JP2022505189A - 新規な工程 - Google Patents
新規な工程 Download PDFInfo
- Publication number
- JP2022505189A JP2022505189A JP2021521138A JP2021521138A JP2022505189A JP 2022505189 A JP2022505189 A JP 2022505189A JP 2021521138 A JP2021521138 A JP 2021521138A JP 2021521138 A JP2021521138 A JP 2021521138A JP 2022505189 A JP2022505189 A JP 2022505189A
- Authority
- JP
- Japan
- Prior art keywords
- pyrazole
- isopropyl
- hexahydro
- reaction mixture
- added
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- 238000000034 method Methods 0.000 title claims abstract description 37
- 150000003839 salts Chemical class 0.000 claims abstract description 29
- 239000002904 solvent Substances 0.000 claims description 62
- 238000004128 high performance liquid chromatography Methods 0.000 claims description 52
- WVCORPDIFAZDQV-UHFFFAOYSA-N 1,2,3,5,6,7-hexahydro-s-indacen-4-amine Chemical compound NC1=C2CCCC2=CC2=C1CCC2 WVCORPDIFAZDQV-UHFFFAOYSA-N 0.000 claims description 26
- OQIHVCDANZPVDQ-UHFFFAOYSA-N 3-iodo-1-propan-2-ylpyrazole Chemical compound CC(C)N1C=CC(I)=N1 OQIHVCDANZPVDQ-UHFFFAOYSA-N 0.000 claims description 22
- PQNFLJBBNBOBRQ-UHFFFAOYSA-N indane Chemical compound C1=CC=C2CCCC2=C1 PQNFLJBBNBOBRQ-UHFFFAOYSA-N 0.000 claims description 20
- MECWXEINLHIGIW-UHFFFAOYSA-N 1-propan-2-ylpyrazol-3-amine Chemical compound CC(C)N1C=CC(N)=N1 MECWXEINLHIGIW-UHFFFAOYSA-N 0.000 claims description 15
- GHNBPPOAWRAEJT-UHFFFAOYSA-N 1-propan-2-ylpyrazole-3-sulfonamide Chemical compound C(C)(C)N1N=C(C=C1)S(=O)(=O)N GHNBPPOAWRAEJT-UHFFFAOYSA-N 0.000 claims description 14
- BVADIEGMRNCQSZ-UHFFFAOYSA-N 3-nitro-1-propan-2-ylpyrazole Chemical compound CC(C)N1C=CC([N+]([O-])=O)=N1 BVADIEGMRNCQSZ-UHFFFAOYSA-N 0.000 claims description 12
- MZRUFMBFIKGOAL-UHFFFAOYSA-N 5-nitro-1h-pyrazole Chemical compound [O-][N+](=O)C1=CC=NN1 MZRUFMBFIKGOAL-UHFFFAOYSA-N 0.000 claims description 11
- 239000002253 acid Substances 0.000 claims description 11
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 11
- IEJIGPNLZYLLBP-UHFFFAOYSA-N dimethyl carbonate Chemical compound COC(=O)OC IEJIGPNLZYLLBP-UHFFFAOYSA-N 0.000 claims description 10
- MKAURAAKBUQECD-UHFFFAOYSA-N 8-nitro-3,5,6,7-tetrahydro-2h-s-indacen-1-one Chemical compound [O-][N+](=O)C1=C2CCCC2=CC2=C1C(=O)CC2 MKAURAAKBUQECD-UHFFFAOYSA-N 0.000 claims description 8
- 125000000217 alkyl group Chemical group 0.000 claims description 6
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims description 6
- -1 (1,2,3,5,6,7-hexahydro-s-indacene-4-yl) carbamoyl Chemical group 0.000 claims description 5
- NBBJYMSMWIIQGU-UHFFFAOYSA-N Propionic aldehyde Chemical compound CCC=O NBBJYMSMWIIQGU-UHFFFAOYSA-N 0.000 claims description 4
- IZLJNKUQAFQERG-UHFFFAOYSA-N 4-nitro-3,5,6,7-tetrahydro-2h-s-indacen-1-one Chemical compound [O-][N+](=O)C1=C2CCCC2=CC2=C1CCC2=O IZLJNKUQAFQERG-UHFFFAOYSA-N 0.000 claims description 3
- XWHULFGKSFGDAD-UHFFFAOYSA-N 1-(2,3-dihydro-1h-inden-5-yl)propan-1-one Chemical class CCC(=O)C1=CC=C2CCCC2=C1 XWHULFGKSFGDAD-UHFFFAOYSA-N 0.000 claims description 2
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 abstract description 24
- MTOUOUSKXWSTAX-UHFFFAOYSA-N 1-(1,2,3,5,6,7-hexahydro-s-indacen-4-yl)-3-(1-propan-2-ylpyrazol-3-yl)sulfonylurea Chemical compound C1CCC2=C(C=3CCCC=3C=C12)NC(=O)NS(=O)(=O)C1=NN(C=C1)C(C)C MTOUOUSKXWSTAX-UHFFFAOYSA-N 0.000 abstract description 23
- 201000010099 disease Diseases 0.000 abstract description 14
- 150000001875 compounds Chemical class 0.000 abstract description 11
- 208000035475 disorder Diseases 0.000 abstract description 10
- 239000008194 pharmaceutical composition Substances 0.000 abstract description 10
- 108010001946 Pyrin Domain-Containing 3 Protein NLR Family Proteins 0.000 abstract description 7
- 230000002265 prevention Effects 0.000 abstract description 4
- 230000005764 inhibitory process Effects 0.000 abstract description 3
- 102000000874 Pyrin Domain-Containing 3 Protein NLR Family Human genes 0.000 abstract 1
- 238000010586 diagram Methods 0.000 abstract 1
- 239000011541 reaction mixture Substances 0.000 description 121
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 93
- 238000006243 chemical reaction Methods 0.000 description 72
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 64
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 48
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 48
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 37
- 239000000203 mixture Substances 0.000 description 34
- 239000000243 solution Substances 0.000 description 34
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 32
- 239000012044 organic layer Substances 0.000 description 29
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 27
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 24
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 24
- 239000010410 layer Substances 0.000 description 24
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 22
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 22
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 21
- 239000000047 product Substances 0.000 description 18
- 239000007787 solid Substances 0.000 description 18
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 17
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 16
- 238000005160 1H NMR spectroscopy Methods 0.000 description 15
- 229910052763 palladium Inorganic materials 0.000 description 15
- NLKNQRATVPKPDG-UHFFFAOYSA-M potassium iodide Chemical compound [K+].[I-] NLKNQRATVPKPDG-UHFFFAOYSA-M 0.000 description 15
- 239000012265 solid product Substances 0.000 description 14
- VTEOHCVWRXWJEI-UHFFFAOYSA-N 3-chloro-1-(2,3-dihydro-1h-inden-5-yl)propan-1-one Chemical compound ClCCC(=O)C1=CC=C2CCCC2=C1 VTEOHCVWRXWJEI-UHFFFAOYSA-N 0.000 description 13
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 13
- 239000003054 catalyst Substances 0.000 description 13
- MYSIWXGHUDXAJD-UHFFFAOYSA-N methyl N-(1-propan-2-ylpyrazol-3-yl)sulfonylcarbamate Chemical group C1=CC(=NN1C(C)C)S(=O)(=O)NC(=O)OC MYSIWXGHUDXAJD-UHFFFAOYSA-N 0.000 description 13
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 12
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 12
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 12
- 239000012467 final product Substances 0.000 description 12
- LPXPTNMVRIOKMN-UHFFFAOYSA-M sodium nitrite Chemical compound [Na+].[O-]N=O LPXPTNMVRIOKMN-UHFFFAOYSA-M 0.000 description 12
- 238000003109 Karl Fischer titration Methods 0.000 description 11
- 239000002585 base Substances 0.000 description 11
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 11
- 239000011734 sodium Substances 0.000 description 11
- 239000000725 suspension Substances 0.000 description 11
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 10
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 10
- 229910052739 hydrogen Inorganic materials 0.000 description 10
- 239000001257 hydrogen Substances 0.000 description 10
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 10
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 9
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 8
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 8
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 description 8
- 102100022691 NACHT, LRR and PYD domains-containing protein 3 Human genes 0.000 description 7
- 239000003153 chemical reaction reagent Substances 0.000 description 7
- 239000012043 crude product Substances 0.000 description 7
- 239000012954 diazonium Substances 0.000 description 7
- IJGRMHOSHXDMSA-UHFFFAOYSA-O diazynium Chemical compound [NH+]#N IJGRMHOSHXDMSA-UHFFFAOYSA-O 0.000 description 7
- 238000003756 stirring Methods 0.000 description 7
- JWUJQDFVADABEY-UHFFFAOYSA-N 2-methyltetrahydrofuran Chemical compound CC1CCCO1 JWUJQDFVADABEY-UHFFFAOYSA-N 0.000 description 6
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical group [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 6
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 6
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 6
- PXHVJJICTQNCMI-UHFFFAOYSA-N Nickel Chemical compound [Ni] PXHVJJICTQNCMI-UHFFFAOYSA-N 0.000 description 6
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 6
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 6
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 6
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 6
- RAHZWNYVWXNFOC-UHFFFAOYSA-N Sulphur dioxide Chemical compound O=S=O RAHZWNYVWXNFOC-UHFFFAOYSA-N 0.000 description 6
- 229910052799 carbon Inorganic materials 0.000 description 6
- 239000000460 chlorine Chemical group 0.000 description 6
- 229910052801 chlorine Inorganic materials 0.000 description 6
- 239000007789 gas Substances 0.000 description 6
- 239000000543 intermediate Substances 0.000 description 6
- 229910052751 metal Inorganic materials 0.000 description 6
- 239000002184 metal Substances 0.000 description 6
- 235000010288 sodium nitrite Nutrition 0.000 description 6
- LXDKNEXOGZDIAC-UHFFFAOYSA-N 3,5,6,7-tetrahydro-2h-s-indacen-1-one Chemical compound C1=C2C(=O)CCC2=CC2=C1CCC2 LXDKNEXOGZDIAC-UHFFFAOYSA-N 0.000 description 5
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical group [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 5
- 239000007818 Grignard reagent Substances 0.000 description 5
- 238000012369 In process control Methods 0.000 description 5
- DQPBABKTKYNPMH-UHFFFAOYSA-N amino hydrogen sulfate Chemical compound NOS(O)(=O)=O DQPBABKTKYNPMH-UHFFFAOYSA-N 0.000 description 5
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Chemical group BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 5
- 229910052794 bromium Inorganic materials 0.000 description 5
- 239000012065 filter cake Substances 0.000 description 5
- 239000000706 filtrate Substances 0.000 description 5
- 150000004795 grignard reagents Chemical class 0.000 description 5
- 238000010965 in-process control Methods 0.000 description 5
- IUYHWZFSGMZEOG-UHFFFAOYSA-M magnesium;propane;chloride Chemical group [Mg+2].[Cl-].C[CH-]C IUYHWZFSGMZEOG-UHFFFAOYSA-M 0.000 description 5
- 238000004519 manufacturing process Methods 0.000 description 5
- GBMDVOWEEQVZKZ-UHFFFAOYSA-N methanol;hydrate Chemical compound O.OC GBMDVOWEEQVZKZ-UHFFFAOYSA-N 0.000 description 5
- 239000012299 nitrogen atmosphere Substances 0.000 description 5
- 239000003880 polar aprotic solvent Substances 0.000 description 5
- 239000002798 polar solvent Substances 0.000 description 5
- 229910000027 potassium carbonate Inorganic materials 0.000 description 5
- AKHNMLFCWUSKQB-UHFFFAOYSA-L sodium thiosulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=S AKHNMLFCWUSKQB-UHFFFAOYSA-L 0.000 description 5
- 235000019345 sodium thiosulphate Nutrition 0.000 description 5
- INUNLMUAPJVRME-UHFFFAOYSA-N 3-chloropropanoyl chloride Chemical compound ClCCC(Cl)=O INUNLMUAPJVRME-UHFFFAOYSA-N 0.000 description 4
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 4
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 4
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 4
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 description 4
- GZDFHIJNHHMENY-UHFFFAOYSA-N Dimethyl dicarbonate Chemical compound COC(=O)OC(=O)OC GZDFHIJNHHMENY-UHFFFAOYSA-N 0.000 description 4
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical group C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 4
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 description 4
- OFBQJSOFQDEBGM-UHFFFAOYSA-N Pentane Chemical compound CCCCC OFBQJSOFQDEBGM-UHFFFAOYSA-N 0.000 description 4
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 4
- 239000012267 brine Substances 0.000 description 4
- 239000003610 charcoal Substances 0.000 description 4
- 208000022993 cryopyrin-associated periodic syndrome Diseases 0.000 description 4
- 235000010300 dimethyl dicarbonate Nutrition 0.000 description 4
- 235000019253 formic acid Nutrition 0.000 description 4
- 239000011630 iodine Substances 0.000 description 4
- 229910052740 iodine Inorganic materials 0.000 description 4
- FMKOJHQHASLBPH-UHFFFAOYSA-N isopropyl iodide Chemical compound CC(C)I FMKOJHQHASLBPH-UHFFFAOYSA-N 0.000 description 4
- 239000012452 mother liquor Substances 0.000 description 4
- 125000001979 organolithium group Chemical group 0.000 description 4
- 239000011591 potassium Substances 0.000 description 4
- 229910052700 potassium Inorganic materials 0.000 description 4
- 238000000746 purification Methods 0.000 description 4
- 229910052708 sodium Inorganic materials 0.000 description 4
- MFRIHAYPQRLWNB-UHFFFAOYSA-N sodium tert-butoxide Chemical compound [Na+].CC(C)(C)[O-] MFRIHAYPQRLWNB-UHFFFAOYSA-N 0.000 description 4
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 4
- WMOVHXAZOJBABW-UHFFFAOYSA-N tert-butyl acetate Chemical compound CC(=O)OC(C)(C)C WMOVHXAZOJBABW-UHFFFAOYSA-N 0.000 description 4
- 239000003643 water by type Substances 0.000 description 4
- ATRRKUHOCOJYRX-UHFFFAOYSA-N Ammonium bicarbonate Chemical compound [NH4+].OC([O-])=O ATRRKUHOCOJYRX-UHFFFAOYSA-N 0.000 description 3
- 229910000013 Ammonium bicarbonate Inorganic materials 0.000 description 3
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 3
- 239000004215 Carbon black (E152) Substances 0.000 description 3
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 3
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 3
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 3
- WTKZEGDFNFYCGP-UHFFFAOYSA-N Pyrazole Chemical compound C=1C=NNC=1 WTKZEGDFNFYCGP-UHFFFAOYSA-N 0.000 description 3
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 3
- 235000012538 ammonium bicarbonate Nutrition 0.000 description 3
- 239000001099 ammonium carbonate Substances 0.000 description 3
- 239000000010 aprotic solvent Substances 0.000 description 3
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 3
- 239000011521 glass Substances 0.000 description 3
- GNOIPBMMFNIUFM-UHFFFAOYSA-N hexamethylphosphoric triamide Chemical compound CN(C)P(=O)(N(C)C)N(C)C GNOIPBMMFNIUFM-UHFFFAOYSA-N 0.000 description 3
- 229930195733 hydrocarbon Natural products 0.000 description 3
- 150000002430 hydrocarbons Chemical class 0.000 description 3
- 229940098779 methanesulfonic acid Drugs 0.000 description 3
- 229910017604 nitric acid Inorganic materials 0.000 description 3
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 3
- RUOJZAUFBMNUDX-UHFFFAOYSA-N propylene carbonate Chemical compound CC1COC(=O)O1 RUOJZAUFBMNUDX-UHFFFAOYSA-N 0.000 description 3
- 229910000029 sodium carbonate Inorganic materials 0.000 description 3
- 239000011780 sodium chloride Substances 0.000 description 3
- FVAUCKIRQBBSSJ-UHFFFAOYSA-M sodium iodide Chemical compound [Na+].[I-] FVAUCKIRQBBSSJ-UHFFFAOYSA-M 0.000 description 3
- 208000026326 Adult-onset Still disease Diseases 0.000 description 2
- FERIUCNNQQJTOY-UHFFFAOYSA-N Butyric acid Natural products CCCC(O)=O FERIUCNNQQJTOY-UHFFFAOYSA-N 0.000 description 2
- DEHKNMGXSDOHMI-UHFFFAOYSA-N C1(CCC2CC3CCC=C3C=C12)=O Chemical compound C1(CCC2CC3CCC=C3C=C12)=O DEHKNMGXSDOHMI-UHFFFAOYSA-N 0.000 description 2
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 2
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- OIFBSDVPJOWBCH-UHFFFAOYSA-N Diethyl carbonate Chemical compound CCOC(=O)OCC OIFBSDVPJOWBCH-UHFFFAOYSA-N 0.000 description 2
- 206010016207 Familial Mediterranean fever Diseases 0.000 description 2
- 208000035690 Familial cold urticaria Diseases 0.000 description 2
- 239000002841 Lewis acid Substances 0.000 description 2
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 2
- 201000002795 Muckle-Wells syndrome Diseases 0.000 description 2
- 239000007868 Raney catalyst Substances 0.000 description 2
- 229910000564 Raney nickel Inorganic materials 0.000 description 2
- KJTLSVCANCCWHF-UHFFFAOYSA-N Ruthenium Chemical compound [Ru] KJTLSVCANCCWHF-UHFFFAOYSA-N 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 2
- 108060008682 Tumor Necrosis Factor Proteins 0.000 description 2
- 230000001476 alcoholic effect Effects 0.000 description 2
- VSCWAEJMTAWNJL-UHFFFAOYSA-K aluminium trichloride Chemical compound Cl[Al](Cl)Cl VSCWAEJMTAWNJL-UHFFFAOYSA-K 0.000 description 2
- 235000019270 ammonium chloride Nutrition 0.000 description 2
- VZTDIZULWFCMLS-UHFFFAOYSA-N ammonium formate Chemical compound [NH4+].[O-]C=O VZTDIZULWFCMLS-UHFFFAOYSA-N 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- 239000012300 argon atmosphere Substances 0.000 description 2
- 239000012298 atmosphere Substances 0.000 description 2
- 239000011575 calcium Substances 0.000 description 2
- 229910052791 calcium Inorganic materials 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- 239000012141 concentrate Substances 0.000 description 2
- 235000009508 confectionery Nutrition 0.000 description 2
- 239000013078 crystal Substances 0.000 description 2
- 238000002425 crystallisation Methods 0.000 description 2
- 230000008025 crystallization Effects 0.000 description 2
- 239000002552 dosage form Substances 0.000 description 2
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- 229910052731 fluorine Inorganic materials 0.000 description 2
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- 230000002401 inhibitory effect Effects 0.000 description 2
- 150000007529 inorganic bases Chemical class 0.000 description 2
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- 150000007517 lewis acids Chemical class 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 239000011777 magnesium Substances 0.000 description 2
- 229910052749 magnesium Inorganic materials 0.000 description 2
- 125000004170 methylsulfonyl group Chemical group [H]C([H])([H])S(*)(=O)=O 0.000 description 2
- 229910052759 nickel Inorganic materials 0.000 description 2
- 231100000252 nontoxic Toxicity 0.000 description 2
- 230000003000 nontoxic effect Effects 0.000 description 2
- 208000025487 periodic fever syndrome Diseases 0.000 description 2
- 239000000546 pharmaceutical excipient Substances 0.000 description 2
- 229910052697 platinum Inorganic materials 0.000 description 2
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- 238000002360 preparation method Methods 0.000 description 2
- 238000002953 preparative HPLC Methods 0.000 description 2
- 239000003586 protic polar solvent Substances 0.000 description 2
- 230000000717 retained effect Effects 0.000 description 2
- 238000004366 reverse phase liquid chromatography Methods 0.000 description 2
- 229910052703 rhodium Inorganic materials 0.000 description 2
- 239000010948 rhodium Substances 0.000 description 2
- MHOVAHRLVXNVSD-UHFFFAOYSA-N rhodium atom Chemical compound [Rh] MHOVAHRLVXNVSD-UHFFFAOYSA-N 0.000 description 2
- 229910052707 ruthenium Inorganic materials 0.000 description 2
- 239000001509 sodium citrate Substances 0.000 description 2
- NASFKTWZWDYFER-UHFFFAOYSA-N sodium;hydrate Chemical group O.[Na] NASFKTWZWDYFER-UHFFFAOYSA-N 0.000 description 2
- 239000012453 solvate Substances 0.000 description 2
- 208000026082 sterile multifocal osteomyelitis with periostitis and pustulosis Diseases 0.000 description 2
- 208000011580 syndromic disease Diseases 0.000 description 2
- 125000001889 triflyl group Chemical group FC(F)(F)S(*)(=O)=O 0.000 description 2
- HRXKRNGNAMMEHJ-UHFFFAOYSA-K trisodium citrate Chemical compound [Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O HRXKRNGNAMMEHJ-UHFFFAOYSA-K 0.000 description 2
- 229940038773 trisodium citrate Drugs 0.000 description 2
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- 239000011701 zinc Substances 0.000 description 2
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- FZZMTSNZRBFGGU-UHFFFAOYSA-N 2-chloro-7-fluoroquinazolin-4-amine Chemical compound FC1=CC=C2C(N)=NC(Cl)=NC2=C1 FZZMTSNZRBFGGU-UHFFFAOYSA-N 0.000 description 1
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- 206010000748 Acute febrile neutrophilic dermatosis Diseases 0.000 description 1
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- USFZMSVCRYTOJT-UHFFFAOYSA-N Ammonium acetate Chemical compound N.CC(O)=O USFZMSVCRYTOJT-UHFFFAOYSA-N 0.000 description 1
- 239000005695 Ammonium acetate Substances 0.000 description 1
- 208000001839 Antisynthetase syndrome Diseases 0.000 description 1
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- 208000009137 Behcet syndrome Diseases 0.000 description 1
- LSNNMFCWUKXFEE-UHFFFAOYSA-M Bisulfite Chemical compound OS([O-])=O LSNNMFCWUKXFEE-UHFFFAOYSA-M 0.000 description 1
- ZBMZKGUMDUYAER-UHFFFAOYSA-N CC(C)N1C=CC(=N1)S(=O)(=O)NC(=O)NC2=C3CCCC3=CC4=C2CCC4.O.[Na] Chemical compound CC(C)N1C=CC(=N1)S(=O)(=O)NC(=O)NC2=C3CCCC3=CC4=C2CCC4.O.[Na] ZBMZKGUMDUYAER-UHFFFAOYSA-N 0.000 description 1
- 208000024172 Cardiovascular disease Diseases 0.000 description 1
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- 108700036803 Deficiency of interleukin-1 receptor antagonist Proteins 0.000 description 1
- 241001475178 Dira Species 0.000 description 1
- QXNVGIXVLWOKEQ-UHFFFAOYSA-N Disodium Chemical class [Na][Na] QXNVGIXVLWOKEQ-UHFFFAOYSA-N 0.000 description 1
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- 229910004039 HBF4 Inorganic materials 0.000 description 1
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- 206010061218 Inflammation Diseases 0.000 description 1
- 208000003456 Juvenile Arthritis Diseases 0.000 description 1
- 206010059176 Juvenile idiopathic arthritis Diseases 0.000 description 1
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 1
- 208000018501 Lymphatic disease Diseases 0.000 description 1
- 101710126825 NACHT, LRR and PYD domains-containing protein 3 Proteins 0.000 description 1
- 238000005481 NMR spectroscopy Methods 0.000 description 1
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- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 206010000496 acne Diseases 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
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- 206010053552 allodynia Diseases 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 235000019257 ammonium acetate Nutrition 0.000 description 1
- 229940043376 ammonium acetate Drugs 0.000 description 1
- 150000003863 ammonium salts Chemical class 0.000 description 1
- 201000003308 autosomal dominant familial periodic fever Diseases 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- 201000011510 cancer Diseases 0.000 description 1
- VNWKTOKETHGBQD-YPZZEJLDSA-N carbane Chemical compound [10CH4] VNWKTOKETHGBQD-YPZZEJLDSA-N 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- 150000001768 cations Chemical class 0.000 description 1
- 208000015114 central nervous system disease Diseases 0.000 description 1
- 238000012512 characterization method Methods 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- DEZRYPDIMOWBDS-UHFFFAOYSA-N dcm dichloromethane Chemical compound ClCCl.ClCCl DEZRYPDIMOWBDS-UHFFFAOYSA-N 0.000 description 1
- 206010012601 diabetes mellitus Diseases 0.000 description 1
- 150000004683 dihydrates Chemical class 0.000 description 1
- SMBQBQBNOXIFSF-UHFFFAOYSA-N dilithium Chemical compound [Li][Li] SMBQBQBNOXIFSF-UHFFFAOYSA-N 0.000 description 1
- 239000003085 diluting agent Substances 0.000 description 1
- UXGNZZKBCMGWAZ-UHFFFAOYSA-N dimethylformamide dmf Chemical compound CN(C)C=O.CN(C)C=O UXGNZZKBCMGWAZ-UHFFFAOYSA-N 0.000 description 1
- 229910001873 dinitrogen Inorganic materials 0.000 description 1
- KCIDZIIHRGYJAE-YGFYJFDDSA-L dipotassium;[(2r,3r,4s,5r,6r)-3,4,5-trihydroxy-6-(hydroxymethyl)oxan-2-yl] phosphate Chemical class [K+].[K+].OC[C@H]1O[C@H](OP([O-])([O-])=O)[C@H](O)[C@@H](O)[C@H]1O KCIDZIIHRGYJAE-YGFYJFDDSA-L 0.000 description 1
- 230000006806 disease prevention Effects 0.000 description 1
- CETRZFQIITUQQL-UHFFFAOYSA-N dmso dimethylsulfoxide Chemical compound CS(C)=O.CS(C)=O CETRZFQIITUQQL-UHFFFAOYSA-N 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 125000001153 fluoro group Chemical group F* 0.000 description 1
- 208000024908 graft versus host disease Diseases 0.000 description 1
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- 208000015181 infectious disease Diseases 0.000 description 1
- 208000027866 inflammatory disease Diseases 0.000 description 1
- 230000004054 inflammatory process Effects 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 238000007917 intracranial administration Methods 0.000 description 1
- 238000007918 intramuscular administration Methods 0.000 description 1
- 238000007912 intraperitoneal administration Methods 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- 201000002215 juvenile rheumatoid arthritis Diseases 0.000 description 1
- 208000017169 kidney disease Diseases 0.000 description 1
- 238000004811 liquid chromatography Methods 0.000 description 1
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 1
- 229910052744 lithium Inorganic materials 0.000 description 1
- DBTNVRCCIDISMV-UHFFFAOYSA-L lithium;magnesium;propane;dichloride Chemical compound [Li+].[Mg+2].[Cl-].[Cl-].C[CH-]C DBTNVRCCIDISMV-UHFFFAOYSA-L 0.000 description 1
- SZAVVKVUMPLRRS-UHFFFAOYSA-N lithium;propane Chemical group [Li+].C[CH-]C SZAVVKVUMPLRRS-UHFFFAOYSA-N 0.000 description 1
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- 208000018555 lymphatic system disease Diseases 0.000 description 1
- 238000004949 mass spectrometry Methods 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
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- 208000030159 metabolic disease Diseases 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 150000004682 monohydrates Chemical class 0.000 description 1
- YBSZEWLCECBDIP-UHFFFAOYSA-N n-[bis(dimethylamino)phosphoryl]-n-methylmethanamine Chemical compound CN(C)P(=O)(N(C)C)N(C)C.CN(C)P(=O)(N(C)C)N(C)C YBSZEWLCECBDIP-UHFFFAOYSA-N 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 239000012454 non-polar solvent Substances 0.000 description 1
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 230000000737 periodic effect Effects 0.000 description 1
- 208000020016 psychiatric disease Diseases 0.000 description 1
- 208000009954 pyoderma gangrenosum Diseases 0.000 description 1
- 230000002285 radioactive effect Effects 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 102000005962 receptors Human genes 0.000 description 1
- 108020003175 receptors Proteins 0.000 description 1
- 230000002829 reductive effect Effects 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 208000009169 relapsing polychondritis Diseases 0.000 description 1
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- 208000023504 respiratory system disease Diseases 0.000 description 1
- 230000037432 silent mutation Effects 0.000 description 1
- 208000017520 skin disease Diseases 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000009518 sodium iodide Nutrition 0.000 description 1
- 230000000392 somatic effect Effects 0.000 description 1
- LXMSZDCAJNLERA-ZHYRCANASA-N spironolactone Chemical compound C([C@@H]1[C@]2(C)CC[C@@H]3[C@@]4(C)CCC(=O)C=C4C[C@H]([C@@H]13)SC(=O)C)C[C@@]21CCC(=O)O1 LXMSZDCAJNLERA-ZHYRCANASA-N 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
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- 230000009885 systemic effect Effects 0.000 description 1
- 238000011200 topical administration Methods 0.000 description 1
- 230000000699 topical effect Effects 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 150000004684 trihydrates Chemical class 0.000 description 1
- 238000004704 ultra performance liquid chromatography Methods 0.000 description 1
- 238000005292 vacuum distillation Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
- C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
- C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D231/14—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members 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
- C07D231/18—One oxygen or sulfur atom
-
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
- C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
- C07D231/06—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
- C07D231/08—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with oxygen or sulfur atoms directly attached to ring carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C201/00—Preparation of esters of nitric or nitrous acid or of compounds containing nitro or nitroso groups bound to a carbon skeleton
- C07C201/06—Preparation of nitro compounds
- C07C201/08—Preparation of nitro compounds by substitution of hydrogen atoms by nitro groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C205/00—Compounds containing nitro groups bound to a carbon skeleton
- C07C205/45—Compounds containing nitro groups bound to a carbon skeleton the carbon skeleton being further substituted by at least one doubly—bound oxygen atom, not being part of a —CHO group
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C209/00—Preparation of compounds containing amino groups bound to a carbon skeleton
- C07C209/30—Preparation of compounds containing amino groups bound to a carbon skeleton by reduction of nitrogen-to-oxygen or nitrogen-to-nitrogen bonds
- C07C209/32—Preparation of compounds containing amino groups bound to a carbon skeleton by reduction of nitrogen-to-oxygen or nitrogen-to-nitrogen bonds by reduction of nitro groups
- C07C209/36—Preparation of compounds containing amino groups bound to a carbon skeleton by reduction of nitrogen-to-oxygen or nitrogen-to-nitrogen bonds by reduction of nitro groups by reduction of nitro groups bound to carbon atoms of six-membered aromatic rings in presence of hydrogen-containing gases and a catalyst
-
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- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C211/00—Compounds containing amino groups bound to a carbon skeleton
- C07C211/43—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton
- C07C211/57—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton having amino groups bound to carbon atoms of six-membered aromatic rings being part of condensed ring systems of the carbon skeleton
- C07C211/61—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton having amino groups bound to carbon atoms of six-membered aromatic rings being part of condensed ring systems of the carbon skeleton with at least one of the condensed ring systems formed by three or more rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
- C07C45/45—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by condensation
- C07C45/455—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by condensation with carboxylic acids or their derivatives
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- C07—ORGANIC CHEMISTRY
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- C07C49/587—Unsaturated compounds containing a keto groups being part of a ring
- C07C49/657—Unsaturated compounds containing a keto groups being part of a ring containing six-membered aromatic rings
- C07C49/665—Unsaturated compounds containing a keto groups being part of a ring containing six-membered aromatic rings a keto group being part of a condensed ring system
- C07C49/675—Unsaturated compounds containing a keto groups being part of a ring containing six-membered aromatic rings a keto group being part of a condensed ring system having three rings
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- C07C49/76—Ketones containing a keto group bound to a six-membered aromatic ring
- C07C49/80—Ketones containing a keto group bound to a six-membered aromatic ring containing halogen
- C07C49/813—Ketones containing a keto group bound to a six-membered aromatic ring containing halogen polycyclic
-
- 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
- A61K31/415—1,2-Diazoles
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- C07C2602/00—Systems containing two condensed rings
- C07C2602/02—Systems containing two condensed rings the rings having only two atoms in common
- C07C2602/04—One of the condensed rings being a six-membered aromatic ring
- C07C2602/08—One of the condensed rings being a six-membered aromatic ring the other ring being five-membered, e.g. indane
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- C07C2603/04—Ortho- or ortho- and peri-condensed systems containing three rings
- C07C2603/06—Ortho- or ortho- and peri-condensed systems containing three rings containing at least one ring with less than six ring members
- C07C2603/10—Ortho- or ortho- and peri-condensed systems containing three rings containing at least one ring with less than six ring members containing five-membered rings
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Abstract
【選択図】なし
Description
(a) 3-ニトロ-1H-ピラゾールをiPr-X(ここでXは、脱離基である)と接触させて、1-イソプロピル-3-ニトロ-1H-ピラゾールを得るステップ:
(b) 1-イソプロピル-3-ニトロ-1H-ピラゾールを還元して、1-イソプロピル-3-アミノ-1H-ピラゾールを得るステップ:
(c) 1-イソプロピル-3-アミノ-1H-ピラゾールを1-イソプロピル-3-ヨード-1H-ピラゾールに変換するステップ:
(d) 1-イソプロピル-3-ヨード-1H-ピラゾールを1-イソプロピル-1H-ピラゾール-3-スルホンアミドに変換するステップ:
(e) 1-イソプロピル-1H-ピラゾール-3-スルホンアミドを1-イソプロピル-3-(アルコキシカルボニルアミノスルホニル)-1H-ピラゾールに変換するステップ:
から選択される1つまたは複数のステップを含む、工程を提供する。
(d) グリニャール試薬または有機リチウム試薬での処理と、続く二酸化硫黄ガスでの処理と、続くヒドロキシルアミン-O-スルホン酸での処理とにより、1-イソプロピル-3-ヨード-1H-ピラゾールを1-イソプロピル-1H-ピラゾール-3-スルホンアミドに変換するステップ:
(e) 塩基の存在下での炭酸ジメチルまたはピロ炭酸ジメチルでの処理により、1-イソプロピル-1H-ピラゾール-3-スルホンアミドを1-イソプロピル-3-(メトキシカルボニルアミノスルホニル)-1H-ピラゾールに変換するステップ:
を含む、工程が提供される。
(a) 塩基の存在下で3-ニトロ-1H-ピラゾールを2-ヨード-プロパンと接触させて、1-イソプロピル-3-ニトロ-1H-ピラゾールを得るステップ:
(b) 1-イソプロピル-3-ニトロ-1H-ピラゾールを還元して、1-イソプロピル-3-アミノ-1H-ピラゾールを得るステップ:
(c) 硫酸および亜硝酸ナトリウムの水溶液での処理と、続くヨウ化カリウムでの処理とにより、1-イソプロピル-3-アミノ-1H-ピラゾールを1-イソプロピル-3-ヨード-1H-ピラゾールに変換するステップ:
(d) グリニャール試薬または有機リチウム試薬での処理と、続く二酸化硫黄ガスでの処理と、続くヒドロキシルアミン-O-スルホン酸での処理とにより、1-イソプロピル-3-ヨード-1H-ピラゾールを1-イソプロピル-1H-ピラゾール-3-スルホンアミドに変換するステップ:
(e) 塩基の存在下での炭酸ジメチルまたはピロ炭酸ジメチルでの処理により、1-イソプロピル-1H-ピラゾール-3-スルホンアミドを1-イソプロピル-3-(メトキシカルボニルアミノスルホニル)-1H-ピラゾールに変換するステップ:
を含む、工程が提供される。
(i) 2,3-ジヒドロ-1H-インデンをYCH2CH2COZ(ここでYおよびZは、脱離基である)と接触させて、置換された1-(2,3-ジヒドロ-1H-インデン-5-イル)プロパン-1-オンを得るステップ:
(ii) 該置換された1-(2,3-ジヒドロ-1H-インデン-5-イル)プロパン-1-オンを酸と接触させて、1,2,3,5,6,7-ヘキサヒドロ-s-インダセン-1-オンを得るステップ:
(iii) 1,2,3,5,6,7-ヘキサヒドロ-s-インダセン-1-オンを4-ニトロ-1,2,3,5,6,7-ヘキサヒドロ-s-インダセン-1-オンおよび/または8-ニトロ-1,2,3,5,6,7-ヘキサヒドロ-s-インダセン-1-オンに変換するステップ:
(iv) 4-ニトロ-1,2,3,5,6,7-ヘキサヒドロ-s-インダセン-1-オンおよび/または8-ニトロ-1,2,3,5,6,7-ヘキサヒドロ-s-インダセン-1-オンを還元して、1,2,3,5,6,7-ヘキサヒドロ-s-インダセン-4-アミンを得るステップ:
から選択される1つまたは複数のステップを含む、工程を提供する。
(i) ルイス酸の存在下で2,3-ジヒドロ-1H-インデンを3-クロロプロピオニルクロリドと接触させて、3-クロロ-1-(2,3-ジヒドロ-1H-インデン-5-イル)プロパン-1-オンを得るステップ:
(ii)3-クロロ-1-(2,3-ジヒドロ-1H-インデン-5-イル)プロパン-1-オンを酸と接触させて、1,2,3,5,6,7-ヘキサヒドロ-s-インダセン-1-オンを得るステップ:
(iii)硫酸および硝酸での処理により、1,2,3,5,6,7-ヘキサヒドロ-s-インダセン-1-オンを4-ニトロ-1,2,3,5,6,7-ヘキサヒドロ-s-インダセン-1-オンおよび/または8-ニトロ-1,2,3,5,6,7-ヘキサヒドロ-s-インダセン-1-オンに変換するステップ:
(iv) 4-ニトロ-1,2,3,5,6,7-ヘキサヒドロ-s-インダセン-1-オンおよび/または8-ニトロ-1,2,3,5,6,7-ヘキサヒドロ-s-インダセン-1-オンを還元して、1,2,3,5,6,7-ヘキサヒドロ-s-インダセン-4-アミンを得るステップ:
を含む、工程が提供される。
(i)炎症;
(ii)自己免疫性疾患;
(iii)癌;
(iv)感染;
(v)中枢神経系疾患;
(vi)代謝疾患;
(vii)心血管疾患;
(viii)呼吸器疾患;
(ix)肝臓疾患;
(x)腎臓疾患;
(xi)眼科疾患;
(xii)皮膚疾患;
(xiii)リンパ病;
(xiv)精神障害;
(xv)移植片対宿主病;
(xvi)アロディニア;
(xvii)糖尿病に関連する病気;および
(xviii)個体がNLRP3の生殖系または体細胞系非サイレント突然変異を担うことが決定された任意の疾患、
から選択される。
(i)クリオピリン関連周期熱症候群(CAPS);
(ii)マックル・ウェルズ症候群(MWS);
(iii)家族性感冒自己炎症性症候群(FCAS);
(iv)新生児期発症多臓器性炎症性疾患(NOMID);
(v)家族性地中海熱(FMF);
(vi)化膿性関節炎・壊疽性膿皮症・ざ瘡症候群(PAPA);
(vii)高免疫グロブリンDおよび周期性発熱症候群(HIDS);
(viii)腫瘍壊死因子(TNF)受容体関連周期性症候群(TRAPS);
(ix)全身若年性特発性関節炎;
(x)成人発症スチル病(AOSD);
(xi)再発性多発性軟骨炎;
(xii)シュニッツラー症候群;
(xiii)スウィート症候群;
(xiv)ベーチェット病;
(xv)抗合成酵素症候群;
(xvi)インターロイキン1受容体アンタゴニスト欠損症(DIRA);ならびに
(xvii)A20ハプロ不全症(HA20)
から選択される。
他に断りがなければ、全ての溶媒、試薬および化合物が、購入され、さらに精製されずに使用された。
DCM ジクロロメタン
DMF N,N-ジメチルホルムアミド
DMSO ジメチルスルホキシド
eq 当量
HMPA ヘキサメチルホスホルアミド
iPr イソプロピル
MTBE メチルtert-ブチルエーテル
Pd/C パラジム炭素
10%Pd/C 炭素に吸着された10w/w%Pd
5%Pd/C 炭素に吸着された5w/w%Pd
prep-HPLC 分取高速液体クロマトグラフィー
THF テトラヒドロフラン
vol 容量
NMR法:
VNMRJを用い、以下の分光計:Agilent 500MHz、400MHzもしくは300MHz分光計、Bruker BioSpin AG 400MHz分光計、Bruker 500MHz分光計、またはVarian 400MHz分光計、のうちの1つにおいて293~298K(20~25℃)で、NMRスペクトルを実行した。
反応スキーム1(ステップa~c)および反応スキーム2(ステップi~iv(方法A)):Waters-Acquity UPLCシステムをPDA検出器およびSQD質量検出器と共に使用した。
反応スキーム1(ステップa~c)および反応スキーム2(ステップi~iv(方法A)):Waters Alliance HPLCシステムをPDA検出器と共に使用して、逆相クロマトグラフィーを実施した。
1-イソプロピル-3-(メトキシカルボニルアミノスルホニル)-1H-ピラゾール (6)
1-イソプロピル-3-(メトキシカルボニルアミノスルホニル)-1H-ピラゾール (6)を、反応スキーム1に示された反応系列に従って調製した。
オフホワイト色固体
産出量:14.5Kg
収率:68.2%
融点:45~48℃
1H NMR(DMSO-d6;400MHz):1.45(d, 6H),4.65(sept,1H),7.06(s,1H),and 8.12(s,1H)。
MS:(M+H+)=156.10
水分量(カールフィッシャー滴定による):≦1.0%
HPLC純度:98.61%
HPLC[X-bridge C18カラム、4.6×150mm、3.5μm、移動相A=水中の10mM重炭酸アンモニウム、移動相B=アセトニトリル、勾配プログラム(時間/%B)=0/10、7/90、15/90、15.01/10;流速1mL/分、温度=25℃):Rt=6.11分]
緑黒色液体
産出量:11.5Kg
収率:98.54%
1H NMR(DMSO-d6;400MHz):1.35(d,6H),4.18(sept,1H),4.45(br s,2H),5.37(s,1H),and 7.28(s,1H)。
MS:(M+H+)=126.17
HPLC純度:98.61%
HPLC[X-ブリッジC18カラム、4.6×150mm、3.5μm、移動相A=水中の10mM重炭酸アンモニウム、移動相B=アセトニトリル、勾配プログラム(時間/%B)=0/10、7/90、15/90、15.01/10;流速1mL/分、温度=25℃):Rt=3.84分]
*2:亜硝酸ナトリウム溶液を調製するために、亜硝酸ナトリウム(7.27Kg)固体を、25~30℃の水(61L)に緩やかに添加した(吸熱反応)。
*3:水酸化ナトリウム溶液を調製するために、水酸化ナトリウム(6.1Kg)を25~30℃の水(122L)に緩やかに添加した。
*4:チオ硫酸ナトリウム溶液を調製するために、チオ硫酸ナトリウム(6Kg)を25~30℃の水(122L)に緩やかに添加し、調製された溶液を二部に分割した。
淡黄色液体
産出量:12.03Kg(バッチ1)+5.3Kg(バッチ2)=17.33Kg
全体的収率(バッチ1とバッチ2の組み合わせ):75.34%
1H NMR(CDCl3;500MHz):1.50(d,6H),4.51(sept,1H),6.39(s,1H),and 7.25(s,1H)。
MS:(M+H+)=236.06
HPLC純度:99.28%
HPLC[X-ブリッジC18カラム、4.6×150mm、3.5μm、移動相A=水中の10mM重炭酸アンモニウム、移動相B=アセトニトリル、勾配プログラム(時間/%B)=0/10、7/90、15/90、15.01/10;流速1mL/分、温度=25℃):Rt=6.98分]
褐色~黄色の固体
産出量:186.6g
収率:93.1%
1H NMR(DMSO-d6;400MHz):7.92(d,J=2.28Hz,1H),7.39(s,2H),6.57(d,J=2.28Hz,1H),4.57(sept,J=6.67Hz,1H),and 1.43(d,J=6.59Hz,6H)。
乾物含量:99.24w/w%
HPLC純度:99.71%
白色固体
産出量:12.0g
収率:91.9%
1H NMR(DMSO-d6;400MHz):12.09(br s,1H),8.01(d,J=2.28Hz,1H),6.76(d,J=2.28Hz,1H),4.61(sept,J=6.67Hz,1H),3.59(s,3H),and 1.43(d,J=6.59Hz,6H)。
乾物含量:99.12w/w%
HPLC純度:99.69%
1,2,3,5,6,7-ヘキサヒドロ-s-インダセン-4-アミン(16)を、反応スキーム2に示された反応系列に従って調製した。
オフホワイト色固体
産出量:50.8Kg
収率:65.59%
1H NMR(CDCl3;500MHz):7.81(s,1H),7.75(d,J=8.0Hz,1H),7.31(d,J=8.0Hz,1H),3.93(t,J=7.0Hz,2H),3.45(t,J=7.0Hz,2H),2.97,(t,J=7.50Hz,4H),and 2.15-2.09(m,2H)。
水分量(カールフィッシャー滴定による):≦0.5%
HPLC純度:99.57%
淡褐色固体
14:15の重量比は、9.6:1であった。
合わせた産出量(14+15):31.40Kg
合わせた収率(14+15):59.2%
1H NMR(CDCl3;400MHz):7.45(s,1H),3.13-3.06(m,2H),3.08-2.97(m,4H),2.82-2.76(m,2H),and 2.25-2.16(m,2H)。
水分量(カールフィッシャー滴定による):≦0.5%
HPLC純度:91.61%
オフホワイト色固体
産出量:13.90Kg(2バッチ)
収率:51.2%
1H NMR(DMSO-d6;300MHz):6.33(s,1H),4.50(br s,2H,NH2),2.70(t,4H),2.57(t,4H),and 2.00-1.90(m,4H)。
水分量(カールフィッシャー滴定による):0.173%
HPLC純度:95.43%
1,2,3,5,6,7-ヘキサヒドロ-s-インダセン-4-アミン(16)(34Kg)を、25~30℃で250Lの清潔で乾燥した反応器に加えた。トルエン(13.9L)を25~30℃で加えて、反応混合物を25~30℃で30分間撹拌した。メタノール(41.7L)を25~30℃の反応混合物に加えた。反応混合物を25~30℃で30分間撹拌し、-5~0℃に冷却して、-5~0℃で30分間撹拌した。固体生成物を濾過し、低温メタノール(13.9L)で洗浄して、40~45℃で6時間乾燥させた。
淡褐色固体
産出量:11.40Kg
収率:42.2%
1H NMR(DMSO-d6;300MHz):6.33(s,1H),4.50(br s,2H,NH2),2.70(t,4H),2.57(t,4H),and 2.00-1.90(m,4H)。
水分量(カールフィッシャー滴定による):≦0.5%
HPLC純度:98.43%
淡黄色~褐色の固体
産出量:360.0g
収率:82%
1H NMR(DMSO-d6;400MHz):7.84(s,1H),7.78(d,1H),7.37(d,1H),3.92(t,2H),3.52(t,2H),2.92(t,4H),and 2.05(m,2H)。
水分量(カールフィッシャー滴定による):0.16%
HPLC純度:98%
褐色固体
14:15の重量比は7:1であった。
合わせた産出量(14+15):217g
合わせた産出量(14+15):60%
1H NMR(DMSO-d6;400MHz):7.66(s,1H),3.08(t,2H),2.98(t,2H) 2.88(t,2H),2.72(t,2H) and 2.12(m,2H)。
水分量(カールフィッシャー滴定による):0.72%
HPLC純度:96.44%
淡褐色固体
産出量:8g
収率:45%
1H NMR(DMSO-d6;400MHz):6.33(s,1H),4.52(s,2H,NH2),2.72(m,4H),2.62(m,4H),and 1.96(m,4H)。
水分量(カールフィッシャー滴定による):0.55%
HPLC純度:99.32%
淡褐色固体
産出量:6.5g
収率:37%
1H NMR(DMSO-d6;400MHz):6.33(s,1H),4.52(s,2H,NH2),2.72(m,4H),2.62(m,4H),and 1.96(m,4H)。
水分量(カールフィッシャー滴定による):0.49%
HPLC純度:98.29%
N-((1,2,3,5,6,7-ヘキサヒドロ-s-インダセン-4-イル)カルバモイル)-1-イソプロピル-1H-ピラゾール-3-スルホンアミド(17)を、反応スキーム3に示された反応に従って調製した。
1-イソプロピル-3-(メトキシカルボニルアミノスルホニル)-1H-ピラゾール(6)(20.0g、1eq)および1,2,3,5,6,7-ヘキサヒドロ-s-インダセン-4-アミン(16)(1.05eq、14.7g)を、炭酸ジメチル(5vol、100mL)に懸濁させて、50℃に加熱した。1容量(20mL)の溶媒を真空下で留去して、反応混合物をさらに85℃に加熱して、85℃で7時間10分撹拌した。もう1容量(20mL)の溶媒を85℃で留去して、反応混合物を85℃で19時間撹拌した。温度をさらに95℃に上昇させて、撹拌を5時間継続した後、反応物を30℃に冷却した。IPCで、99.3%の変換が示された。2-MeTHF(5vol、100mL)を、30℃で35分かけて緩やかに添加した。懸濁液を30分かけて20℃に冷却し、20℃でさらに3.5時間維持した。懸濁液を濾過して母液ですすぎ、その後、2-MeTHF/n-ヘプタン(1:1、4vol、80mL)混合物およびn-ヘプタン(4vol、80mL)ですすいだ。濾過ケークを真空乾燥して、生成物をもたらした。
オフホワイト色~褐色の固体
産出量:26.80g
収率:85.3%
1H NMR(DMSO-d6;400MHz):10.83(br s,1H),8.06(s,1H),7.99(d,J=2.28Hz,1H),6.94(s,1H),6.75(d,J=2.28Hz,1H),4.62(sept,J=6.67Hz,1H),2.78(t,J=7.22Hz,4H),2.57(t,J=7.22Hz,4H),1.93(quin,J=7.35Hz,4H),and 1.43(d,J=6.84Hz,6H)。
HPLC純度:99.02%
N-((1,2,3,5,6,7-ヘキサヒドロ-s-インダセン-4-イル)カルバモイル)-1-イソプロピル-1H-ピラゾール-3-スルホンアミド(17)を、一ナトリウム一水和物塩に変換した。
オフホワイト色固体
産出量:4.01g
収率:91%
1H NMR(D2O;400MHz):7.74(d,J=2.53Hz,1H),7.07(s,1H),6.68(d,J=2.53Hz,1H),4.58(sept,J=6.76Hz,1H),2.85(t,J=7.35Hz,4H),2.67(t,J=7.35Hz,4H),2.01(quin,J=7.35Hz,4H),and 1.49(d,J=6.84Hz,6H)。
水分量(カールフィッシャー滴定による):5.2%
HPLC純度:99.26%
Claims (13)
- Rが、メチルである、請求項1に記載の工程。
- 前記溶媒が、炭酸ジメチルを含む、請求項1または2に記載の工程。
- 1-イソプロピル-3-(アルコキシカルボニルアミノスルホニル)-1H-ピラゾール:
(a) 3-ニトロ-1H-ピラゾールをiPr-X(ここでXは、脱離基である)と接触させて、1-イソプロピル-3-ニトロ-1H-ピラゾールを得るステップ:
(b) 1-イソプロピル-3-ニトロ-1H-ピラゾールを還元して、1-イソプロピル-3-アミノ-1H-ピラゾールを得るステップ:
(c) 1-イソプロピル-3-アミノ-1H-ピラゾールを1-イソプロピル-3-ヨード-1H-ピラゾールに変換するステップ:
(d) 1-イソプロピル-3-ヨード-1H-ピラゾールを1-イソプロピル-1H-ピラゾール-3-スルホンアミドに変換するステップ:
(e) 1-イソプロピル-1H-ピラゾール-3-スルホンアミドを1-イソプロピル-3-(アルコキシカルボニルアミノスルホニル)-1H-ピラゾールに変換するステップ:
から選択される1つまたは複数のステップを含む、工程。 - 前記1-イソプロピル-3-(アルコキシ-カルボニルアミノスルホニル)-1H-ピラゾールが、請求項4に記載の工程により調製される、請求項1~3のいずれか1項に記載の工程。
- 1,2,3,5,6,7-ヘキサヒドロ-s-インダセン-4-アミン:
(i) 2,3-ジヒドロ-1H-インデンをYCH2CH2COZ(ここでYおよびZは、脱離基である)と接触させて、置換された1-(2,3-ジヒドロ-1H-インデン-5-イル)プロパン-1-オンを得るステップ:
(ii) 前記置換された1-(2,3-ジヒドロ-1H-インデン-5-イル)プロパン-1-オンを酸と接触させて、1,2,3,5,6,7-ヘキサヒドロ-s-インダセン-1-オンを得るステップ:
(iii) 1,2,3,5,6,7-ヘキサヒドロ-s-インダセン-1-オンを4-ニトロ-1,2,3,5,6,7-ヘキサヒドロ-s-インダセン-1-オンおよび/または8-ニトロ-1,2,3,5,6,7-ヘキサヒドロ-s-インダセン-1-オンに変換するステップ:
(iv) 4-ニトロ-1,2,3,5,6,7-ヘキサヒドロ-s-インダセン-1-オンおよび/または8-ニトロ-1,2,3,5,6,7-ヘキサヒドロ-s-インダセン-1-オンを還元して、1,2,3,5,6,7-ヘキサヒドロ-s-インダセン-4-アミンを得るステップ:
から選択される1つまたは複数のステップを含む、工程。 - 前記1,2,3,5,6,7-ヘキサヒドロ-s-インダセン-4-アミンが、請求項6に記載の工程により調製される、請求項1、2、3または5のいずれか1項に記載の工程。
- 請求項1~7のいずれか1項に記載の工程により得ることが可能な、または得られるN-((1,2,3,5,6,7-ヘキサヒドロ-s-インダセン-4-イル)カルバモイル)-1-イソプロピル-1H-ピラゾール-3-スルホンアミドまたはその塩。
- 98%以上、または98.5%以上、または98.6%以上、または98.7%以上、または98.8%以上、または98.9%以上、または99%以上、または99.1%以上、または99.2%以上、または99.3%以上のHPLC純度を有する、請求項8に記載のN-((1,2,3,5,6,7-ヘキサヒドロ-s-インダセン-4-イル)カルバモイル)-1-イソプロピル-1H-ピラゾール-3-スルホンアミドまたはその塩。
- 98%以上、または98.5%以上、または98.6%以上、または98.7%以上、または98.8%以上、または98.9%以上、または99%以上、または99.1%以上、または99.2%以上、または99.3%以上のHPLC純度を有するN-((1,2,3,5,6,7-ヘキサヒドロ-s-インダセン-4-イル)カルバモイル)-1-イソプロピル-1H-ピラゾール-3-スルホンアミド。
- Rが、メチルである、請求項11に記載の1-イソプロピル-3-(アルコキシカルボニルアミノスルホニル)-1H-ピラゾール。
- 98%以上、または98.5%以上、または99%以上、または99.5%以上、または99.6%以上、または99.7%以上のHPLC純度を有する、請求項11または12に記載の1-イソプロピル-3-(アルコキシカルボニルアミノスルホニル)-1H-ピラゾール。
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