CN103012224B - Production process of medicinal sulphaguanidine - Google Patents
Production process of medicinal sulphaguanidine Download PDFInfo
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- CN103012224B CN103012224B CN201210584928XA CN201210584928A CN103012224B CN 103012224 B CN103012224 B CN 103012224B CN 201210584928X A CN201210584928X A CN 201210584928XA CN 201210584928 A CN201210584928 A CN 201210584928A CN 103012224 B CN103012224 B CN 103012224B
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Abstract
The invention discloses a production process of medicinal sulphaguanidine, and belongs to the field of medicine chemical industry. The production process comprises the following steps of: sequentially adding specified amounts of sulfanilamide, sodium carbonate and guanidine nitrate at a feeding mol ratio of (1.2-1.5): 1.0: (1.5-1.8); adding a catalyst and a cocatalyst, and heating; vacuumizing when the temperature is increased to 120 DEG C; continuing to raise the temperature to 125-145 DEG C until the materials are completely melted; sealing the reaction system; preserving the heat and reacting for 1-3hours, adding pure water which is in equal weight with the raw materials; stirring; naturally cooling to 50 DEG C; adding a NaOH water solution which counts for 29% ( the weight of the solution is 0.2-0.4 time as much as the weight of the raw materials); cooling to 20-30 DEG C; filtering; rinsing a crude product until the pH value is at 7.0-7.5; adding active carbon into the solution, boiling, absorbing and decoloring; coarsely filtering by a filter membrane of 0.45 microns; finely filtering by a filter membrane of 0.22 microns; ultra-filtering by a hollow fiber, and collecting a filtrate; cooling the filtrate to room temperature, centrifuging, drying by a fluidized bed, internally packing and externally packing to obtain the final product.
Description
Technical field
The invention provides a kind of production technique of medicinal sulfanilylguanidine, belong to field of medicine and chemical technology.
Background technology
Sulfanilylguanidine (Sulfaguanidine) is the white, needle-shaped crystals powder.Odorless, tasteless, meet the sun exposure color and deepen gradually.190～193 ℃ of fusing points.Be slightly soluble in water, ethanol, acetone, be dissolved in diluted mineral acid and boiling water, be insoluble to cold sodium hydroxide solution, can treat various bacillary dysenterys, enteritis, also can be used for preventing that bacterium before intestinal surgery from infecting.The industrial preparative method of sulfanilylguanidine is melting in soda ash by sulfanilamide (SN) and Guanidinium nitrate, the decompression condensation makes, the applicant finds aborning, utilizes published technology to have such defect: the reaction of (1) sulfanilamide (SN) and Guanidinium nitrate is difficult to fully, causes product yield not high.(2) former technique finished product foreign matter content is higher, and especially endotoxin content is higher.The finished product of producing with prior art does not meet the pharmaceutical grade quality standard.
The structural formula of sulfanilylguanidine (Sulfaguanidine) is as follows:
US2592860 A discloses a kind of preparation method of sulfanilylguanidine, is by sulfanilamide (SN), sodium carbonate, and nitroguanidine, heating 130-140 ℃, decompression, reheat 165-170 ℃ of reaction, adds water cooling to 100 ℃, adding decolorizing with activated carbon, filtration, obtains product sulfanilylguanidine.Yet the method long reaction time, temperature of reaction is high, wayward, and impurity is more.
Yang Yong was " sulfanilylguanidine synthesising process research " (2002, " Chinese excellent MA theses full-text database ") in a kind of preparation method of sulfanilylguanidine is disclosed: sulfanilylguanidine is a kind of useful antimicrobial drug and medicine intermediate, chlorsulfonic acid, Acetanilide, Guanidinium nitrate be take in this paper is raw material, through chlorosulphonation, condensation, hydrolysis reaction makes sulfanilylguanidine, is an economically viable synthetic route.This paper is studied numerous influence factors of chlorosulfonation, in chlorosulfonation, examined the different catalysts consumption at the differential responses temperature, the differential responses time is on the impact of chlorosulphonation product yield, optimal reaction temperature and catalyst levels have been determined, make the chlorosulphonation productive rate reach 89.6%, wherein the mol ratio of chlorsulfonic acid and Acetanilide is reduced to 3.8:1.In condensation reaction, solvent is selected, and examined the differential responses temperature, the impact of product yield under the differential responses time.Finally hydrolysis reaction has been carried out to condition experiment, determined the hydrolysis top condition.Make the total recovery of sulfanilylguanidine reach 80.1%, purity is 99.3%, with existing, take the production technique that sulfanilamide (SN) is raw material and compares, and the raw materials cost of the product per ton of sulfanilylguanidine reduces approximately 15%.Yet the method reactions steps is longer, and production cost is high, and yield is lower.
The various synthetic methods that obtain according to the retrieval prior art, whether the consideration raw material is easy to get, whether technique adapts to the situations such as suitability for industrialized production, and the present invention gropes by lot of experiments, finally select with sulfanilamide (SN), sodium carbonate, nitroguanidine is raw material, through catalysis, heat tracing, refining purifying, make sulfanilylguanidine.The method simple process, the reaction times shortens greatly, and the product recovery rate is higher, and environmentally safe.
Therefore, sulfanilylguanidine production method provided by the present invention has overcome in the aforesaid method that yield is not high, finished product impurity and the higher problem of endotoxin content, has the reaction times short, and production cost is low, and the product recovery rate is higher, the advantage of good product purity.
Summary of the invention
The present invention proposes a kind of method of improved production sulfanilylguanidine, to overcome in prior art, yield is not high, finished product impurity and the higher problem of endotoxin content.
The method that the present invention relates to produce sulfanilylguanidine comprises following steps:
Steps A: by sulfanilamide (SN), sodium carbonate and Guanidinium nitrate be take the ratio that mol ratio is 1.2-1.5:1.0:1.5-1.8 and are fed intake, and add catalyzer and promotor;
Step B: when temperature rises to 120 ℃, open vacuum, ammonia and carbonic acid gas are taken out in decompression;
Step C: continue to be warming up between 125～145 ℃, to the complete melting of material, confined reaction system, insulation reaction 1～3 hour;
Step D: add the weight purified water such as raw material, stir, naturally cool to 50 ℃, add the NaOH aqueous solution, be cooled to 20～30 ℃, filter, crude product wash with water to pH be 7.0～7.5;
Step e: add gac in solution, boil, adsorb, decolour, through 0.45 μ m filter membrane coarse filtration, Hollow Fiber Ultrafiltration is filtered, passed through to 0.22 μ m filter membrane essence, collects filtrate;
Step F: filtrate is cooled to room temperature, centrifugal, fluidised bed drying, Nei Bao, outsourcing.Filtrate is cooled to room temperature, centrifugal, fluidised bed drying, Nei Bao, outsourcing, obtains the finished product.
Wherein, the present invention relates to produce the sulfanilamide (SN) described in the steps A of sulfanilylguanidine, the molar ratio optimum of sodium carbonate and Guanidinium nitrate is 1.26:1.0:1.73.
The present invention relates to produce catalyzer described in the steps A of sulfanilylguanidine and be a kind of in ferrous chloride, iron trichloride, tindichloride, cuprous chloride or dichloride copper.
The present invention relates to produce catalyzer described in the steps A of sulfanilylguanidine and be preferably dichloride copper.
The present invention relates to produce promotor described in the steps A of sulfanilylguanidine and be a kind of in Tetramethyl Ethylene Diamine or quadrol, be preferably Tetramethyl Ethylene Diamine.
The consumption that the present invention relates to produce catalyzer described in the steps A of sulfanilylguanidine is about the 1-5% (mol ratio) of sulfanilamide (SN) consumption.
The present invention relates to produce the 2-10% (mol ratio) that promotor described in the steps A of sulfanilylguanidine is about the sulfanilamide (SN) consumption.
The concentration that the present invention relates to produce the NaOH aqueous solution in the step D of sulfanilylguanidine is the 25-35% weight ratio.
The present invention relates to produce 0.2～0.4 times that in the step D of sulfanilylguanidine, NaOH aqueous solution weight is raw material weight.
The present invention relates to produce that in the step e of sulfanilylguanidine, activated carbon dosage is raw material weight 1%; Adding boiling time after gac is 30min, filter membrane by 0.45 μ m, 0.22 μ m aperture carries out coarse filtration and essence filter again, again filtrate is carried out to ultrafiltration by ultra-filtration membrane, described ultra-filtration membrane adopts hollow fiber ultrafiltration membrane, the mould material of described ultra-filtration membrane is polysulfone membrane, Polysulfonamide or polyacrylonitrile film, ultra-filtration membrane is inlet pressure control at 1.75Mpa, and tubular fibre stockline flow velocity is 1m/s.
The sulfanilylguanidine that sulfanilylguanidine production technique of the present invention obtains can be used as medicinal sulfanilylguanidine, is widely used in field of medicaments.
According to technical scheme of the present invention, can, by adding suitable auxiliary material to make the pharmaceutical preparation of certain forms in the sulfanilylguanidine made, comprise tablet, capsule, injection liquid, infusion solutions, injectable sterile powder etc.
Compared with prior art, the present invention has following excellent results:
1. the present invention adds catalyzer and promotor, has significantly reduced temperature of reaction, has shortened the reaction times;
2. best molar ratio of the present invention is that 1.26:1.0:1.73 is by the design orthogonal test, optimizes gained, with this ratio, feeds intake, and by above-mentioned explained hereafter, product yield can reach 94.38%, compares former technique, and product yield increases greatly;
3. sulfanilylguanidine is insoluble to cold NaOH, and step D separates out the sulfanilylguanidine in stoste substantially, and product yield increases greatly; Secondly, in step D, add NaOH can impel bacterial cell dead broken, be conducive to step e and remove the bacterial endotoxin in finished product, quality product obviously improves; The 3rd, step D makes with extra care by step e after separating out crude product again, and the impurity in finished product significantly reduces;
4. step e is after charcoal absorption decolouring, then, through 0.45 μ m filter membrane coarse filtration, 0.22 filter of μ m filter membrane essence and Hollow Fiber Ultrafiltration, can effectively remove insoluble impurities and bacterial endotoxin in finished product, and quality product obviously improves;
Step D of the present invention, E also can be used as from chemical grade sulfanilylguanidine refining the method for pharmaceutical grade sulfanilylguanidine;
6. production technique of the present invention is simple, less demanding to Workplace, and the quality product of producing meets the pharmaceutical grade standard fully.
The accompanying drawing explanation
Fig. 1: sulfanilamide (SN), sodium carbonate and Guanidinium nitrate reactive chemistry equation.
Fig. 2: pharmaceutical grade sulfanilylguanidine production technological process.
Embodiment
Drop into successively the sulfanilamide (SN) 416.5kg of specified amount, sodium carbonate 203.6kg and Guanidinium nitrate 407.3kg, add dichloride copper 5kg and quadrol 7kg, stirring 0.5 hour post-heating heats up, equitemperature rises to 120 ℃ and opens vacuum, ammonia is taken out in decompression and 0.5 hour follow-up continuing of carbonic acid gas is warming up to 125 ℃, the complete melting of material, the confined reaction system, insulation reaction adds the 1000kg purified water such as raw material after 2 hours, stir, naturally cool to 50 ℃, the NaOH aqueous solution 300kg that to add content be 25%, be cooled to 25 ℃, filter, crude product wash with water to pH be 7.0, by the crude product sulfanilylguanidine after filtration washing, add gac 10kg, then adding water to cumulative volume is 5500L, quickly heat up to and boil, be incubated micro-boiling 30 minutes, decolouring, through coarse filtration, filtrate is collected in essence filter and ultrafiltration.Filtrate is cooled to room temperature, centrifugal, fluidised bed drying, Nei Bao, outsourcing.The final finished product 250kg that obtains, yield is 94.3%, purity reaches the 99.8%(HPLC method).
By the sulfanilylguanidine finished product that obtains by " regulation that Chinese pharmacopoeia is 2010 editions is analyzed, and quality is up to specification.
Embodiment 2
Drop into successively the sulfanilamide (SN) 400kg of specified amount, sodium carbonate 200kg and Guanidinium nitrate 400kg, add tindichloride 4kg and Tetramethyl Ethylene Diamine 8kg, stirring 0.5 hour post-heating heats up, equitemperature rises to 120 ℃ and opens vacuum, ammonia is taken out in decompression and 0.5 hour follow-up continuing of carbonic acid gas is warming up to 145 ℃, the complete melting of material, the confined reaction system, insulation reaction adds the 1000kg purified water such as raw material after 3 hours, stir, naturally cool to 50 ℃, the NaOH aqueous solution 300kg that to add content be 30%, be cooled to 25 ℃, filter, crude product wash with water to pH be 7.0, by the crude product sulfanilylguanidine after filtration washing, add gac 10kg, then adding water to cumulative volume is 5500L, quickly heat up to and boil, be incubated micro-boiling 30 minutes, decolouring, through coarse filtration, filtrate is collected in essence filter and ultrafiltration.Filtrate is cooled to room temperature, centrifugal, fluidised bed drying, Nei Bao, outsourcing.The final finished product 248kg that obtains, yield is 93.5%, purity reaches the 99.7%(HPLC method).
By the sulfanilylguanidine finished product that obtains by " regulation that Chinese pharmacopoeia is 2010 editions is analyzed, and quality is up to specification.
Embodiment 3
Drop into successively the sulfanilamide (SN) 400kg of specified amount, sodium carbonate 200kg and Guanidinium nitrate 400kg, add iron trichloride 5kg and quadrol 6kg, stirring 0.5 hour post-heating heats up, equitemperature rises to 120 ℃ and opens vacuum, ammonia is taken out in decompression and 0.5 hour follow-up continuing of carbonic acid gas is warming up to 135 ℃, the complete melting of material, the confined reaction system, insulation reaction adds the 1000kg purified water such as raw material after 1 hour, stir, naturally cool to 50 ℃, the NaOH aqueous solution 300kg that to add content be 30%, be cooled to 25 ℃, filter, crude product wash with water to pH be 7.0, by the crude product sulfanilylguanidine after filtration washing, add gac 10kg, then adding water to cumulative volume is 5500L, quickly heat up to and boil, be incubated micro-boiling 30 minutes, decolouring, through coarse filtration, filtrate is collected in essence filter and ultrafiltration.Filtrate is cooled to room temperature, centrifugal, fluidised bed drying, Nei Bao, outsourcing.The final finished product 245kg that obtains, yield is 92.4%, purity reaches the 99.5%(HPLC method).
Claims (5)
1. the production technique of a medicinal sulfanilylguanidine, is characterized in that, comprises following steps:
A: by sulfanilamide (SN), sodium carbonate and Guanidinium nitrate be take the ratio that mol ratio is 1.2-1.5:1.0:1.5-1.8 and are fed intake, and add catalyzer and promotor;
B: when temperature rises to 120 ℃, open vacuum, ammonia and carbonic acid gas are taken out in decompression;
C: continue to be warming up between 125～145 ℃, to the complete melting of material, confined reaction system, insulation reaction 1～3 hour;
D: add the weight purified water such as raw material, stir, naturally cool to 50 ℃, add the NaOH aqueous solution, be cooled to 20～30 ℃, filter, crude product wash with water to pH be 7.0～7.5;
E: add gac in solution, boil, adsorb, decolour, through 0.45 μ m filter membrane coarse filtration, Hollow Fiber Ultrafiltration is filtered, passed through to 0.22 μ m filter membrane essence, collects filtrate;
F: filtrate is cooled to room temperature, centrifugal, fluidised bed drying, Nei Bao, outsourcing;
Wherein, in described steps A, catalyzer is a kind of in ferrous chloride, iron trichloride, tindichloride, cuprous chloride or dichloride copper, and the consumption of the described catalyzer 1-5% mol ratio that is the sulfanilamide (SN) consumption;
In described steps A, promotor is a kind of in Tetramethyl Ethylene Diamine or quadrol, and the described promotor 2-10% mol ratio that is the sulfanilamide (SN) consumption; And,
In described step D, the concentration of the NaOH aqueous solution is the 25-35% weight ratio, and NaOH aqueous solution weight is raw material weight 0.2～0.4 times.
2. production technique according to claim 1, is characterized in that, the sulfanilamide (SN) described in steps A, and the molar ratio of sodium carbonate and Guanidinium nitrate is 1.2-1.5:1.0:1.5-1.8.
3. production technique according to claim 1, is characterized in that, the sulfanilamide (SN) described in steps A, and the molar ratio of sodium carbonate and Guanidinium nitrate is 1.26:1.0:1.73.
4. production technique according to claim 1, is characterized in that, catalyzer described in steps A is dichloride copper.
5. production technique according to claim 1, is characterized in that, in step e, activated carbon dosage is raw material weight 1%; Adding boiling time after gac is 30min, filter membrane by 0.45 μ m, 0.22 μ m aperture carries out coarse filtration and essence filter again, again filtrate is carried out to ultrafiltration by ultra-filtration membrane, described ultra-filtration membrane adopts hollow fiber ultrafiltration membrane, the mould material of described ultra-filtration membrane is polysulfone membrane, Polysulfonamide or polyacrylonitrile film, ultra-filtration membrane is inlet pressure control at 1.75Mpa, and tubular fibre stockline flow velocity is 1m/s.
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| CN106187830A (en) * | 2016-07-06 | 2016-12-07 | 南通天泽化工有限公司 | A kind of preparation method of sulfaguanidine |
| CN114853639B (en) * | 2022-05-31 | 2024-02-23 | 湖南吴赣药业有限公司 | Safe continuous production method of sulfadiazine |
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| GB586175A (en) * | 1943-08-09 | 1947-03-10 | Monsanto Australia Proprietary | Production of sulphanilylguanidine |
| US2592860A (en) * | 1946-06-29 | 1952-04-15 | Squibb & Sons Inc | Process for preparing sulfathiazole |
| GB774823A (en) * | 1954-02-10 | 1957-05-15 | Chemie Linz Ag | Improvements in and relating to a process for producing benzenesulfonylguanidines |
| CN1034719A (en) * | 1988-12-29 | 1989-08-16 | 昆山制药厂 | A kind of method of producing sulfapyrimidine |
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2012
- 2012-12-30 CN CN201210584928XA patent/CN103012224B/en active Active
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB586175A (en) * | 1943-08-09 | 1947-03-10 | Monsanto Australia Proprietary | Production of sulphanilylguanidine |
| US2592860A (en) * | 1946-06-29 | 1952-04-15 | Squibb & Sons Inc | Process for preparing sulfathiazole |
| GB774823A (en) * | 1954-02-10 | 1957-05-15 | Chemie Linz Ag | Improvements in and relating to a process for producing benzenesulfonylguanidines |
| CN1034719A (en) * | 1988-12-29 | 1989-08-16 | 昆山制药厂 | A kind of method of producing sulfapyrimidine |
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| 吴和明等.硝酸胍的精制.《江苏化工》.1995,第23卷(第4期), |
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| 磺胺脒合成工艺研究;杨勇;《中国优秀硕士论文全文数据库-工程科技I辑》;20021231(第2期);4-5 * |
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Application publication date: 20130403 Assignee: Hunan Xiangyikang Pharmaceutical Co., Ltd. Assignor: Hunan Er-Kang Pharmaceutical Co., Ltd. Contract record no.: 2014430000028 Denomination of invention: Production process of medicinal sulphaguanidine Granted publication date: 20131204 License type: Exclusive License Record date: 20140411 |
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