NO148374B - PROCEDURE FOR THE PREPARATION OF 9- (2,6-DIHALOGENBENZYL) -ADENINES - Google Patents
PROCEDURE FOR THE PREPARATION OF 9- (2,6-DIHALOGENBENZYL) -ADENINESInfo
- Publication number
- NO148374B NO148374B NO780284A NO780284A NO148374B NO 148374 B NO148374 B NO 148374B NO 780284 A NO780284 A NO 780284A NO 780284 A NO780284 A NO 780284A NO 148374 B NO148374 B NO 148374B
- Authority
- NO
- Norway
- Prior art keywords
- residue
- formula
- hydroxy
- group
- benzenesulfonyl
- Prior art date
Links
- 238000000034 method Methods 0.000 title claims description 15
- 238000002360 preparation method Methods 0.000 title claims description 5
- 238000006243 chemical reaction Methods 0.000 claims description 13
- -1 hydroxybenzenesulfonylurea Chemical compound 0.000 claims description 13
- 150000003839 salts Chemical class 0.000 claims description 11
- 235000013877 carbamide Nutrition 0.000 claims description 9
- 125000006239 protecting group Chemical group 0.000 claims description 8
- 125000000217 alkyl group Chemical group 0.000 claims description 6
- 150000001412 amines Chemical class 0.000 claims description 6
- 239000012948 isocyanate Substances 0.000 claims description 6
- 125000002252 acyl group Chemical group 0.000 claims description 5
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 5
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 5
- 150000002513 isocyanates Chemical class 0.000 claims description 5
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 5
- 150000003672 ureas Chemical class 0.000 claims description 5
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 claims description 4
- 239000002253 acid Substances 0.000 claims description 4
- 125000001931 aliphatic group Chemical group 0.000 claims description 4
- 239000004202 carbamide Substances 0.000 claims description 4
- 229940112021 centrally acting muscle relaxants carbamic acid ester Drugs 0.000 claims description 4
- 150000001714 carbamic acid halides Chemical class 0.000 claims description 3
- 150000002148 esters Chemical class 0.000 claims description 3
- JOYRKODLDBILNP-UHFFFAOYSA-N urethane group Chemical group NC(=O)OCC JOYRKODLDBILNP-UHFFFAOYSA-N 0.000 claims description 3
- IULJSGIJJZZUMF-UHFFFAOYSA-N 2-hydroxybenzenesulfonic acid Chemical class OC1=CC=CC=C1S(O)(=O)=O IULJSGIJJZZUMF-UHFFFAOYSA-N 0.000 claims description 2
- 125000003118 aryl group Chemical group 0.000 claims description 2
- GEYWNEMSQYTCSK-UHFFFAOYSA-N benzenesulfonyl(hydroxy)carbamic acid Chemical class ON(C(O)=O)S(=O)(=O)C1=CC=CC=C1 GEYWNEMSQYTCSK-UHFFFAOYSA-N 0.000 claims description 2
- VYNLZVGCOCVFAQ-UHFFFAOYSA-N benzenesulfonyl(hydroxy)carbamothioic S-acid Chemical class ON(C(O)=S)S(=O)(=O)C1=CC=CC=C1 VYNLZVGCOCVFAQ-UHFFFAOYSA-N 0.000 claims description 2
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical group OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 claims description 2
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 2
- FZUZBOMGVBKFBG-UHFFFAOYSA-N n-(oxomethylidene)-2-phenylmethoxybenzenesulfonamide Chemical class O=C=NS(=O)(=O)C1=CC=CC=C1OCC1=CC=CC=C1 FZUZBOMGVBKFBG-UHFFFAOYSA-N 0.000 claims description 2
- GYHSDCAQMDKVKI-SFHVURJKSA-N n-cyclopropyl-4-hydroxy-n-[(2r)-2-hydroxy-2-phenylpropyl]benzenesulfonamide Chemical compound C([C@@](O)(C)C=1C=CC=CC=1)N(S(=O)(=O)C=1C=CC(O)=CC=1)C1CC1 GYHSDCAQMDKVKI-SFHVURJKSA-N 0.000 claims description 2
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 2
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 claims description 2
- 125000004432 carbon atom Chemical group C* 0.000 claims 1
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 27
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 24
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 18
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 18
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 14
- 239000000047 product Substances 0.000 description 14
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 12
- 239000000243 solution Substances 0.000 description 12
- JEICAUJOTCALLH-UHFFFAOYSA-N 1-cyclohexyl-3-(4-hydroxyphenyl)sulfonylurea Chemical compound OC1=CC=C(C=C1)S(=O)(=O)NC(=O)NC1CCCCC1 JEICAUJOTCALLH-UHFFFAOYSA-N 0.000 description 11
- 238000002844 melting Methods 0.000 description 11
- 230000008018 melting Effects 0.000 description 11
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 11
- PAFZNILMFXTMIY-UHFFFAOYSA-N cyclohexylamine Chemical compound NC1CCCCC1 PAFZNILMFXTMIY-UHFFFAOYSA-N 0.000 description 10
- WUESWDIHTKHGQA-UHFFFAOYSA-N cyclohexylurea Chemical compound NC(=O)NC1CCCCC1 WUESWDIHTKHGQA-UHFFFAOYSA-N 0.000 description 9
- DIRCLGLKRZLKHG-UHFFFAOYSA-N 4-hydroxybenzenesulfonamide Chemical compound NS(=O)(=O)C1=CC=C(O)C=C1 DIRCLGLKRZLKHG-UHFFFAOYSA-N 0.000 description 8
- 239000003610 charcoal Substances 0.000 description 8
- 239000000155 melt Substances 0.000 description 8
- 235000011121 sodium hydroxide Nutrition 0.000 description 8
- 229910021529 ammonia Inorganic materials 0.000 description 7
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 6
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 6
- 150000001875 compounds Chemical class 0.000 description 6
- 229910000027 potassium carbonate Inorganic materials 0.000 description 6
- 238000001953 recrystallisation Methods 0.000 description 6
- 238000003756 stirring Methods 0.000 description 6
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 5
- 238000001816 cooling Methods 0.000 description 5
- 239000000706 filtrate Substances 0.000 description 5
- 239000002244 precipitate Substances 0.000 description 5
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 4
- XXROGKLTLUQVRX-UHFFFAOYSA-N allyl alcohol Chemical compound OCC=C XXROGKLTLUQVRX-UHFFFAOYSA-N 0.000 description 4
- 239000008280 blood Substances 0.000 description 4
- 210000004369 blood Anatomy 0.000 description 4
- 239000007795 chemical reaction product Substances 0.000 description 4
- 230000000694 effects Effects 0.000 description 4
- 238000004519 manufacturing process Methods 0.000 description 4
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- 206010067125 Liver injury Diseases 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- VXVVUHQULXCUPF-UHFFFAOYSA-N cycloheptanamine Chemical compound NC1CCCCCC1 VXVVUHQULXCUPF-UHFFFAOYSA-N 0.000 description 3
- 238000001035 drying Methods 0.000 description 3
- 231100000234 hepatic damage Toxicity 0.000 description 3
- 210000004185 liver Anatomy 0.000 description 3
- 230000008818 liver damage Effects 0.000 description 3
- 230000001681 protective effect Effects 0.000 description 3
- 239000011541 reaction mixture Substances 0.000 description 3
- ATANGCPKQSWNGR-UHFFFAOYSA-N (4-hydroxyphenyl)sulfonylurea Chemical compound OC1=CC=C(C=C1)S(=O)(=O)NC(=O)N ATANGCPKQSWNGR-UHFFFAOYSA-N 0.000 description 2
- HWUDQLQVYFTXEO-UHFFFAOYSA-N 3-cyclohexyl-1,1-diphenylurea Chemical compound C=1C=CC=CC=1N(C=1C=CC=CC=1)C(=O)NC1CCCCC1 HWUDQLQVYFTXEO-UHFFFAOYSA-N 0.000 description 2
- KSMVBYPXNKCPAJ-UHFFFAOYSA-N 4-Methylcyclohexylamine Chemical compound CC1CCC(N)CC1 KSMVBYPXNKCPAJ-UHFFFAOYSA-N 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Chemical compound OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 2
- 241000700159 Rattus Species 0.000 description 2
- JIBJQONHKOUNIW-UHFFFAOYSA-N [4-[ethoxycarbonyl(methyl)sulfamoyl]phenyl] acetate Chemical compound C(C)(=O)OC1=CC=C(C=C1)S(=O)(=O)N(C(=O)OCC)C JIBJQONHKOUNIW-UHFFFAOYSA-N 0.000 description 2
- 229960000583 acetic acid Drugs 0.000 description 2
- 239000003513 alkali Substances 0.000 description 2
- 238000009835 boiling Methods 0.000 description 2
- VDTNNGKXZGSZIP-UHFFFAOYSA-N carbutamide Chemical compound CCCCNC(=O)NS(=O)(=O)C1=CC=C(N)C=C1 VDTNNGKXZGSZIP-UHFFFAOYSA-N 0.000 description 2
- 230000000973 chemotherapeutic effect Effects 0.000 description 2
- KQWGXHWJMSMDJJ-UHFFFAOYSA-N cyclohexyl isocyanate Chemical compound O=C=NC1CCCCC1 KQWGXHWJMSMDJJ-UHFFFAOYSA-N 0.000 description 2
- NISGSNTVMOOSJQ-UHFFFAOYSA-N cyclopentanamine Chemical compound NC1CCCC1 NISGSNTVMOOSJQ-UHFFFAOYSA-N 0.000 description 2
- DMBHHRLKUKUOEG-UHFFFAOYSA-N diphenylamine Chemical compound C=1C=CC=CC=1NC1=CC=CC=C1 DMBHHRLKUKUOEG-UHFFFAOYSA-N 0.000 description 2
- NCXFVCBNKIOMTG-UHFFFAOYSA-N ethyl N-(4-hydroxyphenyl)sulfonyl-N-methylcarbamate Chemical compound OC1=CC=C(C=C1)S(=O)(=O)N(C(=O)OCC)C NCXFVCBNKIOMTG-UHFFFAOYSA-N 0.000 description 2
- 230000007062 hydrolysis Effects 0.000 description 2
- 238000006460 hydrolysis reaction Methods 0.000 description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- XMJHPCRAQCTCFT-UHFFFAOYSA-N methyl chloroformate Chemical group COC(Cl)=O XMJHPCRAQCTCFT-UHFFFAOYSA-N 0.000 description 2
- 239000003921 oil Substances 0.000 description 2
- 235000019198 oils Nutrition 0.000 description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- ZEEVUCZSBNXSDF-UHFFFAOYSA-N (4-sulfamoylphenyl) acetate Chemical compound CC(=O)OC1=CC=C(S(N)(=O)=O)C=C1 ZEEVUCZSBNXSDF-UHFFFAOYSA-N 0.000 description 1
- IPTMXQAHRWNVME-UHFFFAOYSA-N 1-(4-hydroxyphenyl)sulfonyl-3-(4-methylcyclohexyl)urea Chemical compound OC1=CC=C(C=C1)S(=O)(=O)NC(=O)NC1CCC(CC1)C IPTMXQAHRWNVME-UHFFFAOYSA-N 0.000 description 1
- XTOIXRVYTKSKMX-UHFFFAOYSA-N 1-cycloheptyl-3-(3-hydroxyphenyl)sulfonylurea Chemical compound OC=1C=C(C=CC1)S(=O)(=O)NC(=O)NC1CCCCCC1 XTOIXRVYTKSKMX-UHFFFAOYSA-N 0.000 description 1
- UQEMABBQTKMXJY-UHFFFAOYSA-N 1-cyclohexyl-1-(4-hydroxyphenyl)sulfonylurea Chemical compound NC(=O)N(C1CCCCC1)S(=O)(=O)C1=CC=C(O)C=C1 UQEMABBQTKMXJY-UHFFFAOYSA-N 0.000 description 1
- XYVOXPAMIONNKY-UHFFFAOYSA-N 1-cyclooctyl-3-(4-hydroxyphenyl)sulfonylurea Chemical compound OC1=CC=C(C=C1)S(=O)(=O)NC(=O)NC1CCCCCCC1 XYVOXPAMIONNKY-UHFFFAOYSA-N 0.000 description 1
- XNWFRZJHXBZDAG-UHFFFAOYSA-N 2-METHOXYETHANOL Chemical compound COCCO XNWFRZJHXBZDAG-UHFFFAOYSA-N 0.000 description 1
- MOXDGMSQFFMNHA-UHFFFAOYSA-N 2-hydroxybenzenesulfonamide Chemical class NS(=O)(=O)C1=CC=CC=C1O MOXDGMSQFFMNHA-UHFFFAOYSA-N 0.000 description 1
- FEUISMYEFPANSS-UHFFFAOYSA-N 2-methylcyclohexan-1-amine Chemical compound CC1CCCCC1N FEUISMYEFPANSS-UHFFFAOYSA-N 0.000 description 1
- JYDYHSHPBDZRPU-UHFFFAOYSA-N 3-methylcyclohexan-1-amine Chemical compound CC1CCCC(N)C1 JYDYHSHPBDZRPU-UHFFFAOYSA-N 0.000 description 1
- XKQZGGLHJYTXJA-UHFFFAOYSA-N 4-hydroxybenzenesulfonyl chloride Chemical class OC1=CC=C(S(Cl)(=O)=O)C=C1 XKQZGGLHJYTXJA-UHFFFAOYSA-N 0.000 description 1
- 241000416162 Astragalus gummifer Species 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-M Bicarbonate Chemical class OC([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-M 0.000 description 1
- POAOQQQJSWVVRL-UHFFFAOYSA-N C1CCCC(CC1)NC(=O)NS(=O)(=O)C2=CC=C(C=C2)O Chemical compound C1CCCC(CC1)NC(=O)NS(=O)(=O)C2=CC=C(C=C2)O POAOQQQJSWVVRL-UHFFFAOYSA-N 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- 108010010803 Gelatin Proteins 0.000 description 1
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- 241000283973 Oryctolagus cuniculus Species 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- 229940100389 Sulfonylurea Drugs 0.000 description 1
- JLRGJRBPOGGCBT-UHFFFAOYSA-N Tolbutamide Chemical compound CCCCNC(=O)NS(=O)(=O)C1=CC=C(C)C=C1 JLRGJRBPOGGCBT-UHFFFAOYSA-N 0.000 description 1
- 229920001615 Tragacanth Polymers 0.000 description 1
- CIUQDSCDWFSTQR-UHFFFAOYSA-N [C]1=CC=CC=C1 Chemical compound [C]1=CC=CC=C1 CIUQDSCDWFSTQR-UHFFFAOYSA-N 0.000 description 1
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 239000012670 alkaline solution Substances 0.000 description 1
- 125000004453 alkoxycarbonyl group Chemical group 0.000 description 1
- 150000001408 amides Chemical class 0.000 description 1
- 239000008346 aqueous phase Substances 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 230000003385 bacteriostatic effect Effects 0.000 description 1
- 239000002585 base Substances 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 description 1
- 125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 150000004649 carbonic acid derivatives Chemical class 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- SZGLLXJFYCJRPP-UHFFFAOYSA-N cycloheptylurea Chemical compound NC(=O)NC1CCCCCC1 SZGLLXJFYCJRPP-UHFFFAOYSA-N 0.000 description 1
- HSOHBWMXECKEKV-UHFFFAOYSA-N cyclooctanamine Chemical compound NC1CCCCCCC1 HSOHBWMXECKEKV-UHFFFAOYSA-N 0.000 description 1
- 239000008298 dragée Substances 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- IDGUHHHQCWSQLU-UHFFFAOYSA-N ethanol;hydrate Chemical compound O.CCO IDGUHHHQCWSQLU-UHFFFAOYSA-N 0.000 description 1
- 125000003754 ethoxycarbonyl group Chemical group C(=O)(OCC)* 0.000 description 1
- 235000019439 ethyl acetate Nutrition 0.000 description 1
- AOCYHPQXGJBAQQ-UHFFFAOYSA-N ethyl n-sulfonylcarbamate Chemical compound CCOC(=O)N=S(=O)=O AOCYHPQXGJBAQQ-UHFFFAOYSA-N 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- 239000012362 glacial acetic acid Substances 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- 150000004679 hydroxides Chemical class 0.000 description 1
- 229940078979 liver therapy drug Drugs 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- GBMDVOWEEQVZKZ-UHFFFAOYSA-N methanol;hydrate Chemical compound O.OC GBMDVOWEEQVZKZ-UHFFFAOYSA-N 0.000 description 1
- 125000001160 methoxycarbonyl group Chemical group [H]C([H])([H])OC(*)=O 0.000 description 1
- DCGPFYKAXLRGBP-UHFFFAOYSA-N methyl N-(4-hydroxyphenyl)sulfonylcarbamate Chemical compound COC(NS(=O)(=O)C1=CC=C(C=C1)O)=O DCGPFYKAXLRGBP-UHFFFAOYSA-N 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 150000004682 monohydrates Chemical class 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- UYWQUFXKFGHYNT-UHFFFAOYSA-N phenylmethyl ester of formic acid Natural products O=COCC1=CC=CC=C1 UYWQUFXKFGHYNT-UHFFFAOYSA-N 0.000 description 1
- GKKCIDNWFBPDBW-UHFFFAOYSA-M potassium cyanate Chemical compound [K]OC#N GKKCIDNWFBPDBW-UHFFFAOYSA-M 0.000 description 1
- 230000003449 preventive effect Effects 0.000 description 1
- 125000001501 propionyl group Chemical group O=C([*])C([H])([H])C([H])([H])[H] 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 229940124530 sulfonamide Drugs 0.000 description 1
- 150000003456 sulfonamides Chemical class 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 235000012222 talc Nutrition 0.000 description 1
- 235000010487 tragacanth Nutrition 0.000 description 1
- 239000000196 tragacanth Substances 0.000 description 1
- 229940116362 tragacanth Drugs 0.000 description 1
- 230000007306 turnover Effects 0.000 description 1
- 235000015112 vegetable and seed oil Nutrition 0.000 description 1
- 239000008158 vegetable oil Substances 0.000 description 1
- 235000021419 vinegar Nutrition 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D473/00—Heterocyclic compounds containing purine ring systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
- C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
- C07D513/04—Ortho-condensed systems
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Saccharide Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
- Preparation Of Compounds By Using Micro-Organisms (AREA)
Description
Fremgangsmåte til fremstilling av hydroksybenzolsulfonylurinstoffer. Process for the production of hydroxybenzenesulfonylureas.
Det er kjent at sulfonylurinstoffer som It is known that sulfonylureas such as
N- (4-amino-benzolsulf onyl) -N'-butyl-urinstof f N-(4-amino-benzenesulfonyl)-N'-butyl-urea f
og N- (4-metyl-benzolsulfonyl) -N'-butyl-urinstoff har en gunstig virkning ved bestemte and N-(4-methyl-benzenesulfonyl)-N'-butylurea has a beneficial effect in certain
leverskader. Disse forbindelser fører imidler-tid som allerede kjent til en sterk senkning liver damage. However, as already known, these compounds lead to a strong lowering
av blodsukkerspeilet, dessuten har N-(4-amino-benzolsulfonyl)-N'-butyl-urinstoff også of the blood sugar mirror, moreover, has N-(4-amino-benzenesulfonyl)-N'-butyl-urea as well
dessuten en i denne forbindelse uønsket bakte-riostatisk effekt. Disse forbindelser har følge-lig for generell leverterapi betraktelige ulem-per. moreover, an undesirable bacteriostatic effect in this connection. Consequently, these compounds have considerable disadvantages for general liver therapy.
Det er blitt funnet at hydroksybenzolsul-fonyl-urinstoffer med den generelle formel It has been found that hydroxybenzenesulfonyl ureas of the general formula
hvori R betyr en 5 til 8 karbonatomholdig wherein R means a 5 to 8 carbon-containing
cykloalkyl- eller cykloalkenylrest og deres cycloalkyl or cycloalkenyl radical and theirs
salter har en sterk leverbeskyttelsesvirkning salts have a strong liver protective effect
uten å senke blodsukkerspeilet eller å ha en without lowering the blood sugar level or having one
kjemoterapeutisk effekt. Oppfinnelsens gjen-stand er fremstillingen av slike hydroksybenzolsulfonylurinstoffer. chemotherapeutic effect. The object of the invention is the production of such hydroxybenzenesulfonylureas.
Fremgangsmåten ifølge oppfinnelsen er The method according to the invention is
karakterisert ved at man characterized by the fact that one
I. omsetter hydroksybenzolsulfonamidet I. reacts the hydroxybenzenesulfonamide
med formel with formula
eventuelt i form av egnede salter, possibly in the form of suitable salts,
a) med isocyanater av formel R-NCO eller b) med karbaminsyreestere av formel R-NH-COOR', hvori R' betyr en lavmolekylær alkylgruppe eller en fenylrest eller, med tilsvarende monotiokarbaminsyre-estere eller c) med karbaminsyrehalogenider av formel R-NH-CO-hal., eller d) med urinstoffer av formel R-NH-CO-NH2 som på den side av molekylet som er vendt bort fra resten R likeledes kan være substituert med resten R eller med en eller to fenylrester, som også kan være forbundet med hverandre enten direkte eller over en bro, eller som kan være substituert med en fortrinnsvis lavmolekylær alifatisk eller aromatisk acylrest eller med nitrogruppen, idet eventuelt OH-gruppen under omsetningen er beskyttet med en acyl- eller benzylrest og denne rest avspaltes etter foretatt omsetning eller at man II. omsetter aminet med formel R-NH2, eventuelt i form av deres salter, med a) hydroksybenzolsulfonyl-karbaminsyreestere med formel hvori R' betyr en lavmolekylær alkylgruppe eller en fenylrest, eller tilsvarende hydroksybenzolsulfonyl-monotiokarba-minsyreestere eller b) med hydroksybenzolsulfonylurinstoff med formel som på den side som vender bort fra urin-stoffmolekylets sulfonylgruppe er usub-stituert eller mono- eller disubstituert med alkylgrupper eller arylrester eller monosubstituert med en fortrinnsvis lavmolekylær alifatisk eller aromatisk syrerest, eller omsetter med tilsvarende bis-(hydroksy-benzolsulfonyl)-urinstoffer idet man kan gjennomføre reaksjonen også med slike hydroksybenzolsulfonsyrederivater, hvori hydroksygruppen er beskyttet med en acylrest eller med benzylgruppen og fjerner beskyttelsesgruppene hvis disse ikke allerede avspaltes under reaksjonen, eller c) omsetter med acyloksy- eller benzyloksy-benzolsulfonyl-isocyanater eller d) omsetter med acyloksy- eller benzyloksyl-benzol-sulfonyl-karbaminsyrehalogenider a) with isocyanates of the formula R-NCO or b) with carbamic acid esters of the formula R-NH-COOR', in which R' means a low molecular weight alkyl group or a phenyl radical or, with corresponding monothiocarbamic acid esters or c) with carbamic acid halides of the formula R-NH -CO-hal., or d) with ureas of the formula R-NH-CO-NH2 which, on the side of the molecule facing away from the residue R, can likewise be substituted with the residue R or with one or two phenyl residues, which can also be connected to each other either directly or via a bridge, or which may be substituted with a preferably low molecular weight aliphatic or aromatic acyl residue or with the nitro group, possibly the OH group during the reaction is protected with an acyl or benzyl residue and this residue is cleaved off after the reaction has been carried out or that one II. reacts the amine of formula R-NH2, optionally in the form of their salts, with a) hydroxybenzenesulfonyl-carbamic acid esters of formula in which R' means a low molecular weight alkyl group or a phenyl residue, or corresponding hydroxybenzenesulfonyl monothiocarbamic acid esters or b) with hydroxybenzenesulfonylurea of formula which, on the side facing away from the sulfonyl group of the urea molecule, is unsubstituted or mono- or di-substituted with alkyl groups or aryl residues or mono-substituted with a preferably low molecular weight aliphatic or aromatic acid residue, or reacts with corresponding bis-(hydroxy-benzenesulfonyl) ureas in that the reaction can also be carried out with such hydroxybenzenesulfonic acid derivatives, in which the hydroxy group is protected with an acyl residue or with the benzyl group and the protective groups are removed if these are not already split off during the reaction, or c) react with acyloxy- or benzyloxy-benzenesulfonyl isocyanates or d) react with acyloxy- or benzyloxy-benzene-sulfonyl-carbamic acid halides
og avspalter beskyttelsesgruppen, and cleaves the protecting group,
og overfører de dannede produkter eventuelt ved hjelp av baser til de tilsvarende salter. and transfers the formed products possibly using bases to the corresponding salts.
Ved fremgangsmåtene kan de som ut-gangsstoffer anvendte m- og p-hydroksyben-zolsulfonylklorider resp. de tilsvarende amider, -karbaminsyreestere, -urinstoffer anvendes så vel i fri form som også i form av forbindelser hvor hydroksygruppen er beskyttet med en senere avspaltbar rest. Som beskyttelsesgrupper anvendes fortrinnsvis acylrester som ace-tyl, propionyl, benzoyl, alkoksykarbonylrester som metoksy-karbonyl-, etoksy-karbonyl-, benzyloksy-karbonylrester så vel som benzyl-gruppene. For så vidt beskyttelsesgruppen ikke allerede avspaltes under reaksjonen kan de fjernes fra de dannede N-(acyloksy-benzol-sulfonyl)- resp. N-(benzyloksy-benzolsulfonyl)-N'-cykloalkyl-urinstoffer eller deres derivater ved hydrolyse med alkali eller syrer eller fjernes hydrogenolytisk. In the methods, the m- and p-hydroxybenzenesulfonyl chlorides used as starting materials can resp. the corresponding amides, -carbamic acid esters, -ureas are used both in free form and also in the form of compounds where the hydroxy group is protected with a later cleavable residue. Acyl residues such as acetyl, propionyl, benzoyl, alkoxycarbonyl residues such as methoxycarbonyl, ethoxycarbonyl, benzyloxycarbonyl as well as the benzyl groups are preferably used as protecting groups. As long as the protective group is not already split off during the reaction, they can be removed from the formed N-(acyloxy-benzene-sulfonyl)- or N-(benzyloxy-benzenesulfonyl)-N'-cycloalkylureas or their derivatives by hydrolysis with alkali or acids or removed hydrogenolytically.
Anvendelsen av beskyttelsesgrupper mu-liggjør som videre fremgangsmåte til fremstilling av hydroksybenzolsulfonylurinstoffer omsetningen av acylerte hydroksybenzolsul-fonylisocyanater resp. -karbaminsyrehalogenider med aminer av formel FUNrL,^eller også derivater av slike forbindelser som formylerte forbindelser. Fra de dannede produkter avspaltes beskyttelsesgruppen og den eventuelt med aminene inntrådte gruppe etterpå med hydrolyse. The use of protecting groups enables the conversion of acylated hydroxybenzenesulfony isocyanates or -carbamic acid halides with amines of the formula FUNrL,^ or also derivatives of such compounds as formylated compounds. From the products formed, the protecting group and any group introduced with the amines are subsequently removed by hydrolysis.
Som aminer kan det for omsetningen bl.a. anvendes: cyklopentylamin, cykloheksylamin, cykloheptylamin, cyklooksylamin, 2-, 3- og 4-metylcykloheksylamin, A 2-cyklopentylamin, A--cykloheksenylamin. Istedenfor de nevnte aminer kan det også anvendes de av disse fremstilte karbaminsyreestere, karbaminsyrehalogenider eller urinstoffer for reaksjonen med egnede hydroksybenzolsulfonamider. As amines, the turnover can include are used: cyclopentylamine, cyclohexylamine, cycloheptylamine, cyclooxylamine, 2-, 3- and 4-methylcyclohexylamine, A 2-cyclopentylamine, A-cyclohexenylamine. Instead of the mentioned amines, the carbamic acid esters, carbamic acid halides or ureas produced from these can also be used for the reaction with suitable hydroxybenzenesulfonamides.
Utførelsesformene av fremgangsmåten ifølge oppfinnelsen kan med hensyn til reak-sjonsbetingelser varieres vidtgående og til-passes de eventuelle forhold. Eksempelvis kan omsetningene gjennomføres under anvendelse av oppløsningsmidler ved værelsetemperatur eller ved forhøyet temperatur. The embodiments of the method according to the invention can be widely varied with regard to reaction conditions and adapted to the possible conditions. For example, the reactions can be carried out using solvents at room temperature or at an elevated temperature.
Andre fremgangsmåter til fremstilling av hydroksybenzolsulfonylurinstoffene er gjen-stand for norske patenter (pat. nr. 110 342). Other methods for the production of the hydroxybenzenesulfonylureas are the subject of Norwegian patents (pat. no. 110 342).
De benzolsulfonylurinstoffer som fåes ved fremgangsmåten ifølge oppfinnelsen er p.g.a. deres farmakologiske egenskaper verdifulle legemidler. De nye forbindelser utmerker seg spesielt ved en nekrotrop leverbeskyttelsesvirkning. Den følgende tabell viser for noen av hydrobenzolsulfonylurinstoffene fremstillet ifølge oppfinnelsen og som her er anvendt som eksempler nedsettelsen av allylalkoholens nekrosedannende virkning på rotter. Verdiene ble sammenlignet med leverbeskadigelse av lignende ikke med N-(4-hydroksybenzolsul-fonyl) -N'-cykloheksyl-urinstoff behandlede kontrolldyr. Målemetoden for leverbeskadigel-sene og virkningen av nekrotrope stoffer er beskrevet av W. Eger (sammenlign Arznei-mittelforschung 7, 601 (3 957)). The benzenesulfonylureas obtained by the method according to the invention are due to their pharmacological properties valuable drugs. The new compounds are particularly distinguished by a necrotrophic liver protective effect. The following table shows, for some of the hydrobenzenesulfonylureas produced according to the invention and which are used here as examples, the reduction of the necrosis-forming effect of allyl alcohol on rats. The values were compared with liver damage of similar control animals not treated with N-(4-hydroxybenzenesulfonyl)-N'-cyclohexylurea. The method of measuring liver damage and the effect of necrotropic substances is described by W. Eger (compare Arznei-mittelforschung 7, 601 (3 957)).
Fra tabellen fremgår det at eksempelvis N- (4-hydroksy-benzolsulf onyl) -N'-cykloheksyl-urinstoff i en dosering på 50 mg/100 g på rotter nedsetter allylalkoholens nekrosedannende virkning i preventivprøven med 65 %. I en dosering på 25 mg/100 g oppnås en nekrotrop virkning av preparatet omtrent 45 %. From the table it appears that, for example, N-(4-hydroxy-benzenesulfonyl)-N'-cyclohexyl urea in a dosage of 50 mg/100 g in rats reduces the necrosis-forming effect of allyl alcohol in the preventive test by 65%. In a dosage of 25 mg/100 g, a necrotropic effect of the preparation of approximately 45% is achieved.
Fremgangsmåteproduktene er spesielt egnet som leverbeskyttelsesstoffer da de enten ikke forårsaker noen eller bare praktisk talt ubetydelig blodsukkersenkning og heller ikke har noen kjemoterapeutisk virkning som for et sulfonamid. Eksempelvis fører den perorale administrering av 400 mg/kg med N-(4-hydroksy-benzolsulfonyl)-N'-cykloheksyl-urinstoff på kaniner ikke til noen blodsukker-speilsenkning. The process products are particularly suitable as hepatoprotectors as they either cause no or only practically negligible lowering of blood sugar and also have no chemotherapeutic effect as for a sulfonamide. For example, the peroral administration of 400 mg/kg of N-(4-hydroxy-benzenesulfonyl)-N'-cyclohexylurea to rabbits does not lead to any lowering of blood glucose levels.
Fremgangsmåteproduktene skal fortrinnsvis anvendes til fremstilling av oralt eller parenteralt administrerbare preparater med leverbeskyttelsesvirkning og kan appliseres som sådanne eller i form av salter. Til salt-dannelsen kan det eksempelvis anvendes: alkaliske midler, som alkali- eller jordalkalihydr-oksyder, -karbonater eller- bikarbonater, videre fysiologisk tålbare organiske baser. The process products are preferably used for the production of orally or parenterally administrable preparations with a liver protective effect and can be applied as such or in the form of salts. For salt formation, for example, alkaline agents, such as alkali or alkaline earth hydroxides, carbonates or bicarbonates, and physiologically tolerable organic bases can be used.
Som medisinske tilberedningsformer kan det anvendes tabletter, kapsler, drageer, opp-løsninger og suspensjoner som inneholder fremgangsmåteproduktene eller deres salter ved siden av de vanlig indifferente bære- og hjelpestoffer, som melkesukker, stivelse, gela-tin, magnesiumstearat, planteolje, talkum, tragant, vann o.l. Tablets, capsules, dragees, solutions and suspensions containing the process products or their salts in addition to the usual indifferent carrier and auxiliaries such as milk sugar, starch, gelatin, magnesium stearate, vegetable oil, talc, tragacanth can be used as medical preparation forms. , water etc.
Eksempel 1. Example 1.
N- (^- hydroksy- benzolsulfonyl) - N-(^- hydroxy- benzenesulfonyl)-
N'- cykloheksyl- urinstoff. N'-cyclohexyl urea.
34,6 g 4-hydroksy-benzolsulfonamid opp-løses i 800 ml aceton og oppvarmes etter tilsetning av 83 g malt kaliumkarbonat i en time til kokning. Nu tilsettes 25 g cykloheksylisocyanat; reaksjonsblandingen kokes ennu ytterligere i 15 timer. Etter acetonets avdestillering i vakuum oppløses det gjenblivende residuum i vann, oppløsningen klares med kull og filtratet surgjøres med fortynnet saltsyre. Det utfelte bunnfall suges fra og omkrystalliseres fra vandig metanol. Man får således N-(4-hydroksy-benzolsulfonyl)-N'-cykloheksyl-urinstoff i form av hvite krystaller med smeltepunkt 192—194°C (utbytte 37—40 g). 34.6 g of 4-hydroxybenzenesulfonamide are dissolved in 800 ml of acetone and heated after adding 83 g of ground potassium carbonate for one hour until boiling. Now add 25 g of cyclohexyl isocyanate; the reaction mixture is boiled for a further 15 hours. After the acetone has been distilled off in a vacuum, the remaining residue is dissolved in water, the solution is clarified with charcoal and the filtrate is acidified with dilute hydrochloric acid. The precipitate that has formed is sucked off and recrystallized from aqueous methanol. N-(4-hydroxy-benzenesulfonyl)-N'-cyclohexylurea is thus obtained in the form of white crystals with a melting point of 192-194°C (yield 37-40 g).
På analog måte vil man av 4-hydroksy-benzolsulfonamid og A<3->cykloheksenyl-isocyanat få N-(4-hydroksy-benzolsulf onyl-N'-( A 3-cykloheksenyl) -urinstof f, som etter omkrystallisering fra etanol og god tørkning ved 120°C smelter ved 166—168°C. In an analogous way, from 4-hydroxy-benzenesulfonamide and A<3->cyclohexenyl isocyanate, N-(4-hydroxy-benzenesulfonyl-N'-( A 3-cyclohexenyl)-urea is obtained, which after recrystallization from ethanol and good drying at 120°C melts at 166-168°C.
Eksempel 2. Example 2.
N- ( 4- hydroksy- benzolsulf onyl) - N-(4-hydroxy-benzenesulfonyl)-
N'- cykloheksyl- urinstoff. N'-cyclohexyl urea.
14,4 g N-(4-karbometoksy-oksy-benzolsulf onyl)-karbaminsyremety lester med smeltepunkt 126—130°C (fremstillet ved omsetning av 4-hydroksy-benzolsulfonamid med den 2,5 dobbelte molare mengde klormaursyremetyl- 14.4 g of N-(4-carbomethoxy-oxy-benzenesulfonyl)-carbamic acid methyl ester with a melting point of 126-130°C (produced by reacting 4-hydroxy-benzenesulfonamide with the 2.5 times the molar amount of chloroformic acid methyl
ester i nærvær av malt kaliumkarbonat og aceton) blandes med 10 g cykloheksylamin og oppvarmes i 35 minutter ved 130 °C. Reaksjonsproduktet oppløses i eddikester og opp-løsningen utrystes flere ganger med fortynnet ammoniakk (1 : 25). De samlede alkaliske opp-løsninger klargjøres med kull og filtratet sur-gjøres med fortynnet saltsyre. Det utfelte bunnfall suges fra og omkrystalliseres fra fortynnet metanol under kulltilsetning. Man får N- (4-hydroksy-benzolsulf onyl) -N'-cykloheksyl-urinstoff med smeltepunkt 192—194°C. Produktet er identisk med det etter isocyanat-metoden dannede (sammenlign eksempel 1). ester in the presence of ground potassium carbonate and acetone) is mixed with 10 g of cyclohexylamine and heated for 35 minutes at 130 °C. The reaction product is dissolved in acetic acid and the solution is shaken several times with diluted ammonia (1:25). The combined alkaline solutions are clarified with charcoal and the filtrate acidified with dilute hydrochloric acid. The precipitate that has formed is sucked off and recrystallized from diluted methanol while charcoal is added. N-(4-hydroxy-benzenesulfonyl)-N'-cyclohexyl urea with a melting point of 192-194°C is obtained. The product is identical to that formed by the isocyanate method (compare example 1).
Eksempel 3. Example 3.
N- ( lf- hydroksy- benzolsulfonyl) - N-( lf- hydroxy- benzenesulfonyl)-
N'- cykloheksyl- urinstoff. N'-cyclohexyl urea.
11,6 g N-( 4-hydroksy-benzolsulf onyl)-karbaminsyremetylester med smeltepunkt 160—162°C (fremstillet ved omsetning av 4-hydroksy-benzolsulfonamid med klormaur-syremetylester i nærvær av malt kaliumkarbonat og aceton og behandling av det først resulterende sulfonyluretan med fortynnet natronlut i varmen) sammenblandes med 5 g cykloheksylamin og oppvarmes i 45 minutter på 140—145°C. Den resulterende smelte behandler man med fortynnet ammoniakk, filtrerer fra uoppløselige deler og surgjør filtratet med fortynnet saltsyre. Det således dannede N'-(4-hydroksy-benzolsulfonyl)-N'-cykloheksyl-urinstoff smelter etter omkrystallisering fra metanol ved 192—194°C og er identisk med de etter andre metoder fremstilte produkter. 11.6 g of N-(4-hydroxy-benzenesulfonyl)-carbamic acid methyl ester with melting point 160-162°C (produced by reacting 4-hydroxy-benzenesulfonamide with chloroformic acid methyl ester in the presence of ground potassium carbonate and acetone and treating the first resulting sulphonylurethane with diluted caustic soda in the heat) is mixed with 5 g of cyclohexylamine and heated for 45 minutes at 140-145°C. The resulting melt is treated with dilute ammonia, filtered from insoluble parts and acidified with dilute hydrochloric acid. The N'-(4-hydroxy-benzenesulfonyl)-N'-cyclohexylurea thus formed melts after recrystallization from methanol at 192-194°C and is identical to the products produced by other methods.
Eksempel 4. Example 4.
N-( 4- hydroksy- benzolsulf onyl)-N'- ( 4'- metyl- cykloheksyl)- urinstoff: 21,6 g N-(4-hydroksy-benzolsulfonyl)-urinstoff med smeltepunkt 186—187°C (fremstillet ved koking av 4-hydroksy-benzolsulfonamid med kaliumcyanat i vandig etanol) kokes i 400 ml toluol og 80 ml glykolmono-metyleter under tilsetning av 6 g iseddik med 12,4 g 4-metyl-cykloheksylamin i 21/2 time under tilbakeløp. Reaksjonsproduktet utrystes med 1%-ig natronlut; de forenede vandige faser klargjøres med kull og surgjøres med fortynnet saltsyre. Det utfelte produkt opp-løses il %-ig ammoniakk, oppløsningen klares igjen med kull og filtratet surgjøres. Man frasuger det utfelte bunnfall og omkrystalliserer det for fortynnet metanol. Man får N-(4-hydroksybenzolsulf onyl) -N'- (4'-metyl- cykloheksyl-urinstoff som hemihydrat med smeltepunkt 102—104 °C i et utbytte på 12 g. N-(4-hydroxy-benzenesulfonyl)-N'-(4'-methyl-cyclohexyl)-urea: 21.6 g N-(4-hydroxy-benzenesulfonyl)-urea with melting point 186-187°C (prepared by boiling of 4-hydroxy-benzenesulfonamide with potassium cyanate in aqueous ethanol) is boiled in 400 ml of toluene and 80 ml of glycol mono-methyl ether while adding 6 g of glacial acetic acid with 12.4 g of 4-methyl-cyclohexylamine for 21/2 hours under reflux. The reaction product is shaken with 1% caustic soda; the combined aqueous phases are clarified with charcoal and acidified with dilute hydrochloric acid. The precipitated product is dissolved in 1% ammonia, the solution is clarified again with charcoal and the filtrate is acidified. The precipitate that has formed is sucked off and recrystallized from diluted methanol. This gives N-(4-hydroxybenzenesulfonyl)-N'-(4'-methyl- cyclohexylurea as hemihydrate with melting point 102-104 °C in a yield of 12 g.
På analog måte får man fra N-(4-hydroksy-benzol-sulfonyl)-urinstoff og cyklopentylamin N-(4-hydroksy-benzol-sulfonyl)-N'-cyklopentyl-urinstoff med smeltepunkt 185— 187°C (etter omkrystallisering fra eddikester) . In an analogous manner, from N-(4-hydroxy-benzenesulfonyl)-urea and cyclopentylamine N-(4-hydroxy-benzene-sulfonyl)-N'-cyclopentyl urea with a melting point of 185-187°C (after recrystallization from vinegars).
På samme måte får man ved anvendelse av cykloheptylamin N-(4-hydroksy-benzolsulfonyl)-N'-cykloheptyl-urinstoff, som smelter etter omkrystallisering fra eddikester ved 176—178° C. In the same way, using cycloheptylamine gives N-(4-hydroxy-benzenesulfonyl)-N'-cycloheptylurea, which melts after recrystallization from acetic ester at 176-178°C.
Ved anvendelse av cyklooktylamin får man etter samme metode en N-(4-hydroksy-benzolsulf onyl) -N'-cyklooktyl-urinstoff, som By using cyclooctylamine, a N-(4-hydroxy-benzenesulfonyl)-N'-cyclooctylurea is obtained by the same method, which
etter omkrystallisering fra fortynnet etanol after recrystallization from dilute ethanol
fremkommer som monohydrat og har smeltepunkt 122—124° C. appears as monohydrate and has a melting point of 122-124° C.
Eksempel 5. Example 5.
N- ( 4- hydroksy- benzolsulf onyl) - N-(4-hydroxy-benzenesulfonyl)-
N'- cykloheksyl- urinstoff. N'-cyclohexyl urea.
10,8 g 4-acetoksy-benzolsulfonamid og en oppløsning av 2 g natriumhydroksyd i 4 ml vann has i 30 ml aceton. Til oppløsningen drypper man under isavkjøling og omrøring 6,5 g cykloheksylisocyanat, etteromrører inn-til isocyanatlukten er forsvunnet, avdamper det meste av acetonet og blander residuet med vann og syre. Produktet (etter omkrystallisering (smeltepunkt 172—174°C) oppvarmes med 100 ml 2 n-natronlut i 1/2 time på dampbad, oppløsningen klares med kull, surgjøres, produktet suges fra og omkrystalliseres fra etanol/vann. N- (4-hydroksy-benzolsulf onyl) - N'-cykloheksyl-urinstoff smelter etter tørk-ning ved 100°C ved 192—194°C. 10.8 g of 4-acetoxy-benzenesulfonamide and a solution of 2 g of sodium hydroxide in 4 ml of water are dissolved in 30 ml of acetone. Add 6.5 g of cyclohexyl isocyanate to the solution under ice-cooling and stirring, stir until the isocyanate smell has disappeared, evaporate most of the acetone and mix the residue with water and acid. The product (after recrystallization (melting point 172-174°C) is heated with 100 ml of 2n sodium hydroxide solution for 1/2 hour on a steam bath, the solution is clarified with charcoal, acidified, the product is suctioned off and recrystallized from ethanol/water. N- (4- hydroxy-benzenesulfonyl) - N'-cyclohexyl-urea melts after drying at 100°C at 192-194°C.
Eksempel 6. Example 6.
N- ( 3- hydroksy- benzolsulfonyl) - N-(3-hydroxy-benzenesulfonyl)-
N'- cykloheptyl- urinstoff. N'-cycloheptyl urea.
23 g 3-hydroksy-benzolsulfonyl-karbamin-syremetylester sammenblandes med 14 g cykloheptylamin og oppvarmes i oljebad i en time ved 130 °C. Det oppstår en klar smelte, hvorfra metanol unnviker. Man lar det avkjøle, behandler produktet med omtrent 1 %-ig ammoniakk, filtrerer og surgjør. Det utfelte stoff adskilles og omkrystalliseres av vann under tilsetning av litt etanol. Det dannede N-(3-hydroksybenzolsulfonyl)-N'-cykloheptyl-urinstoff smelter ved 108—110° C, 23 g of 3-hydroxy-benzenesulfonyl-carbamic acid methyl ester are mixed with 14 g of cycloheptylamine and heated in an oil bath for one hour at 130 °C. A clear melt occurs, from which methanol escapes. It is allowed to cool, the product is treated with approximately 1% ammonia, filtered and acidified. The precipitated substance is separated and recrystallized from water while adding a little ethanol. The formed N-(3-hydroxybenzenesulfonyl)-N'-cycloheptylurea melts at 108-110° C,
Eksempel 7. Example 7.
N- f Jf- hydroksy- benzolsulfonyl) - N- f Jf- hydroxy- benzenesulfonyl) -
N'- cykloheksyl- urinstoff. N'-cyclohexyl urea.
27,3 g 4-acetoksy-benzolsulfonyl-metyl-uretan (fremstillet av 4-hydroksy-benzolsulfonyl-metyluretan og acetanhydrid i pyridin) blandes godt med 9,9 g cykloheksylamin og oppvarmes i bad i 1 time ved 130 °C. Det oppstår en klar smelte hvorfra metanolet unnviker. Man lar det avkjøle, opptar reaksjonsproduktet i 100 ml 2 n natronlut og oppvarmer i 1/2 time på dampbad. 27.3 g of 4-acetoxy-benzenesulfonyl-methyl-urethane (prepared from 4-hydroxy-benzenesulfonyl-methyl-urethane and acetic anhydride in pyridine) is mixed well with 9.9 g of cyclohexylamine and heated in a bath for 1 hour at 130 °C. A clear melt occurs from which the methanol escapes. It is allowed to cool, the reaction product is taken up in 100 ml of 2 N caustic soda and heated for 1/2 hour on a steam bath.
Oppløsningen klares med kull og surgjø-res etter avkjøling. Man frasuger det utfelte produkt og omkrystalliserer det fra etanol/ vann. N- (4-hydroksy-benzol-sulfonyl) -N'-cykloheksyl-urinstoffet har smeltepunkt 192— 194°C. The solution is clarified with charcoal and acidified after cooling. The precipitated product is suctioned off and recrystallized from ethanol/water. The N-(4-hydroxy-benzene-sulfonyl)-N'-cyclohexylurea has a melting point of 192-194°C.
Eksempel 8. Example 8.
N- ( 4- hydroksy- benzolsulf onyl) - N-(4-hydroxy-benzenesulfonyl)-
N'- cykloheksyl- urinstoff. N'-cyclohexyl urea.
17,3 g 4-hydroksy-benzolsulfonamid oppvarmes med 27,6 g pulverisert kaliumkarbonat og 250 ml dimetylformamid i 4 timer under omrøring ved 100°C. Deretter tilsettes 55,8 g N,N-difenyl-N'-cykloheksyl-urinstoff og oppvarmer under omrøring i ytterligere 4 timer ved 100 °C. Reaksjonsblandingen helles etter avkjøling i 3 i vann, oppløsningen blandes med noe fortynnet natronlut og avkjøles med is. Man filtrerer, surgjør filtratet med fortynnet saltsyre og omfeller det frasugde bunnfall fra fortynnet ammoniakk. N-(4-hydroksy-benzol-sulfonyl) -N'-cykloheksyl-urinstoff omkrystalliseres.fra metanol og smelter etter tørkning ved 192—194°C. 17.3 g of 4-hydroxybenzenesulfonamide are heated with 27.6 g of powdered potassium carbonate and 250 ml of dimethylformamide for 4 hours with stirring at 100°C. 55.8 g of N,N-diphenyl-N'-cyclohexyl urea are then added and heated with stirring for a further 4 hours at 100 °C. After cooling, the reaction mixture is poured into water, the solution is mixed with some diluted caustic soda and cooled with ice. Filter, acidify the filtrate with dilute hydrochloric acid and reprecipitate the aspirated precipitate from dilute ammonia. N-(4-hydroxy-benzene-sulfonyl)-N'-cyclohexyl-urea is recrystallized from methanol and melts after drying at 192-194°C.
Eksempel 9. Example 9.
N- ( 4- hydroksy- benzolsulf onyl) - N-(4-hydroxy-benzenesulfonyl)-
N'- cykloheksyl- urinstoff. N'-cyclohexyl urea.
17,3 g 4-hydroksy-benzolsulfonamid oppvarmes med 27,6 g pulverisert kaliumkarbonat og 250 ml dimetylformamid i 4 timer under omrøring ved 110 °C. Deretter tilsetter man 58,8 g NPN-difenyl-N'-cykloheksyl-urinstoff. etteromrører i 4 timer ved 110 °C, heller ut i vann og avkjøler etter tilsetning av noen dråper konsentrert natronlut. Det utskilte difenylamin og ikke omsatt difenylcyklohek-syl-urinstoff suges fra og filtratet surgjøres med fortynnet saltsyre. Man frasuger den krystallinske utfelling, gjenutfeller med 1 %-ig ammoniakk og omkrystalliserer fra metanol-vann. Det dannede N-(4-hydroksy-benzolsulfonyl)-N'-cykloheksyl-urinstoff smelter ved 192 til 193 °C. 17.3 g of 4-hydroxybenzenesulfonamide are heated with 27.6 g of powdered potassium carbonate and 250 ml of dimethylformamide for 4 hours with stirring at 110 °C. 58.8 g of NPN-diphenyl-N'-cyclohexyl urea are then added. stir again for 4 hours at 110 °C, pour into water and cool after adding a few drops of concentrated caustic soda. The secreted diphenylamine and unreacted diphenylcyclohexylurea are sucked off and the filtrate is acidified with dilute hydrochloric acid. The crystalline precipitate is suctioned off, reprecipitated with 1% ammonia and recrystallized from methanol-water. The formed N-(4-hydroxy-benzenesulfonyl)-N'-cyclohexylurea melts at 192 to 193°C.
Eksempel 10. Example 10.
N- ( 4- hydroksy- benzolsulf onyl) - N-(4-hydroxy-benzenesulfonyl)-
N'- cykloheksyl- urinstoff. N'-cyclohexyl urea.
8,7 g 4-hydroksy-benzolsulfonamid blandes godt med 12 g malt kaliumkarbonat og 15,7 g cykloheksyl-karbamidsyremetylester og oppvarmes i oljebad i 3 timer ved 130 °C. Etter avkjøling blander man reaksjonsblandingen med vann, fjerner overskytende karba-midsyreester ved ekstrahering med eter og surgjør den vandige oppløsning. Det utfelte produkt suges fra, gjenutfelles fra 1 %-ig ammoniakk og omkrystalliseres fra metanol. Det dannede N-(4-hydroksybenzol-sulfonyl)-N'-cykloheksylurinstoff smelter ved 192 til 193 °C. 8.7 g of 4-hydroxybenzenesulfonamide is mixed well with 12 g of ground potassium carbonate and 15.7 g of cyclohexyl urea methyl ester and heated in an oil bath for 3 hours at 130 °C. After cooling, the reaction mixture is mixed with water, excess urea ester is removed by extraction with ether and the aqueous solution is acidified. The precipitated product is suctioned off, reprecipitated from 1% ammonia and recrystallized from methanol. The formed N-(4-hydroxybenzenesulfonyl)-N'-cyclohexylurea melts at 192 to 193°C.
Eksempel 11. Example 11.
N - ( 4- hydroksy- benzolsulf onyl) - N - ( 4- hydroxy- benzenesulf onyl) -
N'- cykloheksyl- urinstoff. N'-cyclohexyl urea.
27,3 g 4-acetoksybenzolsulfonyl-metyl-uretan (fremstillet av 4-hydroksy-benzolsulfonyl-metyluretan og acetanhydrid i pyridin) blandes godt med 9,9 g cykloheksylamin og oppvarmes i bad i 1 time ved 130°C. Det oppstår en klar smelte hvorfra metanol unnviker. Man lar det avkjøle og opptar reaksjonsproduktet i 100 ml 2-n-natronlut og oppvarmer en 1/2 time på dampbad. Oppløsningen klares med kull og surgjøres etter avkjøling. Man frasuger det utfelte produkt og omkrystalliserer det fra etanol-vann. Smeltepunkt for N- (4-hydroksy-benzolsulfonyl) -N'-cykloheksyl-urinstoff ligger ved 192 til 194°C. 27.3 g of 4-acetoxybenzenesulfonyl-methyl-urethane (prepared from 4-hydroxy-benzenesulfonyl-methyl-urethane and acetic anhydride in pyridine) is mixed well with 9.9 g of cyclohexylamine and heated in a bath for 1 hour at 130°C. A clear melt occurs from which methanol escapes. It is allowed to cool and the reaction product is taken up in 100 ml of 2-n sodium hydroxide solution and heated for 1/2 hour on a steam bath. The solution is clarified with charcoal and acidified after cooling. The precipitated product is suctioned off and recrystallized from ethanol-water. The melting point of N-(4-hydroxy-benzenesulfonyl)-N'-cyclohexylurea is 192 to 194°C.
Claims (1)
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US05/766,326 US4100159A (en) | 1977-02-07 | 1977-02-07 | Process for preparation of 9-(2,6-dihalobenzyl)adenines |
US05/768,235 US4098787A (en) | 1977-02-14 | 1977-02-14 | Process for preparation of 9-(dihalobenzyl) adenines |
US84391977A | 1977-10-20 | 1977-10-20 |
Publications (3)
Publication Number | Publication Date |
---|---|
NO780284L NO780284L (en) | 1978-08-08 |
NO148374B true NO148374B (en) | 1983-06-20 |
NO148374C NO148374C (en) | 1983-09-28 |
Family
ID=27419624
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
NO780284A NO148374C (en) | 1977-02-07 | 1978-01-26 | PROCEDURE FOR PREPARING 9- (2,6-DIHALOGENBENZYL) -ADENINES. |
Country Status (23)
Country | Link |
---|---|
JP (1) | JPS53124294A (en) |
AR (1) | AR225000A1 (en) |
AT (1) | AT361008B (en) |
CH (1) | CH636614A5 (en) |
DD (1) | DD136744A5 (en) |
DE (1) | DE2804723A1 (en) |
DK (1) | DK36078A (en) |
EG (1) | EG13333A (en) |
ES (1) | ES466647A1 (en) |
FI (1) | FI64596C (en) |
FR (1) | FR2379536A1 (en) |
GB (1) | GB1586537A (en) |
GR (1) | GR64457B (en) |
IE (1) | IE46399B1 (en) |
IL (1) | IL53922A (en) |
IT (1) | IT1105174B (en) |
NL (1) | NL7800896A (en) |
NO (1) | NO148374C (en) |
NZ (1) | NZ186357A (en) |
PL (1) | PL118655B1 (en) |
PT (1) | PT67606B (en) |
SE (1) | SE440355B (en) |
YU (1) | YU27778A (en) |
Families Citing this family (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4900826A (en) * | 1981-09-24 | 1990-02-13 | Kohjin Co., Ltd. | Process for preparing N6,9-disubstituted adenine |
EP0411467A3 (en) * | 1989-08-01 | 1992-03-04 | Lonza Ag | Process for the preparation of pure adenin |
Family Cites Families (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US3846426A (en) * | 1971-03-03 | 1974-11-05 | Int Minerals & Chem Corp | 6-amino-9-(substituted benzyl) purines and their n{11 oxides |
-
1978
- 1978-01-23 FI FI780200A patent/FI64596C/en not_active IP Right Cessation
- 1978-01-25 DK DK36078A patent/DK36078A/en not_active Application Discontinuation
- 1978-01-25 NL NL7800896A patent/NL7800896A/en not_active Application Discontinuation
- 1978-01-26 NO NO780284A patent/NO148374C/en unknown
- 1978-01-26 SE SE7800977A patent/SE440355B/en not_active IP Right Cessation
- 1978-01-30 IL IL53922A patent/IL53922A/en unknown
- 1978-01-31 AR AR270912A patent/AR225000A1/en active
- 1978-01-31 NZ NZ186357A patent/NZ186357A/en unknown
- 1978-02-02 PT PT67606A patent/PT67606B/en unknown
- 1978-02-02 GR GR55327A patent/GR64457B/en unknown
- 1978-02-03 DE DE19782804723 patent/DE2804723A1/en active Granted
- 1978-02-03 FR FR7803115A patent/FR2379536A1/en active Granted
- 1978-02-03 DD DD78203555A patent/DD136744A5/en unknown
- 1978-02-03 ES ES466647A patent/ES466647A1/en not_active Expired
- 1978-02-03 CH CH124478A patent/CH636614A5/en not_active IP Right Cessation
- 1978-02-04 PL PL1978204447A patent/PL118655B1/en unknown
- 1978-02-06 AT AT79778A patent/AT361008B/en not_active IP Right Cessation
- 1978-02-06 YU YU00277/78A patent/YU27778A/en unknown
- 1978-02-06 IE IE253/78A patent/IE46399B1/en unknown
- 1978-02-06 GB GB4691/78A patent/GB1586537A/en not_active Expired
- 1978-02-06 EG EG76/78A patent/EG13333A/en active
- 1978-02-06 IT IT47941/78A patent/IT1105174B/en active
- 1978-02-07 JP JP1290178A patent/JPS53124294A/en active Pending
Also Published As
Publication number | Publication date |
---|---|
IE780253L (en) | 1978-08-07 |
NO148374C (en) | 1983-09-28 |
NO780284L (en) | 1978-08-08 |
SE7800977L (en) | 1978-08-08 |
IT1105174B (en) | 1985-10-28 |
FI780200A (en) | 1978-08-08 |
EG13333A (en) | 1981-06-30 |
JPS53124294A (en) | 1978-10-30 |
PT67606A (en) | 1978-03-01 |
AR225000A1 (en) | 1982-02-15 |
IE46399B1 (en) | 1983-06-01 |
PL204447A1 (en) | 1979-06-04 |
IL53922A0 (en) | 1978-04-30 |
FR2379536A1 (en) | 1978-09-01 |
IL53922A (en) | 1981-02-27 |
FI64596B (en) | 1983-08-31 |
SE440355B (en) | 1985-07-29 |
DK36078A (en) | 1978-08-08 |
DE2804723A1 (en) | 1978-08-10 |
AT361008B (en) | 1981-02-10 |
FI64596C (en) | 1983-12-12 |
FR2379536B1 (en) | 1983-10-07 |
NZ186357A (en) | 1981-03-16 |
NL7800896A (en) | 1978-08-09 |
ES466647A1 (en) | 1980-12-16 |
IT7847941A0 (en) | 1978-02-06 |
GR64457B (en) | 1980-03-24 |
ATA79778A (en) | 1980-07-15 |
GB1586537A (en) | 1981-03-18 |
PL118655B1 (en) | 1981-10-31 |
DE2804723C2 (en) | 1990-11-29 |
PT67606B (en) | 1980-03-03 |
CH636614A5 (en) | 1983-06-15 |
YU27778A (en) | 1983-12-31 |
DD136744A5 (en) | 1979-07-25 |
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