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The synthetic method of 4-amino-2-chloro-3-nitropyridine

A technology of nitropyridine and synthesis method, applied in the synthesis field of 4-amino-2-chloro-3-nitropyridine, can solve the problem of inability to separate by column chromatography, changing mobile phase ratio, poor separation effect, etc. question

Active Publication Date: 2016-05-04
HEBEI UNIVERSITY OF SCIENCE AND TECHNOLOGY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0004] There are also some reports on the preparation method of 4-amino-2-chloro-3-nitropyridine in the prior art, but the yield of the produced product is low, such as the world patent WO2007047793 is a cyclopentenol nucleoside compound intermediate The synthesis of body and the method for treating virus infection, adopt 2-chloro-4-aminopyridine as raw material, 70% fuming nitric acid and concentrated sulfuric acid are used as mixed acid, carry out nitration reaction, adopt silica gel column chromatography to carry out separation product, obtain 70% of 4-amino-2-chloro-3-nitropyridine and 25% of 4-amino-2-chloro-5-nitropyridine, and 5% of impurities
[0005] The world patent WO200684281 is a preparation of nucleoside derivatives of E1 active enzyme inhibitors, using 2-chloro-4-aminopyridine as raw material, 90% fuming nitric acid and concentrated sulfuric acid as mixed acid for nitration reaction, and the obtained product is The mixture of 4-amino-2-chloro-3-nitropyridine and 4-amino-2-chloro-5-nitropyridine is separated by flash column chromatography, and the mobile phase used is dichloromethane: ethyl acetate 1:4 ester, 44% of 4-amino-2-chloro-3-nitropyridine was obtained, but the product was obtained in low yield
And the dichloromethane in the mobile phase is very volatile in the air, which may cause the ratio of the mobile phase to change, the separation effect is not good, column chromatography cannot separate a large number of products, and the activity of fuming nitric acid is higher at the same time , but its price is relatively expensive, which greatly limits its industrial production

Method used

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  • The synthetic method of 4-amino-2-chloro-3-nitropyridine

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Experimental program
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Embodiment

[0030] Embodiment 1 A kind of synthetic method of 4-amino-2-chloro-3-nitropyridine

[0031] A kind of synthetic method of 4-amino-2-chloro-3-nitropyridine adopts 2-chloro-4-aminopyridine as raw material, and 65% nitric acid and concentrated sulfuric acid are used as mixed acid to carry out nitration reaction to prepare 4-amino-2- Chloro-3-nitropyridine generates 4-amino-2-chloro-5-nitropyridine at the same time, and the corresponding pure product is obtained after recrystallization and purification. The process is as follows:

[0032] .

[0033] Its synthetic method is carried out according to the following sequence of steps:

[0034] 1) Dissolve 200g of 2-chloro-4-aminopyridine in 1200mL of concentrated sulfuric acid at 0°C, add dropwise 1000mL of 65% nitric acid, after the addition, react at 15°C for 2h, then pour into ice In water, stir at 0°C, add NH 3 Regulate the pH to be 3, separate out white powdery solid I, filter;

[0035] 2) Dissolve the white powdery solid I ...

Embodiment 2

[0039] Embodiment 2 A kind of synthetic method of 4-amino-2-chloro-3-nitropyridine

[0040] A kind of synthetic method of 4-amino-2-chloro-3-nitropyridine adopts 2-chloro-4-aminopyridine as raw material, and 65% nitric acid and concentrated sulfuric acid are used as mixed acid to carry out nitration reaction to prepare 4-amino-2- Chloro-3-nitropyridine generates 4-amino-2-chloro-5-nitropyridine at the same time, and the corresponding pure product is obtained after recrystallization and purification. The process is as follows:

[0041] .

[0042] Its synthetic method is carried out according to the following sequence of steps:

[0043] 1) At 0°C, dissolve 200g of 2-chloro-4-aminopyridine in 1800mL of concentrated sulfuric acid, add dropwise 1000mL of 65% concentrated nitric acid, after the dropwise addition, react at 20°C for 2h, then pour into Stir in ice water at 0°C, add NH 3 Regulate pH to be 3, separate out white powdery solid I, filter; Then,

[0044] 2) Dissolve th...

Embodiment 3-124

[0048] The synthetic method of embodiment 3-124-amino-2-chloro-3-nitropyridine

[0049] Embodiment 3-7 is respectively a kind of synthetic method of 4-amino-2-chloro-3-nitropyridine, and the difference between them and Example 1 is that the technical parameters involved in the synthetic method are different, specifically as follows Show:

[0050]

[0051]

[0052] Note: Isomer purity and yield refer to the total purity and yield of 4-amino-2-chloro-3-nitropyridine and 4-amino-2-chloro-5-nitropyridine.

[0053] Embodiments 8-12 are respectively a kind of synthetic method of 4-amino-2-chloro-3-nitropyridine, and they differ from Example 2 only in that the technical parameters involved in the synthetic method are different, specifically as follows Show:

[0054]

[0055]

[0056] Note: Isomer purity and yield refer to the total purity and yield of 4-amino-2-chloro-3-nitropyridine and 4-amino-2-chloro-5-nitropyridine.

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Abstract

The invention discloses a method for synthesizing 4-amino-2-chlorine-3-nitro pyridine. The method comprises the following steps: adopting 65% nitric acid and concentrated sulfuric acid as mixed acid for nitratlon reaction, wherein the yield of the prepared isomer 4-amino-chlorine-3-nitro pyridine and 4-amino-2-chlorine-5-nitro pyridine is 95 to 98%, the purity is 95 to 99.5%, and subsequently purifying through recrystallization, effectively separating the prepared 4-amino-2-chlorine-3-nitro pyridine and 4-amino-2-chlorine-5-nitro pyridine, wherein the yield of the prepared 4-amino-2-chlorine-3-nitro pyridine is 75 to 85%, the purity of the prepared 4-amino-2-chlorine-3-nitro pyridine is 95 to 99%, the yield of the prepared 4-amino-2-chlorine-5-nitro pyridine is 15 to 25%, and the purity of the prepared 4-amino-2-chlorine-5-nitro pyridine is 95 to 99%. The method is applicable to preparation of 4-amino-2-chlorine-3-nitro pyridine and 4-amino-2-chlorine-5-nitro pyridine, and medicines such as an E1 active enzyme inhibitor, an adenosine homocysteine hydrolase inhibitor, a PLK1 recombinant protein inhibitor and benzimidazole can be further prepared.

Description

technical field [0001] The invention belongs to the field of pharmacy and relates to a synthesis method of 4-amino-2-chloro-3-nitropyridine. Background technique [0002] 4-Amino-2-chloro-3-nitropyridine is an intermediate of antiviral hydrolase inhibitors, which can resist vaccinia virus, smallpox virus, human cytomegalovirus, zoster virus, HIV virus, H 1 N 1 and H 3 N 2 Viruses, etc.; or an intermediate of a nucleoside derivative (E1 activity enzyme inhibitor), used to treat cell proliferation disorders, including cancer, inflammation and neurological disorders. [0003] 4-Amino-2-chloro-5-nitropyridine is an intermediate of benzimidazole derivatives, which is used to treat diseases such as bone development disorders; it is also an intermediate of a PLK1 recombinant protein inhibitor, which is used to treat cell proliferation Disease, especially cancer. [0004] There are also some reports on the preparation method of 4-amino-2-chloro-3-nitropyridine in the prior art,...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D213/73
CPCC07D213/73
Inventor 于奕峰徐世霞张越
Owner HEBEI UNIVERSITY OF SCIENCE AND TECHNOLOGY
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