CN103910687A - Preparation method of 4-(p-anilinesulfonamide)-5-methoxy-6 chloropyrimidine - Google Patents
Preparation method of 4-(p-anilinesulfonamide)-5-methoxy-6 chloropyrimidine Download PDFInfo
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- CN103910687A CN103910687A CN201410083347.7A CN201410083347A CN103910687A CN 103910687 A CN103910687 A CN 103910687A CN 201410083347 A CN201410083347 A CN 201410083347A CN 103910687 A CN103910687 A CN 103910687A
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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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Abstract
The invention relates to a preparation method of 4-(p-anilinesulfonamide)-5-methoxy-6 chloropyrimidine. The preparation method comprises following steps: (a) 1-butyl-3-methylimidazolium chloride and sulfanilamide sodium are delivered into a reaction container, 5-methoxy-4,6-dichloropyrimidine is added after stirring, and reaction is carried out at a temperature of 88 to 92 DEG C for 0.5 to 2h so as to obtain a mixture; (b) dilute hydrochloric acid is added into the mixture so as to adjust pH value to 7.0 to 7.2, the mixture is cooled to 15 to 20 DEG C for crystallization, and a mother liquor and a filter residue are obtained via centrifugation; and (c) the mother liquor is heated to 68 to 72 DEG C, dilute hydrochloric acid is added to adjust pH value to 3.8 to 4.1, discharging is performed when an obtained mixed material is still hot, and finished products are obtained via centrifuge dewatering. According to the preparation method of 4-(p-anilinesulfonamide)-5-methoxy-6 chloropyrimidine, 1-butyl-3-methylimidazolium chloride is taken as a solvent to replace DMF which is high in boiling point, and distillation recovery of DMF is not needed, so that on the one hand, demands on production equipment are wakened, and on the other hand, energy consumption of enterprises is reduced greatly, and demands of the state on energy saving and environmental protection are satisfied.
Description
Technical field
The present invention relates to a kind of preparation method of sulphormethoxine intermediate, be specifically related to the preparation method of a kind of 4-(p-amino benzene sulfonyl)-5-methoxyl group-6 chloropyrimide.
Background technology
Sulphormethoxine, chemistry 4-(p-amino benzene sulfonyl)-5 by name, 6-dimethoxypyridin, be generally used for the treatment of inflammation, as upper respiratory tract infection tonsillitis, bacillary dysentery enteritis, skin infections etc., also can coordinate with other drug, be used for the treatment of pulmonary tuberculosis, lymphoid tuberculosis.Sulphormethoxine has experienced several generations' research and development, and its production technique is progressively stable, is specially following preparation process: step (1):
Step (2):
Step (3):
Step (4):
Step (5):
Wherein, 4-(p-amino benzene sulfonyl)-5-methoxyl group-6 chloropyrimide is the intermediate of preparation in step (4), and its productive rate directly affects productive rate and the cost of sulphormethoxine.Granted publication number is the preparation method that the Chinese invention patent of CN102304095B discloses a kind of 4-(p-amino benzene sulfonyl)-5-methoxyl group-6 chloropyrimide, at DMF (N, dinethylformamide) in by sulfanilamide (SN) sodium and 5-methoxyl group-4,6-dichloro pyrimidine reacts.Although DMF is good solvent, its boiling point higher (reaching 150 ℃), thereby in removal process, need to expend a large amount of production capacities, and not only increase the operation cost of enterprise, and be also great test to production unit, easily cause 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 preparation method of 4-(p-amino benzene sulfonyl)-5-methoxyl group-6 chloropyrimide that does not need to use DMF.
For achieving the above object, the technical solution used in the present invention is: the preparation method of a kind of 4-(p-amino benzene sulfonyl)-5-methoxyl group-6 chloropyrimide, comprises the following steps:
(a) in reaction vessel, add respectively chlorination 1-butyl-3-Methylimidazole, sulfanilamide (SN) sodium, add 5-methoxyl group-4 after stirring, 6-dichloro pyrimidine reacts and within 0.5～2 hour, forms mixture at 88～92 ℃;
(b) in described mixture, add dilute hydrochloric acid to regulate pH to 7.0～7.2, be cooled to subsequently 15～20 ℃ of crystallizations, centrifugation obtains mother liquor and filter residue;
(c) described mother liquor is warming up to 68～72 ℃, drips subsequently dilute hydrochloric acid and regulate pH to 3.8～4.1, discharging while hot, centrifuge dehydration obtains final product.
Optimally, in step (b), described mixture is checked pH value before being cooled to 15～20 ℃ of crystallizations.
Optimally, in step (b), described filter residue is with recycling after deionized water wash.
Optimally, described dilute hydrochloric acid concentration is 10～15wt%.
Optimally, in step (c), more than 90 ℃ hot wash for described final product, and be placed at 105～115 ℃ dry.
Because technique scheme is used, the present invention compared with prior art has following advantages: the preparation method of 4-of the present invention (p-amino benzene sulfonyl)-5-methoxyl group-6 chloropyrimide, 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 unit, can greatly reduce on the other hand the energy consumption of enterprise, meet the requirement of country about energy-conserving and environment-protective.
Embodiment
The preparation method of 4-of the present invention (p-amino benzene sulfonyl)-5-methoxyl group-6 chloropyrimide, 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 ℃; (b) in described mixture, add dilute hydrochloric acid to regulate pH to 7.0～7.2, be cooled to subsequently 15～20 ℃ of crystallizations, centrifugation obtains mother liquor and filter residue; (c) described mother liquor is warming up to 68～72 ℃, drips subsequently dilute hydrochloric acid and regulate pH to 3.8～4.1, discharging while hot, centrifuge dehydration obtains final product.Utilize chlorination 1-butyl-3-methyl miaow to substitute high boiling DMF as solvent, no longer need Distillation recovery DMF, weakened the requirement to production unit on the one hand, can greatly reduce on the other hand the energy consumption of enterprise, meet the requirement of country about energy-conserving and environment-protective.
In actual mechanical process, add dilute hydrochloric acid to regulate after pH, mixture pH value still may produce fuctuation within a narrow range, and therefore, in step (b), mixture is checked pH value before being cooled to 15～20 ℃ of crystallizations.And now crystallized product is sulfanilamide (SN), be important pharmaceutical intermediate, after its crystallization, (being filter residue) is with recycling after deionized water wash.And in step (c), drip dilute hydrochloric acid adjusting pH to 3.8～4.1, and the hydrochloric acid that preferred mass concentration is 10～15%, it is slow that acidifying speed is like this wanted, and time for adding can be at 20～40 minutes; More than 90 ℃ hot wash for the final product obtaining after centrifugal, and be placed at 105～115 ℃ dry, 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 chloropyrimide, and concrete charge ratio is as shown in table 1:
Table 1 reaction raw materials and charge ratio thereof
| Material name | Charging capacity (kg) | Molecular weight | Mole number | 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 into about 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 ℃, survey pH value 8～9, open if desired water coolant,, survey pH value 8～9, insulation reaction 1.5 hours when the control temperature to 88～92 ℃;
(b) then, add the hydrochloric acid of 10～15% concentration, regulate pH to 7.0～7.2, check constant, be cooled to 15～20 ℃, centrifugation, be washed with water to mother liquid coming clear till, continue to dry, take out, both must reclaim approximately (being filter residue, 120kg) of sulfanilamide (SN);
(c) centrifuge mother liquor is all proceeded in acid out pot, regulate temperature to 68～72 ℃, the hydrochloric acid that dropping concentration is 10～15% carries out acidifying, and controlling acidifying terminal pH is 3.8～4.1, requires acidifying speed to want slow, control time for adding at 20～40 minutes, then, discharging while hot, centrifuge dehydration, get rid of most mother liquor and clarify with more than 90 ℃ hot wash to liquid outlet in time, dry discharging; To consolidate material be placed under 105～115 ℃ of conditions dry, until moisture≤0.5% is qualified.Feeding had both obtained condenses 120, yield: 77.5%, and content >=90%, fusing point >=193 ℃.
Above-described embodiment is only explanation technical conceive of the present invention and feature; its object is to allow person skilled in the art can understand content of the present invention and implement according to this; can not limit the scope of the invention with this; all equivalences that spirit is done according to the present invention change or modify, 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 chloropyrimide, is characterized in that, comprises the following steps:
(a) in reaction vessel, add respectively chlorination 1-butyl-3-Methylimidazole, sulfanilamide (SN) sodium, add 5-methoxyl group-4 after stirring, 6-dichloro pyrimidine reacts and within 0.5～2 hour, forms mixture at 88～92 ℃;
(b) in described mixture, add dilute hydrochloric acid to regulate pH to 7.0～7.2, be cooled to subsequently 15～20 ℃ of crystallizations, centrifugation obtains mother liquor and filter residue;
(c) described mother liquor is warming up to 68～72 ℃, drips subsequently dilute hydrochloric acid and regulate pH to 3.8～4.1, discharging while hot, centrifuge dehydration obtains final product.
2. the preparation method of 4-according to claim 1 (p-amino benzene sulfonyl)-5-methoxyl group-6 chloropyrimide, is characterized in that: in step (b), described mixture is checked pH value before being cooled to 15～20 ℃ of crystallizations.
3. the preparation method of 4-according to claim 1 (p-amino benzene sulfonyl)-5-methoxyl group-6 chloropyrimide, is characterized in that: in step (b), described filter residue is with recycling after deionized water wash.
4. the preparation method of 4-according to claim 1 (p-amino benzene sulfonyl)-5-methoxyl group-6 chloropyrimide, is characterized in that: described dilute hydrochloric acid concentration is 10～15wt%.
5. the preparation method of 4-according to claim 1 (p-amino benzene sulfonyl)-5-methoxyl group-6 chloropyrimide, it is characterized in that: in step (c), more than 90 ℃ hot wash for described final product, and be placed at 105～115 ℃ dry.
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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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| CN103910687B CN103910687B (en) | 2016-05-11 |
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Citations (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 |
| CN1569843A (en) * | 2004-04-29 | 2005-01-26 | 常熟市南湖实业化工厂 | Preparation method for sulfadoxine |
| CN102304094A (en) * | 2011-09-23 | 2012-01-04 | 常熟市南湖实业化工有限公司 | Preparation method of sulfadoxine and intermediate thereof |
| CN102304095A (en) * | 2011-09-23 | 2012-01-04 | 常熟市南湖实业化工有限公司 | Preparation method 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 |
| 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 |
| 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 |
-
2014
- 2014-03-10 CN CN201410083347.7A patent/CN103910687B/en not_active Expired - Fee Related
Patent Citations (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 |
| CN1569843A (en) * | 2004-04-29 | 2005-01-26 | 常熟市南湖实业化工厂 | Preparation method for sulfadoxine |
| CN102304094A (en) * | 2011-09-23 | 2012-01-04 | 常熟市南湖实业化工有限公司 | Preparation method of sulfadoxine and intermediate thereof |
| CN102304095A (en) * | 2011-09-23 | 2012-01-04 | 常熟市南湖实业化工有限公司 | Preparation method 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 |
| 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 |
| 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 |
Non-Patent Citations (3)
| Title |
|---|
| 上海第二制药厂: "4-磺胺-5,6-二甲氧基嘧啶(周效磺胺)的合成", 《医药工业》, no. 7, 31 December 1971 (1971-12-31), pages 4 - 5 * |
| 王玉炉: "《有机合成化学》", 31 January 2014, 科学出版社, article "4.离子液体在有机合成中的应用" * |
| 马子川,等: "《生活中的化学》", 30 June 2011, 北京师范大学出版社, article "4.离子液体的应用" * |
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Granted publication date: 20160511 Termination date: 20170310 |