Preparation method of 2-amino-5-bromopyridine

A technology of aminopyridine and bromopyridine, which is applied in the field of preparation of pharmaceutical intermediates, can solve the problems of increased reaction temperature, energy consumption, and low product yield, and achieves the goals of improving yield and purity, increasing yield, and increasing conversion rate of raw materials Effect

Inactive Publication Date: 2018-01-05
UNIV OF JINAN
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  • Description
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Problems solved by technology

[0003] Chinese patent CN103755628A is prepared by dropping the saturated acetone solution containing N-bromosuccinimide into the acetone solution of 2-aminopyridine. The method uses a large amount of solvent, -10~-5 o The reaction temperature of C also greatly increases the energy consumption
In the reaction, not only active reagents such as liquid bromine and acetic anhydride are used, but also the increased protection and deprotection operations produce a large amount of waste water, and the product yield is low

Method used

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  • Preparation method of 2-amino-5-bromopyridine

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Experimental program
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Effect test

Embodiment 1

[0019] Dissolve 50 g of 2-aminopyridine in 200 mL of acetone, cool the solution to -5~-3 °C, add bromine in acetone solution (42.4 g of bromine / 200 mL of acetone) dropwise under stirring, and control the reaction temperature at - 5~0 ℃, after the dropwise addition, react for 0.5 h until the raw materials are completely reacted; the temperature of the solution is adjusted to -1~1 ℃, and 47.3 g of solid N-bromosuccinimide is added in batches, and the temperature of the reaction solution is controlled at 3~5 ℃, the reaction was continued for 1 h after the addition, and then the acetone was recovered by distillation under reduced pressure at 30 ℃ to obtain a brownish yellow solid; at 0~5℃, the brownish yellow solid was added to 94 g of potassium hydroxide aqueous solution with a mass fraction of 17.45%, and stirred , filtered, and the filter cake was recrystallized by adding 250 mL of 95% ethanol to obtain 82.7 g of brown crystals of 2-amino-5-bromopyridine, with a yield of 90% and...

Embodiment 2

[0022] Dissolve 50 g of 2-aminopyridine in 200 mL of acetone, cool the solution to -5~-3 °C, add bromine in acetone solution (42.4 g of bromine / 200 mL of acetone) dropwise under stirring, and control the reaction temperature at - 5~0 ℃, after the dropwise addition, react for 0.5 h until the raw materials are completely reacted; the temperature of the solution is adjusted to -1~1 ℃, and 47.5 g of solid N-bromosuccinimide is added in batches, and the temperature of the reaction solution is controlled at 1~3 ℃, the reaction was continued for 1 h after the feeding was completed, and then the acetone was recovered by distillation under reduced pressure at 28 ℃ to obtain a brown-yellow solid; Stir and wash, filter, and add 250 mL of 95% ethanol to the filter cake for recrystallization to obtain 82.2 g of brown crystals of 2-amino-5-bromopyridine, with a yield of 89.5% and a purity of 99.2%. The filtrate is all transferred to the next step.

[0023] Dissolve 14.8 g (89.4 mmol) of pot...

Embodiment 3

[0025] Dissolve 50 g of 2-aminopyridine in 200 mL of acetone, cool the solution to -5~-3 °C, add bromine in acetone solution (42.4 g of bromine / 200 mL of acetone) dropwise under stirring, and control the reaction temperature at - 5~0 ℃, react for 0.5 h after the dropwise addition until the raw materials are completely reacted; adjust the solution temperature to -1~1 ℃, add 49 g of solid N-bromosuccinimide in batches, and control the temperature of the reaction solution at 0~2 ℃, the reaction was continued for 1 h after the feeding was completed, and then the acetone was recovered by distillation under reduced pressure at 34 ℃ to obtain a brown-yellow solid; Wash, filter, and add 250 mL of 95% ethanol to the filter cake for recrystallization to obtain 83.6 g of brown crystals of 2-amino-5-bromopyridine, with a yield of 90.5% and a purity of 99.0%.

[0026]Dissolve 14.8 g (89.4 mmol) of potassium bromate into the succinimide aqueous solution recovered in the previous step, add 1...

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Abstract

The invention discloses a preparation method of 2-amino-5-bromopyridine. The preparation method is characterized in that 2-aminopyridine is used as the raw material, and two different bromination agents, namely bromine and N-bromo-succinimide (NBS), are sequentially added; the reaction temperature is strictly controlled, and thus 2-amino-5-bromopyridine can be quickly prepared with high yield andhigh purity; and the preparation method is applicable to industrial production. Additionally, a high-purity by-product, namely succinimide, is separated out in the preparation process and is brominated into high-purity NBS through potassium bromide, potassium bromate and sulfuric acid; and the NBS is applied to the synthesizing of 2-amino-5-bromopyridine in the method and has the same effect as the commercial NBS. According to the method, the quantity of used NBS is decreased, the raw material conversion rate is increased, and the bromination agents are recycled, so that the cost is greatly decreased; the main byproduct is only inorganic salt potassium sulfate; and the synthesizing method is green and environmentally friendly.

Description

technical field [0001] The invention belongs to the technical field of synthesis of pharmaceutical intermediates, and relates to a preparation method of pharmaceutical intermediates. Background technique [0002] 2-Amino-5-bromopyridine is an important pharmaceutical intermediate that can be used to synthesize PI 3 Kinase inhibitors, halopyridyl and thiazolyl thiourea compounds, aminopyridine derivatives selective for dopamine D 3 Receptor agonists, synthetic imidazo[1,2-a]pyridine compounds VEGFR-2 inhibitors and other drugs, also used in the treatment of autoimmune diseases, inflammatory diseases, cardiovascular diseases, neurodegenerative diseases, allergies, etc. many diseases. [0003] Chinese patent CN103755628A is prepared by dropping the saturated acetone solution containing N-bromosuccinimide into the acetone solution of 2-aminopyridine. This method uses a large amount of solvent, -10~-5 o The reaction temperature of C also greatly increases the energy consumptio...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D213/73
Inventor 高令峰郑庚修刘景宝付凯谷海洋
Owner UNIV OF JINAN
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