Tris(hydroxymethyl)aminomethane hydrochloride preparation method

Abstract

The present invention relates to a tris(hydroxymethyl)aminomethane hydrochloride preparation method and, specifically, to a high-purity tris(hydroxymethyl)aminomethane hydrochloride preparation method, which does not use a main solvent, and thus is economical and eco-friendly. The tris(hydroxymethyl)aminomethane hydrochloride preparation method of the present invention exhibits a high conversion rate and selectivity, and provides an economical and eco-friendly preparation method by establishing a solvent recovery and reuse system that recirculates a hydrocarbon solvent, which is an antisolvent, during crystallization, and minimizes solvent loss.

Description

Method for preparing tris(hydroxymethyl)aminomethane hydrochloride

[0001] The present invention relates to a method for manufacturing tris(hydroxymethyl)aminomethane hydrochloride, and specifically, to providing a method for manufacturing tris(hydroxymethyl)aminomethane hydrochloride without using a main solvent during the reaction, thereby providing an economical, environmentally friendly, and high-purity tris(hydroxymethyl)aminomethane hydrochloride.

[0002]

[0003] Tris(hydroxymethyl)aminomethane hydrochloride, along with Tris(hydroxymethyl)aminomethane, is one of the most widely used buffers in biopharmaceutical processes. Good's buffers are a series of buffer systems widely used in biochemical and biological experiments, developed by Norman Good in 1966 to create pH buffers optimized for biological research. Good's buffers are stable within the physiological pH range (approximately 6.0–8.0) and are used in various experiments due to their high compatibility with biological samples. Recently, phosphate-buffered saline (PBS) and Tris(hydroxymethyl)aminomethane are among the types of buffers frequently used in biopharmaceutical processes. Buffers used in biological preparations are selected based on specific requirements, and more specialized and stable buffer systems are expected to gain attention in the future. In particular, it is highly likely that a wider variety of buffers will be developed and utilized to ensure the stability of biopharmaceuticals, the efficiency of protein purification, and the optimization of cell culture conditions. Currently, tris(hydroxymethyl)aminomethane and tris(hydroxymethyl)aminomethane hydrochloride are the most widely used. Tris(hydroxymethyl)aminomethane is used as a basic buffer, while tris(hydroxymethyl)aminomethane hydrochloride is frequently used in combination with it as an acid buffer to adjust the desired pH (7–9).

[0004] A method for preparing tris(hydroxymethyl)aminomethane hydrochloride comprises forming a solution of tris(hydroxymethyl)aminomethane hydrochloride in a mixture of an aqueous solution and an effective co-solvent, and crystallizing a tris(hydroxymethyl)aminomethane solvate from this solution.

[0005] The process of producing hydrochloride salts involves using an aqueous hydrochloric acid solution or using hydrochloric acid gas and acyl chloride series to generate hydrochloric acid gas as a byproduct.

[0006] In addition, the amount of wastewater can be reduced by using the hydrochloric acid gas and acetates produced by adding acyl chloride dropwise after dissolving the reactants in anhydrous ethanol solvent, and using them as a solvent for hydrochloride salts and crystallization under anhydrous conditions. Acyl chlorides such as acetyl chloride, propionyl chloride, and butyryl chloride can be used, and the use of acetyl chloride is most preferable. When acetyl chloride is used in anhydrous ethanol solvent, hydrochloric acid gas and ethyl acetate are produced, which can form hydrochloride salts.

[0007] Hydrochloric acid aqueous solution and hydrochloric acid gas are currently used according to existing disclosed methods; however, since the method of producing hydrochloric acid salts using hydrochloric acid gas itself is very dangerous, hydrochloric acid aqueous solution is currently used as a substitute.

[0008] A conventional method for producing tris(hydroxymethyl)aminomethane hydrochloride is known as a concentration and purification method that uses a polar solvent, such as water or acetonitrile, in an aqueous hydrochloric acid solution to concentrate the intermediate solvate.

[0009] The method of concentrating a product through vacuum evaporation (Patent Document 1 JP2021-080175A) requires high equipment and operating costs, and heat exchange efficiency may be reduced due to internal contamination, and appropriate determination and management of the evaporation concentration ratio is required. Therefore, the development of a method that can improve the disadvantages of the conventional method of producing tris(hydroxymethyl)aminomethane hydrochloride through the concentration of intermediate solvates is required.

[0010] When an aqueous hydrochloric acid solution is used, a significant amount of tris(hydroxymethyl)aminomethane hydrochloride is dissolved in the hydrochloric acid solution, resulting in an actual production yield of about 75% to 80%. Also, when crystallizing tris(hydroxymethyl)aminomethane hydrochloride, a large amount of solvent is used, and as it becomes concentrated, the amount of wastewater increases.

[0011] Against this backdrop, the inventors have made diligent efforts to provide a method for producing tris(hydroxymethyl)aminomethane hydrochloride with a high yield. As a result, they have solved the conventional problems by using a method for producing tris(hydroxymethyl)aminomethane hydrochloride solvate by adding only an aqueous hydrochloric acid solution dropwise to tris(hydroxymethyl)aminomethane, and have completed the present invention by confirming a hydrochloride with a high yield.

[0012]

[0013] [Prior Art Literature]

[0014] [Patent Literature]

[0015] 1. JP2021-080175A

[0016]

[0017] The present invention aims to provide a method for producing tris(hydroxymethyl)aminomethane hydrochloride.

[0018]

[0019] A first aspect of the present invention for achieving the aforementioned objective comprises the step of preparing a reaction product by mixing an aqueous hydrochloric acid solution and tris(hydroxymethyl)aminomethane;

[0020] A step of refluxing the above reactants; and

[0021] The present invention provides a method for preparing tris(hydroxymethyl)aminomethane hydrochloride, comprising the step of cooling the above-mentioned refluxed reaction product and then crystallizing it using a hydrocarbon solvent as an antisolvent.

[0022]

[0023] The method for producing tris(hydroxymethyl)aminomethane hydrochloride according to the present invention does not generate high exothermic reactions, provides high conversion rates and selectivity, and allows for the reuse of the antisolvent, making it economical and environmentally friendly.

[0024]

[0025] Figure 1 shows the NMR data of tris(hydroxymethyl)aminomethane hydrochloride prepared in Example 1.

[0026]

[0027] The present invention will be described in more detail below.

[0028] The term "Tris(hydroxymethyl)aminomethane hydrochloride (Tris-HCl)" in this invention refers to a compound in which hydrochloric acid (HCl) is bonded to a basic compound called Tris. This compound is primarily used as a buffer in biochemistry and molecular biology; it is useful for neutralizing the basic properties of Tris to adjust the pH to a desired range, and because it excels at maintaining a stable pH, it may be widely used in protein, enzyme reactions, and DNA and RNA work. In particular, Tris(hydroxymethyl)aminomethane hydrochloride is used to adjust pH to acidic levels and may play an important role in precise pH control in biological experiments.

[0029] As described above, the conventional manufacturing method for tris(hydroxymethyl)aminomethane hydrochloride has several issues, including the danger caused by the use of hydrochloric acid gas, reduced efficiency due to high operating costs and energy consumption resulting from manufacturing via vacuum evaporation using water as the main solvent, increased wastewater volume, and reduced yield.

[0030] Accordingly, the present invention aims to resolve the above problems by providing a method for producing tris(hydroxymethyl)aminomethane hydrochloride that includes steps of refluxing and cooling without using a main solvent during the reaction.

[0031] The step of preparing a reaction product by mixing the above aqueous hydrochloric acid solution and tris(hydroxymethyl)aminomethane may be a step of increasing the yield and preventing wastewater generation by mixing only the aqueous hydrochloric acid solution and tris(hydroxymethyl)aminomethane without using a main solvent.

[0032] The term “main solvent” in the present invention refers to the solvent used to dissolve tris(hydroxymethyl)aminomethane and react it with an aqueous hydrochloric acid solution using a solvent such as water in the aforementioned background technology and Comparative Example 1 below.

[0033] The present invention is characterized by not using a main solvent. By not using a main solvent, the present invention may provide the effect of solving the problem of reduced efficiency when using a main solvent and reducing wastewater generation.

[0034] The term "aqueous hydrochloric acid solution" in this invention refers to a strongly acidic solution formed by dissolving hydrogen chloride (HCl) in water; this solution can exist at various concentrations, and its acidity varies depending on the concentration. The aqueous hydrochloric acid solution exhibits strong acidity as HCl molecules dissolve in water and dissociate into hydrogen ions (H+) and chloride ions (Cl-). The aqueous hydrochloric acid solution can react with Tris to neutralize the Tris base through an acid-base reaction and form Tris hydrochloride (Tris-HCl).

[0035] The above aqueous hydrochloric acid solution may be included in an amount of 1 to 1.5 parts by weight based on 1 part by weight of tris(hydroxymethyl)aminomethane. Preferably, it may be added in an amount of 1 to 1.3 parts by weight.

[0036] The above aqueous hydrochloric acid solution may be included in an amount of 1 to 1.5 mol based on 1 mol of tris(hydroxymethyl)aminomethane. Preferably, it may be added in an amount of 1 to 1.3 mol.

[0037] If the aqueous hydrochloric acid solution is included in an amount of less than 1 part by weight based on 1 part by weight of tris(hydroxymethyl)aminomethane, there may be raw materials remaining that have not reacted, and if it is included in an amount exceeding 1.5 parts by weight, the excessive use of the aqueous hydrochloric acid solution causes severe exothermic reaction, a rapid decrease in pH, and an excess amount of hydrochloric acid in the subsequent process, which may cause corrosion of the reaction device or wastewater treatment problems.

[0038] The above aqueous hydrochloric acid solution may be mixed by a dropwise method.

[0039] The term “drop-wise” in the present invention refers to a method of slowly adding an aqueous hydrochloric acid solution drop by drop. Through the drop-wise method, the reaction rate can be controlled while controlling the precise amount, and excessive reaction may be prevented. Furthermore, since a large amount of fume is generated when Tris reacts with the aqueous hydrochloric acid solution, the drop-wise method of the present invention may be a method to minimize fume generation and may provide the effect of reducing the amount of wastewater.

[0040] The step of refluxing the above reaction product may be a step of removing impurities and increasing the purity of the hydrochloride salt through repeated evaporation and condensation of the above reaction product.

[0041] The term “reflux” in this invention may refer to cooling the vapor generated by heating the reactants to return it to a liquid state and allowing it to fall back into the reaction vessel, thereby maintaining the reactants in a liquid state to sustain the reaction and increase the yield. It may also refer to a process in which the reactants generated by the reaction of tris(hydroxymethyl)aminomethane and an aqueous hydrochloric acid solution evaporate, condense in a cooler, and return to the reactants to maintain the concentration of the solution, thereby helping to sustain the reaction at a constant temperature for a sufficient amount of time. Furthermore, it may refer to the formation of tris(hydroxymethyl)aminomethane hydrochloride through the reflux process.

[0042] The above refluxing step may be performed at a temperature of 50°C to 120°C, preferably at a temperature of 50°C to 100°C, 50°C to 90°C, and more preferably at a temperature of 70°C to 90°C. More preferably, stirring may be performed at 75°C to 85°C until the reaction is completed. The above temperature may refer to the reflux temperature.

[0043] The temperature of the above refluxing step may provide a balance between the reaction rate and the impurity level, and if it exceeds 120°C, the reaction rate may increase, leading to the problem of promoting unwanted side reactions.

[0044] In addition, the above-mentioned refluxing step may be performed under atmospheric pressure, but is not limited thereto.

[0045] The step of cooling the above-mentioned refluxed reactant and crystallizing it using a hydrocarbon solvent as an antisolvent; may be a step for separating the refluxed reactant with higher purity, and may be for crystallizing the hydrochloride salt into a crystal form to facilitate storage and preservation.

[0046] In the present invention, the crystallization step comprises a first crystallization step of stirring the refluxed reactant at 50 to 70°C;

[0047] A second crystallization step of stirring the above reaction mixture at 20 to 30°C; and

[0048] The above reaction mixture may include a third crystallization step of stirring at -10°C to 10°C.

[0049] The first crystallization step is a step of stirring the refluxed reactants at 50 to 70°C, and crystal nuclei may be generated by this step. The step may be performed for 30 minutes to 2 hours.

[0050] The second crystallization step is a step of stirring the reaction mixture that underwent the first crystallization step at 20 to 30°C, and a white crystalline solid may be produced by this step. The step may be performed for 1 to 3 hours.

[0051] The third crystallization step is a step of stirring the reaction mixture that underwent the second crystallization step at -10°C to 10°C. This step may be carried out in the presence of a hydrocarbon solvent as an antisolvent.

[0052] The term “antisolvent” in the present invention may serve to distinguish the phases of the solvent and the solute or to control the solubility of specific components (impurities).

[0053] The above antisolvent may be used to selectively remove impurities and efficiently separate hydrochloride salts in the crystallization step to obtain high-purity crystals.

[0054] The term “crystallization” in the present invention may refer to solidifying a refluxed reactant by cooling, and the step of cooling and crystallizing the refluxed reactant may refer to increasing purity. Additionally, since the hydrocarbon solvent used as an antisolvent in the crystallization step is reused by using a dropwise method, the amount of wastewater is reduced, thereby providing an environmentally friendly manufacturing method.

[0055] The term “hydrocarbon solvent” in the present invention may be an anti-solvent used in the crystallization step, and may provide an economical and environmentally friendly manufacturing method by preventing high exothermic reaction immediately after the reaction when Tris and an aqueous hydrochloric acid solution react, providing high conversion rate and selectivity compared to when water is used as a solvent, and allowing the hydrocarbon solvent used in the crystallization step to be recovered and reused as a crystallization solvent in subsequent reactions.

[0056] The above hydrocarbon solvent may contain a hydroxyl group.

[0057] The above hydrocarbon solvent may include one or more selected from the group consisting of methanol, ethanol, n-propanol, isopropanol, and butanol, and methanol or ethanol may be most preferred.

[0058] The above hydrocarbon solvent may be included in an amount of 0.1 to 5 parts by weight based on 1 part by weight of tris(hydroxymethyl)aminomethane.

[0059] If the hydrocarbon solvent is included in an amount of less than 0.1 parts by weight based on 1 part by weight of tris(hydroxymethyl)aminomethane, the yield and purity may be lowered, and if it exceeds 5 parts by weight, the process costs may be excessively high and the solubility of the hydrochloride may increase, which may result in a lower yield.

[0060] The above step may be performed for 10 minutes to 1 hour.

[0061] It may further include a washing or filtration step after the crystallization step.

[0062] The hydrochloride salt produced by the above manufacturing method may have a yield of 85% to 100% and a purity of 95% to 100%.

[0063] In a specific embodiment, it was confirmed that the method for producing the environmentally friendly tris(hydroxymethyl)aminomethane hydrochloride of the present invention provides tris(hydroxymethyl)aminomethane hydrochloride with a high yield and high purity.

[0064] The advantages and features of the present invention, and the methods for achieving them, will become clear by referring to the experimental and manufacturing examples described in detail below. However, the present invention is not limited to the experimental and manufacturing examples disclosed below, but may be implemented in various different forms, and is provided merely to ensure that the disclosure of the present invention is complete and to fully inform those skilled in the art of the scope of the invention.

[0065]

[0066] The present invention will be explained in more detail below through examples. These examples are intended to explain the invention more specifically, and the scope of the invention is not limited by these examples.

[0067]

[0068] Example 1: Tris(hydroxymethyl)aminomethane hydrochloride

[0069] An apparatus for producing hydrochloride was prepared by placing a 1L round-bottom flask equipped with a thermocouple to measure the internal temperature on a stirrer and vertically connecting a reflux condenser to the flask. 1 mol of tris(hydroxymethyl)aminomethane was added to the 1L round-bottom flask to make it solvent-free. 1.1 mol of a 35% aqueous hydrochloric acid solution was filled into a dropping funnel and introduced into the reactor at a uniform rate for 30 minutes. The reflux temperature of the reactor was maintained at 80°C and stirred sufficiently for 1 hour until the reaction was complete, after which the temperature of the reactor was cooled to 60°C. After stirring at 60°C for 1 hour, it was cooled back to room temperature and stirred sufficiently for 2 hours. When a white crystalline solid was formed, 0.25 L of the antisolvent methanol was added and treated as a slurry; the temperature was then cooled to 5°C and stirred for 30 minutes. When a sufficient amount of solid was produced, the white crystalline solid was washed with 0.25 L of methanol using a vacuum filter, and then filtered. Afterward, the composition of the product was analyzed by NMR (nuclear magnetic resonance) to confirm whether tris(hydroxymethyl)aminomethane was consumed.

[0070] In the present invention, FIG. 1 is the NMR data of tris(hydroxymethyl)aminomethane hydrochloride prepared in Example 1, and it can be confirmed that tris(hydroxymethyl)aminomethane hydrochloride was produced ( 1 H NMR (600 MHz, DO) δ 3.65 (s, 6H)).

[0071]

[0072] Example 2

[0073] Tris(hydroxymethyl)aminomethane hydrochloride was prepared using a different antisolvent than in Example 1. Specifically, tris(hydroxymethyl)aminomethane hydrochloride was prepared in the same manner as in Example 1, except that ethanol was used as the crystallization antisolvent and the reflux temperature was increased to 85°C.

[0074]

[0075] Example 3

[0076] Tris(hydroxymethyl)aminomethane hydrochloride was prepared in the same manner as in Example 1, except that isopropanol was used as the crystallization antisolvent and the reflux temperature was increased to 80 degrees.

[0077]

[0078] Example 4

[0079] Tris(hydroxymethyl)aminomethane hydrochloride was prepared in the same manner as in Example 1, except that the ratio of tris(hydroxymethyl)aminomethane to aqueous hydrochloric acid solution was 1:1.

[0080]

[0081] Example 5

[0082] Tris(hydroxymethyl)aminomethane hydrochloride was prepared in the same manner as in Example 1, except that the ratio of tris(hydroxymethyl)aminomethane to aqueous hydrochloric acid solution was 1:1.3.

[0083]

[0084] Example 6

[0085] Tris(hydroxymethyl)aminomethane hydrochloride was prepared in the same manner as in Example 1, except that the ratio of tris(hydroxymethyl)aminomethane to aqueous hydrochloric acid solution was 1:1.5.

[0086]

[0087] Comparative Example 1

[0088] An apparatus for the preparation of hydrochloride salts was prepared by placing a 1L round-bottom flask equipped with a thermocouple to measure the internal temperature on a stirrer and vertically connecting a reflux condenser to the flask. 1 mol of tris(hydroxymethyl)aminomethane was added to the 1L round-bottom flask, and H2O was added as the main solvent to dissolve the reaction mixture. At room temperature, 1.1 mol of a 35% aqueous hydrochloric acid solution was placed in a dropping funnel and introduced into the reactor at a uniform rate for 30 minutes. The reactor temperature was maintained at room temperature, and after stirring sufficiently for 3 hours until the reaction was complete, water was removed by vacuum evaporation to obtain a pale yellow solid. The obtained solid was analyzed by NMR (nuclear magnetic resonance) to confirm whether the tris(hydroxymethyl)aminomethane had been consumed.

[0089]

[0090] Comparative Example 2

[0091] Tris(hydroxymethyl)aminomethane hydrochloride was prepared in the same manner as Comparative Example 1, except that H2O was not used as the main solvent.

[0092]

[0093] Comparative Example 3

[0094] Tris(hydroxymethyl)aminomethane hydrochloride was prepared in the same manner as Comparative Example 1, except that the ratio of tris(hydroxymethyl)aminomethane to aqueous hydrochloric acid solution was 1:1.

[0095]

[0096] Comparative Example 4

[0097] Tris(hydroxymethyl)aminomethane hydrochloride was prepared in the same manner as Comparative Example 1, except that the product was cooled to room temperature instead of vacuum evaporation when obtaining the product.

[0098]

[0099] Comparative Example 5

[0100] Tris(hydroxymethyl)aminomethane hydrochloride was prepared in the same manner as Comparative Example 1, except that the ratio of tris(hydroxymethyl)aminomethane to aqueous hydrochloric acid solution was 1:1.3.

[0101]

[0102] Comparative Example 6

[0103] Tris(hydroxymethyl)aminomethane hydrochloride was prepared in the same manner as Comparative Example 1, except that the ratio of tris(hydroxymethyl)aminomethane to aqueous hydrochloric acid solution was 1:1.5.

[0104]

[0105] Comparative Example 1 Comparative Example 2 Comparative Example 3 Comparative Example 4 Comparative Example 5 Comparative Example 6 Example 1 Example 2 Example 3 Example 4 Example 5 Example 6 Ratio (TRIS / HCl) 1:1.11:1.11:11:1.11:1.3 1:1.5 1:1.11:1.11:1.11:1.3 1:1.5 Main Solvent H2O None H2OH2OH2OH2O None None None None None Temperature Change (°C) 25→50 25→70 25→45 25→50 25→50 25→50 25→70 25→70 25→70 25→70 25→75 25→75 Reaction Temperature Room temperature 3hr Room temperature 3hr Room temperature 3hr Room temperature 3hr Room temperature 3hr Room temperature 3hr 75°C 1hr 85°C 1hr 80°C 1hr 75°C 1hr 75°C 1hr 75°C 1hr Crystallization Vacuum Evaporation Vacuum Evaporation Vacuum Evaporation Cooling Vacuum Evaporation Vacuum Evaporation 60°C Cooling 1hr Crystal Nucleation 65°C Cooling 1hr Crystal Nucleation 60°C Cooling 1hr Crystal Nucleation 60°C Cooling 1hr Crystal Nucleation 55°C Cooling 1hr Crystal Nucleation 50°C Cooling 1hr Crystal Nucleation Crystallization Semi-solvent------Cooling to Room Temperature 2hr after Methanol treatment Cooling to Room Temperature 2hr after Ethanol treatment Cooling to Room Temperature 2hr after Isopropanol treatment Cooling to Room Temperature 2hr after Methanol treatment Cooling to Room Temperature 2hr after Methanol treatment Cooling to Room Temperature 2hr after Methanol treatment Cooling to Room Temperature 2hr after Methanol treatment Slurry washing------OOOOOOStationary washingOOOOOOColorLight yellowLight yellowLight yellow crystal XLight yellowLight yellowwhitewhitewhitewhitewhitewhite Crystalline form powderpowderpowder-powderpowderCrystalCrystalCrystalCrystalCrystalCrystalYield 70% 75% 70% -73% 75% 85% 90% 85% 83% 88% 90%Purity 98.5% 99.0% 98.0% -98.3% 98.1% 99.9% 99.7% 99.4% 99.3% 100% 100%

[0106]

[0107] As shown in Table 1, compared to Comparative Examples 1 and 3, which used water as a solvent and solidified by vacuum evaporation, and Comparative Example 2, which used vacuum evaporation, Examples 1 to 3, which crystallized using reflux and hydrocarbon solvents without using a main solvent, can be confirmed to obtain tris(hydroxymethyl)aminomethane hydrochloride crystals with high yield and high purity.

[0108] In addition, it can be confirmed that high yield and high purity tris(hydroxymethyl)aminomethane hydrochloride crystals can be obtained even when the ratio of tris(hydroxymethyl)aminomethane to aqueous hydrochloric acid solution is varied (Examples 4 to 6).

[0109] By summing the embodiments of the present invention, it can be confirmed that the present invention provides an environmentally friendly method for manufacturing tris(hydroxymethyl)aminomethane hydrochloride, and that tris(hydroxymethyl)aminomethane hydrochloride with the highest yield and purity can be obtained.

[0110]

[0111] From the foregoing description, those skilled in the art to which the present invention pertains will understand that the present invention may be implemented in other specific forms without altering its technical concept or essential features. In this regard, the embodiments described above should be understood as illustrative in all respects and not restrictive. The scope of the present invention should be interpreted as including all modifications or variations derived from the meaning and scope of the claims set forth below and their equivalents, rather than from the detailed description above.

[0112]

[0113] The method for producing tris(hydroxymethyl)aminomethane hydrochloride according to the present invention does not generate high exothermic reactions, provides high conversion rates and selectivity, and allows for the reuse of the antisolvent, making it economical and environmentally friendly.

Claims

1. A step of preparing a reaction product by mixing an aqueous hydrochloric acid solution and tris(hydroxymethyl)aminomethane; A step of refluxing the above reactants; and A method for preparing tris(hydroxymethyl)aminomethane hydrochloride, comprising the step of cooling the above-mentioned refluxed reaction product and then crystallizing it using a hydrocarbon solvent as an antisolvent.

2. In Paragraph 1, A method for preparing tris(hydroxymethyl)aminomethane hydrochloride, wherein an aqueous hydrochloric acid solution is included in an amount of 1 to 1.5 parts by weight based on 1 part by weight of tris(hydroxymethyl)aminomethane.

3. In Paragraph 1, A method for preparing tris(hydroxymethyl)aminomethane hydrochloride, wherein the aqueous hydrochloric acid solution is mixed dropwise.

4. In Paragraph 1, A method for preparing tris(hydroxymethyl)aminomethane hydrochloride, wherein the hydrocarbon solvent contains a hydroxyl group.

5. In Paragraph 1, A method for preparing tris(hydroxymethyl)aminomethane hydrochloride, wherein the hydrocarbon solvent comprises one or more selected from the group consisting of methanol, ethanol, n-propanol, isopropanol, and butanol.

6. In Paragraph 1, A method for preparing tris(hydroxymethyl)aminomethane hydrochloride, wherein the hydrocarbon solvent is included in an amount of 0.1 to 5 parts by weight based on 1 part by weight of tris(hydroxymethyl)aminomethane.

7. In Paragraph 1, A method for preparing tris(hydroxymethyl)aminomethane hydrochloride, wherein the refluxing step is performed at a temperature of 50°C to 120°C.

8. In Paragraph 1, The crystallization step involves stirring the refluxed reactants at 50 to 70°C; A step of stirring the above reaction mixture at 20 to 30°C; and A method for preparing tris(hydroxymethyl)aminomethane hydrochloride, comprising the step of stirring the above reaction mixture at -10℃ to 10℃.

9. In Paragraph 1, A method for producing tris(hydroxymethyl)aminomethane hydrochloride, wherein the hydrochloride is produced with a yield of 85% to 100%.

10. In Paragraph 1, A method for producing tris(hydroxymethyl)aminomethane hydrochloride, wherein the hydrochloride is produced with a purity of 95% to 100%.

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