SK132498A3 - Pyrrolopyrrolone derivatives as inhibitors of neutrophil elastase - Google Patents

Info

Publication number

SK132498A3

SK132498A3 SK1324-98A SK132498A SK132498A3 SK 132498 A3 SK132498 A3 SK 132498A3 SK 132498 A SK132498 A SK 132498A SK 132498 A3 SK132498 A3 SK 132498A3

Authority

SK

Slovakia

Prior art keywords

rel

pyrrol

methanesulfonyl

isopropyl

compound

Prior art date

1996-03-28

Links

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• Global Dossier
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• 108010028275 Leukocyte Elastase Proteins 0.000 title description 4
• 102000016799 Leukocyte elastase Human genes 0.000 title description 4
• 239000003112 inhibitor Substances 0.000 title description 4
• ACJSMQZKXAMMRA-UHFFFAOYSA-N 1h-pyrrolo[3,2-b]pyrrol-5-one Chemical class N1C=CC2=NC(=O)C=C21 ACJSMQZKXAMMRA-UHFFFAOYSA-N 0.000 title 1
• 150000001875 compounds Chemical class 0.000 claims abstract description 386
• 239000000203 mixture Substances 0.000 claims abstract description 105
• 238000000034 method Methods 0.000 claims abstract description 101
• 230000008569 process Effects 0.000 claims abstract description 19
• 206010006451 bronchitis Diseases 0.000 claims abstract description 12
• 206010006458 Bronchitis chronic Diseases 0.000 claims abstract description 9
• 208000007451 chronic bronchitis Diseases 0.000 claims abstract description 9
• 239000003814 drug Substances 0.000 claims abstract description 4
• -1 (CH 2) m -NR 4 R 5 Chemical group 0.000 claims description 98
• 125000004432 carbon atom Chemical group C* 0.000 claims description 79
• 125000000217 alkyl group Chemical group 0.000 claims description 71
• IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 58
• 229910052757 nitrogen Inorganic materials 0.000 claims description 58
• 238000002360 preparation method Methods 0.000 claims description 43
• 150000003839 salts Chemical class 0.000 claims description 43
• VIXWGKYSYIBATJ-UHFFFAOYSA-N pyrrol-2-one Chemical compound O=C1C=CC=N1 VIXWGKYSYIBATJ-UHFFFAOYSA-N 0.000 claims description 32
• 125000003342 alkenyl group Chemical group 0.000 claims description 31
• 125000003118 aryl group Chemical group 0.000 claims description 27
• 125000004433 nitrogen atom Chemical group N* 0.000 claims description 26
• 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 24
• 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 22
• NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 claims description 19
• 230000015572 biosynthetic process Effects 0.000 claims description 19
• 239000002253 acid Substances 0.000 claims description 18
• 229920006395 saturated elastomer Polymers 0.000 claims description 18
• 125000001424 substituent group Chemical group 0.000 claims description 18
• 239000001257 hydrogen Substances 0.000 claims description 17
• 229910052739 hydrogen Inorganic materials 0.000 claims description 17
• RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 claims description 16
• 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 16
• 125000006239 protecting group Chemical group 0.000 claims description 16
• UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 15
• 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 13
• 125000005907 alkyl ester group Chemical class 0.000 claims description 12
• 125000005843 halogen group Chemical group 0.000 claims description 12
• 125000001072 heteroaryl group Chemical group 0.000 claims description 12
• 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 claims description 11
• XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 claims description 11
• 239000008194 pharmaceutical composition Substances 0.000 claims description 11
• 229910052717 sulfur Inorganic materials 0.000 claims description 11
• 239000000126 substance Substances 0.000 claims description 10
• PVOAHINGSUIXLS-UHFFFAOYSA-N 1-Methylpiperazine Chemical compound CN1CCNCC1 PVOAHINGSUIXLS-UHFFFAOYSA-N 0.000 claims description 9
• 125000003545 alkoxy group Chemical group 0.000 claims description 9
• 229910052801 chlorine Inorganic materials 0.000 claims description 9
• 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 9
• 229910052736 halogen Inorganic materials 0.000 claims description 9
• 150000002367 halogens Chemical class 0.000 claims description 9
• YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 claims description 8
• GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 claims description 8
• 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 8
• 125000001462 1-pyrrolyl group Chemical group [*]N1C([H])=C([H])C([H])=C1[H] 0.000 claims description 7
• NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 7
• 125000004414 alkyl thio group Chemical group 0.000 claims description 7
• GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 7
• 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 7
• PXBRQCKWGAHEHS-UHFFFAOYSA-N dichlorodifluoromethane Chemical compound FC(F)(Cl)Cl PXBRQCKWGAHEHS-UHFFFAOYSA-N 0.000 claims description 7
• 238000004519 manufacturing process Methods 0.000 claims description 7
• 230000002265 prevention Effects 0.000 claims description 7
• 239000012453 solvate Substances 0.000 claims description 7
• 239000011593 sulfur Substances 0.000 claims description 7
• ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 6
• 229910052794 bromium Inorganic materials 0.000 claims description 6
• 229910052799 carbon Inorganic materials 0.000 claims description 6
• 125000006297 carbonyl amino group Chemical group [H]N([*:2])C([*:1])=O 0.000 claims description 6
• 239000000460 chlorine Substances 0.000 claims description 6
• WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 5
• 239000004480 active ingredient Substances 0.000 claims description 5
• 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 5
• 238000010511 deprotection reaction Methods 0.000 claims description 5
• 150000002148 esters Chemical class 0.000 claims description 5
• 229910052760 oxygen Inorganic materials 0.000 claims description 5
• 238000006268 reductive amination reaction Methods 0.000 claims description 5
• 208000006545 Chronic Obstructive Pulmonary Disease Diseases 0.000 claims description 4
• 125000003647 acryloyl group Chemical group O=C([*])C([H])=C([H])[H] 0.000 claims description 4
• 125000005018 aryl alkenyl group Chemical group 0.000 claims description 4
• XYOVOXDWRFGKEX-UHFFFAOYSA-N azepine Chemical compound N1C=CC=CC=C1 XYOVOXDWRFGKEX-UHFFFAOYSA-N 0.000 claims description 4
• 125000004435 hydrogen atom Chemical class [H]* 0.000 claims description 4
• 125000004193 piperazinyl group Chemical group 0.000 claims description 4
• 125000001544 thienyl group Chemical group 0.000 claims description 4
• CYRMSUTZVYGINF-UHFFFAOYSA-N trichlorofluoromethane Chemical compound FC(Cl)(Cl)Cl CYRMSUTZVYGINF-UHFFFAOYSA-N 0.000 claims description 4
• KAESVJOAVNADME-UHFFFAOYSA-N Pyrrole Chemical compound C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 claims description 3
• 125000001309 chloro group Chemical group Cl* 0.000 claims description 3
• 239000003085 diluting agent Substances 0.000 claims description 3
• 125000002541 furyl group Chemical group 0.000 claims description 3
• 125000005842 heteroatom Chemical group 0.000 claims description 3
• 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 3
• 125000000168 pyrrolyl group Chemical group 0.000 claims description 3
• 238000005694 sulfonylation reaction Methods 0.000 claims description 3
• 125000003831 tetrazolyl group Chemical group 0.000 claims description 3
• 125000004044 trifluoroacetyl group Chemical group FC(C(=O)*)(F)F 0.000 claims description 3
• SDGKUVSVPIIUCF-UHFFFAOYSA-N 2,6-dimethylpiperidine Chemical compound CC1CCCC(C)N1 SDGKUVSVPIIUCF-UHFFFAOYSA-N 0.000 claims description 2
• 125000004105 2-pyridyl group Chemical group N1=C([*])C([H])=C([H])C([H])=C1[H] 0.000 claims description 2
• 125000003368 amide group Chemical group 0.000 claims description 2
• METKIMKYRPQLGS-UHFFFAOYSA-N atenolol Chemical compound CC(C)NCC(O)COC1=CC=C(CC(N)=O)C=C1 METKIMKYRPQLGS-UHFFFAOYSA-N 0.000 claims description 2
• 125000004494 ethyl ester group Chemical group 0.000 claims description 2
• 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 2
• 238000005932 reductive alkylation reaction Methods 0.000 claims description 2
• 125000006413 ring segment Chemical group 0.000 claims description 2
• RWSOTUBLDIXVET-UHFFFAOYSA-O sulfonium group Chemical group [SH3+] RWSOTUBLDIXVET-UHFFFAOYSA-O 0.000 claims description 2
• 230000006103 sulfonylation Effects 0.000 claims description 2
• 125000004434 sulfur atom Chemical group 0.000 claims description 2
• LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 claims description 2
• 238000002560 therapeutic procedure Methods 0.000 claims description 2
• KAKQVSNHTBLJCH-UHFFFAOYSA-N trifluoromethanesulfonimidic acid Chemical compound NS(=O)(=O)C(F)(F)F KAKQVSNHTBLJCH-UHFFFAOYSA-N 0.000 claims description 2
• DSILUGCORMLHPA-UHFFFAOYSA-N 2,3,3a,4,6,6a-hexahydro-1h-pyrrolo[3,2-b]pyrrol-5-one Chemical compound N1CCC2NC(=O)CC21 DSILUGCORMLHPA-UHFFFAOYSA-N 0.000 claims 5
• 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 claims 5
• 125000004195 4-methylpiperazin-1-yl group Chemical group [H]C([H])([H])N1C([H])([H])C([H])([H])N(*)C([H])([H])C1([H])[H] 0.000 claims 2
• DLFVBJFMPXGRIB-UHFFFAOYSA-N Acetamide Chemical compound CC(N)=O DLFVBJFMPXGRIB-UHFFFAOYSA-N 0.000 claims 2
• 125000000719 pyrrolidinyl group Chemical group 0.000 claims 2
• AYKBFCREVQLSOZ-UHFFFAOYSA-N 4-propyl-1,2,3,3a,6,6a-hexahydropyrrolo[3,2-b]pyrrol-5-one Chemical compound C1CNC2CC(=O)N(CCC)C21 AYKBFCREVQLSOZ-UHFFFAOYSA-N 0.000 claims 1
• 125000004648 C2-C8 alkenyl group Chemical group 0.000 claims 1
• 159000000007 calcium salts Chemical class 0.000 claims 1
• 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims 1
• SRJOCJYGOFTFLH-UHFFFAOYSA-N isonipecotic acid Chemical compound OC(=O)C1CCNCC1 SRJOCJYGOFTFLH-UHFFFAOYSA-N 0.000 claims 1
• YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 660
• XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 489
• OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 345
• 239000000243 solution Substances 0.000 description 282
• 239000000543 intermediate Substances 0.000 description 271
• LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 258
• VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 196
• 238000001819 mass spectrum Methods 0.000 description 185
• 238000004809 thin layer chromatography Methods 0.000 description 184
• RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 166
• WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 146
• 239000011541 reaction mixture Substances 0.000 description 133
• WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 130
• 239000007787 solid Substances 0.000 description 112
• CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 110
• VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 97
• 239000000377 silicon dioxide Substances 0.000 description 92
• VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 91
• 239000002904 solvent Substances 0.000 description 91
• QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 90
• 238000006243 chemical reaction Methods 0.000 description 88
• 235000019441 ethanol Nutrition 0.000 description 87
• XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 85
• ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 78
• UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 72
• ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 69
• HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 56
• 239000007858 starting material Substances 0.000 description 56
• 229910052943 magnesium sulfate Inorganic materials 0.000 description 55
• 235000019341 magnesium sulphate Nutrition 0.000 description 55
• FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 54
• 239000000284 extract Substances 0.000 description 52
• YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 52
• 229910021529 ammonia Inorganic materials 0.000 description 45
• 238000003818 flash chromatography Methods 0.000 description 41
• 239000000047 product Substances 0.000 description 38
• PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 36
• 239000003921 oil Substances 0.000 description 35
• 235000019198 oils Nutrition 0.000 description 35
• 235000017557 sodium bicarbonate Nutrition 0.000 description 34
• 229910000030 sodium bicarbonate Inorganic materials 0.000 description 34
• 229910052938 sodium sulfate Inorganic materials 0.000 description 33
• 235000011152 sodium sulphate Nutrition 0.000 description 33
• 239000002585 base Substances 0.000 description 30
• IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 29
• 229910000041 hydrogen chloride Inorganic materials 0.000 description 29
• 239000012299 nitrogen atmosphere Substances 0.000 description 27
• XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 26
• 239000000843 powder Substances 0.000 description 26
• QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 25
• CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 23
• CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 22
• 238000003756 stirring Methods 0.000 description 22
• NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 21
• RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 20
• BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 20
• 238000001914 filtration Methods 0.000 description 19
• HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 18
• 239000000725 suspension Substances 0.000 description 17
• ASOKPJOREAFHNY-UHFFFAOYSA-N 1-Hydroxybenzotriazole Chemical compound C1=CC=C2N(O)N=NC2=C1 ASOKPJOREAFHNY-UHFFFAOYSA-N 0.000 description 15
• IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 15
• 102000016387 Pancreatic elastase Human genes 0.000 description 15
• 108010067372 Pancreatic elastase Proteins 0.000 description 15
• 239000006260 foam Substances 0.000 description 15
• YNESATAKKCNGOF-UHFFFAOYSA-N lithium bis(trimethylsilyl)amide Chemical compound [Li+].C[Si](C)(C)[N-][Si](C)(C)C YNESATAKKCNGOF-UHFFFAOYSA-N 0.000 description 14
• DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical class OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 13
• 239000000706 filtrate Substances 0.000 description 13
• 238000003786 synthesis reaction Methods 0.000 description 13
• FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 description 12
• SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 description 12
• YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 12
• 238000010521 absorption reaction Methods 0.000 description 12
• WTEOIRVLGSZEPR-UHFFFAOYSA-N boron trifluoride Chemical compound FB(F)F WTEOIRVLGSZEPR-UHFFFAOYSA-N 0.000 description 12
• 201000010099 disease Diseases 0.000 description 12
• 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 12
• 238000010992 reflux Methods 0.000 description 12
• 239000000741 silica gel Substances 0.000 description 11
• 229910002027 silica gel Inorganic materials 0.000 description 11
• 229910000029 sodium carbonate Inorganic materials 0.000 description 11
• VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 10
• MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 10
• 238000004587 chromatography analysis Methods 0.000 description 10
• 239000012458 free base Substances 0.000 description 10
• 230000005484 gravity Effects 0.000 description 10
• 210000004072 lung Anatomy 0.000 description 10
• 229910000027 potassium carbonate Inorganic materials 0.000 description 10
• 239000012321 sodium triacetoxyborohydride Substances 0.000 description 10
• JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-diisopropylethylamine Substances CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 9
• FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 9
• 229960000583 acetic acid Drugs 0.000 description 9
• 239000003054 catalyst Substances 0.000 description 9
• 238000004296 chiral HPLC Methods 0.000 description 9
• 239000012230 colorless oil Substances 0.000 description 9
• 239000012442 inert solvent Substances 0.000 description 9
• QAOWNCQODCNURD-UHFFFAOYSA-N sulfuric acid Substances OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 9
• 244000166102 Eucalyptus leucoxylon Species 0.000 description 8
• 235000004694 Eucalyptus leucoxylon Nutrition 0.000 description 8
• 235000019502 Orange oil Nutrition 0.000 description 8
• HSDAJNMJOMSNEV-UHFFFAOYSA-N benzyl chloroformate Chemical compound ClC(=O)OCC1=CC=CC=C1 HSDAJNMJOMSNEV-UHFFFAOYSA-N 0.000 description 8
• 230000000694 effects Effects 0.000 description 8
• 239000003480 eluent Substances 0.000 description 8
• CQRPUKWAZPZXTO-UHFFFAOYSA-M magnesium;2-methylpropane;chloride Chemical compound [Mg+2].[Cl-].C[C-](C)C CQRPUKWAZPZXTO-UHFFFAOYSA-M 0.000 description 8
• 239000010502 orange oil Substances 0.000 description 8
• NXJCBFBQEVOTOW-UHFFFAOYSA-L palladium(2+);dihydroxide Chemical compound O[Pd]O NXJCBFBQEVOTOW-UHFFFAOYSA-L 0.000 description 8
• 238000000746 purification Methods 0.000 description 8
• DYHSDKLCOJIUFX-UHFFFAOYSA-N tert-butoxycarbonyl anhydride Chemical compound CC(C)(C)OC(=O)OC(=O)OC(C)(C)C DYHSDKLCOJIUFX-UHFFFAOYSA-N 0.000 description 8
• IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 7
• 102000004190 Enzymes Human genes 0.000 description 7
• 108090000790 Enzymes Proteins 0.000 description 7
• 235000019270 ammonium chloride Nutrition 0.000 description 7
• 239000012298 atmosphere Substances 0.000 description 7
• 230000004054 inflammatory process Effects 0.000 description 7
• 230000014759 maintenance of location Effects 0.000 description 7
• 239000011347 resin Substances 0.000 description 7
• 229920005989 resin Polymers 0.000 description 7
• 239000011780 sodium chloride Substances 0.000 description 7
• 229910000104 sodium hydride Inorganic materials 0.000 description 7
• 229910015900 BF3 Inorganic materials 0.000 description 6
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