A carborane derivative, a preparation method and application thereof

Abstract

The application belongs to the field of organic synthesis and specifically relates to a carborane derivative, a preparation method and application thereof, and the carborane derivative is a compound with a carborane pyrrolidine structure or a pharmaceutically acceptable salt thereof. The carborane derivative can be used as a boron neutron capture therapy drug and can increase the boron content in tumor cells. When the carborane derivative is applied to the field of catalysis, the carborane derivative has good catalytic performance.

Description

Technical Field

[0001] This invention belongs to the field of organic synthesis, specifically relating to a carborane derivative, its preparation method, and its application. Background Technology

[0002] Carboranes are a class of cage-like molecular clusters composed of carbon, boron, and hydrogen. Their unique structure and bonding mechanisms give them excellent thermal and chemical stability, as well as unique stereoaromatic properties (Russ. Chem. Bull., 1993, 42(8), 1283). They hold great promise for applications in catalysts (Chem. Eur. J., 2015, 21, 1184), luminescent materials, pharmaceuticals, and supramolecular structures (Synthesis, 2020, 52, 337). L-4-dihydroxyphenylalanine (BPA), a second-generation boron drug used in boron neutron capture therapy (BNCT), has a boron content of only 5%, while carboranes have a higher boron content, making them an important boron source for designing third-generation boron drugs for BNCT.

[0003] Pyrrolidines are a class of five-membered non-aromatic nitrogen heterocycles widely found in natural products and drug molecules, and their derivatives have extensive applications in drug design and catalysis. For example, the N-substituted pyrrolidine procyclidine can treat epilepsy (Formula V), and the 3-substituted pyrrolidine rolipram can treat depression (Formula VI). The applications of 2-substituted pyrrolidines are even more widespread. 2-pyrrolidine ethers, amides, and tetrazolium derivatives (Formula VII) can be used as catalysts for Michael addition reactions; 2-alkylpyrrolidine (R)-bgugaine (Formula VIII) has antifungal properties; and 2-pyrrolidine carboxylic acid-proline (Formula IX) is an important amino acid in organisms. Given the special structures and wide applications of 2-substituted pyrrolidines and carboranes, introducing a high-boron-content carborane alkyl group at the 2-position of pyrrolidines is expected to improve their biological activity and catalytic performance.

[0004]

[0005] No such compounds have been reported, therefore the development of new 2-substituted pyrrolidine carborane derivatives is of great significance for expanding the range of drugs and catalysts. Summary of the Invention

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

[0007] To achieve the above objectives, the technical solution of the present invention is as follows:

[0008] A carborane derivative, said carborane derivative being a compound of formula I or a pharmaceutically acceptable salt thereof:

[0009]

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

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

[0012]

[0013] The Boc group is a tert-butyloxycarbonyl group.

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

[0015] In this context, A, B, C, or D represent relative configurations.

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

[0017]

[0018] Where M is sodium, potassium, cesium, or hydrogen, and R 6 It can be 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] In this context, E or F represents the relative configuration, and M represents sodium, potassium, cesium, or hydrogen.

[0022] The carborane derivatives of the present invention can be used as drugs in boron neutron capture therapy.

[0023] Meanwhile, the carborane derivatives of the present invention exhibit good catalytic performance when applied in the field of catalysis, providing a highly efficient catalyst, especially suitable for the asymmetric addition reaction of acetone with 3,3-dimethylbutyraldehyde.

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

[0025] The technical solution of this invention is:

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

[0027] 1) React o-carborane with a base in the first solvent at 0±5℃ for 0.5-2h, then add compound II and react at -20℃~5℃ for 4-6h to obtain carborane derivative of formula I.

[0028]

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

[0030] 2) The compound shown in Formula I reacts with the catalyst in the second solvent and reacts at 0–30 °C for 0.5–2 h to obtain compound A or B with the structure of Formula III.

[0031]

[0032] The present invention uses o-carborane and proline derivatives as raw materials to prepare carborane pyrrolidone, and then catalyzes it to obtain a catalyst-carborane pyrrolidone derivative that can be used in BNCT and catalysis. The present invention is simple to operate, the raw materials are readily available, and stereoisomers with specific configurations can be obtained.

[0033] As a further improvement, the alkali is butyllithium, R 5 One of -MgX, more preferably R 5 It is one of methyl or isopropyl; X = Br or Cl, thus, proline derivatives can react fully with ortho-carborane.

[0034] Preferably, the first solvent is one of tetrahydrofuran, diethyl ether, and ethylene glycol dimethyl ether. Therefore, the reactants have high solubility in these substances, and selecting them as reaction solvents facilitates a full reaction between the reactants, thereby 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, in step 1), the reaction temperature after adding compound II is -20℃ to 5℃, and the reaction time is 4-6h. In this way, the activity of the catalyst is maintained, which can better promote the reaction.

[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 the full 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 hydride, borane tetrahydrofuran complex, lithium tri-tert-butoxy aluminum hydride, sodium bis(2-methoxyethoxy)aluminum hydride, and lithium tri-sec-butylborohydride. Thus, the compound of formula II can be readily converted into the compound with configuration A.

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

[0040] 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 in step 2) is 0-30°C, and the reaction time is 0.5-2 hours. This allows the catalyst activity to be maintained and promotes the reaction in a better manner.

[0043] The aforementioned carborane derivatives can be used as boron drugs in boron neutron capture therapy and as catalysts. Attached Figure Description

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

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

[0046] Figure 3 This is the 1H NMR spectrum of compound B in Example 7;

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

[0048] Figure 5 This is a single-crystal diffraction pattern of compound F in Example 19. Detailed Implementation

[0049] This 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 them.

[0052] Preferably, the R 2 C1-C4 alkyl groups 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] Where A, B, C or D represent relative configurations, and Boc is tert-butyloxycarbonyl.

[0055] This invention provides a nested carborane derivative, wherein the nested carborane is a compound represented by Formula IV.

[0056]

[0057] Where M is sodium, potassium, cesium, or hydrogen, and R 5 It can be 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] In this context, E or F represents the relative configuration, and M represents 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 ortho-carborane, compound II with a base in the first solvent yields carborane derivatives of formula I;

[0063]

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

[0065] 2) The compound shown in Formula I reacts with a catalyst in a second solvent to give a compound A or B with the structure of Formula III.

[0066]

[0067] The present invention uses o-carborane and proline derivatives as raw materials to prepare carborane pyrrolidone, and then catalyzes it to obtain a catalyst-carborane pyrrolidone alcohol derivative that can be used in BNCT and catalysis. The present invention is simple to operate, the raw materials are readily available, and carborane pyrrolidone with specific configurations can be obtained.

[0068] The present invention will be further described below with reference to specific embodiments, but the scope of protection of the present invention is not limited thereto.

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

[0070] I. Examples of Carborane Derivatives and Their Preparation Methods

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

[0072]

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

[0074] Under nitrogen protection, o-borane (1.44 g, 10 mmol) and n-butyllithium (2.5 M, 4 ml, 10 mmol) were added to 28.8 g of tetrahydrofuran and stirred at 0 °C for 1 h. Then, 1-(tert-butyl)-2-methylpyrrolidine-1,2-dicarboxylic acid ester (2.29 g, 10 mmol) was added, and the mixture was stirred at -10 °C for 5 h. The aqueous phase was separated, and the organic layer was distilled under reduced pressure and subjected to column chromatography (petroleum ether / ethyl acetate = 20 / 1, v / v) to give compound I (3.15 g, 9.23 mmol). 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, extracted with ethyl acetate, and the solvent was removed by distillation under reduced pressure. The mixture was then subjected to column chromatography (petroleum ether / ethyl acetate = 10 / 1, v / v) to give compound A (3.05 g), with an overall yield of 88.8%.

[0075] The 1H NMR spectrum of the product prepared in Example 1 is shown below. 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 shown below. 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] As can be seen from the 1H NMR and 1B NMR data of Example 1, 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 includes the following steps:

[0081] Under nitrogen protection, o-carborane (1.44 g, 10 mmol) and isopropyl magnesium chloride (1.44 g, 14 mmol) were added to 50.4 g of diethyl ether and stirred at 0 °C for 2 h. Then, 1-(tert-butyl)-2-methylpyrrolidine-1,2-dicarboxylic acid ester (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 and subjected to column chromatography (petroleum ether / ethyl acetate = 20 / 1, v / v) to give compound I (3.12 g, 9.15 mmol). Compound I was dissolved in 109.3 g of tetrahydrofuran, and a borane tetrahydrofuran complex (1.18 g, 13.7 mmol) was added. The mixture was stirred at 15 °C for 1 h, extracted with ethyl acetate, and the solvent was removed by distillation under reduced pressure. The mixture was then subjected to column chromatography (petroleum ether / ethyl acetate = 10 / 1, v / v) to give compound A (3.025 g), with an overall 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 includes the following steps:

[0085] Under nitrogen protection, o-carborane (1.44 g, 10 mmol) and n-butyllithium (6 ml, 15 mmol) were added to 93.7 g of ethylene glycol dimethyl ether and stirred at 0 °C for 1.5 h. Then, 1-(tert-butyl)-2-methylpyrrolidine-1,2-dicarboxylic acid ester (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 and subjected to column chromatography (petroleum ether / ethyl acetate = 20 / 1, v / v) to give compound I (3.09 g, 9.05 mmol). 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, extracted with ethyl acetate, and the solvent was removed by distillation under reduced pressure. The mixture was then subjected to column chromatography (petroleum ether / ethyl acetate = 10 / 1, v / v) to give compound A (2.95 g), with an overall yield of 85%.

[0086] Example 4: The carborane derivative in this example is compound A.

[0087] The structural formula is:

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

[0089] Under nitrogen protection, o-borane (1.44 g, 10 mmol) and n-butyllithium (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. Then, 1-(tert-butyl)-2-methylpyrrolidine-1,2-dicarboxylic acid ester (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 and subjected to column chromatography (petroleum ether / ethyl acetate = 20 / 1, v / v), to obtain compound I, (3.18 g, 9.31 mmol); compound I was dissolved in 174.8 g of methanol, and sodium bis(2-methoxyethoxy)aluminum hydride (4.14 g, 20.5 mmol) was added. The mixture was stirred at 20 °C for 1.5 h, extracted with ethyl acetate, the solvent was removed by vacuum distillation, and column chromatography (petroleum ether / ethyl acetate = 10 / 1, v / v) was performed to give compound A, 2.91 g, with an overall 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 includes the following steps:

[0093] Under nitrogen protection, o-carborane (1.44 g, 10 mmol) and n-butyllithium (4.8 mL, 12 mmol) were added to 64.9 g of tetrahydrofuran and stirred at 3 °C for 1 h. Then, 1-(tert-butyl)-2-methylpyrrolidine-1,2-dicarboxylic acid ester (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 and subjected to column chromatography (petroleum ether / ethyl acetate = 20 / 1, v / v) to give compound I (3.07 g, 8.99 mmol). Compound I was dissolved in 214.9 g of methanol, and tri-sec-butylborohydride (5.12 g, 26.9 mmol) was added. The mixture was stirred at 25 °C for 1.5 h, extracted with ethyl acetate, and the solvent was removed by distillation under reduced pressure. The mixture was then subjected to column chromatography (petroleum ether / ethyl acetate = 10 / 1, v / v) to give compound A (2.86 g), with an overall 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 includes the following steps:

[0097] Under nitrogen protection, o-carborane (1.44 g, 10 mmol) and methyl magnesium bromide (1.43 g, 12 mmol) were added to 14.4 g of diethyl ether and stirred at 0 °C for 2 h. Then, 1-(tert-butyl)-2-ethylpyrrolidine-1,2-dicarboxylic acid ester (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 and subjected to column chromatography (petroleum ether / ethyl acetate = 20 / 1, v / v) to give compound I (3.06 g, 8.96 mmol). Compound I was dissolved in 45.9 g of ethanol, and lithium aluminum hydride (0.408 g, 10.7 mmol) was added. The mixture was stirred at 0 °C for 1.5 h, extracted with ethyl acetate, and the solvent was removed by distillation under reduced pressure. The mixture was then subjected to column chromatography (petroleum ether / ethyl acetate = 10 / 1, v / v) to give compound A (2.92 g), with an overall yield of 84.6%.

[0098] Using this embodiment, compound R of formula II can be obtained. 4 When compound III is prepared using ethyl or propyl groups, the specific preparation and application effects should be comparable to those in this example, based on the similarity of properties between C1-C3 alkyl groups.

[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 includes the following steps:

[0103] Under nitrogen protection, o-borane (1.44 g, 10 mmol) and n-butyllithium (4.4 ml, 11 mmol) were added to 72.11 g of diethyl ether, and the mixture was stirred at 0 °C for 1 h. Then, 1-(tert-butyl)-2-methylpyrrolidine-1,2-dicarboxylic acid ester (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 and subjected to column chromatography (petroleum ether / ethyl acetate = 20 / 1, v / v). Compound I (3.12 g, 9.13 mmol) was obtained. Compound I was dissolved in 46.7 g of n-hexane, and diisobutylaluminum hydride (DIBAL-H) ​​(18.26 ml, 18.2 mmol) was added. The mixture was stirred at 30 °C for 1.5 h, extracted with ethyl acetate, and the solvent was removed by vacuum distillation. The mixture was then subjected to column chromatography (dichloromethane / methanol = 20 / 1, v / v) to obtain compound B (3.02 g), with an overall yield of 87.8%.

[0104] The 1H NMR spectrum of the product prepared in Example 7 is shown below. 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 shown below. 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 following structural formula:

[0107]

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

[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 following structural formula:

[0113]

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

[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 following structural formula:

[0119]

[0120] The synthesis method was carried out according to Example 8, except that 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 following structural formula:

[0124]

[0125] The synthesis method was carried out according to Example 8, except that 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, with the following structural formula:

[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), stirred at room temperature for 10 h, 10 mL of water was added to the reaction, the aqueous layer was washed with ethyl acetate, alkalized with 4 M NaOH aqueous solution (10 mL), and extracted with ethyl acetate (4 × 10 mL). The combined organic layers were dried with 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, with the following structural formula:

[0136]

[0137] Compound B obtained in Example 7 was synthesized according to the method described in 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 following structural formula:

[0142]

[0143] Under nitrogen protection, o-carborane (1.44 g, 10 mmol) and n-butyllithium (4.4 ml, 11 mmol) were added to 72.11 g of tetrahydrofuran. The mixture was stirred at 0 °C for 1 h, and then 1-(tert-butyl)-2-methylpyrrolidine-1,2-dicarboxylic acid ester (2.92 g, 12 mmol) was added. The mixture was stirred at -20 °C for 5 h. The aqueous phase was separated, and the organic layer was distilled under reduced pressure and subjected to column chromatography (petroleum ether / ethyl acetate = 20 / 1, v / v) to give compound I (3.2 g, 9.3 mmol). Compound I was dissolved in ethanol, and CsF (2.82 g, 18.6 mmol) was added. The mixture was 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 give 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 following structural formula:

[0148]

[0149] 0.5 mmol of the compound obtained in Example 14 was dissolved in 5 ml of methanol, 0.8 ml of concentrated hydrochloric acid was added, and the mixture was stirred at room temperature for 3 h. The mixture was then distilled under reduced pressure and column chromatography was used 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), with the following structural formula:

[0154]

[0155] 1.2 mmol of compound C obtained from Example 12 was added to 12 ml of ethanol, 2.4 mmol of CsF was added, the mixture was heated under reflux for 20 h, and then distilled under reduced pressure. The resulting 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), with the following structural formula:

[0160]

[0161] 0.5 mmol of compound E (M = Cs) prepared according to Example 16 was added to 5 ml of methanol and 0.25 ml of 1 M HCl, stirred at room temperature for 30 min, 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), with the following structural formula:

[0166]

[0167] Using compound D obtained in Example 13 as a raw material, the synthesis method was carried out in accordance with 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), with the following structural formula:

[0172]

[0173] Using the product obtained in Example 18 as raw material, the synthesis method was carried out in accordance with 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] II. 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 in Comparative Example 1. Compound 2 is used as a comparative example.

[0179] Cellular boron uptake tests were performed on the carborane derivatives prepared in Examples 1-19, the compound of Comparative Example 1, and the compound of Comparative Example 2.

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

[0181] The culture medium was removed by aspiration, and excess culture medium was washed away from the cells with cold phosphate buffer (PBS buffer, pH 7.4) at 2–10 °C. The cells were then incubated with 2 mg / mL streptomycin solution (Source Leaf, BR, 7000 u / g) at 4 °C for 4 h, after which the streptomycin solution was discarded. The cells were then washed with PBS buffer (pH 7.4), and lysed with RIPA lysis buffer (Radio Immunoprecipitation Assay Lysis buffer, Maclean, sterile). The cell lysates were collected, and the supernatant was collected by centrifugation at 10000 rpm. Boron analysis of the supernatant was performed using inductively coupled plasma atomic emission spectrometry (ICP-AES). The results of boron uptake tests for different boron compounds are shown in Table 1 below.

[0182] Table 1. Results of cellular boron uptake tests for compounds in Examples 1-19 and Comparative Examples 1-2.

[0183]

[0184]

[0185] As can be seen from Table 1, for every 10 of the compounds in Examples 1-19 6 The boron content per cell was above 193.1 nmol, significantly higher than that of compound 1 (15.8 nmol) and compound 2 (67.07 nmol) per 10 cells. 6 Boron content per cell and boron uptake per cell.

[0186] The results above show that the compound of the present invention is easily absorbed by glioma cells and can accumulate in high concentrations within tumor cells, with a concentration of approximately 10... 6 The boron content in a single cell can reach up to 336.6 nmol. The boron concentration of the compound of the present invention in tumor cells is 12-21 times that of BPA. It 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 treatment.

[0187] III. Application of carborane derivatives as catalysts

[0188] The catalytic performance of the carborane derivatives prepared in Examples 1-19 as catalysts was evaluated using the asymmetric addition reaction of acetone with 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, followed by 0.15 mmol of the carborane derivative of this invention. The mixture was stirred at room temperature until the 3,3-dimethylbutyraldehyde reaction was complete or its content remained unchanged. The reaction was then stopped. A suitable amount of saturated NH4Cl solution and ethyl acetate were added while stirring. The layers were separated, and the aqueous phase was thoroughly extracted with ethyl acetate. The combined organic phases were dried over MgSO4, separated by column chromatography (silica gel, hexane / ethyl acetate = 3:7, v / v), and concentrated to obtain the corresponding chiral alcohol.

[0189] Table 2 Catalytic performance based on carborane derivatives and comparative examples of L-proline as catalysts

[0190]

[0191]

[0192] As shown in Table 2, the catalysts prepared based on the carborane derivatives of the present invention exhibit good catalytic activity for the asymmetric addition reaction of acetone and 3,3-dimethylbutyraldehyde. The yield and optical purity are superior to those of the reaction directly using L-proline as a chiral catalyst. This indicates that the carborane derivatives provided by the present invention have good catalytic activity and enantioselectivity, and have potential applications in the field of chiral synthesis.

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

Claims

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

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 a tert-butyloxycarbonyl group.

3. A carborane derivative, characterized in that, The carborane derivative is any one of A, B, C, and D. In this context, A, B, C, or D represent relative configurations.

4. A method for preparing the carborane derivative A or B according to claim 3, characterized in that, The preparation method includes the following steps: 1) Mix o-carborane with a base in the first solvent at 0±5 o React at C for 0.5-2 hours, then add compound II and react at -20°C. o C~5 o The reaction was carried out at C for 4-6 hours to obtain the carborane derivative of formula I. ， Where R 4 It is a C1-C3 alkyl group; 2) The compound shown in Formula I and the catalyst are reacted in a second solvent at a temperature of 0–30 °C. o The reaction is carried out at C for 0.5-2 h to obtain compound A or B with the structure of formula III; 。 5. The method for preparing a carborane derivative A or B according to claim 4, characterized in that, The alkali is butyllithium, R 5 One of -MgX; the R 5 It is one of methyl or 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 carborane derivative A or B according to claim 4, characterized in that, When the catalyst is one of sodium borohydride, lithium aluminum hydride, borane tetrahydrofuran complex, lithium tri-tert-butoxy aluminum hydride, sodium bis(2-methoxyethoxy)aluminum hydride, or lithium tri-sec-butylborohydride, compound A is obtained; when the catalyst is diisobutylaluminum hydride (DIBAL-H), compound B is obtained; the molar ratio of compound I to catalyst is 1:(1~3).

8. A nested carborane derivative, characterized in that, The nested carborane is a compound represented by formula IV. ， Formula IV, Where M is sodium, potassium, cesium, or hydrogen, and R 6 It can be either Boc or hydrogen.

9. A nested carborane derivative, characterized in that, The nested carborane derivative is either E or F; ， In this context, E or F represents the relative configuration, and M represents sodium, potassium, cesium, or hydrogen.

10. The use of the carborane derivative according to any one of claims 1-3, 8 and 9 in the preparation of boron neutron capture therapeutic drugs or as a catalyst in the asymmetric addition reaction of acetone with 3,3-dimethylbutyraldehyde.

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