CN101560183A - Method for preparing 5-bromo-2-methylpyridine - Google Patents
Method for preparing 5-bromo-2-methylpyridine Download PDFInfo
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- CN101560183A CN101560183A CNA2009100973274A CN200910097327A CN101560183A CN 101560183 A CN101560183 A CN 101560183A CN A2009100973274 A CNA2009100973274 A CN A2009100973274A CN 200910097327 A CN200910097327 A CN 200910097327A CN 101560183 A CN101560183 A CN 101560183A
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Abstract
The invention discloses a method for preparing intermediate 5-bromo-2-methylpyridine. In the prior art, the dosage of aluminium trichloride is large; the catalytic effect is poor; the by-products are more; the yield of products is low; and the obtained products are difficult to separate. The method comprises the following steps: reacting diethyl malonate with alkali metal to generate salts, dripping 5-nitryl-2-chloropyridine into the salts for condensation reaction, and subsequently performing decarboxylation on the obtained product under acidic condition to obtain 5-nitryl-2-methylpyridine; performing hydrogenation reduction on the 5-nitryl-2-methylpyridine under the catalysis of Pd/C catalyst to obtain 5-amido-2-methylpyridine; and reacting the 5-amido-2-methylpyridine with acid to generate salts, dripping bromine, dripping a sodium nitrite water solution, and obtaining the 5-bromo-2-methylpyridine. The method has mild reaction conditions, easy operation, simple post-treatment, good catalytic effect, high yield of each step and high yield of final products, and is particularly suitable for industrialized production.
Description
Technical field
The present invention relates to organic chemistry filed, specifically a kind of preparation method of intermediate 5-bromo-2-picoline.
Background technology
5-bromo-2-picoline is a kind of important intermediate, mainly as medicine intermediate, organic synthesis intermediate, organic solvent, also can be used for aspects such as DYE PRODUCTION, pesticide producing and spices.
At present the main synthetic route of domestic and foreign literature report is to be that raw material, aluminum chloride are under the condition of catalyzer and liquid bromine reaction (Bioorganic﹠amp with the 2-picoline; MedicinalChemistry, 16 (4): 1992-2010,2008; Journal of MedicinalChemistry, 30 (5): 871-880,1987), its product is the mixture of 5-bromo-2-picoline and 3-bromo-2-picoline, the yield of 5-bromo-2-picoline only about 16%.
The shortcoming of this method is that the consumption of aluminum chloride is big, and catalytic effect is poor; Bromine can carry out bromo in a plurality of positions, and by product is many, and product yield is low; The boiling point of products therefrom 5-bromo-2-picoline and the boiling point of 3-bromo-2-picoline nearer (199.05 ℃ and 201.71 ℃) separate relatively difficulty, need special rectifier unit, the suitability for industrialized production difficulty.
Summary of the invention
Technical problem to be solved by this invention is to overcome the defective that above-mentioned prior art exists, and the preparation method of the 5-bromo-2-picoline of a kind of excellent catalytic effect, convenient post-treatment, suitable suitability for industrialized production is provided.
For this reason, the present invention adopts following technical scheme: the preparation method of 5-bromo-2-picoline, its step is as follows: 1) reaction of diethyl malonate and basic metal generates salt, and then Dropwise 5-nitro-2-chloropyridine carries out condensation reaction, and decarboxylation gets 5-nitro-2-picoline under acidic conditions afterwards;
2) 5-nitro-2-picoline is under the catalysis of Pd/C catalyzer, hydrogenating reduction, and suction filtration and solvent evaporated get 5-amino-2-methyl pyridine;
3) 5-amino-2-methyl pyridine earlier generates salt with acid, is cooled to 0～-10 ℃, and dripping bromine drips sodium nitrite in aqueous solution then, afterwards with solution furnishing alkalescence, extracts, dry, evaporate to dryness gets 5-bromo-2-picoline again.
Synthetic route of the present invention is as follows:
As further technical scheme of the present invention, described basic metal is sodium or hydrogen sodium.
As further technical scheme of the present invention, the temperature when described Pd/C carries out catalytic reduction is 15～40 ℃, and the too low then reduction of temperature is not thorough, and the required time is longer, and the too high then pyridine ring of temperature is reduced, and can produce a large amount of by products.
As further technical scheme of the present invention, after having reacted, solvent adopts underpressure distillation to reclaim, and solvent is reclaimed totally as far as possible, helps product content and improves.
The present invention has following beneficial effect: the reaction conditions gentleness, and easy handling, aftertreatment is simple, amplifies easily and produces, and is fit to very much suitability for industrialized production; Excellent catalytic effect, per step yield is higher, the yield height of final product; Raw material 5-nitro-2-chloropyridine low price, production cost is low.
The invention will be further described below by embodiment.
Embodiment
The preparation of embodiment 1:5-nitro-2-picoline (3)
(42mL, 1.28mol) (4.8g, mixture 0.2mol) slowly are warming up to 90 ℃, stir 1h, are warming up to 120 ℃ again and stir the 30min postcooling to room temperature with hydrogen sodium with diethyl malonate.(25g, toluene 0.16mol) (200mL) solution dropwises Dropwise 5-nitro-2-chloropyridine (2), and reaction solution is warming up to 110 ℃ of reaction 1.5h, is cooled to stirring at room 15h.Remove solvent under reduced pressure, add 6N HCl (200mL), temperature rising reflux 4h postcooling is to room temperature.Yellow soda ash furnishing alkalescence, and the usefulness ethyl acetate extraction (6 * 100mL), merge organic phase, anhydrous sodium sulfate drying 6h.Filter, filtrate decompression solvent evaporated solvent gets crude product 5-nitro-2-picoline (3), 20.4g, 94%.
1HNMR(400MHz，CDCl
3)：δ9.34(s，1H)，8.41(m，1H)，7.37(m，1H)，2.74(s，3H)。
The preparation of embodiment 2:5-nitro-2-picoline (3)
With diethyl malonate (42mL, 1.28mol) and sodium (4.6g, mixture 0.2mol) slowly are warming up to 90 ℃, stir 2h, are warming up to 100 ℃ again and stir the 50min postcooling to room temperature.(25g, toluene 0.16mol) (200mL) solution dropwises Dropwise 5-nitro-2-chloropyridine (2), and reaction solution is warming up to 110 ℃ of reaction 1.5h, is cooled to stirring at room 15h.Remove solvent under reduced pressure, add 6N HCl (200mL), temperature rising reflux 4h postcooling is to room temperature.Yellow soda ash furnishing alkalescence, and the usefulness ethyl acetate extraction (6 * 100mL), merge organic phase, anhydrous sodium sulfate drying 6h.Filter, filtrate decompression solvent evaporated solvent gets crude product 5-nitro-2-picoline (3), 20.0g, 93%.
1HNMR(400MHz，CDCl
3)：δ9.34(s，1H)，8.41(m，1H)，7.37(m，1H)，2.74(s，3H)。
The preparation of embodiment 3:5-amino-2-methyl pyridine (4)
With 5-nitro-2-picoline (3) (13g, 94.1mmoL) and 10%Pd/C (0.1) 1,4-dioxane solution to feed hydrogen to pressure be 0.4MPa, be warming up to 30 ℃, reaction 16h.Be cooled to room temperature, filter, the filtrate decompression evaporate to dryness gets solid 5-amino-2-methyl pyridine (4), 9.9g, 97%.
1HNMR(400MHz，CDCl
3)：δ8.61(s，1H)，7.29(m，1H)，7.25(m，1H)，4.0(s，2H)，2.55(s，3H)。
The preparation of embodiment 4:5-bromo-2-picoline (1)
Bathe under the cooling at cryosel, with 5-amino-2-methyl pyridine (4) (8.64g, 80mmoL) add 48%HBr (40mL, 0.35mol) in, finish, be cooled to-5 ℃, slowly the dropping liquid bromine (12mL, 0.24mol), about 30min.Be added dropwise in 1.5h then that (temperature control finishes below 0 ℃ for 13.8g, the solution that 0.2mol) is made into, and stirs 30min by water (20mL) and Sodium Nitrite.Then with NaOH (30g, 0.75moL) and water (30mL) slowly add, make temperature be no more than 20 ℃.The reaction solution ethyl acetate extraction (4 * 25mL), anhydrous sodium sulfate drying 6h.Filter, the filtrate decompression solvent evaporated gets solid 5-bromo-2-picoline (1), 12.6g, 92%.
1HNMR(400MHz，CDCl
3)：δ8.87(s，1H)，8.17(m，1H)，7.61(m，1H)，2.55(s，3H)。
The above only is preferred embodiment of the present invention, is not technical scheme of the present invention is done any pro forma restriction.Every foundation technical spirit of the present invention all falls within the scope of protection of the present invention any simple modification, equivalent variations and modification that above embodiment did.
Claims (4)
1, the preparation method of 5-bromo-2-picoline, its step is as follows: 1) reaction of diethyl malonate and basic metal generates salt, and then Dropwise 5-nitro-2-chloropyridine carries out condensation reaction, and decarboxylation gets 5-nitro-2-picoline under acidic conditions afterwards;
2) 5-nitro-2-picoline is under the catalysis of Pd/C catalyzer, hydrogenating reduction, and suction filtration and solvent evaporated get 5-amino-2-methyl pyridine;
3) 5-amino-2-methyl pyridine earlier generates salt with acid, is cooled to 0～-10 ℃, and dripping bromine drips sodium nitrite in aqueous solution then, afterwards with solution furnishing alkalescence, extracts, dry, evaporate to dryness gets 5-bromo-2-picoline again.
2, preparation method according to claim 1 is characterized in that described basic metal is sodium or hydrogen sodium.
3, preparation method according to claim 1 and 2, the temperature when it is characterized in that described hydrogenating reduction is 15～40 ℃.
4, preparation method according to claim 3 is characterized in that reclaiming solvent and adopts underpressure distillation.
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| CN2009100973274A CN101560183B (en) | 2009-04-07 | 2009-04-07 | Method for preparing 5-bromo-2-methylpyridine |
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| CN2009100973274A CN101560183B (en) | 2009-04-07 | 2009-04-07 | Method for preparing 5-bromo-2-methylpyridine |
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Cited By (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104974082A (en) * | 2015-07-26 | 2015-10-14 | 陈吉美 | Preparation method of 2-methyl-4-bromopyridine |
| 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 |
| CN109232399A (en) * | 2018-11-12 | 2019-01-18 | 上海毕得医药科技有限公司 | A kind of synthetic method of bromo- 2- methyl -3- (trifluoromethyl) pyridine of 5- |
-
2009
- 2009-04-07 CN CN2009100973274A patent/CN101560183B/en not_active Expired - Fee Related
Cited By (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104974082A (en) * | 2015-07-26 | 2015-10-14 | 陈吉美 | Preparation method of 2-methyl-4-bromopyridine |
| 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 |
| CN109232399A (en) * | 2018-11-12 | 2019-01-18 | 上海毕得医药科技有限公司 | A kind of synthetic method of bromo- 2- methyl -3- (trifluoromethyl) pyridine of 5- |
| CN109232399B (en) * | 2018-11-12 | 2022-02-15 | 上海毕得医药科技股份有限公司 | Synthetic method of 5-bromo-2-methyl-3- (trifluoromethyl) pyridine |
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| CN101560183B (en) | 2011-02-02 |
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