A method for synthesizing sulfacetamide sodium

Abstract

This invention discloses a method for synthesizing sodium sulfacetamide. The method includes: (1) mixing sulfanilamide, a base, and a solvent, adding acetic anhydride to carry out an acetylation reaction, adjusting the pH to 4-5 after the reaction, cooling to crystallize, filtering and drying to obtain a sulfacetamide intermediate; (2) carrying out a salt-forming reaction of sulfacetamide, water, and sodium hydroxide solution, adding an organic solvent to crystallize, and obtaining sodium sulfacetamide. This invention uses water as the preferred reaction solvent and triethylamine as the base, and adopts a one-time addition of acetic anhydride to obtain sulfacetamide in high yield under mild conditions, and then purifies it by salt formation to obtain sodium sulfacetamide. This method is simple to operate, has mild reaction conditions, high product yield and purity, low production cost, and is environmentally friendly. It solves the problems of cumbersome operation and low yield in the prior art, and is easy to promote and apply industrially.

Description

Technical Field

[0001] This invention belongs to the field of chemical synthesis technology, specifically relating to a method for synthesizing sodium sulfacetamide. Background Technology

[0002] Sodium sulfacetamide is a representative derivative of sulfonamide drugs, widely used in the pharmaceutical, agricultural, and industrial fields due to its highly effective antibacterial activity, low toxicity, and good water solubility. In the pharmaceutical field, as a broad-spectrum antibacterial agent, it is usually used in the form of eye drops to treat eye infections such as bacterial conjunctivitis, trachoma, and blepharitis. In the agricultural field, it is used as a veterinary drug to prevent and treat bacterial diseases in livestock and poultry, and has the potential to be developed into an antibacterial agent for specific crops. In the industrial field, its related chemical structure is also used as a synthetic intermediate for fine chemicals.

[0003] With the increasing market demand and quality requirements for sodium sulfacetamide, developing a more optimized synthesis method is imperative. In existing technologies, the synthesis of sodium sulfacetamide generally involves an acetylation reaction between sulfanilamide and acetic anhydride to produce crude sulfacetamide, followed by the addition of hydrochloric acid to adjust the pH and precipitate sulfacetamide, and finally, a reaction with sodium hydroxide to prepare sodium sulfacetamide. This process suffers from low reaction conversion rates and numerous byproducts. Excess unreacted sulfanilamide after the reaction needs to be filtered out, and the pH of the mother liquor needs to be adjusted. The preparation process is cumbersome, which is detrimental to both product quality improvement and environmental protection.

[0004] Existing literature reports optimization of the acetylation step by adjusting reaction temperature, reaction time, and adding organic bases (4-dimethylaminopyridine, pyridine), but the yield of sulfacetamide sodium has not been significantly improved. Furthermore, these methods suffer from complex operation steps, the need for segmented addition of acetic anhydride, unstable reaction yields, cumbersome processes, and high production costs, making them difficult to promote and apply in the industrial field. Therefore, developing a low-cost, high-yield, and high-purity method for synthesizing sulfacetamide sodium based on existing technologies meets market demands, has significant practical value, and can provide important technical support for the industrial production of sulfacetamide sodium. Summary of the Invention

[0005] The purpose of this invention is to overcome the shortcomings of existing technologies and provide a method for synthesizing sodium sulfacetamide. This method is simple, operates under mild conditions, requires minimal equipment, and has good atom economy. It can obtain the target product in high yield and high purity, making it suitable for industrial production.

[0006] To achieve the above objectives, the technical solution adopted by the present invention is as follows: A method for synthesizing sodium sulfacetamide includes the following steps: S1: Sulfonamide, base and reaction solvent are added to the reaction vessel in sequence. After heating to the reaction temperature and stirring evenly, acetic anhydride is added to carry out the acetylation reaction. After the reaction is completed by keeping the temperature and stirring, the pH of the reaction solution is adjusted to 4-5. The mixture is cooled in an ice-water bath and stirred to crystallize. The filter cake is collected by suction filtration and dried to obtain sulfacetamide. The base is an organic or inorganic base, preferably any one of triethylamine, potassium tert-butoxide, sodium tert-butoxide, 1,8-diazabicyclo[5.4.0]undec-7-ene, sodium bicarbonate, sodium carbonate, potassium bicarbonate, and potassium carbonate, with triethylamine being the most preferred.

[0007] The solvent is water or an organic solvent, preferably any one of methanol, ethanol, water, N,N-dimethylformamide, acetonitrile, and ethyl acetate, with water being the most preferred.

[0008] The amount of alkali used is 1.1-1.4 times the molar amount of sulfonamide, most preferably 1.2 times. The amount of acetic anhydride used is 1.0 to 4.0 times the molar amount of sulfonamide, most preferably 3.0 times.

[0009] The acetylation reaction temperature is 30℃-60℃, with a maximum of 60℃; the reaction time is 30 minutes-120 minutes, with a maximum of 120 minutes. The acetic anhydride is added all at once.

[0010] S2: Add the sulfacetamide and sodium hydroxide solution obtained in step S1 and water to a reaction vessel, stir at 40-60℃ (preferably 50℃) until the solid is completely dissolved, add anhydrous ethanol and cool in an ice-water bath to precipitate sodium sulfacetamide crystals, filter, wash and dry to obtain sodium sulfacetamide.

[0011] The sodium hydroxide solution is a 10wt%-20wt% aqueous sodium hydroxide solution or a 5wt%-10wt% sodium hydroxide ethanol solution, preferably a 10wt% aqueous sodium hydroxide solution.

[0012] The reaction synthesis route is as follows (sulfonamide is converted to sulfacetamide I via S1, and then to sulfacetamide sodium II via S2): Compared with the prior art, the beneficial effects of the present invention are as follows: 1. This invention optimizes the reaction system of sulfa acetylation. By using water as the reaction solvent and triethylamine as the base, highly selective acetylation of sulfa is achieved, and sulfacetamide can be obtained in one step with a high yield. The yield of sulfacetamide can reach 99%, and the final yield of sodium sulfacetamide can reach 97%, which is much higher than the yield of existing synthesis methods. 2. The reaction conditions of this invention are mild, requiring no special reaction equipment. Acetic anhydride can be added in one go without the need for segmented dropwise addition. Unreacted raw materials do not need to be filtered and separated in advance. High-purity sulfacetamide can be obtained by one-step crystallization simply by adjusting the pH. The post-processing operation is simple, greatly simplifying the production process. 3. The reagents used in this invention are green and low in corrosiveness, causing little damage to equipment, resulting in less waste emissions, high atom utilization, and low production costs. They combine economic and environmental benefits and are more suitable for large-scale industrial production. Attached Figure Description

[0013] Figure 1 The image shows the 1H NMR spectrum of sulfacetamide obtained in Example 9.

[0014] Figure 2 The image shows the carbon NMR spectrum (¹³C NMR) of sulfacetamide obtained in Example 9.

[0015] Figure 3 The image shows the 1H NMR spectrum of sodium sulfacetamide obtained in Example 9. Detailed Implementation

[0016] The present invention will be further described in detail below with reference to the embodiments, but the scope of protection of the present invention is not limited thereto. Unless otherwise specified, the reagents used in the following embodiments can be purchased commercially.

[0017] Example 1: Synthesis of sulfacetyl (investigating different solvents) Sulfonamide (1.00 g, 5.8 mmol), triethylamine (0.98 mL, 7.0 mmol), and 3 mL of different reaction solvents (methanol, ethanol, water, N,N-dimethylformamide, acetonitrile, ethyl acetate) were added sequentially to a reaction tube. The mixture was stirred at 60 °C for 15 minutes, and then acetic anhydride (1.65 mL, 17.4 mmol) was added all at once. The reaction was continued at 60 °C for 2 hours with stirring. After the reaction was completed, the pH of the reaction solution was adjusted to 4-5 with 1 mol / L dilute hydrochloric acid. The solution was then transferred to an ice-water bath for cooling and stirring for 30 minutes. The mixture was filtered, and the filter cake was dried in an 80 °C oven to obtain sulfacetamide.

[0018] The solvents used and their corresponding yields were: methanol (29%), ethanol (44%), water (99%), N,N-dimethylformamide (76%), acetonitrile (70%), and ethyl acetate (71%). The results showed that water was the highest solvent yield. The product obtained in water was purified by alcohol crystallization to give a white solid with a yield of 99%.

[0019] Example 2: Synthesis of sulfacetyl (investigating different bases) Sulfonamide (1.00 g, 5.8 mmol), water (3 mL), and different bases (7.0 mmol) were added sequentially to the reaction tube. The mixture was stirred at 60 °C for 15 minutes, and then acetic anhydride (1.65 mL, 17.4 mmol) was added all at once. The reaction was continued at 60 °C for 2 hours with stirring. Subsequent treatment was the same as in Example 1.

[0020] The bases used and their corresponding yields were as follows: potassium tert-butoxide (63%), sodium tert-butoxide (77%), sodium bicarbonate (71%), sodium carbonate (71%), potassium bicarbonate (68%), potassium carbonate (66%), 1,8-diazabicyclo[5.4.0]undec-7-ene (79%), and triethylamine (99%). The results showed that triethylamine was the most effective.

[0021] Example 3: Synthesis of sulfacetamide (investigating reaction temperature) Sulfonamide (1.00 g, 5.8 mmol), water (3 mL), and triethylamine (0.98 mL, 7.0 mmol) were added sequentially to the reaction tube. The mixture was stirred for 15 minutes at different temperatures, and then acetic anhydride (1.65 mL, 17.4 mmol) was added all at once. The reaction was continued with stirring for 2 hours at the corresponding temperature. Subsequent treatment was the same as in Example 1. The reaction temperatures and corresponding yields were: 30 °C (95%), 40 °C (96%), 50 °C (97%), and 60 °C (99%). The results showed that 60 °C was the optimal reaction temperature.

[0022] Example 4: Synthesis of sulfacetamide (investigating reaction time) Sulfonamide (1.00 g, 5.8 mmol), water (3 mL), and triethylamine (0.98 mL, 7.0 mmol) were added sequentially to the reaction tube. The mixture was stirred at 60 °C for 15 minutes, and then acetic anhydride (1.65 mL, 17.4 mmol) was added all at once. The reaction was continued at 60 °C for different time periods. Subsequent treatment was the same as in Example 1. The reaction times and corresponding yields were: 0.5 h (75%), 1 h (79%), 1.5 h (89%), and 2 h (99%). The results showed that the highest yield was obtained after a reaction time of 2 hours.

[0023] Example 5: Synthesis of sulfacetyl (investigating the amount of alkali used) Sulfonamide (1.00 g, 5.8 mmol), water (3 mL), and different equivalents of triethylamine were added sequentially to the reaction tube. The mixture was stirred at 60 °C for 15 minutes, and then acetic anhydride (1.65 mL, 3.0 mmol) was added all at once. The reaction was continued at 60 °C with stirring for 2 hours. Subsequent treatment was the same as in Example 1. The triethylamine equivalents and corresponding yields were 1.1 eq. (83%), 1.2 eq. (99%), 1.3 eq. (94%), and 1.4 eq. (88%), respectively. The results indicate that the optimal amount of triethylamine was 1.2 eq.

[0024] Example 6: Synthesis of sulfacetyl (investigating the amount of acetic anhydride used) Sulfonamide (1.00 g, 5.8 mmol), water (3 mL), and triethylamine (0.98 mL, 1.2 mmol) were added sequentially to the reaction tube. The mixture was stirred at 60 °C for 15 minutes, and then different equivalents of acetic anhydride were added all at once. The reaction was continued at 60 °C with stirring for 2 hours. Subsequent treatment was the same as in Example 1. The acetic anhydride equivalents and corresponding yields were 1.0 eq. (33%), 2.0 eq. (57%), 3.0 eq. (99%), and 4.0 eq. (99%), respectively. The results showed that the highest yield was achieved with an acetic anhydride amount of 3.0 eq.

[0025] Example 7: Synthesis of sodium sulfacetamide (solvent investigation) Sulfamethoxam (0.5 g, 2.3 mmol) prepared in Example 1 (using water as solvent) was added to a reaction tube along with 2.3 mL of a 10% sodium hydroxide aqueous solution. Different reaction solvents (4 mL) were then added, and the mixture was stirred at 50 °C until the solid was completely dissolved. Anhydrous ethanol (10 mL) was then added, and the mixture was cooled in an ice-water bath. After sodium sulfacetamide crystals had completely precipitated, the mixture was filtered, washed with a small amount of ice-cold ethanol, and dried to obtain a white solid. The reaction solvents and their corresponding yields were: methanol (27%), ethanol (14%), and water (97%). This shows that water yielded the highest amount of sodium sulfacetamide when used as the reaction solvent.

[0026] Example 8: Synthesis of sodium sulfacetamide (investigating the concentration of alkaline solution) The sulfacetyl (0.5 g, 2.3 mmol) prepared in Example 1 (using water as a solvent) was added to a reaction tube along with water (4 mL). Different concentrations and forms of alkaline solutions (1.1 mmol of sodium hydroxide) were then added, and the mixture was stirred at 50 °C until the solid was completely dissolved. Anhydrous ethanol (5 mL) was then added, and the mixture was cooled in an ice-water bath to crystallize. Subsequent processing was the same as in Example 7. The alkalis used and their corresponding yields were: solid sodium hydroxide (0.12 g, 22%), 5% sodium hydroxide ethanol solution (0.26 g, 48%), 10% sodium hydroxide aqueous solution (0.52 g, 97%), and 20% sodium hydroxide aqueous solution (0.52 g, 97%). It is evident that a high yield of sodium sulfacetyl sodium can be obtained with a sodium hydroxide aqueous solution of 10% or higher. Considering both cost and yield, a 10% sodium hydroxide aqueous solution is preferred.

[0027] Example 9: Preferred process for synthesizing sodium sulfacetamide according to the present invention S1: Add 1.0 g sulfanilamide, 0.98 mL triethylamine, and 3.0 mL water sequentially to a reaction flask. Stir at 60 °C for 10 minutes, then add 1.65 mL acetic anhydride all at once. Continue stirring at 60 °C for 2 hours. Adjust the pH to 4-5 by adding 1 mol / L hydrochloric acid dropwise. Cool in an ice-water bath and stir for 30 minutes. Filter and dry the filter cake in an 80 °C oven to obtain 1.2 g sulfacetamide, with a yield of 99% and an HPLC purity of 99.2%. The structure of the obtained sulfacetyl was characterized. Figure 1 , 2 The results are as follows: 1 H NMR (500 MHz, CDCl3) δ 9.15 (s, 1H), 8.08 (d, J = 10, 2H), 7.68 (t, J = 5 Hz, 1H), 7.59 (t, J = 5 Hz, 2H), 2.10 (s, 3H); 13 C NMR (126 MHz, CDCl3) δ 168.5, 138.5, 134.1, 129.1, 128.3, 23.6. S2: Add 0.5 g of sulfacetamide to a reaction flask, add 2.3 mL of 10 wt% sodium hydroxide aqueous solution and 4.0 mL of water, stir at 50 °C until the solid is completely dissolved, add 5.0 mL of anhydrous ethanol, cool in an ice-water bath to crystallize, after the crystals have completely precipitated, filter, wash the filter cake with a small amount of anhydrous ethanol, and dry under vacuum to obtain 0.52 g of white sodium sulfacetamide crystals, with a yield of 97% and an HPLC purity of 99.5%.

[0028] The structure of the obtained sodium sulfacetamide was characterized. Figure 3 The results are as follows: 1 H NMR (500 MHz, DMSO- d6 ) δ 7.76 – 7.72 (m, 4H), 7.23 (s, 1H), 2.08 (s, 3H), the structure is correct.

Claims

1. A method for synthesizing sodium sulfacetamide, characterized in that, Includes the following steps: (1) Mix sulfonamide, base and solvent, add acetic anhydride to carry out acetylation reaction, adjust the pH of the reaction system to 4-5 after the reaction is completed, cool, crystallize, filter and dry to obtain sulfacetamide; (2) The sulfacetyl and sodium hydroxide solution obtained in step (1) is mixed with water to carry out a salt formation reaction. After the reaction, an organic solvent is added to crystallize and obtain sodium sulfacetyl.

2. The synthesis method according to claim 1, characterized in that, In step (1), the alkali is an organic alkali or an inorganic alkali; the solvent is water or an organic solvent.

3. The synthesis method according to claim 2, characterized in that, In step (1), the base is any one of triethylamine, potassium tert-butoxide, sodium tert-butoxide, 1,8-diazabicyclo[5.4.0]undec-7-ene, sodium bicarbonate, sodium carbonate, potassium bicarbonate, and potassium carbonate; the solvent is any one of water, methanol, ethanol, N,N-dimethylformamide, acetonitrile, and ethyl acetate.

4. The synthesis method according to claim 3, characterized in that, In step (1), the base is triethylamine and the solvent is water.

5. The synthesis method according to any one of claims 1 to 4, characterized in that, In step (1), the amount of alkali used is 1.1-1.4 times the molar amount of sulfonamide; the amount of acetic anhydride used is 1.0-4.0 times the molar amount of sulfonamide.

6. The synthesis method according to claim 5, characterized in that, In step (1), the amount of alkali used is 1.2 times the molar amount of sulfonamide; the amount of acetic anhydride used is 3.0 times the molar amount of sulfonamide.

7. The synthesis method according to any one of claims 1 to 4, characterized in that, In step (1), the temperature of the acetylation reaction is 30℃-60℃ and the reaction time is 30-120 minutes.

8. The synthesis method according to claim 7, characterized in that, In step (1), the acetylation reaction is carried out at a temperature of 60°C for 120 minutes; and the acetic anhydride is added in one step.

9. The synthesis method according to claim 1, characterized in that, In step (2), the sodium hydroxide solution is a 10wt%-20wt% sodium hydroxide aqueous solution or a 5wt%-10wt% sodium hydroxide ethanol solution; the temperature of the salt formation reaction is 40-60℃; and the organic solvent added during crystallization is anhydrous ethanol.

10. The synthesis method according to claim 9, characterized in that, In step (2), the sodium hydroxide solution is a 10 wt% sodium hydroxide aqueous solution; the temperature of the salt formation reaction is 50 °C.

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