# US 8,569,498 B2 · Process for the preparation of piperazine compounds and hydrochloride salts thereof

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- Number: US 8,569,498 B2
- Document ID: US8569498B2
- Status: Granted
- Kind: B2
- Application number: 13/140,281
- Filed: 2009-12-18
- Published: 2011-11-10
- Granted: 2013-10-29
- Earliest claimed: 2008-12-18
- Assignees: Richter Gedeon Nyrt.
- Applicants: Laszlo Czibula; Balint Juhasz; Eva Againe Csongor; Ferenc Sebok; Janos Galambos; Katalin Nogradi
- Inventors: Laszlo Czibula; Balint Juhasz; Eva Againe Csongor; Ferenc Sebok; Janos Galambos; Katalin Nogradi
- Web page: https://patentgrep.com/patent/US8569498B2

## CPC

- C07D 295/135: with the ring nitrogen atoms and the substituent nitrogen atoms separated by carbocyclic rings or by carbon chains interrupted by carbocyclic rings
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)

## 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 alts 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 a base then adding a carbonic acid derivative of general formula (VI) wherein R is alkyl with C1-6 straight or branched chain or C1-2 fully halogenated alkyl, 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.

## Claims

### Claim 1

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
a monocyclic, bicyclic or tricyclic C3-14 cycloalkyl group,
R1 and R2 together with the adjacent nitrogen form a saturated or unsaturated monocyclic or bicyclic heterocyclic ring which may contain further heteroatoms selected from oxygen, nitrogen, or sulphur atoms,
and hydrochloric acid salts thereof comprising 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 a base then adding a carbonic acid derivative of general formula (VI)
R—O—CO—Z (VI)
wherein R is alkyl with C1-6 straight or branched chain or C1-2 fully halogenated alkyl, 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 thereof.

### Claim 2 (depends on 1)

The process according to claim 1 wherein the carbonic acid derivative of general formula (VI) is a chloroformate ester or bis(trichloromethyl)carbonate.

### Claim 3 (depends on 1)

The process according to claim 1 wherein the reaction of compounds of general formula (IV) and (V) is carried out in situ without isolation of the compound of general formula (IV).