TWI771827B - 製造６－羧基苯並㗁唑衍生物之有效方法 - Google Patents
製造６－羧基苯並㗁唑衍生物之有效方法 Download PDFInfo
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- TWI771827B TWI771827B TW109144467A TW109144467A TWI771827B TW I771827 B TWI771827 B TW I771827B TW 109144467 A TW109144467 A TW 109144467A TW 109144467 A TW109144467 A TW 109144467A TW I771827 B TWI771827 B TW I771827B
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- Prior art keywords
- compound
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- dichlorophenyl
- acid
- octane
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- 238000000034 method Methods 0.000 title claims description 154
- 230000008569 process Effects 0.000 title claims description 10
- FRNTUFQKHQMLSE-UHFFFAOYSA-N 1,3-benzoxazole-6-carboxylic acid Chemical class OC(=O)C1=CC=C2N=COC2=C1 FRNTUFQKHQMLSE-UHFFFAOYSA-N 0.000 title 1
- 150000001875 compounds Chemical class 0.000 claims abstract description 115
- -1 4-Amino-3-hydroxybenzoic acid compound Chemical class 0.000 claims abstract description 44
- 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 abstract description 32
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 147
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 claims description 82
- 238000006243 chemical reaction Methods 0.000 claims description 69
- 239000007787 solid Substances 0.000 claims description 66
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 49
- 239000002904 solvent Substances 0.000 claims description 49
- 150000003839 salts Chemical class 0.000 claims description 46
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 44
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 42
- NFPYJDZQOKCYIE-UHFFFAOYSA-N 4-amino-3-hydroxybenzoic acid Chemical compound NC1=CC=C(C(O)=O)C=C1O NFPYJDZQOKCYIE-UHFFFAOYSA-N 0.000 claims description 40
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 37
- 239000000203 mixture Substances 0.000 claims description 36
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 claims description 33
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 33
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 32
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical group CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 32
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 30
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 claims description 30
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 29
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 claims description 28
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 27
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 claims description 26
- 238000001914 filtration Methods 0.000 claims description 25
- 238000002360 preparation method Methods 0.000 claims description 23
- 239000003377 acid catalyst Substances 0.000 claims description 22
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 claims description 21
- MBBZMMPHUWSWHV-BDVNFPICSA-N N-methylglucamine Chemical compound CNC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO MBBZMMPHUWSWHV-BDVNFPICSA-N 0.000 claims description 21
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 19
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 claims description 19
- 235000019439 ethyl acetate Nutrition 0.000 claims description 18
- 229960003194 meglumine Drugs 0.000 claims description 18
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 16
- AITPVVOLHGIEAL-UHFFFAOYSA-N 1-(3,5-dichlorophenyl)-4-methyl-2,6,7-trioxabicyclo[2.2.2]octane Chemical compound ClC=1C=C(C=C(C=1)Cl)C12OCC(CO1)(CO2)C AITPVVOLHGIEAL-UHFFFAOYSA-N 0.000 claims description 15
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims description 15
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 15
- 125000006239 protecting group Chemical group 0.000 claims description 15
- RDOXTESZEPMUJZ-UHFFFAOYSA-N anisole Chemical compound COC1=CC=CC=C1 RDOXTESZEPMUJZ-UHFFFAOYSA-N 0.000 claims description 14
- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Chemical compound ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 claims description 14
- 238000000634 powder X-ray diffraction Methods 0.000 claims description 13
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 13
- 239000003054 catalyst Substances 0.000 claims description 12
- 238000003756 stirring Methods 0.000 claims description 12
- 229940098779 methanesulfonic acid Drugs 0.000 claims description 11
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 8
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 claims description 7
- 229910052739 hydrogen Inorganic materials 0.000 claims description 7
- 239000001257 hydrogen Substances 0.000 claims description 7
- 238000002955 isolation Methods 0.000 claims description 7
- UZKWTJUDCOPSNM-UHFFFAOYSA-N methoxybenzene Substances CCCCOC=C UZKWTJUDCOPSNM-UHFFFAOYSA-N 0.000 claims description 7
- MGUDUGADCXBSPR-UHFFFAOYSA-N 1-(3,5-dichlorophenyl)-4-phenyl-2,6,7-trioxabicyclo[2.2.2]octane Chemical compound ClC=1C=C(C=C(C=1)Cl)C12OCC(CO1)(CO2)C1=CC=CC=C1 MGUDUGADCXBSPR-UHFFFAOYSA-N 0.000 claims description 6
- FATHWSKQHXEZKP-UHFFFAOYSA-N 1-(3,5-dichlorophenyl)-4-propan-2-yl-2,6,7-trioxabicyclo[2.2.2]octane Chemical compound ClC=1C=C(C=C(C=1)Cl)C12OCC(CO1)(CO2)C(C)C FATHWSKQHXEZKP-UHFFFAOYSA-N 0.000 claims description 6
- CXKCZFDUOYMOOP-UHFFFAOYSA-N 3,5-dichlorobenzoic acid Chemical compound OC(=O)C1=CC(Cl)=CC(Cl)=C1 CXKCZFDUOYMOOP-UHFFFAOYSA-N 0.000 claims description 6
- PMJKNVMOZFBJPJ-UHFFFAOYSA-N 4-tert-butyl-1-(3,5-dichlorophenyl)-2,6,7-trioxabicyclo[2.2.2]octane Chemical compound C1=C(C=C(C=C1Cl)C12OCC(CO2)(C(C)(C)C)CO1)Cl PMJKNVMOZFBJPJ-UHFFFAOYSA-N 0.000 claims description 6
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical group [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 6
- 125000000217 alkyl group Chemical group 0.000 claims description 6
- 238000001035 drying Methods 0.000 claims description 6
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 6
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 5
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 5
- XTRDLSXSSULJQC-UHFFFAOYSA-N 2-(3,5-dichlorophenyl)-2-methoxy-1,3-dioxolane Chemical compound ClC=1C=C(C=C(C=1)Cl)C1(OCCO1)OC XTRDLSXSSULJQC-UHFFFAOYSA-N 0.000 claims description 4
- HIVMXOVQLQJRGA-UHFFFAOYSA-N 1-(3,5-dichlorophenyl)-2,7,8-trioxabicyclo[3.2.1]octane Chemical compound ClC=1C=C(C=C(C=1)Cl)C12OCCC(CO1)O2 HIVMXOVQLQJRGA-UHFFFAOYSA-N 0.000 claims description 3
- YMNYFSCXEATFLL-UHFFFAOYSA-N 1-(3,5-dichlorophenyl)-4-ethyl-2,6,7-trioxabicyclo[2.2.2]octane Chemical compound ClC=1C=C(C=C(C=1)Cl)C12OCC(CO1)(CO2)CC YMNYFSCXEATFLL-UHFFFAOYSA-N 0.000 claims description 2
- NTIZESTWPVYFNL-UHFFFAOYSA-N Methyl isobutyl ketone Chemical compound CC(C)CC(C)=O NTIZESTWPVYFNL-UHFFFAOYSA-N 0.000 claims description 2
- UIHCLUNTQKBZGK-UHFFFAOYSA-N Methyl isobutyl ketone Natural products CCC(C)C(C)=O UIHCLUNTQKBZGK-UHFFFAOYSA-N 0.000 claims description 2
- 125000003545 alkoxy group Chemical group 0.000 claims description 2
- 125000001475 halogen functional group Chemical group 0.000 claims description 2
- 125000001971 neopentyl group Chemical group [H]C([*])([H])C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 2
- 125000003944 tolyl group Chemical group 0.000 claims description 2
- KAESVJOAVNADME-UHFFFAOYSA-N 1H-pyrrole Natural products C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 claims 20
- 125000005605 benzo group Chemical group 0.000 claims 7
- 150000000190 1,4-diols Chemical class 0.000 claims 3
- 150000001335 aliphatic alkanes Chemical class 0.000 claims 3
- 239000007983 Tris buffer Substances 0.000 claims 1
- 150000003851 azoles Chemical class 0.000 claims 1
- 150000002905 orthoesters Chemical class 0.000 abstract description 15
- BCMCBBGGLRIHSE-UHFFFAOYSA-N 1,3-benzoxazole Chemical class C1=CC=C2OC=NC2=C1 BCMCBBGGLRIHSE-UHFFFAOYSA-N 0.000 abstract description 5
- 238000004519 manufacturing process Methods 0.000 abstract description 5
- 239000011541 reaction mixture Substances 0.000 description 50
- 239000000243 solution Substances 0.000 description 44
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 39
- 239000000047 product Substances 0.000 description 39
- 239000002585 base Substances 0.000 description 24
- 239000002253 acid Substances 0.000 description 23
- FVGIGEHGGDHKTI-UHFFFAOYSA-N COC(OC)(OC)c1cc(Cl)cc(Cl)c1 Chemical compound COC(OC)(OC)c1cc(Cl)cc(Cl)c1 FVGIGEHGGDHKTI-UHFFFAOYSA-N 0.000 description 22
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 21
- TXEIIPDJKFWEEC-UHFFFAOYSA-N tafamidis Chemical class O1C2=CC(C(=O)O)=CC=C2N=C1C1=CC(Cl)=CC(Cl)=C1 TXEIIPDJKFWEEC-UHFFFAOYSA-N 0.000 description 18
- 238000004128 high performance liquid chromatography Methods 0.000 description 17
- JMMWKPVZQRWMSS-UHFFFAOYSA-N isopropanol acetate Natural products CC(C)OC(C)=O JMMWKPVZQRWMSS-UHFFFAOYSA-N 0.000 description 17
- 238000005160 1H NMR spectroscopy Methods 0.000 description 15
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 15
- 239000000706 filtrate Substances 0.000 description 14
- 238000005481 NMR spectroscopy Methods 0.000 description 12
- 238000005406 washing Methods 0.000 description 11
- 239000000463 material Substances 0.000 description 10
- 230000015572 biosynthetic process Effects 0.000 description 9
- 239000013078 crystal Substances 0.000 description 9
- 238000010966 qNMR Methods 0.000 description 9
- 108010071690 Prealbumin Proteins 0.000 description 8
- 102000009190 Transthyretin Human genes 0.000 description 8
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-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
- 238000003786 synthesis reaction Methods 0.000 description 8
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 8
- 238000004458 analytical method Methods 0.000 description 7
- 239000006227 byproduct Substances 0.000 description 7
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N dimethyl sulfoxide Natural products CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 7
- 229940011051 isopropyl acetate Drugs 0.000 description 7
- GWYFCOCPABKNJV-UHFFFAOYSA-N isovaleric acid Chemical compound CC(C)CC(O)=O GWYFCOCPABKNJV-UHFFFAOYSA-N 0.000 description 7
- 238000001294 liquid chromatography-tandem mass spectrometry Methods 0.000 description 7
- 239000002244 precipitate Substances 0.000 description 7
- 239000002002 slurry Substances 0.000 description 7
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 6
- 230000008859 change Effects 0.000 description 6
- 239000007788 liquid Substances 0.000 description 6
- KZMGYPLQYOPHEL-UHFFFAOYSA-N Boron trifluoride etherate Chemical compound FB(F)F.CCOCC KZMGYPLQYOPHEL-UHFFFAOYSA-N 0.000 description 5
- 238000002425 crystallisation Methods 0.000 description 5
- 238000010438 heat treatment Methods 0.000 description 5
- 150000004677 hydrates Chemical class 0.000 description 5
- 239000010410 layer Substances 0.000 description 5
- 238000010992 reflux Methods 0.000 description 5
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 4
- PXXLQQDIFVPNMP-UHFFFAOYSA-N 3-(diethylcarbamoyl)benzoic acid Chemical compound CCN(CC)C(=O)C1=CC=CC(C(O)=O)=C1 PXXLQQDIFVPNMP-UHFFFAOYSA-N 0.000 description 4
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 4
- 230000008025 crystallization Effects 0.000 description 4
- 238000004821 distillation Methods 0.000 description 4
- 239000012535 impurity Substances 0.000 description 4
- TVMXDCGIABBOFY-UHFFFAOYSA-N octane Chemical compound CCCCCCCC TVMXDCGIABBOFY-UHFFFAOYSA-N 0.000 description 4
- 239000012044 organic layer Substances 0.000 description 4
- 235000015320 potassium carbonate Nutrition 0.000 description 4
- 229910000027 potassium carbonate Inorganic materials 0.000 description 4
- 239000012453 solvate Substances 0.000 description 4
- 239000000725 suspension Substances 0.000 description 4
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 3
- VTUKKVHSZDBIPA-UHFFFAOYSA-N 3,5,8-trioxabicyclo[2.2.2]octane Chemical compound O1CC2COC1OC2 VTUKKVHSZDBIPA-UHFFFAOYSA-N 0.000 description 3
- 238000009835 boiling Methods 0.000 description 3
- 238000001460 carbon-13 nuclear magnetic resonance spectrum Methods 0.000 description 3
- 238000001816 cooling Methods 0.000 description 3
- 239000003814 drug Substances 0.000 description 3
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 3
- 238000002474 experimental method Methods 0.000 description 3
- 238000003306 harvesting Methods 0.000 description 3
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 3
- 231100000252 nontoxic Toxicity 0.000 description 3
- 230000003000 nontoxic effect Effects 0.000 description 3
- 239000012071 phase Substances 0.000 description 3
- ILJSQTXMGCGYMG-UHFFFAOYSA-N triacetic acid Chemical compound CC(=O)CC(=O)CC(O)=O ILJSQTXMGCGYMG-UHFFFAOYSA-N 0.000 description 3
- KDHYEQYWOYBACO-UHFFFAOYSA-N 2-(hydroxymethyl)-2-propan-2-ylpropane-1,3-diol Chemical compound CC(C)C(CO)(CO)CO KDHYEQYWOYBACO-UHFFFAOYSA-N 0.000 description 2
- MSWZFWKMSRAUBD-IVMDWMLBSA-N 2-amino-2-deoxy-D-glucopyranose Chemical compound N[C@H]1C(O)O[C@H](CO)[C@@H](O)[C@@H]1O MSWZFWKMSRAUBD-IVMDWMLBSA-N 0.000 description 2
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 description 2
- LTNUSYNQZJZUSY-UHFFFAOYSA-N 3,3-dimethylbutanal Chemical compound CC(C)(C)CC=O LTNUSYNQZJZUSY-UHFFFAOYSA-N 0.000 description 2
- IJFXRHURBJZNAO-UHFFFAOYSA-N 3-hydroxybenzoic acid Chemical compound OC(=O)C1=CC=CC(O)=C1 IJFXRHURBJZNAO-UHFFFAOYSA-N 0.000 description 2
- HSJKGGMUJITCBW-UHFFFAOYSA-N 3-hydroxybutanal Chemical compound CC(O)CC=O HSJKGGMUJITCBW-UHFFFAOYSA-N 0.000 description 2
- YGHRJJRRZDOVPD-UHFFFAOYSA-N 3-methylbutanal Chemical compound CC(C)CC=O YGHRJJRRZDOVPD-UHFFFAOYSA-N 0.000 description 2
- 208000031229 Cardiomyopathies Diseases 0.000 description 2
- UKNMTNQYWPULNX-OBGWFSINSA-N ClC=1C=C(C=C(C=1)Cl)/C(/OC)=[N+](\C1=CC=CC=C1)/C Chemical compound ClC=1C=C(C=C(C=1)Cl)/C(/OC)=[N+](\C1=CC=CC=C1)/C UKNMTNQYWPULNX-OBGWFSINSA-N 0.000 description 2
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 2
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 2
- XUIIKFGFIJCVMT-LBPRGKRZSA-N L-thyroxine Chemical compound IC1=CC(C[C@H]([NH3+])C([O-])=O)=CC(I)=C1OC1=CC(I)=C(O)C(I)=C1 XUIIKFGFIJCVMT-LBPRGKRZSA-N 0.000 description 2
- AFBPFSWMIHJQDM-UHFFFAOYSA-N N-methylaniline Chemical compound CNC1=CC=CC=C1 AFBPFSWMIHJQDM-UHFFFAOYSA-N 0.000 description 2
- 206010036105 Polyneuropathy Diseases 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- 229940121767 Transthyretin stabilizer Drugs 0.000 description 2
- YZCKVEUIGOORGS-NJFSPNSNSA-N Tritium Chemical compound [3H] YZCKVEUIGOORGS-NJFSPNSNSA-N 0.000 description 2
- 238000002441 X-ray diffraction Methods 0.000 description 2
- 150000007513 acids Chemical class 0.000 description 2
- JUHORIMYRDESRB-UHFFFAOYSA-N benzathine Chemical compound C=1C=CC=CC=1CNCCNCC1=CC=CC=C1 JUHORIMYRDESRB-UHFFFAOYSA-N 0.000 description 2
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 2
- MSWZFWKMSRAUBD-UHFFFAOYSA-N beta-D-galactosamine Natural products NC1C(O)OC(CO)C(O)C1O MSWZFWKMSRAUBD-UHFFFAOYSA-N 0.000 description 2
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- OEYIOHPDSNJKLS-UHFFFAOYSA-N choline Chemical compound C[N+](C)(C)CCO OEYIOHPDSNJKLS-UHFFFAOYSA-N 0.000 description 2
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- ZBCBWPMODOFKDW-UHFFFAOYSA-N diethanolamine Chemical compound OCCNCCO ZBCBWPMODOFKDW-UHFFFAOYSA-N 0.000 description 2
- HPNMFZURTQLUMO-UHFFFAOYSA-N diethylamine Chemical compound CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 description 2
- 238000004090 dissolution Methods 0.000 description 2
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- 229960002442 glucosamine Drugs 0.000 description 2
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 2
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- DTUQWGWMVIHBKE-UHFFFAOYSA-N phenylacetaldehyde Chemical compound O=CCC1=CC=CC=C1 DTUQWGWMVIHBKE-UHFFFAOYSA-N 0.000 description 2
- 230000000704 physical effect Effects 0.000 description 2
- 230000007824 polyneuropathy Effects 0.000 description 2
- 239000004810 polytetrafluoroethylene Substances 0.000 description 2
- 229920001343 polytetrafluoroethylene Polymers 0.000 description 2
- 230000017854 proteolysis Effects 0.000 description 2
- 238000000425 proton nuclear magnetic resonance spectrum Methods 0.000 description 2
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Images
Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
- C07D263/52—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings condensed with carbocyclic rings or ring systems
- C07D263/54—Benzoxazoles; Hydrogenated benzoxazoles
- C07D263/56—Benzoxazoles; Hydrogenated benzoxazoles with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 2
- C07D263/57—Aryl or substituted aryl radicals
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/42—Oxazoles
- A61K31/423—Oxazoles condensed with carbocyclic rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D317/00—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms
- C07D317/08—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3
- C07D317/10—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 not condensed with other rings
- C07D317/32—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 not condensed with other rings 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 ring carbon atoms
- C07D317/34—Oxygen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D493/00—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system
- C07D493/12—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system in which the condensed system contains three hetero rings
- C07D493/18—Bridged systems
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Epidemiology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Medicinal Chemistry (AREA)
- Public Health (AREA)
- Pharmacology & Pharmacy (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
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| US11970468B1 (en) | 2023-10-23 | 2024-04-30 | King Faisal University | 2-(benzo[d]oxazol-2-yl)-N′-(3,5-dichlorobenzoyloxy)acetimidamide as an antimicrobial compound |
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| WO2004056315A2 (en) * | 2002-12-19 | 2004-07-08 | The Scripps Research Institute | Compositions and methods for stabilizing transthyretin and inhibiting transthyretin misfolding |
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| GB8703975D0 (en) | 1987-02-20 | 1987-03-25 | Wellcome Found | Pesticidal compounds |
| GB8809316D0 (en) * | 1987-05-11 | 1988-05-25 | Ici America Inc | Heterocyclic ketones |
| JP5419545B2 (ja) | 2009-05-25 | 2014-02-19 | 株式会社トクヤマ | オルトエステル化合物の製造方法 |
| US8168683B2 (en) | 2009-10-15 | 2012-05-01 | E. I. Du Pont De Nemours And Company | Fluorinated vinylidene cationic surfactant |
| TWI550071B (zh) * | 2011-03-25 | 2016-09-21 | 捷恩智股份有限公司 | 原酸酯化合物、液晶組成物及液晶顯示元件 |
| RU2586330C2 (ru) * | 2011-09-16 | 2016-06-10 | Пфайзер Инк. | Твердые формы ингибитора диссоциации транстиретина |
| US9499527B2 (en) * | 2012-05-10 | 2016-11-22 | Cellix Bio Private Limited | Compositions and methods for the treatment of familial amyloid polyneuropathy |
| PT4349406T (pt) * | 2014-09-08 | 2026-02-04 | Pfizer | Formas sólidas cristalinas de 6-carboxi-2-(3,5-diclorofenil)-benzoxazol para utilização como medicamento |
| CN107344927A (zh) * | 2016-05-05 | 2017-11-14 | 苏州晶云药物科技有限公司 | Tafamidis葡甲胺盐的晶型E及其制备方法和用途 |
| US10766893B2 (en) * | 2017-12-20 | 2020-09-08 | H. Lundbeck A/S | 1H-pyrazolo[4,3-b]pyridines as PDE1 inhibitors |
| EP4077287B1 (en) | 2019-12-20 | 2025-11-19 | Pfizer Ireland Pharmaceuticals Unlimited Company | Efficient process for making 6-carboxy benzoxazole derivatives |
-
2020
- 2020-12-16 EP EP20828342.4A patent/EP4077287B1/en active Active
- 2020-12-16 WO PCT/IB2020/062040 patent/WO2021124158A1/en not_active Ceased
- 2020-12-16 CA CA3165298A patent/CA3165298A1/en active Pending
- 2020-12-16 TW TW109144467A patent/TWI771827B/zh active
- 2020-12-16 CN CN202080096991.1A patent/CN115135639B/zh active Active
- 2020-12-16 JP JP2022537301A patent/JP2023507399A/ja active Pending
- 2020-12-16 BR BR112022012097A patent/BR112022012097A2/pt not_active Application Discontinuation
- 2020-12-16 MX MX2022007787A patent/MX2022007787A/es unknown
- 2020-12-16 HR HRP20251570TT patent/HRP20251570T1/hr unknown
- 2020-12-16 KR KR1020227024529A patent/KR20220114626A/ko not_active Withdrawn
- 2020-12-16 US US17/757,740 patent/US12410145B2/en active Active
- 2020-12-16 ES ES20828342T patent/ES3055912T3/es active Active
- 2020-12-16 IL IL294115A patent/IL294115A/en unknown
- 2020-12-16 AU AU2020406455A patent/AU2020406455B2/en active Active
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2004056315A2 (en) * | 2002-12-19 | 2004-07-08 | The Scripps Research Institute | Compositions and methods for stabilizing transthyretin and inhibiting transthyretin misfolding |
| US7214696B2 (en) * | 2002-12-19 | 2007-05-08 | The Scripps Research Institute | Compositions and methods for stabilizing transthyretin and inhibiting transthyretin misfolding |
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| Title |
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| 期刊 Firlin et al, Green Chemistry, 2019, 21(19), p5298-5305 Continuous flow/waste-minimized synthesis of benzoxazoles catalysed by heterogeneous manganese systems Green Chemistry 21 Royal Society of Chemistry 2019 全文 |
| 期刊 Joncker et al, Bioorganic & Medicinal Chemistry Letters, 2012,22, p4998-5002 Benzoxazole and benzothiazole amides as novel pharmacokinetic enhancers of HIV protease inhibitors Bioorganic & Medicinal Chemistry Letters 22 Elsevier 2012 5001;期刊 Firlin et al, Green Chemistry, 2019, 21(19), p5298-5305 Continuous flow/waste-minimized synthesis of benzoxazoles catalysed by heterogeneous manganese systems Green Chemistry 21 Royal Society of Chemistry 2019 全文 * |
Also Published As
| Publication number | Publication date |
|---|---|
| ES3055912T3 (en) | 2026-02-16 |
| AU2020406455B2 (en) | 2024-02-15 |
| TW202136222A (zh) | 2021-10-01 |
| EP4077287A1 (en) | 2022-10-26 |
| BR112022012097A2 (pt) | 2022-08-30 |
| JP2023507399A (ja) | 2023-02-22 |
| CN115135639A (zh) | 2022-09-30 |
| US20230090609A1 (en) | 2023-03-23 |
| EP4077287C0 (en) | 2025-11-19 |
| HRP20251570T1 (hr) | 2026-01-30 |
| WO2021124158A1 (en) | 2021-06-24 |
| EP4077287B1 (en) | 2025-11-19 |
| MX2022007787A (es) | 2022-07-19 |
| US12410145B2 (en) | 2025-09-09 |
| KR20220114626A (ko) | 2022-08-17 |
| IL294115A (en) | 2022-08-01 |
| CN115135639B (zh) | 2025-04-01 |
| AU2020406455A1 (en) | 2022-07-14 |
| CA3165298A1 (en) | 2021-06-24 |
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