Synthesis method of imino spiro benzofuran compound
Through the [3+2] cycloaddition reaction under the action of phosphine catalyst, the efficient synthesis of spirocyclobenzofuran compounds is achieved using MBH carbonate and iminobenzofuran derivatives, solving the problem of low synthesis efficiency and selectivity in the prior art, and the reaction conditions are mild.
Patent Information
- Application Number
- CN202510195133.7
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2025-02-21
- Publication Date
- 2025-05-13
- Estimated Expiration
- Not applicable · inactive patent
AI Technical Summary
The existing methods have low efficiency and selectivity for synthesis of spirocyclic benzofuran compounds, and the reaction conditions are relatively harsh, making it difficult to meet the needs of drug synthesis.
Using the [3+2] cycloaddition reaction based on phosphine catalyzed, the reaction of Morita-Baylis-Hillman (MBH) carbonate and iminobenzofuran derivatives under the action of phosphine catalysts is achieved to achieve the efficient synthesis of iminospirocyclobenzofuran compounds.
This method can efficiently synthesize iminospirocyclobenzofuran compounds under mild reaction conditions, which has the advantages of simplicity and efficiency, and avoids the problem of harsh reaction conditions in traditional methods.
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Figure CN119977927A_ABST
Abstract
Description
Technical Field
[0001] The invention belongs to the technical field of pharmaceutical intermediate synthesis, and particularly relates to a method for synthesizing an iminospirocyclic benzofuran compound. Background Art
[0002] The information disclosed in this background technology section is only intended to enhance the understanding of the overall background of the invention, and should not necessarily be regarded as an admission or any form of suggestion that the information constitutes the prior art already known to a person skilled in the art.
[0003] Spirocyclic compounds have unique three-dimensional structures and rigid frameworks that can significantly enhance their interactions with receptor binding sites, thus consolidating their important position in the drug discovery process. As a common structural unit, spirocyclic benzofuran compounds are widely present in various natural products, bioactive molecules and drugs.
[0004]
[0005] like Figure 1 Among the natural products and drug molecules containing spirocyclic benzofuran structures shown in the article, Laurentristich-4-ol has 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 tests; Ganoleucin D was found to have a good inhibitory effect on HMG-CoA reductase. However, the existing methods for synthesizing these complex structure compounds have low efficiency and selectivity, and the reaction conditions are relatively harsh, so it is urgent to develop an efficient and simple method for synthesizing such spirocyclic compounds. Summary of the invention
[0006] Based on the wide application of spirocyclic benzofuran compounds in medicinal chemistry and in order to solve the deficiencies of the prior art, the purpose of the present invention is to provide a method for synthesizing iminospirocyclic benzofuran compounds. The present invention provides a new method based on a phosphine-catalyzed [3+2] cycloaddition reaction, by which iminospirocyclic benzofuran compounds can be efficiently synthesized. The method uses Morita-Baylis-Hillman (MBH) carbonate and iminobenzofuran derivatives to react under the catalysis of a phosphine catalyst, and can obtain iminospirocyclic benzofuran compounds under mild reaction conditions.
[0007] In order to achieve the above object, the present invention is implemented through the following technical solutions: The synthesis method of an iminospirocyclic benzofuran compound comprises the following contents: Under heating conditions, the iminobenzofuran derivative and MBH carbonate undergo a [3+2] cycloaddition reaction in the presence of a phosphine catalyst to obtain an iminospirocyclic benzofuran compound, and the reaction equation is:
[0008] Preferably, in the synthesis reaction of the iminospirocyclic benzofuran compound, the temperature is 30-120° C. and the time is 6-24 h.
[0009] Preferably, in the synthesis reaction of the iminospirocyclic benzofuran compound, the phosphine catalyst is at least one of diphenylcyclohexylphosphine, ethyldiphenylphosphine and tri-p-tolylphosphine.
[0010] Preferably, in the synthesis reaction of the iminospirocyclic benzofuran compound, the solvent comprises at least one of toluene, benzene, fluorobenzene and bromobenzene.
[0011] 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).
[0012] The beneficial effects achieved by one or more technical solutions of the present invention are as follows: In the present invention, the iminobenzofuran derivative and MBH carbonate undergo a [3+2] cycloaddition reaction under heating conditions and the action of a phosphine catalyst to obtain an iminospirocyclic benzofuran compound. The method has the advantages of a simple and efficient synthesis route and mild reaction conditions. BRIEF DESCRIPTION OF THE DRAWINGS
[0013] The accompanying drawings in the specification, which constitute a part of the present invention, are used to provide a further understanding of the present invention. The exemplary embodiments of the present invention and their descriptions are used to explain the present invention and do not constitute improper limitations on the present invention.
[0014] Figure 1 Natural products and drug molecules containing spirocyclic benzofuran structures Figure 2 H-NMR Spectra of Iminospirobenzofuran Compounds DETAILED DESCRIPTION
[0015] In order to enable those skilled in the art to more clearly understand the technical solution of the present invention, the technical solution of the present invention will be described in detail below in conjunction with specific embodiments.
[0016] Embodiment 1:
[0017] Under nitrogen protection, 50 mL of toluene, iminobenzofuran derivative (3.75 g, 10 mmol) and MBH carbonate (4.5 g, 12 mmol) were added to the reaction bottle, and diphenylcyclohexylphosphine (0.54 g, 2 mmol) was added under 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 4.93 g of iminospirobenzofuran compound was obtained by column chromatography separation with a yield of 78%.
[0018] The H NMR spectra of the iminospirocyclic benzofuran compounds are shown in the 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). Embodiment 2:
[0019]
[0020] Under nitrogen protection, 50 mL of toluene, iminobenzofuran derivative (3.75 g, 10 mmol) and MBH carbonate (4.5 g, 12 mmol) were added to the reaction bottle, and diphenylethylphosphine (0.43 g, 2 mmol) was added under 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 4.55 g of iminospirobenzofuran compound was obtained by column chromatography separation with a yield of 72%.
[0021] Embodiment 3:
[0022] Under nitrogen protection, 50 mL of toluene, iminobenzofuran derivative (3.75 g, 10 mmol) and MBH carbonate (4.5 g, 12 mmol) were added to the reaction bottle, and diphenylcyclohexylphosphine (0.54 g, 2 mmol) was added under 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 4.74 g of iminospirobenzofuran compound was obtained by column chromatography separation with a yield of 75%.
[0023] Embodiment 4:
[0024] Under nitrogen protection, 50 mL of benzene, iminobenzofuran derivative (3.75 g, 10 mmol) and MBH carbonate (4.5 g, 12 mmol) were added to the reaction bottle, and diphenylcyclohexylphosphine (0.54 g, 2 mmol) was added under 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 3.99 g of iminospirobenzofuran compound was obtained by column chromatography separation with a yield of 63%.
[0025] Embodiment 5:
[0026] Under nitrogen protection, 50 mL of toluene, iminobenzofuran derivative (3.75 g, 10 mmol) and MBH carbonate (4.5 g, 12 mmol) were added to the reaction bottle, and diphenylcyclohexylphosphine (0.54 g, 2 mmol) was added under 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 4.81 g of iminospirobenzofuran compound was obtained by column chromatography separation with a yield of 76%.
[0027] The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention. For those skilled in the art, the present invention may have various modifications and variations. Any modification, equivalent replacement, improvement, etc. made within the spirit and principle of the present invention shall be included in the protection scope of the present invention.
Claims
1. A method for synthesizing an iminospirocyclic benzofuran compound, comprising the following contents: Under heating conditions, iminobenzofuran derivatives and MBH carbonate undergo [3+2] cycloaddition reaction in the presence of a phosphine catalyst to obtain iminospirocyclic benzofuran compounds.
2. The method according to claim 1, characterized in that In the synthesis reaction of the iminospirocyclic benzofuran compound, the temperature is 30-120° C. and the time is 6-24 h.
3. The method according to claim 1, characterized in that In the synthesis reaction of the iminospirocyclic benzofuran compound, the phosphine catalyst is one of diphenylcyclohexylphosphine, ethyldiphenylphosphine and tri-p-tolylphosphine.
4. The method according to claim 1, characterized in that In the synthesis reaction of the iminospirocyclic benzofuran compound, the solvent is one of toluene, benzene, fluorobenzene and bromobenzene.
5. The method according to claim 1, characterized in that 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).