JP2008308458A - Production method of pyridinecarbonyl compound - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a method for commercially producing a pyridinecarbonyl compound (4) in almost the same yield as that by conventional methods, without causing the deposition of a chloro(trichloromethyl)pyridine compound which is a raw material for the pyridinecarbonyl compound. <P>SOLUTION: The manufacturing method of the pyridinecarbonyl compound represented by formula (4) (wherein R<SP>4</SP>is a hydrogen atom or a 1-4C alkyl group) comprises heating a mixture of the chloro(trichloromethyl)pyridine compound with concentrated sulfuric acid in an aromatic hydrocarbon compound bearing an electron-withdrawing group as a solvent and subsequently causing the thus-obtained intermediate to react with water or an alcohol. <P>COPYRIGHT: (C)2009,JPO&INPIT

Description

  The present invention is useful for formula (4) useful as an agrochemical intermediate:

（式中、Ｒ^４は水素原子又は炭素数１〜４のアルキル基を表す。）で示されるピリジンカルボニル化合物（以下、ピリジンカルボニル化合物（４）という。）の製造方法に関する。

(Wherein R ⁴ represents a hydrogen atom or an alkyl group having 1 to 4 carbon atoms) and relates to a method for producing a pyridinecarbonyl compound (hereinafter referred to as pyridinecarbonyl compound (4)).

  Conventionally, as a method for producing the pyridinecarbonyl compound (4), the formula (1):

で示されるクロロ（トリクロロメチル）ピリジン化合物（以下、クロロ（トリクロロメチル）ピリジン化合物（１）という。）と濃硫酸との混合物を無溶媒条件下で加熱した後、アルコールと反応せしめる方法が知られている（例えば、特許文献１参照）。かかる収率は８０％〜９５％程度である。また、アルコールに代えて水を用いれば、ピリジンカルボン酸類が得られる。
特開平１１−１３０７５２号公報

A method is known in which a mixture of chloro (trichloromethyl) pyridine compound (hereinafter referred to as chloro (trichloromethyl) pyridine compound (1)) and concentrated sulfuric acid is heated under solvent-free conditions and then reacted with alcohol. (For example, refer to Patent Document 1). Such yield is about 80% to 95%. If water is used instead of alcohol, pyridinecarboxylic acids can be obtained.
Japanese Patent Laid-Open No. 11-130752

The present inventor tried to produce a pyridinecarbonyl compound (4) according to a conventional method using 2-chloro-6-trichloromethylpyridine as a chloro (trichloromethyl) pyridine compound (1) as a raw material. During the heating of the mixture of 6-trichloromethylpyridine and concentrated sulfuric acid, it was found that 2-chloro-6-trichloromethylpyridine was deposited on the upper part of the reactor and the cooler part. Such a phenomenon may cause a decrease in yield, and on an industrial scale, cleaning of the reactor after completion of the reaction becomes complicated, so that the conventional method is still not satisfactory for industrial implementation. Absent.
Accordingly, an object of the present invention is to provide a method capable of industrially producing a pyridinecarbonyl compound (4) in a yield similar to that of the conventional method without precipitating the raw material chloro (trichloromethyl) pyridine compound (1). It is to provide.

  The present inventor has intensively studied to solve the above problems. As a result, it was found that the above precipitation does not occur when a mixture of 2-chloro-6-trichloromethylpyridine and concentrated sulfuric acid is heated in a solvent. However, when an aromatic hydrocarbon solvent substituted with an aliphatic or alicyclic hydrocarbon group such as o-xylene, mesitylene, tetrahydronaphthalene is used, the reaction mixture after completion of the reaction is colored black. Purification difficulties were expected. As a result of further examination, formula (2):

（式中、Ｒ^１は電子吸引性基を表し、Ｒ^２は水素原子又は炭素数１〜４のアルキル基を表す。）で示される芳香族炭化水素化合物（以下、芳香族炭化水素化合物（２）という。）を反応溶媒として用いれば、反応液が黒色に着色することなしに原料である２−クロロ−６−トリクロロメチルピリジンの析出もなく従来法と同程度の収率でピリジンカルボニル化合物（４）を製造できることを見出し、本発明を完成させるに至った。
即ち、本発明は、クロロ（トリクロロメチル）ピリジン化合物（１）と濃硫酸との混合物を、溶媒である芳香族炭化水素化合物（２）中で加熱した後、得られた中間生成物を水又は式（３）：
Ｒ^３−ＯＨ （３）
（式中、Ｒ^３は炭素数１〜４のアルキル基を表す。）で示されるアルコール（以下、アルコール（３）という。）と反応せしめることを特徴とするピリジンカルボニル化合物（４）の製造方法に関する。

(Wherein R ¹ represents an electron-withdrawing group, and R ² represents a hydrogen atom or an alkyl group having 1 to 4 carbon atoms) (hereinafter referred to as aromatic hydrocarbon compound (2 )) As a reaction solvent, the reaction solution is not colored black, and the raw material 2-chloro-6-trichloromethylpyridine is not precipitated, and the pyridinecarbonyl compound ( It was found that 4) can be produced, and the present invention has been completed.
That is, in the present invention, a mixture of a chloro (trichloromethyl) pyridine compound (1) and concentrated sulfuric acid is heated in an aromatic hydrocarbon compound (2) as a solvent, and then the obtained intermediate product is converted into water or Formula (3):
R ³ —OH (3)
(Wherein R ³ represents an alkyl group having 1 to 4 carbon atoms) and a method for producing a pyridinecarbonyl compound (4), characterized by reacting with an alcohol (hereinafter referred to as alcohol (3)) About.

  By the production method of the present invention, the pyridinecarbonyl compound (4) can be easily obtained industrially and easily in the same yield as the conventional one, without precipitating the chloro (trichloromethyl) pyridine compound (1) as compared with the conventional method. be able to.

The present invention is described in detail below.
In formula (2), R ¹ represents an electron-withdrawing group, preferably a nitro group or an acyl group, and particularly preferably a nitro group. Examples of the acyl group include an acetyl group, an ethylcarbonyl group, a propylcarbonyl group, and a butylcarbonyl group, and an acetyl group is preferable. Examples of the alkyl group having 1 to 4 carbon atoms represented by R ² include linear or branched alkyl groups having 1 to 4 carbon atoms, and specifically include, for example, a methyl group, an ethyl group, and a propyl group. , Isopropyl group, butyl group, isobutyl group, sec-butyl group and tert-butyl group.

In formula (3), examples of the alkyl group having 1 to 4 carbon atoms represented by R ³ include the same alkyl group as the alkyl group having 1 to 4 carbon atoms represented by R ² described above.

In formula (4), the alkyl group having 1 to 4 carbon atoms represented by R ⁴ includes the same alkyl group as the alkyl group having 1 to 4 carbon atoms represented by R ² described above.

  Specific examples of the chloro (trichloromethyl) pyridine compound (1) include 2-chloro-6-trichloromethylpyridine, 3-chloro-6-trichloromethylpyridine, 4-chloro-6-trichloromethylpyridine and 5-chloro- Examples include 6-trichloromethylpyridine, and 2-chloro-6-trichloromethylpyridine is preferable.

  Specific examples of the aromatic hydrocarbon compound (2) include nitrobenzene, 2-nitrotoluene, 3-nitrotoluene, 4-nitrotoluene, acetophenone, 2′-methylacetophenone, 3′-methylacetophenone, 4′-methylacetophenone, propio Examples include phenone, butyrophenone, and isobutyrophenone.

  Specific examples of the alcohol (3) include methanol, ethanol, propanol, isopropanol, butanol, isobutanol, sec-butanol and tert-butanol.

  Specific examples of the pyridinecarbonyl compound (4) include 2-chloro-6-pyridinecarboxylic acid, 3-chloro-6-pyridinecarboxylic acid, 4-chloro-6-pyridinecarboxylic acid, and 5-chloro-6-pyridinecarboxylic acid. Acid, methyl 2-chloro-6-pyridinecarboxylate, methyl 3-chloro-6-pyridinecarboxylate, methyl 4-chloro-6-pyridinecarboxylate, methyl 5-chloro-6-pyridinecarboxylate, 2-chloro- Ethyl 6-pyridinecarboxylate, ethyl 3-chloro-6-pyridinecarboxylate, ethyl 4-chloro-6-pyridinecarboxylate, ethyl 5-chloro-6-pyridinecarboxylate, propyl 2-chloro-6-pyridinecarboxylate Propyl 3-chloro-6-pyridinecarboxylate, propyl 4-chloro-6-pyridinecarboxylate, Propyl 6-pyridinecarboxylate, isopropyl 2-chloro-6-pyridinecarboxylate, isopropyl 3-chloro-6-pyridinecarboxylate, isopropyl 4-chloro-6-pyridinecarboxylate, 5-chloro-6-pyridinecarboxyl Isopropyl acid, butyl 2-chloro-6-pyridinecarboxylate, butyl 3-chloro-6-pyridinecarboxylate, butyl 4-chloro-6-pyridinecarboxylate, butyl 5-chloro-6-pyridinecarboxylate, 2-chloro -6-pyridinecarboxylic acid isobutyl, 3-chloro-6-pyridinecarboxylic acid isobutyl, 4-chloro-6-pyridinecarboxylic acid isobutyl, 5-chloro-6-pyridinecarboxylic acid isobutyl, 2-chloro-6-pyridinecarboxylic acid sec-butyl, 3-chloro-6-pyridinecarboxylic acid ec-butyl, sec-butyl 4-chloro-6-pyridinecarboxylate, sec-butyl 5-chloro-6-pyridinecarboxylate, tert-butyl 2-chloro-6-pyridinecarboxylate, 3-chloro-6-pyridine Examples include tert-butyl carboxylate, tert-butyl 4-chloro-6-pyridinecarboxylate and tert-butyl 5-chloro-6-pyridinecarboxylate.

  In the production method of the present invention, the aromatic hydrocarbon compound (2) solution of the chloro (trichloromethyl) pyridine compound (1) is heated to the reaction temperature, and then concentrated sulfuric acid is slowly added dropwise and then reacted at the same temperature. After obtaining the product, the intermediate product obtained is usually added to water or alcohol (3) cooled to 30 ° C. or lower. The concentrated sulfuric acid used in the present invention is usually 95% to 98% concentrated sulfuric acid. The amount of the concentrated sulfuric acid used is usually 1.0 mol or more, preferably 1.0 to 3.0 mol, particularly preferably 1.1 to 2 mol per mol of the chloro (trichloromethyl) pyridine compound (1). 0.0 mole. Moreover, the dripping speed | rate and dripping time of concentrated sulfuric acid should just be suitably determined with the reaction raw material, reaction scale, etc.

  The amount of the aromatic hydrocarbon compound (2) used is usually 0.5 parts by weight or more, preferably 0.6 to 3.0 parts by weight with respect to 1 part by weight of the chloro (trichloromethyl) pyridine compound (1). is there.

  The heating temperature is usually 100 ° C to 160 ° C, preferably 120 ° C to 140 ° C.

  The intermediate product obtained by the above-described method is presumed to be an intermediate product described in Patent Document 1 (Japanese Patent Application Laid-Open No. 11-130752).

  Water or alcohol (3) can be used alone or in admixture with a solvent inert to the reaction. Examples of the solvent inert to the reaction include aromatic hydrocarbon solvents such as toluene and xylene, and aliphatic or alicyclic hydrocarbon solvents such as hexane and cyclohexane. The usage-amount of water or alcohol (3) is 1 weight part or more normally with respect to 1 weight part of chloro (trichloromethyl) pyridine compounds (1), Preferably it is 2-10 weight part.

In order to isolate the pyridinecarbonyl compound (4) from the reaction mixture containing the pyridinecarbonyl compound (4) thus obtained, for example, the following method is exemplified.
When the pyridinecarbonyl compound (4) is isolated from the reaction mixture obtained by adding the product to water, the resulting reaction mixture is used at a pH of 10 to 12 using a base aqueous solution such as sodium hydroxide or lithium hydroxide. After adjusting to the range, the aqueous layer obtained by liquid separation is adjusted to a pH range of 1 to 3 using an aqueous acid solution such as hydrochloric acid, so that the pyridinecarbonyl compound (4) is precipitated. The pyridinecarbonyl compound (4) can be obtained by isolation by a desired isolation operation.
When the pyridinecarbonyl compound (4) is isolated from the reaction mixture obtained by adding the product to the alcohol (3), the excess alcohol (3) is removed by concentration, and then the pyridinecarbonyl compound (4) is added. After dissolving and adding to a mixed solvent of water and an organic solvent insoluble in water (for example, an aromatic hydrocarbon solvent such as toluene and xylene) and water, the obtained organic layer is concentrated to obtain a pyridinecarbonyl compound ( 4) can be obtained.

  EXAMPLES Next, although an Example demonstrates this invention further more concretely, this invention is not limited at all by the following examples.

Example 1
To a mixture of 100 g (0.433 mol) of 2-chloro-6-trichloropyridine and 100 g of nitrobenzene, 58.1 g (0.563 mol) of 95% by weight concentrated sulfuric acid was added dropwise at 135 ° C. over 1 hour. After dripping, it reacted at 135 degreeC for 2 hours. The solution color after the reaction was light yellow. The obtained product was cooled to 80 ° C., and then added to 500 mL of 0 ° C. water over 1 hour. The obtained reaction mixture was adjusted to pH 11 by adding 48% by weight aqueous sodium hydroxide solution, and adjusted to pH 2-3 by adding concentrated hydrochloric acid to the aqueous layer obtained by adding 100 mL of toluene and separating the solution. did. The precipitated white crystals were filtered, washed with water and toluene, and then dried under reduced pressure to obtain 56 g of 6-chloro-2-pyridinecarboxylic acid (yield 82%) as a white solid.

Example 2
To a mixture of 100 g (0.433 mol) of 2-chloro-6-trichloropyridine and 80 g of nitrobenzene, 71.5 g (0.693 mol) of 95 wt% concentrated sulfuric acid was added dropwise at 135 ° C. for 30 minutes. After the dropwise addition, the mixture was reacted at 135 ° C. for 3 hours, and the obtained product was cooled to 80 ° C. and then added to 250 g of ethanol at 20 ° C. over 1 hour. The obtained reaction mixture was concentrated to remove excess ethanol, and water and toluene were added for extraction and liquid separation, and then the obtained organic layer was concentrated to obtain a concentrated residue. The concentrated residue was purified by distillation to obtain 64 g (yield 80%) of ethyl 6-chloro-2-pyridinecarboxylate as a white solid.

Comparative Example 1
According to the method described in JP-A-11-130752, a mixture of 10 g (0.0433 mol) of 2-chloro-6-trichloromethylpyridine and 5.81 g (0.0563 mol) of 95% by weight concentrated sulfuric acid was heated to 135 ° C. When heated, a white solid was deposited on the top of the reactor and the cooler during heating. As a result of NMR analysis of the white solid, it was consistent with the NMR value of 2-chloro-6-trichloromethylpyridine. The weight of the white solid was 1.3 g (5.6 mmol). The NMR analysis results of white crystals and 2-chloro-6-trichloromethylpyridine are shown below.

NMR spectrum of white crystals
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 7.42 (1H, d, J = 7.8 Hz), 7.80 (1H, t, J = 7.8 Hz), 7.95 (1H, d, J = 7.8Hz)
NMR spectrum value of 2-chloro-6-trichloromethylpyridine
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 7.42 (1H, d, J = 7.8 Hz), 7.80 (1H, t, J = 7.8 Hz), 7.95 (1H, d, J = 7.8Hz)

  The reaction mixture obtained after completion of the reaction was worked up according to Example 1 to obtain 4.8 g of 6-chloro-2-pyridinecarboxylic acid (yield 70%).

Experimental Examples 1-3
The reaction was carried out in the same manner as in Example 1 except that the nitrobenzene of Example 1 was replaced with the aromatic hydrocarbon compound (2) shown in Table 1. When such a solvent was used, the reaction liquid became dark brown from the beginning of the addition of 95% by weight concentrated sulfuric acid, and the reaction liquid became black after the entire amount of concentrated sulfuric acid was added.

Claims (1)

Formula (1):

A mixture of a chloro (trichloromethyl) pyridine compound represented by the following formula (2):

(In the formula, R ¹ represents an electron-withdrawing group, R ² represents a hydrogen atom or an alkyl group having 1 to 4 carbon atoms), and after heating in an aromatic hydrocarbon compound represented by The product is water or formula (3):
R ³ —OH (3)
(Wherein R ³ represents an alkyl group having 1 to 4 carbon atoms) is reacted with an alcohol represented by formula (4):

(Wherein R ⁴ represents a hydrogen atom or an alkyl group having 1 to 4 carbon atoms).