JP3868534B2 - Process for producing sulfonamide derivatives and intermediates - Google Patents
Process for producing sulfonamide derivatives and intermediates Download PDFInfo
- Publication number
- JP3868534B2 JP3868534B2 JP12944796A JP12944796A JP3868534B2 JP 3868534 B2 JP3868534 B2 JP 3868534B2 JP 12944796 A JP12944796 A JP 12944796A JP 12944796 A JP12944796 A JP 12944796A JP 3868534 B2 JP3868534 B2 JP 3868534B2
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- Japan
- Prior art keywords
- group
- producing
- represented
- chloroindole
- formula
- 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.)
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- 238000000034 method Methods 0.000 title claims description 22
- 239000000543 intermediate Substances 0.000 title 1
- 229940124530 sulfonamide Drugs 0.000 title 1
- 150000003456 sulfonamides Chemical class 0.000 title 1
- HFFXLYHRNRKAPM-UHFFFAOYSA-N 2,4,5-trichloro-n-(5-methyl-1,2-oxazol-3-yl)benzenesulfonamide Chemical compound O1C(C)=CC(NS(=O)(=O)C=2C(=CC(Cl)=C(Cl)C=2)Cl)=N1 HFFXLYHRNRKAPM-UHFFFAOYSA-N 0.000 claims description 24
- -1 Amine hydrochloride Chemical class 0.000 claims description 19
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 claims description 18
- 238000006243 chemical reaction Methods 0.000 claims description 15
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 claims description 14
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 13
- 150000002828 nitro derivatives Chemical class 0.000 claims description 12
- 239000000203 mixture Substances 0.000 claims description 10
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 9
- 235000019270 ammonium chloride Nutrition 0.000 claims description 9
- 239000002904 solvent Substances 0.000 claims description 9
- 125000005843 halogen group Chemical group 0.000 claims description 6
- 125000003118 aryl group Chemical group 0.000 claims description 5
- 125000000623 heterocyclic group Chemical group 0.000 claims description 5
- 229910052742 iron Inorganic materials 0.000 claims description 5
- YBBRCQOCSYXUOC-UHFFFAOYSA-N sulfuryl dichloride Chemical class ClS(Cl)(=O)=O YBBRCQOCSYXUOC-UHFFFAOYSA-N 0.000 claims description 5
- 229910052801 chlorine Inorganic materials 0.000 claims description 4
- 125000001309 chloro group Chemical group Cl* 0.000 claims description 4
- 239000000460 chlorine Substances 0.000 claims description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 30
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 27
- 239000000243 solution Substances 0.000 description 15
- 238000004519 manufacturing process Methods 0.000 description 14
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 13
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 12
- 238000007796 conventional method Methods 0.000 description 12
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 11
- 150000001875 compounds Chemical class 0.000 description 11
- SLBNABPPSZSXHN-UHFFFAOYSA-N 3-chloro-1h-indol-7-amine Chemical compound NC1=CC=CC2=C1NC=C2Cl SLBNABPPSZSXHN-UHFFFAOYSA-N 0.000 description 8
- QDGYVAQMPDTWIE-UHFFFAOYSA-N 3-chloro-7-nitro-1h-indole Chemical compound [O-][N+](=O)C1=CC=CC2=C1NC=C2Cl QDGYVAQMPDTWIE-UHFFFAOYSA-N 0.000 description 8
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 8
- SETFNECMODOHTO-UHFFFAOYSA-N indisulam Chemical compound C1=CC(S(=O)(=O)N)=CC=C1S(=O)(=O)NC1=CC=CC2=C1NC=C2Cl SETFNECMODOHTO-UHFFFAOYSA-N 0.000 description 8
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 7
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 6
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 6
- CCDREQPJNRWDNR-UHFFFAOYSA-N 3-chloro-1h-indol-7-amine;hydron;chloride Chemical compound Cl.NC1=CC=CC2=C1NC=C2Cl CCDREQPJNRWDNR-UHFFFAOYSA-N 0.000 description 5
- BBZBFSPWJFJXHM-UHFFFAOYSA-N 4-amino-n-(3-chloro-1h-indol-7-yl)benzenesulfonamide Chemical compound C1=CC(N)=CC=C1S(=O)(=O)NC1=CC=CC2=C1NC=C2Cl BBZBFSPWJFJXHM-UHFFFAOYSA-N 0.000 description 5
- 230000015572 biosynthetic process Effects 0.000 description 5
- XIRQTZRAGLZGMD-UHFFFAOYSA-N n-(3-chloro-1h-indol-7-yl)-4-cyanobenzenesulfonamide Chemical compound C1=CC=C2C(Cl)=CNC2=C1NS(=O)(=O)C1=CC=C(C#N)C=C1 XIRQTZRAGLZGMD-UHFFFAOYSA-N 0.000 description 5
- MWMNDMPVPIGLOT-UHFFFAOYSA-N n-(3-chloro-1h-indol-7-yl)-4-nitrobenzenesulfonamide Chemical compound C1=CC([N+](=O)[O-])=CC=C1S(=O)(=O)NC1=CC=CC2=C1NC=C2Cl MWMNDMPVPIGLOT-UHFFFAOYSA-N 0.000 description 5
- 238000003786 synthesis reaction Methods 0.000 description 5
- LLFQHNCOIPUFIJ-UHFFFAOYSA-N 4-sulfamoylbenzenesulfonyl chloride Chemical compound NS(=O)(=O)C1=CC=C(S(Cl)(=O)=O)C=C1 LLFQHNCOIPUFIJ-UHFFFAOYSA-N 0.000 description 4
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 4
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 4
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 4
- BTANRVKWQNVYAZ-UHFFFAOYSA-N butan-2-ol Chemical compound CCC(C)O BTANRVKWQNVYAZ-UHFFFAOYSA-N 0.000 description 4
- 239000013078 crystal Substances 0.000 description 4
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 4
- 239000000047 product Substances 0.000 description 4
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 4
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- 239000000126 substance Substances 0.000 description 4
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- XETHKDXYIHSHDT-UHFFFAOYSA-N C1=CC2=C(C(=C1)N)NC(=C2)Cl.Cl Chemical compound C1=CC2=C(C(=C1)N)NC(=C2)Cl.Cl XETHKDXYIHSHDT-UHFFFAOYSA-N 0.000 description 3
- DVOWXLZJPVGDLR-UHFFFAOYSA-N C1=CC2=C(C=C1N)C=C(N2)Cl.Cl Chemical compound C1=CC2=C(C=C1N)C=C(N2)Cl.Cl DVOWXLZJPVGDLR-UHFFFAOYSA-N 0.000 description 3
- KKGFTVCRHLNYKQ-UHFFFAOYSA-N C1=CC2=C(C=C1N)NC(=C2)Cl.Cl Chemical compound C1=CC2=C(C=C1N)NC(=C2)Cl.Cl KKGFTVCRHLNYKQ-UHFFFAOYSA-N 0.000 description 3
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 125000000217 alkyl group Chemical group 0.000 description 3
- 125000003277 amino group Chemical group 0.000 description 3
- 239000007864 aqueous solution Substances 0.000 description 3
- 239000000706 filtrate Substances 0.000 description 3
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 3
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 3
- 238000009776 industrial production Methods 0.000 description 3
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 3
- 239000012299 nitrogen atmosphere Substances 0.000 description 3
- 239000011541 reaction mixture Substances 0.000 description 3
- 229920006395 saturated elastomer Polymers 0.000 description 3
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 3
- 235000017557 sodium bicarbonate Nutrition 0.000 description 3
- XPQFGYKWSPDVJU-UHFFFAOYSA-N 2-chloro-4-nitro-1H-indole Chemical compound [O-][N+](=O)c1cccc2[nH]c(Cl)cc12 XPQFGYKWSPDVJU-UHFFFAOYSA-N 0.000 description 2
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical group [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 2
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 2
- AMQJEAYHLZJPGS-UHFFFAOYSA-N N-Pentanol Chemical compound CCCCCO AMQJEAYHLZJPGS-UHFFFAOYSA-N 0.000 description 2
- JRNVZBWKYDBUCA-UHFFFAOYSA-N N-chlorosuccinimide Chemical compound ClN1C(=O)CCC1=O JRNVZBWKYDBUCA-UHFFFAOYSA-N 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- 125000003545 alkoxy group Chemical group 0.000 description 2
- 230000000052 comparative effect Effects 0.000 description 2
- 238000005695 dehalogenation reaction Methods 0.000 description 2
- 125000002541 furyl group Chemical group 0.000 description 2
- ZSIAUFGUXNUGDI-UHFFFAOYSA-N hexan-1-ol Chemical compound CCCCCCO ZSIAUFGUXNUGDI-UHFFFAOYSA-N 0.000 description 2
- 125000001041 indolyl group Chemical group 0.000 description 2
- 239000012046 mixed solvent Substances 0.000 description 2
- 239000012044 organic layer Substances 0.000 description 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 2
- 239000002798 polar solvent Substances 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- 125000004076 pyridyl group Chemical group 0.000 description 2
- 125000005493 quinolyl group Chemical group 0.000 description 2
- 238000001953 recrystallisation Methods 0.000 description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 2
- 125000001544 thienyl group Chemical group 0.000 description 2
- TXUICONDJPYNPY-UHFFFAOYSA-N (1,10,13-trimethyl-3-oxo-4,5,6,7,8,9,11,12,14,15,16,17-dodecahydrocyclopenta[a]phenanthren-17-yl) heptanoate Chemical compound C1CC2CC(=O)C=C(C)C2(C)C2C1C1CCC(OC(=O)CCCCCC)C1(C)CC2 TXUICONDJPYNPY-UHFFFAOYSA-N 0.000 description 1
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- WTFWZOSMUGZKNZ-UHFFFAOYSA-N 1H-indol-7-amine Chemical compound NC1=CC=CC2=C1NC=C2 WTFWZOSMUGZKNZ-UHFFFAOYSA-N 0.000 description 1
- SODLPTKYLLFMKK-UHFFFAOYSA-N 2-chloro-5-nitro-1H-indole Chemical compound [O-][N+](=O)c1ccc2[nH]c(Cl)cc2c1 SODLPTKYLLFMKK-UHFFFAOYSA-N 0.000 description 1
- SHSGHHJMFJVMDI-UHFFFAOYSA-N 2-chloro-6-nitro-1H-indole Chemical compound [O-][N+](=O)c1ccc2cc(Cl)[nH]c2c1 SHSGHHJMFJVMDI-UHFFFAOYSA-N 0.000 description 1
- JYBUPTYYZSEHLA-UHFFFAOYSA-N 2-chloro-7-nitro-1h-indole Chemical compound [O-][N+](=O)C1=CC=CC2=C1NC(Cl)=C2 JYBUPTYYZSEHLA-UHFFFAOYSA-N 0.000 description 1
- QZBOWJXHXLIMGD-UHFFFAOYSA-N 2-cyanobenzenesulfonamide Chemical compound NS(=O)(=O)C1=CC=CC=C1C#N QZBOWJXHXLIMGD-UHFFFAOYSA-N 0.000 description 1
- IBHFPQVONMGFLC-UHFFFAOYSA-N 3-chloro-4-nitro-1h-indole Chemical compound [O-][N+](=O)C1=CC=CC2=C1C(Cl)=CN2 IBHFPQVONMGFLC-UHFFFAOYSA-N 0.000 description 1
- VFIAOMIKIHVUKN-UHFFFAOYSA-N 3-chloro-5-nitro-1h-indole Chemical compound [O-][N+](=O)C1=CC=C2NC=C(Cl)C2=C1 VFIAOMIKIHVUKN-UHFFFAOYSA-N 0.000 description 1
- GCGXDRXRRBVHAM-UHFFFAOYSA-N 3-chloro-6-nitro-1h-indole Chemical compound [O-][N+](=O)C1=CC=C2C(Cl)=CNC2=C1 GCGXDRXRRBVHAM-UHFFFAOYSA-N 0.000 description 1
- DBMFYTQPPBBKHI-UHFFFAOYSA-N 4-cyanobenzenesulfonyl chloride Chemical compound ClS(=O)(=O)C1=CC=C(C#N)C=C1 DBMFYTQPPBBKHI-UHFFFAOYSA-N 0.000 description 1
- PUPBEGMQWLQKFS-UHFFFAOYSA-N 4-n-(1h-indol-7-yl)benzene-1,4-disulfonamide Chemical compound C1=CC(S(=O)(=O)N)=CC=C1S(=O)(=O)NC1=CC=CC2=C1NC=C2 PUPBEGMQWLQKFS-UHFFFAOYSA-N 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical group [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- QGZKDVFQNNGYKY-UHFFFAOYSA-O Ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 description 1
- YHFNQDLCMJSUOZ-UHFFFAOYSA-N C1=CC(=C2C(=C1)NC=C2Cl)N.Cl Chemical compound C1=CC(=C2C(=C1)NC=C2Cl)N.Cl YHFNQDLCMJSUOZ-UHFFFAOYSA-N 0.000 description 1
- HEOZJCBQOUSZGE-UHFFFAOYSA-N C1=CC(=C2C=C(NC2=C1)Cl)N.Cl Chemical compound C1=CC(=C2C=C(NC2=C1)Cl)N.Cl HEOZJCBQOUSZGE-UHFFFAOYSA-N 0.000 description 1
- FHNRKOJNEZMRFC-UHFFFAOYSA-N C1=CC2=C(C=C1N)C(=CN2)Cl.Cl Chemical compound C1=CC2=C(C=C1N)C(=CN2)Cl.Cl FHNRKOJNEZMRFC-UHFFFAOYSA-N 0.000 description 1
- PZFLBQKQKNITQR-UHFFFAOYSA-N C1=CC2=C(C=C1N)NC=C2Cl.Cl Chemical compound C1=CC2=C(C=C1N)NC=C2Cl.Cl PZFLBQKQKNITQR-UHFFFAOYSA-N 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound 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 1
- JLTDJTHDQAWBAV-UHFFFAOYSA-N N,N-dimethylaniline Chemical compound CN(C)C1=CC=CC=C1 JLTDJTHDQAWBAV-UHFFFAOYSA-N 0.000 description 1
- 241001483078 Phyto Species 0.000 description 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
- 229910021626 Tin(II) chloride Inorganic materials 0.000 description 1
- DSVGQVZAZSZEEX-UHFFFAOYSA-N [C].[Pt] Chemical compound [C].[Pt] DSVGQVZAZSZEEX-UHFFFAOYSA-N 0.000 description 1
- 125000004442 acylamino group Chemical group 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 125000004390 alkyl sulfonyl group Chemical group 0.000 description 1
- 125000004397 aminosulfonyl group Chemical group NS(=O)(=O)* 0.000 description 1
- 125000005427 anthranyl group Chemical group 0.000 description 1
- 229910052786 argon Inorganic materials 0.000 description 1
- 125000004429 atom Chemical group 0.000 description 1
- 125000003828 azulenyl group Chemical group 0.000 description 1
- FFBHFFJDDLITSX-UHFFFAOYSA-N benzyl N-[2-hydroxy-4-(3-oxomorpholin-4-yl)phenyl]carbamate Chemical compound OC1=C(NC(=O)OCC2=CC=CC=C2)C=CC(=C1)N1CCOCC1=O FFBHFFJDDLITSX-UHFFFAOYSA-N 0.000 description 1
- 238000007664 blowing Methods 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 238000005660 chlorination reaction Methods 0.000 description 1
- HEDRZPFGACZZDS-UHFFFAOYSA-N chloroform Substances ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 1
- 229960001701 chloroform Drugs 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 125000004093 cyano group Chemical group *C#N 0.000 description 1
- 125000000753 cycloalkyl group Chemical group 0.000 description 1
- 238000004042 decolorization Methods 0.000 description 1
- RHPIJWYTYJJCFU-UHFFFAOYSA-L diacetyloxyaluminum;hydrate Chemical compound O.CC(=O)O[Al]OC(C)=O RHPIJWYTYJJCFU-UHFFFAOYSA-L 0.000 description 1
- 238000010586 diagram Methods 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 238000004992 fast atom bombardment mass spectroscopy Methods 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 125000001153 fluoro group Chemical group F* 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 125000002883 imidazolyl group Chemical group 0.000 description 1
- 125000003454 indenyl group Chemical group C1(C=CC2=CC=CC=C12)* 0.000 description 1
- 239000011261 inert gas Substances 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 125000005956 isoquinolyl group Chemical group 0.000 description 1
- 239000010410 layer Substances 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 125000001624 naphthyl group Chemical group 0.000 description 1
- 125000004593 naphthyridinyl group Chemical group N1=C(C=CC2=CC=CN=C12)* 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 125000005542 phthalazyl group Chemical group 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 125000004309 pyranyl group Chemical group O1C(C=CC=C1)* 0.000 description 1
- 125000003226 pyrazolyl group Chemical group 0.000 description 1
- 125000005412 pyrazyl group Chemical group 0.000 description 1
- 125000000714 pyrimidinyl group Chemical group 0.000 description 1
- 125000000168 pyrrolyl group Chemical group 0.000 description 1
- 125000002294 quinazolinyl group Chemical group N1=C(N=CC2=CC=CC=C12)* 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- JVBXVOWTABLYPX-UHFFFAOYSA-L sodium dithionite Chemical compound [Na+].[Na+].[O-]S(=O)S([O-])=O JVBXVOWTABLYPX-UHFFFAOYSA-L 0.000 description 1
- 239000001119 stannous chloride Substances 0.000 description 1
- 235000011150 stannous chloride Nutrition 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 125000000446 sulfanediyl group Chemical group *S* 0.000 description 1
- 125000006296 sulfonyl amino group Chemical group [H]N(*)S(*)(=O)=O 0.000 description 1
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- Indole Compounds (AREA)
Description
【０００１】
【産業上の利用分野】
本発明は、特開平7-165708号公報あるいは特願平7-37456号等に開示された、医薬として優れた作用を有するスルホンアミド誘導体(II)の、工業的に優れた新規製造方法に関する。
【０００２】
【従来技術】
スルホンアミド誘導体(II)製造にあたり必要な合成中間体の製造法として、例えば、特開平7-165708号公報の製造例10には、3-クロロ-7-ニトロインドールを塩化第一錫および塩酸と反応させて、7-アミノ-3-クロロインドールを製造する方法が記載されている。［従来法(1)］
【０００３】
【化７】
また同中間体の製法として、特願平7-37456号の製造例1には、水酸化ナトリウムの存在下に3-クロロ-7-ニトロインドールとハイドロサルファイトナトリウムを反応させて、7-アミノ-3-クロロインドールを製造する方法が記載されている。［従来法(2)］
【０００５】
【化８】
次に、スルホンアミド誘導体(II)の従来製造法として、特開平7-165708号公報の実施例19には、7-アミノインドールと4-クロロスルホニルベンゼンスルホンアミドを反応させてN-(7-インドリル)-1,4-ベンゼンジスルホンアミドとし、次いでN-クロロコハク酸イミドと反応させて、N-(3-クロロ-7-インドリル)-1,4-ベンゼンジスルホンアミドを製造する方法が記載されている。［従来法(3)］
【０００７】
【化９】
さらに、特願平7-37456号の製造例4には、7-アミノ-3-クロロインドールと4-シアノベンゼンスルホニルクロリドを反応させて、N-(3-クロロ-7-インドリル)-4-シアノベンゼンスルホンアミドを製造する方法が記載されている。［従来法(4)］
【０００９】
【化１０】
【本発明が解決しようとする問題点】
しかし、上記従来法(1)あるいは同(2)に記載された、3-クロロ-7-ニトロインドールを還元して、7-アミノ-3-クロロインドールを製造する方法は収率が低く（従来法(1)；67%、同(2)；77%）、工業的製法としては不十分であった。また生成した7-アミノ-3-クロロインドールは不安定であり、極めて酸化されやすい問題点があった。
【００１１】
次に、上記従来法(3)に記載された、N-(3-クロロ-7-インドリル)-1,4-ベンゼンジスルホンアミドを製造する方法においても、やはりトータル収率が45.3%と低く、工業的製法として十分なものではなかった。また、従来法(3)においては最終工程において塩素化を行うが、その際に置換位置選択性が低く過剰反応が起こりやすく、N-クロロ体、インドール骨格の他位置への多付加体などの副生成物が生じ、精製が困難となる欠点もあった。
【００１２】
さらに、上記従来法(4)に記載された、N-(3-クロロ-7-インドリル)-4-シアノベンゼンスルホンアミドを製造する方法においても収率が77.2%であり、工業的製法としてと必ずしも満足できるものではなかった。
【００１３】
このように、医薬として優れた作用を有するスルホンアミド誘導体(II)の、工業的に優れた製造方法は、まだ確立されていないのが現状であり、新たな優れた方法が求められていた。
【００１４】
【課題を解決するための手段】
本発明者らは、上記問題点の改善を目指して鋭意研究を進めてきた。その結果、ニトロ化合物(III)を鉄および塩化アンモニウムと反応させてアミン塩酸塩(I)とし、次いで塩化スルホニル誘導体と反応させることにより、目的とするスルホンアミド誘導体(II)が収率・純度よく製造することを見出し本発明を完成するに至った。
具体的には、下記一般式で表されるニトロ化合物(III)
【００１５】
【化１１】
（式中、Ｘはハロゲン原子を意味する。）
を鉄および塩化アンモニウムと反応させて下記一般式で表されるアミン塩酸塩(I)
【００１７】
【化１２】
（式中、Ｘは前記と同様の意味を有する。）
とし、次いで一般式ＲＳＯ2Ｃｌで表される塩化スルホニル誘導体（Ｒは置換されていてもよい芳香環または置換されていてもよい複素環を意味する。）を反応させる下記一般式で表されるスルホンアミド誘導体(II)の製造法に関する。
【００１９】
【化１３】
（式中、ＲおよびＸは前記と同様の意味を有する。）
本製造法をまとめて工程図で示すと、以下の通りである。
【００２１】
【化１４】
ここで、各一般式中におけるＸはハロゲン原子を意味し、より具体的には塩素原子、臭素原子、フッ素原子またはヨウ素原子を挙げることができるが、中でも塩素原子または臭素原子がより好ましく、塩素原子がさらに好ましい。
また同じくＲは、置換されていてもよい芳香環または置換されていてもよい複素環を意味する。芳香環としてより具体的には、例えばフェニル基、インデニル基、ナフチル基、アズレニル基、アンスラニル基などを挙げることができ、中でもフェニル基がより好ましいが限定されない。複素環としてより具体的には、例えばピリジル基、ピラジル基、ピリミジル基、ピロリル基、イミダゾリル基、ピラゾリル基、インドリル基、イソキノリル基、キノリル基、フタラジル基、ナフチリジニル基、キノキサニル基、キナゾリニル基、フラニル基、ピラニル基、チエニル基などを挙げることができ、中でもピリジル基、キノリル基、フラニル基、チエニル基がより好ましいが限定されない。
【００２３】
なお、芳香環または複素環は置換されていてもよく、置換基として具体的には、例えばスルファモイル基、カルバモイル基、低級アルキル基、シクロアルキル基、ハロゲン化低級アルキル基、低級アルコキシ基、ハロゲン原子、シアノ基、ニトロ基、チオ低級アルコキシ基、低級アルキルスルホニル基、低級アルキル基で置換されていてもよいアミノ基、アシルアミノ基、スルホニルアミノ基などを挙げることができ、スルファモイル基がより好ましいが限定されない。
【００２４】
ニトロ化合物(III)として、さらに具体的には、例えば以下の化合物を挙げることができるが、これらに限定されない。
(1) 7-ニトロ-3-クロロインドール
(2) 6-ニトロ-3-クロロインドール
(3) 5-ニトロ-3-クロロインドール
(4) 4-ニトロ-3-クロロインドール
(5) 7-ニトロ-2-クロロインドール
(6) 6-ニトロ-2-クロロインドール
(7) 5-ニトロ-2-クロロインドール
(8) 4-ニトロ-2-クロロインドール
【００２５】
アミン塩酸塩(I)として、さらに具体的には、例えば以下の化合物を挙げることができるが、これらに限定されない。
(1) 7-アミノ-3-クロロインドール塩酸塩
(2) 6-アミノ-3-クロロインドール塩酸塩
(3) 5-アミノ-3-クロロインドール塩酸塩
(4) 4-アミノ-3-クロロインドール塩酸塩
(5) 7-アミノ-2-クロロインドール塩酸塩
(6) 6-アミノ-2-クロロインドール塩酸塩
(7) 5-アミノ-2-クロロインドール塩酸塩
(8) 4-アミノ-2-クロロインドール塩酸塩
【００２６】
スルホンアミド誘導体(II)として、さらに具体的には、例えば以下の化合物を挙げることができるが、これらに限定されない。
(1) N-(3-クロロ-7-インドリル)-1,4-ベンゼンジスルホンアミド
(2) N-(3-クロロ-7-インドリル)-4-シアノベンゼンスルホンアミド
(3) N-(3-クロロ-7-インドリル)-4-ニトロベンゼンスルホンアミド
(4) N-(3-クロロ-7-インドリル)-4-アミノベンゼンスルホンアミド
(5) N-(3-クロロ-7-インドリル)-4-(メタンスルホンアミド)ベンゼンスルホンアミド
(6) 3-クロロ-N-(3-クロロ-7-インドリル)ベンゼンスルホンアミド
(7) 4-カルバモイル-N-(3-クロロ-7-インドリル)ベンゼンスルホンアミド
(8) N-(3-クロロ-7-インドリル)-4-(メトキシカルボニルアミノ)ベンゼンスルホンアミド
(9) N-(3-クロロ-7-インドリル)-4-(N-メトキシスルファモイル)ベンゼンスルホンアミド
(10) N-(3-クロロ-7-インドリル)-4-(ジメチルアミノスルホニルアミノ)ベンゼンスルホンアミド
【００２７】
次いで本発明にかかる各工程を詳細に説明する。（前記［化１４］参照）
(1) 工程１
ニトロ化合物(III)を鉄および塩化アンモニウムと反応させてアミン塩酸塩(I)を製造する工程であり、具体的にはニトロ基をアミノ基に還元する工程である。一般的にニトロ基をアミノ基に還元する方法は数多くあるが、本発明にかかるニトロ化合物(III)のように分子内にハロゲン原子を有する場合、ハロゲン原子も還元されて脱ハロゲン化反応が同時に進行する問題点があった。例えば、特開平7-165708号公報の製造例10に記載されている、白金−炭素触媒を用いた還元法では、脱塩素体が主に生成し、目的物が十分に得られない。
しかし、本発明方法では、脱ハロゲン化は全く起こらず、ニトロ基のみ選択的に還元することができる。
本工程は、通常はシンセティック・コミュニケーションズ(Synthetic Comunications),22(22),3189-3195,1992. に記載された方法に従って実施することができるが、本発明におけるより好ましい反応条件を示せば以下の通りである。
【００２８】
溶媒は水または極性溶媒が好ましく、２種以上の混合溶媒を用いることもできる。極性溶媒として具体的には、例えば、メタノール、エタノール、1-プロパノール、2-プロパノール、1-ブタノール、2-ブタノール、3-ブタノール、ペンタノール、ヘキサノール等の低級アルコール類、アセトニトリル、テトラヒドロフラン、ジメチルスルホキシドなどの水と混和する溶媒等を挙げることができるが、メタノール、エタノール、1-プロパノール、2-プロパノールがより好ましく、2-プロパノールがさらに好ましい。最も好ましいのは、水と2-プロパノールの混合溶媒である。なお、溶媒の使用量は限定されず、通常はニトロ化合物(III)に対し１〜100倍重量を用いる。
【００２９】
鉄は比表面積の多い形態のものが好ましく、具体的には鉄粉を挙げることができる。鉄粉の使用量も限定されないが、通常はニトロ化合物(III)に対し１〜100倍重量を用いる。
【００３０】
塩化アンモニウムは粉末を直接添加してもよいが、通常は水溶液として加える。塩化アンモニウムの使用量も限定されず、通常はニトロ化合物(III)に対し0.01〜100当量を用いるが、好ましくは0.1〜10当量である。
【００３１】
反応条件も限定されないが、通常はニトロ化合物(III)と溶媒を混合し、ここに塩化アンモニウムの水溶液を加えて撹拌を続ける。この際、反応温度も限定されず、0℃〜溶媒還流温度において実施することができるが、30〜90℃がより好ましい。なお、50℃で実施した場合、約２時間程度で反応が終了する。なお、本工程は窒素、アルゴン等の不活性ガス存在下に行うことにより、さらに高純度・無着色の目的物を得ることができる。
【００３２】
反応終了後には反応液を塩基性とし、溶媒で抽出し、さらに塩化水素／酢酸エチルあるいは塩化水素ガス吹き込み等で処理して、目的とするアミン塩酸塩(I)を得ることができる。また生成物は、再結晶等によりさらに精製することもできる。
【００３３】
(2) 工程２
本工程は、アミン塩酸塩(I)と塩化スルホニル誘導体を反応させてスルホンアミド誘導体(II)を製造する工程である。本工程は通常のスルホンアミド化の常法に従って、実施することができるが、好ましくは、ピリジン、トリエチルアミン、ジメチルアニリン、炭酸カリウム等の脱塩酸剤存在下に行う。
【００３４】
また本発明においては、工程１を実施してアミン塩酸塩(I)を単離した後、工程２を実施してもよいし、アミン塩酸塩(I)を単離せずに工程１・２を連続反応として行うこともできる。
【００３５】
ここで、本発明における合成中間体である7-アミノ-3-クロロインドール塩酸塩は新規化合物である。一方、従来知られていた7-アミノ-3-クロロインドールの遊離体は酸化的に極めて不安定であり、従来法においては、遊離体として単離した後、次いでスルホンアミド化を行っていたが、合成中間体として保存できず、製造中の取り扱いに細心の注意を要し、スルホンアミド化後の精製も非常に困難であるなど、多くの問題点を有していた。しかし、塩酸塩にすることにより、安定性が飛躍的に向上し、上記問題点がすべて解決されるだけでなく、続くスルホンアミド化工程においては、遊離体に戻さず塩酸塩のまま利用することができ、工業的に極めて大きな有用性を有している。このように、新規化合物である7-アミノ-3-クロロインドール塩酸塩は、従来知られていた遊離体に対し、非常に重要な価値を持つ化合物である。
【００３６】
続いて本発明を具体的に説明するため、以下に実施例および比較例を掲げるが、本発明がこれらに限定されないことは言うまでもない。
【実施例】
実施例１ 7- アミノ -3- クロロインドール塩酸塩の合成
【００３７】
【化１５】
3-クロロ-7-ニトロインドール 9.83gと2-プロパノール(300ml)の混合物に、窒素雰囲気下、鉄粉 11.17g、塩化アンモニウム 21.4gの水(300ml)溶液を加え、60℃の油浴中にて2時間加熱攪拌した。反応液を濾過し、残渣をエタノール(300ml)で洗い込み、濾液を約半量まで減圧濃縮した。ここに水(100ml)、ジエチルエーテル(400ml)と1N-水酸化ナトリウム水溶液(200ml)を加えて分液し、有機層を飽和炭酸水素ナトリウム水溶液(300ml)、水(300ml)、飽和食塩水(300ml)で順次洗い、無水硫酸マグネシウムで乾燥後、約半量まで濃縮した。ここに4N-塩化水素／酢酸エチル溶液(50ml)を加え、析出した結晶を濾取し、ジエチルエーテル(300ml)で洗い、真空乾燥して標題化合物 9.64gを得た。(収率；95%、純度；99.8%)
【００３９】
1H-NMR(500MHz,DMSO-d6)； δ(ppm) 11.73(1H,s)、11.50-7.70(3H,br)、7.67(1H,d,J=2.7Hz)、7.45-7.40(1H,m)、7.17-7.12(2H,m).
FAB-MS； m/z=167 (MH+).
【００４０】
比較例１ 7- アミノ -3- クロロインドールの合成
特願平7-37456号の製造例1に従って、1N-水酸化ナトリウムの存在下に3-クロロ-7-ニトロインドールとハイドロサルファイトナトリウムで還元し、7-アミノ-3-クロロインドールを得た。（収率：77%、純度；86%）
【００４１】
同様にして0.25N-水酸化ナトリウムを用いて7-アミノ-3-クロロインドールを得た。（収率：42%、純度；98.7%）
【００４２】
実施例２ N-(3- クロロ -7- インドリル )-1,4- ベンゼンジスルホンアミドの合成
【００４３】
【化１６】
7-アミノ-3-クロロインドール塩酸塩 2.18gとテトラヒドロフラン(36ml)の混合物に、氷冷下、ピリジン(2.6ml)、4-クロロスルホニルベンゼンスルホンアミド 2.80gを順次加え、1.5時間攪拌した。反応液を減圧濃縮し、残渣に酢酸エチル(350ml)、0.5N-塩酸(300ml)を加えて分液し、有機層を飽和食塩水(200ml)で2回、飽和炭酸水素ナトリウム水溶液(250ml)、飽和食塩水(200ml)で順次洗い、無水硫酸マグネシウムで乾燥後、減圧濃縮した。残渣を酢酸エチル(350ml)に溶解し、活性炭 2gを加えて80℃の油浴中で30分間脱色した。活性炭を濾去した後、減圧濃縮して標題化合物 4.09gを得た。(収率；98.7%)
【００４５】
実施例３ N-(3- クロロ -7- インドリル )-1,4- ベンゼンジスルホンアミドの合成 3-クロロ-7-ニトロインドール 590mgと2-プロパノール(10ml)の混合物に、窒素雰囲気下、鉄粉 503mg、塩化アンモニウム 32mgの水(2ml)溶液を加え、60℃の油浴にて2時間加熱攪拌した。反応液を氷冷し、受器に1N-塩酸(3ml)を入れておき、活性炭 590mgを敷いたセライトを通して濾過し、残渣を酢酸エチル(15ml)で洗い込んだ。この濾液を氷冷し、ピリジン(0.97ml)、4-クロロスルホニルベンゼンスルホンアミド 767mgの酢酸エチル(5ml)溶液を順次加え、そのまま3時間攪拌した。反応液を1N-塩酸(10ml)で2回、飽和炭酸水素ナトリウム水溶液(10ml)で2回、飽和食塩水(10ml)で1回順次洗い、活性炭、無水硫酸マグネシウムで脱色、乾燥した後溶媒を留去し、白色の標題化合物 1.0gを得た。（収率；86.3%）
【００４６】
実施例４ N-(3- クロロ -7- インドリル )-1,4- ベンゼンジスルホンアミドの合成 3-クロロ-7-ニトロインドール 100g、2-プロパノール(1.2L)の混合物に、窒素雰囲気下、塩化アンモニウム 5.44gの水(300ml)溶液を加え、60℃の水浴で加熱した後、鉄粉 28.4gを40分間隔で3回加え、それぞれ2-プロパノール(100ml)で洗い込んだ。1時間加熱攪拌した後、反応液を氷冷し、受器に1N-塩酸(510ml)を入れておき、活性炭 50gを敷いたセライトを通して濾過し、2-プロパノール(100ml)と酢酸エチル(1L)で洗い込んだ。この濾液を氷冷し、ピリジン(165ml)、4-クロロスルホニルベンゼンスルホンアミド 143.1gの酢酸エチル(700ml)溶液を加え、そのまま19時間攪拌した。反応液を1N-塩酸(1.5L)で2回、水(200ml)、飽和炭酸水素ナトリウム水溶液(1.5L)、飽和食塩水(200ml)で順次洗い、活性炭 30g、無水硫酸マグネシウム 100gで脱色、乾燥した後濾過し、酢酸エチル(500ｍl)で洗った。溶媒を一部留去して約1Lとした後、トルエン(2L)を加え、60℃で1時間加熱攪拌後、さらに酢酸エチルを留去し、析出した結晶を濾過、トルエン、ヘキサンで洗浄、減圧乾燥し、白色の標題化合物 184.1gを得た。（収率：93.8%、純度；99.2%）
上記の結晶にアセトン(1.1L)を加え、加熱溶解後、水(1.1L)をゆっくり加え、一晩室温で攪拌して析出した結晶を濾過し、(1:2)アセトン／水混合液(700ml)で洗った後減圧乾燥し、白色の標題化合物 157.0gを得た。(再結晶収率；85%、純度；99.8%)[0001]
[Industrial application fields]
The present invention relates to a novel industrially superior process for producing a sulfonamide derivative (II) having an excellent action as a pharmaceutical, disclosed in Japanese Patent Application Laid-Open No. 7-165708 or Japanese Patent Application No. 7-37456.
[0002]
[Prior art]
As a production method of a synthetic intermediate necessary for the production of the sulfonamide derivative (II), for example, in Production Example 10 of JP-A-7-165708, 3-chloro-7-nitroindole is mixed with stannous chloride and hydrochloric acid. A method for reacting to produce 7-amino-3-chloroindole is described. [Conventional method (1)]
[0003]
[Chemical 7]
As a method for producing the intermediate, Production Example 1 of Japanese Patent Application No. 7-37456 includes the reaction of 3-chloro-7-nitroindole with sodium hydrosulfite in the presence of sodium hydroxide to produce 7-amino A process for producing -3-chloroindole is described. [Conventional method (2)]
[0005]
[Chemical 8]
Next, as a conventional method for producing a sulfonamide derivative (II), Example 19 of JP-A No. 7-165708 includes a reaction of 7-aminoindole with 4-chlorosulfonylbenzenesulfonamide to produce N- (7- Indolyl) -1,4-benzenedisulfonamide is described, followed by a reaction with N-chlorosuccinimide to produce N- (3-chloro-7-indolyl) -1,4-benzenedisulfonamide. Yes. [Conventional method (3)]
[0007]
[Chemical 9]
Further, in Production Example 4 of Japanese Patent Application No. 7-37456, 7-amino-3-chloroindole and 4-cyanobenzenesulfonyl chloride are reacted to form N- (3-chloro-7-indolyl) -4- A method for producing cyanobenzenesulfonamide is described. [Conventional method (4)]
[0009]
[Chemical Formula 10]
[Problems to be solved by the present invention]
However, the method for producing 7-amino-3-chloroindole by reducing 3-chloro-7-nitroindole described in the conventional method (1) or (2) has a low yield (conventional method). Law (1); 67%, (2); 77%), which was insufficient as an industrial production method. Also, the produced 7-amino-3-chloroindole was unstable and had a problem of being easily oxidized.
[0011]
Next, also in the method for producing N- (3-chloro-7-indolyl) -1,4-benzenedisulfonamide described in the conventional method (3), the total yield is still as low as 45.3%, It was not sufficient as an industrial production method. In the conventional method (3), chlorination is carried out in the final step. At that time, the substitution site selectivity is low and an excessive reaction is likely to occur, such as N-chloro form, multi-adducts at other positions of the indole skeleton, etc. There was also a disadvantage that a by-product was generated and purification was difficult.
[0012]
Further, in the method for producing N- (3-chloro-7-indolyl) -4-cyanobenzenesulfonamide described in the conventional method (4), the yield is 77.2%, and as an industrial production method, It was not always satisfactory.
[0013]
Thus, an industrially excellent method for producing a sulfonamide derivative (II) having an excellent action as a pharmaceutical has not yet been established, and a new and superior method has been demanded.
[0014]
[Means for Solving the Problems]
The inventors of the present invention have been diligently researching to improve the above problems. As a result, by reacting the nitro compound (III) with iron and ammonium chloride to give an amine hydrochloride (I) and then with a sulfonyl chloride derivative, the desired sulfonamide derivative (II) is obtained in high yield and purity. The inventors have found that it has been produced and have completed the present invention.
Specifically, the nitro compound (III) represented by the following general formula
[0015]
Embedded image
(In the formula, X means a halogen atom.)
Amine hydrochloride (I) represented by the following general formula:
[0017]
Embedded image
(In the formula, X has the same meaning as described above.)
And then a sulfonyl chloride derivative represented by the general formula RSO 2 Cl (R represents an optionally substituted aromatic ring or an optionally substituted heterocycle) is represented by the following general formula: The present invention relates to a process for producing a sulfonamide derivative (II).
[0019]
Embedded image
(In the formula, R and X have the same meaning as described above.)
The production method is collectively shown in the process diagram as follows.
[0021]
Embedded image
Here, X in each general formula means a halogen atom, and more specifically, a chlorine atom, a bromine atom, a fluorine atom or an iodine atom can be mentioned, among which a chlorine atom or a bromine atom is more preferable, Atoms are more preferred.
Similarly, R means an optionally substituted aromatic ring or an optionally substituted heterocyclic ring. More specifically, examples of the aromatic ring include a phenyl group, an indenyl group, a naphthyl group, an azulenyl group, and an anthranyl group. Among them, a phenyl group is more preferable, but is not limited. More specifically, examples of the heterocyclic ring include pyridyl group, pyrazyl group, pyrimidyl group, pyrrolyl group, imidazolyl group, pyrazolyl group, indolyl group, isoquinolyl group, quinolyl group, phthalazyl group, naphthyridinyl group, quinoxanyl group, quinazolinyl group, and furanyl. Group, pyranyl group, thienyl group and the like can be mentioned, among which pyridyl group, quinolyl group, furanyl group and thienyl group are more preferable, but not limited.
[0023]
In addition, the aromatic ring or the heterocyclic ring may be substituted, and specific examples of the substituent include, for example, a sulfamoyl group, a carbamoyl group, a lower alkyl group, a cycloalkyl group, a halogenated lower alkyl group, a lower alkoxy group, and a halogen atom. , A cyano group, a nitro group, a thio lower alkoxy group, a lower alkylsulfonyl group, an amino group optionally substituted with a lower alkyl group, an acylamino group, a sulfonylamino group, and the like. Not.
[0024]
More specific examples of the nitro compound (III) include, but are not limited to, the following compounds.
(1) 7-nitro-3-chloroindole
(2) 6-nitro-3-chloroindole
(3) 5-Nitro-3-chloroindole
(4) 4-Nitro-3-chloroindole
(5) 7-Nitro-2-chloroindole
(6) 6-Nitro-2-chloroindole
(7) 5-Nitro-2-chloroindole
(8) 4-Nitro-2-chloroindole [0025]
More specific examples of amine hydrochloride (I) include, but are not limited to, the following compounds.
(1) 7-amino-3-chloroindole hydrochloride
(2) 6-amino-3-chloroindole hydrochloride
(3) 5-Amino-3-chloroindole hydrochloride
(4) 4-Amino-3-chloroindole hydrochloride
(5) 7-amino-2-chloroindole hydrochloride
(6) 6-amino-2-chloroindole hydrochloride
(7) 5-Amino-2-chloroindole hydrochloride
(8) 4-Amino-2-chloroindole hydrochloride
More specific examples of the sulfonamide derivative (II) include, but are not limited to, the following compounds.
(1) N- (3-Chloro-7-indolyl) -1,4-benzenedisulfonamide
(2) N- (3-Chloro-7-indolyl) -4-cyanobenzenesulfonamide
(3) N- (3-Chloro-7-indolyl) -4-nitrobenzenesulfonamide
(4) N- (3-Chloro-7-indolyl) -4-aminobenzenesulfonamide
(5) N- (3-Chloro-7-indolyl) -4- (methanesulfonamide) benzenesulfonamide
(6) 3-Chloro-N- (3-chloro-7-indolyl) benzenesulfonamide
(7) 4-carbamoyl-N- (3-chloro-7-indolyl) benzenesulfonamide
(8) N- (3-Chloro-7-indolyl) -4- (methoxycarbonylamino) benzenesulfonamide
(9) N- (3-Chloro-7-indolyl) -4- (N-methoxysulfamoyl) benzenesulfonamide
(10) N- (3-Chloro-7-indolyl) -4- (dimethylaminosulfonylamino) benzenesulfonamide
Next, each step according to the present invention will be described in detail. (Refer to [Formula 14] above)
(1) Process 1
This is a step of producing amine hydrochloride (I) by reacting nitro compound (III) with iron and ammonium chloride, specifically, a step of reducing a nitro group to an amino group. In general, there are many methods for reducing a nitro group to an amino group. However, when the molecule has a halogen atom as in the nitro compound (III) according to the present invention, the halogen atom is also reduced and the dehalogenation reaction is simultaneously performed. There was a problem going on. For example, in the reduction method using a platinum-carbon catalyst described in Production Example 10 of JP-A-7-165708, a dechlorinated product is mainly produced, and the target product cannot be obtained sufficiently.
However, in the method of the present invention, no dehalogenation occurs, and only the nitro group can be selectively reduced.
This step can usually be carried out according to the method described in Synthetic Communications, 22 (22), 3189-3195, 1992. Street.
[0028]
The solvent is preferably water or a polar solvent, and two or more kinds of mixed solvents can also be used. Specific examples of the polar solvent include lower alcohols such as methanol, ethanol, 1-propanol, 2-propanol, 1-butanol, 2-butanol, 3-butanol, pentanol, and hexanol, acetonitrile, tetrahydrofuran, and dimethyl sulfoxide. Examples thereof include solvents miscible with water, such as methanol, ethanol, 1-propanol and 2-propanol, more preferably 2-propanol. Most preferred is a mixed solvent of water and 2-propanol. In addition, the usage-amount of a solvent is not limited, Usually, 1-100 times weight is used with respect to nitro compound (III).
[0029]
Iron is preferably in a form with a large specific surface area, and specific examples include iron powder. The amount of iron powder used is not limited, but usually 1 to 100 times the weight of the nitro compound (III) is used.
[0030]
Ammonium chloride may be added directly as a powder, but is usually added as an aqueous solution. The amount of ammonium chloride used is not limited and is usually 0.01 to 100 equivalents, preferably 0.1 to 10 equivalents, relative to the nitro compound (III).
[0031]
Although reaction conditions are not limited, usually, nitro compound (III) and a solvent are mixed, and an aqueous solution of ammonium chloride is added thereto and stirring is continued. At this time, the reaction temperature is not limited, and the reaction can be carried out at 0 ° C. to the solvent reflux temperature, but 30 to 90 ° C. is more preferable. When carried out at 50 ° C., the reaction is completed in about 2 hours. In addition, this process can be performed in the presence of an inert gas such as nitrogen or argon to obtain a higher-purity and non-colored target product.
[0032]
After completion of the reaction, the reaction solution is made basic, extracted with a solvent, and further treated with hydrogen chloride / ethyl acetate or hydrogen chloride gas blowing to obtain the desired amine hydrochloride (I). The product can be further purified by recrystallization or the like.
[0033]
(2) Process 2
This step is a step for producing the sulfonamide derivative (II) by reacting the amine hydrochloride (I) with the sulfonyl chloride derivative. Although this step can be carried out according to a conventional method for sulfonamidation, it is preferably carried out in the presence of a dehydrochlorinating agent such as pyridine, triethylamine, dimethylaniline, potassium carbonate or the like.
[0034]
In the present invention, after step 1 is carried out to isolate amine hydrochloride (I), step 2 may be carried out, or steps 1 and 2 may be carried out without isolating amine hydrochloride (I). It can also be carried out as a continuous reaction.
[0035]
Here, 7-amino-3-chloroindole hydrochloride, which is a synthetic intermediate in the present invention, is a novel compound. On the other hand, the conventionally known 7-amino-3-chloroindole free form is extremely oxidatively unstable, and in the conventional method, it was isolated as a free form and then sulfonamidated. However, it could not be stored as a synthetic intermediate, required careful handling during production, and had many problems such as being extremely difficult to purify after sulfonamidation. However, the use of hydrochloride not only dramatically improves the stability and solves all of the above problems, but in the subsequent sulfonamidation process, the hydrochloride must be used as it is without returning to the free form. It is extremely useful from an industrial point of view. Thus, 7-amino-3-chloroindole hydrochloride, which is a novel compound, is a compound having a very important value with respect to conventionally known educts.
[0036]
Subsequently, in order to specifically describe the present invention, examples and comparative examples are listed below, but it goes without saying that the present invention is not limited thereto.
【Example】
Example 1 Synthesis of 7- amino -3 -chloroindole hydrochloride
Embedded image
To a mixture of 9.83 g of 3-chloro-7-nitroindole and 2-propanol (300 ml), add a solution of 11.17 g of iron powder and 21.4 g of ammonium chloride in water (300 ml) under a nitrogen atmosphere. And stirred for 2 hours. The reaction mixture was filtered, the residue was washed with ethanol (300 ml), and the filtrate was concentrated under reduced pressure to about half volume. Water (100 ml), diethyl ether (400 ml) and 1N-aqueous sodium hydroxide solution (200 ml) were added thereto for liquid separation, and the organic layer was saturated sodium bicarbonate aqueous solution (300 ml), water (300 ml), saturated saline ( 300 ml), dried over anhydrous magnesium sulfate, and concentrated to about half volume. A 4N-hydrogen chloride / ethyl acetate solution (50 ml) was added thereto, and the precipitated crystals were collected by filtration, washed with diethyl ether (300 ml), and dried in vacuo to give 9.64 g of the title compound. (Yield: 95%, purity: 99.8%)
[0039]
1 H-NMR (500 MHz, DMSO-d 6 ); δ (ppm) 11.73 (1H, s), 11.50-7.70 (3H, br), 7.67 (1H, d, J = 2.7 Hz), 7.45-7.40 (1H , m), 7.17-7.12 (2H, m).
FAB-MS; m / z = 167 (MH + ).
[0040]
Comparative Example 1 Synthesis of 7- amino -3 -chloroindole According to Preparation Example 1 of Japanese Patent Application No. 7-37456, 3-chloro-7-nitroindole and hydrosal in the presence of 1N-sodium hydroxide Reduction with phyto sodium gave 7-amino-3-chloroindole. (Yield: 77%, purity; 86%)
[0041]
Similarly, 7-amino-3-chloroindole was obtained using 0.25N sodium hydroxide. (Yield: 42%, purity; 98.7%)
[0042]
Example 2 Synthesis of N- (3- chloro- 7- indolyl ) -1,4- benzenedisulfonamide
Embedded image
To a mixture of 2.18 g of 7-amino-3-chloroindole hydrochloride and tetrahydrofuran (36 ml), pyridine (2.6 ml) and 2.80 g of 4-chlorosulfonylbenzenesulfonamide were successively added under ice cooling, and the mixture was stirred for 1.5 hours. The reaction mixture was concentrated under reduced pressure, and ethyl acetate (350 ml) and 0.5N hydrochloric acid (300 ml) were added to the residue to separate the layers. The organic layer was washed twice with saturated brine (200 ml) and saturated aqueous sodium hydrogen carbonate solution (250 ml). The extract was washed successively with saturated brine (200 ml), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was dissolved in ethyl acetate (350 ml), 2 g of activated carbon was added, and decolorization was performed in an oil bath at 80 ° C. for 30 minutes. The activated carbon was filtered off and concentrated under reduced pressure to give 4.09 g of the title compound. (Yield; 98.7%)
[0045]
Example 3 Synthesis of N- (3- chloro- 7- indolyl ) -1,4- benzenedisulfonamide Iron powder was added to a mixture of 590 mg of 3-chloro-7-nitroindole and 2-propanol (10 ml) under a nitrogen atmosphere. A solution of 503 mg and ammonium chloride 32 mg in water (2 ml) was added, and the mixture was heated and stirred in an oil bath at 60 ° C. for 2 hours. The reaction solution was ice-cooled, 1N-hydrochloric acid (3 ml) was placed in a receiver, filtered through Celite covered with 590 mg of activated carbon, and the residue was washed with ethyl acetate (15 ml). The filtrate was ice-cooled, a solution of pyridine (0.97 ml) and 4-chlorosulfonylbenzenesulfonamide (767 mg) in ethyl acetate (5 ml) was successively added, and the mixture was stirred as it was for 3 hours. The reaction solution was washed twice with 1N hydrochloric acid (10 ml), twice with saturated aqueous sodium hydrogen carbonate solution (10 ml) and once with saturated brine (10 ml), decolorized with activated carbon and anhydrous magnesium sulfate, dried, and then the solvent was removed. Distilled off to give 1.0 g of white title compound. (Yield; 86.3%)
[0046]
Example 4 Synthesis of N- (3- chloro- 7- indolyl ) -1,4- benzenedisulfonamide A mixture of 100 g of 3-chloro-7-nitroindole and 2-propanol (1.2 L) was chlorinated under a nitrogen atmosphere. A solution of ammonium 5.44 g in water (300 ml) was added and heated in a water bath at 60 ° C., then 28.4 g of iron powder was added three times at intervals of 40 minutes, and each was washed with 2-propanol (100 ml). After stirring for 1 hour, the reaction mixture was ice-cooled, 1N-hydrochloric acid (510 ml) was placed in the receiver, filtered through celite with 50 g of activated carbon, 2-propanol (100 ml) and ethyl acetate (1 L) Washed in with. The filtrate was ice-cooled, a solution of pyridine (165 ml) and 4-chlorosulfonylbenzenesulfonamide 143.1 g in ethyl acetate (700 ml) was added, and the mixture was stirred as it was for 19 hours. Wash the reaction solution twice with 1N-hydrochloric acid (1.5 L), water (200 ml), saturated aqueous sodium hydrogen carbonate solution (1.5 L), saturated brine (200 ml) in this order, decolorize with activated carbon 30 g and anhydrous magnesium sulfate 100 g, and dry The solution was then filtered and washed with ethyl acetate (500 ml). After partially distilling off the solvent to about 1 L, toluene (2 L) was added, and after stirring for 1 hour at 60 ° C., ethyl acetate was further distilled off, and the precipitated crystals were filtered, washed with toluene and hexane, Drying under reduced pressure gave 184.1 g of the white title compound. (Yield: 93.8%, purity; 99.2%)
Acetone (1.1 L) was added to the above crystals, dissolved with heating, water (1.1 L) was slowly added, and the crystals precipitated by stirring at room temperature overnight were filtered, and a (1: 2) acetone / water mixture ( 700 ml) and then dried under reduced pressure to obtain 157.0 g of a white title compound. (Recrystallization yield: 85%, purity: 99.8%)
Claims (6)
と一般式ＲＳＯ2Ｃｌで表される塩化スルホニル誘導体（Ｒは置換されていてもよい芳香環または置換されていてもよい複素環を意味する。）を反応させることを特徴とする下記一般式で表されるスルホンアミド誘導体(II)の製造法。
And a sulfonyl chloride derivative represented by the general formula RSO 2 Cl (R represents an aromatic ring which may be substituted or a heterocyclic ring which may be substituted). A process for producing the represented sulfonamide derivative (II).
を鉄および塩化アンモニウムと反応させて下記一般式で表されるアミン塩酸塩(I)
とし、次いで一般式ＲＳＯ2Ｃｌで表される塩化スルホニル誘導体（Ｒは前記と同様の意味を有する。）を反応させることを特徴とする下記一般式で表されるスルホンアミド誘導体(II)の製造法。
Amine hydrochloride (I) represented by the following general formula:
And then reacting with a sulfonyl chloride derivative represented by the general formula RSO 2 Cl (R has the same meaning as described above), to produce a sulfonamide derivative (II) represented by the following general formula Law.
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| JP12944796A JP3868534B2 (en) | 1996-05-24 | 1996-05-24 | Process for producing sulfonamide derivatives and intermediates |
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| JP12944796A JP3868534B2 (en) | 1996-05-24 | 1996-05-24 | Process for producing sulfonamide derivatives and intermediates |
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| JP4418430B2 (en) * | 2003-09-10 | 2010-02-17 | エーザイ・アール・アンド・ディー・マネジメント株式会社 | Method for producing sulfonamide-containing indole compound |
| PL1666463T3 (en) * | 2003-09-10 | 2011-04-29 | Eisai R&D Man Co Ltd | Crystal of sulfonamide-containing indole compound and process for producing the same |
| JPWO2006054456A1 (en) | 2004-11-17 | 2008-05-29 | エーザイ・アール・アンド・ディー・マネジメント株式会社 | Crystals of bicyclic heterocycle-containing sulfonamide compounds |
| CN108822002B (en) * | 2018-06-21 | 2020-05-05 | 中南大学 | A kind of method of ultrasonic-assisted synthesis of N-arylsulfonamide |
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