CN102977026A - Preparation method of 4-methylpyrazole - Google Patents
Preparation method of 4-methylpyrazole Download PDFInfo
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- CN102977026A CN102977026A CN2012104959704A CN201210495970A CN102977026A CN 102977026 A CN102977026 A CN 102977026A CN 2012104959704 A CN2012104959704 A CN 2012104959704A CN 201210495970 A CN201210495970 A CN 201210495970A CN 102977026 A CN102977026 A CN 102977026A
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Abstract
The invention discloses a preparation method of 4-methylpyrazole. According to the method, concentrated sulfuric acid and hydrazine hydrate are utilized as raw materials. The method comprises the following steps of: performing a heating reflux reaction to generate hydrazine sulfate; adding sulfuric acid, hydrazine sulfate and potassium iodide into a reactor; adding isobutyraldehyde while stirring continuously so as to conduct a heating reflux reaction; after the reaction, adjusting the pH value of the reaction liquid to 7; sequentially extracting, drying and evaporating out a solvent to obtain a crude product of 4-methylpyrazole; performing primary reduced-pressure distillation of the crude product, and purifying; adding the product after primary purification into the mixed liquid of ethyl acetate and petroleum ether, and recrystallizing; and finally performing reduced-pressure distillation again to obtain a refined product of 4-methylpyrazole. According to the invention, the preparation of 4-methylpyrazole can be performed under normal pressure; the preparation method is simple and favorable for industrial production; and moreover, the product 4-methylpyrazole has relatively high purity, the impurity content of a single product is less than 0.1%, and the quality requirements are completely met.
Description
Technical field
The present invention relates to a kind of preparation method of medicine, belong to the pharmaceutical chemistry field, particularly relate to a kind of preparation method of 4-methylpyrazole.
Background technology
Methylpyrazole is that drugs approved by FDA is mainly used in the rescue of the alcohol poisonings such as ethylene glycol, ethanol, methyl alcohol by a kind of alcohol dehydrogenase enzyme inhibitors that Orphan Medical company produces at the beginning of 1998.
At present, also there is relevant document to report about methylpyrazole.Such as: 1, H.R.Merkle etc. carries out comparatively deep research to the methyl substituted pyrazoles.Synthetic namely the reaction in the presence of sulfuric acid by isobutyric aldehyde and hydrazine hydrate of methylpyrazole obtains in the document, and yield is 49%.The shortcoming that this synthetic method exists is because the isobutyric aldehyde boiling point only has 64 ℃, so Merkle etc. adopts autoclave, by volume pump isobutyric aldehyde is added the reactor reaction, comparatively loaded down with trivial details, the trouble of its experimental implementation.2, Liao Wenwen etc. is added drop-wise in the sulfuric acid under isobutyric aldehyde and the hydrazine hydrate mixing normal pressure, and yield reaches 45.2%.Although this synthetic method has been avoided reaction under high pressure.But the shortcoming that this synthetic method exists is in the reaction process because the existence of the vitriol oil produces more impurity in the reaction, color is more black, and purity is inadequate.
Summary of the invention
The technical problem to be solved in the present invention is the shortcoming that exists in the synthetic prior art of present methylpyrazole, and a kind of preparation method of methylpyrazole is provided.Utilize technical solution of the present invention to prepare methylpyrazole, can operate under condition of normal pressure, the preparation method is simple, and products obtained therefrom purity is higher.
In order to address the above problem, the technical solution used in the present invention is:
The invention provides a kind of preparation method of 4-methylpyrazole, described preparation method may further comprise the steps:
The preparation of a, hydrazonium sulfate:
Take the vitriol oil and hydrazine hydrate as raw material, according to the vitriol oil and hydrazine hydrate between the two mass ratio be that the ratio of 1:1.0～1.5 takes by weighing two kinds of raw materials, at first the vitriol oil that takes by weighing is added in the reaction vessel, and stir, the reaction vessel that adds the vitriol oil is put into the low-temp reaction device lowers the temperature, make reactor temperature be down to-10～0 ℃, under this temperature, slowly add hydrazine hydrate, 1～2h hydrazine hydrate dropwises, its temperature is controlled at 0～10 ℃ and continuous stirring reaction 2～2.5h, carries out suction filtration after the reaction, the gained filter cake washs with dehydrated alcohol, filter cake after the washing carries out drying, obtains hydrazonium sulfate after the drying;
The preparation of b, 4-methylpyrazole crude product:
Take the hydrazonium sulfate of step a preparation and isobutyric aldehyde as main raw material, at first successively sulfuric acid, hydrazonium sulfate and potassiumiodide are joined in the reactor with reflux, under 5～15 ℃ of agitation conditions, drip isobutyric aldehyde, last 1.5～2h and dropwise, isobutyric aldehyde dropwises post-heating to 100 ℃ back flow reaction 4h; After back flow reaction finishes its reaction solution is cooled to 0～5 ℃, then transferring to reacting liquid pH value with sodium hydroxide solution is 6, and then adding the pH value that saturated sodium bicarbonate solution transfers to reaction solution is 7, controls 20～30 ℃ of reacting liquid temperatures during regulating the pH value; Then adopting ethyl acetate is that 7 reaction solution extracts to regulating the pH value
,The gained organic phase adopts anhydrous magnesium sulfate drying 30～40min after the extraction, and then distilling off solvent obtains the 4-methylpyrazole crude product;
Described hydrazonium sulfate and the sulfuric acid mol ratio between the two is 1:2.0～5.0; Hydrazonium sulfate and the isobutyric aldehyde mol ratio between the two is 1:1.0～1.5; Hydrazonium sulfate and the potassiumiodide mol ratio between the two is 1:0.01～0.02; Described hydrazonium sulfate and the ethyl acetate ratio between the two is 1g:3～10ml;
The rectifying of c, 4-methylpyrazole crude product:
Be to carry out underpressure distillation under the condition of 0.090～0.097mPa in vacuum tightness with step b gained 4-methylpyrazole crude product, collect 110～116 ℃ of cuts, obtain clarifying colourless or weak yellow liquid, be the 4-methylpyrazole of first purification;
Making with extra care of d, 4-methylpyrazole:
The first 4-methylpyrazole that obtains of purifying of step c is added in the reactor, add the mixing solutions of ethyl acetate and sherwood oil, stir 30～35min; Place-5～0 ℃ to place 2 hours gained solution, carry out suction filtration after the placement, the gained filter cake is with 0 ℃ of petroleum ether, be to carry out underpressure distillation under the condition of 0.090～0.097mPa in vacuum tightness with the filter cake after the washing, collect 110～116 ℃ of cuts, obtain clarified colorless liquid, be the 4-methylpyrazole highly finished product;
The 4-methylpyrazole that described first purification obtains and the mixed solution of ethyl acetate and the sherwood oil ratio between the two is 1g:1～5ml; The volume ratio of described ethyl acetate and the two mixing of sherwood oil is 1:3.0～8.0.
According to the preparation method of above-mentioned 4-methylpyrazole, the mass percentage concentration of the vitriol oil described in the step a is 98%; The mass percentage concentration of described hydrazine hydrate is 80%.
According to the preparation method of above-mentioned 4-methylpyrazole, the filter cake described in the step a after the washing carries out drying, and its drying conditions is 40 ℃ of lower forced air dryings 2 hours.
According to the preparation method of above-mentioned 4-methylpyrazole, the mass percentage concentration of sulfuric acid described in the step b is 70%; The mass percentage concentration of described sodium hydroxide solution is 50%; The mass percentage concentration of described sodium hydrogen carbonate solution is 9%.
Positive beneficial effect of the present invention:
1, utilize technical solution of the present invention to prepare methylpyrazole, can operate under condition of normal pressure, the preparation method is simple, is conducive to suitability for industrialized production.The drawback that technical solution of the present invention has avoided the available technology adopting autoclave to react.
2, the product 4-methylpyrazole purity of utilizing technical solution of the present invention to prepare is higher, and single foreign matter content satisfies specification of quality (the correlation detection data of products obtained therefrom of the present invention see table 1 for details) fully less than 0.1%.
The detection data of table 1 product of the present invention
Four, description of drawings:
The atlas analysis of Fig. 1 embodiment of the invention 1 products obtained therefrom 4-methylpyrazole;
The atlas analysis of Fig. 2 embodiment of the invention 2 products obtained therefrom 4-methylpyrazoles;
The atlas analysis of Fig. 3 embodiment of the invention 3 products obtained therefrom 4-methylpyrazoles.
Five, embodiment:
Further set forth the present invention below in conjunction with embodiment, but do not limit content of the present invention.
Embodiment 1:
The preparation method of 4-methylpyrazole of the present invention, this preparation method's detailed step is as follows:
The preparation of a, hydrazonium sulfate:
Take the vitriol oil (mass percentage concentration is as 98%) and hydrazine hydrate (mass percentage concentration is as 80%) as raw material, according to the vitriol oil and hydrazine hydrate between the two mass ratio be that the ratio of 1:1.0 takes by weighing two kinds of raw materials, at first the vitriol oil that takes by weighing is added in the reaction vessel, and stir, the reaction vessel that adds the vitriol oil is put into the low-temp reaction device lowers the temperature, make reactor temperature be down to-10 ℃, under this temperature, slowly add hydrazine hydrate, the 1h hydrazine hydrate dropwises, its temperature is controlled at 0 ℃ and continuous stirring reaction 2h, carry out suction filtration after the reaction, the gained filter cake washs with dehydrated alcohol, filter cake after the washing carries out drying (its drying conditions is 40 ℃ of lower forced air dryings 2 hours), obtains hydrazonium sulfate after the drying;
The preparation of b, 4-methylpyrazole crude product:
Take the hydrazonium sulfate of step a preparation and isobutyric aldehyde as main raw material, at first successively sulfuric acid (mass percentage concentration is 70%), hydrazonium sulfate and potassiumiodide are joined in the reactor with reflux, under 5 ℃ of agitation conditions, drip isobutyric aldehyde, last 1.5h and dropwise, isobutyric aldehyde dropwises post-heating to 100 ℃ back flow reaction 4h; Back flow reaction is cooled to 0 ℃ with its reaction solution after finishing, then using sodium hydroxide solution (mass percentage concentration is 50%) to transfer to reacting liquid pH value is 6, then adding the pH value that saturated sodium bicarbonate solution (mass percentage concentration is 9%) transfers to reaction solution is 7, controls 20 ℃ of reacting liquid temperatures during regulating pH value; Then adopting ethyl acetate is that 7 reaction solution extracts to regulating the pH value
,The gained organic phase adopts anhydrous magnesium sulfate drying 30min after the extraction, and then distilling off solvent obtains the 4-methylpyrazole crude product;
Described hydrazonium sulfate and the sulfuric acid mol ratio between the two is 1:2.0; Hydrazonium sulfate and the isobutyric aldehyde mol ratio between the two is 1:1.0; Hydrazonium sulfate and the potassiumiodide mol ratio between the two is 1:0.01; Described hydrazonium sulfate and the ethyl acetate ratio between the two is 1g:3ml;
The rectifying of c, 4-methylpyrazole crude product:
Be to carry out underpressure distillation under the condition of 0.090mPa in vacuum tightness with step b gained 4-methylpyrazole crude product, collect 116 ℃ of cuts, obtain clarifying colourless or weak yellow liquid, be the 4-methylpyrazole of first purification;
Making with extra care of d, 4-methylpyrazole:
The first 4-methylpyrazole that obtains of purifying of step c is added in the reactor, add the mixing solutions of ethyl acetate and sherwood oil, stir 30min; Place-5 ℃ to place 2 hours gained solution, carry out suction filtration after the placement, the gained filter cake is with 0 ℃ of petroleum ether, be to carry out underpressure distillation under the condition of 0.090mPa in vacuum tightness with the filter cake after the washing, collect 116 ℃ of cuts, obtain clarified colorless liquid, be the 4-methylpyrazole highly finished product;
The 4-methylpyrazole that described first purification obtains and the mixed solution of ethyl acetate and the sherwood oil ratio between the two is 1g:1ml; The volume ratio of described ethyl acetate and the two mixing of sherwood oil is 1:3.0.
Embodiment 2:
The preparation method of 4-methylpyrazole of the present invention, this preparation method's detailed step is as follows:
The preparation of a, hydrazonium sulfate:
Take the vitriol oil (mass percentage concentration is as 98%) and hydrazine hydrate (mass percentage concentration is as 80%) as raw material, according to the vitriol oil and hydrazine hydrate between the two mass ratio be that the ratio of 1:1.3 takes by weighing two kinds of raw materials, at first the vitriol oil that takes by weighing is added in the reaction vessel, and stir, the reaction vessel that adds the vitriol oil is put into the low-temp reaction device lowers the temperature, make reactor temperature be down to-5 ℃, under this temperature, slowly add hydrazine hydrate, 1.5h hydrazine hydrate dropwises, its temperature is controlled at 5 ℃ and continuous stirring reaction 2.2h, carry out suction filtration after the reaction, the gained filter cake washs with dehydrated alcohol, filter cake after the washing carries out drying (its drying conditions is 40 ℃ of lower forced air dryings 2 hours), obtains hydrazonium sulfate after the drying;
The preparation of b, 4-methylpyrazole crude product:
Take the hydrazonium sulfate of step a preparation and isobutyric aldehyde as main raw material, at first successively sulfuric acid (mass percentage concentration is 70%), hydrazonium sulfate and potassiumiodide are joined in the reactor with reflux, under 10 ℃ of agitation conditions, drip isobutyric aldehyde, last 1.8h and dropwise, isobutyric aldehyde dropwises post-heating to 100 ℃ back flow reaction 4h; Back flow reaction is cooled to 3 ℃ with its reaction solution after finishing, then using sodium hydroxide solution (mass percentage concentration is 50%) to transfer to reacting liquid pH value is 6, then adding the pH value that saturated sodium bicarbonate solution (mass percentage concentration is 9%) transfers to reaction solution is 7, controls 25 ℃ of reacting liquid temperatures during regulating pH value; Then adopting ethyl acetate is that 7 reaction solution extracts to regulating the pH value
,The gained organic phase adopts anhydrous magnesium sulfate drying 35min after the extraction, and then distilling off solvent obtains the 4-methylpyrazole crude product;
Described hydrazonium sulfate and the sulfuric acid mol ratio between the two is 1:3.5; Hydrazonium sulfate and the isobutyric aldehyde mol ratio between the two is 1:1.2; Hydrazonium sulfate and the potassiumiodide mol ratio between the two is 1:0.015; Described hydrazonium sulfate and the ethyl acetate ratio between the two is 1g:6ml;
The rectifying of c, 4-methylpyrazole crude product:
Be to carry out underpressure distillation under the condition of 0.095mPa in vacuum tightness with step b gained 4-methylpyrazole crude product, collect 112 ℃ of cuts, obtain clarifying colourless or weak yellow liquid, be the 4-methylpyrazole of first purification;
Making with extra care of d, 4-methylpyrazole:
The first 4-methylpyrazole that obtains of purifying of step c is added in the reactor, add the mixing solutions of ethyl acetate and sherwood oil, stir 32min; Place-2 ℃ to place 2 hours gained solution, carry out suction filtration after the placement, the gained filter cake is with 0 ℃ of petroleum ether, be to carry out underpressure distillation under the condition of 0.095mPa in vacuum tightness with the filter cake after the washing, collect 112 ℃ of cuts, obtain clarified colorless liquid, be the 4-methylpyrazole highly finished product;
The 4-methylpyrazole that described first purification obtains and the mixed solution of ethyl acetate and the sherwood oil ratio between the two is 1g:3ml; The volume ratio of described ethyl acetate and the two mixing of sherwood oil is 1:5.0.
Embodiment 3:
The preparation method of 4-methylpyrazole of the present invention, this preparation method's detailed step is as follows:
The preparation of a, hydrazonium sulfate:
Take the vitriol oil (mass percentage concentration is as 98%) and hydrazine hydrate (mass percentage concentration is as 80%) as raw material, according to the vitriol oil and hydrazine hydrate between the two mass ratio be that the ratio of 1:1.5 takes by weighing two kinds of raw materials, at first the vitriol oil that takes by weighing is added in the reaction vessel, and stir, the reaction vessel that adds the vitriol oil is put into the low-temp reaction device lowers the temperature, make reactor temperature be down to 0 ℃, under this temperature, slowly add hydrazine hydrate, the 2h hydrazine hydrate dropwises, its temperature is controlled at 10 ℃ and continuous stirring reaction 2.5h, carry out suction filtration after the reaction, the gained filter cake washs with dehydrated alcohol, filter cake after the washing carries out drying (its drying conditions is 40 ℃ of lower forced air dryings 2 hours), obtains hydrazonium sulfate after the drying;
The preparation of b, 4-methylpyrazole crude product:
Take the hydrazonium sulfate of step a preparation and isobutyric aldehyde as main raw material, at first successively sulfuric acid (mass percentage concentration is 70%), hydrazonium sulfate and potassiumiodide are joined in the reactor with reflux, under 15 ℃ of agitation conditions, drip isobutyric aldehyde, last 2h and dropwise, isobutyric aldehyde dropwises post-heating to 100 ℃ back flow reaction 4h; Back flow reaction is cooled to 5 ℃ with its reaction solution after finishing, then using sodium hydroxide solution (mass percentage concentration is 50%) to transfer to reacting liquid pH value is 6, then adding the pH value that saturated sodium bicarbonate solution (mass percentage concentration is 9%) transfers to reaction solution is 7, controls 30 ℃ of reacting liquid temperatures during regulating pH value; Then adopting ethyl acetate is that 7 reaction solution extracts to regulating the pH value
,The gained organic phase adopts anhydrous magnesium sulfate drying 40min after the extraction, and then distilling off solvent obtains the 4-methylpyrazole crude product;
Described hydrazonium sulfate and the sulfuric acid mol ratio between the two is 1:5.0; Hydrazonium sulfate and the isobutyric aldehyde mol ratio between the two is 1:1.5; Hydrazonium sulfate and the potassiumiodide mol ratio between the two is 1:0.02; Described hydrazonium sulfate and the ethyl acetate ratio between the two is 1g:10ml;
The rectifying of c, 4-methylpyrazole crude product:
Be to carry out underpressure distillation under the condition of 0.097mPa in vacuum tightness with step b gained 4-methylpyrazole crude product, collect 110 ℃ of cuts, obtain clarifying colourless or weak yellow liquid, be the 4-methylpyrazole of first purification;
Making with extra care of d, 4-methylpyrazole:
The first 4-methylpyrazole that obtains of purifying of step c is added in the reactor, add the mixing solutions of ethyl acetate and sherwood oil, stir 35min; Place 0 ℃ to place 2 hours gained solution, carry out suction filtration after the placement, the gained filter cake is with 0 ℃ of petroleum ether, be to carry out underpressure distillation under the condition of 0.097mPa in vacuum tightness with the filter cake after the washing, collect 110 ℃ of cuts, obtain clarified colorless liquid, be the 4-methylpyrazole highly finished product;
The 4-methylpyrazole that described first purification obtains and the mixed solution of ethyl acetate and the sherwood oil ratio between the two is 1g:5ml; The volume ratio of described ethyl acetate and the two mixing of sherwood oil is 1:8.0.
Claims (4)
1. the preparation method of a 4-methylpyrazole is characterized in that, described preparation method may further comprise the steps:
The preparation of a, hydrazonium sulfate:
Take the vitriol oil and hydrazine hydrate as raw material, according to the vitriol oil and hydrazine hydrate between the two mass ratio be that the ratio of 1:1.0～1.5 takes by weighing two kinds of raw materials, at first the vitriol oil that takes by weighing is added in the reaction vessel, and stir, the reaction vessel that adds the vitriol oil is put into the low-temp reaction device lowers the temperature, make reactor temperature be down to-10～0 ℃, under this temperature, slowly add hydrazine hydrate, 1～2h hydrazine hydrate dropwises, its temperature is controlled at 0～10 ℃ and continuous stirring reaction 2～2.5h, carries out suction filtration after the reaction, the gained filter cake washs with dehydrated alcohol, filter cake after the washing carries out drying, obtains hydrazonium sulfate after the drying;
The preparation of b, 4-methylpyrazole crude product:
Take the hydrazonium sulfate of step a preparation and isobutyric aldehyde as main raw material, at first successively sulfuric acid, hydrazonium sulfate and potassiumiodide are joined in the reactor with reflux, under 5～15 ℃ of agitation conditions, drip isobutyric aldehyde, last 1.5～2h and dropwise, isobutyric aldehyde dropwises post-heating to 100 ℃ back flow reaction 4h; After back flow reaction finishes its reaction solution is cooled to 0～5 ℃, then transferring to reacting liquid pH value with sodium hydroxide solution is 6, and then adding the pH value that saturated sodium bicarbonate solution transfers to reaction solution is 7, controls 20～30 ℃ of reacting liquid temperatures during regulating the pH value; Then adopting ethyl acetate is that 7 reaction solution extracts to regulating the pH value
,The gained organic phase adopts anhydrous magnesium sulfate drying 30～40min after the extraction, and then distilling off solvent obtains the 4-methylpyrazole crude product;
Described hydrazonium sulfate and the sulfuric acid mol ratio between the two is 1:2.0～5.0; Hydrazonium sulfate and the isobutyric aldehyde mol ratio between the two is 1:1.0～1.5; Hydrazonium sulfate and the potassiumiodide mol ratio between the two is 1:0.01～0.02; Described hydrazonium sulfate and the ethyl acetate ratio between the two is 1g:3～10ml;
The rectifying of c, 4-methylpyrazole crude product:
Be to carry out underpressure distillation under the condition of 0.090～0.097mPa in vacuum tightness with step b gained 4-methylpyrazole crude product, collect 110～116 ℃ of cuts, obtain clarifying colourless or weak yellow liquid, be the 4-methylpyrazole of first purification;
Making with extra care of d, 4-methylpyrazole:
The first 4-methylpyrazole that obtains of purifying of step c is added in the reactor, add the mixing solutions of ethyl acetate and sherwood oil, stir 30～35min; Place-5～0 ℃ to place 2 hours gained solution, carry out suction filtration after the placement, the gained filter cake is with 0 ℃ of petroleum ether, be to carry out underpressure distillation under the condition of 0.090～0.097mPa in vacuum tightness with the filter cake after the washing, collect 110～116 ℃ of cuts, obtain clarified colorless liquid, be the 4-methylpyrazole highly finished product;
The 4-methylpyrazole that described first purification obtains and the mixed solution of ethyl acetate and the sherwood oil ratio between the two is 1g:1～5ml; The volume ratio of described ethyl acetate and the two mixing of sherwood oil is 1:3.0～8.0.
2. the preparation method of 4-methylpyrazole according to claim 1, it is characterized in that: the mass percentage concentration of the vitriol oil described in the step a is 98%; The mass percentage concentration of described hydrazine hydrate is 80%.
3. the preparation method of 4-methylpyrazole according to claim 1 is characterized in that: the filter cake described in the step a after the washing carries out drying, and its drying conditions is 40 ℃ of lower forced air dryings 2 hours.
4. the preparation method of 4-methylpyrazole according to claim 1, it is characterized in that: the mass percentage concentration of sulfuric acid described in the step b is 70%; The mass percentage concentration of described sodium hydroxide solution is 50%; The mass percentage concentration of described sodium hydrogen carbonate solution is 9%.
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| CN112358448A (en) * | 2020-09-30 | 2021-02-12 | 南通新邦化工科技有限公司 | Novel industrial production method of pyrazole |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1261351A (en) * | 1997-06-23 | 2000-07-26 | 巴斯福股份公司 | Method for producing substituted pyrazoles |
| CN101163679A (en) * | 2005-04-21 | 2008-04-16 | 罕用药物有限公司 | Method of preparing ultrapure 4-methylpyrazole |
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Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1261351A (en) * | 1997-06-23 | 2000-07-26 | 巴斯福股份公司 | Method for producing substituted pyrazoles |
| CN101163679A (en) * | 2005-04-21 | 2008-04-16 | 罕用药物有限公司 | Method of preparing ultrapure 4-methylpyrazole |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN112358448A (en) * | 2020-09-30 | 2021-02-12 | 南通新邦化工科技有限公司 | Novel industrial production method of pyrazole |
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Application publication date: 20130320 |