Method for constructing crinine by utilizing natural light to induce carbonylation reaction
The synthesis of Manjuslanting alkali was solved by a two-step process of natural light-induced carbonylation reaction, using 2-bromonaniline and benzo[d][1,3]dioxopenten-5-ylboric acid, and the synthesis in the prior art was solved The complex method is a problem, which achieves green and mild reaction conditions, simple operating technology and efficient Manjusan Dinding alkali synthesis.
Patent Information
- Application Number
- CN202411409912.4
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2024-10-09
- Publication Date
- 2025-01-10
AI Technical Summary
The synthesis method of Manjulanding alkali in the prior art is complex and does not meet the requirements of green chemistry, and lacks simple and gentle reaction conditions.
The two-step method of natural light-induced carbonylation was used, using 2-bromoaniline and benzo[d][1,3]dioxopenten-5-ylboric acid as raw materials, and was successfully synthesized by arylation and carbonylation reaction. Manjusan Ding alkali has mild reaction conditions and meets the development requirements of green chemistry.
It provides a novel synthesis route with simple and easy-to-get raw materials and green and mild reaction conditions, and a simple operating process, which improves the synthesis efficiency and environmental protection of Manjus and Landing alkali.
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Figure CN119285645A_ABST
Abstract
Description
Technical Field
[0001] The invention relates to the technical fields of medicine, clinic, cell biology and the like, and in particular to a new method for constructing clenandin by utilizing natural light-induced carbonylation reaction. Background Art
[0002] Crinum is a traditional Chinese medicine that has the effects of promoting blood circulation, dispersing blood stasis, reducing swelling and relieving pain. It is mainly used to treat pharyngitis, traumatic injuries, carbuncle, boils, and snake bites. The special effects of Crinum also provide new ideas and directions for future drug development and disease treatment.
[0003] Under this research background, we proposed a method to construct clonin by using natural light-induced carbonylation reaction. The synthetic route is as follows:
[0004]
[0005] The clenandin synthesized by the present invention has the following structural formula:
[0006]
[0007] The invention synthesizes clonin by a two-step method of natural light-induced carbonylation reaction, providing a novel synthetic route for the synthesis of this type of compound. The raw materials involved in this route are cheap and easily available, the reaction conditions are green and mild, and the reaction route is simple. Summary of the invention
[0008] The present invention relates to a method for constructing clenin by using a natural light-induced carbonylation reaction. The method uses 2-bromoaniline and benzo[d][1,3]dioxol-5-ylboronic acid as reaction raw materials to successfully construct clenin by two steps of arylation and natural light carbonylation reaction. The method has the characteristics of simple and easy-to-obtain raw materials, concise synthesis steps, green and mild reaction conditions, and simple operation process.
[0009] The technical solution of the present invention is as follows.
[0010] The synthesis of clenandin is carried out by a two-step method using a natural light-induced carbonylation reaction. The synthesis route is as follows:
[0011]
[0012] In the above method, the clonin is prepared from compound 1 (2-bromoaniline) and compound 2 (benzo[d][1,3]dioxol-5-ylboronic acid) through two reaction steps of arylation and natural light-induced carbonylation reaction; the specific steps are as follows:
[0013] (1) Compound 1 (2-bromoaniline) is placed in a container, and compound 2 (benzo[d][1,3]dioxol-5-ylboronic acid), cesium carbonate, [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex are added, and the mixture is heated to 110°C in a solvent mixture (tetrahydrofuran / water = 10:1) and stirred under reflux for 16 hours. After the reaction is completed, the mixture is cooled to room temperature, extracted, separated and purified to obtain compound 3 (2-(benzo[d][1,3]dioxol-5-yl)aniline) to achieve the arylation process.
[0014] (2) Compound 3 (2-(Benzo[d][1,3]dioxol-5-yl)aniline) was placed in a test tube, and a catalyst, additive, and solvent were added. A balloon filled with carbon monoxide gas was placed on the tube, and the tube was stirred to react under natural light. After the reaction was completed, the balloon was removed, and the reaction solution was purified by column chromatography to obtain clematine.
[0015] In the above method: the reaction container of the specific step (2) is a test tube; the metal palladium is palladium acetate, palladium trifluoroacetate, palladium chloride, tetrakis(triphenylphosphine)palladium; the additive is tetrabutylammonium bromide, tetrabutylammonium iodide, tetrabutylammonium hexafluorophosphate, tetraethylammonium bromide.
[0016] In the above method, the solvent in the specific step (2) is acetonitrile.
[0017] In the above method, the reaction temperature in the specific step (2) is room temperature.
[0018] Compared with the prior art, the advantages of the present invention are: the method has a novel synthesis method, successfully synthesizes clematine by utilizing natural light-induced carbonylation reaction, the reaction raw materials are simple and easy to obtain, the reaction conditions are mild, and it meets the development requirements of green chemistry. BRIEF DESCRIPTION OF THE DRAWINGS
[0019] Figure 1 is the hydrogen nuclear magnetic resonance spectrum of compound 3 (2-(benzo[d][1,3]dioxol-5-yl)aniline) obtained in Example 1;
[0020] Figure 2 is the carbon NMR spectrum of compound 3 (2-(benzo[d][1,3]dioxol-5-yl)aniline) obtained in Example 1;
[0021] Figure 3 is the hydrogen nuclear magnetic resonance spectrum of clenandin obtained in Example 2-12;
[0022] Figure 4 is the carbon nuclear magnetic resonance spectrum of clenandin obtained in Example 2-12; DETAILED DESCRIPTION
[0023] The invention will be further described below through specific embodiments.
[0024] Example 1
[0025] Synthesis of Compound 3 (2-(Benzo[d][1,3]dioxol-5-yl)aniline)
[0026] In a 100 mL round-bottom flask, 1 mmol of 2-bromoaniline and 1 mmol of benzo[d][1,3]dioxol-5-ylboronic acid were added, and then 3 mmol of cesium carbonate and 0.1 mmol of [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex were added. 10 ml of tetrahydrofuran and 1 ml of water were added, and the mixture was heated to 110 degrees Celsius and refluxed with stirring for 16 hours. After the reaction was completed, the mixture was cooled to room temperature, diluted with water (30 mL), and extracted with ethyl acetate (50 mL × 3). The combined organic layer was dried over anhydrous sodium sulfate, and the solvent was removed by rotary evaporation under reduced pressure. The mixture was then separated and purified by column chromatography to obtain compound 3 (2-(benzo[d][1,3]dioxol-5-yl)aniline) with a yield of 63%.
[0027] The structural characterization data of the compound 3 (2-(benzo[d][1,3]dioxol-5-yl)aniline) obtained in Example 1 are as follows: (see Figure 1 and Figure 2 )
[0028] 1 H NMR (500 MHz, CDCl3) δ 7.17 (td, J = 7.6, 1.6 Hz, 1H), 7.13 (dd, J= 7.5, 1.6 Hz, 1H), 6.98 (d, J = 1.6 Hz, 1H), 6.96-6.91 (m, 2H), 6.84 (td, J= 7.5, 1.2 Hz, 1H), 6.79 (dd, J= 8.0, 1.2 Hz, 1H), 6.03 (s, 2H), 3.74 (s,2H).
[0029] 13 C NMR (125 MHz, CDCl3) δ 147.94, 146.76, 143.57, 133.31, 130.48,128.39, 127.36, 122.44, 118.66, 115.63, 109.68, 108.69, 101.13.
[0030] Based on the above data, the structure of the obtained compound 3 (2-(benzo[d][1,3]dioxol-5-yl)aniline) is as follows:
[0031]
[0032] Example 2
[0033] Synthesis of Crinidine
[0034] Add 0.1 mmol of compound 3 (2-(benzo[d][1,3]dioxol-5-yl)aniline), 0.005 mmol of palladium acetate, 0.1 mmol of tetrabutylammonium bromide, and 0.1 mmol of acetic acid to a test tube, add 3 ml of acetonitrile as a solvent, put on a balloon containing carbon monoxide as a carbonyl source, and stir the reaction under natural light. After four hours, remove the balloon and slowly vent the unreacted carbon monoxide. The reaction solution is evaporated under reduced pressure to remove the solvent, and then separated and purified by column chromatography to obtain the compound citrinin with a yield of 82%.
[0035] Example 3
[0036] Add 0.1 mmol of compound 3 (2-(benzo[d][1,3]dioxol-5-yl)aniline), 0.005 mmol of palladium trifluoroacetate, 0.1 mmol of tetrabutylammonium bromide, and 0.1 mmol of acetic acid to a test tube, add 3 ml of acetonitrile as a solvent, put on a balloon containing carbon monoxide as a carbonyl source, and stir the reaction under natural light. After four hours, remove the balloon and slowly vent the unreacted carbon monoxide. The reaction solution is evaporated under reduced pressure to remove the solvent, and then separated and purified by column chromatography to obtain the compound citrinin with a yield of 42%.
[0037] Example 4
[0038] Add 0.1 mmol of compound 3 (2-(benzo[d][1,3]dioxol-5-yl)aniline), 0.005 mmol of palladium chloride, 0.1 mmol of tetrabutylammonium bromide, and 0.1 mmol of acetic acid to a test tube, add 3 ml of acetonitrile as a solvent, put on a balloon containing carbon monoxide as a carbonyl source, and stir the reaction under natural light. After four hours, remove the balloon and slowly vent the unreacted carbon monoxide. The reaction solution is evaporated under reduced pressure to remove the solvent, and then separated and purified by column chromatography to obtain the compound citrinin, with a yield of 0%.
[0039] Example 5
[0040] Compound 3 (2-(benzo[d][1,3]dioxol-5-yl)aniline) 0.1 mmol, tetrakis(triphenylphosphine)palladium 0.005 mmol, tetrabutylammonium bromide 0.1 mmol, acetic acid 0.1 mmol, acetonitrile 3 ml as solvent, a balloon containing carbon monoxide as a carbonyl source was added to the test tube, and the reaction was stirred under natural light. After four hours, the balloon was removed and the unreacted carbon monoxide was slowly vented. The reaction solution was evaporated under reduced pressure to remove the solvent, and then separated and purified by column chromatography to obtain the compound citrinin with a yield of 73%.
[0041] Example 6
[0042] Add 0.1 mmol of compound 3 (2-(benzo[d][1,3]dioxol-5-yl)aniline), 0.005 mmol of palladium acetate, 0.1 mmol of tetrabutylammonium iodide, and 0.1 mmol of acetic acid to a test tube, add 3 ml of acetonitrile as a solvent, put on a balloon containing carbon monoxide as a carbonyl source, and stir the reaction under natural light. After four hours, remove the balloon and slowly vent the unreacted carbon monoxide. The reaction solution is evaporated under reduced pressure to remove the solvent, and then separated and purified by column chromatography to obtain the compound citrinin with a yield of 79%.
[0043] Example 7
[0044] Add 0.1 mmol of compound 3 (2-(benzo[d][1,3]dioxol-5-yl)aniline), 0.005 mmol of palladium acetate, 0.1 mmol of tetrabutylammonium acetate, and 0.1 mmol of acetic acid to a test tube, add 3 ml of acetonitrile as a solvent, put on a balloon containing carbon monoxide as a carbonyl source, and stir the reaction under natural light. After four hours, remove the balloon and slowly vent the unreacted carbon monoxide. The reaction solution is evaporated under reduced pressure to remove the solvent, and then separated and purified by column chromatography to obtain the compound citrinin with a yield of 47%.
[0045] Example 8
[0046] Add 0.1 mmol of compound 3 (2-(benzo[d][1,3]dioxol-5-yl)aniline), 0.005 mmol of palladium acetate, 0.1 mmol of tetraethylammonium bromide, and 0.1 mmol of acetic acid to a test tube, add 3 ml of acetonitrile as a solvent, put on a balloon containing carbon monoxide as a carbonyl source, and stir the reaction under natural light. After four hours, remove the balloon and slowly vent the unreacted carbon monoxide. The reaction solution is evaporated under reduced pressure to remove the solvent, and then separated and purified by column chromatography to obtain the compound citrinin with a yield of 80%.
[0047] The structural characterization data of clenin obtained in Example 2-9 are as follows: (see Figure 3 and Figure 4 )
[0048] 1 H NMR (500 MHz, DMSO-d6) δ 7.97 (s, 1H), 7.78 (dd, J = 8.2, 1.3 Hz, 1H), 7.29 (dd, J = 7.8, 6.2 Hz, 1H), 7.11 (td, J = 7.4, 1.3 Hz, 1H), 7.00 (d,J = 8.0 Hz, 1H), 6.91 (d, J = 1.7 Hz, 1H), 6.83 (dd, J = 8.0, 1.7 Hz, 1H), 6.06 (s, 2H).
[0049] 13 C NMR (125 MHz, DMSO-d6) δ 153.87, 147.92, 147.09, 136.23, 133.45,132.81, 130.67, 127.96, 124.24, 124.00, 123.13, 109.94, 109.08, 101.57.
[0050] HRMS (ESI): m / z calculated for C 14 H9NO3 requires 240.0655 for [M+H] + ,found 240.0648.
[0051] The structure of the obtained clonin inferred from the above data is as follows:
[0052] .
Claims
1. A method for constructing clenandin by using natural light-induced carbonylation reaction, characterized in that: The synthetic route is as follows: .
2. The method for constructing clenandin by utilizing natural light-induced carbonylation reaction according to claim 1, characterized in that: The clonin alkaloid is prepared by two steps of arylation and natural light-induced carbonylation of compound 1 (2-bromoaniline) and compound 2 (benzo[d][1,3]dioxol-5-ylboronic acid); the compound 1 is 2-bromoaniline, and the compound 2 is benzo[d][1,3]dioxol-5-ylboronic acid; The specific steps are as follows: (1) Compound 1 (2-bromoaniline) is placed in a container, compound 2 (benzo[d][1,3]dioxol-5-ylboronic acid), cesium carbonate, [1,1'-bis(diphenylphosphino)ferrocene] dichloropalladium dichloromethane complex are added, and the mixture is heated to 110 degrees Celsius in a solvent mixture (tetrahydrofuran / water = 10:1) and stirred and refluxed for 16 hours. After the reaction is completed, the mixture is cooled to room temperature, extracted, separated and purified to obtain compound 3 (2-(benzo[d][1,3]dioxol-5-yl)aniline) to achieve the arylation process; (2) Compound 3 (2-(Benzo[d][1,3]dioxol-5-yl)aniline) was placed in a test tube, and a catalyst, additive, and solvent were added. A balloon filled with carbon monoxide gas was placed on the tube, and the tube was stirred to react under natural light. After the reaction was completed, the balloon was removed, and the reaction solution was purified by column chromatography to obtain clematine.
3. The method for constructing clenandin by utilizing natural light-induced carbonylation reaction according to claim 2, characterized in that: The reaction container of the specific step (2) is a test tube; the metal palladium is palladium acetate, palladium trifluoroacetate, palladium chloride, tetrakis(triphenylphosphine)palladium; and the additive is tetrabutylammonium bromide, tetrabutylammonium iodide, tetrabutylammonium hexafluorophosphate, and tetraethylammonium bromide.
4. The method for constructing clenandin by utilizing natural light-induced carbonylation reaction according to claim 2, characterized in that: In the specific step (2), the solvent is acetonitrile.
5. The method for constructing clenandin by utilizing natural light-induced carbonylation reaction according to claim 2, characterized in that: The reaction temperature in the specific step (2) is room temperature.