CN109232412A - The preparation method of the chloro- nicotinonitrile of 2- - Google Patents
The preparation method of the chloro- nicotinonitrile of 2- Download PDFInfo
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- CN109232412A CN109232412A CN201811256987.8A CN201811256987A CN109232412A CN 109232412 A CN109232412 A CN 109232412A CN 201811256987 A CN201811256987 A CN 201811256987A CN 109232412 A CN109232412 A CN 109232412A
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- chloro
- nicotinonitrile
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- added dropwise
- oxo
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D213/84—Nitriles
- C07D213/85—Nitriles in position 3
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pyridine Compounds (AREA)
Abstract
The invention proposes a kind of preparation methods of the chloro- nicotinonitrile of 2-, it include: that N- oxo niacinamide is dissolved in organic solvent, it maintains 25 ± 5 DEG C and methylsufonyl chloride is added dropwise into the organic solvent dissolved with N- oxo niacinamide under nitrogen protection, it is added dropwise, 1 ± 0.5h of insulated and stirred, maintain 25 ± 5 DEG C of dropwise addition organic bases, it is added dropwise, 1 ± 0.5h of insulated and stirred, it is warming up to 65 ± 10 DEG C, 4 ± 1h of insulated and stirred, heat preservation finishes to obtain chloride reaction solution, chloride reaction solution is evaporated under reduced pressure, until without the outflow of visible liquid, add water, temperature is controlled at 65 ± 5 DEG C, stir 1 ± 0.5h, it is cooled to 30 ± 5 DEG C, stir 30 ± 10min, the chloro- nicotinonitrile wet product of 2- is obtained by filtration, preparation method of the present invention is simple, it selects Raw material is simple easy, and pollution is lower, while can be improved yield, has good application value.
Description
Technical field
The present invention relates to chemical intermediate preparation technical field more particularly to a kind of preparation sides of the chloro- nicotinonitrile of 2-
Method.
Background technique
2- chlorine apellagrin is important fine-chemical intermediate, can be used for a variety of drugs, insecticide, fungicide and herbicide
Intermediate feed, the chloro- nicotinonitrile of 2- is then the key intermediate for preparing 2- chlorine apellagrin.
The process of the synthesis chloro- nicotinonitrile of 2- generallys use nicotinonitrile oxidation preparation N- oxo nicotinoyl at present
The chloro- nicotinonitrile of 2- is prepared using N- oxo niacinamide chloro in amine, which, which is now subjected to, is widely applied,
However its technical process still has more deficiency, the yield of product is still not high enough.
Summary of the invention
In view of this, the invention proposes a kind of technique it is simpler rationally, the chloro- 3- cyano pyrrole of the higher 2- of product yield
The preparation method of pyridine.
The technical scheme of the present invention is realized as follows: the present invention provides a kind of preparation sides of the chloro- nicotinonitrile of 2-
Method, comprising: N- oxo niacinamide is dissolved in organic solvent and obtains N- oxo nicotinamide soln, maintains 25 ± 5 DEG C and in nitrogen
Methylsufonyl chloride is added dropwise into the organic solvent dissolved with N- oxo nicotinamide soln under protection, is added dropwise, insulated and stirred 1 ±
0.5h maintains 25 ± 5 DEG C and organic base is added dropwise into N- oxo nicotinamide soln, is added dropwise, and protects to N- oxo nicotinamide soln
Temperature 1 ± 0.5h of stirring, is warming up to 65 ± 10 DEG C, 4 ± 1h of insulated and stirred, heat preservation finishes to obtain chloride reaction solution, to chloride
Reaction solution is evaporated under reduced pressure, and until without the outflow of visible liquid, adds water, controls temperature at 65 ± 5 DEG C, stirs 1 ± 0.5h, drop
Temperature stirs 30 ± 10min, the chloro- nicotinonitrile wet product of 2- is obtained by filtration to 30 ± 5 DEG C.
On the basis of above technical scheme, it is preferred that by mass percent be 100% in terms of, the N- oxo niacinamide:
Organic solvent: methylsufonyl chloride: organic base: the mass ratio of water is 1:(5-10): (1.5-2.5): (0.4-1.5): (2-4).
On the basis of above technical scheme, it is preferred that the temperature of the vacuum distillation be 35~65 DEG C, pressure be 20~
40kPa。
On the basis of above technical scheme, it is preferred that the organic solvent is methylene chloride or chloroform.
Still more preferably, the organic base is triethylamine or Tri-n-Propylamine.
On the basis of above technical scheme, it is preferred that the time for adding of the methylsufonyl chloride is 20-40min.
On the basis of above technical scheme, it is preferred that the time for adding of the organic base is 30-60min.
On the basis of above technical scheme, it is preferred that the time for being warming up to 65 ± 10 DEG C is 2-3h.
The preparation method of the chloro- nicotinonitrile of 2- of the invention has the advantages that compared with the existing technology
The present invention tracks comparison by TLC and uses different heating rates, different dropping temperatures and different time for adding
It was found that the conversion ratio of reaction can be made to be optimal value when carrying out dropwise addition methylsufonyl chloride and organic base using 25 DEG C, and control
Heating rate also can be improved the conversion ratio of the chloro- nicotinonitrile of 2- in 10~15 DEG C/h, to improve yield；
Preparation method of the present invention is simple, it is simple easy to select raw material, and pollution is lower, while can be improved yield, has
Good application value.
Specific embodiment
Below in conjunction with embodiment of the present invention, the technical solution in embodiment of the present invention is carried out clearly and completely
Description, it is clear that described embodiment is only some embodiments of the invention, rather than whole embodiments.Base
Embodiment in the present invention, it is obtained by those of ordinary skill in the art without making creative efforts all
Other embodiments shall fall within the protection scope of the present invention.
Embodiment 1:
It weighs 50g methylene chloride to be added in 250ml three-necked flask, weighs 10gN- oxo niacinamide and be added to three mouthfuls of burnings
In bottle, control temperature is passed through nitrogen displacement into three-necked flask in 25 ± 5 DEG C, stirring and dissolving, and keeps in three-necked flask as nitrogen
Gas atmosphere, weighs 15g methylsufonyl chloride and is added dropwise in three-necked flask, and time for adding 22min is added dropwise, insulated and stirred
30min, keeping temperature is 25 ± 5 DEG C, weighs 4g triethylamine and is added dropwise in three-necked flask, time for adding 41min is dripped
Finish, insulated and stirred 30min is warming up to 55 DEG C, heating-up time 2h10min, insulated and stirred 3h, obtains chloride reaction solution, will
Chloride reaction solution, which is transferred in revolving bottle, to be evaporated under reduced pressure, and revolving temperature is 35 DEG C, and revolving pressure is 20kPa, until can not
See that liquid flows out, stop revolving, measure 20ml water and revolving bottle is added, be warming up to 60 DEG C, stir 30min, is cooled to 25 DEG C, stirring
The chloro- nicotinonitrile wet product of 2- is obtained by filtration in 20min.
Embodiment 2:
It weighs 80g chloroform to be added in 250ml three-necked flask, weighs 10gN- oxo niacinamide and be added in three-necked flask,
Temperature is controlled at 25 ± 5 DEG C, stirring and dissolving is passed through nitrogen displacement into three-necked flask, and keeps in three-necked flask as nitrogen gas
Atmosphere weighs 20g methylsufonyl chloride and is added dropwise in three-necked flask, and time for adding 25min is added dropwise, insulated and stirred 1h, keeps
Temperature is 25 ± 5 DEG C, weighs 10g Tri-n-Propylamine and is added dropwise in three-necked flask, time for adding 35min is added dropwise, and heat preservation is stirred
1h is mixed, 65 DEG C, heating-up time 2h30min, insulated and stirred 4h is warming up to and obtains chloride reaction solution, by chloride reaction solution
It is transferred in revolving bottle and is evaporated under reduced pressure, revolving temperature is 50 DEG C, and revolving pressure is that 30kPa stops until flowing out without visible liquid
Spin-ended steaming measures 30ml water and revolving bottle is added, be warming up to 65 DEG C, stir 1h, be cooled to 30 DEG C, stirs 30min, 2- is obtained by filtration
Chloro- nicotinonitrile wet product.
Embodiment 3:
It weighs 100g methylene chloride to be added in 250ml three-necked flask, weighs 10gN- oxo niacinamide and be added to three mouthfuls of burnings
In bottle, control temperature is passed through nitrogen displacement into three-necked flask in 25 ± 5 DEG C, stirring and dissolving, and keeps in three-necked flask as nitrogen
Gas atmosphere, weighs 25g methylsufonyl chloride and is added dropwise in three-necked flask, and time for adding 36min is added dropwise, insulated and stirred
1.5h, keeping temperature is 25 ± 5 DEG C, weighs 15g triethylamine and is added dropwise in three-necked flask, time for adding 55min is dripped
Finish, insulated and stirred 1.5h is warming up to 75 DEG C, heating-up time 3h, insulated and stirred 5h and obtains chloride reaction solution, by chloride
Reaction solution is transferred in revolving bottle and is evaporated under reduced pressure, and revolving temperature is 65 DEG C, and revolving pressure is 40kPa, until without visible liquid
Outflow stops revolving, measures 40ml water and revolving bottle is added, be warming up to 70 DEG C, stir 1.5h, be cooled to 35 DEG C, stir 40min,
The chloro- nicotinonitrile wet product of 2- is obtained by filtration.
Comparative example:
It weighs 100g chloroform to be added in 250ml three-necked flask, weighs 10gN- oxo niacinamide and be added to three-necked flask
In, temperature is controlled at 25 ± 5 DEG C, and stirring and dissolving weighs 25g methylsufonyl chloride and is added dropwise in three-necked flask, and time for adding is
2min is added dropwise, insulated and stirred 1.5h, and keeping temperature is 25 ± 5 DEG C, weighs 15g triethylamine and is added dropwise in three-necked flask, drips
It is 5min between added-time, is added dropwise, insulated and stirred 1.5h, is warming up to 75 DEG C, heating-up time 30min, insulated and stirred 5h and obtains
Chloride reaction solution is transferred in revolving bottle and is evaporated under reduced pressure by chloride reaction solution, and revolving temperature is 65 DEG C, rotates pressure
Stop revolving until flowing out without visible liquid for 40kPa, measure 40ml water and revolving bottle is added, be warming up to 70 DEG C, stirs 1.5h, drop
Temperature stirs 40min, the chloro- nicotinonitrile wet product of 2- is obtained by filtration to 35 DEG C.
The chloro- nicotinonitrile wet product drying of 2- prepared by above-described embodiment and comparative example, weighing, and to the 2- of drying
Chloro- nicotinonitrile carries out related substance detection, and correlated results is as follows:
| Project | Embodiment 1 | Embodiment 2 | Embodiment 3 | Comparative example |
| Yield/g | 9.29 | 9.25 | 9.39 | 8.60 |
| Yield/% | 95.2 | 94.8 | 96.3 | 88.2 |
| Related substance/% | 99.6 | 99.5 | 99.6 | 99.5 |
The foregoing is merely better embodiments of the invention, are not intended to limit the invention, all of the invention
Within spirit and principle, any modification, equivalent replacement, improvement and so on be should all be included in the protection scope of the present invention.
Claims (8)
1. a kind of preparation method of the chloro- nicotinonitrile of 2-, which is characterized in that the preparation method includes: by N- oxo nicotinoyl
Amine, which is dissolved in organic solvent, obtains N- oxo nicotinamide soln, maintains 25 ± 5 DEG C and under nitrogen protection to N- oxo niacinamide
Methylsufonyl chloride is added dropwise in solution, is added dropwise, 1 ± 0.5h of insulated and stirred, 25 ± 5 DEG C of maintenance is into N- oxo nicotinamide soln
Organic base is added dropwise, is added dropwise, to N- oxo nicotinamide soln 1 ± 0.5h of insulated and stirred, is warming up to 65 ± 10 DEG C, insulated and stirred
4 ± 1h, heat preservation are finished to obtain chloride reaction solution, be evaporated under reduced pressure to chloride reaction solution, until being without the outflow of visible liquid
Only, add water, control temperature at 65 ± 5 DEG C, stir 1 ± 0.5h, be cooled to 30 ± 5 DEG C, stir 30 ± 10min, 2- is obtained by filtration
Chloro- nicotinonitrile wet product.
2. the preparation method of the chloro- nicotinonitrile of 2- as described in claim 1, which is characterized in that be with mass percent
100% meter, the N- oxo niacinamide: organic solvent: methylsufonyl chloride: organic base: the mass ratio of water is 1:(5-10):
(1.5-2.5)∶(0.4-1.5)∶(2-4)。
3. the preparation method of the chloro- nicotinonitrile of 2- as described in claim 1, which is characterized in that the temperature of the vacuum distillation
Degree is 35~65 DEG C, and pressure is 20~40kPa.
4. the preparation method of the chloro- nicotinonitrile of 2- as described in claim 1, which is characterized in that the organic solvent is two
Chloromethanes or chloroform.
5. the preparation method of the chloro- nicotinonitrile of 2- as described in claim 1, which is characterized in that the organic base is three second
Amine or Tri-n-Propylamine.
6. the preparation method of the chloro- nicotinonitrile of 2- as described in claim 1, which is characterized in that the methylsufonyl chloride
Time for adding is 20-40min.
7. the preparation method of the chloro- nicotinonitrile of 2- as described in claim 1, which is characterized in that the dropwise addition of the organic base
Time is 30-60min.
8. the preparation method of the chloro- nicotinonitrile of 2- as described in claim 1, which is characterized in that described to be warming up to 65 ± 10
DEG C time be 2-3h.
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Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPH08301847A (en) * | 1995-04-28 | 1996-11-19 | Koei Chem Co Ltd | Production of 2-chloro-3-substituted pyridine |
| CN101108824A (en) * | 2007-08-17 | 2008-01-23 | 黑龙江省石油化学研究院 | Method for synthesizing 2- chlorine -3- cyanogen radical pyridine with 3- cyanogen radical pyridine |
| CN101117332A (en) * | 2006-08-04 | 2008-02-06 | 浙江医药股份有限公司新昌制药厂 | Preparation method of 2-chloronicotinic acid |
| CN101941943A (en) * | 2010-09-07 | 2011-01-12 | 浙江工业大学 | Synthesis method of 2-chlorine-3-cyanopyridine |
-
2018
- 2018-10-25 CN CN201811256987.8A patent/CN109232412A/en active Pending
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPH08301847A (en) * | 1995-04-28 | 1996-11-19 | Koei Chem Co Ltd | Production of 2-chloro-3-substituted pyridine |
| CN101117332A (en) * | 2006-08-04 | 2008-02-06 | 浙江医药股份有限公司新昌制药厂 | Preparation method of 2-chloronicotinic acid |
| CN101108824A (en) * | 2007-08-17 | 2008-01-23 | 黑龙江省石油化学研究院 | Method for synthesizing 2- chlorine -3- cyanogen radical pyridine with 3- cyanogen radical pyridine |
| CN101941943A (en) * | 2010-09-07 | 2011-01-12 | 浙江工业大学 | Synthesis method of 2-chlorine-3-cyanopyridine |
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Application publication date: 20190118 |