Method for preparing 2-chloronicotinic acid

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

Active Publication Date: 2015-05-06
JIANGSU ZHONGBANG PHARMA
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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 has low yield due to the low selectivity of 2-position chlorination (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.Lap

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Examples

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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 a green and environment-friendly method for preparing 2-chloronicotinic acid. The implementation process of the method comprises the following steps: generating aldehyde sodium ethenolate by taking acetaldehyde, sodium methylate and methyl formate as raw materials; reacting with methyl alcohol to generate 1,1-dimethoxy propionaldehyde; reacting with malononitrile to generate a cyclization precursor; and carrying out cyclization, chlorination and cyan-hydrolysis to generate the 2-chloronicotinic acid. The method provided by the invention is novel in line, mild in reaction condition of each step, relatively high in yield, less in generated wastewater and beneficial for reducing the production cost of the 2-chloronicotinic acid, and has industrialization condition. By selecting industrialization products such as the acetaldehyde, the sodium methylate and the methyl formate as raw materials which are easy to get, low in cost, mild and efficient in reaction condition, green and environment-friendly, the invention provides a new way which is novel and efficient and can be used for industrially producing the 2-chloronicotinic 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 has low yield due to the low selectivity of 2-position chlorination (Hiroshi Yamanaka.Site-selectivity in the Reaction of Pyridine 1-Oxides with P...

Claims

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Application Information

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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
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