JPH04112873A - Production of pyrazole-5-carboxylic acid esters - Google Patents

Abstract

PURPOSE:To obtain a compound useful as an intermediate for agricultural chemical, especially plant disease damage controlling agent by reacting 3-alkyl-1 H-pyrazole-5-carboxylic acid esters with a sulfonate derivative. CONSTITUTION:A compound expressed by formula I (R<2> and R<3> are lower alkyl) is reacted with a compound expressed by the formula R<1>-OSO2-R<4> (R<1> is 1-6C alkyl, 3-6C cycloalkyl, 1-6C alkyl halide, 2 or 3-tetrahydrofuranyl, etc.; R<4> is 1-4C alkyl, 1-4C alkyl halide or phenyl which may be substituted), preferably in the presence of an acid acceptor (e.g. tributylamine) without using any solvent at 50-200 deg.C for 3-8hr to provide the compound expressed by formula II. In the above-mentioned reaction of the compound expressed by formula I with the sulfonate compound expressed by formula II, the sulfonate is used in equimolar amount to slightly excess amount based on 1mol of the compound expressed by formula I and the acid acceptor is used in an amount of 1-1.5mol by mol based on the compound,expressed by formula I.

Description

Detailed Description of the Invention [Field of Industrial Application] The present invention relates to a method for producing novel 1-substituted-3-alkyl-IH-pyrazole-5-carboxylic acid esters, and this compound is It is useful as an intermediate for agricultural chemicals, especially plant disease control agents.

[Conventional technology]

Surnal Pure Practiche Hemi (J
, Prakt, Chem, Vol. 143, p. 259 (1935), when methyl 3-methylpyrazole-5-carboxylate is reacted with methyl iodide, only methyl 15-dimethylpyrazole-3-carboxylate is produced. It is reported that it can be obtained.

Furthermore, JP-A-1-168675 has an example in which 3(5) methylpyrazole-5(3)-carboxylic acid esters are alkylated with dialkyl sulfuric acid.

Furthermore, as an example of an alkylation reaction using a sulfonate derivative, the Journal of the American Chemical Society, Vol. 55, p. Although examples of synthesizing butylaniline are described,
- There are no examples in which the pyrazole derivative represented by formula (II) has been attempted.

[The problem that the invention attempts to solve]

J. Prakt, Chem, vol. 143, 25.
In the technique of page 9 (1935), the target 1-place-3
-Alkyl-IH-pyrazole-5-carboxylic acid esters cannot be obtained.

In addition, the technique disclosed in JP-A-1-168675 is limited to readily available dialkyl sulfuric acid, methyl form, and ethyl form, so that the number of carbon atoms in the alkyl group is only 1 or 2. The introduction of various substituents is not possible.

An object of the present invention is to establish a method for producing 1-substituted 3-alkyl-IH-pyrazole-5-carboxylic acid esters useful as intermediates for agricultural chemicals.

[Means for solving problems]

As a result of intensive studies to solve the above-mentioned problems, we found that the desired 1-
It was discovered that substituted-3-alkyl-IH pyrazole-5-carphonic acid esters can be obtained, and the present invention was completed.

The present invention has the general formula CI) Acid esters are useful as intermediates in the production of agricultural chemicals, particularly plant disease control agents [Japanese Patent Application No. 01-181822].

Next, the production method of the present invention will be specifically explained using a reaction scheme.

(Hereinafter, blank space) (In the formula, R1 is an alkyl group having 1 to 6 carbon atoms, 3 carbon atoms
-6 cycloalkyl group, C4-6 cycloalkylalkyl group, C1-6 halogenated alkyl group,
It represents an alkoxyalkyl group having 2 to 6 carbon atoms, a 2- or 3-tetrahydrofuranyl group, or a 2- or 3-tetrahydrothienyl group, and R2 and R3 each represent a lower alkyl group.

The present invention relates to a method for producing l-substituted-3-alkyl-IH-pyrazole-5-carboxylic acid esters.

l-Substituted-3-alkyl-IH-pyrazole-5-carbo produced by the production method according to the present invention Reaction scheme 1 Reaction scheme 2 (n) (I) (wherein R', R2, R', R ' respectively represent the above meanings.) [Explanation of Reaction Scheme 1] First, the sulfonate derivative as a raw material is mixed with an alcohol and a sulfonyl chloride derivative (I) as shown in the following reaction scheme.
V).

R' -OH+ Cff5O2R'-R'
-03O2R'(IV) CI) In this reaction, halogenated hydrocarbons such as methylene chloride, chloroform, and 1,2-dichloroethane can be used as the solvent.

As the acid acceptor, it is preferable to use an organic base such as triethylamine and pyridine.

The reaction temperature can range from about -50°C to the boiling point of the solvent, and is usually preferably from -20°C to about room temperature.

Further, the reaction time is about 1 to 2 hours until the open circuit reaction is completed.

Next, the sulfonate derivative CI) obtained in this way
In the reaction between 3-alkyl-IH-pyrazole 5-carboxylic acid ester (II) and the raw material 3-alkyl-IH-pyrazole 5-carboxylic acid ester (II), the molar ratio of each is preferably from 1 to 1 to a slight excess of the sulfonate derivative (I[). It is possible to use a solvent or not, and the reaction proceeds more quickly in the absence of a solvent.

When a solvent is used, it is preferably a polar organic solvent such as N,N-dimethylacetamide (DMA) or hexamethylphosphoric triamide (HMPA).

Although the reaction proceeds even if no additives are used, tertiary amines such as triethylamine, tributylamine, and pyridine are used as acid acceptors in addition to the raw material 3-alkyl-IH-pyrazole-5-carboxylic acid ester. It is preferable to add 1 to 1.5 times the mole of the compound [■].

The reaction temperature is preferably between 50 and 200°C, particularly 8
0~150℃. The reaction time is determined by the correlation with temperature, and is usually 3 to 8 hours.
The conversion rate of H-pyrazole-5-carboxylic acid ester (I[) becomes almost constant.

After the reaction is completed, the mixture is neutralized with an aqueous hydrochloric acid solution, extracted with an organic solvent, washed with aqueous sodium bicarbonate, dried, and then concentrated and the solvent is distilled off.

By distilling or column purifying this crude product, the desired l-substituted-3-alkyl-IH pyrazole-5-
Carboxylic acid esters are obtained.

Specific examples of sulfonyl chloride derivatives include alkylsulfonyl chlorides such as methanesulfonyl chloride and ethanesulfonyl chloride; unsubstituted or substituted phenylsulfonyl chlorides such as benzenesulfonyl chloride and toluenesulfonyl chloride F; Furthermore, halogenated alkylsulfonyl chlorides such as trichloromethanesulfonyl chloride and trifluoromethanesulfonyl chloride may be mentioned, and various other heterocyclic sulfonyl chlorides may also be used.

Reaction scheme 3 p2 (I) Alkali. That is, the reaction is carried out in a binary solvent system of alcohols such as methanol and ethanol and water in the presence of an inorganic base such as sodium hydroxide and potassium hydroxide at room temperature to the reflux temperature of the solvent.

After the reaction is completed, the target 1-substituted-3-alkyl-IH-pyrazole-5 is obtained by cooling and adding an acid to adjust the pH to 4 to 5.
- Carboxylic acid derivative (V) is precipitated. Further, a purified product can be obtained by filtration or extraction with a solvent, followed by recrystallization from water.

(V) 1-substituted-3-alkyl-IH-pyrazole-5-carboxylic acid esters (I) obtained in the above reaction scheme 1
is the desired l-substituted-3-alkyl-IH-
(V) (VI) The l-substituted-3-alkyl- obtained in the above reaction scheme 3 can be easily converted into the pyrazole-5-carphonic acid derivative (V).
The desired 1-substituted-3-alkyl- IH-pyrazole-5-carboxylic acid chloride derivative (VI) is easily obtained.

The reaction temperature can range from room temperature to the reflux temperature of the solvent.

After the reaction is completed, excess thionyl chloride or the solvent is distilled off, and then the target product (VI) can be purified by distillation under reduced pressure.

The intermediate obtained by the production method of the present invention as described above is converted into an agricultural and horticultural fungicide according to the following reaction formulas (1) to (5).

Salt (VI) Group [■] [■] [■] B (IX) (VI) (X I ) [■] (IX) R' (X) (VI) CXII) R' B (X) (in the formula R1 and R2 each have the above meanings, and B is 2
-thienyl group, 3-thienyl group, 2-furyl group or 3
-Represents a furyl group. ) (1) Easily produced by reacting the l-substituted 1-3-alkyl-IH-pyrazole-5-carboxylic acid chloride derivative (VI) obtained by the production method of the present invention with the aminoacetonitrile derivative [■] in the presence of a base. A bactericidal pyrazolamide-substituted acetonitrile derivative [■] is obtained.

(2) The bactericidal pyrazolamide-substituted acetonitrile derivative [■] is reacted with hydrogen sulfide using a base as a catalyst to obtain the pyrazolamide-substituted acetothiocarbamoyl derivative (IX), which is a similar bactericide.

(3) Furthermore, by reacting the fungicide pyrazolamide-substituted acetonitrile derivative [■] with hydroxyamine, a pyrazolamide-substituted acetamide oxime derivative CX), which is a similar fungicide, can be obtained.

(4) Also, 1-substitution-3 obtained by the production method of the present invention
-Alkyl-IH-pyrazole-5-carboxylic acid chloride derivative (VI) and aminoacetothiocarbamoyl derivative (XI) are reacted in the presence of a base to obtain a pyrazolamide-substituted acetothiocarbamoyl derivative (IX), which is a fungicide. .

(5) Also, 1-substituted- obtained by the production method of the present invention
By reacting the 3-alkyl-IH-pyrazole-5-carboxylic acid chloride derivative (VI) and the aminoacetamidoxime derivative (XII) in the presence of a base, the pyrazoleamide-substituted acetamidoxime derivative (X), which is a fungicide, can be obtained. .

The 1-substituted-3-alkyl-IH-pyrazolamide substituted derivative [■], (IX) or [X] derived from the intermediate obtained by the production method of the present invention can be used for potato late blight, tomato late blight, and grapes. It has shown extremely high control effects against algal and fungal diseases such as mildew and cucumber rot.

Hereinafter, the manufacturing method of the present invention will be explained by giving specific examples, but the present invention is not limited to these.

(Hereinafter, blank spaces) Reference Example 1 30 g of 2-propanol was dissolved in 300 ml of methylene chloride, and 76 g of triethylamine was added under cooling, and then 63 g of methanesulfonyl chloride was added dropwise. After the dropwise addition was completed, the mixture was stirred at room temperature for 1 hour. Furthermore, it was washed successively with IN-hydrochloric acid, aqueous sodium bicarbonate, and saturated brine, and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain 63 g of the desired methanesulfonic acid isopropyl ester as a light yellow oil. (Yield 85%).

Example 1 20 g of 3-methyl-IH-pyrazole-5-carboxylic acid ethyl ester, 40 g of isopropyl methanesulfonate
and 33 g of tri-n-butylamine without solvent.
The reaction was carried out at 00°C for 1 hour and at 140°C for 2 hours. After cooling, diethyl ether was added, and the mixture was washed successively with IN-hydrochloric acid, aqueous sodium bicarbonate, and saturated brine, and then dried over anhydrous sodium sulfate.

The solvent was distilled off under reduced pressure, and the resulting residue was distilled to obtain 16 g of the desired 1-isopropyl-3-methyl-IH-pyrazole-5-carboxylic acid ethyl ester. (1
), p, 128-141°C/23mmHg, yield 6
3%).

Example 2 1-isopropyl-3-methyl-IH-pyrazole-5
- 15.4 g of carboxylic acid ethyl ester in 100 ml of potassium hydroxide aqueous solution and 100 ml of ethanol
Add to the mixed solution of 1 and react at room temperature for 2 hours. Then, ethanol was distilled off under reduced pressure and diluted with IN-hydrochloric acid.1) Hl, O~2
．． The mixture was adjusted to 0, ethyl acetate was added, and the organic layer was separated. After washing with saturated brine, it was dried over anhydrous sodium sulfate.

The solvent was distilled off under reduced pressure to give l-isopropyl-3methyl-I
12.6 g of H-pyrazole-5-carboxylic acid was obtained as crystals. (Yield 96%).

Example 3 1-isopropyl-3-methyl-IH-pyrazole-5
- 11 parts of benzene was added to 505 g of carboxylic acid, and 500 ml of thionyl chloride was added dropwise. After the dropwise addition was completed, the mixture was heated under reflux for 5 hours.

After the reaction was completed, the solvent was distilled off under reduced pressure, and the resulting residue was distilled to obtain 543 g of the desired 1-isopropyl-3-methyl-IH-pyrazole-5-carboxylic acid chloride. (
87-90°C/9 mmHg, yield 96.9%).

Compounds that can be similarly synthesized by the production method of the present invention are shown in Table 1 below.

(Hereafter, margin.) Table 1 In the compound represented by -THT Hs tHs 47.9 In Table 1, n represents normal, i represents iso, and C represents ci.

Next, the pyrazole derivative, which is the active ingredient of the agricultural and horticultural fungicide derived from the intermediate obtained by the production method of the present invention, will be explained by specifically citing reference examples.

1-cyclopentyl-3-methyl-IH-pyrazole-
5-carboxylic acid chloride (4.2 g) was added, and the mixture was stirred for 1 hour and then at room temperature for 5 hours.

After filtering off the resulting solid, the solvent was distilled off, and the resulting oil was purified by column chromatography to obtain N-(cyano-2-thienylmethyl)-1-cyclopentyl-3-
Methyl-IH-pyrazole-5 carboxamide (4,1
g) was obtained.

(Hereafter, blank space) α-(2-thienyl)aminoacetonitrile (2.8g
) and triethylamine (2.1 g) were dissolved in 50 ml of tetrahydrofuran (THF) and cooled with water in Example 5 (Compound No.

6) Thereafter, stirring was continued for 5 hours at room temperature, and the reaction was completed.

Subsequently, the reaction solution was concentrated, and the residue was washed with water.

The obtained crystals were further recrystallized from ethyl acetate to obtain N-[3-thienyl(thiocarbamoyl)methyl)-1-isopropyl-3-methyl-IH-pyrazole-5-carboxamide (5.1 g). Obtained crystals.

(Hereafter, blank) α-(3-thienyl)aminoacetothioamide (3,4
g) (0.02 mol) in tetrahydrofuran (THF
), followed by triethylamine (2,4
g) Add (0,024 mol).

While stirring this mixture under water cooling, a solution of l-isopropyl-3-methyl-IH-pyrazole-5-carboxylic acid chloride (3.7 g) (0.02 mol) in 12 ml of tetrahydrofuran (THF) was prepared. was dripped.

Example 6 (Synthesis of compound Nα18) After stirring, the temperature was returned to room temperature, and stirring was continued for an additional 3 hours.

After the reaction was completed and concentrated, the residual aroma was dispersed in a solution of water and chloroform. When the 0-form layer was concentrated, crude crystals were obtained. The desired α-(I-cyclopropylmethyl-3-methyl-pyrazol-5-yl-carbonylamino)=(2-thienyl)acetamide is obtained by recrystallizing the crude crystals from a mixed solvent of ethanol and diethyl ether. 7.5 g of oxime crystals were obtained.

Pyrazole derivatives that can be synthesized in the same manner are shown in Table 2, and their physical properties are shown in Table 3.

(Hereinafter, blank space) 6.3 g (0.03 mol) of α-(2-thienyl)aminoacetamidoxime hydrochloride was dissolved in 80 g of acetonitrile.
6.7 g (0,066 mol) of triethylamine was added to neutralize the mixture. Subsequently, this solution was cooled on ice,
There, ■-cyclopropylmethyl-3-methyl-IH
-Pyrazole-5-carboxylic acid chloride 6,0 g
(0.03 mol) was added dropwise. In the compounds shown in Table 3 ('H-NMR (7) 7''-9 and a) under water cooling for 2 hours, 2-T in Table 2 represents 2-thienyl, 3- T represents 3-thienyl.

During the compound 0° Solvent CDC13 CDC1j 10 DMSOd-6 CDC/ff + DMSOd-6 δpn (standard material TMS) 1, 45-2.97 (ns 6H), 2.16 (s,
3H) 5, 44 (quint, l) L J'7.8
Hz), 6.26 (d, 11-1. J=7, 2)
(ri, 6.29 (S, IH) 6, 75-7.00 (
Nail IH), 7.05-7.35 (1 durability).

7, 62 (d, l J = 7.2Hz) 1, 44 (d,
6K J=6.68Z), '2.28(S, 3
H) 5,46(qQ, 1)L J=6.6Hz),
6.01 (d, 1 le J-7, 8Hz), 6.
51N3+, 80(a 21(), 7.40-7.
60(tr+IH), 7.1lTh7.85(a
IH), 8.23 (d, 1 Lunia, 8Hz)
, 9.48(brs, 18), 9.61(brs
, IH) 1, 43 ((L fRJ=6.61(, ),
l 26(s, 3f()5, 36(qq, 1)L
J=6.6HZ), 6.07((L IH, J=7
, 8Hz), 6.49(s, IH), 7.10=
7.40(z 21().

7, 40-7.65 甑IH), 8.08 (d, 1 le J = 7. 洲,).

9, 51 (brs, 21 () Melting point (°C) 115-117 191-193 Compound pain.

Solvent CDCl 3 10 DMSOd-6 CDCi' 2 + DMSOd-6 δppm (standard material TMS) Melting point (°C) 0, 1! y-0,60 (nh 4H), O, 1.5
0 (a IH), Z 18 (s, 3H), 422 (
(L 2H, J=6.6Hz), 6.08 (d.

IH, J=7.8Hz), 6.49(s, IH),
6.7 (h (3,95187-190 (Kame IH),
6.95-7.30 koshiki resistance), 8. ρ(d, 1le J=7
, 8Hz), 9.35 (brs, IH), 9.
65 (brs, IH) 0, le (i), closed (tortoise 4H),
0. Outside 1.55 (Kame IH).

2, 20(s, 3H), 424(d, 2)t J
=7.8Hz).

5, 37 (brs, 2H), 5.91 ((L l)
L J = 9.0H2).

6, 49 (s, IH), 6.72-7.25 (a
3H).

8, 48 ((L 1) L J = 9.0H2), 8.5
5 (brs, IH) 17'7 to 180 (hereinafter, blank) Next, general formula [■] (IX) derived from the compound of the present invention
), (X) has efficacy as an active ingredient of an agricultural and horticultural fungicide, which will be specifically explained with reference to test examples.

The formulation used was prepared as follows.

The active ingredient compounds (active ingredients) are indicated by compound numbers in Table 1 above.

In addition, in the following formulation examples, "part J" means "part J by weight."

Formulation example ■ Wettable powder Compound of the present invention 5 parts Siegrite PPP 87 parts (Mixture of kaolinite and sericite: Siegrite Kogyo Trade name) Tsurupol 5039...Mark... 5 parts Carplex #80 3 parts (white carbon: Shionogi & Co., Ltd. ■ trade name) or more are mixed and ground uniformly to make a wettable powder. When used, the above-mentioned hydrating agent is diluted 100 to 10,000 times and sprayed so that the amount of active ingredient is 10 to 1000 g per hectare.

Test Example 1 Cucumber blight prevention effect test When cucumbers (cultivar Aogoku Hanshiro) grown in pots with a diameter of 7 cm reached the 1st or 2nd leaf stage, a test sample of an emulsion prepared according to Formulation Example 2 above was applied. The compound was diluted with water to adjust to 100 ppm and sprayed in 20 ml per pot using a spray gun. The day after spraying, cucumbers and diseased bacteria (Pseudoperonos)
spore suspension (2x 1
0' pieces/ml), temperature 25°C9 humidity 9
They were placed in a 5% or higher inoculation box overnight.

Thereafter, the plants were placed in a greenhouse, and the proportion of lesions formed on the inoculated leaves 7 days after inoculation was measured, and the control value was calculated according to the following formula.

The results of this test are shown in Table 4.

Table 4 (Treatment concentration: 50 ppm) Test Example 2 Cucumber and disease-curing effect test When cucumbers (variety: Aigoku Hanshiro) grown in pots with a diameter of 7 cm reached the 1st or 2nd leaf stage, disease bacteria were transferred to the cucumbers. (Pseudope
ronospora cubensis) was sprayed and placed in an inoculation box at a temperature of 25° C. and a humidity of 95% or higher overnight for inoculation. The next day, the test compound in the form of an emulsion prepared according to Formulation Example 2 was diluted with water, adjusted to 1100 pp, and sprayed in an amount of 20 ml per pot using a spray gun. Thereafter, the plants were placed in a greenhouse, and the ratio of lesions formed 7 days after inoculation to the inoculated leaves was measured, and the control value was calculated according to the following formula.

The results of this test are shown in Table 5.

Table 5 (Treatment concentration: 50 ppm) Compound Nα Control value Table 6 shows the results of this chemical damage test.

Table 6 (Treatment concentration: 501) pm) Test Example 3 Tomato late blight preventive effect test When tomatoes (cultivar: Fukuju) grown in 8-an diameter pots reached the 3-leaf stage, the following formulations were applied according to Formulation Examples 1 to 3 above. dilute the hydrating powder prepared with water to achieve a predetermined concentration of the active ingredient,
It was sprayed at 20ml per pot using a spray gun. The day after spraying, tomato late blight fungus (Phytophthora
After spraying a spore suspension (2 x 10' spores/ml) of 1nfestans and keeping it in an inoculation box at a temperature of 20°C and a humidity of 95% or higher for 5 days, the ratio of the area of lesions formed to the inoculated leaves was measured. Then, the control value was calculated according to the following formula.

Test Example 4 Curative effect test on tomato late blight When tomatoes (cultivar: Fukuju) grown in pots with a diameter of 8 cm reached the 3-leaf stage, tomato late blight fungus (Phytophth)
spore suspension (2X1
0s/ml) was sprayed and kept in an inoculation box at a temperature of 20° C. and a humidity of 95% or higher for one day and night. After that, the above formulation examples 1 to 3
Dilute the hydrating agent prepared according to the method with water to give the desired concentration of the active ingredient, and spray it with a spray gun at 2 times per pot.
Sprayed 0ml.

After air-drying, the pot was placed in the inoculation box described above, and the proportion of the area of lesions formed after 5 days to the inoculated leaves was measured, and the control value was calculated according to the following formula.

Mujopyeong-ku Saraken Round Practice The results of this test are shown in Table 7.

No. table (Processing concentration: ppm) Compound Nα Control value Drug damage

Claims (1)

[Claims] General formula [II]: ▲There are mathematical formulas, chemical formulas, tables, etc.▼ [II] (In the formula, R^2 and R^3 each represent a lower alkyl group.) 3 -Alkyl-1H-pyrazole-5-carboxylic acid esters and general formula [III]: R^1-OSO_2-R^4 [III] (wherein, R^1 is an alkyl group having 1 to 6 carbon atoms, carbon Number 3
-6 cycloalkyl group, C4-6 cycloalkylalkyl group, C1-6 halogenated alkyl group,
It represents an alkoxyalkyl group having 2 to 6 carbon atoms, a 2 or 3-tetrahydrofuranyl group, or a 2 or 3-tetrahydrothienyl group, and R^4 is an alkyl group having 1 to 4 carbon atoms, or an alkyl group having 1 to 4 carbon atoms. Represents a halogenated alkyl group or an optionally substituted phenyl group. ) General formula [I] ▲There are mathematical formulas, chemical formulas, tables, etc.▼[I] (In the formula, R^1, R^2 and R 1-substituted-3-alkyl-1H- represented by
Method for producing pyrazole-5-carboxylic acid esters.