Preparation method of a piperazine sulfonic acid buffer

Abstract

The present invention provides a preparation method of a piperazine sulfonic acid buffer, which comprises the following steps: piperazine reacts with compound 1 having the general structural formula shown in Formula I under the action of an acid-binding agent to generate piperazine sultone having the general structural formula shown in Formula II; the piperazine sultone undergoes a hydrolysis reaction to obtain a piperazine sulfonic acid buffer having the general structural formula shown in Formula III; wherein, the general structural formula shown in Formula I is, the general structural formula shown in Formula II is, the general structural formula shown in Formula III is, and m and n each independently selected from any integer between 2-6. Each step of the reaction of the present invention is complete, which can effectively avoid the hydrolysis of raw materials and by-products generated by high-temperature dehydration. In particular, the hydrolysis reaction will not form inorganic salts, and the target product is easy to separate and purify during the preparation process, so as to obtain a piperazine sulfonic acid buffer with high purity at the pharmaceutical grade.

Description

Technical Field

[0001] The present invention belongs to the technical field of organic chemistry, and particularly relates to a preparation method of piperazine sulfonic acid buffer agents. Background Art

[0002] Piperazine sulfonic acid buffer agents are zwitterionic biological buffer agents. For example, piperazine sulfonic acid buffer agents include 4-(2-hydroxyethyl)piperazine-1-ethanesulfonic acid (HEPES), 4-(2-hydroxyethyl)piperazine-1-propanesulfonic acid (HEPPS), 3-(2-hydroxyethyl)piperazine-2-hydroxypropanesulfonic acid (HEPPSO) and their corresponding sodium salts HEPES-Na, HEPPS-Na, HEPPSO-Na, etc. They have good buffering capacity within a certain pH range and can maintain a constant pH of the solution system for a long time.

[0003] Taking HEPES as an example. The patent with publication number CN112159367B discloses a production method of 4-(2-hydroxyethyl)piperazine-1-ethanesulfonic acid. Using sodium 2-hydroxyethanesulfonate and 2-hydroxyethylpiperazine as raw materials, the reaction is carried out through a continuous production mode in a pipeline; the post-treatment is carried out by ion exchange with a hydrogen-type cation exchange resin; finally, 4-(2-hydroxyethyl)piperazine-1-ethanesulfonic acid is obtained. The patent with publication number CN110683995A discloses a preparation method of piperazine ethanesulfonic acid derivatives. Using 2-hydroxyethylpiperazine and sodium 2-chloroethanesulfonate as raw materials, and then by forming a salt with triethylamine, triethylamine hydrochloride that is soluble in water and ethanol can be directly removed from the system, reducing the desalting method using ion exchange resin. Finally, the obtained product has relatively high purity.

[0004] In the existing technologies not listed, the preparation of HEPES usually uses 2-chloroethanesulfonic acid, vinylsulfonic acid or 2-hydroxyethanesulfonic acid as raw materials and reacts under alkaline conditions to obtain the sodium salt, potassium salt or ammonium salt of HEPES. In such reactions, there are often small amounts of unreacted raw materials remaining in the reaction products, as well as by-products of hydrolysis and high-temperature dehydration. At the same time, a small amount of inorganic salts will be formed during the acid adjustment process of the product, resulting in difficulties in product separation and purification, and it is very difficult to obtain pharmaceutical-grade high-purity 4-(2-hydroxyethyl)piperazine-1-ethanesulfonic acid. For this reason, the commonly used purification methods are ion exchange resin method and nanofiltration method. However, the main problems of these two methods are: 1. A large amount of industrial wastewater will be generated during the purification process, which is difficult to treat and seriously pollutes the soil and groundwater; 2. Resin regeneration requires a large amount of acid and alkali; 3. The purity of the target product obtained is not high enough, and further separation and purification are often required; 4. The purification amount of the product is low, the efficiency is low, and thus the cost is high.

[0005] Generally speaking, the above problems existing in the preparation process of piperazine sulfonic acid buffers have hindered the large-scale application of sulfonic acid compounds, especially hindered their becoming materials in the field of biological buffer reagents. Therefore, there is an urgent need in the industry for a preparation method of piperazine sulfonic acid buffers with high purity, simple process operation and high yield. Summary of the Invention

[0006] Aiming at the deficiencies of the prior art, the purpose of the present invention is to provide a preparation method of piperazine sulfonic acid buffers, which will not form inorganic salts during the hydrolysis process, so as to be easy to carry out post-treatment and obtain piperazine sulfonic acid buffers with high purity.

[0007] To achieve this purpose, the present invention adopts the following technical solutions:

[0008] The first purpose of the present invention is to provide a preparation method of piperazine sulfonic acid buffers, including the following steps: piperazine reacts with compound 1 with the general structural formula shown in formula I under the action of an acid-binding agent to generate piperazine sultone with the general structural formula shown in formula II; the piperazine sultone undergoes a hydrolysis reaction to obtain a piperazine sulfonic acid buffer with the general structural formula shown in formula III;

[0009] Among them,

[0010] The general structural formula shown in formula I is

[0011] The general structural formula shown in formula II is

[0012] The general structural formula shown in formula III is

[0013] m and n each independently selected from any integer between 2 and 6.

[0014] Among them, m and n are each independently 2, 3, 4, 5 or 6.

[0015] Preferably, the molar ratio of the compound 1, the piperazine and the acid-binding agent is 1:(1 - 2):(0.5 - 2);

[0016] More preferably, the acid-binding agent is triethylamine.

[0017] Among them, the molar ratio of the compound 1, the piperazine and the acid-binding agent is 1:1:0.5, 1:1:1, 1:1:1.5, 1:1:2, 1:1.5:0.5, 1:1.5:1, 1:1.5:1.5, 1:1.5:2, 1:2:0.5, 1:2:1, 1:2:1.5 or 1:2:2, etc., but not limited to the above-listed values, and other unlisted values within the above numerical range are equally applicable.

[0018] Preferably, the substitution reaction further includes a first aprotic solvent, which is one selected from anhydrous N,N-dimethylacetamide, anhydrous N,N-dimethylformamide, and anhydrous pyridine;

[0019] More preferably, the reaction temperature of the substitution reaction is 0-20°C, and the reaction time is 3-5 h.

[0020] Among them, the temperature of the substitution reaction can be 0°C, 1°C, 2°C, 3°C, 4°C, 5°C, 6°C, 7°C, 8°C, 9°C, 10°C, 11°C, 12°C, 13°C, 14°C, 15°C, 16°C, 17°C, 18°C, 19°C or 20°C, etc., and the reaction time can be 3 h, 3.5 h, 4 h, 4.5 h or 5 h, etc., but is not limited to the values listed above, and other unlisted values within the above value range are equally applicable.

[0021] Preferably, the hydrolysis reaction further includes an ethanol solution with a water content of 10-20%. The hydrolysis reaction needs to be carried out under acidic conditions, and the pH range of the acidic conditions is 5-6, and the hydrolysis temperature is 0-50°C 。

[0022] Among them, the hydrolysis reaction further includes an ethanol solution with a water content that can be 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19% or 20%, etc., the pH value of the acidic conditions can be 5, 5.5 or 6, etc., and the hydrolysis temperature can be 0°C, 5°C, 10°C, 15°C, 20°C, 25°C, 30°C, 35°C, 40°C, 45°C or 50°C, etc., but is not limited to the values listed above, and other unlisted values within the above value range are equally applicable.

[0023] Preferably, the preparation of compound 1 includes the following steps:

[0024] S1. React compound 2 with the general formula shown in Formula IV with a chlorinating reagent to obtain compound 3 with the general formula shown in Formula V;

[0025] S2. React compound 3 with compound 4 with the general formula shown in Formula VI under the action of an acid-binding agent to obtain compound 1;

[0026] Among them,

[0027] The general formula shown in Formula IV is wherein N is one selected from H, alkali metal elements lithium, sodium, and potassium;

[0028] The general formula shown in Formula V is

[0029] The general formula shown in Formula VI is

[0030] m and n are each independently selected from any integer between 2 and 6.

[0031] Among them, m and n are each independently 2, 3, 4, 5 or 6.

[0032] Preferably, in step S1, the substitution reaction further includes a second aprotic solvent, and the compound 2 is added slowly in portions to the second aprotic solvent dissolving the chlorinating reagent;

[0033] More preferably, the second aprotic solvent includes one of dichloromethane, chloroform, 1,2-dichloroethane;

[0034] More preferably, the chlorinating reagent includes at least one of thionyl chloride, sulfonyl chloride, chlorine, phosphorus pentachloride, thionyl chloride, phosphorus oxychloride, phosphorus trichloride.

[0035] Preferably, in step S1, the molar ratio of the compound 2 to the chlorinating reagent in the feed is 1:(1.5 - 5);

[0036] More preferably, the temperature of the substitution reaction is 20 - 60 °C, and the reaction time is 3 - 5 h.

[0037] Among them, in step S1, the molar ratio of the compound 2 to the chlorinating reagent in the feed can be 1:1.5, 1:2, 1:2.5, 1:3, 1:3.5, 1:4, 1:4.5 or 1:5, etc.; the temperature of the substitution reaction can be 20 °C, 25 °C, 30 °C, 35 °C, 40 °C, 45 °C, 50 °C, 55 °C or 60 °C, etc., and the reaction time can be 3 h, 3.5 h, 4 h, 4.5 h or 5 h, etc., but is not limited to the values listed above, and other unlisted values within the above numerical range are equally applicable.

[0038] Preferably, in step S2, the esterification reaction further includes a third aprotic solvent;

[0039] Preferably, the third aprotic solvent is one selected from dichloromethane, chloroform, 1,2-dichloroethane, and the acid-binding agent is triethylamine.

[0040] Preferably, in step S2, the molar ratio of the compound 3, the compound 4 and the acid-binding agent in the feed is 1:(1.5 - 2):(1 - 2);

[0041] Preferably, the reaction temperature of the esterification reaction is -20 - 25 °C, and the reaction time is 12 - 18 h.

[0042] Among them, in step S2, the molar ratio of the compound 3, the compound 4 and the acid-binding agent is 1:1.5:1, 1:1.5:1.5, 1:1.5:2, 1:2:1, 1:2:1.5 or 1:2:2, etc.; the reaction temperature of the esterification reaction can be -20°C, -15°C, -10°C, -5°C, 0°C, 5°C, 10°C, 15°C, 20°C or 25°C, etc.; the reaction time can be 12h, 13h, 14h, 15h, 16h, 17h or 18h, etc., but it is not limited to the values listed above, and other unlisted values within the above value range are equally applicable.

[0043] Preferably, the piperazine sulfonic acid buffer includes and its sodium salt, and its sodium salt.

[0044] Compared with the prior art, the present invention has the following beneficial effects:

[0045] The present invention provides a preparation method of a piperazine sulfonic acid buffer. A substitution reaction occurs between piperazine and compound 1 with the general structural formula shown in formula I under the action of an acid-binding agent to obtain piperazine sultone; the piperazine sultone directly undergoes a hydrolysis reaction to obtain the piperazine sulfonic acid buffer; each step of the reaction in the present invention is complete, which can effectively avoid the hydrolysis of raw materials and by-products generated by high-temperature dehydration. In particular, the hydrolysis reaction will not form inorganic salts, and the target product is easy to separate and purify during the preparation process, so as to obtain a piperazine sulfonic acid buffer with high purity at the pharmaceutical grade. Specific Embodiments

[0046] The technical solutions of the present invention will be further described below through specific embodiments. Those skilled in the art should understand that the embodiments are only for helping to understand the present invention and should not be regarded as specific limitations to the present invention.

[0047] Example 1

[0048] This example provides a preparation method of 4-(2-hydroxyethyl)piperazine-1-ethanesulfonic acid, including the following steps:

[0049] S1. Add 4 mol of thionyl chloride to 1 L of dichloromethane, heat to 50°C until reflux, and slowly add a total of 2 mol of chloroethylsulfonic acid to the above solution in small portions and multiple times for a substitution reaction for 4 h. After distilling off the solvent under reduced pressure, collect the light yellow fraction above 80°C, and thus obtain

[0050] S2. Add 1.8 mol of chloroethanol and 2.25 mol of triethylamine to 1.1 L of dichloromethane, lower the temperature of the system to -20°C, and slowly dropwise add a solution containing 1.5 mol of A dichloromethane solution was added dropwise over about 1 h, and the esterification reaction was carried out for more than 12 h. Bubbles were generated during the reaction. After the reaction was completed, it was cooled to room temperature, and the insoluble substances were removed by filtration. After removing dichloromethane, dichloromethane was added again. After stirring, the solvent was removed again. The operation was repeated many times, and finally a colorless paste was obtained, namely

[0051] S3. Add 680 mL of anhydrous solvent N,N-dimethylacetamide, 2 mol of triethylamine, and 1 mol Cool to 0 °C, and then add an anhydrous N,N-dimethylacetamide solution containing 1 mol of piperazine. The substitution reaction was carried out for 13 h; after filtration, the filtrate was concentrated to a viscous state at 45 Pa and an internal temperature of 120 °C, and cooled to room temperature to obtain

[0052] At 0 - 5 °C, add an aqueous ethanol solution with a water content of 10% to the above-prepared Adjust the pH value of the solution to about 5 - 6, stir to carry out the hydrolysis reaction, and white crystalline solids precipitate; after filtration, the filter cake was obtained, and then an 80% aqueous ethanol solution was added, and crystallization was carried out by stirring many times, and the product was rinsed with ethanol 2 - 3 times to obtain a moist product and dried to obtain a pharmaceutical-grade 4-hydroxyethylpiperazineethanesulfonic acid with a yield of 80%, a purity of 99.3%, and a content of 30% aqueous solution (clear solubility)

[0053] Example 2

[0054] This example provides a method for preparing 4-hydroxyethylpiperazineethanesulfonic acid, which is basically the same as Example 1, except that in step S1, chloroethylsulfonic acid is replaced with sodium chloroethylsulfonate, and finally a pharmaceutical-grade 4-hydroxyethylpiperazineethanesulfonic acid with a yield of 79%, a purity of 99.2%, and a content of 30% aqueous solution (clear solubility) is obtained

[0055] Example 3

[0056] This example provides a method for preparing 4-hydroxyethylpiperazineethanesulfonic acid, the steps of which are the same as those in Example 1, except that in step S1, 10 mol of the chlorinating reagent phosphorus oxychloride is added, and the substitution reaction is carried out for 3 h. Finally, a pharmaceutical-grade 4-hydroxyethylpiperazineethanesulfonic acid with a yield of 81%, a purity of 99.2%, and a content of 30% aqueous solution (clear solubility) is obtained

[0057] Example 4

[0058] This example provides a method for preparing sodium 4 - (2 - hydroxyethyl) piperazine - 1 - ethanesulfonate, which is basically the same as Example 1. The difference is that the preparation method further includes the steps of adding a small amount of pure water to the obtained 4 - (2 - hydroxyethyl) piperazine - 1 - ethanesulfonic acid at room temperature, stirring until dissolved and clear, dropping sodium hydroxide alkali solution, adjusting the pH to 9.5 - 10.5, adding absolute ethanol, precipitating white solid, filtering, and drying to finally obtain solid crystalline powder, namely sodium 4 - (2 - hydroxyethyl) piperazine - 1 - ethanesulfonate, with a yield of 78% and a purity of 99%.

[0059] Example 5

[0060] This example provides a method for preparing 4 - (2 - hydroxypropyl) piperazine - 1 - propanesulfonic acid, including the following steps:

[0061] S1. Add 6 mol of phosphorus trichloride to 1 L of dichloromethane, heat to 50 °C until reflux, and slowly add a total of 2 mol of 3 - hydroxy - 1 - propanesulfonic acid to the above - mentioned solution in small portions. Carry out substitution reaction for 4 h, distill off the solvent under reduced pressure, and collect the light - yellow fraction above 80 °C, which is obtained.

[0062] S2. Add 2.25 mol of chloroethanol and 3 mol of triethylamine to 1.1 L of dichloromethane, lower the temperature of the system to - 20 °C, and slowly dropwise add the dichloromethane solution dissolving 1.5 mo over about 1 h while stirring, carry out esterification reaction for more than 12 h. Bubbles are generated during the reaction process. After the reaction is completed, cool to room temperature, filter to remove insoluble substances, remove dichloromethane, then add dichloromethane again, stir and then remove the solvent again. Repeat the operation multiple times to finally obtain a colorless paste, which is

[0063] S3. Add 680 mL of anhydrous solvent N,N - dimethylacetamide, 2 mol of triethylamine, and 1 mo to the reaction flask, lower the temperature to 0 °C, then add the anhydrous N,N - dimethylacetamide solution dissolving 1 mol of piperazine, and carry out substitution reaction for 13 h; after filtration, concentrate the filtrate to a viscous state at 45 Pa and an internal temperature of 120 °C, and cool to room temperature to obtain

[0064] At 0 - 5 °C, add an ethanol - aqueous solution with a water content of 10% to the above - prepared , and adjust the pH value of the solution to about 5 - 6, stir to carry out hydrolysis reaction, and precipitate white crystalline solid; after filtration, obtain the filter cake, then add 80% ethanol - aqueous solution, stir and crystallize multiple times, and wash with ethanol 2 - 3 times to obtain a moist product and dry it to obtain pharmaceutical - grade 4 - (2 - hydroxypropyl) piperazine - 1 - propanesulfonic acid with a yield of 80%, a purity of 99.1%, and a content of 30% aqueous solution (clear solubility).

[0065] Example 6

[0066] This example provides a preparation method of sodium 4-hydroxyethylpiperazinepropanesulfonate, which is basically the same as that of Example 5. The difference is that the preparation method further includes the steps of adding a small amount of pure water to the obtained pharmaceutical-grade 4-hydroxyethylpiperazinepropanesulfonic acid at room temperature, stirring until dissolved and clear, dropping an alkali solution to adjust the pH to 10-11, adding absolute ethanol, precipitating a white solid, filtering, and drying to finally obtain a solid crystalline powder, namely sodium 4-hydroxyethylpiperazinepropanesulfonate, with a yield of 76% and a purity of 99.2%.

[0067] The present invention provides a preparation method of a piperazine sulfonic acid buffer. A piperazine sulfonolactone is obtained by a substitution reaction of piperazine with a compound 1 having the general structural formula shown in Formula I under the action of an acid-binding agent; the piperazine sulfonolactone directly undergoes a hydrolysis reaction to obtain a piperazine sulfonic acid buffer. The reactions in each step of the present invention are complete, which can effectively avoid by-products generated by hydrolysis of raw materials and high-temperature dehydration. In particular, the hydrolysis reaction will not form inorganic salts, and the target product in the preparation process is easy to separate and purify, so as to obtain a pharmaceutical-grade high-purity piperazine sulfonic acid buffer.

[0068] The applicant declares that the present invention uses the above examples to illustrate a preparation method of a piperazine sulfonic acid buffer of the present invention, but the present invention is not limited to the above examples, that is, it does not mean that the present invention must rely on the above examples to be implemented. Those skilled in the art should understand that any improvement to the present invention, the equivalent replacement of each raw material of the product of the present invention, the addition of auxiliary components, and the selection of specific methods, etc., all fall within the protection scope and the disclosure scope of the present invention.

Claims

1. A preparation method of a piperazine sulfonic acid buffer, characterized in that, It includes the following steps: piperazine and compound 1 with the general structural formula shown in Formula I undergo a substitution reaction under the action of an acid-binding agent to generate piperazine sultone with the general structural formula shown in Formula II; the piperazine sultone undergoes a hydrolysis reaction to obtain a piperazine sulfonic acid buffer with the general structural formula shown in Formula III. Wherein, The general structural formula shown in Formula I is The general structural formula shown in Formula II is The general structural formula shown in Formula III is m and n each independently selected from any integer between 2 and 6.

2. The preparation method according to claim 1, wherein The molar ratio of compound 1, piperazine and the acid-binding agent is 1:(1 - 2):(0.5 - 2).

3. The preparation method according to claim 2, wherein The acid-binding agent is triethylamine.

4. The preparation method according to any one of claims 1-3, characterized in that, The substitution reaction also includes a first aprotic solvent, and the first aprotic solvent is one selected from anhydrous N,N-dimethylacetamide, anhydrous N,N-dimethylformamide, and anhydrous pyridine.

5. The preparation method according to claim 4, characterized in that, The reaction temperature of the substitution reaction is 0 - 20 °C, and the reaction time is 3 - 5 h.

6. According to the preparation method described in any one of claims 1-3, characterized in that, The hydrolysis reaction also includes an ethanol solution with a water content of 10-20%. The hydrolysis reaction needs to be carried out under acidic conditions, and the pH range of the acidic conditions is 5-6. The hydrolysis temperature is 0-50°C 。 7. According to the preparation method described in claim 1, wherein The preparation of compound 1 includes the following steps: S1. Compound 2 with the general structural formula shown in Formula IV undergoes a substitution reaction with a chlorinating reagent to obtain compound 3 with the general structural formula shown in Formula V; S2. Compound 3 and compound 4 with the general structural formula shown in Formula VI undergo an esterification reaction under the action of an acid-binding agent to obtain compound 1; Wherein, The general structural formula shown in Formula IV is wherein N is one selected from H, and alkali metal elements lithium, sodium, and potassium; The general structural formula shown in Formula V is The general structural formula shown in Formula VI is m and n each independently selected from any integer between 2 and 6.

8. The preparation method according to claim 7, characterized in that In step S1, the substitution reaction also includes a second aprotic solvent, and compound 2 is added slowly in portions to the second aprotic solvent dissolving the chlorinating reagent.

9. The preparation method according to claim 8, characterized in that, The second aprotic solvent is one of dichloromethane, chloroform, and 1,2-dichloroethane.

10. The preparation method according to claim 8, characterized in that, The chlorinating reagent is at least one of thionyl chloride, sulfonyl chloride, chlorine, phosphorus pentachloride, thionyl chloride, phosphorus oxychloride, and phosphorus trichloride.

11. According to the preparation method described in any one of claims 7-10, characterized in that, In step S1, the molar ratio of compound 2 to the chlorinating reagent is 1:(1.5 - 5).

12. According to the preparation method described in claim 11, wherein, In step S1, the reaction temperature of the substitution reaction is 20 - 60 °C, and the reaction time is 3 - 5 h.

13. According to the preparation method described in any one of claims 7-10, characterized in that, In step S2, the esterification reaction also includes a third aprotic solvent.

14. The preparation method according to claim 13, wherein, The third aprotic solvent is one selected from dichloromethane, chloroform, and 1,2-dichloroethane, and the acid-binding agent is triethylamine.

15. The preparation method according to any one of claims 7-10, characterized in that, In step S2, the molar ratio of compound 3, compound 4 and the acid-binding agent is 1:(1.5 - 2):(1 - 2).

16. The preparation method according to claim 15, wherein The reaction temperature of the esterification reaction is -20 - 25 °C, and the reaction time is 12 - 18 h.

17. The preparation method according to any one of claims 1-3, characterized in that, The piperazine sulfonic acid buffer is 18. Use of the preparation method according to any one of claims 1 - 17 in the preparation of sodium 4-hydroxyethylpiperazineethanesulfonate and sodium 4-hydroxyethylpiperazinepropanesulfonate.

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