HUE034409T2 - Process for the preparation of isoquinoline compounds - Google Patents
Process for the preparation of isoquinoline compounds Download PDFInfo
- Publication number
- HUE034409T2 HUE034409T2 HUE13740184A HUE13740184A HUE034409T2 HU E034409 T2 HUE034409 T2 HU E034409T2 HU E13740184 A HUE13740184 A HU E13740184A HU E13740184 A HUE13740184 A HU E13740184A HU E034409 T2 HUE034409 T2 HU E034409T2
- Authority
- HU
- Hungary
- Prior art keywords
- aryl
- substituted
- alkyl
- heteroaryl
- hydrogen
- Prior art date
Links
- 125000001072 heteroaryl group Chemical group 0.000 claims description 560
- 125000003118 aryl group Chemical group 0.000 claims description 538
- 125000000217 alkyl group Chemical group 0.000 claims description 491
- 125000000623 heterocyclic group Chemical group 0.000 claims description 469
- 239000001257 hydrogen Substances 0.000 claims description 417
- 229910052739 hydrogen Inorganic materials 0.000 claims description 417
- 150000001875 compounds Chemical class 0.000 claims description 411
- 238000006243 chemical reaction Methods 0.000 claims description 356
- 150000002431 hydrogen Chemical class 0.000 claims description 222
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 216
- 238000000034 method Methods 0.000 claims description 200
- 125000003107 substituted aryl group Chemical group 0.000 claims description 190
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 164
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 149
- 239000000203 mixture Substances 0.000 claims description 131
- 125000000547 substituted alkyl group Chemical group 0.000 claims description 128
- 229910052760 oxygen Inorganic materials 0.000 claims description 126
- 239000001301 oxygen Substances 0.000 claims description 120
- -1 sublimates Chemical group 0.000 claims description 110
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 105
- 125000005346 substituted cycloalkyl group Chemical group 0.000 claims description 94
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 85
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 80
- 229910052757 nitrogen Inorganic materials 0.000 claims description 71
- 125000001424 substituent group Chemical group 0.000 claims description 65
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 64
- 238000002360 preparation method Methods 0.000 claims description 58
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 57
- 229960000583 acetic acid Drugs 0.000 claims description 55
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 48
- 229910052799 carbon Inorganic materials 0.000 claims description 47
- 125000003545 alkoxy group Chemical group 0.000 claims description 46
- 229910052736 halogen Inorganic materials 0.000 claims description 46
- 125000004432 carbon atom Chemical group C* 0.000 claims description 45
- 150000002367 halogens Chemical class 0.000 claims description 45
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 45
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 35
- 239000002253 acid Substances 0.000 claims description 35
- 150000003839 salts Chemical class 0.000 claims description 32
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 claims description 31
- 150000001721 carbon Chemical group 0.000 claims description 31
- 238000004519 manufacturing process Methods 0.000 claims description 26
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 22
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 21
- 125000005415 substituted alkoxy group Chemical group 0.000 claims description 21
- 125000000304 alkynyl group Chemical group 0.000 claims description 19
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 18
- 239000004471 Glycine Substances 0.000 claims description 16
- 150000001412 amines Chemical class 0.000 claims description 16
- 239000012362 glacial acetic acid Substances 0.000 claims description 16
- 150000002148 esters Chemical class 0.000 claims description 15
- 239000012298 atmosphere Substances 0.000 claims description 14
- 230000008569 process Effects 0.000 claims description 14
- 239000003054 catalyst Substances 0.000 claims description 12
- 239000000126 substance Substances 0.000 claims description 11
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 10
- 239000012299 nitrogen atmosphere Substances 0.000 claims description 10
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical group [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 7
- 125000004122 cyclic group Chemical group 0.000 claims description 7
- 125000000000 cycloalkoxy group Chemical group 0.000 claims description 7
- 150000007513 acids Chemical class 0.000 claims description 5
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 claims description 4
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 claims description 4
- 108090000623 proteins and genes Proteins 0.000 claims description 4
- 238000010992 reflux Methods 0.000 claims description 4
- 125000005338 substituted cycloalkoxy group Chemical group 0.000 claims description 4
- 239000010936 titanium Substances 0.000 claims description 4
- 102000004190 Enzymes Human genes 0.000 claims description 3
- 108090000790 Enzymes Proteins 0.000 claims description 3
- 150000001732 carboxylic acid derivatives Chemical class 0.000 claims description 3
- 150000002170 ethers Chemical class 0.000 claims description 3
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 3
- 229910052719 titanium Inorganic materials 0.000 claims description 3
- RTAQQCXQSZGOHL-UHFFFAOYSA-N Titanium Chemical compound [Ti] RTAQQCXQSZGOHL-UHFFFAOYSA-N 0.000 claims description 2
- 125000001246 bromo group Chemical group Br* 0.000 claims description 2
- 125000004404 heteroalkyl group Chemical group 0.000 claims description 2
- 230000007062 hydrolysis Effects 0.000 claims description 2
- 238000006460 hydrolysis reaction Methods 0.000 claims description 2
- 229910052703 rhodium Inorganic materials 0.000 claims description 2
- 150000001298 alcohols Chemical class 0.000 claims 3
- 125000001931 aliphatic group Chemical group 0.000 claims 3
- 229920000180 alkyd Polymers 0.000 claims 3
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims 3
- 125000001475 halogen functional group Chemical group 0.000 claims 3
- 150000003573 thiols Chemical class 0.000 claims 3
- 240000004808 Saccharomyces cerevisiae Species 0.000 claims 2
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims 1
- KPZGRMZPZLOPBS-UHFFFAOYSA-N 1,3-dichloro-2,2-bis(chloromethyl)propane Chemical compound ClCC(CCl)(CCl)CCl KPZGRMZPZLOPBS-UHFFFAOYSA-N 0.000 claims 1
- 229940126062 Compound A Drugs 0.000 claims 1
- FKLJPTJMIBLJAV-UHFFFAOYSA-N Compound IV Chemical compound O1N=C(C)C=C1CCCCCCCOC1=CC=C(C=2OCCN=2)C=C1 FKLJPTJMIBLJAV-UHFFFAOYSA-N 0.000 claims 1
- DSLZVSRJTYRBFB-LLEIAEIESA-N D-glucaric acid Chemical compound OC(=O)[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C(O)=O DSLZVSRJTYRBFB-LLEIAEIESA-N 0.000 claims 1
- 206010016717 Fistula Diseases 0.000 claims 1
- NLDMNSXOCDLTTB-UHFFFAOYSA-N Heterophylliin A Natural products O1C2COC(=O)C3=CC(O)=C(O)C(O)=C3C3=C(O)C(O)=C(O)C=C3C(=O)OC2C(OC(=O)C=2C=C(O)C(O)=C(O)C=2)C(O)C1OC(=O)C1=CC(O)=C(O)C(O)=C1 NLDMNSXOCDLTTB-UHFFFAOYSA-N 0.000 claims 1
- 240000007472 Leucaena leucocephala Species 0.000 claims 1
- 235000010643 Leucaena leucocephala Nutrition 0.000 claims 1
- ZOKXTWBITQBERF-UHFFFAOYSA-N Molybdenum Chemical compound [Mo] ZOKXTWBITQBERF-UHFFFAOYSA-N 0.000 claims 1
- 241000630329 Scomberesox saurus saurus Species 0.000 claims 1
- RAHZWNYVWXNFOC-UHFFFAOYSA-N Sulphur dioxide Chemical group O=S=O RAHZWNYVWXNFOC-UHFFFAOYSA-N 0.000 claims 1
- 150000001335 aliphatic alkanes Chemical class 0.000 claims 1
- 125000004183 alkoxy alkyl group Chemical group 0.000 claims 1
- 239000000956 alloy Substances 0.000 claims 1
- 229910045601 alloy Inorganic materials 0.000 claims 1
- KCNKJCHARANTIP-SNAWJCMRSA-N allyl-{4-[3-(4-bromo-phenyl)-benzofuran-6-yloxy]-but-2-enyl}-methyl-amine Chemical compound C=1OC2=CC(OC/C=C/CN(CC=C)C)=CC=C2C=1C1=CC=C(Br)C=C1 KCNKJCHARANTIP-SNAWJCMRSA-N 0.000 claims 1
- 230000000386 athletic effect Effects 0.000 claims 1
- 235000013405 beer Nutrition 0.000 claims 1
- XIWFQDBQMCDYJT-UHFFFAOYSA-M benzyl-dimethyl-tridecylazanium;chloride Chemical compound [Cl-].CCCCCCCCCCCCC[N+](C)(C)CC1=CC=CC=C1 XIWFQDBQMCDYJT-UHFFFAOYSA-M 0.000 claims 1
- 210000004556 brain Anatomy 0.000 claims 1
- ZNHJHNVKZCADIU-UHFFFAOYSA-N carbamic acid;sulfuric acid Chemical compound NC(O)=O.OS(O)(=O)=O ZNHJHNVKZCADIU-UHFFFAOYSA-N 0.000 claims 1
- 125000004965 chloroalkyl group Chemical group 0.000 claims 1
- 238000003776 cleavage reaction Methods 0.000 claims 1
- 239000003086 colorant Substances 0.000 claims 1
- 238000002485 combustion reaction Methods 0.000 claims 1
- 125000004966 cyanoalkyl group Chemical group 0.000 claims 1
- 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 1
- 125000003963 dichloro group Chemical group Cl* 0.000 claims 1
- 229940079593 drug Drugs 0.000 claims 1
- 239000003814 drug Substances 0.000 claims 1
- 230000004064 dysfunction Effects 0.000 claims 1
- 239000000835 fiber Substances 0.000 claims 1
- 230000003890 fistula Effects 0.000 claims 1
- 239000003292 glue Substances 0.000 claims 1
- 125000000592 heterocycloalkyl group Chemical group 0.000 claims 1
- 239000007788 liquid Substances 0.000 claims 1
- 229920002521 macromolecule Polymers 0.000 claims 1
- 229910052750 molybdenum Inorganic materials 0.000 claims 1
- 239000011733 molybdenum Substances 0.000 claims 1
- SYSQUGFVNFXIIT-UHFFFAOYSA-N n-[4-(1,3-benzoxazol-2-yl)phenyl]-4-nitrobenzenesulfonamide Chemical class C1=CC([N+](=O)[O-])=CC=C1S(=O)(=O)NC1=CC=C(C=2OC3=CC=CC=C3N=2)C=C1 SYSQUGFVNFXIIT-UHFFFAOYSA-N 0.000 claims 1
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims 1
- 235000012830 plain croissants Nutrition 0.000 claims 1
- 239000012429 reaction media Substances 0.000 claims 1
- 230000033764 rhythmic process Effects 0.000 claims 1
- 230000007017 scission Effects 0.000 claims 1
- DCKVNWZUADLDEH-UHFFFAOYSA-N sec-butyl acetate Chemical compound CCC(C)OC(C)=O DCKVNWZUADLDEH-UHFFFAOYSA-N 0.000 claims 1
- 238000004513 sizing Methods 0.000 claims 1
- 239000002002 slurry Substances 0.000 claims 1
- 230000000087 stabilizing effect Effects 0.000 claims 1
- 230000003068 static effect Effects 0.000 claims 1
- 150000003431 steroids Chemical class 0.000 claims 1
- 125000004001 thioalkyl group Chemical group 0.000 claims 1
- 230000001131 transforming effect Effects 0.000 claims 1
- 239000005526 vasoconstrictor agent Substances 0.000 claims 1
- 230000003442 weekly effect Effects 0.000 claims 1
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 138
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 114
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 99
- 238000004128 high performance liquid chromatography Methods 0.000 description 73
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 57
- 125000005843 halogen group Chemical group 0.000 description 57
- 239000000243 solution Substances 0.000 description 55
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 52
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 46
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 39
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 39
- 235000011054 acetic acid Nutrition 0.000 description 39
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical group C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 description 32
- ROSDSFDQCJNGOL-UHFFFAOYSA-N Dimethylamine Chemical compound CNC ROSDSFDQCJNGOL-UHFFFAOYSA-N 0.000 description 28
- 210000004027 cell Anatomy 0.000 description 24
- 239000002585 base Substances 0.000 description 23
- 125000002183 isoquinolinyl group Chemical class C1(=NC=CC2=CC=CC=C12)* 0.000 description 23
- 239000000725 suspension Substances 0.000 description 23
- 239000011521 glass Substances 0.000 description 21
- 239000012535 impurity Substances 0.000 description 21
- 239000003153 chemical reaction reagent Substances 0.000 description 19
- 239000002904 solvent Substances 0.000 description 17
- 238000003786 synthesis reaction Methods 0.000 description 17
- 125000004104 aryloxy group Chemical group 0.000 description 16
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 16
- 125000003342 alkenyl group Chemical group 0.000 description 15
- 230000015572 biosynthetic process Effects 0.000 description 15
- 238000005984 hydrogenation reaction Methods 0.000 description 15
- MYMOFIZGZYHOMD-UHFFFAOYSA-N Dioxygen Chemical compound O=O MYMOFIZGZYHOMD-UHFFFAOYSA-N 0.000 description 14
- 238000004587 chromatography analysis Methods 0.000 description 14
- 238000007796 conventional method Methods 0.000 description 14
- 125000005017 substituted alkenyl group Chemical group 0.000 description 14
- 125000004426 substituted alkynyl group Chemical group 0.000 description 14
- 239000007787 solid Substances 0.000 description 12
- 102000003951 Erythropoietin Human genes 0.000 description 11
- 108090000394 Erythropoietin Proteins 0.000 description 11
- 125000004414 alkyl thio group Chemical group 0.000 description 11
- 229940105423 erythropoietin Drugs 0.000 description 11
- 239000010410 layer Substances 0.000 description 11
- OXCMYAYHXIHQOA-UHFFFAOYSA-N potassium;[2-butyl-5-chloro-3-[[4-[2-(1,2,4-triaza-3-azanidacyclopenta-1,4-dien-5-yl)phenyl]phenyl]methyl]imidazol-4-yl]methanol Chemical compound [K+].CCCCC1=NC(Cl)=C(CO)N1CC1=CC=C(C=2C(=CC=CC=2)C2=N[N-]N=N2)C=C1 OXCMYAYHXIHQOA-UHFFFAOYSA-N 0.000 description 11
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 10
- 125000002252 acyl group Chemical group 0.000 description 10
- 125000004423 acyloxy group Chemical group 0.000 description 10
- 238000003556 assay Methods 0.000 description 10
- 238000000605 extraction Methods 0.000 description 10
- 238000001914 filtration Methods 0.000 description 10
- 238000006386 neutralization reaction Methods 0.000 description 10
- 238000001556 precipitation Methods 0.000 description 10
- 125000006239 protecting group Chemical group 0.000 description 10
- 238000003756 stirring Methods 0.000 description 10
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 description 10
- 230000000694 effects Effects 0.000 description 9
- 230000004048 modification Effects 0.000 description 9
- 238000012986 modification Methods 0.000 description 9
- FVAUCKIRQBBSSJ-UHFFFAOYSA-M sodium iodide Chemical compound [Na+].[I-] FVAUCKIRQBBSSJ-UHFFFAOYSA-M 0.000 description 9
- 125000004442 acylamino group Chemical group 0.000 description 8
- 125000000266 alpha-aminoacyl group Chemical group 0.000 description 8
- 125000005110 aryl thio group Chemical group 0.000 description 8
- XPHVSEHSKXETDK-UHFFFAOYSA-N butyl 1-[(dimethylamino)methyl]-4-hydroxy-7-phenylsulfanylisoquinoline-3-carboxylate Chemical compound C1=CC2=C(O)C(C(=O)OCCCC)=NC(CN(C)C)=C2C=C1SC1=CC=CC=C1 XPHVSEHSKXETDK-UHFFFAOYSA-N 0.000 description 8
- 239000000706 filtrate Substances 0.000 description 8
- 125000005553 heteroaryloxy group Chemical group 0.000 description 8
- 125000005844 heterocyclyloxy group Chemical group 0.000 description 8
- VGIVLIHKENZQHQ-UHFFFAOYSA-N n,n,n',n'-tetramethylmethanediamine Chemical compound CN(C)CN(C)C VGIVLIHKENZQHQ-UHFFFAOYSA-N 0.000 description 8
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 8
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 8
- 108090000765 processed proteins & peptides Proteins 0.000 description 8
- 206010021143 Hypoxia Diseases 0.000 description 7
- 239000002841 Lewis acid Substances 0.000 description 7
- 229920001410 Microfiber Polymers 0.000 description 7
- 230000002378 acidificating effect Effects 0.000 description 7
- 125000005325 aryloxy aryl group Chemical group 0.000 description 7
- 125000005368 heteroarylthio group Chemical group 0.000 description 7
- 150000007517 lewis acids Chemical class 0.000 description 7
- 238000003760 magnetic stirring Methods 0.000 description 7
- YTWDBRIDKWWANA-UHFFFAOYSA-N methyl 4-hydroxy-7-phenoxyisoquinoline-3-carboxylate Chemical compound C1=CC2=C(O)C(C(=O)OC)=NC=C2C=C1OC1=CC=CC=C1 YTWDBRIDKWWANA-UHFFFAOYSA-N 0.000 description 7
- 239000003658 microfiber Substances 0.000 description 7
- 238000002156 mixing Methods 0.000 description 7
- 229910052763 palladium Inorganic materials 0.000 description 7
- YOZBGTLTNGAVFU-UHFFFAOYSA-N roxadustat Chemical compound C1=C2C(C)=NC(C(=O)NCC(O)=O)=C(O)C2=CC=C1OC1=CC=CC=C1 YOZBGTLTNGAVFU-UHFFFAOYSA-N 0.000 description 7
- 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 description 7
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 6
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 6
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 6
- 230000008878 coupling Effects 0.000 description 6
- 238000010168 coupling process Methods 0.000 description 6
- 238000005859 coupling reaction Methods 0.000 description 6
- 125000005366 cycloalkylthio group Chemical group 0.000 description 6
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 6
- 208000035475 disorder Diseases 0.000 description 6
- 230000007954 hypoxia Effects 0.000 description 6
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 6
- 210000001519 tissue Anatomy 0.000 description 6
- NYILPNIUMFHXBD-UHFFFAOYSA-N 2-[(4-hydroxy-1-methyl-5-phenoxyisoquinoline-3-carbonyl)amino]acetic acid Chemical compound C1=CC=C2C(C)=NC(C(=O)NCC(O)=O)=C(O)C2=C1OC1=CC=CC=C1 NYILPNIUMFHXBD-UHFFFAOYSA-N 0.000 description 5
- ZLDYCVXVGXUSBB-UHFFFAOYSA-N 2-[(4-hydroxy-1-methyl-6-phenoxyisoquinoline-3-carbonyl)amino]acetic acid Chemical compound C=1C=C2C(C)=NC(C(=O)NCC(O)=O)=C(O)C2=CC=1OC1=CC=CC=C1 ZLDYCVXVGXUSBB-UHFFFAOYSA-N 0.000 description 5
- VZWBCVNPMRVNEF-UHFFFAOYSA-N 2-[(4-hydroxy-1-methyl-8-phenoxyisoquinoline-3-carbonyl)amino]acetic acid Chemical compound C=12C(C)=NC(C(=O)NCC(O)=O)=C(O)C2=CC=CC=1OC1=CC=CC=C1 VZWBCVNPMRVNEF-UHFFFAOYSA-N 0.000 description 5
- MHMUTVWPLKKCIN-UHFFFAOYSA-N 2-[[4-hydroxy-6-(4-methoxyphenoxy)-1-methylisoquinoline-3-carbonyl]amino]acetic acid Chemical compound C1=CC(OC)=CC=C1OC1=CC=C(C(C)=NC(C(=O)NCC(O)=O)=C2O)C2=C1 MHMUTVWPLKKCIN-UHFFFAOYSA-N 0.000 description 5
- JPXYINYXIDIDQY-UHFFFAOYSA-N 2-[[4-hydroxy-7-(4-methoxyphenoxy)-1-methylisoquinoline-3-carbonyl]amino]acetic acid Chemical compound C1=CC(OC)=CC=C1OC1=CC=C(C(O)=C(N=C2C)C(=O)NCC(O)=O)C2=C1 JPXYINYXIDIDQY-UHFFFAOYSA-N 0.000 description 5
- LKVMLPCINLEIRV-UHFFFAOYSA-N 2-[[6-(3,5-difluorophenoxy)-4-hydroxy-1-methylisoquinoline-3-carbonyl]amino]acetic acid Chemical compound C=1C=C2C(C)=NC(C(=O)NCC(O)=O)=C(O)C2=CC=1OC1=CC(F)=CC(F)=C1 LKVMLPCINLEIRV-UHFFFAOYSA-N 0.000 description 5
- AWHJVFRHVNXXDF-UHFFFAOYSA-N 2-[[7-(3,5-difluorophenoxy)-4-hydroxy-1-methylisoquinoline-3-carbonyl]amino]acetic acid Chemical compound C1=C2C(C)=NC(C(=O)NCC(O)=O)=C(O)C2=CC=C1OC1=CC(F)=CC(F)=C1 AWHJVFRHVNXXDF-UHFFFAOYSA-N 0.000 description 5
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 5
- 125000000524 functional group Chemical group 0.000 description 5
- 230000002401 inhibitory effect Effects 0.000 description 5
- 230000007935 neutral effect Effects 0.000 description 5
- 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 description 5
- 239000007858 starting material Substances 0.000 description 5
- 125000001544 thienyl group Chemical group 0.000 description 5
- 238000005160 1H NMR spectroscopy Methods 0.000 description 4
- BTQCNYDOVASZJD-UHFFFAOYSA-N 5-phenoxy-3h-2-benzofuran-1-one Chemical compound C=1C=C2C(=O)OCC2=CC=1OC1=CC=CC=C1 BTQCNYDOVASZJD-UHFFFAOYSA-N 0.000 description 4
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- 150000002894 organic compounds Chemical class 0.000 description 1
- 125000000962 organic group Chemical group 0.000 description 1
- 239000012044 organic layer Substances 0.000 description 1
- 238000006053 organic reaction Methods 0.000 description 1
- 235000006408 oxalic acid Nutrition 0.000 description 1
- 239000007800 oxidant agent Substances 0.000 description 1
- 125000004430 oxygen atom Chemical group O* 0.000 description 1
- 125000003854 p-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Cl 0.000 description 1
- NXJCBFBQEVOTOW-UHFFFAOYSA-L palladium(2+);dihydroxide Chemical compound O[Pd]O NXJCBFBQEVOTOW-UHFFFAOYSA-L 0.000 description 1
- 239000008188 pellet Substances 0.000 description 1
- 239000000137 peptide hydrolase inhibitor Substances 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 125000004934 phenanthridinyl group Chemical group C1(=CC=CC2=NC=C3C=CC=CC3=C12)* 0.000 description 1
- 125000004625 phenanthrolinyl group Chemical group N1=C(C=CC2=CC=C3C=CC=NC3=C12)* 0.000 description 1
- 125000001791 phenazinyl group Chemical group C1(=CC=CC2=NC3=CC=CC=C3N=C12)* 0.000 description 1
- 125000001484 phenothiazinyl group Chemical group C1(=CC=CC=2SC3=CC=CC=C3NC12)* 0.000 description 1
- 125000001644 phenoxazinyl group Chemical group C1(=CC=CC=2OC3=CC=CC=C3NC12)* 0.000 description 1
- 125000004592 phthalazinyl group Chemical group C1(=NN=CC2=CC=CC=C12)* 0.000 description 1
- 125000005545 phthalimidyl group Chemical group 0.000 description 1
- 230000000704 physical effect Effects 0.000 description 1
- 235000015108 pies Nutrition 0.000 description 1
- 125000004193 piperazinyl group Chemical group 0.000 description 1
- 229910052697 platinum Inorganic materials 0.000 description 1
- 229920000642 polymer Polymers 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 102000004196 processed proteins & peptides Human genes 0.000 description 1
- 239000000651 prodrug Substances 0.000 description 1
- 229940002612 prodrug Drugs 0.000 description 1
- 125000001042 pteridinyl group Chemical group N1=C(N=CC2=NC=CN=C12)* 0.000 description 1
- 125000000561 purinyl group Chemical group N1=C(N=C2N=CNC2=C1)* 0.000 description 1
- 125000003373 pyrazinyl group Chemical group 0.000 description 1
- 125000002098 pyridazinyl group Chemical group 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 125000000719 pyrrolidinyl group Chemical group 0.000 description 1
- 125000002294 quinazolinyl group Chemical group N1=C(N=CC2=CC=CC=C12)* 0.000 description 1
- 125000002943 quinolinyl group Chemical group N1=C(C=CC2=CC=CC=C12)* 0.000 description 1
- 125000001567 quinoxalinyl group Chemical group N1=C(C=NC2=CC=CC=C12)* 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 230000008707 rearrangement Effects 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 210000002345 respiratory system Anatomy 0.000 description 1
- 230000004044 response Effects 0.000 description 1
- 239000010948 rhodium Substances 0.000 description 1
- MHOVAHRLVXNVSD-UHFFFAOYSA-N rhodium atom Chemical compound [Rh] MHOVAHRLVXNVSD-UHFFFAOYSA-N 0.000 description 1
- 238000007363 ring formation reaction Methods 0.000 description 1
- 238000007142 ring opening reaction Methods 0.000 description 1
- 229910052707 ruthenium Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- MOTOGHHLNTXPTI-UHFFFAOYSA-M sodium;5-hydroxy-2,5-dioxopentanoate Chemical compound [Na+].OC(=O)CCC(=O)C([O-])=O MOTOGHHLNTXPTI-UHFFFAOYSA-M 0.000 description 1
- 239000012453 solvate Substances 0.000 description 1
- 239000004334 sorbic acid Substances 0.000 description 1
- 230000006641 stabilisation Effects 0.000 description 1
- 238000011105 stabilization Methods 0.000 description 1
- PXQLVRUNWNTZOS-UHFFFAOYSA-N sulfanyl Chemical compound [SH] PXQLVRUNWNTZOS-UHFFFAOYSA-N 0.000 description 1
- 150000003460 sulfonic acids Chemical class 0.000 description 1
- 230000000153 supplemental effect Effects 0.000 description 1
- 125000003718 tetrahydrofuranyl group Chemical group 0.000 description 1
- 125000001984 thiazolidinyl group Chemical group 0.000 description 1
- 125000000335 thiazolyl group Chemical group 0.000 description 1
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- 125000000464 thioxo group Chemical group S=* 0.000 description 1
- 229910052718 tin Inorganic materials 0.000 description 1
- 230000000451 tissue damage Effects 0.000 description 1
- 231100000827 tissue damage Toxicity 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
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- 238000012546 transfer Methods 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
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- 230000014616 translation Effects 0.000 description 1
- 125000004044 trifluoroacetyl group Chemical group FC(C(=O)*)(F)F 0.000 description 1
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 1
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 1
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- 229940116269 uric acid Drugs 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
- C07D217/22—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the nitrogen-containing ring
- C07D217/26—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P39/00—General protective or antinoxious agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
- A61P7/06—Antianaemics
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Toxicology (AREA)
- Diabetes (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Hematology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Other In-Based Heterocyclic Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Epidemiology (AREA)
- Preparation Of Compounds By Using Micro-Organisms (AREA)
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| DE602004031114D1 (de) | 2003-06-06 | 2011-03-03 | Fibrogen Inc | Stickstoffhaltige heteroarylverbindungen und deren verwendungen zur erhoehung des gehaltes von endogenem erythropoietin |
| CN105037323A (zh) | 2008-11-14 | 2015-11-11 | 菲布罗根有限公司 | 作为hif羟化酶抑制剂的苯并噻喃衍生物 |
| US8883823B2 (en) | 2012-07-16 | 2014-11-11 | Fibrogen, Inc. | Crystalline forms of a prolyl hydroxylase inhibitor |
| CN103435546B (zh) | 2012-07-16 | 2016-08-10 | 菲布罗根有限公司 | 制备异喹啉化合物的方法 |
| BR112015001101A2 (pt) | 2012-07-16 | 2017-06-27 | Fibrogen Inc | formas cristalinas de um inibidor de prolil hidroxilase |
| KR20220164069A (ko) | 2013-06-06 | 2022-12-12 | 피브로겐, 인크. | Hif 하이드록실라제 억제자의 약학적 제형 |
| CN103694172A (zh) * | 2013-12-26 | 2014-04-02 | 辽宁亿灵科创生物医药科技有限公司 | 含氮杂芳基化合物的衍生物 |
| CA2959688C (en) | 2014-09-02 | 2024-02-27 | Sunshine Lake Pharma Co., Ltd. | Quinolone compounds and their use to treat diseases related to hypoxia inducible factor and/or erythropoietin |
| WO2016045125A1 (en) * | 2014-09-28 | 2016-03-31 | Merck Sharp & Dohme Corp. | Inhibitors of hif prolyl hydroxylase |
| CN104447547B (zh) * | 2014-11-10 | 2017-04-19 | 苏州康润医药有限公司 | 4‑氨基异喹啉‑8‑甲酸甲酯的合成方法 |
| CN106146490B (zh) * | 2015-03-27 | 2018-10-23 | 沈阳三生制药有限责任公司 | 被芳氧基或杂芳氧基取代的5-羟基-1,7-萘啶化合物、其制备方法及其制药用途 |
| CN104892509B (zh) * | 2015-06-04 | 2018-03-09 | 苏州明锐医药科技有限公司 | 诺得司他的制备方法 |
| CN106187888A (zh) * | 2016-07-18 | 2016-12-07 | 江苏德源药业股份有限公司 | Fg‑4592单晶及其制备方法 |
| CN106478503A (zh) * | 2016-09-29 | 2017-03-08 | 上海勋和医药科技有限公司 | Roxadustat中间体的制备方法 |
| CZ2016627A3 (cs) | 2016-10-07 | 2018-04-18 | Zentiva, K.S. | Způsob přípravy (7-fenoxy-4-hydroxy-1-methylisochinolin-3-karbonyl)glycinu (roxadustatu) a jeho intermediátů založený na souběžném otevírání oxazolového kruhu, štěpení etheru a tvorbě iminu |
| CN107954931B (zh) * | 2016-10-17 | 2021-06-22 | 上海医药集团青岛国风药业股份有限公司 | 一种诺得司他的制备方法 |
| CN110225753B (zh) * | 2017-01-28 | 2022-12-09 | 金凯(辽宁)生命科技股份有限公司 | 用于制备5-苯氧基-1(3h)异苯并呋喃酮的方法 |
| CA3083672A1 (en) * | 2017-12-01 | 2019-06-06 | Dr. Reddy's Laboratories Limited | Process for the preparation of roxadustat and its intermediates |
| CN109956870A (zh) * | 2017-12-14 | 2019-07-02 | 南京卡文迪许生物工程技术有限公司 | 一种罗沙司他的合成方法及其中间体化合物 |
| CN110218184B (zh) * | 2018-03-01 | 2022-09-27 | 广东东阳光药业有限公司 | 诺德司他共晶及其制备方法 |
| CN110272386B (zh) * | 2018-03-16 | 2022-09-09 | 上海医药集团青岛国风药业股份有限公司 | 一种诺得司他的制备方法 |
| CN110526813B (zh) * | 2018-05-24 | 2022-06-28 | 杭州科巢生物科技有限公司 | 异喹啉化合物的制备方法及其中间体 |
| CN110028431B (zh) | 2018-06-05 | 2021-01-08 | 沈阳化工大学 | 一种三氟乙基硫醚（亚砜）取代苯类化合物及其用途 |
| CA3118752A1 (en) | 2018-11-09 | 2020-05-14 | Vivace Therapeutics, Inc. | Bicyclic compounds |
| CN109776415B (zh) * | 2019-03-07 | 2020-11-17 | 福建南方制药股份有限公司 | 一种Roxadustat中间体的制备方法 |
| ES3014444T3 (en) | 2019-04-16 | 2025-04-22 | Vivace Therapeutics Inc | Bicyclic compounds |
| RU2709493C1 (ru) * | 2019-08-01 | 2019-12-18 | Марат Феликсович Фазылов | Способ получения роксадустата |
| US20220340532A1 (en) | 2019-08-07 | 2022-10-27 | Teva Pharmaceuticals International Gmbh | Processes for the preparation of roxadustat and intermediates thereof |
| CN112441975B (zh) * | 2019-09-03 | 2023-10-31 | 西藏嘉信景天药业有限公司 | 一种罗沙司他重要中间体的制备方法 |
| WO2021073623A1 (zh) * | 2019-10-18 | 2021-04-22 | 上海迪赛诺化学制药有限公司 | 一种制备异喹啉酮类化合物的方法 |
| CN112679431B (zh) * | 2019-10-18 | 2023-05-05 | 上海迪赛诺化学制药有限公司 | 一种制备异喹啉酮类化合物的方法 |
| CN112679430B (zh) * | 2019-10-18 | 2023-05-05 | 上海迪赛诺化学制药有限公司 | 一种制备异喹啉酮类化合物的方法 |
| CN113444042A (zh) * | 2020-03-27 | 2021-09-28 | 南京海润医药有限公司 | 一种罗沙司他的制备方法 |
| CN115867537A (zh) * | 2020-04-21 | 2023-03-28 | 迈兰实验室有限公司 | 改进的罗沙司他的制备方法 |
| CN111533691A (zh) * | 2020-06-08 | 2020-08-14 | 重庆三圣实业股份有限公司 | 一种罗沙司他的制备方法 |
| CN113801060B (zh) * | 2020-06-13 | 2025-06-27 | 苏州鹏旭医药科技有限公司 | 一种多取代异喹啉化合物的制备方法 |
| CN114539149A (zh) * | 2020-06-19 | 2022-05-27 | 济川(上海)医学科技有限公司 | 一种含异喹啉环的化合物、其制备方法及其应用 |
| CN112409258B (zh) * | 2020-11-20 | 2025-11-25 | 杭州科巢生物科技有限公司 | 一种罗沙司他的制备方法 |
| CN114644589A (zh) * | 2020-12-17 | 2022-06-21 | 鲁南制药集团股份有限公司 | 一种化合物n-[（4-羟基--1-甲基-3-异喹啉基）羰基]-甘氨酸的制备方法 |
| CN114671807A (zh) * | 2020-12-24 | 2022-06-28 | 联化科技（德州）有限公司 | 一种1-取代异喹啉类化合物的制备方法 |
| US20230101768A1 (en) * | 2021-08-13 | 2023-03-30 | The Board Of Regents Of The University Of Texas System | Method to treat manganese toxicity and manganese-induced parkinsonism in humans |
| CN116178260A (zh) * | 2021-11-26 | 2023-05-30 | 四川国康药业有限公司 | 一种治疗肾性贫血的化合物及其制备方法 |
| CN115124467A (zh) * | 2022-07-11 | 2022-09-30 | 天津力生制药股份有限公司 | 一种罗沙司他关键中间体的制备方法 |
| CN117105862A (zh) * | 2023-07-26 | 2023-11-24 | 北京福元医药股份有限公司 | 一种罗沙司他及其中间体的制备方法 |
| CN117486797A (zh) * | 2023-11-23 | 2024-02-02 | 传健生物医药(厦门)有限公司 | 一种罗沙司他关键中间体及罗沙司他的制备方法 |
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