PROCESS FOR THE PREPARATION OF 1,5-DISUBSTITUTED-3-AMINO-1,2,4-TRIAZOLES AND SUBSTITUTED AMINOGUANIDINES AS INTERMEDIATE COMPOUNDS

Abstract: New process for the preparation of 1,5-disubstituted-3-amino-1,2,4-triazoles of the general formula (I), wherein the meaning of R is C1-5alkyl group; C3-13cycloalkyl-C0-4alkyl group, optionally substituted by one or more C1-3alkyl group; phenyl-C0-2alkyl-, (CH2)n-morpholino-, piperidino-, pyrrolidino- or piperazino-group, optionally substituted by one or more halogen atom, C1-3alkyl group, C1-3alkoxy group, n is 1-5, R<1>, R<2>, R<3>, and R<4> stand independently for hydrogen, halogen, C1-6alkyl group, C1-3alkoxy group or trifuluoromethyl group, with the proviso that of the substituents R<1>, R<2>, R<3>, and R<4> at least one stands for hydrogen.

Description: PROCESS FOR THE PREPARATION OF 1 , 5-DISUBSTITUATED-3-AMIN0-1 , 2 , 4-TRIAZOLES AND SUBSTITUTED AMINOGUANIDINES AS INTERMEDIATE COMPOUNDS The invention relates to a process for the preparation of l,5-disubstituted-3-amino-l,2,4- triazoles of the general formula (I), wherein the meaning of R is -salkyl group; C 3 -ι 3 cycloalkyl-Co- 4 alkyl group, optionally substituted by one or more 15 Cι- 3 alkyl group; phenyl-Co- alkyl-, (CH ) n -morpholino-, piperidino-, pyrrolidino- or piperazino-group, optionally substituted by one or more halogen atom, C]- 3 alkyl group, Cι- 3 alkoxy group, n is 1-5, R 1 , R 2 , R 3 , and R 4 independently stand for hydrogen, halogen, C h alky! group, Cι- 3 alkoxy 20 group or trifluoromethyl group, with the proviso that at least one of the substituents R 1 , R 2 , R 3 , and R 4 stands for hydrogen. l,5-disubstituted-3-ammo-l,2,4-triazoles of the general formula (I) are intermediates to the therapeutically useful compounds of the general formula (VI), described in patent application WO 98/51686. For the synthesis of 3-amino-l,2,4-triazoles the route starting from amino-guanidine is known for a long time (K.T. Potts. Chem. Rev. 61, (1961)): an aminoguanidine salt is treated with a suitable acid at high temperature, or the isolated acylaminoguanidine is treated with alkali and/or subjected to thermal ring closure. Except for ring closures in acetic acid, yields are low to medium. The case is similar when the aminoguanidine is prepared by Schotten-Baumann acylation, where hydrolysis takes place as a competing reaction. The isolated acylaminoguanidine derivative is then cyclized thermally, at 180°C in DMSO or with NaOEt (J. Med. Chem. 41. 2985-93 (1998)). Reactions of aminoguanidines with esters leading to 3-amino-l,2,4-triazoles are also known (J. Med. 41, 2985 (1998); and Chem Rev. 61, 87 (1961)). Synthesis of l-substituted-3-amino-triazoles cannot be solved economically by preparation and subsequent substitution of the amino-triazoles, since reactivities of the nitrogens in positions 1 and 2 towards electrophiles are almost the same, therefore derivatives substituted in position 1 and in position 2 are equally formed, approximately in the same ratio. Separation of the isomers which have very similar physico-chemical properties is not easy and usually can only be solved by chromatography, which in industrial scale is expensive and complicated. There is only one example to find in the literature where a substituted aminoguanidine is cyclized to 1,2,4-triazole. The substituted aminoguanidine is synthesized step-by step starting from hydrazide and cyanamide, the ring closure is carried out by thermolysis in pyridine hydrochloride. The synthesis, however, does not utilize some reasonable possibilities given in the aminoguanidine structure [Ger. Offen. 1,808,677 (C.A. 72, 90561m 1970)]. We have found, to our surprise, that the l,5-disubstituted-3-amino-l,2,4-triazoles of the general formula (I) can be prepared in good yield via a regioselective synthesis, by the reaction of the aminoguanidine derivative of the general formula (IN) R— CH. ■ ΝH — ΝH — C -ΝH (IN) ΝH, with the acid derivative of the general formula (N), in the presence of sodium- or potassium-alcoholate. This means that of the four nitrogens of the aminoguanidine, the acylation took place exclusively on the one in desired position. By-products were not obtained even by working up the mother-liquor. A further surprise was that the aminoguanidine, which is sensitive to bases (Houben- ^ Weil NIII, 193.), furnished the product in good yield, this means that decomposition of the aminoguanidine was avoided. The subject of our invention, in agreement with the above, is a process for the preparation of l,5-disubstituted-3-amino-l,2,4-triazoles of the general formula (I), wherein the meaning of R is C,- 5 alkyl group; C 3 - 13 cycloalkyl-C 0 - 4 alkyl group, optionally substituted by one or more Cι- 3 alkyl group; phenyl-Co- 2 alkyl-, (CH 2 ) n -morpholino- 5 piperidino-, pyrrolidino- or piperazino-group, optionally substituted by one or more halogen atom, Cι- 3 alkyl group, C^aϋ-oxy group, n is 1-5, R 1 , R 2 , R 3 , and R 4 stand independently for hydrogen, halogen, Cι- 6 alkyl group, Cι- 3 alkoxy group or trifluoromethyl group, with the proviso that of the substituents R 1 , R 2 , R 3 , and R at least one stands for hydrogen, which comprises reacting an aldehyde of the general formula (II) RCHO (II) - wherein the meaning of R is the same as defined above- with an aminoguanidine of the general formula (III) NH or its salt, and treating the resulting aminoguanidine derivative of the general formula (IN) R — CH 2 ΝH — ΝH ■ C -ΝH (IN) ΝH, - wherein the meaning of R is the same as defined above- with the acid derivative of the general formula (N) - wherein the meanings of R 1 , R 2 , R 3 , and R 4 are the same as defined above and R 5 stands for hydrogen atom or for -salkyl group- in the presence of an alkali alcoholate. The aldehydes of formula II are commercially available or they can be prepared by methods known from the literature. In the process according to the invention for alkali alcoholate preferably sodium- or potassium alcoholate is used. For compound of the general formula (II) preferably 1-cyclohexylacetaldehyde, and for the acid derivative of the general formula (N) preferably methyl 2,5-dimethoxy-4- methylbenzoate are applied. Our process is demonstrated by the following examples: Example 1 51J4g of cyclohexylethylaminoguanidine HC1 salt and 49.4g of ethyl 2,5-dimethoxy- 4-methylbenzoate are dissolved in 150ml of methanol, to the solution 28g of sodium methylate in methanol are added and the reaction mixture is refluxed for 5 hours. After addition of diluted alkali the mixture is refluxed for an additional hour and cooled. The resulting crystals are filtered off, washed and dried, to obtain 55Jg (67%) of l-(2- cyclohexylethyl)-5-(2,5-dimethoxy-4-methylphenyl)-3-amino-l,2,4-triazole. Mp.: 136-137°C. Purity by HPLC 99.5%. Preparation of the starting cyclohexylethylaminoguanidine HC1 : 11.05 g (0J mol) of aminoguanidine hydrochloride are dissolved in 150 ml of 96% ethanol and 12.62 g (0J mol) of 1 -cyclohexylacetaldehyde are added. The resulting Schiff-base is hydrogenated under atmospheric pressure, at room temperature, using palladium on charcoal catalyst. At the end the catalyst is filtered off, the filtrate is evaporated, the residue is crystallized from water, to obtain 17.2 g (78 %) of product. Mp.: 132-134°C. Examples 2-43 Applying the procedure as described in Example 1 and using the appropriate starting materials the following products can be prepared (R 4 =H), see Table 1. Table 1

Claims: Claims 1) Process for the preparation of l,5-disubstituted-3-amino-l,2,4-triazoles of the general formula (I), wherein the meaning of R is C]. 5 alkyl group; C 3 -] 3 cycloalkyl-Co. alkyl group, optionally substituted by one or more Cι- 3 alkyl group; phenyl-C 0 - 2 alkyl-, (CH 2 ) n -morpholino-, piperidino-, pyrrolidino- or piperazino-group, optionally substituted by one or more halogen atom, Cι- 3 alkyl group, Cι- 3 alkoxy group, n is 1-5, R 1 , R 2 , R 3 , and R 4 stand independently for hydrogen, halogen, Cι- 6 alkyl group, Cι- 3 alkoxy group or trifluoromethyl group, with the proviso that of the substituents R 1 , R 2 , R 3 , and R at least one stands for hydrogen, which comprises reacting an aldehyde of the general formula (II) RCHO (ID •- « **, wherein the meaning of R is defined above- with an aminoguanidine of the general formula (III) NH or its salt, and treating the resulting aminoguanidine derivative of the general formula (IN) R — CH. NH — NH - C -NH I I (IN) NH, wherein the meaning of R is defined above- with the acid derivative of the general formula (N) wherein the meanings of R 1 , R 2 , R 3 , and R 4 are defined above and R 5 stands for hydrogen atom or for Cι- 5 alkyl group- in the presence of an alkali alcoholate. 2) The process defined in Claim 1, which comprises the use of sodium- or potassium alcoholate as alkali alcoholate. 3) The process defined in Claim 1, which comprises the use of 1-cyclohexylacetaldehyde for compound of the general formula (II). 4) The process defined in Claim 1, which comprises the use of methyl 2,5-dimethoxy-4- methylbenzoate for compound of the general formula (N). 5) Compounds of the general formula (IN), R— CH 2 ΝH- -ΝH — C -ΝH. I I (IN) .- *** - ΝH, wherein the meaning of R is Cι- 5 alkyl group; C 3 -ι 3 cycloalkyl-C 0 - 4 alkyl group, optionally substituted by one or more Cϊ- 3 alkyl group; phenyl-C 0 - 2 alkyl-, (CH 2 ) n -morpholino-, piperidino-, pyrrolidino- or piperazino-group, optionally substituted by one or more halogen atom, d- 3 alkyl group, C^alkoxy group.

Inventors: BOKOTEY SANDOR, CSIKOS EVA, GOENCZI CSABA, HAJDU FELIX, HEJA GERGELY, HERMECZ ISTVAN, PODANYI BENJAMIN, SANTANE CSUTOR ANDREA, SZOMOR TIBORNE, SZVOBODA GYOERGYNE, BOKOTEY, SANDOR, CSIKOS, EVA, GOENCZI, CSABA, HAJDU, FELIX, HEJA, GERGELY, HERMECZ, ISTVAN, PODANYI, BENJAMIN, SANTANE CSUTOR, ANDREA, SZOMOR, TIBORNE, SZVOBODA, GYOERGYNE
Applicants: BOKOTEY SANDOR, CSIKOS EVA, GOENCZI CSABA, HAJDU FELIX, HEJA GERGELY, HERMECZ ISTVAN, PODANYI BENJAMIN, SANOFI SYNTHELABO, SANTANE CSUTOR ANDREA, SZOMOR TIBORNE, SZVOBODA GYOERGYNE, BOKOTEY, SANDOR, CSIKOS, EVA, GOENCZI, CSABA, HAJDU, FELIX, HEJA, GERGELY, HERMECZ, ISTVAN, PODANYI, BENJAMIN, SANOFI-SYNTHELABO, SANTANE CSUTOR, ANDREA, SZOMOR, TIBORNE, SZVOBODA, GYOERGYNE
Application year: 2001
Main classification: C07D249
IPC codes: C07C281, C07D249, C07D295