Method for preparing 2, 3-dibromopropanesulfonic acid

Abstract

The invention belongs to the field of medical intermediates, and particularly relates to a method for preparing 2, 3-dibromopropanesulfonic acid, which is characterized in that purified sodium allysulfonate is used as a raw material to prepare the 2, 3-dibromopropanesulfonic acid, and the 2, 3-dibromopropanesulfonic acid is obtained by optimizing the molar ratio of sodium allysulfonate, bromine and sodium bromide, the reaction temperature, the solvent volume, the refining temperature, the refining solvent volume and other parameters. The purity of the 2, 3-dibromopropanesulfonic acid is obviously improved; and compared with a reaction liquid, the solid powder is easier to store. Meanwhile, impurities are controllable, and remarkable help is provided for subsequent synthesis of high-purity sodium 2, 3-dimercaptopropanesulfonate. Compared with an existing method, the method has the advantages of relatively low production cost, high safety, good stability and repeatability, capability of being amplified, simple and convenient post-treatment process and controllable impurities, and has a very good application prospect.

Description

Technical Field

[0001] The invention belongs to the technical field of pharmaceutical intermediate preparation, and specifically relates to a method for preparing 2,3-dibromopropanesulfonic acid. Background Art

[0002] 2,3-Dibromopropane-1-sulfonic acid is an important pharmaceutical intermediate of sodium 2,3-dimercaptopropane sulfonate. Its synthesis method is of great significance for the industrial synthesis and synthesis purity of sodium 2,3-dimercaptopropane sulfonate.

[0003] The current production process uses sodium allyl sulfonate or epichlorohydrin as a raw material to dissolve in water, and then adds bromine dropwise at room temperature to obtain an aqueous solution of sodium dibromopropane sulfonate. This method only obtains a reaction solution without subsequent treatment operations, and a large amount of uncontrollable impurities are generated, which has a great impact on the purity of the subsequent synthesis of sodium 2,3-dimercaptopropane sulfonate.

[0004] The preparation method reported in the literature is as follows: Reference document China Invention Patent Publication No.: CN106478476B discloses a method for preparing sodium dithiopropanesulfonate, which is to dissolve sodium allyl sulfonate in alkali solution, add bromine dropwise at room temperature, and obtain an aqueous solution of sodium dibromopropanesulfonate. However, this method has the following negative shortcomings: during the reaction, a large amount of sodium 2-hydroxy-3-bromo-propanesulfonate or sodium 2-bromo-3-hydroxy-propanesulfonate by-products is easily generated, the content of sodium dibromopropanesulfonate in the reaction solution is about 70%, and the generated hydrobromic acid makes the reaction solution strongly acidic, with a pH value of less than 0.5; the entire reaction system is not suitable for the production and preparation of pharmaceutical intermediates.

[0005] In addition, the inventors studied the commercially available sodium allyl sulfonate raw materials and found that most of them have very low purity. The sodium allyl sulfonate marked as having a purity of 98% has an actual purity of about 85% after high performance liquid chromatography analysis. If this type of sodium allyl sulfonate raw material is not purified, it will significantly affect the yield and purity of subsequent pharmaceutical intermediates.

[0006] Based on this, the present invention is proposed. Summary of the invention

[0007] The object of the present invention is to provide a method for preparing 2,3-dibromopropanesulfonic acid to solve the above-mentioned problems.

[0008] A method for preparing 2,3-dibromopropanesulfonic acid comprises the following steps:

[0009] Step 1, after mixing the sodium allyl sulfonate raw material and the first solvent, heating to reflux state, stirring and keeping warm for reaction, cooling to below 60° C. after the reaction, filtering, concentrating and drying the filtrate to obtain purified sodium allyl sulfonate;

[0010] Step 2, add the second solvent and sodium bromide to the purified sodium allyl sulfonate, mix and 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, stir and react at 5±3°C to obtain a 2,3-dibromopropane sulfonate sodium reaction solution;

[0011] Step 3, adding acid solution to the sodium 2,3-dibromopropanesulfonate reaction solution, stirring and reacting at 20-30° C., and concentrating under reduced pressure until no liquid is evaporated to obtain a crude 2,3-dibromopropanesulfonic acid product;

[0012] 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 with suction 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 with suction to obtain the 2,3-dibromopropanesulfonic acid.

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

[0014] As a further improvement, in step 1, the first solvent is an ethanol solution with a volume fraction of 90%.

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

[0016] As a further improvement, in step 2, if the bromine added is excessive and the solution is yellow, sodium bisulfite is added until the yellow color fades, and the mixture is stirred and reacted at 2 to 15° C. for 30 minutes to obtain a sodium 2,3-dibromopropanesulfonate reaction solution.

[0017] As a further improvement, in step 2, the second solvent is water.

[0018] As 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] As a further improvement, in step 2, the volume ratio of the second solvent to the sodium allyl sulfonate raw material is 1:1.

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

[0021] As a further improvement, in step 3, the acid solution used is hydrochloric acid, and the molar ratio of hydrochloric acid to 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 adding bromine dropwise in the present invention, if the volume of the second solvent is too large, the final yield of sodium 2,3-dibromopropanesulfonate will be low.

[0027] The 2,3-dibromopropanesulfonic acid obtained by the present invention is used as a key intermediate of the sodium 2,3-dimercaptopropanesulfonate drug and as a starting material in the reaction. The maximum single impurity of the final product prepared by the present invention can be controlled within 1%, and the total impurity is controlled within 2.5%, which is conducive to impurity removal in subsequent reaction steps and has low impurity removal difficulty.

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

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

[0030] 2. Compared with the existing methods, the present invention has relatively low production cost, high safety, good stability and repeatability, can be scaled up, simple post-processing process, controllable impurities, and has good application prospects. DETAILED DESCRIPTION

[0031] The present invention is further described in detail below through specific examples.

[0032] Example 1

[0033] Purification of starting materials: Add 90% ethanol solution (5V, 500mL) by volume to sodium allyl sulfonate raw material (1V, 100mL) at room temperature, heat to reflux, stir for 1h, cool to 60°C, filter, concentrate and dry the filtrate to obtain purified sodium allyl sulfonate.

[0034] Synthesis of aqueous solution of sodium dibromopropanesulfonate: Add purified water (1V, 100mL) to purified sodium allylsulfonate (1.0eq), start stirring, and add sodium bromide (0.18eq). Cool to 2-5℃ in an ice-water bath, add bromine (1.0eq) dropwise, and control the internal temperature to 5±3℃; after the addition, stir at 5±3℃ for 1.5h (if there is an excess of bromine, the solution will be yellow, and a small amount of sodium bisulfite can be added at this time until the yellow color fades, and stir at 2-15℃ for 30min) to obtain a sodium 2,3-dibromopropanesulfonate reaction solution.

[0035] Acidification of reaction solution: Add 1.1 eq of hydrochloric acid to the sodium 2,3-dibromopropanesulfonate reaction solution, keep warm at 20-30°C and stir for 14 h; concentrate under reduced pressure until no liquid is evaporated to obtain crude 2,3-dibromopropanesulfonic acid.

[0036] Purification of crude 2,3-dibromopropanesulfonic acid: Add purified water (0.5V, 50mL) to the crude 2,3-dibromopropanesulfonic acid, heat to reflux to dissolve, keep warm and stir for 30min, cool to 50°C, keep warm and crystallize for 1h, filter and obtain a filter cake. The filter cake is transferred to a reaction bottle, purified water (0.5V, 50mL) is added, heat to reflux to dissolve, keep warm and stir for 30min, then cool to 0-5°C, keep warm and crystallize for 1h, filter and obtain a white solid, the final product 2,3-dibromopropanesulfonic acid, with a yield of 56.5% (HPLC content 97.8%).

[0037] Example 2

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

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

[0040] Solvent selection water 95% ethanol 90% ethanol Methanol Dichloromethane 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 a 95% ethanol solution by volume. As can be seen from Table 1, the solvent used to purify the sodium allyl sulfonate raw material is preferably a 90% ethanol solution by volume in terms of comprehensive yield and purity.

[0042] Example 3

[0043] In the step of synthesizing the aqueous solution of sodium dibromopropane sulfonate in Example 1, different volumes of purified water were added to the purified sodium allyl sulfonate (1.0 eq). The residual results of the starting material sodium allyl sulfonate are shown in Table 2:

[0044] Table 2: Residue of starting materials at different solvent volumes

[0045] Solvent volume 1V Water 2V Water 3V Water 4V Water Sodium Allyl Sulfonate Residue 3.1％ 7.9％ 14.2％ 21.46％ Yield 56.5％ 44.32％ 40.06％ 37.54％

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

[0047] Example 4

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

[0049] Table 3: Purification effect of different solvents on sodium dibromopropanesulfonate at 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] As can be seen from Table 3, water is preferably used as the solvent for synthesizing sodium dibromopropanesulfonate.

[0052] Example 5

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

[0054] Table 4: Differences between 2,3-dibromopropanesulfonic acid with and without acidification under the same process

[0055]

[0056]

[0057] Example 6

[0058] In Example 1, if sodium bromide is replaced with 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; in the final product, the proportion of sodium 3-chloro-2-bromopropanesulfonate will reach more than 30%.

[0059] Example 7

[0060] In the step of synthesizing the aqueous solution of sodium dibromopropane sulfonate in Example 1, the internal temperature of the reactants needs to be controlled at 5±3°C when bromine is added dropwise; if the reaction temperature is at room temperature, the final reaction will produce a large amount of impurities, including but not limited to sodium 3-bromoallyl sulfonate, sodium 2-bromopropane sulfonate, sodium 3-bromopropane sulfonate, sodium 2-bromoallyl sulfonate and other genotoxic impurities; the impurity content is too high and purification is no longer possible.

[0061] The above are only preferred embodiments of the present invention and are not intended to limit the present invention. For those skilled in the art, the present invention may have various modifications and variations. Any modification, equivalent replacement, improvement, etc. made within the spirit and principle of the present invention shall be included in the protection scope of the present invention.

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, heating to reflux state, stirring and keeping warm for reaction, cooling to below 60° C. after the reaction, filtering, concentrating and drying the filtrate to obtain purified sodium allyl sulfonate; Step 2, add the second solvent and sodium bromide to the purified sodium allyl sulfonate, mix and 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, stir and react at 5±3°C to obtain a 2,3-dibromopropane sulfonate sodium reaction solution; Step 3, adding acid solution to the sodium 2,3-dibromopropanesulfonate reaction solution, stirring and reacting at 20-30° C., and concentrating under reduced pressure until no liquid is evaporated to obtain a crude 2,3-dibromopropanesulfonic acid product; 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 with suction 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 with suction to obtain the 2,3-dibromopropanesulfonic acid.

2. A method for preparing 2,3-dibromopropanesulfonic acid according to claim 1, characterized in that: In step 1, the first solvent is one or more of water, methanol, and ethanol.

3. A method for preparing 2,3-dibromopropanesulfonic acid according to claim 1, characterized in that: In step 1, the first solvent is an ethanol solution with a volume fraction of 90%.

4. 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.

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

6. A method for preparing 2,3-dibromopropanesulfonic acid according to claim 1, characterized in that: In step 2, the second solvent is water.

7. 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.

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

1.

9. 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.

10. A method for preparing 2,3-dibromopropanesulfonic acid according to claim 1, characterized in that: In step 3, the acid solution 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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