CN105254575B - A kind of synthetic method of sulphadiazine - Google Patents
A kind of synthetic method of sulphadiazine Download PDFInfo
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- CN105254575B CN105254575B CN201510787846.9A CN201510787846A CN105254575B CN 105254575 B CN105254575 B CN 105254575B CN 201510787846 A CN201510787846 A CN 201510787846A CN 105254575 B CN105254575 B CN 105254575B
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- sulphoamidine
- sulphadiazine
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- mda
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
- C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
- C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more 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, directly attached to ring carbon atoms
- C07D239/69—Benzenesulfonamido-pyrimidines
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- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
Abstract
The invention discloses a kind of synthetic method of sulphadiazine, is that method of the invention has reaction condition gentle, and the reaction time is short, high conversion rate using sulphoamidine and MDA as Material synthesis, beneficial to the advantage of industrialized production.
Description
Technical field
The present invention relates to a kind of synthetic method of sulphadiazine, belong to organic chemical synthesis field.
Background technology
Sulfa drugs（sulfonamides；sulfa drugs）, it is that the synthesis that a kind of yield is big, wide in variety is anti-infective
Medicine, occupy critical role in the development and production of medicine.Find Prontosil within 1932, start the new century of chemotherapy
Member.It is the basic structure for producing antibacterial action that nineteen thirty-five, Trefonel and its colleague, which demonstrate sulfa drugs,.Make a general survey of sulfa drug
The development of thing, the sulfa drugs of getting up early synthesis are largely eliminated, and only sulphadiazine is still applied to clinic.It is now multi-purpose
Infection caused by treatment sensitive bacterial and other sensitive pathogenic microorganisms.
Sulphadiazine is crystallization or the powder of white or off-white color, odorless, tasteless, and it is dark to meet photochromic gradual change.In ethanol or third
Slightly soluble in ketone, it is insoluble in water, it is readily soluble in sodium hydroxide test solution or ammonia solution, dissolved in watery hydrochloric acid.Its molecular formula is as follows：
The synthetic method of sulphadiazine is different, and summing up mainly has two types：
（1）Route using N-acetylsulfanilyl chloride as initiation material
Using N-acetylsulfanilyl chloride and 2- aminopyrimidines as initiation material, under conditions of anhydrous pyridine makees condensing agent
Reacted, through steps such as basic hydrolysis, acid neutralizations, you can obtain free sulphadiazine compound, reaction equation is as follows：
Condensation：
Hydrolyze and refined：
（2）Synthetic route using sulphoamidine as initiation material
With sulphoamidine（Sulfamidine, SG）With corresponding " C3compounds " with reactivity be condensed instead
Should.Et such as using propilolic alcohol as Material synthesis2NCH=CHCHO, the [(CH using vinyl ethyl ether as Material synthesis3)2N+=CN-CH=
CHOC2H5]O-PCl2Deng " C3compounds ".
In above synthetic route, method（1）It is more commonly used, but its raw material N-acetylsulfanilyl chloride easily hydrolyzes,
So that the free acid increase in reaction solution, causes to weaken pyridine condensation efficiency, hinders being smoothed out for whole condensation reaction, therefore its is right
The moisture of raw material and the degree of drying of equipment require more strict, and condensation reaction time is grown.Method（2）There is also compared with
More problems, by propilolic alcohol to have two step compressive reactions in the method for Material synthesis, security is poor, and equipment investment is more；By vinyl
Ether synthetic method medium vinyl ether low boiling point（36℃）, it is necessary to huge refrigeration system, power consumption is high, and security is poor.
The content of the invention
The invention discloses a kind of synthetic method of sulphadiazine, and gentle with reaction condition, the reaction time is short, operation letter
It is single, high conversion rate, beneficial to the advantage of industrialized production.This method comprises the following steps：
Sulphoamidine completes ring-closing condensation reaction with MDA in the presence of condensing agent sodium methoxide, after reaction terminates, reclaims first
Alcohol, then adjust its pH, charcoal absorption decolouring, filtering, crystallization, dry etc. through alkali lye and operate to obtain sulphadiazine compound；It is special
Sign is：
Further, the preparation method of the sulphoamidine is as follows：
A is by NH4Cl with（NH4）2CO3After mixing according to a certain percentage, activated-carbon catalyst is added, dicyandiamide is added and adds
Heat keeps 30 ~ 35min to melting, at 150 ~ 180 DEG C；；The purpose that ammonium carbonate is added in the reaction is on the one hand to reduce
The acidity of product, reduce corrosiveness of the product to equipment；On the other hand, the guanidine carbonate of generation shortens following step B
Reaction time and reduce the addition of carbonate, and make it that reaction is more abundant；Activated-carbon catalyst can promote NH4Cl
With（NH4）2CO3Caused NH3The fracture of H-C keys in molecule, the activation energy of generation guanidinesalt is reduced, so as to reduce the temperature of reaction.
B adds sulfanilamide (SN) into above fused solution, and carbonate continues to melt, and 145 ~ 190 DEG C are warming up in 25min, keeps 30min；
After C will add boiling water in mixture obtained by step B, gained suspension is cooled to 40 DEG C, obtains sulphoamidine crude product.
Further, NH4Cl with（NH4）2CO3Mol ratio be 1:1.5-1:3.
Further, the addition of activated-carbon catalyst is 0.5%-1.5%.
Further, sulphoamidine and MDA mol ratio are 1:1.2-1:2.
Further, condensing agent is the methanol solution of 25% sodium methoxide, and its dosage is reactant sulphoamidine and the total matter of MDA
1-2 times of amount.
Further, cyclic condensation temperature is 60-80 DEG C, reaction time 2-4h.
Further, alkali lye used is saturated calcium hydroxide solution, pH 9-10.5.
Further, activated carbon dosage is the 8% of decolouring liquid quality.
The technique effect and advantage of the present invention is：
On the one hand, the present invention selects dicyandiamide and NH4The method of Cl reactions prepares sulphoamidine, the method by the generation of guanidinesalt and
The generation of sulphoamidine is completed in a step, and the raw material of use is ammonium salt, dicyandiamide, sulfanilamide (SN), due to being completed in single step reaction,
Amino on phenyl ring need not be protected so that the preparation process of whole sulphoamidine is simple, and the time is short, and reduces NH3
Discharge, product quality is high.The sulphoamidine prepared needs not move through purification operations and just may apply to follow-up sulphadiazine
Synthesis in, so as to simplify reactions steps, saved cost.On the other hand, the present invention is carried out from sulphoamidine and MDA
Ring-closing condensation reaction generates target product sulphadiazine, and reaction speed is fast, and reaction condition is gentle, and yield is high, and is used in course of reaction
To methanol can be recycled recycling, it is subsequently easy to the purification operations of product sulphadiazine.The conjunction of whole sulphadiazine
Into process to the less demanding of equipment and raw material, raw material is readily available, and is reacted and is easily carried out.
Embodiment
Illustrate the technical scheme of invention below by way of specific instantiation.It should be understood that one or more that the present invention mentions
Individual method and step does not repel other method step before and after the combination step also be present or specifically mentioned at these the step of
Between can also insert other method step；It should also be understood that these embodiments are merely to illustrate the present invention rather than limitation originally
The scope of invention.Moreover, unless otherwise indicated, the numbering of various method steps is only to differentiate the convenient tool of various method steps, and
It is non-to be altered or modified for the ordering or the enforceable scope of the restriction present invention, its relativeness of limitation various method steps,
In the case where changing technology contents without essence, when being also considered as the enforceable category of the present invention.
Embodiment 1：A kind of synthetic method of sulphadiazine comprises the following steps：
A is by 8.6g NH4Cl and 23.1g（NH4）2CO3After mixing according to a certain percentage, activated-carbon catalyst is added, then add
Enter 32g dicyandiamides to be heated to melting, 30min is kept at 150 DEG C；
B adds 80g into above fused solution to be continued to melt, is warming up in 25min to amino sulfanilamide (SN), 70g sodium carbonate
150 DEG C, keep 30min；
400ml boiling water is added in mixture obtained by C to step B, after stirring, gained suspension is cooled to 40 DEG C,
Filtering, obtains sulphoamidine crude product.
The methanol solution 93g of 25% sodium methoxide, sulphoamidine crude product 33g are added into flask successively, stirs lower addition MDA
13.5g, 65 DEG C are warming up to, react 2h, complete ring-closing condensation reaction, sulphadiazine crude product is obtained after reclaiming methanol.Add water into crude product
200ml, heating, pH to 9.5, Quan Ronghou is adjusted with saturated calcium hydroxide, adds activated carbon 20g, decolourized in 80 DEG C of heating.Cross
Filter, 0.5g ammonium chlorides are added in filtrate, with 10% vinegar acid for adjusting pH to 5.2.Crystal is separated out, is filtered after cold, washing, dry sulphur
Amic metadiazine fine work, yield 89%, purity 98.0%.
Embodiment 2：A kind of synthetic method of sulphadiazine comprises the following steps：
A is by 8.6g NH4Cl and 30.9g（NH4）2CO3After mixing according to a certain percentage, activated-carbon catalyst is added, then add
Enter 32g dicyandiamides to be heated to melting, 30min is kept at 170 DEG C；
B adds 80g into above fused solution to be continued to melt, is warming up in 25min to amino sulfanilamide (SN), 70g sodium carbonate
150 DEG C, keep 30min；
400ml boiling water is added in mixture obtained by C to step B, after stirring, gained suspension is cooled to 40 DEG C,
Filtering, obtains sulphoamidine crude product.
The methanol solution 93g of 25% sodium methoxide, sulphoamidine crude product 33g are added into flask successively, stirs lower addition MDA
12.0g, 70 DEG C are warming up to, react 2.5h, complete ring-closing condensation reaction, sulphadiazine crude product is obtained after reclaiming methanol.Add into crude product
Water 200ml, heating, pH to 10.0, Quan Ronghou is adjusted with saturated calcium hydroxide, adds activated carbon 18g, decolourized in 80 DEG C of heating.
Filter, 0.5g ammonium chlorides are added in filtrate, with 10% vinegar acid for adjusting pH to 5.2.Crystal is separated out, filters, washing, dries after cold
Sulphadiazine fine work, yield 91%, purity 96.9%.
Embodiment 3：A kind of synthetic method of sulphadiazine comprises the following steps：
A is by 8.6g NH4Cl and 46.2g（NH4）2CO3After mixing according to a certain percentage, activated-carbon catalyst is added, then add
Enter 32g dicyandiamides to be heated to melting, 30min is kept at 180 DEG C；
B adds 80g into above fused solution to be continued to melt, is warming up in 25min to amino sulfanilamide (SN), 70g sodium carbonate
150 DEG C, keep 30min；
400ml boiling water is added in mixture obtained by C to step B, after stirring, gained suspension is cooled to 40 DEG C,
Filtering, obtains sulphoamidine crude product.
Add the methanol solution 100g of 25% sodium methoxide, sulphoamidine crude product 40g into flask successively, stir and lower add the third two
Aldehyde 14.5g, 60 DEG C are warming up to, react 4h, complete ring-closing condensation reaction, sulphadiazine crude product is obtained after reclaiming methanol.Add into crude product
Water 200ml, heating, pH to 10.5, Quan Ronghou is adjusted with saturated calcium hydroxide, adds activated carbon 20g, decolourized in 80 DEG C of heating.
Filter, 0.5g ammonium chlorides are added in filtrate, with 10% vinegar acid for adjusting pH to 5.2.Crystal is separated out, filters, washing, dries after cold
Sulphadiazine fine work, yield 90%, purity 97.1%.
Claims (5)
1. a kind of synthetic method of sulphadiazine, its building-up process are as follows：The work of sulphoamidine and MDA in condensing agent sodium methoxide
With lower completion ring-closing condensation reaction, after reaction terminates, reclaim methanol, then adjust its pH through alkali lye, charcoal absorption is decolourized, filtering,
Crystallization, dry sulphadiazine compound；The preparation method of the sulphoamidine is as follows：
A, by NH4Cl and (NH4)2CO3After mixing according to a certain percentage, activated-carbon catalyst is added, dicyandiamide is added and is heated to
Melting, 30-35min is kept at 150-180 DEG C；
B, into above fused solution, addition sulfanilamide (SN), carbonate continue to melt, and 145-190 DEG C is warming up in 25min, keep
30min；
C, after boiling water being added in mixture obtained by step B, gained suspension is cooled to 40 DEG C, filtering, obtains sulphoamidine crude product；
NH4Cl and (NH4)2CO3Mol ratio be 1:1.5-1:3；
Sulphoamidine is 1 with MDA mol ratio:1.2-2；
Condensing agent is the methanol solution of 25% sodium methoxide, and its dosage is 1-2 times of reactant sulphoamidine and MDA gross mass.
2. according to the method for claim 1, it is characterised in that the addition of activated-carbon catalyst is 0.5%-1.5%.
3. according to the method for claim 1, it is characterised in that cyclic condensation temperature is 60-80 DEG C, reaction time 2-4h.
4. according to the method for claim 1, it is characterised in that alkali lye used is saturated calcium hydroxide solution, pH 9-
10.5。
5. according to the method for claim 1, it is characterised in that activated carbon dosage is the 8% of decolouring liquid quality.
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN112480014A (en) * | 2019-09-11 | 2021-03-12 | 重庆康乐制药有限公司 | Synthetic method of sulfadiazine |
| CN110642788A (en) * | 2019-10-24 | 2020-01-03 | 广州大学 | Preparation method of 5-bromo-2-substituted pyrimidine compounds |
| CN110818625A (en) * | 2019-12-09 | 2020-02-21 | 苏州黄河制药有限公司 | Preparation method of sulfasalazine |
| CN111269187A (en) * | 2020-03-18 | 2020-06-12 | 湖南吴赣药业有限公司 | Environment-friendly synthesis method of sulfadiazine |
| CN114853639B (en) * | 2022-05-31 | 2024-02-23 | 湖南吴赣药业有限公司 | Safe continuous production method of sulfadiazine |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US2435002A (en) * | 1942-01-30 | 1948-01-27 | Ciba Pharm Prod Inc | Process for the manufacture of para-aminobenzene-sulphonamidopyrimidines |
| SU471360A1 (en) * | 1971-12-21 | 1975-05-25 | Всесоюзный Научно-Исследовательский Химико-Фармацевтический Институт Им.С.Орджоникидзе | The method of obtaining-aminobenzenesulfonylguanidine |
| CN1034719A (en) * | 1988-12-29 | 1989-08-16 | 昆山制药厂 | A kind of method of producing sulfapyrimidine |
-
2015
- 2015-11-17 CN CN201510787846.9A patent/CN105254575B/en active Active
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US2435002A (en) * | 1942-01-30 | 1948-01-27 | Ciba Pharm Prod Inc | Process for the manufacture of para-aminobenzene-sulphonamidopyrimidines |
| SU471360A1 (en) * | 1971-12-21 | 1975-05-25 | Всесоюзный Научно-Исследовательский Химико-Фармацевтический Институт Им.С.Орджоникидзе | The method of obtaining-aminobenzenesulfonylguanidine |
| CN1034719A (en) * | 1988-12-29 | 1989-08-16 | 昆山制药厂 | A kind of method of producing sulfapyrimidine |
Non-Patent Citations (4)
| Title |
|---|
| 含氮六元杂环类化合物合成研究;赵淑娟.;《中国优秀硕士学位论文全文数据库·工程科技I辑》;20041215(第04期);正文第28页1.2.1节路线一合成反应方程式 * |
| 用丙炔醇合成磺胺嘧啶;В.И.赫米里夫斯基，徐百汇.;《化学世界》;19560131;第11卷(第1期);第32-34页 * |
| 磺胺脒合成工艺研究;杨勇.;《中国优秀硕士学位论文全文数据库•工程科技I辑》;20021215(第02期);正文第4页式2.6-2.7、例2 * |
| 缩醛法生产磺胺嘧啶;陈晓晨.;《中国医药工业杂志》;19921231;第23卷(第12期);第537-538页实验部分一至四节 * |
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