CN103408430A - Synthesis method of 2-methyl-4-nitrobenzoic acid - Google Patents
Synthesis method of 2-methyl-4-nitrobenzoic acid Download PDFInfo
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- CN103408430A CN103408430A CN2013103896346A CN201310389634A CN103408430A CN 103408430 A CN103408430 A CN 103408430A CN 2013103896346 A CN2013103896346 A CN 2013103896346A CN 201310389634 A CN201310389634 A CN 201310389634A CN 103408430 A CN103408430 A CN 103408430A
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Abstract
The invention discloses a synthesis method of 2-methyl-4-nitrobenzoic acid. The method is used for synthesizing the 2-methyl-4-nitrobenzoic acid by taking 4-dimethylnitrobenzene as a basic raw material and dilute nitric acid as an oxidant. A free radical initiator and a phase transfer catalyst which are added in the reaction process can be used for remarkably increasing the reaction yield and ensuring that the yield of the 2-methyl-4-nitrobenzoic acid as an oxidation product is up to 83.5%. The method disclosed by the invention is mild in reaction condition, capable of avoiding high temperature and high pressure, good in selectivity, high in yield and suitable for engineering application.
Description
Technical field
The present invention relates to the method for a kind of synthetic 2-methyl-4-nitrobenzoic acid, the rare nitric acid of especially a kind of employing, as oxygenant, becomes raw material 4-nitro o-Xylol selective oxidation the method for 2-methyl-4-nitrobenzoic acid.
Background technology
2-methyl-4-nitrobenzoic acid, as a kind of important medical chemistry intermediate, can be used for synthetic V2 receptor antagonist-tolvaptan.
At present, synthetic 2-methyl-4-nitrobenzoic acid adopts following two kinds of approach usually: the cyan-hydrolysis of (1) 2-methyl-4-nitrobenzonitrile is that the benzoic amino oxygen of carboxyl (2) 4-amino-2-methyl turns to nitro.But synthetic above two kinds of raw materials need complicated preparation process.In addition, few people's method of studying the methyl that adopts selective oxidation 4-nitro o-Xylol prepares 2-methyl-4-nitrobenzoic acid.Reason is, the strong sucting electronic effect of nitro has increased the oxidized difficulty of methyl greatly.Generally only having employing strong oxidizer (such as potassium permanganate, potassium bichromate etc.) could be very successfully carboxyl by the methyl exhaustive oxidation.But above method for oxidation environmental pollution is serious, does not meet the requirement of Green Chemistry.When adopting the more friendly rare nitric acid of environment to carry out oxidation, usually need again harsher reaction conditions (such as high temperature, high pressure etc.), to having relatively high expectations of equipment, and there is great potential safety hazard.As can be seen here, along with the development of environmental economy, the conventional production methods of 2-methyl-4-nitrobenzoic acid does not have sustainable developability, needs a kind of more friendly method of environment badly and replaces.It will be a good developing direction that a kind of find gentleness, environmental protection green oxidation method is carried out oxidation 4-nitro o-Xylol.
Summary of the invention
The invention provides a kind of 4-of take nitro o-Xylol and be basic raw material, adopt rare nitric acid as oxygenant, the method for synthetic 2-methyl-4-nitrobenzoic acid.The present invention adds in reaction process radical initiator and phase-transfer catalyst can obviously improve reaction yield, can make the productive rate of oxidation products 2-methyl-4-nitrobenzoic acid reach 83.5%.The inventive method reaction conditions gentleness, selectivity is good, and yield is high, is suitable for through engineering approaches to be used.
Can realize by following scheme for achieving the above object, the method for a kind of synthetic 2-methyl-4-nitrobenzoic acid comprises the following steps:
Step 1, in reactor, add 4-nitro o-Xylol, radical initiator and phase-transfer catalyst;
Step 2, in reactor, add magnetic agitation after rare nitric acid, temperature reaction again;
After step 3, reaction finish, purification by liquid extraction.
Radical initiator described in step 1 be Diisopropyl azodicarboxylate, 2,2'-Azobis(2,4-dimethylvaleronitrile),
N-hydroxyphthalimide,
NA kind of in-ethanoyl phthalic imidine, benzoyl peroxide or cyclohexanone peroxide, described radical initiator is 0.05-0.5 with the ratio of 4-nitro o-Xylol amount of substance.
Phase-transfer catalyst described in step 1 is a kind of in benzyltriethylammoinium chloride, Tetrabutyl amonium bromide, tetrabutylammonium chloride, cetyl trimethylammonium bromide or cetyl trimethylammonium bromide, and described phase-transfer catalyst is 0.01-0.1 with the ratio of 4-nitro o-Xylol amount of substance.
Rare nitric acid mass concentration described in step 2 is 10%-60%, and described nitric acid is 1-10 with the ratio of 4-nitro o-Xylol amount of substance.
Temperature of reaction 50-150 ℃ described in step 2.
The inventive method is compared with traditional technology, and significant advantage is: the rare nitric acid of (1) novel method application is nitrating agent, replaces traditional potassium permanganate and potassium bichromate, has improved the spatter property of industrial building-up reactions, has reduced environmental pollution.(2) the inventive method can selectivity become carboxyl by the 4-position methyl oxidation of 4-nitro o-Xylol, and purpose (3) the present invention who reaches synthetic 2-methyl-4-nitrobenzoic acid adds radical initiator and phase transfer catalysis agent can improve the productive rate of oxidation products in reaction process.(4) reaction conditions gentleness of the present invention, avoid high temperature, high pressure, and reaction safety improves greatly.
Embodiment
Below with specific embodiment, carry out process in detail, the 4-nitro o-Xylol of namely take is raw material, and adopting rare nitric acid is oxygenant, under radical initiator and phase-transfer catalyst existence, the method of synthetic 2-methyl 4-nitrobenzoic acid, example do not represent the invention scope of restriction this patent.
Concrete reactions steps is as follows:
1. in reactor, add 4-nitro o-Xylol, radical initiator and phase-transfer catalyst, and radical initiator is 0.05-0.5 with the ratio of 4-nitro o-Xylol amount of substance, phase-transfer catalyst is 0.01-0.1 with the ratio of 4-nitro o-Xylol amount of substance;
2. in reactor, add certain density rare nitric acid again, and nitric acid is 1-10 with the ratio of 4-nitro o-Xylol amount of substance;
3. temperature of reactor is set as to 50-150 ℃, magnetic agitation, fully reaction;
4., after reaction finishes, be down to room temperature.Then add 2,4-dinitrotoluene (DNT) as internal standard substance, ethyl acetate extraction, organic phase washes with water to neutrality, anhydrous sodium sulfate drying.Carry out liquid-phase chromatographic analysis, by marker method, calculate the amount of product 2-methyl 4-nitrobenzoic acid.
Embodiment 1
In 100 mL there-necked flasks, add 4-nitro o-Xylol (0.76 g, 5.0 mmol), Diisopropyl azodicarboxylate (0.04 g, 0.25 mmol), cetyl trimethylammonium bromide (0.018 g, 0.05 mmol), 10% nitric acid (3.17 g, 5.0 mmol), magnetic agitation, reaction, follow the tracks of reaction process with TLC under 50 ℃.Reaction is down to room temperature after finishing.Add 2,4-dinitrotoluene (DNT) (0.10 g) as internal standard substance, ethyl acetate (5 mL * 3) extraction three times, merge organic phase, is washed with water to neutrality, anhydrous sodium sulfate drying.Carry out liquid-phase chromatographic analysis, the quality that calculates product 2-methyl 4-nitrobenzoic acid by marker method is 0.55 g, and productive rate is 60.4%.
Embodiment 2
In 100 mL there-necked flasks, add 4-nitro o-Xylol (0.75 g, 5.0 mmol), 2,2'-Azobis(2,4-dimethylvaleronitrile) (0.31 g, 1.24 mmol), tetrabutylammonium chloride (0.07 g, 0.25 mmol), 30% nitric acid (5.21 g, 24.8 mmol), magnetic agitation, reaction, follow the tracks of reaction process with TLC under 100 ℃.Reaction is down to room temperature after finishing.Add 2,4-dinitrotoluene (DNT) (0.10 g) as internal standard substance, ethyl acetate (5 mL * 3) extraction three times, merge organic phase, is washed with water to neutrality, anhydrous sodium sulfate drying.Carry out liquid-phase chromatographic analysis, the quality that calculates product 2-methyl 4-nitrobenzoic acid by marker method is 0.64 g, and productive rate is 71.2%.
Embodiment 3
In 100 mL there-necked flasks, add 4-nitro o-Xylol (0.75 g, 5.0 mmol),
N-hydroxyphthalimide (0.40 g, 2.48 mmol), benzyltriethylammoinium chloride (0.11 g, 0.5 mmol), 60% nitric acid (5.21 g, 49.6 mmol), magnetic agitation, reaction, follow the tracks of reaction process with TLC under 150 ℃.Reaction is down to room temperature after finishing.Add 2,4-dinitrotoluene (DNT) (0.10 g) as internal standard substance, ethyl acetate (5 mL * 3) extraction three times, merge organic phase, is washed with water to neutrality, anhydrous sodium sulfate drying.Carry out liquid-phase chromatographic analysis, the quality that calculates product 2-methyl 4-nitrobenzoic acid by marker method is 0.48 g, and productive rate is 53.4%.
Embodiment 4
In 100 mL there-necked flasks, add 4-nitro o-Xylol (0.76 g, 5.0 mmol),
N-ethanoyl phthalic imidine (0.48 g, 2.5 mmol), Tetrabutyl amonium bromide (0.16 g, 0.5 mmol), 60% nitric acid (5.21 g, 49.6 mmol), magnetic agitation, reaction, follow the tracks of reaction process with TLC under 150 ℃.Reaction is down to room temperature after finishing.Add 2,4-dinitrotoluene (DNT) (0.10 g) as internal standard substance, ethyl acetate (5 mL * 3) extraction three times, merge organic phase, is washed with water to neutrality, anhydrous sodium sulfate drying.Carry out liquid-phase chromatographic analysis, the quality that calculates product 2-methyl 4-nitrobenzoic acid by marker method is 0.51 g, and productive rate is 56.0%.
Embodiment 5
In 100 mL there-necked flasks, add 4-nitro o-Xylol (0.76 g, 5.0 mmol), benzoyl peroxide (0.30 g, 1.26 mmol), benzyltriethylammoinium chloride (0.06 g, 0.25 mmol), 30% nitric acid (5.21 g, 24.8 mmol), magnetic agitation, reaction, follow the tracks of reaction process with TLC under 100 ℃.Reaction is down to room temperature after finishing.Add 2,4-dinitrotoluene (DNT) (0.10 g) as internal standard substance, ethyl acetate (5 mL * 3) extraction three times, merge organic phase, is washed with water to neutrality, anhydrous sodium sulfate drying.Carry out liquid-phase chromatographic analysis, the quality that calculates product 2-methyl 4-nitrobenzoic acid by marker method is 0.76 g, and productive rate is 83.5%.
Embodiment 6
In 100 mL there-necked flasks, add 4-nitro o-Xylol (0.75 g, 5.0 mmol), cyclohexanone peroxide (0.11 g, 0.25 mmol), palmityl trimethyl ammonium chloride (0.016 g, 0.05 mmol), 10% nitric acid (3.17 g, 5.0 mmol), magnetic agitation, reaction, follow the tracks of reaction process with TLC under 50 ℃.Reaction is down to room temperature after finishing.Add 2,4-dinitrotoluene (DNT) (0.10 g) as internal standard substance, ethyl acetate (5 mL * 3) extraction three times, merge organic phase, is washed with water to neutrality, anhydrous sodium sulfate drying.Carry out liquid-phase chromatographic analysis, the quality that calculates product 2-methyl 4-nitrobenzoic acid by marker method is 0.61 g, and productive rate is 67.9%.
Comparative Examples 1
In 100 mL there-necked flasks, add 4-nitro o-Xylol (0.75 g, 5.0 mmol), 30% nitric acid (5.21 g, 24.8 mmol), magnetic agitation, reaction, follow the tracks of reaction process with TLC under 100 ℃.Reaction is down to room temperature after finishing.Add 2,4-dinitrotoluene (DNT) (0.10 g) as internal standard substance, ethyl acetate (5 mL * 3) extraction three times, merge organic phase, is washed with water to neutrality, anhydrous sodium sulfate drying.Carry out liquid-phase chromatographic analysis, the quality that calculates product 2-methyl 4-nitrobenzoic acid by marker method is 0.08 g, and productive rate is 8.9%.
As can be known from above-described embodiment and Comparative Examples, while adopting rare nitric acid to carry out oxidation to 4-nitro o-Xylol, add above-mentioned radical initiator and phase-transfer catalyst can improve to some extent the productive rate of oxidation products 2-methyl 4-nitrobenzoic acid.
Claims (5)
1. the synthetic method of 2-methyl-4-nitrobenzoic acid is characterized in that comprising the following steps:
Step 1, in reactor, add 4-nitro o-Xylol, radical initiator and phase-transfer catalyst;
Step 2, in reactor, add magnetic agitation after rare nitric acid, temperature reaction again;
After step 3, reaction finish, purification by liquid extraction.
2. the synthetic method of 2-methyl according to claim 1-4-nitrobenzoic acid; it is characterized in that the radical initiator described in step 1 is a kind of in Diisopropyl azodicarboxylate, 2,2'-Azobis(2,4-dimethylvaleronitrile), HP, N-ethanoyl phthalic imidine, benzoyl peroxide or cyclohexanone peroxide, described radical initiator is 0.05-0.5 with the ratio of 4-nitro o-Xylol amount of substance.
3. the synthetic method of 2-methyl according to claim 1-4-nitrobenzoic acid, it is characterized in that the phase-transfer catalyst described in step 1 is a kind of in benzyltriethylammoinium chloride, Tetrabutyl amonium bromide, tetrabutylammonium chloride, cetyl trimethylammonium bromide or cetyl trimethylammonium bromide, described phase-transfer catalyst is 0.01-0.1 with the ratio of 4-nitro o-Xylol amount of substance.
4. the synthetic method of 2-methyl according to claim 1-4-nitrobenzoic acid, is characterized in that the rare nitric acid mass concentration described in step 2 is 10%-60%, and described nitric acid is 1-10 with the ratio of 4-nitro o-Xylol amount of substance.
5. the synthetic method of 2-methyl according to claim 1-4-nitrobenzoic acid, is characterized in that the temperature of reaction 50-150 ℃ described in step 2.
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN104447348A (en) * | 2014-12-25 | 2015-03-25 | 甘肃银光化学工业集团有限公司 | Method for preparing 3-methyl-4-nitrobenzoic acid by oxidizing with nitric acid |
| CN105218375A (en) * | 2015-10-31 | 2016-01-06 | 丁玉琴 | A kind of synthetic method of 2-methyl-4-nitrobenzoic acid |
| CN116283598A (en) * | 2023-03-31 | 2023-06-23 | 浙江科技学院 | Method for preparing 3-methyl-4-nitrobenzoic acid by nitric acid continuous oxidation |
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| CN101648944A (en) * | 2004-02-20 | 2010-02-17 | 贝林格尔.英格海姆国际有限公司 | Viral polymerase inhibitors |
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| CN101648944A (en) * | 2004-02-20 | 2010-02-17 | 贝林格尔.英格海姆国际有限公司 | Viral polymerase inhibitors |
Non-Patent Citations (2)
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN104447348A (en) * | 2014-12-25 | 2015-03-25 | 甘肃银光化学工业集团有限公司 | Method for preparing 3-methyl-4-nitrobenzoic acid by oxidizing with nitric acid |
| CN105218375A (en) * | 2015-10-31 | 2016-01-06 | 丁玉琴 | A kind of synthetic method of 2-methyl-4-nitrobenzoic acid |
| CN116283598A (en) * | 2023-03-31 | 2023-06-23 | 浙江科技学院 | Method for preparing 3-methyl-4-nitrobenzoic acid by nitric acid continuous oxidation |
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