NZ580948A - Processes for preparing (R)-2-methylpyrrolidine and (S)-2-methylpyrrolidine derivatives and tartrate andor hydrochloride salts thereof - Google Patents

Info

Publication number

NZ580948A

NZ580948A NZ580948A NZ58094808A NZ580948A NZ 580948 A NZ580948 A NZ 580948A NZ 580948 A NZ580948 A NZ 580948A NZ 58094808 A NZ58094808 A NZ 58094808A NZ 580948 A NZ580948 A NZ 580948A

Authority

NZ

New Zealand

Prior art keywords

methylpyrrolidine

methyl

tartrate

phenyl

pyrrolidin

Prior art date

2007-05-03

Links

• Espacenet
• Global Dossier
• Discuss

• RGHPCLZJAFCTIK-RXMQYKEDSA-N (R)-2-methylpyrrolidine Chemical compound C[C@@H]1CCCN1 RGHPCLZJAFCTIK-RXMQYKEDSA-N 0.000 title claims abstract description 45
• FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 title claims abstract description 30
• 238000000034 method Methods 0.000 title claims description 156
• 230000008569 process Effects 0.000 title claims description 67
• RGHPCLZJAFCTIK-YFKPBYRVSA-N (2s)-2-methylpyrrolidine Chemical class C[C@H]1CCCN1 RGHPCLZJAFCTIK-YFKPBYRVSA-N 0.000 title description 159
• 229940095064 tartrate Drugs 0.000 title description 3
• 150000003840 hydrochlorides Chemical class 0.000 title 1
• LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims abstract description 152
• 239000000203 mixture Substances 0.000 claims abstract description 125
• 239000002904 solvent Substances 0.000 claims abstract description 108
• 239000003054 catalyst Substances 0.000 claims abstract description 103
• 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 abstract description 94
• 239000002585 base Substances 0.000 claims abstract description 90
• 238000005984 hydrogenation reaction Methods 0.000 claims abstract description 82
• 239000012458 free base Substances 0.000 claims abstract description 36
• MUUWQYQRBFVTIB-UHFFFAOYSA-N 5-methyl-2,3-dihydro-1h-pyrrole Chemical compound CC1=CCCN1 MUUWQYQRBFVTIB-UHFFFAOYSA-N 0.000 claims abstract description 33
• 150000003839 salts Chemical class 0.000 claims abstract description 25
• 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 abstract description 10
• 238000004519 manufacturing process Methods 0.000 claims abstract description 7
• OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 127
• 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 75
• BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical group [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 claims description 37
• 230000003287 optical effect Effects 0.000 claims description 21
• IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 17
• 238000001953 recrystallisation Methods 0.000 claims description 17
• 229910052697 platinum Inorganic materials 0.000 claims description 15
• 229910052757 nitrogen Inorganic materials 0.000 claims description 14
• 239000007789 gas Substances 0.000 claims description 11
• 238000004587 chromatography analysis Methods 0.000 claims description 9
• 239000007787 solid Substances 0.000 claims description 8
• HHLFWLYXYJOTON-UHFFFAOYSA-N glyoxylic acid Chemical compound OC(=O)C=O HHLFWLYXYJOTON-UHFFFAOYSA-N 0.000 claims description 6
• 239000013078 crystal Substances 0.000 claims description 5
• 238000011084 recovery Methods 0.000 claims 4
• XKJMBINCVNINCA-UHFFFAOYSA-N Alfalone Chemical compound CON(C)C(=O)NC1=CC=C(Cl)C(Cl)=C1 XKJMBINCVNINCA-UHFFFAOYSA-N 0.000 claims 2
• OLVCTBRABXEFAA-UHFFFAOYSA-N [Pt+3]=O Chemical group [Pt+3]=O OLVCTBRABXEFAA-UHFFFAOYSA-N 0.000 claims 1
• 238000012986 modification Methods 0.000 claims 1
• 230000004048 modification Effects 0.000 claims 1
• 238000010899 nucleation Methods 0.000 claims 1
• 150000001875 compounds Chemical class 0.000 abstract description 126
• 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 131
• 239000000243 solution Substances 0.000 description 78
• 125000000217 alkyl group Chemical group 0.000 description 72
• 238000006243 chemical reaction Methods 0.000 description 69
• YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 52
• -1 chloropropyl Chemical group 0.000 description 51
• 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 51
• 125000002572 propoxy group Chemical group [*]OC([H])([H])C(C([H])([H])[H])([H])[H] 0.000 description 51
• WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 48
• NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 42
• RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 40
• 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 36
• 150000001412 amines Chemical class 0.000 description 34
• ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 33
• 229910052739 hydrogen Inorganic materials 0.000 description 32
• 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
• BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 28
• ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 27
• 239000003153 chemical reaction reagent Substances 0.000 description 27
• CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 25
• JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 25
• 125000003118 aryl group Chemical group 0.000 description 24
• 229910052736 halogen Inorganic materials 0.000 description 24
• YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 24
• 229960001270 d- tartaric acid Drugs 0.000 description 23
• 150000002367 halogens Chemical class 0.000 description 23
• 239000000047 product Substances 0.000 description 23
• 239000001257 hydrogen Substances 0.000 description 22
• 239000000543 intermediate Substances 0.000 description 22
• RGHPCLZJAFCTIK-UHFFFAOYSA-N 2-methylpyrrolidine Chemical compound CC1CCCN1 RGHPCLZJAFCTIK-UHFFFAOYSA-N 0.000 description 20
• 125000000753 cycloalkyl group Chemical group 0.000 description 20
• 125000005843 halogen group Chemical group 0.000 description 19
• 238000002360 preparation method Methods 0.000 description 19
• KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 18
• AVFZOVWCLRSYKC-UHFFFAOYSA-N 1-methylpyrrolidine Chemical compound CN1CCCC1 AVFZOVWCLRSYKC-UHFFFAOYSA-N 0.000 description 17
• WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 17
• YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 description 17
• YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 17
• 125000003545 alkoxy group Chemical group 0.000 description 17
• AHVYPIQETPWLSZ-UHFFFAOYSA-N N-methyl-pyrrolidine Natural products CN1CC=CC1 AHVYPIQETPWLSZ-UHFFFAOYSA-N 0.000 description 16
• 150000001408 amides Chemical class 0.000 description 16
• 125000002887 hydroxy group Chemical group [H]O* 0.000 description 16
• 229910000027 potassium carbonate Inorganic materials 0.000 description 16
• QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 15
• 229910052799 carbon Inorganic materials 0.000 description 15
• 239000011541 reaction mixture Substances 0.000 description 15
• UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 14
• MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 14
• 239000003446 ligand Substances 0.000 description 14
• AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 13
• UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 12
• 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
• 238000003786 synthesis reaction Methods 0.000 description 11
• RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 10
• DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 10
• 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 10
• 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 10
• 125000004093 cyano group Chemical group *C#N 0.000 description 10
• 238000001914 filtration Methods 0.000 description 10
• 125000001072 heteroaryl group Chemical group 0.000 description 10
• 125000000623 heterocyclic group Chemical group 0.000 description 10
• 235000015320 potassium carbonate Nutrition 0.000 description 10
• 229910000029 sodium carbonate Inorganic materials 0.000 description 10
• 230000009466 transformation Effects 0.000 description 10
• XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 10
• IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 9
• KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 9
• 150000001298 alcohols Chemical class 0.000 description 9
• 125000003710 aryl alkyl group Chemical group 0.000 description 9
• 125000004429 atom Chemical group 0.000 description 9
• 125000000592 heterocycloalkyl group Chemical group 0.000 description 9
• 125000004435 hydrogen atom Chemical group [H]* 0.000 description 9
• 150000002576 ketones Chemical class 0.000 description 9
• 229910052760 oxygen Inorganic materials 0.000 description 9
• 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 9
• 230000002829 reductive effect Effects 0.000 description 9
• 125000001424 substituent group Chemical group 0.000 description 9
• 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 9
• 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
• GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 description 8
• 230000008901 benefit Effects 0.000 description 8
• 230000015572 biosynthetic process Effects 0.000 description 8
• 238000011065 in-situ storage Methods 0.000 description 8
• 238000002955 isolation Methods 0.000 description 8
• 230000037361 pathway Effects 0.000 description 8
• 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
• 125000004432 carbon atom Chemical group C* 0.000 description 7
• 150000001732 carboxylic acid derivatives Chemical class 0.000 description 7
• 229910052802 copper Inorganic materials 0.000 description 7
• 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 7
• 150000002431 hydrogen Chemical class 0.000 description 7
• 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 7
• ISWSIDIOOBJBQZ-UHFFFAOYSA-N phenol group Chemical group C1(=CC=CC=C1)O ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 7
• 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 7
• 125000006239 protecting group Chemical group 0.000 description 7
• 150000003892 tartrate salts Chemical class 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
• 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 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
• JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-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
• CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 6
• 125000003158 alcohol group Chemical group 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
• XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 6
• 125000001188 haloalkyl group Chemical group 0.000 description 6
• 229910052751 metal Inorganic materials 0.000 description 6
• 239000002184 metal Substances 0.000 description 6
• TVPRCLHSULCNLV-UHFFFAOYSA-N pyridazin-3-one Chemical compound O=C1C=CC=N[N]1 TVPRCLHSULCNLV-UHFFFAOYSA-N 0.000 description 6
• 239000012279 sodium borohydride Substances 0.000 description 6
• 229910000033 sodium borohydride Inorganic materials 0.000 description 6
• 229910052717 sulfur 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
• LWIHDJKSTIGBAC-UHFFFAOYSA-K tripotassium phosphate Chemical compound [K+].[K+].[K+].[O-]P([O-])([O-])=O LWIHDJKSTIGBAC-UHFFFAOYSA-K 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
• AAILEWXSEQLMNI-UHFFFAOYSA-N 1h-pyridazin-6-one Chemical compound OC1=CC=CN=N1 AAILEWXSEQLMNI-UHFFFAOYSA-N 0.000 description 5
• FJHKZEVPGYADEG-NVPAJSRCSA-N 2-[4-[3-[(2r)-2-methylpyrrolidin-1-yl]propoxy]phenyl]-3,4-diazabicyclo[4.1.0]hept-2-en-5-one Chemical compound C[C@@H]1CCCN1CCCOC1=CC=C(C=2C3CC3C(=O)NN=2)C=C1 FJHKZEVPGYADEG-NVPAJSRCSA-N 0.000 description 5
• 101100347605 Arabidopsis thaliana VIII-A gene Proteins 0.000 description 5
• 125000004649 C2-C8 alkynyl group Chemical group 0.000 description 5
• 102000004384 Histamine H3 receptors Human genes 0.000 description 5
• 108090000981 Histamine H3 receptors Proteins 0.000 description 5
• VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 5
• RRHGJUQNOFWUDK-UHFFFAOYSA-N Isoprene Chemical compound CC(=C)C=C RRHGJUQNOFWUDK-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
• 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
• 230000008878 coupling Effects 0.000 description 5
• 238000010168 coupling process Methods 0.000 description 5
• 238000005859 coupling reaction Methods 0.000 description 5
• 150000002148 esters Chemical class 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
• 238000010992 reflux Methods 0.000 description 5
• 229910000104 sodium hydride Inorganic materials 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
• RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 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
• XUKROCVZGZNGSI-AWEZNQCLSA-N 3-[4-[3-[(2s)-2-methylpyrrolidin-1-yl]propoxy]phenyl]-1h-pyridazin-6-one Chemical compound C[C@H]1CCCN1CCCOC1=CC=C(C2=NNC(=O)C=C2)C=C1 XUKROCVZGZNGSI-AWEZNQCLSA-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
• DLFVBJFMPXGRIB-UHFFFAOYSA-N Acetamide Chemical compound CC(N)=O DLFVBJFMPXGRIB-UHFFFAOYSA-N 0.000 description 4
• 125000004648 C2-C8 alkenyl group Chemical group 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
• NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 4
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• 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
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• 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
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• 229910000073 phosphorus hydride Inorganic materials 0.000 description 1
• 125000004482 piperidin-4-yl group Chemical group N1CCC(CC1)* 0.000 description 1
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• 229920000642 polymer Polymers 0.000 description 1
• 229910052700 potassium Inorganic materials 0.000 description 1
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• 229910000028 potassium bicarbonate Inorganic materials 0.000 description 1
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• TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 description 1
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• 239000010970 precious metal Substances 0.000 description 1
• 125000000075 primary alcohol group Chemical group 0.000 description 1
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• 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
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• NGXSWUFDCSEIOO-UHFFFAOYSA-N pyrrolidin-3-amine Chemical compound NC1CCNC1 NGXSWUFDCSEIOO-UHFFFAOYSA-N 0.000 description 1
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• 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
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• 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
• JZUHHDAETNVMRM-UHFFFAOYSA-N tert-butyl 4-[4-(3-chloropropoxy)phenyl]-3-oxopiperazine-1-carboxylate Chemical compound O=C1CN(C(=O)OC(C)(C)C)CCN1C1=CC=C(OCCCCl)C=C1 JZUHHDAETNVMRM-UHFFFAOYSA-N 0.000 description 1
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• 125000003944 tolyl group Chemical group 0.000 description 1
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• 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