CN104003942A - 5-methoxyl-4,6-dichloropyrimidine preparing method capable of preventing temperature fluctuation phenomenon from occurring - Google Patents
5-methoxyl-4,6-dichloropyrimidine preparing method capable of preventing temperature fluctuation phenomenon from occurring Download PDFInfo
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- CN104003942A CN104003942A CN201410083319.5A CN201410083319A CN104003942A CN 104003942 A CN104003942 A CN 104003942A CN 201410083319 A CN201410083319 A CN 201410083319A CN 104003942 A CN104003942 A CN 104003942A
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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
- C07D239/32—One oxygen, sulfur or nitrogen atom
- C07D239/34—One oxygen atom
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Abstract
The invention relates to a 5-methoxyl-4,6-dichloropyrimidine preparing method capable of preventing a temperature fluctuation phenomenon from occurring. The preparing method comprises the following steps that: (a) phosphorus oxychloride is added into a reaction container, then, organic solvents containing 4,6-dyhydroxyl-5-methoxyl pyrimidine sodium are added into the reaction container in a dropwise manner, and a reflux reaction is carried out for 2 to 6 hours at 110 to 120 DEG C to obtain a reaction mixture; (b) the reaction mixture is added into deionized water to be hydrolyzed, still standing layering is carried out, and a first water layer and a first organic solvent layer are formed; (c) alkali liquor is added into the first organic solvent layer for regulating the pH value to 6.5 to 7, the still standing layering is carried out again, and a second water layer and a second organic solvent layer are formed; and (d) the second organic solvent layer is distilled for removing the contained organic solvents. The organic solvents containing the 4,6-dyhydroxyl-5-methoxyl pyrimidine sodium are added into the reaction container in a dropwise manner, so the 4,6-dyhydroxyl-5-methoxyl pyrimidine sodium is diluted by the organic solvents; the adding speed of the 4,6-dyhydroxyl-5-methoxyl pyrimidine sodium can be controlled; the temperature of the reaction system can also be controlled; and the temperature fluctuation phenomenon cannot occur.
Description
Technical field
The present invention relates to a kind of preparation method of sulphormethoxine intermediate, be specifically related to a kind of 5-methoxyl group-4 of not producing dirt string temperature phenomenon, 6-dichloro pyrimidine preparation method.
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.The research Ji that sulphormethoxine has experienced several generations is sent out, and its dirt production art is progressively stable, is specially following preparation process:
Wherein, 5-methoxyl group-4,6-dichloro pyrimidine is the intermediate of preparation in step (3), its productive rate directly affects productive rate and the cost of sulphormethoxine.Granted publication number a kind of 5-methoxyl group-4 that have been the public Ji of the Chinese invention patent of CN102304095B, the preparation method of 6-dichloro pyrimidine, by in container, by 4,6-dihydroxyl-5-methoxy pyrimidine sodium and Phosphorus Oxychloride, back flow reaction at 110～120 DEG C makes for 0.5 hour above.But easily there is the string temperature phenomenon of burst in above-mentioned reaction, approximately ten to 20 minutes, be unfavorable for the control of temperature of reaction in the time adding 4,6-dihydroxyl-5-methoxy pyrimidine sodium.
Summary of the invention
The present invention seeks to provide in order to overcome the deficiencies in the prior art a kind of there will not be to go here and there 5-methoxyl group-4 of warm phenomenon, the preparation method of 6-dichloro pyrimidine.
For achieving the above object, the technical solution used in the present invention is: a kind of 5-methoxyl group-4 that do not produce the warm phenomenon of string, and 6-dichloro pyrimidine preparation method, comprises the following steps:
(a) in reaction vessel, add Phosphorus Oxychloride, drip wherein subsequently the organic solvent that contains 4,6-dihydroxyl-5-methoxy pyrimidine sodium, at 110～120 DEG C, back flow reaction obtains reaction mixture for 2～6 hours;
(b) described reaction mixture is added in deionized water and is hydrolyzed, stratification forms the first water layer and the first organic solvent layer;
(c) in the first described organic solvent layer, add alkali lye to regulate pH value to 6.5～7, stratification forms the second water layer and the second organic solvent layer again;
(d) get the second organic solvent layer distillation and remove organic solvent wherein.
Optimally, in step (a), described reaction vessel is also connected with hydrogen chloride gas absorption unit.
Optimally, in described step (a), after adding Phosphorus Oxychloride in reaction vessel, first use steam heating reaction vessel to 70 DEG C, be more naturally warming up to 80 DEG C.
Optimally, in step (a), described in contain 4,6-dihydroxyl-5-methoxy pyrimidine sodium the time for adding of organic solvent be 0.5～1.5 hour.
Optimally, described organic solvent is trieline.
Optimally, in step (b), described reaction mixture is first cooled to below 90 DEG C before adding in deionized water.
Optimally, in step (b), described hydrolysis temperature is no more than 60 DEG C.
Optimally, in described step (b), after stratification, the first water layer is repeatedly extracted with organic solvent, merge organic solvent layer.
Optimally, in step (d), described distillation condition is: vapor pressure is no more than 0.2MPa, 105～115 DEG C of distillation temperatures.
Because technique scheme is used, the present invention compared with prior art has following advantages: the present invention does not produce 5-methoxyl group-4 of dirt string temperature phenomenon, 6-dichloro pyrimidine preparation method, on the one hand back flow reaction 2～6 hours at 110～120 DEG C, can fully carry out reaction; On the other hand to dripping and contain 4 in reaction vessel, the organic solvent of 6-dihydroxyl-5-methoxy pyrimidine sodium, make 4,6-dihydroxyl-5-methoxy pyrimidine sodium is diluted by organic solvent, can control 4,6-dihydroxyl-5-methoxy pyrimidine sodium add speed, can control again the temperature of reaction system, there will not be the warm phenomenon of string.
Embodiment
The present invention does not produce 5-methoxyl group-4 of dirt string temperature phenomenon, 6-dichloro pyrimidine preparation method, comprise the following steps: (a) in reaction vessel, add Phosphorus Oxychloride, drip and contain 4 wherein subsequently, the organic solvent of 6-dihydroxyl-5-methoxy pyrimidine sodium, at 110～120 DEG C, back flow reaction obtains reaction mixture for 2～6 hours; (b) described reaction mixture is added in deionized water and is hydrolyzed, stratification forms the first water layer and the first organic solvent layer; (c) in the first described organic solvent layer, add alkali lye to regulate pH value to 6.5～7, stratification forms the second water layer and the second organic solvent layer again; (d) get the second organic solvent layer distillation and remove organic solvent wherein.On the one hand back flow reaction 2～6 hours at 110～120 DEG C, can fully carry out reaction; On the other hand to dripping and contain 4 in reaction vessel, the organic solvent of 6-dihydroxyl-5-methoxy pyrimidine sodium, make 4,6-dihydroxyl-5-methoxy pyrimidine sodium is diluted by organic solvent, can control 4,6-dihydroxyl-5-methoxy pyrimidine sodium add speed, can control again the temperature of reaction system, there will not be the warm phenomenon of string.
Owing to can produce dirt hydrogen chloride gas in reaction process, for protection of the environment, should on reaction vessel, be connected with hydrogen chloride gas absorption unit.In step (a), after adding Phosphorus Oxychloride in reaction vessel, first use steam heating reaction vessel to 70 DEG C, be more naturally warming up to 80 DEG C, prevent that rate of heating is too fast, make Phosphorus Oxychloride distillation.In step (a), the time for adding of the organic solvent that contains 4,6-dihydroxyl-5-methoxy pyrimidine sodium is preferably 0.5～1.5 hour, and the chemical reaction in reaction vessel is more steady like this, can be too inviolent.The organic solvent using in reaction process is common trieline.In step (b), described reaction mixture is first cooled to below 90 DEG C before adding in deionized water, prevents that its temperature is too high in the time adding in deionized water, but product splash; And hydrolysis temperature is preferably no more than 60 DEG C, otherwise can cause the dirt of sending out of side reaction; After stratification, the first water layer is repeatedly extracted with organic solvent, merge organic solvent layer, improve productive rate as far as possible.In step (d), described distillation condition is: vapor pressure is no more than 0.2MPa, 105～115 DEG C of distillation temperatures.
Below in conjunction with specific embodiment, the present invention is described in more detail:
Embodiment 1
This example provides a kind of 5-methoxyl group-4, the preparation method of 6-dichloro pyrimidine, and concrete charge ratio is as shown in table 1:
Table 1 reaction raw materials and charge ratio thereof
Specific operation process is as follows:
(a) in dry chlorination reaction pot, add 825kg Phosphorus Oxychloride, beat Ji and reflux and hydrogen chloride gas absorption unit, steam heating chlorination reaction pot to 70 DEG C, closes steam natural and is warming up to 80 DEG C; Ji is established and dripped the trieline control feed time that contains 4,6-dihydroxyl-5-methoxy pyrimidine sodium is 0.5～1.5 hour, makes interior temperature control at 80～95 DEG C; Heating, 110～120 DEG C of backflow insulation reaction 4 hours;
(b) reaction mixture of above-mentioned formation is added in deionized water and is hydrolyzed, control temperature and be no more than 60 DEG C, stratification forms water layer and trieline layer, to trieline extraction three times for water layer, merges trieline layer;
(c) in above-mentioned trieline layer, add soda ash solution to regulate pH value to 6.5～7, stratification forms water layer and trieline layer again;
(d) get that trieline layer puts into that still pot normal pressure is concentrated, distillation, reclaim trieline, control vapor pressure and be no more than 0.2MPa, finally control 105～115 DEG C of distillation temperatures, steam off, till underpressure distillation is extremely flowed out without trieline again, blowing.
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 (9)
1. avoid going here and there 5-methoxyl group-4 that warm phenomenon produces for one kind, 6-dichloro pyrimidine preparation method, is characterized in that, comprises the following steps:
(a) in reaction vessel, add Phosphorus Oxychloride, drip wherein subsequently the organic solvent that contains 4,6-dihydroxyl-5-methoxy pyrimidine sodium, at 110～120 DEG C, back flow reaction obtains reaction mixture for 2～6 hours;
(b) described reaction mixture is added in deionized water and is hydrolyzed, stratification forms the first water layer and the first organic solvent layer;
(c) in the first described organic solvent layer, add alkali lye to regulate pH value to 6.5～7, stratification forms the second water layer and the second organic solvent layer again;
(d) get the second organic solvent layer distillation and remove organic solvent wherein.
2. according to claim 1ly avoid going here and there 5-methoxyl group-4 that warm phenomenon produces dirt, 6-dichloro pyrimidine preparation method, is characterized in that: in step (a), described reaction vessel is also connected with hydrogen chloride gas absorption unit.
3. according to claim 1ly avoid going here and there 5-methoxyl group-4 that warm phenomenon produces, 6-dichloro pyrimidine preparation method, it is characterized in that: in described step (a), after adding Phosphorus Oxychloride in reaction vessel, first use steam heating reaction vessel to 70 DEG C, be more naturally warming up to 80 DEG C.
4. according to claim 1ly avoid going here and there 5-methoxyl group-4 that warm phenomenon produces, 6-dichloro pyrimidine preparation method, it is characterized in that: in step (a), described in contain 4,6-dihydroxyl-5-methoxy pyrimidine sodium the time for adding of organic solvent be 0.5～1.5 hour.
5. according to claim 1ly avoid going here and there 5-methoxyl group-4 that warm phenomenon produces, 6-dichloro pyrimidine preparation method, is characterized in that: described organic solvent is trieline.
6. according to claim 1ly avoid going here and there 5-methoxyl group-4 that warm phenomenon produces dirt, 6-dichloro pyrimidine preparation method, is characterized in that: in step (b), described reaction mixture is first cooled to below 90 DEG C before adding in deionized water.
7. according to claim 1ly avoid going here and there 5-methoxyl group-4 that warm phenomenon produces, 6-dichloro pyrimidine preparation method, is characterized in that: in step (b), described hydrolysis temperature is no more than 60 DEG C.
8. according to claim 1ly avoid going here and there 5-methoxyl group-4 that warm phenomenon produces, 6-dichloro pyrimidine preparation method, it is characterized in that: in described step (b), after stratification, the first water layer is repeatedly extracted with organic solvent, merge organic solvent layer.
9. according to claim 1ly avoid going here and there 5-methoxyl group-4 that warm phenomenon produces, 6-dichloro pyrimidine preparation method, is characterized in that: in step (d), described distillation condition is: vapor pressure is no more than 0.2MPa, 105～115 DEG C of distillation temperatures.
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| CN201410083319.5A CN104003942A (en) | 2014-03-10 | 2014-03-10 | 5-methoxyl-4,6-dichloropyrimidine preparing method capable of preventing temperature fluctuation phenomenon from occurring |
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Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101484441A (en) * | 2006-07-06 | 2009-07-15 | 艾尼纳制药公司 | Modulators of metabolism and the treatment of disorders related thereto |
| WO2011017296A1 (en) * | 2009-08-04 | 2011-02-10 | Schering Corporation | 4, 5, 6-trisubstituted pyrimidine derivatives as factor ixa inhibitors |
| 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 |
-
2014
- 2014-03-10 CN CN201410083319.5A patent/CN104003942A/en active Pending
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101484441A (en) * | 2006-07-06 | 2009-07-15 | 艾尼纳制药公司 | Modulators of metabolism and the treatment of disorders related thereto |
| WO2011017296A1 (en) * | 2009-08-04 | 2011-02-10 | Schering Corporation | 4, 5, 6-trisubstituted pyrimidine derivatives as factor ixa inhibitors |
| 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 |
Non-Patent Citations (1)
| Title |
|---|
| 吴晓琼等: ""4,6-二氯-5-甲氧基嘧啶的合成新法"", 《安徽农业科学》, vol. 38, no. 15, 20 May 2010 (2010-05-20) * |
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Application publication date: 20140827 |