A continuous method for the synthesis of phenylglycinamide ethyl ester

Abstract

The application discloses a continuous synthesis method of benzylaminoethyl acetate. The continuous flow synthesis method can realize accurate control of reaction conditions, improve the selectivity and purity of products. In addition, the continuous flow synthesis method feeds the reactants at a suitable rate, avoids violent reaction under high concentration, and improves the safety of the production reaction. By designing a continuous flow micro-reaction module, glycine ethyl ester hydrochloride and a catalyst triethylamine are dissolved in toluene under a nitrogen atmosphere to obtain a homogeneous material A; another reactant benzaldehyde is material B. By adjusting the liquid flow meter, the feeding rate of A is adjusted to 36.96 ml / min, and the feeding rate of material B is controlled to 4.41 ml / min by a liquid plunger pump. After material A and material B are continuously synthesized in the micro-reaction module, the products flow into the product storage tank.

Description

Technical Field

[0001] This invention relates to a continuous synthesis method for ethyl phenylmethylaminoethyl, specifically in the field of methionine intermediate preparation technology using continuous flow equipment. Background Technology

[0002] Methionine, also known as methionine, has the molecular formula C5H10. 11 NO2S appears as white, thin, flaky crystals or powder, has a distinctive odor, and a slightly sweet taste. Methionine is one of the basic building blocks of proteins and is the only sulfur-containing amino acid required for animal growth. It is widely used in pharmaceuticals, nutritional products, food additives, and feed additives.

[0003] In recent years, due to the increasing scarcity of protein feed resources, the addition of specific essential amino acids to feed has become increasingly common. Currently, methionine is in short supply in the Chinese market, and ethyl phenylmethylene aminoacetate is an important intermediate in the synthesis of green methionine.

[0004] The existing batch synthesis method for ethyl benzenemethylaminoethyl, an intermediate of methionine, is cumbersome and has low yield. Therefore, it is necessary to improve the preparation method of ethyl benzenemethylaminoethyl. Summary of the Invention

[0005] In view of this, the purpose of the present invention is to provide a continuous method for synthesizing ethyl phenylmethyleneaminoethyl acetate, so as to solve the problems of cumbersome operation, improved raw material utilization, shortened reaction time, and low yield in existing synthesis methods.

[0006] To achieve the above objectives, the embodiments of the present invention provide the following technical solutions:

[0007] A continuous method for synthesizing ethyl benzenemethyleneaminoethyl, the method comprising the following steps:

[0008] S1: Glycine ethyl ester hydrochloride and triethylamine catalyst are dissolved in toluene solvent and mixed evenly in a stirring device to obtain homogeneous material A; benzaldehyde reactant is material B;

[0009] S2: Material A is fed into the continuous flow microreactor via a liquid plunger pump and material B is metered via a liquid flow meter to synthesize ethyl phenylmethyleneaminoethyl.

[0010] Preferably, in the synthesis method S1, the molar ratio of glycine ethyl ester hydrochloride: triethylamine: benzaldehyde is 1:(0.7-1):(1-1.5), and particularly preferably 1:(0.7-1):(1-1.2).

[0011] Preferably, in the synthesis method S1, the process pressure inside the continuous flow microreactor 1 is atmospheric pressure, the feed flow rate of material A is 5-40 ml / min, the feed flow rate of material B is 0.5-5 ml / min, the residence time of materials A and B in the continuous flow microreactor is 1-5 min, and the controlled temperature of the reactor is 80-120℃.

[0012] Preferably, in the synthesis method S1, the triethylamine is used as a base catalyst, and its pH range is 7 to 12, particularly preferably 7 to 10.

[0013] Preferably, in the synthesis method S1, the organic solvent is one of toluene, dichloroethane, and tetrahydrofuran, with toluene being particularly preferred.

[0014] Preferably, in the synthesis method S1, the method for preparing ethyl phenylmethylaminoethyl ester using a continuous flow microreactor is characterized in that the weight ratio of glycine ethyl ester hydrochloride to toluene in solution A is 1:1 to 10.

[0015] The continuous flow reactor or tubular reactor is made of silicon carbide, Hastelloy, glass, 304 or 316 stainless steel, etc.; the feed pump is a liquid plunger pump; and the stirring vessel is a magnetic stirrer.

[0016] Beneficial effects: This invention uses a continuous flow microreactor to synthesize ethyl benzenemethyleneaminoethyl. The reaction temperature is 80–120℃, the reaction time is 1–5 min, the yield reaches 89.5%, and the purity reaches 90.3%. This continuous flow microreactor method has the characteristics of short reaction time, simple operation, high efficiency and safety, providing a basis for industrial scale-up. Attached Figure Description

[0017] To make the objectives, technical solutions, and beneficial effects of this invention clearer, the following figures are provided:

[0018] Figure 1 This is a schematic flowchart of a continuous synthesis method for ethyl benzenemethyleneaminoethyl. Detailed Implementation

[0019] The present invention will be further described below with reference to the accompanying drawings and embodiments, but the scope of protection of the present invention is not limited to the scope described in the embodiments.

[0020] A continuous method for the synthesis of ethyl benzenemethyleneaminoethyl:

[0021] Example 1

[0022] (1) Weigh 69.79 g (0.5 mol) glycine ethyl ester hydrochloride and 50.595 g (0.5 mol) triethylamine and dissolve them in 139.58 g toluene under nitrogen protection to form material A. Add 37.14 g (0.35 mol) benzaldehyde to form material B. Connect solution A and solution B to the inlet of a continuous flow microreactor under nitrogen protection as reaction reagents.

[0023] The flow rate of solution A was 36.96 ml / min, and the flow rate of solution B was 4.41 ml / min. The reaction temperature of the continuous flow microreactor was controlled at 80–120 °C, and the residence time was 1 min. The resulting reaction solution C was continuously transported to a storage tank. After post-processing, the product yield reached 89.5%, and the purity reached 90.3%.

[0024] In batch reactors, glycine ethyl ester hydrochloride and benzaldehyde are prone to producing byproducts during synthesis due to pH changes, resulting in lower yields and lower purity of ethyl phenylmethylaminoethyl ester. Using a continuous flow microreactor process can improve the yield and purity of the product.

[0025] Example 2

[0026] This embodiment is the same as Embodiment 1, except that the residence time is 5 minutes. The flow rate of solution A is 7.40 ml / min, and the flow rate of solution B is 0.88 ml / min. The reaction temperature of the continuous flow microreactor is controlled at 80–120°C, and the residence time is 5 minutes. The resulting reaction solution C is continuously transported to a storage tank. After post-processing, the product yield reaches 88.1%, and the purity reaches 88.3%.

[0027] Example 3

[0028] This embodiment is the same as Example 1, except that the organic solvent used in this embodiment is tetrahydrofuran. 69.79 g (0.5 mol) of glycine ethyl ester hydrochloride and 50.595 g (0.5 mol) of triethylamine were weighed and dissolved in 139.58 g of tetrahydrofuran under nitrogen protection to form material A. 37.14 g (0.35 mol) of benzaldehyde was added to form material B. Solutions A and B were connected to the inlet of a continuous flow microreactor under nitrogen protection as reaction reagents.

[0029] The flow rate of solution A was 36.96 ml / min, and the flow rate of solution B was 4.41 ml / min. The reaction temperature of the continuous flow microreactor was controlled at 80–120 °C, and the residence time was 1 min. The resulting reaction solution C was continuously transported to a storage tank. After post-processing, the product yield reached 79.0%, and the purity was 88.2%.

[0030] Example 4

[0031] This embodiment is the same as Example 1, except that the organic solvent used in this embodiment is dichloroethane. 69.79 g (0.5 mol) of glycine ethyl ester hydrochloride and 50.595 g (0.5 mol) of triethylamine were weighed and dissolved in 139.58 g of dichloroethane under nitrogen protection to form material A. 37.14 g (0.35 mol) of benzaldehyde was added to form material B. Solutions A and B were connected to the inlet of a continuous flow microreactor under nitrogen protection as reaction reagents.

[0032] The flow rate of solution A was 36.96 ml / min, and the flow rate of solution B was 4.41 ml / min. The reaction temperature of the continuous flow microreactor was controlled at 80–120 °C, and the residence time was 1 min. The resulting reaction solution C was continuously transported to a storage tank. After post-processing, the product yield reached 89.0%, and the purity was 88.2%.

[0033] Comparative Example 1

[0034] Glycine ethyl ester hydrochloride and triethylamine were dissolved in toluene under nitrogen protection. Benzaldehyde was added, with a molar ratio of glycine ethyl ester hydrochloride to triethylamine and benzaldehyde of 1:1:0.7. The addition was completed in an oil bath, and the mixture was refluxed at 85–110 °C for 4 h. After the reaction was complete, the mixture was concentrated, and water and ethyl acetate were added for extraction. The extracted organic phase was washed with water and saturated brine, dried over anhydrous sodium sulfate, and filtered to obtain a concentrated brown oily substance (ethyl phenylmethylaminoethyl ester). The yield was 80.0%, and the purity was 77.0%.

[0035] Comparative Example 2

[0036] Glycine ethyl ester hydrochloride, anhydrous sodium sulfate, and benzaldehyde were dissolved in tetrahydrofuran. Triethylamine was slowly added dropwise with stirring. The molar ratio of glycine ethyl ester hydrochloride to benzaldehyde and triethylamine was 1:1:0.7. The reaction was carried out at room temperature for 24 hours. The mixture was filtered, and the tetrahydrofuran was removed by vacuum distillation to obtain a brown oily substance (ethyl phenylmethylaminoethyl ester) with a yield of 76.2% and a purity of 56.4%.

[0037] Comparative Example 3

[0038] Glycine ethyl ester hydrochloride, anhydrous magnesium sulfate, and benzaldehyde were dissolved in dichloromethane. Triethylamine was added with stirring. The molar ratio of glycine ethyl ester hydrochloride to benzaldehyde and triethylamine was 1:1.2:1. The addition was completed in a water bath, and the reaction was carried out at room temperature for 24 hours. After the reaction was completed, the mixture was filtered, concentrated under reduced pressure, and the dichloromethane was removed to obtain a brown oily substance (ethyl phenylmethyleneaminoethyl acetate) with a yield of 80.1% and a purity of 64.3%.

Claims

1. A continuous method for preparing ethyl benzenemethyleneaminoethyl, wherein the starting materials are glycine ethyl ester hydrochloride and benzaldehyde, characterized in that, The steps include the following: S1: Glycine ethyl ester hydrochloride and triethylamine catalyst are dissolved in toluene solvent and mixed evenly in a stirring device to obtain homogeneous material A; benzaldehyde reactant is material B, the molar ratio of glycine ethyl ester hydrochloride:triethylamine:benzaldehyde is 1:(0.7~1):(1~1.5), the process pressure in the continuous flow microreactor is atmospheric pressure, the feed flow rate of material A is 5~40 ml / min, the feed flow rate of material B is 0.5~5 ml / min, the residence time of material A and material B in the continuous flow microreactor is 1~5 min, and the controlled temperature of the reactor is 80~120℃; S2: Material A is fed into the continuous flow microreactor via a liquid plunger pump and material B is metered via a liquid flow meter to synthesize ethyl phenylmethylene aminoethyl.

2. The preparation method according to claim 1, characterized in that, The triethylamine described herein serves as an alkaline catalyst with a pH range of 7–12.

3. The preparation method according to claim 1, characterized in that, The weight ratio of glycine ethyl ester hydrochloride to toluene in material A is 1:1~10.

4. The preparation method according to claim 1, characterized in that, The continuous flow microreactor is made of silicon carbide, Hastelloy, or glass.

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