CN105294564A - Synthetic method of 5-amino-1-(2-hydroxyethyl)pyrazole - Google Patents
Synthetic method of 5-amino-1-(2-hydroxyethyl)pyrazole Download PDFInfo
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- CN105294564A CN105294564A CN201510902099.9A CN201510902099A CN105294564A CN 105294564 A CN105294564 A CN 105294564A CN 201510902099 A CN201510902099 A CN 201510902099A CN 105294564 A CN105294564 A CN 105294564A
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- hydroxyethyl
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
- C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
- C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D231/14—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three 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, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D231/38—Nitrogen atoms
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Abstract
The invention discloses a synthetic method of 5-amino-1-(2-hydroxyethyl)pyrazole. The synthetic method comprises the following steps: carrying out heating reflux reaction on beta-diazanyl ethanol and 3,3-dimethoxy propionitrile by taking water as a solvent for 2-3 hours; then dropwise adding a sodium hydroxide solution, and further carrying out the heating reflux reaction; cooling after the reaction, adding hydrochloric acid to regulate pH to be 5-6; and drying reaction liquid by distillation, adding a mixed liquid of toluene and methanol, heating and mixing until dissolution, and carrying out cooling crystallization to obtain 5-amino-1-(2-hydroxyethyl)pyrazole. According to the synthetic method, decarboxylic reaction in a traditional process is avoided, the yield is greatly increased, furthermore, the process route is short, the operation is simple, and industrial production is easily realized.
Description
Technical field
The present invention relates to a kind of synthetic method of 5-amino-1-(2-hydroxyethyl) pyrazoles, belong to medical art.
Background technology
Wincef is forth generation cephalosporin analog antibiotic, it all has good activity to gram-positive microorganism and Gram-negative bacteria, to the streptococcus aureus of methicillin resistance, Pseudomonas aeruginosa, there is good anti-microbial activity especially, highly stable to β-lactamase in addition, at present in state's listings such as Japan, be widely used clinically.
5-amino-1-(2-hydroxyethyl) pyrazoles is an important intermediate in Wincef building-up process.5-amino-1-(2-hydroxyethyl) pyrazoles, English name: 5-Amino-1-(2-hydroxyethyl) pyrazole, chemical formula: C
5h
9n
3o.Chemical structural formula is as follows.
Document " optimization of synthesis of 5-amino-1-(2-hydroxyethyl) pyrazoles " (Wang Guijun. Hebei chemical industry [J] .2011 07 phase) disclose two kinds of synthetic methods of 5-amino-1-(2-hydroxyethyl) pyrazoles.Synthetic method 1: adopt β-hydrazinoethanol and the cyclization of 3-methoxy acrylonitrile one step to generate 5-amino-1-(2-hydroxyethyl)-pyrazoles, the shortcoming of the method is the domestic not production of raw material 3-methoxy acrylonitrile, relies on import.Synthetic method 2: with ethyl ethoxy-methylene-cyanoacetate and hydroxyethylhydrazine for raw material, obtain product 5-amino-1-(2-hydroxyethyl)-pyrazoles through cyclization, alkaline hydrolysis, acidifying, decarboxylation four-step reaction.During the method cyclization generation 5-amino-1-(2-hydroxyethyl)-4-formic acid-pyrazoles, yield is higher, but continuing down reaction needed carries out decarboxylic reaction, and yield of this reaction is generally about 60%, and therefore the overall yield of this synthetic route is lower.
Summary of the invention
Instant invention overcomes above-mentioned the deficiencies in the prior art, provide a kind of synthetic method of new 5-amino-1-(2-hydroxyethyl) pyrazoles, this synthetic method is simple, easy handling, and suitability for industrialized is produced.
Technical scheme of the present invention is: a kind of synthetic method of 5-amino-1-(2-hydroxyethyl) pyrazoles, is characterized in that,
(1) take water as solvent, β-hydrazinoethanol (chemical compounds I) and 3,3-dimethoxypropionitrile (compound ii) heating reflux reaction 2 ~ 3 hours;
(2) then dripping concentration is that the sodium hydroxide solution of 20 ~ 50wt% continues back flow reaction 2 ~ 3 hours;
(3) be cooled to 20 ~ 30 DEG C after completion of the reaction, add salt acid for adjusting pH to 5 ~ 6; Evaporate to dryness reaction solution, after adding mixed solution (mass ratio of toluene and methyl alcohol is 10 ~ 13:1) the heated and stirred dissolving of toluene and methyl alcohol, then crystallization of lowering the temperature obtains 5-amino-1-(2-hydroxyethyl) pyrazoles (compound III).
Synthetic route of the present invention is as follows:
Preferably, the mol ratio of described step (1) β-hydrazinoethanol and 3,3-dimethoxypropionitrile is 1.0 ~ 1.1:1.
Preferably, the consumption of described step (1) water is 5 ~ 10ml/g (β-hydrazinoethanol), is preferably 6 ~ 8ml/g (β-hydrazinoethanol).
Preferably, the concentration of described step (2) sodium hydroxide solution is 30wt%, and the mol ratio of sodium hydroxide and 3,3-dimethoxypropionitrile is 1.1 ~ 1.2:1.
Preferably, the mass ratio of described step (3) toluene and methyl alcohol is 11:1.
Preferably, the concentration of described step (3) hydrochloric acid is 0.5-3mol/L.
Preferably, the heated and stirred of described step (3) is dissolved as and is heated to 45-60 DEG C.
The invention has the beneficial effects as follows: compare existing synthetic method, synthetic method of the present invention had both avoided the decarboxylic reaction existed in traditional technology, substantially increased yield (yield >=90% of product, purity >=99.5%), and technique is short out, simple to operate, be easy to suitability for industrialized production.
Embodiment
Following examples further illustrate of the present invention, but the present invention is not limited thereto.
Embodiment 1
Getting 150g β-hydrazinoethanol adds in 2000ml reaction flask, then 1000ml purified water is added, add 3 again, 3-dimethoxypropionitrile 222g, heating reflux reaction 2 hours, then slowly drips 30% sodium hydroxide 300g, continues heating reflux reaction 2 hours, be cooled to 20 DEG C after completion of the reaction, adjust pH to 5 with the hydrochloric acid of 1mol/L.Evaporated under reduced pressure reaction solution, then adds toluene 440g, methyl alcohol 40g, is heated to 50 DEG C of stirring and dissolving 30 minutes, then cools to 10 DEG C, stirring and crystallizing 2 hours, filters, with 10g methanol wash filter cake, solid 231.2g is obtained, yield 94.2%, purity 99.53% after oven dry.
Embodiment 2
Getting 75g β-hydrazinoethanol adds in 1000ml reaction flask, then 500ml purified water is added, add 3 again, 3-dimethoxypropionitrile 110g, heating reflux reaction 2 hours, then 30% sodium hydroxide 150g is slowly dripped, continue heating reflux reaction 2 hours, be cooled to 25 DEG C after completion of the reaction, PH to 6 is adjusted with 1mol/L hydrochloric acid, evaporated under reduced pressure reaction solution, then toluene 220g is added, methyl alcohol 20g, be heated to 52 DEG C of stirring and dissolving 30 minutes, then 10 DEG C are cooled to, stirring and crystallizing 2 hours, filter, with 5g methanol wash filter cake, solid 115.4g is obtained after oven dry, yield 94.6%, purity 99.57%.
Embodiment 3
Getting 150g β-hydrazinoethanol adds in 2000ml reaction flask, then 1000ml purified water is added, add 3 again, 3-dimethoxypropionitrile 220g, heating reflux reaction 2.5 hours, then slowly drips 30% sodium hydroxide 305g, continues heating reflux reaction 2.5 hours, be cooled to 22 DEG C after completion of the reaction, adjust pH to 5 with the hydrochloric acid of 1.5mol/L.Evaporated under reduced pressure reaction solution, then adds toluene 420g, methyl alcohol 40g, is heated to 50 DEG C of stirring and dissolving 30 minutes, then cools to 10 DEG C, stirring and crystallizing 2 hours, filters, with 10g methanol wash filter cake, solid 231.7g is obtained, yield 94.8%, purity 99.52% after oven dry.
Embodiment 4
Getting 75g β-hydrazinoethanol adds in 1000ml reaction flask, then 550ml purified water is added, add 3 again, 3-dimethoxypropionitrile 111g, heating reflux reaction 2.5 hours, then 30% sodium hydroxide 148g is slowly dripped, continue heating reflux reaction 2.5 hours, be cooled to 25 DEG C after completion of the reaction, pH to 6 is adjusted with 1mol/L hydrochloric acid, evaporated under reduced pressure reaction solution, then toluene 250g is added, methyl alcohol 20g, be heated to 52 DEG C of stirring and dissolving 30 minutes, then 10 DEG C are cooled to, stirring and crystallizing 2 hours, filter, with 5g methanol wash filter cake, solid 116.2g is obtained after oven dry, yield 94.7%, purity 99.61%.
Claims (9)
1. a synthetic method for 5-amino-1-(2-hydroxyethyl) pyrazoles, is characterized in that,
(1) take water as solvent, β-hydrazinoethanol and 3,3-dimethoxypropionitrile heating reflux reaction 2 ~ 3 hours;
(2) then dripping concentration is that the sodium hydroxide solution of 20 ~ 50wt% continues back flow reaction 2 ~ 3 hours;
(3) be cooled to 20 ~ 30 DEG C after completion of the reaction, add salt acid for adjusting pH to 5 ~ 6; Evaporate to dryness reaction solution, after adding the mixed solution heated and stirred dissolving of toluene and methyl alcohol, then crystallization of lowering the temperature obtains 5-amino-1-(2-hydroxyethyl) pyrazoles; The mass ratio of described toluene and methyl alcohol is 10 ~ 13:1.
2. the synthetic method of a kind of 5-amino-1-(2-hydroxyethyl) pyrazoles as claimed in claim 1, it is characterized in that, the mol ratio of described step (1) β-hydrazinoethanol and 3,3-dimethoxypropionitrile is 1.0 ~ 1.1:1.
3. the synthetic method of a kind of 5-amino-1-(2-hydroxyethyl) pyrazoles as claimed in claim 1, is characterized in that, described step (1) is with the use gauge of β-hydrazinoethanol, and the consumption of water is 5 ~ 10ml/g.
4. the synthetic method of a kind of 5-amino-1-(2-hydroxyethyl) pyrazoles as claimed in claim 3, is characterized in that, described step (1) is with the use gauge of β-hydrazinoethanol, and the consumption of water is 6 ~ 8ml/g.
5. the synthetic method of a kind of 5-amino-1-(2-hydroxyethyl) pyrazoles as claimed in claim 1, it is characterized in that, the concentration of described step (2) sodium hydroxide solution is 30wt%.
6. the synthetic method of a kind of 5-amino-1-(2-hydroxyethyl) pyrazoles as claimed in claim 1, it is characterized in that, the mol ratio of described step (2) sodium hydroxide and 3,3-dimethoxypropionitrile is 1.1 ~ 1.2:1.
7. as the synthetic method of a kind of 5-amino-1-(2-hydroxyethyl) pyrazoles in claim 1-6 as described in any one, it is characterized in that, in described step (3), the mass ratio of toluene and methyl alcohol is 11:1.
8., as the synthetic method of a kind of 5-amino-1-(2-hydroxyethyl) pyrazoles in claim 1-6 as described in any one, it is characterized in that, the concentration of described step (3) hydrochloric acid is 0.5-3mol/L.
9., as the synthetic method of a kind of 5-amino-1-(2-hydroxyethyl) pyrazoles in claim 1-6 as described in any one, it is characterized in that, the heated and stirred of described step (3) is dissolved as and is heated to 45-60 DEG C.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN113698348A (en) * | 2021-09-07 | 2021-11-26 | 安徽华甬新材料股份有限公司 | Preparation method of 4, 5-diamino-1- (2-hydroxyethyl) pyrazole sulfate |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPH01156963A (en) * | 1987-09-29 | 1989-06-20 | Ube Ind Ltd | Production of 1-substituted 5-aminopyrazole |
| EP1342716A2 (en) * | 2002-02-22 | 2003-09-10 | Eastman Chemical Company | Preparation of 4,5-diamino-1-(2'-hydroxyethyl)-pyradazole and acid addition salts thereof |
| CN101367764A (en) * | 2007-08-17 | 2009-02-18 | 长沙理工大学 | Novel synthesis process for 5-amino-1-hydroxyethyl pyrazole or the like |
| CN103819405A (en) * | 2012-11-19 | 2014-05-28 | 王香善 | Method for preparing N-(1-(2-formyloxy ethyl)-1H-pyrazole-5-base) formamide |
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2015
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Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPH01156963A (en) * | 1987-09-29 | 1989-06-20 | Ube Ind Ltd | Production of 1-substituted 5-aminopyrazole |
| EP1342716A2 (en) * | 2002-02-22 | 2003-09-10 | Eastman Chemical Company | Preparation of 4,5-diamino-1-(2'-hydroxyethyl)-pyradazole and acid addition salts thereof |
| CN101367764A (en) * | 2007-08-17 | 2009-02-18 | 长沙理工大学 | Novel synthesis process for 5-amino-1-hydroxyethyl pyrazole or the like |
| CN103819405A (en) * | 2012-11-19 | 2014-05-28 | 王香善 | Method for preparing N-(1-(2-formyloxy ethyl)-1H-pyrazole-5-base) formamide |
Non-Patent Citations (3)
| Title |
|---|
| 姚鹏: "以氰基乙醛为中间体合成吡唑类化合物", 《化学试剂》 * |
| 郭俊晶，等: "中间体-（2-羟乙基）-3-氨基-4-羧基吡唑的合成研究", 《中国药学杂志》 * |
| 黄朋勉,等: "5- 氨基-1-羟乙基吡唑的合成研究", 《精细化工中间体》 * |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN113698348A (en) * | 2021-09-07 | 2021-11-26 | 安徽华甬新材料股份有限公司 | Preparation method of 4, 5-diamino-1- (2-hydroxyethyl) pyrazole sulfate |
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