Process for the preparation of piperazine derivatives

This application is a National Stage application under 35 U.S.C. §371 of International Application No. PCT/HU2009/000110, having an International Filing Date of Dec. 18, 2009, which claims the benefit of priority of HU Application No. P08 00766, having a filing date of Dec. 18, 2008, all of which are incorporated herein in their entirety.

The present invention relates to a new process for the preparation of trans-N-{4-{2-[4-(2,3-dichlorophenyl)-piperazine-1-il]-ethyl}-cyclohexyl}-carbamid derivatives of general formula (I).

Compounds of general formula (I) were originally disclosed in the Hungarian Patent Specification No. P0302451 as D3/D2 receptor antagonists. In the P0302451 specification three reaction routes (A, B, C methods) are given for the preparation of compounds of formula (I). According to method “A” an amine derivative is reacted with a (tio)carbamoylchloride compound. In Example 3, Method A of P0302451 the amine is reacted with N,N-dimethyl-carbamoylchloride in anhydrous condition in the presence of triethylamine.

From the industrial point of view drawbacks of the above “A” procedure are the long reaction time (48 hours) and poor yield (65%). Besides, the end product obtained should be purified in an additional recrystallization step.

Our aim was to provide a process lacking the disadvantages of the previous process, i.e. to prepare compounds of formula (I) by an easy-to-working up manner with a shorter reaction time and better yield.

In the course of our experiments we have surprisingly found that when the compound of formula (III)

or a salt and/or a hydrate and/or a solvate thereof is reacted with a carbamoylchloride of general formula (II)

wherein

R 1 and R 2 represent independently C 1-6 alkyl with straight or branched chain optionally substituted with aryl group, or C 2-7 alkenyl group containing 1-3 double bonds, or monocyclic, bicyclic or tricyclic aryl group optionally substituted with one or more C 1-6 alkoxy, trifluoro-C1-6 alkoxy, C1-6 alkoxycarbonyl, C1-6 alkanoyl, aryl, C1-6 alkyltio, halogen or cyano groups, or optionally substituted monocyclic, bicyclic or tricyclic cycloalkyl group, or

R 1 and R 2 together with the adjacent nitrogen atom may form an optionally substituted, saturated or unsaturated, monocyclic or bicyclic heterocyclic ring which may contain further heteroatoms selected from oxygen, nitrogen or sulphur atoms

in the mixture of a solvent and a concentrated aqueous basic solution in the presence of a tetra alkyl-ammonium salt as phase transfer catalyst a compound of general formula (I)

wherein R 1 and R 2 are as described above—is obtained with high yield (above 90%) and short reaction time.

Applying the process according to the invention the working-up process becomes easier: the organic and aqueous phases are separated then after aqueous washing of the organic phase the solvent is removed by distillation and the end product is obtained.

The invention relates to a new process for the preparation of compounds of general formula (I)

wherein

R 1 and R 2 represent independently C 1-6 alkyl with straight or branched chain optionally substituted with aryl group, or C 2-7 alkenyl group containing 1-3 double bonds, or monocyclic, bicyclic or tricyclic aryl group optionally substituted with one or more C 1-6 alkoxy, trifluoro-C1-6 alkoxy, C1-6 alkoxycarbonyl, C1-6 alkanoyl, aryl, C1-6 alkyltio, halogen or cyano groups, or optionally substituted monocyclic, bicyclic or tricyclic cycloalkyl group, or

R 1 and R 2 together with the adjacent nitrogen atom may form an optionally substituted, saturated or unsaturated, monocyclic or bicyclic heterocyclic ring which may contain further heteroatoms selected from oxygen, nitrogen or sulphur atoms.

The advantages of the invention are that the reaction time becomes shorter and the end product can be recovered from the reaction mixture in high purity without further purification, wherein the yield is over 90%.

When R 1 and R 2 represent aryl, the aryl moiety may be a group selected from phenyl, tolyl, naphthyl and phenanthryl groups.

In the procedure according to the invention the compound of formula (III)

or a salt and/or a hydrate and/or a solvate thereof is reacted with a carbamoylchloride of general formula (II)

wherein R 1 and R 2 are described above, in the mixture of a solvent and a concentrated basic solution in the presence of a phase transfer catalyst. In this manner the end product is obtained with shorter reaction time (9-10 hours) and good yield (above 90%).

In a preferred embodiment of the invention the concentrated base is an aqueous solution of an alkali hydroxide, for example NaOH or KOH.

The phase transfer catalyst is a tetraalkylammonium salt, wherein the alkyl moiety may have a C1-6 straight or branched chain. In the choice of a suitable phase transfer catalyst the easy handling can be an important factor. Preferred phase transfer catalysts are the tetra-n-butyl ammonium salts or tetramethylammonium salts, wherein the salt forming anion may be sulphate, chloride or bromide anion.

Suitable solvents, which can be used in the process according to the invention include neutral water immiscible solvents, for example toluene, dichloromethane, chlorobenzene or xylene. In a preferred embodiment of the invention preferably dichloromethane can be used as solvent.

In the working-up step of the process according to the invention the organic and aqueous phases are separated, then after aqueous washing of the organic phase the solvent is removed by distillation and the desired end product is obtained.

The invention is further illustrated by the following non-limiting Examples.