A method for synthesizing 4-(2-hydroxyethyl)-1-piperazinepropanesulfonic acid

Abstract

The present application relates to the technical field of organic synthesis, in particular to a synthesis method of 4-(2-hydroxyethyl)-1-piperazinepropanesulfonic acid, which uses N-hydroxyethylpiperazine and 1,3-propane sulfonic acid lactone as raw materials, and reacts in an alkaline environment of monohydric alcohol, and then is filtered, decolorized, recrystallized, dried and the like to obtain 4-(2-hydroxyethyl)-1-piperazinepropanesulfonic acid.The synthesis method is easy to operate, has high product quality, and is environment-friendly, and the anhydrous monohydric alcohol and water in the reaction can be recycled.

Description

TECHNICAL FIELD

[0001] The present application relates to the technical field of organic synthesis, and particularly relates to a synthesis method of 4-(2-hydroxyethyl)-1-piperazinepropanesulfonic acid. BACKGROUND

[0002] Zwitterionic buffers are used exclusively in biological and biochemical research. This kind of buffer has good water solubility, high chemical stability, resistance to enzymatic and non-enzymatic degradation, minimal influence of medium concentration, temperature and ion composition on buffer capacity, no interference to biology and no toxicity to cells, and strong compatibility with biological systems. At present, more than twenty kinds of zwitterionic buffers have been developed, such as HEPPS, HEPES, MOPS, CAPS and the like.

[0003] 4-(2-hydroxyethyl)-1-piperazinepropanesulfonic acid (HEPPS) is used as a zwitterionic buffer in ultra-thin isoelectric focusing gel agents, and is used for enhancing the resolution of phosphoglucomutase. Moreover, it is found through research that 4-(2-hydroxyethyl)-1-piperazinepropanesulfonic acid has various effects, such as reducing Aβ-aggregation-induced memory deficits in mice and rescuing cognitive deficits, being used for verifying the influence of pH changes on proteolytic activity of postmidgut gland (PMG) contents and anteromidgut gland (AMG) tissue homogenate, resuspending peptides after enzymolysis, being used for processing brain-derived extracellular vesicle (EV) proteins and 16-fold isobaric tandem mass tag (TMT) peptide labeling, and the like.

[0004] The prior art CN 112028855 A discloses a synthesis method of 4-hydroxyethylpiperazineethanesulfonic acid (HEPES) which is extremely similar in structure, and needs sodium 2-chloroethyl sulfonate and N-hydroxyethylpiperazine to react at high temperature, and further needs to be subjected to multiple solid-liquid separation, decolorization, acidification and extraction to obtain the product. SUMMARY

[0005] In view of the technical problem of complex preparation method in the prior art, the present application provides a synthesis method of 4-(2-hydroxyethyl)-1-piperazinepropanesulfonic acid which is easy to obtain raw materials, simple to operate, high in product quality and friendly to the environment.

[0006] The present application provides a synthesis method of 4-(2-hydroxyethyl)-1-piperazinepropanesulfonic acid, and the reaction route is as follows:

[0007] ;

[0008] comprising the following steps:

[0009] (1) N-hydroxyethylpiperazine is mixed with anhydrous monohydric alcohol, stirred and heated to 30-50 DEG C, a base is added to adjust the pH to alkaline, 1,3-propane sultone is added in portions, the temperature is controlled to be no more than 50 DEG C during the reaction, and a mixed solution is obtained after the reaction is completed, wherein the pH of the mixed solution is 8.35-8.52;

[0010] (2) The mixed solution is heated to 75-85 DEG C, and kept for 4-6 h, impurities are removed by hot filtration after the heating is completed, the filtrate is cooled to 0-5 DEG C, and kept for 4-6 h for crystallization, and the filter cake is obtained by suction filtration after the heating is completed;

[0011] (3) The filter cake is mixed with water, heated to 60-65 DEG C to obtain a clear solution, acetic acid is added to adjust the pH to 5-5.5, activated carbon is added for decolorization, the decolorization is kept for 2-3 h, then precision filtration is carried out to obtain a viscous filtrate, anhydrous monohydric alcohol is added to the viscous filtrate for stirring and dispersion, the temperature is cooled to 0-5 DEG C, and kept for 4-6 h for crystallization, and the refined product is obtained by suction filtration;

[0012] (4) The refined product is dried to obtain 4-(2-hydroxyethyl)-1-piperazinepropanesulfonic acid.

[0013] Further, in step (1), the volume of anhydrous monohydric alcohol is 1.8-2 mL / g based on the amount of N-hydroxyethylpiperazine.

[0014] Further, in step (1), the molar ratio of N-hydroxyethylpiperazine to 1,3-propane sultone is 1:1.02-1.5. If the amount of 1,3-propane sultone is too large, the raw material will be wasted.

[0015] Further, in step (1), the base for adjusting the pH is selected from one of sodium hydroxide, sodium carbonate and potassium carbonate.

[0016] Further, in steps (1) and (3), the anhydrous monohydric alcohol is selected from one of anhydrous methanol, anhydrous ethanol, anhydrous propanol and anhydrous butanol.

[0017] Further, in steps (1) and (3), the anhydrous monohydric alcohol is selected from anhydrous methanol or anhydrous ethanol.

[0018] Further, in step (3), the amount of activated carbon added is 1.9‰-5‰ of the mass of the filter cake.

[0019] Further, in step (3), the alcohol-water mixed phase non-viscous filtrate is removed by precision filtration, the water obtained by distillation is used in step (3) of the next batch, and the remaining anhydrous monohydric alcohol is used in step (3) of the next batch.

[0020] The beneficial effects of the present application are as follows:

[0021] The application provides a preparation method of 4-(2-hydroxyethyl)-1-piperazinepropanesulfonic acid, which uses N-hydroxyethylpiperazine and 1,3-propane sulfonic acid lactone as raw materials, anhydrous monohydric alcohol as a solvent, and reacts in an alkaline environment, without adding other organic solvents in the reaction process, without high temperature and high pressure conditions, with high reaction degree, simple purification, and the content of the obtained crude product can reach the index requirement (more than 99.0%) after one recrystallization purification. In addition, the anhydrous monohydric alcohol involved can be directly recycled and applied to the next batch, the utilization rate is more than 80%, the water obtained by distillation of the alcohol and water mixed phase which is not a viscous liquid and is filtered out can be used in the next batch, and the discharge of waste water is reduced. The application is a green and efficient 4-(2-hydroxyethyl)-1-piperazinepropanesulfonic acid synthesis process, and can be popularized and applied industrially. BRIEF DESCRIPTION OF DRAWINGS

[0022] Figure 1 It is the infrared spectrum of the product 4-(2-hydroxyethyl)-1-piperazinepropanesulfonic acid obtained in Example 1. DETAILED DESCRIPTION

[0023] In order for those skilled in the art to better understand the technical solutions in the application, the technical solutions in the embodiments of the application will be clearly and completely described below. Obviously, the described embodiments are only some of the embodiments of the application, rather than all the embodiments. Based on the embodiments in the application, all other embodiments obtained by those skilled in the art without creative labor should belong to the protection scope of the application.

[0024] Example 1

[0025] A synthesis method of 4-(2-hydroxyethyl)-1-piperazinepropanesulfonic acid, and the specific steps are as follows:

[0026] (1) 130g of N-hydroxyethylpiperazine and 260mL of anhydrous ethanol are added to a reaction bottle, mixed and stirred, and heated to 50℃, then 2.5g of a 33% sodium hydroxide solution is slowly added dropwise to the reaction bottle, and then 125g of 1,3-propane sulfonic acid lactone is added in several portions, the reaction process is slightly exothermic, the temperature in the reaction process is controlled to be not more than 50℃, the reaction time is 4h, and after the reaction is completed, a mixed solution is obtained, and the pH of the mixed solution is 8.5;

[0027] (2) the mixed solution is heated to 75℃ and kept for 6h, after the heat preservation reaction is completed, impurities and other insoluble substances are removed by hot filtration, the filtrate is slowly cooled to 0℃, and kept for 4h, after the heat preservation is completed, filtration is performed, and 260g of a filter cake is obtained, and the content of the dry product of the filter cake is 96.5%;

[0028] (3) The filter cake is added into 300 mL of deionized water, heated to 60°C to obtain a solution, 1.5 mL of acetic acid is then added to adjust the pH to 5.5, and then 0.5 g of activated carbon of type 767 is added for adsorption and decolorization, and the temperature is kept for 2 h, and then hot precision filtration is performed to obtain a non-viscous filtrate of an alcohol-water mixture and a desolventized viscous substance, and the desolventized viscous substance is added with 200 mL of anhydrous ethanol for dispersion, stirring and dispersion are performed for 1 h, the temperature is slowly reduced to 0°C, and the temperature is kept for 4 h, and then suction filtration is performed to obtain 215 g of refined crude product, and 240 mL of water obtained by distillation of the non-viscous filtrate of the alcohol-water mixture can be used for the next batch, and the remaining 180 mL of anhydrous ethanol is directly used for the next batch;

[0029] (4) The refined crude product is dried in a blast drying oven at 50°C for 5 h to obtain 198.1 g of product 4-(2-hydroxyethyl)-1-piperazinepropanesulfonic acid, with a yield of 78.6% and a content of 99.4%.

[0030] The 0.1M 4-(2-hydroxyethyl)-1-piperazinepropanesulfonic acid aqueous solution is detected: the pH is 5.5, and the ultraviolet-visible absorption test is 0.01 at 260 nm and 0.012 at 280 nm, which meets the index requirements of commercial 4-(2-hydroxyethyl)-1-piperazinepropanesulfonic acid.

[0031] As Figure 1 The product is subjected to infrared testing to obtain an infrared spectrum, and then the content is determined by point titration and compared with the infrared standard spectrum to determine that the product is 4-(2-hydroxyethyl)-1-piperazinepropanesulfonic acid.

[0032] Example 2

[0033] A synthesis method of 4-(2-hydroxyethyl)-1-piperazinepropanesulfonic acid, and the specific steps are as follows:

[0034] (1) 130 g of N-hydroxyethylpiperazine, 260 mL of anhydrous methanol and 2.1 g of sodium carbonate are added into a reaction bottle, mixed and stirred, and heated to 50°C, and then 125 g of 1,3-propane sulfonic acid lactone is added in portions, the reaction process is slightly exothermic, the temperature during the reaction process is controlled to be not more than 50°C, the reaction time is 4 h, and after the reaction is completed, a mixed solution is obtained, and the pH of the mixed solution is 8.5;

[0035] (2) The mixed solution is heated to 75°C and kept for 6 h, and then hot filtration is performed to remove impurities and other insoluble substances, the filtrate is slowly cooled to 0°C, kept for 4 h, and then suction filtration is performed to obtain 245 g of filter cake, and the content of the dry product of the filter cake is 97.2%;

[0036] (3) The filter cake was added to 290 mL of deionized water, heated to 60°C to obtain a clear solution, 2.0 mL of acetic acid was added to adjust the pH to 5.4, then 0.5 g of activated carbon type 767 was added for adsorption and decolorization, and the temperature was maintained for 2 h, then hot precision filtration was performed to obtain a non-viscous filtrate of alcohol-water mixture and a desolventized viscous material, the desolventized viscous material was added with 200 mL of anhydrous methanol for dispersion, stirred for 1 h, slowly cooled to 0°C, and maintained for 4 h, then filtered to obtain 215 g of refined product, and 230 mL of water obtained by distillation of the non-viscous filtrate of alcohol-water mixture was used for the next batch, and the remaining 180 mL of anhydrous methanol was directly used for the next batch;

[0037] (4) The refined product was dried in a blast oven at 50°C for 5 h to obtain 190.3 g of 4-(2-hydroxyethyl)-1-piperazinepropanesulfonic acid, with a yield of 75.3% and a content of 99.55%.

[0038] The 0.1M 4-(2-hydroxyethyl)-1-piperazinepropanesulfonic acid aqueous solution was detected: the pH was 5.3, and the ultraviolet-visible absorption test value was 0.014 at 260 nm and 0.011 at 280 nm, meeting the index requirements of commercial 4-(2-hydroxyethyl)-1-piperazinepropanesulfonic acid.

[0039] Example 3

[0040] A method for synthesizing 4-(2-hydroxyethyl)-1-piperazinepropanesulfonic acid, the specific steps are as follows:

[0041] (1) 325 g of N-hydroxyethylpiperazine and 600 mL of anhydrous methanol were added to a reaction bottle, mixed and stirred, and heated to 50°C, then 6.25 g of 33% sodium hydroxide solution was slowly added dropwise, and then 313 g of 1,3-propane sulfone lactone was added in portions, the reaction was slightly exothermic, and the temperature was controlled to be not more than 50°C during the reaction, the reaction time was 4 h, and after the reaction was completed, a mixed solution was obtained, and the pH of the mixed solution was 8.52

[0042] (2) The mixed solution was heated to 75°C and maintained for 6 h, then hot filtration was performed to remove impurities and other insoluble substances, the filtrate was slowly cooled to 0°C, maintained for 4 h, then filtered, and 630 g of filter cake was obtained, and the dry content of the filter cake was 96.2%;

[0043] (3) The filter cake is added into 750 mL of deionized water, heated to 60°C to obtain a solution, then 6.5 mL of acetic acid is added to adjust the pH to 5.4, then 1.2 g of activated carbon of type 767 is added for adsorption and decolorization, and the temperature is kept for 2 h, then hot precision filtration is performed to obtain a non-viscous filtrate of alcohol-water mixture and a desolventized viscous substance, the desolventized viscous substance is added with 500 mL of anhydrous ethanol for dispersion, stirring and dispersion are performed for 1 h, the temperature is slowly reduced to 0°C, and the temperature is kept for 4 h, then suction filtration is performed to obtain 550 g of refined product, 640 mL of water obtained by distillation of the non-viscous filtrate of alcohol-water mixture can be used for the next batch, and the remaining 450 mL of anhydrous ethanol is directly used for the next batch;

[0044] (4) The refined product is dried in a blast oven at 50°C for 6 h to obtain 468.5 g of 4-(2-hydroxyethyl)-1-piperazinepropanesulfonic acid, with a yield of 74.3% and a content of 99.65%.

[0045] The 0.1M 4-(2-hydroxyethyl)-1-piperazinepropanesulfonic acid aqueous solution is detected: the pH is 5.4, and the ultraviolet-visible absorption test is 0.013 at 260 nm and 0.009 at 280 nm, which meets the index requirements of commercial 4-(2-hydroxyethyl)-1-piperazinepropanesulfonic acid.

[0046] Example 4

[0047] A method for synthesizing 4-(2-hydroxyethyl)-1-piperazinepropanesulfonic acid, the specific steps are as follows:

[0048] (1) 130 g of N-hydroxyethylpiperazine and 260 mL of anhydrous ethanol are added into a reaction bottle, mixed and stirred, and heated to 30°C, then 2.5 g of a 33% sodium hydroxide solution is slowly added dropwise into the reaction bottle, and then 183 g of 1,3-propane sulfone lactone is added in portions, the reaction process is slightly exothermic, the temperature during the reaction process is controlled to be not more than 50°C, the reaction time is 5 h, and after the reaction is completed, a mixed solution is obtained, and the pH of the mixed solution is 8.35;

[0049] (2) The mixed solution is heated to 85°C and kept for 4 h, then hot filtration is performed to remove impurities and other insoluble substances, the filtrate is slowly cooled to 0°C, kept for 4 h, then suction filtration is performed after the keeping is completed, and 255 g of filter cake is obtained, and the content of the dry product of the filter cake is 96.0%;

[0050] (3) The filter cake is added into 300 mL of deionized water, heated to 60°C to obtain a solution, then 1.5 mL of acetic acid is added to adjust the pH to 5.5, then 0.5 g of activated carbon type 767 is added for adsorption and decolorization, and the decolorization is kept for 3 h, then hot precision filtration is performed to obtain a non-viscous filtrate of alcohol-water mixed phase and a desolventized viscous substance, the desolventized viscous substance is added with 200 mL of anhydrous ethanol for dispersion, stirring and dispersion are performed for 1 h, slow cooling is performed to 0°C, and the temperature is kept for 6 h of crystallization, and suction filtration is performed to obtain 220 g of refined product, 240 mL of water obtained by distillation of the non-viscous filtrate of alcohol-water mixed phase can be used for the next batch, and the remaining 180 mL of anhydrous ethanol is directly used for the next batch.

[0051] (4) The refined product is dried in a blast drying oven at 50°C for 5 h to obtain 194.0 g of product 4-(2-hydroxyethyl)-1-piperazinepropanesulfonic acid, with a yield of 76.9% and a content of 99.4%.

[0052] The 0.1M 4-(2-hydroxyethyl)-1-piperazinepropanesulfonic acid aqueous solution is detected: the pH is 5.5, and the ultraviolet-visible absorption test is 0.013 at 260 nm and 0.010 at 280 nm, which meets the index requirements of commercial 4-(2-hydroxyethyl)-1-piperazinepropanesulfonic acid.

[0053] Although the present application has been described in detail by referring to the preferred embodiments thereof, it is to be understood that the present application is not limited to them. Variations and modifications are possible in the scope of the present application, as defined by the appended claims, without departing from the spirit and essence thereof. Any skilled person in the art can easily make modifications or replacements to the embodiments of the present application without departing from the technical scope disclosed in the present application, and these modifications or replacements should be covered within the protection scope of the present application.

Claims

1. A method for synthesizing 4-(2-hydroxyethyl)-1-piperazine propanesulfonic acid, characterized in that, The reaction route is as follows: ； Includes the following steps: (1) N-hydroxyethylpiperazine is mixed with anhydrous monohydric alcohol, stirred and heated to 30-50℃, and alkali is added to adjust the pH to alkaline. 1,3-propanesulfonic acid lactone is added in portions, and the temperature is controlled not to exceed 50℃ during the reaction. After the reaction is completed, a mixed solution is obtained with a pH of 8.35-8.

52. (2) Heat the mixture to 75-85℃ and keep it at that temperature for 4-6 hours. After the temperature is maintained, remove impurities by hot filtration. Cool the filtrate to 0-5℃ and keep it at that temperature for 4-6 hours to crystallize. After the temperature is maintained, filter the filtrate to obtain the filter cake. (3) Mix the filter cake with water, heat it to 60-65℃ to obtain a clear solution, add acetic acid to adjust the pH to 5-5.5, add activated carbon to keep warm and decolorize, keep warm and decolorize for 2-3 hours, then filter precisely to obtain a viscous filtrate, add anhydrous monohydric alcohol to the viscous filtrate and stir to disperse, cool to 0-5℃, keep warm and crystallize for 4-6 hours, and filter to obtain a refined wet product; (4) After drying the refined wet product, 4-(2-hydroxyethyl)-1-piperazine propanesulfonic acid is obtained; In step (1), the molar ratio of N-hydroxyethylpiperazine and 1,3-propanesulfonate lactone is 1:1.02-1.

5.

2. The method for synthesizing 4-(2-hydroxyethyl)-1-piperazine propanesulfonic acid as described in claim 1, characterized in that, In step (1), the volume of anhydrous monohydric alcohol is 1.8-2 mL / g, based on the amount of N-hydroxyethylpiperazine used.

3. The method for synthesizing 4-(2-hydroxyethyl)-1-piperazine propanesulfonic acid as described in claim 1, characterized in that, In step (1), the alkali used to adjust the pH is selected from sodium hydroxide, sodium carbonate, or potassium carbonate.

4. The method for synthesizing 4-(2-hydroxyethyl)-1-piperazine propanesulfonic acid as described in claim 1, characterized in that, In steps (1) and (3), the anhydrous monohydric alcohol is selected from one of anhydrous methanol, anhydrous ethanol, anhydrous propanol and anhydrous butanol.

5. The method for synthesizing 4-(2-hydroxyethyl)-1-piperazine propanesulfonic acid as described in claim 4, characterized in that, In steps (1) and (3), the anhydrous monohydric alcohol is selected from anhydrous methanol or anhydrous ethanol.

6. The method for synthesizing 4-(2-hydroxyethyl)-1-piperazine propanesulfonic acid as described in claim 1, characterized in that, In step (3), the amount of activated carbon added is 1.9‰-5‰ of the filter cake mass.

7. The method for synthesizing 4-(2-hydroxyethyl)-1-piperazine propanesulfonic acid as described in claim 1, characterized in that, In step (3), the non-viscous filtrate of the alcohol-water mixture is removed by precision filtration. The water obtained by distillation is used for the next batch of step (3), and the remaining anhydrous monohydric alcohol is used for the next batch of step (3).

Images