CN106349159A - 3-chloro-2-cyano-5-trifluoromethyl pyridine preparation method - Google Patents
3-chloro-2-cyano-5-trifluoromethyl pyridine preparation method Download PDFInfo
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Abstract
The invention discloses a 3-chloro-2-cyano-5-trifluoromethyl pyridine preparation method. The method includes steps: (1) dissolving 3-chloro-2-R-5-trifluoromethyl pyridine into a solvent A, adding an activating agent, performing heating reflux for 4-6h, cooling to 20-30 DEG C to obtain reaction liquid, filtering the reaction liquid to obtain a filter cake, and subjecting the filter cake to vacuum drying for 1-2h at 40-50 DEG C to obtain organic salt; (2) adding cyanide and the organic salt obtained at the step (1) into a solvent B and water, stirring for reaction for 2-3h at 0-80 DEG C to obtain mixed liquid, and standing the mixed liquid for layering to obtain an organic phase a; adding hydrochloric acid into the organic phase a to adjust pH to 2-4, standing for layering to obtain an acid water layer and an organic layer, and adding water to wash the organic layer until pH is 6-7, so that washed water and an organic phase b are obtained. By the preparation process, nitrile solvents such as acetonitrile and propionitrile are avoided while low-toxicity solvents such as dichloromethane hardly soluble in water are adopted, conception ingenuity is achieved, solvent recycling is realized, and accordingly production cost is reduced, and environment pollution is abated.
Description
Technical field
The present invention relates to pharmaceutical technology field, the specifically preparation method of 3- chloro- 2- cyano group -5- trifluoromethyl pyridine.
Background technology
At present the preparation method of 3- chloro- 2- cyano group -5- trifluoromethyl pyridine includes introducing cyano group or activation from pyridine 2
Pyridine n- oxide or n- alkyl pyridine, wherein from the method for 2 introducing cyano group of pyridine, including in dimethyl sulfoxide or dimethyl
Carry out the replacement of halogen, especially bromine or fluorine, above method has all used the heavy metal of copper or nickel in Methanamide polar solvent
Reagent, and suffer from the drawback that, low yield, produce toxic waste liquid using heavy metal it is difficult to reclaim polar solvent, therefore uncomfortable
Close industrialization production.
Patent cn1147474c proposes with acetonitrile or propionitrile as solvent, is activator with 4-dimethylaminopyridine, uses
Cyanogran. carries out reacting the method preparing 3- chloro- 2- cyano group -5- trifluoromethyl pyridine for cyanide.Although this method avoid weight
Metal reagent, but there is problems in that 1) consumption of this patent Cyanogran. is 1.0-2.5 molar equivalent, preferably 1.4-1.6 mole
Equivalent, the consumption of Cyanogran. is still larger；2) reaction use the nitrile solvents such as acetonitrile or propionitrile, due to select solvent with water-soluble
Solution performance is good, and in processing procedure, solvent loss is big after the reaction, and the bad washing of unreacted Cyanogran. removes, and secondly selects
The toxicity of solvent is high, and processing safety is poor.Both the above shortcoming is not suitable for industrialized great production.
Content of the invention
For solving the above problems, it is an object of the invention to provide the preparation side of 3- chloro- 2- cyano group -5- trifluoromethyl pyridine
Method.
The present invention for achieving the above object, is achieved through the following technical solutions:
A kind of preparation method of 3- chloro- 2- cyano group -5- trifluoromethyl pyridine, comprises the following steps:
1. chloro- for 3- 2-r base -5- trifluoromethyl pyridine is dissolved in solvent a, is then added thereto to activator, is heated to reflux 4 ~ 6
Hour, it is cooled to 20 ~ 30 DEG C, obtains reactant liquor, gained reacting liquid filtering obtains filter cake, by gained filter cake at 40 ~ 50 DEG C
Vacuum drying 1 ~ 2 hour, obtains organic salt；
Wherein 3- chloro- 2-r base -5- trifluoromethyl pyridine is 1:1 ~ 3 with the mol ratio of activator；3- chloro- 2-r base -5- fluoroform
The mass volume ratio of yl pyridines and solvent a is 1g:15 ~ 25ml；
Described r base is chlorine, bromine or fluorine；Described solvent a be methanol, ethanol, acetone, butanone, dichloromethane, dichloroethanes or
Chloroform；Described activator is triethylamine, 4- pyrollidinopyridine or 4-dimethylaminopyridine；
2. by step, 1. gained organic salt, cyanide are added in solvent b and water, and at 0 ~ 80 DEG C, stirring reaction 2 ~ 3 hours, obtain
To mixed liquor, gained mixed liquor stratification obtains organic faciess a；It is 2 ~ 4 that gained organic faciess a addition hydrochloric acid is adjusted its ph
Stratification afterwards, obtains sour water layer and organic layer, and gained organic layer is added water washing to ph to 6 ~ 7, the water after wash with
Organic faciess b；
The amount that the addition of wherein cyanide presses step 1. middle 3- chloro- 2-r base -5- trifluoromethyl pyridine calculates, cyanide and 3-
The mol ratio of chloro- 2-r base -5- trifluoromethyl pyridine is 1 ~ 1.5:1；
Cyanide and solvent b mass volume ratio are 1g:10 ~ 15ml, and the volume ratio of solvent b and water is 2 ~ 10:1；
Described cyanide is hydrocyanic acid, ammonium cyanide, potassium cyanide, Cyanogran., lithium cyanide, magnesium cyanide or Cyanogas (Am. Cyanamid).；
Described solvent b is dichloromethane, dichloroethanes or chloroform；
3. by step 2. gained organic faciess b air-distillation vacuum distillation to after 60 DEG C, vacuum 2mmhg, kettle temperature 70 ~ 120 are collected
DEG C fraction be 3- chloro- 2- cyano group -5- trifluoromethyl pyridine.
Preferably, the water after step 2. middle washing and sour water layer are merged and obtain merging sour water layer, be then passed through following step
Rapid process reclaims activator: will merge sour water layer and add sodium hydroxide to adjust ph to 8 ~ 9, and be subsequently adding three extractions of dichloromethane
Take, merging sour water layer and the volume ratio of dichloromethane during extraction every time is 1:1, merges organic faciess, is added to steaming by organic for gained
Evaporate kettle, dichloromethane is reclaimed in air-distillation, when kettle temperature rises to 60 DEG C, close heating, stand and be 20 ~ 30 DEG C to temperature, then
Add ethyl acetate in distillating still, be heated to flowing back, then distillating still be cooled to 0 ~ 5 DEG C, sucking filtration, obtain filter cake, by institute
Obtain filter cake drying under reduced pressure and obtain activator；Wherein ethyl acetate and the volume ratio of organic faciess are 1:1.
Preferably, described cyanide is Cyanogran. or potassium cyanide.
Preferably, described activator is 4-dimethylaminopyridine.
Preferably, the volume ratio of solvent b and water is 5 ~ 8:1, and described solvent b is dichloromethane.
Preferably, described solvent a is acetone or butanone.
Preferably, described r base is chlorine.
The preparation method of further preferred 3- chloro- 2- cyano group -5- trifluoromethyl pyridine, comprises the following steps:
1. 2,3- bis- chloro-5-trifluoromethylpyridine is dissolved in solvent a, is then added thereto to activator, is heated to reflux 5 little
When, it is cooled to 25 DEG C, obtains reactant liquor, gained reacting liquid filtering obtains filter cake, gained filter cake is vacuum dried at 45 DEG C
1.5 hours, obtain organic salt；
Wherein 2,3- bis- chloro-5-trifluoromethylpyridine and the mol ratio of activator are 1:2；3- chloro- 2-r base -5- trifluoromethyl pyrrole
The mass volume ratio of pyridine and solvent a is 1g:20ml；
Described solvent a is acetone；Described activator is 4-dimethylaminopyridine；
2. by step, 1. gained organic salt, cyanide are added in solvent b and water, and at 10 DEG C, stirring reaction 2 hours, are mixed
Close liquid, gained mixed liquor stratification obtains organic faciess a；By gained organic faciess a addition hydrochloric acid adjust its ph be 4 after stand
Layering, obtains sour water layer and organic layer, and gained organic layer is added water washing to ph to 6, the water after being washed and organic faciess b；
Wherein cyanide addition press step 1. in 2,3- bis- chloro-5-trifluoromethylpyridine amount calculate, cyanide and 2,3-
The mol ratio of two chloro-5-trifluoromethylpyridines is 1.1:1；
Cyanide and solvent b mass volume ratio are 1g:12ml, and the volume ratio of solvent b and water is 5:1；
Described cyanide is potassium cyanide；Described solvent b is dichloromethane；
3. by step 2. gained organic faciess b air-distillation vacuum distillation to after 60 DEG C, vacuum 2mmhg, kettle temperature 70 ~ 120 are collected
DEG C fraction be 3- chloro- 2- cyano group -5- trifluoromethyl pyridine；
4. the water after step 2. middle washing and sour water layer are merged and obtain merging sour water layer, add sodium hydroxide to merging sour water layer
Adjust ph to 8, be subsequently adding three extractions of dichloromethane, merging sour water layer and the volume ratio of dichloromethane during extraction every time is 1:
1, merge organic faciess, be added to distillating still by organic for gained, dichloromethane is reclaimed in air-distillation, when kettle temperature rises to 60 DEG C, close
Close heating, stand and be 25 DEG C to temperature, then in distillating still, add ethyl acetate, be heated to flowing back, then distillating still dropped
Temperature to 0 ~ 5 DEG C, sucking filtration, obtain filter cake, gained filter cake drying under reduced pressure obtained activator；The body of wherein ethyl acetate and organic faciess
Long-pending ratio is 1:1.
The present invention has the advantage that compared to existing technology
The preparation method of the 3- chloro- 2- cyano group -5- trifluoromethyl pyridine of the present invention includes salt-forming reaction and cyanalation reaction two step,
The yield of two steps can reach more than 85%, and the consumption of cyanide is only 1 ~ 1.5 molar equivalent, the use of the cyanide of minimizing,
Reduce the difficulty of the pollution to environment and improvement；The preparation technology of the present invention avoids the nitrile solvents such as acetonitrile and propionitrile, and
Using low poison solvents such as dichloromethane insoluble,practically with water, it is skillfully constructed it is easy to be layered, and wash away unreacted cyanide,
And solvent being recycled and reused, thus reducing production cost, decreasing environmental pollution；The preparation side of the present invention
Method operating procedure is few, and the requirement to instrument and equipment is low, and the waste liquid of production is easily processed, with low cost, has huge industry raw
Produce and be worth.
Specific embodiment
It is an object of the invention to provide the preparation method of 3- chloro- 2- cyano group -5- trifluoromethyl pyridine, by following technical side
Case is realized:
A kind of preparation method of 3- chloro- 2- cyano group -5- trifluoromethyl pyridine, comprises the following steps:
1. chloro- for 3- 2-r base -5- trifluoromethyl pyridine is dissolved in solvent a, is then added thereto to activator, is heated to reflux 4 ~ 6
Hour, it is cooled to 20 ~ 30 DEG C, obtains reactant liquor, gained reacting liquid filtering obtains filter cake, by gained filter cake at 40 ~ 50 DEG C
Vacuum drying 1 ~ 2 hour, obtains organic salt；
Wherein 3- chloro- 2-r base -5- trifluoromethyl pyridine is 1:1 ~ 3 with the mol ratio of activator；3- chloro- 2-r base -5- fluoroform
The mass volume ratio of yl pyridines and solvent a is 1g:15 ~ 25ml；
Described r base is chlorine, bromine or fluorine；Described solvent a be methanol, ethanol, acetone, butanone, dichloromethane, dichloroethanes or
Chloroform；Described activator is triethylamine, 4- pyrollidinopyridine or 4-dimethylaminopyridine；
2. by step, 1. gained organic salt, cyanide are added in solvent b and water, and at 0 ~ 80 DEG C, stirring reaction 2 ~ 3 hours, obtain
To mixed liquor, gained mixed liquor stratification obtains organic faciess a；It is 2 ~ 4 that gained organic faciess a addition hydrochloric acid is adjusted its ph
Stratification afterwards, obtains sour water layer and organic layer, and gained organic layer is added water washing to ph to 6 ~ 7, the water after wash with
Organic faciess b；
The amount that the addition of wherein cyanide presses step 1. middle 3- chloro- 2-r base -5- trifluoromethyl pyridine calculates, cyanide and 3-
The mol ratio of chloro- 2-r base -5- trifluoromethyl pyridine is 1 ~ 1.5:1；
Cyanide and solvent b mass volume ratio are 1g:10 ~ 15ml, and the volume ratio of solvent b and water is 2 ~ 10:1；
Described cyanide is hydrocyanic acid, ammonium cyanide, potassium cyanide, Cyanogran., lithium cyanide, magnesium cyanide or Cyanogas (Am. Cyanamid).；
Described solvent b is dichloromethane, dichloroethanes or chloroform；
3. by step 2. gained organic faciess b air-distillation vacuum distillation to after 60 DEG C, vacuum 2mmhg, kettle temperature 70 ~ 120 are collected
DEG C fraction be 3- chloro- 2- cyano group -5- trifluoromethyl pyridine.
Preferably, the water after step 2. middle washing and sour water layer are merged and obtain merging sour water layer, be then passed through following step
Rapid process reclaims activator: will merge sour water layer and add sodium hydroxide to adjust ph to 8 ~ 9, and be subsequently adding three extractions of dichloromethane
Take, merging sour water layer and the volume ratio of dichloromethane during extraction every time is 1:1, merges organic faciess, is added to steaming by organic for gained
Evaporate kettle, dichloromethane is reclaimed in air-distillation, when kettle temperature rises to 60 DEG C, close heating, stand and be 20 ~ 30 DEG C to temperature, then
Add ethyl acetate in distillating still, be heated to flowing back, then distillating still be cooled to 0 ~ 5 DEG C, sucking filtration, obtain filter cake, by institute
Obtain filter cake drying under reduced pressure and obtain activator；Wherein ethyl acetate and the volume ratio of organic faciess are 1:1.
Preferably, described cyanide is Cyanogran. or potassium cyanide.
Preferably, described activator is 4-dimethylaminopyridine.
Preferably, the volume ratio of solvent b and water is 5 ~ 8:1, and described solvent b is dichloromethane.
Preferably, described solvent a is acetone or butanone.
Preferably, described r base is chlorine.
The preparation method of further preferred 3- chloro- 2- cyano group -5- trifluoromethyl pyridine, comprises the following steps:
1. 2,3- bis- chloro-5-trifluoromethylpyridine is dissolved in solvent a, is then added thereto to activator, is heated to reflux 5 little
When, it is cooled to 25 DEG C, obtains reactant liquor, gained reacting liquid filtering obtains filter cake, gained filter cake is vacuum dried at 45 DEG C
1.5 hours, obtain organic salt；
Wherein 2,3- bis- chloro-5-trifluoromethylpyridine and the mol ratio of activator are 1:2；3- chloro- 2-r base -5- trifluoromethyl pyrrole
The mass volume ratio of pyridine and solvent a is 1g:20ml；
Described solvent a is acetone；Described activator is 4-dimethylaminopyridine；
2. by step, 1. gained organic salt, cyanide are added in solvent b and water, and at 10 DEG C, stirring reaction 2 hours, are mixed
Close liquid, gained mixed liquor stratification obtains organic faciess a；By gained organic faciess a addition hydrochloric acid adjust its ph be 4 after stand
Layering, obtains sour water layer and organic layer, and gained organic layer is added water washing to ph to 6, the water after being washed and organic faciess b；
Wherein cyanide addition press step 1. in 2,3- bis- chloro-5-trifluoromethylpyridine amount calculate, cyanide and 2,3-
The mol ratio of two chloro-5-trifluoromethylpyridines is 1.1:1；
Cyanide and solvent b mass volume ratio are 1g:12ml, and the volume ratio of solvent b and water is 5:1；
Described cyanide is potassium cyanide；Described solvent b is dichloromethane；
3. by step 2. gained organic faciess b air-distillation vacuum distillation to after 60 DEG C, vacuum 2mmhg, kettle temperature 70 ~ 120 are collected
DEG C fraction be 3- chloro- 2- cyano group -5- trifluoromethyl pyridine；
4. the water after step 2. middle washing and sour water layer are merged and obtain merging sour water layer, add sodium hydroxide to merging sour water layer
Adjust ph to 8, be subsequently adding three extractions of dichloromethane, merging sour water layer and the volume ratio of dichloromethane during extraction every time is 1:
1, merge organic faciess, be added to distillating still by organic for gained, dichloromethane is reclaimed in air-distillation, when kettle temperature rises to 60 DEG C, close
Close heating, stand and be 25 DEG C to temperature, then in distillating still, add ethyl acetate, be heated to flowing back, then distillating still dropped
Temperature to 0 ~ 5 DEG C, sucking filtration, obtain filter cake, gained filter cake drying under reduced pressure obtained activator；The body of wherein ethyl acetate and organic faciess
Long-pending ratio is 1:1.
The activator of the present invention is nucleophilic tertiary carbon material, specially tertiary amine or can contain substituted pyridine, such as triethylamine etc.
Trialkylamine, 4- pyrollidinopyridine, dialkylaminopyridinium, particularly dimethylamino naphthyridine, 4-dimethylaminopyridine
(dmap), n- alkyl imidazole or n- alkyl triazole.
Below in conjunction with specific embodiment, the invention will be further described.
Embodiment 1
A kind of preparation method of 3- chloro- 2- cyano group -5- trifluoromethyl pyridine, comprises the following steps:
1. chloro- for 1.82kg3- 2- chloro-5-trifluoromethylpyridine is dissolved in 27.231l methanol, is then added thereto to
1.0119kg triethylamine, is heated to reflux 4 hours, is cooled to 20 DEG C, obtains reactant liquor, gained reacting liquid filtering obtains filter cake,
Gained filter cake is vacuum dried 1 hour at 40 DEG C, obtains organic salt；
2. by step, 1. gained organic salt, 0.27kg hydrocyanic acid are added in 2.7l dichloromethane and 1.35l water, stir at 0 DEG C
Mix reaction 3 hours, obtain mixed liquor, gained mixed liquor stratification obtains organic faciess a；Gained organic faciess a are added hydrochloric acid
Adjusting its ph is stratification after 2, obtains sour water layer and organic layer, gained organic layer is added water washing to ph to 6, is washed
Water afterwards and organic faciess b；
3. by step 2. gained organic faciess b air-distillation vacuum distillation to after 60 DEG C, vacuum 2mmhg, kettle temperature 70 ~ 120 are collected
DEG C fraction be 3- chloro- 2- cyano group -5- trifluoromethyl pyridine 1.77kg, yield 85.7%.
Embodiment 2
A kind of preparation method of 3- chloro- 2- cyano group -5- trifluoromethyl pyridine, comprises the following steps:
1. bromo- for chloro- for 2.60kg3- 2- 5- trifluoromethyl pyridine is dissolved in 65l ethanol, is then added thereto to 4.47kg4- pyrrole
Cough up alkyl pyridine, be heated to reflux 6 hours, be cooled to 30 DEG C, obtain reactant liquor, gained reacting liquid filtering obtains filter cake, by institute
Obtain filter cake to be vacuum dried 2 hours at 50 DEG C, obtain organic salt；
2. by step, 1. gained organic salt, 0.525kg lithium cyanide are added in 7.88l dichloroethanes and 788ml water, at 80 DEG C
Stirring reaction 2 hours, obtains mixed liquor, and gained mixed liquor stratification obtains organic faciess a；Gained organic faciess a are added salt
It is stratification after 4 that acid adjusts its ph, obtains sour water layer and organic layer, gained organic layer is added water washing to ph to 7, is washed
Water after washing and organic faciess b；
3. by step 2. gained organic faciess b air-distillation vacuum distillation to after 60 DEG C, vacuum 2mmhg, kettle temperature 70 ~ 120 are collected
DEG C fraction be 3- chloro- 2- cyano group -5- trifluoromethyl pyridine 1.82kg, yield 88.1%.
Embodiment 3
A kind of preparation method of 3- chloro- 2- cyano group -5- trifluoromethyl pyridine, comprises the following steps:
1. fluoro- for chloro- for 2.745kg3- 2- 5- trifluoromethyl pyridine is dissolved in 49.41l acetone, is then added thereto to
1.478kg4- dimethyl aminopyridine, is heated to reflux 5 hours, is cooled to 24 DEG C, obtains reactant liquor, by gained reacting liquid filtering,
Obtain filter cake, gained filter cake is vacuum dried 1.5 hours at 44 DEG C, obtains organic salt；
2. by step, 1. gained organic salt, 0.588kg Cyanogran. are added in 8.232l chloroform and 1.029l water, at 20 DEG C
Lower stirring reaction 2.5 hours, obtains mixed liquor, and gained mixed liquor stratification obtains organic faciess a；Gained organic faciess a are added
Enter hydrochloric acid to adjust its ph is stratification after 3, obtains sour water layer and organic layer, and gained organic layer is added water washing to ph to 6.5,
Water after being washed and organic faciess b；
3. by step 2. gained organic faciess b air-distillation vacuum distillation to after 60 DEG C, vacuum 2mmhg, kettle temperature 70 ~ 120 are collected
DEG C fraction be 3- chloro- 2- cyano group -5- trifluoromethyl pyridine 1.84kg, yield 89%.
Embodiment 4
A kind of preparation method of 3- chloro- 2- cyano group -5- trifluoromethyl pyridine, comprises the following steps:
1. by 2.16kg2,3- bis- chloro-5-trifluoromethylpyridine is dissolved in 43.2l acetone, is then added thereto to activator
2.46kg4- dimethyl aminopyridine, is heated to reflux 5 hours, is cooled to 25 DEG C, obtains reactant liquor, by gained reacting liquid filtering,
Obtain filter cake, gained filter cake is vacuum dried 1.5 hours at 45 DEG C, obtains organic salt；
2. by step, 1. gained organic salt, 0.716kg potassium cyanide are added in 8.60l dichloromethane and 1.72l water, at 10 DEG C
Stirring reaction 2 hours, obtains mixed liquor, and gained mixed liquor stratification obtains organic faciess a；Gained organic faciess a are added salt
It is stratification after 4 that acid adjusts its ph, obtains sour water layer and organic layer, gained organic layer is added water washing to ph to 6, is washed
Water after washing and organic faciess b；
3. by step 2. gained organic faciess b air-distillation vacuum distillation to after 60 DEG C, vacuum 2mmhg, kettle temperature 70 ~ 120 are collected
DEG C fraction be 3- chloro- 2- cyano group -5- trifluoromethyl pyridine 1.88kg, yield 91%；
4. the water after step 2. middle washing and sour water layer are merged and obtain merging sour water layer, add sodium hydroxide to merging sour water layer
Adjust ph to 8, be subsequently adding three extractions of dichloromethane, merging sour water layer and the volume ratio of dichloromethane during extraction every time is 1:
1, merge organic faciess, be added to distillating still by organic for gained, dichloromethane is reclaimed in air-distillation, when kettle temperature rises to 60 DEG C, close
Close heating, stand and be 25 DEG C to temperature, then in distillating still, add ethyl acetate, be heated to flowing back, then distillating still dropped
Temperature to 0 ~ 5 DEG C, sucking filtration, obtain filter cake, gained filter cake drying under reduced pressure obtained activator；The body of wherein ethyl acetate and organic faciess
Long-pending ratio is 1:1.
Embodiment 5
Water after embodiment 3 step 2. middle washing and sour water layer are merged and obtains merging sour water layer, be then passed through at following steps
Reason reclaims 4- pyrollidinopyridine: will merge sour water layer and add sodium hydroxide to adjust ph to 8, and be subsequently adding three extractions of dichloromethane
Take, merging sour water layer and the volume ratio of dichloromethane during extraction every time is 1:1, merges organic faciess, is added to steaming by organic for gained
Evaporate kettle, dichloromethane is reclaimed in air-distillation, when kettle temperature rises to 60 DEG C, close heating, stand and be 30 DEG C to temperature, then to steaming
Evaporate addition ethyl acetate in kettle, be heated to flowing back, then distillating still be cooled to 0 ~ 5 DEG C, sucking filtration, obtain filter cake, gained is filtered
Cake drying under reduced pressure obtains 4- pyrollidinopyridine；Wherein ethyl acetate and the volume ratio of organic faciess are 1:1.
Claims (8)
1. a kind of 3- chloro- 2- cyano group -5- trifluoromethyl pyridine preparation method it is characterised in that: comprise the following steps:
1. chloro- for 3- 2-r base -5- trifluoromethyl pyridine is dissolved in solvent a, is then added thereto to activator, is heated to reflux 4 ~ 6
Hour, it is cooled to 20 ~ 30 DEG C, obtains reactant liquor, gained reacting liquid filtering obtains filter cake, by gained filter cake at 40 ~ 50 DEG C
Vacuum drying 1 ~ 2 hour, obtains organic salt；
Wherein 3- chloro- 2-r base -5- trifluoromethyl pyridine is 1:1 ~ 3 with the mol ratio of activator；3- chloro- 2-r base -5- fluoroform
The mass volume ratio of yl pyridines and solvent a is 1g:15 ~ 25ml；
Described r base is chlorine, bromine or fluorine；Described solvent a be methanol, ethanol, acetone, butanone, dichloromethane, dichloroethanes or
Chloroform；Described activator is triethylamine, 4- pyrollidinopyridine or 4-dimethylaminopyridine；
2. by step, 1. gained organic salt, cyanide are added in solvent b and water, and at 0 ~ 80 DEG C, stirring reaction 2 ~ 3 hours, obtain
To mixed liquor, gained mixed liquor stratification obtains organic faciess a；It is 2 ~ 4 that gained organic faciess a addition hydrochloric acid is adjusted its ph
Stratification afterwards, obtains sour water layer and organic layer, and gained organic layer is added water washing to ph to 6 ~ 7, the water after wash with
Organic faciess b；
The amount that the addition of wherein cyanide presses step 1. middle 3- chloro- 2-r base -5- trifluoromethyl pyridine calculates, cyanide and 3-
The mol ratio of chloro- 2-r base -5- trifluoromethyl pyridine is 1 ~ 1.5:1；
Cyanide and solvent b mass volume ratio are 1g:10 ~ 15ml, and the volume ratio of solvent b and water is 2 ~ 10:1；
Described cyanide is hydrocyanic acid, ammonium cyanide, potassium cyanide, Cyanogran., lithium cyanide, magnesium cyanide or Cyanogas (Am. Cyanamid).；
Described solvent b is dichloromethane, dichloroethanes or chloroform；
3. by step 2. gained organic faciess b air-distillation vacuum distillation to after 60 DEG C, vacuum 2mmhg, kettle temperature 70 ~ 120 are collected
DEG C fraction be 3- chloro- 2- cyano group -5- trifluoromethyl pyridine.
2. 3- according to claim 1 chloro- 2- cyano group -5- trifluoromethyl pyridine preparation method it is characterised in that: will walk
Water after rapid 2. middle washing and sour water layer merging obtain merging sour water layer, are then passed through steps of processing and reclaim activator: will
Merging sour water layer adds sodium hydroxide to adjust ph to 8 ~ 9, is subsequently adding three extractions of dichloromethane, merges sour water during extraction every time
The volume ratio of layer and dichloromethane is 1:1, merges organic faciess, is added to distillating still by organic for gained, dichloro is reclaimed in air-distillation
Methane, when kettle temperature rises to 60 DEG C, closes heating, stands and be 20 ~ 30 DEG C to temperature, then adds acetic acid second in distillating still
Ester, is heated to flowing back, then distillating still is cooled to 0 ~ 5 DEG C, and sucking filtration obtains filter cake, gained filter cake drying under reduced pressure is lived
Agent；Wherein ethyl acetate and the volume ratio of organic faciess are 1:1.
3. 3- according to claim 1 chloro- 2- cyano group -5- trifluoromethyl pyridine preparation method it is characterised in that: described
Cyanide is Cyanogran. or potassium cyanide.
4. 3- according to claim 1 chloro- 2- cyano group -5- trifluoromethyl pyridine preparation method it is characterised in that: described
Activator is 4-dimethylaminopyridine.
5. 3- according to claim 1 chloro- 2- cyano group -5- trifluoromethyl pyridine preparation method it is characterised in that: solvent
The volume ratio of b and water is 5 ~ 8:1, and described solvent b is dichloromethane.
6. 3- according to claim 1 chloro- 2- cyano group -5- trifluoromethyl pyridine preparation method it is characterised in that: described
Solvent a be acetone or butanone.
7. 3- according to claim 1 chloro- 2- cyano group -5- trifluoromethyl pyridine preparation method it is characterised in that: described
R base be chlorine.
8. 3- according to claim 1 chloro- 2- cyano group -5- trifluoromethyl pyridine preparation method it is characterised in that: include
Following steps:
1. 2,3- bis- chloro-5-trifluoromethylpyridine is dissolved in solvent a, is then added thereto to activator, is heated to reflux 5 little
When, it is cooled to 25 DEG C, obtains reactant liquor, gained reacting liquid filtering obtains filter cake, gained filter cake is vacuum dried at 45 DEG C
1.5 hours, obtain organic salt；
Wherein 2,3- bis- chloro-5-trifluoromethylpyridine and the mol ratio of activator are 1:2；3- chloro- 2-r base -5- trifluoromethyl pyrrole
The mass volume ratio of pyridine and solvent a is 1g:20ml；
Described solvent a is acetone；Described activator is 4-dimethylaminopyridine；
2. by step, 1. gained organic salt, cyanide are added in solvent b and water, and at 10 DEG C, stirring reaction 2 hours, are mixed
Close liquid, gained mixed liquor stratification obtains organic faciess a；By gained organic faciess a addition hydrochloric acid adjust its ph be 4 after stand
Layering, obtains sour water layer and organic layer, and gained organic layer is added water washing to ph to 6, the water after being washed and organic faciess b；
Wherein cyanide addition press step 1. in 2,3- bis- chloro-5-trifluoromethylpyridine amount calculate, cyanide and 2,3-
The mol ratio of two chloro-5-trifluoromethylpyridines is 1.1:1；
Cyanide and solvent b mass volume ratio are 1g:12ml, and the volume ratio of solvent b and water is 5:1；
Described cyanide is potassium cyanide；Described solvent b is dichloromethane；
3. by step 2. gained organic faciess b air-distillation vacuum distillation to after 60 DEG C, vacuum 2mmhg, kettle temperature 70 ~ 120 are collected
DEG C fraction be 3- chloro- 2- cyano group -5- trifluoromethyl pyridine；
4. the water after step 2. middle washing and sour water layer are merged and obtain merging sour water layer, add sodium hydroxide to merging sour water layer
Adjust ph to 8, be subsequently adding three extractions of dichloromethane, merging sour water layer and the volume ratio of dichloromethane during extraction every time is 1:
1, merge organic faciess, be added to distillating still by organic for gained, dichloromethane is reclaimed in air-distillation, when kettle temperature rises to 60 DEG C, close
Close heating, stand and be 25 DEG C to temperature, then in distillating still, add ethyl acetate, be heated to flowing back, then distillating still dropped
Temperature to 0 ~ 5 DEG C, sucking filtration, obtain filter cake, gained filter cake drying under reduced pressure obtained activator；The body of wherein ethyl acetate and organic faciess
Long-pending ratio is 1:1.
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| CN112390747A (en) * | 2020-11-03 | 2021-02-23 | 内蒙古佳瑞米精细化工有限公司 | Combined preparation method of 2-cyano-3-chloro-5-trifluoromethylpyridine and succinonitrile |
| CN112390746A (en) * | 2020-11-03 | 2021-02-23 | 内蒙古佳瑞米精细化工有限公司 | Method for inhibiting generation of 2-cyano-3-chloro-5-trifluoromethylpyridine precursor impurity |
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| CN112390747A (en) * | 2020-11-03 | 2021-02-23 | 内蒙古佳瑞米精细化工有限公司 | Combined preparation method of 2-cyano-3-chloro-5-trifluoromethylpyridine and succinonitrile |
| CN112390746A (en) * | 2020-11-03 | 2021-02-23 | 内蒙古佳瑞米精细化工有限公司 | Method for inhibiting generation of 2-cyano-3-chloro-5-trifluoromethylpyridine precursor impurity |
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