Method for preparing 5-methoxytryptamine by one-pot method

Abstract

The invention discloses a method for preparing 5-methoxytryptamine by a one-pot method, which comprises the following steps: by taking 1, 2, 3, 4-tetrahydro-6-methoxy-1-oxo-beta-carboline as a raw material, neutralizing by using strong acid instead of traditional acetic acid during ring-opening reaction, and carrying out decarboxylation reaction on a ring-opening product without separating to prepare the 5-methoxytryptamine. The method can completely avoid the generation of sodium acetate in the ring-opening reaction in the traditional technology, reduces the influence on the next decarboxylation reaction, and can directly perform the decarboxylation reaction without separating the ring-opening product, thereby effectively solving the problem that the decarboxylation reaction needs to be directly performed in the prior art. According to the method for preparing the 5-methoxytryptamine by using the 2, 3, 4-tetrahydro-6-methoxy-1-oxo-beta-carboline as the raw material, the defects that weak acid is left and an intermediate needs to be separated in the method are overcome, and the reaction route is shortened. The method improves the product yield and purity, has the advantages of simplicity and convenience in operation, high product purity, less three wastes and low cost, and is suitable for large-scale industrial production.

Description

Technical Field

[0001] This invention relates to the field of organic intermediate synthesis technology, and in particular to a one-pot method for preparing 5-methoxytryptamine from 1,2,3,4-tetrahydro-6-methoxy-1-oxo-β-carbaline as a raw material. Background Technology

[0002] 5-Methoxytryptamine is one of the important intermediates in the synthesis of melatonin. In early synthetic routes, the Fisher indole synthesis was widely used to construct its indole ring structure. This method typically uses carbonyl compounds such as p-methoxyphenylhydrazine and 4-cyano-2-butanone as raw materials, and carries out a cyclization reaction under the catalysis of strong acids such as polyphosphoric acid and concentrated sulfuric acid to obtain the key intermediate 5-methoxytryptamine-3-acetonitrile. The disadvantage of this method is that the system is strongly acidic after the reaction. Traditional post-treatment usually involves quenching with ice water and then adjusting to neutrality with a strong alkaline solution such as sodium hydroxide. This process is violently exothermic and easily generates an overly alkaline environment locally, leading to side reactions such as decomposition and polymerization of the sensitive indole product, generating tar-like substances, which reduces the product yield and purity, makes subsequent extraction and separation difficult, and results in a complex process and a large amount of waste.

[0003] To simplify the process and avoid the challenges of strong acid post-treatment, a synthetic route using 1,2,3,4-tetrahydro-6-methoxy-1-oxo-β-carboline as a key intermediate was subsequently developed. After ring-opening of β-carboline under alkaline conditions, conventional processes typically employ acetic acid for neutralization to remove excess alkali. However, this method has the drawback of generating sodium acetate as a byproduct. Sodium acetate is difficult to completely remove in the subsequent decarboxylation reaction, and its residue can conflict with reaction conditions, potentially inhibiting the decarboxylation reaction or triggering side reactions, leading to unsatisfactory yield and purity of the final product, 5-methoxytryptamine. To avoid this impact, a separation and purification step must be added after ring-opening to remove sodium acetate, resulting in a longer process flow, increased costs, and hindering industrial production. Summary of the Invention

[0004] The purpose of this invention is to overcome the shortcomings of the prior art and provide a one-pot method for preparing 5-methoxytryptamine, using 1,2,3,4-tetrahydro-6-methoxy-1-oxo-β-carbaline as raw material. This method improves the yield and purity while reducing the generation of by-products and shortening the reaction route, thereby facilitating the industrial production and application of 5-methoxytryptamine.

[0005] The objective of this invention is achieved through the following technical solution:

[0006] The present invention provides a one-pot method for preparing 5-methoxytryptamine, comprising the following steps:

[0007] (1) A sodium hydroxide aqueous solution with a concentration of 20-30%, preferably 23-26%, is mixed with ethanol at a mass ratio of ethanol:sodium hydroxide aqueous solution = 0.8-0.9:1, preferably 0.85-0.88:1, to obtain a mixed solution;

[0008] (2) 1,2,3,4-tetrahydro-6-methoxy-1-oxo-β-carbaline is added to the mixed solution and reacted at 70-100°C until dissolved. The reaction time is 6-10 h, preferably 7-8 h, to obtain the reaction solution.

[0009] (3) The ethanol in the reaction solution is removed by concentration, and the remaining reaction solution is neutralized with a strong acid to pH 6-7 to obtain a solution system;

[0010] (4) A strong acid is introduced into the solution system, and the acid concentration of the solution system is controlled at 3.0-5.0%, preferably 3.5-4.5%, the reaction temperature is 90-110℃, preferably 95-105℃, and the holding time is 3-5h; then the temperature is lowered to 50℃, and the pH of the solution system is adjusted to 5.0-8.0, preferably 6.0-7.0, with soda ash, and then the pH is adjusted to 11-12 with a 30% sodium hydroxide aqueous solution. The decarboxylation product obtained is 5-methoxytryptamine, with a product purity of 98.77-98.87% and a yield of 87.8-88.3%.

[0011] Furthermore, in step (3) of this invention, the neutralization time with added strong acid is 1-2 hours. The strong acid includes hydrochloric acid, sulfuric acid, sulfonic acid, or nitric acid.

[0012] The present invention has the following beneficial effects:

[0013] (1) Simplify reaction steps and improve reaction efficiency: Since no difficult-to-remove byproducts are generated, the ring-opening reaction solution can be directly used for the next decarboxylation reaction, realizing a one-pot method to shorten the reaction route, simplifying the separation and purification steps of intermediates, significantly shortening the production cycle and improving production efficiency.

[0014] (2) Avoid post-treatment of byproducts: Strong acid neutralization is used instead of traditional glacial acetic acid neutralization, which completely avoids the interference of sodium acetate on the decarboxylation reaction.

[0015] (3) Improve product yield and purity: Eliminate the side reaction introduced by sodium acetate, make the decarboxylation reaction more thorough, and improve product purity, i.e., from 97.35% to 98.77-98.87%; pH control is more precise, reduce product decomposition, and improve product yield, i.e. from 86.5% to 87.8-88.3%.

[0016] (4) Green and environmentally friendly, conducive to industrialization: This invention avoids the generation of sodium acetate, reduces the mixing of sodium acetate with other inorganic salts, makes wastewater treatment simpler and more efficient, and is safe and easy to operate, making it very suitable for large-scale industrial production. Attached Figure Description

[0017] The present invention will now be described in further detail with reference to the embodiments and accompanying drawings:

[0018] Figure 1 This is a schematic diagram of the process flow according to an embodiment of the present invention;

[0019] Figure 2 The results are HPLC detection results of 5-methoxytryptamine prepared in Example 1 of this invention;

[0020] Figure 3 This is the HPLC detection result of 5-methoxytryptamine prepared in Example 2 of this invention;

[0021] Figure 4 This is the HPLC detection result of 5-methoxytryptamine prepared in Example 3 of this invention;

[0022] Figure 5 This is the HPLC detection result of 5-methoxytryptamine prepared in a comparative ratio. Detailed Implementation

[0023] Example 1:

[0024] This embodiment describes a one-pot method for preparing 5-methoxytryptamine, such as... Figure 1 As shown, the steps are as follows:

[0025] (1) Mix 306g of 25% sodium hydroxide aqueous solution with 330ml of 95% ethanol to obtain a mixed solution;

[0026] (2) Add 135g of 1,2,3,4-tetrahydro-6-methoxy-1-oxo-β-carbaline to the above mixed solution and react at 90℃ until dissolved. The reaction time is 8h to obtain the reaction solution.

[0027] (3) The ethanol in the above reaction solution is removed by concentration, and the remaining reaction solution is neutralized with 31% hydrochloric acid (the dropping time is controlled at 1.5h) until pH=6 to obtain the solution system;

[0028] (4) Pass 210 ml of 31% hydrochloric acid into the above solution system, control the acid concentration of the solution system to 4.0%, the reaction temperature to 103℃, and the holding time to 3h; then cool down to 50℃, adjust the pH of the solution system to 7.0 with soda ash, and then adjust the pH to 11-12 with 30% sodium hydroxide aqueous solution. The decarboxylation product obtained is 5-methoxytryptamine.

[0029] like Figure 2 As shown, the 5-methoxytryptamine prepared in this example had a purity of 98.87% and a yield of 88.3% as determined by HPLC.

[0030] Example 2:

[0031] This embodiment describes a one-pot method for preparing 5-methoxytryptamine, such as... Figure 1 As shown, the steps are as follows:

[0032] (1) Mix 306g of 26% sodium hydroxide aqueous solution with 330ml of 95% ethanol to obtain a mixed solution;

[0033] (2) 135g of 1,2,3,4-tetrahydro-6-methoxy-1-oxo-β-carbamoline was added to the above mixed solution and reacted at 85℃ until dissolved. The reaction time was 8h to obtain the reaction solution.

[0034] (3) The ethanol in the above reaction solution is removed by concentration, and the remaining reaction solution is neutralized with 31% hydrochloric acid (the dropping time is controlled at 1.5h) until pH=7 to obtain the solution system;

[0035] (4) Pass 230 ml of 31% hydrochloric acid into the above solution system, control the acid concentration of the solution system to 5.0%, the reaction temperature to 99℃, and the holding time to 3h; then cool down to 50℃, adjust the pH of the solution system to 6.0 with soda ash, and then adjust the pH to 11-12 with 30% sodium hydroxide aqueous solution. The decarboxylation product obtained is 5-methoxytryptamine.

[0036] like Figure 3 As shown, the 5-methoxytryptamine prepared in this example had a purity of 98.77% and a yield of 87.8% as determined by HPLC.

[0037] Example 3:

[0038] This embodiment describes a one-pot method for preparing 5-methoxytryptamine, such as... Figure 1 As shown, the steps are as follows:

[0039] (1) Mix 306g of 23% sodium hydroxide aqueous solution with 330ml of 95% ethanol to obtain a mixed solution;

[0040] (2) Add 135g of 1,2,3,4-tetrahydro-6-methoxy-1-oxo-β-carbaline to the above mixed solution and react at 90℃ until dissolved. The reaction time is 8h to obtain the reaction solution.

[0041] (3) The ethanol in the above reaction solution is removed by concentration, and the remaining reaction solution is neutralized with 31% hydrochloric acid (the dropping time is controlled at 1.5h) until pH=6 to obtain the solution system;

[0042] (4) Pass 210 ml of 31% hydrochloric acid into the above solution system, control the acid concentration of the solution system to 4.0%, the reaction temperature to 102℃, and the holding time to 3h; then cool down to 50℃, adjust the pH of the solution system to 6.0 with soda ash, and then adjust the pH to 11-12 with 30% sodium hydroxide aqueous solution. The decarboxylation product obtained is 5-methoxytryptamine.

[0043] like Figure 4 As shown, the 5-methoxytryptamine prepared in this example had a purity of 98.81% and a yield of 88% as determined by HPLC.

[0044] Comparative example:

[0045] The conventional preparation method for 5-methoxytryptamine, as shown in this comparative example, includes the following steps:

[0046] (1) Mix 306g of 25% sodium hydroxide aqueous solution with 330ml of 95% ethanol to obtain a mixed solution;

[0047] (2) Add 135g of 1,2,3,4-tetrahydro-6-methoxy-1-oxo-β-carbaline to the above mixed solution and react at 90℃ until dissolved. The reaction time is 8h to obtain the reaction solution.

[0048] (3) The above reaction solution does not need to be concentrated. It is directly neutralized with glacial acetic acid (the dropping time is controlled at 1.5h) until pH=6. After filtration, a small amount of sodium acetate residue is washed away with hot water. After filtration again, the ring-opening product 2-carboxy-5-methoxytryptamine is obtained.

[0049] (4) Add the dried 2-carboxy-5-methoxytryptamine to 1400 ml of 4% hydrochloric acid aqueous solution, the reaction temperature is 105℃, and the heat is kept for 3 hours after dissolution; then cool down to 50℃, adjust the pH of the system to 7.0 with soda ash, and then adjust the pH to 11-12 with 30% sodium hydroxide aqueous solution. The decarboxylation product obtained is 5-methoxytryptamine.

[0050] like Figure 5 As shown, the 5-methoxytryptamine prepared in this comparative example had a purity of 97.35% by HPLC and a yield of 86.5%.

Claims

1. A process for the one-pot preparation of 5-methoxytryptamine, characterized in that Includes the following steps: (1) A 20-30% sodium hydroxide aqueous solution and ethanol are mixed at a mass ratio of ethanol:sodium hydroxide aqueous solution = 0.8-0.9:1 to obtain a mixed solution; (2) 1,2,3,4-tetrahydro-6-methoxy-1-oxo-β-carbaline was added to the mixed solution and reacted at 70-100°C until dissolved for 6-10 hours to obtain a reaction solution; (3) The ethanol in the reaction solution is removed by concentration, and the remaining reaction solution is neutralized with a strong acid to pH 6-7 to obtain a solution system; (4) A strong acid is introduced into the solution system, and the acid concentration of the solution system is controlled at 3.0-5.0%, the reaction temperature is 90-110℃, and the holding time is 3-5h; then the temperature is lowered to 50℃, the pH of the solution system is adjusted to 5.0-8.0 with soda ash, and then the pH is adjusted to 11-12 with a 30% sodium hydroxide aqueous solution. The decarboxylation product obtained is 5-methoxytryptamine, the purity of the product is 98.77-98.87%, and the yield is 87.8-88.3%.

2. The process for one-pot preparation of 5-methoxytryptamine as claimed in claim 1 wherein: The concentration of the sodium hydroxide aqueous solution in step (1) is 23-26%; the mass ratio of ethanol to sodium hydroxide aqueous solution is 0.85-0.88:

1.

3. The process for one pot preparation of 5-methoxytryptamine as claimed in claim 1 wherein: The reaction time in step (2) is 7 to 8 hours.

4. The method for preparing 5-methoxytryptamine in a one-pot process according to claim 1, characterized in that: The neutralization time for adding strong acid in step (3) is 1 to 2 hours.

5. The method for preparing 5-methoxytryptamine in a one-pot process according to claim 1, characterized in that: In step (4), the acid concentration is 3.5-4.5%, the reaction temperature is 95-105℃, and the pH of the solution system is adjusted to 6.0-7.0 using soda ash.

6. The method for preparing 5-methoxytryptamine in a one-pot process according to claim 1, characterized in that: The strong acids include hydrochloric acid, sulfuric acid, sulfonic acid, or nitric acid.

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