CN104945338A - Process for preparing sulfachloropyrazine sodium - Google Patents
Process for preparing sulfachloropyrazine sodium Download PDFInfo
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- CN104945338A CN104945338A CN201510344896.XA CN201510344896A CN104945338A CN 104945338 A CN104945338 A CN 104945338A CN 201510344896 A CN201510344896 A CN 201510344896A CN 104945338 A CN104945338 A CN 104945338A
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- sulfaclozine
- sulfatyf
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
- C07D241/02—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings
- C07D241/10—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
- C07D241/14—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D241/20—Nitrogen atoms
- C07D241/22—Benzenesulfonamido pyrazines
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention relates to a process for preparing sulfachloropyrazine sodium and belongs to the technical field of chemical synthesis. The process comprises the steps of taking dimethylformamide and dimethylbenzene as solvents, taking potassium carbonate as an acid-binding agent, causing 2,6-dichloropyrazine and 4-aminobenzenesulfonamide to react at 140-145 DEG C to generate sulfaclozine, adding water to perform mixing to total dissolution, performing standing layering, performing aqueous phase shifting to a decolorizer, adding activated carbon to perform decoloration, transferring filtrate into an acid adjustment kettle, using glacial acetic acid to perform acid adjustment of the pH to 5-6, and performing centrifugation to obtain sulfaclozine wet products; adding methanol, water and sodium hydroxide into a salt reactor, adding the sulfaclozine wet products, performing heating to 50-55 DEG C, using 30% sodium hydroxide aqueous solution to adjust the pH to 12-13, adding activated carbon to perform decoloration, transferring filtrate to a crystallizer, performing cooling to 10-15 DEG C, and performing crystallization, centrifugation and drying to obtain white powder-shaped sulfachloropyrazine sodium. Compared with method reported in documents, the process has the advantages of less production equipment, short working hours, low energy consumption and easiness in achieving clean production.
Description
Technical field
The present invention relates to a kind of medicine being used for the treatment of coccidiosis of chicken---the preparation technology of sulfaclozine sodium, belongs to chemosynthesis technical field.
Background technology
Sulfaclozine sodium, chemical name: N-(the chloro-3-pyrazinyl of 5-) 4-aminobenzene sulfonamide sodium salt-hydrate is white or pale yellow powder, soluble in water.Sulfaclozine sodium has wide spectrum coccidiostat activity, is widely used in prevention and therapy coccidiosis of chicken, and its Antibacterial Mechanism is identical with Sulfaquinoxaline Sodium CP2000, with PABA Competitive assays dihydrofolate synthetase, hinder the synthesis of dihydrofolic acid, finally affect the synthesis of nucleoprotein, suppress the growth and reproduction of coccidia.Mainly act on coccidia s-generation schizont, also have restraining effect to first-generation schizont.Peak of action after infection the 4th day.Application this product does not affect host and produces immunizing power to coccidia, and the anti-microbial effect stronger than Sulfaquinoxaline Sodium CP2000.Also certain curative effect is had to chicken cholera, typhoid fever.
Within 1945, American Cyanamid Co. is in the preparation were established first proposing sulfaclozine sodium, and chemical equation is as follows:
Step one: the preparation of Sulfatyf
There is nucleophilic substitution reaction under certain condition and generate Sulfatyf in dichloropyrazine (2,3-dichloropyrazine or 2,5-dichloropyrazine or 2,6-dichloropyrazine) and 4-aminobenzene sulfonamide;
Step 2: the preparation of sulfaclozine sodium
Sulfatyf and sodium hydroxide react under certain condition and generate Sulfatyf sodium salt.
The preparation technology of the sulfaclozine sodium of domestic and international report is based on this route, but the processing condition adopted are not quite similar, and mainly contain following two kinds:
The processing condition provided in patent GB612385, the US2475673 of processing condition American Cyanamid Co.'s application in, 1945 are as follows:
The preparation process condition of step one, Sulfatyf
By 100 parts of dichloropyrazines, 115 parts of 4-aminobenzene sulfonamides, 92 parts of salt of wormwood add in suitable reactor, be heated to 123 DEG C, material starts frit reaction, generate carbonic acid gas and overflow reaction system, release reaction heat simultaneously, the temperature of material is made to rise to rapidly 152 DEG C, dichloropyrazine is back in reactor through condenser condenses, when carbonic acid gas overflows, reaction terminates, be cooled to 152 DEG C, add 630 parts of water stirring and dissolving, the dichloropyrazine that 35 parts have neither part nor lot in reaction is reclaimed through wet distillation, then leftover materials are cooled to 10 DEG C, make the 4-aminobenzene sulfonamide crystallization having neither part nor lot in reaction, through being separated, dry 17 parts of sulfanilamide (SN), be 3 by analysis mother liquor hydrochloric acid adjust pH, the Sulfatyf of generation is separated out, through centrifugation, dry Sulfatyf crude product 115 parts, reaction yield is that 88%(is to participate in the dichloropyrazine reacted).
The preparation process condition of step 2, sulfaclozine sodium
Sulfatyf crude product sodium hydroxide is become sodium salt, makes it water-soluble, add activated carbon decolorizing, then Sulfatyf is being obtained according to the method described in step one, carry out purifying (this process is referred to as " alkali, sour intermodulation method "), and then use sodium hydroxide salify, freezing and crystallizing.
These processing condition have following shortcoming:
1), reaction solvent is not added in this technique, be warming up to 123 DEG C, material melts starts reaction, exothermic heat of reaction makes temperature of reaction rise rapidly most 152 DEG C, easy generation punching material, and reaction system is solid-liquid two-phase, because temperature of reaction is higher, namely there is side reaction, i.e. two molecule dichloropyrazines and 4-aminobenzene sulfonamide reaction generation two (4-aminobenzene sulfonamide base) pyrazine, the physico-chemical property of this by product and the physico-chemical property of Sulfatyf similar, not easily remove by " alkali, sour intermodulation method " method, thus affect the quality of final finished.
2), " alkali, sour intermodulation method " technique of preparing Sulfatyf can produce a large amount of brine wastes, is unfavorable for the biochemical treatment of waste water.
Processing condition two, the patent of being applied for by Yangzhou Milky Way pharmaceutcal corporation, Ltd, the processing condition in CN102617489A are as follows:
The preparation process condition of step one, Sulfatyf
By under dichloropyrazine, 4-aminobenzene sulfonamide, salt of wormwood and phase-transfer catalyst four butyl bromation amine or benzyltriethylammoinium chloride catalysis, in 100 ~ 120 DEG C of insulation reaction 6 ~ 15h in toluene, then through reclaiming toluene, reaction mass is lowered the temperature, add water, acid is adjusted, and is separated, dry Sulfatyf, and reaction yield reaches 86 ~ 87%.
The preparation process condition of step 2, sulfaclozine sodium
First Sulfatyf is used sodium hydroxide salify, obtained Sulfatyf sodium-hydrate crude product, then use methyl alcohol-methylene dichloride mixed solvent to carry out recrystallization, detect through HPLC, purity is greater than 99.5%.
These processing condition have following shortcoming:
1), this technique in the preparation process of sulfaclozine sodium, reaction terminate after need Distillation recovery toluene.
2), this technique has three processes, the i.e. preparation of Sulfatyf, the preparation of Sulfatyf sodium-hydrate crude product and sulfaclozine sodium hydrate crystallization are refining, the sulfaclozine sodium of preparation needs to carry out an one-step refining again, technological process is more loaded down with trivial details, and the total recovery of three processes is 71.2%.
Preparation process condition in the patent CA645868A of processing condition American Cyanamid Co.'s application in three, 1945
The preparation process condition of step one, Sulfatyf
By dichloropyrazine, 4-aminobenzene sulfonamide, salt of wormwood, glidant in 70 ~ 160 DEG C, carry out frit reaction, then through adding water decolorization, acid adjust pH is 8.8, cooling, and excessive 4-aminobenzene sulfonamide is separated out, filtrate is warming up to 70 DEG C, being adjusted to pH value with acid is 5.8, and the Sulfatyf of generation is separated out, through centrifugation, dry Sulfatyf crude product.
This operational path has following shortcoming:
1), in this technique the consumption of 4-aminobenzene sulfonamide is 4 times of theoretical amount, greatly excessive, and reaction terminates the rear 4-aminobenzene sulfonamide needing removing not participate in reaction, and technics comparing is loaded down with trivial details.
2), in this technique salt of wormwood is 1.78 times of theoretical amount, greatly excessive, will remove the acid amount that the salt of wormwood not participating in reaction needs to consume larger after reaction terminates.
3), in this technique, glidant kind and consumption affect larger on the yield of product.
4), in this technique temperature of reaction is 70 ~ 160 DEG C, relevant with glidant kind used.
Summary of the invention
The present invention adopts new processing condition to prepare sulfaclozine sodium, shortens the reaction times, improves reaction yield, achieves the recovery of solvent, reduces production cost, further illustrates the present invention how to realize below by specific embodiment:
The preparation process condition of step one, Sulfatyf
By 100 parts of dichloropyrazines, 110 parts of 4-aminobenzene sulfonamides, 100 parts of salt of wormwood, 51 parts of dimethyl formamides, 150 parts of dimethylbenzene are put in reactor, stir and are warming up to 140 ~ 145 DEG C, and insulation reaction 5h, divide water outlet simultaneously.80 ~ 90 DEG C are cooled to after insulation reaction terminates, add 1000 parts of water, stir 1h and all dissolve to solid, stop stirring, layering after standing 1h, lower floor's aqueous phase proceeds in decolorizer, adds 30 parts of gacs, in 90 ~ 100 DEG C of insulation decolouring 2h, filtering gac while hot, filtrate proceeds to acid and adjusts in still, and be adjusted to 5 ~ 6 with Glacial acetic acid, then centrifugation obtains 500 ~ 550 parts of Sulfatyf wet products (water content is about 50%).
The preparation process condition of step 2, sulfaclozine sodium
By 350 parts of methyl alcohol, 75 parts of water and 35 parts of sodium hydroxide are put in salt-forming reactor, stir 1h, 500 ~ 550 of step one gained parts of Sulfatyf wet products (water content is about 50%) are added, stirring is warming up to 50 ~ 55 DEG C, with the aqueous sodium hydroxide solution adjust pH 12 ~ 13 of 30%, add 25 parts of gacs, be warming up to 70 ~ 75 DEG C, insulation decolouring 2h, filtered while hot gac, filtrate proceeds in crystallizer, be cooled to 10 ~ 15 DEG C, crystallization 3h, centrifugation, dry white powder 255 parts, by infrared absorption spectrum (IR) (see Fig. 1) and differential thermal and thermogravimetric analysis (DSC and TG) (see Fig. 2), prove Sulfatyf sodium-hydrate, the total molar yield 78.5% of two-step reaction is (to participate in 2 of reaction, 6-dichloropyrazine meter).
accompanying drawing illustrates:
Fig. 1 is infrared spectrogram; Fig. 2 is differential thermal analysis (rate of heat flow-temperature) curve and thermogravimetric analysis (weight percentage-temperature) graphic representation.
Claims (1)
1. a preparation technology for sulfaclozine sodium, is characterized in that it in turn includes the following steps:
(1), by 150 parts of dichloropyrazines, 175 parts of 4-aminobenzene sulfonamides, 138 parts of salt of wormwood and 51 parts of N, dinethylformamide and 150 parts of dimethylbenzene drop in reactor, be warming up to 140 ~ 145 DEG C, insulation reaction is to overflowing from reaction system without carbon dioxide;
(2), by temperature of reaction system be down to 70 ~ 80 DEG C, add 1000 parts of water, stir and make the dissolution of solid in reaction system complete, stratification;
(3), the aqueous phase of lower floor separated, proceed in decoloring reaction device, add 30 parts of gacs, be warming up to 90 ~ 100 DEG C of decolouring 3h, filtering adsorbent charcoal while hot, filtrate proceeds to acid and adjusts in still, with Glacial acetic acid adjust pH 5-6, separate out nefrosulfin piperazine, centrifugation obtains 500 ~ 550 parts of nefrosulfin piperazine wet products (water content is about 50%);
(4), by remaining for upper strata dimethylbenzene phase recovery;
(5), by 350 parts of methyl alcohol, 75 parts of water and 35 parts of sodium hydroxide are put in salt-forming reactor, stir 1h, 500 ~ 550 parts of Sulfatyf wet products (water content is about 50%) of step (3) gained are added, stirring is warming up to 50 ~ 55 DEG C, with the aqueous sodium hydroxide solution adjust pH 12 ~ 13 of 30%, add 25 parts of gacs, be warming up to 70 ~ 75 DEG C, insulation decolouring 2h, filtered while hot gac, filtrate proceeds in crystallizer, be cooled to 10 ~ 15 DEG C, crystallization 3h, centrifugation, dry white powder 255 parts, by infrared absorption spectrum (IR) and differential thermal and thermogravimetric analysis (DSC and TG), prove Sulfatyf sodium-hydrate, the total molar yield 78.5% of two-step reaction is (to participate in 2 of reaction, 6-dichloropyrazine meter).
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| CN201510344896.XA CN104945338A (en) | 2015-06-23 | 2015-06-23 | Process for preparing sulfachloropyrazine sodium |
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| CN201510344896.XA CN104945338A (en) | 2015-06-23 | 2015-06-23 | Process for preparing sulfachloropyrazine sodium |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111217760A (en) * | 2020-03-27 | 2020-06-02 | 湖南吴赣药业有限公司 | Synthetic method of sulfachloropyrazine sodium |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPH05331150A (en) * | 1992-05-29 | 1993-12-14 | Koei Chem Co Ltd | Production of 2-alkoxy-3-sulfanylamidopyrazine |
| CN102212035A (en) * | 2011-04-25 | 2011-10-12 | 扬州天和药业有限公司 | Preparation method for sulfamethoxypyrazine |
| CN102617489A (en) * | 2012-03-21 | 2012-08-01 | 扬州天和药业有限公司 | Preparation method of sulfaclozine sodium |
-
2015
- 2015-06-23 CN CN201510344896.XA patent/CN104945338A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPH05331150A (en) * | 1992-05-29 | 1993-12-14 | Koei Chem Co Ltd | Production of 2-alkoxy-3-sulfanylamidopyrazine |
| CN102212035A (en) * | 2011-04-25 | 2011-10-12 | 扬州天和药业有限公司 | Preparation method for sulfamethoxypyrazine |
| CN102617489A (en) * | 2012-03-21 | 2012-08-01 | 扬州天和药业有限公司 | Preparation method of sulfaclozine sodium |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111217760A (en) * | 2020-03-27 | 2020-06-02 | 湖南吴赣药业有限公司 | Synthetic method of sulfachloropyrazine sodium |
| CN111217760B (en) * | 2020-03-27 | 2021-11-26 | 湖南吴赣药业有限公司 | Synthetic method of sulfachloropyrazine sodium |
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Application publication date: 20150930 |