A method for constructing dehydrorutaecarpine using electrochemical oxidative carbonylation reaction
Dehydrorutaecarpine was synthesized by a two-step electrochemical oxidative carbonylation reaction, which solved the problem of high temperature and highly toxic reagents in traditional synthesis methods, achieved an efficient and simple synthesis route, and met the requirements of green chemistry.
Patent Information
- Application Number
- CN202410657512.9
- Authority / Receiving Office
- CN · China
- Patent Type
- Patents(China)
- Current Assignee / Owner
- Filing Date
- 2024-05-25
- Publication Date
- 2025-10-03
- Estimated Expiration
- 2044-05-25
AI Technical Summary
The existing traditional synthesis method of dehydrorutaecarpine requires high temperature and toxic reagents, the reaction steps are cumbersome, the efficiency is low, and it is difficult to achieve the requirements of green chemistry.
A two-step electrochemical oxidative carbonylation method was adopted to synthesize dehydrorutaecarpine using aniline and 1-bromo-9H-pyrido[3,4-b]indole as raw materials through arylation and electrochemical carbonylation reactions. The reaction conditions were mild, the raw materials were readily available, and the steps were simple.
The efficient synthesis of dehydrorutaecarpine was achieved, which meets the development requirements of green chemistry. The raw materials are easily available, the reaction conditions are mild, and the synthesis route is simple.
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Figure CN118726995B_ABST
Abstract
Description
Technical Field
[0001] The present invention relates to the technical fields of medicine, clinic, cell biology and the like, and in particular to a new method for constructing dehydrorutaecarpine by utilizing an electrochemical oxidative carbonylation reaction. Background Art
[0002] Evodia rutaecarpa, a traditional Chinese medicine, is the dried, nearly mature fruit of the Rutaceae plant. First recorded in Shennong's Classic of Materia Medica, it has been used clinically for centuries. Dehydrorutaecarpine, one of the active ingredients in Evodia rutaecarpa, has been shown to protect nerve cells, regulate body temperature, relieve pain and inflammation, and lower blood pressure. Dehydrorutaecarpine and its derivatives have been reported as potential multifunctional drugs for the treatment of Alzheimer's disease. Traditional synthesis of dehydrorutaecarpine primarily uses isatoic anhydride as a raw material. The reaction often requires high temperatures and the addition of equivalent amounts of oxidants or toxic reagents. The reaction is complex and inefficient. The commonly used synthetic routes are as follows.
[0003] Against this backdrop, we proposed a novel method for constructing dehydrorutaecarpine using an electrochemical carbonylation reaction. The synthetic route is as follows:
[0004]
[0005] The dehydrorutaecarpine synthesized by the present invention has the following structural formula:
[0006]
[0007] This invention synthesizes dehydrogenated rutaecarpine through a two-step electrochemical oxidative 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 mild, and the reaction route is simple. Summary of the Invention
[0008] The present invention relates to a method for synthesizing a dehydrorutaecarpine compound using an electrochemical oxidative carbonylation reaction. This method uses aniline and 1-bromo-9H-pyrido[3,4-b]indole as raw materials, successfully constructing the dehydrorutaecarpine compound through a two-step arylation and electrochemical oxidative carbonylation reaction. This method features readily available raw materials, concise synthetic steps, mild reaction conditions, and a simple operational process.
[0009] The technical solutions of the present invention are as follows.
[0010] Dehydrorutaecarpine is synthesized by a two-step electrochemical oxidative carbonylation reaction. The synthesis route is as follows:
[0011]
[0012] In the above method, the dehydrorutaecarpine is prepared from compound 1 (aniline) and compound 2 (1-bromo-9H-pyrido[3,4-b]indole) through two reaction steps of arylation and electrochemical carbonylation. The specific steps are as follows:
[0013] (1) Compound 1 (aniline) was placed in a container, and compound 2 (1-bromo-9H-pyrido[3,4-b]indole) was added. The mixture was stirred at 170°C for 7 hours. TLC (thin layer chromatography) was used to monitor the reaction until it was complete. The mixture was filtered, extracted, and separated and purified to obtain compound 3 (N-phenyl-9H-pyrido[3,4-b]indole-1-amine), thus completing the arylation process.
[0014] (2) Compound 3 (N-phenyl-9H-pyrido[3,4-b]indole-1-amine) was placed in a two-necked Shrek reaction tube, and an electrolyte, a catalyst, and a solvent were added. A balloon filled with carbon monoxide gas was placed on the tube, and graphite felt was used as an anode and nickel foam was used as a cathode. The reaction was stirred at a current of 2 mA. After the reaction was completed, the balloon was removed, the reaction solution was filtered, extracted, and purified by column chromatography to obtain dehydrorutaecarpine; the catalyst was metal palladium; and the electrolyte was ammonium salt.
[0015] In the above method, the reaction vessel of the specific step (2) is a glass two-necked Shrek reaction tube; the catalyst is palladium chloride, palladium acetate, dichlorodiacetonitrile palladium, trifluoroacetate palladium or bistriphenylphosphine palladium dichloride; the electrolyte is tetrabutylammonium hexafluorophosphate, tetramethylammonium acetate, tetrabutylammonium acetate, lithium perchlorate.
[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 existing technology, the advantages of the present invention are: the method has a novel synthesis method, dehydrorutaecarpine is successfully synthesized by 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 (N-phenyl-9H-pyrido[3,4-b]indol-1-amine) obtained in Example 1;
[0020] Figure 2 is the carbon NMR spectrum of compound 3 (N-phenyl-9H-pyrido[3,4-b]indol-1-amine) obtained in Example 1;
[0021] Figure 3is the H NMR spectrum of dehydrorutaecarpine obtained in Example 2-12;
[0022] Figure 4 is the carbon NMR spectrum of dehydrorutaecarpine 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 (N-phenyl-9H-pyrido[3,4-b]indol-1-amine)
[0026] To a 25 mL test tube, 1 mmol of aniline and 1 mmol of 1-bromo-9H-pyrido[3,4-b]indole were added and stirred at 170°C for 7 hours. After completion of the reaction, as determined by TLC (thin-layer chromatography), the reaction mixture was cooled to room temperature and quenched with 10 mL of water. Saturated sodium bicarbonate solution was then added, and the reaction mixture was extracted with 30 mL of ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate, and the solvent was removed by rotary evaporation under reduced pressure. The product was then isolated and purified by column chromatography to yield compound 3 (N-phenyl-9H-pyrido[3,4-b]indole-1-amine) in a 52% yield.
[0027] The structural characterization data of compound 3 (N-phenyl-9H-pyrido[3,4-b]indol-1-amine) obtained in Example 1 are as follows: (See Figure 1 and Figure 2 )
[0028] 1 H NMR (500 MHz, DMSO-d6) δ 11.32 (d, J = 12.9 Hz, 1H), 8.79 (d, J =13.1 Hz, 1H), 8.16 (dd, J = 13.1, 7.6 Hz, 1H), 7.93 (dd, J = 22.3, 7.1 Hz,3H), 7.71 (dd, J = 12.7, 7.9 Hz, 1H), 7.59 (dd, J = 13.0, 5.3 Hz, 1H), 7.54(s, 1H), 7.35 (dt, J = 15.4, 7.5 Hz, 2H), 7.25 (q, J = 7.5, 6.5 Hz, 1H), 6.95(q, J = 9.8, 7.4 Hz, 1H);
[0029] 13C NMR (125 MHz, DMSO-d6) δ 142.91, 142.18, 139.55, 136.21, 129.19,127.61, 127.55, 124.25, 122.06, 121.73, 121.07, 119.84, 118.43, 112.60,107.68.
[0030] Based on the above data, the structure of compound 3 (N-phenyl-9H-pyrido[3,4-b]indol-1-amine) is as follows:
[0031]
[0032] Compound 3 (N-phenyl-9H-pyrido[3,4-b]indol-1-amine)
[0033] Example 2
[0034] Synthesis of Dehydrorutaecarpine
[0035] A 25 mL two-necked Schreck reaction tube was charged with 0.2 mmol of compound 3 (N-phenyl-9H-pyrido[3,4-b]indol-1-amine), 0.03 mmol of palladium dichloride, 0.04 mmol of tetrabutylammonium hexafluorophosphate, and 0.8 mmol of trifluoroacetic acid. Acetonitrile (5 mL) was added as the solvent. A balloon containing carbon monoxide was placed over the tube as a carbonyl source. A graphite felt was used as the anode and nickel foam as the cathode. The reaction was stirred at 2 mA. After completion of the reaction, as determined by TLC (thin-layer chromatography), the reaction solution was cooled to room temperature, the balloon was removed, and unreacted carbon monoxide was slowly vented. The reaction solution was filtered, and the filtrate was evaporated under reduced pressure to remove the solvent. The filtrate was then purified by column chromatography to obtain dehydrorutaecarpine in a 57% yield.
[0036] Example 3
[0037] A 25 mL two-necked Schreck reaction tube was charged with 0.2 mmol of compound 3 (N-phenyl-9H-pyrido[3,4-b]indol-1-amine), 0.03 mmol of palladium acetate, 0.04 mmol of tetrabutylammonium hexafluorophosphate, and 0.8 mmol of trifluoroacetic acid. Acetonitrile (5 mL) was added as the solvent. A balloon containing carbon monoxide was placed over the tube as a carbonyl source. A graphite felt was used as the anode and nickel foam as the cathode. The reaction was stirred at 2 mA. After completion of the reaction, as determined by TLC (thin-layer chromatography), the reaction solution was cooled to room temperature, the balloon was removed, and unreacted carbon monoxide was slowly vented. The reaction solution was filtered, and the filtrate was evaporated under reduced pressure to remove the solvent. The filtrate was then purified by column chromatography to obtain dehydrorutaecarpine in a 61% yield.
[0038] Example 4
[0039] In a 25 mL two-necked Schreck reaction tube, 0.2 mmol of compound 3 (N-phenyl-9H-pyrido[3,4-b]indol-1-amine), 0.03 mmol of dichlorodiacetonitrile palladium, 0.04 mmol of tetrabutylammonium hexafluorophosphate, and 0.8 mmol of trifluoroacetic acid were added. 5 mL of acetonitrile was added as the solvent. A balloon containing carbon monoxide was placed over the tube as a carbonyl source. A graphite felt was used as the anode and nickel foam as the cathode. The reaction was stirred at 2 mA. After completion of the reaction, as determined by TLC (thin-layer chromatography), the reaction solution was cooled to room temperature, the balloon was removed, and unreacted carbon monoxide was slowly vented. The reaction solution was filtered, and the filtrate was evaporated under reduced pressure to remove the solvent. The filtrate was then purified by column chromatography to obtain dehydrorutaecarpine in a 49% yield.
[0040] Example 5
[0041] A 25 mL two-necked Schreck reaction tube was charged with 0.2 mmol of compound 3 (N-phenyl-9H-pyrido[3,4-b]indol-1-amine), 0.03 mmol of palladium trifluoroacetate, 0.04 mmol of tetrabutylammonium hexafluorophosphate, and 0.8 mmol of trifluoroacetic acid. Acetonitrile (5 mL) was added as the solvent. A balloon containing carbon monoxide was placed over the tube as a carbonyl source. A graphite felt was used as the anode and nickel foam as the cathode. The reaction was stirred at 2 mA. After completion of the reaction, as determined by TLC (thin-layer chromatography), the reaction solution was cooled to room temperature, the balloon was removed, and unreacted carbon monoxide was slowly vented. The reaction solution was filtered, and the filtrate was evaporated under reduced pressure to remove the solvent. The filtrate was then purified by column chromatography to obtain dehydrorutaecarpine in a 73% yield.
[0042] Example 6
[0043] In a 25 mL two-necked Schreck reaction tube, 0.2 mmol of compound 3 (N-phenyl-9H-pyrido[3,4-b]indol-1-amine), 0.03 mmol of bistriphenylphosphine palladium dichloride, 0.04 mmol of tetrabutylammonium hexafluorophosphate, and 0.8 mmol of trifluoroacetic acid were added. 5 mL of acetonitrile was added as the solvent. A balloon containing carbon monoxide was placed over the tube as a carbonyl source. A graphite felt was used as the anode and nickel foam as the cathode. The reaction was stirred at 2 mA. After completion of the reaction, as determined by TLC (thin-layer chromatography), the reaction solution was cooled to room temperature, the balloon was removed, and unreacted carbon monoxide was slowly vented. The reaction solution was filtered, and the filtrate was evaporated under reduced pressure to remove the solvent. The filtrate was then purified by column chromatography to obtain dehydrorutaecarpine in a 37% yield.
[0044] Example 7
[0045] In a 25 mL two-necked Schreck reaction tube, 0.2 mmol of compound 3 (N-phenyl-9H-pyrido[3,4-b]indol-1-amine), 0.03 mmol of palladium trifluoroacetate, 0.04 mmol of tetramethylammonium acetate, and 0.8 mmol of trifluoroacetic acid were added. 5 mL of acetonitrile was added as the solvent. A balloon containing carbon monoxide was placed over the tube as a carbonyl source. A graphite felt was used as the anode and nickel foam as the cathode. The reaction was stirred at 2 mA. After completion of the reaction, as determined by TLC (thin-layer chromatography), the reaction solution was cooled to room temperature, the balloon was removed, and unreacted carbon monoxide was slowly vented. The reaction solution was filtered, and the filtrate was evaporated under reduced pressure to remove the solvent. The filtrate was then purified by column chromatography to obtain dehydrorutaecarpine in a 45% yield.
[0046] Example 8
[0047] In a 25 mL two-necked Schreck reaction tube, 0.2 mmol of compound 3 (N-phenyl-9H-pyrido[3,4-b]indol-1-amine), 0.03 mmol of palladium trifluoroacetate, 0.04 mmol of tetrabutylammonium acetate, and 0.8 mmol of trifluoroacetic acid were added. 5 mL of acetonitrile was added as the solvent. A balloon containing carbon monoxide was placed over the tube as a carbonyl source. A graphite felt was used as the anode and nickel foam as the cathode. The reaction was stirred at 2 mA. After completion of the reaction, as determined by TLC (thin-layer chromatography), the reaction solution was cooled to room temperature, the balloon was removed, and unreacted carbon monoxide was slowly vented. The reaction solution was filtered, and the filtrate was evaporated under reduced pressure to remove the solvent. The filtrate was then purified by column chromatography to obtain dehydrorutaecarpine in a 49% yield.
[0048] Example 9
[0049] A 25 mL two-necked Schreck reaction tube was charged with 0.2 mmol of compound 3 (N-phenyl-9H-pyrido[3,4-b]indol-1-amine), 0.03 mmol of palladium trifluoroacetate, 0.04 mmol of lithium perchlorate, and 0.8 mmol of trifluoroacetic acid. Acetonitrile (5 mL) was added as the solvent. A balloon containing carbon monoxide was placed over the tube as a carbonyl source. A graphite felt was used as the anode and nickel foam as the cathode. The reaction was stirred at 2 mA. After completion of the reaction, as determined by TLC (thin-layer chromatography), the reaction solution was cooled to room temperature, the balloon was removed, and unreacted carbon monoxide was slowly vented. The reaction solution was filtered, and the filtrate was evaporated under reduced pressure to remove the solvent. The filtrate was then purified by column chromatography to obtain dehydrorutaecarpine in a 47% yield.
[0050] The structural characterization data of dehydrorutaecarpine obtained in Example 2-9 are as follows: (See Figure 3 and Figure 4 )
[0051] 1H NMR (500 MHz, DMSO-d6) δ 12.72 (d, J = 8.0 Hz, 1H), 8.63 (d, J =7.4 Hz, 1H), 8.35 (d, J = 8.0 Hz, 1H), 8.17 (d, J = 8.2 Hz, 1H), 7.93 (t, J =7.5 Hz, 1H), 7.84 (d, J = 7.8 Hz, 2H), 7.69 (d, J = 8.2 Hz, 1H), 7.51 (q, J =6.9 Hz, 2H), 7.29 (t, J = 7.4 Hz, 1H);
[0052] 13 C NMR (125 MHz, DMSO-d6) δ 159.00, 147.59, 140.51, 140.44, 135.45,129.51, 127.62, 127.34, 126.28, 125.11, 122.22, 121.47, 121.07, 120.80,118.29, 116.35, 113.28, 108.67;
[0053] The structure of dehydrorutaecarpine obtained based on the above data is as follows:
[0054]
[0055] Dehydrorutaecarpine.
Claims
1. A method for constructing dehydrorutaecarpine by electrochemical oxidative carbonylation reaction, characterized in that: The dehydrorutaecarpine is prepared by two steps of arylation and electrochemical carbonylation of compound 1 and compound 2; compound 1 is aniline and compound 2 is 1-bromo-9H-pyrido[3,4-b]indole; the synthesis route is as follows: , the specific steps are as follows: (1) Compound 1 is placed in a container, compound 2 is added, and the mixture is stirred at 170°C for 7 hours. TLC (thin layer chromatography) is used to monitor the reaction until it is complete. Compound 3 is then filtered, extracted, separated, and purified to achieve arylation. (2) Compound 3 is placed in a glass two-necked Shrek reaction tube, and an electrolyte, catalyst, additive and solvent are added. A balloon filled with carbon monoxide gas is placed on the tube, and graphite felt is used as an anode and nickel foam is used as a cathode. The reaction is stirred at a current of 2 mA. After the reaction is completed, the balloon is removed, the reaction solution is filtered, extracted, and purified by column chromatography to obtain dehydrorutaecarpine; the catalyst is palladium chloride or palladium acetate or dichlorodiacetonitrile palladium or trifluoroacetate or bistriphenylphosphine palladium dichloride; the additive is trifluoroacetic acid; and the electrolyte is an ammonium salt or lithium perchlorate.
2. The method for constructing dehydrorutaecarpine by electrochemical oxidative carbonylation reaction according to claim 1, characterized in that: The ammonium salt is tetrabutylammonium hexafluorophosphate, tetramethylammonium acetate or tetrabutylammonium acetate.
3. The method for constructing dehydrorutaecarpine by electrochemical oxidative carbonylation reaction according to claim 1, characterized in that: The solvent in the specific step (2) is acetonitrile.
4. The method for constructing dehydrorutaecarpine by electrochemical oxidative carbonylation reaction according to claim 1, characterized in that: The reaction temperature in the specific step (2) is room temperature.