HU191095B - Process for the production of 3,5 diamino-1,2,4-triazole-derivatives - Google Patents

Abstract

The invention relates to a process for the preparation of Dihydroaryloxyalkylamino-1,2,4-triazole derivatives of general formula I, wherein R1 and R2 are identical or different and independently of one another for hydrogen, C1-5 alkyl, C2-5 alkenyl, aralkyl or C3-7 cycloalkyl or together with the nitrogen atom to which they are attached form a 5-10 membered, saturated or at least one double bond-containing heterocyclic ring and R3 is C1-4 alkyl or C1-4 hydroxyalkyl, and pharmaceutically acceptable acid addition salts from that. Formula I

Description

The present invention relates to a novel process for the preparation of dihydroaryloxyalkylamino-1,2,4-triazole derivatives of the formula (I) wherein R ₁ R ₂ N ^; together form a pyrrolidino ring, R ₃ is C 1 -C 4 alkyl, by reducing the aryloxyalkylamine of formula (II) wherein R 1 and R ₂ are as defined above, to give the ) dihydro-aryloxy-alkylamine of formula - wherein R and _R2 are as defined above - is reacted with N-cyano-imino ditioszénsavdimetilészterrel and (IV) isothiourea of the formula - wherein R _(and R ₂ is as defined above, an ( Reaction with a substituted hydrazine of formula V wherein R ₃ is as defined above.

The compounds of formula I are histamine H ₂ receptor blockers and, as such, antagonize histamine-stimulated gastric acid secretion. They can be used in anti-ulcer therapy,

The only known process for the preparation of compounds of formula I is described in U.S. Pat. European Patent Application 4,108,960 discloses that they can be prepared by Birch reduction of the aryloxyalkylamino-1,2,4-triazole derivatives of formula (VI) in the Na / NH ₃ system.

The disadvantage of the process is that besides the desired 5-alkylanylmethyl dihydro derivative of formula (I), an isomeric 3-alkylaminomethyl dihydro derivative of formula (VII) is also formed in the cyclohexadiene ring. Because of the foregoing, obtaining an isomeric unit product is complicated, in particular, making the process of separation losses in the final step of the long synthesis uneconomical.

According to the invention, all these disadvantages can be eliminated. The process involves the reduction of the aryloxyalkylamino compound of formula (II) as the major component in the preparation of a novel dihydroaryloxyalkylamine derivative of formula (III) which is not known in the art, either alone or with N-cyanoiminodithioic in a reaction-inert solvent, a new dihydroaryloxyalkyl-isothiourea derivative of formula (IV), not previously described in the literature, is reacted alone with a substituted hydrazine of formula (V) or in a reaction-inert solvent of formula (I). yielding the final product, which can, if desired, be converted into a pharmaceutically acceptable salt in a known manner,

Reduction of the starting aryloxyalkylamino derivative of formula (II) to the dihydroaryloxyalkylamino derivative of formula (III) is a liquid at temperatures between -85 ° C and 33 ° C. in ammonia by the addition of 1.1 to 4.5 molar equivalents of phenolic sodium. 2.5 molar equivalents of metal sodium are particularly preferred.

The reduction of the compound of formula (II) to the compound of formula (III) yields a small amount of the dihydroaryloxyalkylamine derivative of the compound of formula (VIII). The isomers of formulas (III) and (VIII) may be isolated by distillation or, if desired, converted directly into a mixture of isothioureas of formulas (IV) and (IX).

The reaction of the compound of formula (III) with dimethyl ester of N-cyanoiminodithioic acid in protic or aprotic organic solvents, preferably C 1-4 alcohol, dimethylformamide, ether, halogenated organic solvents, aromatic solvents, acetonitrile is carried out at a temperature of 20-120 ° C. . The use of isopropyl alcohol solvent is particularly preferred. Preferably, the amount of N-cyanoiminodithioic acid dimethyl ester is 1.0 eq.

When a mixture of the isomers (III) and (VIII) is used instead of the compound (H1), the compound (IV) is separated from the resulting compound (IX) by crystallization.

The cyclization of the compound of formula (IV) with a substituted hydrazine of formula (V) can be carried out in a protic or aprotic organic solvent, preferably C 1-4 alcohol, ether, or aromatic solvents, at a temperature of 20-120 ° C. Particularly preferred is the use of a n-butanol solvent. Preferably, 1.0 to 1.5 molar equivalents of the substituted hydrazine of formula (V) are used.

The present invention therefore relates to a process for the preparation of dihydroaryloxyalkylamino-1,2,4-triazole derivatives of the general formula (I) wherein R ₁ R ₂ N together form a pyrrolidino ring, R ₃ is 1-4. alkyl - preparing such a way that the aryloxy-alkylamine of formula (II): - wherein R, and _R2 are as defined above - is reduced to give (III) dihydro-acyloxy alkilaniint - wherein _R, and R ₂ is as defined above - is reacted with N-cyanoimino-dithiocarboxylic acid dimethyl ester to give isothiourea of formula IV where R 1 and R ₂ are as defined above with a substituted hydrazine of formula V where R ₃ is as defined above. reacted.

The present invention provides a more isomerically uniform product of formula (I), a more economical separation of the intermediate (VIII) and (IX) leading to the undesired product (VII) at an early stage of the synthesis and a simpler reaction route. and shorter.

The invention is illustrated by the following examples, without limiting our claims thereto.

Example 1

Preparation of 3- [5- (1-Pyrrolidinylmethyl) -1,4-cyclohexadienyloxy] 1-propanamine

a) To 19.9 g (0.085 mole) of 3- [3- (1-pyrrolidinylmethyl) phenoxy] -1-propanamine was added 19.8 g (0.425 mole) of ethyl alcohol and 500 ml of ammonia was condensed to the solution thus obtained. 10.00 g (0.425 mol) of chopped metal sodium are added to the system cooled in an acetone-dry ice bath at -85 ° C, so that the next portion of sodium is added after the reaction mixture becomes colorless. After addition of 1 g of sodium, the cooling bath is removed and the reaction is continued at -33 ° C. After the last dose of sodium, the blue color persists for 2.5 to 3 hours. After the final decolorization, the mixture was refluxed for 30 minutes and ammonium chloride (29.7 g, 0.555 mol) was added to the reaction mixture. Evaporation of ammonia

After 191 095 the residue is taken up in 400 ml of diethyl ether. The inorganic salt was filtered off and washed with diethyl ether (6 x 100 mL). The combined ethereal solutions were removed in vacuo under vacuum. The residue thus obtained is fractionally distilled under vacuum. 18.6 g of 1 mmHg at 162-168 ° C are obtained in the form of hot material. The product thus obtained is a 4: 1 mixture of the title compound and 3- (3- (1-pyrrolidinylmethyl) -1,4-cyclohexadienyl) oxy] -1-propane amine. The isomeric mixture was again fractionally distilled at 1 mm Hg. THE

16.5 g of product, b.p. 166-168 ° C, is more than 90% pure for the title compound. Yield 73.9%.

b) The procedure described in a) is followed, except that 4.4 g (0.19 mol) of sodium are used instead of 10 g of sodium metal. After redistillation, 15.1 g of product is obtained which is boiling at 165-167 ° C. Yield: 67.6%.

Example 2

Preparation of 3-cyano-2-methyl-1- (3- (5- (1-pyrro] idinylmethyl) -1,4-cyclohexadienyloxy] propyl] isothiocarbanide

a) 3- [5- (1-Pyrrolidinylmethyl) -1,4-cyclohexadienyloxy] -1-propanamine (9 g, 0.038 mol) obtained according to any one of Examples 1 a) -b) is dissolved in 10 ml of isopropyl alcohol at room temperature. To the solution thus obtained

5.5 g (0.038 mol) of dimethyl ester of N-cyanoimino-dithiocarboxylic acid are added. The reaction starts at room temperature with methylmercaptan leaving. After half an hour, the reaction mixture is heated to reflux. After refluxing for 1.5 hours, the reaction mixture was evaporated to dryness in vacuo. The honey-like residue thus obtained was dissolved in 40 ml of acetonitrile with heating. Upon cooling, the crystals which precipitate were filtered off and washed with acetonitrile. This gives 1.1 g of 3-cyano-2-methyl-3- (3- (1-pyrrolidinylmethyl) -1,4-cyclohexadienyloxy] propyl} -isothiourea, m.p. 117-119 ° C. Yield: 11.5 g, Rf: 0.45 (ethyl acetate: pyridine: water: acetic acid 60:20:11: 6).

b) Proceed as in a) with the modification that 40 ml of di-n-propyl ether is used as the solvent and reflux for 5 hours. This way

11.4 g of honey are obtained. Rf: 0.44 in the eluent according to (a). Production is quantitative. The compound is identical to the product obtained in Example a).

c) The procedure of Example a) was followed by the modification of 40 ml of chloroform as the solvent and refluxing for 4.5 hours. This way

11.5 g of honey are obtained. Rf: 0.45 in the run of Example a). Production is quantitative. The product is identical to that obtained in Example a).

d) The procedure of Example a) was followed, except that 100 ml of benzene was used as solvent and the refluxing time was 10 hours. The material thus obtained weighed 11.3 g. Rf: 0.45 in the run of Example a). The material is the same as that obtained in Example a).

f) Proceed as in a) with the modification that 40 ml of acetonitrile are used as solvent and reflux for 4.5 hours. 11.5 g of material are thus obtained. Rf: 0.44 in the run of Example a). Room and quantitative. The product is identical to the compound prepared in Example a).

g) 3- (5- (1-Pyrrolidinylmethyl) -1,4-cyclohexadienyloxy) -1-propanamine (9 g, 0.031 mol) obtained according to any one of Examples 1 (a) to (b) is dissolved in 10 ml of dimethylformamide at room temperature. To the solution thus obtained

5.5 g (0.038 mol) of N-cyanoiminodithionouscarbonic acid dinethyl ester were added and the reaction mixture was heated at 120 ° C for 5 hours. The cooled solution was then poured into water (100 mL) and extracted with chloroform (4 x 30 mL). The combined chloroform phases were dried on _MgSO4 and filtered. The solvent was evaporated in vacuo. The residue was dissolved in 35 ml of acetonitrile with heating. The resulting crystals from the resulting solution were cooled by filtration, washed with acetonitrile, (0.8 g, 3-cyano-2-methyl-1- (3- (3- (1-pyrrolidinyl) yl) melting at 116-118 ° C). ll) -1,4-Cyclohexadienyloxy] -propyl} -isothiourea, The mother liquor was evaporated to give 9.2 g of honey-like material, Rf 0.46, in the same manner as in a) Example.

Example 3

^and methyl N - {3- [5- (1-pyrid roli di nilme ylmethyl) -1,4-cyclohexadienyl-yloxy] propyl) -lH-l, 2,4-triazole-3,5-diamine a

a) 9-g (0.027 mol) of 3-cyano-2-methyl-1- {3- [5- (1-pyrrolidinylmethyl) -1,4-cyclohexadienyloxy] prepared according to any one of Examples 2a-g). -propyl} -isothiourea is dissolved in 20 ml of n-butyl alcohol at room temperature. To the resulting solution was added methyl hydrazine (1.24 g, 0.027 mmol). The reaction starts immediately, leaving methyl mercaptan in the system. After 20 minutes, the reaction mixture is heated to reflux. After boiling for 20 hours, the solvent was evaporated in vacuo. The honey-like material thus obtained was poured into 20 ml of cyclolyxane and 5 ml of acetonitrile and placed in a refrigerator. The precipitated crystals were filtered off and washed with acetonitrile.

Yield: 7.5 g (83.8%), m.p. 81-84 ° C. The crude product was recrystallized from ethyl acetate: cyclohexane (1: 4, 60 mL). Yield: 6.8 g (76%), m.p. 86-87 ° C.

b) Proceed as in a) except that di-n-propyl ether is used as the solvent. Recrystallization gave 5.4 g (60.3%) of a melting point of 85-87 ° C. The compound is identical to the product obtained in Example a).

c) Proceed as in a) except that benzene is used as solvent. Recrystallization gave 5.1 g (57%) of a melting point of 85-88 ° C. The compound is identical to the product obtained in Example a).

d) Proceed as in a), with the difference3

191,095 gels using 1.86 g (0.041 mol) of methylhydrazine. Recrystallization gave 6.6 g (73.9%) of product, m.p. 85-87 ° C. Compound azonos is identical to the product obtained in Example a).

Claims (3)

Process for the preparation of the dihydroaryloxyalkylamino-1,2,4-triazole derivatives of the general formula (I) wherein R ₁ R ₂ together form a pyrrolidino ring, R ₃ is a C 1 -C 4 alkyl group. characterized in that the aryloxyalkylamine of formula (11) wherein R 1 and R ₂ are as defined below is reduced to give (111). Dilydro-aryloxyalkylamine of Formula 5, wherein R 1 and R ₂ are as defined above, is reacted with N-cyanoiminodithioic acid dinethyl ester to give isothiourea of Formula IV, wherein R 1 and R ₂ are as defined above. Formula (V) With 10 substituted hydrazines wherein R ₃ is as defined above.