US 2015036.1099A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2015/0361099 A1 COUGHLN et al. (43) Pub. Date: Dec. 17, 2015 (54) PROCESSES FOR MAKING ALKYLATED (52) U.S. Cl. ARYLPPERAZINE AND ALKYLATED CPC ............ C07D 519/00 (2013.01); C07D 417/08 ARYLPPERDINE COMPOUNDS (2013.01); C07D 261/20 (2013.01); C07D INCLUDING NOVELINTERMEDIATES 209/56 (2013.01); C07D 417/12 (2013.01); C07D 215/227 (2013.01); C07D401/12 (71) Applicant: Johnson Matthey Public Limited (2013.01); C07D 403/12 (2013.01); C07D Company, London (GB) 275/06 (2013.01); C07D 311/20 (2013.01); C07D 413/12 (2013.01) (72) Inventors: Daniel J. COUGHILIN, Mullica Hill, NJ (US); Jeremy C. Wilt, Marlborough, MA (US); Da-Ming GOU, Burlington, (57) ABSTRACT MA (US) Novel processes, and intermediates, for making alkylated (21) Appl. No.: 14/737,599 arylpiperazine and alkylated arylpiperidine compounds of the general formulas (I) and (VII), respectively (22) Filed: Jun. 12, 2015 Related U.S. Application Data (I) (60) Provisional application No. 62/012,701, filed on Jun. 16, 2014. y - N-Air, Publication Classification R R2 (51) Int. Cl. (VII) C07D 519/00 (2006.01) CO7D 26L/20 (2006.01) C07D 209/56 (2006.01) C07D 417/12 (2006.01) R R2 CO7D 413/2 (2006.01) CO7D 40/12 (2006.01) CO7D 403/2 (2006.01) wherein, R and R are individually selected from hydrogen, C07D 275/06 (2006.01) alkyl, substituted or alkyl; n=0, 1, or 2: Y-NRR, ORs, or CO7D 3L/20 (2006.01) SRs, where R and Ra are individually selected from acyl or CO7D 417/08 (2006.01) sulfonyl, and where Rs is aryl or heteroaryl, or heterocyclic; C07D 215/227 (2006.01) and Ar is an aryl, heteroaryl, or heterocyclic compound. US 2015/0361099 A1 Dec. 17, 2015 PROCESSES FOR MAKING ALKYLATED ARYLPPERAZINE AND ALKYLATED (I) ARYLPPERDINE COMPOUNDS INCLUDING NOVELINTERMEDIATES Y ( N NHAir CROSS-REFERENCE TO RELATED ) (TV / APPLICATIONS R R 0001. This application claims priority of U.S. Provisional (VII) Patent Application No. 62/012,701, filed Jun. 16, 2014, the disclosures of which are incorporated herein by reference in their entireties for all purposes. R R2 FIELD OF THE INVENTION 0002 The present disclosure provides processes for mak wherein, R and R are individually selected from hydrogen, ing alkylated arylpiperazine and alkylated arylpiperidine unsubstituted alkyl, and Substituted alkyl, or R and R2 are compounds as well as novel intermediate compounds formed connected to form a 5 to 8 carbon cyclic ring; n is 0, 1, or 2; during those processes. Y is NRR, ORs, or SRs, where R and R are individually selected from acyl or Sulfonyl, wherein R and R may be BACKGROUND OF THE INVENTION connected to form a substituted or unsubstituted cyclic or 0003. The piperazines are a broad class of chemical com bicyclic ring, and wherein Rs is aryl or heteroaryl, or hetero pounds, many with important pharmacological properties, cyclic; and Ar is an aryl or heteroaryl group. which contain a core piperazine functional group. Many cur 0007 Novel intermediate compounds, made during the rently notable pharmaceutical drugs contain a piperazine ring processes described and claimed herein, are also disclosed. as part of their molecular structure. Examples include: anti anginals (ranolazine, trimetazidine); antidepressants (amox BRIEF DESCRIPTION OF THE DRAWINGS apine, befuraline, buspirone, flesinoxan, gepirone, ipsa 0008 No drawings. pirone, nefazodone, piberaline, tandospirone, traZodone, villazodone, Zalospirone); antihistamines (buclizine, mecloz DETAILED DESCRIPTION OF THE INVENTION ine, cinnarizine, cyclizine, hydroxy Zine, cetirizine, levoceti rizine, niaprazine); antipsychotics (fluphenazine, perphena Definitions Zine, trifluoperazine, prochlorperazine, thiothixene, 0009. Unless otherwise stated, the following terms used in flupentiXol, Zuclopenthixol, amperozide, aripiprazole, lurasi this application, including the specification and claims, have done, clozapine, olanzapine, peroSpirone, Ziprasidone); uro the definitions given below. It must be noted that, as used in logicals (sildenafil. Vardenafil). the specification and the appended claims, the singular forms 0004 Piperidine is also widely used building block and “a”, “an and “the include plural referents unless the context chemical reagent in the synthesis of organic compounds, clearly dictates otherwise. including pharmaceuticals. Similar to piperazine, piperidine 0010 All numerical designations, such as, weight, pH, and its derivatives are ubiquitous building blocks in the Syn temperature, time, concentration, and molecular weight, thesis of pharmaceuticals and fine chemicals. For example, including ranges, are approximations which are varied by the piperidine structure is found in the following classes of 10%. It is to be understood, although not always explicitly pharmaceuticals: SSRI (selective serotonin reuptake inhibi stated, that all numerical designations are preceded by the tors) (paroxetine); analeptics/nootropics (stimulants) (meth term “about.” It also is to be understood, although not always ylphenidate, ethylphenidate, pipradrol, desoxypipradrol); explicitly stated, that the reagents described herein are merely SERM (selective estrogen receptor modulators) (raloxifene); exemplary and that equivalents of Such are known in the art. vasodilators (minoxidil); neuroleptics (antipsychotics) (ris 0011. In reference to the present disclosure, the technical peridone, thioridazine, haloperidol, droperidol, and scientific terms used in the descriptions herein will have mesoridazine); opioids (pethidine, meperidine, loperamide). the meanings commonly understood by one of ordinary skill 0005 Considering their prevalence in the formation of a in the art, unless specifically defined otherwise. Accordingly, variety of important pharmaceutical compounds, there is a the following terms are intended to have the following mean need for new and improved processes for making both pip ings. erazine and piperidine compounds, including intermediates 0012 Compounds described herein can comprise one or and derivatives thereof, that minimizes the formation of more asymmetric centers, and thus can exist in various iso unwanted by-products and eliminates the need for additional meric forms, e.g., enantiomers and/or diastereomers. purification steps where product is lost. 0013 For example, the compounds described herein can be in the form of an individual enantiomer, diastereomer or SUMMARY OF THE INVENTION geometric isomer, or can be in the form of a mixture of 0006. The present disclosure provides processes for mak Stereoisomers, including racemic mixtures and mixtures ing alkylated arylpiperazine and alkylated arylpiperidine enriched in one or more stereoisomer. Isomers can be isolated compounds, including intermediates and derivatives thereof. from mixtures by methods known to those skilled in the art, More specifically, the present invention provides processes including chiral high pressure liquid chromatography for making a variety of alkylated arylpiperazine and alkylated (HPLC) and the formation and crystallization of chiral salts: arylpiperidine compounds of the general formulas (I) and or preferred isomers can be prepared by asymmetric synthe (VII), respectively, ses. The invention additionally encompasses compounds US 2015/0361099 A1 Dec. 17, 2015 described herein as individual isomers substantially free of eroaryl groups that contain one or more nitrogen atoms, the other isomers, and alternatively, as mixtures of various iso point of attachment can be a carbon or nitrogen atom, as CS. Valency permits. Heteroaryl bicyclic ring systems can include 0014 When a range of values is listed, it is intended to one or more heteroatoms in one or both rings. “Heteroaryl' encompass each value and Sub-range within the range. For includes ring systems wherein the heteroaryl ring, as defined example “C. alkyl is intended to encompass, C, C, C, above, is fused with one or more carbocyclic or heterocyclic C4. Cs. Co. C1-6. C1-s: C-4 C1-3. C1-2, C2-6. C2-s: C2-4 C2-3. groups wherein the point of attachment is on the heteroaryl C3-6. C3-5. C3-4 C4-6. C4. 53 and Cs-6 alkyl. ring, and in Such instances, the number of ring members 0015. As used herein, the term “alkyl means the monova continue to designate the number of ring members in the lent linear or branched Saturated hydrocarbon moiety, con heteroaryl ring system. “Heteroaryl also includes ring sys sisting solely of carbon and hydrogenatoms, having from one tems wherein the heteroaryl ring, as defined above, is fused to twelve carbon atoms. “Lower alkyl refers to an alkyl with one or more aryl groups wherein the point of attachment group of one to six carbonatoms, i.e., C-C alkyl. Examples is either on the aryl or heteroaryl ring, and in Such instances, of alkyl groups include, but are not limited to, methyl, ethyl, the number of ring members designates the number of ring propyl, isopropyl, isobutyl, sec-butyl, tert-butyl, pentyl, members in the fused (arylheteroaryl) ring system. Bicyclic n-hexyl, octyl, dodecyl, and the like. “Branched alkyl heteroaryl groups wherein one ring does not contain a het means, for example, isopropyl, isobutyl, and tert-butyl. Spe eroatom (e.g., indolyl, quinolinyl, carbazolyl, and the like) cifically included within the definition of “alkyl are those the point of attachment can be on either ring, i.e., either the aliphatic hydrocarbon chains that are optionally Substituted. ring bearing a heteroatom (e.g., 2-indolyl) or the ring that 0016. As used herein, the term “alkylene' means a linear