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
- C07D403/02—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
- 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
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Pyrrole Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Cosmetics (AREA)
- Catalysts (AREA)
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US92735607P | 2007-05-03 | 2007-05-03 | |
| US60/927,356 | 2007-05-03 | ||
| PCT/US2008/005702 WO2008137087A1 (en) | 2007-05-03 | 2008-05-02 | Processes for preparing (r)-2-methylpyrrolidine and (s)-2-methylpyrrolidine and tartrate salts thereof |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| AU2008248168A1 AU2008248168A1 (en) | 2008-11-13 |
| AU2008248168B2 true AU2008248168B2 (en) | 2013-03-21 |
Family
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Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| AU2008248168A Ceased AU2008248168B2 (en) | 2007-05-03 | 2008-05-02 | Processes for preparing (R)-2-methylpyrrolidine and (S)-2-methylpyrrolidine and tartrate salts thereof |
Country Status (14)
| Country | Link |
|---|---|
| EP (1) | EP2152669A1 (https=) |
| JP (1) | JP5698887B2 (https=) |
| KR (1) | KR20100017565A (https=) |
| CN (1) | CN101679237A (https=) |
| AU (1) | AU2008248168B2 (https=) |
| BR (1) | BRPI0810330A2 (https=) |
| CA (1) | CA2686033A1 (https=) |
| EA (1) | EA019031B1 (https=) |
| IL (1) | IL201627A (https=) |
| MX (1) | MX2009011787A (https=) |
| NZ (1) | NZ580948A (https=) |
| UA (1) | UA99913C2 (https=) |
| WO (1) | WO2008137087A1 (https=) |
| ZA (1) | ZA200907643B (https=) |
Families Citing this family (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| HRP20130044T1 (hr) | 2006-07-25 | 2013-02-28 | Cephalon, Inc. | Derivati piridizinona |
| US8383657B2 (en) | 2007-12-21 | 2013-02-26 | Abbott Laboratories | Thiazolylidine urea and amide derivatives and methods of use thereof |
| EP2752406A1 (en) | 2008-01-30 | 2014-07-09 | Cephalon, Inc. | Substituted pyridazine derivatives which have histamine H3 antagonist activity |
| MX2017008430A (es) * | 2014-12-23 | 2018-03-23 | Cephalon Inc | Métodos para preparar derivados de 2,4-diaminopirimidina bíclica fusionada. |
| BR112021003440A2 (pt) * | 2018-09-07 | 2021-05-18 | Sanofi | sais de 6-(2,4-diclorofenil)-5-[4-[(3s)-1-(3-fluoropropil) pirrolidin-3-il]oxifenil]-8,9-di-hidro-7h-benzo[7]anuleno-2-carboxilato de metila e seu processo de preparação |
Family Cites Families (20)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE3329974A1 (de) | 1983-08-19 | 1985-02-28 | Bayer Ag, 5090 Leverkusen | Herstellung von hydrierten nitrilkautschuken |
| DE3433392A1 (de) | 1984-09-12 | 1986-03-20 | Bayer Ag, 5090 Leverkusen | Hydrierung nitrilgruppenhaltiger ungesaettigter polymerer |
| FR2714849B1 (fr) | 1994-01-13 | 1996-04-05 | Inst Francais Du Petrole | Procédé de préparation d'un catalyseur d'hydrogénation soluble en phase liquide organique. |
| DE4403479A1 (de) | 1994-02-04 | 1995-08-10 | Basf Ag | Verfahren zur Herstellung von Hydroxylammoniumsalzen |
| WO2004024707A2 (en) * | 2002-09-16 | 2004-03-25 | Abbott Laboratories | Process for preparing amine type substituted benzofurans |
| US7153889B2 (en) | 2002-11-12 | 2006-12-26 | Abbott Laboratories | Bicyclic-substituted amines as histamine-3 receptor ligands |
| CN100543050C (zh) | 2004-03-08 | 2009-09-23 | 独立行政法人科学技术振兴机构 | 高分子担载金属簇组合物 |
| US7145005B2 (en) | 2004-05-12 | 2006-12-05 | Abbott Laboratories | 2-(6-{2-[(2R)-2-Methyl-1-pyrrolidin-1-yl]-ethyl}-2-naphthalen-2-yl)-2H-pyridazin-3-one salts and their preparation |
| DE602005004404T2 (de) | 2004-06-02 | 2009-01-15 | F. Hoffmann-La Roche Ag | Als histamin-3-rezeptorliganden einsetzbare naphthalene-derivate |
| CA2588867A1 (en) | 2004-12-01 | 2006-06-08 | Banyu Pharmaceutical Co., Ltd. | Substituted pyridone derivative |
| AU2005316337A1 (en) | 2004-12-17 | 2006-06-22 | Janssen Pharmaceutica, N.V. | Tetrahydroisoquinoline compounds for treatment of CNS disorders |
| EP1848696A1 (en) | 2005-01-21 | 2007-10-31 | Schering Corporation | Imidazole and benzimidazole derivates useful as histamine h3 antagonists |
| CA2602336A1 (en) | 2005-03-31 | 2006-10-05 | Ucb Pharma S.A. | Compounds comprising an oxazole or thiazole moiety, processes for making them, and their uses |
| GB0514812D0 (en) | 2005-07-19 | 2005-08-24 | Glaxo Group Ltd | Compounds |
| CA2627234A1 (en) | 2005-10-27 | 2007-05-03 | Ucb Pharma, S.A. | Compounds comprising a lactam or a lactam derivative moiety, processes for making them, and their uses |
| ATE525072T1 (de) | 2006-02-09 | 2011-10-15 | Athersys Inc | Pyrazole zur behandlung von adipositas und anderen zns-erkrankungen |
| WO2007099423A1 (en) | 2006-03-02 | 2007-09-07 | Pfizer Products Inc. | 1-pyrrolidine indane derivatives as histamine-3 receptor antagonists |
| CA2643055A1 (en) | 2006-03-13 | 2007-09-20 | Pfizer Products Inc. | Tetralines antagonists of the h-3 receptor |
| WO2008005338A1 (en) | 2006-06-29 | 2008-01-10 | Arena Pharmaceuticals, Inc. | Modulators of the histamine h3-receptor useful for the treatment of disorders related thereto |
| HRP20130044T1 (hr) * | 2006-07-25 | 2013-02-28 | Cephalon, Inc. | Derivati piridizinona |
-
2008
- 2008-05-02 BR BRPI0810330-5A2A patent/BRPI0810330A2/pt not_active IP Right Cessation
- 2008-05-02 CN CN200880021225A patent/CN101679237A/zh active Pending
- 2008-05-02 AU AU2008248168A patent/AU2008248168B2/en not_active Ceased
- 2008-05-02 EP EP08754205A patent/EP2152669A1/en not_active Withdrawn
- 2008-05-02 MX MX2009011787A patent/MX2009011787A/es active IP Right Grant
- 2008-05-02 WO PCT/US2008/005702 patent/WO2008137087A1/en not_active Ceased
- 2008-05-02 UA UAA200912476A patent/UA99913C2/ru unknown
- 2008-05-02 KR KR1020097025141A patent/KR20100017565A/ko not_active Ceased
- 2008-05-02 JP JP2010507416A patent/JP5698887B2/ja not_active Expired - Fee Related
- 2008-05-02 CA CA002686033A patent/CA2686033A1/en not_active Abandoned
- 2008-05-02 EA EA200971019A patent/EA019031B1/ru not_active IP Right Cessation
- 2008-05-02 NZ NZ580948A patent/NZ580948A/en not_active IP Right Cessation
-
2009
- 2009-10-19 IL IL201627A patent/IL201627A/en not_active IP Right Cessation
- 2009-10-30 ZA ZA2009/07643A patent/ZA200907643B/en unknown
Non-Patent Citations (1)
| Title |
|---|
| SAKURAI, R. et al., Crystal Growth and Design, 2006, vol 6, pages 1606-1610 * |
Also Published As
| Publication number | Publication date |
|---|---|
| UA99913C2 (ru) | 2012-10-25 |
| AU2008248168A1 (en) | 2008-11-13 |
| JP5698887B2 (ja) | 2015-04-08 |
| CN101679237A (zh) | 2010-03-24 |
| MX2009011787A (es) | 2009-11-13 |
| WO2008137087A1 (en) | 2008-11-13 |
| BRPI0810330A2 (pt) | 2014-10-14 |
| JP2010526142A (ja) | 2010-07-29 |
| IL201627A0 (en) | 2010-05-31 |
| CA2686033A1 (en) | 2008-11-13 |
| IL201627A (en) | 2014-06-30 |
| ZA200907643B (en) | 2014-03-26 |
| NZ580948A (en) | 2011-04-29 |
| KR20100017565A (ko) | 2010-02-16 |
| EA019031B1 (ru) | 2013-12-30 |
| EP2152669A1 (en) | 2010-02-17 |
| EA200971019A1 (ru) | 2010-04-30 |
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