阅读说明：本技术 一种无溶剂合成3-(n-吗啉基)-2-羟基丙磺酸的方法 (Method for synthesizing 3- (N-morpholinyl) -2-hydroxypropanesulfonic acid without solvent ) 是由 杨庆锁 董悦刚 高先通 张德秋 王松林 于 2021-08-18 设计创作，主要内容包括：本发明涉及一种无溶剂合成3-(N-吗啉基)-2-羟基丙磺酸的方法,属于有机合成的技术领域。本发明采用吗啉和3-氯-2-羟基丙烷磺酸钠,再无溶剂的条件下反应,反应结束后酸化获得3-(N-吗啉基)-2-羟基丙磺酸。相比于原有3-(N-吗啉基)-2-羟基丙磺酸的生产工艺,本发明原料易得,操作简单,工艺收率高且稳定,产品质量优良。避免了现有技术收率低,工艺复杂问题。(The invention relates to a solvent-free synthesis method of 3- (N-morpholinyl) -2-hydroxypropanesulfonic acid, belonging to the technical field of organic synthesis. Morpholine and 3-chloro-2-hydroxy propane sodium sulfonate are adopted to react under the condition of no solvent, and 3- (N-morpholinyl) -2-hydroxy propane sulfonic acid is obtained by acidification after the reaction is finished. Compared with the original production process of 3- (N-morpholinyl) -2-hydroxypropanesulfonic acid, the method has the advantages of easily available raw materials, simple operation, high and stable process yield and excellent product quality. The problems of low yield and complex process in the prior art are avoided.)

1. A method for synthesizing 3- (N-morpholinyl) -2-hydroxypropanesulfonic acid without solvent is characterized in that the reaction formula is as follows:

the specific method comprises the following steps:

(1) putting morpholine into a reactor, stirring and heating to 40-80 ℃; then adding anhydrous sodium carbonate, and continuing to keep the temperature and stir for 20 min;

(2) weighing 3-chloro-2-hydroxy propane sodium sulfonate, and adding the sodium sulfonate into a reactor in batches;

(3) after the feeding is finished, heating, stirring and reacting for 2 hours in a heat preservation way;

(4) stopping heating after heat preservation is finished, dropping hydrochloric acid after temperature reduction, adjusting the pH value of the system to 4.5-5, carrying out hot filtration, and collecting a filter cake I and filtrate;

(5) cooling the filtrate to 5-10 ℃, carrying out heat preservation and crystallization for 2 hours, and carrying out suction filtration to obtain a filter cake II; and drying the filter cake I and the filter cake II together to obtain the 3- (N-morpholinyl) -2-hydroxypropanesulfonic acid.

2. The method according to claim 1, wherein the charging molar ratio of morpholine to sodium 3-chloro-2-hydroxypropanesulfonate is 1.5-2.5: 1.

3. The method of claim 1, wherein the amount of sodium carbonate or potassium carbonate added is 0.01-0.05 g/g based on the amount of sodium 3-chloro-2-hydroxypropanesulfonate added.

4. The method according to claim 1, wherein the reaction temperature in the step (3) is 90 to 110 ℃.

5. The method according to claim 1, wherein in the step (4), the heat filtration temperature is 40 to 60 ℃.

6. The method according to claim 1, wherein the 3- (N-morpholinyl) -2-hydroxypropanesulfonic acid is purified as follows:

(1) adding 3- (N-morpholinyl) -2-hydroxypropanesulfonic acid into methanol, stirring and heating to reflux, adding water into the reaction solution until the reaction system is clear, adding activated carbon, and performing heat preservation, adsorption and decoloration for 1 h;

(2) filtering while hot after the heat preservation is finished, cooling the filtrate to 5 ℃, and then carrying out heat preservation and crystallization for 2 hours;

(3) carrying out suction filtration, and drying a filter cake for 4 hours by air blowing at 55 ℃ to obtain 3- (N-morpholinyl) -2-hydroxypropanesulfonic acid; concentrating the filtrate with methanol, cooling and crystallizing, and recovering the residual 3- (N-morpholinyl) -2-hydroxypropanesulfonic acid.

7. The method according to claim 6, wherein the amount of methanol added is 1.5 to 2.5ml/g based on the amount of 3- (N-morpholino) -2-hydroxypropanesulfonic acid charged.

8. The method according to claim 6, wherein the water is added in an amount of 0.2 to 0.5ml/ml based on the amount of methanol fed.

Technical Field

The invention belongs to the technical field of organic synthesis, and particularly relates to a method for synthesizing 3- (N-morpholinyl) -2-hydroxypropanesulfonic acid without a solvent.

Background

3- (N-morpholinyl) -2-hydroxypropanesulfonic acid (MOPSO), a novel zwitterionic buffer for biological research. pH buffer range of MOPSO: 6.2 to 7.6; the pKa at 25 deg.c is 6.95, and is used mainly in biochemical research, such as new type of zwitterion buffer for biological research. Because the molecular structure of the compound contains hydroxyl with stronger activity and hydrophilic sulfonic acid group, the compound is easy to generate substitution and elimination reactions, is an important functional monomer in the synthetic polymer industry, can also be used as an organic chemical intermediate, and is a relatively important multifunctional substance. The CN106117163A patent discloses a MOPSO synthesis method, wherein morpholine is formed by dehydration and cyclization of diethanolamine, and then the morpholine is reacted with sodium 2-hydroxypropanesulfonate to generate MOPSO, the operation process is complicated, a heavy metal catalyst is required for catalytic reaction, a strong-acid styrene cation exchange resin is required for impurity exchange, ammonia water and glacial acetic acid are used for refining, and the reaction process temperature is 200-240 ℃, so that the MOPSO synthesis method has great difference with the technology and is not beneficial to production. The patent US4169950A Amino-hydroxy-alkyl sulfonic acid zwitterions discloses a MOPSO synthesis process, water is used as a solvent, sodium ions are removed through Dowex 50 cation exchange, a crude product can be obtained only by concentrating and redispersing an eluate, the operation is complex, the yield is low, the reaction condition is harsh, the cost is high, three wastes are more, the industrial production is not met, and the method is not favorable for the purpose of environmental protection.

Disclosure of Invention

Aiming at the problems of complex operation, high cost, more three wastes and the like in the prior art, the invention provides a solvent-free 3- (N-morpholinyl) -2-hydroxypropanesulfonic acid synthesis process to solve the problems.

A method for synthesizing 3- (N-morpholinyl) -2-hydroxypropanesulfonic acid without solvent has the following reaction formula:

the specific method comprises the following steps:

(1) putting morpholine into a reactor, stirring and heating to 40-80 ℃; then adding anhydrous sodium carbonate, and continuing to keep the temperature and stir for 20 min;

(2) weighing 3-chloro-2-hydroxy propane sodium sulfonate, and adding the sodium sulfonate into a reactor in batches;

(3) after the feeding is finished, heating, stirring and reacting for 2 hours in a heat preservation way;

(4) stopping heating after heat preservation is finished, dropping hydrochloric acid after temperature reduction, adjusting the pH value of the system to 4.5-5, carrying out hot filtration, and collecting a filter cake I and filtrate;

(5) cooling the filtrate to 5-10 ℃, carrying out heat preservation and crystallization for 2 hours, and carrying out suction filtration to obtain a filter cake II; and drying the filter cake I and the filter cake II together to obtain the 3- (N-morpholinyl) -2-hydroxypropanesulfonic acid. The methanol recovered from the filtrate can be reused.

Preferably, the feeding molar ratio of the morpholine to the sodium 3-chloro-2-hydroxypropanesulfonate is 1.5-2.5: 1.

Preferably, the feeding amount of the sodium carbonate or the potassium carbonate is 0.01-0.05 g/g based on the feeding amount of the sodium 3-chloro-2-hydroxypropanesulfonate.

Preferably, in the step (3), the reaction temperature is 90-110 ℃.

Preferably, in the step (4), the heat filtering temperature is 40-60 ℃.

Preferably, the purification method of the 3- (N-morpholinyl) -2-hydroxypropanesulfonic acid is as follows:

(1) adding 3- (N-morpholinyl) -2-hydroxypropanesulfonic acid into methanol, stirring and heating to reflux, adding water into the reaction solution until the reaction system is clear, adding activated carbon, and performing heat preservation, adsorption and decoloration for 1 h;

(2) filtering while hot after the heat preservation is finished, cooling the filtrate to 5 ℃, and then carrying out heat preservation and crystallization for 2 hours;

(3) carrying out suction filtration, and drying a filter cake for 4 hours by air blowing at 55 ℃ to obtain 3- (N-morpholinyl) -2-hydroxypropanesulfonic acid; concentrating the filtrate with methanol, cooling and crystallizing, and recovering the residual 3- (N-morpholinyl) -2-hydroxypropanesulfonic acid.

Preferably, the adding amount of the methanol is 1.5-2.5 ml/g based on the feeding amount of the 3- (N-morpholinyl) -2-hydroxypropanesulfonic acid.

Preferably, the addition amount of the water is 0.2-0.5 ml/ml based on the feeding amount of the methanol.

The invention has the beneficial effects that:

compared with the original production process of 3- (N-morpholinyl) -2-hydroxypropanesulfonic acid, the method has the advantages of easily available raw materials, simple operation, high and stable process yield and excellent product quality. The problems of low yield and complex process in the prior art are avoided. The method adopts morpholine and 3-chloro-2-hydroxypropanesulfonic acid sodium salt as raw materials, does not add other solvents in the reaction process, has high reaction degree and simple purification, can produce a crude product which can meet the requirements of customer indexes after one-time refining and purification, is a green and efficient MOPSO production technology, and can be industrially popularized.

Detailed Description

In order to make those skilled in the art better understand the technical solutions in the present invention, the technical solutions in the embodiments of the present invention will be clearly and completely described below, and it is obvious that the described embodiments are only a part of the embodiments of the present invention, and not all embodiments. All other embodiments, which can be derived by a person skilled in the art from the embodiments given herein without making any creative effort, shall fall within the protection scope of the present invention.

Example 1

A method for synthesizing 3- (N-morpholinyl) -2-hydroxypropanesulfonic acid without solvent comprises the following specific steps:

(1) putting 87g of morpholine into a 1L three-necked bottle, stirring and heating to 60 ℃; then 2g of anhydrous sodium carbonate is added to continue to be stirred for 20min under heat preservation, and at the moment, the reaction bottle is in a solid-liquid two-phase mixed state;

(2) weighing 98g of 3-chloro-2-hydroxypropane sodium sulfonate, adding into a reaction bottle by 3 times, wherein the system generates slight heat in the adding process;

(3) after the addition is finished, heating to 95 ℃, stirring and preserving heat for reaction for 2 hours, wherein the system is changed from a solid-liquid mixed slurry state to a viscous state and is slightly yellowish;

(4) stopping heating after heat preservation is finished, cooling to 60 ℃, dropwise adding 20g of hydrochloric acid, adjusting the pH of the system to 4.5-5, filtering, and collecting a filter cake I and filtrate;

(5) cooling the filtrate to 5-10 ℃, carrying out heat preservation and crystallization for 2 hours, and carrying out suction filtration to obtain a filter cake II; and drying the filter cake I and the filter cake II together to obtain 120g of 3- (N-morpholinyl) -2-hydroxypropanesulfonic acid.

(6) Adding 3- (N-morpholinyl) -2-hydroxypropanesulfonic acid into 300ml of methanol, stirring and heating to reflux, adding 100ml of water into the reaction solution until the reaction system is clear, adding 1.0g of activated carbon, and keeping the temperature for adsorption and decoloration for 1 h;

(7) filtering while hot after the heat preservation is finished, cooling the filtrate to 5 ℃, and then carrying out heat preservation and crystallization for 2 hours;

(8) filtering, and air-blast drying the filter cake at 55 ℃ for 4 hours to obtain 93.75g of 3- (N-morpholinyl) -2-hydroxypropanesulfonic acid with the yield of 83.3 percent; the content of the potentiometric titration detection is 99.62%; ultraviolet: 260 nm: 0.070; 290 nm: 0.061; pH: 4.16.

(9) and (3) concentrating the filtrate obtained in the step (8), cooling and crystallizing, and recovering 9.9g of residual 3- (N-morpholinyl) -2-hydroxypropanesulfonic acid, wherein the distilled methanol can be put into the next kettle for refining. 103.65g of 3- (N-morpholinyl) -2-hydroxypropanesulfonic acid was obtained in total yield of 92.1%.

Example 2

(1) Putting 700g of morpholine into a 5L three-necked bottle, stirring and heating to 60 ℃; then adding 16g of anhydrous sodium carbonate, and continuing to stir for 20min under the condition of heat preservation, wherein the reaction bottle is in a solid-liquid two-phase mixed state;

(2) 785g of 3-chloro-2-hydroxypropanesulfonic acid sodium salt is weighed and added into a reaction bottle by 3 times, and the system generates slight heat in the adding process;

(3) after the addition is finished, heating to 98 ℃, stirring and preserving heat for reaction for 2.5 hours, wherein the system is changed from a solid-liquid mixed slurry state to a viscous state and is slightly yellowish;

(4) stopping heating after heat preservation is finished, cooling to 60 ℃, dropwise adding 165g of hydrochloric acid, adjusting the pH of the system to 4.5-5, filtering, and collecting a filter cake I and filtrate;

(5) cooling the filtrate to 5-10 ℃, carrying out heat preservation and crystallization for 2 hours, and carrying out suction filtration to obtain a filter cake II; and drying the filter cake I and the filter cake II together to obtain 955g of 3- (N-morpholinyl) -2-hydroxypropanesulfonic acid.

(6) Adding 3- (N-morpholinyl) -2-hydroxypropanesulfonic acid into 2400ml of methanol, stirring and heating to reflux, adding 750ml of water into the reaction solution until the reaction system is clear, adding 10g of activated carbon, and keeping the temperature for adsorption and decoloration for 1 h;

(7) filtering while hot after the heat preservation is finished, cooling the filtrate to 5 ℃, and then carrying out heat preservation and crystallization for 2 hours;

(8) filtering, and drying the filter cake for 4 hours at 55 ℃ by air blast to obtain 738g of 3- (N-morpholinyl) -2-hydroxypropanesulfonic acid with the yield of 79.69 percent; the content of potentiometric titration detection is 99.52 percent; ultraviolet: 260 nm: 0.072; 290 nm: 0.060; pH: 4.12.

(9) and (3) concentrating the filtrate obtained in the step (8), cooling and crystallizing, and recovering 79.2g of residual 3- (N-morpholinyl) -2-hydroxypropanesulfonic acid. 817.2g of 3- (N-morpholinyl) -2-hydroxypropanesulfonic acid was obtained in total yield of 90.7%.

Example 3

(1) Putting 6.96kg of morpholine into a 50L three-necked bottle, stirring and heating to 50 ℃; then adding 160g of anhydrous sodium carbonate, and continuing to stir for 20min under the condition of heat preservation, wherein the inside of the reaction bottle is in a solid-liquid two-phase mixed state;

(2) weighing 7.84kg of 3-chloro-2-hydroxypropanesulfonic acid sodium salt, adding the 3-chloro-2-hydroxypropanesulfonic acid sodium salt into a reaction bottle by 3 times, wherein the system generates slight heat in the adding process;

(3) after the addition is finished, heating to 98 ℃, stirring and preserving heat for reaction for 2.5 hours, wherein the system is changed from a solid-liquid mixed slurry state to a viscous state and is slightly yellowish;

(4) stopping heating after heat preservation is finished, cooling to 60 ℃, dropwise adding 1650g of hydrochloric acid, adjusting the pH value of the system to 4.5-5, filtering, and collecting a filter cake I and filtrate;

(5) cooling the filtrate to 5-10 ℃, carrying out heat preservation and crystallization for 2 hours, and carrying out suction filtration to obtain a filter cake II; and drying the filter cake I and the filter cake II together to obtain 9.85kg of 3- (N-morpholinyl) -2-hydroxypropanesulfonic acid.

(6) Adding 3- (N-morpholinyl) -2-hydroxypropanesulfonic acid into 25L of methanol, stirring and heating to reflux, adding 7.5kg of water into the reaction solution until the reaction system is clear, adding 100g of activated carbon, and keeping the temperature for adsorption and decoloration for 1 h;

(7) filtering while hot after the heat preservation is finished, cooling the filtrate to 5 ℃, and then carrying out heat preservation and crystallization for 2 hours;

(8) filtering, and air-blast drying the filter cake at 55 ℃ for 4 hours to obtain 7.42kg of 3- (N-morpholinyl) -2-hydroxypropanesulfonic acid with the yield of 79.1 percent; the content is 99.45%; ultraviolet: 260 nm: 0.068; 290 nm: 0.063; pH: 4.26.

(9) and (4) concentrating the filtrate obtained in the step (8), cooling and crystallizing, and recovering 628g of residual 3- (N-morpholinyl) -2-hydroxypropanesulfonic acid. 8.04kg of 3- (N-morpholinyl) -2-hydroxypropanesulfonic acid is prepared in total yield of 89.42%.

Although the present invention has been described in detail by way of preferred embodiments, the present invention is not limited thereto. Various equivalent modifications or substitutions can be made on the embodiments of the present invention by those skilled in the art without departing from the spirit and scope of the present invention, and these modifications or substitutions are within the scope of the present invention/any person skilled in the art can easily conceive of the changes or substitutions within the technical scope of the present invention. Therefore, the protection scope of the present invention shall be subject to the protection scope of the claims.