Synthesis method of imino spiro benzofuran compound
The synthesis of iminospirocyclic benzofuran compounds via phosphine-catalyzed [3+2] cycloaddition reaction solves the problems of low synthesis efficiency and harsh reaction conditions in existing technologies, achieving efficient synthesis and significant antibacterial activity.
Patent Information
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- LIAOCHENG KINGE SYNTHETIC MATERIAL
- Filing Date
- 2026-01-28
- Publication Date
- 2026-05-05
AI Technical Summary
Existing methods for synthesizing spirocyclic benzofuran compounds have low efficiency and selectivity, and require harsh reaction conditions, making them difficult to meet the needs of drug synthesis.
An iminospirocyclic benzofuran compound was synthesized by a phosphine-catalyzed [3+2] cycloaddition reaction, in which an iminobenzofuran derivative reacted with MBH carbonate under the action of a phosphine catalyst.
An efficient synthesis of iminospirocyclic benzofuran compounds under mild conditions was achieved, exhibiting excellent antibacterial activity and significant inhibitory effects against Gram-positive bacteria.
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Figure CN121974879A_ABST
Abstract
Description
Technical Field
[0001] This invention belongs to the field of pharmaceutical intermediate synthesis technology, specifically relating to a method for synthesizing iminospirocyclic benzofuran compounds. Background Technology
[0002] The information disclosed in this background section is intended only to enhance understanding of the overall background of the invention and is not necessarily to be construed as an admission or in any way implying that such information constitutes prior art known to those skilled in the art.
[0003] Spirocyclic compounds possess unique three-dimensional structures and rigid frameworks, which significantly enhance their interactions with receptor binding sites, thus solidifying their important role in drug discovery. Spirocyclic benzofurans, as a common structural unit, are widely found in various natural products, bioactive molecules, and drugs.
[0004] As attached Figure 1 The natural products and drug molecules containing spirocyclic benzofuran structures shown in the paper, such as Laurentristich-4-ol, have been established as an anticancer agent; Spiroapplanatumine K and Q, isolated from Ganoderma lucidum, have inhibitory activity against JAK3 kinase; Involucratustone B, collected from the rhizome of Stahlianthus involucratus, showed excellent anticancer effects in U-2OS and SMMC-7721 cytotoxicity assays; and Ganoleucin D was found to have good inhibitory effects on HMG-CoA reductase. However, existing methods for synthesizing these complex compounds have low efficiency and selectivity, and the reaction conditions are relatively harsh. Therefore, there is an urgent need to develop an efficient and concise method for synthesizing such spirocyclic compounds. Summary of the Invention
[0005] Based on the wide application of spirocyclic benzofuran compounds in medicinal chemistry, and to address the shortcomings of existing technologies, the present invention aims to provide a method for synthesizing iminospirocyclic benzofuran compounds. This invention provides a novel method based on a phosphine-catalyzed [3+2] cycloaddition reaction, which enables the efficient synthesis of iminospirocyclic benzofuran compounds. This method utilizes Morita-Baylis-Hillman (MBH) carbonate to react with iminobenzofuran derivatives under phosphine catalysis, yielding iminospirocyclic benzofuran compounds under mild reaction conditions.
[0006] To achieve the above objectives, the present invention is implemented through the following technical solution: A method for synthesizing iminospirocyclic benzofuran compounds, including the following: Under heating conditions, iminobenzofuran derivatives and MBH carbonates undergo a [3+2] cycloaddition reaction in the presence of a phosphine catalyst to yield iminospirocyclic benzofuran compounds. The reaction equation is as follows:
[0007] Preferably, in the synthesis reaction of iminospirocyclic benzofuran compounds, the temperature is 30~120 ℃ and the time is 6~24h.
[0008] Preferably, in the synthesis reaction of the iminospirocyclic benzofuran compound, the phosphine catalyst is at least one of diphenylcyclohexylphosphine, ethyldiphenylphosphine, and tri-p-tolylphosphine.
[0009] Preferably, in the synthesis reaction of iminospirocyclic benzofuran compounds, the solvent includes at least one of toluene, benzene, fluorobenzene, and bromobenzene.
[0010] Preferably, in the synthesis reaction of the iminospirocyclic benzofuran compound, the molar ratio of the iminobenzofuran derivative, MBH carbonate, and phosphine catalyst is 1:(1~1.5):(0.05~0.3).
[0011] The beneficial effects achieved by one or more technical solutions of the present invention are as follows: In this invention, an iminobenzofuran derivative and MBH carbonate undergo a [3+2] cycloaddition reaction under heating conditions and with the aid of a phosphine catalyst to yield an iminospirocyclic benzofuran compound. This method has the advantages of a simple and efficient synthetic route and mild reaction conditions. The synthesized iminospirocyclic benzofuran compound exhibits excellent antibacterial activity against Gram-positive bacteria, including Staphylococcus aureus and Bacillus subtilis. Attached Figure Description
[0012] The accompanying drawings, which form part of this invention, are used to provide a further understanding of the invention. The illustrative embodiments of the invention and their descriptions are used to explain the invention and do not constitute an improper limitation of the invention.
[0013] Figure 1 Natural products and drug molecules containing spirocyclic benzofuran structures.
[0014] Figure 2 1H NMR spectrum of iminospirocyclic benzofuran compounds Detailed Implementation
[0015] To enable those skilled in the art to better understand the technical solution of the present invention, the technical solution of the present invention will be described in detail below with reference to specific embodiments.
[0016] Example 1:
[0017] Under nitrogen protection, 50 mL of toluene, an iminobenzofuran derivative (3.75 g, 10 mmol), and MBH carbonate (4.5 g, 12 mmol) were added to a reaction flask. Diphenylcyclohexylphosphine (0.54 g, 2 mmol) was then added with stirring, and the mixture was rapidly stirred at 60 °C for 12 hours. After the reaction was complete, the solvent was removed by vacuum distillation, and the product was separated by column chromatography to obtain 4.93 g of the iminospirocyclic benzofuran compound, with a yield of 78%.
[0018] The 1H NMR spectra of the iminospirocyclic benzofuran compound are attached. Figure 2 Shown, 1H NMR (500 MHz,Chloroform-d) δ 7.91 – 7.86 (m, 1H), 7.65 – 7.59 (m, 2H), 7.28 – 7.18 (m,5H), 7.14 – 7.08 (m, 2H), 7.09 – 7.02 (m, 2H), 6.66 – 6.61 (m, 2H), 6.52 –6.47 (m, 2H), 4.74 (dd, J = 12.7, 3.4 Hz, 1H), 4.43 (dd, J = 12.8, 4.4 Hz,1H), 3.73 (dq, J = 10.7, 7.1 Hz, 1H), 3.59 (dq, J = 10.8, 7.1 Hz, 1H), 3.51(dd, J = 4.3, 3.4 Hz, 1H), 2.34 (s, 3H), 0.73 (t, J = 7.2 Hz, 3H).
[0019] Example 2:
[0020] Under nitrogen protection, 50 mL of toluene, an iminobenzofuran derivative (3.75 g, 10 mmol), and MBH carbonate (4.5 g, 12 mmol) were added to a reaction flask. Diphenylethylphosphine (0.43 g, 2 mmol) was then added with stirring, and the mixture was rapidly stirred at 60 °C for 12 hours. After the reaction was complete, the solvent was removed by vacuum distillation, and the product was separated by column chromatography to obtain 4.55 g of the iminospirocyclic benzofuran compound, with a yield of 72%.
[0021] Example 3:
[0022] Under nitrogen protection, 50 mL of toluene, an iminobenzofuran derivative (3.75 g, 10 mmol), and MBH carbonate (4.5 g, 12 mmol) were added to a reaction flask. Diphenylcyclohexylphosphine (0.54 g, 2 mmol) was then added with stirring, and the mixture was rapidly stirred at 70 °C for 12 hours. After the reaction was complete, the solvent was removed by vacuum distillation, and the product was separated by column chromatography to obtain 4.74 g of the iminospirocyclic benzofuran compound, with a yield of 75%.
[0023] Example 4:
[0024] Under nitrogen protection, 50 mL of benzene, an iminobenzofuran derivative (3.75 g, 10 mmol), and MBH carbonate (4.5 g, 12 mmol) were added to a reaction flask. Diphenylcyclohexylphosphine (0.54 g, 2 mmol) was then added with stirring, and the mixture was rapidly stirred at 60 °C for 12 hours. After the reaction was complete, the solvent was removed by vacuum distillation, and the product was separated by column chromatography to obtain 3.99 g of the iminospirocyclic benzofuran compound, with a yield of 63%.
[0025] Example 5:
[0026] Under nitrogen protection, 50 mL of toluene, an iminobenzofuran derivative (3.75 g, 10 mmol), and MBH carbonate (4.5 g, 12 mmol) were added to a reaction flask. Diphenylcyclohexylphosphine (0.54 g, 2 mmol) was then added with stirring, and the mixture was rapidly stirred at 60 °C for 14 hours. After the reaction was complete, the solvent was removed by vacuum distillation, and the product was separated by column chromatography to obtain 4.81 g of the iminospirocyclic benzofuran compound, with a yield of 76%.
[0027] We evaluated the in vitro antibacterial activity of the iminospirocyclic benzofuran compound synthesized in Example 1 against Staphylococcus aureus, Bacillus subtilis, Escherichia coli, and Pseudomonas aeruginosa. The antibacterial activity results showed that the iminospirocyclic benzofuran compound exhibited moderate antibacterial activity against the tested Gram-positive bacteria, including Staphylococcus aureus and Bacillus subtilis. Against Staphylococcus aureus (S. aureus ATCC31007), its minimum inhibitory concentration (MIC) was 1-2 μg / mL, demonstrating an inhibitory effect comparable to vancomycin.
[0028]
[0029] The above description is merely a preferred embodiment of the present invention and is not intended to limit the invention. Various modifications and variations can be made to the present invention by those skilled in the art. Any modifications, equivalent substitutions, improvements, etc., made within the spirit and principles of the present invention should be included within the scope of protection of the present invention.
Claims
1. A method for synthesizing iminospirocyclic benzofuran compounds, comprising the following: under heating conditions, iminobenzofuran derivatives and MBH carbonate undergo a [3+2] cycloaddition reaction in the presence of a phosphine catalyst to obtain iminospirocyclic benzofuran compounds.
2. The method as described in claim 1, characterized in that, In the synthesis reaction of iminospirocyclic benzofuran compounds, the temperature is 30~120 °C and the time is 6~24 h.
3. The method as described in claim 1, characterized in that, In the synthesis reaction of iminospirocyclic benzofuran compounds, the phosphine catalyst is one of diphenylcyclohexylphosphine, ethyldiphenylphosphine, and tri-tolylphosphine.
4. The method as described in claim 1, characterized in that, In the synthesis reaction of iminospirocyclic benzofuran compounds, the solvent is one of toluene, benzene, fluorobenzene, and bromobenzene.
5. The method as described in claim 1, characterized in that, In the synthesis reaction of iminospirocyclic benzofuran compounds, the molar ratio of the iminobenzofuran derivative, MBH carbonate, and phosphine catalyst is 1:(1~1.5):(0.05~0.3).