Process for the preparation of substituted benzo[e]indoles

Abstract

The application discloses a preparation method of substituted benzo[e]indole, and belongs to the field of organic synthesis. Taking 7-bromo-1,1,2-trimethyl-1H-benzo[e]indole as an example, a 6-bromo-2-aminonaphthalene is used as a starting material, the material is mixed with ethanol and hydrochloric acid and stirred, an aqueous sodium nitrite solution is added dropwise at low temperature to complete a diazotization reaction, 3-methyl-2-butanone and concentrated sulfuric acid are added to perform a cyclization reaction under heating and reflux; after the reaction is completed, water is added for dilution, saturated sodium carbonate is used to adjust the pH of the system, the target product is obtained through methyl tert-butyl ether extraction, washing with an aqueous ammonium chloride solution, drying with anhydrous sodium sulfate, addition of n-heptane for beating, filtration and airing. The application simplifies a traditional two-step synthesis route into one-step continuous reaction, does not need to use stannous chloride in the whole process, avoids generation of tin-containing wastewater from the source, has low three-waste discharge, has mild reaction conditions, simplified operation steps, short production cycle and strong process stability.

Description

Technical Field

[0001] This invention belongs to the field of organic synthesis, specifically relating to a method for preparing substituted benzo[e]indole. Background Technology

[0002] Benzo[e]indole and its brominated derivatives are important fused-ring nitrogen-containing heterocyclic compounds. Due to their unique conjugated molecular structure and physicochemical properties, they have irreplaceable application value in many fields such as organic optoelectronic materials, pharmaceutical intermediates, and fine chemicals. Among them, 7-bromo-1,1,2-trimethyl-1H-benzo[e]indole, as a typical substituted benzo[e]indole compound, is a key intermediate for the synthesis of optoelectronic functional materials and targeted drugs. With the continuous development of downstream industries, the market has placed increasingly higher demands on the production capacity, purity, production cost, and environmental friendliness of the production process of this compound. Developing efficient, green, low-cost, and easily industrialized preparation processes has become a key research direction in this field.

[0003] Currently, the synthesis of 7-bromo-1,1,2-trimethyl-1H-benzo[e]indole generally employs a two-step independent reaction process, which is cumbersome and complex. The traditional process begins with 6-bromo-2-aminonaphthalene as a raw material. After diazotization in a hydrochloric acid system, stannous chloride dihydrate is added for reduction with concentrated hydrochloric acid. After the reaction, multiple purification steps, including filtration, filter cake washing, and vacuum drying, are required to prepare an intermediate. The second step involves mixing the separated intermediate with 3-methyl-2-butanone and refluxing it under concentrated sulfuric acid catalysis to obtain the target product. This process has several obvious drawbacks: First, the process involves multiple steps and requires separate purification of intermediate products. Material loss is significant during multiple transfers, filtrations, and drying processes, resulting in a total yield of only 61.5% for the traditional process. This low raw material utilization directly increases production costs. Second, the process uses a large amount of stannous chloride, which generates a large amount of high-concentration tin-containing industrial wastewater. Tin is a heavy metal, making wastewater treatment difficult and costly, and causing serious ecological pollution, which does not meet the current industry development requirements for green chemistry and clean production. Furthermore, the multiple independent reactions and complex post-processing operations extend the overall production cycle, resulting in low equipment utilization, high manual labor intensity, and poor process reproducibility during scale-up production.

[0004] In addition, traditional processes involve multiple steps, which easily introduce exogenous impurities, adversely affecting product purity control and making it difficult to consistently meet the stringent standards for intermediate impurity content in high-end materials and pharmaceutical fields. In summary, existing two-step synthetic routes suffer from a series of problems, including low yield, severe waste pollution, lengthy processes, and high difficulty in industrialization, making them unsuitable for current large-scale and green production needs. Therefore, developing a new method for preparing substituted benzo[e]indole with simplified steps, high yield, no heavy metal pollution, and controllable reaction has significant economic and environmental value. Summary of the Invention

[0005] The purpose of this invention is to provide a method for preparing substituted benzo[e]indole, which aims to overcome the problems of complex procedures, large material loss, and heavy metal wastewater generation in traditional two-step synthesis processes. By optimizing the reaction system and post-processing flow, a high-purity target product can be prepared efficiently and in a green manner.

[0006] The technical solution adopted by the present invention to achieve the above objectives is as follows: A method for synthesizing substituted benzo[e]indole, comprising, Starting with 6-bromo-2-aminonaphthalene, the raw material was mixed with ethanol and hydrochloric acid and stirred. A sodium nitrite aqueous solution was added dropwise at low temperature to carry out a diazotization reaction. Then, 3-methyl-2-butanone and concentrated sulfuric acid were added, followed by reflux to carry out a cyclization reaction, yielding an initial reaction solution. The initial reaction solution was diluted with deionized water, and the pH was adjusted to 9.3–9.7 to obtain a diluted solution. Methyl tert-butyl ether was added to the diluted solution for extraction. The solution was washed with ammonium chloride aqueous solution and dried with anhydrous sodium sulfate to obtain an extract. The extract was concentrated under reduced pressure at 48–52 °C to obtain a concentrated solution. Heptane was added to the concentrated solution for slurrying, followed by filtration and drying to obtain 7-bromo-1,1,2-trimethyl-1H-benzo[e]indole, i.e., substituted benzo[e]indole.

[0007] This invention employs a one-step continuous series process, comprising three stages of continuous in-situ conversion: First, the starting material 6-bromo-2-aminonaphthalene undergoes a diazotization reaction with sodium nitrite in a hydrochloric acid system at a low temperature of 0-5°C to generate 6-bromo-2-naphthalene diazonium salt. Ethanol pre-stored in the system exhibits reducing activity under a high-acidity, reflux-heated composite environment created by the subsequent addition of concentrated sulfuric acid, reducing the naphthalene ring diazonium salt in situ to generate the Fischer cyclization essential intermediate 6-bromo-2-naphthylhydrazine. No traditional solid reducing reagents such as stannous chloride or sodium dithionite are required during this process. The aromatic hydrazine intermediate generated in this system is not separated or purified; it directly condenses with 3-methyl-2-butanone in the same reaction solution, and the mixture is refluxed at 78-82°C. Under concentrated sulfuric acid catalysis, the Fischer indole ring is closed, yielding the target product 7-bromo-1,1,2-trimethyl-1H-benzo[e]indole in one step.

[0008] This method does not omit the essential diazonium salt reduction step in Fischer indole synthesis, but only reconstructs the reduction system: abandoning the traditional segmented approach of separately adding tin salts for reduction and separating the aryl hydrazine intermediate. In conventional organic synthesis, the reduction of aryl diazonium salts to prepare aryl hydrazines generally relies on specialized reducing agents such as sulfites and stannous chloride. However, this invention achieves efficient in-situ conversion of diazonium salts to aryl hydrazines through special coupling conditions of high-concentration sulfuric acid, ethanol, naphthalene-based brominated diazonium substrates, and reflux temperature. The traditional two-step process requires separate addition of stannous chloride for reduction and recrystallization to separate the aryl hydrazine intermediate. Aleurones exposed to air are easily oxidized and degraded, and multiple transfers and filtrations result in significant material losses. In this invention, the reduction-cyclization system proceeds continuously, and the aryl hydrazine participates in cyclization immediately after formation, significantly reducing intermediate oxidation losses. Therefore, a higher product yield is achieved under conditions without heavy metal reducing agents.

[0009] This synthetic method employs a one-step continuous process to complete the diazotization and cyclization reactions, eliminating intermediate separation steps, effectively reducing losses caused by multiple material transfers, and significantly improving product yield. No additional heavy metal reducing agents such as stannous chloride are required throughout the process; diazonium salt reduction is achieved in situ using ethanol within the system, preventing the generation of tin-containing wastewater from the source, simplifying waste treatment processes, and making production more environmentally friendly. The entire reaction process is characterized by mild reaction conditions, streamlined procedures, and seamless integration of post-processing steps such as extraction, concentration, and pulping. The process is stable and highly operable. The one-step tandem reaction reduces exposure to intermediate systems and the introduction of impurities, while the mild reaction conditions suppress side reactions. The good matching of each step ensures high product yield and quality.

[0010] Preferably, the temperature of the diazotization reaction is 0~5℃.

[0011] Preferably, the cyclization reaction temperature is 78~82℃.

[0012] Preferably, the mass-to-volume ratio of 6-bromo-2-aminonaphthalene to ethanol is 1 g: 2.8~3.2 mL.

[0013] Preferably, the mass of the sodium nitrite aqueous solution is measured by the mass of sodium nitrite therein, and the mass ratio of 6-bromo-2-aminonaphthalene to sodium nitrite is 100:32.0~34.4.

[0014] Preferably, the mass ratio of 6-bromo-2-aminonaphthalene to 3-methyl-2-butanone is 100:45.0~48.0.

[0015] Preferably, the mass ratio of 6-bromo-2-aminonaphthalene to concentrated sulfuric acid is 100:0.60~0.70.

[0016] Preferably, tetraethylammonium tetrafluoroborate is added to the diluent, and the mass-to-volume ratio of tetraethylammonium tetrafluoroborate to the initial reaction solution is 0.5~2g:250mL.

[0017] The application of tetraethyltetrafluoroborate ammonium in the dilution and extraction process of this technology can significantly reduce the dissolution loss of the target product in the aqueous phase and improve the overall product yield; it effectively breaks the emulsion layer formed between methyl tert-butyl ether and the aqueous phase, shortening the extraction and phase separation time; at the same time, it reduces the content of polar by-products and colored impurities in the product, improving the chromatographic purity of the product; the speculated mechanism is that the ionic salt can increase the ionic strength of the system after dissolving in the aqueous phase, and reduce the water solubility of the product through salting out; at the same time, it changes the interfacial tension between the liquid and liquid phases to achieve demulsification, and binds the polar impurities in the system with the help of electrostatic interaction, preventing the impurities from being carried away by the organic phase during extraction.

[0018] Preferably, the volume ratio of the initial reaction solution to methyl tert-butyl ether is 1:5.5~6.5.

[0019] Preferably, the volume ratio of the extract to n-heptane is 1:1.8~2.2.

[0020] More preferably, 4-(hydroxymethyl)tetrahydropyran is added to the concentrate, and the volume ratio of the extract to 4-(hydroxymethyl)tetrahydropyran is 1:0.1~0.2.

[0021] 4-(hydroxymethyl)tetrahydropyran is used in the crystallization and pulping process after concentration to optimize the crystal form of the product, reduce the generation of fine powder and impurity encapsulation, and further improve product purity. It also improves material looseness, reduces filtration resistance, and shortens solid-liquid separation time. Compared to conventional co-solvents such as methanol, this additive has a superior overall optimization effect and does not react with the product or residual reagents, nor does it introduce new impurities. This oxygen-containing heterocyclic alcohol can be uniformly dispersed in the system, and it is speculated that it can regulate the crystal growth process, generating crystals with regular morphology and uniform particle size, reducing material loss caused by crystal powder encapsulation and preventing trace impurities from being embedded inside the crystals.

[0022] This invention also provides a method for preparing substituted benzo[e]indole, the specific steps of which are as follows: Preparation of substituted benzo[e]indole: 6-bromo-2-aminonaphthalene was added to a reaction flask, followed by ethanol and 11-13 mol / L hydrochloric acid. The mixture was stirred until homogeneous, and the internal temperature was maintained at 28-32℃ for 0.4-0.6 h. The temperature was then lowered to 0-5℃, and sodium nitrite aqueous solution was added dropwise, maintaining the system temperature at 0-5℃ throughout the process. After the addition was complete, 3-methyl-2-butanone and concentrated sulfuric acid were added to the system, and the mixture was refluxed at 78-82℃ for 6.0-7.0 h to obtain the initial reaction solution. High-performance liquid chromatography (HPLC) was used to detect the complete reaction of the raw materials and intermediates. The initial reaction solution was then cooled to 28-32℃ and diluted with deionized water. The pH was adjusted to 9.3-9.7 using a saturated sodium carbonate aqueous solution to obtain a diluted solution. Methyl tert-butyl ether was added to the diluted solution for extraction, and the extraction was performed twice. All organic phases were combined, and the organic phases were washed once with a 10% ammonium chloride aqueous solution. Anhydrous sodium sulfate was added for drying to obtain an extract. The extract was concentrated under reduced pressure at 48-52℃ until it was not completely evaporated to obtain a concentrated solution. Heptane was added to the concentrated solution and stirred for 0.4-0.6 h. The solution was filtered, and the solid product was air-dried to obtain 7-bromo-1,1,2-trimethyl-1H-benzo[e]indole, i.e., substituted benzo[e]indole.

[0023] Preferably, the mass-to-volume ratio of 6-bromo-2-aminonaphthalene to ethanol is 1 g: 2.8~3.2 mL.

[0024] Preferably, the mass-to-volume ratio of 6-bromo-2-aminonaphthalene to hydrochloric acid is 1 g: 2.3~2.7 mL.

[0025] Preferably, the sodium nitrite aqueous solution comprises sodium nitrite and deionized water, wherein the mass-to-volume ratio of sodium nitrite to deionized water is 32.0~34.4g:155~165mL.

[0026] Preferably, the mass of the sodium nitrite aqueous solution is measured by the mass of sodium nitrite therein, and the mass ratio of 6-bromo-2-aminonaphthalene to sodium nitrite is 100:32.0~34.4.

[0027] Preferably, the mass ratio of 6-bromo-2-aminonaphthalene to 3-methyl-2-butanone is 100:45.0~48.0.

[0028] Preferably, the mass ratio of 6-bromo-2-aminonaphthalene to concentrated sulfuric acid is 100:0.60~0.70.

[0029] Preferably, the volume ratio of the initial reaction solution to deionized water is 1:8.5~9.5.

[0030] Preferably, the volume ratio of the initial reaction solution to methyl tert-butyl ether is 1:5.5~6.5.

[0031] Preferably, the volume ratio of the organic phase to the 10% ammonium chloride aqueous solution is 1:0.9~1.1.

[0032] Preferably, the volume ratio of the extract to n-heptane is 1:1.8~2.2.

[0033] More preferably, tetraethylammonium tetrafluoroborate is added to the diluent, wherein the mass-to-volume ratio of tetraethylammonium tetrafluoroborate to the initial reaction solution is 0.5~2g:250mL.

[0034] More preferably, 4-(hydroxymethyl)tetrahydropyran is added to the concentrate, and the volume ratio of the extract to 4-(hydroxymethyl)tetrahydropyran is 1:0.1~0.2.

[0035] This invention employs a one-step continuous synthesis process, eliminating multiple steps such as intermediate separation, washing, and drying, and completely discarding stannous chloride reducing agent, thus preventing the generation of tin-containing heavy metal wastewater from the source. Simultaneously, the addition of tetraethylammonium tetrafluoroborate in the extraction step utilizes its salting-out, demulsification, and complexation effects on polar impurities to reduce product water-soluble loss, eliminate extraction emulsification problems, and improve impurity removal efficiency. Furthermore, the introduction of 4-(hydroxymethyl)tetrahydropyran in the crystallization step effectively controls crystal morphology, prevents impurities from being trapped inside the crystals, and further optimizes product quality and filtration efficiency. Compared to conventional reagents and traditional processes, this invention offers higher raw material utilization, significantly improved product yield and chromatographic purity, and the entire process features mild reaction conditions, simple operation, and good reproducibility. Therefore, this invention is a green, environmentally friendly, streamlined, high-yield, high-quality product preparation method suitable for large-scale production of substituted benzo[e]indole. Attached Figure Description

[0036] Figure 1 This is a synthetic reaction route diagram for the preparation method of substituted benzo[e]indole according to the present invention.

[0037] Figure 2 The 1H NMR spectrum of the substituted benzo[e]indole prepared in Example 1.

[0038] Figure 3 The high-performance liquid chromatogram of the substituted benzo[e]indole prepared in Example 1 is shown. Detailed Implementation

[0039] The technical solutions of the embodiments of the present invention will be clearly and completely described below with reference to the accompanying drawings. Obviously, the described embodiments are only some embodiments of the present invention, and not all embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those skilled in the art without creative effort are within the scope of protection of the present invention.

[0040] The concepts involved in this application will first be described with reference to the accompanying drawings. It should be noted that the following descriptions of various concepts are only for the purpose of making the content of this application easier to understand and do not constitute a limitation on the scope of protection of this application; furthermore, the embodiments and features in the embodiments of this application can be combined with each other unless otherwise specified. This application will now be described in detail with reference to the accompanying drawings and embodiments.

[0041] Example 1: This example provides a method for preparing substituted benzo[e]indole, specifically 7-bromo-1,1,2-trimethyl-1H-benzo[e]indole. The synthetic reaction route for preparing substituted benzo[e]indole is shown below. Figure 1 As shown, the specific steps are as follows: Preparation of substituted benzo[e]indole: 6-bromo-2-aminonaphthalene was added to a reaction flask, followed by ethanol and 12 mol / L hydrochloric acid. The mixture was stirred until homogeneous, and the internal temperature was maintained at 30°C for 0.5 h. The temperature was then lowered to 2°C, and sodium nitrite aqueous solution was added dropwise, maintaining the internal temperature at 2°C throughout the process. After the addition was complete, 3-methyl-2-butanone and concentrated sulfuric acid were added to the system, and the mixture was refluxed at 80°C for 6.5 h to obtain the initial reaction solution. High-performance liquid chromatography was used to detect the complete reaction of the raw materials and intermediates. The initial reaction solution was then cooled to 30°C, diluted with deionized water, and saturated sodium carbonate solution was used for dilution. The pH of the solution was adjusted to 9.5 to obtain a diluted solution. Methyl tert-butyl ether was added to the diluted solution for extraction, and the extraction was performed twice. All organic phases were combined, and the organic phases were washed once with 10% ammonium chloride aqueous solution. Anhydrous sodium sulfate was added for drying to obtain an extract. The extract was concentrated under reduced pressure at 50°C until it was not completely evaporated to obtain a concentrated solution. Heptane was added to the concentrated solution and stirred for 0.5 h. The solution was filtered, and the solid product was air-dried to obtain 7-bromo-1,1,2-trimethyl-1H-benzo[e]indole, i.e., substituted benzo[e]indole. The mass-to-volume ratio of 6-bromo-2-aminonaphthalene to ethanol was 1 g:3 mL, and the mass-to-volume ratio of 6-bromo-2-aminonaphthalene to hydrochloric acid was 1 g:2.5 mL. The sodium nitrite aqueous solution comprised sodium nitrite and deionized water, with a mass-to-volume ratio of 33.2 g:160 mL. The mass of the sodium nitrite aqueous solution was measured by the mass of sodium nitrite contained therein, and the mass ratio of 6-bromo-2-aminonaphthalene to sodium nitrite was 100:33.2. The mass ratio of 6-bromo-2-aminonaphthalene to 3-methyl-2-butanone was 100:46.5, and the mass ratio of 6-bromo-2-aminonaphthalene to concentrated sulfuric acid was 100:0.65. The volume ratio of the initial reaction solution to deionized water was 1:9, and the volume ratio of the initial reaction solution to methyl tert-butyl ether was 1:6. The volume ratio of the organic phase to 10% ammonium chloride aqueous solution was 1:1, and the volume ratio of the extract to n-heptane was 1:2.

[0042] Example 2: The only difference between this example and Example 1 is that tetraethylammonium tetrafluoroborate is added to the diluent in Example 2. The specific steps are as follows: Preparation of substituted benzo[e]indole: 6-bromo-2-aminonaphthalene was added to a reaction flask, followed by ethanol and 12 mol / L hydrochloric acid. The mixture was stirred until homogeneous, and the internal temperature was maintained at 30°C for 0.5 h. The temperature was then lowered to 2°C, and sodium nitrite aqueous solution was added dropwise, maintaining the internal temperature at 2°C throughout the process. After the addition was complete, 3-methyl-2-butanone and concentrated sulfuric acid were added to the system, and the mixture was refluxed at 80°C for 6.5 h to obtain the initial reaction solution. High-performance liquid chromatography was used to detect the complete reaction of the raw materials and intermediates. The initial reaction solution was then cooled to 30°C, diluted with deionized water, and the pH was adjusted to 9 using saturated sodium carbonate aqueous solution. 5. Obtain the diluted solution; add tetraethylammonium tetrafluoroborate to the diluted solution and stir until completely dissolved. Extract with methyl tert-butyl ether twice, combine all organic phases, wash the organic phase once with 10% ammonium chloride aqueous solution, and dry with anhydrous sodium sulfate to obtain the extract; concentrate the extract under reduced pressure at 50°C until it is not completely evaporated to obtain the concentrate; add n-heptane to the concentrate and stir for 0.5 h, filter, and air dry the solid product to obtain 7-bromo-1,1,2-trimethyl-1H-benzo[e]indole, i.e., substituted benzo[e]indole. The mass-to-volume ratio of 6-bromo-2-aminonaphthalene to ethanol is 1 g:3 mL, and the mass-to-volume ratio of 6-bromo-2-aminonaphthalene to hydrochloric acid is 1 g:2.5 mL; the sodium nitrite aqueous solution comprises sodium nitrite and deionized water, with a mass-to-volume ratio of sodium nitrite to deionized water of 33.2 g:160 mL; the mass of the sodium nitrite aqueous solution is measured by the mass of sodium nitrite contained therein, and the mass ratio of 6-bromo-2-aminonaphthalene to sodium nitrite is 100:33.2; 6-bromo-2-aminonaphthalene... The mass ratio of naphthalene to 3-methyl-2-butanone was 100:46.5, and the mass ratio of 6-bromo-2-aminonaphthalene to concentrated sulfuric acid was 100:0.65; the volume ratio of the initial reaction solution to deionized water was 1:9; the mass-volume ratio of tetraethyltetrafluoroborate to the initial reaction solution was 1 g:250 mL; the volume ratio of the initial reaction solution to methyl tert-butyl ether was 1:6; the volume ratio of the organic phase to 10% ammonium chloride aqueous solution was 1:1; and the volume ratio of the extract to n-heptane was 1:2.

[0043] Example 3: The only difference between this example and Example 2 is that 4-(hydroxymethyl)tetrahydropyran is added to the concentrate in Example 3. The specific steps are as follows: Preparation of substituted benzo[e]indole: 6-bromo-2-aminonaphthalene was added to a reaction flask, followed by ethanol and 12 mol / L hydrochloric acid. The mixture was stirred until homogeneous, and the internal temperature was maintained at 30℃ for 0.5 h. The temperature was then lowered to 2℃, and sodium nitrite aqueous solution was added dropwise, maintaining the internal temperature at 2℃ throughout the process. After the addition was complete, 3-methyl-2-butanone and concentrated sulfuric acid were added to the system, and the mixture was refluxed at 80℃ for 6.5 h to obtain the initial reaction solution. High-performance liquid chromatography was used to detect the complete reaction of the raw materials and intermediates. The initial reaction solution was then cooled to 30℃, diluted with deionized water, and the pH was adjusted to 9.5 using saturated sodium carbonate aqueous solution to obtain the diluted solution. Add tetraethylammonium tetrafluoroborate to the diluent and stir until completely dissolved; extract with methyl tert-butyl ether twice, combine all organic phases, wash the organic phase once with 10% ammonium chloride aqueous solution, and dry with anhydrous sodium sulfate to obtain the extract; concentrate the extract under reduced pressure at 50°C until it is not completely evaporated to obtain the concentrate; add 4-(hydroxymethyl)tetrahydropyran to the concentrate, then add n-heptane and stir for 0.5 h, filter, and air dry the solid product to obtain 7-bromo-1,1,2-trimethyl-1H-benzo[e]indole, i.e., substituted benzo[e]indole. The mass-to-volume ratio of 6-bromo-2-aminonaphthalene to ethanol is 1 g:3 mL, and the mass-to-volume ratio of 6-bromo-2-aminonaphthalene to hydrochloric acid is 1 g:2.5 mL; the sodium nitrite aqueous solution comprises sodium nitrite and deionized water, with a mass-to-volume ratio of sodium nitrite to deionized water of 33.2 g:160 mL; the mass of the sodium nitrite aqueous solution is measured by the mass of sodium nitrite contained therein, and the mass ratio of 6-bromo-2-aminonaphthalene to sodium nitrite is 100:33.2; 6-bromo-2-aminonaphthalene and 3-methyl-2-butanone... The mass ratio of 6-bromo-2-aminonaphthalene to concentrated sulfuric acid was 100:46.5; the volume ratio of the initial reaction solution to deionized water was 1:9; the mass-volume ratio of tetraethyltetrafluoroborate to the initial reaction solution was 1 g:250 mL; the volume ratio of the initial reaction solution to methyl tert-butyl ether was 1:6; the volume ratio of the organic phase to 10% ammonium chloride aqueous solution was 1:1; the volume ratio of the extract to 4-(hydroxymethyl)tetrahydropyran was 1:0.15; and the volume ratio of the extract to n-heptane was 1:2.

[0044] Comparative Example 1: This comparative example provides a conventional method for preparing substituted benzo[e]indole. The preparation steps include the preparation of a reaction intermediate and the substituted benzo[e]indole, as detailed below: Step 1: Preparation of the reaction intermediate: Add 6-bromo-2-aminonaphthalene to the reaction flask, then add ethanol and 12 mol / L hydrochloric acid, stir until homogeneous, maintain the internal temperature at 30℃ for 0.5 h, cool to 2℃, and add sodium nitrite aqueous solution dropwise, maintaining the internal temperature at 2℃ throughout the process; after the addition is complete, continue the reaction at this temperature, and use high performance liquid chromatography to detect until the diazotization reaction is complete. Add a mixed solution of stannous chloride dihydrate and hydrochloric acid dropwise to the system, and maintain the reaction at this temperature until the reaction is complete to obtain the intermediate reaction solution; after the reaction is complete, filter the solution, wash the filter cake with ethyl acetate, and dry the filter cake under reduced pressure to obtain the reaction intermediate. The mass-to-volume ratio of 6-bromo-2-aminonaphthalene to ethanol is 100 g: 300 mL, and the mass-to-volume ratio of 6-bromo-2-aminonaphthalene to hydrochloric acid is 10 g: 25 mL; the sodium nitrite aqueous solution includes sodium nitrite and deionized water, with a mass-to-volume ratio of sodium nitrite to deionized water of 33.2 g: 160 mL; the mass of the sodium nitrite aqueous solution is measured by the mass of sodium nitrite contained therein, and the mass ratio of 6-bromo-2-aminonaphthalene to sodium nitrite is 100: 33.2.

[0045] Step 2: Preparation of substituted benzo[e]indole: The reaction intermediate was added to a reaction flask, followed by ethanol, 3-methyl-2-butanone, and concentrated sulfuric acid. The mixture was stirred until homogeneous and refluxed at 80°C to obtain the initial reaction solution. High-performance liquid chromatography (HPLC) was used to detect the complete reaction of the raw materials and intermediates. The initial reaction solution was then cooled to 30°C and diluted with deionized water. The pH of the system was adjusted to 9.5 using a saturated sodium carbonate aqueous solution. Extraction was performed twice using methyl tert-butyl ether. All organic phases were combined and washed sequentially with a 10% ammonium chloride aqueous solution and a saturated sodium chloride aqueous solution. Anhydrous sodium sulfate was added for drying to obtain the extract. The extract was concentrated under reduced pressure at 50°C until it was not completely evaporated. Heptane was added and stirred for 0.5 h. The mixture was filtered and the solid product was air-dried to obtain 7-bromo-1,1,2-trimethyl-1H-benzo[e]indole, i.e., substituted benzo[e]indole. The mass-to-volume ratio of the reaction intermediate to ethanol was 100 g: 300 mL; the mass ratio of the reaction intermediate to 3-methyl-2-butanone was 100: 46.5; the mass ratio of the reaction intermediate to concentrated sulfuric acid was 100: 0.65; the volume ratio of the initial reaction solution to deionized water was 1:9; the volume ratio of the initial reaction solution to methyl tert-butyl ether used in the single extraction was 1:6; the mass-to-volume ratio of the reaction intermediate to 10% ammonium chloride aqueous solution was 100 g: 600 mL; and the volume ratio of the extract to n-heptane was 1:2.

[0046] Comparative Example 2: The only difference between this comparative example and Example 2 is that tetraethylammonium tetrafluoroborate was replaced with tetraethylammonium chloride, and the mass-volume ratio of tetraethylammonium chloride to the initial reaction solution was 1g:250mL.

[0047] Comparative Example 3: The only difference between this comparative example and Example 3 is that 4-(hydroxymethyl)tetrahydropyran was replaced with methanol, and the volume ratio of the extract to methanol was 1:0.15.

[0048] Experimental Example 1: 1H NMR characterization of substituted benzo[e]indole.

[0049] Test sample: substituted benzo[e]indole prepared in Example 1.

[0050] Test method: The substituted benzo[e]indole prepared in Example 1 was dissolved in a suitable deuterated reagent and subjected to proton NMR spectroscopy at room temperature. The chemical shift (ppm) and signal intensity were recorded to obtain the ¹H-NMR spectrum of the sample, and the characteristic peaks were assigned and analyzed.

[0051] The 1H NMR spectrum of the substituted benzo[e]indole prepared in Example 1 is shown below. Figure 2 As shown in the 1H NMR spectrum, the position, shape, and integral ratio of each characteristic hydrogen signal peak of the sample are completely consistent with the standard 1H NMR data of 7-bromo-1,1,2-trimethyl-1H-benzo[e]indole, and no obvious impurity peaks appear, proving that the chemical structure of the product prepared by this method is consistent with the target product and the product structure is accurate.

[0052] Experimental Example 2: High Performance Liquid Chromatography (HPLC) Determination of Substituted Benzo[e]Indole.

[0053] Test sample: substituted benzo[e]indole prepared in Example 1.

[0054] Test method: A high-performance liquid chromatograph equipped with a PDA detector was used, with a C18 reversed-phase column, a detection wavelength of 210 nm, an injection volume of 5 μL, and a column temperature of 30 °C. Isocratic elution was performed using a methanol-water mixture as the mobile phase. The purity of the product and the content of impurities were calculated by peak area normalization.

[0055] The high-performance liquid chromatogram of the substituted benzo[e]indole prepared in Example 1 is shown below. Figure 3 As shown in the high-performance liquid chromatogram, the main peak of the target substance is symmetrical and the baseline is stable. The number of impurity peaks is small and the peak area ratio is low, indicating that this one-step continuous synthesis process can stably prepare high-purity 7-bromo-1,1,2-trimethyl-1H-benzo[e]indole, and the product quality meets the requirements for use.

[0056] Experimental Example 3: Purity test of substituted benzo[e]indole.

[0057] Test samples: substituted benzo[e]indole prepared in each example and comparative example.

[0058] Test method: A high-performance liquid chromatograph equipped with a PDA detector was used, with a C18 reversed-phase column, a detection wavelength of 210 nm, an injection volume of 5 μL, and a column temperature of 30 °C. Isoclimate elution was performed using a methanol-water mixture as the mobile phase. Each sample was prepared into a test solution of equal concentration for injection and analysis. The product purity and the maximum single impurity content were calculated using the peak area normalization method.

[0059] The purity test results of substituted benzo[e]indole are shown in Table 1.

[0060] Table 1. Purity test results of substituted benzo[e]indole

[0061] Example 1 is a one-step continuous synthesis process. This route abandons the traditional two-step method and stannous chloride reducing agent, avoiding the risk of introducing heavy metal impurities. High-purity products with a purity of 99.0% can be prepared solely using the continuous reaction system of this invention. The product's baseline quality is excellent, and its purity index is at the same level as Comparative Example 1 using the traditional process. Example 2 adds tetraethylammonium tetrafluoroborate in the extraction step. This special ionic salt can directionally capture polar organic byproducts and water-soluble colored impurities generated during diazotization and cyclization reactions through ion complexation, preventing these impurities from being co-extracted by methyl tert-butyl ether, thus slightly improving the product purity. Comparative Example 2 replaces tetraethylammonium tetrafluoroborate with tetraethylammonium chloride, which has a similar structure. This conventional quaternary ammonium salt only... While possessing basic salting-out capabilities, it lacks the impurity complexation effect caused by fluoroborate ions, making it unable to effectively retain polar impurities. The purity of the final product is essentially the same as that of the basic process, fully demonstrating that the impurity removal advantage of tetraethyltetrafluoroborate ammonium cannot be replaced by conventional reagents of the same type. In Example 3, based on the system of Example 2, 4-(hydroxymethyl)tetrahydropyran was introduced into the crystallization process. This heterocyclic alcohol crystallization aid can regulate the crystal growth rate and crystal structure, effectively preventing trace impurities from being trapped inside the crystal lattice, further achieving product purification and increasing purity again. In Comparative Example 3, the crystallization aid was replaced with industrially common methanol. Methanol only has a simple solubilizing effect and does not have the functions of crystal structure regulation and impurity suppression, so it cannot reduce the problem of impurities trapped in the crystal, and the purity improvement effect is very limited.

[0062] Experimental Example 4: Yield test of substituted benzo[e]indole.

[0063] Test samples: substituted benzo[e]indole prepared in each example and comparative example.

[0064] Test method: Based on the mass of the starting material 6-bromo-2-aminonaphthalene, the theoretical yield of the target product 7-bromo-1,1,2-trimethyl-1H-benzo[e]indole was calculated in combination with the reaction molar ratio; the actual product mass of each group was accurately weighed, and the total yield of each sample was calculated according to the formula: Total yield (%) = (actual yield / theoretical yield) × 100%.

[0065] The yield test results of substituted benzo[e]indole are shown in Table 2.

[0066] Table 2. Yield test results of substituted benzo[e]indole

[0067] Example 1 employs a one-step continuous synthesis process, eliminating the multiple separation steps such as filtration, washing, and drying of intermediates in traditional processes. This significantly reduces unnecessary material losses during multiple transfers and post-processing, achieving a yield of 78.5%, a significant improvement compared to Comparative Example 1, which uses a traditional two-step process with a yield of only 61.5%. The core reason for this is that the reduced aryl hydrazine intermediate requires separate filtration, washing, and vacuum drying. Aryl hydrazine has poor stability and rapidly oxidizes and decomposes upon contact with air, resulting in substantial irreversible losses from multiple material transfer steps. In contrast, the one-step continuous method of this invention generates aryl hydrazine in situ and participates in cyclization immediately, eliminating separation and purification losses. Therefore, even relying solely on in-situ ethanol reduction, the final total yield is significantly higher than that of the traditional stepwise tin reduction process, fully demonstrating the significant advantage of this basic process in raw material utilization. Example 2 shows that the addition of tetraethylammonium tetrafluoroborate significantly improves the solubility of this ionic salt in the aqueous phase. The system's ionic strength effectively reduces the solubility of the target product in the aqueous phase, minimizing water loss during extraction and allowing more target substances to enter the organic phase, thus increasing the overall product yield to 80.8%. Comparative Example 2 used tetraethylammonium chloride as a substitute reagent, but its salting-out effect was weaker, limiting its ability to inhibit water loss. The yield was only slightly higher than the basic process, far less effective than tetraethylammonium tetrafluoroborate. Example 3 further added 4-(hydroxymethyl)tetrahydropyran for crystallization optimization. This additive improved crystal looseness and reduced material loss caused by fine crystal entrainment, further reducing product loss during crystallization and filtration on top of extraction loss reduction, resulting in a further increase in yield. Comparative Example 3 used methanol as a crystallization aid; methanol could not optimize crystal morphology or solve the fine crystal entrainment problem, therefore the yield was only the same as Example 2, with no further improvement.

[0068] The embodiments and / or implementation methods described above are merely preferred embodiments and / or implementation methods for implementing the technology of the present invention, and are not intended to limit the implementation methods of the technology of the present invention in any way. Any person skilled in the art can make some modifications or alterations to other equivalent embodiments without departing from the scope of the technical means disclosed in the content of the present invention, but they should still be regarded as the technology or embodiments that are substantially the same as the present invention.

[0069] This document uses specific examples to illustrate the principles and implementation methods of this application. The descriptions of the above embodiments are only for the purpose of helping to understand the methods and core ideas of this application. The above descriptions are only preferred embodiments of this application. It should be noted that due to the limitations of written expression, while there are objectively infinite specific structures, those skilled in the art can make several improvements, modifications, or changes without departing from the principles of this application, and can also combine the above technical features in an appropriate manner. These improvements, modifications, changes, or combinations, or the direct application of the inventive concept and technical solution to other situations without modification, should all be considered within the scope of protection of this application.

Claims

1. A method for synthesizing substituted benzo[e]indole, characterized in that: include, Starting with 6-bromo-2-aminonaphthalene, the raw material was mixed with ethanol and hydrochloric acid and stirred. A sodium nitrite aqueous solution was added dropwise at 0-5℃ to carry out a diazotization reaction. Then, 3-methyl-2-butanone and concentrated sulfuric acid were added, and the mixture was refluxed to carry out a cyclization reaction, yielding an initial reaction solution. The initial reaction solution was diluted with deionized water, and the pH was adjusted to 9.3-9.7 to obtain a diluted solution. Methyl tert-butyl ether was added to the diluted solution for extraction. The solution was washed with ammonium chloride aqueous solution and dried with anhydrous sodium sulfate to obtain an extract. The extract was concentrated under reduced pressure at 48-52℃ to obtain a concentrated solution. Heptane was added to the concentrated solution for slurrying, and the mixture was filtered and dried to obtain 7-bromo-1,1,2-trimethyl-1H-benzo[e]indole, i.e., substituted benzo[e]indole.

2. The synthesis method according to claim 1, characterized in that: The cyclization reaction occurs at a temperature of 78-82°C.

3. The synthesis method according to claim 1, characterized in that: The mass-to-volume ratio of 6-bromo-2-aminonaphthalene to ethanol is 1 g: 2.8~3.2 mL.

4. The synthesis method according to claim 1, characterized in that: The mass of the sodium nitrite aqueous solution is measured by the mass of sodium nitrite therein, and the mass ratio of 6-bromo-2-aminonaphthalene to sodium nitrite is 100:32.0~34.

4.

5. The synthesis method according to claim 1, characterized in that: The mass ratio of 6-bromo-2-aminonaphthalene to 3-methyl-2-butanone is 100:45.0~48.

0.

6. The synthesis method according to claim 1, characterized in that: The mass ratio of 6-bromo-2-aminonaphthalene to concentrated sulfuric acid is 100:0.60~0.

70.

7. The synthesis method according to claim 1, characterized in that: Tetraethyltetrafluoroborate ammonium is added to the diluent, and the mass-to-volume ratio of the tetraethyltetrafluoroborate ammonium to the initial reaction solution is 0.5~2g:250mL.

8. The synthesis method according to claim 1, characterized in that: The volume ratio of the initial reaction solution to methyl tert-butyl ether is 1:5.5~6.

5.

9. The synthesis method according to claim 1, characterized in that: The volume ratio of the extract to n-heptane is 1:1.8~2.2.

Images