A method for the synthesis of a biphenyl aldehyde intermediate
By using catalysts such as bipyridine, 2,2,6,6-tetramethylpiperidine oxide and N-methylimidazolium, combined with air oxidants, the problem of excessive oxidizing power in the synthesis of biphenylaldehyde intermediates was solved, achieving efficient, low-cost and environmentally friendly preparation of biphenylaldehyde intermediates.
Patent Information
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- SUZHOU NOVARTIS PHARMA TECHONOLOGY CO LTD
- Filing Date
- 2024-12-26
- Publication Date
- 2026-06-26
AI Technical Summary
In existing technologies, the synthesis methods for biphenylaldehyde intermediates are too oxidizing, prone to over-oxidation, have low yields, and generate a large amount of waste after the reaction, resulting in high costs and making them unsuitable for industrial production.
Using bipyridine, 2,2,6,6-tetramethylpiperidine oxide, N-methylimidazolium and halogenated cuprous compounds as catalysts and air as an oxidant, the intermediate biphenylaldehyde is prepared through a mild oxidation reaction, avoiding the use of large amounts of oxidant and reducing the generation of waste.
This method enables the efficient and low-cost synthesis of biphenylaldehyde intermediates. The product is not easily over-oxidized, has high conversion and yield, high purity, and reduces the generation of waste.
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Figure CN122277378A_ABST
Abstract
Description
Technical Field
[0001] This invention belongs to the field of pharmaceutical chemical industry, and specifically relates to a method for synthesizing a biphenylaldehyde intermediate. Background Technology
[0002] Compounds containing biphenylaldehyde structural units exhibit excellent biological activities in anti-HIV-1 virus, anti-tumor, anti-cell proliferation, anti-epileptic, anti-hypertensive, anti-inflammatory, antioxidant, and anti-parasitic effects. In addition, these compounds can also be used as metal ligands.
[0003] The structural formula of the biphenylaldehyde compound is as follows:
[0004]
[0005] Compound B is a key intermediate in the preparation of biphenyl aldehyde. Traditional methods for preparing aldehydes by alcohol oxidation include PCC oxidation, PDC oxidation, Jones oxidation, Dess-Martin oxidation, and IBX oxidation. However, these methods are highly oxidizing and prone to over-oxidation, resulting in low yields. Swern oxidation produces odorous dimethyl sulfide.
[0006] In recent years, TEMPO (2,2,6,6-tetramethylpiperidine oxygen radical) has shown excellent catalytic performance as a catalyst when using strong oxidizing agents, such as sodium hypochlorite, m-CPBA, KHSO5, NaBrO2, H5IO6, and trichloroisocyanuric acid, as stoichiometric oxidants to oxidize alcohols. However, these reactions have low atom utilization and require the addition of excess sodium thiosulfate as a reducing agent for quenching, resulting in significant amounts of waste.
[0007] The Journal of the American Chemical Society (2020), 142(11), 5017-5023, disclosed the use of TEMPO as a catalyst for oxidation reactions. However, the co-catalyst Cu(MeCN)OTf used in this study is expensive and not suitable for industrial production.
[0008] Therefore, developing a mild, efficient, and low-cost oxidation system is extremely important for this reaction. Summary of the Invention
[0009] The purpose of this invention is to provide a method for synthesizing a biphenylaldehyde intermediate.
[0010] To achieve the technical objective of this invention, the technical solution of this invention is as follows:
[0011] This invention provides a method for synthesizing a biphenyl aldehyde intermediate, wherein compound B is prepared by an oxidation reaction of compound A in the presence of a catalyst.
[0012]
[0013] The oxidation reaction catalysts are bipyridine (Bpy), 2,2,6,6-tetramethylpiperidine oxide (TEMPO), N-methylimidazole (NMI), and cuprous halogen compounds.
[0014] The preferred preparation process for the benzyl aldehyde intermediate of the present invention is as follows:
[0015]
[0016] Compound A, cuprous chloride, bipyridine (Bpy), 2,2,6,6-tetramethylpiperidine oxide (TEMPO), and N-methylimidazole (NMI) were added to the solvent; air was introduced below the liquid surface, and the mixture was stirred at room temperature for 12-24 hours until the reaction was complete. The mixture was then washed with water and separated, and the organic phase was used directly for the next step.
[0017] The solvent for the oxidation reaction is a hydrophobic solvent, preferably ethyl acetate, 2-methyltetrahydrofuran, isopropyl acetate, methyl tert-butyl ether, or toluene.
[0018] The oxidation reaction temperature is 10–50°C, with room temperature being more preferred.
[0019] In the oxidation reaction, the molar ratio of compound A to cuprous chloride ranges from 1:0.04 to 0.06, with a preferred molar ratio of 1:0.05.
[0020] In the oxidation reaction, the molar ratio of compound A to Bpy (2,2'-bipyridine) ranges from 1:0.04 to 0.06, with a preferred molar ratio of 1:0.05.
[0021] In the oxidation reaction, the molar ratio of compound A to TEMPO ranges from 1:0.04 to 0.06, with a preferred molar ratio of 1:0.05.
[0022] In the oxidation reaction, the molar ratio of compound A to NMI ranges from 1:0.04 to 0.06, with a preferred molar ratio of 1:0.05.
[0023] The beneficial effects of this invention are: simple process, low cost, avoidance of the use of a large amount of oxidant, use of air as oxidant, water as by-product, reduction of the generation of three wastes, mild reaction conditions, the product is not easily over-oxidized, high conversion rate, high yield, and high purity. Detailed Implementation
[0024] To further understand the present invention, a method for synthesizing a biphenyl aldehyde intermediate provided by the present invention will be described in detail below with reference to embodiments. It should be understood that these embodiments are described only to further illustrate the features of the present invention, and are not intended to limit the scope of the present invention or the scope of the claims.
[0025] Example 1:
[0026] Weigh 1 g of compound A, 0.05 equivalents of cuprous chloride, 0.05 equivalents of Bpy (2,2'-bipyridine), 0.05 equivalents of TEMPO, and 0.05 equivalents of NMI into ethyl acetate (10 ml). Stir to obtain a solution. Aeration is introduced into the solution at room temperature, and the mixture is stirred for 12 hours at room temperature until the reaction is complete. Wash with water (10 ml), separate the layers, and concentrate the organic phase to dryness. Use directly in the next step; purity 98%, yield 97%.
[0027] Example 2:
[0028] Weigh 1 g of compound A, 0.05 equivalents of cuprous chloride, 0.05 equivalents of Bpy (2,2'-bipyridine), 0.05 equivalents of TEMPO, and 0.05 equivalents of NMI into 10 ml of 2-methyltetrahydrofuran. Stir to obtain a solution. Aeration is introduced into the solution at room temperature, and the mixture is stirred for 12 hours until the reaction is complete. Wash with 10 ml of water, separate the layers, and concentrate the organic phase to dryness. Use directly in the next step; purity 96%, yield 94%.
[0029] Example 3
[0030] Weigh 1 g of compound A, 0.05 equivalents of cuprous chloride, 0.05 equivalents of Bpy (2,2'-bipyridine), 0.05 equivalents of TEMPO, and 0.05 equivalents of NMI into 10 ml of isopropyl acetate, and then stir to obtain a solution. Air is bubbled into the solution at room temperature, and the mixture is stirred for 12 hours at room temperature until the reaction is complete. Wash with 10 ml of water, separate the layers, and concentrate the organic phase to dryness for use in the next step; purity 97%, yield 95%.
[0031] Example 4
[0032] Weigh 1 g of compound A, 0.05 equivalents of cuprous chloride, 0.05 equivalents of Bpy (2,2'-bipyridine), 0.05 equivalents of TEMPO, and 0.05 equivalents of NMI into methyl tert-butyl ether (10 ml), and stir to obtain a solution. Air is bubbled into the solution at room temperature, and the mixture is stirred for 12 hours at room temperature until the reaction is complete. The solution is washed with water (10 ml), separated, and the organic phase is concentrated to dryness and used directly in the next step; purity 90%, yield 86%.
[0033] Example 5
[0034] Weigh 1 g of compound A, 0.05 equivalents of cuprous chloride, 0.05 equivalents of Bpy (2,2'-bipyridine), 0.05 equivalents of TEMPO, and 0.05 equivalents of NMI into toluene (10 ml), and stir to obtain a solution. Air is bubbled into the solution at room temperature, and the mixture is stirred for 12 hours at room temperature until the reaction is complete. The solution is washed with water (10 ml), separated, and the organic phase is concentrated to dryness and used directly in the next step; purity 95%, yield 93%.
Claims
1. A method for synthesizing a biphenyl aldehyde intermediate, characterized in that, Compound B is prepared by oxidation of compound A in the presence of a catalyst and with air as the oxidant.
2. The synthesis method according to claim 1, characterized in that, The catalysts for the above oxidation reactions are bipyridine (Bpy), 2,2,6,6-tetramethylpiperidine oxide (TEMPO), N-methylimidazolium (NMI), and cuprous halogen compounds.
3. The synthesis method according to claim 1 or 2, characterized in that, The above-mentioned oxidation reaction preparation process is as follows: Compound A, cuprous chloride, bipyridine (Bpy), 2,2,6,6-tetramethylpiperidine oxide (TEMPO) and N-methylimidazole (NMI) are added to the solvent; air is introduced to below the liquid surface, and after stirring for 12-24 hours, the reaction is completed. Water is added to wash and separate the liquid, and the organic phase is directly used for the next step.
4. The synthesis method according to claim 1 or 3, characterized in that, The solvent used in the oxidation reaction is a hydrophobic solvent.
5. The synthesis method according to claim 1 or 3, characterized in that, The oxidation reaction temperature is 10–50°C.
6. The synthesis method according to claim 3, characterized in that, In the oxidation reaction, the molar ratio of compound A to cuprous chloride ranges from 1:0.04 to 0.
06.
7. The synthesis method according to claim 3, characterized in that, The molar ratio of compound A to Bpy (2,2'-bipyridine) in the oxidation reaction is in the range of 1:0.04 to 0.
06.
8. The synthesis method according to claim 3, characterized in that, The molar ratio of compound A to TEMPO in the oxidation reaction is in the range of 1:0.04 to 0.
06.
9. The synthesis method according to claim 3, characterized in that, The molar ratio of compound A to NMI in the oxidation reaction is in the range of 1:0.04 to 0.
06.
10. The synthesis method according to claim 4, characterized in that, The solvent for the oxidation reaction can be selected from ethyl acetate, 2-methyltetrahydrofuran, isopropyl acetate, methyl tert-butyl ether, or toluene.