CN116396302A - Indole compound and preparation method thereof - Google Patents

Indole compound and preparation method thereof Download PDF

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CN116396302A
CN116396302A CN202310374594.1A CN202310374594A CN116396302A CN 116396302 A CN116396302 A CN 116396302A CN 202310374594 A CN202310374594 A CN 202310374594A CN 116396302 A CN116396302 A CN 116396302A
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CN116396302B (en
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郭凯
陈锋
秦红
方正
杨照
刘成扣
段金电
王昌盛
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Nanjing Tech University
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Abstract

The invention belongs to the field of organic chemistry, and relates to an indole compound and a preparation method thereof. Carrying out substitution reaction on the compound I and the compound II under alkaline conditions to obtain a compound III; and carrying out coupling reaction on the compound III under the catalysis of phosphine ligand to prepare a compound IV-1 or a compound IV-2, namely an indole compound. The invention adopts a micro-channel modularized reaction device to take 2- (1H-indole-2-yl) phenol and 3-p-toluenesulfonyloxy oxetane as raw materials for substitution reaction, and the obtained product compound III is directly put into the next reaction without purification; and then the compound III is catalyzed by phosphine ligand to prepare the compound IV. The two new indole compounds prepared by the invention have potential application value in serving as lead compounds for designing anticancer drugs, and have potential application value in serving as standard substances. The synthesis method of the invention has simple operation, low energy consumption and high yield.

Description

Indole compound and preparation method thereof
Technical Field
The invention belongs to the field of organic chemistry, and relates to an indole compound and a preparation method thereof.
Background
Indole is used as an important fine chemical raw material, is widely applied to the fields of medicines, pesticides, fragrances, food and feed additives, dyes and the like, and new application fields are continuously developed, and the indole compound is widely focused due to the environment friendliness of natural compounds, so that the indole compound becomes a heterocyclic chemical raw material at home and abroad, and has a wide development prospect. In the aspect of medicine, indole has unique chemical structure, so that the derived medicines and pesticides have unique physiological activity, and many natural substances with strong physiological activity are derivatives of indole, and are attractive to the world, and can be used for synthesizing antipyretic analgesics, stimulants, antihypertensive vasodilators, antihistamines and the like.
According to the reports of domestic and foreign documents on indole derivatives, no report on the structure of a novel indole derivative is provided. The known medicine with a structure similar to the structure in the invention is vincristine, which is a dimeric indole structure with a catharanthine ring and a vindoline ring connected by a carbon bridge; the marine alkaloid eudragin has antiproliferative activity on p-388 lymphoma cells, and is expected to be used as a lead compound for the design of anticancer drugs.
Microreactor technology has great potential in the current synthesis reactions. Microreactors have the fundamental feature that the chemical reaction is controlled in as small a space as possible, the size of the chemical reaction space being typically of the order of micrometers or even nanometers. Microreactors have a number of advantages over batch reactions, such as: the specific surface area is extremely large, the real-time online quantity is small, the fluid is continuous flow in the micro-reactor, almost no back mixing exists, the mass transfer and heat transfer efficiency is high, the process is easy to control, the side reaction is less, the industrial production is easy, and the like.
Disclosure of Invention
The invention aims to solve the technical problem of providing a novel indole compound aiming at the defects of the prior art.
The invention also solves the problem of providing a preparation method of the indole compound, which adopts a micro-reaction technology and is simple and convenient to operate.
In order to solve the technical problems, the invention adopts the following technical scheme:
the invention discloses an indole compound, which has a structural formula shown as formula IV-1 or formula IV-2:
Figure BDA0004169885220000021
the invention further discloses a preparation method of the indole compound, which comprises the steps of carrying out substitution reaction on the compound I and the compound II under an alkaline condition to obtain a compound III; carrying out coupling reaction on the compound III under the catalysis of phosphine ligand to prepare a compound IV-1 or a compound IV-2, namely an indole compound;
Figure BDA0004169885220000022
wherein the phosphine ligand-1 has the structural formula of
Figure BDA0004169885220000023
Wherein the phosphine ligand-2 has the structural formula of
Figure BDA0004169885220000024
Wherein, when the phosphine ligand used in the preparation process is phosphine ligand-1, the compound IV-1 is prepared; when the phosphine ligand used in the preparation process is phosphine ligand-2, compound IV-2 is prepared.
In some embodiments, the alkaline conditions are controlled to be alkaline by adding an aqueous alkaline solution; the alkaline aqueous solution is potassium carbonate aqueous solution, potassium tert-butoxide aqueous solution, sodium tert-butoxide aqueous solution or cesium carbonate aqueous solution, preferably cesium carbonate aqueous solution; the molar ratio of the compound I to the compound II to the alkali in the alkaline aqueous solution is 1:1 to 1.5:2.5 to 4, preferably 1:1:3, a step of; the substitution reaction is carried out at a reaction temperature of 90-120 ℃, preferably 100 ℃; the mass ratio of the compound III to the phosphine ligand is 1:0.1 to 0.4, preferably 1:0.18 to 0.25; the coupling reaction is carried out at a temperature of 70-90 ℃, preferably 80 ℃.
In some embodiments, the indoles described above are prepared by employing conventional reactors or microchannel modular reaction devices.
Preferably, the indole compound is prepared by adopting a micro-channel modularized reaction device, and the preparation method comprises the following steps:
(1) Dissolving a compound I in a first organic solvent to obtain a first mixed solution; dissolving a compound II in a first organic solvent to obtain a second mixed solution; pumping the first mixed solution, the second mixed solution and the alkaline aqueous solution into a first micro-mixer in a micro-channel modularized reaction device respectively at the same time, pumping the mixed solution into the first micro-reactor for substitution reaction after full mixing, and extracting and separating the reaction solution through a first separation device after reaction to obtain effluent containing a compound III;
(2) Dissolving phosphine ligand in a second organic solvent to obtain a third mixed solution; pumping the third mixed solution and the effluent containing the compound III obtained in the step (1) into a second micro-mixer in a micro-channel modularized reaction device respectively, fully mixing, pumping into a second micro-reactor for coupling reaction, and carrying out post-treatment on the reaction solution after the reaction is finished.
In some embodiments, in step (1), the first organic solvent is N, N-dimethylformamide, dimethylsulfoxide, dimethylacetamide or N, N-diisopropylethylamine, preferably N, N-dimethylformamide; the concentration of the compound I in the first mixed solution is 0.2-1.0 mol/L, preferably 0.32-0.5 mol/L, and more preferably 0.4mol/L; the concentration of the compound II in the second mixed solution is 0.2-1.5 mol/L, preferably 0.25-0.5 mol/L, and more preferably 0.4mol/L; the alkaline aqueous solution is potassium carbonate aqueous solution, potassium tert-butoxide aqueous solution, sodium tert-butoxide aqueous solution or cesium carbonate aqueous solution, preferably cesium carbonate aqueous solution; the concentration of the alkali in the alkaline aqueous solution is 2.0-4.0 mol/L, preferably 2.5-3.5 mol/L, more preferably 3.0mol/L; the molar ratio of the compound I to the compound II to the alkali in the alkaline aqueous solution is 1:1 to 1.5:2.5 to 4, preferably 1:1:3.
in some embodiments, in step (1), the first mixture is pumped into the first micromixer in the microchannel modular reactor at a flow rate of 0.04 to 0.40mL/min, preferably 0.05 to 0.15mL/min, more preferably 0.10mL/min; the flow rate of the second mixed liquid pumped into the first micro-mixer in the micro-channel modularized reaction device is 0.04-0.50 mL/min, preferably 0.05-0.15 mL/min, and more preferably 0.10mL/min; the flow rate of the alkaline aqueous solution pumped into the first micro mixer in the micro-channel modularized reaction device is 0.01-0.20 mL/min, preferably 0.02-0.06 mL/min, and more preferably 0.04mL/min; the volume of the first micro-reactor is 4-40 mL, preferably 4-16 mL, more preferably 10mL; the substitution reaction is carried out at a temperature of 90 to 120 ℃, preferably 100 ℃.
In some embodiments, in step (2), the second organic solvent is chlorobenzene or toluene, preferably chlorobenzene; the concentration of the phosphine ligand in the third mixed solution is 0.025-0.10 mol/L, preferably 0.05-0.055 mol/L.
In some embodiments, in step (2), the concentration of compound III in the effluent containing compound III is from 0.2 to 0.4mol/L, preferably from 0.3 to 0.35mol/L; the mass ratio of the compound III to the phosphine ligand is 1:0.1 to 0.4, preferably 1:0.18 to 0.25.
In some embodiments, in step (2), the third mixture is pumped into the second micromixer in the microchannel modular reactor at a flow rate of 0.02 to 0.06mL/min, preferably 0.04 to 0.06mL/min, more preferably 0.05mL/min; the flow rate of the effluent liquid containing the compound III pumped into the second micro mixer in the micro-channel modularized reaction device is 0.1-0.8 mL/min, preferably 0.3-0.5 mL/min, and more preferably 0.4mL/min; the volume of the second micro-reactor is 4-40 mL, preferably 4-16 mL, more preferably 10mL; the coupling reaction is carried out at a temperature of 70-90 ℃, preferably 80 ℃.
In some embodiments, the microchannel modular reactor comprises a connecting conduit, a first feed pump, a second feed pump, a third feed pump, a fourth feed pump, a fifth feed pump, a first micromixer, a second micromixer, a first separation device, a first microreactor, a second microreactor, and a receiving device; the first feeding pump, the second feeding pump and the third feeding pump are connected to the first micro mixer in parallel through pipelines; the first micro-mixer, the first micro-reactor, the first separation device and the fourth feed pump are sequentially connected in series through pipelines; the fourth feed pump and the fifth feed pump are connected to the second micromixer in parallel through a pipeline; the second micro-mixer, the second micro-reactor and the receiving device are sequentially connected in series through pipelines.
Wherein the diameter of the connecting pipeline is 0.5-4 mm, the length is 10-70 cm, and the preferential range is 10-40 cm; the diameter of the pipeline of the first micro-reactor is 0.5-4 mm, preferably 0.5-2 mm; the diameter of the pipeline of the second micro-reactor is 0.5-4 mm, preferably 0.5-2 mm. Although the ultra-thin pipe diameter can effectively increase the specific surface area, the ultra-thin pipe diameter can cause the problems of liquid flowing pressure rise, blockage, pipe bursting and the like, and the material connecting pipe used in the invention needs to be controlled in the preferred range.
The feeding pump is an accurate and low-pulsation pump, and is input into the micro mixer and equipment behind the micro mixer, so that materials can continuously pass through the micro-channel modularized reaction device and the residence time of the materials can be controlled; the feed pump is an HPLC pump or a syringe pump, preferably an HPLC pump.
Wherein, according to the need, connect raw materials storage tank and product collecting bottle respectively at the end to end in order to realize continuous operation.
The first micro mixer and the second micro mixer are of T type, Y type or inverted Y type, preferably Y type.
Wherein the first micro-reactor and the second micro-reactor are pipeline reactors or heart-shaped structural reactors, and are preferably pipeline reactors.
Wherein the reaction temperature of the first micro-reactor and the second micro-reactor is controlled by heating an oil bath pot.
The application of the indole compounds in the lead compounds as anti-cancer drug design is also within the protection scope of the invention.
The application of the indole compounds as standard substances is also within the protection scope of the invention.
Indole is fused with N-heterocycle and O-heterocycle in the structure of the compound IV-1 or the compound IV-2 prepared by the preparation method, and the N-heterocycle and O-heterocycle fused with indole are important fused heterocyclic motifs ([ 1]G.Pan,L.Lu,W.Zhuang,Q.Huang,J Org Chem 2021,86,16753-16763 ]; [2]N.Yadav,T.Khanam,A.Shukla,N.Rai,K.Hajela,R.Ramachandran,Org Biomol Chem 2015,13,5475-5487 ]) which are found in a plurality of pharmaceutically active compounds. For example, MK-8742,2, 13-cyclohexyl-6, 7 dihydrobenzo [6,7] [1,4] oxazepino [4,5-a ] indole-10-carboxylic acid and MK-32814 have proven to be promising therapeutic agents for the treatment of hepatitis C virus and thus, efficient and compact synthesis of such backbone analogs may provide a meaningful clue to the development of new molecular candidates for biological activity research. Meanwhile, the tricyclic dihydrobenzooxazepine and tetracyclic indole derivatives can specifically target bacterial DNA ligase and can be distinguished from human DNA ligase I, so that the novel antibacterial drug can be developed by people.
The beneficial effects are that:
(1) The invention provides two new chemical structures of indole derivatives, wherein an oxetane is introduced into the original structure of 2- (1H-indole-2-yl) phenol, and ring opening is further carried out through different phosphine ligands, so that the chemical structures of the two new indole derivatives with different structures are obtained; the indole compound prepared has potential application value in serving as a lead compound for designing anticancer drugs and has potential application value in serving as a standard substance.
(2) The invention adopts a micro-channel modularized reaction device to take 2- (1H-indole-2-yl) phenol and 3-p-toluenesulfonyloxy oxetane as raw materials for substitution reaction, and the obtained product compound III is directly put into the next reaction without purification; and then the compound III is catalyzed by phosphine ligand to prepare the compound IV-1 or the compound IV-2. The synthesis method has the advantages of simple operation, low energy consumption and high yield.
Drawings
The foregoing and/or other advantages of the invention will become more apparent from the following detailed description of the invention when taken in conjunction with the accompanying drawings and detailed description.
FIG. 1 is a schematic diagram of a synthesis route of a microchannel reactor employed in the present invention;
FIG. 2 is a reaction equation for synthesizing indole compounds according to the present invention;
FIG. 3 is a nuclear magnetic resonance hydrogen spectrum of the compound IV-1;
FIG. 4 is a nuclear magnetic resonance carbon spectrum of the compound IV-1;
FIG. 5 is a nuclear magnetic resonance hydrogen spectrum of the compound IV-2;
FIG. 6 is a nuclear magnetic resonance carbon spectrum of the compound IV-2;
FIG. 7 is a nuclear magnetic resonance hydrogen spectrum of compound III;
FIG. 8 shows nuclear magnetic resonance carbon spectrum of compound III.
Detailed Description
The invention will be better understood from the following examples. However, it will be readily appreciated by those skilled in the art that the description of the embodiments is provided for illustration only and should not limit the invention as described in detail in the claims.
The 2- (1H-indol-2-yl) phenol used in the embodiment of the invention has the purity of more than or equal to 95 percent and is obtained from the manufacturer: shanghai is available from medical science and technology Co., ltd; 3-p-toluenesulfonyloxy oxetane with purity not less than 97% and manufacturer source: shanghai is available from medical science and technology Co., ltd; phosphine ligand-1, purity: not less than 98%, manufacturer source: shanghai is available from medical science and technology Co., ltd; phosphine ligand-2, purity: not less than 98%, manufacturer source: shanghai is available from medical science and technology Co., ltd.
FIG. 1 is a schematic diagram of a synthetic route of a microchannel reactor employed in the present invention, the microchannel modular reactor comprising a connecting conduit, a first feed pump, a second feed pump, a third feed pump, a fourth feed pump, a fifth feed pump, a first micromixer, a second micromixer, a first separation device, a first microreactor, a second microreactor, and a receiving device; the first feed pump, the second feed pump and the third feed pump are connected to the first micromixer in parallel through pipelines; the first micro-mixer, the first micro-reactor, the first separation device and the fourth feed pump are sequentially connected in series through a pipeline; the fourth feed pump and the fifth feed pump are connected to the second micromixer in parallel through a pipeline; the second micro-mixer, the second micro-reactor and the receiving device are sequentially connected in series through a pipeline.
Wherein, the diameter of the connecting pipeline is 1mm, and the length is 15cm; the diameter of the pipeline of the first micro-reactor is 1mm; the diameter of the pipeline of the second micro-reactor is 1mm. Although the ultra-thin pipe diameter can effectively increase the specific surface area, the ultra-thin pipe diameter can cause the problems of liquid flowing pressure rise, blockage, pipe bursting and the like, and the material connecting pipe used in the invention needs to be controlled in the preferred range.
The feeding pump is an accurate and low-pulsation pump, and is input into the micro mixer and equipment behind the micro mixer, so that materials can continuously pass through the micro-channel modularized reaction device and the residence time of the materials can be controlled; the feed pump was an HPLC pump.
Wherein, according to the need, connect raw materials storage tank and product collecting bottle respectively at the end to end in order to realize continuous operation.
The first micro mixer and the second micro mixer are Y-shaped.
Wherein, the first micro-reactor and the second micro-reactor are pipeline reactors.
Wherein the reaction temperature of the first micro-reactor and the second micro-reactor is controlled by heating an oil bath.
FIG. 2 shows the reaction equation for synthesizing indole compounds according to the present invention.
Example 1
(1) 2- (1H-indol-2-yl) phenol (0.020 mol) is dissolved in N, N-dimethylformamide solution (50 mL) to obtain a first mixed solution; 3-p-toluenesulfonyloxy oxetane (0.020 mol) was dissolved in N, N-dimethylformamide (50 mL) to obtain a second mixed solution; cesium carbonate (0.060 mol) was dissolved in deionized water (20 mL) to give an aqueous cesium carbonate solution. Pumping the first mixed solution, the second mixed solution and the cesium carbonate aqueous solution into a first micromixer in a microchannel modularized reaction device respectively and simultaneously for full mixing, wherein the pumping flow rate of the first mixed solution is 0.10mL/min, the pumping flow rate of the second mixed solution is 0.10mL/min, and the pumping flow rate of the cesium carbonate aqueous solution is 0.04mL/min; then pumped into a first microreactor (10 mL) and substitution reactions were performed at 100deg.C. After the completion of the reaction, the reaction mixture was collected in a first separation device (containing water and 50mL of chlorobenzene) and subjected to extraction to obtain an effluent containing compound III at a concentration of 0.32mol/L, with a yield of 80% (4.24 g) by HPLC. FIG. 7 shows the nuclear magnetic resonance hydrogen spectrum of the compound III, and FIG. 8 shows the nuclear magnetic resonance carbon spectrum of the compound III.
(2) Phosphine ligand-1 (0.0011 mol,0.85 g) was dissolved in chlorobenzene (20 mL) to give a third mixture; pumping the third mixed solution and the effluent containing the compound III obtained in the step (1) into a second micro mixer in a micro-channel modularized reaction device respectively at the same time for fully mixing, wherein the pumping flow rate of the third mixed solution is 0.054mL/min, and the pumping flow rate of the effluent containing the compound III is 0.40mL/min; then pumped into a second microreactor (10 mL) and the coupling reaction was performed at 80 ℃. After the reaction, water (50 mL) and ethyl acetate (50 mL) were added to the reaction effluent containing the compound IV-1, the solution was extracted, the organic phase was washed with water (50 mL. Times.2), dried over anhydrous sodium sulfate, filtered, the solvent was distilled off under reduced pressure, and the crude product was purified by a silica gel column to obtain the compound IV-1 in a yield of 76.3%. FIG. 3 shows the nuclear magnetic resonance hydrogen spectrum of the compound IV-1, and FIG. 4 shows the nuclear magnetic resonance carbon spectrum of the compound IV-1.
Example 2
(1) 2- (1H-indol-2-yl) phenol (0.020 mol) is dissolved in N, N-dimethylformamide solution (50 mL) to obtain a first mixed solution; 3-p-toluenesulfonyloxy oxetane (0.020 mol) was dissolved in N, N-dimethylformamide (50 mL) to obtain a second mixed solution; cesium carbonate (0.060 mol) was dissolved in deionized water (20 mL) to give an aqueous cesium carbonate solution. Pumping the first mixed solution, the second mixed solution and the cesium carbonate aqueous solution into a first micromixer in a microchannel modularized reaction device respectively and simultaneously for full mixing, wherein the pumping flow rate of the first mixed solution is 0.10mL/min, the pumping flow rate of the second mixed solution is 0.10mL/min, and the pumping flow rate of the cesium carbonate aqueous solution is 0.04mL/min; then pumped into a first microreactor (10 mL) and substitution reactions were performed at 100deg.C. After the completion of the reaction, the reaction mixture was collected in a first separation device (containing water and 50mL of chlorobenzene) and subjected to extraction to obtain an effluent containing compound III at a concentration of 0.32mol/L, with a yield of 80% (4.24 g) by HPLC.
(2) Phosphine ligand-2 (0.001 mol,0.87 g) was dissolved in chlorobenzene (20 mL) to give a third mixed solution; pumping the third mixed solution and the effluent containing the compound III obtained in the step (1) into a second micro mixer in a micro-channel modularized reaction device respectively at the same time for fully mixing, wherein the pumping flow rate of the third mixed solution is 0.053mL/min, and the pumping flow rate of the effluent containing the compound III is 0.40mL/min; then pumped into a second microreactor (10 mL) and the coupling reaction was performed at 80 ℃. After the reaction, water (50 mL) and ethyl acetate (50 mL) were added to the reaction effluent containing the compound IV-2, the solution was extracted, the organic phase was washed with water (50 mL. Times.2), dried over anhydrous sodium sulfate, filtered, the solvent was distilled off under reduced pressure, and the crude product was purified by a silica gel column to obtain the compound IV-2 in a yield of 72.2%. FIG. 5 shows the nuclear magnetic resonance hydrogen spectrum of the compound IV-2, and FIG. 6 shows the nuclear magnetic resonance carbon spectrum of the compound IV-2.
Example 3
The preparation process is identical to example 1, except that:
in the step (1), the pumping flow rate of the first mixed solution is 0.05mL/min, the pumping flow rate of the second mixed solution is 0.05mL/min, and the pumping flow rate of the cesium carbonate aqueous solution is 0.02mL/min; the volume of the first microreactor was 4mL. The yield of compound III obtained was 75.6%.
In the step (2), the pumping flow rate of the third mixed solution is 0.041mL/min, and the pumping flow rate of the effluent liquid containing the compound III is 0.30mL/min; the volume of the second microreactor was 4mL. The yield of the compound IV-1 was 72.3%.
Example 4
The preparation method is the same as in example 2, except that:
in the step (1), the pumping flow rate of the first mixed solution is 0.05mL/min, the pumping flow rate of the second mixed solution is 0.05mL/min, and the pumping flow rate of the cesium carbonate aqueous solution is 0.02mL/min; the volume of the first microreactor was 4mL. The yield of compound III obtained was 75.6%.
In the step (2), the pumping flow rate of the third mixed solution is 0.041mL/min, and the pumping flow rate of the effluent liquid containing the compound III is 0.30mL/min; the volume of the second microreactor was 4mL. The yield of the obtained compound IV-2 was 69.8%.
Example 5
The preparation process is identical to example 1, except that:
in the step (1), the pumping flow rate of the first mixed solution is 0.15mL/min, the pumping flow rate of the second mixed solution is 0.15mL/min, and the pumping flow rate of the cesium carbonate aqueous solution is 0.06mL/min; the volume of the first microreactor was 16mL. The yield of compound III obtained was 76.1%.
In the step (2), the pumping flow rate of the third mixed solution is 0.06mL/min, and the pumping flow rate of the effluent liquid containing the compound III is 0.50mL/min; the volume of the second microreactor was 16mL. The yield of the obtained compound IV-1 was 73.4%.
Example 6
The preparation method is the same as in example 2, except that:
in the step (1), the pumping flow rate of the first mixed solution is 0.15mL/min, the pumping flow rate of the second mixed solution is 0.15mL/min, and the pumping flow rate of the cesium carbonate aqueous solution is 0.06mL/min; the volume of the first microreactor was 16mL. The yield of compound III obtained was 76.1%.
In the step (2), the pumping flow rate of the third mixed solution is 0.06mL/min, and the pumping flow rate of the effluent liquid containing the compound III is 0.50mL/min; the volume of the second microreactor was 16mL. The yield of the obtained compound IV-2 was 70.1%.
Example 7: synthesis of Compound IV-1 in a conventional reaction flask
(1) To a three-necked flask, 2- (1H-indol-2-yl) phenol (4.2 g, 0.020mol), 3-p-toluenesulfonyloxy oxetane (4.6 g, 0.020mol), cesium carbonate (19.5 g,0.060 mol), 50mL of N, N-dimethylformamide solution and 20mL of water were added and reacted at 100℃for 12 hours. After the completion of the reaction, the reaction mixture was cooled to room temperature, 30mL of water and 50mL of ethyl acetate were added to the reaction mixture, the separated liquid was extracted, the organic phase was washed with water (50 ml×2), dried over anhydrous sodium sulfate, filtered, and the solvent was distilled off under reduced pressure, and the crude product was purified by a silica gel column (developer: ethyl acetate/n-hexane=1/8) to give compound III, namely, 2- (2- (oxetan-3-oxy) phenyl) -1H-indole in a yield of 70.5%.
(2) Compound III (2.1 g,8 mmol) and phosphine ligand-1 (420 mg) were dissolved in 35mL of chlorobenzene, and reacted at 80℃for 12 hours. After the completion of the reaction, the reaction mixture was cooled to room temperature, 50mL of water and 50mL of ethyl acetate were added to the reaction mixture, the mixture was separated by extraction, the organic phase was washed with water (50 mL. Times.2), dried over anhydrous sodium sulfate, filtered, and the solvent was removed by distillation under reduced pressure, and the silica gel column was separated (developer: ethyl acetate/n-hexane=1/8) to give compound iv-1 in a yield of 65.1%.
Example 8: synthesis of Compound IV-2 in a conventional reaction flask
(1) To a three-necked flask, 2- (1H-indol-2-yl) phenol (4.2 g, 0.020mol), 3-p-toluenesulfonyloxy oxetane (4.6 g, 0.020mol), cesium carbonate (19.5 g,0.060 mol), 50mL of N, N-dimethylformamide solution and 20mL of water were added and reacted at 100℃for 12 hours. After the completion of the reaction, the reaction mixture was cooled to room temperature, 30mL of water and 50mL of ethyl acetate were added to the reaction mixture, the separated liquid was extracted, the organic phase was washed with water (50 ml×2), dried over anhydrous sodium sulfate, filtered, and the solvent was distilled off under reduced pressure, and the crude product was purified by a silica gel column (developer: ethyl acetate/n-hexane=1/8) to give compound III, namely, 2- (2- (oxetan-3-oxy) phenyl) -1H-indole in a yield of 70.5%.
(2) Compound III (2.1 g,8 mmol) and phosphine ligand-2 (420 mg) were dissolved in 35mL of chlorobenzene, and reacted at 80℃for 12 hours. After the completion of the reaction, the reaction mixture was cooled to room temperature, 50mL of water and 50mL of ethyl acetate were added to the reaction mixture, the mixture was separated by extraction, the organic phase was washed with water (50 mL. Times.2), dried over anhydrous sodium sulfate, filtered, and the solvent was removed by distillation under reduced pressure, and the silica gel column was separated (developer: ethyl acetate/n-hexane=1/8) to give compound iv-2 in a yield of 60.6%.
The invention provides an indole compound, a method for preparing the indole compound, and a thought and a method for preparing the indole compound, and the method for specifically realizing the technical scheme are a plurality of methods and paths, the above is only a preferred embodiment of the invention, and it should be pointed out that a plurality of improvements and modifications can be made by one of ordinary skill in the art without departing from the principle of the invention, and the improvements and modifications are also regarded as the protection scope of the invention. The components not explicitly described in this embodiment can be implemented by using the prior art.

Claims (14)

1. The indole compound is characterized in that the structural formula of the indole compound is shown as formula IV-1 or formula IV-2:
Figure FDA0004169885210000011
2. the method for preparing indole compounds according to claim 1, wherein the compound I and the compound II undergo substitution reaction under alkaline conditions to obtain a compound III; carrying out coupling reaction on the compound III under the catalysis of phosphine ligand to prepare a compound IV-1 or a compound IV-2, namely an indole compound;
Figure FDA0004169885210000012
wherein the phosphine ligand-1 has the structural formula of
Figure FDA0004169885210000013
Wherein the phosphine ligand-2 has the structural formula of
Figure FDA0004169885210000014
3. The method according to claim 2, wherein the alkaline condition is controlled to be alkaline by adding an alkaline aqueous solution; the alkaline aqueous solution is potassium carbonate aqueous solution, potassium tert-butoxide aqueous solution, sodium tert-butoxide aqueous solution or cesium carbonate aqueous solution; the molar ratio of the compound I to the compound II to the alkali in the alkaline aqueous solution is 1:1 to 1.5:2.5 to 4; the substitution reaction is carried out at the reaction temperature of 90-120 ℃; the mass ratio of the compound III to the phosphine ligand is 1:0.1 to 0.4; the coupling reaction is carried out at a temperature of 70-90 ℃.
4. The method of claim 2, wherein the reaction is carried out using a conventional reactor or a microchannel modular reaction apparatus.
5. The method of claim 4, wherein the method comprises the steps of:
(1) Dissolving a compound I in a first organic solvent to obtain a first mixed solution; dissolving a compound II in a first organic solvent to obtain a second mixed solution; pumping the first mixed solution, the second mixed solution and the alkaline aqueous solution into a first micro-mixer in a micro-channel modularized reaction device respectively at the same time, pumping the mixed solution into the first micro-reactor for substitution reaction after full mixing, and extracting and separating the reaction solution through a first separation device after reaction to obtain effluent containing a compound III;
(2) Dissolving phosphine ligand in a second organic solvent to obtain a third mixed solution; pumping the third mixed solution and the effluent containing the compound III obtained in the step (1) into a second micro-mixer in a micro-channel modularized reaction device respectively, fully mixing, pumping into a second micro-reactor for coupling reaction, and carrying out post-treatment on the reaction solution after the reaction is finished.
6. The method according to claim 5, wherein in the step (1), the first organic solvent is N, N-dimethylformamide, dimethylsulfoxide, dimethylacetamide or N, N-diisopropylethylamine; the concentration of the compound I in the first mixed solution is 0.2-1.0 mol/L; the concentration of the compound II in the second mixed solution is 0.2-1.5 mol/L; the alkaline aqueous solution is potassium carbonate aqueous solution, potassium tert-butoxide aqueous solution, sodium tert-butoxide aqueous solution or cesium carbonate aqueous solution; the concentration of alkali in the alkaline aqueous solution is 2.0-4.0 mol/L; the molar ratio of the compound I to the compound II to the alkali in the alkaline aqueous solution is 1:1 to 1.5:2.5 to 4.
7. The method according to claim 5, wherein in the step (1), the flow rate of the first mixture pumped into the first micromixer in the microchannel modular reactor is 0.04-0.40 mL/min; the flow rate of the second mixed liquid pumped into the first micro-mixer in the micro-channel modularized reaction device is 0.04-0.50 mL/min; the flow rate of the alkaline aqueous solution pumped into the first micro mixer in the micro-channel modularized reaction device is 0.01-0.20 mL/min; the volume of the first micro-reactor is 4-40 mL; the substitution reaction is carried out at a temperature of 90-120 ℃.
8. The process of claim 5, wherein in step (2), the second organic solvent is chlorobenzene or toluene; the concentration of the phosphine ligand in the third mixed solution is 0.025-0.10 mol/L.
9. The process according to claim 5, wherein in the step (2), the concentration of the compound III in the effluent containing the compound III is 0.2 to 0.4mol/L; the mass ratio of the compound III to the phosphine ligand is 1:0.1 to 0.4.
10. The method according to claim 5, wherein in the step (2), the flow rate of the third mixture pumped into the second micromixer in the microchannel modular reactor is 0.02-0.06 mL/min; the flow rate of the effluent liquid containing the compound III pumped into a second micro mixer in the micro-channel modularized reaction device is 0.1-0.8 mL/min; the volume of the second micro-reactor is 4-40 mL; the coupling reaction is carried out at a temperature of 70-90 ℃.
11. The method of claim 5, wherein the microchannel modular reactor comprises a connecting conduit, a first feed pump, a second feed pump, a third feed pump, a fourth feed pump, a fifth feed pump, a first micromixer, a second micromixer, a first separation device, a first microreactor, a second microreactor, and a receiving device; the first feeding pump, the second feeding pump and the third feeding pump are connected to the first micro mixer in parallel through pipelines; the first micro-mixer, the first micro-reactor, the first separation device and the fourth feed pump are sequentially connected in series through pipelines; the fourth feed pump and the fifth feed pump are connected to the second micromixer in parallel through a pipeline; the second micro-mixer, the second micro-reactor and the receiving device are sequentially connected in series through pipelines.
12. The preparation method according to claim 11, wherein the connecting pipeline has a diameter of 0.5-4 mm and a length of 10-70 cm; the diameter of the pipeline of the first micro-reactor is 0.5-4 mm; the diameter of the pipeline of the second micro-reactor is 0.5-4 mm.
13. The use of an indole compound according to claim 1 as a lead compound for anticancer drug design.
14. Use of an indole compound according to claim 1 as a standard.
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Publication number Priority date Publication date Assignee Title
US20050282863A1 (en) * 2004-03-31 2005-12-22 Council Of Scientific & Industrial Research Novel-N substituted dihydrobenzothiepino, dihydrobenzoxepino and tetrahydro benzocyclohepta indoles as selective estrogen receptor modulators
CN101039947A (en) * 2004-08-09 2007-09-19 布里斯托尔-迈尔斯斯奎布公司 Inhibitors of hcv replication
WO2017193288A1 (en) * 2016-05-10 2017-11-16 The Hong Kong Polytechnic University Shenzhen Research Institute Synthesis of phosphine ligands bearing tunable linkage: methods of their use in catalysis

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20050282863A1 (en) * 2004-03-31 2005-12-22 Council Of Scientific & Industrial Research Novel-N substituted dihydrobenzothiepino, dihydrobenzoxepino and tetrahydro benzocyclohepta indoles as selective estrogen receptor modulators
CN101039947A (en) * 2004-08-09 2007-09-19 布里斯托尔-迈尔斯斯奎布公司 Inhibitors of hcv replication
WO2017193288A1 (en) * 2016-05-10 2017-11-16 The Hong Kong Polytechnic University Shenzhen Research Institute Synthesis of phosphine ligands bearing tunable linkage: methods of their use in catalysis

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