KR830001276B1 - Method for preparing substituted heterocycle benzamide - Google Patents
Method for preparing substituted heterocycle benzamide Download PDFInfo
- Publication number
- KR830001276B1 KR830001276B1 KR1019790000155A KR790000155A KR830001276B1 KR 830001276 B1 KR830001276 B1 KR 830001276B1 KR 1019790000155 A KR1019790000155 A KR 1019790000155A KR 790000155 A KR790000155 A KR 790000155A KR 830001276 B1 KR830001276 B1 KR 830001276B1
- Authority
- KR
- South Korea
- Prior art keywords
- water
- added
- methoxy
- filtered
- solution
- Prior art date
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- KXDAEFPNCMNJSK-UHFFFAOYSA-N Benzamide Chemical compound NC(=O)C1=CC=CC=C1 KXDAEFPNCMNJSK-UHFFFAOYSA-N 0.000 title claims description 38
- 125000000623 heterocyclic group Chemical group 0.000 title claims description 3
- 238000000034 method Methods 0.000 title description 5
- 239000002253 acid Substances 0.000 claims description 32
- 238000004519 manufacturing process Methods 0.000 claims description 3
- 125000002924 primary amino group Chemical class [H]N([H])* 0.000 claims 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 250
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 150
- 239000000243 solution Substances 0.000 description 130
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 124
- 239000000047 product Substances 0.000 description 111
- 238000002844 melting Methods 0.000 description 108
- 230000008018 melting Effects 0.000 description 108
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 96
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 77
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 70
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 63
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 60
- -1 phosphor anhydride Chemical class 0.000 description 58
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 57
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 55
- 239000013078 crystal Substances 0.000 description 50
- 239000002244 precipitate Substances 0.000 description 49
- 239000002585 base Substances 0.000 description 47
- 239000000203 mixture Substances 0.000 description 45
- 230000005484 gravity Effects 0.000 description 44
- 238000010992 reflux Methods 0.000 description 42
- UIIMBOGNXHQVGW-UHFFFAOYSA-N sodium;hydron;carbonate Chemical compound [Na+].OC(O)=O UIIMBOGNXHQVGW-UHFFFAOYSA-N 0.000 description 41
- 239000000725 suspension Substances 0.000 description 40
- 229910021529 ammonia Inorganic materials 0.000 description 35
- 239000003610 charcoal Substances 0.000 description 35
- 238000006243 chemical reaction Methods 0.000 description 35
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 33
- 239000012670 alkaline solution Substances 0.000 description 33
- 239000000706 filtrate Substances 0.000 description 32
- 239000012429 reaction media Substances 0.000 description 31
- 229940086542 triethylamine Drugs 0.000 description 31
- 238000003756 stirring Methods 0.000 description 30
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 28
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 27
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 26
- 229960000583 acetic acid Drugs 0.000 description 26
- 238000001816 cooling Methods 0.000 description 26
- 235000011054 acetic acid Nutrition 0.000 description 25
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 24
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 24
- 150000001875 compounds Chemical class 0.000 description 23
- 239000002904 solvent Substances 0.000 description 23
- 229940032007 methylethyl ketone Drugs 0.000 description 21
- 239000003921 oil Substances 0.000 description 20
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 16
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 16
- 238000009835 boiling Methods 0.000 description 16
- YOETUEMZNOLGDB-UHFFFAOYSA-N 2-methylpropyl carbonochloridate Chemical compound CC(C)COC(Cl)=O YOETUEMZNOLGDB-UHFFFAOYSA-N 0.000 description 15
- RIFGWPKJUGCATF-UHFFFAOYSA-N ethyl chloroformate Chemical compound CCOC(Cl)=O RIFGWPKJUGCATF-UHFFFAOYSA-N 0.000 description 13
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 13
- 235000019341 magnesium sulphate Nutrition 0.000 description 13
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 12
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 12
- 239000007787 solid Substances 0.000 description 12
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 description 11
- 239000012074 organic phase Substances 0.000 description 11
- FWZCSDNSXJJNLH-UHFFFAOYSA-N (1-cyclohexylpyrrolidin-2-yl)methanamine Chemical compound NCC1CCCN1C1CCCCC1 FWZCSDNSXJJNLH-UHFFFAOYSA-N 0.000 description 10
- 238000010438 heat treatment Methods 0.000 description 10
- OJVNCXHGGYYOPH-UHFFFAOYSA-N 4-amino-5-ethylsulfonyl-2-methoxybenzoic acid Chemical compound CCS(=O)(=O)C1=CC(C(O)=O)=C(OC)C=C1N OJVNCXHGGYYOPH-UHFFFAOYSA-N 0.000 description 9
- 239000006229 carbon black Substances 0.000 description 9
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 9
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 9
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 8
- YARZWCAMQSVZLU-UHFFFAOYSA-N (1-cyclopentylpyrrolidin-2-yl)methanamine Chemical compound NCC1CCCN1C1CCCC1 YARZWCAMQSVZLU-UHFFFAOYSA-N 0.000 description 7
- YEVQOPOKMKTXMD-UHFFFAOYSA-N 2,3-dimethoxy-5-sulfamoylbenzoic acid Chemical compound COC1=CC(S(N)(=O)=O)=CC(C(O)=O)=C1OC YEVQOPOKMKTXMD-UHFFFAOYSA-N 0.000 description 7
- 150000001408 amides Chemical class 0.000 description 7
- 239000008346 aqueous phase Substances 0.000 description 7
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 7
- 238000000354 decomposition reaction Methods 0.000 description 7
- 239000011541 reaction mixture Substances 0.000 description 7
- 150000003839 salts Chemical class 0.000 description 7
- WWZAQUJXWBZQLQ-UHFFFAOYSA-N 1-(cyclopropylmethyl)pyrrolidin-3-amine Chemical compound C1C(N)CCN1CC1CC1 WWZAQUJXWBZQLQ-UHFFFAOYSA-N 0.000 description 6
- AXCPXYJCYHYDDH-UHFFFAOYSA-N 2,4-dimethoxy-5-methylsulfonylbenzoic acid Chemical compound COC1=CC(OC)=C(S(C)(=O)=O)C=C1C(O)=O AXCPXYJCYHYDDH-UHFFFAOYSA-N 0.000 description 6
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 6
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 6
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 6
- 235000017557 sodium bicarbonate Nutrition 0.000 description 6
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 6
- GEHJYWRUCIMESM-UHFFFAOYSA-L sodium sulfite Chemical compound [Na+].[Na+].[O-]S([O-])=O GEHJYWRUCIMESM-UHFFFAOYSA-L 0.000 description 6
- SBSSXCKDVHHANA-UHFFFAOYSA-N 1-(cyclohexylmethyl)pyrrolidin-3-amine Chemical compound C1C(N)CCN1CC1CCCCC1 SBSSXCKDVHHANA-UHFFFAOYSA-N 0.000 description 5
- XFZMCFJADJFEBB-UHFFFAOYSA-N 2-methoxy-5-sulfamoylbenzoyl chloride Chemical compound COC1=CC=C(S(N)(=O)=O)C=C1C(Cl)=O XFZMCFJADJFEBB-UHFFFAOYSA-N 0.000 description 5
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 5
- 150000001412 amines Chemical class 0.000 description 5
- 150000002148 esters Chemical class 0.000 description 5
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 5
- 150000007524 organic acids Chemical class 0.000 description 5
- 238000001953 recrystallisation Methods 0.000 description 5
- ILWRPSCZWQJDMK-UHFFFAOYSA-N triethylazanium;chloride Chemical compound Cl.CCN(CC)CC ILWRPSCZWQJDMK-UHFFFAOYSA-N 0.000 description 5
- KEQGZUUPPQEDPF-UHFFFAOYSA-N 1,3-dichloro-5,5-dimethylimidazolidine-2,4-dione Chemical compound CC1(C)N(Cl)C(=O)N(Cl)C1=O KEQGZUUPPQEDPF-UHFFFAOYSA-N 0.000 description 4
- NGNBDVOYPDDBFK-UHFFFAOYSA-N 2-[2,4-di(pentan-2-yl)phenoxy]acetyl chloride Chemical compound CCCC(C)C1=CC=C(OCC(Cl)=O)C(C(C)CCC)=C1 NGNBDVOYPDDBFK-UHFFFAOYSA-N 0.000 description 4
- KQSUBSBZIKTNAD-UHFFFAOYSA-N 2-methoxy-6-methyl-3-propan-2-yl-5-sulfamoylbenzoyl chloride Chemical compound COC1=C(C(C)C)C=C(S(N)(=O)=O)C(C)=C1C(Cl)=O KQSUBSBZIKTNAD-UHFFFAOYSA-N 0.000 description 4
- OSABGJPPVZBJPX-UHFFFAOYSA-N 4-chloro-5-ethylsulfonyl-2-methoxybenzoyl chloride Chemical compound CCS(=O)(=O)C1=CC(C(Cl)=O)=C(OC)C=C1Cl OSABGJPPVZBJPX-UHFFFAOYSA-N 0.000 description 4
- 241001397173 Kali <angiosperm> Species 0.000 description 4
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 4
- 238000007112 amidation reaction Methods 0.000 description 4
- 239000007864 aqueous solution Substances 0.000 description 4
- XTHPWXDJESJLNJ-UHFFFAOYSA-N chlorosulfonic acid Substances OS(Cl)(=O)=O XTHPWXDJESJLNJ-UHFFFAOYSA-N 0.000 description 4
- 238000001704 evaporation Methods 0.000 description 4
- 238000001914 filtration Methods 0.000 description 4
- 239000012530 fluid Substances 0.000 description 4
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- KJFMBFZCATUALV-UHFFFAOYSA-N phenolphthalein Chemical compound C1=CC(O)=CC=C1C1(C=2C=CC(O)=CC=2)C2=CC=CC=C2C(=O)O1 KJFMBFZCATUALV-UHFFFAOYSA-N 0.000 description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 4
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- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 4
- TZOCBFJIISELCS-UHFFFAOYSA-N 2,3-dimethoxy-5-sulfamoylbenzoyl chloride Chemical compound COC1=CC(S(N)(=O)=O)=CC(C(Cl)=O)=C1OC TZOCBFJIISELCS-UHFFFAOYSA-N 0.000 description 3
- ATGSLQBVSZNJMT-UHFFFAOYSA-N 2,5-dichloropentan-1-amine;hydrochloride Chemical compound Cl.NCC(Cl)CCCCl ATGSLQBVSZNJMT-UHFFFAOYSA-N 0.000 description 3
- SWKGOTXIMPKBFY-UHFFFAOYSA-N 3,5-dichloro-2-prop-2-ynoxybenzoic acid Chemical compound OC(=O)C1=CC(Cl)=CC(Cl)=C1OCC#C SWKGOTXIMPKBFY-UHFFFAOYSA-N 0.000 description 3
- NGGPBZVCIOCQCV-UHFFFAOYSA-N 4-acetamido-5-ethylsulfinyl-2-methoxybenzoic acid Chemical compound CCS(=O)C1=CC(C(O)=O)=C(OC)C=C1NC(C)=O NGGPBZVCIOCQCV-UHFFFAOYSA-N 0.000 description 3
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- FDCPRDKOLWKALM-UHFFFAOYSA-N 5-chlorosulfonyl-2,4-dimethoxybenzoic acid Chemical compound COC1=CC(OC)=C(S(Cl)(=O)=O)C=C1C(O)=O FDCPRDKOLWKALM-UHFFFAOYSA-N 0.000 description 3
- WSDVZXXVUDLABA-UHFFFAOYSA-N 5-ethylsulfonyl-2,4-dimethoxybenzoic acid Chemical compound CCS(=O)(=O)C1=CC(C(O)=O)=C(OC)C=C1OC WSDVZXXVUDLABA-UHFFFAOYSA-N 0.000 description 3
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 3
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- 239000005711 Benzoic acid Substances 0.000 description 3
- 241000282472 Canis lupus familiaris Species 0.000 description 3
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 3
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- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 3
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 3
- 241000700159 Rattus Species 0.000 description 3
- 229920002472 Starch Polymers 0.000 description 3
- ATJFFYVFTNAWJD-UHFFFAOYSA-N Tin Chemical compound [Sn] ATJFFYVFTNAWJD-UHFFFAOYSA-N 0.000 description 3
- QLNWBWMECAJMBK-UHFFFAOYSA-N [1-(cycloheptylmethyl)pyrrolidin-2-yl]methanamine Chemical compound NCC1CCCN1CC1CCCCCC1 QLNWBWMECAJMBK-UHFFFAOYSA-N 0.000 description 3
- BCXIHNPGQKJBMF-UHFFFAOYSA-N [1-(cyclohexylmethyl)pyrrolidin-2-yl]methanamine Chemical compound NCC1CCCN1CC1CCCCC1 BCXIHNPGQKJBMF-UHFFFAOYSA-N 0.000 description 3
- QFIYFROFRTUSPW-UHFFFAOYSA-N [1-(cyclopropylmethyl)pyrrolidin-2-yl]methanamine Chemical compound NCC1CCCN1CC1CC1 QFIYFROFRTUSPW-UHFFFAOYSA-N 0.000 description 3
- VMWNQDUVQKEIOC-CYBMUJFWSA-N apomorphine Chemical compound C([C@H]1N(C)CC2)C3=CC=C(O)C(O)=C3C3=C1C2=CC=C3 VMWNQDUVQKEIOC-CYBMUJFWSA-N 0.000 description 3
- 229960004046 apomorphine Drugs 0.000 description 3
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- VAYGXNSJCAHWJZ-UHFFFAOYSA-N dimethyl sulfate Chemical compound COS(=O)(=O)OC VAYGXNSJCAHWJZ-UHFFFAOYSA-N 0.000 description 3
- 238000004090 dissolution Methods 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
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- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 3
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- JZMJDSHXVKJFKW-UHFFFAOYSA-M methyl sulfate(1-) Chemical compound COS([O-])(=O)=O JZMJDSHXVKJFKW-UHFFFAOYSA-M 0.000 description 3
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 3
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- 238000002360 preparation method Methods 0.000 description 3
- FVAUCKIRQBBSSJ-UHFFFAOYSA-M sodium iodide Chemical compound [Na+].[I-] FVAUCKIRQBBSSJ-UHFFFAOYSA-M 0.000 description 3
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- CMMWOLZRVDEAQJ-UHFFFAOYSA-N (1-cyclooctylpyrrolidin-2-yl)methanamine Chemical compound NCC1CCCN1C1CCCCCCC1 CMMWOLZRVDEAQJ-UHFFFAOYSA-N 0.000 description 2
- DXDVIHWHNZVPOK-UHFFFAOYSA-N (1-cyclopropylpyrrolidin-2-yl)methanamine Chemical compound NCC1CCCN1C1CC1 DXDVIHWHNZVPOK-UHFFFAOYSA-N 0.000 description 2
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 2
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- TVMQLKVUYYNICJ-UHFFFAOYSA-N 2,4-dimethoxy-5-sulfanylbenzoic acid Chemical compound COC1=CC(OC)=C(C(O)=O)C=C1S TVMQLKVUYYNICJ-UHFFFAOYSA-N 0.000 description 2
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- HJJJPERYRODDDE-UHFFFAOYSA-N 3,5-dichloro-n-[(1-cyclohexylpyrrolidin-2-yl)methyl]-2-prop-2-ynoxybenzamide Chemical compound ClC1=CC(Cl)=C(OCC#C)C(C(=O)NCC2N(CCC2)C2CCCCC2)=C1 HJJJPERYRODDDE-UHFFFAOYSA-N 0.000 description 2
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- JEZWENIMQLYTHI-UHFFFAOYSA-N 4-amino-2-methoxy-5-methylbenzenecarbothioic s-acid Chemical compound COC1=CC(N)=C(C)C=C1C(O)=S JEZWENIMQLYTHI-UHFFFAOYSA-N 0.000 description 2
- BVCKAIGDWABZIE-UHFFFAOYSA-N 4-amino-5-ethylsulfanyl-2-methoxybenzoic acid Chemical compound CCSC1=CC(C(O)=O)=C(OC)C=C1N BVCKAIGDWABZIE-UHFFFAOYSA-N 0.000 description 2
- RULZQBUMBPGFBO-UHFFFAOYSA-N 4-amino-n-[(1-cyclohexylpyrrolidin-2-yl)methyl]-2-methoxy-5-methylsulfinylbenzamide Chemical compound COC1=CC(N)=C(S(C)=O)C=C1C(=O)NCC1N(C2CCCCC2)CCC1 RULZQBUMBPGFBO-UHFFFAOYSA-N 0.000 description 2
- PVMQHXAMKMMDNP-UHFFFAOYSA-N 4-amino-n-[(1-cyclohexylpyrrolidin-2-yl)methyl]-5-ethylsulfonyl-2-methoxybenzamide Chemical compound C1=C(N)C(S(=O)(=O)CC)=CC(C(=O)NCC2N(CCC2)C2CCCCC2)=C1OC PVMQHXAMKMMDNP-UHFFFAOYSA-N 0.000 description 2
- VKSIXLFJMGWHAC-UHFFFAOYSA-N 4-amino-n-[1-(1-cyclopropylpyrrolidin-2-yl)ethyl]-5-ethylsulfonyl-2-methoxybenzamide Chemical compound C1=C(N)C(S(=O)(=O)CC)=CC(C(=O)NC(C)C2N(CCC2)C2CC2)=C1OC VKSIXLFJMGWHAC-UHFFFAOYSA-N 0.000 description 2
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Landscapes
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Abstract
내용 없음.No content.
Description
본 발명은 다음 일반식(1)의 치환 헤테로싸이클 벤즈아미드의 제법에 관한 것이다.This invention relates to the manufacturing method of substituted heterocycle benzamide of following General formula (1).
본 발명은 또한 약리학적으로 허용되는 산의 부가염, 4가 암모늄염, 산화물 및 일반식(1)을 갖는 화합물의 좌선성 및 우선성 이성체 등에 관한 것이다.The present invention also relates to the pharmacologically acceptable addition salts of tetraacids, tetravalent ammonium salts, oxides, and the sitenic and preferential isomers of compounds having the general formula (1).
본 발명의 화합물은 다음 일반식(2)의 산과 다음 일반식(3)의 아민과 반응시켜 제조된다.The compound of the present invention is prepared by reacting an acid of the following general formula (2) with an amine of the following general formula (3).
아미드화 반응은 원 위치에서 또는 중간 유도체가 분리되었을 때 수행할 수 있다.The amidation reaction can be carried out in situ or when the intermediate derivative is separated.
또한 유리산과 유리아민을 예컨대 실리콘 테트라클로라이드 트리클로로페닐실란, 포스포르무수물, 카르보디이미드 또는 알콕시아세틸렌등과 같은 축합제의 존제하에 반응시킬 수 있다.The free acid and free amine can also be reacted in the presence of a condensing agent such as, for example, silicon tetrachloride trichlorophenylsilane, phosphor anhydride, carbodiimide or alkoxyacetylene.
일반식(1)의 화합물은 일반식(2)의 산 또는 상술한 반응 유도체와 다음 일반식(4)의 디할로알킬아민과 반응시켜 다음 일반식(5)의 화합물을 얻은 후에 다음 일반식(6)의 아민과 반응시켜 얻는다.The compound of formula (1) is reacted with an acid of formula (2) or the above-mentioned reaction derivative with dihaloalkylamine of formula (4) to obtain a compound of formula (5), and then It is obtained by reacting with the amine of 6).
본 발명에 따른 화합물의 제조방법을 다음 도표에 도시 하였다.The preparation of the compounds according to the invention is shown in the following table.
아미드화 반응은 용매와 함께 또는 용매 없이도 일어날 수 있다.The amidation reaction can occur with or without a solvent.
용매로 사용된 방법의 몇가지 예로는, 아미드화 반응에 관하여 불활성인 알코올, 폴리을, 케톤, 벤젠, 톨루엔, 디옥산, 클로로포름 및 디에틸렌글리콜디메틸 에테르등이 있다. 또한 원료로 사용된 과량의 아민은 용매로서 사용할 수도 있다. 반응혼합물이 아미드화하는 동안 예를들면 상술한 용매의 비점까지 가열하는 것이 바람직하다.Some examples of methods used as solvents include alcohols, poly, ketones, benzene, toluene, dioxane, chloroform and diethylene glycol dimethyl ether, which are inert with respect to the amidation reaction. In addition, the excess amine used as a raw material can also be used as a solvent. It is preferred to heat the reaction mixture, for example, to the boiling point of the solvent described above, during the amidation.
본 발명의 방법에 의해 얻어진 화합물은 필요하다면 제약학적으로 허용되는 무기산 또는 유기한 예컨대 염산, 하이드로브롬산, 황산, 인산, 옥살산, 아세트산, 타르타르산, 구연산 또는 메탄-설폰산등과 같은 산부가염과 반응시킬 수 있다.The compounds obtained by the process of the invention are reacted with acid addition salts, if necessary, with pharmaceutically acceptable inorganic or organic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, oxalic acid, acetic acid, tartaric acid, citric acid or methane-sulfonic acid. You can.
필요하다면, 알킬설페이트 또는 할라이드를 주어진 4가 암모늄염과 동일하게 반응시킬 수 있다.If desired, the alkylsulfate or halide can be reacted in the same manner as the given tetravalent ammonium salt.
또한 공지의 방법으로 예컨대 과산화수소 및 이산화망간은 상용하는 N-산화물과 산화시킬 수 있다.In addition, known methods such as hydrogen peroxide and manganese dioxide can be oxidized with commercially available N-oxides.
[실시예 1]Example 1
N-(1-싸이클로헥실-2-피롤리디닐-메틸)-2-메톡시-4-아미노-5-클로로벤즈아미드N- (1-cyclohexyl-2-pyrrolidinyl-methyl) -2-methoxy-4-amino-5-chlorobenzamide
240g의 2-메톡시-4-아세트아미노-5-클로로-벤조산(0.985몰) 960ml의 아세톤 및 99.5g의 트리에틸아민(0.985몰)을 교반기, 온도계 및 적하깔대기가 장착되어 있는 3ℓ 용량의 플라스크에 주입하였다. 산을 거의 완전하게 용해시켰다. 반응매체를 0℃로 냉각시켜서 산의 트리에틸아민염을 결정시켰다.240 g 2-methoxy-4-acetamino-5-chloro-benzoic acid (0.985 mol) A 3 l flask equipped with 960 ml acetone and 99.5 g triethylamine (0.985 mol) with a stirrer, thermometer and dropping funnel Injected into. The acid was dissolved almost completely. The reaction medium was cooled to 0 deg. C to determine the triethylamine salt of the acid.
107g의 에틸 클로로포르메이트(0.985몰)를 현탁액에 적가하는데, 온도는 0° 내지 5℃로 유지시키고 1시간 30분동안 실시하였다. 교반을 30분간 더 계속한 후에 188g의 1-싸이클로헥실-2-아미노-메틸피롤리딘을 1시간 이상 온도를 10-15℃로 유지시키면서 적가 하였다. 피롤리딘을 모두 가하였을때 교반을 10℃에서 1/2시간 동안 더 계속한 후에 1시간 동안 실온에서 유지시켰다. 염기 결정을 배수하고 아세톤으로 세척 하였다. 침전물을 1ℓ의 물에 즉시 용해시켜서 트리에틸아민 하이드로클로라이드를 용해시켰다. 배수하여 Cl-이온이 제거될 때까지 물로 세척하여 50℃로 건조 시켜서 262g을 얻었다.107 g of ethyl chloroformate (0.985 mol) was added dropwise to the suspension, the temperature was kept at 0 ° -5 ° C. and carried out for 1 hour 30 minutes. After further stirring for 30 minutes, 188 g of 1-cyclohexyl-2-amino-methylpyrrolidine was added dropwise while maintaining the temperature at 10-15 ° C for at least 1 hour. When all of the pyrrolidine was added, stirring was continued for a further 1/2 hour at 10 ° C. and then maintained at room temperature for 1 hour. Base crystals were drained and washed with acetone. The precipitate was immediately dissolved in 1 L of water to dissolve triethylamine hydrochloride. Drained, washed with water until the Cl - ion is removed, dried at 50 ℃ to give 262g.
아세톤 모액을 진공하에서 증발시켜서 일정량이 되도록 하였다.The acetone mother liquor was evaporated under vacuum to a certain amount.
이론치 139g에 대하여 161g을 얻었다.161 g was obtained with respect to 139 g of theoretical values.
790ml의 2.5N알코올성 칼리(2×0.985몰) 및 423g의 조잡한 아세틸화염기를 환류 냉각기에 장착된 2ℓ 용량의 플라스크에 가하였다. 혼합물을 2시간동안 가열하여 환류 시켰다. 용액을 목탄으로 여과시킨 후에 6ℓ의 물로 희석시켰다. 탈아세틸화염기를 액상형태로 침전시켜서 철야 방치한 후에 결정체를 배수하고, 물로 세척하여 공기중에서 건조시킨 다음 40℃에서 건조시켰다. 324g의 생성물을 얻었다. 융점 115-116℃.790 ml of 2.5N alcoholic kali (2 x 0.985 moles) and 423 g of crude acetylchloride were added to a 2 L flask equipped with a reflux condenser. The mixture was heated to reflux for 2 hours. The solution was filtered through charcoal and then diluted with 6 L of water. After the deacetylated base was precipitated in liquid form and left overnight, the crystals were drained, washed with water, dried in air and then dried at 40 ° C. 324 g of product were obtained. Melting point 115-116 ° C.
324g의 염기를 625ml의 아세톤-니트릴에 완전히 용해시켰다. 혼탁용액을 목탄을 통과하여 비등점에서 여과시킨 후에 냉각시켰다. 염기 재결정체를 배수하고, 아세토-니트릴로 세척하고 건조시켜서 290g의 회갈색물질을 얻었다. 염기를 목탄을 거쳐서 여과시켜서 580ml의 아세토 니트릴에 2번 재결정하여 여전히 회갈색인 271g의 생성물을 얻었다.324 g of base were completely dissolved in 625 ml of acetone-nitrile. The cloudy solution was filtered through boiling charcoal at boiling point and then cooled. The base recrystallization was drained, washed with aceto-nitrile and dried to give 290 g of an off-brown substance. The base was filtered through charcoal and recrystallized twice in 580 ml of acetonitrile to give 271 g of still greyish brown product.
271g의 염기를 2.7ℓ의 물 및 필요한 염산에 용해시켰다. 용액을 목탄으로 여과시킨 후에, 염기를 20% 암모니아를 가하여 침전시켰다. 처음의 액상을 24시간 동안 방치하여 결정 시켰다. 결정을 배수하고 물로 세척하여 40℃의 오븐에서 건조시켰다. 얻어진 256g을 510ml의 아세토 니트릴에서 재결정 시켰다. 비등액을 여과한 후에 냉각시켜서, 재결정 된 염기를 배수하고 아세토 니트릴로 세척하여 공기중에 건조시킨 후에 건조시킨 후에 50℃에서 다시 건조시켰다. 235g의 N-(1-싸이클로헥실-2-피롤리디닐메틸)-2-메톡시-4-아미노-4-클로로벤즈아미드를 얻었다. 융점 123-124℃ 수율 65%271 g of base were dissolved in 2.7 L of water and the required hydrochloric acid. After the solution was filtered through charcoal, the base was precipitated by addition of 20% ammonia. The first liquid was left to stand for 24 hours to determine. The crystals were drained, washed with water and dried in an oven at 40 ° C. 256 g of the obtained product was recrystallized from 510 ml of acetonitrile. The boiling liquid was filtered and then cooled, and the recrystallized base was drained, washed with acetonitrile, dried in air and then dried again at 50 ° C. 235 g of N- (1-cyclohexyl-2-pyrrolidinylmethyl) -2-methoxy-4-amino-4-chlorobenzamide was obtained. Melting Point 123-124 ℃ Yield 65%
[실시예 2]Example 2
N-(1-싸이클로펜틸-2-피롤리디닐메틸)-2-메톡시-4-클로로-5-에틸설포닐벤즈아미드N- (1-cyclopentyl-2-pyrrolidinylmethyl) -2-methoxy-4-chloro-5-ethylsulfonylbenzamide
2-메톡시-4-클로로-5-클로로설포닐벤조산2-methoxy-4-chloro-5-chlorosulfonylbenzoic acid
4ℓ의 클로로설폰산을 교반기 및 온도계가 장착되어 있는 6ℓ용량의 삼각 플라스크에 가하여 15℃로 냉각시켰다.4 L of chlorosulfonic acid was added to a 6 L Erlenmeyer flask equipped with a stirrer and a thermometer and cooled to 15 ° C.
563g의 2-메톡시-4-클로로벤조산(3.01몰)을 분류물에 가하여 온도가 상승되도록 방치하였다. 벤조산을 20분동안 가하고 온도를 50℃에 도달 시켰다. 혼합물을 즉시 80℃로 가열한 후 온도를 40℃로 하강하도록 방치 하였다.563 g of 2-methoxy-4-chlorobenzoic acid (3.01 mol) was added to the fraction and left to rise in temperature. Benzoic acid was added for 20 minutes and the temperature reached 50 ° C. The mixture was immediately heated to 80 ° C. and then left to drop to 40 ° C.
반응혼합물을 30kg의 얼음위에 주입하여 침전물을 배수하여 물로 세척하고 50℃에서 건조시켰다. 764g(89%)의 생성물을 얻었다. 융점 179℃The reaction mixture was poured onto 30 kg of ice, and the precipitate was drained, washed with water, and dried at 50 ° C. 764 g (89%) of the product were obtained. Melting point 179 ℃
2-메톡시-4-클로로-5-에틸설포닐벤조산2-methoxy-4-chloro-5-ethylsulfonylbenzoic acid
3ℓ의 물, 740g의 소디움 설파이트 및 535g의 중탄산나트륨을 교반기, 온도계 및 냉각기가 장착되어 있는 10ℓ용량의 3각 플라스크에 가하였다. 혼합물을 70℃로 가열하고 903g의 2-메톡시-4-클로로-5-클로로설포닐 벤조산을 분류물에 가하였다. 이때 온도는 70-75℃를 유지 하였다.3 L of water, 740 g of sodium sulfite and 535 g of sodium bicarbonate were added to a 10 L three-necked flask equipped with a stirrer, thermometer and cooler. The mixture was heated to 70 ° C. and 903 g of 2-methoxy-4-chloro-5-chlorosulfonyl benzoic acid was added to the fraction. At this time, the temperature was maintained at 70-75 ℃.
3시간 동안 75℃로 유지 시킨후에 25℃로 온도를 떨어뜨렸다. 750ml의 에탄올을 주입한 후에 950g의 중탄산 나트륨을 조심스럽게 가하였다. 끝으로 1,270g의 에틸 아이오다이드 및 2,250ml의 에탄올을 가하였다. 매체는 35℃에서 천천히 가열하여 환류 시키고, 환류는 17시간동안 82℃에서 유지 시켰다.After holding at 75 ° C. for 3 hours, the temperature was dropped to 25 ° C. After injecting 750 ml of ethanol, 950 g of sodium bicarbonate was carefully added. Finally, 1270 g of ethyl iodide and 2250 ml of ethanol were added. The medium was slowly heated to reflux at 35 ° C. and reflux was maintained at 82 ° C. for 17 hours.
알코올, 물 및 에틸 아이오다이드의 혼합물을 3ℓ를 진공하에서 증류시킨후에 농축액의 3ℓ의 물을 가하였다. 이를 약 1,100ml의 염산으로 pH1로 산성화 시키고 약 10℃로 냉각시킨후에 배수하고 3ℓ의 물로 세척하였다. 생성물을 300g의 중탄산나트륨을 함유하는 3ℓ의 물에 용해시켰다. 2시간동안 교반하여 비가용성 부분을 여별 하였다. 100g의 베지타블 블랙(begetable black)을 여과액에 가한 후에 이를 교반하고 블랙(black)을 여별하였다. 생성물을 1.18비중의 염산 약 300ml로 산성화시켜서 침전 시켰다.3 L of the mixture of alcohol, water and ethyl iodide were distilled off under vacuum followed by addition of 3 L of water in concentrate. It was acidified to pH 1 with about 1,100 ml of hydrochloric acid, cooled to about 10 ° C., then drained and washed with 3 L of water. The product was dissolved in 3 liters of water containing 300 g of sodium bicarbonate. Stir for 2 hours to filter the insoluble portion. 100 g of vegetable black was added to the filtrate, followed by stirring and filtration of black. The product was acidified with about 300 ml of hydrochloric acid in 1.18 specific gravity to precipitate.
2-메톡시-4-클로로-5-에틸설포닐 벤조일 클로라이드2-methoxy-4-chloro-5-ethylsulfonyl benzoyl chloride
139g의 2-메톡시-4-클로로-5-에틸설포닐 벤조산 200ml의 티오닐 클로라이드 및 0.5ml의 데미틸포름아미드를 교반기, 온도계, 냉각기가 장착되어 있는 플라스크에 가하였다.139 g of 2-methoxy-4-chloro-5-ethylsulfonyl benzoic acid 200 ml thionyl chloride and 0.5 ml demiformylamide were added to a flask equipped with a stirrer, thermometer and cooler.
혼합물을 가열하여 환류 시키고, 방치한 후에 용액을 증발시켰다. 잔사를 200ml의 톨루엔으로 처리한 후에 결정을 톨루엔으로 세척하고 진공 건조기에서 건조시켜서 117g의 2-메톡시-4-클로로-5-에틸설포닐벤조일 클로라이드를 얻었다. (융점 115-117℃, 수율 79%)The mixture was heated to reflux and the solution was evaporated after standing. After the residue was treated with 200 ml of toluene, the crystals were washed with toluene and dried in a vacuum drier to give 117 g of 2-methoxy-4-chloro-5-ethylsulfonylbenzoyl chloride. (Melting point 115-117 ° C, yield 79%)
N-(1-싸이클로펜틸-2-피롤리디닐메틸)-2-메톡시-4-클로로-5-에틸 설포닐벤즈아미드N- (1-cyclopentyl-2-pyrrolidinylmethyl) -2-methoxy-4-chloro-5-ethyl sulfonylbenzamide
54g의 1-싸이클로펜틸-2-아미노메틸-피롤리딘(0.32몰) 및 300ml의 메틸-에틸-케톤을 교반기 및 온도계가 장착되어 있는 1ℓ용량의 플라스크에 가하였다. 용액을 10℃로 냉각시킨 후에 89g의 2-메톡시-4-클로로-5-에틸설포닐 벤조일 클로라이드(0.30몰)를 반응중에 가하였다. 반응매체를 실온에서 2시간교반하여 철야 방치 하였다. 결정체를 여과하고 100ml의 메틸-에틸-케톤으로 3번 세척하여 60℃의 오븐에서 건조시켰다. 85g의 생성물을 얻었다. 융점 165-170℃54 g of 1-cyclopentyl-2-aminomethyl-pyrrolidine (0.32 mole) and 300 ml of methyl-ethyl-ketone were added to a 1 L flask equipped with a stirrer and thermometer. After the solution was cooled to 10 ° C., 89 g of 2-methoxy-4-chloro-5-ethylsulfonyl benzoyl chloride (0.30 mol) was added during the reaction. The reaction medium was left stirring overnight at room temperature. The crystals were filtered off, washed three times with 100 ml of methyl-ethyl-ketone and dried in an oven at 60 ° C. 85 g of product were obtained. Melting Point 165-170 ℃
하이드로 클로라이드를 400ml의 메틸-에틸-케톤에서 재결정 시켰다. 생성물을 여과하고 소량의 용매로 세척하여 50℃의 오븐에서 건조시켜서 69g(49.5%)의 생성물을 얻었다. 융점 및 분해점 160℃Hydrochloride was recrystallized in 400 ml of methyl-ethyl-ketone. The product was filtered off, washed with a small amount of solvent and dried in an oven at 50 ° C. to yield 69 g (49.5%) of product. Melting point and decomposition point 160 ℃
[실시예 3]Example 3
N-(1-싸이클로프로필메틸-2-피롤리디닐메틸)-2,3-디메톡시-5-설파모일벤즈아미드N- (1-cyclopropylmethyl-2-pyrrolidinylmethyl) -2,3-dimethoxy-5-sulfamoylbenzamide
2,3-디메톡시-5-설파모일 벤조일 클로라이드2,3-dimethoxy-5-sulfamoyl benzoyl chloride
419g(1.6몰)의 2,3-디메톡시-5-설파모일 벤조산 및 1,351g(11.35몰)의 티오닐 클로라이드를 교반기, 온도계 및 소다 거품기에 연결된 냉각기가 장착되어 있는 2ℓ용량의 플라스크에 가하였다. 혼합물을 1시간 동안 환류시킨 후에 과량의 티오닐클로라이드를 진공하에서 제거 하였다. 잔사를 1000ml의 헥산에 용해시키고 여과하여 500ml의 석유에테르로 2번 세척하고, 진공 건조기에서 건조시켜서 424g(수율 94.8%)의 2,3-디메톡시-5-설파모일벤조일 클로라이드를 얻었다. 융점 153℃419 g (1.6 moles) of 2,3-dimethoxy-5-sulfamoyl benzoic acid and 1,351 g (11.35 moles) of thionyl chloride were added to a 2 L flask equipped with a chiller connected to an agitator, thermometer and soda bubbler. . After the mixture was refluxed for 1 hour, excess thionylchloride was removed under vacuum. The residue was dissolved in 1000 ml of hexane, filtered, washed twice with 500 ml of petroleum ether and dried in a vacuum drier to give 424 g (yield 94.8%) of 2,3-dimethoxy-5-sulfamoylbenzoyl chloride. Melting point 153 ℃
N-(1-싸이클로프로필-메틸-2-피롤리디닐-메틸)-2,3-디메톡시-5-설파모일 벤즈아미드N- (1-cyclopropyl-methyl-2-pyrrolidinyl-methyl) -2,3-dimethoxy-5-sulfamoyl benzamide
20g(0.13몰)의 1-싸이클로프로필-메틸-2-아미노-메틸-피롤리딘 및 150ml의 메틸-에틸-케톤을 교반기, 온도계 및 냉각기가 장착되어 있는 500ml용량의 플라스크에 가하였다. 36.3g(0.13몰)의 2,3-디메톡시-5-설파모일 벤조일 클로라이드를 또한 주입하여 온도를 15-20℃로 유지시켰다. 얻어진 껄쭉한 페이스트(paste)를 170ml의 물로 희석시키고 상온에서 1시간동안 반응 시켰다. 이를 건조상태로 증발시켜서 잔사를 200ml의 물에 용해시키고 과량의 암모니아로 알카리성으로 만들었다. 염기를 침전시켜서 서서히 결정시켰다. 결정을 여과하여 물로 세척하여 50℃의 오븐에서 건조 시켜서 50g(수율 97%)의 N-(1싸이클로프로필-메틸-2-피롤리디닐-메틸) 2,3-디메톡시-5-설파모일 벤즈아미드를 얻었다. 이를 부틸 아세테이트로 3번 재결정시켜서 26g(50.5%)의 결정을 얻었다. 결정을 규정(normal) 염산에 용해 시켜서 여과하고 규정소다로 알카리성으로 하여 재여과 하였다. 이를 이온이 완전히 사라질 때까지 물로 세척하고 오븐(50℃)에서 건조시켜서 24g(46.6%)의 결정을 얻었다. 융점 136℃(이들은 물에 불용성이다)20 g (0.13 mole) of 1-cyclopropyl-methyl-2-amino-methyl-pyrrolidine and 150 ml of methyl-ethyl-ketone were added to a 500 ml flask equipped with a stirrer, thermometer and cooler. 36.3 g (0.13 mol) of 2,3-dimethoxy-5-sulfamoyl benzoyl chloride were also injected to maintain the temperature at 15-20 ° C. The resulting thick paste was diluted with 170 ml of water and reacted at room temperature for 1 hour. It was evaporated to dryness and the residue was dissolved in 200 ml of water and made alkaline with excess ammonia. It was slowly determined by precipitating the base. The crystals were filtered, washed with water and dried in an oven at 50 ° C. to yield 50 g (yield 97%) of N- (1 cyclopropyl-methyl-2-pyrrolidinyl-methyl) 2,3-dimethoxy-5-sulfamoyl benz An amide was obtained. It was recrystallized three times with butyl acetate to give 26 g (50.5%) of crystals. The crystals were dissolved in normal hydrochloric acid, filtered and alkaline filtered with soda and refiltered. It was washed with water until the ions disappeared completely and dried in an oven (50 ° C.) to yield 24 g (46.6%) of crystals. Melting point 136 ° C (these are insoluble in water)
분석 이론치 실측치Analytical Theory
S% 8.06 8.13S% 8.06 8.13
[실시예 4]Example 4
N-(1-싸이클로프로필-메틸-2-피롤리디닐-메틸)-2-메톡시-4-아미노-5-에틸설포닐-벤즈아미드N- (1-cyclopropyl-methyl-2-pyrrolidinyl-methyl) -2-methoxy-4-amino-5-ethylsulfonyl-benzamide
2-메톡시-4-아미노-5-에틸티오벤조산2-methoxy-4-amino-5-ethylthiobenzoic acid
159g의 2-메톡시-4-아미노-5-메르캅토벤조산, 355cm3의 물 및 160cm3의 소다 알카리액을 냉각기가 장착된 플라스크에 가하였다. 혼합물을 고체가 용해 할때까지 가열한 후에 123g의 에틸설페이트를 가하였다. 혼합물을 가열하여 환류시키고 10cm3의 30% 소다 알카리액으로 처리하여 1시간동안 환류시키기 위하여 가열하였다. 이를 냉각시키고 800cm3의 물을 가하여 용액을 여과하였다. 침전물을 에테르의 존재하에 100cm3의 농염산을 가하여 얻었다. 이를 배수하고159g of 2- methoxy-4-amino-5-mercapto-benzoic acid, soda alkaline solution of 355cm 3 of water and 160cm 3 of were added to a flask equipped with a condenser. The mixture was heated until the solids dissolved and then 123 g of ethyl sulfate was added. The mixture was heated to reflux and treated with 10 cm 3 of 30% soda alkaline solution and heated to reflux for 1 hour. It was cooled and the solution was filtered by adding 800 cm 3 of water. A precipitate was obtained by adding 100 cm 3 of concentrated hydrochloric acid in the presence of ether. Drain it
2-메톡시-4-아미노-5-에틸설포닐벤조산2-methoxy-4-amino-5-ethylsulfonylbenzoic acid
123g의 2-메톡시-4-아미노-5-에틸 티오벤조산을 542cm3의 아세트산에 완전히 용해 시켰다. 용액을 35℃로 냉각시킨 후 185cm3의 131vol의 과산화수소수를 소량 가하고 온도를 80℃로 상승 시켰다.123 g of 2-methoxy-4-amino-5-ethyl thiobenzoic acid was completely dissolved in 542 cm 3 of acetic acid. The solution was then cooled to 35 ℃ was added a small amount of hydrogen peroxide in a 185cm 3 131vol the temperature was raised to 80 ℃.
온도를 40℃로 내려서 혼합물의 온도를 얼마동안 유지시킨 후에 10℃로 냉각시켰다. 형성된 침전물을 배수하고 아세트산으로 세척하고 건조 시켜서 600m3의 물 및 100cm3의 20% 암모니아에 용해 시켰다. 형성된 침전물을 70cm3의 농염산을 가하여 냉각 시키고 배수하여 물로 세척하고 건조시켜 61.5g의 수화 2-메톡시-4-아미노-5-에틸설포닐 벤조산을 얻었다. (수율 42%, 융점 95-100℃)The temperature was lowered to 40 ° C. to maintain the temperature of the mixture for some time and then cooled to 10 ° C. The precipitate formed was drained, washed with acetic acid and dried to dissolve in 600 m 3 of water and 100 cm 3 of 20% ammonia. The precipitate formed was cooled by adding 70 cm 3 of concentrated hydrochloric acid, drained, washed with water and dried to obtain 61.5 g of hydrated 2-methoxy-4-amino-5-ethylsulfonyl benzoic acid. (Yield 42%, Melting Point 95-100 ° C)
N-(1-싸이클로프로필-메틸-2-피롤리디닐-메틸)-2-메톡시-4-아미노-5-에틸설포닐-벤즈아미드N- (1-cyclopropyl-methyl-2-pyrrolidinyl-methyl) -2-methoxy-4-amino-5-ethylsulfonyl-benzamide
31.3g(0.31몰)의 트리에틸아민, 400ml의 테트라하이드로푸란 및 80.3g(0.31몰)의 2-메톡시-4-아미노-5-에틸설포닐벤조산을 교반기, 온도계, 냉각기 및 적하 깔대기가 장착되어 있는 1ℓ 용량의 플라스크에 가하였다. 고무와 같은 침전물을 서서히 분쇄하였다. 실온에서 30분 경과 후에 0℃로 냉각시켜서 33.6g(0.31몰)의 에틸 클로로포르메이트를 적가 하였다.31.3 g (0.31 mole) triethylamine, 400 ml tetrahydrofuran and 80.3 g (0.31 mole) 2-methoxy-4-amino-5-ethylsulfonylbenzoic acid equipped with a stirrer, thermometer, cooler and dropping funnel To a 1 L flask. A precipitate, such as rubber, was slowly milled. After 30 minutes at room temperature, 33.6 g (0.31 mol) of ethyl chloroformate was added dropwise by cooling to 0 ° C.
이를 1시간 동안 교반하면서 0-5℃의 온도를 유지하였다. 62g(0.40몰)의 1-(싸이클로프로필-메틸)-2-아미노-메틸-피롤리딘을 적가 하면서 온도를 동일 수준으로 유지 시켰다. 걸쭉한 침전물이 형성되었다. 반응 매체를 실온에서 2시간 더 교반한후에 철야 방치 하였다. 생성된 결정을 여과하고 100ml의 테트라하이드로푸란으로 2번 세척하고 50℃의 오븐에서 건조시켜서 91g(74.3%)의 결정을 얻었다. 600ml의 90% 알코올에서 재결정 시키고 여과하여 50ml의 알코올로 2번 세척하고 40℃의 오븐에서 건조시켰다. 81.5g(수율 66.5%)의 N-(1-싸이클로프로필-메틸-2-피롤리디닐-메틸)-2-메톡시-4-아미노-5-에틸설포닐 벤즈아미드)를 얻었다. 융점 181℃It was kept at 0-5 ° C. with stirring for 1 hour. 62 g (0.40 mole) of 1- (cyclopropyl-methyl) -2-amino-methyl-pyrrolidine was added dropwise to maintain the temperature at the same level. A thick precipitate formed. The reaction medium was left to stand overnight after further stirring at room temperature. The resulting crystals were filtered, washed twice with 100 ml of tetrahydrofuran and dried in an oven at 50 ° C. to give 91 g (74.3%) of crystals. Recrystallized from 600 ml of 90% alcohol, filtered, washed twice with 50 ml of alcohol and dried in an oven at 40 ℃. 81.5 g (yield 66.5%) of N- (1-cyclopropyl-methyl-2-pyrrolidinyl-methyl) -2-methoxy-4-amino-5-ethylsulfonyl benzamide) was obtained. Melting point 181 ℃
분석 이론치 실측치Analytical Theory
S% 8.11 8.06S% 8.11 8.06
[실시예 5]Example 5
N-(1-싸이클로프로필-2-피롤리디닐메틸)-2-메톡시-5-설파모일 벤즈아미드N- (1-cyclopropyl-2-pyrrolidinylmethyl) -2-methoxy-5-sulfamoyl benzamide
2,5-디클로로펜틸아민 하이드로클로라이드2,5-dichloropentylamine hydrochloride
1.010g(10몰)의 테트라하이드로푸릴아민을 기게적 교반기, 황산을 함유하는 거품기에 연결된 냉각기, 가스유입관 및 황산을 통하여 미리 거품을 일게 하여 건조시킨 염산 유출물을 10ℓ용량의 플라스크에 가하여 냉각기를 통과시키면서 온도를 100-110℃로 유지 시켰다.1.010 g (10 mol) of tetrahydrofurylamine was added to a 10 liter flask by adding a hydrochloric acid effluent, which was previously bubbled through a mechanical stirrer, a cooler connected with a sulfuric acid bubbler, a gas inlet tube and sulfuric acid, and dried. The temperature was maintained at 100-110 ° C. while passing through.
반응은 출발시에 발열 반응을 하였다. 유입구 및 유출구에서 가스의 유동이 동일할 때, 관을 제거하고 반응매체를 60℃로 냉각 시켰다. 4ℓ의 클로로포름을 교반시켰다. 온도를 30℃로 내리고 1500ml의 티오닐 클로라이드를 적가하였다. 환류하에서 2시간이 지나면 2,5-디클로로펜틸아민 하이드로클로라이드가 침전된다. 이를 여과하고 클로로포름으로 세척하여 70°에서 건조시켜서 1,512g(수율 78.5%)의 생성물을 얻었다. 융점 160℃The reaction was exothermic at the start. When the flow of gas at the inlet and outlet was the same, the tube was removed and the reaction medium was cooled to 60 ° C. 4 L of chloroform was stirred. The temperature was lowered to 30 ° C. and 1500 ml of thionyl chloride was added dropwise. After 2 hours at reflux, 2,5-dichloropentylamine hydrochloride precipitates. It was filtered, washed with chloroform and dried at 70 ° to give 1512 g (yield 78.5%) of product. Melting point 160 ℃
2-메톡시-5-설파모일-벤조일클로라이드2-methoxy-5-sulfamoyl-benzoylchloride
400ml의 디클로로에탄올중의 23.1g(0.1몰)의 2-메톡시-5-설파모일-벤조산 및 1ml의 디메틸포름 아미드를 기계적교반기 적하깔대기 및 냉각기가 장착되어 있는 1ℓ 용량의 플라스크에 가하였다. 11ml(0.15몰)의 티오닐 클로라이드를 신속히 교반하여 매체를 고체가 완전히 용해될 때까지 가열하여 환류시켰다.23.1 g (0.1 mol) of 2-methoxy-5-sulfamoyl-benzoic acid and 1 ml of dimethylformamide in 400 ml of dichloroethanol were added to a 1 L flask equipped with a mechanical stirrer funnel and cooler. 11 ml (0.15 mole) of thionyl chloride was stirred rapidly to reflux the medium by heating until the solid was completely dissolved.
50℃로 냉각시킨 후 매체를 여과하여 얻어진 클로라이드를 진공건조기에서 건조시켜서 20.2g의 2-메톡시-5-설파모일-벤조일-클로라이드를 얻었다. 융점 167℃(분해)After cooling to 50 ° C., the medium was filtered and the resulting chloride was dried in a vacuum dryer to give 20.2 g of 2-methoxy-5-sulfamoyl-benzoyl-chloride. Melting point 167 ° C (decomposition)
분석 이론치 실측치Analytical Theory
Cl% 14.22% 14.6%Cl% 14.22% 14.6%
N-(2,5-디클로로펜틸)-2-메톡시-5-설파모일-벤즈아미드N- (2,5-dichloropentyl) -2-methoxy-5-sulfamoyl-benzamide
500ml의 디클로로에탄중의 77.5g(0.4몰)의 2,5-디클로로펜틸아민 하이드로 클로라이드를 교반기, 온도계 냉각기 및 적하 깔대기가 장착되어 있는 2ℓ용량의 플라스크에 가한 후에 112ml의 트리에틸아민을 가하였다. 1ℓ의 메틸에틸케톤중의 100g(0.4몰)의 2-메톡시-5-설파모일-벤조일 클로라이드 용액을 주입하면서 온도를 20℃로 유지시켰다.77.5 g (0.4 mol) of 2,5-dichloropentylamine hydrochloride in 500 ml of dichloroethane were added to a 2 L flask equipped with a stirrer, thermometer cooler and dropping funnel followed by 112 ml of triethylamine. The temperature was maintained at 20 ° C. while injecting 100 g (0.4 mol) of 2-methoxy-5-sulfamoyl-benzoyl chloride solution in 1 L of methyl ethyl ketone.
반응이 1시간 진행된 후에 트리에틸아민 하이드로 클로라이드의 침전물을 여과하여 여과액을 진공하에서 증발 시켰다. 침전물을 1ℓ의 물에 용해 시켰다. 결정을 그대로 여과하고 100ml의 이소프로판올로 2번 세척하였다. 이를 증발시킨 여과액의 잔사에 가하여 고체를 1,600ml의 이소프로판올에서 재결정 시켰다. 결정을 여과하고 이소프로판올로 세척하여 40℃의 오븐에서 건조시켜 101g(68.4%)의 N-(2,5-디클로로펜틸)-2-메톡시-5-설파모이-벤즈아미드를 회수 하였다. 융점 148℃After the reaction proceeded for 1 hour, the precipitate of triethylamine hydrochloride was filtered and the filtrate was evaporated in vacuo. The precipitate was dissolved in 1 L of water. The crystals were filtered off and washed twice with 100 ml of isopropanol. This was added to the residue of the evaporated filtrate and the solid was recrystallized from 1,600 ml of isopropanol. The crystals were filtered, washed with isopropanol and dried in an oven at 40 ° C. to recover 101 g (68.4%) of N- (2,5-dichloropentyl) -2-methoxy-5-sulfamoy-benzamide. Melting point 148 ℃
N-(1-싸이클로프로필-2-피롤리디닐메틸)-2-메톡시-5-설파모일-벤즈아미드N- (1-cyclopropyl-2-pyrrolidinylmethyl) -2-methoxy-5-sulfamoyl-benzamide
36.9g(0.1몰)의 N-(2,5-디클로로펜틸)-2-메톡시-5-설파모일-벤즈아미드 및 57g의 싸이클로프로필아민을 250ml용량의 플라스크에 가하였다. 이를 6시간 동안 환류시키고 철야 방치한 후에 5시간동안 다시 환류 시켰다. 얻어진 현탁액을 300ml의 물 및 50g의 얼음에 주입 하였다. 흰색의 침전을 물로 세척하고 60℃의 오븐에서 건조시켰다. 융점이 163℃이고 중량이 29.5g(83.6%)였다. 이를 2ℓ의 아세토니트릴에 용해시켜서 카본 블랙의 존재하에 여과 시켰다. 여과액을 결정시키기 위하여 방치 하였다. 얻어진 결정을 여과하고 아세토니트릴로 세척하여 40℃에서 건조 시켰다. 67g(수율 74.9%)의 N-(1-싸이클로-프로필-2-피롤리디닐메틸)-2-메톡시-5-설파모일-벤즈아미드를 회수 하였다. 융점 180℃36.9 g (0.1 mol) of N- (2,5-dichloropentyl) -2-methoxy-5-sulfamoyl-benzamide and 57 g of cyclopropylamine were added to a 250 ml flask. It was refluxed for 6 hours, allowed to stand again overnight for 5 hours. The suspension obtained was poured into 300 ml of water and 50 g of ice. The white precipitate was washed with water and dried in an oven at 60 ° C. It had a melting point of 163 ° C. and a weight of 29.5 g (83.6%). It was dissolved in 2 L of acetonitrile and filtered in the presence of carbon black. It was left to determine the filtrate. The obtained crystals were filtered off, washed with acetonitrile and dried at 40 ° C. 67 g (yield 74.9%) of N- (1-cyclo-propyl-2-pyrrolidinylmethyl) -2-methoxy-5-sulfamoyl-benzamide was recovered. Melting Point 180 ℃
분석 이론치 실측치Analytical Theory
N% 11.89 11.74N% 11.89 11.74
S% 9.07 9.16S% 9.07 9.16
[실시예 6]Example 6
N-(1-싸이클로프로필-2-피롤리딜메틸)-2-메톡시-4-아미노-5-디메틸-설파모일벤즈아미드N- (1-cyclopropyl-2-pyrrolidylmethyl) -2-methoxy-4-amino-5-dimethyl-sulfamoylbenzamide
2-메톡시-4-아미노-5-디메틸설파모일 벤조산2-methoxy-4-amino-5-dimethylsulfamoyl benzoic acid
환류 냉각기가 장착되어 4ℓ용량의 플라스크에 735ml의 물 및 365ml의 소다알카리액(3×1.22몰)에 용해시킨 300g의 2-메톡시-4-아미노-5-설파모일 벤조산(1.22몰)을 가하고 308g의 메틸설페이트(2×1.22몰)을 가하여 매체를 가열하여 환류시켰다. 이를 냉각시키고 다시 메틸화 시켰다. 즉 122ml의 소디알카리액 및 154g의 메틸 설페이트로 처리하고 다시 61ml의 알카리액 및 77g의 메틸 설페이트로 처리 하였다. 반응매체를 약
생성물을 609ml의 아세트산에서 재결정하여 배수하여 60ml의 아세트산으로 세척한 후에 물로 세척하여 50℃에서 건조시켰다. 239g(71%)의 흰색 생성물을 얻었다. 융점 187-189℃The product was recrystallized from 609 ml of acetic acid and drained, washed with 60 ml of acetic acid and then washed with water and dried at 50 ° C. 239 g (71%) of white product were obtained. Melting point 187-189 ℃
N-(1-싸이클로프로필-2-피롤리딜메틸)-2-메톡시-4-아미노-5-디메틸설파모일 벤즈아미드N- (1-cyclopropyl-2-pyrrolidylmethyl) -2-methoxy-4-amino-5-dimethylsulfamoyl benzamide
68.5g의 2-메톡시-4-아미노-5-디메틸설파모이 벤조산(0.25몰), 740ml의 물 및 25.4g의 트리에틸아민(0.25몰)을 교반기, 온도계, 냉각기 및 적하 깔대기가 장착되어 있는 2ℓ용량의 플라스크에 가하였다. 용액을 약 0℃로 냉각시키고 34.1g의 이소부틸 클로로프로메이트(0.25몰)을 적가 하였다. 혼합물을 실온에서 40분동안 반응시킨 후에 냉각시켜서 42g의 1-싸이클로프로필-2-아미노메틸-피롤리딘을 적가하면서 온도를 0-5℃로 유지시켰다. 매체를 실온에서 3시간 동안 반응시킨 후에 용액을 진공하에서 건조 시켰다. 잔사를 250ml의 물 및 50ml의 염산에 용해 시켰다. 용액을 125ml의 메틸렌 클로라이드로 2번 추출하여 제거 하였다. 수성상을 70ml의 소다알카리액으로 알카리성으로 만들었다. 오일을 침전 시켰다. 서시히 결정시킨 결정을 배수하고 물로 세척하여 50℃의 오븐에서 건조시켰다.68.5 g of 2-methoxy-4-amino-5-dimethylsulfamobenzoic acid (0.25 mol), 740 ml of water and 25.4 g of triethylamine (0.25 mol) are equipped with a stirrer, thermometer, cooler and dropping funnel It was added to a 2 liter flask. The solution was cooled to about 0 ° C. and 34.1 g of isobutyl chloropromate (0.25 mole) was added dropwise. The mixture was allowed to react at room temperature for 40 minutes and then cooled to keep the temperature at 0-5 ° C. with 42 g of 1-cyclopropyl-2-aminomethyl-pyrrolidine added dropwise. The solution was allowed to react at room temperature for 3 hours and then the solution was dried under vacuum. The residue was dissolved in 250 ml of water and 50 ml of hydrochloric acid. The solution was removed by extraction twice with 125 ml of methylene chloride. The aqueous phase was made alkaline with 70 ml of soda alkaline solution. The oil precipitated out. Slowly determined crystals were drained, washed with water and dried in an oven at 50 ° C.
79g의 생성물을 얻어 1,975ml의 에틸아세테이트에서 재결정시켜서 38.2g의 마이드를 얻었다.79 g of product was obtained and recrystallized in 1,975 ml of ethyl acetate to obtain 38.2 g of amide.
융점 170℃Melting point 170 ℃
[실시예 7]Example 7
N-(1-싸이클로헥실-2-피롤리딜메틸)-2-메톡시-4,5-아지미도 벤즈아미드N- (1-cyclohexyl-2-pyrrolidylmethyl) -2-methoxy-4,5-azimido benzamide
117g의 5-카르보메톡시-6-메톡시-벤조트리아졸(0.565몰) 52ml의 물 및 154g의 1-싸이클로헥실-2-아미노메틸-피롤리딘(0.565몰 50% 과량)을 환류 냉각기가 장착되어 있는 500ml 용량의 플라스크에 가하였다. 현탁액을 수욕상에서 가열하여 신속히 응해 시켰다. 8시간 30분 동안 가열을 계속 하였다. 얻어진 시료는 희석산에 완전히 용해 시켰다.117 g of 5-carbomethoxy-6-methoxy-benzotriazole (0.565 mole) 52 ml of water and 154 g of 1-cyclohexyl-2-aminomethyl-pyrrolidine (0.565 mole 50% excess) were added to a reflux condenser. It was added to an installed 500 ml flask. The suspension was heated in a water bath to quickly settle. Heating was continued for 8 hours 30 minutes. The obtained sample was completely dissolved in dilute acid.
용액을 500ml의 물로 희석시켰다. 염기가 신속히 결정화 되었다. 이를 배수하고 물로 세척하여 50℃의 오븐에서 건조 시켰다. 143g의 생성물을 얻었다. 융점 115-118℃(명백하지는 않다)The solution was diluted with 500 ml of water. The base crystallized rapidly. Drained and washed with water and dried in an oven at 50 ℃. 143 g of product was obtained. Melting Point 115-118 ° C (not obvious)
140g의 염기를 450ml의 물에 현탁시키고 33ml의 염산(비중 1.18)을 가하였다. 하이드로 클로라이드가 즉시 형성되었다. 이는 비등할때 생성되는데 얻어진 용액을 여과한 후에 냉각시켰다. 하이드로 클로라이드가 걸죽한 덩어리로 결정되었다. 이를 배수하여 50ml의 빙수로 세척하고 건조 하였다. 오랜시간동안 배수하면 생성물은 다량의 물을 보유하게 된다. 144g의 생성물을 얻었다. 융점 153-155℃(명백하지는 않다) 144g의 하이드로클로라이드를 700ml의 뜨거운 물에 용해시켜서 용액을 목탄으로 여과하여 염기140 g of base was suspended in 450 ml of water and 33 ml of hydrochloric acid (specific gravity 1.18) was added. Hydrochloride formed immediately. This is produced when boiling and the resulting solution is filtered and then cooled. Hydrochloride was determined as a thick mass. It was drained, washed with 50 ml of ice water and dried. After a long drain, the product retains a large amount of water. 144 g of product were obtained. Melting Point 153-155 ° C. (not obvious) 144 g of hydrochloride is dissolved in 700 ml of hot water and the solution is filtered through charcoal
염기를 250ml의 이소프로판올에 용해시켜서 가열하였다. 현탁액을 냉각시키키고 배수하여 30ml의 이소프로판올로 세척하여 공기중에서 건조시킨 후에 50℃에서 건조 시켰다. 114g의 N-(1-싸이클로헥실-2-피롤리딜메틸)-2-메톡시-4,5-아지미도벤즈아미드를 얻었다. 융점 173-174℃ 수율 56%The base was dissolved in 250 ml of isopropanol and heated. The suspension was cooled, drained, washed with 30 ml of isopropanol, dried in air and then dried at 50 ° C. 114 g of N- (1-cyclohexyl-2-pyrrolidylmethyl) -2-methoxy-4,5-azimidobenzamide was obtained. Melting Point 173-174 ° C Yield 56%
[실시예 8]Example 8
N-(1-싸이클로프로필메틸-2-피롤리딜메틸)-2-메톡시-3-이소프로필-5-설파모일-6-메틸벤즈아미드N- (1-cyclopropylmethyl-2-pyrrolidylmethyl) -2-methoxy-3-isopropyl-5-sulfamoyl-6-methylbenzamide
2-메톡시-3-이소프로필-6-메틸벤조 산2-methoxy-3-isopropyl-6-methylbenzoic acid
262g의 0-티모트산(1.35몰), 270ml의 40% 소다알카리액 및 400ml의 물을 교반기, 온도계, 냉각기 및 적하깔대기가 장착되어 있는 3ℓ용량의 플라스크에 가하였다. 용액을 환류시키기 위하여 가열하고 255ml의 디메틸설페이트를 적가하였다. 환류를 30분동안 유지시킨 후에 70ml의 소다알카리액을 가하고 65ml의 디메틸 설페이트를 적가 하였다. 반응이 진행되도록 15분간 방치하고 pH를 20ml의 소다를 가하여 8~9로 맞추었다. 현탁액을 약 10℃로 냉각 시켰다. 이를 80ml의 염산으로 산성화시키고 현탁액을 200ml의 에테르로 3번 추출하였다. 유기상을 진공하에서 증발 시켰다.262 g of 0-timothy acid (1.35 moles), 270 ml of 40% soda alkaline solution and 400 ml of water were added to a 3 L flask equipped with a stirrer, thermometer, cooler and dropping funnel. The solution was heated to reflux and 255 ml of dimethylsulfate were added dropwise. After maintaining reflux for 30 minutes, 70 ml of soda alkaline solution was added and 65 ml of dimethyl sulfate was added dropwise. The reaction was allowed to proceed for 15 minutes and the pH was adjusted to 8-9 by adding 20 ml of soda. The suspension was cooled to about 10 ° C. It was acidified with 80 ml of hydrochloric acid and the suspension was extracted three times with 200 ml of ether. The organic phase was evaporated in vacuo.
오일 잔사를 95℃에서 675ml의 에탄올중에서 형성한 작은 구형의 칼리 180g의 용액에 가하였다. 이를 환류시키기 위하여 1시간동안 가열하고 냉각 시켰다. 후에 현탁액을 증발시켜 잔사를 물에 용해 시켰다. 액상을 염산으로 pH1로 산성화시키고 현탁액을 300ml의 에테르로 3번 추출하였다. 유기상을 물로 세척하고 마그네슘 설페이트 상에서 건조시키고 여과시켜서 용매를 진공하에서 건조 시켰다.The oil residue was added to a solution of 180 g of small spherical Kali formed in 675 ml of ethanol at 95 ° C. In order to reflux it was heated and cooled for 1 hour. The suspension was then evaporated to dissolve the residue in water. The liquid phase was acidified to pH 1 with hydrochloric acid and the suspension was extracted three times with 300 ml of ether. The organic phase was washed with water, dried over magnesium sulphate and filtered to dry the solvent in vacuo.
잔사를 250ml의 석유에테르에서 재결정시켜, 유출하여 100ml의 석유에테르로 3번 세척하고 흰색결정ㅇㄹ 40℃의 오븐에서 건조 시켰다.The residue was recrystallized in 250 ml of petroleum ether, spilled, washed three times with 100 ml of petroleum ether, and dried in an oven at 40 ° C. in white crystals.
217g(77%)의 생성물을 얻었다. 융점 68℃217 g (77%) of product were obtained. Melting point 68 ℃
2-메톡시-3-이소프로필-5-설파모일-6-메틸벤조산2-methoxy-3-isopropyl-5-sulfamoyl-6-methylbenzoic acid
1,200ml의 클로로설폰산을 교반기 및 온도계가 장착되어 있는 4ℓ용량의 플라스크에 가하였다. 250g의 2-메톡시-3-이소프로필-6-메틸벤조산(1.20몰)을 반응중에 10-15℃에서 가하였다. 혼합물을 실온에서 9시간 동안 교반한 후에 방치하였다. 용액을 분쇄시킨 얼음이 있는 20ℓ반응조에 적가하였다. 교반을 효과있게 하려면 주기적으로 얼음을 가하여 5℃ 이하로 항상 유지시켜야 한다. 모두 10-11kg의 얼음을 사용 하였다.1,200 ml of chlorosulfonic acid was added to a 4 L flask equipped with a stirrer and thermometer. 250 g of 2-methoxy-3-isopropyl-6-methylbenzoic acid (1.20 mol) was added at 10-15 ° C. during the reaction. The mixture was stirred at rt for 9 h and then left. The solution was added dropwise to a 20 L reactor with crushed ice. To be effective, stirring should be done periodically to keep the temperature below 5 ° C. Both 10-11 kg of ice were used.
침전을 여과 시키고 물로 세척한 후에 800ml의 23% 암모니아에 주입하여 -5 내지 +5℃로 유지시켰다.The precipitate was filtered off, washed with water and then injected into 800 ml of 23% ammonia to maintain -5 to +5 ° C.
고체가 완전히 용해 되었을때, 용액을 방지한 후에 카본블랙의 존재하에서 여과 하였다. 여과액을 500ml의 염산(비중 1.18)으로 산성화 하였다. 이를 냉각기에서 결정화하여 여과하고 물로 세척하였다. 흰색 결정을 50℃의 오븐에서 건조시켜서 291g(84%)의 생성물을 얻었다. 융점 198℃When the solid was completely dissolved, the solution was prevented and then filtered in the presence of carbon black. The filtrate was acidified with 500 ml of hydrochloric acid (specific gravity 1.18). It was crystallized in a cooler, filtered and washed with water. The white crystals were dried in an oven at 50 ° C. to give 291 g (84%) of product. Melting Point 198 ℃
2-메톡시-3-이소프로필-5-설파모일-6-메틸벤조일 클로라이드2-methoxy-3-isopropyl-5-sulfamoyl-6-methylbenzoyl chloride
72g의 2-메톡시-3-이소프로필-5-설파모일-6-메틸벤조산(0.25몰), 250ml의 클로로포름, 23ml의 티오닐클로라이드 및 3방울의 디메틸포름아미드를 교반기 및 냉각기가 장착되어 있는 1ℓ용량의 플라스크에 가하였다. 혼합물을 환류시키기 위하여 1.5시간 동안 가열한 후 18ml의 티오닐 클로라이드를 가하고 환류를 1.5시간 동안 계속하였다. 고체가 완전히 용해 되었다.72 g of 2-methoxy-3-isopropyl-5-sulfamoyl-6-methylbenzoic acid (0.25 mol), 250 ml of chloroform, 23 ml of thionyl chloride and 3 drops of dimethylformamide are equipped with a stirrer and a cooler. It was added to a 1 L flask. The mixture was heated to reflux for 1.5 h and then 18 ml of thionyl chloride was added and reflux continued for 1.5 h. The solid was completely dissolved.
용액을 냉각시키고 진공하에서 증발시킨 후에 100ml의 클로로포름을 잔사에 가하여 증발을 계속하여 오일잔사를 얻었다.After cooling the solution and evaporating under vacuum, 100 ml of chloroform was added to the residue to continue evaporation to obtain an oil residue.
N-(1-싸이클로프로필메틸-2-피롤리딜메틸)-2-메톡시-3-이소프로필-5-설파모일-6-메틸벤즈아미드N- (1-cyclopropylmethyl-2-pyrrolidylmethyl) -2-methoxy-3-isopropyl-5-sulfamoyl-6-methylbenzamide
4.3g의 1-싸이클로프로필메틸-2-아미노메틸-피롤리딘(0.028몰) 및 40ml의 메틸에틸 케톤을 교반기, 온도계 및 적하깔대기가 장착되어 있는 250ml의 용량의 플라스크에 가하였다. 혼합물을 약 10℃로 냉각시키고 용액을 50ml의 메틸-에틸-케톤 중의 7.6g의 2-메톡시-3-이소프로필-5-설파모일-6메틸벤조일 클로라이드(0.025몰)를 적가 하였다. 혼합물을 실온에서 1시간 동안 반응시킨 후에 진공하에서 증발시켰다. 잔사를 100ml의 물 및 10ml의 염산(비중 1.18)에 용해 시켰다. 용액을 진공하에서 흡수시켜 용매의 최후의 미량을 제거 하였다. 불용성의 성분을 여별하여 여액을 15ml의 암모니아(비중 0.91)로 알카리액으로 만들었다. 형성된 침전을 여과하여 물로 세척하고 50ml의 에틸아세테이트에서 젖은 채로 재결정시켰다. 2.5g(24%)의 생성물을 얻었다. 융점 125℃4.3 g of 1-cyclopropylmethyl-2-aminomethyl-pyrrolidine (0.028 mol) and 40 ml of methylethyl ketone were added to a 250 ml flask equipped with a stirrer, thermometer and dropping funnel. The mixture was cooled to about 10 ° C. and the solution was added dropwise to 7.6 g 2-methoxy-3-isopropyl-5-sulfamoyl-6methylbenzoyl chloride (0.025 mol) in 50 ml of methyl-ethyl-ketone. The mixture was allowed to react for 1 hour at room temperature and then evaporated in vacuo. The residue was dissolved in 100 ml of water and 10 ml of hydrochloric acid (specific gravity 1.18). The solution was absorbed under vacuum to remove the last traces of solvent. The insoluble components were filtered off and the filtrate was made alkaline with 15 ml of ammonia (0.91 specific gravity). The precipitate formed was filtered off, washed with water and recrystallized wet in 50 ml of ethyl acetate. 2.5 g (24%) of the product were obtained. Melting point 125 ℃
[실시예 9]Example 9
N-(1-싸이클로펜틸-2-피롤리딜메틸)-2-메톡시-3-이소프로필-5-설파모일-6-메틸벤즈아미드N- (1-cyclopentyl-2-pyrrolidylmethyl) -2-methoxy-3-isopropyl-5-sulfamoyl-6-methylbenzamide
3.4g의 1-싸이클로펜틸-2-아미노메틸피롤리딘(0.020몰) 및 40ml의 메틸-에틸-케톤을 교반기, 온도계 및 적하깔대기가 장착되어 있는 250ml 용량의 플라스크에 가하였다. 혼합물을 약 +10℃로 냉각시킨 후에 40ml의 메틸-에틸-케톤중의 5.5g의 2-메톡시-3-이소프로필-5-설파모일-6-메틸벤조일 클로라이드(0.018몰)를 적가하였다. 혼합물을 실온에서 1시간 반응시킨 후 용매를 진공하에서 증발시켜서 잔사를 100ml의 염산(비중 1.18)에 용해 시켰다. 불용성인 점착성 생성물을 여별하여 여액을 15ml의 암모니아(비중 0.91)로 알카리액으로 만들었다. 형성시킨 침전물을 여과하고 물로 세척한 후에 30ml의 에틸아세테이트에서 재결정 하였다. 결정을 여과하고 소량의 용매로 세척하여 50℃의 오븐에서 건조시켜서 1.3g(17%)의 생성물을 얻었다. 융점 196℃3.4 g of 1-cyclopentyl-2-aminomethylpyrrolidine (0.020 mol) and 40 ml of methyl-ethyl-ketone were added to a 250 ml flask equipped with a stirrer, thermometer and dropping funnel. After cooling the mixture to about + 10 ° C., 5.5 g of 2-methoxy-3-isopropyl-5-sulfamoyl-6-methylbenzoyl chloride (0.018 mol) in 40 ml of methyl-ethyl-ketone was added dropwise. The mixture was allowed to react at room temperature for 1 hour, and then the solvent was evaporated under vacuum to dissolve the residue in 100 ml of hydrochloric acid (specific gravity 1.18). The insoluble sticky product was filtered off and the filtrate was made alkaline with 15 ml of ammonia (0.91 specific gravity). The precipitate formed was filtered off, washed with water and recrystallized from 30 ml of ethyl acetate. The crystals were filtered off, washed with a small amount of solvent and dried in an oven at 50 ° C. to yield 1.3 g (17%) of product. Melting Point 196 ℃
[실시예 10]Example 10
N-(1-싸이클로헥실-2-피롤리딜메틸)-2-메톡시-3-이소프로필-5-설파모일-6-메틸벤즈아미드N- (1-cyclohexyl-2-pyrrolidylmethyl) -2-methoxy-3-isopropyl-5-sulfamoyl-6-methylbenzamide
4.4g의 1-싸이클로헥실메틸-2-아미노 메틸피롤리딘(0.22몰) 및 40ml의 메틸-에틸-케톤을 교반기, 온도계 및 적하깔때기가 장착되어 있는 250ml용량의 플라스크에 가하였다. 혼합물을 약 10℃로 냉각시키고 40ml의 메틸-에틸-케톤중의 6.1g의 2-메톡시-3-이소프로필-5-설파모일-6-메틸벤조일 클로라이드(0.20몰)의 용액을 적가하였다. 반응매체를 실온에서 1시간 동안 교반시킨 후에 용액을 진공하에서 증발 시켰다. 잔사를 100ml의 물 및 10ml의 염산(비중 1.18)에 용해 시켰다. 불용성인 점성생성물을 여별 하였다. 여과액을 15ml의 암모니아(비중 0.91)로 알카리액으로 만들었다. 오일을 염석(Saltedout)분리한 후에 서서히 결정화시켰다. 결정을 여별하고 물로 세척하여 50ml의 이소프로필 에테르에서 습윤 상태로 결정시켰다. 1.4g의 생성물을 얻었다.4.4 g of 1-cyclohexylmethyl-2-amino methylpyrrolidine (0.22 mole) and 40 ml of methyl-ethyl-ketone were added to a 250 ml flask equipped with a stirrer, thermometer and dropping funnel. The mixture was cooled to about 10 ° C. and a solution of 6.1 g 2-methoxy-3-isopropyl-5-sulfamoyl-6-methylbenzoyl chloride (0.20 mol) in 40 ml of methyl-ethyl-ketone was added dropwise. After stirring the reaction medium at room temperature for 1 hour, the solution was evaporated in vacuo. The residue was dissolved in 100 ml of water and 10 ml of hydrochloric acid (specific gravity 1.18). Insoluble viscous products were separated. The filtrate was made alkaline with 15 ml of ammonia (specific gravity 0.91). The oil was slowly crystallized after salted out separation. The crystals were filtered and washed with water to determine the wet state in 50 ml of isopropyl ether. 1.4 g of product was obtained.
이를 50ml 물, 1ml의 염산(비중 1.18) 및 30ml의 아세톤에 용해시켰다. 50ml의 물을 가하고, 아세톤을 진공하에서 증류하였다. 잔존하는 수용액을 2ml의 암모니아(비중 1.91)로 알카리액으로 만들었다. 형성시킨 침전을 여과하고 물로 세척하여 50℃의 오븐에서 건조시켰다. 1.2g(13%)의 생성물을 얻었다. 약 90℃의 점성 점도에서 용해한다. NMR 및 IR스펙트럼가 시도하였던 구조와 일치하였다.It was dissolved in 50 ml water, 1 ml hydrochloric acid (specific gravity 1.18) and 30 ml acetone. 50 ml of water were added and the acetone was distilled under vacuum. The remaining aqueous solution was made alkaline with 2 ml of ammonia (specific gravity 1.91). The precipitate formed was filtered off, washed with water and dried in an oven at 50 ° C. 1.2 g (13%) of the product were obtained. Dissolve at a viscosity viscosity of about 90 ° C. NMR and IR spectra were consistent with the structures tried.
[실시예 11]Example 11
N-(1-노르보르닐-2-피롤리딜메틸)-2-메톡시-5-메틸-설포닐벤즈아미드N- (1-norbornyl-2-pyrrolidylmethyl) -2-methoxy-5-methyl-sulfonylbenzamide
69g의 2-메톡시-5-메틸설포닐벤조산(0.30몰), 360ml의 아세톤, 120ml의 물 및 30.3g의 티리에틸아민(0.30몰)을 교반기, 온도계, 냉각기 및 적하깔대기가 장착되어 있는 1ℓ용량의 플라스크에 가하였다. 용액을 0℃로 냉각시킨 후에 40.8의 이소부틸 클로로포로메이트(0.30몰)를 적가하였다. 혼합물을 실온에서 30분간 교반한 후에 0℃로 다시 냉각시켰다. 58.2g의 1-노르보르닐-2-아미노메틸 피롤리딘(0.30몰)을 적가하였다. 반응혼합물을 실온에서 3시간동안 교반한 후에 증발시켰다. 반사를 500ml의 물 및 80ml의 염산(비중 1.18)에 용해시켰다. 용액을 활성탄 3S로 여과하여 여액을 120ml의 소다 알카리액으로 알카리성으로 만들었다. 상층의 혼탁 오일을 따라 버리고 500ml의 물로 세척한 후에 약 60℃에서 90ml의 에틸아세테이트에 용해시켰다. 생성된 결정을 냉동시켜서 여과하고 물로 세척하여 60℃의 오븐에서 건조시켰다. 72g의 생성물을 얻었다. (융점 125℃) 150ml의 이소프로판올에서 재결정시켜 62g(51%)의 아미드를 얻었다. 융점 132℃1 g of 69 g of 2-methoxy-5-methylsulfonylbenzoic acid (0.30 mole), 360 ml of acetone, 120 ml of water and 30.3 g of thiriethylamine (0.30 mole) with a stirrer, thermometer, cooler and dropping funnel Was added to a volume of flask. After cooling the solution to 0 ° C., 40.8 isobutyl chloroformate (0.30 mol) was added dropwise. The mixture was stirred at rt for 30 min and then cooled back to 0 ° C. 58.2 g of 1-norbornyl-2-aminomethyl pyrrolidine (0.30 mol) was added dropwise. The reaction mixture was stirred at room temperature for 3 hours and then evaporated. The reflection was dissolved in 500 ml of water and 80 ml of hydrochloric acid (specific gravity 1.18). The solution was filtered with activated carbon 3S to make the filtrate alkaline with 120 ml of soda alkaline solution. The upper turbid oil was discarded and washed with 500 ml of water and then dissolved in 90 ml of ethyl acetate at about 60 ° C. The resulting crystals were frozen, filtered, washed with water and dried in an oven at 60 ° C. 72 g of product were obtained. (Melting point 125 ° C.) Recrystallization in 150 ml of isopropanol gave 62 g (51%) of amide. Melting point 132 ℃
[실시예 12]Example 12
N-(1-(2'-노르보르닐)-2-피롤리딜)메틸)-2-메톡시-4-아미노-5-에틸-설포닐-벤즈아미드N- (1- (2'-Norbornyl) -2-pyrrolidyl) methyl) -2-methoxy-4-amino-5-ethyl-sulfonyl-benzamide
26g의 2-메톡시-4-아미노-5-에틸설포닐벤조산(0.1몰), 100ml의 아세톤, 26ml의 물 및 10g의 트리에틸아민(0.1몰)을 교반기, 온도계, 냉각기 및 적하깔대기가 장착되어 있는 500ml용량의 플라스크에 가하였다. 산이 용해되었을 때 용액을 5℃로 냉각시키고 14g의 이소부틸클로로 포르메이트(0.102몰)을 적가하였다. 반응 매체를 5℃-10℃에서 30분간 교반하여 다시 5℃로 냉각 시켰다. 20g의 1-(2'-노르보닐)-2-아미노메틸 피롤리딘(0.103몰)을 적가한 후에 매체를 실온에서 2시간 동안 반응시켰다. 용매를 진공하에서 증발시키고 점성 잔사를 200ml의 물 및 50ml의 아세트산에 용해 시켰다. 용액을 여과하여 여액을 500ml의 소다 알카리액으로 알카리성으로 만들었다. 생성물을 냉각기에서 결정시켜서 여과하고, 물로 세척하여 오븐에서 건조시킨 다음 200ml의 메탄올에서 재결정 시켰다. 여과된 흰색결정을 소량의 냉각시킨 메탄올로 세척하고 50℃의 오븐에서 건조시켜서 25g(57%)의 생성물을 얻었다. 융점 175℃26 g 2-methoxy-4-amino-5-ethylsulfonylbenzoic acid (0.1 mol), 100 ml acetone, 26 ml water and 10 g triethylamine (0.1 mol) are equipped with a stirrer, thermometer, cooler and dropping funnel To a 500 ml flask. When the acid was dissolved the solution was cooled to 5 ° C. and 14 g of isobutylchloro formate (0.102 mol) was added dropwise. The reaction medium was stirred at 5 ° C-10 ° C for 30 minutes and cooled to 5 ° C. After adding 20 g of 1- (2'-norbornyl) -2-aminomethyl pyrrolidine (0.103 mol) dropwise, the medium was allowed to react for 2 hours at room temperature. The solvent was evaporated in vacuo and the viscous residue was dissolved in 200 ml of water and 50 ml of acetic acid. The solution was filtered to make the filtrate alkaline with 500 ml of soda alkaline solution. The product was crystallized in a cooler, filtered, washed with water, dried in an oven and recrystallized from 200 ml of methanol. The filtered white crystals were washed with a small amount of cooled methanol and dried in an oven at 50 ° C. to give 25 g (57%) of product. Melting point 175 ℃
[실시예 13]Example 13
N-(1-노르보르닐-2-피롤리딜메틸)-2-메톡시-4-브로모-5-설파모일 벤즈아미드N- (1-norbornyl-2-pyrrolidylmethyl) -2-methoxy-4-bromo-5-sulfamoyl benzamide
2-메톡시-4-브로모-5-클로로설포닐-벤조 산2-methoxy-4-bromo-5-chlorosulfonyl-benzoic acid
비중 1.766(4.55몰)인 300ml의 클로로설폰산을 교반기, 온도계 및 냉각기가 장착되어 있는 1ℓ용량의 플라스크에 가하고 69.3g의 2-메톡시-4-브로모벤조산(0.30몰)을 가하였다. 반응이 서서히 발열 반응되고 온도는 모든 벤조산이 가해짐에 따라서 40℃에 도달 하였다. 반응 매체를 80℃로 가열시킨 다음에 다시 실온으로 회복시켰다. 갈색 용액을 2kg의 분쇄시킨 얼음위로 서서히 가하였다.300 ml of chlorosulfonic acid having a specific gravity of 1.766 (4.55 mol) was added to a 1 L flask equipped with a stirrer, a thermometer, and a cooler, and 69.3 g of 2-methoxy-4-bromobenzoic acid (0.30 mol) was added thereto. The reaction was exothermic slowly and the temperature reached 40 ° C. as all benzoic acid was added. The reaction medium was heated to 80 ° C. and then returned to room temperature. The brown solution was added slowly over 2 kg of crushed ice.
형성시킨 침전물을 여과하고 물로 50℃ 세척하여 50℃의 오븐에서 4시간 동안 건조 시켰다. 94g의 생성물을 얻었다. 융점 194℃The precipitate formed was filtered and washed with water at 50 ° C. and dried in an oven at 50 ° C. for 4 hours. 94 g of product were obtained. Melting Point 194 ℃
2-메톡시-4-브로모-5-설파모일-벤조산2-methoxy-4-bromo-5-sulfamoyl-benzoic acid
1,290ml의 22°B
2-메톡시-4-브로모-5-설파모일-벤조일 클로라이드2-methoxy-4-bromo-5-sulfamoyl-benzoyl chloride
183ml의 티오닐 클로라이드(비중 1.64), 61g의 2-메톡시-4-브로모-5-설파모일-벤조산(0.197몰) 및 2방울의 디메틸포름아미드를 교반기, 냉각기 및 온도계가 장착되어 있는 500ml용량의 플라스크에 가하여 점차로 가열하여 환류 시켰다. 환류는 2시간 동안 지속한 후에 과량의 SOCl2를 진공하에서 증류시켜 제거 하였다. 잔사를 100ml의 톨루엔에 용해시커서 진공하에서 제거시킨 후에 생성물을 180ml의 헥산에 용해시키고 배수시켜 40ml의 헥산으로 세척하고 2시간 동안 오븐에서 건조 시켰다. 62g(96%)의 생성물을 얻었다. 185℃(분해)183 ml of thionyl chloride (specific gravity 1.64), 61 g of 2-methoxy-4-bromo-5-sulfamoyl-benzoic acid (0.197 moles) and 2 drops of dimethylformamide, 500 ml with stirrer, cooler and thermometer It was added to a flask of a volume and gradually heated to reflux. Reflux was continued for 2 hours and then excess SOCl 2 was removed by distillation under vacuum. The residue was dissolved in 100 ml of toluene and removed under vacuum, then the product was dissolved in 180 ml of hexane, drained, washed with 40 ml of hexane and dried in an oven for 2 hours. 62 g (96%) of the product were obtained. 185 ° C (decomposition)
N-(1-노르보르닐-2-피롤리딜메틸)-2-메톡시-4-브로모-5-설파모일-벤즈아미드N- (1-Norbornyl-2-pyrrolidylmethyl) -2-methoxy-4-bromo-5-sulfamoyl-benzamide
65g의 1-노르보르닐-2-아미노-메틸-피롤리딘(0.335몰) 및 500ml의 메틸-에틸-케톤을 교반기, 온도계 및 적하깔대기가 장착되어 있는 3ℓ용량의 플라스크에 가하였다. 용액을 5ℓ로 냉각시킨 다음 109의 2-메톡시-4-브로모-5-설파모일-벤조일 클로라이드의 여과시킨 용액을 적가 하였다.65 g of 1-norbornyl-2-amino-methyl-pyrrolidine (0.335 mol) and 500 ml of methyl-ethyl-ketone were added to a 3 L flask equipped with a stirrer, thermometer and dropping funnel. The solution was cooled to 5 L and then a filtered solution of 109 2-methoxy-4-bromo-5-sulfamoyl-benzoyl chloride was added dropwise.
반응매체를 실온으로 회복 되도록 방치한 후에 24시간 동안 방치하였다. 형성된 침전물을 여과하므로 세척하여 60℃의 오븐에서 건조시켜서 146g의 생성물을 얻었다. 융점 250℃이상 이를 4ℓ의 끓는 물에 현탁시키고 200ml의 암모니아를 가하였다. 이 현탁액을 80℃에서 1시간 동안 교반 하였다. 40℃로 냉각시키고 여과시켰다. 흰색 결정을 물로 세척한 다음에 200ml의 물에서 재 현탁 시켰다. 100ml의 아세트산을 가하여 얻어진 용액을 목탄으로 여과시켜서 염기를 350ml의 암모니아를 가하여 침전 시켰다. 결정을 배수하고 물로 세척하여 60℃의 오븐에서 건조시켜 115g(71%)의 아미드를 얻었다. 융점 202℃The reaction medium was allowed to recover to room temperature and then left for 24 hours. The precipitate formed was filtered off and washed and dried in an oven at 60 ° C. to yield 146 g of product. It has a melting point of 250 ° C. or higher and it is suspended in 4 L of boiling water and 200 ml of ammonia is added. This suspension was stirred at 80 ° C. for 1 hour. Cool to 40 ° C. and filter. The white crystals were washed with water and then resuspended in 200 ml of water. The solution obtained by adding 100 ml of acetic acid was filtered through charcoal, and the base was precipitated by adding 350 ml of ammonia. The crystals were drained, washed with water and dried in an oven at 60 ° C. to yield 115 g (71%) of amide. Melting point 202 ℃
[실시예 14]Example 14
N-(1-싸이클로헵틸-2-피롤리디닐메틸)-2-메톡시-4-클로로-5-에틸설포닐-벤조아미드N- (1-cycloheptyl-2-pyrrolidinylmethyl) -2-methoxy-4-chloro-5-ethylsulfonyl-benzoamide
39g의 1-싸이클로헵틸-2-아미노메틸피롤리딘(0.200몰) 및 150ml의 메틸-에틸-케톤을 교반기, 온도계, 냉각기 및 적하깔대기가 장착되어 있는 1ℓ용량의 플라스크에 가하였다. 용액을 10℃로 냉각시킨 다음 반응중에 55g의 2-메톡시-4-클로로-5-에틸-설포닐-벤조일 클로라이드를 가하였다. 반응 매체를 실온에서 8시간 동안 교반한 후에 방치하였다.39 g of 1-cycloheptyl-2-aminomethylpyrrolidine (0.200 mol) and 150 ml of methyl-ethyl-ketone were added to a 1 L flask equipped with a stirrer, thermometer, cooler and dropping funnel. The solution was cooled to 10 ° C. and then 55 g of 2-methoxy-4-chloro-5-ethyl-sulfonyl-benzoyl chloride was added during the reaction. The reaction medium was left for 8 hours after stirring at room temperature.
침전물을 여과하고 소량의 에탄올로 세척하여 오븐에서 건조 시켰다. 수율 78g(85.5%) 융점 150-170℃(분해) 하이드로 클로라이드를 500ml의 물에 높은 온도에서 용해 시켰다. 용액을 3S 블랙의 존재하에 여과시킨 후에 여액을 60ml의 소다알칼리액으로 알칼이성으로 하였다. 오일을 침전 시켰다. 얼음조에서 2일 경과후에 형성된 결정을 여과하고 물로 세척하여 40℃의 오븐에서 건조 시켰다.The precipitate was filtered off, washed with a small amount of ethanol and dried in an oven. Yield 78 g (85.5%) Melting Point 150-170 ° C. (Decomposition) Hydrochloride was dissolved in 500 ml of water at high temperature. The solution was filtered in the presence of 3S black and the filtrate was alkaline with 60 ml of soda alkaline solution. The oil precipitated out. Crystals formed after 2 days in an ice bath were filtered, washed with water and dried in an oven at 40 ℃.
52.5g의 생성물을 얻어서 200ml의 물 및 7g의 아세트산에 용해 시켰다. 용액을 10%로 희석시키고 카본블랙 존재하에 여과 시켰다. 생성물을 130ml의 1N 소다로 알카리성 용액으로 하여 지침 전시켰다. 오일을 결정시킨 다음에 여과하여 물로 세척하고 오븐에서 건조 시켰다. 생성물을 100ml의 이소프로판올에서 재결정 하였다. 43g(51%)의 생성물을 얻었다. 융점 110℃52.5 g of product were obtained and dissolved in 200 ml of water and 7 g of acetic acid. The solution was diluted to 10% and filtered in the presence of carbon black. The product was guided as an alkaline solution with 130 ml of 1N soda. The oil was determined and then filtered, washed with water and dried in an oven. The product was recrystallized in 100 ml of isopropanol. 43 g (51%) of the product was obtained. Melting point 110 ℃
[실시예 15]Example 15
N-(1-싸이클로헥실-메틸-3-피롤리디닐)-2-메톡시-4-아미노-5-싸이클로벤즈아미드N- (1-cyclohexyl-methyl-3-pyrrolidinyl) -2-methoxy-4-amino-5-cyclobenzamide
8g의 2-메톡시-4-아미노-5-클로로벤조산(0.040몰), 50ml의 아세톤 및 4g의 트리에틸아민(0.040몰)을 교반기, 온도계 및 적하깔대기가 장착되어 있는 250ml용량의 플라스크에 가하였다. 현탁액을 냉각시키고 5.5g의 이소부틸 클로로포르메이트(0.040몰)을 0-5℃에서 적가 하였다. 반응 매체를 0-5℃의 온도에서 45분간 교반 하였다. 8g의 1-싸이클로헥실-메틸-3-아미노피롤리딘(0.044몰)을 적가하였다. 반응물을 실온에서 2시간 동안 방치한 후에 80ml의 물을 가하여 아세톤을 제거하였다. 생성물을 남아 있는 물에8 g of 2-methoxy-4-amino-5-chlorobenzoic acid (0.040 mol), 50 ml of acetone and 4 g of triethylamine (0.040 mol) were added to a 250 ml flask equipped with a stirrer, thermometer and dropping funnel. It was. The suspension was cooled and 5.5 g of isobutyl chloroformate (0.040 mol) was added dropwise at 0-5 ° C. The reaction medium was stirred for 45 minutes at a temperature of 0-5 ° C. 8 g of 1-cyclohexyl-methyl-3-aminopyrrolidine (0.044 mol) was added dropwise. The reaction was left at room temperature for 2 hours and then 80 ml of water was added to remove acetone. To the remaining water
이를 여과하여 150ml물 및 5ml의 농염산에 재용해시켰다. 용액을 목탄으로 여과하고 여액을 10ml의 암모니아(비중 0.91)로 알카리성으로 만들었다. 점성의 침전물을 여과하고 80ml의 물 및 5ml의 염산에 용해시켰다. 생성물을 용해시켜서 하이드로 클로라이드를 매우 신속하게 침전시켰다. 이를 배수하고 물로 세척하여 50℃에서 건조시켰다. 10.4g의 생성물을 얻어서 100ml의 뜨거운 물에 용해시켰다. 용액을 10ml의 소다알카리액으로 알카리성으로 하였다. 오일 침전을 냉각시켜 결정화하였다. 이를 배수하고 물It was filtered and redissolved in 150 ml of water and 5 ml of concentrated hydrochloric acid. The solution was filtered through charcoal and the filtrate was alkaline with 10 ml of ammonia (0.91 specific gravity). The viscous precipitate was filtered off and dissolved in 80 ml of water and 5 ml of hydrochloric acid. Hydrochloride precipitated very quickly by dissolving the product. It was drained, washed with water and dried at 50 ° C. 10.4 g of product was obtained and dissolved in 100 ml of hot water. The solution was alkaline with 10 ml of soda alkaline solution. The oil precipitate was cooled to crystallize. Drain the water
[실시예 16]Example 16
N-(1-싸이클로프로필메틸-3-피롤리딜)-2-메톡시-4-브로모-5-메틸-설포닐-벤즈아미드N- (1-cyclopropylmethyl-3-pyrrolidyl) -2-methoxy-4-bromo-5-methyl-sulfonyl-benzamide
2-메톡시-4-브로모-5-메틸설포닐 벤조산2-methoxy-4-bromo-5-methylsulfonyl benzoic acid
66g의 소디움 설파이트, 80g의 중탄산나트륨 및 280ml의 물을 교반기, 온도계, 냉각기 및 적하깔대기가 장착되어 있는 플라스크에 가하였다. 혼합물을 60℃로 가열한 후에 92.4g의 2-메톡시-4-브로모-5-클로로설포닐 벤조산을 가하였다.66 g sodium sulfite, 80 g sodium bicarbonate and 280 ml water were added to a flask equipped with a stirrer, thermometer, cooler and dropping funnel. The mixture was heated to 60 ° C. and then 92.4 g of 2-methoxy-4-bromo-5-chlorosulfonyl benzoic acid was added.
반응매체를 60-70℃로 3시간 동안 가열하였을 때 60g의 중탄산나트륨을 가하고 106g의 디메틸설페이트를 서서히 주입하였다. 혼합물을 가열하여 환류시킨 후에 냉각시키고 염산으로 산성화 하였다. 형성된 침전을 배수하고 50℃의 오븐에서 건조시킨 후에 250ml의 끓는 물에 주입하였다. 형성된 현탁액을 비점에서 교반하고 고온에서 여과한 후에 결정을 50℃의 오븐에서 건조시켰다. 34g의 2-메톡시-4-브로모-5-메틸설포닐 벤조산을 얻었다. 융점 225-258℃ 수율 39.3%When the reaction medium was heated to 60-70 ° C. for 3 hours, 60 g of sodium bicarbonate was added thereto, and 106 g of dimethyl sulfate was slowly injected. The mixture was heated to reflux, cooled and acidified with hydrochloric acid. The precipitate formed was drained and dried in an oven at 50 ° C. and then poured into 250 ml of boiling water. The resulting suspension was stirred at boiling point and filtered at high temperature before the crystals were dried in an oven at 50 ° C. 34 g of 2-methoxy-4-bromo-5-methylsulfonyl benzoic acid were obtained. Melting Point 225-258 ° C Yield 39.3%
N-(1-싸이클로프로필메틸-3-피롤리디닐)-2-메톡시-4-브로모-5-메틸설포닐-벤즈아미드N- (1-cyclopropylmethyl-3-pyrrolidinyl) -2-methoxy-4-bromo-5-methylsulfonyl-benzamide
9.3g의 2-메톡시-4-브로모-5-메틸설포닐벤조산(0.030몰), 70ml의 아세톤, 10ml의 물 및 비중 0.72(0.030)인 4.2ml의 트리에틸아민을 교반기, 온도계 및 적하깔대기가 장착되어 있는 250ml 용량의 플라스크에 가하였다. 얻어진 용액을 약 0℃로 냉각시켰다. 4.2g의 이소부틸 클로로포르메이트(0.030몰)를 적가하여 반응매체를 0-5℃의 온도에서 30분 동안 교반시킨 후에 4.7g의 1-싸이클로프로필메틸-3-아미노피롤리딘(0.033몰)을 적가하였다.9.3 g of 2-methoxy-4-bromo-5-methylsulfonylbenzoic acid (0.030 mol), 70 ml of acetone, 10 ml of water and 4.2 ml of triethylamine having a specific gravity of 0.72 (0.030) were added with a stirrer, thermometer and dropwise addition. It was added to a 250 ml flask equipped with a funnel. The resulting solution was cooled to about 0 ° C. 4.2 g of isobutyl chloroformate (0.030 mol) was added dropwise and the reaction medium was stirred at a temperature of 0-5 ° C. for 30 minutes, followed by 4.7 g of 1-cyclopropylmethyl-3-aminopyrrolidine (0.033 mol). Was added drop wise.
반응을 실온에서 2시간 동안 계속한 후에 50ml의 물 및 5ml의 소다알카리액을 가하였다. 아세톤을 진공하에서 증발시키고 물에 불용성인 오일을 각각 50ml의 메틸렌 클로라이드로 2번에 걸쳐 추출하였다.The reaction was continued for 2 hours at room temperature before 50 ml of water and 5 ml of soda alkaline solution were added. Acetone was evaporated in vacuo and oil insoluble in water was extracted twice with 50 ml of methylene chloride each time.
유기용액을 마그네슘 설페이트상에서 건조시키고 여과하여 여액을 진공하에서 건조시켰다. 점성이 있는 잔사를 90ml의 뜨거운 이소프로판올에 용해시켰다. 용액을 6N 염기성 에탄올 7ml로 산성화시켰다. 하이드로 클로라이드를 냉동기에서 결정시킨 후에 결정을 여과하고 소량의 이소프로판올로 세척하여 50℃의 오븐에서 건조시켰다. 생성물을 40ml의 미온수에 용해시켜서 용액을 여과한 후에 5ml의 소다 알카리액으로 알카리성으로 하였다. 염기를 오일의 형태로 침전시켰다. 상층의 수성상을 따라내고 잔사를 100ml의 메틸이소부틸케톤에 고온에서 용해시켰다. 냉동기에서 결정화시켜서 생성물을 여과하고 소량의 메틸이소부틸케톤으로 세척한 후에 물로 세척하고 50℃의 오븐에서 건조시켰다. 5.4g(42%)의 생성물을 얻었다.The organic solution was dried over magnesium sulphate and filtered to dry the filtrate under vacuum. The viscous residue was dissolved in 90 ml of hot isopropanol. The solution was acidified with 7 ml 6N basic ethanol. After hydrochloride was determined in the freezer, the crystals were filtered off, washed with a small amount of isopropanol and dried in an oven at 50 ° C. The product was dissolved in 40 ml of lukewarm water and the solution was filtered before being alkaline with 5 ml of soda alkaline solution. The base was precipitated in the form of an oil. The aqueous phase of the upper layer was decanted and the residue was dissolved in 100 ml of methyl isobutyl ketone at high temperature. The product was filtered by crystallization in a freezer, washed with a small amount of methylisobutylketone, then with water and dried in an oven at 50 ° C. 5.4 g (42%) of the product were obtained.
융점 147℃Melting point 147 ℃
[실시예 17]Example 17
N-[1-싸이클로헥세닐)-메틸-2-피롤리딜메틸]-2,3-디메톡시-5-설파모일-벤즈아미드N- [1-cyclohexenyl) -methyl-2-pyrrolidylmethyl] -2,3-dimethoxy-5-sulfamoyl-benzamide
13g의 2,3-디메톡시-5-설파모일-벤조산(0.05몰), 150ml의 아세톤, 35ml의 물 및 5g의 트리에틸아민(0.05몰)을 교반기, 온도계, 냉각기 및 적하깔대기가 장착되어 있는 500ml 용량의 플라스크에 가하였다. 혼합물을 0-5℃로 냉각시키고 5.5g의 에틸클로로포르메이트(0.05몰)을 적가하였다. 반응 매체를 침전이 완전히 용해될 때까지 교반한 후에 0℃로 재냉각시켜서 9.7g의 1-(1-싸이클로헥세닐)-메틸-2-아미노메틸-피롤리딘(0.05몰)을 적가하였다.13 g of 2,3-dimethoxy-5-sulfamoyl-benzoic acid (0.05 mol), 150 ml of acetone, 35 ml of water and 5 g of triethylamine (0.05 mol) are equipped with a stirrer, thermometer, cooler and dropping funnel It was added to a 500 ml flask. The mixture was cooled to 0-5 ° C. and 5.5 g ethylchloroformate (0.05 mol) was added dropwise. 9.7 g of 1- (1-cyclohexenyl) -methyl-2-aminomethyl-pyrrolidine (0.05 mol) was added dropwise by stirring the reaction medium until the precipitate completely dissolved and then recooled to 0 ° C.
매체를 실온에서 5시간 동안 반응시킨 후 방치하였다. 용매를 진공하에서 증발시켜서 잔사를 150ml의 염산(비중 1.18)에 용해시켰다. 상층의 불용성 오일을 따라내고, 수용액을 13ml의 암모니아(비중 0.91)로 알카리성으로 만들었다. 형성된 침전을 여과하고, 물로 세척하여 120ml의 이소프로판올에서 재결정시켰다. 6.1g의 생성물을 얻어서 250ml의 이소프로판올에서 재결정시켰다. 수율 4.5%(21%) 융점 169℃The medium was allowed to react for 5 hours at room temperature and then left. The solvent was evaporated under vacuum to dissolve the residue in 150 ml of hydrochloric acid (specific gravity 1.18). The insoluble oil of the upper layer was decanted and the aqueous solution was made alkaline with 13 ml of ammonia (0.91 specific gravity). The precipitate formed was filtered off, washed with water and recrystallized from 120 ml of isopropanol. 6.1 g of product were obtained and recrystallized in 250 ml of isopropanol. Yield 4.5% (21%) Melting Point 169 ℃
[실시예 18]Example 18
N-(1-싸이클로헥실-2-피롤리딜-메틸)-2-프로파르길옥시-3,5-디클로로벤즈아미드N- (1-cyclohexyl-2-pyrrolidyl-methyl) -2-propargyloxy-3,5-dichlorobenzamide
메틸 2-프로파르길옥시-3,5-디클로로벤조에이트Methyl 2-propargyloxy-3,5-dichlorobenzoate
밀폐된 교반기, 냉각기 및 온도계가 장착되어 있는 5ℓ 용량의 플라스크를 사용하였다. 320g의 메틸 3,5-디클로로살리실레이트(1.45몰), 1,280ml의 메틸-에틸-케톤 및 177g의 프로파르길 브로마이드(1.45몰+3% 과량)을 플라스크에 가한 후에 200g의 탄산칼륨(1.45몰) 및 21.5g의 소디움 아이오다이드(0.145몰)을 가하였다. 걸쭉한 펄프(pulp)를 얻었는데 환류시키기 위해서는 유체가 적당하다. 8시간 동안 환류를 지속시켰다.A 5 L flask equipped with a sealed stirrer, cooler and thermometer was used. 320 g of methyl 3,5-dichlorosalicylate (1.45 mol), 1,280 ml of methyl-ethyl-ketone and 177 g of propargyl bromide (1.45 mol + 3% excess) were added to the flask followed by 200 g of potassium carbonate (1.45 Mole) and 21.5 g sodium iodide (0.145 mole) were added. A thick pulp was obtained with a fluid suitable for reflux. Reflux was continued for 8 hours.
메틸-에틸-케톤의 일부를 증류시켜서 잔사를 2.8ℓ의 물에 용해시켜서 무기물 염을 용해시켰다.A portion of methyl-ethyl-ketone was distilled off to dissolve the residue in 2.8 L of water to dissolve the inorganic salts.
침전을 배수하고 중성이 될때까지 물로 세척하여 공기중에서 건조시켰다. 372g(99%)의 에스테르를 얻었다. 융점 78-78℃The precipitate was drained and washed with water until neutral and dried in air. 372 g (99%) of ester were obtained. Melting point 78-78 ℃
2-프로파르길옥시-3,5-디클로로-벤조산2-propargyloxy-3,5-dichloro-benzoic acid
720ml의 뜨거운 에탄올(95°)에 용해된 327g의 메틸 2-프로파르길옥시-3,5-디클로로벤조에이트(1.45몰)을 환류 냉각기가 장착되어 있는 2ℓ 용량의 플가스크에 가하였다.327 g of methyl 2-propargyloxy-3,5-dichlorobenzoate (1.45 moles) dissolved in 720 ml of hot ethanol (95 °) were added to a 2 L capacity flask equipped with a reflux condenser.
145ml의 소다알카리액(1.45몰)을 가하고 용액을 1시간동안 가열하여 환류시켰다. 환류를 계속 유지 시키면서 1ℓ의 물을 가하여 반응을 완료시켰다. 용액을 냉각시키고, 6.2ℓ의 물을 가한 후에 목탄으로 여과하였다. 산을 170ml의 농염산을 가하여 침전시켰다. 흰색 침전을 배수시키고 물로 세척한 후 60℃의 오븐에서 건조시켰다.145 ml of soda alkaline solution (1.45 mol) was added and the solution was heated to reflux for 1 hour. The reaction was completed by adding 1 liter of water while maintaining reflux. The solution was cooled down and 6.2 liters of water was added before it was filtered over charcoal. The acid was precipitated by adding 170 ml of concentrated hydrochloric acid. The white precipitate was drained, washed with water and dried in an oven at 60 ° C.
340g의 2-프로파르길옥시-3,5-디클로로-벤조산을 얻었다. 수율 95.5% 융점 163-164℃340 g of 2-propargyloxy-3,5-dichloro-benzoic acid were obtained. Yield 95.5% Melting Point 163-164 ° C
2-프로파르길옥시-3,5-디클로로-벤조일 클로라이드2-propargyloxy-3,5-dichloro-benzoyl chloride
86g의 2-프로파르길옥시-3,5-디클로로벤조산(0.35몰)을 반응시켰다.86 g of 2-propargyloxy-3,5-dichlorobenzoic acid (0.35 mol) was reacted.
83.5g의 티오닐 클로라이드(2×0.35 몰)을 환류 냉각기가 장착되어 있는 500ml 용량의 플라스크에 가하였다. 이어서 유기산의 약 반을 가하였다. 결과의 현탁액을 수욕상에서 서서히 가열시켰다. 1시간내에 모두 용해되었다. 용액을 냉각시키고 산의 나머지 부분을 가하였다. 모두 용해될 때까지 혼합물을 가열하는데 45분이 걸렸다.83.5 g of thionyl chloride (2 x 0.35 moles) was added to a 500 ml flask equipped with a reflux condenser. Then about half of the organic acid was added. The resulting suspension was slowly heated on a water bath. All dissolved within 1 hour. The solution was cooled and the rest of the acid was added. It took 45 minutes to heat the mixture until all dissolved.
과량의 티오닐 클로라이드를 진공하에서 증류하여 일정량이 되도록 하였다. 잔존하는 산 염화물을 결정시켰다. 중량:90g 수율 97% 융점 63-64℃Excess thionyl chloride was distilled off under vacuum to a constant amount. The remaining acid chlorides were determined. Weight: 90 g Yield 97% Melting Point 63-64 ° C
N-(1-싸이클로헥실-2-피롤리딜-메틸)-2-프로파르길옥시-3,5-디클로로벤즈아미드N- (1-cyclohexyl-2-pyrrolidyl-methyl) -2-propargyloxy-3,5-dichlorobenzamide
190ml의 클로로포름에 용해시킨 64g의 1-싸이클로헥실-2-아미노메틸-피롤리딘(0.35몰)을 교반기 및 온도계가 장착되어 있는 500ml 용량의 플라스크에 용해시켰다.64 g of 1-cyclohexyl-2-aminomethyl-pyrrolidine (0.35 mole) dissolved in 190 ml of chloroform were dissolved in a 500 ml flask equipped with a stirrer and thermometer.
용액을 5℃로 냉각시킨 후에 92g의 미세한 분말로 된 2-프로파르길옥시-3,5-디클로로벤조일 클로라이드(0.35몰)를 약 1시간 동안의 반응중에 서서히 가하였다. 온도는 5-10℃로 유지시켰다. 산 염화물을 가할 때와 마찬가지로 서서히 용해시켰다. 온도를 상승시킨 후에 반응을 완결시켰다. 반응혼합물을 1ℓ의 물에 용해시킨 후에 클로로포름을 증류시켰다. 남겨진 수용액을 목탄으로 여과하고 20% 암모니아를 가하여 염기를 침전시켰다. 서서히 결정시켜서 배수하고 물로 세척하여 40℃의 온도에서 건조시켰다.After cooling the solution to 5 ° C., 92 g of fine powdered 2-propargyloxy-3,5-dichlorobenzoyl chloride (0.35 mole) was added slowly during the reaction for about 1 hour. The temperature was kept at 5-10 ° C. The solution was slowly dissolved as when acid chloride was added. After raising the temperature, the reaction was completed. The reaction mixture was dissolved in 1 L of water and then chloroform was distilled off. The remaining aqueous solution was filtered through charcoal and 20% ammonia was added to precipitate the base. The crystals were slowly drained, washed with water and dried at a temperature of 40 ° C.
137g의 생성물을 얻었다. 융점 79-80℃137 g of product were obtained. Melting point 79-80 ℃
137g의 염기를 275ml의 이소프로판올에서 재결정시켜서 106g의 생성물을 얻었다. 융점 84-85℃137 g of base was recrystallized in 275 ml of isopropanol to yield 106 g of product. Melting point 84-85 ℃
생성물을 1.5ℓ의 물 및 29ml의 농염산에서 용해시켜 정제하였다. 용액을 목탄으로 여과한 후에 20%암모니아를 가하였다. 염기를 서서히 결정시켜서 이온이 제거될 때까지 물로 세척하고, 40℃의 오븐에서 건조시켰다.The product was purified by dissolving in 1.5 L of water and 29 ml of concentrated hydrochloric acid. The solution was filtered through charcoal and then 20% ammonia was added. The base was slowly crystallized and washed with water until ions were removed and dried in an oven at 40 ° C.
104g의 N-(1-싸이클로헥실-2-피롤리디닐-메틸)-2-프로파르길 옥시-3,5-디클로로-벤즈아미드를 얻었는데 흰색 물질이었다. 융점 84-85℃104 g of N- (1-cyclohexyl-2-pyrrolidinyl-methyl) -2-propargyl oxy-3,5-dichloro-benzamide was obtained which was a white substance. Melting point 84-85 ℃
[실시예 19]Example 19
N-(1-(1'아다만틸)-2-피롤리딜-메틸)-2-메톡시-5-설파모일 벤즈아미드N- (1- (1'adamantyl) -2-pyrrolidyl-methyl) -2-methoxy-5-sulfamoyl benzamide
55g의 1-(1'아다만틸)-2-아미노-메틸-피롤리딘(0.235몰), 300ml의 메틸-에틸-케톤 및 100ml의 물을 교반기, 온도계, 냉각기 및 적하깔대기가 장착되어 있는 2ℓ 용량의 플라스크에 가하였다.55 g of 1- (1'adamantyl) -2-amino-methyl-pyrrolidine (0.235 mol), 300 ml of methyl-ethyl-ketone and 100 ml of water are equipped with a stirrer, thermometer, cooler and dropping funnel It was added to a 2 L flask.
700ml의 메틸-에틸-케톤중의 58g의 메톡시-5-설파모일-벤조일클로라이드(0.23몰)의 여과된 용액을 온도를 약 20℃로 유지시키면서 적가하였다.A filtered solution of 58 g methoxy-5-sulfamoyl-benzoylchloride (0.23 mol) in 700 ml methyl-ethyl-ketone was added dropwise while maintaining the temperature at about 20 ° C.
반응매체를 1시간 동안 교반한 다음 여과하였다. 결정을 물로 세척하고 50℃의 오븐에서 건조시켜서 60g의 생성물을 얻었다. 융점 250-270℃ 이를 80ml의 빙초산을 함유하는 1ℓ의 물에 용해시켰다. 경질의 불용성 성분을 여별하고 pH가 8-9가 되도록 암모니아를 가하여 생성물을 침전시켰다.The reaction medium was stirred for 1 hour and then filtered. The crystals were washed with water and dried in an oven at 50 ° C. to give 60 g of product. Melting Point 250-270 ° C. It was dissolved in 1 L of water containing 80 ml of glacial acetic acid. The light insoluble component was filtered off and the product precipitated by addition of ammonia to pH 8-9.
52g의 생성물을 얻었다. 융점 245℃52 g of product was obtained. Melting point 245 ℃
700ml의 메티랑세토 아세테이트에서 재결정시킨 후에 디옥산에서 재결정시켜서 산 염기를 통과시켜서 28g의 생성물을 얻었다. 융점 250℃Recrystallized from 700 ml of methilanceto acetate and then recrystallized from dioxane to pass an acid base to give 28 g of product. Melting point 250 ℃
[실시예 20]Example 20
N(1-(1'-아다만틸)-2-피롤리디닐-메틸)-2-메톡시-5-메틸-설포닐 벤즈아미드N (1- (1'-adamantyl) -2-pyrrolidinyl-methyl) -2-methoxy-5-methyl-sulfonyl benzamide
46g의 1-(1'-아다만틸)-2-아미노-메틸-피롤리딘(0.2몰), 300ml의 메틸-에틸-케톤 및 50ml의 물을 교반기, 온도계 및 냉각기가 장착되어 있는 1ℓ 용량의 플라스크에 가한 후에 41g의 2-메톡시-4-메틸-설포닐-벤조일 클로라이드(0.16몰)을 가하였다.46 g of 1- (1'-adamantyl) -2-amino-methyl-pyrrolidine (0.2 mol), 300 ml of methyl-ethyl-ketone and 50 ml of water in 1 liter volume with stirrer, thermometer and cooler To the flask was added 41 g of 2-methoxy-4-methyl-sulfonyl-benzoyl chloride (0.16 mol).
매체를 20℃에서 2시간 동안 반응시킨 후에 용액은 진공하에서 증발시켰다. 300ml의 물 및 30ml의 40% 소다알카리액을 잔사에 가하였다. 현탁액을 여과하여 점성물질을 500ml의 비등 에탄올에 용해시켰다.After the medium was reacted at 20 ° C. for 2 hours, the solution was evaporated under vacuum. 300 ml of water and 30 ml of 40% soda alkaline solution were added to the residue. The suspension was filtered to dissolve the viscous material in 500 ml of boiling ethanol.
생성물을 여과시키고 냉각시켜서 결정시켰다.The product was determined by filtration and cooling.
생성물을 여과하고 500ml의 에탄올에서 2번 재결정시켰다. 35g(49%)의 흰색 결정을 얻었다. 융점 174℃The product was filtered off and recrystallized twice in 500 ml of ethanol. 35 g (49%) of white crystals were obtained. Melting point 174 ℃
[실시예 21]Example 21
N(1'-아다만틸) 2-피롤리디닐-메틸-2-메톡시-4,5-아지미도 벤즈아미드N (1'-adamantyl) 2-pyrrolidinyl-methyl-2-methoxy-4,5-azimido benzamide
70g의 1-(1'-아다만틸)-2-아미노-메틸-피롤리딘(0.3몰)을 함유하는 400ml의 부탄올중의 56.5g의 메틸 2-메톡시-4,5-아지미도-벤조에이트(0.27몰)을 80℃에서 온도계가 장착되어 있는 1ℓ 용량의 플라스크에 주입하여 70℃의 오븐에서 60분간 반응시켰다.56.5 g of methyl 2-methoxy-4,5-azimido- in 400 ml of butanol containing 70 g of 1- (1'-adamantyl) -2-amino-methyl-pyrrolidine (0.3 mole) Benzoate (0.27 mol) was injected into a 1 L flask equipped with a thermometer at 80 ° C, and reacted for 60 minutes in an oven at 70 ° C.
경질불용성 물질을 고온에서 여별하고 여액을 냉각시켜 증발시켰다.The light insoluble material was filtered at high temperature and the filtrate was cooled and evaporated.
잔사를 600ml의 물 및 60ml의 염산(비중 1.18)에 뜨거운 상태에서 용해시켰다. 용액을 카본 블랙으로 여과시킨 후에 얼음조에 주입하였다. 하이드로 클로라이드 침전을 여과시키고 오븐에서 건조시켜서 87g의 생성물을 얻었다. 이를 800ml의 뜨거운 물에 용해시킨 후에 목탄으로 여과시켰다. 염기는 195ml의 1N 소다를 가하여 침전시켰다. 이를 냉각시키고 500ml의 클로로포름을 가하여 혼합물을 여과하고 물로 세척한 후에 소량의 클로로포름 및 이소프로판올로 세척하여 50℃의 오븐에서 건조시켰다.The residue was dissolved in 600 ml of water and 60 ml of hydrochloric acid (specific gravity 1.18) in hot state. The solution was filtered through carbon black and then poured into an ice bath. The hydrochloride precipitate was filtered off and dried in an oven to give 87 g of product. It was dissolved in 800 ml of hot water and filtered through charcoal. The base was precipitated by adding 195 ml of 1N soda. It was cooled, 500 ml of chloroform was added, the mixture was filtered, washed with water, washed with a small amount of chloroform and isopropanol and dried in an oven at 50 ° C.
53g의 염기를 얻어서 500ml의 물 및 20ml의 뜨거운 농염산에 용해시켰다. 하이드로 클로라이드를 냉각시켜 침전시켰다. 이를 여별하여 물로 세척하고 50℃의 오븐에서 건조시켰다. 48g을 얻어서 500ml의 뜨거운 물에 재용해시켰다. 107ml의 1N 소다를 가하여 혼합물을 냉각시키고, 500ml의 클로로포름을 가하여 흰색 침전을 여별하였다. 이를 물로 세척하고 소량의 이소프로판올로 세척하였다. 40g의 생성물을 얻었다. 하이드로 클로라이드-염기를 다시 통과시켜 31.5g(28.6%)의 염기를 얻었다. 융점 251℃53 g of base were obtained and dissolved in 500 ml of water and 20 ml of hot concentrated hydrochloric acid. Hydrochloride was precipitated by cooling. It was filtered and washed with water and dried in an oven at 50 ° C. 48 g were obtained and redissolved in 500 ml of hot water. 107 ml of 1N soda was added to cool the mixture, and 500 ml of chloroform was added to filter out white precipitate. It was washed with water and with a small amount of isopropanol. 40 g of product were obtained. The hydrochloride-base was passed again to give 31.5 g (28.6%) of base. Melting point 251 ℃
[실시예 22]Example 22
N(1-(1'-아다만틸)-2-피롤 리디닐-메틸))-2-메톡시-5-에틸-설포닐 벤즈아미드N (1- (1'-adamantyl) -2-pyrrolidinyl-methyl))-2-methoxy-5-ethyl-sulfonyl benzamide
70g의 1-(1'-아다만틸)-2-아미노 메틸피롤 리딘(0.3몰), 400ml의 메틸-에틸-케톤 및 150ml의 물을 교반기 및 온도계가 장착되어 있는 1ℓ용량의 플라스크에 가하였다.70 g of 1- (1'-adamantyl) -2-amino methylpyrrolidin (0.3 mol), 400 ml of methyl-ethyl-ketone and 150 ml of water were added to a 1 L flask equipped with a stirrer and thermometer. .
78g의 2-메톡시-5-에틸설포닐벤조일 클로라이드를 반응중에 용액에 가하였다.78 g of 2-methoxy-5-ethylsulfonylbenzoyl chloride was added to the solution during the reaction.
발열반응을 하여 온도를 40℃로 상승시켰다. 매체를 3시간 동안 반응시킨 후에 건조시켜 증발시켜 잔사를 500ml의 메틸렌 클로라이드에 용해시켰다. 유기용액을 200ml의 10% 소다로 세척한 후에 마그네슘 설페이트 상에서 건조시켰다. 이를 여과시킨 후에 메틸렌 클로라이드를 증발시켰다. 점성 잔사를 500ml의 비등 메탄올에 용해시켰다. 생성물을 냉각시켜 결정시키고 여과하여 400ml의 메탄올에서 2번 재결정시켰다.The exothermic reaction raised the temperature to 40 ° C. The medium was allowed to react for 3 hours, then dried and evaporated to dissolve the residue in 500 ml of methylene chloride. The organic solution was washed with 200 ml of 10% soda and then dried over magnesium sulfate. After it was filtered the methylene chloride was evaporated. The viscous residue was dissolved in 500 ml of boiling methanol. The product was cooled, determined, filtered and recrystallized twice from 400 ml of methanol.
51.5g(37.7)을 얻었다. 융점 약 103℃51.5 g (37.7) was obtained. Melting Point About 103 ℃
[실시예 23]Example 23
N-(1-싸이클로펜틸-2-피롤리디닐-메틸)-2-메톡시-5-설파모일-벤즈아미드 약 90℃에서 뜨거운 115ml의 글리콜에 용해시킨 23g의 메틸 2-메톡시-5-설파모일 벤조 에이트(0.09몰)를 교반기 및 온도계가 장착되어 있는 500ml 용량의 플라스크에 가하였다. 용액을 50℃로 냉각시켜서 에스테르를 재결정시켰다.N- (1-cyclopentyl-2-pyrrolidinyl-methyl) -2-methoxy-5-sulfamoyl-benzamide 23 g methyl 2-methoxy-5- dissolved in 115 ml of hot glycol at about 90 ° C. Sulfamoyl benzoate (0.09 mol) was added to a 500 ml flask equipped with a stirrer and thermometer. The solution was cooled to 50 ° C. to recrystallize the ester.
19g의 1-싸이클로펜틸-2-아미노-메틸-피롤리딘을 가하였다. 얻어진 현탁액을 50℃로 유지시켰다. 30시간 경과 후 에스테르는 완전히 용해되었다. 시료가 아세트산에서 완전히 가용성이라는 것이 확인될 때까지 연속적으로 용액을 가열시켰다. 150ml의 물을 가하고 침전을 배수하여 물로 세척하고 건조시켰다. 23g(68)의 벤즈아미드를 얻었다. 융점 147-148℃ 벤즈아미드 하이드로 클로라이드는 비교적 물에 불용성이므로 벤즈아미드를 비등점에서 물 및 염산에 염기를 용해시켜서 정제하였다. 얻어진 용액을 목탄 1g으로 여과시켰다.19 g of 1-cyclopentyl-2-amino-methyl-pyrrolidine was added. The suspension obtained was kept at 50 ° C. After 30 hours the ester was completely dissolved. The solution was heated continuously until it was confirmed that the sample was completely soluble in acetic acid. 150 ml of water was added and the precipitate was drained, washed with water and dried. 23 g (68) benzamide was obtained. Melting Point 147-148 ° C. Because benzamide hydrochloride is relatively insoluble in water, benzamide was purified by dissolving base in water and hydrochloric acid at boiling point. The resulting solution was filtered through 1 g of charcoal.
냉각시켰을때 하이드로 클로라이드가 침전되었다. 이를 배수하고 25ml의 냉수로 세척하여 건조시켰다. 21g(84%)의 하이드로 클로라이드를 얻었다. 융점 237-238℃ 하이드로 클로라이드를 150ml의 뜨거운물에 용해시켜서 용액을 3g의 목탄으로 여과시키고 6ml의 NH4CH를 가하였다. 염기를 처음에 점성상태에서 침전시키고 난 후에 고체화 시켰다. 배수하고 물로 세척하고 건조시켰다.Hydrochloride precipitated when cooled. It was drained, washed with 25 ml of cold water and dried. 21 g (84%) of hydrochloride were obtained. Melting point 237-238 ° C. Hydrochloride was dissolved in 150 ml of hot water, the solution was filtered through 3 g of charcoal and 6 ml of NH 4 CH was added. The base was initially precipitated in viscous state and then solidified. Drained, washed with water and dried.
18g의 흰색 고체를 얻었다. 융점156-157℃ 총수율 53%18 g of a white solid were obtained. Melting Point 156-157 ℃ Total Yield 53%
[실시예 24]Example 24
N-(1-싸이클로헥실-2-피롤리디닐-메틸)-2-메톡시-5-ㅅㄹ파모일-벤즈아미드N- (1-cyclohexyl-2-pyrrolidinyl-methyl) -2-methoxy-5-spaphayl-benzamide
118g의 에틸 2-메톡시-5-설파모일-벤조에이트, 41mml의 물 및 100g의 1-싸이클로헥실-2-아미노 메틸-피롤리딘을 냉각기가 장착되어 있는 500ml용량의 플라스크에 가하였다. 얻어진 현탁액을 90-95℃에서 수욕상에서 가열하였다. 에스테르를 서서히 용해시키면 2시간 30분 후에는 거의 완전하게 용해되었다. 형성된 염기를 결정시켰다. 사용된 시료가 희석산에서 모두 용해될 때까지 가열을 계속하였다. 얻어진 생성물을 희석된 아세트산에 용해시키고 용액을 목탄으로 여과한 후에 염기를 20% 암모니아로 침전시켰118 g of ethyl 2-methoxy-5-sulfamoyl-benzoate, 41 mmol of water and 100 g of 1-cyclohexyl-2-amino methyl-pyrrolidine were added to a 500 ml flask equipped with a cooler. The suspension obtained was heated at 90-95 ° C. on a water bath. When the ester was slowly dissolved, it was almost completely dissolved after 2 hours and 30 minutes. The base formed was determined. Heating was continued until all of the sample used dissolved in dilute acid. The resulting product was dissolved in diluted acetic acid and the solution was filtered through charcoal and then the base was precipitated with 20% ammonia.
150g의 하이드로클로라이드를 회수 하였다. 융점 245-250℃150 g of hydrochloride was recovered. Melting point 245-250 ℃
뜨거운 1200ml의 물에 재용해시키고, 용액을 목탄으로 여과하여 염기를 40ml의 20%암모니아를 가하여 침전시켰다. 염기를 처음에 유체상태로 침전시킨 뒤에 고체화시켰다. 이를 배수하고, 물로 세척하여 40℃에서 건조시켰다; 생성물은 흰색이고 Cl-이온을 함유 하였다.Redissolved in hot 1200 ml of water, the solution was filtered through charcoal and the base precipitated by addition of 40 ml of 20% ammonia. The base was initially precipitated in fluid state and then solidified. It was drained, washed with water and dried at 40 ° C .; The product was white and contained Cl - ions.
119g의 염기를 480ml의 물 및 필요한 만큼의 아세트산에 용해시켰다. 얻어진 용액을 목탄으로 여과한 후에 염기를 20% 암모니아를 가하여 재침전시켰다. 이를 배수하고 물로세척하여 45℃에서 건조시켰다.119 g of base were dissolved in 480 ml of water and as needed acetic acid. The resulting solution was filtered through charcoal and the base was reprecipitated with 20% ammonia. It was drained, washed with water and dried at 45 ° C.
111g의 N-(1-싸이클로헥실-2-피롤리디닐-메틸)-2-메톡시-5-설파모일-벤즈아미드를 얻었다. 융점 194-195℃ 총수율 70% I.R. 스펙트럼으로 분석하였더니 생성물은 2다형 혼합물 형태임이 밝혀졌다.111 g of N- (1-cyclohexyl-2-pyrrolidinyl-methyl) -2-methoxy-5-sulfamoyl-benzamide was obtained. Melting Point 194-195 ℃ Total Yield 70% I.R. Spectral analysis revealed that the product was in the form of a bipolymorph.
[실시예 25]Example 25
N-(1-싸이클로헥실-2-피롤리디닐-메틸)-2-메톡시-4-아미노-5-에틸설포닐-벤즈아미드N- (1-cyclohexyl-2-pyrrolidinyl-methyl) -2-methoxy-4-amino-5-ethylsulfonyl-benzamide
교반기, 온도계, 적하깔대기가 장착되어 있는 1ℓ용량의 플라스크를 사용하였다. 98g의 2-메톡시-4-아미노-5-에틸설포닐-벤조산(0.378몰)을 392ml의 아세톤에 용해시키고, 38g의 트리에틸아민(0.378몰)을 가하였다. 유기산의 트리에틸아민 염을 곧 결정시켰다.A 1 L flask equipped with a stirrer, thermometer, and dropping funnel was used. 98 g of 2-methoxy-4-amino-5-ethylsulfonyl-benzoic acid (0.378 mole) was dissolved in 392 ml of acetone, and 38 g of triethylamine (0.378 mole) was added. Triethylamine salt of organic acid was soon determined.
현탁액을 0℃로 냉각시킨 후 41g의 에틸 클로로포르메이트(0.378몰)을 0-5℃에서 적가 하였다. 염을 서서히 용해시키고 트리에틸아민 하이드로 클로라이드를 미세한 흰색 결정으로 침전시켰다.After cooling the suspension to 0 ° C., 41 g of ethyl chloroformate (0.378 mole) was added dropwise at 0-5 ° C. The salt was slowly dissolved and triethylamine hydrochloride precipitated out as fine white crystals.
유입단계에서 일단 매체를 5℃에서
여액을 진공하에서 증류시켜 일정량이 되도록 하였다. 얻어진 잔사를 800ml의 물 및 35ml의 염산에 용해시켰다. 용액을 목탄으로 여과한 후에 40ml의 20% 암모니아로 알카리성으로 만들었다. 염기를 오일형태로 침전시켜서 여과하여 메틸렌클로라이드로 추출하였다. 얻어진 유기용액을 물로 여러번 세척하고 탄산칼륨상에서 건조시켰다. 메틸렌클로라이드를 진공하에서 증발시켜서 일정량이 되도록 하였다. 151g의 잔사를 300ml의 뜨거운 이소프로필 알코올에 용해시켰다. 염기를 냉각시켜서 결정시켰다. 이를 배수하고 이소프로판올로 세척하여 45℃에서 건조시켰다. 125g의 생성물을 얻었다.The filtrate was distilled under vacuum to a certain amount. The obtained residue was dissolved in 800 ml of water and 35 ml of hydrochloric acid. The solution was filtered through charcoal and then made alkaline with 40 ml of 20% ammonia. The base was precipitated in oil form, filtered and extracted with methylene chloride. The organic solution obtained was washed several times with water and dried over potassium carbonate. Methylene chloride was evaporated under vacuum to a constant amount. 151 g of residue was dissolved in 300 ml of hot isopropyl alcohol. Determined by cooling the base. It was drained, washed with isopropanol and dried at 45 ° C. 125g of product was obtained.
융점 162-163℃. 1ℓ의 물 및 38ml의 농염산에 재용해시켰다. 얻어진 용액을 목탄으로 여과하여 20% 암모니아를 가하여 알카리성으로 하였다. 침전된 염기는 처음에 점성상태였다가 후에 결정화되었다. 이를 배수하고 물로 세척하여 50℃의 오븐에서 건조시켰다.Melting point 162-163 ° C. Redissolved in 1 L water and 38 ml concentrated hydrochloric acid. The obtained solution was filtered through charcoal and made alkaline by adding 20% ammonia. The precipitated base was initially viscous and later crystallized. It was drained, washed with water and dried in an oven at 50 ° C.
123g을 얻었다. 염기는 소량의 물을 함유 하였다. 이를 355ml의 메탄올에서 결정시켜서 100g의 N-(1-싸이클로헥실-2-피롤리디닐-메틸)-2-메톡시-4-아미노-5-에틸설포닐벤즈아미드를 수집하였다.123 g was obtained. The base contained a small amount of water. It was crystallized in 355 ml of methanol to collect 100 g of N- (1-cyclohexyl-2-pyrrolidinyl-methyl) -2-methoxy-4-amino-5-ethylsulfonylbenzamide.
[실시예 26]Example 26
N-(1-싸이클로헥실메틸-2-피롤리디닐-메틸-2,3-디메톡시-5-설파모일 벤즈아미드N- (1-cyclohexylmethyl-2-pyrrolidinyl-methyl-2,3-dimethoxy-5-sulfamoyl benzamide
26.1g의 2,3-디메톡시-5-설파모일-벤조산(0.10몰)40ml의 물, 200ml의 아세톤 및 10.1g의 트리에틸아민(0.10몰)을 교반기, 온도계 및 적하깔대기가 장착되어 있는 500ml용량의 플라스크에 가하였다. 용액을 0-5℃로 냉각시켜서 10.9g의 에틸클로로포르메이트(0.10몰)를 적가 하였다. 1시간 30분동안 교반하고 온도는 약 5℃로 유지시켰다. 19.6g의 1-싸이클로헥실메틸-2-아미노메틸 피롤리딘(0.10몰)을 적가하였다. 이를 점진적으로 더욱 더 가하여 침전물을 형성시켰다. 반응매체를 실온에서 교반한 후에 방치하였26.1 g 2,3-dimethoxy-5-sulfamoyl-benzoic acid (0.10 mole) 40 ml water, 200 ml acetone and 10.1 g triethylamine (0.10 mole) 500 ml with stirrer, thermometer and dropping funnel Was added to a volume of flask. The solution was cooled to 0-5 ° C. and 10.9 g of ethylchloroformate (0.10 mol) was added dropwise. Stir for 1 hour 30 minutes and maintain the temperature at about 5 ° C. 19.6 g of 1-cyclohexylmethyl-2-aminomethyl pyrrolidine (0.10 mol) was added dropwise. This was gradually added to form a precipitate. The reaction medium was left at room temperature after stirring.
생성물을 300ml의 물 및 10ml의 아세트산에 용해시켜서 그 용액을 여과하여 여액을 20ml의 암모니아(비중 0.91)로 알카리성으로 하였다. 이를 냉각기에서 결정시켜서 여과하고 물로 세척하오 50℃의 오븐에서 건조시켰다. 28.5g의 생성물을 얻었다. 수율 65% 융점 189℃The product was dissolved in 300 ml of water and 10 ml of acetic acid and the solution was filtered to make the filtrate alkaline with 20 ml of ammonia (specific gravity 0.91). It was determined in a cooler, filtered and washed with water and dried in an oven at 50 ° C. 28.5 g of product were obtained. Yield 65% Melting Point 189 ℃
[실시예 27]Example 27
N-(1-싸이클로헥실-2-피롤리디닐)-2,3-메틸디메톡시-5-메틸설파모일 벤즈아미드N- (1-cyclohexyl-2-pyrrolidinyl) -2,3-methyldimethoxy-5-methylsulfamoyl benzamide
125.5g의 메틸 2,3-디메톡시-5-메틸설파모일 벤조에이트 (0.434 몰) 및 500ml의 에틸렌 글리콜을 1ℓ용량의 플라스크에 가하여 모두가 용해되도록 90℃로 가열하였다. 이를 50℃로 냉각시켰다. 95g의 1-싸이클로헥실-2-아미노메틸피롤리딘을 가하였다. 반응 혼합물을 50℃에서 106시간 동안 유지시켰다. 반응 진행중에 형성된 염기를 침전시켰다. 현탁액을 1.7ℓ의 물 및 52ml의 농염산(비중 1.18)에 용해시켰다. 얻어진 용액을 목탄으로 여과하고 염기는 60ml의 20% 암모니아로 침전시켰다. 처음에 유체상태였으나 후에 고체화되었다. 이를 배수하고 물로 세척하여 40℃에서 건조시켜 176.5g의 생성물을 호수하였다.125.5 g of methyl 2,3-dimethoxy-5-methylsulfamoyl benzoate (0.434 mole) and 500 ml of ethylene glycol were added to a 1 L flask and heated to 90 ° C. to dissolve all. It was cooled to 50 ° C. 95 g of 1-cyclohexyl-2-aminomethylpyrrolidine was added. The reaction mixture was maintained at 50 ° C. for 106 hours. The base formed during the reaction was precipitated. The suspension was dissolved in 1.7 L water and 52 ml concentrated hydrochloric acid (specific gravity 1.18). The resulting solution was filtered through charcoal and the base precipitated with 60 ml of 20% ammonia. It was initially fluid but later solidified. It was drained, washed with water and dried at 40 ° C. to 171.7 g of product.
융점 161-162℃Melting Point 161-162 ℃
염기를 2ℓ의 끓는 물에 현탁시킨 후에 43g의 85% 인산용액 및 200ml의 물을 가하였다. 결과의 용액을 목탄으로 여과시킨 후에 냉각시켰다.The base was suspended in 2 liters of boiling water followed by 43 g of 85% phosphoric acid solution and 200 ml of water. The resulting solution was filtered through charcoal and then cooled.
결정시킨 포스페이트를 배수하고, 200ml의 빙수로 세척하여 45℃에서 건조시켰다. 151g의 흰색 생성물을 얻었다.The crystallized phosphate was drained, washed with 200 ml of ice water and dried at 45 ° C. 151 g of white product were obtained.
포스페이트를 1,800ml의 뜨거운 물에 용해시키고 염기는 42ml의 소다 알카리액에 의해 침전시켰다. 현탁액을 냉각 시키고 여과시켰다. 침전을 물로 세척하고 45℃에서 건조시켜서 121g의 벤즈아미드를 얻었다. 융점 162-164℃ 수율 64%Phosphate was dissolved in 1,800 ml of hot water and the base was precipitated with 42 ml of soda alkaline solution. The suspension was cooled and filtered. The precipitate was washed with water and dried at 45 ° C. to give 121 g of benzamide. Melting Point 162-164 ° C Yield 64%
[실시예 28]Example 28
N-(1-싸이클로헥실-2-피롤리디닐메틸)2,3-디메틸-5-메틸설파모일-벤즈아미드N- (1-cyclohexyl-2-pyrrolidinylmethyl) 2,3-dimethyl-5-methylsulfamoyl-benzamide
55g의 2,3-디메톡시-5-메틸설파모일 벤조산, 300ml의 테트라하이드로 푸란 및 20.2g의 트리에틸아민을 교반기, 온도계 및 적하깔대기가 장착되어 있는 1ℓ 용량의 플라스크에 가하였다. 현탁액을 30분간 교반시키고 냉각시켰다. 27.3g의 이소부틸클로로포르메이트를 0-5℃에서 적가한 후에 45분 동안 같은 온도에서 반응시켰다. 40g의 1-싸이클로헥실-2-아미노-메틸-피롤리딘을 0-5℃에서 이어서 적가하여 같은 온도에서 30분동안 교반시킨 후에 2시간 동안 실온에서 교반하였다. 이를 방치하고, 침전을 여별하여 100ml의 냉각시킨 테트라하이드로푸란으로 세척하고 40℃의 오븐에서 건조시켰다. 91g의 생성물을 얻어서 500ml의 끓는 물에 현탁시켜서 1시간동안 교반하였다. 생성물을 뜨거운 상태에서 여별하고 60℃의 오븐에서 건조시켰다.55 g of 2,3-dimethoxy-5-methylsulfamoyl benzoic acid, 300 ml of tetrahydrofuran and 20.2 g of triethylamine were added to a 1 L flask equipped with a stirrer, thermometer and dropping funnel. The suspension was stirred for 30 minutes and cooled. 27.3 g of isobutylchloroformate was added dropwise at 0-5 ° C. and then reacted at the same temperature for 45 minutes. 40 g of 1-cyclohexyl-2-amino-methyl-pyrrolidine was then added dropwise at 0-5 ° C. and stirred for 30 minutes at the same temperature followed by 2 hours at room temperature. It was left to stand, the precipitate was filtered off, washed with 100 ml of cooled tetrahydrofuran and dried in an oven at 40 ° C. 91 g of product were obtained, suspended in 500 ml of boiling water and stirred for 1 hour. The product was filtered hot and dried in an oven at 60 ° C.
얻어진 60g의 생성물을 290ml의 0.5N 염산에 용해시키고 활성탄 3S로 여과하였다.The resulting 60 g product was dissolved in 290 ml 0.5N hydrochloric acid and filtered over activated carbon 3S.
여액을 20% 암모니아로 알카리성으로 하고 침전을 배수하고 물로 세척한 후 뜨거운 420ml의 90% 에탄올에 재용해 시켰다. 냉각기에서 재결정하여 여과하고 물로 세척하여 50℃의 오븐에서 건조시켰다.The filtrate was alkaline with 20% ammonia, the precipitate was drained and washed with water and redissolved in hot 420 ml of 90% ethanol. Recrystallized from the cooler, filtered, washed with water and dried in an oven at 50 ° C.
55g의 생성물을 얻었다. 융점 166℃ 수율 63%55 g of product were obtained. Melting Point 166 ℃ Yield 63%
[실시예 29]Example 29
N-(1-싸이클로헥실-2-피롤리디닐메틸-2-메톡시-5-메틸설파모일-벤즈아미드N- (1-cyclohexyl-2-pyrrolidinylmethyl-2-methoxy-5-methylsulfamoyl-benzamide
123g의 에틸 2-메톡시-5-메틸설파모일 벤조에이트 40ml의 물 및 98g의 1-싸이클로헥실-2-아미노메틸-피롤리딘을 환류 냉각기가 장착되어 있는 500ml용량의 플라스크에 가하였다. 현탁액을 90-95℃에서 수욕상에서 가열하였다. 10분 후에 에스테르는 완전히 용해되었다. 8시간동안 가열을 계속하였다. 반응매체를 냉각시키고 염기를 결정시켰다. 800ml의 물 및 필요한 아세트산에 재용해 시켰다. 용액을 목탄으로 여과하고 염기를 결정을 촉진시키기 위하여 에테르 존재하에 20% 암모니아를 가하여 침전시켰다.123 g of ethyl 2-methoxy-5-methylsulfamoyl benzoate 40 ml of water and 98 g of 1-cyclohexyl-2-aminomethyl-pyrrolidine were added to a 500 ml flask equipped with a reflux condenser. The suspension was heated at 90-95 ° C. on a water bath. After 10 minutes the ester was completely dissolved. Heating was continued for 8 hours. The reaction medium was cooled and the base was determined. Redissolved in 800 ml of water and the required acetic acid. The solution was filtered through charcoal and the base precipitated by addition of 20% ammonia in the presence of ether to facilitate crystallization.
침전을 배수하고 물로 세척하여 45℃의 오븐에서 건조시켰다. 153g의 생성물을 얻었다.The precipitate was drained and washed with water and dried in an oven at 45 ° C. 153 g of product were obtained.
융점 142-145℃Melting Point 142-145 ℃
재결정된 염기를 2310ml의 무수 에탄올중의 목탄을 통과시켜서 여과시켜 118g의 생성물을 얻었다. 융점 149-151℃The recrystallized base was filtered through charcoal in 2310 ml of absolute ethanol to give 118 g of product. Melting point 149-151 ℃
두번째 재결정은 240ml의 무수에탄올에서 목탄을 통과하여 여과시켜서 수행하였다. N-(1-싸이클로헥실-2-피롤리디닐메틸)-2-메톡시-5-메틸-설파모일-벤즈아미드를 황색을 띈 흰색 결정의 형태로 얻었다. 융점 149-151℃ 수율 57%A second recrystallization was carried out by filtering through charcoal in 240 ml of anhydrous ethanol. N- (1-cyclohexyl-2-pyrrolidinylmethyl) -2-methoxy-5-methyl-sulfamoyl-benzamide was obtained in the form of yellowish white crystals. Melting Point 149-151 ℃ Yield 57%
스펙트럼에 의해 2개의 결정성 혼합물임이 밝혀졌다.The spectra revealed that it was a two crystalline mixture.
[실시예 30]Example 30
N-(1-싸이클로프로필-2-피롤리디닐 메틸)-2-메톡시-5-메틸 설피닐 벤즈아미드N- (1-cyclopropyl-2-pyrrolidinyl methyl) -2-methoxy-5-methyl sulfinyl benzamide
53.5g의 2-메톡시-5-메틸 설피틸 벤조산, 740ml의 아세톤 140ml의 물 및 35ml의 트리에틸아민(비중 0.726)을 교반기, 온도계 및 적하깔대기가 장착되어 있는 2ℓ용량의 플라스크에 가하였다. 용액을 0-5℃로 냉각시킨 후에 34.1g의 이소부틸 클로로포르메이트를 적가하였다. 혼합물을 45분 동안 20℃에서 교반한 후에 0℃로 냉각시켰다. 42g의 1-싸이클로프로필-2-아미노 메틸 피롤리딘을 적가하였다. 혼합물을 실온에서 반응시켜서 방치 하였다. 용매를 진공하에서 증발시켰다. 오일 잔사를 250ml의 물 및 50ml의 염산(비중 1.18)에 용해시켜서 125ml의 메틸렌 클로라이드로 2번 추출하였다. 수성상을 70ml의 소다 알카리액으로 알카리성으로 하였다. 황색 오일이 염으로 생성되었다. 이를 250ml의 메틸렌 클로라이드로 3번 추출하고 유기상을 100ml의 물로 3번 세척하여 마그네슘 설페이트상에서 건조시켰다. 용액을 여과하고 용매를 증발시켰다. 오일 잔사를 얻어서 500ml의 에탄올에 용해시키고 동량의 구연산을 가하였다.53.5 g 2-methoxy-5-methyl sulfityl benzoic acid, 740 ml acetone 140 ml water and 35 ml triethylamine (specific gravity 0.726) were added to a 2 L flask equipped with a stirrer, thermometer and dropping funnel. After cooling the solution to 0-5 ° C. 34.1 g isobutyl chloroformate was added dropwise. The mixture was stirred at 20 ° C. for 45 minutes and then cooled to 0 ° C. 42 g of 1-cyclopropyl-2-amino methyl pyrrolidine was added dropwise. The mixture was left to react at room temperature. The solvent was evaporated in vacuo. The oil residue was dissolved in 250 ml of water and 50 ml of hydrochloric acid (specific gravity 1.18) and extracted twice with 125 ml of methylene chloride. The aqueous phase was alkaline with 70 ml of soda alkaline solution. Yellow oil was formed as a salt. It was extracted three times with 250 ml of methylene chloride and the organic phase was washed three times with 100 ml of water and dried over magnesium sulfate. The solution was filtered and the solvent evaporated. An oil residue was obtained, dissolved in 500 ml of ethanol and the same amount of citric acid was added.
이를 진공하에서 증발시켜 잔사를 1000ml의 비등 이소프로판올에 용해시킨 후에 냉각시켰다. 현탁액을 여별하여 잔사 페이스트를 600ml의 물에 용해시켰다. 용액을 목탄으로 여과한 후에 여액을 진공하에서 증발시켰다.It was evaporated under vacuum to dissolve the residue in 1000 ml of boiling isopropanol and then cooled. The suspension was filtered and the residue paste was dissolved in 600 ml of water. The solution was filtered through charcoal and the filtrate was evaporated in vacuo.
흡윤성(hygroscopic)이 매우 큰 결정성 잔사를 얻었다. 융점 70℃ NMR 스펙트럼과 일치하였다.Crystalline residues with very high hygroscopicity were obtained. Melting point was consistent with 70 ℃ NMR spectrum.
[실시예 31]Example 31
N-(1-싸이클로펜틸-2-피롤리디닐 메틸)-2-메톡시-4-아미노-5-설파모일 벤즈아미드N- (1-cyclopentyl-2-pyrrolidinyl methyl) -2-methoxy-4-amino-5-sulfamoyl benzamide
104g의 메틸 2-메톡시-4-아미노-5-설파모일 벤조에이트(0.40몰), 100.8g의 1-싸이클로펜틸-2-아미노메틸 피롤리딘(0.60몰) 및 36g의 물을 교반기, 온도계 및 냉각기가 장착되어 있는 1ℓ 용량의 플라스크에 가하였다. 혼합물을 90-95℃로 가열하여 방치한 후에 다시 95℃로 가열하여 형성된 메탄올을 증류하여 제거하였다. 반응시에 얻어진 반응매체의 시료를 아세트산의 희석용액에 완전히 용해시켰다.104 g of methyl 2-methoxy-4-amino-5-sulfamoyl benzoate (0.40 mole), 100.8 g of 1-cyclopentyl-2-aminomethyl pyrrolidine (0.60 mole) and 36 g of water are stirrer, thermometer And a 1 L flask equipped with a cooler. The mixture was left to heat to 90-95 ° C. and then heated to 95 ° C. to distill off the methanol formed. A sample of the reaction medium obtained at the time of reaction was completely dissolved in a dilute solution of acetic acid.
500ml의 물을 현탁액에 가하여 냉각시켜서 여과하였다. 침전을 물로 세척하고 500ml 물에 재현탁시켜서 50ml의 아세트산으로 산성화시켰다. 얻어진 용액을 카본블랙의 존재하에서 여과시키고 여액을 150ml의 암모니아로 알카성으로 만들었다. 침전을 배수하고 물로 세척하여 건조시켰다. 123g의 생성물을 얻었다. 융점 225℃ 이를 210ml의 물 및 600ml의 디메틸포름아미드의 용액에서 2번 재결정 시켰다.500 ml of water was added to the suspension, cooled and filtered. The precipitate was washed with water and resuspended in 500 ml water and acidified with 50 ml acetic acid. The resulting solution was filtered in the presence of carbon black and the filtrate was alkaline with 150 ml of ammonia. The precipitate was drained and washed with water to dryness. 123 g of product were obtained. Melting point 225 ° C. It was recrystallized twice in a solution of 210 ml of water and 600 ml of dimethylformamide.
소량의 용매를 함유하는 93g의 생성물을 얻었다. 결정을 500ml의 물 및 30ml의 아세트산에 재용해시키고 목탄으로 여과하였다. 100ml의 암모니아를 여액에 가하여 염기를 침전시켰다. 흰색 침전을 배수하고, 물로 세척하여 60℃의 오븐에서 건조시켰다.93 g of product containing a small amount of solvent were obtained. The crystals were redissolved in 500 ml of water and 30 ml of acetic acid and filtered over charcoal. 100 ml of ammonia was added to the filtrate to precipitate the base. The white precipitate was drained, washed with water and dried in an oven at 60 ° C.
80g의 아민을 얻었다. 융점 232℃ 수율 50.5%80 g of amine was obtained. Melting Point 232 ℃ Yield 50.5%
[실시예 32]Example 32
N-(1-싸이클로헥실-2-피롤리디닐메틸)-2-메톡시-4-아미노-5-메틸설파모일 벤즈아미드N- (1-cyclohexyl-2-pyrrolidinylmethyl) -2-methoxy-4-amino-5-methylsulfamoyl benzamide
58.5g의 2-메톡시-4-아미노-5-메틸설파모일 벤조산 및 585ml의 아세톤을 교반기, 온도계 및 적하깔대기가 장착되어 있는 2ℓ 용량의 플라스크에 가하였다. 혼합물을 교반하고 22.7g의 트리에틸 아민을 가하였다. 서서히 결정시킨 후에 점착성의 침전을 형성시켜서 45분간 교반하여 현탁액을 0℃로 냉각시켰다.58.5 g of 2-methoxy-4-amino-5-methylsulfamoyl benzoic acid and 585 ml of acetone were added to a 2 L flask equipped with a stirrer, thermometer and dropping funnel. The mixture was stirred and 22.7 g triethyl amine were added. After slow determination, a sticky precipitate was formed and stirred for 45 minutes to cool the suspension to 0 < 0 > C.
24.4g의 에틸 클로로포르메이트를 0-5℃에서 적가하였다. 45분간 0-5℃에서 교반시켜서 45.5g의 1-싸이클로헥실-2-아미노메틸-피롤리딘을 적가하였다. 매체를 30분간 냉각 반응시킨 후에 실온에서 방치하였다. 트리에틸아민 하이드로클로라이드 침전을 여별하고 100ml의 아세톤으로 세척하였다. 유기용액을 진공하에서 증발시키고 건조시켰다. 잔사를 500ml의 물 및 50ml의 농염산에 용해시켰다.24.4 g of ethyl chloroformate was added dropwise at 0-5 ° C. 45.5 g of 1-cyclohexyl-2-aminomethyl-pyrrolidine was added dropwise by stirring at 0-5 ° C. for 45 min. The medium was allowed to cool for 30 minutes and then left at room temperature. Triethylamine hydrochloride precipitate was filtered off and washed with 100 ml of acetone. The organic solution was evaporated in vacuo and dried. The residue was dissolved in 500 ml of water and 50 ml of concentrated hydrochloric acid.
수성상을 250ml의 메틸렌 클로라이드로 추출하여 제거하였다. 수용성을 70ml의 소다 알카리액으로 알카리성으로 만들고, 현탁액을 250ml의 메틸렌 클로라이드로 2번 추출하였다. 유기상을 250ml의 물로 2번 세척하고, 마그네슘 설페이트 상에서 건조시킨 후에 진공하에서 증발시켜 건조시켰다. 잔사를 400ml의 이소프로판올에 용해시켜서 100ml의 염산성 이소프로판올(
76g을 얻었다. 융점 약 200℃(분해)76 g was obtained. Melting Point Approx. 200 ° C (Decomposition)
생성물을 500ml의 에탄올에서 재결정시키고 3일 동안 얼음조에 방치하여 얻어진 흰색 결정을 배수하고 60ml의 냉각에탄올로 2번 세척하여 30℃의 오븐에서 건조시킨 후에 60℃에서 건조시켰다.The product was recrystallized in 500 ml of ethanol and left in an ice bath for 3 days, the white crystals obtained were drained, washed twice with 60 ml of cold ethanol, dried in an oven at 30 ° C. and then dried at 60 ° C.
64g의 하이드로 클로라이드를 얻었다. 융점 208℃(분해)64 g of hydrochloride were obtained. Melting Point 208 ° C (Decomposition)
[실시예 33]Example 33
N-(1-싸이클로헥실 메틸-2-피롤리디닐-메틸)-2-메톡시-4-아미노-5-에틸설포닐-벤즈아미드N- (1-cyclohexyl methyl-2-pyrrolidinyl-methyl) -2-methoxy-4-amino-5-ethylsulfonyl-benzamide
25.9g의 2-메톡시-4-아미노-5-에틸설포닐 벤조산, 40ml의 물, 200ml의 아세톤, 13.9ml의 트리에틸아민(비중 0.726)을 교반기, 온도계 및 적하깔대기가 장착되어 있는 500ml 용량의 플라스크에 가하였다. 용액을 약 0-5℃로 냉각시키고 10.9g의 에틸 클로로포르메이트를 적가하였다. 혼합물을 40분 동안 0℃에서 교반시켰다. 19.6g의 1-사이클로헥실-메틸-2-아미노메틸 피롤리딘을 적가하였다. 혼합물을 실온에서 2시간동안 교반시키고 방치하였다. 아세톤을 진공하에서 증발시켜서 잔사를 100ml의 물 및 25ml의 아500 ml volume with 25.9 g 2-methoxy-4-amino-5-ethylsulfonyl benzoic acid, 40 ml water, 200 ml acetone, 13.9 ml triethylamine (specific gravity 0.726) equipped with a stirrer, thermometer and dropping funnel Was added to the flask. The solution was cooled to about 0-5 ° C. and 10.9 g of ethyl chloroformate was added dropwise. The mixture was stirred at 0 ° C. for 40 minutes. 19.6 g of 1-cyclohexyl-methyl-2-aminomethyl pyrrolidine was added dropwise. The mixture was stirred at room temperature for 2 hours and left. Acetone was evaporated under vacuum to give a residue of 100 ml of water and 25 ml of acetone.
25g(57%)의 생성물을 회수하였다. 융점 155℃25 g (57%) of product was recovered. Melting point 155 ℃
[실시예 34]Example 34
N-(1-싸이클로헥실-2-피롤리디닐메틸)-2-메톡시-4-아미노-5-메틸설피닐벤즈아미드N- (1-cyclohexyl-2-pyrrolidinylmethyl) -2-methoxy-4-amino-5-methylsulfinylbenzamide
2-메톡시-4-아미노-5-메틸티오 벤조산2-methoxy-4-amino-5-methylthio benzoic acid
3,600ml의 메탄올을 교반기, 온도계, 냉각기 및 적하깔대기가 정착되어 있는 6ℓ 용량의 플라스크에 가하고 반응중에 495g의 칼리(84% 펠레트(pellet) 형태)를 가하였다. 온도를 60℃에 도달시켜 칼리를 완전히 용해시켰다. 375g의 메틸 2-메톡시-4-아미노-5-티오시아노 벤조에이트를 가한 후에 280ml의 메틸아이오다이드(비중 2.28)를 적가하면서 온도를 55-60℃로 유지하였다. 혼합물을 가열하여 환류시킨 후에 15℃로 냉각시켰다. 무기염을 여별하였다. 여액을 진공하에서 증발시켜서 건조하였다.3,600 ml of methanol was added to a 6 L flask equipped with a stirrer, thermometer, cooler and dropping funnel and 495 g of Kali (84% pellet form) was added during the reaction. The temperature was reached at 60 ° C. to completely dissolve Kali. After adding 375 g of methyl 2-methoxy-4-amino-5-thiocyano benzoate, 280 ml of methyl iodide (specific gravity 2.28) was added dropwise while maintaining the temperature at 55-60 ° C. The mixture was heated to reflux and then cooled to 15 ° C. Inorganic salts were filtered out. The filtrate was evaporated to dryness in vacuo.
고체잔사를 1,500ml의 물에 용해시켜서 이 용액을 베지타블 블랙 존재하에 여과시킨 후에 여액의 pH를 염산으로 2-3으로 산성화시켰다. 형성된 침전을 배수하고, 물로 세척하여 50℃의 오븐에서 건조시켰다.The solid residue was dissolved in 1,500 ml of water and the solution was filtered in the presence of vegetable black and the pH of the filtrate was acidified to 2-3 with hydrochloric acid. The precipitate formed was drained, washed with water and dried in an oven at 50 ° C.
수율 260g(81%) 융점 143℃Yield 260g (81%) Melting Point 143 ℃
2-메톡시-4-아세트이미노-5-메틸-티오-벤조산2-methoxy-4-acetimino-5-methyl-thio-benzoic acid
260g의 2-메톡시-4-아미노-5-메틸-티오-벤조산 및 520ml의 아세트산을 교반기, 온도계, 냉각기 및 적하깔대기가 장착되어 있는 2ℓ 용량의 플라스크에 가하였다. 123ml의 아세트 무수물(비중 1.082)을 서서히 주입하였다. 온도를 40℃가 되도록 상승시켰다. 반응 혼합물을 85℃에서 1시간 30분 동안 가열하여 냉각시키고 1,000g의 얼음 및 1,000ml의 물위에 주입하였다. 침전을 형성시켜서 여과하고 물로 세척하여 50℃의 오븐에서 건조시켰다. 278g(89%)의 생성물을 얻었다. 융점 165℃260 g of 2-methoxy-4-amino-5-methyl-thio-benzoic acid and 520 ml of acetic acid were added to a 2 L flask equipped with a stirrer, thermometer, cooler and dropping funnel. 123 ml of acetic anhydride (specific gravity 1.082) were slowly injected. The temperature was raised to 40 ° C. The reaction mixture was cooled by heating at 85 ° C. for 1 hour 30 minutes and poured onto 1,000 g ice and 1,000 ml water. A precipitate was formed, filtered, washed with water and dried in an oven at 50 ° C. 278 g (89%) of the product were obtained. Melting point 165 ℃
2-메톡시-4-아세트아미노-5-메틸-설피닐-벤조산2-methoxy-4-acetamino-5-methyl-sulfinyl-benzoic acid
127.5g의 2-메톡시-4-아세트아미노-5-메틸-티오-벤조산 및 200ml의 아세트산을 교반기, 온도계, 냉각기 및 적하깔대기가 장착되어 있는 500ml 용량의 플라스크에 가하였다. 100ml의 아세트산중의 110vol의 과산화수소 용액 50ml를 생성된 현탁액에 적가하였다. 반응은 발열반응이었다. 냉각시켜서 온도를 20-30℃로 유지시켰다. 도입단계 완료 30분 후에 용액이 맑아졌다. 2시간 이상 25-30℃의 온도를 유지시켰다. 용매를 진공하에서 증발시켜 건조시키고 점성잔사를 250ml의 아세톤에 용해시켰다. 형성된 결정을 여과하고 소량의 아세톤으로 세척하여 50℃의 오븐에서 건조시켰다.127.5 g of 2-methoxy-4-acetamino-5-methyl-thio-benzoic acid and 200 ml of acetic acid were added to a 500 ml flask equipped with a stirrer, thermometer, cooler and dropping funnel. 50 ml of a 110 vol hydrogen peroxide solution in 100 ml acetic acid was added dropwise to the resulting suspension. The reaction was exothermic. Cool to maintain the temperature at 20-30 ° C. Thirty minutes after the completion of the introduction step, the solution became clear. The temperature of 25-30 degreeC was maintained over 2 hours. The solvent was evaporated in vacuo to dryness and the viscous residue was dissolved in 250 ml of acetone. The crystals formed were filtered off, washed with a small amount of acetone and dried in an oven at 50 ° C.
110g(81%)의 생성물을 얻었다. 융점 196℃110 g (81%) of the product were obtained. Melting Point 196 ℃
N-(1-싸이클로헥실-2-피롤리디닐-메틸)-2-메톡시-4-아미노-5-메틸-설피닐-벤즈아미드N- (1-cyclohexyl-2-pyrrolidinyl-methyl) -2-methoxy-4-amino-5-methyl-sulfinyl-benzamide
81.3g의 2-메톡시-4-아세트아미노-5-메틸설포닐-벤조산(0.30몰), 600ml의 아세톤, 120ml의 물 및 41.7ml의 트리에틸아민(비중 0.726, 0.30몰)을 교반기, 온도계, 냉각기 및 적하깔대기가 장착되어 있는 1ℓ 용량의 플라스크에 가하였다. 혼합물을 0℃로 냉각시키고 40.8g의 이소부틸 클로로포르메이트(0.30몰)를 적가하였다. 냉각조를 제거하여 30분간 교반시키고 0℃로 다시 냉각시켜서 54.6g의 1-싸이클로헥실-2-아미노메틸-피롤리딘(0.30몰)을 적가하였다. 혼합물을 1시간 동안 실온에서 교반시키면서 반응시킨 다음 방치하였다. 용액을 증발시켜 건조시켰다. 페이스트를 얻어서 200ml의 소다 및 400ml의 물에 용해시켰다. 2시간동안 가열하여 환류시키고 낮은 온도에서 50ml의 혼합물을 증류하여 제거한 후에 다시 환류시켰다. 반응매체를 방치한 다음 현탁액을 200ml의 메틸렌 클로라이드로 4번 추출하였다. 유기상을 300ml의 10% 염산으로 2번 세척하고 수성상을 카본 블랙으로 여과하여 여액을 300ml의 40% 소다로 알칼성으로 만들었다. 현탁액을 각각 300ml의 메틸렌 클로라이드로 3번 추출하였다. 유기용액을 물로 세척하고 마그네슘 설페이트상에서 건조시켰다. 용액을 여과하고 증발시켜 건조시켰다. 42.5(36%)의 벤즈아미드를 얻었다; 이것은 결정이 아니다.81.3 g of 2-methoxy-4-acetamino-5-methylsulfonyl-benzoic acid (0.30 mole), 600 ml of acetone, 120 ml of water and 41.7 ml of triethylamine (0.726, 0.30 molar in specific weight) were mixed with a stirrer and a thermometer. The flask was added to a 1 L flask equipped with a cooler and a dropping funnel. The mixture was cooled to 0 ° C. and 40.8 g of isobutyl chloroformate (0.30 mol) was added dropwise. The cooling bath was removed, stirred for 30 minutes, cooled to 0 ° C., and 54.6 g of 1-cyclohexyl-2-aminomethyl-pyrrolidine (0.30 mol) was added dropwise. The mixture was allowed to react with stirring for 1 hour at room temperature and then left to stand. The solution was evaporated to dryness. The paste was obtained and dissolved in 200 ml of soda and 400 ml of water. The mixture was heated to reflux for 2 hours and 50 ml of the mixture was distilled off at a low temperature and then refluxed again. After the reaction medium was left, the suspension was extracted four times with 200 ml of methylene chloride. The organic phase was washed twice with 300 ml of 10% hydrochloric acid and the aqueous phase was filtered through carbon black to make the filtrate alkaline with 300 ml of 40% soda. The suspension was extracted three times with 300 ml of methylene chloride each. The organic solution was washed with water and dried over magnesium sulphate. The solution was filtered and evaporated to dryness. 42.5 (36%) of benzamide was obtained; This is not a decision.
생성물을 150ml의 이소프로판올에 용해시키고 22.7g의 구연산용액, 200ml의 이소프로판올중의 물을 뜨거운 상태에서 가하였다. 증발시켜서 건조시키고 500ml의 물에 용해시켜서 3S 카본블랙의 존재하에 여과하였다. 여액을 진공하에서 증발시켜 건조시켰다.The product was dissolved in 150 ml of isopropanol and 22.7 g of citric acid solution and water in 200 ml of isopropanol were added hot. Evaporated to dryness, dissolved in 500 ml of water and filtered in the presence of 3S carbon black. The filtrate was evaporated to dryness in vacuo.
50.3g(29%)의 생성물을 얻었다. 융점 125℃ NMR 및 IR 스펙트럼이 생성물의 구조와 일치하였다.50.3 g (29%) of the product were obtained. Melting point 125 ° C. NMR and IR spectra were consistent with the structure of the product.
[실시예 35]Example 35
N-(1-싸이클로펜틸-2-피롤리디닐 메틸)-2-메톡시-4-아미노-5-에틸-설피닐 벤즈아미드N- (1-cyclopentyl-2-pyrrolidinyl methyl) -2-methoxy-4-amino-5-ethyl-sulfinyl benzamide
2-메톡시-4-아세트아미노-5-에틸설피닐 벤조산2-methoxy-4-acetamino-5-ethylsulfinyl benzoic acid
123.7g의 2-메톡시-4-아세트아미노-5-에틸 티오벤조산 및 184ml의 아세트산을 교반기, 온도계, 냉각기 및 적하깔대기가 장착되어 있는 1ℓ 용량의 플라스크에 가하였다. 103ml의 아세트산중의 110vol, 과산화수소의 46.5ml 용액을 적가하였다. 반응은 발열반응이고, 온도를 약 30℃로 유지시켰다. 생성물을 완전히 용해시킨 후에 흰 침전이 생겼다. 교반을 1시간 동안 계속한 후에 현탁액을 10℃로 냉각시켰다. 침전을 배수하고, 아세트산으로 세척하여 50℃의 오븐에서 건조시켰다.123.7 g of 2-methoxy-4-acetamino-5-ethyl thiobenzoic acid and 184 ml of acetic acid were added to a 1 L flask equipped with a stirrer, thermometer, cooler and dropping funnel. 110 vol, 46.5 ml of hydrogen peroxide in 103 ml of acetic acid were added dropwise. The reaction was exothermic and the temperature was maintained at about 30 ° C. After complete dissolution of the product a white precipitate formed. Stirring was continued for 1 hour before the suspension was cooled to 10 ° C. The precipitate was drained, washed with acetic acid and dried in an oven at 50 ° C.
90g의 생성물을 얻었다. 융점 199℃(수율 69%)90 g of product was obtained. Melting Point 199 ° C (Yield 69%)
N-(1-싸이클로펜틸-2-피롤리디닐-메틸)-2-메톡시-4-아미노-5-에틸설피닐 벤즈아미드N- (1-cyclopentyl-2-pyrrolidinyl-methyl) -2-methoxy-4-amino-5-ethylsulfinyl benzamide
85.5g의 2-메톡시-4-아세트아미노-5-에틸설피닐 벤조산, 85ml의 물, 342ml의 아세톤 및 31g의 트리에틸 아민을 교반기; 온도계 및 적하깔대기가 장착되어 있는 1ℓ 용량의 플라스크에 가하였다. 혼합물을 고체가 용해될 때까지 교반한 후에 32.5g의 에틸 클로로포르메이트를 적가하면서 온도를 약 10℃로 유지시켰다. 반응 매체를 30분간 실온에서 교반시킨 후에 5-10℃로 냉각시키고 50.4g의 1-싸이클로펜틸-2-아미노메틸-피롤리딘을 1시간의 과정에 걸쳐 적가하였다. 교반을 실온에서 2시간 동안 계속시킨 후에85.5 g 2-methoxy-4-acetamino-5-ethylsulfinyl benzoic acid, 85 ml of water, 342 ml of acetone and 31 g of triethyl amine were stirred; The flask was added to a 1 L flask equipped with a thermometer and dropping funnel. The mixture was stirred until the solids dissolved and then the temperature was maintained at about 10 ° C. with 32.5 g of ethyl chloroformate added dropwise. The reaction medium was stirred at room temperature for 30 minutes, then cooled to 5-10 ° C. and 50.4 g of 1-cyclopentyl-2-aminomethyl-pyrrolidine was added dropwise over the course of 1 hour. After stirring was continued for 2 hours at room temperature
65g의 생성물을 얻었다(융점 168℃). 200ml의 이소프로판올 및 10ml 물에서 재결정시켰다. 용액을 24시간 동안 냉각시킨 후에 결정을 여별하여 건조시켰다. 33g의 생성물을 얻었다. 융점 183℃(수율 28%)65g of product was obtained (melting point 168 ° C). Recrystallized from 200 ml of isopropanol and 10 ml water. After cooling the solution for 24 hours, the crystals were filtered off and dried. 33 g of product was obtained. Melting point 183 ° C (yield 28%)
[실시예 36]Example 36
N-(1-싸이클로펜틸-2-피롤리디닐 메틸)-2,4-디메톡시-5-에틸설포닐 벤즈아미드N- (1-cyclopentyl-2-pyrrolidinyl methyl) -2,4-dimethoxy-5-ethylsulfonyl benzamide
2,4-디메톡시-5-클로로설포닐 벤조산2,4-dimethoxy-5-chlorosulfonyl benzoic acid
1,800ml의 클로로설폰산을 교반기 및 온도계가 장착되어 있는 4ℓ 용량의 플라스크에 가하고 10℃로 냉각시켰다. 328g의 미세하게 분쇄된 2,4-디메톡시 벤조산을 45분간의 반응중에 가하여 온도를 10-15℃로 유지시켰다. 처음과 마찬가지로 산을 서서히 용해시켰다. 산을 모두 가했을 때 용액을 55℃로 서서히 가열시키고 온도를 5시간 동안 유지시켰다. 용액을 철야 방치한 후에 17kg의 얼음에 소량씩 적가하면서 교반하고, 외부 냉각시켰다. 침전시킨 산을 배수하고 물로 세척하여 공기중에서 건조시켰다.1,800 ml of chlorosulfonic acid was added to a 4 L flask equipped with a stirrer and thermometer and cooled to 10 ° C. 328 g of finely ground 2,4-dimethoxy benzoic acid was added during the reaction for 45 minutes to maintain the temperature at 10-15 ° C. As in the beginning, the acid was slowly dissolved. When all the acid was added the solution was slowly heated to 55 ° C. and the temperature was maintained for 5 hours. After leaving the solution overnight, the solution was added dropwise to 17 kg of ice in small portions, followed by external cooling. The precipitated acid was drained, washed with water and dried in air.
456g을 얻었다. 수율 90%456 g was obtained. Yield 90%
2,4-디메톡시-5-메르캅토벤조산2,4-dimethoxy-5-mercaptobenzoic acid
145g의 2,4-디메톡시-5-클로로설포닐 벤조산, 393ml의 아세트산 및 230.5g의 주석을 교반기, 온도계 및 적하깔대기가 장착되어 있는 6ℓ 용량의 플라스크에 가하고 걸쭉한 현탁액을 40℃로 가열하였다.145 g of 2,4-dimethoxy-5-chlorosulfonyl benzoic acid, 393 ml of acetic acid and 230.5 g of tin were added to a 6 L flask equipped with a stirrer, thermometer and dropping funnel and the thick suspension was heated to 40 ° C.
1,009ml의 염산(비중 1.18)을 적가하면서 온도를 40-45℃로 유지시키기 위하여 냉각시켰다.1,009 ml of hydrochloric acid (specific gravity 1.18) was added dropwise while cooling to maintain the temperature at 40-45 ° C.
반응은 발열반응이다. 현탁액을 서서히 용해시키고, 더 많은 산을 가하였으나 주석영은 첨가 반응을 통하여 약 중간쯤에서 침전되었다. 산을 모두 가하고 주석이 용해될 때가지 수욕을 55-60℃로 가열하였다.The reaction is exothermic. The suspension was slowly dissolved and more acid was added but tin spirit precipitated about midway through the addition reaction. All the acid was added and the water bath was heated to 55-60 ° C. until the tin dissolved.
2ℓ의 물을 가하고 침전된 산을 배수하고 460ml의 10% 염산으로 세척한 후에 물로 세척하였다. 물 및 필요한 량의 소다에서 즉시 재융해시켜서 용액을 목탄으로 여과시키고, 농염산을 가하여 산을 재침전시켰다. 침전을 배수하고, 물로 세척하여 40℃의 오븐에서 건조시켜서 86.5g을 얻었다. 수율 78%2 L of water was added and the precipitated acid was drained and washed with 460 ml of 10% hydrochloric acid followed by water. The solution was immediately re-melted in water and the required amount of soda, filtered through charcoal, and concentrated hydrochloric acid was added to reprecipitate the acid. The precipitate was drained, washed with water and dried in an oven at 40 ° C. to give 86.5 g. Yield 78%
2,4-디메톡시-5-에틸 티오 벤조산2,4-dimethoxy-5-ethyl thiobenzoic acid
환류 냉각기가 장착되어 있는 2ℓ 용량의 플라스크에서 173g의 2,4-디메톡시-5-메르캅토벤조산을 525ml의 물 및 162ml의 소다알카리액에 용해시키고 135g의 에틸설페이트를 가하였다. 얻어진 용액을 가열하여 환류시켰다. 이를 냉각시킨 후에, 40.5ml의 소다알카리액 및 76g의 에틸설페이트로 에틸화 하였다.In a 2-liter flask equipped with a reflux condenser, 173 g of 2,4-dimethoxy-5-mercaptobenzoic acid was dissolved in 525 ml of water and 162 ml of soda alkaline solution and 135 g of ethyl sulfate were added. The obtained solution was heated to reflux. After cooling it was ethylated with 40.5 ml of soda alkaline solution and 76 g of ethyl sulfate.
매체를 매우 낮은 알카리성을 가질 때까지 동일한 방법으로 가열하였다.The medium was heated in the same way until it had very low alkalinity.
40ml의 소다알카리액을 가하고 매체를
염산을 가하여 산을 침전시키고, 배수하여 물로 세척하였다. 물 및 중탄산나트륨에 즉시 재용해시켜서, 용액을 목탄으로 여별하여 불용성 물질을 제거하였다. 농염산을 가하여 산을 재침전시켰다. 배수하고 물로 세척하여 40℃의 오븐에서 건조시켰다. 144g(74%)의 생성물을 얻었다. 융점 94-96℃Hydrochloric acid was added to precipitate the acid, drained and washed with water. Immediately redissolved in water and sodium bicarbonate, the solution was filtered with charcoal to remove insoluble matter. Concentrated hydrochloric acid was added to reprecipitate the acid. Drain, wash with water and dry in oven at 40 ° C. 144 g (74%) of the product were obtained. Melting point 94-96 ℃
2,4-디메톡시-5-에틸설포닐 벤조산2,4-dimethoxy-5-ethylsulfonyl benzoic acid
124g의 2,4-디메톡시-5-에틸 티오벤조산 및 765ml의 아세트산을 환류 냉각기가 장착되어 있는 3ℓ용량의 플라스크에 가하여 고체가 모두 용해되도록 서서히 가열하였다. 112vol 과산화수소의 306ml를 가하였다. 용액이 즉시 맑아졌다. 3시간 동안 서서히 비등시키고 끝으로 과량의 과산화수소를 파괴시킥 위하여 불꽃없이 1시간동안 가열하였다.124 g of 2,4-dimethoxy-5-ethyl thiobenzoic acid and 765 ml of acetic acid were added to a 3 L flask equipped with a reflux condenser and slowly heated to dissolve all solids. 306 ml of 112 vol hydrogen peroxide were added. The solution cleared immediately. The mixture was boiled slowly for 3 hours and finally heated for 1 hour without flame to destroy excess hydrogen peroxide.
2,4-디메톡시-5-에틸설포닐 벤조산을 냉각시켜 결정시켰다. 이를 배수하고, 120ml의 아세트산으로 세척하고 물로 세척하여 40℃에서 건조시켰다. 99g의 생성물을 회수하였다. 융점 207-208° 수율 70%It was determined by cooling 2,4-dimethoxy-5-ethylsulfonyl benzoic acid. It was drained, washed with 120 ml of acetic acid and washed with water and dried at 40 ° C. 99 g of product was recovered. Melting Point 207-208 ° Yield 70%
2,4-디메톡시-5-에틸설포닐 벤조일 클로라이드2,4-dimethoxy-5-ethylsulfonyl benzoyl chloride
82.2g의 2,3-디메톡시-5-에틸설포닐 벤조산, 165ml의 티오닐 클로라이드 및 3방울의 D.M.F.를 교반기, 환류냉각기 및 온도계가 장착되어 있는 500ml 용량의 플라스크에 가하였다.82.2 g of 2,3-dimethoxy-5-ethylsulfonyl benzoic acid, 165 ml of thionyl chloride and 3 drops of D.M.F. were added to a 500 ml flask equipped with a stirrer, reflux cooler and thermometer.
현탁액을 서서히 가열하여 환류시켰다. 1시간 30분 경과후에 온도를 78-79℃로 안정시켰다. 2시간 동안 가열을 계속한 후에 용액을 약간 냉각시켜서 과량의 티오닐 클로라이드를 진공하에서 증류하여 제거하였다. 고체잔사를 125ml의 이소프로필 에테르에 용해시키고 결정을 여별하였다. 이를 125ml의 이소프로필 에테르로 세척하고 1시간동안 45-50℃의 오븐에서 건조시킨 후에 진공하에서 건조기에 보관하였다.The suspension was heated to reflux slowly. After 1 hour and 30 minutes, the temperature was stabilized at 78-79 ° C. After continuing heating for 2 hours, the solution was cooled slightly to remove excess thionyl chloride by distillation under vacuum. The solid residue was dissolved in 125 ml of isopropyl ether and the crystals were filtered off. It was washed with 125 ml of isopropyl ether and dried in an oven at 45-50 ° C. for 1 hour before being stored in a drier under vacuum.
86g의 산클로라이드(98%)를 얻었다. 융점 186℃86 g of acid chloride (98%) were obtained. Melting point 186 ℃
N-(1-싸이클로펜틸-2-피롤리디닐 메틸)-2,4-디메톡시-5-에틸설포닐-벤즈아미드N- (1-cyclopentyl-2-pyrrolidinyl methyl) -2,4-dimethoxy-5-ethylsulfonyl-benzamide
33.6g의 1-싸이클로펜틸-2-아미노-메틸 피롤리딘 및 200ml의 메틸-에틸-케톤을 교반기, 온도계, 냉각기가 장착되어 있는 1ℓ 용량의 플라스크에 가하였다. 용액을 냉각시켜서 58.5g의 2,4-디메톡시-5-에틸설포닐 벤조일 클로라이드(0.2몰)을 반응중에 약 45분이상 가하면서 온도를 0-5℃로 유지시켰다.33.6 g of 1-cyclopentyl-2-amino-methyl pyrrolidine and 200 ml of methyl-ethyl-ketone were added to a 1 L flask equipped with a stirrer, thermometer and cooler. The solution was cooled to keep the temperature at 0-5 ° C. while adding 58.5 g of 2,4-dimethoxy-5-ethylsulfonyl benzoyl chloride (0.2 mol) for at least about 45 minutes during the reaction.
얻어진 용액을 30분간 5℃에서 방치하고 실온에서 2시간 30분 동안 유지시켰다. 침전 형성후에 1시간동안 실온에서 교반시켰다. 하이드로클로라이드 결정을 여과하고 50ml의 메틸-에틸케톤으로 세척하고 50-60℃의 오븐에서 건조시켰다. 82g의 하이드로 클로라이드를 얻었다. 융점 186℃The resulting solution was left at 5 ° C. for 30 minutes and kept at room temperature for 2 hours 30 minutes. After precipitation formed, it was stirred for 1 hour at room temperature. The hydrochloride crystals were filtered off, washed with 50 ml of methyl-ethylketone and dried in an oven at 50-60 ° C. 82 g of hydrochloride were obtained. Melting point 186 ℃
생성물을 400ml의 물에 용해시키고 목탄의 존재하에서 여과시켰다. 여액을 75ml의 물로 희석된 25ml의 희석 알카리액으로 알카리성으로 만들었다. 침전을 신속히 결정시켰다. 배수하고 물로 세척하여 50-60℃의 오븐에서 건조시켰다. 69g의 생성물을 얻었다. 융점 113℃The product was dissolved in 400 ml of water and filtered in the presence of charcoal. The filtrate was alkaline with 25 ml of diluted alkaline liquid diluted with 75 ml of water. Precipitation was quickly determined. Drain, wash with water and dry in oven at 50-60 ° C. 69 g of product was obtained. Melting point 113 ℃
염기를 210ml의 70% 에탄올에서 재결정시켰다. 결정을 철야 냉각시키고 배수하여 70ml의 90°에탄올로 세척한 후에 100ml의 물로 2번 세척하였다. 50℃의 오븐에서 건조시켰다.The base was recrystallized in 210 ml of 70% ethanol. The crystals were cooled overnight, drained and washed with 70 ml of 90 ° ethanol and then twice with 100 ml of water. It was dried in an oven at 50 ° C.
62g(73%)의 벤즈아미드를 얻었다. 융점 162℃62 g (73%) of benzamide was obtained. Melting point 162 ℃
[실시예 37]Example 37
N-(1-싸이클로헵틸-2-피롤리디닐 메틸)-2-메톡시-5-메틸-설포닐-벤즈아미드N- (1-cycloheptyl-2-pyrrolidinyl methyl) -2-methoxy-5-methyl-sulfonyl-benzamide
52g의 1-싸이클로헵틸-2-아미노-메틸-피롤리딘 및 240ml의 물을 교반기, 냉각기 및 온도계가 장착되어 있는 500ml 용량의 플라스크에 가하였다. 이를 0℃로 냉각시킨 후에 62.1g의 2-메톡시-5-메틸설포닐-벤조일 클로라이드(0.250몰)을 반응중에 가하면서 온도를 0-5℃로 유지시켰다. 온도를 약 20℃로 상승시켰다. 발열반응이 시작되어 온도가 30℃로 상승하였다. 반응을 30분간 더 계속한 후에 용액을 활성탄 3s의 존재하에서 여과시켰다. 여액을 80ml의 물로 희석시킨 20ml의 소다 알카리액으로 알카리성으로 만들었다. 침전이 처음에는 탄력성이 있다가 후에 결정화되었다. 배수하고 물로 세척하여 50℃의 오븐에서 건조시켰다. 90.5g을 얻었다. 융점 112-114℃52 g of 1-cycloheptyl-2-amino-methyl-pyrrolidine and 240 ml of water were added to a 500 ml flask equipped with a stirrer, cooler and thermometer. After cooling to 0 ° C., 62.1 g of 2-methoxy-5-methylsulfonyl-benzoyl chloride (0.250 mol) was added during the reaction to maintain the temperature at 0-5 ° C. The temperature was raised to about 20 ° C. The exothermic reaction started and the temperature rose to 30 ° C. The reaction was continued for another 30 minutes before the solution was filtered in the presence of activated carbon 3s. The filtrate was alkaline with 20 ml of soda alkaline solution diluted with 80 ml of water. Precipitation was initially elastic and later crystallized. Drained, washed with water and dried in an oven at 50 ° C. 90.5 g were obtained. Melting point 112-114 ℃
염기를 각각 30%의 물을함유하는 225ml 메탄올 및 200ml의 메탄올로 2번 재결정하였다. 흰색 결정을 배수하고 40℃의 오븐에서 건조시켰다. 54g의 생성물을 얻었다. 융점 118℃ 수율 53%The base was recrystallized twice with 225 ml methanol and 200 ml methanol each containing 30% water. The white crystals were drained and dried in an oven at 40 ° C. 54 g of product was obtained. Melting Point 118 ° C Yield 53%
[실시예 38]Example 38
N-(1-싸이클로헵틸-메틸-2-피롤리디닐 메틸)-2-메톡시-4-아미노-5-메틸-설파모일 벤즈 아미드N- (1-cycloheptyl-methyl-2-pyrrolidinyl methyl) -2-methoxy-4-amino-5-methyl-sulfamoyl benzamide
6.5g의 2-메톡시-4-아미노-5-메틸 설파모일 벤조산, 75ml의 아세톤, 14ml의 물 및 3.5ml의 트리에틸아민(비중 0.726)을 교반기, 온도계, 냉각기 및 적하 깔대기가 장착되어 있는 250ml 용량 플라스크에 가하였다. 용액을 0-5℃로 냉각시키고 2.7g의 에틸 클로로포르메이트를 적가하였다. 반응매체를 45분동안 실온에서 교반시킨 후에 다시 0℃로 냉각시켰다. 6.8g의 1-싸이클로헵틸메틸-2-아미노메틸 피롤리딘을 적가하였다. 매체를 2시간 동안 반응시킨 후에 방치하였다. 용매를 제거하고 고체잔사를 50ml의 물 및 20ml의 염산(비중 1.18)에 용해시켰다. 얻어진 현탁액을 암모니아로 알카리성으로 만들었다. 50ml의 메틸렌 클로라이드로 3번 추출하였다. 유기상을 50ml의 물로 2번 세척하고 마그네슘 설페이트상에서 건조시켜 여과하였다. 여액을 진공하에서 증발시켜 건조시켰다. 잔사를 80ml의 물 및 20ml의 염산(비중 1.18)에 용해시켰다. 하이드로 클로라이드를 결정시켰다. 배수하고 물로 세척하여 50℃의 오븐에서 건조시켰다. 7g의 생성물을 얻었다. 융점 약 230℃6.5 g of 2-methoxy-4-amino-5-methyl sulfamoyl benzoic acid, 75 ml of acetone, 14 ml of water and 3.5 ml of triethylamine (specific gravity 0.726) are equipped with a stirrer, thermometer, cooler and dropping funnel It was added to a 250 ml flask. The solution was cooled to 0-5 ° C. and 2.7 g ethyl chloroformate was added dropwise. The reaction medium was stirred at room temperature for 45 minutes and then cooled to 0 ° C. 6.8 g of 1-cycloheptylmethyl-2-aminomethyl pyrrolidine was added dropwise. The medium was allowed to react for 2 hours and then left. The solvent was removed and the solid residue was dissolved in 50 ml of water and 20 ml of hydrochloric acid (specific gravity 1.18). The resulting suspension was alkaline with ammonia. Extracted three times with 50 ml of methylene chloride. The organic phase was washed twice with 50 ml of water, dried over magnesium sulphate and filtered. The filtrate was evaporated to dryness in vacuo. The residue was dissolved in 80 ml of water and 20 ml of hydrochloric acid (specific gravity 1.18). Hydro chloride was determined. Drained, washed with water and dried in an oven at 50 ° C. 7 g of product was obtained. Melting Point About 230 ℃
이를 300ml의 에탄올에서 재결정시켜서 4.3g(35$)의 벤즈아미드 하이드로 클로라이드를 얻었다.It was recrystallized in 300 ml of ethanol to give 4.3 g ($ 35) of benzamide hydrochloride.
융점 228℃Melting point 228 ℃
[실시예 39]Example 39
N-(1-싸이클로헵틸 메틸-2-피롤리디닐 메틸)-2-메톡시-4-아미노-5-에틸 설포닐 벤즈아미드N- (1-cycloheptyl methyl-2-pyrrolidinyl methyl) -2-methoxy-4-amino-5-ethyl sulfonyl benzamide
4.9g의 2-메톡시-4-아미노-5-에틸 설포닐 벤조산, 57ml의 아세톤, 10ml의 물 및 2.6ml의 트리에틸아민(비중 0.726)을 교반기, 온도계, 냉각기 및 적하깔대기가 장착되어 있는 250ml 용량의 플라스크에 가하였다. 용액을 0-5℃로 냉각시키고 2.1g의 에틸 클로로포르메이트를 적가하였다. 반응매체를 45분간 실온에서 교반시킨 후에 0℃로 냉각시켰다. 5.3g의 1-싸이클로헵틸 메틸-2-아미노메틸 피롤리딘을 적가하였다. 매체를 4시간 동안 교반한 후에 철야 방치하였다. 용매를 증발시켜 건조시키고 잔사를 60ml의 물 및 15ml의 염산(비중 1.18)에 용해시켰다. 추출은 50ml의 메틸렌 클로라이드로 3번 수행하였다. 유기상을 마그네슘 설페이트상에서 건조시키고 여과시켰다. 용매를 진공하에서 증발시켰다. 잔사를 100ml의 물에 용해시켰다. 용액을 카본 블랙 존재하에 여과하여 여액을 약 7ml의 암모니아(비중 0.91)로 알카리성으로 만들었다. 검이 침전되었다. 이를 50ml의 메틸렌 클로라이드로 3번 추출하였다. 유기상을 50ml의 물로 2번 세척하고 마그네슘 설페이트상에서 건조시키고 여과하였다. 용매를 진공하에서 증발시켜서 잔사를 100ml의 이소프로판올에서 재결정시켰다. 4.5g(52%)의 생성물을 얻었다. 융점 156℃4.9 g of 2-methoxy-4-amino-5-ethyl sulfonyl benzoic acid, 57 ml of acetone, 10 ml of water and 2.6 ml of triethylamine (specific gravity 0.726) are equipped with a stirrer, thermometer, cooler and dropping funnel. It was added to a 250 ml flask. The solution was cooled to 0-5 ° C. and 2.1 g of ethyl chloroformate was added dropwise. The reaction medium was stirred at room temperature for 45 minutes and then cooled to 0 ° C. 5.3 g of 1-cycloheptyl methyl-2-aminomethyl pyrrolidine was added dropwise. The medium was stirred for 4 hours and then left overnight. The solvent was evaporated to dryness and the residue was dissolved in 60 ml of water and 15 ml of hydrochloric acid (specific gravity 1.18). Extraction was performed three times with 50 ml of methylene chloride. The organic phase was dried over magnesium sulphate and filtered. The solvent was evaporated in vacuo. The residue was dissolved in 100 ml of water. The solution was filtered in the presence of carbon black to make the filtrate alkaline with about 7 ml of ammonia (specific gravity 0.91). The gum precipitated. It was extracted three times with 50 ml of methylene chloride. The organic phase was washed twice with 50 ml of water, dried over magnesium sulphate and filtered. The residue was recrystallized from 100 ml of isopropanol by evaporation of the solvent under vacuum. 4.5 g (52%) of product was obtained. Melting point 156 ℃
[실시예 40]Example 40
N-(1-싸이클로프로필메틸-2-피롤리디닐 메틸)-2,4-디메톡시-5-메틸-설포닐 벤즈아미드N- (1-cyclopropylmethyl-2-pyrrolidinyl methyl) -2,4-dimethoxy-5-methyl-sulfonyl benzamide
2,4-디메톡시-5-메틸설포닐 벤조산2,4-dimethoxy-5-methylsulfonyl benzoic acid
930ml의 물, 208g의 소디움 설파이트 및 277g의 중탄산나트륨을 밀폐된 교반기, 환류냉각기 및 온도계가 장착되어 있는 6ℓ 용량의 플라스크에 가하였다. 이들을 70-80℃로 가여하고 309g의 2,4-디메톡시-5-클로로설포닐 벤조산을 서서히 가하였다.930 ml of water, 208 g of sodium sulfite and 277 g of sodium bicarbonate were added to a 6 L flask equipped with a sealed stirrer, reflux cooler and thermometer. They were added to 70-80 ° C. and 309 g of 2,4-dimethoxy-5-chlorosulfonyl benzoic acid was added slowly.
많은 량의 CO2를 산을 용해시키면서 동시에 발생시켰다. 산을 유입하는데 45분이 걸렸다. 가열을 70-80℃에서 2시간 더 계속하여 반응을 완결시켰다. 용액의 pH를 7로 하였다.Large amounts of CO 2 were generated simultaneously with dissolution of the acid. It took 45 minutes to get the acid in. Heating was continued for 2 hours at 70-80 ° C. to complete the reaction. The pH of the solution was set to 7.
220cc의 30% 소다알카리액, 1,120ml의 무수알코올 및 470g의 메틸 아이오다이드를 반응혼합물에 가하여 서서히 환류시켜 가열하였다. 3시간 30분 경과후에 중량이 감소되었고 용액은 페놀프탈레인에 의해 단지 약간 알카리성임이 판명되었다.220 cc of 30% soda-alkaline solution, 1,120 ml of anhydrous alcohol and 470 g of methyl iodide were added to the reaction mixture and heated to reflux slowly. After 3 hours and 30 minutes the weight was reduced and the solution was found to be only slightly alkaline by phenolphthalein.
50g의 메틸아이오다이드 및 110cc의 소다알카리액을 가하고 매체를 가열하여 다시 환류시켰다. 처음의 환류온도를 점진적으로 65℃로 상승시키고 후에 75℃로 상승시켰다. 다른 중량의 손실이 명백하지만 용액을 알카리성으로 남아 있었다. 8시간 동안 함께 가열을 계속하였다.50 g of methyl iodide and 110 cc of soda alkaline solution were added and the medium was heated to reflux again. The initial reflux temperature was gradually raised to 65 ° C. and then to 75 ° C. The other weight loss was apparent but the solution remained alkaline. Heating was continued together for 8 hours.
500ml의 알코올로 여별하였다. 잔사를 2ℓ의 물에 용해시키고 무기염을 용해시켰다. 약간 혼탁된 용액을 얻어서 목탄으로 여과시켰다. 2,4-디메톡시-5-메틸설포닐 벤조산을 콩고레드가 변할 때까지 농염산을 가하여 침전시켰다. 배수하고, 물로 세척하여 60℃에서 건조시켰다.Filtered with 500 ml of alcohol. The residue was dissolved in 2 L of water and the inorganic salts were dissolved. A slightly cloudy solution was obtained and filtered over charcoal. 2,4-Dimethoxy-5-methylsulfonyl benzoic acid was precipitated by adding concentrated hydrochloric acid until the Congo red changed. Drained, washed with water and dried at 60 ° C.
255g의 생성물을 얻었다. (89%)255 g of product were obtained. (89%)
2,4-디메톡시-5-메틸-설포닐-벤조일 클로라이드2,4-dimethoxy-5-methyl-sulfonyl-benzoyl chloride
161g의 2,4-디메톡시-5-메틸설포닐-벤조산을 반응시켰다. 590g의 티오닐 클로라이드, 5방울의 디메틸포름아미드 및 약 반 정도의 유기산을 환류냉각기가 장착되어 있는 2ℓ 용량의 플라스크에 가하였다. 결과의 현탁액을 55℃의 수욕상에서 약 5시간 동안 가열하였다. 나머지 반의 유기산을 가하여 20분동안 60-65℃에서 가열을 계속한 후에 45분동안 70-75℃에서 가열하였다. 매체가 유체로 되어 황색으로 변하였다. 산을 서서히 용해시키면서 산클로라이드를 결정시켰다. 반응이 끝났을 때 과량의 티오닐클로라이드를 일정량이 되도록 증류시켜서 진공하에서 반응을 완료하였다.161 g of 2,4-dimethoxy-5-methylsulfonyl-benzoic acid was reacted. 590 g of thionyl chloride, 5 drops of dimethylformamide and about half of the organic acid were added to a 2 L flask equipped with a reflux condenser. The resulting suspension was heated on a 55 ° C. water bath for about 5 hours. The other half of the organic acid was added and heating continued at 60-65 ° C. for 20 minutes followed by heating at 70-75 ° C. for 45 minutes. The medium turned fluid and turned yellow. Acid chlorides were determined while slowly dissolving the acid. At the end of the reaction, the excess thionyl chloride was distilled off to a certain amount to complete the reaction under vacuum.
169g(98%)의 산클로라이드를 얻었다. 융점 200℃(분해)169 g (98%) of acid chloride were obtained. Melting Point 200 ° C (Decomposition)
N-(1-싸이클로프로필 메틸-2-피롤리디닐메틸)-2,4-디메톡시-5-메틸 설포닐 벤즈아미드N- (1-cyclopropyl methyl-2-pyrrolidinylmethyl) -2,4-dimethoxy-5-methyl sulfonyl benzamide
74g의 1-싸이클로프로필메틸-2-아미노메틸-피롤리딘 및 460ml의 클로로포름을 교반기 및 온도계가 장착되어 있는 1ℓ 용량의 플라스크에 가하였다. 134g의 미세하게 분쇄시킨 2,4-디메톡시-5-메틸설포닐 벤조일 클로라이드를 서서히 가하였다.74 g of 1-cyclopropylmethyl-2-aminomethyl-pyrrolidine and 460 ml of chloroform were added to a 1 L flask equipped with a stirrer and thermometer. 134 g of finely ground 2,4-dimethoxy-5-methylsulfonyl benzoyl chloride was added slowly.
빙욕에서 냉각시켜 온도를 5-10℃로 유지시켰다. 산 클로라이드의 각 부분은즉시 용해하였다. 도입하는데 1시간이 걸렸다. 교반을 1시간 동안 5℃에서 계속하고 난 후에 실온에서 1시간 동안 계속하였다.Cooling in an ice bath kept the temperature at 5-10 ° C. Each part of the acid chloride dissolved immediately. It took an hour to introduce. Stirring was continued at 5 ° C. for 1 hour and then at room temperature for 1 hour.
얻어진 용액을 1ℓ의 물에 용해시켜서 클로로포름을 증류시켜 제거하였다. 현탁액에 남아있는 경질 침전을 배수하고 세척하여 건조시켰다. 6g의 2,4-디메톡시-5-메틸설포닐 벤조산을 회수하였다.The resulting solution was dissolved in 1 L of water and chloroform was distilled off. The hard precipitate remaining in the suspension was drained, washed and dried. 6 g of 2,4-dimethoxy-5-methylsulfonyl benzoic acid was recovered.
융점 208-310℃Melting point 208-310 ℃
수용액을 페놀프탈레인이 변할 때까지 20% 암모니아를 가하여 알카리성으로 만들었다.The aqueous solution was made alkaline by adding 20% ammonia until the phenolphthalein changed.
에테르는 염기를 결정시키는데 촉진시켜 준다. 생성물을 배수시키고 물로 세척하여 45℃에서 건조시켰다. 153g(81%)의 생성물을 얻었다. 융점 193-196℃Ethers facilitate the determination of bases. The product was drained, washed with water and dried at 45 ° C. 153 g (81%) of the product were obtained. Melting Point 193-196 ℃
900ml의 아세토니트릴에서 재결정시켜서 133g의 벤즈아미드를 회수하였다.133 g of benzamide was recovered by recrystallization in 900 ml of acetonitrile.
융점 190-191℃ 총수율 70%Melting Point 190-191 ℃ Total Yield 70%
[실시예 41]Example 41
N-(1-싸이클로 옥틸메틸-2-피롤리디닐메틸)-2,3-디메톡시-5-설파모일 벤즈아미드N- (1-cyclooctylmethyl-2-pyrrolidinylmethyl) -2,3-dimethoxy-5-sulfamoyl benzamide
13g의 2,3-디메톡시-5-설파모일 벤조산, 130ml의 아세톤, 28ml의 물 및 7ml의 트리에틸아민(비중 0.726)을 교반기, 온도계, 냉각기 및 적하깔대기가 장착되어 있는 250ml 용량의 플라스크에 가하였다.13 g of 2,3-dimethoxy-5-sulfamoyl benzoic acid, 130 ml of acetone, 28 ml of water and 7 ml of triethylamine (specific gravity 0.726) were placed in a 250 ml flask equipped with a stirrer, thermometer, cooler and dropping funnel. Was added.
결과의 현탁액을 0℃로 냉각시킨 후에 5.4g의 에틸 클로로포르메이트를 적가하여 실온에서 반응하도록 방치하였다. 0℃로 다시 냉각시킨 후에 13.8g의 1-싸이클로옥틸-2-아미노메틸-피롤리딘을 적가하였다. 반응매체를 실온으로 다시 유지하여 방치시켰다.After cooling the resulting suspension to 0 ° C., 5.4 g of ethyl chloroformate was added dropwise and allowed to react at room temperature. After cooling back to 0 ° C., 13.8 g of 1-cyclooctyl-2-aminomethyl-pyrrolidine was added dropwise. The reaction medium was left at room temperature again.
용매를 진공하에서 증발시키고 잔사를 100ml의 물 및 20ml의 염산(비중 1.18)에 용해시켰다. 용액을 250ml의 메틸렌 클로라이드로 3번 추출하였다. 3개의 상이 형성되었다. 수용액 및 중간층을 25ml의 암모니아(비중 0.91)로 알카리성으로 만들었다. 침전된 검을 서서히 결정시켰다. 생성물을 여과하고 물로 세척하여 40℃의 오븐에서 건조시켰다. 100ml의 이소프로판올에서 재결정시킨 생성물을 여과하고 소량의 이소프로판올로 세척하여 50℃에서 건조시켰다. 수율 8.6g(38%) 융점 164℃The solvent was evaporated in vacuo and the residue was dissolved in 100 ml of water and 20 ml of hydrochloric acid (specific gravity 1.18). The solution was extracted three times with 250 ml of methylene chloride. Three phases were formed. The aqueous and intermediate layers were alkaline with 25 ml of ammonia (specific gravity 0.91). The precipitated gum was slowly determined. The product was filtered off, washed with water and dried in an oven at 40 ° C. The product recrystallized in 100 ml of isopropanol was filtered off, washed with a small amount of isopropanol and dried at 50 ° C. Yield 8.6g (38%) Melting Point 164 ℃
[실시예 42]Example 42
N-(1-싸이클로헵틸메틸-2-피롤리디닐메틸)-2,3-디메톡시-5-설파모일 벤즈아미드N- (1-cycloheptylmethyl-2-pyrrolidinylmethyl) -2,3-dimethoxy-5-sulfamoyl benzamide
13g의 2,3-디메톡시-5-설파모일 벤조산, 150ml의 아세톤 28ml의 물 및 7ml의 트리에틸아민(비중 0.726)을 교반기, 온도계, 냉각기 및 적하깔대기가 장착되어 있는 250ml 용량의 플라스크에 가하였다.13 g of 2,3-dimethoxy-5-sulfamoyl benzoic acid, 150 ml of acetone 28 ml of water and 7 ml of triethylamine (specific gravity 0.726) were added to a 250 ml flask equipped with a stirrer, thermometer, cooler and dropping funnel. It was.
얻어진 용액을 0-5℃로 냉각시켰다. 5.4g의 에틸 클로로포르메이트를 적가하여 반응매체를 45분간 실온에서 교반하고 0℃로 다시 냉각시켰다. 13.7g의 1-싸이클로헵틸 메틸-2-아미노메틸-피롤리딘을 적가하였다. 매체를 1시간 동안 실온에서 교반한 후에 방치하였다. 형성된 결정을 배수하고 물로 세척하여 30℃의 오븐에서 건조시켰다. 수율 22.3g(98%) 융점 180℃The resulting solution was cooled to 0-5 ° C. 5.4 g of ethyl chloroformate was added dropwise and the reaction medium was stirred at room temperature for 45 minutes and cooled back to 0 ° C. 13.7 g of 1-cycloheptyl methyl-2-aminomethyl-pyrrolidine was added dropwise. The medium was left to stir at room temperature for 1 hour. The crystals formed were drained, washed with water and dried in an oven at 30 ° C. Yield 22.3 g (98%) Melting Point 180 ° C
생성물을 400ml의 이소프로판올에서 재결정시켜 14.3g의 (63%) 아미드를 회수하였다. 융점 180℃The product was recrystallized in 400 ml of isopropanol to recover 14.3 g (63%) amide. Melting Point 180 ℃
[실시예 43]Example 43
N-(1-싸이클로프로필메틸-3-피롤리디닐)-2-메톡시-5-설파모일-벤즈아미드N- (1-cyclopropylmethyl-3-pyrrolidinyl) -2-methoxy-5-sulfamoyl-benzamide
30g의 1-싸이클로프로필메틸-3-아미노-피롤리딘 및 300ml의 물을 교반기, 온도계 및 냉각기가 장착되어 있는 1ℓ 용량의 플라스크에 가하였다. 혼합물을 10℃로 냉각시키고 50g의 2-메톡시-5-설파모일 벤조일클로라이드를 반응중에 가하였다. 얻어진 현탁액의 온도를 약 20℃로 상승시킨 후에 1시간동안 30℃에서 가열하였다. 얻어진 용액을 목탄으로 여과시킨 후에 20% 암모니아로 알카리성으로 만들었다. 점착성 침전을 형성시킨 후에 즉시 결정화 되었다. 결정을 여과하고 물로 세척하여 50℃의 오븐에서 건조시켰다. 66g의 생성물을 얻었다. 융점 142℃ 생성물을 400ml의 에탄올에서 재결정 시켰다.30 g of 1-cyclopropylmethyl-3-amino-pyrrolidine and 300 ml of water were added to a 1 L flask equipped with a stirrer, thermometer and cooler. The mixture was cooled to 10 ° C. and 50 g of 2-methoxy-5-sulfamoyl benzoylchloride was added during the reaction. The temperature of the obtained suspension was raised to about 20 ° C. and then heated at 30 ° C. for 1 hour. The resulting solution was filtered through charcoal and made alkaline with 20% ammonia. Crystallized immediately after forming a sticky precipitate. The crystals were filtered off, washed with water and dried in an oven at 50 ° C. 66 g of product was obtained. Melting point 142 ° C. The product was recrystallized in 400 ml of ethanol.
45g의 N-(1-싸이클로프로필메틸-3-피롤리디닐)-2-메톡시-5-설파모일-벤즈아미드를 얻었다. 융점 150℃ 수율 64%45 g of N- (1-cyclopropylmethyl-3-pyrrolidinyl) -2-methoxy-5-sulfamoyl-benzamide was obtained. Melting Point 150 ℃ Yield 64%
[실시예 44]Example 44
N-(1-싸이클로헥실메틸-3-피롤리디닐)-2-메톡시-5-메틸설포닐벤즈아미드N- (1-cyclohexylmethyl-3-pyrrolidinyl) -2-methoxy-5-methylsulfonylbenzamide
36.4g의 1-싸이클로헥실메틸-3-아미노-피롤리딘 및 200ml의 물을 교반기 및 온도계가 장착되어 있는 500ml 용량의 플라스크에 가하였다. 용액을 5℃로 냉각시킨 후에 47.4g의 2-메톡시-5-메틸설포닐 벤조일 클로라이드를 반응중에 가하였다. 현탁액을 2시간 동안 20℃에서 교반한 후에 1시간 동안 30℃에서 교반하였다. 반응매체를 방치한 후에 30ml의 염산(비중 1.18)으로 강하게 산성화시켰다. 경질 불용성 물질을 여별하고 염기를 60ml의 소다알카리액으로 알카리성으로 만들어 침전시켰다. 염기를 처음에는 오36.4 g of 1-cyclohexylmethyl-3-amino-pyrrolidine and 200 ml of water were added to a 500 ml flask equipped with a stirrer and thermometer. After the solution was cooled to 5 ° C., 47.4 g of 2-methoxy-5-methylsulfonyl benzoyl chloride was added during the reaction. The suspension was stirred at 20 ° C. for 2 hours and then at 30 ° C. for 1 hour. After leaving the reaction medium, it was strongly acidified with 30 ml of hydrochloric acid (specific gravity 1.18). The light insoluble material was filtered off and the base was made alkaline with 60 ml of soda alkaline solution to precipitate. The base at first
생성물은 600ml의 메탄올에서 뜨거운 상태에서 여과하여 재결정 하였다. 재결정 시키기 위하여 냉각기에서 철야방치하였다. 결정을 여과하여 소량의 메탄올로 세척하고 60℃의 오븐에서 건조시켰다.The product was recrystallized by filtration in hot state in 600 ml of methanol. It was left overnight in the cooler to recrystallize. The crystals were filtered off, washed with a small amount of methanol and dried in an oven at 60 ° C.
51g의 N-(1-싸이클로헥실메틸-3-피롤리디닐)-2-메톡시-5-메틸설포닐-벤즈아미드를 얻었다.51 g of N- (1-cyclohexylmethyl-3-pyrrolidinyl) -2-methoxy-5-methylsulfonyl-benzamide was obtained.
융점 157℃ 수율 68%Melting Point 157 ° C Yield 68%
[실시예 45]Example 45
N-(1-싸이클로프로필메틸-3-피롤리디닐)-2-메톡시-4-아미노-5-메틸설파모일 벤즈아미드N- (1-cyclopropylmethyl-3-pyrrolidinyl) -2-methoxy-4-amino-5-methylsulfamoyl benzamide
7.8g의 2-메톡시-4-아미노-5-메틸설파모일 벤조산, 70ml의 아세톤, 10ml의 물 및 3g의 트리에틸아민을 교반기, 온도계 및 적하깔대기가 장착되어 있는 250ml 용량의 플라스크에 가하였다. 용액을 약 0℃로 냉각시키고 4.3g의 이소클로로포르메이트를 적가하였다. 0-5℃의 온도에서 45분간 교반시킨 후에 4.6g의 1-싸이클로프로필메틸-3-아미노-피롤리딘을 적가하였다. 매체를 실온에서 2시간 동안 반응시키고 70ml의 물 및 7ml의 소다알카리액을 가하였다. 아세톤을 진공하에서 증발시켜 수성상을 10ml의 염산(비중 1.18)으로 산성화 시켰다.7.8 g 2-methoxy-4-amino-5-methylsulfamoyl benzoic acid, 70 ml acetone, 10 ml water and 3 g triethylamine were added to a 250 ml flask equipped with a stirrer, thermometer and dropping funnel. . The solution was cooled to about 0 ° C. and 4.3 g of isochloroformate was added dropwise. After stirring for 45 minutes at a temperature of 0-5 ° C., 4.6 g of 1-cyclopropylmethyl-3-amino-pyrrolidine was added dropwise. The medium was allowed to react at room temperature for 2 hours and 70 ml of water and 7 ml of soda alkaline solution were added. Acetone was evaporated under vacuum to acidify the aqueous phase with 10 ml of hydrochloric acid (specific gravity 1.18).
수성상을 15ml의 암모니아로 알카리성으로 만들었다. 검을 침전시켜 여과한 후에 30ml의 물로 3번 여과하여 세척하였다. 점성 잔사를, 90ml의 이소프로판 및 10ml의 물에 뜨거운 상태에서 용해시켰다. 용액을 뜨거운 상태에서 여과한 후에 냉각기에 넣어 결정시켰다. 결정을 여과하고 물로 세척하여 50℃의 오븐에서 건조 시켰다. 5.8g(50%)의 생성물을 얻었다. 융점 177℃The aqueous phase was alkaline with 15 ml of ammonia. The gum was precipitated and filtered and then washed three times with 30 ml of water. The viscous residue was dissolved in 90 ml of isopropane and 10 ml of water hot. The solution was filtered while hot and placed in a cooler to determine. The crystals were filtered off, washed with water and dried in an oven at 50 ° C. 5.8 g (50%) of the product were obtained. Melting point 177 ℃
[실시예 46]Example 46
N-(1-싸이클로프로필메틸-3-피롤리디닐)-2-메톡시-4-아미노-5-에틸-설포닐-벤즈아미드N- (1-cyclopropylmethyl-3-pyrrolidinyl) -2-methoxy-4-amino-5-ethyl-sulfonyl-benzamide
64.8g의 2-메톡시-4-아미노-5-에틸설포닐 벤조산, 650ml의 아세톤 및 25.2g의 트리에틸아민을 교반기, 온도계 및 적하깔대 기가 장착되어 있는 1ℓ 용량의 플라스크에 가하였다. 고체를 완전히 용해시킨 후에 트리에틸아민염을 신속히 침전시켰다. 반응 매체를 0℃로 냉각시키고 35g의 이소부틸 클로로포르메이트를 적가하였다. 매체를 45분간 0-5℃에서 교반시킨 후에 35g의 1-싸이클로프로필메틸-3-아미노피롤 리딘을 적가 하였다. 반응을 실온에서 2시간 동안 지속시킨 후에 500ml의 물을 가하고 아세톤을 진공64.8 g of 2-methoxy-4-amino-5-ethylsulfonyl benzoic acid, 650 ml of acetone and 25.2 g of triethylamine were added to a 1 L flask equipped with a stirrer, thermometer and dropping funnel. The triethylamine salt precipitated rapidly after complete solid dissolution. The reaction medium was cooled to 0 ° C. and 35 g of isobutyl chloroformate was added dropwise. After stirring the medium at 0-5 ° C. for 45 minutes, 35 g of 1-cyclopropylmethyl-3-aminopyrrolidine was added dropwise. After the reaction was continued for 2 hours at room temperature, 500 ml of water was added and the acetone was vacuumed.
[실시예 47]Example 47
N-(1-싸이클로헥실메틸-3-피롤리디닐)-2-메톡시-4-아미노-5-에틸-설포닐-벤즈아미드N- (1-cyclohexylmethyl-3-pyrrolidinyl) -2-methoxy-4-amino-5-ethyl-sulfonyl-benzamide
7.8g의 2-메톡시-4-아미노-5-에틸설포닐 벤조산, 70ml의 아세톤, 10ml의 물 및 3g의 트리에틸아민을 교반기, 온도계 및 적하깔대기가 장착되어 있는 250ml 용량의 플라스크에 가하였다. 혼합물을 0℃로 냉각시키고 4.1g의 이소부틸클로로포르메이트를 적가하였다. 45분간 0℃에서 교반하여 6g의 1-싸이클로헥실메틸-3-아미노-피롤리딘을 적가 하였다.7.8 g 2-methoxy-4-amino-5-ethylsulfonyl benzoic acid, 70 ml acetone, 10 ml water and 3 g triethylamine were added to a 250 ml flask equipped with a stirrer, thermometer and dropping funnel. . The mixture was cooled to 0 ° C. and 4.1 g of isobutylchloroformate was added dropwise. 6 g of 1-cyclohexylmethyl-3-amino-pyrrolidine was added dropwise by stirring at 0 ° C. for 45 min.
반응을 실온에서 2시간 동안 지속시키고, 80ml의 물 및 5ml의 소다알카리액을 가한 후에, 아세톤을 진공하에서 증발시켰다. 오일을 따라내어 100ml의 물로 2번 세척한 후에 50ml에틸 아세테이트에 뜨거운 상태에서 용해시켰다. 냉각기에서 냉각시켜서 결정을 여별하고 소량의 에틸아세테이트로 세척하고 50℃의 오븐에서 건조시켰다. 9.4g의 벤즈아미드를 얻었다. 융점 146℃(74%)The reaction was continued for 2 hours at room temperature, after addition of 80 ml of water and 5 ml of soda alkaline solution, the acetone was evaporated in vacuo. The oil was decanted and washed twice with 100 ml of water and then dissolved in 50 ml of ethyl acetate in hot state. The crystals were filtered off by cooling in a cooler, washed with a small amount of ethyl acetate and dried in an oven at 50 ° C. 9.4 g of benzamide was obtained. Melting Point 146 ° C (74%)
[실시예 48]Example 48
N-(1-싸이클로헥실메틸-3-피롤리디닐)-2-메톡시-4-아미노-5-에틸설피닐벤즈아미드N- (1-cyclohexylmethyl-3-pyrrolidinyl) -2-methoxy-4-amino-5-ethylsulfinylbenzamide
8.5g의 2-메톡시-4-아세트아미노-5-에틸설피닐 벤조산, 70ml의 아세톤, 10ml의 물 및 3g의 트리에틸아민을 교반기, 온도계 및 적하깔대기가 장착되어 있는 250ml 용량의 플라스크에 가하였다. 용액을 약 0℃로 냉각시킨 후에 4.2g의 이소부틸 클로로 프로메이트를 적가 하였다. 45분간 0℃에서 교반기킨 후에 6g의 1-싸이클로헥실-메틸-3-아미노-피롤리딘을 적가하였다. 2시간동안 실온에서 반응시키고 50ml의 물을 가하고 아세톤을 진공하에서 증발시켰다. 10ml의 소다 및 50ml의 물을 수성잔사에 가하고, 5시간8.5 g 2-methoxy-4-acetamino-5-ethylsulfinyl benzoic acid, 70 ml acetone, 10 ml water and 3 g triethylamine were added to a 250 ml flask equipped with a stirrer, thermometer and dropping funnel. It was. After cooling the solution to about 0 ° C., 4.2 g of isobutyl chloro promate was added dropwise. After stirring for 45 min at 0 ° C., 6 g of 1-cyclohexyl-methyl-3-amino-pyrrolidine was added dropwise. The reaction was allowed to react at room temperature for 2 hours, 50 ml of water was added and the acetone was evaporated in vacuo. 10 ml of soda and 50 ml of water are added to the aqueous residue, and 5 hours
8.2g의 생성물을 얻었다. 융점 143℃, 이를 90ml의 에틸 아세테이트에서 2번 재결정시켜서 6.8g의 아미드를 회수하였다. 융점 146℃8.2 g of product was obtained. Melting point 143 ° C., which was recrystallized twice in 90 ml of ethyl acetate to recover 6.8 g of amide. Melting point 146 ℃
[실시예 49]Example 49
N-(1-싸이클로프로필메틸-3-피롤 리디닐)-2-4-디메톡시-5-에틸설포닐 벤즈아미드N- (1-cyclopropylmethyl-3-pyrrolidinyl) -2-4-dimethoxy-5-ethylsulfonyl benzamide
8.2g의 2,4-디메톡시-5-에틸설포닐 벤조산, 70ml의 아세톤, 10ml의 물 및 4.2ml의 트리에틸아민(비증 0.726)을 교반기, 온도계 및 적하깔대기가 장착되어 있는 250ml 용량의 플라스크에 가하였다. 얻어진 용액을 냉각시킨 후에 4.2g의 이소부틸클로로포로메이트를 적가하면서 온도를 약 0℃로 유지하였다. 매체를 45분간 그 온도에서 반응시킨 후에 4.6g의 1-싸이클로프로필메틸-3-아미노피롤리딘을 적가 하였다. 2시간동안 상온에서 교반한 후에 50ml의 물 및 5ml의 소다알카리액을 가하였다. 아세톤을 진공하에서 증발시키고 불용성 오일을 50ml의 메틸렌클로라이드로 3번 추출하였다. 유기상을 50ml의 물로 2번 세척한 후에 마그네슘설페이트상에서 건조시킨 후에 여과하고, 증발시켜서 건조 시켰다. 오일잔사를 80ml의 부틸아세테이트에서 뜨거운 상태에 용해시켰다. 용액을 여과한 후에 냉각기에 결정 시키기 위해서 주입하였다. 결정을 배수하고 소량의 에테르로 세척하여 50℃의 오븐에서 건조 시켰다. 8g(67%)의 생성물을 얻었다. 융점 106℃250 ml flask with 8.2 g of 2,4-dimethoxy-5-ethylsulfonyl benzoic acid, 70 ml of acetone, 10 ml of water and 4.2 ml of triethylamine (ascension 0.726) equipped with a stirrer, thermometer and dropping funnel Was added. After cooling the obtained solution, the temperature was kept at about 0 degreeC, dropwise adding 4.2 g of isobutylchloroformate. After the medium was reacted at that temperature for 45 minutes, 4.6 g of 1-cyclopropylmethyl-3-aminopyrrolidine was added dropwise. After stirring at room temperature for 2 hours, 50 ml of water and 5 ml of soda alkaline solution were added. Acetone was evaporated in vacuo and the insoluble oil was extracted three times with 50 ml of methylene chloride. The organic phase was washed twice with 50 ml of water and then dried over magnesium sulfate, filtered and evaporated to dryness. The oil residue was dissolved hot in 80 ml of butyl acetate. The solution was filtered and then injected into the cooler to determine. The crystals were drained and washed with a small amount of ether and dried in an oven at 50 ° C. 8 g (67%) of the product were obtained. Melting point 106 ℃
[실시예 50]Example 50
N-(1-싸이클로프로필메틸-3-피롤리디닐 메틸)-2,3-디메톡시-5-설파모일 벤즈아미드N- (1-cyclopropylmethyl-3-pyrrolidinyl methyl) -2,3-dimethoxy-5-sulfamoyl benzamide
6.6g의 2,3-디메톡시-5-설파모일 벤조산, 50ml의 아세톤, 10ml의 물 및 3.6ml의 트리에틸아민(비증 0.726)을 교반기, 온도계 및 적하깔대기가 장착되어 있는 250ml 용량의 플라스크에 가하였다. 용액을 0-5℃로 냉각시키고 3.6g의 이소부틸클로로 포르메이트를 적가 하였다. 30분간 동일한 온도를 유지시켜 반응시킨 후에 4.8g의 1-싸이클로프로필메틸-3-아미노메틸-피롤 리딘을 적가 하였다. 반응매체를 실온에서 1시간동안 교반시킨 후에 50ml의 물을 가하고 아세톤을 진공하에서 증발시켰다. 잔사를 비등하는 에틸 아세테이트에 용해 시켰다. 뜨거운 상태로 결정시킨 결정을 냉각시키고 여과하여 50℃의 오븐에서 건조시켰다. 2.7g(27%)의 생성물을 얻었다. 융점 146℃6.6 g of 2,3-dimethoxy-5-sulfamoyl benzoic acid, 50 ml of acetone, 10 ml of water, and 3.6 ml of triethylamine (ascension 0.726) were placed in a 250 ml flask equipped with a stirrer, thermometer and dropping funnel. Was added. The solution was cooled to 0-5 ° C. and 3.6 g of isobutylchloro formate was added dropwise. After reacting at the same temperature for 30 minutes, 4.8 g of 1-cyclopropylmethyl-3-aminomethyl-pyrrolidine was added dropwise. After the reaction medium was stirred at room temperature for 1 hour, 50 ml of water was added and the acetone was evaporated in vacuo. The residue was dissolved in boiling ethyl acetate. The crystals, which were determined to be hot, were cooled, filtered and dried in an oven at 50 ° C. 2.7 g (27%) of the product were obtained. Melting point 146 ℃
[실시예 51]Example 51
N-(1-싸이클로헥실메틸-3-피롤리디닐)-2,3-디메톡시-5-설파모일 벤즈아미드N- (1-cyclohexylmethyl-3-pyrrolidinyl) -2,3-dimethoxy-5-sulfamoyl benzamide
7.85g의 2,3-디메톡시-5-설파모일 벤조산, 50ml의 아세톤, 10ml의 물 및 3g의 트리에틸아민을 교반기, 온도계 및 적하깔대기가 장착되어 있는 250ml 용량의 플라스크에 가하였다. 혼합물을 0℃로 냉각시키고 4.2g의 이소부틸클로로포르메이트를 적가하였다. 혼합물을 45분간 0℃에서 교반한 후에 6g의 1-싸이클로헥실 메틸-3-아미노-피롤리딘을 적가 하였다. 2시간 동안 실온에서 교반시킨 후에 80ml의 물을 가하고 아세톤을 진공하에서 증발 시켰다. 생성물이 결정되었다. 이를 여과하고 물로 세척한 후에 150ml의 물 및 20ml의 염산에 재용해 시켰다. 용액을 목탄으로 여과하고 여액을 암모니아로 알카리성으로 만들었다. 오일을 침전시키고, 서서히 결정시켰다. 결정을 배수하고 물로 세척하여 50℃의 오븐에서 건조시켰다. 6.8g(53%)의 생성물을 얻었다. 융점 167℃7.85 g of 2,3-dimethoxy-5-sulfamoyl benzoic acid, 50 ml of acetone, 10 ml of water and 3 g of triethylamine were added to a 250 ml flask equipped with a stirrer, thermometer and dropping funnel. The mixture was cooled to 0 ° C. and 4.2 g of isobutylchloroformate was added dropwise. The mixture was stirred at 0 ° C. for 45 min before 6 g of 1-cyclohexyl methyl-3-amino-pyrrolidine was added dropwise. After stirring for 2 hours at room temperature, 80 ml of water was added and the acetone was evaporated in vacuo. The product was determined. It was filtered and washed with water and redissolved in 150 ml of water and 20 ml of hydrochloric acid. The solution was filtered through charcoal and the filtrate was alkaline with ammonia. The oil precipitated out and slowly determined. The crystals were drained, washed with water and dried in an oven at 50 ° C. 6.8 g (53%) of the product were obtained. Melting point 167 ℃
[실시예 52]Example 52
N-(1-싸이클로프로필메틸-3-피롤리디닐)-2-메톡시-5-에틸설포닐-벤즈아미드N- (1-cyclopropylmethyl-3-pyrrolidinyl) -2-methoxy-5-ethylsulfonyl-benzamide
7.3g의 2-메톡시-5-에틸설포닐벤조산, 70ml의 아세톤, 10ml의 물 및 4g의 트리에틸아민을 교반기, 온도계 및 적하깔대기가 장착되어 있는 250ml 용량의 플라스크에 가하였다. 용액을 약 0℃로 냉각시키고 4.2g의 이소부틸 클로로포르메이트를 적가 하였다. 반응매체를 45분간 0-5℃에서 교반시킨 후에 4.6g의 1-싸이클로프로필메틸-3-아미노-피롤리딘(0.033몰)을 적가하였다. 매체를 2시간 동안 반응시켰다.7.3 g 2-methoxy-5-ethylsulfonylbenzoic acid, 70 ml acetone, 10 ml water and 4 g triethylamine were added to a 250 ml flask equipped with a stirrer, thermometer and dropping funnel. The solution was cooled to about 0 ° C. and 4.2 g of isobutyl chloroformate was added dropwise. The reaction medium was stirred at 0-5 ° C. for 45 minutes and then 4.6 g of 1-cyclopropylmethyl-3-amino-pyrrolidine (0.033 mol) was added dropwise. The medium was reacted for 2 hours.
50ml의 물 및 5ml의 40% 소다알카리액을 가하였다. 아세톤을 진공하에서 증발시켜서 얻어진 현탁액을 50ml의 메틸렌 클로라이드로 2번 추출하였다. 유기상을 마그네슘 설페이트상에서 건조시키고 여과하여 용매를 진공하에서 증발시켰다. 잔사오일을 80ml의 이소프로판올에 용해시켰다. 7ml의 염산성에탄올
[실시예 53]Example 53
N-(1-싸이클로프로필메틸-3-피롤리디닐 메틸)-2-메톡시-5-설파모일 벤즈아미드N- (1-cyclopropylmethyl-3-pyrrolidinyl methyl) -2-methoxy-5-sulfamoyl benzamide
5.8g의 2-메톡시-5-설파모일 벤조산, 50ml의 아세톤, 10ml의 물 및 3.6ml의 트리에틸아민(비중 0.726)을 교반기, 온도계 및 적하깔대기가 장착되어 있는 250ml 용량의 플라스크에 가하였다. 용액을 약 10℃로 냉각시킨 후에, 3.6g의 이소부틸클로로포르메이트를 적가하였다 .매체를 30분간 0℃에서 반응시킨 후에 4.5g의 1-싸이클로프로필메틸-2-아미노-피롤리딘을 적가하여 주입하였다. 매체를 1시간동안 실온에서 반응시키고, 50ml의 물을 가하고 아세톤을 진공하에서 증발시켰다. 반응매체를 50ml의 물로 더욱5.8 g of 2-methoxy-5-sulfamoyl benzoic acid, 50 ml of acetone, 10 ml of water and 3.6 ml of triethylamine (specific gravity 0.726) were added to a 250 ml flask equipped with a stirrer, thermometer and dropping funnel. . After cooling the solution to about 10 ° C., 3.6 g of isobutylchloroformate was added dropwise. 4.5 g of 1-cyclopropylmethyl-2-amino-pyrrolidine was added dropwise after the medium was reacted at 0 ° C. for 30 minutes. By injection. The medium was allowed to react for 1 hour at room temperature, 50 ml of water was added and the acetone was evaporated in vacuo. Add 50 ml of water to the reaction medium
[실시예 54]Example 54
N-(1-싸이클로옥틸-2-피롤리디닐 메틸)-2,4-디메톡시-5-메틸-설포닐 벤즈아미드N- (1-cyclooctyl-2-pyrrolidinyl methyl) -2,4-dimethoxy-5-methyl-sulfonyl benzamide
13g의 2,4-디메톡시-5-메틸설포닐 벤조산, 150ml의 아세톤, 28ml의 물 및 7ml의 트리에틸아민(비중 0.726)을 교반기, 온도계, 냉각기 및 적하깔대기가 장착되어 있는 250ml 용량의 플라스크에 가하였다. 현탁액을 0-5℃로 냉각시키고 5.4g의 에틸클로로 포르메이트를 적가하였다. 혼합물을 45분간 실온에서 교반하고 약 0℃로 냉각시켰다. 13.8g의 1-싸이클로옥틸-2-아미노메틸-피롤리딘을 적가 하였다. 완전히 용해 시켰다. 반응매체를 실온에서 교반시킨 후에 방치하였다. 용매를 진공하에서 건조시키고 잔사를 100ml의 물 및 20ml의 염산(비중 1.18)에 용해시켰다. 유기상을 50ml의 메틸렌 클로라이드로 3번 추출하여, 마그네슘 설페이트상에서 건조시키고 여과하여 진공하에서 증발시켜건조 시켰다. 잔사를 100ml의 물에 용해시켰다. 용액을 카본블랙의 존재하에서 여과하여, 여액을 10ml의 암모니아로 알카리성으로 만들었다. 검을 침전시켜 50ml의 메틸렌 클로라이드로 3번 추출하고 유기용액을 50ml의 물로 2번 세척하고 마그네슘설페이트상에서 건조시켰다. 이를 여과하고, 용매를 진공하에서 증발시킨 후에 잔사를 200ml의 이소프로판올에서 재결정시켰다. 결정을 여별하고 소량의 냉각된 이소프로판올로 2번 세척하여 50℃의 오븐에서 건조시켰다. 수율 14.2g(63%) 융점 158-159℃250 ml flask with 13 g 2,4-dimethoxy-5-methylsulfonyl benzoic acid, 150 ml acetone, 28 ml water and 7 ml triethylamine (specific gravity 0.726) equipped with a stirrer, thermometer, cooler and dropping funnel Was added. The suspension was cooled to 0-5 ° C. and 5.4 g ethylchloro formate was added dropwise. The mixture was stirred for 45 minutes at room temperature and cooled to about 0 ° C. 13.8 g of 1-cyclooctyl-2-aminomethyl-pyrrolidine was added dropwise. Completely dissolved. The reaction medium was left to stir at room temperature. The solvent was dried under vacuum and the residue was dissolved in 100 ml of water and 20 ml of hydrochloric acid (specific gravity 1.18). The organic phase was extracted three times with 50 ml of methylene chloride, dried over magnesium sulfate, filtered and evaporated to dryness in vacuo. The residue was dissolved in 100 ml of water. The solution was filtered in the presence of carbon black, and the filtrate was alkaline with 10 ml of ammonia. The gum was precipitated and extracted three times with 50 ml of methylene chloride and the organic solution was washed twice with 50 ml of water and dried over magnesium sulfate. It was filtered and the solvent was evaporated under vacuum and the residue was recrystallized in 200 ml of isopropanol. The crystals were filtered off and washed twice with a small amount of cooled isopropanol and dried in an oven at 50 ° C. Yield 14.2 g (63%) Melting Point 158-159 ° C
[실시예 55]Example 55
N-(1-사이클로펜틸-2-피롤리디닐 메틸)-2,4-디메톡시-5-메틸설포닐 벤즈아미드N- (1-cyclopentyl-2-pyrrolidinyl methyl) -2,4-dimethoxy-5-methylsulfonyl benzamide
91g의 2,4-디메톡시-5-메틸설포닐 벤조산, 400ml의 아세톤, 130ml의 물 및 48.6ml의 트리에틸아민을 교반기, 온도계 및 적하깔대기가 장착되어 있는 1ℓ 용량의 플라스크에 가하였다. 약 10℃에서 47.6g의 이소부틸 클로로 포르메이트를 얻어진 용액에 적가하였다. 40분간 교반시킨 후에 58.5g의 1-싸이클로펜틸-2-아미노메틸-피롤리딘을 약 0℃에서 적가하여 주입하였다. 침전은 실온에서 교반 30분 후에 나타났다. 반응하도록 방치시킨 후에 침전을 여별하고 물로 세척하여 건조시켰다. 74g의 조잡한 생성물들을 얻었다. 융점 198℃91 g of 2,4-dimethoxy-5-methylsulfonyl benzoic acid, 400 ml of acetone, 130 ml of water and 48.6 ml of triethylamine were added to a 1 L flask equipped with a stirrer, thermometer and dropping funnel. 47.6 g of isobutyl chloro formate was added dropwise to the obtained solution at about 10 ° C. After stirring for 40 minutes, 58.5 g of 1-cyclopentyl-2-aminomethyl-pyrrolidine was added dropwise at about 0 ° C. Precipitation appeared after 30 minutes of stirring at room temperature. After allowing to react, the precipitate was filtered off, washed with water and dried. 74 g of crude products were obtained. Melting Point 198 ℃
여액을 진공하에서 증발시키고 건조 시켰다. 잔사를 200ml의 물 및 20ml의 소다알카리액에 용해시켰다. 불용성 생성물을 여별하고 물로 세척하여 오븐에서 건조시켰다. 최종 생성물의 중량 47gThe filtrate was evaporated in vacuo and dried. The residue was dissolved in 200 ml of water and 20 ml of soda alkaline solution. Insoluble product was filtered off, washed with water and dried in an oven. 47 g weight of final product
첫번째 및 두번째 생성물의 혼합물을 40ml의 염산(비중 1.18)을 함유하는 1,300ml의 물에 용해시켰다. 용액을 5g의 목탄의 존재하에 여과하고 생성물을 45ml의 소다알카리액을 가하여 재 침전시켰다. 검을 형성시키고 서서히 결정시켰다. 생성물을 여별하고 물로 세척하여 60℃의 오븐에서 건조시켰다. 95g의 아미드를 얻었다.The mixture of the first and second product was dissolved in 1,300 ml of water containing 40 ml of hydrochloric acid (specific gravity 1.18). The solution was filtered in the presence of 5 g of charcoal and the product was reprecipitated by adding 45 ml of soda alkaline solution. A gum was formed and slowly determined. The product was filtered and washed with water and dried in an oven at 60 ° C. 95 g of amide was obtained.
결정을 2,500ml의 비등아세토 니트릴에 용해시켰다. 용액을 여과하고 냉각기에서 냉각시켰다. 침전을 배수하고, 소량의 아세토 니트릴로 세척한 후에 물로 세척하고 50℃의 오븐에서 건조시켰다.The crystals were dissolved in 2,500 ml of boiling acetonitrile. The solution was filtered and cooled in a cooler. The precipitate was drained and washed with a small amount of acetonitrile followed by water and dried in an oven at 50 ° C.
73g(51%)의 생성물을 얻었다. 융점 212℃73 g (51%) of product was obtained. Melting point 212 ℃
본 발명의 생성물은 캡슐, 정제, 환약, 과립형태 또는 주사할 수 있는 용액의 형태로 사용된다; 이들의 조제는 본질적으로 공지된 것이다. 본 발명의 화합물에 대하여 불활성인 물질은 예컨대 락토오스, 마그네슘 스테아린산염, 전분, 활석, 셀룰로오스, 레비리트, 알카리금속 라우릴-설페이트, 사카로스 및 약의 제조에 일반적으로 사용되는 부형제로 사용될 수 있다.The products of the invention are used in the form of capsules, tablets, pills, granules or injectable solutions; Their preparation is known per se. Inerts to the compounds of the present invention can be used as excipients which are commonly used in the manufacture of, for example, lactose, magnesium stearate, starch, talc, cellulose, levirite, alkali metal lauryl-sulfate, saccharose and drugs.
화합물을 한번 또는 그 이상의 단계로 하루에 50-750ml의 량을 취하여 투여할 수 있다. 제약학적 제조에 관한 다음의 실시예는 본 발명의 화합 물로부터 통상적인 방법으로 제조된다.The compound may be administered in an amount of 50-750 ml per day, in one or more steps. The following examples of pharmaceutical preparation are prepared by conventional methods from the compounds of the present invention.
[실시예 56]-정제(1정제당)Example 56 Tablet (per tablet)
[실시예 57]-캡슐(1정제당)Example 57 Capsules (per tablet)
[실시예 58]-주사용 용액(2ml당)Example 58 Injection Solution (per 2 ml)
[실시예 59]-주사용 용액(2ml당)Example 59 Injection Solution (per 2 ml)
정제로 조제하기 위하여 선택된 화합물을 계속적으로 희석하여 전분 및 락토오스와 혼합시켰다; 혼합물을 메틸셀룰로오스와 함께 과립하였다. 레비리트, 스테아린산 마그네슘 및 활석을 압축시키기 전에 과립에 가하였다.Compounds selected for preparation into tablets were continuously diluted and mixed with starch and lactose; The mixture was granulated with methylcellulose. Levirite, magnesium stearate and talc were added to the granules before compacting.
메틸셀룰로오스대신에 다른 적당한 과립제 예컨대 에틸셀룰로오스, 폴리비닐 피롤리돈 또는 전분 페이스트를 쓸 수 있다. 스테아린산 마그네슘 대신에 스테아린산을 쓸 수 있다. 주사용 용액을 제조할 때에는, 본 발명의 화합물을 다음의 산에서 용해 시킬수 있다; 예컨데 염산 또는 레불린산, 글루콘산, 또는 글루코헵톤산등이 있다.Instead of methylcellulose other suitable granules such as ethylcellulose, polyvinyl pyrrolidone or starch paste can be used. Stearic acid can be used instead of magnesium stearate. When preparing injectable solutions, the compounds of the present invention can be dissolved in the following acids; For example hydrochloric or levulinic acid, gluconic acid, or glucoheptonic acid.
용액은 무균 조건하에서 제조하고, 소디움 클로라이드와 같은 알카리금속 클로라이드 등장성(isotonic)으로 만든 후에 방부제를 가하였다. 또한 어떤 방부제의 첨가 없이도 동일용액을 제조할 수 있다; 앰풀을 질소하에서 충전시킨 후에 1/2시간 동안 100℃에서 살균시켰다. 본 발명의 화합물에 대한 약리학적시험 및 특히 이들 화합물의제토력의 연구(개에 피하 투여되는 아포모르핀에 대한 길항작용이 동일개의 공지의 화합물보다 5-20배 크다)로 중추신경계에 강한 효력을 갖는다고 생각된다. 그들의 저독성 및 강직증과 같은 바람직하지 못한 부작용이 없으므로 일반적으로 특히 중요하다.The solution was prepared under aseptic conditions and made into an alkali metal chloride isotonic, such as sodium chloride, followed by the addition of preservatives. It is also possible to prepare the same solution without the addition of any preservatives; Ampoules were filled under nitrogen and then sterilized at 100 ° C. for 1/2 hour. Pharmacological tests on the compounds of the present invention and in particular the study of the potency of these compounds (antagonism of apomorphine administered subcutaneously to dogs is 5-20 times greater than the same known compounds) have a strong effect on the central nervous system. It is thought to have. This is generally of particular importance since there are no undesirable side effects such as their low toxicity and anemia.
본 발명 화합물의 급성 독성은 생쥐에서 연구되었는데 치사량 50을 다음표에 기재하였다.Acute toxicity of the compounds of the present invention was studied in mice, where lethal dose 50 is described in the following table.
수컷쥐에 대한 LD50(mg/kg)LD 50 (mg / kg) for male rats
화합물 1:N-(1-싸이클로프로필메틸-2-피롤리디닐메틸)-2,3-디메톡시-5-설파모일 벤즈아미드Compound 1: N- (1-cyclopropylmethyl-2-pyrrolidinylmethyl) -2,3-dimethoxy-5-sulfamoyl benzamide
화합물 2:N-(1-싸이클로프로필메틸-2-피롤리디닐메틸)-2-메톡시-4-아미노-5-메틸설포닐벤즈아미드Compound 2: N- (1-cyclopropylmethyl-2-pyrrolidinylmethyl) -2-methoxy-4-amino-5-methylsulfonylbenzamide
화합물 3:N-(1-싸이클로프로필-2-피롤리디닐메틸)-2-메톡시-5-설파모일 벤즈아미드Compound 3: N- (1-cyclopropyl-2-pyrrolidinylmethyl) -2-methoxy-5-sulfamoyl benzamide
화합물 4:N-(1-싸이클로펜틸-2-피롤리디닐메틸)-2-메톡시-5-설파모일 벤즈아미드Compound 4: N- (1-cyclopentyl-2-pyrrolidinylmethyl) -2-methoxy-5-sulfamoyl benzamide
화합물5:N-(1-사이클로헥실-2-피롤리디닐메틸)-2-메톡시-5-설파모일 벤즈아미드Compound 5: N- (1-cyclohexyl-2-pyrrolidinylmethyl) -2-methoxy-5-sulfamoyl benzamide
화합물 6:N-(1-싸이클로헥실-2-피롤리디닐메틸)-2-메톡시-4-아미노-5-에틸설포닐 벤즈아미드Compound 6: N- (1-cyclohexyl-2-pyrrolidinylmethyl) -2-methoxy-4-amino-5-ethylsulfonyl benzamide
화합물 7:N-(1-싸이클로헥실-2-피롤리디닐메틸)-2,3-디메톡시-5-메틸설파모일 벤즈아미드Compound 7: N- (1-cyclohexyl-2-pyrrolidinylmethyl) -2,3-dimethoxy-5-methylsulfamoyl benzamide
화합물 8:N-(1-싸이클로헥실-2-피롤리디닐메틸)-2-메톡시-4-아미노-5-클로로 벤즈아미드Compound 8: N- (1-cyclohexyl-2-pyrrolidinylmethyl) -2-methoxy-4-amino-5-chloro benzamide
화합물 9:N-(1-싸이클로헥실-2-피롤리디닐메틸)-2-메톡시-5-메틸설파모일 벤즈아미드Compound 9: N- (1-cyclohexyl-2-pyrrolidinylmethyl) -2-methoxy-5-methylsulfamoyl benzamide
화합물 10:N-(1-싸이클로헥실-2-피롤리디닐메틸)-2-메톡시-4,5-아지미도 벤즈아미드Compound 10: N- (1-cyclohexyl-2-pyrrolidinylmethyl) -2-methoxy-4,5-azimido benzamide
화합물 11:N-(1-싸이클로헥실-2-피롤리디닐메틸)-2-프로파르길옥시-3,5-디클로로 벤즈아미드Compound 11: N- (1-cyclohexyl-2-pyrrolidinylmethyl) -2-propargyloxy-3,5-dichloro benzamide
화합물 12:N-(1-(1'-아다만틸)-2-피롤리디닐메틸)-2-메톡시-5-메틸설포닐 벤즈아미드Compound 12: N- (1- (1'-adamantyl) -2-pyrrolidinylmethyl) -2-methoxy-5-methylsulfonyl benzamide
화합물 13:N-(1-(1'-아다만틸)-2-피롤리디닐메틸)-2-메톡시-5-설파모일 벤즈아미드Compound 13: N- (1- (1'-adamantyl) -2-pyrrolidinylmethyl) -2-methoxy-5-sulfamoyl benzamide
화합물 14:N-(1-(1'-아다만틸)-2-피롤리디닐메틸)-2-메톡시-5-에틸설포닐 벤즈아미드Compound 14: N- (1- (1'-adamantyl) -2-pyrrolidinylmethyl) -2-methoxy-5-ethylsulfonyl benzamide
화합물 15:N-(1-(1'-아다만틸)-2-피롤리디닐메틸)-2-메톡시-4,5-아지미도 벤즈아미드Compound 15: N- (1- (1'-adamantyl) -2-pyrrolidinylmethyl) -2-methoxy-4,5-azimido benzamide
화합물 16:N-(1-싸이클로헵틸-2-피롤리디닐메틸)-2-메톡시-5-메틸설포닐 벤즈아미드Compound 16: N- (1-cycloheptyl-2-pyrrolidinylmethyl) -2-methoxy-5-methylsulfonyl benzamide
화합물 17:N-(1-싸이클로헥실메탈-3-피롤리디닐)-2-메톡시-5-메틸설포닐 벤즈아미드Compound 17: N- (1-cyclohexylmetal-3-pyrrolidinyl) -2-methoxy-5-methylsulfonyl benzamide
화합물 18:N-(1-싸이클로헥실-2-피롤리디닐메틸)-2-메톡시-4-아미노-5-메틸설파모일 벤즈아미드Compound 18: N- (1-cyclohexyl-2-pyrrolidinylmethyl) -2-methoxy-4-amino-5-methylsulfamoyl benzamide
화합물 19:N-(1-싸이클로프로필메틸-3-피롤리디닐)-2-메톡시-5-설파모일 벤즈아미드Compound 19: N- (1-cyclopropylmethyl-3-pyrrolidinyl) -2-methoxy-5-sulfamoyl benzamide
화합물 20:N-(1-싸이클로펜틸-2-피롤리디닐메틸)-2-메톡시-4-클로로-5-에틸설포닐 벤즈아미드Compound 20: N- (1-cyclopentyl-2-pyrrolidinylmethyl) -2-methoxy-4-chloro-5-ethylsulfonyl benzamide
화합물 21:N-(1-싸이클로펜틸-2-피롤리디닐메틸)-2-메톡시-4-클로로-5-에틸설포닐 벤즈아미드Compound 21: N- (1-cyclopentyl-2-pyrrolidinylmethyl) -2-methoxy-4-chloro-5-ethylsulfonyl benzamide
화합물 22:N-(1-싸이클로헥실메틸-2-피롤리디닐메틸)-2-메톡시-4-아미노-5-에틸설포닐 벤즈아미드Compound 22: N- (1-cyclohexylmethyl-2-pyrrolidinylmethyl) -2-methoxy-4-amino-5-ethylsulfonyl benzamide
화합물 23:N-(1-(2'-노르보르닐)-2-피롤리디닐메틸)-2-메톡시-4-아미노-5-에틸설포닐 벤즈아미드Compound 23: N- (1- (2'-norbornyl) -2-pyrrolidinylmethyl) -2-methoxy-4-amino-5-ethylsulfonyl benzamide
아포모르핀에 대한 항구토력을 Chen 및 Ensor. 방법에 의해 개에서 측정하였다.The port of defense against apomorphine is Chen and Ensor. It was measured in dogs by the method.
본 발명의 화합물을 아포모르핀에 피하 투여하기 30분전에 10㎍/kg의 투여량으로 피하 투여하여 다음의 결과를 얻었다.The compound of the present invention was administered subcutaneously at a dose of 10 µg / kg 30 minutes before subcutaneous administration to apomorphine to obtain the following results.
개에 대한 피하투여 ED50(㎍/ㅏㅎ)Subcutaneous administration ED 50 (㎍ / ㅏㅎ) for dogs
본 발명의 화합물은 사실상 강직 작용이 없다. 벤즈아미드를 수컷쥐에 피하투여 하였다. 강직상태에 대한 기준은 4cm 높이의 나무상자에 조심스럽게 놓았을 때 익숙치 못하고 편안하지 않은 자세로 놓여지게 되어 쥐가 뒷다리를 따로 따로 30초 동안 움직일 수 없는 상태이다. 강직 작용은 효과가 최대일 때, 즉 생성물을 투여후 5-6시간 후에 측정하였다.The compounds of the present invention have virtually no tonic action. Benzamide was administered subcutaneously to male rats. The criterion for stiffness is that, when carefully placed in a 4cm high wooden box, it is placed in an unfamiliar and uncomfortable position, so that the rat cannot move the hind legs separately for 30 seconds. The degradation action was measured when the effect was at its maximum, ie 5-6 hours after administration of the product.
투여량 100mg/kg에서 화합물 2, 5, 6, 9, 10, 13, 15, 18, 19, 20, 21 및 23은 강직작용이 조금도 나타나지 않았으며 200mg/kg의 투여량에서 화합물 1, 7, 12 및 14는 동물의 10%에 강직상태가 나타났다.Compounds 2, 5, 6, 9, 10, 13, 15, 18, 19, 20, 21, and 23 showed no degradation at 100 mg / kg and Compound 1, 7, at 200 mg / kg. 12 and 14 were stiff in 10% of the animals.
Claims (1)
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| KR1019790000155A KR830001276B1 (en) | 1979-01-19 | 1979-01-19 | Method for preparing substituted heterocycle benzamide |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| KR1019790000155A KR830001276B1 (en) | 1979-01-19 | 1979-01-19 | Method for preparing substituted heterocycle benzamide |
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| Publication Number | Publication Date |
|---|---|
| KR830001276B1 true KR830001276B1 (en) | 1983-07-01 |
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| KR1019790000155A KR830001276B1 (en) | 1979-01-19 | 1979-01-19 | Method for preparing substituted heterocycle benzamide |
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|---|---|
| KR (1) | KR830001276B1 (en) |
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1979
- 1979-01-19 KR KR1019790000155A patent/KR830001276B1/en active
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