A preparation method of a nickel-based metal organic framework for constructing drug intermediates through C-H bond oxidation

Abstract

This invention discloses a method for preparing a nickel-based metal-organic framework for constructing pharmaceutical intermediates through C-H bond oxidation and its catalytic application, belonging to the field of fine chemical synthesis. This invention employs a solvothermal synthesis strategy, using triphenylphosphinocarboxylic acid ligand HBPB as the organic linking unit, and reacting it with Ni²⁺ from nickel nitrate hexahydrate, nickel chloride, or nickel acetate tetrahydrate. + Coordination was used to prepare a three-dimensional porous metal-organic framework material, Ni-L. This invention details the preparation steps and process parameters for the intermediate HBPB ligand and Ni-L crystals. The prepared Ni-L exhibits large porosity, chemical stability, and abundant catalytic active sites. It can activate inert C-H bonds via hydrogen atom transfer under photoexcitation, efficiently catalyzing the oxidation reaction of tetrahydroisoquinoline and its derivatives under oxygen atmosphere and light irradiation conditions. The yield of the target product can reach over 90%. It has advantages such as low raw material cost, simple synthetic route, high selectivity and conversion rate, and environmental friendliness, making it suitable for the efficient synthesis of pharmaceutical intermediates.

Description

Technical Field

[0001] This invention relates to the field of nickel-based metal technology, and more particularly to a method for preparing a nickel-based metal organic framework for constructing pharmaceutical intermediates by CH bond oxidation. Background Technology

[0002] Direct functionalization of CH bonds is an important strategy in modern organic synthetic chemistry because it can efficiently and concisely transform inert CH bonds into high-value functional groups (such as CO, CN, and CC bonds), and has wide applications in the synthesis of drug molecules, natural products, and functional materials. Traditional CH bond oxidation methods typically rely on noble metal catalysts (such as palladium and rhodium) or strong oxidants, which suffer from high costs, poor selectivity, and environmental pollution. Therefore, developing efficient, green, and economical CH bond oxidation catalytic systems has become one of the research hotspots in synthetic chemistry.

[0003] Metal-organic frameworks (MOFs), as an emerging type of porous crystalline material, have shown great potential in CH bond oxidation reactions due to their highly tunable pore structure, abundant active sites, and excellent catalytic performance. MOFs can achieve efficient catalysis not only through the synergistic effect of metal nodes and organic ligands, but also improve reaction selectivity through pore confinement effects. Furthermore, the structural designability of MOFs allows for the optimization of catalytic performance for specific reactions, providing a novel solution for CH bond oxidation.

[0004] This patent describes a highly efficient and green CH bond oxidation catalytic system based on nickel-based metal-organic frameworks (Ni-MOFs) for the construction of drug intermediates. This system not only overcomes the limitations of traditional methods but also achieves high selectivity and high conversion rates through the structural advantages of Ni-MOFs, providing an economical and sustainable new route for drug molecule synthesis. Summary of the Invention

[0005] To overcome the limitations of existing technologies, the objective of this invention is to propose a method for preparing and applying a nickel-based metal-organic framework (MOF) for the activation and oxidation of inert CH bonds. The MOF compound prepared by this method possesses large pores, enabling effective adsorption of substrates and thus promoting efficient reaction between the catalytic site and the substrate. Simultaneously, this framework material can reach a high-energy state through photoexcitation and activate the inert CH bond via hydrogen atom transfer, ultimately successfully oxidizing the bond.

[0006] To achieve the above objectives and solve the problems in the prior art, the technical solution adopted in this invention is as follows: a solvothermal synthesis method is used, employing triphenylphosphinocarboxylic acid ligand HBPB as the organic linking unit, and combining it with Ni² in a nickel salt. + Ion coordination was used to construct the metal-organic framework material Ni-L. The basic equation for its synthesis reaction is: Ni2++L→Ni-L; The ligand L is HBPB; The transition metal cobalt salt is selected from one of nickel nitrate hexahydrate, nickel chloride, or nickel acetate tetrahydrate. The ligand HBPB has the following molecular structure (A).

[0007] The preparation method includes the following steps: Step 1: In glacial acetic acid solvent (5.0~8.0 mL), add bromine water and triphenylphosphine at a molar ratio of 3.5~5.5:1, and stir continuously at 70~80℃ for 3~4 hours. After natural cooling and vacuum filtration, the resulting solid is washed three times with glacial acetic acid (100~150 mL) to obtain a pale yellow crude intermediate 1. This product is dehydrated in a vacuum drying oven at 60~75℃ to obtain high-purity intermediate 1.

[0008] Step 2: Dissolve intermediate 1 (1.2~2 mol) and p-4-boronate pyridine (molar ratio 1.5~3:1) in a dioxane / water mixed solvent (60~70 mL, volume ratio 1:2~3:5), then add potassium carbonate or cesium carbonate (2~3 mol) and palladium catalyst (0.01~0.015 mol). After the reaction is completed in 22~25 hours under nitrogen protection, the mixture is separated by extraction, purified by column chromatography (elution system: n-hexane / dichloromethane = 3:1~2:1), and distilled under reduced pressure to obtain yellow HBPB powder, which is then dried under vacuum at 60~75℃ for later use.

[0009] Step 3: Disperse the HBPB ligand and nickel salt in a molar ratio of 2:3 to 3:3 in a mixed solvent of N,N-dimethylformamide / water (6 to 10 mL, volume ratio 1:1 to 2). In a forced-air drying oven, gradually increase the temperature to 100 to 160°C. After cooling, red Ni-L crystals precipitate, which are then separated to obtain the target product.

[0010] Application of nickel-based metal-organic frameworks in the catalytic oxidation of tetrahydroisoquinoline.

[0011] The beneficial effects of this invention are: a method for preparing a nickel-based metal-organic framework for inert CH bond activation oxidation reaction and its application, wherein the preparation method uses Ni2+ in transition metal nickel salt as the metal node and triphenylphosphocarboxylic acid ligand L as the linker, and obtains the metal-organic framework coordination polymer by solvothermal method, the synthetic route of which is as follows: Ni2++L→Ni L, where the ligand L is HBPB, and the transition metal cobalt salt is selected from nickel nitrate hexahydrate, nickel chloride, or nickel acetate tetrahydrate; compared with existing technologies, this method prepares metal-organic framework compounds with a three-dimensional porous structure that readily interacts with the substrate, exposing a large number of Ni metal nodes in the three-dimensional channels. Simultaneously, the raw materials are inexpensive, the yield is high, and the resulting compound exhibits stable chemical properties, making it easy to apply in practical situations. As a compound, Ni-L achieves a yield of up to 95% in the catalytic oxidation of CH bonds. Attached Figure Description

[0012] Figure 1 This is a flowchart illustrating the preparation process of the Ni-L compound of the present invention.

[0013] Figure 2 This is a crystal structure diagram of the compound Ni-L of the present invention.

[0014] Figure 3 The image shows the XRD pattern of the compound Ni-L from this invention.

[0015] Figure 4 The graph shows the change in yield over time of the Ni-L compound catalytic oxidation reaction of tetrahydroisoquinoline under illumination. Detailed Implementation

[0016] The technical solutions in the embodiments of the present invention will be clearly and completely described below with reference to the accompanying drawings. Obviously, the described embodiments are only some embodiments of the present invention, and not all embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those skilled in the art without creative effort are within the scope of protection of the present invention.

[0017] Please see the appendix Figure 1 - Appendix Figure 4 This invention provides a method for preparing a nickel-based metal-organic framework for inert CH bond activation oxidation reaction and its application.

[0018] Example 1: In glacial acetic acid solvent (7.0 mL), bromine water and triphenylphosphine were added at a molar ratio of 3.5–5.5:1, and the mixture was stirred continuously at 70 °C for 4 hours. After natural cooling and vacuum filtration, the resulting solid was washed three times with glacial acetic acid (150 mL) to obtain a pale yellow crude intermediate 1. This product was dehydrated in a vacuum drying oven at 60 °C to obtain high-purity intermediate 1. ¹H NMR (400 MHz, CDCl₃, ppm): δ 7.78 (d, J = 12.7 Hz, 6H), 7.27 (d, 6H). Intermediate 1 (1.2 mol) and p-4-boronate pyridine (molar ratio 2:1) were dissolved in a dioxane / water mixed solvent (60 mL, volume ratio 1:2), followed by the addition of potassium carbonate or cesium carbonate (2 mol) and palladium catalyst (0.01 mol). After 25 hours of reaction under nitrogen protection, the mixture was separated by extraction, purified by column chromatography (elution system: n-hexane / dichloromethane = 3:1), and distilled under reduced pressure to obtain a yellow HBPB powder, which was dried under vacuum at 60 °C for later use. ¹H NMR (400 MHz, CDCl₃, ppm): δ 8.11 (d, 2H), δ 7.87 (m, 6H), 7.45 (d, 2H), 7.47 (m, 6H). HBPB ligand and nickel salt were dispersed in a 2:3 molar ratio in a mixed solvent of N,N-dimethylformamide / water (6 mL, volume ratio 1:1). The mixture was reacted in a drying oven with a gradient heating to 120 °C. After cooling, red Ni-L crystals precipitated, which were separated to obtain the target product (37.0 mg, yield 52%). Its crystal structure diagram is shown below. Figure 1 As shown, its XRD pattern is as follows. Figure 2 As shown. Elemental analysis revealed the following values ​​for the compound NiC29H20N2PO9: Calculated values: C, 52.28%; H, 3.20%; N, 4.45%; Measured values: C, 52.78%; H, 3.29%; N, 4.85%. Example 2: The ligand HBPB (62.9 mg, 0.1 mmol) and nickel chloride (12.0 mg, 0.11 mmol) from Example 1 were weighed and added to 6 mL of N,N-dimethylformamide / water mixed solvent with a volume ratio of 1:2. The mixture was heated to 100 °C in a forced-air drying oven and cooled to room temperature to precipitate red crystals, thus obtaining the target compound Ni-L (33.0 mg, yield 47%).

[0019] Example 3: The ligand HBPB (52.9 mg, 0.1 mmol) and nickel acetate tetrahydrate (24.0 mg, 0.11 mmol) from Example 1 were weighed and added to 6 mL of N,N-dimethylformamide / water mixed solvent with a volume ratio of 1:2. The mixture was heated to 100°C in a forced-air drying oven and cooled to room temperature to precipitate green crystals, thus obtaining the target compound Ni-L (24.0 mg, yield 33%).

[0020] Example 4: Ni-L catalytic oxidation of tetrahydroisoquinoline In a 20 mL photoreaction tube, 5 mL of acetonitrile solution was added, followed by 5.0 mg of Ni-L and 13.3 mg of tetrahydroisoquinoline. The reactor was placed in an oxygen atmosphere and irradiated with a 400 nm LED light source for 12 h. 14.0 mg of the target compound was generated, with a yield of 95.2%. The reaction yield over time is shown in the graph below. Figure 3 As shown.

[0021] Implementation Example 5: Ni-L catalytic oxidation of 2-phenyl-1,2,3,4-tetrahydroisoquinoline In a 20 mL photoreactor, 5 mL of acetonitrile solution was added, followed by 5.0 mg of Ni-L and 20.9 mg of 2-phenyl-1,2,3,4-tetrahydroisoquinoline. The reactor was placed in an oxygen atmosphere and irradiated with a 400 nm LED light source for 12 h, resulting in the formation of 21.0 mg of the target compound, with a yield of 94.1%.

[0022] Example 6 Using Ce BTP-catalyzed oxidation of 2,3-diphenyl-1,2,3,4-tetrahydroisoquinoline In a 20 mL photoreactor, 5 mL of acetonitrile solution was added, followed by 5.0 mg of Ni-L and 28.5 mg of 2,3-diphenyl-1,2,3,4-tetrahydroisoquinoline. The reactor was placed in an oxygen atmosphere and irradiated with a 400 nm LED light source for 12 h, resulting in the formation of 27.0 mg of the target compound, with a yield of 90.3%.

[0023]

[0024] A solvothermal synthesis strategy was employed, using the triphenylphosphinocarboxylic acid ligand H3ACA as the organic linking unit, and reacting with Ni² in a transition metal nickel salt. + Ion coordination is used to construct Ni-L metal-organic framework materials. The general formula for the synthesis reaction is as follows: Ni²⁺L→Ni L; The ligand L is HBPB; The transition metal cobalt salt is selected from one of nickel nitrate hexahydrate, nickel chloride, or nickel acetate tetrahydrate. The ligand HBPB has the following molecular structure (A).

[0025] Although embodiments of the invention have been shown and described, it will be understood by those skilled in the art that various changes, modifications, substitutions and alterations can be made to these embodiments without departing from the principles and spirit of the invention, the scope of which is defined by the appended claims and their equivalents.

Claims

1. A method for preparing a nickel-based metal-organic framework for constructing pharmaceutical intermediates by CH bond oxidation, characterized in that, Using triphenylphosphocarboxylic acid ligand HBPB as the organic ligand, and Ni²-containing + Ni-L metal-organic framework materials are synthesized from nickel salts via a solvothermal coordination method. The general reaction formula is: Ni² + +L→Ni-L, where L is the HBPB ligand; The nickel salt is selected from one of nickel nitrate hexahydrate, nickel chloride, and nickel acetate tetrahydrate. This invention uses HBPB (triphenylphosphocarboxylic acid ligand) with a specific structure as an organic linker, and binds it to Ni²⁺ via a solvothermal method. + A novel nickel-based metal-organic framework (MOF) material, NiL, was successfully synthesized through coordination. A search of domestic and international literature and patent databases revealed no prior reports of MOFs constructed using HBPB as a ligand; both this ligand and the NiL material are disclosed for the first time. Existing triphenylphosphine-based MOFs all employ tricarboxylic acid-substituted ligands (such as H3tpp), while the HBPB ligand of this invention introduces a pyridine group through a Suzuki coupling reaction, forming a structure where the carboxyl group and pyridine nitrogen are coordinated, resulting in Ni²⁺. + It provides a unique coordination environment, which significantly affects its photocatalytic performance.

2. The method for preparing a nickel-based metal-organic framework for constructing a drug intermediate by CH bond oxidation according to claim 1, characterized in that, Includes the following steps: S1: In glacial acetic acid solvent, bromine water and triphenylphosphine were added at a molar ratio of 3.5~5.5:

1. The mixture was stirred at 70~80℃ for 3~4 hours. After cooling, vacuum filtration, washing with glacial acetic acid, and vacuum drying, intermediate 1 was obtained. S2: Intermediate 1 and p-4-boron ester pyridine were dissolved in a dioxane / water mixed solvent. Potassium carbonate or cesium carbonate and palladium catalyst were added. The mixture was reacted under nitrogen protection. After extraction, column chromatography purification, and vacuum distillation, HBPB ligand was obtained. S3: HBPB ligand and nickel salt were dispersed in a N,N-dimethylformamide / water mixed solvent. The mixture was heated to 100~160℃ in a gradient manner. After cooling, red Ni-L crystals precipitated. The target product was obtained by separation.

3. The method for preparing a nickel-based metal-organic framework for constructing a drug intermediate by CH bond oxidation according to claim 1, characterized in that, In step S2, the molar ratio of intermediate 1 to p-4-boronate pyridine is 1.5 to 3:1, and the column chromatography eluent is n-hexane / dichloromethane = 3:1 to 2:1; in step S3, the molar ratio of HBPB ligand to nickel salt is 2:3 to 3:

3.

4. The method for preparing a nickel-based metal-organic framework for constructing a drug intermediate by CH bond oxidation according to claim 1, characterized in that, The Ni-L prepared by any of the methods described in claim 1 is used to catalyze the oxidation reaction of tetrahydroisoquinoline and its derivatives, thereby activating and oxidizing inert CH bonds under light and oxygen atmosphere. The preparation method includes the following steps: Step S1: In glacial acetic acid solvent (5.0~8.0 mL), add bromine water and triphenylphosphine at a molar ratio of 3.5~5.5:1, and stir continuously at 70~80℃ for 3~4 hours. After natural cooling and vacuum filtration, the resulting solid is washed three times with glacial acetic acid (100~150 mL) to obtain a pale yellow crude intermediate 1. This product is dehydrated in a vacuum drying oven at 60~75℃ to obtain high-purity intermediate 1. Step S2: Dissolve intermediate 1 (1.2~2 mol) and p-4-boronate pyridine (molar ratio 1.5~3:1) in a dioxane / water mixed solvent (60~70 mL, volume ratio 1:2~3:5), then add potassium carbonate or cesium carbonate (2~3 mol) and palladium catalyst (0.01~0.015 mol). After the reaction is completed in 22~25 hours under nitrogen protection, the mixture is separated by extraction, purified by column chromatography (elution system: n-hexane / dichloromethane = 3:1~2:1), and distilled under reduced pressure to obtain yellow HBPB powder, which is then dried under vacuum at 60~75℃ for later use. Step S3: Disperse the HBPB ligand and nickel salt in a molar ratio of 2:3 to 3:3 in a mixed solvent of N,N-dimethylformamide / water (6 to 10 mL, volume ratio 1:1 to 2). In a forced-air drying oven, gradually increase the temperature to 100 to 160°C. After cooling, red Ni-L crystals precipitate, which are then separated to obtain the target product. Application of nickel-based metal-organic framework compounds prepared by the method according to the claims in the catalytic oxidation of tetrahydroisoquinoline.

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