JPH1149753A - Production of 2-chloronicotinic acid - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide an advantageous method for industrially producing 2- chloronicotinic acid from nicotinic acid N-oxide as a raw material. SOLUTION: This method for producing 2-chloronicotinic acid comprises reacting nicotinic acid N-oxide with phosphorus oxychloride and thionyl chloride.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention relates to a method for producing 2-chloronicotinic acid.

[0002]

2. Description of the Related Art 2-Chloronicotinic acid is a compound useful as a synthetic intermediate for pharmaceuticals, agricultural chemicals and the like. Conventionally, as a method for producing 2-chloronicotinic acid using nicotinic acid N-oxide as a starting material, nicotinic acid in phosphorus oxychloride is used.
A method of reacting N-oxide with phosphorus pentachloride is known [J. Org. Chem. , 19 , 1663 (195
4) and Hungarian Patent Specification HU 33,46
4].

There is also a method of reacting nicotinic acid N-oxide with phosphorus oxychloride in the presence of a large amount of triethylamine or a hydrochloride thereof (Hungarian Patent Specification HU 66,392).

Furthermore, a method of reacting nicotinic acid N-oxide with phosphorus oxychloride in the presence of a large amount of triethylamine and ammonium chloride has also been disclosed (Hungarian Patent Specification HU 22, 161).

[0005] However, these methods have disadvantages in that wastewater treatment problems due to the use of a large amount of phosphorus pentachloride and use of a large amount of an organic base material which is difficult to recover.

[0006]

SUMMARY OF THE INVENTION An object of the present invention is to provide an advantageous method for industrially producing 2-chloronicotinic acid from nicotinic acid N-oxide as a raw material.

[0007]

DISCLOSURE OF THE INVENTION The present invention relates to nicotinic acid
The present invention relates to a method for producing 2-chloronicotinic acid, comprising reacting N-oxide with phosphorus oxychloride and thionyl chloride.

According to the method of the present invention, the desired 2-chloronicotinic acid can be industrially advantageously produced. That is, according to the method of the present invention, highly pure 2-chloronicotinic acid can be obtained with a simple operation in a high yield of 50% or more.

The mixing ratio of the nicotinic acid N-oxide and the phosphorus oxychloride is not particularly limited and can be appropriately selected. It is preferable to use 6 times mol.

On the other hand, the mixing ratio of nicotinic acid N-oxide and thionyl chloride is not particularly limited and can be appropriately selected. It is preferable to use 0.8 to 1.5 times mol.

Generally, when chlorinating using thionyl chloride, a small amount of dimethylformamide (DM
It is known that the presence of F) results in an increased reaction effect. However, in the case of the present invention, the addition of DMF had the opposite effect, leading to a considerable reduction in yield.

A preferred embodiment of the method of the present invention will be described below. One of them is usually 50 to 130 ° C, preferably 60 to 120 ° C, particularly preferably 70 to 95 ° C.
A clear solution is obtained by gradually adding nicotinic acid N-oxide to phosphorus oxychloride, which is kept at a temperature of ° C., while stirring and keeping the temperature. Thereafter, a small amount of thionyl chloride was added while maintaining the temperature, and 1 to 3 after the addition was completed.
In this method, heating and stirring are continued for about an hour to hydrolyze the obtained reaction product.

Second, nicotinic acid N-oxide is suspended in phosphorus oxychloride at about room temperature, and this suspension is heated with stirring, and when a clear liquid is obtained, thionyl chloride is gradually added dropwise. This is a method in which heating and stirring are continued for about 3 hours after the completion of dropping, and the obtained reaction product is hydrolyzed.

In the present invention, hydrolysis can be performed as described above. As the hydrolysis conditions, conventional hydrolysis conditions can be widely applied, for example, decomposition in a cooled alkaline aqueous solution, acidification (for example, pH 2) after sufficient cooling.
Then, the precipitated crystals may be separated and dried, or the above reaction product may be added to the fine ice water with stirring.

[0015]

EXAMPLES Hereinafter, the present invention will be described specifically with reference to Synthesis Examples of the compounds of the present invention. However, these are merely examples of preferred embodiments, and the present invention is not limited by these Examples. Absent.

Example 1 A small amount of nicotinic acid N-oxide (10 g, 71.9 mmol) was added to 35 ml (58.3 g, 380 mmol) of phosphorus oxychloride while stirring at room temperature to gradually give an emulsion. When the addition is complete, the emulsion is heated in an oil bath to keep the temperature of the emulsion at 75-80C. When a pale yellow clear liquid was obtained, thionyl chloride (12.83
g, 108 mmol) at 80 ° C. or lower over 20 to 30 minutes. After completion of the dropping, the temperature of the oil bath is raised to 115 to 1
The temperature is raised to 20 ° C., and heating and stirring are continued at this temperature for 2 hours. After the reaction is completed, when the temperature of the reaction solution falls to room temperature,
Excess phosphorus oxychloride is recovered under reduced pressure. In order to sufficiently recover phosphorus oxychloride, 20 to 30 ml of dichloromethane is added to the remaining yellow viscous liquid to make a homogeneous liquid, and then dichloromethane is distilled off again under reduced pressure. Residual phosphorus oxychloride also distills. When this operation is repeated two or three times, most of the phosphorus oxychloride is distilled off. While vigorously stirring the remaining yellow viscous liquid, 1
Add a small amount to 00 g of fine ice water. After stirring for 2 hours,
The precipitated white crystals of 2-chloronicotinic acid, which is the desired product, are collected by filtration, washed with water and dried. 6.10 g of 2-chloronicotinic acid having a melting point of 180-181 ° C. (decomposition) were obtained. Yield 54%.

The embodiments of the present invention are listed below. (1) A process for producing 2-chloronicotinic acid, comprising reacting nicotinic acid N-oxide with phosphorus oxychloride and thionyl chloride. (2) A method for producing 2-chloronicotinic acid, wherein nicotinic acid N-oxide is added first while stirring phosphorus oxychloride, and then thionyl chloride is added and reacted. (3) A method for producing 2-chloronicotinic acid, wherein nicotinic acid N-oxide is dispersed in phosphorus oxychloride, and thionyl chloride is added to react. (4) The method according to (1), (2) or (3), wherein the reaction product 2-chloronicotinic acid chloride obtained by reacting nicotinic acid N-oxide with phosphorus oxychloride and thionyl chloride is hydrolyzed. -A process for producing chloronicotinic acid.

[0018]

According to the present invention, it is possible to provide a novel method for producing highly pure 2-chloronicotinic acid in a high yield of 50% or more by industrially simple means.

Claims (1)

[Claims] 1. A method for producing 2-chloronicotinic acid, comprising reacting nicotinic acid N-oxide with phosphorus oxychloride and thionyl chloride.