NO751158L - - Google Patents
Info
- Publication number
- NO751158L NO751158L NO751158A NO751158A NO751158L NO 751158 L NO751158 L NO 751158L NO 751158 A NO751158 A NO 751158A NO 751158 A NO751158 A NO 751158A NO 751158 L NO751158 L NO 751158L
- Authority
- NO
- Norway
- Prior art keywords
- formula
- compounds
- carbon atoms
- above meaning
- stands
- Prior art date
Links
- 150000001875 compounds Chemical class 0.000 claims description 96
- 238000000034 method Methods 0.000 claims description 38
- 125000004432 carbon atom Chemical group C* 0.000 claims description 32
- 239000000203 mixture Substances 0.000 claims description 31
- 125000000217 alkyl group Chemical group 0.000 claims description 26
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 19
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 19
- 239000000460 chlorine Substances 0.000 claims description 19
- 229910052801 chlorine Inorganic materials 0.000 claims description 19
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 18
- 229910052794 bromium Inorganic materials 0.000 claims description 18
- 239000001257 hydrogen Substances 0.000 claims description 17
- 229910052739 hydrogen Inorganic materials 0.000 claims description 17
- -1 methylenedioxy group Chemical group 0.000 claims description 13
- 239000003960 organic solvent Substances 0.000 claims description 13
- 150000001412 amines Chemical class 0.000 claims description 10
- 125000001424 substituent group Chemical group 0.000 claims description 7
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 6
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 6
- 238000002360 preparation method Methods 0.000 claims description 4
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 4
- 229910052736 halogen Inorganic materials 0.000 claims description 3
- 150000002367 halogens Chemical class 0.000 claims description 3
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 3
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 2
- 125000002252 acyl group Chemical group 0.000 claims description 2
- 125000003545 alkoxy group Chemical group 0.000 claims description 2
- 125000004429 atom Chemical group 0.000 claims description 2
- 229910052731 fluorine Inorganic materials 0.000 claims description 2
- 239000011737 fluorine Substances 0.000 claims description 2
- ZZYXNRREDYWPLN-UHFFFAOYSA-N pyridine-2,3-diamine Chemical class NC1=CC=CN=C1N ZZYXNRREDYWPLN-UHFFFAOYSA-N 0.000 claims description 2
- 150000002431 hydrogen Chemical class 0.000 claims 4
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 61
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 42
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 38
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 33
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 30
- 239000011541 reaction mixture Substances 0.000 description 28
- 238000006243 chemical reaction Methods 0.000 description 26
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 24
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 24
- 238000002844 melting Methods 0.000 description 19
- 230000008018 melting Effects 0.000 description 19
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 19
- 239000007858 starting material Substances 0.000 description 18
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 15
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 15
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 13
- DTTLJUGHKIRCHU-UHFFFAOYSA-N 1-[2,6-bis(tert-butylamino)-4-methylpyridin-3-yl]ethanone Chemical compound CC(=O)C1=C(C)C=C(NC(C)(C)C)N=C1NC(C)(C)C DTTLJUGHKIRCHU-UHFFFAOYSA-N 0.000 description 12
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 12
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 12
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 11
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 11
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 10
- 229910021529 ammonia Inorganic materials 0.000 description 10
- 238000003756 stirring Methods 0.000 description 10
- 239000007787 solid Substances 0.000 description 9
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 8
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 8
- 239000002585 base Substances 0.000 description 8
- 125000004435 hydrogen atom Chemical class [H]* 0.000 description 8
- 239000000155 melt Substances 0.000 description 8
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 description 8
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 7
- 239000002253 acid Substances 0.000 description 7
- 125000003277 amino group Chemical group 0.000 description 7
- 239000000706 filtrate Substances 0.000 description 7
- 239000002244 precipitate Substances 0.000 description 7
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 6
- PCLIMKBDDGJMGD-UHFFFAOYSA-N N-bromosuccinimide Chemical compound BrN1C(=O)CCC1=O PCLIMKBDDGJMGD-UHFFFAOYSA-N 0.000 description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 6
- 238000009835 boiling Methods 0.000 description 6
- 230000007062 hydrolysis Effects 0.000 description 6
- 238000006460 hydrolysis reaction Methods 0.000 description 6
- 239000012299 nitrogen atmosphere Substances 0.000 description 6
- 239000012071 phase Substances 0.000 description 6
- 230000035484 reaction time Effects 0.000 description 6
- MPSXGPCFLAGJOM-UHFFFAOYSA-M 2-tert-butyl-5-methyl-1,2-oxazol-2-ium;perchlorate Chemical compound [O-]Cl(=O)(=O)=O.CC1=CC=[N+](C(C)(C)C)O1 MPSXGPCFLAGJOM-UHFFFAOYSA-M 0.000 description 5
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 5
- 235000019270 ammonium chloride Nutrition 0.000 description 5
- 238000001953 recrystallisation Methods 0.000 description 5
- 229920006395 saturated elastomer Polymers 0.000 description 5
- 239000002904 solvent Substances 0.000 description 5
- 229960000583 acetic acid Drugs 0.000 description 4
- 239000006227 byproduct Substances 0.000 description 4
- 238000004519 manufacturing process Methods 0.000 description 4
- 229940098779 methanesulfonic acid Drugs 0.000 description 4
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 4
- 229910052757 nitrogen Inorganic materials 0.000 description 4
- 238000005406 washing Methods 0.000 description 4
- XKJCOKCJVCRUCC-UHFFFAOYSA-N 4-(tert-butylamino)but-3-en-2-one Chemical compound CC(=O)C=CNC(C)(C)C XKJCOKCJVCRUCC-UHFFFAOYSA-N 0.000 description 3
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 3
- ZHNUHDYFZUAESO-UHFFFAOYSA-N Formamide Chemical class NC=O ZHNUHDYFZUAESO-UHFFFAOYSA-N 0.000 description 3
- 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 3
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 3
- UFECPKAKRSESFO-UHFFFAOYSA-N [2,6-bis(tert-butylamino)-4-methylpyridin-3-yl]-(4-methoxyphenyl)methanone Chemical compound C1=CC(OC)=CC=C1C(=O)C1=C(C)C=C(NC(C)(C)C)N=C1NC(C)(C)C UFECPKAKRSESFO-UHFFFAOYSA-N 0.000 description 3
- 150000001335 aliphatic alkanes Chemical class 0.000 description 3
- 239000012298 atmosphere Substances 0.000 description 3
- 238000001816 cooling Methods 0.000 description 3
- 239000013078 crystal Substances 0.000 description 3
- 239000011261 inert gas Substances 0.000 description 3
- VLTRZXGMWDSKGL-UHFFFAOYSA-N perchloric acid Chemical compound OCl(=O)(=O)=O VLTRZXGMWDSKGL-UHFFFAOYSA-N 0.000 description 3
- 150000003839 salts Chemical class 0.000 description 3
- 239000000741 silica gel Substances 0.000 description 3
- 229910002027 silica gel Inorganic materials 0.000 description 3
- 229910052938 sodium sulfate Inorganic materials 0.000 description 3
- 235000011152 sodium sulphate Nutrition 0.000 description 3
- 239000000725 suspension Substances 0.000 description 3
- 230000007306 turnover Effects 0.000 description 3
- IBYHHJPAARCAIE-UHFFFAOYSA-N 1-bromo-2-chloroethane Chemical compound ClCCBr IBYHHJPAARCAIE-UHFFFAOYSA-N 0.000 description 2
- RFVNQOYZRLBIKM-UHFFFAOYSA-N 2,6-bis(tert-butylamino)-4-methylpyridine-3-carbonitrile Chemical compound CC1=CC(NC(C)(C)C)=NC(NC(C)(C)C)=C1C#N RFVNQOYZRLBIKM-UHFFFAOYSA-N 0.000 description 2
- YRUWBPLELOUSGL-UHFFFAOYSA-N 2-n,6-n-ditert-butyl-4-methylpyridine-2,6-diamine Chemical compound CC1=CC(NC(C)(C)C)=NC(NC(C)(C)C)=C1 YRUWBPLELOUSGL-UHFFFAOYSA-N 0.000 description 2
- AEJLSLGWCJYFSJ-UHFFFAOYSA-N 4-tert-butyliminobut-3-en-2-one Chemical compound CC(=O)C=C=NC(C)(C)C AEJLSLGWCJYFSJ-UHFFFAOYSA-N 0.000 description 2
- OKKJLVBELUTLKV-MZCSYVLQSA-N Deuterated methanol Chemical compound [2H]OC([2H])([2H])[2H] OKKJLVBELUTLKV-MZCSYVLQSA-N 0.000 description 2
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 2
- WTDHULULXKLSOZ-UHFFFAOYSA-N Hydroxylamine hydrochloride Chemical compound Cl.ON WTDHULULXKLSOZ-UHFFFAOYSA-N 0.000 description 2
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 2
- 239000005909 Kieselgur Substances 0.000 description 2
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 2
- GXFVBARLVRVLBB-UHFFFAOYSA-N N'-tert-butyl-3-hydroxybut-2-enimidamide Chemical compound CC(O)=CC(N)=NC(C)(C)C GXFVBARLVRVLBB-UHFFFAOYSA-N 0.000 description 2
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 2
- JRNVZBWKYDBUCA-UHFFFAOYSA-N N-chlorosuccinimide Chemical compound ClN1C(=O)CCC1=O JRNVZBWKYDBUCA-UHFFFAOYSA-N 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 2
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 description 2
- NSMRSVDYDOIYDI-UHFFFAOYSA-N [2,6-bis(tert-butylamino)-4-methylpyridin-3-yl]-(4-methylphenyl)methanone Chemical compound C1=CC(C)=CC=C1C(=O)C1=C(C)C=C(NC(C)(C)C)N=C1NC(C)(C)C NSMRSVDYDOIYDI-UHFFFAOYSA-N 0.000 description 2
- 150000007513 acids Chemical class 0.000 description 2
- PNEYBMLMFCGWSK-UHFFFAOYSA-N aluminium oxide Inorganic materials [O-2].[O-2].[O-2].[Al+3].[Al+3] PNEYBMLMFCGWSK-UHFFFAOYSA-N 0.000 description 2
- 230000003178 anti-diabetic effect Effects 0.000 description 2
- 239000008346 aqueous phase Substances 0.000 description 2
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- 239000007795 chemical reaction product Substances 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- 150000004292 cyclic ethers Chemical class 0.000 description 2
- 238000000354 decomposition reaction Methods 0.000 description 2
- 238000009826 distribution Methods 0.000 description 2
- 150000002170 ethers Chemical class 0.000 description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 2
- 239000000284 extract Substances 0.000 description 2
- 239000012458 free base Substances 0.000 description 2
- 238000010438 heat treatment Methods 0.000 description 2
- 229910000042 hydrogen bromide Inorganic materials 0.000 description 2
- 150000002466 imines Chemical class 0.000 description 2
- 238000011065 in-situ storage Methods 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 229910052744 lithium Inorganic materials 0.000 description 2
- WMFOQBRAJBCJND-UHFFFAOYSA-M lithium hydroxide Inorganic materials [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 2
- 239000012452 mother liquor Substances 0.000 description 2
- 229910052708 sodium Inorganic materials 0.000 description 2
- 239000011734 sodium Substances 0.000 description 2
- HEMHJVSKTPXQMS-UHFFFAOYSA-M sodium hydroxide Inorganic materials [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- UOCLXMDMGBRAIB-UHFFFAOYSA-N 1,1,1-trichloroethane Chemical compound CC(Cl)(Cl)Cl UOCLXMDMGBRAIB-UHFFFAOYSA-N 0.000 description 1
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 1
- PAAZPARNPHGIKF-UHFFFAOYSA-N 1,2-dibromoethane Chemical compound BrCCBr PAAZPARNPHGIKF-UHFFFAOYSA-N 0.000 description 1
- LZDKZFUFMNSQCJ-UHFFFAOYSA-N 1,2-diethoxyethane Chemical compound CCOCCOCC LZDKZFUFMNSQCJ-UHFFFAOYSA-N 0.000 description 1
- LFEZMJUFVUJNQU-UHFFFAOYSA-N 1-[2,6-bis(3-ethylpentan-3-ylamino)-4-methylpyridin-3-yl]ethanone Chemical compound CCC(CC)(CC)NC1=CC(C)=C(C(C)=O)C(NC(CC)(CC)CC)=N1 LFEZMJUFVUJNQU-UHFFFAOYSA-N 0.000 description 1
- CWMNYSLYDBGOTB-UHFFFAOYSA-N 1-[2,6-bis(tert-butylamino)-5-chloro-4-methylpyridin-3-yl]ethanone Chemical compound CC(=O)C1=C(C)C(Cl)=C(NC(C)(C)C)N=C1NC(C)(C)C CWMNYSLYDBGOTB-UHFFFAOYSA-N 0.000 description 1
- YQMLRAVBHWPIDV-UHFFFAOYSA-N 1-[4-ethyl-2,6-bis(propan-2-ylamino)pyridin-3-yl]propan-1-one Chemical compound CCC(=O)C1=C(CC)C=C(NC(C)C)N=C1NC(C)C YQMLRAVBHWPIDV-UHFFFAOYSA-N 0.000 description 1
- PBVVFZFNUKRVAN-UHFFFAOYSA-N 1-[4-methyl-2,6-bis(2-methylbutan-2-ylamino)pyridin-3-yl]ethanone Chemical compound CCC(C)(C)NC1=CC(C)=C(C(C)=O)C(NC(C)(C)CC)=N1 PBVVFZFNUKRVAN-UHFFFAOYSA-N 0.000 description 1
- BFRIWOUNDAXKGA-UHFFFAOYSA-N 1-[5-bromo-2,6-bis(tert-butylamino)-4-methylpyridin-3-yl]ethanone Chemical compound CC(=O)C1=C(C)C(Br)=C(NC(C)(C)C)N=C1NC(C)(C)C BFRIWOUNDAXKGA-UHFFFAOYSA-N 0.000 description 1
- CAQYAZNFWDDMIT-UHFFFAOYSA-N 1-ethoxy-2-methoxyethane Chemical compound CCOCCOC CAQYAZNFWDDMIT-UHFFFAOYSA-N 0.000 description 1
- LGBNJSRHTJEQTO-UHFFFAOYSA-N 2,6-bis(tert-butylamino)-4-methylpyridine-3-carboxamide Chemical compound CC1=CC(NC(C)(C)C)=NC(NC(C)(C)C)=C1C(N)=O LGBNJSRHTJEQTO-UHFFFAOYSA-N 0.000 description 1
- LSPMHHJCDSFAAY-UHFFFAOYSA-N 2,6-dichloro-4-methylpyridine-3-carbonitrile Chemical compound CC1=CC(Cl)=NC(Cl)=C1C#N LSPMHHJCDSFAAY-UHFFFAOYSA-N 0.000 description 1
- HIXDQWDOVZUNNA-UHFFFAOYSA-N 2-(3,4-dimethoxyphenyl)-5-hydroxy-7-methoxychromen-4-one Chemical compound C=1C(OC)=CC(O)=C(C(C=2)=O)C=1OC=2C1=CC=C(OC)C(OC)=C1 HIXDQWDOVZUNNA-UHFFFAOYSA-N 0.000 description 1
- ZQFPHQHAADNTGN-UHFFFAOYSA-N 2-tert-butyl-5-methyl-1,2-oxazol-2-ium Chemical compound CC1=CC=[N+](C(C)(C)C)O1 ZQFPHQHAADNTGN-UHFFFAOYSA-N 0.000 description 1
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 1
- CSDQQAQKBAQLLE-UHFFFAOYSA-N 4-(4-chlorophenyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine Chemical compound C1=CC(Cl)=CC=C1C1C(C=CS2)=C2CCN1 CSDQQAQKBAQLLE-UHFFFAOYSA-N 0.000 description 1
- AGQOIYCTCOEHGR-UHFFFAOYSA-N 5-methyl-1,2-oxazole Chemical compound CC1=CC=NO1 AGQOIYCTCOEHGR-UHFFFAOYSA-N 0.000 description 1
- VDNUTZHQBCSVKM-UHFFFAOYSA-N 6-(tert-butylamino)-2-chloro-4-methylpyridine-3-carbonitrile Chemical compound CC1=CC(NC(C)(C)C)=NC(Cl)=C1C#N VDNUTZHQBCSVKM-UHFFFAOYSA-N 0.000 description 1
- 244000186140 Asperula odorata Species 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 1
- 101150041968 CDC13 gene Proteins 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
- FKLJPTJMIBLJAV-UHFFFAOYSA-N Compound IV Chemical compound O1N=C(C)C=C1CCCCCCCOC1=CC=C(C=2OCCN=2)C=C1 FKLJPTJMIBLJAV-UHFFFAOYSA-N 0.000 description 1
- KIWBPDUYBMNFTB-UHFFFAOYSA-N Ethyl hydrogen sulfate Chemical compound CCOS(O)(=O)=O KIWBPDUYBMNFTB-UHFFFAOYSA-N 0.000 description 1
- 235000008526 Galium odoratum Nutrition 0.000 description 1
- 238000003747 Grignard reaction Methods 0.000 description 1
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 1
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 1
- SUAKHGWARZSWIH-UHFFFAOYSA-N N,N‐diethylformamide Chemical compound CCN(CC)C=O SUAKHGWARZSWIH-UHFFFAOYSA-N 0.000 description 1
- 208000008589 Obesity Diseases 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 1
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 1
- FQLVRQBCOMRZTC-UHFFFAOYSA-N [2,6-bis(tert-butylamino)-4-methylpyridin-3-yl]-phenylmethanone Chemical compound CC1=CC(NC(C)(C)C)=NC(NC(C)(C)C)=C1C(=O)C1=CC=CC=C1 FQLVRQBCOMRZTC-UHFFFAOYSA-N 0.000 description 1
- XUDGZWNCMGQWKH-UHFFFAOYSA-K [Br-].[Mg+2].[Li+].[Br-].[Br-] Chemical compound [Br-].[Mg+2].[Li+].[Br-].[Br-] XUDGZWNCMGQWKH-UHFFFAOYSA-K 0.000 description 1
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 1
- 125000002015 acyclic group Chemical group 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 238000013019 agitation Methods 0.000 description 1
- 150000008044 alkali metal hydroxides Chemical class 0.000 description 1
- 150000004703 alkoxides Chemical class 0.000 description 1
- 150000003973 alkyl amines Chemical class 0.000 description 1
- 150000005215 alkyl ethers Chemical class 0.000 description 1
- 150000001409 amidines Chemical class 0.000 description 1
- 150000001450 anions Chemical class 0.000 description 1
- 230000003579 anti-obesity Effects 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 230000031709 bromination Effects 0.000 description 1
- 238000005893 bromination reaction Methods 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 125000002057 carboxymethyl group Chemical group [H]OC(=O)C([H])([H])[*] 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- 239000003610 charcoal Substances 0.000 description 1
- 238000005660 chlorination reaction Methods 0.000 description 1
- 239000002026 chloroform extract Substances 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 238000003776 cleavage reaction Methods 0.000 description 1
- 150000001983 dialkylethers Chemical class 0.000 description 1
- 239000003085 diluting agent Substances 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000000921 elemental analysis Methods 0.000 description 1
- 238000010828 elution Methods 0.000 description 1
- 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 230000008020 evaporation Effects 0.000 description 1
- 230000002349 favourable effect Effects 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 239000012362 glacial acetic acid Substances 0.000 description 1
- 229940093915 gynecological organic acid Drugs 0.000 description 1
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 1
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 1
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-M hydrogensulfate Chemical compound OS([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-M 0.000 description 1
- 229910052500 inorganic mineral Inorganic materials 0.000 description 1
- 239000013067 intermediate product Substances 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- 150000002576 ketones Chemical class 0.000 description 1
- 125000005647 linker group Chemical group 0.000 description 1
- ZCSHNCUQKCANBX-UHFFFAOYSA-N lithium diisopropylamide Chemical class [Li+].CC(C)[N-]C(C)C ZCSHNCUQKCANBX-UHFFFAOYSA-N 0.000 description 1
- TWRXJAOTZQYOKJ-UHFFFAOYSA-L magnesium chloride Substances [Mg+2].[Cl-].[Cl-] TWRXJAOTZQYOKJ-UHFFFAOYSA-L 0.000 description 1
- 229910001629 magnesium chloride Inorganic materials 0.000 description 1
- 229910052987 metal hydride Inorganic materials 0.000 description 1
- 150000004681 metal hydrides Chemical class 0.000 description 1
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 1
- JZMJDSHXVKJFKW-UHFFFAOYSA-M methyl sulfate(1-) Chemical compound COS([O-])(=O)=O JZMJDSHXVKJFKW-UHFFFAOYSA-M 0.000 description 1
- DVSDBMFJEQPWNO-UHFFFAOYSA-N methyllithium Chemical compound C[Li] DVSDBMFJEQPWNO-UHFFFAOYSA-N 0.000 description 1
- 239000011707 mineral Substances 0.000 description 1
- 235000010755 mineral Nutrition 0.000 description 1
- FJLHLDBEZKTSOK-UHFFFAOYSA-N n-ethyl-n-methylformamide Chemical compound CCN(C)C=O FJLHLDBEZKTSOK-UHFFFAOYSA-N 0.000 description 1
- KERBAAIBDHEFDD-UHFFFAOYSA-N n-ethylformamide Chemical compound CCNC=O KERBAAIBDHEFDD-UHFFFAOYSA-N 0.000 description 1
- 150000002825 nitriles Chemical class 0.000 description 1
- 235000020824 obesity Nutrition 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 150000002894 organic compounds Chemical class 0.000 description 1
- 239000012074 organic phase Substances 0.000 description 1
- TWNQGVIAIRXVLR-UHFFFAOYSA-N oxo(oxoalumanyloxy)alumane Chemical compound O=[Al]O[Al]=O TWNQGVIAIRXVLR-UHFFFAOYSA-N 0.000 description 1
- VLTRZXGMWDSKGL-UHFFFAOYSA-M perchlorate Inorganic materials [O-]Cl(=O)(=O)=O VLTRZXGMWDSKGL-UHFFFAOYSA-M 0.000 description 1
- 239000003208 petroleum Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 1
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 1
- 125000001501 propionyl group Chemical group O=C([*])C([H])([H])C([H])([H])[H] 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 239000012429 reaction media Substances 0.000 description 1
- 230000007017 scission Effects 0.000 description 1
- 239000002002 slurry Substances 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 239000012312 sodium hydride Substances 0.000 description 1
- 229910000104 sodium hydride Inorganic materials 0.000 description 1
- 239000011877 solvent mixture Substances 0.000 description 1
- YBRBMKDOPFTVDT-UHFFFAOYSA-N tert-butylamine Chemical compound CC(C)(C)N YBRBMKDOPFTVDT-UHFFFAOYSA-N 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 238000004809 thin layer chromatography Methods 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/72—Nitrogen atoms
- C07D213/74—Amino or imino radicals substituted by hydrocarbon or substituted hydrocarbon radicals
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D213/81—Amides; Imides
- C07D213/82—Amides; Imides in position 3
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D213/84—Nitriles
- C07D213/85—Nitriles in position 3
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D261/00—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings
- C07D261/02—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings
- C07D261/04—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pyridine Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Plural Heterocyclic Compounds (AREA)
Description
Fremgangsmåte for fremstilling av nyeProcedure for manufacturing new ones
organiske forbindelser.organic compounds.
Foreliggende oppfinnelse vedrorer en fremgangsmåte for fremstilling av nye diaminopyridiner med formel I The present invention relates to a process for the production of new diaminopyridines of formula I
hvori R og R' er like eller forskjellige og i det enkelte tilfelle betyr en sekundær eller tertiær alkylgruppe med opptil 7 karbonatomer, R^ står for hydrogen eller en alkylgruppe med 1-4 karbonatomer, og enten R£ betyr hydrogen hvis R^ står for hydrogen, eller R2 betyr hydrogen, klor eller brom hvis R^står for en alkylgruppe med 1-4 karbonatomer, R^betyr hydrogen, en cyanogruppe eller en rest med formel -COR^, hvori R^ betyr amino, en alkylgruppe med 1-4 karbonatomer eller en rest med formel II in which R and R' are the same or different and in each case means a secondary or tertiary alkyl group with up to 7 carbon atoms, R^ stands for hydrogen or an alkyl group with 1-4 carbon atoms, and either R£ means hydrogen if R^ stands for hydrogen, or R2 means hydrogen, chlorine or bromine if R^ stands for an alkyl group with 1-4 carbon atoms, R^ means hydrogen, a cyano group or a residue of formula -COR^, in which R^ means amino, an alkyl group with 1- 4 carbon atoms or a residue of formula II
hvori enten R^, R^og R^er like eller forskjellige og i det enkelte tilfelle betyr hydrogen, fluor, klor, brom eller en alkyl-eller en alkoksy^gruppe med i det enkelte tilfelle l>-3 karbonatomer, med den betingelse at R^, R^ og R^ikke står for halogen in which either R^, R^ and R^ are the same or different and in the individual case means hydrogen, fluorine, chlorine, bromine or an alkyl or an alkoxy group with in the individual case 1>-3 carbon atoms, with the condition that R^, R^ and R^ do not stand for halogen
i or to sti 11 ing av fenylresten eller 2 av subs ti tuen tene R,-, R^og R^, hvis disse befinner seg på nabostående karbonatomer, sammen betyr en metylendioksygruppe, og den annen av disse substituenter har den ovennevnte betydning, med den betingelse at hvis R^står for en cyanogruppe, er R og R<1>like eller forskjellige og betyr i det enkelte tilfelle en tert.alkylrest med 4-7 karbonatomer. i or to sti 11 ing of the phenyl residue or 2 of the substituents R,-, R^ and R^, if these are located on neighboring carbon atoms, together mean a methylenedioxy group, and the second of these substituents has the above meaning, with the condition that if R^ stands for a cyano group, R and R<1> are the same or different and mean in the individual case a tert.alkyl residue with 4-7 carbon atoms.
Forbindelsene med formel I kan overfores i sine salter og omvendt. The compounds of formula I can be transferred in their salts and vice versa.
Det særegne ved fremgangsmåten i henhold til oppfinnelsen er at enten The peculiarity of the method according to the invention is that either
a) forbindelser med formel Ia,a) compounds of formula Ia,
hvori R, R<1>og R^har den ovennevnte betydning og R^1 har den wherein R, R<1> and R^ have the above meaning and R^1 has that
saimme betydning som R^, med den unntagelse at denne ikke kan stå for en alkanoylgruppe, fremstilles ved at forbindelser med formel the same meaning as R^, with the exception that this cannot stand for an alkanoyl group, is prepared by compounds of the formula
III III
hvori R^ og R^<1>har den ovennevnte betydning og enten X og X' er like eller forskjellige og i det enkelte tilfelle står for klor in which R^ and R^<1> have the above meaning and either X and X' are the same or different and in each case stand for chlorine
eller brom, eller en av substituentene X og X<1>betyr klor eller brom og den annen står for R-NH- eller R'-NH-, hvori R og R<*>har den ovennevnte betydning, omsettes med et amin eller en aminblanding med formel IV or bromine, or one of the substituents X and X<1>means chlorine or bromine and the other stands for R-NH- or R'-NH-, in which R and R<*>have the above meaning, are reacted with an amine or an amine mixture of formula IV
hvori R/R' har den, ovennevnte betydning, b) eller forbindelser med formel Ib^ hvori R og R' har den ovennevnte betydning, R^<»>betyr en alkylgruppe med 1-4 karbonatomer og R^• står for en alkylgruppe med 1-4 karbonatomer eller står for en rest med formel II, fremstilles ved at forbindelser med formel Va hvori R og R^' har den ovennevnte betydning, i nærvær av en sterk base omsettes med forbindelser med formel VI in which R/R' has the above-mentioned meaning, b) or compounds of formula Ib^ in which R and R' have the above-mentioned meaning, R^<»> means an alkyl group with 1-4 carbon atoms and R^• stands for an alkyl group with 1-4 carbon atoms or represents a residue of formula II, is prepared by reacting compounds of formula Va in which R and R^' have the above meaning in the presence of a strong base with compounds of formula VI
hvori R' og R^<1>har den ovennevnte betydning, eller wherein R' and R^<1> have the above meaning, or
c) forbindelser med formel ISc) compounds of formula IS
hvori R, R', R^ og har den ovennevnte betydning, fremstilles in which R, R', R^ and have the above meaning, are produced
ved at forbindelser med formel Idin that compounds of formula Id
\ hvori R, R R^og R^har den ovennevnte betydning og R^" står for en alkylgruppe med 1-4 karbonatomer, hydrolyseres eller \ in which R, R R^ and R^ have the above meaning and R^" stands for an alkyl group with 1-4 carbon atoms, is hydrolyzed or
d) forbindelser med formel led) compounds of formula le
hvori R, R<1>, R^1 og R^har den ovennevnte betydning, og R^ 1 står for klor eller brom, fremstilles ved at forbindelser med formel If in which R, R<1>, R^1 and R^ have the above meaning, and R^ 1 stands for chlorine or bromine, are prepared by compounds of formula If
hvori R, R', R^1 og R^har den ovennevnte betydning, kloreres eller bromeres i et inert organisk losningsmiddel, eller in which R, R', R^1 and R^ have the above meaning, are chlorinated or brominated in an inert organic solvent, or
e) forbindelser med formel lge) compounds of formula lg
hvori R, R', og R^har den ovennevnte betydning og R^<1>" betyr en alkylgruppe med 1-4 karbonatomer, fremstilles ved at forbindelser med formel VIII, in which R, R', and R^ have the above meaning and R^<1>" means an alkyl group with 1-4 carbon atoms, are prepared by compounds of formula VIII,
hvori R, R', R^ og R^•<1>har den ovennevnte betydning, hydrolyseres. in which R, R', R^ and R^•<1> have the above meaning, are hydrolyzed.
Den under a) angitte fremgangsmåte kan gjennomfores som beskrevetThe procedure specified under a) can be carried out as described
i det folgende:in the following:
Omsetningen av forbindelsene med formel III med forbindelseneThe reaction of the compounds of formula III with the compounds
med formel IV skjer hensiktsmessig ved temperaturer fra 20 til 200°C, foretrukket ved 160 til 180°C, idet det foretrekkes å gjennomfore" omsetningen ved hoyére temperaturer hvis dét anvendes aminer med formel IV, med stort volum og sterisk hindring, f.eks. tert.alkylaminer. Omsetningen skjer hensiktsmessig i et inert organisk losningsmiddel, f.eks. en alkanol med 1-4 karbonatomer, f.eks. etanol. I stedet for et inert organisk losningsmiddel kan et overskudd av aminet danne reaksjonsmediet. with formula IV conveniently takes place at temperatures from 20 to 200°C, preferably at 160 to 180°C, as it is preferred to carry out the reaction at higher temperatures if amines with formula IV are used, with a large volume and steric hindrance, e.g. .tert.alkylamines. The reaction conveniently takes place in an inert organic solvent, e.g. an alkanol with 1-4 carbon atoms, e.g. ethanol. Instead of an inert organic solvent, an excess of the amine can form the reaction medium.
Med hjelp av omsetningen kan det innfores to aminogrupper, hvis i forbindelsene med formel III X og X' i det enkelte tilfelle står for klor eller brom, eller betyr en enkelt aminogruppe hvis en av disse substituenter allerede betyr en aminogruppe. With the help of the reaction, two amino groups can be introduced, if in the compounds of formula III X and X' in the individual case stand for chlorine or bromine, or mean a single amino group if one of these substituents already means an amino group.
Hvis to aminogrupper innfores anvendes to ekvivalenter av forbindelsene med formel IV og hvis det innfores en aminogruppe, minst en ekvivalent av forbindelsene med formel IV. Et lite overskudd f.eks. 10% av aminokomponenten anvendes hensiktsmessig som syrebindende middel. If two amino groups are introduced, two equivalents of the compounds of formula IV are used and if one amino group is introduced, at least one equivalent of the compounds of formula IV is used. A small surplus e.g. 10% of the amino component is suitably used as an acid-binding agent.
I forbindelsen med formel III står X og X', hvis de betyr halogen foretrukket for klor. Hvis i de onskede sluttprodukter R ,og R' er forskjellige, og X og X<*>i utgangsforbindelsene med formel III i det enkelte tilfelle betyr klor eller brom, anvender man en blanding av aminer med formel IV, hvorved det erholdes en blanding av sluttprodukter. Disse kan separeres på i og for seg kjent måte. For fremstilling av slike blandet substituerte forbindelsar er det dog hensiktsmessig at man som utgangsforbindelser anvender forbindelser med formel Illa In the compound of formula III, X and X' are, if they mean halogen, preferred to chlorine. If in the desired end products R and R' are different, and X and X<*> in the starting compounds with formula III in the individual case means chlorine or bromine, a mixture of amines with formula IV is used, whereby a mixture of end products. These can be separated in a manner known per se. For the production of such mixed-substituted compounds, it is however appropriate to use compounds of formula Illa as starting compounds
hvori R.^og 1 har den ovennevnte betydning og enten X^står for klor eller brom og X1' står for R'-NH- eller X1står for R-NH- og X' står for klor eller brom. Disse utgangsforbindelser kan imidlertid også anvendes for fremstilling av forbindelser med formel Ia, hvori R og R' er like. Forbindelser med formel Illa kan fremstilles ved at forbindelser med formel IIIb hvori R.^og R^ 1 har den ovennevnte betydning og X2og X2 1 er like eller forskjellige og i de enkelte tilfeller står for klor eller brom, omsettes med et amin med formel IV. Omsetningen av forbindelsene med formel Illb med forbindelsene med formel IV gjennomfores hensiktsmessig ved temperaturer på 20 til 25°C, hensiktsmessig i et inert organisk losningsmiddel som f.eks. en alkano1 med 1-4 karbonatomer, spesielt etanol. Omsetningen, hvori forbindelsene med formler Illb og IV hensiktsmessig anvendes i et forhold på 1:1, forer til en blanding av forbindelser med formel Illa, hvori enten X^står for en aminogruppe, som tilsvarer den anvendte forbindelse IV, eller forer til en forbindelse med formel Illa, hvori X1<1>står for en aminogruppe, som tilsvarer den anvendte forbindelse med formel IV. Sammensetningen av denne blanding avhenger av naturen av det anvendte amin. F.eks. vil relativt sterisk uhindrede aminer, foretrukket erstatte hydrogenatomet i 2-stillingen. I allefall kan de.enkelte isomerer for anvendelse i fremgangsmåten a) separeres og renses på i og for seg kjent måte. Den under avsnitt b) angitte fremgangsmåter kan gjennomfores som beskrevet i det folgendes in which R.^ and 1 have the above meaning and either X^ stands for chlorine or bromine and X1' stands for R'-NH- or X1 stands for R-NH- and X' stands for chlorine or bromine. However, these starting compounds can also be used for the preparation of compounds of formula Ia, in which R and R' are the same. Compounds of formula Illa can be prepared by reacting compounds of formula IIIb in which R 1 and R 1 have the above-mentioned meaning and X 2 and X 2 1 are the same or different and in the individual cases stand for chlorine or bromine, with an amine of formula IV . The reaction of the compounds of formula IIIb with the compounds of formula IV is suitably carried out at temperatures of 20 to 25°C, suitably in an inert organic solvent such as e.g. an alkano1 with 1-4 carbon atoms, especially ethanol. The reaction, in which the compounds of formulas IIIb and IV are suitably used in a ratio of 1:1, leads to a mixture of compounds of formula IIIa, in which either X represents an amino group, which corresponds to the compound IV used, or leads to a compound with formula Illa, in which X1<1> stands for an amino group, which corresponds to the compound of formula IV used. The composition of this mixture depends on the nature of the amine used. E.g. relatively sterically unhindered amines will preferably replace the hydrogen atom in the 2-position. In any case, the individual isomers for use in method a) can be separated and purified in a manner known per se. The procedures specified under section b) can be carried out as described in the following
De ved omsetningen av forbindelsene med formel Va med forbindelsen med formel VI anvendte sterke baser er f.eks. et lavere alkyl-. litium, f.eks. metyl—eller n-butyl-litium, natrium eller kalium lavere alkoksyder, f.eks. natriummetoksyd eller kalium-t-butoksyd, alkalimetallhydroksyder, f.eks. litium-, natrium- eller kaliumhydroksyd, metallhydrider som f.eks. natrium- eller ka3sium-hydrid, og litium-di-isopropylamider, foretrukket det sistnevnte eller n-butyllitium. Foretrukket anvendes en ekvivalent av basen regnet på forbindelsene med formel VI. Omsetningen gjennomfores hensiktsmessig ved temperaturer fra 15 til 60°C, foretrukket fra 20 til 30°C under inert gassatmosfære, foretrukket nitrogenatmosfære. Omsetningen skjer hensiktsmessig i et inert organisk losningsmiddel, f.eks. en acyklisk eter med 5-10 karbonatomer, The strong bases used in the reaction of the compounds of formula Va with the compound of formula VI are e.g. a lower alkyl-. lithium, e.g. methyl or n-butyl lithium, sodium or potassium lower alkoxides, e.g. sodium methoxide or potassium t-butoxide, alkali metal hydroxides, e.g. lithium, sodium or potassium hydroxide, metal hydrides such as sodium or calcium hydride, and lithium di-isopropylamides, preferably the latter or n-butyllithium. An equivalent of the base calculated on the compounds of formula VI is preferably used. The reaction is suitably carried out at temperatures from 15 to 60°C, preferably from 20 to 30°C under an inert gas atmosphere, preferably a nitrogen atmosphere. The reaction conveniently takes place in an inert organic solvent, e.g. an acyclic ether of 5-10 carbon atoms,
en cyklisk eter, f.eks. p-dioksan eller tetrahydrofuran, en 2-lavere-alkoksyetyleter, f.eks. bis-2-metoksyetyleter eller bis-2-etoksyetyleter, og en lavere alkyleter av etylenglykol, f.eks. 1,2-dimetoksyetan, 1,2-dietoksyetan eller l-etoksy-2-metoksy-etan. Tetrahydrofuran og p-dioksan foretrekkes. Blandinger av disse losningsmidler med alkaner, f.eks. med 6-10 karbonatomer, a cyclic ether, e.g. p-dioxane or tetrahydrofuran, a 2-lower alkoxyethyl ether, e.g. bis-2-methoxyethyl ether or bis-2-ethoxyethyl ether, and a lower alkyl ether of ethylene glycol, e.g. 1,2-dimethoxyethane, 1,2-diethoxyethane or 1-ethoxy-2-methoxyethane. Tetrahydrofuran and p-dioxane are preferred. Mixtures of these solvents with alkanes, e.g. with 6-10 carbon atoms,
kan likeledes anvendes. Reaksjonstiden kan utgjore f.eks. 30can also be used. The reaction time can e.g. 30
til 180 minutter, spesielt 30 til 120 minutter. Molforholdet mellom amidinet med formel VI og ketoketonimidet med formel V utgjor hensiktsmessig -l^l selv om et lite overskudd, f .eks. opptil 10% av det sistnevnte, likeledes kan anvendes. Ved gjennomforingen av fremgangsmåten b) kommer man ofte frem til ikke-identifiserbare biprodukter. De onskede forbindelser med to 180 minutes, especially 30 to 120 minutes. The molar ratio between the amidine of formula VI and the ketoketonimide of formula V conveniently amounts to -l^l even if a small excess, e.g. up to 10% of the latter can also be used. When carrying out method b), non-identifiable by-products are often obtained. The desired connections with
formel Ib kan imidlertid isoleres fra blandingen på i og for seg kjent måte. Biproduktene kan imidlertid hensiktsmessig etter isolering likeledes overfores i forbindelsene med formel Ib. Hensiktsmessig oppvarmes for dette biproduktene ved temperatur formula Ib can, however, be isolated from the mixture in a manner known per se. The by-products can, however, suitably, after isolation, also be transferred into the compounds of formula Ib. For this purpose, the by-products are heated at temperature
på 35 til 70°C, foretrukket 40 til 60°C i et inert organisk losningsmiddel, f.eks. et losningsmiddel som beskrevet ovenfor for fremgangsmåten b), eller en lavere alkohol, som etanol, metanol eller isopropanol, eller en vandig blanding. Oppvarmingen bor foretrukket gjennomfores i 1 til 60, foretrukket 5 til 30 minutter. of 35 to 70°C, preferably 40 to 60°C in an inert organic solvent, e.g. a solvent as described above for method b), or a lower alcohol, such as ethanol, methanol or isopropanol, or an aqueous mixture. The heating should preferably be carried out for 1 to 60, preferably 5 to 30 minutes.
Utgangsforbindelsene med formel VI kan hensiktsmessig erholdesThe starting compounds of formula VI can conveniently be obtained
ved at forbindelser med formel Vin that compounds of formula V
hvori ' og R' har den ovennevnte betydning, eller en forbindelse med formel VII wherein ' and R' have the above meaning, or a compound of formula VII
hvori R' og R^<1>har den ovennevnte betydning og A~ er et anion som ikke deltar i reaksjonen, f.eks. et perklorat, tetrafluor-borat, metylsulfat, etylsulfat, bisulfat, klorid, bromid, jodid eller p-toluensulfonat, omsettes med ammoniakk. in which R' and R^<1> have the above meaning and A~ is an anion which does not participate in the reaction, e.g. a perchlorate, tetrafluoroborate, methyl sulfate, ethyl sulfate, bisulfate, chloride, bromide, iodide or p-toluenesulfonate, is reacted with ammonia.
Omsetningen av forbindelsene med formel V eller forbindelsene med formel VII med ammoniakk gjennomfores hensiktsmessig i et inert organisk losningsmiddel, f.eks. metylenklorid, idet man for dette anvender vannfri flytende ammoniakk. Reaksjonen skjer hensiktsmessig ved temperaturer på-40 til -60°C under omroring, f.eks.. The reaction of the compounds of formula V or the compounds of formula VII with ammonia is conveniently carried out in an inert organic solvent, e.g. methylene chloride, using anhydrous liquid ammonia for this. The reaction conveniently takes place at temperatures of -40 to -60°C with stirring, e.g.
i 5 til 6 0 minutter. Omsetningen skjer hensiktsmessig i inert gassatmosfære, f.eks. nitrogenatmosfære. for 5 to 60 minutes. The turnover conveniently takes place in an inert gas atmosphere, e.g. nitrogen atmosphere.
Forbindelsene med formel V, omfattende de forbindelser med formelThe compounds of formula V, including those compounds of formula
Va, som i fremgangsmåten under avsnitt b) anvendes som utgangsforbindelser, er enten kjente eller kan fremstilles på i og for seg kjent måte fra kjente utgangsforbindelser. En hensiktsmessig fremgangsmåte består deri at tilsvarende forbindelser med formel VII omsettes med en base under anvendelse av den av Woodward et Va, which in the method under section b) are used as starting compounds, are either known or can be prepared in a manner known per se from known starting compounds. A suitable method consists in that corresponding compounds of formula VII are reacted with a base using that of Woodward et
al., i J.Am.Chem. Soc. 88, 3169-3170, beskrevne fremgangsmåte. Fremgangsmåten gjennomfores foretrukket slik at det som base anvendes et trietylamin og som inert organisk losningsmiddel metylendiklorid. For denne reaksjon er temperaturer på -10 til 0°C hensiktsmessig, og reaksjonstiden kan f.eks. utgjore mellom 15 minutter og 4 timer. Ammoniakk kan likeledes anvendes herfor, dog foretrekkes dette ikke om det er onskelig å isolere forbindelsene med formel V, idet ammoniakk reagerer med disse som ovenfor beskrevet og gir herved forbindelser med formel VI. al., in J. Am. Chem. Soc. 88, 3169-3170, described method. The method is preferably carried out so that a triethylamine is used as a base and methylene dichloride as an inert organic solvent. For this reaction, temperatures of -10 to 0°C are appropriate, and the reaction time can e.g. make between 15 minutes and 4 hours. Ammonia can also be used for this purpose, although this is not preferred if it is desirable to isolate the compounds of formula V, since ammonia reacts with these as described above and thereby gives compounds of formula VI.
De erholdte forbindelser med formler V og VI kan isoleres ogThe obtained compounds with formulas V and VI can be isolated and
renses på i og for seg kjent måte.cleaned in a manner known per se.
Begge utgangsforbindelser i fremgangsmåten b) kan erholdes ved at forbindelser med formel VII behandles med ammoniakk. Et alternativ til fremgangsmåten b) utgjor derfor fremstillingen av disse utgangsmaterialer in situ og muligens bare som et midlertidig opptredende mellomprodukt. I denne fremgangsmåtevariant behandles en forbindelse med formel VII. med ammoniakk hensiktsmessig ved temperaturer på 15 til 30°C, foretrukket 15 til 25°C. Omsetningen gjennomfores hensiktsmessig under anvendelse av Both starting compounds in method b) can be obtained by treating compounds of formula VII with ammonia. An alternative to method b) therefore constitutes the production of these starting materials in situ and possibly only as a temporary intermediate product. In this process variant, a compound of formula VII is treated. with ammonia conveniently at temperatures of 15 to 30°C, preferably 15 to 25°C. The turnover is carried out appropriately using
vannfri ammoniakk i et inert organisk losningsmiddel. Egnede løsningsmidler er halogenerte lavere alkaner som metyldiklorid, 1,2-dikloretan, 1,2-di-brornetan, kloroform, 1,1,1-trikloretan - anhydrous ammonia in an inert organic solvent. Suitable solvents are halogenated lower alkanes such as methyl dichloride, 1,2-dichloroethane, 1,2-dibromoethane, chloroform, 1,1,1-trichloroethane -
og 1-brom-2-kloretan, dialkyleteré med 5-10 karbonatomer, cykliske etere som p-dioksan eller tetrahydrofuran, N,N-dimetylacetamid og maursyreamider, f.eks. formamid og dets mono- eller di-lavere and 1-bromo-2-chloroethane, dialkyl ethers with 5-10 carbon atoms, cyclic ethers such as p-dioxane or tetrahydrofuran, N,N-dimethylacetamide and formic acid amides, e.g. formamide and its mono- or di-lowers
alkylderivater, som N-etylformamid',.. N./.N-dimetylformamid eller dietyl-formamid eller N-metyl-N-etylformamid. Halogenerte lavere alkaner, spesielt metylendiklorid foretrekkes. Omsetningen gjennomfores hensiktsmessig i en inert gassatmosfære, f.eks. alkyl derivatives, such as N-ethylformamide',.. N./.N-dimethylformamide or diethyl-formamide or N-methyl-N-ethylformamide. Halogenated lower alkanes, especially methylene dichloride are preferred. The reaction is suitably carried out in an inert gas atmosphere, e.g.
i nitrogenatmosfære, og reaksjonstiden utgjor f.eks. 2 til 10in a nitrogen atmosphere, and the reaction time is e.g. 2 to 10
dager, spesielt 3 til 5 dager. Forholdet mellom ammoniakk og forbindelser med formel VII kan utgjore opptil 3:2, men det foretrekkes å tilsette ammoniakk i et stort 5- til 200-dobbelt overskudd. days, especially 3 to 5 days. The ratio between ammonia and compounds of formula VII can be up to 3:2, but it is preferred to add ammonia in a large 5- to 200-fold excess.
Den under c) angitte fremgangsmåte kan gjennomfores som beskrevetThe procedure specified under c) can be carried out as described
i det folgende:in the following:
Hydrolysen av forbindelsene med formel Id kan gjennomfores på iThe hydrolysis of the compounds of formula Id can be carried out on i
og for seg kjent måte, f.eks. under anvendelse av vandige mineralsyrer, f.eks. saltsyre, eller organiske - syrer, f.eks. metansulfonsyre. Fremgangsmåten skjer hensiktsmessig i et inert organisk losningsmiddel, f.eks. en lavere alkohol, som metanol, and known manner, e.g. using aqueous mineral acids, e.g. hydrochloric acid, or organic acids, e.g. methanesulfonic acid. The procedure conveniently takes place in an inert organic solvent, e.g. a lower alcohol, such as methanol,
og hensiktsmessig ved temperaturer på 50 til 70°C, foretrukket ved koketemperaturen for reaksjonsblandingen. Reaksjonstiden kan f.eks. utgjore 90 minutter til 5 timer, spesielt 150 minutter til 4 timer. Foretrukket anvender man fra 1,02 til 1,1 ekvivalenter syre og fra 1,2 til 2 ekvivalenter vann. Hydrolysen kan hensiktsmessig likeledes gjennomfores med en base, f.eks. hydroksylaminhydroklorid, idet reaksjonstemperaturen hensiktsmessig skal utgjore 20 til 50°C, foretrukket 20 til 30°C og reaksjonstiden f.eks. 5 til 120 minutter. and suitably at temperatures of 50 to 70°C, preferably at the boiling temperature of the reaction mixture. The reaction time can e.g. make 90 minutes to 5 hours, especially 150 minutes to 4 hours. Preferably, from 1.02 to 1.1 equivalents of acid and from 1.2 to 2 equivalents of water are used. The hydrolysis can also suitably be carried out with a base, e.g. hydroxylamine hydrochloride, the reaction temperature being suitably 20 to 50°C, preferably 20 to 30°C and the reaction time e.g. 5 to 120 minutes.
Den under avsnitt d) angitte fremgangsmåte kan gjennomfores som beskrevet i det folgende: Kloreringen eller bromeringen av forbindelsene med formel If gjennomfores hensiktsmessig under anvendelse av N-klor- eller N-brom-succinimid som klorerings- eller bromeringsmiddel. I stedet for disse klorerings- eller bromeringsmidler kan det for dette formål likeledes anvendes en losning av gassformet klor eller flytende brom i et inert organisk losningsmiddel. Reaksjonstemperaturen skal hensiktsmessig utgjore 0 til 30°C, foretrukket The method indicated under section d) can be carried out as described in the following: The chlorination or bromination of the compounds of formula If is suitably carried out using N-chloro- or N-bromosuccinimide as chlorinating or brominating agent. Instead of these chlorinating or brominating agents, a solution of gaseous chlorine or liquid bromine in an inert organic solvent can also be used for this purpose. The reaction temperature should suitably be 0 to 30°C, preferably
20 til 2 5°C hvis N-klor- eller N-bromsuccinimid anvendes og fra 20 to 25°C if N-chloro- or N-bromosuccinimide is used and from
0 til 10°C hvis klor eller brom anvendes. Egnede løsningsmidler er lavere alkanoler som etanol og karbontetraklorid, eller hvis klor eller brom anvendes, iseddik. Reaksjonsvarigheten kan utgjore fra J5til 12 timer, foretrukket fra 1 til 3 timer. 0 to 10°C if chlorine or bromine is used. Suitable solvents are lower alkanols such as ethanol and carbon tetrachloride, or if chlorine or bromine are used, glacial acetic acid. The reaction duration can be from 5 to 12 hours, preferably from 1 to 3 hours.
Den under avsnitt ei angitte fremgangsmåte kan gjennomfores som beskrevet i det folgende: The procedure specified under paragraph one can be carried out as described in the following:
Hydrolysen av forbindelsene med formel VIII kan gjennomforesThe hydrolysis of the compounds of formula VIII can be carried out
på en for hydrolyse av animiraer til ketoner vanlig måte, f.eks. under anvendelse av en syre, foretrukket eddiksyre. Foretrukket anvendes en fortynnet syre, spesielt en 0,01 til 0,1N eddiksyre. Reaksjonstemperaturen utgjor foretrukket 60 til 100°C og reaksjonstidene fra 5 til 120 minutter. in a usual way for the hydrolysis of animiras to ketones, e.g. using an acid, preferably acetic acid. Preferably, a dilute acid is used, especially a 0.01 to 0.1 N acetic acid. The reaction temperature is preferably 60 to 100°C and the reaction times from 5 to 120 minutes.
De erholdte forbindelser med formel I kan isoleres og renses på i og for seg kjent måte. The obtained compounds of formula I can be isolated and purified in a manner known per se.
Den under avsnitt b) beskrevne fremgangsmåte anvendes foretrukket for fremstilling av forbindelser med formel Ib, hvori den ene eller begge substituenter R og R' står for tert.alkyl. The method described under section b) is preferably used for the preparation of compounds of formula Ib, in which one or both substituents R and R' stand for tert-alkyl.
Forbindelsene med formler III, IV og VII som anvendes som utgangsforbindelser, er enten kjente eller kan fremstilles på i og for seg kjent måte fra kjente utgangsforbindelser, f.eks. som beskrevet i det etterfølgende eksempel 2a) for forbindelsene med formel VII. The compounds with formulas III, IV and VII which are used as starting compounds are either known or can be prepared in a manner known per se from known starting compounds, e.g. as described in the following example 2a) for the compounds of formula VII.
Forbindelsene med formel VIII, som anvendes som utgangsforbindelser i fremgangsmåten e), kan f.eks. fremstilles ved at en forbindelse med formel Ihn, hvori har den ovennevnte betydning og RQ og R • er like eller forskjellige og i det enkelte tilfelle betyr et sekundært eller tertiært alkyl med opptil 7 karbonatomer, i et inert organisk losningsmiddel omsettes med forbindelser med formel IX The compounds of formula VIII, which are used as starting compounds in method e), can e.g. is prepared by reacting a compound of formula Ihn, in which it has the above meaning and RQ and R • are the same or different and in the individual case a secondary or tertiary alkyl with up to 7 carbon atoms, in an inert organic solvent with compounds of formula IX
hvori R^<11>' har den ovennevnte betydning og Q står for litium-magnesiumbromid eller -magnesiumklorid og det erholdte adukt deretter hydrolyseres. in which R^<11>' has the above-mentioned meaning and Q stands for lithium-magnesium bromide or -magnesium chloride and the resulting adduct is then hydrolysed.
Omsetningen av forbindelsene med formel Ihn med forbindelseneThe turnover of the compounds of formula Ihn with the compounds
med formel IX kan gjennomfores på en for overforing av et nitril i et imin ved hjelp av en Grignard-reaksjon vanlig måte. Foretrukket anvendes for omsetningen minst 3, foretrukket 3,01 til 20 ekvivalenter av forbindelsene med formel IX, og omsetningen gjennomføres hensiktsmessig ved temperaturer fra 0 til 100°C, foretrukket ved koketemperaturen for reaksjonsblandingen. Egnede løsningsmidler er etere, som tetrahydrofuran, eller dietyleter, spesielt deres blandinger, og reaksjonsvarigheten kan f.eks. utgjore 2 til 24 timer. Den etterfølgende hydrolyse kan f.eks. gjennomfores på en for hydrolyse av litium eller Grignard-adukter vanlig måte, f.eks. ved hjelp av vandig ammoniumklorid, ved temperaturer på f.eks. -10 til 0°C. with formula IX can be carried out in a usual manner for the conversion of a nitrile into an imine by means of a Grignard reaction. Preferably, at least 3, preferably 3.01 to 20 equivalents of the compounds of formula IX are used for the reaction, and the reaction is conveniently carried out at temperatures from 0 to 100°C, preferably at the boiling temperature of the reaction mixture. Suitable solvents are ethers, such as tetrahydrofuran, or diethyl ether, especially their mixtures, and the reaction duration can e.g. make 2 to 24 hours. The subsequent hydrolysis can e.g. carried out in a way usual for the hydrolysis of lithium or Grignard adducts, e.g. using aqueous ammonium chloride, at temperatures of e.g. -10 to 0°C.
Om onsket kan de erholdte forbindelser med formel VIII isoleres og renses på i og for seg kjent måte. Forbindelsene erholdes dog in situ og kan også således anvendes uten ytterligere rensing i det neste fremgangsmåtetrinn. If desired, the obtained compounds of formula VIII can be isolated and purified in a manner known per se. However, the compounds are obtained in situ and can thus also be used without further purification in the next method step.
Forbindelsene med formel Ihn, som anvendes for fremstilling av utgangsforbindelsene under avsnitt e), befinner seg utenfor beskyttelsesområdet i henhold til formel I og er enten kjente eller kan fremstilles på i og for seg kjent måte fra kjent utgangsmaterial, f.eks. under anvendelse av en fremgangsmåte som er analog med fremgangsmåten a). The compounds of formula Ihn, which are used for the preparation of the starting compounds under section e), are outside the scope of protection according to formula I and are either known or can be prepared in a manner known per se from known starting material, e.g. using a method analogous to method a).
Forbindelsene med formel I utmerker seg ved en overordentlig gunstig terapeutisk virkning. Spesielt utmerker forbindelsene med formel I seg ved en fedmebekjempende virkning og en anti-diabetisk virkning. Forbindelsene kan derfra anvendes for bekjemping av fedme og som antidiabetika. Den dose som tilfores daglig av forbindelsene med formel I skal utgjore fra 75 til 1500 mg, som likeledes kan tilfores i mindre mengder på 20 til 750 mg 2-4 ganger daglig eller i retardform. En foretrukket daglig dose utgjor fra 150 til 450 mg, eventuelt tilfort i 3 The compounds of formula I are distinguished by an extremely favorable therapeutic effect. In particular, the compounds of formula I are distinguished by an anti-obesity effect and an anti-diabetic effect. The compounds can then be used to combat obesity and as antidiabetics. The daily dose of the compounds of formula I should be from 75 to 1500 mg, which can also be administered in smaller amounts of 20 to 750 mg 2-4 times a day or in slow-release form. A preferred daily dose is from 150 to 450 mg, possibly supplemented in 3
doser på 50 til 150 mg eller i retardform.doses of 50 to 150 mg or in slow-release form.
Forbindelsene med formel I kan tilfores i form av de fri baser eller i form av deres farmasoytisk tålbare syreaddisjonssalter som har den samme grad av virkning som de fri baser.. For salt-dannelse egnede syrer er saltsyre, bromhydrogensyre og metansulfonsyre. The compounds of formula I can be supplied in the form of the free bases or in the form of their pharmaceutically acceptable acid addition salts which have the same degree of action as the free bases. Acids suitable for salt formation are hydrochloric acid, hydrobromic acid and methanesulfonic acid.
Forbindelsene med formel I kan blandes med vanlig farmasoytisk tålbare fortynningsmidler eller bærere og kan blandes sammen med andre tilsetninger og tilfores i form av kapsler. The compounds of formula I can be mixed with usual pharmaceutically acceptable diluents or carriers and can be mixed together with other additives and supplied in the form of capsules.
De foætrukne betydninger av R, R<1>, R^, R^og R^er de folgende: R : tert.alkyl med 4-7 karbonatomer, foretrukket 4-6 karbon atomer, spesielt tert.butyl,; The preferred meanings of R, R<1>, R^, R^ and R^ are the following: R: tert.alkyl with 4-7 carbon atoms, preferably 4-6 carbons atoms, especially tert.butyl,;
R': tert.alkyl med 4-7, foretrukket 4-6 karbonatomer, spesielt R': tert.alkyl with 4-7, preferably 4-6 carbon atoms, in particular
tert.butyl,; tert.butyl,;
R^: alkyl med 1-4, foretrukket 1-3 karbonatomer, spesielt etyl R^: alkyl with 1-4, preferably 1-3 carbon atoms, especially ethyl
eller metyl,or methyl,
R2: hydrogen eller brom, foretrukket hydrogen,R2: hydrogen or bromine, preferably hydrogen,
R3: hydrogen, cyano eller -C0R41'1 hvori R^'' betyr alkyl med 1-4 karbonatomer, spesielt 1-3 karbonatomer, amino eller en gruppe med formel Ila, hvori R5<1>og • er like eller forskjellige og i det enkelte tilfelle betyr hydrogen, etyl, metyl, metoksy eller etoksy. R3: hydrogen, cyano or -C0R41'1 in which R^'' means alkyl with 1-4 carbon atoms, especially 1-3 carbon atoms, amino or a group of formula IIa, in which R5<1> and • are the same or different and in the individual case means hydrogen, ethyl, methyl, methoxy or ethoxy.
R har foretrukket den samme betydning som R' og R^har spesielt en annen betydning enn cyano eller karboksymetyl bg står foretrukket for hydrogen, acetyl, propionyl eller 4-metoksy-»-benzoyl. R has preferably the same meaning as R' and R' has in particular a different meaning than cyano or carboxymethyl bg preferably stands for hydrogen, acetyl, propionyl or 4-methoxy-»-benzoyl.
De spesielt foretrukne forbindelsesgrupper er dem som kombinerer de ovennevnte betydninger, spesielt dem som utgjor en kombinasjon av alle foretrukne betydninger. Den spesielt foretrukne forbindelse er 3-acetyl-2,6-di-t-butyl-amino-4-metylpyridin. The particularly preferred linking groups are those which combine the above meanings, especially those which constitute a combination of all preferred meanings. The particularly preferred compound is 3-acetyl-2,6-di-t-butyl-amino-4-methylpyridine.
Eksempel 1; 2, 6- di- t- butylamino- 3- cyano- 4- metyl- pyridinExample 1; 2, 6- di- t-butylamino- 3- cyano- 4- methyl- pyridine
1 g 2,6-diklor-3-cyano-4-metylpyridin og tilnærmet 40 ml t-butyl-amin (destillert over natriumhydrid) oppvarmet i en autoklav ved 200°C i 5 timer. En videre oppvarming i 4 timer ved den samme temperatur forer ikke til noen endring i reaksjonsblandingen. Reaksjonsblandingen settes bort over natten og inndampes deretter under redusert trykk. Herved erholdes en gummiaktig rest. Denne gummiaktige faste rest fordeles mellom vann, som inneholder små, mengder natriumkarbonat, og kloroform og den vandige fase ekstraheres deretter to ganger med kloroform. De tre kloroformfaser forenes, torres over vannfritt natriumsulfat og inndampes ved redusert trykk. Resten loses i 10 ml kloroform og losningen fortynnes med heksan vtil 70sml. Den herved dannede lille mengde krystaller frafiltreres og filtratet innfores i en kolonne hvori det befinner seg en oppslemming av 50 ml silikagel i heksan som inneholder 20% kloroform, idet elueringen skjer med den samme losningsmiddelblanding. De forste 130 ml av eluatet kastes og de etterfølgende 100 ml eluat inndampes, idet 6-t-butylamino-2-klor-3-cyano-4-metylpyridin med smeltepunkt 109°C erholdes. 1 g of 2,6-dichloro-3-cyano-4-methylpyridine and approximately 40 ml of t-butylamine (distilled over sodium hydride) heated in an autoclave at 200°C for 5 hours. A further heating for 4 hours at the same temperature does not lead to any change in the reaction mixture. The reaction mixture is set aside overnight and then evaporated under reduced pressure. This results in a rubbery residue. This gummy solid residue is partitioned between water, containing small amounts of sodium carbonate, and chloroform and the aqueous phase is then extracted twice with chloroform. The three chloroform phases are combined, dried over anhydrous sodium sulfate and evaporated under reduced pressure. The residue is dissolved in 10 ml of chloroform and the solution is diluted with hexane to 70 ml. The small amount of crystals thus formed is filtered off and the filtrate is introduced into a column in which there is a slurry of 50 ml of silica gel in hexane containing 20% chloroform, the elution taking place with the same solvent mixture. The first 130 ml of the eluate is discarded and the subsequent 100 ml of eluate is evaporated, whereby 6-t-butylamino-2-chloro-3-cyano-4-methylpyridine with a melting point of 109°C is obtained.
De neste fraksjoner som inneholder den onskede forbindelse, forenes, inndampes ved redusert trykk og tilsettes heksan. Etter fjernelse av heksan ved redusert trykk krystalliseres resten i et kjoleskap hvorved 2,6-di-t-butylamino-3-cyano-4-metylpyridin med smeltepunkt 134-138°C.erholdes. The next fractions containing the desired compound are combined, evaporated under reduced pressure and hexane is added. After removal of hexane at reduced pressure, the residue is crystallized in a refrigerator whereby 2,6-di-t-butylamino-3-cyano-4-methylpyridine with a melting point of 134-138°C is obtained.
Eksempel 2:Example 2:
Under anvendelse av den i eksempel 1 beskrevne fremgangsmåte og egnede utgangsforbindelser i omtrent ekvivalente mengder kommer man frem til folgende forbindelser: a) 2,6-di-t-butylamino-3(4'-metoksybenzoyl)-4-metylpyridin med smeltepunkt 12 7-129°C, b) 2,6-di-t-butylamino-4-metylpyridin hvis metansulfonat smelter ved 179-182°C, Using the method described in example 1 and suitable starting compounds in approximately equivalent quantities, the following compounds are obtained: a) 2,6-di-t-butylamino-3(4'-methoxybenzoyl)-4-methylpyridine with melting point 12 7 -129°C, b) 2,6-di-t-butylamino-4-methylpyridine whose methanesulfonate melts at 179-182°C,
c) ,2,6-di-t-butylaminopyridin,c) ,2,6-di-t-butylaminopyridine,
d) 3-benzoyl-2,6-di-t-butylamino-4-metylpyridin,d) 3-benzoyl-2,6-di-t-butylamino-4-methylpyridine,
e) 2,6-di-t-butylamino-3-(4'-metylbenzoyl)-4-metylpyridin,e) 2,6-di-t-butylamino-3-(4'-methylbenzoyl)-4-methylpyridine,
f) 2,6-di-sek.-butylamino-4-metylpyridin,f) 2,6-di-sec.-butylamino-4-methylpyridine,
g) 2-.£-amylamino-6-t-butylamino-4-metylpyridin ogg) 2-α-amylamino-6-t-butylamino-4-methylpyridine and
h) 2,6-di-t-butylamino-3-karbamoyl-4-metylpyridin.h) 2,6-di-t-butylamino-3-carbamoyl-4-methylpyridine.
Eksempel 3: 3- acetyl- 2, 6- di- t- butvlamino- 4- metylpvridinExample 3: 3-acetyl-2,6-di-t-butylamino-4-methylpyridine
a) 2-t-butyl-5-metylisoxazoliuma) 2-t-butyl-5-methylisoxazolium
En blanding av 1 kg 5-metylisoxazol og 892 g t-butanol omrores under nitrogen ved 0°C og tilsettes deretter langsomt i lopet av 2*2time under sterk omroring ved 0 til 5°C 6,37 kg 60%^ '/ perklorsyre. Den oppnådde suspensjon får anta romtemperatur og omrores over natten. Reaksjonsblåndingen tilsettes deretter langsomt til en blanding av 20 1 tetrahydrofuran og 10 leter ved 0 til 10°C i lopet av 2 timer under omroring. Den erholdte blanding avkjoles deretter til -5°C og omrores deretter i ytterligere 2 timer. Det derved utfelte 2-t-butyl-5-metylisoxa-zolium-perklorat frafiltreres og vaskes med eter. Forbindelsen smelter ved 120 til 122°C. En ytterligere mengde av forbindelsene erholdes fra moderluten. Denne mengde smelter ved 118 til 121°C. A mixture of 1 kg of 5-methylisoxazole and 892 g of t-butanol is stirred under nitrogen at 0°C and then slowly added over 2*2 hours with vigorous stirring at 0 to 5°C 6.37 kg of 60%^ '/ perchloric acid . The resulting suspension is allowed to reach room temperature and stirred overnight. The reaction mixture is then added slowly to a mixture of 20 1 tetrahydrofuran and 10 liters at 0 to 10°C over the course of 2 hours with stirring. The resulting mixture is then cooled to -5°C and then stirred for a further 2 hours. The thereby precipitated 2-t-butyl-5-methylisoxazolium perchlorate is filtered off and washed with ether. The compound melts at 120 to 122°C. A further amount of the compounds is obtained from the mother liquor. This amount melts at 118 to 121°C.
b) N^-t-butyl-3-hydroksybu^b) N-t-butyl-3-hydroxybu^
I) En losning av 100 g 2-t-butyl-5-metvylisoxazoliumperkloratI) A solution of 100 g of 2-t-butyl-5-methylisoxazolium perchlorate
i 200 ml metylenklorid tilsettes under omroring til en blanding av 60 ml vannfri ammoniakk og 240 ml metylenklorid ved -50°C i nitrogenatmosfære. Reaksjonsblandingen settes deretter bort for antagelse av romtemperatur og vaskes deretter med en mettet koksaltlosning. Metylenkloridfasen torres over vannfritt magnesiumsulfat. Etter fjernelse av metylenkloridet ved redusert trykk erholdes en rest. Den omkrystalliseres fra etylacetat idet man kommer frem til N•-t-butyl-3-hydroksybutenamidin med smeltepunkt 118-120°C. Ved videre omkrystallisering fra etylacetat erholdes et smeltepunkt på 126-129°C. in 200 ml of methylene chloride is added with stirring to a mixture of 60 ml of anhydrous ammonia and 240 ml of methylene chloride at -50°C in a nitrogen atmosphere. The reaction mixture is then set aside to assume room temperature and then washed with a saturated sodium chloride solution. The methylene chloride phase is dried over anhydrous magnesium sulfate. After removal of the methylene chloride at reduced pressure, a residue is obtained. It is recrystallized from ethyl acetate to obtain N•-t-butyl-3-hydroxybutenamidine with a melting point of 118-120°C. Upon further recrystallization from ethyl acetate, a melting point of 126-129°C is obtained.
II) En losning av 900 g 2-t-butyl-5-metylisoxazoliumperkloratII) A solution of 900 g of 2-t-butyl-5-methylisoxazolium perchlorate
i 1,8 1 metylenklorid, som ble torret over aluminiumoksyd, tilsettes en blanding av 900 ml nydestillert ammoniakk og 900 ml metylenklorid som ble torret over aluminiumoksyd, med -50 til in 1.8 l of methylene chloride, which was dried over alumina, is added a mixture of 900 ml of freshly distilled ammonia and 900 ml of methylene chloride which was dried over alumina, with -50 to
-60°C under omroring. Deretter settes reaksjonsblandingen bort til den har antatt romtemperatur og omrores over natten. Overskudd av ammoniakk fjernes ved hjelp av et sugeapparat ved 20 -60°C with stirring. The reaction mixture is then set aside until it has reached room temperature and stirred overnight. Excess ammonia is removed using a suction device at 20
til 25°C i lopet av 1 time. Det dannede bunnfall frafiltreres og vaskes med metylenklorid. De forenede filtrater og vaskevæsker vaskes to ganger med hver gang 2 1 av mettet vandig kaliumkarbonat- to 25°C over the course of 1 hour. The precipitate formed is filtered off and washed with methylene chloride. The combined filtrates and washing liquids are washed twice, each time with 2 1 of saturated aqueous potassium carbonate-
losning, torres over vannfritt natriumsulfat og frafiltreres. Etter fjernelse av metylenklorid under redusert trykk og en temperatur på omtrent 45°C erholdes en rest som etter omkrystallisering fra etylacetat og ettervasking med etylacetat/ eter gir N<1->t-butyl-3-hydroksybutenamidin med smeltepunkt 126-129°C. En ytterligere mengde som likeledes kan erholdes smelter ved 119-125°C. solution, dried over anhydrous sodium sulfate and filtered off. After removal of methylene chloride under reduced pressure and a temperature of approximately 45°C, a residue is obtained which, after recrystallization from ethyl acetate and washing with ethyl acetate/ether, gives N<1->t-butyl-3-hydroxybutenamidine with a melting point of 126-129°C. A further quantity which can likewise be obtained melts at 119-125°C.
c) 4-t-butyMmino-3-buten-2-onc) 4-t-butylamino-3-buten-2-one
En blanding av 700 ml trietylamin og 1,5 1 metylenklorid torres A mixture of 700 ml of triethylamine and 1.5 l of methylene chloride is dried
over aluminiumoksyd og avkjoles til en temperatur på -10 tilover aluminum oxide and cooled to a temperature of -10 to
-5°C. Deretter tilsettes i små porsjoner <1> kg 2-t-butyl-5-metylisoxazolium-perklorat i lopet av 2^ time idet temperaturen av reaksjonsblandingen holdes på -5 til 0°C under sterk omroring. Etter avsluttet tilsetning* omrores reaksjonsblandingen i ytterligere 1 time ved -5 til 0°C. Deretter innfores reaksjonsblandingen i 38 1 karbontetraklorid ved romtemperatur under sterk omroring, idet et oljeaktig faststoff utfelles. Deretter tilsettes 7,5 kg vannfritt natriumsulfat og reaksjonsblandingen omrores i 30 minutter. Suspensjonen frafiltreres og den erholdte rest vaskes med karbontetraklorid. De forenede filtrater og vaskevæsker inndampes ved 50°C og redusert trykk hvorved en mork orangegul olje erholdes. Ved destillasjon i hoyvakuum (0,8 mm Hg) ved 54-55°C kommer man frem til 4-t-butyllmino-3-buten-2-on. -5°C. Next, <1> kg of 2-t-butyl-5-methylisoxazolium perchlorate is added in small portions over the course of 2 hours, while the temperature of the reaction mixture is kept at -5 to 0°C with vigorous stirring. After completion of the addition*, the reaction mixture is stirred for a further 1 hour at -5 to 0°C. The reaction mixture is then introduced into 38 1 of carbon tetrachloride at room temperature with vigorous stirring, an oily solid being precipitated. 7.5 kg of anhydrous sodium sulphate are then added and the reaction mixture is stirred for 30 minutes. The suspension is filtered off and the residue obtained is washed with carbon tetrachloride. The combined filtrates and washing liquids are evaporated at 50°C and reduced pressure whereby a dark orange-yellow oil is obtained. Distillation in high vacuum (0.8 mm Hg) at 54-55°C yields 4-t-butylamino-3-buten-2-one.
d) §-acetyl-2^6-di-t-butylamino-4^d) β-acetyl-2^6-di-t-butylamino-4^
I) 3,17 g av det i fremgangsmåtetrinn b) erholdte N'-t-butyl-3-hydroksybutenamidin oppslemmes i 20 ml tetrahydrofuran og suspensjonen tilsettes en blanding av 12,7 ml av 1,6 molar losning av en butyllitium i heksan under nitrogenatmosfære. Den etter-følgende eksoterme reaksjon gir en losning med en temperatur på 40°C. Losningen omrores ved 30 tik 40°C i 45 minutter og tilsettes deretter 2,8 g av det i fremgangsmåtetrinn c) erholdte 4-t-butyl-imino-3-buten-2-on i 8 ml tetrahydrofuran ved 30 til 38°C, fulgt av en ytterligere tilsetning av 2 ml tetrahydrofuran. Etter 10 minutter oppstår et bunnfall. Omroringen fortsettes i ytterligere I) 3.17 g of the N'-t-butyl-3-hydroxybutenamidine obtained in method step b) is suspended in 20 ml of tetrahydrofuran and the suspension is added to a mixture of 12.7 ml of a 1.6 molar solution of a butyllithium in hexane under nitrogen atmosphere. The subsequent exothermic reaction gives a solution with a temperature of 40°C. The solution is stirred at 30 tik 40°C for 45 minutes and then 2.8 g of the 4-t-butyl-imino-3-buten-2-one obtained in method step c) is added in 8 ml of tetrahydrofuran at 30 to 38°C , followed by a further addition of 2 ml of tetrahydrofuran. After 10 minutes a precipitate occurs. The agitation is continued further
35 minutter og reaksjonsblandingen settes bort over natten, (tynnsjiktskromatografering av reaksjonsblandingen etter 45 minutter og den folgende morgen er den samme). Reaksjonsblandingen avkjoles -5°C og blandingen tilsettes 2 ml av en mettet ammoniumkloridlosning. Deretter tilsettes tilstrekkelig kloroform og et spor av metanol hvorved det dannes en losning. Denne inndampes ved redusert trykk hvorved det erholdes en blanding av olje og faststoffer. Blandingen fordeles mellom kloroform og vann og en mindre del (ca. ^ g) av en hvit uopploselig substans frafiltreres. Den vandige fase ekstraheres på nytt med kloroform og kloroformfasen kombineres med kloroformfasen" fra den til å begynne med foretatte fordeling. De forenede kloroformfaser torres over vannfritt magnesiumsulfat, filtreres og inndampes til en brun olje. Den brune olje loses i en liten mengde metanol ved 40°C og til 35 minutes and the reaction mixture is set aside overnight, (thin layer chromatography of the reaction mixture after 45 minutes and the following morning is the same). The reaction mixture is cooled to -5°C and 2 ml of a saturated ammonium chloride solution is added to the mixture. Sufficient chloroform and a trace of methanol are then added, whereby a solution is formed. This is evaporated at reduced pressure, whereby a mixture of oil and solids is obtained. The mixture is distributed between chloroform and water and a small portion (approx. ^ g) of a white insoluble substance is filtered off. The aqueous phase is extracted again with chloroform and the chloroform phase is combined with the chloroform phase" from the initial distribution. The combined chloroform phases are dried over anhydrous magnesium sulfate, filtered and evaporated to a brown oil. The brown oil is dissolved in a small amount of methanol at 40 °C and up
den erholdte losning tilsettes vann til det oppstår en varig uklarhet. Derved utkrystallisere 3-acetyl-2,6-di-t-butylamino-4-metylpyridin i form av gule nåler. Etter vasking med små mengder av en 1:1 blanding av metanol og vann smelter forbindelsen ved 127-128°C. water is added to the solution obtained until a permanent cloudiness occurs. Thereby 3-acetyl-2,6-di-t-butylamino-4-methylpyridine crystallizes out in the form of yellow needles. After washing with small amounts of a 1:1 mixture of methanol and water, the compound melts at 127-128°C.
N.M.R. (CDC13): 1,43 6 (9 Broton-Singlett)N.M.R. (CDC13): 1.43 6 (9 Broton Singlet)
1,47 § (9 Proton-Singiett)Section 1.47 (9 Proton-Singiett)
2,32 S (3 Proton-Singlett)2.32 S (3 Proton Singlet)
2,43 (3 Proton-Singlett)2.43 (3 Proton Singlet)
4,60 S (1 bredt Proifconbånd utbyttbar)4.60 S (1 wide Proifcon band replaceable)
5,47 (1 ^br ed >rqton Singl ett)5.47 (1 ^br ed >rqton Single)
9, 94 8 { 1 bredt Protonbånd utbyttbar)9, 94 8 { 1 wide Proton band exchangeable)
I.R. (CHC13): 3440, 2985, 1720.(forholdsmessig svak), 1605-1580, 1525, 1450, 1420, 1390, I.R. (CHC13): 3440, 2985, 1720.(relatively weak), 1605-1580, 1525, 1450, 1420, 1390,
1360, 1290, 1210, 960 cm"<1>. 1360, 1290, 1210, 960 cm"<1>.
U.V. (CH,0H)Smaks222 ^ (£= 13,650)UV (CH,0H)Smaks222 ^ (£= 13.650)
* maks267 T (6= 15'°00) * max 267 T (6= 15'°00)
maks286 m/(6= 10'670) max 286 m/(6= 10'670)
Amaks368 T (6= 20'500) Amaks368 T (6= 20'500)
II) En blanding av 468 g av det i fremgangsmåtetrinn b) erholdte N'-t-butyl-3-hydroksybutenamidin og 6 1 vannfritt tetrahydrofuran omrores under nitrogen ved romtemperatur og tilsettes deretter dråpevis 1,92 1 av en 1,6 molarjlosning av n-butyllitium i heksan med en slik hastighet at reaksjonsblandingen forblir ved en temperatur på 20 til 40°C. Etter avsluttet tilsetning omrores reaksjonsblandingen ved romtemperatur i ytterligere 1 time. Deretter tilsettes en losning av 417 g av det i fremgangsmåtetrinn II) A mixture of 468 g of the N'-t-butyl-3-hydroxybutenamidine obtained in method step b) and 6 1 of anhydrous tetrahydrofuran is stirred under nitrogen at room temperature and then 1.92 1 of a 1.6 molar solution of n -butyllithium in hexane at such a rate that the reaction mixture remains at a temperature of 20 to 40°C. After the addition is complete, the reaction mixture is stirred at room temperature for a further 1 hour. A solution of 417 g of it is then added in process step
c) erholdte 4-t-butylimino-3-buten-2-on i 2 1 vannfritt tetrahydrofuran dråpevis under avkjoling slik at reaksjonstemperaturen c) obtained 4-t-butylimino-3-buten-2-one in 2 1 anhydrous tetrahydrofuran dropwise while cooling so that the reaction temperature
forblir ved 20 til 25°C. Etter avsluttet tilsetning omrores reaksjonsblandingen over natten ved romtemperatur og tilsettes deretter med omtrent 1,2 1 av en mettet vandig ammoniumkloridlosning hvorved det dannes et voluminost hvitt bunnfall. 12 1 metanol og 12 kg vannfritt natriumsulfat tilsettes deretter og reaksjonsblandingen filtreres gjennom diåtomejord. Filtratet inndampes ved redusert trykk til torrhet og resten loses i 25 1 kloroform. Kloroformlosningen vaskes 2 ganger med 25 1 mengder" .av vann og en gang med 25 1 av en mettet vandig natriumklorid-losning, torres over vannfritt natriumsulfat og filtreres gjennom silikagel. Det klare gule filtrat inndampes til torrhet ved omtrent 50°C under redusert trykk og tilsettes 5 1 petroleter under avkjoling. Herved erholdes 3-acetyl-2,6-di-t-butylamino-4-metylpyridin med smeltepunkt 127-129°C. remains at 20 to 25°C. After the addition is complete, the reaction mixture is stirred overnight at room temperature and then approximately 1.2 1 of a saturated aqueous ammonium chloride solution is added, whereby a voluminous off-white precipitate is formed. 12 1 of methanol and 12 kg of anhydrous sodium sulphate are then added and the reaction mixture is filtered through diatomaceous earth. The filtrate is evaporated under reduced pressure to dryness and the residue is dissolved in 25 1 chloroform. The chloroform solution is washed twice with 25 L of water and once with 25 L of a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate and filtered through silica gel. The clear yellow filtrate is evaporated to dryness at about 50°C under reduced pressure and 5 1 of petroleum ether are added while cooling.This gives 3-acetyl-2,6-di-t-butylamino-4-methylpyridine with a melting point of 127-129°C.
Den fri base av forbindelsen kan overfores i sitt hydrobromid ved dråpevis tilsetning av en 1,6 N losning av gassformet hydrogen-bromid i eter til en losning av den fri base i eter ved 0 til 10°C under etterfølgende omroring i 1 time. Det dannede bunnfall vaskes med eter og ekstraheres med kloroform. Ekstraktet tilsettes aktivert dyrekuli, ■ blandingen filtreres gjennom diatome-jord, filtratet inndampes ved redusert trykk og herved erholdes hydro-bromidet av 3-acetyl-2,6-di-t-butylamino-4-metylpyridin med smeltepunkt 172-175°C. The free base of the compound can be converted into its hydrobromide by dropwise addition of a 1.6 N solution of gaseous hydrogen bromide in ether to a solution of the free base in ether at 0 to 10°C with subsequent stirring for 1 hour. The precipitate formed is washed with ether and extracted with chloroform. The extract is added to activated animal charcoal, ■ the mixture is filtered through diatomaceous earth, the filtrate is evaporated at reduced pressure and thereby the hydrobromide of 3-acetyl-2,6-di-t-butylamino-4-methylpyridine is obtained with a melting point of 172-175°C.
Som ovenfor beskrevet, men med erstatning av eterisk hydrogen-bromidlosning med en 5,5 N losning av gassformet hydrogenklorid i eter eller en losning av metansulfonsyre i eter erholdes hydrokloridet av den ovennevnte forbindelse med smeltepunkt 164-166°C og metansulfonatet av den ovennevnte forbindelse med smeltepunkt 118-121°C.. As described above, but with replacement of ethereal hydrogen bromide solution with a 5.5 N solution of gaseous hydrogen chloride in ether or a solution of methanesulfonic acid in ether, the hydrochloride of the above-mentioned compound with melting point 164-166°C and the methanesulfonate of the above-mentioned compound are obtained with melting point 118-121°C..
Eksempel 4: 3- acetyl- 2, 6- di- t- butylamino- 4- metylpyridinExample 4: 3-acetyl-2,6-di-t-butylamino-4-methylpyridine
a) Ikke identifisert biprodukta) Unidentified by-product
73,6 ml av en 1,622 M losning av n-butyllitium i heksan (119 mmol) 73.6 mL of a 1.622 M solution of n-butyllithium in hexane (119 mmol)
tilsettes til en losning av 18,6 g av det i fremgangsmåtetrinn b) i eksempel 3 erholdte N<1->t-butyl-3-hydroksybutenamidin i tetrahydrofuran ved 2 5 til 40°C under nitrogen. Etter avslutning av den forste eksoterme reaksjon avkjoles reaksjonsblandingen til romtemperatur ved omroring i lopet av 1 time. Deretter tilsettes en losning av 16,6^g av det i fremgangsmåtetrinn c) i eksempel 3 erholdte 4-t-butylimino-3-buten-2-on i tetrahydrofuran dråpevis ved Romtemperatur (23-25°C). Reaksjonsblandingen omrores over natten. Deretter tilsettes 4 ml av en mettet vandig ammoniumkloridlosning, fulgt av tilstrekkåig metanol til å oppnå en mork-fagget losning. Denne inndampes ved redusert trykk. Den erholdte rest fordeles mellom kloroform og vann og^det uopploselige hvite faststoff isoleres ved filtrering. Dette stoff smelter ved 130°C (under spalting). is added to a solution of 18.6 g of the N<1->t-butyl-3-hydroxybutenamidine obtained in method step b) in example 3 in tetrahydrofuran at 25 to 40°C under nitrogen. After completion of the first exothermic reaction, the reaction mixture is cooled to room temperature by stirring over the course of 1 hour. A solution of 16.6 g of the 4-t-butylimino-3-buten-2-one obtained in method step c) in example 3 in tetrahydrofuran is then added dropwise at room temperature (23-25°C). The reaction mixture is stirred overnight. Next, 4 ml of a saturated aqueous ammonium chloride solution is added, followed by sufficient methanol to obtain a cloudy solution. This is evaporated at reduced pressure. The residue obtained is distributed between chloroform and water and the insoluble white solid is isolated by filtration. This substance melts at 130°C (during decomposition).
Elementæranalyse: C 55,8-56%Elemental analysis: C 55.8-56%
H 8,3-8,4% H 8.3-8.4%
N 11,7% N 11.7%
N.M.R. (CD3OD): 1,43 $ (Singlett)N.M.R. (CD3OD): $1.43 (Single)
1,47 S (Singlett)1.47 S (Singlet)
2,23 S (Singlett)2.23 S (Singlet)
4,80 S (Singlett)4.80 S (Singlet)
I.R. (Nujol): 3370, 3280, 3120, 2880-2890, 1605, 1580, I.R. (Nujol): 3370, 3280, 3120, 2880-2890, 1605, 1580,
1500, 1460, 1420, 1400, 1385, 1370,.1255, 1500, 1460, 1420, 1400, 1385, 1370,.1255,
1240, 1230, 1180, 1125, 1095, 1050, 1010, 1240, 1230, 1180, 1125, 1095, 1050, 1010,
990, 970 cm"<1>; 990, 970 cm"<1>;
U.V. (metanol): 218 mja (6=4431% losning)UV (methanol): 218 mja (6=4431% release)
264 mu (6=638 1% losning)264 mu (6=638 1% discharge)
365 mu (£,=6501% losning)365 mu (£,=6501% discharge)
Kloroformf asen fra fordelingen mellom kloroform og vann torres og inndampes under redusert trykk, idet det oppnås et brunt faststoff. Ved behandling av det brune faststoff med metylenklorid erholdes The chloroform phase from the distribution between chloroform and water is dried and evaporated under reduced pressure, obtaining a brown solid. On treatment of the brown solid with methylene chloride is obtained
et uloselig faststoff med smeltepunkt 130°C (under spalting).an insoluble solid with a melting point of 130°C (under decomposition).
b) 3-acetyl-2^6-di-t-butylamin-4-metylb) 3-acetyl-2^6-di-t-butylamine-4-methyl
I) En liten mengde av forbindelsen fra reaksjonstrinn a) I) A small amount of the compound from reaction step a)
omkrystalliseres fra metanol/vann idet 3-acetyl-2,6-di-t-butylamino-4-metylpyridin erholdes i form.av et gult kloroformloselig bunnfall med smeltepunkt 127-128°C (smeltepunktet av en blanding av denne forbindelse med den samme på annen måte erholdte forbindelse niedsettes ikke. is recrystallized from methanol/water whereby 3-acetyl-2,6-di-t-butylamino-4-methylpyridine is obtained in the form of a yellow chloroform-insoluble precipitate with a melting point of 127-128°C (the melting point of a mixture of this compound with the same connection obtained in other ways is not discounted.
II) Den i fremgangsmåtetrinn a) erholdte forbindelse oppvarmes til koking i 5 minutter i vandig metanol. Herved utfelles gule krystaller som frafiltreres og vaskes med en 1:1 blanding av metanol. Det således erholdte 3-acetyl-2,6-di-t-butylamino-4-metylpyridin smelter ved 127-128°'©. II) The compound obtained in method step a) is heated to boiling for 5 minutes in aqueous methanol. This precipitates yellow crystals which are filtered off and washed with a 1:1 mixture of methanol. The 3-acetyl-2,6-di-t-butylamino-4-methylpyridine thus obtained melts at 127-128°'©.
Eksempel 5: 2,6-di-t-butylamino-3-(4'-metoksybenzoyl)-4-metvlpyridin Example 5: 2,6-di-t-butylamino-3-(4'-methoxybenzoyl)-4-methylpyridine
a)N^-t-butyl-3-hydroksy-3-^ a) N 3 -t-butyl-3-hydroxy-3-
N'-t-butyl-3-hydroksy-3-(4'-metoksyfenylj-propenamidinet med N'-t-butyl-3-hydroxy-3-(4'-methoxyphenylj-propenamidine with
smeltepunkt 166-168°C kan erholdes under anvendelse av de i eksemplene 3 a) og 3 b) beskrevne fremgangsmåter under anvendelse av egnede utgangsforbindelser i omtrent ekvivalente mengder. melting point 166-168°C can be obtained using the methods described in examples 3 a) and 3 b) using suitable starting compounds in approximately equivalent amounts.
b) 2^6-di-t-butylamino-3(4'-metoksybenzoyl)-4-metylpyridinb) 2^6-di-t-butylamino-3(4'-methoxybenzoyl)-4-methylpyridine
1,24 ml av en 1,6 molar losning av n-butyllitium i heksan tilsettes 1.24 ml of a 1.6 molar solution of n-butyllithium in hexane is added
langsomt en losning av 500 mg N<1->t-butyl-3-hydroksy-3-(4'-metoksy-fenyl)-propenamidin i 10 ml tort tetrahydrofuran som omrores under nitrogen. Temperaturen i reaksjonsblandingen stiger under tilsetningen 35°C. Reaksjonsblandingen omrores i 15 minutter og tilsettes deretter langsomt 2,2 ml av en 1 M losning av det under anvendelse av fremgangsmåtetrinn c) i eksempel 3 erholdte 4-t-butylamino-3-buten-2-on i dioksan. Reaksjonsblandingen omrores deretter i ytterligere 1 time og tilsettes .1 ml av en mettet vandig ammoniumkloridlosning. Reaksjonsblandingen ekstraheres med kloroform og vann og kloroform uttrekket torres over natriumsulfat. Etter inndampingen ved redusert trykk erholdes en olje. Denne loses i eter og den eteriske losning vaskes med 2 N saltsyre gg deretter to ganger med vann, torres over vannfritt natriumsulfat og inndampes ved redusert trykk. Resten omkrystalliseres fra eter/heptan hvorved 2,6-di-t-butylamino-3-(4J'-metoksybenzoyl)-4-metylpyridin med smeltepunkt 127-129 oC erholdes. slowly a solution of 500 mg of N<1->t-butyl-3-hydroxy-3-(4'-methoxy-phenyl)-propenamidine in 10 ml of dry tetrahydrofuran which is stirred under nitrogen. The temperature in the reaction mixture rises during the addition to 35°C. The reaction mixture is stirred for 15 minutes and then 2.2 ml of a 1 M solution of the 4-t-butylamino-3-buten-2-one obtained using method step c) in example 3 in dioxane is slowly added. The reaction mixture is then stirred for a further 1 hour and .1 ml of a saturated aqueous ammonium chloride solution is added. The reaction mixture is extracted with chloroform and water and the chloroform extract is dried over sodium sulphate. After evaporation at reduced pressure, an oil is obtained. This is dissolved in ether and the ethereal solution is washed with 2 N hydrochloric acid and then twice with water, dried over anhydrous sodium sulfate and evaporated under reduced pressure. The residue is recrystallized from ether/heptane whereby 2,6-di-t-butylamino-3-(4'-methoxybenzoyl)-4-methylpyridine with melting point 127-129 oC is obtained.
Eksempel 6: 3- acetyl- 2, 6- di- t- butylamino4- metylpyridin Example 6: 3-acetyl-2,6-di-t-butylamino4-methylpyridine
Omtrent 60 ml vannfri ammoniakk kondenseres i en beholder som inneholder 60 ml metylenklorid. Réaksjonsblandingen holdes ved en temperatur som ikke overstiger -30°C. Deretter tilsettes hurtig en losning av 50 g 2-t-butyl-^5-metyl-isoxazolium-perklorat i 100 ml metylenklorid. Reaksjonsblandingen settes bort Ibil den har antatt romtemperatur og omrores deretter i 4 dager ved romtemperatur. Deretter fjernes metylenkloridet under redusert trykk, idet det dannes et gummiaktig faststoff som etter behandling med vann går over i et gult faststoff. Etter omkrystallisering fra metanol/vann erholdes 3-acetyl-2,6-di-t-butylamino-4-metylpyridin med smeltepunkt 128-129°C. About 60 ml of anhydrous ammonia is condensed in a container containing 60 ml of methylene chloride. The reaction mixture is kept at a temperature that does not exceed -30°C. A solution of 50 g of 2-t-butyl-5-methyl-isoxazolium perchlorate in 100 ml of methylene chloride is then quickly added. The reaction mixture is set aside until it has reached room temperature and is then stirred for 4 days at room temperature. The methylene chloride is then removed under reduced pressure, as a rubbery solid is formed which, after treatment with water, turns into a yellow solid. After recrystallization from methanol/water, 3-acetyl-2,6-di-t-butylamino-4-methylpyridine is obtained with a melting point of 128-129°C.
Eksempel 7:Example 7:
Under anvendelse av fremgangsmåten i et av eksemplene 3-6 og egnede utgangsforbindelser i omtrent ekvivalente mengder kommer man frem til forbindelsene i eksempel 3 (bare analogt med eksempel 5), 2a) (analogt med eksemplene 3, 4 og 5), 2 b) og 2 e) og de etterfølgende forbindelser: Using the method in one of examples 3-6 and suitable starting compounds in approximately equivalent amounts, one arrives at the compounds in example 3 (only analogous to example 5), 2a) (analogous to examples 3, 4 and 5), 2 b) and 2 e) and the following compounds:
a) 2,6-di-isopropylamino-4-etyl-3-propionylpyridin/a) 2,6-di-isopropylamino-4-ethyl-3-propionylpyridine/
b) 3-acetyl-2,6-di-t-amylamino-4-metylpyridin,b) 3-acetyl-2,6-di-t-amylamino-4-methylpyridine,
c) 2,6-di-t-butylamino-3-(4'-metylbenzoyl)-4-metylpyridin,c) 2,6-di-t-butylamino-3-(4'-methylbenzoyl)-4-methylpyridine,
d) 2,6-di-t-butylamino-4-etyl-3,—propionylpyridin ogd) 2,6-di-t-butylamino-4-ethyl-3,-propionylpyridine and
e) 3-acetyl-2,6-di-(1,l-dietylpropylamino)-4-metylpyridin. e) 3-acetyl-2,6-di-(1,1-diethylpropylamino)-4-methylpyridine.
Eksempel 8: 2, 6- di- t- butylamino- 4- metylpyridinExample 8: 2,6-di-t-butylamino-4-methylpyridine
En blanding av 4,22 g 3-acetyl-2,6-di-t-butylamino-4-metylpyridin, 1 ml metansulfonsyre og 0,5 ml vann i 50 ml metanol og oppvarmes" i 3 timer til koking. Det ved avkjoling dannede bunnfall frafiltreres og filtratet inndampes. Ved behandling av resten med etere erholdes 2, 6-di-fc-butylamino-4-metylpyridin-metansulfonat med smeltepunkt 168°C (under spalting). Etter omkrystallisering fra etylacetat smelter forbindelsen ved 181-182°C. En ytterligere mengde med smeltepunkt 179-181°C erholdes fra moderluten. A mixture of 4.22 g of 3-acetyl-2,6-di-t-butylamino-4-methylpyridine, 1 ml of methanesulfonic acid and 0.5 ml of water in 50 ml of methanol and heated for 3 hours to boiling. That on cooling formed precipitates are filtered off and the filtrate is evaporated. By treating the residue with ethers, 2,6-di-fc-butylamino-4-methylpyridine-methanesulfonate is obtained with a melting point of 168°C (with cleavage). After recrystallization from ethyl acetate, the compound melts at 181-182° C. A further amount with a melting point of 179-181°C is obtained from the mother liquor.
Eksempel 9:Example 9:
Under, anvendelse av den i eksempel 8 beskrevne fremgangsmåte og tilsvarende utgangsforbindelser i omtrent ekvivalente mengder kommer man frem til forbindelsene i eksemplene 2c), 2 f) og 2 g). Using the method described in example 8 and corresponding starting compounds in approximately equivalent amounts leads to the compounds in examples 2c), 2f) and 2g).
Eksempel 10: 31- acetyl- 5- brom- 2, 6- di- t- butylamino- 4- metylpyridin Example 10: 31-acetyl-5-bromo-2,6-di-t-butylamino-4-methylpyridine
534 mg N-bromsuccinimid (omkrystallisert fra vann) tilsettes i små porsjoner til en losning av 831 mg 3-acetyl-2, 6-di-t-butylamino-4-metylpyridin i 20 ml karbontetraklorid og 5 ml etanol og reaksjonsblandingen settes bort over natten ved romtemperatur. Reaksjonsblandingen inndampes ved redusert trykk og resten 534 mg of N-bromosuccinimide (recrystallized from water) is added in small portions to a solution of 831 mg of 3-acetyl-2, 6-di-t-butylamino-4-methylpyridine in 20 ml of carbon tetrachloride and 5 ml of ethanol and the reaction mixture is set aside over overnight at room temperature. The reaction mixture is evaporated under reduced pressure and the residue
fordeles mellom eter og vann. Den organiske fase torres over vannfritt natriumsulfat og inndampes ved redusert trykk. Herved erholdes gule krystaller. Etter omkrystalllsering fra metanol/ vann erholdes 3-acetyl-5-brom—2,6-di-t-butylamino-4-metylpyridin med smeltepunkt 99-100°C. is distributed between ether and water. The organic phase is dried over anhydrous sodium sulfate and evaporated under reduced pressure. This results in yellow crystals. After recrystallization from methanol/water, 3-acetyl-5-bromo-2,6-di-t-butylamino-4-methylpyridine with melting point 99-100°C is obtained.
Eksempel 11:Example 11:
Under anvendelse av den i eksempel 10 beskrevne fremgangsmåteUsing the method described in example 10
og tilsvarende utgangsforbindelser i omtrent ekvivalente mengder erholdes 3-acetyl-5-klor-2,6-di-t-butylamino-4-metylpyridin. and corresponding starting compounds in roughly equivalent amounts, 3-acetyl-5-chloro-2,6-di-t-butylamino-4-methylpyridine is obtained.
Eksempel 12: 3- acetyl- 2, 6- di- t- butylaminopyridinExample 12: 3-acetyl-2,6-di-t-butylaminopyridine
250 ml av en 0,4 molar losning av metyllitium i dietyleter tilsettes dråpevis en losning av 6 g 3-cyano-2,6-di-t-butylaminopyridin i 350 ml tort tetrahydrofuran ved -15°C under omroring og nitrogenatmosfære. Deretter settes blandingen bort til den antar romtemperatur og deretter oppvarmes den i 4 timer til koking. Etter avsluttet koking avkjoles til 0°C og blandingen tilsettes en losning av 17 g ammoniumklorid i 100 ml vann ved -4 til -10°C. Tetrahydrofuran og eter fjernes ved redusert trykk og resten fordeles mellom metylenklorid og vann. Metylen-kloridsjiktet torres over vannfritt natriumsulfat og metylenkloridet fjernes deretter ved redusert trykk. Det erholdte rå imin (forbindelsen med formel VIII) tilsettes deretter til 100 ml av en 0,01 N eddiksyre og blandingen oppvarmes i 2 timer ved 80°C. Deretter avkjoles blandingen og ekstraheres med metylenklorid. Metylenkloridekstrakten> jinhdampes under redusert trykk og det erholdte rå 3-acetyl-2,6-di-t-butylaminopyridin renses ved kromatografering på silikagel. 250 ml of a 0.4 molar solution of methyllithium in diethyl ether is added dropwise to a solution of 6 g of 3-cyano-2,6-di-t-butylaminopyridine in 350 ml of dry tetrahydrofuran at -15°C under stirring and nitrogen atmosphere. Then the mixture is set aside until it assumes room temperature and then it is heated for 4 hours to boiling. After boiling is finished, cool to 0°C and a solution of 17 g of ammonium chloride in 100 ml of water at -4 to -10°C is added to the mixture. Tetrahydrofuran and ether are removed under reduced pressure and the residue is distributed between methylene chloride and water. The methylene chloride layer is dried over anhydrous sodium sulfate and the methylene chloride is then removed under reduced pressure. The crude imine obtained (the compound of formula VIII) is then added to 100 ml of a 0.01 N acetic acid and the mixture is heated for 2 hours at 80°C. The mixture is then cooled and extracted with methylene chloride. The methylene chloride extract is evaporated under reduced pressure and the crude 3-acetyl-2,6-di-t-butylaminopyridine obtained is purified by chromatography on silica gel.
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DD (1) | DD119230A5 (en) |
DE (1) | DE2514558A1 (en) |
DK (1) | DK142675A (en) |
FI (1) | FI750998A (en) |
FR (1) | FR2267102A1 (en) |
IL (1) | IL47066A0 (en) |
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DE3134945A1 (en) * | 1981-09-03 | 1983-03-17 | Bayer Ag, 5090 Leverkusen | SUBSTITUTED 2-AMINO-3,4-DIHYDROPYRIDINE DERIVATIVES, METHOD FOR THE PRODUCTION THEREOF AND THEIR USE IN MEDICINAL PRODUCTS |
DE3637829A1 (en) * | 1986-11-06 | 1988-05-11 | Asta Pharma Ag | NEW 2,6-DIAMINO-3-HALOGENOBENZYLPYRIDINE AND METHOD FOR THE PRODUCTION THEREOF AND THEIR USE IN PHARMACEUTICALS |
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- 1975-04-03 FI FI750998A patent/FI750998A/fi not_active Application Discontinuation
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AU8003675A (en) | 1976-10-14 |
DD119230A5 (en) | 1976-04-12 |
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DE2514558A1 (en) | 1975-10-23 |
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