CN103910687B - The preparation method of 4-(p-amino benzene sulfonyl)-5-methoxyl group-6 chlorine pyrimidine - Google Patents
The preparation method of 4-(p-amino benzene sulfonyl)-5-methoxyl group-6 chlorine pyrimidine Download PDFInfo
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- CN103910687B CN103910687B CN201410083347.7A CN201410083347A CN103910687B CN 103910687 B CN103910687 B CN 103910687B CN 201410083347 A CN201410083347 A CN 201410083347A CN 103910687 B CN103910687 B CN 103910687B
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- methoxyl group
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- benzene sulfonyl
- amino benzene
- chlorine pyrimidine
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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)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The present invention relates to the preparation method of a kind of 4-(p-amino benzene sulfonyl)-5-methoxyl group-6 chlorine pyrimidine, comprise the following steps: (a) in reaction vessel, add respectively chlorination 1-butyl-3-methylimidazole, sulfanilamide (SN) sodium, after stirring, add 5-methoxyl group-4,6-dichloro pyrimidine reacts and within 0.5～2 hour, forms mixture at 88～92 DEG C; (b) in described mixture, add watery hydrochloric acid to regulate pH to 7.0～7.2, be cooled to subsequently 15～20 DEG C of crystallizations, centrifugation obtains mother liquor and filter residue; (c) described mother liquor is warming up to 68～72 DEG C, drips subsequently watery hydrochloric acid and regulate pH to 3.8～4.1, discharging while hot, centrifugal dehydration obtains end product. The preparation method of 4-of the present invention (p-amino benzene sulfonyl)-5-methoxyl group-6 chlorine pyrimidine, utilize chlorination 1-butyl-3-methyl miaow to substitute high boiling DMF as solvent, no longer need Distillation recovery DMF, weaken on the one hand the requirement to production equipment, can greatly reduce on the other hand the energy consumption of enterprise, meet the requirement of country about energy-conserving and environment-protective.
Description
Technical field
The present invention relates to a kind of preparation method of sulfamethoxine intermediate, be specifically related to a kind of 4-(P-aminobenzene-sulfonamideBase) preparation method of-5-methoxyl group-6 chlorine pyrimidine.
Background technology
Sulfamethoxine, chemistry 4-(p-amino benzene sulfonyl)-5 by name, 6-dimethoxypyridin, is generally used for inflammationTreatment, as infection of the upper respiratory tract tonsillitis, bacillary dysentery enteritis, skin infection etc., also can coordinate with other drug, is used for the treatment of lungTuberculosis, scrofula. Sulfamethoxine has experienced several generations' research and development, and its production technology is progressively stable, is specially following systemStandby step: step (1):
Step (2):
Step (3):
Step (4):
Step (5):
Wherein, 4-(p-amino benzene sulfonyl)-5-methoxyl group-6 chlorine pyrimidine is the intermediate of preparation in step (4), itsProductive rate directly affects productive rate and the cost of sulfamethoxine. Granted publication number is that the Chinese invention patent of CN102304095B disclosesThe preparation method of a kind of 4-(p-amino benzene sulfonyl)-5-methoxyl group-6 chlorine pyrimidine is at DMF (DMF)Middle by sulfanilamide (SN) sodium and 5-methoxyl group-4,6-dichloro pyrimidine reacts. Although DMF is good solvent, its boiling point is higher(reaching 150 DEG C), thereby in removal process, need to expend a large amount of production capacities, not only increase the operation cost of enterprise, and rightProduction equipment is also great test, easily causes it to scrap.
Summary of the invention
The present invention seeks to provide in order to overcome the deficiencies in the prior art a kind of does not need to use the 4-of DMF (to aminoBenzene sulfonamido) preparation method of-5-methoxyl group-6 chlorine pyrimidine.
For achieving the above object, the technical solution used in the present invention is: a kind of 4-(p-amino benzene sulfonyl)-5-methoxyThe preparation method of base-6 chlorine pyrimidine, comprises the following steps:
(a) in reaction vessel, add respectively chlorination 1-butyl-3-methylimidazole, sulfanilamide (SN) sodium, after stirring, add 5-methoxyBase-4,6-dichloro pyrimidine reacts and within 0.5～2 hour, forms mixture at 88～92 DEG C;
(b) in described mixture, add watery hydrochloric acid to regulate pH to 7.0～7.2, be cooled to subsequently 15～20 DEG C of crystallizations,Centrifugation obtains mother liquor and filter residue;
(c) described mother liquor is warming up to 68～72 DEG C, drips subsequently watery hydrochloric acid and regulate pH to 3.8～4.1, go out while hotMaterial, centrifugal dehydration obtains end product.
Optimally, in step (b), described mixture is checked pH value before being cooled to 15～20 DEG C of crystallizations.
Optimally, in step (b), described filter residue is with recycling after deionized water washing.
Optimally, described watery hydrochloric acid concentration is 10～15wt%.
Optimally, in step (c), more than 90 DEG C hot wash for described end product, and be placed at 105～115 DEG C dryDry.
Because technique scheme is used, the present invention compared with prior art has following advantages: 4-of the present invention is (to aminoBenzene sulfonamido) preparation method of-5-methoxyl group-6 chlorine pyrimidine, utilizes chlorination 1-butyl-3-methyl miaow to substitute as solvent highThe DMF of boiling point, no longer needs Distillation recovery DMF, has weakened the requirement to production equipment on the one hand, on the other hand can be greatlyReduce the energy consumption of enterprise, meet the requirement of country about energy-conserving and environment-protective.
Detailed description of the invention
The preparation method of 4-of the present invention (p-amino benzene sulfonyl)-5-methoxyl group-6 chlorine pyrimidine, comprises the following steps:(a) in reaction vessel, add respectively chlorination 1-butyl-3-methylimidazole, sulfanilamide (SN) sodium, after stirring, add 5-methoxyl group-4,6-bis-Chlorine pyrimidine reacts and within 0.5～2 hour, forms mixture at 88～92 DEG C; (b) in described mixture, add watery hydrochloric acid to regulatePH to 7.0～7.2, are cooled to 15～20 DEG C of crystallizations subsequently, and centrifugation obtains mother liquor and filter residue; (c) described mother liquor is heated upTo 68～72 DEG C, drip subsequently watery hydrochloric acid and regulate pH to 3.8～4.1, discharging while hot, centrifugal dehydration obtains end product. Utilize chlorineChange 1-butyl-3-methyl miaow and substitute high boiling DMF as solvent, no longer need Distillation recovery DMF, weakened life on the one handThe requirement of product equipment, can greatly reduce the energy consumption of enterprise on the other hand, meets the requirement of country about energy-conserving and environment-protective.
In actual mechanical process, add watery hydrochloric acid to regulate after pH, mixture pH value still may produce fuctuation within a narrow range, because ofIn this step (b), mixture is checked pH value before being cooled to 15～20 DEG C of crystallizations. And now crystallized product is sulfanilamide (SN), is importantPharmaceutical intermediate, after its crystallization, (being filter residue) is with recycling after deionized water washing. And in step (c), drip rareSalt acid for adjusting pH to 3.8～4.1, the hydrochloric acid that preferred mass concentration is 10～15%, it is slow that acidifying speed is like this wanted, and time for adding canWith at 20～40 minutes; More than 90 DEG C hot wash for the end product obtaining after centrifugal, and be placed at 105～115 DEG C dryDry, the convenient reaction for next step.
Below in conjunction with specific embodiment, the present invention is described in more detail:
Embodiment 1
This example provides the preparation method of a kind of 4-(p-amino benzene sulfonyl)-5-methoxyl group-6 chlorine pyrimidine, specifically feeds intakeProportioning is as shown in table 1:
Table 1 reaction raw materials and charge ratio thereof
| Material name | Inventory (kg) | Molecular weight | Molal quantity | Mol ratio |
| 5-methoxyl group-4,6-dichloro pyrimidine | 88 | 179 | 0.4916 | 1 |
| Sulfanilamide (SN) sodium | 200～210 | 194 | 1.031～1.082 | 1.89～2.20 |
| Chlorination 1-butyl-3-methylimidazole | 270 | |||
| Hydrochloric acid (15%) | 120 | 36.5 | 0.986 | 1.003 |
Specific operation process is as follows:
(a) 270kg chlorination 1-butyl-3-methylimidazole is dropped in dry condensation reaction pot, start and stir and drop intoAbout 100kg sulfanilamide (SN) sodium, then drop into 88kg5-methoxyl group-4,6-dichloro pyrimidine, finally drops into remaining half sulfanilamide (SN) sodium in the lump;Naturally be warming up to 60 DEG C, survey pH value 8～9, open if desired cooling water, while controlling temperature to 88～92 DEG C, survey pH value 8～9, guarantorTemperature reaction 1.5 hours;
(b) then, add the hydrochloric acid of 10～15% concentration, regulate pH to 7.0～7.2, check constantly, be cooled to 15～20DEG C, centrifugation, be washed with water to mother liquid coming clear till, continue to dry, take out, both must reclaim sulfanilamide (SN) approximately (be filter residue,120kg)；
(c) centrifuge mother liquor is all proceeded in acid out pot, regulate temperature to 68～72 DEG C, dropping concentration is 10～15%Hydrochloric acid carries out acidifying, and controlling acidifying terminal pH is 3.8～4.1, requires acidifying speed to want slow, controls time for adding at 20～40 pointsClock, then, discharging while hot, centrifugal dehydration, gets rid of most mother liquor and clarifies with more than 90 DEG C hot wash to liquid outlet in time, dries outMaterial; To consolidate material be placed under 105～115 DEG C of conditions dry, until moisture≤0.5% is qualified. Feeding had both obtained condensation product 120,Yield: 77.5%, content >=90%, fusing point >=193 DEG C.
Above-described embodiment is only explanation technical conceive of the present invention and feature, and its object is to allow person skilled in the artScholar can understand content of the present invention and implement according to this, can not limit the scope of the invention with this, all according to the present inventionThe equivalence that Spirit Essence is done changes or modifies, within all should being encompassed in protection scope of the present invention.
Claims (5)
1. a preparation method for 4-(p-amino benzene sulfonyl)-5-methoxyl group-6 chlorine pyrimidine, is characterized in that, comprises followingStep:
(a) in reaction vessel, add respectively chlorination 1-butyl-3-methylimidazole, sulfanilamide (SN) sodium, after stirring, add 5-methoxyl group-4,6-dichloro pyrimidine reacts and within 0.5～2 hour, forms mixture at 88～92 DEG C;
(b) in described mixture, add watery hydrochloric acid to regulate pH to 7.0～7.2, be cooled to subsequently 15～20 DEG C of crystallizations, centrifugalSeparate to obtain mother liquor and filter residue;
(c) described mother liquor is warming up to 68～72 DEG C, drips subsequently watery hydrochloric acid and regulate pH to 3.8～4.1, discharging while hot, fromThe heart end product that dewaters to obtain.
2. the preparation method of 4-according to claim 1 (p-amino benzene sulfonyl)-5-methoxyl group-6 chlorine pyrimidine, its spyLevy and be: in step (b), described mixture is checked pH value before being cooled to 15～20 DEG C of crystallizations.
3. the preparation method of 4-according to claim 1 (p-amino benzene sulfonyl)-5-methoxyl group-6 chlorine pyrimidine, its spyLevy and be: in step (b), described filter residue is with recycling after deionized water washing.
4. the preparation method of 4-according to claim 1 (p-amino benzene sulfonyl)-5-methoxyl group-6 chlorine pyrimidine, its spyLevy and be: described watery hydrochloric acid concentration is 10～15wt%.
5. the preparation method of 4-according to claim 1 (p-amino benzene sulfonyl)-5-methoxyl group-6 chlorine pyrimidine, its spyLevy and be: in step (c), more than 90 DEG C hot wash for described end product, and be placed at 105～115 DEG C dry.
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| Application Number | Priority Date | Filing Date | Title |
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| CN201410083347.7A CN103910687B (en) | 2014-03-10 | 2014-03-10 | The preparation method of 4-(p-amino benzene sulfonyl)-5-methoxyl group-6 chlorine pyrimidine |
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| CN201410083347.7A CN103910687B (en) | 2014-03-10 | 2014-03-10 | The preparation method of 4-(p-amino benzene sulfonyl)-5-methoxyl group-6 chlorine pyrimidine |
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| CN103910687A CN103910687A (en) | 2014-07-09 |
| CN103910687B true CN103910687B (en) | 2016-05-11 |
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Family Cites Families (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| RO63432A2 (en) * | 1974-02-25 | 1978-05-15 | Bucuresti Medicamente | PROCESS FOR OBTAINING 4-SULFANYLAMIDO-5-METHOXY-6-CHLORPYRIMIDINE |
| CN1272327C (en) * | 2004-04-29 | 2006-08-30 | 常熟市南湖实业化工厂 | Preparation method for sulfadoxine |
| CN102304095B (en) * | 2011-09-23 | 2013-10-16 | 常熟市南湖实业化工有限公司 | Preparation method of sulfadoxine |
| CN102304094B (en) * | 2011-09-23 | 2014-03-26 | 常熟市南湖实业化工有限公司 | Preparation method of sulfadoxine and intermediate thereof |
| CN102516183A (en) * | 2011-09-23 | 2012-06-27 | 常熟市南湖实业化工有限公司 | Method for preparing sulfadoxine and its intermediate |
| CN102432550A (en) * | 2011-09-23 | 2012-05-02 | 常熟市南湖实业化工有限公司 | Methods for preparing sulfadoxine and intermediate of sulfadoxine |
| CN102391189A (en) * | 2011-09-23 | 2012-03-28 | 常熟市南湖实业化工有限公司 | Preparation method of sulfadoxine |
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Granted publication date: 20160511 Termination date: 20170310 |