HU201324B - New process for production of substituated 1,2,4-triasole (4,3-a)-piridin-2 (2h)-on - Google Patents

Abstract

Pure substd. 1,2,4-triazolo- (4,3-a)-pyridine-3(2H)-one of general formula (I) a known antidepressant is prepd. by a novel method and at high yields in a dipolar aprotic solvent from 1,2,4-tri:azolo-(4,3-a)-pyridine -3(2H)-one of general formula (II) and 1-(3'-chloro-propyl)-4-(m-chlorophenyl- piperazine-hydrochloride of general formula (III) in the presence of an alkali-carbonate or powdered sodium-hydroxide condensing agent. The resulting base (I) is opt. - converted to a corresponding salt.

Description

The present invention provides 2- {3- [4- (3-chlorophenyl) -1-piperazinyl] propyl} -1,2,4-triazolo [4,3-a] pyridine-3 (2H) -one and its pharmaceutically acceptable acid addition salts.

The compound of formula (I) has antidepressant activity and is useful in the treatment of psychosomatic disorders. Several methods are known in the art for preparing this compound, but with significant disadvantages.

No. 1,117,068. United Kingdom Patent Number 1,2,4-triazolo [4,3-a] pyridin-3 (2H) -one-t-in dioxane using a 50X aqueous solution of sodium hydroxide as a condensing agent. It is reacted with 1- (3'-chloropropyl) -4- (3-chlorophenyl) piperazine base (III) at reflux for 20 hours. Alternatively, a compound of Formula VI (wherein R 'is chloro) is reacted with a substituted piperazine of Formula V. Triethylamine (U.S. Patent No. 3,381,009) is used as an acid scavenger.

No. 8135 M. According to the French pharmaceutical patent, the compound of formula (I) is obtained with the 1,2,4-triazolo (4,3-a] pyrimidin-3 (2H) -one of formula (II) and the 1- (3'-chloro) is prepared by the reaction of propyl) -4- (3-chlorophenyl) piperazine with condensation in dioxane using sodium hydride as the condensing agent.

No. 2,318,871. 1,2,4-triazolo [4,3-a] pyridin-3 (2H) -one and 1- (3'-hydroxypropyl) -4- (3-chloro) -phenyl, piperazine in the presence of a dicyclohexylcarbodiimide condensing agent According to South African Patent Application No. 7,206,070, triazolo-pyridine derivatives of formula I are prepared by reacting 1,2,4-triazolo [4,3-a] Pyridin-3 (2H) -one is reacted with a compound of formula IV: when R is hydroxy then dicyclohexylcarbodiimide, and when R is chlorine then sodium hydride is the condensing agent. The compound of formula (VI) (wherein R 'is chlorine or bromine) is reacted first with diethanolamine and then with richloroaniline.

From the processes disclosed, it is clear that only 1,2,4-triazolo [4,3-a] pyridin-3 (2H, -one) of formula II and 1- (3'-) of formula III are commercially available. Chloropropyl) -4- (3-chlorophenyl, piperazine base) The above reaction is carried out on dioxane and the condensing agent is either aqueous sodium hydroxide solution or sodium hydride (or in some cases sodium amide). The disadvantage of the former process is its very long reaction time, which results not only in the poor utilization of the manufacturing equipment, but also in the decomposition of the reagents, thereby adversely affecting both production and quality. lies.

It is also known that 1- (3'-5-chloropropyl, -4- (3-chlorophenyl) piperazine of formula (III) used as a reagent is stable in salt form only (preferably the hydrochloride salt), it must always be liberated from its salt immediately before use, with an additional operation, which usually results in a loss of 15-20% (US Patent 4,254,124).

It is an object of the present invention to provide a process which does not require a long reaction time, does not produce explosive or pollutant gases (hydrogen, ammonia) and 1- (3'-chloropropyl) -4- (3- may also be used in the form of the chlorophenyl) piperazine hydrochloride salt.

We have found that the compound of formula (I) and its pharmaceutically acceptable salts of 1,2,4-triazolo [4,3-a] pyridin-3 (2H) -one in very good yield, high purity, are contaminating the environment. elimination and short reaction time can be carried out in large scale on a large scale and can be readily accomplished by converting 1,2,4-triazolo [4,3-a] pyridin-3 (2H, -on) of formula II In a C 1-4 alkyl, 2-C 1-4 alkali acid amide, as the dipolar aprotic solvent, the hydrochloride salt of the piperazine derivative (III) is reacted with an alkali metal carbonate or powdered sodium hydroxide.

Lithium carbonate, potassium carbonate and sodium carbonate can be used as the alkali metal carbonate.

The reaction can be carried out over a wide temperature range (70-110 ° C), preferably at ° C.

Suitable solvents are all dipolar aprotic solvents such as dimethylacetamide, dimethylsulfoxide, hexamethylphosphoramide, acetonitrile, preferably dimethylformamide. The reaction is preferably effected by the addition of a catalytic amount of an alkali metal iodide, preferably sodium iodide.

The above procedure gives the compound of formula (I) in excellent yield (90-96%) with high purity (melting point about 10 ° C higher than that described in the literature).

Synthesis is well-feasible under industrial conditions, does not require any special equipment, and does not require the generation of by-products that pollute the environment.

The reaction does not require extremely low or high temperatures and is carried out in a short time (1-3 hours).

Further details of the process are illustrated by the following examples:

-2HU 201324 Β

Example 1

2- {3 '- [4- (m-chlorophenyl) piperazinyl] propyl} -l, 2,4-triazolo [4,3-a] pyridin-3 (2H) -one

135.1 g (1.0 mole) of 1,2,4-triazolo [4,3-a] pyridin-3 (2H) -one, 325.2 g (1.05 mole) of 4 - ((m)). -chlorophenyl) -1-piperazinyl] -propyl chloride monohydrochloride, 76.0 g (0.55 mol) of powdered potassium carbonate in 1350 cm ^{3 of} dimethylacetamide in the presence of 20.0 g of triethylamine at 75 ° C. reaction for 2-3 hours.

The starting material content of the reaction mixture was monitored by TLC on silica gel in THF. At the end of the reaction, no starting material can be detected. After completion of the reaction, the solvent was evaporated in vacuo, water was added to the residue, and the product was isolated by benzene extraction. After benzene deprotection, the crude product is crystallized from isopropyl alcohol.

Yield: 381.8 g (93.5%)

M.p .: 95-97 ° C (Literature: 85-87 ° C)

Content (titrated with perchloric acid): 99.9% Hydrochloride m.p .: 231 ° C

Claims (3)

PATENT CLAIMS 1. A process for the preparation of the substituted 1,2-triazolo (4,3-a) pyridin-3 (2H) -one of formula (I) by treating the compounds of formula (II) and (III) with an inorganic condensing agent containing an alkali metal ion. preferably by reaction with an alkali iodide in the presence of a catalyst, characterized in that the 1,2,4-triazolo [4,3-a] pyridin-3 (2H) -one of formula (II) is alkyl in 2-C 1-4 alkali acid amide, as an aprotic solvent, with 1- (3-chloropropyl) -4- (m-chlorophenyl, piperazine hydrochloride of formula III), an alkali metal carbonate 5 or powdered sodium hydroxide in the presence of a condensing agent. 2. The process according to claim 1, wherein the dipolar aprotic solvent is dimethylacetamide, preferably dimethylformamide. 3). Process according to any one of claims 1 to 3, characterized in that the alkali metal carbonate is sodium carbonate or potassium carbonate. Example 2 2- {3 '- [4- (m-chlorophenyl, -l-piperazinyl] propyl) -l, 2,4-triazolo [4,3-a) pyridin-3 (2H) -one 13.5 g (0.1 mol) of 1,2,4-triazolo [4,3-a] pyridin-3 (2H) -one, 32.5 g (0.105 mol) of 4-yl (3'- chlorophenyl, -1-piperazinyl] -propyl chloride monohydrochloride, 8.8 g (0.22 mol) of powdered sodium hydroxide in 150 cm ^{3 of} dimethylformamide in the presence of 0.8 g of sodium iodide. After 2 hours, the starting material is no longer detectable by thin layer chromatography on silica gel in tetrahydrofuran. crystallized from alcohol. Yield: 35.2 g (95.0%) Melting point: 95-97 ° C (Literary melting point: 85-87 ° C) 50 Content (titrated with perchloric acid: 99.9% Hydrochloric salt, m.p. 231 ° C