JPS624272A - 5-substituted thiopyrazole derivative - Google Patents

Abstract

NEW MATERIAL:A 1-alkyl-3-chloro-4-carboxy-5-substituted thiopyrazole derivative expressed by formula I (R<1> is lower alkyl; R<2> is H or lower alkyl; R<3> is H, lower alkyl, benzyl, alkali metal atom or formula II). EXAMPLE:3-Chloro-4-ethoxycarbonyl-5-mercapto-1-methylpyrazole. USE:An intermediate for medicines, agricultural chemicals, etc. PREPARATION:A compound expressed by formula III is reacted with a sulfur compound e.g. sodium hydrosulfide, sodium disulfide or alkyl mercaptan, in an inert solvent, e.g. DMF, as necessary, in the presence of a base, e.g. NaOH, NaH or triethylamine, at room temperature - the reflux temperature of the solvent to afford the aimed compound expressed by formula I.

Description

DETAILED DESCRIPTION OF THE INVENTION Field of Industrial Application The present invention relates to 1-alkyl-5-chloro-4-carboxy-
5-Substituted thiopyrazole derivatives.

More specifically, the present invention relates to the general formula (1): [In the formula, R1 is a lower alkyl group, IR2 is a hydrogen atom or a lower alkyl group, and R3 is a hydrogen atom, a lower alkyl group, a benzyl group, an alkali metal atom or an elementary atom. or a lower alkyl group. 1-alkyl-3-chloro-4 represented by
-carboxy-5-substituted thiopyrazole derivatives.

1-Alkyl-3-chloro-4-carboxy-5-substituted thiopyrazole derivatives are useful as intermediates for pharmaceuticals, agricultural chemicals, and the like. For example, it is useful as an intermediate for the herbicide described in Japanese Patent Application No. 59-55126.

That is, the pyrazole sulfonamide derivative (9) is derived by referring to the methods described in European Patent Publication No. 87780, JP-A-59-122488, and the like.

(1) (Inclination [In the formula, R', R2 and R5 have the same meanings as above]
The sulfonamide derivative (6) can be further converted into a desired active ingredient compound of a herbicide according to the method described in the aforementioned patent application specification (Japanese Patent Application No. 59-55126).

Prior Art 1) The following methods are conventionally known as methods for producing 4-carboxy-5-substituted thiovirazole derivatives.

5 (Refer to Japanese Patent Application Laid-open No. 122488/1988) (Heterocycles, 6 volumes.

(See page 1865, 1977) (See Japanese Unexamined Patent Publication No. 55-9062) (Chemische Berichte)
(Refer to Volume 114, Page 2450, 1981) (Chemical abstract)
Abstru-cts), Volume 86, 189791Y19
From the above, the substituents on the other pyrazole ring carbon (3-position of the pyrazole ring) in the 4-carboxy-3-tR-substituted f-opyrazole conductor are as follows.

It can be seen that the compound (I) of the present invention in which a halogen atom such as a chlorine atom, which is a hydrogen atom, an alkyl group, a carboxylic acid ester name amine group, etc., is a new compound that has not been described in any literature.

On the other hand, it is also difficult to synthesize the compound (2) * of the present invention by referring to the conventional techniques (1) to (5) above for the reasons shown below.

In the above reaction formula (1), as raw materials [R' in the formula,
R2 has the same meaning as above. J is required, but it is difficult to obtain because it is a new compound that has not been described in any literature.

In the above reaction formulas (2) and (3), the substituent at the 3-position of the pyrazole ring is limited to a hydrogen atom or an alkyl group, as shown in the second reaction formula. Therefore, it cannot be applied to the synthesis of the compound (I) of the present invention in which a halogen is introduced at the 6-position of the pyrazole ring.

In the reaction of the above reaction formula (4), 1) The reaction does not necessarily have a good yield.

2) Referring to this reaction, (I) When synthesizing tl-, it is possible to use C-C3C-Co□CHS instead of υ as a raw material for acetylene dicarboxylic acid ester, but regarding its reactivity and the formation of isomers. is unknown.

s) c, tc and CCo2CH are expensive and non-industrial (Chemische Beric
hte) Volume 92.

(1950 pages, 1959) It requires expensive reagents (CH, Li) and special reaction conditions (reaction temperature -80°C), and cannot be used as a general industrial material.

From the above, the above reaction formula (4) cannot be said to be a preferable method for synthesizing the compound (I)' of the present invention.

II) On the other hand, the virazole sulfonamide derivative (]I
The method for producing I is described in Japanese Patent Application No. 59-55126 as follows.

CH.

The characteristics of this synthesis method are 1) It is necessary to use an expensive lithiation reagent such as lithium diisopropylamide.

2) The reaction must be carried out at extremely low temperatures (-60°C). There are problems such as (industrially, it is disadvantageous in terms of equipment, operation, and energy costs).

Because lithiation reagents are expensive, they are hardly used as industrial raw materials, especially as reagents for the production of pesticides.In addition, when performing extremely low-temperature reactions, it is impossible to use general reaction equipment, so for example, large-sized Problems will arise in terms of new equipment such as refrigerators, energy to lower the temperature, and operation of reaction control.

For the above reasons, the nine methods are not only suitable for laboratory production, but also industrially inexpensive to produce pyrazole sulfonamide derivatives (
6) cannot be said to be a method for obtaining.

Problems to be Solved by the Invention The object of the present invention is to provide a new synthetic route for obtaining pyrazole sulfonamide derivatives (odors) that is easy and industrial.

The compound of the present invention has the general formula (z) [In the formula, R', R' and R5 have the same meanings as above.

] It is very easy to induce the pyrazole sulfonamide derivative (n) using the p2 compound of the present invention.

However, there is a chlorine atom at the 3rd position of the pyrazole ring.

The synthesis of the compound (1) of the present invention having a carboxy group at the 4-position and a substituted thio group at the 5-position is difficult to achieve by referring to the prior art described above. A synthesis method was needed.

At the same time, it is necessary to provide an industrial and inexpensive manufacturing method that does not use expensive lithiation reagents or low-temperature reaction conditions as disclosed in the above-mentioned Japanese Patent Application No. 59-55126.

From the above, it has become necessary to supply a new intermediate that is industrially inexpensive and can be easily induced into the pyrazole sulfonamide derivative position.

Means for Solving the Problems and Invention 11 The present inventors expressed the general formula (2): [In the formula, R1 represents a lower alkyl group, and R2 represents a hydrogen atom or a lower alkyl group. ] The dilogenovirazole derivative represented by is mixed with a sulfur compound such as sodium hydrosulfide, sodium disulfide, alkyl mercaptan, benzyl mercaptan, etc. in an inert solvent such as ethanol, dimethylformamide, or dioxane, and if necessary, sodium hydroxide, By reacting in the presence of a base such as sodium hydride, sodium alcoholade, triethylamine, etc., the general formula (1): [In the formula, B 1 , B 2 and R3 have the same meanings as above. ] It was discovered that a pyrazole derivative represented by the following can be obtained. The compound of the present invention represented by the general formula (I) is a new compound that has not been described in any literature, and the herbicide described in Japanese Patent Application No. 59-55126 can be improved by using the compound of the present invention. The present invention was completed by discovering that high yield and high quality can be obtained.

In addition to the above, methanol is also used as a reaction solvent.

Tetrahydrofuran, dimethylacetamide.

Toluene, xylene, dimethyl sulfoxide, etc.

In addition to the above, examples of sulfur compounds include potassium hydrosulfide and sodium sulfide; examples of bases include potassium hydroxide and sodium alcolade in addition to the above.

Metallic sodium, pyridine, etc. can also be used. The reaction temperature ranges from room temperature to the reflux temperature of the solvent.

In addition, during the synthesis of the compound (I) of the present invention, the formation of an isomer compound with the structure shown below in which the chlorine atom at the 5th position is substituted (wherein R+, R2 and Rs have the same meanings as above) was not observed. It was also found that the reaction was highly selective.

Although the dihalogenopyrazole derivative (2) used as a raw material is also a new compound, it can be easily synthesized using the following reaction formula. (See Reference Example +, 2.5 below) [In the formula, R' and R2 have the same meanings as above. [Effects of the invention (1) A novel pyrazole derivative α) useful as a pharmaceutical and agricultural intermediate is obtained.

(2) By using the compound (I) of the present invention, pyrazole sulfonamide derivatives (I[
) is obtained.

(3) Compared to the method described in Japanese Patent Application No. 59-55126, an expensive lithiation reagent and special reaction conditions (reaction temperature -60°C) are not required. In other words, it is an industrial and cheaper synthesis method compared to conventional methods.

Example 1 Synthesis of 5-chloro-4-ethoxycarbonyl-5-mercapto-1-methylpyrazole 3.5-dichloro-4-
Ethoxycarbonyl-1-methylpyrazole 5.1? ,
A mixture of sodium hydrosulfide A 4.69 (containing about 70%) and dimethylformamide 20-2 was heated at 80°C.
Stir for hours. After the reaction is complete, pour into excess ice water.

Acidify with concentrated hydrochloric acid and remove the precipitated crystals.

After drying, crude target product 52 was obtained. The obtained crystals were washed with diisopropyl ether to obtain 4.69'i of pure target product.

Melting point 66-67°C (yield 91%) Synthesis of luthiovirazole In 1)-1 above, except that methyl mercaptan sodium salt was used instead of sodium bisulfide.
+)-+ The title compound 4.82 was obtained. Yield 8
9, melting point 46-47°C Example 3 Synthesis of 5-benzylthio-3-chloro-4-ethoxycarbonyl-1-methylpyrazole In the above 1)-1, hydrogen sulfide) benzyl mercaptan sodium salt instead of IJium. The title compound 6.27 was obtained in the same manner as in t+)-1 except that t+)-1 was used. Yield 87%, melting point 53
~54°C Example 4 Synthesis of 6-chloro-4-meth)*dicarbonyl-5-mercapto-1-methylpyrazole In Example 1, instead of 3.5-dichloro-4-ethoxycarbonyl-1-methylpyrazole, 5 .5-
The title objective compound 5.62 was obtained according to Example 1, except that 6.59f of dichloro-4-methoxycarbonyl-1-methylpyrazole was used.

Melting point: 87-89°C (Yield: 90%) Reference Example 1 Synthesis of s,s-cyclo-4-ethoxycarbonyl-1-methylpyrazole (mis,s-cyclo-4-ethoxycarbonyl-1-
8.82 ml of methyl pyrazole was dissolved in 100 g of concentrated hydrochloric acid, and 20 rIL of an aqueous solution of 8.82 sodium nitrite was added.
It was added dropwise at 15 to -20°C to effect diazotization. °This diazonium salt solution was mixed with copper sulfate pentahydrate 562. It was added dropwise to a solution of 281 g of sodium chloride and 100 g of water at room temperature. After the dropwise addition, the mixture was gradually heated and stirred at 50°C for 15 hours, and a small amount of cuprous chloride was added to complete the second reaction. An excess amount of water was added to the reaction mixture, extracted with chloroform, washed with water, dried, and the solvent was distilled off under reduced pressure to obtain the crude target product 102.
Get a friend. By washing the precipitated crystals with diisopropyl ether, pure target product 7.9r was obtained.

Melting point 66-67°C (Yield 74%) Reference Example 2 Synthesis of s,5-cyclo-4-ethoxycarbonyl-1-methylpyrazole (alternative method) 1) Synthesis of 3,5-dichloro-4-ethoxycarbonylpyrazole 5 .5-diamino-4-ethoxycarbonylpyrazole 22.7 ? (dissolved in concentrated hydrochloric acid 400% and added nitrous acid)
A 50-aqueous solution of IJum 247 was added dropwise at -10 to 0°C to diazotize.

This diazonium salt solution was mixed with copper sulfate pentahydrate 167f,
The mixture was added dropwise to a solution of 128 g of sodium chloride and 690 g of water at room temperature. After the dropwise addition, the mixture was gradually heated and stirred at 50°C for 1.5 hours.

Add a small amount of cuprous chloride to complete the second reaction.

An excess amount of water was added to the reaction mixture, extracted with chloroform, washed with water, dried, and then the solvent was distilled off under reduced pressure to obtain the crude target product 26.7 f't-crystals. By washing the obtained crystals with diimpropyl ether,
A friend of pure object 2521.

Melting point: 111-112°C (yield: 83%) 11) 3.
Synthesis of 5-dichloro-4-ethoxycarbonyl-1=methylpyrazole 2.62 kg of sodium hydride (containing 55%) was suspended in 50 rntK of tetrahydrofuran. 1.5-cyclorho4
-Ethoxycarbonyl-pyrazole 102 solution in tetrahydrofuran (30 g) was added dropwise at 10°C. Room temperature stirring 3
0 minutes later.

Methyl iodide 7 and 79 were added dropwise at room temperature, and the mixture was stirred under heating and reflux for t5 hours. After the reaction, ice water was added under water cooling, and after neutralization with concentrated hydrochloric acid, the organic layer was separated, and the aqueous layer was extracted with diethyl ether. The organic layers were combined, washed with water, dried, and the solvent was distilled off under reduced pressure to obtain crude target product 1@2 as crystals. Melting point 66-67°C (yield 95%) Reference Example 3 Synthesis of 5.5-dichloro-4-methoxycarbonyl-1-methylpyrazole In Reference Example 1, 3.5-diamino-4-ethoxycarbonyl-1- Instead of methyl pyrazole, 3,5-
The title compound 7.49 was synthesized according to Reference Example 1 except for using diamino-4-methoxycarbonyl-1-methylpyrazole 8.52. Melting point 58-59°C (yield 71%) Reference example 4 Synthesis of 6-chloro-4-ethoxycarbonyl-+-mefvirazole-5-sulfonamide 1) 5-chloro-5
-Synthesis of chlorosulfonyl-4-ethoxycarbonyl-1-methylpyrazole 3-chloro-4-ethoxycarbonyl-5-mercapto-1-methylpyrazole5.62
was suspended in 40rnt of acetic acid and water+Om/ and bubbled with chlorine for a total of 50 minutes at 10-15°C with vigorous stirring. Thereafter, the mixture was stirred at 5°C for 15 minutes, poured into an excess amount of ice water, and extracted with diethyl ether. Wash the organic layer with water,
Dry.

What is the boiling point of Lolide −?

1559C/0.2mmH? Met.

1t) Synthesis of 5-chloro-4-ethoxycarbonyl-1-methylpyrazole-5-sulfonamide 6-chloro-5-chlorosulfonyl-4-ethoxycarbonyl-1-methylpyrazole 6,9 obtained in 1) above f Dissolved in ethyl dichloride/70-, ammonium carbonate 4.
I? It was added in the f chamber. After stirring overnight at room temperature, the solid was separated and the furnace liquid was concentrated to obtain the target product as crystals. The obtained crystals were washed with diisopropyl ether to obtain pure target compound 5.5y. Melting point 121
~123℃.

(1)→It) annual yield of 81%) Reference Example 5 Synthesis of 5-chloro-4-ethoxycarbonyl-1-methylpyrazole-5-sulfonamide (alternative method)

Claims (1)

[Claims] (1) General formula (I): ▲There are mathematical formulas, chemical formulas, tables, etc.▼(I) [In the formula, R^1 is a lower alkyl group, R^2 is a hydrogen atom or a lower alkyl group, and R^3 is a lower alkyl group. Hydrogen atom, lower alkyl group, benzyl group, alkali metal atom, or ▲ formula,
There are chemical formulas, tables, etc. ▼ (R^1 is a lower alkyl group,
R^2 represents a hydrogen atom or a lower alkyl group. ) is shown. ] 5-substituted thiopyrazole derivative.