A process for the synthesis of 5-halo-substituted indole-2-carboxylic acids or 5-halo-substituted indole-2-carboxylic acid esters

Abstract

The application discloses a synthesis method of 5-halo-substituted indole-2-carboxylic acid or 5-halo-substituted indole-2-carboxylic acid ester, which is prepared from substituted indole-2-carboxylic acid and substituted indole-2-carboxylic acid ester, reacts with N-halogenated succinimide, selectively halogenates 3 and 5 positions on the indole ring, and then is reduced to selectively remove halogen on the 3 position, so as to obtain 5-halo-substituted indole-2-carboxylic acid or 5-halo-substituted indole-2-carboxylic acid ester. The product has a purity greater than 99.5%, and a total yield greater than 95%. The synthesis method has the advantages of high synthesis yield, simple operation, high quality of the prepared 5-halo-substituted indole-2-carboxylic acid and 5-halo-substituted indole-2-carboxylic acid ester, and relatively low cost.

Description

Technical Field

[0001] This invention relates to the field of organic synthesis technology, and specifically to a method for synthesizing 5-halo-substituted indole-2-carboxylic acid or 5-halo-substituted indole-2-carboxylic acid esters. Background Technology

[0002] Substituted indole-2-carboxylic acids and their esters are important organic synthetic intermediates. Their derivatives, such as 5-bromoindole-2-carboxylic acid, have wide applications in medicinal chemistry and pharmaceutical research and development, organic synthesis, and materials science. In medicinal chemistry and pharmaceutical research and development, these derivatives are crucial frameworks for constructing protein kinase inhibitors.

[0003] Orforglipron, an oral small-molecule GLP-1 receptor agonist currently in phase III clinical trials, is synthesized using 5-bromoindole-2-carboxylic acid as a key raw material. Its annual demand is approximately 300-500 tons, demonstrating significant market value. In the field of organic synthesis, these derivatives serve as multifunctional building blocks for synthesizing more complex natural product analogs or functional materials. In materials science, these derivatives can be used to synthesize organic molecules or polymers with special optical and electrical properties, such as precursors for organic light-emitting diodes (OLEDs) or sensors.

[0004] In existing literature, Tani et al. reported a regioselective, non-reductive C3-Debromination of Indole Nucleus in their 1996 article, "Regioselective and Non-reductive C3-Debromination of Indole Nucleus." This method uses sulfuric acid and lithium bromide in acetic acid solvent, with the addition of 1,3-dimethoxybenzene or N-methylpyrrole as a bromine scavenger, achieving C3-specific debromination of various 3-bromoindole-2-carboxylic acid ester derivatives in yields greater than 80%. However, this method suffers from the characteristics of strong acid and corrosion, leading to demanding equipment requirements, high wear and tear, and unsuitability for functional groups unstable in acids. Furthermore, this method also suffers from poor compatibility, numerous potential side reactions, and high cost.

[0005] Another method, mentioned in a 2003 article titled "Novel 3,4-Dihydroquinolin-2(1H)-one Inhibitors of Human Glycogen Phosphorylase a" published in *Bioorganic and Medicinal Chemistry Letters*, uses substituted aniline as a starting material. First, it undergoes ortho-directional iodination with iodine in the presence of silver sulfate to generate a 2-iodoaniline derivative. Then, this intermediate undergoes a one-pot coupling-cyclization reaction with pyruvate in DMF at 105 °C in the presence of a palladium catalyst (Pd(OAc)2) and a base (DABCO) to directly construct an indole ring, thus yielding the target substituted indole-2-carboxylic acid. While this method provides a feasible chemical route for constructing substituted indole-2-carboxylic acids, it relies on noble metal catalysts, resulting in high production costs, complex operation, and susceptibility to fluctuations in overall yield and operational efficiency. Furthermore, some of the raw materials used in the reaction pose safety concerns in industrial production. Summary of the Invention

[0006] The technical problem to be solved by the present invention is to overcome the defects of existing methods for synthesizing 5-halo-substituted indole-2-carboxylic acid and its esters, such as strong acid corrosion, dependence on precious metals, high cost and complex operation, and to provide a synthesis method that is easy to obtain raw materials, simple to operate, mild under mild conditions, high yield, good purity and environmentally friendly.

[0007] This invention utilizes substituted indole-2-carboxylic acid or substituted indole-2-carboxylic acid esters in a two-step reaction involving dihalogenation and monounsaturation to obtain 5-halo-substituted indole-2-carboxylic acid and 5-halo-substituted indole-2-carboxylic acid esters with high purity. The synthetic route is as follows: .

[0008] Specifically: Step 1: Using substituted indole-2-carboxylic acid or substituted indole-2-carboxylic acid ester and N-halosuccinimide as raw materials, add them to solvent A and react in an ice bath for 6-8 hours. After monitoring the completion of the reaction, filter and evaporate the solvent to dryness. Slurry the ethyl acetate and filter again to obtain a white solid powder of 3,5-dihalo-substituted indole-2-carboxylic acid or 3,5-dihalo-substituted indole-2-carboxylic acid ester with a purity of 99% and a yield of 98%.

[0009] In this step, the N-halosuccinimide is 2.1-2.3 equivalents of substituted indole-2-carboxylic acid or substituted indole-2-carboxylic acid ester.

[0010] In this step, solvent A is one or more of tetrahydrofuran, dichloromethane, methanol, or ethyl acetate, and its amount is 5-10 times the mass of the substituted indole-2-carboxylic acid or the substituted indole-2-carboxylic acid ester.

[0011] In this step, the reaction temperature is 0-5℃.

[0012] Step 2: Dissolve 3,5-dihalo-substituted indole-2-carboxylic acid or 3,5-dihalo-substituted indole-2-carboxylic acid ester in a solvent, then add iron powder and ammonium chloride, or iron powder and hydrochloric acid, or zinc powder and acetic acid, or manganese powder and ammonium chloride, or zinc powder and ammonium chloride, preferably iron powder and ammonium chloride. Heat and stir for 5-10 hours. After monitoring the reaction to ensure completion, perform post-processing to obtain a white solid powder of 5-halo-substituted indole-2-carboxylic acid or 5-halo-substituted indole-2-carboxylic acid ester, with a purity of 99.5% and a yield of 95%. In this step, solvent B is one or more of ethanol aqueous solution, methanol or ethyl acetate, and the concentration of the ethanol aqueous solution is 70-90%.

[0013] In this step, the specific reduction conditions are one or more combinations of iron powder and ammonium chloride, iron powder and hydrochloric acid, zinc powder and acetic acid, manganese powder and ammonium chloride, palladium on carbon and hydrogen, Raney nickel and hydrogen, and zinc powder and ammonium chloride.

[0014] In this step, the reaction temperature is 70-90℃.

[0015] In this step, post-processing can be performed using any of the following methods: Method 1: Filtration, evaporation of the filtrate to dryness, washing with water to remove water, addition of ethyl acetate to slurry, and filtration to obtain the product; Method 2: Filtration, evaporation of the filtrate until only the aqueous phase remains, addition of alkaline water, followed by extraction with ethyl acetate to remove impurities, retention of the aqueous layer, acidification of the aqueous layer, precipitation of the solid, and obtaining the product.

[0016] In this step, the alkaline water is any one of sodium carbonate aqueous solution, sodium hydroxide aqueous solution, and potassium hydroxide aqueous solution, and the acid used for acidification of the aqueous layer is any one or a combination of more than one of hydrochloric acid, sulfuric acid, oxalic acid, citric acid, methanesulfonic acid, phosphoric acid, and acetic acid.

[0017] This invention designs a synthetic method for 5-halo-substituted indole-2-carboxylic acid or 5-halo-substituted indole-2-carboxylic acid esters. Using substituted indole-2-carboxylic acid or substituted indole-2-carboxylic acid esters as raw materials, the indole ring is halogenated by electrophilic substitution reaction, and then the halogen at the 3-position is selectively removed by reductive dehalogenation reaction, thereby obtaining 5-halo-substituted indole-2-carboxylic acid or 5-halo-substituted indole-2-carboxylic acid esters. This application adopts a self-designed synthetic route, which has the advantages of simplicity and high efficiency.

[0018] In the method of this invention, all solvents can be condensed and recycled after the reaction. The product is purified by recrystallization using a single, safe solvent. The 5-halo-substituted indole-2-carboxylic acid or 5-halo-substituted indole-2-carboxylic acid ester obtained after purification has high purity, high yield, and excellent quality.

[0019] The reaction raw materials used in this application are all safe, inexpensive, and environmentally friendly common materials. For example, the only byproduct generated in step one is succinimide, which is easily separated, safe, and pollution-free. The raw materials used in step two are all very common and readily available chemical raw materials, characterized by low cost and high efficiency. The generated byproducts are corresponding salts or oxides, such as ferric chloride and iron(III) oxide, which are easy to handle and have extremely low environmental pollution. Furthermore, the synthetic route used in this application has simple conditions, no harsh requirements, is easy to operate, and has no potential hazards. Therefore, the synthetic method for 5-halo-substituted indole-2-carboxylic acid or 5-halo-substituted indole-2-carboxylic acid esters of this application has no harsh conditions, is simple to operate, is environmentally friendly, and can synthesize high-content 5-halo-substituted indole-2-carboxylic acid or 5-halo-substituted indole-2-carboxylic acid esters with high yield, resulting in significant social and economic benefits. It is a synthetic method with readily available raw materials, simple operation, low waste, and high yield. Attached Figure Description

[0020] Figure 1 This is the HPLC chromatogram of 5-bromoindole-2-carboxylic acid obtained in Example 1 of this invention; Figure 2 The 1H NMR spectrum of 5-bromoindole-2-carboxylic acid obtained in Example 1 of this invention; Figure 3 This is the HPLC chromatogram of bromoindole-2-carboxylic acid obtained in Example 2 of the present invention. Detailed Implementation

[0021] The present invention will be further described below with reference to specific embodiments in order to better understand the technical solution.

[0022] Unless otherwise specified, all reagents used in the embodiments of this invention are commercially available; and all equipment models used are conventional equipment in the field unless otherwise specified.

[0023] Example 1: Synthesis of 5-bromoindole-2-carboxylic acid The synthetic route is as follows: ; Step 1: Dissolve 50 g of indole-2-carboxylic acid in 250 mL of tetrahydrofuran, then place the solution in an ice-water bath and stir to cool it down to below 5°C. Add 115 g of N-bromosuccinimide, and monitor the reaction for 6 hours until completion. Filter the solution and wash with tetrahydrofuran. After solvent removal, crystallize the solution with ethyl acetate at a lower temperature, filter, and dry to obtain 94.22 g of off-white crystals of 3,5-dibromoindole-2-carboxylic acid, with a yield of 89.49%.

[0024] Step 2: Dissolve 50 g of 3,5-dibromoindole-2-carboxylic acid and 50 g of ammonium chloride in 500 mL of 80% ethanol. Under stirring and heating to 80℃, add 35 g of iron powder. Maintain the temperature at 70-90℃ and allow the addition to be complete for 2 hours. Continue the reaction under controlled temperature for 6 hours. Add 17.2 g of hydrochloric acid and stir for 30 min. After filtration, concentrate the solution and beat with ethyl acetate. Filter to obtain 35.5 g of off-white powdery solid 5-bromoindole-2-carboxylic acid, with a yield of 94.33% and an HPLC purity of ≥99.36%.

[0025] The HPLC chromatogram of the product obtained in this embodiment is shown below. Figure 1 As shown, the proton NMR spectrum is as follows: Figure 2 As shown.

[0026] Example 2: Synthesis of 5-bromoindole-2-carboxylic acid Step 1: Dissolve 20 g of indole-2-carboxylic acid in 100 mL of tetrahydrofuran, then place the solution in an ice-water bath and stir to cool. While the temperature is below 5°C, add 46.38 g of N-bromosuccinimide. After 8 h of reaction, the solution is filtered and washed with tetrahydrofuran. After solvent removal, crystallize with ethyl acetate at a lower temperature. Filter and dry to obtain 12.8 g of off-white crystals of 3,5-dibromoindole-2-carboxylic acid, with a yield of 85.03%.

[0027] Step 2: Mix 1 g of 3,5-dibromoindole-2-carboxylic acid with 10 mL of glacial acetic acid, stir and heat to 80°C, then add 0.82 g of zinc powder. Continue the reaction under controlled temperature for 5 h, monitoring for completeness. After treatment, 0.6 g of 5-bromoindole-2-carboxylic acid was obtained, with a yield of 79.7% and an HPLC purity ≥98.43%.

[0028] The HPLC chromatogram of the product obtained in this embodiment is shown below. Figure 3 As shown.

[0029] Example 3: Synthesis of 5-bromoindole-2-carboxylic acid Step 1: Dissolve 50 g of indole-2-carboxylic acid in 250 mL of tetrahydrofuran, protect from light with aluminum foil, and place in an ice-water bath. Add 121.5 g of N-bromosuccinimide at a temperature below 5°C. Monitor the reaction for 8 h until complete. Filter and wash with tetrahydrofuran. After solvent removal, slurry and filter with ethyl acetate. Repeat three times, combine the results, and dry to obtain 35.5 g of off-white crystals of 3,5-dibromoindole-2-carboxylic acid, yield 94.33%.

[0030] Step 2: Dissolve 1 g of 3,5-dibromoindole-2-carboxylic acid in 10 mL of methanol, then add 0.2 g of palladium on carbon, replace with hydrogen, and react at 25-30℃ for 6 h. Monitor the reaction to ensure it is complete, filter and process to obtain 0.62 g of 5-bromoindole-2-carboxylic acid, with a yield of 82.38% and an HPLC content ≥98%.

[0031] Example 4: Synthesis of ethyl 5-bromoindole-2-carboxylate Step 1: Dissolve 5 g of ethyl indole-2-carboxylate in 30 mL of tetrahydrofuran, add 10.3 g of N-bromosuccinimide after an ice-water bath, stir for 4 h, and filter after monitoring the reaction to ensure it is complete. Remove the solvent and slurry with ethyl acetate. Filter again to obtain 8 g of solid ethyl 3,5-dibromoindole-2-carboxylate, with a yield of 87.24%.

[0032] Step 2: Dissolve 1 g of ethyl 3,5-dibromoindole-2-carboxylate and 1 g of ammonium chloride in 10 mL of 80% ethanol. While stirring and heating to 80°C, add 0.65 g of iron powder and maintain the temperature for 5 h. After monitoring the reaction to ensure complete reaction, filter and concentrate the solution, then dry to obtain 0.6 g of solid ethyl 5-bromoindole-2-carboxylate, with a yield of 77.72% and an HPLC purity ≥97%.

[0033] Example 5: Synthesis of ethyl 5-bromoindole-2-carboxylate Step 1: Dissolve 10 g of indole-2-carboxylic acid in 50 mL of tetrahydrofuran, add 17.2 g of N-chlorosuccinimide in an ice-water bath, and after monitoring the reaction to ensure completeness, filter and evaporate to dryness. Pulp the mixture with ethyl acetate and filter to obtain 13 g of solid 3,5-dichloroindole-2-carboxyl, with a yield of 91.07%.

[0034] Step 2: Dissolve 1 g of 3,5-dichloroindole-2-carboxylic acid and 1.2 g of ammonium chloride in 10 mL of 80% ethanol solution. Stir and heat to 80℃. Under dissolved conditions, add 0.82 g of iron powder and continue the reaction at controlled temperature for 5 h. After monitoring that the reaction is complete, add 0.4 g of hydrochloric acid dropwise, stir for a period of time, filter, evaporate to dryness at 60℃, and then slurry with ethyl acetate. Filter to obtain 0.68 g of solid, yield 95.43%, HPLC purity ≥96%.

[0035] Example 6: 5-Bromo-4-methylindole-2-carboxylic acid Step 1: 4-Methylindole-2-carboxylic acid was dissolved in 25 mL of tetrahydrofuran. After an ice-water bath, 10.55 g of N-bromosuccinimide was added. The reaction was monitored for 5 h until it was complete. After filtration and evaporation to dryness, the mixture was slurried with ethyl acetate and filtered to obtain 8.5 g of solid 3,5-dibromo-4-methylindole-2-carboxylic acid, with a yield of 89.44%.

[0036] Step 2: Dissolve 5 g of 3,5-dibromo-4-methylindole-2-carboxyl group and 4.9 g of ammonium chloride in 50 mL of 80% ethanol. Heat the solution in a water bath to 80℃, then add 3.5 g of iron powder. Monitor the reaction for 6 h until complete. Filter and concentrate the solution, then dry to obtain 3.3 g of 5-bromo-4-methylindole-2-carboxylic acid, with a yield of 86.49% and an HPLC purity ≥97%.

Claims

1. A method for synthesizing a 5-halo-substituted indole-2-carboxylic acid or a 5-halo-substituted indole-2-carboxylic acid ester, characterized in that... Includes the following steps: 1) Using substituted indole-2-carboxylic acid or substituted indole-2-carboxylic acid ester, N-halosuccinimide or corresponding halogen as raw materials, after dissolving in solvent A, the reaction is carried out under ice bath to generate 3,5-dihalo-substituted indole-2-carboxylic acid or 3,5-dihalo-substituted indole-2-carboxylic acid ester. 2) Dissolve 3,5-dihalo-substituted indole-2-carboxylic acid or 3,5-dihalo-substituted indole-2-carboxylic acid ester in solvent B, react under specific reducing conditions, and after post-treatment, obtain 5-halo-substituted indole-2-carboxylic acid or 5-halo-substituted indole-2-carboxylic acid ester.

2. The method for synthesizing a 5-halo-substituted indole-2-carboxylic acid or a 5-halo-substituted indole-2-carboxylic acid ester as described in claim 1, characterized in that... The structural formulas of 5-halo-substituted indole-2-carboxylic acid or 5-halo-substituted indole-2-carboxylic acid esters are as follows: ； In the formula, R1 is selected from any one of H, Br, Cl, I, and Cl-C3, R2 is selected from any one of H, Cl-C6, and X is selected from any one of Cl, Br, and I.

3. The method for synthesizing a 5-halo-substituted indole-2-carboxylic acid or a 5-halo-substituted indole-2-carboxylic acid ester as described in claim 1, characterized in that, In step 1), the amount of N-halosuccinimide or the corresponding halogen is 2.1-2.3 equivalents of the amount of substituted indole-2-carboxylic acid or substituted indole-2-carboxylic acid ester.

4. The method for synthesizing a 5-halo-substituted indole-2-carboxylic acid or a 5-halo-substituted indole-2-carboxylic acid ester as described in claim 1, characterized in that, In step 1), solvent A is one or more of tetrahydrofuran, dichloromethane, methanol, or ethyl acetate, and its amount is 5-10 times the mass of the substituted indole-2-carboxylic acid or the substituted indole-2-carboxylic acid ester.

5. The method for synthesizing a 5-halo-substituted indole-2-carboxylic acid or a 5-halo-substituted indole-2-carboxylic acid ester as described in claim 1, characterized in that, In step 1), the reaction temperature is 0-5℃ and the reaction time is 6-8 hours.

6. The method for synthesizing a 5-halo-substituted indole-2-carboxylic acid or a 5-halo-substituted indole-2-carboxylic acid ester as described in claim 1, characterized in that, In step 2), solvent B is one or more of ethanol aqueous solution, methanol or ethyl acetate, and the concentration of the ethanol aqueous solution is 70-90%.

7. The method for synthesizing a 5-halo-substituted indole-2-carboxylic acid or a 5-halo-substituted indole-2-carboxylic acid ester as described in claim 1, characterized in that, The specific reduction conditions in step 2) are one or more combinations of iron powder and ammonium chloride, iron powder and hydrochloric acid, zinc powder and acetic acid, manganese powder and ammonium chloride, palladium on carbon and hydrogen, Raney nickel and hydrogen, and zinc powder and ammonium chloride.

8. The method for synthesizing a 5-halo-substituted indole-2-carboxylic acid or a 5-halo-substituted indole-2-carboxylic acid ester as described in claim 1, characterized in that, In step 2), the reaction temperature is 70-90℃ and the reaction time is 5-10 hours.

9. The method for synthesizing a 5-halo-substituted indole-2-carboxylic acid or a 5-halo-substituted indole-2-carboxylic acid ester as described in claim 1, characterized in that, In step 2), choose any of the following post-processing methods: Method 1: Filtration, evaporation of the filtrate to dryness, washing with water to remove water, addition of ethyl acetate to slurry, and filtration to obtain the product; Method 2: Filtration, evaporation of the filtrate until only the aqueous phase remains, addition of alkaline water, followed by extraction with ethyl acetate to remove impurities, retention of the aqueous layer, acidification of the aqueous layer, precipitation of the solid, and obtaining the product.

10. The method for synthesizing a 5-halo-substituted indole-2-carboxylic acid or a 5-halo-substituted indole-2-carboxylic acid ester as described in claim 9, characterized in that, The alkaline solution is any one of sodium carbonate aqueous solution, sodium hydroxide aqueous solution, and potassium hydroxide aqueous solution, and the acid used for acidification of the aqueous layer is any one or a combination of more than one of hydrochloric acid, sulfuric acid, oxalic acid, citric acid, methanesulfonic acid, phosphoric acid, and acetic acid.

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