NO128328B - - Google Patents
Download PDFInfo
- Publication number
- NO128328B NO128328B NO00510/70A NO51070A NO128328B NO 128328 B NO128328 B NO 128328B NO 00510/70 A NO00510/70 A NO 00510/70A NO 51070 A NO51070 A NO 51070A NO 128328 B NO128328 B NO 128328B
- Authority
- NO
- Norway
- Prior art keywords
- compound
- general formula
- formula
- methoxymethyl
- chloro
- Prior art date
Links
- 150000001875 compounds Chemical class 0.000 claims description 101
- 238000000034 method Methods 0.000 claims description 10
- 150000003839 salts Chemical class 0.000 claims description 9
- 125000002088 tosyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1C([H])([H])[H])S(*)(=O)=O 0.000 claims description 5
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 4
- 125000002252 acyl group Chemical group 0.000 claims description 4
- 239000000460 chlorine Substances 0.000 claims description 4
- 229910052801 chlorine Inorganic materials 0.000 claims description 4
- 229910052736 halogen Inorganic materials 0.000 claims description 4
- 125000004170 methylsulfonyl group Chemical group [H]C([H])([H])S(*)(=O)=O 0.000 claims description 4
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 4
- 229940053197 benzodiazepine derivative antiepileptics Drugs 0.000 claims description 3
- 150000002367 halogens Chemical class 0.000 claims description 3
- 238000002360 preparation method Methods 0.000 claims description 3
- 125000000217 alkyl group Chemical group 0.000 claims description 2
- 125000003310 benzodiazepinyl group Chemical class N1N=C(C=CC2=C1C=CC=C2)* 0.000 claims 1
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 108
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 39
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 36
- 239000000243 solution Substances 0.000 description 36
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 33
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 25
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 24
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 24
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 23
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 22
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 22
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 20
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 20
- 239000003960 organic solvent Substances 0.000 description 20
- 229960000583 acetic acid Drugs 0.000 description 17
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 15
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 15
- -1 mesyloxy, tosyloxy group Chemical group 0.000 description 15
- 239000011541 reaction mixture Substances 0.000 description 15
- 229930195733 hydrocarbon Natural products 0.000 description 14
- 150000002430 hydrocarbons Chemical class 0.000 description 14
- 150000002170 ethers Chemical class 0.000 description 13
- 239000002585 base Substances 0.000 description 12
- 239000012362 glacial acetic acid Substances 0.000 description 12
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 11
- QGZKDVFQNNGYKY-UHFFFAOYSA-N ammonia Natural products N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 11
- 238000006243 chemical reaction Methods 0.000 description 11
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 10
- XUIMIQQOPSSXEZ-UHFFFAOYSA-N Silicon Chemical compound [Si] XUIMIQQOPSSXEZ-UHFFFAOYSA-N 0.000 description 10
- 150000001298 alcohols Chemical class 0.000 description 10
- 239000003513 alkali Substances 0.000 description 10
- 239000000499 gel Substances 0.000 description 10
- 229910052710 silicon Inorganic materials 0.000 description 10
- 239000010703 silicon Substances 0.000 description 10
- KXLMWAXKAWGBBX-UHFFFAOYSA-N 7-chloro-1-(methoxymethyl)-5-phenyl-3h-1,4-benzodiazepin-2-one Chemical compound N=1CC(=O)N(COC)C2=CC=C(Cl)C=C2C=1C1=CC=CC=C1 KXLMWAXKAWGBBX-UHFFFAOYSA-N 0.000 description 9
- 150000008280 chlorinated hydrocarbons Chemical class 0.000 description 9
- 239000000284 extract Substances 0.000 description 9
- 238000001953 recrystallisation Methods 0.000 description 9
- 239000007858 starting material Substances 0.000 description 9
- 238000003756 stirring Methods 0.000 description 9
- 239000002253 acid Substances 0.000 description 8
- 238000002425 crystallisation Methods 0.000 description 8
- 230000008025 crystallization Effects 0.000 description 8
- 238000010992 reflux Methods 0.000 description 8
- XJUZRXYOEPSWMB-UHFFFAOYSA-N Chloromethyl methyl ether Chemical compound COCCl XJUZRXYOEPSWMB-UHFFFAOYSA-N 0.000 description 7
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 7
- 238000003776 cleavage reaction Methods 0.000 description 7
- 235000019439 ethyl acetate Nutrition 0.000 description 7
- 239000000706 filtrate Substances 0.000 description 7
- 230000007017 scission Effects 0.000 description 7
- 229910000104 sodium hydride Inorganic materials 0.000 description 7
- 239000012312 sodium hydride Substances 0.000 description 7
- 239000000725 suspension Substances 0.000 description 7
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 6
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 6
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 6
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 6
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 6
- 238000001704 evaporation Methods 0.000 description 6
- 230000008020 evaporation Effects 0.000 description 6
- NUJOXMJBOLGQSY-UHFFFAOYSA-N manganese dioxide Chemical compound O=[Mn]=O NUJOXMJBOLGQSY-UHFFFAOYSA-N 0.000 description 6
- 239000000047 product Substances 0.000 description 6
- 229910052938 sodium sulfate Inorganic materials 0.000 description 6
- 235000011152 sodium sulphate Nutrition 0.000 description 6
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 5
- 229910021529 ammonia Inorganic materials 0.000 description 5
- 239000001961 anticonvulsive agent Substances 0.000 description 5
- 238000001816 cooling Methods 0.000 description 5
- 239000000155 melt Substances 0.000 description 5
- 239000000203 mixture Substances 0.000 description 5
- 230000003647 oxidation Effects 0.000 description 5
- 238000007254 oxidation reaction Methods 0.000 description 5
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 5
- 235000011121 sodium hydroxide Nutrition 0.000 description 5
- SJVYDWSMIBNNAD-UHFFFAOYSA-N 7-chloro-1-(methoxymethyl)-5-phenyl-4,5-dihydro-3H-1,4-benzodiazepin-2-one Chemical compound ClC=1C=CC2=C(C(NCC(N2COC)=O)C2=CC=CC=C2)C1 SJVYDWSMIBNNAD-UHFFFAOYSA-N 0.000 description 4
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 4
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 4
- 230000001773 anti-convulsant effect Effects 0.000 description 4
- 229960003965 antiepileptics Drugs 0.000 description 4
- 230000000694 effects Effects 0.000 description 4
- ZKQFHRVKCYFVCN-UHFFFAOYSA-N ethoxyethane;hexane Chemical compound CCOCC.CCCCCC ZKQFHRVKCYFVCN-UHFFFAOYSA-N 0.000 description 4
- 238000002844 melting Methods 0.000 description 4
- 230000008018 melting Effects 0.000 description 4
- CWCAUFWLFIUQHP-UHFFFAOYSA-N motrazepam Chemical compound N=1CC(=O)N(COC)C2=CC=C(N(=O)=O)C=C2C=1C1=CC=CC=C1 CWCAUFWLFIUQHP-UHFFFAOYSA-N 0.000 description 4
- 239000012071 phase Substances 0.000 description 4
- LARVUPCHJCRZIC-UHFFFAOYSA-N 7-chloro-1-(methoxymethyl)-4-oxido-5-phenyl-3H-1,4-benzodiazepin-4-ium-2-one Chemical compound ClC=1C=CC2=C(C(=[N+](CC(N2COC)=O)[O-])C2=CC=CC=C2)C1 LARVUPCHJCRZIC-UHFFFAOYSA-N 0.000 description 3
- MSMDONYJVMGDOT-UHFFFAOYSA-N 7-chloro-4-hydroxy-1-(methoxymethyl)-5-phenyl-3,5-dihydro-1,4-benzodiazepin-2-one Chemical compound ClC=1C=CC2=C(C(N(CC(N2COC)=O)O)C2=CC=CC=C2)C1 MSMDONYJVMGDOT-UHFFFAOYSA-N 0.000 description 3
- CWRVKFFCRWGWCS-UHFFFAOYSA-N Pentrazole Chemical compound C1CCCCC2=NN=NN21 CWRVKFFCRWGWCS-UHFFFAOYSA-N 0.000 description 3
- 229910052783 alkali metal Inorganic materials 0.000 description 3
- 150000004703 alkoxides Chemical class 0.000 description 3
- 150000001408 amides Chemical class 0.000 description 3
- 239000003795 chemical substances by application Substances 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 150000004678 hydrides Chemical class 0.000 description 3
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 3
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 3
- 238000002955 isolation Methods 0.000 description 3
- 239000012280 lithium aluminium hydride Substances 0.000 description 3
- 239000000463 material Substances 0.000 description 3
- 239000002480 mineral oil Substances 0.000 description 3
- 235000010446 mineral oil Nutrition 0.000 description 3
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 3
- 239000012299 nitrogen atmosphere Substances 0.000 description 3
- 239000003921 oil Substances 0.000 description 3
- 235000019198 oils Nutrition 0.000 description 3
- ODZPKZBBUMBTMG-UHFFFAOYSA-N sodium amide Chemical compound [NH2-].[Na+] ODZPKZBBUMBTMG-UHFFFAOYSA-N 0.000 description 3
- 239000002904 solvent Substances 0.000 description 3
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 description 3
- 238000012360 testing method Methods 0.000 description 3
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 3
- YYROPELSRYBVMQ-UHFFFAOYSA-N 4-toluenesulfonyl chloride Chemical compound CC1=CC=C(S(Cl)(=O)=O)C=C1 YYROPELSRYBVMQ-UHFFFAOYSA-N 0.000 description 2
- QGZFAWYCUXVHOD-UHFFFAOYSA-N 5-chloro-1-(methoxymethyl)-3-phenylindole-2-carbaldehyde Chemical compound ClC=1C=C2C(=C(N(C2=CC1)COC)C=O)C1=CC=CC=C1 QGZFAWYCUXVHOD-UHFFFAOYSA-N 0.000 description 2
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 2
- HFTLINCYGBTCPU-UHFFFAOYSA-N Cl.NCC=1N(C2=CC=C(C=C2C1C1=CC=CC=C1)Cl)COC Chemical compound Cl.NCC=1N(C2=CC=C(C=C2C1C1=CC=CC=C1)Cl)COC HFTLINCYGBTCPU-UHFFFAOYSA-N 0.000 description 2
- WTDHULULXKLSOZ-UHFFFAOYSA-N Hydroxylamine hydrochloride Chemical compound Cl.ON WTDHULULXKLSOZ-UHFFFAOYSA-N 0.000 description 2
- 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 2
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Chemical compound OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 2
- KFSLWBXXFJQRDL-UHFFFAOYSA-N Peracetic acid Chemical compound CC(=O)OO KFSLWBXXFJQRDL-UHFFFAOYSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 2
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 2
- 238000010521 absorption reaction Methods 0.000 description 2
- 230000010933 acylation Effects 0.000 description 2
- 238000005917 acylation reaction Methods 0.000 description 2
- 229910001854 alkali hydroxide Inorganic materials 0.000 description 2
- 150000008044 alkali metal hydroxides Chemical class 0.000 description 2
- 239000008346 aqueous phase Substances 0.000 description 2
- 125000003118 aryl group Chemical group 0.000 description 2
- 150000001557 benzodiazepines Chemical class 0.000 description 2
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 2
- 229910052794 bromium Inorganic materials 0.000 description 2
- 239000003054 catalyst Substances 0.000 description 2
- 238000009903 catalytic hydrogenation reaction Methods 0.000 description 2
- 229940061627 chloromethyl methyl ether Drugs 0.000 description 2
- 238000004587 chromatography analysis Methods 0.000 description 2
- 229940117975 chromium trioxide Drugs 0.000 description 2
- WGLPBDUCMAPZCE-UHFFFAOYSA-N chromium trioxide Inorganic materials O=[Cr](=O)=O WGLPBDUCMAPZCE-UHFFFAOYSA-N 0.000 description 2
- GAMDZJFZMJECOS-UHFFFAOYSA-N chromium(6+);oxygen(2-) Chemical compound [O-2].[O-2].[O-2].[Cr+6] GAMDZJFZMJECOS-UHFFFAOYSA-N 0.000 description 2
- 239000013078 crystal Substances 0.000 description 2
- 238000006297 dehydration reaction Methods 0.000 description 2
- NPOMSUOUAZCMBL-UHFFFAOYSA-N dichloromethane;ethoxyethane Chemical compound ClCCl.CCOCC NPOMSUOUAZCMBL-UHFFFAOYSA-N 0.000 description 2
- MDKXBBPLEGPIRI-UHFFFAOYSA-N ethoxyethane;methanol Chemical compound OC.CCOCC MDKXBBPLEGPIRI-UHFFFAOYSA-N 0.000 description 2
- WBTKTOHWTWDQCC-UHFFFAOYSA-N ethyl 7-chloro-1-(methoxymethyl)-2-oxo-5-phenyl-3H-1,4-benzodiazepine-3-carboxylate Chemical compound CCOC(=O)C1N=C(C2=CC=CC=C2)C2=CC(Cl)=CC=C2N(COC)C1=O WBTKTOHWTWDQCC-UHFFFAOYSA-N 0.000 description 2
- 239000012467 final product Substances 0.000 description 2
- 239000012634 fragment Substances 0.000 description 2
- 239000001257 hydrogen Substances 0.000 description 2
- 229910052739 hydrogen Inorganic materials 0.000 description 2
- 238000006317 isomerization reaction Methods 0.000 description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 238000001819 mass spectrum Methods 0.000 description 2
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 2
- 239000003158 myorelaxant agent Substances 0.000 description 2
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 2
- 239000007800 oxidant agent Substances 0.000 description 2
- MUMZUERVLWJKNR-UHFFFAOYSA-N oxoplatinum Chemical compound [Pt]=O MUMZUERVLWJKNR-UHFFFAOYSA-N 0.000 description 2
- 239000000825 pharmaceutical preparation Substances 0.000 description 2
- UYWQUFXKFGHYNT-UHFFFAOYSA-N phenylmethyl ester of formic acid Natural products O=COCC1=CC=CC=C1 UYWQUFXKFGHYNT-UHFFFAOYSA-N 0.000 description 2
- 239000011574 phosphorus Substances 0.000 description 2
- 229910052698 phosphorus Inorganic materials 0.000 description 2
- FAIAAWCVCHQXDN-UHFFFAOYSA-N phosphorus trichloride Chemical compound ClP(Cl)Cl FAIAAWCVCHQXDN-UHFFFAOYSA-N 0.000 description 2
- 125000005543 phthalimide group Chemical group 0.000 description 2
- 229910003446 platinum oxide Inorganic materials 0.000 description 2
- 229910052708 sodium Inorganic materials 0.000 description 2
- 239000011734 sodium Substances 0.000 description 2
- 238000004611 spectroscopical analysis Methods 0.000 description 2
- 125000001424 substituent group Chemical group 0.000 description 2
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 2
- 238000001665 trituration Methods 0.000 description 2
- NWZSZGALRFJKBT-KNIFDHDWSA-N (2s)-2,6-diaminohexanoic acid;(2s)-2-hydroxybutanedioic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O.NCCCC[C@H](N)C(O)=O NWZSZGALRFJKBT-KNIFDHDWSA-N 0.000 description 1
- USVVENVKYJZFMW-ONEGZZNKSA-N (e)-carboxyiminocarbamic acid Chemical class OC(=O)\N=N\C(O)=O USVVENVKYJZFMW-ONEGZZNKSA-N 0.000 description 1
- ROXAFEIDZVHGFX-UHFFFAOYSA-N 1,3,4,5-tetrahydro-1,4-benzodiazepin-2-one Chemical compound N1C(=O)CNCC2=CC=CC=C21 ROXAFEIDZVHGFX-UHFFFAOYSA-N 0.000 description 1
- ADFXKUOMJKEIND-UHFFFAOYSA-N 1,3-dicyclohexylurea Chemical compound C1CCCCC1NC(=O)NC1CCCCC1 ADFXKUOMJKEIND-UHFFFAOYSA-N 0.000 description 1
- ANILELZNVKYUSS-UHFFFAOYSA-N 1-(methoxymethyl)-7-nitro-4-oxido-5-phenyl-3H-1,4-benzodiazepin-4-ium-2-one Chemical compound COCN1C(C[N+](=C(C2=C1C=CC(=C2)[N+](=O)[O-])C2=CC=CC=C2)[O-])=O ANILELZNVKYUSS-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
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 1
- XVMSFILGAMDHEY-UHFFFAOYSA-N 6-(4-aminophenyl)sulfonylpyridin-3-amine Chemical compound C1=CC(N)=CC=C1S(=O)(=O)C1=CC=C(N)C=N1 XVMSFILGAMDHEY-UHFFFAOYSA-N 0.000 description 1
- VQGXPDYKHUEPSZ-UHFFFAOYSA-N 7-chloro-1-(methoxymethyl)-4-(4-methylphenyl)sulfonyl-5-phenyl-3,5-dihydro-1,4-benzodiazepin-2-one Chemical compound ClC=1C=CC2=C(C(N(CC(N2COC)=O)S(=O)(=O)C2=CC=C(C=C2)C)C2=CC=CC=C2)C1 VQGXPDYKHUEPSZ-UHFFFAOYSA-N 0.000 description 1
- OYDOSVDEZOUZIM-UHFFFAOYSA-N 7-chloro-1-(methoxymethyl)-5-phenyl-5H-1,4-benzodiazepin-2-one Chemical compound ClC=1C=CC2=C(C(N=CC(N2COC)=O)C2=CC=CC=C2)C1 OYDOSVDEZOUZIM-UHFFFAOYSA-N 0.000 description 1
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-M Bicarbonate Chemical compound OC([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-M 0.000 description 1
- 238000006418 Brown reaction Methods 0.000 description 1
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 description 1
- 108010010803 Gelatin Proteins 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- AVXURJPOCDRRFD-UHFFFAOYSA-N Hydroxylamine Chemical compound ON AVXURJPOCDRRFD-UHFFFAOYSA-N 0.000 description 1
- 241000699670 Mus sp. Species 0.000 description 1
- PCLIMKBDDGJMGD-UHFFFAOYSA-N N-bromosuccinimide Chemical compound BrN1C(=O)CCC1=O PCLIMKBDDGJMGD-UHFFFAOYSA-N 0.000 description 1
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 1
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 1
- 239000007868 Raney catalyst Substances 0.000 description 1
- NPXOKRUENSOPAO-UHFFFAOYSA-N Raney nickel Chemical compound [Al].[Ni] NPXOKRUENSOPAO-UHFFFAOYSA-N 0.000 description 1
- 229910000564 Raney nickel Inorganic materials 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 description 1
- MSCVBODAWSTJSD-UHFFFAOYSA-N [7-chloro-1-(methoxymethyl)-2-oxo-5-phenyl-3,5-dihydro-1,4-benzodiazepin-4-yl] acetate Chemical compound C(C)(=O)ON1CC(N(C2=C(C1C1=CC=CC=C1)C=C(C=C2)Cl)COC)=O MSCVBODAWSTJSD-UHFFFAOYSA-N 0.000 description 1
- ARKPVOPQMSRARV-UHFFFAOYSA-N [N+](=O)([O-])C=1C=CC2=C(C(=NC(C(N2OC)=O)C)C2=CC=CC=C2)C1 Chemical compound [N+](=O)([O-])C=1C=CC2=C(C(=NC(C(N2OC)=O)C)C2=CC=CC=C2)C1 ARKPVOPQMSRARV-UHFFFAOYSA-N 0.000 description 1
- 229960001413 acetanilide Drugs 0.000 description 1
- 150000001242 acetic acid derivatives Chemical class 0.000 description 1
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 1
- 150000008065 acid anhydrides Chemical class 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 230000001476 alcoholic effect Effects 0.000 description 1
- 229910000102 alkali metal hydride Inorganic materials 0.000 description 1
- 150000008046 alkali metal hydrides Chemical class 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 229940125681 anticonvulsant agent Drugs 0.000 description 1
- 239000002249 anxiolytic agent Substances 0.000 description 1
- 230000000949 anxiolytic effect Effects 0.000 description 1
- 229940005530 anxiolytics Drugs 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 125000003435 aroyl group Chemical group 0.000 description 1
- 239000012965 benzophenone Substances 0.000 description 1
- XSCHRSMBECNVNS-UHFFFAOYSA-N benzopyrazine Natural products N1=CC=NC2=CC=CC=C21 XSCHRSMBECNVNS-UHFFFAOYSA-N 0.000 description 1
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 description 1
- 125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 239000000872 buffer Substances 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 150000001718 carbodiimides Chemical class 0.000 description 1
- 239000012876 carrier material Substances 0.000 description 1
- 239000003638 chemical reducing agent Substances 0.000 description 1
- VXIVSQZSERGHQP-UHFFFAOYSA-N chloroacetamide Chemical compound NC(=O)CCl VXIVSQZSERGHQP-UHFFFAOYSA-N 0.000 description 1
- 238000011097 chromatography purification Methods 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 238000006114 decarboxylation reaction Methods 0.000 description 1
- 230000018044 dehydration Effects 0.000 description 1
- GGRWZBVSUZZMKS-UHFFFAOYSA-N demoxepam Chemical compound C12=CC(Cl)=CC=C2NC(=O)C[N+]([O-])=C1C1=CC=CC=C1 GGRWZBVSUZZMKS-UHFFFAOYSA-N 0.000 description 1
- YLMFADKHVIEJOY-UHFFFAOYSA-N dichloromethane;ethoxyethane;ethyl acetate Chemical compound ClCCl.CCOCC.CCOC(C)=O YLMFADKHVIEJOY-UHFFFAOYSA-N 0.000 description 1
- WGLUMOCWFMKWIL-UHFFFAOYSA-N dichloromethane;methanol Chemical compound OC.ClCCl WGLUMOCWFMKWIL-UHFFFAOYSA-N 0.000 description 1
- 239000008298 dragée Substances 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 230000008030 elimination Effects 0.000 description 1
- 238000003379 elimination reaction Methods 0.000 description 1
- 239000003995 emulsifying agent Substances 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- 239000012259 ether extract Substances 0.000 description 1
- FSLOLRKVZPTMHC-UHFFFAOYSA-N ethyl 5-chloro-3-phenyl-1h-indole-2-carboxylate Chemical compound CCOC(=O)C=1NC2=CC=C(Cl)C=C2C=1C1=CC=CC=C1 FSLOLRKVZPTMHC-UHFFFAOYSA-N 0.000 description 1
- DTKOQJNQMOCKQU-UHFFFAOYSA-N ethyl 7-chloro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepine-3-carboxylate Chemical compound C12=CC(Cl)=CC=C2NC(=O)C(C(=O)OCC)N=C1C1=CC=CC=C1 DTKOQJNQMOCKQU-UHFFFAOYSA-N 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 235000019253 formic acid Nutrition 0.000 description 1
- 125000000524 functional group Chemical group 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- 229940093915 gynecological organic acid Drugs 0.000 description 1
- 150000004820 halides Chemical class 0.000 description 1
- 150000008282 halocarbons Chemical class 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- IKDUDTNKRLTJSI-UHFFFAOYSA-N hydrazine monohydrate Substances O.NN IKDUDTNKRLTJSI-UHFFFAOYSA-N 0.000 description 1
- 238000006698 hydrazinolysis reaction Methods 0.000 description 1
- 150000002431 hydrogen Chemical class 0.000 description 1
- 238000005984 hydrogenation reaction Methods 0.000 description 1
- 150000004679 hydroxides Chemical class 0.000 description 1
- 229910010272 inorganic material Inorganic materials 0.000 description 1
- 239000011147 inorganic material Substances 0.000 description 1
- 239000013067 intermediate product Substances 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 239000011976 maleic acid Substances 0.000 description 1
- 125000000325 methylidene group Chemical group [H]C([H])=* 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 229940035363 muscle relaxants Drugs 0.000 description 1
- PBMIETCUUSQZCG-UHFFFAOYSA-N n'-cyclohexylmethanediimine Chemical compound N=C=NC1CCCCC1 PBMIETCUUSQZCG-UHFFFAOYSA-N 0.000 description 1
- VEJJCRAVOYFKAU-UHFFFAOYSA-N n-(2-benzoylphenyl)-2-(1,3-dioxoisoindol-2-yl)acetamide Chemical compound O=C1C2=CC=CC=C2C(=O)N1CC(=O)NC1=CC=CC=C1C(=O)C1=CC=CC=C1 VEJJCRAVOYFKAU-UHFFFAOYSA-N 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- AKPLHCDWDRPJGD-UHFFFAOYSA-N nordazepam Chemical compound C12=CC(Cl)=CC=C2NC(=O)CN=C1C1=CC=CC=C1 AKPLHCDWDRPJGD-UHFFFAOYSA-N 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 150000007530 organic bases Chemical group 0.000 description 1
- 230000003204 osmotic effect Effects 0.000 description 1
- 230000020477 pH reduction Effects 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- 150000004965 peroxy acids Chemical class 0.000 description 1
- DDBREPKUVSBGFI-UHFFFAOYSA-N phenobarbital Chemical compound C=1C=CC=CC=1C1(CC)C(=O)NC(=O)NC1=O DDBREPKUVSBGFI-UHFFFAOYSA-N 0.000 description 1
- 229960002695 phenobarbital Drugs 0.000 description 1
- LFSXCDWNBUNEEM-UHFFFAOYSA-N phthalazine Chemical compound C1=NN=CC2=CC=CC=C21 LFSXCDWNBUNEEM-UHFFFAOYSA-N 0.000 description 1
- 229920001515 polyalkylene glycol Polymers 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 239000011347 resin Substances 0.000 description 1
- 229920005989 resin Polymers 0.000 description 1
- 238000007363 ring formation reaction Methods 0.000 description 1
- 239000005060 rubber Substances 0.000 description 1
- 229940125723 sedative agent Drugs 0.000 description 1
- 239000000932 sedative agent Substances 0.000 description 1
- 239000013049 sediment Substances 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 235000012222 talc Nutrition 0.000 description 1
- RUPAXCPQAAOIPB-UHFFFAOYSA-N tert-butyl formate Chemical group CC(C)(C)OC=O RUPAXCPQAAOIPB-UHFFFAOYSA-N 0.000 description 1
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 description 1
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 1
- 229940099259 vaseline Drugs 0.000 description 1
- 235000015112 vegetable and seed oil Nutrition 0.000 description 1
- 239000008158 vegetable oil Substances 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
- 239000011701 zinc Substances 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/04—Indoles; Hydrogenated indoles
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C271/00—Derivatives of carbamic acids, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
- C07C271/06—Esters of carbamic acids
- C07C271/08—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms
- C07C271/10—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms
- C07C271/22—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms to carbon atoms of hydrocarbon radicals substituted by carboxyl groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/04—Indoles; Hydrogenated indoles
- C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
- C07D209/12—Radicals substituted by oxygen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K1/00—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length
- C07K1/006—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length of peptides containing derivatised side chain amino acids
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Genetics & Genomics (AREA)
- Medicinal Chemistry (AREA)
- Life Sciences & Earth Sciences (AREA)
- Biochemistry (AREA)
- Biophysics (AREA)
- General Health & Medical Sciences (AREA)
- Analytical Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Molecular Biology (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Plural Heterocyclic Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Pyridine Compounds (AREA)
Description
Nærværende oppfinnelse vedrorer en analogifremgangsmåte £>r fremstilling av benzodiazepinderivater med den generelle formel The present invention relates to an analogous method for the preparation of benzodiazepine derivatives with the general formula
hvor betyr klor eller nitro' såvel som salter av disse forbindelser. where means chlorine or nitro' as well as salts of these compounds.
Helt særlig foretrukket er den forbindelse med formel I, hvor R^betyr nitro, d.v.s. 7-nitro-5-fenyl-l-metoksymetyl-1,3-dihydro-2H-1,4-benzodiazepin-2-on. Particularly preferred is the compound of formula I, where R₂ means nitro, i.e. 7-nitro-5-phenyl-1-methoxymethyl-1,3-dihydro-2H-1,4-benzodiazepine-2-one.
Fremgangsmåten ifolge oppfinnelsen karakteriseres ved,at man The method according to the invention is characterized by the fact that
a) omsetter en forbindelse med den generelle formel a) reacts a compound with the general formula
hvor har foran angitte betydning, where has the meaning set out above,
med en forbindelse med den generelle formel with a compound of the general formula
hvor X betyr halogen, where X means halogen,
eller at man or that one
b) cykliserer en forbindelse med den generelle formel b) cyclizes a compound of the general formula
hvor R^har foran angitt betydning, where R^ has previously stated meaning,
eller at man or that one
c) desoksyderer en forbindelse med den generelle formel c) deoxidizes a compound of the general formula
hvor R^har foran angitte betydning, where R^ has the above meaning,
eller at man or that one
d) dehydratiserer en forbindelse med den generelle formel d) dehydrates a compound of the general formula
hvor R-^ har foran angitte betydning, where R-^ has the above meaning,
eller at man or that one
e) oksyderer henholdsvis dehydrogenerer en forbindelse med den generelle formel e) oxidizes or dehydrogenates a compound with the general formula
hvor har foran angitte betydning, where has the meaning set out above,
ved 4,5-bindingen, at the 4,5 bond,
eller at man or that one
f) forsåper og dekarboksylerer en forbindelse med den generelle formel f) saponifies and decarboxylates a compound of the general formula
hvor R^har foran angitte betydning, og where R^ has the previously stated meaning, and
R2betyr lavere alkyl, R2 means lower alkyl,
eller at man or that one
g) overforer en forbindelse med den generelle formel g) transfers a compound with the general formula
hvor R1har foran angitte betydning, og where R1 has the previously stated meaning, and
R.j betyr acyl, < R.j means acyl, <
med en base til den tilsvarende 4,5-dehydroforbindelse, eller at man with a base to the corresponding 4,5-dehydro compound, or that one
h) overforer en forbindelse med den generelle formel h) transfers a compound with the general formula
hvor R-^ har foran angitte betydning, og where R-^ has the above meaning, and
R 4 betyr en mesyl- eller tosylgruppe, R 4 means a mesyl or tosyl group,
.med en sterk base til den tilsvarende 4,5-dehydroforbindelse, eller at man .with a strong base to the corresponding 4,5-dehydro compound, or that one
i) omleier en forbindelse med den generelle formel i) rearranges a compound with the general formula
hvor R, har foran angitte betydning, where R, has the above meaning,
til den tilsvarende 4,5-dehydroforbindelse to the corresponding 4,5-dehydro compound
og at man and that man
hvis onsket overforer en oppnådd forbindelse til et salt. if desired, converts an obtained compound into a salt.
Omsetningen av en forbindelse med formel II med en forbindelse med formel III kan gjennomfores i et inert organisk opplbs-ningsmiddel eller blandinger derav, som hydrokarboner, f.eks. benzen, toluen og lignende, dimetylformamid, etere som dioksan, tetrahydrofuran, alkoholer som tertiært butanol og lignende. Egnede temperaturer er f.eks. mellom -50°C og 120°C. I stedet for X i betydningen av halogen kan en eller annen ekvivalent uttredende gruppe som en mesyloksy-, tosyloksygruppe eller lignende anvendes. Det er hensiktsmessig å omdanne en forbindelse med formel II for omsetningen med en forbindelse med formel III forst i et 1-alkalimetall-derivat. Dette 1-alkali-metaltderivat kan f.eks. fremstilles ved hjelp av et lavere alkalialkoholat som natriummetylat, et alkalimetallhydrid som natriumhydrid, et alkalimetallamid som natr.iumamid og lignende midler. Omsetningen av en forbindelse med formel II med en . forbindelse med formel III kan dog også finne sted i nærvær av en base som alkalihydroksyder, f.eks. natriumhydroksyd eller trietylamin. The reaction of a compound of formula II with a compound of formula III can be carried out in an inert organic solvent or mixtures thereof, such as hydrocarbons, e.g. benzene, toluene and the like, dimethylformamide, ethers such as dioxane, tetrahydrofuran, alcohols such as tertiary butanol and the like. Suitable temperatures are e.g. between -50°C and 120°C. Instead of X in the sense of halogen, some equivalent leaving group such as a mesyloxy, tosyloxy group or the like can be used. It is expedient to convert a compound of formula II for the reaction with a compound of formula III first into a 1-alkali metal derivative. This 1-alkali metal derivative can e.g. is prepared using a lower alkali alcoholate such as sodium methylate, an alkali metal hydride such as sodium hydride, an alkali metal amide such as sodium amide and similar agents. The reaction of a compound of formula II with a . compound of formula III can, however, also take place in the presence of a base such as alkali hydroxides, e.g. sodium hydroxide or triethylamine.
Cykliseringen av en forbindelse med formel IV til en forbindelse med formel I kan finne sted i alkalisk, noytralt eller surt miljo og i et vilkårlig inert organisk opplosningsmiddel som hydrokarboner, klorerte hydrokarboner, etere, iseddik, alkoholer, dimetylformamid og lignende. Temperatur og trykk er ikke kritiske faktorer, dog er det hensiktsmessig å arbeide ved temperaturer i et område på ca. o - 150°C. The cyclization of a compound of formula IV to a compound of formula I can take place in an alkaline, neutral or acidic environment and in any inert organic solvent such as hydrocarbons, chlorinated hydrocarbons, ethers, glacial acetic acid, alcohols, dimethylformamide and the like. Temperature and pressure are not critical factors, however it is appropriate to work at temperatures in a range of approx. o - 150°C.
Desoksydasjonen av en forbindelse med formel V kan f.eks. oppnås ved hydrogenering i nærvær av Raney-nikkel, hensiktsmessig i et inert organisk opplosningsmiddel som hydrokarboner f.eks. benzen, toluen, alkoholer, etere som dioksan, eddikester og lignende, ved romtemperatur og normaltrykk eller for-hoyet trykk eller ved behandling med et fosfortrihalogenid, som fosfortriklorid, hensiktsmessig i et inert organisk opplosningsmiddel som hydrokarboner, f.eks. benzen og lignende, klorerte hydrokarboner og ved romtemperatur, selv om temperaturer over og under romtemperatur likeledes kan anvendes. Desoksydasjonen kan også finne sted med sink og iseddik i et organisk opplosningsmiddel som iseddik, klorerte hydrokarboner, etere, alkoholer og lignende og hensiktsmessig ved temperaturer mellom ca. -20 til 50°C. Anvendelsen av et bestemt desoksydasjonsmid-del retter seg vidtgående etter de i molekylet tilstedeværende funksjonelle grupper, for om mulig å unngå ugunstige sidere-aksjoner. Man désoksyderer derfor ved tilstedeværelsen av en nitrogruppe i molekylet- hensiktsmessig med et fosfortrihalogenid. The deoxidation of a compound of formula V can e.g. is obtained by hydrogenation in the presence of Raney nickel, suitably in an inert organic solvent such as hydrocarbons e.g. benzene, toluene, alcohols, ethers such as dioxane, acetates and the like, at room temperature and normal pressure or elevated pressure or by treatment with a phosphorus trihalide, such as phosphorus trichloride, suitably in an inert organic solvent such as hydrocarbons, e.g. benzene and the like, chlorinated hydrocarbons and at room temperature, although temperatures above and below room temperature can also be used. The deoxidation can also take place with zinc and glacial acetic acid in an organic solvent such as glacial acetic acid, chlorinated hydrocarbons, ethers, alcohols and the like and suitably at temperatures between approx. -20 to 50°C. The use of a specific deoxidation agent is largely based on the functional groups present in the molecule, in order to avoid unfavorable side effects if possible. Deoxidation is therefore carried out by the presence of a nitro group in the molecule - suitably with a phosphorus trihalide.
Dehydratiseringen av en forbindelse med formel VI gir tilsvarende forbindelser med en dobbeltbinding i 4,5-stilling og kan f.eks. finne sted med et karbodiimid som cykloheksylkarbodi-imid og lignende. Reaksjonen gjennomføres hensiktsmessig "i et inert organisk opplosningsmiddel som hydrokarboner f.eks. benzen, toluen$etere som dioksan og lignende. Egnede temperaturer er f.eks. mellom -20° og 100°C. Hyppig blir ved denne dehydratiseringsreaksjon dannelsen av et tilsvarende isomert 3,4-dehydro-derivat med formel XI iakttatt. Denne sistnevnte forbindelse kan dog lett isomeriseres til 4,5-dehydro-forbindelsen, f.eks. ved behandling med en base som alkalialkoksyder, f.eks. natriummetoksyd, trietylamin og lignende.Oksydasjonen av en forbindelse med formel VII gir tilsvarende forbindelser med en dobbeltbinding i 4,5-stilling og kan f. eks. finne sted med brom, klor, azodikarboksylsyreestere, f. eks. dietylesteren, halogensuccinimider, f.eks. bromsuccini-mid, halogenamider, f.eks. kloracetamid og lignende. Man arbeider hensiktsmessig i et inert organisk opplosningsmiddel som hydrokarboner, f.eks. benzen, toluen og lignende, halo-generte hydrokarboner som tetraklorkarbon, etere som dioksan, tetrahydrofuran og lignende, og fortrinnsvis ved en temperatur mellom ca. -30 og 100°C. The dehydration of a compound of formula VI gives corresponding compounds with a double bond in the 4,5-position and can e.g. take place with a carbodiimide such as cyclohexylcarbodiimide and the like. The reaction is conveniently carried out in an inert organic solvent such as hydrocarbons, e.g. benzene, toluene ethers such as dioxane and the like. Suitable temperatures are, for example, between -20° and 100°C. Frequently, this dehydration reaction results in the formation of a corresponding isomeric 3,4-dehydro derivative of formula XI observed.However, this latter compound can be easily isomerized to the 4,5-dehydro compound, for example by treatment with a base such as alkali alkoxides, for example sodium methoxide, triethylamine and the like The oxidation of a compound of formula VII gives corresponding compounds with a double bond in the 4,5-position and can e.g. take place with bromine, chlorine, azodicarboxylic acid esters, e.g. the diethyl ester, halosuccinimides, e.g. bromosuccinimide , halogen amides, e.g. chloroacetamide and the like. One conveniently works in an inert organic solvent such as hydrocarbons, e.g. benzene, toluene and the like, halogenated hydrocarbons such as tetrachlorocarbon, ethers such as dioxane, tetrahydrofuran and the like, and preferably at a temperature between approx. -30 and 100°C.
Forbindelser med formel VIII kan forsåpes til de tilsvarende 3-karboksylsure salter, f.eks. ved behandling med alkalihydroksyder som natriumhydroksyd, kaliumhydroksyd, jordalkali-hydroksyder som tertiære organiske baser som trietylamin. Dekarboksyleringen av disse 3-karboksylsure salter inntrer langsomt ved henstand, fortere ved oppvarmning og spontant ved ansyring. Compounds of formula VIII can be saponified into the corresponding 3-carboxylic acid salts, e.g. by treatment with alkali hydroxides such as sodium hydroxide, potassium hydroxide, alkaline earth hydroxides such as tertiary organic bases such as triethylamine. The decarboxylation of these 3-carboxylic acid salts occurs slowly on standing, faster on heating and spontaneously on acidification.
Syreavspaltningen fra en forbindelse med formel IX kan oppnås med en base som alkalihydrider,. som natriumhydrid, trietylamin, alkaliamider som natriumamid, alkalialkoksyder som natriummetoksyd og lignende i vannfritt medium. Man arbeider derved hensiktsmessig i et inert organisk opplosningsmiddel som etere, alkoholer f.eks. etanol, hydrokarboner, f.eks. benzen, toluen, dimetylformamid og lignende, og ved temperaturer mellom -4o'° til 120°C. Acylgruppen i betydningen kan være en lavere alkanoyl-, som acetyl-, aroyl-, som benzoyl, tosyl eller mésylgruppe. The acid elimination from a compound of formula IX can be achieved with a base such as alkali hydrides. such as sodium hydride, triethylamine, alkali amides such as sodium amide, alkali alkoxides such as sodium methoxide and the like in an anhydrous medium. One therefore works appropriately in an inert organic solvent such as ethers, alcohols, e.g. ethanol, hydrocarbons, e.g. benzene, toluene, dimethylformamide and the like, and at temperatures between -4o'° to 120°C. The acyl group in the meaning can be a lower alkanoyl group, such as acetyl, aroyl group, such as benzoyl, tosyl or mesyl group.
Ved syreavspaltningen kan dog også en forbindelse med formel XII opptre som mellomprodukt, som omdannes tilsvarende den senere angitte metode til sluttproduktet med formel I. During the acid cleavage, however, a compound of formula XII can also appear as an intermediate product, which is converted in accordance with the method specified later to the final product of formula I.
Avspaltningen av en mesyl- eller tosylgruppe fra en forbindelse med formel X kan oppnås med en sterk base som alkalihydrider, f.eks. natriumhydrid, alkalialkoksyder som natriummetoksyd, trietylamin og alkaliamider som natriumamid og lignen de i vannfritt medium. Man arbeider derved hensiktsmessig i The cleavage of a mesyl or tosyl group from a compound of formula X can be achieved with a strong base such as alkali hydrides, e.g. sodium hydride, alkali alkoxides such as sodium methoxide, triethylamine and alkali amides such as sodium amide and the like in anhydrous medium. One thereby works appropriately in
et inert organisk opplosningsmiddel som etere, alkoholer som etanol, hydrokarboner som benzen, toluen, dimetylformamid og lignende og ved temperaturer mellom 0°-120°C. Også ved denne reaksjon kan en isomer.forbindelse med formel XX opptre, som isomeriseres til sluttproduktet med formel I. an inert organic solvent such as ethers, alcohols such as ethanol, hydrocarbons such as benzene, toluene, dimethylformamide and the like and at temperatures between 0°-120°C. Also in this reaction, an isomer compound of formula XX can occur, which isomerizes to the final product of formula I.
Isomeriseringen av en forbindelse med formel XI kan oppnås ved behandling med en base som alkalialkoholater, f.eks. natriummetoksyd, alkalihydrider, som natriumhydrid, trietylamin og lignende. Reaksjonen skjer hensiktsmessig i et inert organisk opplosningsmiddel som hydrokarboner, etere, alkoholer og lignende og ved temperaturer mellom -40° og 120°C. The isomerization of a compound of formula XI can be achieved by treatment with a base such as alkali alcoholates, e.g. sodium methoxide, alkali hydrides, such as sodium hydride, triethylamine and the like. The reaction conveniently takes place in an inert organic solvent such as hydrocarbons, ethers, alcohols and the like and at temperatures between -40° and 120°C.
Med hensyn til de utgangsmaterialer som anvendes ved fremgangsmåten ifolge oppfinnelsen er folgende å si: Forbindelsene med formel II og III er kjente henholdsvis kan lett fremstilles i analogi til kjente fremgangsmåter.Forbindelsene med formel VIII kan oppnås i analogi til den foranstående definerte fremgangsmåtevariant b). 4-oksydene med formel V kan oppnås, såfremt de ikke er tilgjengelige i analogi til den foran under a) definerte fremgangsmåtevariant, ved oksydasjon av den tilsvarende 4-desoksy-forbindelse, f. eks. ved behandling med persyrer, som pereddiksyre i et organisk opplosningsmiddel som eddiksyre, klorerte hydrokarboner som metylenklorid og lignende. With regard to the starting materials used in the method according to the invention, the following is to be said: The compounds of formula II and III are known or can be easily prepared in analogy to known methods. The compounds of formula VIII can be obtained in analogy to the above-defined method variant b). The 4-oxides of formula V can be obtained, provided they are not available in analogy to the process variant defined above under a), by oxidation of the corresponding 4-deoxy compound, e.g. by treatment with peracids, such as peracetic acid in an organic solvent such as acetic acid, chlorinated hydrocarbons such as methylene chloride and the like.
Forbindelsene med formel IV kan på kjent måte fremstilles f. eks. ved reaksjon av et karbobenzoksyglycylamido-benzofenon med den generelle formel The compounds of formula IV can be prepared in a known manner, e.g. by reaction of a carbobenzoxyglycylamido-benzophenone with the general formula
eller et 2'-benzoyl-ftalimido-acetanilid med den generelle formel eller et tertiært-butoksy-glycylamidobenzofenon med den generelle formel or a 2'-benzoyl-phthalimido-acetanilide of the general formula or a tertiary-butoxy-glycylamidobenzophenone of the general formula
hvor i formlene XII, XIII og XIV har foran angitte where in the formulas XII, XIII and XIV have previously indicated
betydning, importance,
med en forbindelse med formel III og deretter avspaltning av karbobenzoksyresten, henholdsvis ftalimidresten eller den with a compound of formula III and then cleavage of the carbobenzoxyl residue, respectively the phthalimide residue or it
tertiære-butoksykarbonylresten.. tertiary-butoxycarbonyl residue..
Reaksjonen av en forbindelse med formelene XII, XIII eller XIV med en forbindelse med formel III kan finne sted på den for omsetningen av en forbindelse med formel II med en forbindelse med formel III angitte måte. The reaction of a compound of the formulas XII, XIII or XIV with a compound of the formula III can take place in the manner indicated for the reaction of a compound of the formula II with a compound of the formula III.
Avspaltningen av karbobenzoksyresten kan f.eks. gjennomfores ved katalytisk hydrogenering eller ved hjelp av en halogenhydrogensyre i nærvær av eddiksyre. The cleavage of the carbobenzoxyl residue can e.g. is carried out by catalytic hydrogenation or by means of a hydrohalic acid in the presence of acetic acid.
Den katalytiske hydrogenering kan finne sted i iseddik/HCl eller etanol/HCl og lignende. Avspaltningen ved hjelp av en halogenhydrogensyre i iseddik kan finne sted i nærvær av et inert organisk opplosningsmiddel som klorerte hydrokarboner, f.eks. metylenklorid og lignende og ved temperaturer mellom -20% og romtemperatur. Avspaltningen av ftalimidresten foretas hensiktsmessig ved hydrazinolyse i et inert organisk opplosningsmiddel som alkoholer, etere som dioksan, dimetylformamid og lignende og ved temperaturer mellom romtemperatur og 150°C. Avspaltningen av tert.-butoksykarbonylresten kan gjennomfores med trifluoreddiksyre og i et organisk opplosningsmiddel som hydrokarboner, klorerte hydrokarboner, iseddik eller trifluoreddiksyre og hensiktsmessig ved romtemperatur. The catalytic hydrogenation can take place in glacial acetic acid/HCl or ethanol/HCl and the like. The cleavage using a hydrohalic acid in glacial acetic acid can take place in the presence of an inert organic solvent such as chlorinated hydrocarbons, e.g. methylene chloride and the like and at temperatures between -20% and room temperature. The cleavage of the phthalimide residue is conveniently carried out by hydrazinolysis in an inert organic solvent such as alcohols, ethers such as dioxane, dimethylformamide and the like and at temperatures between room temperature and 150°C. The cleavage of the tert.-butoxycarbonyl residue can be carried out with trifluoroacetic acid and in an organic solvent such as hydrocarbons, chlorinated hydrocarbons, glacial acetic acid or trifluoroacetic acid and suitably at room temperature.
Således erholdte forbindelser med formel IV kan cykliseres uten isolering til benzodiazepin-derivater med formel I. Thus obtained compounds of formula IV can be cyclized without isolation to benzodiazepine derivatives of formula I.
Videre kan den forbindelse med formel IV, hvor R^ betyr klor, oppnås idet man omsetter forbindelsen med formel Furthermore, the compound of formula IV, where R 1 means chlorine, can be obtained by reacting the compound of formula
med en forbindelse med den generelle formel III, reduserer den erholdte forbindelse méd formel oksyderer den erholdte forbindelse med formel with a compound of the general formula III, reduces the obtained compound of the formula oxidizes the obtained compound of the formula
til det tilsvarende 2-karboksaldehyd, to the corresponding 2-carboxaldehyde,
oksimerer denne forbindelse og reduserer den erholdte forbindelse med formel oxidises this compound and reduces the obtained compound of formula
deretter til forbindelsen med formel og oksyderer denne forbindelse til den tilsvarende forbindelse med formel IV. Man kan dog også overfore forbindelsen med formel XVI på kjent måte til amidet med den generelle formel then to the compound of formula and oxidizes this compound to the corresponding compound of formula IV. However, the compound of formula XVI can also be transferred in a known manner to the amide of the general formula
og redusere denne forbindelse til den tilsvarende forbindelse med formel XIX. and reducing this compound to the corresponding compound of formula XIX.
Reduksjonen av forbindelsen med formel XVI og XVIII finner "hensiktsmessig sted med et reduksjonsmiddel som litiumaluminiumhydrid og i et inert organisk opplosningsmiddel som etere, f.eks. tetrahydrofuran og lignende. The reduction of the compound of formula XVI and XVIII conveniently takes place with a reducing agent such as lithium aluminum hydride and in an inert organic solvent such as ethers, eg tetrahydrofuran and the like.
Oksydasjonen av forbindelsen med formel XVII finner hensiktsmessig sted med et oksydasjonsmiddel som mangandioksyd og i et inert, organisk opplosningsmiddel som hydrokarboner, f.eks. benzen, toluen, klorerte hydrokarboner som metylenklorid og ved temperaturer mellom romtemperatur og reaksjonsblandingens tilbakelopstemperatur. Oksimeringen av det oppnådde 2-karboks aldehyd oppnås med hydroksylamin. Man arbeider hensiktsmessig også her i et opplosningsmiddel som vann, alkoholer, etere, trietylamin, pyridin og lignende og ved temperaturer mellom romtemperatur og reaksjonsblandingens tilbakelopstemperatur. The oxidation of the compound of formula XVII conveniently takes place with an oxidizing agent such as manganese dioxide and in an inert, organic solvent such as hydrocarbons, e.g. benzene, toluene, chlorinated hydrocarbons such as methylene chloride and at temperatures between room temperature and the reflux temperature of the reaction mixture. The oxidation of the 2-carboxaldehyde obtained is achieved with hydroxylamine. Here too, it is appropriate to work in a solvent such as water, alcohols, ethers, triethylamine, pyridine and the like and at temperatures between room temperature and the reflux temperature of the reaction mixture.
Oksydasjonen av forbindelsen med formel XIX kan finne sted med et oksydasjonsmiddel som kromtrioksyd i iseddik. Forbindelsen med formel XIX oksyderes og cykliseres hensiktsmessig uten isolering av den tilsvarende forbindelse med formel IV. The oxidation of the compound of formula XIX can take place with an oxidizing agent such as chromium trioxide in glacial acetic acid. The compound of formula XIX is oxidized and cyclized appropriately without isolation of the corresponding compound of formula IV.
Forbindelser med formel XVI kan oppnås ved reduksjon av et tilsvarende 4-oksyd med den generelle formel V i nærvær av platinoksyd. Compounds of formula XVI can be obtained by reduction of a corresponding 4-oxide of the general formula V in the presence of platinum oxide.
Man arbeider hensiktsmessig i et organisk opplosningsmiddel som iseddik, alkoholer og ved en temperatur mellom ca. 0° og 50°C, fortrinnsvis ved romtemperatur. One works appropriately in an organic solvent such as glacial acetic acid, alcohols and at a temperature between approx. 0° and 50°C, preferably at room temperature.
Forbindelser med formel VI kan også omsettes ved reaksjon av en forbindelse med den generelle formel Compounds of formula VI can also be reacted by reaction of a compound of the general formula
hvor R-^ har foran angitte betydning, med en forbindelse med den generelle formel where R-^ has the above meaning, with a compound of the general formula
hvor Z betyr Li, MgJ ellerMgBr. where Z means Li, MgJ or MgBr.
Man arbeider hensiktsmessig i et inert organisk opplosningsmiddel, som etere, hydrokarboner og ved temperaturer mellom -60°C og reaksjonsblandingens tilbakelopstemperatur. Forbindelser med formel XXI kan på sin side fremstilles ved innforing av substituenten i 1-stilling av én i 1-stilling usubstituert forbindelse i analogi til varianten a). It is appropriate to work in an inert organic solvent, such as ethers, hydrocarbons and at temperatures between -60°C and the reflux temperature of the reaction mixture. Compounds of formula XXI can, in turn, be prepared by introducing the substituent in the 1-position of one unsubstituted compound in the 1-position in analogy to variant a).
Forbindelser med formel VII kan fremstilles ved omsetning av en tilsvarende 1-usubstituert forbindelse med en forbindelse med formel III i analogi til varianten a). Compounds of formula VII can be prepared by reacting a corresponding 1-unsubstituted compound with a compound of formula III in analogy to variant a).
Forbindelser med formel IX kan fremstilles ved acylering av en tilsvarende 4-hydroksy-substituert forbindelse med formel VI. Egnede acyleringsmidler er f.eks. syreanhydrider som eddiksyrean-hydrid, syrehalogenider og lignende. Man arbeider "hensiktsmessig i nærvær av en base som syreakseptor som pyridin og lignende og i et organisk opplosningsmiddel som hydrokarboner, klorerte hydrokarboner , etere og lignende ved temperaturer mellom -50° og 100°C. Compounds of formula IX can be prepared by acylation of a corresponding 4-hydroxy-substituted compound of formula VI. Suitable acylating agents are e.g. acid anhydrides such as acetic anhydride, acid halides and the like. It is appropriate to work in the presence of a base as an acid acceptor such as pyridine and the like and in an organic solvent such as hydrocarbons, chlorinated hydrocarbons, ethers and the like at temperatures between -50° and 100°C.
Forbindelser med formel X kan fremstilles ved acylering av en tilsvarende 4,5-dihydro-forbindelse med formel VII eller ana-loger derav, som man oppnår i analogi til fremstillingen av forbindelser med formel VII, f.eks. med et tosyl- eller mesyl-halogenid. Man arbeider hensiktsmessig i et inert organisk opplosningsmiddel som hydrokarboner, f.eks. benzen, klorerte hydrokarboner og lignende og i nærvær av en syreakseptor som pyridin og lignende og ved temperaturer mellom 0 C og reak-sj onsblandingens tilbakelopstemperatur. Compounds of formula X can be prepared by acylation of a corresponding 4,5-dihydro compound of formula VII or analogues thereof, which is obtained in analogy to the preparation of compounds of formula VII, e.g. with a tosyl or mesyl halide. One works appropriately in an inert organic solvent such as hydrocarbons, e.g. benzene, chlorinated hydrocarbons and the like and in the presence of an acid acceptor such as pyridine and the like and at temperatures between 0 C and the reflux temperature of the reaction mixture.
Forbindelsene med formel XI kan fremstilles fra tilsvarende forbindelser med formel IX hhv. X på den heri beskrevne måte. Dessuten kan forbindelser med formel XI fremstilles ved innforing av en substituent i en 1-usubstituert forbindelse i analogi til metode a). Ved denne reaksjon kan dog også samtidig en isomerisering til en 4,5-dehydroforbindelse finne sted. The compounds of formula XI can be prepared from corresponding compounds of formula IX or X in the manner described herein. Furthermore, compounds of formula XI can be prepared by introducing a substituent into a 1-unsubstituted compound in analogy to method a). In this reaction, however, an isomerization to a 4,5-dehydro compound can also take place at the same time.
Det er herved å påpeke at de aktuelle utgangsmaterialer ikke . nodvendigvis må anvendes i isolert tilstand, men kan også omsettes videre uten isolering fra reaksjonsblåndingen i hvilken de ble fremstilt. It is hereby pointed out that the starting materials in question do not . must necessarily be used in an isolated state, but can also be reacted further without isolation from the reaction mixture in which they were prepared.
Forbindelser med den generelle formel I, som innehar basisk karakter, danner syreaddisjonssalter med uorganiske eller organiske syrer som klorhydrogensyre, fosforsyre, bromhydro- gensyre, sitronsyre, svovelsyre, eddiksyre, maursyre, raysyre, maleinsyre, p-toluénsulfonsyre og lignende.. Compounds of the general formula I, which have a basic character, form acid addition salts with inorganic or organic acids such as hydrochloric acid, phosphoric acid, hydrobromic acid, citric acid, sulfuric acid, acetic acid, formic acid, maleic acid, p-toluenesulfonic acid and the like.
Forbindelser med den generelle formel I såvel som deres farma-søytisk anvendbare salter kan anvendes som aritikonvulsiva,<;>muskelrelaksantier, sedativa og anxiolytika. Den antikonvulsive aktivitet demonstreres, når mus, som er'blitt administrert forbindelsene med formel I eller deres salter, underkastes pen-tametylentetrazolproven. F . eks ." viser 7-nitro-5-fenyl-l-metoksy-metyl-1,3-dihydro-2H-1,4-benzodiazepin-2-onet, som oppviser en LD^0på 600-1200 mg/kg (p.o.) ved provningen av antikonvulsiv aktivitet i pentetrazolproven i tilslutning til metoden avOrloff (Proe. Soc. Exptl. Biol. Med. 70254-257 1949) en APR 2,0 av 0,5 mg/kg (p.o.) [under APR 2,0 forstår man den dose i mg/kg av et antikonvulsivum som bevirker det dobbelte pentetra-zolforbruk overfor den ubehandlede kontrollgruppe]. I motset-ning dertil viser fenobarbital, et vanlig antikonvilsivum, en APR 2,0 på 30 mg/kg. Den muskelrelakserende aktivitet kan demonstreres i proven på roterstav. F.eks. viser det foran nevnte 7-nitro-5-fenyl-l-metoksymetyl-1,3-dihydro-2H-1,4-benzodiazepin- 2-on en HDj-Q på 2 mg/kg (p.o.). Compounds of the general formula I as well as their pharmaceutically usable salts can be used as anticonvulsants, muscle relaxants, sedatives and anxiolytics. The anticonvulsant activity is demonstrated when mice administered the compounds of formula I or their salts are subjected to the pentamethylenetetrazole test. F . ex ." shows 7-nitro-5-phenyl-1-methoxy-methyl-1,3-dihydro-2H-1,4-benzodiazepine-2-one, which exhibits an LD^0 of 600-1200 mg/kg (p.o. ) in the testing of anticonvulsant activity in the pentetrazole sample in accordance with the method of Orloff (Proe. Soc. Exptl. Biol. Med. 70254-257 1949) an APR 2.0 of 0.5 mg/kg (p.o.) [under APR 2.0 is understood as the dose in mg/kg of an anticonvulsant that causes twice the pentetrazole consumption compared to the untreated control group]. In contrast, phenobarbital, a common anticonvulsant, shows an APR 2.0 at 30 mg/kg. The muscle relaxant activity can be demonstrated in the rotator rod test. For example, the aforementioned 7-nitro-5-phenyl-1-methoxymethyl-1,3-dihydro-2H-1,4-benzodiazepine-2-one shows an HDj-Q of 2 mg/kg (p.o.).
Forbindelser med formel I såvel som deres farmasoytisk anvendbare salter kan derfor finne anvendelse som legemidler, f.eks. Compounds of formula I as well as their pharmaceutically usable salts can therefore find use as pharmaceuticals, e.g.
i form av farmasøytiske preparater, hvilke inneholder dem eller deres salter i blanding med et for den enterale eller parente-rale administrasjon egnet framasoytisk organisk eller uorganisk bæremateriale, som f.eks. vann, gelatin, melkesukker, stivelse, magnesiumstearat, talkum, vegetabilske oljer, gummi, polyalky-lenglykoler, vaselin osv.. De farmasoytiske preparater kan foreligge i fast form, f.eks. som tabletter, dragéer, supposi-torier, kapsler, eller i flytende form, f.eks. som oppløsnin-ger, suspensjoner eller emulsjoner. Eventuelt er de sterili-sert og hhv. eller inneholder hjelpestoffer, som konserve-rings-, stabiliserings-, fuktnings- eller emulgeringsmidler, - salter til forandring av det osmotiske trykk eller puffer. De kan også inneholde enda andre terapeutisk verdifulle stoffer. Doseringen finner sted etter individuelle krav, dog er en in the form of pharmaceutical preparations, which contain them or their salts in admixture with a framazoitic organic or inorganic carrier material suitable for enteral or parenteral administration, such as e.g. water, gelatin, milk sugar, starch, magnesium stearate, talc, vegetable oils, rubber, polyalkylene glycols, vaseline, etc. The pharmaceutical preparations can be in solid form, e.g. as tablets, dragees, suppositories, capsules, or in liquid form, e.g. as solutions, suspensions or emulsions. If necessary, they are sterilized and resp. or contains auxiliaries, such as preservatives, stabilisers, wetting agents or emulsifiers, - salts for changing the osmotic pressure or buffers. They may also contain other therapeutically valuable substances. The dosage takes place according to individual requirements, although one
dosering på 0,1 mg/kg - 10 mg/kg/dag foretrukket. dosage of 0.1 mg/kg - 10 mg/kg/day preferred.
De folgende eksempler illustrerer ..oppfinnelsen: The following examples illustrate the invention:
EKSEMPEL 1 EXAMPLE 1
8,1 g (0,15 mol) natriummetylat tilsettes under roring til en på -15° avkjolt opplosning av 28 g (0,1 mol) 1,3-dihydro-7-nitro-5-fenyl-2H-1,4-benzodiazepinT2-on i 150 ml dimetylformamid. Efter at det var rort i 10 minutter ved -15° til -10°, ble det avkjolt til -50° og ved -50° til -40° tildryppes 12 8.1 g (0.15 mol) of sodium methylate are added with stirring to a -15° cooled solution of 28 g (0.1 mol) 1,3-dihydro-7-nitro-5-phenyl-2H-1,4 -benzodiazepineT2-one in 150 ml of dimethylformamide. After it had been stirred for 10 minutes at -15° to -10°, it was cooled to -50° and at -50° to -40°, 12
ml (0,16 mol) klormetyl-metyleter. Etter tilsetningen lar man temperaturen stige innen 15 minutter til -20°. Den morkebrune reaksjonsblåndingen helles på 1 1 vann og det utfelte materiale skilles fra. Dette opptas i metylenklorid, metylenkloridopplosningen vaskes med vann, torkes over natriumsulfat og inndampes. Resten krystalliserer fra eter og omkrystalliserer fra benzen-alkohol, idet man oppnår 14,5 g 1,3-dihydro-1-(metok-symetyl)-7-nitro-5-fenyl-2H-1,4-benzodiazepin-2-on med smp. ml (0.16 mol) of chloromethyl methyl ether. After the addition, the temperature is allowed to rise within 15 minutes to -20°. The dark brown reaction mixture is poured onto 1 1 water and the precipitated material is separated. This is taken up in methylene chloride, the methylene chloride solution is washed with water, dried over sodium sulphate and evaporated. The residue crystallizes from ether and recrystallizes from benzene-alcohol, obtaining 14.5 g of 1,3-dihydro-1-(methoxymethyl)-7-nitro-5-phenyl-2H-1,4-benzodiazepine-2- on with m.p.
139 - 141°. 139 - 141°.
EKSEMPEL 2 EXAMPLE 2
En opplosning av 13,5 g 7-klor-l,3-dihydro-5-fenyl-2H-1,4-benzodiazepin-2-on i 150 ml dimetylformamid avkjoles på -10° A solution of 13.5 g of 7-chloro-1,3-dihydro-5-phenyl-2H-1,4-benzodiazepine-2-one in 150 ml of dimethylformamide is cooled to -10°
og tilsettes 4 g natriummetylat. Etter roring i lopet av 15 minutter ved -10° til 0° under nitrogenatmosfære, avkjoles det til -40° og tildryppes 6 ml klormetylmetyleter. Etter tilsetningen lar man temperaturen stige innen 30 minutter til 0°. Reaksjonsblandingen helles på 1 1 vann og den utskilte harpiks skilles fra. Denne opptas i metylenklorid, opplosningen vaskes med vann, torkes over natriumsulfat og inndampes. Resten kromatograferes på 300 g silisiumgel med opplosningsmiddel systemet metylenklorid:etylacetat 9:1. Det ikke krystal-lint erholdte, kromatografisk rene 7-klor-l,3-dihydro-l-(met-oksymetyl) -5-f enyl- 2H-1 , 4-benzodiazepin- 2-on viser de folgende spektroskopiske data. and 4 g of sodium methylate are added. After stirring for 15 minutes at -10° to 0° under a nitrogen atmosphere, it is cooled to -40° and 6 ml of chloromethyl methyl ether are added dropwise. After the addition, the temperature is allowed to rise to 0° within 30 minutes. The reaction mixture is poured onto 1 1 of water and the separated resin is separated. This is taken up in methylene chloride, the solution is washed with water, dried over sodium sulphate and evaporated. The residue is chromatographed on 300 g of silicon gel with the solvent system methylene chloride:ethyl acetate 9:1. The non-crystalline, chromatographically pure 7-chloro-1,3-dihydro-1-(methoxymethyl)-5-phenyl-2H-1,4-benzodiazepine-2-one shows the following spectroscopic data.
Massespektrum:M *^314 Mass spectrum: M *^314
Hovedfragmenter ved 286 ' (M®-CO) 269 Major fragments at 286 ' (M®-CO) 269
6) e 6) e
(Mw<->CH2OCH3) (Mw<->CH2OCH3)
NMR-spektrum: 7,8 - 7,1 ppm (multiplet), 8 aromatiske protoner $ NMR spectrum: 7.8 - 7.1 ppm (multiplet), 8 aromatic protons $
[CDCL3J5,40 ppm (doublet) og 4,88 ppm (doublet), [CDCL3J5.40 ppm (doubled) and 4.88 ppm (doubled),
AB-system med J=lOeps, N-CH^,-0; AB system with J=lOeps, N-CH^,-0;
4,84 ppm (doublet) og 3,83 ppm (doublet), AB-system med J=10,5 eps, C^-protoner; 4.84 ppm (doublet) and 3.83 ppm (doublet), AB system with J=10.5 eps, C^ protons;
3,37 ppm (singlet), OCH^. 3.37 ppm (singlet), OCH^.
E KSEMPEL 3 EXAMPLE 3
A) Fremstilling av utgangsprodukter A) Production of output products
En opplosning av 28,7 g 7-klor-l,3-dihydro-5-fenyl-2H-1,4-benzodiazepin-2-on-4-oksyd i 200ml dimetylformamid tilsettes ved -20° med 8,1 g natriummetoksyd og rores i 5 minutter. A solution of 28.7 g of 7-chloro-1,3-dihydro-5-phenyl-2H-1,4-benzodiazepine-2-one-4-oxide in 200 ml of dimethylformamide is added at -20° with 8.1 g of sodium methoxide and stirred for 5 minutes.
Ved -20° tildryppes under roring 12 ml klordimetyleter. Etter tilsetningen lar man uten avkjoling opplosningen rore i ytterligere 30 minutter. Reaksjonsblåndingen helles på 1 1 vann og opparbeides som vanlig. Krystallisasjon av råproduktet ved podning av metanol-eter gir 11,5 g 7-klor-l,3-dihydro-l-(metoksymetyl)-5-fenyl-2H-1,4-benzodiazepin-2-on-4-oksyd, At -20°, 12 ml of chlorodimethyl ether are added dropwise while stirring. After the addition, the solution is allowed to stir for a further 30 minutes without cooling. The reaction mixture is poured onto 1 1 water and worked up as usual. Crystallization of the crude product by grafting methanol-ether yields 11.5 g of 7-chloro-1,3-dihydro-1-(methoxymethyl)-5-phenyl-2H-1,4-benzodiazepine-2-one-4-oxide,
som etter omkrystallisasjon fra alkohol smelter ved 161-166°.Podekrystaller oppnås ved kromatografi på silisiumgel med opplosningsmiddelsystemet metylenklorid:etylacetat 1:1. which after recrystallization from alcohol melts at 161-166°. Seed crystals are obtained by chromatography on silicon gel with the solvent system methylene chloride: ethyl acetate 1:1.
På analog måte kan også fremstille 1,3-dihydro-l-(metoksymetyl)-7-nitro-5-fenyl-2H-1,4-benzodiazepin-2-on-4-oksyd, som etter omkrystallisasjon fra métylenklorid/etylacetat oppviser et smeltepunkt på 212-215°C. B) Videre forarbeidelse av de ovenfor nevnte utgangsprodukter. In an analogous manner, 1,3-dihydro-1-(methoxymethyl)-7-nitro-5-phenyl-2H-1,4-benzodiazepine-2-one-4-oxide can also be prepared, which after recrystallization from methylene chloride/ethyl acetate exhibits a melting point of 212-215°C. B) Further processing of the above-mentioned output products.
0,8 ml fosfortriklorid tilsettes til en opplosning av 1 g 1,3-dihydro-1-(metoksymetyl)-7-nitro-5-fenyl-2H-1,4-benzodiazepin-2-on-4-bksyd i 15 ml metylenklorid. Etter 1 times henstand ved 0.8 ml of phosphorus trichloride is added to a solution of 1 g of 1,3-dihydro-1-(methoxymethyl)-7-nitro-5-phenyl-2H-1,4-benzodiazepine-2-one-4-boxyd in 15 ml methylene chloride. After 1 hour's delay at
romtemperatur vaskes oppløsningen med 10%'s sodaoppløsning, torkes over natriumsulf at bg inndampes.' Krystallisasjon av resten fra alkohol gir 0,6 g 1,3-dihydro-l-(metoksy-metyl )-7-nitro-5-fenyl-2H-1,4-benzodiazepin-2-on med smp. 139 - 141°. room temperature, the solution is washed with a 10% soda solution, dried over sodium sulphate until the solution is evaporated.' Crystallization of the residue from alcohol gives 0.6 g of 1,3-dihydro-1-(methoxymethyl)-7-nitro-5-phenyl-2H-1,4-benzodiazepine-2-one with m.p. 139 - 141°.
EKSEMPEL 4 EXAMPLE 4
Til en på -lO° avkjolt opplosning av 0,95 g 7-klor-l-(metoksy-metyl) -5- f enyl-1 ,3,4,5-tetrahydro-2H-l,4-benzodiazepin-2-on i 15 ml kloroform tilsettes 12 ml av en 0,5 molar opplosning av brom i kloroform. Efter at det er rort i 30minutter ved 0-5°, tilsettes 25 ml 2-n natronlut<p>g det rores i 30 minutter. Kloroformfasen skilles fra, vaskes med fortynnet natronlut og vann, torkes og inndampes. Resten kromatograferes på 30 g silisiumgel med 10% etylacetat i metylenklorid. Man oppnår 0,63 g 7-klor-l,3-dihydro-l-(metoksymetyl)-5-fenyl-2H-1,4-benzodiazepin-2-on. To a -10° cooled solution of 0.95 g of 7-chloro-1-(methoxy-methyl)-5-phenyl-1,3,4,5-tetrahydro-2H-1,4-benzodiazepine-2- on in 15 ml of chloroform, 12 ml of a 0.5 molar solution of bromine in chloroform is added. After it has been stirred for 30 minutes at 0-5°, 25 ml of 2-n caustic soda is added and it is stirred for 30 minutes. The chloroform phase is separated, washed with dilute caustic soda and water, dried and evaporated. The residue is chromatographed on 30 g of silicon gel with 10% ethyl acetate in methylene chloride. 0.63 g of 7-chloro-1,3-dihydro-1-(methoxymethyl)-5-phenyl-2H-1,4-benzodiazepine-2-one is obtained.
Utgangsmaterialet'kan fremstilles som folger: The starting material' can be produced as follows:
4,5 g sinkstov innfores porsjonsvis i en opplosning av 3,3 g 7-klor-l, 3-dihydro-l-.(metoksymetyl) -5-f enyl- 2H-1, 4-benzodiazepin-2-on-4-oksyd i 40 ml metylenklorid og 10 ml iseddik. Efter avsluttet tilsetning rores i 30 minutter, filtreres fra og filtratet vaskes med vandig ammoniakk og med vann, metylenkloridopplosningen torkes og inndampes. Krystallisasjon av resten fra alkohol gir 2,4 g 7-klor-l,3,4,5-tetrahydro-1-(metoksymetyl)-5-fenyl-2H-1,4-benzodiazepin-2-on med smp. 135 - 136°. Smeltepunktet stiger ved omkrystallisasjon fra alkohol til 136 - 138°. 4.5 g of zinc dust are introduced portionwise into a solution of 3.3 g of 7-chloro-1,3-dihydro-1-(methoxymethyl)-5-phenyl-2H-1,4-benzodiazepine-2-one-4 -oxide in 40 ml methylene chloride and 10 ml glacial acetic acid. After the addition is finished, the mixture is stirred for 30 minutes, filtered off and the filtrate is washed with aqueous ammonia and with water, the methylene chloride solution is dried and evaporated. Crystallization of the residue from alcohol gives 2.4 g of 7-chloro-1,3,4,5-tetrahydro-1-(methoxymethyl)-5-phenyl-2H-1,4-benzodiazepine-2-one with m.p. 135 - 136°. The melting point rises on recrystallization from alcohol to 136 - 138°.
EKSEMPEL 5 EXAMPLE 5
0,67 g 7-klor-4-hydroksy-l-(metoksymetyl)-5-fenyl-1,3,4,5-tetrahydro-2H-1,4-benzodiazepin-2-on og0,63 g dicykloheksyl-karbodiimid kokes i 20 ml toluen i 16 timer under tilbakelop. Dicykloheksylurinstoffet suges opp og filtratet ekstraheres 0.67 g 7-chloro-4-hydroxy-1-(methoxymethyl)-5-phenyl-1,3,4,5-tetrahydro-2H-1,4-benzodiazepine-2-one and 0.63 g dicyclohexylcarbodiimide boiled in 20 ml of toluene for 16 hours under reflux. The dicyclohexylurea is sucked up and the filtrate extracted
tre ganger med 2-n saltsyre. Esktraktene innstilles alkalisk med ammoniakk og ekstraheres med metylenklorid. De torkede uttrekk inndampes og resten kromatograferes på 15 g silisiumgel three times with 2-n hydrochloric acid. The extracts are made alkaline with ammonia and extracted with methylene chloride. The dried extracts are evaporated and the residue is chromatographed on 15 g of silicon gel
med 10%eddikester i metylenklorid, hvorved 0,25 g rent 7-klor-1.3- dihydro-l-(metoksymetyl)-5-fenyl-2H-1,4-benzodiazepin-2- with 10% acetic ester in methylene chloride, whereby 0.25 g of pure 7-chloro-1,3-dihydro-1-(methoxymethyl)-5-phenyl-2H-1,4-benzodiazepine-2-
on med de i eksempel 2 angitte spektroskopiske egenskaper oppnås. on with the spectroscopic properties indicated in example 2 are obtained.
Utgangsmaterialet kan fremstilles som folger: The starting material can be produced as follows:
3.3 g 7-klor-l,3-dihydro-l-(metoksymetyl)-5-fenyl-2H-l,4-benzodiazepin-2-on-4-oksyd hydreres i nærvær av 0,3 g platinaoksyd ved atmosfæretrykk og værelsetemperatur. Efter opptagelse av 400 ml hydrogen skilles katalysatoren fra og det inndampes. Resten opptas i benzen og opplosningen ekstraheres med 2-n saltsyre. Den derpå med vann vaskede benzen-fase torkes og inndampes. Krystallisasjon av resten fra metanol gir 1,1 g 7-klor-4-hydroksy-l-(metoksymetyl)-5-fenyl-1,3,4,5-tetrahydro-2H-1,4-benzodiazepin-2-on med smp. 168 - 17 2°. Det rene produkt smelter efter omkrystallisasjon fra metanol 3.3 g of 7-chloro-1,3-dihydro-1-(methoxymethyl)-5-phenyl-2H-1,4-benzodiazepine-2-one-4-oxide is hydrated in the presence of 0.3 g of platinum oxide at atmospheric pressure and room temperature . After absorption of 400 ml of hydrogen, the catalyst is separated and evaporated. The residue is taken up in benzene and the solution is extracted with 2-N hydrochloric acid. The benzene phase, which is then washed with water, is dried and evaporated. Crystallization of the residue from methanol gives 1.1 g of 7-chloro-4-hydroxy-1-(methoxymethyl)-5-phenyl-1,3,4,5-tetrahydro-2H-1,4-benzodiazepine-2-one with m.p. 168 - 17 2°. The pure product melts after recrystallization from methanol
ved 173 - 175°. at 173 - 175°.
Saltsyreuttrekkene innstilles alkalisk med sodaopplosning og ekstraheres med metylenklorid. De torkede uttrekk inndampes og resten likeledes krystalliseres fra metanol. Man oppnår 1.4 g 7-klor-l-(metoksymetyl)-5-fenyl-1,3,4,5-tetrahydro-2H-1.4- benzodiazepin-2-on. The hydrochloric acid extracts are made alkaline with soda solution and extracted with methylene chloride. The dried extracts are evaporated and the residue is likewise crystallized from methanol. 1.4 g of 7-chloro-1-(methoxymethyl)-5-phenyl-1,3,4,5-tetrahydro-2H-1,4-benzodiazepine-2-one is obtained.
EKSEMPEL 6 EXAMPLE 6
En vandig opplosning av 0,37 g 2-amino-2•-benzoyl-4'-klor-N-(metoksymetyl)-acetanilid-hydroklorid innstilles alkalisk med fortynnet ammoniakk og den utskilte base ekstraheres med metylenklorid. De over natriumsulfat torkede uttrekk inndampes og resten oppkokes i 10 ml metanol. Efter fornyet inndampning oppnår man0,28 g tynnskiktskromatografisk ensartet 7-klor-l,3-dihydro-l-(metoksymetyl)-5-fenyl-2H-1,4-benzodiazepin- 2-on med de i eksempel 2 angitte spektroskopiske data. An aqueous solution of 0.37 g of 2-amino-2•-benzoyl-4'-chloro-N-(methoxymethyl)-acetanilide hydrochloride is made alkaline with dilute ammonia and the precipitated base is extracted with methylene chloride. The extracts dried over sodium sulphate are evaporated and the residue boiled in 10 ml of methanol. After renewed evaporation, one obtains 0.28 g of thin-layer chromatographically uniform 7-chloro-1,3-dihydro-1-(methoxymethyl)-5-phenyl-2H-1,4-benzodiazepine-2-one with the spectroscopic data given in example 2.
Utgangsmaterialet kan fremstilles som folger: The starting material can be produced as follows:
Til en på -10° avkjolt opplosning av 12,7 g 2'-benzoyl-2- To a -10° cooled solution of 12.7 g of 2'-benzoyl-2-
(benzyloksykarbonyl) amino-4.'-klor-acetanilid i ;150 ml (benzyloxycarbonyl)amino-4.'-chloroacetanilide in ;150 ml
, dimetylf ormamid tilsettes 2 ,.2 g natriumhydridsuspénsjon (50%' ig i mineralolje). Efter 15 minutters roring tildryppes ved -10° 3,6 g klordimetyleter."Efter tilsetningen rores videre uten avkjoling i 1 time. Reaksjonsblandingen helles på 1 liter vann og ekstraheres flere ganger med eter.:- De torkede eteruttrekk inndampes og den erholdte rest kromatograferes på 300 g silisiumgel med 10% eddikester i metylenklorid. Det erholdte tynnskiktskromatografisk ensartede 2'-benzoyl-2-(benzyloksykarbonyl)amino-4'-klor-N-metoksymetyl-acetanilid viser de folgende spektroskopiske egenskaper: , dimethylformamide is added to 2.2 g of sodium hydride suspension (50% strength in mineral oil). After 15 minutes of stirring, 3.6 g of chlorodimethyl ether are added dropwise at -10°. After the addition, stirring continues without cooling for 1 hour. The reaction mixture is poured into 1 liter of water and extracted several times with ether.:- The dried ether extracts are evaporated and the residue obtained is chromatographed on 300 g of silicon gel with 10% acetate in methylene chloride. The obtained thin-layer chromatographically uniform 2'-benzoyl-2-(benzyloxycarbonyl)amino-4'-chloro-N-methoxymethyl-acetanilide shows the following spectroscopic properties:
Massespektrum: M ® : 466, Mass spectrum: M ® : 466,
Hovedfragmenter: ved § 274, 244, 214, 180, 108, 105, 91, 77 NMR-spektrum i CDC13: 3,05 ppm, singlet, OCH^Main fragments: at § 274, 244, 214, 180, 108, 105, 91, 77 NMR spectrum in CDCl3: 3.05 ppm, singlet, OCH^
3,9 ppm, doubletJ=5 Hz, -CH2~NH 3.9 ppm, doubletJ=5 Hz, -CH2~NH
4,87 ppm, sentrum av et AB-system, 4.87 ppm, the center of an AB system,
N-CH2-0 N-CH2-0
5,08 ppm, singlet, -OCH2-C6H55.08 ppm, singlet, -OCH 2 -C 6 H 5
5,72 ppm, "breites triplet", J=5 Hz, -NH-7,1-8 ppm, aromatiske protoner 5.72 ppm, "breites triplet", J=5 Hz, -NH-7.1-8 ppm, aromatic protons
2,4 g 21-benzoyl-2- (benzyloksykarbonyl)amino-41-klor-N- (metoksy-metyl )-acetanilid hydreres i nærvær av 500 mg palladiumkull 2.4 g of 21-benzoyl-2-(benzyloxycarbonyl)amino-41-chloro-N-(methoxymethyl)-acetanilide is hydrated in the presence of 500 mg of palladium charcoal
(5%'ig) og 360 mg hydrogenklorid. Efter 30 minutter kommer hydrogenopptagelsen til stillstand. Katalysatoren filtreres fra og filtratet inndampes ved 30° i vakuum. Resten krystalliseres ved rivning med metylenklorid-etylacetat-eter. Efter gjenopplosning fra metylenklorid-eddikester oppnår man 2-amino-2 '-benz.oyl-4 '-klor-N-(metoksymetyl)-acetanilid-hydroklorid med smp. 117 - 125°. (5%) and 360 mg hydrogen chloride. After 30 minutes, the hydrogen absorption comes to a standstill. The catalyst is filtered off and the filtrate is evaporated at 30° in vacuum. The residue is crystallized by trituration with methylene chloride-ethyl acetate-ether. After re-dissolving from methylene chloride-acetic ester, 2-amino-2'-benzoyl-4'-chloro-N-(methoxymethyl)-acetanilide hydrochloride is obtained with m.p. 117 - 125°.
EKSEMPEL 7 EXAMPLE 7
1 g 2'-benzoyl-4<1->klor-N-(metoksymetyl)-2-ftalimido-acetanilid kokes i 30 ml alkohol i nærvær av 0,4 ml hydrazin-hydrat i 1 1/2 timer under tilbakelop. Efter avkjSlingen oppsuges det fra utkrystallisert ftalazin, filtratet inndampes, resten opptas i eter,.den erholdte opplosning filtreres flere ganger og den efter inndampningen gjenblivende rest kromato-graf eres på 15 g silisiumgel med 10% eddikester i metylenklorid. Man oppnår således 0,6 g rent 7-klor-l,3-dihydro-1-(metoksymetyl)-5-fenyl-2H-1,4-benzodiazepin-2-on. 1 g of 2'-benzoyl-4<1->chloro-N-(methoxymethyl)-2-phthalimido-acetanilide is boiled in 30 ml of alcohol in the presence of 0.4 ml of hydrazine hydrate for 1 1/2 hours under reflux. After cooling, it is sucked up from crystallized phthalazine, the filtrate is evaporated, the residue is taken up in ether, the solution obtained is filtered several times and the residue remaining after evaporation is chromatographed on 15 g of silicon gel with 10% acetate in methylene chloride. 0.6 g of pure 7-chloro-1,3-dihydro-1-(methoxymethyl)-5-phenyl-2H-1,4-benzodiazepine-2-one is thus obtained.
Utgangsmaterialet kan fremstilles som folger: The starting material can be produced as follows:
Til en pa o -10 o avkjolt opplosning av 8,4 g 2 1-benzoyl-4'-klor-2-ftalimido-acetanilid (smp. 218 - 220°) i 150 ml dimetylformamid tilsettes 1,5 g natriumhydridsuspénsjon (50%'ig i mineralolje). Efter at det er rdrt i 15 minutter, tildryppes ved -lo° 1.5 g of sodium hydride suspension (50% 'ig in mineral oil). After it has been stirred for 15 minutes, it is added dropwise at -lo°
2,3 ml klordimetyleter. Efter tilsetningen lar man temperaturen stige innen 30 minutter til værelsetemperatur og heller reaksjonsblåndingen på 500 ml vann og 10 ml 2-n eddiksyre. 2.3 ml of chlorodimethyl ether. After the addition, the temperature is allowed to rise to room temperature within 30 minutes and the reaction mixture is poured into 500 ml of water and 10 ml of 2-n acetic acid.
Det utfelte material skilles fra, opptas i metylenklorid, oppløsningen torkes og inndampes. Resten kromatograferes på The precipitated material is separated, taken up in methylene chloride, the solution is dried and evaporated. The residue is chromatographed on
200 g silisiumgel med 10% eddikester i metylenklorid. De homogene fraksjoner krystalliserer ved rivning med eter. 200 g silicon gel with 10% acetate in methylene chloride. The homogeneous fractions crystallize by trituration with ether.
Man oppnår 5,8 g rent 2'-benzoyl-4<1->klor-N-(metoksymetyl)-2-ftalimidoacetanilid med smp. 150 - 152°. 5.8 g of pure 2'-benzoyl-4<1->chloro-N-(methoxymethyl)-2-phthalimidoacetanilide with m.p. 150 - 152°.
EKSEMPEL 8 EXAMPLE 8
En opplosning av 1,5 g kromtrioksyd i 1,5 ml vann fortynnes A solution of 1.5 g of chromium trioxide in 1.5 ml of water is diluted
med 15 ml iseddik og tilsettes ved 20° porsjonsvis med 1,8 g 2-aminometyl-5-klor-l-(metoksymetyl)-3-fenylindol-hydroklorid. Efter tilsetningen rores i 1 1/2 timer ved værelsetemperatur. Under tilsetning av is innstilles alkalisk med konsentrert ammoniakk og basene ekstraheres med metylenklorid. De med natriumsulfat torkede uttrekk inndampes og resten kromatograferes på 40 g silisiumgel med 10% eddikester i metylenklorid, hvorved 0,25 g rent 7-klor-l,3-dihydro-l-(metoksymetyl)-5-fenyl-2H-l,4-benzodiazepin-2-on oppnås. with 15 ml of glacial acetic acid and add 1.8 g of 2-aminomethyl-5-chloro-1-(methoxymethyl)-3-phenylindole hydrochloride in portions at 20°. After the addition, stir for 1 1/2 hours at room temperature. With the addition of ice, the mixture is made alkaline with concentrated ammonia and the bases are extracted with methylene chloride. The sodium sulfate-dried extracts are evaporated and the residue is chromatographed on 40 g of silicon gel with 10% acetate in methylene chloride, whereby 0.25 g of pure 7-chloro-1,3-dihydro-1-(methoxymethyl)-5-phenyl-2H-1, 4-benzodiazepine-2-one is obtained.
Utgangsmaterialet kan fremstilles som folger: The starting material can be produced as follows:
8,1 g natriummetylat tilsettes til en på -20° avkjolt opplosning av 5-klor-3-fenylindol-2-karboksylsyre-etylester i 150 ml dimetylformamid. Éfter 10 minutter avkjoles på -40° og tildryppes 12 ml klordimetyleter. Man lar temperaturen stige i lopet av 30 minutter til 10°, heller på vann., skiller den utskilte olje fra, ekstraherer den vandige fase med heksan og forener., uttrekkene med oljen. Den torkede opplosning inndampes og. resten ppploses i 100 ml eter . Denne opplosning inndryppes ved O - 5° i en suspensjon på 17 g litiumaluminiumhydrid i 150 ml eter. Efter tilsetningen lar man rore i 15 minutter uten avkjoling og hydrolyserer ved tildrypning av 35 ml vann. Bunnfallet suges fra, filtratet torkes med natriumsulfat og inndampes. Krystallisasjon av resten fra eter-heksan gir 18,6 g 5-klor-l-(metoksymetyl)-3-fenylindol-2-metanol, som efter omkrystallisasjon fra eter-heksan smelter ved 135 - 136°. 37 g mangandioksyd tilsettes til en opplosning av 6,7 g 5-klor-1-(metoksymetyl)-3-fenylindol-2-metanol i 150 ml metylenklorid. 8.1 g of sodium methylate are added to a -20° cooled solution of 5-chloro-3-phenylindole-2-carboxylic acid ethyl ester in 150 ml of dimethylformamide. After 10 minutes, cool to -40° and add 12 ml of chlorodimethyl ether dropwise. The temperature is allowed to rise in the course of 30 minutes to 10°, rather on water., the separated oil is separated, the aqueous phase is extracted with hexane and the extracts are combined with the oil. The dried solution is evaporated and the residue is dissolved in 100 ml of ether. This solution is added dropwise at 0 - 5° to a suspension of 17 g of lithium aluminum hydride in 150 ml of ether. After the addition, stir for 15 minutes without cooling and hydrolyze by adding 35 ml of water drop by drop. The sediment is sucked from, the filtrate is dried with sodium sulfate and evaporated. Crystallization of the residue from ether-hexane yields 18.6 g of 5-chloro-1-(methoxymethyl)-3-phenylindole-2-methanol, which after recrystallization from ether-hexane melts at 135 - 136°. 37 g of manganese dioxide are added to a solution of 6.7 g of 5-chloro-1-(methoxymethyl)-3-phenylindole-2-methanol in 150 ml of methylene chloride.
I denne rorte suspensjon innfores efter 4 timer ytterligere In this stirred suspension, a further one is introduced after 4 hours
30 g mangandioksyd. Så rores videre i 20 timer. Efter filtrering gjennom Celit konsentreres filtratet og resten krystalliserer fra alkohol. Man oppnår 5,9 g nåler av 5-klor-1-(metoksymetyl)-3-fenylindol-2-karboksaldehyd med smp. 30 g of manganese dioxide. Then stir for 20 hours. After filtration through Celite, the filtrate is concentrated and the residue crystallizes from alcohol. 5.9 g needles of 5-chloro-1-(methoxymethyl)-3-phenylindole-2-carboxaldehyde with m.p.
104 - 105°. 104 - 105°.
En blanding av 5,8 g 5-klor-l-(metoksymetyl)-3-fenylindol-2-karboksaldehyd, 3,9 g kaliumhydroksyd, 4,2 g hydroksylamin-hydroklorid, 60 mi alkohol og 6 ml vann kokes i 45 minutter under tilbakelop. Ved tilsetning av reaksjonsblandingen med vann felles 5-klor-l- (metoksymetyl)-3-fenylindol-2-karboksaldehyd-oksim ut i krystallin form. Efter avkjolingen på 0° suges krystallene opp, vaskes med kaldt vann og torkes, (5,7 g). A mixture of 5.8 g of 5-chloro-1-(methoxymethyl)-3-phenylindole-2-carboxaldehyde, 3.9 g of potassium hydroxide, 4.2 g of hydroxylamine hydrochloride, 60 ml of alcohol and 6 ml of water is boiled for 45 minutes during backflow. On addition of the reaction mixture with water, 5-chloro-1-(methoxymethyl)-3-phenylindole-2-carboxaldehyde oxime precipitates in crystalline form. After cooling to 0°, the crystals are sucked up, washed with cold water and dried, (5.7 g).
Smp. efter omkrystallisasjon fra alkohol 155 - 156°. Temp. after recrystallization from alcohol 155 - 156°.
5,5 g 5-klor-l-(metoksymetyl)-3-fenylindol-2-karboksaldoksim innfores porsjonsvis i en rort suspensjon av 3 g litiumaluminiumhydrid i 150 ml eter. Reaksjonsblandingen oppvarmes i 2 timer ved tilbakelop og står så til henstand natten over. 5.5 g of 5-chloro-1-(methoxymethyl)-3-phenylindole-2-carboxaldoxime are introduced portionwise into a stirred suspension of 3 g of lithium aluminum hydride in 150 ml of ether. The reaction mixture is heated for 2 hours at reflux and then allowed to stand overnight.
Ved tildrypning av 15 ml vann hydrolyseres det. Det By adding 15 ml of water, it is hydrolysed. The
uorganiske materiale suges opp, filtratet torkes med natriumsulfat inorganic material is sucked up, the filtrate is dried with sodium sulphate
og inndampes. Oppløsningen av resten i alkohol innstilles med alkoholisk saltsyre på pH 4 - 5, konsentreres i vakuum og tilsettes med eter inntil begynnende krystallisasjon. Man oppnår 3,9 g 2-aminometyl-5-klor-l-(metoksymetyl)-3-fenyl-indol-hydroklorid, som efter omkrystallisasjon fra metanol-eter smelter ved 186 - 187°. and evaporated. The solution of the residue in alcohol is adjusted with alcoholic hydrochloric acid to pH 4 - 5, concentrated in vacuo and added with ether until crystallization begins. 3.9 g of 2-aminomethyl-5-chloro-1-(methoxymethyl)-3-phenyl-indole hydrochloride are obtained, which after recrystallization from methanol-ether melts at 186 - 187°.
EKSEMPEL 9 EXAMPLE 9
A) Fremstilling av utgangsproduktet A) Production of the starting product
0,8 g natriumhydridsuspénsjon (50%'ig i mineralolje) innfores 0.8 g of sodium hydride suspension (50% in mineral oil) is introduced
i en til -10° kjolt opplosning av 3,42 g 7-klor-l,3-dihydro-5-fenyl-2H-1,4-benzodiazepin-2-on-3-karboksylsyreetylester i 30 ml dimetylformamid. Efter at det er rort om i 30 minutter ved -10°, avkjoles til -40° og tilsettes 1,3 ml klordimetyleter. Man lar temperaturen stige i lopet av 30 minutter til -10° og heller reaksjonsblandingen på 100 ml vann og 10 ml 2-n eddiksyre. Det utfelte produkt skilles fra og tas opp i metylenklorid. Den torkede metylenkloridopplosning dampes inn og resten krystalliserer fra metylenklorid-eter, (1,6 g). Man får 7-klor-l,3-dihydro-l-(metoksymetyl)-5-fenyl-2H-1,4-benzodiazepin- 2-on- 3-karboksylsyreetylester , som etter omkrystallisasjon fra metylenklorid-eter smelter ved 161-164°. in a cooled to -10° solution of 3.42 g of 7-chloro-1,3-dihydro-5-phenyl-2H-1,4-benzodiazepine-2-one-3-carboxylic acid ethyl ester in 30 ml of dimethylformamide. After it has been stirred for 30 minutes at -10°, it is cooled to -40° and 1.3 ml of chlorodimethyl ether is added. The temperature is allowed to rise over 30 minutes to -10° and the reaction mixture is poured into 100 ml of water and 10 ml of 2-n acetic acid. The precipitated product is separated and taken up in methylene chloride. The dried methylene chloride solution is evaporated and the residue crystallizes from methylene chloride ether, (1.6 g). 7-chloro-1,3-dihydro-1-(methoxymethyl)-5-phenyl-2H-1,4-benzodiazepine-2-one-3-carboxylic acid ethyl ester is obtained, which after recrystallization from methylene chloride-ether melts at 161-164 °.
B) Videre forarbeidelse av forannevnte utgangsprodukt B) Further processing of the aforementioned starting product
3,9 g 7-klor-l,3-dihydro-l-(metoksymetyl)-5-fenyl-2H-1,4-benzodiazepin-2-on-3-karboksylsyreetylester opploses i 40 ml dioksan og rores i nærvær av 6 ml 2-n natronlut og 30 ml vann i 6 timer ved værelsestemperatur under nitrogenatmosfære. Reak-sj onsblandingen rystes ut med eter, den vandige fase skilles fra og ansyres med 2-n saltsyre inntil det utfelte materiale igjen går i opplosning. Derpå innstilles alkalisk med ammoniakk og basen ekstraheres med metylenklorid. Efter kromatografisk rensning av'den rå base oppnår man 2,1 g 7-klor-l,3-dihydro-l-(metoksymetyl)-5-fenyl-2H-1,4-benzodiazepin-2-on. 3.9 g of 7-chloro-1,3-dihydro-1-(methoxymethyl)-5-phenyl-2H-1,4-benzodiazepine-2-one-3-carboxylic acid ethyl ester are dissolved in 40 ml of dioxane and stirred in the presence of 6 ml of 2-N caustic soda and 30 ml of water for 6 hours at room temperature under a nitrogen atmosphere. The reaction mixture is shaken out with ether, the aqueous phase is separated and acidified with 2N hydrochloric acid until the precipitated material dissolves again. It is then made alkaline with ammonia and the base is extracted with methylene chloride. After chromatographic purification of the crude base, 2.1 g of 7-chloro-1,3-dihydro-1-(methoxymethyl)-5-phenyl-2H-1,4-benzodiazepine-2-one is obtained.
EKSEMPEL 10 EXAMPLE 10
.2 g 4^acetoksy-7-klor-l-(metoksymetyl)-5-fenyl-1,3,4,5-tetra-hydro-2H-1,4-benzodiazepin-2-on kokes i 30 ml alkohol og 5 ml .2 g of 4^acetoxy-7-chloro-1-(methoxymethyl)-5-phenyl-1,3,4,5-tetrahydro-2H-1,4-benzodiazepine-2-one are boiled in 30 ml of alcohol and 5 ml
trietylamin i 30" minutter under tilbakelop. Den efter inndampningen i vakuum utfelte rest kromatograferés på 50 g silisiumgel med 10 % etylacetat i metylenklorid. Forst elueres 1,3 g 7-klor-l,5-dihydro-l-(metoksymetyl)-5-fenyl-2H-1,4-benzodiazepin- 2-on. Denne forbindelse viser efter krystallisasjon fra eter-heksan et smp. på 126 - 129°. Derefter elueres 0,4 g av det isomere 7-klor-l,3-dihydro-l-(metoksymetyl)-5-fenyl-2H-1,4-benzodiazepin-2-on. triethylamine for 30 minutes under reflux. The residue precipitated after evaporation in vacuum is chromatographed on 50 g of silicon gel with 10% ethyl acetate in methylene chloride. First, 1.3 g of 7-chloro-1,5-dihydro-1-(methoxymethyl)-5 is eluted -phenyl-2H-1,4-benzodiazepine-2-one. After crystallization from ether-hexane, this compound shows a melting point of 126 - 129°. Then 0.4 g of the isomeric 7-chloro-1,3- dihydro-1-(methoxymethyl)-5-phenyl-2H-1,4-benzodiazepine-2-one.
Utgangsmaterialet kan fremstilles som folger: The starting material can be produced as follows:
En opplosning av 3,3 g 7-klor-l-(metoksymetyl)-4-hydroksy-5-fenyl-1,3,4,5-tetrahydro-2H-1,4-benzodiazepin-2-on i 20 ml pyridin tilsettes med 10 ml acetanhydrid og står til henstand i 48 timer ved værelsestemperatur. Efter inndampningen i va-kumm fordeler man resten mellom eter og 2-n saltsyre. Eter-fasen vaskes med bikarbonatopplosning og vann, torkes og inndampes. Krystallisasjon av resten fra eter-heksan gir 3,1 g 4-acetoksy-7-klor-l-(metoksymetyl)-5-fenyl-1,3,4,5-tetrahydro-2H-1,4-benzodiazepin-2-on med smp. 95 - 10 3°. Ved omkrystallisasjon fra metanol forbedrer smeltepunktet seg til 103 - 106°. A solution of 3.3 g of 7-chloro-1-(methoxymethyl)-4-hydroxy-5-phenyl-1,3,4,5-tetrahydro-2H-1,4-benzodiazepine-2-one in 20 ml of pyridine is added with 10 ml of acetic anhydride and allowed to stand for 48 hours at room temperature. After evaporation in vacuo, the residue is partitioned between ether and 2-n hydrochloric acid. The ether phase is washed with bicarbonate solution and water, dried and evaporated. Crystallization of the residue from ether-hexane gives 3.1 g of 4-acetoxy-7-chloro-1-(methoxymethyl)-5-phenyl-1,3,4,5-tetrahydro-2H-1,4-benzodiazepine-2- on with m.p. 95 - 10 3°. On recrystallization from methanol, the melting point improves to 103 - 106°.
EKSEMPEL . 11 EXAMPLE . 11
0,3 g 7-klor-l,5-dihydro-l-(metoksymetyl)-5-fenyl-2H-1,4-benzodiazepin-2-on står til henstand i en opplosning av 0,1 g batrium i 10 ml alkohol i 30 minutter ved værelsetemperatur. Reaksjonsblandingen noytraliseres ved tilsetning av iseddik og inndampes i vakuum. Resten fordeles mellom 10%'ig sodaopplds-ning og metylenklorid. Den efter inndampningen av den torkede metylenkloridopplosningen erholdte rest kromatograferes på 20 g siliumgel med 10%eddikester i metylenklorid. Man oppnår 0,23 g 7-klor-l,3-dihydro-l-(metoksymetyl)-5-fenyl-2H-1,4-benzodiazepin-2-on. 0.3 g of 7-chloro-1,5-dihydro-1-(methoxymethyl)-5-phenyl-2H-1,4-benzodiazepine-2-one is suspended in a solution of 0.1 g of sodium in 10 ml alcohol for 30 minutes at room temperature. The reaction mixture is neutralized by adding glacial acetic acid and evaporated in a vacuum. The remainder is distributed between a 10% soda solution and methylene chloride. The residue obtained after the evaporation of the dried methylene chloride solution is chromatographed on 20 g of silica gel with 10% acetic ester in methylene chloride. 0.23 g of 7-chloro-1,3-dihydro-1-(methoxymethyl)-5-phenyl-2H-1,4-benzodiazepine-2-one is obtained.
EKSEMPEL 12 EXAMPLE 12
0,4 g natriummetoksyd tilsettes til en opplosning av 1 g 7-klor-1-(metoksymetyl)-5-fenyl-4-(p-toluensulfonyl)-1,3,4,5- 0.4 g of sodium methoxide is added to a solution of 1 g of 7-chloro-1-(methoxymethyl)-5-phenyl-4-(p-toluenesulfonyl)-1,3,4,5-
tetrahydro-2H-1,4-benzodiazepin-2-on i 20 ml dimetylformamid. tetrahydro-2H-1,4-benzodiazepine-2-one in 20 ml of dimethylformamide.
Under nitrogenatmosfære rores i lbpet av.30 minutter, så nøy-traliseres med iseddik og inndampes, i vakuum. Resten opptas i eter og ekstraheres tre ganger med 2-n saltsyre. De med eter vaskede uttrekk innstilles alkalisk med konsentrert ammoniakk og ekstraheres tre ganger med metylenklorid. De torkede mety-lenkloriduttrekk gir efter inndampningen 0,6 g gul olje, som efter kromatografi på 20 g silisiumgel med lo% eddikester i metylenklorid gir0,4 g 7-klor-l,3-dihydro-l-(metoksymetyl)-5-fenyl-2H-1,4-benzodiazepin-2-on. Under a nitrogen atmosphere, the mixture is stirred for 30 minutes, then neutralized with glacial acetic acid and evaporated in vacuo. The residue is taken up in ether and extracted three times with 2-N hydrochloric acid. The ether-washed extracts are made alkaline with concentrated ammonia and extracted three times with methylene chloride. After evaporation, the dried methylene chloride extracts give 0.6 g of yellow oil, which after chromatography on 20 g of silicon gel with 10% acetate in methylene chloride gives 0.4 g of 7-chloro-1,3-dihydro-1-(methoxymethyl)-5- phenyl-2H-1,4-benzodiazepine-2-one.
Utgangsmaterialet kan fremstilles som folger: The starting material can be produced as follows:
En opplosning av 3,2 g 7-klor-l-(metoksymetyl)-5-fenyl-1,3,4,5-tetrahydro-2H-1,4-benzodiazepin-2-on i 20 ml pyridin tilsettes med 2,3 g tosylklorid og står til henstand 3 timer ved værelsetemperatur. Efter fjerningen av pyridinet i vakuum fordeles resten mellom metylenklorid og 2-n saltsyre. Metylen-kloridfasen vaskes derpå med 10%'ig.sodaopplosning og vann, A solution of 3.2 g of 7-chloro-1-(methoxymethyl)-5-phenyl-1,3,4,5-tetrahydro-2H-1,4-benzodiazepine-2-one in 20 ml of pyridine is added with 2, 3 g of tosyl chloride and leave to stand for 3 hours at room temperature. After the removal of the pyridine in vacuo, the residue is distributed between methylene chloride and 2-n hydrochloric acid. The methylene chloride phase is then washed with 10% soda solution and water,
torkes<p>g inndampes. Den krystalline rest omkrystalliseres fra metanol-metylenklorid. Man oppnår 7-klor-l-(metoksymetyl)-5-fenyl-4-(p-toluensulfonyl)-1,3,4,5-tetrahydro-2H-1,4-benzodiazepin- 2-on med smp. 218 - 220°. dried<p>and evaporated. The crystalline residue is recrystallized from methanol-methylene chloride. One obtains 7-chloro-1-(methoxymethyl)-5-phenyl-4-(p-toluenesulfonyl)-1,3,4,5-tetrahydro-2H-1,4-benzodiazepine-2-one with m.p. 218 - 220°.
Claims (1)
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CH225569A CH562220A5 (en) | 1969-02-14 | 1969-02-14 |
Publications (1)
Publication Number | Publication Date |
---|---|
NO128328B true NO128328B (en) | 1973-10-29 |
Family
ID=4229492
Family Applications (2)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
NO00510/70A NO128328B (en) | 1969-02-14 | 1970-02-13 | |
NO00292/73A NO128110B (en) | 1969-02-14 | 1973-01-24 |
Family Applications After (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
NO00292/73A NO128110B (en) | 1969-02-14 | 1973-01-24 |
Country Status (23)
Country | Link |
---|---|
AT (10) | AT302321B (en) |
BE (1) | BE745852A (en) |
BR (1) | BR6915093D0 (en) |
CA (1) | CA971960A (en) |
CH (1) | CH562220A5 (en) |
CS (1) | CS159260B2 (en) |
DE (1) | DE2005508A1 (en) |
DK (1) | DK137899B (en) |
DO (1) | DOP1970001703A (en) |
ES (1) | ES376528A1 (en) |
FI (1) | FI49965C (en) |
FR (1) | FR2034550B1 (en) |
GB (5) | GB1306454A (en) |
IE (2) | IE33991B1 (en) |
IL (2) | IL33821A (en) |
IS (1) | IS1906A7 (en) |
NL (1) | NL156401B (en) |
NO (2) | NO128328B (en) |
OA (1) | OA03435A (en) |
PL (1) | PL80826B1 (en) |
RO (5) | RO58075A (en) |
SE (1) | SE358393B (en) |
SU (11) | SU428603A3 (en) |
Families Citing this family (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
BE787117A (en) * | 1971-08-04 | 1973-02-05 | Hoffmann La Roche | BENZODIAZEPINE DERIVATIVES |
JPS4867288A (en) * | 1971-12-14 | 1973-09-13 | ||
US3932637A (en) * | 1974-07-22 | 1976-01-13 | Sumitomo Chemical Company, Limited | Methods and compositions for improving the feed intake of meat producing animals |
CA1163266A (en) * | 1980-07-31 | 1984-03-06 | Albert E. Fischli | Benzodiazepine derivatives |
Family Cites Families (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US3136815A (en) * | 1959-12-10 | 1964-06-09 | Hoffmann La Roche | Amino substituted benzophenone oximes and derivatives thereof |
-
1969
- 1969-02-14 CH CH225569A patent/CH562220A5/xx not_active IP Right Cessation
- 1969-12-15 BR BR215093/69A patent/BR6915093D0/en unknown
-
1970
- 1970-02-02 IL IL33821A patent/IL33821A/en unknown
- 1970-02-04 CA CA073,934A patent/CA971960A/en not_active Expired
- 1970-02-05 OA OA53847A patent/OA03435A/en unknown
- 1970-02-06 IE IE618/73A patent/IE33991B1/en unknown
- 1970-02-06 DE DE19702005508 patent/DE2005508A1/en not_active Ceased
- 1970-02-06 IE IE156/70A patent/IE33988B1/en unknown
- 1970-02-10 SU SU1666627A patent/SU428603A3/en active
- 1970-02-10 SU SU1691526A patent/SU421195A3/en active
- 1970-02-10 SU SU1691525A patent/SU415880A3/en active
- 1970-02-10 SU SU1691943A patent/SU404253A3/ru active
- 1970-02-10 SU SU1400104A patent/SU497774A3/en active
- 1970-02-10 SU SU1691944A patent/SU402219A3/ru active
- 1970-02-10 SU SU1691947A patent/SU406360A3/ru active
- 1970-02-10 SU SU1658463A patent/SU406359A3/ru active
- 1970-02-10 SU SU1691948A patent/SU453841A3/en active
- 1970-02-10 SU SU1665719A patent/SU431673A3/ru active
- 1970-02-11 GB GB6675372A patent/GB1306454A/en not_active Expired
- 1970-02-11 GB GB3375172A patent/GB1306452A/en not_active Expired
- 1970-02-11 CS CS95470*#A patent/CS159260B2/cs unknown
- 1970-02-11 GB GB4314272A patent/GB1306455A/en not_active Expired
- 1970-02-11 GB GB645070A patent/GB1306451A/en not_active Expired
- 1970-02-12 IS IS1906A patent/IS1906A7/en unknown
- 1970-02-12 DO DO1970001703A patent/DOP1970001703A/en unknown
- 1970-02-12 BE BE745852D patent/BE745852A/en unknown
- 1970-02-13 AT AT505571A patent/AT302321B/en not_active IP Right Cessation
- 1970-02-13 AT AT504971A patent/AT302316B/en not_active IP Right Cessation
- 1970-02-13 DK DK72870AA patent/DK137899B/en not_active Application Discontinuation
- 1970-02-13 PL PL1970138780A patent/PL80826B1/en unknown
- 1970-02-13 AT AT505771A patent/AT302323B/en not_active IP Right Cessation
- 1970-02-13 NL NL7002084.A patent/NL156401B/en not_active IP Right Cessation
- 1970-02-13 AT AT131770A patent/AT299208B/en not_active IP Right Cessation
- 1970-02-13 ES ES376528A patent/ES376528A1/en not_active Expired
- 1970-02-13 AT AT505171A patent/AT302317B/en not_active IP Right Cessation
- 1970-02-13 AT AT505071A patent/AT301555B/en not_active Expired
- 1970-02-13 FR FR707005175A patent/FR2034550B1/fr not_active Expired
- 1970-02-13 AT AT505271A patent/AT302318B/en not_active IP Right Cessation
- 1970-02-13 SE SE01893/70A patent/SE358393B/xx unknown
- 1970-02-13 AT AT505471A patent/AT302320B/en not_active IP Right Cessation
- 1970-02-13 FI FI700400A patent/FI49965C/en active
- 1970-02-13 AT AT505371A patent/AT302319B/en not_active IP Right Cessation
- 1970-02-13 AT AT505671A patent/AT302322B/en not_active IP Right Cessation
- 1970-02-13 NO NO00510/70A patent/NO128328B/no unknown
- 1970-02-14 RO RO62467A patent/RO58075A/ro unknown
- 1970-02-14 RO RO68268A patent/RO57030A/ro unknown
- 1970-02-14 RO RO68267A patent/RO57028A/ro unknown
- 1970-02-14 RO RO68266A patent/RO57160A/ro unknown
- 1970-02-14 RO RO68269A patent/RO57161A/ro unknown
- 1970-05-12 GB GB3385272A patent/GB1306453A/en not_active Expired
-
1971
- 1971-05-13 SU SU1657960A patent/SU517258A3/en active
-
1973
- 1973-01-24 NO NO00292/73A patent/NO128110B/no unknown
- 1973-05-22 IL IL7342330A patent/IL42330A0/en unknown
Also Published As
Similar Documents
Publication | Publication Date | Title |
---|---|---|
US3261828A (en) | 3h-1,4-benzodiazepine-2,5(1h,4h)-dione compounds | |
NO153262B (en) | PROCEDURE FOR PREPARING A FAT MIXTURE. | |
NO147914B (en) | INTERMEDIATE IN THE PREPARATION OF PHARMACOLOGICAL ACTIVE IMIDAZOLE (1,5-A) (1,4) DIAZEPINE COMPOUNDS | |
NO135173B (en) | ||
US3770763A (en) | N-(2-(nitro-1-imidazoly)ethyl)imides | |
CA1090333A (en) | Process for the manufacture of diazepine derivatives | |
NO128328B (en) | ||
US3784542A (en) | Benzodiazepin-2-ones | |
NO117366B (en) | ||
NO843376L (en) | benzodiazepine | |
US3886214A (en) | Benzodiazepin-2-ones and processes for the preparation thereof | |
US3374225A (en) | Aminobenzodiazepine compounds and methods | |
US3732211A (en) | 1-acyloxyether-1,4-benzodiazepin-2-ones and methods for their preparation | |
US4001408A (en) | Substituted heterocyclic compounds, processes and composition including those | |
Ogata et al. | 5-Aryl-1, 5-dihydro-2H-1, 4-benzodiazepin-2-one derivatives as antianxiety agents | |
US3595874A (en) | 3,4,5,10-tetrahydroazepino(2,3-b)indol-5a (2h)-ols | |
US3148183A (en) | Delta4 and delta4, 6-17alpha-acyloxy-20-oxo-steroid-[3, 2-c] pyrazoles of the pregnane series | |
SU430552A1 (en) | Method for producing benzodiazepine derivatives | |
US3634419A (en) | 17-azasteroids | |
NO136410B (en) | ||
US3772271A (en) | 1-acylamidoalkyl-benzodiazepin-2-ones | |
NO153261B (en) | VISCOSITY INDEX IMPROVING ADDITIVE MIXTURE AND LUBRICANT CONTAINING THIS MIXTURE | |
NO742737L (en) | ||
CH573926A5 (en) | Benzodiazepines | |
US4138572A (en) | Malonanilic derivatives |