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Method for preparing 5-bromo-2-methylpyridine

A technology of picoline and chloropyridine, which is applied in the field of preparation of intermediate 5-bromo-2-picoline, can solve the problems of large amount of aluminum trichloride, difficulty in industrialized production, low product yield and the like, and can achieve production Low cost, good catalytic effect and high yield

Inactive Publication Date: 2009-10-21
ZHEJIANG MEDICINE CO LTD XINCHANG PHAMACEUTICAL FACTORY
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0005] The shortcoming of this method is that the consumption of aluminum trichloride is big, and catalytic effect is poor; Bromine can carry out bromination in multiple positions, and by-product is many, and product yield is low; The boiling point of gained product 5-bromo-2-picoline and The boiling points of 3-bromo-2-methylpyridine are relatively close (199.05°C and 201.71°C), and the separation is relatively difficult, requiring special rectification equipment, and industrial production is difficult

Method used

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Embodiment 1

[0017] Embodiment 1: the preparation of 5-nitro-2-picoline (3)

[0018] A mixture of diethyl malonate (42 mL, 1.28 mol) and sodium hydrogen (4.8 g, 0.2 mol) was slowly heated to 90°C, stirred for 1 h, then heated to 120°C and stirred for 30 min, then cooled to room temperature. A solution of 5-nitro-2-chloropyridine (2) (25 g, 0.16 mol) in toluene (200 mL) was added dropwise. After the addition was complete, the reaction solution was heated to 110° C. for 1.5 h, cooled to room temperature and stirred for 15 h. The solvent was evaporated under reduced pressure, 6N HCl (200 mL) was added, the temperature was raised to reflux for 4 h and then cooled to room temperature. Make alkaline with sodium carbonate, extract with ethyl acetate (6×100 mL), combine organic phases, and dry over anhydrous sodium sulfate for 6 h. After suction filtration, the filtrate was evaporated to dryness under reduced pressure to obtain the crude product 5-nitro-2-picoline (3), 20.4 g, 94%. 1 HNMR (400MH...

Embodiment 2

[0019] Embodiment 2: Preparation of 5-nitro-2-picoline (3)

[0020] A mixture of diethyl malonate (42 mL, 1.28 mol) and sodium (4.6 g, 0.2 mol) was slowly warmed up to 90°C, stirred for 2 h, then raised to 100°C and stirred for 50 min, then cooled to room temperature. A solution of 5-nitro-2-chloropyridine (2) (25 g, 0.16 mol) in toluene (200 mL) was added dropwise. After the addition was complete, the reaction solution was heated to 110° C. for 1.5 h, cooled to room temperature and stirred for 15 h. The solvent was evaporated under reduced pressure, 6N HCl (200 mL) was added, the temperature was raised to reflux for 4 h and then cooled to room temperature. Make alkaline with sodium carbonate, extract with ethyl acetate (6×100 mL), combine organic phases, and dry over anhydrous sodium sulfate for 6 h. After suction filtration, the filtrate was evaporated to dryness under reduced pressure to obtain the crude product 5-nitro-2-picoline (3), 20.0 g, 93%. 1 HNMR (400MHz, CDCl 3...

Embodiment 3

[0021] Embodiment 3: Preparation of 5-amino-2-picoline (4)

[0022] 5-Nitro-2-methylpyridine (3) (13g, 94.1mmoL) and 10%Pd / C(0.1)1,4-dioxane solution was passed into hydrogen until the pressure was 0.4MPa, and the temperature was raised to 30 °C, reacted for 16h. Cool to room temperature, filter, and evaporate the filtrate to dryness under reduced pressure to give 5-amino-2-picoline (4) as a solid, 9.9 g, 97%. 1 HNMR (400MHz, CDCl 3 ): δ8.61(s, 1H), 7.29(m, 1H), 7.25(m, 1H), 4.0(s, 2H), 2.55(s, 3H).

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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 [0001] The invention relates to the field of organic chemistry, in particular to a preparation method of an intermediate 5-bromo-2-picoline. Background technique [0002] 5-Bromo-2-picoline is an important intermediate, mainly used as pharmaceutical intermediates, organic synthesis intermediates, organic solvents, and can also be used in the production of dyes, pesticides and spices. [0003] At present, the main synthetic route reported in domestic and foreign literature is to react with liquid bromine under the condition of 2-picoline as a raw material and aluminum trichloride as a catalyst (Bioorganic & Medicinal Chemistry, 16 (4): 1992-2010, 2008; Journal of Medicinal Chemistry, 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 is only Around 16%. [0004] [0005] The shortcoming of this method is that the consumption of aluminum trichloride is big, and catalytic effect i...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D213/61B01J23/44
Inventor 沈大冬张伯引孙斌
Owner ZHEJIANG MEDICINE CO LTD XINCHANG PHAMACEUTICAL FACTORY
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