Preparation method of B (4) site alkylated carborane compound

Abstract

The invention discloses a preparation method of a B (4) site alkyl carborane compound, and belongs to the field of organic synthesis. The method comprises the following steps: heating 1-carboxyl-carborane, alpha-carbonyl sulfoxide ylide, sodium acetate or potassium acetate and a ruthenium catalyst in an organic solvent for reaction; and after the reaction is finished, separating by utilizing column chromatography, and collecting a solid to obtain the B (4) site alkylated carborane compound. According to the invention, the cheap ruthenium metal catalyst is adopted to directly activate the B-H bond of carborane, so that the method has the characteristics of mild reaction conditions, no need of silver salt, high yield and relatively low preparation cost, and post-modification of active pharmaceutical molecules can be realized.

Description

Technical Field

[0001] The invention belongs to the field of organic synthesis, and particularly relates to a method for preparing a B(4) site alkylated carborane compound. Background Art

[0002] Carborane (closo-C2B 10 H 12 ) is an icosahedral cage compound composed of carbon, boron and hydrogen, and is a three-dimensional aromatic analog of benzene σ. Carborane has the characteristics of rigid structure, high boron content, high thermal and chemical stability, and low toxicity. Due to these characteristics, carborane is widely used as a structural unit in many fields such as coordination chemistry, material chemistry, medicinal chemistry, supramolecular chemistry, etc. In recent years, it has received special attention in the treatment of cancer with boron neutron capture therapy (BNCT).

[0003] In recent years, significant progress has been made in the functionalization of carborane BH. In the transition metal-catalyzed carborane BH functionalization, a large number of BH bond arylation, alkynylation, and alkenylation have been reported, but BH bond alkylation still faces certain challenges. Among carborane derivatives, alkylated carboranes, especially monoalkylated carboranes, have attracted much attention due to their beneficial applications (cross-coupling, cyclization, bioconjugation, etc.). Therefore, it is very urgent to use easily available and structurally diverse alkylating agents to synthesize alkylated carborane compounds.

[0004] The currently developed methods for alkylation of carborane BH bonds include 1) dialkylation of carborane B(4,5) sites by oxidative coupling of allyl alcohol using noble metal rhodium as catalyst and silver salt as additive; 2) alkylation of 1-pyridyl carborane B(4) sites by noble metal rhodium catalyst; 3) alkylation of carborane B(4) sites and B(3,5) sites by noble metal iridium catalyst and silver salt as additive. The above methods require the use of expensive metal catalysts, or the addition of silver salts, or harsh reaction conditions.

[0005] Therefore, it is of great significance to develop a method for synthesizing boron-site alkylated carborane compounds using catalysts with safe, mild reaction conditions and low usage costs. Summary of the invention

[0006] In view of the shortcomings of the prior art, the object of the present invention is to provide a method for synthesizing a boron site monoalkylated carborane compound by catalyzing the activation of carborane BH using a ruthenium catalyst. The method only requires one step of reaction, is simple to operate, and the catalyst is cheap and readily available, and is easy to achieve large-scale production.

[0007] The object of the present invention can be achieved by the following technical scheme: A method for preparing a B (4) site alkylated carborane compound, comprising the following steps: using 1-carboxyl-carborane a and α-carbonyl sulfoxide ylide b as raw materials, heating and reacting in an organic solvent in the presence of a ruthenium catalyst and an additive to obtain a carborane B (4) site alkylated alkylation product c; the chemical reaction equation is expressed as follows:

[0008]

[0009] Wherein: R1 is C1-C4 alkyl, phenyl or substituted phenyl, the substituent in the substituted phenyl is selected from C1-C4 alkyl, C1-C4 alkoxy or trifluoromethyl; R2 is C3-C20 cycloalkyl, C5-C6 cycloalkyl containing nitrogen / oxygen heteroatoms, thienyl, furyl, phenyl or substituted phenyl, the substituent in the substituted phenyl is selected from at least one of halogen, C1-C4 alkyl, C1-C4 alkoxycarbonyl, C1-C4 alkoxy, trifluoromethyl, nitro and phenyl.

[0010] Furthermore, in the above technical solution, the catalyst is selected from [Ru(p-cymene)Cl2] or [Ru(benzene)Cl2]2.

[0011] Furthermore, in the above technical solution, the additive is selected from sodium acetate or potassium acetate.

[0012] Furthermore, in the above technical solution, the organic solvent is selected from hexafluoroisopropanol, tetrahydrofuran or trifluoroethanol.

[0013] Furthermore, in the above technical solution, the molar ratio of the 1-carboxyl-carborane a and the α-carbonyl sulfoxide ylide b is 1:1-1.5.

[0014] Furthermore, in the above technical solution, the heating reaction temperature is 40-100° C. The preferred reaction temperature is 60° C.

[0015] Furthermore, in the above technical solution, the molar ratio of the 1-carboxyl-carborane a to the ruthenium catalyst is 1:0.02-0.05.

[0016] Furthermore, in the above technical scheme, after the reaction is completed, the reaction system is cooled to room temperature, the solvent is drained under reduced pressure to obtain a crude product, and then separated by column chromatography; the eluent is a mixed solvent of petroleum ether and dichloromethane, and the volume ratio of petroleum ether to dichloromethane is 1.5:1.

[0017] The invention uses low-cost [Ru(benzene)Cl2]2 as a catalyst and carboxyl as a traceless directing group to synthesize a B(4) site monoalkylated carborane compound. DETAILED DESCRIPTION

[0018] Example 1

[0019] Using compound a1 and compound b1 as templates, the reaction conditions were optimized as shown in the following table:

[0020]

[0021] On this basis, the organic solvent, reaction temperature, feed ratio and reaction atmosphere were further optimized, and the optimal conditions for the synthesis of c1 were screened out as label 8: 1.0 equivalent a1, 1.5 equivalent b1, 2.5 mol% [Ru(benzene)Cl2]2, 1.0 equivalent sodium acetate or potassium acetate, 60°C, reaction in hexafluoroisopropanol (0.1M) for 3 hours, yield 99%. The characterization data of compound c1 are consistent with the literature (Chem. Sci., 2021, 12, 15563-15571).

[0022]

[0023] 1a (0.1 mmol), 2a (0.15 mmol), catalyst (5 mol%), additive (0.1 mmol), HFIP (1.0 mL), nitrogen atmosphere.

[0024] Example 2

[0025]

[0026] A method for preparing a B(4) site monoalkylated carborane compound using the reaction conditions of Example 1, Label 8: 1-carboxyl-carborane a1 (0.1 mmol) and α-carbonyl sulfoxide ylide b2 (0.15 mmol) were added to hexafluoroisopropanol (1.0 mL), followed by the addition of [Ru(benzene)Cl2]2 (0.0025 mmol) and sodium acetate (0.1 mmol), and the mixture was reacted at 60°C for 3 h under a nitrogen atmosphere. The corresponding B(4) site monoalkylated carborane compound c2 was obtained after post-treatment with a yield of 91%. 1 H NMR (600MHz, CDCl3) δ7.88(d,J=8.0Hz,2H),7.44(d,J=7.4Hz,2H),7.37(t,J=7.3Hz,1H),7.34–7.24(m,4H)(aryl CH),4.38(s,1H,cage CH),2.94(d,J=13.5Hz,1H),2.89(d,J=13.5Hz,1H)(B-CH2),2.42(s,3H,CH3).

[0027] Example 3

[0028]

[0029] The method of preparing the B(4) site monoalkylated carborane compound by using Example 2 is as follows: 1-carboxyl-carborane a1 (0.1 mmol) and α-carbonyl sulfoxide ylide b3 (0.15 mmol) are added to hexafluoroisopropanol (1.0 mL), followed by the addition of [Ru(benzene)Cl2]2 (0.0025 mmol) and sodium acetate (0.1 mmol), and the reaction is carried out at 60°C for 3 h under a nitrogen atmosphere to obtain the corresponding B(4) site monoalkylated carborane compound c3 with a yield of 95%. 1 H NMR(400MHz, CDCl3)δ7.97(m 1H),7.45(d,J=7.8Hz,1H),7.40–7.35(m,1H),7.34–7.27(m,2H),7.01–6.87(m,2H)(aryl CH),4.38(s,1H,cage CH),3.88(s,3H,CH3),2.92(d,J=13.4Hz,1H),2.86(d,J=13.4Hz,1H)(B-CH2).

[0030] Example 4

[0031]

[0032] The method of preparing the B(4) site monoalkylated carborane compound by using Example 2 is as follows: 1-carboxyl-carborane a1 (0.1 mmol) and α-carbonyl sulfoxide ylide b4 (0.15 mmol) are added to hexafluoroisopropanol (1.0 mL), followed by the addition of [Ru(benzene)Cl2]2 (0.0025 mmol) and potassium acetate (0.1 mmol), and the reaction is carried out at 60°C under a nitrogen atmosphere for 3 h to obtain the corresponding B(4) site monoalkylated carborane compound c4 with a yield of 80%. 1 H NMR(400MHz, CDCl3)δ8.08–7.98(m,2H),7.50–7.43(m,2H),7.42–7.36(m,1H),7.36–7.27(m,4H)(aryl CH),4.36(s,1H,cage CH),2.96(d,J=13.5Hz,1H),2.90(d,J=13.5Hz,1H)(B-CH2).

[0033] Example 5

[0034] The method for preparing the B(4) site monoalkylated carborane compound according to Example 2 is as follows: 1-carboxyl-carborane a1 (0.1 mmol) and other α-carbonyl sulfoxide ylides (b5-c30) 0.1 mmol are added to hexafluoroisopropanol (1.0 mL), followed by the addition of [Ru(benzene)Cl2]2 (0.0025 mmol) and sodium acetate (0.1 mmol), and the reaction is carried out at 60° C. for 3 h under a nitrogen atmosphere to obtain the corresponding B(4) site monoalkylated carborane compounds c5-c30. The results are shown below:

[0035]

[0036]

[0037] Example 6

[0038] The method for preparing the B(4) site monoalkylated carborane compound according to Example 2 was as follows: 0.1 mmol of 1-carboxyl-carborane (a2-a8) and α-carbonyl sulfoxide ylide b1 were added to hexafluoroisopropanol (1.0 mL), followed by the addition of [Ru(benzene)Cl2]2 (0.0025 mmol) and sodium acetate (0.1 mmol), and the mixture was reacted at 60° C. for 3 h under a nitrogen atmosphere to obtain the corresponding B(4) site monoalkylated carborane compounds (c31-c37). The results are shown below:

[0039]

[0040] Example 7

[0041]

[0042] The B(4) site monoalkylated carborane was post-modified to synthesize the potential BNCT drug d. 3t (0.1mmol, 43mg), N-(tert-butyloxycarbonyl)-L-cysteine ​​methyl ester (0.2mmol, 47mg) and potassium phosphate (0.2mmol, 43mg), N,N-dimethylformamide (1.0mL) were added to the reaction tube and reacted at room temperature for 12h to obtain the monoalkylated carborane compound d containing the boron pharmacophore / fluorine / amino acid B(4) site, with a yield of 51%. 1H NMR(600MHz, CDCl3)δ7.52–7.46(m,2H),7.43–7.38(m,1H),7.37–7.32(m,2H)(aryl CH),5.33(d,J=7.8Hz,1H,NH),4.58(q,J=5.6Hz,1H,CHNH),4.44(s,1H,cage CH),3.69(s,3H,OCH3),3.55(dd,J=14.2,4.7Hz,1H),3.39(dd,J=14.2,5.0Hz,1H,SCH2),2.91(s,2H,B-CH2),1.40(s,9H, t Bu-CH3).

[0043] The above description of the embodiments is to facilitate the understanding and use of the invention by those skilled in the art. It is obvious that those skilled in the art can easily make various modifications to these embodiments and apply the general principles described herein to other embodiments without creative work. Therefore, the present invention is not limited to the above embodiments, and improvements and modifications made by those skilled in the art based on the disclosure of the present invention without departing from the scope of the present invention should be within the scope of protection of the present invention.

Claims

1. A method for preparing a B(4) site alkylated carborane compound, characterized in that: The method comprises the following steps: using 1-carboxyl-carborane a and α-carbonyl sulfoxide ylide b as raw materials, heating and reacting in an organic solvent in the presence of a ruthenium catalyst and an additive, to obtain a carborane B (4) site alkylation product c; the chemical reaction equation is as follows: Wherein: R1 is C1-C4 alkyl, phenyl or substituted phenyl, the substituent in the substituted phenyl is selected from C1-C4 alkyl, C1-C4 alkoxy or trifluoromethyl; R2 is C3-C20 cycloalkyl, C5-C6 cycloalkyl containing nitrogen / oxygen heteroatoms, thienyl, furyl, phenyl or substituted phenyl, the substituent in the substituted phenyl is selected from at least one of halogen, C1-C4 alkyl, C1-C4 alkoxycarbonyl, C1-C4 alkoxy, trifluoromethyl, nitro and phenyl.

2. The method for preparing the B(4) site alkylated carborane compound according to claim 1, characterized in that: The ruthenium catalyst is selected from [Ru(p-cymene)Cl2] or [Ru(benzene)Cl2]2.

3. The method for preparing the B(4) site alkylated carborane compound according to claim 1, characterized in that: The molar ratio of the 1-carboxyl-carborane a to the ruthenium catalyst is 1:0.02-0.

05.

4. The method for preparing the B(4) site alkylated carborane compound according to claim 1, characterized in that: The additive is selected from sodium acetate or potassium acetate.

5. The method for preparing the B(4) site alkylated carborane compound according to claim 1, characterized in that: The organic solvent is selected from hexafluoroisopropanol, tetrahydrofuran or trifluoroethanol.

6. The method for preparing the B(4) site alkylated carborane compound according to claim 1, characterized in that: The molar ratio of the 1-carboxyl-carborane a to the α-carbonyl sulfoxide ylide b is 1:1-1.

5.

7. The method for preparing the B(4) site alkylated carborane compound according to claim 1, characterized in that: The heating reaction temperature is 40-100°C.

8. The method for preparing the B(4) site alkylated carborane compound according to any one of claims 1 to 7, characterized in that: After the reaction was completed, the reaction system was cooled to room temperature, the solvent was drained off under reduced pressure to obtain a crude product, which was then separated by column chromatography; the eluent was a mixed solvent of petroleum ether and dichloromethane, and the volume ratio of petroleum ether to dichloromethane was 1.5:1.

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