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Preparation method of 2-chloro-3-aminopyridine

A technology of aminopyridine and nitropyridine, applied in the field of preparation of 2-chloro-3-aminopyridine, can solve the problems of high price, complicated operation, difficult operation, etc., and achieves reduction of production cost, improvement of reaction yield, and simplified purification effect of steps

Active Publication Date: 2012-07-04
SINO HIGH CHINA
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AI Technical Summary

Problems solved by technology

[0009] In the above several methods for preparing 2-chloro-3-aminopyridine, the shortcoming of method (1) is that the chlorination of 3-aminopyridine one-step method must obtain a certain amount of by-products such as 4-chloro-3-aminopyridine, 2 , 5-dichloro-3-aminopyridine, etc., resulting in a darker color of the product, which is difficult to refine and purify
Although it can be recrystallized multiple times with organic solvents, the quality still cannot meet the high requirements, and repeated crystallization leads to low product yield, increased cost and cumbersome operation
CN 101514185A Although the by-product 2,5-dichloro-3-aminopyridine is converted into the raw material 3-aminopyridine, it needs to be separated from the product first, and then reduced to the raw material 3-aminopyridine by catalytic hydrogenation Pyridine, difficult to operate, little practical value
The chemical reduction method used in the method (2) is very serious to the corrosion of the equipment and the pollution of the environment, and the development has been restricted at present.
In method (3), the source of raw material 2-chloronicotinamide is limited, the price is expensive, and the operation is relatively troublesome
In method (4), need to use noble metal catalyst, increased preparation cost

Method used

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Experimental program
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Effect test

Embodiment 1

[0036] Embodiment 1: the preparation of N-alkyl-3-nitro-2-pyridone

[0037] 2-Pyridone (100g, 1.05mol) was added to a four-necked flask filled with concentrated sulfuric acid (200mL), and then a mixture of fuming nitric acid (67mL) and concentrated sulfuric acid (100mL) was added to the above-mentioned four-necked flask . The temperature of the whole process was controlled below 40°C, and stirred for 2h under this condition. Then, ice (900 g) and 40% NaOH (150 mL) solution were added to the reaction liquid. The mixture was extracted with toluene (1000 mL×3), the organic phases were combined and the precipitated crystals were filtered off. Concentrate and cool the filtrate to precipitate 3-nitro-2-pyridone; recrystallize with methanol to remove a small amount of 5-nitro-2-pyridone with relatively high solubility to obtain 3-nitro-2-pyridone Ketone 31.6g, m.p.224~225℃.

[0038] 3-nitro-2-pyridone (28g, 0.2mol) was dissolved in DMF (20mL), and then 10% KOH (16.8g, 0.3mol) aqu...

Embodiment 2

[0039] Embodiment 2: the preparation of 3-nitro-2-chloropyridine

[0040] Add N-methyl-3-nitro-2-pyridone (20 g, 0.13 mol) into a four-necked flask equipped with a reflux condenser, a thermometer and a stirring blade, and heat to 130° C. to dissolve it; then slowly Triphosgene (16.2 g, 0.054 mol) was added and the reaction mass was liquid. After the chlorination reaction is finished, add an appropriate amount of 40% NaOH aqueous solution (w / w) for treatment, adjust the pH to be weakly alkaline, and then carry out steam distillation to obtain 19.25 g of 2-chloro-3-nitropyridine with a yield of 93% , the content is 98.6%.

Embodiment 3

[0041] Embodiment 3: Preparation of 2-chloro-3-aminopyridine

[0042] In a nitrogen atmosphere, the TiCl 4 (2 mL, 0.018 mol) was slowly added into anhydrous tetrahydrofuran (50 mL) which was continuously stirred, and the temperature was controlled at 0°C. Further Mg (0.95 g, 0.04 mol) was added to the obtained yellow suspension, followed by reflux for 3 h to obtain a black suspension.

[0043] 2-Chloro-3-nitropyridine (16 g, 0.1 mol) was added portionwise to the above suspension at 0°C. The reaction mixture was stirred at room temperature for 1 h, then water (500 mL) and 25% aqueous ammonia solution (500 mL) were added. The mixture was extracted with ether (500 mL×5). MgSO for organic phase 4 After drying, it was evaporated to obtain 12.7 g of 2-chloro-3-aminopyridine with a yield of 98% and a content of 99.1%.

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Abstract

The invention discloses a new preparation method of 2-chloro-3-aminopyridine. The method comprises the following steps of: using 2-pyridone as the raw material to perform a nitration reaction and an N-alkylation reaction for amino protection to obtain N-alkyl-3-nitro-2-pyridone, then adding a proper chlorinating agent to perform a directional chlorination reaction and a dealkylation protection reaction to obtain 2-chloro-3-nitropyridine, and finally reducing to obtain 2-chloro-3-aminopyridine. The method has cheap and available raw materials, high selectivity, fewer by-products and high yield.

Description

technical field [0001] The invention belongs to the field of fine chemicals, in particular to a preparation method of 2-chloropyridine compounds, in particular to a preparation method of 2-chloro-3-aminopyridine using 2-pyridone as a raw material. Background technique [0002] Aminopyridine compounds are a kind of cyclic ammonia substances with heterocyclic structure, which are widely used in many fields of organic chemical industry. The new compounds obtained by replacing the benzene ring with pyridine have higher biological activity, or lower toxicity, or higher systemic and selectivity, so pyridine intermediates have been developed rapidly. [0003] 2-Chloro-3-aminopyridine is a class of very useful pyridine derivatives, and it is an important pharmaceutical and pesticide intermediate. It can be used as a viscosity regulator, and can be used to synthesize anti-peptic ulcer drugs pirenzepine, diazepine anti-AIDS drugs, and leukotriene biosynthesis inhibitors, and can be u...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D213/73
Inventor 汤浩严留新杲婷张海娟陈年海
Owner SINO HIGH CHINA
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