CN118239878A - A kind of synthetic method of indole-3-propionic acid - Google Patents

Abstract

The invention discloses a synthesis method of indole-3-propionic acid, and belongs to the technical field of organic synthesis. The method comprises the following steps: (1) Reacting indole with a compound shown in a formula A in the presence of a catalyst to obtain a compound shown in a formula B; (2) Under alkaline conditions, the compound shown in the formula B undergoes hydrolysis reaction to obtain indole-3-propionic acid. The catalyst is at least one of ZrCl ₄、AlCl₃ and SnCl ₄. The method has the advantages of simple operation, less byproducts, high yield and high product purity. The method has low requirements on equipment, low reagent toxicity and low price, and is convenient for industrialized amplified production. The method has the advantages of wide reagent sources and short production period, and can realize mass production in a short time.

Description

A kind of synthetic method of indole-3-propionic acid

Technical Field

The invention belongs to the technical field of organic synthesis, and particularly relates to a method for synthesizing indole-3-propionic acid.

Background technique

Indole-3-propionic acid is an indole derivative metabolized by tryptophan in the intestinal microbiota. It has anti-inflammatory, antioxidant and immunomodulatory effects, and is essential for maintaining intestinal barrier homeostasis. In the presence of indole, indole-3-propionic acid can activate the pregnane X receptor to inhibit the NF-κB signaling pathway to inhibit enteritis. In addition, indole-3-propionic acid can also maintain intestinal barrier homeostasis by inhibiting TNF-α and activating TLR4, and is expected to become a new type of green feed additive.

At present, there are few patents for synthesizing indole-3-propionic acid, mainly including biological method and chemical method. For example, Chinese invention patents CN117327721A and CN113677802A respectively realize the whole-cell catalytic process of producing indole-3-propionic acid with tryptophan as substrate by constructing engineering strains and original strains. However, the problems of synthesizing indole-3-propionic acid by biological method are: 1) the production capacity and production efficiency of the product are easily affected by the growth of microorganisms; 2) the product preparation cycle is long, and it needs to go through multiple complex steps such as microbial culture, fermentation, bacterial liquid concentration, extraction and purification, and the cost is high. International patent WO2008024914A2 synthesizes indole-3-propionic acid by chemical method. The patent uses indole, acrylic acid, acetic acid and acetic anhydride as raw materials. Under nitrogen protection conditions, indole-3-propionic acid is obtained by reacting at 50°C for 64 hours. However, after the reaction, the excess acetic anhydride needs to be removed by distillation, and there are many by-products that need to be processed, and the yield is only 36%. This method has harsh reaction conditions, many byproducts, low yield, and complex process. Therefore, it is urgent to develop a convenient, fast, and economical synthesis route to produce cheap indole-3-propionic acid.

Summary of the invention

In view of the deficiencies in the prior art, the present invention provides a method for synthesizing indole-3-propionic acid. The method has simple process, low production cost, high yield and is convenient for industrial production.

The method for synthesizing indole-3-propionic acid provided by the present invention comprises the following steps:

(1) reacting indole with the compound represented by formula A in the presence of a catalyst to obtain a compound represented by formula B;

In formula A and formula B, R ₁ is a C ₁ -C ₆ straight chain or branched chain alkyl group, specifically an ethyl group;

(2) Under alkaline conditions, the compound represented by formula B is hydrolyzed to obtain indole-3-propionic acid.

In step (1) of the above method, the catalyst may be at least one of ZrCl ₄ , AlCl ₃ and SnCl ₄ ;

The reaction is carried out in an organic solvent;

The organic solvent is at least one of dichloromethane, tetrahydrofuran and N,N-dimethylformamide;

The molar ratio of indole, the compound represented by formula A, and the catalyst (such as ZrCl ₄ ) can be 1:(1.0-1.5):(0.1-0.3) (preferably, the endpoint value 0.1 is not desirable), specifically 1:1.2:0.2-0.3;

The mass ratio of indole to the organic solvent is 1:(20-50);

The reaction temperature may be 20 to 50°C and the reaction time may be 4 to 8 hours;

The reaction is carried out under magnetic stirring;

After the reaction is completed, a saturated sodium bicarbonate aqueous solution is added to adjust the pH value of the system, and ethyl acetate is added for extraction to obtain an organic phase, which is subjected to silica gel column chromatography to obtain a compound represented by formula B;

The pH value of the system is 8.0-8.5, and the eluent in the silica gel chromatography column is ethyl acetate:petroleum ether=1:3 (v/v).

The operation of step (2) of the above method is: adding sodium hydroxide aqueous solution to the compound represented by formula B, stirring at room temperature for a certain period of time, adding acid to adjust the pH, and filtering to obtain white powdery indole-3-propionic acid.

The mass concentration of the sodium hydroxide aqueous solution is 1% to 10%, the mass ratio of the compound represented by formula B to the sodium hydroxide aqueous solution can be 1:(4 to 10), the stirring time is 3 to 12 hours, and the final pH value of the system is 1 to 6.

Compared with the prior art, the indole-3-propionic acid synthesis process of the present invention has the following characteristics:

1) The method of the present invention is simple to operate, has few by-products, high yield and high product purity.

2) The method of the present invention has low requirements on equipment, low reagent toxicity, low price, and is convenient for industrial scale-up production.

3) The reagents of the method of the present invention are widely available, the production cycle is short, and mass production can be carried out in a short time.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a reaction equation for synthesizing indole-3-propionic acid according to the present invention.

FIG. 2 is a hydrogen nuclear magnetic resonance spectrum of indole-3-propionic acid prepared in Example 1 of the present invention.

FIG3 is a carbon NMR spectrum of indole-3-propionic acid prepared in Example 1 of the present invention.

Detailed ways

The present invention is further described in detail below in conjunction with specific embodiments, and the examples provided are only for illustrating the present invention, rather than for limiting the scope of the present invention. The examples provided below can be used as a guide for further improvements by those of ordinary skill in the art, and do not constitute a limitation of the present invention in any way.

The experimental methods in the following examples, unless otherwise specified, are all conventional methods, and are performed according to the techniques or conditions described in the literature in the field or according to the product instructions. The materials, reagents, etc. used in the following examples, unless otherwise specified, can all be obtained from commercial channels.

The specifications and sources of the reagents used in the following examples are as follows:

Indole, ethyl acrylate, and _ZrCl4 were purchased from Shanghai MacLean Biochemical Technology Co., Ltd., and dichloromethane, ethyl acetate, petroleum ether, hydrochloric acid, sodium hydroxide, and sodium bicarbonate were purchased from Shanghai Sinopharm Chemical Reagent Co., Ltd. All of them were analytically pure reagents.

Example 1. Synthesis of indole-3-propionic acid

(1) Indole, ethyl acrylate, and _ZrCl4 were added to a round-bottom flask at a molar ratio of 1:1.2:0.2, and dichloromethane (30 times the mass of indole) was added, and the mixture was stirred at room temperature (25°C) for 6 hours. After the reaction was completed, an appropriate amount of saturated sodium bicarbonate aqueous solution was added to adjust the pH value of the system to 8.0-8.5, and ethyl acetate was added for extraction to obtain an organic phase, and silica gel column chromatography (ethyl acetate: petroleum ether = 1:3 (v/v)) was performed to obtain indole-3-propionic acid ethyl ester with a yield of 87% and a purity of 97%.

(2) 100 g of ethyl indole-3-propionate was added to 500 g of sodium hydroxide aqueous solution (sodium hydroxide mass concentration 10%), stirred at room temperature for 6 h, and then diluted hydrochloric acid was added to adjust the pH to 1-3. The mixture was filtered to obtain white powdery indole-3-propionic acid with a yield of 100% and a purity of 96%.

Example 2: Synthesis of indole-3-propionic acid

(1) Indole, ethyl acrylate, and AlCl ₃ were added to a round-bottom flask in a molar ratio of 1:1.2:0.2, and dichloromethane (30 times the mass of indole) was added, and stirred at room temperature (25°C) for 6 hours. After the reaction was completed, an appropriate amount of saturated sodium bicarbonate aqueous solution was added to adjust the pH value of the system to 8.0-8.5, and ethyl acetate was added for extraction to obtain an organic phase, and silica gel column chromatography (ethyl acetate: petroleum ether = 1:3 (v/v)) was performed to obtain indole-3-propionic acid ethyl ester with a yield of 72% and a purity of 98%.

(2) 100 g of ethyl indole-3-propionate was added to 500 g of sodium hydroxide aqueous solution (sodium hydroxide mass concentration 10%), stirred at room temperature for 6 h, and then diluted hydrochloric acid was added to adjust the pH to 1-3. The mixture was filtered to obtain white powdery indole-3-propionic acid with a yield of 100% and a purity of 95%.

Example 3. Synthesis of indole-3-propionic acid

(1) Indole, ethyl acrylate, and _SnCl4 were added to a round-bottom flask at a molar ratio of 1:1.2:0.2, and dichloromethane (30 times the mass of indole) was added, and stirred at room temperature (25°C) for 6 hours. After the reaction was completed, an appropriate amount of saturated sodium bicarbonate aqueous solution was added to adjust the pH value of the system to 8.0-8.5, and ethyl acetate was added for extraction to obtain an organic phase, and silica gel column chromatography (ethyl acetate: petroleum ether = 1:3 (v/v)) was performed to obtain indole-3-propionic acid ethyl ester with a yield of 76% and a purity of 96%.

(2) 100 g of ethyl indole-3-propionate was added to 500 g of sodium hydroxide aqueous solution (sodium hydroxide mass concentration 10%), stirred at room temperature for 6 h, and then diluted hydrochloric acid was added to adjust the pH to 1-3. The mixture was filtered to obtain white powdery indole-3-propionic acid with a yield of 100% and a purity of 96%.

Comparative Example 1

Indole, ethyl acrylate, and ZrCl ₄ were added to a round-bottom flask at a molar ratio of 1:1.2:0.05, and dichloromethane (30 times the mass of indole) was added, and the mixture was stirred at room temperature (25°C) for 6 hours. After the reaction was completed, an appropriate amount of saturated sodium bicarbonate aqueous solution was added to adjust the pH value of the system to 8.0-8.5, and ethyl acetate was added for extraction to obtain an organic phase, and silica gel column chromatography (ethyl acetate: petroleum ether = 1:3 (v/v)) was performed to obtain indole-3-propionic acid ethyl ester with a yield of 43%.

The results showed that the yield of the target product was low, indicating that the amount of catalyst ZrCl ₄ added was too low and could not effectively promote the reaction.

Comparative Example 2

Indole, ethyl acrylate, and ZrCl ₄ were added to a round-bottom flask at a molar ratio of 1:2:0.2, and dichloromethane (30 times the mass of indole) was added, and stirred at room temperature (25°C) for 6 hours. After the reaction was completed, an appropriate amount of saturated sodium bicarbonate aqueous solution was added to adjust the pH value of the system to 8.0-8.5, and ethyl acetate was added for extraction to obtain an organic phase, and silica gel column chromatography (ethyl acetate: petroleum ether = 1:3 (v/v)) was performed to obtain indole-3-propionic acid ethyl ester with a yield of 18%.

The results showed that the yield of the target product was low and a large amount of by-products were generated, indicating that the amount of ethyl acrylate added was too large, and a side reaction occurred with indole during the reaction, resulting in competitive inhibition of the synthesis of the target product.

Comparative Example 3

Indole, ethyl acrylate, and ZrCl ₄ were added to a round-bottom flask at a molar ratio of 1:1.2:0.5, and dichloromethane (30 times the mass of indole) was added, and stirred at room temperature (25°C) for 6 hours. After the reaction was completed, an appropriate amount of saturated sodium bicarbonate aqueous solution was added to adjust the pH value of the system to 8.0-8.5, and ethyl acetate was added for extraction to obtain an organic phase, and silica gel column chromatography (ethyl acetate: petroleum ether = 1:3 (v/v)) was performed to obtain indole-3-propionic acid ethyl ester with a yield of 52% and a purity of 73%.

The results showed that the purity of the target product was low, indicating that the addition of too much catalyst ZrCl ₄ would introduce more by-products that were difficult to separate, increase the difficulty of product separation, and reduce product purity.

Comparative Example 4

Indole, ethyl acrylate, and ZrCl ₄ were added to a round-bottom flask at a molar ratio of 1:0.8:0.2, and dichloromethane (30 times the mass of indole) was added, and stirred at room temperature (25°C) for 8 hours. After the reaction was completed, an appropriate amount of saturated sodium bicarbonate aqueous solution was added to adjust the pH value of the system to 8.0-8.5, and ethyl acetate was added for extraction to obtain an organic phase, and silica gel column chromatography (ethyl acetate: petroleum ether = 1:3 (v/v)) was performed to obtain indole-3-propionic acid ethyl ester with a yield of 46% and a purity of 79%.

The results showed that the yield of the target product was low, indicating that the amount of ethyl acrylate added was too small, resulting in more by-products and reducing the purity of the product.

Comparative Example 5

Indole, ethyl acrylate, and AlCl ₃ were added to a round-bottom flask at a molar ratio of 1:1.2:0.05, and dichloromethane (30 times the mass of indole) was added, and stirred at room temperature (25°C) for 8 hours. After the reaction was completed, an appropriate amount of saturated sodium bicarbonate aqueous solution was added to adjust the pH value of the system to 8.0-8.5, and ethyl acetate was added for extraction to obtain an organic phase, and silica gel column chromatography (ethyl acetate: petroleum ether = 1:3 (v/v)) was performed to obtain indole-3-propionic acid ethyl ester with a yield of 23%.

The results showed that the yield of the target product was low, indicating that the amount of catalyst AlCl ₃ added was too small and could not effectively promote the reaction.

Comparative Example 6

Indole, ethyl acrylate, and SnCl ₄ were added to a round-bottom flask at a molar ratio of 1:1.2:0.1, and dichloromethane (30 times the mass of indole) was added, and stirred at room temperature (25°C) for 8 hours. After the reaction was completed, an appropriate amount of saturated sodium bicarbonate aqueous solution was added to adjust the pH value of the system to 8.0-8.5, and ethyl acetate was added for extraction to obtain an organic phase, and silica gel column chromatography (ethyl acetate: petroleum ether = 1:3 (v/v)) was performed to obtain indole-3-propionic acid ethyl ester with a yield of 31%.

The results showed that the yield of the target product was low, indicating that the amount of catalyst SnCl ₄ added was too small and could not effectively promote the reaction.

Comparative Example 7

Indole, ethyl acrylate, and indium bromide (InBr ₃ ) were added to a round-bottom flask in a molar ratio of 1:1.2:0.2, and dichloromethane (30 times the mass of indole) was added, and stirred at room temperature (25°C) for 8 hours. After the reaction was completed, an appropriate amount of saturated sodium bicarbonate aqueous solution was added to adjust the pH value of the system to 8.0-8.5, and ethyl acetate was added for extraction to obtain an organic phase, and silica gel column chromatography (ethyl acetate: petroleum ether=1:3 (v/v)) was performed to obtain indole-3-propionic acid ethyl ester with a yield of 15% and a purity of 59%.

The results showed that the yield of the target product was low and the product purity was low, indicating that the catalytic efficiency of the catalyst InBr ₃ was low and a large amount of by-products were generated.

The present invention has been described in detail above. For those skilled in the art, without departing from the purpose and scope of the present invention, and without the need to carry out unnecessary experimental conditions, the present invention can be implemented in a wide range under equivalent parameters, concentrations and conditions. Although the present invention provides specific embodiments, it should be understood that the present invention can be further improved. In a word, according to the principles of the present invention, the application is intended to include any changes, uses or improvements to the present invention, including departure from the disclosed scope in the application, and changes made with conventional techniques known in the art.

Claims (9)

1. A synthetic method of indole-3-propionic acid comprises the following steps:

(1) Reacting indole with a compound shown in a formula A in the presence of a catalyst to obtain a compound shown in a formula B;

In the formula A and the formula B, R ₁ is a linear or branched alkyl of C ₁-C₆;

(2) Under alkaline conditions, the compound shown in the formula B undergoes hydrolysis reaction to obtain indole-3-propionic acid.

2. The method of claim 1, wherein in step (1), the catalyst is at least one of ZrCl ₄、AlCl₃ and SnCl ₄.

3. The process according to claim 1, wherein in step (1), the reaction is carried out in an organic solvent;

The organic solvent is at least one of dichloromethane, tetrahydrofuran and N, N-dimethylformamide.

4. The method according to claim 1, wherein in step (1), the molar ratio of indole, the compound of formula a, and the catalyst is 1: (1.0-1.5): (0.1-0.3).

5. The method according to claim 1, wherein in the step (1), the reaction is carried out at a temperature of 20 to 50 ℃ for a time of 4 to 8 hours.

6. The method according to claim 1, wherein in the step (1), after the reaction is completed, a saturated sodium bicarbonate aqueous solution is added, the pH value of the system is adjusted, ethyl acetate is added for extraction, an organic phase is obtained, and silica gel column chromatography is performed to obtain the compound shown in the formula B.

7. The method according to claim 6, wherein the pH value of the system is 8.0-8.5, and the leaching solution in the silica gel chromatographic column is ethyl acetate: petroleum ether=1:3, v/v.

8. The method of claim 1, wherein the operation of step (2) is: adding sodium hydroxide aqueous solution into the compound shown in the formula B, stirring for a certain time at normal temperature, adding acid to adjust pH, and carrying out suction filtration to obtain white powdery indole-3-propionic acid.

9. The method according to claim 8, wherein the mass concentration of the aqueous sodium hydroxide solution is 1-10%, and the mass ratio of the compound represented by formula B to the aqueous sodium hydroxide solution is 1: (4-10), stirring time is 3-12 h, and final pH value of the system is 1-6.