Preparation method of sulfaguanidine

Abstract

The invention belongs to the technical field of organic synthesis, and particularly relates to a preparation method of sulfaguanidine. The invention provides a preparation method of sulfaguanidine, which comprises the following steps: mixing p-acetamidobenzene sulfonyl chloride, guanidine salt, strong base and ketone solvent for the first time, and then carrying out condensation reaction to obtain sulfaguanidine; mixing acetylsulfaguanidine with water for the second time, then adjusting the pH value to 8-9, and adding amide hydrolase for hydrolysis to obtain sulfaguanidine. According to the preparation method provided by the invention, a biological enzyme method is introduced for hydrolysis, so that the hydrolysis efficiency is high, the product conversion rate is high, the enzyme can be repeatedly recycled, the mother liquor is simple in component, can be directly recycled and reused, is simple to treat, and does not cause pressure to environmental protection; the raw materials are cheap and easy to obtain, the preparation cost is low, the reaction conditions are mild, the operation is simple and convenient, and industrial safe production is facilitated; the sulfaguanidine prepared by the preparation method provided by the invention has relatively high purity and relatively high yield.

Description

TECHNICAL FIELD

[0001] The application belongs to the technical field of organic synthesis, and particularly relates to a preparation method of sulfaguanidine. BACKGROUND

[0002] Sulfaguanidine, also known as sulfaguanidine, is a kind of sulfonamides, belongs to a kind of low-grade sulfonamides, can inhibit bacteria, is a white needle-like crystalline powder, odorless, bitter, gradually changes color when exposed to light, is a very important fine chemical intermediate raw material; mainly used for producing sulfadiazine, sulfamethazine and other high-grade sulfonamides.

[0003] At present, there are many reports on the synthesis process of sulfaguanidine, which is mainly prepared by condensation reaction of industrial sulfonamide, guanidine nitrate, sodium carbonate, and the preparation process needs to be reacted at high temperature of 150-170 DEG C, and a large amount of ammonia, carbon dioxide and water vapor will be generated in the reaction process, which has serious safety hazards in production. SUMMARY

[0004] Therefore, the application provides a preparation method of sulfaguanidine, and the preparation method has mild reaction conditions, simple operation and high industrial production safety.

[0005] In order to solve the above technical problems, the application provides a preparation method of sulfaguanidine, which comprises the following steps: The p-acetamidobenzenesulfonyl chloride, guanidine salt, strong base and ketone solvent are first mixed to carry out condensation reaction, so as to obtain acetylsulfaguanidine; The acetylsulfaguanidine and water are secondly mixed to adjust the pH value to 8-9, and then the amide hydrolase is added to carry out hydrolysis, so as to obtain sulfaguanidine.

[0006] Preferably, the first mixing comprises the following steps: The guanidine salt, strong base and ketone solvent are mixed, and then cooled to 5-15 DEG C, and the p-acetamidobenzenesulfonyl chloride is added in batches.

[0007] Preferably, the guanidine salt comprises guanidine nitrate or guanidine hydrochloride; The strong base comprises a strong base solution, and the strong base solution comprises a sodium hydroxide solution or a potassium hydroxide solution; The ketone solvent comprises acetone, methyl ethyl ketone or 2-pentanone.

[0008] Preferably, the mass concentration of the strong base solution is 28-50%; The mass ratio of the guanidine salt and the p-acetamidobenzenesulfonyl chloride is 1:1.8-2.8; The mass ratio of the guanidine salt and the ketone solvent is 1:9-15.5; The mass ratio of the guanidine salt and the strong base solution is 1:1.1-1.9.

[0009] Preferably, the condensation reaction temperature is 20-30℃, and the time is 3-4h.

[0010] Preferably, the pH value adjusting agent includes potassium hydroxide, lithium hydroxide or sodium hydroxide. The amide hydrolase includes amide hydrolase SJ0018E1, amide hydrolase SJ0018E3 or amide hydrolase SJ0018E7.

[0011] Preferably, the mass ratio of acetylsulfaguanidine to water in the second mixing system is 1:10-35. The amide hydrolase is added in an amount of 80-300U / g of substrate.

[0012] Preferably, the hydrolysis temperature is 20-35℃, and the time is 3-4h.

[0013] Preferably, after the hydrolysis, the following steps are further included: the hydrolysis product and water are third mixed and then refluxed, activated carbon is added to the system after the refluxing for decolorization, and then filtration is performed, the filtrate obtained by the filtration is crystallized, and the sulfaguanidine is obtained.

[0014] Preferably, the mass ratio of the hydrolysis product to water in the third mixing system is 1:8.5-25. The mass ratio of the hydrolysis product to activated carbon is 1:0.01-0.05. The decolorization temperature is 90-105℃, and the time is 28-32min.

[0015] The present application provides a preparation method of sulfaguanidine, including the following steps: acetylaminobenzenesulfonyl chloride, guanidine salt, strong base and ketone solvent are first mixed and then subjected to condensation reaction to obtain acetylsulfaguanidine; the acetylsulfaguanidine and water are second mixed, the pH value is adjusted to 8-9, amide hydrolase is added for hydrolysis, and sulfaguanidine is obtained. The preparation method provided by the present application introduces biological enzyme hydrolysis, has high hydrolysis efficiency and high product conversion rate, the enzyme can be repeatedly used for multiple cycles, the mother liquor water composition is simple and can be directly recycled, and the treatment is simple and does not cause pressure on environmental protection; in the present application, raw materials are cheap and easy to obtain, the preparation cost is low, the reaction condition is mild, the operation is simple, and the industrialized safe production is facilitated; the sulfaguanidine prepared according to the preparation method provided by the present application has high purity and high yield. BRIEF DESCRIPTION OF DRAWINGS

[0016] Figure 1 A flow chart for preparing high-purity sulfaguanidine by taking acetone as a solvent and taking guanidine hydrochloride as a guanidine salt; Figure 2 The H NMR spectrum of acetylsulfaguanidine prepared in Example 1; 1 H NMR spectrum; Figure 3 The mass spectrum of acetylsulfaguanidine prepared in Example 1 is shown in Figure 1. Figure 4 The liquid chromatogram of acetylsulfaguanidine prepared in Example 1 is shown in Figure 2. Figure 5 The liquid chromatogram of acetylsulfaguanidine prepared in Example 1 is shown in Figure 2. Figure 6 The infrared spectrum of acetylsulfaguanidine prepared in Example 1 and sulfaguanidine standard is shown in Figure 3. DETAILED DESCRIPTION

[0017] The present application provides a preparation method of sulfaguanidine, comprising the following steps: The acetylsulfaguanidine is obtained by condensation reaction of p-acetamidobenzenesulfonyl chloride, guanidine salt, strong base and ketone solvent. The sulfaguanidine is obtained by hydrolysis of acetylsulfaguanidine and water after adjusting pH value to 8-9 and adding amidohydrolase.

[0018] The present application obtains acetylsulfaguanidine by condensation reaction of p-acetamidobenzenesulfonyl chloride, guanidine salt, strong base and ketone solvent. As a specific embodiment of the present application, the first mixing can comprise the following steps: mixing guanidine salt, strong base and ketone solvent, and then cooling to 5-15℃, and then adding p-acetamidobenzenesulfonyl chloride (ASC) in batches. As a specific embodiment of the present application, the guanidine salt can comprise guanidine nitrate or guanidine hydrochloride; the strong base can comprise strong base solution, which can comprise sodium hydroxide solution or potassium hydroxide solution; the ketone solvent can comprise acetone, methyl ethyl ketone or 2-pentanone; the mass concentration of the strong base solution can be 28-50%, and can also be 30-40%; the mass ratio of the guanidine salt and p-acetamidobenzenesulfonyl chloride can be 1:1.8-2.8, and can specifically be 1:2, 1:2.2, 1:2.4 or 1:2.6; the mass ratio of the guanidine salt and ketone solvent can be 1:9-15.5, and can specifically be 1:10, 1:11, 1:13 or 1:15; the mass ratio of the guanidine salt and strong base solution can be 1:1.1-1.9, and can specifically be 1:1.5, 1:1.7 or 1:1.8. In the present application, the mixing of guanidine salt, strong base and ketone solvent can be carried out at room temperature, and the temperature of the room temperature can be 20-35℃, and can also be 25-30℃; the present application can cool the mixed system to 5-15℃, or 10-13℃, and then add p-acetamidobenzenesulfonyl chloride in batches. The present application does not have special limitation on the number of times of adding p-acetamidobenzenesulfonyl chloride in batches, as long as the temperature of the mixed system can be maintained; there is slight heat release during the addition of p-acetamidobenzenesulfonyl chloride, and the addition in batches is beneficial to temperature control, so as to avoid the increase of the temperature of the mixed system.

[0019] As a specific embodiment of the present application, the temperature of the condensation reaction can be 20-30 DEG C, and can be specifically 22 DEG C, 25 DEG C or 28 DEG C; the time of the condensation reaction can be 3-4 h, and can be specifically 3.5 h.

[0020] As a specific embodiment of the present application, the condensation reaction can further comprise distilling the system after the condensation reaction to obtain recovered ketone solvent; adding water to the system after the distillation to perform beating, filtering and drying to obtain the acetosulfoneguanidine. The present application does not have special requirements for the distillation, and the conventional method in the art can be used. As a specific embodiment of the present application, the temperature of the beating can be 50-60 DEG C, and can be specifically 53-55 DEG C; the time of the beating can be 1.8-2.2 h, and can be specifically 2 h. The present application does not have special limitations for the filtering and drying, and the conventional method in the art can be used. The present application removes the inorganic salt impurities in the system by the beating.

[0021] In the present application, the structural formula of the acetosulfoneguanidine is .

[0022] The present application uses ketone solvent as the medium for the condensation reaction, and the reaction condition is mild. The ketone solvent can be recovered and recycled after the reaction.

[0023] After obtaining the acetosulfoneguanidine, the present application adjusts the pH value of the mixture of the acetosulfoneguanidine and water to 8-9, adds amide hydrolase to hydrolyze to obtain sulfoneguanidine. As a specific embodiment of the present application, the pH value adjusting agent can comprise potassium hydroxide, lithium hydroxide or sodium hydroxide; the present application can add the pH value adjusting agent in the form of solution; the present application does not have special limitations for the amount of the pH value adjusting agent, as long as the required pH value can be met.

[0024] As a specific embodiment of the present application, the amide hydrolase can comprise amide hydrolase SJ0018E1, amide hydrolase SJ0018E3 or amide hydrolase SJ0018E7.

[0025] As a specific embodiment of the present application, the water can be pure water; the mass ratio of the acetosulfoneguanidine to water in the second mixed system can be 1:10-35, and can be specifically 1:20-33, and can be specifically 1:30.6, 1:31 or 1:32; the dosage of the amide hydrolase can be 80-300 U / g of substrate, and can be specifically 100-250 U / g of substrate.

[0026] As a specific embodiment of the present application, the temperature of the hydrolysis can be 20-35 DEG C, and can be specifically 25-30 DEG C; the time of the hydrolysis can be 3-4 h, and can be specifically 3 h, 3.5 h or 4 h.

[0027] As a specific embodiment of the present application, the post-hydrolysis processing can further include the following steps: separating the sulfaguanidine suspension and recovering the amidohydrolase by a 60-mesh screen, repeatedly washing the screen with the sulfaguanidine suspension, mixing the washing liquid and the sulfaguanidine suspension, and filtering to obtain the sulfaguanidine wet crude product and the filtrate, respectively; and the filtrate containing a small amount of amidohydrolase can be reused.

[0028] As a specific embodiment of the present application, the post-hydrolysis processing can further include: refluxing the post-hydrolysis product (sulfaguanidine crude product) and water in a third mixture, adding activated carbon to the refluxed system for decolorization, filtering, crystallizing the filtrate obtained by filtering, drying the solid obtained by crystallization, and obtaining the sulfaguanidine; the mass ratio of the post-hydrolysis product to water in the third mixture can be 1:8.5-25, and can be specifically 1:10, 1:13, 1:15, 1:20 or 1:23; the present application promotes the dissolution of the sulfaguanidine crude product by refluxing; and the mass ratio of the post-hydrolysis product to activated carbon can be 1:0.01-0.05, and can be specifically 1:0.02 or 1:0.04.

[0029] As a specific embodiment of the present application, the decolorization temperature can be 90-105°C, and can also be 95-100°C; and the decolorization time can be 28-32 min, and can be specifically 30 min.

[0030] As a specific embodiment of the present application, the crystallization can be cooling crystallization, and the present application does not have special requirements for the cooling crystallization, and a conventional method in the art can be used.

[0031] The preparation method provided by the present application has the advantages of simple process route, cheap and easily available raw materials, low cost, mild reaction conditions, green environmental protection, simple operation and convenience for industrial production. Figure 1 A flow chart for preparing high-purity sulfaguanidine using acetone as a solvent and guanidine hydrochloride as a guanidine salt.

[0032] In order to further illustrate the present application, the technical solutions provided by the present application are described in detail below in combination with examples, but they should not be understood as limiting the scope of protection of the present application.

[0033] Example 1 Condensation reaction: acetamidobenzenesulfonyl chloride (100 g) was added in batches, and then the temperature was raised to 25°C for a 4 h condensation reaction. After the reaction was completed, acetone was recovered by distillation until it was evaporated, and the collected acetone was used in the next batch of feeding. Water was added to the distilled system, the temperature was raised to 55°C and stirred for 2 hours, filtered, and dried to obtain 98g of the intermediate acetylsulfanilamide.

[0034] Enzymatic hydrolysis reaction: Add 3000g of pure water and 98g of acesulfame potassium to the reactor, stir and heat to 30℃±5℃, add amide hydrolase SJ0018E1, the amount of enzyme added is 100U / g substrate, the pH of the system is adjusted to 8.0 with 2N sodium hydroxide during the reaction, and the hydrolysis reaction is carried out at 30℃±5℃ for 3h. The system after hydrolysis reaction was separated using a 60-mesh sieve to obtain sulfaguanidine suspension and recovered amide hydrolase SJ0018E1. The sieve was then repeatedly rinsed with the obtained sulfaguanidine suspension, and the rinsing liquids were combined. The rinsing liquid and suspension were combined and filtered to collect the wet crude sulfaguanidine product. The filtrate can be reused.

[0035] Refining and purification: Add 1300g of tap water and 100g of wet crude sulfanilamide to the reactor, heat to 102±2℃ and reflux to dissolve, add 2g of activated carbon and decolorize for 30min; filter the decolorized system, cool and crystallize the filtrate, filter again, set aside the filtrate, the filter cake is sulfanilamide, dry to obtain 78g of refined sulfanilamide, liquid phase purity is 99.38%, the total molar yield is 85.07% (based on ASC).

[0036] The acesulfame potassium guanidine prepared in Example 1 was analyzed by 1H NMR spectroscopy, and the results were obtained. 1 H NMR spectrum as shown Figure 2 As shown. Figure 2 middle 1 H NMR (DMSO, 400MHz) δ10.2013 (s,1H), 7.6874 (m,4H), 6.6782 (s,4H), 2.0755 (s,3H).

[0037] The acesulfame potassium prepared in Example 1 was subjected to mass spectrometry detection, and the resulting spectrum is shown below. Figure 3 As shown, the molecular weight of the target intermediate is M=256.28, with MS+ showing a significant response: M+1=256.99, M+23=278.97, 2M+23=535, etc., and MS- also showing a response: M-1=254.98.

[0038] according to Figure 2 and Figure 3 The results confirmed that the intermediate prepared in Example 1 was acesulfame potassium guanidine.

[0039] The acesulfame potassium prepared in Example 1 was detected by liquid chromatography, and the resulting chromatogram is shown below.Figure 4 The results obtained from the liquid chromatography detection are listed in Table 1.

[0040] Table 1 Liquid chromatography detection results of acetylsulfaguanidine prepared in Example 1

[0041] As shown in Table 1 and Figure 4 It can be seen that the acetylsulfaguanidine prepared by the present application has high purity.

[0042] The fine sulfaguanidine prepared in Example 1 was subjected to liquid chromatography detection, and the obtained chromatogram is shown in Figure 5 The results obtained from the liquid chromatography detection are listed in Table 2.

[0043] Table 2 Liquid chromatography detection results of fine sulfaguanidine prepared in Example 1

[0044] As shown in Table 2 and Figure 5 It can be seen that the sulfaguanidine prepared by the present application has high purity.

[0045] The fine sulfaguanidine prepared in Example 1 and the sulfaguanidine standard were subjected to infrared detection, and the obtained infrared spectra are shown in Figure 6 As shown in Figure 6 It can be seen that the infrared spectrum of the fine sulfaguanidine prepared in Example 1 is completely matched with the infrared spectrum of the standard sulfaguanidine, indicating that the prepared product is sulfaguanidine.

[0046] Example 2 Condensation reaction: Into a reaction kettle, acetone (2500 g), guanidine hydrochloride 225 g, and 32% sodium hydroxide solution 375 g were added, and after being uniformly mixed, the temperature was lowered to 10°C, and p-acetylamino-benzenesulfonyl chloride (500 g) was added in batches, and then the temperature was raised to 25°C for 4 h of condensation reaction. After the reaction was completed, acetone was recovered by distillation until dryness, and the collected acetone was reused in the next batch of feeding. Water was added to the system after distillation, and the temperature was raised to 55°C for 2 h of stirring and beating. After filtration and drying, the intermediate acetylsulfaguanidine 490 g was obtained.

[0047] Enzymatic hydrolysis reaction: Into a reaction kettle, pure water 15 kg and acetylsulfaguanidine (490 g) were added, and after stirring, the temperature was raised to 30°C±5°C. Acylamide hydrolase SJ0018E1 was added, and the enzyme amount was 100 U / g of substrate. During the reaction, 2N sodium hydroxide was used to control the pH value of the system to 8.0, and the hydrolysis reaction was carried out at 30°C±5°C for 3 h. The hydrolysis reaction system is separated by using a 60-mesh sieve to obtain a sulfaguanidine suspension and recover the amidohydrolase SJ0018E1. The obtained sulfaguanidine suspension is repeatedly used to rinse the sieve, and the rinsing liquid is combined. The rinsing liquid and the suspension are combined and filtered to obtain wet sulfaguanidine crude product. The filtered filtrate can be reused.

[0048] Refining and purification: Tap water 6500 g and sulfaguanidine wet crude product (500 g) are added into a reaction kettle, and the mixture is dissolved by refluxing at 102±2°C. Activated carbon (10 g) is added, and the mixture is decolorized for 30 min. The decolorized system is filtered, and the obtained filtrate is cooled and crystallized. The filtrate is used for the next step, and the filter cake is sulfaguanidine. After drying, 390 g of fine sulfaguanidine is obtained.

[0049] Example 3 Condensation reaction: Into a reaction kettle, acetone (25 kg), guanidine hydrochloride (2.25 kg), and a 32% sodium hydroxide solution (3.75 kg) are added. After mixing, the mixture is cooled to 10°C, and p-acetylamino-benzenesulfonyl chloride (5.0 kg) is added in batches. Then, the mixture is warmed to 25°C for 4 h of condensation reaction. After the reaction, the acetone is recovered by distillation until dryness. The collected acetone is used in the next batch. Into the distilled system, water is added, and the mixture is stirred and pulped at 55°C for 2 h. The mixture is filtered and dried to obtain 4.9 kg of intermediate acetylsulfaguanidine.

[0050] Enzymatic hydrolysis reaction: Into a reaction kettle, pure water (150 kg) and acetylsulfaguanidine (4.9 kg) are added. The mixture is stirred and warmed to 30±5°C. Amidohydrolase SJ0018E1 is added, and the enzyme amount is 100 U / g of substrate. During the reaction, the pH value of the system is controlled at 8.0 by using 2N sodium hydroxide. The hydrolysis reaction is carried out at 30±5°C for 3 h. The hydrolysis reaction system is separated by using a 60-mesh sieve to obtain a sulfaguanidine suspension and recover the amidohydrolase SJ0018E1. The obtained sulfaguanidine suspension is repeatedly used to rinse the sieve, and the rinsing liquid is combined. The rinsing liquid and the suspension are combined and filtered to obtain wet sulfaguanidine crude product. The filtered filtrate can be reused.

[0051] Refining and purification: Into a reaction kettle, tap water (65 kg) and sulfaguanidine wet crude product (5 kg) are added. The mixture is dissolved by refluxing at 102±2°C. Activated carbon (100 g) is added, and the mixture is decolorized for 30 min. The decolorized system is filtered, and the obtained filtrate is cooled and crystallized. The filtrate is used for the next step, and the filter cake is sulfaguanidine. After drying, 3.9 kg of fine sulfaguanidine is obtained.

[0052] The fine sulfaguanidine prepared in Examples 1-3 was detected by liquid chromatography, and the purity of the fine sulfaguanidine was listed in Table 3.

[0053] Table 3 Purity and yield of fine sulfaguanidine prepared in Examples 1-3

[0054] As can be seen from the results in Table 3, the preparation method provided by the present application can prepare sulfaguanidine with high purity and high yield.

[0055] Although the above examples have made a detailed description of the present application, it is only a part of the embodiments of the present application, but not all the embodiments, and people can also obtain other embodiments according to the present embodiments without creativity, which all belong to the protection scope of the present application.

Claims

1. A method for preparing sulfaguanidine, characterized in that, Includes the following steps: A condensation reaction is carried out after first mixing acetaminobenzenesulfonyl chloride, guanidine salt, strong base and ketone solvent to obtain acesulfame guanidine; After mixing acesulfame potassium and water, the pH was adjusted to 8-9, and then amide hydrolase was added for hydrolysis to obtain sulfame potassium.

2. The method for preparing sulfaguanidine according to claim 1, characterized in that, The first mixing includes the following steps: After mixing guanidine salt, strong base and ketone solvent, the mixture is cooled to 5~15℃, and then p-acetaminobenzenesulfonyl chloride is added in batches.

3. The method for preparing sulfaguanidine according to claim 1 or 2, characterized in that, The guanidine salt includes guanidine nitrate or guanidine hydrochloride; The strong base includes a strong base solution, which includes a sodium hydroxide solution or a potassium hydroxide solution. The ketone solvents include acetone, methyl ethyl ketone, or 2-pentanone.

4. The method for preparing sulfaguanidine according to claim 3, characterized in that, The mass concentration of the strong alkali solution is 28-50%; The mass ratio of the guanidine salt to p-acetaminobenzenesulfonyl chloride is 1:1.8~2.8; The mass ratio of the guanidine salt to the ketone solvent is 1:9~15.5; The mass ratio of the guanidine salt to the strong alkali solution is 1:1.1~1.

9.

5. The method for preparing sulfaguanidine according to claim 4, characterized in that, The condensation reaction is carried out at a temperature of 20-30°C for 3-4 hours.

6. The method for preparing sulfaguanidine according to claim 1, characterized in that, pH adjusters include potassium hydroxide, lithium hydroxide, or sodium hydroxide. The amide hydrolase includes amide hydrolase SJ0018E1, amide hydrolase SJ0018E3, or amide hydrolase SJ0018E7.

7. The method for preparing sulfaguanidine according to claim 1 or 6, characterized in that, In the second mixing system, the mass ratio of acesulfame potassium to water is 1:10~35; The dosage of the amide hydrolase is 80~300 U / g substrate.

8. The method for preparing sulfaguanidine according to claim 7, characterized in that, The hydrolysis temperature is 20~35℃ and the time is 3~4h.

9. The method for preparing sulfaguanidine according to claim 1, characterized in that, The hydrolysis process further includes: mixing the hydrolyzed product with water and then refluxing the mixture; adding activated carbon to the refluxed system for decolorization and then filtering; and crystallizing the filtrate to obtain the sulfanilidine.

10. The method for preparing sulfaguanidine according to claim 9, characterized in that, In the third mixing system, the mass ratio of the hydrolyzed product to water is 1:8.5~25; The mass ratio of the hydrolyzed product to activated carbon is 1:0.01~0.05; The decolorization temperature is 90~105℃, and the time is 28~32min.

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