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A method for preparing 2-chloronicotinic acid

A technology of chloronicotinic acid and methyl formate, applied in the direction of organic chemistry and the like, can solve the problems of difficult to obtain raw materials, harsh requirements, large equipment investment, etc., and achieve the effects of easy availability of raw materials, mild and efficient reaction conditions, and low price.

Active Publication Date: 2017-02-22
JIANGSU ZHONGBANG PHARMA
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  • Application Information

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Problems solved by technology

[0003] At present, there are few literature reports on the method of synthesizing 2-chloronicotinic acid in China, and there are mainly four synthetic routes: (1) use nicotinic acid as raw material to prepare nicotinic acid-N-oxide, and then combine the oxide with POCl 3 Chlorination reaction prepares 2-chloronicotinic acid, and this method is because the selectivity of 2-position chlorination is not high and yield is low (Hiroshi Yamanaka.Site-selectivity in the Reaction of Pyridine 1-Oxides with Phosphoryl Chloride); (2) with 2 -Chloro-3-cyanopyridine is used as raw material to synthesize 2-chloronicotinic acid. The raw material of this method is difficult to obtain, so the possibility of industrialization is low (Delarge and C.L. Lapiere. Pyridinecar-boxysulfonic and Pyridine disulfonic Acid); (3) With 2-chloro-3-methylpyridine as raw material, the 3-methyl group is oxidized to carboxyl by mixed acid oxidation. This method requires harsh conditions, equipment investment is large, and waste water is produced. It is difficult to industrialized production (J.Cano mondejar , Juan Ferre, Gerardo.Span ES[P]:5011982); (4) Synthesize 2-chloronicotinic acid with 2-chloroaneonicotinoid as a raw material. This method is not only difficult to obtain raw materials, but also immature in process, basically not industrialized Conditions

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  • A method for preparing 2-chloronicotinic acid
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  • A method for preparing 2-chloronicotinic acid

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Experimental program
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Effect test

Embodiment 1

[0029] (1) Add compound (I) (44g, 1.0mol), compound (II) (85g, 1.0mol) into a 250mL four-neck flask, slowly add compound (III) (60g, 1.0mol) dropwise, and control the temperature to low At 25°C, after the dropwise addition, the temperature was raised to 40°C for 2 hours to obtain compound a (the reaction product of this step was detected by gas chromatography, the purity was 85%, and the yield was 90%, calculated as acetaldehyde).

[0030] (2) Add 100g of methanol into a 500mL four-necked bottle, and slowly add compound a (189g) and sulfuric acid dropwise at the same time. After 1 hour, the salt was removed by suction filtration, and 111 g of compound b was obtained after purification by vacuum distillation (the reaction product of this step was detected by gas chromatography, the purity was 88%, and the yield was 92%).

[0031] (3) Compound b (111 g), toluene (400 g), malononitrile (66 g, 1.0 mol), and ammonium acetate (2 g) were added into a 1000 mL four-necked flask, and ke...

Embodiment 2

[0036] (1) Add compound (I) (44g, 1.0mol), compound (II) (127.5g, 1.5mol) into a 250mL four-neck flask, slowly add compound (III) (90g, 1.5mol) dropwise, and control the temperature Lower than 10°C, after the dropwise addition, the temperature was raised to 0°C for 2 hours to obtain 189g of compound a (the reaction product of this step was detected by gas chromatography, the purity was 87%, and the yield was 45%, calculated as acetaldehyde).

[0037](2) Add 100g of methanol into a 500mL four-necked bottle, and slowly add compound a (189g) and sulfuric acid dropwise at the same time, control the temperature below 20°C, and the pH value below 2. After 1 hour, the salt was removed by suction filtration, and 47 g of compound b was obtained after purification by vacuum distillation (the reaction product of this step was detected by gas chromatography, the purity was 88%, and the yield was 78%).

[0038] (3) Compound b (47g), toluene (400g), malononitrile (66g, 1.0mol) and ammonium ...

Embodiment 3

[0043] (1) Add compound (I) (44g, 1.0mol), compound (II) (425g, 5.0mol) into a 250mL four-neck flask, slowly add compound (III) (300g, 5.0mol) dropwise, and control the temperature to low At 25°C, after the dropwise addition, the temperature was raised to 80°C for 2 hours to obtain 189g of compound a (the reaction product of this step was detected by gas chromatography, the purity was 83%, and the yield was 79%, calculated as acetaldehyde).

[0044] (2) Add 100g of methanol into a 500mL four-necked bottle, and slowly add compound a (189g) and sulfuric acid dropwise at the same time. After 1 hour, the salt was removed by suction filtration, and 86 g of compound b was obtained after purification by vacuum distillation (the reaction product of this step was detected by gas chromatography, the purity was 88%, and the yield was 82%).

[0045] (3) Compound b (86g), toluene (400g), malononitrile (66g, 1.0mol) and ammonium acetate (2g) were added into a 1000mL four-necked flask, and k...

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Abstract

The invention discloses an environment-friendly method for preparing 2-chloronicotinic acid. The implementation process of the present invention is as follows, using acetaldehyde, sodium methylate, and methyl formate as raw materials to generate sodium aldehyde vinyl alcoholate, then react with methanol to generate 1,1,-dimethoxypropanal, and then react with malononitrile to generate The cyclization precursor is then cyclized, chlorinated, and cyanohydrolyzed to generate 2-chloronicotinic acid. The invention has a novel route, mild reaction conditions in each step, high yield, and produces a small amount of waste water, which is conducive to reducing the production cost of 2-chloronicotinic acid and meets the conditions for industrialization. Select industrial products: acetaldehyde, sodium methoxide, and methyl formate as raw materials, the raw materials are easy to get, the price is cheap, the reaction conditions are mild and efficient, and green and environmentally friendly. A new route to acid.

Description

technical field [0001] The invention belongs to the field of organic chemistry, and in particular relates to a method for preparing 2-chloronicotinic acid. Background technique [0002] 2-Chloronicotinic acid, also known as 2-chloronicotinic acid, is a key pharmaceutical intermediate for the synthesis of the anti-AIDS drug nevirapine. It is widely used in the synthesis and research and development of medicines, pesticides, and veterinary drugs, and has high application value and market value. [0003] At present, there are few literature reports on the method of synthesizing 2-chloronicotinic acid in China, and there are mainly four synthetic routes: (1) use nicotinic acid as raw material to prepare nicotinic acid-N-oxide, and then combine the oxide with POCl 3 Chlorination reaction prepares 2-chloronicotinic acid, and this method is because the selectivity of 2-position chlorination is not high and yield is low (Hiroshi Yamanaka.Site-selectivity in the Reaction of Pyridine ...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D213/803C07D213/80
CPCC07D213/80C07D213/803
Inventor 高倩钱勇薛谊徐强赵华阳韩小军
Owner JIANGSU ZHONGBANG PHARMA