JP2001158774A - Method for producing 6-trifluoromethylnicotinic acids - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a method for producing 6-trifluoromethylnicotinic acids useful as an intermediate for an agrochemical or a medicine. SOLUTION: This method for producing the 6-trifluoromethylnicotinic acids represented by general formula (I) [wherein, A is COOR1 group (R1 is an ester- forming residue), a carboxy group or a cyano group] is characterized in that a compound represented by general formula (II) [wherein, B is COOR1 group (R1 is an ester-forming residue) or a cyano group] is subjected to a condensing and cyclizing reaction with a compound represented by general formula (III) (wherein, R2 is an alkyl group, an alkenyl group, an alkynyl group or a phenyl group) to provide the objective 6-trifluoromethylnicotinic acids.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention relates to a compound represented by the following general formula (I) which is useful as an intermediate for producing agricultural chemicals or pharmaceuticals.
The invention relates to a novel process for the production of trifluoromethylnicotinic acids.

[0002]

2. Description of the Related Art 6-trifluoromethylnicotinic acid or an alkyl ester thereof included in the compound of the following general formula (I) can be produced, for example, by the method described in JP-A-11-199564. 6-trifluoromethylnicotinonitrile included in the compound of the following general formula (I) is described, for example, in Tetrahedron lett. 39 (43) 7965-7966 (19).
98) and the like.
Compounds of the following general formula (II) are described in, for example,
It can be produced by the method described in U.S. Pat. Further, the compound of the following general formula (III) can be produced, for example, by the method described in Chem. Lett. 1976.499. In addition, a compound similar to the compound of the following general formula (I) can be produced by the method described in EP Publication No. 522392. However, there is no known method for producing a compound of the following general formula (I) by subjecting a compound of the following general formula (II) and a compound of the following general formula (III) to condensation and ring-closing reactions.

[0003]

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

[0004]

According to the present invention, there is provided a compound represented by the general formula (I):

Embedded image (Wherein A is a COOR1 group (R1 is an ester-forming residue), a carboxyl group or a cyano group), a method for producing 6-trifluoromethylnicotinic acids represented by the general formula (II):

[0005]

Embedded image Wherein B is a COOR1 group (R1 is an ester-forming residue) or a cyano group;
General formula (III);

[0006]

Embedded image (Wherein R 2 is an alkyl group, an alkenyl group, an alkynyl group or a phenyl group)
The present invention also relates to a method for producing the above-mentioned 6-trifluoromethylnicotinic acid, which comprises subjecting a condensation reaction and a ring closure reaction.

A in the general formula (I) and B in the general formula (II) contain a COOR1 group. R1 contained in this COOR1 group is an ester-forming residue. Examples of the substituent that can be used for R1 include an alkyl group, an alkenyl group, an alkynyl group, and a phenyl group, and an alkyl group is preferable. Examples of the alkyl group include a linear or branched C1-6 alkyl group such as a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group and a tertiary butyl group. And an ethyl group.

The substituent which can be used as R2 in the general formula (III) includes an alkyl group, an alkenyl group, an alkynyl group and a phenyl group, and an alkyl group is preferred. Examples of the alkyl group include a linear or branched C1-6 alkyl group such as a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group and a tertiary butyl group.

The condensation reaction and the ring closure reaction are carried out continuously, and the general formula (I)
The amount of the compound of the general formula (III) and the compound of the general formula (III) to be used varies depending on the kind of the compound of the general formula (II) and other reaction conditions to be described later. The compound of the general formula (II) is used in a ratio of 0.7 to 2.0 mol per 1 mol.

The reaction temperature and reaction time of the condensation and ring closure reactions vary depending on the kind of the compound of the formula (II) and other reaction conditions described below, and cannot be specified unconditionally. However, the reaction temperature is usually -20 to +120. ° C and the reaction time is usually 0.1 to 12 hours.

In order to efficiently carry out the condensation and ring closure reactions, it is desirable to carry out the reaction in the presence of a base. Specific examples of the base used include hydrides of alkali metals such as sodium hydride and potassium hydride; alkyl lithiums such as n-butyllithium and t-butyllithium; 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 Tertiary bases such as triethylamine, dimethylaniline, diethylaniline and 4-dimethylaminopyridine. 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), the amount of the solvent used, the difference in the reaction conditions, and the like.
Although it cannot be specified unconditionally, a base is usually used in a ratio of 0.7 to 3.0 equivalents per 1 mol of the compound of the general formula (III).

For efficient condensation and ring closure of the compound of the formula (III) with the compound of the formula (II), the reaction is preferably carried out in the presence of a solvent. As a form of the solvent present in the reaction, a solution in which the compound of the general formula (III) or the compound of the general formula (II) is dissolved in a solvent, or a solution in which one of the compounds is dissolved, To the other compound,
There is a form in which a solution in which a base is dissolved in a solvent is added to a reaction system in which both compounds are dissolved. Specific examples of the solvent used include 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; And alcohols such as ethanol; basic heterocyclic compounds such as pyridine and quinoline. These solvents can be used alone or in combination. The amount of the solvent used in the condensation and ring closure reactions depends on the type of the compound of the general formula (II),
Although it depends on the reaction conditions and cannot be specified unconditionally, it is usually 1 to 1 part by weight of the compound of the general formula (III).
The solvent is used in a proportion of 30 parts by weight.

As described above, various conditions in the condensation and ring closure reactions described above, that is, various amounts which vary depending on the amount of the compound of the general formula (III) and the general formula (II) and the kind of the compound of the general formula (II) In setting each of the reaction conditions, the reaction temperature and the reaction time, they can be appropriately selected from the numerical values shown for each condition and combined.

In the compound of the general formula (II), B is COOR1
In the case of a compound which is a group, condensation and ring-closing reaction with a compound of the general formula (III) results in formation of a compound of the general formula (I) when A is a COOR1 group, ie, 6-trifluoromethylnicotinic acid ester. You. In the case where B in the compound of the general formula (II) is a cyano group, the compound represented by the general formula (III)
As a result of the condensation with the compound of the formula (I) and the ring closing reaction, a compound of the general formula (I) in which A is a cyano group, that is, 6-trifluoromethylnicotinonitrile is produced.

The compound of the general formula (I) wherein A is a carboxyl group, ie, 6-trifluoromethylnicotinic acid, is a compound of the aforementioned 6-trifluoromethylnicotinic acid ester or 6-trifluoromethylnicotinic acid ester
It is obtained by hydrolyzing trifluoromethylnicotinonitrile. 6-trifluoromethylnicotinic acid can also be obtained by performing a hydrolysis reaction continuously with the above-mentioned condensation and ring-closing reaction. Let
6-trifluoromethylnicotinic acid ester or 6-
After obtaining trifluoromethylnicotinonitrile, it needs to be hydrolyzed in the presence of a solvent such as water; alcohols such as methanol, ethanol or mixtures thereof. Most preferably, water is used among the above solvents. Examples of the existence form of the solvent include 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. The amount of the solvent used in the hydrolysis reaction varies depending on the reaction conditions and the like, and cannot be specified unconditionally, but is usually 1 to 30 parts by weight based on 1 part by weight of the reaction product product of the condensation and ring closure reaction. used. In the case where the above-mentioned condensation, ring-closing reaction and hydrolysis reaction are carried out continuously, if an alcohol is used as a solvent during the condensation and ring-closure reaction, it can be used as it is in the subsequent hydrolysis reaction.

In order to carry out the hydrolysis reaction efficiently, it is desirable to carry out the reaction in the presence of a base and / or a mineral acid. Specific examples of the base used include hydroxides of alkali metals such as sodium hydroxide and potassium hydroxide; sodium methoxide, sodium ethoxide,
Alkoxides such as potassium methoxide and potassium t-butoxide are exemplified. Specific examples of the mineral acid used include hydrochloric acid, sulfuric acid, nitric acid, and mixtures thereof. These bases and / or mineral acids can be used alone or in combination. In this case, the amount of the base and / or mineral acid used depends on the type of the product of the condensation and ring-closing reaction, the difference in the reaction conditions and the like, and cannot be specified unconditionally. 0.7 to 3.
Used in a proportion of 0 equivalents. In the case where the condensation and ring-closing reaction and the hydrolysis reaction are continuously performed, if a base that can be used in both reactions is used during the condensation and ring-closing reactions, it is not necessary to add a new base during the hydrolysis reaction. ,
The process can be simplified.

The reaction temperature and the reaction time in the hydrolysis reaction vary depending on the amount of the base and / or mineral acid used, their type and the like, and cannot be specified unconditionally, but the reaction temperature is usually 0 to 120 ° C. The time is usually from 0.1 to 12 hours.

In setting the various conditions in the above-mentioned hydrolysis reaction, that is, the amount of the solvent used, the reaction temperature and the reaction time, each is appropriately selected and combined from the numerical values indicated for each condition. be able to.

The selective combination of various conditions in the above-mentioned condensation and ring closure reactions can be further appropriately selected and combined with the selective combination of various conditions in the above-mentioned hydrolysis reaction.

The 6-trifluoromethylnicotinic acid of the general formula (I), which is the target compound, is converted after the completion of the condensation and the ring closure reaction.
Alternatively, after the completion of the hydrolysis reaction following the condensation and ring closure reactions, the reaction product is isolated by subjecting the reaction product to a usual post-treatment such as solid-liquid separation, washing, and drying.

[0021]

DESCRIPTION OF THE PREFERRED EMBODIMENTS Some preferred embodiments of the present invention will be described below. (1) The compound of the general formula (II) and the compound of the general formula (III) are subjected to a condensation and ring-closing reaction.
-A method for producing trifluoromethylnicotinic acid ester or 6-trifluoromethylnicotinonitrile.

(2) 6-trifluoromethylnicotinic acid wherein a compound of the general formula (II) and a compound of the general formula (III) wherein B is a COOR1 group are subjected to a condensation and ring-closing reaction. Method for producing ester.

(3) 6-trifluoromethylnicotino wherein a compound of the general formula (II) and a compound of the general formula (III) wherein B is a cyano group are subjected to a condensation and ring-closing reaction. Nitrile production method.

(4) The compound of the general formula (II) and the compound of the general formula (III) are condensed and ring-closed to give 6
-A process for producing 6-trifluoromethylnicotinic acid, which comprises producing trifluoromethylnicotinic acid ester or 6-trifluoromethylnicotinonitrile and then subjecting this to hydrolysis.

(5) When B is a COOR1 group, the compound of the general formula (II) and the compound of the general formula (III) are subjected to a condensation and ring-closing reaction to produce 6-trifluoromethylnicotinic acid ester And then subjecting it to a hydrolysis reaction to produce 6-trifluoromethylnicotinic acid.

(6) When B is a cyano group, the compound of the general formula (II) and the compound of the general formula (III) are subjected to a condensation and ring-closing reaction to produce 6-trifluoromethylnicotinonitrile. And then subjecting it to a hydrolysis reaction to produce 6-trifluoromethylnicotinic acid.

[0027]

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

Example 1 <Synthesis of 6-trifluoromethylnicotinic acid methyl ester> 4-butoxy-1,1,1-trifluoro-3-
20 ml of tetrahydrofuran containing 1.96 g (0.01 mol) of buten-2-one and 1.01 g (0.01 mol) of methyl 3-aminoacrylate
After 1.52 g (0.015 mol) of triethylamine was added dropwise to the solution at room temperature, the mixture was refluxed for 5.75 hours. After completion of the reaction, the solvent was distilled off under reduced pressure, and the obtained reaction mixture was poured into water. After neutralization with dilute hydrochloric acid, the mixture was extracted with ethyl acetate, and the organic layer was washed with saturated saline. After the organic layer was dried over sodium sulfate, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography. 0.30 g of 6-trifluoromethylnicotinic acid methyl ester (14.6% yield, 1H-NMR (400 MHz, CD
Cl3) 3.96ppm, s, 3H, 7.72ppm, d, 1H, J = 8Hz, 8.42pp
m, d, 1H, J = 8 Hz, 9.23 ppm, s, 1H).

Example 2 <Synthesis of 6-trifluoromethylnicotinic acid> 52 g of methyl 3-aminoacrylate (16.7% by weight in methanol)
086 mol), 33.3 g (0.173 mol) of sodium methoxide (28% by weight methanol solution) was added at -5 ° C or less, and 4-ethoxy-1,1,1-trifluoro-3-butene-2-
15.6 g (0.093 mol) of ON was added at -5 ° C or lower. The temperature of the reaction mixture was gradually raised and heated to reflux for 3 hours. Water 3
After the mixture was heated under reflux for further 30 minutes, it was concentrated under reduced pressure. The reaction product was washed five times with 20 ml of methylene chloride and then poured into 50 ml of water. After adjusting the pH to 2 with concentrated hydrochloric acid, the crude product was filtered. The crude product was repulped and washed with water under heating, filtered, washed with water and dried to obtain 7.03 g of 6-trifluoromethylnicotinic acid (42.8% yield, melting point 170 to 176)
° C, 1H-NMR (400MHz, DMSO-d6) 8.04ppm, d, 1H, J = 8Hz,
8.54ppm, dd, 1H, J = 2Hz, 8Hz, 9.21ppm, d, 1H, J = 2H
z, 13.8ppm, br, 1H,).

[0030]

According to the method of the present invention, both the compound of the general formula (II) and the compound of the general formula (III) are subjected to a condensation and ring-closing reaction to give 6-trifluoromethylnicotinic acid ester or 6-trifluoromethylnicotinic acid ester. By producing and hydrolyzing -trifluoromethylnicotinonitrile, the target product 6-trifluoromethylnicotinic acid can be easily produced. In this reaction, the desired product can be produced in a high yield under mild reaction conditions with fewer reaction steps compared to the conventional one.

 ────────────────────────────────────────────────── ─── Continuing on the front page (72) Inventor Toru Wakabayashi 2-3-1 Nishi-Shibukawa, Kusatsu-shi, Shiga Ishihara Sangyo Co., Ltd. Central Research Laboratory F-term (reference) 4C055 AA01 BA02 BA06 BA13 CA02 CA57 CA59 CB01 CB02 DA01 FA23 FA37

Claims (5)

[Claims] 1. A compound of the general formula (I): (Wherein A is a COOR1 group (R1 is an ester-forming residue), a carboxyl group or a cyano group), a method for producing 6-trifluoromethylnicotinic acids represented by the general formula (II): Embedded image (Wherein B is a COOR 1 group (R 1 is an ester-forming residue) or a cyano group), and a compound represented by the general formula (III): (Wherein R 2 is an alkyl group, an alkenyl group, an alkynyl group or a phenyl group)
A method for producing the above 6-trifluoromethylnicotinic acids, wherein the condensation and the ring closure reaction are carried out. 2. In the general formula (I), A is a COOR1 group (R1
Is a ester-forming residue) or a carboxyl group, and B in the general formula (II) is a COOR1 group (R1 is an ester-forming residue). 3. The method according to claim 2, wherein B in the general formula (II) is a C1-6 alkoxycarbonyl group, and R2 in the general formula (III) is a C1-6 alkyl group. 4. The process according to claim 1, wherein the condensation and the ring closure are carried out in the presence of a base and / or a solvent. 5. The method according to claim 1, wherein a hydrolysis reaction is carried out after the condensation and the ring closure reaction.