WO2010070370A1 - Process for the preparation of piperazine compounds and hydrochloride salts thereof - Google Patents

Process for the preparation of piperazine compounds and hydrochloride salts thereof Download PDF

Info

Publication number
WO2010070370A1
WO2010070370A1 PCT/HU2009/000109 HU2009000109W WO2010070370A1 WO 2010070370 A1 WO2010070370 A1 WO 2010070370A1 HU 2009000109 W HU2009000109 W HU 2009000109W WO 2010070370 A1 WO2010070370 A1 WO 2010070370A1
Authority
WO
WIPO (PCT)
Prior art keywords
general formula
compound
temperature
added
optionally substituted
Prior art date
Application number
PCT/HU2009/000109
Other languages
French (fr)
Other versions
WO2010070370A8 (en
Inventor
Lászlό CZIBULA
Bálint JUHÁSZ
Éva ÁGAINÉ CSONGOR
Ferenc Sebök
János Galambos
Katalin NΌGRÁDI
Original Assignee
Richter Gedeon Nyrt.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority to JP2011541614A priority Critical patent/JP5744751B2/en
Priority to SI200930610T priority patent/SI2358691T1/en
Application filed by Richter Gedeon Nyrt. filed Critical Richter Gedeon Nyrt.
Priority to BRPI0923380A priority patent/BRPI0923380B8/en
Priority to NZ592906A priority patent/NZ592906A/en
Priority to UAA201109012A priority patent/UA102422C2/en
Priority to US13/140,281 priority patent/US8569498B2/en
Priority to CA2744073A priority patent/CA2744073C/en
Priority to MX2011006590A priority patent/MX2011006590A/en
Priority to IN2904KON2011 priority patent/IN2011KN02904A/en
Priority to PL09797146T priority patent/PL2358691T3/en
Priority to EA201170808A priority patent/EA019329B1/en
Priority to CN200980150466.7A priority patent/CN102256954B/en
Priority to AU2009329295A priority patent/AU2009329295B2/en
Priority to SG2011030962A priority patent/SG171716A1/en
Priority to RS20130147A priority patent/RS52738B/en
Priority to ES09797146T priority patent/ES2407182T3/en
Priority to DK09797146.9T priority patent/DK2358691T3/en
Priority to EP09797146.9A priority patent/EP2358691B8/en
Publication of WO2010070370A1 publication Critical patent/WO2010070370A1/en
Publication of WO2010070370A8 publication Critical patent/WO2010070370A8/en
Priority to IL212640A priority patent/IL212640A/en
Priority to HK12101213.5A priority patent/HK1160849A1/en
Priority to HRP20130394AT priority patent/HRP20130394T1/en
Priority to SM201300063T priority patent/SMT201300063B/en

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/12—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms
    • C07D295/135—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms with the ring nitrogen atoms and the substituent nitrogen atoms separated by carbocyclic rings or by carbon chains interrupted by carbocyclic rings

Definitions

  • the invention relates to a new process for the preparation of trans N- ⁇ 4- ⁇ 2-[4-(2,3- dichlorophenyl)-piperazine-l-yl]-ethyl ⁇ -cyclohexyl ⁇ -carbamide compounds of general formula (I)
  • R 1 and R 2 represent independently
  • the base form of the compounds of general formula (I) was originally disclosed in the Hungarian Patent Specification No. P0302451.
  • three reaction routes (A, B, C methods) are given for the preparation of the base form of compounds of formula (I).
  • A a suitable amine is reacted with a (thio)carbamoylchloride to give the end products of general formula (I).
  • the "A” procedure gives the product with a yield of only 65% and with very long reaction time.
  • Method B an iso(thio)cyanate is reacted with an amine compound.
  • Drawback of the "B” process is that using this procedure only the compound of general formula (I) may be prepared wherein one of the R 1 and R 2 groups represents hydrogen.
  • a suitable amine is transformed to an iso(thio)cyanate derivative then this iso(thio)cyanate derivative is reacted with an amine to give the desired end products of formula (I).
  • the total yield of Method C is very low, only 52%.
  • Drawbacks of the "A” and “C” procedures are the long reaction times (48 and 20 hours) and poor yields (65% and 52%). Besides, in the “A” and “C” procedures the end product obtained should be purified in an additional purification (recrystallization) step to give the product in suitable quality.
  • R is C 1-6 straight or branched alkyl or fully halogenated C 1-2 alkyl, Z is -O-R or -X, wherein R is as described above, X is halogen, then reacting the compound of general formula (IV) obtained
  • Ri and R 2 represent independently hydrogen or
  • R 1 and R 2 together with the adjacent nitrogen may form a saturated or unsaturated optionally substituted monocyclic or bicyclic heterocyclic ring which may contain further heteroatoms, selected from oxygen, nitrogen or sulphur atoms we get the compounds of general formula (I)
  • R 1 and R 2 are as described above with very high yield.
  • the invention relates to a new process for the preparation of compounds of general formula (I)
  • R 1 and R 2 represent independently hydrogen or
  • the aryl group represents for example phenyl, tolyl, naphthyl or phenanthryl groups.
  • R is C 1-6 alkyl with straight or branched chain or Ci -2 fully halogenated alkyl
  • Z is - O-R or -X, wherein R is as described above, X is halogen to give a compound of general formula (IV)
  • Suitable solvents which can be used in the process according to the invention include inert, water immiscible solvents, for example toluene, dichloromethane, chlorobenzene or xylene. In a preferred embodiment of the invention the solvent is dichloromethane.
  • Suitable bases which can be used in the process according to the invention include organic bases, preferably tertiary amines, for example triethylamine.
  • the alkyl group may be for example trichloromethyl or pentachloroethyl group.
  • the carbonic acid derivative is chloroformic acid ester or bis-trichloromethylcarbonate.
  • the reaction between the compounds of general formula (IV) and (V) may be carried out in such a manner, that after an isolation step the urethane compound of general formula (IV) is reacted with an amine of general formula (V).
  • the above reaction is preferably may be performed in situ in an inert solvent in such a way that an appropriate amine of general formula (V) is added to the reaction mixture of formulas of (III) and (VI). hi this latter case, starting from the compound of formula (III) via the non-isolated compound of general formula (IV) we get the compound of general formula (I) in high yield of over 90%.
  • the advantages of the process according to the invention are as follows: the yield increases from 52-65% to 95%, and by using the procedure besides the N-monosubstituted compounds of formula (I) N-disubstituted compounds can be obtained too.
  • the invention relates to a process for the preparation the trans N- ⁇ 4- ⁇ 2-[4-(2,3- dichlorophenyl)-piperazine-l-yl]-ethyl ⁇ -cyclohexyl ⁇ -carbamide base of general formula (I) and the hydrochloride salts thereof.
  • the base is not isolated but after an aqueous dilution the reaction mixture is acidified with hydrochloric acid to pH 2-4, then the reaction mixture is converted to an aqueous suspension by distillation and the hydrochloride salt of the compound of general formula (I) is isolated in high purity ad yield of over 90%.
  • the reaction mixture obtained was added to a solution of 13 g dimethylamine in 100 ml isopropyl alcohol (IPA) (40 ml, 0.12 mol) cooled at a temperature between 0-(-10)°C during which the temperature of the reaction mixture was kept under 0 0 C. After stirring at a temperature between 0-(-5)°C for 30 minutes to the reaction mixture 100 ml of distilled water was added under stirring. Then the pH of the aqueous phase was adjusted to 7-8 by adding concentrated hydrochloric acid and volume of the reaction mixture was concentrated to 130 ml under vacuum. To the reaction mixture obtained additional 70 ml of distilled water was added and the mixture was concentrated to 170 ml under vacuum. The suspension was stirred at 20-25 0 C for one hour and the product obtained was isolated by filtration.
  • IPA isopropyl alcohol
  • the reaction mixture obtained was added to a solution of 13 g dimethylamine in 100 ml isopropyl alcohol (IPA) (40 ml, 0.12 mol) cooled at a temperature between 0-(-10)°C during which the temperature of the reaction mixture was kept under 0 0 C. After stirring at a temperature between 0-(-5)°C for 30 minutes 100 ml of distilled water was added to the reaction mixture under stirring. Then the pH of the aqueous phase is adjusted to 2-3 by adding concentrated hydrochloric acid and the reaction mixture was concentrated to 130 ml, additional 70 ml of distilled water was added and the mixture was concentrated to 170 ml. The suspension was stirred at 20-25 0 C for one hour and the product obtained was isolated by filtration.
  • IPA isopropyl alcohol
  • the reaction mixture obtained was added to a solution of 13 g dimethylamine in 100 ml isopropyl alcohol (IPA) (40 ml, 0,12 mol) cooled at a temperature between 0-(-10)°C during which the temperature of the reaction mixture was kept under 0 0 C.
  • IPA isopropyl alcohol
  • 100 ml of distilled water was added and the pH of the aqueous phase was adjusted to 2-3 by adding concentrated hydrochloric acid.
  • the reaction mixture was concentrated to 130 ml under vacuum then additional 70 ml of water was added and the mixture was concentrated to 170 ml.
  • the suspension was stirred at a temperature between 20-25 0 C for one hour and the product obtained was isolated by filtration. In this manner 6.7 g of title compound was obtained. Yield: 96 %. Melting point: 221-224 0 C
  • the reaction mixture obtained was added to a solution of methylamine in isopropyl alcohol (IPA) (60 ml, 12.5 g/100 ml) cooled at a temperature between 0-(-10)°C during which the temperature of the reaction mixture was kept under 0 0 C. After stirring at a temperature between 0-(-5)°C for 30 minutes to the reaction mixture 130 ml of distilled water was added 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 vacuum and additional 70 ml of distilled water was added. The suspension was stirred at a temperature between 20-25°C for one hour and the product obtained was isolated by filtration.
  • IPA isopropyl alcohol
  • reaction mixture was added to the solution of 10.44 g (0.12 mol) morpholine in 70 ml of isopropyl alcohol (IPA) cooled at a temperature between 0-(-10)°C during which the temperature of the reaction mixture was kept under 0°C.
  • IPA isopropyl alcohol
  • 100 ml of distilled water was added under stirring and the pH of the aqueous phase was adjusted to 7-8 by adding concentrated hydrochloric acid.
  • the reaction mixture was concentrated to 130 ml under vacuum and additional 100 ml of distilled water was added. Volume of the reaction mixture was decreased to 150 ml in vacuum.
  • the suspension was stirred at a temperature between 20-25°C for one hour and the product obtained was isolated by filtration. In this manner 6.55 g of title compound was obtained. Yield: 93 %. Melting point: 204-206°C (decomp).
  • the reaction mixture obtained was added to a solution of 10.44 g of (0.12 mol) morpholine in 70 ml of isopropyl alcohol (IPA) cooled to a temperature between 0-(-10)°C during which the temperature of the reaction mixture was kept under 0°C. After stirring at 0-10 0 C for 30 minutes to the reaction mixture 100 ml of distilled water was added under stirring then the pH of the aqueous phase was adjusted to 2-3. The reaction mixture was concentrated to 130 ml under vacuum and further 100 ml of distilled water was added. Then the volume of the reaction mixture was decreased to 150 ml under vacuum. The suspension was stirred at a temperature between 20-25°C for one hour and the product obtained was isolated by filtration. In this manner 7.1 g of title product was obtained. Yield: 94 %. Melting point: 197 0 C (decomp.).

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Hydrogenated Pyridines (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

The invention relates to a new process for the preparation of compounds of general formula (I) and hydrochloric acid alts and/or hydrates and/or solvates thereof, by dissolving suspending trans 4-[2-[4-(2,3-dichlorophenyl)-piperazine1-il]-cyclohexylamine of formula (III) or a salt or a hydrate or a solvate thereof in an inert solvent in the presence 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.

Description

Process for the preparation of piperazine compounds and hydrochloride salts thereof
Technical field The invention relates to a new process for the preparation of trans N-{4-{2-[4-(2,3- dichlorophenyl)-piperazine-l-yl]-ethyl}-cyclohexyl}-carbamide compounds of general formula (I)
Figure imgf000002_0001
wherein R1 and R2 represent independently
- hydrogen or
- C1-6 alkyl with straight or branched chain optionally substituted with aryl group, or
- Ri and R2 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
- C2-7 alkenyl containing 1-3 double bonds, or
- monocyclic, bicyclic or tricyclic aril group optionally substituted with one or more Ci-6- alkoxy, trifluoro-Ci-6-alkoxy, Ci-6 alkoxycarbonyl, Ci-6 alkanoyl, aryl, Ci-6 alkylthio, cyano groups or halogen atom
- optionally substituted monocyclic, bicyclic, or tricyclic C3-I4 cycloalkyl group and hydrochloride salts and/or hydrates and/or solvates thereof. Description of the prior art
The base form of the compounds of general formula (I) was originally disclosed in the Hungarian Patent Specification No. P0302451. In the specification three reaction routes (A, B, C methods) are given for the preparation of the base form of compounds of formula (I). In the method ,,A" a suitable amine is reacted with a (thio)carbamoylchloride to give the end products of general formula (I). According to the A Method of P0302451 the "A" procedure gives the product with a yield of only 65% and with very long reaction time. According to Method B an iso(thio)cyanate is reacted with an amine compound. Drawback of the "B" process is that using this procedure only the compound of general formula (I) may be prepared wherein one of the R1 and R2 groups represents hydrogen. According to the "C" Method of P0302451 a suitable amine is transformed to an iso(thio)cyanate derivative then this iso(thio)cyanate derivative is reacted with an amine to give the desired end products of formula (I). The total yield of Method C is very low, only 52%. Drawbacks of the "A" and "C" procedures are the long reaction times (48 and 20 hours) and poor yields (65% and 52%). Besides, in the "A" and "C" procedures the end product obtained should be purified in an additional purification (recrystallization) step to give the product in suitable quality.
Brief description of the invention
Our aim was to develop a process which provides both unsubstituted and mono- and disubstituted carbamide compounds of general formula (I) with excellent yield.
We have surprisingly found that by reacting trans 4-{2-[4-(2,3-dichlorophenyl)- piperazine-1-yl] -ethyl }-cyclohexylamine of formula (III)
Figure imgf000003_0001
(III) or a salt and/or a hydrate and/or a solvate thereof with a carbonic acid derivative of general formula (VI)
R-O-CO-Z (VI)
wherein R is C1-6 straight or branched alkyl or fully halogenated C1-2 alkyl, Z is -O-R or -X, wherein R is as described above, X is halogen, then reacting the compound of general formula (IV) obtained
Figure imgf000004_0001
wherein R is as described above , with an amine derivative of general formula (V)
Ri
NH
(V)
wherein
Ri and R2 represent independently hydrogen or
- Ci-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 Ci-6 alkoxy, trifluoro-Ci-6 alkoxy, C1-6 alkoxycarbonyl, C1-6 alcanoyl, aryl, Ci-6 alkyltio, halogen, or cyano groups, or
- optionally substituted monocyclic, bicyclic or tricyclic C3-I4 cycloalkyl group, or R1 and R2 together with the adjacent nitrogen may form a saturated or unsaturated optionally substituted monocyclic or bicyclic heterocyclic ring which may contain further heteroatoms, selected from oxygen, nitrogen or sulphur atoms we get the compounds of general formula (I)
Figure imgf000005_0001
(I)
wherein R1 and R2 are as described above with very high yield.
Detailed description of the invention
The invention relates to a new process for the preparation of compounds of general formula (I)
Figure imgf000005_0002
(I)
wherein R1 and R2 represent independently hydrogen or
Ci-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 group optionally substituted with one or more C1-6 alkoxy, trifluoro-Ci-6 alkoxy, C1-6 alkoxycarbonyl, C1-6 alcanoyl, aryl, Ci-6 alkyltio, halogen, or cyano groups, or optionally substituted monocyclic, bicyclic or tricyclic C3-14 cycloalkyl group, or - R1 and R2 together with the adjacent nitrogen may 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 hydrochloride salts, and/or hydrates and/or solvates thereof.
In the meanings of Rj and R2 the aryl group represents for example phenyl, tolyl, naphthyl or phenanthryl groups.
Performing the process according to the invention the trans 4-{2-[4-(2,3- dichlorophenyl)-piperazine-l-yl] -ethyl }-cyclohexyl-amine compound of formula (III)
Figure imgf000006_0001
or a salt or a hydrate or a solvate thereof is dissolved or suspended in an inert solvent in the presence of a base and reacted with a carbonic acid derivative of general formula (VI)
R-O-CO-Z (VI)
wherein R is C1-6 alkyl with straight or branched chain or Ci-2 fully halogenated alkyl, Z is - O-R or -X, wherein R is as described above, X is halogen to give a compound of general formula (IV)
Figure imgf000007_0001
wherein R is C1-6 alkyl or fully halogenated Ci-2 alkyl group. Then the compound of general formula (IV) obtained is reacted with an amine of general formula (V)
R
NH
R2
wherein Ri and R2 are as described above to give a compound of general formula (I). The above reaction may be carried out in situ in an inert solvent or after the isolation of the compound of general formula (IV).
Suitable solvents, which can be used in the process according to the invention include inert, water immiscible solvents, for example toluene, dichloromethane, chlorobenzene or xylene. In a preferred embodiment of the invention the solvent is dichloromethane. Suitable bases, which can be used in the process according to the invention include organic bases, preferably tertiary amines, for example triethylamine.
In the substituents meanings of the carbonic acid derivatives of general formula (VI) when R represents fully halogenated alkyl group, the alkyl group may be for example trichloromethyl or pentachloroethyl group. In a preferred embodiment of the invention the carbonic acid derivative is chloroformic acid ester or bis-trichloromethylcarbonate.
Performing the process according to the invention the reaction between the compounds of general formula (IV) and (V) may be carried out in such a manner, that after an isolation step the urethane compound of general formula (IV) is reacted with an amine of general formula (V). However, owing to the bad isolability of compounds of general formula (IV) the above reaction is preferably may be performed in situ in an inert solvent in such a way that an appropriate amine of general formula (V) is added to the reaction mixture of formulas of (III) and (VI). hi this latter case, starting from the compound of formula (III) via the non-isolated compound of general formula (IV) we get the compound of general formula (I) in high yield of over 90%. hi the light of the technical literature the advantages of the process according to the invention are as follows: the yield increases from 52-65% to 95%, and by using the procedure besides the N-monosubstituted compounds of formula (I) N-disubstituted compounds can be obtained too.
The invention relates to a process for the preparation the trans N-{4-{2-[4-(2,3- dichlorophenyl)-piperazine-l-yl]-ethyl}-cyclohexyl}-carbamide base of general formula (I) and the hydrochloride salts thereof.
In an embodiment of the invention to give the trans N-{4-{2-[4-(2,3- dichlorophenyl)-piperazine-l-yl] -ethyl }-cyclohexyl} -carbamide base of general formula (I) work-up of the reaction mixture is carried out in such a manner that after an aqueous dilution the reaction mixture is extracted with an organic solvent and the base compound of formula (I) may be isolated by a known manner preferably by removing the solvent.
In a preferred embodiment of the invention the base is not isolated but after an aqueous dilution the reaction mixture is acidified with hydrochloric acid to pH 2-4, then the reaction mixture is converted to an aqueous suspension by distillation and the hydrochloride salt of the compound of general formula (I) is isolated in high purity ad yield of over 90%.
Examples
The invention is illustrated by the following non-limiting examples.
Example 1
Trans N-(4-{2-[4-(2,3-dichlorophenyl)-piperazine-l-yl]-ethyl}-cyclohexyl)-carbamic acid methylester
6.45 g (0.015 mol) of dihydrochloride of compound of formula (III) was added to a mixture of 125 ml dichloromethane and 12.25 ml triethylamine and the thick suspension obtained was stirred at a temperature between 20-250C for one hour. The so obtained suspension was added to a solution of 2.3 ml (0.03 mol) methyl chloroformate in 25 ml of dichloromethane at a temperature between 5-100C. The reaction mixture obtained was stirred at a temperature between 20-250C for 3 hours then extracted with 3x150 ml (150 g) of distilled water. The organic phase was evaporated in vacuum and the residue was recrystallized from methanol. In this manner 4.5 g of the title product was obtained. Yield: 72 %. Melting point: 143-147 0C
Example 2
Trans N-(4-{2-[4-(2,3-dichlorophenyl)-piperazine-l-yl]-ethyl}-cyclohexyI)-carbamic acid isopropylester
6.45 g (0.015 mol) of dihydrochloride of compound of formula (III) was added to a mixture of 125 ml dichloromethane and 12.25 ml of triethylamine and the thick suspension obtained was stirred at a temperature between 20-25°C-on for one hour. The suspension was added to a solution of 3.7 g (0.03 mol) of isopropyl chloroformate in 30 ml of toluene at a temperature between 5-100C. The reaction mixture was stirred at a temperature between 20-250C for 3 hours and then extracted with 3x150 ml (150 g) of distilled water. The organic phase was evaporated in vacuum and the residue obtained was recrystallized from isopropanole. In this manner 4,4 g of title compound was obtained. Yield: 67 %. Melting point: 128-1310C
Example 3
Trans 4-{2-[4-(2,3-dichlorophenyl)-piperazine-l-yl]-ethyl}-N,N-dimethylcarbamoyl- cyclohexylamine
6.45 g (0.015 mol) of dihydrochloride of compound of formula (III) was added to a mixture of 125 ml of dichloromethane and 12.25 ml of triethylamine and the thick suspension obtained was stirred at a temperature between 20-250C for one hour. The suspension was added to a solution of 4.9 g of bis(trichloromethyl)carbonate in 50 ml of dichloromethane at a temperature between -5-(-10)°C for one hour. The reaction mixture obtained was added to a solution of 13 g dimethylamine in 100 ml isopropyl alcohol (IPA) (40 ml, 0.12 mol) cooled at a temperature between 0-(-10)°C during which the temperature of the reaction mixture was kept under 00C. After stirring at a temperature between 0-(-5)°C for 30 minutes to the reaction mixture 100 ml of distilled water was added under stirring. Then the pH of the aqueous phase was adjusted to 7-8 by adding concentrated hydrochloric acid and volume of the reaction mixture was concentrated to 130 ml under vacuum. To the reaction mixture obtained additional 70 ml of distilled water was added and the mixture was concentrated to 170 ml under vacuum. The suspension was stirred at 20-250C for one hour and the product obtained was isolated by filtration.
In this manner 6.6 g of title compound was obtained. Yield: 95 % Melting point: 208-211 0C
Example 4
Trans 4-{2-[4-(2,3-dichlorophenyl)-piperazine-l-yl]-ethyl}-N,N-dimethylcarbamoyl- cyclohexylamine hydrochloride
6.45 g (0.015 mol) dihydrochloride of formula (III) was added to a mixture of 125 ml of dichloromethane and 12.25 ml of triethylamine and the thick suspension obtained was stirred at a temperature between 20-250C for one hour. The suspension was added to the solution of 4.9 g of bis(trichloromethyl)carbonate in 50 ml of dichloromethane at a temperature between -5-(-10)°C for one hour. The reaction mixture obtained was added to a solution of 13 g dimethylamine in 100 ml isopropyl alcohol (IPA) (40 ml, 0.12 mol) cooled at a temperature between 0-(-10)°C during which the temperature of the reaction mixture was kept under 00C. After stirring at a temperature between 0-(-5)°C for 30 minutes 100 ml of distilled water was added to the reaction mixture under stirring. Then the pH of the aqueous phase is adjusted to 2-3 by adding concentrated hydrochloric acid and the reaction mixture was concentrated to 130 ml, additional 70 ml of distilled water was added and the mixture was concentrated to 170 ml. The suspension was stirred at 20-250C for one hour and the product obtained was isolated by filtration.
In this manner 6.7 g of title compound was obtained. Yield: 96 % Melting point: 221 -224 0C
Example 5
Trans 4- {2- [4-(2,3-dichlorophenyl)-piperazine- 1 -yl] -ethyl}-N,N-dimethylcarbamoiI- cyclohexylamine hydrochloride
6.72 g (0.015 mol) dihydrochloride monohydrate of compound of formula (III) was added to a mixture of 125 ml of dichloromethane and 12.25 ml of triethylamine and the thick suspension obtained was stirred at a temperature between 20-25 0C for one hour. The suspension was added to the solution of 4.9 g of bis(trichloromethyl)carbonate in 50 ml of dichloromethane at a temperature between -5-(-10)°C for one hour. The reaction mixture obtained was added to a solution of 13 g dimethylamine in 100 ml isopropyl alcohol (IPA) (40 ml, 0,12 mol) cooled at a temperature between 0-(-10)°C during which the temperature of the reaction mixture was kept under 00C. After stirring at a temperature between 0-(-5)°C for 30 minutes to the reaction mixture 100 ml of distilled water was added and the pH of the aqueous phase was adjusted to 2-3 by adding concentrated hydrochloric acid. The reaction mixture was concentrated to 130 ml under vacuum then additional 70 ml of water was added and the mixture was concentrated to 170 ml. The suspension was stirred at a temperature between 20-250C for one hour and the product obtained was isolated by filtration. In this manner 6.7 g of title compound was obtained. Yield: 96 %. Melting point: 221-224 0C Example 6
1-Trans {4-[2-[4-(2,3-dichlorophenyl)-piperazine-l-yl]-ethyl]-cyclohexyl}carbamide
6.45 g (0.015 mol) dihydrochloride of compound of formula (III) was added to a mixture of 160 ml of dichloromethane and 12.8 ml of triethylamine and the thick suspension obtained was stirred at a temperature between 20-250C for one hour. The suspension was added to the solution of 4.9 g of bis(trichloromethyl)carbonate in 75 ml of dichloromethane at a temperature between -5-(-10)°C for one hour. The reaction mixture obtained was added to a solution of ammonia in methanol (110 ml, 17g/100ml) cooled at a temperature between 0-(- 10)°C during which the temperature of the reaction mixture was kept under 00C. After stirring at a temperature between 0-(-5)°C for 30 minutes the reaction mixture was concentrated to 100 ml in vacuum then 800 ml of distilled water was added. The suspension was stirred at 20- 25°C for one hour and the product obtained was isolated by filtration. In this manner 5.6 g of title compound was obtained. Yield: 94 %.
Melting point: 221-224 0C
Example 7 Trans N-{4-{2-[4-(2,3-dichlorophenyl)-piperazine-l-yl]-ethyl}-cyclohexyl}-N'- methylcarbamide hydrochloride
6.45 g (0.015 mol) dihydrochloride of compound of formula (III) was added to a mixture of 125 ml of dichloromethane and 12.25 ml of triethylamine and the thick suspension obtained was stirred at a temperature between 20-25°C for one hour. The suspension was added to the solution of 4.9 g of bis(trichloromethyl)carbonate in 50 ml of dichloromethane at a temperature between -5-(-10)°C for one hour. The reaction mixture obtained was added to a solution of methylamine in isopropyl alcohol (IPA) (60 ml, 12.5 g/100 ml) cooled at a temperature between 0-(-10)°C during which the temperature of the reaction mixture was kept under 00C. After stirring at a temperature between 0-(-5)°C for 30 minutes to the reaction mixture 130 ml of distilled water was added 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 vacuum and additional 70 ml of distilled water was added. The suspension was stirred at a temperature between 20-25°C for one hour and the product obtained was isolated by filtration.
In this manner 6.6 g of title compound was obtained.
Yield: 95 %.
Melting point: 230-255 0C.
Example 8 Trans N-{4-{2-[4-(2,3-dichlorophenyl)-piperazine-l-yl]-ethyl}-cyclohexylcarbamide hydrochloride
6.45 g (0.015 mol) dihydrochloride of compound of formula (III) was added to a mixture of 160 ml of dichloromethane and 12.8 ml of triethylamine and the thick suspension obtained was stirred at a temperature between 20-25°C for one hour. The suspension was added to a solution of 4.9 g of bis(trichloromethyl)carbonate in 75 ml of dichloromethane at a temperature between -5-(-10)°C for one hour. The raction mixture obtained was added to a solution of ammonia in methanol (110 ml, 17 g/ 100 ml) cooled at a temperature between 0-(- 10)°C during which the temperature of the reaction mixture was kept under 00C. After stirring at 0-10°C for 30 minutes the reaction mixture was concentrated to 20 ml in vacuum then 140 ml of distilled water was added. The pH of the aqueous phase was adjusted to 2-3 by adding concentrated hydrochloric acid. The suspension was stirred at a temperature between 20- 25°C for one hour and the product obtained was isolated by filtration. In this manner 5.86 g of title compound was obtained. Yield: 90%.
Melting point: 250-253 °C (decomp.). Example 9
Trans N-{4-{2-[4-(2,3-dichlorophenyl)-piperazine-l-yl]-ethyl}-cyclohexyl}-morpholine-4- carbonic amide
6.45 g (0.015 mol) dihydrochloride of compound of formula (III) was added to a mixture of 125 ml of dichloromethane and 12.25 ml of triethylamine and the thick suspension obtained was stirred at a temperature between 20-250C for one hour. The suspension was added to a solution of 4.9 g of bis(trichloromethyl)carbonate in 50 ml of dichloromethane at a temperature between -5-(-10) °C for one hour. The so obtained reaction mixture was added to the solution of 10.44 g (0.12 mol) morpholine in 70 ml of isopropyl alcohol (IPA) cooled at a temperature between 0-(-10)°C during which the temperature of the reaction mixture was kept under 0°C. After stirring at 0-10°C for 30 minutes to the reaction mixture 100 ml of distilled water was added under stirring and the pH of the aqueous phase was adjusted to 7-8 by adding concentrated hydrochloric acid. The reaction mixture was concentrated to 130 ml under vacuum and additional 100 ml of distilled water was added. Volume of the reaction mixture was decreased to 150 ml in vacuum. The suspension was stirred at a temperature between 20-25°C for one hour and the product obtained was isolated by filtration. In this manner 6.55 g of title compound was obtained. Yield: 93 %. Melting point: 204-206°C (decomp).
Example 10
Trans N-{4-{2-[4-(2,3-dichlorophenyl)-piperazine-l-yl]-ethyl}-cyclohexyl}-morpholine-4- carbonic amide hydrochloride
6.45 g (0.015 mol) dihydrochloride of compound of formula (III) was added to a mixture of 125 ml dichloromethane and 12.25 ml of triethylamine and the thick suspension obtained was stirred at a temperature between 20-250C for one hour. The suspension was added to a solution of 4.9 g of bis(trichloromethyl)carbonate in 50 ml of dichloromethane ata temperature between -5-(-1O)0C for one hour. The reaction mixture obtained was added to a solution of 10.44 g of (0.12 mol) morpholine in 70 ml of isopropyl alcohol (IPA) cooled to a temperature between 0-(-10)°C during which the temperature of the reaction mixture was kept under 0°C. After stirring at 0-100C for 30 minutes to the reaction mixture 100 ml of distilled water was added under stirring then the pH of the aqueous phase was adjusted to 2-3. The reaction mixture was concentrated to 130 ml under vacuum and further 100 ml of distilled water was added. Then the volume of the reaction mixture was decreased to 150 ml under vacuum. The suspension was stirred at a temperature between 20-25°C for one hour and the product obtained was isolated by filtration. In this manner 7.1 g of title product was obtained. Yield: 94 %. Melting point: 197 0C (decomp.).

Claims

Claims
1. Process for the preparation of compounds of general formula (I)
Figure imgf000016_0001
(I) wherein R1 and R2 represent independently hydrogen or
- Cj-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 C 1-6 alkoxy, trifluoro-C1-6 alkoxy, C1-6-alkoxycarbonil, Ci-6alkanoyl, aryl, C1-6 alkylthio, halogen or cyano, or
- optionally substituted monocyclic, bicyclic or tricyclic C3-14 cycloalkyl group,
- Ri 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 characterized in that dissolving or suspending trans 4-{2-[4-(2,3-dichlorophenyl)-piperazine-l-il]-ethyl}- cyclohexylamine of formula (III)
Figure imgf000016_0002
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 C 1-6 straight or branched chain or Ci-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
Figure imgf000017_0001
wherein R is as described above, in situ or, optionally in isolated state with an amine of general formula (V)
R
NH
R2 wherein Rj 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.
2. A process according to claim 1 characterized in that the carbonic acid derivative of general formula (VI) is a chloro formate ester or bis(trichloromethyl)carbonate.
3. A process according to claim 1 characterized in that the reaction of compounds of general formula (IV) and (V) is carried out in situ without isolation of the compound of general formula (IV).
PCT/HU2009/000109 2008-12-18 2009-12-18 Process for the preparation of piperazine compounds and hydrochloride salts thereof WO2010070370A1 (en)

Priority Applications (22)

Application Number Priority Date Filing Date Title
AU2009329295A AU2009329295B2 (en) 2008-12-18 2009-12-18 Process for the preparation of piperazine compounds and hydrochloride salts thereof
CN200980150466.7A CN102256954B (en) 2008-12-18 2009-12-18 Diethylenediamine compound and the preparation method of hydrochlorate thereof
BRPI0923380A BRPI0923380B8 (en) 2008-12-18 2009-12-18 PROCESS FOR PREPARATION OF TRANS COMPOUNDS OF N-{4-{2-[4-(2,3-DICHLOROPHENYL)-PIPERAZINE-1-YL]-ETHYL}-CYCLOHEXYL}-CARBAMIDE AND HYDROCHLORIDE SALTS THEREOF
SI200930610T SI2358691T1 (en) 2008-12-18 2009-12-18 Process for the preparation of piperazine compounds and hydrochloride salts thereof
UAA201109012A UA102422C2 (en) 2008-12-18 2009-12-18 Process for the preparation of piperazine compounds and hydrochloride salts thereof
US13/140,281 US8569498B2 (en) 2008-12-18 2009-12-18 Process for the preparation of piperazine compounds and hydrochloride salts thereof
SG2011030962A SG171716A1 (en) 2008-12-18 2009-12-18 Process for the preparation of piperazine compounds and hydrochloride salts thereof
MX2011006590A MX2011006590A (en) 2008-12-18 2009-12-18 Process for the preparation of piperazine compounds and hydrochloride salts thereof.
IN2904KON2011 IN2011KN02904A (en) 2008-12-18 2009-12-18
PL09797146T PL2358691T3 (en) 2008-12-18 2009-12-18 Process for the preparation of piperazine compounds and hydrochloride salts thereof
EA201170808A EA019329B1 (en) 2008-12-18 2009-12-18 Process for the preparation of piperazine compounds and hydrochloride salts thereof
JP2011541614A JP5744751B2 (en) 2008-12-18 2009-12-18 Process for the preparation of piperazine compounds and their hydrochlorides
NZ592906A NZ592906A (en) 2008-12-18 2009-12-18 Process for the preparation of piperazine compounds and hydrochloride salts thereof
CA2744073A CA2744073C (en) 2008-12-18 2009-12-18 Process for the preparation of piperazine compounds and hydrochloride salts thereof
RS20130147A RS52738B (en) 2008-12-18 2009-12-18 Process for the preparation of piperazine compunds and hydrochloride salts thereof
ES09797146T ES2407182T3 (en) 2008-12-18 2009-12-18 Process for preparing piperazine compounds and hydrochloric salts thereof
DK09797146.9T DK2358691T3 (en) 2008-12-18 2009-12-18 Process for the preparation of piperazine compounds and hydrochloride salts thereof
EP09797146.9A EP2358691B8 (en) 2008-12-18 2009-12-18 Process for the preparation of piperazine compounds and hydrochloride salts thereof
IL212640A IL212640A (en) 2008-12-18 2011-05-03 Process for the preparation of piperazine compounds and hydrochloride salts thereof
HK12101213.5A HK1160849A1 (en) 2008-12-18 2012-02-08 Process for the preparation of piperazine compounds and hydrochloride salts thereof
HRP20130394AT HRP20130394T1 (en) 2008-12-18 2013-05-06 Process for the preparation of piperazine compounds and hydrochloride salts thereof
SM201300063T SMT201300063B (en) 2008-12-18 2013-06-11 Process for the preparation of piperazine compounds and their hydrochloride salts

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
HUP0800765 2008-12-18
HU0800765A HUP0800765A2 (en) 2008-12-18 2008-12-18 A new process for the preparation of piperazine derivatives and their hydrochloric salts

Publications (2)

Publication Number Publication Date
WO2010070370A1 true WO2010070370A1 (en) 2010-06-24
WO2010070370A8 WO2010070370A8 (en) 2011-04-28

Family

ID=89988674

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/HU2009/000109 WO2010070370A1 (en) 2008-12-18 2009-12-18 Process for the preparation of piperazine compounds and hydrochloride salts thereof

Country Status (28)

Country Link
US (1) US8569498B2 (en)
EP (1) EP2358691B8 (en)
JP (1) JP5744751B2 (en)
CN (1) CN102256954B (en)
AU (1) AU2009329295B2 (en)
BR (1) BRPI0923380B8 (en)
CA (1) CA2744073C (en)
CY (1) CY1113923T1 (en)
DK (1) DK2358691T3 (en)
EA (1) EA019329B1 (en)
ES (1) ES2407182T3 (en)
GE (1) GEP20125712B (en)
HK (1) HK1160849A1 (en)
HR (1) HRP20130394T1 (en)
HU (1) HUP0800765A2 (en)
IL (1) IL212640A (en)
IN (1) IN2011KN02904A (en)
MX (1) MX2011006590A (en)
NZ (1) NZ592906A (en)
PL (1) PL2358691T3 (en)
PT (1) PT2358691E (en)
RS (1) RS52738B (en)
SG (1) SG171716A1 (en)
SI (1) SI2358691T1 (en)
SM (1) SMT201300063B (en)
TW (1) TWI460164B (en)
UA (1) UA102422C2 (en)
WO (1) WO2010070370A1 (en)

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2011073705A1 (en) * 2009-12-17 2011-06-23 Richter Gedeon Nyrt. Novel process for the preparation of piperazine compounds and hydrochloride salts thereof
WO2014180165A1 (en) 2013-05-08 2014-11-13 上海医药工业研究院 Benzoisothiazole compounds and use in preparation of antipsychotic drugs
US9636344B2 (en) 2011-04-05 2017-05-02 Bayer Intellectual Property Gmbh Substituted 2,3-dihydroimidazo[1,2-C]quinazoline salts
CN108586389A (en) * 2018-06-29 2018-09-28 成都福柯斯医药技术有限公司 A kind of new method of synthesis Cariliprazine
EP4400495A1 (en) 2023-01-11 2024-07-17 Richter Gedeon Nyrt. Dopamine d3/d2 receptor modulating compounds

Families Citing this family (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
HUP0700353A2 (en) * 2007-05-18 2008-12-29 Richter Gedeon Nyrt Metabolites of (thio)carbamoyl-cyclohexane derivatives
US7875610B2 (en) * 2007-12-03 2011-01-25 Richter Gedeon Nyrt. Pyrimidinyl-piperazines useful as D3/D2 receptor ligands
EP2251011B1 (en) * 2008-02-21 2012-04-04 Richter Gedeon Nyrt. Solid preparation for oral administration
PL2317852T3 (en) 2008-07-16 2015-05-29 Richter Gedeon Nyrt Pharmaceutical formulations containing dopamine receptor ligands
HU230067B1 (en) 2008-12-17 2015-06-29 Richter Gedeon Nyrt Novel piperazine salt and preparation method thereof
HUP0800766A2 (en) 2008-12-18 2010-11-29 Richter Gedeon Vegyeszet Process for the preparation of piperazine derivatives
US11274087B2 (en) 2016-07-08 2022-03-15 Richter Gedeon Nyrt. Industrial process for the preparation of cariprazine
CN110317182B (en) * 2018-03-29 2021-10-15 上虞京新药业有限公司 Preparation method of cariprazine
US11547707B2 (en) 2019-04-10 2023-01-10 Richter Gedeon Nyrt. Carbamoyl cyclohexane derivatives for treating autism spectrum disorder
CN111892556A (en) * 2019-05-06 2020-11-06 北京万全德众医药生物技术有限公司 Process for preparing cariprazine
CN110372557B (en) * 2019-08-06 2021-05-18 上海勋和医药科技有限公司 Cyclohexanamines D3/D2Partial receptor agonists
CN113912565A (en) * 2020-07-11 2022-01-11 广东东阳光药业有限公司 Novel crystal form of cariprazine and preparation method thereof

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005012266A1 (en) * 2003-08-04 2005-02-10 Richter Gedeon Vegyészeti Gyár Rt. (thio) carbamoyl-cyclohexane derivatives as d3/d2 receptor antagonists
WO2008142461A1 (en) 2007-05-18 2008-11-27 Richter Gedeon Nyrt. Metabolites of (thio)carbamoyl-cyclohexane derivatives

Family Cites Families (27)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4957921A (en) 1989-12-06 1990-09-18 Warner-Lambert Company Substituted cyclohexanols as central nervous system agents
US5047406A (en) 1989-12-06 1991-09-10 Warner-Lambert Co. Substituted cyclohexanols as central nervous system agents
ATE372966T1 (en) 1994-03-25 2007-09-15 Isotechnika Inc IMPROVED EFFECTIVENESS OF DRUGS THROUGH DEUTERATION
US6334997B1 (en) 1994-03-25 2002-01-01 Isotechnika, Inc. Method of using deuterated calcium channel blockers
US5977110A (en) 1995-09-22 1999-11-02 Warner-Lambert Company Substituted cyclohexylamines as central nervous systems agents
US6528529B1 (en) 1998-03-31 2003-03-04 Acadia Pharmaceuticals Inc. Compounds with activity on muscarinic receptors
KR100672186B1 (en) 1998-03-31 2007-01-19 아카디아 파마슈티칼스 인코포레이티드 Compounds with activity on muscarinic receptors
SE9802208D0 (en) 1998-06-22 1998-06-22 Astra Pharma Inc Novel compounds
US6489341B1 (en) 1999-06-02 2002-12-03 Sepracor Inc. Methods for the treatment of neuroleptic and related disorders using sertindole derivatives
US7122576B2 (en) 2001-02-27 2006-10-17 Plata-Salaman Carlos R Carbamate compounds for use in preventing or treating bipolar disorder
US6566550B2 (en) 2001-06-21 2003-05-20 Pfizer Inc Substituted aromatic ethers as inhibitors of glycine transport
HU227543B1 (en) 2001-09-28 2011-08-29 Richter Gedeon Nyrt N-[4-(2-piperazin- and 2-piperidin-1-yl-ethyl)-cyclohexyl]-sulfon- and sulfamides, process for their preparation, their use and pharmaceutical compositions containing them
SE0200301D0 (en) 2002-02-01 2002-02-01 Axon Biochemicals Bv Thio-carbostyril derivative
US6919342B2 (en) 2003-06-05 2005-07-19 Abbott Gmbh & Co. Kg Triazole compounds suitable for treating disorders that respond to modulation of the dopamine D3 receptor
DE102004047517A1 (en) 2004-09-28 2006-03-30 Merck Patent Gmbh Novel crystal form of (3-cyano-1H-indol-7-yl) - [4- (4-fluorophenethyl) -piperazin-1-yl] -methanone, hydrochloride
HUP0500170A3 (en) 2005-02-03 2007-11-28 Richter Gedeon Nyrt Piperazine derivatives, process for producing them and pharmaceutical compositions containing them
GT200600414A (en) 2005-09-12 2007-09-20 PIPERAZINE COMPOSITE GLUCURANATE SALT
KR20150023937A (en) 2007-05-11 2015-03-05 리히터 게데온 닐트. Novel solvate and crystalline forms of carbamoyl-cyclohexane derivatives
HU230748B1 (en) 2007-05-11 2018-02-28 Richter Gedeon Nyrt New piperazine salt and process for its preparation
HUP0700369A2 (en) 2007-05-24 2009-04-28 Richter Gedeon Nyrt Use of (thio)-carbamoyl-cyclohexane derivatives in the manufacture of a medicament for the treatment in the manufacture of a medicament for the treatment of schizophrenia
HUP0700370A2 (en) 2007-05-24 2009-04-28 Richter Gedeon Nyrt Use of (thio)-carbamoyl-cyclohexane derivatives in the manufacture of a medicament for the treatment of acute mania
MX2010001171A (en) 2007-08-01 2010-03-01 Lundbeck & Co As H Use of kncq potassium channel openers for reducing symptoms of or treating disorders or conditions wherein the dopaminergic system is disrupted.
US7875610B2 (en) 2007-12-03 2011-01-25 Richter Gedeon Nyrt. Pyrimidinyl-piperazines useful as D3/D2 receptor ligands
EP2251011B1 (en) 2008-02-21 2012-04-04 Richter Gedeon Nyrt. Solid preparation for oral administration
PL2317852T3 (en) 2008-07-16 2015-05-29 Richter Gedeon Nyrt Pharmaceutical formulations containing dopamine receptor ligands
HU230067B1 (en) 2008-12-17 2015-06-29 Richter Gedeon Nyrt Novel piperazine salt and preparation method thereof
HUP0800766A2 (en) 2008-12-18 2010-11-29 Richter Gedeon Vegyeszet Process for the preparation of piperazine derivatives

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005012266A1 (en) * 2003-08-04 2005-02-10 Richter Gedeon Vegyészeti Gyár Rt. (thio) carbamoyl-cyclohexane derivatives as d3/d2 receptor antagonists
HUP0302451A2 (en) 2003-08-04 2005-05-30 Richter Gedeon Vegyészeti Gyár Rt. (thio)carbamoyl-cyclohexane derivatives, process for producing them and pharmaceutical compositions containing them
WO2008142461A1 (en) 2007-05-18 2008-11-27 Richter Gedeon Nyrt. Metabolites of (thio)carbamoyl-cyclohexane derivatives

Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2011073705A1 (en) * 2009-12-17 2011-06-23 Richter Gedeon Nyrt. Novel process for the preparation of piperazine compounds and hydrochloride salts thereof
US9636344B2 (en) 2011-04-05 2017-05-02 Bayer Intellectual Property Gmbh Substituted 2,3-dihydroimidazo[1,2-C]quinazoline salts
US10383876B2 (en) 2011-04-05 2019-08-20 Bayer Intellectual Property Gmbh Substituted 2,3-dihydroimidazo[1,2-c]quinazoline salts
WO2014180165A1 (en) 2013-05-08 2014-11-13 上海医药工业研究院 Benzoisothiazole compounds and use in preparation of antipsychotic drugs
CN108586389A (en) * 2018-06-29 2018-09-28 成都福柯斯医药技术有限公司 A kind of new method of synthesis Cariliprazine
EP4400495A1 (en) 2023-01-11 2024-07-17 Richter Gedeon Nyrt. Dopamine d3/d2 receptor modulating compounds
WO2024150068A2 (en) 2023-01-11 2024-07-18 Richter Gedeon Nyrt. Dopamine d3/d2 receptor modulating compounds

Also Published As

Publication number Publication date
EA201170808A1 (en) 2011-12-30
RS52738B (en) 2013-08-30
CY1113923T1 (en) 2016-07-27
TWI460164B (en) 2014-11-11
WO2010070370A8 (en) 2011-04-28
BRPI0923380B1 (en) 2022-05-24
CA2744073C (en) 2016-07-12
CA2744073A1 (en) 2010-06-24
IN2011KN02904A (en) 2015-07-10
EP2358691B1 (en) 2013-03-20
HUP0800765A2 (en) 2010-11-29
SMT201300063B (en) 2013-07-09
UA102422C2 (en) 2013-07-10
HK1160849A1 (en) 2012-08-17
NZ592906A (en) 2013-07-26
JP5744751B2 (en) 2015-07-08
DK2358691T3 (en) 2013-05-21
AU2009329295A1 (en) 2010-06-24
BRPI0923380A2 (en) 2015-07-28
BRPI0923380B8 (en) 2022-07-19
CN102256954B (en) 2016-09-28
PT2358691E (en) 2013-05-22
ES2407182T3 (en) 2013-06-12
SG171716A1 (en) 2011-07-28
TW201033180A (en) 2010-09-16
JP2012512861A (en) 2012-06-07
SI2358691T1 (en) 2013-07-31
US8569498B2 (en) 2013-10-29
EP2358691A1 (en) 2011-08-24
HU0800765D0 (en) 2009-03-02
EP2358691B8 (en) 2013-05-01
IL212640A0 (en) 2011-07-31
HRP20130394T1 (en) 2013-06-30
IL212640A (en) 2014-06-30
PL2358691T3 (en) 2013-08-30
EA019329B1 (en) 2014-02-28
MX2011006590A (en) 2011-07-12
GEP20125712B (en) 2012-12-10
AU2009329295B2 (en) 2014-02-06
CN102256954A (en) 2011-11-23
US20110275804A1 (en) 2011-11-10

Similar Documents

Publication Publication Date Title
EP2358691B1 (en) Process for the preparation of piperazine compounds and hydrochloride salts thereof
JP2012512861A5 (en)
TWI382973B (en) Process
US20040167157A1 (en) Process for preparation of amidine derivatives
US20110269959A1 (en) Process for the preparation of piperazine derivatives
HU227074B1 (en) An optically active carbamic acid derivative, method for producing the same and use as a pharmaceutical intermediate
WO2011073705A1 (en) Novel process for the preparation of piperazine compounds and hydrochloride salts thereof
JP3850838B2 (en) Process for producing trans-4-amino-1-cyclohexanecarboxylic acid derivative
RU2272036C2 (en) Method for preparing mesylate derivatives of piperazine
CS198297B2 (en) Method of producing derivatives of urea
KR920000895B1 (en) Process for the production of indoles
EP2062881A1 (en) Process for making N-(diphenylmethyl)piperazines
US20060183903A1 (en) Piperazine derivatives and their use as synthesis intermediates
US6172228B1 (en) Process for producing piperazinesulfonamide derivatives and salts thereof
SU450402A3 (en) The method of obtaining the basic alkyl esters of thiol-carbamic acid
JP2001089451A (en) Production of aminopyridines
WO2012101475A1 (en) An improved process for the preparation of antihistaminic drugs via a novel carbamate intermediate

Legal Events

Date Code Title Description
WWE Wipo information: entry into national phase

Ref document number: 200980150466.7

Country of ref document: CN

121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 09797146

Country of ref document: EP

Kind code of ref document: A1

WWE Wipo information: entry into national phase

Ref document number: 212640

Country of ref document: IL

WWE Wipo information: entry into national phase

Ref document number: 2009329295

Country of ref document: AU

Ref document number: 2744073

Country of ref document: CA

Ref document number: 592906

Country of ref document: NZ

Ref document number: 2009797146

Country of ref document: EP

ENP Entry into the national phase

Ref document number: 2009329295

Country of ref document: AU

Date of ref document: 20091218

Kind code of ref document: A

WWE Wipo information: entry into national phase

Ref document number: 2011541614

Country of ref document: JP

Ref document number: MX/A/2011/006590

Country of ref document: MX

NENP Non-entry into the national phase

Ref country code: DE

WWE Wipo information: entry into national phase

Ref document number: 2904/KOLNP/2011

Country of ref document: IN

WWE Wipo information: entry into national phase

Ref document number: 201170808

Country of ref document: EA

ENP Entry into the national phase

Ref document number: 12301

Country of ref document: GE

Kind code of ref document: P

WWE Wipo information: entry into national phase

Ref document number: a201109012

Country of ref document: UA

WWE Wipo information: entry into national phase

Ref document number: 13140281

Country of ref document: US

REG Reference to national code

Ref country code: BR

Ref legal event code: B01A

Ref document number: PI0923380

Country of ref document: BR

WWE Wipo information: entry into national phase

Ref document number: P-2013/0147

Country of ref document: RS

ENP Entry into the national phase

Ref document number: PI0923380

Country of ref document: BR

Kind code of ref document: A2

Effective date: 20110620