Preparation method of 2-amino-4-fluoropyridine

A technology of fluoropyridine and amino, which is applied in the field of preparation of 2-amino-4-fluoropyridine, can solve the problems of large amount of three wastes, high cost, expensive raw materials, etc., and achieve the effect of safe operation, simple operation and short steps

Inactive Publication Date: 2018-08-24
SHANGHAI LINKCHEM TECH CO LTD
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0004] Patent WO201100790761 reported that 2-chloro-4-fluoropyridine was used as the starting material, 2-Boc amino-4-fluoropyridine was obtained through palladium catalysis, and the final product was obtained by removing the protecting group. The raw material of this route is more expensive, and the Noble metal catalyst, so the cost is high, only suitable for the preparation of a small amount of compounds
Another preparation route, using mixed acid nitration technology, uses a large amount of sulfuric acid, and the amount of post-treatment three wastes is very large, which is not suitable for industrial production

Method used

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  • Preparation method of 2-amino-4-fluoropyridine
  • Preparation method of 2-amino-4-fluoropyridine

Examples

Experimental program
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Embodiment 1

[0020] Embodiment 1: Preparation of 2-amino 4-fluoropyridine

[0021] Slowly add 580 grams of 2-pyridinecarboxylic acid into 1.68 kilograms of thionyl chloride, add 48 grams of sodium bromide therein, and reflux the reaction solution for 2-16 hours until the reaction of the raw materials is complete, and the thionyl chloride is recovered. Obtain 680 grams of 4-chloropyridine-2-acyl chloride; 4-chloropyridine-2-acyl chloride is added in batches to 4 kg of 30% aqueous ammonia, stirred at room temperature for 5-16 hours until the reaction is complete, and most of the water is removed , the temperature was lowered to 0-5° C., and a white solid was precipitated and dried to obtain 4-chloropyridine-2-amide, 550 g, with a yield of 95%. 1 H NMR (300MHz, DMSO-d 6 ): δ8.60(d, J=5.7Hz, 1H), 8.16(bs, 1H), 8.01(d, J=2.1Hz, 1H), 7.78(bs, 1H), 7.74(d, J=2.1Hz , 1H).

[0022] Add 550 grams of 4-chloropyridine-2-amide in batches to 10 kg of sodium hypochlorite solution with a mass concentra...

Embodiment 2

[0024] Embodiment 2: the preparation of 2-amino 4-fluoropyridine

[0025] Slowly add 40 grams of 2-pyridinecarboxylic acid into 116 grams of thionyl chloride. After the addition is complete, add 1 gram of N,N-dimethylformamide to it, and reflux the reaction solution for 2-16 hours until the reaction of the raw materials is complete. Thionyl chloride was recovered to obtain 46 grams of 4-chloropyridine-2-acyl chloride; 4-chloropyridine-2-acyl chloride was dissolved in 200 ml of 1,4-dioxane, and ammonia gas was passed into it for 5-16 hours After the reaction was completed, most of the solvent was removed, the temperature was lowered to 0-5° C., and a white solid was precipitated and dried to obtain 4-chloropyridine-2-amide, 37 g, with a yield of 93%.

[0026] Add 35 grams of 4-chloropyridine-2-amide in batches to the calcium hypochlorite aqueous solution, which is prepared from 78 grams of calcium hypochlorite and 1 liter of water, and heat up to 60-80°C for reaction after addi...

Embodiment 3

[0028] Embodiment 3: Preparation of 2-amino 4-fluoropyridine

[0029] Slowly add 160 grams of 2-pyridinecarboxylic acid into 460 grams of thionyl chloride. After the addition, 35 grams of sodium chloride is added thereto, and the reaction solution is refluxed for 2-16 hours until the reaction of the raw materials is complete, and the thionyl chloride is recovered. Obtain 170 grams of 4-chloropyridine-2-acyl chloride; 4-chloropyridine-2-acyl chloride was dissolved in 2000 milliliters of tetrahydrofuran, and ammonia gas was passed into it for 5-16 hours until the reaction was complete, most of the solvent was removed, and the temperature was lowered to 0 -5°C, a white solid was precipitated and dried to obtain 4-chloropyridine-2-amide, 132 g, yield 90%.

[0030] Slowly add 236 grams of bromine dropwise into aqueous sodium hydroxide solution prepared by dissolving 118 grams of sodium hydroxide in 1 liter of water, and add 120 grams of 4-chloropyridine-2-amide to the reaction solu...

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Abstract

The invention discloses a preparation method of 2-amino-4-fluoropyridine, comprising the synthetic steps of 1, subjecting 2-pyridinecarboxylic acid as a raw material to reaction in the presence of thionyl chloride and a salt to obtain 4-chloropyridine-2-acyl chloride, and subjecting 4-chloropyridine-2-acyl chloride the presence of ammonia to obtain 4-chloropyridine-2-amide; 2, subjecting 4-chloropyridine-2-amide to Hofmann rearrangement reaction to obtain 2-amino-4-chloropyridine; 3, subjecting 2-amino-4-chloropyridine to halogen exchange to obtain 2-amino-4-fluoropyridine. The problems of theexisting preparation method, such as long synthetic path, operational complexity, high pollution of three wastes, poor atomic economy, low yield and high manufacture cost, are solved.

Description

technical field [0001] The invention relates to the field of organic synthesis chemistry, in particular to a preparation method of 2-amino-4-fluoropyridine, which plays an important role in the field of new drug research. Background technique [0002] Pyridine compounds are currently one of the most widely developed and applied varieties of heterocyclic compounds. Among natural products, many are derivatives of pyridine, including niacin, niacinamide, isoniazid, nicotine, and strychnium Sub alkali, vitamin B6 and so on. Organic fluorine compounds usually have very special physical and chemical properties, and are widely used in the pharmaceutical industry. Among the new drugs currently on the market, 15-20% are organic fluorine compounds; due to the specific biological activity and biological adaptability of fluorine atoms , The curative effect of fluorine-containing drugs is several times stronger than that of general drugs, such as the sedative droperidol; the antineoplas...

Claims

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Application Information

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IPC IPC(8): C07D213/73
CPCC07D213/73
Inventor 梁驻军
Owner SHANGHAI LINKCHEM TECH CO LTD
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