Synthesis method of B (4)-aryl chalcogenide-C (1)-pyridine-o-carborane derivative

Abstract

The invention discloses a synthesis method of a B (4)-aryl chalcogenide-C (1)-pyridine-o-carborane derivative, which comprises the following steps: by taking C (1)-pyridine-C (2)-methyl-o-carborane and diaryl diselenide as raw materials, reacting in an air atmosphere under the conditions of a catalyst and an oxidizing agent at the temperature of 60-80 DEG C for 2-3 hours, thereby obtaining the B (4)-aryl chalcogenide-C (1)-pyridine-o-carborane derivative. Diaryl diselenide, diaryl disulfide or diphenyl tellurium ether is selectively coupled with B (4)-H, and the B (4)-aryl chalcogenide-C (1)-pyridine-o-carborane derivative is synthesized. According to the invention, B (4)-H is activated by utilizing the positioning effect of pyridine, diaryl diselenide, diaryl disulfide or diphenyl telluride is taken as a coupling unit, and selective aryl selenylation, aryl vulcanization and aryl tellurization of C (1)-pyridine-o-carborane B (4)-H are realized under mild conditions, so that a series of B (4)-aryl chalcogenide-C (1)-pyridine-o-carborane derivatives are obtained. The invention provides an economical and efficient method for selective selenylation, sulfuration and tellurization of a B-H bond of o-carborane, and lays a material and technical foundation for further development of application of the B (4)-aryl chalcogenide-C (1)-pyridine-o-carborane derivative in the field of BNCT.

Description

Technical Field

[0001] The present invention belongs to the technical field of organic synthetic chemistry, and more specifically, relates to a method for synthesizing a B(4)-arylsulfide-C(1)-pyridine-o-carborane derivative. Background Art

[0002] Since its discovery in 1963, icosahedral carborane has important application value in metal organic / coordination chemistry, nonlinear optics, boron neutron capture therapy (BNCT), nanomaterials, etc. due to its unique three-dimensional structure, high boron content, and good thermal and chemical stability. Therefore, selectively introducing functional groups into the boron and carbon vertices of carborane through BH and CH functionalization has attracted widespread attention.

[0003] Organic selenides are an important class of organic synthetic building blocks, widely present in candidate drugs, functional materials, organic ligands and catalysts. For example, selenocysteamine is a selenoamino acid with significant anticancer activity. It can induce apoptosis of cancer cells and inhibit cancer cell proliferation, so it can be used to treat a variety of cancers. Among organic selenides, aryl selenide units are often present in lead drug molecules and bioactive compounds. Therefore, organic selenium compounds show broad application prospects in drug development and medical applications. Organic selenides have significant antioxidant, anti-inflammatory, anticancer, antibacterial and antiviral activities, so they can be used to develop new antibiotics, antivirals, antioxidants, anti-inflammatory and anticancer drugs. These drugs can be used to treat diseases such as cardiovascular diseases, neurodegenerative diseases, arthritis, asthma and cancer.

[0004] BNCT is a method of treating cancer by irradiating boron-containing compounds with neutron beams. Selenide is coupled with carborane to form a selenide-carborane complex, which can be designed as a targeted delivery system to precisely deliver boron compounds to the tumor site, improve the therapeutic effect and reduce damage to normal tissues. The selenide-carborane complex can also be used as a contrast agent for imaging diagnosis of tumors. Because aryl selenides have important applications in drug development and functional organic materials, the synthesis method of aryl selenides has always been an important research topic in the field of organic synthetic chemistry.

[0005] After the 1990s, with the development of synthesis technology, a large number of carborane structures were successfully synthesized and showed strong potential as BNCT boron carriers. 10 H 11 , whose structural formula is The drug molecules can react with the reductase in cancer cells to form highly reactive intermediates, which will immediately react with biological molecules such as DNA, proteins and lipids in cancer cells, thereby inhibiting the activity of tumor cells. (See Morris JH, Peters GS, Koldaeva E, Spryshkova R, Borisov G, Synthesis and Characterization of 7-(CH3)3N-4-{2,4-(NO2)2C6H3S}-nido-7-CB 10 H 11 and ItsBiodistribution in C57B16 Mice Bearing B16 Melanoma[J].Appl.Organomet.Chem.1995,9,323-325)

[0006] Fenoprofen is a widely used nonsteroidal anti-inflammatory drug (NSAID, structural formula ), used to treat rheumatoid arthritis, degenerative joint disease, ankylosing spondylitis and gout (see Hairui J, Zaozao Q. Recent Advances in Transition Metal-Catalyzed BH Bond Activation for Synthesis of o-Carborane Derivatives with B-Heteroatom Bond [J]. Chin. J. Org. Chem. 2023, 43: 1045). Reaction with oxygen-containing compounds of the same main group as selenium and sulfur and carborane to obtain carborane analogs of fenoprofen They are superior to the original drugs in terms of tumor cell toxicity. Their anti-tumor effects are achieved by inhibiting proliferation and do not rely on apoptosis enzymes to cause cell apoptosis. Summary of the invention

[0007] An object of the present invention is to solve at least the above problems and / or disadvantages and to provide at least the advantages which will be described hereinafter.

[0008] In order to achieve these objects and other advantages according to the present invention, a method for synthesizing a B(4)-arylsulfide-C(1)-pyridine-o-carborane derivative is provided, comprising: As a raw material, in the air atmosphere, under the conditions of a catalyst and an oxidant, in a solvent at a certain temperature, react with diaryl diselenide, diaryl disulfide or diphenyl ditelluride for a certain time, and use diaryl diselenide, diaryl disulfide or diphenyl ditelluride to selectively couple with B(4)-H to synthesize B(4)-arylsulfide-C(1)-pyridine-o-carborane derivatives; wherein R1 is one of hydrogen, methyl, isopropyl, n-butyl and phenyl;

[0009] The structural formula of diaryl diselenide is:

[0010]

[0011] Among them, R2 is one of hydrogen, phenyl, substituted phenyl, and benzyl, and the substituent in the substituted phenyl is one of methyl, ethyl, methoxy, methylthio, trifluoromethoxy, acetyl, trifluoromethyl, halogen, cyano, and nitro.

[0012] Preferably, the catalyst is dichloro(pentamethylcyclopentadienyl)rhodium dimer [Cp*RhCl2]2, and the amount of the catalyst used is 2% to 3% of the molar amount of C(1)-pyridine-C(2)-methyl-o-carborane.

[0013] Preferably, the oxidant is silver acetate, and the amount of silver acetate used is twice the molar amount of C(1)-pyridine-C(2)-methyl-o-carborane.

[0014] Preferably, the reaction temperature is 20-30° C., and the reaction time is 12-36 h.

[0015] Preferably, when R1 is methyl, The synthesis method of C(1)-pyridine-C(2)-methyl-o-carborane comprises:

[0016] S1. Under an argon atmosphere, o-carborane and tetrahydrofuran are added to a reaction vessel in sequence, the reaction vessel is placed in an ice-water bath and stirred, and after the system temperature drops to 0°C, n-butyl lithium solution is slowly added using a syringe, and the system is stirred in an ice-water bath at 0°C for 1 hour; after 1 hour, 2-fluoropyridine is added to the reaction vessel, and the reaction vessel is transferred to an oil bath at 60-80°C for 1-3 hours, and after the reaction is completed, acetone is added to the system for quenching; the reaction is extracted with ethyl acetate, washed three times with saturated ammonium chloride and sodium chloride aqueous solution in sequence, the organic phase is collected, and dried with anhydrous sodium sulfate; after drying for 2 hours, the organic phase is concentrated under reduced pressure, and the product is separated and purified by column chromatography, and petroleum ether is used as an eluent to separate and obtain C(1)-pyridine-o-carborane;

[0017] S2. Under an argon atmosphere, C(1)-pyridine-o-carborane and tetrahydrofuran are added to a reaction vessel in sequence, the reaction vessel is placed in an ice-water bath and stirring is started, after the system temperature drops to 0°C, n-butyl lithium solution is slowly added using a syringe, and the system is stirred in an ice-water bath at 0°C for reaction for 1 hour; after 1 hour, iodomethane is added to the reaction vessel, and the reaction flask is transferred to an oil bath at 60-80°C for reaction for 2 hours, after the reaction is completed, acetone is added to the system for quenching; the reaction is extracted with ethyl acetate, washed three times with saturated ammonium chloride and sodium chloride aqueous solution in sequence, the organic phase is collected, and dried with anhydrous sodium sulfate; after drying for 2 hours, the organic phase is concentrated under reduced pressure, and the product is separated and purified by column chromatography, and petroleum ether and ethyl acetate are used as eluents in a volume ratio of 20-100:1 to separate and obtain C(1)-pyridine-C(2)-methyl-o-carborane.

[0018] Preferably, in S1, the concentration of the n-butyl lithium solution is 1.6 M, and the dosage ratio of o-carborane, tetrahydrofuran, n-butyl lithium and 2-fluoropyridine is 10 mmol:100 mL:30-35 mmol:12 mmol.

[0019] Preferably, in S2, the concentration of the n-butyl lithium solution is 1.6 M, and the usage ratio of C(1)-pyridine-o-carborane, tetrahydrofuran, n-butyl lithium and iodomethane is 5 mmol:50 mL:15-20 mmol:6 mol.

[0020] The invention discloses an application of a B(4)-arylsulfide-C(1)-pyridine-o-carborane derivative. The B(4)-arylsulfide-C(1)-pyridine-o-carborane derivative is applied to a boron compound targeted delivery drug, a contrast agent for tumor imaging diagnosis, and a boron carrier drug for boron neutron capture therapy.

[0021] The present invention has at least the following beneficial effects:

[0022] 1. The present invention utilizes the positioning effect of pyridine to activate B(4)-H, uses diaryl diselenide as the source of aryl selenium, and realizes the selective aryl selenization of C(1)-pyridine-o-carborane B(4)-H under mild conditions, thereby obtaining a series of B(4)-aryl selenium-C(1)-pyridine-o-carborane derivatives. This method provides an economical and efficient method for the selective selenization of the BH bond of o-carborane, and lays a material and technical foundation for the further development of the application of B(4)-aryl selenium-C(1)-pyridine-o-carborane derivatives in the field of BNCT.

[0023] 2. The reaction conditions of the present invention are mild, and the reaction can be carried out at room temperature, under conditions of anhydrous oxygen sensitivity, etc.

[0024] 3. The present invention has good applicability of functional groups, including methyl, ethyl, methoxy, methylthio, trifluoromethoxy, acetyl, trifluoromethyl, halogen, cyano, nitro, etc. And the present invention is not only applicable to diaryl diselenide, but also to diaryl disulfide and diphenyl ditelluride.

[0025] 4. The present invention has good selectivity and high yield, simple reaction system and convenient post-processing.

[0026] 5. The present invention combines organic selenide, organic sulfide, organic telluride and carborane, making them have important potential application prospects and value in cancer treatment. This combination can improve the targeting and therapeutic effect of boron neutron capture therapy, enhance anti-cancer activity, reduce side effects, and provide real-time imaging diagnosis.

[0027] 6. The present invention provides a novel method for the selective functionalization of o-carborane, and provides new ideas for further designing the selective functionalization of o-carborane B(4)-H and the diversified synthesis of o-carborane derivatives.

[0028] Other advantages, objectives and features of the present invention will be embodied in part through the following description, and in part will be understood by those skilled in the art through study and practice of the present invention. BRIEF DESCRIPTION OF THE DRAWINGS

[0029] Figure 1 is 3a in Example 1 of the present invention 1 HNMR;

[0030] Figure 2 is 3a in Example 1 of the present invention 13 CNMR;

[0031] Figure 3 is 3b in Example 2 of the present invention 1 HNMR;

[0032] Figure 4 is 3b in Example 2 of the present invention 13 CNMR;

[0033] Figure 5 is 3d in Example 3 of the present invention 1 HNMR;

[0034] Figure 6 is 3d in Example 3 of the present invention 13 CNMR;

[0035] Figure 7 is 3i in Example 4 of the present invention 1 HNMR;

[0036] Figure 8 is 3i in Example 4 of the present invention 13 CNMR;

[0037] Fig. 9 is 3s in Example 5 of the present invention 1 HNMR;

[0038] Fig.10 is 3s in Example 5 of the present invention 13 CNMR;

[0039] Fig.11 is 3t in Example 6 of the present invention 1 HNMR;

[0040] Fig.12 is 3t in Example 6 of the present invention 13 CNMR;

[0041] Fig.13 is 5a in Example 7 of the present invention 1 HNMR;

[0042] Fig.14 is 5a in Example 7 of the present invention 13 CNMR;

[0043] Fig.15 is 5f in Example 8 of the present invention 1 HNMR;

[0044] Fig.16 is 5f in Example 8 of the present invention 13 CNMR;

[0045] Fig.17 is 5i in Example 9 of the present invention 1 HNMR;

[0046] Fig.18 is 5i in Example 9 of the present invention 13 CNMR;

[0047] Fig.19 is 7a in Example 10 of the present invention 1 HNMR;

[0048] Fig. 20 is 7a in Example 10 of the present invention 13 CNMR. DETAILED DESCRIPTION

[0049] The present invention is further described in detail below in conjunction with the accompanying drawings so that those skilled in the art can implement the invention with reference to the description.

[0050] It should be understood that the terms such as “having”, “including” and “comprising” used herein do not exclude the existence or addition of one or more other elements or combinations thereof.

[0051] Example 1

[0052] This embodiment provides a method for synthesizing B(4)-aryl selenium-C(1)-pyridine-C(2)-methyl-o-carborane 3a, which specifically comprises:

[0053] Step 1: Prepare C(1)-pyridine-o-carborane. The synthetic chemical formula is:

[0054]

[0055] Under argon atmosphere, o-carborane (1.44 g, 10 mmol) and dry tetrahydrofuran (THF) (100 mL) were added to a dry 250 mL round-bottom flask. The reaction flask was placed in an ice-water bath and stirred. After the system temperature dropped to 0 ° C, 20 mL of n-butyl lithium (1.6 M, 30 mmol, 3 eq) was slowly added using a syringe, and the system was stirred in an ice-water bath at 0 ° C for 1 hour. After 1 h, 1 mL of 2-fluoropyridine (12 mmol, 1.2 eq) was added to the reaction flask, and the reaction flask was transferred to an oil bath at 70 ° C for 2 h. The degree of reaction was detected by TLC plate. After the reaction was completed, acetone was added to the system for quenching. The reaction was extracted with ethyl acetate, washed three times with saturated ammonium chloride (NH4Cl) and sodium chloride (NaCl) aqueous solution, and the organic phase was collected and dried over anhydrous sodium sulfate (Na2SO4). After drying for 2 h, the organic phase was concentrated under reduced pressure and the product was separated and purified by column chromatography using petroleum ether as eluent to obtain 1.8 g of the product with a yield of 81%.

[0056] Step 2: Prepare C(1)-pyridine-C(2)-methyl-o-carborane derivatives. The synthetic chemical formula is:

[0057]

[0058] Under argon atmosphere, C(1)-pyridine-o-carborane (1.1 g, 5 mmol) and dry tetrahydrofuran (THF) (50 mL) were added to a dry 100 mL round-bottom flask. The reaction flask was placed in an ice-water bath and stirred. After the system temperature dropped to 0°C, 10 mL of n-butyl lithium (1.6 M, 15 mmol, 3 eq) was slowly added using a syringe, and the system was stirred in an ice-water bath at 0°C for 1 h. After 1 h, 374 μL of iodomethane (6 mmol, 1.2 eq) was added to the reaction flask, and the reaction flask was transferred to an oil bath at 70°C for 2 h. The degree of reaction was detected by TLC plate. After the reaction was completed, acetone was added to the system for quenching. The reaction was extracted with ethyl acetate, washed three times with saturated ammonium chloride (NH4Cl) and sodium chloride (NaCl) aqueous solution, and the organic phase was collected and dried with anhydrous sodium sulfate (Na2SO4). After drying for 2 h, the organic phase was concentrated under reduced pressure and the product was separated and purified by column chromatography using petroleum ether:ethyl acetate in a volume ratio of 20:1 as eluent to separate 1 g of the product with a yield of 85%.

[0059] Step 3: Prepare B(4)-aryl selenium-C(1)-pyridine-C(2)-methyl-o-carborane. The synthetic chemical formula is:

[0060]

[0061] In an air atmosphere, C(1)-pyridine-C(2)-methyl-o-carborane 1a (23.5 mg, 0.1 mmol), diphenyl diselenide 2a (37.4 mg, 0.12 mmol), hexafluoroisopropanol (HFIP) (1 mL), dichloro(pentamethylcyclopentadienyl)rhodium dimer (1.5 mg, 2.5 mol%), and silver acetate (33.4 mg, 0.2 mmol) were added to a dry 10 mL round-bottom flask in sequence, and the mixture was reacted at room temperature for 24 h. The reaction was monitored by TLC plate. After the reaction was completed, ethyl acetate was added to quench the reaction, the system was filtered with filter paper, concentrated under reduced pressure, and separated and purified by column chromatography, using petroleum ether:ethyl acetate = 20:1 as eluent, to obtain 36 mg of product 3a, with a yield of 92%.

[0062] like Figure 1 and Figure 2 The NMR data shown:

[0063] 1H NMR (600MHz, CDCl3, ppm): δ8.68-8.67(m,1H),7.80-7.77(m,1H),7.68-7.67(d,1H,J=6Hz) ,7.44-7.41(m,1H),7.24-7.21(m,3H),7.14-7.12(dd,2H,J=6Hz),1.77(s,3H,Cage-CH3);

[0064] 13 C{ 1 H}NMR (150MHz, CDCl3, ppm): δ149.3,148.0,137.0,136.2,128.5,127.8,127.4,126.5,124.7,80.3,78.5,23.6; 11 B{ 1 H}NMR (160MHz, CDCl3, ppm): δ-1.2[1B,B(4)-Se],-2.8(2B),-8.0(1B),-8.7(1B),-10.3(3B),-11.4(2B); HRMS(ESI)m / z calcd forC 14 H 22 B 10 NSe + (M+H) + 394.1843, found 394.1861.

[0065] Taking C(1)-pyridine-C(2)-methyl-o-carborane (1a) and diphenyl diselenide (2a) as raw materials to prepare B(4)-aryl selenium-C(1)-pyridine-C(2)-methyl-o-carborane (3a) as an example, the reaction conditions were optimized as follows:

[0066]

[0067]

[0068] All reactions were carried out under air atmosphere with 0.1 mmol 1a, 0.2 mmol 2a and 1 mL solvent at 40 °C for 24 h. Isolated yield: 0.1 mmol 1a, 0.12 mmol 2a were reacted at room temperature.

[0069] After condition screening, the optimal condition for the synthesis of 3a was No. 44: C(1)-pyridine-C(2)-methyl-o-carborane 1a (0.1mmol, 23.5mg) and diphenyl diselenide 2a (37.4mg, 0.12mmol) as raw materials, Cp*RhCl2 (2.5mol%, 1.5mg) as catalyst, AgOAc (0.2mmol, 33.4mg) as oxidant, reacted in 1mL HFIP at room temperature for 24h, and obtained the best yield of 92%.

[0070] Example 2

[0071] This embodiment provides a method for synthesizing B(4)-aryl selenium-C(1)-pyridine-C(2)-methyl-o-carborane 3b, and the synthetic chemical equation is:

[0072]

[0073] Specifically include:

[0074] In an air atmosphere, add the following formula into a dry 10 mL round-bottom flask: C(1)-pyridine-C(2)-methyl-o-carborane 1a (23.5 mg, 0.1 mmol), 0.12 mmol 40.8 mg structural formula is The diaryl diselenide 2b, hexafluoroisopropanol (HFIP) (1 mL), dichloro(pentamethylcyclopentadienyl)rhodium dimer (1.5 mg, 2.5 mol%), and silver acetate (33.4 mg, 0.2 mmol) were reacted at room temperature for 24 h, and the reaction was monitored by TLC plate. After the reaction, ethyl acetate was added to quench the reaction, and the system was filtered with filter paper, concentrated under reduced pressure, and separated and purified by column chromatography, using petroleum ether: ethyl acetate = 20:1 as the eluent, and 40 mg of product 3b was separated, with a yield of 99%.

[0075] like Figure 3 and Figure 4 The NMR data shown:

[0076] 1 H NMR (400MHz, CDCl3, ppm): δ8.69-8.67(m,1H),7.82-7.77(m,1H),7.70-7.68(m,1H),7.44-7 .41(m,1H),7.12-7.09(m,2H),6.95-6.93(m,2H),2.29(s,3H,-CH3),1.77(s,3H,Cage-CH3);

[0077] 13 C{ 1H}NMR (100MHz, CDCl3, ppm): δ149.3,148.1,137.3,137.0,136.1,129.4,126.5,124.7,124.2,80.3,78.4,23.6,21.2; 11 B{ 1 H}NMR (128MHz, CDCl3, ppm): δ-1.3[1B,B(4)-Se],-2.7(2B),-8.7(2B),-10.3(3B),-11.4(2B); HRMS(ESI)m / z calcd forC 15 H 24 B 10 NSe + (M+H) + 408.1999, found 408.2009.

[0078] Example 3

[0079] This embodiment provides a method for synthesizing B(4)-aryl selenium-C(1)-pyridine-C(2)-methyl-o-carborane 3d, and the synthetic chemical equation is:

[0080]

[0081] In an air atmosphere, C(1)-pyridine-C(2)-methyl-o-carborane 1a (23.5 mg, 0.1 mmol), The diaryl diselenide 2d (44.6 mg, 0.12 mmol), hexafluoroisopropanol (HFIP) (1 mL), dichloro(pentamethylcyclopentadienyl)rhodium dimer (1.5 mg, 2.5 mol%), and silver acetate (33.4 mg, 0.2 mmol) were reacted at room temperature for 24 h, and the reaction was detected by TLC plate. After the reaction was completed, ethyl acetate was added to quench the reaction, and the system was filtered with filter paper, concentrated under reduced pressure, and separated and purified by column chromatography, using a volume ratio of petroleum ether: ethyl acetate = 8:1 as the eluent, and 35.5 mg of product 3d was separated, with a yield of 85%.

[0082] like Figure 5 and Figure 6 The NMR data shown:

[0083] 1H NMR (500MHz, CDCl3, ppm): δ8.70-8.68(m,1H),7.82-7.78(m,1H),7.70-7.69(m,1H),7.44-7. 41(m,1H),7.13-7.10(m,2H),6.69-6.66(m,2H),3.77(s,3H,-OCH3),1.77(s,3H,Cage-CH3);

[0084] 13 C{ 1 H}NMR (125MHz, CDCl3, ppm): δ159.2,149.2,148.1,137.4,137.0,126.5,124.7,118.2,114.2,80.2,78.5,55.2,23.6; 11 B{ 1 H}NMR (160MHz, CDCl3, ppm): δ-1.3[1B,B(4)-Se],-2.7(2B),-8.7(2B),-10.4(3B),-11.4(2B); HRMS(ESI)m / z calcd forC 15 H 24 B 10 NOSe + (M+H) + 424.1948, found 424.1963.

[0085] Example 4

[0086] This embodiment provides a method for synthesizing B(4)-aryl selenium-C(1)-pyridine-C(2)-methyl-o-carborane 3i, and the synthetic chemical equation is:

[0087]

[0088] In an air atmosphere, C(1)-pyridine-C(2)-methyl-o-carborane 1a (23.5 mg, 0.1 mmol), The diaryl diselenide 2i (56.4 mg, 0.12 mmol), hexafluoroisopropanol (HFIP) (1 mL), dichloro(pentamethylcyclopentadienyl)rhodium dimer (1.5 mg, 2.5 mol%), and silver acetate (33.4 mg, 0.2 mmol) were reacted at room temperature for 24 h, and the reaction was detected by TLC plate. After the reaction, ethyl acetate was added to quench the reaction, and the system was filtered with filter paper, concentrated under reduced pressure, and separated and purified by column chromatography, using petroleum ether: ethyl acetate = 20:1 as the eluent, and 44.1 mg of product 3i was separated, with a yield of 94%.

[0089] like Figure 7 and Figure 8 The NMR data shown:

[0090] 1 H NMR (400MHz, CDCl3, ppm): δ8.68-8.66(m,1H),7.82-7.78(m,1H),7.69-7.67(m,1H) ),7.45-7.41(m,1H),7.27-7.23(m,2H),7.11-7.08(m,2H),1.77(s,3H,Cage-CH3);

[0091] 13 C{ 1 H}NMR (100MHz, CDCl3, ppm): δ149.3,148.0,137.9,137.1,131.7,126.7,126.4,124.8,122.1,80.4,78.5,23.6; 11 B{ 1 H}NMR (128MHz, CDCl3, ppm): δ-1.2[1B,B(4)-Se],-3.1(2B),-8.7(2B),-10.1(3B),-11.4(2B); HRMS(ESI)m / z calcd for C 14 H 21 B 10 NBrSe + (M+H) + 472.0947, found 472.0998.

[0092] Example 5

[0093] This embodiment provides a method for synthesizing B(4)-benzylselenium-C(1)-pyridine-C(2)-methyl-o-carborane 3s, and the synthetic chemical equation is:

[0094]

[0095] In an air atmosphere, C(1)-pyridine-C(2)-methyl-o-carborane 1a (23.5 mg, 0.1 mmol), Dibenzyl diselenide 2s (40.6 mg, 0.12 mmol), hexafluoroisopropanol (HFIP) (1 mL), dichloro(pentamethylcyclopentadienyl)rhodium dimer (1.5 mg, 2.5 mol%), silver acetate (33.4 mg, 0.2 mmol), reacted at room temperature for 24 h, and the reaction was detected by TLC plate. After the reaction was completed, ethyl acetate was added to quench the reaction, the system was filtered with filter paper, concentrated under reduced pressure, and separated and purified by column chromatography, using petroleum ether: ethyl acetate = 20:1 as the eluent, and 37.7 mg of product 3s was separated, with a yield of 93%.

[0096] like Fig. 9 and Fig.10 The NMR data shown:

[0097] 1 H NMR (400MHz, CDCl3, ppm): δ8.67-8.66(m,1H),7.79-7.72(m,2H),7.41-7.37( m,1H),7.21-7.13(m,5H),3.81-3.66(q,2H,J=12Hz),1.80(s,3H,Cage-CH3);

[0098] 13 C{ 1 H}NMR (100MHz, CDCl3, ppm): δ149.3,148.2,140.1,137.1,128.8,128.3,126.5,126.3,124.7,80.7,78.0,28.0,23.6; 11 B{ 1 H}NMR (128MHz, CDCl3, ppm): δ-1.4[1B,B(4)-Se],-3.1(2B),-8.6(2B),-9.4(1B),-10.5(3B),-11.2(1B); HRMS(ESI)m / z calcd forC 15 H 24 B 10 NSe + (M+H) + 408.1999,found 408.2002.

[0099] Example 6

[0100] This embodiment provides a method for synthesizing B(4)-phenylselenium-C(1)-pyridine-o-carborane 3t, and the synthetic chemical equation is:

[0101]

[0102] In an air atmosphere, add the following formula into a dry 10 mL round-bottom flask: C(1)-pyridine-o-carborane 1b (22.1 mg, 0.1 mmol), structural formula Diphenyl diselenide 2a (37.4 mg, 0.12 mmol), hexafluoroisopropanol (HFIP) (1 mL), dichloro(pentamethylcyclopentadienyl)rhodium dimer (1.5 mg, 2.5 mol%), silver acetate (33.4 mg, 0.2 mmol), reacted at room temperature for 24 h, and the reaction was detected by TLC plate. After the reaction, ethyl acetate was added to quench the reaction, the system was filtered with filter paper, concentrated under reduced pressure, and separated and purified by column chromatography, using petroleum ether: ethyl acetate = 20:1 as eluent, and 26.1 mg of product 3t was separated, with a yield of 67%.

[0103] like Fig.11 and Fig.12 The NMR data shown:

[0104] 1 H NMR (600MHz, CDCl3, ppm): δ8.46-8.45(m,1H),7.81-7.78(m,1H),7.67-7.65(d,1H,J=12Hz),7.40 -7.38(m,1H),7.29-7.27(m,2H),7.24-7.23(m,1H),7.16-7.13(dd,2H,J=12Hz),4.96(s,1H,Cage CH);

[0105] 13 C{ 1 H}NMR (150MHz, CDCl3, ppm): δ149.0,148.9,136.7,135.9,128.8,127.7,127.6,124.5,123.6,74.8,59.5; 11 B{ 1 H}NMR (160MHz, CDCl3, ppm): δ-1.6(1B),-2.3(1B),-4.0[1B,B(4)-Se],-6.8(1B),-10.2(3B),-12.3(1B),-14.5(2B); HRMS(ESI)m / z calcd forC 13 H 20 B10 NSe + (M+H) + 380.1686, found 380.1697.

[0106] Example 7

[0107] This embodiment provides a method for synthesizing B(4)-phenylthio-C(1)-pyridine-C(2)-methyl-o-carborane 5a, and the synthetic chemical equation is:

[0108]

[0109] In an air atmosphere, C(1)-pyridine-C(2)-methyl-o-carborane 1a (23.5 mg, 0.1 mmol), The mixture was reacted with diphenyl disulfide 4a (26.2 mg, 0.12 mmol), hexafluoroisopropanol (HFIP) (1 mL), dichloro(pentamethylcyclopentadienyl)rhodium dimer (1.5 mg, 2.5 mol%), and silver acetate (33.4 mg, 0.2 mmol) at room temperature for 24 h, and the reaction was monitored by TLC plate. After the reaction was completed, ethyl acetate was added to quench the reaction, and the system was filtered with filter paper, concentrated under reduced pressure, and separated and purified by column chromatography, using petroleum ether: ethyl acetate = 20:1 as the eluent, and 31.9 mg of product 5a was separated, with a yield of 93%.

[0110] like Fig.13 and Fig.14 The NMR data shown:

[0111] 1 H NMR (600MHz, CDCl3, ppm): δ8.70-8.69(m,1H),7.82-7.79(m,1H),7.72-7.71(d,1H,J=6Hz),7.45-7. 43(m,1H),7.21-7.19(m,1H),7.16-7.14(dd,2H,J=6Hz),7.10-7.08(m,2H),1.78(s,3H,Cage-CH3);

[0112] 13 C{ 1 H}NMR (150MHz, CDCl3, ppm): δ149.3,147.7,137.0,134.9,133.8,128.5,127.4,126.7,124.7,80.7,77.9,23.5; 11 B{ 1H}NMR (160MHz, CDCl3, ppm): δ1.0[1B,B(4)-S],-1.6(1B),-3.5(1B),-8.4(1B),-9.1(1B),-10.0(2B),-11.5(2B),-12.0(1B); HRMS(ESI)m / z calcd for C 14 H 22 B 10 NS + (M+H) + 346.2398, found 346.2399.

[0113] Example 8

[0114] This embodiment provides a method for synthesizing B(4)-arylthio-C(1)-pyridine-C(2)-methyl-o-carborane 5f, and the synthetic chemical equation is:

[0115]

[0116] In an air atmosphere, C(1)-pyridine-C(2)-methyl-o-carborane 1a (23.5 mg, 0.1 mmol), The diaryl disulfide 4f (37.0 mg, 0.12 mmol), hexafluoroisopropanol (HFIP) (1 mL), dichloro(pentamethylcyclopentadienyl)rhodium dimer (1.5 mg, 2.5 mol%), and silver acetate (33.4 mg, 0.2 mmol) were reacted at room temperature for 24 h, and the reaction was detected by TLC plate. After the reaction was completed, ethyl acetate was added to quench the reaction, and the system was filtered with filter paper, concentrated under reduced pressure, and separated and purified by column chromatography, using petroleum ether: ethyl acetate = 20:1 as the eluent, and 24.1 mg of product 5f was separated, with a yield of 62%.

[0117] like Fig.15 and Fig.16 The NMR data shown:

[0118] 1 H NMR (400MHz, CDCl3, ppm): δ8.68-8.66(m,1H),8.04-8.01(m,2H),7.85-7.81(m,1H) ),7.74-7.71(m,1H),7.48-7.45(m,1H),7.33-7.30(m,2H),1.78(s,3H,Cage-CH3);

[0119] 13 C{ 1H}NMR (100MHz, CDCl3, ppm): δ149.4,147.5,147.0,143.4,137.3,135.0,126.6,125.0,123.4,81.0,78.0,23.5; 11 B{ 1 H}NMR (128MHz, CDCl3, ppm): δ-0.1[1B,B(4)-S],-1.4(2B),-3.5(2B),-9.2(1B),-9.9(1B),-11.0(2B),-11.8(1B); HRMS(ESI)m / z calcdfor C 14 H 21 B 10 N2O2S + (M+H) + 391.2248, found 391.2259.

[0120] Example 9

[0121] This embodiment provides a method for synthesizing B(4)-thiophenesulfide-C(1)-pyridine-C(2)-methyl-o-carborane 5i, and the synthetic chemical equation is:

[0122]

[0123] In an air atmosphere, C(1)-pyridine-C(2)-methyl-o-carborane 1a (23.5 mg, 0.1 mmol), The dithiophene disulfide 4i (27.6 mg, 0.12 mmol), hexafluoroisopropanol (HFIP) (1 mL), dichloro(pentamethylcyclopentadienyl)rhodium dimer (1.5 mg, 2.5 mol%), and silver acetate (33.4 mg, 0.2 mmol) were reacted at room temperature for 24 h, and the reaction was detected by TLC plate. After the reaction was completed, ethyl acetate was added to quench the reaction, and the system was filtered with filter paper, concentrated under reduced pressure, and separated and purified by column chromatography, using a volume ratio of petroleum ether: ethyl acetate = 20:1 as an eluent, and 28 mg of product 5i was separated, with a yield of 80%.

[0124] like Fig.17 and Fig.18 The NMR data shown:

[0125] 1H NMR (400MHz, CDCl3, ppm): δ8.74-8.72(m,1H),7.87-7.83(m,1H),7.81-7.78(m,1H),7.47-7 .44(m,1H),7.19-7.17(m,1H),6.86-6.84(m,1H),6.70-6.69(m,1H),1.78(s,3H,Cage-CH3);

[0126] 13 C{ 1 H}NMR (100MHz, CDCl3, ppm): δ149.4,147.4,137.1,134.2,132.0,128.5,127.1,126.7,124.9,80.7,78.1,23.5; 11 B{ 1 H}NMR (128MHz, CDCl3, ppm): δ0.5[1B,B(4)-S],-1.5(1B),-3.3(1B),-8.9(2B),-10.0(2B),-11.4(2B),-11.9(1B); HRMS(ESI)m / zcalcd for C 12 H 20 B 10 NS2 + (M+H) + 352.1962, found 352.1976.

[0127] Example 10

[0128] This embodiment provides a method for synthesizing B(4)-phenyltellurium-C(1)-pyridine-C(2)-methyl-o-carborane 7a, and the synthetic chemical formula is:

[0129]

[0130] In an air atmosphere, C(1)-pyridine-C(2)-methyl-o-carborane 1a (23.5 mg, 0.1 mmol), Diphenyl ditelluride 6a (49.1 mg, 0.12 mmol), hexafluoroisopropanol (HFIP) (1 mL), dichloro(pentamethylcyclopentadienyl)rhodium dimer (1.5 mg, 2.5 mol%), and silver acetate (33.4 mg, 0.2 mmol) were reacted at room temperature for 24 h, and the reaction was monitored by TLC plate. After the reaction was completed, ethyl acetate was added to quench the reaction, and the system was filtered with filter paper, concentrated under reduced pressure, and separated and purified by column chromatography, using petroleum ether: ethyl acetate = 20:1 as the eluent, and 35.3 mg of product 7a was separated, with a yield of 81%.

[0131] like Fig.19 and Fig. 20 The NMR data shown:

[0132] 1 H NMR (600MHz, CDCl3, ppm): δ8.66-8.65 (m, 1H), 7.77-7.75 (dd, 1H, J = 6Hz), 7.64-7.63 (d, 1H, J = 6Hz), 7.52-7 .51(d,2H,J=6Hz),7.41-7.39(m,1H),7.28-7.25(m,1H),7.09-7.07(dd,2H,J=6Hz),1.77(s,3H,Cage-CH3);

[0133] 13 C{ 1 H}NMR (150MHz, CDCl3, ppm): δ149.3,148.9,140.7,137.1,128.7,127.7,126.1,124.7,108.7,80.3,79.1,23.8; 11 B{ 1 H}NMR (128MHz, CDCl3, ppm): δ-0.8(1B),-2.5(1B),-7.7(2B),-9.0(3B),-10.2(2B),-12.5[1B,B(4)-Te]; HRMS(ESI)m / z calcd forC 14 H 22 B 10 NTe + (M+H) + 444.1739, found 444.1745.

[0134] The number of devices and processing scales described here are used to simplify the description of the present invention. Applications, modifications and variations of the present invention will be obvious to those skilled in the art.

[0135] Although the embodiments of the present invention have been disclosed as above, they are not limited to the applications listed in the specification and the implementation modes, and they can be fully applied to various fields suitable for the present invention. For those familiar with the art, additional modifications can be easily implemented. Therefore, without departing from the general concept defined by the claims and the scope of equivalents, the present invention is not limited to the specific details and the illustrations shown and described herein.

Claims

1. A method for synthesizing a B(4)-arylsulfide-C(1)-pyridine-o-carborane derivative, characterized in that: include: by As a raw material, in the air atmosphere, under the conditions of a catalyst and an oxidant, in a solvent at a certain temperature, react with diaryl diselenide, diaryl disulfide or diphenyl ditelluride for a certain time, and use diaryl diselenide, diaryl disulfide or diphenyl ditelluride to selectively couple with B(4)-H to synthesize B(4)-arylsulfide-C(1)-pyridine-o-carborane derivatives; wherein R1 is one of hydrogen, methyl, isopropyl, n-butyl and phenyl; The structural formula of diaryl diselenide is: Among them, R2 is one of hydrogen, phenyl, substituted phenyl, and benzyl, and the substituent in the substituted phenyl is one of methyl, ethyl, methoxy, methylthio, trifluoromethoxy, acetyl, trifluoromethyl, halogen, cyano, and nitro.

2. The method for synthesizing the B(4)-arylsulfide-C(1)-pyridine-o-carborane derivative according to claim 1, characterized in that: The catalyst is dichloro (pentamethylcyclopentadienyl) rhodium dimer [Cp*RhCl2]2, and the amount of the catalyst used is 2% to 3% of the molar amount of C(1)-pyridine-C(2)-methyl-o-carborane.

3. The method for synthesizing the B(4)-arylsulfide-C(1)-pyridine-o-carborane derivative according to claim 1, characterized in that: The oxidant is silver acetate, and the amount of silver acetate used is twice the molar amount of C(1)-pyridine-C(2)-methyl-o-carborane.

4. The method for synthesizing the B(4)-arylsulfide-C(1)-pyridine-o-carborane derivative according to claim 1, characterized in that: The reaction temperature is 20-30° C., and the reaction time is 12-36 hours.

5. The method for synthesizing the B(4)-arylsulfide-C(1)-pyridine-o-carborane derivative according to claim 1, characterized in that: When R1 is methyl, The synthesis method of C(1)-pyridine-C(2)-methyl-o-carborane comprises: S1. Under an argon atmosphere, o-carborane and tetrahydrofuran are added to a reaction vessel in sequence, the reaction vessel is placed in an ice-water bath and stirred, and after the system temperature drops to 0°C, n-butyl lithium solution is slowly added using a syringe, and the system is stirred in an ice-water bath at 0°C for 1 hour; after 1 hour, 2-fluoropyridine is added to the reaction vessel, and the reaction vessel is transferred to an oil bath at 60-80°C for 1-3 hours, and after the reaction is completed, acetone is added to the system for quenching; the reaction is extracted with ethyl acetate, washed three times with saturated ammonium chloride and sodium chloride aqueous solution in sequence, the organic phase is collected, and dried with anhydrous sodium sulfate; after drying for 2 hours, the organic phase is concentrated under reduced pressure, and the product is separated and purified by column chromatography, and petroleum ether is used as an eluent to separate and obtain C(1)-pyridine-o-carborane; S2. Under an argon atmosphere, C(1)-pyridine-o-carborane and tetrahydrofuran are added to a reaction vessel in sequence, the reaction vessel is placed in an ice-water bath and stirring is started, after the system temperature drops to 0°C, n-butyl lithium solution is slowly added using a syringe, and the system is stirred in an ice-water bath at 0°C for reaction for 1 hour; after 1 hour, iodomethane is added to the reaction vessel, and the reaction flask is transferred to an oil bath at 60-80°C for reaction for 2 hours, after the reaction is completed, acetone is added to the system for quenching; the reaction is extracted with ethyl acetate, washed three times with saturated ammonium chloride and sodium chloride aqueous solution in sequence, the organic phase is collected, and dried with anhydrous sodium sulfate; after drying for 2 hours, the organic phase is concentrated under reduced pressure, and the product is separated and purified by column chromatography, and petroleum ether and ethyl acetate are used as eluents in a volume ratio of 20-100:1 to separate and obtain C(1)-pyridine-C(2)-methyl-o-carborane.

6. The method for synthesizing the B(4)-arylsulfide-C(1)-pyridine-o-carborane derivative according to claim 5, characterized in that: In the S1, the concentration of the n-butyl lithium solution is 1.6 M, and the usage ratio of o-carborane, tetrahydrofuran, n-butyl lithium and 2-fluoropyridine is 10 mmol:100 mL:30-35 mmol:12 mmol.

7. The method for synthesizing the B(4)-arylsulfide-C(1)-pyridine-o-carborane derivative according to claim 5, characterized in that: In S2, the concentration of the n-butyl lithium solution is 1.6 M, and the usage ratio of C(1)-pyridine-o-carborane, tetrahydrofuran, n-butyl lithium and iodomethane is 5 mmol:50 mL:15-20 mmol:6 mol.

8. Use of a B(4)-arylsulfide-C(1)-pyridine-o-carborane derivative, wherein the B(4)-arylsulfide-C(1)-pyridine-o-carborane derivative is synthesized by the method for synthesizing a B(4)-arylsulfide-C(1)-pyridine-o-carborane derivative according to any one of claims 1 to 7, characterized in that: The B(4)-arylsulfide-C(1)-pyridine-o-carborane derivative is applied to boron compound targeted delivery drugs, contrast agents for tumor imaging diagnosis, and boron carrier drugs for boron neutron capture therapy.

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