Preparation Process of Sodium 1,4-Butanedisulfonate

Abstract

The present invention belongs to the technical field of acyclic compounds, and in particular to a preparation process of 1,4-butanedisulfonic acid sodium. Tetrahydrofuran, sodium bromide aqueous solution, catalyst, concentrated sulfuric acid and sodium sulfite aqueous solution are reacted, cooled and ultrafiltered, and trapped liquid is collected; the trapped liquid is cooled and crystallized and then centrifuged and dried to obtain 1,4-butanedisulfonic acid sodium. The present invention adopts a microchannel reactor to react, instead of the traditional kettle reaction of 1,4-dibromobutane to form 1,4-butanedisulfonic acid sodium, reduces the risk in chemical production, and bromination reaction and sulfonation reaction are completed in one step to reduce the use of solvent, and the obtained product 1,4-butanedisulfonic acid sodium has high purity and high conversion rate.

Description

Technical Field

[0001] The invention belongs to the technical field of acyclic compounds, and particularly relates to a preparation process of sodium 1,4-butanedisulfonate. Background Art

[0002] Liver disease treatment drugs can be categorized as antiviral, immunomodulatory, and liver-protective drugs. Antiviral drugs are widely used in clinical practice, but they are highly toxic and can cause significant damage to the human body. Immunomodulatory drugs are difficult to develop and manufacture, resulting in high costs and high prices. Therefore, liver-protective drugs are highly competitive in the liver disease market. Sodium 1,4-butanedisulfonate is an intermediate for 1,4-butanedisulfonate adenosylmethionine. 1,4-Butanedisulfonate adenosylmethionine is a stable salt form of adenosylmethionine, commonly found in injectable or oral formulations. 1,4-Butanedisulfonate adenosylmethionine is an important methyl donor in the body, participating in liver transmethylation, transsulfuration, and aminopropylation reactions. These reactions are crucial for liver cell repair, detoxification (such as glutathione synthesis), and bile excretion. Furthermore, sodium 1,4-butanedisulfonate has a wide range of applications in chemical pharmaceuticals, analysis, environmental protection, and the production of amino oligosaccharides and alkaloids.

[0003] Sodium 1,4-butanedisulfonate is usually prepared from 1,4-dibromobutane or 1,4-butanediol. The use of 1,4-dibromobutane as a raw material has the disadvantages of a long production cycle and insufficient utilization of the reaction raw materials.

[0004] Chinese patent CN 113416156 A discloses a method for preparing sodium 1,4-butanedisulfonate. The method involves adding 1,4-dibromobutane and a cosolvent to an aqueous sodium sulfite solution to obtain a mixed solution. The mixed solution is then heated under reflux to obtain sodium 1,4-butanedisulfonate. The cosolvent comprises ethanol and n-butanol. This patent utilizes a traditional reactor-based production process, which has a long production cycle and low yield. It also requires 1,4-dibromobutane as a raw material and requires a strong power and heat source. Summary of the Invention

[0005] The present invention aims to provide a preparation process of sodium 1,4-butanedisulfonate. The process adopts a microchannel reactor for reaction, replacing the traditional kettle reaction of reacting 1,4-dibromobutane to produce sodium 1,4-butanedisulfonate, thereby reducing the risk in chemical production. The bromination reaction and the sulfonation reaction are completed in one step, reducing the use of solvents. The prepared sodium 1,4-butanedisulfonate has high purity and high conversion rate.

[0006] The preparation process of sodium 1,4-butanedisulfonate of the present invention comprises the following steps:

[0007] (1) Tetrahydrofuran, sodium bromide aqueous solution, catalyst, concentrated sulfuric acid and sodium sulfite aqueous solution are reacted, cooled and ultrafiltered, and the retentate is collected;

[0008] (2) The retentate is cooled and crystallized, then centrifuged and dried to obtain sodium 1,4-butanedisulfonate.

[0009] The mass concentration of the sodium bromide aqueous solution in step (1) is 40-60%, and the temperature of the sodium bromide aqueous solution is 60-65°C.

[0010] In step (1), the catalyst is aluminum sulfate, and the amount of the catalyst added is 1 / 600-1 / 500 of the mass of tetrahydrofuran.

[0011] The mass concentration of concentrated sulfuric acid in step (1) is 95-98%.

[0012] In step (1), the mass concentration of the sodium sulfite aqueous solution is 0.22-0.23 g / ml, and the temperature of the sodium sulfite aqueous solution is 75-85°C.

[0013] In step (1), the volume ratio of tetrahydrofuran, sodium bromide aqueous solution, concentrated sulfuric acid and sodium sulfite aqueous solution is 5:6.5-9.8:3.8-4:70-75.

[0014] The reaction in step (1) is carried out using a microchannel reactor.

[0015] In step (1), the reaction temperature is 95-115° C. and the reaction time is 63-72 s.

[0016] In step (1), the temperature is lowered to 40-50°C, and the pore size of the ultrafiltration membrane used in ultrafiltration is 0.001-0.02 microns.

[0017] In step (1), the catalyst is first mixed into a sodium bromide aqueous solution to obtain a sodium bromide aqueous solution mixed with the catalyst, and then tetrahydrofuran, the sodium bromide aqueous solution mixed with the catalyst, concentrated sulfuric acid and a sodium sulfite aqueous solution are added to a microchannel reactor for reaction.

[0018] In step (2), the cooling temperature is 0-5°C and the crystallization time is 1-2 hours.

[0019] The present invention uses tetrahydrofuran and sodium sulfite to prepare sodium 1,4-butanedisulfonate through bromination and sulfonation reactions. The reaction is carried out in a mixed system of aqueous and organic phases. Traditional catalysts, such as tetrabutylammonium bromide, are ineffective in catalyzing the bromination reaction in aqueous systems, further affecting the subsequent sulfonation reaction. Therefore, traditional catalysts are not suitable for the reaction system of the present invention. The present invention uses a composite catalyst system of sodium bromide, concentrated sulfuric acid, and aluminum sulfate, which greatly improves the purity and conversion rate of the product sodium 1,4-butanedisulfonate.

[0020] In the prior art, when sodium 1,4-butanedisulfonate is prepared using 1,4-dibromobutane as a raw material, the generated sodium bromide is present in the aqueous phase and part of the product. The aqueous phase is almost completely discarded, making sodium bromide difficult to recycle. The inclusion of sodium bromide in the product reduces the purity of the product. The present invention uses sodium bromide as a reaction catalyst, which can be recycled.

[0021] The reaction mechanism of the present invention is as follows:

[0022] Tetrahydrofuran first opens its ring under the action of sulfuric acid and bromide ions. Tetrahydrofuran is protonated and reacts with bromide ions to generate 1-bromo-4-butanol. The hydroxyl group is then protonated and dehydrated and reacts with bromide ions to generate 1,4-dibromobutane. At the same time, sulfuric acid and sodium bromide react under water to generate more electrophilic hydrobromic acid. At this time, bromide ions are more conducive to the generation of S N 1 and S N Reaction 2. The carbon connected to the bromine element in 1,4-dibromobutane is protonated again and reacts with sodium sulfite to form sodium 1,4-butanedisulfonate.

[0023] The present invention uses aluminum sulfate as a Lewis acid catalyst. The Lewis acid catalyst combines with the Lewis base in the substrate to reduce the reaction activation energy and significantly accelerate the reaction rate. The main reason why the present invention uses aluminum sulfate instead of aluminum bromide is that aluminum bromide is not easy to store, has strong corrosiveness, and easily generates hydrogen bromide gas when it comes into contact with water, which is not conducive to the dissolution and preparation of materials before the reaction. The sulfate ions ionized by aluminum sulfate in water will increase the concentration of sulfate ions in the reaction system, and then cooperate with the sulfate ions in sulfuric acid to increase the protonity of hydrogen ions and promote the ring-opening effect of sulfuric acid. Aluminum sulfate can ionize aluminum ions in water. Aluminum ions can change valence states and are rich, which is conducive to surface electron transfer. The aluminum ions ionized by aluminum sulfate are bromine elements that generate S N 1 and S N 2 reactions provide a more protic environment.

[0024] In the present invention, sodium bromide as a raw material provides more bromide ions, which are more likely to form the ionic form of hydrobromic acid under acidic conditions. This results in a higher bromide ion concentration than when bromine gas is directly introduced, which is more conducive to the reaction. Sodium bromide is regenerated after the sulfonation reaction, ensuring a constant excess of bromide ions. According to reaction kinetics, the raw material tetrahydrofuran and the intermediate bromide product continuously decrease, the total amount of bromine remains unchanged, and the proportion of bromine continuously increases, allowing the reaction to proceed toward the formation of sodium 1,4-butanedisulfonate, resulting in a more thorough reaction. Furthermore, the regenerated sodium bromide can be returned to the reaction system for recycling.

[0025]

[0026] The present invention utilizes a composite catalytic system of sodium bromide, concentrated sulfuric acid and aluminum sulfate to replace a traditional catalyst, so that raw materials such as tetrahydrofuran can react in a mixed system of an aqueous phase and an organic phase, thereby reducing the use of bromine gas, allowing sodium bromide, aluminum sulfate and sulfuric acid to be recycled, and controlling the total heat of the reaction, thereby greatly reducing production risks. A single mixed reaction reduces the risk of raw material storage.

[0027] The beneficial effects of the present invention are as follows:

[0028] (1) The present invention adopts a composite catalytic system of sodium bromide, concentrated sulfuric acid and aluminum sulfate and a microchannel reaction method to prepare sodium 1,4-butanedisulfonate, recovers and utilizes sodium bromide and other substitution products that enter the aqueous phase during the bromination process, reduces the use of bromine gas, realizes continuous automatic production, and greatly improves the degree of automation and safety; ultrafiltration is performed by membrane separation, replacing the liquid separation operation, and effectively improves the purity of the final product.

[0029] (2) The present invention has the characteristics of simple process, greatly shortened production cycle and high product output.

[0030] (3) The present invention makes full use of the discarded sodium bromide in the aqueous solution of traditional technology as raw material. Through the synergistic catalytic effect of aluminum sulfate, sodium bromide and concentrated sulfuric acid, the reaction between the organic phase and the aqueous phase is broken through, the conversion rate is greatly improved, and the use of organic solvents is effectively reduced. BRIEF DESCRIPTION OF THE DRAWINGS

[0031] Figure 1 It is the sodium 1,4-butanedisulfonate obtained in Example 1. 1 H NMR spectrum. DETAILED DESCRIPTION

[0032] The present invention is further described below with reference to the following examples.

[0033] Example 1

[0034] (1) A sodium bromide aqueous solution with a mass concentration of 40% is preheated to 60°C and then added with aluminum sulfate solid having a mass of 1 / 500 of that of tetrahydrofuran to obtain a sodium bromide aqueous solution mixed with aluminum sulfate preheated to 60°C; tetrahydrofuran, the sodium bromide aqueous solution mixed with aluminum sulfate preheated to 60°C, concentrated sulfuric acid and a sodium sulfite aqueous solution preheated to 80°C are added to a microchannel reactor for reaction, and after cooling to 40°C, ultrafiltration is performed using an ultrafiltration membrane with a pore size of 0.02 μm, and the retentate is collected;

[0035] The flow rate of tetrahydrofuran was 5 ml / min, the mass concentration of concentrated sulfuric acid was 98%, the flow rate of concentrated sulfuric acid was 4.0 ml / min, the flow rate of the sodium bromide aqueous solution mixed with aluminum sulfate was 9.75 ml / min, the mass concentration of the sodium sulfite aqueous solution was 0.225 g / ml, the flow rate of the sodium sulfite aqueous solution was 70 ml / min, the reaction temperature was 95° C., and the reaction residence time was 63 s.

[0036] (2) The retentate was cooled to 0°C and crystallized for 1 hour, then centrifuged and dried to obtain sodium 1,4-butanedisulfonate.

[0037] Liquid chromatography analysis showed that the purity of sodium 1,4-butanedisulfonate was 99.54% and the conversion rate was 86% (based on tetrahydrofuran). 1 H NMR spectrum is shown in Figure 1 , 1 The H NMR spectrum parameters are: 1 HNMR (600MHz, D2O): δ2.95 (s, 4H), 1.90 (s, 4H).

[0038] Example 2

[0039] (1) A sodium bromide aqueous solution with a mass concentration of 50% is preheated to 62°C and then added with aluminum sulfate solid with a mass of 1 / 550 of tetrahydrofuran to obtain a sodium bromide aqueous solution mixed with aluminum sulfate preheated to 62°C; tetrahydrofuran, the sodium bromide aqueous solution mixed with aluminum sulfate preheated to 62°C, concentrated sulfuric acid and a sodium sulfite aqueous solution preheated to 75°C are added to a microchannel reactor for reaction, and after cooling to 50°C, ultrafiltration is performed using an ultrafiltration membrane with a pore size of 0.01 μm, and the retentate is collected;

[0040] The flow rate of tetrahydrofuran was 5 ml / min, the mass concentration of concentrated sulfuric acid was 95%, the flow rate of concentrated sulfuric acid was 3.9 ml / min, the flow rate of sodium bromide aqueous solution mixed with aluminum sulfate was 7.8 ml / min, the mass concentration of sodium sulfite aqueous solution was 0.22 g / ml, the flow rate of sodium sulfite aqueous solution was 72 ml / min, the reaction temperature was 115° C., and the reaction residence time was 66 s.

[0041] (2) The retentate was cooled to 5°C and crystallized for 2 hours, then centrifuged and dried to obtain sodium 1,4-butanedisulfonate.

[0042] Liquid chromatography analysis showed that the purity of sodium 1,4-butanedisulfonate was 99.56% and the conversion rate was 86.5% (based on tetrahydrofuran).

[0043] Example 3

[0044] (1) A sodium bromide aqueous solution with a mass concentration of 60% is preheated to 65°C and then added with aluminum sulfate solid having a mass of 1 / 600 of that of tetrahydrofuran to obtain a sodium bromide aqueous solution mixed with aluminum sulfate preheated to 65°C; tetrahydrofuran, the sodium bromide aqueous solution mixed with aluminum sulfate preheated to 65°C, concentrated sulfuric acid and a sodium sulfite aqueous solution preheated to 85°C are added to a microchannel reactor for reaction, and after cooling to 45°C, ultrafiltration is performed using an ultrafiltration membrane with a pore size of 0.001 μm, and the retentate is collected;

[0045] The flow rate of tetrahydrofuran was 5 ml / min, the mass concentration of concentrated sulfuric acid was 97%, the flow rate of concentrated sulfuric acid was 3.8 ml / min, the flow rate of the sodium bromide aqueous solution mixed with aluminum sulfate was 6.5 ml / min, the mass concentration of the sodium sulfite aqueous solution was 0.23 g / ml, the flow rate of the sodium sulfite aqueous solution was 75 ml / min, the reaction temperature was 100° C., and the reaction residence time was 72 s.

[0046] (2) The retentate was cooled to 2°C and crystallized for 1.5 hours, then centrifuged and dried to obtain sodium 1,4-butanedisulfonate.

[0047] Liquid chromatography analysis showed that the purity of sodium 1,4-butanedisulfonate was 99.60% and the conversion rate was 87% (based on tetrahydrofuran).

[0048] Comparative Example 1

[0049] No aluminum sulfate was added, and the other steps were the same as in Example 1.

[0050] Liquid chromatography analysis showed that the purity of sodium 1,4-butanedisulfonate was 99.08% and the conversion rate was 67.2% (based on tetrahydrofuran).

[0051] Comparative Example 2

[0052] Without the addition of aqueous sodium bromide solution, the reaction could not proceed.

[0053] Comparative Example 3

[0054] Without the addition of concentrated sulfuric acid, the reaction cannot proceed.

Claims

1. A preparation process for sodium 1,4-butanedisulfonate, characterized in that The steps include: (1) Tetrahydrofuran, sodium bromide aqueous solution, catalyst, concentrated sulfuric acid and sodium sulfite aqueous solution are reacted, cooled and ultrafiltered, and the retentate is collected; (2) The retentate is cooled and crystallized, then centrifuged and dried to obtain sodium 1,4-butanedisulfonate; In step (1), the catalyst is aluminum sulfate; The mass concentration of the sodium sulfite aqueous solution in step (1) is 0.22-0.23 g / ml; In step (1), the volume ratio of tetrahydrofuran, sodium bromide aqueous solution, concentrated sulfuric acid and sodium sulfite aqueous solution is 5:6.5-9.8:3.8-4:70-75; The reaction in step (1) is carried out using a microchannel reactor.

2. The preparation process of 1,4-butanedisulfonic acid sodium according to claim 1, is characterized in that The mass concentration of the sodium bromide aqueous solution in step (1) is 40-60%, and the temperature of the sodium bromide aqueous solution is 60-65°C.

3. The preparation process of 1,4-butanedisulfonic acid sodium according to claim 1, is characterized in that The amount of catalyst added in step (1) is 1 / 600-1 / 500 of the mass of tetrahydrofuran.

4. The preparation process of 1,4-butanedisulfonic acid sodium according to claim 1, is characterized in that The mass concentration of concentrated sulfuric acid in step (1) is 95-98%.

5. The preparation process of 1,4-butanedisulfonic acid sodium according to claim 1, is characterized in that The temperature of the sodium sulfite aqueous solution in step (1) is 75-85°C.

6. The preparation process of sodium 1,4-butanedisulfonate according to claim 1, is characterized in that In step (1), the reaction temperature is 95-115° C. and the reaction time is 63-72 s.

7. The preparation process of 1,4-butanedisulfonic acid sodium according to claim 1, is characterized in that In step (1), the temperature is lowered to 40-50°C, and the pore size of the ultrafiltration membrane used in ultrafiltration is 0.001-0.02 microns.

8. The preparation process of 1,4-butanedisulfonic acid sodium according to claim 1, is characterized in that In step (2), the cooling temperature is 0-5°C and the crystallization time is 1-2 hours.

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