A process for the preparation of 2,3-dibromopropanesulfonic acid

Abstract

The application belongs to the field of medical intermediates, and particularly relates to a method for preparing 2,3-dibromopropanesulfonic acid, which takes purified sodium allylsulfonate as raw material to prepare 2,3-dibromopropanesulfonic acid, and by optimizing the molar ratio of sodium allylsulfonate, bromine and sodium bromide, the reaction temperature, the solvent volume, the refining temperature, the refining solvent volume and other parameters, the purity of 2,3-dibromopropanesulfonic acid is significantly improved; solid powder can be obtained, which is easier to store than reaction liquid. Meanwhile, the impurities are controllable, which provides significant help for subsequent synthesis of high-purity 2,3-dimercaptopropanesulfonic acid sodium. Compared with the existing method, the production cost is relatively low, the safety is high, the stability and repeatability are good, the method can be scaled up, the post-treatment process is simple, the impurities are controllable, and the method has a good application prospect.

Description

TECHNICAL FIELD

[0001] The application belongs to the technical field of medical intermediate preparation, and particularly relates to a method for preparing 2,3-dibromopropane-1-sulfonic acid. BACKGROUND

[0002] 2,3-dibromopropane-1-sulfonic acid is an important pharmaceutical intermediate of sodium 2,3-dimercaptosulfonate, and its synthesis method is of great significance to the industrialized synthesis and purity of sodium 2,3-dimercaptosulfonate.

[0003] The current production process uses sodium allylsulfonate or epichlorohydrin as a raw material to be dissolved in water, and bromine is added dropwise at room temperature to obtain an aqueous solution of sodium dibromopropane sulfonate. This method only obtains the reaction liquid without subsequent treatment operation, and uncontrollable impurities are generated, which greatly affects the purity of the subsequent synthesis of sodium 2,3-dimercaptosulfonate.

[0004] The current literature reports the following method for preparation: Referring to the “Preparation method of sodium dimercaptosulfonate” disclosed in the Chinese invention patent publication No. CN106478476B, sodium allylsulfonate is dissolved in lye, and bromine is added dropwise at room temperature to obtain an aqueous solution of sodium dibromopropane sulfonate. However, this method has the following disadvantages: during the reaction, a large amount of 2-hydroxy-3-bromo-propane sulfonate or 2-bromo-3-hydroxy-propane sulfonate by-products are easily generated, the content of sodium dibromopropane sulfonate in the reaction liquid is about 70%, and the generated hydrobromic acid makes the reaction liquid strongly acidic with a pH value less than 0.5; the entire reaction system is not suitable for the production and preparation of pharmaceutical intermediates.

[0005] In addition, the inventors have found that most of the commercially available sodium allylsulfonate raw materials have very low purity. The actual purity of sodium allylsulfonate with a purity of 98% is about 85% after high-performance liquid chromatography analysis. If such sodium allylsulfonate raw materials are not purified, the yield and purity of the subsequent pharmaceutical intermediates will be significantly affected.

[0006] Based on this, the present application is proposed. SUMMARY

[0007] The purpose of the present application is to provide a method for preparing 2,3-dibromopropane-1-sulfonic acid to solve the above problems.

[0008] A method for preparing 2,3-dibromopropane-1-sulfonic acid, comprising the following steps:

[0009] Step 1: After the sodium allylsulfonate raw material and the first solvent are mixed, the temperature is raised to the reflux state for heat preservation and stirring reaction. After the reaction is completed, the temperature is lowered to below 60℃, and then filtered, concentrated and dried to obtain purified sodium allylsulfonate.

[0010] Step 2, add a second solvent, sodium bromide, to the purified sodium allyl sulfonate, mix, and cool to 2-5°C in an ice water bath, then add bromine dropwise while controlling the internal temperature to 5±3°C; after the dropwise addition, maintain the temperature at 5±3°C and stir to react, to obtain a 2,3-dibromopropane sulfonic acid sodium reaction solution;

[0011] Step 3, add an acid solution to the 2,3-dibromopropane sulfonic acid sodium reaction solution, maintain the temperature at 20-30°C and stir to react, then concentrate under reduced pressure until no liquid is evaporated, to obtain 2,3-dibromopropane sulfonic acid crude product;

[0012] Step 4, add a third solvent to the 2,3-dibromopropane sulfonic acid crude product, heat to reflux to dissolve and maintain stirring, then cool to 50°C, maintain the temperature, and crystallize, then filter to obtain a filter cake; add a fourth solvent to the filter cake, heat to reflux to dissolve and maintain stirring, then cool to 0-5°C, maintain the temperature, and crystallize, then filter to obtain the 2,3-dibromopropane sulfonic acid.

[0013] In a further improvement, in Step 1, the first solvent is one or more of water, methanol, and ethanol.

[0014] In a further improvement, in Step 1, the first solvent is a 90% ethanol solution by volume.

[0015] In a further improvement, in Step 1, the volume ratio of the sodium allyl sulfonate raw material to the first solvent is 1:5.

[0016] In a further improvement, in Step 2, if the bromine added dropwise is excessive, the solution is yellow, and sodium bisulfite is added until the yellow color disappears, then maintain the temperature at 2-15°C and stir to react for 30 min, to obtain the 2,3-dibromopropane sulfonic acid sodium reaction solution.

[0017] In a further improvement, in Step 2, the second solvent is water.

[0018] In a further improvement, in Step 2, the molar ratio of the purified sodium allyl sulfonate, sodium bromide, and bromine is 1:0.18:1.

[0019] In a further improvement, in Step 2, the volume ratio of the second solvent to the sodium allyl sulfonate raw material is 1:1.

[0020] In a further improvement, in Step 3, the acid solution used is one or more of hydrochloric acid, sulfuric acid, and nitric acid.

[0021] In a further improvement, in Step 3, the acid solution used is hydrochloric acid, and the molar ratio of the hydrochloric acid to the purified sodium allyl sulfonate is 1:1.

[0022] and / or,

[0023] In step 4, the third solvent and the fourth solvent are both water, and the volume ratio of the third solvent to the sodium allyl sulfonate raw material is 1:0.5;

[0024] and / or,

[0025] The volume ratio of the fourth solvent to the sodium allyl sulfonate raw material is 1:0.5.

[0026] The inventors found in experiments that, in the process of the bromine drop reaction of the application, if the volume of the second solvent is too large, the yield of the final 2,3-dibromopropane sulfonate sodium is not high.

[0027] The 2,3-dibromopropane sulfonate obtained by the application is a key intermediate of 2,3-dimercapto propane sulfonate sodium medicine, and is used as a starting material in the reaction. The maximum single impurity of the end product prepared by the application can be controlled within 1%, and the total impurity can be controlled within 2.5%, which is beneficial to impurity removal in subsequent reaction steps and low impurity removal difficulty.

[0028] Compared with the prior art, the application has the following beneficial effects:

[0029] 1. The application uses purified sodium allyl sulfonate as a raw material to prepare 2,3-dibromopropane sulfonate. By optimizing the molar ratio of sodium allyl sulfonate, bromine, sodium bromide, reaction temperature, solvent volume, refining temperature, and refining solvent volume, the purity (as high as 97.8%) and yield (as high as 56.5%) of 2,3-dibromopropane sulfonate are significantly improved. Solid powder can be obtained, which is easier to store than reaction liquid. At the same time, impurities are controllable, which provides significant help for the subsequent synthesis of high-purity 2,3-dimercapto propane sulfonate sodium.

[0030] 2. Compared with the prior art, the application has relatively low production cost, high safety, good stability and repeatability, can be scaled up, has a simple post-treatment process, controllable impurities, and has a good application prospect. DETAILED DESCRIPTION

[0031] The application will be further described in detail below through specific examples.

[0032] Example 1

[0033] Purification of the starting material: sodium allyl sulfonate raw material (1V, 100mL) is added to a 90% ethanol solution (5V, 500mL) at room temperature, heated to refluxing state, and stirred for 1h, then cooled to 60℃ and filtered. The filtrate is concentrated and dried to obtain purified sodium allyl sulfonate.

[0034] Synthesis of aqueous solution of sodium 2,3-dibromopropane sulfonate: To the purified sodium allyl sulfonate (1.0 eq) was added purified water (1 V, 100 mL) and stirring was started. Sodium bromide (0.18 eq) was added. The temperature was lowered to 2-5 °C in an ice water bath. Bromine (1.0 eq) was added dropwise while controlling the internal temperature at 5±3 °C. After the addition was completed, the solution was stirred at 5±3 °C for 1.5 h. If the solution was yellow due to excess bromine, a small amount of sodium bisulfite was added until the yellow color disappeared. The solution was stirred at 2-15 °C for 30 min. The reaction solution of sodium 2,3-dibromopropane sulfonate was obtained.

[0035] Acidification of the reaction solution: 1.1 eq of hydrochloric acid was added to the reaction solution of sodium 2,3-dibromopropane sulfonate. The solution was stirred at 20-30 °C for 14 h. The solution was concentrated under reduced pressure until no liquid was distilled off. The crude sodium 2,3-dibromopropane sulfonate was obtained.

[0036] Purification of the crude sodium 2,3-dibromopropane sulfonate: The crude sodium 2,3-dibromopropane sulfonate was dissolved in purified water (0.5 V, 50 mL) by heating to reflux. The solution was stirred at reflux for 30 min. The temperature was lowered to 50 °C and the solution was stirred at this temperature for 1 h. The solution was filtered. The filter cake was transferred to a reaction flask. Purified water (0.5 V, 50 mL) was added and the solution was dissolved by heating to reflux. The solution was stirred at reflux for 30 min. The temperature was lowered to 0-5 °C and the solution was stirred at this temperature for 1 h. The white solid was filtered. The final product, sodium 2,3-dibromopropane sulfonate, was obtained in a yield of 56.5% (HPLC purity 97.8%).

[0037] Example 2

[0038] In the purification step of the starting material of Example 1, the solvents used for the purification of the sodium allyl sulfonate raw material were water, 95% ethanol solution by volume, methanol, and dichloromethane, respectively. The yield and purity of the corresponding purified sodium allyl sulfonate were shown in Table 1.

[0039] Table 1: Purification effect of different solvents on sodium allyl sulfonate raw material under the same solvent volume

[0040] Solvent selection Water 95% Ethanol 90% Ethanol Methanol Methylene Chloride Purity 91.12％ 85.54％ 89.84％ 84.77％ 88.15％ Yield 45.22％ 95.7％ 92.52％ 93.72％ 95.78％

[0041] In Table 1, 90% ethanol refers to 95% ethanol solution by volume. As shown in Table 1, the solvent used for the purification of the sodium allyl sulfonate raw material was preferably 90% ethanol solution by volume in terms of the overall yield and purity.

[0042] Example 3

[0043] In the synthesis of aqueous solution of sodium 2,3-dibromopropane sulfonate step of Example 1, purified water was added to the purified sodium allyl sulfonate (1.0 eq) in different volumes. The residual amount of the starting material, sodium allyl sulfonate, was shown in Table 2.

[0044] Table 2: Residual amount of starting material under different solvent volumes

[0045] Solvent volume 1 V water 2 V water 3 V water 4 V water Sodium allyl sulfonate residue 3.1％ 7.9％ 14.2％ 21.46％ Yield 56.5％ 44.32％ 40.06％ 37.54％

[0046] From Table 2, in the step of synthesizing the aqueous solution of sodium dibromopropanesulfonate in Example 1, 1V purified water (relative to the volume of the allyl sulfonate raw material) was added to the purified allyl sulfonate (1.0 eq), and the residual rate of allyl sulfonate was the lowest.

[0047] Example 4

[0048] In the step of synthesizing the aqueous solution of sodium dibromopropanesulfonate in Example 1, different solvents (1V, 100 mL) were added to the purified allyl sulfonate (1.0 eq), and finally the yield and purity of sodium dibromopropanesulfonate were shown in Table 3:

[0049] Table 3: Purification effect of different solvents on sodium dibromopropanesulfonate under the same solvent volume

[0050] Solvent selection Water Anhydrous Ethanol 95% Ethanol Purity 97.8％ 89.4％ 93.6％ Yield 78.5％ 89.7％ 87.3％

[0051] From Table 3, it can be seen that water is preferred as the solvent for synthesizing sodium dibromopropanesulfonate.

[0052] Example 5

[0053] In Example 1, if the reaction solution of 2,3-dibromopropanesulfonic acid sodium was not acidified, the yield and purity of the finished product were shown in Table 4:

[0054] Table 4: Difference between acidification and non-acidification of 2,3-dibromopropanesulfonic acid under the same process

[0055]

[0056]

[0057] Example 6

[0058] In Example 1, if sodium bromide is replaced by an equivalent amount of sodium chloride in the step of synthesizing the aqueous solution of sodium dibromopropanesulfonate, a large amount of by-products will be produced; and the proportion of 3-chloro-2-bromopropanesulfonic acid sodium in the final product will reach more than 30%.

[0059] Example 7

[0060] In the step of synthesizing the aqueous solution of sodium dibromopropanesulfonate in Example 1, the internal temperature of the reactant needs to be controlled at 5±3℃ when bromine is added dropwise; if the reaction temperature is at room temperature, a large amount of impurities will be produced in the final reaction, including but not limited to 3-bromoallyl sulfonate, 2-bromopropanesulfonate, 3-bromopropanesulfonate, 2-bromoallyl sulfonate and other genotoxic impurities; too many impurities cannot be purified.

[0061] The above merely describes the preferred embodiments of the present application, and is not used to limit the present application. Any modification, equivalent replacement, improvement, etc. made within the spirit and principle of the present application shall be included in the protection scope of the present application.

Claims

1. A method for preparing 2,3-dibromopropanesulfonic acid, characterized in that: The following steps are involved: Step 1: After mixing the sodium allyl sulfonate raw material and the first solvent, the mixture is heated to reflux and stirred for reaction. After the reaction, the mixture is cooled to below 60° C., filtered, and the filtrate is concentrated and dried to obtain purified sodium allyl sulfonate; Step 2: Add the second solvent and sodium bromide to the purified sodium allyl sulfonate, mix, cool in an ice-water bath to 2-5°C, add bromine dropwise, and control the internal temperature to 5±3°C; after the addition is complete, stir and react at 5±3°C to obtain a 2,3-dibromopropanesulfonic acid sodium reaction solution; Step 3, adding acid solution to the reaction solution of sodium 2,3-dibromopropanesulfonate, stirring and reacting at 20-30° C., and concentrating under reduced pressure until no liquid is distilled off to obtain crude 2,3-dibromopropanesulfonic acid; Step 4, adding a third solvent to the crude 2,3-dibromopropanesulfonic acid, heating to reflux to dissolve and keeping warm with stirring, then cooling to 50°C, keeping warm for crystallization, filtering to obtain a filter cake; adding a fourth solvent to the filter cake, heating to reflux to dissolve and keeping warm with stirring, then cooling to 0-5°C, keeping warm for crystallization, filtering to obtain the 2,3-dibromopropanesulfonic acid; In step 1, the first solvent is a 90% ethanol solution by volume; In step 2, the second solvent is water; the volume ratio of the second solvent to the sodium allyl sulfonate raw material is 1:

1.

2. A method for preparing 2,3-dibromopropanesulfonic acid according to claim 1, characterized in that: In step 1, the volume ratio of the sodium allyl sulfonate raw material to the first solvent is 1:

5.

3. A method for preparing 2,3-dibromopropanesulfonic acid according to claim 1, characterized in that: In step 2, if the added bromine is excessive and the solution turns yellow, sodium bisulfite is added until the yellow color fades, and the mixture is stirred and reacted at 2-15° C. for 30 minutes to obtain a sodium 2,3-dibromopropanesulfonate reaction solution.

4. A method for preparing 2,3-dibromopropanesulfonic acid according to claim 1, characterized in that: In step 2, the molar ratio of the purified sodium allyl sulfonate, sodium bromide, and bromine is 1:0.18:

1.

5. A method for preparing 2,3-dibromopropanesulfonic acid according to claim 1, characterized in that: In step 3, the acid solution used is one or more of hydrochloric acid, sulfuric acid, and nitric acid.

6. A method for preparing 2,3-dibromopropanesulfonic acid according to claim 1, characterized in that: In step 3, the acid used is hydrochloric acid, and the molar ratio of hydrochloric acid to purified sodium allyl sulfonate is 1.1:1; and / or, In step 4, the third solvent and the fourth solvent are both water, and the volume ratio of the third solvent to the sodium allyl sulfonate raw material is 1:0.5; and / or, The volume ratio of the fourth solvent to the sodium allyl sulfonate raw material is 1:0.5.

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