CN102617489B - Preparation method of sulfaclozine sodium - Google Patents
Preparation method of sulfaclozine sodium Download PDFInfo
- Publication number
- CN102617489B CN102617489B CN201210075197.6A CN201210075197A CN102617489B CN 102617489 B CN102617489 B CN 102617489B CN 201210075197 A CN201210075197 A CN 201210075197A CN 102617489 B CN102617489 B CN 102617489B
- Authority
- CN
- China
- Prior art keywords
- sodium
- mixed solvent
- sulfaclozine
- sulfaclozine sodium
- preparation
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Active
Links
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention discloses a preparation method of sulfaclozine sodium, belonging to the technical field of chemical synthesis. According to the method, a process condition and a production process are changed, the conventional high-temperature frit reaction between 2,3-dichloropyrazine, sulfanilamide and potassium carbonate is changed, an appropriate solvent is taken as a dissociation agent, an appropriate catalyst is added, the transformation ratio is increased, and the product quality is improved. During refining of a crude product, 'acid and alkali refining' is changed into binary mixed solvent recrystallization, so that the production of a large amount of salt-containing waste water is reduced, and the product purity is increased.
Description
Technical field
The present invention relates to that a kind of sulfamido anticoccidial drug---the preparation method of sulfaclozine sodium, belongs to chemosynthesis technical field.
Background technology
Sulfaclozine sodium, chemical name: the chloro-2-pyrazinyl of 4-amido-N-(6-) benzsulfamide sodium one water thing.White or pale yellow powder.This product can be fought for dihydrofolate synthetase, affects the synthetic of dihydrofolic acid, thus the growth and breeding of anti-bacteria and coccidia.This product is similar to sulfaquinoxaline to the effect feature of poultry coccidia, but the stronger anti-microbial effect of tool even can be treated fowl cholera and fowl typhoid, and when therefore the most applicable coccidiosis breaks out, treatment is used.
The preparation method of existing sulfaclozine sodium, raw material 2,6-dichloropyrazine and the condensation of a part sulfanilamide (SN) obtain condenses 2 one p-amino benzene sulfonyls-6-chloropyrazine, and condenses is after separating-purifying, and sodium hydroxide solution salt-forming reaction obtains target product.
Preparation method (the US2 of report in the past, 475,673), condensation reaction is that dry method is carried out, excessive solid sulfanilamide (SN), 2,6-dichloropyrazine and Anhydrous potassium carbonate drop into reactor, temperature is raised to 123 DEG C and slowly melts rear reaction, once reaction is carried out, temperature can rise to rapidly 152 DEG C, and continues reaction.But this dry process reaction low conversion rate, by product is many, and excessive responseless sulfanilamide (SN) will remove by filter in advance, and then regulates the pH value of mother liquor, separates out target product Sulfatyf.Make side reaction increase because temperature of reaction is too high, a part 2,6-dichloropyrazine can with two molecule sulfanilamide (SN) condensations, generate 2,6-bis-p-amino benzene sulfonyl pyrazines, the existence of this by product has affected the quality of end product.
The traditional process for purification of sulfaclozine sodium is that " acid, alkaline process " is refining, in alkaline aqueous solution, allow sulfaclozine sodium heating for dissolving, add activated carbon decolorizing, filter activity charcoal, filtrate furnishing acidity, separate out and isolate Sulfatyf, and then allow Sulfatyf in alkaline solution, form sodium salt, freezing and crystallizing.Soda acid is bought and sold back and forth like this, produces a large amount of brine wastes, is unfavorable for the biochemical treatment of waste water.
In addition, ' acid, soda finishing method ' product purity is low.Product major impurity turns out to be 2,6-, bis-p-amino benzene sulfonyl pyrazine sodium salts through the online detection of HPLC-MS.This impurity is condensation reaction by product, and content reaches 0.6% left and right, and common ' acid, alkaline process ' refining being difficult for removes, and can not meet latest edition European Pharmacopoeia and be less than 0.2%, the requirement that total impurities is less than 0.5% about the maximum single impurity of medicinal substance.Due to sulfaclozine sodium and 2,6-bis-p-amino benzene sulfonyl pyrazine sodium salt physical propertiess are similar, bad with single solvent refining effect, select binary mixed solvent refining after screening, utilize material at different solvents, the dissolubility property under differing temps carries out separation and purification.
Summary of the invention
The object of the invention is to provide a kind of handled easily, transformation efficiency is high, by product is few, the sulfaclozine sodium practical system Preparation Method that product purity is high.
The present invention includes following steps:
1), taking toluene as solvent, under the effect of phase-transfer catalyst and solid water-free salt of wormwood, sulfanilamide (SN) and 2,3-dichloropyrazine carry out condensation reaction, then, by reactant and hydrochloric acid reaction, make Sulfatyf;
2) Sulfatyf is reacted with sodium hydroxide, make sulfaclozine sodium crude product;
3), by sulfaclozine sodium crude product heating for dissolving in binary mixed solvent, through recrystallization, make refining sulfaclozine sodium; Described binary mixed solvent is the mixed solvent of methyl alcohol and methylene dichloride.
Condensation reaction of the present invention is not that dry method is carried out, and be selected in water solubleness little and can with the solvent of water azeotropic, to take byproduct of reaction moisture content out of.In reactant, add phase-transfer catalyst that inorganic solid Anhydrous potassium carbonate is contacted better with organic reaction liquid, promote reaction to carry out, improved transformation efficiency and quality product.Crude product refining through decolorizing with activated carbon recrystallization, obtains sulfaclozine sodium finished product after changing into and dissolving with binary mixed solvent, reduced the generation of a large amount of brine wastes, improved product purity.
Setting-up point of the present invention is 100～120 DEG C, and the time is 6～15 hours.
Described phase-transfer catalyst is Tetrabutyl amonium bromide or Bian TEBA.
Described 2, the molar ratio of 3-dichloropyrazine and sulfanilamide (SN) is 1 ︰ 1.
In described binary mixed solvent, the mixing quality ratio of methyl alcohol and methylene dichloride is 2 ︰ 1.
Embodiment
1, prepare Sulfatyf:
Example one: add 25 grams of (0.145 mole) sulfanilamide (SN) and 21.6 grams of (0.145 moles) 2 in there-necked flask, 3-dichloropyrazine, with the dissolving of 60ml toluene.Add 22.4 grams of salt of wormwood (0.16 mole) and 2 grams of Tetrabutyl amonium bromides (0.006 mole) to be heated to 110 ~ 115 DEG C, in 110 ~ 115 DEG C of insulation back flow reaction 10 hours, separate moisture simultaneously.Reaction finishes, and reclaim under reduced pressure toluene reaches 115 DEG C to temperature of reaction, reclaims toluene and finishes, reaction solution cools to 78 ~ 82 DEG C, adds 40 grams of tap water, with salt acid for adjusting pH value 4.5 ~ 5.0, is cooled to 25 DEG C, filter and wash, obtain 35.5 grams of Sulfatyfs, yield 86%.
Example two: add 35 grams of (0.2 mole) sulfanilamide (SN) and 29.8 grams of (0.2 moles) 2 in there-necked flask, 3-dichloropyrazine, with the dissolving of 84ml toluene.Add 31.4 grams of salt of wormwood (0.22 mole) and 2.5 grams of Bian TEBAs (0.011 mole) to be heated to 110 ~ 115 DEG C, in 110 ~ 115 DEG C of insulation back flow reaction 8 hours, separate moisture simultaneously.Reaction finishes, and reclaim under reduced pressure toluene reaches 115 DEG C to temperature of reaction, reclaims toluene and finishes, and reaction solution cools to 80 DEG C, adds 60 grams of tap water, with salt acid for adjusting pH value 4.5 ~ 5.0, is cooled to 25 DEG C, filters and washes, and obtains 50.3 grams of Sulfatyfs, yield 87%.
2, prepare sulfaclozine sodium:
In there-necked flask, add 30 grams of (0.145 mole) Sulfatyfs and 120 grams of purified water, be warming up to 60 DEG C, add 16 grams of 40% sodium hydroxide solutions,, be warmed up to 70 DEG C, add 0.5 gram of gac, 75 DEG C of insulation decolourings 30 minutes, filter activity charcoal, filtrate is cooled to 0 DEG C, filtration product obtains 31.5 grams of sulfaclozine sodium one water thing crude products, yield 92%
3, refining sulfaclozine sodium:
By 50 grams of sulfaclozine sodiums, 135 ml methanol-dichloromethane solvent (2:1 w/w) heating for dissolving for crude product, add 2 grams of activated carbon, be heated to reflux, decolour 1 hour.Filtered while hot, filtrate is cooled to below 5 DEG C, filters to obtain 45 grams of sulfaclozine sodium fine work, yield 90%.Detect through HPLC, purity is greater than 99.5%.
Reaction formula of the present invention is as follows:
Claims (2)
1. a kind of preparation method of sulfaclozine sodium, comprises the following steps:
1) taking toluene as solvent, under the effect of phase-transfer catalyst and solid water-free salt of wormwood, sulfanilamide (SN) and 2,3-dichloropyrazine are carried out to condensation reaction, then, by reactant and hydrochloric acid reaction, make Sulfatyf; Described setting-up point is 100～120 DEG C, and the time is 6～15 hours;
2) Sulfatyf is reacted with sodium hydroxide, make sulfaclozine sodium crude product;
3) adopt binary mixed solvent to dissolve sulfaclozine sodium crude product, through recrystallization, make refining sulfaclozine sodium; Described binary mixed solvent is the mixed solvent of methyl alcohol and methylene dichloride;
It is characterized in that described phase-transfer catalyst is Tetrabutyl amonium bromide or Bian TEBA;
Described 2, the molar ratio of 3-dichloropyrazine and sulfanilamide (SN) is 1 ︰ 1.
2. a kind of preparation method of sulfaclozine sodium according to claim 1, is characterized in that in described binary mixed solvent, the mixing quality ratio of methyl alcohol and methylene dichloride is 2 ︰ 1.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201210075197.6A CN102617489B (en) | 2012-03-21 | 2012-03-21 | Preparation method of sulfaclozine sodium |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201210075197.6A CN102617489B (en) | 2012-03-21 | 2012-03-21 | Preparation method of sulfaclozine sodium |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN102617489A CN102617489A (en) | 2012-08-01 |
| CN102617489B true CN102617489B (en) | 2014-07-02 |
Family
ID=46557751
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201210075197.6A Active CN102617489B (en) | 2012-03-21 | 2012-03-21 | Preparation method of sulfaclozine sodium |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN102617489B (en) |
Families Citing this family (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104910081A (en) * | 2014-03-15 | 2015-09-16 | 菏泽市方明制药有限公司 | Preparation method of sulfachloropyrazine sodium |
| CN104945338A (en) * | 2015-06-23 | 2015-09-30 | 郑州福源动物药业有限公司 | Process for preparing sulfachloropyrazine sodium |
| CN111303044A (en) * | 2020-03-27 | 2020-06-19 | 湖南吴赣药业有限公司 | Synthetic method of sulfachloropyridazine sodium |
| CN111217760B (en) * | 2020-03-27 | 2021-11-26 | 湖南吴赣药业有限公司 | Synthetic method of sulfachloropyrazine sodium |
| CN113318078A (en) * | 2021-06-09 | 2021-08-31 | 四川恒通动保生物科技有限公司 | Preparation method of sulfachloropyrazine sodium and trimethoprim soluble powder |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US2475673A (en) * | 1945-06-26 | 1949-07-12 | American Cyanamid Co | Aminobenzenesulfonamidohalopyrazines and method of preparing same |
| CN102212035A (en) * | 2011-04-25 | 2011-10-12 | 扬州天和药业有限公司 | Preparation method for sulfamethoxypyrazine |
-
2012
- 2012-03-21 CN CN201210075197.6A patent/CN102617489B/en active Active
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US2475673A (en) * | 1945-06-26 | 1949-07-12 | American Cyanamid Co | Aminobenzenesulfonamidohalopyrazines and method of preparing same |
| CN102212035A (en) * | 2011-04-25 | 2011-10-12 | 扬州天和药业有限公司 | Preparation method for sulfamethoxypyrazine |
Also Published As
| Publication number | Publication date |
|---|---|
| CN102617489A (en) | 2012-08-01 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN102617489B (en) | Preparation method of sulfaclozine sodium | |
| CN108658858B (en) | Preparation and refining method of hydroxychloroquine and preparation method of sulfate thereof | |
| CN101941969B (en) | Preparation method of moxifloxacin hydrochloride | |
| CN102060860B (en) | Preparation method of Marbofloxacin | |
| CN109336892B (en) | Preparation method of tofacitinib impurity | |
| CN109134287B (en) | Purification method of byproduct sodium chloride in betaine or betaine hydrochloride production | |
| CN106349245A (en) | Sitagliptin phosphate impurities, method for preparing same and application of sitagliptin phosphate impurities | |
| CN103923019A (en) | Preparation method of 2-hydroxy-4-amino-5-fluoropyrimidine | |
| CN102911176A (en) | Preparation method of pemetrexed disodium | |
| CN104844602A (en) | Preparation method of Linagliptin | |
| CN113636973B (en) | Industrial preparation method of 4- (6-aminopyridine-3-yl) piperazine-1-carboxylic acid tert-butyl ester | |
| CN101781264B (en) | Production method of 1-methyl-5-mercapto-1,2,3,4-tetrazole | |
| CN101914064B (en) | Method for preparing sulfachlororyridazine sodium | |
| CN102127081B (en) | Preparation method of adenine | |
| CN109553645B (en) | Method for extracting low-content erythromycin A in fermentation solution | |
| CN106279197B (en) | The purifying of isobide reaction solution and crystallization processes | |
| CN102212035A (en) | Preparation method for sulfamethoxypyrazine | |
| CN111217760B (en) | Synthetic method of sulfachloropyrazine sodium | |
| CN108558776B (en) | Preparation method of 2, 4-diamino-5-nitroso-6-hydroxypyrimidine and guanine | |
| CN110713471B (en) | Synthetic method of trimetazidine hydrochloride | |
| CN105198905A (en) | Method for preparing ultrapure marbofloxacin through purification | |
| CN105732660A (en) | Preparation method of levofloxacin intermediate | |
| CN105175316B (en) | A kind of method for preparing laxative picosulfate sodium | |
| CN104557724A (en) | Telmisartan amorphous crystal and preparation method thereof | |
| CN104418810A (en) | New synthetic route of levosimendan |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C14 | Grant of patent or utility model | ||
| GR01 | Patent grant | ||
| ASS | Succession or assignment of patent right |
Owner name: JIANGSU TIANHE PHARMACEUTICAL CO., LTD. Free format text: FORMER OWNER: YANGZHOU TIANHE PHARMACEUTICAL CO., LTD. Effective date: 20150316 |
|
| C41 | Transfer of patent application or patent right or utility model | ||
| TR01 | Transfer of patent right |
Effective date of registration: 20150316 Address after: 225200, No. 1, Sanjiang Avenue, Yanjiang Development Zone, Jiangdu District, Jiangsu, Yangzhou Patentee after: Sky, Jiangsu and pharmaceutical Co. Ltd Address before: 225200, 86, twin tree road, fairy town, Jiangdu District, Jiangsu, Yangzhou Patentee before: Zhejiang Tianhe Pharmaceutical Co., Ltd. |