CN103214421A - Industrialization production method of 2-mercapto-1-methylimidazole - Google Patents
Industrialization production method of 2-mercapto-1-methylimidazole Download PDFInfo
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- CN103214421A CN103214421A CN201210531795XA CN201210531795A CN103214421A CN 103214421 A CN103214421 A CN 103214421A CN 201210531795X A CN201210531795X A CN 201210531795XA CN 201210531795 A CN201210531795 A CN 201210531795A CN 103214421 A CN103214421 A CN 103214421A
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Abstract
The invention relates to an industrialization production method of antithyroid drug 2-mercapto-1-methylimidazole. The method comprises: (a) reacting vinyl acetate with bromine in absolute ethyl alcohol, regulating a pH value into alkalescence after reaction, obtaining a bromoacetaldehyde diethyl acetal crude product after extraction and desolventization, and directly adding the bromoacetaldehyde diethyl acetal crude product into a next step of reaction; (b) performing aminolysis reaction of bromoacetaldehyde diethyl acetal and methylamine aqueous solution, and after completing reaction, obtaining methylamino acetal through distilling, separating and purifying after extraction and de-watering; (3) dropping hydrochloric acid into aqueous solution of methylamino acetal and potassium rhodanide; removing water in the reaction solution by reduced pressure distillation after reaction, removing a part insoluble in ethyl acetate from the obtained solid, dissolving residual solid into water with pH being 1-2, crystallizing to obtain 2-mercapto-1-methylimidazole with purity higher than 99%, and then vacuum-drying to obtain a finished product. The production method has a short product line, can obtain 2-mercapto-1-methylimidazole with high purity, and has a strong industrialization prospect.
Description
Technical field
The invention belongs to the organic synthesis field, relate to the preparation method of 2-sulfydryl-1-Methylimidazole, particularly 2-sulfydryl-1-Methylimidazole industrialized preparing process.
Background technology
2-sulfydryl-1-Methylimidazole is an antithyroid drug.Its mechanism of action is to suppress Tiroidina endoperoxide enzyme, inhales poly-the arrive oxidation of iodide in the Tiroidina and the coupling of tyrosine thereby hinder, and hinders the synthetic of thyroxine (T4) and trilute (T3).Animal experimental observation reduces the level of thyroid stimulating antibody in the circulation of blood to suppressing the bone-marrow-derived lymphocyte synthetic antibody, makes the suppressor T cell functional rehabilitation normal.Be applicable to various types of hyperthyroidisms, comprise Graves disease (accompany autoimmune function disorder, Tiroidina anthorisma, expophthalmos can be arranged), thyroid adenoma, nodular goiter and thyroid carcinoma institute causer.
J.Am.Chem.Soc., 71,4000. put down in writing the amido acetal of replacement and the derivative of thiocyanic acid prepared in reaction 2-sulfydryl-1-Methylimidazole (1949), but given in the literary composition only is to apply to laboratory scale little quantitative response, and do not provide in the literary composition yet complete 2-sulfydryl-1-Methylimidazole synthetic schemes and this step reaction only is provided.
In addition, in the scope that the contriver understands, do not find complete 2-sulfydryl-1-Methylimidazole synthetic schemes, particularly be applicable to the method for suitability for industrialized production.
Summary of the invention
It is shorter to the purpose of this invention is to provide a kind of route, simple to operate, can obtain highly purified 2-sulfydryl-1-Methylimidazole industrialized preparing process.
The objective of the invention is to be achieved through the following technical solutions:
A kind of 2-sulfydryl-1-Methylimidazole industrialized preparing process, may further comprise the steps:
(a) in dehydrated alcohol, with vinyl-acetic ester and bromine reaction, after reaction finishes with the reaction solution pH regulator to 〉=8, behind dichloromethane extraction, distillation removes to desolvate and obtains the bromacetal crude product and directly drop into next step reaction.Reaction formula is as follows:
Preferably, step (a) is carried out under protection of inert gas.
(b) bromacetal and aqueous methylamine solution issue ammonifying at 3-4MPa pressure and separate reaction, reacting liquid temperature is controlled between 100-120 ℃, reaction is finished afterreaction liquid through extracting, dewatering, and purifying by fractionation by distillation obtains the methylamino acetal.Reaction formula is as follows:
Described fractionation by distillation process specifically comprises: reaction solution is removed methylene dichloride through after extraction, dewatering 50 ℃ of left and right sides air distillations; Ooze 40 ℃ of left and right sides underpressure distillation to absence of liquid with water pump again; Residual liquid is used two stage pump instead 100 ℃ of left and right sides underpressure distillation, and the overhead product that obtains is the methylamino acetal.
(c) hydrochloric acid is dropped in the aqueous solution of methylamino acetal and potassium sulfocyanate, reacting liquid temperature is controlled between 30-50 ℃ in the dropping process; Reaction is finished the underpressure distillation of afterreaction liquid except that anhydrating, the gained solid dissolves once more with ethyl acetate, behind the elimination insolubles, ethyl acetate is removed in underpressure distillation, remaining solid is dissolved in purified water, regulate pH to 1-2, crystallisation by cooling obtains purity greater than 2-sulfydryl-1-Methylimidazole of 99%, and vacuum drying promptly gets the finished product.Reaction formula is as follows:
Preferably, used reaction vessel also comprises device for absorbing tail gas in the step (c).
Preferably, used concentration of hydrochloric acid is 1mol/L in the step (c).
Embodiment
Embodiment 1
(a) 480 kilograms of dehydrated alcohols of suction in No. 1 reactor, 180 kilograms of vinyl-acetic esters are taken out material and are finished, the vacuum in the nitrogen balance reactor.Reacting liquid temperature is controlled at about 5 ℃ in the reaction process, and 335 kilograms of bromines are pressed in No. 1 reactor, adds in about 10 hours.Be warming up to 30 ℃ after bromine adds, insulation reaction is to reaction solution sampling GC detection intermediate≤1.0%, i.e. stopped reaction.
Stir and in No. 1 reactor, to change the concentration for preparing in advance down over to be 16.7% aqueous sodium carbonate to reaction solution pH be 8, add 540 kilograms of methylene dichloride again, stirred 30 minutes, tell organic layer.
In No. 2 reactors, add 300 kg of water and 60 kilograms of sodium-chlor, after stirring and dissolving is complete, add the organic layer of telling in aforementioned No. 1 reactor again, stir standing demix after 30 minutes.The organic layer concentrating under reduced pressure of telling is removed methylene dichloride and is obtained the bromacetal crude product, and GC detects purity 84.0%, productive rate 68.2%.
(b) suction 260kg bromacetal crude product in No. 3 autoclaves, 1000kg 40% 1 first ammonia soln, closed reactor.Being warming up to reacting liquid temperature is 100 ℃, and still is pressed 3MPa.Reaction finishes the back and adds 1000 kilograms of methylene dichloride stirrings 30 minutes, tells organic layer.
In No. 4 reactors, add 500 kg of water and 100 kilograms of sodium-chlor, after stirring and dissolving is complete, add the organic layer of telling in aforementioned No. 3 reactors again, stir standing demix after 30 minutes.The organic layer of telling after methylene dichloride is removed in following about the 50 ℃ distillations of normal pressure, changes the water pump underpressure distillation into, controls about 40 ℃, is distilled to absence of liquid and oozes.Residual liquid changes the two stage pump underpressure distillation into, maintains the temperature at about 100 ℃, obtains overhead product 108kg, is the methylamino acetal, and it is 95% that GC detects purity, and productive rate is 66.2%.
(c) in No. 5 reactors, add 410 kilograms of methylamino acetals, 270 kilograms of potassium sulfocyanates and 500 kilograms of purified water, after the stirring at room dissolving fully, drip 1000 kilograms in the 1mol/L dilute hydrochloric acid for preparing in advance in No. 5 reactors, the control reacting liquid temperature is about 30 ℃.
After reaction finished, the reaction solution underpressure distillation removed and anhydrates, and the gained solid dissolves once more with ethyl acetate, and behind the elimination insolubles, ethyl acetate is removed in underpressure distillation.After the gained solid is dissolved in purified water, regulate pH to 1, crystallisation by cooling obtains purity greater than 99% product, and vacuum drying promptly gets the finished product 150kg of 2-sulfydryl-1-Methylimidazole, and productive rate is 47.2%.
Embodiment 2
(a) 480 kilograms of dehydrated alcohols of suction in No. 1 reactor, 180 kilograms of vinyl-acetic esters are taken out material and are finished, the vacuum in the nitrogen balance reactor.Reacting liquid temperature is controlled at about 5 ℃ in the reaction process, and 335 kilograms of bromines are pressed in No. 1 reactor, adds in about 10 hours.Be warming up to 30 ℃ after bromine adds, insulation reaction is to reaction solution sampling GC detection intermediate≤1.0%, i.e. stopped reaction.
Stir and in No. 1 reactor, to change the concentration for preparing in advance down over to be 16.7% aqueous sodium carbonate to reaction solution pH be 10, add 540 kilograms of methylene dichloride again, stirred 30 minutes, tell organic layer.
In No. 2 reactors, add 300 kg of water and 60 kilograms of sodium-chlor, after stirring and dissolving is complete, add the organic layer of telling in aforementioned No. 1 reactor again, stir standing demix after 30 minutes.The organic layer concentrating under reduced pressure of telling is removed methylene dichloride and is obtained the bromacetal crude product, and GC detects purity 84.0%, productive rate 68.2%.
(b) suction 260kg bromacetal crude product in No. 3 autoclaves, 1000kg 40% 1 first ammonia soln, closed reactor.Being warming up to reacting liquid temperature is 120 ℃, and still is pressed 4MPa.Reaction finishes the back and adds 1000 kilograms of methylene dichloride stirrings 30 minutes, tells organic layer.
In No. 4 reactors, add 500 kg of water and 100 kilograms of sodium-chlor, after stirring and dissolving is complete, add the organic layer of telling in aforementioned No. 3 reactors again, stir standing demix after 30 minutes.The organic layer of telling after methylene dichloride is removed in following about the 50 ℃ distillations of normal pressure, changes the water pump underpressure distillation into, controls about 40 ℃, is distilled to absence of liquid and oozes.Residual liquid changes the two stage pump underpressure distillation into, maintains the temperature at about 100 ℃, obtains overhead product 106kg, is the methylamino acetal, and it is 95% that GC detects purity, and productive rate is 64.8%.
(c) in No. 5 reactors, add 410 kilograms of methylamino acetals, 270 kilograms of potassium sulfocyanates and 500 kilograms of purified water, connect a device for absorbing tail gas that saturated solution of sodium carbonate is housed; After the stirring at room dissolving fully, drip 1000 kilograms in the 1mol/L dilute hydrochloric acid for preparing in advance in No. 5 reactors, the control reacting liquid temperature is about 30 ℃.
After reaction finished, the reaction solution underpressure distillation removed and anhydrates, and the gained solid dissolves once more with ethyl acetate, and behind the elimination insolubles, ethyl acetate is removed in underpressure distillation.After the gained solid is dissolved in purified water, regulate pH to 1, crystallisation by cooling obtains purity greater than 99% product, and vacuum drying promptly gets the finished product 150kg of 2-sulfydryl-1-Methylimidazole, and productive rate is 46.8%.
Embodiment 3
(a) 480 kilograms of dehydrated alcohols of suction in No. 1 reactor, 180 kilograms of vinyl-acetic esters are taken out material and are finished, the vacuum in the nitrogen balance reactor.Reacting liquid temperature is controlled at about 5 ℃ in the reaction process, and 335 kilograms of bromines are pressed in No. 1 reactor, adds in about 10 hours.Be warming up to 30 ℃ after bromine adds, insulation reaction is to reaction solution sampling GC detection intermediate≤1.0%, i.e. stopped reaction.
Stir and in No. 1 reactor, to change the concentration for preparing in advance down over to be 16.7% aqueous sodium carbonate to reaction solution pH be 9, add 540 kilograms of methylene dichloride again, stirred 30 minutes, tell organic layer.
In No. 2 reactors, add 300 kg of water and 60 kilograms of sodium-chlor, after stirring and dissolving is complete, add the organic layer of telling in aforementioned No. 1 reactor again, stir standing demix after 30 minutes.The organic layer concentrating under reduced pressure of telling is removed methylene dichloride and is obtained the bromacetal crude product, and GC detects purity 84.0%, productive rate 68.2%.
(b) suction 260kg bromacetal crude product in No. 3 autoclaves, 1000kg 40% 1 first ammonia soln, closed reactor.Being warming up to reacting liquid temperature is 110 ℃, and still is pressed 3MPa.Reaction finishes the back and adds 1000 kilograms of methylene dichloride stirrings 30 minutes, tells organic layer.
In No. 4 reactors, add 500 kg of water and 100 kilograms of sodium-chlor, after stirring and dissolving is complete, add the organic layer of telling in aforementioned No. 3 reactors again, stir standing demix after 30 minutes.The organic layer of telling after methylene dichloride is removed in following about the 50 ℃ distillations of normal pressure, changes the water pump underpressure distillation into, controls about 40 ℃, is distilled to absence of liquid and oozes.Residual liquid changes the two stage pump underpressure distillation into, maintains the temperature at about 100 ℃, obtains overhead product 110kg, is the methylamino acetal, and it is 95% that GC detects purity, and productive rate is 67.3%.
(c) in No. 5 reactors, add 410 kilograms of methylamino acetals, 270 kilograms of potassium sulfocyanates and 500 kilograms of purified water, after the stirring at room dissolving fully, drip 1000 kilograms in the 1mol/L dilute hydrochloric acid for preparing in advance in No. 5 reactors, the control reacting liquid temperature is about 40 ℃.
After reaction finished, the reaction solution underpressure distillation removed and anhydrates, and the gained solid dissolves once more with ethyl acetate, and behind the elimination insolubles, ethyl acetate is removed in underpressure distillation.After the gained solid is dissolved in purified water, regulate pH to 1, crystallisation by cooling obtains purity greater than 99% product, and vacuum drying promptly gets the finished product 150kg of 2-sulfydryl-1-Methylimidazole, and productive rate is 46.4%.
Embodiment 4
(a) 480 kilograms of dehydrated alcohols of suction in No. 1 reactor, 180 kilograms of vinyl-acetic esters are taken out material and are finished, the vacuum in the nitrogen balance reactor.Reacting liquid temperature is controlled at about 5 ℃ in the reaction process, and 335 kilograms of bromines are pressed in No. 1 reactor, adds in about 10 hours.Be warming up to 30 ℃ after bromine adds, insulation reaction is to reaction solution sampling GC detection intermediate≤1.0%, i.e. stopped reaction.
Stir and in No. 1 reactor, to change the concentration for preparing in advance down over to be 16.7% aqueous sodium carbonate to reaction solution pH be 8, add 540 kilograms of methylene dichloride again, stirred 30 minutes, tell organic layer.
In No. 2 reactors, add 300 kg of water and 60 kilograms of sodium-chlor, after stirring and dissolving is complete, add the organic layer of telling in aforementioned No. 1 reactor again, stir standing demix after 30 minutes.The organic layer concentrating under reduced pressure of telling is removed methylene dichloride and is obtained the bromacetal crude product, and GC detects purity 84.0%, productive rate 68.2%.
(b) suction 260kg bromacetal crude product in No. 3 autoclaves, 1000kg 40% 1 first ammonia soln, closed reactor.Being warming up to reacting liquid temperature is 100 ℃, and still is pressed 3MPa.Reaction finishes the back and adds 1000 kilograms of methylene dichloride stirrings 30 minutes, tells organic layer.
In No. 4 reactors, add 500 kg of water and 100 kilograms of sodium-chlor, after stirring and dissolving is complete, add the organic layer of telling in aforementioned No. 3 reactors again, stir standing demix after 30 minutes.The organic layer of telling after methylene dichloride is removed in following about the 50 ℃ distillations of normal pressure, changes the water pump underpressure distillation into, controls about 40 ℃, is distilled to absence of liquid and oozes.Residual liquid changes the two stage pump underpressure distillation into, maintains the temperature at about 100 ℃, obtains overhead product 108kg, is the methylamino acetal, and it is 95% that GC detects purity, and productive rate is 66.2%.
(c) in No. 5 reactors, add 410 kilograms of methylamino acetals, 270 kilograms of potassium sulfocyanates and 500 kilograms of purified water, after the stirring at room dissolving fully, drip 1000 kilograms in the 1mol/L dilute hydrochloric acid for preparing in advance in No. 5 reactors, the control reacting liquid temperature is about 50 ℃.
After reaction finished, the reaction solution underpressure distillation removed and anhydrates, and the gained solid dissolves once more with ethyl acetate, and behind the elimination insolubles, ethyl acetate is removed in underpressure distillation.After the gained solid is dissolved in purified water, regulate pH to 2, crystallisation by cooling obtains purity greater than 99% product, and vacuum drying promptly gets the finished product 148kg of 2-sulfydryl-1-Methylimidazole, and productive rate is 46.5%.
More than describe preferred embodiment of the present invention in detail.Should be appreciated that those of ordinary skill in the art need not creative work and just can design according to the present invention make many modifications and variations.Therefore, all technician in the art all should be in the determined protection domain by claims under this invention's idea on the basis of existing technology by the available technical scheme of logical analysis, reasoning, or a limited experiment.
Claims (5)
1. the industrialized preparing process of 2-sulfydryl-1-Methylimidazole is characterized in that may further comprise the steps:
(a) in dehydrated alcohol, with vinyl-acetic ester and bromine reaction, after reaction finishes with the reaction solution pH regulator to 〉=8, behind dichloromethane extraction, distillation removes to desolvate and obtains the bromacetal crude product and directly drop into next step reaction;
(b) bromacetal and aqueous methylamine solution issue ammonifying at 3-4MPa pressure and separate reaction, reacting liquid temperature is controlled between 100-120 ℃, reaction is finished afterreaction liquid through after extraction, dewatering, and purifying by fractionation by distillation obtains the methylamino acetal;
(c) hydrochloric acid is dropped in the aqueous solution of methylamino acetal and potassium sulfocyanate, reacting liquid temperature is controlled between 30-50 ℃ in the dropping process; Reaction is finished the underpressure distillation of afterreaction liquid except that anhydrating, the gained solid dissolves once more with ethyl acetate, behind the elimination insolubles, ethyl acetate is removed in underpressure distillation, remaining solid is dissolved in purified water, regulate pH to 1-2, crystallisation by cooling obtains purity greater than 2-sulfydryl-1-Methylimidazole of 99%, and vacuum-drying promptly gets the finished product.
2. the method for claim 1 is characterized in that, step (a) is carried out under protection of inert gas.
3. the method for claim 1 is characterized in that, after the fractionation by distillation purification process refers to that specifically the reaction solution process extracts, dewaters in the step (b), removes methylene dichloride 50 ℃ of left and right sides air distillations; Ooze 40 ℃ of left and right sides underpressure distillation to absence of liquid with water pump again; Residual liquid is used two stage pump instead 100 ℃ of left and right sides underpressure distillation, and the overhead product that obtains is the methylamino acetal.
4. the method for claim 1 is characterized in that, reaction vessel used in the step (c) also is connected with device for absorbing tail gas.
5. as any described method of claim 1-4, it is characterized in that used concentration of hydrochloric acid is 1mol/L in the step (c).
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105541724A (en) * | 2016-01-21 | 2016-05-04 | 武汉科福新药有限责任公司 | Preparation method of methimazole |
| CN107162983A (en) * | 2017-06-12 | 2017-09-15 | 常州市天华制药有限公司 | A kind of synthesis of methimazole and process for purification |
| CN107353253A (en) * | 2017-05-25 | 2017-11-17 | 北京万鹏朗格医药科技有限公司 | A kind of preparation method of methimazole |
| CN107602476A (en) * | 2017-10-10 | 2018-01-19 | 浦拉司科技（上海）有限责任公司 | A kind of preparation method of the methylimidazole of 2 sulfydryl 1 |
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Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105541724A (en) * | 2016-01-21 | 2016-05-04 | 武汉科福新药有限责任公司 | Preparation method of methimazole |
| CN105541724B (en) * | 2016-01-21 | 2018-03-30 | 武汉科福新药有限责任公司 | The preparation method of methimazole |
| CN107353253A (en) * | 2017-05-25 | 2017-11-17 | 北京万鹏朗格医药科技有限公司 | A kind of preparation method of methimazole |
| CN107162983A (en) * | 2017-06-12 | 2017-09-15 | 常州市天华制药有限公司 | A kind of synthesis of methimazole and process for purification |
| CN107162983B (en) * | 2017-06-12 | 2020-04-28 | 常州市天华制药有限公司 | Synthesis and refining method of methimazole |
| CN107602476A (en) * | 2017-10-10 | 2018-01-19 | 浦拉司科技（上海）有限责任公司 | A kind of preparation method of the methylimidazole of 2 sulfydryl 1 |
| CN107602476B (en) * | 2017-10-10 | 2020-06-26 | 浦拉司科技（上海）有限责任公司 | Preparation method of 2-mercapto-1-methylimidazole |
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