CN108484408A - A kind of preparation method of rubigan nitromethane - Google Patents
A kind of preparation method of rubigan nitromethane Download PDFInfo
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- CN108484408A CN108484408A CN201810208519.7A CN201810208519A CN108484408A CN 108484408 A CN108484408 A CN 108484408A CN 201810208519 A CN201810208519 A CN 201810208519A CN 108484408 A CN108484408 A CN 108484408A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C201/00—Preparation of esters of nitric or nitrous acid or of compounds containing nitro or nitroso groups bound to a carbon skeleton
- C07C201/06—Preparation of nitro compounds
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C249/00—Preparation of compounds containing nitrogen atoms doubly-bound to a carbon skeleton
- C07C249/04—Preparation of compounds containing nitrogen atoms doubly-bound to a carbon skeleton of oximes
- C07C249/08—Preparation of compounds containing nitrogen atoms doubly-bound to a carbon skeleton of oximes by reaction of hydroxylamines with carbonyl compounds
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Abstract
The present invention relates to a kind of preparation methods of rubigan nitromethane, belong to medical pesticide intermediate field.Method provided by the present invention need not carry out repeated recrystallize, and process is simple, and yield is higher, up to 95% or more.The purity of rubigan nitromethane is higher, safety easy to operate, and reaction is related to physical security, at low cost, is suitble to industrial mass production.
Description
Technical field
The present invention relates to a kind of preparation methods of rubigan nitromethane, belong to medical pesticide intermediate field.
Background technology
Rubigan nitromethane is the important intermediate of cyproconazole.Cyproconazole is to endanger agriculture forest and husbandry production for preventing
Harmful organism (pest, evil mite, nematode, pathogen, weeds and muroid) and coordinate plant growth a kind of fungicide, can be with it
Its fungicide is used in mixed way.Entitled 2- (4- the chlorphenyls) -3- cyclopropyl -1- (1H-1,2,4- triazol-1-yls) of cyproconazole chemistry
Butyl- 2- alcohol, structural formula are as follows：
Xiamen University's journal (natural science edition) the 38th phase (author in 1999：Chen Daimo etc.) it describes and is made with sodium bicarbonate
Alkali synthesizes oxime in ethyl alcohol or methanol；《J Chem Res》1st phase (author in 2000：Sharghi etc.) it describes and is made with CaO
Alkali reacts synthesis oxime at 130 DEG C, this reaction requires temperature high, and equipment requirement is high, production cost is high；《Green Chem》
The 4th phase (author of volume 3 in 2001：Guo etc.) it describes in super acids TiO2/SO4 2-The method of the lower synthesis oxime of effect, but apply this
Super acids require 130 DEG C of reaction temperature, subsequent processing acid to also increase cost, and reaction route is as follows：
《Chinese Journal of Pharmaceuticals》35th phase (author in 2004：Zhang Jianjun) describe 4-chloro-benzaldehyde, hydrochloric acid hydroxyl
Amine, calcium carbonate carry out that 4-chloro-benzaldehyde oxime is obtained by the reaction in ethanol.The technique does alkali at room temperature, with cheap calcium carbonate,
A series of oxime compound is synthesized, yield reaches 80% or more.But ether has been used in extraction after reacting, and is unfavorable for industrializing
Production.
《This Jouranl》The 75th phase (author of nineteen fifty-three：Iffland etc.) it describes oxime is converted into nitroparaffin chemical combination
Object, but this reaction process is carried out in three steps finally is restored with sodium borohydride first by oxime bromination, then with nitric acid nitrating, this
Process is more complex and the relatively low no practical value of yield.
Other synthetic methods, if halogen compounds directly nitrifies into rubigan nitromethane, but the yield of this reaction
It is relatively low, about 50-60%.Rubigan chloromethanes is obtained as rubigan hydroxy methane carries out chlorination reaction by thionyl chloride, then
Nitration reaction is carried out by sodium nitrite and obtains rubigan nitromethane.But since thionyl chloride has strong corrosive, and easily
It deliquesces and is thermally decomposed to generate poisonous gas, sodium nitrite also belongs to extremely toxic substance.So this reaction is not suitable for industrial production.
Based on the above issues, a kind of economy is provided, dangerous smaller, operation is simpler and suitable industrial production pair
The preparation process of chlorphenyl nitromethane is a technical problem to be solved urgently.
Invention content
The object of the present invention is to provide a kind of preparation methods of rubigan nitromethane, include the following steps：
Step (1)：Addition reaction carries out addition reaction in solvent A using 4-chloro-benzaldehyde as raw material with hydroxylamine hydrochloride,
It is washed after reaction, suction filtration obtains 4-chloro-benzaldehyde oxime；
Step (2)：Oxidation reaction, by the obtained 4-chloro-benzaldehyde oxime in step (1) in solvent B, in oxidant
Effect is lower to carry out oxidation reaction, is washed with water after reaction, suction filtration obtains rubigan nitromethane；
Reaction route is as follows：
It theoretically sees, aldehyde and azanol reaction generate oxime and oxime is oxidized obtains nitro compound, this two each step is all
It is feasible.The present invention's, it is critical that using classical reaction, the feasible reaction of two theories is together in series.
In one embodiment of the invention, the solvent A in the step (1) be methanol, ethyl alcohol, propyl alcohol, isopropanol,
Ethylene glycol, water or acetonitrile.
In one embodiment of the invention, the solvent A in the step (1) is water.
In one embodiment of the invention, the molar ratio of the 4-chloro-benzaldehyde and hydroxylamine hydrochloride in the step (1)
Ranging from 1:1-2.5.
In one embodiment of the invention, the molar ratio of the 4-chloro-benzaldehyde and hydroxylamine hydrochloride in the step (1)
It is 1:1.3.
In one embodiment of the invention, the reaction temperature of the step (1) is 50~90 DEG C.
In one embodiment of the invention, the reaction temperature of the step (1) is 70 DEG C.
In one embodiment of the invention, the dosage of the solvent A in the step (1) is 4-chloro-benzaldehyde weight
4~6 times.
In one embodiment of the invention, the solvent B in the step (2) is formic acid, acetic acid, trifluoroacetic acid, first
Acid, sodium formate, acetic acid, sodium acetate, phosphoric acid.
In one embodiment of the invention, the solvent B in the step (2) is acetic acid or sodium acetate.
In one embodiment of the invention, the dosage of the solvent B solvents in the step (2) is 4-chloro-benzaldehyde oxime
1.0~2.0 times of molal weight.
In one embodiment of the invention, the dosage of the solvent B solvents in the step (2) is 4-chloro-benzaldehyde oxime
1.4 times of molal weight.
In one embodiment of the invention, the reaction temperature of the step (2) is 25~110 DEG C.
In one embodiment of the invention, the reaction temperature of the step (2) is 80~85 DEG C.
In one embodiment of the invention, the solvent B of the step (2) is acetic acid or sodium acetate, and reaction temperature is
80~85 DEG C.
In one embodiment of the invention, the oxidant of the step (2) be hydrogen peroxide, it is Peracetic acid, oxygen, smelly
Oxygen or potassium permanganate.
In one embodiment of the invention, the oxidant of the step (2) is hydrogen peroxide or Peracetic acid.
In one embodiment of the invention, the oxidant of the step is hydrogen peroxide or Peracetic acid, the step
(2) additive amount of hydrogen peroxide is the 120~400% of chlorobenzaldehyde oxime mass fraction in, and the additive amount of the Peracetic acid is chlorine
The 200~400% of benzaldoxime mass fraction
It is an advantage of the invention that：
Product need not carry out repeated recrystallize, and process is simple, and yield is higher, up to 95% or more.Rubigan nitro first
The purity of alkane is higher, safety easy to operate, and reaction is related to physical security, at low cost, is suitble to industrial mass production.
Description of the drawings
Fig. 1：Chromatogram.
Specific implementation mode
The present invention is further described with reference to specific embodiment, but the present invention is not limited only to these implementations
Example.
Calculation of yield method：Yield C=m (product/g)/m (theoretical product weight/g) × 100%
4-chloro-benzaldehyde oxime and rubigan nitromethane UPLC (SHIMADZU LC-30A system) detection method：
Shim-C18 column (75 × 2.0mm, 1.6 μm), 40 DEG C, flow velocity 0.1mL/min of column temperature, methanol/water
=80/20,10 μ L of sample size, setting wavelength 254nm.
The influence of the preparation of 1 reaction temperature 4-chloro-benzaldehyde oxime of embodiment
4-chloro-benzaldehyde 14.1g is added in the 250mL four-hole boiling flasks equipped with condenser pipe, thermometer and blender
(0.1mol), hydroxylamine hydrochloride 9.1g (0.13mol), pure water 70-80mL, start blender and start to stir, water-bath heating.Reaction
Temperature and time are as shown in table 1, after reaction, remove heating device, are cooled to room temperature.Use multiplex vavuum pump of circulating water type
It filters, obtains white crystal, three times with the pure water of 300m.White solid 4-chloro-benzaldehyde oxime is obtained, it is dry.
The influence of 1 reaction temperature 4-chloro-benzaldehyde oxime yield of table
As shown in Table 1, it is 70 DEG C~80 that the yield of different reaction temperature 4-chloro-benzaldehydes, which has certain influence, reaction temperature,
DEG C it is that yield is 95% or more.
The preparation of 2 4-chloro-benzaldehyde oxime of embodiment
4-chloro-benzaldehyde 14.1g is added in the 250mL four-hole boiling flasks equipped with condenser pipe, thermometer and blender
(0.1mol), hydroxylamine hydrochloride 9.1g (0.13mol), pure water 70-80mL, start blender and start to stir, water-bath heating.70
It is reacted 2 hours under the conditions of DEG C, after reaction, removes heating device, be cooled to room temperature.It is taken out with multiplex vavuum pump of circulating water type
Filter, obtains white crystal, three times with the pure water of 300m.White solid 4-chloro-benzaldehyde oxime is obtained, dry, weighing, it is left to obtain 14.9g
The right side, yield is up to 96.1%, 104.8-107.5 DEG C of fusing point, HPLC：96.4%.
The influence of the preparation of 3 reaction temperature 4-chloro-benzaldehyde oxime of embodiment
In the four-hole boiling flask equipped with condenser pipe, thermometer and blender be added 14.11g (0.1mol) 4-chloro-benzaldehyde,
9g (0.13mol) hydroxylamine hydrochloride, pure water 100mL, start blender and start to stir, water-bath heating.Reaction temperature and time
As shown in table 2, after reaction, heating device is removed, is cooled to room temperature.It is filtered, is obtained white with multiplex vavuum pump of circulating water type
Crystal, three times with the pure water of 100mL.White solid 4-chloro-benzaldehyde oxime is obtained, it is dry.
The influence of 2 reaction temperature 4-chloro-benzaldehyde oxime yield of table
As shown in Table 1, it is 70 DEG C~80 that the yield of different reaction temperature 4-chloro-benzaldehydes, which has certain influence, reaction temperature,
DEG C it is that yield is 90% or more.
The preparation of 4 4-chloro-benzaldehyde oxime of embodiment
In the four-hole boiling flask equipped with condenser pipe, thermometer and blender be added 14.11g (0.1mol) 4-chloro-benzaldehyde,
9g (0.13mol) hydroxylamine hydrochloride, pure water 100mL, start blender and start to stir, water-bath heating.It is reacted under the conditions of 70 DEG C
1.5 hours, after reaction, heating device is removed, be cooled to room temperature.It is filtered with multiplex vavuum pump of circulating water type, obtains white crystalline substance
Body, three times with the pure water of 100mL.White solid 4-chloro-benzaldehyde oxime, dry, weigh to obtain 14.7g or so, and yield can
Up to 94.8%.
The preparation of 5 4-chloro-benzaldehyde oxime of embodiment
7.1 (50mmol) 4-chloro-benzaldehydes, 9g (130mmol) hydroxylamine hydrochloride, pure water 50mL, start blender and start to stir
It mixes, water-bath heating.It is reacted 1.5 hours under the conditions of 70 DEG C, after reaction, removes heating device, be cooled to room temperature.With following
Ring ability of swimming multiplex vavuum pump filters, and obtains white crystal, three times with the pure water of 50mL.White solid 4-chloro-benzaldehyde oxime is obtained,
Dry, weigh to obtain 7.43g or so, and yield is up to 95.9%.
The influence of the synthesis of 6 reaction temperature rubigan nitromethane of embodiment
4-chloro-benzaldehyde oxime 23.5g is added in the 250mL four-hole boiling flasks equipped with condenser pipe, thermometer and blender
(0.15mol), 30% hydrogen peroxide 78g (excessive 300%), acetic acid 30.4g, sodium acetate 2.0g, start agitating and heating.Reaction temperature
And the time is as shown in table 3, the reaction was complete for TLC monitorings.After reaction, it is cooled to 20-25 DEG C, the pure water of 150ml is added again
Stir half an hour.It filters, obtains orange/yellow solid, three times with the pure water of 300ml.Rubigan nitromethane is obtained, it is dry.
Influence of 3 reaction temperature of table to rubigan nitromethane yield
As shown in Table 1, the yield of different reaction temperature 4-chloro-benzaldehydes has certain influence, and reaction temperature is 100 DEG C~
110 DEG C are that yield is 85% or more.
The synthesis of 7 rubigan nitromethane of embodiment
4-chloro-benzaldehyde oxime 23.5g is added in the 250mL four-hole boiling flasks equipped with condenser pipe, thermometer and blender
(0.15mol), 30% hydrogen peroxide 78g (excessive 300%), acetic acid 30.4g, sodium acetate 2.0g, start agitating and heating.At 100 DEG C
Under the conditions of react 6 hours, TLC monitoring the reaction was complete.After reaction, it is cooled to 20-25 DEG C, the pure water that 150ml is added stirs again
Mix half an hour.It filters, obtains orange/yellow solid, three times with the pure water of 300ml.Rubigan nitromethane is obtained, it is dry, it weighs
Obtain product 19.8g, yield 86.74%, HPLC：97.9%.
The synthesis of 7 rubigan nitromethane of embodiment
4-chloro-benzaldehyde oxime 2.35g (15mmol), 30% hydrogen peroxide 7.8g (excessive 300%), acetic acid 3g, sodium acetate
0.2g starts agitating and heating.Reaction temperature and time are as shown in table 4, and the reaction was complete for TLC monitorings.After reaction, it removes and adds
Thermal is cooled to 20-25 DEG C, and the pure water that 15ml is added is stirred for half an hour.It filters, obtains orange/yellow solid, it is pure with 30ml
Water washing is three times.Rubigan nitromethane is obtained, it is dry.
Influence of 4 reaction time of table to rubigan nitromethane yield
As shown in Table 1, the yield of different reaction temperature 4-chloro-benzaldehydes has certain influence, reaction time in 6~7h, to obtain
Rate is 80% or more.
The synthesis of 8 rubigan nitromethane of embodiment
4-chloro-benzaldehyde oxime 2.35g (15mmol), 30% hydrogen peroxide 7.8g (excessive 300%), acetic acid 3g, sodium acetate
0.2g starts agitating and heating.It is reacted 6 hours under the conditions of 100 DEG C, the reaction was complete for TLC monitorings.After reaction, heating is removed
Device is cooled to 20-25 DEG C, and the pure water that 15ml is added is stirred for half an hour.It filters, orange/yellow solid is obtained, with the pure water of 30ml
Washing is three times.Rubigan nitromethane is obtained, dry, weigh to obtain product 1.94g, yield 85.8%, HPLC：98.5%.
HRMS calcd for C7H7ClNO2：172.0165；found：172.0159.
1 peaks rubigan nitromethane HPLC table of table
<Peak table>
PDA Chl 254nm
| Peak number | Retention time | Area | Highly | Concentration | Concentration unit | Area % |
| 1 | 1.894 | 56613 | 4283 | 0.000 | 0.320 | |
| 2 | 2.349 | 123621 | 5600 | 0.000 | 0.699 | |
| 3 | 2.608 | 69810 | 7695 | 0.000 | 0.395 | |
| 4 | 2.878 | 17416789 | 1309321 | 0.000 | 98.549 | |
| 5 | 4.320 | 6462 | 519 | 0.000 | 0.037 | |
| It amounts to | 17673296 | 1327418 | 100.000 |
Although the present invention has been described by way of example and in terms of the preferred embodiments, it is not limited to the present invention, any to be familiar with this skill
The people of art can do various change and modification, therefore the protection model of the present invention without departing from the spirit and scope of the present invention
Enclosing be subject to what claims were defined.
Claims (10)
1. a kind of preparation method of rubigan nitromethane, which is characterized in that described method includes following steps：
Step (1)：Using 4-chloro-benzaldehyde as raw material, addition reaction is carried out with hydroxylamine hydrochloride in solvent A, is washed after reaction, taken out
Filter obtains 4-chloro-benzaldehyde oxime；
Step (2)：By the obtained 4-chloro-benzaldehyde oxime in step (1) in solvent B, aoxidized under the action of oxidant
Reaction, is washed with water after reaction, and suction filtration obtains rubigan nitromethane；
Reaction route is as follows：
2. according to the method described in claim 1, it is characterized in that, solvent A in the step (1) be water, ethyl alcohol, propyl alcohol,
Isopropanol, ethylene glycol, methanol or acetonitrile.
3. according to the method described in claim 1, it is characterized in that, the reaction temperature of the step (1) is 50~90 DEG C.
4. according to the method described in claim 1, it is characterized in that, the dosage of A is 4-chloro-benzaldehyde weight in the step (1)
4~6 times.
5. according to the method described in claim 1, it is characterized in that, the solvent B in the step (2) is formic acid, acetic acid, trifluoro
Acetic acid, formic acid, sodium formate, acetic acid, sodium acetate, phosphoric acid.
6. according to the method described in claim 1, it is characterized in that, the dosage of solvent B solvents is to chlorobenzene in the step (2)
1.0~2.0 times of formaldoxime molal weight.
7. according to the method described in claim 1, it is characterized in that, the reaction temperature of the step (2) is 25~110 DEG C.
8. according to the method described in claim 1, it is characterized in that, the oxidant of the step (2) is hydrogen peroxide, peroxide second
Acid, oxygen, ozone or potassium permanganate.
9. according to the method described in claim 8, it is characterized in that, the additive amount of hydrogen peroxide is chlorobenzene first in the step (2)
The 120~400% of aldoxime mass fraction, the additive amount of the Peracetic acid be chlorobenzaldehyde oxime mass fraction 200~
400%.
10. the rubigan nitromethane being prepared according to any the methods of claim 1-9.
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5072056A (en) * | 1989-09-26 | 1991-12-10 | Carter-Wallace, Inc. | Synthesis of 2-phenyl-1,3-propanediol |
| CN102643213A (en) * | 2012-04-11 | 2012-08-22 | 暨明医药科技（苏州）有限公司 | Preparation method of 3, 5-dimethyl-4-bromomethylbenzonitrile |
-
2018
- 2018-03-14 CN CN201810208519.7A patent/CN108484408A/en active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5072056A (en) * | 1989-09-26 | 1991-12-10 | Carter-Wallace, Inc. | Synthesis of 2-phenyl-1,3-propanediol |
| CN102643213A (en) * | 2012-04-11 | 2012-08-22 | 暨明医药科技（苏州）有限公司 | Preparation method of 3, 5-dimethyl-4-bromomethylbenzonitrile |
Non-Patent Citations (1)
| Title |
|---|
| SERGEY V. TSUKANOV: "Development of an Intermittent-Flow Enantioselective Aza-Henry Reaction Using an Arylnitromethane and Homogeneous Bronsted Acid−Base Catalyst with Recycle", 《ORGANIC PROCESS RESEARCH & DEVELOPMENT》 * |
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