0112] The fourth catalyst includes Pd(OTFA)2.

[0113] Wherein, the amount of the aryl / heteroaryl boronic acid is 1.5-2.0eq, preferably 2.0eq; the amount of the third ligand is 10mol%-20mol%, preferably 10mol%; the amount of the fourth catalyst is 5mol%-10mol%, preferably 5mol%; the amount of the base is 2.0-3.0eq, preferably 3.0eq; the total concentration of the reaction solution containing all reaction substrates is 0.1M;

[0114] Wherein, the reaction temperature is 100°C and the reaction time is 24h.

[0115] In a specific embodiment, the method includes the following steps: placing a stirring bar of appropriate size into a Schlenk tube and drying it for later use; weighing monopyridyl brominated B (9,10) m-carborane, aryl / heteroaryl boronic acid, 1,4-bis (dicyclohexylphosphine) butane bis (tetrafluoroborate), palladium trifluoroacetate, and potassium phosphate in sequence and adding them to the dried Schlenk tube; replacing nitrogen three times; adding toluene and tightening the stopcock to seal; placing in a 100°C oil bath and reacting for 24 hours; after the reaction is completed, filtering with a syringe filled with cotton and diatomaceous earth and rotary evaporating to obtain a crude product; separating with a chromatographic column (petroleum ether / ethyl acetate, petroleum ether / dichloromethane).

[0116] Specifically, the present invention provides a method for Suzuki coupling of monopyridyl brominated B(9,10)-carborane, the specific steps of which are as follows:

[0117] Step 1: Place a stirring bar of appropriate size into a Schlenk tube and dry it for later use.

[0118] Step 2, weighing monopyridyl brominated B(9,10)-carborane, aryl / heteroaryl boronic acid, 1,4-bis(dicyclohexylphosphino)butane bis(tetrafluoroborate), palladium trifluoroacetate, and potassium phosphate in sequence and adding them into a dried Schlenk tube;

[0119] Step 3, replace nitrogen three times;

[0120] Step 4, after adding toluene, tighten the stopcock to seal;

[0121] Step 5, placing in a 100°C oil bath and reacting for 24 hours;

[0122] Step 6: After the reaction is completed, filter with a needle tube filled with cotton and diatomaceous earth and then rotary evaporate to obtain a crude product;

[0123] Step seven, separation using a chromatography column (petroleum ether / ethyl acetate, petroleum ether / dichloromethane).

[0124] The monopyridyl brominated B(9,10)carborane is 0.1-0.2 mmol, preferably 0.2 mmol.

[0125] Wherein, the aryl / heteroaryl boronic acid includes 2,4-dimethoxyphenylboronic acid, 3,4,5-trimethoxyphenylboronic acid, 6-methoxynaphthalene-2-boric acid, 2,6-dimethoxypyridine-3-boric acid, 2-methoxy-5-pyridineboric acid, 1-methylindole-5-boric acid, preferably 3,4,5-trimethoxyphenylboric acid;

[0126] Wherein, the amount of the aryl / heteroaryl boronic acid is 1.5-2.0eq, preferably 2.0eq; the amount of the 1,4-bis(dicyclohexylphosphino)butane bis(tetrafluoroborate) is 10mol%-20mol%, preferably 10mol%; the amount of the palladium trifluoroacetate is 5mol%-10mol%, preferably 5mol%; the amount of the potassium phosphate is 2.0-3.0eq, preferably 3.0eq; the total concentration of the reaction solution containing all reaction substrates is 0.1M;

[0127] The reaction temperature is 100° C., the reaction time is 24 h, and the volume of toluene is 2 ml.

[0128] Wherein, the column chromatography separation eluent ratio is 40:1-20:1, preferably, 40:1 (petroleum ether / ethyl acetate).

[0129] The present invention also provides an aryl / heteroaryl / alkenyl meta-carborane derivative obtained by the synthesis method. The meta-carborane derivative has a structure in which the B(9) and B(10) positions of the meta-carborane are substituted by aryl, heteroaryl or alkenyl groups individually or simultaneously; preferably, the structure is a carborane structure in which the B(9) and B(10) positions of the meta-carborane are substituted by aryl, heteroaryl and alkenyl groups simultaneously.

[0130] The present invention also provides a drug or pharmaceutical composition containing the aromatic substituted meta-carborane. Preferably, it includes a HIF-1α analog containing a meta-carborane structure as shown in formula (4b) or (4c):

[0131]

[0132] The present invention also proposes a synthesis method of the aryl / heteroaryl / alkenyl substituted meta-carborane, the aryl / heteroaryl / alkenyl substituted meta-carborane derivative, and the drug or drug composition for evaluating the effects of drugs on the survival and cycle of Hela cells under hypoxic culture conditions, in the preparation of new therapeutic drugs for anaplastic thyroid cancer and polypoidal choroidal vasculopathy, in the preparation of cardiovascular drugs, hypertension drugs, cardiomyopathy drugs, in the preparation of HIF-1α inhibitor drugs, in the generation of transition metal complexes, oxidative fatty alcohols or short-chain olefin difunctionalization reactions, and in the preparation of new liquid crystal material skeleton precursors.

[0133] The prior art synthesizes dibrominated metacarborane by a two-step method, while the present invention realizes the one-step synthesis of dibrominated metacarborane by improving the prior art conditions, shortening the reaction time, improving the reaction yield, and reducing the generation of by-products. The present invention successfully realizes the one-step synthesis of dibrominated B(9,10) metacarborane by replacing the mixed solvent, adjusting the reaction temperature and the amount of bromine used, breaking through the cumbersome two-step synthesis method of synthesizing monobrominated B(9,10) metacarborane from B(9,10) metacarborane and then synthesizing dibrominated B(9,10) metacarborane, greatly improving the efficiency of the experiment and shortening the reaction time.

[0134] The beneficial effects of the present invention include: the reaction system of the present invention is compatible with not only electron-rich or electron-neutral aryl or alkenyl boronic acid substrates, but also fluorine, thiomethyl, hydroxyl and other functional groups. Large sterically hindered aryl boronic acid substrates and aryl boronic acids with luminescent material unit structures were also tried, and corresponding coupling products were obtained under the optimized reaction system. The continuous Suzuki method provides a platform for the application of meta-carborane in the fields of medicinal chemistry and luminescent materials, and the present invention has broad application prospects. However, the existing synthesis method cannot selectively synthesize meta-carborane derivatives substituted with diaryl or heterocyclic aromatic groups at the B (9) and B (10) positions, and the aromatic functional group introduced by the method of the present invention has a wide range of functional group compatibility that previous synthesis methods do not have, such as compatibility with strong coordinating groups of pyridine, sulfur-containing heterocycles of thiophene, and multi-substituted olefin functional groups. BRIEF DESCRIPTION OF THE DRAWINGS

[0135] In order to more clearly illustrate the embodiments of the present disclosure or the technical solutions in the prior art, the drawings required for use in the embodiments or the description of the prior art will be briefly introduced below. Obviously, the drawings described below are only some embodiments of the present disclosure. For ordinary technicians in this field, other drawings can be obtained based on these drawings without paying any creative work.

[0136] Figure 1 This is the hydrogen spectrum of p-methoxyphenyl substituted meta-carborane.

[0137] Figure 2 This is the carbon spectrum of p-methoxyphenyl substituted meta-carborane.

[0138] Figure 3 The boron spectrum of p-methoxyphenyl-substituted m-carborane is not decoupled.

[0139] Figure 4 It is the boron spectral decoupling of p-methoxyphenyl substituted meta-carborane.

[0140] Figure 5 is the hydrogen spectrum of the biarylated m-carborane substituted with p-methoxyphenyl and 3,4,5-trimethoxyphenyl.

[0141] Figure 6 This is the carbon spectrum of biarylated m-carborane substituted with p-methoxyphenyl and 3,4,5-trimethoxyphenyl.

[0142] Figure 7 Boron spectral decoupling of p-methoxyphenyl and 3,4,5-trimethoxyphenyl substituted diarylated m-carboranes.

[0143] Figure 8 The boron spectra of the biarylated meta-carboranes substituted with p-methoxyphenyl and 3,4,5-trimethoxyphenyl are not decoupled.

[0144] Fig. 9 This is the single crystal structure of a bi-arylated meta-carborane substituted with p-methoxyphenyl and 3,4,5-trimethoxyphenyl.

[0145] Fig.10 This is the hydrogen spectrum of 2,6-dimethoxypyridine-3-phenyl substituted biarylated meta-carborane.

[0146] Fig.11 This is the carbon spectrum of 2,6-dimethoxypyridine-3-phenyl substituted biarylated meta-carborane.

[0147] Fig.12 Boron spectral decoupling of bis-arylated meta-carborane substituted with 2,6-dimethoxypyridine-3-phenyl.

[0148] Fig.13 The boron spectrum of the diarylated meta-carborane substituted with 2,6-dimethoxypyridine-3-phenyl is not decoupled. DETAILED DESCRIPTION

[0149] The invention is further described in detail in conjunction with the following specific examples and drawings. The process, conditions, experimental methods, etc. for implementing the present invention, except for the contents specifically mentioned below, are all common knowledge and common common sense in the art, and the present invention has no special restrictions. The protection content of the present invention is not limited to the following examples. Without departing from the spirit and scope of the inventive concept, the changes and advantages that can be thought of by those skilled in the art are included in the present invention, and the attached claims are the scope of protection.

[0150] Obviously, the described embodiments are only some embodiments of the present disclosure, rather than all embodiments. The following description of at least one exemplary embodiment is actually only illustrative and is by no means intended to limit the present disclosure and its application or use. Based on the embodiments in the present disclosure, all other embodiments obtained by ordinary technicians in the field without creative work are within the scope of protection of the present disclosure.

[0151] In all examples shown and discussed herein, any specific values ​​should be interpreted as merely exemplary and not as limiting. Therefore, other examples of the exemplary embodiments may have different values.

[0152] The present invention innovatively proposes a method for synthesizing an aryl / heteroaryl / alkenyl substituted m-carborane, wherein m-carborane is used as a raw material, an electrophilic substitution reaction occurs in a first solvent in the presence of a first catalyst and a bromine element, and a B(9,10)-position dibrominated m-carborane is generated in one step, and then the B(9,10)-position dibrominated m-carborane and an aryl / heteroaryl / alkenyl boronic acid reagent are used as raw materials, and a palladium-catalyzed Suzuki coupling reaction occurs in a corresponding second solvent in the presence of a second catalyst, a first ligand, a base and an additive, to achieve a selective monoarylation reaction of m-carborane B(9,10), and then the reaction is carried out using a catalyst. Using monoaryl / heteroaryl / alkenylated brominated B(9,10) carborane as a raw material, a palladium-catalyzed Suzuki coupling reaction occurs in a third solvent under the action of a third catalyst, a second ligand, and a base, to achieve a carborane derivative with a diaryl / heteroaryl / alkenylated substitution at the B(9,10) position; and / or, using monopyridylated brominated B(9,10) carborane and an aryl / heteroaryl boronic acid reagent as raw materials, a palladium-catalyzed Suzuki coupling reaction occurs in a fourth solvent in the presence of a fourth catalyst, a third ligand, and a base, to generate a B(9,10) disubstituted carborane. The present invention proposes a series of monoaryl / heteroaryl / alkenyl-substituted carboranes and diaryl / heteroaryl / alkenyl-substituted carboranes, as well as drugs, pharmaceutical compositions, and applications thereof containing aryl / heteroaryl / alkenyl-substituted carboranes as HIF-1α inhibitors. The invention has broad application prospects and provides a platform for the application of meta-carborane in the fields of medicinal chemistry and luminescent materials through continuous Suzuki coupling.

[0153] Example 1 One-step synthesis of B (9,10) dibromocarborane

[0154]

[0155] The specific operations are as follows:

[0156] Dry the three-necked flask for use, weigh out m-carborane (0.7211 g, 5 mmol) and add it to the three-necked flask, start stirring, replace nitrogen three times (Note: This reaction is extremely sensitive to air, and the number of nitrogen replacements must be strictly guaranteed), then add 16 mL of redistilled dichloromethane and 4 ml of 1,1-dichloroethane to dissolve, and the solution is colorless and clear. Incremental method Weigh out Br2 (1.7578 g, 11 mmol) in a 10 mL glass bottle, add 4 ml of 1,2-dichloroethane to dilute under a nitrogen atmosphere, and quickly add the solution to the three-necked flask, at which time the solution turns dark brown. Transfer the flask to a cold bath at -78 ° C (dry ice / acetone), then weigh out aluminum chloride (0.0266 g, 1.0 mmol) and quickly add it to the flask, remove the cold bath after reacting for 30 minutes, and stir at room temperature for 2 hours. After the reaction was completed, saturated aqueous sodium thiosulfate solution was added to quench the reaction. After the solution was allowed to stand and separate into layers, the aqueous layer was extracted three times with dichloromethane. The organic layers were combined, dried by adding magnesium sulfate, and then filtered and concentrated using a rotary evaporator. The crude product was separated by column chromatography (petroleum ether / dichloromethane = 20:1) to obtain 1.1778 g, with a yield of 78%.

[0157] By adjusting parameters such as temperature, bromine, solvent and catalyst, the effect of reaction conditions on product yield was studied. The experimental results are shown in the following table:

[0158] Optimization of Preparation Conditions of B(9,10)-Dibromocarborane

[0159]

[0160] Note 1: Isolation yield

[0161] Example 2: Suzuki coupling of B(9,10)-ortho-dibromo-substituted carborane

[0162]

[0163] The specific operations are as follows:

[0164] Place a stirrer of suitable size in a Schlenk bottle and dry for use. Weigh 9,12-dibromocarborane (0.0604g, 0.2mmol), p-methoxyarylboronic acid (0.0456g, 0.3mmol), tricyclohexylphosphine tetrafluoroborate (0.0074g, 0.02mmol), palladium acetate (0.0022g, 0.010mmol), potassium phosphate (0.1274g, 0.6mmol) in sequence and add to the Schlenk bottle after drying, replace nitrogen three times, add 2ml of toluene, then tighten the stopcock to seal and add to a 100°C oil bath and react for 24h. After the reaction is completed, add saturated sodium chloride aqueous solution, separate, and extract the water layer three times with EA. After the organic layers are combined, add anhydrous magnesium sulfate to dry, filter and evaporate to obtain a crude product. The product was separated by chromatography column with PE / EA (40:1) as eluent, and 46.0 mg of product was obtained with a yield of 70%.

[0165] 1 H NMR (600MHz, CDCl3) δ: 7.47 (d, J = 8.2 Hz, 2H), 6.89 (d, J = 8.4 Hz, 2H), 3.81 (s, 3H), 2.99 (s, 2H). 13 C NMR (151MHz, CDCl3) δ: 159.70, 134.59, 113.40, 55.03, 51.62. 11 B NMR (193MHz, CDCl3) δ: 0.02 (s, 1B), -5.87 (s, 1B), -6.41 (d, J = 206.0Hz, 2B), -13. 07(d,J=148.4Hz,2B),-13.82(d,J=138.9Hz,2B),-20.69(s,1B),-21.61(s,1B). 11 B{ 1 H}NMR(193MHz, CDCl3)δ:0.00(1B),-5.80(1B),-6.50(2B),-13.11(2B),-13.74(2B),-20.84(1B),-21.14(1B).HRMS(EI-TOF):m / z calcd.for C9B 10 H 17 OBr[M+H] + :329.1429.Found:329.1461.

[0166] By adjusting parameters such as solvent and ligand, the effect of reaction conditions on product yield was studied. The experimental results are shown in the following table:

[0167] Ligand screening

[0168]

[0169] Note 1: GC yield; Note 2: XPhos-Pd-G3 (5 mol%); Note 3: SPhos-Pd-G3 (5 mol%)

[0170] The ligands are as follows:

[0171]

[0172] Solvent Screening Table

[0173]

[0174] Note 1: GC yield.

[0175] Example 3: Suzuki coupling of B(9,10)-ortho-dibromo-substituted carborane

[0176]

[0177] The specific operations are as follows:

[0178] Place a stirrer of suitable size in a Schlenk bottle and dry for use. Weigh 9,12-dibromocarborane (0.0604g, 0.2mmol), 4-methylthiophenylboronic acid (0.0504g, 0.3mmol), tricyclohexylphosphine tetrafluoroborate (0.0074g, 0.02mmol), palladium acetate (0.0022g, 0.010mmol), potassium phosphate (0.1274g, 0.6mmol) in sequence and add to the Schlenk bottle after drying, replace nitrogen three times, add 2ml of toluene, then tighten the stopcock to seal and add to a 100°C oil bath and react for 24h. After the reaction is completed, add saturated sodium chloride aqueous solution, separate, and extract the water layer three times with EA. After the organic layer is combined, add anhydrous magnesium sulfate to dry, filter and evaporate to obtain a crude product. The product was separated by chromatography column with PE / EA (20:1) as eluent, and 44.0 mg of product was obtained with a yield of 64%.

[0179] 1 H NMR (400MHz, CDCl3) δ: 7.46 (d, J = 8.0 Hz, 1H), 7.22 (d, J = 8.2 Hz, 1H), 3.01 (s, 1H), 2.48 (s, 2H). 13 C NMR (151MHz, CDCl3) δ: 138.30, 133.77, 125.77, 51.77, 15.53. 11B NMR(193MHz, CDCl3)δ:-0.27(s,1H),-5.88(s,1B),-6.40(d,J=200.5Hz,2B),-12.99(d,J=15 1.5Hz, 2B), -13.77 (d, J = 148.8Hz, 2B), -20.34 (d, J = 117.4Hz, 1B), -21.11 (d, J = 179.1Hz, 1B). 11 B{ 1 H}NMR(193MHz, CDCl3)δ:-0.30(1B),-5.81(1B),-6.47(2B),-13.02(2B),-13.73(2B),-20.53(1B),-21.10(1B).

[0180] HRMS(EI-TOF):m / z calcd.for C9B 10 H 17 BrS[M+H] + :345.1201.Found:345.1223.

[0181] Example 4: Suzuki coupling of B(9,10)-ortho-dibromo-substituted carborane

[0182]

[0183] The specific operations are as follows:

[0184] Place a stirrer of appropriate size in a Schlenk bottle and dry it for later use. Weigh 9,12-dibromocarborane (0.0604g, 0.2mmol), p-hydroxyphenylboronic acid (0.0414g, 0.3mmol), tricyclohexylphosphine tetrafluoroborate (0.0074g, 0.02mmol), palladium acetate (0.0022g, 0.010mmol), potassium phosphate (0.1274g, 0.6mmol) in sequence and add them to the dried Schlenk bottle, replace nitrogen three times, add 2ml of toluene, then tighten the stopcock to seal and add it to a 100℃ oil bath and react for 24h. After the reaction is completed, add saturated sodium chloride aqueous solution, separate the layers, and extract the water layer with EA three times. Combine the organic layers, add anhydrous magnesium sulfate to dry, filter and evaporate to obtain the crude product. Separate with a chromatographic column, the eluent is PE / EA (8:1), and finally obtain 22.0mg of the product with a yield of 35%.

[0185] 1 H NMR (400MHz, CD3OD) δ: 7.31 (d, J = 8.4Hz, 2H), 6.73–6.69 (m, 2H), 3.61 (s, 2H). 13C NMR (101MHz, CD3OD) δ: 156.95, 134.25, 114.21, 52.27. 11 B NMR (193MHz, MeOD) δ: 0.06 (s, 1B), -5.98 (s, 1B), -6.57 (d, J = 228.6Hz, 2B), -13. 06(d,J=149.6Hz,2B),-13.78(d,J=127.3Hz,2B),-20.54(s,1B),-21.51(s,1B). 11 B{ 1 H}NMR(193MHz,MeOD)δ:-0.13(1B),-5.96(1B),-6.74(2B),-13.10(2B),-13.68(2B),-21.02(2B).

[0186] HRMS(EI-TOF):m / z calcd.for C8B 10 H 15 BrO[M+H] + :315.1273.Found:315.1297.

[0187] Example 5: Suzuki coupling of B(9,10)-ortho-dibromo-substituted carborane

[0188]

[0189] The specific operations are as follows:

[0190] Place a suitable size of stirring bar in a Schlenk bottle and dry for use. Weigh 9,12-dibromocarborane (0.0604g, 0.2mmol), 3-fluoro-4-methylphenylboronic acid (0.0462g, 0.3mmol), tricyclohexylphosphine tetrafluoroborate (0.0074g, 0.02mmol), palladium acetate (0.0022g, 0.010mmol), potassium phosphate (0.1274g, 0.6mmol) in sequence and add to the Schlenk bottle after drying, replace nitrogen three times, add 2ml of toluene, then tighten the stopcock to seal and add to a 100°C oil bath, and react for 24h. After the reaction is completed, add saturated sodium chloride aqueous solution, separate, and extract the water layer three times with EA. After the organic layer is combined, add anhydrous magnesium sulfate to dry, filter and evaporate to obtain a crude product. The product was separated by chromatography column with PE / EA (20:1) as eluent, and 33.0 mg of product was obtained with a yield of 50%.

[0191] 1H NMR (600MHz, CDCl3) δ: 7.19 (t, J = 9.4Hz, 2H), 7.12 (t, J = 7.6Hz, 1H), 2.77 (s, 2H), 2.25 (s, 3H). 13 C NMR (101MHz, CDCl3) δ: 131.12 (d, J = 4.5Hz), 128.56 (d, J = 3.1Hz), 124.24, 124.07, 119.45, 119.24, 47.27, 14.34 (d, J = 3.7Hz). 11 B NMR(193MHz, CDCl3)δ:8.34(s,1B),-2.38(s,1B),-8.17(d,J=157.7Hz,2B),-15.23(d,J=178 .9Hz,2B),-16.16(d,J=179.8Hz,2B),-22.63(d,J=180.6Hz,1B),-26.62(d,J=181.6Hz,1B). 11 B{ 1 H}NMR(193MHz, CDCl3)δ:8.36(1B),-2.37(1B),-8.18(2B),-15.20(2B),-16.21(2B),-22.64(1B),-26.64(1B). 19 F NMR (565MHz, CDCl3) δ: -119.09 (t, J = 9.0Hz).

[0192] HRMS(EI-TOF):m / z calcd.for C9B 10 H 16 FBr[M+H] + :331.1386.Found:331.1484.

[0193] Example 5: Suzuki coupling of B(9,10)-ortho-dibromo-substituted carborane

[0194]

[0195] The specific operations are as follows:

[0196] Place a stirrer of appropriate size in a Schlenk bottle and dry it for later use. Weigh 9,12-dibromocarborane (0.0604g, 0.2mmol), 2,6-dimethoxypyridine-3-boric acid (0.0549g, 0.3mmol), tricyclohexylphosphine tetrafluoroborate (0.0074g, 0.02mmol), palladium acetate (0.0022g, 0.010mmol), potassium phosphate (0.1274g, 0.6mmol) in sequence and add them to the Schlenk bottle after drying, replace nitrogen three times, add 2ml of toluene, then tighten the stopcock to seal and add it to a 100℃ oil bath and react for 24h. After the reaction is completed, add saturated sodium chloride aqueous solution, separate the layers, and extract the water layer three times with EA. Combine the organic layers, add anhydrous magnesium sulfate to dry, filter and evaporate to obtain a crude product. The product was separated by chromatography column with PE / EA (20:1) as eluent, and 53.0 mg of product was obtained with a yield of 74%.

[0197] 1 H NMR (600MHz, CDCl3) δ: 7.66 (d, J = 7.8 Hz, 1H), 6.31 (d, J = 7.9 Hz, 1H), 3.91 (s, 6H), 2.98 (s, 2H). 13 C NMR (101MHz, CDCl3) δ: 164.91, 163.48, 147.68, 100.65, 53.33, 52.84, 51.72. 11 B NMR(193MHz, CDCl3)δ:-1.78(s,1B),-5.83(s,1B),-6.32(d,J=188.5Hz,2B),-12 .97(s,2B),-13.80(s,2B),-20.26(d,J=227.1Hz,1B),-21.35(d,J=193.8Hz,1B). 11 B{ 1 H}NMR(193MHz, CDCl3)δ:-1.77(1B),-5.79(1B),-6.36(2B),-13.41(2B),-13.61(2B),-20.17(1B),-21.42(1B).HRMS(EI-TOF):m / z calcd.for C9B 10 H 18 BrNO2[M+H] + :360.1487.Found:360.1494.

[0198] Example 6: Suzuki coupling of B(9,10)-ortho-dibromo-substituted carborane

[0199]

[0200] The specific operations are as follows:

[0201] Place a stirrer of appropriate size in a Schlenk bottle and dry for use. Weigh 9,12-dibromocarborane (0.0604g, 0.2mmol), 1-naphthaleneboric acid (0.0516g, 0.3mmol), TMAPF6 (2.0eq), tricyclohexylphosphine tetrafluoroborate (0.0074g, 0.02mmol), palladium acetate (0.0022g, 0.010mmol), potassium phosphate (0.1274g, 0.6mmol) in sequence and add to the dried Schlenk bottle, replace nitrogen three times, add 2ml of toluene, then tighten the stopcock to seal and add to a 100°C oil bath and react for 24h. After the reaction is completed, add saturated sodium chloride aqueous solution, separate, and extract the water layer three times with EA. Combine the organic layers, add anhydrous magnesium sulfate to dry, filter and evaporate to obtain a crude product. The product was separated by chromatography column with PE / EA (20:1) as eluent, and 45.0 mg of product was obtained with a yield of 47%.

[0202] 1 H NMR (400MHz, CDCl3) δ: 8.77 (d, J = 8.0Hz, 1H), 7.93–7.81 (m, 3H), 7.52–7.43 (m, 3H), 3.14 (s, 2H). 13 C NMR (101MHz, CDCl3) δ: 136.16, 135.32, 133.80, 129.22, 129.02, 127.54, 125.52, 125.18, 124.97, 52.18. 11 B NMR(193MHz, CDCl3)δ:-0.29(s,1B),-5.20(s,1B),-6.25(d,J=157.4Hz,2B),-12 .75(s,2B),-13.55(s,2B),-19.56(d,J=180.1Hz,1B),-21.22(d,J=184.1Hz,1B). 11 B{ 1 H}NMR(193MHz, CDCl3)δ:-0.29(1B),-5.19(1B),-6.26(2B),-13.10(2B),-13.25(2B),-19.55(1B),-21.21(1B).

[0203] HRMS(EI-TOF):m / z calcd.for C 12 B 10 H 17 Br[M+H] +:349.1480.Found:349.1493.

[0204] Example 7: Suzuki coupling of B(9,10)-ortho-dibromo-substituted carborane

[0205]

[0206] The specific operations are as follows:

[0207] Place a stirrer of appropriate size in a Schlenk bottle and dry for use. Weigh 9,12-dibromocarborane (0.0604g, 0.2mmol), 6-methoxynaphthalene-2-boric acid (0.0606g, 0.3mmol), TMAPF6 (2.0eq), tricyclohexylphosphine tetrafluoroborate (0.0074g, 0.02mmol), palladium acetate (0.0022g, 0.010mmol), potassium phosphate (0.1274g, 0.6mmol) in sequence and add to the dried Schlenk bottle, replace nitrogen three times, add 2ml of toluene, then tighten the stopcock to seal and add to a 100°C oil bath and react for 24h. After the reaction is completed, add saturated sodium chloride aqueous solution, separate the layers, and extract the water layer three times with EA. Combine the organic layers, add anhydrous magnesium sulfate to dry, filter and evaporate to obtain a crude product. The product was separated by chromatography column with PE / EA (20:1) as eluent, and 55.0 mg of product was obtained with a yield of 73%.

[0208] 1 H NMR (400MHz, CDCl3) δ: 7.95 (s, 1H), 7.73 (dd, J = 19.2, 8.4Hz, 3H), 7.63 (d, J = 8.2Hz, 1H), 7.17–7.10 (m, 3H), 3.92 (s, 3H), 3.03 (s, 2H). 13 C NMR (151MHz, CDCl3) δ: 157.71, 134.33, 133.11, 131.23, 129.68, 128.77, 125.90, 118.54, 105.51, 55.33, 51.75. 11 B NMR (193MHz, CDCl3) δ: 0.16 (s, 1B), -5.72 (s, 1B), -6.27 (d, J = 212.6Hz, 2B), -12. 95(d,J=143.2Hz,2B),-13.67(d,J=133.6Hz,2B),-20.63(s,1B),-21.54(s,1B). 11 B{ 1H}NMR(193MHz, CDCl3)δ:-0.17(1B),-5.70(1B),-6.39(2B),-12.99(2B),-13.60(2B),-20.57(1B),-21.06(1B).

[0209] HRMS(EI-TOF):m / z calcd.for C 13 B 10 H 19 BrO[M+H] + :379.1586.Found:379.1616.

[0210] Example 7: Suzuki coupling of B(9,10)-ortho-dibromo-substituted carborane

[0211]

[0212] The specific operations are as follows:

[0213] Place a stirrer of appropriate size in a Schlenk bottle and dry for use. Weigh 9,12-dibromocarborane (0.0604g, 0.2mmol), 9-phenanthreneboric acid (0.0666g, 0.3mmol), TMAPF6 (2.0eq), tricyclohexylphosphine tetrafluoroborate (0.0074g, 0.02mmol), palladium acetate (0.0022g, 0.010mmol), potassium phosphate (0.1274g, 0.6mmol) in sequence and add to the Schlenk bottle after drying, replace nitrogen three times, add 2ml of toluene, then tighten the stopcock to seal and add to a 100°C oil bath and react for 24h. After the reaction is completed, add saturated sodium chloride aqueous solution, separate, and extract the water layer three times with EA. After the organic layers are combined, add anhydrous magnesium sulfate to dry, filter and evaporate to obtain a crude product. The product was separated by chromatography column with PE / EA (20:1) as eluent, and 42.0 mg of product was obtained with a yield of 52%.

[0214] 1 H NMR (400MHz, CDCl3) δ8.89-8.85(m,1H),8.78-8.75(m,1H),8.67(d,J=8.2Hz,1H),7.92-7.89(m,1H),3.17(s,2H). 13 C NMR (151MHz, CDCl3) δ: 137.24, 134.63, 131.43, 130.62, 130.34, 128.95, 128.36, 126.88, 126.44, 125.97, 125.67, 123.09, 122.29, 52.21. 11B NMR(193MHz, CDCl3)δ:-0.30(s,1B),-5.18(s,1B),-6.26(d,J=151.8Hz,2B ),-12.82(s,2B),-13.60(s,2B),-19.31(s,1B),-21.25(d,J=179.1Hz,1B). 11 B{ 1 H}NMR(193MHz, CDCl3)δ:-0.25(1B),-5.18(1B),-6.28(2B),-13.23(4B),-19.40(1B),-21.22(1B).

[0215] HRMS(EI-TOF):m / z calcd.for C 16 B 10 H 19 Br[M+H] + :399.1637.Found:399.1660.

[0216] Example 8: Suzuki coupling of B(9,10)-ortho-dibromo-substituted carborane

[0217]

[0218] The specific operations are as follows:

[0219] Place a stirrer of appropriate size in a Schlenk bottle and dry for use. Weigh 9,12-dibromocarborane (0.0604g, 0.2mmol), 4-(9H-carbazole-9-yl)phenylboronic acid (0.0861g, 0.3mmol), TMAPF6 (2.0eq), tricyclohexylphosphine tetrafluoroborate (0.0074g, 0.02mmol), palladium acetate (0.0022g, 0.010mmol), potassium phosphate (0.1274g, 0.6mmol) in sequence and add to the Schlenk bottle after drying, replace nitrogen three times, add 2ml of toluene, then tighten the stopcock to seal and add to a 100°C oil bath and react for 24h. After the reaction is completed, add saturated sodium chloride aqueous solution, separate the layers, and extract the water layer three times with EA. Combine the organic layers, add anhydrous magnesium sulfate to dry, filter and evaporate to obtain a crude product. The product was separated by chromatography column with PE / EA (20:1) as eluent, and 37.0 mg of product was obtained with a yield of 40%.

[0220] 1H NMR (400MHz, CDCl3) δ: 8.07 (d, J=7.7Hz, 2H), 7.69 (d, J=8.1Hz, 2H), 7.43 (dd, J= 12.7,8.2Hz,4H),7.33(dd,J=11.3,4.0Hz,2H),7.21–7.17(m,2H),2.99(s,2H). 13 C NMR (101MHz, CDCl3) δ: 140.81, 137.46, 134.85, 126.11, 125.87, 123.36, 120.24, 119.82, 110.08, 52.05. 11 B NMR(193MHz, CDCl3)δ:-0.42(s,1B),-5.71(s,1B),-6.19(d,J=186.0Hz,2B),-12 .83(d,J=142.1Hz,2B),-13.57(d,J=142.6Hz,2B),-20.56(s,1B),-21.32(s,1B). 11 B{ 1 H}NMR(193MHz, CDCl3)δ:-0.33(1B),-6.18(1B),-12.88(2B),-13.53(2B),-13.74(2B),-20.37(1B),-21.73(1B).

[0221] HRMS(EI-TOF):m / z calcd.for C 20 B 10 H 22 BrN[M+H] + :464.1902.Found:464.1937.

[0222] Example 9: Suzuki coupling of B(9,10)-ortho-dibromo-substituted carborane

[0223]

[0224] The specific operations are as follows:

[0225] Place a stirrer of appropriate size in a Schlenk bottle and dry for use. Weigh 9,12-dibromocarborane (0.0604g, 0.2mmol), 4-boric acid triphenylamine (0.0867g, 0.3mmol), TMAPF6 (2.0eq), tricyclohexylphosphine tetrafluoroborate (0.0074g, 0.02mmol), palladium acetate (0.0022g, 0.010mmol), potassium phosphate (0.1274g, 0.6mmol) in sequence and add to the Schlenk bottle after drying, replace nitrogen three times, add 2ml of toluene, then tighten the stopcock to seal and add to a 100°C oil bath and react for 24h. After the reaction is completed, add saturated sodium chloride aqueous solution, separate, and extract the water layer three times with EA. After the organic layers are combined, add anhydrous magnesium sulfate to dry, filter and evaporate to obtain a crude product. The product was separated by chromatography column with PE / EA (20:1) as eluent, and 40.0 mg of product was obtained with a yield of 43%.

[0226] 1 H NMR (400MHz, CDCl3) δ: 7.31 (d, J = 8.4Hz, 2H), 7.17 (dd, J = 9.2, 6.5Hz, 4H), 7.04 (d, J = 7.6Hz, 4H), 6.93 (dd, J = 7.8, 5.6Hz, 4H), 2.91 (s, 2H). 13 C NMR (151MHz, CDCl3) δ: 146.69, 146.51, 133.14, 128.14, 123.53, 121.73, 121.53, 50.61. 11 B NMR (193MHz, CDCl3) δ: 0.03 (s, 1B), -5.85 (s, 1B), -6.38 (d, J = 205.6Hz, 2B) ,-13.07(d,J=151.9Hz,2B),-13.47(s,2B),-20.70(s,1B),-21.59(s,1B). 11 B{ 1 H}NMR(193MHz, CDCl3)δ:0.75(1B),0.15(1B),-5.83(2B),-6.39(1B),-13.09(2B),-13.70(1B),-21.13(2B).

[0227] HRMS(EI-TOF):m / z calcd.for C 20 B 10 H 24 BrN[M+H] + :466.2059.Found:466.2071.

[0228] Example 10: Suzuki coupling of B(9,10)-ortho-dibromo-substituted carborane

[0229]

[0230] The specific operations are as follows:

[0231] Place a suitable size of stirring bar in a Schlenk bottle and dry for use. Weigh 9,12-dibromocarborane (0.0604g, 0.2mmol), cyclohexene-1-ylboronic acid (0.0378g, 0.3mmol), tricyclohexylphosphine tetrafluoroborate (0.0147g, 0.040mmol), palladium acetate (0.0044g, 0.020mmol), potassium phosphate (0.1274g, 0.6mmol) in sequence and add to the Schlenk bottle after drying, replace nitrogen three times, add 2ml of toluene, then tighten the stopcock to seal and add to a 100°C oil bath, and react for 24h. After the reaction is completed, add saturated sodium chloride aqueous solution, separate, and extract the water layer three times with EA. After the organic layer is combined, add anhydrous magnesium sulfate to dry, filter and evaporate to obtain a crude product. The product was separated by chromatography column, and the eluent was PE / EA (20:1). Finally, 38.0 mg of the product was obtained with a yield of 62%.

[0232] 1 H NMR (400MHz, CDCl3) δ5.97(s,1H),2.87(s,2H),2.11-2.08(m,4H),1.57-1.65(m,4H). 13 C NMR (101MHz, CDCl3) δ: 133.15, 52.40, 50.01, 28.75, 25.77, 22.30, 21.24. 11 BNMR(193MHz, CDCl3)δ:0.23(s,1B),-6.52(s,1B),-7.01(d,J=188.4Hz,2B),-13 .45(d,J=166.3Hz,2B),-14.31(d,J=166.4Hz,2B),-20.78(s,1B),-21.73(s,1B). 11 B{ 1 H}NMR(193MHz, CDCl3)δ:-0.88(1B),-5.64(1B),-6.33(2B),-13.10(2B),-13.46(2B),-21.08(1B),-21.70(1B).HRMS(EI-TOF):m / z calcd.for C8B 10 H 19 Br[M+H] +:303.1637.Found:303.1666.

[0233] Example 11: Suzuki coupling of B(9,10) monoaryl-substituted bromocarborane

[0234]

[0235] The specific operations are as follows:

[0236] Place a stirrer of appropriate size in a Schlenk bottle and dry for use. Weigh monoaryl brominated metacarborane (0.0658g, 0.2mmol), 3,4,5-trimethoxyphenylboronic acid (0.0636g, 0.3mmol), 1,4-bis(dicyclohexylphosphine)butane bis(tetrafluoroborate) (0.0126g, 0.02mmol), palladium trifluoroacetate (0.0033g, 0.010mmol), potassium phosphate (0.1274g, 0.6mmol) in sequence and add to the dried Schlenk bottle, replace nitrogen three times, add 2ml of toluene, then tighten the stopcock to seal and add to a 100℃ oil bath and react for 24h. After the reaction is completed, add saturated sodium chloride aqueous solution, separate the layers, and extract the water layer three times with EA. Combine the organic layers, add anhydrous magnesium sulfate to dry, filter and evaporate to obtain a crude product. The product was separated by chromatography column with PE / EA (40:1) as eluent, and 46.0 mg of product was obtained with a yield of 54%.

[0237] 1 H NMR (400MHz, CDCl3) δ7.33(d,J=8.4Hz,2H),6.77(d,J=8.6Hz,2H),6.46(s,2H),3.78(s,3H),3.75(s,3H),3.65(s,6H),3.01(s,2H). 13 C NMR (151MHz, CDCl3) δ158.95,151.84,137.04,134.11,112.85,110.00,60.28,55.37,54.64,50.86. 11 B NMR (193MHz, CDCl3) δ0.24, -7.15 (d, J = 154.1Hz), -13.31 (d, J = 118.7Hz), -20.09 (d, J = 133.8Hz). 11 B{ 1 H}NMR(193MHz, CDCl3)δ0.24,-7.21,-13.38,-20.11.HRMS(EI-TOF):m / z calcd.forC 18 B 10 H28 O4[M+H]+:416.2991.Found:416.3003.

[0238] By adjusting parameters such as temperature, catalyst and ligand, the effect of reaction conditions on product yield was studied. The experimental results are shown in the following table:

[0239] Temperature screening [1] surface

[0240]

[0241] Note 1: 9-Bromo-10-p-methoxyphenylcarborane (0.1 mmol), 3,4,5-trimethoxyphenylboronic acid (1.5 equiv.), palladium trifluoroacetate (5 mol%), 1,4-bis(dicyclohexylphosphino)butane bis(tetrafluoroborate), potassium phosphate (3.0 equiv.), toluene (0.1 M), 24 h.

[0242] Note 2: 1 HNMR yield.

[0243] Screening of transition metal catalysts [1] surface

[0244]

[0245] Note 1: 9-Bromo-10-p-methoxyphenylcarborane (0.1 mmol), 3,4,5-trimethoxyarylboronic acid (1.5 equiv.), palladium (5 mol%), tricyclohexylphosphine tetrafluoroborate (10 mol%), potassium phosphate (3.0 equiv.), toluene (0.1 M), 100°C, 24 h.

[0246] Note 2: 1 HNMR yield.

[0247] Note 3: GC calibration

[0248] Ligand screening [1] surface

[0249]

[0250]

[0251] Note 1: 9-bromo-10-p-methoxyphenylcarborane (0.1 mmol), 3,4,5-trimethoxyarylboronic acid (1.5 equiv.), palladium trifluoroacetate (5 mol%), L (10 mol%), potassium phosphate (3.0 equiv.), toluene (0.1 M), 100°C, 24 h.

[0252] Note 2: 1HNMR yield.

[0253] Note 3: GC calibration

[0254]

[0255] Example 12: Suzuki coupling of B(9,10) monoaryl-substituted bromocarborane

[0256]

[0257] The specific operations are as follows:

[0258] Place a stirrer of appropriate size in a Schlenk bottle and dry it for later use. Weigh monoaryl brominated metacarborane (0.0658g, 0.2mmol), 3,4-methylenebenzeneboronic acid (0.0498g, 0.3mmol), 1,4-bis(dicyclohexylphosphine)butane bis(tetrafluoroborate) (0.0126g, 0.02mmol), palladium trifluoroacetate (0.0033g, 0.010mmol), potassium phosphate (0.1274g, 0.6mmol) in sequence and add them to the dried Schlenk bottle, replace nitrogen three times, add 2ml of toluene, then tighten the stopcock to seal and add it to a 100℃ oil bath and react for 24h. After the reaction is completed, add saturated sodium chloride aqueous solution, separate the layers, and extract the water layer three times with EA. Combine the organic layers, add anhydrous magnesium sulfate to dry, filter and evaporate to obtain a crude product. The product was separated by chromatography column with PE / EA (40:1) as eluent, and 40.0 mg of product was obtained with a yield of 54%.

[0259] 1 H NMR (400MHz, CDCl3) δ7.27(s,1H),7.25(s,1H),6.84(s,1H),6.81(s,1H),6.73 (d,J=8.6Hz,1H),6.65(d,J=7.7Hz,1H),5.86(s,2H),3.75(s,3H),2.97(s,2H). 13 C NMR (151MHz, CDCl3) δ158.74,146.59,133.98,126.49,107.57,99.91,54.51,50.51. 11 B NMR (193MHz, CDCl3) δ0.37, -7.43 (d, J = 152.8Hz), -13.33 (d, J = 158.9Hz), -20.18 (d, J = 177.8Hz). 11 B{ 1H}NMR(193MHz,CDCl3)δ0.37,-7.41,-13.32,-20.14.HRMS(EI-TOF):m / zcalcd.for C 16 H 22 B 10 O3[M+H]+:370.2572.Found:370.2574.

[0260] Example 13: Suzuki coupling of B(9,10) monoaryl-substituted bromocarborane

[0261]

[0262] The specific operations are as follows:

[0263] Place a stirrer of appropriate size in a Schlenk bottle and dry it for later use. Weigh monoaryl brominated metacarborane (0.0658g, 0.2mmol), 3,4-dimethoxyphenylboronic acid (0.0546g, 0.3mmol), 1,4-bis(dicyclohexylphosphine)butane bis(tetrafluoroborate) (0.0126g, 0.02mmol), palladium trifluoroacetate (0.0033g, 0.010mmol), potassium phosphate (0.1274g, 0.6mmol) in sequence and add them to the dried Schlenk bottle, replace nitrogen three times, add 2ml of toluene, then tighten the stopcock to seal and add it to a 100℃ oil bath and react for 24h. After the reaction is completed, add saturated sodium chloride aqueous solution, separate the layers, and extract the water layer three times with EA. Combine the organic layers, add anhydrous magnesium sulfate to dry, filter and evaporate to obtain a crude product. The product was separated by chromatography column with PE / EA (40:1) as eluent, and 20.0 mg of product was obtained with a yield of 26%.

[0264] 1 H NMR (400MHz, CDCl3) δ7.30(d,J=8.1Hz,2H),6.94(d,J=7.8Hz,1H),6.74(d,J=8.7H z,2H),6.70(d,J=8.0Hz,2H),3.81(s,3H),3.74(s,3H),3.62(s,3H),2.99(s,2H). 13 C NMR (151MHz, CDCl3) δ148.42,147.84,134.46,125.93,116.32,113.17,110.51,55.54,55.41,54.97,51.13. 11B NMR (193MHz, CDCl3) δ0.28, -7.21 (d, J = 142.4Hz), -13.32 (d, J = 145.0Hz), -20.15 (d, J = 172.5Hz). 11 B{ 1 H}NMR(193MHz, CDCl3)δ0.31,-7.23,-13.40,-20.27.HRMS(EI-TOF):m / z calcd.for C 17 H 26 B 10 O3[M+H]+:386.2885.Found:386.2904.

[0265] Example 14: Suzuki coupling of B(9,10) monoaryl-substituted bromocarborane

[0266]

[0267] The specific operations are as follows:

[0268] Place a stirrer of appropriate size in a Schlenk bottle and dry it for later use. Weigh monoaryl brominated meta-carborane (0.0658g, 0.2mmol), 2,6-dimethoxypyridine-3-boric acid (0.0549g, 0.3mmol), 1,4-bis(dicyclohexylphosphine)butane bis(tetrafluoroborate) (0.0126g, 0.02mmol), palladium trifluoroacetate (0.0033g, 0.010mmol), potassium phosphate (0.1274g, 0.6mmol) in sequence and add them to the dried Schlenk bottle, replace nitrogen three times, add 2ml of toluene, then tighten the stopcock to seal and add it to a 100℃ oil bath and react for 24h. After the reaction is completed, add saturated sodium chloride aqueous solution, separate the layers, and extract the water layer three times with EA. Combine the organic layers, add anhydrous magnesium sulfate to dry, filter and evaporate to obtain a crude product. The product was separated by chromatography column with PE / EA (40:1) as eluent, and 38.0 mg of product was obtained with a yield of 49%.

[0269] 1 H NMR (400MHz, CDCl3) δ7.48(s,1H),7.27(s,2H),6.72(d,J=8.5Hz,2H),6.14(d,J=7.9Hz,1H),3.86(s,3H),3.77(s,3H),3.75(s,3H),2.97(s,2H). 13C NMR (151MHz, CDCl3) δ164.70,162.98,159.02,147.52,134.28,112.99,100.16,54.96,53.27,52.60,51.06. 11 BNMR(193MHz, CDCl3)δ-0.55(d,J=359.6Hz),-7.13(d,J=147.8Hz),-13.45(d,J=153.9Hz),-20.03(t,J=156.0Hz). 11 B{ 1 H}NMR(193MHz, CDCl3)δ-0.53(d,J=357.3Hz),-7.12,-13.42,-19.92(d,J=123.7Hz).HRMS(EI-TOF):m / z calcd.for C 16 H 25 B 10 NO3[M+H]+:387.2837.Found:387.2835.

[0270] Example 15: Suzuki coupling of B(9,10) monoaryl-substituted bromocarborane

[0271]

[0272] The specific operations are as follows:

[0273] Place a stirrer of appropriate size in a Schlenk bottle and dry it for later use. Weigh monoaryl brominated meta-carborane (0.0658g, 0.2mmol), 2-methoxy-5-pyridineboronic acid (0.0456g, 0.3mmol), 1,4-bis(dicyclohexylphosphine)butane bis(tetrafluoroborate) (0.0126g, 0.02mmol), palladium trifluoroacetate (0.0033g, 0.010mmol), potassium phosphate (0.1274g, 0.6mmol) in sequence and add them to the dried Schlenk bottle, replace nitrogen three times, add 2ml of toluene, then tighten the stopcock to seal and add it to a 100℃ oil bath and react for 24h. After the reaction is completed, add saturated sodium chloride aqueous solution, separate the layers, and extract the water layer three times with EA. Combine the organic layers, add anhydrous magnesium sulfate to dry, filter and evaporate to obtain a crude product. The product was separated by chromatography column with PE / EA (40:1) as eluent, and 30.0 mg of product was obtained with a yield of 42%.

[0274] 1H NMR (400MHz, CDCl3) δ8.12 (s, 1H), 7.45 (d, J = 10.0Hz, 1H), 7.28 (s, 2H), 6.75 ( d,J=8.5Hz,2H),6.55(d,J=8.3Hz,1H),3.90(s,3H),3.76(s,3H),3.02(s,2H). 13 C NMR (151MHz, CDCl3) δ163.63,159.29,150.45,143.58,134.37,113.28,109.87,54.95,53.27,51.28. 11 B NMR (193MHz, CDCl3) δ -0.16 (d, J = 276.0Hz), -7.36 (d, J = 150.5Hz), -13.24 (d, J = 145.4Hz). 11 B{ 1 H}NMR(193MHz, CDCl3)δ-0.12(d,J=277.5Hz),-7.32,-13.20,-20.02.HRMS(EI-TOF):m / z calcd.for C 15 H 23 B 10 NO2[M+H]+:357.2732.Found:357.2708.

[0275] Example 16: Suzuki coupling of B(9,10) monoaryl-substituted bromocarborane

[0276]

[0277] The specific operations are as follows:

[0278] Place a stirrer of appropriate size in a Schlenk bottle and dry it for later use. Weigh monoaryl brominated meta-carborane (0.0658g, 0.2mmol), N-methylindole-5-boric acid (0.0525g, 0.3mmol), 1,4-bis(dicyclohexylphosphine)butane bis(tetrafluoroborate) (0.0126g, 0.02mmol), palladium trifluoroacetate (0.0033g, 0.010mmol), potassium phosphate (0.1274g, 0.6mmol) in sequence and add them to the dried Schlenk bottle, replace nitrogen three times, add 2ml of toluene, then tighten the stopcock to seal and add it to a 100℃ oil bath and react for 24h. After the reaction is completed, add saturated sodium chloride aqueous solution, separate the layers, and extract the water layer three times with EA. Combine the organic layers, add anhydrous magnesium sulfate to dry, filter and evaporate to obtain a crude product. The product was separated by chromatography column with PE / EA (40:1) as eluent, and 36.0 mg of product was obtained with a yield of 48%.

[0279] 1 H NMR (400MHz, CDCl3) δ7.68 (s, 1H), 7.29 (d, J = 8.6Hz, 2H), 7.21 (dd, J = 8.2, 1.3Hz, 1H), 7.13 (d, J = 8.3Hz, 1H), 6.95 (d, J = 3.1Hz, 1H), 6.69 (d, J = 8.5Hz, 2H), 6.39 (dd, J = 3.0, 0.8Hz, 1H), 3.71 (s, 6H), 2.98 (s, 2H). 13 C NMR (151MHz, CDCl3) δ159.07,136.58,134.57,126.99,126.12,113.11,108.35,100.86,54.97,50.94,32.73. 11 B NMR (193MHz, CDCl3) δ0.88 (d, J = 180.8Hz), -7.26 (d, J = 150.0Hz), -13.27 (d, J = 145.6Hz), -20.27 (d, J = 166.9Hz). 11 B{ 1 H}NMR(193MHz, CDCl3)δ0.92(d,J=184.2Hz),-7.26,-13.27,-20.19.HRMS(EI-TOF):m / z calcd.for C 18 H 25 B 10 NO[M+H]+:379.2939.Found:379.2932.

[0280] Example 17: Suzuki coupling of B(9,10) monoaryl-substituted bromocarborane

[0281]

[0282] The specific operations are as follows:

[0283] Place a stirrer of appropriate size in a Schlenk bottle and dry it for later use. Weigh monoaryl brominated metacarborane (0.0658g, 0.2mmol), 2,4-dimethoxyphenylboronic acid (0.0546g, 0.3mmol), 1,4-bis(dicyclohexylphosphine)butane bis(tetrafluoroborate) (0.0126g, 0.02mmol), palladium trifluoroacetate (0.0033g, 0.010mmol), potassium phosphate (0.1274g, 0.6mmol) in sequence and add them to the dried Schlenk bottle, replace nitrogen three times, add 2ml of toluene, then tighten the stopcock to seal and add it to a 100℃ oil bath and react for 24h. After the reaction is completed, add saturated sodium chloride aqueous solution, separate the layers, and extract the water layer three times with EA. Combine the organic layers, add anhydrous magnesium sulfate to dry, filter and evaporate to obtain a crude product. The product was separated by chromatography column with PE / EA (40:1) as eluent, and 50.0 mg of product was obtained with a yield of 64%.

[0284] 1 H NMR (400MHz, CDCl3) δ7.30 (d, J = 10.4Hz, 3H), 6.72 (d, J = 8.6Hz, 2H), 6.38 (dd, J = 8.3 ,2.3Hz,1H),6.31(d,J=2.2Hz,1H),3.77(d,J=9.0Hz,6H),3.59(s,3H),2.97(s,2H). 13 C NMR (151MHz, CDCl3) δ162.93,160.34,158.45,136.48,133.81,112.44,103.95,97.56,54.64,54.32,50.56. 11 B NMR (193MHz, CDCl3) δ -0.34 (d, J = 224.5Hz), -6.93 (d, J = 151.5Hz), -13.45 (d, J = 139.0Hz), -20.44 (d, J = 149.8Hz). 11 B{ 1 H}NMR(193MHz, CDCl3)δ-0.35(d,J=230.7Hz),-6.94,-13.45,-20.07(d,J=125.9Hz).HRMS(EI-TOF):m / zcalcd.for C 17H 26 B 10 O3[M+H]+:386.2885.Found:386.2891.

[0285] Example 18: Suzuki coupling of B(9,10) monoaryl-substituted bromocarborane

[0286]

[0287] The specific operations are as follows:

[0288] Place a stirrer of appropriate size in a Schlenk bottle and dry it for later use. Weigh monoaryl brominated meta-carborane (0.0658g, 0.2mmol), cyclohexene-1-ylboronic acid (0.0378g, 0.3mmol), 1,4-bis(dicyclohexylphosphine)butane bis(tetrafluoroborate) (0.0126g, 0.02mmol), palladium trifluoroacetate (0.0033g, 0.010mmol), potassium phosphate (0.1274g, 0.6mmol) in sequence and add them to the dried Schlenk bottle, replace nitrogen three times, add 2ml of toluene, then tighten the stopcock to seal and add it to a 100℃ oil bath and react for 24h. After the reaction is completed, add saturated sodium chloride aqueous solution, separate the layers, and extract the water layer three times with EA. Combine the organic layers, add anhydrous magnesium sulfate to dry, filter and evaporate to obtain a crude product. The product was separated by chromatography column with PE / EA (40:1) as eluent, and 42.0 mg of product was obtained with a yield of 64%.

[0289] 1 H NMR (400MHz, CDCl3) δ7.37(d,J=8.2Hz,2H),6.80(d,J=8.4Hz,2H),5.85(s,1H),3.79(s,3H),2.85(s,2H),1.96(s,2H),1.82(s,2H),1.44(s,4H). 13 C NMR (151MHz, CDCl3) δ159.18,134.36,133.04,113.05,55.08,50.46,29.99,26.88,23.40,22.35. 11 B NMR (193MHz, CDCl3) δ7.89–-2.63(m), -7.78(d,J=157.3Hz), -13.89(d,J=152.3Hz), -20.54(d,J=177.2Hz). 11 B{ 1H}NMR(193MHz, CDCl3)δ0.14(d,J=210.1Hz),-7.76,-13.86,-20.54.HRMS(EI-TOF):m / zcalcd.forC 15 H 26 B 10 O[M+H]+:330.2986.Found:330.2986.

[0290] Example 19: Suzuki coupling of B(9,10) monoaryl-substituted bromocarborane

[0291]

[0292] The specific operations are as follows:

[0293] Place a stirrer of appropriate size in a Schlenk bottle and dry it for later use. Weigh monoaryl brominated metacarborane (0.0658g, 0.2mmol), 4-methylthiophenylboronic acid (0.0504g, 0.3mmol), 1,4-bis(dicyclohexylphosphine)butane bis(tetrafluoroborate) (0.0126g, 0.02mmol), palladium trifluoroacetate (0.0033g, 0.010mmol), potassium phosphate (0.1274g, 0.6mmol) in sequence and add them to the dried Schlenk bottle, replace nitrogen three times, add 2ml of toluene, then tighten the stopcock to seal and add it to a 100℃ oil bath and react for 24h. After the reaction is completed, add saturated sodium chloride aqueous solution, separate the layers, and extract the water layer three times with EA. Combine the organic layers, add anhydrous magnesium sulfate to dry, filter and evaporate to obtain a crude product. The product was separated by chromatography column with PE / EA (40:1) as eluent, and 32.0 mg of product was obtained with a yield of 43%.

[0294] 1 H NMR (400MHz, CDCl3) δ7.28 (s, 4H), 7.07 (d, J = 8.2Hz, 2H), 6.74 (d, J = 8.6Hz, 2H), 3.77 (s, 3H), 3.01 (s, 2H), 2.45 (s, 3H). 13 C NMR (151MHz, CDCl3) δ159.25,137.27,134.50,133.80,125.67,113.22,55.02,51.23,15.64. 11 B NMR (193MHz, CDCl3) δ0.40, -7.34 (d, J = 156.4Hz), -13.29 (d, J = 149.7Hz), -19.62. 11 B{ 1H}NMR(193MHz,CDCl3)δ0.46,-7.30,-13.28,-20.01.HRMS(EI-TOF):m / z calcd.for C 16 H 24 B 10 OS[M+H]+:372.2551.Found:372.2553.

[0295] Example 20: Suzuki coupling of B(9,10) monoaryl-substituted bromocarborane

[0296]

[0297] The specific operations are as follows:

[0298] Place a stirrer of appropriate size in a Schlenk bottle and dry it for later use. Weigh monoaryl brominated metacarborane (0.0658g, 0.2mmol), p-hydroxyphenylboronic acid (0.0414g, 0.3mmol), 1,4-bis(dicyclohexylphosphine)butane bis(tetrafluoroborate) (0.0126g, 0.02mmol), palladium trifluoroacetate (0.0033g, 0.010mmol), potassium phosphate (0.1274g, 0.6mmol) in sequence and add them to the dried Schlenk bottle, replace nitrogen three times, add 2ml of toluene, then tighten the stopcock to seal and add it to a 100℃ oil bath and react for 24h. After the reaction is completed, add saturated sodium chloride aqueous solution, separate the layers, and extract the water layer three times with EA. Combine the organic layers, add anhydrous magnesium sulfate to dry, filter and evaporate to obtain a crude product. The product was separated by chromatography column with PE / EA (40:1) as eluent, and 18.0 mg of the product was obtained with a yield of 26%.

[0299] Example 21: Suzuki coupling of B(9,10) monoaryl-substituted bromocarborane

[0300]

[0301] The specific operations are as follows:

[0302] Place a stirrer of appropriate size in a Schlenk bottle and dry it for later use. Weigh monoaryl brominated carborane (0.0658g, 0.2mmol), p-methoxyarylboronic acid (0.0456g, 0.3mmol), 1,4-bis(dicyclohexylphosphine)butane bis(tetrafluoroborate) (0.0126g, 0.02mmol), palladium trifluoroacetate (0.0033g, 0.010mmol), potassium phosphate (0.1274g, 0.6mmol) in sequence and add them to the dried Schlenk bottle, replace nitrogen three times, add 2ml of toluene, then tighten the stopcock to seal and add it to a 100℃ oil bath and react for 24h. After the reaction is completed, add saturated sodium chloride aqueous solution, separate the layers, and extract the water layer three times with EA. Combine the organic layers, add anhydrous magnesium sulfate to dry, filter and evaporate to obtain a crude product. The product was separated by chromatography column with PE / EA (40:1) as eluent, and 31.0 mg of product was obtained with a yield of 43%.

[0303] 1 H NMR (400MHz, CDCl3) δ7.16 (s, 4H), 6.64 (d, J = 8.4Hz, 4H), 3.66 (s, 6H), 2.90 (s, 2H). 13 C NMR (151MHz, CDCl3) δ159.19,134.53,113.17,55.02. 11 B NMR (193MHz, CDCl3) δ0.44, -7.30 (d, J = 158.0Hz), -13.31 (d, J = 155.4Hz), -20.13 (d, J = 165.6Hz). 11 B{ 1 H}NMR(193MHz, CDCl3)δ0.41,-7.31,-13.32,-20.10.HRMS(EI-TOF):m / z calcd.for C 16 H 24 B 10 O2[M+H]+:356.2779.Found:356.2782.

[0304] Example 22: Suzuki coupling of B(9,10) monoaryl-substituted bromocarborane

[0305]

[0306] The specific operations are as follows:

[0307] Place a stirrer of appropriate size in a Schlenk bottle and dry it for later use. Weigh monoaryl brominated meta-carborane (0.0658g, 0.2mmol), 6-methoxynaphthalene-2-boric acid (0.0606g, 0.3mmol), 1,4-bis(dicyclohexylphosphine)butane bis(tetrafluoroborate) (0.0126g, 0.02mmol), palladium trifluoroacetate (0.0033g, 0.010mmol), potassium phosphate (0.1274g, 0.6mmol) in sequence and add them to the dried Schlenk bottle, replace nitrogen three times, add 2ml of toluene, then tighten the stopcock to seal and add it to a 100℃ oil bath and react for 24h. After the reaction is completed, add saturated sodium chloride aqueous solution, separate the layers, and extract the water layer three times with EA. Combine the organic layers, add anhydrous magnesium sulfate to dry, filter and evaporate to obtain a crude product. The product was separated by chromatography column with PE / EA (40:1) as eluent, and 24.0 mg of product was obtained with a yield of 30%.

[0308] 1 H NMR (400MHz, CDCl3) δ7.75 (s, 1H), 7.60 (d, J = 8.7Hz, 1H), 7.51 (d, J = 8.1Hz, 1H), 7.39 (d, J = 7.9Hz, 1H),7.24(s,2H),7.10–7.00(m,1H),6.66(d,J=8.0Hz,1H),3.87(s,3H),3.69(s,3H),3.01(s,2H). 13 C NMR (151MHz, CDCl3) δ158.11,156.37,133.44,132.87,131.78,130.47,128.53,127.66,124.50,117.19,112.09,104.35,54.24,50.13. 11 BNMR (193MHz, CDCl3) δ0.54, -7.22 (d, J = 143.0Hz), -13.27 (d, J = 154.8Hz), -20.07 (d, J = 197.0Hz). 11 B{ 1 H}NMR(193MHz,CDCl3)δ0.57,-7.13,-13.20,-20.07.HRMS(EI-TOF):m / zcalcd.for C 20 H 26 B 10 O2[M+H]+:406.2936.Found:406.2953.

[0309] Example 23: Suzuki coupling of B(9,10) monoaryl-substituted bromocarborane

[0310]

[0311] The specific operations are as follows:

[0312] Place a stirrer of appropriate size in a Schlenk bottle and dry it for later use. Weigh monoaryl brominated metacarborane (0.0658g, 0.2mmol), dibenzofuran-2-boric acid (0.0636g, 0.3mmol), 1,4-bis(dicyclohexylphosphine)butane bis(tetrafluoroborate) (0.0126g, 0.02mmol), palladium trifluoroacetate (0.0033g, 0.010mmol), potassium phosphate (0.1274g, 0.6mmol) in sequence and add them to the dried Schlenk bottle, replace nitrogen three times, add 2ml of toluene, then tighten the stopcock to seal and add it to a 100℃ oil bath and react for 24h. After the reaction is completed, add saturated sodium chloride aqueous solution, separate the layers, and extract the water layer three times with EA. Combine the organic layers, add anhydrous magnesium sulfate to dry, filter and evaporate to obtain a crude product. The product was separated by chromatography column with PE / EA (40:1) as eluent, and 36.0 mg of product was obtained with a yield of 43%.

[0313] Example 24: Suzuki coupling of B(9,10) pyridine-substituted bromocarborane

[0314]

[0315] The specific operations are as follows:

[0316] Place a stirrer of appropriate size into a Schlenk tube and dry for later use. Pyridine-substituted bromocarborane (0.0722 g, 0.2 mmol), 2,6-dimethoxypyridine-3-boric acid (0.0732 g, 0.4 mmol), 1,4-bis(dicyclohexylphosphine)butane bis(tetrafluoroborate) (0.0126 g, 0.02 mmol), palladium trifluoroacetate (0.0033 g, 0.010 mmol), potassium phosphate (0.1698 g, 0.8 mmol) were weighed in sequence and added to the dried Schlenk bottle, nitrogen was replaced three times, 2 ml of toluene was added, the stopcock was tightened to seal and added to a 100 ° C oil bath, and the reaction was carried out for 24 hours. After the reaction was completed, the crude product was obtained by filtering with a needle tube with cotton and diatomaceous earth pressed and rotating. Separation was performed using a chromatographic column (petroleum ether / ethyl acetate, petroleum ether / dichloromethane) to obtain 44.4 mg with a yield of 53%.

[0317] 1H NMR (600MHz, CDCl3) δ7.48(d,J=7.9Hz,2H),6.12(d,J=7.9Hz,2H),3.84(s,6H),3.74(s,6H),2.94(s,2H).1 3 C NMR (151MHz, CDCl3) δ158.64,156.90,141.37,94.05,47.32,46.61,45.22. 11 B NMR (193MHz, CDCl3) δ -6.27, -11.72 (d, J = 163.0Hz), -18.27 (d, J = 164.2Hz), -24.51 (d, J = 181.2Hz). 11 B{ 1 H}NMR(193MHz, CDCl3)δ-6.24,-11.70,-18.26,-24.52.HRMS(EI-TOF):m / z calcd.for C 16 B 10 H 26 O4N2[M+H]+:418.2896.Found:418.2898.

[0318] Example 25: Suzuki coupling of B(9,10) pyridine-substituted bromocarborane

[0319]

[0320] The specific operations are as follows:

[0321] Place a stirrer of appropriate size into a Schlenk tube and dry it for later use. Weigh pyridine-substituted bromocarborane (0.0722 g, 0.2 mmol), 6-methoxypyridine-3-boric acid (0.0612, 0.4 mmol), 1,4-bis(dicyclohexylphosphine)butane bis(tetrafluoroborate) (0.0126 g, 0.02 mmol), palladium trifluoroacetate (0.0033 g, 0.010 mmol), potassium phosphate (0.1698 g, 0.8 mmol) in turn and add them to the dried Schlenk bottle, replace nitrogen three times, add 2 ml of toluene, tighten the stopcock to seal and add it to a 100 ° C oil bath, and react for 24 hours. After the reaction is completed, filter with a needle tube with cotton and diatomaceous earth pressed and rotate to obtain a crude product. Separate with a chromatographic column (petroleum ether / ethyl acetate = 50:1) to obtain 25.7 mg, with a yield of 33%.

[0322] 1H NMR (400MHz, CDCl3) δ8.08(s,1H),7.48(t,J=8.7Hz,2H),6.53(d,J=8.3Hz,1H),6.15(d,J=7.9Hz,1H),3.85(d,J=7.2Hz,6H),3.74(s,3H),2.98(s,2H). 13 C NMR (151MHz, CDCl3) δ164.68,163.74,163.20,150.63,147.51,143.30,109.75,100.48,53.33,53.16,52.67,51.37. 11 B NMR (193MHz, CDCl3) δ0.87–-3.45 (m), -7.10 (d, J = 158.3Hz), -13.47 (d, J = 122.6Hz), -19.69 (d, J = 88.2Hz). 11 B{ 1 H}NMR(193MHz, CDCl3)δ-1.07(d,J=67.2Hz),-7.09,-13.30,-19.80.HRMS(EI-TOF):m / z calcd.For C 15 H 24 B 10 N2O3[M+H]+:388.2790.Found:388.2786.

[0323] Example 26: Suzuki coupling of B(9,10) pyridine-substituted bromocarborane

[0324]

[0325] The specific operations are as follows:

[0326] Place a stirrer of appropriate size into a Schlenk tube and dry it for later use. Weigh pyridine-substituted bromocarborane (0.0722 g, 0.2 mmol), 3,4,5-trimethoxyphenylboronic acid (0.0848 g, 0.4 mmol), 1,4-bis(dicyclohexylphosphine)butane bis(tetrafluoroborate) (0.0126 g, 0.02 mmol), palladium trifluoroacetate (0.0033 g, 0.010 mmol), potassium phosphate (0.1698 g, 0.8 mmol) in turn and add them to the dried Schlenk bottle, replace nitrogen three times, add 2 ml of toluene, tighten the stopcock to seal and add it to a 100 ° C oil bath, and react for 24 hours. After the reaction is completed, filter with a needle tube with cotton and diatomaceous earth pressed and rotate to obtain a crude product. Separate with a chromatographic column (petroleum ether / ethyl acetate = 50:1) to obtain 49.4 mg, with a yield of 55%.

[0327] Example 27: Suzuki coupling of B(9,10) pyridine-substituted bromocarborane

[0328]

[0329] The specific operations are as follows:

[0330] Place a stirrer of appropriate size into a Schlenk tube and dry it for later use. Weigh pyridine-substituted bromocarborane (0.0722 g, 0.2 mmol), 2,4-dimethoxyphenylboronic acid (0.0728 g, 0.4 mmol), 1,4-bis(dicyclohexylphosphine)butane bis(tetrafluoroborate) (0.0126 g, 0.02 mmol), palladium trifluoroacetate (0.0033 g, 0.010 mmol), potassium phosphate (0.1698 g, 0.8 mmol) in turn and add them to the dried Schlenk bottle, replace nitrogen three times, add 2 ml of toluene, tighten the stopcock to seal and add it to a 100 ° C oil bath, and react for 24 hours. After the reaction is completed, filter with a needle tube with cotton and diatomaceous earth pressed and rotate to obtain a crude product. Separate with a chromatographic column (petroleum ether / ethyl acetate = 50:1) to obtain 29.3 mg, with a yield of 35%.

[0331] 1 H NMR (400MHz, CDCl3) δ7.46(d,J=7.9Hz,1H),7.29(d,J=4.8Hz,1H),6.36(dd,J=8.3,2.4Hz,1H),6.28( d,J=2.3Hz,1H),6.11(d,J=7.9Hz,1H),3.85(s,3H),3.77(d,J=1.2Hz,6H),3.57(s,3H),2.95(s,2H). 13 C NMR (151MHz, CDCl3) δ164.65,163.31,162.76,160.71,147.33,136.81,104.36,99.88,97.91,76.89,55.15,54.78,53.31,52.61,51.15. 11 B NMR (193MHz, CDCl3) δ -1.32 (d, J = 150.5Hz), -6.86 (d, J = 148.4Hz), -13.56 (d, J = 151.1Hz), -19.83 (d, J = 171.1Hz). 11 B{ 1H}NMR(193MHz, CDCl3)δ-1.31(d,J=154.7Hz),-6.84,-13.51,-19.77.HRMS(EI-TOF):m / z calcd.For C 15 H 24 B 10 N2O3[M+H]+:417.2943.Found:417.2946.

[0332] Example 28 Cellular Activity Test of HIF-1α Analogs Containing Metacarborane Structure

[0333] The HIF-1α analogue containing a meta-carborane structure proposed by the present invention has the following structure:

[0334]

[0335] The cell activity test of the above drug analogs is carried out, and the specific operation steps are as follows:

[0336] The cultured cells were subcultured into 6-well plates. Immediately after the cells were seeded, they were placed in a low-oxygen incubator and cultured for 24 hours. The original culture medium was discarded, and the plates were washed once with PBS. The prepared working solution 2 was added to the corresponding wells, 1 ml per well.

[0337] Continue hypoxic culture for 48 h, digest the cells, collect samples, and prepare for staining.

[0338] Apoptosis staining: The digested cells were resuspended in Binding Buffer (10X), 300ul per well, and then stained with AnnexinV-FITC, 1.5ul per well, incubated at room temperature for 15mins, and then PI was added, 1.5ul per well, incubated at room temperature for 5mins, and detected by the machine.

[0339] Cycle staining: After digestion, discard the supernatant of the cells, fix them with 70% ethanol, and incubate them at -20°C overnight. Centrifuge the fixed cells at 1200rpm for 3mins, discard the supernatant, wash twice with PBS, and then stain them with the cell cycle detection kit (BD 550825), 400ul per well, incubate at room temperature for 15mins, and detect them on the machine.

[0340] Note: EDTA-free trypsin is required for cell apoptosis sampling.

[0341] Experimental results: After four independent repeated experiments, it was found that the HIF-1α analogs containing meta-carborane structure shown in (4b) and (4c) had a significant effect on Hela cell apoptosis at 4uM (p value < 0.05), while the effect was not obvious at 2uM.

[0342] Example 29 contains a diaryl carborane structure (the product structure of Example 27) as a new type of pyridine organic ligand containing a double nitrogen atom in a coupling reaction.

[0343] The meta-carborane structure (product structure of Example 27) proposed by the present invention has the structure shown on the left as follows:

[0344]

[0345] The structure on the left can be used with transition metal ions such as palladium, iridium, and ruthenium that have catalytic activity in various organic synthesis reactions to form a 1:1 complex in an organic solvent such as acetonitrile, dichloromethane, and toluene. As shown in the structure on the right of the figure above, the new complex has the activity of catalyzing the oxidation of fatty alcohols in organic synthesis reactions to form fatty aldehydes or fatty ketones (left in the figure below). At the same time, the ligand can catalyze the difunctionalization reaction of short-chain olefins, which are basic chemicals in the petrochemical industry, to form high-value-added polyhydroxyalkane compounds (right in the figure below), as shown in the figure below:

[0346]

[0347] Example 30 contains the use of a bisaryl carborane structure (the product structure of Example 21) as a skeleton precursor for a novel liquid crystal material.

[0348] Traditional liquid crystal materials have poor stability to ultraviolet light, but the biaryl carborane proposed in the present invention has increased structural stability due to the introduction of highly thermodynamic and ultraviolet stable carborane, and can therefore be used as a new liquid crystal material skeleton for derivatization. The biaryl carborane structure (product structure of Example 21) removes the methyl group in the methoxy group under the action of the boron tribromide reagent BBr3, and the obtained bisphenol hydroxyl structure obtains a bipentyl substituted structure under the action of a base and n-pentyl bromide. This type of structure is shown in the figure below:

[0349]

[0350] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as those commonly understood by those skilled in the art of the present invention. The terms used in the specification of the present invention herein are only for the purpose of describing specific embodiments and are not intended to limit the present invention.

[0351] As used in the present invention, the terms "include" and "comprising" are open expressions, that is, including the contents specified in the present invention but not excluding other contents.

[0352] As used herein, the term "and / or" includes any and all combinations of one or more of the associated listed items.

[0353] The protection content of the present invention is not limited to the above embodiments. Without departing from the spirit and scope of the present invention, changes and advantages that can be thought of by those skilled in the art are included in the present invention and are protected by the attached claims.

Claims

1. A method for synthesizing an aryl / heteroaryl / alkenyl substituted meta-carborane derivative, characterized in that: The method comprises the following steps: Step 1: using m-carborane as a raw material, an electrophilic substitution reaction occurs in a first solvent in the presence of a first catalyst and a bromine element to generate B(9,10)-position dibromom-carborane; Step 2: Using the B(9,10)-dibromocarborane prepared in step 1 and an aryl / heteroaryl / alkenyl boronic acid reagent as raw materials, a palladium-catalyzed Suzuki coupling reaction is carried out in a second solvent under the action of a second catalyst, a first ligand, a base and an additive to achieve a selective monoaryl / heteroaryl / alkenylation reaction of the B(9,10)-dibromocarborane to generate a monoaryl / heteroaryl / alkenyl brominated B(9,10)-carborane; The monoaryl / heteroaryl / alkenylated brominated B(9,10)carborane includes monoarylized brominated B(9,10)carborane, monopyridylated brominated B(9,10)carborane, and monoalkenylated brominated B(9,10)carborane; Step 3: using the monoarylated brominated B(9,10)-carborane and an aryl / heteroaryl / alkenyl boronic acid reagent as raw materials, in the presence of a third catalyst, a second ligand, and a base, a palladium-catalyzed Suzuki coupling reaction is carried out in a third solvent to achieve a diaryl / heteroaryl / alkenyl substituted carborane at the B(9,10) position; and / or, The monopyridyl brominated B(9,10) meta-carborane and an aryl / heteroaryl boronic acid reagent are used as raw materials, and a palladium-catalyzed Suzuki coupling reaction is carried out in a fourth solvent in the presence of a fourth catalyst, a third ligand and a base to generate a B(9,10) disubstituted meta-carborane.

2. The synthesis method according to claim 1, characterized in that In the synthesis method, The step 1 is a one-pot method for synthesizing B(9,10)-dibromocarborane: using m-carborane and a bromine reagent as raw materials, an electrophilic substitution reaction occurs in a first solvent in the presence of a first catalyst to generate B(9,10)-dibromocarborane; as shown in reaction formula (A): Wherein, the first catalyst is anhydrous aluminum chloride; the first solvent is one or both of dichloromethane and 1,2-dichloroethane; The amount of the meta-carborane is 2.0-5.0 mmol; the amount of the bromine element is 2.0-2.5 eq.

3. The synthesis method according to claim 1, characterized in that In the synthesis method, The second step is a Suzuki coupling method for the mono-aryl / heteroaryl / alkenylated brominated meta-carborane at position B(9): using the di-brominated meta-carborane at position B(9,10) and the aryl / heteroaryl / alkenyl boronic acid reagent as raw materials, and in the presence of the second catalyst, the first ligand, a base and an additive, a Suzuki coupling reaction is carried out in the second solvent to generate the aryl / heteroaryl / alkenylated brominated B(9,10) meta-carborane; the method is shown in reaction formula (B): Among them, the R group includes the following: The molar amount of the dibromocarborane at position B (9, 10) is 0.1-0.2 mmol; the second catalyst is a palladium catalyst, including Pd(dba)2, Pd2(dba)3, Pd(acac)2, Pd(OTFA)2, Pd(OAc)2, Pd(OPiv)2, Pd(MeCN)2Cl2, PdCl2; the second solvent is toluene; the first ligand includes XPhos, SPhos, DavePhos, RuPh os, BrettPhos, 2-dicyclohexylphosphino-2'-methylbiphenyl, 1-dimethylamino-2-(diadamantylphosphine)benzene, tri-tert-butylphosphine tetrafluoroborate, tricyclohexylphosphine tetrafluoroborate, tricyclohexylphosphine, tricyclopentylphosphine tetrafluoroborate, tert-butyldicyclohexylphosphine tetrafluoroborate, bis(dicyclohexylphosphinophenyl) ether, 9,9-dimethyl-4,5-bis(dicyclohexylphosphino)-9H-xanthene, bis(cyclohexylphosphino)ferrocene, 1,3-bis(dicyclohexylphosphino)propane bis(tetrafluoroborate acid salt); the base includes K2CO3, KOAc, K3PO4, Na2CO3, Cs2CO3, CsF, TMSOK; the additive includes TBAI, TMAI, TMAPF6, TMABF4, TEAPF6; the aryl / heteroaryl / alkenyl boronic acid reagent includes phenylboronic acid, 4-methoxyphenylboronic acid, 3-methoxyphenylboronic acid, 3,4-dimethoxyphenylboronic acid, 2,4-dimethoxyphenylboronic acid, 3,4,5-trimethoxyphenylboronic acid, 3,5-dimethyl Phenylboric acid, 4-methyl-3-fluorophenylboric acid, 3,4-(methylenedioxy)phenylboric acid, 2-benzyloxyphenylboric acid, 4-thiomethylphenylboric acid, 4-hydroxyphenylboric acid, 2,6-dimethoxypyridine-3-boric acid, 2-methoxy-5-pyridineboric acid, 3-thiopheneboric acid, 1-naphthaleneboric acid, 6-methoxynaphthalene-2-boric acid, 9-phenanthreneboric acid, dibenzothiophene-2-boric acid, 4-(carbazol-9-yl)phenylboric acid, 9-phenylcarbazole-3-boric acid, 4-boric acid triphenylamine, cyclohexene-1-ylboric acid; The amount of the aryl / heteroaryl / alkenyl boronic acid is 1.5-2.0 eq; the amount of the first ligand is 10 mol%-20 mol%; the amount of the second catalyst is 5 mol%-10 mol%; the amount of the base is 2.0-3.0 eq; the total concentration of the reaction solution containing all reaction substrates is 0.1 M, 0.2 M, 0.05 M; The reaction temperature is 80°C, 90°C, 100°C, 110°C, and 120°C; the reaction time is 12h, 18h, and 24h.

4. The synthesis method according to claim 1, characterized in that The step 3 is a method for Suzuki coupling of monoarylated brominated B(9,10)carborane: using the monoarylated brominated B(9,10)carborane and an aryl / heteroaryl / alkenyl boronic acid reagent as raw materials, a palladium-catalyzed Suzuki coupling reaction is carried out in the third solvent in the presence of the third catalyst, the second ligand, and the base to generate a biaryl / heteroaryl / alkenyl substituted carborane at the B(9,10) position. The synthesis method is shown in reaction formula (C): Wherein, R includes the following groups: Wherein, the molar amount of the monoarylated brominated B(9,10)carborane is 0.1-0.2 mmol; The second ligand includes tricyclohexylphosphine tetrafluoroborate, 1,3-bis(dicyclohexylphosphine)propane bis(tetrafluoroborate), dicyclohexyl(2-methylphenyl)phosphine, phenyldicyclohexylphosphine, triphenylphosphine, [(4-(N,N-dimethylamino)phenyl]dicyclohexylphosphine, tri(2-methoxyphenyl)phosphine, p-anisyldiphenylphosphine, tri(2,4,6-trimethoxyphenyl)phosphine, tri(2,4-dimethoxyphenyl)phosphine, bis(dicyclohexylphosphine)methane bis(tetrafluoroborate), 1,3-bis(1-adamantyl)imidazole tetrafluoroborate, 1,4-bis(dicyclohexylphosphine)butane bis(tetrafluoroborate); The third catalyst is a palladium catalyst, including Pd(dba)2, Pd2(dba)3, Pd(acac)2, Pd(OTFA)2, Pd(OAc)2, Pd(OPiv)2; The base comprises K3PO4; The third solvent is toluene; The aryl / heteroaryl / alkenyl boronic acid includes 4-methoxyphenylboronic acid, 3,4-dimethoxyphenylboronic acid, 2,4-dimethoxyphenylboronic acid, 3,4,5-trimethoxyphenylboronic acid, 3,4-(methylenedioxy)phenylboronic acid, 6-methoxynaphthalene-2-boric acid, 4-thiomethylphenylboronic acid, 2,6-dimethoxypyridine-3-boric acid, 2-methoxy-5-pyridineboric acid, cyclohexene-1-ylboric acid, 1-methylindole-5-boric acid; The amount of the aryl / heteroaryl / alkenyl boronic acid is 1.5-2.0 eq; the amount of the second ligand is 10 mol%-20 mol%; the amount of the third catalyst is 5 mol%-10 mol%; the amount of the base is 2.0-3.0 eq; the total concentration of the reaction solution containing all reaction substrates is 0.1 M; The reaction temperature is 90°C, 100°C, and 110°C; the reaction time is 12h, 18h, and 24h.

5. The synthesis method according to claim 1, characterized in that The step 3 is a method for Suzuki coupling of monopyridyl brominated B(9,10)-carborane: using the monopyridyl brominated B(9,10)-carborane and an aryl / heteroaryl boronic acid reagent as raw materials, a palladium-catalyzed Suzuki coupling reaction occurs in the fourth solvent in the presence of the fourth catalyst, a base, and a third ligand to generate a B(9,10) disubstituted-carborane. The synthesis method is shown in reaction formula (D): Among them, the R group includes the following: Wherein, the molar amount of the monopyridyl brominated B(9,10)-carborane is 0.1-0.2 mmol; The aryl / heteroaryl boronic acid includes 2,4-dimethoxyphenylboronic acid, 3,4,5-trimethoxyphenylboronic acid, 6-methoxynaphthalene-2-boric acid, 2,6-dimethoxypyridine-3-boric acid, 2-methoxy-5-pyridineboric acid, 1-methylindole-5-boric acid; The third ligand includes 1,4-bis(dicyclohexylphosphino)butane bis(tetrafluoroborate); The base comprises potassium phosphate; The fourth catalyst comprises Pd(OTFA)2; The fourth solvent is toluene; Wherein, the amount of the aryl / heteroaryl boronic acid is 1.5-2.0 eq; the amount of the third ligand is 10 mol%-20 mol%; the amount of the fourth catalyst is 5 mol%-10 mol%; the amount of the base is 2.0-3.0 eq; the total concentration of the reaction solution containing all reaction substrates is 0.1 M; Wherein, the reaction temperature is 100°C; and the reaction time is 24h.

6. An aryl / heteroaryl / alkenyl substituted meta-carborane derivative obtained by the synthesis method according to any one of claims 1 to 5.

7. The aryl / heteroaryl / alkenyl substituted meta-carborane derivative according to claim 6, characterized in that: The structure of the meta-carborane derivative has the carborane B(9) and B(10) positions being substituted by aryl, heteroaryl or alkenyl groups either individually or simultaneously; Includes the following: Monoaryl / heteroaryl / alkenyl substituted carborane derivatives: Bis-aryl / heteroaryl / alkenyl substituted carborane derivatives:

8. A drug or a pharmaceutical composition, characterized in that The drug or pharmaceutical composition comprises the aryl / heteroaryl / alkenyl substituted meta-carborane as claimed in claim 6 or 7.

9. The drug or pharmaceutical composition according to claim 8, characterized in that It includes HIF-1α analogs containing a meta-carborane structure as shown in formula (4b) and (4c):

10. The synthesis method of the aryl / heteroaryl / alkenyl substituted carborane derivatives as described in claims 1-5, the aryl / heteroaryl / alkenyl substituted carborane derivatives as described in claims 6 or 7, or the drugs or drug compositions as described in claims 8 and 9 are used in evaluating the effects of drugs on the survival and cycle of Hela cells under hypoxic culture conditions, in preparing drugs for treating anaplastic thyroid cancer and polypoidal choroidal vasculopathy, in preparing cardiovascular drugs, hypertension drugs, cardiomyopathy drugs, in preparing drugs for HIF-1α inhibitors, in generating transition metal complexes to oxidize fatty alcohols or short-chain olefin difunctionalization reactions, and in preparing new liquid crystal material skeleton precursors.

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