CN103497108A - Synthesis method of p-hydroxy-beta-nitrostyrene - Google Patents
Synthesis method of p-hydroxy-beta-nitrostyrene Download PDFInfo
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- CN103497108A CN103497108A CN201310431907.9A CN201310431907A CN103497108A CN 103497108 A CN103497108 A CN 103497108A CN 201310431907 A CN201310431907 A CN 201310431907A CN 103497108 A CN103497108 A CN 103497108A
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Abstract
The invention discloses a synthesis method of p-hydroxy-beta-nitrostyrene, which comprises the following step: synthesizing p-hydroxybenzaldehyde and nitromethane used as raw materials into p-hydroxy-beta-nitrostyrene by using ammonium acetate as a catalyst and glacial acetic acid as a solvent, wherein an antioxidant anhydrous hydroquinone is added to protect the raw material p-hydroxybenzaldehyde from oxidation, and toluene is added in the later reaction period to take the generated water out of the reaction system, so that the reaction proceeds in the positive reaction direction. The method has the advantages of low reaction cost, high product yield, simple after-treatment and the like, and the yield of the hydroxy-beta-nitrostyrene can reach higher than 92%.
Description
Technical field
The present invention relates to the synthetic method of a kind of alpha-aromatic-β-nitroethylene compounds, particularly relate to a kind of synthetic method to hydroxy-beta-nitrostyrolene.
Background technology
Alpha-aromatic-β-nitroethylene compounds not only has obvious sterilization, anti-tumor activity, and is broad-spectrum organic synthesis intermediate.This is the strong electrophilic character due to nitryl group, makes nitroethylene have obvious electron deficiency feature, is subject to the nucleophilic reagent attack, is good dienophile.By diverse ways, the nitro in alpha-aromatic-β-nitroethylene compounds can be transformed into to multiple functional group, thereby generate as dissimilar compounds such as amine, oxime, hydroxyl, nitrile, aldehyde, alcohol, ketone, heterocycles.
To hydroxy-beta-nitrostyrolene (p-hydroxy-β-nitrostyrene), be the representative species of alpha-aromatic-β-nitroethylene compounds, molecular formula C
8h
7nO
3, structural formula is as follows, molecular weight 165.15, and yellow needle-like crystal, fusing point 167-171 ℃, be dissolved in ether, ethanol, dithiocarbonic anhydride, benzene, is slightly soluble in hot water.
Be a kind of medicine intermediate that has DEVELOPMENT PROSPECT to hydroxy-beta-nitrostyrolene, can synthesize many useful intermediates and medicine by hydroxy-beta-nitrostyrolene is set out, as Uteramin, bezafibrate etc.Along with to the developing rapidly of hydroxy-beta-nitrostyrolene derived product, hydroxy-beta-nitrostyrolene is day by day become to comparatively well sold and in short supply pharmaceutical prod, apply extremely extensive.
About the report to hydroxy-beta-nitrostyrolene synthetic method, be mainly to utilize p-Hydroxybenzaldehyde and Nitromethane 99Min. to carry out condensation reaction at present, just used catalyst and solvent are had nothing in common with each other.
Wang Xiuran, Wan Yubao (to synthesizing of hydroxy-beta-nitrostyrolene. Anqing Teachers College's journal natural science edition, 1999,5 (4): 64-65) take p-Hydroxybenzaldehyde and Nitromethane 99Min. as raw material, aniline is made catalyzer, ethanol is solvent, and reflux 8h is synthetic to hydroxy-beta-nitrostyrolene, yield 65.4%.Reaction is easy to control, and target product is easily separated, purifying, but reaction yield is on the low side, long reaction time, complex operation.
Aquatic foods open ring, Wu Mao (Uteramin synthetic. chemical industry in Jiangsu Province, 1999,27 (1): 24-25) take p-Hydroxybenzaldehyde and Nitromethane 99Min. is raw material, under Glacial acetic acid, ammonium acetate effect, reflux 3h has synthesized hydroxy-beta-nitrostyrolene, yield 60%.The method reaction times is short, easy and simple to handle, be easy to control, but yield is on the low side.Simultaneously, aquatic foods open ring, and it is raw material that Wu Mao be take the P-benzyloxybenzaldehyde of benzyl protection, has synthesized under the same conditions to benzyloxy-beta-nitrostyrene yield 75%.P-Hydroxybenzaldehyde with benzyl protection is synthesized, and yield can improve 15%, this may be aldehyde radical with the Nitromethane 99Min. condensation time, exposed phenolic hydroxyl group can affect the polarization of carbonyl, has reduced the condensation reaction yield; Acidity due to phenolic hydroxyl group has affected the oxidation of Sauerstoffatom to carbon-carbon double bond and nitro simultaneously.Although the benzyl protection phenolic hydroxyl group can improve 15% yield, the process of introducing and sloughing benzyl has obviously increased reactions steps, has extended the reaction times, has increased the usage quantity of reaction raw materials simultaneously, has increased reaction cost.
In prior art, the general ethyl alcohol recrystallization method purifying that adopts is to hydroxy-beta-nitrostyrolene crude product.Because under normal temperature, to hydroxy-beta-nitrostyrolene, the solubleness in ethanol is also larger, simultaneously to hydroxy-beta-nitrostyrolene less stable in hot ethanol, easily transform, although therefore recrystallization method can access the product that purity is very high, but, in the process of heating for dissolving and cooling recrystallization, the loss amount of product is also larger.
Summary of the invention
The purpose of this invention is to provide that a kind of reaction conditions is gentle, cost is low, be easy to the industrialized synthetic method to hydroxy-beta-nitrostyrolene, and improve the yield of reaction.
A kind of method of purification to hydroxy-beta-nitrostyrolene is provided, and further to improve the yield of product, is another goal of the invention of the present invention.
Of the present invention is that to take p-Hydroxybenzaldehyde and Nitromethane 99Min. be raw material to hydroxy-beta-nitrostyrolene synthetic method, and ammonium acetate is catalyzer, and glacial acetic acid is solvent, adopts the Knoevenagel reaction to prepare, and its chemical equation is as follows.
Synthetic method of the present invention comprises the following steps:
A). glacial acetic acid is placed to 30-50min according to the amount of substance of 1:0.7-2 than mixing with anhydrous Resorcinol;
B). according to p-Hydroxybenzaldehyde: the amount of substance ratio of Nitromethane 99Min.: glacial acetic acid=1:1-3:9-18, a) in solution, add p-Hydroxybenzaldehyde and Nitromethane 99Min. to step, the ammonium acetate that adds again paranitrobenzaldehyde quality 10-60%, be warming up to 60-110 ℃ of reaction 2-8h;
C). than being 1:4-8, in reaction solution, add toluene according to the amount of substance of p-Hydroxybenzaldehyde and toluene, in the time of the azeotrope of dephlegmate and toluene, continue to react 30-40min, obtain containing the reaction solution to hydroxy-beta-nitrostyrolene after cooling.
Wherein, described ammonium acetate can divide two steps to add, and first adds the ammonium acetate of 60-70% mass parts, is warming up to 60-110 ℃ of reaction 1-2h, then adds the ammonium acetate of remaining mass parts, holding temperature reaction 2-6h.
The present invention also provides a kind of method of purification to hydroxy-beta-nitrostyrolene, the method is by containing after cooling, the reaction solution of hydroxy-beta-nitrostyrolene to be poured in frozen water and separated out yellow mercury oxide, this system is heated to 60-70 ℃, stir the lower ethanol that slowly drips, to precipitation dissolving fully, solution is poured in frozen water again, separated out the glassy yellow crystal, suction filtration, drying obtain hydroxy-beta-nitrostyrolene.
The present invention adds the anhydrous Resorcinol of antioxidant and places for some time in glacial acetic acid; to eliminate Peracetic Acid; and the oxygen in absorption system; hydroxyl and aldehyde radical in subsequent reactions in protection raw material p-Hydroxybenzaldehyde; prevent that it is oxidized, thereby effectively raise the utilization ratio of raw material.
Simultaneously, the present invention utilizes the character of toluene and water azeotropic, in the reaction later stage, adds toluene, in time Knoevenagel is reacted to deuterogenic water and takes reaction system out of, and reaction is successfully carried out to the positive reaction direction.Through evidence, with the method that does not add toluene, compare, the product yield of the inventive method has obtained increasing substantially.
Purification of products method provided by the invention and recrystallization method are relatively, reaction solution is not filtered, but directly system is heated to 60-70 ℃ after pouring in frozen water and separating out yellow mercury oxide, drip ethanol to resolution of precipitate, again pour in frozen water and separate out the glassy yellow crystal.The product purity obtained with method of purification of the present invention is higher than 98%, and can obviously reduce the loss of product in purification process.
The inventive method, by taking above-mentioned measure, makes the yield of hydroxy-beta-nitrostyrolene is brought up to more than 92% from the highest 75% of existing report.The advantages such as compared with the prior art, it is low that the inventive method has reaction cost, and product yield is high, and aftertreatment is simple.
The accompanying drawing explanation
Fig. 1 is the infrared spectrogram to hydroxy-beta-nitrostyrolene that embodiment 1 prepares.
Embodiment
Get the 10mL glacial acetic acid, add the anhydrous Resorcinol of 0.02g, standing 45 minutes.
3.66g (0.03mol) p-Hydroxybenzaldehyde, 5.1mL (0.09mol) Nitromethane 99Min., above-mentioned 10mL glacial acetic acid, 1g ammonium acetate are added in the 250mL there-necked flask that magnetic stirring apparatus, thermometer and reflux condensing tube are housed successively, be heated to 120 ℃ of reactions 1 hour under stirring, add again the 0.39g ammonium acetate, maintain 120 ℃ of reactions 3 hours.
Change reflux into water distilling apparatus, add 8mL toluene, steam cut, stopped reaction after half an hour.
Reaction finish and cooling after, reactant is poured in appropriate frozen water, separate out yellow mercury oxide.Do not filtered, directly this system is heated to 60-70 ℃, stir the lower ethanol that slowly drips, dissolve fully to precipitation, then solution is poured in appropriate frozen water, separate out rapidly the glassy yellow crystal, suction filtration, in vacuum drier, 40-45 ℃ of drying, obtain product 4.59g, yield 92.9%, purity 99.876%.
With the fusing point of micro melting point apparatus test purification after product, be 168.5-170.0 ℃, with literature value, conform to.
Adopt the Analec Fourier infrared spectrograph to be tested the purification after product, spectrogram is shown in Fig. 1, wherein 3402.19cm
-1for the characteristic peak of-OH stretching vibration, 3043.46cm
-1for the characteristic peak of C-H stretching vibration on aromatic ring, 1600.80cm
-1for the characteristic peak of-C=C-stretching vibration, 1487.01cm
-1for the characteristic peak of alkene C-H formation vibration, 1321.14cm
-1for the characteristic peak of-N=O symmetrical stretching vibration, 742.54cm
-1for the characteristic peak (trans) of alkene C-H formation vibration, prove that the product generated is to hydroxy-beta-nitrostyrolene.
Embodiment 2
Get the 20mL glacial acetic acid, add the anhydrous Resorcinol of 0.04g, standing 30 minutes.
3.66g (0.03mol) p-Hydroxybenzaldehyde, 1.7mL (0.03mol) Nitromethane 99Min., above-mentioned 20mL glacial acetic acid, 0.77g ammonium acetate are added in the 250mL there-necked flask that magnetic stirring apparatus, thermometer and reflux condensing tube are housed successively, be heated to 80 ℃ of reactions 1 hour under stirring, add again the 0.39g ammonium acetate, maintain 80 ℃ of reactions 3 hours.
Change reflux into water distilling apparatus, add 8mL toluene, steam cut, stopped reaction after half an hour.
Reaction finish and cooling after, reactant is poured in appropriate frozen water, separate out yellow mercury oxide.Do not filtered, directly this system is heated to 60-70 ℃, stir the lower ethanol that slowly drips, dissolve fully to precipitation, then solution is poured in appropriate frozen water, separate out rapidly the glassy yellow crystal, suction filtration, in vacuum drier, 40-45 ℃ of drying, obtain product 4.56g, yield 92.30%, purity 98.836%.
With the fusing point of micro melting point apparatus test purification after product, be 168-171. ℃, with literature value, conform to.
Embodiment 3
Get the 15mL glacial acetic acid, add the anhydrous Resorcinol of 0.03g, standing 45 minutes.
3.66g (0.03mol) p-Hydroxybenzaldehyde, 5.1mL (0.09mol) Nitromethane 99Min., above-mentioned 15mL glacial acetic acid, 0.26g ammonium acetate are added in the 250mL there-necked flask that magnetic stirring apparatus, thermometer and reflux condensing tube are housed successively, be heated to 100 ℃ of reactions 1 hour under stirring, add again the 0.12g ammonium acetate, maintain 100 ℃ of reactions 3 hours.
Change reflux into water distilling apparatus, add 6mL toluene, steam cut, stopped reaction after half an hour.
Reaction finish and cooling after, reactant is poured in appropriate frozen water, separate out yellow mercury oxide.Do not filtered, directly this system is heated to 60-70 ℃, stir the lower ethanol that slowly drips, dissolve fully to precipitation, then solution is poured in appropriate frozen water, separate out rapidly the glassy yellow crystal, suction filtration, in vacuum drier, 40-45 ℃ of drying, obtain product 4.57g, yield 92.45%, purity 99.324%.
With the fusing point of micro melting point apparatus test purification after product, be 167-170.0 ℃, with literature value, conform to.
Embodiment 4
Get the 10mL glacial acetic acid, add the anhydrous Resorcinol of 0.05g, standing 45 minutes.
3.66g (0.03mol) p-Hydroxybenzaldehyde, 3.4mL (0.06mol) Nitromethane 99Min., above-mentioned 10mL glacial acetic acid, 0.64g ammonium acetate are added in the 250mL there-necked flask that magnetic stirring apparatus, thermometer and reflux condensing tube are housed successively, be heated to 60 ℃ of reactions 1 hour under stirring, add again the 0.46g ammonium acetate, maintain 60 ℃ of reactions 5 hours.
Change reflux into water distilling apparatus, add 10mL toluene, steam cut, stopped reaction after half an hour.
Reaction finish and cooling after, reactant is poured in appropriate frozen water, separate out yellow mercury oxide.Do not filtered, directly this system is heated to 60-70 ℃, stir the lower ethanol that slowly drips, extremely precipitation is dissolved fully, then solution is poured in appropriate frozen water, separated out rapidly the glassy yellow crystal, suction filtration, 40-45 ℃ of drying in vacuum drier, obtain product 4.55g, yield 92%, purity 98.173%.
With the fusing point of micro melting point apparatus test purification after product, be 168-170.0 ℃, with literature value, conform to.
Claims (3)
1. the synthetic method to hydroxy-beta-nitrostyrolene comprises the following steps:
A). glacial acetic acid is placed to 30-50min according to the amount of substance of 1:0.7-2 than mixing with anhydrous Resorcinol;
B). according to p-Hydroxybenzaldehyde: the amount of substance ratio of Nitromethane 99Min.: glacial acetic acid=1:1-3:9-18, a) in solution, add p-Hydroxybenzaldehyde and Nitromethane 99Min. to step, the ammonium acetate that adds again paranitrobenzaldehyde quality 10-60%, be warming up to 60-110 ℃ of reaction 2-8h;
C). than being 1:4-8, in reaction solution, add toluene according to the amount of substance of p-Hydroxybenzaldehyde and toluene, in the time of the azeotrope of dephlegmate and toluene, continue to react 30-40min, obtain containing the reaction solution to hydroxy-beta-nitrostyrolene after cooling.
2. the synthetic method to hydroxy-beta-nitrostyrolene according to claim 1, it is characterized in that described ammonium acetate divides two steps to add, first add the ammonium acetate of 60-70% mass parts, be warming up to 60-110 ℃ of reaction 1-2h, the ammonium acetate that adds again remaining mass parts, holding temperature reaction 2-6h.
3. the method for purification to hydroxy-beta-nitrostyrolene, that cooling containing poured in frozen water and separated out yellow mercury oxide the reaction solution of hydroxy-beta-nitrostyrolene, this system is heated to 60-70 ℃, stir the lower ethanol that slowly drips, to precipitation dissolving fully, solution is poured in frozen water again, separated out the glassy yellow crystal, suction filtration, drying obtain hydroxy-beta-nitrostyrolene.
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Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN108586259A (en) * | 2018-07-09 | 2018-09-28 | 上海华堇生物技术有限责任公司 | A kind of new preparation process of 2- methoxyl groups-beta-nitrostyrene |
| CN108623462A (en) * | 2018-06-19 | 2018-10-09 | 上海华堇生物技术有限责任公司 | A kind of new preparation process of 4- hydroxy-betas-nitrostyrolene |
| CN109651120A (en) * | 2019-01-25 | 2019-04-19 | 河北海力香料股份有限公司 | A kind of preparation method of 4- (4- formvlphenoxv) benzaldehyde |
| CN111606815A (en) * | 2020-07-01 | 2020-09-01 | 珠海安哲生物科技有限公司 | Preparation method of phenylephrine hydrochloride impurity standard |
| CN112250581A (en) * | 2020-11-20 | 2021-01-22 | 湖南海利常德农药化工有限公司 | Preparation method of trans-4-chloro-beta-nitrostyrene |
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| JP4193850B2 (en) * | 2006-02-03 | 2008-12-10 | トヨタ自動車株式会社 | Start control device for internal combustion engine |
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Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108623462A (en) * | 2018-06-19 | 2018-10-09 | 上海华堇生物技术有限责任公司 | A kind of new preparation process of 4- hydroxy-betas-nitrostyrolene |
| CN108586259A (en) * | 2018-07-09 | 2018-09-28 | 上海华堇生物技术有限责任公司 | A kind of new preparation process of 2- methoxyl groups-beta-nitrostyrene |
| CN109651120A (en) * | 2019-01-25 | 2019-04-19 | 河北海力香料股份有限公司 | A kind of preparation method of 4- (4- formvlphenoxv) benzaldehyde |
| CN111606815A (en) * | 2020-07-01 | 2020-09-01 | 珠海安哲生物科技有限公司 | Preparation method of phenylephrine hydrochloride impurity standard |
| CN111606815B (en) * | 2020-07-01 | 2022-02-11 | 珠海安哲生物科技有限公司 | Preparation method of phenylephrine hydrochloride impurity standard |
| CN112250581A (en) * | 2020-11-20 | 2021-01-22 | 湖南海利常德农药化工有限公司 | Preparation method of trans-4-chloro-beta-nitrostyrene |
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