DD235642A1 - PROCESS FOR THE PREPARATION OF 4- (OMEGA-AMINOALKYL) THIAZOLENE - Google Patents

Abstract

The invention relates to a process for the preparation of 4- (v-aminoalkyl) thiazoles. Such compounds have significance as pharmaceuticals, for example with gastric juice secretion-inhibiting effect. The invention is intended to produce 4- (v-aminoalkyl) thiazoles which carry a monosubstituted amine radical in the v position, wherein only one process step is required and starting materials are used which do not yet contain the Thiazolgeruest. This is done according to the invention in such a way that thioacyllactamimines with substituted methyl halides and optionally a base are advantageously reacted in an organic solvent to the 4- (v-aminoalkyl) thiazoles of the general formula I. The invention can be used in the chemical and pharmaceutical industries.

Description

(CH ₂ ) _n -HR ¹

in which R is hydrogen, an alkyl, aryl, heteroaryl or substituted or unsubstituted amine radical, R ^{1 is} an alkyl, aryl or benzyl radical, R ^{2 is} an electron-withdrawing radical, for example an aryl, vinyl, carbonyl, Sulfonyl, heteroaryl, cyano or nitro radical and η 3,4 or 5, are prepared by reacting a Thioacyllactamimins of the general formula II

wi *

R ¹ S

with the meaning explained for R, R ¹ and η

with a substituted methyl halide of the general formula III

R ² -CH ₂ -Hal III

with the meaning explained for R ² and in the shark a halogen and optionally with a base such as, for example, an amine, an alkali hydroxide or alcoholate or a metal hydride, advantageously in an organic solvent.

The process according to the invention makes it possible to prepare 4- (w-aminoalkyl) thiazoles of the general formula I with monosubstituted amine substituents in the ω position of the 4-position alkyl radical. The compounds obtained are novel, they are obtained by way of a hitherto unknown ring transformation in only one reaction step, which includes the construction of the Thiazolgerüstes and simultaneously the formation of the 4- (a> -Aminoalkyl) substituent. Surprisingly, in the reaction of the thioacyl lactamimine of general formula II with the methyl halide of general formula III, even if the latter is used in excess, neither alkylation of the 4 - (-> amino) function nor alkylation of a 2-amino group occurs , Also, in the case of compounds II (R = NH ₂ ) in the reaction with substituted methyl halides III no sulfides are obtained with formal H ₂ S cleavage, as was expected from the prior art.

embodiments

The prepared according to the different variants 4- (co-aminoalkyl) thiazoles of the general formula I are summarized in Table 1.

option A

0.1 mol of thioacyl lactamimine of the general formula II are admixed with 25 ml of acetonitrile and 0.1 mol of substituted methyl halide of the general formula II (HaI = Br). The mixture is refluxed for 10 minutes and, after cooling, 0.2 mol of triethylamine are added. The mixture is then heated under reflux for a further 5 minutes. The precipitated on cooling from the reaction mixture end product of general formula I is filtered off with suction and recrystallized.

Variant B

Analog variant A, but a substituted methyl halide of general formula III (HaI = CI) and only 0.1 mol of triethylamine is used.

Variant C

Analog variant A, but without the use of triethylamine. The reaction mixture is refluxed for 30 minutes after combining the components without interruption.

Variant D

Analog variant A, but methanol is used as solvent instead of the acetonitrile.

Variant E

Analog variant A, but instead of triethylamine, a solution of 2.3 g of sodium in 20 ml of methanol is used.

Variant G

A mixture of 0.1 mol of thioacyl lactamimine of the general formula II, 25 ml of acetonitrile, 0.1 mol of substituted methyl halide of the general formula III (HaI = Br) and 0.2 mol of triethylamine is allowed to stand at room temperature for 24 hours. Subsequently, as described under variant A worked up.

Variant H

A mixture of 0.1 mole of thioacyl lactamimine of the general formula II, 25 ml of chloroform and 0.1 mole of substituted methyl halide of the general formula III (Hal = Cl) is refluxed for 15 minutes. The solid product formed is filtered off with suction and introduced into 20 ml of acetonitrile. After adding 0.2 mol of triethylamine, the mixture is boiled for 20 minutes.

The resulting end product of general formula I is filtered off and recrystallized.

The prepared according to the different variants 4- (co-aminoalkyl) thiazoles of the general formula I.

R R ¹ R ' η Schmp./T Ausb./Var. % 4-CH ₃ OC ₆ H ₄ ¹¹ CH ₃ 4-BrC ₆ H ₄ CO 3 208-209 78 / D (Methanol) 59 / G 4-CH ₃ OC ₆ H ₄ ²¹ CH ₃ CN 3 220-222 86 / A (Acetonitrile) NH ₂ ¹ ' CH ₃ 4-NO ₂ C ₆ H ₄ 3 280-282 85 / A (DMF) 79 / E NH ₂ ²¹ CH ₃ 2,4- (NO ₂ J ₂ -C ₆ H ₃ 3 181-182 61 / B (DMF) C ₆ H ₅ NH ¹¹ CH ₃ 4-NO ₂ C ₆ H ₄ 3 235-237 80 / A (Glacial acetic acid / acetonitrile) 62 / C 82 / F C ₆ H ₅ NH ²¹ CH ₃ 2-pyridyl 3 110-112 73 / A (Chloroform) C ₆ H ₅ NH ¹¹ CH ₃ NO ₂ 3 208-210 67 / A (Methanol) 4-CH ₃ OC ₆ H ₄ ¹¹ CH ₃ (CN) ₂ C = C- 3 185-186 74 / A (C ₆ H ₅ ) - (Acetonitrile) 4-CIC ₆ H ₄ ²¹ C ₆ H ₅ 2-pyridyl 3 107 57 / H (Cyclohexane) ¹¹ substance is present as hydrobromide ²¹ substance is present as hydrochloride - ':. - -

Claims (2)

Claim: 1. Process for the preparation of 4 - (&) - aminoalkyl) -thiazoles of the general formula I, in which R is hydrogen, an alkyl, aryl, heteroaryl or substituted or unsubstituted amine radical, R ^{1 is} an alkyl, aryl or benzyl radical, R ^{2 is} an electron-withdrawing radical, for example an aryl, vinyl, carbonyl, Sulfonyl, heteroaryl, cyano or nitro radical and η 3,4 or 5, characterized in that a Thioacyilactamimin the general formula II ST-C-R with the meaning explained for R, R ¹ and η with a substituted methyl halide of the general formula IN R ² is -CH _O -Hal III - with the meaning explained for R ² and in the shark is a halogen and, if appropriate, reacted with a base advantageously in an organic solvent. 2. The method according to claim 1, characterized in that as the base, for example, an amine, an alkali metal hydroxide or alcoholate or a metal hydride is used. Field of application of the invention The invention relates to a process for the preparation of 4 - (&) - aminoalkyl) thiazoles. Such compounds have significance as pharmaceuticals, for example with gastric juice secretion-inhibiting effect. Characteristic of the known technical solutions It is known that 4- (a> -Aminoalkyl) thiazoles can be prepared by reaction of associated 4- (cü-haloalkyl) thiazoles with amines (DE 3332148). This method has the disadvantage that difficult-to-access starting materials are required and only compounds are prepared which carry a disubstituted amino group in the ω-position. In addition, the thiazole skeleton of the used 4- (w-haloalkyl) thiazoles must be constructed in a separate, upstream synthesis step, so that starting from open-chain starting products at least two stages of synthesis are required. Furthermore, it is known (DD 207376) that 4 - (&> - aminoalkyl) thiazoles can be prepared by a two-step process from 1-bromo-co-phthalimidoalkan-2-ones and thioamides. This process has the disadvantage that the 1-bromo -> phthalimidoalkane-2-ones are difficult to access and two synthesis steps are required starting from open-chain starting products. In addition, only 4- (a) -aminoalkyl) thiazoles can be prepared by this process which carry an unsubstituted amino group in the ω-position. Furthermore, it is known that secondary amines readily react with alkyl halides under alkylation (S.Hauptmann et al: Textbook of Organic Chemistry, p 435, VEB German publishing house for basic industries, Leipzig, 1976). Finally, it is known (CHSingh et al .: Indian J. of Chemistry 21B, 1 [1982]) that sulfides are formed in the reaction of N-unsubstituted thioamides with alkyl halides with formal H ₂ S elimination. Object of the invention The aim of the invention is to produce 4- (co-aminoalkyl) thiazoles, which carry a monosubstituted amine radical in the ^ position, using starting materials without Thiazolgerüst in a one-step process economically advantageous. Explanation of the essence of the invention The invention has for its object to develop a process for the preparation of 4- (co-aminoalkyl) thiazoles, which allows to synthesize compounds with monosubstituted amine substituents in the ω-position in a single step, using readily available starting materials, the still contain no thiazole skeleton. According to the invention this object is achieved in that 4- (o) -Aminoalkyl) thiazoles of the general formula I,