Synthesis method of glycine ethyl ester hydrochloride

Abstract

The invention discloses a glycine ethyl ester hydrochloride synthesis method, which comprises: (1) adding glycine and absolute ethyl alcohol into a reactor, continuously introducing dry hydrogen chloride, carrying out pre-reaction treatment, and carrying out final reaction treatment; (2) cooling the reaction liquid, and then carrying out centrifugal separation treatment; (3) adding a water removal agent into the reaction mother liquor, carrying out water removal treatment, then carrying out centrifugal separation treatment to obtain a solid, namely the water-absorbed water removal agent, and an obtained filtrate, namely the water-removed mother liquor, and supplementing absolute ethyl alcohol into the water-removed mother liquor for recycling; and (4) carrying out regeneration treatment on the water removal agent after water absorption. According to the novel method for synthesizing glycine ethyl ester hydrochloride, high-temperature backflow is not needed, a water-carrying agent is not introduced, a solvent and water do not need to be separated from mother liquor through rectification, water in the reaction mother liquor is removed through a water removal agent at the room temperature, the mother liquor obtained after water removal can be recycled, and the water removal agent can be regenerated and reused.

Description

Technical Field

[0001] The present invention relates to the field of chemical engineering technology, and particularly relates to a method for synthesizing glycine ethyl ester hydrochloride. Background Art

[0002] With the increasingly widespread application of amino acid ester compounds in the fields of medicine, chemical engineering, pesticides, food, cosmetics, etc., their synthesis technology has become a research hotspot in recent years. Among them, glycine ethyl ester hydrochloride is a simple and important pharmaceutical intermediate, which is widely used in the fields of pesticides and medicine. As a non-bulk chemical, its price is generally high, and the product has a high added value.

[0003] The traditional production process of glycine ethyl ester hydrochloride is to heat glycine and acid ethanol (hydrogen chloride ethanol) to reflux, and then through cooling crystallization, centrifugal separation, washing, and drying to obtain the product. The optimized process is to add glycine to anhydrous ethanol, heat and introduce hydrogen chloride gas until the reaction is complete, then cool and crystallize, and then through crystallization separation, washing, and drying to obtain the product. However, since glycine ethyl ester hydrochloride is obtained by the esterification reaction of glycine and ethanol, water will be generated, and the presence of water will cause hydrolysis of glycine ethyl ester hydrochloride, reducing the product yield. At the same time, glycine ethyl ester hydrochloride will turn yellow in the presence of water, affecting the product quality. Therefore, how to reduce the influence of the water generated by the esterification reaction has always been an important issue concerned by relevant enterprises and researchers.

[0004] In order to remove the water generated by esterification in the reaction system and recycle the reaction mother liquor, there are mainly two improved processes at present:

[0005] One is to introduce a water-carrying agent. For example, in the Chinese patent application with the publication number CN108484421A, glycine, ethanol, and hydrogen chloride are fed in a certain proportion to form a salt by esterification, and a water-carrying agent benzene is added. Through high-temperature azeotropic distillation, the water generated by the esterification reaction is separated from the system by the water-carrying agent. Although this invention application improves the product conversion rate and can realize the recycling of the mother liquor, the introduction of the highly toxic water-carrying agent benzene in the process will cause product quality problems and requires high-temperature azeotropic distillation, resulting in large energy consumption.

[0006] The other is mother liquor rectification. For example, in the Chinese patent application with the publication number CN115466188A, glycine is mixed with anhydrous ethanol, heated until the reaction solution refluxes stably, then hydrogen chloride is introduced for reaction. After the reaction is completed, the solution is cooled, crystallized, separated, and dried to obtain the product. The mother liquor is separated by rectification to obtain an anhydrous hydrogen chloride alcohol solution, which is directly used for feeding; the bottom material is separated by vacuum distillation to obtain an aqueous hydrochloric acid solution. This invention does not use a water-carrying agent, but the mother liquor needs to be rectified after each reaction, resulting in large energy consumption; and it will produce an aqueous hydrochloric acid solution, generating a large amount of waste salt during the alkali neutralization treatment process. Summary of the Invention

[0007] The main object of the present invention is to provide a method for synthesizing glycine ethyl ester hydrochloride, so as to solve the problem that the reaction mother liquor cannot be recycled due to the water generated in the esterification reaction of synthesizing glycine ethyl ester hydrochloride, as well as the problem of high energy consumption existing in both process routes of the prior art, and at the same time, the addition of a water-carrying agent leads to product quality problems.

[0008] To achieve the above object, the present invention provides a method for synthesizing glycine ethyl ester hydrochloride, comprising the following steps:

[0009] (1): Add glycine and absolute ethanol to a reactor, heat up to the pre-reaction temperature, then continuously introduce dry hydrogen chloride, carry out pre-reaction treatment, and then heat up to the final reaction temperature to carry out final reaction treatment to obtain a reaction solution;

[0010] (2): Cool the reaction solution, and then carry out centrifugal separation treatment. The obtained solid is the glycine ethyl ester hydrochloride product, and the obtained filtrate is the reaction mother liquor;

[0011] (3): Add a water remover to the reaction mother liquor to carry out water removal treatment, and then carry out centrifugal separation treatment. The obtained solid is the water-absorbed water remover, and the obtained filtrate is the mother liquor after water removal. Add absolute ethanol to the mother liquor after water removal for recycling;

[0012] (4): Regenerate the water-absorbed water remover for repeated use.

[0013] Further, in step (1), the mass ratio of glycine to absolute ethanol is 1:2.5 - 4, and the mass ratio of glycine to the introduced dry hydrogen chloride is 1:1.2 - 1.8.

[0014] Further, in step (1), the pre-reaction temperature is 38 - 40 °C, and the pre-reaction time is 0.8 - 1.2 h.

[0015] Further, in step (1), the final reaction temperature is 58 - 60 °C, and the final reaction time is 2 - 2.5 h.

[0016] Further, in step (2), the cooling treatment is to cool naturally to 20 - 25 °C.

[0017] Further, in step (3), the water remover is selected from highly active adsorbent materials that can selectively absorb liquid water.

[0018] Further, in step (3), the water remover is selected from 3A molecular sieve or spherical silica gel.

[0019] Further, in step (3), the mass ratio of the added water remover to the added glycine in step (1) is 1:0.6 - 1.4, and the water removal treatment time is 1 - 15 min.

[0020] Further, in step (4), the regeneration treatment is carried out by thermal desorption. The thermal desorption temperature is 110-180 °C, and the acidic water obtained by thermal desorption can be recycled and used as the water for refining and purifying glycine ethyl ester hydrochloride.

[0021] The main mechanism of the present invention is as follows: 3A molecular sieve is selected in the present invention. Its pore size is roughly the same as that of water molecules, while other molecules in the reaction mother liquor of glycine ethyl ester hydrochloride are all larger than water molecules. After water molecules enter the 3A molecular sieve, due to their similar sizes, they are not easy to come out, thus achieving the effect of removing water from the reaction mother liquor and realizing the recycling of the reaction mother liquor; spherical silica gel is selected in the present invention, which is a highly active adsorbent nano-porous material with a nano-porous structure inside. There are a large number of hydroxyl groups on its surface. The hydrogen in water molecules is more active than the hydrogen in alcohol hydroxyl groups. Affinity is generated by the mutual attraction between the hydroxyl groups in the spherical silica gel and water molecules, thereby removing the water in the reaction mother liquor, and then realizing the recycling of the reaction mother liquor.

[0022] The beneficial effects of the present invention are reflected in:

[0023] The present invention provides a new method for synthesizing glycine ethyl ester hydrochloride, which does not require high-temperature reflux, does not introduce water-carrying agents, the mother liquor does not need to be rectified to separate the solvent and water, uses a water remover at room temperature to remove the water in the reaction mother liquor, the mother liquor after water removal can be recycled, and the water remover can be regenerated and reused. It has the advantages of mild operating conditions, environmental protection, low energy consumption, and simple operation, and solves the problems in the current production technology such as high energy consumption cost for realizing the recycling of the reaction mother liquor, introduction of water-carrying agents with relatively high toxicity, and more waste water and waste salts generated from the rectification of the mother liquor. Description of the Drawings

[0024] Figure 1 It is a flow chart of the synthesis method of glycine ethyl ester hydrochloride of the present invention. Detailed Embodiments

[0025] In order to make those skilled in the art more clearly understand the technical solutions described in the present invention, the following examples are listed for illustration. It should be noted that the following examples do not limit the scope of protection required by the present invention.

[0026] Unless otherwise specified, the raw materials, reagents or devices used in the following examples can be obtained from conventional commercial channels or can be obtained by existing known methods; unless otherwise specified, the methods used in the embodiments of the present invention are all methods mastered by those skilled in the art. Among them:

[0027] 3A molecular sieve, implementing the national standard GB / T 10504-2017, with the model of 3A and a pore size of 3 angstroms (0.3 nanometers);

[0028] Spherical silica gel, with the execution standard HG / T 2765.4-2005, and the average pore diameter is less than 1.5 - 2.0 nanometers.

[0029] For the flow chart of the synthesis method of ethyl glycine hydrochloride in the present invention, please refer to Figure 1 .

[0030] Example 1

[0031] Synthesis of ethyl glycine hydrochloride

[0032] Add 750 g of glycine and 2250 g of absolute ethanol into a reactor equipped with a stirrer, thermometer, condenser, vent pipe, and tail gas absorber. Heat up to 40 °C, and start continuously introducing dry hydrogen chloride gas. The ventilation flow rate of the hydrogen chloride gas is 2.78 g / min. Pre-react at a pre-reaction temperature of 40 °C for 1 h, then heat up to 60 °C, and react at a final reaction temperature of 60 °C for 2 h to obtain a reaction solution; let the reaction solution cool down to 20 °C naturally, and then perform centrifugal separation. The obtained 1368 g of solid is the ethyl glycine hydrochloride product, and the obtained filtrate is the reaction mother liquor. The purity of the ethyl glycine hydrochloride product detected by HPLC is 96.50%, the content of glycine hydrochloride is 1.68%, and the yield of ethyl glycine hydrochloride is 94.58%;

[0033] Add 1200 g of 3A molecular sieve into the reaction mother liquor, dehydrate at room temperature for 2 min, and then perform centrifugal separation. The obtained solid is the 3A molecular sieve after water absorption, and the obtained 1690 g of filtrate is the mother liquor after dehydration. Add 560 g of absolute ethanol to the mother liquor after dehydration to obtain a recycled mother liquor for continuous recycling; perform thermal desorption on the 3A molecular sieve after water absorption at 170 °C for 3 h to obtain a regenerated 3A molecular sieve for continuous recycling. The acidic water recovered by thermal desorption can be used as the water for refining and purifying ethyl glycine hydrochloride.

[0034] Example 2

[0035] Synthesis of ethyl glycine hydrochloride

[0036] 750 g of glycine and 2250 g of the recycled mother liquor obtained in Example 1 were added to a reactor equipped with a stirrer, a thermometer, a condenser, a vent pipe, and a tail gas absorber. The temperature was raised to 40 °C, and dry hydrogen chloride gas was continuously introduced. The ventilation flow rate of the hydrogen chloride gas was 2.78 g / min. A preliminary reaction was carried out at a preliminary reaction temperature of 40 °C for 1 h, then the temperature was raised to 60 °C, and a reaction was carried out at a final reaction temperature of 60 °C for 2 h to obtain a reaction solution; the reaction solution was naturally cooled to 20 °C, and then centrifuged. The 1380 g of solid obtained was the glycine ethyl ester hydrochloride product, and the filtrate obtained was the reaction mother liquor. The purity of the glycine ethyl ester hydrochloride product detected by HPLC was 94.63%, the glycine hydrochloride content was 1.89%, and the yield of glycine ethyl ester hydrochloride was 93.56%.

[0037] Example 3

[0038] Synthesis of Glycine Ethyl Ester Hydrochloride

[0039] 600 g of glycine and 2550 g of absolute ethanol were added to a reactor equipped with stirring, a thermometer, a condenser, a vent pipe, and a tail gas absorber. The temperature was raised to 38 °C, and dry hydrogen chloride gas was continuously introduced. The ventilation flow rate of the hydrogen chloride gas was 2.70 g / min. A preliminary reaction was carried out at a preliminary reaction temperature of 38 °C for 1.2 h, then the temperature was raised to 58 °C, and a reaction was carried out at a final reaction temperature of 58 °C for 2.5 h to obtain a reaction solution; the reaction solution was naturally cooled to 25 °C, and then centrifuged. The 1357 g of solid obtained was the glycine ethyl ester hydrochloride product, and the filtrate obtained was the reaction mother liquor. The purity of the glycine ethyl ester hydrochloride product detected by HPLC was 97.60%, the glycine hydrochloride content was 1.36%, and the yield of glycine ethyl ester hydrochloride was 94.88%;

[0040] 600 g of spherical silica gel was added to the reaction mother liquor, and water was removed at room temperature for 10 min, and then centrifuged. The solid obtained was the spherical silica gel after water absorption, and the 1940 g of filtrate obtained was the mother liquor after water removal. 610 g of absolute ethanol was added to the mother liquor after water removal to obtain a recycled mother liquor for recycling; the spherical silica gel after water absorption was thermally desorbed at 120 °C for 2 h to obtain the regenerated spherical silica gel for continuous recycling. The acidic water recovered by thermal desorption could be used as the water for refining and purifying glycine ethyl ester hydrochloride.

[0041] Example 4

[0042] Synthesis of Glycine Ethyl Ester Hydrochloride

[0043] 750 g of glycine and 2550 g of the recycled mother liquor obtained in Example 3 were added to a reactor equipped with a stirrer, a thermometer, a condenser, a vent pipe, and a tail gas absorber. The temperature was raised to 38 °C, and dry hydrogen chloride gas was introduced. The gas flow rate of hydrogen chloride gas was 2.70 g / min. The pre-reaction was carried out at a pre-reaction temperature of 38 °C for 1.2 h, and then the temperature was raised to 58 °C. The reaction was carried out at a final reaction temperature of 60 °C for 2.5 h to obtain a reaction solution. The reaction solution was naturally cooled to 25 °C and then centrifuged. The 1375 g of solid obtained was the glycine ethyl ester hydrochloride product, and the filtrate obtained was the reaction mother liquor. The purity of the glycine ethyl ester hydrochloride product detected by HPLC was 95.94%, the content of glycine hydrochloride was 1.89%, and the yield of glycine ethyl ester hydrochloride was 94.51%.

[0044] Comparative Example 1

[0045] Synthesis of glycine ethyl ester hydrochloride

[0046] 600 g of glycine and 2400 g of absolute ethanol were added to a reaction kettle equipped with a stirrer, a thermometer, a condenser, a vent pipe, and a tail gas absorption device. Dry hydrogen chloride gas was introduced. The gas flow rate of hydrogen chloride gas was 400 g / h. The temperature in the kettle was raised to 45 °C, and the heating temperature was adjusted to the ethanol reflux temperature of 78 °C for reaction. After 3 h of gas introduction, the reaction was stopped, and the temperature was lowered to 10 °C. Then the reaction solution was centrifuged. The solid obtained was washed with alcohol and dried to obtain 1062 g of glycine ethyl ester hydrochloride product. The purity of the glycine ethyl ester hydrochloride product detected by HPLC was 96.60%, the content of glycine hydrochloride was 1.90%, and the yield of glycine ethyl ester hydrochloride was 91.90%.

[0047] Ethanol was added to the filtrate obtained by the above centrifugation to make it 2400 g. According to the above steps, 600 g of glycine was added for recycling. After the reaction was completed, the reaction solution was centrifuged. The solid obtained was washed with alcohol and dried to obtain 1050 g of glycine ethyl ester hydrochloride product. The purity of the glycine ethyl ester hydrochloride product detected by HPLC was 86.50%, the content of glycine hydrochloride was 10.45%, and the yield of glycine ethyl ester hydrochloride was 81.33%.

[0048] The above are only the preferred embodiments of the present invention and are not intended to limit the present invention. Any modifications, equivalent replacements, improvements, etc. made within the spirit and principles of the present invention shall be included in the protection scope of the present invention.

Claims

1. A method for synthesizing glycine ethyl ester hydrochloride, characterized in that, It includes the following steps: (1): Add glycine and absolute ethanol into a reactor, heat up to the pre-reaction temperature, then continuously introduce dry hydrogen chloride for pre-reaction treatment, and then heat up to the final reaction temperature for final reaction treatment to obtain a reaction solution; (2): Cool down the reaction solution, and then perform centrifugal separation. The obtained solid is the glycine ethyl ester hydrochloride product, and the obtained filtrate is the reaction mother liquor; (3): Add a water remover to the reaction mother liquor for water removal treatment, and then perform centrifugal separation. The obtained solid is the water remover after water absorption, and the obtained filtrate is the mother liquor after water removal. Add absolute ethanol to the mother liquor after water removal for recycling; (4): Regenerate the water remover after water absorption for reuse.

2. The synthesis method of ethyl glycine hydrochloride according to claim 1, wherein In step (1), the mass ratio of glycine to absolute ethanol is 1:2.5 - 4, and the mass ratio of glycine to the introduced dry hydrogen chloride is 1:1.2 - 1.

8.

3. The synthesis method of ethyl glycine hydrochloride according to claim 1, characterized in that, In step (1), the pre-reaction temperature is 38 - 40 °C, and the pre-reaction time is 0.8 - 1.2 h.

4. The synthesis method of ethyl glycine hydrochloride according to claim 1, characterized in that, In step (1), the final reaction temperature is 58 - 60 °C, and the final reaction time is 2 - 2.5 h.

5. The synthesis method of ethyl glycine hydrochloride according to claim 1, characterized in that, In step (2), the cooling treatment is to naturally cool down to 20 - 25 °C.

6. The synthesis method of ethyl glycine hydrochloride according to claim 1, characterized in that, In step (3), the water remover is a highly active adsorbent material that can selectively absorb liquid water.

7. The synthesis method of ethyl glycine hydrochloride according to claim 6, wherein, In step (3), the water remover is 3A molecular sieve or spherical silica gel.

8. The synthesis method of ethyl glycine hydrochloride according to claim 1, characterized in that, In step (3), the mass ratio of the added water remover to the added glycine in step (1) is 1: 0.6 - 1.4, and the water removal treatment time is 1 - 15 min.

9. The synthesis method of ethyl glycine hydrochloride according to claim 1, wherein, In step (4), the regeneration treatment is by thermal desorption. The thermal desorption temperature is 110 - 180 °C, and the acidic water obtained by thermal desorption can be recycled as the water for refining and purifying glycine ethyl ester hydrochloride.

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