CN103864701B - The preparation method of 4-sulfanilamide-5-methoxyl group-6-chloropyrimide - Google Patents
The preparation method of 4-sulfanilamide-5-methoxyl group-6-chloropyrimide Download PDFInfo
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- CN103864701B CN103864701B CN201410084410.9A CN201410084410A CN103864701B CN 103864701 B CN103864701 B CN 103864701B CN 201410084410 A CN201410084410 A CN 201410084410A CN 103864701 B CN103864701 B CN 103864701B
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- 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 discloses the preparation method of a kind of 4 sulfanilamide 5 methoxyl group 6 chloropyrimide, comprise the steps: 1) chlorination reaction: reactor puts into phosphorous oxychloride, adds 5 methoxyl groups 4,6 dihydroxy pyrimidine disodiums, insulation reaction, recovered under reduced pressure phosphorous oxychloride, add trichloro ethylene, put into water, stirring；Dividing and remove trichloro ethylene layer, then add trichloro ethylene, repeatedly extract, blowing, natural air drying, then will add methanol, heating for dissolving in thick chloride input refining kettle, discharging is dried, is obtained 5 methoxyl group 4,6 dichloro pyrimidines；2) condensation reaction: first put in reaction pot by dimethyl sulfoxide, puts into 5 methoxyl group 4,6 dichloro pyrimidines, sulfanilamide sodium, regulation pH value, is pressed into cooling pan, and centrifugation sulfanilamide, by mother solution suction Decolouring pot, add activated carbon, filter isolating active charcoal, mother solution press-in crystallizing pan；Acid out, dries discharging, is dried, cooling discharging, obtains product.Preparation method yield of the present invention is high, does not destroy product, and by-product is less.
Description
Technical field
The invention belongs to chemical drugs intermediate preparing technical field, be specifically related to the preparation method of a kind of 4-sulfanilamide-5-methoxyl group-6-chloropyrimide.
Background technology
4-sulfanilamide-5-methoxyl group-6-chloropyrimide is the significant process intermediate preparing the chemical drugs such as sulfadoxine.In 4-sulfanilamide-5-methoxyl group-6-chloropyrimide preparation process, traditional preparation is usually with dimethylformamide as solvent, but use dimethylformamide as solvent, there is the significant shortcoming of following some: reaction needs to carry out solvent recovery after terminating, recovery time is longer, temperature drift, destroys product, causing by-product many, yield is the highest.
Therefore, it is necessary to the technology of preparing for existing 4-sulfanilamide-5-methoxyl group-6-chloropyrimide is improved.
Summary of the invention
It is an object of the invention to provide the preparation method of a kind of 4-sulfanilamide-5-methoxyl group-6-chloropyrimide, its yield is high, does not destroy product, and by-product is less.
For achieving the above object, the technical scheme is that the preparation method designing a kind of 4-sulfanilamide-5-methoxyl group-6-chloropyrimide, comprise the steps:
1) chlorination reaction: put into 650～950 mass parts phosphorous oxychlorides in reactor, add 245 mass parts 5-methoxyl group-4,6-dihydroxy pyrimidine disodium, controlling to add speed, interior temperature is heated to 80～140 DEG C, insulation reaction 2～6 hours, recovered under reduced pressure phosphorous oxychloride is dry to material, interior temperature is cooled to less than 80 DEG C, adds trichloro ethylene, stirs, put to hydrolyzer, in hydrolyzer, put into 1000～3000 mass parts water, open stirring, control hydrolysis temperature≤80 DEG C；Divide and remove trichloro ethylene layer, then add trichloro ethylene, repeatedly extracting 3～7 times, trichloro ethylene layer is put into boiler and is reclaimed trichloro ethylene, final control vapo(u)rizing temperature 80～130 DEG C, steam off, blowing, natural air drying, to loss on drying≤3%, obtains thick chloride, again thick chloride is put in refining kettle and adds 1～the methanol of 5 times amount, be heated to 50～70 DEG C of dissolvings, the most molten after be cooled to 0～30 DEG C, discharging, centrifugal rejection filter, discharging is dried, obtain 170～240 mass parts 5-methoxyl group-4,6-dichloro pyrimidine；Wherein, total input amount of trichloro ethylene is 1000 mass parts；
2) condensation reaction: first 50～100 mass parts dimethyl sulfoxide are put in the reaction pot being dried, start stirring, put into 105 mass parts 5-methoxyl groups-4, 6-dichloro pyrimidine, 230～300 mass parts sulfanilamide sodium, it is heated to 70～100 DEG C, regulation pH value is to 8～10, it is incubated 1～4 hour, insulation terminates to add 200～700 mass parts hot water, after all dissolving, press-in cooling pan, it is subsequently adding 10%～15% hydrochloric acid, regulation PH to 6～8, it is cooled to 5～25 DEG C, centrifugation sulfanilamide, be washed with water to mother liquid coming clear till, dry, by mother solution suction Decolouring pot, it is heated to 50～90 DEG C, add 2 mass parts activated carbons, decolour 20～40 minutes, filter isolating active charcoal, mother solution press-in crystallizing pan；At the hydrochloric acid acid out of 50～90 DEG C of droppings 10%～15%, acid out terminal pH value is 3.0～5.1, is then centrifuged for dehydration, clarifying with hot wash to liquid outlet, dry discharging, in circulation baking oven, 80～130 DEG C are dried, cooling discharging, obtains 140～180 mass parts 4-sulfanilamide-5-methoxyl group-6-chloropyrimide.
Advantages of the present invention and having the beneficial effects that: provide the preparation method of a kind of 4-sulfanilamide-5-methoxyl group-6-chloropyrimide, its yield is high, does not destroy product, and by-product is less.
Detailed description of the invention
Below in conjunction with embodiment, the detailed description of the invention of the present invention is further described.Following example are only used for clearly illustrating technical scheme, and can not limit the scope of the invention with this.
The technical scheme that the present invention is embodied as is:
Embodiment 1
The preparation method of a kind of 4-sulfanilamide-5-methoxyl group-6-chloropyrimide, comprises the steps:
1) chlorination reaction: put into 650kg phosphorous oxychloride in reactor, add 5-methoxyl group-4 of 245kg, 6-dihydroxy pyrimidine disodium, controlling to add speed, interior temperature is heated to 80 DEG C, insulation reaction 2 hours, recovered under reduced pressure phosphorous oxychloride is dry to material, interior temperature is cooled to less than 80 DEG C, adds trichloro ethylene, stirs, put to hydrolyzer, in hydrolyzer, put into 1000kg water, open stirring, control hydrolysis temperature≤80 DEG C；Divide and remove trichloro ethylene layer, then add trichloro ethylene, repeatedly extracting 3 times, trichloro ethylene layer is put into boiler and is reclaimed trichloro ethylene, final control vapo(u)rizing temperature 80 DEG C, steam off, blowing, natural air drying, to loss on drying≤3%, obtains thick chloride, again thick chloride is put in refining kettle the methanol adding 1 times amount, is heated to 50 DEG C of dissolvings, the most molten after be cooled to 0 DEG C, discharging, centrifugal rejection filter, discharging is dried, obtain 5-methoxyl group-4 of 170kg, 6-dichloro pyrimidine；Wherein, total input amount of trichloro ethylene is 1000kg；
2) condensation reaction: first 50kg dimethyl sulfoxide is put in the reaction pot being dried, start stirring, put into the 5-methoxyl group-4 of 105kg, 6-dichloro pyrimidine, 230kg sulfanilamide sodium, it is heated to 70 DEG C, regulation pH value is to 8, it is incubated 1 hour, insulation terminates to add 200kg hot water, after all dissolving, press-in cooling pan, it is subsequently adding 10% hydrochloric acid, regulation PH to 6, it is cooled to 5 DEG C, centrifugation sulfanilamide, be washed with water to mother liquid coming clear till, dry, by mother solution suction Decolouring pot, it is heated to 50 DEG C, add 2kg activated carbon, decolour 20 minutes, filter isolating active charcoal, mother solution press-in crystallizing pan；At the hydrochloric acid acid out of 50 DEG C of droppings 10%, acid out terminal pH value is 3.0, is then centrifuged for dehydration, clarifies with hot wash to liquid outlet, dries discharging, and in circulation baking oven, 80 DEG C are dried, and cooling discharging obtains the 4-sulfanilamide-5-methoxyl group-6-chloropyrimide of 140kg.
Embodiment 2
The preparation method of a kind of 4-sulfanilamide-5-methoxyl group-6-chloropyrimide, comprises the steps:
1) chlorination reaction: put into 950kg phosphorous oxychloride in reactor, add 5-methoxyl group-4 of 245kg, 6-dihydroxy pyrimidine disodium, controlling to add speed, interior temperature is heated to 140 DEG C, insulation reaction 6 hours, recovered under reduced pressure phosphorous oxychloride is dry to material, interior temperature is cooled to less than 80 DEG C, adds trichloro ethylene, stirs, put to hydrolyzer, in hydrolyzer, put into 3000kg water, open stirring, control hydrolysis temperature≤80 DEG C；Divide and remove trichloro ethylene layer, then add trichloro ethylene, repeatedly extracting 7 times, trichloro ethylene layer is put into boiler and is reclaimed trichloro ethylene, final control vapo(u)rizing temperature 130 DEG C, steam off, blowing, natural air drying, to loss on drying≤3%, obtains thick chloride, again thick chloride is put in refining kettle the methanol adding 5 times amount, is heated to 70 DEG C of dissolvings, the most molten after be cooled to 30 DEG C, discharging, centrifugal rejection filter, discharging is dried, obtain 5-methoxyl group-4 of 240kg, 6-dichloro pyrimidine；Wherein, total input amount of trichloro ethylene is 1000kg；
2) condensation reaction: first 50～100kg dimethyl sulfoxide are put in the reaction pot being dried, start stirring, put into the 5-methoxyl group-4 of 105kg, 6-dichloro pyrimidine, 300kg sulfanilamide sodium, it is heated to 100 DEG C, regulation pH value is to 10, it is incubated 4 hours, insulation terminates to add 700kg hot water, after all dissolving, press-in cooling pan, it is subsequently adding 15% hydrochloric acid, regulation PH to 8, it is cooled to 25 DEG C, centrifugation sulfanilamide, be washed with water to mother liquid coming clear till, dry, by mother solution suction Decolouring pot, it is heated to 90 DEG C, add 2kg activated carbon, decolour 40 minutes, filter isolating active charcoal, mother solution press-in crystallizing pan；At the hydrochloric acid acid out of 90 DEG C of droppings 15%, acid out terminal pH value is 5.1, is then centrifuged for dehydration, clarifies with hot wash to liquid outlet, dries discharging, and in circulation baking oven, 130 DEG C are dried, and cooling discharging obtains the 4-sulfanilamide-5-methoxyl group-6-chloropyrimide of 180kg.
Embodiment 3
The preparation method of a kind of 4-sulfanilamide-5-methoxyl group-6-chloropyrimide, comprises the steps:
1) chlorination reaction: put into 750kg phosphorous oxychloride in reactor, add 5-methoxyl group-4 of 245kg, 6-dihydroxy pyrimidine disodium, controlling to add speed, interior temperature is heated to 100 DEG C, insulation reaction 4 hours, recovered under reduced pressure phosphorous oxychloride is dry to material, interior temperature is cooled to less than 80 DEG C, adds trichloro ethylene, stirs, put to hydrolyzer, in hydrolyzer, put into 2000kg water, open stirring, control hydrolysis temperature≤80 DEG C；Divide and remove trichloro ethylene layer, then add trichloro ethylene, repeatedly extracting 5 times, trichloro ethylene layer is put into boiler and is reclaimed trichloro ethylene, final control vapo(u)rizing temperature 100 DEG C, steam off, blowing, natural air drying, to loss on drying≤3%, obtains thick chloride, again thick chloride is put in refining kettle the methanol adding 3 times amount, is heated to 60 DEG C of dissolvings, the most molten after be cooled to 20 DEG C, discharging, centrifugal rejection filter, discharging is dried, obtain 5-methoxyl group-4 of 200kg, 6-dichloro pyrimidine；Wherein, total input amount of trichloro ethylene is 1000kg；
2) condensation reaction: first 80kg dimethyl sulfoxide is put in the reaction pot being dried, start stirring, put into the 5-methoxyl group-4 of 105kg, 6-dichloro pyrimidine, 270kg sulfanilamide sodium, it is heated to 90 DEG C, regulation pH value is to 9, it is incubated 3 hours, insulation terminates to add 500kg hot water, after all dissolving, press-in cooling pan, it is subsequently adding 13% hydrochloric acid, regulation PH to 7, it is cooled to 15 DEG C, centrifugation sulfanilamide, be washed with water to mother liquid coming clear till, dry, by mother solution suction Decolouring pot, it is heated to 70 DEG C, add 2kg activated carbon, decolour 30 minutes, filter isolating active charcoal, mother solution press-in crystallizing pan；At the hydrochloric acid acid out of 70 DEG C of droppings 13%, acid out terminal pH value is 4.1, is then centrifuged for dehydration, clarifies with hot wash to liquid outlet, dries discharging, and in circulation baking oven, 100 DEG C are dried, and cooling discharging obtains the 4-sulfanilamide-5-methoxyl group-6-chloropyrimide of 160kg.
The above is only the preferred embodiment of the present invention; it should be pointed out that, for those skilled in the art, on the premise of without departing from the technology of the present invention principle; can also make some improvements and modifications, these improvements and modifications also should be regarded as protection scope of the present invention.
Claims (1)
- The preparation method of 1.4-sulfanilamide-5-methoxyl group-6-chloropyrimide, it is characterised in that comprise the steps:1) chlorination reaction: put into 650～950 mass parts phosphorous oxychlorides in reactor, add 245 mass parts 5-methoxyl group-4,6-dihydroxy pyrimidine disodium, interior temperature is heated to 80～140 DEG C, insulation reaction 2～6 hours, recovered under reduced pressure phosphorous oxychloride is dry to material, and interior temperature is cooled to less than 80 DEG C, add trichloro ethylene, stir, put to hydrolyzer, hydrolyzer is put into 1000～3000 mass parts water, open stirring, control hydrolysis temperature≤80 DEG C；Divide and remove trichloro ethylene layer, then add trichloro ethylene, repeatedly extracting 3～7 times, trichloro ethylene layer is put into boiler and is reclaimed trichloro ethylene, final control vapo(u)rizing temperature 80～130 DEG C, steam off, blowing, natural air drying, to loss on drying≤3%, obtains thick chloride, again thick chloride is put in refining kettle and adds 1～the methanol of 5 times amount, be heated to 50～70 DEG C of dissolvings, the most molten after be cooled to 0～30 DEG C, discharging, centrifugal rejection filter, discharging is dried, obtain 170～240 mass parts 5-methoxyl group-4,6-dichloro pyrimidine；Wherein, total input amount of trichloro ethylene is 1000 mass parts；2) condensation reaction: first 50～100 mass parts dimethyl sulfoxide are put in the reaction pot being dried, start stirring, put into 105 mass parts 5-methoxyl groups-4, 6-dichloro pyrimidine, 230～300 mass parts sulfanilamide sodium, it is heated to 70～100 DEG C, regulation pH value is to 8～10, it is incubated 1～4 hour, insulation terminates to add 200～700 mass parts hot water, after all dissolving, press-in cooling pan, it is subsequently adding 10%～15% hydrochloric acid, regulation pH to 6～8, it is cooled to 5～25 DEG C, centrifugation sulfanilamide, be washed with water to mother liquid coming clear till, dry, by mother solution suction Decolouring pot, it is heated to 50～90 DEG C, add 2 mass parts activated carbons, decolour 20～40 minutes, filter isolating active charcoal, mother solution press-in crystallizing pan；At the hydrochloric acid acid out of 50～90 DEG C of droppings 10%～15%, acid out endpoint pH is 3.0～5.1, is then centrifuged for dehydration, clarifying with hot wash to liquid outlet, dry discharging, in circulation baking oven, 80～130 DEG C are dried, cooling discharging, obtains 140～180 mass parts 4-sulfanilamide-5-methoxyl group-6-chloropyrimide.
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|---|---|---|---|---|
| CN1633418A (en) * | 2000-09-25 | 2005-06-29 | 埃科特莱茵药品有限公司 | Arylalkane-sulfonamides having endothelin-antagonist activity |
| US20090286810A1 (en) * | 2008-05-19 | 2009-11-19 | Moore Ii Bob M | Pyrimidine Non-Classical Cannabinoid Compounds and Related Methods of Use |
| CN102219749A (en) * | 2010-04-14 | 2011-10-19 | 上海京新生物医药有限公司 | Method for preparing rosuvastatin calcium |
| 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 |
| CN102311393A (en) * | 2011-09-23 | 2012-01-11 | 常熟市金申医化制品有限责任公司 | Preparation method of sulfadoxine |
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Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1633418A (en) * | 2000-09-25 | 2005-06-29 | 埃科特莱茵药品有限公司 | Arylalkane-sulfonamides having endothelin-antagonist activity |
| US20090286810A1 (en) * | 2008-05-19 | 2009-11-19 | Moore Ii Bob M | Pyrimidine Non-Classical Cannabinoid Compounds and Related Methods of Use |
| CN102219749A (en) * | 2010-04-14 | 2011-10-19 | 上海京新生物医药有限公司 | Method for preparing rosuvastatin calcium |
| 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 |
| CN102311393A (en) * | 2011-09-23 | 2012-01-11 | 常熟市金申医化制品有限责任公司 | Preparation method of sulfadoxine |
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Address after: 215500 No.8, Xinyu village, Shanghu Town, Changshu City, Suzhou City, Jiangsu Province Patentee after: Jiangsu Jinshen Pharmaceutical Technology Co., Ltd Address before: 215500 No.8, Xinyu village, Shanghu Town, Changshu City, Suzhou City, Jiangsu Province Patentee before: CHANGSHU JINSHEN MEDICAL CHEMISTRY PRODUCTS Co.,Ltd. |
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