Preparation method of high-purity 2-(diethylamino) acetamide

Abstract

The invention discloses a preparation method of high-purity 2-(diethylamino) acetamide, which comprises the following steps: S1, carrying out amine nucleophilic substitution reaction on methyl chloroacetate and diethylamine in an alkaline environment to obtain 2-diethylamino methyl acetate; s2, carrying out amine esterification reaction on methyl 2-diethylaminoacetate and ammonia water in the presence of a catalyst, extracting with an organic solvent after the reaction is finished, and separating to obtain an organic phase containing 2-diethylaminoacetamide; s3, washing the organic phase with water, and then concentrating to recover the organic solvent, so as to obtain a concentrated residue; s4, carrying out high-vacuum rectification on the concentrated residues, so as to obtain white solid 2-diethylaminoacetamide; according to the present invention, the cheap and easily available raw materials are adopted, the three-step reaction route is short, the operation condition is mild, the catalyst and the ammonia are supplemented to the water phase after the amine esterification reaction, and then the water phase is recycled, such that the generation of the high ammonia nitrogen wastewater is effectively reduced, and the prepared 2-(diethylamino) acetamide has characteristics of high purity and good yield.

Description

Technical Field

[0001] This invention relates to the technical field of organic chemical synthesis, specifically to a method for preparing high-purity 2-(diethylamino)acetamide. Background Technology

[0002] 2-(Diethylamino)acetamide is an important pharmaceutical chemical intermediate, mainly used in the synthesis of the local anesthetic lidocaine hydrochloride. With the development of the pharmaceutical industry, higher requirements are being placed on its purity and the economic efficiency and environmental friendliness of large-scale production.

[0003] Currently, there are a few reported synthetic routes for this compound in existing technologies. For example, the literature (A metal-free approach for transamidation of amides with amines in aqueous media, Tetrahedron Letters, 2015) mainly focuses on the application of its subsequent transamidation reaction rather than the synthetic process itself. For the synthesis of 2-(diethylamino)acetamide, existing technologies mainly include the following routes: routes starting with specific expensive raw materials or reagents (such as those reported in WO2013 / 40222A1, etc.), which have high raw material costs and poor industrial economics; routes with lengthy or complex reaction steps (such as those reported in Journal of Organic Chemistry, 1947, etc.), which have low production efficiency and are not conducive to large-scale production; and routes with unsatisfactory product purity, difficult post-processing, or the generation of large amounts of difficult-to-treat wastewater (such as those reported in Justus Liebigs Annalen der Chemie, 1908, etc.), which are difficult to meet the quality standards of high-purity drug intermediates and the requirements of green production.

[0004] In summary, existing synthetic methods generally suffer from problems such as unavailable or expensive raw materials, complex processes, low product purity, and poor environmental friendliness. Therefore, there is an urgent need in this field to develop a method for preparing high-purity 2-(diethylamino)acetamide that uses inexpensive and readily available raw materials, has a short process, is easy to operate, produces high-purity products, has stable yields, and is environmentally friendly. Summary of the Invention

[0005] The purpose of this invention is to provide a method for preparing high-purity 2-(diethylamino)acetamide, so as to solve the problems mentioned in the background art.

[0006] To achieve the above objectives, the present invention provides the following technical solution: a method for preparing high-purity 2-(diethylamino)acetamide, the preparation method comprising the following steps:

[0007] S1: Methyl chloroacetate is reacted with diethylamine in an alkaline environment to undergo an amine nucleophilic substitution reaction to obtain methyl 2-diethylaminoacetate;

[0008] S2: Methyl 2-diethylaminoacetate was subjected to an amination reaction with ammonia in the presence of a catalyst. After the reaction was completed, the mixture was extracted with an organic solvent to separate the organic phase containing 2-diethylaminoacetamide.

[0009] S3: The organic phase is washed with water and then concentrated to recover the organic solvent, yielding a concentrated residue;

[0010] S4: The concentrated residue was subjected to high-vacuum distillation to obtain a white solid 2-diethylaminoacetamide.

[0011] Preferably, the alkaline environment is formed by an inorganic base and a first organic solvent, wherein the inorganic base includes potassium carbonate and the first organic solvent includes acetonitrile.

[0012] Preferably, the temperature of the amine nucleophilic substitution reaction is 70-85°C, and the reaction time is 3.5-4.5 hours.

[0013] Preferably, the molar ratio of methyl chloroacetate to diethylamine is 1:1.1-1.3, and the molar ratio of inorganic base to methyl chloroacetate is 1:1.

[0014] Preferably, the catalyst is composed of a metal salt and an ammonium salt, wherein the metal salt includes copper sulfate pentahydrate and the ammonium salt includes ammonium chloride.

[0015] Preferably, the amination reaction is carried out in a pressure vessel at a pressure of 0.05-0.1 MPa, a temperature of 30-35°C, and a reaction time of 4-6 hours. Ammonia water is obtained by passing ammonia gas through water until saturation.

[0016] Preferably, the molar ratio of methyl 2-diethylaminoacetate to ammonia is 1:10-15.

[0017] Preferably, the organic solvent includes dichloromethane.

[0018] Preferably, the high-vacuum distillation operates at a pressure of 1-5 mmHg, collecting fractions with a boiling point of 110-120°C.

[0019] Preferably, the aqueous phase remaining after separating the organic phase is recycled for the next batch of amination reaction after replenishing the catalyst and ammonia.

[0020] Compared with the prior art, the beneficial effects of the present invention are:

[0021] The present invention provides a method for preparing high-purity 2-(diethylamino)acetamide. While ensuring product quality, this method uses inexpensive and readily available methyl chloroacetate and diethylamine as starting materials. Through a mild and concise three-step reaction, a target product with a purity higher than 99.0% can be obtained. By recycling the aqueous phase after the amine esterification reaction, the treatment difficulty and discharge volume of high ammonia nitrogen wastewater are effectively reduced. The overall process route is clear, the operation is simple, and the yield is high, providing a feasible and more environmentally friendly synthesis route for large-scale production. Attached Figure Description

[0022] Figure 1 This is the GC spectrum of methyl 2-(diethylamino)acetate of the present invention;

[0023] Figure 2 This is the GC spectrum of 2-(diethylamino)acetamide of the present invention;

[0024] Figure 3 This is the mass spectrum of 2-(diethylamino)acetamide of the present invention;

[0025] Figure 4 The 1H NMR spectrum of 2-(diethylamino)acetamide of this invention is shown below.

[0026] Figure 5 The 13C NMR spectrum of 2-(diethylamino)acetamide of this invention is shown. Detailed Implementation

[0027] 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 embodiments of the present invention, and not all embodiments. Based on the 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.

[0028] Please see Figures 1 to 5 This invention provides a technical solution: a method for preparing high-purity 2-(diethylamino)acetamide, the preparation method comprising the following steps:

[0029] S1: Methyl chloroacetate is reacted with diethylamine in an alkaline environment to give methyl 2-diethylaminoacetate. The alkaline environment is formed by an inorganic base and a first organic solvent, the inorganic base including potassium carbonate and the first organic solvent including acetonitrile.

[0030] S2: Methyl 2-diethylaminoacetate is reacted with ammonia in the presence of a catalyst. The temperature for the nucleophilic substitution reaction of the amine is 70-85℃, the reaction time is 3.5-4.5 hours, the molar ratio of methyl chloroacetate to diethylamine is 1:1.1-1.3, the molar ratio of inorganic base to methyl chloroacetate is 1:1, and the catalyst is composed of a metal salt and an ammonium salt, including copper sulfate pentahydrate and ammonium chloride. The esterification reaction is carried out in a pressure vessel at a pressure of 0.05-0.1 MPa, a temperature of 30-35℃, and a reaction time of 4-6 hours. Ammonia is obtained by bubbling ammonia gas into water until saturation. The molar ratio of methyl 2-diethylaminoacetate to ammonia is 1:10-15. After the reaction, the mixture is extracted with an organic solvent to separate the organic phase containing 2-diethylaminoacetamide.

[0031] S3: The organic phase is washed with water and then concentrated to recover the organic solvent, including dichloromethane, to obtain a concentrated residue;

[0032] S4: The concentrated residue is subjected to high-vacuum distillation at an operating pressure of 1-5 mmHg. The fraction with a boiling point of 110-120℃ is collected. After separating the organic phase, the remaining aqueous phase is recycled for the next batch of amination reaction after adding catalyst and ammonia to obtain a white solid 2-diethylaminoacetamide.

[0033] Example 1:

[0034] In a reaction flask, 87.77 g (1.2 mol) of diethylamine, 138.21 g (1 mol) of potassium carbonate, and 425 mL of acetonitrile were added sequentially and stirred until homogeneous. 108.52 g (1 mol) of methyl chloroacetate was slowly added dropwise. After the addition was complete, the temperature was raised to 80 °C and the reaction was maintained at this temperature for 4 h. After the reaction was complete, the temperature was lowered to room temperature, filtered, and the filtrate was concentrated to dryness under reduced pressure to obtain 142.70 g of transparent oily methyl 2-(diethylamino)acetate with a purity of 99.84% and a yield of 98.28%.

[0035] Potassium carbonate, as an inorganic base, plays a crucial role in neutralizing the HCl released during the reaction, thus shifting the reaction equilibrium to the right; it also maintains the alkalinity of the reaction system, preventing diethylamine from being protonated and losing its nucleophilicity; acetonitrile, as a polar aprotic solvent, can effectively dissolve organic reactants and bases, and its aprotic properties are conducive to the formation and stability of diethylamine anions, thereby efficiently attacking methyl chloroacetate.

[0036] The preferred reaction temperature is 80°C and the preferred reaction time is 4 hours. This mild temperature range is sufficient to provide the activation energy required for the reaction, promotes efficient nucleophilic substitution, and effectively avoids side reactions caused by excessive temperature, such as ester hydrolysis and amidation. The 4-hour reaction time ensures complete reaction and high conversion rate.

[0037] An appropriate excess of diethylamine is intended to ensure that methyl chloroacetate is completely consumed, thereby improving reaction efficiency and product yield. The stoichiometric ratio of potassium carbonate is sufficient to neutralize the generated HCl and maintain the alkalinity of the system. An excess may increase the difficulty and cost of post-processing.

[0038] Example 2:

[0039] Add 500g of water, 25g (0.1mol) of copper sulfate pentahydrate, and 21.4g (0.4mol) of ammonium chloride to a pressure vessel and stir until homogeneous. Purge with ammonia gas until saturated, control the pressure inside the vessel at 0.05-0.1MPa, pump in 130.68g (0.9mol) of methyl 2-(diethylamino)acetate, and stir the reaction at 30-35℃ for 4-6 hours. After the reaction is complete, extract with dichloromethane 4 times, 250mL each time, allow to stand and separate into layers, combine the organic phases, and recycle the upper aqueous phase.

[0040] The copper ions in copper sulfate pentahydrate act as Lewis acids, which can activate the carbonyl group of esters, making it more susceptible to attack by ammonia nucleophiles. Ammonium chloride provides ammonium ions, which form a dynamic equilibrium with ammonia in the reaction medium. By forming a more active intermediate or regulating the local microenvironment, it significantly promotes the aminolysis reaction of esters and ammonia, thereby increasing the reaction rate and selectivity.

[0041] Introducing ammonia gas to saturation and maintaining a slight positive pressure ensures a high concentration of ammonia in the reaction system, which is a key kinetic factor driving the complete amine esterification reaction. This reaction is an exothermic or mild process. A low temperature of 30-35℃ can meet the reaction requirements and effectively suppress side reactions such as over-amidation and hydrolysis, while also facilitating the dissolution of ammonia in the solution and maintaining pressure stability.

[0042] High-concentration ammonia water can be prepared on-site by passing ammonia gas through water until it is saturated. This method is more flexible and economical than using commercial concentrated ammonia water, and it is easier to control the actual amount of ammonia added. Dichloromethane has good solubility for the target product 2-(diethylamino)acetamide, and it is immiscible with water and has a density greater than water. This facilitates the efficient transfer of the product from the aqueous phase to the organic phase through liquid-liquid extraction, achieving preliminary separation and purification. Its low boiling point, about 40°C, also makes it easy to recover and reuse the product through distillation in subsequent steps.

[0043] Example 3:

[0044] The above-mentioned 2-(diethylamino)acetamide organic phase was added to the reaction flask, washed once with 10 mL of water, and the aqueous phase was separated. After washing, the organic phase was distilled at atmospheric pressure to recover dichloromethane. The residue was then subjected to high-vacuum distillation, and the fraction was collected at 110℃-120℃ (2 mmHg) to obtain 110.54 g of white solid 2-(diethylamino)acetamide with a purity of 99.86% and a yield of 94.33%.

[0045] Under high vacuum, the boiling point of the compound is significantly reduced, allowing heat-sensitive amide compounds to be distilled and separated at relatively low temperatures. This avoids decomposition, polymerization, or structural changes at high temperatures. By precisely controlling the collection of the fraction with a specific boiling range of 110-120℃ (2 mmHg), it is possible to effectively separate the product from impurities with similar boiling points, such as unreacted raw materials and byproducts, ultimately obtaining a white solid product with a purity exceeding 99.0%.

[0046] The 2-(diethylamino)acetamide prepared in Example 3 was subjected to 1H NMR and 13C NMR tests, respectively, and the results are as follows: Figure 3 and Figure 4 As shown, the specifics are as follows:

[0047] MS: The measured value of [M+H]+ was 131.2.

[0048] The atomic numbers of this substance are as follows:

[0049]

[0050] The 1H NMR spectra of this impurity are shown in Table 1 below:

[0051] Table 1 ¹H NMR Measurement Results

[0052] Chemical shift (ppm) Proton number Multiplicity Belonging 7.14 2 d H-3 2.86 2 s H-4 2.45-2.51 4 q H-6、8 0.95-0.98 6 t H-7、9

[0053] The 13C NMR spectra of this impurity are shown in Table 2 below:

[0054] Table 2 13CNMR Measurement Results

[0055] Chemical shift (ppm) carbon type number of carbon atoms Belonging 174.97 Quaternary carbon 1 C2 57.50 Secondary carbon 1 C4 48.23 Secondary carbon 2 C6、8 12.44 Primary carbon 2 C7、9

[0056] The gas chromatography conditions described above are as follows:

[0057] Column: Agilent HP-1 (30m × 0.32mm, 0.50um);

[0058] Column temperature: Initially 120℃, hold for 2 min, then increase to 210℃ at 10℃ / min and hold for 35 min;

[0059] Inlet temperature: 200℃;

[0060] Detector temperature: 250℃;

[0061] Detector: FID, shunt ratio 5:1;

[0062] Injection method: direct injection, injection volume 1 μL;

[0063] Carrier gas: high-purity nitrogen, flow rate 3.0 ml / min.

[0064] Although embodiments of the invention have been shown and described, it will be understood by those skilled in the art that various changes, modifications, substitutions and alterations can be made to these embodiments without departing from the principles and spirit of the invention, the scope of which is defined by the appended claims and their equivalents.

Claims

1. A method for preparing high-purity 2-(diethylamino)acetamide, characterized in that: The preparation method includes the following steps: S1: Methyl chloroacetate is reacted with diethylamine in an alkaline environment to undergo an amine nucleophilic substitution reaction to obtain methyl 2-(diethylamino)acetate; S2: Methyl 2-(diethylamino)acetate was reacted with ammonia in the presence of a catalyst and then extracted with an organic solvent to obtain an organic phase containing 2-(diethylamino)acetamide. S3: The organic phase is washed with water and then concentrated to recover the organic solvent, yielding a concentrated residue; S4: The concentrated residue was subjected to high-vacuum distillation to obtain a white solid 2-(diethylamino)acetamide.

2. The method for preparing high-purity 2-(diethylamino)acetamide according to claim 1, characterized in that: The alkaline environment is formed by an inorganic base and a first organic solvent, wherein the inorganic base includes potassium carbonate and the first organic solvent includes acetonitrile.

3. The method for preparing high-purity 2-(diethylamino)acetamide according to claim 1, characterized in that: The amine nucleophilic substitution reaction is carried out at a temperature of 70-85℃ for a reaction time of 3.5-4.5 hours.

4. The method for preparing high-purity 2-(diethylamino)acetamide according to claim 1, characterized in that: The molar ratio of methyl chloroacetate to diethylamine is 1:1.1-1.3, and the molar ratio of inorganic base to methyl chloroacetate is 1:

1.

5. The method for preparing high-purity 2-(diethylamino)acetamide according to claim 1, characterized in that: The catalyst is composed of a metal salt and an ammonium salt, the metal salt including copper sulfate pentahydrate and the ammonium salt including ammonium chloride.

6. The method for preparing high-purity 2-(diethylamino)acetamide according to claim 1, characterized in that: The amination reaction is carried out in a pressure vessel at a pressure of 0.05-0.1 MPa, a temperature of 30-35°C, and a time of 4-6 hours. Ammonia water is obtained by passing ammonia gas through water until saturation.

7. The method for preparing high-purity 2-(diethylamino)acetamide according to claim 1, characterized in that: The molar ratio of methyl 2-(diethylamino)acetate to ammonia is 1:10-15.

8. The method for preparing high-purity 2-(diethylamino)acetamide according to claim 1, characterized in that: The organic solvent includes dichloromethane.

9. The method for preparing high-purity 2-(diethylamino)acetamide according to claim 1, characterized in that: The high-vacuum distillation operates at a pressure of 1-5 mmHg, collecting fractions with a boiling point of 110-120℃.

10. The method for preparing high-purity 2-(diethylamino)acetamide according to claim 1, characterized in that: The remaining aqueous phase after separating the organic phase is recycled for the next batch of amination reaction after replenishing the catalyst and ammonia.

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