1,4-Cyclohexylamine Derivatives and Processes

(19) TZZ¥Z _T

(11) EP 3 057 942 B1

(12) EUROPEAN PATENT SPECIFICATION

(45) Date of publication and mention (51) Int Cl.: of the grant of the patent: C07D 233/61 (2006.01) C07C 275/26 (2006.01) 14.06.2017 Bulletin 2017/24 C07D 295/033 (2006.01) C07D 295/04 (2006.01) C07D 295/135 (2006.01) (21) Application number: 14806411.6 (86) International application number: (22) Date of filing: 14.10.2014 PCT/IB2014/065293

(87) International publication number: WO 2015/056164 (23.04.2015 Gazette 2015/16)

(54) 1,4-CYCLOHEXYLAMINE DERIVATIVES AND PROCESSES FOR THE PREPARATION THEREOF 1,4-CYCLOHEXYLAMINDERIVATE UND VERFAHREN ZUR HERSTELLUNG DAVON DÉRIVÉS DE 1,4-CYCLOHEXYLAMINE ET LEURS PROCÉDÉS DE PRÉPARATION

(84) Designated Contracting States: (56) References cited: AL AT BE BG CH CY CZ DE DK EE ES FI FR GB WO-A1-2005/012266 WO-A1-2010/070369 GR HR HU IE IS IT LI LT LU LV MC MK MT NL NO PL PT RO RS SE SI SK SM TR • VA GAI-CSONGOR ET AL: "Discovery of cariprazine (RGH-188): A novel antipsychotic (30) Priority: 14.10.2013 IT MI20131693 acting on dopamine D/Dreceptors", BIOORGANIC & MEDICINAL CHEMISTRY (43) Date of publication of application: LETTERS, PERGAMON, AMSTERDAM, NL, vol. 24.08.2016 Bulletin 2016/34 22, no. 10, 28 March 2012 (2012-03-28), pages 3437-3440, XP028479275, ISSN: 0960-894X, DOI: (73) Proprietor: Chemo Research, S.L. 10.1016/J.BMCL.2012.03.104 [retrieved on 28050 Madrid (ES) 2012-04-04] • AGAI-CSONGOR ET AL: "Novel sulfonamides (72) Inventors: having dual dopamine D2 and D3 receptor affinity • TADDEI, Maurizio show in vivo antipsychotic efficacy with I-53035 Monteriggioni (IT) beneficial cognitive and EPS profile", • CINI, Elena BIOORGANIC & MEDICINAL CHEMISTRY I-50050 Gambassi Terme (IT) LETTERS, PERGAMON, AMSTERDAM, NL, vol. • RASPARINI, Marcello 17,no. 19, 14 September 2007(2007-09-14), pages I-28074 Ghemme (IT) 5340-5344, XP022249712, ISSN: 0960-894X, DOI: 10.1016/J.BMCL.2007.08.015 cited in the (74) Representative: Palladino, Saverio Massimo et al application Notarbartolo & Gervasi S.p.A. Corso di Porta Vittoria, 9 20122 Milano (IT)

Note: Within nine months of the publication of the mention of the grant of the European patent in the European Patent Bulletin, any person may give notice to the European Patent Office of opposition to that patent, in accordance with the Implementing Regulations. Notice of opposition shall not be deemed to have been filed until the opposition fee has been paid. (Art. 99(1) European Patent Convention). EP 3 057 942 B1

Printed by Jouve, 75001 PARIS (FR) EP 3 057 942 B1

Description

Field of the invention

5 [0001] The present invention relates to an industrially viable and advantageous process for the preparation of Car- iprazine or of intermediates useful in the synthesis thereof.

State of the art

10 [0002] N-[trans-4-[2-[4-(2,3-dichlorophenyl)piperazin-1-yl]ethyl]cyclohexyl]-N’,N’-1-dimethylurea, generally known as Cariprazine, is an antipsychotic useful in the treatment of positive and negative symptoms associated to schizophrenia

due to its ability to act as a partial agonist of dopamine receptors 2D/D3. This compound has the following chemical structure:

[0003] Due to its activity as a partial agonist, Cariprazine inhibits dopamine receptors when these are over-stimulated (performing an antagonist function) or stimulating the same receptors when the level of endogenous dopamine is too low. 25 [0004] Cariprazine also acts on 5-HT1a receptors, although its affinity towards the latter is considerably lower than that for dopamine receptors. [0005] Cariprazine and other similar compounds were first disclosed in international patent application WO 2005/012266 A1. This application describes two alternative routes of synthesis for the preparation of Cariprazine, as schematized below: 30

[0006] According to a first possibility, Cariprazine can be prepared starting from amine (A) by treatment with dimethylcarbamoyl chloride; alternatively, it is possible to treat amine (A) with triphosgene (CO(OCCl3)2) to transform it into 40 thecorresponding isocyanate (F), and reactingthe latterwith dimethyl amine. Drawbacksassociated with these processes are in the former case the high toxicity and probable cancerogenicity of dimethylcarbamoyl chloride; in the latter case, the need to use triphosgene (an extremely dangerous compound) or one of its precursor in order to prepare isocyanate ( F). [0007] The amine (A), starting compound for the procedures described in the application cited above, can be prepared according to the procedure described in international patent application WO 2003/029233 A1, schematized below, by 45 reductive amination of N-Boc protected trans-(4-aminocyclohexyl)acetaldehyde (B) with 1-(2,3-dichlorophenyl)piperazine (C) in the presence of sodium triacetoxyborohydride to yield N-Boc protected trans-4-(2-(4-(2,3-dichlorophenyl)piperazin-1-yl)ethyl)cyclohexylamine (D), which is subsequently converted into the hydrochloride salt of amine ( A) by treatment with a solution of hydrogen chloride in ethyl acetate:

[0008] The N-Boc protected trans-(4-aminocyclohexyl)acetaldehyde (B), in its turn, can be prepared starting from 4- nitrophenylacetic acid which is reduced to 4-aminocyclohexylacetic acid and subsequent separation of cis- and trans-iso-

2 EP 3 057 942 B1

mers by fractional crystallization of the hydrochloride salts of the corresponding ethyl esters, as described in international patent application WO 2010/070368 A1. Ester E( ), with the desired stereochemistry, is then converted into aldehyde (B) by protecting the amino group with di- tert-butyldicarbonate (Boc 2O)and selective reduction withdi-iso-butylaluminium hydride (Dibal-H) at -78 °C: 5

10 [0009] A drawback consists in the need to carry out said reaction at cryogenic temperatures to avoid the formation of significant amounts of the alcohol, product of over-reduction of the desired aldehyde. Performing a reaction at cryogenic temperatures at the industrial scale, although feasible, entails the use of appropriate equipments not always available in multipurpose plants. 15 [0010] An alternative procedure for the preparation of Cariprazine has been disclosed in international patent application WO 2010/070369 A1. This synthetic approach involves the reduction of ethyl ester ( G) to yield the corresponding alcohol which, activated as mesylate, is reacted with 1-(2,3-dichlorophenyl)piperazineC ) ( to yield N-Boc protected trans- 4-(2-(4-(2,3-dichlorophenyl)piperazin-1 - yl)ethyl)cyclohexylamine (D):

[0011] However, it is known that alkyl sulfonates (e.g. mesylates and tosylates) and alkyl halides, due to their alkylating properties, are considered genotoxic or potential genotoxic substances, as they can react with the DNA leading to mutations (Organic Process Research & Development (2010), 14, 1021-1026 and citations therein). 30 [0012] An innovative synthetic approach for the preparation of substituted amines by direct alkylation of alcohols, known as "hydrogen borrowing", has been recently described in ChemCatChem (2011), 3, 1853-1864. [0013] This emerging technology is very attractive from the standpoint of chemical processes sustainability because it allows the substitution of highly reactive compounds, such as alkyl halides, mesylates or tosylates with less reactive compounds, such as alcohols, further to allowing a reduction in the number of synthetic steps. 35 [0014] Since in pharmaceutical active principles very low amounts of genotoxic or potentially genotoxic substances are generally tolerated, pharmaceutical companies are strongly interested in developing processes not entailing the use of alkylating reagents, according to the "Quality by Design" approach, that is increasingly required by regulatory agencies. [0015] It is an object of the present invention to provide a method for preparing Cariprazine or intermediates useful in the synthesis thereof, characterized by high yields avoiding the use of dangerous reagents and providing the desired 40 products with a purity appropriate for use in pharmaceuticals.

Summary of the invention

[0016] These objectives are achieved with the present invention which, in a first aspect thereof, relates to a process 45 for the preparation of piperazines of general formula ( II) or salts thereof:

said process comprising the following synthetic steps:

55 a) preparing an alcohol of general formula (I)

3 EP 3 057 942 B1

5 1 wherein R is selected between -C(O)N(CH3)2 or an amine protecting group (Pg); b) directly alkylating the 1-(2,3-dichlorophenyl)piperazine (C) with the alcohol of general formula (I):

15 [0017] Suitable amine protecting groups (Pg) are the carbamates, for exampletert- butoxycarbonyl (Boc) or benzy- loxycarbonyl (Cbz).

Detailed description of the invention 20 [0018] All terms used in the present application, unless otherwise indicated, must be interpreted in their ordinary meaning as known in the field. Other more specific definitions for some terms used in the present application are given below and are intended to be applied uniformly to the entire description and claims, unless otherwise indicated. [0019] The symbol (dashed bond) present in some of the formulas of the description and the claims indicates 25 that the substituent is directed below the plane of the sheet. [0020] The symbol (wedge bond) present in some of the formulas of the description and the claims indicates that the substituent is directed above the plane of the sheet. [0021] The compounds prepared by the processes of the present invention can exist, be used or be isolated in the form of 1,4-cis or 1,4-trans-isomers of the cyclohexane. It should be understood that the processes of the present 30 invention may give rise to these isomers in purified form or mixtures thereof. The procedures for the purification and characterization of these compounds are known to the man skilled in the art and include, for example, fractional crystallization techniques or chromatography. The compounds object of the present invention preferably possess 1,4- trans relative configuration. [0022] In general, the nomenclature used in this Application is based on AUTONOM™ v.4.0, a Beilstein Institute 35 computerized system for the generation of IUPAC systematic nomenclature. If there is a discrepancy between a depicted structure and a name given to that structure, the depicted structure should be considered correct. [0023] Furthermore, if the stereochemistry of a structure or a portion of a structure is not indicated with, for example, wedge or dashed bonds, the structure or portion of the structure has to be interpreted as encompassing all of its stereoisomers. 40 [0024] It should also be understood that each compound described in the present invention can represent a salt or a co-crystal thereof. [0025] According to its most general aspect, the present invention relates to the preparation of piperazines of general formula (II) or salts thereof. [0026] The first step of the process of the invention, a), consists in the preparation of an alcohol of general formula 45 (I). This step can be performed according to three alternative routes of synthesis a.i), a.ii) and a.iii). 1 [0027] The synthetic scheme a.i) can be carried out when R = -C(O)N(CH3)2 and includes the following steps:

a.i.1) treating aminoester (IV) with carbonyldiimidazole (CDI):

55 a.i.2) converting imidazolide (V) into urea (VI) by treatment with dimethylamine or a salt thereof:

4 EP 3 057 942 B1

5 a.i.3) reducing the ester portion of urea (VI) to provide the alcohol of formula (I’):

wherein R3 is chosen among an optionally substituted linear or branched C1-C6 alkyl (e.g. methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, tert-butyl) or benzyl. Step a.i.1) includes the treatment of aminoester ( IV) (optionally in 15 the form of a salt) con CDI to obtain imidazolide (V). The N-acylation reaction is normally carried out in an aprotic polar solvent, e.g. dimethylacetamide, dimethylformamide, N-methylpyrrolidone, dimethylsulfoxide, tetrahydrofuran, acetonitrile, ethyl acetate or a mixture thereof. The amount of CDI useful for the aim is between 1 and 1.5 equivalents with respect to the amount of aminoester (IV) used, preferably comprised between 1.1 and 1.3 equivalents.

20 [0028] The next step a.i.2) entails the transformation of imidazolide ( V), optionally isolated, into urea ( VI) by treatment with dimethylamine (or a salt thereof) in an aprotic polar solvent, such as for example, dimethylacetamide, dimethylformamide, N-methylpyrrolidone, ethyl acetate, tetrahydrofuran, acetonitrile, or in a chlorinated solvent, such as dichloromethane, or a mixture thereof. Dimethylamine or the salt thereof are used in a amount between 1 and 1.5 equivalents with respect to the amount of imidazolide (V) used. 25 [0029] When urea (VI) is used in the form of a salt thereof (e.g. its hydrochloride salt) it is required the addition of an organic base, such as a tertiary amine, e.g. triethylamine,N, N-diisopropylethylamine, N,N-diisopropylmethylamine, N-methylmorpholine or N,N-dicyclohexylmethylamine. The amount of base is between 1 and 2.5 equivalents with respect to the amount of the salt of dimethylamine used, preferably 2 equivalents. [0030] The last step a.i.3) entails the reduction of the ester portion of urea ( VI) to obtain the alcohol of general formula 30 (I’). This step can be carried out by treatment with a reducing agent capable to selectively reduce an ester into an alcohol in the presence of an urea, for example chosen among Dibal-H, sodium borohydride (NaBH4), calcium borohydride (Ca(BH4)2) or lithium borohydride (LiBH 4) in a amount between 1 and 5 equivalents, preferably between 2 and 3 equivalents, with respect to the amount of urea ( VI) used. When this step is carried out using Dibal-H as the reducing agent, polar or apolar aprotic solvents, such as toluene, tetrahydrofuran, dichloromethane or a mixture thereof can be used; 35 when this step is carried out with a boron-containing reducing agent, suitable solvents are ethers, such as tetrahydrofuran, optionally in mixture with an alcohol, such as methanol. [0031] The alternative synthetic scheme a.ii) can be performed when R 1 is an amino protecting group (Pg) and includes the following steps:

40 a.ii.1) protecting the amino group of aminoester (IV):

a.ii.2) reducing the ester portion of carbamate (V’) to obtain alcohol (I"):

wherein R3 and Pg have the meanings given above. 55 [0032] Step a.ii.1) includes the protection of amino group as a carbamate according to one of the procedures described in Theodora W. Green, Protective Groups in Organic Synthesis, John Wiley & Sons (1999), pages 503-550, which are herein incorporated by reference. Preferably this step can be performed by treatment withtert di--butyldicarbonate

5 EP 3 057 942 B1

(Boc2O), benzyl chloroformate (CbzCl),N- (benzyloxycarbonyloxy)succinimide (Cbz-OSu) or dibenzyl dicarbonate (Cbz2O) in an aprotic polar solvent, such as for example dimethylacetamide, dimethylformamide, N-methylpyrrolidone, ethyl acetate, tetrahydrofuran, acetonitrile, or in a chlorinated solvent, such as dichloromethane, or a mixture thereof, optionally in the presence of a tertiary amine. 5 [0033] The following step a.ii.2) entails the reduction of the ester portion of carbamate ( V’) to obtain alcohol ( I") using one of the methods known in the field, for example one of those described above to carry out step a.i.3). 1 [0034] Scheme a.iii) can be performed when R = -C(O)N(CH3)2 and includes the following steps:

a.iii.1) converting aminoester ( IV) or a salt thereof into urea ( VI) by treatment with a compound of general formula ( VII): 10

wherein R4 is imidazol-1-yl; a.iii.2) reducing the ester portion of urea ( VI) to yield alcohol (I’).

20 [0035] Step a.iii.1) includes the treatment of aminoester (IV), or a salt thereof (preferably its hydrochloride salt), with a compound of general formula (VII) to yield urea (VI). [0036] The acylation reaction is normally carried out in an aprotic polar solvent, for example one of those described above to perform step a.i.1). The amount of compound of general formula ( VII) may vary between 1 and 1.5 equivalents with respect to the amount of aminoester (IV) used, preferably 1.2 equivalents. 25 [0037] When aminoester (IV) is used in the form of a salt thereof (such as its hydrochloride) it is required the addition of an organic base such as a tertiary amine, e.g. triethylamine, N,N-diisopropylethylamine, N,N-diisopropylmethylamine, N-methylmorpholine or N,N-dicyclohexylmethylamine. The amount of base is between 1 and 5 equivalents with respect to the amount of the salt of aminoester ( IV) used, preferably 3 equivalents. [0038] The next step a.iii.2) entails the reduction of the ester portion of urea ( VI) to obtain alcohol (I’) using one of the 30 procedures described above to perform step a.i.3). [0039] The second operation of the process of the invention, b), consists in the direct alkylation of the 1-(2,3-dichlorophenyl)piperazine (C) with an alcohol of general formula (I) (in particular, with an alcohol of formulaI’ )( or (I"), as described above). [0040] The direct alkylation of the 1-(2,3-dichlorophenyl)piperazine C( ) with the alcohol I() to yield a piperazine of 35 general formula (II) is normally carried out in the presence of a catalyst comprising a transition metal, optionally in the presence of a ligand, in an apolar solvent (e.g. cyclohexane, xylene or preferably toluene) or in a protic or aprotic polar solvent (for example 1,4-dioxane, tetrahydrofuran, methyltetrahydrofuran, 1,2-dimethoxyethane,tert -butyl alcohol or preferably tert-amyl alcohol). [0041] The transition metal is preferably chosen among rhodium, nickel, palladium, platinum, iridium, ruthenium or a 40 mixture thereof and can be used in metallic form (oxidation state zero) or in the form of a salt or of a coordination complex thereof. [0042] Said transition metal can optionally be supported on a solid matrix, such as carbon, silica or alumina or an organic polymer matrix. Alternatively it can be used in the form of nanoparticles. [0043] Preferably the reaction is performed under homogenous catalysis conditions and the transition metal is used 45 in the form of a coordination complex soluble in the reaction medium, optionally coordinated with a mono- or polidentate ligand, preferably a phosphine. [0044] Useful catalysts include for example ruthenium supported on carbon, alumina or magnetite, such as 5 RuCl3*(H2O)x, Ru(OH)x/TiO2 o Ru(OH)x/Al2O3, η ( -C5Ph4O)2HRu2H(CO)4 (Shvo catalyst), [Ru(p-cymene)Cl2]2, [Ru3(CO)12], [RuH2(CO)(PPh3)3], [RuH2(PPh3)4], [RuH(CO)(PPh3)4], [RuCl2(PPh3)4], [RuHCl(CO)(PPh3)3], 50 6 [Ru(arene)Cl2]2 (wherein arene is benzene, p-cymene o mesitylene), or (( η -p-cymene)Ru(L)(Cl)][PF6] (wherein L is an N-heterocyclic carbene ligand such as for example, 3-methyl-1-(2-picolyl)imidazol-2-ylidene or 3-isopropyl-1-(2-picolyl)imidazol-2-ylidene). [0045] Alternatively the catalyst can be iridium-based, for example [Cp*IrCl 2]2, [Ir(COD)Cl]2, [Cp*Ir(NH3)3][I]2, or IrCl3 wherein COD is 1,4-cyclooctadiene and Cp* is pentamethylcyclopentadienyl. 55 [0046] In case of homogenous catalysis, said transition metal can be coordinated with a bidentate phosphine, such as dppf, DPEPhos, Xantphos or BINAP:

6 EP 3 057 942 B1

[0047] The molar amount of catalyst is comprised between 1/10000 and 1/10 with respect to the amount of alcohol of 10 general formula (I) used. [0048] The 1-(2,3-dichlorophenyl)piperazine (C) used as starting compound in the alkylation reaction is commercially available and can be prepared according to standard techniques in organic synthesis. [0049] Preferablythe alcohol used as reagent in the direct alkylation of 1-(2,3-dichlorophenyl)piperazine ( C)in operation b) of the process, is a trans-2-(4-aminocyclohexyl)ethanol of general formula (IA): 15

20 [0050] In this case, the process leads to the formation of a piperazine of general formula ( IIA) in which the substituents attached to cyclohexane ring possess 1,4-trans relative configuration:

30 [0051] In a further preferred aspect of the invention, the compounds of general formulaII" ),( reported below, are

converted into a partial agonist of D2/D3 receptors (II’), a salt or a co-crystal thereof:

[0052] The process of this preferred aspect of the invention includes the following steps: 40 b’) directly alkylating the 1-(2,3-dichlorophenyl)piperazine (C) with the alcohol of general formula ( I"):

50 c) deprotecting the compound of general formula (II"):

d) converting the piperazine of general formula (III) or a salt thereof into a partial agonist of D 2/D3 receptors (II’) by

7 EP 3 057 942 B1

treatment with a compound of general formula ( VIII):

10 [0053] Step b’) corresponds to operation b) of the process object of the most general aspect of the present invention, using, in the place of alcohol (I), the alcohol of general formula ( I"):

[0054] Step c) includes the deprotection of the compound of general formula ( II"). This step can be performed using one of the methods known to the person skilled in the art, for example one of those described in Theodora W. Green, 20 Protective Groups in Organic Synthesis, John Wiley & Sons (1999), pages 503-550, which are herein incorporated by reference. For example, this step can be carried out by treatment with phosphoric acid, trifluoroacetic acid (TFA), a solution of hydrogen chloride in water or in an organic solvent, or by treatment with formic acid. [0055] The next step d) involves the transformation of piperazine of general formula ( III) or a salt thereof into a partial

agonist of D2/D3 receptors (II’) by treatment with a compound of formula ( VIII): 25

30 2 wherein R is selected between imidazol-1-yl or -N(CH 3)2. [0056] This operation can be performed according to two alternative synthetic schemes, d.i) and d.ii). 2 [0057] Scheme d.i) can be carried out when R is -N(CH3)2, and includes the treatment of the piperazine of general formula (III) or a salt thereof with an urea of formula (VIII’): 35

[0058] This reaction can be performed for example following the procedure described above for carrying out step a.iii.1). [0059] The alternative scheme d.ii) can be performed when R 2 is imidazol-1-yl and included the following steps: 45 d.ii.1) treating the piperazine of general formula ( III) or a salt thereof with carbonyldiimidazole (compound of formula (VIII) when R2 is imidazol-1-yl):

55 d.ii.2) treating the imidazolide of general formula ( II"’) with dimethylamine or a salt thereof to obtain a partial agonist

of D2/D3 receptors (II’).

[0060] The acylation object of step d.ii.1) can be performed for example using one of the procedures described above

8 EP 3 057 942 B1

for carrying out step a.iii.1). [0061] The next step d.ii.2) entails the treatment of the imidazolide of general formula (II"’), optionally isolated, with dimethylamine (or a salt thereof) to yield a partial agonist of D 2/D3 receptors ( II’). This step can be performed for example as described above for carrying out step a.i.2). 5 [0062] Said partial agonist of D2/D3 receptors (II’) obtained by the processes object of the present invention can be converted into a salt (preferably the hydrochloride) or a co-crystal thereof in a further optional step. [0063] When the piperazines of general formula ( II), or any other of the compounds described in the present application, are obtained with a degree of chemical purity not suitable for the inclusion in a medicament, the processes object of the present invention entail a further step of purification, for example through chromatography or crystallization, optionally 10 after formation of an addition compound, such as for example a salt or a co-crystal, or by washing with an organic solvent or an aqueous solution, optionally after pH adjustment. [0064] Further aspects of the present invention are the compounds ( I’), (II"’), (V) and (VI) and their stereoisomers. [0065] The invention will be further illustrated by the following examples, in which the following abbreviations have been used: 15 Xantphos: 4,5-Bis(diphenylphosphino)-9,9-dimethylxantene; TFA: trifluoroacetic acid; CDI: 1,1’-carbonyldiimidazole; THF: tetrahydrofuran; 20 Dibal-H: di-iso-butylaluminum hydride; DMF: dimethylformamide.

Example 1

25 Preparation of trans-tert-butyl 4-(2-(4-(2,3-dichlorophenyl)piperazin-1-yl)ethyl)cyclohexyl carbamate

[0066]

[0067] Alcohol 1 (50 mg, 0.20 mmol), 1-(2,3-dichlorophenyl)piperazine (55 mg, 0.24 mmol), Ru3(CO)12 (5 mg, 7.8 mmol) and Xantphos (7 mg, 12.1 mmol) are dissolved in toluene (5 mL) and the mixture is heated to the reflux temperature of the solvent for 12 hours. After solvent evaporation, the product is purified by flash chromatography eluting with

CHCl3/MeOH 9:1. 56 mg of compound 2 are obtained (yield: 60%). 40 1 H NMR: (400 MHz, CDCl3): δ 0.98-1.05 (m, 4H), 1.19-1.21 (m, 1 H), 1.36-1.40 (m, 11 H), 1.72-1.75 (m, 2H), 1.94-1.96 (m, 2H), 2.36-2.40 (m, 2H), 2.58 (m, 4H), 3.02 (m, 4H), 3.33 (m, 1 H), 4.36 (m, 1 H), 6.90-6.93 (m, 1 H), 7.06-7.11 (m, 2H).

Example 2

45 Preparation of trans-4-(2-(4-(2,3-dichlorophenyl)piperazin-1-yl)ethyl)cyclohexylamine.

[0068]

55 [0069] Compound 2 (300 mg, 0.66 mmol) is dissolved in a 4:1 mixture of CH 2Cl2/TFA (3 mL). The mixture is allowed to react for 12 hours. After solvent evaporation, the product is purified by flash chromatography eluting with CHCl 3/MeOH 8:2. 205 mg of compound 3 are obtained (yield: 87%). 1 H NMR: (400 MHz, CDCl3): δ 1.06-1.16 (m, 2H), 1.35-1.41 (m, 3H), 1.63-1.69 (m, 2H), 1.86-2.05 (m, 4H), 3.02-3.31

9 EP 3 057 942 B1

(m, 7H), 3.44-3.47 (m, 2H), 3.63-3.67 (m, 2H), 7.08-6.09 (m, 1 H), 7.23 (m, 2H).

Example 3

5 Preparation of N-[trans-4-[2-[4-(2,3-dichlorophenyl)-1-piperazinyl]ethyl]cyclohexyl]-N’,N’-dimethyl urea.

[0070]

[0071] CDI (86 mg, 0.53 mmol) and compound 3 (170 mg, 0.48 mmol) are dissolved in a mixture of DMF (500m L) and CH3CN (1.5 mL); the resulting mixture is allowed to react at room temperature for 2 hours. After solvent evaporation, the product is purified by flash chromatography eluting with CHCl3/MeOH 9:1. 147 mg of compound4 are obtained 20 (yield: 68%). 1 H NMR: (400 MHz, CDCl3): δ 1.02-1.43 (m, 7H), 1.77-1.81 (m, 2H), 2.02-2.05 (m, 2H), 2.41 (t, J = 7.6 Hz, 2H), 2.61 (m, 4H), 3.04 (m, 4H) 3.74-3.76 (m, 1 H), 6.91-6.92 (m, 1 H), 6.99-7.11 (m, 3H), 7.46-7.49 (m, 1 H), 7.65 (s, 1 H), 8.21 (s, 1 H). 13 C NMR: (100 MHz, CDCl3): δ 31.4 (2C), 32.2 (2C), 33.3, 34.9, 50.3, 50.8 (2C), 52.9 (2C), 56.1, 116.1, 118.2, 121.4, 25 124.2, 127.0, 129.2, 134.6, 135.7, 148.1, 150.7.

[0072] Compound 4 (110 mg, 0.24 mmol) is dissolved in CH 2Cl2 (3 mL); to this solution, dimethylamine hydrochloride (19 mg, 0.24 mmol) and triethylamine (52 mg, 72 mL, 0.51 mmol) are added. The mixture is allowed to react at room temperature for 18 hours. After solvent evaporation, the product is purified by flash chromatography eluting with CHCl3/MeOH 9:1. 76 mg of Cariprazine are obtained (yield: 73%). 30 Example 4

Preparation of trans-3-(4-(2-hydroxyethyl)cyclohexyl)-1,1-dimethylurea.

35 [0073]

[0074] To a 0 °C cooled solution of compound 6 (500 mg, 1.95 mmol) in THF (20 mL), Dibal-H (solution 1 M in THF, 5.85 mL, 5.85 mmol) is added; the mixture is allowed to react for 2 hours at 0 °C. 500m L of H2O are added and the mixture is warmed to room temperature. After about 30 minutes a colloidal precipitate forms; about 500 mg of Na 2SO4 45 are added and after 30 minutes the mixture is filtered on a celite cake. After solvent evaporation, the product is purified by flash chromatography eluting with CHCl3/MeOH 9:1, obtaining 352 mg of compound 7 (yield: 84%). 1 H NMR: (400 MHz, CDCl3): δ 0.86-1.02 (m, 4H), 1.21-1.23 (m, 1 H), 1.32 (q,J = 6.8 Hz, 2H), 1.62-1.65 (m, 2H), 1.82-1.85 (m, 2H), 2.736 (s, 6H), 3.38-3.41 (m, 1H), 3.49 (q, J = 6.8 Hz, 2H), 4.27 (d, J = 7.2 Hz, 1 H). 13 C NMR: (100 MHz, CDCl3): δ 31.5 (2C), 33.0, 33.3 (2C), 35.6 (2C), 39.2, 49.4, 59.7, 157.5. 50 Example 5

Preparation of N-[trans-4-[2-[4-(2,3-dichlorophenyl)-1-piperazinyl]ethyl]cyclohexyl]-N’,N’-dimethyl urea.

55 [0075]

10 EP 3 057 942 B1

[0076] Alcohol 7 (45 mg, 0.21 mmol), 1-(2,3-dichlorophenyl)piperazine (55 mg, 0.24 mmol), Ru3(CO)12 (5 mg, 7.8 10 mmol) and Xantphos (7 mg, 12.1 mmol) are dissolved in toluene (5 mL) and the mixture is heated to the reflux temperature of the solvent for 12 hours. After solvent evaporation, the product is purified by flash chromatography eluting with CHCl3/MeOH 9:1. 46 mg of Cariprazine are obtained (yield: 52%).

Example 6 15 Preparation of ethyl trans-2-(4-(dimethylcarbamoylamino)cyclohexyl)acetate

[0077]

25 [0078] CDI (81 mg, 0.50 mmol) and compound 5 (100 mg, 0.45 mmol) are dissolved in a mixture of DMF (500m L) and CH 3CN (1.5 mL); the resulting mixture is allowed to react at room temperature for 12 hours. After solvent evaporation, the product is purified by flash chromatography eluting with CHCl 3/MeOH 9:1. 45 mg of compound 8 are obtained (yield: 36%). 30 1 H NMR: (400 MHz, CDCl 3): δ 1.02-1.31 (m, 7H), 1.66-1.78 (m, 3H), 2.00-2.02 (m, 2H), 2.15 (d, J = 7.2 Hz, 2H), 3.67-3.75 (m, 1 H), 4.06 (q, J = 7.2 Hz, 2H), 6.93 (s, 1H), 7.22 (d, J = 7.6 Hz, 1H), 7.42 (s, 1H), 8.12 (s, 1H). 13 C NMR: (100 MHz, CDCl3): δ 13.8, 31.0 (2C), 31.9 (2C), 33.4, 40.9, 49.8, 60.0, 116.1, 129.1, 135.5, 147.9, 172.6. [0079] Compound 8 (45 mg, 0.16 mmol) is dissolved in CH 2Cl2 (2 mL); to this solution, dimethylamine hydrochloride (13 mg, 0.16 mmol) and triethylamine (34 mg, 47 mL, 0.34 mmol) are added. The mixture is allowed to react at room 35 temperature for 18 hours. After solvent evaporation, the product is purified by flash chromatography eluting with

CHCl3/MeOH 9:1. 32 mg of compound 6 are obtained (yield: 78%). 1 H NMR: (400 MHz, CDCl3): δ 1.01-1.07 (m, 4H), 1.13 (t, J = 7.2 Hz, 3H), 1.62-1.67 (m, 3H), 1.87-1.89 (m, 2H), 2.06 (d, J = 6.4 Hz, 2H), 2.76 (s, 6H), 3.43-3.47 (m, 1 H), 3.39 (q, J = 7.2 Hz, 2H), 4.21 (d, J = 7.2 Hz, 1H). 13 C NMR: (100 MHz, CDCl3): δ 13.7, 31.2 (2C), 33.1 (2C), 33.7, 35.6 (2C), 41.0, 49.0, 59.6, 157.3. 172.4. 40 Example 7

Preparation of N-[trans-4-[2-[4-(2,3-dichlorophenyl)-1-piperazinyl]ethyl]cyclohexyl]-N’,N’-dimethyl urea.

45 [0080]

55 [0081] The dihydrochloride salt of compound 3 (17.0 g, 39.6 mmol) is suspended at room temperature in CH 2Cl2 (150 mL), then triethylamine (13.6 g, 134.6 mmol) and CDI (7.7 g, 47.5 mmol) are slowly added. The mixture is maintained

under stirring for 30 minutes (until complete CO 2 evolution) at room temperature, then dimethylamine hydrochloride (4.2 g, 51.5 mmol) is added, and the mixture is allowed to react at room temperature for 36 hours.

11 EP 3 057 942 B1

[0082] When the reaction is complete, the mixture is cooled to 0-5 °C and stirred for 2 hours, then it is filtered and the solid obtained is washed with water. The product is dried at 45 °C under reduced pressure yielding 14.0 g of the desired compound (yield: 83%). [0083] The solid obtained can be further crystallized by methanol, iso-propanol, acetonitrile or ethyl acetate. 5

Claims

1. Process for the preparation of piperazines of general formula (II) or salts thereof: 10

said process comprising the following synthetic steps:

a) preparing an alcohol of general formula ( I) 20

25 1 wherein R is selected between -C(O)N(CH3)2 or a protecting group of amines (Pg); b) directly alkylating 1-(2,3-dichlorophenyl)piperazine (C) with the alcohol of general formula ( I):

35 1 2. Process according to claim 1, wherein R is -C(O)N(CH3)2, and step a) is carried out according to the synthetic scheme a.i) including the following steps:

a.i.1) treating aminoester (IV) with carbonyldiimidazole (CDI): 40

45 a.i.2) converting imidazolide (V) into urea (VI) by treatment with dimethylamine or a salt thereof:

a.i.3) reducing the ester portion of urea ( VI) to yield the alcohol of formula (I’):

12 EP 3 057 942 B1

wherein R3 is chosen among a linear or branched C1-C6 alkyl and benzyl.

1 3. Process according to claim 1, wherein R is -C(O)N(CH3)2, and step a) is carried out according to the synthetic scheme a.iii) including the following steps: 5 a.iii.1) converting aminoester (IV) or a salt thereof into urea ( VI) by treating with a compound of general formula (VII):

15 wherein R4 is imidazol-1-yl; a.iii.2) reducing the ester portion of urea ( VI) to yield alcohol (I’); wherein R3 is chosen among a linear or branched C1-C6 alkyl and benzyl.

4. Process according to any one of the preceding claims, wherein step b) is carried out in the presence of a catalyst 20 comprising a transition metal, in an apolar solvent or in a protic or aprotic polar solvent.

5. Process according to claim 4, wherein the transition metal is chosen among rhodium, nickel, palladium, platinum, iridium, ruthenium or a mixture thereof and is used in metallic form or in the form of a salt or a coordination complex thereof. 25 6. Process according to any one of claims 4 and 5, wherein step b) is carried out under homogenous catalysis conditions and the transition metal is used in the form of a coordination complex soluble in the reaction medium.

7. Process according to any one of the previous claims, further comprising the following steps: 30 b’) directly alkylating 1-(2,3-dichlorophenyl)piperazine (C) with the alcohol of general formula (I"):

40 c) deprotecting the compound of general formula (II"):

d) converting the piperazine of general formula ( III) or a salt thereof into a partial agonist of D 2/D3 receptors (II’) by treatment with a compound of general formula (VIII): 50

2 wherein R is selected between imidazol-1-yl and -N(CH 3)2.

13 EP 3 057 942 B1

2 8. Process according to claim 7 wherein, when R is -N(CH 3)2, step d) is carried out according to the synthetic scheme d.i) including the treatment of the piperazine of general formula ( III) or a salt thereof with an urea of formula ( VIII’):

10 9. Process according to claim 7 wherein, when R2 is imidazol-1-yl, step d) is carried out according to the synthetic scheme d.ii) including the following steps:

d.ii.1) treating the piperazine of general formula (III) or a salt thereof with carbonyldiimidazole: 15

d.ii.2) treating the imidazolide of general formula (II"’) with dimethylamine or a salt thereof to obtain a partial

agonist of D2/D3 receptors (II’).

25 10. Process according to any one of the preceding claims, wherein the alcohol used as reagent in the alkylation reaction of 1-(2,3-dichlorophenyl)piperazine in operation b) or b’), is a trans-2-(4-aminocyclohexyl)ethanol of general formula (IA):

and said alkylation reaction leads to the formation of a piperazine of general formula ( IIA) in which the substituents 35 attached to cyclohexane ring possess 1,4-trans relative configuration:

11. 3-[4-(2-hydroxyethyl)cyclohexyl]-1,1-dimethylurea (I’):

50 12. N-[4-[2-[4-(2,3-dichlorophenyl)piperazin-1-yl]ethyl]cyclohexyl]imidazol-1-carboxamide (II"’):

13. Imidazolide of formula (V):

14 EP 3 057 942 B1

5 wherein R3 is chosen among a linear or branched C1-C6 alkyl and benzyl.

14. Urea of formula (VI):

15 wherein R3 is chosen among a linear or branched C1-C6 alkyl and benzyl.

15. Use of compounds of formula (II"’) or (V) for the preparation of Cariprazine.

20 Patentansprüche

1. Verfahren zur Herstellung von Piperazinen der allgemeinen Formel (II) oder ihren Salzen:

30 wobei das Verfahren die folgenden Syntheseschritte umfasst:

a) Herstellen eines Alkohols der allgemeinen Formel (I)

40 1 wobei R zwischen -C(O)N(CH3)2 oder einer Schutzgruppe von Aminen (Pg) ausgewählt wird; b) direktes Alkylieren von 1-(2,3-Dichlorphenyl)piperazin (C) mit dem Alkohol der allgemeinen Formel (I):

1 2. Verfahren nach Anspruch 1, wobei R -C(O)N(CH3)2 ist, und Schritt a) nach dem Syntheseschema a.i) mit den folgenden Schritten durchgeführt wird: 55 a.i.1) Behandeln von Aminoester (IV) mit Carbonyldiimidazol (CDI):

15 EP 3 057 942 B1

a.i.2) Umwandeln von Imidazolid (V) in Harnstoff (VI) durch Behandeln mit Dimethylamin oder einem seiner Salze: 10

a.i.3) Reduzieren des Esteranteils von Harnstoff (VI) unter Erhalt von Alkohol der Formel (I’):

25 wobei R3 wird unter einem linearen oder verzweigten C1-C6-Alkyl und Benzyl ausgewählt wird.

1 3. Verfahren nach Anspruch 1, wobei R -C(O)N(CH3)2 ist, und Schritt a) nach dem Syntheseschema a.iii) mit den folgenden Schritten durchgeführt wird: 30 a.iii.1) Umwandeln von Aminoester (IV) oder einem seiner Salze in Harnstoff VI( ) durch Behandeln mit einer Verbindung der allgemeinen Formel (VII):

wobei R4 Imidazol-1-yl ist; a.iii.2) Reduzieren des Esteranteils von Harnstoff (VI) unter Erhalt von Alkohol (I’); wobei R3 unter einem linearen oder verzweigten C1-C6-Alkyl und Benzyl ausgewählt wird. 45 4. Verfahren nach einem der vorhergehenden Ansprüche, wobei Schritt b) in Gegenwart eines Katalysators, der ein Übergangsmetall umfasst, in einem apolaren Lösungsmittel oder in einem protischen oder aprotischen polaren Lösungsmittel durchgeführt wird.

50 5. Verfahren nach Anspruch 4, wobei das Übergangsmetall unter Rhodium, Nickel, Palladium, Platin, Iridium, Ruthe- nium oder einer ihrer Mischungen ausgewählt wird und in meta llischer Form oder in Form eines Salzes oder eines Koordinationskomplexes davon verwendet wird.

6. Verfahren nach einem der Ansprüche 4 und 5, wobei Schritt b) unter homogenen Katalysebedingungen durchgeführt 55 wird,und das Übergangsmetall in Formeines Koordinationskomplexes verwendetwird, derin demReaktionsmedium löslich ist.

7. Verfahren nach einem der vorhergehenden Ansprüche, das ferner die folgenden Schritte umfasst:

16 EP 3 057 942 B1

b ’) direktes Alkylieren von 1-(2,3-Dichlorphenyl)piperazin (C) mit dem Alkohol der allgemeinen Formel ( I"):

c) Entschützen der Verbindung der allgemeinen Formel ( II"):

20 d) Umwandeln des Piperazins der allgemeinen Formel ( III) oder eines seiner Salze in einen partiellen Agonisten von D2/D3-Rezeptoren (II’) durch Behandeln mit einer Verbindung der allgemeinen Formel ( VIII):

30 2 wobei R zwischen Imidazol-1-yl und -N(CH3)2 ausgewählt wird.

2 8. Verfahren nach Anspruch 7, wobei, wenn R -N(CH3)2 ist, Schritt d) nach dem Syntheseschema d.i) mit dem Be- handeln des Piperazins der allgemeinen Formel ( III) oder einem seiner Salze mit einem Harnstoff der Formel ( VIII’) 35 durchgeführt wird:

45 9. Verfahren nachAnspruch 7, wobei,wenn R 2 Imidazol-1-yl ist, Schritt d) nach dem Syntheseschema d.ii) mit folgenden Schritten durchgeführt wird:

d.ii.1) Behandeln des Piperazins der allgemeinen Formel (III) oder einem seiner Salze mit Carbonyldiimidazol:

55 d.ii.2) Behandeln des Imidazolids der allgemeinen Formel ( II"’) mit Dimethylamin oder einem seiner Salze, um einen partiellen Agonisten von D2/D3-Rezeptoren (II’) zu erhalten.

17 EP 3 057 942 B1

10. Verfahren nach einem der vorhergehenden Ansprüche, wobei der Alkohol, der als Reaktant in der Alkylierungsre- aktion von 1-(2,3-Dichlorphenyl)piperazin in Vorgang b) oder b’) verwendet wird, ein trans-2-(4-Aminocyclohe- xyl)ethanol der allgemeinen Formel (IA) ist:

10 und die Alkylierungsreaktion zur Bildung eines Piperazins der allgemeinen Formel IIA( ) führt, in welchem die an den Cyclohexanring gebundenen Substituenten relative 1,4-trans-Konfiguration besitzen:

20 11. 3-[4-(2-Hydroxyethyl)cyclohexyl]-1,1-dimethylharnstoff (I’):

30 12. N-[4-[2-[4-(2,3-Dichlorphenyl)piperazin-1-yl]ethyl]cyclohexyl]imidazol-1-car-boxamid (II"’):

13. Imidazolid der Formel (V): 40

wobei R3 unter einem linearen oder verzweigten C1-C6-Alkyl und Benzyl ausgewählt ist.

50 14. Harnstoff der Formel (VI):

wobei R3 unter einem linearen oder verzweigten C1-C6-Alkyl und Benzyl ausgewählt ist.

18 EP 3 057 942 B1

15. Verwendung von Verbindungen der Formel (II"’) oder (V) zur Herstellung von Cariprazin.

Revendications 5 1. Procédé de préparation de pipérazines de formule générale (II) ou de sels de celles-ci :

ledit procédé comprenant les étapes de synthèse suivantes : 15 a) la préparation d’un alcool de formule générale (I)

1 dans laquelle R est choisi entre -C(O)N(CH3)2 ou un groupe protecteur d’amines (Pg) ; b) l’alkylation directe de la 1-(2,3-dichlorophényl)pipérazine (C) avec l’alcool de formule générale (I) : 25

1 2. Procédé selon la revendication 1, dans lequel R est -C(O)N(CH3)2, et l’étape a) est réalisée selon le schéma de synthèse a.i) comprenant les étapes suivantes : 35 a.i.1) le traitement d’un aminoester (IV) avec le carbonyldiimidazole (CDI) :

a.i.2) la conversion de l’imidazolide (V) en urée (VI) par traitement avec la diméthylamine ou un sel de celle-ci :

50 a.i.3) la réduction de la partie ester de l’urée (VI) pour donner l’alcool de formule (I’) :

3 dans laquelle R est choisi parmi un alkyle en C 1 à C6 linéaire ou ramifié et le benzyle.

19 EP 3 057 942 B1

1 3. Procédé selon la revendication 1, dans lequel R est -C(O)N(CH3)2, et l’étape a) est réalisée selon le schéma de synthèse a.iii) comprenant les étapes suivantes :

a.iii.1) la conversion de l’aminoester (IV) ou d’un sel de celui-ci en urée (VI) par traitement avec un composé 5 de formule générale (VII) :

dans laquelle R4 est un imidazol-1-yle ; a.iii.2) la réduction de la partie ester de l’urée (VI) pour donner un alcool (I’) ; 15 3 dans lequel R est choisi parmi un alkyle en C 1 à C6 linéaire ou ramifié et le benzyle.

4. Procédé selon l’une quelconque des revendications précédentes, dans lequel l’étape b) est réalisée en présence d’un catalyseur comprenant un métal de transition, dans un solvant apolaire ou dans un solvant polaire protique ou aprotique. 20 5. Procédé selon la revendication 4, dans lequel le métal de transition est choisi parmi le rhodium, le nickel, le palladium, le platine, l’iridium, le ruthénium ou un mélange de ceux-ci et est utilisé sous forme métallique ou sous la forme d’un sel ou d’un complexe de coordination de celui-ci.

25 6. Procédé selon l’une quelconque des revendications 4 et 5, dans lequel l’étape b) est réalisée dans des conditions de catalyseur homogène et le métal de transition est utilisé sous la forme d’un complexe de coordination soluble dans le milieu réactionnel.

7. Procédé selon l’une quelconque des revendications précédentes, comprenant en outre les étapes suivantes : 30 b’) l’alkylation directe de la 1-(2,3-dichlorophényl)pipérazine (C) avec l’alcool de formule générale (I") :

40 c) la déprotection du composé de formule générale (II") :

d) la conversion de la pipérazine de formule générale (III) ou d’un sel de celle-ci en un agoniste partiel des

récepteurs D2/D3 (II’) par traitement avec un composé de formule générale (VIII) : 50

2 dans laquelle R est choisi entre l’imidazol-1-yle et -N(CH3)2.

20 EP 3 057 942 B1

2 8. Procédé selon la revendication 7, dans lequel, quand R est -N(CH3)2, l’étape d) est réalisée selon le schéma de synthèse d.i) comprenant le traitement de la pipérazine de formule générale (III) ou d’un sel de celle-ci avec une urée de formule (VIII’) :

9. Procédé selon la revendication 7, dans lequel, quand R 2 est un imidazol-1-yle, l’étape d) est réalisée selon le schéma de synthèse d.ii) comprenant les étapes suivantes :

15 d.ii.1) le traitement de la pipérazine de formule générale (III) ou d’un sel de celle-ci avec le carbonyldiimidazole :

d.ii.2) le traitement de l’imidazolide de formule générale (II’’’) avec la diméthylamine ou un sel de celle-ci pour

obtenir un agoniste partiel des récepteurs D2/D3 (II’). 25 10. Procédé selon l’une quelconque des revendications précédentes, dans lequel l’alcool utilisé comme réactif dans la réaction d’alkylation de la 1-(2,3-dichlorophényl)pipérazine dans l’opération b) ou b’) est un trans-2-(4-aminocyclohexyl)éthanol de formule générale (IA) :

35 et ladite réaction d’alkylation conduit à la formation d’une pipérazine de formule générale (IIA) dans laquelle les substituants fixés au cycle cyclohexane possèdent une configuration relative 1,4-trans :

11. 3-[4-(2-Hydroxyéthyl)cyclohexyl]-1,1-diméthyl-urée (I’) : 45

50 12. N-[4-[2-[4-(2,3-Dichlorophényl)pipérazin-1-yl]éthyl]cyclohexyl]imidazol-1-carboxamide (II"’) :

21 EP 3 057 942 B1

13. Imidazolide de formule (V) :

3 dans laquelle R est choisi parmi un alkyle en C 1 à C6 linéaire ou ramifié et le benzyle.

10 14. Urée de formule (VI) :

3 dans laquelle R est choisi parmi un alkyle en C 1 à C6 linéaire ou ramifié et le benzyle.

15. Utilisation des composés de formule (II"’) ou (V) pour la préparation de la cariprazine. 20

22 EP 3 057 942 B1

REFERENCES CITED IN THE DESCRIPTION

This list of references cited by the applicant is for the reader’s convenience only. It does not form part of the European patent document. Even though great care has been taken in compiling the references, errors or omissions cannot be excluded and the EPO disclaims all liability in this regard.

Patent documents cited in the description

• WO 2005012266 A1 [0005] • WO 2010070368 A1 [0008] • WO 2003029233 A1 [0007] • WO 2010070369 A1 [0010]

Non-patent literature cited in the description

• Organic Process Research & Development, 2010, • THEODORA W. GREEN. Protective Groups in Or- vol. 14, 1021-1026 [0011] ganic Synthesis. John Wiley & Sons, 1999, 503-550 • ChemCatChem, 2011, vol. 3, 1853-1864 [0012] [0032] [0054]