DD248589A1 - PROCESS FOR THE PRODUCTION OF SUBSTITUTED 1,2,4-TRIAZOLENE - Google Patents

Abstract

Process for the preparation of substituted 1,2,4-triazoles. Such compounds are important for the production of drugs with gastric juice secretion-inhibiting effect and of dyes. The aim of the invention is to make previously unknown substituted 1,2,4-triazoles accessible in a simple manner, which carry in 5-position a gesaettigte side chain with at least 4 members, at least the last represents a heteroatom. This is done according to the invention in such a way that a hydrazine is reacted with a thioamide derivative, a salt, an imide acid derivative or with a nitrile to form a substituted 1,2,4-triazole of the general formula I. The invention can be used in the chemical and pharmaceutical industries. Formula I

Description

in the R and R ^{1 are} identical or different hydrogen, an alkyl or aryl radical or R ^{1 is} a substituted or unsubstituted amino group, X and Y are identical or different, oxygen, sulfur or an amine radical and m is 0, 1, 2 or 3 and η 1, 2, 3 or 4 or X is a substituted or unsubstituted methylene group and m is 0, 1, 2 or 3 and η is 0, 1, 2, 3 or 4, in which case the sum of m + η is at least 2 must be prepared by reacting a hydrazine of the general formula II

R-NH-NH ₂ II

with the meaning explained for R

with a thioamide derivative of the general formula IM

¹¹¹ ^ C = NCR ¹ III

(CH ₂ ) -Y '

with the meaning given for R ¹ , X, Y, m and η, optionally in the presence of an alkylating agent such as, for example, an alkyl halide or dialkyl sulfate, optionally in an organic solvent or water. Substituted 1,2,4-triazoles of the general formula I, in which Y represents an amine radical, can also be prepared according to the invention by reacting a hydrazine of the general formula II with the meaning explained for R with a salt of the general formula IV

2 η

with the meaning explained for R ', X, m and η and in the Y a substituted nitrogen atom, Z "an acid residue anion, such as Cl", Br ", I", CH ₃ SO ₄ ", BF ₄ " or CIO ₄ ", and Z 'represents a leaving group such as a substituted or unsubstituted mercapto group or a halogen, or with an imidic acid derivative of the general formula V

with the meaning explained for X, R ', m and η and in the Y is a nitrogen atom and Z ^{1 is} a leaving group, such as a substituted mercapto group or a halogen, optionally in an organic solvent or water. Finally, according to the invention substituted 1,2,4-triazoles of the general formula I in which R 'is an amino group and R is hydrogen, also by reaction of hydrazine with a nitrile of the general formula Vl

X- (CH) ν

• I ..., ^m C = N-CU-VI

CCH ₂ ) _n -Y '

optionally with the meaning explained for X, Y, m and η in an organic solvent or water.

The inventive method is simple and requires only one step. It allows to prepare substituted 1,2,4-triazoles bearing in the 5-position a saturated side chain having at least 4 members, at least the last being a heteroatom. The products are obtained in such purity that they can be brought into an analytically pure form by simple recrystallization. Surprisingly, both the heteroatom-substituted side chain and the 1,2,4-triazole skeleton are simultaneously formed in a reaction, although none of these structural elements are present in the starting materials used. The starting materials used are unknown except for compound VI (X = Y = S, η = 2, m = 0). The compounds of the general formula I which are prepared are likewise novel and have significance for the preparation of medicaments having a gastric juice secretion-inhibiting action and of dyes.

embodiments

The substituted 1,2,4-triazoles of the general formula I prepared according to the various variants are listed in Table.

Variant A A mixture of 0.1 mol of nitrile of the general formula VI and 0.2 mol of 70% hydrazine hydrate is heated to boiling for 5 minutes. The precipitated on cooling end product of general formula I is filtered off with suction and recrystallized.

Variant B 0.1 mol of a salt of the general formula IV (Z '= SCH ₃ , Z "= I") are dissolved in a little acetonitrile and admixed with 0.12 mol of a hydrazine of the general formula II. The mixture is refluxed for 10 minutes. The precipitate formed after extensive distilling off the solvent is filtered off with suction and recrystallized.

Variant C A mixture of 0.1 mol of a salt of the general formula IV (Z ¹ = SCH ₂ CH ₃ , Z - - CH ₃ CH ₂ SO ₄ -) and 1 mol of 70% hydrazine hydrate is heated under reflux for 10 minutes and analogously variant B worked up.

Variant D Analogous variant B, but a salt of the general formula IV (Z ¹ = Cl, Z "= CIO ₄ ") is used.

Variant E 0.1 mol of the thioamide derivative of the general formula III are admixed with 100 ml of acetonitrile and 0.1 mol of dimethyl sulfate. The mixture is heated under reflux for 10 minutes and, after cooling, mixed with 0.12 mol of hydrazine of the general formula II. The mixture is boiled for a further 15 minutes and then concentrated by half. The end product is filtered off and recrystallized.

Variant F A mixture of 0.1 mol of thioamide derivative of the general formula III and 1 mol of 70% hydrazine hydrate is refluxed for 5 hours and worked up analogously to Variant B.

Variant G Analogous variant B, however, 0.1 mol of an imidic acid derivative of the general formula V (Z ¹ = SCH ₃ ) is used.

Variant H Analog variant A, but 50 ml of acetonitrile are used as solvent.

-4- 284 589

Table 1: The prepared according to the different variants substituted 1,2,4-triazoles of the general formula IR ¹ RXY m η

Schmp. ⁰ C

Ausb./Var. % d. Th.

NH ₂ H NH ₂ H NH ₂ H NH ₂ C ₆ H ₅ NHC ₆ H ₅ H NHC ₆ H ₅ C ₆ H ₅ 4-CIC ₆ H ₄ C ₆ H ₅ 4-CH ₃ OC ₈ H ₄ ² I 4-NO ₂ C ₆ H ₄

CH ₂

CH ₂

CH ₂

CH ₂

CH ₂

CH ₂

CH ₂

NH

NH

NCH ₃

NCH ₃

NCH ₃

NCH ₃

NCH ₃

143-145

(Acetonitrile)

147-149

(Water)

155-159 "

(Water)

83-85

(Water)

184-185

(Water)

238-240

(Water)

146-148

(Water)

230-232

(Ethanol)

52 / A 57 / G

49 / A 43 / H

49 / B

61 / C 28 / F 36 / E

40 / E

71 / B 63 / D

Substance melts with decomposition

² substance is present as hydroiodide. Optionally, hydriodic acid is added to the mixture.

Claims (5)

claims: ,1 " "" HY- (CH ₀ ) -X- (CH in the R and R ^{1 are} identical or different hydrogen, an alkyl or aryl radical or R ^{1 is} a substituted or unsubstituted amino group, X and Y are identical or different, oxygen, sulfur or an amine radical and m is 0, 1, 2 or 3 and η 1, 2, 3 or 4 or X is a substituted or unsubstituted methylene group and m is 0, 1, 2 or 3 and η is 0, 1, 2, 3 or 4, wherein in each case the sum of m + η is at least 2 must, characterized in that a) a hydrazine of the general formula II R-NH-NH ₂ · II with the meaning explained for R with a thioamide derivative of the general formula IM ^m - ^ C = WC-R '"III reacted with the meaning explained for R ¹ , X, Y, m and η or that b) a hydrazine of the general formula II with the meaning explained for R with a salt of the general formula IV I ^ ¹¹¹ CH = CR ¹ Z IV (CH ₂ ) _n -Y ^ _Ζ 1 a substituted nitrogen atom with stated for R ^1, X, η and m meaning and in which Y, Z "an acid radical anion, such as Cl-, Br", I ", CH ₃ SO _4", BF ₄ "or CIO ₄ "and Z ^{1 represents} a leaving group, such as a substituted or unsubstituted mercapto group or a halogen, to a substituted 1,2,4-triazole of general formula I, wherein Y is an amine radical, reacted or c) a hydrazine of the general formula II with the meaning explained for R with an imidic acid derivative of the general formula V CCH ₀ ) -Y * Al with the meaning explained for X, R ¹ , η and m and in which Y is a nitrogen atom and Z ^{1 is} a leaving group such as a substituted mercapto group or a halogen, to a substituted 1,2,4-triazole of the general Formula I, wherein Y is a substituted or unsubstituted amino group, reacted or that d) hydrazine with a nitrile of the general formula Vl X- (CH _? ) V. VI I - ^{2 m} C = W-CH with the meaning explained for X, Y, m and η to give a substituted 1,2,4-triazole of the general formula I in which R ^{1 is} an amino group and R is hydrogen. 1. Process for the preparation of substituted 1,2,4-triazoles of the general formula I, 2. The method according to claim 1, characterized in that optionally in the presence of an organic solvent, for example of acetonitrile, dimethylformamide, dioxane, chloroform or an alcohol is reacted. 3. The method according to claim 1, characterized in that optionally reacted in the presence of water. 4. The method according to claim 1 a, characterized in that optionally in the presence of an alkylating agent, for example an alkyl halide or a dialkyl sulfate is reacted. Field of application of the invention The invention relates to a process for the preparation of substituted 1,2,4-triazoles. Such compounds are important for the preparation of drugs with gastric juice secretion-inhibiting activity and azo dyes. Characteristic of the known technical solutions It is generally known that 1,2,4-triazoles can be obtained by reacting hydrazines with diacylamines [A. Einhorn et al .: Liebigs Ann. Chem. 343, 233 (1905)] or derivatives of diacylamines, such as N-acylamidines [Y. Lin et al .: J. Org. Chem. 44, 4160 (1979); U. Bechstein, J. Liebscher: DD 227 703], 2-aza-3-chloropropeniminium salts [J. Liebscher, A. Rumler: J. prakt. Chem. 326, (1984)] or N-acylimido esters (M.A. Perez et al .: Synthesis 1983, 483). These processes are not suitable for the preparation of substituted 1,2,4-triazoles which are known in 5 position carry a saturated side chain with at least 4 members, at least the last represents a heteroatom. Once, no starting products are known for such substituted 1,2,4-triazoles and, secondly, in a possible conceivable synthesis of such starting materials with competing ring closure reactions to be expected, leading to saturated compounds. Object of the invention The aim of the invention is to hitherto unknown substituted 1,2,4-triazoles, which carry in the 5-position a saturated side chain having at least 4 members, wherein at least the last represents a heteroatom, in a simple manner. Explanation of the essence of the invention The object of the invention is to develop a simple process for preparing hitherto unknown substituted 1,2,4-triazoles, which makes it possible to make available representatives who carry in the 5-position a saturated side chain with at least 4 members, at least the last represents a heteroatom. According to the invention this object is achieved in that substituted 1,2,4-triazoles of the general formula I,