NO328549B1 - Oksazolidinonderivater med antibiotisk aktivitet - Google Patents

Info

Publication number

NO328549B1

NO328549B1 NO20025091A NO20025091A NO328549B1 NO 328549 B1 NO328549 B1 NO 328549B1 NO 20025091 A NO20025091 A NO 20025091A NO 20025091 A NO20025091 A NO 20025091A NO 328549 B1 NO328549 B1 NO 328549B1

Authority

NO

Norway

Prior art keywords

alkyl

ring

alkoxy

optionally substituted

hydrogen

Prior art date

2000-04-25

Links

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• IZXIZTKNFFYFOF-UHFFFAOYSA-N 2-Oxazolidone Chemical class O=C1NCCO1 IZXIZTKNFFYFOF-UHFFFAOYSA-N 0.000 title description 61
• 230000003115 biocidal effect Effects 0.000 title description 7
• 125000000217 alkyl group Chemical group 0.000 claims abstract description 392
• 150000001875 compounds Chemical class 0.000 claims abstract description 232
• 239000001257 hydrogen Substances 0.000 claims abstract description 124
• 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 124
• 229910052757 nitrogen Inorganic materials 0.000 claims abstract description 111
• UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims abstract description 67
• 238000000034 method Methods 0.000 claims abstract description 66
• 150000003839 salts Chemical class 0.000 claims abstract description 64
• 150000002148 esters Chemical class 0.000 claims abstract description 53
• 125000004433 nitrogen atom Chemical group N* 0.000 claims abstract description 48
• 125000004432 carbon atom Chemical group C* 0.000 claims abstract description 34
• 238000001727 in vivo Methods 0.000 claims abstract description 26
• 238000002360 preparation method Methods 0.000 claims abstract description 25
• PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims abstract description 24
• 125000001072 heteroaryl group Chemical group 0.000 claims abstract description 23
• 239000011737 fluorine Substances 0.000 claims abstract description 22
• 229910052731 fluorine Inorganic materials 0.000 claims abstract description 22
• QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims abstract description 19
• 125000004043 oxo group Chemical group O=* 0.000 claims abstract description 18
• 230000008569 process Effects 0.000 claims abstract description 12
• 125000000464 thioxo group Chemical group S=* 0.000 claims abstract description 10
• 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 7
• -1 2-cyanoethenyl Chemical group 0.000 claims description 226
• IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 119
• 125000003545 alkoxy group Chemical group 0.000 claims description 108
• 229910052799 carbon Inorganic materials 0.000 claims description 86
• 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 80
• 125000001424 substituent group Chemical group 0.000 claims description 80
• 125000004453 alkoxycarbonyl group Chemical group 0.000 claims description 69
• 150000001721 carbon Chemical group 0.000 claims description 69
• 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 claims description 69
• YLQBMQCUIZJEEH-UHFFFAOYSA-N Furan Chemical compound C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 63
• JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 63
• RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 claims description 62
• 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 49
• 125000004093 cyano group Chemical group *C#N 0.000 claims description 44
• 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 43
• 125000005236 alkanoylamino group Chemical group 0.000 claims description 42
• 125000002252 acyl group Chemical group 0.000 claims description 39
• 229910052717 sulfur Inorganic materials 0.000 claims description 39
• 150000003852 triazoles Chemical class 0.000 claims description 38
• 229910052760 oxygen Inorganic materials 0.000 claims description 36
• 229910052736 halogen Inorganic materials 0.000 claims description 34
• 150000002367 halogens Chemical class 0.000 claims description 34
• 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 34
• 125000005842 heteroatom Chemical group 0.000 claims description 33
• UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 32
• 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 31
• 125000003282 alkyl amino group Chemical group 0.000 claims description 30
• KAESVJOAVNADME-UHFFFAOYSA-N Pyrrole Chemical compound C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 claims description 28
• YTPLMLYBLZKORZ-UHFFFAOYSA-N Thiophene Chemical compound C=1C=CSC=1 YTPLMLYBLZKORZ-UHFFFAOYSA-N 0.000 claims description 24
• 238000006243 chemical reaction Methods 0.000 claims description 24
• 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 23
• 125000006239 protecting group Chemical group 0.000 claims description 21
• 125000004122 cyclic group Chemical group 0.000 claims description 20
• CZPWVGJYEJSRLH-UHFFFAOYSA-N Pyrimidine Chemical compound C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 claims description 19
• 125000002619 bicyclic group Chemical group 0.000 claims description 19
• 125000002950 monocyclic group Chemical group 0.000 claims description 19
• 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 19
• FZWLAAWBMGSTSO-UHFFFAOYSA-N Thiazole Chemical compound C1=CSC=N1 FZWLAAWBMGSTSO-UHFFFAOYSA-N 0.000 claims description 18
• 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims description 18
• 150000002431 hydrogen Chemical class 0.000 claims description 16
• CTAPFRYPJLPFDF-UHFFFAOYSA-N isoxazole Chemical compound C=1C=NOC=1 CTAPFRYPJLPFDF-UHFFFAOYSA-N 0.000 claims description 16
• 150000003536 tetrazoles Chemical class 0.000 claims description 16
• ZCQWOFVYLHDMMC-UHFFFAOYSA-N Oxazole Chemical compound C1=COC=N1 ZCQWOFVYLHDMMC-UHFFFAOYSA-N 0.000 claims description 15
• WTKZEGDFNFYCGP-UHFFFAOYSA-N Pyrazole Chemical compound C=1C=NNC=1 WTKZEGDFNFYCGP-UHFFFAOYSA-N 0.000 claims description 15
• 125000004457 alkyl amino carbonyl group Chemical group 0.000 claims description 15
• 125000001153 fluoro group Chemical group F* 0.000 claims description 15
• ZLTPDFXIESTBQG-UHFFFAOYSA-N isothiazole Chemical compound C=1C=NSC=1 ZLTPDFXIESTBQG-UHFFFAOYSA-N 0.000 claims description 15
• PBMFSQRYOILNGV-UHFFFAOYSA-N pyridazine Chemical compound C1=CC=NN=C1 PBMFSQRYOILNGV-UHFFFAOYSA-N 0.000 claims description 15
• XSCHRSMBECNVNS-UHFFFAOYSA-N quinoxaline Chemical compound N1=CC=NC2=CC=CC=C21 XSCHRSMBECNVNS-UHFFFAOYSA-N 0.000 claims description 15
• 229920006395 saturated elastomer Polymers 0.000 claims description 15
• 230000000844 anti-bacterial effect Effects 0.000 claims description 14
• 125000001624 naphthyl group Chemical group 0.000 claims description 14
• OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 13
• AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 claims description 12
• 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 12
• 229930192474 thiophene Natural products 0.000 claims description 12
• 125000000753 cycloalkyl group Chemical group 0.000 claims description 11
• LFGREXWGYUGZLY-UHFFFAOYSA-N phosphoryl Chemical group [P]=O LFGREXWGYUGZLY-UHFFFAOYSA-N 0.000 claims description 10
• 125000006163 5-membered heteroaryl group Chemical group 0.000 claims description 9
• 125000004423 acyloxy group Chemical group 0.000 claims description 9
• 125000003342 alkenyl group Chemical group 0.000 claims description 9
• 125000004466 alkoxycarbonylamino group Chemical group 0.000 claims description 9
• 125000000304 alkynyl group Chemical group 0.000 claims description 9
• 230000015572 biosynthetic process Effects 0.000 claims description 9
• 239000003814 drug Substances 0.000 claims description 9
• 125000004390 alkyl sulfonyl group Chemical group 0.000 claims description 8
• 239000000460 chlorine Substances 0.000 claims description 8
• 125000004029 hydroxymethyl group Chemical group [H]OC([H])([H])* 0.000 claims description 8
• 238000006467 substitution reaction Methods 0.000 claims description 8
• 125000004849 alkoxymethyl group Chemical group 0.000 claims description 7
• 125000005115 alkyl carbamoyl group Chemical group 0.000 claims description 7
• 125000004397 aminosulfonyl group Chemical group NS(=O)(=O)* 0.000 claims description 7
• 150000001540 azides Chemical class 0.000 claims description 7
• 125000001589 carboacyl group Chemical group 0.000 claims description 7
• 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims description 7
• 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 7
• KDCGOANMDULRCW-UHFFFAOYSA-N 7H-purine Chemical compound N1=CNC2=NC=NC2=C1 KDCGOANMDULRCW-UHFFFAOYSA-N 0.000 claims description 6
• 125000005742 alkyl ethenyl group Chemical group 0.000 claims description 6
• 229910052801 chlorine Inorganic materials 0.000 claims description 6
• FLBAYUMRQUHISI-UHFFFAOYSA-N 1,8-naphthyridine Chemical compound N1=CC=CC2=CC=CN=C21 FLBAYUMRQUHISI-UHFFFAOYSA-N 0.000 claims description 5
• GOJUJUVQIVIZAV-UHFFFAOYSA-N 2-amino-4,6-dichloropyrimidine-5-carbaldehyde Chemical group NC1=NC(Cl)=C(C=O)C(Cl)=N1 GOJUJUVQIVIZAV-UHFFFAOYSA-N 0.000 claims description 5
• 125000000676 alkoxyimino group Chemical group 0.000 claims description 5
• 125000004471 alkyl aminosulfonyl group Chemical group 0.000 claims description 5
• 125000004429 atom Chemical group 0.000 claims description 5
• WCZVZNOTHYJIEI-UHFFFAOYSA-N cinnoline Chemical compound N1=NC=CC2=CC=CC=C21 WCZVZNOTHYJIEI-UHFFFAOYSA-N 0.000 claims description 5
• 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 5
• LFSXCDWNBUNEEM-UHFFFAOYSA-N phthalazine Chemical compound C1=NN=CC2=CC=CC=C21 LFSXCDWNBUNEEM-UHFFFAOYSA-N 0.000 claims description 5
• JWVCLYRUEFBMGU-UHFFFAOYSA-N quinazoline Chemical compound N1=CN=CC2=CC=CC=C21 JWVCLYRUEFBMGU-UHFFFAOYSA-N 0.000 claims description 5
• GAMYYCRTACQSBR-UHFFFAOYSA-N 4-azabenzimidazole Chemical compound C1=CC=C2NC=NC2=N1 GAMYYCRTACQSBR-UHFFFAOYSA-N 0.000 claims description 4
• ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 4
• 125000002947 alkylene group Chemical group 0.000 claims description 4
• 150000001412 amines Chemical class 0.000 claims description 4
• 239000012458 free base Substances 0.000 claims description 4
• 239000012948 isocyanate Substances 0.000 claims description 4
• 150000002513 isocyanates Chemical class 0.000 claims description 4
• 238000004519 manufacturing process Methods 0.000 claims description 4
• 150000000177 1,2,3-triazoles Chemical class 0.000 claims description 3
• 238000006352 cycloaddition reaction Methods 0.000 claims description 3
• 125000000596 cyclohexenyl group Chemical group C1(=CCCCC1)* 0.000 claims description 3
• 125000002433 cyclopentenyl group Chemical group C1(=CCCC1)* 0.000 claims description 3
• 125000003170 phenylsulfonyl group Chemical group C1(=CC=CC=C1)S(=O)(=O)* 0.000 claims description 3
• JOYRKODLDBILNP-UHFFFAOYSA-N urethane group Chemical group NC(=O)OCC JOYRKODLDBILNP-UHFFFAOYSA-N 0.000 claims description 3
• 229910014033 C-OH Inorganic materials 0.000 claims description 2
• 229910014570 C—OH Inorganic materials 0.000 claims description 2
• 125000005605 benzo group Chemical group 0.000 claims description 2
• 125000005144 cycloalkylsulfonyl group Chemical group 0.000 claims description 2
• 239000003085 diluting agent Substances 0.000 claims description 2
• 150000002460 imidazoles Chemical class 0.000 claims description 2
• 238000011065 in-situ storage Methods 0.000 claims description 2
• 125000005740 oxycarbonyl group Chemical group [*:1]OC([*:2])=O 0.000 claims description 2
• UEZVMMHDMIWARA-UHFFFAOYSA-M phosphonate Chemical compound [O-]P(=O)=O UEZVMMHDMIWARA-UHFFFAOYSA-M 0.000 claims description 2
• 102220315634 rs1196125127 Human genes 0.000 claims description 2
• 125000002221 trityl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1C([*])(C1=C(C(=C(C(=C1[H])[H])[H])[H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 claims description 2
• VLEWPUAJXGTELZ-AWEZNQCLSA-N (5r)-3-[3,5-difluoro-4-[1-(2-hydroxyacetyl)-3,6-dihydro-2h-pyridin-4-yl]phenyl]-5-(triazol-1-ylmethyl)-1,3-oxazolidin-2-one Chemical compound C1N(C(=O)CO)CCC(C=2C(=CC(=CC=2F)N2C(O[C@@H](CN3N=NC=C3)C2)=O)F)=C1 VLEWPUAJXGTELZ-AWEZNQCLSA-N 0.000 claims 1
• FHJCJBPWKZHSEN-HNNXBMFYSA-N (5r)-3-[3-fluoro-4-[1-(2-hydroxyacetyl)-3,6-dihydro-2h-pyridin-4-yl]phenyl]-5-(triazol-1-ylmethyl)-1,3-oxazolidin-2-one Chemical compound C1N(C(=O)CO)CCC(C=2C(=CC(=CC=2)N2C(O[C@@H](CN3N=NC=C3)C2)=O)F)=C1 FHJCJBPWKZHSEN-HNNXBMFYSA-N 0.000 claims 1
• WEAHPPKQVCDMNK-ZDUSSCGKSA-N (5r)-3-[4-(1,1-dioxo-3,6-dihydro-2h-thiopyran-4-yl)-3,5-difluorophenyl]-5-(triazol-1-ylmethyl)-1,3-oxazolidin-2-one Chemical group FC1=CC(N2C(O[C@@H](CN3N=NC=C3)C2)=O)=CC(F)=C1C1=CCS(=O)(=O)CC1 WEAHPPKQVCDMNK-ZDUSSCGKSA-N 0.000 claims 1
• CGNMDHQKTIKGFO-YOEHRIQHSA-N (5r)-3-[4-[1-[(2s)-2,3-dihydroxypropanoyl]-3,6-dihydro-2h-pyridin-4-yl]-3,5-difluorophenyl]-5-(triazol-1-ylmethyl)-1,3-oxazolidin-2-one Chemical compound C1N(C(=O)[C@@H](O)CO)CCC(C=2C(=CC(=CC=2F)N2C(O[C@@H](CN3N=NC=C3)C2)=O)F)=C1 CGNMDHQKTIKGFO-YOEHRIQHSA-N 0.000 claims 1
• GJMOJANWUFOKHV-YJBOKZPZSA-N (5r)-3-[4-[1-[(2s)-2,3-dihydroxypropanoyl]-3,6-dihydro-2h-pyridin-4-yl]-3-fluorophenyl]-5-(triazol-1-ylmethyl)-1,3-oxazolidin-2-one Chemical compound C1N(C(=O)[C@@H](O)CO)CCC(C=2C(=CC(=CC=2)N2C(O[C@@H](CN3N=NC=C3)C2)=O)F)=C1 GJMOJANWUFOKHV-YJBOKZPZSA-N 0.000 claims 1
• 150000002118 epoxides Chemical class 0.000 claims 1
• 230000004048 modification Effects 0.000 claims 1
• 238000012986 modification Methods 0.000 claims 1
• 102220024746 rs199473444 Human genes 0.000 claims 1
• 239000003242 anti bacterial agent Substances 0.000 abstract description 7
• YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 365
• XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 216
• OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 165
• 239000000203 mixture Substances 0.000 description 140
• 238000005481 NMR spectroscopy Methods 0.000 description 138
• 239000000047 product Substances 0.000 description 131
• CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 108
• RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 107
• VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 97
• WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 82
• 229910001868 water Inorganic materials 0.000 description 80
• XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 79
• ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 73
• 235000019439 ethyl acetate Nutrition 0.000 description 73
• LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 61
• 239000000243 solution Substances 0.000 description 59
• UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 57
• 229910052943 magnesium sulfate Inorganic materials 0.000 description 54
• 235000019341 magnesium sulphate Nutrition 0.000 description 54
• 239000002904 solvent Substances 0.000 description 53
• VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 49
• 238000003756 stirring Methods 0.000 description 46
• 239000000377 silicon dioxide Substances 0.000 description 43
• AFABGHUZZDYHJO-UHFFFAOYSA-N 2-Methylpentane Chemical compound CCCC(C)C AFABGHUZZDYHJO-UHFFFAOYSA-N 0.000 description 42
• 238000004587 chromatography analysis Methods 0.000 description 41
• IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 39
• ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 39
• 239000007787 solid Substances 0.000 description 32
• 238000001704 evaporation Methods 0.000 description 30
• 239000012267 brine Substances 0.000 description 29
• 230000008020 evaporation Effects 0.000 description 29
• HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 29
• 229910000030 sodium bicarbonate Inorganic materials 0.000 description 28
• 235000017557 sodium bicarbonate Nutrition 0.000 description 28
• WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 24
• 239000000284 extract Substances 0.000 description 22
• YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 21
• 239000011541 reaction mixture Substances 0.000 description 21
• 239000003921 oil Substances 0.000 description 20
• 235000019198 oils Nutrition 0.000 description 20
• 239000011347 resin Substances 0.000 description 20
• 229920005989 resin Polymers 0.000 description 20
• CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 18
• JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 18
• VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 16
• 238000001816 cooling Methods 0.000 description 15
• 239000007858 starting material Substances 0.000 description 15
• KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 14
• MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 14
• 238000001914 filtration Methods 0.000 description 14
• 239000012044 organic layer Substances 0.000 description 14
• BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 14
• 238000000746 purification Methods 0.000 description 14
• 238000010992 reflux Methods 0.000 description 14
• QGZKDVFQNNGYKY-UHFFFAOYSA-N ammonia Natural products N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 13
• KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 12
• DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 12
• 230000000694 effects Effects 0.000 description 12
• 239000002244 precipitate Substances 0.000 description 12
• 125000006570 (C5-C6) heteroaryl group Chemical group 0.000 description 11
• 238000003820 Medium-pressure liquid chromatography Methods 0.000 description 11
• 239000012359 Methanesulfonyl chloride Substances 0.000 description 11
• 239000000706 filtrate Substances 0.000 description 11
• 239000005457 ice water Substances 0.000 description 11
• RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 10
• KJUGUADJHNHALS-UHFFFAOYSA-N 1H-tetrazole Chemical group C=1N=NNN=1 KJUGUADJHNHALS-UHFFFAOYSA-N 0.000 description 10
• QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 10
• PXIPVTKHYLBLMZ-UHFFFAOYSA-N Sodium azide Chemical compound [Na+].[N-]=[N+]=[N-] PXIPVTKHYLBLMZ-UHFFFAOYSA-N 0.000 description 10
• 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 10
• 239000000651 prodrug Substances 0.000 description 10
• 229940002612 prodrug Drugs 0.000 description 10
• 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 10
• QCQCHGYLTSGIGX-GHXANHINSA-N 4-[[(3ar,5ar,5br,7ar,9s,11ar,11br,13as)-5a,5b,8,8,11a-pentamethyl-3a-[(5-methylpyridine-3-carbonyl)amino]-2-oxo-1-propan-2-yl-4,5,6,7,7a,9,10,11,11b,12,13,13a-dodecahydro-3h-cyclopenta[a]chrysen-9-yl]oxy]-2,2-dimethyl-4-oxobutanoic acid Chemical compound N([C@@]12CC[C@@]3(C)[C@]4(C)CC[C@H]5C(C)(C)[C@@H](OC(=O)CC(C)(C)C(O)=O)CC[C@]5(C)[C@H]4CC[C@@H]3C1=C(C(C2)=O)C(C)C)C(=O)C1=CN=CC(C)=C1 QCQCHGYLTSGIGX-GHXANHINSA-N 0.000 description 9
• HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 9
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