JPH06128243A - Production of thiadiazoles - Google Patents

Abstract

PURPOSE:To easily produce the subject compound useful as pharmaceuticals, agrichemicals, etc., under a mild condition by oxidizing a thioamide compound with a dialkyl sulfoxide and a haloiminium salt. CONSTITUTION:The objective 3,5-disubstituted-1,2,4-thiadiazole of formula IV is produced by oxidizing a thioamide compound of formula I (R<3> is aromatic group, heterocyclic group, alkyl, etc.) with a dialkyl sulfoxide of formula II (R<4> and R<5> are alkyl) and a haloiminium salt of formula III (R<1> and R<2> are lower alkyl; X is halogen; (n) is 2 or 3). The reaction is preferably carried out at room temperature or thereabout by adding about 1mol of the compound of formula II and about 1mol of the compound of formula III to 1mol of the compound of formula I. The reaction may be carried out without using a solvent or by using methylene chloride, etc., as a solvent. The compound of formula III is e.g. 2-chloro-1,3-dimethylimidazolium chloride.

Description

Detailed Description of the Invention

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a method for industrially producing thiadiazoles which are useful as medicines and agricultural chemicals.

[0002]

BACKGROUND OF THE INVENTION Thiadiazoles are many compounds having physiological activity and are useful as pharmaceuticals and agricultural chemicals. In addition, thiadiazoles are also used as dye synthesis intermediates and photographic materials, and are industrially useful compounds [F. K
urzer in “Advances in Het
erocyclic Chemistry ”, ed b
y A. R. Katritzky, Academic
Press, New York, N .; Y. , Vol.
5, pp. 119-204, (1965)].

Among the thiadiazoles, many methods have already been reported as a method for producing 3,5-disubstituted-1,2,4-thiadiazoles, such as intermolecular cyclization reaction with the same molecule and heterogeneous molecule. It is roughly divided into the intermolecular cyclization reaction and the oxidative dimerization reaction of the same molecule. Above all, the oxidative dimerization reaction of the same molecule is the most general and important production method, and the method by the oxidation reaction of thioamides is particularly useful.

As a conventional method for producing thiadiazoles by the oxidation reaction of thioamides, sulfur monochloride [J. Chem. Soc. 123 ,
964 (1923)], thionyl chloride, sulfuryl chloride [Sci. Papers Inst. Ph
ys. Chem. Res. (Tokyo) 7 , 237
(1928)], phosphorus pentachloride [Zh. Obshch. K
him. 30 , 3031 (1960)] and ammonium persulfate [J. Prak
t. Chem. 69 , 44 (1904)], hydrogen peroxide solution [Pharmaceutical magazine, 58 , 809 (1938)], sodium persulfate-cupric chloride [Izv. Akad. Nauk
SSSR, Ser. Khim. , (5) 1143 (19
86)] and the like using a peroxide, ozone [Bul
l. Soc. Chem. France D 272 (1
949)] and bis (p-methoxyphenyl) selenium oxide [Bull. Chem. Soc. Jpn. , 55 ,
641 (1982)] is known.

[0005]

However, according to the method of using a halogenating agent as an oxidant, hydrogen halide having a strong corrosive property is generated, so that a special reaction vessel is required for implementation on an industrial scale. Also, it had to be equipped with equipment such as an alkali washing tower. Further, according to this method, since the reaction system becomes strongly acidic, it cannot be applied to thioamides having a functional group weak against acid, or there is a drawback that the yield is lowered.

On the other hand, the method using a peroxide produces a by-product such as a nitrile, an amide or a carboxylic acid due to its strong oxidizing power, and the target product has a low yield. Further, the method using ozone has a problem in the apparatus and is difficult to carry out on an industrial scale. Furthermore, the method using bis (p-methoxyphenyl) selenium oxide is economically disadvantageous because the oxidizing agent is expensive.

Accordingly, it is an object of the present invention to provide a method for industrially producing thiadiazoles under mild conditions without being affected by the properties of the starting thioamides.

[0008]

Under such circumstances, the present inventor has conducted diligent research to find out a new production method of thiadiazoles, and as a result, thioamides are represented by dialkyl sulfoxide and the following general formula (1). The present invention has been completed by finding that the thiadiazoles can be industrially advantageously produced under mild conditions if the haloiminium salt is oxidized.

The production method of the present invention is shown, for example, by the following reaction formula.

[0010]

[Chemical 2]

(Where R¹And R²Are the same or different
Represents a lower alkyl group, R ³Has a substituent
Optionally substituted aromatic or heterocyclic group or substituent
Represents an alkyl or alkenyl group which may have
And R^FourAnd R^FiveAre the same or different and
Represents a kill group, X is a halogen atom, and n is an integer of 2 or 3.
Indicates the number)

That is, the present invention is characterized in that a thioamide (2) is oxidized with a dialkyl sulfoxide (3) and a haloiminium salt (1), which is a 3,5-disubstituted-1,2,4-thiadiazole ( It provides the manufacturing method of 4).

The haloiminium salt used in the present invention is represented by the general formula (1). In the formula, R ¹ and R ²
Examples of the lower alkyl group represented by are methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group,
Examples thereof include an isobutyl group, and among them, a methyl group and an ethyl group are particularly preferable. Further, examples of the halogen atom represented by X include a fluorine atom, a chlorine atom, a bromine atom and an iodine atom, and among them, a chlorine atom is particularly preferable. Specific preferred examples of the haloiminium salt (1) include 2-
Chloro-1,3-dimethylimidazolium chloride,
2-chloro-1,3-dimethyl-3,4,5,6-tetrahydropyrimidinium chloride and the like can be mentioned.

This haloiminium salt (1) is obtained by, for example, adding a compound represented by the general formula (7), which is known as an easily available solvent, to oxalyl halogenide, phosphorus trihalide, phosphorus pentahalide, oxyhalogen. It can be easily obtained by reacting a halogenating agent known per se such as phosphorus bromide, phosgene, trichloromethyl chloroformate and the like. In this reaction, either compound (7) or a halogenating agent is dissolved in a suitable solvent such as carbon tetrachloride,
The other is added little by little to this, and the reaction is further carried out at room temperature to 70 ° C. for several hours to several tens of hours. The haloiminium salt (1) thus obtained can be isolated, but the reaction solution can also be used in the reaction of the present invention without isolation.

The thioamides which are the raw material compounds used in the method of the present invention are not particularly limited, and examples thereof include those represented by the formula (2). In the formula, the group represented by R ³ is an aromatic or heterocyclic group which may have a substituent or an alkyl or alkenyl group which may have a substituent. Since the method selectively oxidizes only the thioamide group, it may contain an ether bond or a double bond. Preferred as R ³ are aromatic or heterocyclic groups.

To carry out the method of the present invention, dialkyl sulfoxide (3) is added to 1 mol of thioamides (2).
About 1 mol and about 1 mol of the haloiminium salt (1) may be added, and the reaction may be performed near room temperature. The reaction solvent does not have to be used, but a solvent that does not participate in the reaction, such as a halogenated hydrocarbon such as dichloromethane or dichloroethane, a hydrocarbon, an ether, or an aromatic hydrocarbon can also be used. Further, even when the reaction apparatus is carried out on an industrial scale, it is possible to use an ordinary stainless steel reaction kettle instead of a special reaction kettle such as glass lining. In the method of the present invention, since the haloiminium salt (1) is changed to the water-soluble compound (7), separation and purification are easy. Therefore, isolation of the desired thiadiazoles from the reaction mixture can be easily performed by a conventional method such as distillation or recrystallization.

[0017]

Industrial Applicability According to the method of the present invention, thiadiazoles can be produced industrially advantageously under mild conditions.

Example 1 Preparation of 3,5-diphenyl-1,2,4-thiadiazole: Thiobenzamide 5.0 in 100 ml of methylene chloride.
g (36 mmol) and dimethyl sulfoxide 3.4 g (4
4 mmol) was added, and a solution of 2-chloro-1,3-dimethylimidazolinium chloride (7.4 g, 44 mmol) in methylene chloride (50 ml) was added dropwise under ice cooling. Then, at room temperature 2
After stirring for 6 hours, the reaction solution was gradually added to 200 ml of concentrated aqueous ammonia while cooling with ice. After standing overnight, the organic layer was separated, washed with water and dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure to obtain a pale yellow crystalline residue. This residue was subjected to silica gel chromatography (solvent:
Purification with (n-hexane / ethyl acetate) gave 4.0 g (yield 93%) of a pure product of the title compound. mp. 89.1 ℃

Example 2 Preparation of 3,5-di (3-pyridyl) -1,2,4-thiadiazole: Thionicotinic acid amide 5.0 g (36 mmol) and dimethyl sulfoxide 3.4 g (44 mmol) in 100 ml of methylene chloride. Was added and under ice cooling, 2-chloro-
1,3-Dimethylimidazolinium chloride 7.3g
A solution of (43 mmol) in 50 ml of methylene chloride was added dropwise. Then, after continuing stirring at room temperature for 66 hours, the reaction solution was added to aqueous ammonia to separate the organic layer. The aqueous layer was extracted with methylene chloride, the organic layers were combined and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained brown crystalline residue was purified by silica gel chromatography (solvent: chloroform / methanol) to give 4.0 g of the title compound (yield 93
%) Was obtained. mp. 134.6 ℃

Claims (1)

[Claims] 1. A thioamide is prepared by converting a thioamide into a dialkyl sulfoxide and the following general formula (1): (Wherein R ¹ and R ² are the same or different and each represents a lower alkyl group, X represents a halogen atom, and n represents an integer of 2 or 3) and oxidation is carried out using a haloiminium salt. Characterized 3,5-disubstituted-1,2,
Method for producing 4-thiadiazole.