Process for preparing indole-3-carboxylic acid derivatives

Abstract

The present invention provides a new synthetic method for preparing indole-3-carboxylic acid (ICA) derivatives, which are building blocks used as important starting materials for the production of several artificial drugs. An efficient, safe, easy-to-operate, and cost-effective method for preparing several ICA derivatives has been introduced in a very simple manner. The rapid synthesis of several important starting materials for ICA derivatives utilizing readily available starting materials, reagents, and solvents indicates that this novel method is functional group tolerant. The preparation method does not involve the use of reducing agents or transition metals, in one-pot, economically feasible, and easy-to-operate conditions. ICA derivatives are generated from isatin derivatives in one step, and this approach is important for a wide range of applications in terms of drug development and material synthesis.

Description

[Technical Field]

[0001] The present invention relates to a synthetic method for preparing indole-3-carboxylic acid (ICA) derivatives, which are building blocks used as important starting materials for the production of several artificial drugs. [Background technology]

[0002] Indole-3-carboxylic acid (ICA) derivatives are a common building block motif in many natural products and are used in the production of several artificial drugs, such as tropisetron and dolasetron. Their derivatives are also widely used as (a) anticancer drugs (CPI-1205), (b) serotonin 5-HT4 and 5-HT6 antagonists, (c) EphB3 receptor tyrosine kinase inhibitors, and (d) potential therapeutic agents for Alzheimer's disease. Existing synthetic methods for preparing ICA derivatives have several problems, including the need for expensive transition metal catalysts, the preparation of designed directing groups, and multi-step procedures. In fact, there is no straightforward route to synthesize this key intermediate, which can be produced smoothly and in a short time from readily available starting materials, a process that can be solved by the present invention.

[0003] It can be noted in the journal "Org. Lett. 2018, 20, pp. 4540-4544" that a series of Corey-Tchaikovsky reactions of isatin, spiroepoxy-, or spiroaziridineoxindoles with sulfur ylides led to the discovery of a unique reaction scheme that allows simple and direct access to a series of spirocyclopropyloxindoles in one pot.

[0004] [ka]

[0005] It can be noted that in the journal "Chem Heterocycl Compd 19, pp. 40-42 (1983)" two new methods for synthesizing the indolylglyoxal structure were proposed as simple methods for the preparation of 3-indolylglyoxal. The first method consists of the oxidation of 3-hydroxyacetylindole with a dimethyl sulfoxide-oxalyl chloride complex, but for some reason it cannot be adequately applied to the preparation of substituted indolylglyoxals. In the second case, the easily synthesized 3-indolylglyoxal chloride is reduced to the corresponding aldehyde in good yield using trialkyltin hydrides.

[0006] [ka]

[0007] It can be noted in the journal Synthesis 2016;48(10):1421-1436 that dimethyl sulfoxide is generally characterized as a solvent and oxidant, rather than as a substrate, building block, or synthon in organic chemistry. However, many reports have recently been published demonstrating that dimethyl sulfoxide fulfills these roles. This review article provides a comprehensive overview of the literature on this topic up to the end of 2015. Synthetic transformations utilizing the "CSC," "C," and "CS" fragments of dimethyl sulfoxide as building blocks are systematically summarized. Recent highlights include DMSO-based oxidation, DMSO-based methylthiomethylation (-CH2SMe), DMSO as a one-carbon synthon, DMSO-based methylation (-Me), DMSO-based methylenation (-CH2-), DMSO-based cyclization / aromatization (=CH-), DMSO-based formylation (-CHO), DMSO-based cyanation (-CN), DMSO as a synthon for "SC" functionality, DMSO-based thiomethylation (-SMe), and DMSO-based methylsulfonylation (-SO2Me).

[0008] It can be seen in the journal "Adv. Synth. Catal. 2020, 362, pp. 65-86" that dimethyl sulfoxide (DMSO) has a long history of use as a polar solvent and active pharmaceutical ingredient over the past several decades. However, in the last decade, DMSO has attracted the attention of scientists as a source of oxygen, carbon, or sulfur in a wide range of organic syntheses. This review classifies and summarizes the latest findings in this field based on the application of DMSO as a single or two synthons.

[0009] [ka]

[0010] The journal Synthesis 1981; 1981(3): 165-185 discusses selected uses of activated dimethyl sulfoxide reagents in organic synthesis, with emphasis on low-temperature studies. The reaction of dimethyl sulfoxide with acetic anhydride, oxalyl chloride, t-butyl hypochlorite, or halogens (among others) at appropriate temperatures affords intermediate dimethyl sulfonium salts. These salts have been particularly useful in the synthesis of sulfinimines and sulfoximines, as well as in the selective oxidation of structurally diverse alcohols to the corresponding carbonyl compounds.

[0011] [ka]

[0012] It can be referred to that US Patent Application No. 20110059953A1 reports the synthesis of several biologically active compounds using N-(9-ethyl-9H-carbazol-3-yl)-2,2,2-trifluoro-acetamide or the indole derivative 1H-indole-3-carboxamide to treat subjects with lesions or tumors in which p53 has the Y220C mutation. Their invention relates to compounds that can bind to p53 protein molecules.

[0013] [ka]

[0014] In the journal Bioorg. Med. Chem. Lett. 15 (2005) pp. 2734-2737, a new series of novel mast cell tryptase inhibitors was reported, characterized by the use of an indole structure as a hydrophobic substituent on an m-benzylaminepiperidine template. The best members of this series exhibit good in vitro activity and excellent selectivity over other serine proteases. The synthesis and SAR evaluation of a new class of small molecule mast cell tryptase inhibitors were reported. These compounds are an extension of the tryptase program and are highly potent and orally bioavailable inhibitors.

[0015] [ka]

[0016] It can be seen that in patent application No. JP2001261642A, their recent report reports the use of some indole-3-carboxylic acid derivatives as raw materials for pharmaceutical and agrochemical purposes.

[0017] [ka]

[0018] It is to be noted that patent application WO2012 / 114252A1 reports a number of novel indole and pyrrolopyridine amide derivatives and their use as pharmaceuticals. The present invention also relates to related aspects, including methods for preparing the compounds, pharmaceutical compositions containing one or more compounds, and their use, in particular, as orexin receptor antagonists. These compounds are utilized in the prevention or treatment of disorders such as sleep disorders, stress-related syndromes, addiction, cognitive disorders, psychiatric disorders, neurological disorders, eating disorders, or alcohol use disorders.

[0019] [ka]

[0020] Patent application WO2014 / 172759A1 is a noteworthy study of the preparation of various important amide derivatives starting from indole derivatives and using substituted indole-3-carboxylic acids as intermediates. These amide compounds are useful for the positive modulation of alpha 7 nicotinic acetylcholine receptors (α7nAChRs). The present invention also relates to the use of these compounds in the treatment or prevention of a wide range of diseases, including neurodegenerative, neuropsychiatric, and inflammatory diseases, in which positive modulation of α7nAChRs is beneficial.

[0021] [ka]

[0022] In the journal "J. Org. Chem. 2018, 83, pp. 5639-5649," Okada et al. demonstrated that N-phenylindole-3-carboxylic acid undergoes alkenylation at the C-4 position via regioselective C-H bond cleavage when treated with alkenes such as acrylates, acrylamides, and acrylonitrile in the presence of a rhodium(III) catalyst and a silver salt oxidant. The information obtained in this study will be useful for designing new catalytic substitution reactions for important benzo-fused heteroarenes in pharmaceutical and material chemistry.

[0023] [ka]

[0024] In the journal "Org. Lett. 2016, 18, pp. 5496-5499," a novel method for achieving regioselectivity between the C-2 and C-4 positions of the indole skeleton was disclosed by modifying the properties of the ketone directing group. While methyl ketone as the directing group exclusively provided C-2 alkenylation products, trifluoromethyl ketone shifted the selectivity to C-4, demonstrating that the electronic properties of the directing group control the unusual selectivity between five-membered and six-membered metallacycles. Screening of other carbonyl-derived directing groups revealed that strong and weak directing groups exhibited opposite selectivity.

[0025] Several other methods for the synthesis of indole-3-carboxylic acid derivatives have been reported in the academic literature. The synthetic routes mainly fall into four different categories: a) C-H bond activation strategies, b) C-Br bond activation strategies, c) electrophilic substitution strategies, and d) electrocatalytic C-N bond formation strategies.

[0026] [ka]

[0027] Recently, C–H bond activation strategies have become important tools for various synthetic transformations, but they have several limitations, such as the necessity of transition metals, and are in most cases not applicable to large-scale preparations.

[0028] In the journal "J. Org. Chem. 2008, 73, pp. 2476-2479," it is reported that β-(2-iodoanilino) ester derivatives can be converted to indole-3-carboxylic acid ester derivatives via intramolecular α-arylation in the presence of catalytic amounts of Pd(PPh3)4 and potassium phenoxide. The preparation of directing groups from 2-iodoaniline derivatives and methyl acrylate also has other disadvantages, and the use of Pd on an industrial scale is uneconomical. Furthermore, the intramolecular α-arylation of this β-(2-iodoanilino) ester reaction resulted in low yields.

[0029] The Cu-catalyzed C-N bond formation via C-X (X = Br) bond activation using the Ullmann reaction has been a promising approach for the preparation of indole-3-carboxylic acids. Various N-alkylated and N-arylated derivatives of methyl 1H-indole-3-carboxylate have been synthesized using methyl 2-(2-bromophenyl)-2-formylacetate and different primary amines using Cu catalysts. [J. Org. Chem. 2008, 73, pp. 4275-4278] In fact, the preparation of the starting material, methyl 2-(2-bromophenyl)acetate, is a multi-step process, very expensive, and a major problem in industrial preparations. This reaction requires many reagents and solvents, such as methyl formate, primary amines, K3PO4, NaH, MeOH, and DMF. However, they did not investigate simple NH-free indole-3-carboxylates.

[0030] Another promising route for preparing indole-3-carboxylic acid derivatives for large-scale applications is the Friedel-Crafts reaction of indole derivatives. In the journal "J. Org. Chem. 2016, 81, pp. 4226-4234," the Friedel-Crafts reaction, specifically the trifluoroacetylation of indole derivatives using trifluoroacetic acid at 100 °C, is reported to produce indolyl trifluoromethyl ketone derivatives, precursors of indole-3-carboxylic acids. After hydrolysis of these ketone derivatives (refluxing in MeOH in the presence of NaOH), the indole-3-carboxylic acid derivatives are obtained.

[0031] Another method for carrying out the Friedel-Crafts reaction in the presence of a Lewis acid (MeAlCl or EtAlCl) under 3.0 MPa CO pressure was reported in Tetrahedron 72 (2016), pp. 734–745. They obtained very low yields of indole-3-carboxylic acid in the case of NH-free indoles. The main drawbacks of these reactions in large-scale industrial preparations are the need for various indole derivatives, expensive Lewis acids, and high pressures.

[0032] Electrocatalytic C-N bond formation is a significant development in modern synthetic chemistry. Recently, the Karchava group disclosed a new synthetic strategy based on electrocatalytic intramolecular C-N bond formation using 3-amino-2-(2-bromophenyl)acrylate in a t-BuOK / DMF system at 125 °C for the synthesis of N-functionalized indole-3-carboxylates. [Org. Lett. 2018, 20, pp. 7358-7362] Due to the drawbacks of complexity and the high cost of starting materials and high-temperature reactions, industrial preparation is extremely difficult.

[0033] All previous literature reports indicate that the key intermediate indole-3-carboxylic acid derivatives are prepared by expensive multi-step methods. Therefore, there is a dire need in the state of the art for a simple and efficient synthetic method for indole-3-carboxylic acid derivatives. [Prior art documents] [Patent documents]

[0034] [Patent Document 1] U.S. Patent Application No. 20110059953A1 [Patent Document 2] Patent application number JP2001261642A [Patent Document 3] Patent application WO2012 / 114252Al [Patent Document 4] Patent application WO2014 / 172759Al [Non-patent literature]

[0035] [Non-Patent Document 1] Org. Lett. 2018, 20, pp. 4540-4544 [Non-patent document 2] Chem Heterocycl Compd 19, pp. 40-42 (1983) [Non-patent document 3] Synthesis 2016;48(10):1421~1436 pages [Non-patent document 4] Adv. Synth. Catal. 2020, 362, pp. 65-86 [Non-patent document 5] Synthesis 1981;1981(3):pp.165~185 [Non-patent document 6] Bioorg. Med. Chem. Lett. 15(2005) pp. 2734-2737 [Non-Patent Document 7] J. Org. Chem. 2018, 83, pp. 5639-5649 [Non-patent document 8] Org. Lett. 2016, 18, pp. 5496-5499 [Non-Patent Document 9] J. Org. Chem. 2008, 73, pp. 2476-2479 [Non-Patent Document 10] J. Org. Chem. 2008, 73, pp. 4275-4278 [Non-Patent Document 11] J. Org. Chem. 2016, 81, pp. 4226-4234 [Non-Patent Document 12] Tetrahedron 72, (2016), pp. 734-745 [Non-Patent Document 13] Org. Lett. 2018, 20, pp. 7358-7362 Summary of the Invention [Problem to be solved by the invention]

[0036] The main objective of the present invention is to provide a simple, cost-effective, one-pot synthesis of indole-3-carboxylic acid (ICA) derivatives in high yields, utilizing cheaper starting materials.

[0037] Another object of the present invention is to provide a method for the synthesis of indole-3-carboxylic acid (ICA) derivatives, in which the entire reduction step (formation of ICA derivatives) is carried out under mild conditions without the treatment of any external reducing agent.

[0038] Yet another object of the present invention is to provide a synthetic methodology for synthesizing ICA derivatives, which has application for the synthesis of the marketed drug tropisetron.

[0039] Yet another object of the present invention is to provide a synthetic method for synthesizing ICA derivatives in a very short reaction time (approximately 2 hours) under mild reaction conditions.

[0040] Yet another object of the present invention is to provide a commercially viable method for the synthesis of ICA derivatives. The reaction proceeded smoothly under inert conditions at atmospheric pressure. No transition metal catalyst is required for this single-step transformation.

[0041] Yet another object of the present invention is to provide a variety of functional groups that are easily manipulated and well tolerated, and therefore this approach is important for the preparation of several key intermediates of indole-3-carboxylic acid derivatives for the synthesis of commercial drugs. [Means for solving the problem]

[0042] FIG. 1 depicts the direct synthesis of indole-3-carboxylic acid derivatives from isatin derivatives. (wherein R1 and R2 are independently hydrogen, linear or branched (C1-C12), perfluoro(C1-C12)alkyl, (C3-C12)cycloalkyl, (C6-C12)bicycloalkyl, (C3-C14)tricycloalkyl, (C6-C10)aryl, (C6-C10)aryl(C1-C6)alkyl, (C1-C6)alkyl(C6-C10)aryl, (C6-C10)aryl(C1-C3)alkoxy, perfluoro(C6-C10)aryl, perfluoro(C6-C10)aryl selected from the group consisting of (C1-C3)alkyl, (C5-C10)heteroaryl, (C5-C10)heteroaryl(C1-C3)alkyl, hydroxy, (C1-C12)alkoxy, (C3-C12)cycloalkoxy, (C6-C12)bicycloalkoxy, (C7-C14)tricycloalkoxy, (C6-C10)aryloxy(C1-C3)alkyl, (C6-C10)aryloxy, (C5-C10)heteroaryloxy, (C1-C6)acyloxy, halogen, nitro, and amino; R3 is selected from the group consisting of hydrogen, deuterium, and straight or branched chain (C1-C12); C is carbon or 13 (labeled carbon) [Brief explanation of the drawings]

[0043] [Figure 1] 1 depicts the direct synthesis of indole-3-carboxylic acid derivatives from isatin derivatives. Accordingly, the present invention provides a method for the synthesis of indole-3-carboxylic acid (ICA) compounds of formula 2.

[0044] [ka]

[0045] (In the formula, R1 and R2 are independently selected from the group consisting of hydrogen, linear or branched (C1-C12), perfluoro(C1-C12) alkyl, (C3-C12) cycloalkyl, (C6-C12) bicycloalkyl, (C3-C14) tricycloalkyl, (C6-C10) aryl, (C6-C10) aryl(C1-C6) alkyl, (C1-C6) alkyl(C6-C10) aryl, (C6-C10) aryl(C1-C3) alkoxy, perfluoro(C6-C10) aryl, perfluoro(C6-C10) aryl(C (C1-C3)alkyl, (C5-C10)heteroaryl, (C5-C10)heteroaryl(C1-C3)alkyl, hydroxy, (C1-C12)alkoxy, (C3-C12)cycloalkoxy, (C6-C12)bicycloalkoxy, (C7-C14)tricycloalkoxy, (C6-C10)aryloxy(C1-C3)alkyl, (C6-C10)aryloxy, (C5-C10)heteroaryloxy, (C1-C6)acyloxy, halogen, nitro, and amino; R3 is selected from the group consisting of hydrogen, deuterium, and straight or branched chain (C1-C12); C is carbon or 13 (labeled carbon) The method comprises: i. degassing the isatin derivative of Formula 1 and the solvent of Formula 3 in a two-necked round-bottom flask equipped with a magnetic stirrer by freeze-pump-thaw method to obtain a degassed mixture;

[0046] [ka]

[0047] (In the formula, R 1、 R2 and R3 are the same as above) ii. adding sodium hydride [NaH] to the degassed mixture obtained in step (i) at room temperature ranging from 25 to 35°C for a period ranging from 5 to 10 minutes, followed by gradually warming the mixture to 70 to 100°C while maintaining it at 1 atmosphere for a period ranging from 1 to 24 hours to obtain a solution; iii. cooling the solution obtained in step (ii) at room temperature in the range of 25-35°C, followed by quenching with cold 1N HCl solution; iv. Extracting the organic portion with EtOAc containing brine, drying over Na2SO4, concentrating under reduced pressure and purifying by silica gel column chromatography using petroleum ether / ethyl acetate (4:1) as eluent to obtain the compound of formula 1; Includes.

[0048] In one embodiment of the present invention, the yield of the compound of formula 2 is in the range of 50-83%.

[0049] In another embodiment, the present invention provides a compound of formula A:

[0050] [ka]

[0051] wherein X=H or cyclohexyl; Y=

[0052] [ka]

[0053] and R1 and R2 are independently selected from the group consisting of hydrogen, linear or branched (C1-C12), perfluoro(C1-C12) alkyl, (C3-C12) cycloalkyl, (C6-C12) bicycloalkyl, (C3-C14) tricycloalkyl, (C6-C10) aryl, (C6-C10) aryl(C1-C6) alkyl, (C1-C6) alkyl(C6-C10) aryl, (C6-C10) aryl(C1-C3) alkoxy, perfluoro(C6-C10) aryl, perfluoro(C6-C10) aryl(C (C1-C3)alkyl, (C5-C10)heteroaryl, (C5-C10)heteroaryl(C1-C3)alkyl, hydroxy, (C1-C12)alkoxy, (C3-C12)cycloalkoxy, (C6-C12)bicycloalkoxy, (C7-C14)tricycloalkoxy, (C6-C10)aryloxy(C1-C3)alkyl, (C6-C10)aryloxy, (C5-C10)heteroaryloxy, (C1-C6)acyloxy, halogen, nitro, and amino; R3 is selected from the group consisting of hydrogen, deuterium, and straight or branched chain (C1-C12); C is carbon or 13 (labeled carbon)

[0054] In yet another aspect of the invention, the compound of formula A is selected from the group consisting of:

[0055] [ka]

[0056] In yet another aspect of the present invention, compounds of formula 2 are used to prepare the marketed drug tropisetron (4) and potential bioactive indole compounds of formula A disclosed herein.

[0057] In yet another embodiment of the present invention, the method is used to prepare a C13 labeled ICA compound of formula 2aa.

[0058] In yet another embodiment of the present invention, the above method is used to prepare deuterated ICA compounds of formulas 2ab-2af.

[0059] In yet another aspect of the present invention, the approach in the production of several key intermediate indole-3-carboxylic acid derivatives is important because the synthetic methods for ICA derivatives are tolerant enough to explore a range of functional groups in the substrates.

[0060] In yet another embodiment of the present invention, NaH is used as a reagent under mild reaction conditions. DETAILED DESCRIPTION OF THE INVENTION

[0061] For convenience, before further describing the present disclosure, certain terms and examples used herein will now be explained. These definitions should be read in light of the remainder of the disclosure and understood by those of ordinary skill in the art. While the terms used herein have meanings that are recognized and known to those of ordinary skill in the art, for convenience and completeness, certain terms and their meanings are set forth below. The present invention will now be described in detail in connection with certain preferred and optional embodiments so that its various aspects may be more fully understood and appreciated.

[0062] The articles "a," "an," and "the" are used to refer to one or to more than one (ie, to at least one) of the grammatical article.

[0063] The terms "comprise" and "comprising" are used in an inclusive and open sense, meaning that additional elements may be included. It is not intended to be interpreted as "consists of only."

[0064] The terms "comprise" and "comprising" are used in an inclusive and open sense, meaning that additional elements may be included. They are not intended to be interpreted as "consists of only." Throughout this specification, unless the context requires otherwise, the word "comprise" and variations such as "comprises" and "comprising" shall be understood to mean the inclusion of a stated element, step, or group of elements or steps, but not the exclusion of all other elements, steps, or groups of elements or steps.

[0065] Ratios, concentrations, amounts, and other numerical data may be expressed herein in a range format, with the understanding that such range format is used merely for convenience and brevity and should be interpreted flexibly to include not only the numerical values ​​explicitly recited as the limits of the range, but also all individual numerical values ​​or subranges, as if each numerical value and subrange were expressly written.

[0066] This disclosure provides synthetic methods for preparing important starting materials, indole-3-carboxylic acid (ICA) derivatives, which are widely used as building blocks in numerous natural products and are used in the production of several artificial drugs, such as tropisetron and dolasetron, and their derivatives are widely used as (a) anticancer drugs (CPI-1205), (b) serotonin 5-HT4 and 5-HT6 antagonists, (c) EphB3 receptor tyrosine kinase inhibitors, and (d) potential treatments for Alzheimer's disease.

[0067] The present invention provides a simple, one-pot method for preparing indole-3-carboxylic acid derivatives from isatin derivatives. This conversion utilizes mild sodium hydride, resulting in a lower price per kilogram compared to other reducing agents. Furthermore, isatin is a cheaper starting material than indole / other functional directing groups used in reported literature. The present invention discloses a method for obtaining indole-3-carboxylic acid derivatives without the use of any reducing agent or transition metal, making it a one-pot, economically feasible, operationally simple, and fast method suitable for industrial production. Therefore, the present invention provides a new method for preparing indole-3-carboxylic acid derivatives.

[0068] An efficient, safe, operationally simple, and cost-effective method for preparing several ICA derivatives has been introduced in a very straightforward manner. The rapid synthesis of several key starting materials for ICA derivatives using readily available starting materials, reagents, and solvents demonstrates the excellent functional group tolerance of this novel method. A unique feature of this simple approach is the production of various novel ICA derivatives (overall reduction products) in one pot under economically feasible and operationally simple conditions, independent of treatment with any reducing agent or transition metal. This is the first report of ICA derivatives being produced in a single step from isatin derivatives. Therefore, the study of this method is important for a wide range of applications in drug development and material synthesis.

[0069] Existing synthetic methods for preparing ICA derivatives have several problems, such as the need for expensive transition metal catalysts, the preparation of designed directing groups, and multi-step operations. In fact, there is no direct route to synthesize this important intermediate that can be produced smoothly and in a short time from readily available starting materials, which can be solved by the present invention. In the present invention, only one step is involved to prepare the product from an isatin derivative.

[0070] The present invention was extended to synthesize the marketed drug tropisetron using indole-3-carboxylic acid as the key starting material.

[0071] The reaction was carried out using N-protected isatin or its derivatives to prepare the building block key intermediate indole-3-carboxylic acid (ICA) derivatives.

[0072] In this invention, several ICA derivatives can be prepared by the following procedure, in which DMSO is used as the solvent and reactant, and NaH is used as the base. Before adding NaH, the reaction mixture was degassed by freeze-degassing. After degassing, NaH was added portionwise through a solid addition funnel and stirred at room temperature (30 °C) for 10 min. The reaction mixture was then gradually warmed to 80 °C and maintained for 2 h. After complete conversion was monitored by TLC, the mixture was cooled to room temperature (30 °C) and quenched with cold 1N HCl solution. The organic portion was extracted with EtOAc containing brine, dried over Na2SO4, and concentrated under reduced pressure. Finally, purification by silica gel column chromatography (230-400 mesh) using petroleum ether / ethyl acetate (4:1) as the eluent afforded the desired 1-ethyl-1H-indole-3-carboxylic acid (2a) in 82% yield. To avoid column purification, recrystallization was performed by dissolving the crude reaction mixture in warm ethanol, but the same yield was obtained.

[0073] In the present invention, no reducing agent, Lewis acid, or transition metal catalyst was used, and various ICA derivatives could be formed under milder conditions (NaH in DMSO at 80° C.).

[0074] The reaction was fast (approximately 2 h), simple, tolerated a variety of functional groups, and performed smoothly under optimal atmospheric conditions.

[0075] This one-pot, easy-to-operate method works well with bottle-grade DMSO (which should not contain dissolved oxygen) and for large-scale operation, making it economically viable.

[0076] While the subject matter has been described with reference to particular embodiments, this description is not meant to be construed in a limiting sense. Various modifications of the disclosed embodiments, as well as alternative embodiments of the subject matter, will be apparent to those skilled in the art upon reference to the description of the subject matter. Accordingly, it is contemplated that such modifications may be made without departing from the spirit or scope of the subject matter as defined.

[0077] General procedure for the preparation of 1-ethyl-1H-indole-3-carboxylic acid (2a)

[0078] [ka]

[0079] Milligram-scale reactions N-ethyl isatin (1 equiv., 0.2 mmol, 35 mg) and DMSO solvent (2 mL, 0.1 M) were transferred to a 10 mL two-neck round-bottom flask equipped with a magnetic stirrer under an inert atmosphere. The entire reaction mixture was then degassed by freeze-degassing. After degassing, NaH (sodium hydride) (6 equiv., 1.2 mmol) was added portionwise through a solid addition funnel and stirred at room temperature (25–35 °C) for 10 min. The reaction mixture was then gradually warmed to 80 °C and maintained for 2 h. Complete conversion was monitored by TLC, after which it was cooled to room temperature and quenched with cold 1 N HCl solution (20 mL). The organic portion was extracted with EtOAc (3 × 20 mL) containing brine, dried over NaSO, and concentrated under reduced pressure. Finally, purification by silica gel column chromatography (230-400 mesh) using petroleum ether / ethyl acetate (4:1) as the eluent afforded the desired 1-ethyl-1H-indole-3-carboxylic acid (2a) in 82% yield (31 mg). To avoid column purification, a recrystallization technique was performed by dissolving the crude reaction mixture in warm ethanol, and the same yield was obtained.

[0080] Gram-scale reactions N-ethyl isatin (1 eq, 5.7 mmol, 1 g) and DMSO solvent (57 mL, 0.1 M) were transferred to a 100 mL two-neck round-bottom flask equipped with a magnetic stirrer under an inert atmosphere. The entire reaction mixture was then degassed by freeze-degassing. After degassing, NaH (6 eq, 34.2 mmol) was added portionwise through a solid addition funnel and stirred at room temperature (30 °C) for 10 min. The reaction mixture was then gradually warmed to 80 °C and maintained for 2 h. Complete conversion was monitored by TLC, followed by cooling to room temperature and quenching with cold 1 N HCl solution (200 mL). The organic portion was extracted with EtOAc (3 × 100 mL) containing brine, dried over NaSO, and concentrated under reduced pressure. Finally, purification by silica gel column chromatography (230-400 mesh) using petroleum ether / ethyl acetate (4:1) as the eluent afforded the desired 1-ethyl-1H-indole-3-carboxylic acid (2a) in 75% yield (808 mg). To avoid column purification, a recrystallization technique was performed by dissolving the crude reaction mixture in warm ethanol, and the same yield was obtained.

[0081] The synthesis of 2b–2af followed the procedure described above. In the case of 1za, 1zb, and 1zc, deprotection occurred during the reaction to give indole-3-carboxylic acid 2z.

[0082] [Table 1A]

[0083] [Table 1B]

[0084] [Table 1C] [Example]

[0085] The present disclosure will now be described using examples, which are intended to illustrate the operation of the present disclosure and are not intended to imply any limitation on the scope of the disclosure. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. Although methods and materials similar or equivalent to those described herein can be used to practice the disclosed methods and compositions, exemplary methods, devices, and materials are described herein. It should be understood that the present disclosure is not limited to the specific methods and experimental conditions described, as such methods and conditions may be applied.

[0086] The following examples are offered for illustrative purposes and should not be construed as limiting the scope of the invention in any way.

[0087] Example 1 Preparation of some N-substituted indole-3-carboxylic acids (compounds represented by formulae 2b-e) Substituted indoline-2,3-dione (1 equiv., 0.2 mmol) and DMSO solvent (2 mL, 0.1 M) were transferred to a 10 mL two-neck round-bottom flask equipped with a magnetic stirrer under an inert atmosphere. The entire reaction mixture was then degassed by freeze-degassing. After degassing, NaH (6 equiv., 1.2 mmol) was added portionwise through an addition funnel and stirred at room temperature (30 °C) for 10 min. The reaction mixture was then gradually warmed to 80 °C and maintained for 2 h. Complete conversion was monitored by TLC, after which it was cooled to room temperature (30 °C) and quenched with cold 1 N HCl solution (20 mL). The organic portion was extracted with EtOAc (3 × 20 mL) containing brine, dried over Na2SO4, and concentrated under reduced pressure. Finally, purification by silica gel column chromatography (230–400 mesh) using petroleum ether / ethyl acetate (4:1) as the eluent afforded the desired indole-3-carboxylic acid derivatives (2b–e) in 55–65% yields.

[0088] Example 2 Preparation of 1-ethyl-indole-3-carboxylic acid derivatives (compounds represented by formulas 2f-k) The 1-ethylindoline-2,3-dione derivative (1 equiv., 0.2 mmol) and DMSO solvent (2 mL, 0.1 M) were transferred to a 10 mL two-neck round-bottom flask equipped with a magnetic stirrer under an inert atmosphere. The entire reaction mixture was then degassed by freeze-degassing. After degassing, NaH (6 equiv., 1.2 mmol) was added portionwise through an addition funnel and stirred at room temperature (26 °C) for 10 min. The reaction mixture was then gradually warmed to 80 °C and maintained for 2 h. Complete conversion was monitored by TLC, after which it was cooled to room temperature (26 °C) and quenched with cold 1 N HCl solution (20 mL). The organic portion was extracted with EtOAc (3 × 20 mL) containing brine, dried over Na2SO4, and concentrated under reduced pressure. Finally, purification by silica gel column chromatography (230–400 mesh) using petroleum ether / ethyl acetate (4:1) as the eluent afforded the desired 1-ethylindole-3-carboxylic acid derivatives (2f–k) in 53–83% yields.

[0089] Example 3 Preparation of 1-methylindole-3-carboxylic acid (compounds represented by formulas 2l-p) The 1-methylindoline-2,3-dione derivative (1 equiv., 0.2 mmol) and DMSO solvent (2 mL, 0.1 M) were transferred to a 10 mL two-neck round-bottom flask equipped with a magnetic stirrer under an inert atmosphere. The entire reaction mixture was then degassed by freeze-degassing. After degassing, NaH (6 equiv., 1.2 mmol) was added portionwise through an addition funnel and stirred at room temperature (30 °C) for 10 min. The reaction mixture was then gradually warmed to 80 °C and maintained for 2 h. Complete conversion was monitored by TLC, after which it was cooled to room temperature (30 °C) and quenched with cold 1 N HCl solution (20 mL). The organic portion was extracted with EtOAc (3 × 20 mL) containing brine, dried over Na2SO4, and concentrated under reduced pressure. Finally, purification by silica gel column chromatography (230-400 mesh) using petroleum ether / ethyl acetate (4:1) as the eluent afforded the desired 1-methylindole-3-carboxylic acid derivatives (2l-p) in 38-64% yields.

[0090] Example 4 Preparation of N-arylindole-3-carboxylic acids (compounds represented by formulas 2q-w) 1-Arylindoline-2,3-diones (1 equiv., 0.2 mmol) and DMSO solvent (2 mL, 0.1 M) were transferred to a 10 mL two-neck round-bottom flask equipped with a magnetic stirrer under an inert atmosphere. The entire reaction mixture was then degassed by freeze-degassing. After degassing, NaH (6 equiv., 1.2 mmol) was added portionwise through an addition funnel and stirred at room temperature (28 °C) for 10 min. The reaction mixture was then gradually warmed to 80 °C and maintained for 2 h. Complete conversion was monitored by TLC, after which it was cooled to room temperature (28 °C) and quenched with cold 1 N HCl solution (20 mL). The organic portion was extracted with EtOAc (3 × 20 mL) containing brine, dried over Na2SO4, and concentrated under reduced pressure. Finally, purification by silica gel column chromatography (230–400 mesh) using petroleum ether / ethyl acetate (4:1) as the eluent afforded the desired 1-ethyl-5-fluoro-1H-indole-3-carboxylic acids (2q–w) in 37–80% yields.

[0091] Example 5 Preparation of 1-aryl-1H-indole-3-carboxylic acid derivatives (compounds represented by formulas 2x to 2y) The 1-arylindoline-2,3-dione derivative (1 equiv., 0.2 mmol) and DMSO solvent (2 mL, 0.1 M) were transferred to a 10 mL two-neck round-bottom flask equipped with a magnetic stirrer under an inert atmosphere. The entire reaction mixture was then degassed by freeze-degassing. After degassing, NaH (6 equiv., 1.2 mmol) was added portionwise through an addition funnel and stirred at room temperature (30 °C) for 10 min. The reaction mixture was then gradually warmed to 80 °C and maintained for 2 h. Complete conversion was monitored by TLC, after which it was cooled to room temperature (30 °C) and quenched with cold 1 N HCl solution (20 mL). The organic portion was extracted with EtOAc (3 × 20 mL) containing brine, dried over Na2SO4, and concentrated under reduced pressure. Finally, purification by silica gel column chromatography (230–400 mesh) using petroleum ether / ethyl acetate (4:1) as the eluent afforded the desired 1-aryl-1H-indole-3-carboxylic acid derivatives (2x–2y) in 66–80% yields.

[0092] Example 6 Preparation of 1H-indole-3-carboxylic acid (compound represented by formula 2z) The corresponding N-substituted indoline-2,3-dione (1 equiv., 0.2 mmol) and DMSO solvent (2 mL, 0.1 M) were transferred to a 10 mL two-neck round-bottom flask equipped with a magnetic stirrer under an inert atmosphere. The entire reaction mixture was then degassed by freeze-degassing. After degassing, NaH (6 equiv., 1.2 mmol) was added portionwise through an addition funnel and stirred at room temperature (28 °C) for 10 min. The reaction mixture was then gradually warmed to 80 °C and maintained for 2 h. Complete conversion was monitored by TLC, after which it was cooled to room temperature (28 °C) and quenched with cold 1 N HCl solution (20 mL). The organic portion was extracted with EtOAc (3 × 20 mL) containing brine, dried over Na2SO4, and concentrated under reduced pressure. Finally, purification by silica gel column chromatography (230-400 mesh) using petroleum ether / ethyl acetate (4:1) as the eluent afforded the desired 1H-indole-3-carboxylic acids (2z) in 40-47% yields.

[0093] Example 7 1-Ethyl(13 C-C2) Preparation of 1H-indole-3-carboxylic acid (compound represented by formula 2aa) In a 10 mL two-necked round-bottom flask equipped with a magnetic stirrer, 1-ethylindoline-2,3-dione (1 equiv., 0.2 mmol) and DMSO solvent (1 mL) were added under an inert atmosphere. 13 C DMSO solvent (0.1 mL) was transferred. The entire reaction mixture was then degassed by freeze-degassing. After degassing, NaH (6 equiv., 1.2 mmol) was added portionwise through an addition funnel and stirred at room temperature (27 °C) for 10 min. The reaction mixture was then gradually warmed to 80 °C and maintained for 2 h. After complete conversion was monitored by TLC, it was cooled to room temperature (27 °C) and quenched with cold 1 N HCl solution (20 mL). The organic portion was extracted with EtOAc (3 × 20 mL) containing brine, dried over Na2SO4, and concentrated under reduced pressure. Finally, purification by silica gel column chromatography (230-400 mesh) using petroleum ether / ethyl acetate (4:1) as the eluent afforded the desired 1-ethyl ( 13 C-C2) 1H-indole-3-carboxylic acid (2aa) was obtained.

[0094] Example 8 Preparation of some N-substituted (C2-deuterated) 1H-indole-3-carboxylic acid derivatives (compounds represented by formulae 2ab-ad) Substituted indoline-2,3-dione (1 equiv., 0.2 mmol) and DMSO-d6 solvent (1 mL, 0.2 M) were transferred to a 10 mL two-neck round-bottom flask equipped with a magnetic stirrer under an inert atmosphere. The entire reaction mixture was then degassed by freeze-degassing. After degassing, NaH (6 equiv., 1.2 mmol) was added portionwise through an addition funnel and stirred at room temperature (30 °C) for 10 min. The reaction mixture was then gradually warmed to 80 °C and maintained for 2 h. Complete conversion was monitored by TLC, after which it was cooled to room temperature (30 °C) and quenched with cold 1 N HCl solution (20 mL). The organic portion was extracted with EtOAc (3 × 20 mL) containing brine, dried over Na2SO4, and concentrated under reduced pressure. Finally, purification by silica gel column chromatography (230–400 mesh) using petroleum ether / ethyl acetate (4:1) as the eluent afforded the desired N-substituted (C2-deuterated) 1H-indole-3-carboxylic acid derivatives (2ab–ad) in 54–80% yields.

[0095] Example 9 Preparation of 1-ethyl(C2-deuterated)-indole-3-carboxylic acid derivatives (compounds represented by formula 2ae) 1-Ethyl-5-methylindoline-2,3-dione (1 equiv., 0.2 mmol) and DMSO-d6 solvent (2 mL, 0.1 M) were transferred to a 10 mL two-neck round-bottom flask equipped with a magnetic stirrer under an inert atmosphere. The entire reaction mixture was then degassed by freeze-degassing. After degassing, NaH (6 equiv., 1.2 mmol) was added portionwise through an addition funnel and stirred at room temperature (30 °C) for 10 min. The reaction mixture was then gradually warmed to 80 °C and maintained for 2 h. Complete conversion was monitored by TLC, after which it was cooled to room temperature (30 °C) and quenched with cold 1 N HCl solution (20 mL). The organic portion was extracted with EtOAc (3 × 20 mL) containing brine, dried over Na2SO4, and concentrated under reduced pressure. Finally, purification by silica gel column chromatography (230–400 mesh) using petroleum ether / ethyl acetate (4:1) as the eluent afforded the desired 1-ethyl (C2-deuterated) 1H-indole-3-carboxylic acid derivative (2ae) in 65% yield.

[0096] Example 10 Preparation of 1-(4-(tert-butyl)phenyl)(C2-deuterated)-indole-3-carboxylic acid derivatives (compounds represented by formula 2af) 1-(4-(tert-butyl)phenyl)indoline-2,3-dione (1 equiv., 0.2 mmol) and DMSO-d6 solvent (2 mL, 0.1 M) were transferred to a 10 mL two-neck round-bottom flask equipped with a magnetic stirrer under an inert atmosphere. The entire reaction mixture was then degassed by the freeze-pump-thaw method. After degassing, NaH (6 equiv., 1.2 mmol) was added portionwise through an addition funnel and stirred at room temperature (30 °C) for 10 min. The reaction mixture was then gradually warmed to 80 °C and maintained for 2 h. Complete conversion was monitored by TLC, followed by cooling to room temperature (30 °C) and quenching with cold 1 N HCl solution (20 mL). The organic portion was extracted with EtOAc (3 × 20 mL) containing brine, dried over Na2SO4, and concentrated under reduced pressure. Finally, purification by silica gel column chromatography (230–400 mesh) using petroleum ether / ethyl acetate (4:1) as the eluent afforded the desired 1-(4-(tert-butyl)phenyl)(C2-deuterated) 1H-indole-3-carboxylic acid derivative (2af) in 57% yield.

[0097] Example 11 Preparation of 5-HT3 receptor antagonist tropisetron (4)

[0098] [ka]

[0099] A clean, oven-dried 25 mL two-neck round-bottom flask containing a magnetic stir bar was charged with 500 mg (3.1 mmol, 1 equiv.) of indole-3-carboxylic acid (2z) under a N2 atmosphere. 4 mL of DCM and 0.2 mL (0.4 equiv.) of trifluoroacetic acid (TFA) were added at room temperature (33 °C). After stirring for 5 min, 1 mL of (CF3CO)2O (7.2 mmol, 2.3 equiv.) was added dropwise to the reaction mixture at 0 °C. The mixture was then warmed to room temperature and stirred for 2 h to activate the acidic group. The mixture was then transferred to -5 °C, and 4 mL of tropine solution (3) (450 mg, 1 equiv.) (prepared in 4 mL of DCM under inert conditions) was added dropwise over 30 min and maintained for 4 h. After confirming complete conversion by TLC, the entire reaction mixture was quenched with 100 mL of ice-cold 1 N NaOH solution and subsequently worked up with EtOAc and brine. The organic layer was then passed through NaSO, allowed to stand, concentrated on a rotary evaporator, and then dissolved in EtOAc for crystallization to give 710 mg (81%) of the desired tropisetron (4).

[0100] Example 12 Preparation of the imide N-cyclohexyl-N-(cyclohexylcarbamoyl)-1-ethyl-1H-indole-3-carboxamide (5)

[0101] [ka]

[0102] N-Ethylindole-3-carboxylic acid (2a) (1 equiv, 0.3 mmol, 57 mg) and DMF solvent (4 mL, 0.075 M) were transferred to a 10 mL two-neck round-bottom flask equipped with a magnetic stirrer under an inert atmosphere. The entire reaction mixture was cooled to 0 °C using crushed ice. DCC (3.0 equiv), DMAP (0.1 equiv), and HO (1.5 equiv) were then slowly added to the reaction mixture. The mixture was then warmed to room temperature (33 °C) and stirred for 36 h. Complete conversion was monitored by TLC, followed by quenching with HO. The organic portion was extracted with EtOAc (3 × 20 mL) containing brine, dried over NaSO, and concentrated under reduced pressure. Finally, the product was purified by silica gel column chromatography (230–400 mesh) using petroleum ether / ethyl acetate (4:1) as the eluent to give the desired imide compound 5 in 68% yield (81 mg).

[0103] Example 13 Preparation of the glucokinase activator amide 1-ethyl-N-(thiazol-2-yl)-1H-indole-3-carboxamide (7)

[0104] [ka]

[0105] N-Ethylindole-3-carboxylic acid (2a) (1 equiv., 0.4 mmol, 76 mg) and DCM (4 mL, 0.1 M) were transferred to a 10 mL two-necked round-bottom flask equipped with a magnetic stirrer under an inert atmosphere, followed by thiazol-2-amine (6) (1.1 equiv., 44 mg). The entire reaction mixture was cooled to 0 °C using crushed ice. EDC.HCl (2.5 equiv.) and DMAP (2 equiv.) were then slowly added to the reaction mixture. The mixture was then warmed to room temperature (33 °C) and stirred for 12 h. Complete conversion was monitored by TLC, followed by quenching with aqueous NaHCO3. The organic portion was extracted with EtOAc (3 × 20 mL) containing brine, dried over Na2SO4, and concentrated under reduced pressure. Finally, purification by silica gel column chromatography (230-400 mesh) using petroleum ether / ethyl acetate (2.3:1) as the eluent afforded the desired amide compound 7 in 77% yield (83 mg).

[0106] Example 14 Preparation of the directing group amide 1-ethyl-N-(quinolin-8-yl)-1H-indole-3-carboxamide (9)

[0107] [ka]

[0108] N-Ethylindole-3-carboxylic acid (2a) (1 equiv., 0.4 mmol, 76 mg) and DCM (4 mL, 0.1 M) were transferred to a 10 mL two-necked round-bottom flask equipped with a magnetic stirrer under an inert atmosphere, followed by 8-aminoquinoline (8) (1.1 equiv., 64 mg). The entire reaction mixture was cooled to 0 °C using crushed ice. EDC.HCl (2.5 equiv.) and DMAP (2 equiv.) were then slowly added to the reaction mixture. The mixture was then warmed to room temperature (33 °C) and stirred for 12 h. Complete conversion was monitored by TLC, followed by quenching with aqueous NaHCO3. The organic portion was extracted with EtOAc (3 × 20 mL) containing brine, dried over Na2SO4, and concentrated under reduced pressure. Finally, purification by silica gel column chromatography (230-400 mesh) using petroleum ether / ethyl acetate (2.3:1) as the eluent afforded the desired amide compound 9 in 72% yield (91 mg).

[0109] Advantages of the invention The main advantages of the present invention are:

[0110] The present invention provides a simple, feasible, straightforward, economically viable and operationally simple one-pot method.

[0111] This synthesis method has relatively simple procedures, mild reaction conditions, high yields (up to 83%), and a concise method with moderate to good yields.

[0112] The method is less time consuming than existing methods.

[0113] Isatin has been used as a cheaper starting material than indoles / other engineered starting materials.

[0114] No reducing agents, transition metals, Lewis acids or expensive reagents are used.

[0115] The subsequent isolation method for the product is very simple and lends itself to both small-scale laboratory preparations and large-scale industrial production.

[0116] Subsequent product isolation in this method uses work-up (using EtOAc and brine) and crystallization methods, avoiding existing methods that use hazardous chemicals in some steps and give moderate to low yields. Therefore, this method is safer and has better yields than existing methods.

[0117] This method has been used to prepare marketed drugs such as tropisetron in high yield, and several other drugs, such as dolasetron, can be produced at low cost, in high yield, and are suitable for industrial production.

[0118] Bottle-grade solvent (DMSO) works very well in the absence of dissolved oxygen, making this method useful for large-scale synthesis. At low temperatures (60-70 °C), this conversion occurs and gives the desired product at slightly less than optimal conditions.

[0119] The technical problem to be solved by the present invention is to overcome the drawbacks of existing synthetic methods for preparing key starting materials, such as the use of high temperatures and large amounts of solvents, complex multi-step operations, high-cost chemicals, and other drawbacks that make industrialization difficult. Therefore, the present method is more cost-effective than existing methods.

[0120] The reported yield of the patented procedure is not explicitly mentioned. In this invention, various key starting materials were produced in one step, indicating that the invented method is feasible for several functional groups. No expensive reagents, reactants, or solvents are used in this novel transformation. It is surprising that bottle-grade DMSO (which should be free of dissolved oxygen) works so well in this transformation. The transformation occurs at atmospheric pressure, making the operation simple, economically viable, and effective for industrial preparation.

[0121] There is an urgent need for better, environmentally friendly, and industrially feasible methods. The established method of the present invention provides a simple, one-step strategy for synthesizing several ICA derivatives from the readily available starting material isatin using NaH and DMSO or DMSO-d6 complex in high yields, simple reaction procedures, and mild reaction conditions. These derivatives are widely used as artificial drugs. To improve the efficiency and practicality of this reaction, the present invention provides a new, simple, and feasible method that is low-cost, high-yield, and suitable for industrial production.

[0122] The unique feature of this reaction is the use of a solvent (DMSO (dimethyl sulfoxide) / DMSO-d6) as a reactant and the formation of ICA derivatives in good to excellent yields without the use of any reducing agents or transition metals.

Claims

1. 1. A method for synthesizing an indole-3-carboxylic acid (ICA) compound of formula 2, comprising: 【Chemistry 1】 (In the formula, R 1 and R 2 are independently hydrogen, straight-chain or branched (C1-C12), perfluoro(C1-C12)alkyl, (C3-C12)cycloalkyl, (C6-C12)bicycloalkyl, (C3-C14)tricycloalkyl, (C6-C10)aryl, (C6-C10)aryl(C1-C6)alkyl, (C1-C6)alkyl(C6-C10)aryl, (C6-C10)aryl(C1-C3)alkoxy, perfluoro(C6-C10)aryl, perfluoro(C6-C10)aryl(C1-C 3) selected from the group consisting of alkyl, (C5-C10)heteroaryl, (C5-C10)heteroaryl(C1-C3)alkyl, hydroxy, (C1-C12)alkoxy, (C3-C12)cycloalkoxy, (C6-C12)bicycloalkoxy, (C7-C14)tricycloalkoxy, (C6-C10)aryloxy(C1-C3)alkyl, (C6-C10)aryloxy, (C5-C10)heteroaryloxy, (C1-C6)acyloxy, halogen, nitro, and amino; R 3 is selected from the group consisting of hydrogen, deuterium, and straight or branched chain (C1-C12); C is carbon or 13 (labeled carbon) i. degassing the isatin derivative of formula 1 and the solvent of formula 3 in a two-necked round-bottom flask equipped with a magnetic stirrer by freeze-degassing to obtain a degassed mixture; 【Chemistry 2】 (In the formula, R 1、 R 2 , and R 3 is the same as above) ii. adding sodium hydride [NaH] to the degassed mixture obtained in step (i) at room temperature ranging from 25 to 35°C for a period ranging from 5 to 10 minutes, followed by gradually warming the mixture to 70 to 100°C while maintaining a pressure of 1 atmosphere for a period ranging from 1 to 24 hours to obtain a solution; iii. cooling the solution obtained in step (ii) at room temperature in the range of 25-35°C, followed by quenching with cold 1N HCl solution; iv. Extract the organic portion with EtOAc containing brine and add Na 2 SO 4 and drying the mixture, concentrating it under reduced pressure, and purifying it by silica gel column chromatography using petroleum ether / ethyl acetate (4:1) as the eluent to obtain the compound of formula 1. A method comprising:

2. 10. The method of claim 1, wherein the yield of the compound of formula 2 is in the range of 50 to 83%.

3. A method for preparing the marketed drug tropisetron (4) and potential bioactive indole compounds of formula A below, comprising the method of claim 1. 【Transformation 3】 (In the formula, X=H or cyclohexyl; Y= 【Chemistry 4】 and R 1 and R 2 are independently hydrogen, straight-chain or branched (C1-C12), perfluoro(C1-C12)alkyl, (C3-C12)cycloalkyl, (C6-C12)bicycloalkyl, (C3-C14)tricycloalkyl, (C6-C10)aryl, (C6-C10)aryl(C1-C6)alkyl, (C1-C6)alkyl(C6-C10)aryl, (C6-C10)aryl(C1-C3)alkoxy, perfluoro(C6-C10)aryl, perfluoro(C6-C10)aryl(C1-C 3) selected from the group consisting of alkyl, (C5-C10)heteroaryl, (C5-C10)heteroaryl(C1-C3)alkyl, hydroxy, (C1-C12)alkoxy, (C3-C12)cycloalkoxy, (C6-C12)bicycloalkoxy, (C7-C14)tricycloalkoxy, (C6-C10)aryloxy(C1-C3)alkyl, (C6-C10)aryloxy, (C5-C10)heteroaryloxy, (C1-C6)acyloxy, halogen, nitro, and amino; R 3 is selected from the group consisting of hydrogen, deuterium, and straight or branched chain (C1-C12); C is carbon or 13 (labeled carbon) 4. The compound of formula A, 【Transformation 5】 4. The method of claim 3, selected from the group consisting of:

5. Using the above method, a C13-labeled ICA compound of formula 2aa below was prepared. 【Transformation 6】 The method of claim 1, wherein

6. Using the above method, deuterated ICA compounds of formulas 2ab to 2af below can be prepared. 【Transformation 7】 The method of claim 1, wherein

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