Synthesis method of 3-fluorine-4-aminopyridine

A technology of aminopyridine and synthesis method, which is applied in the direction of organic chemistry, can solve the problems of easy explosion, low yield, difficult separation and purification, etc., and achieve the effect of high total yield, simple operation process and improved safety

Active Publication Date: 2010-10-20
上海联友制药技术有限公司 +2
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0008] The purpose of the present invention is to provide a synthetic method of 3-fluoro-4-aminopyridine with high yield, safe reaction, low pollution and easy industrial pr

Method used

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  • Synthesis method of 3-fluorine-4-aminopyridine
  • Synthesis method of 3-fluorine-4-aminopyridine
  • Synthesis method of 3-fluorine-4-aminopyridine

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0020] 1). Preparation of 3-fluoro-4-pyridinecarboxylic acid

[0021] In a 250ml reaction flask, add 60ml of anhydrous tetrahydrofuran and 5.7g of diisopropylamine, cool to -25°C, add 22.5ml of 2.5M n-butyllithium dropwise, and keep the reaction solution at -30~-25°C After reacting for 1.5 hours, cool to -70°C, add 5.0g of 3-fluoropyridine, react at -70°C for 3 hours, slowly inject carbon dioxide gas, and warm the reaction solution to room temperature. Add 30ml of water dropwise into the reaction flask. Concentrate and distill off tetrahydrofuran. The pH of the reaction solution was adjusted to 3-5 with 2mol / l hydrochloric acid. At this point a large amount of solid appeared. The reaction was stirred at room temperature for 1 hour. Filter to get white solid powder. The powder was dried at 45° C. for 24 hours to obtain 6.5 g of product with a yield of 90% and a purity of 98%.

[0022] 1H-NMR (300MHz, D 2 O): 8.51(d, 2H), 8.42(dd, 1H), 7.57(t, 1H).

[0023] 2). Preparati...

Embodiment 2

[0049] 1). Preparation of methyl 3-fluoro-4-pyridinecarboxylate

[0050] In a 250ml reaction flask, add 480ml of anhydrous methanol and 71g of 3-fluoro-4-pyridinecarboxylic acid. Add 89.2 g of thionyl chloride dropwise to the reaction flask. After the dropwise addition, the reaction solution was heated to reflux. The reaction solution was refluxed for 24 hours. The reaction was cooled to room temperature. The solvent and excess thionyl chloride were distilled off to obtain a crude product. The crude product was washed with 200 ml of petroleum ether to obtain 71 g of methyl 3-fluoro-4-picolinate, with a yield of 91% and a purity of 96%.

[0051] 1H-NMR (300MHz, CD 3 OD): 9.08(d, 1H), 8.85(d, 1H), 8.34(t, 1H), 4.02(s, 3H).

[0052] 2) Preparation of ethyl 3-fluoro-4-pyridinecarboxylate

[0053] In a 250ml reaction flask, add 480ml of absolute ethanol and 71g of 3-fluoro-4-pyridinecarboxylic acid. Add 89.2 g of thionyl chloride dropwise to the reaction flask. After the d...

Embodiment 3

[0074] 1) Preparation of 3-fluoro-4-pyridinecarboxamide (optimum conditions)

[0075] In a 250ml reaction flask, add 50ml of anhydrous methanol and 5.0g of methyl 3-fluoro-4-picolinate. The reaction solution was cooled to -20~0°C. Slowly feed 15 g of ammonia gas into the reaction flask at -20 to 0 degrees. After the addition of ammonia gas was completed, the reaction solution was warmed up to room temperature and stirred at room temperature for 6 hours. Ammonia and solvent were evaporated under reduced pressure to obtain 4.1 g of a light yellow solid product with a yield of 91% and a purity of 96%.

[0076] 1H-NMR (300MHz, CDCl 3 ): 8.60 (m, 2H), 7.94 (t, 1H), 6.67 (br s, 1H), 6.41 (br s, 1H).

[0077] 2) Preparation of 3-fluoro-4-pyridinecarboxamide (tetrahydrofuran)

[0078] In a 250ml reaction flask, add 50ml tetrahydrofuran and 5.0g methyl 3-fluoro-4-picolinate. The reaction solution was cooled to -20~0°C. Slowly feed 15 g of ammonia gas into the reaction flask at -20...

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Abstract

The invention relates to 3-fluorine-4-aminopyridine, in particular to a synthesis method of the 3-fluorine-4-aminopyridine, mainly aiming at solving the technical problems of low yield, difficult separation and purification, easy explosion and the like of the existing synthesis method. The method has the technical scheme of: 1) taking 3-fluorine pyridine (1-A) as a raw material, using strong base to remove proton, carrying out reaction with carbon dioxide, and obtaining 3-fluorine-4-pyridine carboxylic acid or metal salt (1B); 2) carrying out esterification reaction on the compound (1B), and obtaining 3-fluorine-4-pyridine formic ether (1C); 3) carrying out ammonolysis reaction on the 3-fluorine-4-pyridine formic ether (1C), and generating 3-fluorine-4-pyridine carboxamide (1D); and 4) carrying out Hofmann degradation reaction on the 3-fluorine-4-pyridine carboxamide (1D), and generating the 3-fluorine-4-aminopyridine (1). The 3-fluorine-4-aminopyridine is an important intermediate for synthesizing multiple new medicines.

Description

technical field [0001] The present invention relates to 3-fluoro-4-aminopyridine, in particular to a synthesis method of 3-fluoro-4-aminopyridine, which plays an important role in the field of new drug research. Background technique [0002] At present, more and more fluorine-containing heterocyclic compounds appear in new drug structures. 3-Fluoro-4-aminopyridine is an important intermediate in the synthesis of various new drugs. It is an intermediate in the synthesis of transforming growth factor-β inhibitor (I) and an intermediate in the synthesis of thrombin inhibitor (II). [0003] [0004] Compound (I) Compound (II) [0005] USUS20030926793 discloses a method for synthesizing 3-fluoro-4-aminopyridine (Formula 1). The method uses 3-fluoropyridine as a raw material, oxidizes it with hydrogen peroxide to obtain pyridine nitrogen oxide, and then nitrates it with mixed acid at high temperature. Reaction to obtain nitro compounds, and then reduction of nitro compounds t...

Claims

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Application Information

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IPC IPC(8): C07D213/73
Inventor 施雄伟郭振荣刘小宁朱乐荣
Owner 上海联友制药技术有限公司
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