CN103910629A - Method used for smooth and steady preparation of 2-methoxypropandioic acid ethyl methyl ester - Google Patents
Method used for smooth and steady preparation of 2-methoxypropandioic acid ethyl methyl ester Download PDFInfo
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- CN103910629A CN103910629A CN201410083316.1A CN201410083316A CN103910629A CN 103910629 A CN103910629 A CN 103910629A CN 201410083316 A CN201410083316 A CN 201410083316A CN 103910629 A CN103910629 A CN 103910629A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C67/00—Preparation of carboxylic acid esters
- C07C67/30—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group
- C07C67/333—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group by isomerisation; by change of size of the carbon skeleton
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C67/00—Preparation of carboxylic acid esters
- C07C67/30—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group
- C07C67/317—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group by splitting-off hydrogen or functional groups; by hydrogenolysis of functional groups
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F1/00—Compounds containing elements of Groups 1 or 11 of the Periodic System
- C07F1/04—Sodium compounds
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Abstract
The invention relates to a method used for smooth and steady preparation of 2-methoxypropandioic acid ethyl methyl ester. The method comprises following steps: (a) methyl methoxyacetate and diethyl oxalate are delivered into a reaction container, and a mixed solution is obtained via mixing; (b) solid sodium methylate is dispersed in diethyl oxalate, an obtained mixture is added into the mixed solution dropwise, and an obtained mixed material is reacted for 2 to 8h at a temperature of 50 to 60 DEG C so as to obtain a reaction liquid; (c) an organic solvent, water, and an acid solution are delivered into another reaction container for mixing, the reaction liquid is added, a temperature of an obtained material is controlled below 15 DEG C, pH value is adjusted to 1 to 2, and the material is allowed to stand so as to obtain a water layer and an organic solvent layer; (d) the organic solvent layer is collected and is subjected to distillation so as to remove the organic solvent, and an obtained product is subjected to decarbonylation at a temperature of 178 to 182 DEG C under a vacuum degree of -0.04 to -0.053MPa for 2 to 6h, and fractions obtained under a vacuum degree of -0.095MPa at a temperature above 170 DEG C are collected. According to the method, solid sodium methylate is dispersed in diethyl oxalate which is not too active, and then the obtained mixture is added into the mixed solution dropwise, so that reaction fierce degree of the whole system after adding of solid sodium methylate can be reduced effectively, and smoothness of the reaction is ensured.
Description
Technical field
The present invention relates to a kind of preparation method of sulphormethoxine intermediate, be specifically related to a kind of method of steadily preparing methoxy propyl diacid methyl ethyl ester.
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, methoxy propyl diacid methyl ethyl ester is the intermediate of preparation in step (1), 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 sulphormethoxine, wherein methoxy propyl diacid methyl ethyl ester by methoxy menthyl acetate and excessive oxalic acid diethyl ester under sodium methylate, react and further decarboxylation form, be specially methoxy menthyl acetate and excessive oxalic acid diethyl ester under the effect of solid-state sodium methylate to be no more than the conditioned response of 65 ℃, after decarboxylation finishes, divide after low-boiling-point substance through separation column vacuum fractionation.But methoxy menthyl acetate and oxalic acid diethyl ester are under the effect under solid sodium methylate, react violent and discharge amount of heat, easily cause reactor temperature sharply to raise, and cause dangerous generation, are unfavorable for the security control of production plant.
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 the methoxy propyl diacid methyl ethyl ester that can reduce dissipation of heat in reaction process.
For achieving the above object, the technical solution used in the present invention is: a kind of method of steadily preparing methoxy propyl diacid methyl ethyl ester, comprises the following steps:
(a) in reaction vessel, add methoxy menthyl acetate and oxalic acid diethyl ester, after mixing, form mixed solution;
(b) after solid sodium methylate being scattered in oxalic acid diethyl ester, drop in described mixed solution, at 50～60 ℃, react and within 2～8 hours, form reaction solution;
(c) in another container, add respectively organic solvent, water and acid solution, after mixing, add described reaction solution, control temperature 15 ℃ following and regulate between pH to 1～2, leave standstill and form water layer and organic solvent layer;
(d) getting described organic solvent layer distills and removes organic solvent, be decarbonylation reaction 2～6 hours under-0.04～-0.053MPa condition with being placed on 178～182 ℃, vacuum tightness, finally collect vacuum tightness and be-0.095MPa is following, 170 ℃ of above cuts.
Optimally, in step (a), described mixed solution is cooled to below 10 ℃.
Optimally, in step (b), described rate of addition is 1～10 drop/sec.
Optimally, in step (c), described water layer extracts repeatedly with organic solvent again.
Optimally, in step (c), described organic solvent, water and acid solution stir and are cooled to 10 ℃ and add reaction solution after following again.
Optimally, in step (c), described organic solvent is trieline, and described acid solution is hydrochloric acid.
Optimally, in step (d), after described organic solvent is collected, be washed with water to pH=6～7, recycle.
Optimally, the mol ratio of described methoxy menthyl acetate, oxalic acid diethyl ester, sodium methylate, acid solution is 1: 1.05～1.15: 1.05～1.12: 1.05～1.12.
Because technique scheme is used, the present invention compared with prior art has following advantages: the present invention steadily prepares the method for methoxy propyl diacid methyl ethyl ester, after solid sodium methylate being scattered in more inactive oxalic acid diethyl ester, drop to again in mixed solution, can effectively reduce the reaction severity that adds whole system after solid sodium methylate, guarantee steadily carrying out of reaction, be conducive to reaction vessel temperature to be controlled in 50～60 ℃, reduce the generation of side reaction, thereby improve the productive rate of methoxy propyl diacid methyl ethyl ester.
Embodiment
The present invention steadily prepares the method for methoxy propyl diacid methyl ethyl ester, comprises the following steps: (a) in reaction vessel, add methoxy menthyl acetate and oxalic acid diethyl ester, after mixing, form mixed solution; (b) after solid sodium methylate being scattered in oxalic acid diethyl ester, drop in described mixed solution, at 50～60 ℃, react and within 2～8 hours, form reaction solution; (c) in another container, add respectively organic solvent, water and acid solution, after mixing, add described reaction solution, control temperature 15 ℃ following and regulate between pH to 1～2, leave standstill and form water layer and organic solvent layer; (d) getting described organic solvent layer distills and removes organic solvent, be decarbonylation reaction 2～6 hours under-0.04～-0.053MPa condition with being placed on 178～182 ℃, vacuum tightness, finally collect vacuum tightness and be-0.095MPa is following, 170 ℃ of above cuts.In the present invention, after solid sodium methylate being scattered in more inactive oxalic acid diethyl ester, drop to again in mixed solution, can effectively reduce the reaction severity that adds whole system after solid sodium methylate, guarantee steadily carrying out of reaction, be conducive to reaction vessel temperature to be controlled in 50～60 ℃, reduce the generation of side reaction, thereby improve the productive rate of methoxy propyl diacid methyl ethyl ester.
In order further to control the fierce degree of reaction, adding before solid sodium methylate and mixed solution should be cooled to below 10 ℃, and it is 1～10 drop/sec to the speed dripping in mixed solution containing the oxalic acid diethyl ester liquid of solid sodium methylate.In order to improve the productive rate of methoxy propyl diacid methyl ethyl ester, water layer extracts repeatedly with organic solvent again, thereby water-soluble methoxy propyl diacid methyl ethyl ester is fully extracted.In the process of acidifying, in step (c), organic solvent, water and acid solution stir and are cooled to 10 ℃ and add wherein reaction solution after following again, and organic solvent is preferably trieline, and acid solution is preferably hydrochloric acid.To reduce the pollution to environment in order reducing production costs simultaneously, in step (d), after organic solvent is collected, to be washed with water to pH=6～7, recycle.The mol ratio of methoxy menthyl acetate, oxalic acid diethyl ester, sodium methylate, acid solution is preferably 1: 1.05～and 1.15: 1.05～1.12: 1.05～1.12, wherein oxalic acid diethyl ester refers to the total amount of using in step (a) and step (b).
Below in conjunction with specific embodiment, the present invention is described in more detail:
Embodiment 1
This example provides a kind of method of steadily preparing methoxy propyl diacid methyl ethyl ester, 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) 175kg methoxy menthyl acetate and 150kg oxalic acid diethyl ester are dropped in the mixed ester pot of drying in advance, be uniformly mixed, and be cooled to below 10 ℃, put into the Ke Shi reactor of drying in advance;
(b) 130kg solid sodium ethanol is scattered in 150kg oxalic acid diethyl ester, drop to (time for adding was controlled in 1～2 hour) in above-mentioned Ke Shi reactor with the speed of 10 drops/sec, control reacting liquid temperature between 50～60 ℃, insulation reaction 4 hours;
(c) in dilution pot, add in advance 280L trieline and be cooled to below 20 ℃, then the reaction solution in Ke Shi reactor being pressed in dilution pot, stirring cooling; The 350L trieline liquid that adds 500L water, 200L technical hydrochloric acid and the last extracting of last consignment of to apply mechanically at acidifying pot, stirs and is cooled to below 10 ℃; Diluent in dilution pot is pressed in acidifying pot, controls temperature below 15 ℃, regulate pH value between 1.0～2.0, stir 15 minutes, stratification, separates lower floor's trieline liquid in transfer pot; Remaining water layer extracts 7 times with trieline again, and first three time adds trieline 200L at every turn, adds 150L latter three times, adds 350L, after extraction, directly applies mechanically to next batch for the 7th time;
(d) by the air distillation in recovery pot of trieline extracting solution, reclaim trichloroethylene solvent, be warming up to after 105～110 ℃, change underpressure distillation into, until can not steam trieline, the trieline of recovery overlaps for this Ke Shi reaction process to pH value 6～7 through water washing; Proceeding in Ke Shi still pot steaming the to the greatest extent reaction solution of trieline, is under the condition of-0.04～-0.053MPa at 180 ± 2 ℃, vacuum tightness, decarbonylation reaction 4 hours; Change subsequently high vacuum underpressure distillation into, collect the cuts below vacuum tightness-0.095MPa, more than 170 ℃, be finally distilled to till 180～190 ℃, obtain final 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 (8)
1. a method of steadily preparing methoxy propyl diacid methyl ethyl ester, is characterized in that, comprises the following steps:
(a) in reaction vessel, add methoxy menthyl acetate and oxalic acid diethyl ester, after mixing, form mixed solution;
(b) after solid sodium methylate being scattered in oxalic acid diethyl ester, drop in described mixed solution, at 50～60 ℃, react and within 2～8 hours, form reaction solution;
(c) in another container, add respectively organic solvent, water and acid solution, after mixing, add described reaction solution, control temperature 15 ℃ following and regulate between pH to 1～2, leave standstill and form water layer and organic solvent layer;
(d) getting described organic solvent layer distills and removes organic solvent, be decarbonylation reaction 2～6 hours under-0.04～-0.053MPa condition with being placed on 178～182 ℃, vacuum tightness, finally collect vacuum tightness and be-0.095MPa is following, 170 ℃ of above cuts.
2. the method for steadily preparing methoxy propyl diacid methyl ethyl ester according to claim 1, is characterized in that: in step (a), described mixed solution is cooled to below 10 ℃.
3. the method for steadily preparing methoxy propyl diacid methyl ethyl ester according to claim 1, is characterized in that: in step (b), described rate of addition is 1～10 drop/sec.
4. the method for steadily preparing methoxy propyl diacid methyl ethyl ester according to claim 1, is characterized in that: in step (c), described water layer extracts repeatedly with organic solvent again.
5. the method for steadily preparing methoxy propyl diacid methyl ethyl ester according to claim 1, is characterized in that: in step (c), described organic solvent, water and acid solution stir and be cooled to 10 ℃ and add reaction solution after following again.
6. the method for steadily preparing methoxy propyl diacid methyl ethyl ester according to claim 1, is characterized in that: in step (c), described organic solvent is trieline, and described acid solution is hydrochloric acid.
7. the method for steadily preparing methoxy propyl diacid methyl ethyl ester according to claim 1, is characterized in that: in step (d), after described organic solvent is collected, be washed with water to pH=6～7, recycle.
8. the method for steadily preparing methoxy propyl diacid methyl ethyl ester according to claim 1, is characterized in that: the mol ratio of described methoxy menthyl acetate, oxalic acid diethyl ester, sodium methylate, acid solution is 1: 1.05～1.15: 1.05～1.12: 1.05～1.12.
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104447327A (en) * | 2014-12-13 | 2015-03-25 | 常熟市金申医化制品有限责任公司 | Preparation method of methyl ethyl methoxymalonate |
| CN105085255A (en) * | 2015-08-12 | 2015-11-25 | 大连九信生物化工科技有限公司 | Synthesis technology for imidazolone herbicide intermediate 2-alkoxy-3-oxo-succinic acid diester |
| CN109557200A (en) * | 2018-11-23 | 2019-04-02 | 重庆康乐制药有限公司 | A method of use gas chromatography monitoring methoxyl group oxalacetic acid methyl ethyl ester decarbonylation for methoxy propyl diacid methyl ethyl ester reaction end |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
-
2014
- 2014-03-10 CN CN201410083316.1A patent/CN103910629A/en active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104447327A (en) * | 2014-12-13 | 2015-03-25 | 常熟市金申医化制品有限责任公司 | Preparation method of methyl ethyl methoxymalonate |
| CN105085255A (en) * | 2015-08-12 | 2015-11-25 | 大连九信生物化工科技有限公司 | Synthesis technology for imidazolone herbicide intermediate 2-alkoxy-3-oxo-succinic acid diester |
| CN109557200A (en) * | 2018-11-23 | 2019-04-02 | 重庆康乐制药有限公司 | A method of use gas chromatography monitoring methoxyl group oxalacetic acid methyl ethyl ester decarbonylation for methoxy propyl diacid methyl ethyl ester reaction end |
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Application publication date: 20140709 |