CN103896834B - 2-Cyano-3-cyclobutylpyridine and chemical synthesis method thereof - Google Patents
2-Cyano-3-cyclobutylpyridine and chemical synthesis method thereof Download PDFInfo
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- CN103896834B CN103896834B CN201410067820.2A CN201410067820A CN103896834B CN 103896834 B CN103896834 B CN 103896834B CN 201410067820 A CN201410067820 A CN 201410067820A CN 103896834 B CN103896834 B CN 103896834B
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- 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
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Abstract
The invention relates to a 2-cyano-3-cyclobutylpyridine and a chemical synthesis method thereof. According to the method, The 2-cyano-3-cyclobutylpyridine is prepared from 3-bromo-2-methylpyridine by virtue of four steps of reactions. The method is high in synthesis route yield and simple and convenient to operate.
Description
Technical field
The present invention relates to a kind of 2- cyano group -3- cyclobutyl pyridine and its chemical synthesis process.
Background technology
Small ring compound is combined with reactive precursor structure and can give the higher activity of a lot of medicines and drug effect.Especially near
Going deep into new drug development over year, is that the research of small ring compound especially cyclopropyl and cyclobutyl compound provides contract
Machine.
2- cyano group -3- cyclobutyl pyridine as a kind of important small ring compound, especially in various medicament research and development in have
Wilderness demand, therefore the study on the synthesis of this compound is had important practical significance.
Content of the invention
It is an object of the invention to provide a kind of efficient chemical synthetic method of 2- cyano group -3- cyclobutyl pyridine.
Technical scheme is as follows：
A kind of chemical synthesis process of 2- cyano group -3- cyclobutyl pyridine is it is characterised in that with 3- bromine-2-methylpyridine be
Raw material, has synthesized 2- cyano group -3- cyclobutyl pyridine through four-step reaction, and its synthetic route is as follows：
Described chemical synthesis process is：
（A）By 3- bromine-2-methylpyridine, Tetramethylene. base Grignard reagent and catalyst acetic acid palladium be added to dry ether or
In tetrahydrofuran solvent, reaction obtains 2- methyl -3- cyclobutyl pyridine；
（B）2- methyl -3- cyclobutyl pyridine and selenium dioxide are added in Isosorbide-5-Nitrae-dioxane solvent, temperature reaction,
Obtain 3- cyclobutyl -2- pyridine carboxaldehyde；
(C) by 3- cyclobutyl -2- pyridine carboxaldehyde and hydroxylammonium sulfate, a certain amount of alkali and organic solvent are added, reaction obtains
3- cyclobutyl -2- pyridine first oxime；Described alkali is one of potassium carbonate, sodium carbonate, potassium bicarbonate or sodium bicarbonate, You Jirong
Agent is methanol or ethanol；
(D) 3- cyclobutyl -2- pyridine first oxime is added drop-wise in phosphorus oxychloride, dehydration generates 3- cyclobutyl -2- cyanopyridine.
Further, the reaction temperature of described step A is -20 20 DEG C.
Further, the reaction temperature of described step B is 60 110 DEG C.
Further, the reaction temperature of described step C is 10 60 DEG C.
Further, the reaction temperature of described step D is 50 110 DEG C.
The beneficial effects of the present invention is：The chemical synthesis process of the present invention, with 3- bromine-2-methylpyridine as raw material, warp
Four-step reaction has synthesized 2- cyano group -3- cyclobutyl pyridine, improves yield, and the synthesis for this compound provides a kind of efficiently conjunction
The method becoming.
Specific embodiment
In order to deepen the understanding to the present invention, below in conjunction with embodiment, the invention will be further described, following enforcement
Example is only used for explaining the present invention, does not constitute limiting the scope of the present invention.
Embodiment 1
The synthesis of 2- methyl -3- cyclobutyl pyridine：
Add 250mL absolute ether, 3- bromine-2-methylpyridine 50.0g and acid chloride 4.0g in there-necked flask, system is dropped
Temperature arrives -10 DEG C, is slowly added dropwise cyclobutyl magnesium bromide diethyl ether solution（Content 55.0g）.After completion of dropping, continue reaction.Reaction knot
Shu Hou, adds aqueous ammonium chloride solution 800mL, is extracted with ethyl acetate（200mL×3）, sodium bicarbonate washing, saturated common salt is washed
Wash, anhydrous sodium sulfate drying, be concentrated to give 2- methyl -3- cyclobutyl pyridine 38.2g（89.2%）.
The synthesis of 3- cyclobutyl -2- pyridine carboxaldehyde：
1,4- dioxane 250mL, 2- methyl -3- cyclobutyl pyridine 35.0g and selenium dioxide is added in there-necked flask
40.0g, 100 DEG C of reactions of heating.After reaction terminates, filter, be concentrated to give crude product, ethanol/water recrystallization obtains 3- cyclobutyl -2- pyrrole
Pyridine formaldehyde 27.3g（71.2%）.
The synthesis of 3- cyclobutyl -2- pyridine first oxime：
Ethanol 250mL, 3- cyclobutyl -2- pyridine carboxaldehyde 25.0g potassium carbonate 20.0g and oxammonium sulfate. is added in there-necked flask
20.0g, reacts at 30 DEG C.After reaction terminates, add ethyl acetate 200mL, wash organic faciess, saturated common salt is washed, anhydrous sulfur
Sour sodium is dried, dense 3- cyclobutyl -2- pyridine first oxime 26.5g（97.0%）.
The synthesis of 3- cyclobutyl -2- cyanopyridine：
Add phosphorus oxychloride 150mL in there-necked flask, be slowly added into 3- cyclobutyl -2- pyridine first oxime 25.0g, be heated to back
Stream reaction.After reaction terminates, it is concentrated to dryness, adds dichloromethane 200mL, add 5% sodium bicarbonate solution 200mL, point liquid, water
Wash organic faciess, saturated common salt is washed, anhydrous sodium sulfate drying, dense 3- cyclobutyl -2- cyanopyridine 16.3g（72.6%）.
Embodiment 2
The synthesis of 2- methyl -3- cyclobutyl pyridine：
Add 250mL anhydrous tetrahydro furan, 3- bromine-2-methylpyridine 50.0g and acid chloride 4.0g in there-necked flask, by body
System cools to 0 DEG C, is slowly added dropwise cyclobutyl magnesium bromide tetrahydrofuran solution（Content 55.0g）.After completion of dropping, continue reaction.
After reaction terminates, add aqueous ammonium chloride solution 800mL, be extracted with ethyl acetate（200mL×3）, sodium bicarbonate washing, saturation is eaten
Salt water washing, anhydrous sodium sulfate drying, it is concentrated to give 2- methyl -3- cyclobutyl pyridine 38.7g（90.4%）.
The synthesis of 3- cyclobutyl -2- pyridine carboxaldehyde：
1,4- dioxane 250mL, 2- methyl -3- cyclobutyl pyridine 35.0g and selenium dioxide is added in there-necked flask
40.0g, 80 DEG C of reactions of heating.After reaction terminates, filter, be concentrated to give crude product, ethanol/water recrystallization obtains 3- cyclobutyl -2- pyrrole
Pyridine formaldehyde 26.1g（68.1%）.
The synthesis of 3- cyclobutyl -2- pyridine first oxime：
Ethanol 250mL, 3- cyclobutyl -2- pyridine carboxaldehyde 25.0g sodium carbonate 20.0g and oxammonium sulfate. is added in there-necked flask
20.0g, reacts at 30 DEG C.After reaction terminates, add ethyl acetate 200mL, wash organic faciess, saturated common salt is washed, anhydrous sulfur
Sour sodium is dried, dense 3- cyclobutyl -2- pyridine first oxime 25.3g（92.6%）.
The synthesis of 3- cyclobutyl -2- cyanopyridine：
Add phosphorus oxychloride 150mL in there-necked flask, be slowly added into 3- cyclobutyl -2- pyridine first oxime 25.0g, be heated to 70
DEG C reaction.After reaction terminates, it is concentrated to dryness, adds dichloromethane 200mL, add 5% sodium bicarbonate solution 200mL, point liquid, water
Wash organic faciess, saturated common salt is washed, anhydrous sodium sulfate drying, dense 3- cyclobutyl -2- cyanopyridine 13.7g（61.0%）.
Embodiment 3
The synthesis of 2- methyl -3- cyclobutyl pyridine：
Add 250mL absolute ether, 3- bromine-2-methylpyridine 50.0g and acid chloride 4.0g in there-necked flask, system is dropped
Temperature, to 10 DEG C, is slowly added dropwise cyclobutyl magnesium bromide diethyl ether solution（Content 55.0g）.After completion of dropping, continue reaction.Reaction terminates
Afterwards, add aqueous ammonium chloride solution 800mL, be extracted with ethyl acetate（200mL×3）, sodium bicarbonate washing, saturated common salt is washed
Wash, anhydrous sodium sulfate drying, be concentrated to give 2- methyl -3- cyclobutyl pyridine 36.3g（84.8%）.
The synthesis of 3- cyclobutyl -2- pyridine carboxaldehyde：
1,4- dioxane 250mL, 2- methyl -3- cyclobutyl pyridine 35.0g and selenium dioxide is added in there-necked flask
40.0g, 90 DEG C of reactions of heating.After reaction terminates, filter, be concentrated to give crude product, ethanol/water recrystallization obtains 3- cyclobutyl -2- pyrrole
Pyridine formaldehyde 26.7g（69.6%）.
The synthesis of 3- cyclobutyl -2- pyridine first oxime：
Ethanol 250mL, 3- cyclobutyl -2- pyridine carboxaldehyde 25.0g potassium carbonate 20.0g and oxammonium sulfate. is added in there-necked flask
20.0g, reacts at 40 DEG C.After reaction terminates, add ethyl acetate 200mL, wash organic faciess, saturated common salt is washed, anhydrous sulfur
Sour sodium is dried, dense 3- cyclobutyl -2- pyridine first oxime 26.1g（95.5%）.
The synthesis of 3- cyclobutyl -2- cyanopyridine：
Add phosphorus oxychloride 150mL in there-necked flask, be slowly added into 3- cyclobutyl -2- pyridine first oxime 25.0g, be heated to 60
DEG C reaction.After reaction terminates, it is concentrated to dryness, adds dichloromethane 200mL, add 5% sodium bicarbonate solution 200mL, point liquid, water
Wash organic faciess, saturated common salt is washed, anhydrous sodium sulfate drying, dense 3- cyclobutyl -2- cyanopyridine 14.2g（63.2%）.
Claims (1)
1. a kind of chemical synthesis process of 2- cyano group -3- cyclobutyl pyridine is it is characterised in that be former with 3- bromine-2-methylpyridine
Material, has synthesized 2- cyano group -3- cyclobutyl pyridine through four-step reaction, its synthetic route is as follows：
Described chemical synthesis process is：
(A) 3- bromine-2-methylpyridine, Tetramethylene. base Grignard reagent and catalyst acetic acid palladium are added to dry ether or tetrahydrochysene
In THF solvent, reaction obtains 2- methyl -3- cyclobutyl pyridine；
(B) 2- methyl -3- cyclobutyl pyridine and selenium dioxide are added in Isosorbide-5-Nitrae-dioxane solvent, temperature reaction, obtain
3- cyclobutyl -2- pyridine carboxaldehyde；
(C) by 3- cyclobutyl -2- pyridine carboxaldehyde and oxammonium sulfate., a certain amount of alkali and organic solvent are added, reaction obtains 3- ring
Butyl -2- pyridine first oxime；Described alkali is one of potassium carbonate, sodium carbonate, potassium bicarbonate or sodium bicarbonate, and organic solvent is
Methanol or ethanol；
(D) 3- cyclobutyl -2- pyridine first oxime is added drop-wise in phosphorus oxychloride, dehydration generates 2- cyano group -3- cyclobutyl pyridine；
Wherein, the reaction temperature of described step A is -20 20 DEG C；The reaction temperature of described step B is 60 110 DEG C；Described step
The reaction temperature of rapid C is 10 60 DEG C；The reaction temperature of described step D is 50 110 DEG C.
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| CN107686464A (en) * | 2017-10-24 | 2018-02-13 | 锦州医科大学 | A kind of synthetic method of the picolinic acid of 2 formoxyl 4 |
| CN111909077A (en) * | 2020-09-02 | 2020-11-10 | 南通大学 | 2- (1-bromocyclobutyl) pyridine and synthesis method thereof |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101602720A (en) * | 2009-04-29 | 2009-12-16 | 南通醋酸化工股份有限公司 | The synthetic method of 2-cyanopyridine |
| 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 |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101602720A (en) * | 2009-04-29 | 2009-12-16 | 南通醋酸化工股份有限公司 | The synthetic method of 2-cyanopyridine |
| 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 |
|---|
| 4-Cyanophenols bearing metabolically robust substituents;Patrick S. Johnson，等;《Tetrahedron Letters》;20110418;第52卷;3226页左栏第1段，scheme1-3 * |
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Inventor after: Zhu Jinli Inventor after: Sun Tongming Inventor after: Wang Miao Inventor after: Ding Jinjin Inventor after: Tang Yanfeng Inventor after: Mao Jiarong Inventor after: Guo Xiaoqing Inventor before: Tang Yanfeng Inventor before: Sun Tongming Inventor before: Wang Miao Inventor before: Ding Jinjin Inventor before: Zhu Jinli Inventor before: Mao Jiarong Inventor before: Guo Xiaoqing |
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