WO2023142797A1

WO2023142797A1 - Preparation process for sulfonic acid-containing compound

Info

Publication number: WO2023142797A1
Application number: PCT/CN2022/140658
Authority: WO
Inventors: 袁永坤; 顾临
Original assignee: 苏州亚科科技股份有限公司
Priority date: 2022-01-28
Filing date: 2022-12-21
Publication date: 2023-08-03
Also published as: CN114591266A

Abstract

Relating to the technical field of biological buffer reagent synthesis, provided is a preparation process for a sulfonic acid-containing compound and a slat thereof, comprising the following preparation steps: reacting a compound 1 with a compound 2 to obtain a compound 3; reacting the compound 3 with an M-containing reagent to obtain a crude product of an M-containing slat corresponding to a sulfonic acid-containing compound 4; and after acidification reaction, obtaining a crude product of the sulfonic acid-containing compound 4. Finally, the high-pure sulfonic acid-containing compound 4 and the salt thereof are obtained by performing purification process on the crude products of the sulfonic acid-containing compound 4 and a salt thereof. Raw materials used in the preparation method are low in cost and simple in operation, the obtained product is high in purity and suitable for industrial production, and the obtained product can satisfy requirements of the field of biological buffers on purity, impurity content, and cost.

Description

A kind of preparation technology of the compound containing sulfonic acid group

technical field

The application belongs to the technical field of synthesis of biological buffer reagents, and in particular relates to a preparation process of a compound containing a sulfonic acid group.

Background technique

Compounds containing sulfonic acid groups, such as PIPES, MOPS, HEPES, MES and the corresponding sodium salts PIPES-2Na, MOPS-Na, HEPES-Na, MES-Na, are important hydrogen ion buffers, within a certain pH range It has good buffer capacity and can maintain a constant pH for a long time. Generally, a sulfonic acid group-containing compound contained in the culture medium at a concentration of 20 mmol/L as a buffering agent can have good buffering capacity, and the sulfonic acid group-containing compound has no toxic effect on cells.

Chinese patent CN110683995A discloses two preparation methods of piperazineethanesulfonic acid derivatives, both of which start the reaction by preheating in the early stage of feeding, and then reheat the reaction to a certain extent to control the 2-hydroxy The side reaction between ethylpiperazine and sodium 2-chloroethylsulfonate makes the reaction relatively thorough; reduce the amount of NaOH solution added during the reaction, reduce the generation of NaCl in the reaction system, and subsequently pass the reaction with triethylamine The method of salt formation forms triethylamine hydrochloride soluble in water and ethanol, which can be directly removed from the system, reducing the desalination process using ion exchange resins; using ethanol/water mixed solution for recrystallization, effectively reducing The residue of inorganic salts is eliminated, and the purity of the final product is relatively high.

But in general, the number of patents involving sodium salt products among compounds containing sulfonic acid groups is relatively small. Among the existing patents, there are still many problems in the preparation process: the raw materials of the product are not easy to obtain, the manufacturing cost is high, and there are many wastes. wait. Therefore hinder the large-scale application of the compound of sulfonic acid group, especially hinder it from becoming the material of biological buffer reagent field.

Based on the above-mentioned deficiencies and defects, this application aims to disclose a preparation process of a compound containing sulfonic acid groups, so that it has important industrial application value in the fields of biological buffer reagents, etc. The raw materials of the preparation and purification process disclosed in this application Easy to obtain, low product manufacturing cost, simple preparation method, and can realize mass production and application in large quantities.

Contents of the invention

The following is an overview of the topics described in detail in this article. This summary is not intended to limit the scope of the claims.

In order to overcome the deficiencies in the prior art, the first purpose of the present application is to provide a preparation process for a compound containing sulfonic acid groups. The preparation method is simple, the raw materials used are easy to obtain, the product manufacturing cost is low, and the product obtained is easy to prepare. The yield is high, and the prepared sulfonic acid group-containing compound is purified to obtain a high-purity sulfonic acid group-containing compound boutique, which meets the requirements for purity, impurity content, and cost in the field of biological buffer reagents.

Realize that the first purpose of the present application can be achieved by taking the following technical solutions:

A preparation process for a compound containing a sulfonic acid group and a salt thereof, comprising the following preparation steps:

Preparation step S1: react compound 1 with compound 2 to obtain compound 3;

Preparation step S2: react the above compound 3 with an M-containing reagent to obtain a crude product of the M-containing salt corresponding to the compound 4 containing a sulfonic acid group, and after acidification, obtain a crude product of the compound 4 containing a sulfonic acid group;

Wherein, the structural formula of compound 1 is the general structure shown in formula I:

The structural formula of compound 2 is the general structure shown in formula II:

_H2C ＝CH-Cm _-2H2 _(m-2) _-SO2 - _OR1 ;

Formula II

Y is one of O, NH, and NR; R is a group that is saturated or unsaturated, contains straight or branched chains, contains heteroatoms or does not contain heteroatoms, and can be terminated by one of sulfonate, hydroxyl, and sulfonate One of the C ₁ -C ₃₀ hydrocarbon groups substituted by groups; R ₁ is one of the C ₁ -C ₃₀ hydrocarbon groups that are saturated or unsaturated, straight or branched, heteroatom-containing or non-heteroatom-free; m is an integer greater than or equal to 2; when m=2, compound 2 is H ₂ C=CH-SO ₂ -OR ₁ ; M in the M-containing reagent is one of NH ₄ ⁺ and metal elements;

The structural formula of compound 3 is the general structure shown in formula III:

The structural formula of compound 4 is the general structure shown in formula IV:

Further, the corresponding M-containing salt of compound 4 containing sulfonic acid group also includes the hydrate of the corresponding M-containing salt of compound 4 containing sulfonic acid group;

Further, the compound 4 containing a sulfonic acid group also includes the corresponding hydrate of the compound 4 containing a sulfonic acid group.

Wherein the general formula structure corresponding to the compound of the general formula structure shown in formula IV contains M salt as shown in formula IV':

When Y in compound 4 is NC _m H _2m -SO ₂ -OH, compound 1 has the general structure

at least one of

In the preparation step S1, compound 1 is reacted with compound 2 to prepare a compound whose general structure is represented by formula V; wherein the general structure represented by formula V is:

In the preparation step S2, the compound with the general structure of formula V is reacted with the M-containing reagent to obtain the crude salt corresponding to the compound with the general structure of formula VI containing sulfonic acid groups; after the acidification reaction, the general structure is obtained as the formula The compound containing sulfonic acid groups of VI, or the corresponding hydrate; the general structure shown in formula VI is:

Wherein the general formula structure corresponding to the compound of general formula structure shown in formula VI contains M salt as shown in formula VI':

Further, the compound containing sulfonic acid group is piperazine-N,N'-di(2-ethanesulfonic acid), 3-morpholinepropanesulfonic acid, 4-hydroxyethylpiperazineethanesulfonic acid, 2- Morpholineethanesulfonic acid or the piperazine-N,N'-di(2-ethanesulfonic acid), 3-morpholinepropanesulfonic acid, 4-hydroxyethylpiperazineethanesulfonic acid, 2-morpholineethanesulfonic acid acid sodium salt.

Further, when Y is NR, R is one of C ₁ -C ₃₀ hydrocarbon groups whose terminal is substituted by one of sulfonate, hydroxyl, and sulfonate, and Y is NC _m H _2m -SO ₂ -OH, NC _m H _2m -OH, NC _m H _2m -CO-OH.

Further, the M reagent is an M-containing element, an M-containing base, an M-containing oxide, a M-containing salt or their precursors, double salts, hydrates, solvent complexes, and hydrogen halide complexes. A combination of one or more than two.

Further, in the preparation step S1, the reaction temperature is -50-200°C, the reaction pressure is -0.05-1MPa, and the reaction time is 0.1-72 hours; in the preparation step S2, the reaction temperature is -50-200°C, and the reaction pressure is -0.05-1MPa, the reaction time is 0.1-72 hours.

Further, in the preparation step S1, the molar ratio of compound 1 to compound 2 is 1:(0.1-10); in the preparation step S2, the molar ratio of compound 3 to the M-containing reagent is 1:(0.1-10).

Further, in the preparation step S1, at least one of a catalyst or an auxiliary agent is used for the reaction.

Further, in the preparation step S1, compound 1 is reacted with an M-containing reagent in a reaction solvent A, and the reaction solvent A is methanol, ethanol, acetone, tetrahydrofuran, ethyl acetate, dimethyl carbonate, diethyl carbonate, diethyl ether , acetonitrile, dioxane, N,N-dimethylformamide, dimethyl sulfoxide; in preparation step S2, compound 3 reacts with M-containing reagent in reaction solvent B, and the reaction Solvent B is methanol, ethanol, acetone, tetrahydrofuran, ethyl acetate, dimethyl carbonate, diethyl carbonate, ether, acetonitrile, dioxane, N,N-dimethylformamide, dimethyl sulfoxide at least one of .

Further, a purification step is also included, and the purification step is as follows:

Under dry conditions, using a dry airtight device or under dry gas purging, dissolve the crude product containing a sulfonic acid group, or its salt, in the purification solvent obtained in the preparation step S2, and then recrystallize, filter, and dry , to obtain refined compounds containing sulfonic acid groups.

Further, the purification solvent is methanol, ethanol, acetone, tetrahydrofuran, ethyl acetate, dimethyl carbonate, diethyl carbonate, ether, acetonitrile, dioxane, N,N-dimethylformamide, di One or more combinations of methyl sulfoxide.

Compared with the prior art, the beneficial effects of the present application are:

1. The present application discloses a preparation process for a compound containing sulfonic acid groups and its salt. The preparation method is simple, and the raw materials used are easy to obtain. The prepared product has the advantages of low water content and dryness, and improves the yield of the product. The overall The cost of the product is reduced, and it is suitable for industrialized production and is suitable for application in the fields of life science, in vitro diagnosis or medicine.

2. This application is a preparation process of a compound containing sulfonic acid groups and its salt. The generated by-products and impurities are easy to purify and separate, so the purification process is simple, and the impurities in the product can reach high purity without going through complicated purification processes. According to practical application standards, after purification, high-purity sulfonic acid group-containing compound boutiques are obtained, which meet the requirements for purity, impurity content, and cost in the field of biological buffer reagents. The product preparation process is simplified, the product yield is high, the product purity is high, and the production and quality requirements of large-scale applications can be met.

Other aspects will become apparent after reading and understanding the detailed description.

Detailed ways

Hereinafter, the present application will be further described in conjunction with specific implementation methods. It should be noted that, on the premise of not conflicting, the various embodiments or technical features described below can be combined arbitrarily to form new embodiments. It should be noted that the terms used in the examples are for describing specific implementations and do not limit the protection scope of the present application. In addition, the raw materials used in this application are generally commercially available products, so there is no need to specifically limit their sources.

The pressure values mentioned in this patent application, unless otherwise specified, refer to gauge pressure. Gauge pressure refers to the amount by which the total absolute pressure exceeds the surrounding atmospheric pressure or the pressure at a certain point in the liquid that is higher than the atmospheric pressure.

The yield is calculated as the percentage ratio of the actual product quality to the theoretical product quality, and the theoretical product quality is calculated with the non-excessive raw materials in the reaction equation.

Reaction temperature, unless otherwise specified, generally refers to the oil bath temperature of the reaction.

The purity of the product was analyzed by acid-base titration.

NMR analysis test, using Bruker (Bruker's AVANCE 400 mega-NMR spectrometer.

Embodiment 1: Preparation of piperazine-N, N'-bis(2-ethanesulfonic acid) disodium (PIPES-2Na)

The preparation of piperazine-N, N'-bis(2-ethanesulfonic acid) disodium comprises the following preparation steps:

Preparation step S1:

Under stirring conditions, add 100g of compound 1, 631.6g of compound 2, and acetonitrile as the reaction solvent to a 1L dry reactor, wherein, compound 1 is piperazine, and compound 2 is ethyl vinylsulfonate; compound 1, compound The molar ratio of 2 is 1:4, the reaction temperature is 70°C, the reaction pressure is 0.1MPa (gauge pressure), and the reaction time is 4h.

After the reaction was completed, the temperature was lowered to normal temperature, the reaction solution was rotatably evaporated under reduced pressure to remove the solvent, and then concentrated to prepare the crude compound 3.

Preparation step S2:

Under the condition of stirring, add the above-mentioned 100g compound 3, reaction solvent methanol, and 33.5g M-containing reagent into a 1L dry reactor, wherein the M-containing reagent is sodium hydroxide; the molar ratio of compound 3 to the M-containing reagent is 1: 3. The reaction temperature is 30°C, the reaction pressure is 0 MPa (gauge pressure), and the reaction time is 5 hours.

After the reaction was completed, the temperature was lowered to normal temperature, the reaction liquid was rotatably evaporated under reduced pressure to remove the solvent, and then concentrated to prepare the crude product of piperazine-N,N'-bis(2-ethanesulfonic acid) disodium with a yield of 75%.

Preparation step S3:

Under dry conditions, using dry airtight equipment, the crude piperazine-N,N'-bis(2-ethanesulfonate) disodium obtained in the preparation step S2 was dissolved in the purification solvent diethyl carbonate, and recrystallized. Crystallize at low temperature, filter, and dry to obtain a refined compound containing sulfonic acid groups; the purity of the product is 99.8%.

The NMR characterization data are as follows: ¹ H NMR (400MHz, D ₂ O): δ3.8ppm, 2.9ppm, 2.6ppm, 2.0ppm.

Embodiment 2: Preparation of piperazine-N, N'-two (2-ethanesulfonic acid) (PIPES)

The preparation of 3-morpholine propanesulfonic acid comprises following preparation steps:

Preparation step S1:

Under stirring conditions, add 100g of compound 1, 1743g of compound 2, and acetone as a reaction solvent to a 1L dry reactor; wherein, compound 1 is piperazine, and compound 2 is propyl vinylsulfonate; compound 1, compound 2 The molar ratio is 1:10, the reaction temperature is 40°C, the reaction pressure is 0.2MPa (gauge pressure), and the reaction time is 15h.

After the reaction was completed, it was lowered to normal temperature, and the reaction solution was rotatably evaporated under reduced pressure to remove the solvent, and then concentrated to prepare the crude product of compound 3.

Preparation step S2:

Under the condition of stirring, add the above-mentioned 100g compound 3, the reaction solvent tetrahydrofuran, and 21.7g M-containing reagent into a 1L dry reactor; wherein the M-containing reagent is sodium bicarbonate, and the molar ratio of compound 3 to the M-containing reagent is 1: 1. The reaction temperature is 65°C, the reaction pressure is 0.2MPa (gauge pressure), and the reaction time is 1h.

After the reaction was completed, the temperature was lowered to normal temperature, the reaction solution was rotatably evaporated under reduced pressure to remove the solvent, and then concentrated to prepare a crude product of piperazine-N,N'-bis(2-ethanesulfonic acid) disodium.

Preparation step S3:

Dissolve the crude piperazine-N,N'-bis(2-ethanesulfonic acid) disodium prepared in step S2 in ethanol, use glacial acetic acid to adjust the pH to 4-5, stir, cool and clean the crystal, filter, and dry to obtain Piperazine-N,N'-di(2-ethanesulfonic acid).

Preparation step S4:

Under dry conditions, using dry airtight equipment, dissolve the piperazine-N,N'-di(2-ethanesulfonic acid) obtained in the preparation step S3 in the purification solvent ethanol, perform recrystallization under low temperature conditions, filter, After drying, the refined compound containing sulfonic acid group was obtained; the yield of piperazine-N,N'-bis(2-ethanesulfonic acid) was 70%, and the purity of the product was 99.9%.

The NMR characterization data are as follows: ¹ H NMR (400MHz, D ₂ O): δ3.5ppm, 3.4ppm.

Embodiment 3: the preparation of 3-morpholine propanesulfonate sodium (MOPS-Na)

The preparation technology of 3-morpholine propanesulfonate sodium comprises following preparation steps:

Preparation step S1:

Under stirring conditions, add 100g of compound 1, 234.2g of compound 2, and the reaction solvent N,N-dimethylformamide into a 1L dry reactor; wherein, compound 1 is morpholine, and compound 2 is allyl sulfonate Acid methyl ester; the molar ratio of compound 1 and compound 2 is 1:1.5, the reaction temperature is 100°C, the reaction pressure is 0.4MPa (gauge pressure), and the reaction time is 1h.

Preparation step S2:

Under stirring conditions, add the above-mentioned 100g compound 3, the reaction solvent dimethyl sulfoxide, and 237.7g M-containing reagent to a 1L dry reactor; wherein the M-containing reagent is sodium carbonate; the molar ratio of compound 3 to the M-containing reagent The ratio is 1:5, the reaction temperature is 60°C, the reaction pressure is 0MPa (gauge pressure), and the reaction time is 5h.

After the reaction was completed, the temperature was lowered to normal temperature, the reaction liquid was rotatably evaporated under reduced pressure to remove the solvent, and concentrated to prepare a crude product of 3-morpholine propanesulfonate, the crude product yield of 3-morpholine propanesulfonate was 72%.

Preparation step S3:

Under dry conditions, using dry airtight equipment, the crude product 3-morpholinepropanesulfonate obtained in the preparation step S2 was dissolved in the purification solvent dimethyl carbonate, recrystallized, crystallized at low temperature, filtered, and dried. A refined compound containing sulfonic acid groups is obtained; the product has a purity of 99.6%.

Embodiment 4: the preparation of 3-morpholine propanesulfonic acid (MOPS)

Dissolve the crude sodium 3-morpholinepropanesulfonate prepared in Example 3 in methanol, use dilute hydrochloric acid solution to adjust the pH to 4-5, stir, cool and clean the crystal, filter, and dry to obtain the crude product 3-morpholinepropanesulfonic acid ;

Under dry conditions, using dry and airtight equipment, dissolve the crude product 3-morpholine propanesulfonic acid in the purification solvent methanol, carry out recrystallization, crystallize under low temperature conditions, filter and dry to obtain the refined product; 3-morpholine propanesulfonic acid The overall yield of acid was 71% (total yield of synthesis and purification) with a purity of 99.6%.

The NMR characterization data are as follows: ¹ H NMR (400MHz, D ₂ O): δ4.2ppm, 3.9ppm, 3.6ppm, 3.4ppm, 3.3ppm, 3.1ppm, 2.3ppm.

Embodiment 5: the preparation of 4-hydroxyethylpiperazine ethanesulfonate sodium (HEPES-Na)

A preparation process for a compound containing sulfonic acid groups, comprising the following preparation steps:

Preparation step S1:

Under stirring conditions, add 100g of compound 1, 147.7g of compound 2, and the reaction solvent dioxane into a 1L dry reactor; wherein, compound 1 is 4-hydroxyethylpiperazine, and compound 2 is vinylsulfonic acid n-hexyl ester; the molar ratio of compound 1 and compound 2 is 1:1, the reaction temperature is 140°C, the reaction pressure is 1MPa (gauge pressure), and the reaction time is 24h.

Preparation step S2:

Under stirring conditions, add the above-mentioned 100g compound 3, the reaction solvent dimethyl carbonate, and 167.5g M-containing reagent to a 1L dry reactor; wherein, the M-containing reagent is sodium methylate; the molar ratio of compound 3 to the M-containing reagent The ratio is 1:10, the reaction temperature is 30°C, the reaction pressure is 0MPa (gauge pressure), and the reaction time is 24h.

After the reaction was completed, it was lowered to normal temperature, and the reaction liquid was evaporated under reduced pressure to remove the solvent, concentrated, and the crude product of 4-hydroxyethylpiperazineethanesulfonate was prepared, and the yield of the crude product of 4-hydroxyethylpiperazineethanesulfonate was 69%. .

Preparation step S3:

Under dry conditions, using dry airtight equipment, dissolve the crude product sodium 4-hydroxyethylpiperazineethanesulfonate obtained in the preparation step S2 in the purification solvent diethyl carbonate, perform recrystallization, crystallize under low temperature conditions, and filter , dried to obtain 4-hydroxyethylpiperazine ethanesulfonate sodium product; the purity is 99.7%.

The NMR characterization data are as follows: ¹ H NMR (400MHz, D ₂ O): δ3.7ppm, 3.1ppm, 2.8ppm, 2.6ppm.

Embodiment 6: Preparation of 4-hydroxyethylpiperazineethanesulfonic acid (HEPES)

The preparation technology of 4-hydroxyethylpiperazineethanesulfonic acid comprises following preparation steps:

Preparation step S1:

Under stirring conditions, add 100g of compound 1, 732.1g of compound 2, and ether as a reaction solvent into a 1L dry reactor; wherein, compound 1 is 4-hydroxyethylpiperazine, and compound 2 is ethyl vinylsulfonate; The molar ratio of compound 1 and compound 2 is 1:7, the reaction temperature is 25° C., the reaction pressure is 0 MPa (gauge pressure), and the reaction time is 72 h.

After the reaction was completed, it was lowered to normal temperature, the solvent was removed by rotary evaporation under reduced pressure, and concentrated to prepare the crude compound 3.

Preparation step S2:

Under the condition of stirring, add above-mentioned 100g compound 3, reaction solvent N,N-dimethylformamide, 207.5g M-containing reagent in 1L dry reactor; Wherein, M-containing reagent is potassium carbonate; Compound 3 and containing The molar ratio of M reagent is 1:4, the reaction temperature is 100°C, the reaction pressure is 0.1MPa (gauge pressure), and the reaction time is 36h.

After the reaction was completed, the temperature was lowered to normal temperature, the reaction liquid was rotatably evaporated under reduced pressure to remove the solvent, and then concentrated to prepare the crude product of potassium 4-hydroxyethylpiperazineethanesulfonate.

Preparation step S3:

Dissolve the potassium 4-hydroxyethylpiperazineethanesulfonate prepared in step S2 in methanol, use dilute sulfuric acid to adjust the pH to 4-5, stir, cool and clean the crystals, filter, and dry to obtain 4-hydroxyethylpiperazineethanesulfonate Sulfonic acid, 71% yield.

Preparation step 4:

Under dry conditions, using dry airtight equipment, the crude product 4-hydroxyethylpiperazineethanesulfonic acid obtained in the preparation step S3 was dissolved in the purification solvent diethyl carbonate, recrystallized, crystallized under low temperature conditions, filtered, Dry to obtain fine product; the purity of 4-hydroxyethylpiperazineethanesulfonic acid product is 99.7%.

The NMR characterization data are as follows: ¹ H NMR (400MHz, D ₂ O): δ4.0ppm, 3.3ppm, 3.2ppm, 3.1ppm.

Embodiment 7: the preparation of 2-morpholineethanesulfonate potassium (MES-K)

The preparation technology of potassium 2-morpholineethanesulfonate comprises following preparation steps:

Preparation step S1:

Under stirring conditions, add 100g of compound 1, 140g of compound 2, and the reaction solvent N,N-dimethylformamide into a 1L dry reactor; wherein, compound 1 is morpholine, and compound 2 is methyl vinylsulfonate Esters; the molar ratio of compound 1 and compound 2 is 1:1, the reaction temperature is 25°C, the reaction pressure is 0.1MPa (gauge pressure), and the reaction time is 54h.

Preparation step S2:

Under the condition of stirring, add above-mentioned 100g compound 3, reaction solvent dioxane, 40.3g M-containing reagent in 1L dry reactor; Wherein, M-containing reagent is potassium hydroxide; The mole of compound 3 and M-containing reagent The ratio is 1:1.5, the reaction temperature is 80°C, the reaction pressure is 0.2MPa (gauge pressure), and the reaction time is 15h.

After the reaction was completed, the temperature was lowered to normal temperature, the reaction solution was evaporated under reduced pressure to remove the solvent, and then concentrated to prepare the crude product of potassium 2-morpholineethanesulfonate with a yield of 76%.

Preparation step S3:

Under dry conditions, using dry airtight equipment, the crude product of potassium 2-morpholineethanesulfonate obtained in the preparation step S2 was dissolved in the purification solvent diethyl carbonate, recrystallized, crystallized under low temperature conditions, filtered, and dried. The refined product is obtained; the purity of the 2-morpholine ethanesulfonate potassium product is 99.5%.

The NMR characterization data are as follows: ¹ H NMR (400MHz, D ₂ O): δ3.8ppm, 3.2ppm, 2.9ppm, 2.7ppm.

Embodiment 8: the preparation of 2-morpholineethanesulfonic acid (MES)

The preparation technology of 2-morpholineethanesulfonic acid comprises following preparation steps:

Preparation step S1:

Under stirring conditions, add 100g of compound 1, 258.3g of compound 2, and the reaction solvent tetrahydrofuran into a 1L dry reactor; wherein, compound 1 is morpholine, compound 2 is propyl vinyl sulfonate; compound 1, compound 2 The molar ratio is 1:1.5, the reaction temperature is 50°C, the reaction pressure is 0.1MPa (gauge pressure), and the reaction time is 24h.

Preparation step S2:

Under the condition of stirring, add above-mentioned 100g compound 3, reaction solvent ethanol, 57.5g M-containing reagent in 1L dry reactor; Wherein, M-containing reagent is ammonia water (25%); The molar ratio of compound 3 and M-containing reagent The ratio is 1:2, the reaction temperature is 50°C, the reaction pressure is 0.1MPa (gauge pressure), and the reaction time is 12h.

After the reaction was completed, the temperature was lowered to normal temperature, the reaction liquid was rotatably evaporated under reduced pressure to remove the solvent, and then concentrated to prepare the crude product of 2-morpholine ammonium ethanesulfonate with a yield of 68%.

Preparation step S3:

Dissolve the crude ammonium 2-morpholineethanesulfonate prepared in step S2 in ethanol, adjust the pH to 4-5 with glacial acetic acid, stir, cool and clean the crystal, filter, and dry to obtain crude 2-morpholineethanesulfonate.

Preparation step S4:

Under dry conditions, using dry airtight equipment, the crude 2-morpholineethanesulfonic acid obtained in the preparation step S3 was dissolved in the purification solvent dimethyl carbonate, recrystallized, crystallized at low temperature, filtered, and dried to obtain A fine product of compounds containing sulfonic acid groups; the purity of the product is 99.6%.

The NMR characterization data are as follows: ¹ H NMR (400MHz, D ₂ O): δ4.2ppm, 3.9ppm, 3.6ppm, 3.4ppm, 3.3ppm.

It can be seen from the above experiments that the sulfonic acid group-containing compound prepared in the embodiment has high purity and less impurity content, which can meet the requirements of the application field, and the product yield of the preparation method described in the application can reach up to 76%. The yield has also been improved, and the product purity can reach up to 99.9%.

The above-mentioned implementation mode is only the preferred implementation mode of the present application, which cannot limit the protection scope of the present application. Scope of protection claimed.

Claims

A preparation process for a compound containing a sulfonic acid group and a salt thereof, wherein,

Preparation step S1: react compound 1 with compound 2 to obtain compound 3;

Preparation step S2: reacting the above-mentioned compound 3 with an M-containing reagent to obtain a crude product of the M-containing salt corresponding to the compound 4 containing a sulfonic acid group; after an acidification reaction, a crude product of the compound 4 containing a sulfonic acid group is obtained;

Wherein, the structural formula of compound 1 is the general structure shown in formula I:

The structural formula of compound 2 is the general structure shown in formula II:

H2C ＝CH-Cm -2H2 (m-2) -SO2 - OR1 ;

Formula II

Y is one of O, NH, and NR; R is a group that is saturated or unsaturated, contains straight or branched chains, contains heteroatoms or does not contain heteroatoms, and can be terminated by one of sulfonate, hydroxyl, and sulfonate One of the C 1 -C 30 hydrocarbon groups substituted by groups; R 1 is one of the C 1 -C 30 hydrocarbon groups that are saturated or unsaturated, straight or branched, heteroatom-containing or non-heteroatom-free; m is an integer greater than or equal to 2; when m=2, compound 2 is, H 2 C=CH-SO 2 -OR 1 ; M in the M-containing reagent is one of NH 4 + and metal elements;

The structural formula of compound 3 is the general structure shown in formula III:

The structural formula of compound 4 is the general structure shown in formula IV:
The preparation process of a kind of compound containing sulfonic acid group and salt thereof according to claim 1, wherein,

When Y in compound 4 is NC m H 2m -SO 2 -OH, compound 1 has the general structure

at least one of

In the preparation step S1, compound 1 is reacted with compound 2 to prepare a compound whose general structure is represented by formula V;

The general structure shown in formula V is:

In the preparation step S2, the compound with the general structure of formula V is reacted with the M-containing reagent to obtain the crude salt corresponding to the compound with the general structure of formula VI containing sulfonic acid groups; after the acidification reaction, the general structure is obtained as the formula A compound containing a sulfonic acid group of VI, or a corresponding hydrate;

The general structure shown in formula VI is:
The preparation process of a compound containing sulfonic acid groups and salts thereof according to any one of claims 1-2, wherein,

The M-containing salt corresponding to the compound 4 containing the sulfonic acid group also includes the hydrate of the M-containing salt corresponding to the compound 4 containing the sulfonic acid group;

The compound 4 containing a sulfonic acid group also includes the corresponding hydrate of the compound 4 containing a sulfonic acid group.
A preparation process for a compound containing a sulfonic acid group and a salt thereof according to any one of claims 1-2, wherein the compound containing a sulfonic acid group is piperazine-N,N'-bis(2-ethane sulfonic acid), 3-morpholinepropanesulfonic acid, 4-hydroxyethylpiperazineethanesulfonic acid, 2-morpholineethanesulfonic acid or the piperazine-N,N'-di(2-ethanesulfonic acid), One of the sodium salts of 3-morpholinepropanesulfonic acid, 4-hydroxyethylpiperazineethanesulfonic acid, and 2-morpholineethanesulfonic acid.
A preparation process for a sulfonic acid group-containing compound and its salt according to any one of claims 1-2, wherein, when Y is NR, R is a group whose end is covered with one of sulfonate, hydroxyl, and sulfonate One of substituted C 1 -C 30 hydrocarbon groups, Y is NC m H 2m -SO 2 -OH, NC m H 2m -OH, NC m H 2m -CO-OH.
The preparation process of a sulfonic acid group-containing compound and its salt according to any one of claims 1-2, wherein the M reagent is an M-containing element, an M-containing base, an M-containing oxide, or an M-containing salts or their precursors, double salts, hydrates, solvent complexes, hydrogen halide complexes, or a combination of two or more.
The preparation process of a sulfonic acid group-containing compound and its salt according to any one of claims 1-2, wherein, in the preparation step S1, the reaction temperature is -50-200°C, and the reaction pressure is -0.05-1MPa, The reaction time is 0.1-72 hours; in the preparation step S2, the reaction temperature is -50-200° C., the reaction pressure is -0.05-1 MPa, and the reaction time is 0.1-72 hours.
The preparation process of a compound containing a sulfonic acid group and its salt according to any one of claims 1-2, wherein, in the preparation step S1, the molar ratio of compound 1 to compound 2 is 1: (0.1-10); In the preparation step S2, the molar ratio of the compound 3 to the M-containing reagent is 1:(0.1-10).
The preparation process of a compound containing sulfonic acid group and its salt according to any one of claims 1-2, wherein, in the preparation step S1, compound 1 and compound 2 are reacted in reaction solvent A, and said reaction solvent A At least one of methanol, ethanol, acetone, tetrahydrofuran, ethyl acetate, dimethyl carbonate, diethyl carbonate, diethyl ether, acetonitrile, dioxane, N,N-dimethylformamide, dimethyl sulfoxide One; in the preparation step S2, the compound 3 reacts with the M-containing reagent in a reaction solvent B, and the reaction solvent B is methanol, ethanol, acetone, tetrahydrofuran, ethyl acetate, dimethyl carbonate, diethyl carbonate, ether , acetonitrile, dioxane, N,N-dimethylformamide, and dimethyl sulfoxide.
The preparation process of a sulfonic acid group-containing compound and its salt according to any one of claims 1-2, wherein, in the preparation step S1, at least one of a catalyst or an auxiliary agent is used for the reaction.
The preparation process of a compound containing a sulfonic acid group and its salt according to any one of claims 1-10, wherein, further comprising the following preparation steps:

Under dry conditions, using a dry airtight device or under dry gas purging, dissolve the crude product containing a sulfonic acid group, or its salt, in the purification solvent obtained in the preparation step S2, and then recrystallize, filter, and dry , to obtain refined compounds containing sulfonic acid groups.
The preparation process of a compound containing sulfonic acid group and its salt according to claim 11, wherein the purification solvent is methanol, ethanol, acetone, tetrahydrofuran, ethyl acetate, dimethyl carbonate, diethyl carbonate , ether, acetonitrile, dioxane, N,N-dimethylformamide, dimethyl sulfoxide, or a combination of two or more.