JP5142241B2 - Method for producing nicotinic acid ester compound - Google Patents

Description

  The present invention relates to an efficient method for producing a 2-mercaptonicotinic acid ester compound.

  It has been reported that derivatives of 2-mercaptonicotinic acid have various physiological activities. For example, a sulfenylurea derivative has a malignant cell growth inhibitory action (Non-Patent Document 1), a metal complex has an antimicrobial action (Non-Patent Document 2), an amide derivative has an antimicrobial action (Non-patent Document 3), and a hydrazide derivative. There are known rodenticides (Patent Document 1) and the like. It is important that the 2-mercaptonicotinic acid ester compound is a starting material for these physiologically active compounds and is efficiently synthesized.

As a method of forming a 2-mercaptonicotinic acid ester compound, a method of heating a carboxylic acid and an alcohol in an esterification reaction in the presence of an acid such as hydrochloric acid or sulfuric acid is already known (Non-Patent Document 4). This method has a problem of treatment of waste acid remaining after the reaction. In the reaction using sulfuric acid, which is the latter of these, it is known that an alkylation reaction occurs together with esterification, and the target ester compound cannot be obtained (Non-patent Document 5). In recent years, it has been necessary to consider low environmental load. In the case of supplying an acid into the reaction system, it is necessary to supply the acid in a controlled state with the aim of avoiding by-products as much as possible in consideration of the properties of the reaction raw materials. In general, a method using a dehydration condensing agent is known as a method for producing an ester compound. However, in these reactions, a by-product is always generated, which causes a problem in processing.
In order to avoid such a situation, changing the reaction raw materials has been studied. For example, it is known to synthesize an acid chloride using thionyl chloride and react an alcohol to produce an ester compound. In this method, it becomes a violent reaction and a lot of by-products are generated, which is not a fundamental solution (Non-patent Document 5).

  Based on the above background, when a 2-mercaptonicotinic acid compound is used as a starting material and a 2-mercaptonicotinic acid ester compound is formed, the desired product is obtained with high selectivity, and the remaining catalyst and catalyst There is an urgent need to establish a method that produces less waste from the by-products that have reacted with.

US Patent No. 2824876. M. J. Gill et al., Bioorg. Med. Chem. Lett., 9, 2321 (1999). K. Nomiya et al., Bull. Chem. Soc. Jpn., 73, 1143 (2000). M. Pregnolato et al., Pharmaco, 55, 669 (2000). M. Masaki and S. Matsunami, Bull. Chem. Soc. Jpn., 49, 3274 (1976). L. Katz et al., J. Org. Chem., 19, 711 (1954).

  An object of the present invention is to form a 2-mercaptonicotinic acid ester compound from a 2-mercaptonicotinic acid compound as a starting material, and to obtain a target product with high selectivity and to react with the remaining catalyst and the catalyst. It is to provide a method with less waste such as living things.

  In the reaction of esterifying 2-mercaptonicotinic acid with sulfuric acid, an abnormal alkylation reaction occurs. The reason is that the alcohol used reacts with sulfuric acid to produce a certain alkylating agent. In order to suppress this reaction, a method for suppressing the reaction of alcohol with sulfuric acid while keeping the acid function of sulfuric acid was considered. Therefore, the present inventors, as a result of intensive research on a method for producing a 2-mercaptonicotinic acid ester compound using a 2-mercaptonicotinic acid compound as a starting material, as a result of esterifying the 2-mercaptonicotinic acid compound, It has been found that when an acidic ion exchange resin is used as a catalyst, the target product can be obtained with high selectivity, and the remaining catalyst and waste such as by-products reacted with the catalyst are reduced, and the esterification reaction proceeds effectively. Thus, the present invention has been completed.

（式中、Ｒ^１は、炭素数１〜８の鎖状あるいは炭素数３〜８の環状のアルキル基、炭素数１〜８のアルコキシル基、炭素数２〜１２のアルコキシカルボニル基、フェニル基、及びハロゲン原子から選ばれる基又は原子を表す。Ｒ^１が複数ある場合は、各Ｒ^１は互いに同一であっても異なっていてもよく、ｎは、０または１〜３の整数である。Ｒ^２は、炭素数１〜６のアルキル基を示す。）

（式中、Ｒ^１は、炭素数１〜８の鎖状あるいは炭素数３〜８の環状のアルキル基、炭素数１〜８のアルコキシル基、炭素数２〜１２のアルコキシカルボニル基、フェニル基、及びハロゲン原子から選ばれる基又は原子を表す。Ｒ^１が複数ある場合は、各Ｒ^１は互いに同一であっても異なっていてもよく、ｎは、０または１〜３の整数である。）

（Ｒ^２は、炭素数１〜６のアルキル基を示す。） According to the present invention, the following inventions are provided.
In the method for producing a 2-mercaptonicotinic acid ester compound represented by the following general formula (A), the 2-mercaptonicotinic acid compound represented by the following general formula (B) is represented by the following general formula (C): A method for producing a 2-mercaptonicotinic acid ester compound, wherein an acidic ion exchange resin is used when reacting the alcohol compound.

(In the formula, R ¹ is a chain alkyl group having 1 to 8 carbon atoms or a cyclic alkyl group having 3 to 8 carbon atoms, an alkoxyl group having 1 to 8 carbon atoms, an alkoxycarbonyl group having 2 to 12 carbon atoms, a phenyl group, and if .R ¹ represents a group or atom selected from a halogen atom is more, each R ¹ may be the being the same or different, n is an integer of 0 or 1 to 3 .R ² represents an alkyl group having 1 to 6 carbon atoms.)

(In the formula, R ¹ is a chain alkyl group having 1 to 8 carbon atoms or a cyclic alkyl group having 3 to 8 carbon atoms, an alkoxyl group having 1 to 8 carbon atoms, an alkoxycarbonyl group having 2 to 12 carbon atoms, a phenyl group, and if .R ¹ represents a group or atom selected from a halogen atom is more, each R ¹ may be the being the same or different, n is an integer of 0 or 1-3.)

(R ² represents an alkyl group having 1 to 6 carbon atoms.)

The 2-mercaptonicotinic acid ester compound obtained in the present invention is a raw material for herbicides and fungicides.
According to the present invention, a 2-mercaptonicotinic acid ester compound can be synthesized with high yield. The side reaction, which is a problem that occurs when conventional acid is simply supplied, does not occur, the selectivity of the target substance is good, and the catalyst used reacts with the raw material to form a substance that is difficult to separate. In addition, when the catalyst is separated at the end of the reaction, it can be easily separated by filtration, can be reused, and the generated waste has less effect.

前記式中、Ｒ^１は、炭素数１〜８の鎖状あるいは炭素数３〜８の環状のアルキル基、炭素数１〜８のアルコキシル基、炭素数２〜１２のアルコキシカルボニル基、フェニル基、及びハロゲン原子から選ばれる基又は原子を示す。Ｒ^１が複数ある場合は、各Ｒ^１は互いに同一であっても異なっていてもよく、ｎは、０または１〜３の整数である。
Ｒ^２は、炭素数１〜６のアルキル基を示す。 The target compound of the present invention is a 2-mercaptonicotinic acid ester compound represented by the following general formula (A).

In the above formula, R ¹ is a chain alkyl group having 1 to 8 carbon atoms or a cyclic alkyl group having 3 to 8 carbon atoms, an alkoxyl group having 1 to 8 carbon atoms, an alkoxycarbonyl group having 2 to 12 carbon atoms, a phenyl group, And a group or atom selected from halogen atoms. When R ¹ are a plurality, each R ¹ may be the being the same or different, n is an integer of 0 or 1-3.
R ² represents an alkyl group having 1 to 6 carbon atoms.

Specific examples of the alkyl group for R ¹ include methyl, ethyl, propyl, isopropyl, butyl, t-butyl, isobutyl, pentyl, isopentyl, hexyl, isohexyl, heptyl, octyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclo A heptyl, a cyclooctyl group, etc. are mentioned.
Specific examples of the alkoxyl group for R ¹ include methoxy, ethoxy, propoxy, isopropoxy, cyclopropoxy, butoxy, isobutoxy, t-butoxy, pentyloxy, hexyloxy, cyclohexyloxyl groups and the like.
Specific examples of the alkoxycarbonyl group for R ¹ include methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, cyclopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, t-butoxycarbonyl, pentyloxycarbonyl, hexyloxycarbonyl, Examples thereof include a cyclohexyloxycarbonyl group.
Examples of the halogen atom for R ¹ include fluorine, chlorine, bromine and iodine.
Specific examples of the alkyl group for R ² include methyl, ethyl, propyl, isopropyl, butyl, t-butyl, isobutyl, pentyl, isopentyl, hexyl, isohexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl group and the like.

式中、Ｒ^１は、炭素数１〜８の鎖状あるいは炭素数３〜８の環状のアルキル基、炭素数１〜８のアルコキシル基、炭素数２〜１２のアルコキシカルボニル基、フェニル基、及びハロゲン原子から選ばれる基又は原子を表す。Ｒ^１が複数ある場合は、各Ｒ^１は互いに同一であっても異なっていてもよく、ｎは、０または１〜３の整数である。
前記式中、Ｒ^１は、前記一般式（Ａ）により示される２−メルカプトニコチン酸エステル化合物のＲ^１の場合と同じである。

式中、Ｒ^２は、炭素数１〜６の環状のアルキル基を示す。
前記式中、Ｒ^２は、前記一般式（Ａ）により示される２−メルカプトニコチン酸エステル化合物のＲ^２の場合と同じである。 The method for producing the 2-mercaptonicotinic acid ester compound represented by the general formula (A) is as follows.
The 2-mercaptonicotinic acid compound represented by the following general formula (B) is reacted with an alcohol compound represented by the following general formula (C) in the presence of an acidic ion exchange resin.

In the formula, R ¹ is a chain alkyl group having 1 to 8 carbon atoms or a cyclic alkyl group having 3 to 8 carbon atoms, an alkoxyl group having 1 to 8 carbon atoms, an alkoxycarbonyl group having 2 to 12 carbon atoms, a phenyl group, and A group or atom selected from halogen atoms is represented. When R ¹ are a plurality, each R ¹ may be the being the same or different, n is an integer of 0 or 1-3.
In the above formula, R ¹ is the same as R ¹ of the 2-mercaptonicotinic acid ester compound represented by the general formula (A).

Wherein, ^{R 2} represents a cyclic alkyl group having 1 to 6 carbon atoms.
In the above formula, R ² is the same as R ² of the 2-mercaptonicotinic acid ester compound represented by the general formula (A).

  The catalyst used in this reaction is an acidic ion exchange resin. The acidic ion exchange resin is not particularly limited as long as it is a known one, and a sulfonic acid type, a carboxylic acid type and the like can be used, and a strong acidic ion exchange resin such as a sulfonic acid type is preferably used. There are no particular restrictions on the type of acidic ion exchange resin, but examples include Amberlite (registered trademark), Amberlyst (registered trademark), Dowex (registered trademark), and Nafion (registered trademark). Trademark) or the like. Either a gel type or a porous type can be used. A particle size range of about 25 to 120 [mu] m can be used, and a cross-linking degree of any range can be used, but a cross-linking degree of 2 to 30% is most preferable. The amount of the acidic ion exchange resin used is usually 0.01 times to 10 times, preferably 0.1 to 1 times the weight of mercaptonicotinic acid.

  This reaction uses an alcohol compound as a reaction reagent and reaction solvent, but is in the form of a mixed solvent with an organic solvent such as chloroform, benzene, toluene, xylene, chlorobenzene, dichlorobenzene, anisole, acetonitrile, tetrahydrofuran, 1,4-dioxane. You can use it in

Reaction temperature can be performed at the temperature of the range of 50 to 150 degreeC. When the temperature is lower than this temperature range, the reaction time is delayed, and when it is too high beyond this range, there are many abnormal decomposition reactions and side reactions. Therefore, the temperature range is preferably in the range of 70 ° C to 120 ° C.
The reaction time depends on the reaction temperature and the type of alcohol compound, and cannot be determined in general, but is usually 5 to 20 hours.

(B) and (C), which are raw materials for the reaction, are known substances.
If an example of the manufacturing method of (B) is given, the manufacturing method by a 2-chloronicotinic acid compound and sodium hydrosulfide can be mentioned.
(C) may be a commercially available compound.

Specific examples of the 2-mercaptonicotinic acid ester compound obtained by the present invention are compounds represented by the following chemical formulas (1) to (3). However, it is not limited to these compounds.

These compounds of the present invention are used as raw materials for herbicides and fungicides.

Next, the present invention will be described in detail with reference to examples.
Examples described below are examples of typical compounds for facilitating the understanding of the present invention, and the present invention is not limited thereto. Further, the produced compounds (1) to (3) correspond to the compounds (1) to (3) shown above.

  In a glass container having an internal volume of 200 ml, 2-mercaptonicotinic acid (1000 mg, 6.4 mmol) was dissolved in ethanol (100 ml), Amberlyst (registered trademark) (Amberlyst 15,500 mg) was added, and the mixture was heated under reflux for 15 Stir for hours. After the acidic ion exchange resin was filtered off, ethanol was distilled off under reduced pressure to obtain ethyl 2-mercaptonicotinate of compound (1) as the target product (yield: 53%). Melting point 101.1-102.0 ° C.

  The same reaction was carried out using Amberlite (registered trademark) (Amberlite IR-120H) instead of Amberlist in Example 1 to obtain ethyl 2-mercaptonicotinate as the target compound (1) (yield) : 41%).

  The same reaction was carried out using Nafion (registered trademark) (NafionNR50) instead of Amberlyst in Example 1 to obtain ethyl 2-mercaptonicotinate as the target compound (1) (yield: 61%) ).

The same reaction was carried out using methanol instead of ethanol in Example 1, to obtain methyl 2-mercaptonicotinate of the target compound, compound (2) (yield: 63%).
Melting point 132.1-136.0 ° C. (literature value: 185-190 ° C.).

The same reaction was carried out using 6-methyl-2-mercaptonicotinic acid instead of 2-mercaptonicotinic acid in Example 1, and the target compound (3), ethyl 6-methyl-2-mercaptonicotinate, was obtained. Obtained (yield: 39%).
Melting point 129.1-130.4 ° C (literature value: 129-131 ° C).

Comparative Example 1
In a glass container having an internal volume of 100 ml, 2-mercaptonicotinic acid (1000 mg, 6.4 mmol) was dissolved in ethanol (50 ml), sulfuric acid (2 ml) was added, and the mixture was stirred for 10 hours under reflux with heating. After adding water and neutralizing sulfuric acid with an aqueous sodium carbonate solution, the product was extracted with methylene chloride. The organic layer was washed with water and dried over magnesium sulfate, and the solvent was removed under reduced pressure. Although the crude product was distilled under reduced pressure, the target compound (1) ethyl 2-mercaptonicotinate was not obtained, and the product was ethyl 2-ethylthionicotinate (yield 27%).

Comparative Example 2
In Comparative Example 1, the same reaction was performed using methanol instead of ethanol. The product obtained by recrystallizing the crude product from methanol-water was methyl 2-methylthionicotinate (yield 58%) instead of the target compound (2) methyl 2-mercaptonicotinate. It was.

Claims (1)

In the method for producing a 2-mercaptonicotinic acid ester compound represented by the general formula (A), the 2-mercaptonicotinic acid compound represented by the general formula (B) and the general formula (C The alcohol compound represented by this is made to react at the temperature of the range of 50-150 degreeC , The manufacturing method of the 2-mercaptonicotinic acid ester compound characterized by the above-mentioned.

(In the formula, R1 represents a chain alkyl group having 1 to 8 carbon atoms or a cyclic alkyl group having 3 to 8 carbon atoms, an alkoxyl group having 1 to 8 carbon atoms, an alkoxycarbonyl group having 2 to 12 carbon atoms, a phenyl group, and Represents a group or an atom selected from a halogen atom, and when there are a plurality of R1, each R1 may be the same as or different from each other, and n is 0 or an integer of 1 to 3. R2 is carbon Represents an alkyl group of formula 1. )

(In the formula, R1 represents a chain alkyl group having 1 to 8 carbon atoms or a cyclic alkyl group having 3 to 8 carbon atoms, an alkoxyl group having 1 to 8 carbon atoms, an alkoxycarbonyl group having 2 to 12 carbon atoms, a phenyl group, and Represents a group or an atom selected from halogen atoms, and when there are a plurality of R1, each R1 may be the same as or different from each other, and n is an integer of 0 or 1 to 3).

(R2 represents an alkyl group having 1 carbon atom.)