CN110683983A - Preparation method of 2-methyl-4-bromopyridine - Google Patents
Preparation method of 2-methyl-4-bromopyridine Download PDFInfo
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- CN110683983A CN110683983A CN201911175439.7A CN201911175439A CN110683983A CN 110683983 A CN110683983 A CN 110683983A CN 201911175439 A CN201911175439 A CN 201911175439A CN 110683983 A CN110683983 A CN 110683983A
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- methyl
- nitropyridine
- bromopyridine
- dripped
- aminopyridine
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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
- C07D213/61—Halogen atoms or nitro radicals
Abstract
The invention belongs to the field of organic synthesis, and particularly relates to a preparation method of 2-methyl-4-bromopyridine, which comprises the following steps: (1) reacting diethyl malonate with alkali metal to generate salt, then dropwise adding a toluene solution of 2-chloro-4-nitropyridine to perform condensation reaction, and then decarboxylating under an acidic condition to obtain 2-methyl-4-nitropyridine; (2) carrying out hydrogenation reduction on 2-methyl-4-nitropyridine under the catalysis of Pd/C by using methanol as a solvent, carrying out suction filtration, and concentrating the filtrate to obtain 2-methyl-4-aminopyridine; (3) the 2-methyl-4-aminopyridine and acid are firstly mixed to generate salt, the salt is cooled to minus 10 ℃ to 0 ℃, bromine is dripped, sodium nitrite aqueous solution is dripped after the bromine is dripped, the pH value of the solution is adjusted to be alkaline after the dripping, and then the 2-methyl-4-bromopyridine is obtained after extraction, drying and concentration. The beneficial effects of the invention are as follows: the reaction condition is mild, the operation is easy, the post-treatment is simple, the scale-up production is easy, and the method is very suitable for industrial production; the catalytic effect is good, and the yield is high; the raw materials are cheap, and the production cost is low.
Description
Technical Field
The invention belongs to the field of organic synthesis, and particularly relates to a preparation method of 2-methyl-4-bromopyridine.
Background
Pyridine and its derivatives are widely distributed in nature. Many plant components such as alkaloids contain pyridine ring compounds in their structures, which are the basis for the production of many important compounds, which are essential raw materials for the production of pharmaceuticals, pesticides, dyes, surfactants, rubber aids, feed additives, food additives, adhesives, etc. 2-methyl-4-bromopyridine is an important intermediate, is mainly used as a medical intermediate, an organic synthesis intermediate and an organic solvent, and is also used for producing dyes, spices, pesticides and the like.
At present, the reported synthetic method of 2-methyl-4-bromopyridine has the defects of low yield, long process route and the like.
Disclosure of Invention
The invention aims to overcome the technical defects of multiple routes and low yield in the prior art and provide a preparation method of 2-methyl-4-bromopyridine, which is high in yield and suitable for industrial production.
In order to solve the technical problems, the technical scheme adopted by the invention is as follows:
a preparation method of 2-methyl-4-bromopyridine comprises the following steps:
(1) reacting diethyl malonate with alkali metal to generate salt, then dropwise adding a toluene solution of 2-chloro-4-nitropyridine to perform condensation reaction, and then decarboxylating under an acidic condition to obtain 2-methyl-4-nitropyridine;
(2) carrying out hydrogenation reduction on 2-methyl-4-nitropyridine under the catalysis of Pd/C by using methanol as a solvent, carrying out suction filtration, and concentrating the filtrate to obtain 2-methyl-4-aminopyridine;
(3) the 2-methyl-4-aminopyridine and acid are firstly mixed to generate salt, the salt is cooled to minus 10 ℃ to 0 ℃, bromine is dripped, sodium nitrite aqueous solution is dripped after the bromine is added, the pH value of the solution is adjusted to be alkaline after the dripping, and then the 2-methyl-4-bromopyridine is obtained after extraction, drying and concentration.
Further, the molar ratio of diethyl malonate, alkali metal and 2-chloro-4-nitropyridine is 5-6: 1.1-1.3: 1.
further, the alkali metal is selected from: one of metal sodium and metal potassium.
Further, the hydrogenation reduction reaction in the step (2) is carried out in an autoclave, the reduction temperature is 20-40 ℃, and the reduction pressure is 0.5 MPa.
Further, the suction filtration step in the step (2) adopts diatomite for assisting filtration, and a filter cake is washed by a small amount of dichloromethane.
The reaction equation of the invention is as follows:
the beneficial effects of the invention are as follows: the reaction condition is mild, the operation is easy, the post-treatment is simple, the scale-up production is easy, and the method is very suitable for industrial production; the catalytic effect is good, and the yield is high; the raw materials are cheap, and the production cost is low.
Detailed Description
The present invention will be further described with reference to the following specific examples. These examples are purely illustrative and are intended to be a detailed description of the invention and should not be taken as limiting the invention.
Example 1
(1) Preparation of 2-methyl-4-nitropyridine: a mixture of diethyl malonate (80ml, 0.5mol) and sodium (2.53g, 0.11mol) was oil-bathed to 90 ℃ and stirred for 1h, warmed to 120 ℃ and stirred for 45min and then cooled to room temperature. Dropwise adding a toluene solution of 2-chloro-4-nitropyridine (15.6g, 0.1mol), heating the reaction solution to 110 ℃ to react for 1.5h after the dropwise adding is finished, cooling to room temperature and stirring for 15 h. The solvent was evaporated under reduced pressure, 6N hydrochloric acid (100ml) was added, and the mixture was refluxed for 3.5 hours and cooled to room temperature. Adjusting pH to alkalinity with saturated sodium carbonate solution, extracting with ethyl acetate, combining the base phases, drying with anhydrous sodium sulfate, filtering, concentrating to obtain 2-methyl-4-nitropyridine with a molar yield of 92%.
(2) Preparation of 2-methyl-4-aminopyridine: 2-methyl-4-nitropyridine (13.8g, 0.1mol) was dissolved in a methanol solution, 10% Pd/C (0.1g) was added, and the reaction was carried out in an autoclave under a pressure of 0.5MPa with hydrogen, and the temperature was raised to 20 ℃ for 15 hours. Monitoring by thin layer chromatography until the reaction is complete, cooling to room temperature, assisting filtration with diatomite, washing filter cake with dichloromethane, thus preventing Pd/C from igniting, and concentrating the filtrate to obtain 2-methyl-4-aminopyridine with a molar yield of 94%.
(3) Preparation of 2-methyl-4-bromopyridine: under the cooling of an ice salt bath, 2-methyl-4-aminopyridine (10.8g, 0.1mol) is added into 48 percent HBr (46ml, 0.4mol), after the addition is finished, the solution is cooled to-5 ℃, liquid bromine (15ml, 0.3mol) is slowly dripped, after the addition is finished for 30-35min, then 40 percent sodium nitrite solution 42g is dripped below 0 ℃, after the addition is finished within 1-1.1h, the solution is continuously stirred below 0 ℃ for 30min, then 50 percent sodium hydroxide solution is slowly added below 20 ℃ to adjust the pH value to 9, the reaction solution is extracted by ethyl acetate, a basal layer is dried by anhydrous sodium sulfate, filtered and concentrated to obtain 2-methyl-4-bromopyridine, and the molar yield is 95 percent.
Example 2
(1) Preparation of 2-methyl-4-nitropyridine: a mixture of diethyl malonate (80ml, 0.5mol) and sodium (2.76g, 0.12mol) was oil-bathed to 90 deg.C, stirred for 1h, warmed to 120 deg.C, stirred for 45min and then cooled to room temperature. Dropwise adding a toluene solution of 2-chloro-4-nitropyridine (15.6g, 0.1mol), heating the reaction solution to 110 ℃ to react for 1.5h after the dropwise adding is finished, cooling to room temperature and stirring for 15 h. The solvent was evaporated under reduced pressure, 6N hydrochloric acid (100ml) was added, and the mixture was refluxed for 3.5 hours and cooled to room temperature. Adjusting pH to alkalinity with saturated sodium carbonate solution, extracting with ethyl acetate, combining the base phases, drying with anhydrous sodium sulfate, filtering and concentrating to obtain 2-methyl-4-nitropyridine with a molar yield of 95%.
(2) Preparation of 2-methyl-4-aminopyridine: 2-methyl-4-nitropyridine (13.8g, 0.1mol) was dissolved in a methanol solution, 10% Pd/C (0.1g) was added, and the reaction was carried out in an autoclave under a pressure of 0.5MPa with hydrogen, and the temperature was raised to 30 ℃ for 15 hours. Monitoring by thin layer chromatography until the reaction is complete, cooling to room temperature, assisting filtration with diatomite, washing filter cake with dichloromethane, thus preventing Pd/C from igniting, and concentrating the filtrate to obtain 2-methyl-4-aminopyridine with a molar yield of 97%.
(3) Preparation of 2-methyl-4-bromopyridine: the procedure is as in example 1.
Example 3
(1) Preparation of 2-methyl-4-nitropyridine: a mixture of diethyl malonate (80ml, 0.5mol) and sodium (2.99g, 0.13mol) was oil-bathed to 90 deg.C, stirred for 1h, warmed to 120 deg.C, stirred for 45min and then cooled to room temperature. Dropwise adding a toluene solution of 2-chloro-4-nitropyridine (15.6g, 0.1mol), heating the reaction solution to 110 ℃ to react for 1.5h after the dropwise adding is finished, cooling to room temperature and stirring for 15 h. The solvent was evaporated under reduced pressure, 6N hydrochloric acid (100ml) was added, and the mixture was refluxed for 3.5 hours and cooled to room temperature. Adjusting pH to alkalinity with saturated sodium carbonate solution, extracting with ethyl acetate, combining the base phases, drying with anhydrous sodium sulfate, filtering, concentrating to obtain 2-methyl-4-nitropyridine with a molar yield of 95%.
(2) Preparation of 2-methyl-4-aminopyridine: 2-methyl-4-nitropyridine (13.8g, 0.1mol) was dissolved in a methanol solution, 10% Pd/C (0.1g) was added, and the reaction was carried out in an autoclave under a pressure of 0.5MPa with hydrogen, and the temperature was raised to 40 ℃ for 15 hours. Monitoring by thin-layer chromatography until the reaction is complete, cooling to room temperature, assisting filtration by diatomite, washing filter cakes by dichloromethane, thus preventing Pd/C from catching fire, and concentrating the filtrate to obtain 2-methyl-4-aminopyridine with the molar yield of 95%.
(3) Preparation of 2-methyl-4-bromopyridine: the procedure is as in example 1.
Claims (5)
1. A preparation method of 2-methyl-4-bromopyridine is characterized by comprising the following steps:
(1) reacting diethyl malonate with alkali metal to generate salt, then dropwise adding a toluene solution of 2-chloro-4-nitropyridine to perform condensation reaction, and then decarboxylating under an acidic condition to obtain 2-methyl-4-nitropyridine;
(2) carrying out hydrogenation reduction on 2-methyl-4-nitropyridine under the catalysis of Pd/C by using methanol as a solvent, carrying out suction filtration, and concentrating the filtrate to obtain 2-methyl-4-aminopyridine;
(3) the 2-methyl-4-aminopyridine and acid are firstly mixed to generate salt, the salt is cooled to minus 10 ℃ to 0 ℃, bromine is dripped, sodium nitrite aqueous solution is dripped after the bromine is added, the pH value of the solution is adjusted to be alkaline after the dripping, and then the 2-methyl-4-bromopyridine is obtained after extraction, drying and concentration.
2. The method for preparing 2-methyl-4-bromopyridine according to claim 1, wherein the molar ratio of diethyl malonate, alkali metal and 2-chloro-4-nitropyridine is 5-6: 1.1-1.3: 1.
3. the process according to claim 1, wherein the alkali metal is selected from the group consisting of: one of metal sodium and metal potassium.
4. The process for producing 2-methyl-4-bromopyridine according to claim 1 or 2, wherein the hydrogenation reduction in the step (2) is carried out in an autoclave at a temperature of 20 to 40 ℃ and a reduction pressure of 0.5 MPa.
5. The method for preparing 2-methyl-4-bromopyridine according to claim 3, wherein the suction filtration step in the step (2) is assisted by diatomite, and the filter cake is washed with a small amount of dichloromethane.
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