CN101353317B - Preparation of 4-bromo-2,6-difluorobenzonitrile - Google Patents
Preparation of 4-bromo-2,6-difluorobenzonitrile Download PDFInfo
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- CN101353317B CN101353317B CN2008100793760A CN200810079376A CN101353317B CN 101353317 B CN101353317 B CN 101353317B CN 2008100793760 A CN2008100793760 A CN 2008100793760A CN 200810079376 A CN200810079376 A CN 200810079376A CN 101353317 B CN101353317 B CN 101353317B
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Abstract
The invention discloses a preparation method of 4-bromo-2, 6-difluorobenzonitrile. In the preparation method, tetrahydrofuran, potassium tert butoxide, petroleum ether, 3, 5-difluorobromobenzene, DMF and n-butyllithium with the proportion of n-butyllithium: 3, 5-difluorobromobenzene, which is equal to 1.2:1 and the proportion of DMF: 3, 5-difluorobromobenzene, which is equal to1.6:1 are taken as raw materials to produce 4-bromo-2, 6-difluorobenzaldehyde, and methanoic acid, 4-bromo-2, 6-difluorobenzaldehyde and hydroxylamine hydrochloride with the weight ratio of the methanoic acid, the 4-bromo-2, 6-difluorobenzaldehyde and the hydroxylamine hydrochloride equal to 4:1:1.4 are taken as raw materials to prepare the 4-bromo-2, 6-difluorobenzonitrile. The preparation steps of the 4-bromo-2, 6-difluorobenzonitrile are as follows: A: the raw materials are added to a three-necked flask according to the proportion, and are heated and refluxed for 10 hours at normal pressure; B: a solvent is distilled at normal pressure, then corresponding volume of water is added to the system to continuously distill, and the 4-bromo-2, 6-difluorobenzonitrile is carried out; and C: the distilled aqueous solution is naturally cooled to the room temperature and is carried out suction filtration; a filter cake is washed with water to be neutral, and the product is obtained. The method for preparing the 4-bromo-2, 6-difluorobenzonitrile of the invention takes the 3, 5-difluorobromobenzene as a basic raw material which is cheap, and the whole process engineering is low in cost, so the 4-bromo-2, 6-difluorobenzonitrile is applicable to mass production. The preparation method does not adopt the hypertoxic potassium cyanide and strong corrosive substances such as sulfuric acid, bromine, and the like, which are adopted in the existing process, thus reducing the environmental pollution.
Description
Technical field
The present invention relates to a kind of preparation method of midbody compound of liquid crystalline cpd, belong to chemical field.
Background technology
4-bromo-2, the chemical formula of 6-difluorobenzonilyile does
It is a kind of midbody compound of present widely used preparation liquid crystal material.It generally is with 2 at present, and the 6-difluoroaniline is a raw material, through bromination diazotization and the synthetic liquid crystal intermediates 4-bromo-2 of sandermer reaction, 6-difluorobenzonilyile.Its reaction formula is generally following:
Technical matters in the above-mentioned reaction formula is complicated, uses bromine, Potssium Cyanide, the vitriol oil in the raw material, and they not only have extremely strong corrodibility, and toxicity is big, during production environmental pollution serious, and yield is lower, cost is higher.
Summary of the invention
The technical issues that need to address of the present invention provide a kind of midbody compound for preparing liquid crystalline cpd---4-bromo-2, the new preparation method of 6-difluorobenzonilyile.This method can reduce the pollution to environment, reduces production costs.
For solving the problems of the technologies described above, the present invention takes following technical scheme.
A kind of 4-bromo-2, the preparation method of 6-difluorobenzonilyile, used raw material comprises formic acid, 4-bromo-2,6-difluorobenzaldehyde, oxammonium hydrochloride; Raw materials used weight ratio is: formic acid/4-bromo-2,6-difluorobenzaldehyde/oxammonium hydrochloride=4/1/1.4; Its preparation process comprises the steps:
Steps A is reinforced
In there-necked flask, add formic acid and 4-bromo-2 in proportion, 6-difluorobenzaldehyde, oxammonium hydrochloride; Reflux is 10 hours under normal pressure.
Step B distillation
Steam solvent at normal pressure, and then in system, add the water continuation distillation of respective volume, take product out of---4-bromo-2,6-difluorobenzonilyile.
Step C suction filtration
The aqueous solution that distills out is cooled to room temperature, suction filtration then naturally; The filter cake water is washed till neutrality.Gained white plates crystalline solid promptly is product of the present invention.
Adopt method of the present invention to produce 4-bromo-2,6-difluorobenzonilyile, its yield >=80%; Gc content is more than or equal to 99.5%.
Above-mentioned preparation 4-bromo-2, used 4-bromo-2 in the 6-difluorobenzonilyile process, the preparation method of 6-difluorobenzaldehyde is:
Preparation 4-bromo-2; The used raw material of 6-difluorobenzaldehyde has: THF (technical grade), potassium tert.-butoxide, sherwood oil (technical grade), 3; 5-difluoro bromobenzene (gc content GC >=99%), DMF (being N, dinethylformamide), butyllithium (density is 2.4mol/L); The ratio of main raw material should be followed: butyllithium/3,5-difluoro bromobenzene=1.2mol/1mol, DMF/3,5-difluoro bromobenzene=1.6mol/1mol.
Comprise the steps: in the preparation process
Step 1 is prepared
Polytetrafluoroethylsealed sealed whisking appliance, constant pressure funnel, low-reading thermometer, nitrogen protection device are installed on the low temperature still; And do fire prevention, fire extinguishing is prepared.
Step 2 is reinforced
In the low temperature still, add THF (THF) and 3 in proportion, 5-difluoro bromobenzene, sherwood oil, potassium tert.-butoxide.Fill denitrogen gas three times, under nitrogen protection, open liquid nitrogen cooling.
Step 3 drips
When being cooled to below-80 ℃, should strengthen stirring velocity, and under nitrogen protection, slowly drip the butyl lithium solution of requirement, in 1.5～2 hours butyl lithium solution dripped off, temperature can not be higher than-80 ℃ in the dropping process.
Step 4 insulation
After dripping off butyl lithium solution, continued under-80 ℃～-100 ℃ temperature low-temp reaction 1 hour.
Step 5 drips
After the insulation reaction, in solution, dripping DMF and THF (THF) in proportion; And controlled temperature is lower than-90 ℃ in the dropping process.
Step 6 stirs
After dropwising, be warming up to-20 ℃ while stirring naturally, emit reaction soln.
Step 7 hydrolysis
The mixed solution that in the solution of step 6 gained, adds concentrated hydrochloric acid and water in proportion carries out acidifying to above-mentioned solution, and stirs 1～1.5 hour.Stop then stirring, pour solution into separating funnel, solution is divided into two-layer up and down, and the upper strata is an organic phase, and lower floor is a water, and organic phase is put into beaker; Add an amount of THF at the lower floor aqueous phase, stirred 5 minutes, operate the samely, make the solution layering, water is emitted, twice organic phase is integrated with in the same container.
Step 8 distillation
Organic phase in the beaker is poured in the matrass, and normal pressure steams solvent, and when Heating temperature to 80 ℃, the water that in system, adds respective amount continues to be distilled to till 100 ℃.
Step 9 suction filtration
Make above-mentioned reaction solution be cooled to room temperature, suction filtration, the filter cake water is washed till neutrality, with behind twice filter cake of an amount of petroleum ether filter cake being dried, has both got product.Petroleum ether liquid and recrystallization mother liquor merge, and preserve in the lump.
Through the 4-bromo-2 of gained after the above-mentioned steps, the yield of the product of 6-difluorobenzaldehyde >=80%, the product appearance of gained is a white plates crystalline solid.
Owing to adopted technique scheme, the technical progress that the present invention obtained is:
The present invention prepares 4-bromo-2, and the method for 6-difluorobenzonilyile is with 3, and the 5-difluoro bromobenzene is a basic material, and 3, the low price of 5-difluoro bromobenzene, whole technological process cost is low, is convenient to mass production.This method is not used the Potssium Cyanide and materials such as the sulfuric acid with severe corrosive, bromine of severe toxicity, therefore can reduce the pollution to environment.
Embodiment
Do further explanation in the face of the present invention down.
One, preparation 4-bromo-2, the 6-difluorobenzaldehyde
Preparation 4-bromo-2; The used raw material of 6-difluorobenzaldehyde has: THF (technical grade), potassium tert.-butoxide, sherwood oil (technical grade), 3; 5-difluoro bromobenzene (gc content GC >=99%), DMF (being N, dinethylformamide), butyllithium (density is 2.4mol/L); The material ratio of main raw material should be followed: butyllithium/3,5-difluoro bromobenzene=1.2mol/1mol, DMF/3,5-difluoro bromobenzene=1.6mol/1mol; Instrument used in the preparation process mainly contains: 5 liters of low temperature stills ,-150～100 ℃ low-reading thermometer, constant pressure funnel, nitrogen steel cylinder, water-circulating pump, liquid nitrogen container, butyllithium storage tank etc.
Preparation 4-bromo-2 comprises the steps: in the process of 6-difluorobenzaldehyde
Step 1 is prepared: must clean out before 5 liters of low temperature stills use, guarantee clean and dry.
Polytetrafluoroethylsealed sealed whisking appliance, constant pressure funnel, low-reading thermometer, nitrogen protection device are installed on 5 liters of low temperature stills.
Key points for operation: prepare woven asbesto and paper, flash arrestor; Indoor all inflammable and explosive chemical substances have been cleared up.
Step 2 is reinforced: in 5 liters of low temperature stills, add 2000mlTHF (THF) and 386g3,5-difluoro bromobenzene, 1L sherwood oil (60～90 ℃), 313.6g potassium tert.-butoxide.Fill denitrogen gas three times, under nitrogen protection, open liquid nitrogen cooling.
Key points for operation: potassium tert.-butoxide uses up the back and notes sealing, puts into moisture eliminator and preserves, and prevents the moisture absorption.
Step 3 drips: when being cooled to below-80 ℃, should strengthen stirring velocity, and slowly drip butyl lithium solution, in 1.5～2 hours the 1L butyl lithium solution dripped off, temperature can not be higher than-80 ℃ in the dropping process.
Key points for operation: must under nitrogen protection, drip butyl lithium solution.
Step 4 insulation: after dripping off butyl lithium solution, continued under-80 ℃～-100 ℃ temperature low-temp reaction 1 hour.
Key points for operation: notice that temperature can not be lower than-120 ℃, when temperature was lower than below-120 ℃, reaction solution can freeze, and stirred motionless.
Step 5 drips: after the insulation reaction, in solution, dripping the DMF of 250g and the THF (THF) of 0.5L; And controlled temperature is lower than-90 ℃ in the dropping process.
Key points for operation: approximately drip about 1 hour.DMF uses up the back and preserves with the raw material band sealing.
Step 6 stirs: after dropwising, be warming up to-20 ℃ while stirring naturally, emit reaction liquid.
Step 7 hydrolysis: the mixing solutions that in above-mentioned solution, adds 200ml concentrated hydrochloric acid and 500ml water carries out acidifying to above-mentioned solution, stirs 1～1.5 hour.Stop then stirring, pour solution into separating funnel, solution is divided into two-layer up and down, and the upper strata is an organic phase, and lower floor is a water, and organic phase is put into beaker; Add 200 milliliters of THFs at the lower floor aqueous phase, stirred 5 minutes, operate the samely, make the solution layering, water is emitted, twice organic phase is integrated with in the same beaker.
Step 8 distillation: organic phase in the beaker is poured in the matrass, and normal pressure steams solvent, when Heating temperature to 80 ℃; For preventing the overheated side reaction that takes place; Must in system, add 1L water and continue distillation, till 100 ℃, the interior floating a large amount of solids of aqueous phase of beaker this moment.
Step 9 suction filtration: reaction solution is cooled to room temperature, suction filtration, and the filter cake water is washed till neutrality, with behind twice filter cake of 500ml petroleum ether filter cake being dried, has both got product.Filtrating is put into waste liquid barrel.
Key points for operation: petroleum ether liquid and recrystallization mother liquor merge, and preserve in the lump.
Through the 4-bromo-2 of gained after the above-mentioned steps, the actual output >=356g of 6-difluorobenzaldehyde; And theoretical yield should be 444g; Adopt yield >=80% of the product of method production of the present invention, the product appearance of gained is a white plates crystalline solid.
Two, preparation 4-bromo-2, the 6-difluorobenzonilyile
Preparation 4-bromo-2, the 4-bromo-2 that obtains above the used raw material of 6-difluorobenzonilyile comprises, the 6-difluorobenzaldehyde also comprises formic acid and oxammonium hydrochloride; Raw materials used weight ratio is: formic acid/4-bromo-2,6-difluorobenzaldehyde/oxammonium hydrochloride=4/1/1.4; Used production equipment comprises: adopt the there-necked flask (capacity is 2L) of built-in prolong, there-necked flask guarantees clean and dry with the sealing of fluorine four sealing materials.Its preparation process comprises the steps:
Steps A is reinforced: in the 2L there-necked flask, add the formic acid of 400ml and the 4-bromo-2 of 100g, 6-difluorobenzaldehyde, 97g oxammonium hydrochloride.Formic acid plays the solvent dehydration effect, 4-bromo-2, and 6-difluorobenzaldehyde and oxammonium hydrochloride reaction, reflux is 10 hours under the normal pressure.
Step B distillation: steam solvent at normal pressure, and then in system, add 1L water continuation distillation, take product out of, product is a 4-bromo-2, the 6-difluorobenzonilyile.
Step C suction filtration: the aqueous solution that distills out is cooled to room temperature, suction filtration naturally; The filter cake water is washed till neutrality.The gained white solid promptly is a product of the present invention.
Adopt method of the present invention to produce 4-bromo-2, the 6-difluorobenzonilyile, raw materials used is that its theoretical yield should be 98g under the situation of above-mentioned quantity; Actual output >=78g, yield >=80%.
The product of gained is a white plates crystalline solid, and gc content is more than or equal to 99.5%.
The main points that should be noted that when adopting aforesaid method of the present invention: want the operation of strict control anhydrous and oxygen-free when butyllithium uses, the solvent of reaction usefulness must pass through except that water treatment (control moisture≤5/10000ths) before use.The THF that uses is the not barreled of opening or bottled reagent in this way, drying-free, otherwise need add sodium Metal 99.5 or Pottasium Hydroxide dry 24 hours.Butyllithium is under nitrogen protection, to be pressed in the reaction kettle with nitrogen.
Routine inspection: check whether whether used glassware is clean, dry, have crackle.Whether inspection low temperature still is clean, dry, and whether sealing-ring has twined raw material band.
Claims (3)
1. 4-bromo-2, the preparation method of 6-difluorobenzonilyile is characterized in that: used raw material comprises formic acid, 4-bromo-2,6-difluorobenzaldehyde, oxammonium hydrochloride; Raw materials used weight ratio is formic acid/4-bromo-2,6-difluorobenzaldehyde/oxammonium hydrochloride=4/1/1.4;
The preparation process comprises the steps
Steps A is reinforced
In reactor drum, add formic acid and 4-bromo-2 in proportion, 6-difluorobenzaldehyde, oxammonium hydrochloride, reflux is 10 hours under normal pressure;
Step B distillation
Steam solvent at normal pressure, and then in system, add entry continuation distillation, take 4-bromo-2 out of, the 6-difluorobenzonilyile;
Step C suction filtration
The aqueous solution that distills out is cooled to room temperature, suction filtration naturally; The filter cake water is washed till neutrality, promptly gets 4-bromo-2 of the present invention, the 6-difluorobenzonilyile.
2. the described 4-bromo-2 of claim 1, the preparation method of 6-difluorobenzaldehyde is characterized in that: preparation 4-bromo-2, the used main raw material of 6-difluorobenzaldehyde has THF, potassium tert.-butoxide, sherwood oil, 3,5-difluoro bromobenzene, DMF, butyllithium; The molar ratio of main raw material is butyllithium/3,5-difluoro bromobenzene=1.2/1, DMF/3,5-difluoro bromobenzene=1.6/1.
3. the described 4-bromo-2 of claim 2, the preparation method of 6-difluorobenzaldehyde is characterized in that the preparation process comprises the steps:
Step 1 is prepared
Polytetrafluoroethylsealed sealed whisking appliance, constant pressure funnel, low-reading thermometer, nitrogen protection device are installed on the low temperature still;
Step 2 is reinforced
In the low temperature still, add THF and 3 in proportion, 5-difluoro bromobenzene, sherwood oil, potassium tert.-butoxide fill denitrogen gas three times, under nitrogen protection, open liquid nitrogen cooling;
Step 3 drips
When being cooled to below-80 ℃, should strengthen stirring velocity, and under nitrogen protection, slowly drip the butyl lithium solution of requirement, in 1.5～2 hours butyl lithium solution dripped off, temperature can not be higher than-80 ℃ in the dropping process;
Step 4 insulation
After dripping off butyl lithium solution, continued under-80 ℃～-100 ℃ temperature low-temp reaction 1 hour;
Step 5 drips
After the insulation reaction, in solution, drip DMF and THF in proportion; And controlled temperature is lower than-90 ℃ in the dropping process;
Step 6 stirs
After dropwising, be warming up to-20 ℃ while stirring naturally, emit reaction soln;
Step 7 hydrolysis
The mixed solution that in the solution of step 5 gained, adds concentrated hydrochloric acid and water in proportion carries out acidifying to above-mentioned solution, and stirs 1～1.5 hour; Stop then stirring, pour solution into separating funnel; The organic phase on upper strata is put into container behind the separatory, adds an amount of THF at lower floor's aqueous phase, stirs 5 minutes, and water is emitted, and organic phase is integrated with in the same container;
Step 8 distillation
Organic phase is poured in the water distilling apparatus, and normal pressure steams solvent, and when Heating temperature to 80 ℃, the water that in system, adds respective amount continues to be distilled to till 100 ℃;
Step 9 suction filtration
Make above-mentioned reaction solution be cooled to room temperature, suction filtration, the filter cake water is washed till neutrality, with behind twice filter cake of an amount of petroleum ether filter cake being dried, has both got product.
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| CN2008100793760A CN101353317B (en) | 2008-09-12 | 2008-09-12 | Preparation of 4-bromo-2,6-difluorobenzonitrile |
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| CN2008100793760A CN101353317B (en) | 2008-09-12 | 2008-09-12 | Preparation of 4-bromo-2,6-difluorobenzonitrile |
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| CN102531992A (en) * | 2012-01-11 | 2012-07-04 | 河南省科学院高新技术研究中心 | Preparation method for pyrrolecarbonitrile |
| CN102659544A (en) * | 2012-05-02 | 2012-09-12 | 上海中新裕祥化工有限公司 | Method for preparing 2,3-difluorobenzaldehyde |
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Non-Patent Citations (2)
| Title |
|---|
| 李耀华.4-溴-2 6-二氟苯基氰的合成.《广州化学》.2003 |
| 李耀华.4-溴-2,6-二氟苯基氰的合成.《广州化学》.2003,第28卷(第2期),9-13. * |
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