Synthetic process of indole-3-lactic acid (ILA)
Indole-3-lactic acid was successfully synthesized through the ring-opening reaction of indole with methyl ethylene oxide carboxylate and alkaline hydrolysis, solving the problem of high cost in existing technologies and realizing efficient and low-cost chemical synthesis of indole-3-lactic acid.
Patent Information
- Application Number
- CN202510972687.3
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2025-07-15
- Publication Date
- 2025-11-07
AI Technical Summary
Existing biosynthetic methods for indole-3-lactic acid are costly, and there is an urgent need for a simple and low-cost chemical synthesis method.
Indole, ethylene oxide methyl carboxylate, a phase transfer catalyst, and water were used to initiate a ring-opening reaction to generate methyl indole-3-lactic acid, which was then hydrolyzed with a base and an alcohol to obtain indole-3-lactic acid.
A high-yield synthesis of indole-3-lactic acid was achieved, which is simple to operate, highly atom-economical, environmentally friendly, and low-cost.
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Abstract
Description
TECHNICAL FIELD
[0001] The present application relates to the technical field of organic synthesis, and particularly relates to a synthesis method of indole-3-lactic acid. BACKGROUND
[0002] Indole is a kind of basic component with high stability and wide application in organic synthesis. In the organic chemistry and pharmaceutical industry, there is a high demand for the functional group transformation of indole. However, due to the high reactivity of indole, it is not easy to obtain a certain single compound when synthesizing its derivatives. In recent years, the functional group transformation of indole has attracted widespread attention, and thus a number of mild and practical functional group transformation methods have been generated, including the synthesis of substituted indole from phenylhydrazine and the functional group transformation on the indole ring.
[0003] Indole-3-lactic acid (ILA) is an indole metabolite produced by some lactobacillus through metabolism of tryptophan, and can improve the occurrence of colorectal cancer through epigenetic regulation of CD8+ T cell immunity, and may be a new drug against colon cancer, and has broad application prospects.
[0004] At present, indole-3-lactic acid is mainly prepared by biological synthesis method, and L-tryptophan is converted into 3-(3-indolyl)-2-oxo propanoic acid by microorganism, and then the generated 3-(3-indolyl)-2-oxo propanoic acid is subjected to hydrolysis reaction to generate indole-3-lactic acid. However, this method has high cost. At present, it is urgent to provide a chemical synthesis method of indole-3-lactic acid with simple operation and low cost. SUMMARY
[0005] Therefore, the present application provides a synthesis method of indole-3-lactic acid. The synthesis method provided by the present application has simple operation, high atom economy, low cost, environmental friendliness, and high yield of indole-3-lactic acid.
[0006] In order to achieve the above-mentioned application purposes, the present application provides the following technical solutions:
[0007] A synthesis method of indole-3-lactic acid comprises the following steps:
[0008] indole, oxirane carboxylate methyl ester, phase transfer catalyst and water are mixed to carry out ring-opening reaction to obtain indole-3-lactic acid methyl ester;
[0009] indole-3-lactic acid methyl ester, base, alcohol and water are mixed to carry out hydrolysis reaction to obtain indole-3-lactic acid.
[0010] Preferably, the phase transfer catalyst comprises one or more of tetrabutylammonium bromide, tetrabutylammonium iodide, dodecyltrimethylammonium chloride and tetradecyltrimethylammonium chloride.
[0011] Preferably, the molar ratio of the indole and the oxirane carboxylic acid methyl ester is 1:1-1.5.
[0012] Preferably, the molar ratio of the indole and the phase transfer catalyst is 1:0.4-0.6.
[0013] Preferably, the temperature of the ring-opening reaction is 80-120℃, and the time is 10-15h.
[0014] Preferably, the base is an alkali hydroxide.
[0015] Preferably, the alkali hydroxide comprises one or more of lithium hydroxide, sodium hydroxide and potassium hydroxide.
[0016] Preferably, the molar ratio of the indole-3-lactic acid methyl ester and the base is 1:1.5-2.5.
[0017] Preferably, the alcohol is methanol; and the volume ratio of the alcohol and water in the hydrolysis reaction is 1:1-2.
[0018] Preferably, the temperature of the hydrolysis reaction is 20-30℃, and the time is 12-36h.
[0019] The present application provides a synthesis method of indole-3-lactic acid, comprising the following steps: mixing indole, oxirane carboxylic acid methyl ester, phase transfer catalyst and water to perform ring-opening reaction, to obtain indole-3-lactic acid methyl ester; mixing the indole-3-lactic acid methyl ester, base, alcohol and water to perform hydrolysis reaction, to obtain indole-3-lactic acid. The present application catalyzes the ring-opening reaction of indole and oxirane carboxylic acid methyl ester by using a phase transfer catalyst, to generate indole-3-lactic acid methyl ester, which can then be hydrolyzed by using a lye to synthesize indole-3-lactic acid (ILA) at a high yield. The method provided by the present application has simple operation, mild reaction conditions, high atom economy, no participation of other additives, environmental friendliness, low cost, high yield of indole-3-lactic acid, and wide application prospect. DETAILED DESCRIPTION
[0020] The present application provides a synthesis method of indole-3-lactic acid, comprising the following steps:
[0021] mixing indole, oxirane carboxylic acid methyl ester, phase transfer catalyst and water to perform ring-opening reaction, to obtain indole-3-lactic acid methyl ester;
[0022] mixing the indole-3-lactic acid methyl ester, base, alcohol and water to perform hydrolysis reaction, to obtain indole-3-lactic acid.
[0023] In the present application, the synthesis route of the indole-3-lactic acid is shown in formula I:
[0024]
[0025] The synthesis method of the present application is described in detail below in combination with Formula I.
[0026] In the present application, the phase transfer catalyst preferably comprises one or more of tetrabutylammonium bromide, tetrabutylammonium iodide, dodecyltrimethylammonium chloride and tetradecyltrimethylammonium chloride; the molar ratio of the indole and the methyl oxirane carboxylate is preferably 1:1-1.5, and specifically can be 1:1; the molar ratio of the indole and the phase transfer catalyst is preferably 1:0.4-0.6, and specifically can be 1:0.5; the amount ratio of the indole and water is preferably 1 mmol:(1-3) mL, and specifically can be 1 mmol:2 mL; the temperature of the ring-opening reaction is preferably 80-120°C, and in the examples can be 100°C; the time of the ring-opening reaction is preferably 10-15 h, and specifically can be 12 h; and the ring-opening reaction is preferably performed under TLC monitoring.
[0027] After the ring-opening reaction is completed, the present application preferably cools the obtained product liquid to room temperature, then performs ether extraction, dries the obtained extraction phase with anhydrous sodium sulfate, and removes the ether to obtain methyl indole-3-lactate.
[0028] After obtaining the methyl indole-3-lactate, the present application mixes the methyl indole-3-lactate, a base, an alcohol and water to perform a hydrolysis reaction to obtain indole-3-lactic acid. In the present application, the base is preferably an alkali metal hydroxide; the alkali metal hydroxide preferably comprises one or more of lithium hydroxide, sodium hydroxide and potassium hydroxide; the molar ratio of the methyl indole-3-lactate and the base is preferably 1:1.5-2.5, and specifically can be 1:2; the alcohol is preferably methanol; the volume ratio of the alcohol and water in the hydrolysis reaction is preferably 1:1-2, and specifically can be 1:1; the amount of the methyl indole-3-lactate and the alcohol is preferably 1 mmol:(1-2) mL, and specifically can be 1 mmol:1 mL; the temperature of the hydrolysis reaction is preferably 20-30°C, and specifically can be 25°C; and the time of the hydrolysis reaction is preferably 12-36 h, and specifically can be 24 h.
[0029] After the hydrolysis reaction is completed, the present application preferably washes the obtained product liquid with ether, adjusts the pH value to 2-3 with hydrochloric acid, then performs ether extraction to obtain an organic phase, and spins the organic phase to dryness to obtain indole-3-lactic acid, which is a white to light pink solid.
[0030] The technical solutions in the present application will be described clearly and completely below in combination with the embodiments in the present application. Obviously, the described embodiments are only some of the embodiments of the present application, rather than all the embodiments. Based on the embodiments in the present application, all the other embodiments obtained by those skilled in the art without creative work fall within the scope of protection of the present application.
[0031] Example 1
[0032] Indole 1170 mg (10 mmol), oxirane carboxylic acid methyl ester 1020 mg (10 mmol), tetrabutylammonium bromide 1611.84 mg (5 mmol) were added into a reaction bottle, 20 mL of water was added, and stirring was carried out at 100 °C for 12 h. After the reaction was completed, the reaction was cooled to room temperature, extracted with ether three times, and then the organic phase was combined, dried with anhydrous sodium sulfate, and rotary evaporated to obtain indole-3-lactic acid methyl ester 2080 mg with a yield of 95%.
[0033] Indole-3-lactic acid methyl ester 2080 mg (9.49 mmol), lithium hydroxide 454.6 mg (18.98 mmol) were added into a flask, a mixed solvent of 9.5 mL of methanol and 9.5 mL of water was injected into the flask, and then indole-3-lactic acid methyl ester was hydrolyzed by stirring at 25 °C for 24 h. The obtained product solution was washed with ether 30 mL three times, the ether was discarded, the water layer was adjusted to pH 2 with 1M hydrochloric acid, the water phase was extracted with ether three times (30 mL of ether was used each time), the organic phase was combined, and rotary evaporated to obtain indole-3-lactic acid 1902 mg with a yield of 98%.
[0034] The structure identification data of the product are as follows:
[0035] 1 H NMR (400 MHz, CDCl3) δ 8.09 (S, 1H), 7.67-7.65 (d, J = 8.0 Hz 1H), 7.39-7.37 (d, J = 8 Hz, 1H), 7.24-7.2 (t, J = 7.4 Hz, 1H), 7.13 (s, 1H), 2.41 (s, 3H), 4.58-4.55 (dd, J = 6.5, 4.3 Hz, 1H), 3.24-3.19 (dd, J = 14.7, 4.0 Hz, 1H).
[0036] 13 C NMR (101 MHz, DMSO-d6) δ 117, 136.50, 127.41, 123.0, 121.72, 119.81, 118.80, 111.10, 110.81, 74.32, 34.30.
[0037] MS: m / z, found: 206.10
[0038] The above merely describes the preferred embodiments of the present application, and it should be pointed out that those skilled in the art can make several improvements and refinements without departing from the principles of the present application, and these improvements and refinements should also be considered as falling within the protection scope of the present application.
Claims
1. A method for the synthesis of indole-3-lactic acid, characterized in that, The method comprises the following steps: mixing indole, oxirane carboxylic acid methyl ester, phase transfer catalyst and water to carry out ring-opening reaction to obtain indole-3-lactic acid methyl ester; mixing the indole-3-lactic acid methyl ester, base, alcohol and water to carry out hydrolysis reaction to obtain indole-3-lactic acid.
2. The method of synthesis of claim 1, wherein, The phase transfer catalyst comprises one or more of tetrabutylammonium bromide, tetrabutylammonium iodide, dodecyltrimethylammonium chloride and tetradecyltrimethylammonium chloride.
3. The method of synthesis of claim 1, wherein, The molar ratio of the indole and the oxirane carboxylic acid methyl ester is 1:1-1.
5.
4. The method of synthesis of claim 1, wherein, The molar ratio of the indole and the phase transfer catalyst is 1:0.4-0.
6.
5. The method of synthesis of claim 1, wherein, The ring-opening reaction is carried out at a temperature of 80-120°C for 10-15 hours.
6. The method of synthesis of claim 1, wherein, The base is an alkali metal hydroxide.
7. The method of synthesis of claim 6, wherein, The alkali metal hydroxide comprises one or more of lithium hydroxide, sodium hydroxide and potassium hydroxide.
8. The method of synthesis of claim 1 or 6, wherein, The molar ratio of the indole-3-lactic acid methyl ester and the base is 1:1.5-2.
5.
9. The method of synthesis of claim 1, wherein, The alcohol is methanol; and the volume ratio of the alcohol and water in the hydrolysis reaction is 1:1-2.
10. The method of synthesis of claim 1, wherein, The hydrolysis reaction is carried out at a temperature of 20-30°C for 12-36 hours.