CN103910683A - Preparation method of 5-methoxy-4,6-dichloropyrimidine - Google Patents
Preparation method of 5-methoxy-4,6-dichloropyrimidine Download PDFInfo
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- CN103910683A CN103910683A CN201410083320.8A CN201410083320A CN103910683A CN 103910683 A CN103910683 A CN 103910683A CN 201410083320 A CN201410083320 A CN 201410083320A CN 103910683 A CN103910683 A CN 103910683A
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- Prior art keywords
- organic solvent
- preparation
- layer
- methoxyl group
- dichloro 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
- C07D239/32—One oxygen, sulfur or nitrogen atom
- C07D239/34—One oxygen atom
Abstract
The invention relates to a preparation method of 5-methoxy-4,6-dichloropyrimidine. The preparation method comprises following steps: (a) phosphorus trichloride is delivered into a reaction container, 4,6-dihydroxy-5-methoxypyrimidine sodium is added with uniform speed in 0.5 to 1.5h, and an obtained mixed material is subjected to reflux reaction at a temperature of 110 to 120 DEG C for 2 to 6h so as to obtain a reaction mixture; (b) the reaction mixture is cooled to a temperature below 90 DEG C, an organic solvent is added, an obtained material is stirred so as to realize dissolving, deionized water is added for hydrolysis, and an obtained product is allowed to stand so as to obtain a first water layer and a second organic solvent layer; (c) alkali liquor is added into the first organic solvent layer so as to adjust pH value to 6.5 to 7, an obtained mixture is allowed to stand so as to obtain a second water layer and a second organic solvent layer; and (d) the second organic solvent layer is subjected to distillation so as to remove the solvent. According to the preparation method, phosphorus trichloride is used for replacing hypertoxic phosphorus oxychloride, so that production cost is reduced, and threats of chemicals on personal safety of operators are reduced.
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, the preparation method of 6-dichloro pyrimidine.
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, 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 is that the Chinese invention patent of CN102304095B discloses a kind of 5-methoxyl group-4, 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; Most importantly use hypertoxic Phosphorus Oxychloride, serious threat operator's is healthy, does not meet planning and the requirement of country about environment protection.
Summary of the invention
The present invention seeks to provide in order to overcome the deficiencies in the prior art a kind of 5-methoxyl group-4 of relative environmental protection, 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, and the preparation method of 6-dichloro pyrimidine, comprises the following steps:
(a) in reaction vessel, add phosphorus trichloride, and be warming up to 70～80 DEG C, in 0.5～1.5 hour, at the uniform velocity add wherein 4,6-dihydroxyl-5-methoxy pyrimidine sodium, control temperature at 80～95 DEG C, within 2～6 hours, obtain reaction mixture with being placed on back flow reaction at 110～120 DEG C;
(b) described mixture is cooled to below 90 DEG C, and adds organic solvent stirring and dissolving, be hydrolyzed subsequently in impouring deionized water, 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, described organic solvent is trieline.
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: 5-of the present invention methoxyl group-4, the preparation method of 6-dichloro pyrimidine, use phosphorus trichloride to substitute hypertoxic Phosphorus Oxychloride on the one hand, not only reduce production cost, also reduced the threat of chemical to operator's personnel safety; By controlling the speed that adds of 4,6-dihydroxyl-5-methoxy pyrimidine sodium, control the temperature of reaction system on the other hand, guarantee not occur going here and there warm phenomenon.
Embodiment
5-of the present invention methoxyl group-4, the preparation method of 6-dichloro pyrimidine, comprise the following steps: (a) in reaction vessel, add phosphorus trichloride, and be warming up to 70～80 DEG C, in 0.5～1.5 hour, add wherein 4,6-dihydroxyl-5-methoxy pyrimidine sodium, controls temperature at 80～95 DEG C, within 2～6 hours, obtains reaction mixture with being placed on back flow reaction at 110～120 DEG C; (b) described mixture is cooled to below 90 DEG C, and adds organic solvent stirring and dissolving, be hydrolyzed subsequently in impouring deionized water, 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.Use phosphorus trichloride to substitute hypertoxic Phosphorus Oxychloride on the one hand, not only reduced production cost, also reduced the threat of chemical to operator's personnel safety; By controlling the speed that adds of 4,6-dihydroxyl-5-methoxy pyrimidine sodium, control the temperature of reaction system on the other hand, guarantee not occur going here and there warm phenomenon.
Owing to can produce hydrogen chloride gas in reaction process, for protection of the environment, should on reaction vessel, be connected with hydrogen chloride gas absorption unit.Hydrolysis temperature is preferably no more than 60 DEG C, otherwise can cause the generation 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 trichloride, open and reflux and hydrogen chloride gas absorption unit, be steam heated to 70 DEG C, close steam natural and be warming up to 80 DEG C, start slowly to add 4,6-dihydroxyl-5-methoxy pyrimidine sodium, control and add speed, making feed time is 0.5～1.5 hour, and interior temperature control is at 80～95 DEG C; To the heating of chlorination reaction pot, the insulation reaction that refluxes at 110～120 DEG C 4 hours;
(b) underpressure distillation, recovery Phosphorus Oxychloride (350kg) are done to reacting clout; Close cap relief valve, be cooled to below 90 DEG C, add 900L trieline, stirring and dissolving; In hydrolyzer, put in advance 1500Kg water, under the condition constantly stirring, the material in chlorination reaction pot is put into hydrolyzer, cooling, make hydrolysis temperature be no more than 60 DEG C; Stir hydrolysis 15 minutes, leave standstill layering in 10 minutes, get lower floor for the first time extracting trieline liquid to pass a bridge pot in; Add trieline 300L again, stir 15 minutes extracting water layers, leave standstill 10 minutes, layering, obtains trieline extract for the second time; Add again 200L trieline, stir 15 minutes, leave standstill layering in 10 minutes, get for the third time trieline extract to passing a bridge in pot; Then three trieline extracts of passing a bridge in pot are pressed in washing pot;
(c) with in soda ash solution and trieline extract to pH=6.5～7, and close pot cover, wash 30 minutes from bottom to top with water and survey pH6.5～7 with test paper, washing is finished, and closes water, leaves standstill 10 minutes, branch vibration layer, trieline feed liquid is put into the pot of passing a bridge, then it is to be distilled to be pressed into high-order storage tank;
(d) trieline feed liquid is put into still pot normal pressure and concentrated, distill, reclaim trieline, control vapor pressure and be no more than 0.2MPa, final 105～115 DEG C of the distillation temperatures of controlling, steam off, then underpressure distillation to without trieline flow out till, blowing, natural air drying is to weight loss on drying≤3%, muriate fusing point >=52 DEG C, rewinding, pulverizing, obtain 210kg product.
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 (6)
1. 5-methoxyl group-4, the preparation method of 6-dichloro pyrimidine, is characterized in that, comprises the following steps:
(a) in reaction vessel, add phosphorus trichloride, and be warming up to 70～80 DEG C, in 0.5～1.5 hour, add wherein 4,6-dihydroxyl-5-methoxy pyrimidine sodium, control temperature at 80～95 DEG C, within 2～6 hours, obtain reaction mixture with being placed on back flow reaction at 110～120 DEG C;
(b) described mixture is cooled to below 90 DEG C, and adds organic solvent stirring and dissolving, be hydrolyzed subsequently in impouring deionized water, 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. 5-according to claim 1 methoxyl group-4, the preparation method of 6-dichloro pyrimidine, is characterized in that: in step (a), described reaction vessel is also connected with hydrogen chloride gas absorption unit.
3. 5-according to claim 1 methoxyl group-4, the preparation method of 6-dichloro pyrimidine, is characterized in that: described organic solvent is trieline.
4. 5-according to claim 1 methoxyl group-4, the preparation method of 6-dichloro pyrimidine, is characterized in that: in step (b), described hydrolysis temperature is no more than 60 DEG C.
5. 5-according to claim 1 methoxyl group-4, the preparation method of 6-dichloro pyrimidine, is characterized in that: in described step (b), after stratification, the first water layer is repeatedly extracted with organic solvent, merge organic solvent layer.
6. 5-according to claim 1 methoxyl group-4, the preparation method of 6-dichloro pyrimidine, 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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| Application Number | Priority Date | Filing Date | Title |
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| CN201410083320.8A CN103910683A (en) | 2014-03-10 | 2014-03-10 | Preparation method of 5-methoxy-4,6-dichloropyrimidine |
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| CN201410083320.8A CN103910683A (en) | 2014-03-10 | 2014-03-10 | Preparation method of 5-methoxy-4,6-dichloropyrimidine |
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Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3249603A (en) * | 1960-08-09 | 1966-05-03 | Hoffmann La Roche | Novel pyrimidine sulfanilamides and processes for their preparation |
| CN1343665A (en) * | 2000-09-15 | 2002-04-10 | 台州市沙星化工有限公司 | Process for preparing 4,6-dichloro-2-methiopyrimidine |
| 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 |
| EP2592154A1 (en) * | 2011-11-09 | 2013-05-15 | Cellzome Ag | Immobilization products and methods for the identification of histone demethylase interacting molecules and for the purification of histone demethylase proteins |
-
2014
- 2014-03-10 CN CN201410083320.8A patent/CN103910683A/en active Pending
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3249603A (en) * | 1960-08-09 | 1966-05-03 | Hoffmann La Roche | Novel pyrimidine sulfanilamides and processes for their preparation |
| CN1343665A (en) * | 2000-09-15 | 2002-04-10 | 台州市沙星化工有限公司 | Process for preparing 4,6-dichloro-2-methiopyrimidine |
| 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 |
| EP2592154A1 (en) * | 2011-11-09 | 2013-05-15 | Cellzome Ag | Immobilization products and methods for the identification of histone demethylase interacting molecules and for the purification of histone demethylase proteins |
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》 * |
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Application publication date: 20140709 |