NO115842B - - Google Patents
Info
- Publication number
- NO115842B NO115842B NO15123363A NO15123363A NO115842B NO 115842 B NO115842 B NO 115842B NO 15123363 A NO15123363 A NO 15123363A NO 15123363 A NO15123363 A NO 15123363A NO 115842 B NO115842 B NO 115842B
- Authority
- NO
- Norway
- Prior art keywords
- methoxymethyl
- group
- residue
- alkoxy
- compounds
- Prior art date
Links
- 150000001875 compounds Chemical class 0.000 claims description 39
- 125000003277 amino group Chemical group 0.000 claims description 23
- 239000002253 acid Substances 0.000 claims description 20
- 150000003839 salts Chemical class 0.000 claims description 20
- 125000005843 halogen group Chemical group 0.000 claims description 19
- 125000002252 acyl group Chemical group 0.000 claims description 8
- 238000000034 method Methods 0.000 claims description 8
- 230000009467 reduction Effects 0.000 claims description 8
- 125000003396 thiol group Chemical group [H]S* 0.000 claims description 8
- 230000007062 hydrolysis Effects 0.000 claims description 7
- 238000006460 hydrolysis reaction Methods 0.000 claims description 7
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 6
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 6
- QGZKDVFQNNGYKY-UHFFFAOYSA-O ammonium group Chemical group [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 claims description 5
- PXDBUWPMANSAFI-UHFFFAOYSA-N 4-amino-n-pyrimidin-4-ylbenzenesulfonamide Chemical class C1=CC(N)=CC=C1S(=O)(=O)NC1=CC=NC=N1 PXDBUWPMANSAFI-UHFFFAOYSA-N 0.000 claims description 4
- 238000002360 preparation method Methods 0.000 claims description 4
- 230000008569 process Effects 0.000 claims description 4
- 125000004390 alkyl sulfonyl group Chemical group 0.000 claims description 3
- 125000001424 substituent group Chemical group 0.000 claims description 3
- 125000002843 carboxylic acid group Chemical group 0.000 claims 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 60
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 50
- 239000000243 solution Substances 0.000 description 44
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 36
- -1 methoxy, ethoxy Chemical group 0.000 description 35
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 33
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 28
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 27
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 26
- 239000002244 precipitate Substances 0.000 description 26
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 22
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 21
- 239000000203 mixture Substances 0.000 description 21
- 238000002844 melting Methods 0.000 description 20
- 230000008018 melting Effects 0.000 description 20
- 229960000583 acetic acid Drugs 0.000 description 19
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 18
- 238000006243 chemical reaction Methods 0.000 description 18
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 17
- 239000000706 filtrate Substances 0.000 description 16
- 238000001953 recrystallisation Methods 0.000 description 15
- DLFVBJFMPXGRIB-UHFFFAOYSA-N Acetamide Chemical compound CC(N)=O DLFVBJFMPXGRIB-UHFFFAOYSA-N 0.000 description 14
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 14
- 239000000155 melt Substances 0.000 description 14
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 13
- 238000001816 cooling Methods 0.000 description 13
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 13
- 239000007858 starting material Substances 0.000 description 13
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 12
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 12
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 12
- GETQZCLCWQTVFV-UHFFFAOYSA-N anhydrous trimethylamine Natural products CN(C)C GETQZCLCWQTVFV-UHFFFAOYSA-N 0.000 description 12
- 239000000047 product Substances 0.000 description 12
- 239000011734 sodium Substances 0.000 description 12
- 229910052708 sodium Inorganic materials 0.000 description 12
- 238000003756 stirring Methods 0.000 description 12
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 11
- 229940124530 sulfonamide Drugs 0.000 description 11
- 125000003545 alkoxy group Chemical group 0.000 description 10
- 239000003054 catalyst Substances 0.000 description 9
- 239000003795 chemical substances by application Substances 0.000 description 9
- AUYLLSDPDMYNTF-UHFFFAOYSA-N 4-amino-N-[6-methoxy-2-(methoxymethyl)pyrimidin-4-yl]benzenesulfonamide Chemical compound NC1=CC=C(C=C1)S(=O)(=O)NC1=CC(=NC(=N1)COC)OC AUYLLSDPDMYNTF-UHFFFAOYSA-N 0.000 description 8
- 125000000217 alkyl group Chemical group 0.000 description 8
- 235000011121 sodium hydroxide Nutrition 0.000 description 8
- FDDDEECHVMSUSB-UHFFFAOYSA-N sulfanilamide Chemical compound NC1=CC=C(S(N)(=O)=O)C=C1 FDDDEECHVMSUSB-UHFFFAOYSA-N 0.000 description 8
- 150000003456 sulfonamides Chemical class 0.000 description 8
- JEOBFTOIMFEXNK-UHFFFAOYSA-N 6-chloro-2-(methoxymethyl)pyrimidin-4-amine Chemical compound COCC1=NC(N)=CC(Cl)=N1 JEOBFTOIMFEXNK-UHFFFAOYSA-N 0.000 description 7
- 239000012362 glacial acetic acid Substances 0.000 description 7
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Substances [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 7
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 6
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 6
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-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
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 6
- 238000009835 boiling Methods 0.000 description 6
- 125000004432 carbon atom Chemical group C* 0.000 description 6
- 229910052751 metal Inorganic materials 0.000 description 6
- 239000002184 metal Substances 0.000 description 6
- LQNUZADURLCDLV-UHFFFAOYSA-N nitrobenzene Chemical compound [O-][N+](=O)C1=CC=CC=C1 LQNUZADURLCDLV-UHFFFAOYSA-N 0.000 description 6
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 5
- RVEGXZSTKXPVPB-UHFFFAOYSA-N S(=O)(=O)(O)Cl.C(=O)(OCC)NC1=CC=CC=C1 Chemical compound S(=O)(=O)(O)Cl.C(=O)(OCC)NC1=CC=CC=C1 RVEGXZSTKXPVPB-UHFFFAOYSA-N 0.000 description 5
- 239000003513 alkali Substances 0.000 description 5
- 229910021529 ammonia Inorganic materials 0.000 description 5
- 239000003085 diluting agent Substances 0.000 description 5
- 229910052757 nitrogen Inorganic materials 0.000 description 5
- OISVCGZHLKNMSJ-UHFFFAOYSA-N 2,6-dimethylpyridine Chemical compound CC1=CC=CC(C)=N1 OISVCGZHLKNMSJ-UHFFFAOYSA-N 0.000 description 4
- AUNQXUFJXZBTIV-UHFFFAOYSA-N 2-(methoxymethyl)pyrimidin-4-amine Chemical compound COCC1=NC=CC(N)=N1 AUNQXUFJXZBTIV-UHFFFAOYSA-N 0.000 description 4
- HUKHOBYZPBKOQG-UHFFFAOYSA-N 4-amino-N-[6-chloro-2-(methoxymethyl)pyrimidin-4-yl]benzenesulfonamide Chemical compound NC1=CC=C(C=C1)S(=O)(=O)NC1=CC(=NC(=N1)COC)Cl HUKHOBYZPBKOQG-UHFFFAOYSA-N 0.000 description 4
- JHQXVCAOBDYYTL-UHFFFAOYSA-N 6-methoxy-2-(methoxymethyl)pyrimidin-4-amine Chemical compound COCC1=NC(N)=CC(OC)=N1 JHQXVCAOBDYYTL-UHFFFAOYSA-N 0.000 description 4
- PXHVJJICTQNCMI-UHFFFAOYSA-N Nickel Chemical compound [Ni] PXHVJJICTQNCMI-UHFFFAOYSA-N 0.000 description 4
- 125000004442 acylamino group Chemical group 0.000 description 4
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 4
- 235000014113 dietary fatty acids Nutrition 0.000 description 4
- 239000000194 fatty acid Substances 0.000 description 4
- 229930195729 fatty acid Natural products 0.000 description 4
- 229910052739 hydrogen Inorganic materials 0.000 description 4
- 239000001257 hydrogen Substances 0.000 description 4
- 238000006386 neutralization reaction Methods 0.000 description 4
- 125000004430 oxygen atom Chemical group O* 0.000 description 4
- 239000011541 reaction mixture Substances 0.000 description 4
- 239000002904 solvent Substances 0.000 description 4
- 239000000126 substance Substances 0.000 description 4
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 description 4
- VZTVSUKTMWSTOG-UHFFFAOYSA-N 2-(2-methoxyethyl)-6-methylpyrimidin-4-amine Chemical compound COCCC1=NC(C)=CC(N)=N1 VZTVSUKTMWSTOG-UHFFFAOYSA-N 0.000 description 3
- WTVXSDIYBZLDIN-UHFFFAOYSA-N 2-(ethoxymethyl)-6-methoxypyrimidin-4-amine Chemical compound C(C)OCC1=NC(=CC(=N1)OC)N WTVXSDIYBZLDIN-UHFFFAOYSA-N 0.000 description 3
- LRAIBXGPDUQUBD-UHFFFAOYSA-N 4-chloro-2-(methoxymethyl)-6-methylpyrimidine Chemical compound COCC1=NC(C)=CC(Cl)=N1 LRAIBXGPDUQUBD-UHFFFAOYSA-N 0.000 description 3
- QLPMACVIRPWEKZ-UHFFFAOYSA-N 4-chloro-6-(methoxymethyl)-2-methylpyrimidine Chemical compound COCC1=CC(Cl)=NC(C)=N1 QLPMACVIRPWEKZ-UHFFFAOYSA-N 0.000 description 3
- QOOQUMTZWQEHTR-UHFFFAOYSA-N 4-chloro-6-(methoxymethyl)pyrimidine Chemical compound COCC1=CC(Cl)=NC=N1 QOOQUMTZWQEHTR-UHFFFAOYSA-N 0.000 description 3
- KZCDPEWXWGDVKM-UHFFFAOYSA-N 6-ethoxy-2-(methoxymethyl)pyrimidin-4-amine Chemical compound CCOC1=CC(N)=NC(COC)=N1 KZCDPEWXWGDVKM-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
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- IYXGSMUGOJNHAZ-UHFFFAOYSA-N Ethyl malonate Chemical compound CCOC(=O)CC(=O)OCC IYXGSMUGOJNHAZ-UHFFFAOYSA-N 0.000 description 3
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 3
- 241001465754 Metazoa Species 0.000 description 3
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 3
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- 150000007513 acids Chemical class 0.000 description 3
- 125000002947 alkylene group Chemical group 0.000 description 3
- 235000019270 ammonium chloride Nutrition 0.000 description 3
- 239000013078 crystal Substances 0.000 description 3
- 238000004821 distillation Methods 0.000 description 3
- LBAQSKZHMLAFHH-UHFFFAOYSA-N ethoxyethane;hydron;chloride Chemical compound Cl.CCOCC LBAQSKZHMLAFHH-UHFFFAOYSA-N 0.000 description 3
- 150000004665 fatty acids Chemical class 0.000 description 3
- 150000004820 halides Chemical class 0.000 description 3
- 238000010438 heat treatment Methods 0.000 description 3
- 239000005457 ice water Substances 0.000 description 3
- KERKSHQWMCWPBT-UHFFFAOYSA-N n-phenylacetamide;sulfurochloridic acid Chemical compound OS(Cl)(=O)=O.CC(=O)NC1=CC=CC=C1 KERKSHQWMCWPBT-UHFFFAOYSA-N 0.000 description 3
- 229940072033 potash Drugs 0.000 description 3
- 239000011591 potassium Substances 0.000 description 3
- 229910052700 potassium Inorganic materials 0.000 description 3
- 235000015320 potassium carbonate Nutrition 0.000 description 3
- 150000003230 pyrimidines Chemical class 0.000 description 3
- 235000017557 sodium bicarbonate Nutrition 0.000 description 3
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 3
- QAOWNCQODCNURD-UHFFFAOYSA-N sulfuric acid Substances OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 3
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 2
- XTAUZKNANNHWQL-UHFFFAOYSA-N 2-(methoxymethyl)-6-propan-2-yloxypyrimidin-4-amine Chemical compound COCC1=NC(=CC(=N1)OC(C)C)N XTAUZKNANNHWQL-UHFFFAOYSA-N 0.000 description 2
- JIQYMVXNVNFXIP-UHFFFAOYSA-N 2-methoxyethanimidamide;hydrochloride Chemical compound Cl.COCC(N)=N JIQYMVXNVNFXIP-UHFFFAOYSA-N 0.000 description 2
- BSKHPKMHTQYZBB-UHFFFAOYSA-N 2-methylpyridine Chemical compound CC1=CC=CC=N1 BSKHPKMHTQYZBB-UHFFFAOYSA-N 0.000 description 2
- CSIFGMFVGDBOQC-UHFFFAOYSA-N 3-iminobutanenitrile Chemical compound CC(=N)CC#N CSIFGMFVGDBOQC-UHFFFAOYSA-N 0.000 description 2
- KRGDUBQLCSQJJK-UHFFFAOYSA-N 3-methoxypropanimidamide;hydrochloride Chemical compound Cl.COCCC(N)=N KRGDUBQLCSQJJK-UHFFFAOYSA-N 0.000 description 2
- JEGIGVNQAHMOII-UHFFFAOYSA-N 4,6-dichloro-2-(methoxymethyl)pyrimidine Chemical compound COCC1=NC(Cl)=CC(Cl)=N1 JEGIGVNQAHMOII-UHFFFAOYSA-N 0.000 description 2
- GRDXCFKBQWDAJH-UHFFFAOYSA-N 4-acetamidobenzenesulfonyl chloride Chemical compound CC(=O)NC1=CC=C(S(Cl)(=O)=O)C=C1 GRDXCFKBQWDAJH-UHFFFAOYSA-N 0.000 description 2
- URJHIPLGBLDXIC-UHFFFAOYSA-N 4-amino-N-[2-(methoxymethyl)pyrimidin-4-yl]benzenesulfonamide Chemical compound NC1=CC=C(C=C1)S(=O)(=O)NC1=NC(=NC=C1)COC URJHIPLGBLDXIC-UHFFFAOYSA-N 0.000 description 2
- NXYKSXZSDOBSNH-UHFFFAOYSA-N 4-chloro-2,6-bis(methoxymethyl)pyrimidine Chemical compound COCC1=CC(Cl)=NC(COC)=N1 NXYKSXZSDOBSNH-UHFFFAOYSA-N 0.000 description 2
- 239000005711 Benzoic acid Substances 0.000 description 2
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 2
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 2
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 2
- 239000007868 Raney catalyst Substances 0.000 description 2
- 229910000564 Raney nickel Inorganic materials 0.000 description 2
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 2
- 239000000654 additive Substances 0.000 description 2
- 125000001931 aliphatic group Chemical group 0.000 description 2
- 150000001339 alkali metal compounds Chemical class 0.000 description 2
- 229910052784 alkaline earth metal Inorganic materials 0.000 description 2
- 150000001409 amidines Chemical class 0.000 description 2
- HOPRXXXSABQWAV-UHFFFAOYSA-N anhydrous collidine Natural products CC1=CC=NC(C)=C1C HOPRXXXSABQWAV-UHFFFAOYSA-N 0.000 description 2
- 125000003118 aryl group Chemical group 0.000 description 2
- 239000002585 base Substances 0.000 description 2
- 230000008901 benefit Effects 0.000 description 2
- 229940092714 benzenesulfonic acid Drugs 0.000 description 2
- 235000010233 benzoic acid Nutrition 0.000 description 2
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 2
- 229910052794 bromium Inorganic materials 0.000 description 2
- HQABUPZFAYXKJW-UHFFFAOYSA-N butan-1-amine Chemical compound CCCCN HQABUPZFAYXKJW-UHFFFAOYSA-N 0.000 description 2
- 125000004063 butyryl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- 239000001569 carbon dioxide Substances 0.000 description 2
- 229910002092 carbon dioxide Inorganic materials 0.000 description 2
- 150000004649 carbonic acid derivatives Chemical class 0.000 description 2
- 150000001732 carboxylic acid derivatives Chemical group 0.000 description 2
- 230000000973 chemotherapeutic effect Effects 0.000 description 2
- 239000000460 chlorine Substances 0.000 description 2
- 229910052801 chlorine Inorganic materials 0.000 description 2
- UTBIMNXEDGNJFE-UHFFFAOYSA-N collidine Natural products CC1=CC=C(C)C(C)=N1 UTBIMNXEDGNJFE-UHFFFAOYSA-N 0.000 description 2
- 238000009833 condensation Methods 0.000 description 2
- 230000005494 condensation Effects 0.000 description 2
- HPYNZHMRTTWQTB-UHFFFAOYSA-N dimethylpyridine Natural products CC1=CC=CN=C1C HPYNZHMRTTWQTB-UHFFFAOYSA-N 0.000 description 2
- IDGUHHHQCWSQLU-UHFFFAOYSA-N ethanol;hydrate Chemical compound O.CCO IDGUHHHQCWSQLU-UHFFFAOYSA-N 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 230000003301 hydrolyzing effect Effects 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 150000002739 metals Chemical class 0.000 description 2
- 230000003472 neutralizing effect Effects 0.000 description 2
- HKTBRYQNVRPBCF-UHFFFAOYSA-N nitrobenzene;sulfurochloridic acid Chemical compound OS(Cl)(=O)=O.[O-][N+](=O)C1=CC=CC=C1 HKTBRYQNVRPBCF-UHFFFAOYSA-N 0.000 description 2
- 150000007530 organic bases Chemical group 0.000 description 2
- 125000004817 pentamethylene group Chemical group [H]C([H])([*:2])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[*:1] 0.000 description 2
- 229910000027 potassium carbonate Inorganic materials 0.000 description 2
- 235000011181 potassium carbonates Nutrition 0.000 description 2
- 125000001501 propionyl group Chemical group O=C([*])C([H])([H])C([H])([H])[H] 0.000 description 2
- 238000007127 saponification reaction Methods 0.000 description 2
- GGCZERPQGJTIQP-UHFFFAOYSA-N sodium;9,10-dioxoanthracene-2-sulfonic acid Chemical compound [Na+].C1=CC=C2C(=O)C3=CC(S(=O)(=O)O)=CC=C3C(=O)C2=C1 GGCZERPQGJTIQP-UHFFFAOYSA-N 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- GFYHSKONPJXCDE-UHFFFAOYSA-N sym-collidine Natural products CC1=CN=C(C)C(C)=C1 GFYHSKONPJXCDE-UHFFFAOYSA-N 0.000 description 2
- HTSGKJQDMSTCGS-UHFFFAOYSA-N 1,4-bis(4-chlorophenyl)-2-(4-methylphenyl)sulfonylbutane-1,4-dione Chemical compound C1=CC(C)=CC=C1S(=O)(=O)C(C(=O)C=1C=CC(Cl)=CC=1)CC(=O)C1=CC=C(Cl)C=C1 HTSGKJQDMSTCGS-UHFFFAOYSA-N 0.000 description 1
- VOGSVUQENSCLHU-UHFFFAOYSA-N 2,6-bis(methoxymethyl)-1h-pyrimidin-4-one Chemical compound COCC1=CC(O)=NC(COC)=N1 VOGSVUQENSCLHU-UHFFFAOYSA-N 0.000 description 1
- GZQNTJUBUHAMCD-UHFFFAOYSA-N 2-(2-methoxyethyl)pyrimidin-4-amine Chemical compound COCCC1=NC=CC(N)=N1 GZQNTJUBUHAMCD-UHFFFAOYSA-N 0.000 description 1
- DWAJCKKINDTXEC-UHFFFAOYSA-N 2-(ethoxymethyl)-4-hydroxy-1h-pyrimidin-6-one Chemical compound CCOCC1=NC(O)=CC(=O)N1 DWAJCKKINDTXEC-UHFFFAOYSA-N 0.000 description 1
- SUYJAOGGIGEQIC-UHFFFAOYSA-N 2-(methoxymethyl)-6-methyl-1h-pyrimidin-4-one Chemical compound COCC1=NC(C)=CC(O)=N1 SUYJAOGGIGEQIC-UHFFFAOYSA-N 0.000 description 1
- XNWFRZJHXBZDAG-UHFFFAOYSA-N 2-METHOXYETHANOL Chemical compound COCCO XNWFRZJHXBZDAG-UHFFFAOYSA-N 0.000 description 1
- WPYUCWSMVJJWFI-UHFFFAOYSA-N 2-ethoxyacetonitrile Chemical compound CCOCC#N WPYUCWSMVJJWFI-UHFFFAOYSA-N 0.000 description 1
- UQUIVPXCXXIPML-UHFFFAOYSA-N 2-ethoxyethanimidamide;hydrochloride Chemical class Cl.CCOCC(N)=N UQUIVPXCXXIPML-UHFFFAOYSA-N 0.000 description 1
- QKPVEISEHYYHRH-UHFFFAOYSA-N 2-methoxyacetonitrile Chemical compound COCC#N QKPVEISEHYYHRH-UHFFFAOYSA-N 0.000 description 1
- XMSFMNAYWPDMBJ-UHFFFAOYSA-N 2-methoxyethanimidamide Chemical compound COCC(N)=N XMSFMNAYWPDMBJ-UHFFFAOYSA-N 0.000 description 1
- WLJVXDMOQOGPHL-PPJXEINESA-N 2-phenylacetic acid Chemical compound O[14C](=O)CC1=CC=CC=C1 WLJVXDMOQOGPHL-PPJXEINESA-N 0.000 description 1
- PYDUJAPRBBVWSO-UHFFFAOYSA-N 4,6-dichloro-2-(ethoxymethyl)pyrimidine Chemical compound CCOCC1=NC(Cl)=CC(Cl)=N1 PYDUJAPRBBVWSO-UHFFFAOYSA-N 0.000 description 1
- PDAPVUSPOGTKAZ-UHFFFAOYSA-N 4-amino-N-[2-(ethoxymethyl)-6-methoxypyrimidin-4-yl]benzenesulfonamide Chemical compound NC1=CC=C(C=C1)S(=O)(=O)NC1=CC(=NC(=N1)COCC)OC PDAPVUSPOGTKAZ-UHFFFAOYSA-N 0.000 description 1
- YWQRHJFLDFXWQM-UHFFFAOYSA-N 4-amino-N-[6-(methoxymethyl)-2-methylpyrimidin-4-yl]benzenesulfonamide Chemical compound NC1=CC=C(C=C1)S(=O)(=O)NC1=CC(=NC(=N1)C)COC YWQRHJFLDFXWQM-UHFFFAOYSA-N 0.000 description 1
- WIIURJFRTWLHJC-UHFFFAOYSA-N 4-amino-N-[6-ethoxy-2-(methoxymethyl)pyrimidin-4-yl]benzenesulfonamide Chemical compound NC1=CC=C(C=C1)S(=O)(=O)NC1=CC(=NC(=N1)COC)OCC WIIURJFRTWLHJC-UHFFFAOYSA-N 0.000 description 1
- QWAQJFVZUYMNTP-UHFFFAOYSA-N 4-amino-n-[2-(methoxymethyl)-6-methylpyrimidin-4-yl]benzenesulfonamide Chemical compound COCC1=NC(C)=CC(NS(=O)(=O)C=2C=CC(N)=CC=2)=N1 QWAQJFVZUYMNTP-UHFFFAOYSA-N 0.000 description 1
- PJDDSABKCQXOGC-UHFFFAOYSA-N 4-chloro-6-methoxy-2-(methoxymethyl)pyrimidine Chemical compound COCC1=NC(Cl)=CC(OC)=N1 PJDDSABKCQXOGC-UHFFFAOYSA-N 0.000 description 1
- AVELSBXWALYUPN-UHFFFAOYSA-N 4-hydroxy-2-(methoxymethyl)-1h-pyrimidin-6-one Chemical compound COCC1=NC(O)=CC(O)=N1 AVELSBXWALYUPN-UHFFFAOYSA-N 0.000 description 1
- IKGGFUSHTLTYIT-UHFFFAOYSA-N 4-methoxy-3-oxobutanoic acid Chemical compound COCC(=O)CC(O)=O IKGGFUSHTLTYIT-UHFFFAOYSA-N 0.000 description 1
- TUWLYFAEAPMOJS-UHFFFAOYSA-N 6-(methoxymethyl)-1h-pyrimidin-4-one Chemical compound COCC1=CC(O)=NC=N1 TUWLYFAEAPMOJS-UHFFFAOYSA-N 0.000 description 1
- ZEEJRACEEDQANN-UHFFFAOYSA-N 6-(methoxymethyl)pyrimidin-4-amine Chemical compound COCC1=CC(N)=NC=N1 ZEEJRACEEDQANN-UHFFFAOYSA-N 0.000 description 1
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 1
- 208000035143 Bacterial infection Diseases 0.000 description 1
- KYEBOOPUUWAYBK-UHFFFAOYSA-N C(C)(=O)NC1=CC=C(C=C1)S(=O)(=O)NC1=CC(=NC(=N1)COC)C Chemical compound C(C)(=O)NC1=CC=C(C=C1)S(=O)(=O)NC1=CC(=NC(=N1)COC)C KYEBOOPUUWAYBK-UHFFFAOYSA-N 0.000 description 1
- YBGAMOJCPBPKTJ-UHFFFAOYSA-N COCC1=NC(COC)=NC(NS(C(C=C2)=CC=C2N)(=O)=O)=C1 Chemical compound COCC1=NC(COC)=NC(NS(C(C=C2)=CC=C2N)(=O)=O)=C1 YBGAMOJCPBPKTJ-UHFFFAOYSA-N 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- 241000192125 Firmicutes Species 0.000 description 1
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 1
- 241000699670 Mus sp. Species 0.000 description 1
- JLTDJTHDQAWBAV-UHFFFAOYSA-N N,N-dimethylaniline Chemical compound CN(C)C1=CC=CC=C1 JLTDJTHDQAWBAV-UHFFFAOYSA-N 0.000 description 1
- 230000006181 N-acylation Effects 0.000 description 1
- PHSPJQZRQAJPPF-UHFFFAOYSA-N N-alpha-Methylhistamine Chemical compound CNCCC1=CN=CN1 PHSPJQZRQAJPPF-UHFFFAOYSA-N 0.000 description 1
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 description 1
- 241000295644 Staphylococcaceae Species 0.000 description 1
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 1
- YSVZGWAJIHWNQK-UHFFFAOYSA-N [3-(hydroxymethyl)-2-bicyclo[2.2.1]heptanyl]methanol Chemical compound C1CC2C(CO)C(CO)C1C2 YSVZGWAJIHWNQK-UHFFFAOYSA-N 0.000 description 1
- 125000000738 acetamido group Chemical group [H]C([H])([H])C(=O)N([H])[*] 0.000 description 1
- XPOLVIIHTDKJRY-UHFFFAOYSA-N acetic acid;methanimidamide Chemical compound NC=N.CC(O)=O XPOLVIIHTDKJRY-UHFFFAOYSA-N 0.000 description 1
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 1
- 150000008065 acid anhydrides Chemical class 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 239000013543 active substance Substances 0.000 description 1
- 238000005917 acylation reaction Methods 0.000 description 1
- 150000001447 alkali salts Chemical class 0.000 description 1
- 239000012670 alkaline solution Substances 0.000 description 1
- 125000005236 alkanoylamino group Chemical group 0.000 description 1
- 125000001118 alkylidene group Chemical group 0.000 description 1
- 239000004411 aluminium Substances 0.000 description 1
- 229910052782 aluminium Inorganic materials 0.000 description 1
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 description 1
- 150000001408 amides Chemical class 0.000 description 1
- 238000007098 aminolysis reaction Methods 0.000 description 1
- 150000005005 aminopyrimidines Chemical class 0.000 description 1
- 239000000908 ammonium hydroxide Substances 0.000 description 1
- 230000000844 anti-bacterial effect Effects 0.000 description 1
- 125000000751 azo group Chemical group [*]N=N[*] 0.000 description 1
- 208000022362 bacterial infectious disease Diseases 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 238000007664 blowing Methods 0.000 description 1
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- AXCZMVOFGPJBDE-UHFFFAOYSA-L calcium dihydroxide Chemical class [OH-].[OH-].[Ca+2] AXCZMVOFGPJBDE-UHFFFAOYSA-L 0.000 description 1
- 235000011116 calcium hydroxide Nutrition 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 239000012876 carrier material Substances 0.000 description 1
- 150000001805 chlorine compounds Chemical class 0.000 description 1
- 238000003776 cleavage reaction Methods 0.000 description 1
- 239000013065 commercial product Substances 0.000 description 1
- 239000007859 condensation product Substances 0.000 description 1
- 238000000354 decomposition reaction Methods 0.000 description 1
- WCQOBLXWLRDEQA-UHFFFAOYSA-N ethanimidamide;hydrochloride Chemical compound Cl.CC(N)=N WCQOBLXWLRDEQA-UHFFFAOYSA-N 0.000 description 1
- PSLIMVZEAPALCD-UHFFFAOYSA-N ethanol;ethoxyethane Chemical compound CCO.CCOCC PSLIMVZEAPALCD-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
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 230000008020 evaporation Effects 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 125000001153 fluoro group Chemical group F* 0.000 description 1
- 238000005187 foaming Methods 0.000 description 1
- 238000004508 fractional distillation Methods 0.000 description 1
- 238000005194 fractionation Methods 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 150000008282 halocarbons Chemical class 0.000 description 1
- 229910052736 halogen Inorganic materials 0.000 description 1
- 230000035876 healing Effects 0.000 description 1
- 238000005984 hydrogenation reaction Methods 0.000 description 1
- 238000007327 hydrogenolysis reaction Methods 0.000 description 1
- 150000004679 hydroxides Chemical class 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 239000003701 inert diluent Substances 0.000 description 1
- 208000015181 infectious disease Diseases 0.000 description 1
- 150000007529 inorganic bases Chemical class 0.000 description 1
- 239000000543 intermediate Substances 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 125000000654 isopropylidene group Chemical group C(C)(C)=* 0.000 description 1
- 125000000400 lauroyl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- 239000000395 magnesium oxide Substances 0.000 description 1
- CPLXHLVBOLITMK-UHFFFAOYSA-N magnesium oxide Inorganic materials [Mg]=O CPLXHLVBOLITMK-UHFFFAOYSA-N 0.000 description 1
- AXZKOIWUVFPNLO-UHFFFAOYSA-N magnesium;oxygen(2-) Chemical compound [O-2].[Mg+2] AXZKOIWUVFPNLO-UHFFFAOYSA-N 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 125000000325 methylidene group Chemical group [H]C([H])=* 0.000 description 1
- 230000005012 migration Effects 0.000 description 1
- 238000013508 migration Methods 0.000 description 1
- TXXWBTOATXBWDR-UHFFFAOYSA-N n,n,n',n'-tetramethylhexane-1,6-diamine Chemical compound CN(C)CCCCCCN(C)C TXXWBTOATXBWDR-UHFFFAOYSA-N 0.000 description 1
- PKOFBDHYTMYVGJ-UHFFFAOYSA-N n-(4-sulfamoylphenyl)acetamide Chemical compound CC(=O)NC1=CC=C(S(N)(=O)=O)C=C1 PKOFBDHYTMYVGJ-UHFFFAOYSA-N 0.000 description 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 229910052759 nickel Inorganic materials 0.000 description 1
- 150000002825 nitriles Chemical class 0.000 description 1
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 1
- 229910000510 noble metal Inorganic materials 0.000 description 1
- 125000001117 oleyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])/C([H])=C([H])\C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 239000012074 organic phase Substances 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 229910052763 palladium Inorganic materials 0.000 description 1
- 125000000913 palmityl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 1
- 239000003208 petroleum Substances 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 229910052698 phosphorus Inorganic materials 0.000 description 1
- 239000011574 phosphorus Substances 0.000 description 1
- 235000011118 potassium hydroxide Nutrition 0.000 description 1
- JVXZJEUVAOVXIX-UHFFFAOYSA-N propan-2-one;pyridine Chemical compound CC(C)=O.C1=CC=NC=C1 JVXZJEUVAOVXIX-UHFFFAOYSA-N 0.000 description 1
- 125000002572 propoxy group Chemical group [*]OC([H])([H])C(C([H])([H])[H])([H])[H] 0.000 description 1
- IDXKTTNFXPPXJY-UHFFFAOYSA-N pyrimidin-1-ium;chloride Chemical compound Cl.C1=CN=CN=C1 IDXKTTNFXPPXJY-UHFFFAOYSA-N 0.000 description 1
- VTGOHKSTWXHQJK-UHFFFAOYSA-N pyrimidin-2-ol Chemical class OC1=NC=CC=N1 VTGOHKSTWXHQJK-UHFFFAOYSA-N 0.000 description 1
- 230000008707 rearrangement Effects 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- LMHHRCOWPQNFTF-UHFFFAOYSA-N s-propan-2-yl azepane-1-carbothioate Chemical compound CC(C)SC(=O)N1CCCCCC1 LMHHRCOWPQNFTF-UHFFFAOYSA-N 0.000 description 1
- 230000007017 scission Effects 0.000 description 1
- 239000013049 sediment Substances 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- MGWMPVXITSXYNK-UHFFFAOYSA-N sodium;n-(4-sulfamoylphenyl)acetamide Chemical compound [Na].CC(=O)NC1=CC=C(S(N)(=O)=O)C=C1 MGWMPVXITSXYNK-UHFFFAOYSA-N 0.000 description 1
- 238000000859 sublimation Methods 0.000 description 1
- 230000008022 sublimation Effects 0.000 description 1
- ZZORFUFYDOWNEF-UHFFFAOYSA-N sulfadimethoxine Chemical compound COC1=NC(OC)=CC(NS(=O)(=O)C=2C=CC(N)=CC=2)=N1 ZZORFUFYDOWNEF-UHFFFAOYSA-N 0.000 description 1
- PXQLVRUNWNTZOS-UHFFFAOYSA-N sulfanyl Chemical class [SH] PXQLVRUNWNTZOS-UHFFFAOYSA-N 0.000 description 1
- 229910052717 sulfur Inorganic materials 0.000 description 1
- 239000011593 sulfur Substances 0.000 description 1
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 description 1
- 150000003512 tertiary amines Chemical class 0.000 description 1
- 125000000383 tetramethylene group Chemical group [H]C([H])([*:1])C([H])([H])C([H])([H])C([H])([H])[*:2] 0.000 description 1
- 230000000699 topical effect Effects 0.000 description 1
- 125000005270 trialkylamine group Chemical group 0.000 description 1
- 125000005208 trialkylammonium group Chemical group 0.000 description 1
- IMFACGCPASFAPR-UHFFFAOYSA-N tributylamine Chemical compound CCCCN(CCCC)CCCC IMFACGCPASFAPR-UHFFFAOYSA-N 0.000 description 1
- 230000007306 turnover Effects 0.000 description 1
- 210000001635 urinary tract Anatomy 0.000 description 1
- 210000002700 urine Anatomy 0.000 description 1
- 125000003774 valeryl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 239000000052 vinegar Substances 0.000 description 1
- 235000021419 vinegar Nutrition 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
- C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
- C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
- C07D239/69—Benzenesulfonamido-pyrimidines
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
Landscapes
- Chemical & Material Sciences (AREA)
- Health & Medical Sciences (AREA)
- Organic Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- Epidemiology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Medicinal Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
Description
Fremgangsmåte til fremstilling av abtibakterielt virksomme 6-(p-aminobenzolsulfonamido)-pyrimidiner. Process for the preparation of antibacterially active 6-(p-aminobenzenesulfonamido)-pyrimidines.
Gjenstanden for foreliggende oppfinnelse er fremstilling av 6-(p-aminobenzolsulfonamido)-pyrimidiner med formelen The object of the present invention is the production of 6-(p-aminobenzenesulfonamido)-pyrimidines with the formula
hvori en av restene Rt og R2betyr en lavere-alkoksy-lavere-alkylrest, og den annen betyr et hydrogenatom, et halogenatom, en lavere alkylrest, en lavere alkoksyrest, en lavere alkoksy-lavere-alkylrest, eller lavere-alkoksy-lavere-alkoksyrest og deres Nj-acylderivater. wherein one of the radicals Rt and R2 means a lower-alkyl-lower-alkyl radical, and the other means a hydrogen atom, a halogen atom, a lower-alkyl radical, a lower-alkoxy acid radical, a lower-alkyl-lower-alkyl radical, or a lower-alkoxy-lower-alkoxy acid radical and their Nj-acyl derivatives.
I de nye forbindelser er lavere alkylrest, særlig slike med 1—5 karbonatomer, slik som metyl-, etyl-, n-propyl- eller isopropylrester eller rette eller forgrenete, i vilkårlig stilling forbundne butyl- eller pentylrester. Lavere-alkoksyrester er f. eks. slike som inneholder de ovenfornevnte alkylrester, særlig metoksy-, etoksy- eller propok-syrester. In the new compounds, lower alkyl residues, especially those with 1-5 carbon atoms, such as methyl, ethyl, n-propyl or isopropyl residues or straight or branched butyl or pentyl residues connected in any position. Lower carboxylic acid residues are e.g. those containing the above-mentioned alkyl residues, especially methoxy, ethoxy or propoxy acid residues.
De lavere-alkoksyrester som inneholdes i de lavere-alkoksylaverealkylrester er f. eks. de ovennevnte. Alkylenrestene som forbinder oksygen-atomet med pyrimidinkjernen, er fortrinnsvis alkylenrester med 1—5, særlig 1—3 karbonatomer, slik som metylenrester, i vilkårlig stilling forbundne etylen-, propylen-, butylen- eller pen-tylenrester. Lavere-alkoksylavere-alkylrester er særlig rester med formelen RO-(CH2)n-, hvori R betyr en alkylrest med 1—3 karbonatomer og n er et helt tall på 1—3. The lower alkoxy acid residues contained in the lower alkoxy lower alkyl residues are e.g. the above mentioned. The alkylene residues which connect the oxygen atom to the pyrimidine nucleus are preferably alkylene residues with 1-5, especially 1-3 carbon atoms, such as methylene residues, ethylene, propylene, butylene or pentylene residues connected in any position. Lower alkoxy lower alkyl residues are particularly residues with the formula RO-(CH2)n-, in which R means an alkyl residue with 1-3 carbon atoms and n is an integer of 1-3.
De alkoksygrupper som inneholdes i de lavere-alkoksy-lavere-alkoksyrester er f. eks. de ovenfor nevnte. Den alkylenrest som forbinder disse alkoksygrupper med det oksygenatom som befinner seg ved pyrimidinkjernen, har mellom alkoksygruppen og den nevnte oksygenatom minst to karbonatomer og inneholder fortrinnsvis 2—5 karbonatomer, og betyr spesielt 1,2-etylen, videre 1,2-, 2,3- eller 1,3-propylen, rett-kjedet eller forgrenet, i vilkårlig stilling forbun-det butylen eller pentylen, som imidlertid skiller nabo-oksygenatomene med minst to karbonatomer. The alkoxy groups that are contained in the lower-alkyl-lower-alkyl-acid residues are e.g. those mentioned above. The alkylene residue which connects these alkoxy groups to the oxygen atom located at the pyrimidine nucleus has between the alkoxy group and the aforementioned oxygen atom at least two carbon atoms and preferably contains 2-5 carbon atoms, and in particular means 1,2-ethylene, further 1,2-, 2, 3- or 1,3-propylene, straight-chain or branched, in any position connected to butylene or pentylene, which, however, separates the neighboring oxygen atoms by at least two carbon atoms.
Som halogenatomer kommer særlig Mor-eller fluoratomer på tale. Examples of halogen atoms include Mor or fluorine atoms in particular.
Som Nj-acylderivater skal særlig nevnes slike hvori acylresten er en lavere alifatisk eller en aromatisk eller aralifatisk karbonsyrerest, f. eks. en karbalkoksyrest, slik som karbetoksyresten, eller fortrinnsvis resten av en fettsyre, f. eks. en lavere fettsyre, slik som propionyl-, butyryl-, va-leryl- eller kaproylrest, eller av en høyere fettsyre, f. eks. lauroyl-, palmityl- eller oleylrest, av en fenylfettsyre, slik som fenyleddiksyre, eller en benzosyre, slik som benzosyren. I første rekke er imidlertid acylresten acetylresten. As Nj-acyl derivatives, particular mention should be made of those in which the acyl residue is a lower aliphatic or an aromatic or araliphatic carboxylic acid residue, e.g. a carbalkoxy residue, such as the carbethoxy residue, or preferably the residue of a fatty acid, e.g. a lower fatty acid, such as a propionyl, butyryl, valeryl or caproyl residue, or of a higher fatty acid, e.g. lauroyl, palmityl or oleyl residue, of a phenyl fatty acid, such as phenylacetic acid, or a benzoic acid, such as benzoic acid. However, primarily the acyl residue is the acetyl residue.
De nye forbindelser har gode antibakterielle egenskaper. F. eks. oppviser de ved eksperimen-tell infeksjon på dyr, f. eks. mus, en meget god helbredelsesvirkning mot gram-positive bakte-rier, slik som f. eks. streptokokker, stafylokok-ker, pneumokokker og kolibasiller. De har like overfor sammenlignbare kjente forbindelser for-deler. Således er den mengde sulfonamid som etter gjennomførte forsøk er utskilt i menneske-urin vesentlig mindre acetylert. De kan derfor tjene som kemoterapeutika, f. eks. ved bakte-rielle infeksjoner, særlig av urinveiene. De er imidlertid også egnet som tilsetninger til dyre-formidler, og kan tjene som mellomprodukter for fremstilling av andre verdifulle kemoterapeutika. The new compounds have good antibacterial properties. For example do they exhibit experimental infection in animals, e.g. mice, a very good healing effect against gram-positive bacteria, such as e.g. streptococci, staphylococci, pneumococci and colibacilli. They have advantages similar to those of comparable known compounds. Thus, the amount of sulfonamide that is excreted in human urine after experiments has been carried out is significantly less acetylated. They can therefore serve as chemotherapeutics, e.g. in bacterial infections, especially of the urinary tract. However, they are also suitable as additives to animal mediators, and can serve as intermediates for the production of other valuable chemotherapeutics.
Særlig skal fremheves forbindelser med formlene Connections with the formulas must be highlighted in particular
hvori R5og R(, betyr lavere alkylrester og n betyr 1, 2 eller 3, og særlig 6-(p-aminobenzol-sulfonamido) -2- (metoksymetyl) -4-metoksy-pyrimidin samt N,-acylderivatene av disse forbindelser. Oppfinnelsen vedrører altså en fremgangs^måte til fremstilling av 6-(p-aminobenzolsulf onamido)-pyrimidiner med formelen hvori en av restene R, og R, betyr en lavere-alkoksy-lavere-alkylrest og den andre betyr et hydrogenatom, et halogenatom, en lavere alkylrest, en lavere alkoksyrest, en lavere-alkoksy-lavere-alkylrest eller en lavere-alkoksy-lavere-alkoksyrest og deres ^-acylderivater, og erkarakterisert veda) at man omsetter en forbindelse med formelen med en forbindelse med formelen idet Y betyr en fri aminogruppe og Ytbetyr et halogenatom, eller Y betyr et halogenatom, en fri eller substituert merkaptogruppe, en alkylert hydroksylgruppe, en alkylsulfonylgruppe eller en ammoniumgruppe og Ytbetyr en fri aminogruppe, Z betyr aminogruppen eller en ved reduksjon eller hydrolyse i aminogruppen overfør-bar substituent Zv og Rj og R2 har den angitte betydning, eller b) at man omsetter en forbindelse med formelen hvori Z har den ovenfor angitte betydning og en av restene R/ og R2' betyr en lavere-alkoksy-lavere-alkylrest og den annen en ammoniumgruppe eller halogenatom, med et lavere-alkanolat eller lavere-alkoksy-lavere-alkanolat, og i de dannede forbindelser som inneholder resten Z, hydrolyserer resp. reduserer Z, til aminogruppen og/eller hydrolyserer eller aminolyserer dannede bis-p-Z-benzolsulfonylforbindelser og/ eller hvis ønsket, Nt-acylerer dannede forbindelser og/eller overfører dannede frie forbindelser i deres salter eller dannede salter i de frie forbindelser. Denne omsetning foregår på i og for seg kjent måte. Ved omsetningen av et p-Z-ben-zolsulfonsyrehalogenid fremfor alt kloridet, med en forbindelse med formel in which R5 and R(, mean lower alkyl residues and n means 1, 2 or 3, and in particular 6-(p-aminobenzene-sulfonamido)-2-(methoxymethyl)-4-methoxy-pyrimidine as well as the N,-acyl derivatives of these compounds. The invention thus relates to a process for the preparation of 6-(p-aminobenzenesulfonamido)-pyrimidines with the formula in which one of the residues R, and R, means a lower- alkyl-lower-alkyl residue and the other means a hydrogen atom, a halogen atom, a lower alkyl residue, a lower alkoxy acid residue, a lower-alkyl-lower-alkyl residue or a lower-alkyl-lower-alkyl-acid residue and their ^-acyl derivatives, and is characterized by) reacting a compound of the formula with a compound of the formula where Y means a free amino group and Yt means a halogen atom, or Y means a halogen atom, a free or substituted mercapto group, an alkylated hydroxyl group, an alkylsulfonyl group or an ammonium group and Yt means a free amino group, Z means the amino group or a by reduction or hydrolysis in the amino group overf volatile substituent Zv and Rj and R2 have the indicated meaning, or b) that one reacts a compound with the formula in which Z has the above-mentioned meaning and one of the radicals R/ and R2' means a lower-alkyl-lower-alkyl radical and the other an ammonium group or halogen atom, with a lower-alkanolate or lower-alkoxy-lower-alkanolate, and in the compounds formed containing the residue Z, hydrolyze resp. reduces Z, to the amino group and/or hydrolyzes or aminolyzes formed bis-p-Z-benzenesulfonyl compounds and/or if desired, Nt-acylates formed compounds and/or transfers formed free compounds into their salts or formed salts into the free compounds. This turnover takes place in a manner known per se. In the reaction of a p-Z-benzenesulfonic acid halide above all the chloride, with a compound of the formula
idet Z, R, og R2har den ovenfor nevnte betydning, anvendes de vanlige kondensasj onsmidler, f. eks. alkalikarbonater, fremfor alt imidlertid ' tertiære organiske baser, som pyridin, picolin, lutidin, collidin, lavere trialkylaminer, som tri-metyl- eller trietylamin, eller N,N'-tetraalkyl-diaminoalkaner, som f. eks. N,N'-teterametyl-(OiCoVdiaminoheksan, eller selve aminopyrimidi-net, og.eventuelt i vanlige fortynningsmidler som since Z, R, and R2 have the meaning mentioned above, the usual condensation agents are used, e.g. alkali carbonates, above all, however, tertiary organic bases, such as pyridine, picoline, lutidine, collidine, lower trialkylamines, such as trimethyl- or triethylamine, or N,N'-tetraalkyldiaminoalkanes, such as e.g. N,N'-tetramethyl-(OiCoVdiaminohexane, or the aminopyrimidine itself, and possibly in common diluents such as
vann, benzol, toluol, metylenklorid, kloroform, metyletylketon, aceton, dioksan, nitrobenzol og lignende eller blandinger herav. Derved lar alt etter reaksjonsbetingelser, som kondensasjonsmidler, reaksjonstemperatur, fortynningsmidler eller anvendelse av et overskudd av sulfonsyre-halogenid, bis-p-Z-benzolsulfonylforbindelsene seg fremstille som biprodukter eller som hoved-produkt som på i og for seg kjent måte lar seg hydrolysere eller aminolysere i mono-p-Z-benzolsulfonylforbindelser eventuelt samtidig med en eventuell hydrolyse av resten Zrwater, benzene, toluene, methylene chloride, chloroform, methyl ethyl ketone, acetone, dioxane, nitrobenzene and the like or mixtures thereof. Thereby, depending on the reaction conditions, such as condensation agents, reaction temperature, diluents or the use of an excess of sulfonic acid halide, the bis-p-Z-benzenesulfonyl compounds can be produced as by-products or as the main product which can be hydrolyzed or aminolyzed in a manner known per se mono-p-Z-benzenesulfonyl compounds optionally simultaneously with a possible hydrolysis of the residue Zr
Ved omsetningen av et p-Z-benzolsulfon-syreamid med en forbindelse med formel II, hvori Y betyr et halogenatom, og Z har den angitte betydning anvender man p-Z-benzolsulfon-syreamidet hensiktsmessig i form av et metallsalt, f. eks. et alkali- eller jordalkalimetall-salt, eller arbeider i nærvær av slike saltdan-nende kondensasjonsmidler. Ved anvendelse av 6-alkylsulfonyl- eller 6-ammonium-2-R1-R-R2-pyrimidiner har det dessuten vist seg som spe-silet fordelaktig anvendelsen av et syreamid som et laverealkanoylamid, f. eks. acetamid eller dimetylformamid, som fortynningsmiddel. Sist-nevnte fremgangsmåte gående ut fra 6-halogen-, alkylsulfonyl- eller -ammoniumpyrimidiner, har den fordel at de er meget godt gjennomførbare med p-Z-benzol-sulfonsyreamider, hvori Z an-gir den frie aminogruppe, mens ved de øvrige fremgangsmåter Z hensiktsmessig betyr en ved reduksjon eller hydrolyse i aminogruppen over-førbar rest Zj. In the reaction of a p-Z-benzenesulfonic acid amide with a compound of formula II, in which Y means a halogen atom, and Z has the indicated meaning, the p-Z-benzenesulfonic acid amide is suitably used in the form of a metal salt, e.g. an alkali or alkaline earth metal salt, or working in the presence of such salt-forming condensing agents. When using 6-alkylsulfonyl or 6-ammonium-2-R1-R-R2-pyrimidines, the use of an acid amide such as a lower alkanoyl amide, e.g. acetamide or dimethylformamide, as diluent. The last-mentioned method, based on 6-halogen, alkylsulfonyl or -ammonium pyrimidines, has the advantage that they are very easily carried out with p-Z-benzenesulfonic acid amides, in which Z denotes the free amino group, while in the other methods Z is appropriate means a transferable residue Zj by reduction or hydrolysis in the amino group.
Resten i formel II er f. eks. en ammonium- The remainder in formula II is e.g. an ammonium
gruppe, slik som en trialkylammoniumgruppe, som på kjent måte kan omdannes til en lavere alkoksyrest eller til en lavere-alkoksy-lavere-alkyloksyrest. Denne omdannelse foregår på vanlig måte, f. eks. ved omsetning med lavere alkanolater eller lavere-alkoksy-lavere-alkanolater, f. eks. alkalimetallforbindelsene. group, such as a trialkylammonium group, which can be converted in a known manner to a lower alkoxy acid residue or to a lower-alkyloxy-lower-alkyloxy acid residue. This conversion takes place in the usual way, e.g. by reaction with lower alkanolates or lower-alkyl-lower-alkanolates, e.g. the alkali metal compounds.
Y kan f. eks. også være en hydroksylgruppe som på vanlig måte, f. eks. ved behandling med halogenider av svovel eller fosfor, slik som fosforoksyklorid eller fosfortribromid, kan overføres til et halogenatom. Y can e.g. also be a hydroxyl group which in the usual way, e.g. on treatment with halides of sulfur or phosphorus, such as phosphorus oxychloride or phosphorus tribromide, can be transferred to a halogen atom.
Den etterfølgende omdannelse av resten Zlftil aminogruppen foregår på i for seg kjent måte. The subsequent conversion of the residue Z to the amino group takes place in a manner known per se.
Resten Zler hensiktsmessig en rest som er vanlig i sulfonamidkjemien og som kan omdannes til aminogruppen, fremfor alt en ved reduksjon eller hydrolyse til aminogruppen omdann-bar rest. Rester som kan omdannes til aminogruppen ved hydrolyse er f. eks. acylaminogrupper, fremfor alt alifatiske acylaminogrupper, slik som karbalkoksyaminogrupper, f. eks. kar-betoksyaminogruppen, alkanoylaminogruppen, slik som propionyl-, butyryl- eller kaproylamino-gruppen, fremfor alt acetylaminogruppen, diha-logenfosforylaminogruppen, f. eks. diklorfosfor-ylaminogruppen, eller metylidenaminogruppen, slik som f. eks. alkyliden- eller benzylidenamino-gruppen, fremfor alt isopropyliden- eller benzyl-idenaminogruppen. Acylresten i acylaminogrup-pen kan også være acylrester av to-basiske syrer. Således kan man også anvende utgangsstoffer . med formelen The residue Z is suitably a residue which is common in sulfonamide chemistry and which can be converted into the amino group, above all a residue which can be converted into the amino group by reduction or hydrolysis. Residues that can be converted to the amino group by hydrolysis are e.g. acylamino groups, above all aliphatic acylamino groups, such as carbaloxyamino groups, e.g. the car-bethoxyamino group, the alkanoylamino group, such as the propionyl, butyryl or caproylamino group, above all the acetylamino group, the dihalophosphorylamino group, e.g. the dichlorophosphorylamino group, or the methylideneamino group, such as e.g. the alkylidene or benzylideneamino group, above all the isopropylidene or benzylideneamino group. The acyl residue in the acylamino group can also be acyl residues of dibasic acids. Thus, starting materials can also be used. with the formula
hvori R betyr acylresten av en to-verdig syre, fremfor alt kullsyre, eller f. eks. også av en al-kandikarbonsyre, og Yu R,' og R2' har den angitte betydning. En rest som ved reduksjonen kan omdannes til aminogruppen er f. eks. en ved hydrogenolyse spaltbar acyl-aminogruppe, slik som karboben-zokysaminogruppen eller nitrogruppen, eller en azogruppe, slik som en aryl-, fremfor alt fenyl-azogruppe, idet det ved siste tilfelle særlig anvendes forbindelser med formelen in which R means the acyl residue of a divalent acid, above all carbonic acid, or e.g. also of an al-candicarboxylic acid, and Yu R,' and R 2' have the indicated meaning. A residue that can be converted to the amino group during the reduction is e.g. an acyl-amino group cleavable by hydrogenolysis, such as the carbobenzoxysamino group or the nitro group, or an azo group, such as an aryl, above all phenyl-azo group, in the latter case in particular compounds of the formula are used
som utgangsmaterialet, hvori Y1, R^ og R2' har den angitte betydning. as the starting material, wherein Y 1 , R 1 and R 2 ' have the indicated meaning.
Hydrolysen, aminolysen, henholdsvis reduksjonen av de nevnte grupper, utføres på i og for seg kjent måte. The hydrolysis, aminolysis, respectively the reduction of the aforementioned groups, is carried out in a manner known per se.
En særlig fordelaktig arbeidsmåte består i at man omsetter p-acetylamino-benzolsulfoklorid med en 6-amino-2-R1-4-R2-pyrimidin og hydrolyserer kondensasjonsproduktet. A particularly advantageous working method consists in reacting p-acetylamino-benzene sulphochloride with a 6-amino-2-R1-4-R2-pyrimidine and hydrolysing the condensation product.
Nj-acyleringen utføres på vanlig måte under anvendelse av N^acylerende middel.. Slike er fremfor alt syreanhydrider eller -halogenider, slik som klorider. Reaksjonen utføres hensiktsmessig i nærvær av basiske midler, slik som anorganiske eller organiske baser, f. eks. alkalikarbonater eller tertiære aminer, slik som pyridin, pikolin, lutidin, kollidin, trimetylamin, trietylamin, tributylamin eller 1,6-bis-dimetyl-amino-heksan, og i nærvære av inerte fortynningsmidler, særlig organiske oppløsningsmidler, slik som dioksan, benzol, toluol, halogenerte hyd-rokarboner, f. eks. metylenklorid eller kloroform, dimetylformamid, lavere alifatiske ketoner, slik som aceton eller metyletylketon, eller eventuelt selve det basiske middel, slik som f. eks. pyridin eller blandinger av disse, slik som særlig pyridin-aceton. Fordelaktig arbeider man i mest mulig vannfritt medium. Anvendes et syrehalogenid kan man også anvende et metallsalt av sulf ona-midet, f. eks. et alkalisalt eller bedre sølvsaltet, hvorved den ovenfor anbefalte tilsettelse av basiske midler overflødiggjøres. Det er imidlertid intet i veien for deres ekstra anvendelse, f. eks. som fortynningsmiddel. The N-acylation is carried out in the usual way using an N-acylating agent. Such are above all acid anhydrides or -halides, such as chlorides. The reaction is conveniently carried out in the presence of basic agents, such as inorganic or organic bases, e.g. alkali carbonates or tertiary amines, such as pyridine, picoline, lutidine, collidine, trimethylamine, triethylamine, tributylamine or 1,6-bis-dimethylamino-hexane, and in the presence of inert diluents, especially organic solvents, such as dioxane, benzene, toluene, halogenated hydrocarbons, e.g. methylene chloride or chloroform, dimethylformamide, lower aliphatic ketones, such as acetone or methyl ethyl ketone, or optionally the basic agent itself, such as e.g. pyridine or mixtures thereof, such as in particular pyridine-acetone. It is advantageous to work in a medium that is as water-free as possible. If an acid halide is used, a metal salt of the sulfonamide can also be used, e.g. an alkali salt or better the silver salt, whereby the addition of basic agents recommended above is made redundant. However, there is nothing in the way of their additional use, e.g. as a diluent.
Ved Nj-acyleringen av forbindelse, hvori Z betyr aminogruppen, må det tas hensyn til at reaksjonen utføres under milde betingelser og under anvendelse av omtrent ekvimolekylare mengder av reaksjonsdeltagerne for å unngå at det dannes NpN^bis-acylforbindelser eller ved acylvandring N4-acylforbindelser. Fordelaktig arbeider man derfor ved lave temperaturer, f. eks. under 40°C, slik som mellom 10 og 30°C, og i vannfritt medium. Ved anvendelse av syrehalo-genidet anbefales det å gå ut fra metallsaltene av sulfonamidet, slik som sølvsaltet. In the Nj-acylation of a compound in which Z means the amino group, care must be taken that the reaction is carried out under mild conditions and using approximately equimolecular amounts of the reaction participants to avoid the formation of NpN^bis-acyl compounds or, in the case of acyl migration, N4-acyl compounds. It is therefore advantageous to work at low temperatures, e.g. below 40°C, such as between 10 and 30°C, and in anhydrous medium. When using the acid halide, it is recommended to proceed from the metal salts of the sulfonamide, such as the silver salt.
Innfører man acylresten i N^nitrogenato-met i en forbindelse hvori Z ikke betyr aminogruppen, går man fortrinnsvis ut fra forbindelser hvori Z betyr en gruppe som ved reduksjon kan overføres til aminogruppen. Denne re-duseres da på i og for seg kjent måte, hensiktsmessig under unngåelse av hydrolyserende betingelser og høyere temperaturer for å hindre avspaltning eller omleiring av N,-acylresten ved N,-nitrogenatomet. Særlig egnet er reduksjonen med hydrogen i nærvær av katalysatorer, f. eks. edelmetallkatalysatorer, slik som palladium på kull. If you introduce the acyl residue in the N-nitrogen atom in a compound in which Z does not mean the amino group, you preferably proceed from compounds in which Z means a group which can be transferred to the amino group by reduction. This is then reduced in a manner known per se, expediently avoiding hydrolyzing conditions and higher temperatures in order to prevent cleavage or rearrangement of the N,-acyl residue at the N,-nitrogen atom. Particularly suitable is the reduction with hydrogen in the presence of catalysts, e.g. noble metal catalysts, such as palladium on charcoal.
I erholdte forbindelser kan man innenfor rammen av de til å begynne med definerte slutt-stoffer på vanlig måte omdanne substituenter eller erstatte med hydrogen. Således kan man f. eks. erstatte halogenatomer, slik som klor eller brom, med lavere alkoksyrester eller lavere-alkoksy-lavere-alkoksyrester, f. eks. ved omsetning med lavere alkanolater eller lavere-alkoksy-lavere-alkanolater, f. eks. alkalimetallforbindelsene, eller man kan erstatte halogenatomer på vanlig måte, f. eks. ved hydrering i nærvær av katalysatorer, slik som nikkelkatalysatorer, med hydrogen. In the compounds obtained, within the framework of the initially defined final substances, substituents can be converted in the usual way or replaced with hydrogen. Thus, one can e.g. replace halogen atoms, such as chlorine or bromine, with lower olefinic residues or lower-alkoxy-lower-alkoic residues, e.g. by reaction with lower alkanolates or lower-alkyl-lower-alkanolates, e.g. the alkali metal compounds, or one can replace halogen atoms in the usual way, e.g. by hydrogenation in the presence of catalysts, such as nickel catalysts, with hydrogen.
Alt etter fremgangsmåtebetingelsene og utgangsstoffene får man sluttstoffene i fri form eller i form av deres salter som likeledes innbe-fattes i oppfinnelsen. Som salter er spesielt å nevne metallsalter, særlig slike med alkali-, jordalkali- eller j ordmetaller, slik som natrium, kalium, kalcium, magnesium eller aluminium. Saltene av de nye forbindelser kan på i og for seg kjent måte overføres til de frie forbindelser, f. eks. ved reaksjon med sure midler, slik som syrer. På den annen side kan erholdte frie sulfonamider, som ved Nj-nitrogenatomet oppviser et hydrogenatom, omdannes til deres salter ved omsetning med baser, særlig med terapeutiske anvendelige baser, slik som hydroksyder av alkali-, jordalkali- eller jordmetaller, f. eks. natrium-, kalium- eller kalsiumhydroksyder. Depending on the process conditions and the starting substances, the final substances are obtained in free form or in the form of their salts, which are likewise included in the invention. As salts, special mention should be made of metal salts, especially those with alkali, alkaline earth or earth metals, such as sodium, potassium, calcium, magnesium or aluminium. The salts of the new compounds can be transferred to the free compounds in a manner known per se, e.g. by reaction with acidic agents, such as acids. On the other hand, free sulfonamides obtained, which have a hydrogen atom at the N-nitrogen atom, can be converted into their salts by reaction with bases, in particular with therapeutically applicable bases, such as hydroxides of alkali, alkaline earth or earth metals, e.g. sodium, potassium or calcium hydroxides.
Disse eller andre salter av de nye forbindelser kan også tjene til rensning av de erholdte sulfonamidforbindelser, idet man overfører de frie sulfonamider til saltene og skiller disse fra, og setter de frie sulfonamider i frihet fra saltene igjen. På grunn av det nære slektskap mellom de nye forbindelser i fri form og i form av deres salter, skal i det foregående og i det følgende med frie forbindelser likeledes forstås de tilsvarende salter. These or other salts of the new compounds can also be used to purify the sulphonamide compounds obtained, by transferring the free sulphonamides to the salts and separating them, and setting the free sulphonamides free from the salts again. Due to the close relationship between the new compounds in free form and in the form of their salts, in the preceding and in the following, free compounds shall also be understood as the corresponding salts.
For reaksjonen ifølge oppfinnelsen anvendes fortrinnsvis slike utgangsstoffer som gir de ovenfor nevnte foretrukne forbindelser. For the reaction according to the invention, such starting materials are preferably used which give the above-mentioned preferred compounds.
Utgangsstoffene er delvis kjent eller kan, såfremt de er nye, fås ifølge i og for seg kjente fremgangsmåter. The starting materials are partially known or, if they are new, can be obtained according to methods known per se.
De som utgangsstoffer anvendte 2-lavere-alkoksy-lavere-alkyl-4-R4-6-R7-pyrimidiner, hvori R4 betyr et hydrogenatom, et halogenatom, en lavere alkoksyrest eller en lavere-alkoksy-lavere-alkoksyrest og R7betyr en fri hydroksyl-, merkapto- eller aminogruppe, eller en substituert merkaptogruppe, slik som en alkyl- eller benzylmerkaptogruppe, eller et halogenatom, slik som klor eller brom, kan f. eks. fås når man omsetter amidiner av lavere-alkoksy-lavere-alkansyrer eller deres salter med malonsyre-dietylester eller diacetonitril og, om ønskes, i erholdte forbindelser omdanner hydroksygrupper i 4- og/eller 6-stilling til halogenatomer og/eller hydroksygrupper i 6-stilling til merkaptogrupper og/eller halogenatomer i 6-stilling til frie eller substituerte merkaptogrupper, eller til frie aminogrupper og eventuelt omdanner frie merkaptogrupper i 6-stilling til substituerte merkaptogrupper og/eller frie eller substituerte merkaptogrupper til frie aminogrupper, og/eller omdanner halogenatomer i 4-stilling til lavere alkoksygrupper eller lavere-alkoksy-lavere-alkoksygrupper, eller erstatter med hydrogen. Those used as starting materials 2-lower-alkoxy-lower-alkyl-4-R4-6-R7-pyrimidines, in which R4 means a hydrogen atom, a halogen atom, a lower alkoxy acid residue or a lower-alkoxy-lower-alkyl acid residue and R7 means a free hydroxyl -, mercapto or amino group, or a substituted mercapto group, such as an alkyl or benzyl mercapto group, or a halogen atom, such as chlorine or bromine, can e.g. obtained when one reacts amidines of lower-alkoxy-lower-alkanoic acids or their salts with malonic acid diethyl ester or diacetonitrile and, if desired, in the obtained compounds convert hydroxy groups in the 4- and/or 6-position to halogen atoms and/or hydroxy groups in the 6- position to mercapto groups and/or halogen atoms in the 6-position to free or substituted mercapto groups, or to free amino groups and optionally converts free mercapto groups in the 6-position to substituted mercapto groups and/or free or substituted mercapto groups to free amino groups, and/or converts halogen atoms in 4-position to lower alkoxy groups or lower-alkyl-lower-alkyl groups, or replaces with hydrogen.
De ovenfor nevnte amidiner fås f. eks. når man omdanner tilsvarende lavere-alkoksy-lave-realkansyrenitriler til deres imidoetere og omsetter disse med ammoniakk. The above-mentioned amidines are obtained, e.g. when one converts corresponding lower-alkyl-lower-real alkanoic acid nitriles into their imidoethers and reacts these with ammonia.
De nevnte reaksjoner utføres på i og for seg kjent måte, fortrinnsvis i nærvær av fortyn ningsmidler og eventuelt ved forhøyet temperatur, og/ellef i nærvær av kondensasjonsmidler. The aforementioned reactions are carried out in a manner known per se, preferably in the presence of diluents and possibly at an elevated temperature, and/or in the presence of condensing agents.
De nye forbindelser kan anvendes f. eks. i The new compounds can be used e.g. in
form av farmasøytiske preparater, som inneholder det aktive stoff i blanding med ett for ente-ral, parenteral eller topikal anvendelse egnet farmasøytiske, organiske eller anorganiske, fast eller flytende bæremateriale. form of pharmaceutical preparations, which contain the active substance in admixture with a pharmaceutical, organic or inorganic, solid or liquid carrier material suitable for enteral, parenteral or topical application.
De nye virksomme forbindelser kan også finne anvendelse som tilsetning av dyrefor-midler. The new active compounds can also be used as additives to animal products.
Oppfinnelsen beskrives i de følgende ek-sempler. Temperaturen er angitt i Celsiusgrader. The invention is described in the following examples. The temperature is indicated in degrees Celsius.
Eksempel 1.Example 1.
En blanding av 19,3 g 2-(metoksymetyl)-4,6-diklorpyrimidin, 17,2 g p-amino-benzolsulfona-mid og 13,8 g vannfri potteaske oppvarmes i 2 timer til 150°C, hvorved karbondioksyd unn-viker under oppskumming. Ved avkjøling stiv-ner reaksjonsblandingen, den tilsettes 150 cm3 vann, og det uoppløste p-amino-benzolsulfona-mid skilles fra<p>g filtratet nøytraliseres med konsentrert saltsyre, hvorved 6-(p-amino-benzol-sulf onamido) -2- (metoksy metyl) -4-klor-pyrimidin med formelen A mixture of 19.3 g of 2-(methoxymethyl)-4,6-dichloropyrimidine, 17.2 g of p-amino-benzenesulfonamide and 13.8 g of anhydrous pot ash is heated for 2 hours to 150°C, whereby carbon dioxide escapes gives way during foaming. On cooling, the reaction mixture solidifies, 150 cm3 of water is added to it, and the undissolved p-amino-benzenesulfonamide is separated from<p>g the filtrate is neutralized with concentrated hydrochloric acid, whereby 6-(p-amino-benzene-sulfonamido)-2 -(methoxy methyl)-4-chloro-pyrimidine of the formula
faller ut. Det renses ved utkokning med vann og omkrystallisasj on fra alkohol. Smeltepunkt 150—151°C. falling out. It is purified by boiling with water and recrystallization from alcohol. Melting point 150-151°C.
Det som utgangsprodukt anvendte 2-(metoksymetyl(5-4,6-diklor-pyrimidin fremstilles som følger: 355 g metoksyacetonitril settes til 300 ems etanol og ved 0°C innføres saltsyre som er tør-ket over konsentrert svovelsyre inntil metning. Man lar reaksjonsblandingen stå natten over i kjøleskap ved 5°C. Deretter suges raskt fra og det ennå eterfuktige metoksyacetimino-etyleterhydroklorid innføres under avkjøling i 500 cm<»>12 pst.-ig ammoniakalsk etanol. Etter 12 timers omrystning frafiltreres det utfelte ammoniumklorid og filtratet inndampes i vakuum ved 50°C. Metoksyacetamidin-hydroklorid utkrystalliserer og smelter etter omkrystallisasj on fra etanol - eter ved 70°C. The 2-(methoxymethyl(5-4,6-dichloro-pyrimidine) used as starting product is prepared as follows: 355 g of methoxyacetonitrile is added to 300 ems ethanol and at 0°C hydrochloric acid is introduced which has been dried over concentrated sulfuric acid until saturation. leave the reaction mixture overnight in a refrigerator at 5° C. Then quickly suction off and the still ether-moist methoxyacetimino ethyl ether hydrochloride introduced under cooling into 500 cm<»>12% ammoniacal ethanol. After 12 hours of shaking, the precipitated ammonium chloride is filtered off and the filtrate is evaporated in vacuum at 50° C. Methoxyacetamidine hydrochloride crystallizes out and melts after recrystallization from ethanol - ether at 70° C.
148 g av dette amidin-hydroklorid oppløses sammen med 160 g malonsyre-dietylester i 300 cm3 metanol, og ved 50 °C lar man en natrium - metylatoppløsning av 69 g natrium og 700 cm<3>metanol dryppe til under omrøring innen 1 time og omrører ved denne temperatur i 12 timer. Reaksjonsblandingen inndampes i vakuum til tørrhet. Resten oppløser man i varmt vann, nøytraliserer med iseddik. Ved avkjøling utskil-les 4,6-dihydroksy-2- (metoksymetyl) -pyrimidin krystallinsk. Stoffet spaltes ved 210°C. 148 g of this amidine hydrochloride are dissolved together with 160 g of malonic acid diethyl ester in 300 cm3 of methanol, and at 50 °C a sodium methylate solution of 69 g of sodium and 700 cm3 of methanol is allowed to drip in with stirring within 1 hour and stirring at this temperature for 12 hours. The reaction mixture is evaporated in vacuo to dryness. The rest is dissolved in warm water, neutralized with glacial acetic acid. On cooling, 4,6-dihydroxy-2-(methoxymethyl)-pyrimidine separates out crystalline. The substance decomposes at 210°C.
78 g av denne forbindelse oppvarmes sammen med 300 cm<3>fosforoksyklorid og 101 g tri- 78 g of this compound are heated together with 300 cm<3>phosphorus oxychloride and 101 g of tri-
Btylamin ved 140°C i oljebad i iy2time. Ved fraksjonert destillasjon får man direkte 2-(met-Dksymetyl)-4,6-diklorpyrimidin i ren form, smeltepunkt 41 °C. Butylamine at 140°C in an oil bath for iy2 hours. By fractional distillation, 2-(meth-Doxymethyl)-4,6-dichloropyrimidine is obtained directly in pure form, melting point 41 °C.
Eksempel 2.Example 2.
35,3 g p-acetylamino-benzolsulfoklorid opp-løses i 100 g nitrobenzol. Under omrøring inn-føres 17,3 g 2-(metoksymetyl)-4-klor-6-amino-pyrimidin ved 60 °C, det røres videre i 20 min. og deretter innledes ved samme temperatur 10 g trimetylamin i gassform. Etter 2 timer drives trimetylaminet av ved tilsetning av 5-n. natronlut og oppvarmning til 100—105°C og forsåpes. Nitrobenzolet skilles fra og fra det vandige lag får man det med det i eksempel 1 fremstilte produkt identiske 6-(p-amino-benzolsulfonamido)-2-(metoksymetyl)-4-klorpyrimidin ved nøytrali-sasjon med konsentrert saltsyre. 35.3 g of p-acetylaminobenzene sulphochloride are dissolved in 100 g of nitrobenzene. While stirring, 17.3 g of 2-(methoxymethyl)-4-chloro-6-amino-pyrimidine are introduced at 60 °C, stirring continues for 20 min. and then 10 g of trimethylamine in gaseous form are introduced at the same temperature. After 2 hours, the trimethylamine is driven off by the addition of 5-n. caustic soda and heating to 100-105°C and saponification. The nitrobenzene is separated from the aqueous layer and the identical 6-(p-amino-benzenesulfonamido)-2-(methoxymethyl)-4-chloropyrimidine is obtained with the product prepared in example 1 by neutralization with concentrated hydrochloric acid.
Eksempel 3.Example 3.
10 g 2-(metoksyetyl)-4-metyl-6-aminopyri-midin og 15 g p-acetylaminobenzolsulfo-klorid oppløses i 100 cm<:i>pyridin. Blandingen holdes 1 time ved 90 °C, filtreres varmt og det erholdte filtrat bringes på en pH 2—3 med konsentrert saltsyre. Det frafiltrerte bunnfall oppvarmes med 250 cm3 2-n. natronlut i 2 timer i 90—95°C, oppløsningen filtreres varmt, behandles med aktiv-kull og innstilles på pH lik 6, under isav-kjøling med 50 pst. eddiksyre. Det krystallinske utfelte 6- (p-aminobenzolsulfonamido) -2- (metoksyetyl)-4-metylpyrimidin med formelen 10 g of 2-(methoxyethyl)-4-methyl-6-aminopyrimidine and 15 g of p-acetylaminobenzene sulphochloride are dissolved in 100 cm<:i>pyridine. The mixture is held for 1 hour at 90 °C, filtered hot and the filtrate obtained is brought to a pH of 2-3 with concentrated hydrochloric acid. The filtered precipitate is heated with 250 cm3 2-n. caustic soda for 2 hours at 90-95°C, the solution is filtered hot, treated with activated charcoal and adjusted to pH equal to 6, under ice-cooling with 50 per cent acetic acid. The crystalline precipitated 6-(p-aminobenzenesulfonamido)-2-(methoxyethyl)-4-methylpyrimidine of the formula
smelter etter omkrystallisasj on fra etanol/vann ved 244—245°C. melts after recrystallization from ethanol/water at 244-245°C.
Det som utgangsmateriale anvendte 2-(metoksyetyl)-4-metyl-6-aminopyrimidin kan fås som følger: I en oppløsning av 85 g p-metoksypropioni-tril og 60 ems etanol innledes ved 0°C over konsentrert svovelsyre inntil metning. Det utfelte p-metoksypropionimino-etyleterhydroklorid suges fra og fremdeles eterfuktig innføres det i 200 cm» 16 pst.-ig ammoniakalsk etanol, blandingen rystes i 12 timer og det utfelte ammoniumklorid frafiltreres. Oppløsningen inndampes i vakuum ved 50 °C, den krystallinske masse oppslemmes deretter med eter og frafiltreres. (3-metoksy-propionamidin-hydroklorid smelter etter omkrystallisasj on fra etan ol/eter ved 85— 86°C. 13,8 g {3-metoksypropionamidin-hydroklorid og 8,2 g diacetonitril pulveriseres sammen og oppvarmes med 50 cm<3>iseddik i 8 timer ved 120°C. Det erholdte bunnfall frafiltreres og det .krystalliseres fra vann. Man får således 2-(metoksyetyl)-4-metyl-6-aminopyrimidin med smeltepunkt 254—255°C. På analog måte som beskrevet ovenfor, kan man av p-acetylaminobenzol-sulfonylklorid og 2-(met6ksyetyl)-6-amino-pyrimidin, 2-(metoksy-etyl) -4-klor-6-aminopyrimidin, 2- (metoksyetyl) -4-metoksy-6-aminopyrimidin, 4- (metoksymetyl)-6-aminopyrimidin, 2-klor-4-(metoksymetyl)-6-aminopyrimidin, 2-metoksy-4-(metoksymetyl) -6-aminopyrimidin, 2,4-di- (metoksymetyl ) - 6-aminopyrimidin, 2 -metyl -4 - (met - oksyetyl)-6-aminopyrimidin, 2-klor-4- (metoksyetyl)-6-aminopyrimidin, eller 2-metoksy-4-(metoksyetyl)-6-aminopyrimidin få 6-(p-aminobenzolsulfonamido)-2-(metoksyetyl)-, 6-(p-aminobenzolsulfonamido)-2-(metoksyetyl)-4-klor-, 6-(p-aminobenzalsuJ!fonamido)-2-(metoksyetyl)-4 -metoksy, 6- (p-aminobenzolsulfonamido) -4-(metoksymetyl)-, 6- (p-aminobenzolsulfonamido) -2-klor-4- (metoksymetyl) -, 6- (p-aminobenzolsulf onamido) -2-metoksy-4- (metoksymetyl)- 6-(p-aminobenzolsulfonamido)-2,4-di-(metoksymetyl)-, 6-(p-aminobenzolsulfonami- . do) -2-metyl-4- (metoksyetyl) -, 6- (p-aminobenzolsulfonamido)-2-klor-4-(metoksyetyl)- henholdsvis 6- (p-aminobenzolsulf onamido) -2-metoksy-4- (metoksyetyl) -pyrimidin. The 2-(methoxyethyl)-4-methyl-6-aminopyrimidine used as starting material can be obtained as follows: A solution of 85 g p-methoxypropionitrile and 60 ems ethanol is introduced at 0°C over concentrated sulfuric acid until saturation. The precipitated p-methoxypropionimino ethyl ether hydrochloride is sucked off and, still moist with ether, it is introduced into 200 cc of 16% ammoniacal ethanol, the mixture is shaken for 12 hours and the precipitated ammonium chloride is filtered off. The solution is evaporated in vacuo at 50 °C, the crystalline mass is then slurried with ether and filtered off. (3-Methoxypropionamidine hydrochloride melts after recrystallization from ethanol/ether at 85-86°C. 13.8 g of {3-methoxypropionamidine hydrochloride and 8.2 g of diacetonitrile are pulverized together and heated with 50 cm<3> glacial acetic acid for 8 hours at 120° C. The resulting precipitate is filtered off and crystallized from water. 2-(methoxyethyl)-4-methyl-6-aminopyrimidine is thus obtained with a melting point of 254-255° C. In an analogous manner to that described above , one can from p-acetylaminobenzenesulfonyl chloride and 2-(methoxyethyl)-6-amino-pyrimidine, 2-(methoxyethyl)-4-chloro-6-aminopyrimidine, 2-(methoxyethyl)-4-methoxy-6- aminopyrimidine, 4-(methoxymethyl)-6-aminopyrimidine, 2-chloro-4-(methoxymethyl)-6-aminopyrimidine, 2-methoxy-4-(methoxymethyl)-6-aminopyrimidine, 2,4-di-(methoxymethyl)- 6-aminopyrimidine, 2-methyl-4-(methoxyethyl)-6-aminopyrimidine, 2-chloro-4-(methoxyethyl)-6-aminopyrimidine, or 2-methoxy-4-(methoxyethyl)-6-aminopyrimidine get 6 -(p-aminobenzenesulfonamido)-2-(methoxyethyl)-, 6-(p-aminobenzenesulfonamido)-2-(methoxy ethyl)-4-chloro-, 6-(p-aminobenzalsulfonamido)-2-(methoxyethyl)-4-methoxy, 6-(p-aminobenzenesulfonamido)-4-(methoxymethyl)-, 6-(p-aminobenzenesulfonamido) -2-chloro-4-(methoxymethyl)-, 6-(p-aminobenzenesulfonamido)-2-methoxy-4-(methoxymethyl)- 6-(p-aminobenzenesulfonamido)-2,4-di-(methoxymethyl)-, 6-(p-aminobenzenesulfonami- . do) -2-methyl-4-(methoxyethyl)-, 6-(p-aminobenzenesulfonamido)-2-chloro-4-(methoxyethyl)- respectively 6-(p-aminobenzenesulfonamido)-2-methoxy-4-(methoxyethyl ) -pyrimidine.
Eksempel 4.Example 4.
8 g 2-(metoksymetyl)-6-amino-pyrimidin og 17 g p-karbetoksyaminobenzolsulfoklorid opplø-ses i 100 ems pyridin, blandingen står natten over og filtreres, og filtratet innstilles på pH — 2—3 med saltsyre 1:1. Det f raf Utrerte bunnfall oppvarmes 1 time ved 90°C med 200 cm<3>2-n. natronlut. Oppløsningen tilsettes aktiv-kull, filtreres varmt og fra filtratet utfelles under isav-kjøling 6-(p-aminobenzolsulfonamido)-2-(metoksymetyl) -pyrimidin med formelen 8 g of 2-(methoxymethyl)-6-amino-pyrimidine and 17 g of p-carbethoxyaminobenzene sulfochloride are dissolved in 100 ems pyridine, the mixture is left overnight and filtered, and the filtrate is adjusted to pH — 2-3 with hydrochloric acid 1:1. The f raf Untreated precipitate is heated for 1 hour at 90°C with 200 cm<3>2-n. baking soda. Activated carbon is added to the solution, filtered hot and 6-(p-aminobenzenesulfonamido)-2-(methoxymethyl)-pyrimidine with the formula is precipitated from the filtrate under ice-cooling
med 50 pst.-ig eddiksyre ved pH 5—6. Smeltepunkt 237—238°C etter omkrystallisasj on fra etanol/vann. with 50% acetic acid at pH 5-6. Melting point 237-238°C after recrystallization from ethanol/water.
Det som utgangsmateriale anvendte 2-(metoksy-metyl)-6-aminopyrimidin kan fås som følger: 38,6 g 2-(metoksymetyl)-4,6-diklor-pyrimidin bringes til reaksjon med 250 cm<3>12 pst.-ig ammoniakkalsk etanol i autoklav i 10 timer ved 80°C. Etter avkjøling inndampes blandingen til tørrhet. Fra resten får man ved omkrystallisa-sjon fra vann 2-(metoksymetyl)-4-klor-6-ami-no-pyrimidin i form av hvite nåler med smeltepunkt 102°C. The 2-(methoxymethyl)-6-aminopyrimidine used as starting material can be obtained as follows: 38.6 g of 2-(methoxymethyl)-4,6-dichloropyrimidine is reacted with 250 cm<3>12% ig ammoniacal ethanol in an autoclave for 10 hours at 80°C. After cooling, the mixture is evaporated to dryness. From the residue, recrystallization from water gives 2-(methoxymethyl)-4-chloro-6-amino-pyrimidine in the form of white needles with a melting point of 102°C.
17,3 g 2-(metoksymetyl)-4-klor-6-aminopy-rimidin hydreres under tilsetning av 3 g 5 pst.-ig palladium-aktivkullkatalysator og 4,4 g mag-nesiumoksyd som saltsyreakseptor i 250 cm3 abs. etanol. Katalysatoren frafiltreres og oppløsnin-gen inndampes til tørrhet. Resten opptas i vann, nøytraliseres med eddiksyre og oppløsningen ekstraheres med kloroform. Etter avdestillering av oppløsningsmiddelet omkrystalliseres resten 17.3 g of 2-(methoxymethyl)-4-chloro-6-aminopyrimidine is hydrogenated with the addition of 3 g of 5% palladium activated carbon catalyst and 4.4 g of magnesium oxide as hydrochloric acid acceptor in 250 cm 3 abs. ethanol. The catalyst is filtered off and the solution is evaporated to dryness. The residue is taken up in water, neutralized with acetic acid and the solution extracted with chloroform. After distilling off the solvent, the residue is recrystallized
fra eddikester/petroleter. Man får således 2-(metoksymetyl)-6-amino-pyrimidin med smeltepunkt 111—112°C. from vinegar/petroleum ether. This gives 2-(methoxymethyl)-6-amino-pyrimidine with a melting point of 111-112°C.
Eksempel 5.Example 5.
10,7 g 2-(metoksymetyl) -4- (p-metoksyetok-sy)-6-aminopyrimidin, oppløst i 100 cm3 abs. pyridin, tilsettes porsjonsvis 14,5 g p-karbetoksyaminobenzolsulfoklorid, oppløsningen omrøres i 72 timer ved romtemperatur, deretter helles på 10.7 g of 2-(methoxymethyl)-4-(p-methoxyethoxy)-6-aminopyrimidine, dissolved in 100 cm 3 abs. pyridine, 14.5 g of p-carbethoxyaminobenzene sulphochloride are added in portions, the solution is stirred for 72 hours at room temperature, then poured onto
is/saltsyre under bibeholdelse av pH = 2, hvorved 6- (p-karbetoksy-aminobenzolsulf onamido) - 2-(metoksymetyiy-4- (p-metoksyetoksy)-pyrtmi-din faller ut, og har et smeltepunkt 105—106°C. Forsåpning foregår ved 1 times kokning med 250 cm3 l-n. natronlut. Ved ansyring med iseddik, faller 6-(p-aminobenzolsulfonamido)-2-(metoksymetyl) -4-(p-metoksyetoksy) -pyrimidin med formelen ice/hydrochloric acid while maintaining pH = 2, whereby 6-(p-carbethoxy-aminobenzenesulfonamido)-2-(methoxymethyl-4-(p-methoxyethoxy)-pyrimidine precipitates out, and has a melting point of 105-106°C . Saponification takes place by boiling for 1 hour with 250 cm3 l-n sodium hydroxide solution. When acidified with glacial acetic acid, 6-(p-aminobenzenesulfonamido)-2-(methoxymethyl)-4-(p-methoxyethoxy)-pyrimidine falls with the formula
ut og har smeltepunkt 87°C. out and has a melting point of 87°C.
Det som utgangsprodukt anvendte 2-(metoksy-metyl)-4- (p-metoksyetoksy)-6-aminopy-rimidin dannes ved reaksjon av 17,3 g 2-(metoksymetyl)-4-klor-6-aminopyrimidin med en oppløsning på 5 g natrium i 50 cm<3>glykolmono-metyleter ved 24 timers oppvarmning ved 100°C. Deretter fjernes overskudd av eter, resten oppslemmes i vann, nøytraliseres med iseddik, frafiltreres, og det godt tørkete 2-(metoksymetyl) - 4- (p-metoksyetoksy) -6-aminopyrimidin omkrystalliseres fra eddikester og har smeltepunkt 104°C. The 2-(methoxymethyl)-4-(p-methoxyethoxy)-6-aminopyrimidine used as starting product is formed by reaction of 17.3 g of 2-(methoxymethyl)-4-chloro-6-aminopyrimidine with a solution of 5 g sodium in 50 cm<3>glycol mono-methyl ether by heating for 24 hours at 100°C. Excess ether is then removed, the residue is slurried in water, neutralized with glacial acetic acid, filtered off, and the well-dried 2-(methoxymethyl)-4-(p-methoxyethoxy)-6-aminopyrimidine is recrystallized from acetic ester and has a melting point of 104°C.
Eksempel 6.Example 6.
17,2 g 2-(metoksymetyl)-4-metyl-6-klorpyri-midin oppløses i 160 cm.3 8,5 pst.-ig benzolisk trimetylaminoppløsning og står i 5 dager. Deretter avdestilleres benzolet i vakuum og tilsettes 100 cm3 abs. eter. 6-trimetylammoniumforbin-delsen suges fra og settes til en smelte av 47 g N4-acetylsulfanilamid-natrium og 48 g acetamid ved 95—100°C i løpet av 10 min., oppvarmes videre i iy2time ved 105°C og acetamidet avdestilleres i vakuum. Deretter oppløses resten i 100 cm<3>vann, nøytraliseres med iseddik og gjø-res sodaalkalisk, står natten over i isskap, frafiltreres overskudd av N4-acetylsulfanilamid, filtratet innstilles på pH 4—5, hvorved 6-(p-acetylaminobenzolsulf onamido) -2- (metoksymetyl)-4-metylpyrimidin faller ut etter noen timer. (Etter omkrystallisasj on fra vann, er smeltepunktet 194—195°C.) Acetylforbindelsen forsåpes med 100 cm<3>2-n. natronlut i 2 timer til 6- (p-aminobenzolsulfonamido) -2- (metoksymetyl)-4-metylpyrimidin med formelen 17.2 g of 2-(methoxymethyl)-4-methyl-6-chloropyrimidine are dissolved in 160 cm.3 of 8.5% benzolic trimethylamine solution and allowed to stand for 5 days. The benzene is then distilled off in a vacuum and 100 cm3 of abs. ether. The 6-trimethylammonium compound is sucked off and added to a melt of 47 g of N4-acetylsulfanilamide sodium and 48 g of acetamide at 95-100°C over the course of 10 min., further heated for iy2h at 105°C and the acetamide is distilled off in a vacuum . The residue is then dissolved in 100 cm<3>water, neutralized with glacial acetic acid and made alkaline, left overnight in an icebox, excess N4-acetylsulfanilamide is filtered off, the filtrate is adjusted to pH 4-5, whereby 6-(p-acetylaminobenzenesulfonamido) -2-(Methoxymethyl)-4-methylpyrimidine precipitates after a few hours. (After recrystallization from water, the melting point is 194-195°C.) The acetyl compound is saponified with 100 cm<3>2-n. caustic soda for 2 hours to 6-(p-aminobenzenesulfonamido)-2-(methoxymethyl)-4-methylpyrimidine of the formula
som faller ut etter nøytralisasjon med eddiksyre. which precipitates after neutralization with acetic acid.
Det som utgangsmateriale anvendte 2-(metoksymetyl) -4-metyl-6-klorpyrimidin fremstilles som følger: 62 g av det i eksempel 1 beskrevne metoksyacetamidin-hydroklorid kondenseres med 65 g aceteddikester med 34,5 g natrium i 200 cm<3>metanol, idet man oppvarmer i 8 timer til 50°C. Metanolet avdestilleres, resten oppløses i vann, nøytraliseres med eddiksyre og deretter inndampes oppløsningen til tørrhet. Den godt tørkede rest ekstraheres med eter. Det erholdte 2-(metoksymetyl) -4-metyl-6-hydroksypyrimidin omkrystalliseres fra eter og har smeltepunkt 103°C. The 2-(methoxymethyl)-4-methyl-6-chloropyrimidine used as starting material is prepared as follows: 62 g of the methoxyacetamidine hydrochloride described in example 1 is condensed with 65 g of acetate diester with 34.5 g of sodium in 200 cm<3>methanol , heating for 8 hours to 50°C. The methanol is distilled off, the residue is dissolved in water, neutralized with acetic acid and then the solution is evaporated to dryness. The well-dried residue is extracted with ether. The 2-(methoxymethyl)-4-methyl-6-hydroxypyrimidine obtained is recrystallized from ether and has a melting point of 103°C.
38,5 g av denne forbindelse oppvarmes med 150 ml fosforoksyklorid og 25 g trietylamin ved 140°C i 2 timer i oljebad. Fosforoksykloridet avdestilleres i vakuum, resten innføres i ammoniakalsk isvann, og deretter rystes ut med metylenklorid. Ved destillasjon får man 2-(metoksymetyl)-4-metyl-6-klor-pyrimidin. Kokepunkt 0,6 : 73°C. 38.5 g of this compound are heated with 150 ml of phosphorus oxychloride and 25 g of triethylamine at 140°C for 2 hours in an oil bath. The phosphorus oxychloride is distilled off in a vacuum, the residue is introduced into ammoniacal ice water, and then shaken out with methylene chloride. Distillation gives 2-(methoxymethyl)-4-methyl-6-chloro-pyrimidine. Boiling point 0.6 : 73°C.
Eksempel 7.Example 7.
En blanding av 20,0 g sulfanilamid, 20,0 g acetamid og 16 g vannfri potteaske tildryppes ved 130°C under omrøring 10,0 g 2-metyl-4-(metoksymetyl)-6-klor-pyrimidin. Det oppvarmes i 4 timer til 140°C, og deretter avkjøles og tilsettes 100 cm3 vann. Det utfelte bunnfall frafiltreres, og filtratet tilsettes 2-n. saltsyre inntil en pH-verdi på 6—7. Etter noen henstand, faller det ut et bunnfall som frafiltreres og røres ut med 100 cm<3>vann ved 70—80°C. Den uopp-løselige del omkrystalliseres av alkohol. Man får således 6- (p-aminobenzolsulfonamido) -2-metyl-4-(metoksymetyl)-pyrimidin med formelen A mixture of 20.0 g of sulfanilamide, 20.0 g of acetamide and 16 g of anhydrous pot ash is added dropwise at 130°C with stirring to 10.0 g of 2-methyl-4-(methoxymethyl)-6-chloro-pyrimidine. It is heated for 4 hours to 140°C, and then cooled and 100 cm3 of water is added. The precipitate that precipitates is filtered off, and the filtrate is added to 2-n. hydrochloric acid up to a pH value of 6-7. After some delay, a precipitate falls out which is filtered off and stirred with 100 cm<3> of water at 70-80°C. The insoluble part is recrystallized from alcohol. One thus obtains 6-(p-aminobenzenesulfonamido)-2-methyl-4-(methoxymethyl)-pyrimidine with the formula
som krystaller med smeltepunkt 187—190°C. as crystals with a melting point of 187-190°C.
Det som utgangsmateriale anvendte 2-metyl-4- (metoksymetyl) -6-klor-pyrimidin kan fremstilles som følger: En oppløsning av 2,2 g natrium i 50 cm.3 abs. alkohol tilsettes 5,0 g acetamidin-hydroklorid og det omrøres 15 min. ved romtemperatur. Heretter tilsettes 8,0 g y-metoksy-aceteddikester og det oppvarmes til kokning i løpet av 4 timer. Oppløsningen inndampes nå i vakuum. Det blir tilbake en fast rest som man koker ut med 100 cm3 metylenklorid. Etter inndampning av opp-løsningsmiddelet blir det tilbake krystallinsk 2-metyl-4- (metoksymetyl) -6-hydroksy-pyrimi din, som etter sublimasjon smelter ved 173— 174°C. The 2-methyl-4-(methoxymethyl)-6-chloropyrimidine used as starting material can be prepared as follows: A solution of 2.2 g of sodium in 50 cm.3 abs. alcohol, 5.0 g of acetamidine hydrochloride is added and it is stirred for 15 min. at room temperature. 8.0 g of γ-methoxyacetate are then added and heated to boiling over the course of 4 hours. The solution is now evaporated in vacuo. A solid residue remains which is boiled off with 100 cm3 of methylene chloride. After evaporation of the solvent, crystalline 2-methyl-4-(methoxymethyl)-6-hydroxy-pyrimi remains your, which after sublimation melts at 173-174°C.
10,0 g av dette hydroksy-pyrimidin innføres i 100 cm<3>fosforoksyklorid. Etter tilsetning av 5,0 g dimetylanilin røres 4 timer ved romtemperatur og deretter inndampes i vakuum. Resten oppløses i 100 cm<3>metylenklorid, og oppløsnin-gen helles i kald, 3 pst.-ig ammoniumhydroksyd-oppløsning. Etter god gjennomrystning, skiller man fra den organiske fase, tørker over natri-umsulfat og avdestillerer oppløsningsmiddelet. Ved destillasjon av resten, får man 2-metyl-4-(metoksymetyl)-6-klor-pyrimidin, som koker ved 90—100°C/11 mm. 10.0 g of this hydroxypyrimidine is introduced into 100 cm<3>phosphorus oxychloride. After adding 5.0 g of dimethylaniline, the mixture is stirred for 4 hours at room temperature and then evaporated in vacuo. The residue is dissolved in 100 cm<3> methylene chloride, and the solution is poured into cold, 3% ammonium hydroxide solution. After thorough shaking, the organic phase is separated, dried over sodium sulphate and the solvent is distilled off. Distillation of the residue gives 2-methyl-4-(methoxymethyl)-6-chloropyrimidine, which boils at 90-100°C/11 mm.
Eksempel 8.Example 8.
5,4 g 6-(p-aminobenzolsulfonamido) - 2-(metoksymetyl) -4-metoksypyrimidin suspende-res i 10 cm<3>aceton og 1,3 g pyridin. Deretter tildryppes 2,2 g acetanhydrid i løpet av 10 min., det røres videre i 5 timer og deretter står det hele i 2 dager, hvorved det faller ut et hvitt produkt. Etter tilsetning av 20 cm<3>2—3 pst.-ig ammoniakk under isavkjøling, suges raskt fra og man får Nj-acetyl-6-(p-aminobenzolsulfonamido) -2- (metoksymetyl) -4-metoksypyrimidin med formelen 5.4 g of 6-(p-aminobenzenesulfonamido)-2-(methoxymethyl)-4-methoxypyrimidine are suspended in 10 ml of acetone and 1.3 g of pyridine. Then 2.2 g of acetic anhydride are added dropwise over the course of 10 min., stirring continues for 5 hours and then the whole thing stands for 2 days, during which a white product precipitates. After adding 20 cm<3>2-3% ammonia under ice-cooling, suction is quickly taken off and N-acetyl-6-(p-aminobenzenesulfonamido)-2-(methoxymethyl)-4-methoxypyrimidine is obtained with the formula
som etter omkrystallisasj on av etanol smelter ved 178—179°C. which after recrystallization from ethanol melts at 178-179°C.
Eksempel 9.Example 9.
18,3 g 2-(metoksymetyl)-4-etoksy-6-amino-pyrimidin oppløses i 200 cm<3>pyridin, tilsettes porsjonsvis 29 g p-karbetoksyaminobenzolsulfoklorid, blandingen omrøres i 48 timer ved romtemperatur, deretter helles den på isvann og pH-verdien innstilles på ca. 2 ved tilsetning av konsentrert saltsyre. Bunnfallet suges fra, kokes 1 time med 500 cm<3>l-n. natronlut, og den varme 18.3 g of 2-(methoxymethyl)-4-ethoxy-6-amino-pyrimidine are dissolved in 200 cm<3>pyridine, 29 g of p-carbethoxyaminobenzene sulphochloride are added in portions, the mixture is stirred for 48 hours at room temperature, then it is poured into ice water and The pH value is set to approx. 2 by adding concentrated hydrochloric acid. The precipitate is sucked off, boiled for 1 hour with 500 cm<3>l-n. baking soda, and the hot
oppløsning behandles med aktivkull, filtreres og bringes på en pH-verdi på 5,5—6 under isav-kjøling med eddiksyre. 6-(p-aminobenzolsulfonamido)-2-(metoksymetyl)-4-etoksypyrimidin med formelen solution is treated with activated carbon, filtered and brought to a pH value of 5.5-6 under ice-cooling with acetic acid. 6-(p-aminobenzenesulfonamido)-2-(methoxymethyl)-4-ethoxypyrimidine of the formula
Det som utgangsprodukt anvendte 2-(metoksymetyl) -4-etoksy-6-aminopyrimidin fremstilles som følger: En natriumetylatoppløsning av 4,6 g natrium i 100 cm3 etanol tilsettes 17,3 g 2-(metoksymetyl)-4-klor-6-aminopyrimidin og blandingen omrøres i 20 timer ved 60°C. For fullstendig ut-skilling av natriumsaltet, innføres karbondioksyd og det tilsettes 50 cm<3>abs. eter, saltet frafiltreres og filtratet inndampes til tørrhet. 2-(metoksymetyl)-4-etoksy-6-aminopyrimidin The 2-(methoxymethyl)-4-ethoxy-6-aminopyrimidine used as starting product is prepared as follows: A sodium ethylate solution of 4.6 g of sodium in 100 cm3 of ethanol is added to 17.3 g of 2-(methoxymethyl)-4-chloro-6- aminopyrimidine and the mixture is stirred for 20 hours at 60°C. For complete separation of the sodium salt, carbon dioxide is introduced and 50 cm<3>abs is added. ether, the salt is filtered off and the filtrate is evaporated to dryness. 2-(Methoxymethyl)-4-ethoxy-6-aminopyrimidine
med formelenwith the formula
smelter etter omkrystallisasj on fra tetraklorkarbon ved 99°C. melts after recrystallization from carbon tetrachloride at 99°C.
Eksempel 10.Example 10.
En oppløsning av 19,7 g 2-(metoksymetyl) - 4-isopropoksy-6-aminopyrimidin i 250 cm?> abs. pyridin tilsettes porsjonsvis 29 g p-karbetoksyaminobenzolsulfoklorid og omrøres i 12 timer ved romtemperatur. Deretter helles oppløsningen på en blanding av is/saltsyre, således at pH-verdien forblir ca. 2. Bunnfallet suges fra og forsåpes i 1 time ved 90°C med 500 cm<3>l-n. natronlut. Ved tilsetning av eddiksyre, får man 6-(p-aminobenzolsulf onamido)-2-(metoksymetyl )-4-isopropoksy-pyrimidin med formelen A solution of 19.7 g of 2-(methoxymethyl)-4-isopropoxy-6-aminopyrimidine in 250 cm?> abs. pyridine is added in portions to 29 g of p-carbethoxyaminobenzene sulphochloride and stirred for 12 hours at room temperature. The solution is then poured onto a mixture of ice/hydrochloric acid, so that the pH value remains approx. 2. The precipitate is sucked off and saponified for 1 hour at 90°C with 500 cm<3>l-n. baking soda. By adding acetic acid, 6-(p-aminobenzenesulfonamido)-2-(methoxymethyl)-4-isopropoxy-pyrimidine is obtained with the formula
som etter omkrystallisasj on fra metanol smelter ved 166°C. Det som utgangsmateriale anvendte 2-(metoksymetyl)-4-isopropoksy-6-aminopyrimidin dannes ved 24 timers omsetning av 17,3 g 2-(metoksymetyl)-4-klor-6-aminopyrimidin med en natriumisopropylatoppløsning av 4,6 g natrium og 200 cm<3>isopropanol ved 60°C. Forbindelsen med formelen which after recrystallization from methanol melts at 166°C. The 2-(methoxymethyl)-4-isopropoxy-6-aminopyrimidine used as starting material is formed by reacting for 24 hours 17.3 g of 2-(methoxymethyl)-4-chloro-6-aminopyrimidine with a sodium isopropylate solution of 4.6 g of sodium and 200 cm<3>isopropanol at 60°C. The connection with the formula
smelter etter omkrystallisasj on fra benzol ved 84°C. melts after recrystallization from benzene at 84°C.
Eksempel 11.Example 11.
En oppløsning av 18,3 g 2-(etoksymetyl)-4-metoksy-6-aminopyrimidin i 250 cm3 abs. pyridin tilsettes porsjonsvis 29 g p-karbetoksyaminobenzolsulfoklorid, og det omrøres 24 timer ved romtemperatur, og deretter helles oppløsningen på en blanding av is og saltsyre, således at pH-verdien forblir ca. 2 og temperaturen forblir under 10°C. Det frasugete bunnfall oppvarmes i 1 time med 500 cm3 l-n. natronlut til 90°C, og til slutt under tilsetning av aktivkull. Etter filtre-ring ansyres under isavkjøling med iseddik, hvorved 6- (p-aminobenzolsulfonamido) -2- (etok-symetyl)-4-metoksypyrimidin med formelen A solution of 18.3 g of 2-(ethoxymethyl)-4-methoxy-6-aminopyrimidine in 250 cm 3 abs. pyridine is added in portions to 29 g of p-carbethoxyaminobenzene sulphochloride, and it is stirred for 24 hours at room temperature, and then the solution is poured onto a mixture of ice and hydrochloric acid, so that the pH value remains approx. 2 and the temperature remains below 10°C. The aspirated sediment is heated for 1 hour with 500 cm3 l-n. caustic soda to 90°C, and finally with the addition of activated charcoal. After filtration, acidify under ice-cooling with glacial acetic acid, whereby 6-(p-aminobenzenesulfonamido)-2-(ethoxymethyl)-4-methoxypyrimidine with the formula
faller ut, og har smeltepunkt 154°C. precipitates out, and has a melting point of 154°C.
Det som utgangsprodukt anvendte 2-(etok-symetyl)-4-metoksy-6-aminopyrimidin kan fremstilles som følger: I en oppløsning av 122, g etoksyacetonitril og 69 g etanol innledes ved 0°C saltsyre som er tør-ket over konsentrert svovelsyre inntil metning. Det frasugede etoksyacetimino-etyleter-hydroklorid innføres i 600 cm3 12 pst.-ig ammoniakalsk etanol, blandingen rystes i 12 timer og det utfelte ammoniumklorid frafiltreres, og filtratet inndampes ved 50°C. Den krystallinske masse oppslemmes deretter med eter og frasuges. 95 g av dette etoksyacetamidin-hydroklorid innføres i en natriummetylatoppløsning av 47,5 g natrium og 800 cm<3>metanol. Man tildrypper ved romtemperatur 110 g malonsyredietylester og oppvarmer i 16 timer til 60°C. Blandingen inndampes til tørrhet og opptas i vann. Ved nøytralisering med iseddik, faller 2-(etoksy-metyl)-4,6-dihydroksypyrimidin ut, og har smeltepunkt 219°C (under spaltning). 68 g av denne forbindelse kloreres med 300 cm3 fosforoksyklorid og 110 ems trietylamin. Ved fraksjonering får man 2-(etoksymetyl)-4,6-di-klorpyrimidin, kokepunkt 0,03 : 49°C. The starting product 2-(ethoxymethyl)-4-methoxy-6-aminopyrimidine can be prepared as follows: In a solution of 122 g of ethoxyacetonitrile and 69 g of ethanol, hydrochloric acid which has been dried over concentrated sulfuric acid is introduced at 0°C until saturation. The aspirated ethoxyacetimino ethyl ether hydrochloride is introduced into 600 cm3 of 12% ammoniacal ethanol, the mixture is shaken for 12 hours and the precipitated ammonium chloride is filtered off, and the filtrate is evaporated at 50°C. The crystalline mass is then slurried with ether and filtered off. 95 g of this ethoxyacetamidine hydrochloride is introduced into a sodium methylate solution of 47.5 g of sodium and 800 cm3 of methanol. 110 g of malonic acid diethyl ester are added dropwise at room temperature and heated for 16 hours to 60°C. The mixture is evaporated to dryness and taken up in water. Upon neutralization with glacial acetic acid, 2-(ethoxy-methyl)-4,6-dihydroxypyrimidine precipitates out, and has a melting point of 219°C (under decomposition). 68 g of this compound is chlorinated with 300 cm3 of phosphorus oxychloride and 110 ems of triethylamine. Fractionation gives 2-(ethoxymethyl)-4,6-dichloropyrimidine, boiling point 0.03 : 49°C.
54,9 g av denne forbindelse oppvarmes med ca. 200 cm<3>flytende ammoniakk i autoklav i 10 timer til 70°C. Etter avblåsing av ammoniakken 54.9 g of this compound is heated with approx. 200 cm<3>liquid ammonia in an autoclave for 10 hours at 70°C. After blowing off the ammonia
omkrystalliseres resten av vann. 2-(etoksyme-tyl)-4-klor-6-aminopyrimidin smelter ved 117— 118°C. the rest of the water is recrystallized. 2-(Ethoxymethyl)-4-chloro-6-aminopyrimidine melts at 117-118°C.
44,8 g av dette pyrimidin oppvarmes med en natriummetylatoppløsning av 11 g natrium i 300 cm<3>metanol i 24 timer ved 50°C. Deretter nøytraliseres med eddiksyre, inndampes til tørr-het, oppslemmes i vann og resten omkrystalliseres fra tetraklorkarbon. Man får således 2-(etoksymetyl)-4-metoksy-6-amino-pyrimidin 44.8 g of this pyrimidine is heated with a sodium methylate solution of 11 g of sodium in 300 cm<3>methanol for 24 hours at 50°C. It is then neutralized with acetic acid, evaporated to dryness, slurried in water and the residue recrystallized from carbon tetrachloride. 2-(Ethoxymethyl)-4-methoxy-6-amino-pyrimidine is thus obtained
med smeltepunkt 108°C.with melting point 108°C.
Eksempel 12.Example 12.
En oppløsning av 13,9 g 2-(metoksymetyl) - 6-aminopyrimidin i 100 cm<3>pyridin tilsettes ved 50°C porsjonsvis 24 g p-nitrobenzolsulfoklorid. Etter 48 timers omrøring frafiltreres bunnfallet, filtratet helles på is og pH-verdien innstilles med konsentrert saltsyre på 2—3. Bunnfallet hydreres med Raney-nikkel i en alkalisk etanol-vannblanding. Katalysatoren frafiltreres og filtratet inndampes, hvorved 6-(p-aminobenzolsulfonamido) -2- (metoksymetyl) -pyrimidin faller ut. Dette smelter etter omkrystallisasj on fra etanol/vann ved 237—238°C. A solution of 13.9 g of 2-(methoxymethyl)-6-aminopyrimidine in 100 cm<3>pyridine is added at 50°C in portions to 24 g of p-nitrobenzene sulfochloride. After 48 hours of stirring, the precipitate is filtered off, the filtrate is poured onto ice and the pH value is adjusted with concentrated hydrochloric acid to 2-3. The precipitate is hydrated with Raney nickel in an alkaline ethanol-water mixture. The catalyst is filtered off and the filtrate is evaporated, whereby 6-(p-aminobenzenesulfonamido)-2-(methoxymethyl)-pyrimidine precipitates out. This melts after recrystallization from ethanol/water at 237-238°C.
Eksempel 13.Example 13.
En smelte av 17,2 g sulfanilamid, 14 g vannfri potteaske og 7,5 g acetamid tilsettes ved 115°C porsjonsvis 10,1 g 2,4-di-(metoksymetyl)-6-klor-pyrimidin. Etter avsluttet gassutvikling omrø-res 1 time, blandingen opptas i 100 cm3 vann, og oppløsningen behandles ved 90°C med aktivkull. pH-verdien for den filtrerte oppløsning innstilles på omtrent 8-8,2, hvorved overskudd av sulfanilamid faller ut ved avkjøling. Dette frafiltreres. Ved nøytralisering av oppløsningen, faller 6- (p-aminobenzolsulf onamido) -2,4-di- (metoksymetyl)-pyrimidin med formelen A melt of 17.2 g of sulfanilamide, 14 g of anhydrous pot ash and 7.5 g of acetamide is added at 115°C in portions to 10.1 g of 2,4-di-(methoxymethyl)-6-chloro-pyrimidine. After gas evolution has ended, the mixture is stirred for 1 hour, the mixture is taken up in 100 cm3 of water, and the solution is treated at 90°C with activated charcoal. The pH value of the filtered solution is set to approximately 8-8.2, whereby excess sulfanilamide precipitates on cooling. This is filtered out. Upon neutralization of the solution, 6-(p-aminobenzenesulfonamido)-2,4-di-(methoxymethyl)-pyrimidine of the formula
ut. Smeltepunkt 125—126°C etter omkrystallisa-sjon fra etanol-vann. out. Melting point 125-126°C after recrystallization from ethanol-water.
Det som utgangsprodukt anvendte 2,4-di-metoksymetyl)-6-klor-pyrimidin kan fremstilles som følger: 13 g metoksyacetamidin i 100 cm<3>abs. etanol og 20 g (3-keto-y-metoksy-smørsyreester settes til en oppløsning av 5,9 g kalium i 100 cm<3>abs. etanol, og oppvarmes 4 timer under tilbakeløps-kjøling. Oppløsningsmiddelet avdestilleres, resten opptas i vann, nøytraliseres og oppløsningen utrystes med metylenklorid. Oppløsningen tørkes, og etter avdestillering av metylenkloridet blir det tilbake 2,4-di-(metoksymetyl)-6-hydroksy-pyrimidin, som omkrystalliseres fra eddikester og har smeltepunkt 98—99°C. 15 g av denne forbindelse kloreres med fos foroksyklorid under tilsetning av trietylamin, fosforoksykloridet avdestilleres, resten helles på is, nøytraliseres med ammoniakk og rystes ut med metylenklorid. Den tørkete oppløsning frak-sjoneres. 2,4-di-(metoksymetyl)-6-klor-pyrimidin har et kokepunkt på 0,15 : 77—78,5°C. The 2,4-dimethoxymethyl)-6-chloropyrimidine used as starting product can be prepared as follows: 13 g of methoxyacetamidine in 100 cm<3>abs. ethanol and 20 g of (3-keto-γ-methoxy-butyric acid ester are added to a solution of 5.9 g of potassium in 100 cm<3>abs. ethanol, and heated for 4 hours under reflux cooling. The solvent is distilled off, the residue is taken up in water , is neutralized and the solution is shaken out with methylene chloride. The solution is dried, and after distilling off the methylene chloride, 2,4-di-(methoxymethyl)-6-hydroxy-pyrimidine remains, which is recrystallized from acetic acid and has a melting point of 98-99°C. 15 g of this compound is chlorinated with phos phoroxychloride with the addition of triethylamine, the phosphorus oxychloride is distilled off, the residue is poured onto ice, neutralized with ammonia and shaken out with methylene chloride. The dried solution is fractionated. 2,4-di-(methoxymethyl)-6-chloro-pyrimidine has a boiling point of 0.15 : 77-78.5°C.
Eksempel 14.Example 14.
9,0 g 4-(metoksymetyl)-6-klor-pyrimidin dryppes under omrøring ved 130°C til en blanding av 18,0 g sulfanilamid, 18,0 g acetamid og 15 g vannfritt kaliumkarbonat. Etter 4 timer 9.0 g of 4-(methoxymethyl)-6-chloropyrimidine is added dropwise with stirring at 130°C to a mixture of 18.0 g of sulfanilamide, 18.0 g of acetamide and 15 g of anhydrous potassium carbonate. After 4 hours
avkjøles og det tilsettes 100 cm<3>vann. Det utfelte bunnfall filtreres fra, og filtratet tilsettes 2-n. saltsyre inntil det er oppnådd en pH-verdi på 6—7. Etter noe ntid faller det ut et bunnfall som omkrystalliseres av alkohol. Man får 6-(p-aminobenzolsulfonamido)-4-(metoksymetyl)-pyridin med formelen. is cooled and 100 cm<3> of water is added. The precipitate that precipitates is filtered off, and the filtrate is added to 2-n. hydrochloric acid until a pH value of 6-7 is achieved. After some time a precipitate falls out which is recrystallized from alcohol. 6-(p-aminobenzenesulfonamido)-4-(methoxymethyl)pyridine is obtained with the formula.
som krystaller med smeltepunkt 207—209°C. as crystals with a melting point of 207-209°C.
Det som utgangsmateriale anvendte 4-(metoksymetyl)-6-klor-pyrimidin kan fremstilles som følger: En oppløsning av 4,7 g natrium i 200 cm<3>alkohol tilsettes 10,4 g formamidin-acetat og 16,4 g y-metoksy-aceteddikester. Man rører i 10 timer ved 50°C, filtrerer fra utfelt bunnfall og inndamper filtratet til tørrhet. Resten oppløser man i vann og oppløsningen nøytraliseres ved tilset-ningen av 2-n. saltsyre. Man inndamper til tørr-het. Det blir tilbake en rest som man koker ut med metylenklorid. Ekstrakten tørkes og inndampes. Resten tilsettes litt aceton, hvoretter 4-hydroksy-6-(metoksymeyl)-pyrimidin faller ut i form av krystaller med smeltepunkt 155°C. 8 g av ovennevnte forbindelse røres med 50 cm<3>fosforoksyklorid etter tilsetning av 3 g trietylamin i 10 timer ved romtemperatur. Deretter inndampes i vakuum, resten oppløses i metylenklorid og helles i 3 pst.-ig ammoniakk. Metylen-kloridoppløsningen inndampes. Ved destillasjon får man 4-klor-6-(metoksymetyl)-pyrimidin, som koker ved 90—93°C/12 mm. The 4-(methoxymethyl)-6-chloro-pyrimidine used as starting material can be prepared as follows: A solution of 4.7 g of sodium in 200 cm<3>alcohol is added to 10.4 g of formamidine acetate and 16.4 g of y- methoxy-acetate. The mixture is stirred for 10 hours at 50°C, the precipitate is filtered and the filtrate is evaporated to dryness. The remainder is dissolved in water and the solution is neutralized by the addition of 2-n. hydrochloric acid. Evaporate to dryness. A residue remains which is boiled off with methylene chloride. The extract is dried and evaporated. A little acetone is added to the residue, after which 4-hydroxy-6-(methoxymethyl)-pyrimidine precipitates in the form of crystals with a melting point of 155°C. 8 g of the above-mentioned compound are stirred with 50 cm<3>phosphorus oxychloride after the addition of 3 g of triethylamine for 10 hours at room temperature. It is then evaporated in a vacuum, the residue is dissolved in methylene chloride and poured into 3% ammonia. The methylene chloride solution is evaporated. Distillation gives 4-chloro-6-(methoxymethyl)-pyrimidine, which boils at 90-93°C/12 mm.
Eksempel 15.Example 15.
En oppløsning av 8,5 g 2-(metoksymetyl)-4-metoksy-6-amino-pyrimidin i 75 cm<3>pyridin tilsettes under omrøring innen 30 min. 13 g p-acetylamino-benzolsulfonylklorid. Etter avslutning av reaksjonen oppvarmes 1 time til 90°C. Deretter tilsettes 750 cm<3>vann og under isavkjøling innstilles pH-verdien ved tilsetning av konsentrert saltsyre på ca. 2. Det utfelte bunnfall kokes i 2 timer med 500 cm<3>2-n. natronlut, den alkaliske oppløsning frafiltreres og filtratet nøytraliseres ennå varm med konsentrert saltsyre. Derved ut- skilles det dannete 6-(p-aminobenzolsulfonamido) -2-(metoksymetyl)-4-metoksypyrimidin med formelen A solution of 8.5 g of 2-(methoxymethyl)-4-methoxy-6-amino-pyrimidine in 75 cm<3>pyridine is added with stirring within 30 minutes. 13 g of p-acetylamino-benzenesulfonyl chloride. After completion of the reaction, heat to 90°C for 1 hour. 750 cm<3> of water is then added and, under ice cooling, the pH value is adjusted by adding concentrated hydrochloric acid of approx. 2. The precipitate is boiled for 2 hours with 500 cm<3>2-n. caustic soda, the alkaline solution is filtered off and the filtrate is neutralized while still hot with concentrated hydrochloric acid. Thereby, the formed 6-(p-aminobenzenesulfonamido)-2-(methoxymethyl)-4-methoxypyrimidine is separated with the formula
krystallinsk. Det smelter etter omkrystallisasj on fra alkohol ved 139—140°C. crystalline. It melts after recrystallization from alcohol at 139-140°C.
Det som utgangsstoff anvendte 2-metoksymetyl-4-metoksy-6-amino-pyrimidin kan fremstilles som følger: 17,3 g 2-(metoksymetyl)-4-klor-6-aminopy-rimidin oppløses i autoklav i 150 cm<3>metanol og dertil settes 10,8 g natriummetylat. Reaksjonsblandingen holdes under omrystning i 10 timer ved 120°C, og deretter inndampes til tørrhet etter avkjøling. 2-metoksymetyl-6-amino-4-metoksy-pyrimidin med formelen The starting material 2-methoxymethyl-4-methoxy-6-amino-pyrimidine can be prepared as follows: 17.3 g of 2-(methoxymethyl)-4-chloro-6-aminopyrimidine is dissolved in an autoclave at 150 cm<3> methanol and to this is added 10.8 g of sodium methylate. The reaction mixture is stirred for 10 hours at 120°C, and then evaporated to dryness after cooling. 2-Methoxymethyl-6-amino-4-methoxy-pyrimidine of the formula
smelter ved 93—94°C. melts at 93-94°C.
Eksempel 16.Example 16.
8,5 g 2-(metoksymetyl)-4-metoksy-6-amino-pyrimldin oppløses i 75 cm<3>pyridin og tilsettes porsjonsvis 12 g p-nitro-benzolsulfoklorid. Etter avslutning av den eksoterme reaksjon, røres opp-løsningen videre i 24 timer, heller på is og gjør oppløsningen sur med konsentrert saltsyre til en pH-verdi på 2—3. Bunnfallet oppløses i 250 cm<3>70 pst.-ig etanol under tilsetning av natronlut og hydreres med Raneynikkel som katalysa-tor. Katalysatoren frafiltreres, oppløsningen inndampes til tørrhet, digereres med litt vann og frafiltreres igjen. Etter omkrystallisasj on fra etanol får man 6-(p-amino-benzolsulfonamido)-2-(metoksymetyl) -4-metoksy-pyrimidin med smeltepunkt 139—140°C. 8.5 g of 2-(methoxymethyl)-4-methoxy-6-amino-pyrimidine are dissolved in 75 cm<3>pyridine and 12 g of p-nitro-benzene sulphochloride are added in portions. After completion of the exothermic reaction, the solution is further stirred for 24 hours, poured onto ice and acidified with concentrated hydrochloric acid to a pH value of 2-3. The precipitate is dissolved in 250 cm<3>70% ethanol with the addition of caustic soda and hydrated with Raney nickel as a catalyst. The catalyst is filtered off, the solution is evaporated to dryness, digested with a little water and filtered off again. After recrystallization from ethanol, 6-(p-amino-benzenesulfonamido)-2-(methoxymethyl)-4-methoxy-pyrimidine with melting point 139-140°C is obtained.
Eksempel 17.Example 17.
34,4 g sulfanilamid, 27,6 g kaliumkarbonat og 2 g acetamid oppvarmes under omrøring til ca. 120°C. Deretter tildryppes i løpet av 10 min. 8,8 g 2-(metoksymetyl)-4-metoksy-6-klorpyrimi-din og det røres videre i 2 timer ved 140°C. Den avkjølte masse behandles med 75 cm<3>vann og klares ved 90 °C under anvendelse av aktivkull. Filtratets pH-verdi innstilles på 8—8,2, og blandingen avkjøles til 15°C. Det ikke omsatte sulfanilamid frafiltreres og filtratet innrøres således i eddiksiirt isvann at pH-verdien stadig for- 34.4 g of sulfanilamide, 27.6 g of potassium carbonate and 2 g of acetamide are heated with stirring to approx. 120°C. Then drip over 10 min. 8.8 g of 2-(methoxymethyl)-4-methoxy-6-chloropyrimidine and it is stirred further for 2 hours at 140°C. The cooled mass is treated with 75 cm<3> of water and clarified at 90 °C using activated charcoal. The filtrate's pH value is set to 8-8.2, and the mixture is cooled to 15°C. The unreacted sulfanilamide is filtered off and the filtrate is stirred into acetic acid ice water in such a way that the pH value constantly
blir ca. 5. Det med det i eksempel 15 fremstilte produkt identiske 6-(p-amino-benzolsulfonamido)-2-(metoksymetyl)-4-metoksypyrimidin faller dermed ut. will be approx. 5. The 6-(p-amino-benzenesulfonamido)-2-(methoxymethyl)-4-methoxypyrimidine identical to the product prepared in example 15 thus precipitates out.
Eksempel 18.Example 18.
I et bomberør omsettes 16,4 g 6-(p-aminobenzol-sulf onamido)-2-(metoksymetyl) -4-klor-pyrimidin med 13,5 g natriummetylat i 250 cm<3>metanol i 24 timer ved 160°C. Oppløsningen inndampes til 100 cm<3>. Ved innrøring i vann og nøy-tralisering med eddiksyre, får man det med det i eksempel 15 fremstilte produkt identiske 6-(p-amino benzolsulfonamido) -2- (metoksymetyl) -4-metoksypyrimidin. In a bomb tube, 16.4 g of 6-(p-aminobenzene-sulfonamido)-2-(methoxymethyl)-4-chloro-pyrimidine are reacted with 13.5 g of sodium methylate in 250 cm<3>methanol for 24 hours at 160°C . The solution is evaporated to 100 cm<3>. By stirring in water and neutralizing with acetic acid, 6-(p-amino benzenesulfonamido)-2-(methoxymethyl)-4-methoxypyrimidine, which is identical to the product prepared in example 15, is obtained.
Eksempel 19.Example 19.
3,9 g 6-(p-amino-benzolsulfonamido)-2-(metoksymetyl) -4- (trimetylammonium) -pyrimi-dinklorid omsettes i bomberør med 0,6 g natriummetylat i 50 cm<3>abs. metanol ved 100 °C i 8 timer. Oppløsningen inndampes og man får, 3.9 g of 6-(p-amino-benzenesulfonamido)-2-(methoxymethyl)-4-(trimethylammonium)-pyrimidine chloride are reacted in a bomb tube with 0.6 g of sodium methylate in 50 cm<3>abs. methanol at 100 °C for 8 h. The solution is evaporated and you get,
ved innrøring av oppløsningen i vann og nøy-tralisering med eddiksyre, med det i eksempel 15 fremstilte produkt identiske 6-(p-amino-benzol-sulf onamido) -2-(metoksymetyl) -4-metoksy-pyrimidin. by stirring the solution in water and neutralizing with acetic acid, with the product prepared in example 15 identical 6-(p-amino-benzene-sulfonamido)-2-(methoxymethyl)-4-methoxy-pyrimidine.
Det som utgangsstoff anvendte 6-(p-aminobenzolsulf onamido) -2- (metoksymetyl) -4-trime-tylammoniumpyrimidin-klorid, får man, når man lar 8,2 g 6-(p-amino-benzolsulfonamido)-2-(metoksymetyl)-4-klorpyrimidin stå i 3 dager med 40 cm<3>8,5 pst.-ig benzolisk trimetylamin-oppløsning, avdestillerer benol i vakuum, ryster resten med 100 ml abs. eter, hvorved den gule forurensning går i oppløsning og suger fra saltet. The starting material 6-(p-aminobenzenesulfonamido)-2-(methoxymethyl)-4-trimethylammonium pyrimidine chloride is obtained, when 8.2 g of 6-(p-aminobenzenesulfonamido)-2-( methoxymethyl)-4-chloropyrimidine stand for 3 days with 40 cm<3>8.5% benzolic trimethylamine solution, distill off the benzol in vacuum, shake the residue with 100 ml of abs. ether, whereby the yellow impurity dissolves and absorbs from the salt.
Sammenligningsforsøk.Comparison experiment.
Preparatet 6- (p-aminobenzol-sulfonamido) - 2-metoksymetyl-4-metoksypyrimidin (I) ble med hensyn til dets kjemoterapeutiske virkning sam-menlignet med det kjente handelsprodukt 6-(p-aminobenzol-sulf onamido)-2,4-dimetoksypyri-midin (II). Følgende tabell viser at forbindelse I er overlegen overfor forbindelse II med hensyn til den kjemoterapeutiske virkning. The preparation 6-(p-aminobenzene-sulfonamido)-2-methoxymethyl-4-methoxypyrimidine (I) was compared with respect to its chemotherapeutic effect with the known commercial product 6-(p-aminobenzene-sulfonamido)-2,4- dimethoxypyrimidine (II). The following table shows that compound I is superior to compound II with respect to the chemotherapeutic effect.
Claims (1)
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CH1473462A CH441364A (en) | 1962-12-14 | 1962-12-14 | Process for the production of new sulfonamides |
CH244763 | 1963-02-26 | ||
CH1313463 | 1963-10-25 |
Publications (1)
Publication Number | Publication Date |
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NO115842B true NO115842B (en) | 1968-12-16 |
Family
ID=27173721
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
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NO15123363A NO115842B (en) | 1962-12-14 | 1963-12-13 |
Country Status (8)
Country | Link |
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DE (2) | DE1445607A1 (en) |
DK (3) | DK116284B (en) |
ES (1) | ES294470A1 (en) |
FI (1) | FI43991B (en) |
FR (1) | FR3731M (en) |
GB (2) | GB1021395A (en) |
NO (1) | NO115842B (en) |
SE (2) | SE311654B (en) |
Family Cites Families (1)
Publication number | Priority date | Publication date | Assignee | Title |
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GB886693A (en) * | 1959-03-04 | 1962-01-10 | Ici Ltd | Heterocyclic compounds |
-
1963
- 1963-12-10 DE DE19631445607 patent/DE1445607A1/en active Pending
- 1963-12-10 DK DK574463A patent/DK116284B/en unknown
- 1963-12-10 DE DE1963C0031632 patent/DE1248055B/en active Pending
- 1963-12-13 ES ES294470A patent/ES294470A1/en not_active Expired
- 1963-12-13 SE SE1392663A patent/SE311654B/xx unknown
- 1963-12-13 FI FI246363A patent/FI43991B/fi active
- 1963-12-13 NO NO15123363A patent/NO115842B/no unknown
- 1963-12-16 GB GB49640/63A patent/GB1021395A/en not_active Expired
- 1963-12-16 GB GB4964163A patent/GB1035917A/en not_active Expired
-
1964
- 1964-03-06 FR FR966452A patent/FR3731M/en active Active
-
1965
- 1965-05-07 DK DK231865A patent/DK115550B/en unknown
- 1965-05-07 DK DK231765A patent/DK117634B/en unknown
-
1966
- 1966-12-28 SE SE17797/66A patent/SE321476B/xx unknown
Also Published As
Publication number | Publication date |
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GB1035917A (en) | 1966-07-13 |
DK117634B (en) | 1970-05-19 |
FI43991B (en) | 1971-04-30 |
DK115550B (en) | 1969-10-20 |
DE1445607A1 (en) | 1968-12-05 |
ES294470A1 (en) | 1964-06-01 |
GB1021395A (en) | 1966-03-02 |
DK116284B (en) | 1969-12-29 |
DE1248055B (en) | 1967-08-24 |
SE311654B (en) | 1969-06-23 |
SE321476B (en) | 1970-03-09 |
FR3731M (en) | 1965-12-06 |
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