Industrialized synthesis method of indolopyrrolocarbazole propionitrile compound and intermediate thereof

Abstract

The application discloses an industrial synthesis method of an indolopyrrolocarbazole propionitrile compound and an intermediate thereof, and belongs to the technical field of organic synthesis and preparation of pharmaceutical intermediates. The method comprises the following steps: taking tryptamine as a starting material, sequentially performing amino tert-butyloxy carbonyl protection, indole nitrogen cyanoethylation, 2,3-dichloro-5,6-dicyano-1,4-benzoquinone oxidation, deprotection and salt formation, amide condensation, acetic anhydride ring closure, low-temperature oxidation ring closure and deacetylation, and obtaining the target compound. The cyanoethylation reaction solution can be directly transferred to the oxidation step, and the key intermediate is separated by salt formation solidification, water precipitation, beating and filtration. The method realizes the synergy of functional group preposition, skeleton construction and intermediate separation, reduces the dependence on preparative column chromatography, and is convenient for scale-up preparation.

Description

Technical Field

[0001] This invention relates to the fields of organic synthesis and pharmaceutical intermediate preparation technology, specifically to a method for synthesizing indo-pyrrolo-carbazole propionitrile compounds and their intermediates, and more particularly to an industrial synthesis method suitable for scale-up preparation of 5,6,7,13-tetrahydro-13-methyl-5-oxo-12H-indo-[2,3-a]pyrrolo-[3,4-c]carbazole-12-propionitrile and its intermediates. Background Technology

[0002] Indolocarbazole compounds, characterized by the fusion of aromatic fused rings and nitrogen-containing heterocycles, are a commonly used skeletal structure in the study of protein kinase inhibitors and related pharmacological mechanisms. 5,6,7,13-tetrahydro-13-methyl-5-oxo-12H-indolo[2,3-a]pyrrolo[3,4-c]carbazole-12-propionitrile can be used to study protein kinase inhibition and related signaling pathways. With the ongoing efforts in drug screening, pharmacological mechanism validation, and drug registration, research-grade and application-grade samples place higher demands on product purity, batch stability, and batch supply capabilities. Traditional laboratory synthesis methods, aimed at preparing small quantities of samples, can no longer consistently meet these application requirements.

[0003] However, the target compound simultaneously contains multiple indole structural units, nitrogen-containing fused rings, lactam structures, and propionitrile side chains. Its preparation process involves the sequential introduction of multiple functional groups, continuous transformation of similar intermediates, and multi-stage ring-closure reactions. The formation sequence of each functional group not only affects the activity and ring-closure selectivity of subsequent reaction sites but also alters the polarity, solubility, and solid precipitation properties of the intermediates. If the route design is based solely on the possibility of a single-step reaction without simultaneously considering the separation morphology of the intermediates and subsequent processing methods, intermediates that are difficult to precipitate or directly purify are easily formed, thereby increasing the frequency of column chromatography, repeated extraction, and concentration.

[0004] Chinese invention patent application publication CN1035667A discloses indolofaradazole derivatives and their preparation methods, with some examples employing silica gel chromatography and crystallization to separate the products. This prior art demonstrates that such highly fused nitrogen-containing heterocyclic compounds face common process challenges in selective functionalization, isomer control, and separation and purification. When these challenges are compounded in a continuous synthetic route involving side chain pre-positioning, amide linkage, pyrrolidone ring formation, and oxidative ring closure, they further increase solvent consumption, extend equipment downtime, increase waste generation, and cause batch quality fluctuations, hindering the scale-up and stable operation of the synthetic route.

[0005] The technical problem this invention aims to solve is that existing laboratory preparation routes for the target indole-pyrrolo-carbazole propionitrile compound often suffer from difficulties in coordinating the functional group formation sequence, reaction site activity, and intermediate separation morphology during the stepwise construction of a complex fused polycyclic skeleton. This leads to some key intermediates being difficult to process using conventional industrial methods, and also results in increased purification burden, increased solvent and waste consumption, reduced production efficiency, and insufficient batch stability during scale-up. Therefore, how to simultaneously coordinate the feasibility of the chemical reaction and the feasibility of industrial separation becomes the core technical problem this invention seeks to solve. Summary of the Invention

[0006] To address the aforementioned technical problems, this invention provides an industrial synthesis method for indopolopyrrolocarbazole propionitrile compounds and their intermediates. The indopolopyrrolocarbazole propionitrile compound is 5,6,7,13-tetrahydro-13-methyl-5-oxo-12H-indopolo[2,3-a]pyrrolo[3,4-c]carbazole-12-propionitrile. The method utilizes early functional group pre-positioning, intermediate state transformation, pyrrolidone skeleton pre-organization, and final-stage low-temperature oxidation ring closure, enabling the chemical reaction and industrial separation processing to proceed synergistically along the same process chain.

[0007] Step S1 involves reacting tryptophan with di-tert-butyl dicarbonate to protect the amino group of tryptophan with a tert-butyloxycarbonyl group, yielding a tert-butyloxycarbonyl-protected tryptophan intermediate. By blocking the free amino group of tryptophan at the beginning of the route, the likelihood of this free amino group competing for reaction in subsequent cyanoethylation and oxidation reactions is reduced, and the resulting intermediate has a stable form suitable for subsequent separation and transposition.

[0008] Step S2 involves reacting the tert-butoxycarbonyl-protected tryptamine intermediate with acrylonitrile via an indole nitrogen-position cyanoethylation reaction in the presence of benzyltrimethylammonium hydroxide, yielding a cyanoethylated intermediate. This cyanoethylation reaction is carried out before the formation of the fused polycyclic skeleton, allowing for the pre-introduction of the desired propionitrile side chain at a stage where molecular complexity is low and the indole nitrogen position still exhibits good reactivity selectivity.

[0009] Step S3 involves oxidizing the cyanoethylated intermediate with 2,3-dichloro-5,6-dicyano-1,4-benzoquinone, converting the indole 3-position side chain of the cyanoethylated intermediate into a ketone-containing carbamate intermediate. The oxidation reaction is carried out with the amino group protected by a tert-butoxycarbonyl group to establish the carbonyl-containing reaction site required for subsequent amide condensation while minimizing interference from the free amino group.

[0010] Step S4 involves removing the tert-butoxycarbonyl protecting group of the ketone-containing carbamate intermediate using hydrochloric acid, and then salting the resulting amine group to obtain an amine salt intermediate. Deprotection restores the condensation reactivity of the amine group, while salt formation allows the amine salt intermediate to form a solid form suitable for pulping, filtration, and drying, thus achieving both reactivity release and intermediate solidification at the same process node.

[0011] Step S5 involves reacting the amine salt intermediate with 1-methyl-3-indoleacetic acid in the presence of N-methylimidazolium and N,N,N′,N′-tetramethylchloroformamidin hexafluorophosphate to obtain a bisindoleamide intermediate. This amide condensation reaction links a first indole structural unit containing a propionitrile side chain to a second indole structural unit, providing a bisindole skeleton with a predetermined linkage for the subsequent formation of the pyrrolidone ring.

[0012] Step S6 involves subjecting the bisindoleamide intermediate to a ring-closure reaction in the presence of acetic anhydride and triethylamine to obtain an acetyl-protected pyrrolidone intermediate. This ring-closure reaction forms an acetyl-protected pyrrolidone structure in the bisindoleamide intermediate and pre-organizes the relative positions of the two indole structural units and subsequent ring-closure sites to reduce the spatial degrees of freedom that can occur during the final oxidative fusion process.

[0013] Step S7 involves subjecting the acetyl-protected pyrrolidone intermediate to low-temperature oxidative ring closure under the action of a bis(trifluoroacetoxy)iodobenzene and boron trifluoride diethyl ether complex, yielding an acetyl-protected indolanopyrrolocarbazole propionitrile intermediate. The oxidative ring closure is performed under an inert atmosphere, with the boron trifluoride diethyl ether complex added dropwise at a low temperature, allowing the intermediate, which already has a pre-organized pyrrolidone structure, to complete intramolecular oxidative ring closure, forming an indolanopyrrolocarbazole fused polycyclic skeleton.

[0014] Step S8 involves removing the acetyl group from the acetyl-protected indolopyrrolocarbazole propionitrile intermediate under the action of potassium carbonate to obtain 5,6,7,13-tetrahydro-13-methyl-5-oxo-12H-indolo[2,3-a]pyrrolo[3,4-c]carbazole-12-propionitrile.

[0015] In the above technical solution, the cyanoethylation reaction solution obtained in step S2, after passing the test, is directly used in step S3 without separation. The amine salt intermediate obtained in step S4 is solidified into a filterable solid through salt formation. The bisindoleamide intermediate obtained in step S5 is precipitated into water to form a filterable solid. The acetyl-protected pyrrolidone intermediate obtained in step S6 is separated by precipitation and filtration after the reaction. The acetyl-protected indolophyropyrrolocarbazole propionitrile intermediate obtained in step S7 is separated by pulping and filtration. Thus, the process of gradually building the molecular framework is interconnected with the intermediate state transformation process, forming a process chain that coordinates reaction advancement, solid release, and subsequent sequence transitions.

[0016] As a further technical solution, step S1 includes: dissolving tryptamine in methanol, adding a methanol solution of di-tert-butyl dicarbonate dropwise at room temperature, and reacting at 25 degrees Celsius for 1 hour; after the reaction is completed, concentrating to remove methanol, slurrying the obtained crude product with petroleum ether, filtering and drying to obtain the tert-butyloxycarbonyl protected tryptamine intermediate.

[0017] As a further technical solution, step S2 includes: dissolving the tert-butyloxycarbonyl protected tryptamine intermediate and acrylonitrile in a mixed solvent composed of tetrahydrofuran and 1,4-dioxane; cooling the resulting reaction system to 0 degrees Celsius; adding a tetrahydrofuran solution of benzyltrimethylammonium hydroxide; then heating to 25 degrees Celsius and reacting for 1 hour; detecting the reaction using liquid chromatography-mass spectrometry; and after passing the detection, directly using the resulting reaction solution in step S3.

[0018] As a further technical solution, step S3 includes: adding water to the reaction solution obtained in step S2, adding 2,3-dichloro-5,6-dicyano-1,4-benzoquinone in batches at room temperature and reacting for 1 hour; concentrating after the reaction is completed, slurrying the obtained solid with dichloromethane and filtering to remove insoluble matter; washing the obtained filtrate sequentially with a 5% sodium hydroxide aqueous solution and saturated brine, drying and rapidly treating with a silica gel short column, and then concentrating to obtain the ketone-containing carbamate intermediate.

[0019] As a further technical solution, step S4 includes: dissolving the ketone-containing carbamate intermediate in a 1,4-dioxane solution of hydrochloric acid and reacting it at room temperature for 1 hour; concentrating the solution after the reaction is complete, slurrying the resulting solid with ethyl acetate, filtering, washing with ethyl acetate and drying to obtain the amine salt intermediate.

[0020] As a further technical solution, step S5 includes: dissolving the amine salt intermediate, 1-methyl-3-indoleacetic acid and N-methylimidazolium in acetonitrile, adding N,N,N′,N′-tetramethylchloroformamidin hexafluorophosphate in batches at room temperature and reacting for 1 hour; adding the resulting reaction solution to water to precipitate the bisindoleamide intermediate, collecting the solid by filtration, slurrying with ethanol, and obtaining the bisindoleamide intermediate by filtration and drying.

[0021] As a further technical solution, step S6 includes: adding the bisindoleamide intermediate and triethylamine to acetic anhydride and reacting at 130 degrees Celsius for 12 hours; cooling and filtering after the reaction is completed, washing and drying the resulting filter cake with ethyl acetate to obtain the acetyl-protected pyrrolidone intermediate.

[0022] As a further technical solution, step S7 includes: dissolving the acetyl-protected pyrrolidone intermediate in dichloromethane, adding bis(trifluoroacetoxy)iodobenzene, and cooling to -40 degrees Celsius under nitrogen protection; adding a dichloromethane solution of boron trifluoride diethyl ether complex dropwise at -35 degrees Celsius to -40 degrees Celsius, and continuing the reaction for 2 hours after the addition is complete; concentrating after the reaction is complete, filtering, washing with dichloromethane, slurrying with ethanol, filtering again, and drying to obtain the acetyl-protected indolophorone carbazopropionitrile intermediate.

[0023] As a further technical solution, step S8 includes: adding the acetyl-protected indolophore-pyrrolocarbazole propionitrile intermediate to methanol, then adding an aqueous solution of potassium carbonate, and reacting at 50 degrees Celsius for 4 hours; after the reaction is completed, filtering to collect the solid and drying it to obtain the target compound.

[0024] As a further technical solution, except that step S3 uses a short silica gel column for rapid processing, the industrial synthesis method does not use preparative column chromatography.

[0025] Beneficial effects Compared with the prior art, the present invention has the following beneficial effects: Firstly, this invention, through the sequential arrangement of tert-butyloxycarbonyl protection, indole nitrogen-position cyanoethylation, side chain oxidation in the protected state, deprotection and salt formation, amide condensation, pyrrolidone pre-organization, low-temperature oxidative fusion, and final deprotection, selectively pre-positions the propionitrile side chain before the formation of the fused skeleton, and forms a sterically constrained pyrrolidone intermediate before the final oxidative ring closure. This allows key functional groups and ring-closing sites to be formed step by step in a sequence suitable for subsequent reactions, which helps to reduce side reactions caused by multi-site selective modification and unconstrained oxidative ring closure in the later stages.

[0026] Secondly, this invention sets up multiple separable intermediate nodes in the process of gradually increasing molecular complexity by directly transferring the reaction solution, deprotecting and forming salts, precipitating in water, precipitating after reaction, slurrying and filtering. This allows key intermediates to be processed by conventional solid-liquid separation operations, reducing the dependence on preparative column chromatography and coordinating the chemical reactivity with the intermediate separation morphology.

[0027] Thirdly, this invention reduces the number of operational steps requiring repeated fine purification by creating a continuous process chain from pre-positioning of preceding functional groups, release of intermediate solids, pre-organization of the framework, and controlled oxidation ring-closing at the final stage. Low-temperature controlled dropwise addition and an inert atmosphere enhance the condition control of the final oxidation ring-closing process, which helps reduce the burden of solvents and manual handling, improves the process utilization efficiency of unit equipment, and enhances the controllability and batch stability of the batch preparation process. Attached Figure Description

[0028] Figure 1This is a flowchart illustrating the overall industrial synthesis process of this invention. Figure 2 This is a chemical structural transformation route diagram of compounds 1 to 9 of the present invention; Figure 3 This is a schematic diagram of the interface between the chemical reaction and the intermediate separation in this invention; Figure 4 This is a schematic diagram of the two-level framework construction and low-temperature oxidation loop closure of the present invention; Figure 5 The image shows the proton nuclear magnetic resonance spectrum of target compound 9. Detailed Implementation

[0029] To make the objectives, technical solutions, and advantages of this invention clearer, the invention will be further described in detail below with reference to the accompanying drawings and embodiments. It should be understood that the specific embodiments described herein are for illustrative purposes only and are not intended to limit the invention.

[0030] The overall industrial synthesis process of this invention is as follows: Figure 1 As shown, the structural transformation relationships of compounds 1 to 9 are as follows: Figure 2 As shown, the interface between the chemical reaction and the intermediate is as follows: Figure 3 As shown, the two-level framework construction and the closed-loop relationship of low-temperature oxidation are as follows: Figure 4 As shown, the proton NMR spectrum of target compound 9 is as follows: Figure 5 As shown.

[0031] In the following examples, compound 1 is tryptamine; compound 2 is a tert-butyloxycarbonyl-protected tryptamine intermediate; compound 3 is an intermediate after introducing a cyanoethyl side chain at the nitrogen position of indole; compound 4 is a ketone-containing carbamate intermediate formed by side chain oxidation; compound 5 is an amine salt intermediate formed after removing the tert-butyloxycarbonyl group and forming a salt; compound 6 is a bisindoleamide intermediate formed after linking a second indole fragment; compound 7 is an acetyl-protected pyrrolidone intermediate formed by anhydride ring closure; compound 8 is an acetyl-protected indolopyrrolocarbazol-propionitrile intermediate formed by oxidative ring closure; and compound 9 is the target compound 5,6,7,13-tetrahydro-13-methyl-5-oxo-12H-indolo[2,3-a]pyrrolo[3,4-c]carbazol-12-propionitrile.

[0032] All equivalents mentioned in each step are calculated with the main reaction substrate of that step as 1.00 equivalent. The reaction endpoint is determined by thin-layer chromatography or liquid chromatography-mass spectrometry. The yields mentioned in each step are separation yields, which are equal to the amount of actual product obtained divided by the amount of theoretical product calculated based on the main reaction substrate, and then multiplied by 100%.

[0033] Example 1 This example illustrates the preparation of compound 2.

[0034] 127.0 g of compound 1, tryptamine, was added to a reaction vessel. The amount of substance of compound 1 was 792.66 mmol, or 1.00 equivalent. 1 L of methanol was added to dissolve compound 1.

[0035] Separately, 181.7 g of di-tert-butyl dicarbonate was dissolved in 1 liter of methanol. The molar amount of di-tert-butyl dicarbonate was 832.29 mmol, equivalent to 1.05 equivalents. The methanol solution of di-tert-butyl dicarbonate was added dropwise to the methanol solution of compound 1 at room temperature. After the addition was complete, the reaction was continued with stirring at room temperature for 1 hour.

[0036] Thin-layer chromatography (TLC) was used to monitor the reaction progress. After the reaction of compound 1 was complete, methanol was removed by vacuum concentration to obtain an oily crude product. 1.5 L of petroleum ether was added to the crude product for slurrying, converting compound 2 from the oily crude product system into a filterable solid. The solid was collected by filtration and dried to obtain 196 g of white solid compound 2, with a separation yield of 94.98% and a purity of 100%. The structural transformation sites of compound 2 are shown in [reference needed]. Figure 2 .

[0037] In this embodiment, the tert-butyloxycarbonyl protection not only prevents the free amino group from competing with the subsequent basic cyanoethylation and oxidation processes, but also allows the intermediate to be converted from an oily crude product to a solid state via petroleum ether slurrying. This step simultaneously serves two functions: controlling reaction selectivity and adjusting the intermediate's physical state.

[0038] Example 2 This example illustrates the preparation of the reaction solution of compound 3 and its direct conversion.

[0039] A total of 187.0 g of compound 2 was added to the reaction vessel. The amount of compound 2 was 718.32 mmol, or 1.00 equivalent. 76.2 g of acrylonitrile was then added. The amount of acrylonitrile was 1.44 mol, or 2.00 equivalent.

[0040] Add 1 L of 1,4-dioxane and 1 L of tetrahydrofuran to disperse or dissolve the reactants. Cool the resulting reaction system to 0°C. Separately dissolve 12.0 g of benzyltrimethylammonium hydroxide in 1 L of tetrahydrofuran. The amount of benzyltrimethylammonium hydroxide is 71.83 mmol, or 0.10 equivalents. Add this tetrahydrofuran solution to the cooled reaction system.

[0041] After the addition of the reactants, the reaction system was slowly heated to 25 degrees Celsius and stirred at 25 degrees Celsius for 1 hour. The reaction progress was monitored using liquid chromatography-mass spectrometry. The monitoring showed that compound 2 was completely converted, yielding a cyanoethylated reaction solution containing compound 3. The resulting reaction solution was not concentrated, extracted, or separated by column chromatography and was directly used as the reaction raw material in Example 3.

[0042] In this embodiment, the cyanoethyl side chain is introduced at the tryptophan stage, where molecular complexity is relatively low, avoiding selective nitrogen site modification under conditions of multiple nitrogen-containing sites coexisting after the fused backbone is formed. The reaction solution directly proceeds to the next step, thus eliminating an intermediate separation node.

[0043] Example 3 This example illustrates the preparation of compound 4.

[0044] Take the reaction solution containing compound 3 obtained in Example 2. This reaction solution contains a total of 200 grams of compound 3, equivalent to 638.16 mmol, or 1.00 equivalent. Add 200 mL of water to the reaction solution. Add 282 g of 2,3-dichloro-5,6-dicyano-1,4-benzoquinone in portions at room temperature. The amount of the oxidant is 1.24 mol, or 2.00 equivalent. After the addition is complete, continue stirring at room temperature for 1 hour.

[0045] Thin-layer chromatography was used to monitor the reaction progress. After the reaction was complete, the solvent was removed by concentration to obtain a solid mixture. Dichloromethane was added to the solid mixture for slurrying, and the insoluble solids were removed by filtration. The filter cake was washed with dichloromethane, and the washings and filtrate were combined. The resulting organic phase was washed twice with a 5% (w / w) aqueous sodium hydroxide solution, and then once with saturated brine. The organic phase was separated and dried with anhydrous sodium sulfate. The dried organic phase was rapidly processed by a short silica gel column and then concentrated to obtain 160 g of compound 4, equivalent to 488.73 mmol, with a separation yield of 76.57%.

[0046] Liquid chromatography-mass spectrometry (LC-MS) analysis showed that the characteristic ion peak had a mass-to-charge ratio of 272.1. The structural transformation position of compound 4 is shown in [reference needed]. Figure 2 .

[0047] In this embodiment, the amino group retains its tert-butyloxycarbonyl group protection during oxidation, allowing the oxidant to preferentially act on the predetermined side chain and form the ketone-containing structure required for subsequent amide condensation. This step connects with the direct sequence conversion in Example 2, demonstrating the sequential relationship of first pre-setting the cyanoethyl side chain and then establishing the carbonyl-containing reaction site under protected conditions.

[0048] Example 4 This example illustrates the preparation of compound 5.

[0049] 160 g of compound 4 was added to a reaction vessel. The amount of compound 4 was 488.73 mmol, or 1.00 equivalent. 1.5 L of 1,4-dioxane hydrochloric acid solution with a concentration of 4 mol / L was added to dissolve or disperse compound 4. The resulting reaction solution was stirred at room temperature for 1 hour.

[0050] The reaction progress was monitored using liquid chromatography-mass spectrometry (LC-MS). After the removal of the tert-butyloxycarbonyl group, the solvent was removed by concentration, yielding a solid containing the amine salt. Ethyl acetate was added to the obtained solid for slurry preparation. The filter cake was collected by filtration and washed with ethyl acetate. After drying, 128 g of a white solid, compound 5, was obtained, with a separation yield of 99.46%. LC-MS detection showed a positive ion peak mass-to-charge ratio of 228.4. The salt formation, solidification, and separation interface of compound 5 are described in [reference needed]. Figure 3 .

[0051] This embodiment restores the condensation reaction activity of the amine group by removing the protecting group, and forms a stable solid from the amine intermediate by salt formation with hydrochloric acid, thereby enabling the release of reactivity and industrial solid-liquid separation to be completed at the same time.

[0052] Example 5 This example illustrates the preparation of compound 6.

[0053] A total of 114.0 g of compound 5 was added to the reaction vessel. The molar amount of compound 5 was 432.14 mmol, or 1.00 equivalent. 85.9 g of 1-methyl-3-indoleacetic acid (453.75 mmol, or 1.10 equivalent) was added. 124.2 g of N-methylimidazole (1.51 mol, or 3.50 equivalent) was added. Two liters of acetonitrile were added to dissolve or homogeneously disperse the above materials.

[0054] 145.5 g of N,N,N′,N′-tetramethylchloromethanesulfonium hexafluorophosphate (518.56 mmol, 1.20 equivalents) was added in portions at room temperature. After addition, stirring was continued at room temperature for 1 hour. The resulting reaction solution was poured into water, causing compound 6 to precipitate. The filter cake was collected and then slurried with ethanol. After slurrying, it was filtered again, the filter cake was collected and dried, yielding 160 g of compound 6, with a separation yield of 93.10%.

[0055] Liquid chromatography-mass spectrometry (LC-MS) analysis showed a positive ion peak mass-to-charge ratio of 399.1. The structural transformation position of compound 6 is shown in [reference needed]. Figure 2 The interface for water precipitation and ethanol pulping is shown below. Figure 3 .

[0056] This embodiment completes the amide linkage between a first indole structural unit containing a propionitrile side chain and a second indole structural unit substituted with a 1-methyl group. The condensation product can be precipitated in water and further pulped with ethanol, indicating that this condensation system not only connects the two indole fragments but also works in conjunction with the subsequent solid-state separation interface.

[0057] Example 6 This example illustrates the preparation of compound 7.

[0058] 160.0 g of compound 6 was added to a reaction vessel. The amount of compound 6 was 401.53 mmol, or 1.00 equivalent. 480 mL of triethylamine and 3 L of acetic anhydride were added. The resulting reaction system was heated to 130°C and stirred at 130°C for 12 hours.

[0059] The reaction progress was monitored using liquid chromatography-mass spectrometry (LC-MS). Monitoring showed that heating was stopped after the conversion of compound 6 was complete. The reaction system was filtered, and the filter cake was collected. The filter cake was washed with a small amount of ethyl acetate and dried to obtain 140.0 g of compound 7, with a separation yield of 82.54%. LC-MS showed that the mass-to-charge ratio of the positive ion peak was 423.2. The secondary skeletal structure relationship of compounds 6 to 9 is shown in [reference needed]. Figure 4 .

[0060] In this embodiment, an acetyl-protected pyrrolidone structure is formed through intramolecular ring closure of the amide backbone. This structure pre-constrains the relative positions of the two indole fragments and the subsequent ring-closure sites, transforming the subsequent high-valent iodine oxidation reaction from a highly flexible cross-segment coupling to a backbone-constrained intramolecular fusion.

[0061] Example 7 This example illustrates the preparation of compound 8.

[0062] A total of 50.0 g of compound 7 was added to the reaction vessel. The molar amount of compound 7 was 118.35 mmol, or 1.00 equivalent. 2.5 L of dichloromethane was added to dissolve compound 7. 56.0 g of bis(trifluoroacetoxy)iodobenzene was added, with a molar amount of 130.18 mmol, or 1.10 equivalent. The reaction system was cooled to -40°C under nitrogen protection.

[0063] Separately, take 20.2 g of boron trifluoride diethyl ether complex, equivalent to 17.5 mL and 142.02 mmol, totaling 1.20 equivalents. Dissolve the boron trifluoride diethyl ether complex in 2.5 L of dichloromethane. Add this solution dropwise to the reaction system under controlled temperature, maintaining the reaction temperature between -35°C and -40°C during the addition. After the addition is complete, continue stirring within the specified temperature range for 2 hours.

[0064] After the reaction was complete, the reaction solution was concentrated to reduce the volume to approximately 500 mL. The concentrate was filtered, and the filter cake was washed with dichloromethane. The filter cake was collected, slurried with ethanol, filtered again, washed with ethanol, and dried to obtain 28.0 g of compound 8, with a separation yield of 56.27%. Liquid chromatography-mass spectrometry (LC-MS) showed a positive ion peak mass-to-charge ratio of 421.4. The low-temperature oxidative fusion position of compound 8 is shown in [reference needed]. Figure 4 .Show.

[0065] In this embodiment, compound 7 already possesses a pyrrolidone pre-structure, and the bis(trifluoroacetoxy)iodobenzene and boron trifluoride diethyl ether complex further promotes oxidative fusion at the two predetermined sites. Nitrogen protection, low temperature range, and temperature-controlled dropwise addition constitute the reaction control conditions for this step. The separation yield of this step is lower than that of the aforementioned steps, indicating that this step is a key control point in the entire process route.

[0066] Example 8 This example illustrates the preparation of target compound 9.

[0067] A total of 27.7 g of compound 8 was added to a reaction vessel. The molar amount of compound 8 was 65.88 mmol, or 1.00 equivalent. 2.4 L of methanol was added to dissolve or homogeneously disperse compound 8. Separately, 27.3 g of potassium carbonate was dissolved in 600 mL of water. The molar amount of potassium carbonate was 197.64 mmol, or 3.00 equivalent. This potassium carbonate aqueous solution was added to the methanol system containing compound 8.

[0068] The reaction system was heated to 50°C and stirred at 50°C for 4 hours. After the reaction was complete, the mixture was filtered directly, the filter cake was collected and dried, yielding 20 grams of target compound 9, with a separation yield of 80.23% and a purity of 98.5%. Liquid chromatography-mass spectrometry (LC-MS) analysis showed that the mass-to-charge ratio of the positive ion peak was 379.1.

[0069] The proton NMR data of compound 9 are as follows: 400 MHz, deuterated dimethyl sulfoxide, chemical shift 9.39, doublet, coupling constant 7.2 Hz, 1 hydrogen atom; 8.66, singlet, 1 hydrogen atom; 8.07, doublet, coupling constant 7.6 Hz, 1 hydrogen atom; 7.96, doublet, coupling constant 8.0 Hz, 1 hydrogen atom; 7.73, doublet, coupling constant 8.0 Hz, 1 hydrogen atom. 7.60 to 7.53, multiplet, 2 hydrogens; 7.42, triplet, coupling constant 7.2 Hz, 1 hydrogen; 7.32, triplet, coupling constant 7.6 Hz, 1 hydrogen; 5.14, triplet, coupling constant 6.8 Hz, 2 hydrogens; 4.97, singlet, 2 hydrogens; 4.19, singlet, 3 hydrogens; 2.88, triplet, coupling constant 6.8 Hz, 2 hydrogens. The proton NMR spectrum of compound 9 is shown below. Figure 5 As shown.

[0070] In this embodiment, compound 8 undergoes a deacetylation reaction using a reaction system composed of methanol and water. The target compound can be directly collected by filtration after the reaction, eliminating the need for preparative column chromatography and completing the final conversion from the acetyl-protected fused intermediate to the target compound.

[0071] The above embodiments demonstrate that the early functional group pre-positioning, oxidation under protected conditions, deprotection and salt formation solidification, second indole fragment linkage, pyrrolidone pre-organization, low-temperature oxidative fusion, and final deprotection can be carried out sequentially. Except for compound 4, which is rapidly processed using a short silica gel column, the other key intermediates are mainly processed through direct transfer, salt formation, precipitation, pulping, filtration, and drying, so that the framework construction and intermediate separation form an interconnected process relationship.

[0072] The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention. All modifications, equivalent substitutions and improvements made within the spirit and principles of the present invention should be included within the protection scope of the present invention.

Claims

1. An industrial synthesis method for indopolopyrrolocarbazole propionitrile compounds and their intermediates, wherein the indopolopyrrolocarbazole propionitrile compound is 5,6,7,13-tetrahydro-13-methyl-5-oxo-12H-indopolo[2,3-a]pyrrolo[3,4-c]carbazole-12-propionitrile, characterized in that, Includes the following steps: Step S1 involves reacting tryptamine with di-tert-butyl dicarbonate to protect the amino group of the tryptamine with a tert-butyloxycarbonyl group, thereby obtaining a tert-butyloxycarbonyl-protected tryptamine intermediate. Step S2 involves reacting the tert-butoxycarbonyl protected tryptamine intermediate with acrylonitrile in the presence of benzyltrimethylammonium hydroxide to undergo an indole nitrogen-position cyanoethylation reaction, yielding a cyanoethylated intermediate. Step S3: The cyanoethylated intermediate is oxidized with 2,3-dichloro-5,6-dicyano-1,4-benzoquinone to convert the indole 3-position side chain of the cyanoethylated intermediate into a ketone-containing carbamate intermediate. Step S4: Use hydrochloric acid to remove the tert-butoxycarbonyl protecting group of the ketone-containing carbamate intermediate, and make the amino group formed after deprotection form a salt to obtain an amine salt intermediate; Step S5 involves reacting the amine salt intermediate with 1-methyl-3-indoleacetic acid in the presence of N-methylimidazolium and N,N,N′,N′-tetramethylchloroformamidin hexafluorophosphate to obtain a bisindoleamide intermediate. Step S6 involves subjecting the bisindoleamide intermediate to a cyclization reaction in the presence of acetic anhydride and triethylamine to obtain an acetyl-protected pyrrolidone intermediate. Step S7: The acetyl-protected pyrrolidone intermediate is subjected to low-temperature oxidative cyclization in the presence of a bis(trifluoroacetoxy)iodobenzene and a boron trifluoride diethyl ether complex to obtain an acetyl-protected indolopyrrolocarbazol propionitrile intermediate. Step S8: The acetyl-protected indolopyrrolocarbazole propionitrile intermediate is deacetylated in the presence of potassium carbonate to obtain 5,6,7,13-tetrahydro-13-methyl-5-oxo-12H-indolo[2,3-a]pyrrolo[3,4-c]carbazole-12-propionitrile. In step S2, the cyanoethylation reaction solution obtained is used directly in step S3 without separation; the amine salt intermediate obtained in step S4 is solidified by salt formation to form a filterable solid; the bisindoleamide intermediate obtained in step S5 is precipitated in water to form a filterable solid; the acetyl-protected pyrrolidone intermediate obtained in step S6 is separated by precipitation and filtration after reaction; and the acetyl-protected indolopyrrolocarbazole propionitrile intermediate obtained in step S7 is separated by pulping and filtration.

2. The industrial synthesis method according to claim 1, characterized in that, Step S1 includes: dissolving tryptamine in methanol, adding a methanol solution of di-tert-butyl dicarbonate dropwise at room temperature, and reacting at 25 degrees Celsius for 1 hour; after the reaction is completed, concentrating to remove methanol, slurrying the obtained crude product with petroleum ether, filtering and drying to obtain the tert-butyloxycarbonyl protected tryptamine intermediate.

3. The industrial synthesis method according to claim 1, characterized in that, Step S2 includes: dissolving the tert-butoxycarbonyl protected tryptamine intermediate and acrylonitrile in a mixed solvent composed of tetrahydrofuran and 1,4-dioxane; cooling the resulting reaction system to 0 degrees Celsius; adding a tetrahydrofuran solution of benzyltrimethylammonium hydroxide; then heating to 25 degrees Celsius and reacting for 1 hour; and performing liquid chromatography-mass spectrometry on the obtained cyanoethylation reaction solution. After passing the detection, the cyanoethylation reaction solution is directly used in step S3.

4. The industrial synthesis method according to claim 1, characterized in that, Step S3 includes: adding water to the cyanoethylation reaction solution obtained in step S2, adding 2,3-dichloro-5,6-dicyano-1,4-benzoquinone in batches at room temperature and reacting for 1 hour; after the reaction is completed, concentrating to remove the solvent, slurrying the obtained solid with dichloromethane, filtering to remove insoluble matter; washing the obtained filtrate successively with a 5% sodium hydroxide aqueous solution and saturated brine, drying and rapidly treating with a silica gel short column, and then concentrating to obtain the ketone-containing carbamate intermediate.

5. The industrial synthesis method according to claim 1, characterized in that, Step S4 includes: dissolving the ketone-containing carbamate intermediate in a 1,4-dioxane solution of hydrochloric acid and reacting at room temperature for 1 hour; after the reaction is completed, concentrating to remove the solvent, slurrying the obtained solid with ethyl acetate, filtering, washing with ethyl acetate and drying to obtain the amine salt intermediate.

6. The industrial synthesis method according to claim 1, characterized in that, Step S5 includes: dissolving the amine salt intermediate, 1-methyl-3-indoleacetic acid, and N-methylimidazolium in acetonitrile; adding N,N,N′,N′-tetramethylchloromethacinium hexafluorophosphate in batches at room temperature and reacting for 1 hour; adding the resulting reaction solution to water to precipitate the bisindoleamide intermediate; collecting the solid by filtration; slurrying with ethanol; and obtaining the bisindoleamide intermediate by filtration and drying.

7. The industrial synthesis method according to claim 1, characterized in that, Step S6 includes: adding the bisindoleamide intermediate and triethylamine to acetic anhydride and reacting at 130 degrees Celsius for 12 hours; cooling and filtering after the reaction is complete, washing and drying the resulting filter cake with ethyl acetate to obtain the acetyl-protected pyrrolidone intermediate.

8. The industrial synthesis method according to claim 1, characterized in that, Step S7 includes: dissolving the acetyl-protected pyrrolidone intermediate in dichloromethane, adding bis(trifluoroacetoxy)iodobenzene, and cooling to -40°C under nitrogen protection; adding a dichloromethane solution of boron trifluoride diethyl ether complex dropwise at -35°C to -40°C, and continuing the reaction for 2 hours after the addition is complete; concentrating the solution after the reaction is complete, filtering, washing with dichloromethane, slurrying with ethanol, filtering again, and drying to obtain the acetyl-protected indolophorone carbazole propionitrile intermediate.

9. The industrial synthesis method according to claim 1, characterized in that, Step S8 includes: dispersing or dissolving the acetyl-protected indolopyrrolocarbazole propionitrile intermediate in methanol, adding an aqueous potassium carbonate solution, and reacting at 50 degrees Celsius for 4 hours; after the reaction is completed, filtering to collect the solid and drying it to obtain the 5,6,7,13-tetrahydro-13-methyl-5-oxo-12H-indolo[2,3-a]pyrrolo[3,4-c]carbazole-12-propionitrile.

10. The industrial synthesis method according to any one of claims 1 to 9, characterized in that: Step S1 uses petroleum ether to separate the tert-butyloxycarbonyl-protected tryptamine intermediate; the cyanoethylated reaction solution obtained in step S2, after passing the test, directly enters step S3; step S4 uses ethyl acetate to separate the amine salt intermediate; step S5 uses water precipitation and ethanol to separate the bisindoleamide intermediate; step S6 uses filtration to separate the acetyl-protected pyrrolidone intermediate; step S7 uses ethanol to separate the acetyl-protected indolopyrrolocarbazole propionitrile intermediate; except for step S3 which uses a short silica gel column for rapid processing, the industrial synthesis method does not use preparative column chromatography.

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