JPH0311065A - Production of pyridyl phenyl ketone compound - Google Patents

Abstract

PURPOSE:To readily produce a pyridyl phenyl ketone compound in high purity and yield by reacting a pyridylcarboxylic acid halide with a substituted benzene using trifluoromethanesulfonic acid as a catalyst. CONSTITUTION:A compound expressed by formula I (X is halogen, hydrocarbonsulfonyl or hydrocarbonoxy; Y is halogen; n is 0-4) or salt thereof is reacted with a compound expressed by formula II (R is hydrocarbon; m is 1-5) in the presence of trifluoromethanesulfonic acid as a catalyst to afford a pyridyl phenyl ketone [e.g. 2-chloro-5-(3,4-dimethoxybenzoyl)pyridyl] expressed by formula III. The objective compound can be readily produced from easily available raw materials in good yield and high purity by the above-mentioned method with formation of by-products in an extremely small amount. The reaction operation is also simple with a short reaction process and the aforementioned method is industrially advantageous. The resultant compound is useful as a raw material compound for agricultural chemicals, such as germicide, and various medicines.

Description

DETAILED DESCRIPTION OF THE INVENTION (Industrial Field of Application) The present invention relates to a method for producing a pyridylphenyl ketone compound represented by the following formula [+] or a salt thereof.

The pyridylphenyl ketone compound obtained by the method of the present invention is useful as a raw material compound for agricultural chemicals such as fungicides and various pharmaceuticals.

(Prior art and problems to be solved by the invention) As a method for producing a substituted pyridylphenyl ketone compound, for example,
A method is known in which nicotinic acid chloride and substituted benzenes are reacted in the presence of anhydrous aluminum chloride [Liebigs A.
nn, Chem, 930 (19g2).

However, in this method, the substituent on the benzene ring is chlorine.

In the case of fluorine and nitro groups, the yield is good, but in the case of methoxy groups and t-butyl groups, the yield is extremely low, and a large amount of anhydrous aluminum chloride is required, the operation is complicated, and it is not suitable for industrial use. The manufacturing method is not satisfactory.

(Means for Solving the Problems) The present inventors have proposed a method for producing a pyridyl phenyl ketone compound from a pyridyl carbonyl halide and a substituted benzene more easily, with higher purity, and in a higher yield.
As I continued my intensive research, I discovered that iodine,
Perchloric acid.

8F3・(C,Hs)to, H! So4. CH35
O3H, CF3COOH.

Cl5O3H, FeC15,5nC1*+ Although the reaction hardly progresses even when acids such as polyphosphoric acid, montmorillonite, and cation exchange resins are used, the reaction progresses extremely smoothly only with trifluoromethanesulfonic acid, and moreover, with pyridyl It has been found that phenylketone compounds can be obtained in extremely good yields. Based on these findings, the present inventors conducted various further studies and completed the present invention.

That is, the present invention provides a compound or a salt thereof represented by the general formula [wherein, A general formula [wherein R represents a hydrocarbon group and m represents an integer from 1 to 5] is reacted in the presence of trifluoromethanesulfonic acid [wherein the symbols are The present invention relates to a method for producing a pyridylphenyl ketone or a salt thereof represented by the above definition.

In the above general formula, the hydrocarbon sulfonyl group represented by X is preferably an alkylsulfonyl group, an arylsulfonyl group, or an aralkylsulfonyl group.

The alkylsulfonyl group preferably has 1 to 10 carbon atoms.
Alkylsulfonyl groups, such as linear or branched alkylsulfonyl groups having 1 to 10 carbon atoms such as methylsulfonyl, ethylsulfonyl, propylsulfonyl, isopropylsulfonyl, and hexylsulfonyl; carbon atoms such as cyclopropylsulfonyl and cyclohexylsulfonyl; A cyclic alkylsulfonyl group having numbers 3 to 6 is used.

As the arylsulfonyl group, preferably an arylsulfonyl group having 6 to 10 carbon atoms such as benzenesulfonyl and naphthalenesulfonyl is used.

As the aralkylsulfonyl group, preferably used is an aralkylsulfonyl group having 7 to 19 carbon atoms such as benzylsulfonyl, phenethylsulfonyl, naphthalenemethylsulfonyl, phenacylsulfonyl, and tritylsulfonyl.

The hydrocarbonoxy group represented by X is preferably an alkoxy group, an aryloxy group, or an aralkyloxy group.

Alkoxy groups are preferably methoxy, ethoxy, propoxy, impropoxy, butoxy, imbutoxy, t
- An alkoxy group having 1 to 6 carbon atoms such as butoxy, pentyloxy, hexyloxy, etc. is used.

The aryloxy group is preferably phenoxy.

6 to 12 carbon atoms such as naphthoxy, biphenylyloxy, etc.
aryloxy groups are used.

The aralkyloxy group is preferably benzyloxy, naphthylmethyloxy, or phenacyloxy.

An aralkyloxy group having 7 to 19 carbon atoms such as trityloxy is used.

The aryl group in the arylsulfonyl group and aryloxy group represented by X may be substituted with 1 to 5 substituents, and examples of such substituents include (
1) halogen atoms (e.g. fluorine, chlorine, bromine, iodine, etc.), (2) aryl groups having 6 to 10 carbon atoms optionally substituted with nitro groups or halogens (e.g. phenyl, p-nitrophenyl, p -chlorophenyl),
(3) Alkyl group having 1 to 4 carbon atoms (e.g. methyl,
ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, etc.), (4) alkoxy groups having 1 to 4 carbon atoms (e.g., methoxy, methoxy, propoxy, isopropoxy, butoxy, imbutoxy, t-butoxy, etc.) ) etc. are used.

The hydrocarbon group represented by R is preferably an alkyl group, an aryl group, or an aralkyl group.

Alkyl groups are preferably methyl, ethyl, propyl,
An alkyl group having 1 to 6 carbon atoms such as isopropyl, butyl, t-butyl, pentyl, hexyl and the like is used.

The aryl group is preferably phenyl or naphthyl.

An aryl group having 6 to 12 carbon atoms such as biphenylyl is used.

Aralkyl groups are preferably benzyl, naphthylmethyl,
Aralkyl groups having 7 to 19 carbon atoms such as phenacyl and trityl are used.

The halogen atom represented by X is fluorine.

Chlorine, bromine, iodine, etc. are used.

The halogen atom represented by Y is preferably chlorine,
Bromine etc. are used.

R is preferably an alkyl group having 1 to 6 carbon atoms, particularly preferably a methyl group.

n is an integer from 0 to 4, preferably l.

m is an integer from 1 to 5, preferably an integer from 1 to 3, and more preferably 2.

As the salt of compound [1], [I[[], acid addition salts such as inorganic acid addition salts and organic acid addition salts are used. Examples of inorganic acids that can generate inorganic acid addition salts include hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, and phosphoric acid; examples of organic acids that can generate organic addition salts include p-toluenesulfonic acid,
Methanesulfonic acid, -t' acid, 1fluoroacetic acid, trifluoromethanesulfonic acid, etc. are used.

In this reaction, compound [11] is used in an amount of about 0.5 to 10 mol, preferably about 1.5 to 2.5 mol, per mol of compound [111] or a salt thereof.

Trifluoromethanesulfonic acid is used in an amount of about 1 mmol to 1 mol, preferably about 10 mmol to 100' mmol, per 1 mol of compound [I[II or its salt].

This reaction is carried out without a solvent or in a solvent that does not adversely affect the reaction.

Examples of such solvents include hydrocarbons such as isooctane, decane, cyclohexane, and decalin; aromatic hydrocarbons such as benzene and toluene; halogenated aromatic hydrocarbons such as chlorobenzene and dichlorobenzene;
Halogenated hydrocarbons such as dichloromethane, chloroform, 1,2-dichloroethane, 1,1.1-trichloroethane, trichloroethylene, tetrachloroethylene, carbon tetrachloride, ethers such as isopropyl ether and dioxane, nitriles such as acetonitrile, methyl ethyl ketone, Ketones such as methyl isobutyl ketone are used. Preferred are aromatic hydrocarbons, halogenated aromatic hydrocarbons, and halogenated hydrocarbons.

Among these, halogenated aromatic hydrocarbons such as benzene and chlorobenzene are particularly preferred.

These solvents are used alone. Alternatively, two or more types can be mixed in an appropriate ratio, for example 1:1 to 1:1.
They may be used by mixing at a ratio of 0.

When aromatic hydrocarbons or halogenated aromatic hydrocarbons are used as a solvent, compound [II[] reacts with the aromatic hydrocarbons or halogenated aromatic hydrocarbons in addition to compound [1]. This is generally expected. However, in the reaction of the present invention, contrary to this prediction, compound [1] hardly reacts with the aromatic hydrocarbons or halogenated aromatic hydrocarbons of the solvent, but quickly reacts with compound [1], The desired compound [II or a salt thereof is produced in high yield.

This reaction is preferably carried out by violently boiling the reaction solution or by vigorously blowing an inert gas into the reaction solution. If necessary, this reaction may be carried out with stirring.

Examples of the inert gas include nitrogen and helium.

Argon, air, etc. are used. It is preferable to use the inert gas after drying it (for example, by passing it through concentrated sulfuric acid).

The reaction temperature is usually about 20 to 200'C, preferably about 70 to 140'C.

The reaction time varies depending on reaction conditions such as reaction temperature, but
Usually about 10 minutes to 20 hours, preferably about 1 hour to 1 hour
The range is 0 hours.

The compound [I] or a salt thereof obtained in this way is
It can be isolated and purified by means known per se, such as concentration, vacuum concentration, extraction, dissolution, crystallization, recrystallization, and chromatography.

Compound [1] or a salt thereof can be prepared by a method known per se (for example,
Organic Synthesis
esis) Collective Volume 4 (Call
.

Vol. 4) p. 88 (1963)] or a method similar thereto.

Compound [11] can be prepared by known or per se known methods [e.g.
(For example, Organic Synthesis
5ynthesis) Collective Volume 1
(Coil, Vol. 1) p. 58 (1963)] or a method analogous thereto.

Compound [1] or a salt thereof is used as a raw material for agricultural chemicals and medicines.

For example, compound [1] or a salt thereof is disclosed in Japanese Patent Application No. 0f-041.
According to the method described in No. 034, a compound [IVl or a salt thereof] which exhibits an excellent control effect against downy mildew and late blight on vegetables and fruit trees can be derived.

Further, the compound [■] or a salt thereof can be produced by the method shown in the scheme below.

0-120°C (IV) or a salt thereof In the above formula, R1 is a hydrogen atom, a halogen atom (e.g. chlorine,
bromine, etc.) or lower alkyl groups (e.g., methyl, ethyl,
n-propyl, n-butyl, t-7'thyl, etc.), R' is a lower alkyl group (eg, methyl).

ethyl, n-propyl, n-butyl, t-butyl, etc.) or a phenyl group, Hal is a halogen atom (eg, chlorine, bromine, iodine, etc.), and other symbols have the same meanings as above.

Raw material compound [Vl is, for example, U, S, P, 3.06
It can be manufactured by the method described in 6140 etc.

The compound [1'Vl or a salt thereof can be dissolved or dispersed in a suitable liquid carrier (e.g., a solvent) and mixed with or adsorbed onto a suitable solid carrier (e.g., a diluent, a bulking agent), and can be prepared as required. In this case, add an emulsifier,
Suspending agents, spreading agents, penetrating agents, dispersing agents, wetting agents, demulcents, stabilizers, etc. are added and used as dosage forms such as emulsions, wettable powders, oils, powders, and granules. These formulations can be prepared by known methods.

The weight ratio of the compound [IVl or its salt to the entire sterilized preparation is about 1 to 80% by weight for emulsions and wettable powders;
Approximately 0.1 to 10% by weight is appropriate for oils, powders, etc., and approximately 5 to 50% by weight for granules, but the blending ratio should be changed as appropriate depending on the conditions of use and disease occurrence. It can also happen.

When used, emulsions and wettable powders are preferably diluted with water and the like (for example, 100 to 5000 times) and then dispersed.

When compound [IV] or its salt is used as an agricultural fungicide, the amount used depends on the growth stage of the target plant.

Although it varies depending on various conditions such as growth conditions, type of disease, state of onset, time of application or method of application of the drug, generally the compound [■] or its salt is about 3 to 300 g per 10 ares, preferably about 10 to 10 logs. It should be adjusted so that Further, the concentration used may be such that the active ingredient is in a range of about 10 to 1000 ppm.

This fungicide can be used not only on plant seeds, but also at any stage from seedling to harvest, and by applying it to plants before the onset of plant diseases, it can not only prevent the onset of plant diseases, but can also be used regularly. It may be used on plants immediately after the onset of disease in accordance with the law.

How to use: spray directly on plants, direct dusting.

May be irrigated or seed coated. Furthermore, the amount, concentration, or method of use may be changed as appropriate, as long as it is used safely and effectively for plants.

Compound [IV] or its salt exhibits excellent amphoteric resistance, so it does not run off even when it rains, exhibits particularly excellent pesticidal effects during the rainy season, and reduces disease damage to vegetables and fruit trees.

It can be used as an excellent fungicide.

(Effects of the Invention) According to the method of the present invention, the compound [+] or a salt thereof can be easily produced from readily available raw materials in a high yield and with very few by-products (with high purity).

The reaction operation is simple and the reaction steps are short, making it extremely useful as an industrial production method.

Next, the present invention will be described in more detail using Examples, Comparative Examples, and Reference Examples, but the present invention should not be limited to these.

The following symbols used in the following examples and reference examples have the following meanings.

S: singlet d: doublet m: multi-bullet dd: double-doublet Unless otherwise specified, % indicates weight %.

(Example) Example 1 Production of 2-chloro-5-(3,4-dimethoxybenzoyl)pyridine 5.0 g of 6-chloronicotinic acid chloride and 10 g of veratrol were dissolved in 100 ml of chlorobenzene, and 0.0 g of trifluoromethanesulfonic acid was dissolved in 100 ml of chlorobenzene. .4g was added.

The reaction solution was heated under reflux for 9 hours while vigorously blowing dry nitrogen gas into the reaction solution. After the reaction, when the temperature was returned to room temperature, crystals precipitated, which were collected by filtration and washed with diethyl ether to obtain 5.8 g of the title compound as white crystals. Melting point 169-171'C NMR (CDCI, l) δI) pTll 3.93
(3H, s), 3.97 (3H, s), 6°9
7 (IH, d, J=91tz), 7.37 (IH
, dd, J=9 and 1.5Hz), 7°43 (IH
,s), 7.50(IH,d, J=9tlz),
8.08 (1fL dd, J=9 and 1.5)1z)
, 8.10<IH,d, J=1.5)1z)IR(
Liquid paraffin) cm-' 1630 Example 2 Preparation of 2-chloro-5-(4-methoxybenzoyl)pyridine 2 g of 6-chloronicotinic acid chloride and 4 g of anisole
g was dissolved in 50 ml of chlorobenzene, and 0.15 g of trifluoromethanesulfone M was added. The reaction solution was heated under reflux for 8 hours while vigorously blowing dry nitrogen gas into the reaction solution. After the reaction, when the temperature was returned to room temperature, crystals precipitated, which were collected by filtration and washed with diethyl ether to obtain 1.9 g of the title compound as white crystals.

Melting point 148-149°C NMR (CDC13) δppm 3.90 (3H, s)
, 7.00 (2H, d, J=911z), 7.47
(IH, d, J=911z), 7.83(2)1.
d, J=9Hz), 8.07([1, dd, J
=9 and 1.5Hz), 8.77(1)1. d,
1.5Hz) IR (liquid paraffin) cm-' 1
635 Comparative Example 1 2-chloro=5- (
Preparation of 3,4-dimethoxybenzoyl)pyridine 5 g of 6-chloronicotinic acid chloride and 10 g of veratrol were dissolved in 100 ml of chlorobenzene. 4.2 g of anhydrous aluminum chloride was added to this, heated under reflux for 8 hours, and then cooled to room temperature.

This was poured into cold water, extracted with dichloromethane, the organic layer was dried over magnesium sulfate, and then concentrated under reduced pressure.

The residue was isolated and purified by silica gel column chromatography, but only traces of the title compound were obtained.

Comparative Example 2 Production of 2-chloro-5-(3°4-dimethoxybenzoyl)pyridine in the presence of various catalysts 6-chloronicotinic acid chloride Ig and veratrol 2g were dissolved in chlorobenzene 3Qml. The catalyst shown in Table 1 was added to the mixture, heated under reflux for 8 hours, and then cooled to room temperature.

This was poured into cold water, extracted with dichloromethane, and the presence or absence of the formation of 2-chloro-5-(3,4-dimethoxybenzoylpyridine) in the dichloromethane solution was determined by thin layer chromatography (developing solvent: 〇-hexane: ethyl acetate = 2:1), but no formation was observed in either case.

2 Iodine 0.15 Perchloric acid (70% by weight) 0.58F3・(CA
L) to 0.8+1. So,
0.9C) 13SO3110,7 CF, C0OHO,6 CISO3H0,6 FeC1a 0.92SnCI*
1.1 Polyphosphoric acid
1 Montmorillonite 1 K-10o (manufactured by Nissan Girdler Catalyst Co., Ltd.) Cation exchange resin 0.5 (Ka, Ioa ~ 51, [F], manufactured by Depore Co., Ltd.) Reference example 1 60% sodium hydride ( Paraffin impregnated) 132mg
was suspended in 10me of 1,2-dimethoxyethane, and 68% of diethylphosphonoacetic acid morpholide was added to this with stirring.
A solution of 8 mg dissolved in 5 g of 1,2-dimethoxyethane was added dropwise. Next, 2(4-chlorophenoxy)-5
800 mg of -(3,4-dimethoxybenzoyl)pyridine (manufactured by the method described in Japanese Patent Application No. 1-41034) was added, and the mixture was heated under reflux for 8 hours. After concentrating the reaction solution, it was dissolved in ether, washed with water, and dried over anhydrous magnesium sulfate.The solvent was distilled off, and the resulting oil was purified by silica gel column chromatography (eluted with ethyl acetate).
-[3-(2-(4-chlorophenoxy)-5-pyridyl)-3-(3,4-dimethoxyphenyl)acryloyl 1 330 mg of morpholine was obtained.

Based on candy-like solid NMR data, it was confirmed that it was a mixture of E-form and 2-form at a ratio of about 2:3.

NMR(CDC(2s)δppm: 3.00~
3. TO(SR,m), 3.83(38,s),
3.85 (3H, s), 6.20 and 6.33 (lt
l, s, sHE body and 2 body), 6.67-7.6
7 (9H, m), 8.07 and 8.17 (1 [(.

d, d; E body and 2 bodies)

Claims (1)

[Claims] General formula▲ Numerical formula, chemical formula, table, etc.▼ [In the formula, X is a halogen atom, a hydrocarbon sulfonyl group, or a hydrocarbon oxy group, Y is a halogen atom, and n is an integer from 0 to 4. Compounds or their salts represented by the general formula ▲ Numerical formulas, chemical formulas, tables, etc. A method for producing a pyridylphenyl ketone compound or its salt represented by the general formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ [Symbols in the formula have the same meanings as above] characterized by the reaction in the presence of lomethanesulfonic acid. .