CN109748800A - A kind of preparation method of pair of nitrobenzyl alcohol - Google Patents
A kind of preparation method of pair of nitrobenzyl alcohol Download PDFInfo
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Abstract
The present invention relates to the preparation methods of a kind of pair of nitrobenzyl alcohol.Specifically, the preparation method is using para-nitrotoluene as raw material, by bromination, hydrolysis, purification, it is made to nitrobenzyl alcohol.In the technique, intermediate purifies without isolation, and the reaction dissolvent of bromination and hydrolysis is water, and can be recycled and apply repeatedly, while simplifying operation, reduces production cost, reduces waste water and exhaust gas discharge.Preparation method of the invention has many advantages, such as easy to operate, small investment, environmentally protective, suitable industrial production.
Description
Technical field
The invention belongs to fine chemical product synthesis technical fields, and in particular to the preparation method of a kind of pair of nitrobenzyl alcohol.
Background technique
To nitrobenzyl alcohol also known as 4- nitrobenzyl alcohol or p nitrobenzyl alcohol, it is a kind of important fine chemicals, is closing
At pharmaceutical field, train multiple key intermediates of southern class antibiotic, for example, 2- diazonium acetoacetate to nitrobenzyl alcohol ester, to nitro
Benzylalcohol malonic acid monoester, Meropenem side chain etc. require using to nitrobenzyl alcohol as starting material.
Currently, preparation is to nitrobenzyl alcohol, there are mainly five types of methods: 1) patent CN104370746, which is announced with para-nitrotoluene, is
Raw material is obtained through chloro to nitro benzyl chloride, then purified, basic hydrolysis, distillation and etc. obtain to nitrobenzyl alcohol.This side
Method, feed stock conversion is low, and product need to be by multiple distillation purifying, and energy consumption is high, and production efficiency is low, is unsuitable for industrial production.2) Cai
Spring (publication " chemical industry in Jiangsu Province ", 2000,1:30-30.) using benzyl chloride as raw material, through para nitration, purification, hydrolysis and etc.
To nitrobenzyl alcohol.That there is also para-selectivities is poor for this method nitration reaction, and uses a large amount of nitration mixture, and environmental pollution is big equal to be lacked
Point is not suitable for industrial production.3) Wei Changmei (publication is in " fine-chemical intermediate ", 2004,21 (9): 714-716.) is with benzylalcohol
For raw material, through hydroxyl protection, para nitration, purification and basic hydrolysis and etc. obtain to nitrobenzyl alcohol.Technique nitrification contraposition
Poor selectivity, and a large amount of nitration mixture are used, environmental pollution is big, is also unsuitable for industrial production.4) (publication is in " chemistry and life by Liang great Wei
Object engineering ", 2014,31 (12): 51-53.) using para-nitrotoluene as raw material, it is obtained to nitrobenzyl bromine, then through brominating agent
Acetic acid is generated to nitrobenzyl alcohol ester with acetic acid sodium reaction, then hydrolysis is obtained to nitrobenzyl alcohol under alkaline condition.This method needs pure
Changing has the intermediate of high sensitization and toxicity to nitrobenzyl bromine, and first hydrolyzes again at ester, more step chemical reactions, and operation is multiple
It is miscellaneous.
Fifth method is the report of patent CN 105348107 using para-nitrotoluene as raw material, and halogenated aryl hydrocarbon is solvent, warp
Bromination and hydrolysis two-step reaction are obtained to nitrobenzyl alcohol organic phase, then obtain paranitrobenzaldehyde through oxidation.This method bromination is complete
Cheng Hou, direct alkaline hydrolysis considerably increase the dosage of alkali, and after the completion of hydrolysis, water layer not recovery increases waste water row
The halogenated aryl hydrocarbon difficult solvent recovery put, and used, there was only 55 to the purity of nitrobenzyl alcohol in the organic phase reacted~
60%, paranitrobenzaldehyde content reaches 15~20%, and purification difficulty is big, and yield is low.
Para-nitrotoluene bromination method is that one kind is most suitable for the industrialized method of nitrobenzyl alcohol at present, but due to the prior art
In the method for report, the organic solvent that bromination reaction is used recycles difficulty, and the usage amount of hydrolysis aqueous solvent is big, and waste water is more,
It is therefore desirable to develop the green synthesis process that one with low investment, at low cost, the three wastes are few.
Summary of the invention
In view of the deficiencies of the prior art, the present invention provides one kind is with low investment, the three wastes are few, it is industrial to nitrobenzyl to be suitble to
The environment-friendly preparation method thereof of alcohol.
In order to achieve the above object, the technical scheme adopted by the invention is that: the preparation method of a kind of pair of nitrobenzyl alcohol,
Be characterized by using para-nitrotoluene as starting material, through bromination, hydrolysis, purification and etc. obtain to nitrobenzyl alcohol product, tool
Body rises to bromination reaction temperature the following steps are included: 1) be added to the water para-nitrotoluene, initiator is added, with bromating agent bromine
Changing to reaction terminates, stratification, and water layer set uses down batch bromination reaction；2) water and moderate strength are added in obtained oil reservoir
Inorganic base, temperature rising reflux to reaction terminate, stratification, and water layer is applied to down while hot in batch hydrolysis；3) in obtained water
It solves and refining solvent dissolution is added in oil reservoir, after the crystallization that cools down, filtering is obtained to nitrobenzyl alcohol.
In the preferred embodiments of the present invention, the dosage of water is para-nitrotoluene inventory in the step 1)
0.5~5 times, preferably 1 times.
In the preferred embodiments of the present invention, bromination reaction temperature is 51-65 DEG C in the step 1), preferably 58-
60℃。
In the preferred embodiments of the present invention, initiator is selected from benzoyl peroxide, mistake in the step 1)
Aoxidize two carbonic acid two (2- ethylhexyl), azodiisobutyronitrile, azobisisovaleronitrile, azobisisoheptonitrile, preferably benzoyl peroxide
Formyl；The dosage of initiator is the 1~5% of para-nitrotoluene weight, preferably 2%.
In the preferred embodiments of the present invention, bromating agent is bromine or hydrogen bromide/hydrogen peroxide, bromine in the step 1)
Agent dosage is 1.0~1.2 times of theoretical amount.
In the preferred embodiments of the present invention, bromination water recovery number is 0~30 time in the step 1), excellent
It selects 10 times.
In the preferred embodiments of the present invention, the dosage of water is the 5 of para-nitrotoluene inventory in the step 2)
~15 times, preferably 8 times.
In the preferred embodiments of the present invention, moderate strength inorganic base is selected from sodium bicarbonate, carbon in the step 2)
Sour sodium and potassium carbonate, preferably sodium carbonate；The dosage of the alkali is 0.8~1.2 times, preferably 1.0 times of theoretical amount.
In the preferred embodiments of the present invention, hydrolysis water recovery number is 0~6 time in the step 2), excellent
It selects 4 times.
In the preferred embodiments of the present invention, refining solvent is selected from toluene, dichloroethanes, acetic acid in the step 3)
The mixture of one or more of ethyl ester, isobutyl acetate, preferably toluene；Refining solvent usage amount is para-nitrotoluene
1~5 times of inventory, preferably 3 times.
In the preferred embodiments of the present invention, in the step 3) crystallization temperature be 0~40 DEG C, preferably 10~20
℃。
The present invention has advantageous effect in that compared with the existing preparation method to nitrobenzyl alcohol:
(1) organic solvent is not added in bromination reaction of the present invention, reduces costs, and reduces pollution.
(2) intermediate of the present invention purifies without isolation, simplifies operation, reduces production cost, improves production efficiency.
(3) recovery bromination of the present invention and hydrolysis water, reduce the usage amount of water, improve product yield, apply
To the waste water of last batch of, bromine content is high, can be used as bromine water sale, while increasing economic efficiency, realizes the zero-emission of waste water
It puts.
(4) method of the invention is easy to operate, mild condition, and green cleaning can be prepared efficiently at low cost to nitrobenzyl
Alcohol is suitble to industrialized production
Detailed description of the invention
Fig. 1 is the key reaction equation in the preparation method of the present invention to nitrobenzyl alcohol.
Fig. 2 is the HPLC spectrogram obtained to nitrobenzyl alcohol of embodiment 1.
Fig. 3 is the HPLC spectrogram obtained to nitrobenzyl alcohol of comparative example 1.
Specific embodiment
In order to make professional and technical personnel in the field better understand the present invention, the present invention is carried out below with reference to embodiment
It is further described, but is not limitation of the present invention.It is all according to any this field made by the disclosure of invention
Same replacement, all belongs to the scope of protection of the present invention.
Embodiment 1:
400 kilograms of para-nitrotoluene and 400 kg of water are put into 5000L reaction kettle, are warming up to 58~60 DEG C, are added 8
Kilogram benzoyl peroxide is added dropwise 246 kilograms of bromine, after drop finishes, and continues to be added dropwise 175 kilograms of 30% hydrogen peroxide, and reaction is to reacting
Liquid color takes off to the greatest extent, and stratification extracts supernatant water layer out while hot (water layer is inserted in next group bromination reaction).Be added 3200 kg of water and
155 kilograms of sodium carbonate, temperature rising reflux, after hydrolysis, stratification, extracting supernatant water layer out while hot, (water layer is inserted in next while hot
Criticize hydrolysis), organic layer is added 1200 kilograms of toluene while hot, is warming up to 60~70 DEG C of dissolutions, is down to 10~20 DEG C of crystallizations, mistake
Filter, dry to 357 kilograms of nitrobenzyl alcohol, yield 79.9%, liquid phase purity 99.6%.
Under same reaction conditions, bromination water and hydrolysis water jacket the results are shown in Table 1 with the influence to product yield and quality.
Table 1
Embodiment 2:
400 kilograms of para-nitrotoluene and 400 kg of water are put into 5000L reaction kettle, are warming up to 51~55 DEG C, are added 8
Kilogram different cyanogen in heptan of azo two is added dropwise 235 kilograms of bromine, after drop finishes, and continues to be added dropwise 200 kilograms of 30% hydrogen peroxide, and reaction is to reacting
Liquid color takes off to the greatest extent, stratification, extracts supernatant water layer out while hot (water layer is applied to down batch bromination reaction).It is public that organic layer is added 2800
Jin water and 270 kilograms of sodium bicarbonates, temperature rising reflux, after hydrolysis, stratification, extracting supernatant water layer out while hot, (water layer is while hot
It is inserted in next group hydrolysis), organic layer is added 1200 kilograms of toluene while hot, is warming up to 60~70 DEG C of dissolutions, is down to 10~20
DEG C crystallization, filtering is dry to 335 kilograms of nitrobenzyl alcohol, yield 75.0%, liquid phase purity 99.3%.
Embodiment 3:
400 kilograms of para-nitrotoluene and 800 kg of water are put into 5000L reaction kettle, are warming up to 56~58 DEG C, are added 6
Kilogram azodiisobutyronitrile is added dropwise 257 kilograms of bromine, after drop finishes, and continues to be added dropwise 175 kilograms of 30% hydrogen peroxide, and reaction is to reacting
Liquid color takes off to the greatest extent, stratification, extracts supernatant water layer out while hot (water layer is applied to down batch bromination reaction).It is public that organic layer is added 2000
Jin water and 139 kilograms of sodium carbonate, temperature rising reflux, after hydrolysis, stratification, extracting supernatant water layer out while hot, (water layer covers while hot
Enter next group hydrolysis), organic layer is added 1600 kilograms of ethyl acetate while hot, is warming up to 60~70 DEG C of dissolutions, is down to 0~10
DEG C crystallization, filtering is dry to 331 kilograms of nitrobenzyl alcohol, yield 74.1%, liquid phase purity 99.2%.
Embodiment 4:
400 kilograms of para-nitrotoluene and 600 kg of water are put into 5000L reaction kettle, are warming up to 58~60 DEG C, are added 4
Kilogram azobisisovaleronitrile is added dropwise 246 kilograms of bromine, after drop finishes, and continues to be added dropwise 175 kilograms of 30% hydrogen peroxide, and reaction is to reacting
Liquid color takes off to the greatest extent, stratification, extracts supernatant water layer out while hot (water layer is applied to down batch bromination reaction).It is public that organic layer is added 3600
Jin water and 161 kilograms of potassium carbonate, temperature rising reflux, after hydrolysis, stratification, extracting supernatant water layer out while hot, (water layer covers while hot
Enter next group hydrolysis), organic layer is added 800 kilograms of isobutyl acetate while hot, is warming up to 60~70 DEG C of dissolutions, it is down to 20~
30 DEG C of crystallizations, filtering is dry to 345 kilograms of nitrobenzyl alcohol, yield 77.3%, liquid phase purity 99.5%.
Embodiment 5:
400 kilograms of para-nitrotoluene and 400 kg of water are put into 5000L reaction kettle, are warming up to 51~55 DEG C, are added 6
Kilogram benzoyl peroxide is added dropwise 235 kilograms of bromine, after drop finishes, and continues to be added dropwise 185 kilograms of 30% hydrogen peroxide, and reaction is to reacting
Liquid color takes off to the greatest extent, stratification, extracts supernatant water layer out while hot (water layer is applied to down batch bromination reaction).It is public that organic layer is added 3200
Jin water and 186 kilograms of sodium carbonate, temperature rising reflux, after hydrolysis, stratification, extracting supernatant water layer out while hot, (water layer covers while hot
Enter next group hydrolysis), organic layer is added 2000 kilograms of dichloroethanes while hot, is warming up to 60~70 DEG C of dissolutions, is down to 0~10
DEG C crystallization, filtering is dry to 338 kilograms of nitrobenzyl alcohol, yield 75.6%, liquid phase purity 99.8%.
Embodiment 6:
400 kilograms of para-nitrotoluene and 400 kg of water are put into 5000L reaction kettle, are warming up to 58~60 DEG C, are added 6
Kilogram benzoyl peroxide is added dropwise 246 kilograms of bromine, after drop finishes, and continues to be added dropwise 175 kilograms of 30% hydrogen peroxide, and reaction is to reacting
Liquid color takes off to the greatest extent, stratification, extracts supernatant water layer out while hot (water layer is applied to down batch bromination reaction).It is public that organic layer is added 4000
Jin water and 201 kilograms of potassium carbonate, temperature rising reflux, after hydrolysis, stratification, extracting supernatant water layer out while hot, (water layer covers while hot
Enter next group hydrolysis), organic layer is added 1200 kilograms of toluene while hot, is warming up to 60~70 DEG C of dissolutions, is down to 30~40 DEG C
Crystallization, filtering is dry to 341 kilograms of nitrobenzyl alcohol, yield 76.3%, liquid phase purity 99.4%.
Embodiment 7:
400 kilograms of para-nitrotoluene and 540 kilogram of 48% hydrogen bromide are put into 5000L reaction kettle, are warming up to 62~65
DEG C, 6 kilograms of benzoyl peroxides are added, 364 kilograms of 30% hydrogen peroxide is added dropwise, reaction to reaction solution color is taken off to the greatest extent, stratification,
Extract supernatant water layer out while hot.3200 kg of water and 186 kilograms of sodium carbonate are added in organic layer, and temperature rising reflux after hydrolysis, is stood
Layering extracts supernatant water layer (water layer is inserted in next group hydrolysis while hot) out while hot, and organic layer is added 800 kilograms of toluene while hot,
60~70 DEG C of dissolutions are warming up to, 20~30 DEG C of crystallizations are down to, are filtered, dry to 348 kilograms of nitrobenzyl alcohol, yield 77.9%,
Liquid phase purity 99.1%.
Embodiment 8:
400 kilograms of para-nitrotoluene and 590 kilogram of 48% hydrogen bromide are put into 5000L reaction kettle, are warming up to 58~60
DEG C dissolution, is added 8 kilograms of dicetyl peroxydicarbonates two (2- ethylhexyl), 391 kilograms of 30% hydrogen peroxide is added dropwise, reaction is to reaction solution
Color is moved back to the greatest extent, and stratification extracts supernatant water layer out while hot.2800 kg of water and 221 kilograms of potassium carbonate are added in organic layer, heat up back
Stream, after hydrolysis, stratification extracts supernatant water layer (water layer is inserted in next group hydrolysis while hot) out while hot, and organic layer is taken advantage of
Heat is added 800 kilograms of isobutyl acetate, is warming up to 60~70 DEG C of dissolutions, is down to 0~10 DEG C of crystallization, filters, dry to nitro
346 kilograms of benzylalcohol, yield 77.4%, liquid phase purity 99.3%.
Comparative example 1:
Referenced patent CN 105348107
In the reactor, addition 80g chlorobenzene, 13.7g para-nitrotoluene, 2.7g azobisisovaleronitrile, at 50 DEG C,
9.6g bromine is slowly added dropwise in 30min, after being added dropwise, agitating and heating back flow reaction to bromine color fade.In 30min
The hydrogen peroxide of 7.0g 27.5% is slowly added dropwise, is stirred at reflux reaction 3h.The potassium carbonate of 68.5g 20% is added in this reaction solution
Aqueous solution is stirred at reflux reaction 30h, and after being distilled to recover chlorobenzene, cooling and standings layering is separated containing p nitrobenzyl alcohol organic phase
(to nitrobenzyl alcohol HPLC purity 58.3%) is added 27.4g toluene, is warming up to 60~70 DEG C of dissolutions, is down to 10~20 DEG C of crystallizations,
Filtering, it is dry to nitrobenzyl alcohol 6.5g, yield 42.5%, HPLC purity 91.5%.
Claims (11)
1. the preparation method of a kind of pair of nitrobenzyl alcohol, which is characterized in that itself the following steps are included:
1) para-nitrotoluene is added to the water, rises to bromination reaction temperature, initiator is added, with brominating agent to reacting knot
Beam, stratification, water layer set use down batch bromination reaction；
2) water and moderate strength inorganic base, temperature rising reflux to reaction are added in obtained oil reservoir terminates, and stratification, water layer is taken advantage of
Heat is applied to down in batch hydrolysis；
3) refining solvent dissolution is added in obtained hydrolysis oil reservoir, after the crystallization that cools down, filtering is obtained to nitrobenzyl alcohol.
2. preparation method according to claim 1, which is characterized in that the dosage of water is para-nitrotoluene in the step 1)
0.5~5 times of inventory.
3. preparation method according to claim 1, which is characterized in that bromination reaction temperature is 51-65 in the step 1)
DEG C, preferably 58-60 DEG C.
4. preparation method according to claim 1, which is characterized in that initiator is selected from benzoyl peroxide first in the step 1)
Acyl, dicetyl peroxydicarbonate two (2- ethylhexyl), azodiisobutyronitrile, azobisisovaleronitrile, azobisisoheptonitrile, preferably peroxide
Change benzoyl；The dosage of initiator is the 1~5% of para-nitrotoluene weight, preferably 2%.
5. preparation method according to claim 1, which is characterized in that bromating agent is bromine or bromination in the step 1)
Hydrogen/hydrogen peroxide, bromating agent dosage are 1.0~1.2 times of theoretical amount.
6. preparation method according to claim 1, which is characterized in that bromination water recovery number is in the step 1)
0~30 time, preferably 10 times.
7. preparation method according to claim 1, which is characterized in that the dosage of water is para-nitrotoluene in the step 2)
5~15 times of inventory, preferably 8 times.
8. preparation method according to claim 1, which is characterized in that moderate strength inorganic base is selected from carbon in the step 2)
Sour hydrogen sodium, sodium carbonate and potassium carbonate, preferably sodium carbonate；The dosage of the alkali is 0.8~1.2 times, preferably 1.0 times of theoretical amount.
9. preparation method according to claim 1, which is characterized in that hydrolysis water recovery number is in the step 2)
0~6 time, preferably 4 times.
10. preparation method according to claim 1, which is characterized in that refining solvent is selected from toluene, two in the step 3)
The mixture of one or more of chloroethanes, ethyl acetate, isobutyl acetate, preferably toluene；Refining solvent usage amount
For 1~5 times of para-nitrotoluene inventory, preferably 3 times.
11. preparation method according to claim 1, which is characterized in that crystallization temperature is 0~40 DEG C in the step 3),
It is preferred that 10~20 DEG C.
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111499511A (en) * | 2020-04-20 | 2020-08-07 | 浙江燎原药业股份有限公司 | Preparation of clopidogrel intermediate α -bromo (2-chloro) methyl phenylacetate by circularly using aqueous solution method |
| CN114516820A (en) * | 2022-02-25 | 2022-05-20 | 山东艾孚特科技有限公司 | Method for preparing 2-diazo-acetoacetic acid p-nitrobenzyl ester |
| CN114773203A (en) * | 2022-05-25 | 2022-07-22 | 浙江华洲药业有限公司 | Production process of p-nitrobenzyl alcohol |
| CN116574009A (en) * | 2023-06-01 | 2023-08-11 | 山东艾孚特科技有限公司 | Preparation method of p-nitrobenzyl alcohol |
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| CN101323575A (en) * | 2007-06-15 | 2008-12-17 | 南京理工大学 | Synthetic method of nitrobenzene methyl aldehyde |
| CN102603534A (en) * | 2011-01-18 | 2012-07-25 | 张争鸣 | New process for synthesizing p-nitrobenzaldehyde |
| CN105348107A (en) * | 2014-08-22 | 2016-02-24 | 南京理工大学 | Preparation method of p-nitrobenzaldehyde |
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2017
- 2017-11-08 CN CN201711088382.8A patent/CN109748800A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101323575A (en) * | 2007-06-15 | 2008-12-17 | 南京理工大学 | Synthetic method of nitrobenzene methyl aldehyde |
| CN102603534A (en) * | 2011-01-18 | 2012-07-25 | 张争鸣 | New process for synthesizing p-nitrobenzaldehyde |
| CN105348107A (en) * | 2014-08-22 | 2016-02-24 | 南京理工大学 | Preparation method of p-nitrobenzaldehyde |
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111499511A (en) * | 2020-04-20 | 2020-08-07 | 浙江燎原药业股份有限公司 | Preparation of clopidogrel intermediate α -bromo (2-chloro) methyl phenylacetate by circularly using aqueous solution method |
| CN114516820A (en) * | 2022-02-25 | 2022-05-20 | 山东艾孚特科技有限公司 | Method for preparing 2-diazo-acetoacetic acid p-nitrobenzyl ester |
| CN114773203A (en) * | 2022-05-25 | 2022-07-22 | 浙江华洲药业有限公司 | Production process of p-nitrobenzyl alcohol |
| CN114773203B (en) * | 2022-05-25 | 2023-12-15 | 浙江华洲药业有限公司 | Production process of p-nitrobenzyl alcohol |
| CN116574009A (en) * | 2023-06-01 | 2023-08-11 | 山东艾孚特科技有限公司 | Preparation method of p-nitrobenzyl alcohol |
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