JPH08198860A - Process for producing 2- (1H-1,2,4-triazol-1-yl) acetophenones - Google Patents

Abstract

(57) [Summary] The present invention is useful as a raw material for producing antifungal agents and agricultural chemicals. 2- (1H-1,2,4-triazol-1-yl)
The present invention relates to a new method for producing acetophenones. [Structure] A 1,2,4-triazoleacetic acid derivative protected with a carboxyl protecting group is reacted with a reactive derivative of benzoic acid which may have a phenyl group substituted in the presence of a base and a metal halide, and then, A method for producing 2- (1H-1,2,4-triazol-1-yl) acetophenones, which comprises deesterification and decarboxylation. [Effect] The production method of the present invention produces 2- (1H-1,2,4-triazol-1-yl) acetophenones, which are useful as raw materials for producing antifungal agents and agricultural chemicals, in high purity and high yield. In addition, the reaction time of each step is usually 1 to 5
The time is relatively short, the purification process is simple, scale-up is easy, and it is industrially useful.

Description

Detailed Description of the Invention

[0001]

FIELD OF THE INVENTION The present invention is useful as a raw material for producing antifungal agents or agricultural chemicals.

[Chemical 7] (In the formula, R ¹ and R ² are the same or different and each represents a hydrogen atom, a lower alkyl group, a lower alkoxy group, a cyano group, a nitro group, a halogeno lower alkyl group, a lower alkylsulfonyl group or a halogen atom.) 2-
The present invention relates to a method for producing (1H-1,2,4-triazol-1-yl) acetophenones. That is, specifically, the general formula [4]

Embedded image (In the formula, R represents a carboxyl protecting group.) The 1,2,4-triazoleacetic acid derivative represented by the general formula [3]

[Chemical 9] (In the formula, R ¹ and R ² are the same or different and each represents a hydrogen atom, a lower alkyl group, a lower alkoxy group, a cyano group, a nitro group, a halogeno lower alkyl group, a lower alkylsulfonyl group or a halogen atom.) By reacting a reactive derivative of benzoic acid represented by the formula [5] with a base and a metal halide.

[Chemical 10] (In the formula, R ¹ , R ² and R have the same meanings as described above.) 3-phenyl-2- (1H-
1,2,4-triazol-1-yl) propionic acid ester derivative is obtained, followed by deesterification and decarboxylation of the general formula [1]

[Chemical 11] (In the formula, R ¹ and R ² have the same meanings as described above.) A method for producing 2- (1H-1,2,4-triazol-1-yl) acetophenones is provided. Is.

[0002]

2. Description of the Related Art Heretofore, as a method for producing a compound of the general formula [1], for example, JP-B-59-13512 and 59-532.
The method described in No. 66 is known. That is, the general formula [2]

[Chemical 12] (In the formula, R ¹ and R ² have the same meanings as described above; X represents a halogen atom.) The acetophenone derivative represented by the general formula is reacted with 1,2,4-triazole. This is a method for obtaining the compound of [1] (Production method 1). Also, Journal of Heterocyclic Chemistry [J.Heterocyclic.Chem.], Volume 30,
The methods described in p. 1405 (1993) and in Journal of Organic Chemistry [J.Org.Chem.], 54, p.731 (1989) are known. That is, the compound of the general formula [2] is reacted with 4-amino-1,2,4-triazole and then subjected to a deamination reaction to obtain the compound of the general formula [1] (Production method 2 ).

[0003]

The production method 1 is a production method in which about 20% of the 4-substituted triazole is produced as a by-product and the yield is as low as 40%. Further, the compound of the general formula [2] is extremely irritating, and its handling is difficult.
On the other hand, the production method 2 uses a compound of the general formula [2] and an expensive 4-amino-1,2,4-triazole which are irritating, although the by-product of the 4-position substitution product of triazole can be suppressed. There is a need. The object of the present invention is to produce 2- (1H-1,2,4-) of high yield and high purity on an industrial scale.
It is to provide a novel method for producing triazol-1-yl) acetophenones.

[0004]

Under these circumstances, the inventors of the present invention have conducted diligent studies, and as a result, have shown that a reactive derivative of benzoic acid represented by the general formula [3] and a reactive derivative of the general formula [4] are used. The 1,2,4-triazoleacetic acid derivative represented by the reaction is reacted in the presence of a base and a metal halide to give 3-phenyl-2- (1H- represented by the general formula [5].
1,2,4-triazol-1-yl) propionic acid ester derivative is obtained, and then deesterified and decarboxylated to give 2- (1H-1,2,4) of the general formula [1].
The -triazol-1-yl) acetophenone derivative can be produced in high purity and high yield, and the reaction time of each step is usually relatively short at about 1 to 5 hours, the purification step is simple, and scale-up is easy. Then, they found that they were industrially useful and completed the present invention.

The present invention will be described in detail below. In the present specification, unless otherwise specified, the halogen atom means a fluorine atom, a chlorine atom, a bromine atom and an iodine atom; the lower alkyl group means, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, a linear or branched C _1-5 alkyl group such as sec-butyl, isobutyl, tert-butyl and pentyl; a lower alkoxy group includes, for example, methoxy, ethoxy, n-propoxy,
C such as isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy and pentyloxy
_1-5 alkoxy group; halogeno lower alkyl group means, for example, halogeno-C ₁ such as fluoromethyl, chloromethyl, bromomethyl, dichloromethyl, trifluoromethyl, trichloromethyl, chloroethyl, dichloroethyl, trichloroethyl and chloropropyl. _-5 alkyl group; a lower alkylsulfonyl group is, for example,
A C _1-5 alkylsulfonyl group such as methylsulfonyl, ethylsulfonyl, n-propylsulfonyl, isopropylsulfonyl, n-butylsulfonyl, isobutylsulfonyl, sec-butylsulfonyl, tert-butylsulfonyl and pentylsulfonyl; a protecting group for a carboxyl group Is all groups which can be used as a usual protecting group for a carboxyl group, such as methyl, ethyl, n-propyl, iso-propyl, 1,1-dimethylpropyl, n-butyl and tert-butyl. Lower alkyl group; aryl group such as phenyl and naphthyl; al-lower alkyl group such as benzyl, diphenylmethyl, trityl, p-nitrobenzyl, p-methoxybenzyl and bis (p-methoxyphenyl) methyl; 2-tetrahydropyranyl And 2-tet Oxygen-containing heterocyclic groups such as Hidorofuraniru; 2,2,2 halogeno-lower alkyl groups such as trichloroethyl; cycloalkyl groups such as cyclohexyl; methoxymethyl, 2-lower alkylsilyl group, such as (trimethylsilyl) ethyl
Lower alkoxy lower alkyl groups such as methoxyethoxymethyl and 2- (trimethylsilyl) ethoxymethyl; al-lower alkoxy lower alkyl groups such as benzyloxymethyl; 1,1-dimethyl-2-propenyl,
Lower alkenyl groups such as 3-methyl-3-butynyl and allyl and trimethylsilyl, triethylsilyl,
Lower alkyl-substituted silyl groups such as triisopropylsilyl, diethylisopropylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl, diphenylmethylsilyl and tert-butylmethoxyphenylsilyl are shown, respectively.

The compounds of the general formulas [1], [4] and [5] may be corresponding salts. Examples of the salt include salts in commonly known basic groups, specifically, salts with mineral acids such as hydrochloric acid, hydrobromic acid and sulfuric acid; and methanesulfonic acid, benzenesulfonic acid. , P-toluenesulfonic acid, mesitylenesulfonic acid and naphthalenesulfonic acid, and salts thereof with sulfonic acids.

Examples of the reactive derivative of the general formula [3] include acid halides such as acid chloride and acid bromide; acid imidazolide; and carbonic acid monoethyl ester.
Examples thereof include a mixed acid anhydride with a carbonic acid monoester such as carbonic acid monoisobutyl ester and a mixed acid anhydride with a lower alkanoic acid which may be substituted with halogen such as pivalic acid and trichloroacetic acid.

The compound of the general formula [4] or the general formula [3]
In the reactive derivative of, when the isomers (for example, optical isomers, geometric isomers and tautomers) exist, the present invention may use the isomers,
Solvates and crystals of various shapes may be used. Next, the production method of the present invention will be described.

In the compound of the general formula [4] and the reactive derivative of the general formula [3] used in the production method of the present invention, preferred compounds are those in which R ¹ and R ² are a lower alkyl group, a lower alkoxy group or a halogen atom. And R is a lower alkyl group, an aryl group or an al-lower alkyl group, and the reactive derivative is an acid halide or an acid imidazolide. More preferable compounds are R ¹ and R ² Or a compound which is a chlorine atom, R is a methyl, ethyl or tert-butyl group, and the reactive derivative is an acid chloride or an acid imidazolide. The compound of the general formula [1] is
For example, it can be manufactured according to the following manufacturing route.

[0010]

[Chemical 13]

The compound of the general formula [5] can be obtained by reacting the reactive derivative of the general formula [3] with the compound of the general formula [4] in the presence of a base and a metal halide. The amount of the compound of the general formula [4] used may be 1 to 5 times, preferably 1 to 3 times the mol of the reactive derivative of the general formula [3]. The base used in this reaction is preferably a tertiary amine such as triethylamine. The amount of base used is
It may be 2 to 10 times mol, preferably 2 to 3 times mol, of the metal halide used. The metal halide used in this reaction is preferably magnesium chloride or the like. The amount of the metal halide used may be 1 to 5 times, preferably 1 to 3 times the mol of the reactive derivative of the general formula [3]. For example, in the case of magnesium chloride, it may be 1 to 5 times, preferably 1 to 3 times the mol of the reactive derivative of the general formula [3]. The solvent used in this reaction is not particularly limited as long as it does not adversely influence the reaction, and examples thereof include aromatic hydrocarbons such as benzene, toluene and xylene; ethers such as dioxane and tetrahydrofuran; chloroform and methylene. Examples thereof include halogenated hydrocarbons such as chloride; amides such as N, N-dimethylformamide; and sulfoxides such as dimethyl sulfoxide. These solvents may be used alone or in combination of two or more. This reaction is usually
-20 to 50 ° C, preferably 0 to 25 ° C, 30 minutes to 24 hours,
Preferably, it may be carried out for 1 to 5 hours.

The compound of the general formula [1] can be obtained by a method known in the prior art, for example, the organic synthesis collective volume [Organic Synthetic Volume].
ses collective volume] Vol. 4, p. 708, etc., and can be obtained by subjecting to deesterification and decarboxylation. Next, a method for producing the compound of the general formula [4] or a salt thereof, which is a raw material used in the method of the present invention, will be described. The compound of the general formula [4] or a salt thereof can be produced, for example, according to the production route shown below.

[0013]

Embedded image

The reactive derivative of the general formula [3], which is the raw material used in the method of the present invention, can be prepared by a method known in the related art, for example, Experimental Chemistry Course, Volume 20,
P. 209 and Angevante Chemie Internal
Edition English [Angew. Chem. Int. E
d. Engl.], Vol. 18, page 72 and the like.

The compound of the general formula [4] is, for example, 1,
It can be obtained by reacting 2,4-triazole and halogenoacetic acid ester in the presence of a base. Examples of the base used in this reaction include organic bases such as 1,8-diazabicyclo [5.4.0] -7-undecene and 1,5-diazabicyclo [4.3.0] non-5-ene; Alkali metals such as sodium and potassium; Alkali metal hydroxides such as lithium hydroxide, sodium hydroxide and potassium hydroxide; Alkali metal alkoxides such as sodium methoxide and potassium tertiary butoxide; Alkali metal hydrides such as sodium hydride Is mentioned. The amount of the base used may be 1 to 3 times mols of 1,2,4-triazole, and preferably 1
It may be up to 1.5 times mol. The solvent used in this reaction is not particularly limited as long as it does not adversely influence the reaction, and examples thereof include aromatic hydrocarbons such as benzene, toluene and xylene; ethers such as dioxane and tetrahydrofuran; chloroform and methylene. Halogenated hydrocarbons such as chlorides; alcohols such as methanol and ethanol; amides such as N, N-dimethylformamide; sulfoxides such as dimethyl sulfoxide and water, and these solvents may be used alone or in combination of two or more. You may mix and use. This reaction is generally carried out at -50 to 100 ° C, preferably 0 to
It may be carried out at 50 ° C. for 10 minutes to 24 hours, preferably 30 minutes to 3 hours.

Next, the production examples of the compound of the present invention will be specifically described with reference to Reference Examples and Examples, but the present invention is not limited thereto.

Example 1 Magnesium chloride (5.7 g) was suspended in a mixed solution of methylene chloride (40 ml) and N, N-dimethylformamide (5 ml) to give 2- (1H-1,2,4-triazol-1-yl).
10.0 g of acetic acid tert-butyl ester and 12.1 g of triethylamine are added, and the mixture is stirred at 25 ° C. for 1 hour. Then, under ice cooling, 9.6 g of 2,4-difluorobenzoic acid chloride was added dropwise, and the mixture was stirred at 25 ° C for 5 hours. 50 ml of water is added to the reaction mixture, and the pH is adjusted to 2.0 with 6N hydrochloric acid. The organic layer is separated, washed successively with water and saturated brine, dried over anhydrous magnesium sulfate, and the solvent is distilled off under reduced pressure. The obtained residue was subjected to silica gel column chromatography [eluent;
n-Hexane: ethyl acetate = 4: 1] to give 3- (2,4-difluorophenyl) -3 as a pale yellow solid.
-Oxo-2- (1H-1,2,4-triazole-1-
Yl) propionic acid tert-butyl ester 14.5 g (yield 8
2.4%). IR (KBr) cm ^-1 : 3100,1754,1738,1500 NMR (CDCl ₃ ) δ: 1.39 (s, 9H), 6.7-8.3 (m, 4H), 7.96 (s, 1H),
8.46 (s, 1H)

Example 2 3- (2,4-difluorophenyl) -3-oxo-2
10 ml of 6N hydrochloric acid was added to 10.0 g of-(1H-1,2,4-triazol-1-yl) propionic acid tert-butyl ester, and the mixture was heated under reflux for 1 hour. After cooling the reaction mixture to 20 ° C., 10 ml of toluene is added and the pH is adjusted to 8.5 with a 3N aqueous sodium hydroxide solution. The precipitated crystals were collected by filtration under ice cooling to give 1- (2,4-difluorophenyl) -2- as pale yellow crystals.
(1H-1,2,4-triazol-1-yl) ethanone
6.2 g (yield 90.0%) are obtained. Mp: 105.3-106.9 ℃ IR (KBr) cm -1: 3050,1690,1510 NMR (CDCl 3) δ: 5.57 (d, 2H, 3Hz), 6.7-8.3 (m, 3H), 7.93 (s,
1H), 8.20 (s, 1H)

Example 3 (1) 200.0 g of 2,4-difluorobenzoic acid was suspended in 1000 ml of methylene chloride, 180.6 g of thionyl chloride and 2 ml of N, N-dimethylformamide were added, and the mixture was heated under reflux for 3 hours. After distilling off the solvent under reduced pressure, methylene chloride
400 ml is added to obtain a solution of 2,4-difluorobenzoic acid chloride. (2) To 200 ml of N, N-dimethylformamide, 69.8 g of sodium hydroxide and 118.0 g of 1,2,4-triazole were added, and the mixture was stirred at 45 ° C for 1 hour. The reaction mixture is cooled to 30 ° C., 238.2 g of chloroacetic acid tert-butyl ester is added dropwise, and the mixture is stirred at 45 ° C. for 1 hr. To the reaction mixture was added 600 ml of methylene chloride and 160 g of synthetic zeolite, filtered,
2- (1H-1,2,4-triazol-1-yl) acetic acid
tert-Butyl ester and 2- (1H-1,2,4-triazol-4-yl) acetic acid tert-butyl ester solution are obtained. 156.6 g of magnesium chloride and 320.0 g of triethylamine are added to this solution, and the mixture is stirred at 25 ° C for 30 minutes. The solution prepared in (1) was added dropwise to the reaction mixture under ice cooling.
Stir for 5 hours at ° C. Then, 600 ml of water is added, the pH is adjusted to 2.0 with 6N hydrochloric acid, and the organic layer is separated. To the obtained organic layer is added 430 ml of 6N hydrochloric acid, and the temperature is raised to 85 ° C. while distilling methylene chloride. After cooling to 20 ℃, toluene
Add 400 ml and adjust the pH to 8.5 with 3N aqueous sodium hydroxide. The precipitated crystals were collected by filtration under ice cooling to give 1
-(2,4-difluorophenyl) -2- (1H-1,
230.0 g (yield 81.5%) of 2,4-triazol-1-yl) ethanone are obtained. Mp: 105.3-106.9 ℃ IR (KBr) cm -1: 3050,1690,1510 NMR (CDCl 3) δ: 5.57 (d, 2H, 3Hz), 6.7-8.3 (m, 3H), 7.93 (s,
1H), 8.20 (s, 1H)

Example 4 In the same manner as in Example 3, except that 5.2 g of 2,4-dichlorobenzoic acid was used instead of 2,4-difluorobenzoic acid, 1
-(2,4-dichlorophenyl) -2- (1H-1,2,
5.2 g of 4-triazol-1-yl) ethanone (yield 75.6
%). Mp: 114.4-116.5 ℃ IR (KBr) cm -1: 3080,1690,1510 NMR (CDCl 3) ppm: 5.61 (s, 2H), 7.2-7.7 (m, 3H), 7.95 (s, 1
H), 8.23 (s, 1H)

Reference Example 1 10 ml of N, N-dimethylformamide was added to sodium hydroxide.
Add 3.5 g and 5.9 g of 1,2,4-triazole and stir at 45 ° C. for 1 hour. After cooling the reaction mixture to 30 ° C,
Chloroacetic acid tert-butyl ester 11.9 g was added dropwise at 45 ° C.
Stir for 1 hour. 100 ml of ethyl acetate and 100 ml of water are added, the pH is adjusted to 2.5 with 6N hydrochloric acid, and the organic layer is separated. 100 ml of water is added to the obtained organic layer and the pH is adjusted to 8.0 with a saturated aqueous sodium hydrogen carbonate solution, and then the organic layer is separated. The obtained organic layer is washed with saturated saline and then dried over anhydrous magnesium sulfate, and the solvent is distilled off under reduced pressure. The residue was purified by distillation to give 2- (1H-1,2,4) colorless crystals.
-Triazol-1-yl) acetic acid tert-butyl ester
10.5 g (yield 75.2%) is obtained. Melting point: 56.9-58.5 ° C IR (KBr) cm ^-1 : 3110,1740,1510 NMR (CDCl ₃ ) δ: 1.41 (s, 9H), 4.87 (s, 2H), 7.95 (s, 1H), 8.18
(s, 1H)

[0022]

INDUSTRIAL APPLICABILITY The production method of the present invention is useful as a raw material for producing antifungal agents and agricultural chemicals 2- (1H-1,2,4-)
Triazol-1-yl) acetophenones can be produced in high purity and high yield, and the reaction time in each step is usually relatively short at about 1 to 5 hours, and the purification step is simple,
Easy to scale up and industrially useful.

Claims (2)

[Claims] Claims: (Wherein R represents a carboxyl protecting group; R ¹ and R
² is the same or different and is a hydrogen atom, a lower alkyl group,
A lower alkoxy group, a cyano group, a nitro group, a halogeno lower alkyl group, a lower alkylsulfonyl group or a halogen atom is shown. ) 3-phenyl-2- (1H
1,2,4-triazol-1-yl) propionic acid ester derivative is deesterified and decarboxylated. (In the formula, R ¹ and R ² have the same meanings as described above.) A method for producing 2- (1H-1,2,4-triazol-1-yl) acetophenones. 2. (In the formula, R represents a carboxyl-protecting group.) The 1,2,4-triazoleacetic acid derivative represented by (In the formula, R ¹ and R ² are the same or different and each represents a hydrogen atom, a lower alkyl group, a lower alkoxy group, a cyano group, a nitro group, a halogeno lower alkyl group, a lower alkylsulfonyl group or a halogen atom.) Reacting a reactive derivative of benzoic acid to a base and a metal halide, (In the formula, R ¹ , R ² and R have the same meanings as described above.) 3-phenyl-2- (1H-
1,2,4-triazol-1-yl) propionic acid ester derivative is obtained, followed by deesterification and decarboxylation. (In the formula, R ¹ and R ² have the same meanings as described above.) A method for producing 2- (1H-1,2,4-triazol-1-yl) acetophenones.