JPH09169733A - Production of 4-trifluoromethylnicotinic acid - Google Patents

Abstract

PROBLEM TO BE SOLVED: To produce a 4-trifluoromethylnicotinic acid useful as agrochemicals, etc., in high yield by reacting an amino-trifluoro-buten-one with a specific compound in a smaller number of reactional steps under milder conditions as compared with those of a conventional method according to a new method using the compounds as raw materials. SOLUTION: The condensation reaction of a 4-amino-1,1,1-trifluoro-3-buten-2- one of formula I with a compound of the formula ACO2 R [A is (R'O)CH=CH or (R'O)2 CHCH2 (R' is an alkyl); R is a residue capable of forming an ester] is initially carried out to provide a compound of formulas II and/or III and a salt thereof. The cyclizing and hydrolytic reactions of the resultant reactional product are then performed in the presence of preferably a base and a solvent at 10-80 deg.C for 2-16hr to afford the objective compound of formula IV. The condensation reaction is preferably conducted in the presence of sodium borohydride and the solvent by using 1.02-1.06mol compound of the formula ACO2 R based on 1mol compound of formula I. The reactional temperature of the condensation reaction is usually -20 to 1-100 deg.C and the reactional time is preferably 0.3-6hr.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a novel method for producing 4-trifluoromethylnicotinic acid represented by the following formula (V) or a salt thereof, which is useful as an active ingredient of agricultural chemicals or a precursor for manufacturing agricultural chemicals or pharmaceuticals. And intermediates thereof.

[0002]

As a method for producing 4-trifluoromethylnicotinic acid, the method described in JP-A-6-321903 and the method described in JP-A-7-10841 are known. The former has many reaction steps and is complicated, and the reaction conditions are severe, and the latter also has many reaction steps and is complicated. Therefore, these methods require improvement in industrial production such as high cost.

[0003]

The problem to be solved by the present invention is to produce a target compound in a high yield under a mild reaction condition with a small number of reaction steps.

[0004]

The present invention provides a compound of formula (V);

Embedded image

A process for producing 4-trifluoromethylnicotinic acid or a salt thereof represented by the formula (I):

Embedded image

A compound represented by the general formula (II); A
CO ₂ R ... (II) (wherein R is an ester-forming residue,
A is (R'O) CH = CH- group or (R'O) ₂ CH
A CH ₂ — group. However, R ′ is an alkyl group) and the compound represented by the formula (III) which is a reaction product is subjected to a condensation reaction;

Embedded image

Compounds (including salts thereof) represented by the formula (wherein R is an ester-forming residue) and / or general formula (IV);

[0008]

Embedded image (Wherein R and R ′ are as described above) (including salts thereof), and then the reaction product is subjected to ring closure and hydrolysis reaction.
-A method for producing trifluoromethylnicotinic acid or a salt thereof. The present invention also relates to a compound of the general formula (III) or a salt thereof, which is an intermediate for producing the compound of the formula (V), a compound of the general formula (IV) or a salt thereof.

Examples of the ester-forming residue represented by R in the general formulas (II), (III) and (IV) include an alkyl group, an alkenyl group, an alkynyl group and a phenyl group, and an alkyl group is preferable. . The compound of the general formula (II) includes the compound of the general formula (II-1); (R'O) ₂ CHCH ₂
CO ₂ R ... (II-1) (wherein R is an ester-forming residue and R ′ is an alkyl group) and a compound represented by the general formula (II-2); (R′O) CH = CHCO ₂ R ... (II
-2) (wherein R is an ester-forming residue and R'is an alkyl group), and there are two types of compounds, and an alkyl group related to R in these compounds and R The alkyl group represented by ′ is a linear or branched alkyl group having 1 to 6 carbon atoms, for example, a methyl group,
Examples thereof include an ethyl group, a propyl group, an isopropyl group, a butyl group, and a tertiary butyl group. Among them, a methyl group and an ethyl group are preferable, and a methyl group is more preferable. The alkyl groups represented by R and R'in formula (II-1) or (II-2) may be the same or different, but are preferably the same.

The reaction flow of the method for producing 4-trifluoromethylnicotinic acid or a salt thereof according to the present invention will be described below in detail.

Embedded image (In the formula, R is an ester-forming residue, and A is (R'O) C.
H = CH- group or (R'O) ₂ CHCH ₂ - is a radical. However, R'is an alkyl group)

The amount of the compound of formula (I) and the compound of general formula (II) used in the condensation reaction varies depending on the kind of the compound of general formula (II) and other reaction conditions described below, and cannot be unconditionally specified. Usually, the compound of the general formula (II) is used in a proportion of 1.0 to 1.2 mol, preferably 1.02 to 1.06 mol, relative to 1 mol of the compound of the formula (I).

The reaction temperature and reaction time of the condensation reaction differ depending on the kind of the compound of the general formula (II) and other reaction conditions described below and cannot be specified unconditionally, but the reaction temperature is usually from -20 to + 100 ° C. The reaction time is usually 0.1 to 12 hours, preferably 0.3 to 6 hours.

As described above, the compound of the general formula (II) includes the compound of the general formula (II-1) and the compound of the general formula (II-2). Depending on which compound is used in the condensation reaction. Since the reaction conditions of the reaction will change, they will be described below.

First, the reaction conditions when the condensation reaction is carried out using the compound of general formula (II-1) as the compound of general formula (II) will be described. The reaction temperature in this case is preferably -10 to + 75 ° C, and it is desirable to carry out the reaction in the presence of a base in order to carry out the condensation reaction efficiently. Specific examples of the base used include hydrides of alkali metals such as sodium hydride and potassium hydride; alkyl lithiums such as n-butyl lithium and t-butyl lithium; alkali metals such as sodium and potassium;
Alkali metal hydroxides such as sodium hydroxide and potassium hydroxide; alkoxides such as sodium methoxide, sodium ethoxide, potassium methoxide and potassium t-butoxide; basic heterocyclic compounds such as pyridine and quinoline. Among them, alkali metal hydrides are preferable, and sodium hydride is particularly preferable. These bases can be used alone or in combination. The amount of the base used in this case varies depending on the type of the compound of the general formula (II-1), the presence or absence of the use of a solvent, the difference in the reaction conditions, and the like, and cannot be unconditionally specified, but it is On the other hand, 1.0 to 1.2 equivalents, and preferably 1.02 to 1.06 equivalents of the base are usually used.

In order to efficiently carry out the condensation reaction between the compound of formula (I) and the compound of general formula (II-1), it is desirable to carry out the reaction in the presence of a solvent. The solvent is present in the reaction in the form of a compound of formula (I) or a compound of general formula (II
In a reaction system in which each solution in which the compound of -1) is dissolved in a solvent is reacted, or in which a solution in which one of the compounds is dissolved is reacted with the other compound, or both compounds are dissolved There is a mode in which a solution of a base dissolved in a solvent is added. Specific solvents used are polar aprotic solvents such as N, N-dimethylformamide and acetonitrile; halogenated hydrocarbons such as methylene chloride and chloroform; ethers such as diethyl ether and tetrahydrofuran; methanol. , Alcohols such as ethanol; basic heterocyclic compounds such as pyridine and quinoline, and polar aprotic solvents are preferable, and among them, N, N-
Dimethylformamide is particularly desirable. These solvents can be used alone or in combination. The amount of the solvent used in the condensation reaction varies depending on the type of the compound of the general formula (II-1), the presence or absence of a base, the difference in the reaction conditions, etc., and cannot be specified unconditionally. On the other hand, the solvent is usually used in a proportion of 1 to 30 parts by weight, preferably 4 to 15 parts by weight.

The compound of the above formula (I) and the general formula (II-1)
In the condensation reaction with the compound of formula (III), the compound of formula (III) or a salt thereof is produced via the compound of formula (IV) or a salt thereof. This is because, out of the two R'O groups present in the compound of general formula (II-1), only one is eliminated first to form the compound of general formula (IV) or a salt thereof. Then, when the other R'O group remaining in the compound of the general formula (IV) or the salt thereof is eliminated, the compound of the general formula (III) or the salt thereof is produced. That is,

[0017]

Embedded image 2 in which R and R ′ are as described above
The stepwise reaction produces compounds of general formula (III) (including salts thereof) and / or compounds of general formula (IV) (including salts thereof). In order to obtain only the compound of the general formula (IV) or a salt thereof, it is possible to obtain 0.2-
It is necessary to carry out the condensation reaction for 4 hours to completely advance only the first stage reaction. In order to obtain the compound of the general formula (III) or the salt thereof from the compound of the general formula (IV) or the salt thereof thus obtained, the condensation is conducted at a high temperature of 40 to 75 ° C. for 0.1 to 2 hours. It is necessary to carry out the reaction and allow the second stage reaction to proceed.

Next, the reaction conditions when the condensation reaction is carried out using the compound of the general formula (II-2) as the compound of the general formula (II) will be described. The condensation reaction in this case is carried out in the presence of a base or an acid. Further, since the reaction mechanism is different between the reaction in the presence of a base and the reaction in the presence of an acid, it will be described in detail below.

When the compound of formula (I) and the compound of general formula (II-2) are subjected to a condensation reaction in the presence of a base, the reaction temperature is preferably -10 to + 65 ° C. In particular, when an alkali metal hydride or alkyl lithium is used as the base, the reaction can be carried out at room temperature of 0 to 30 ° C. Specific examples of the base used include hydrides of alkali metals such as sodium hydride and potassium hydride; alkyl lithiums such as n-butyl lithium and t-butyl lithium; alkali metals such as sodium and potassium; Alkali metal hydroxides such as sodium hydroxide and potassium hydroxide; sodium methoxide, sodium ethoxide, potassium methoxide, potassium t
-Alkoxides such as butoxide. These bases can be used alone or in combination.

The compound of the above formula (I) and the general formula (II-2)
In the presence of a base with a compound of
The compound (III) or a salt thereof is produced via the compound of the general formula (IV) or a salt thereof. That is,

Embedded image The reaction proceeds by the reaction mechanism as described above to produce a compound of the general formula (III) (including a salt thereof) and / or a compound of the general formula (IV) (including a salt thereof). The reaction product produced may be a compound of the general formula (III) or a salt thereof, a compound of the general formula (IV) or a salt thereof, or a mixture thereof depending on the reaction conditions. It depends.

When the compound of formula (I) and the compound of general formula (II-2) are subjected to a condensation reaction in the presence of an acid,

Embedded image

The reaction proceeds by a reaction mechanism such as
It is considered that the reaction of forming the compound (III) proceeds. The reaction temperature in this case is preferably -10 to +1.
00 ° C. Specific examples of the acid used include strong inorganic acids such as concentrated sulfuric acid, concentrated hydrochloric acid, concentrated nitric acid, and phosphoric acid; strong organic acids such as methanesulfonic acid, p-toluenesulfonic acid, and trifluoromethanesulfonic acid. And so on. These acids can be used alone or in combination.

Among the above-mentioned acids or bases, it is preferable to use an alkali metal hydride or alkyl lithium, and it is particularly preferable to use an alkali metal hydride. Among them, it is most desirable to use sodium hydride. The amount of the base or acid used in the condensation reaction when the compound of the general formula (II-2) is used varies depending on the type of the compound of the general formula (II-2), the use of a solvent, the difference in reaction conditions, etc. Although it cannot be unconditionally specified, the base or acid is usually used in a ratio of 1.0 to 1.2 equivalents, preferably 1.02 to 1.06 equivalents, relative to 1 mol of the compound of the formula (I).

In order to efficiently carry out the condensation reaction between the compound of formula (I) and the compound of general formula (II-2), it is desirable to carry out the reaction in the presence of a solvent. The solvent is present in the reaction in the form of a compound of formula (I) or a compound of general formula (II
Each of the solutions in which the compound of -2) was dissolved in a solvent was reacted, or the solution in which one of the compounds was dissolved was reacted with the other compound, or both compounds were dissolved in the solvent. There is a form in which a solution is reacted with a solution in which an acid or a base is dissolved in a solvent. Specifically used solvents are polar aprotic solvents such as N, N-dimethylformamide and acetonitrile;
Halogenated hydrocarbons such as methylene chloride and chloroform; Ethers such as diethyl ether and tetrahydrofuran; Alcohols such as methanol and ethanol; Aromatic hydrocarbons such as benzene and toluene;
Examples thereof include basic heterocyclic compounds such as pyridine and quinoline. Among them, polar aprotic solvents are preferable, and N, N-dimethylformamide is particularly preferable. These solvents can be used alone or in combination. When a polar aprotic solvent is mixed with at least one solvent selected from halogenated hydrocarbons, ethers and aromatic hydrocarbons, it is equivalent to the case where a polar aprotic solvent is used alone. The effect is obtained. Among these combinations of solvents, N, N-dimethylamide and toluene are preferably mixed and used in the range of 1: 100 to 100: 1, preferably 2: 1 to 4: 1. The amount of the solvent used in the condensation reaction varies depending on the type of the compound of the general formula (II), the presence or absence of a base, the difference in the reaction conditions, etc., and cannot be specified unconditionally. Usually 1 to 30 parts by weight, preferably 4
The solvent is used in a proportion of ˜15 parts by weight.

Various conditions in the condensation reaction described above, that is, various reactions depending on the amounts of the compound of the formula (I) and the compound of the general formula (II) and the kind of the compound of the general formula (II). When setting the conditions, the reaction temperature and the reaction time, they can be appropriately selected from the numerical values in the normal range and the numerical values in the desirable range shown for each condition and combined with each other.

When the condensation reaction is carried out in the presence of a base containing an alkali metal, the compound of the general formula (III) is

Embedded image

(Wherein Met is an alkali metal element and R is as described above) to form a salt, and the compound of the general formula (IV) is

Embedded image

Since a salt represented by the formula (wherein Met, R and R ′ are as described above) is formed, the reaction product of the condensation reaction may contain these salts.
In such a case, after completion of the condensation reaction, the reaction product is neutralized with a mineral acid such as hydrochloric acid or sulfuric acid to give a compound represented by the general formula (I
The compound of II) and / or the compound of general formula (IV) can be obtained in high yield.

The compound of the general formula (III) and / or the compound of the general formula (IV) is isolated by performing post-treatments such as solid-liquid separation, washing and drying after the completion of the condensation reaction. The compound of the general formula (III) has the following tautomers,
Especially, it is easily isomerized in a solvent.

Embedded image

Thus, in the isolated compound of general formula (III), the general formula (III '):

Embedded image

A compound represented by may be included.
Further, the compound of the general formula (IV) also has the following tautomers.

Embedded image

In order to efficiently carry out the ring closure and the hydrolysis reaction of the product of the condensation reaction, it is desirable to carry out the reaction in the presence of a base. Specific examples of the base used include alkali metals such as sodium and potassium; hydroxides of alkali metals such as sodium hydroxide and potassium hydroxide; sodium methoxide, sodium ethoxide, potassium methoxide, potassium t. -Alkoxides such as butoxide; basic heterocyclic compounds such as pyridine and quinoline, and the like. Among them, alkali metals, alkali metal alkoxides or alkali metal hydroxides are preferable, and among them, sodium or sodium methoxide. Is especially desirable. These bases can be used alone or in combination. The amount of the base used in the ring closure and the hydrolysis reaction varies depending on the presence or absence of the use of a solvent and the reaction conditions, and cannot be specified unconditionally.
The base is used in a ratio of 2.0 equivalents, preferably 0.5 to 1.2 equivalents.

In order to efficiently carry out the ring closure and hydrolysis reaction, it is desirable to carry out the reaction in the presence of a solvent. The existing form of the solvent in the reaction includes a form in which the reaction is performed in the solvent, a form in which the solvent is added to the reaction system of the reaction, and the like. Specific examples of the solvent used include water; alcohols such as methanol and ethanol, and these can be used alone or in combination or in combination. Among the solvents, alcohols are preferable, and methanol or ethanol is particularly preferable. The amount of the solvent used in the ring-closing and hydrolysis reaction cannot be unconditionally determined depending on the presence or absence of a base and the difference in the reaction conditions, but is usually 1 to 30 parts by weight, preferably 4 parts by weight with respect to 1 part by weight of the product of the condensation reaction. The solvent is used in a proportion of ˜15 parts by weight.

The reaction temperature and reaction time in the ring-closing and hydrolysis reaction are as follows, whether or not a solvent or a base is used,
The reaction temperature is usually 0 to 120 ° C., preferably 10 although it cannot be specified unconditionally because it varies depending on the kind of them.
The reaction time is usually 1 to 24 hours, preferably 2 to 16 hours.

In the ring closure and hydrolysis reaction, the desired compound of formula (V) is formed via the cyclic carboxylic acid ester. That is, the ring closure and the hydrolysis reaction are composed of two steps of a ring closure reaction for producing a cyclic carboxylic acid ester from the product of the condensation reaction and a hydrolysis reaction for obtaining the target compound of the formula (V) from the cyclic carboxylic acid ester. . In order to obtain the target compound of the formula (V) in high yield, the ring closure reaction is allowed to proceed completely to obtain a cyclic carboxylic acid ester,
It is desirable that this is hydrolyzed in the presence of water, alcohols or a mixture thereof, preferably water.

The various conditions in the above-mentioned ring-closing and hydrolysis reactions, that is, the presence or absence of a base and a solvent, their amounts, the reaction temperature and the reaction time are set for each condition. Further, it is possible to appropriately select and combine from the values in the normal range and the values in the desired range. The selected combination of various conditions in the condensation reaction can be further appropriately mutually selected and combined with the selected combination of various conditions in the ring closure and hydrolysis reaction.

The desired 4-trifluoromethylnicotinic acid of the formula (V) can be obtained by subjecting the reaction product to post-treatments such as usual solid-liquid separation, washing and drying after completion of the ring closure and the hydrolysis reaction. Isolated.

[0038]

BEST MODE FOR CARRYING OUT THE INVENTION Next, some preferred embodiments of the present invention will be illustrated.

(1) A compound of the formula (I) and a compound of the general formula (II)
The compound of the general formula
A compound of formula (V) (III) (including a salt thereof) and / or a compound of general formula (IV) (including a salt thereof) is obtained, and then the reaction product is subjected to ring closure and hydrolysis reaction. A method for producing fluoromethylnicotinic acid or a salt thereof. (2) The production method of (1), wherein the compound of formula (I) and the compound of general formula (II-1) are subjected to a condensation reaction. (3) The production method of (1), wherein the compound of formula (I) and the compound of general formula (II-2) are subjected to a condensation reaction in the presence of a base or an acid.

(4) The method of (2), wherein the condensation reaction is carried out in the presence of a base and / or a solvent. (5) The method of (3), wherein the condensation reaction is performed in the presence of a solvent. (6) The method according to (1), (2), (3), (4) or (5), wherein the ring closure and the hydrolysis reaction are carried out in the presence of a base and / or a solvent. (7) In the condensation reaction, the compound of the general formula (II) is used in a proportion of 1.0 to 1.2 mol with respect to 1 mol of the compound of the formula (I) (1), (2), (3). The method according to (4), (5) or (6).

(8) A compound of the general formula (III) or a salt thereof. (9) A compound of the general formula (III ′) or a salt thereof. (10) A compound of the general formula (IV) or a salt thereof.

(11) The compound of formula (I) and the compound of general formula (I
The compound of general formula (II
Compounds of I) (including salts thereof) and / or general formula (I)
A method for producing a compound of V) (including a salt thereof). (12) The production method of (11), wherein the compound of formula (I) and the compound of general formula (II-1) are subjected to a condensation reaction. (13) A compound of formula (I) and a compound of general formula (II-2) are subjected to a condensation reaction in the presence of a base or an acid (11).
Manufacturing method. (14) 4-trifluoromethylnicotine of the formula (V) for ring-closing and hydrolyzing a compound of the general formula (III) (including a salt thereof) and / or a compound of the general formula (IV) (including a salt thereof) A method for producing an acid or a salt thereof.

(15) In the condensation reaction, 1.0 to 1.2 mol of the compound of the general formula (II-1) is added to 1 mol of the compound of the formula (I) in the presence of a base and a solvent. 10
After the compound of general formula (IV) is formed by reacting at ~ + 30 ° C for 0.2-4 hours, the compound of the general formula (IV) is added at 40-7
The method of (2) or (12), wherein the compound of the general formula (III) or a salt thereof is obtained by reacting at a high temperature of 5 ° C. for 0.1 to 2 hours.

(16) The method according to (14), wherein the ring closure and the hydrolysis reaction are carried out in the presence of a base and / or a solvent. (17) In the ring closure and hydrolysis reaction, the compound of the general formula (II
The compound of formula (I) and / or the compound of formula (IV) is added in the presence of a base and alcohols at 50 to 120 ° C. to 2-1.
After ring-closing reaction for 2 hours to form a cyclic carboxylic acid ester, this is hydrolyzed in the presence of water, alcohols or a mixture thereof (1) or (1
Method 4).

In an embodiment of the present invention, the reaction conditions described above, that is, the base and / or solvent in the condensation reaction, the base and / or solvent in the ring closure and hydrolysis reaction, the compound of formula (I) and the general formula (II) It is possible to appropriately combine the amount of the compound used in (1), the temperature of the condensation reaction, the temperature of the ring closure and the hydrolysis reaction, and the like.

The general formula (III), which is an intermediate of the present invention,
Preferred compound or salt thereof is N-2-alkoxycarbonylvinyl 4,4,4-trifluoro-
3-oxo-1-butenylamine or a salt thereof,
Among them, N-2-methoxycarbonyl vinyl 4,
4,4-trifluoro-3-oxo-1-butenylamine, N-2-ethoxycarbonylvinyl 4,4,4-
Trifluoro-3-oxo-1-butenylamine or salts thereof are particularly desirable.

Further, the compound of the general formula (IV) which is an intermediate of the present invention
Preferred compound or salt thereof is N-1-alkoxy-2-alkoxycarbonylethyl 4,4,4
-Trifluoro-3-oxo-1-butenylamine or a salt thereof, among which N-1-methoxy-2-methoxycarbonylethyl 4,4,4-trifluoro-
3-oxo-1-butenylamine, N-1-ethoxy-
2-Ethoxycarbonylethyl 4,4,4-trifluoro-3-oxo-1-butenylamine or salts thereof are particularly desirable.

[0048]

The present invention will be described in more detail with reference to the following Examples, which do not limit the present invention.

Example 1 (1) Condensation reaction step 3,3-dimethoxypropionic acid methyl ester 11.
18 g (0.076 mol) and sodium hydride (60
% Oil suspension) (3.04 g, 0.076 mol) was added to 65 ml of N, N-dimethylformamide, and then ice-cooled. Then 4-amino-1,1,
1-trifluoro-3-buten-2-one 10.0 g
(0.072 mol) was gradually added dropwise. After dropping,
The reaction solution was allowed to return to room temperature, reacted for 2 hours with stirring, heated to 50 ° C., and further reacted for 1 hour. After the reaction was completed, the obtained reaction solution was poured into 300 ml of ice water, and concentrated hydrochloric acid was added to neutralize the solution. The precipitate was collected by filtration and washed with cold water to give N-2-methoxycarbonylvinyl 4,4,4-trifluoro-3-oxo-1-butenylamine (melting point 93.0-95.3 ° C) 12. 06 g
Was obtained (75% yield).

(2) Ring-closing and hydrolysis reaction step A solution of 0.87 g (0.038 mol) of metallic sodium in 200 ml of methanol was added to a solution of N-2-methoxycarbonylvinyl 4,4,4 obtained by the condensation reaction.
-Trifluoro-3-oxo-1-butenylamine 1
After adding 2.06 g (0.054 mol), the mixture was reacted with heating under reflux for 12 hours while stirring. After methanol was distilled off under reduced pressure, 50 ml of water and 1.0 g (0.025 mol) of sodium hydroxide were added to the residue, and the mixture was further reacted at room temperature for 2 hours with stirring. After completion of the reaction, 50 ml of diethyl ether was added for extraction, the aqueous layer was made acidic (pH 1-2) with concentrated hydrochloric acid, and then diethyl ether 20 was added again.
Extraction was performed by adding 0 ml. The diethyl ether layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure.
-Trifluoromethylnicotinic acid (melting point 147-149
7.degree. C.) was obtained (74% yield).

Example 2 (1) Condensation reaction step 3,3-dimethoxypropionic acid methyl ester 5.6
3 g (0.038 mol) and sodium hydride (60%
Oil suspension) 1.52 g (0.038 mol)
It was added to 28 ml of N, N-dimethylformamide. To this, 4-amino-1,1,1-trifluoro-3-
Butene-2-one 5.0 g (0.036 mol) N,
A solution dissolved in 5 ml of N-dimethylformamide was gradually added dropwise. After the dropping was completed, the reaction was carried out at 65 ° C. for 20 minutes. After completion of the reaction, the resulting reaction solution was poured into 150 ml of ice water, and concentrated hydrochloric acid was added to neutralize the solution. The precipitate was collected by filtration and washed with cold water to obtain 4.09 g of N-2-methoxycarbonylvinyl 4,4,4-trifluoro-3-oxo-1-butenylamine (yield 51
%).

Example 3 (1) Condensation reaction step 4.53 g of sodium hydride (60% oil suspension)
(0.11 mol) was suspended in 100 ml of N, N-dimethylformamide, and ice-cooled to 5 ° C. Next, 15.0 g (0.11 mol) of 4-amino-1,1,1-trifluoro-3-buten-2-one and 13.14 g (0.1
1 mol) and 20 ml of N, N-dimethylformamide
The solution dissolved in was added dropwise over 30 minutes with vigorous stirring under ice cooling at 5 to 10 ° C. The solution after dripping is 5 to 1
The mixture was further reacted for 2 hours and a half under ice cooling at 0 ° C. After the reaction, after pouring the obtained reaction solution into 500 ml of ice water,
With vigorous stirring, concentrated hydrochloric acid was added to neutralize. The precipitate was collected by filtration, washed with cold water, and the obtained crystal was dried under reduced pressure at 50 ° C. to give a reaction product 19.
98 g was obtained (yield 83%). Obtained melting point 92.0 ° C
When the reaction product of was dissolved in deuterated chloroform and measured by NMR, N-2-methoxycarbonylvinyl 4,4,4
In addition to the peak of 4-trifluoro-3-oxo-1-butenylamine, the peak of N-2-methoxycarbonylethylidene 4,4,4-trifluoro-3-oxo-2-butenylamine was detected.

Example 4 (1) Condensation reaction step 4-amino-1,1,1-trifluoro-3-butene-
2-one 1.50 g (10.8 mmol) and 3-methoxyacrylic acid methyl ester 1.31 g (11.3 mm)
Ol) and 15% of N, N-dimethylformamide dissolved in 15 ml of trifluoromethanesulfonic acid.
g (11.3 mmol) was added at room temperature. Next, this solution was reacted in an oil bath at 90 ° C. for 1 hour with stirring. After completion of the reaction, the obtained reaction solution was poured into 100 ml of ice water and extracted with diethyl ether. The organic layer was dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography,
1.25 g of a reaction product was obtained (yield 51.9%). The obtained reaction product was analyzed by gas chromatography in Example 3
It was confirmed to be the same as the reaction product of.

Example 5 (1) Condensation reaction step 4-amino-1,1,1-trifluoro-3-butene-
2-one 1.50 g (10.8 mmol) and 3-methoxyacrylic acid methyl ester 1.31 g (11.3 mm)
1) and trifluoromethanesulfonic acid 1.70 g (11.
3 mmol) was added at room temperature. Next, add 90 parts of this solution.
The reaction was carried out in an oil bath at ℃ for 1 hour with stirring. After the reaction was completed, the obtained reaction solution was added to 100 ml of ice water.
And extracted with diethyl ether. The organic layer was dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography to obtain 0.92 g of a reaction product (yield 38.2%). The obtained reaction product was confirmed to be the same as the reaction product of Example 3 by gas chromatography.

Example 6 (1) Condensation reaction step 4-amino-1,1,1-trifluoro-3-butene-
2-one 1.50 g (10.8 mmol) and 3-methoxyacrylic acid methyl ester 1.31 g (11.3 mm)
was dissolved in a mixed solvent of 5 ml of N, N-dimethylformamide and 10 ml of toluene, and 1.70 g (11.3 mmol) of trifluoromethanesulfonic acid was added at room temperature. Next, this solution was reacted in an oil bath at 90 ° C. for 1 hour with stirring. After completion of the reaction, the obtained reaction solution was poured into 100 ml of ice water and extracted with diethyl ether. The organic layer was dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography to obtain 1.02 g of a reaction product (yield 42.3%). The obtained reaction product was confirmed to be the same as the reaction product of Example 3 by gas chromatography.

Example 7 (1) Condensation reaction step 4-amino-1,1,1-trifluoro-3-butene-
2-one 1.50 g (10.8 mmol) and 3-methoxyacrylic acid methyl ester 1.31 g (11.3 mm)
ol) and N, N-dimethylformamide (15 ml) dissolved in a solution of trifluoromethanesulfonic acid (1.70 g).
(11.3 mmol) was added at room temperature. Next, this solution was reacted in an oil bath at 60 ° C. for 1 hour with stirring. After the reaction was completed, the obtained reaction solution was mixed with ice water 1
It was poured into 00 ml and extracted with diethyl ether. The organic layer was dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography to obtain 0.42 g of a reaction product (yield 17.4%). The obtained reaction product was confirmed to be the same as the reaction product of Example 3 by gas chromatography.

Example 8 (1) Condensation reaction step 4-amino-1,1,1-trifluoro-3-butene-
2-one 1.50 g (10.8 mmol) and 3-methoxyacrylic acid methyl ester 1.31 g (11.3 mm)
was dissolved in a mixed solvent of 5 ml of N, N-dimethylformamide and 10 ml of toluene, and 1.70 g (11.3 mmol) of trifluoromethanesulfonic acid was added at room temperature. Next, this solution was reacted in an oil bath at 60 ° C. for 2 hours while stirring. After completion of the reaction, the obtained reaction solution was poured into 100 ml of ice water and extracted with diethyl ether. The organic layer was dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography to obtain 1.02 g of a reaction product (yield 42.3%). The obtained reaction product was confirmed to be the same as the reaction product of Example 3 by gas chromatography.

Example 9 (1) Condensation reaction step 4-amino-1,1,1-trifluoro-3-butene-
2-one 1.50 g (10.8 mmol) and 3-methoxyacrylic acid methyl ester 1.31 g (11.3 mm)
was dissolved in a mixed solvent of 5 ml of N, N-dimethylformamide and 10 ml of toluene, and 1.95 g (11.3 mmol) of paratoluenesulfonic acid was added at room temperature. Next, this solution was reacted in an oil bath at 90 ° C. for 2 hours while stirring. After completion of the reaction, the obtained reaction solution was poured into 100 ml of ice water and extracted with diethyl ether. The organic layer was dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography to obtain 0.48 g of a reaction product (yield 19.9%). The obtained reaction product was confirmed to be the same as the reaction product of Example 3 by gas chromatography.

Example 10 (1) Condensation reaction step 4-amino-1,1,1-trifluoro-3-butene-
2-one 1.50 g (10.8 mmol) and 3-methoxyacrylic acid methyl ester 1.31 g (11.3 mm)
ol) was dissolved in a mixed solvent of 5 ml of N, N-dimethylformamide and 10 ml of toluene, and 1.09 g (11.3 mmol) of methanesulfonic acid was added at room temperature. Next, this solution was reacted in an oil bath at 90 ° C. for 1 hour with stirring. After completion of the reaction, the obtained reaction solution was poured into 100 ml of ice water and extracted with diethyl ether. The organic layer was dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography to obtain 0.89 g of a reaction product (yield 3
6.9%). The obtained reaction product was confirmed to be the same as the reaction product of Example 3 by gas chromatography.

Example 11 (1) Condensation reaction step 4-amino-1,1,1-trifluoro-3-butene-
2.00 g (14.4 mmol) of 2-one and 1.70 g (14.6 mm) of methyl ester of 3-methoxyacrylic acid.
ol) was dissolved in 15 ml of toluene, and 560 mg (4.86 mmol) of 85% phosphoric acid was added at room temperature. Next, this solution was reacted in an oil bath at 60 ° C. for 18 hours while stirring. After completion of the reaction, the obtained reaction solution was poured into 100 ml of ice water and extracted with diethyl ether. The organic layer is dried over anhydrous sodium sulfate,
After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography to obtain 1.09 g of a reaction product (yield 3
4.0%). The obtained reaction product was confirmed to be the same as the reaction product of Example 3 by gas chromatography.

Example 12 (1) Condensation reaction step 4-amino-1,1,1-trifluoro-3-butene-
2.00 g (14.4 mmol) of 2-one and 1.70 g (14.6 mm) of methyl ester of 3-methoxyacrylic acid.
was added to 14 ml of dimethyl sulfoxide and 0.4 ml (7.2 mmol) of 98% concentrated sulfuric acid was added at room temperature. Next, this solution was reacted in an oil bath at 60 ° C. for 5 hours while stirring. After completion of the reaction, the obtained reaction solution was poured into 100 ml of ice water and extracted with diethyl ether. The organic layer was dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography to obtain 1.80 g of a reaction product (yield 56.0%). The obtained reaction product was confirmed to be the same as the reaction product of Example 3 by gas chromatography.

Example 13 (2) Ring-closing and hydrolysis reaction step N-2-methoxycarbonylvinyl 4,4,4-trifluoro-3-oxo-1-butenylamine 7.94 g
A solution of (0.036 mol) in 95 ml of methanol was ice-cooled to 5 ° C., and metallic sodium 1.
A solution of 64 g (0.071 mol) in 40 ml of methanol was gradually added dropwise. After the completion of the dropping, the reaction solution was returned to room temperature over 30 minutes and then heated again, and reacted for 3 hours and 45 minutes while stirring under heating under reflux. After distilling off methanol under reduced pressure, 0.85 g of sodium hydroxide was added to the residue.
A solution of (0.021 mol) in 40 ml of water was added, and the mixture was reacted at room temperature with stirring for 2 hours. After completion of the reaction, 50 ml of diethyl ether was added for extraction, the aqueous layer was made acidic (pH 1-2) with concentrated hydrochloric acid, and then 200 ml of diethyl ether was added again for extraction. The diethyl ether layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to give 5.25 g of 4-trifluoromethylnicotinic acid (melting point 145.9 ° C) (yield 77%). The N-2-methoxycarbonylvinyl 4,4,4-trifluoro-3-oxo-1-butenylamine obtained in the above Examples 2 to 12 was used to prepare the above-mentioned Example 1 (2) and Example 13. According to the ring closure and hydrolysis reaction according to the same manner, 4-trifluoromethylnicotinic acid can be produced.

Example 14 (1) Condensation reaction step In a 500 ml four-necked flask equipped with a thermometer, a stirring blade and a dropping funnel, 13.1 g (0.33 mol) of sodium hydride (60% oil suspension) was added. And 140 ml of N, N-dimethylformamide were added, and -5 with a freezing agent.
It cooled to below ° C. Then, 4-amino-
1,1,1-trifluoro-3-buten-2-one 6
72.2 g (0.33%) of a toluene solution containing 3.3%
mol 4-amino-1,1,1-trifluoro-3-
Butene-2-one) was added dropwise with a dropping funnel over 1 hour and 30 minutes while maintaining a temperature of -5 ° C or lower. Next, 38.1 g of 3-methoxyacrylic acid methyl ester
(0.33 mmol) was added dropwise with a dropping funnel over 30 minutes while maintaining a temperature of -5 ° C or lower. After completion of the dropping, the reaction solution was returned to room temperature (18 ° C.), and further reacted for 1 hour and a half while stirring at room temperature. Next, the obtained reaction solution was heated to 60 ° C., toluene was distilled off under reduced pressure over 30 minutes, and the mixture was allowed to cool. The reaction solution cooled down was cooled with ice water (840 ml).
Then, add concentrated hydrochloric acid to adjust the pH to about 3,
The mixture was stirred at 5 ° C or lower for 30 minutes. The precipitated crystals are collected by filtration,
The crystals obtained by washing with 140 ml of water were dried at 40 ° C. for 3 days to obtain 67.0 g of a reaction product (yield 78.1%). When the obtained reaction product was dissolved in deuterated chloroform and NMR was measured, a peak of N-2-methoxycarbonylvinyl 4,4,4-trifluoro-3-oxo-1-butenylamine was detected.

Example 15 (1) Condensation reaction step In a 500 ml four-necked flask equipped with a thermometer, a stirring blade and a dropping funnel, 2.87 g (0.072 mol) of sodium hydride (60% oil suspension) was added. And N, N-
Add 30 ml of dimethylformamide, and use a freezing medium -5
It cooled to below ° C. Then, 4-amino-
1,1,1-trifluoro-3-buten-2-one (purity 99.6%) 10.0 g (0.072 mol), 3-
Methoxyacrylic acid methyl ester 8.31 g (0.0
72 mol) and 10 ml of toluene were added dropwise with a dropping funnel over 1 hour while maintaining a temperature of -5 ° C or lower. After the completion of the dropping, the reaction solution was reacted for 30 minutes while stirring while maintaining the temperature at -5 ° C or lower, and then at room temperature (1
(9 ° C.). After reacting at room temperature for 2 hours with stirring, the obtained reaction solution was heated to 60 ° C., toluene was distilled off under reduced pressure over 1 hour, and the mixture was allowed to cool. The reaction solution which had been allowed to cool was poured into 180 ml of ice water, concentrated hydrochloric acid was added to adjust the pH to about 3, and the mixture was stirred at 5 ° C or lower for 30 minutes.
The precipitated crystal was collected by filtration, washed with 100 ml of water, and the obtained crystal was dried at 40 ° C. for 3 days to obtain 14.1 g of a reaction product (yield 77.2%). When the obtained reaction product was dissolved in deuterated chloroform and NMR was measured, N-2-methoxycarbonylvinyl 4,4,4
A peak for -trifluoro-3-oxo-1-butenylamine was detected.

Example 16 (1) Condensation reaction step In a 500 ml four-necked flask equipped with a thermometer, a stirring blade and a dropping funnel, 4.0 g (0.10 mol) of sodium hydride (60% oil suspension) was added. Then, 41.7 ml of tetrahydrofuran was added, and the mixture was cooled to -5 ° C or lower with a freezing agent. Then to this, 4-amino-1,1,1-
Trifluoro-3-buten-2-one (purity 98.1
%) 14.2 g (0.10 mol) was added dropwise with a dropping funnel over 30 minutes while maintaining a temperature of −5 ° C. or lower.
Next, 3-methoxyacrylic acid methyl ester 11.6
g (0.10 mol) was added dropwise with a dropping funnel over 30 minutes while maintaining a temperature of -5 ° C or lower. After dropping,
After returning the reaction solution to room temperature (19 ° C.), the mixture was reacted at room temperature for 2 hours and 30 minutes with stirring, and then 0.4 g (0.01 mol) of sodium hydride was further added at room temperature and reacted for 30 minutes. After completion of the reaction, the obtained reaction solution is treated with ice water 25
After pouring into 0 ml, concentrated hydrochloric acid was added to adjust the pH to about 3, and the mixture was stirred at 5 ° C or lower for 30 minutes. The precipitated crystals were collected by filtration, washed with 100 ml of water, and the obtained crystals were 40 ° C.
By drying for 3 days, 20.1 g of a reaction product was obtained (yield 73.6%). When the obtained reaction product was dissolved in deuterated chloroform and NMR was measured, N-2-methoxycarbonylvinyl 4,4,4-trifluoro-3 was obtained.
A peak for -oxo-1-butenylamine was detected.

Example 17 (1) Condensation reaction step 183 g of sodium hydride (60% oil suspension)
(4.57 mol) N, N-dimethylformamide 2
Cool the 100 ml solution on ice and bring it to -5 ° C or below, 4
-Amino-1,1,1-trifluoro-3-butene-2
706 g (5.08 mol) of -one was added dropwise. next,
The temperature of this solution is raised, and 589 g (5.08 mo
l) was added dropwise. After completion of the dropwise addition, the mixture was stirred at room temperature for 2 hours. After the reaction was completed, the obtained reaction solution was cooled to 8400 ml of ice water.
And stirred at 5 ° C or lower for 30 minutes. Incidentally, dilute hydrochloric acid was added so that the pH of the ice water was 4 to 5 when the reaction solution was charged. The precipitate is collected by filtration and washed with water to give crystals, which are at 40 ° C.
By drying for 2 days, 1192 g of a reaction product was obtained (yield 84.8%). When the obtained reaction product was dissolved in deuterated chloroform and NMR was measured, in addition to the peak of N-1-methoxy-2-methoxycarbonylethyl 4,4,4-trifluoro-3-oxo-1-butenylamine, N-2-methoxycarbonyl vinyl 4,4,4-
A peak of trifluoro-3-oxo-1-butenylamine was detected. When a part of the obtained reaction product was isolated and purified by silica gel column chromatography,
N-1-methoxy-2-methoxycarbonylethyl 4,4,4-trifluoro-3-oxo-1-butenylamine having a melting point of 68 to 70 ° C. was obtained.

(2) Ring-closing and hydrolysis reaction step Sodium methoxide (28 wt% methanol solution) 1
221 g (6.33 mol) of methanol 1050 ml
The solution was heated to 60 ° C., and the reaction product obtained in (1), N-1-methoxy-2-methoxycarbonylethyl 4,4,4-trifluoro-3-oxo-1-butenylamine, 1076 g ( 4.22 mol) methanol 1
The 830 ml solution was added dropwise. After completion of dropping, heating under reflux 1
After stirring for an hour, 152 g (8.44 mol) of water was added and the mixture was heated under reflux for another 30 minutes. After completion of the reaction, methanol was distilled off under reduced pressure, 2600 ml of water was added to the residue, and the mixture was washed with ethylene dichloride. Acidify the aqueous layer with dilute hydrochloric acid (pH 1 to
After 2), the precipitate was collected by filtration. The crystals obtained by filtration were dried at 40 ° C. for 1 day to obtain 651 g of 4-trifluoromethylnicotinic acid (yield 78.1).
%).

[0068]

According to the method of the present invention, both the compound of formula (I) and the compound of general formula (II) are condensed to form a compound of general formula (III) or a salt thereof, By subjecting this to ring closure and hydrolysis, the desired product 4-trifluoromethylnicotinic acid or a salt thereof can be easily produced. This reaction has a smaller number of reaction steps than the conventional one and can produce the target product in a high yield under mild reaction conditions.

 ─────────────────────────────────────────────────── ─── Continuation of the front page (72) Shigehisa Uebayashi 2-3-1 Nishishibukawa, Kusatsu-shi, Shiga Ishihara Sangyo Co., Ltd. Central Research Laboratory (72) Toyoshi Tanimura 2-chome Nishishibukawa, Kusatsu-shi, Shiga No. 1 Ishihara Sangyo Co., Ltd. Central Research Institute (72) Inventor Noriyuki Horiuchi 2-3-1, Nishi-Shibukawa, Kusatsu City, Shiga Prefecture Ishihara Sangyo Co., Ltd. Central Research Institute

Claims (12)

[Claims] 1. Formula (V); A process for producing 4-trifluoromethylnicotinic acid or a salt thereof represented by the formula (I): And a compound represented by the general formula (II); ACO ₂ R ...
(II) (wherein R is an ester-forming residue and A is (R '
O) CH = CH- group or (R'O) ₂ CHCH ₂ - is a radical. However, R ′ is an alkyl group) and the compound represented by the general formula (I
II); (Wherein R is as described above) and / or general formula (IV); wherein R and R ′ are as described above. The method for producing 4-trifluoromethylnicotinic acid or a salt thereof, which comprises obtaining a compound (including a salt thereof) represented by the formula (1) and then subjecting the reaction product to a ring closure and a hydrolysis reaction. 2. A compound of formula (I) and a compound of general formula (II-
1); (R′O) ₂ CHCH ₂ CO ₂ R ... (II-1) (in the formula,
R is an ester-forming residue, and R'is an alkyl group). 3. A compound of formula (I) and a compound of general formula (II-
2); (R'O) CH = CHCO 2 R ... (II-2) ( wherein, R
Is an ester-forming residue, and R'is an alkyl group)
The production method according to claim 1, wherein the compound represented by: is subjected to a condensation reaction in the presence of a base or an acid. 4. The method according to claim 2, wherein the condensation reaction is carried out in the presence of a base and / or a solvent. 5. The method according to claim 3, wherein the condensation reaction is carried out in the presence of a solvent.
The method described in. 6. The ring-closing and hydrolysis reaction is performed with a base and / or
Alternatively, the method according to claim 1, 2, 3, 4, or 5, which is carried out in the presence of a solvent. 7. A compound of general formula (II) is used in the condensation reaction in a proportion of 1.0 to 1.2 mol per mol of the compound of formula (I). The method according to 5 or 6. 8. A compound of formula (V); A method for producing 4-trifluoromethylnicotinic acid or a salt thereof represented by the following general formula (III); A compound (including a salt thereof) represented by the formula (wherein R is an ester-forming residue) and / or the general formula (IV); (In the formula, R is as described above and R ′ is an alkyl group) A ring-closing and hydrolysis reaction of a compound (including a salt thereof) represented by 4-trifluoromethylnicotinic acid Or the manufacturing method of the salt. 9. The ring-closing and hydrolysis reaction is carried out with a base and / or
Alternatively, the method according to claim 8, which is carried out in the presence of a solvent. 10. A compound represented by the general formula (III): (Wherein R is an ester-forming residue) or a salt thereof. 11. A compound represented by the general formula (III ′); (Wherein R is an ester-forming residue) or a salt thereof. 12. A compound represented by the general formula (IV): (Wherein R is an ester-forming residue and R'is an alkyl group) or a salt thereof.