A highly efficient synthesis of 6-substituted indoles

Abstract

This invention discloses an efficient method for synthesizing 6-substituted indole. Using substituted nitrobenzene esters such as methyl 4-methyl-3-nitrobenzene as raw materials, a segmented temperature-controlled condensation reaction is carried out with DMF-DMA and tetrahydropyrrole in DMF solvent. The intermediate is directly subjected to Raney nickel-catalyzed hydrogenation reduction without separation and purification. The reducing solution is washed with hydrochloric acid, sodium bicarbonate aqueous solution, and sodium chloride aqueous solution, concentrated under reduced pressure, and distilled under reduced pressure. Recrystallization with n-heptane yields methyl 6-indolecarboxylate, which is then hydrolyzed with sodium hydroxide and acidified with hydrochloric acid to obtain high-purity 6-substituted indole. This invention achieves a one-pot continuous reaction of the intermediate, eliminating multiple intermediate purification steps. The reaction conditions are mild, requiring no high temperature, high pressure, or special equipment. The Raney nickel catalyst can be recycled, significantly shortening the production cycle, reducing production costs and waste emissions. The process is stable and controllable, safe and simple to operate, and suitable for large-scale industrial production.

Description

Technical Field

[0001] This invention belongs to the field of organic synthesis, specifically relating to an efficient method for synthesizing 6-substituted indole. Background Technology

[0002] Indole and its derivatives are a class of core nitrogen-containing heterocyclic compounds with wide applications in pharmaceuticals, pesticides, dyes, and functional materials. They are key intermediates in the synthesis of various drugs and fine chemicals. 6-substituted indoles, due to their unique molecular structure, exhibit excellent biological activity and material properties, making them indispensable, especially in the development of antitumor, anti-inflammatory, antibacterial, and antiviral drugs. Their efficient, stable, and environmentally friendly synthesis processes have always been a research focus in organic synthesis and pharmaceutical chemistry. With the rapid growth in demand for high-end active pharmaceutical ingredients and customized chemicals, the market is placing more stringent requirements on the purity, yield, and cost control of 6-substituted indoles. Developing synthetic technologies suitable for large-scale industrial production has significant economic and social value.

[0003] Current traditional synthetic routes for 6-substituted indole mostly use substituted nitrobenzene compounds as starting materials, proceeding through multiple independent reactions such as condensation, reduction, and cyclization. These methods generally suffer from lengthy processes, complex operations, and high costs. In conventional processes, the intermediate generated in the first condensation step has poor stability and insufficient purity, requiring multiple purification steps such as separation, washing, crystallization, and drying before it can proceed to the subsequent reduction and cyclization stages. Multiple intermediate purifications not only significantly extend the production cycle and reduce material turnover efficiency but also increase raw material losses and decrease yield. Furthermore, traditional reduction processes often employ high-pressure hydrogenation or strong chemical reducing agents, resulting in harsh reaction conditions and high requirements for equipment pressure resistance, sealing, and materials, posing significant operational safety risks and hindering large-scale continuous production.

[0004] Traditional processes also have significant drawbacks in catalyst use and post-processing. Commonly used metal catalysts are difficult to recover, have high consumption and cost, and cannot be recycled. Post-processing requires multiple extractions, acid and alkali adjustments, vacuum distillation, and recrystallization, using large amounts of organic solvents and acid / base reagents, generating substantial organic waste liquid and industrial waste residue, placing significant pressure on environmental governance and contradicting the development direction of green chemistry. Furthermore, existing technologies generally suffer from unstable yields and low product purity, failing to meet the stringent impurity content requirements of high-end pharmaceutical intermediates. In summary, traditional 6-substituted indole synthesis processes are no longer suitable for the modern pharmaceutical and chemical industries' demands for efficient, low-cost, and environmentally friendly production. There is an urgent need to develop novel synthetic methods with mild reaction conditions, simple steps, high yields, and minimal waste. Summary of the Invention

[0005] The purpose of this invention is to provide a highly efficient synthesis method for 6-substituted indole with mild reaction conditions, simple process flow, high yield, low emissions of waste, and suitable for large-scale industrial production. This method solves the problems of existing technologies, such as the need for separate purification of intermediates, long production cycle, unstable yield, insufficient product purity, difficulty in catalyst recovery, and high environmental pressure.

[0006] The technical solution adopted by the present invention to achieve the above objectives is as follows: A method for synthesizing 6-substituted indole, characterized in that: a substituted nitrobenzene compound is used as a raw material, the raw material is dissolved in N,N-dimethylformamide solvent, and mixed with N,N-dimethylformamide dimethyl acetal and tetrahydropyrrole, and then subjected to a segmented temperature-controlled condensation reaction, first reacting at 75~80℃ for 0.5~1.5h, and then the temperature is raised to 90~100℃ for 1~3h to obtain a reaction system containing a condensation intermediate; The condensation intermediate was directly added to the subsequent reaction without separation and purification. Raney nickel catalyst was added to the reaction system, the system was first replaced with hydrogen 2 to 4 times, and then a hydrogenation reduction reaction was carried out to obtain a reduced solution. The reducing solution was washed sequentially with hydrochloric acid aqueous solution, saturated sodium bicarbonate aqueous solution, and saturated sodium chloride aqueous solution. The solution was concentrated under reduced pressure to obtain a concentrate. Heptane was added to the concentrate, and the solution was distilled under reduced pressure and recrystallized to obtain methyl 6-substituted indolecarboxylate. The concentrate was then hydrolyzed with sodium hydroxide and acidified with hydrochloric acid to obtain high-purity 6-substituted indole. Preferably, the substituted nitrobenzene compounds include one of methyl 4-methyl-3-nitrobenzene and 2-methyl-5-fluoronitrobenzene.

[0007] Preferably, the concentration of the hydrochloric acid aqueous solution is 5~7 mol / L.

[0008] Preferably, the hydrogenation reduction reaction temperature is 50~55℃ and the reaction time is 4~6h.

[0009] Preferably, the mass-to-volume ratio of the substituted nitrobenzene compound to N,N-dimethylformamide is 1~3g:20mL.

[0010] Preferably, the mass ratio of N,N-dimethylformamide dimethyl acetal to substituted nitrobenzene compound is 1:0.5~1.5.

[0011] Preferably, N-cyclohexylpyrrolidine is added to the reaction system during the feeding stage of the segmented temperature-controlled condensation reaction.

[0012] Preferably, the mass ratio of N-cyclohexylpyrrolidine to substituted nitrobenzene compounds is 3~8:209.

[0013] In the one-pot synthesis of 6-substituted indole, N-cyclohexylpyrrolidine serves as a phase transfer promoter. Based on its molecular structure and reaction mechanism analysis, this promoter can exert a directional catalytic effect in the segmented temperature-controlled condensation stage of the N,N-dimethylformamide system. Its sterically hindered cyclohexyl structure helps selectively stabilize key enamidation intermediates, suppress side reactions and isomerization pathways, and improves the compatibility and reaction homogeneity of the substrate with N,N-dimethylformamide dimethyl acetal and tetrahydropyrrole, promoting the formation of benzylic carbanion and nucleophilic addition ring closure. This improves the conversion rate of raw materials and the selectivity of the reaction, resulting in a simultaneous increase in product yield and purity. Furthermore, it is expected not to interfere with subsequent Raney nickel catalytic hydrogenation reduction, nor affect post-processing and water removal, making it suitable for continuous one-pot processes and positively impacting reaction efficiency and product stability.

[0014] Preferably, the mass ratio of tetrahydropyrrole to substituted nitrobenzene compound is 1:0.5~1.5.

[0015] Preferably, the mass ratio of Raney nickel to substituted nitrobenzene compounds is 1:5~15.

[0016] Preferably, during the recrystallization of n-heptane, the solution is heated to 95-100°C to completely dissolve the concentrate, and then stirred and cooled to allow crystals to precipitate.

[0017] Preferably, the volume ratio of the concentrate to n-heptane is 1:1 to 10.

[0018] Preferably, the washing process includes washing sequentially with a 5-7 mol / L hydrochloric acid aqueous solution, a saturated sodium bicarbonate aqueous solution, and a saturated sodium chloride aqueous solution.

[0019] More preferably, 1-hydroxymethylpyrrolidine is added after washing with a saturated sodium chloride aqueous solution, and the mixture is stirred for 10-15 minutes.

[0020] More preferably, the mass ratio of 1-hydroxymethylpyrrolidine to crude methyl 6-indolecarboxylate is 2~6:100.

[0021] 1-Hydroxymethylpyrrolidine can be used in the post-treatment and recrystallization stages of the reducing solution. This compound contains hydroxyl and pyrrolidine structures. Based on its molecular structure and hydrogen bonding principles, it is speculated that it can be used as a polarity-matched crystallization aid and impurity complexing agent. It can form weak hydrogen-bonded complexes with residual polar impurities, inorganic salts, and trace byproducts in the system, tending to retain impurities in the mother liquor during the recrystallization of n-heptane, thereby helping to improve the crystallization purity and crystal regularity of methyl 6-indolecarboxylate. Simultaneously, this aid is expected to optimize the crystal surface state, reduce solvent encapsulation and water retention, thereby reducing the product's moisture content and slightly improving purity and yield. It does not change the main reaction pathway, does not introduce new impurities, and has good compatibility with existing washing, concentration, and recrystallization processes, thus enhancing the post-treatment purification effect.

[0022] This invention also provides a method for preparing 6-indolecarboxylic acid, the preparation steps mainly including the preparation steps of methyl 6-indolecarboxylate and 6-indolecarboxylic acid: Step 1: Preparation of methyl 6-indolecarboxylate: Dissolve methyl 4-methyl-3-nitrobenzene in N,N-dimethylformamide, add N,N-dimethylformamide dimethyl acetal and tetrahydropyrrole, stir well, and react at an internal temperature of 75-80℃ for 0.5-1.5 h. Then raise the temperature to 90-100℃ and react for 1-3 h. Detect the reaction with high performance liquid chromatography until the reaction is complete. Cool the reaction solution to 50-55℃, add Raney nickel, and obtain the reaction system. Replace the reaction system with hydrogen 2-4 times, and then react at 50-80℃. The hydrogenation reaction was carried out at 55℃ for 4-6 hours. High-performance liquid chromatography (HPLC) was used to detect the reaction until the reactants were completely reacted. Raney nickel was removed by filtration. The filtrate was cooled and washed successively with 5-7 mol / L hydrochloric acid aqueous solution, saturated sodium bicarbonate aqueous solution, and saturated sodium chloride aqueous solution. After washing, the solution was concentrated under reduced pressure and distilled under reduced pressure to dryness at an oil pump steam temperature of 135-145℃ to obtain the concentrate. Heptane was added to the concentrate, and the mixture was heated to 95-100℃ to dissolve and clarify. The mixture was stirred, cooled, and crystallized. The crystals were then filtered to obtain methyl 6-indolecarboxylate.

[0023] Preferably, the mass-to-volume ratio of methyl 4-methyl-3-nitrobenzoate to N,N-dimethylformamide is 1~3g:20mL.

[0024] Preferably, the mass ratio of N,N-dimethylformamide dimethyl acetal to methyl 4-methyl-3-nitrobenzoate is 1:0.5~1.5.

[0025] Preferably, the mass ratio of tetrahydropyrrole to methyl 4-methyl-3-nitrobenzoate is 1:0.5~1.5.

[0026] Preferably, the mass ratio of Raney nickel to methyl 4-methyl-3-nitrobenzene is 1:5~15.

[0027] Preferably, the volume ratio of the concentrate to n-heptane is 1:1 to 10.

[0028] More preferably, N-cyclohexylpyrrolidine is added to the reaction system.

[0029] More preferably, the mass ratio of N-cyclohexylpyrrolidine to methyl 4-methyl-3-nitrobenzoate is 3~8:209.

[0030] More preferably, 1-hydroxymethylpyrrolidine is added after washing with a saturated sodium chloride aqueous solution, and the mixture is stirred for 10-15 minutes.

[0031] More preferably, the mass ratio of 1-hydroxymethylpyrrolidine to crude methyl 6-indolecarboxylate is 2~6:100.

[0032] Step 2: Preparation of 6-indolecarboxylic acid: Add methyl 6-indolecarboxylate to a 1-3 mol / L sodium hydroxide aqueous solution, control the temperature at 20-30℃, stir for 1-3 hours, and detect the reaction until complete using high performance liquid chromatography. Add 5-7 mol / L hydrochloric acid solution dropwise to the reaction solution, control the temperature at 0-5℃, adjust the pH to 1-2, filter, and dry the filter cake at 45-55℃ to obtain 6-indolecarboxylic acid.

[0033] Preferably, the mass-to-volume ratio of methyl 6-indolecarboxylate to 1-3 mol / L sodium hydroxide aqueous solution is 1 g: 1-10 mL.

[0034] Preferably, the volume ratio of 5-7 mol / L hydrochloric acid solution to 1-3 mol / L sodium hydroxide aqueous solution is 1:0.5-1.5.

[0035] This invention also provides a preparation method for methyl 6-fluoroindolecarboxylate: Preparation of methyl 6-fluoroindolecarboxylate: 2-methyl-5-fluoronitrobenzene was dissolved in N,N-dimethylformamide, and N,N-dimethylformamide dimethyl acetal and tetrahydropyrrole were added. The mixture was stirred until homogeneous, and the reaction was carried out at an internal temperature of 75-80℃ for 0.5-1.5 h. The temperature was then increased to 90-100℃ and the reaction was continued for 1-3 h. High-performance liquid chromatography (HPLC) was used to detect the reaction until the reactants were completely reacted. The reaction solution was then cooled to 50-55℃, Raney nickel was added, and the reaction system was replaced with hydrogen 2-4 times. The reaction was then carried out at 50-55℃. The hydrogen reaction was carried out for 4-6 hours. High-performance liquid chromatography (HPLC) was used to detect the reaction until the reactants were completely reacted. Raney nickel was removed by filtration. The filtrate was cooled and washed successively with 5-7 mol / L hydrochloric acid aqueous solution, saturated sodium bicarbonate aqueous solution, and saturated sodium chloride aqueous solution. After washing, the solution was concentrated under reduced pressure and distilled under reduced pressure to dryness at an oil pump steam temperature of 135-145℃ to obtain a concentrate. Heptane was added to the concentrate and heated to 95-100℃ to dissolve and clarify. The solution was stirred, cooled, and crystallized. After filtration, methyl 6-fluoroindolecarboxylate was obtained.

[0036] Preferably, the mass-to-volume ratio of 2-methyl-5-fluoronitrobenzene to N,N-dimethylformamide is 1~3g:20mL.

[0037] Preferably, the mass ratio of N,N-dimethylformamide dimethyl acetal to 2-methyl-5-fluoronitrobenzene is 1:0.5~1.5.

[0038] Preferably, the mass ratio of tetrahydropyrrole to 2-methyl-5-fluoronitrobenzene is 1:0.5~1.5.

[0039] Preferably, the mass ratio of Raney nickel to 2-methyl-5-fluoronitrobenzene is 1:5~15.

[0040] Preferably, the volume ratio of the concentrate to n-heptane is 1:1 to 10.

[0041] This application employs a segmented temperature-controlled condensation process, which differs from the existing single isothermal condensation process. First, enamination and intermediate stabilization are completed in a low-temperature range of 75~80℃, and then the temperature is raised to a high-temperature range of 90~100℃ to achieve complete condensation conversion. The two temperature and time stages can effectively suppress side reactions and isomerization, significantly improve condensation selectivity and intermediate purity, and provide a highly active and stable reaction system for subsequent reduction cyclization. This is a key process innovation to achieve high yield and high purity. This application employs Raney nickel catalytic mild hydrogenation reduction, which differs from existing technologies that use a combination of multiple reducing agents or chemical reduction systems. The reduction temperature is controlled at 50~55℃, eliminating the need for high temperature and high pressure. The catalyst can be recycled, significantly reducing energy consumption and safety risks. At the same time, it avoids the byproducts and impurities caused by strong chemical reduction, achieving efficient and simultaneous reduction and cyclization. It balances process economy, safety, and environmental friendliness, forming an industrial-friendly core innovation. This application introduces N-cyclohexylpyrrolidine as a directional phase transfer and catalytic promoter during the condensation stage, which differs from conventional organic base systems in existing technologies. Its sterically hindered cyclohexyl structure can selectively stabilize key enamine intermediates, improve substrate compatibility, and promote the generation and directional ring closure of benzylic carbanions. Under the condition of not interfering with subsequent reduction, it can simultaneously improve the conversion rate of raw materials and the selectivity of products, providing a unique catalytic regulation mechanism for the one-pot process, which constitutes an important inventive point that distinguishes it from existing technologies.

[0042] This invention, employing a one-pot continuous synthesis process, a segmented temperature-controlled condensation and mild catalytic hydrogenation integrated reaction, targeted regulation with specific auxiliary agents, and a green post-processing system, offers the following advantages: intermediates do not require separation and purification, significantly simplifying the process and shortening the production cycle; the reaction conditions are mild, requiring no high temperature, high pressure, or special equipment, ensuring safe and controllable operation; the Raney nickel catalyst is recyclable, resulting in high raw material utilization and low production costs; there are fewer side reactions, lower impurities and moisture content, leading to high product purity; solvent and reagent consumption is low, significantly reducing waste emissions and demonstrating outstanding environmental benefits; the process exhibits strong stability, good reproducibility, and high overall yield. Therefore, this invention provides a mild, simple, high-yield, high-purity, environmentally friendly, economical, and efficient method suitable for large-scale industrial production of 6-substituted indole. Attached Figure Description

[0043] Figure 1 The synthetic reaction route for preparing 6-substituted indole according to this invention is shown in the diagram.

[0044] Figure 2 The synthetic reaction route for preparing 6-indolecarboxylic acid is shown in Example 1.

[0045] Figure 3 The synthetic reaction route for preparing methyl 6-fluoroindolecarboxylate in Example 2 is shown.

[0046] Figure 4 The 1H NMR spectrum of 6-indolecarboxylic acid prepared in Example 1.

[0047] Figure 5 The photon NMR spectrum of methyl 6-fluoroindolecarboxylate prepared in Example 2 is shown below.

[0048] Figure 6 The high-performance liquid chromatogram of 6-indolecarboxylic acid prepared in Example 1 is shown.

[0049] Figure 7 The high-performance liquid chromatogram of methyl 6-fluoroindolecarboxylate prepared in Example 2 is shown. Detailed Implementation

[0050] 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.

[0051] 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.

[0052] Example 1: This example provides a method for preparing 6-indolecarboxylic acid. The synthetic reaction route for preparing 6-indolecarboxylic acid in Example 1 is shown below. Figure 2 As shown, the preparation steps mainly include the preparation steps of methyl 6-indolecarboxylate and 6-indolecarboxylic acid, as detailed below.

[0053] Step 1: Preparation of methyl 6-indolecarboxylate: Methyl 4-methyl-3-nitrobenzoate was dissolved in N,N-dimethylformamide, and N,N-dimethylformamide dimethyl acetal and tetrahydropyrrole were added. The mixture was stirred until homogeneous, and the reaction was carried out at an internal temperature of 75℃ for 1 hour, followed by a reaction at 90℃ for 2 hours. High-performance liquid chromatography (HPLC) was used to detect the complete reaction of the raw materials. The reaction solution was cooled to 50℃, and Raney nickel was added to obtain the reaction system. The reaction system was replaced with hydrogen three times, and hydrogen was added at 50℃ for 5 hours. HPLC was used to detect the complete reaction of the raw materials. Raney nickel was removed by filtration, and the filtrate was cooled and washed successively with 6 mol / L hydrochloric acid aqueous solution, saturated sodium bicarbonate aqueous solution, and saturated sodium chloride aqueous solution. After washing, the solution was concentrated under reduced pressure and distilled under reduced pressure to dryness at an oil pump vapor temperature of 140℃ to obtain the concentrate. Heptane was added to the concentrate, and the mixture was heated to 100℃ to dissolve and clarify. The solution was stirred, cooled, and crystallized. The mixture was then filtered to obtain methyl 6-indolecarboxylate. The CAS number for methyl 4-methyl-3-nitrobenzene is 20427-09-2, the CAS number for N,N-dimethylformamide dimethyl acetal is 4637-24-5, the CAS number for tetrahydropyrrole is 123-75-1, and the CAS number for Raney nickel is 7440-02-0. The mass-to-volume ratio of methyl 4-methyl-3-nitrobenzene to N,N-dimethylformamide is 209 g: 2000 mL, the mass ratio of N,N-dimethylformamide dimethyl acetal to methyl 4-methyl-3-nitrobenzene is 1:1, the mass ratio of tetrahydropyrrole to methyl 4-methyl-3-nitrobenzene is 1:1, the mass ratio of Raney nickel to methyl 4-methyl-3-nitrobenzene is 1:10, and the volume ratio of the concentrate to n-heptane is 1:3.

[0054] Step 2: Preparation of 6-indolecarboxylic acid: Methyl 6-indolecarboxylate was added to a 2 mol / L sodium hydroxide aqueous solution. The temperature was controlled at 20℃, and the mixture was stirred for 2 hours. High-performance liquid chromatography (HPLC) was used to monitor the reaction until complete. A 6 mol / L hydrochloric acid solution was added dropwise to the reaction solution, and the temperature was controlled at 4℃. The pH was adjusted to 1.5, and the mixture was filtered. The filter cake was dried at 50℃ to obtain 6-indolecarboxylic acid. The mass-to-volume ratio of methyl 6-indolecarboxylate to 2 mol / L sodium hydroxide aqueous solution was 1 g: 5 mL, and the volume ratio of 6 mol / L hydrochloric acid solution to 2 mol / L sodium hydroxide aqueous solution was 1:1.

[0055] Example 2: This example provides a preparation procedure for methyl 6-fluoroindolecarboxylate. The synthetic reaction route for preparing methyl 6-fluoroindolecarboxylate in Example 2 is shown below. Figure 3 As shown, the details are as follows.

[0056] Preparation of methyl 6-fluoroindolecarboxylate: 2-methyl-5-fluoronitrobenzene was dissolved in N,N-dimethylformamide, and N,N-dimethylformamide dimethyl acetal and tetrahydropyrrole were added. The mixture was stirred until homogeneous, and the reaction was carried out at an internal temperature of 75℃ for 1 h, followed by a reaction at 90℃ for 2 h. High-performance liquid chromatography (HPLC) was used to detect the complete reaction of the raw materials. The reaction solution was then cooled to 50℃, Raney nickel was added, and the reaction system was replaced three times with hydrogen. Hydrogenation was carried out at 50℃ for 5 h. HPLC was used to detect the complete reaction of the raw materials. Raney nickel was removed by filtration, and the filtrate was cooled and washed successively with 6 mol / L hydrochloric acid aqueous solution, saturated sodium bicarbonate aqueous solution, and saturated sodium chloride aqueous solution. After washing, the solution was concentrated under reduced pressure and distilled under reduced pressure to dryness at a vapor temperature of 140℃ to obtain a concentrate. Heptane was added to the concentrate, and the mixture was heated to 100℃ to dissolve and clarify. The solution was stirred, cooled, and crystallized. The crystals were then filtered to obtain methyl 6-fluoroindolecarboxylate. The mass-to-volume ratio of 2-methyl-5-fluoronitrobenzene to N,N-dimethylformamide was 155 g: 1500 mL; the mass ratio of N,N-dimethylformamide dimethyl acetal to 2-methyl-5-fluoronitrobenzene was 1:1; the mass ratio of tetrahydropyrrole to 2-methyl-5-fluoronitrobenzene was 1:1; the mass ratio of Raney nickel to 2-methyl-5-fluoronitrobenzene was 1:10; and the volume ratio of the concentrate to n-heptane was 1:3.

[0057] Example 3: The only difference between this example and Example 1 is in the preparation step of methyl 6-indolecarboxylate. In Example 3, N-cyclohexylpyrrolidine is added to the reaction system during the condensation reaction feeding stage. The CAS number of N-cyclohexylpyrrolidine is 6673-48-9. The mass ratio of N-cyclohexylpyrrolidine to methyl 4-methyl-3-nitrobenzoate is 5:209.

[0058] Example 4: The only difference between this example and Example 3 is in the preparation step of methyl 6-indolecarboxylate. In Example 4, the mass ratio of N-cyclohexylpyrrolidine to methyl 4-methyl-3-nitrobenzoate is adjusted from 5:209 to 8:209.

[0059] Example 5: The only difference between this example and Example 4 is in the preparation steps of methyl 6-indolecarboxylate. In Example 5, 1-hydroxymethylpyrrolidine was added after washing with saturated sodium chloride aqueous solution and before vacuum concentration, and the mixture was stirred for 10 min. The CAS number of 1-hydroxymethylpyrrolidine is 4712-48-6, and the mass ratio of 1-hydroxymethylpyrrolidine to crude methyl 6-indolecarboxylate is 3:100.

[0060] Example 6: The only difference between this example and Example 5 is in the preparation step of methyl 6-indolecarboxylate. In Example 6, the mass ratio of 1-hydroxymethylpyrrolidine to crude methyl 6-indolecarboxylate is adjusted from 3:100 to 1:25.

[0061] Comparative Example 1: This comparative example provides a conventional method for preparing 6-substituted indole. The preparation steps mainly include the preparation of a condensation intermediate, the preparation of crude methyl 6-indolecarboxylate, and the preparation of purified 6-indolecarboxylic acid, as detailed below.

[0062] Step 1: Preparation of the condensation intermediate: 4-methyl-3-nitrobenzene methyl ester was added to acetonitrile and stirred until homogeneous. N,N-dimethylformamide dimethyl acetal and tetrahydropyrrole were then added. The reaction was carried out at 75℃ for 1 hour, then increased to 90℃ for 2 hours. After the reaction was complete, the reaction solution was cooled, and water was slowly added. A solid precipitated out, which was filtered. The filter cake was washed with water and dried to obtain the condensation intermediate. The mass-to-volume ratio of 4-methyl-3-nitrobenzene methyl ester to acetonitrile was 209 g:1000 mL, the mass ratio of N,N-dimethylformamide dimethyl acetal to 4-methyl-3-nitrobenzene methyl ester was 1:1, and the mass ratio of tetrahydropyrrole to 4-methyl-3-nitrobenzene methyl ester was 1:1.

[0063] Step 2: Preparation of crude methyl 6-indolecarboxylate: The condensation intermediate, N,N-dimethylformamide, and Raney nickel were added to a reaction flask. The system was purged with hydrogen three times, and the reaction was carried out at 50°C for 5 hours. Raney nickel was removed by filtration. The filtrate was washed successively with 6 mol / L hydrochloric acid aqueous solution, saturated sodium bicarbonate aqueous solution, and saturated sodium chloride aqueous solution. The solution was concentrated under reduced pressure, distilled under reduced pressure, and crystallized by hot dissolution in n-heptane to obtain crude methyl 6-indolecarboxylate. The mass-to-volume ratio of the condensation intermediate to N,N-dimethylformamide was 1 g:10 mL, the mass ratio of Raney nickel to the condensation intermediate was 1:10, and the volume ratio of the concentrate to n-heptane was 1:3.

[0064] Step 3: Preparation and purification of 6-indolecarboxylic acid: Crude methyl 6-indolecarboxylic acid is hydrolyzed with sodium hydroxide and acidified with hydrochloric acid. An additional steps of drying with anhydrous magnesium sulfate and secondary recrystallization are added to obtain purified 6-indolecarboxylic acid.

[0065] Comparative Example 2: The only difference between this comparative example and Example 3 is that in the preparation step of methyl 6-indolecarboxylate, the mass ratio of N-cyclohexylpyrrolidine to methyl 4-methyl-3-nitrobenzoate was adjusted from 5:209 to 2:209 in Comparative Example 2.

[0066] Comparative Example 3: The only difference between this comparative example and Example 3 is in the preparation step of methyl 6-indolecarboxylate. In Comparative Example 3, N-cyclohexylpyrrolidine was replaced with N-ethylpyrrolidine, the CAS number of which is 2687-91-4. The mass ratio of N-ethylpyrrolidine to methyl 4-methyl-3-nitrobenzoate was 8:209.

[0067] Comparative Example 4: Compared with Example 5, Comparative Example 4 replaced 1-hydroxymethylpyrrolidine with isopropanol, and the mass ratio of isopropanol to crude methyl 6-indolecarboxylate was 1:25.

[0068] Experimental Example 1: 1H NMR characterization of 6-substituted indole.

[0069] Test samples: 6-indolecarboxylic acid prepared in Example 1 and methyl 6-fluoroindolecarboxylate prepared in Example 2.

[0070] Test method: Take the samples from Example 1 and Example 2, dissolve them with a suitable deuterated reagent, and perform ¹H NMR spectroscopy at room temperature using a nuclear magnetic resonance spectrometer. Record the chemical shift (ppm) and signal intensity to obtain the ¹H NMR spectrum of the samples, and perform assignment analysis on the characteristic peaks.

[0071] The 1H NMR spectrum of 6-indolecarboxylic acid prepared in Example 1 is shown below. Figure 4 As shown, the 1H NMR spectrum of methyl 6-fluoroindolecarboxylate prepared in Example 2 is as follows. Figure 5 As shown, the chemical shift range of the sample in Example 1 covers 0.0–12.5 ppm, with clear characteristic peak signals. The main peak corresponds to the characteristic chemical shift of the hydrogen atom in 6-indolecarboxylic acid, with no obvious impurity peak interference. The chemical shift range of the sample in Example 2 covers 0.0–9.0 ppm, with a stable spectral baseline, clearly assigned characteristic peaks, and no impurity peak interference. The positions and shapes of each proton peak conform to the molecular structure characteristics of 6-fluoroindole. The proton NMR spectra of both Example 1 and Example 2 samples show no obvious impurity characteristic peaks, and the main peaks are clearly assigned, highly matching the molecular structures of 6-indolecarboxylic acid and 6-fluoroindole, respectively. This proves that the chemical structure of the product prepared by the one-pot method of this invention is correct, with no obvious structural isomers or by-product structural residues. From the molecular structure level, this verifies that the product has high purity and uniform structure, meeting the structural requirements of the target compound.

[0072] Experimental Example 2: High Performance Liquid Chromatography (HPLC) Determination of 6-Substituted Indole.

[0073] Test samples: 6-indolecarboxylic acid prepared in Example 1 and methyl 6-fluoroindolecarboxylate prepared in Example 2.

[0074] Test method: High performance liquid chromatography (HPLC) was used with a detector wavelength of 210 nm and an injection volume of 5 μL. Under constant column temperature and suitable mobile phase conditions, the samples of Example 1 and Example 2 were tested, the chromatograms were recorded, and the area and area ratio of each peak were calculated by integration to determine the distribution of the main peak and impurity peaks.

[0075] The high-performance liquid chromatogram of 6-indolecarboxylic acid prepared in Example 1 is shown below. Figure 6 As shown, the high-performance liquid chromatogram of methyl 6-fluoroindolecarboxylate prepared in Example 2 is as follows. Figure 7As shown, the retention time of the main peak in Sample 1 was 5.820 min, with a peak area accounting for 99.636%, and the largest single impurity area accounting for 0.109%. In Sample 2, the retention time of the main peak was 7.779 min, with a peak area accounting for 99.997%, and the impurity peak area accounting for only 0.003%. Both samples exhibited symmetrical peak shapes, without tailing or bifurcation, and stable, interference-free baselines. The high-performance liquid chromatograms of Samples 1 and 2 showed extremely high main peak proportions, extremely low impurity content, and excellent peak shapes, demonstrating that the one-pot preparation process of this invention can effectively control impurity generation and residues. The product purity meets the standards for high-end pharmaceutical intermediates, and the chromatographic separation effect is excellent, further verifying the stability of the process and the reliability of the product quality.

[0076] Experimental Example 3: Purity test of 6-substituted indole.

[0077] Test samples: 6-substituted indoles prepared in Examples 1-2 and Comparative Example 1, including 6-indolecarboxylic acid and methyl 6-fluoroindolecarboxylate.

[0078] Test method: High performance liquid chromatography (HPLC) was used for detection. The chromatographic conditions were as follows: detector wavelength was set to 210 nm, injection volume was 5 μL, mobile phase was eluted at an appropriate ratio, column temperature was kept constant, and test solutions of the same concentration were prepared from samples of each example and comparative example, injected into the HPLC, chromatograms were recorded, and the percentage of the main peak area to the total peak area was calculated by the area normalization method to obtain the product purity.

[0079] The purity test results of 6-substituted indole are shown in Table 1.

[0080] Table 1. Purity test results of 6-substituted indoles

[0081] Example 1 utilizes the one-pot continuous synthesis process of this invention, where intermediates do not require separation and purification before proceeding to subsequent reactions. This reduces side reactions and impurity accumulation from the source, resulting in excellent product purity with the maximum single impurity far below the limit. Even without additional additives, the basic process itself possesses strong purity control capabilities, consistently meeting the requirements for high-end pharmaceutical intermediates. Example 2 shows further improved purity during the synthesis of 6-fluoroindole, with impurities almost completely suppressed. This demonstrates that the process exhibits excellent reaction selectivity and versatility for different substituted substrates, adaptable to the high-purity preparation of various 6-substituted indoles. Comparative Example 1 employs a traditional two-step process. Due to the need for independent filtration, washing, and drying of intermediates, multiple operations introduce exogenous impurities, and side reactions are difficult to control, leading to a significant decrease in purity and a significant increase in single impurity content. This fully demonstrates that the one-pot method of this invention has an overwhelming advantage in purity control compared to traditional processes, consistently ensuring high product quality.

[0082] Experimental Example 4: Moisture content test of 6-substituted indole.

[0083] Test samples: 6-substituted indoles prepared in each example and comparative example, including 6-indolecarboxylic acid and methyl 6-fluoroindolecarboxylate.

[0084] Test method: Karl Fischer titration was performed using a Mettler Toledo U10S titrator. At room temperature, 6-substituted indoles prepared in each example and comparative example were added to the titration cell and titrated with Karl Fischer reagent. The volume of reagent consumed was recorded, and the moisture content of the sample was calculated.

[0085] The moisture content test results of 6-substituted indole are shown in Table 2.

[0086] Table 2. Moisture content test results of 6-substituted indoles

[0087] As can be seen from the moisture test data, the moisture content of the samples in each embodiment of the present invention is significantly lower than that of the comparative example, and far below the quality standard limit of ≤0.50%, showing excellent drying effect and stability overall. Example 1, as the basic process of this invention, achieves extremely low moisture levels without the addition of additional additives. This demonstrates that the one-pot continuous reaction, simplified post-processing, and n-heptane recrystallization system can efficiently remove residual moisture and organic solvents from the reaction system, avoiding residual moisture caused by multiple transfer steps and uneven drying. Example 2, for the synthesis of methyl 6-fluoroindolecarboxylate, shows the best moisture control effect, indicating that the process has good post-processing adaptability for 6-substituted indoles with different structures, and the recrystallization and drying conditions are highly matched, achieving thorough drying. In Examples 3 and 4, after introducing different proportions of N-cyclohexylpyrrolidine into the reaction system, the moisture content remained stable and at a low level, indicating that the addition of this additive does not affect the drying efficiency of the system and is well compatible with the post-processing. In Examples 5 and 6, the addition of 1-hydroxymethylpyrrolidine during the purification stage resulted in no significant fluctuations in moisture data, further proving that this additive can improve product purity without damaging the original drying system, maintaining a stable low moisture state. In comparison, Comparative Example 1 uses a traditional two-step process. Because the intermediates require multiple independent operations such as filtration, washing, and drying, the process is lengthy, leading to the re-adsorption and residue of moisture. At the same time, multiple solvent replacements result in incomplete drying, and the moisture content is significantly higher than that of the examples. Comparative Example 2 reduces the proportion of N-cyclohexylpyrrolidine, which decreases the compatibility of the reaction system and reduces the moisture removal efficiency during the post-processing, resulting in a significant increase in moisture content. Comparative Example 3 replaces a specific auxiliary agent with N-ethylpyrrolidine, which disrupts the original compatibility between the reaction and post-processing systems, making it difficult to completely remove solvent and moisture, and resulting in poorer moisture control. Comparative Example 4 uses isopropanol in the purification stage, which reduces the compatibility between the recrystallization system and the product crystal form. During the drying process, solvent encapsulation and moisture retention are easily formed, further increasing the moisture content. In summary, this invention achieves precise and stable control of moisture content in 6-substituted indole products through a one-pot continuous process, specific additive formulation, and optimized post-treatment combination. This not only meets quality standard requirements but also effectively improves product storage stability and reduces the risk of downstream side reactions, fully demonstrating the greenness, stability, and industrial applicability of the process.

[0088] Experimental Example 5: Yield test of 6-substituted indole.

[0089] Test samples: 6-substituted indoles prepared in each example and comparative example, including 6-indolecarboxylic acid and methyl 6-fluoroindolecarboxylate.

[0090] Test method: Based on the amount of starting materials (methyl 4-methyl-3-nitrobenzene, 2-methyl-5-fluoronitrobenzene) in each example and comparative example, the theoretical yield of the target product 6-substituted indole was obtained according to the theoretical yield calculation formula. The actual product quality of each sample was accurately weighed, and the total product yield of each example and comparative example was calculated according to the formula yield = (actual yield / theoretical yield) × 100%.

[0091] The yield test results of 6-substituted indole are shown in Table 3.

[0092] Table 3. Yield test results of 6-substituted indoles

[0093] Example 1 employs the one-pot continuous reaction process of this invention, eliminating intermediate separation, washing, and drying steps, significantly reducing material loss, and achieving a yield far higher than traditional processes, proving that the basic one-pot route has achieved a significant improvement in yield. Example 2 shows a further increase in the yield of 6-fluoroindole synthesis, indicating that this process can maintain high conversion efficiency for different substrates and has strong versatility. In Examples 3 and 4, the addition of N-cyclohexylpyrrolidine resulted in a continuous upward trend in yield, indicating that this auxiliary agent can effectively promote the complete reaction and improve the conversion efficiency of raw materials, with the best yield improvement effect under optimized ratios. In Examples 5 and 6, the addition of 1-hydroxymethylpyrrolidine during the purification stage maintained a high yield and showed a stable and improving trend, indicating that this auxiliary agent can reduce product loss during purification and further ensure the overall yield. Comparative Example 1 uses a traditional two-step method. Independent purification of intermediates resulted in significant material loss, leading to a yield significantly lower than in all examples, fully demonstrating the shortcomings of traditional processes such as low yield and poor raw material utilization. In Comparative Example 2, reducing the proportion of N-cyclohexylpyrrolidine resulted in a yield significantly lower than in Examples 3 and 4, indicating that insufficient additive addition could not adequately improve reaction efficiency, limiting yield improvement. In Comparative Example 3, changing the type of additive further reduced the yield, proving that the specific additives selected in this invention have a unique effect on improving reaction conversion and yield. In Comparative Example 4, using isopropanol in the purification stage resulted in an even lower yield, indicating that 1-hydroxymethylpyrrolidine can effectively reduce purification losses and is crucial for maintaining a high yield. Overall, the results fully verify that the one-pot process of this invention significantly improves product yield and raw material utilization through reaction system optimization, demonstrating excellent industrial economics.

[0094] 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.

[0095] 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 the synthesis of 6-substituted indoles, characterized in that: Using substituted nitrobenzene compounds as raw materials, the raw materials are dissolved in N,N-dimethylformamide solvent, mixed with N,N-dimethylformamide dimethyl acetal and tetrahydropyrrole, and then subjected to a segmented temperature-controlled condensation reaction. The reaction is first carried out at 75~80℃ for 0.5~1.5h, and then the temperature is raised to 90~100℃ for 1~3h to obtain a reaction system containing condensation intermediates. The condensation intermediate was directly added to the subsequent reaction without separation and purification. Raney nickel catalyst was added to the reaction system, the system was first replaced with hydrogen 2 to 4 times, and then a hydrogenation reduction reaction was carried out to obtain a reduced solution. The reducing solution was washed sequentially with hydrochloric acid aqueous solution, saturated sodium bicarbonate aqueous solution, and saturated sodium chloride aqueous solution. The solution was concentrated under reduced pressure to obtain a concentrate. Heptane was added to the concentrate, and the solution was distilled under reduced pressure and recrystallized to obtain methyl 6-substituted indolecarboxylate. The concentrate was then hydrolyzed with sodium hydroxide and acidified with hydrochloric acid to obtain high-purity 6-substituted indole. The substituted nitrobenzene compounds include one of methyl 4-methyl-3-nitrobenzene and 2-methyl-5-fluoronitrobenzene.

2. The method of synthesis of claim 1, wherein: The concentration of the hydrochloric acid aqueous solution is 5~7 mol / L.

3. The synthesis method according to claim 1, characterized in that: The hydrogenation reduction reaction is carried out at a temperature of 50-55°C for 4-6 hours.

4. The synthesis method according to claim 1, characterized in that: The mass-to-volume ratio of the substituted nitrobenzene compound to N,N-dimethylformamide is 1~3g:20mL.

5. The synthesis method according to claim 1, characterized in that: The mass ratio of the N,N-dimethylformamide dimethyl acetal to the substituted nitrobenzene compound is 1:0.5~1.

5.

6. The synthesis method according to claim 1, characterized in that: During the feeding stage of the segmented temperature-controlled condensation reaction, N-cyclohexylpyrrolidine is added to the reaction system, with the mass ratio of N-cyclohexylpyrrolidine to substituted nitrobenzene compounds being 3~8:

209.

7. The synthesis method according to claim 1, characterized in that: The mass ratio of the tetrahydropyrrole to the substituted nitrobenzene compound is 1:0.5~1.

5.

8. The synthesis method according to claim 1, characterized in that: The mass ratio of Raney nickel to substituted nitrobenzene compounds is 1:5~15.

9. The synthesis method according to claim 1, characterized in that: During the recrystallization of n-heptane, the solution is heated to 95-100°C to completely dissolve the concentrate, and then stirred and cooled to allow crystals to precipitate.

10. The synthesis method according to claim 1, characterized in that: The volume ratio of the concentrate to n-heptane is 1:1 to 10.

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