Carborane derivative as well as preparation method and application thereof

Abstract

The invention belongs to the field of organic synthesis, and particularly relates to a carborane derivative as well as a preparation method and application thereof, and the carborane derivative is a compound with a carborane pyrrolidine structure or pharmaceutically acceptable salt thereof. The carborane derivative disclosed by the invention can be used as a boron neutron capture therapy drug, and the boron content in tumor cells can be improved. The carborane derivative disclosed by the invention has better catalytic performance when being applied to the field of catalysis.

Description

Technical Field

[0001] The invention belongs to the field of organic synthesis, and specifically relates to a carborane derivative and a preparation method and application thereof. Background Art

[0002] Carborane is a cage-like molecular cluster composed of three elements: carbon, boron, and hydrogen. The unique structure and bonding mode of carborane give it good thermal and chemical stability, and also unique stereoaromaticity (Russ.Chem.Bull.,1993,42(8),1283). It has great application prospects in the fields of catalysts (Chem.Eur.J.,2015,21,1184), luminescent materials, drugs, and supramolecular structures (Synthesis,2020,52,337). The boron content of L-4-dihydroxyphenylalanine (BPA), the second-generation boron drug for boron neutron capture therapy (BNCT), is only 5%. Carborane has a higher boron content and is an important boron source for the design of the third-generation boron drug for boron neutron capture therapy.

[0003] Pyrrolidine is a class of five-membered non-aromatic nitrogen heterocycles widely found in natural products and drug molecules, and its derivatives are widely used in drug design and catalysis. For example, N-substituted pyrrolidine Procyclidine can treat epilepsy (Formula V), and 3-substituted pyrrolidine Rolipram can treat depression (Formula VI). 2-substituted pyrrolidines are more widely used. 2-pyrrolidine ethers, amides, and tetrazole derivatives (Formula VII) can be used as catalysts for Michael addition reactions; 2-alkylpyrrolidine (R)-bgugaine (Formula VIII) can be antifungal; in addition, 2-pyrrolidine carboxylic acid-proline (Formula IX) is an important amino acid in organisms. In view of the special structure and wide application of 2-substituted pyrrolidines and carboranes, introducing a carborane group with a high boron content into the 2-position of pyrrolidine is expected to improve its biological activity and catalytic effect.

[0004]

[0005] Such compounds have not been reported, so the development of new 2-substituted pyrrolidine carborane derivatives is of great significance for expanding the types of drugs and catalysts. Summary of the invention

[0006] The purpose of the present invention is to provide a carborane derivative to solve the problem of low boron concentration in tumor cells of the existing BNCT drug BPA and to improve the catalytic efficiency of pyrrolidine derivative catalysts.

[0007] To achieve the above object, the technical solution of the present invention is:

[0008] A carborane derivative, wherein the carborane derivative is a compound represented by formula I or a pharmaceutically acceptable salt thereof:

[0009]

[0010] Among them, R 1 Selected from Any one of the following. 2 is a C1-C4 alkyl group, R 3 It is a C1-C3 alkyl group optionally substituted with a benzene ring.

[0011] As a further improvement, the carborane derivative includes any one of the following compounds:

[0012]

[0013] The Boc group is tert-butyloxycarbonyl.

[0014] A carborane derivative, characterized in that the carborane derivative is any one of A, B, C, and D

[0015] Among them, A, B, C or D represents the relative configuration.

[0016] A nested carborane derivative, wherein the nested carborane is a compound represented by formula IV,

[0017]

[0018] Wherein, M is sodium, potassium, cesium or hydrogen, R 6 It is either Boc or hydrogen.

[0019] A nested carborane derivative, characterized in that the nested carborane derivative is any one of E or F;

[0020]

[0021] Among them, E or F represents the relative configuration, and M is sodium, potassium, cesium or hydrogen.

[0022] The carborane derivative of the invention can be used as a medicine for boron neutron capture therapy.

[0023] At the same time, when the carborane derivative of the present invention is applied in the catalytic field, it has good catalytic performance and provides a highly efficient catalyst, which is particularly suitable for the asymmetric addition reaction of acetone and 3,3-dimethylbutyraldehyde.

[0024] It should be noted that the carborane of the present invention is a cage-like molecule composed of two carbon hydrogens and ten boron hydrogen vertices.

[0025] The technical solution of the present invention is:

[0026] A method for preparing a carborane derivative A or B, characterized in that the preparation method comprises the following steps:

[0027] 1) reacting o-carborane with a base in a first solvent at 0±5°C for 0.5-2h, then adding a compound of formula II and reacting at -20°C to 5°C for 4-6h to obtain a carborane derivative of formula I;

[0028]

[0029] Where R 4 It is a C1-C3 alkyl group.

[0030] 2) The compound represented by formula I reacts with a catalyst in a second solvent at 0-30° C. for 0.5-2 h to obtain a compound A or B having a structure of formula III.

[0031]

[0032] The preparation method of the present invention uses o-carborane and a proline derivative as raw materials to prepare carborane pyrrolidone, and then catalyzes the preparation to obtain a catalyst-carborane pyrrolidone derivative that can be used in BNCT and the catalytic field. The method of the present invention is simple to operate, the raw materials are easily available, and stereoisomers with specific configurations can be obtained respectively.

[0033] As a further improvement, the base is butyl lithium, R 5 -MgX, more preferably the R 5 is one of methyl and isopropyl; X=Br or Cl, thus, the proline derivative can fully react with o-carborane.

[0034] Preferably, the first solvent is one of tetrahydrofuran, diethyl ether and ethylene glycol dimethyl ether. Thus, the raw materials of the reaction have higher solubility in the above substances, and the above substances are selected as the reaction solvent, which is conducive to sufficient reaction between the raw materials, and then is conducive to improving the yield and purity of the product.

[0035] As a further improvement, the mass ratio of the added o-carborane to the first solvent is 1:(10-65).

[0036] Preferably, the reaction temperature after adding the compound of formula II in step 1) is -20°C to 5°C, and the reaction time is 4-6 hours, thereby maintaining the activity of the catalyst and promoting the reaction well.

[0037] As a further improvement, the molar ratio of the o-carborane to the compound of formula II and the base is 1:(1.0-2.0):(1.0-1.5), which is conducive to sufficient reaction of the raw materials and further improves the yield and purity of the product.

[0038] Preferably, the catalyst is one of sodium borohydride, lithium aluminum tetrahydride, borane tetrahydrofuran complex, lithium tri-tert-butoxyaluminum hydride, sodium bis(2-methoxyethoxy)aluminum hydride, and lithium tri-sec-butylborohydride. Thus, the compound of formula II can be preferably converted into a compound of configuration A.

[0039] Preferably, when the catalyst is diisobutylaluminum hydride (DIBAL-H), a compound having the configuration of compound B is obtained.

[0040] In order to obtain a higher yield, preferably, the molar ratio of the compound of formula I to the catalyst is 1:(1-3).

[0041] As a further improvement, the second solvent is one of methanol, ethanol, tetrahydrofuran and n-hexane, and the mass ratio of the compound of formula I to the second solvent is 1:(15-70).

[0042] Preferably, the reaction temperature of step 2) is 0-30° C. and the reaction time is 0.5-2 h, thereby maintaining the activity of the catalyst and promoting the reaction.

[0043] The carborane derivatives can be used as boron medicines in boron neutron capture therapy and as catalysts. BRIEF DESCRIPTION OF THE DRAWINGS

[0044] Figure 1 is the H NMR spectrum of compound A in Example 1;

[0045] Figure 2 is the NMR boron spectrum of compound A in Example 1;

[0046] Figure 3 is the H NMR spectrum of compound B in Example 7;

[0047] Figure 4 is the NMR boron spectrum of compound B in Example 7;

[0048] Figure 5 This is the single crystal diffraction pattern of compound F in Example 19. DETAILED DESCRIPTION

[0049] The present invention provides a carborane derivative, wherein the carborane derivative is a compound represented by formula I or a pharmaceutically acceptable salt thereof;

[0050]

[0051] Among them, R 1 Selected from Any one of .

[0052] Preferably, the R 2 is a C1-C4 alkyl group, R 3 It is a C1-C3 alkyl group.

[0053] A carborane derivative, characterized in that the carborane derivative is any one of A, B, C, and D

[0054] Wherein, A, B, C or D represents the relative configuration, and Boc is tert-butyloxycarbonyl.

[0055] The present invention provides a nested carborane derivative, wherein the nested carborane is a compound shown in Formula IV,

[0056]

[0057] Wherein, M is sodium, potassium, cesium or hydrogen, R 5 It is either Boc or hydrogen.

[0058] A nested carborane derivative, characterized in that the nested carborane derivative is any one of E or F;

[0059]

[0060] Among them, E or F represents the relative configuration, and M is sodium, potassium, cesium or hydrogen.

[0061] A method for preparing a carborane derivative A or B, characterized in that the preparation method comprises:

[0062] 1) reacting o-carborane, a compound of formula II and a base in a first solvent to obtain a carborane derivative of formula I;

[0063]

[0064] Where R 5 It is a C1-C3 alkyl group.

[0065] 2) The compound represented by formula I reacts with a catalyst in a second solvent to obtain a compound A or B having a structure of formula III.

[0066]

[0067] The preparation method of the invention uses o-carborane and a proline derivative as raw materials to prepare carborane pyrrolidone, and then catalyzes the preparation to obtain a catalyst-carborane pyrrolidone derivative that can be used in BNCT and the catalytic field. The method of the invention is simple to operate, the raw materials are easily available, and carborane pyrrolidines with specific configurations can be obtained respectively.

[0068] The present invention is further described below in conjunction with specific embodiments, but the protection scope of the present invention is not limited thereto.

[0069] Unless otherwise specified, the reagents used in the following examples are all commercially available products.

[0070] 1. Examples of carborane derivatives and preparation methods thereof

[0071] Example 1 The carborane derivative of this example is compound A.

[0072]

[0073] The preparation method of compound A comprises the following steps:

[0074] Under nitrogen protection, o-carborane (1.44 g, 10 mmol) and n-butyl lithium (2.5 M, 4 ml, 10 mmol) were added to 28.8 g of tetrahydrofuran, and the mixture was stirred at 0°C for 1 h. 1-(tert-butyl) 2-methylpyrrolidine-1,2-dicarboxylate (2.29 g, 10 mmol) was added, and the mixture was stirred and reacted at -10°C for 5 h. The aqueous phase was separated, and the organic layer was distilled under reduced pressure. After column chromatography (petroleum ether / ethyl acetate = 20 / 1, v / v), compound I (3.15 g, 9.23 mmol) was obtained. The obtained compound I was dissolved in 78.8 g of methanol, and NaBH4 (0.698 g, 18.4 mmol) was added. The mixture was stirred at 10°C for 0.5 h, and the mixture was extracted with ethyl acetate. The solvent was removed by distillation under reduced pressure. After column chromatography (petroleum ether / ethyl acetate = 10 / 1, v / v), compound A (3.05 g) was obtained, with a total yield of 88.8%.

[0075] The H NMR spectrum of the product prepared in Example 1 is as follows Figure 1 As shown, 1 H NMR (300MHz, CDCl3): δ = 6.07 (d, J = 6.4Hz, 1H), 4.42 (s, 1H), 4.05 (m, 1H), 3.77 (dd, J = 10.1, 8.0Hz, 1H), 3.4-3.3 (m, 2H), 2.0-1.9 (m, 4H), 1.46 (s, 9H).

[0076] The NMR boron spectrum of the product prepared in Example 1 is as follows Figure 2 As shown, 11B NMR(128MHz, CDCl3)δ-3.87(2B),-8.19(1B),-9.25(1B),-12.62(4B),-14.29(2B).

[0077] It can be seen from the data of hydrogen NMR spectrum and boron NMR spectrum of Example 1 that compound A was successfully prepared in Example 1.

[0078] Example 2 The carborane derivative of this example is compound A,

[0079] The structural formula is:

[0080] The preparation method of compound A comprises the following steps:

[0081] Under nitrogen protection, o-borane (1.44 g, 10 mmol) and isopropylmagnesium chloride (1.44 g, 14 mmol) were added to 50.4 g of diethyl ether, and the mixture was stirred at 0°C for 2 h. 1-(tert-butyl) 2-methylpyrrolidine-1,2-dicarboxylate (3.44 g, 15 mmol) was added, and the mixture was stirred at 0°C for 4 h. The aqueous phase was separated, and the organic layer was distilled under reduced pressure. After column chromatography (petroleum ether / ethyl acetate = 20 / 1, v / v), compound I (3.12 g, 9.15 mmol) was obtained. The obtained compound I was dissolved in 109.3 g of tetrahydrofuran, and borane tetrahydrofuran complex (1.18 g, 13.7 mmol) was added. The mixture was stirred at 15°C for 1 h, and the mixture was extracted with ethyl acetate. The solvent was removed by distillation under reduced pressure. After column chromatography (petroleum ether / ethyl acetate = 10 / 1, v / v), compound A (3.025 g) was obtained, with a total yield of 87.6%.

[0082] Example 3 The carborane derivative of this example is compound A,

[0083] The structural formula is:

[0084] The preparation method of compound A comprises the following steps:

[0085] Under nitrogen protection, o-carborane (1.44 g, 10 mmol) and n-butyl lithium (6 ml, 15 mmol) were added to 93.7 g of ethylene glycol dimethyl ether, and the mixture was stirred at 0°C for 1.5 h. 1-(tert-butyl) 2-methylpyrrolidine-1,2-dicarboxylate (4.58 g, 20 mmol) was added, and the mixture was stirred at 0°C for 6 h. The aqueous phase was separated, and the organic layer was distilled under reduced pressure. After column chromatography (petroleum ether / ethyl acetate = 20 / 1, v / v), compound I (3.09 g, 9.05 mmol) was obtained. The obtained compound I was dissolved in 139.0 g of n-hexane, and lithium tri-tert-butoxyaluminum hydride (2.3 g, 9.05 mmol) was added. The mixture was stirred at 5°C for 2 h, and the mixture was extracted with ethyl acetate. The solvent was removed by distillation under reduced pressure. After column chromatography (petroleum ether / ethyl acetate = 10 / 1, v / v), compound A (2.95 g) was obtained, with a total yield of 85%.

[0086] Example 4 The carborane derivative of this example is compound A,

[0087] The structural formula is:

[0088] The preparation method of compound A comprises the following steps:

[0089] Under nitrogen protection, o-carborane (1.44 g, 10 mmol) and n-butyl lithium (4.8 ml, 12 mmol) were added to 79.3 g of tetrahydrofuran, and the mixture was stirred at 5°C for 0.5 h. 1-(tert-butyl) 2-methylpyrrolidine-1,2-dicarboxylate (4.13 g, 18 mmol) was added, and the mixture was stirred at -10°C for 4.5 h. The aqueous phase was separated, and the organic layer was distilled under reduced pressure. The mixture was purified by column chromatography (petroleum ether / ethyl acetate = 20 / 1, v / v) v) to obtain compound I (3.18 g, 9.31 mmol); the obtained compound I was dissolved in 174.8 g of methanol, sodium bis(2-methoxyethoxy)aluminum hydride (4.14 g, 20.5 mmol) was added, stirred at 20° C., reacted for 1.5 h, extracted with ethyl acetate, and the solvent was removed by distillation under reduced pressure. After column chromatography (petroleum ether / ethyl acetate=10 / 1, v / v), compound A (2.91 g) was obtained, with a total yield of 83.8%.

[0090] Example 5 The carborane derivative of this example is compound A,

[0091] The structural formula is:

[0092] The preparation method of compound A comprises the following steps:

[0093] Under nitrogen protection, o-carborane (1.44 g, 10 mmol) and n-butyl lithium (4.8 ml, 12 mmol) were added to 64.9 g of tetrahydrofuran, and the mixture was stirred at 3°C ​​for 1 h. 1-(tert-butyl) 2-methylpyrrolidine-1,2-dicarboxylate (2.29 g, 10 mmol) was added, and the mixture was stirred at 5°C for 4.5 h. The aqueous phase was separated, and the organic layer was distilled under reduced pressure. After column chromatography (petroleum ether / ethyl acetate = 20 / 1, v / v), compound I (3.07 g, 8.99 mmol) was obtained. The obtained compound I was dissolved in 214.9 g of methanol, and lithium tri-sec-butylborohydride (5.12 g, 26.9 mmol) was added. The mixture was stirred at 25°C for 1.5 h, and the mixture was extracted with ethyl acetate. The solvent was removed by distillation under reduced pressure. After column chromatography (petroleum ether / ethyl acetate = 10 / 1, v / v), compound A (2.86 g) was obtained, with a total yield of 82.1%.

[0094] Example 6 The carborane derivative of this example is compound A,

[0095] The structural formula is:

[0096] The preparation method of compound A comprises the following steps:

[0097] Under nitrogen protection, o-carborane (1.44 g, 10 mmol) and methylmagnesium bromide (1.43 g, 12 mmol) were added to 14.4 g of diethyl ether, and the mixture was stirred at 0°C for 2 h. 1-(tert-butyl) 2-ethylpyrrolidine-1,2-dicarboxylate (2.92 g, 12 mmol) was added, and the mixture was stirred at -20°C for 4.5 h. The aqueous phase was separated, and the organic layer was distilled under reduced pressure. After column chromatography (petroleum ether / ethyl acetate = 20 / 1, v / v), compound I (3.06 g, 8.96 mmol) was obtained. The obtained compound I was dissolved in 45.9 g of ethanol, and lithium aluminum tetrahydride (0.408 g, 10.7 mmol) was added. The mixture was stirred at 0°C for 1.5 h, and the mixture was extracted with ethyl acetate. The solvent was removed by distillation under reduced pressure. After column chromatography (petroleum ether / ethyl acetate = 10 / 1, v / v), compound A (2.92 g) was obtained, with a total yield of 84.6%.

[0098] By using this embodiment, the compound R of formula II can be 4 When the group is ethyl or propyl, compound III is prepared. Based on the similarity of the properties of C1-C3 alkyl groups, the specific preparation effect and application effect should be equivalent to those in this embodiment.

[0099] Example 7 The carborane derivative of this example is compound B,

[0100] The structural formula is:

[0101]

[0102] The preparation method of compound B comprises the following steps:

[0103] Under nitrogen protection, o-carborane (1.44 g, 10 mmol) and n-butyl lithium (4.4 ml, 11 mmol) were added to 72.11 g of diethyl ether, and stirred at 0°C for 1 h. 1-(tert-butyl) 2-methylpyrrolidine-1,2-dicarboxylate (2.75 g, 12 mmol) was added, and the mixture was stirred at -20°C for 4.5 h. The aqueous phase was separated, and the organic layer was distilled under reduced pressure. The mixture was purified by column chromatography (petroleum ether / ethyl acetate = 20 / 1, v / v) , compound I (3.12 g, 9.13 mmol) was obtained; the obtained compound I was dissolved in 46.7 g of n-hexane, diisobutylaluminum hydride DIBAL-H (18.26 ml, 18.2 mmol) was added, stirred at 30°C, reacted for 1.5 h, extracted with ethyl acetate, and the solvent was removed by distillation under reduced pressure. After column chromatography (dichloromethane / methanol = 20 / 1, v / v), compound B (3.02 g) was obtained, with a total yield of 87.8%.

[0104] The H NMR spectrum of the product prepared in Example 7 is as follows Figure 3 As shown, 1 H NMR (300MHz, CDCl3): δ = 4.55 (s, 1H), 4.05 (s, 2H), 3.37 (d, J = 37.3Hz, 2H), 2.13 (s, 1H), 2.03-1.86 (m, 3H), 1.79 (dd, J = 12.1, 6.3Hz, 1H), 1.48 (s, 9H).

[0105] The NMR boron spectrum of the product prepared in Example 7 is as follows Figure 4 As shown, 11 B{ 1 H}NMR(128MHz, CDCl3)δ-3.00(1B),-3.97(1B),-8.93(2B),-12.10(3B),-14.02(3B).

[0106] Example 8 The carborane derivative of this example has the structural formula:

[0107]

[0108] Under nitrogen protection, o-carborane (1.44 g, 10 mmol) and n-butyl lithium (2.5 M, 5 ml, 12.5 mmol) were added to 100 ml of tetrahydrofuran, stirred at 0°C for 1 h, 2-methylpyrrolidine-1,2-dicarboxylic acid 1-ethyl ester (2.01 g, 10 mmol) was added, and stirred at -10°C for 5 h. The aqueous phase was separated, and the organic layer was distilled under reduced pressure. After column chromatography (petroleum ether / ethyl acetate = 20 / 1, v / v), 2.9 g of the target compound was obtained.

[0109] Characterization data of the product prepared in Example 8:

[0110] 1 H NMR (300MHz, CDCl3): δ = 4.9-4.74 (m, 1H), 4.19 (d, J = 6.9Hz, 1H), 4.16-3.97 (m, 2 H),3.67-3.36(m,2H),2.44-2.27(m,2H),2.04-1.78(m,2H),1.33-1.11(m,3H).

[0111] 11 B{ 1 H}NMR(128MHz, CDCl3)δ-2.43(2B),-8.44(2B),-13.14(6B).

[0112] Example 9 The carborane derivative of this example has the structural formula:

[0113]

[0114] The synthesis method was carried out according to Example 8, wherein the raw material 2-methylpyrrolidine-1,2-dicarboxylic acid 1-ethyl ester was replaced with 1-benzyl-2-methylpyrrolidine-1,2-dicarboxylate.

[0115] Characterization data of the product prepared in Example 9

[0116] 1 H NMR (300MHz, CDCl3): δ=7.47-7.29(m,5H),5.23-5.01(m,2H),4.89(ddd,J=12.4,9.1,4. 1Hz,1H),4.17(d,J=61.1Hz,1H),3.69-3.46(m,2H),2.44-2.27(m,2H),2.02-1.81(m,2H)

[0117] 11 B{ 1 H}NMR(128MHz,CDCl3)δ-2.43(2B),-8.55(2B),-13.19(6B)

[0118] Example 10 The carborane derivative of this example has the structural formula:

[0119]

[0120] The synthesis method was carried out according to Example 8, wherein the raw material 2-methylpyrrolidine-1,2-dicarboxylic acid 1-ethyl ester was replaced with 1-(4-methylphenyl)sulfonyloxypyrrolidine-2-carboxylic acid methyl ester.

[0121] Characterization data of the product prepared in Example 10

[0122] 1 H NMR (300MHz, CDCl3): δ=7.47-7.29(m,5H),5.23-5.01(m,2H),4.89(ddd,J=12.4,9.1,4. 1Hz,1H),4.17(d,J=61.1Hz,1H),3.69-3.46(m,2H),2.44-2.27(m,2H),2.02-1.81(m,2H)

[0123] Example 11 The carborane derivative of this example has the structural formula:

[0124]

[0125] The synthesis method was carried out according to Example 8, wherein the raw material 2-methylpyrrolidine-1,2-dicarboxylic acid 1-ethyl ester was replaced with 1-benzylpyrrolidine-2-carboxylic acid methyl ester.

[0126] Characterization data of the product prepared in Example 11

[0127] 1 H NMR (300MHz, CDCl3): δ=7.38-7.19(m,5H),4.15(s,1H),3.91(dd,J=9.7,4.7Hz,1H),3.73-3.59(m,2H),3.13(dt,J= 8.7,5.2Hz,1H),2.59(dd,J=16.2,8.1Hz,1H),2.27(ddd,J=12.1,9.4,5.5Hz,1H),1.85(ddd,J=16.4,8.3,5.2Hz,3H)

[0128] 11 B{ 1 H}NMR(128MHz, CDCl3)δ-2.36(1B),-3.13(2B),-9.17(2B),-12.57(2B),-13.62(2B),-14.75(1B)

[0129] Example 12 The carborane derivative of this example is compound C, and its structural formula is:

[0130]

[0131] 0.5 mmol of compound A obtained in Example 1 was added to a mixed solution of ethyl acetate and 3 mol / L hydrochloric acid (1:1, v / v), and stirred at room temperature for 10 h. 10 mL of water was added to the reaction, the aqueous layer was washed with ethyl acetate, basified with 4 M NaOH aqueous solution (10 mL), and extracted with ethyl acetate (4×10 mL). The combined organic layers were dried over MgSO4, filtered, and the solvent was concentrated under reduced pressure to obtain compound C.

[0132] Characterization data of the product prepared in Example 12:

[0133] 1 H NMR (300MHz, CDCl3): δ = 4.11 (s, 1H), 3.84 (d, J = 3.2Hz, 1H), 3.63-3.35 (m, 2H), 3.15-2. 88(m,2H),2.06(td,J=13.2,7.4Hz,2H),1.79(dt,J=19.4,6.2Hz,2H),1.69-1.58(m,1H)

[0134] 11 B NMR(128MHz, CDCl3)δ-3.19(1B),-4.28(1B),δ-8.62(1B),-9.82(1B),δ-1.73(1B),-12.69(5B)

[0135] Example 13 The carborane derivative of this example is compound D, and its structural formula is:

[0136]

[0137] Take compound B obtained in Example 7 and synthesize it according to Example 12.

[0138] Characterization data of the product prepared in Example 13:

[0139] 1 H NMR (300MHz, MeOD-d4): δ = 4.62 (s, 1H), 4.58 (s, 1H), 3.92-3.86 (m, 1H), 3.34-2.32 (m, 2H), 2.20-2.02 (m, 6H);

[0140] 11B NMR(128MHz, CDCl3)δ-2.99(2B),-9.04(2B),-12.40(6B)

[0141] Example 14 The nested carborane derivative of this example has the structural formula:

[0142]

[0143] Under nitrogen protection, o-carborane (1.44 g, 10 mmol) and n-butyl lithium (4.4 ml, 11 mmol) were added to 72.11 g of tetrahydrofuran, stirred at 0°C for 1 h, 1-(tert-butyl) 2-methylpyrrolidine-1,2-dicarboxylate (2.92 g, 12 mmol) was added, and stirred at -20°C for 5 h. The aqueous phase was separated, and the organic layer was distilled under reduced pressure. After column chromatography (petroleum ether / ethyl acetate = 20 / 1, v / v), compound I (3.2 g, 9.3 mmol) was obtained. The obtained compound I was dissolved in ethanol, CsF (2.82 g, 18.6 mmol) was added, and stirred at 80°C for 18 h. After the reaction was completed, the mixture was distilled under reduced pressure, washed with acetone, and dried to obtain 3.1 g of the product.

[0144] Characterization data of the product prepared in Example 14:

[0145] 1 H NMR (300MHz, Methanol-d4) δ4.78-4.69(m,1H),3.55-3.44(m,1H),3.37(s,1H),2.51(d,J=16.4Hz,1H),2.41 -2.09(m,3H),1.85-1.71(m,3H),1.45(d,J=6.3Hz,9H),-2.65(s,1H)

[0146] 11 B{ 1 H}NMR(128MHz, CDCl3)δ-8.2(1B),-10.3(1B),-13.1(1B),-17.2(1B),-18.9(1B),-21.2(1B),-24.1(1B),-32.6(1B),-34.7(1B)

[0147] Example 15 The nested carborane derivative of this example has the structural formula:

[0148]

[0149] 0.5 mmol of the compound obtained in Example 14 was dissolved in 5 ml of methanol, and 0.8 ml of concentrated hydrochloric acid was added. The mixture was stirred at room temperature for 3 h, and the mixture was evaporated under reduced pressure and subjected to column chromatography to obtain the compound.

[0150] Characterization data of the product prepared in Example 15:

[0151] 1 H NMR (300MHz, Methanol-d4)δ=4.65-4.51(m,1H),3.57-3.15(m,2H),2.77-2.36(m,3H),2.10-2.91(m,3H),1.31(s,1H),-2.48(s,1H)

[0152] 11 B{ 1 H}NMR(128MHz, CDCl3)δ-8.1(1B),-9.8(1B),-12.4(1B),-14.4(1B),-16.5(1B),-21.0(1B),-22.7(1B),-32.3(1B),-34.6(1B)

[0153] Example 16 The nested carborane derivative of this example is compound E (M = Cs), and the structural formula is:

[0154]

[0155] 1.2 mmol of the compound C prepared in Example 12 was added to 12 ml of ethanol, and 2.4 mmol of CsF was added. The mixture was heated under reflux for 20 h and distilled under reduced pressure. The obtained compound was washed with acetone to obtain the cesium salt of compound E.

[0156] Characterization data of the product prepared in Example 16:

[0157] 1 H NMR(300MHz,Methanol-d4)δ3.6-3.4(m,2H),3.33(m,1H),3.29-3.11(m,2H),2.22-1.94(m,4H),1.91(s,1H),1.81-1.63(m,2H)

[0158] 11 B{ 1 H}NMR(128MHz, CDCl3)δ-11.4(2B),-14.2(2B),-19.6(1B),-20.9(1B),-22.2(1B),-33.0(1B),-37.1(1B)

[0159] Example 17 The nested carborane derivative of this example is compound E (M = H), and the structural formula is:

[0160]

[0161] To 0.5 mmol of compound E (M=Cs) prepared according to Example 16, 5 ml of methanol and 0.25 ml of 1 M HCl were added, and the mixture was stirred at room temperature for 30 min. The mixture was filtered, washed, and purified by column chromatography (petroleum ether / ethyl acetate=1 / 1, v / v) to obtain compound E.

[0162] Characterization data of the product prepared in Example 17:

[0163] 1 H NMR (300MHz, Acetone-d6) δ4.80 (s, 1H), 4.23 (t, J = 8.8Hz, 2H), 3.78-3.53 (m ,1H),3.40-3.71(m,1H),2.42-2.15(m,6H),1.83-1.71(m,4H),-2.93(s,1H).

[0164] 11 B{ 1 H}NMR(128MHz, CDCl3)δ-11.7(2B),-14.2(2B),-19.5,-20.9,-22.3,-32.9,-37.2.

[0165] Example 18 The nested carborane derivative of this example is compound F (M = Cs), and the structural formula is:

[0166]

[0167] Using compound D obtained in Example 13 as raw material, the synthesis method was carried out by referring to Example 16.

[0168] Characterization data of the product prepared in Example 18:

[0169] 1 H NMR (300MHz, Methanol-d4) δ = 3.76 (s, 1H), 3.67-3.58 (m, 1H), 3.27-3.23 (m, 2H), 2.36-1.94 (m, 5H)

[0170] 11 B{ 1 H}NMR(128MHz, CDCl3)δ-12.2(2B),-13.6,-15.4,-16.9,-18.8,-21.6,-33.4,-37.5

[0171] Example 19 The nested carborane derivative of this example is compound F (M=H), and the structural formula is:

[0172]

[0173] The product obtained in Example 18 was used as raw material and the synthesis method was carried out by referring to Example 17.

[0174] Characterization data of the product prepared in Example 19:

[0175] 1 H NMR (300MHz, Methanol-d4) δ3.97-3.73(m,1H),3.66-3.64(m,1H),3.33(s,1H),3.25(t,J=7.1Hz,2H),2.25-1.95(m,3H),1.41-1.27(m,2H)

[0176] 11 B{ 1 H}NMR(128MHz, CDCl3)δ-11.0,-12.1,-15.8,-17.7,-18.9,-20.9,-32.4,-33.0,-37.0 Figure 5 This is the X-ray single crystal diffraction pattern of compound F.

[0177] 2. Application of carborane derivatives in the preparation of boron neutron capture therapy drugs

[0178] 4-boron-L-phenylalanine (BPA, trade name Steboronine) was used as the compound of Comparative Example 1. As the comparative example 2 compound.

[0179] The carborane derivatives prepared in Examples 1-19, the compound in Comparative Example 1 and the compound in Comparative Example 2 were subjected to a cellular boron uptake test.

[0180] U87MG cells (glioblastoma cells) were plated on a Petri dish at a cell density of 75%, and incubated with the compounds prepared in Examples 1-19, the compound in Comparative Example 1, and the compound in Comparative Example 2 dissolved in DMEM (Dulbecco's Modified Eagle Medium) at 37°C for 6 hours. The boron-containing compounds (i.e., the compounds in Examples 1-19 and Comparative Examples 1 and 2) added to the tissue culture medium were all in an amount relative to the boron content (5×10 -4 mol / L boron) was added in an equimolar concentration.

[0181] The culture medium was removed by suction, and the excess culture medium on the cells was washed off by adding a cold phosphate buffer solution (pH=7.4 PBS buffer) at 2-10°C, and a 2 mg / mL pronase solution (source leaf, BR, 7000u / g) was added. After incubation at 4°C for 4 hours, the pronase solution was discarded, and then washed with a pH=7.4 PBS buffer, and the cells were lysed with RIPA lysis buffer (RadioImmunoprecipitation Assay Lysis buffer, McLean, sterile), and the cell lysate was collected. The supernatant was collected by centrifugation at 10000rpm. The supernatant was analyzed for boron by inductively coupled plasma atomic emission spectrometry (ICP-AES). The test results of boron uptake of different boron compounds are shown in Table 1 below.

[0182] Table 1 Cellular boron uptake test results of the compounds of Examples 1-19 and Comparative Examples 1-2

[0183]

[0184]

[0185] It can be seen from Table 1 that every 10 6 The boron content in each cell was 193.1 nmol or more, which was significantly higher than the 15.8 nmol of the compound in Comparative Example 1 and the 67.07 nmol of the compound in Comparative Example 2. 6 Boron content per cell and cellular boron uptake.

[0186] It can be seen from the above results that the compounds of the present invention are easily absorbed by glioma cells and can accumulate in tumor cells at high concentrations. 6 The maximum boron content of each cell can reach 336.6 nmol. The boron concentration of the compound of the present invention in tumor cells is 12-21 times that of BPA, and can be used as a boron drug in boron neutron capture therapy. Compared with BPA, the compound of the present invention can increase the boron content in tumor cells, thereby reducing the dosage during the treatment process.

[0187] 3. Application of carborane derivatives as catalysts

[0188] The catalytic performance of the carborane derivatives prepared in Examples 1-19 as catalysts was evaluated by using the asymmetric addition reaction of acetone and 3,3-dimethylbutyraldehyde as a template reaction. The specific steps are as follows: 1 ml of acetone and 1 mmol of 3,3-dimethylbutyraldehyde were added to 4 ml of anhydrous chloroform, and 0.15 mmol of the carborane derivative of the present invention was added, and the reaction was stopped after stirring at room temperature until the reaction of 3,3-dimethylbutyraldehyde was completed or the content did not change, and then an appropriate amount of saturated NH4Cl solution and ethyl acetate were added under stirring, the layers were separated, and the aqueous phase was thoroughly extracted with ethyl acetate. The combined organic phase was dried with MgSO4, separated by a chromatographic column (silica gel, hexane / ethyl acetate = 3:7, v / v), and concentrated to obtain the corresponding chiral alcohol.

[0189] Table 2 Catalytic performance of carborane derivatives and comparative example L-proline as catalyst

[0190]

[0191]

[0192] As can be seen from Table 2, the catalyst prepared based on the carborane derivatives of the present invention has a good catalytic effect on the asymmetric addition reaction of acetone and 3,3-dimethylbutyraldehyde, and is superior to the catalytic reaction directly using L-proline as a chiral catalyst in terms of yield and optical purity, indicating that the carborane derivatives provided by the present invention have good catalytic activity and enantioselectivity, and have potential uses in the field of chiral synthesis.

[0193] The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention. Any equivalent structural changes made using the description and drawings of the present invention should also be included in the protection scope of the present invention.

Claims

1. A carborane derivative, characterized in that: The carborane derivative is a compound represented by formula I or a pharmaceutically acceptable salt thereof; Formula I, Among them, R 1 Selected from Any one of R 2 is a C1-C4 alkyl group, R 3 It is a C1-C3 alkyl group optionally substituted with a benzene ring.

2. The carborane derivative according to claim 1, characterized in that The carborane derivatives include any one of the following compounds: The Boc group is tert-butyloxycarbonyl.

3. A carborane derivative, characterized in that: The carborane derivative is any one of A, B, C, and D Among them, A, B, C or D represents the relative configuration.

4. A method for preparing the carborane derivative A or B according to claim 3, characterized in that: The preparation method comprises the following steps: 1) reacting o-carborane with a base in a first solvent at 0±5°C for 0.5-2h, then adding a compound of formula II and reacting at -20°C to 5°C for 4-6h to obtain a carborane derivative of formula I; Where R 4 is a C1-C3 alkyl group; 2) reacting the compound represented by formula I with a catalyst in a second solvent at 0-30° C. for 0.5-2 h to obtain a compound A or B having a structure of formula III; 5. The method for preparing a carborane derivative A or B according to claim 4, characterized in that: The base is butyl lithium, R 5 -MgX; said R 5 It is one of methyl and isopropyl; X=Br or Cl.

6. The method for preparing a carborane derivative A or B according to claim 4, characterized in that: The molar ratio of the o-carborane to the compound of formula II and the base is 1:(1.0-2.0):(1.0-1.5).

7. The method for preparing the carborane derivative A or B according to claim 4, characterized in that: When the catalyst is one of sodium borohydride, lithium aluminum tetrahydride, borane tetrahydrofuran complex, lithium tri-tert-butoxyaluminum hydride, sodium bis(2-methoxyethoxy)aluminum hydride, and lithium tri-sec-butylborohydride, the obtained compound A is obtained; when the catalyst is diisobutylaluminum hydride (DIBAL-H), the obtained compound B is obtained; the molar ratio of the compound of formula I to the catalyst is 1:(1-3).

8. A nested carborane derivative, characterized in that: The nested carborane is a compound shown in Formula IV, Formula IV, Wherein, M is sodium, potassium, cesium or hydrogen, R 6 It is either Boc or hydrogen.

9. A nested carborane derivative, characterized in that: The nested carborane derivative is any one of E or F; Among them, E or F represents the relative configuration, and M is sodium, potassium, cesium or hydrogen.

10. Use of the carborane derivative according to any one of claims 1 to 3, 8 and 9 in the preparation of a boron neutron capture therapy drug or as a catalyst.

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