CN102399191B - Method for synthesizing analgin - Google Patents
Method for synthesizing analgin Download PDFInfo
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- CN102399191B CN102399191B CN 201110432014 CN201110432014A CN102399191B CN 102399191 B CN102399191 B CN 102399191B CN 201110432014 CN201110432014 CN 201110432014 CN 201110432014 A CN201110432014 A CN 201110432014A CN 102399191 B CN102399191 B CN 102399191B
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Abstract
The invention relates to a new production process for an analgesic-antipyretic analgin. In the conventional synthesis route for the analgin, 4-aminoantipyrine (AA) is prepared into the analgin through four reactions, namely formylation, methylation, hydrolysis and condensation, while in the new method, the 4-aminoantipyrine (AA), paraformaldehyde and sodium hydrosulfite are directly subjected to condensation to form 4-N-demethylanalgin, and the 4-N-demethylanalgin and dimethyl sulfate are subjected to methylation under weak alkaline condition to form the analgin. By the process, the original four reactions are reduced to two reactions, the operation is greatly simplified, the cost is reduced, and three wastes are reduced.
Description
Technical field
The invention belongs to the compou nd synthesis technical field, be specifically related to a kind of new synthetic method of antipyretic and analgesic Sulpyrine.
Background technology
Sulpyrine belongs to antipyretic-antalgic and non_steroidal anti_inflammatory drug, and listing is existing 100 years history so far, its determined curative effect, and easy to use, formulation is various, cheap, on clinical medicine, plays an important role for many years.There is extensive market in many countries in the world, especially in developing country, are used widely, and are in great demand.Be mainly used in bringing down a fever, also be used for the treatment of acute arthritis, headache, rheumatic pain, toothache and myalgia etc.Because easily causing untoward reaction, generally do not do at present first-selected medication, only anxious heavy at acute high fever, the state of an illness, again without other efficient solution medicine of a warm nature can with situation under for promptly bringing down a fever.
Sulpyrine is white (injection) or white crystallization or crystalline powder to slightly micro-yellow (pro ore); Odorless, mildly bitter flavor; The aqueous solution is placed rear gradual change yellow.This product is easily molten in water, slightly molten in ethanol, almost insoluble in ether.
The production of most domestic Sulpyrine at present is all as raw material, through methylating and hydrolysis reaction generation quinizine (AT) with pyrazolone; Then use the Sodium Nitrite nitrosification, then reduce with ammonium bisulfite and ammonium sulphite, sulphuric acid hydrolysis, finally neutralize to obtain 4-AA (AA) with liquefied ammonia; 4-AA (AA), through formylation, methylates, and hydrolysis and neutralization generate 4-novalgin (MAA); 4-novalgin (MAA) generates Sulpyrine with formaldehyde, sodium bisulfite condensation.Its synthetic route is long, and cost is high, and by product is many, consumes energy high, also can produce a large amount of reluctant three industrial wastes in building-up process, therefore, finds more economical synthetic method, has great economic benefit and social benefit.
Summary of the invention
The objective of the invention is, for Sulpyrine synthetic provides a kind of new operational path, to reduce production stage, production cost is reduced.
In existing Sulpyrine synthesis technique, 4-AA (AA) is as follows to the synthesis technique of Sulpyrine:
The formylation of above-mentioned technique the first step reaction 4-AA (AA): this reaction 6 hours, pass through numerous and diverse technological processs such as reaction, cooling, crystallization, filtration, yield 88.1%.
Above-mentioned technique second step methylates, hydrolysis reaction: this reaction 5 hours, yield 94.1%.
Above-mentioned technique the 3rd step neutralization reaction: this reaction 6 hours, pass through reaction, cooling, press filtration, decompression numerous and diverse technological process such as anhydrate, use a large amount of sulfuric acid, contaminate environment, yield 98.0%.
The 4th step condensation reaction of above-mentioned technique: this reaction 4 hours, pass through numerous and diverse technological processs, particularly reflux temperature such as heating reflux reaction, cooling, crystallization, filtration too high, affect the quality of Sulpyrine, this reaction yield 93.9%.
Above-mentioned technique total recovery only 76.3%.
Sulpyrine production is the large production of mass-producing, if can improve 1% yield in production technique, reduces by a production stage, saves 1 hours, can produce very large economic benefit.
To 4-AA (AA) in the synthetic route of existing Sulpyrine, the synthesis technique to Sulpyrine is improved in the present invention.4-AA (AA) directly and paraformaldehyde and sodium bisulfite carry out condensation reaction, selectivity obtains 4-N-demethyl Sulpyrine; Then 4-N-demethyl Sulpyrine carries out methylation reaction with methyl-sulfate and obtains Sulpyrine under weak base exists.The present invention shortens to two steps by reaction, and gained Sulpyrine quality product meets pharmacopeia.4-AA after improvement (AA) is as follows to the synthesis route of Sulpyrine:
The synthesis technique the first step of the present invention reaction, 4-AA (AA) directly and paraformaldehyde and sodium bisulfite carry out condensation reaction:
The innovative point of this reaction is: with paraformaldehyde replace formaldehyde optionally sulfonic acid methyl obtain the 4-N-demethyl Sulpyrine (formula II) needed.
Generally, people can adopt formalin to carry out above-mentioned reaction, and we find by experiment, with formaldehyde, carry out above-mentioned reaction, and the reaction non-selectivity, obtain: 4-N-demethyl Sulpyrine, di-substituted (formula II I)
Di-substituted amount is about 20% of 4-N-demethyl Sulpyrine, and is difficult for removing.
We find pleasantly surprisedly: with paraformaldehyde replace formalin optionally sulfonic acid methyl obtain the 4-N-demethyl Sulpyrine of purity more than 96%.
Formula II formula II I
Synthesis technique second step reaction of the present invention: then 4-N-demethyl Sulpyrine carries out methylation reaction with methyl-sulfate and obtains Sulpyrine (structural formula I) under weak base exists.
The innovative point of this reaction is: under the weak base condition, etoh solvent content is controlled at 92-95% and is reacted.
Due to 4-N-demethyl Sulpyrine and Sulpyrine, fast hydrolyzing under sodium hydroxide exists generates 4-AA (AA) and 4-novalgin (MAA), therefore to the condition of methylating of 4-N-demethyl Sulpyrine, need to be explored, we could not obtain Sulpyrine to use sodium hydroxide, raw material 4-AA (AA) only from reaction solution, detected, when we replace sodium hydroxide with sodium bicarbonate, etoh solvent content is controlled at the 92-95% (ethanol of 92-95% simultaneously, all the other are water) certain proportion the time we unexpected find to decompose occur very slow, and its alkalescence enough makes methylation reaction carry out smoothly.After finishing, reaction immediately with the acetic acid neutralization, obtains Sulpyrine after filtration.
But when ethanol content<92%, the hydrolysis of the Sulpyrine of generation is more, when ethanol content>95%, reaction is carried out ground not exclusively.
This reaction conditions gentleness, can react at normal temperatures, and 50～60 ℃ of optimal reaction temperatures, be conducive to guarantee the Sulpyrine quality.
The weakly alkaline material is sodium carbonate, can be also sodium bicarbonate, salt of wormwood, saleratus, preferably sodium bicarbonate.
Structural formula I
Finally we also explore above-mentioned two-step reaction are merged and carries out one pot reaction, i.e. condensation reaction, methylation reaction can adopt the mode of cooking different foods in one pot to carry out in a reactor.Also obtain Sulpyrine, just yield decreases.
Preparation method of the present invention is as follows:
1, the preparation of 4-N-demethyl Sulpyrine
By equimolar 4-AA, sodium bisulfite, paraformaldehyde, join in reactor, content 95% ethanol is made solvent and is also added, and stirs and heating reflux reaction 1～2 hour.Reaction solution is reduced in 45 ℃ of backward reaction solutions and adds solid 4-N-demethyl Sulpyrine to cause crystallization, and high degree of agitation is after half an hour, and solid collected by filtration obtains 4-N-demethyl Sulpyrine.
2, the preparation of Sulpyrine
4-N-demethyl Sulpyrine is dissolved in content 92-95% (92-95% ethanol, all the other are water) ethanol, adds successively methyl-sulfate, sodium carbonate, 4-N-demethyl Sulpyrine, stirring reacting by heating 1～2 hour.Reaction solution is neutralized to pH7-8 with acetic acid, stirs cooling post crystallization and separates out, and solid collected by filtration obtains Sulpyrine.
3, the preparation of Sulpyrine (one kettle way)
By 20.3 gram 4-AAs (AA) (0.1mol), 10.4 gram sodium bisulfite (0.1mol), 3 gram paraformaldehydes (0.1mol) and 100 milliliter of 95% ethanol join in the reaction flask of 250 milliliters, stir and heating reflux reaction 1 hour.Reaction solution stirs and is cooled to 40 ℃, then adds successively 16.5 gram methyl-sulfates (0.13mol), and 10.4 gram sodium bicarbonates (0.13mol) stir and be heated to 60 ℃ of reactions 1 hour.Reaction solution is neutralized to pH7-8 with acetic acid, stirs cooling post crystallization and separates out, and solid collected by filtration obtains Sulpyrine.
Synthesis technique of the present invention, with respect to the synthesis technique of existing Sulpyrine, has obvious beneficial effect, and it is embodied in:
(1) synthesis route is short, the synthesis technique of existing Sulpyrine is reacted to (from AA) by 4 steps and shorten to 2 step reactions.
(2) with short production cycle, deducted numerous and diverse technological process.
(3) leather has removed a large amount of sulfuric acid that former synthesis technique is used, environmental contamination reduction.
(4) three industrial wastes are few, save three wastes processing cost, and reduce the pollution to environment.
(5) final step reaction conditions gentleness, can react at normal temperatures, and 50～60 ℃ of optimal reaction temperatures, be conducive to guarantee the Sulpyrine quality.
(6) especially, yield rises to 80.1% from 76.3% of existing Sulpyrine, will obtain very large economic benefit.
Embodiment
Following enforcement is for further narration the present invention, but it is not any restriction to scope of the present invention.The purity testing of each compound is measured on the HP1100 high performance liquid chromatograph.
The preparation of embodiment 1 4-N-demethyl Sulpyrine
By 20.3 gram 4-AAs (AA) (0.1mol), 10.4 gram sodium bisulfite (0.1mol), 3 gram paraformaldehydes (0.1mol) and 100 milliliter of 95% ethanol join in the reaction flask of 250 milliliters, stir and heating reflux reaction 1 hour.Reaction solution is reduced in 45 ℃ of backward reaction solutions and adds solid 4-N-demethyl Sulpyrine to cause crystallization, and high degree of agitation is after half an hour, and solid collected by filtration obtains 4-N-demethyl Sulpyrine 30.3 grams, and yield is 90%; Fusing point: 217 ℃;
1h NMR (400MHz, DMSO-d
6) δ: 2.18 (s, 3H), 2.80 (s, 3H), 3.78 (d, J=6.96Hz, 2H), 4.00 (m, 1H), 7.25 (m, 1H), 7.45 (m, 4H);
13c NMR (100MHz, DMSO-d
6) δ: 161.8,140.8,135.4,128.9 (2), 125.3,122.1 (2), 120.0,62.4,37.7,10.4.
The preparation of embodiment 2 Sulpyrines
33 gram 4-N-demethyl Sulpyrines (0.1mol) are dissolved in 100 milliliter of 95% ethanol, add successively 16.5 gram methyl-sulfates (0.13mol), 10.4 gram sodium bicarbonates (0.13mol), stir and be heated to 60 ℃ of reactions 1 hour.Reaction solution is neutralized to pH7-8 with acetic acid, stirs cooling post crystallization and separates out, and solid collected by filtration obtains Sulpyrine 31 grams, and yield is 89%; It is 99.5% that HPLC measures purity.
The preparation (one kettle way) of embodiment 3 Sulpyrines
By 20.3 gram 4-AAs (AA) (0.1mol), 10.4 gram sodium bisulfite (0.1mol), 3 gram paraformaldehydes (0.1mol) and 100 milliliter of 95% ethanol join in the reaction flask of 250 milliliters, stir and heating reflux reaction 1 hour.Reaction solution stirs and is cooled to 40 ℃, then adds successively 16.5 gram methyl-sulfates (0.13mol), and 10.4 gram sodium bicarbonates (0.13mol) stir and be heated to 60 ℃ of reactions 1 hour.Reaction solution is neutralized to pH7-8 with acetic acid, stirs cooling post crystallization and separates out, and solid collected by filtration obtains Sulpyrine 26 grams, and yield is 74%; It is 99.3% that HPLC measures purity.
Claims (6)
1. the synthetic method of the described Sulpyrine of structural formula I, is characterized in that obtaining Sulpyrine through methylation reaction by 4-N-demethyl Sulpyrine and methyl-sulfate under the weakly alkaline material exists,
Structural formula I.
2. method according to claim 1 is characterized in that: 4-AA (AA) carries out condensation reaction with paraformaldehyde and sodium bisulfite, and selectivity obtains 4-N-demethyl Sulpyrine, formula II,
Formula II.
3. method according to claim 1, it is characterized in that: the weakly alkaline material is sodium carbonate, can be also sodium bicarbonate, salt of wormwood, saleratus.
4. method according to claim 1, it is characterized in that: the weakly alkaline material is sodium bicarbonate.
5. according to the described method of claim 1 to 4 any one, its preparation technology is as follows:
1. the preparation of 4-N-demethyl Sulpyrine
Using equimolar 4-AA, sodium bisulfite, paraformaldehyde and as 95% ethanol of solvent, join in reactor, stirring heating reflux reaction 1～2 hour, reaction solution is reduced in 45 ℃ of backward reaction solutions and adds solid 4-N-demethyl Sulpyrine to cause crystallization, high degree of agitation is after half an hour, and solid collected by filtration obtains 4-N-demethyl Sulpyrine;
2. the preparation of Sulpyrine
4-N-demethyl Sulpyrine is dissolved in the aqueous ethanolic solution of ethanol content 92-95%, and in aqueous ethanolic solution, 92-95% is ethanol, and all the other are water; Add successively methyl-sulfate, sodium bicarbonate, 4-N-demethyl Sulpyrine, stirring reacting by heating 1～2 hour, reaction solution is neutralized to pH7-8 with acetic acid, stirs cooling post crystallization and separates out, and solid collected by filtration obtains Sulpyrine.
6. method according to claim 1 and 2, it is characterized in that: condensation reaction, methylation reaction adopt the mode of cooking different foods in one pot to carry out in a reactor; By 4-AA, sodium bisulfite, paraformaldehyde, join in 92-95% ethanol, stir and heating reflux reaction, reaction solution stirs cold, then adds successively methyl-sulfate, sodium bicarbonate, stir and heat, reaction solution is neutralized to pH7-8 with acetic acid, stirs cooling post crystallization and separates out, and solid collected by filtration obtains Sulpyrine.
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| CN108440413A (en) * | 2018-04-26 | 2018-08-24 | 山东新华制药股份有限公司 | The preparation method of high quality analgin |
| CN110172038B (en) * | 2018-06-12 | 2022-10-18 | 武汉武药制药有限公司 | Process for preparing analgin magnesium by one-pot method |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CH303081A (en) * | 1951-11-20 | 1954-11-15 | Isler Fritz | Process for the preparation of 1-phenyl-2,3-dimethyl-5-pyrazolone-4-methylamino-methanolsulphonic acid sodium. |
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Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CH303081A (en) * | 1951-11-20 | 1954-11-15 | Isler Fritz | Process for the preparation of 1-phenyl-2,3-dimethyl-5-pyrazolone-4-methylamino-methanolsulphonic acid sodium. |
Non-Patent Citations (6)
| Title |
|---|
| N. M. Kolgina et al..SYNTHESIS OF AMIDOPYRINE AND ANALGIN FROM METHYLENBISMONOMETHYLAMINOANTIPYRINE.《Khimiko-Farmatsevtieheskii Zhurnal》.1968,(第9期),24-26. |
| SYNTHESIS OF AMIDOPYRINE AND ANALGIN FROM METHYLENBISMONOMETHYLAMINOANTIPYRINE;N. M. Kolgina et al.;《Khimiko-Farmatsevtieheskii Zhurnal》;19680930(第9期);24-26 * |
| 安乃近的生产工艺改进;陈启槐等;《药学学报》;19661231(第5期);369 * |
| 江济章等.还原烃化法制备安乃近.《医药工业》.1983,(第1期),1-3. |
| 还原烃化法制备安乃近;江济章等;《医药工业》;19831231(第1期);1-3 * |
| 陈启槐等.安乃近的生产工艺改进.《药学学报》.1966,(第5期),369. |
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Application publication date: 20120404 Assignee: Yuanda Pharmaceutical (China) Co., Ltd. Assignor: Wuhan Wuyao Pharmaceutical Co., Ltd. Contract record no.: 2014420000030 Denomination of invention: Method for synthesizing analgin Granted publication date: 20131218 License type: Exclusive License Record date: 20140414 |
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