TW201144289A - Novel process for the preparation of piperazine compounds and hydrochloride salts thereof - Google Patents

Abstract

The invention relates to a new process for the preparation of compounds of general formula (I) wherein R1 and R2 represent independently hydrogen or C1-6 alkyl with straight or branched chain optionally substituted with aryl group, or C2-7 alkenyl containing 1-3 double bonds, or monocyclic, bicyclic or tricyclic aryl optionally substituted with one or more C1-6 alkoxy, trifluoro-C1-6 alkoxy, C1-6-alkoxycarbonil, C1-6alkanoyl, aryl, C1-6 alkylthio, halogen or cyano, or optionally substituted monocyclic, bicyclic or tricyclic C3-14 cycloalkyl group, R1 and R2 together with the adjacent nitrogen form a saturated or unsaturated optionally substituted monocyclic or bicyclic heterocyclic ring which may contain further heteroatoms selected from oxygen, nitrogen, or sulphur atoms and hydrochloric acid salts and/or hydrates and/or solvates thereof, by dissolving or suspending trans 4-{2-[4-(2, 3-dichlorophenyl)-piperazine-1-il]-ethyl}-cyclohexylamine of formula (III) or a salt or a hydrate or a solvate thereof in an inert solvent in the presence of a base then adding a carbonic acid derivative of general formula (VI) wherein R is alkyl with C1-6 straight or branched chain, partially or fully halogenated C1-2 alkyl or phenyl, Z is -O-R or -X, wherein R is as described above, X is halogen, and reacting the compound of general formula (IV) obtained wherein R is as described above, in situ or, optionally in isolated state with an amine of general formula (V) wherein R1 and R2 are as described above to obtain the compound of general formula (I) and then optionally forming the hydrochloride salts and/or hydrates and/or solvates thereof.

Description

201144289 VI. Description of the Invention [Technical Field to Which the Invention Is Ascribed] The present invention relates to a preparation of trans N-{4-p-t4-(2,3-chlorobenyl)-fluorene-1- of the general formula (I) Novel method for the hydroxy group of the cyclohexyl bromide compound and its hydrochloride and/or hydrate and/or solvate,

Wherein Ri and R2 independently represent -hydrogen, or - a linear or branched Cl-6 alkyl group optionally substituted with an aryl group, or -R! and R2 together with an adjacent nitrogen may form an optionally substituted saturated or unsaturated Monocyclic or bicyclic heterocyclic rings which may contain additional heteroatoms selected from oxygen, nitrogen or sulfur atoms, - C2-7 alkenyl groups containing 1-3 double bonds, or - one or more Cl6 alkanes Oxy, trifluoro-Ci6 alkoxy,

a monocyclic, bicyclic or tricyclic aryl group optionally substituted by Cm oxime forging group, Cl 6 alkyl fluorenyl group, aryl group, Ci 6 alkylthio group, cyano group or halogen atom, - optionally substituted monocyclic ring, Bicyclic or tricyclic c3_14 cycloalkane 201144289 [Prior Art] The base form of the compound of formula (I) was originally disclosed in Hungarian Patent Specification No. P030245 No. 1 provides three reaction pathways in the specification (A, B, Method C) to prepare the base form of the compound of formula (I). In the method ", a suitable amine is reacted with (thio)amine formazanyl chloride to give the final product of formula (I). According to the A method ' ' ' A 〃 procedure of P030245 1 , only a product of 65% yield was obtained with a very long reaction time. According to Method B, the iso(thio)cyanate is reacted with an amine compound. A disadvantage of the oxime process is that only compounds of the formula (I) wherein the 1 and R2 groups represent hydrogen can be prepared using this procedure. Conversion of a suitable amine to an iso(thio)cyanate derivative according to the "C" method of P0302451, followed by reaction of the iso(thio)cyanate derivative with an amine to give a solution of formula (I) Want the final product. The overall yield of Method C was very low, only 52%. The disadvantages of the A〃 and a C〃 procedures are long reaction times (48 and 20 hours) and poor yields (65% and 52%). In addition, in the "A" &"C" procedures, the final product obtained should be purified in an additional purification (recrystallization) step to give the product of the appropriate quality. SUMMARY OF THE INVENTION Our object is to develop a process for providing unsubstituted and monosubstituted and disubstituted urea compounds of formula (I) with excellent yields. We have surprisingly found that by trans 4_ {2-[4-(2,3·dichlorophenyl)-piperidin-1-yl]-ethyl}-cyclohexylamine of the formula (II1) or Salt and / or hydrate and / 201144289 or solvate

Reaction with a carbonic acid derivative of the formula (VI) RO-CO-Z (VI) wherein R is a linear or branched alkyl group, a partially or fully halogenated Cu alkyl group or a phenyl group, and Z is -0-R or - X, wherein R is as described above, X is a halogen, and then the obtained compound of the formula (IV) is obtained

R

(IV) (wherein R is as described above) is reacted with an amine derivative of the formula (V)

Ri

NH / R2 (V) wherein Ri and R2 independently represent -hydrogen, or 201144289 - a linear or branched C^6 alkyl group optionally substituted with an aryl group, or a C2.7 olefin having 1-3 double bonds Or, in the presence of one or more Ci-6 alkoxy, difluoro-Ci-6,

a monocyclic, bicyclic or tricyclic aryl group optionally substituted by Cu alkoxycarbonyl, C,-6 alkylalkyl, aryl, (6. 6 alkylthio, halogen or cyano, or optionally substituted Ring, bicyclic or tricyclic C3., 4-cycloalkyl, or -I and r2 together with adjoining nitrogen may form a randomly substituted saturated or unsaturated monocyclic or bicyclic heterocyclic ring which may be selected from Additional heteroatoms of oxygen, nitrogen or sulfur atoms, we have obtained compounds of the general formula (I) with very high yield

Wherein R! and R2 are as described above. DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a novel process for the preparation of compounds of the general formula (I) and their hydrochlorides and/or hydrates and/or solvates 201144289

Wherein 11! and r2 independently represent -hydrogen, or - a straight or branched <^_6 alkyl group optionally substituted with an aryl group, or a C2-7 alkenyl group having 1-3 double bonds, or - One or more (^_6 alkoxy, trifluoro-Cw alkoxy, C, -6 alkoxycarbonyl, Cm alkanoyl, aryl, Cm alkylthio, halogen or cyano optionally substituted a cyclic, bicyclic or tricyclic aryl group, or an optionally substituted monocyclic, bicyclic or tricyclic C3.14 cycloalkyl group, or -Ri and h together with an adjacent nitrogen may form an optionally substituted saturated or unsubstituted a saturated monocyclic or bicyclic heterocyclic ring which may contain additional heteroatoms selected from oxygen, nitrogen or sulfur atoms. In the sense of R1 and R2, 'aryl represents for example phenyl, tolyl, naphthyl or phenanthryl In carrying out the process according to the invention, trans 4_{2_[4-(2,3-chlorobenyl)-piperidinyl-p-butylethylcyclohexylamine or its salt of formula (ΙΠ) or Hydrate or solvate-9- 201144289 h2n

(III) dissolved or suspended in an inert solvent in the presence of a base and reacted with a carbonic acid derivative of the formula (VI) RO-CO-Z (VI) wherein R is a linear or branched C, -6 alkane, part Or fully dentated or phenyl 'Z is -0-R or -X ' wherein R is as described above and X is halogen to give a compound of formula (IV)

Wherein the caliper is a Ci-6 alkyl group or a fully halogenated c,.2 alkyl group. The obtained compound of the formula (IV) is then reacted with an amine of the formula (V)

NH / R2 (wherein I and r2 are as described above) gives the compound of the formula (I). The above reaction can be carried out in situ in an inert solvent or after separation of the compound of the formula (IV). -10- 201144289 Suitable solvents which can be used in the process according to the invention include inert solvents which are immiscible with water, such as toluene, dichloromethane, chlorobenzene or xylene. In a preferred embodiment of the invention, the solvent is dichloromethane. Suitable bases for use in the process according to the invention include organic bases, preferably tertiary bases such as triethylamine. In the meaning of the substituent of the carbonic acid derivative of the formula (VI), when R represents a partially halogenated alkyl group, the alkyl group may be, for example, a chloromethyl group or a chloroethyl group, and when R represents a completely halogenated alkyl group. The alkyl group can be, for example, trichloromethyl or pentachloroethyl. In a preferred embodiment of the invention, the carbonic acid derivative is chloroformate or bis-trichloromethyl carbonate. In carrying out the process according to the invention, the reaction between the compounds of the formulae (IV) and (V) can be carried out in this manner after the separation step, with the urethane compound of the formula (IV) Amine reaction of formula (V). However, due to the poor separation of the compound of the formula (IV), the above reaction is preferably carried out in such a manner that an appropriate amine of the formula (V) is added to the reaction mixture of the formulae (III) and (VI). It is carried out in an inert solvent. In the latter case, we have obtained a compound of the formula (I) in a high yield of more than 90% via the unseparated compound of the formula (IV) starting from the compound of the formula (III). According to the technical literature, the advantages of the process according to the invention are as follows: • the yield is increased from 52-6 5 % to 95%, and by obtaining an N-monosubstituted compound of the formula (I) by using this procedure, An N-disubstituted compound. The present invention relates to a preparation of trans N-{4-{2-[4-(2,3-dichlorophenyl)-indol-1-yl]-ethyl}-cyclohexyl}- of the formula (1) Urea test and its hydrochloride. -11 - 201144289 The trans-N-{4-{2-[4-(2,3-dichlorophenyl)-piperidin-1-yl]-ethylb-cyclohexyl urea of the general formula (I) is obtained. In the specific example of the present invention, the treatment of the reaction mixture is carried out in such a manner after aqueous dilution, the reaction mixture is extracted with an organic solvent and the alkali compound of the formula (1) can be isolated in a known manner. By removing the solvent. In a preferred embodiment of the invention, the base is not separated, but after aqueous dilution, the reaction mixture is acidified to pH 2 - 4 with hydrochloric acid, and then the reaction mixture is converted to an aqueous suspension by distillation and separated The hydrochloride salt of the general formula of high purity and over 90% yield. [Embodiment] The present invention is illustrated by the following non-limiting examples. Example 1 Trans-(4-{2-[4-(2,3-dichlorophenyl)-piped-1-yl]-ethylcyclohexyl)-carbamic acid methyl ester will be ό.45 The gram of the compound (111) dihydrochloride of the compound (111) was added to a mixture of 125 ml of dichloromethane and ruthenium 2.25 ml of triethylamine and the obtained thick suspension was between 2 Stir at 0 - 2 5 °C for 1 hour. The suspension thus obtained was added to a solution of 2.3 ml of methyl chloroformate in 25 ml of dichloromethane at a temperature of 5-10 °C. The reaction mixture obtained was stirred at a temperature of 20-25 < t for 3 hours' and then extracted with 3 x 150 ml (150 g) of distilled water. The organic phase was evaporated in vacuo and the residue was crystallised from methanol. In this way -12- 201144289 obtained 4. 5 grams of the title product. Yield: 7 2 % Melting point: 1 4 3 - 1 4 7. (: Example 2 trans N-(4-{2-[4-(2,3-dichlorophenylpiperazin-1-yl)hexyl)-carbamic acid isopropyl ester will be 6.45 g (0.015 mol) The second compound of formula (111) is added to 125 ml of dichloromethane and 12.25 ml of triethylamine. The thick suspension obtained is stirred at a temperature between 2 〇 25 ° C. The solution was added to a solution of 3.7 g (〇.〇3 mol) of isopropyl chloroformate in 30· at a temperature of 5-1 Torr. The mixture was stirred at a temperature between 20 and 25 °C. After 3 hours and 150 ml (150 g) of distilled water was extracted. The organic phase was taken in vacuo and the residue obtained was recrystallized from isopropanol. In this way 4.4 g of the title compound. Yield: 6 7 %

Melting point: 1 2 8 -1 3 1 °C Example 3 Trans 4-{2-[4-(2,3--Phenylphenyl)·峨哄·Bujib Ethyldimethylamine-Methylthiol The amine is added to 6.45 g (〇_〇15 mol) of the compound of the formula (m) to 125 ml of dichloromethane # 12.25 ml of triethylamine mixed with L-bib ring I acid salt (and mixed with 1 small E The liter of toluene will react with evaporation in 3x?: in the -Ν, Ν-acidate and '13- 201144289. The thick suspension obtained will be stirred at a temperature between 20-25 °C. The suspension was added to 4.9 g of bis(trichloromethyl)carbonate in a temperature of 50 ml of dichloromethane at -5 · ( -1 0 ° C) over 1 hour. The obtained reaction mixture was added. Up to 0-(-1〇). (: 13 g of dimethyl (40 ml, 0.12 mol) in 1 mL of isopropanol (IPA) under cooling, the reaction mixture was warmed during this period. 〇 ° C or less. Add 100 ml of distilled water to the stirred reaction mixture at a temperature of 0-(-5) ° C for 30 minutes. The pH of the aqueous phase is adjusted by adding concentrated hydrochloric acid to 7 - 8 and concentrate the volume under vacuum to 〖30 ml An additional 70 milliliters of water was added to the obtained reaction mixture and the mixture was vacuumed to 170 ml. The suspension was stirred at 20-25 ° C for 1 hour and the product obtained was isolated by filtration.克克物物. Yield: 9 5 % Melting point: 2 0 8 - 2 1 1 t Example 4 trans 4-{2-[4-(2,3-dichlorophenyl)-piperidin-1-yl] -ethyl dimethylamine-mercaptocyclohexylamine 4.4 g (0.011 mol) trans N-(4-{2-[4-(2,3-yl)-piperidin-1-yl]- Ethyl ethyl}-cyclohexyl)-carbamic acid methyl ester was dissolved in dichloromethane. The obtained solution was added to 1 liter of isopropanol (IPA) cooled at a temperature of 〇-1. After the gram of the solution is maintained at a temperature of 1 degree, the amine solution is maintained, and then the reaction is concentrated and concentrated under distillation to obtain the title compound: -Ν, Ν-dichlorobenzene at 120:-l〇) ° C In the amine-14- 201144289 solution (100 ml, 0.3 mol), the temperature of the reaction mixture during this period was kept below. After stirring at a temperature of 0-(-5) ° C for 30 minutes, 100 ML distilled water is added to the reaction mixture under stirring The pH of the aqueous phase was then adjusted to 7-8 by the addition of concentrated hydrochloric acid and the reaction mixture volume was concentrated to 100 mL under vacuum. An additional 70 mL of distilled water was added to the obtained reaction mixture and The mixture was concentrated to 120 mL under vacuum. The suspension was stirred at 20-25 ° C for 1 hour and the obtained product was isolated by filtration. In this way, 4.3 g of title is obtained. Compound β Yield: 9 5 %

Melting point: 2 0 8 - 2 1 1 °C Example 5 trans 4-{2-[4-(2,3-dichlorophenyl)-indol-1-yl]-ethyl bn, n_ dimethyl Baseline methionylcyclohexylamine hydrochloride 6.45 g (0.015 mol) of the dihydrochloride salt of the compound of formula (III) is added to a mixture of 125 ml of dichloromethane and 12.25 ml of triethylamine and the obtained When the thick suspension is collapsed at a temperature between 20 and 2 ° C, i / J. The suspension was added over 1 hour to between -5 - (-1 〇). A solution of 4.9 g of bis(trichloromethyl) carbonate in 50 liters of dichloromethane was added at a temperature of hydrazine. The obtained reaction mixture was added to a solution of 13 g of dimethylamine (4 ml of '0.12 mol) in 100 ml of isopropanol (IP A) cooled at a temperature of 〇 ( 将 将The temperature of the reaction mixture during this period was kept below 〇 ° C. After stirring at a temperature of 0-(-5) t: for 3 minutes, -15-201144289 100 ml of distilled water was added to the stirred reaction mixture. The ρ 水 of the aqueous phase was then adjusted to 2 · 3 by the addition of concentrated hydrochloric acid and the reaction mixture was concentrated to 1 30 mL, additional 70 mL of distilled water was added and the mixture was concentrated to 17 mL. Stirring at 20 to 5 ° C for 1 hour and the obtained product was isolated by filtration. 6.7 g of the title compound was obtained in this manner. Yield: 9 6 %

Melting point: 2 2 1 - 2 2 4 °C Example 6 trans 4-{2·[4-(2,3-dichlorophenyl)-piperidin-1-yl]-ethyl}-N,N- Dimethylamine-m-decylcyclohexylamine hydrochloride 6.72 g (0.015 mol) of the dihydrochloride monohydrate of the compound of formula (III) was added to a mixture of 125 ml of dichloromethane and 12.25 ml of triethylamine. The thick suspension obtained was stirred at a temperature between 20 and 25 ° C for 1 hour. The suspension was added over 1 hour to a solution of 4.9 g of bis(trichloromethyl)carbonate in 50 ml of dichloromethane at a temperature of -5-(-1) °C. The obtained reaction mixture was added to a solution of 13 g of dimethylamine (4 ml, 0.12 mol) in 100 ml of isopropanol (IPA) cooled at a temperature of 0-(-10) Torr. The temperature of the reaction mixture during this period was kept below 0 °C. After stirring at a temperature of 0-(-5)t for 30 minutes, 100 ml of distilled water was added to the reaction mixture and the pH of the aqueous phase was adjusted to 2 to 3 by adding concentrated hydrochloric acid. The reaction mixture was concentrated to a volume of 1 30 mL under vacuum, then an additional 70 mL of water was then weighed and concentrated -16 - 201144289 was concentrated to 170 ml. The suspension was stirred at a temperature between 20 and 25 ° C for 1 hour and the obtained product was isolated by filtration. In this manner, 6.7 g of the title compound was obtained. Yield: 9 6 %

Melting point: 2 2 1 - 2 2 4 ° C Example 7 1-trans {4-[2-[4-(2,3-dichlorophenyl)-piperidin-1-yl]-ethyl]-cyclo Hexyl}urea 6.45 g (0.015 mol) of the dihydrochloride salt of the compound (in) was added to a mixture of 160 ml of dichloromethane and 12.8 ml of triethylamine and the obtained thick suspension was between 2 Stir at 0 - 2 5 °C for 1 hour. The suspension was added over 1 hour to a solution of 4.9 g of bis(trichloromethyl)carbonate in 75 ml of dichloromethane at a temperature of _ 5 - (-1 〇) t. The obtained reaction mixture was added to an ammonia solution (11 mL, 17 g/100 ml) in methanol cooled at a temperature of 〇_ (丨〇), and the temperature of the reaction mixture during this period was kept at 0 or less. After stirring for 30 minutes at a temperature of 〇-(-5)C, the reaction mixture was concentrated under vacuum to 1 〇〇 ml, followed by the addition of 800 ml of distilled water. The suspension was stirred at 20 - 25 ° C for 1 hour and the obtained product was isolated by filtration. In this manner, 5.6 g of the title compound was obtained. Yield: 9 4 % Melting point: 22 1 -224T: -17- 201144289 Example 8 trans Ν-{4-{2-[4-(2,3·dichlorophenyl)-piperidin-1-yl] -ethylcyclohexyl}-N'-methyl urea hydrochloride 6.45 g (0.015 mol) of the dihydrochloride salt of the compound of formula (III) was added to a mixture of 125 ml of dichloromethane and 12.25 ml of triethylamine. The obtained thick suspension was stirred at a temperature of 20 to 25 ° C for 1 hour. The suspension was added over 1 hour to a solution of 4-9 g of bis(trichloromethyl)carbonate in 50 ml of dichloromethane at a temperature of -5 - (-1 0) °C. The obtained reaction mixture was added to a methylamine solution (60 ml, 12.5 g/100 ml) in isopropanol (IPA) cooled at a temperature of 〇-(-1 〇), during which time The temperature of the reaction mixture is kept below 〇〇c. After stirring at a temperature of 0-(-5) °C for 30 minutes, 130 ml of distilled water was added to the reaction mixture, and then the pH of the aqueous phase was adjusted to 2-3 by adding concentrated hydrochloric acid. The reaction mixture was concentrated to 120 mL in vacuo and an additional 70 mL distilled water was added. The suspension was stirred at a temperature of 20-25 ° C for 1 hour and the obtained product was separated by filtration. In this way 6.6 g of the title compound was obtained. Yield: 9 5 %

Melting point: 230-255 °C Example 9 trans N-{4-{2-[4-(2,3-dichlorophenyl)-piperidinyl]•ethylbucyclohexyl}urea hydrochloride · 45 g (0.015 mol) of the dihydrochloride salt of the compound of formula (m) -18- 201144289 was added to a mixture of 160 ml of dichloromethane and 12.8 ml of triethylamine and the obtained thick suspension was introduced. Stir at a temperature of 20-25 t for 1 hour. The suspension was added over 1 hour to a solution of 4.9 g of bis(trichloromethyl)carbonate in 75 ml of dichloromethane at a temperature of -5 - (-10) °C. The obtained reaction mixture was added to an ammonia solution (110 ml, 17 g/100 ml) in methanol cooled at a temperature of 0-(-10) ° C, and the temperature of the reaction mixture during this period was maintained at 0. Below °c. After stirring for 30 minutes at 〇-1 0 ° C, the reaction mixture was concentrated to 20 mL in vacuo, then 140 ml distilled water was added. The pH of the aqueous phase was adjusted to 2-3 by the addition of concentrated hydrochloric acid. The suspension was stirred at a temperature of 20-25 t for 1 hour and the obtained product was isolated by filtration. In this way, 5 · 8 6 g of the title compound was obtained. Yield: 90% Melting point: 2 5 0 - 2 5 3 ° C (decomposition) Example 1 〇trans N-{4-{2-[4-(2,3-dichlorophenyl)-piperidin-1 -yl]-ethylcyclohexyl}-morpholine-4-guanidiniumamine 6.45 g (0.015 mol) of the dihydrochloride salt of the compound (ill) was added to 125 ml of dichloromethane and 12.25 ml of triethylamine. The resulting thick suspension was stirred for 1 hour at a temperature between 20 and 25 °C. The suspension was added over 1 hour to a solution of 4.9 g of bis(trichloromethyl)carbonate in 50 ml of dichloromethane at a temperature of -5 - (-1 〇) °C. The reaction mixture thus obtained is added to a solution of 10.44 g (0.12 mol) of morpholine in 70 ml of isopropanol (IPA) cooled at -19_(_) °C of -19-201144289 °C. The temperature of the reaction mixture during this period was kept below 〇t. After stirring at 0 to 10 ° C for 30 minutes, 100 ml of distilled water was added to the stirred reaction mixture and the pH of the aqueous phase was adjusted to 7-8 by the addition of concentrated hydrochloric acid. The reaction mixture was concentrated to 130 mL under vacuo and an additional 100 mL distilled water was then weighed. The reaction mixture volume was reduced to 150 ml in vacuo. The suspension was stirred at a temperature between 20 and 25 ° C for 1 hour and the obtained product was isolated by filtration. In this manner, 6.55 g of the title compound was obtained. Yield: 9 3 % Melting point: 204-206 ° C (decomposition) Example 1 1 trans N-{4-{2-[4-(2,3-dichlorophenyl)-piped-1-yl] -ethylbucyclohexyl}-morpholin-4-guanidinium hydrochloride hydrochloride 6.45 g (〇.〇15 mol) of the compound (in) dihydrochloride salt was added to 125 ml of dichloromethane and 12.25 ml. The mixture of triethylamine was stirred and the resulting suspension was stirred at a temperature of 20 to 25 ° C for 1 hour. The suspension was added over 1 hour to a solution of 4.9 g of bis(trichloromethyl)carbonate in 50 ml of dichloromethane at a temperature of -5 - (-1 0) °C. The obtained reaction mixture was added to cool to 〇-(-1 〇). The temperature of the reaction mixture during this period was kept below 10.4 in a solution of 10.44 g (0.12 mol) of morpholine in 70 ml of isopropanol (IPA) at 温度. After stirring at 0 to 10 ° C for 30 minutes, 100 ml of distilled water was added to add 20-201144289 to the stirred reaction mixture, and then the pH of the aqueous phase was adjusted to 2-3. The reaction mixture was concentrated to 130 mL under vacuum and additional 100 mL distilled water was added. The volume of the reaction mixture was then reduced to 15 〇 ml under vacuum. The suspension was stirred at a temperature between 20 and 25 ° C for 1 hour and the obtained product was isolated by filtration. In this way, 7.1 g of the title product was obtained. Yield: 94% Melting point: 1 9 7 t (decomposition) -21 -

Claims (1)

201144289 VII. Scope of Application Patent A method for preparing a compound of the formula (I) and its hydrochloride and/or hydrate and/or solvate Wherein Ri and R2 independently represent -hydrogen, or - a straight or branched CU6 alkyl group substituted with an aryl group in total, or - a C2.7 alkenyl group having a double bond, or - one or more C, -6 alkoxy, trifluoro-(: alkoxy, Ci-6-homoxyl, C|-6 broth, aryl, C|_6 thiol, dentate or aryl Substituted monocyclic, bicyclic or tricyclic aryl, or optionally substituted monocyclic, bicyclic or tricyclic c3_14 cycloalkyl, -Ri and R2 together with adjoining nitrogen form randomly substituted or not a saturated monocyclic or bicyclic heterocyclic ring which may contain additional heteroatoms selected from oxygen, nitrogen or sulfur atoms, the process being characterized by trans- 4-{2-[4-(2) of formula (ΠΙ) ,3·dichlorophenyl)-piperazin-1-yl]-ethyl}-cyclohexylamine or a salt or hydrate or solvate thereof-22- 201144289 h2n Cl (Hi) dissolved or suspended in an inert solvent in the presence of a base followed by the addition of the carbonic acid derivative RO-CO-Z (VI) of the formula (VI) wherein R is a linear or branched (:, .6 alkyl group, Partially or completely halogenated Cm alkyl or phenyl, Z is -〇-R or -X, wherein R is as defined above, X is a halogen, and the obtained compound of the formula (IV) is 〇 (IV) (wherein R is as described above) is reacted in situ or optionally in a separated state with an amine of the formula (V), Ri NH / r2. (wherein Rt and R.2 are as described above), to obtain a compound of the formula (1) And then optionally form its hydrochloride and / or hydrate and / or solvent -23- 201144289. 2. The method of claim 1, wherein the carbonic acid derivative of the formula (VI) is a chloroformate or a bis(H chloromethyl) carbonate. 3. The method of claim 1, wherein the reaction of the compound of the formula (IV) with the compound (V) is carried out on the spot without isolating the compound of the formula (IV). -24- 201144289 Four designated representative maps: (1) The representative representative of the case is: No (2) The symbol of the representative figure is simple: No 201144289 V. If there is a chemical formula in this case, please disclose the chemical formula that best shows the characteristics of the invention. :Form (I)