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A kind of preparation method of 5-fluoro-3-aminopyridine

A technology of aminopyridine and equation, applied in the field of preparation of 5-fluoro-3-aminopyridine, can solve the problems of explosion risk, expensive 3-fluoronicotinic acid, expensive pentafluoropyridine, etc., and does not require high production equipment , Operation process safety, the effect of improving productivity

Active Publication Date: 2020-08-04
上海卡洛化学有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0004] The method for synthesizing 3-amino-5-fluoropyridine at present has Journal of Medicinal Chemistry, 1999, vol.42, # 18p.3701-3710 and WO2007076034 report, adopts 3-fluoronicotinic acid (structural formula is ) as the starting material, under the action of diphenyl phosphoryl azide, rearrange to N-Cbz-3-amino-5-fluoropyridine, and then remove the protecting group Cbz with palladium carbon to obtain 3-amino-5 -Fluoropyridine, this method is that the starting material 3-fluoronicotinic acid is very expensive at first, in addition, use phosphoryl azide diphenyl ester containing azide compound in the reaction process, generate acyl azide intermediate (structural formula) in the reaction process for ), there is a risk of explosion, not suitable for scale-up production
[0005] In addition, the literature Journal of the Chemical Society-Perkin Transactions 1, 1998, #10p.1705-1713 also reported that 3-amino-5-fluoropyridine was obtained through a three-step reaction with pentafluoropyridine, wherein the ammoniation required high pressure, and the other five The market price of flupyridine is very expensive and not suitable for mass production

Method used

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  • A kind of preparation method of 5-fluoro-3-aminopyridine
  • A kind of preparation method of 5-fluoro-3-aminopyridine
  • A kind of preparation method of 5-fluoro-3-aminopyridine

Examples

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Effect test

Embodiment 1

[0046] Embodiment 1: a kind of preparation method of 5-fluoro-3-aminopyridine, comprises following specific operation steps:

[0047] Step 1, the preparation of 2,6-dichloro-3-fluoronicotinamide:

[0048] S1. Add 43g of 2,6-dichloro-5-fluoronicotinic acid to 150ml of toluene, then add 86ml of thionyl chloride, heat to reflux for 3h, and then evaporate toluene and thionyl chloride under reduced pressure to obtain Yellow liquid 2,6-dichloro-3-fluoronicotinoyl chloride;

[0049] S2. Slowly add the yellow liquid in step S1 to 500ml of ammonia water at a rate of 5-10 drops / min, stir for 1h, pressurize and filter, and wash the filter cake twice with water to obtain a white solid 2, 6-dichloro-3-fluoronicotinamide 40g.

[0050] Its reaction equation is:

[0051]

[0052] Step 2, the preparation of 5-fluoronicotinamide:

[0053] Add 30g of 2,6-dichloro-3-fluoronicotinamide to 300ml of methanol, then add 28.8g of triethylamine and 3g of palladium carbon, and continue to feed hyd...

Embodiment 2

[0064] Example 2: A preparation method of 5-fluoro-3-aminopyridine, the difference from Example 1 is: in step 1, S1, 45g of 2,6-dichloro-5-fluoronicotinic acid Add to 160ml of toluene, then add 88ml of thionyl chloride, heat to reflux for 4h, then evaporate toluene and thionyl chloride under reduced pressure to obtain a yellow liquid;

[0065] S2. Slowly add the yellow liquid in step S1 to 500ml of ammonia water at a rate of 5-10 drops / min, stir for 1 hour, pressurize and filter, and wash the filter cake twice with water to obtain a white solid 2,6 -Dichloro-3-fluoronicotinamide 38g.

[0066] In addition, the remaining steps were carried out in the same manner as in Example 1, and 15 g of yellow solid 5-fluoro-3-aminopyridine was obtained, wherein the yield of 5-fluoro-3-aminopyridine was 79.2%.

Embodiment 3

[0067] Example 3: A preparation method of 5-fluoro-3-aminopyridine, the difference from Example 1 is: Step 2, 33g of 2,6-dichloro-3-fluoronicotinamide is added to 320ml of In methanol, then add 28g of inorganic alkali sodium bicarbonate and 2.5g of tetrakis (triphenylphosphine) palladium, and continue to feed hydrogen, filter out tetrakis (triphenylphosphine) palladium after reacting at room temperature for 15h, and get final product 17 g of 5-fluoronicotinamide was obtained. In addition, the remaining steps were carried out in the same manner as in Example 1, and 12 g of yellow solid 5-fluoro-3-aminopyridine was obtained, wherein the yield of 5-fluoro-3-aminopyridine was 63.4%.

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Abstract

The invention discloses a preparation method of 5-fluorine-3-aminopyridine, and belongs to the technical field of pyridine compounds. The preparation method is characterized by comprising the following steps: adding 5-fluoronicotinamide into a hypohalite solution dropwise, and then stirring at 0 to 100 DEG C until a TLC reaction is completed; after the solution is cooled to room temperature, adding a sodium hydroxide solution, continuously stirring for 20 to 40 min, and performing filtering and drying to obtain a 5-fluorine-3-aminopyridine solid. The preparation method not only has a safe operation process, is easy and convenient and has low requirements for production equipment, but also is suitable for enlarging the production on the basis of guaranteeing the product quality and high yield.

Description

technical field [0001] The invention belongs to the technical field of pyridine compounds, more specifically, it relates to a preparation method of 5-fluoro-3-aminopyridine. Background technique [0002] Pyridine is a six-membered heterocyclic compound containing a nitrogen heteroatom. It can be regarded as a compound in which one (CH) in the benzene molecule is replaced by N, so it is also called nitrogen benzene, a colorless or slightly yellow liquid with a foul smell. Its structural formula is: Pyridine and its homologues exist in bone tar, coal tar, gas, shale oil, and petroleum, and pyridine can be used industrially as a denaturant, dyeing aid, and to synthesize a series of products (including pharmaceuticals, disinfectants, dyes etc.) raw materials, has a wide range of application value. [0003] 3-Amino-5-fluoropyridine is an important intermediate, which is mainly used in medicine and organic synthesis. For example, 3-amino-5-fluoropyridine is an important interm...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D213/73
CPCC07D213/73
Inventor 谭君成张银兰
Owner 上海卡洛化学有限公司