CN104974082A - Preparation method of 2-methyl-4-bromopyridine - Google Patents
Preparation method of 2-methyl-4-bromopyridine Download PDFInfo
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- CN104974082A CN104974082A CN201510441516.4A CN201510441516A CN104974082A CN 104974082 A CN104974082 A CN 104974082A CN 201510441516 A CN201510441516 A CN 201510441516A CN 104974082 A CN104974082 A CN 104974082A
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- 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
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Abstract
The invention belongs to the field of organic synthesis and in particular relates to a preparation method of 2-methyl-4-bromopyridine. The preparation method 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 carry out condensation reaction, and then carrying out decarboxylation under the acidic condition to obtain 2-methyl-4-nitropyridine; (2) carrying out hydrogenation reduction on 2-methyl-4-nitropyridine in the presence of a catalyst Pd/C by using methanol as a solvent, carrying out suction filtration and concentrating filtrate to obtain 2-methyl-4-aminopyridine; (3) firstly reacting 2-methyl-4-aminopyridine with acid to generate salt, cooling the salt to minus 10-0 DEG C, dropwise adding bromine, dropwise adding a sodium nitrite water solution after completing dropwise adding bromine, regulating the pH value of the solution to alkalinity after completing dropwise adding the water solution, and then carrying out extraction, drying and concentration to obtain 2-methyl-4-bromopyridine. The preparation method has the beneficial effects that the preparation method is mild in reaction conditions, is easy to operate, is simple in after-treatment, easily achieves large scale production and is very suitable for industrial production; the catalytic effects are good and the yield is high; the raw materials are cheap and the production cost is low.
Description
Technical field
The invention belongs to organic synthesis field, be specifically related to a kind of preparation method of 2-methyl-4-bromopyridine.
Background technology
Pyridine and its derivatives is distributed in nature widely.Many plant constituents are as all contained pyridine ring compound in the structure of alkaloid etc., they are the bases producing many important compound, are indispensable raw materials during medicine, agricultural chemicals, dyestuff, tensio-active agent, rubber ingredients, fodder additives, foodstuff additive, tackiness agent etc. are produced.2-methyl-4-bromopyridine is a kind of important intermediate, is mainly used as medicine intermediate, organic synthesis intermediate, organic solvent, also for the production of dyestuff, spices and agricultural chemicals etc.
At present, there is the shortcomings such as yield is low, operational path is long in the synthetic method of the 2-methyl-4-bromopyridine reported.
Summary of the invention
The object of the invention is to overcome the technical deficiency that in prior art, route is many, productive rate is low, the preparation method that a kind of productive rate is high, be applicable to the 2-methyl-4-bromopyridine of suitability for industrialized production is provided.
For solving the problems of the technologies described above, the technical solution used in the present invention is as follows:
A preparation method for 2-methyl-4-bromopyridine, comprises the steps:
(1) diethyl malonate and basic metal reaction generate salt, then the toluene solution dripping the chloro-4-nitropyridine of 2-carries out condensation reaction, and decarboxylation obtains 2-methyl-4 nitropyridine in acid condition afterwards;
(2) 2-methyl-4-nitropyridine is under Pd/C catalysis, methanol as solvent, hydrogenating reduction, suction filtration, and filtrate concentrates, and obtains 2-methyl-4-aminopyridine;
(3) 2-methyl-4-aminopyridine first generates salt with acid, is cooled to-10 DEG C-0 DEG C, drips bromine, adds dropping sodium nitrite in aqueous solution, dropwises regulator solution pH for alkalescence, then carry out extracting, dry, concentrate, obtain 2-methyl-4-bromopyridine.
Further, the mol ratio of described diethyl malonate, basic metal, the chloro-4-nitropyridine of 2-is 5-6:1.1-1.3:1.
Further, described basic metal is selected from: the one in sodium Metal 99.5, potassium metal.
Further, in described step (2), hydrogenation reduction carries out in autoclave, and reduction temperature is 20-40 DEG C, and reduction pressure is 0.5MPa.
Further, the suction filtration step in described step (2) adopts diatomite drainage, a small amount of washed with dichloromethane of filter cake.
Reaction equation of the present invention is:
Employing the invention has the beneficial effects as follows: reaction conditions is gentle, easy handling, and aftertreatment is simple, easily amplifies production, is very applicable to suitability for industrialized production; Excellent catalytic effect, yield is high; Cost of material is cheap, and production cost is low.
Embodiment
Below in conjunction with specific embodiment, the invention will be further described.These embodiments are illustrative completely, and they are only used for being specifically described the present invention, should not be construed as limitation of the present invention.
Embodiment 1
(1) preparation of 2-methyl-4-nitropyridine: the mixture oil bath of diethyl malonate (80ml, 0.5mol) and sodium (2.53g, 0.11mol) is warming up to 90 DEG C, stirs 1h, after being warming up to 120 DEG C of stirring 45min, be cooled to room temperature.Drip the toluene solution of the chloro-4-nitropyridine (15.6g, 0.1mol) of 2-, dropwise, reaction solution is warming up to 110 DEG C of reaction 1.5h, is cooled to stirring at room temperature 15h.Remove solvent under reduced pressure, add 6N hydrochloric acid (100ml), after temperature rising reflux 3.5h, be cooled to room temperature.Regulate pH to be alkalescence with saturated sodium carbonate solution, be extracted with ethyl acetate, be associated with base phase, anhydrous sodium sulfate drying, suction filtration, concentrated, obtain 2-methyl-4-nitropyridine, molar yield is 92%.
(2) preparation of 2-methyl-4-aminopyridine: be dissolved in methanol solution by 2-methyl-4-nitropyridine (13.8g, 0.1mol), adds 10%Pd/C (0.1g), this reaction is carried out in autoclave, logical hydrogen is 0.5MPa to pressure, is warming up to 20 DEG C, reaction 15h.Thin-layer chromatography monitoring, to reacting completely, is cooled to room temperature, diatomite drainage, filter cake washed with dichloromethane, can prevents Pd/C from catching fire like this, and filtrate concentrates to obtain 2-methyl-4-aminopyridine, and molar yield is 94%.
(3) preparation of 2-methyl-4-bromopyridine: under cryosel bath cooling, by 2-methyl-4-aminopyridine (10.8g, 0.1mol) join 48%HBr(46ml, 0.4mol), add, be cooled to-5 DEG C, slow dropping bromine (15ml, 0.3mol), 30-35min adds, then below 0 DEG C, drip the sodium nitrite solution 42g of 40%, add in 1-1.1h, add and continue to stir 30min below 0 DEG C, then the sodium hydroxide solution regulator solution pH slowly adding 50% below 20 DEG C is 9, reaction solution is extracted with ethyl acetate, there is basic unit's anhydrous sodium sulfate drying, suction filtration, concentrated, obtain 2-methyl-4-bromopyridine, molar yield is 95%.
Embodiment 2
(1) preparation of 2-methyl-4-nitropyridine: the mixture oil bath of diethyl malonate (80ml, 0.5mol) and sodium (2.76g, 0.12mol) is warming up to 90 DEG C, stirs 1h, after being warming up to 120 DEG C of stirring 45min, be cooled to room temperature.Drip the toluene solution of the chloro-4-nitropyridine (15.6g, 0.1mol) of 2-, dropwise, reaction solution is warming up to 110 DEG C of reaction 1.5h, is cooled to stirring at room temperature 15h.Remove solvent under reduced pressure, add 6N hydrochloric acid (100ml), after temperature rising reflux 3.5h, be cooled to room temperature.Regulate pH to be alkalescence with saturated sodium carbonate solution, be extracted with ethyl acetate, be associated with base phase, anhydrous sodium sulfate drying, suction filtration concentrates, and obtain 2-methyl-4-nitropyridine, molar yield is 95%.
(2) preparation of 2-methyl-4-aminopyridine: be dissolved in methanol solution by 2-methyl-4-nitropyridine (13.8g, 0.1mol), adds 10%Pd/C (0.1g), this reaction is carried out in autoclave, logical hydrogen is 0.5MPa to pressure, is warming up to 30 DEG C, reaction 15h.Thin-layer chromatography monitoring, to reacting completely, is cooled to room temperature, diatomite drainage, filter cake washed with dichloromethane, can prevents Pd/C from catching fire like this, and filtrate concentrates to obtain 2-methyl-4-aminopyridine, and molar yield is 97%.
(3) preparation of 2-methyl-4-bromopyridine: step is with embodiment 1.
Embodiment 3
(1) preparation of 2-methyl-4-nitropyridine: the mixture oil bath of diethyl malonate (80ml, 0.5mol) and sodium (2.99g, 0.13mol) is warming up to 90 DEG C, stirs 1h, after being warming up to 120 DEG C of stirring 45min, be cooled to room temperature.Drip the toluene solution of the chloro-4-nitropyridine (15.6g, 0.1mol) of 2-, dropwise, reaction solution is warming up to 110 DEG C of reaction 1.5h, is cooled to stirring at room temperature 15h.Remove solvent under reduced pressure, add 6N hydrochloric acid (100ml), after temperature rising reflux 3.5h, be cooled to room temperature.Regulate pH to be alkalescence with saturated sodium carbonate solution, be extracted with ethyl acetate, be associated with base phase, anhydrous sodium sulfate drying, suction filtration, concentrated, obtain 2-methyl-4-nitropyridine, molar yield is 95%.
(2) preparation of 2-methyl-4-aminopyridine: be dissolved in methanol solution by 2-methyl-4-nitropyridine (13.8g, 0.1mol), adds 10%Pd/C (0.1g), this reaction is carried out in autoclave, logical hydrogen is 0.5MPa to pressure, is warming up to 40 DEG C, reaction 15h.Thin-layer chromatography monitoring, to reacting completely, is cooled to room temperature, diatomite drainage, filter cake washed with dichloromethane, can prevents Pd/C from catching fire like this, and filtrate concentrates to obtain 2-methyl-4-aminopyridine, and molar yield is 95%.
(3) preparation of 2-methyl-4-bromopyridine: step is with embodiment 1.
Claims (5)
1. a preparation method for 2-methyl-4-bromopyridine, is characterized in that comprising the following steps:
(1) diethyl malonate and basic metal reaction generate salt, then the toluene solution dripping the chloro-4-nitropyridine of 2-carries out condensation reaction, and decarboxylation obtains 2-methyl-4 nitropyridine in acid condition afterwards;
(2) 2-methyl-4-nitropyridine is under Pd/C catalysis, methanol as solvent, hydrogenating reduction, suction filtration, and filtrate concentrates, and obtains 2-methyl-4-aminopyridine;
(3) 2-methyl-4-aminopyridine first generates salt with acid, is cooled to-10 DEG C-0 DEG C, drips bromine, adds dropping sodium nitrite in aqueous solution, dropwises regulator solution pH for alkalescence, then carry out extracting, dry, concentrate, obtain 2-methyl-4-bromopyridine.
2. the preparation method of a kind of 2-methyl-4-bromopyridine according to claim 1, is characterized in that the mol ratio of the chloro-4-nitropyridine of described diethyl malonate, basic metal, 2-is 5-6:1.1-1.3:1.
3. the preparation method of a kind of 2-methyl-4-bromopyridine according to claim 1, is characterized in that described basic metal is selected from: the one in sodium Metal 99.5, potassium metal.
4. the preparation method of a kind of 2-methyl-4-bromopyridine according to claim 1 and 2, it is characterized in that in described step (2), hydrogenation reduction carries out in autoclave, reduction temperature is 20-40 DEG C, and reduction pressure is 0.5MPa.
5. the preparation method of a kind of 2-methyl-4-bromopyridine according to claim 3, is characterized in that in described step (2), suction filtration step adopts diatomite drainage, a small amount of washed with dichloromethane of filter cake.
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Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107056692A (en) * | 2017-06-25 | 2017-08-18 | 刘瑞海 | A kind of synthetic method of the bromopyridine of 2,6 dimethyl 3 |
| CN107082759A (en) * | 2017-06-25 | 2017-08-22 | 刘瑞海 | A kind of synthetic method of the bromopyridine of 2,3,4 trimethyl 6 |
| CN107089939A (en) * | 2017-06-25 | 2017-08-25 | 刘瑞海 | A kind of synthetic method of the bromopyridine of 2,5 dimethyl 3 |
| CN107162963A (en) * | 2017-06-25 | 2017-09-15 | 刘瑞海 | A kind of synthetic method of the picoline of 3 bromine 5 |
| CN107162964A (en) * | 2017-06-25 | 2017-09-15 | 刘瑞海 | A kind of synthetic method of the bromopyridine of 2,6 dimethyl 4 |
| CN107311920A (en) * | 2017-06-25 | 2017-11-03 | 刘瑞海 | A kind of synthetic method of the bromopyridine of 2,3,5 trimethyl 6 |
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Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107056692A (en) * | 2017-06-25 | 2017-08-18 | 刘瑞海 | A kind of synthetic method of the bromopyridine of 2,6 dimethyl 3 |
| CN107082759A (en) * | 2017-06-25 | 2017-08-22 | 刘瑞海 | A kind of synthetic method of the bromopyridine of 2,3,4 trimethyl 6 |
| CN107089939A (en) * | 2017-06-25 | 2017-08-25 | 刘瑞海 | A kind of synthetic method of the bromopyridine of 2,5 dimethyl 3 |
| CN107162963A (en) * | 2017-06-25 | 2017-09-15 | 刘瑞海 | A kind of synthetic method of the picoline of 3 bromine 5 |
| CN107162964A (en) * | 2017-06-25 | 2017-09-15 | 刘瑞海 | A kind of synthetic method of the bromopyridine of 2,6 dimethyl 4 |
| CN107311920A (en) * | 2017-06-25 | 2017-11-03 | 刘瑞海 | A kind of synthetic method of the bromopyridine of 2,3,5 trimethyl 6 |
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