The invention relates to a method for synthesizing piperazine-N, Napos; process for the preparation of-bis (2-hydroxypropanesulfonic acid) dihydrate

Abstract

The invention relates to a method for synthesizing piperazine-N, N '-bis (2-hydroxypropanesulfonic acid) dihydrate, and belongs to the technical field of organic chemistry. The method comprises the following steps: opening a channel A and a channel B, enabling piperazine and sodium 3-chloro-2-hydroxypropanesulfonate to react in a micro-channel reactor under the catalysis of sodium hydroxide to obtain piperazine-N, N '-bis (2-hydroxypropanesulfonic acid) disodium salt, enabling the reaction liquid to enter a neutralization unit after the reaction is finished, opening a channel C, adjusting the pH value of the reaction liquid to be 5-6, desalting, and crystallizing to obtain the piperazine-N, N'-bis (2-hydroxypropanesulfonic acid) disodium salt. The invention relates to N, N '-bis (2-hydroxy propanesulfonic acid) dihydrate. Anhydrous piperazine and sodium 3-chloro-2-hydroxypropanesulfonate are adopted as raw materials, the reaction is carried out in the microchannel reactor, the continuous and efficient reaction can be realized, the reaction degree is high, and the content after crystallization and purification can meet the index requirement.

Description

Technical Field

[0001] This invention relates to the field of organic chemistry, and specifically to a method for synthesizing piperazine-N,N'-bis(2-hydroxypropanesulfonic acid) dihydrate. Background Technology

[0002] Piperazine-N,N'-bis(2-hydroxy-propanesulfonic) acid (POPSO) is a commonly used "good" buffer in biochemistry and molecular biology. POPSO is an amphoteric buffer that increases osmotic pressure and has a significant inhibitory effect on anion single-port buffers. It can also be used to treat primary or familial hypercholesterolemia. It can be used in combination with other medications, such as statins, to enhance their cholesterol-lowering effects.

[0003] There are two methods for preparing piperazine-N,N'-bis(2-hydroxypropanesulfonic acid): (1) Using piperazine as a raw material, it first undergoes a nucleophilic addition reaction with propylene oxide to generate N,N'-bis(2-hydroxypropyl)piperazine; then it undergoes a sulfonation reaction with bisulfite (or sulfurous acid) to introduce a sulfonic acid group to obtain piperazine-N,N'-bis(2-hydroxypropanesulfonic acid). This method is the most commonly used preparation method, and the process is relatively mature. However, the epichlorohydrin used will undergo a ring-opening polymerization side reaction at high temperatures, generating polyether impurities, which leads to a decrease in the purity of the intermediate N,N'-bis(2-hydroxypropyl)piperazine, and thus affects the purity of the subsequent products.

[0004] (2) Another method involves using piperazine and sodium 2-hydroxypropanesulfonate as raw materials, reacting them under alkaline conditions (sodium hydroxide catalysis) at 80-100℃ for 8-12 hours, and then acidifying to obtain piperazine-N,N'-bis(2-hydroxypropanesulfonic acid). This method does not require separation of intermediates and is simpler, but the reaction time is too long and the reaction yield is only about 80%, resulting in higher production costs. Summary of the Invention

[0005] To address the problems of low yield and long reaction time in the existing preparation of piperazine-N,N'-bis(2-hydroxypropanesulfonic acid), this invention provides a method for synthesizing piperazine-N,N'-bis(2-hydroxypropanesulfonic acid) dihydrate, thereby solving the above problems.

[0006] The technical solution of this invention is as follows: A method for synthesizing piperazine-N,N'-bis(2-hydroxypropanesulfonic acid) dihydrate, the reaction formula is as follows: ; Includes the following steps: A microchannel reactor was used as the reaction device. Channel A delivered a solution containing piperazine, channel B delivered a solution containing sodium 3-chloro-2-hydroxypropanesulfonate and sodium hydroxide, and channel C delivered an acid solution. First, channels A and B are opened to allow piperazine and sodium 3-chloro-2-hydroxypropanesulfonate to react in a microchannel reactor under the catalysis of sodium hydroxide to obtain piperazine-N,N'-bis(2-hydroxypropanesulfonic acid) disodium salt. After the reaction is completed, the reaction solution enters the neutralization unit, and channel C is opened to adjust the pH of the reaction solution to 5-6. After desalting, the solution is crystallized to obtain piperazine-N,N'-bis(2-hydroxypropanesulfonic acid) dihydrate.

[0007] Furthermore, the molar ratio of piperazine to sodium 3-chloro-2-hydroxypropanesulfonate is 1:2.0~2.1.

[0008] Furthermore, the reaction temperature of piperazine with sodium 3-chloro-2-hydroxypropanesulfonate is 100℃~110℃.

[0009] Furthermore, the number of microchannel reactor reaction modules is 4 to 6, arranged in series.

[0010] Furthermore, the total residence time of piperazine and sodium 3-chloro-2-hydroxypropanesulfonate in the microchannel reactor was 10-15 min.

[0011] Furthermore, the acid solution is one of formic acid, glacial acetic acid, or hydrochloric acid.

[0012] Furthermore, the reaction pressure between piperazine and sodium 3-chloro-2-hydroxypropanesulfonate is 0.5~0.9 MPa.

[0013] Furthermore, after the reaction of piperazine and sodium 3-chloro-2-hydroxypropanesulfonate is complete, some of the water in the reaction solution can be removed by vacuum distillation. Concentration and dehydration reduce the amount of solvent and increase the concentration of the product in the reaction solution.

[0014] Furthermore, the crystallization method is as follows: after the reaction solution is desalted, an alcohol solvent is added, the temperature is lowered to 0~5℃ to crystallize, and the solid-liquid separation yields piperazine-N,N'-bis(2-hydroxypropanesulfonic acid) dihydrate.

[0015] The beneficial effects of this invention are as follows: This invention uses anhydrous piperazine and sodium 3-chloro-2-hydroxypropanesulfonic acid as raw materials. The reaction is carried out in a microchannel reactor, enabling continuous and efficient reaction with a high degree of reaction. After crystallization and purification, the content can meet the required specifications. In addition, the alcohol solvent used for crystallization can be recovered and reused after distillation, reducing the discharge of wastewater and waste liquid. The solvent utilization efficiency is greater than 90%. This is a green and efficient piperazine-N,N'-bis(2-hydroxypropanesulfonic acid) dihydrate technology that can be industrially promoted. Attached Figure Description

[0016] To more clearly illustrate the technical solutions in the embodiments of the present invention or the prior art, the drawings used in the description of the embodiments or the prior art will be briefly introduced below. Obviously, for those skilled in the art, other drawings can be obtained based on these drawings without creative effort.

[0017] Figure 1 This is the infrared spectrum of the piperazine-N,N'-bis(2-hydroxypropanesulfonic acid) dihydrate standard. Figure 2 This is the infrared detection spectrum of the product prepared in Example 1 of the present invention. Detailed Implementation

[0018] To enable those skilled in the art to better understand the technical solutions of this invention, the technical solutions of the embodiments of this invention will be clearly and completely described below with reference to the accompanying drawings. Obviously, the described embodiments are only some embodiments of this invention, and not all embodiments. Based on the embodiments of this invention, all other embodiments obtained by those skilled in the art without creative effort should fall within the scope of protection of this invention.

[0019] The relevant parameters of the microchannel reactor used in this embodiment of the invention are as follows: Microchannel reactor material: Hastelloy.

[0020] Microchannel size: equivalent diameter 1mm.

[0021] Number of reaction modules: 5, arranged in series.

[0022] Heat exchanger type: micro-needle fin type.

[0023] Example 1 A method for synthesizing piperazine-N,N'-bis(2-hydroxypropanesulfonic acid) dihydrate includes the following steps: (1) Raw material preparation: Weigh 172.2g (2mol) of anhydrous piperazine and dissolve it in 300g of water. After mixing, obtain solution A; dissolve 825.8g (4.15mol) of sodium 3-chloro-2-hydroxypropanesulfonate in 900g of water, and then add 336g of sodium hydroxide aqueous solution with a mass fraction of 50%. After mixing, obtain solution B; weigh 336g of hydrochloric acid with a concentration of 36 wt% to obtain solution C.

[0024] (2) Microchannel reaction: Turn on the circulating water cooling system and the high and low temperature integrated heating system, and set the reaction module temperature to 100℃. Set the flow rate of the metering pump for the A channel feed to 6g / min; set the flow rate of the metering pump for the B channel feed to 22g / min. Open the valves before and after the feed pump, and the inlet and outlet valves of the material and oil circuit of the module reactor. Turn on the feed pump to stabilize the pressure at 0.8MPa. The material stays in the reactor for a total of 3.5min. After cooling through the heat exchange system, collect the product at the outlet of the microchannel reactor. The pH of the outlet reaction solution is 10.

[0025] (3) Dehydration: The reaction solution is concentrated under reduced pressure and heated to <70℃. About 600g of water is removed.

[0026] (4) Acidification and desalination: The reaction solution enters the neutralization unit, the flow rate of the metering pump for the feed in channel C is set to 4 g / min, the hydrochloric acid metering pump is turned on, the pH is adjusted to 5-6 by the online pH meter, and the solid salt is removed by filtration.

[0027] (5) Cooling crystallization: The acidified liquid after desalination enters the cooling crystallizer, 1600g of anhydrous ethanol is added, the temperature is lowered to 5℃, and the crystallization is carried out for 3h.

[0028] (6) Centrifugal drying: After the crystallization and heat preservation were completed, centrifugation was performed to obtain 901.6 g of wet piperazine-N,N'-bis(2-hydroxypropanesulfonic acid) dihydrate. After drying at 60℃ for 3 h, 766.1 g of dry product was obtained, with a yield of 96.1%. The product test results were as follows: content (external standard method) 99.82%, moisture 6.0%, and residue on ignition 0.07%.

[0029] Example 2 A method for synthesizing piperazine-N,N'-bis(2-hydroxypropanesulfonic acid) dihydrate includes the following steps: (1) Raw material preparation: Weigh 200g (2.32mol) of anhydrous piperazine and dissolve it in 350g of water. After mixing, obtain solution A; dissolve 912.2g (4.64mol) of sodium 3-chloro-2-hydroxypropanesulfonate in 1050g of water, and then add 390g of 50% sodium hydroxide aqueous solution. After mixing, obtain solution B; weigh 390g of 36 wt% hydrochloric acid to obtain solution C.

[0030] (2) Microchannel reaction: Turn on the circulating water cooling system and the high and low temperature integrated heating system, and set the reaction module temperature to 110℃. Set the flow rate of the metering pump for the A channel feed to 6.96 g / min; set the flow rate of the metering pump for the B channel feed to 25.5 g / min. Open the valves before and after the feed pump, and the inlet and outlet valves of the material and oil circuit of the module reactor. Turn on the feed pump to stabilize the pressure at 0.85 MPa. The material stays in the reactor for a total of 5 minutes. After cooling through the heat exchange system, collect the product at the outlet of the microchannel reactor. The pH of the outlet reaction solution is 10.

[0031] (3) Dehydration: The reaction solution is concentrated under reduced pressure and heated to <70℃. About 700g of water is removed.

[0032] (4) Acidification and desalination: The reaction solution enters the neutralization unit, the flow rate of the metering pump for the feed in channel C is set to 4.65 g / min, the hydrochloric acid metering pump is turned on, the pH is adjusted to 5~6 by the online pH meter, and the solid salt is removed by filtration.

[0033] (5) Cooling crystallization: The acidified liquid after desalination enters the cooling crystallizer, 1860g of anhydrous ethanol is added, the temperature is lowered to 5℃, and the crystallization is carried out for 3h.

[0034] (6) Centrifugal drying: After the crystallization and heat preservation, centrifugation was performed to obtain 1040.5g of wet piperazine-N,N'-bis(2-hydroxypropanesulfonic acid) dihydrate. After drying at 60℃ for 4h, 892.04g of dry product was obtained, with a yield of 96.5%. The product test results were as follows: content (external standard method) 99.72%, moisture 6.2%, and residue on ignition 0.06%.

[0035] Example 3 A method for synthesizing piperazine-N,N'-bis(2-hydroxypropanesulfonic acid) dihydrate includes the following steps: (1) Raw material preparation: Weigh 230g (2.67mol) of anhydrous piperazine and dissolve it in 402.5g of water. After mixing, obtain solution A; dissolve 1050g (5.34mol) of sodium 3-chloro-2-hydroxypropanesulfonate in 1207g of water, and then add 448.5g of 50% sodium hydroxide aqueous solution. After mixing, obtain solution B; weigh 448.5g of 36 wt% hydrochloric acid to obtain solution C.

[0036] (2) Microchannel reaction: Turn on the circulating water cooling system and the high and low temperature integrated heating system, and set the reaction module temperature to 108℃. Set the flow rate of the metering pump for channel A to 8g / min; set the flow rate of the metering pump for channel B to 29g / min. Open the valves before and after the feed pump, and the inlet and outlet valves of the material and oil circuit of the module reactor. Turn on the feed pump to stabilize the pressure at 0.7MPa. The material stays in the reactor for a total of 4min. After cooling through the heat exchange system, collect the product at the outlet of the microchannel reactor. The pH of the outlet reaction solution is 10.

[0037] (3) Dehydration: The reaction solution is concentrated under reduced pressure and heated to <70℃. About 900g of water is removed.

[0038] (4) Acidification and desalination: The reaction solution enters the neutralization unit, the flow rate of the metering pump for the C channel feed is set to 5.5 g / min, the hydrochloric acid metering pump is turned on, the pH is adjusted to 5~6 by the online pH meter, and the solid salt is removed by filtration.

[0039] (5) Cooling crystallization: The acidified liquid after desalination enters the cooling crystallizer, 2300g of anhydrous ethanol is added, the temperature is lowered to 5℃, and the crystallization is carried out for 3h.

[0040] (6) Centrifugal drying: After the crystallization and heat preservation were completed, centrifugation was performed to obtain 1186.32 g of wet piperazine-N,N'-bis(2-hydroxypropanesulfonic acid) dihydrate. After drying at 60℃ for 4 h, 1020.24 g of dry product was obtained, with a yield of 95.9%. The product test results were as follows: content (external standard method) 99.62%, moisture 5.8%, and residue on ignition 0.07%.

[0041] Comparative Example Piperazine-N,N'-bis(2-hydroxypropanesulfonic acid) dihydrate was synthesized using a batch reactor, comprising the following steps: (1) Take a 3L reaction flask, add 1200g of water, and add 825.8g (4.15mol) of sodium 3-chloro-2-hydroxypropanesulfonate and 172.2g (2mol) of anhydrous piperazine while stirring. Then add 336g of 50% sodium hydroxide aqueous solution. Heat the reaction solution to 110℃~115℃ and react for 10h.

[0042] (2) After the reaction is complete, the reaction solution is concentrated under reduced pressure and heated to <70℃. About 600g of water is removed.

[0043] (3) Add concentrated hydrochloric acid to the concentrate to adjust the pH of the reaction solution to 5-6, and then filter to remove solid salt.

[0044] (4) Add 1600g of anhydrous ethanol to the filtrate, cool to 5℃, and keep warm for 3h to allow crystals to precipitate.

[0045] (5) Filter the sample to obtain 741.82 g of wet piperazine-N,N'-bis(2-hydroxypropanesulfonic acid) dihydrate. Dry the sample at 60℃ for 3 h to obtain 623.12 g of dry product. The yield is 78.2%. The product test results are as follows: content (external standard method) 98.82%, moisture 6.5%, and residue on ignition 0.08%.

[0046] Although the present invention has been described in detail with reference to the accompanying drawings and preferred embodiments, the present invention is not limited thereto. Various equivalent modifications or substitutions can be made to the embodiments of the present invention by those skilled in the art without departing from the spirit and essence of the invention, and such modifications or substitutions should all be within the scope of the present invention. Any variations or substitutions that can be easily conceived by those skilled in the art within the technical scope disclosed in the present invention should also be covered within the protection scope of the present invention.

Claims

1. A process for the synthesis of piperazine-N,N'-bis(2-hydroxypropane sulfonic acid) dihydrate, characterized in that, The reaction is as follows: ； The method comprises the following steps: The micro-channel reactor is used as the reaction equipment, channel A is used to transport the solution containing piperazine, channel B is used to transport the solution containing 3-chloro-2-hydroxypropanesulfonic acid sodium and sodium hydroxide, and channel C is used to transport the acid solution; First, channels A and B are opened, and piperazine and 3-chloro-2-hydroxypropanesulfonic acid sodium are allowed to react in the micro-channel reactor under the catalysis of sodium hydroxide to obtain piperazine-N,N'-bis(2-hydroxypropanesulfonic acid) disodium salt; after the reaction is completed, the reaction solution is introduced into a neutralization unit, channel C is opened, the pH of the reaction solution is adjusted to 5-6, and after desalination, piperazine-N,N'-bis(2-hydroxypropanesulfonic acid) dihydrate is obtained by crystallization.

2. A process for the synthesis of piperazine-N,N'-bis(2-hydroxypropane sulfonic acid) dihydrate according to claim 1, characterized in that, The molar ratio of piperazine to 3-chloro-2-hydroxypropanesulfonic acid sodium is 1:2.0-2.

1.

3. A process for the synthesis of piperazine-N,N'-bis(2-hydroxypropane sulfonic acid) dihydrate as claimed in claim 1, wherein, The reaction temperature of piperazine and 3-chloro-2-hydroxypropanesulfonic acid sodium is 100-110 DEG C.

4. A process for the synthesis of piperazine-N,N'-bis(2-hydroxypropane sulfonic acid) dihydrate as claimed in claim 1, wherein, The number of reaction modules of the micro-channel reactor is 4-6, which are arranged in series.

5. A process for the synthesis of piperazine-N,N'-bis(2-hydroxypropane sulfonic acid) dihydrate as claimed in claim 4 wherein, The total residence time of piperazine and 3-chloro-2-hydroxypropanesulfonic acid sodium in the micro-channel reactor is 10-15 min.

6. A process for the synthesis of piperazine-N,N'-bis(2-hydroxypropane sulfonic acid) dihydrate as claimed in claim 1, wherein, The acid solution is one of formic acid, glacial acetic acid or hydrochloric acid.

7. A process for the synthesis of piperazine-N,N'-bis(2-hydroxypropane sulfonic acid) dihydrate as claimed in claim 1, wherein, The reaction pressure of piperazine and 3-chloro-2-hydroxypropanesulfonic acid sodium is 0.5-0.9 MPa.

8. A process for the synthesis of piperazine-N,N'-bis(2-hydroxypropane sulfonic acid) dihydrate as claimed in claim 1, wherein, After the reaction of piperazine and 3-chloro-2-hydroxypropanesulfonic acid sodium is completed, part of the water in the reaction solution can be removed by vacuum distillation.

9. A process for the synthesis of piperazine-N,N'-bis(2-hydroxypropane sulfonic acid) dihydrate as claimed in claim 1, wherein, The method for crystallization is as follows: after desalination of the reaction solution, an alcohol solvent is added, the temperature is reduced to 0-5 DEG C for crystallization, and piperazine-N,N'-bis(2-hydroxypropanesulfonic acid) dihydrate is obtained by solid-liquid separation.

Images