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1,4-Cyclohexylamine Derivatives and Processes

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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: 15 20 [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 35 [0006] According to a first possibility, Cariprazine can be prepared starting from amine (A) by treatment with dimeth- ylcarbamoyl 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)pipera- zine (C) in the presence of sodium triacetoxyborohydride to yield N-Boc protected trans-4-(2-(4-(2,3-dichlorophenyl)pip- erazin-1-yl)ethyl)cyclohexylamine (D), which is subsequently converted into the hydrochloride salt of amine ( A) by treat- ment with a solution of hydrogen chloride in ethyl acetate: 50 55 [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): 20 25 [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: 50 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): 10 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 crys- tallization techniques or chromatography. The compounds object of the present invention preferably possess 1,4- trans relative configuration.
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