A method for synthesizing a compound 3-iodo-1h-indole-2-carboxylic acid

Abstract

A preparation method of 3-iodo-1H-indole-2-carboxylic acid, which comprises the following steps: taking indole-2-carboxylic acid ethyl ester as raw material, converting into 3-formyl-1H-indole-2-carboxylic acid ethyl ester, then converting into 3-iodo-1H-indole-2-carboxylic acid ethyl ester, and finally converting into the target compound 3-iodo-1H-indole-2-carboxylic acid through an ester hydrolysis reaction. The synthesis method realizes the conversion from 3-formyl-1H-indole-2-carboxylic acid ethyl ester to 3-iodo-1H-indole-2-carboxylic acid ethyl ester in a simple method in a key step; finally, the compound 3-iodo-1H-indole-2-carboxylic acid is prepared through simple operation, low cost and relatively mild reaction conditions.

Description

Technical Field

[0001] This invention belongs to the field of organic synthesis technology, specifically relating to a method for synthesizing the compound 3-iodo-1H-indole-2-carboxylic acid. Background Technology

[0002] Indole compounds have a wide range of applications, including pharmaceuticals, pesticides, polymer materials, optoelectronic devices, dyes and pigments, analytical chemistry, and biochemical research. The compound 3-iodo-1H-indole-2-carboxylic acid is an important indole compound and a crucial molecular building block. As a key intermediate, it was used in the synthesis of 3-aminoisocoumarin in the article "Rapid Synthesis of 3-Amino Isocoumarin Derivatives from Ynamides" by Isabelle Gillaizeau et al., and in the synthesis of lactams in the article "Ring closure metathesis of indole 2-carboxylic acid allylamide derivatives" by Jean-Yves Mérour et al.

[0003] In existing technologies, indole-2-carboxylic acid is generally used as a raw material to synthesize the compound 3-iodo-1H-indole-2-carboxylic acid. However, the product is prone to deterioration during the post-processing of this method. Alternatively, ethyl 3-iodo-1H-indole-2-carboxylic acid can be converted into 3-iodo-1H-indole-2-carboxylic acid via ester hydrolysis. Summary of the Invention

[0004] The purpose of this invention is to address the defects in the synthesis of 3-iodo-1H-indole-2-carboxylic acid in the prior art. This invention provides a method for synthesizing 3-iodo-1H-indole-2-carboxylic acid, which has the advantages of low cost, relatively mild reaction conditions, low safety risks, and ideal yield.

[0005] To achieve the above objectives, the present invention adopts the following technical solution:

[0006] A synthetic method for 3-iodo-1H-indole-2-carboxylic acid is disclosed, using compound 1 (i.e., ethyl indole-2-carboxylic acid) as a starting material. The compound is first converted to compound 2 (i.e., ethyl 3-formyl-1H-indole-2-carboxylic acid), then to compound 3 (i.e., ethyl 3-iodo-1H-indole-2-carboxylate), and finally converted to the target compound 4 (i.e., 3-iodo-1H-indole-2-carboxylic acid) via ester hydrolysis. The synthetic route is as follows:

[0007] .

[0008] Furthermore, the method for synthesizing the 3-iodo-1H-indole-2-carboxylic acid includes the following steps:

[0009] (1) At a temperature of -5℃ to 5℃, phosphorus oxychloride was added to N,N-dimethylformamide and stirred for 30-60 minutes while maintaining the temperature at -5℃ to 5℃. Compound 1, namely ethyl indole-2-carboxylate, was dissolved in N,N-dimethylformamide and then added dropwise to the above reaction system. The mixture was stirred for 20-50 minutes at -5℃ to 5℃, and then heated to 50-80℃ for 3-10 hours. After the reaction was completed, the reaction solution was post-treated to obtain compound 2, namely ethyl 3-formyl-1H-indole-2-carboxylate.

[0010] (2) At room temperature, compound 2 was added to organic solvent I and ammonia water, and iodine was slowly added. The mixture was stirred at 20-50°C for 5-10 hours. After the reaction was completed, the reaction solution was post-treated to obtain compound 3, namely ethyl 3-iodo-1H-indole-2-carboxylate.

[0011] (3) Compound 3 was added to water and ethanol, followed by potassium hydroxide, and reacted at 40-80°C for 1-3 hours. After the reaction was completed, the reaction solution was post-treated to obtain compound 4, namely 3-iodo-1H-indole-2-carboxylic acid.

[0012] Furthermore, in step (1), the post-treatment is as follows: after the reaction is completed, the reaction solution is cooled to room temperature, then the reaction solution is poured into ice water, and then the pH is adjusted to 7 with an alkaline aqueous solution. The solution is filtered, the filter cake is washed with water, the filter cake is collected, the obtained solid is dissolved in organic solvent II, the organic phase is dried, and the crude product is concentrated under reduced pressure. The crude product is purified to obtain compound 2, namely ethyl 3-formyl-1H-indole-2-carboxylic acid.

[0013] Furthermore, in step (1), the alkaline aqueous solution is selected from one or more of sodium bicarbonate solution, sodium carbonate solution, potassium carbonate solution, sodium hydroxide solution, or potassium hydroxide solution.

[0014] Furthermore, in step (1), the organic solvent II is selected from one or more of ethyl acetate, butyl acetate, chloroform, toluene, dichloromethane, or dichloroethane.

[0015] Furthermore, in step (1), the purification method is selected from one or more of pulping, column chromatography, recrystallization, or distillation.

[0016] Furthermore, in step (2), the molar ratio of compound 2 to iodine is 1:(1.00-2.00), preferably 1:1.30.

[0017] Furthermore, in step (2), the organic solvent I is selected from one or more of methanol or ethanol.

[0018] Furthermore, in step (2), the mass-to-volume ratio of compound 2 to organic solvent I is 1:(5-40) g / mL.

[0019] Furthermore, in step (2), the post-processing is as follows: after the reaction is completed, the mixture is filtered, the filter cake is collected, the obtained solid is dissolved in organic solvent III, the organic phase is dried, and the crude product is concentrated under reduced pressure; the crude product is purified to obtain compound 3, namely ethyl 3-iodo-1H-indole-2-carboxylate.

[0020] Furthermore, in step (2), the organic solvent III is selected from one or more of ethyl acetate, butyl acetate, chloroform, toluene, dichloromethane, or dichloroethane.

[0021] Furthermore, in step (2), the purification method is selected from one or more of pulping, column chromatography, recrystallization, or distillation.

[0022] Furthermore, in step (2), the acidic aqueous solution is selected from one or more of hydrochloric acid solution, sulfuric acid solution, nitric acid solution, and acetic acid solution.

[0023] Furthermore, in step (2), the organic solvent IV is selected from one or more of ethyl acetate, butyl acetate, chloroform, toluene, dichloromethane, or dichloroethane.

[0024] Furthermore, in step (3), the post-treatment is as follows: after the reaction is completed, the ethanol is removed by vacuum concentration, water is added, the pH is adjusted to 3-5 with acidic aqueous solution, the filter is filtered, the filter cake is collected, the obtained solid is dissolved in organic solvent IV, the organic phase is dried, and the crude product is obtained by vacuum concentration; the crude product is purified to obtain compound 4, namely 3-iodo-1H-indole-2-carboxylic acid.

[0025] Furthermore, in step (3), the purification method is selected from one or more of pulping, column chromatography, recrystallization, or distillation.

[0026] Compared with the prior art, the beneficial effects of the present invention are as follows:

[0027] This invention proposes a method for preparing 3-iodo-1H-indole-2-carboxylic acid. Using ethyl indole-2-carboxylic acid as a raw material, it is first converted to ethyl 3-formyl-1H-indole-2-carboxylic acid, then to ethyl 3-iodo-1H-indole-2-carboxylate, and finally converted to the target compound 3-iodo-1H-indole-2-carboxylic acid via ester hydrolysis. This synthetic method achieves the conversion of ethyl 3-formyl-1H-indole-2-carboxylic acid to ethyl 3-iodo-1H-indole-2-carboxylate using a simple method in key steps; ultimately, the compound 3-iodo-1H-indole-2-carboxylic acid is obtained with simple operation, low cost, and relatively mild reaction conditions. Attached Figure Description

[0028] Figure 1 This is the 1H NMR spectrum of compound 4 in Example 1 of the present invention. Detailed Implementation

[0029] To make the technical solutions and advantages of the embodiments of the present invention clearer, the technical solutions of the embodiments of the present invention will be clearly and completely described below with reference to the accompanying drawings. Obviously, the described embodiments are only some, not all, of the embodiments of the present invention. Based on the described embodiments of the present invention, all other embodiments obtained by those skilled in the art without creative effort are within the scope of protection of the present invention. Unless otherwise defined, the technical or scientific terms used herein should have the ordinary meaning understood by those skilled in the art to which this invention pertains.

[0030] Unless otherwise specified, all reagents and materials used in the following examples are commercially available.

[0031] The following example illustrates a method for preparing 3-iodo-1H-indole-2-carboxylic acid. Using compound 1 (ethyl indole-2-carboxylic acid) as a starting material, it is first converted to compound 2 (ethyl 3-formyl-1H-indole-2-carboxylic acid), then to compound 3 (ethyl 3-iodo-1H-indole-2-carboxylate), and finally, through ester hydrolysis, it is converted to the target compound 4 (3-iodo-1H-indole-2-carboxylic acid). The synthetic route is as follows:

[0032] .

[0033] The technical solution of the present invention will be further explained and illustrated below through embodiments. Example

[0034] In this embodiment, the compound 3-iodo-1H-indole-2-carboxylic acid was synthesized using the following steps:

[0035] (1) At 0°C, phosphorus oxychloride (181.51 g, 1.18 mol, 1.12 eq) was added to N,N-dimethylformamide (360 mL), and stirred for 40 minutes while maintaining the temperature at 0°C. Compound 1, namely indole-2-carboxylic acid ethyl ester (200.00 g, 1.06 mol, 1.00 eq), was dissolved in N,N-dimethylformamide (300 mL), and then added dropwise to the above reaction system. The mixture was stirred at 0°C for 30 minutes, and then heated to 60°C for 4 hours. After the reaction was completed, the reaction solution was cooled to room temperature and then poured into ice water (2.0 L). The pH was then adjusted to 7 with 2M sodium hydroxide aqueous solution. The mixture was filtered, and the filter cake was washed with water (2.0 L). The filter cake was collected, and the resulting solid was dissolved in ethyl acetate (3.0 L). The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography to obtain compound 2, namely ethyl 3-formyl-1H-indole-2-carboxylic acid (yellow powder, weight 223.40 g, purity 98%, yield 95%).

[0036] The characterization data of the obtained compound 2 (ethyl 3-formyl-1H-indole-2-carboxylic acid) by 1H NMR are as follows:

[0037] 1 H NMR (400 MHz, DMSO) δ 12.51 (s, 1H), 10.62 (s, 1H), 8.25 (d, J =8.1 Hz, 1H), 7.58 (d, J = 8.2 Hz, 1H), 7.40 (t, J = 7.6 Hz, 1H), 7.30 (t, J =7.6 Hz, 1H), 4.46 (qd, J = 7.0, 1.9 Hz, 2H), 1.40 (t, J = 7.1 Hz, 3H).

[0038] (2) At room temperature, compound 2 (200.00 g, 920.71 mmol, 1.00 eq) was added to methanol (1400 mL) and ammonia (1400 mL), and iodine (303.79 g, 1.20 mol, 1.30 eq) was slowly added. The mixture was stirred at 25 °C for 7 hours. After the reaction was complete, the mixture was filtered, the filter cake was collected, and the resulting solid was dissolved in ethyl acetate (3.0 L). The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography to obtain compound 3, namely ethyl 3-iodo-1H-indole-2-carboxylate (268.10 g, purity 97%, yield 90%).

[0039] (3) At room temperature, compound 3 (250.00 g, 793.37 mmol, 1.00 eq) was added to water (1.0 L) and ethanol (2.5 L), followed by potassium hydroxide (57.87 g, 1.03 mol, 1.30 eq). The reaction was carried out at 60 °C for 1 hour. After the reaction was completed, the ethanol was removed by vacuum concentration, water (2.0 L) was added, and the pH was adjusted to 4 with 12 M hydrochloric acid aqueous solution. The mixture was filtered, and the filter cake was collected. The obtained solid was dissolved in ethyl acetate (3.0 L), and the organic phase was dried over anhydrous sodium sulfate. The mixture was concentrated under vacuum to obtain the crude product. The crude product was purified by pulping with petroleum ether (3.0 L) to obtain compound 4, namely 3-iodo-1H-indole-2-carboxylic acid (yellow solid, weight 215.30 g, purity 98%, yield 93%).

[0040] The characterization data of the 1H NMR spectrum of the obtained compound 4 (3-iodo-1H-indole-2-carboxylic acid) are as follows:

[0041] 1 H NMR (400 MHz, DMSO) δ 13.27 (s, 1H), 12.13 (s, 1H), 7.43 (dd, J =14.0, 8.2 Hz, 2H), 7.34 – 7.28 (m, 1H), 7.17 (t, J = 7.5 Hz, 1H).

[0042] Examples 2-7

[0043] Examples 2-7 are the same as Example 1, except that the amount of iodine, organic solvent I, reaction temperature, and reaction time in step 2 are adjusted, as shown in Table 1.

[0044] Examples 1-7 were used to investigate the effects of various reaction conditions on the reaction yield in the synthesis of the intermediate compound ethyl 3-iodo-1H-indole-2-carboxylate. The results are shown in Table 1.

[0045] Table 1

[0046] project Compound 2: Iodine (molar ratio) Organic Solvent I Reaction temperature (°C) Reaction time (h) Yield (%) of intermediate compound 3 Example 1 1.0:1.3 methanol 25 7 90 Example 2 1.0:1.0 methanol 25 7 87 Example 3 1.0:1.6 methanol 25 7 90 Example 4 1.0:1.3 ethanol 25 7 89 Example 5 1.0:1.3 methanol 40 7 90 Example 6 1.0:1.3 methanol 25 4 86 Example 7 1.0:1.3 methanol 25 10 90

[0047] Based on the table above, we can see that:

[0048] Comparing Examples 1-3, the reaction effect was better when the molar ratio of compound 2 to iodine was 1.0:1.3.

[0049] Comparing Examples 1 and 4, the reaction can yield the target product in both methanol and ethanol solvents, with methanol showing better performance as a solvent.

[0050] Comparing Examples 1-5, the reaction effect was already good when the reaction temperature was 25°C.

[0051] Comparing Examples 1 and 6-7, the reaction effect was better when the reaction time was 7 hours.

[0052] Finally, it should be noted that the above embodiments are only used to illustrate the technical solutions of this application, and are not intended to limit them. Although this application has been described in detail with reference to the foregoing embodiments, those skilled in the art should understand that modifications can still be made to the technical solutions described in the foregoing embodiments, or equivalent substitutions can be made to some or all of the technical features therein. Such modifications or substitutions do not cause the essence of the corresponding technical solutions to deviate from the scope of the technical solutions of the embodiments of this application.

Claims

1. A method for synthesizing the compound 3-iodo-1H-indole-2-carboxylic acid, characterized in that, Using ethyl indole-2-carboxylate as a starting material, it is first converted to ethyl 3-formyl-1H-indole-2-carboxylate, then to ethyl 3-iodo-1H-indole-2-carboxylate, and finally converted to the target compound 3-iodo-1H-indole-2-carboxylic acid via ester hydrolysis. The synthetic route is as follows: ； The synthesis method includes the following steps: (1) At a temperature of -5℃ to 5℃, phosphorus oxychloride was added to N,N-dimethylformamide and stirred for 30-60 minutes while maintaining the temperature at -5℃ to 5℃. Compound 1, namely ethyl indole-2-carboxylate, was dissolved in N,N-dimethylformamide and then added dropwise to the above reaction system. The mixture was stirred for 20-50 minutes at -5℃ to 5℃, and then heated to 50-80℃ for 3-10 hours. After the reaction was completed, the reaction solution was post-treated to obtain compound 2, namely ethyl 3-formyl-1H-indole-2-carboxylate. (2) At room temperature, compound 2 was added to organic solvent I and ammonia water, and iodine was slowly added. The mixture was stirred at 20-50°C for 5-10 hours. After the reaction was completed, the reaction solution was post-treated to obtain compound 3, namely ethyl 3-iodo-1H-indole-2-carboxylate. (3) Add compound 3 to water and ethanol, then add potassium hydroxide, and react at 40-80℃ for 1-3 hours. After the reaction is completed, the reaction solution is post-treated to obtain compound 4, namely 3-iodo-1H-indole-2-carboxylic acid.

2. The method for synthesizing 3-iodo-1H-indole-2-carboxylic acid according to claim 1, characterized in that, In step (1), the post-treatment is as follows: after the reaction is completed, the reaction solution is cooled to room temperature, then the reaction solution is poured into ice water, and then the pH is adjusted to 7 with an alkaline aqueous solution. The solution is filtered, the filter cake is washed with water, the filter cake is collected, the obtained solid is dissolved in organic solvent II, the organic phase is dried, and the crude product is concentrated under reduced pressure. The crude product is purified to obtain compound 2, namely ethyl 3-formyl-1H-indole-2-carboxylic acid.

3. The method for synthesizing 3-iodo-1H-indole-2-carboxylic acid according to claim 2, characterized in that, In step (1), the alkaline aqueous solution is one or more of sodium bicarbonate solution, sodium carbonate solution, potassium carbonate solution, sodium hydroxide solution, or potassium hydroxide solution.

4. The method for synthesizing 3-iodo-1H-indole-2-carboxylic acid according to claim 2, characterized in that, In step (1), the organic solvent II is one or more of ethyl acetate, butyl acetate, chloroform, toluene, dichloromethane, or dichloroethane.

5. The method for synthesizing 3-iodo-1H-indole-2-carboxylic acid according to claim 1, characterized in that, In step (2), the molar ratio of compound 2 to iodine is 1:(1.00-2.00); The organic solvent I is one or more of methanol or ethanol; The mass-to-volume ratio of compound 2 to organic solvent I is 1:(5-40) g / mL.

6. The method for synthesizing 3-iodo-1H-indole-2-carboxylic acid according to claim 1, characterized in that, In step (2), the post-processing is as follows: after the reaction is completed, the filter cake is collected, the obtained solid is dissolved in organic solvent III, the organic phase is dried, and the crude product is concentrated under reduced pressure; the crude product is purified to obtain compound 3, namely ethyl 3-iodo-1H-indole-2-carboxylate.

7. The method for synthesizing 3-iodo-1H-indole-2-carboxylic acid according to claim 6, characterized in that, In step (2), the organic solvent III is one or more of ethyl acetate, butyl acetate, chloroform, toluene, dichloromethane, or dichloroethane.

8. The method for synthesizing 3-iodo-1H-indole-2-carboxylic acid according to claim 1, characterized in that, In step (3), the post-processing is as follows: after the reaction is completed, the ethanol is removed by vacuum concentration, water is added, the pH is adjusted to 3-5 with acidic aqueous solution, the filter is filtered, the filter cake is collected, the obtained solid is dissolved in organic solvent IV, the organic phase is dried, and the crude product is obtained by vacuum concentration; the crude product is purified to obtain compound 4, namely 3-iodo-1H-indole-2-carboxylic acid.

9. The method for synthesizing 3-iodo-1H-indole-2-carboxylic acid according to claim 8, characterized in that, In step (3), the acidic aqueous solution is one or more of hydrochloric acid solution, sulfuric acid solution, nitric acid solution, or acetic acid solution; The organic solvent IV is one or more of ethyl acetate, butyl acetate, chloroform, toluene, dichloromethane, or dichloroethane.

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