AU2008248168B2 - Processes for preparing (R)-2-methylpyrrolidine and (S)-2-methylpyrrolidine and tartrate salts thereof - Google Patents
Processes for preparing (R)-2-methylpyrrolidine and (S)-2-methylpyrrolidine and tartrate salts thereof Download PDFInfo
- Publication number
- AU2008248168B2 AU2008248168B2 AU2008248168A AU2008248168A AU2008248168B2 AU 2008248168 B2 AU2008248168 B2 AU 2008248168B2 AU 2008248168 A AU2008248168 A AU 2008248168A AU 2008248168 A AU2008248168 A AU 2008248168A AU 2008248168 B2 AU2008248168 B2 AU 2008248168B2
- Authority
- AU
- Australia
- Prior art keywords
- methylpyrrolidine
- methyl
- tartrate
- phenyl
- pyrrolidin
- Prior art date
- Legal status (The legal status 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 status listed.)
- Ceased
Links
- 238000000034 method Methods 0.000 title claims description 157
- RGHPCLZJAFCTIK-RXMQYKEDSA-N (R)-2-methylpyrrolidine Chemical compound C[C@@H]1CCCN1 RGHPCLZJAFCTIK-RXMQYKEDSA-N 0.000 title claims description 70
- 230000008569 process Effects 0.000 title claims description 68
- RGHPCLZJAFCTIK-YFKPBYRVSA-N (2s)-2-methylpyrrolidine Chemical compound C[C@H]1CCCN1 RGHPCLZJAFCTIK-YFKPBYRVSA-N 0.000 title abstract description 203
- 150000003892 tartrate salts Chemical class 0.000 title description 8
- MUUWQYQRBFVTIB-UHFFFAOYSA-N 5-methyl-2,3-dihydro-1h-pyrrole Chemical compound CC1=CCCN1 MUUWQYQRBFVTIB-UHFFFAOYSA-N 0.000 claims abstract description 33
- AVAOHVDRAKDFRF-KLPPUMKISA-N (2r,3r)-2,3-dihydroxybutanedioic acid;(2r)-2-methylpyrrolidine Chemical compound C[C@@H]1CCCN1.OC(=O)[C@H](O)[C@@H](O)C(O)=O AVAOHVDRAKDFRF-KLPPUMKISA-N 0.000 claims description 165
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 152
- 239000000203 mixture Substances 0.000 claims description 123
- 239000002904 solvent Substances 0.000 claims description 107
- 239000003054 catalyst Substances 0.000 claims description 101
- 239000002585 base Substances 0.000 claims description 89
- 238000005984 hydrogenation reaction Methods 0.000 claims description 80
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical group [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 claims description 41
- 239000012458 free base Substances 0.000 claims description 35
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 35
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 claims description 33
- 150000003839 salts Chemical class 0.000 claims description 23
- 230000003287 optical effect Effects 0.000 claims description 21
- 229910052697 platinum Inorganic materials 0.000 claims description 18
- 229910052757 nitrogen Inorganic materials 0.000 claims description 17
- TXFPEBPIARQUIG-UHFFFAOYSA-N 4'-hydroxyacetophenone Chemical compound CC(=O)C1=CC=C(O)C=C1 TXFPEBPIARQUIG-UHFFFAOYSA-N 0.000 claims description 8
- XUKROCVZGZNGSI-CQSZACIVSA-N irdabisant Chemical compound C[C@@H]1CCCN1CCCOC1=CC=C(C2=NNC(=O)C=C2)C=C1 XUKROCVZGZNGSI-CQSZACIVSA-N 0.000 claims description 8
- AAILEWXSEQLMNI-UHFFFAOYSA-N 1h-pyridazin-6-one Chemical compound OC1=CC=CN=N1 AAILEWXSEQLMNI-UHFFFAOYSA-N 0.000 claims description 7
- HHLFWLYXYJOTON-UHFFFAOYSA-N glyoxylic acid Chemical compound OC(=O)C=O HHLFWLYXYJOTON-UHFFFAOYSA-N 0.000 claims description 6
- 238000004519 manufacturing process Methods 0.000 claims description 6
- FEWJPZIEWOKRBE-JCYAYHJZSA-L L-tartrate(2-) Chemical compound [O-]C(=O)[C@H](O)[C@@H](O)C([O-])=O FEWJPZIEWOKRBE-JCYAYHJZSA-L 0.000 claims description 2
- XKJMBINCVNINCA-UHFFFAOYSA-N Alfalone Chemical compound CON(C)C(=O)NC1=CC=C(Cl)C(Cl)=C1 XKJMBINCVNINCA-UHFFFAOYSA-N 0.000 claims 2
- IKHGUXGNUITLKF-UHFFFAOYSA-N Acetaldehyde Chemical compound CC=O IKHGUXGNUITLKF-UHFFFAOYSA-N 0.000 claims 1
- 239000000543 intermediate Substances 0.000 abstract description 23
- 238000002955 isolation Methods 0.000 abstract description 9
- 238000010963 scalable process Methods 0.000 abstract 1
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 130
- 150000001875 compounds Chemical class 0.000 description 129
- FEWJPZIEWOKRBE-LWMBPPNESA-L D-tartrate(2-) Chemical compound [O-]C(=O)[C@@H](O)[C@H](O)C([O-])=O FEWJPZIEWOKRBE-LWMBPPNESA-L 0.000 description 126
- 125000000217 alkyl group Chemical group 0.000 description 106
- 239000000243 solution Substances 0.000 description 78
- 238000006243 chemical reaction Methods 0.000 description 71
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 57
- -1 chloropropyl Chemical group 0.000 description 54
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 53
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 41
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 39
- 125000002572 propoxy group Chemical group [*]OC([H])([H])C(C([H])([H])[H])([H])[H] 0.000 description 36
- 229910052739 hydrogen Inorganic materials 0.000 description 33
- 150000001412 amines Chemical class 0.000 description 31
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 30
- FEWJPZIEWOKRBE-LWMBPPNESA-N levotartaric acid Chemical compound OC(=O)[C@@H](O)[C@H](O)C(O)=O FEWJPZIEWOKRBE-LWMBPPNESA-N 0.000 description 30
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 29
- 125000000753 cycloalkyl group Chemical group 0.000 description 28
- 239000003153 chemical reaction reagent Substances 0.000 description 27
- 229910052736 halogen Inorganic materials 0.000 description 27
- 150000002367 halogens Chemical class 0.000 description 26
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 26
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 25
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 25
- 125000003118 aryl group Chemical group 0.000 description 25
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 24
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 24
- 229960001270 d- tartaric acid Drugs 0.000 description 24
- 239000000047 product Substances 0.000 description 23
- 239000001257 hydrogen Substances 0.000 description 22
- RGHPCLZJAFCTIK-UHFFFAOYSA-N 2-methylpyrrolidine Chemical compound CC1CCCN1 RGHPCLZJAFCTIK-UHFFFAOYSA-N 0.000 description 21
- 125000003545 alkoxy group Chemical group 0.000 description 20
- 229910052799 carbon Inorganic materials 0.000 description 19
- 125000005843 halogen group Chemical group 0.000 description 19
- 238000002360 preparation method Methods 0.000 description 19
- 239000011734 sodium Substances 0.000 description 18
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 17
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 17
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 17
- 238000001953 recrystallisation Methods 0.000 description 17
- AVFZOVWCLRSYKC-UHFFFAOYSA-N 1-methylpyrrolidine Chemical compound CN1CCCC1 AVFZOVWCLRSYKC-UHFFFAOYSA-N 0.000 description 16
- AHVYPIQETPWLSZ-UHFFFAOYSA-N N-methyl-pyrrolidine Natural products CN1CC=CC1 AHVYPIQETPWLSZ-UHFFFAOYSA-N 0.000 description 16
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 16
- SNOOUWRIMMFWNE-UHFFFAOYSA-M sodium;6-[(3,4,5-trimethoxybenzoyl)amino]hexanoate Chemical compound [Na+].COC1=CC(C(=O)NCCCCCC([O-])=O)=CC(OC)=C1OC SNOOUWRIMMFWNE-UHFFFAOYSA-M 0.000 description 16
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 15
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 14
- 239000003446 ligand Substances 0.000 description 14
- 239000011541 reaction mixture Substances 0.000 description 14
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 13
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 13
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 12
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 11
- 150000001721 carbon Chemical group 0.000 description 11
- 239000007789 gas Substances 0.000 description 11
- 125000001072 heteroaryl group Chemical group 0.000 description 11
- 238000003786 synthesis reaction Methods 0.000 description 11
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 10
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 10
- 238000004587 chromatography analysis Methods 0.000 description 10
- 125000004093 cyano group Chemical group *C#N 0.000 description 10
- 238000001914 filtration Methods 0.000 description 10
- 125000000623 heterocyclic group Chemical group 0.000 description 10
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 10
- 230000009466 transformation Effects 0.000 description 10
- AZSFFTYBJRSSKJ-UHFFFAOYSA-N 4-[4-[2-(2-methylpyrrolidin-1-yl)ethyl]phenyl]benzenesulfonic acid Chemical compound CC1CCCN1CCC1=CC=C(C=2C=CC(=CC=2)S(O)(=O)=O)C=C1 AZSFFTYBJRSSKJ-UHFFFAOYSA-N 0.000 description 9
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 9
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 9
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 description 9
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 9
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 9
- 125000003342 alkenyl group Chemical group 0.000 description 9
- 150000001408 amides Chemical class 0.000 description 9
- 125000003710 aryl alkyl group Chemical group 0.000 description 9
- 125000004429 atom Chemical group 0.000 description 9
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 9
- 125000000592 heterocycloalkyl group Chemical group 0.000 description 9
- 150000002576 ketones Chemical class 0.000 description 9
- 125000001424 substituent group Chemical group 0.000 description 9
- OOGWMAIYWGZDRX-CYBMUJFWSA-N (2r)-1-[2-(6-bromonaphthalen-2-yl)ethyl]-2-methylpyrrolidine Chemical compound C[C@@H]1CCCN1CCC1=CC=C(C=C(Br)C=C2)C2=C1 OOGWMAIYWGZDRX-CYBMUJFWSA-N 0.000 description 8
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 description 8
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 8
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 8
- 125000000304 alkynyl group Chemical group 0.000 description 8
- 230000008901 benefit Effects 0.000 description 8
- 230000015572 biosynthetic process Effects 0.000 description 8
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 8
- 150000002431 hydrogen Chemical class 0.000 description 8
- 238000011065 in-situ storage Methods 0.000 description 8
- 230000037361 pathway Effects 0.000 description 8
- 229910000104 sodium hydride Inorganic materials 0.000 description 8
- 239000007787 solid Substances 0.000 description 8
- VQKIKHHXFHNXJT-SNAWJCMRSA-N (4E)-hept-4-en-2-one Chemical compound CC\C=C\CC(C)=O VQKIKHHXFHNXJT-SNAWJCMRSA-N 0.000 description 7
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 7
- PCUZFDAAOXBYTO-UHFFFAOYSA-N 2-bromo-6-ethenylnaphthalene Chemical compound C1=C(C=C)C=CC2=CC(Br)=CC=C21 PCUZFDAAOXBYTO-UHFFFAOYSA-N 0.000 description 7
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 7
- 125000004432 carbon atom Chemical group C* 0.000 description 7
- 229910052802 copper Inorganic materials 0.000 description 7
- UHOVQNZJYSORNB-UHFFFAOYSA-N monobenzene Natural products C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 7
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N phenol group Chemical group C1(=CC=CC=C1)O ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 7
- 125000006239 protecting group Chemical group 0.000 description 7
- TVPRCLHSULCNLV-UHFFFAOYSA-N pyridazin-3-one Chemical compound O=C1C=CC=N[N]1 TVPRCLHSULCNLV-UHFFFAOYSA-N 0.000 description 7
- 230000002829 reductive effect Effects 0.000 description 7
- 229940095064 tartrate Drugs 0.000 description 7
- 229940086542 triethylamine Drugs 0.000 description 7
- FRNRXKFDZXFNKG-UHFFFAOYSA-N (6-bromonaphthalen-2-yl) trifluoromethanesulfonate Chemical compound C1=C(Br)C=CC2=CC(OS(=O)(=O)C(F)(F)F)=CC=C21 FRNRXKFDZXFNKG-UHFFFAOYSA-N 0.000 description 6
- CUMDJLVCVBQTKA-YSSOQSIOSA-N 4-methyl-3-[4-[3-[(2r)-2-methylpyrrolidin-1-yl]propoxy]phenyl]-4,5-dihydro-1h-pyridazin-6-one Chemical class C[C@@H]1CCCN1CCCOC1=CC=C(C=2C(CC(=O)NN=2)C)C=C1 CUMDJLVCVBQTKA-YSSOQSIOSA-N 0.000 description 6
- LCGLNKUTAGEVQW-UHFFFAOYSA-N Dimethyl ether Chemical compound COC LCGLNKUTAGEVQW-UHFFFAOYSA-N 0.000 description 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 6
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 description 6
- 239000007868 Raney catalyst Substances 0.000 description 6
- NPXOKRUENSOPAO-UHFFFAOYSA-N Raney nickel Chemical compound [Al].[Ni] NPXOKRUENSOPAO-UHFFFAOYSA-N 0.000 description 6
- 229910000564 Raney nickel Inorganic materials 0.000 description 6
- 125000003158 alcohol group Chemical group 0.000 description 6
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 6
- 230000003197 catalytic effect Effects 0.000 description 6
- 239000010949 copper Substances 0.000 description 6
- UAOMVDZJSHZZME-UHFFFAOYSA-N diisopropylamine Chemical compound CC(C)NC(C)C UAOMVDZJSHZZME-UHFFFAOYSA-N 0.000 description 6
- 229910052751 metal Inorganic materials 0.000 description 6
- 239000002184 metal Substances 0.000 description 6
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 6
- NFHFRUOZVGFOOS-UHFFFAOYSA-N palladium;triphenylphosphane Chemical compound [Pd].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 NFHFRUOZVGFOOS-UHFFFAOYSA-N 0.000 description 6
- 229910000027 potassium carbonate Inorganic materials 0.000 description 6
- ITMCEJHCFYSIIV-UHFFFAOYSA-M triflate Chemical compound [O-]S(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-M 0.000 description 6
- ASOKPJOREAFHNY-UHFFFAOYSA-N 1-Hydroxybenzotriazole Chemical compound C1=CC=C2N(O)N=NC2=C1 ASOKPJOREAFHNY-UHFFFAOYSA-N 0.000 description 5
- 101100347605 Arabidopsis thaliana VIII-A gene Proteins 0.000 description 5
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical group ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 5
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 5
- 229960000583 acetic acid Drugs 0.000 description 5
- 239000002253 acid Substances 0.000 description 5
- 125000002252 acyl group Chemical group 0.000 description 5
- YKIOKAURTKXMSB-UHFFFAOYSA-N adams's catalyst Chemical group O=[Pt]=O YKIOKAURTKXMSB-UHFFFAOYSA-N 0.000 description 5
- 125000005233 alkylalcohol group Chemical group 0.000 description 5
- 229910052794 bromium Inorganic materials 0.000 description 5
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical group [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 description 5
- 229910000024 caesium carbonate Inorganic materials 0.000 description 5
- 239000003638 chemical reducing agent Substances 0.000 description 5
- 229910052801 chlorine Inorganic materials 0.000 description 5
- 230000008878 coupling Effects 0.000 description 5
- 238000010168 coupling process Methods 0.000 description 5
- 238000005859 coupling reaction Methods 0.000 description 5
- 239000013078 crystal Substances 0.000 description 5
- 150000002148 esters Chemical class 0.000 description 5
- 125000002485 formyl group Chemical group [H]C(*)=O 0.000 description 5
- 125000001188 haloalkyl group Chemical group 0.000 description 5
- 125000005842 heteroatom Chemical group 0.000 description 5
- 229910052740 iodine Inorganic materials 0.000 description 5
- 229940098779 methanesulfonic acid Drugs 0.000 description 5
- NLKNQRATVPKPDG-UHFFFAOYSA-M potassium iodide Chemical compound [K+].[I-] NLKNQRATVPKPDG-UHFFFAOYSA-M 0.000 description 5
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 5
- 102000005962 receptors Human genes 0.000 description 5
- 108020003175 receptors Proteins 0.000 description 5
- 238000010992 reflux Methods 0.000 description 5
- 229910000029 sodium carbonate Inorganic materials 0.000 description 5
- MFRIHAYPQRLWNB-UHFFFAOYSA-N sodium tert-butoxide Chemical compound [Na+].CC(C)(C)[O-] MFRIHAYPQRLWNB-UHFFFAOYSA-N 0.000 description 5
- 239000007858 starting material Substances 0.000 description 5
- BDHFUVZGWQCTTF-UHFFFAOYSA-M sulfonate Chemical compound [O-]S(=O)=O BDHFUVZGWQCTTF-UHFFFAOYSA-M 0.000 description 5
- 150000003512 tertiary amines Chemical class 0.000 description 5
- KZPYGQFFRCFCPP-UHFFFAOYSA-N 1,1'-bis(diphenylphosphino)ferrocene Chemical compound [Fe+2].C1=CC=C[C-]1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=C[C-]1P(C=1C=CC=CC=1)C1=CC=CC=C1 KZPYGQFFRCFCPP-UHFFFAOYSA-N 0.000 description 4
- LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide Chemical compound CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 description 4
- GQHTUMJGOHRCHB-UHFFFAOYSA-N 2,3,4,6,7,8,9,10-octahydropyrimido[1,2-a]azepine Chemical compound C1CCCCN2CCCN=C21 GQHTUMJGOHRCHB-UHFFFAOYSA-N 0.000 description 4
- ITQTTZVARXURQS-UHFFFAOYSA-N 3-methylpyridine Chemical compound CC1=CC=CN=C1 ITQTTZVARXURQS-UHFFFAOYSA-N 0.000 description 4
- FKNQCJSGGFJEIZ-UHFFFAOYSA-N 4-methylpyridine Chemical compound CC1=CC=NC=C1 FKNQCJSGGFJEIZ-UHFFFAOYSA-N 0.000 description 4
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 description 4
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 4
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 description 4
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 description 4
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 4
- 101100030361 Neurospora crassa (strain ATCC 24698 / 74-OR23-1A / CBS 708.71 / DSM 1257 / FGSC 987) pph-3 gene Proteins 0.000 description 4
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- 150000001298 alcohols Chemical class 0.000 description 4
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- SYFVCILCVBDQIK-UHFFFAOYSA-N methyl 2-[[4-[4-[2-(2-methylpyrrolidin-1-yl)ethyl]phenyl]phenyl]sulfonylamino]acetate Chemical compound C1=CC(S(=O)(=O)NCC(=O)OC)=CC=C1C(C=C1)=CC=C1CCN1C(C)CCC1 SYFVCILCVBDQIK-UHFFFAOYSA-N 0.000 description 1
- FMHBARORGRUHDM-UHFFFAOYSA-N methyl 2-[[4-[4-[2-(2-methylpyrrolidin-1-yl)ethyl]phenyl]phenyl]sulfonylamino]propanoate Chemical compound C1=CC(S(=O)(=O)NC(C)C(=O)OC)=CC=C1C(C=C1)=CC=C1CCN1C(C)CCC1 FMHBARORGRUHDM-UHFFFAOYSA-N 0.000 description 1
- 150000004702 methyl esters Chemical class 0.000 description 1
- BLWYXBNNBYXPPL-UHFFFAOYSA-N methyl pyrrolidine-2-carboxylate Chemical compound COC(=O)C1CCCN1 BLWYXBNNBYXPPL-UHFFFAOYSA-N 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 239000002808 molecular sieve Substances 0.000 description 1
- ZNUNHSALNZAAKI-UHFFFAOYSA-N n,n-bis(2-hydroxyethyl)-4-[4-[2-(2-methylpyrrolidin-1-yl)ethyl]phenyl]benzenesulfonamide Chemical compound CC1CCCN1CCC1=CC=C(C=2C=CC(=CC=2)S(=O)(=O)N(CCO)CCO)C=C1 ZNUNHSALNZAAKI-UHFFFAOYSA-N 0.000 description 1
- CEXJLCPGRGREOU-UHFFFAOYSA-N n,n-diethyl-4-[4-[2-(2-methylpyrrolidin-1-yl)ethyl]phenyl]benzenesulfonamide Chemical compound C1=CC(S(=O)(=O)N(CC)CC)=CC=C1C(C=C1)=CC=C1CCN1C(C)CCC1 CEXJLCPGRGREOU-UHFFFAOYSA-N 0.000 description 1
- USQBDGHXHXLCNE-UHFFFAOYSA-N n,n-dimethyl-1-[4-[4-[4-[(2-methylpyrrolidin-1-yl)methyl]-1,3-oxazol-2-yl]phenoxy]butyl]pyrrolidin-3-amine Chemical compound CC1CCCN1CC1=COC(C=2C=CC(OCCCCN3CC(CC3)N(C)C)=CC=2)=N1 USQBDGHXHXLCNE-UHFFFAOYSA-N 0.000 description 1
- FDPGOPOKKSRVOC-UHFFFAOYSA-N n-(1-hydroxy-2-methylpropan-2-yl)-4-[4-[2-(2-methylpyrrolidin-1-yl)ethyl]phenyl]benzenesulfonamide Chemical compound CC1CCCN1CCC1=CC=C(C=2C=CC(=CC=2)S(=O)(=O)NC(C)(C)CO)C=C1 FDPGOPOKKSRVOC-UHFFFAOYSA-N 0.000 description 1
- IEHNOTDWNHHFOS-UHFFFAOYSA-N n-(1-hydroxypropan-2-yl)-4-[4-[2-(2-methylpyrrolidin-1-yl)ethyl]phenyl]benzenesulfonamide Chemical compound C1=CC(S(=O)(=O)NC(CO)C)=CC=C1C(C=C1)=CC=C1CCN1C(C)CCC1 IEHNOTDWNHHFOS-UHFFFAOYSA-N 0.000 description 1
- KAJGYUWXZNAHPI-UHFFFAOYSA-N n-(2-ethoxyethyl)-4-[4-[2-(2-methylpyrrolidin-1-yl)ethyl]phenyl]benzenesulfonamide Chemical compound C1=CC(S(=O)(=O)NCCOCC)=CC=C1C(C=C1)=CC=C1CCN1C(C)CCC1 KAJGYUWXZNAHPI-UHFFFAOYSA-N 0.000 description 1
- KVEZQWOLMSHQCI-UHFFFAOYSA-N n-(2-hydroxyethyl)-4-[4-[2-(2-methylpyrrolidin-1-yl)ethyl]phenyl]benzenesulfonamide Chemical compound CC1CCCN1CCC1=CC=C(C=2C=CC(=CC=2)S(=O)(=O)NCCO)C=C1 KVEZQWOLMSHQCI-UHFFFAOYSA-N 0.000 description 1
- ALARFOCTQMTSGX-UHFFFAOYSA-N n-(2-methoxyethyl)-4-[4-[2-(2-methylpyrrolidin-1-yl)ethyl]phenyl]-n-propan-2-ylbenzenesulfonamide Chemical compound C1=CC(S(=O)(=O)N(C(C)C)CCOC)=CC=C1C(C=C1)=CC=C1CCN1C(C)CCC1 ALARFOCTQMTSGX-UHFFFAOYSA-N 0.000 description 1
- ZLGFDPBROZZHML-UHFFFAOYSA-N n-(2-methoxyethyl)-4-[4-[2-(2-methylpyrrolidin-1-yl)ethyl]phenyl]benzenesulfonamide Chemical compound C1=CC(S(=O)(=O)NCCOC)=CC=C1C(C=C1)=CC=C1CCN1C(C)CCC1 ZLGFDPBROZZHML-UHFFFAOYSA-N 0.000 description 1
- MYOAZOUXICOKKO-UHFFFAOYSA-N n-(2-methoxyethyl)-n-methyl-4-[4-[2-(2-methylpyrrolidin-1-yl)ethyl]phenyl]benzenesulfonamide Chemical compound C1=CC(S(=O)(=O)N(C)CCOC)=CC=C1C(C=C1)=CC=C1CCN1C(C)CCC1 MYOAZOUXICOKKO-UHFFFAOYSA-N 0.000 description 1
- SFUGFWNYJPRZJD-UHFFFAOYSA-N n-(4-fluorophenyl)-2-[2-[4-[3-(2-methylpyrrolidin-1-yl)propoxy]phenyl]-1,3-oxazol-4-yl]acetamide Chemical compound CC1CCCN1CCCOC1=CC=C(C=2OC=C(CC(=O)NC=3C=CC(F)=CC=3)N=2)C=C1 SFUGFWNYJPRZJD-UHFFFAOYSA-N 0.000 description 1
- YVKKENUWMVYTDD-UHFFFAOYSA-N n-(4-fluorophenyl)-4-[4-[2-(2-methylpyrrolidin-1-yl)ethyl]phenyl]benzenesulfonamide Chemical compound CC1CCCN1CCC1=CC=C(C=2C=CC(=CC=2)S(=O)(=O)NC=2C=CC(F)=CC=2)C=C1 YVKKENUWMVYTDD-UHFFFAOYSA-N 0.000 description 1
- SZBWWKVIANJTEU-UHFFFAOYSA-N n-(cyclohexylmethyl)-4-[4-[2-(2-methylpyrrolidin-1-yl)ethyl]phenyl]benzenesulfonamide Chemical compound CC1CCCN1CCC1=CC=C(C=2C=CC(=CC=2)S(=O)(=O)NCC2CCCCC2)C=C1 SZBWWKVIANJTEU-UHFFFAOYSA-N 0.000 description 1
- COTQUFSBYWGOIV-UHFFFAOYSA-N n-(cyclopropylmethyl)-4-[4-[2-(2-methylpyrrolidin-1-yl)ethyl]phenyl]benzenesulfonamide Chemical compound CC1CCCN1CCC1=CC=C(C=2C=CC(=CC=2)S(=O)(=O)NCC2CC2)C=C1 COTQUFSBYWGOIV-UHFFFAOYSA-N 0.000 description 1
- MECMPJWDYLIPKR-UHFFFAOYSA-N n-(cyclopropylmethyl)-n-[[2-[4-[3-(2-methylpyrrolidin-1-yl)propoxy]phenyl]-1,3-oxazol-4-yl]methyl]propan-1-amine Chemical compound C=1OC(C=2C=CC(OCCCN3C(CCC3)C)=CC=2)=NC=1CN(CCC)CC1CC1 MECMPJWDYLIPKR-UHFFFAOYSA-N 0.000 description 1
- OPSAGXZWIWATAU-UHFFFAOYSA-N n-(cyclopropylmethyl)-n-[[4-methyl-2-[4-[3-(2-methylpyrrolidin-1-yl)propoxy]phenyl]-1,3-oxazol-5-yl]methyl]propan-1-amine Chemical compound O1C(C=2C=CC(OCCCN3C(CCC3)C)=CC=2)=NC(C)=C1CN(CCC)CC1CC1 OPSAGXZWIWATAU-UHFFFAOYSA-N 0.000 description 1
- UZXAUBGMLBEYHS-UHFFFAOYSA-N n-[(4-methylphenyl)methyl]-4-[4-[2-(2-methylpyrrolidin-1-yl)ethyl]phenyl]benzenesulfonamide Chemical compound CC1CCCN1CCC1=CC=C(C=2C=CC(=CC=2)S(=O)(=O)NCC=2C=CC(C)=CC=2)C=C1 UZXAUBGMLBEYHS-UHFFFAOYSA-N 0.000 description 1
- OJPIRGUOVXCSRY-UHFFFAOYSA-N n-[1-(hydroxymethyl)cyclopentyl]-4-[4-[2-(2-methylpyrrolidin-1-yl)ethyl]phenyl]benzenesulfonamide Chemical compound CC1CCCN1CCC1=CC=C(C=2C=CC(=CC=2)S(=O)(=O)NC2(CO)CCCC2)C=C1 OJPIRGUOVXCSRY-UHFFFAOYSA-N 0.000 description 1
- XLIZGFWRVQNTBE-UHFFFAOYSA-N n-[2-(4-fluorophenyl)ethyl]-4-[4-[2-(2-methylpyrrolidin-1-yl)ethyl]phenyl]benzenesulfonamide Chemical compound CC1CCCN1CCC1=CC=C(C=2C=CC(=CC=2)S(=O)(=O)NCCC=2C=CC(F)=CC=2)C=C1 XLIZGFWRVQNTBE-UHFFFAOYSA-N 0.000 description 1
- NVXHCRHSRQBDBS-UHFFFAOYSA-N n-[[2-[4-[3-(2-methylpyrrolidin-1-yl)propoxy]phenyl]-1,3-oxazol-4-yl]methyl]cyclopentanamine Chemical compound CC1CCCN1CCCOC1=CC=C(C=2OC=C(CNC3CCCC3)N=2)C=C1 NVXHCRHSRQBDBS-UHFFFAOYSA-N 0.000 description 1
- SWRKPBJSPWFJDH-UHFFFAOYSA-N n-[[2-[4-[3-(2-methylpyrrolidin-1-yl)propoxy]phenyl]-1,3-thiazol-4-yl]methyl]-n-propylbutan-2-amine Chemical compound CCCN(C(C)CC)CC1=CSC(C=2C=CC(OCCCN3C(CCC3)C)=CC=2)=N1 SWRKPBJSPWFJDH-UHFFFAOYSA-N 0.000 description 1
- SOFAPWCQUDLUBN-UHFFFAOYSA-N n-benzhydryl-4-[4-[2-(2-methylpyrrolidin-1-yl)ethyl]phenyl]benzenesulfonamide Chemical compound CC1CCCN1CCC1=CC=C(C=2C=CC(=CC=2)S(=O)(=O)NC(C=2C=CC=CC=2)C=2C=CC=CC=2)C=C1 SOFAPWCQUDLUBN-UHFFFAOYSA-N 0.000 description 1
- NKQGWIKZNFWKQF-UHFFFAOYSA-N n-benzyl-n-(2-hydroxyethyl)-4-[4-[2-(2-methylpyrrolidin-1-yl)ethyl]phenyl]benzenesulfonamide Chemical compound CC1CCCN1CCC1=CC=C(C=2C=CC(=CC=2)S(=O)(=O)N(CCO)CC=2C=CC=CC=2)C=C1 NKQGWIKZNFWKQF-UHFFFAOYSA-N 0.000 description 1
- YAQDYYKNVZIREK-UHFFFAOYSA-N n-benzyl-n-(2-methoxyethyl)-4-[4-[2-(2-methylpyrrolidin-1-yl)ethyl]phenyl]benzenesulfonamide Chemical compound C=1C=C(C=2C=CC(CCN3C(CCC3)C)=CC=2)C=CC=1S(=O)(=O)N(CCOC)CC1=CC=CC=C1 YAQDYYKNVZIREK-UHFFFAOYSA-N 0.000 description 1
- CLYUDPHBQXTMKX-UHFFFAOYSA-N n-benzyl-n-ethyl-4-[4-[2-(2-methylpyrrolidin-1-yl)ethyl]phenyl]benzenesulfonamide Chemical compound C=1C=C(C=2C=CC(CCN3C(CCC3)C)=CC=2)C=CC=1S(=O)(=O)N(CC)CC1=CC=CC=C1 CLYUDPHBQXTMKX-UHFFFAOYSA-N 0.000 description 1
- KIARYUXZSJOOIF-UHFFFAOYSA-N n-cyclohexyl-4-[4-[2-(2-methylpyrrolidin-1-yl)ethyl]phenyl]benzenesulfonamide Chemical compound CC1CCCN1CCC1=CC=C(C=2C=CC(=CC=2)S(=O)(=O)NC2CCCCC2)C=C1 KIARYUXZSJOOIF-UHFFFAOYSA-N 0.000 description 1
- YWCBBOQXMPVSLD-UHFFFAOYSA-N n-cyclopentyl-2-[2-[4-[3-(2-methylpyrrolidin-1-yl)propoxy]phenyl]-1,3-oxazol-4-yl]acetamide Chemical compound CC1CCCN1CCCOC1=CC=C(C=2OC=C(CC(=O)NC3CCCC3)N=2)C=C1 YWCBBOQXMPVSLD-UHFFFAOYSA-N 0.000 description 1
- FORUEZLTXSBDIM-UHFFFAOYSA-N n-cyclopentyl-4-methyl-2-[4-[3-(2-methylpyrrolidin-1-yl)propoxy]phenyl]-1,3-oxazole-5-carboxamide Chemical compound CC1CCCN1CCCOC1=CC=C(C=2OC(=C(C)N=2)C(=O)NC2CCCC2)C=C1 FORUEZLTXSBDIM-UHFFFAOYSA-N 0.000 description 1
- FKUDQYZICIADCS-UHFFFAOYSA-N n-cyclopropyl-4-[4-[2-(2-methylpyrrolidin-1-yl)ethyl]phenyl]benzenesulfonamide Chemical compound CC1CCCN1CCC1=CC=C(C=2C=CC(=CC=2)S(=O)(=O)NC2CC2)C=C1 FKUDQYZICIADCS-UHFFFAOYSA-N 0.000 description 1
- KCWBLQLQPMZHOJ-UHFFFAOYSA-N n-ethyl-4-[4-(2-pyrrolidin-1-ylethyl)phenyl]benzenesulfonamide Chemical compound C1=CC(S(=O)(=O)NCC)=CC=C1C(C=C1)=CC=C1CCN1CCCC1 KCWBLQLQPMZHOJ-UHFFFAOYSA-N 0.000 description 1
- GQLPRIVQAONOIR-UHFFFAOYSA-N n-ethyl-4-[4-[2-(2-methylpyrrolidin-1-yl)ethyl]phenyl]benzenesulfonamide Chemical compound C1=CC(S(=O)(=O)NCC)=CC=C1C(C=C1)=CC=C1CCN1C(C)CCC1 GQLPRIVQAONOIR-UHFFFAOYSA-N 0.000 description 1
- QECNBMJRDWINKS-UHFFFAOYSA-N n-fluoro-1-phenylmethanamine Chemical compound FNCC1=CC=CC=C1 QECNBMJRDWINKS-UHFFFAOYSA-N 0.000 description 1
- RQZFDZYMDZGQOS-UHFFFAOYSA-N n-heptan-4-yl-4-[4-[2-(2-methylpyrrolidin-1-yl)ethyl]phenyl]benzenesulfonamide Chemical compound C1=CC(S(=O)(=O)NC(CCC)CCC)=CC=C1C(C=C1)=CC=C1CCN1C(C)CCC1 RQZFDZYMDZGQOS-UHFFFAOYSA-N 0.000 description 1
- QWLISCJHYITNQF-UHFFFAOYSA-N n-methoxy-1-phenylmethanamine Chemical compound CONCC1=CC=CC=C1 QWLISCJHYITNQF-UHFFFAOYSA-N 0.000 description 1
- SAPUBQYSLGOPQO-UHFFFAOYSA-N n-propyl-1,3-oxazole-5-carboxamide Chemical compound CCCNC(=O)C1=CN=CO1 SAPUBQYSLGOPQO-UHFFFAOYSA-N 0.000 description 1
- PETDBDGHXCNFOL-UHFFFAOYSA-N n-tert-butyl-4-[4-[2-(2-methylpyrrolidin-1-yl)ethyl]phenyl]benzenesulfonamide Chemical compound CC1CCCN1CCC1=CC=C(C=2C=CC(=CC=2)S(=O)(=O)NC(C)(C)C)C=C1 PETDBDGHXCNFOL-UHFFFAOYSA-N 0.000 description 1
- 125000001624 naphthyl group Chemical group 0.000 description 1
- 239000012299 nitrogen atmosphere Substances 0.000 description 1
- 238000010899 nucleation Methods 0.000 description 1
- 239000012044 organic layer Substances 0.000 description 1
- 239000012074 organic phase Substances 0.000 description 1
- 238000006053 organic reaction Methods 0.000 description 1
- MOOYVEVEDVVKGD-UHFFFAOYSA-N oxaldehydic acid;hydrate Chemical compound O.OC(=O)C=O MOOYVEVEDVVKGD-UHFFFAOYSA-N 0.000 description 1
- AHVQYHFYQWKUKB-UHFFFAOYSA-N oxan-4-amine Chemical compound NC1CCOCC1 AHVQYHFYQWKUKB-UHFFFAOYSA-N 0.000 description 1
- 125000004287 oxazol-2-yl group Chemical group [H]C1=C([H])N=C(*)O1 0.000 description 1
- 125000004304 oxazol-5-yl group Chemical group O1C=NC=C1* 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- PIBWKRNGBLPSSY-UHFFFAOYSA-L palladium(II) chloride Chemical compound Cl[Pd]Cl PIBWKRNGBLPSSY-UHFFFAOYSA-L 0.000 description 1
- YJVFFLUZDVXJQI-UHFFFAOYSA-L palladium(ii) acetate Chemical compound [Pd+2].CC([O-])=O.CC([O-])=O YJVFFLUZDVXJQI-UHFFFAOYSA-L 0.000 description 1
- 239000004031 partial agonist Substances 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
- 239000008194 pharmaceutical composition Substances 0.000 description 1
- 229910000073 phosphorus hydride Inorganic materials 0.000 description 1
- 125000004482 piperidin-4-yl group Chemical group N1CCC(CC1)* 0.000 description 1
- BMRZLWYQXYKVRW-UHFFFAOYSA-N piperidine;pyrrolidin-2-one Chemical compound C1CCNCC1.O=C1CCCN1 BMRZLWYQXYKVRW-UHFFFAOYSA-N 0.000 description 1
- 239000002798 polar solvent Substances 0.000 description 1
- 229920000642 polymer Polymers 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 235000015497 potassium bicarbonate Nutrition 0.000 description 1
- 229910000028 potassium bicarbonate Inorganic materials 0.000 description 1
- 239000011736 potassium bicarbonate Substances 0.000 description 1
- 235000015320 potassium carbonate Nutrition 0.000 description 1
- NTTOTNSKUYCDAV-UHFFFAOYSA-N potassium hydride Chemical compound [KH] NTTOTNSKUYCDAV-UHFFFAOYSA-N 0.000 description 1
- 229910000105 potassium hydride Inorganic materials 0.000 description 1
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 239000010970 precious metal Substances 0.000 description 1
- 125000000075 primary alcohol group Chemical group 0.000 description 1
- 150000003141 primary amines Chemical class 0.000 description 1
- QJTVPFORQHLMLX-UHFFFAOYSA-N propan-2-yl 2-[[4-[4-[2-(2-methylpyrrolidin-1-yl)ethyl]phenyl]phenyl]sulfonylamino]propanoate Chemical compound C1=CC(S(=O)(=O)NC(C)C(=O)OC(C)C)=CC=C1C(C=C1)=CC=C1CCN1C(C)CCC1 QJTVPFORQHLMLX-UHFFFAOYSA-N 0.000 description 1
- XUWVIABDWDTJRZ-UHFFFAOYSA-N propan-2-ylazanide Chemical compound CC(C)[NH-] XUWVIABDWDTJRZ-UHFFFAOYSA-N 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 125000006514 pyridin-2-ylmethyl group Chemical group [H]C1=C([H])C([H])=C([H])C(=N1)C([H])([H])* 0.000 description 1
- 239000002469 receptor inverse agonist Substances 0.000 description 1
- 238000004064 recycling Methods 0.000 description 1
- QBERHIJABFXGRZ-UHFFFAOYSA-M rhodium;triphenylphosphane;chloride Chemical compound [Cl-].[Rh].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 QBERHIJABFXGRZ-UHFFFAOYSA-M 0.000 description 1
- SMQUZDBALVYZAC-UHFFFAOYSA-N salicylaldehyde Chemical class OC1=CC=CC=C1C=O SMQUZDBALVYZAC-UHFFFAOYSA-N 0.000 description 1
- 239000012266 salt solution Substances 0.000 description 1
- 230000007017 scission Effects 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- UIIMBOGNXHQVGW-UHFFFAOYSA-M sodium bicarbonate Substances [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 1
- BEOOHQFXGBMRKU-UHFFFAOYSA-N sodium cyanoborohydride Chemical compound [Na+].[B-]C#N BEOOHQFXGBMRKU-UHFFFAOYSA-N 0.000 description 1
- 239000012312 sodium hydride Substances 0.000 description 1
- 239000012321 sodium triacetoxyborohydride Substances 0.000 description 1
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
- 239000012453 solvate Substances 0.000 description 1
- 241000894007 species Species 0.000 description 1
- 239000011593 sulfur Substances 0.000 description 1
- 229960001367 tartaric acid Drugs 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- BFFLLBPMZCIGRM-QMMMGPOBSA-N tert-butyl (2s)-2-(hydroxymethyl)pyrrolidine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CCC[C@H]1CO BFFLLBPMZCIGRM-QMMMGPOBSA-N 0.000 description 1
- ZSBNHRJPLRVNGO-UHFFFAOYSA-N tert-butyl 2-[[4-[4-[2-(2-methylpyrrolidin-1-yl)ethyl]phenyl]phenyl]sulfonylamino]acetate Chemical compound CC1CCCN1CCC1=CC=C(C=2C=CC(=CC=2)S(=O)(=O)NCC(=O)OC(C)(C)C)C=C1 ZSBNHRJPLRVNGO-UHFFFAOYSA-N 0.000 description 1
- XJHKRDSLSGRKDO-UHFFFAOYSA-N tert-butyl 2-[[4-[4-[2-(2-methylpyrrolidin-1-yl)ethyl]phenyl]phenyl]sulfonylamino]propanoate Chemical compound C1=CC(S(=O)(=O)NC(C)C(=O)OC(C)(C)C)=CC=C1C(C=C1)=CC=C1CCN1C(C)CCC1 XJHKRDSLSGRKDO-UHFFFAOYSA-N 0.000 description 1
- PTEHWBIWKFLJPG-UHFFFAOYSA-N tert-butyl 3-oxo-4-(4-phenylmethoxyphenyl)piperazine-1-carboxylate Chemical compound O=C1CN(C(=O)OC(C)(C)C)CCN1C(C=C1)=CC=C1OCC1=CC=CC=C1 PTEHWBIWKFLJPG-UHFFFAOYSA-N 0.000 description 1
- GTYRZGSKTZTHMF-UHFFFAOYSA-N tert-butyl 4-(4-hydroxyphenyl)-3-oxopiperazine-1-carboxylate Chemical compound O=C1CN(C(=O)OC(C)(C)C)CCN1C1=CC=C(O)C=C1 GTYRZGSKTZTHMF-UHFFFAOYSA-N 0.000 description 1
- IDCYNZYRRJOLCA-UHFFFAOYSA-N tert-butyl n-(2-hydroxyethyl)-n-[2-oxo-2-(4-phenylmethoxyanilino)ethyl]carbamate Chemical compound C1=CC(NC(=O)CN(CCO)C(=O)OC(C)(C)C)=CC=C1OCC1=CC=CC=C1 IDCYNZYRRJOLCA-UHFFFAOYSA-N 0.000 description 1
- 150000003526 tetrahydroisoquinolines Chemical class 0.000 description 1
- BRNULMACUQOKMR-UHFFFAOYSA-N thiomorpholine Chemical compound C1CSCCN1 BRNULMACUQOKMR-UHFFFAOYSA-N 0.000 description 1
- XJDNKRIXUMDJCW-UHFFFAOYSA-J titanium tetrachloride Chemical compound Cl[Ti](Cl)(Cl)Cl XJDNKRIXUMDJCW-UHFFFAOYSA-J 0.000 description 1
- 125000003944 tolyl group Chemical group 0.000 description 1
- TUQOTMZNTHZOKS-UHFFFAOYSA-N tributylphosphine Chemical compound CCCCP(CCCC)CCCC TUQOTMZNTHZOKS-UHFFFAOYSA-N 0.000 description 1
- GRGCWBWNLSTIEN-UHFFFAOYSA-N trifluoromethanesulfonyl chloride Chemical compound FC(F)(F)S(Cl)(=O)=O GRGCWBWNLSTIEN-UHFFFAOYSA-N 0.000 description 1
- 125000001889 triflyl group Chemical group FC(F)(F)S(*)(=O)=O 0.000 description 1
- 125000000026 trimethylsilyl group Chemical group [H]C([H])([H])[Si]([*])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 239000011995 wilkinson's catalyst Substances 0.000 description 1
- 229910052727 yttrium Inorganic materials 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D207/06—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with radicals, containing only hydrogen and carbon atoms, attached to ring carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
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- C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
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Abstract
The present invention provides a short, safe, inexpensive, commercially scalable process for preparing (R)- or (S)-2-methylpyrrolidine from 2-methylpyrroline, which does not require the isolation of synthetic intermediates.
Description
WO 2008/137087 PCT/US2008/005702 PROCESSES FOR PREPARING (R)-2-METHYLPYRROLIDINE AND (S)-2-METHYLPYRROLIDINE AND TARTRATE SALTS THEREOF CROSS REFERENCE TO RELATED APPLICATIONS This application claims the benefit of U.S. Provisional Application No. 60/927,356, filed May 3, 2007, the entirety of which is incorporated herein by reference. BACKGROUND OF THE INVENTION (R)- and (S)-2-methylpyrrolidine are starting materials useful in the synthesis of various pharmaceutical products. For example, (R)-2-methylpyrrolidine can be used to 5 prepare many H 3 receptor ligands. For this reason, there has been great interest in developing cost effective routes to prepare (R)- and (S)-2-methylpyrrolidine. But the procedures previously developed either employ costly starting materials or require many tedious synthetic steps. Pu et al. (Org. Process Res. & Dev., 2005, 9, 45-50) discloses the preparation of 10 (R)-2-methylpyrrolidine L-tartrate by fractional crystallization of racemic 2 methylpyrrolidine in the presence of L-tartaric acid. Racemic 2-methylpyrrolidine costs approximately $20/gram. Van de Kuil et al. (Recl. Trav. Chim. Pays-Bas, 1994, 113, 267-277) discloses a four (4) step synthesis of (R)-2-methylpyrrolidine L-tartrate and (S)-2-methylpyrrolidine 15 D-tartrate from 2-methylpyrroline (approximately $5/gram). However, the process is disadvantageous for several reasons. First, the process requires the preparation of three intermediates, two of which must be isolated. Additionally, the process requires isolation of the intermediate HCl salt by in vacuo removal of glacial acetic acid and excess 37% aqueous hydrochloric acid, which is time consuming, expensive, and corrosive. 20 Moreover, the synthesis requires isolation of an intermediate by two sequential flash distillations from potassium hydroxide. Ku et al. (Tetrahedron, 2006, 62, 4584-4589) discloses a four (4) step synthesis of (R)-2-methylpyrrolidine hydrochloride from N-Boc-L-prolinol. The process is disadvantageous for several reasons. First, the process requires the preparation and 25 isolation of three different synthetic intermediates. Second, the process employs the environmentally deleterious solvent dichloromethane, as well as corrosive gaseous hydrochloric acid and phosphoric acid. Third, the process employs expensive lithium iodide (approximately $13/gram). In addition, the resulting hydrochloride salt is very hygroscopic. - 1- Zhao et al. (J Org. Chem., 2006, 71, 4336-4338) discloses a four (4) step synthesis of (R)-2-methylpyrrolidine benzenesulfonate from N-Boc-L-proline. The process is disadvantageous for several reasons. First, the process requires the preparation and isolation of three (3) separate synthetic intermediates. Second, the process employs 5 corrosive reagents such as phosphoric acid, boron trifluoride etherate, sodium hydroxide, sodium borohydride, and Super-Hydride@. A need exists for a process to prepare (R)- and (S)-2-methylpyrrolidine that is short, safe, inexpensive, commercially scalable, and which can be performed without the need to isolate multiple synthetic intermediates. 10 SUMMARY OF THE INVENTION We have surprisingly found that (R)-2-methylpyrrolidine L-tartrate and (S)-2 methylpyrrolidine D-tartrate can be prepared in two steps from inexpensive 2 methylpyrroline using non-corrosive reagents without the necessity of isolating any 15 synthetic intermediates. The invention, the subject of this application is directed to a process for preparing 6- (4-[3-((R)-2-methyl-pyrrolidin-1 -yl)-propoxy]-phenyl} -2H-pyridazin-3-one: H 0 N , NN O 0 N 'R or a pharmaceutically acceptable salt thereof, comprising the steps of: 20 (Ia) hydrogenating 2-methylpyrroline in a mixture comprising an alcohol solvent and a hydrogenation catalyst; (1b) optionally removing the hydrogenation catalyst from the mixture; (1c) dissolving L-tartaric acid in the mixture to form a solution; (1d) crystallizing (R)-2-methylpyrrolidine L-tartrate from the solution; 25 (le) isolating the crystalline (R)-2-methylpyrrolidine L-tartrate; and (2) reacting the (R)-2-methylpyrrolidine L-tartrate with a base to form (R)-2 methylpyrrolidine free base; and - 2- (3) reacting the (R)-2-methylpyrrolidine with 6-[4-(3-halo-propoxy)-phenyl] 2H-pyridazin-3 -one for a time and under conditions sufficient to form 6- {4-[3 ((R)-2-methyl-pyrroidin- 1 -yl)-propoxy] -phenyl) -2H-pyridazin-3-one. In a broader embodiment, the present invention provides processes for preparing 5 (R)-2-methylpyrrolidine L-tartrate, comprising the steps of: (a) hydrogenating 2-methylpyrroline in a mixture comprising an alcohol solvent and a hydrogenation catalyst; (b) optionally removing the hydrogenation catalyst from the mixture; (c) dissolving L-tartaric acid in the mixture to form a solution; 10 (d) crystallizing (R)-2-methylpyrrolidine L-tartrate from the solution; and (e) isolating the crystalline (R)-2-methylpyrrolidine L-tartrate. Preferably, the hydrogenation catalyst is a platinum catalyst. Preferably, the platinum catalyst is platinum (IV) oxide. More preferably, the platinum catalyst is 5% Pt C. 15 Preferably, the alcohol solvent is a mixture of ethanol and methanol. More preferably, the alcohol solvent is a mixture of ethanol and methanol at a ratio of about 2:1 to about 3:1 (v/v). Preferably, step (a) is performed at ambient temperature. Preferably, the platinum catalyst is removed in step (b) by filtration. 20 Preferably, the isolated (R)-2-methylpyrrolidine L-tartrate has an optical purity of at least 50% ee. Optionally, the process further comprises the steps of: (f) recrystallizing the isolated (R)-2-methylpyrrolidine L-tartrate; (g) isolating the recrystallized (R)-2-methylpyrrolidine L-tartrate; and 25 (h) optionally repeating steps (f) and (g). Optionally, the process further comprises the step of reacting the isolated recrystallized (R)-2-methylpyrrolidine L-tartrate with a base to provide (R)-2 methylpyrrolidine. -3- Preferably, the process further comprises the step of converting the prepared (R)-2-methylpyrrolidine L-tartrate into a pharmaceutical composition, preferably an
H
3 receptor ligand, preferably 6-{4-[3-((R)-2-methyl-pyrrolidin-1 -yl)-propoxy]-phenyl} 2H-pyridazin-3-one. 5 H O NN N -3a - WO 2008/137087 PCT/US2008/005702 Preferably, the 6-[4-(3-halo-propoxy)-phenyl]-2H-pyridazin-3-one is prepared by the steps of: (a) contacting 1-(4-hydroxy-phenyl)-ethanone with 1,3-dihalopropane, for a time and under conditions sufficient to form 1-[4-(3-halo-propoxy)-phenyl]-ethanone; and 5 (b) contacting the 1-[4-(3-halo-propoxy)-phenyl]-ethanone with glyoxalic acid for a time and under conditions sufficient to produce 6-[4-(3-halo-propoxy)-phenyl]-2H pyridazin-3-one. The present invention also provides processes for preparing (S)-2 methylpyrrolidine D-tartrate, comprising the steps of: 10 (a) hydrogenating 2-methylpyrroline in a mixture comprising an alcohol solvent and a hydrogenation catalyst; (b) optionally removing the hydrogenation catalyst from the mixture; (c) dissolving D-tartaric acid in the mixture to form a solution; (d) crystallizing (S)-2-methylpyrrolidine D-tartrate from the solution; and 15 (e) isolating the crystalline (S)-2-methylpyrrolidine D-tartrate. Preferably, the hydrogenation catalyst is a platinum catalyst. Preferably, the platinum catalyst is platinum (IV) oxide. More preferably, the platinum catalyst is 5% Pt C. Preferably, the alcohol solvent is a mixture of ethanol and methanol. More 20 preferably, the alcohol solvent is a mixture of ethanol and methanol at a ratio of about 2:1 to about 3:1 (v/v). Preferably, step (a) is performed at ambient temperature. Preferably, the platinum catalyst is removed in step (b) by filtration. Preferably, the isolated (S)-2-methylpyrrolidine D-tartrate has an optical purity of 25 at least 50% ee. Optionally, the process further comprises the steps of: (f) recrystallizing the isolated (S)-2-methylpyrrolidine D-tartrate; (g) isolating the recrystallized (S)-2-methylpyrrolidine D-tartrate; and (h) optionally repeating steps (f) and (g). 30 Optionally, the process further comprises the step of reacting the isolated recrystallized (S)-2-methylpyrrolidine D-tartrate with a base to provide (S)-2 methylpyrrolidine. -4- Optionally, the process further comprises the step of converting the prepared (S)-2 methylpyrrolidine D-tartrate into an H3 receptor ligand, preferably 6- {4-[3-((S)-2-methyl pyrrolidin-1 -yl)-propoxy]-phenyl}-2H-pyridazin-3-one: H 0 N,N NN o O N 5 DETAILED DESCRIPTION OF THE INVENTION Definitions "About" refers to a range of values ± 10% of a specified value; for example, the phrase "about 50" includes ± 10% of 50, or from 45 to 55. 10 "Alcohol solvent" refers to a C 1
-C
6 alkyl alcohol or a mixture of Ci-C 6 alkyl alcohols. "Commercial scale" refers to a single batch of at least about 500 grams. "Crystallizing" refers to causing crystals to form.
"H
3 receptor ligand" refers to a compound that interacts with the histamine H 3 receptor as an antagonist, agonist, or partial agonist. 15 "Heterogeneous catalyst" refers to a hydrogenation catalyst that is not soluble in an alcohol solvent. "Homogeneous catalyst" refers to a hydrogenation catalyst that is soluble in an alcohol solvent. "Hydrogenation catalyst" refers to a composition suitable for catalyzing the reaction of 2 20 methylpyrroline with hydrogen to form 2-methylpyrrolidine. "Isolating" refers to separating a component (e.g., a reagent or product) from a mixture. "Optical purity" refers to the proportion of one enantiomer in a mixture of enantiomers, and is expressed as enantiomeric excess (% ee), which is defined as (IR - SI/(R + S))* 100%, wherein R and S are the respective fractions of enantiomers such that R 25 +S= 1. "Pharmaceutical product" refers to a compound or composition that can be used to treat a disease, condition, or disorder in a human. "Platinum catalyst" refers to a hydrogenation catalyst that contains platinum. "Purifying" refers to increasing the purity of a compound. -5- WO 2008/137087 PCT/US2008/005702 "Purity" refers to the percentage by weight of one component in a mixture. "Solution" refers to a solvent containing a substance(s) that is at least partially dissolved; and which may contain an undissolved (e.g., solid) substance(s). All publications referenced herein are incorporated by reference in their entireties 5 for all purposes. Description The present invention provides processes for preparing (R)-2-methylpyrrolidine L tartrate or (S)-2-methylpyrrolidine D-tartrate, comprising the steps of: (a) hydrogenating 2-methylpyrroline in a mixture comprising an alcohol solvent 10 and a hydrogenation catalyst; (b) optionally removing the hydrogenation catalyst from the mixture; (c) dissolving L-tartaric acid or D-tartaric acid in the mixture to form a solution; (d) crystallizing (R)-2-methylpyrrolidine L-tartrate or (S)-2-methylpyrrolidine D tartrate from the solution; and 15 (e) isolating the crystalline (R)-2-methylpyrrolidine L-tartrate or (S)-2 methylpyrrolidine D-tartrate. Step (a) In step (a), 2-methylpyrroline is hydrogenated in a mixture comprising an alkyl alcohol solvent and a hydrogenation catalyst. The 2-methylpyrroline used in the 20 hydrogenation reaction may be purchased from commercial sources (e.g., Sigma-Aldrich Corp.; St. Louis, MO). An important benefit of the present process is that 2 methylpyrroline is less expensive than other starting materials used for the production of (R)- and (S)-2-methylpyrrolidine. The hydrogenation catalyst used in the reaction may be purchased from 25 commercial sources (e.g., Sigma-Aldrich Corp.; St. Louis, MO). The hydrogenation catalyst can be a homogeneous catalyst or a heterogeneous catalyst. Examples of hydrogenation catalysts include, but are not limited to, platinum catalysts. Examples of platinum catalysts include, but are not limited to, platinum on carbon (Pt/C), platinum (IV) oxide, and mixtures thereof. Examples of homogeneous catalysts include, but are not 30 limited to, chlorotris(triphenylphosphine)rhodium (Wilkinson's catalysts) and catalysts disclosed in U.S. Patent Nos. 4,581,417, 4,631,315, and 5,670,437. Preferably, the hydrogenation catalyst is platinum (IV) oxide. More preferably, the hydrogenation catalyst is 5% Pt-C. -6- WO 2008/137087 PCT/US2008/005702 The alcohol solvent used in the reaction is a Ci-C 6 alkyl alcohol or a mixture of Ci
C
6 alkyl alcohols. Examples of Ci-C 6 alkyl alcohols include, but are not limited to, methanol, ethanol, isopropanol, and n-butanol. Preferably, the alcohol solvent comprises ethanol. Preferably, the alcohol solvent comprises methanol. More preferably, the alcohol 5 solvent is a mixture of ethanol and methanol. More preferably, the alcohol solvent is a mixture of ethanol and methanol at a ratio of about 0.5:1 to about 10:1 (v/v). More preferably, the alcohol solvent is a mixture of ethanol and methanol at a ratio of about 1:1 to about 5:1 (v/v). More preferably, the alcohol solvent is a mixture of ethanol and methanol at a ratio of about 2:1 to about 3:1 (v/v). More preferably, the alcohol solvent is 10 a mixture of ethanol and methanol at a ratio of about 2.4:1 (v/v). The alcohol solvent may be present in any suitable amount in the step (a) reaction mixture. Preferably, the alcohol solvent comprises at least about 50% (w/w) of the reaction mixture. More preferably, the alcohol solvent comprises at least about 70% (w/w) of the reaction mixture. More preferably, the alcohol solvent comprises at least 15 about 90% (w/w) of the reaction mixture. More preferably, the alcohol solvent comprises at least about 95% (w/w) of the reaction mixture. Notably, Ci-C 6 alkyl alcohols are more readily removed from the reaction mixture as compared to acetic acid. In addition, CI
C
6 alkyl alcohols are non-corrosive. The hydrogen (H2) used in the hydrogenation reaction may be added to the reaction 20 mixture as a gas, such as by performing the reaction in a hydrogen atmosphere, or generated in situ, such as by treatment of H 2 PtC 6 or RhCl 3 with NaBH 4 (see Brown and Sivasankaran, J. Am. Chem. Soc. 1962, 84, 2828). In certain embodiments, the hydrogenation reaction is performed by adding gaseous hydrogen to the reaction mixture. In preferred embodiments, the hydrogenation is performed above atmospheric pressure. In 25 certain embodiments, the reaction is performed by generating hydrogen in situ. The hydrogenation reaction may be performed at any suitable temperature. Preferably, the reaction is performed at ambient temperature. An advantage of the present process is that the hydrogenation reaction is performed in a non-corrosive alkyl alcohol solvent. Another advantage of the present 30 process is that the product of the hydrogenation reaction (i.e., 2-methylpyrrolidine) is obtained directly without the need to prepare or isolate intermediates, such as intermediate salts. Step (b) -7- Step (b) is an optional step. In step (b), the hydrogenation catalyst is removed from the hydrogenation reaction mixture. Preferably, the hydrogenation catalyst is removed from the hydrogenation reaction mixture after step (a). Preferably, step (b) is performed prior to step (d), particularly when the hydrogenation catalyst is a 5 heterogeneous catalyst. Suitable methods for removing the hydrogenation catalyst include, but are not limited to, filtering, decanting, and centrifuging. In certain embodiments, the hydrogenation catalyst is removed by filtration. While hydrogenation catalysts are generally precious metal-based, an advantage of the present process is that the hydrogenation catalyst may be removed from the mixture, recycled and reused in 10 subsequent hydrogenation reactions (see, e.g., US 5,554,353 (Schneider et al.); EP 1 739 104 Al (Kobayashi et al.); Setty-Fichman, et al., J. MoL Cat. A: Chem., 1999, 144(1), 159-163. Step (c) 15 In step (c), L-tartaric acid or D-tartaric acid is dissolved in the hydrogenation reaction mixture to form a solution. If the desired product is (R)-2-methylpyrrolidine, then L-tartaric acid is used. If the desired product is (S)-2-methylpyrrolidine, then D-tartaric acid is used. The L-tartaric acid or D-tartaric acid used in the present process may be purchased from commercial sources (e.g., Sigma-Aldrich Corp.; St. Louis, MO). 20 Preferably, the solution formed in step (c) is homogeneous. If the solution is not homogeneous (e.g., contains undissolved particles), the solution is preferably heated to promote dissolution. An advantage of the present process is that it does not require the 2 methylpyrrolidine prepared in the hydrogenation reaction to be isolated from the reaction 25 mixture before the addition of tartaric acid. This makes the process simpler, faster, less expensive, and less wasteful as compared to prior art processes. Step (d) In step (d), (R)-2-methylpyrrolidine L-tartrate or (S)-2-methylpyrrolidine D-tartrate 30 is crystallized from the solution prepared in step (c). If L-tartaric acid is added in step (c), then (R)-2-methylpyrrolidine L-tartrate is crystallized from the solution in step (d). If D tartaric acid is added in step (c), then (S)-2-methylpyrrolidine D-tartrate is crystallized from the solution in step (d). Any suitable method may be used to crystallize (R)-2 methylpyrrolidine L-tartrate or (S)-2-methylpyrrolidine D-tartrate from the solution. In -8- WO 2008/137087 PCT/US2008/005702 certain embodiments, the solution is heated to promote dissolution, and then cooled to induce crystallization. Step (e) 5 In step (e), the crystalline (R)-2-methylpyrrolidine L-tartrate or (S)-2 methylpyrrolidine D-tartrate is isolated. If L-tartaric acid is added in step (c), then (R)-2 methylpyrrolidine L-tartrate is crystallized from the solution in step (d) and isolated in step (e). If D-tartaric acid is added in step (c), then (S)-2-methylpyrrolidine D-tartrate is crystallized from the solution in step (d) and isolated in step (e). Suitable methods for 10 isolating the crystalline (R)-2-methylpyrrolidine L-tartrate or (S)-2-methylpyrrolidine D tartrate include, but are not limited to, filtering, decanting, and centrifuging. An advantage of the present process is that the product can be isolated by simple filtration. Preferably, the (R)-2-methylpyrrolidine L-tartrate or (S)-2-methylpyrrolidine D-tartrate is isolated by filtration. It is understood that the isolated (R)-2-methylpyrrolidine L-tartrate is likely to 15 contain some (S)-2-methylpyrrolidine L-tartrate, and the isolated (S)-2-methylpyrrolidine D-tartrate is likely to contain some (R)-2-methylpyrrolidine D-tartrate, which will reduce the optical purity of the isolated product. Preferably, the isolated (R)-2-methylpyrrolidine L-tartrate or (S)-2-methylpyrrolidine D-tartrate has an optical purity of at least 40% ee. More preferably, the isolated (R)-2-methylpyrrolidine L-tartrate or (S)-2 20 methylpyrrolidine D-tartrate has an optical purity of at least 50% ee. More preferably, the isolated (R)-2-methylpyrrolidine L-tartrate or (S)-2-methylpyrrolidine D-tartrate has an optical purity of at least 55% ee. Optional additional steps 25 The present process for preparing (R)-2-methylpyrrolidine L-tartrate or (S)-2 methylpyrrolidine D-tartrate is advantageous in that it utilizes inexpensive and non corrosive reagents and solvents, can be conveniently and inexpensively conducted at temperatures between 0 *C and 25 'C, requires the preparation of only one intermediate compound, does not require the isolation of synthetic intermediates, permits catalyst 30 recycling, and provides a product that can be isolated by simple filtration and then used in subsequent processes. The isolated product is a tartrate acid addition salt of (R)- or (S)-2 methylpyrrolidine free base. If desired, the salt may be converted to (R)- or (S)-2 methylpyrrolidine free base. The resulting free base may be isolated using techniques -9- WO 2008/137087 PCT/US2008/005702 known in the art. Preferably, the free base may be generated in situ and used in the next synthetic step without isolation. The methods described herein are applicable to both the isolated 2-methylpyrrolidine free base and the 2-methylpyrrolidine free base generated in situ in a reaction mixture. 5 Thus, in certain embodiments the process further comprises the step of: reacting the isolated (R)-2-methylpyrrolidine L-tartrate or (S)-2-methylpyrrolidine D-tartrate with a base to provide (R)-2-methylpyrrolidine or (S)-2-methylpyrrolidine. Suitable bases for use in this reaction include, but are not limited to, ammonium hydroxide, alkali metal hydroxides (e.g., sodium hydroxide, potassium hydroxide), alkylamines (e.g., 10 triethylamine, diisopropylethylamine), and mixtures thereof. Suitable solvents for use in this reaction include, but are not limited to, diethyl ether and dichloromethane. In addition, the 2-methylpyrrolidine free base can be generated from the corresponding tartrate salt using ion-exchange resin using procedures known to those in the art. Preferably, the prepared (R)-2-methylpyrrolidine L-tartrate, (S)-2 15 methylpyrrolidine D-tartrate, (R)-2-methylpyrrolidine, or (S)-2-methylpyrrolidine has an optical purity of at least 50% ee. This means that the major enantiomer constitutes 75% of the mixture, and the minor enantiomer 25% (50% ee = ((0.75-0.25)/(0.75+0.25)* 100%). This level of purity is often sufficient for the product to be used as a reagent in a subsequent synthetic process. For example, when (R)-2-methylpyrrolidine L-tartrate 20 having an optical purity of 50% ee is used to prepare a compound having an additional stereogenic center(s), the reaction will produce a mixture of diastereomers, and the minor diastereomer(s) formed from the (S)-2-methylpyrrolidine may be removed during ordinary purification of the major diastereomer(s) formed from the (R)-2-methylpyrrolidine. If a higher level of optical purity is desired, the obtained (R)-2-methylpyrrolidine 25 L-tartrate or (S)-2-methylpyrrolidine D-tartrate may be recrystallized. Therefore, in certain embodiments the process may further comprise the steps of: (f) recrystallizing the isolated (R)-2-methylpyrrolidine L-tartrate or (S)-2 methylpyrrolidine D-tartrate; (g) isolating the recrystallized (R)-2-methylpyrrolidine L-tartrate or (S)-2 30 methylpyrrolidine D-tartrate; and (h) optionally repeating steps (f) and (g). Step (f) -10- WO 2008/137087 PCT/US2008/005702 In step (f), the (R)-2-methylpyrrolidine L-tartrate or (S)-2-methylpyrrolidine D tartrate isolated in step (e) is recrystallized. Suitable methods for recrystallizing the isolated (R)-2-methylpyrrolidine L-tartrate or (S)-2-methylpyrrolidine D-tartrate include, but are not limited to, dissolving the isolated tartrate salt in a suitable solvent and then 5 cooling the solution to promote crystallization. Suitable recrystallization solvents include, but are not limited to, alcohol solvents. Preferably, the recrystallization solvent is an alcohol solvent comprising at least about 70% (v/v) of ethanol and methanol. More preferably, the recrystallization solvent is an alcohol solvent comprising at least about 70% (v/v) of ethanol and methanol at a ratio of about 1:1 to about 5:1 (v/v). More 10 preferably, the recrystallization solvent is an alcohol solvent comprising at least about 70% (v/v) of ethanol and methanol at a ratio of about 2:1 to about 3:1 (v/v). More preferably, the recrystallization solvent is an alcohol solvent comprising at least about 90% (v/v) of ethanol and methanol. More preferably, the recrystallization solvent is an alcohol solvent comprising at least about 90% (v/v) of ethanol and methanol at a ratio of 15 about 1:1 to about 5:1 (v/v). More preferably, the recrystallization solvent is an alcohol solvent comprising at least about 90% (v/v) of ethanol and methanol at a ratio of about 2:1 to about 3:1 (v/v). Step () 20 In step (g), the recrystallized (R)-2-methylpyrrolidine L-tartrate or (S)-2 methylpyrrolidine D-tartrate is isolated. Suitable methods for isolating the recrystallized tartrate salt include, but are not limited to, filtering, decanting, and centrifuging. Preferably, the recrystallized (R)-2-methylpyrrolidine L-tartrate or (S)-2-methylpyrrolidine D-tartrate is isolated by filtration. 25 Subjecting the tartrate salt isolated in step (e) to a single recrystallization sequence according to steps (f) and (g) preferably provides isolated (R)-2-methylpyrrolidine L tartrate or (S)-2-methylpyrrolidine D-tartrate having an optical purity of at least 80% ee. More preferably, the (R)-2-methylpyrrolidine L-tartrate or (S)-2-methylpyrrolidine D tartrate isolated in step (g) has an optical purity of at least 85% ee. An optical purity of 30 85% ee means that the major enantiomer constitutes more than 92% of the mixture, and the minor enantiomer less than 8% (84% ee = ((0.925-0.075)/(0.925+0.075)* 100%), which is often of sufficient purity for use in subsequent synthetic processes. Step (h) - 11 - WO 2008/137087 PCT/US2008/005702 If higher optical purity is desired, the recrystallization sequence (i.e., steps (f) and (g)) may be repeated one or more times to increase the optical purity of the (R)-2 methylpyrrolidine L-tartrate or (S)-2-methylpyrrolidine D-tartrate. After two recrystallizations, the (R)-2-methylpyrrolidine L-tartrate or (S)-2-methylpyrrolidine D 5 tartrate preferably has an optical purity of at least 90% ee. More preferably, the isolated recrystallized (R)-2-methylpyrrolidine L-tartrate or (S)-2-methylpyrrolidine D-tartrate has an optical purity of at least 93% ee. After three (3) recrystallizations, the (R)-2 methylpyrrolidine L-tartrate or (S)-2-methylpyrrolidine D-tartrate preferably has an optical purity of at least 95% ee. More preferably, the isolated recrystallized (R)-2 10 methylpyrrolidine L-tartrate or (S)-2-methylpyrrolidine D-tartrate has an optical purity of at least 97% ee. After four (4) recrystallizations, the (R)-2-methylpyrrolidine L-tartrate or (S)-2-methylpyrrolidine D-tartrate preferably has an optical purity of at least 98% ee. Free base 15 Optionally, the process may further comprise the step of reacting the isolated recrystallized (R)-2-methylpyrrolidine L-tartrate or (S)-2-methylpyrrolidine D-tartrate with a base to provide (R)-2-methylpyrrolidine or (S)-2-methylpyrrolidine. Suitable bases for use in this reaction include, but are not limited to, ammonium hydroxide, alkali metal hydroxides (e.g., sodium hydroxide, potassium hydroxide), alkylamines (e.g., 20 triethylamine, diisopropylethylamine), and mixtures thereof. Suitable solvents for use in this reaction include, but are not limited to, diethyl ether and dichloromethane. In addition, the 2-methylpyrrolidine free base can be generated from the corresponding tartrate salt using ion-exchange resin using procedures known to those in the art. The resulting free base may be isolated using techniques known in the art. 25 Preferably, the free base may be generated in situ and used in the next synthetic step without isolation. The methods described herein are applicable to both the isolated 2 methylpyrrolidine free base and the 2-methylpyrrolidine free base generated in situ in a reaction mixture. 30 Additional compounds In addition to providing convenient methods of preparing (R)- and (S)-2 methylpyrrolidine and their respective tartaric acid salts, the present invention also provides methods for incorporating 2-methylpyrrolidine into other compounds, in particular, pharmaceutically useful compounds. The (R)-2-methylpyrrolidine L-tartrate or - 12 - WO 2008/137087 PCT/US2008/005702 (S)-2-methylpyrrolidine D-tartrate obtained after steps (e), (g) or (h) may be used. In certain embodiments, an initial step in the conversion may be to transform the (R)-2 methylpyrrolidine L-tartrate or (S)-2-methylpyrrolidine D-tartrate salt form into the corresponding free base form (i.e., (R)-2-methylpyrrolidine or (S)-2-methylpyrrolidine, 5 respectively) by reaction with a base or an ion exchange resin. This (R)-2 methylpyrrolidine or (S)-2-methylpyrrolidine, whether isolated or prepared in situ, may then be used to prepare a number of pharmaceutical compounds, for example, histamine-3 receptor ligands, known in the art. For example, the (R)-2-methylpyrrolidine or (S)-2-methylpyrrolidine prepared by 10 the foregoing processes may be converted into an H 3 receptor antagonist and/or inverse agonist of formula (I): 0 R N O N (I) O R2 wherein R' is F F_* CIN " '1 15 0 FF F F F FF N N F F F F NC
H
3 C
H
3 C
R
2 is pH 3 CH3 N N-N or 20 or a pharmaceutically acceptable salt thereof. - 13 - WO 2008/137087 PCT/US2008/005702 Suitable methods for preparing a compound of formula (I) from 2 methylpyrrolidine are described in WO 2007/009741, and may be adapted for use with the (R)-2-methylpyrrolidine or (S)-2-methylpyrrolidine prepared in accordance with foregoing processes. For example, a solution of 1,1 dimethylethyl 4-{4-[(3 5 chloropropyl)oxy]phenyl}-3-oxo-1-piperazinecarboxylate dissolved in 2 butanone may be provided. Potassium carbonate, potassium iodide and (R)-2-methylpyrrolidine or (S)-2 methylpyrrolidine free base may be added, and the mixture heated at 80*C for 24 hours. The reaction may then be cooled to room temperature and partitioned between EtOAc and water. The organic phase may be dried and concentrated, the residue purified by flash 10 chromatography and the appropriate fractions combined and concentrated to give a BOC protected amine of formula (II): 00 O 0N O R p H3 CH3 (N wherein R 2 is or (i.e., the compound 1,1 -dimethylethyl 4-(4- {[3 (2R-methyl-1-pyrrolidinyl)propyl]oxy}phenyl)-3-oxo-1-piperazinecarboxylate or 1,1 15 dimethylethyl 4-(4-{[3-(2S-methyl-1-pyrrolidinyl)propyl]oxy}phenyl)-3-oxo-1 piperazinecarboxylate). The BOC protecting group in the compound of formula (II) can then be removed (e.g., by reaction with trifluoroacetic acid) to form an amine of formula (III): H N N (III) O R2
CH
3 CH3 20 wherein R 2 is or . The amine of formula (III) can then be reacted with a carboxylic acid chosen from 4-cyanobenzoic acid, 4-(1 -azetidinylcarbonyl)benzoic acid, 2,4-difluorobenzoic acid, 3,5-difluorobenzoic acid, 4-fluorobenzoic acid, 1-methyl 1H-1,2,3-triazole-4-carboxylic acid, 1,5-dimethyl-1H-pyrazole-3-carboxylic acid, 1 methyl-5-oxo-3-pyrrolidinecarboxylic acid, 3,5-dimethyl-4-isoxazolecarboxylic acid, 1,3 - 14 - WO 2008/137087 PCT/US2008/005702 dimethyl-1H-pyrazole-5-carboxylic acid, 2,3-difluorobenzoic acid, 2,5-difluorobenzoic acid, 2,6-difluorobenzoic acid, and 3,4-difluorobenzoic acid to form a compound of formula (I). The 1,1-dimethylethyl-4-{4-[(3-chloropropyl)oxy]phenyl}-3-oxo-1 5 piperazinecarboxylate used in the preparation of the BOC-protected amine of formula (II) can be prepared by reacting 1 -bromo-3-chloropropane with 1,1 -dimethylethyl-4-(4 hydroxyphenyl)-3-oxo-1-piperazinecarboxylate, which can be prepared by catalytic hydrogenolysis of 1,1-dimethylethyl-3-oxo-4-{4-[(phenylmethyl)oxy]phenyl}-1 piperazinecarboxylate, which can be prepared by reacting methanesulfonyl chloride with 10 1,1 -dimethylethyl-(2-hydroxyethyl)[2-oxo-2-({4 [(phenylmethyl)oxy]phenyl}amino)ethyl]carbamate, which can be prepared by BOC protection of N 2 -(2-hydroxyethyl)-N'-{4-[(phenylmethyl)oxy]phenyl}glycinamide, which can be prepared by reacting 4-[(phenylmethyl)oxy] aniline with chloroacetyl chloride and then 2-aminoethanol. 15 As an alternative to BOC, other nitrogen protecting groups known in the art may be used. Examples of suitable nitrogen protecting groups are described in Green, T.W.; Wutz, P.G.M. Protective Groups in Organic Synthesis, 2d ed.; John Wiley and Sons: New York, 1991. Thus one embodiment of the invention relates to a process for preparing a 20 compound of formula (I): 0 R N O R1~N N (I) O R2 wherein R' and R 2 are defined as set forth above comprising the steps of: (la) hydrogenating 2-methylpyrroline in a mixture comprising an alcohol solvent and a hydrogenation catalyst; 25 (lb) optionally removing the hydrogenation catalyst from the mixture; (Ic) dissolving L-tartaric acid in the mixture to form a solution; (1 d) crystallizing (R)-2-methylpyrrolidine L-tartrate from the solution; (le) isolating the crystalline (R)-2-methylpyrrolidine L-tartrate; and - 15 - (2a) converting the isolated (R)-2-methylpyrrolidine L-tartrate into a compound of formula 1. This process may optionally further include the steps of: (1f) recrystallizing the isolated (R)-2-methylpyrrolidine L-tartrate; 5 (1g) isolating the recrystallized (R)-2-methylpyrrolidine L-tartrate; and (Ih) optionally repeating steps (lf) and (Ig). In another embodiment, the invention relates to a process for preparing a compound of formula (1): 0 RJ N O N (I) O R 2 10 wherein R' and R 2 are defined as set forth above comprising the steps of: (1 a) hydrogenating 2-methylpyrroline in a mixture comprising an alcohol solvent and a hydrogenation catalyst; (lb) optionally removing the hydrogenation catalyst from the mixture; (1 c) dissolving L-tartaric acid in the mixture to form a solution; 15 (ld) crystallizing (R)-2-methylpyrrolidine L-tartrate from the solution; (1 e) isolating the crystalline (R)-2-methylpyrrolidine L-tartrate; (10 reacting the (R)-2-methylpyrrolidine L-tartrate with a base to provide (R)-2 methylpyrrolidine; (2) reacting the (R)-2-methylpyrrolidine with a protected amine of formula (Ia) PG' N 0 (:N 20 (Ia) wherein PG is a protecting group, to form a protected amine of formula (II) PG'N O NN O R2 (3) removing the protecting group from the protected amine of formula (II) to form an amine of formula (III) -16- HN O (III); and (4) reacting the amine of formula (III) with a carboxylic acid chosen from 4 cyanobenzoic acid, 4-(1 -azetidinylcarbonyl)benzoic acid, 2,4-difluorobenzoic acid, 3,5 difluorobenzoic acid, 4-fluorobenzoic acid, 1-methyl-lH-1,2,3-triazole-4-carboxylic acid, 5 1,5-dimethyl-1H-pyrazole-3-carboxylic acid, 1-methyl-5-oxo-3-pyrrolidinecarboxylic acid, 3,5-dimethyl-4-isoxazolecarboxylic acid, 1,3-dimethyl-1H-pyrazole-5-carboxylic acid, 2,3-difluorobenzoic acid, 2,5-difluorobenzoic acid, 2,6-difluorobenzoic acid, and 3,4-difluorobenzoic acid to form a compound of formula (I). This process may optionally further include the steps of: 10 (1f) recrystallizing the isolated (R)-2-methylpyrrolidine L-tartrate; (1g) isolating the recrystallized (R)-2-methylpyrrolidine L-tartrate; and (lh) optionally repeating steps (If) and (Ig). Preferably, the protecting group is BOC. Another compound which demonstrates histamine-3 receptor ligand activity is 2 15 (6-{2-[(2R)-2-methyl- 1 -pyrrolidin- l-yl]-ethyl) -2-naphthalen-2-yl)-2H-pyridazin-3 -one. One process for the preparation of this compound is described in US 2005/0256127. 6-Bromo-naphthalen-2-ol can be treated with any suitable trifluoromethanesulfonic reagent in the presence of an organic base to provide a trifluoro-methanesulfonic acid 6 bromo-naphthalen-2-yl ester. Examples of suitable trifluoromethanesulfonic reagents are, 20 for example, trifluoromethanesulfonyl acid anhydride, trifluoromethanesulfonyl chloride, N-phenyltrifluoromethanesulfonimide, trifluoromethanesulfonyl- 1- -H-imidazole, trifluoromethanesulfonyl acid anilide, trifluoromethanesulfony acid-2-nitrophenyl ester, trifluoromethanesulfony- 1 acid-4-nitrophenyl ester. Examples of organic base are, for example, triethylamine, diisopropylamine, diisopropylethylamine, 2,6-lutidine, pyridine, 25 and 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU). The reaction can be accomplished in any suitable organic solvent. Examples of suitable solvents are CH 2 Cl 2 , dimethyl ether (DME), and toluene. The reaction also can be carried out in a biphasic condition where an inorganic base is used. For example, suitable - 17- WO 2008/137087 PCT/US2008/005702 inorganic bases are K 3
PO
4 , NaHCO 3 , Na 2
CO
3 , NaOH, and the like. The preferred solvent is toluene. Typically, the reaction is accomplished in biphasic conditions, for example use of toluene and 30% potassium phosphate, at low temperatures. The preferred temperature range for the reaction is from about -5 *C to about 0 'C. 5 The trifluoro-methanesulfonic acid 6-bromo-naphthalen-2-yl ester is converted to 2-bromo-6-vinyl-naphthalene via reaction with a vinyltrifluoroborate reagent. Suitable vinyltrifluoroborate reagents are, for example, potassium vinyltriflurorborate, 2-vinyl 4,4,5,5-tetramethyl-1,3,2-dioxaborolane, dibutyl vinylboronate. The reagent is used in an ,amount of from about 1.0 molar equivalent to about 1.5 molar equivalents relative to the 10 trifluoro-methanesulfonic acid 6-bromo-naphthalen-2-yl ester. Typically, the reaction is carried out in a polar organic solvent, for example an alcohol, and a basic solution, for example a metal carbonate solution. A preferred solvent is ethanol. Examples of other solvents that can be used for the reaction are n-propanol, iso-propanol, methanol, and other suitable alcohols. The metal carbonate preferably is cesium carbonate. 15 Alternatively, other salts, for example Na 2
CO
3 , and K 3
PO
4 also can be used. The amount of metal carbonate for the reaction is from about 2 molar equivalents to about 4 molar equivalents relative to the trifluoro-methanesulfonic acid 6-bromo-naphthalen-2-yl ester. The reaction is accomplished in the presence of a palladium catalyst and an organic amino base, for example, such as triethylamine, diisopropylamine, and the like. Examples of 20 palladium catalysts for the reaction include, but are not limited to, tetrakis(triphenylphosphine)palladium, PdCl 2 (dppf) 2 , PdC 2 (Ph 3
P)
2 , and PdCl 2
(CH
3
CN)
2 . The preferred palladium catalyst is tetrakis(triphenylphosphine)palladium. 2-Bromo-6-vinyl-naphthalene may treated with an (R)-2-methylpyrrolidine anion generated with n-butyllithium to provide 1-[2-(6-bromo-naphthalen-2-yl)-ethyl]-(R)-2 25 methyl-pyrrolidine. The method described in US2005/0256127 may be improved by preparing (R)- and/or (S)-2-methylpyrrolidine in accordance with foregoing processes. 2 bromo-6-vinyl-naphthalene may then be reacted with an (R)-2-methylpyrrolidine anion generated with n-butyllithium, or any other suitable base, to provide 1-[2-(6-bromo naphthalen-2-yl)-ethyl]-2R-methyl-pyrrolidine. 2-Bromo-6-vinyl-naphthalene may treated 30 with an (R)-2-methylpyrrolidine anion generated with n-butyllithium to provide 1-[2-(6 bromo-naphthalen-2-yl)-ethyl]-(R)-2-methyl-pyrrolidine. Preferably, about 1.2 to about 2.5 molar equivalents of (R)-2-methylpyrrolidine are used for the reaction. The reaction - 18- WO 2008/137087 PCT/US2008/005702 typically is accomplished in an organic solvent, for example, THF, methyl-t-butyl ether (MTBE), Et 2 0, and DME. The preferred solvent is tetrahydrofuran (THF). The n butyllithium is added to a THF solution of (R)-2-methylpyrrolidine in a controlled fashion, typically in a dropwise manner. To this solution is added a THF solution of 2-bromo-6 5 vinyl-naphthalene. Alternatively, it is also suitable to add the THF solution of 2-bromo-6 vinyl-naphthalene to the solution of (R)-2-methylpyrrolidine and n-butyllithium. The reaction is accomplished at below room temperature, typically in a temperature range from about 0 *C to about -20 *C. From about 0.3 to about 0.7 molar equivalents of n butyllithium are used relative to the 2-bromo-6-vinylnaphthalene compound. The 10 resulting compound is 1-[2-(6-bromo-naphthalen-2-yl)-ethyl]-(R)-2-methyl-pyrrolidine. The 1-[2-(6-bromo-naphthalen-2-yl)-ethyl]-(R)-2-methyl-pyrrolidine may then be reacted with 2H-pyridazin-3-one to provide the desired 2-{6-[2-((R)2-methyl-pyrrolidin-1 yl)-ethyl]-naphthalen-2-yl}-2H-pyridazin-3-one compound, which can be further processed to prepare a suitable salt. The reaction is accomplished using 2H-pyridazin-3 15 one, 8-hydroxyquinoline, a copper catalyst in the presence of base. From about 1.0 to about 1.5 molar equivalents of (2H)-pyridazin-3-one are used relative to the 1-[2-(6 bromo-naphthalen-2-yl)-ethyl]-(R)-2-methyl-pyrrolidine. The copper catalyst can be any suitable copper catalyst, for example copper (I) catalysts. Examples of suitable catalysts for the reaction include but are not limited to copper (0) powder, copper (I) chloride, 20 copper (I) bromide, copper (I) iodide, copper (I) oxide, copper (I) acetate, copper (II) chloride, copper (II) bromide, copper (II) iodide, copper (II) oxide, or copper (II) acetate. The preferred copper catalyst is copper (I) chloride. About 0.02 to about 1.0 molar equivalents of copper catalyst are used relative to the 1-[2-(6-bromo-naphthalen-2-yl) ethyl]-(R)-2-methyl-pyrrolidine. Examples of suitable ligands for the reaction include, but 25 are not limited to p-dimethylaminopyridine, pyridine, 3-picoline, 4-picoline, 8 hydroxyquinoline, 7-methyl-8-hydroxyquinoline, 7-n-propyl-8-hydroxyquinoline, 1,10 phenanthroline, and 2,2'-dipyridyl. The preferred ligand is 8-hydroxyquinoline, which is used in an amount of from about 0.02 to about 2.0 molar equivalents relative to the 1-[2 (6-bromo-naphthalen-2-yl)-ethyl]-(R)-2-methyl-pyrrolidine. Preferably, the base is a 30 metal carbonate or a metal alkoxide, for example cesium carbonate, potassium carbonate, sodium carbonate, and sodium tert-butoxide. The preferred base is potassium carbonate, which is used in an amount of from about 1.0 to about 2.0 molar equivalents relative to the 1-[2-(6-bromo-naphthalen-2-yl)-ethyl]-(R)-2-methyl-pyrrolidine. The reaction is - 19accomplished at elevated temperatures in a polar organic solvent. Examples of suitable solvents include but are not limited to N,N-dimethylformamide, N-methylpyrrolidinone, N,N-dimethylacetamide, pyridine, 3-picoline, 4-picoline, and the like. The preferred solvent is dimethylformamide (DMF). Typically, the reaction is accomplished under a 5 nitrogen atmosphere, and the reaction mixture is heated to temperatures of from about 100 'C. to about 160 0 C. The reaction typically can be accomplished in about 10 to about 48 hours. When the reaction is completed and cooled to 25 *C., a non-water miscible solvent, for example ethyl acetate, is added. The organic solution is washed with a brine aqueous solution, for example 25% NaCl solution or other suitable salt solution several times. The 10 organic solution is dried, and concentrated to dryness to give the product. Alternatively, a 2-(6- {2- [(2R)-2-methyl- 1 -pyrrolidin- I -yl] -ethyl } -2-naphthalen-2 yl)-2H-pyridazin-3 -one active agent can be prepared according to procedures described in US 7,153,889, filed on Oct. 22, 2003, at least in, for example, the general procedures and Example 31, or any other suitable procedure for providing a stable active agent. Briefly, 15 for example, a 6-bromo-2-naphthoate is reduced using BH 3 -THF to provide the corresponding alcohol. 6-Bromo-naphthalen-2-yl-methanol is treated with 3(2H) pyridazinone, copper powder, and base to provide 2-[6-(2-hydroxy-ethyl)-naphthalen-2-yl ]-2H-pyridazin-3-one, which is activated with a sulfonate, such as tosylate. (R) 2 methylpyrrolidine that has been prepared in accordance with the foregoing steps (a) to (e), 20 with or without optional steps (f) to (h) and reacting the (R)-2-methylpyrrolidine L-tartrate with a base to provide (R)-2-methylpyrrolidine is provided, and the sulfonate reacted with said (R)-2-methylpyrrolidine to afford 2 -(6- {(2R)2-methyl- I -pyrrolidin- 1 -yl] -ethyl } -2 naphthalen-2-yl)-2H-pyridazin-3 -one. Thus one embodiment of the invention relates to a method of preparing a 2- {6-[2 25 (2-methyl-pyrrolidin- 1 -yl)-ethyl] -naphthalen-2-yl} -2H-pyridazin-3 -one, comprising the steps of: (la) hydrogenating 2-methylpyrroline in a mixture comprising an alcohol solvent and a hydrogenation catalyst; (1b) optionally removing the hydrogenation catalyst from the mixture; 30 (1c) dissolving L-tartaric acid or D-tartaric acid in the mixture to form a solution; - 20 - (1 d) crystallizing (R)-2-methylpyrrolidine L-tartrate or (S)-2-methylpyrrolidine D-tartrate from the solution; (1 e) isolating the crystalline (R)-2-methylpyrrolidine L-tartrate or (S)-2 methylpyrrolidine D-tartrate; and 5 (2a) contacting the (R)-2-methylpyrrolidine L-tartrate with a base to form (R)-2 methylpyrrolidine free base or contacting the (S)-2-methylpyrrolidine D-tartrate with a base for form (S)-2-methylpyrrolidine; (3a) converting trifluoro-methanesulfonic acid 6-bromo-naphthalen-2-yl ester to 2-bromo-6-vinyl-naphthalene; 10 (3b) reacting 2-bromo-6-vinyl-naphthalene with (R)-2-methylpyrrolidine or (S) 2-methylpyrrolidine in the presence of n-butyllithium to provide 1-[2-(6-bromo naphthalen-2-yl)-ethyll-2R-methyl-pyrrolidine or 1-{2-(6-bromo-naphthalen-2-yl)-ethyl] 2S-methyl-pyrrolidine; and (3c) reacting 1-[2-(6-bromo-naphthalen-2-yl)-ethyl]-2-methyl-pyrrolidine with 15 2H-pyridazin-3-one to provide 2- {6-[2-(2-methyl-pyrrolidin- 1 -yl)-ethyl}-naphthalen-2 yl) -2H-pyridazin-3-one. This method may optionally further include the steps of: (1) recrystallizing the isolated (R)-2-methylpyrrolidine L-tartrate; (1 g) isolating the recrystallized (R)-2-methylpyrrolidine L-tartrate; and 20 (lh) optionally repeating steps (If) and (Ig). Additionally, the trifluoro-methanesulfonic acid 6-bromo-naphthalen-2-yl ester may be obtained by: providing 6-bromo-naphthalen-2-ol; and reacting 6-bromo naphthalen-2-ol with a suitable trifluoromethanesulfonic reagent. Exemplary compounds that can be produced using the methods of the present 25 invention include: F0 N Nf0 F 21 WO 2008/137087 PCT/US2008/005702 N N N 0 o to N O N CAC ozN N h 0 N 0 N N-f 5 N NXO:N N rO Nr F N F ye N N N.( O-, FO F O F-Y F N 10 0 - 22 - Ow NN ,N O N-NI Or, F N F and 5 WO 2005/117865 also describes histamine-3-receptor ligands that include a 2 methyl-pyrrolidinyl moiety of the following general formula III-A: 0-A N III-A wherein A is selected from: R (CH2)rm R, N (CH2)m Al' A2 R7 NN or p NI A3 R A4 A5 10 wherein: m is 0, 1, or 2; n is 0, 1 or 2; R 3 is hydrogen or lower alkyl; t is l or 2; 15 R4 is hydrogen or lower alkyl; R5 is lower alkyl or cycloalkyl; - 23 - X is 0, S. or N-R 8 , wherein R 8 is hydrogen or lower alkyl; p is 0, 1 or 2; q is 0, 1 or 2; R 6 is lower alkyl; 5 s is 0, 1 or 2; and R 7 is lower alkyl. Compounds of formula III-A can be prepared according to the Scheme 1: SCHEME 1 HOOH H4 HOH HN or HN HO"" N N N 0o 0 HO-A HO-A O 0 2 N 0>N No A-ON A-O 10 The coupling of carboxylic acids with amines is widely described in literature and the procedures are known to those in the art (For reaction conditions described in literature affecting such reactions see for example: Comprehensive Organic Transformations: A Guide to Functional Group Preparations, 2nd Edition, Richard C. Larock. John Wiley & Sons, New York, NY. 1999). 6-Hydroxy-2-naphthoic acid can conveniently be 15 transformed to the respective amide through coupling with (R)- or (S)-2-methylpyrrolidine that has been prepared in accordance with the foregoing steps (a) to (e) (with or without optional steps (f) to (h)) and reacting the (R)-2-methylpyrrolidine L-tartrate with a base to provide (R)-2-methylpyrrolidine. Any suitable coupling agent can be employed to effect the transformation. For example coupling reagents like 1,1'-carbonyldiimidazole (CDI), 20 N,N'-dicyclohexylcarbodiimide (DCC), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide -24 - WO 2008/137087 PCT/US2008/005702 hydrochloride (EDCI), 1 - [bis(dimethylamino)methylene] - IH-1,2,3-triazolo[4,5 b]pyridinium-3-oxidhexafluorophosphate (HATU), 1-hydroxy-1,2,3-benzotriazole (HOBT), O-benzotriazol- 1 -yl-N,N,N',N'-tetramethyluronium tetrafluoroborate (TBTU) and the like can equally well be employed to affect such transformation. 5 There is no particular restriction on the nature of the solvent to be employed, provided that it has no adverse effect on the reaction or the reagents involved and that it can dissolve the reagents, at least to some extent. Examples for suitable solvents include: DMF, dichloromethane (DCM), dioxane, THF, and the like. Typically, a base is used with the coupling agent. There is no particular restriction on the nature of the base used in this 10 stage, and any base commonly used in this type of reaction may equally be employed here. Examples of such bases include triethylamine and diisopropylethylamine, and the like. The reaction can take place over a wide range of temperatures, and the precise reaction temperature is not critical to the invention. It is convenient to carry out the reaction with heating from ambient temperature to reflux. The time required for the reaction may also 15 vary widely, depending on many factors, notably the reaction temperature and the nature of the reagents. However, a period of from 0.5 h to several days will usually suffice to yield the amide derivative. One exemplary procedure for the preparation of (6-hydroxy-naphthalen-2-yl)-(2 methyl-pyrrolidin-1-yl)-methanone is as follows. A mixture of 6-hydroxy-2-naphthoic 20 acid, 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate, 2.3 mL N ethyldiisopropylamine, and (R) or (S)-2-methyl-pyrrolidine that has been prepared in accordance with the foregoing procedures, is prepared in 10 mL DMF is stirred for 16 hours at room temperature. The mixture is then concentrated to dryness and 50 mL ethyl acetate, 30 mL water and 20 mL NaHCO 3 aq. (10%) is added. The aqueous phase may 25 then be extracted with 50 mL ethyl acetate and the combined organic layers purified with column chromatography on silica. The product fractions may be concentrated to dryness and triturated twice with 20 mL diethyl ether/heptane 1/1, and the residue dried under vacuum at 50 *C. Practice of this method with (R)-2-methylpyrrolidine or (S)-2 methylpyrrolidine prepared in accordance with the methods described herein will produce 30 (6-hydroxy-naphthalen-2-yl)-(2R-methyl-pyrrolidin- 1 -yl)-methanone or (6-hydroxy naphthalen-2-yl)-(2S-methyl-pyrrolidin- 1 -yl)-methanone, which may then be used to produce histamine-3-receptor ligands. -25- WO 2008/137087 PCT/US2008/005702 In order to make the histamine-3-receptor ligands, the foregoing (R) or (S) intermediates are reacted with an alcohol of the formula HO-A (wherein A is defined as above) to form an ether. The syntheses of ethers are widely described in literature and the procedures are known to those in the art. (For reaction conditions described in literature 5 affecting such reactions see for example: Comprehensive Organic Transformations: A Guide to Functional Group Preparations, 2nd Edition, Richard C. Larock. John Wiley & Sons, New York, NY. 1999). The transformation can be affected by employing reaction conditions which are commonly utilized in the so called "Mitsunobu reaction" which is known to those in the art and widely described (Hughes, David L. The Mitsunobu 10 reaction. Organic Reactions (New York) (1992), 42, 335-656.) Conditions employing a trialkylphosphine such as tributylphosphine, triphenylphosphine and the like and a diazo compound like diethyl-azodicarboxylate (DEAD), diisopropylazodicarboxylate (DIAD) (optionally polymer bound), tetramethyl azodicarboxamide and the like in a solvent commonly used in such transformations like tetrahydrofuran (THF), toluene, 15 dichloromethane and the like. There is no particular restriction on the nature of the solvent to be employed, provided that it has no adverse effect on the reaction or the reagents involved and that it can dissolve the reagents, at least to some extent. The reaction can take place over a wide range of temperatures, and the precise reaction temperature is not critical to the invention. Ambient temperature to reflux is generally appropriate. The time 20 required for the reaction may also vary widely, depending on many factors, notably the reaction temperature and the nature of the reagents. However, a period of from 0.5 h to several days will usually suffice to yield the desired compounds. As an alternative, the following synthetic approach may be used: SCHEME 2 0 0
OCH
3 HO-A , OCH 3 H of H HO A-O 0 0 or N 25 A-O A-O - 26 - As shown in Scheme 2, starting alcohol HO-A, wherein A is as described above, is reacted with the methyl ester under Mitsunobu reaction conditions followed by cleavage of the ester. The intermediately formed acid is then coupled with (R)- or (S)-2 methylpyrrolidine, which has been prepared in accordance with the foregoing steps (a) to 5 (e) (with or without optional steps (f) to (h)) and reacting the (R)-2-methylpyrrolidine L tartrate with a base to provide (R)-2-methylpyrrolidine or the (S)-2-methylpyrrolidine D tartrate with a base to provide (S)-2-methylpyrrolidine, to arrive at the desired compound. Suitable coupling agents and conditions are described above. Thus, one embodiment of the invention relates to processes for preparing a 10 compound of formula III-A: "O-A N 111-A wherein the variables are as set forth above, comprising: (1 a) hydrogenating 2-methylpyrroline in a mixture comprising an alcohol solvent and a hydrogenation catalyst; 15 (1b) optionally removing the hydrogenation catalyst from the mixture; (Ic) dissolving L-tartaric acid or D-tartaric acid in the mixture to form a solution; (1 d) crystallizing (R)-2-methylpyrrolidine L-tartrate or (S)-2-methylpyrrolidine D-tartrate from the solution; 20 (1 e) isolating the crystalline (R)-2-methylpyrrolidine L-tartrate or (S)-2 methylpyrrolidine D-tartrate; and (2a) contacting the (R)-2-methylpyrrolidine L-tartrate with a base to form (R)-2 methylpyrrolidine free base or contacting the (S)-2-methylpyrrolidine D-tartrate with a base for form (S)-2-methylpyrrolidine; 25 (3a) contacting a carboxylic acid of the following formula 0 HO OH HO"'1_: with either (R)- or (S)-2-methylpyrrolidine, for a time and under conditions sufficient to form the corresponding amide naphthol; and - 27 - (3b) contacting the amide naphthol with an alcohol of formula HO-A, wherein A is as described above, for a time and under conditions sufficient to provide the corresponding amide ether. This method may optionally further include the steps of: 5 (10 recrystallizing the isolated (R)-2-methylpyrrolidine L-tartrate or (S)-2 methylpyrrolidine D-tartrate; (1g) isolating the recrystallized (R)-2-methylpyrrolidine L-tartrate or (S)-2 methylpyrrolidine D-tartrate; and (lh) optionally repeating steps (1f) and (Ig). 10 Another embodiment relating to processes for the preparation of compounds of formula IlI-A: O-A 0 a N III-A wherein the variables are as set forth above, comprises: (la) hydrogenating 2-methylpyrroline in a mixture comprising an alcohol 15 solvent and a hydrogenation catalyst; (lb) optionally removing the hydrogenation catalyst from the mixture; (1 c) dissolving L-tartaric acid or D-tartaric acid in the mixture to form a solution; (ld) crystallizing (R)-2-methylpyrrolidine L-tartrate or (S)-2-methylpyrrolidine 20 D-tartrate from the solution; (I e) isolating the crystalline (R)-2-methylpyrrolidine L-tartrate or (S)-2 methylpyrrolidine D-tartrate; and (2a) contacting the (R)-2-methylpyrrolidine L-tartrate with a base to form (R)-2 methylpyrrolidine free base or contacting the (S)-2-methylpyrrolidine D-tartrate with a 25 base for form (S)-2-methylpyrrolidine; (3a) contacting an ester naphtholof the following formula 0 N N OCH 3 HO' -28with an alcohol of formula HO-A, wherein A is as previously described, for a time and under conditions sufficient to form the corresponding ester ether; and (3b) contacting the ester ether with either (R)- or (S)-2-methylpyrrolidine, for a time and under conditions sufficient to form the corresponding amide ether. 5 This method may optionally further include the steps of: (10 recrystallizing the isolated (R)-2-methylpyrrolidine L-tartrate or (S)-2 methylpyrrolidine D-tartrate; (Ig) isolating the recrystallized (R)-2-methylpyrrolidine L-tartrate or (S)-2 methylpyrrolidine D-tartrate; and 10 (1h) optionally repeating steps (If) and (1g). Particularly preferred compounds that can be prepared using the methods of the present invention include: (2-methyl-pyrrolidin- I -yl)- {6-[2-(l-methyl-pyrrolidin-2-yl)-ethoxy] -naphthalen-2-yl} methanone; 15 [6-(1 -isopropyl-pyrrolidin-3 -y 1 oxy)-naphthalen-2-yl] -(2 -methyl-pyrrolidin- 1 -yl) methanone; [6-(1-isopropyl-piperidin-4-yloxy-)naphthalen-2-yl]- (2-methyl-pyrrolidin-1-yl) methanone; and [6-(1-isobutyl-piperidin-4-yloxy)-naphthalen-2-y-l]-(2-methyl-pyrrolidin-1-yl) 20 methanone. Another group of compounds that may be prepared from the (R)-2 methylpyrrolidine or (S)-2-methylpyrrolidine produced in accordance with the methods described herein is disclosed in US 2008/0027041A1. Specifically, disclosed in that application are compounds of the general formula IV (R), 2 4 n 25 X Y-(CHR );-R IV and the pharmaceutical salts thereof; wherein: p H3 CH3 N N R' is or N X and X' are each independently CH or N; - 29 - WO 2008/137087 PCT/US2008/005702 Y is S(O)q, 0, or NR 15;
R
2 is R R2 R 12 om 0 0,
R
13 14 14 R14 (iii) 13 14 R 14 R R R R 13 (iv) (v) 5 R12 R12 0 Nj 0 N 0 N N N N I I
RR
3 b Rl 3 b R3a R13a R3 R13a R3 R4 R4 ,R1 14a 'R14a (vi) (vii) (viii) R12 0 or N R13c R1 3 b R4 R14a (ix) wherein: when X and Xa are both CH, then R 2 is meta or para to the Y-(CHR 4 )m-Rlgroup; and -30- WO 2008/137087 PCT/US2008/005702 when either X or Xa are N, then R 2 is para to the Y-(CHR 4 )m-R'group; each R is: independently H, F, Cl, Br, I, OR , NR R 24, NO 2 , CN, CF 3 , Ci-C 6 alkyl, C(=O)R2, C0 2
R
21 , or C(=O)NR R24; or 5 when R 3 is ortho to R 2 , and R 2 is (i), (ii), (iv), (vi), or (ix), then R 3 and R1 4 taken together may form -(CH 2 )s-, -CH 2 Z-, -ZCH 2 -, -ZCH 2
CH
2 - or CH 2
CH
2 Z-; wherein Z is 0, S(O)y, or NR27; or when R3 is ortho to R 2 , and R 2 is (iv), (v), or (viii), then R3 and R " taken together may form -(CH 2 )s-, -CH 2 Z- , -ZCH 2 -, -ZCH 2
CH
2 - or CH 2
CH
2 Z-; or 10 when R 3 is ortho to R 2 , and R 2 is (viii), then R 3 and R1 3 b taken together may form -(CH 2 )s-,
-CH
2 Z- , -ZCH 2 -, -ZCH 2
CH
2 - or CH 2
CH
2 Z-; or when R 3 is ortho to Xa and R2 is ortho to R3 and meta to Xa, then R2 and R3 taken together may form: R 1 N N 0 15 each R 4 is independently H, Ci-C 6 alkyl, or OR, wherein the alkyl group is optionally substituted with 1 to 3 R 20 groups; 12 27 R is H, Ci-C 6 alkyl, cycloalkyl, aryl, arylalkyl, heteroaryl, heterocycloalkyl, C(=O)R2, or 27
CO
2 R 2, wherein the alkyl, cycloalkyl, aryl, arylalkyl, heteroaryl, or heterocycloalkyl group is optionally substituted with 1 to 3 R20 groups; 20 R' 3 and R1 4 are each independently H, Ci-C 6 alkyl, aryl, arylalkyl Ci-C 6 alkoxyl, S(=O)y-Ci-C 6 alkyl, cycloalkyl, heterocycloalkyl, or heteroaryl; R13a 13b 13C14134 Ra, R R', and R 4 a are each independently H, CI-C 6 alkyl; or R' and R' 4 , taken together with the carbon atoms through which they are connected form a fused phenyl, thienyl, pyrrolyl, oxazolyl, pyridinyl, or C 3
-C
6 cycloalkyl ring; or RSb and R' 4 , or R" and 14a 1b 4a 13c 4 25 , or RIob and 14a, or R and R 4 a, taken together with the carbon atoms through which 13 13a 14I4 they are connected form a fused C 3
-C
6 cycloalkyl ring; or R 3 and R , or R and R 4 a taken together with the carbon atom to which they are attached form a C 3 -Cgcycloalkyl ring; provided that no more than one pair of R 3 and R14, R1 3 b and R14, R1 3 and RI 4 a, R 3 b 1a 13C 14 13 1a41a and R 4 a, R and Riaa, R" and Ra, and R' 4 and R 4 a are taken together with the carbon 30 atoms through which they are connected or to which they are attached to form a ring; and -31 - WO 2008/137087 PCT/US2008/005702 wherein the fused phenyl, thienyl, pyrrolyl, oxazolyl, pyridinyl, or cycloalkyl ring is optionally substituted with 1 to 3 R 20 groups; R1 5 is H, CI-C 6 alkyl, C(=O)R 2 , C0 2
R
2 5 ; R20 at each occurrence is independently, H, F, Cl, Br, I, OR 2 1 , OR 2 2 , NR 2 3
R
2 4 , NHOH, 5 NO 2 , CN, CF 3 , CI-C 6 alkyl optionally substituted with OR 26 , C 2
-C
6 alkenyl, C 2
-C
6 alkynyl,
C
3
-C
7 cycloalkylCo-C 4 alkyl, 3- to 7-membered heterocycloalkylCo-C 4 alkyl, phenyl, 5- or 6-membered heteroarylCo-C 4 alkyl, arylalkyl, (=0), C(=O)R , C0 2 R , OC(=O)R, C(=O)NR R2 , NR 27
C(=O)R
21 , NR 27 C(=0)OR 21 , OC(=O)NR 23
R
24 , NR 27 C(=S)R , or S(O)gR 21 ; 10 each R 2 1 is independently H, Ci-C 6 alkyl, aryl, or arylalkyl; each R 22 is independently the residue of an amino acid after the hydroxyl group of the carboxyl group is removed; each R 23 and R 24 is independently selected from H, Ci-C 6 alkyl, and aryl, or R 23 and R 24 , together with the nitrogen atom to which they are attached, form a 3 to 7 membered 15 heterocyclic ring optionally substituted with =0; 25 is CI-C6alkyl, aryl, or alkylaryl; R26 is H, C-C 6 alkyl, aryl, or alkylaryl; R is H or Ci-C 6 alkyl; m is 1, 2, 3, 4, or 5 when R 1 is attached via a nitrogen atom, and m is 0, 1, 2, 3, 4, or 5 20 when R 1 is attached via a carbon atom; n is 1, 2, or 3; q is 0, 1, or 2; s is 1, 2, or 3; and y is 0, 1, or 2. 25 Specific examples of such compounds that can be prepared using the 2 methylpyrrolidine preparation methods of the present invention include: 2-methyl-6-{ 4-[(R)-2-methyl-3-((R)-2-methyl-pyrrolidin-1-yl)-propoxy]-phenyl}-2H pyridazin-3-one; 6-{3,5-difluoro-4-[3-((R)-2-methyl-pyrrolidin-1-yl)-propoxy]-phenyl}-2-methyl-2H 30 pyridazin-3-one; 6-{3-chloro-4-[3-((R)-2-methyl-pyrrolidin-1-yl)-propoxy]-phenyl}-2-methyl-2H pyridazin-3-one; 2,6-dimethyl-5-{4-[3-((R)-2-methyl-pyrrolidin-1-yl)-propoxy]-phenyl}-2H-pyridazin-3 one; -32- WO 2008/137087 PCT/US2008/005702 6-methyl-5- {4-[3-((R)-2-methyl-pyrrolidin- 1 -yl)-propoxy]-phenyl} -2H-pyridazin-3-one; 2-methyl-5- {4-[3-((R)-2-methyl-pyrrolidin- 1 -yl)-propoxy]-phenyl} -2H-pyridazin-3-one; 5- {4-[3-((R)-2-methyl-pyrrolidin- 1 -yl)-propoxy]-phenyl} -2-pyridin-2-yl-2H-pyridazin-3 one; 5 2-(6-methyl-pyridin-2-yl)-5- {4-[3-((R)-2-methyl-pyrrolidin- 1 -yl)-propoxy]-phenyl} -2H pyridazin-3-one; 2-(3-methyl-pyridin-2-yl)-5- {4-[3-((R)-2-methylpyrrolidin- 1 -yl)-propoxy]-phenyl} -2H pyridazin-3-one; 6-methyl-5-{4-[3-((R)-2-methyl-pyrrolidin- 1 -yl)-propoxy]-phenyl} -2-pyridin-2-yl-2H 10 pyridazin-3-one; 6-methyl-2-(3-methyl-pyridin-2-yl)-5- {4-[3-((R)-2-methyl-pyrrolidin- 1 -yl)-propoxy] phenyl} -2H-pyridazin-3 -one; 6-methyl-5- {4-[3-((R)-2-methyl-pyrrolidin- 1 -yl)-propoxy]-phenyl} -2-thiophen-3-yl-2H pyridazin-3-one; 15 5- {4-[3-((S)-2-methyl-pyrrolidin- 1 -yl)-propoxy]-phenyl} -2-pyridin-2-yl-2H-pyridazin-3 one; 6-{4-[3-((R)-2-methyl-pyrrolidin- 1 -yl)-propoxy]-phenyl} -5-pyridin-2-yl-4,5-dihydro-2H pyridazin-3-one; 6-{4-[3-((R)-2-methyl-pyrrolidin- 1 -yl)-propoxy]-phenyl} -5-pyridin-2-yl-2H-pyridazin-3 20 one; 2-(2-fluoro-ethyl)-6- {4-[3-((R)-2-methyl-pyrrolidin- 1 -yl)-propoxy] -phenyl} -2H pyridazin-3-one; 6- {3-fluoro-4-[3-((R)-2-methyl-pyrrolidin- 1 -yl)-propoxy]-phenyl} -2H-pyridazin-3-one; 4-methyl-6- {4-[3-((R)-2-methyl-pyrrolidin- 1 -yl)-propoxy] -phenyl} -4,5-dihydro-2H 25 pyridazin-3-one; 4-methyl-6- {4-[3-((R)-2-methyl-pyrrolidin- 1 -yl)-propoxy]-phenyl } -2H-pyridazin-3-one; 2-methyl-4- {3-[3-((R)-2-methyl-pyrrolidin- 1 -yl)-propoxy]-phenyl} -2,5,6,7-tetrahydro cyclopenta[d]pyridazin- 1-one; 2-isopropyl-5-{4-[3-((R)-2-methyl-pyrrolidin- 1 -yl)-propoxy]-phenyl} -2H-pyridazin-3 30 one; 2-[3-((R)-2-methyl-pyrrolidin- 1 -yl)-propoxy]-5-(6-oxo- 1,6-dihydro-pyridazin-3 yl)-benzonitrile; 2-(2-hydroxyethyl)-6-{4-[3-((R)-2-methyl-pyrrolidin- 1 -yl)-propoxy] -phenyl}-2H pyridazin-3-one; -33- WO 2008/137087 PCT/US2008/005702 6- {4-[(S)-2-methyl-3-((R)-2-methyl-pyrrolidin- 1 -yl)-propoxy]-phenyl} -2H-pyridazin-3 one; 6- {3-methoxy-4-[3-((R)-2-methyl-pyrrolidin- 1 -yl)-propoxy]-phenyl} -2H-pyridazin-3-one; 6- {4-[3-((R)-2-methyl-pyrrolidin- 1 -yl)-propoxy]-phenyl} -2-pyrimidin-2-yl-2H-pyridazin 5 3-one; 6- {6-[3-((R)-2-methyl-pyrrolidin- 1 -yl)-propoxy]-pyridin-3-yl} -2H-pyridazin-3-one; 6-{4-[3-((R)-2-methyl-pyrrplidin- 1 -yl)-propoxy]-phenyl} -2-(2,2,2-trifluoro-ethyl)-4,5 dihydro-2H-pyridazin-3-one; 6- {4-[3-((R)-2-methyl-pyrrolidin- 1 -yl)-propoxy]-phenyl} -2-(2,2,2-trifluoro-ethyl)-2H 10 pyridazin-3-one; 5-{4-[3-((R)-2-methyl-pyrrolidin- 1 -yl)-propoxy]-phenyl} -3,4-diaza-bicyclo[4.2.0]oct-4 en-2-one; 4- {4-[3-((R)-2-methyl-pyrrolidin- 1 -yl)-propoxy]-phenyl} -2,4a,5,6,7,7a-hexahydro cyclopenta[d]pyridazin- 1-one; 15 6- {4-[3-((R)-2-methyl-pyrrolidin- 1 -yl)-propoxy]-phenyl} -4,5-dihydro-2H-pyridazin-3 one; 4,4-dimethyl-6- {4-[3-((R)-2-methyl-pyrrolidin- 1 -yl)-propoxy]-phenyl} -4,5-dihydro-2H pyridazin-3-one; 6-{3-fluoro-4-[3-((R)-2-methyl-pyrrolidin- 1 -yl)-propoxy]-phenyl} -4,5-dihydro-2H 20 pyridazin-3-one; 5,5-dimethyl-6- {4-[3-((R)-2-methyl-pyrrolidin- 1 -yl)-propoxy] -phenyl} -4,5-dihydro-2H pyridazin-3-one; 6-f{4-[3-((R)-2-methyl-pyrrolidin- 1 -yl)-propoxy]-phenyl} -2-pyridin-2-yl-4,5-dihydro-2H pyridazin-3-one; 25 6- {3,5-difluoro-4-[3-((R)-2-methyl-pyrrolidin- 1 -yl)-propoxy] -phenyl } -2H-pyridazin-3 one; 6- {3,5-dibromo-4-[3-((R)-2-methyl-pyrrolidin- 1 -yl)-propoxy]-phenyl} -2H-pyridazin-3 one; 6- {3,5-difluoro-4-[3-((R)-2-methyl-pyrrolidin- 1 -yl)-propoxy] -phenyl} -4,5-dihydro-2H 30 pyridazin-3-one; 5-methyl-6-{4-[3-((R)-2-methyl-pyrrolidin- 1 -yl)-propoxy]-phenyl} -4,5-dihydro-2H pyridazin-3-one racemate; 5-methyl-6-{4-[3-((R)-2-methyl-pyrrolidin-1-yl)-propoxy]-phenyl}-4,5-dihydro-2H pyridazin-3-one diastereomer; -34- WO 2008/137087 PCT/US2008/005702 5-methyl-6-{4-[3-((R)-2-methyl-pyrrolidin- 1 -yl)-propoxy]-phenyl} -4,5-dihydro-2H pyridazin-3-one diastereomer; 6-{(R)-2-methyl-4-[3-(2-methyl-pyrrolidin-1-yl)-propoxy]-phenyl}-4,5-dihydro-2H pyriazin-3-one; 5 2- {4-[3-((R)-2-methyl-pyrrolidin- 1 -yl)-propoxy] -phenyl} -6-phenyl-2H-pyridazin-3-one; 6-methyl-2- {4- [3-((R)-2-methyl-pyrrolidin- 1 -yl)-propoxy] -phenyl } -2H-pyridazin-3-one; 2-f{4-[3-((R)-2-methyl-pyrrolidin-1-yl)-propoxy]-phenyl}-2H-phthalazin-1-one; 2-{4-[3-((R)-2-methyl-pyrrolidin-1-yl)-propoxy]-phenyl}-6-pyridin-3-yl-2H-pyridazin-3 one; 10 3-methyl-4-{4-[3-((R)-2-methyl-pyrrolidin-1-yl)-propoxy]-phenyl}-6H-isoxazolo[3,4 d]pyridazin-7-one; 8-[3-((R)-2-methyl-pyrrolidin- 1 -yl)-propoxy] -5,6-dihydro-2H-benzo [h] cinnolin-3-one; 5-methyl-6- {4-[3 -((R)-2-methyl-pyrrolidin- 1 -yl)-propoxy] -phenyl} -2H-pyridazin-3-one; 5-ethyl-6- {4- [3-((R)-2-methyl-pyrrolidin- 1 -yl)-propoxy] -phenyl} -2H-pyridazin-3-one; 15 8- [3 -(2-methyl-pyrrolidin- 1 -yl)-propoxy] -4,4a,5,6-tetrahydro-2H-benzo [h]cinnolin-3 -one; 6- {2-methoxy-4-[3 -((R)-2-methyl-pyrrolidin- 1 -yl)-propoxy] -phenyl } -2H-pyridazin-3 -one; 6- {2-fluoro-4-[3-((R)-2-methyl-pyrrolidin- 1 -yl)-propoxy] -phenyl} -2H-pyridazin-3-one; 6-{4-[3-((R)-2-methyl-pyrrolidin-1-yl)-propoxy]-phenyl}-2-pyridin-2-yl-2H-pyridazin-3 one;; 20 6-{4-[3-((R)-2-methyl-pyrrolidin-1-yl)-propoxy]-phenyl}-4-pyridin-2-y-4,5-dihydro-2H pyridazin-3-one; 6-{4-[3-((R)-2-methyl-pyrrolidin-1-yl)-propoxy]-phenyl}-4-pyridin-2-yl-2H-pyridazin-3 one; 8-[3-((R)-2-methyl-pyrrolidin-1-yl)-propoxy]-5,6-dihydro-3H-benzo[f]cinnolin-2-one; 25 5-{4- [3 -((R)-2-methyl-pyrrolidin- 1 -yl)-propoxy] -phenyl} -2H-pyridazin-3-one; 2-methoxymethyl-5-{4-[3-((R)-2-methyl-pyrrolidin-1-yl)-propoxy]-phenyl}-2H pyridazin-3-one; 5-{4-[(S)-2-methyl-3-((R)-2-methyl-pyrrolidin-1-yl)-propoxy]-phenyl}-2H-pyridazin-3 one; 30 5-{4-[(R)-2-methyl-3-((R)-2-methyl-pyrrolidin-1-yl)-propoxy]-phenyl}-2H-pyridazin-3 one; 5-{3,5-dibromo-4-[3-((R)-2-methyl-pyrrolidin-1-yl)-propoxy]-phenyl}-2H-pyridazin-3 one; - 35 - WO 2008/137087 PCT/US2008/005702 2-methoxymethyl-5- {2-methyl-4-[3-((R)-2-methyl-pyrrolidin- 1 -yl)-propoxy]-phenyl} -2H pyridazin-3-one; 5-f{2-methyl-4-[3-((R)-2-methyl-pyrrolidin- 1 -yl)-propoxy]-phenyl} -2H-pyridazin-3-one; 4-methoxy-2-methoxymethyl-5-{4-[3-((R)-2-methyl-pyrrolidin- 1 -yl)-propoxy]-phenyl} 5 2H-pyridazin-3-one; 5-methoxy-2-methoxymethyl-4- {4-[3-((R)-2-methyl-pyrrolidin- 1 -yl)-propoxy]-phenyl} 2H-pyridazin-3-one; 5-methoxy-4- {4-[3-((R)-2-methyl-pyrrolidin- 1 -yl)-propoxy]-phenyl} -2H-pyridazin-3-one; 6- {4-[3-((S)-2-methyl-pyrrolidin- 1 -yl)-propoxy]-phenyl} -2H-pyridazin-3 10 -one; 5- {4-[3-((R)-2-methyl-pyrrolidin- 1 -yl)-propoxy]-phenyl} -3,4-diaza-bicyclo[4.1.0]hept-4 en-2-one; 5- {4-[(S)-2-methyl-3-((R)-2-methyl-pyrrolidin- 1 -yl)-propoxy]-phenyl} -3,4-diaza bicyclo[4. 1.0]hept-4-en-2-one; 15 5-{4-[3-((R)-2-methyl-pyrrolidin-1 -yl)-propoxy]-phenyl} -3,4-diaza-bicyclo[4.1.0]hept-4 en-2-one single isomer; 5-{4-[3-((R)-2-methyl-pyrrolidin-1-yl)-propoxy]-phenyl}-3,4-diaza-bicyclo[4.1.0]hept-4 en-2-one single isomer; 6- {4-[2-hydroxy-3-((R)-2-methyl-pyrrolidin- 1 -yl)-propoxy] -phenyl} -2H-pyridazin-3 -one; 20 6-{4-[(S)-2-hydroxy-3-((R)-2-methyl-pyrrolidin-1-yl)-propoxy]-phenyl}-2H-pyridazin-3 one; 6-{4-[(R)-2-hydroxy-3-((R)-2-methyl-pyrrolidin-1-yl)-propoxy]-phenyl}-2H-pyridazin-3 one; and 25 6-cyclopropyl-2-{4-[3-((R)-2-methyl-pyrrolidin-1-yl)-propoxy]-phenyl}-2H-pyridazin-3 one; or a stereoisomeric form, mixture of stereoisomeric forms, or a pharmaceutically acceptable salt thereof. Preferred among these are compounds selected from the group consisting of: 30 5-{4-[3-((R)-2-methyl-pyrrolidin-1-yl)-propoxy]-phenyl}-2-pyridin-2-yl-2H-pyridazin-3 one; 6-{4-[(S)-2-methyl-3-((R)-2-methyl-pyrrolidin-1-yl)-propoxy]-phenyl}-2H-pyridazin-3 one; - 36 - WO 2008/137087 PCT/US2008/005702 4,4-dimethyl-6-{4-[3-((R)-2-methyl-pyrrolidin- 1 -yl)-propoxy]-phenyl} -4,5-dihydro-2H pyridazin-3-one; 5- {4-[3-((R)-2-methyl-pyrrolidin- 1 -yl)-propoxy]-phenyl} -3,4-diaza-bicyclo[4.1.0]hept-4 en-2-one; 5 5- {4-[(S)-2-methyl-3-((R)-2-methyl-pyrrolidin- 1 -yl)-propoxy]-phenyl} -3,4-diaza bicyclo[4. 1.0]hept-4-en-2-one; 5-{4-[3-((R)-2-methyl-pyrrolidin- 1 -yl)-propoxy]-phenyl} -3,4-diaza-bicyclo[4. 1.0]hept-4 en-2-one; 5- {4-[3-((R)-2-methyl-pyrrolidin- 1 -yl)-propoxy]-phenyl} -3,4-diaza-bicyclo[4.1.0]hept-4 10 en-2-one; 5-methyl-6- {4-[3-((R)-2-methyl-pyrrolidin- 1 -yl)-propoxy]-phenyl} -4,5-dihydro-2H pyridazin-3-one one diastereomer; 5-methyl-6- {4-[3-((R)-2-methyl-pyrrolidin- 1 -yl)-propoxy]-phenyl} -4,5-dihydro-2H pyridazin-3-one one diastereomer; 15 5-methyl-6- {4-[3-((R)-2-methyl-pyrrolidin- 1 -yl)-propoxy]-phenyl} -4,5-dihydro-2H pyridazin-3-one; and 6- {4-[3-((R)-2-methyl-pyrrolidin- 1 -yl)-propoxy] -phenyl} -2H-pyridazin-3-one; or a stereoisomeric form, mixture of stereoisomeric forms, or a pharmaceutically acceptable salt thereof. 20 Particularly preferred of the foregoing is the compound is 6-{4-[3-((R)-2-methyl pyrrolidin-1-yl)-propoxy]-phenyl}-2H-pyridazin-3-one, or a stereoisomeric form, mixture of stereoisomeric forms, or a pharmaceutically acceptable salt thereof. This compound may be prepared from (R)-2-methylpyrrolidine prepared in accordance with the methods described above. Scheme 3 sets forth an exemplary process for the preparation of 6-{4-[3 25 ((R)-2-methyl-pyrrolidin- 1 -yl)-propoxy] -phenyl} -2H-pyridazin-3-one. SCHEME 3 -37- WO 2008/137087 PCT/US2008/005702 0 eOH +1 step 2 H 0 N,NH HN ON, O CI * = a or step 3 O N In accordance with Scheme 3, in step 1, a mixture of 1-(4-hydroxyphenyl)ethanone and 3-bromo-l-chloropropane in CH 3
COCH
3 is heated to 65 *C overnight. The mixture is 5 filtered, washed with acetone, and concentrated to dryness. The crude product is dissolved in CH 2 Cl 2 , and washed with saturated NaHCO 3 , NaCl solution and dried over Na 2
SO
4 . Concentration to dryness under vacuum affords product. A mixture of the product from step 1 and glyoxalic acid monohydrate is stirred in 15 mL of acetic acid at 100 "C for 2 h. The solvent is evaporated, water is added to the 10 residue and cooled to 0 *C while conc. aqueous NH 4 0H is added to pH 8. To this mixture, hydrazine hydrate is added and heated to 100 *C for 1 h. The resulting solid may be filtered and washed with water. The crude material may be dissolved in CH 2 Cl 2 /MeOH and purified by column chromatography with CH 2 Cl 2 to 10 % MeOH in CH 2 Cl 2 . A mixture of the product from step 2, K 2
CO
3 , 100 mg of Nal, and R-2 15 methylpyrrolidine hydrochloride in acetonitrile is heated to 80 *C for 2 days. The reaction mixture is then filtered, washed with CH 2 Cl 2 , and concentrated. The residue is dissolved in CH 2
CI
2 , and washed with saturated NaHCO 3 , saturated NaCl, dried with Na 2
SO
4 and concentrated. The residue may be purified by ISCO gradient chromatography with 100%
CH
2 Cl 2 to 5%MeOH: 95% CH 2 C1 2 in 2-aminopropane and then to 10%MeOH: 90% 20 CH 2 Cl 2 in 2-aminopropane to give the product. The free base of the product may be converted to the HCl salt by dissolving in MeOH and adding 0.5 N HCl in EtOH, followed by evaporation of the solvent and crystallization from MeOH: Et 2 0. Thus, one embodiment of the invention relates to processes for preparing a compound of formula IV: - 38 - (R), R2)( X5 Yt(CHR't--R 1 IV, in particular (R)- or (S)-6-{4-[3-(2-Methyl pyrrolidin- 1 -yl)-propoxy] -phenyl } -2H-pyridazin- 3-one, wherein the variables are as set forth above, comprising: (la) hydrogenating 2-methylpyrroline in a mixture comprising an alcohol 5 solvent and a hydrogenation catalyst; (1b) optionally removing the hydrogenation catalyst from the mixture; (Ic) dissolving L-tartaric acid or D-tartaric acid in the mixture to form a solution; (1d) crystallizing (R)-2-methylpyrrolidine L-tartrate or (S)-2-methylpyrrolidine 10 D-tartrate from the solution; (l e) isolating the crystalline (R)-2-methylpyrrolidine L-tartrate or (S)-2 methylpyrrolidine D-tartrate; and (2a) contacting the (R)-2-methylpyrrolidine L-tartrate with a base to form (R)-2 methylpyrrolidine free base or contacting the (S)-2-methylpyrrolidine D-tartrate with a 15 base for form (S)-2-methylpyrrolidine; (3a) contacting 1-(4-hydroxy-phenyl)-ethanone with 1,3-dihalopropane, for a time and under conditions sufficient to form 1-[4-(3-halo-propoxy)-phenyll-ethanone; (3b) contacting the 1-[4-(3-halo-propoxy)-phenyl]-ethanone with glyoxalic acid for a time and under conditions sufficient to produce 6-[4-(3-halo-propoxy)-phenyl]-2H 20 pyridazin-3-one; and (3c) contacting the 6-[4-(3-hal-propoxy)-phenyl]-2H-pyridazin-3-one with either (R)- or (S)-2-methylpyrrolidine, for a time and under conditions sufficient to form the corresponding (R)- or (S)-6-{4-[3-(2-methyl-pyrrolidin-1-yl)-propoxy]-phenyl}-2H pyridazin-3-one. 25 This method may optionally further include the steps of: (1 f) recrystallizing the isolated (R)-2-methylpyrrolidine L-tartrate or (S)-2 methylpyrrolidine D-tartrate; (Ig) isolating the recrystallized (R)-2-methylpyrrolidine L-tartratc or (S)-2 methylpyrrolidine D-tartrate; and 30 (1 h) optionally repeating steps (10 and (1 g). - 39 - WO 2008/137087 PCT/US2008/005702 More generally, the foregoing methodology may be adapted to preparing the compounds described in US 2008/0027041A1 by providing a compound of the formula V: n(R3) <~ Xa R2 r 0-
(CHR
4 )m-Cl V with (R) or (S) 2-methylpyrrolidine hydrochloride, prepared according to the foregoing 5 methodology, K 2
CO
3 and Nal in CH 3 CN and recovering the product. A further embodiment of the invention relates to processes for preparing a compound of formula IV: (R 3) Xa R 2 X Y-(CHR ) -R IV wherein the variables are as set forth above, comprising: 10 (la) hydrogenating 2-methylpyrroline in a mixture comprising an alcohol solvent and a hydrogenation catalyst; (lb) optionally removing the hydrogenation catalyst from the mixture; (Ic) dissolving L-tartaric acid or D-tartaric acid in the mixture to form a solution; 15 (1 d) crystallizing (R)-2-methylpyrrolidine L-tartrate or (S)-2-methylpyrrolidine D-tartrate from the solution; (le) isolating the crystalline (R)-2-methylpyrrolidine L-tartrate or (S)-2 methylpyrrolidine D-tartrate; and (2a) contacting the (R)-2-methylpyrrolidine L-tartrate with a base to form (R)-2 20 methylpyrrolidine free base or contacting the (S)-2-methylpyrrolidine D-tartrate with a base for form (S)-2-methylpyrrolidine; (3a) converting the (R)-2-methylpyrrolidine or the (S)-2-methylpyrrolidine to the compound of formula IV. This method may optionally further include the steps of: 25 (if) recrystallizing the isolated (R)-2-methylpyrrolidine L-tartrate or (S)-2 methylpyrrolidine D-tartrate; (Ig) isolating the recrystallized (R)-2-methylpyrrolidine L-tartrate or (S)-2 methylpyrrolidine D-tartrate; and - 40 - (1 h) optionally repeating steps (10 and (1 g). Exemplary compounds that can be produced according to these methods include (R)- or (S)-6- {4-[3 -(2-methyl-pyrrolidin- 1 -yl)-propoxy] -phenyl.} -2H-pyridazin-3-one: H H 0 NN 0 N, ONN OXN R 5 Preferably, the compound is 6-{4-[3-((R)-2-methyl-pyrrolidin-1-yl)-propoxy]-phenyl} 2H-pyridazin-3-one A further group of histamine-3-receptor ligands that may be prepared using (R) or (S) 2-methylpyrrolidine prepared in accordance with the methods described herein is 10 described in WO 2006/059778. These compounds include compounds of the general formula VI: 0 x2=x, X_ Y O N-R2 x3-x4 p(R ) VI and the pharmaceutical salts thereof; 15 wherein Y is (R) or (S) 2-methylpyrrolidine; R1 each independently represents a hydrogen atom, a hydroxyl group, a halogen atom, a lower alkyl group, a halo-lower alkyl group, a lower alkoxy group, a halo-lower alkoxy group, a lower alkoxy-lower alkyl group, or a halo-lower alkoxy-lower alkyl group; p indicates an integer from 0 to 4; 20 R 2 represents a hydroxyl group, a halogen atom, a lower alkyl group, a halo-lower alkyl group, a lower alkoxy group, a halo-lower alkoxy group, a lower alkoxy-lower alkyl group, or a halo-lower alkoxy-lower alkyl group, or x 2 =x 1 A \ /
R
2 represents a group of the formula, x 3 _x 4 wherein A represents a compound of formula (111-1) or of formula (111-2) -41- WO 2008/137087 PCT/US2008/005702 H (1II-1) (III-2) wherein R3 represents a hydrogen atom, or a cycloalkyl group optionally substituted with a lower alkyl group, a halo-lower alkyl group, a cycloalkyl group, a halogen atom or a hydroxyl group and R4 represents a hydrogen atom, a hydroxyl group, a halogen atom, a lower alkyl group, a halo-lower alkyl 5 group, a lower alkoxy group, a halo-lower alkoxy group, a lower alkoxy-lower alkyl group, or a halo-lower alkoxy-lower alkyl group; m indicates 0 or 1; n indicates 0, 1 or 2; and XI to X 4 each independently represent a carbon atom optionally substituted with a lower alkyl group, a lower alkoxy group, a halo-lower alkoxy group or a halogen atom. 10 Specifically disclosed compounds within this group that can be prepared according to the methods described herein include: 1-methyl-4-{4-[3-((2S)-2-niethyl-1-pyrrolidinyl)propoxy]phenyl}-2(1H)-pyridone; and 1-methyl-4-{4-[3-((2R)-2-methyl-1-pyrrolidinyl)propoxy]phenyl}-2(1H)-pyridone. Such compounds may be prepared by providing an intermediate compound of 15 Formula (VI) wherein Y is Cl, and reacting the compound with (R) or (S) 2 methylpyrrolidine, prepared according to the foregoing methodology, K 2
CO
3 and Nal in
CH
3 CN and recovering the product, much as described above for the compounds of US 2008/0027041A1. Thus, another embodiment of the invention relates to processes for preparing a 20 compound of formula VI: 0 Y / (/ N-R 2 X3-X4 p(R1) VI wherein the variables are as set forth above, comprising: (la) hydrogenating 2-methylpyrroline in a mixture comprising an alcohol solvent and a hydrogenation catalyst; 25 (1 b) optionally removing the hydrogenation catalyst from the mixture; (1c) dissolving L-tartaric acid or D-tartaric acid in the mixture to form a solution; - 42 - (1d) crystallizing (R)-2-methylpyrrolidine L-tartrate or (S)-2-methylpyrrolidine D-tartrate from the solution; (Ie) isolating the crystalline (R)-2-methylpyrrolidine L-tartrate or (S)-2 methylpyrrolidine D-tartrate; and 5 (2a) contacting the (R)-2-methylpyrrolidine L-tartrate with a base to form (R)-2 methylpyrrolidine free base or contacting the (S)-2-methylpyrrolidine D-tartrate with a base for form (S)-2-methylpyrrolidine; (3a) contacting a compound of formula VI wherein Y is Cl with either (R)- or (S)-2-methylpyrrolidine, for a time and under conditions sufficient to form the 10 corresponding amide. This method may optionally further include the steps of: (I f) recrystallizing the isolated (R)-2-methylpyrrolidine L-tartrate or (S)-2 methylpyrrolidine D-tartrate; (1 g) isolating the recrystallized (R)-2-methylpyrrolidine L-tartrate or (S)-2 15 methylpyrrolidine D-tartrate; and (lh) optionally repeating steps (if) and (Ig). Yet another application describing histamine-3 -receptor ligands containing a 2 methylpyrrolidine moiety is WO 2007/105053. This application describes preparation of 20 compounds of the following formula VII: RT R3 VII wherein A is (R) or (S) 2-methyl pyrrolidine; Z, Y, Q, X are independently nitrogen or carbon; 25 R 3 is hydrogen, (Ci-Cs)alkyl, (Ci-Cs)alkoxy, halo, 5 to 6-membered aryl, 5 to 6-membered heteroaryl, hydroxyl, methylene hydroxyl, -(C=O)NR 4 Rs, and S(O)p(Ci-C 4 )alkyl, wherein pis 1 or2; wherein R 4 and R 5 are independently selected from the group consisting of: -43 hydrogen; (Ci-C 8 ) alkyl optionally substituted with 1 to 4 halogens; (C 1 -Cs) alkyl group optionally substituted with a substituent selected from the group consisting of OH, 1 to 4 (Ci-C 4 )alkyl, (C 3
-C
7 )cycloalkyl, (CI-C4)dialkylamino, (C 6 -CIa)aryl optionally substituted with a halogen and optionally substituted with (C 6 -Cio)aryloxy optionally substituted with 5 1 to 2 halogens, and 5 to 1 0-membered heteroaryl optionally substituted with a (C 6 Cio)aryl group and optionally substituted with 1 to 3 (Ci-C 4 )alkyl groups; (C3
C
7 )cycloalkyl; (C 6
-C
14 )aryl; -(C 2
-C
3 )alkyl-O-(Ci-C 3 )alkyl optionally substituted with (CI
C
3 )alkyl; -(C 1
-C
3 )alkyl-C(=O)O-(C-C 3 )alkyl; 3-8-membered heterocycloalkyl optionally substituted with one or more (CI-C 4 )alkylcarbonyl groups; (C 6
-C
1 4)arylsulfony1 optionally 10 substituted with one or more (CI-C 2 )alkyl; 5-10-membered heteroaryl; and (C6-CI4)aryl (Co-C 4 )alkylene-O-(Co-C4)alkyl, wherein each (Co-C 4 )alkyl and each (Co-C 4 )alkylene is optionally substituted with 1 to 4(C,-C 4 )alkyl; or optionally R4 and R 5 , together with the nitrogen to which they attached, form a 4 to 6-membered heterocyclic ring, wherein one of the carbons of said heterocyclic ring that is separated by at least two atoms from said 15 nitrogen in said heterocyclic ring is optionally replaced by 0 or NR 6 , herein R 6 is hydrogen, (C1-C 3 )alkyl, or -C(=O) (C 1
-C
3 )alkyl; and wherein said heterocyclic ring is optionally substituted with halo, (CI-C 3 )alkyl, or hydroxyl;
R
7 is hydrogen; or optionally R3 and R 7 together with two adjacent atoms in the ring comprising Z , Y, Q 20 and X to which they are attached, form a 5- or 6-membered heterocyclic ring; wherein one of the carbons of said heterocyclic ring that is separated by at least two atoms from said nitrogen in said heterocyclic ring is optionally replaced by 0 or NR 8 ; wherein R 8 is hydrogen or (CI-C 3 )alkyl. Scheme 4 illustrates a method for the preparation of compounds having the basic 25 structure of formula VII, where A, R 3 , Y, Q, Z and X are defined as above. Referring to Scheme 4 below, a compound (III-B) can be prepared by treatment of a bromo-tetralone compound of formula (I-B) with (R) or (S) 2-methyl pyrrolidine prepared in accordance with the methods described above and a suitable reducing agent such as NaHB(OAc) 3 in a solvent such as CH 2 C1 2 or DCE, at temperatures ranging from -5 'C to room temperature, 30 preferably at about room temperature, to produce the desired compound of formula (III B). Other suitable reducing agents for this reaction include NaCNBH 3 or NaBH 4 , in solvents such as MeOH or EtOH. Other suitable conditions for this transformation include treatment of the corresponding tetralone of formula (I-B) with (R)- or (S)-2 methylpyrrolidine, prepared in accordance with the procedures of the present invention, in - 44 -
CH
2 Cl 2 or DCE in the presence of 4 A molecular sieves and a base such as TEA at room temperature, followed by treatment with NaBH 4 or NaHB(OAc). Compound III-B can then be treated with an appropriately substituted boronic acid of formula (IV-A), in the presence of a suitable palladium catalyst such as 1,1 5 bis(diphenylphosphino)ferrocene palladium (II) chloride and a suitable aqueous solution of an alkali base such as sodium carbonate and in solvents such as dimethoxy ethane, at temperatures ranging from room temperature to about 100 'C, preferably at about 90 0 C, to produce the desired compound of formula (V-A). Other suitable conditions for this transformation include treatment of the compound of formula (III-B) and the appropriately 10 substituted boronic acid of formula. (IV-A) with tetrakis(triphenylphosphine)palladium(0) and sodium carbonate in ethanol/water mixture at temperatures ranging from 30 *C to 110 'C, preferably at about the reflux temperature, to produce the corresponding compound of formula (V). SCHEME 4 o A NaHB(OAc) 3 A Br Br I-B III-B Pd(dppf) 2 Cl 2 , Aqueous Na 2 C0 3 OH BA Z OH R3 15 IV-A x V-A Thus, one embodiment of the invention relates to processes for preparing a compound of formula VII: A R7 Z Y X R3 QVII - 45 wherein the variables are as set forth above, comprising: (1 a) hydrogenating 2-methylpyrroline in a mixture comprising an alcohol solvent and a hydrogenation catalyst; (lb) optionally removing the hydrogenation catalyst from the mixture; 5 (1 c) dissolving L-tartaric acid or D-tartaric acid in the mixture to form a solution; (ld) crystallizing (R)-2-methylpyrrolidine L-tartrate or (S)-2-methylpyrrolidine D-tartrate from the solution; (1 e) isolating the crystalline (R)-2-methylpyrrolidine L-tartrate or (S)-2 10 methylpyrrolidine D-tartrate; and (2a) contacting the (R)-2-methylpyrrolidine L-tartrate with a base to form (R)-2 methylpyrrolidine free base or contacting the (S)-2-methylpyrrolidine D-tartrate with a base for form (S)-2-methylpyrrolidine; (3a) contacting 6-halo-3,4-dihydro-lH-naphthalen-2-one with either (R)- or (S) 15 2-methylpyrrolidine, for a time and under conditions sufficient to form the corresponding amine; and (3b) contacting the amide with a boronic acid of formula OH R3 wherein the variables are as described above, for a time and under conditions 20 sufficient to provide the compound for formula VII. This method may optionally further include the steps of: (10 recrystallizing the isolated (R)-2-methylpyrrolidine L-tartrate or (S)-2 methylpyrrolidine D-tartrate; (1 g) isolating the recrystallized (R)-2-methylpyrrolidine L-tartrate or (S)-2 25 methylpyrrolidine D-tartrate; and (lh) optionally repeating steps (If) and (lg). Scheme 5 illustrates an alternative method for the preparation of compounds having 30 the basic structure of formula VII, where R 3 is CONR 4 Rs and Y, Z, Q and X are defined as above. Referring to Scheme 5, coupling of the bromide (III-C) and a suitable boronic acid -46 reagent of formula (VI-A) can be carried out as described above in scheme 4 to produce the desired compound of formula (VII). Treatment of the corresponding t-butyl ester derivative of formula (VIII) with trifluoroacetic acid in methylene chloride at room temperature produces the corresponding carboxylic acid (not depicted). Treatment of the 5 carboxylic acid with an amine of formula NHR 4
R
5 , in the presence of a suitable coupling reagent such as HOBT and EDCI, and a tertiary amine such as triethyl amine, can produce the desired compounds of formula (IX). SCHEME 5 OH N o V-A 1. TFA, CH 2
C
2 Br 2. HOBT, EDCI, TEA, R 4
R
5 NH *= a or p Pd(dppf) 2 Cl 2 , aq. Na 2
CO
3 > ll-C Vill NN 4R5RN o ix 10 Alternatively, compounds of formula (IX) can also be prepared by treatment of the carboxylic acid and suitable amine with 2-chloro- 1,3-dimethyl imidazolinium chloride and a suitable base such as diisopropylethyl amine, in solvents such as methylene chloride. In another embodiment are processes for preparing a compound of formula VII: A II z Y X 15 R3 QVII wherein the variables are as set forth above, comprising: (la) hydrogenating 2-methylpyrroline in a mixture comprising an alcohol solvent and a hydrogenation catalyst; (lb) optionally removing the hydrogenation catalyst from the mixture; 20 (1c) dissolving L-tartaric acid or D-tartaric acid in the mixture to form a solution; - 47 - WO 2008/137087 PCT/US2008/005702 (Id) crystallizing (R)-2-methylpyrrolidine L-tartrate or (S)-2-methylpyrrolidine D-tartrate from the solution; (le) isolating the crystalline (R)-2-methylpyrrolidine L-tartrate or (S)-2 methylpyrrolidine D-tartrate; and 5 (2a) contacting the (R)-2-methylpyrrolidine L-tartrate with a base to form (R)-2 methylpyrrolidine free base or contacting the (S)-2-methylpyrrolidine D-tartrate with a base for form (S)-2-methylpyrrolidine; (3a) contacting 1-(6-halo-1,2,3,4-tetrahydro-naphthalen-2-yl)-(R)-2-methyl pyrrolidine or 1-(6-halo-1,2,3,4-tetrahydro-naphthalen-2-yl)-(S)-2-methyl-pyrrolidine with 10 a boronic acid of formula OH OOH O 0 -;f 0 wherein the variables are as described above, for a time and under conditions sufficient to provide a compound of the following formula: N Z Y X 0 O ;and 15 contacting the compound of formula N O Y X 0 0 with an amine for a time and under conditions sufficient to form the compound of formula VII. This method may optionally further include the steps of: -48- (if) recrystallizing the isolated (R)-2-methylpyrrolidine L-tartrate or (S)-2 methylpyrrolidine D-tartrate; (Ig) isolating the recrystallized (R)-2-methylpyrrolidine L-tartrate or (S)-2 methylpyrrolidine D-tartrate; and 5 (1h) optionally repeating steps (10 and (1 g). Specific examples of compounds that may be prepared in accordance with these methods include: (S,R)-3 -[6-(2-Methyl-pyrrolidin- l-yl)-5,6,7,8-tetrahydro-naphthalen-2 yl]-pyridine; (R,R)-3-[6-(2-Methyl-pyrrolidin-1 -yl)-5,6,7,8-tetrahydro-naphthalen-2-yl]-pyridine; 10 (R, R)- 3
[
6 -(2-Methyl-pyrrolidin-1-yl)-5,6,7,8-tetrahydro-naphthalen-2-yl]-benzamide; and (S,R)3-[6-(2-Methyl-pyrrolidin-1-yl)-5,6,7,8-tetra hydro-naphthalen-2-yl]-benzamide. Compounds described in WO 2006/066197 can also be more easily prepared using the (R)- and (S) 2-methylpyrrolidine synthesis of the present invention. WO 2006/066197 15 describes the following compounds of formulas VIII and IX: (R Ar (R5- Ar
(R
4 )m
(R
4 ), N N N L NRI L N R1 VIII-A IX-A And the pharmaceutical salts thereof; wherein 20 L is -O- and n is 1 or 2; or L is -CC- or -CH 2
CH
2 - and n is 0 or 1; R' is -H or is Ci6alkyC 37 cycloaklyl, -COOCi- 6 alkyl, or -COObenzyl, each optionally mono-, di-, or tri-substituted with Ra; where Ra is selected from -OH, -OCI 6 alkyl, phenyl optionally substituted with -OCl4alkyl or halo, -CN, -NO 2 , -N(Rb)Rc, -C(O)N(Rb)Rc , -N(Rb)C(O) Rb, -N(Rb)SO 2 CI 25 6 alkyl, -C(O)Ci- 6 alkyl, -S(O)o-2-CI-alkyl, -SO 2 N(R)'c, -SCF 3 , halo, -CF 3 , -OCF 3 , COOH, and
-COOCI
6 alkyl; wherein Rb and R are each independently -H or -Cs 6 alkyl;
R
4 is -OH, -OCj alkyl,-CF 3 , -C 1
-
6 alkyl, or halo; two R4 substituents may be taken together to form methylene or ethylene; 30 M is 0, 1, or 2; - 49 - WO 2008/137087 PCT/US2008/005702
R
5 is selected from the group consisting of -Ci- 6 alkyl, -OH, -OCi- 6 alkyl, -SCi 6 alkyl, and halo; Ar is an aryl or heteroaryl ring selected from the group consisting of: a) phenyl, optionally mono-, di-, or tri-substituted with RI and optionally di 5 substituted on adjacent carbons with -OCIAalkyleneO-optionally mono or di-substituted with fluoro,
-(CH
2
)
2
-
3 NH-, -(CH 2
)
1
-
2
NH(CH
2 )-, -(CH 2
)
2
-
3 N(Ci 4 alkyl)-, or -(CH 2
)
1
-
2 N(Ci 4 alkyl)(CH 2 )-; where Ri is selected from the group consisting of 1) -OH, -Ci- 6 alkyl, -OCi- 6 alkyl optionally mono-, di-, or tri-substituted with halo, 10 C 2
-
6 alkenyl, -OC 3
-
6 alkenyl, -C 2
-
6 alkynyl optionally substituted with trimethylsilyl, -OC 3 6 alkynyl, -C 3
-
6 cyCloalkyl, -OC 3
-
6 cycloalkyl, -CN, -NO 2 , -N(R )R' , -N(R )C(O)R, N(Rk)SO 2 Ci- 6 alkyl, -C(O)Ci_ 6 alkyl, -S(O)o- 2 -Ci- 6 alkyl, -C(O)N(R')R", SO 2 N(R')R", SCF 3 , halo, -CF 3 , -COOH,
-COOC-
6 alkyl, and -COOC 3
.
7 cycloalkyl; 15 where Rk and R are each independently -H or -Ci- 6 alkyl; where R' and R" are each independently -H or -Ci- 6 alkyl, or R' and R' taken together with their nitrogen of attachment form a 4-8 membered heterocyclic ring having 1 or 2 heteroatom members selected from >0, >S(O)o-2, >NH, and >NCI- 6 alkyl, having 0 or 1 double bond, having 0 or 1 carbonyl members; 20 2) -G-Ar 2 , where G is a bond, -0-, or -S-, and Ar 2 is phenyl or is a monocyclic aromatic hydrocarbon group having five or six ring atoms, having one carbon atom replaced by >0, >S, >NH, or >N(C 1.4alkyl), having up to one additional carbon atom optionally replaced by -N=, each optionally mono-, di-, or tri-substituted with RP; where RP is a substituent independently selected from the group consisting of: -OH, -Ci- 6 clkyl, 25 OCI.
6 alkyl, phenyl, -CN, -NO 2 , -N(R q)Rr-, -C(O)N(R4)Rr, -N(Rq)C(O)Rr,- N(R4)SO2CI-6alkyl, -C(O)CI-6alkyl, -S(O)o-2-Ci. 6 alkyl, -SO2N(R4)R,- SCF 3 , halo, -CF 3 , -OCF 3 , -OCHF 2 , -COOH, and -COOC- 6 alkyl; wherein Rq and Rr are each independently selected from -H, -CI- 6 alkyl, and -C 2 6 alkenyl; and 30 3) a 4-8 membered saturated or partially saturated heterocyclic ring, having 1 or 2 heteroatom members selected from >0, >S(O)o-2, >NH, and >NCI- 6 alkyl, having 0 or 1 carbonyl members, said ring optionally mono-, di-, or tri-substituted with RP; b) phenyl or pyridyl fused at two adjacent carbon ring members to a three membered hydrocarbon moiety to form a fused five membered aromatic ring, which - 50 - WO 2008/137087 PCT/US2008/005702 moiety has one carbon atom replaced by >0, >S, >NH, or >N(C 1 4alkyl), and which moiety has up to one additional carbon atom optionally replaced by -N=, the fused rings optionally mono-, di-, or tri-substituted with R; where R' is a substituent independently selected from the group consisting of: -OH, -Ci- 6 alkyl, -OCi.- 6 alkyl, phenyl, -CN, -NO 2 , 5 N(R")Rv, -C(O)N(Ru)Rv, -N(Ru)C(O)Rv, -N(Ru)SO 2
CI-
6 alkyl, - C(O)CI.
6 alkyl. -S(O)o- 2 -Ci. 6 alkyl,- SO 2 N(R")Rv, -SCF 3 , halo, -CF 3 , -OCF 3 , -OCHF 2 , -COOH, and -COOC- 6 alkyl; where Ru and Rv are each independently -H or -Ci- 6 alkyl; c) phenyl fused at two adjacent ring members to a four membered hydrocarbon 10 moiety to form a fused six membered aromatic ring, which moiety has one or two carbon atoms replaced by -N=, the fused rings optionally mono-, di-, or tri-substituted with R; d) naphthyl, optionally mono-, di-, or tri-substituted with R'; e) a monocyclic aromatic hydrocarbon group having five ring atoms, having a carbon atom which is the point of attachment, having one carbon atom replaced by >0, 15 >S, >NH, or >N(Ci.
4 alkyl), having up to one additional carbon atom optionally replaced by -N=, optionally mono- or di-substituted with Ri and optionally benzofused or pyridofused at two adjacent carbon atoms, where the benzofused or pyridofused moiety is optionally mono-, di-, or tri-substituted with Rt; and f) a monocyclic aromatic hydrocarbon group having six ring atoms, having a 20 carbon atom which is the point of attachment, having one or two carbon atoms replaced by -N=, optionally mono- or di-substituted with Ri and optionally benzofused or pyridofused at two adjacent carbon atoms, where the benzofused or pyridofused moiety is optionally mono- or di-substituted with Ri; and enantiomers, diastereomers, hydrates, solvates and pharmaceutically acceptable salts, esters and aides thereof. 25 These compounds can be prepared, for example, according to Scheme 6. - 51 - WO 2008/137087 PCT/US2008/005702 SCHEME 6
(R
5
)Q-
2
(R
4 )m. (R HO, , .Br (R 4) . HO .CHO A2 HO r O CHO Al A3
(H
5
)
0 2 0 Ar B HO Ar (R m H Ar1~~ 4R rr_,N . (RN, A4 A6
(R
5
)
02 Ar (R4) Ar' N L N R' (R5)0-2 nA-9a
(R
4 )m HN or HN or HOL
N,
1 A8 (R Ar
(R
4 )m A7 NN' A-9b Referring to Scheme 6, reagents of formulae Al, A2, and A5 are commercially 5 available or are prepared according to known methods. 3-5 Hydroxybenzaldehyde derivatives Al are reacted with alcohols A2 according to a Williamson ether synthesis protocol to form ethers A3, using a suitable base such as K 2
CO
3 , Na 2
CO
3 , or NaH, in a solvent such as acetonitrile, with or without catalytic KI or NaI. Alternatively, ethers of formula A3 may be prepared under Mitsunobu conditions where A2 contains a protected 10 hydroxyl in place of the bromide substituent. Reductive amination of the aldehyde functionality of compounds A3 will provide compounds of formula A4. The aldehyde can be treated with a suitable Rl-containing amine, with or without the addition of an activating agent such as a protic or Lewis acid, and with an appropriate reducing agent such as NaBH 4 , NaCNBH 3 , or NaIB(OAc) 3 . Preferred conditions include NaBH 4 in 15 methanol. Alkylation of amines A4 with alpha-haloketones A5 to form ketones A6 is accomplished in the presence of a tertiary amine base such as TEA or DIPEA, in a suitable solvent such as THF or DCM. Cyclization to generate tetrahydroisoquinolines A7 involves effecting cyclization to a tetrahydroisoquinolinium salt by exposure to a suitable protic or Lewis acid, such as methanesulfonic acid (MSA), trifluoroacetic acid (TFA), 20 AlCl 3 , TiC1 4 , or BF 3 *OEt 2 with or without a solvent such as DCM. Preferred conditions - 52 are neat MSA or MSA in DCM. The intermediate salt may be reduced using standard reducing agents such as NaCNBH 3 in an acidic methanol medium. Alternatively, ketones A6 may first be reduced by known methods, including NaBH4, to their corresponding alcohols. Treatment of the intermediate alcohols with MSA in DCM provides cyclic 5 species A7. Finally, the pendant primary alcohol group in compounds A7 may be converted to the corresponding amines A9 by activation to form an appropriate leaving group (such as a mesylate or bromide), followed by displacement of the leaving group with (R)- or (S)-2-methylpyrrolidine that has been prepared in accordance with the present invention. The displacement may be performed using a suitable base such as Na 2
CO
3 , in a 10 polar solvent such as n-BuOH, with or without catalytic KI or Nal. Alternatively, amines A9 may be prepared through oxidation of the alcohol and reductive amination of the resulting aldehyde. Thus, one embodiment of the invention relates to processes for preparing compounds of formulas VIII and IX: (R5)0-2 Ari (R)0-2 Ar
(R
4 )m (R4 5 N L NR1N L N'R1 15 nR VIII-A IX-A wherein the variables are as set forth above, comprising: (la) hydrogenating 2-methylpyrroline in a mixture comprising an alcohol solvent and a hydrogenation catalyst; 20 (lb) optionally removing the hydrogenation catalyst from the mixture; (1c) dissolving L-tartaric acid or D-tartaric acid in the mixture to form a solution; (ld) crystallizing (R)-2-methylpyrrolidine L-tartrate or (S)-2-methylpyrrolidine D-tartrate from the solution; 25 (l e) isolating the crystalline (R)-2-methylpyrrolidine L-tartrate or (S)-2 methylpyrrolidine D-tartrate; and (2a) contacting the (R)-2-methylpyrrolidine L-tartrate with a base to form (R)-2 methylpyrrolidine free base or contacting the (S)-2-methylpyrrolidine D-tartrate with a base for form (S)-2-methylpyrrolidine; 30 (3a) contacting a compound of formula - 53 - (Rs5)0-2 r
(R
4 )m HO t}< L N, wherein the variables are as described above, with either (R)- or (S)-2 methylpyrrolidine, for a time and under conditions sufficient to form the compound of formula VIII-A or IX-A. 5 This method may optionally further include the steps of: (If) recrystallizing the isolated (R)-2-methylpyrrolidine L-tartrate or (S)-2 methylpyrrolidine D-tartrate; (Ig) isolating the recrystallized (R)-2-methylpyrrolidine L-tartrate or (S)-2 methylpyrrolidine D-tartrate; and 10 (1h) optionally repeating steps (1f) and (Ig). Alternatively, 2-methylpyrrolidine-containing compounds may be prepared according to Scheme 7: SCHEME 7
(R(
4 )RM N L a CHO (R5)0-2 nB-1a
(R
4 )m HN or HN NI or HO }<\O CHO n ~(R 4 )M A3 A3 L -CHO B-1b (R4)'. (R5 H2 Ar Br R A5 B2 -r((R)2 Ar (r 44 (R)m O (R QN 1 Q O NR 15 B3 A12 Referring to Scheme 7, ethers of formula A3 may first be converted as described in Scheme A to the corresponding optionally protected amines B 1 using (R)- or (S)-2 methylpyrrolidine that has been prepared in accordance with the present invention. -54- Benzaldehydes B1 may then be transformed into diamines B2, wherein Q is (R)- or (S)-2 methylpyrrolidinyl, using reductive amination protocols as in Scheme A. Alkylation to form ketones B3, and cyclization to produce compounds of formula A12 are accomplished as shown for Scheme 6. 5 Another embodiment of the invention relates to processes for preparing compounds of formulas VIII-A and IX-A comprising: (la) hydrogenating 2-methylpyrroline in a mixture comprising an alcohol solvent and a hydrogenation catalyst; (lb) optionally removing the hydrogenation catalyst from the mixture; 10 (1 c) dissolving L-tartaric acid or D-tartaric acid in the mixture to form a solution; (I d) crystallizing (R)-2-methylpyrrolidine L-tartrate or (S)-2-methylpyrrolidine D-tartrate from the solution; (1e) isolating the crystalline (R)-2-methylpyrrolidine L-tartrate or (S)-2 15 methylpyrrolidine D-tartrate; and (2a) contacting the (R)-2-methylpyrrolidine L-tartrate with a base to form (R)-2 methylpyrrolidine free base or contacting the (S)-2-methylpyrrolidine D-tartrate with a base for form (S)-2-methylpyrrolidine; (3a) contacting a compound of formula
(R(
4 ) R 20 nOkn O CHO wherein the variables are as described above, with either (R)- or (S)-2 methylpyrrolidine, for a time and under conditions sufficient to form the corresponding amine; (3b) converting the amine to the compound of formula VIII-A or IX-A. 25 This method may optionally further include the steps of: (10 recrystallizing the isolated (R)-2-methylpyrrolidine L-tartrate or (S)-2 methylpyrrolidine D-tartrate; (1 g) isolating the recrystallized (R)-2-methylpyrrolidine L-tartrate or (S)-2 methylpyrrolidine D-tartrate; and 30 (lh) optionally repeating steps (1 f) and (1 g). - 55 - WO 2008/137087 PCT/US2008/005702 An exemplary compound that can be made using the methods of the present invention is 4 (4-methoxy-phenyl)-2-methyl-7-[3-(2-methyl-pyrrolidin-1 -yl)-propoxy]-1,2,3,4 tetrahydro-isoqunoline. 5 The methods of the present invention are also useful in the preparation of compounds of the following formulas X and XI, as described in WO 06/078775: n R nR N N/ N N R2 R3 N~r R2 R3 RI RI X XI and the pharmaceutically acceptable salts thereof, wherein: 10 n is 2, 3, 4, or 5 R is R 3 -aryl, R 3 -heteroaryl, R 3 -cycloalkyl, R 3 -heterocycloalkyl, alkyl, haloalkyl, OR 4 ,
-SR
4 or -S(0)1-2R5; R6 R6 R' is H and R2 is R 6 -phenyl or ; or R 1 is R 6 -phenyl or and 15 R2 is H; or R1 and R 2 are independently selected from the group consisting of R 6 -phenyl and ; and X is -0- or -S-; or R 1 and R2, together with the carbon atoms to which they are attached form or R6 R6 ;and X is -O-, -S-, or -NR 7 ; 20 R 3 is 1-3 substituents independently selected from the group consisting of H, alkyl, halo, OH, alkoxy and -NR"R,
R
4 is alkyl, arylalkyl or cycloalkyl; Rs is alkyl, -NR"R2 , R 3 -aryl or R 3 -arylalkyl; - 56 - WO 2008/137087 PCT/US2008/005702 R is 1-3 substituents independently selected from the group consisting of H, alkyl, -CF 3 , halo,
-NO
2 , -CN, -C(O)OR 3 , -C(O)NR"R1 2 , -NR1 4 Ris, -OR 3 and haloalkyl;
R
7 is H, alkyl, -c(O)OR", -C(O)NR"R" or 5 R" and R are independently selected from the group consisting of H, alkyl, cycloalkyl, aryl and arylalkyl; R1 3 is H, alkyl, cycloalkyl or arylalkyl; R1 4 is H , alkyl, cycloalkyl or arylalkyl; and
R
5 is H, alkyl, cycloalkyl, -C(O)OR1 3 , -C(O)NR"R 2 or -CO)R1 3 ; 10 Compounds of formulas X and XI can be prepared according to the following Scheme 8. -57- WO 2008/137087 PCT/US2008/005702 SCHEME 8 F XH R 3 - XH R 3 XH NO2 Step 1 Step 2 ~N O -3- HN'C te HN N NO2 NH2
R
6
NH
2 N N 1 2 3 R 6 4 R6 R
R
3 HNI~QIIYXH Step 3 HN H Step 4 N N Step 5 N 5 R 6 6 R n N3 N R3 N ReN 8a N R3 Step 6 , or / N // N or a N R 7 R 6 8b Referring to Scheme 8, Compound 1 is reacted with an aniline derivative 2 in a 5 suitable solvent such as THF or dioxane, preferably dioxane, at a temperature sufficient to effect the reaction, preferably 50 to 150 'C, to give compound 3. The nitro group of compound 3 is reduced to the amine 4 using hydrogen gas in the presence of a suitable catalyst such as Pd/C, PtO 2 , Raney nickel, preferably Raney Nickel, in a suitable solvent such as methanol, ethanol, or isopropanol, preferably methanol or ethanol. Other reduction 10 methods well known to those versed in the art are also suitable. The primary amine of compound 4 is acylated by reaction with a carboxylic acid in the presence of coupling agents such as DEC and HOBT in a suitable solvent such as ether, THF, or CH 2 C1 2 , preferably CH 2 Cl 2 to give compound 5. Alternatively, the amine - 58 - WO 2008/137087 PCT/US2008/005702 can be acylated by an acid chloride in the presence of a base. Compound 5 in acetic acid is heated for a sufficient time for cyclization to occur. In step 5, if a protecting group is present on the group X, it is removed at this point. Suitable protecting groups for X = 0, N, or S and methods for their removal can be found in Green's Protecting Groups in 5 Organic Synthesis. Compound 6 is reacted with an a, o-dihaloalkane in a suitable solvent such as acetone, THF, ether or the like, preferably acetone, in the presence of a base such as Na 2
CO
3 or K 2
CO
3 , preferably K 2
CO
3 , at a temperature from 0 to 65 'C to give compound 7 wherein Y is halo. A solution of compound 7 in a suitable solvent such as CH 3 CN, THF, ether, or the 10 like, preferably CH 3 CN, is treated with a tertiary amine base such as Et 3 N, DIPEA or the like, preferably DIPEA, followed by (R)- or (S)-2-methylpyrrolidine that has been prepared in accordance with the present invention. The reaction is then heated at a temperature from 0 to 1 00*C to give compound 8. Alternatively, the following Scheme 9 can be followed. 15 SCHEME 9 R / N N R 3 11a XH R R n 1 or/Zr NStep 1 N X Step2 R r NR R R3 NR 2 R3 N R1 RR 9 10 N R3
R
2 R11b Referring to Scheme 9, Compound 9, known in the literature, is reacted with an a, o-dihaloalkane in a suitable solvent such as acetone, THF, ether or the like, preferably acetone, in the presence of a base such as Na 2
CO
3 or K 2
CO
3 , preferably K 2
CO
3 , at a 20 temperature from 0 to 65*C to give compound 10. A solution of compound 10 in a suitable solvent such as CH 3 CN, THF, ether, or the like, preferably CH 3 CN, is treated with a tertiary amine base such as Et 3 N, DIPEA or the like, preferably DIPEA, followed by (R)- or (S)-2-methylpyrrolidine that has been prepared in accordance with the present invention. The reaction is then heated at a temperature from 0 to 1 00*C to give compound 25 11. -59- WO 2008/137087 PCT/US2008/005702 As an alternative, the compounds can be made according to the following Scheme 10. SCHEME 10 R3 XHR3 x YR3 X ,N XH Step 1 t 4 n Step 2 n c* = or 0 2 N 0 2 N 0 2 N 12 13 14 * F xN NO N 2 x X~ND Step 3 H2 NO Step HN
H
2 N'aR N 15 16 N2 O rN 17 R6
R
3 R X Step5 NH Step 6 N Step 7 - N 2 - HNN 18 19
R
6 R
R
4 R3 N"" HN N HN R6 20 5 Referring to Scheme 10, compound 12 is reacted with an cc, o-dihaloalkane in a suitable solvent such as acetone, THF, ether or the like, preferably acetone, in the presence of a base such as Na 2
CO
3 or K 2
CO
3 , preferably K 2
CO
3 , at a temperature from 0 to 65 *C to give compound 13, wherein Y is halo. A solution of compound 13 in a suitable solvent 10 such as CH 3 CN, THF, ether, or the like, preferably CH 3 CN, is treated with a tertiary amine - 60 - WO 2008/137087 PCT/US2008/005702 base such as Et 3 N, DIPEA or the like, preferably DIPEA, followed by (R)- or (S)-2 methylpyrrolidine that has been prepared in accordance with the present invention. The reaction is then heated at a temperature from 0 to 1 00*C to give compound 14. The nitro group of compound 14 is reduced to the amine 15 using H 2 gas in the presence of a 5 suitable catalyst such as Pd/C, PtO 2 , or Raney nickel, preferably Raney Nickel, in a suitable solvent such as methanol, ethanol, or isopropanol, preferably methanol or ethanol. Other reduction methods well known to those versed in the art are also suitable. Still referring to Scheme 10, Compound 15 is reacted with 16 in a suitable solvent such as THF or dioxane, preferably dioxane, at a temperature sufficient to effect the 10 reaction, preferably 50 to 150 *C, to give compound 17. The nitro group of compound 17 is reduced to the amine and subsequently to compound 18. The amine 18 in a suitable solvent such as THF, ether or the like is treated with either thiocarbonyldiimidazole (Q = S) or 1,1 '-carbonyldiimidazole (Q = 0) at a temperature of from 0 to 100 *C, preferably from 25 to 75 'C, to give compound 19. 15 A solution of 19 in a suitable solvent such as DMSO, DMF or the like is treated with a base such as K 2
CO
3 or the like and an alkylating agent R 4 L, in which L is Cl, Br or I, or a mesylate or sulfonate, at a temperature of 0 to 100 'C, preferably from 25 to 75 'C, to give 20. Thus, one embodiment of the invention relates to processes for preparing 20 compounds of formulas X and XI N NO / NC NN N R2 R3 N R R3 R1 R1 X XI wherein the variables are as set forth above; comprising: 25 (la) hydrogenating 2-methylpyrroline in a mixture comprising an alcohol solvent and a hydrogenation catalyst; (l b) optionally removing the hydrogenation catalyst from the mixture; (1c) dissolving L-tartaric acid or D-tartaric acid in the mixture to form a solution; -61 - (1d) crystallizing (R)-2-methylpyrrolidine L-tartrate or (S)-2-methylpyrrolidine D-tartrate from the solution; (1 e) isolating the crystalline (R)-2-methylpyrrolidine L-tartrate or (S)-2 methylpyrrolidine D-tartrate; and 5 (2a) contacting the (R)-2-methylpyrrolidine L-tartrate with a base to form (R)-2 methylpyrrolidine free base or contacting the (S)-2-methylpyrrolidine D-tartrate with a base for form (S)-2-methylpyrrolidine; (3a) converting the (R)- or (S)-2-methylpyrrolidine to the compound of formula VIII or IX. 10 This method may optionally further include the steps of: (10 recrystallizing the isolated (R)-2-methylpyrrolidine L-tartrate or (S)-2 methylpyrrolidine D-tartrate; (ig) isolating the recrystallized (R)-2-methylpyrrolidine L-tartrate or (S)-2 methylpyrrolidine D-tartrate; and 15 (1h) optionally repeating steps (If) and (Ig). Also amenable to the methods of the present inventions are compounds of the following compounds of formulas XII and XIII, described in WO 2007/099423: R3 3 C/AX
R
5 -O d n R 5 -O d n 20 XII XIII or the pharmaceutically acceptable salts thereof, wherein
R
3 is (Ci-&)-alkyl, aryl or heteroaryl, optionally substituted with up to 3 fluorine atoms;
R
4 is hydrogen, halogen, (C 1 6 )-alkyl or (C 3 .7)-cycloalkyl, (CI 1 )-alkoxyl or (C3.7) cycloalkoxyl (optionally substituted with up to 3 fluorine atoms), aryl, heteroaryl; 25 R' is (CR 6
R
9 )m-(CR 0
R
11 ),-B, wherein R 6 , R, R" 0 and R" together with the carbon to which they are attached form a 3-10 member mono- or bi-cyclic ring system; B is a 4-7 member heterocycloalkyl containing up to 3 heteroatoms selected from N, 0, S (e.g., azetidine, pyrrolidine, piperdine, azeplne, morpholine, thiomorpholine, piperazine or 1-4 diazepine) or NR 1R1; - 62 - WO 2008/137087 PCT/US2008/005702
R
8 , R 9 , R' 0 , R", R' and R" are independently selected from hydrogen, C 1
.
6 alkyl, (C 1
.
6 alkyl)-aryl, (C 1
-
6 alkyl)-heteroaryl; or R1 2 and R1 3 together with the nitrogen to which they are attached form a 3-10 member mono- or bi-cyclic ring system (e.g., azepine, piperidine, pyrrolidine or morpholine), and 5 with the proviso that NRR 1 3 is not NH 2 ; m is 0, 1, 2, 3, or 4; n is 0, 1, 2 or 3; and p is 0 to 3. These compounds can be prepared by the general procedure shown in the 10 following Scheme 11. SCHEME 11 4 N R N 4 N b.RR 3 orrcaR3 ~ / H orHN ~ / r n n cn HO d HOd HO/ lila Ilb R 4 N R4 N3 b. b ~ or bC
R
5 0 dR 5 0 la lb Referring to Scheme 11, a ketone of the general formula II, wherein the hydroxyl (-OH) group is unprotected, is reacted with (R)- or (S)-2-methylpyrrolidine that has been 15 prepared in present invention, to generate an amino-phenol of general formula III. This transformation can be accomplished using one or more of the methods and procedures available to those skilled in the art. For example, a ketone of formula II and 2 methylpyrrolidine can be combined in an inert aprotic solvent, like chloroform or dichloromethane, in the presence of a Lewis acid reagent like titanium tetrachloride 20 (TiCl 4 ) or titanium isopropoxide to produce an intermediate imine through the elimination of water. Alternatively, refluxing a solution of II and 2-methylpyrrolidine in a solvent like toluene in the presence of a catalytic amount of para-toluenesulfonic acid, with provision for removal of the water by using a Dean-Stark trap or activated molecular sieves, may also be employed to effectively produce the intermediate imine. This imine may then be 25 converted in situ, or in a separate step following its isolation, to the amino-phenol - 63 - WO 2008/137087 PCT/US2008/005702 intermediate III. This can be accomplished by reduction of the C=N double bond using, for example, boron reagents like sodium borohydride (NaBH 4 ), sodium cyanoborohydride (NaBH 3 CN), sodium triacetoxyborohydride and the like, in reaction inert solvents like dichloromethane, methanol, THF or dioxane. Alternatively, the imine can be reduced 5 using catalytic hydrogenation conditions, e.g., employing hydrogen gas (H 2 ) and a suitable metal catalyst like Raney nickel (RaNi), palladium on carbon (Pd/C) or similar catalysts in a reaction inert solvent like methanol or ethanol and at temperatures in the range of about 20 'C up to the boiling point of the solvent employed and at pressures in the range of about one to five atmospheres of hydrogen gas. Other related examples for the 10 transformation may be found in the literature. Still referring to Scheme 11, the phenolic OH group present in the intermediate of formula III .can be converted to an ether product of the general formula I by alkylation of III with a reagent of the general formula R 5 -A, wherein R 5 is as defined previously and A is a leaving group including halogen (e.g., Cl, Br, I), mesylate (i.e., -OSO 2
CH
3 , or -OMs) 15 or tosylate (i,e., -OSO 2
C
6
H
5 or -OTs), in the presence of a base and in a reaction inert solvent, as depicted in pathway b. Suitable bases will include sodium, potassium or cesium carbonate(s), sodium or potassium bicarbonate(s), sodium or potassium tert butoxide(s), sodium or potassium hydride(s) and the like, with cesium carbonate being preferred. Suitable solvents will include DMF, DMSO, DMA, THF and the like, with 20 DMSO preferred. Thus, one embodiment of the invention relates to processes for preparing compounds of formula XII and XIII: NN 4aN _C C /___
R
3
R
5 -O d R 5 -0 d XII XIII 25 wherein the variables are as set forth above, comprising: (la) hydrogenating 2-methylpyrroline in a mixture comprising an alcohol solvent and a hydrogenation catalyst; (lb) optionally removing the hydrogenation catalyst from the mixture; (lc) dissolving L-tartaric acid or D-tartaric acid in the mixture to form a 30 solution; -64- (1 d) crystallizing (R)-2-methylpyrrolidine L-tartrate or (S)-2-methylpyrrolidine D-tartrate from the solution; (1 e) isolating the crystalline (R)-2-methylpyrrolidine L-tartrate or (S)-2 methylpyrrolidine D-tartrate; and 5 (2a) contacting the (R)-2-methylpyrrolidine L-tartrate with a base to form (R)-2 methylpyrrolidine free base or contacting the (S)-2-methylpyrrolidine D-tartrate with a base for form (S)-2-methylpyrrolidine; (3a) contacting a compound of formula R4 O HO R3 10 with either (R)- or (S)-2-methylpyrrolidine, for a time and under conditions sufficient to form the corresponding amine phenol; and (3b) contacting the amine phenol with an alcohol, for a time and under conditions sufficient to provide the compound of formula XII or XIII. This method may optionally further include the steps of: 15 (1 f) recrystallizing the isolated (R)-2-methylpyrrolidine L-tartrate or (S)-2 methylpyrrolidine D-tartrate; (Ig) isolating the recrystallized (R)-2-methylpyrrolidine L-tartrate or (S)-2 methylpyrrolidine D-tartrate; and (lh) optionally repeating steps (If) and (Ig). 20 The compounds of the present general formulas XII and XIII may also be prepared via the routes shown in the following Scheme 12. -65- WO 2008/137087 PCT/US2008/005702 SCHEME 12 4 0
'
K R3 c R R3orHN R 3 or R R 3 R a HN R.a L R h. H d nr HO dR 5 R0 d IV
R
5 0 d
R
5 d a e. h. R4 0R 3 4 OH 4 L R t S ea k o tga fmHNu II myb R R VII R 5 e0 d w R 5 0 d n V VI Referring to Scheme 12, a phenolic ketone of the general formula 11 may be 5 converted to an ether (pathway c.) by methods generally known to one skilled in the art. For example, the phenol 11 can be reacted with a reagent of general formula R 5 -A in the presence of a base, as described for pathway b in Scheme 1 to produce a ketone of general formula IV. Alternatively, a ketone of the general formula VII, wherein LI is a suitable leaving group (i.e., F, -OMs, etc.), may be reacted with a reagent of general formula R 10 OH in the presence of a suitable base and in an inert solvent to produce an intermediate of general formula IV (pathway e.). The ketone IV so obtained may then be converted, using reductive amination conditions as previously described in Scheme 11 to the desired products of general formula I (pathway d.). In some situations, it may also be advantageous to initially convert the intermediate ketone IV to the corresponding benzylic 15 alcohol of general formula V (pathway f.) by using a reducing agent such as NaBH 4 in a solvent like methanol, then to activate the benzylic alcohol V (pathway g.) to produce an intermediate of formula VI in which L 2 is a leaving group (e.g., OMs, OTs, Cl), and finally to displace the leaving group w with (R)- or (S)-2-methylpyrrolidine that has been prepared in accordance with the foregoing steps (a) to (e) (with or without optional steps 20 (f) to (h)) and reacting the (R)-2-methylpyrrolidine L-tartrate with a base to provide (R)-2 methylpyrrolidine or (S)-2-methylpyrrolidine D-tartrate with a base to provide (S)-2 methylpyrrolidine (pathway h.). Thus, another embodiment of the invention relates to processes for preparing compounds of formula XII and XIII: - 66 - WO 2008/137087 PCT/US2008/005702 4a
R
5 -0 d n R 5 -O d n XII XIII wherein the variables are as set forth above, comprising: (la) hydrogenating 2-methylpyrroline in a mixture comprising an alcohol 5 solvent and a hydrogenation catalyst; (Ib) optionally removing the hydrogenation catalyst from the mixture; (Ic) dissolving L-tartaric acid or D-tartaric acid in the mixture to form a solution; (Id) crystallizing (R)-2-methylpyrrolidine L-tartrate or (S)-2-methylpyrrolidine 10 D-tartrate from the solution; (le) isolating the crystalline (R)-2-methylpyrrolidine L-tartrate or (S)-2 methylpyrrolidine D-tartrate; and (2a) contacting the (R)-2-methylpyrrolidine L-tartrate with a base to form (R)-2 methylpyrrolidine free base or contacting the (S)-2-methylpyrrolidine D-tartrate with a 15 base for form (S)-2-methylpyrrolidine; (3a) contacting a compound of formula R4 0 R3 b HO d with a compound of formula R 5 -LG, wherein LG is a leaving group, for a time and under conditions sufficient to form a compound of formula
R
4 O R3 20 R 5 0 d ;and (3b) contacting the compound of formula R4 O R R3
R
5 0 d - 67 with either (R)- or (S)-2-methylpyrrolidine, for a time and under conditions sufficient to form the compound of formula XII or XIII. This method may optionally further include the steps of: (10 recrystallizing the isolated (R)-2-methylpyrrolidine L-tartrate or (S)-2 5 methylpyrrolidine D-tartrate; (Ig) isolating the recrystallized (R)-2-methylpyrrolidine L-tartrate or (S)-2 methylpyrrolidine D-tartrate; and (1h) optionally repeating steps (If) and (Ig). An exemplary compound that can be prepared using the methods of the present 10 invention is 1-{3-[1-(2-methyl-pyrrolidin-1-yl)-indan-5-yloxy]-propyl}azepane. The methods of the present invention are also suitable for preparing compounds such as those described in WO 2007/094962, for example, those of formulas XIV and XV. 0 N X N yY y R3 R3 *=aor * or N R N R6 N/N R4 R5R4 R 15 XIV XV wherein X is O or NR 7 ; y is 0, 1, or 2;
R
3 is 0-2 of groups selected from halogen, (C 1 8 )alkyl, (Cis)alkoxyl, (C 3 .7)cycloalkyl, 20 (C3.7)cycloalkyl-(C 6 )alkyl, heterocycloalkyl containing 1-3 hetero atoms selected from 0, S, and (C1s)alkyl-O-(C 5 )alky1; R4 and R 6 are independently selected from (C 15 )alkyl, (C 1 g)alkoxy, (C 3 .7)cycloalkyl, (C3.7)cycloalkyl-(C )alkyl, heterocycloalkyl containing 1-3 heteroatoms selected from 0, S, N, (C 1 5 )alkyl-O-(C 1 s)alkyl, amide, (C 1 5 )alkyl-aryl, and CF 3 ; 25 R 5 is selected from the group consisting of hydrogen, (C 1 8 )alkyl, aryl, (C 5 )alkyl-O-(C 5 )alkyl, and (CIs)alkyl-aryl, or -68 - WO 2008/137087 PCT/US2008/005702
R
5 and R4 and the atoms to which they are attached form a fused 5-6 member saturated carbocyclic ring or a fused 10 member bi-cyclic ring system, such as N R N,N R6 \C N R \ or R -R3 1-2 R3 or 5 R 5 and R 6 and the atoms to which they are attached form a fused 5-6 member saturated carbocyclic ring or a fused 10 member bi-cyclic ring system, such as
R
3 N
R
3 R4 ~1-2 R or R4 or
R
5 and R 4 and the atoms to which they are attached form a fused 5-6 member saturated 10 carbocyclic ring to which a 6 member aromatic ring is fused, such as N N R6
-R
3 R3 or
R
5 and R, and the atoms to which they are attached form a fused 5-6 member saturated carbocyclic ring to which a 6 member aromatic ring is fused, such as N N N-R 15 or
R
5 and R 6 and the atoms to which they are attached form a fused benzothiophene or fused benzofuran ring system, such as N - -R 3 N -R3 0 6S -69 - WO 2008/137087 PCT/US2008/005702 where X is NR 7 , R 7 and R 2 taken together are -(CH 2
CH
2 )- to form a two nitrogen containing ring where y is 0 (piperazine) or y is 1 (homopiperazine), and wherein R, is as defined previously, and the pharmaceutically acceptable salts thereof. The above-described compounds having a 2-methylpyrrolidine group may be 5 prepared in accordance with the following schemes. (R)- or (S)-2-methylpyrrolidine that has been prepared in accordance with present invention can be reacted, under conditions known in the art, with 1,3-dichloropropane to produce (R)- or (S)-1-(3-chloro-propyl)-2 methyl-pyrrolidine, which can be used as in the following schemes. SCHEME 13 -_O HO 0 O O N-N N-N HN NH2 BBr 3 EtOH, reflux bN" 6N O *=aorp N--N 10 SCHEME 14 - 70 - WO 2008/137087 PCT/US2008/005702 OMe OMe MeO~ H H ~~
NHNH
2 _
BF
3 -AcOH, Ac 2 O O NN + N H IN/ + N H HH H OMe OH BBr 3 =a___or __o H NaH, Na!, DMFI H H H N H SCHEME 15 OBn BnO 0 0 j NHNH
SBF
3 -Et 2 O, AC 2 0 -I2 N / OH
H
2 __N_______ N-NaH, Nal, DMF N X 5 SCHEME 16 - 71 - WO 2008/137087 PCT/US2008/005702 0- OH OH O BBr 3 , DCM 0 LAH, THF HO N N N or OH
K
2
CO
3 , 2-butanone HO DCM, H 2
SO
4 0-N N N SCHEME 17
NH
2 Br N Br N Pd(OAc) 2 , dppf Br K2CO3, DMF, 90 CBr O tBuONa, PhMe, 90 C / / \NHNH 2 HCI O OH 0 N BBr 3 ,DCM * = aorp N,N- NN NaH, Nal, DMF, 85 C N 5 SCHEME 18 - 72 - WO 2008/137087 PCT/US2008/005702 O 0 O 1 'EtOH, 80 C
NHNH
2 HCI OBn OH O N -Zzz I N "'ClI H, Pd/C ,*= a or p N, THF/MeOH N, NaH, Nal, DMF, 85 C N /N N N -O -O -0 SCHEME 19 Br1.Br BHO N N ClN : N' N~~C NaOtBu, Pd(OAc) 2 , NaH, Nal, DMF, 70 C
NHNH
2 HCI PhMe, 100 C ao *=aorp /00 Thus, another embodiment of the invention relates to processes for preparing compounds of formula XIV and XV: O N X N y y R3-i R3- *= orp *= orp N R 6 /N R 6 N/ Nf R4 5 R4 5 -73- XIV XV wherein the variables are as set forth above, comprising: (I a) hydrogenating 2-methylpyrroline in a mixture comprising an alcohol solvent and a hydrogenation catalyst; 5 (lb) optionally removing the hydrogenation catalyst from the mixture; (1c) dissolving L-tartaric acid or D-tartaric acid in the mixture to form a solution; (Id) crystallizing (R)-2-methylpyrrolidine L-tartrate or (S)-2-methylpyrrolidine D-tartrate from the solution; 10 (1 e) isolating the crystalline (R)-2-methylpyrrolidine L-tartrate or (S)-2 methylpyrrolidine D-tartrate; and (2a) contacting the (R)-2-methylpyrrolidine L-tartrate with a base to form (R)-2 methylpyrrolidine free base or contacting the (S)-2-methylpyrrolidine D-tartrate with a base for form (S)-2-methylpyrrolidine; 15 (3a) converting (R)- or (S)-2-methylpyrrolidine to 1-(3-halo-propyl)-(R)-2 methyl-pyrrolidine or 1-(3-halo-propyl)-(S)-2-methyl-pyrrolidine; and (3b) converting 1-(3-halo-propyl)-(R)-2-methyl-pyrrolidine or 1-(3-halo propyl)-(S)-2-methyl-pyrrolidine to the compound of formula XII or XIII. This method may optionally further include the steps of: 20 (1f) recrystallizing the isolated (R)-2-methylpyrrolidine L-tartrate or (S)-2 methylpyrrolidine D-tartrate; (Ig) isolating the recrystallized (R)-2-methylpyrrolidine L-tartrate or (S)-2 methylpyrrolidine D-tartrate; and (1h) optionally repeating steps (If) and (1g). 25 Exemplary compounds that can be prepared according to the methods of the invention include: 3-Methyl- 1- {4-[3-(2R-methylpyrrolidin-1 -yl)propoxy]phenyl}-4,5-dihydro-1H benzo[g]indazole; 5-Methyl-2- {4-[3-(2R-methylpyrrolidin-1 -yl)propoxy]phenyl} -2H-pyrazole-3 30 carboxylic acid cyclohexylamide; 1- {4-[3-(2-(R)-Methyl-pyrrolidin-1-yl)-propoxy]-phenyl}-5-phenyl-3 trifluoromethyl- 1 H-pyrazole; 3-Methyl-1 - {4-[3 -(2-methyl-pyrrolidin- 1 -yl)-propoxy]-phenyl) } -1H benzo[4,5]thieno[3,2-c]pyrazole; and - 74 - WO 2008/137087 PCT/US2008/005702 3- {4-[3-(2-Methyl-pyrrolidin- 1 -yl)-propoxy] -phenyl} -1 -trifluoromethyl-3H-8-oxa 2,3-diaza-cyclopenta[a]indene. Further compounds that can benefit from the methods of preparing 2 5 methylpyrrolidine as set forth herein include those of formulas XVI and XVII described in WO 2007/048595:
*A
2
A
2 tR3 A2 LI R2a R3 A2 L R2a (H2C)O N R 2 b R4 N R 2 b An w(H 2 C)O Al XVI XVII and pharmaceutically acceptable salts thereof; 10 wherein A' is CH, C-halogen, or; A2 is oxygen or sulfur;
R
2 a is hydrogen, aryl, C,.
6 alkoxy, amino, C 1
.
6 alkyl, C 2
-
6 alkenyl, heteroaryl, C 3
-
8 cycloalkyl, 3-8-membered heterocycloalkyl, acyl, C,.
6 -alkyl aryl, Ci- 6 -alkyl, heteroaryl, Ci- 6 -alkyl cycloalkyl, C1.
6 -alkyl heterocycloalkyl, carboxy, alkoxycarbonyl, 15 aminocarbonyl, CI.
6 -alkyl carboxy, C,.
6 -alkylacyl, C,.
6 -alkylalkoxy, CI.
6 -alkyl alkoxycarbonyl, C .
6 -alkyl aminocarbonyl, Ci.
6 -alkylacylamino, acylamino, C1.
6 -alkyl ureido, CI- 6 -alkyl carbamate, CI- 6 -alkyl amino, C 3
.
8 -cycloalkyl amino, hydroxy, C,.
6 alkyl hydroxy, halogen or cyano; R2b is hydrogen, halogen, C1.
8 -alkyl or C 3
-
8 cycloalkyl; 20 or R2a and R are linked together to form a C 3
.
8 cycloalkyl, a 3-8-membered heterocycloalkyl or an oxo group;
R
3 is hydrogen, halogen, C14 alkyl or C14 alkoxy;
R
4 is hydrogen, halogen, C14 alkyl or C14 alkoxy; L' is -(O)y-(CR 9 aR 9 b)m-(CH 2 )z; 25 R 9 a is hydrogen or unsubstituted C1.
8 alkyl; R 9 is a Ci- 6 -alkyl aryl or unsubstituted CI.
8 alkyl; n is an integer equal to 0, 1 or 2; t is an integer equal to 2, 3 or 4; w is an integer equal to 2, 3 or 4; 30 v is an integer equal to 0 or 1; - 75 - WO 2008/137087 PCT/US2008/005702 m is an integer equal to 0 or 1 ; and z is an integer equal to 0, 1,2 or 3; Similar compounds, such as those described in WO 2006/103045, the entirety of which is incorporated herein for all purposes, can also be prepared according to the 5 methods of the invention. Compounds described above may be prepared according to Scheme 20: SCHEME 20 R3 A*R3A 2 LRa A2 t(CH 2 )O Y t(CH 2 )O N R 2 b I + H N b R 5 * A 1 - R 5 A la R3 is , F dA 2 Y R yl A 2 4 p i + Hi wN R 2 b n
~(CH
2 n A (H 2 ) A 1 lb 10 wherein R 3 is H, F, or Cl, and Y 1 is I or Br. These reactions may be carried out using a catalyst such as copper iodide or palladium acetate, associated with a ligand such as 1 ,2-diamine (e.g. trans- 1,2 diaminocyclohexane), a phosphine (e.g. 1,1 '-bis(diphenylphosphino)ferrocene or 2 (dicyclohexylphosphino)-2'-(N,N-dimethylamino)-biphenyl) or an amino acid (e.g., 15 glycine), in a solvent (such as dioxane, tetrahydrofuran, dimethylformamide or toluene), in the presence of a base (such as potassium phosphate or sodium tert-butylate), at a temperature ranging from 25 *C to 120 *C and under an inert atmosphere (argon or nitrogen). Alternatively, this reaction may be performed according to the methodology described by Klapars A. et al. in J. Am. Chem. Soc. 2002, 124, 7421. 20 Compounds of formulas Ia and lb set forth in Scheme 20 may be prepared using (R) or (S)-2-methylpyrrolidine prepared according to the methods of the instant invention, in accordance with Scheme 21. SCHEME 21 - 76 - WO 2008/137087 PCT/US2008/005702
R
3 R3 Cl-t(CH 2 )O Y *H t(CH2)O Y
R
5
A
1 cc orp R5 A C R4 HR4 RHN *
'(CH
2 )O A 1 * = a or $ w(CH 2 )O A These reactions may be carried out in the presence of a base such as triethylamine or potassium carbonate, in acetonitrile or acetone as solvent, or according to any conventional method known to the man skilled in the art. 5 Thus, one embodiment of the present invention relates to processes for the preparation of compounds of formulas XVI and XVII R3A 2
A
2 2a R3 Ll
R
3 R t(H2C)O N R 2 b R 4 N R 2 b -,n n.
A
1 w(H 2 C)O A' XVI XVII wherein the variables are as set forth above, comprising: 10 (1 a) hydrogenating 2-methylpyrroline in a mixture comprising an alcohol solvent and a hydrogenation catalyst; (Ib) optionally removing the hydrogenation catalyst from the mixture; (Ic) dissolving L-tartaric acid or D-tartaric acid in the mixture to form a solution; 15 (1 d) crystallizing (R)-2-methylpyrrolidine L-tartrate or (S)-2-methylpyrrolidine D-tartrate from the solution; (le) isolating the crystalline (R)-2-methylpyrrolidine L-tartrate or (S)-2 methylpyrrolidine D-tartrate; and (2a) contacting the (R)-2-methylpyrrolidine L-tartrate with a base to form (R)-2 20 methylpyrrolidine free base or contacting the (S)-2-methylpyrrolidine D-tartrate with a base for form (S)-2-methylpyrrolidine; (3a) contacting a compound of formula - 77 - R3 R3 CI-ct(CH2) Y 'C R4 Y
R
5 A or w(CH 2 )O A'
A
2 L R2a wherein Y1 is N n with either (R)- or (S)-2-methylpyrrolidine, for a time and under conditions sufficient to form the compound of formula XVI. This method may optionally further include the steps of: 5 (10 recrystallizing the isolated (R)-2-methylpyrrolidine L-tartrate or (S)-2 methylpyrrolidine D-tartrate; (Ig) isolating the recrystallized (R)-2-methylpyrrolidine L-tartrate or (S)-2 methylpyrrolidine D-tartrate; and (lh) optionally repeating steps (1f) and (Ig). 10 Alternatively, the following Scheme 22 may be implemented, wherein the 2 methylpyrrolidinealkoxy is prepared from (R)- or (S)-2-methylpyrrolidine that has been prepared in accordance with the foregoing steps (a) to (e) (with or without optional steps (f) to (h)) and reacting the (R)-2-methylpyrrolidine L-tartrate with a base to provide (R)-2 15 methylpyrrolidine or (S)-2-methylpyrrolidine D-tartrate with a base to provide (5)-2 methylpyrrolidine, which is then reacted with a reagent such as halo-alkoxy. SCHEME 22 halogen Y [+N CN Y1 t_____ t(CHO
R
5 A x or
R
5
A
1
R
3 HO 4*3 Y R 4 Y RI Yi b halogen A 1 * x or P -(CH 2 )O A 1 The reactions set forth in Scheme 22 may be performed in the presence of a base, 20 such as potassium tert-butylate, cesium carbonate or sodium hydride, in a solvent, such as - 78 - WO 2008/137087 PCT/US2008/005702 dimethylformamide or tetrahydrofuran, in the presence of a palladium- or a copper based catalyst, according to method described by Penning et al. in J. Med. Chem. 2000, 43, 721. Thus, another embodiment of the present invention comprises methods of 5 preparing compounds of formulas XVI and XVII
*A
2
A
2
R
3 A2 L R2a R3 A L R2a t(H2C)O N R 2 b R N R 2 b Al w(H 2 C)O A 1 XVI XVII wherein the variables are as set forth above, comprising: (la) hydrogenating 2-methylpyrroline in a mixture comprising an alcohol 10 solvent and a hydrogenation catalyst; (lb) optionally removing the hydrogenation catalyst from the mixture; (Ic) dissolving L-tartaric acid or D-tartaric acid in the mixture to form a solution; (ld) crystallizing (R)-2-methylpyrrolidine L-tartrate or (S)-2-methylpyrrolidine 15 D-tartrate from the solution; (1 e) isolating the crystalline (R)-2-methylpyrrolidine L-tartrate or (S)-2 methylpyrrolidine D-tartrate; and (2a) contacting the (R)-2-methylpyrrolidine L-tartrate with a base to form (R)-2 methylpyrrolidine free base or contacting the (S)-2-methylpyrrolidine D-tartrate with a 20 base for form (S)-2-methylpyrrolidine; (3a) converting (R)- or (S)-2-methylpyrrolidine to the corresponding 2 methylpyrrolidinylalkyl-OH; (3a) contacting a compound of formula R3 R3 halogen or R4 Yi R A halogen Al
A
2 Ll R2a N R2b 25 wherein Yl is n with either (R)- or (S)-2-methylpyrrolidinylalkyl OH, for a time and under conditions sufficient to form the compound of formula XVI. - 79 - This method may optionally further include the steps of: (1f) recrystallizing the isolated (R)-2-methylpyrrolidine L-tartrate or (S)-2 methylpyrrolidine D-tartrate; (Ig) isolating the recrystallized (R)-2-methylpyrrolidine L-tartrate or (S)-2 5 methylpyrrolidine D-tartrate; and (1h) optionally repeating steps (If) and (1 g). Exemplary compounds that can be prepared according to the methods of the invention include: 1-[3-(4- {4-[(2-methylpyrrolidin-1 -yl)methyl]- 1,3-oxazol-2-yl}phenoxy)propyl 10 piperidine; 2-[(2- {4-[3-(2-methylpyrrolidin-yl)propoxy]phenyl} -1,3-oxazol-4-yl)methyl]-2 azaspiro[5.5]undecane; 4-[(2-methylpyrrolidin-1-yl)methyl]-2- {4-[3-(2-methylpyrrolidin-1-yl)propoxy] phenyl}-1,3-oxazole; 15 1 -isopropyl-4-[3-(4- {4-[(2-methylpiperidin- 1 -yl)methyl]-1,3-oxazol-2-yl} phenoxy)propyl]piperazine; 4-methyl- 1-[3-(4- {4-[(2-methylpyrrolidin-1 -yl)methyl]-1,3-oxazol-2 yl}phenoxy)propyl]piperidine; 2-methyl- 1-[3-(4- {4[(2-methylpyrrolidin- 1 -yl)methyl]-1,3-oxazol-2 20 yl}phenoxy)propylipiperidine; 4- [(2-methylpyrrolidin- 1 -yl)methyi] -2-(4- { 3 -[2-(pyrrolidin- 1 -yl)ethyl) pyrrolidin 1-yl]propoxy}phenyl)-1,3-oxazole; 1-cyclopentyl-4-[3-(4-{4-[(2-methylpyrrolidin-1-yl)methyl]-1,3 oxazol-2 yl}phenoxy)propylipiperazine; 25 N,N-dimethyl-1-[4-(4-{4-[(2-methylpyrrolidin-1-yl)methyl]-1,3-oxazol-2 yl}phenoxy)butyl]pyrrolidin-3-amine; 1-[2-(4-{4-[(2-methylpyrrolidin-1-yl)methyl]-1,3-oxazol-2-yl}phenoxy)ethyl]- 4 (2-pyrrolidin- 1 -ylethyl)piperazine; 2-{4-[3-(2-methylpyrrolidin-1-yl)propoxy]-[3-4-(2-oxo-2-pyrrolidin-1- ylethyl) 30 1,3-oxazole; 1-[(2-{4-[3-(2-methylpyrrolidin-I -yl)propoxy]phenyl]-1,3-oxazol-4-yl)methyl] pyrrolidin-2-one; N-[(2- (4-[3-(2-methylpyrrolidin- 1 -yl)propoxy]phenyl}-1,3-oxazol-4-yl)methy1] N-phenylamine; -80- WO 2008/137087 PCT/US2008/005702 2- {4-[3-(2-methylpyrrolidin- I -yl)propoxy]-[3-4-(2-pyrrolidin- 1 -ylethyl)- 1,3 oxazole; 4-[(2-methyl-i H-imidazol- 1 -yl)methyl]-2-{4-[3-(2-methylpyrrolidin yl)propoxy]phenyl}-1,3-oxazole; 5 1-[(2- {4-[3-(2-methylpyrrolidin- 1 -yl)propoxy]phenyl} -1,3-oxazol-4-yl)methyl] 1H-1,2,4-triazole; 1-[(2-{4-[3-(2-methylpyrrolidin- 1 -yl)propoxy]phenyl- 1,3-oxazol-4-yl)methyl] piperidine; 1-[3-(4-[4-[(2-methylpyrrolidin- 1 -yl)methyl]-1,3-oxazo 1 -2-yl)phenoxy)propyl) 10 azepane; 1-(3- {4-[4-methyl-5-(piperidin- 1 -yl)methyl)- 1,3-oxazol-2-yl]phenoxy}propyl) piperidine; (2R)-4-methyl-2- {[(2-{4-[3-(2-methylpyrrolidin- 1 -yl)propoxy]phenyl} -1,3-oxazol 4-yl)methyl]amino}pentan- 1 -ol; 15 N-[(2- {4-[3-(2-methylpyrrolidin- 1 -yl)propoxy]phenyl} -1,3-oxazol-4-yl)methyl] cyclopentanamine; 1-[4-(4- {4-[(2-methylpyrrolidin- 1 -yl)methyl]-1,3-oxazol-2 yl}phenoxy)butyl]azepane; 1-[2-(4- {4-[(2-methylpyrrolidin- 1 -yl)methyl} -1,3-oxazol-2-yl}phenoxy) 20 ethyl]azepane; N-(1,3-dimethylbutyl)-N-[(2-{4-[3-(2-methylpyrroalin-1-yl)propoxy]phenyl}-1,3 oxazol-4-yl)methyl]amine; N-(cyclopropylmethyl)-N-[(2- {4-[3-(2-methylpyrrolidin- 1 -yl)propoxy]phenyl} 1,3-oxazol-4-yl)methyl]-N-propylamine; 25 1-[(2- (4-[2-(2-methylpyrrolidin- 1 -yl)ethoxy]phenyl} -1,3-oxazol-4-yl)methyl] piperidine; 2-methyl-1-[4-(4-{4-[(2-methylpyrrolidin-1-yl)methyl]-1,3-oxazol-2-yl} phenoxy) butyl]piperidine; 7,8-dimethyl-1-[(2-{4-[3-(2-methylpyrrolidin-1-yl)propoxy]phenyl}-1,3-thiazol-4 30 yl)methyl]-1-azaspiro[4.4]nonane; N-(2-furylmethyl)-N-methyl-N-[(2-{4-[3-(2-methylpyrrodin-1-yl)propoxy] phenyl}-1,3-thiazol-4-yl)methyl]amine; N-(sec-butyl)-N-[(2-{4-[3-(2-methylpyrrolidin-1 yl)propoxy]phenyl}-1,3- thiazol-4-yl)methyl]-N-propylamine; -81- WO 2008/137087 PCT/US2008/005702 1-[(2-[4-(3-(2-methylpyrrolidin- 1 -yl)propoxy]phenyl} -1,3-thiazol-4 yl)methyl]piperidine; 1-[(2- {4-[3-(2-methylpyrrolidin- 1 -yl)propoxy]phenyl} -1,3-oxazol-4-yl acetyl]piperidine; 5 1-[2-(2- {4-[3-(2-methylpyrrolidin- 1 -yl)propoxy]phenyl} -1,3-oxazol-4-yl)ethyl] piperidine; 2- {4-[3-(2-methylpyrrolidin- 1 -yl)propoxy]phenyl} -1,3-thiazole; 4-benzyl- 1- [(2- {4-[3-(2-methylpyrrolidin- 1 -yl)propoxy]phenyl} -1,3-oxazol-4 yl)methyl]piperidine; 10 1-cyclopentyl-4-[(2-{4-[3-(2-methylpyrrolidin-1-yl)propoxy]phenyl}-1,3- oxazol 4-yl)methyllpiperazine; 4-[(2-{4-[3-(2-methylpyrrolidin-1-yl)propoxy]phenyl}-1,3-oxazol-4-yl) carbonyl]morpholine; 1-[(2-{4-[3-(2-methylpyrrolidin-1-yl)propoxy]phenyl}-1,3-oxazol-4-yl) 15 carbonyl]piperidine; 1-cyclopentyl-4-[(2-{4-[3-(2-methylpyrrolidin-1-yl)propoxy]phenyl}-1,3-oxazol 4-yl)carbonyl]piperazine; 4-[(2-methylpyrrolidin-1-yl)methyl]-2-(4-{3-[(2S)-2-(pyrrolidin-1-ylmethyl) pyrrolidinl-yl]propoxy}phenyl)-1,3-oxazole; 20 1-[(2-{3-fluoro-4-[3-(2-methylpyrrolidin-1-yl)propoxy]phenyl}-1,3-oxazol- 4 yl)methyl]piperidine; 1-[(4-methyl-2-{4-[3-(2-methylpyrrolidin-1-yl)propoxy]phenyll-1,3-oxazol- 5 yl)carbonyl]piperidine; N-(cyclopropylmethyl)-4-methyl-2-{4-[3-(2-methylpyrrolidin-1-yl)propoxy] -[3 25 N-propyl- 1,3-oxazole-5-carboxamide; N-cyclopentyl-4-methyl-2-{4-[3-(2-methylpyrrolidin-1-yl)propoxy]phenyl}- 1,3 oxazole-5-carboxamide; 4-[(benzylamino)methyl]-2-{4-[3-(2-methylpyrrolidin-1-yl)propoxy]phenyl}- 1,3 oxazole-5-carboxylate; 30 4-methyl-2-(4-[3-(2-methylpyrrolidin-1-yl)propoxy]phenyl}-1,3-thiazole-5 carboxylate; 2-{4-[3-(2-methylpyrrolidin-1-yl)propoxy]-[3-4-(piperidin-1-ylmethyl)-1,3 oxazole-5-carboxylic acid; - 82 - WO 2008/137087 PCT/US2008/005702 N-(cyclopropylmethyl)-2- {4-[3-(2-methylpyrrolidin-1-yl)propoxyj-phenyl } -N propyl- 1 ,3-oxazole-4-carboxamide; N-cyclopentyl-2- {4-[3 -(2-methylpyrrolidin- 1 -yl)propoxy]phenyl - -1,3 -oxazole-4 carboxamide; 5 N-(4-fluorobenzyl)-2- {4- [3-(2-methylpyrrolidin- 1 -yl)propoxy]phenyl - -1,3 oxazole-4-carboxamide; N-benzyl-4-methyl-2- {4-[3 -(2-methylpyrrolidin- 1-yl)propoxy]phenyl)}- 1,3 oxazole-5-carboxamide; 1 -cyclopentyl-4-[4-methyl-2- {4- [3-(2-methylpyrrolidin-l1-yl)propoxy]phenyl)- 1,3 10 oxazol-5-yl)carbonyl]piperazine; 2- {4-[3-(2-methylpyrrolidin- 1-yl)propoxy] -[3-4-(pyrrolidin- 1-ylcarbonyl)- 1,3 oxazolIe; 4- {(4-methyl-2- (4- [3-(2-methylpyrrolidin- 1-yl)propoxy]phenyl }-1 ,3-oxazol- 5 yl)carbonyl }morpholine; 15 4- {[4-methyl-2-(4-1{3- [(2R)-2-methylpyrrolidin- 1-yl]propoxy}phenyl)- 1,3 - oxazol 5-yl]carbonyl }morpholine; 4- {[4-methyl-2-(4- {3-[(2S)-2-methylpyrrolidin- 1-yl]propoxy}phenyl)- 1,3 - oxazol 5-yl]carbonyl }morpholine; 1 -cyclopentyl-4-[(4-methyl-2- (4- [3-(2-methylpyrrolidin- 1-yl)propoxy]phenyl) 20 1 ,3-oxazol-5-yl)methyljpiperazine; N-(cyclopropylmethyl)-N-[(4-methyl-2- {4-[3-(2-methylpyrrolidin- 1 yl)propoxy]phenyl }-1,3 -oxazol-5-yl)methyl] -N-propylamine; N-benzyl-N-[(4-methyl-2- {4- [3-(2-methylpyrrolidin- 1-yl)propoxyiphenyll- 1,3 oxazolS -yl)methyl] amine; 25 1- [(2- {3 -methoxy-4-[3 -(2-methylpyrrolidin- 1-yl)propoxy]phenyl- 1,3-oxazol- 4 yl)methyl]piperidine; N-(4-chlorobenzyl)-N-[(2- (4- [3-(2-methylpyrrolidin- 1-yl)propoxy]phenyl }-1,3 oxazol-4-yl)methyllamine; N- {(4-methyl-2- {4-[3-(2-methylpyrrolidin- 1-yl)propoxy]phenyl }-1 ,3-oxazol-5 30 yl)methyl] cyclopentanamine; 1- [(5-bromo-2- 14- [3-(2-methylpyrrolidin- 1-yl)propoxy]phenyl }-1,3 -oxazol- 4 yl)methyl]piperidine; 1- {[2-(4-1{3- [(2R)-2-methylpyrrolidin- 1-yl]propoxy} phenyl)- 1,3-oxazol-4-yl methyllpiperidine; - 83 - WO 2008/137087 PCT/US2008/005702 1-{[2-(4-{3-[(2S)-2-methylpyrrolidin-1-yl]propoxy}phenyl)-1 ,3-oxazol-4 yl)methyl]piperidine; 4-[(2-{4-[3-(2-methylpyrrolidin-1-yl)propoxy]phenyl}-1,3-oxazol-4 yl)methyl]morpholine; 5 1-[2-(2-{4-[2-(2-methylpyrrolidin-1-yl)ethoxy]phenyl}-1,3-oxazol-4-yl)ethyl] piperidine; 1-[(2-{4-[3-(2-methylpyrrolidin-1-yl)propoxy]phenyl}-1,3-oxazol-4-yl)methyl] piperidin-2-one; (5S)-l-[(2-{4-[3-(2-methylpyrrolidlin-1-yl)propoxy]phenyl}-1,3-oxazol-4-yl) 10 methyl]-5-(pyrrolidin-1-ylmethyl)pyrrolidin-2-one; 1-[(2-{3-chloro-4-[3-(2-methylpyrrolidin-1-yl)propoxy]phenyl}-1,3-oxazol-4 yl)methyl]piperidine; 2-{3-bromo-4-[3-(2-methylpyrrolidin-1-yl)propoxy]phenyll-4-methyl-1,3 thiazole-5-carboxylate; 15 N-(4-fluorophenyl)-2-(2-{4-[3-(2-methylpyrrolidin-1-yl)propoxy]phenyl}-1, 3 oxazol-4-yl)acetamide; (4aR,8aS)-2-[(2-{4-[3-(2-methylpyrrolidin-1-yl)propoxy]phenyl} 1,3-oxazol-4-yl)methyl]decahydroisoquinoline; 2-{4-[3-(2-methylpyrrolidin-1-yl)propoxy]phenyl}-4-{ [(2S)-2-(pyrrolidin-1 ylmethyl)pyrrolidin-1-yl]carbonyl}-1,3-oxazole; 20 4-[(2-{4-[3-(2-methylpyrrolidin-1-yl)propoxy]phenyl}-1 ,3-oxazol-4 yl)acety]morpholine; N-cyclopentyl-2-(2-{4-[3-(2-methylpyrrolidin-1-yl)propoxy]phenyl}-1,3-oxazol-4 yl)acetamide; N-(cyclopropylmethyl)-2-(2-(4-[3-(2-methylpyrrolidin-1-yl)propoxy]phenyl}-1,3 25 oxazol-4-yl)-N-propylacetamide; 1-[(2-{4-[3-(2-methylpyrrolidin-1-yl)propoxy]phenyl}-1,3-oxazol-4-yl) acetyl]azepane; (5S)-1-[(2-{ 4-[3-(2-methylpyrrolidin-1-yl)propoxy]phenyl)-1,3-oxazol-4-yl) methyl]-5-(morpholin-4-ylmethyl)pyrrolidin-2-one; 30 2-methyl-N-[(2-{4-[3-(2-methylpyrrolidin-1-yl)propoxy]phenyl}-1,3-oxazol-4 yl)methyl]-2H-tetraazol-5-amine; N-(3-methoxyphenyl)-N-[(2-{4-[3-(2-methylpyrrolidin-1-yl)propoxy]phenyl}- 1,3 oxazol-4-yl)methyl]amine; - 84 - WO 2008/137087 PCT/US2008/005702 N-(4-fluorophenyl)-N-[(2- {4-[3-(2-methylpyrrolidin- 1 -yl)propoxy]phenyl} -1,3 oxazol4-yl)methyl]amine; N-[(2- (4-[3-(2-methylpyrrolidin- 1 -yl)propoxy]phenyl} -1,3-oxazol-4 yl)methylpyridin-3-amine; 5 4-[(4-methyl-2- (4-[3-(2-methylpyrrolidin- 1 -yl)propoxy]phenyl }-1,3-oxazol-5 yl)methyl]morpholine; 4-({(2S)-1-[(2-{4-[3-(2-methylpyrrolidin-1-yl)propoxy]phenyl}-1 ,3-oxazol-4 yl)methyl]pyrrolidin-2-yl}methyl)morpholine; 1-[(2-{2-fluoro-4-{3-(2-methylpyrrolidin-1-yl)propoxy]phenyl}-1,3-oxazol-4 10 yl)methyl]piperidine; 4,4-difluoro-1-[(2-{4-[3-(2-methylpyrrolidin-1-yl)propoxyjphenyl}-1,3-oxazol-4 yl)methyl]piperidine; 4-[(4-methyl-2-{6-[3-(2-methylpyrrolidin-1-yl)propoxy]pyridin-3-yl}-1,3- thiazol 5-yl)carbonyl}morpholine; 15 1-(2-{3 ,5-difluoro-4-[3-(2-methylpyrrolidin-1-yl)propoxyjphenyll-1,3-oxazol-4 yl)methyl]piperidine; 4,4-difluoro-1-{(4-methyl-2-{4-[3-(2-methylpyrrolidin-1-yl)propoxy]phenyl}- 1,3 thiazol-5-yl)earbonyl]piperidine; 4,4-difluoro-1-{ {4-methyl-2-(4-{3-[(2R)-2-methylpyrrolidin-1-yl]propoxy} 20 phenyl)-1,3-thiazol-5-ylicarbonyl]piperidine; 4,4-difluoro-1-{[4-methyl-2-(4-{3-[(2S)-2-methylpyrrolidin-1-yl]propoxy] phenyl)- 1,3-thiazol-5-yl} carbonyl)piperidine; 4-[(4-methyl-2- {4- [3-(2-methylpyrrolidin- 1 -yl)propoxy]phenyl }-1,3-thiazol-5 yl)carbonyl]morpholine; 25 4-{[4-methyl-2-(4-{3-[(2R)-2-methylpyrrolidin-1-yl]propoxy}phenyl)-1,3- thiazol 5 yl]carbonyl}morpholine; 4-{[methyl-2-(4-{3-[(2S)-2-methylpyrrolidin-1-yl]propoxy}phenyl)-1,3- thiazol-5 yl]carbonyl}morpholine; 1-[(2-{2-methyl-4-[3-(2-methylpyrrolidin-1-yl)propoxy]phenyl}-1,3-oxazol-4 30 yl)methyl]piperidine; and 1-[(4-methyl-2-{4-[3-(2-methylpyrrolidin-1-yl)propoxy]phenyl}-1,3-thiazol-5 yl)methyl]pyrrolidin-2-one. - 85 - WO 2008/137087 PCT/US2008/005702 Compounds of formulas XVIII and XIX, as described in WO 2008/005338, can also be more readily prepared using the methods of the present invention: 00 R 12
R
11 RIO 00 2 \\ / * N R R 11 RIO R1....N/SR ""/ J-N N J-N R OR I RR4 /RR5 NRNO3 5R8RG
R
6
R
7 R R R 6
R
7 *=a orp XVIII XIX 5 and the pharmaceutically acceptable salts thereof; wherein R' and R 2 are each selected independently from the group consisting of H, C 1 -6 acyl, C 1
.
8 alkyl, C 2
-
8 alkenyl, C 2
-
8 alkynyl, C 3
.
7 cycloalkyl, aryl, heterocyclyl, heteroaryl, aryl-C1.4-alkylenyl, aryloxy-C .4-alkylenyl, heteroaryl-Ci-4-alkylenyl and heteroaryloxy 10 CI.4-alkylenyl, and each R' and R 2 is optionally substituted with 1,2,3,4 or 5 substituents selected independently from the group consisting of C 1
-
6 acyl, C 1
.
6 acyloxy, C 2
-
8 alkenyl,
C
1
.
6 alkoxy, C1-8 alkyl, C 1
.
8 alkylcarboxanide, C 2
-
8 alkynyl, C 1
.
8 alkylsulfonamide, C 1 . salkylsulfinyl, Ci.s 8 alkylsulfonyl, Ci.
8 alkylthio, C1..
8 alkylureyl, amino, aryl, Ci. 8 alkylamino, C 2
-
8 dialkylamino, carbo-C 1
.
6 -alkoxy, carboxamide, carboxy, cyano, C 3 . 15 7 cycloalkyl, C 2
-
8 dialkylcarboxamide, C 2
-
8 dialkylsulfonamide, halogen, C 1
.
6 haloalkoxy, C 1-6 haloalkyl, C i- 6 haloalkylsulfinyl, C 1
.
6 haloalkylsulfonyl, C ..
6 haloalkylthio, heterocyclyl, hydroxyl, thiol, nitro and sulfonamide; wherein each C 1
-
8 alkyl may be further substituted with hydroxyl; substituted with hydroxy; 20 J is -CH 2
CH
2 - or a 1 ,2-C 3
.
7 -cycloalkylenyl group, each optionally substituted with 1, 2, 3 or 4 substituents selected independently from the group consisting of C 1
.
3 alkyl, C. 4 alkoxy, carboxy, cyano, C 1
-
3 haloalkyl, halogen, hydroxyl and oxo; R , R4, R', R6, R7, R", R , and R 2 are each selected independently from the group consisting of H, C 1
-
6 acyl, C 1
-
6 acyloxy, C 2
-
8 alkenyl, C 1
-
6 alkoxy, C 1
.
8 alkyl, C 1
-
8 25 alkylcarboxamide, C 2
-
8 alkynyl, C 1
.
8 alkylsulfonamide, C 1
.
8 alkylsulfinyl, Ci.
8 alkylsulfonyl,
C
1
-
8 alkylthio, C 1
-
8 alkylureyl, amino, C 1
.
8 alkylamino, C 2 -8dialkylamino, carbo-CI- 6 alkoxy, carboxamide, carboxy, cyano, C 3
.
7 cycloalkyl, C2-8 dialkylcarboxamide,C 2
-
8 dialkylsulfonamide, halogen, C 1
-
6 haloalkoxy, C 1
.
6 haloalkyl, C 1
.
6 haloalkylsulfinyl, C 1
.
6 haloalkylsulfonyl, C 1
.
6 haloalkylthio, hydroxyl, thiol, nitro and sulfonamide; 30 and - 86 - WO 2008/137087 PCT/US2008/005702
R
8 and R 9 are each selected independently from the group consisting of H, CI.
8 alkyl, C 2
-
8 alkenyl, C 2
-
8 alkynyl, C 3
.
7 cycloalkyl, aryl, heterocyclyl, heteroaryl, aryl-Cia alkylenyl, aryloxy-Clgalkylenyl, heteroaryl-CiA-alkylenyl and heteroaryloxy-CI alkylenyl, and each R 8 and R 9 is optionally substituted with 1, 2, 3,4, or 5 substituents 5 selected independently from the group consisting of C 1
-
6 acyl, C 1
.
6 acyloxy, C 2
-
8 alkenyl, Ci.
6 alkoxy, C 8 alkyl, Ci.
8 alkylcarboxamide, C 2
-
8 alkynyl, C 1
.
8 alkylsulfonamide, C 1 . 8 alkylsulfinyl, C 1 8 alkylsulfonyl, C 1
.
8 alkylthio, C 1
.
8 alkylureyl, amino, C 8 alkylamino,
C
2
-
8 dialkyIamino, carbo-C1.
6 -alkoxy, carboxamide, carboxy, cyano, C 3
.
7 cycloalkyl, C 2 8 dialkylcarboxamide, C 2
-
8 dialkylsulfonamide, halogen, CI.
6 haloalkoxy, C 1
.
6 haloalkyl, C. 10 6 haloalkylsulfinyl, C 1
.
6 haloalkylsulfonyl, CI- 6 haloalkylthio, hydroxyl, thiol, nitro and sulfonamide; The methods of the present invention of preparing (R) and (S) 2-methylpyrrolidine can be used to more readily prepare the above mentioned compounds. (R)- or (S)-2 methylpyrrolidine can be prepared in accordance with the present invention and reacting 15 the (R)-2-methylpyrrolidine L-tartrate with a base to provide (R)-2-methylpyrrolidine or (S)-2-methylpyrrolidine D-tartrate with a base to provide (S)-2-methylpyrrolidine. The following schemes demonstrate the use of the so prepared 2-methylpyrrolidine. SCHEME 23 00 R1 2
R
11
R
10 R9 R 11
R
10 - ~R 9 H LG' Y XN / X / J-LG 2 5:I R' Y 8 base
R
3 R4 R 5
R
6
R
7
R
6
R
7 Base HN * r ~j(R 15 0) 3 B r (R 1 5 0 )3 Pd(PPh 3
)
4 o O R 12 HO 0- Benzene /S R 9 NO\ /Y Ethanol, Na 2
CO
3 N R RR 6N . + ,\/ J microwave /\51 \R8'' R3HO R R 4
R
5 20 R 3
R
4
R
5
R
6
R
7
R
6
R
7 wherein LG', LG 2 , X, and Y are each independently a leaving group, for example, halogen, triflate and the like and R1 5 is CI.
8 alkyl. SCHEME 24 - 87 - WO 2008/137087 PCT/US2008/005702
R
12
R
11 Rio HN R" R1 0 LX / J-N *=aorS X - / J-LG 2 R3 R 4
R
5
R
6
R
7 R6 R7 /R Base HNR2
(R
15 0) 3 B base
R
11
R
10 Pd(PPh 3
)
4 o R1 2 R R 0 0 RHO - Benzene 1 s* R HOB / / J-N Ethanol, Na 2
CO
3 R N " HO microwave R 2 R3/ R2 R3 5
R
6 7
R
3
R
4 R R R 7 RR4 wherein LG', LG , X, and Y are each independently a leaving group, for example, halogen, triflate and the like and Ri 5 is C1.salkyl. SCHEME 25 Pd(PPh 3
)
4 0 R 12 R R Benzene ,S R R S s OH /R9 Ethanol, Na 2
CO
3 N N -HB + X J-N microwave R 5 5 R 3 R4R5 OH R 6
R
7
R
6
R
7 wherein X is a leaving group, for example halogen, triflate and the like. SCHEME 26 Ri R 1 0 Pd(PPh 3
)
4 0 0 R12 R R 10 R12 Benzene 1 R1 'S/ OH X JN Ethanol, Na2CO3 RN/ -B/O + J-N microwave R 2 / J R 4 R 3Rj 6
R
7 R R 4 5 6
R
7 R 3 R OH R R R R wherein X is a leaving group, for example halogen, triflate and the like. 10 SCHEME 27 R1 2 R
R
10 R12 R" RI R12 R 1 1 RIO R3 C2H ReduR3 OH Activate R3LG 3
R
4
R
5
R
6
R
7
R
4
R
5
R
6
R
7
R
4
R
5
R
6
R
7 =a or p N R' OH
R'
2 R' RIO NH 00 R' 2
R
1 1 RR 12 R" RIO RNR3 base R 3 R
R
4 5 R 6
R
7
R
4
R
5
R
6
R
7
R
4
R
5
R
6
R
7 wherein LG 3 is a leaving group such as sulfonate, triflate, halogen and the like and Z is halogen. SCHEME 28 - 88 - WO 2008/137087 PCT/US2008/005702 R12 R 1
R
1 0 R1 2 R" R1 0 R12 R 11
R
1 0 ilt Reduce -Activate R 3
CO
2 H R 3 OH R 3
LG
3
R
4
R
5
R
6
R
7
R
4
R
5
R
6
R
7
R
4
R
5
R
6
R
7 R9 NH
R
8 base // 2 R" R1 0 //,O R' R" R 10 OH2 N ZHN O=S=0 R R 0 N H NO Z I/i R/ 4 R 9
R
3 /~ N *=orf R 3 /<4- NI\
RR
4 R5 R 6
R
7
R
8
R
4 R5R 6
R
7 'RB R 3 Pl)N8
R
4 R
R
7 R wherein LG 3 is a leaving group such as sulfonate, triflate, halogen and the like and Z is halogen. 5 Thus, another embodiment of the present invention comprises methods of preparing compounds of formulas XVIII and XIX: 00 R 12
R
1 6 R 1 0 0 0 RR J 11 * NQ\& 1
R
11 RIO R 2 \ / J-N\ \ /
"R
3
R
4
R
5 6 3
R
4 8 R R R6 R7 *= orp XVIII XIX wherein the variables are as set forth above, comprising: 10 (la) hydrogenating 2-methylpyrroline in a mixture comprising an alcohol solvent and a hydrogenation catalyst; (lb) optionally removing the hydrogenation catalyst from the mixture; (1c) dissolving L-tartaric acid or D-tartaric acid in the mixture to form a solution; 15 (ld) crystallizing (R)-2-methylpyrrolidine L-tartrate or (S)-2-methylpyrrolidine D-tartrate from the solution; (le) isolating the crystalline (R)-2-methylpyrrolidine L-tartrate or (S)-2 methylpyrrolidine D-tartrate; and (2a) contacting the (R)-2-methylpyrrolidine L-tartrate with a base to form (R)-2 20 methylpyrrolidine free base or contacting the (S)-2-methylpyrrolidine D-tartrate with a base for form (S)-2-methylpyrrolidine; (3a) converting (R)- or (S)-2-methylpyrrolidine the compound of formula XVIII or XIX. - 89 - This method may optionally further include the steps of: (1 f) recrystallizing the isolated (R)-2-methylpyrrolidine L-tartrate or (S)-2 methylpyrrolidine D-tartrate; (1 g) isolating the recrystallized (R)-2-methylpyrrolidine L-tartrate or (S)-2 5 methylpyrrolidine D-tartrate; and (1h) optionally repeating steps (If) and (1g). Exemplary compounds that can be prepared according to the methods of the invention include: 4'-[2-(2-methyl-pyrrolidin-1-yl)-ethyl]-biphenyl-4-sulfonic acid 10 (tetrahydropyran-4-yl)-amide; 2- {4'-[2-(2-methyl-pyrrolidin-1 -yl)-ethyl]-biphenyl -4-sul fony 1}-2,3-dihydro 1H-isoindole; 4'-[2-(2-methyl-pyrrolidin-l-yl )-ethyl] -biphenyl -4-sulfonic acid (pyridin-2 ylmethyl)-amide; 15 4'-[2-(2-methyl-pyrrolidin--yl)-ethyl]-biphenyl-4-sulfonic acid 4 methyl-benzylamide; 4'-[2-(2-methyl-pyrrolidin-l-yl)-ethyl]-biphenyl-4-sulfonic acid (2-ethoxy-ethyl) amide; 4- (4'-[2-(2-methyl-pyrrolidin-1-yl )-ethyl] -bipheny 1 -4-sulfonyl}-thiomorpholine 20 1,1-dioxide; 4'-[2-(2-methyl-pyrrolidin-1-yl)-ethyl]-biphenyl-4-sulfonic acid (2 isopropoxy-ethyl)-amide; 4'-[2-(2-methyl-pyrrolidin-1-yl)-ethyl]biphenyl-4-sulfonic acid (2-phenoxy-ethyl) amide; 25 4'-[2-(2-(2-methyl-pyrrolidin-1-yl)-ethyl]-biphenyl-4-sulfonic acid 4 methoxy-benzylamide; 4'-[2-(2-methyl-pyrrolidin-1-yl)-ethyl]-biphenyl-4-sulfonic acid cyclohexylamide; 2-methyl-1-(2-[4'-(pyrrolidine-l-sulfonyl)-biphenyl-4-yl]-ethyl}-pyrrolidine; 2-{4'-[2-(2-methyl-pyrrolidin-1-yl)-ethyl]-biphenyl-4-sulfonyl)-1,2,3,4 30 tetrahydro-isoquinoline; 4'-[2-(2-methyl-pyrrolidin-l-yl)-ethyl]-biphenyl-4-sulfonic acid benzyl-ethyl amide; 4'-{2-(2-methyl-pyrrolidin-1-yl)-ethyl]-biphenyl-4-sulfonic acid 4-trifluoromethyl -90- WO 2008/137087 PCT/US2008/005702 benzylamide; 1- {2-[4'-(azetidine-l-sulfonyl)-biphenyl-4-yl]-ethyl } -2-methyl-pyrrolidine; 4'-[2-(2-methyl-pyrrolidin-1-y 1)-ethyl] -bipheny 1 -4-sulfonic acid cyclobutylamide; 5 4'-[2-(2-methyl-pyrrolidin-1-yl)-ethyl]-biphenyl-4-sulfonic acid tert butylamide; 4'-[2-(2-methyl-pyrrolidin-1 -yl)-ethyl]-biphenyl -4-sulfonic acid propylamide; 4'-[2-(2-methyl-pyrrolidin-1-yl)-ethyl]-biphenyl-4-sulfonic acid isopropylamide; 4'-[2-(2-methyl-pyrrolidin-1-y1)-ethyl]-biphenyl-4-sulfonic acid methylamide; 10 4'-[2-(2-methyl-pyrrolidin-1-yl)-ethyl]-biphenyl-4-sulfonic acid (2-methoxy ethyl)-amide; 4'-[2-(2-methyl-pyrrolidin-1-yl)-ethyl]-biphenyl-4-sulfonic acid (4 fluoro-phenyl)-amide; 4'-[2-(2-methyl-pyrrolidin-1-yl)-ethyl]-biphenyl-4-sulfonic acid 4 15 fluoro-benzylamide; 4'-[2-(2-methyl-pyrrolidin-1-yl)-ethyl]-biphenyl-4-sulfonic acid 4-chloro benzylamide; 4'- [2-(2-methyl-pyrrolidin-1 -yl)-ethyl]-biphenyl-4-sulfonic acid (2-hydroxy-ethyl) amide; 20 4'-[2-(2-methyl-pyrrolidin-1-yl)-ethyl]-biphenyl-4-sulfonic acid diethylamide; 4'-[2-(2-methyl-pyrrolidin-1-yl)-ethyl]-biphenyl-4-sulfonic acid (1-propyl-butyl) amide; 4'-[2-(2-methyl-pyrrolidin-1-yl)-ethyl]-biphenyl-4-sulfonic acid cyclohexylmethyl-amide; 25 4'-[2-(2-methyl-pyrrolidin-1-y1)-ethyl]-biphenyl-4-sulionic acid benzylamide; 4'-[2-(2-methyl-pyrrolidin-1-yl)-ethyl]-biphenyl-4-sulfonic acid phenylamide; 4'-[2-(2-methyl-pyrrolidin-1-yl)-ethyl]-biphenyl-4-sulfonic acid cyclopropylmethyl-amide; 4'-[2-(2-methyl-pyrrolidin-1-yl)-ethyl]-biphenyl-4-sulfonic acid 30 cyclopentylamide; 4-{4'-[2-(2-methyl-pyrrolidin-1-yl)-ethyl]-biphenyl-4-sulfony1}-morpholine; 1-{4'-[2-(2-methyl-pyrrolidin-1-yl)-ethyl]-biphenyl-4-sulfonyl}-piperidine; 4'-[2-(2-methyl-pyrrolidin-1-y1)-ethyl]-biphenyl-4-sulfonic acid amide; -91- WO 2008/137087 PCT/US2008/005702 4'-[2-(2-methyl-pyrrolidin-1-yl)-ethyl]-biphenyl-4-sulfonic acid cyclopropylamide; 4'-[2-(2-methyl-pyrrolidin-1-yl)-ethyl]-biphenyl-4-sulfonic acid ethylamide; 4'-[2-(2-methyl-pyrrolidin- 1 -yl)-ethyli-biphenyl-4-sulfonic acid (2-methoxy- 1 5 methyl-ethyl)-amide; 1- {4'-[2-(2-methyl-pyrrolidin- 1 -yl)-ethyl]-biphenyl-4-sulfonyl} -pyrrolidin-3-ol; (1- {4'-[2-(2-methyl-pyrrolidin- 1 -yl)-ethyl]-biphenyl-4-sulfonyl } -piperidin-3-yl) methanol; 1- {2-[4'-(aziridine- 1 -sulfonyl)-biphenyl-4-yl] -ethyl } -2-methyl-pyrrolidine; 10 2-(methoxymethyl)- 1 -(4'-(2-(2-methylpyrrolidin- 1-3,1 )ethyl)biphenyl-4 ylsulfonyl)pyrrolidine; 4'-[2-(2-methyl-pyrrolidin-1-yl)-ethyl]-biphenyl-4-sulfonic acid (2-methoxy ethyl)-methyl-amide; 1-(4'-[2-(2-methyl-pyrrolidin-1-yl)-ethyl]-biphenyl-4-sulfonyl}-piperidin-3-ol; 15 propionic acid 1- {4'- [2-(2-methyl-pyrrolidin- 1 -yl)-ethyl] -biphenyl-4-sulfonyl}-. piperidin-4-yl ester; 4'-(2-pyrrolidin-1-yl-ethyl)-biphenyl-4-sulfonic acid ethylamide; (1-{4'-[2-(2-methyl-pyrrolidin-1-yl)-ethyl]-biphenyl-4-sulfonyl}-pyrrolidin-2-yl) methanol; 20 4'-[2-(2-methyl-pyrrolidin-1-yl)-ethyl]-biphenyl-4-sulfonic acid benzyl-(2 hydroxy-ethyl)-amide; 4'-[2-(2-methyl-pyrrolidin-1-yl)-ethyl]-biphenyl-4-sulfonic acid 3,5-dichloro benzylamide; 4'-{2-(2-methyl-pyrrolidin-1 -yl)-ethyl]-biphenyl-4-sulfonic acid acetyl-(2 25 hydroxy-ethyl)-amide; 4'-[2-(2-methyl-pyrrolidin-1-yl)-ethyl]-biphenyl-4-sulfonic acid 3,4-dichloro benzylamide; 4'-[2-(2-methyl-pyrrolidin-1-yl)-ethyl]-biphenyl-4-sulfonic acid (2-hydroxy-1 methyl-ethyl)-amide; 30 propionic acid 2-(1-(4'-[2-(2-methyl-pyrrolidin-1-yl)-ethyl]-biphenyl-4 sulfonyl}-piperidin-4-yl)-ethyl ester; 1-{4'-[2-(2-methyl-pyrrolidin-1-yl)-ethyl]-biphenyl-4-sulfonyl}-piperidine-4 carboxylic acid benzyl ester; acetic acid 2-(acetyl-{4'-[2-(2-methyl-pyrrolidin-1-yl)-ethyl]-biphenyl-4 - 92 - WO 2008/137087 PCT/US2008/005702 sulfonyl}-amino)-ethyl ester; 4'-[2-(2-methyl-pyrrolidin-1-yl)-ethyl]-biphenyl-4-sulfonic acid [2-(4-fluoro phenyl)-ethyl]-amide; 4'-[2-(2-methyl-pyrrolidin-1-yl)-ethyl]-biphenyl-4-sulfonic acid (tetrahydro 5 pyran-4-ylmethyl)-amide; propionic acid 1-(4'-[2-(2-methyl-pyrrolidin-1-yl)-ethyl]-biphenyl-4-sulfonyl} piperidin-4-yl methyl ester; propionic acid 2-(methyl-{4'-[2-(2-methyl-pyrrolidin-1-yl)-ethyl]-biphenyl-4 sulfonyl}-amino)-ethyl ester; 10 4'-[2-(2-methyl-pyrrolidin-1-yl)-ethyl]-biphenyl-4-sulfonic acid (2-methoxyethyl) (tetrahydro-pyran-4-ylmethyl)-amide; 4'-[2-(2-methyl-pyrrolidin-1-yl)-ethyl]-biphenyl-4-sulfonic acid benzhydrylamide; 2-methyl-7-{4-[2-(2-methyl-pyrrolidin-1-yl)-ethyl)-phenyl}-3,4-dihydro-2H benzo[b][1,4,5]oxathiazepine 1,1-dioxide; 15 4'-[2-(2-methyl-pyrrolidin-1-yl)-ethyl]-biphenyl-4-sulfonic acid (2-hydroxy-1,1 dimethyl-ethyl)-amide; propionic acid 1-{4'-[2-(2-methyl-pyrrolidin-1-yl)-ethyl]-biphenyl-4-sulfonyl} pyrrolidin-2-ylmethyl ester; 4'-[2-(2-methyl-pyrrolidin-1-yl)-ethyl]-biphenyl-4-sulfonic acid isobutyl-(2 20 methoxy-ethyl)-amide; 7-{4'-[2-(2-methyl-pyrrolidin- 1 -yl)-ethyl]phenyl)-3,4-dihydro-2H benzo[b][1,4,5]oxathiazepine 1,1-dioxide; 4'-[2-(2-methyl-pyrrolidin-1-yl)-ethyl]-biphenyl]-sulfonic acid (2-hydroxy ethyl)-methyl-amide; 25 4'-[2-(2-methyl-pyrrolidin-1-yl)-ethyl]-biphenyl-4-sulfonic acid bis-(2-hydroxy ethyl)-amide; 4'-[2-(2-methyl-pyrrolidin-1-yl)-ethyl] -biphenyl-4-sulfonic acid isopropyl-(2 methoxy-ethyl)-amide; 4'-[2-(2-methyl-pyrrolidin-1-yl)-ethyl]-biphenyl-4-sulfonic acid (2-hydroxyethyl) 30 isopropyl-amide; 4'-[2-(2-methyl-pyrrolidin-1-yl)-ethyl]-biphenyl-4-sulfonic acid (3 -phenylpropyl) amide; 4'-[2-(2-methyl-pyrrolidin-1-yl)-ethyl]-biphenyl-4-sulfonic acid [2-(2-oxo imidazolidin- 1 -yl)-ethyl] -amide; - 93- WO 2008/137087 PCT/US2008/005702 4'-[2-(2-methyl-pyrrolidin-1-yl)-ethyl]-biphenyl-4-sulfonic acid [3-(2-oxo pyrrolidin-1-yl)-propyl]-amide; 4'-[2-(2-methyl-pyrrolidin-1-yl)-ethyl]-biphenyl-4-sulfonic acid benzyl-(2 methoxy-ethyl)-amide; 5 3-methoxymethyl-1-{4'-[2-(2-methyl-pyrrolidin-1-yl)-ethyl]-biphenyl-4 sulfonyl} -piperidine; 4'- [2-(2-methyl-pyrrolidin- 1 -yl)-ethyl] -biphenyl-4-sulfonic acid phenethylamide; (1-{4'-[2-(2-methyl-pyrrolidin-1-yl)-ethyl]-biphenyl-4-sulfonyl}-piperidin-4- yl) methanol; 10 1-{4'-[2-(2-methyl-pyrrolidin-1-yl)-ethyl]-biphenyl-4-sulfonyl}-piperidine-4 carboxylic acid ethyl ester; 4-(2-ethoxy-ethyl)-1-{4'-[2-(2-methyl-pyrrolidin-1-yl)-ethyl]-biphenyl-4 sulfonyl} -piperidine; 1-(4-{4'- [2-(2-methyl-pyrrolidin- 1 -yl)-ethyll-biphenyl-4-sulfonyl} -piperazin- 1 15 yl)-propan- 1-one; 4'-[2-(2-methyl-pyrrolidin-1-yl)-ethyl)-biphenyl-4-sulfonic acid (pyridin-4 ylmethyl)-amide; 3- {4'-[2-(2-methyl-pyrrolidin- 1 -yl)-ethyl] -biphenyl-4-sulfonylaminol-propionic acid methyl ester; 20 4-ethoxymethyl- 1- {4'- [2-(2-methyl-pyrrolidin- 1 -yl)-ethyl] -biphenyl-4 sulfonyl} -piperidine; (1- {4'-[2-(2-methyl-pyrrolidin- 1 -yl)-ethyli-biphenyl-4-sulfonyl)-piperidin-3 yl)-methanol; 3-methoxy- 1- {4'-[2-(2-methyl-pyrrolidin- 1 -yl)-ethyl] -biphenyl-4-sulfonyl} 25 piperidine; 4'-[2-(2-methyl-pyrrolidin-1-yl)-ethyl]-biphenyl-4-sulfonic acid (pyridin-3 ylmethyl)-amide; 2-(1-{4'-[2-(2-methyl-pyrrolidin-1-yl)-ethyl]-biphenyl-4-sulfonyl}-piperidin-4 yl)-ethanol; 30 2- {4'-[2-(2-methyl-pyrrolidin-1-yl)-ethyl]-biphenyl-4-sulfonylamino}-propionic acid methyl ester; 4'-[2-(2-methyl-pyrrolidin-1-yl)-ethyl]-biphenyl-4-sulfonic acid (1 hydroxymethyl-cyclopentyl)-amide; (1-(4'-[2-(2-methyl-pyrrolidin-1-yl)-ethyl]-biphenyl-4-sulfonyl}-piperidin-2- yl) - 94 - WO 2008/137087 PCT/US2008/005702 methanol; 4'-[2-(2-methyl-pyrrolidin-1-yl)-ethyl]-biphenyl-4-sulfonic acid 4 trifluoromethoxy-benzylamide; 4'-[2-(2-methyl-pyrrolidin-1-yl)-ethyl]-biphenyl-4-sulfonic acid bis-(2 5 methoxy-ethyl)-amide; {4'-[2-(2-methyl-pyrrolidin-1-yl)-ethyl]-biphenyl-4-sulfonylamino)-acetic acid methyl ester; 2-{4'-[2-(2-methyl-pyrrolidin-1-yl)-ethyl]-biphenyl-4-sulfonylamino}-propionic acid isopropyl ester; 10 1-{4'-{2-(2-methyl-pyrrolidin-1-yl)-ethyl]-biphenyl-4-sulfonyl}-pyrrolidine-2 carboxylic acid; 6,7-dimethoxy-2-{4'-[2-(2-methyl-pyrrolidin-1 -yl)-ethyl]-biphenyl-4-sulfonyl} 1,2,3,4-tetrahydro-isoquinoline; 4-methoxy-1-{"2-(2-methyl-pyrrolidin-1-yl)-ethyli-biphenyl-4-sulfonyl} 15 piperidine; 4-{4'-[2-(2-methyl-pyrrolidin-1-yl)-ethyl]-biphenyl-4-sulfonyl)-piperazin-2- one; {4'-[2-(2-methyl-pyrrolidin- 1 -yl)-ethyli-biphenyl-4-sulfonylamino} -acetic acid isopropyl ester; 1-{4'-[2-(2-methyl-pyrrolidin-1-yl)-ethyl]-biphenyl-4-sulfonyll -pyrrolidine-2 20 carboxylic acid methylamide; 3,5-dimethyl-4-{4'-[2-(2-methyl-pyrrolidin-1-yl)-ethyl]-biphenyl-4-sulfonyl) morpholine; propionic acid 1-{4'-[2-(2-methyl-pyrrolidin-1-yl)-ethyl]-biphenyl-4-sulfonyl pyrrolidin-3-yl ester; 25 1-{4'-[2-(2-methyl-pyrrolidin-1-yl)-ethyl)-biphenyl-4-sulfonyl}-piperidin-4-ol;. propionic acid 2-methyl-2-{4'-[2-(2-methyl-pyrrolidin-1-yl)-ethyl]-biphenyl-4 sulfonylamino}-propyl ester; 2-{4'-[2-(2-methyl-pyrrolidin-1-yl)-ethyl]-biphenyl-4-sulfonylamino)-propionic acid tert-butyl ester; 30 1-{4'-[2-(2-methyl-pyrrolidin-1-yl)-ethyl]-biphenyl-4-sulfonyl}-piperidine-4 carboxylic acid; {4'-[2-(2-methyl-pyrrolidin- 1 -yl)-ethyl]-biphenyl-4-sulfonylamino} -acetic acid tert-butyl ester; 4-hydroxy-1-{4'-[2-(2-methyl-pyrrolidin-1-yl)-ethyl]-biphenyl-4-sulfonyl} - 95 - WO 2008/137087 PCT/US2008/005702 pyrrolidine-2-carboxylic acid methyl ester; 4-(2-methoxy-ethyl)-1-{4'-[2-(2-methyl-pyrrolidin-1-yl)-ethyl]-biphenyl-4 sulfonyl}-piperidine; and 4-methoxymethyl-1-{4'-[2-(2-methyl-pyrrolidin-1-yl)-ethyl]-biphenyl-4 5 sulfonyl} -piperidine. EXAMPLES Methodology and Protocols 10 Determination of chiral purity of (R)-2-methylpyrrolidine by Gas Chromatography (GC) Column Chiraldex B-DA, 30m x 0.25mm, 0.25pm df (mfr: Astec - Advanced Separation Technologies, Inc.) or equivalent Injector temperature 150 0 C 15 Split ratio 40:1 Carrier Gas He, constant pressure at 8 psi Injection volume 2 ptL Detection FID at 250 0 C Flow Hydrogen at 30 mL/min 20 Air at 400 mL/min Makeup gas Helium at 30 mL/min Oven program 110 C isothermal for 25 minutes Sample preparation Add trifluoroacetic anhydride (200 pL) to sample (10 mg) in dichloromethane (1 mL). 25 React at 60*C for 15 minutes. Remove solvent under gentle nitrogen stream and add dichloromethane (1 mL) to residue. System suitability resolution between enantiomers should be > 1.2 30 Retention times (R)-2-methylpyrrolidine = 11 minutes (S)-2-methylpyrrolidine = 11.5 minutes Example 1 Synthesis of (R)-2-methylpyrrolidine L-tartrate using 5% Pt-C - 96 - WO 2008/137087 PCT/US2008/005702 2-Methylpyrroline (2.50 g, 30.12 mmol) was hydrogenated at 55 psi at ambient temperature for 16 hours in a mixture of 5% Pt-C (250 mg, catalytic), absolute ethanol (62 mL) and methanol (26 mL). Gas chromatographic analysis showed a 93.7% conversion of starting material to product. The mixture was filtered through Celite@ (4 g) and the 5 filtrate placed in a 250 mL, single-neck round bottom flask with stir bar along with L tartaric acid (3.80 g, 25.32 mmol). The mixture was heated to 25*C until a solution was obtained. Authentic (R)-2-methylpyrrolidine L-tartrate (10.0 mg) was added as seed crystals and the mixture stirred at ambient temperature for 16 hours. The mixture was cooled to 0"C using an ice bath and was stirred for an additional 2 hours. Solids were 10 filtered and then air-dried for 1 hour to provide (R)-2-methylpyrrolidine L-tartrate (3.55 g, 15.09 mmol, 50.1%). Chiral gas chromatographic analysis showed 55% ee, 93% overall purity. Example 2 Synthesis of (R)-2-methylpyrrolidine L-tartrate using Pt(IV) oxide 15 2-Methylpyrroline (2.50 g, 30.12 mmol) was hydrogenated at 55 psi at ambient temperature for 5 hours in a mixture of platinum (IV) oxide (250 mg, catalytic), absolute ethanol (62 mL) and methanol (26 mL). Gas chromatographic analysis showed a 98.3% conversion of starting material to product. The mixture was filtered through Celite@ (4 g) and the filtrate placed in a 250 mL, single-neck round bottom flask with stir bar along with 20 L-tartaric acid (3.80 g, 25.32 mmol). The mixture was heated to 25'C until a solution was obtained. Authentic (R)-2-methylpyrrolidine L-tartrate (100.0 mg) was added as seed crystals and the mixture stirred at 25'C for 8 hours. The mixture was allowed to cool to ambient temperature and was stirred an additional 16 hours. The mixture was cooled to 0*C using an ice bath and was stirred for an additional 2 hours. Solids were filtered, 25 washed with methanol (5 mL), and then air-dried for 1 hour to provide (R)-2 methylpyrrolidine L-tartrate (2.85 g, 12.12 mmol, 40.3%). Chiral gas chromatographic analysis showed 49.2% ee, 75% overall purity. Example 3 Recrystallization of (R)-2-methylpyrrolidine L-tartrate 30 General Recrystallization Procedure: A portion of the product obtained in Example 1 (2.71 g) was placed in a 100 mL, single-neck round bottom flask with stir bar along with absolute ethanol (38 mL) and methanol (16 mL). The mixture was heated to 60*C to form a solution and then allowed to cool to ambient temperature. Authentic (R) 2-methylpyrrolidine L-tartrate (2.50 mg) was added as seed crystals and the mixture was - 97 stirred at ambient temperature for 16 hours, and then at 0"C (ice bath) for 2 more hours. Solids were filtered and dried at 60'C in a vacuum oven with a stream of nitrogen at 29 in. Hg for 1 hour to provide (R)-2-methylpyrrolidine L-tartrate (1.80 g, 66.4% recovery). Chiral gas chromatographic analysis showed 84.9% ee, 93% overall purity. 5 The obtained solids (1.79 g) were further resolved according to the General Recrystallization Procedure using 25 mL absolute ethanol and 11 mL methanol to provide (R)-2-methylpyrrolidine L-tartrate (1.70 g, 95.5% recovery). Chiral gas chromatographic analysis showed 93.4% ee, 97% overall purity. The obtained solids (1.69 g) were further resolved according to the General 10 Recrystallization Procedure using 24 mL of absolute ethanol and 10 mL of methanol to provide (R)-2-methylpyrrolidine L-tartrate (1.58 g, 93.5% recovery). Chiral gas chromatographic analysis showed 96.7% ee, 98% overall purity. The obtained solids (1.57 g) were further resolved according to the General Recrystallization Procedure using 22.5 mL of absolute ethanol and 9.5 mL of methanol, 15 except that no seeding was performed and the obtained crystals were dried for 4 hours, to provide (R)-2-methylpyrrolidine L-tartrate (1.49 g, 94.9% recovery, 6.334 mmol, 21.0% overall yield from 2-methylpyrroline). Chiral gas chromatographic analysis showed 98.4% ee, 99% overall purity. As those skilled in the art will appreciate, numerous modifications and variations 20 of the present invention are possible in light of the above teachings. It is therefore understood that within the scope of the appended claims, the invention may be practiced otherwise than as specifically described herein, and the scope of the invention is intended to encompass all such variations. Comprises/comprising and grammatical variations thereof when used in this 25 specification are to be taken to specify the presence of stated features, integers, steps or components or groups thereof, but do not preclude the presence or addition of one or more other features, integers, steps, components or groups thereof - 98 -
Claims (10)
1. A process for preparing 6-{4-[3-((R)-2-methyl-pyrrolidin-1-yl)-propoxy]-phenyl} 2H-pyridazin-3-one: H 0 N, 5 NN 5 or a pharmaceutically acceptable salt thereof, comprising the steps of: (1 a) hydrogenating 2-methylpyrroline in a mixture comprising an alcohol solvent and a hydrogenation catalyst; (lb) optionally removing the hydrogenation catalyst from the mixture; 10 (1 c) dissolving L-tartaric acid in the mixture to form a solution; (1 d) crystallizing (R)-2-methylpyrrolidine L-tartrate from the solution; (le) isolating the crystalline (R)-2-methylpyrrolidine L-tartrate; and (2) reacting the (R)-2-methylpyrrolidine L-tartrate with a base to form (R)-2 methylpyrrolidine free base; and 15 (3) reacting the (R)-2-methylpyrrolidine with 6-[4-(3-halo-propoxy)-phenyl] 2H-pyridazin-3-one for a time and under conditions sufficient to form 6-(4-[3 ((R)-2-methyl-pyrrolidin- 1 -yl)-propoxy]-phenyl) -2H-pyridazin-3-one.
2. The process according to claim 1, further comprising the step of converting the product of step 3 into a salt. 20
3. The process according to claim 1 or claim 2, wherein the 6-[4-(3-halo-propoxy) phenyl]-2H-pyridazin-3-one is prepared by the steps of: (a) contacting 1-(4-hydroxy-phenyl)-ethanone with 1,3-dihalopropane, for a time and under conditions sufficient to form 1-[4-(3-halo-propoxy)-phenyl] ethanone; and 25 (b) contacting the 1-[4-(3-halo-propoxy)-phenyl]-ethanone with glyoxalic acid for a time and under conditions sufficient to produce 6-[4-(3-halo-propoxy) phenyl]-2H-pyridazin-3 -one.
4. The process according to claim 1 or claim 2, further comprising the steps of: (1f) recrystallizing the isolated (R)-2-methylpyrrolidine L-tartrate; (1g) isolating the recrystallized (R)-2-methylpyrrolidine L-tartrate; and (1h) optionally repeating steps (1f) and (1g).
5. The process according to claim 4 wherein the isolated (R)-2-methylpyrrolidine 5 L-tartrate has an optical purity of at least 50% ee.
6. The process according to claim 1 wherein the hydrogenation catalyst is a platinum catalyst.
7. The process according to claim 6 wherein the platinum catalyst is 5% Pt-C.
8. The process according to claim 6 wherein the platinum catalyst is platinum 0 (IV) oxide.
9. The process according to claim 2 wherein the product of step 3 is converted to an HCI salt.
10. 6-{4-[3-((R)-2-methyl-pyrrolidin-1 -yl)-propoxy]-phenyl}-2H-pyridazin-3-one H o N, N No 5 or a pharmaceutically acceptable salt thereof, prepared by the process according to any one of claims 1 to 9. CEPHALON, INC 20 WATERMARK PATENT AND TRADE MARKS ATTORNEYS 25 P32501AU00 - 100-
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US8383657B2 (en) | 2007-12-21 | 2013-02-26 | Abbott Laboratories | Thiazolylidine urea and amide derivatives and methods of use thereof |
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