JPH07258234A - Production of 1,3,4-oxadiazole-2(3h)-thione compound - Google Patents

Abstract

PURPOSE:To obtain in high yield in a short time without H2S generation the subject compound useful as e.g. a medicine (synthetic intermediate) having anti-tuberculotic activity, analgesic activity, antipyretic activity, etc., by reaction of CS2 with a monoacylhydrazine compound followed by reaction of a specific haloiminium salt. CONSTITUTION:The objective compound is obtained by reaction of CS2 with a monoacylhydrazine compound such as a compound of formula I [R<3> is an organic group such as a (substituted) (cyclo)alkyl, (substituted) alkenyl, (substituted) aromatic group or (substituted) heterocyclic group] in the presence of a base such as triethylamine or NaOH followed by reaction of a haloiminium salt of formula II (R<1> and R<2> each is a lower alkyl; X is a halogen; (n) is 2 or 3).

Description

Detailed Description of the Invention

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a method for producing 1,3,4-oxadiazole-2 (3H) -thiones, and more specifically, to a safe and industrial advantage from monoacylhydrazines. , 3,4-Oxadiazole-2 (3H) -thiones.

[0002]

2. Description of the Related Art 1,3,4-oxadiazole-2 (3
Since H) -thiones have actions such as antituberculous action, analgesic action and antipyretic action, they are used as pharmaceuticals and pharmaceutical intermediates. In addition, this may also be used as a chlorination inhibitor in tetracycline synthesis,
It is a useful compound with a wide range of applications [Adv. Hetero. Che
m., 7 , 183 (1966)].

This 1,3,4-oxadiazole-2
Several methods have already been reported as a method for producing (3H) -thiones. Among them, a method used as a conventional method is a method of reacting monoacylhydrazines with carbon disulfide in the presence of an alkali and then heating and ring-closing in ethanol.

[0004]

However, the above-mentioned method by the heat ring closure generally requires a long time for the reaction. For example, a method for producing 5- (2-furyl) -1,3,4-oxadiazole-2 (3H) -thione [Syntheses of Heter
ocyclic Compounds, Vol. 1, Consultants Bureau (195
9) In p54], it is necessary to heat and reflux in ethanol for 30 to 32 hours. In the production of 5-methyl-1,3,4-oxadiazole-2 (3H) -thione, heating is performed for 1 week or more. Reflux is required, and even if dimethyl sulfoxide is added to accelerate the reaction, heating under reflux for 36 hours is required [J. Am. Chem. Soc., 78 , 4475 (1956)].

Such a method requiring a long reaction time is not only inefficient and uneconomical, but also one of 1,3,4-oxadiazole-2 (3H) -thiones which is unstable to heat. However, there is a drawback that it is not applicable or the yield is low. Further, since hydrogen sulfide gas, which is extremely toxic, is generated during the reaction in the above-mentioned method, great care must be taken when carrying out on an industrial scale, and equipment such as a gas absorption tower must be provided.

Therefore, the object of the present invention is to produce 1,3,4-, which does not generate hydrogen sulfide gas with a high yield in a short reaction time.
An object of the present invention is to provide a method for producing oxadiazole-2 (3H) -thiones.

[0007]

In view of such circumstances, the present inventors have conducted diligent research, and as a result, after reacting monoacylhydrazines with carbon disulfide in the presence of a base, the following general formula (1) ) Is reacted with 1,3,4-oxadiazole-2 (3H) -thione in a high yield in a short time with a high yield and under neutral and mild conditions. The present invention has been completed by finding that a class can be produced.

The present invention is shown by the following reaction formula.

[0009]

[Chemical 2]

[In the formula, R ¹ and R ² are the same or different and each represents a lower alkyl group, X represents a halogen atom, n represents an integer of 2 or 3, and R ³ represents an organic group, B and B'represent a base]

That is, the present invention is characterized in that monoacylhydrazines (2) are reacted with carbon disulfide (3) in the presence of a base (4), and then with a haloiminium salt (1). , 3,4-oxadiazole-2
A method for producing (3H) -thiones is provided.

The haloiminium salt used in the present invention is represented by the general formula (1). In the formula, the lower alkyl group represented by R ¹ and R ² includes a methyl group, an ethyl group, an n-propyl group, Isopropyl group, n-butyl group,
Examples thereof include linear or branched alkyl groups having 1 to 6 carbon atoms such as an isobutyl group. 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-dimethylimidazolinium chloride, 2-chloro-1,3-dimethyl-3,4,5,6-
Examples thereof include tetrahydropyrimidinium chloride.

This haloiminium salt (1) is represented by the above general formula (12) which is known as an easily available solvent.

[0014]

[Chemical 3]

In the compound represented by the formula [wherein R ¹ , R ² and n are the same as defined above], oxalyl halogenide, phosphorus trihalide, phosphorus pentahalide, phosphorus oxyhalide, phosgene, It can be easily obtained by reacting a halogenating agent known per se such as trichloromethyl chloroformate. In this reaction, one of the compound (12) and the halogenating agent is dissolved in a suitable solvent such as carbon tetrachloride and the other is added little by little, and the mixture is further added at room temperature to 70 ° C. for several hours to several dozen. It is carried out by reacting for a time. 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 monoacylhydrazines, which are the starting compounds for the method of the present invention, are preferably those represented by the general formula (2), but in the formula, the group represented by R ³ may have a substituent. Alkyl, cycloalkyl, alkenyl,
Included are aromatic or heterocyclic groups. Here, as the alkyl group, a linear or branched alkyl group having 1 to 20 carbon atoms, for example, methyl group, ethyl group, propyl group, butyl group, pentyl group, hexyl group, heptyl group, octyl group, nonyl group , Decyl group, undecyl group, dodecyl group,
Examples thereof include tridecyl group, tetradecyl group, pentadecyl group, hexadecyl group, heptadecyl group, octadecyl group, nonadecyl group and eicosyl group. The alkenyl group is a linear or branched alkenyl group having 2 to 20 carbon atoms, for example, vinyl, propenyl, allyl, butenyl, pentenyl, hexenyl, heptenyl, octenyl, nonenyl, decenyl, undecenyl, dodecenyl, tridecenyl, tetradecenyl, pentadecenyl. , Hexadecenyl, heptadecenyl, octadecenyl, nonadecenyl,
An eicosenyl group etc. are mentioned. Examples of the aromatic group include phenyl group, tolyl group, xylyl group, biphenylyl, naphthyl and the like. Examples of the heterocyclic group include furyl, furfuryl, thienyl, pyrrolyl, pyridyl, piperidino, piperidyl and quinolyl groups. Examples of the cycloalkyl group include a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group and the like.

Substituents for these groups are not particularly limited, and include hydroxyl group, amino group, alkoxy group, alkylamino group, alkoxyamino group, alkoxycarbonylamino group, alkyl group, alkenyl group and heterocyclic group. And may further include an ether bond or a double bond.

On the other hand, the bases represented by B or B'may be the same or different and may be an organic base or an inorganic base. Specific examples of the base include, for example, triethylamine,
Amine such as tributylamine, N, N-dimethylaniline, pyridine; sodium hydroxide, potassium carbonate, calcium carbonate and the like. The halogen atom represented by X includes a fluorine atom, a chlorine atom, a bromine atom,
The iodine atom is exemplified.

In order to carry out the production method of the present invention, for example, 1 mol of carbon disulfide (3) and 1 mol of base (4) are added to 1 mol of monoacylhydrazines (2) and reacted, About 1 mol of the haloiminium salt (1) and about 1 mol of the base (7) may be added and the reaction may be carried out near room temperature. Needless to say, the addition molar ratio of the raw materials is a theoretical amount and can be appropriately increased or decreased. A reaction time of about 2 to 20 hours is sufficient.

The reaction solvent need not be used,
It is also possible to use 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. 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.

[0021]

According to the production method of the present invention, 1,3,4-oxadiazole-2 (3H) can be obtained in a high yield in a short reaction time.
-Thiones can be produced. In addition, it is safe without generation of toxic hydrogen sulfide, and since the reaction proceeds under mild conditions, no special equipment is required, which is extremely advantageous industrially.

[0022]

The present invention will be further described below with reference to examples, but the present invention is not limited thereto.

Example 1 5-Phenyl-1,3,4-oxadiazole-2 (3
Preparation of (H) -thione: 5.0 g (3) of benzohydrazide in a mixture of 100 ml of benzene and 150 ml of acetonitrile.
7 mmol) and 5.6 g (55 mmol) of triethylamine were added, and 2.8 g (37 mmol) of carbon disulfide was added dropwise thereto. After the completion of stirring, the mixture was stirred at room temperature for 5.5 hours, and then a solution of 2-chloro-1,3-dimethylimidazolinium chloride (7.4 g, 44 mmol) in methylene chloride (25 ml) was slowly added dropwise to the reaction mixture. After the completion, stirring was continued at room temperature for 3 hours, water was added to the reaction solution, and the mixture was extracted with methylene chloride. The extract was dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel chromatography (solvent chloroform-methanol) to obtain 6.2 g (yield 95%) of the title compound.

Mp 218.9-220.8 ° C IRν _max ^KBr cm ^-1 : 3090, 1615, 1575, 1510, 1450, 135
0, 1185, 970

Example 2 Preparation of 5- (2-pyridylmethyl) -1,3,4-oxadiazole-2 (3H) -thione: methylene chloride 10
5.0 g (33 mmol) of 2-pyridylacetohydrazide, 10.0 g (99 mmol) of triethylamine and 2.5 g of carbon disulfide in a mixture of 0 ml and 100 ml of acetonitrile.
(33 mmol) was added, and the mixture was stirred at room temperature for 4 hours, and then a solution of 2-chloro-1,3-dimethylimidazolinium chloride (6.7 g, 40 mmol) in methylene chloride (20 ml) was slowly added dropwise. After completion, stirring was continued at room temperature for 3 hours, then the solvent was distilled off under reduced pressure, and acetonitrile was added to the resulting residue to separate insoluble crystals by filtration. Insoluble crystals are washed with acetonitrile, the washing solution and the filtrate are combined, and the solvent is distilled off under reduced pressure.
8.0 g of residue was obtained. The residue was purified by silica gel chromatography (solvent chloroform-methanol) to obtain 3.7 g (yield 58%) of the title compound.

Mp 163.0 to 163.7 ° C. IRν _max ^KBr cm ⁻¹ : 2700, 2530, 1630, 1600, 1500, 136
0, 1320, 1145, 1060

Example 3 5- (2-hydroxy-1-propyl) -1,3,4-
Preparation of oxadiazole-2 (3H) -thione: 5.0 g (42 mmol) of 3-hydroxybutyrohydrazide, 12.3 of triethylamine in 50 ml of dimethylformamide.
8 g (127 mmol) and 3.2 g of carbon disulfide (42 mmo
l) was added and the mixture was stirred at room temperature for 3 hours. Then, a solution of 8.6 g (51 mmol) of 2-chloro-1,3-dimethylimidazolinium chloride in 30 ml of methylene chloride was slowly added dropwise to the reaction mixture under water cooling, and after completion, stirring was continued for another 3 hours at room temperature. The solvent was distilled off under reduced pressure to obtain a residue. Acetone was added to this residue, insoluble crystals were filtered off, the insoluble crystals were washed with acetone, the filtrate and the washing solution were combined, and the solvent was distilled off under reduced pressure to obtain 23.3 g of a red oily substance. This oily substance was subjected to silica gel chromatography (solvent: chloroform-methanol).
Purification was performed to obtain 6.3 g (yield 93%) of the title compound.

Mp 108.4-109.2 ° C IRν _max ^KBr cm ^-1 : 3290, 3040, 1625, 1505, 1340, 115
5,945

Example 4 5- (1-t-Butoxycarbonylamino-2-hydroxyethyl) -1,3,4-oxadiazole-2 (3
Preparation of H) -Thion: 5.0 g (23 mmol) of 2-t-butoxycarbonylamino-3-hydroxypropionohydrazide, 6.9 g (68 mmol) of triethylamine and 1.7 of carbon disulfide in 60 ml of dimethylformamide.
g (23 mmol) was added, and the mixture was stirred at room temperature for 4 hours. Then
2-Chloro-1,3-dimethylimidazolinium chloride 4.6 g (27 mmol) methylene chloride 1 was added to the reaction solution.
A 6 ml solution was slowly added dropwise, and after completion, stirring was continued at room temperature for another hour. After adding 10 ml of methanol to the reaction solution and allowing it to stand at room temperature, the solvent was distilled off under reduced pressure to obtain a residue. Then, the same operation as in Example 3 was carried out to obtain 4.5 g of the title compound.
(Yield 75%) was obtained.

Amorphous IR ν _max ^KBr cm ⁻¹ : 3300, 1690, 1620, 1500, 1370, 115
5, 1055, 940

Example 5 5-Cyclohexyl-1,3,4-oxadiazole-
Preparation of 2 (3H) -thione: 0.78 g (5.5 mm) of cyclohexane carbohydrazide in 100 ml of methylene chloride.
ol), 1.64 g (16.2 mmol) of triethylamine and 0.42 g (5.4 mmol) of carbon disulfide were added and stirred at room temperature for 4.5 hours. Then, 2-chloro-
1,3-Dimethylimidazolinium chloride 1.10
A solution of g (6.5 mmol) in 7 ml of methylene chloride was slowly added dropwise, and stirring was continued at room temperature for another 3 hours. Example 1 below
Perform the same processing as. 0.59 g (yield 58%) of the title compound was obtained.

Viscous oil IR ν _max ^neat cm ⁻¹ : 3120, 1615, 1575, 1490, 1450, 116
0, 945

Claims (1)

[Claims] 1. A monoacylhydrazine is reacted with carbon disulfide in the presence of a base, and then the following general formula (1): [In the formula, R ¹ and R ² are the same or different and each represents a lower alkyl group, X is a halogen atom, and n is 2 or 3
Of 1,3,4-oxadiazole-reacted with a haloiminium salt represented by
Method for producing 2 (3H) -thiones.