A process for the synthesis of sodium n-alkyl-beta-aminopropionates from alkylamines and 3-halopropionates

Abstract

The application discloses a method for synthesizing N-alkyl-beta-amino propionic acid sodium from alkyl amine and 3-halogenated propionic acid ester, and belongs to the technical field of organic synthesis. Long-chain fatty amine and an alkali catalyst are dissolved in a solvent to form a uniform solution, then 3-halogenated propionic acid ester is slowly added dropwise in the solution to perform a substitution reaction, after the completion of the substitution reaction, a sodium hydroxide solution is added to perform a hydrolysis reaction, and thus N-alkyl-beta-amino propionic acid sodium is obtained. The method has the characteristics of simple operation, mild conditions, easy separation of the product, high yield and the like.

Description

Technical Field

[0001] This invention relates to a method for synthesizing sodium N-alkyl-β-aminopropionate, and particularly to a method for synthesizing sodium N-alkyl-β-aminopropionate from alkylamines and 3-halopropionates, belonging to the field of organic synthesis technology. Background Technology

[0002] Sodium N-alkyl-β-aminopropionate is an important organic compound widely used in pharmaceuticals, pesticides, and cosmetics. In particular, long-chain N-alkyl-β-aminopropionate is used in cosmetics as a moisturizer, emulsifier, antibacterial agent, and skincare ingredient, exhibiting good water solubility, stability, and multiple functions. Its mechanism of action is related to the amino and carboxyl groups in its chemical structure, allowing it to interact with other ingredients to form stable complexes. With increasing consumer demand for the safety and functionality of cosmetics, the demand for this type of product is constantly growing. Therefore, many researchers are dedicated to developing efficient and high-yield methods for the synthesis of sodium N-alkyl-β-aminopropionate. Among the many products, taking sodium laurylaminopropionate as an example, the main synthesis methods include the β-propiolactone method (see synthesis route ① below), the acrylonitrile method (see synthesis route ② below), the methyl acrylate method (see synthesis route ③ below), and the acrylic acid method (see synthesis route ④ below). These methods use dodecylamine as the starting material and react it with relatively inexpensive acrylonitrile, acrylic acid, acrylate, and the more expensive β-propiolactone to synthesize sodium laurylaminopropionate in two steps.

[0003]

[0004] Currently, there are many research reports on the synthesis of sodium laurylaminopropionate, but most methods have problems such as complex operation, low yield, and harsh reaction conditions. Summary of the Invention

[0005] In view of the shortcomings of the existing technology, the purpose of this invention is to provide a method for synthesizing sodium N-alkyl-β-aminopropionate from alkylamines and 3-halopropionates. This method is simple to operate, has mild conditions, and the product is easy to separate, and can achieve high-yield synthesis of sodium N-alkyl-β-aminopropionate.

[0006] To achieve the above-mentioned technical objectives, the present invention provides a method for synthesizing sodium N-alkyl-β-aminopropionate from alkylamines and 3-halopropionates. The method involves dissolving a long-chain fatty amine and an alkaline catalyst in a solvent to form a homogeneous solution, then slowly adding 3-halopropionate to the solution to carry out a substitution reaction. After the substitution reaction is completed, sodium hydroxide solution is added to carry out a hydrolysis reaction to obtain the product.

[0007] The key to the synthesis of sodium N-alkyl-β-aminopropionate in this invention lies in achieving a highly selective substitution reaction between long-chain aliphatic amines and 3-halopropionates. Since the α-H of 3-halopropionates is highly reactive, especially under the action of a base catalyst, it readily undergoes α-β elimination to form acrylic ester byproducts. The key to the technical solution of this invention is twofold: firstly, the long-chain aliphatic amine and the base catalyst are pre-dissolved in a solvent, utilizing the base catalyst to enhance the reactivity of the long-chain aliphatic amine; secondly, the 3-halopropionate is slowly introduced into the solution system, thereby effectively avoiding the intramolecular elimination reaction of the 3-halopropionate and achieving highly selective conversion into the N-alkyl-β-aminopropionate intermediate.

[0008] As a preferred embodiment, the long-chain fatty amine has the following molecular structure: The 3-halopropionate has the following molecular structure: Where R1 is C6~C 18 R1 is an alkyl group; R2 is a C1-C3 alkyl group; X is I, Br or Cl.

[0009] As a preferred embodiment, the 3-halopropionate is further preferably a 3-chloropropionate with high substitution reactivity.

[0010] As a preferred embodiment, the alkaline catalyst includes at least one of sodium hydroxide, potassium hydroxide, pyridine, and potassium carbonate. Preferred alkaline catalysts can all catalyze the substitution reaction between long-chain aliphatic amines and 3-halopropionates, but when sodium hydroxide is chosen as the alkaline catalyst, its catalytic effect on the substitution reaction is significantly better than other alkaline catalysts such as potassium hydroxide, pyridine, and potassium carbonate.

[0011] As a preferred embodiment, the amount of the alkaline catalyst is 50-200% of the molar amount of the long-chain aliphatic amine. With increasing alkaline catalyst dosage, the yield of the substitution reaction product initially increases and then tends to plateau. When the amount of alkaline catalyst reaches 150% of the molar amount of the long-chain aliphatic amine, further increasing the amount of alkaline catalyst has almost no effect on increasing the yield of the substitution reaction product. Therefore, the preferred amount of alkaline catalyst is 150-200% of the molar amount of the long-chain aliphatic amine.

[0012] As a preferred embodiment, the solvent includes at least one selected from water, ethanol, ethyl acetate, tetrahydrofuran, acetonitrile, and DMF. The solvent has a significant impact on the substitution reaction between long-chain aliphatic amines and 3-halopropionates. Numerous experiments have shown that protic solvents are more effective than aprotic solvents in substitution reactions. For example, water or ethanol is more effective than other aprotic solvents such as EA, THF, and acetonitrile. Ethanol is the most effective solvent for the substitution reaction.

[0013] As a preferred embodiment, the molar ratio of the 3-halopropionate to the long-chain fatty amine is 1 to 2:1. An appropriate excess of 3-halopropionate is beneficial for improving the conversion rate of the long-chain fatty amine, thereby increasing the yield of the substitution reaction product. The molar ratio of the 3-halopropionate to the long-chain fatty amine is further preferably 1.1 to 1.5:1.

[0014] As a preferred embodiment, the addition rate of the 3-halopropionate is controlled at 1~10 s per drop. The addition rate of the 3-halopropionate needs to be strictly controlled. If the addition rate is too slow, the reaction efficiency will be low. If the addition rate is too fast, it will lead to excessively high local concentrations of 3-halopropionate, which may easily cause elimination side reactions, thereby further reducing the utilization rate of 3-halopropionate.

[0015] As a preferred embodiment, the substitution reaction conditions are: a temperature of 25~100℃ and a time of 4~6 hours. Temperatures that are too high or too low are detrimental to the substitution reaction. Too low a temperature results in lower substitution efficiency, while too high a temperature increases the probability of intramolecular elimination of the 3-halopropionate. Therefore, a further preferred temperature is 40~80℃.

[0016] As a preferred embodiment, the saponification reaction is performed under the following conditions: a temperature of 80-110°C and a time of 4-6 hours.

[0017] As a preferred embodiment, a long-chain fatty amine and sodium hydroxide are dissolved in ethanol at a molar ratio of 1:1.1~1.5 to form a homogeneous solution. Then, 3-halopropionate, which is 1.5~2.0 times the molar amount of the long-chain fatty amine, is slowly added dropwise to the solution at a rate of 1~10s per drop. The reaction is carried out at 40~80°C for 4~6 hours. Then, sodium hydroxide solution is added and the reaction is carried out at 80~110°C for 0.5~1.5 hours. Finally, acetone is added to precipitate the product.

[0018] The molecular structure of sodium N-alkyl-β-aminopropionate of the present invention is shown below:

[0019]

[0020] Where R1 is C6~C 18 Alkyl groups.

[0021] Compared with existing technologies, the beneficial technical effects of the present invention are as follows:

[0022] The method for synthesizing sodium N-alkyl-β-aminopropionate provided by this invention has the advantages of simple operation, mild conditions, easy product separation, and high yield. Detailed Implementation

[0023] The following specific embodiments are intended to further illustrate the content of the present invention, rather than to limit the scope of protection of the claims.

[0024] Unless otherwise stated, the terms used in this invention generally have the meanings commonly understood by those skilled in the art.

[0025] Unless otherwise specified, the experimental methods used in the following examples are conventional methods.

[0026] Unless otherwise specified, all reagents, materials, instruments, etc. used in the following examples are commercially available.

[0027] The main chemical reaction equations involved in this invention are as follows:

[0028]

[0029] Among them, R 1 C6~C 18 Long-chain alkyl groups, R 2 It is a short-chain alkyl group of C1 to C3, and X is a halogen substituent.

[0030] The following optimization experiment uses dodecylamine and ethyl 3-chloropropionate as an example to explore the optimal reaction conditions.

[0031] The following optimization experiments were conducted according to the following procedure: 1 mol of dodecylamine and an appropriate amount of catalyst were added to the reaction vessel, followed by 100 ml of solvent. The temperature was raised to the required reaction temperature to promote homogeneous mixing of the reactants. Then, ethyl 3-chloropropionate (1.1 equivalents) was slowly added dropwise to the reaction vessel, controlling the dropping rate (1 drop / s) and reaction temperature to ensure a stable reaction. After 5 hours of reaction, TLC was performed. After the reaction was complete, the temperature was raised to 95°C, and an alkaline solution (prepared as a 35% aqueous solution using 1.1 mol NaOH) was added for saponification for 1 hour. After saponification, heating was stopped, and the reactants were cooled to room temperature. The reactants were then post-treated by purifying with 500 g of acetone for 2 hours, followed by filtration and drying to remove impurities and byproducts, yielding high-purity sodium laurylaminopropionate.

[0032] The optimized experimental conditions and the yield of sodium N-dodecyl-β-aminopropionate under the corresponding conditions are as follows:

[0033]

[0034] a: Ethyl 3-chloropropionate, 1.0 equivalent.

[0035] b: Ethyl 3-chloropropionate, 1.5 equivalents.

[0036] c: Ethyl 3-chloropropionate, 2.0 equivalents.

[0037] Experiments 1-4 show that most alkaline catalysts, such as sodium hydroxide, potassium hydroxide, pyridine, and potassium carbonate, can catalyze the smooth progress of substitution reactions, but sodium hydroxide is the most effective catalyst.

[0038] Experiments 1 and 5-10 show that substitution reactions can proceed smoothly in solvents such as water, ethanol, ethyl acetate, tetrahydrofuran, acetonitrile, and DMF. However, the solvent has a significant impact on the substitution reaction. Numerous experiments have shown that substitution reactions are more effective when using protic solvents than non-protic solvents. For example, using water or ethanol as a solvent is more effective than using other non-protic solvents such as EA, THF, and acetonitrile. When using ethanol as a solvent, the substitution reaction is most effective.

[0039] Experiments 1 and 11-14 show that as the reaction temperature increases, the efficiency of the substitution reaction first increases and then decreases, with the best results observed in the range of 40-80℃. Both excessively high and low temperatures are detrimental to the substitution reaction. Too low a temperature results in lower substitution efficiency, while too high a temperature increases the probability of intramolecular elimination of 3-halopropionate.

[0040] Experiments 1 and 15-17 show that as the amount of alkaline catalyst increases, the yield of the substitution reaction product first increases and then tends to level off. When the amount of alkaline catalyst is increased to 150% of the molar amount of long-chain aliphatic amine, further increasing the amount of alkaline catalyst has almost no effect on the increase in the yield of the substitution reaction product.

[0041] Experiments 1 and 18 show that an appropriate excess of 3-halopropionate can compensate for the loss caused by a small amount of 3-halopropionate side reactions, which is beneficial to improving the conversion rate of long-chain aliphatic amines and thus increasing the yield of substitution reaction products. When the amount of ethyl 3-chloropropionate is 1.0 equivalent, the yield of substitution reaction products reaches 89%, indicating that the selectivity of the α-β elimination reaction of ethyl 3-chloropropionate is relatively low, with the vast majority of ethyl 3-chloropropionate undergoing β-substitution.

[0042] Based on the above optimization test results, the optimal experimental scheme was selected: the reaction raw materials are 1 equiv long-chain fatty amine and 1.1 equiv ethyl halopropionate, catalyzed by 1.1 equiv sodium hydroxide, with an appropriate amount of ethanol as solvent, and continuously stirred at 60°C until the raw materials react completely, and then saponification is carried out at 95°C.

[0043] The following examples were conducted under the optimal reaction conditions obtained from the above-described optimization experiments, mainly considering the effects of different substrates on the synthesis of sodium N-alkyl-β-aminopropionate under the optimal reaction conditions.

[0044] Example 1

[0045] In a reaction vessel, 1 mol of dodecylamine and 1.1 mol of NaOH were added, followed by 100 ml of EtOH as a solvent to promote homogeneous mixing of the reactants. After complete dissolution, the temperature was raised to 60°C. Once the temperature was reached, 3-chloropropionate was slowly added dropwise to the reaction vessel, controlling the dropping rate (1 drop / second) and the reaction temperature (60°C) to ensure a stable reaction. After the addition was complete, the reaction proceeded for 5 hours, followed by TLC analysis. After the reaction was complete, the temperature was raised to 95°C, and 1.1 mol of NaOH was added to prepare a 35% aqueous solution for saponification for 1 hour. After saponification, heating was stopped, and the reactants were cooled to room temperature. The reactants were then post-treated by purifying with 3 kg of acetone for 2 hours, followed by filtration, washing, and drying to remove impurities and byproducts, yielding high-purity sodium laurylaminopropionate with a yield of 99%. 1H NMR (400 MHz, CDCl3) δ 3.13 (t, J = 5.8 Hz, 2H), 2.96 – 2.84 (m, 2H), 2.67 (t, J = 5.8 Hz, 2H), 1.74 (ddd, J = 15.5, 11.2, 7.1Hz, 2H), 1.30 – 1.17 (m, 17H), 0.83 – 0.78 (m, 3H). 13C NMR (101 MHz, CDCl3)δ 174.90, 76.21, 47.44, 43.78, 31.80, 30.90, 28.62, 28.54, 28.49, 28.33,28.10, 25.78, 24.83, 21.67, 13.11.

[0046] Example 2

[0047] In a reaction vessel, 1 mol of octadecylamine and 1.1 mol of NaOH were added, followed by 100 ml of EtOH as a solvent to promote homogeneous mixing of the reactants. After complete dissolution, the temperature was raised to 60°C. Once the temperature was reached, 3-chloropropionate was slowly added dropwise to the reaction vessel, controlling the dropping rate (1 drop / second) and the reaction temperature (60°C) to ensure a stable reaction. After the addition was complete, the reaction proceeded for 5 hours, and TLC was performed. After the reaction was complete, the temperature was raised to 95°C, and 1.1 mol of NaOH was added to prepare a 35% aqueous solution for saponification for 1 hour. After saponification, heating was stopped, and the reactants were cooled to room temperature. The reactants were then post-treated by purifying with 3 kg of acetone for 2 hours, followed by filtration, washing, and drying to remove impurities and byproducts, yielding high-purity sodium octadecylamine propionate with a yield of 94%.

[0048] Comparative Example 1

[0049] In a reaction vessel, 1 mol of dodecylamine, 1.1 mol of NaOH, and 1.1 mol of 3-chloropropionate were added. Then, 100 ml of EtOH was added as a solvent to promote homogeneous mixing of the reactants. After complete dissolution, the mixture was heated to 60°C and reacted for 5 hours. The reaction was then analyzed by TLC. After the reaction was complete, the temperature was raised to 95°C, and 1.1 mol of NaOH was added to prepare a 35% aqueous solution for saponification for 1 hour. After saponification, heating was stopped, and the reactants were cooled to room temperature. The reactants were then post-treated by purifying with 3 kg of acetone for 2 hours, followed by filtration, washing, and drying to remove impurities and byproducts, yielding high-purity sodium dodecylamine propionate with a yield of 68%.

[0050] This comparative example illustrates that adding 3-chloropropionate ester to the reaction system all at once resulted in significant side reactions, greatly reducing the yield of sodium dodecylaminopropionate.

Claims

1. A method for synthesizing sodium N-alkyl-β-aminopropionate from alkylamines and 3-halopropionates, characterized in that: After dissolving a long-chain fatty amine and an alkaline catalyst in a solvent to form a homogeneous solution, 3-halopropionate is slowly added dropwise to the solution to carry out a substitution reaction. After the substitution reaction is completed, sodium hydroxide solution is added to carry out a hydrolysis reaction to obtain the product. The long-chain fatty amine has the following molecular structure: ； The 3-halopropionate has the following molecular structure: ； in, R1 is C6~C 18 Alkyl groups; R2 is a C1~C3 alkyl group; X is I, Br, or Cl; The alkaline catalyst includes at least one of sodium hydroxide, potassium hydroxide, pyridine, and potassium carbonate.

2. The method for synthesizing sodium N-alkyl-β-aminopropionate from alkylamines and 3-halopropionates according to claim 1, characterized in that: The amount of the alkaline catalyst used is 50-200% of the molar amount of the long-chain fatty amine.

3. The method for synthesizing sodium N-alkyl-β-aminopropionate from alkylamines and 3-halopropionates according to claim 1, characterized in that: The solvent includes at least one of water, ethanol, ethyl acetate, tetrahydrofuran, acetonitrile, and DMF.

4. The method for synthesizing sodium N-alkyl-β-aminopropionate from alkylamines and 3-halopropionates according to claim 1, characterized in that: The molar ratio of the 3-halopropionate to the long-chain fatty amine is 1~2:

1.

5. The method for synthesizing sodium N-alkyl-β-aminopropionate from alkylamines and 3-halopropionates according to claim 1, characterized in that: The addition rate of the 3-halopropionate is controlled at 1~10 s per drop.

6. A method for synthesizing sodium N-alkyl-β-aminopropionate from an alkylamine and a 3-halopropionate according to claim 1, 3, 4 or 5, characterized in that: The conditions for the substitution reaction are: temperature 25~100℃, time 4~6 hours.

7. The method for synthesizing sodium N-alkyl-β-aminopropionate from alkylamines and 3-halopropionates according to claim 1, characterized in that: The saponification reaction is performed under the following conditions: temperature of 80-110℃ and time of 0.5-1.5 hours.

8. A method for synthesizing sodium N-alkyl-β-aminopropionate from an alkylamine and a 3-halopropionate according to claim 1, 3, 4, 5 or 7, characterized in that: After dissolving a long-chain fatty amine and sodium hydroxide in ethanol at a molar ratio of 1:1.1~1.5 to form a homogeneous solution, 3-halopropionate ester, which is 1.5~2.0 times the molar amount of the long-chain fatty amine, is slowly added dropwise to the solution at a rate of 1~10s per drop. The reaction is carried out at 40~80℃ for 4~6 hours. Then, sodium hydroxide solution is added and the reaction is carried out at 80~110℃ for 0.5~1.5 hours. Finally, acetone is added to precipitate the product.

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