NO121545B - - Google Patents
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- Publication number
- NO121545B NO121545B NO45068A NO45068A NO121545B NO 121545 B NO121545 B NO 121545B NO 45068 A NO45068 A NO 45068A NO 45068 A NO45068 A NO 45068A NO 121545 B NO121545 B NO 121545B
- Authority
- NO
- Norway
- Prior art keywords
- solution
- mol
- benzodiazepine
- chloro
- phenyl
- Prior art date
Links
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 8
- 238000000034 method Methods 0.000 claims description 8
- 238000002360 preparation method Methods 0.000 claims description 7
- 239000003960 organic solvent Substances 0.000 claims description 6
- 125000000217 alkyl group Chemical group 0.000 claims description 5
- 150000002367 halogens Chemical class 0.000 claims description 5
- 229910052736 halogen Inorganic materials 0.000 claims description 4
- 125000004390 alkyl sulfonyl group Chemical group 0.000 claims description 3
- 125000004391 aryl sulfonyl group Chemical group 0.000 claims description 3
- 229940053197 benzodiazepine derivative antiepileptics Drugs 0.000 claims description 3
- 125000000325 methylidene group Chemical group [H]C([H])=* 0.000 claims description 3
- 125000003310 benzodiazepinyl group Chemical class N1N=C(C=CC2=C1C=CC=C2)* 0.000 claims 1
- 125000001589 carboacyl group Chemical group 0.000 claims 1
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 102
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 53
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 45
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 40
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 38
- 239000011541 reaction mixture Substances 0.000 description 34
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 28
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 27
- 150000001875 compounds Chemical class 0.000 description 27
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 26
- 238000002844 melting Methods 0.000 description 26
- 230000008018 melting Effects 0.000 description 26
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 24
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 24
- 239000000203 mixture Substances 0.000 description 23
- 239000003921 oil Substances 0.000 description 23
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 21
- -1 arylsulfonyl halide Chemical class 0.000 description 20
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 19
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 15
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 13
- YYROPELSRYBVMQ-UHFFFAOYSA-N 4-toluenesulfonyl chloride Chemical compound CC1=CC=C(S(Cl)(=O)=O)C=C1 YYROPELSRYBVMQ-UHFFFAOYSA-N 0.000 description 12
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 12
- 238000010992 reflux Methods 0.000 description 12
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 11
- 239000002585 base Substances 0.000 description 11
- 239000012312 sodium hydride Substances 0.000 description 11
- 229910000104 sodium hydride Inorganic materials 0.000 description 11
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 10
- 239000002480 mineral oil Substances 0.000 description 10
- 235000010446 mineral oil Nutrition 0.000 description 10
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 9
- 238000006243 chemical reaction Methods 0.000 description 9
- 239000002027 dichloromethane extract Substances 0.000 description 9
- 239000006185 dispersion Substances 0.000 description 9
- 239000010410 layer Substances 0.000 description 9
- 235000011121 sodium hydroxide Nutrition 0.000 description 8
- AKPLHCDWDRPJGD-UHFFFAOYSA-N nordazepam Chemical compound C12=CC(Cl)=CC=C2NC(=O)CN=C1C1=CC=CC=C1 AKPLHCDWDRPJGD-UHFFFAOYSA-N 0.000 description 7
- 238000001953 recrystallisation Methods 0.000 description 7
- 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
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 6
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 6
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 6
- 239000007858 starting material Substances 0.000 description 6
- 239000002253 acid Substances 0.000 description 5
- 239000013078 crystal Substances 0.000 description 5
- 239000000284 extract Substances 0.000 description 5
- 239000002244 precipitate Substances 0.000 description 5
- 238000003756 stirring Methods 0.000 description 5
- XBWAZCLHZCFCGK-UHFFFAOYSA-N 7-chloro-1-methyl-5-phenyl-3,4-dihydro-2h-1,4-benzodiazepin-1-ium;chloride Chemical compound [Cl-].C12=CC(Cl)=CC=C2[NH+](C)CCN=C1C1=CC=CC=C1 XBWAZCLHZCFCGK-UHFFFAOYSA-N 0.000 description 4
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 4
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 4
- 239000000370 acceptor Substances 0.000 description 4
- 238000001816 cooling Methods 0.000 description 4
- 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 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- NOWKCMXCCJGMRR-UHFFFAOYSA-N Aziridine Chemical compound C1CN1 NOWKCMXCCJGMRR-UHFFFAOYSA-N 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- 239000012359 Methanesulfonyl chloride Substances 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 125000002252 acyl group Chemical group 0.000 description 3
- 230000029936 alkylation Effects 0.000 description 3
- 238000005804 alkylation reaction Methods 0.000 description 3
- 238000009835 boiling Methods 0.000 description 3
- 239000007795 chemical reaction product Substances 0.000 description 3
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 3
- 235000019341 magnesium sulphate Nutrition 0.000 description 3
- QARBMVPHQWIHKH-UHFFFAOYSA-N methanesulfonyl chloride Chemical compound CS(Cl)(=O)=O QARBMVPHQWIHKH-UHFFFAOYSA-N 0.000 description 3
- 239000012044 organic layer Substances 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- 229910052938 sodium sulfate Inorganic materials 0.000 description 3
- 235000011152 sodium sulphate Nutrition 0.000 description 3
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 3
- MAOBFOXLCJIFLV-UHFFFAOYSA-N (2-aminophenyl)-phenylmethanone Chemical compound NC1=CC=CC=C1C(=O)C1=CC=CC=C1 MAOBFOXLCJIFLV-UHFFFAOYSA-N 0.000 description 2
- BRJBYMHIEKOXMQ-UHFFFAOYSA-N 1-(7-chloro-1-methyl-5-phenyl-3,5-dihydro-2H-1,4-benzodiazepin-4-yl)ethanone Chemical compound C12=CC(Cl)=CC=C2N(C)CCN(C(C)=O)C1C1=CC=CC=C1 BRJBYMHIEKOXMQ-UHFFFAOYSA-N 0.000 description 2
- XCEYKKJMLOFDSS-UHFFFAOYSA-N 4-chloro-n-methylaniline Chemical compound CNC1=CC=C(Cl)C=C1 XCEYKKJMLOFDSS-UHFFFAOYSA-N 0.000 description 2
- JSGMWVLRXAWFMH-UHFFFAOYSA-N 7-chloro-1-methyl-5-phenyl-2,3,4,5-tetrahydro-1,4-benzodiazepine Chemical compound C12=CC(Cl)=CC=C2N(C)CCNC1C1=CC=CC=C1 JSGMWVLRXAWFMH-UHFFFAOYSA-N 0.000 description 2
- IAANHXSZJLDKOO-UHFFFAOYSA-N 7-chloro-4-methylsulfonyl-5-phenyl-3,5-dihydro-1h-1,4-benzodiazepin-2-one Chemical compound CS(=O)(=O)N1CC(=O)NC2=CC=C(Cl)C=C2C1C1=CC=CC=C1 IAANHXSZJLDKOO-UHFFFAOYSA-N 0.000 description 2
- GYQOYYFIHYKFEO-UHFFFAOYSA-N 7-chloro-5-phenyl-1,3,4,5-tetrahydro-1,4-benzodiazepin-2-one Chemical compound C12=CC(Cl)=CC=C2NC(=O)CNC1C1=CC=CC=C1 GYQOYYFIHYKFEO-UHFFFAOYSA-N 0.000 description 2
- XYFZZOKPDQAJPG-UHFFFAOYSA-N 7-chloro-5-phenyl-1,5-dihydro-1,4-benzodiazepin-2-one Chemical compound C12=CC(Cl)=CC=C2NC(=O)C=NC1C1=CC=CC=C1 XYFZZOKPDQAJPG-UHFFFAOYSA-N 0.000 description 2
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 2
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 2
- YFDQKRDVFGKWOA-UHFFFAOYSA-N ClC=1C=CC2=C(C(N(CC(N2)=O)S(=O)(=O)C2=CC=C(C=C2)C)C2=C(C=CC=C2)F)C1 Chemical compound ClC=1C=CC2=C(C(N(CC(N2)=O)S(=O)(=O)C2=CC=C(C=C2)C)C2=C(C=CC=C2)F)C1 YFDQKRDVFGKWOA-UHFFFAOYSA-N 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- 230000002378 acidificating effect Effects 0.000 description 2
- 239000003513 alkali Substances 0.000 description 2
- VSCWAEJMTAWNJL-UHFFFAOYSA-K aluminium trichloride Chemical compound Cl[Al](Cl)Cl VSCWAEJMTAWNJL-UHFFFAOYSA-K 0.000 description 2
- HUMNYLRZRPPJDN-UHFFFAOYSA-N benzaldehyde Chemical compound O=CC1=CC=CC=C1 HUMNYLRZRPPJDN-UHFFFAOYSA-N 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
- 239000006227 byproduct Substances 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- 239000000460 chlorine Substances 0.000 description 2
- 229910052801 chlorine Inorganic materials 0.000 description 2
- 239000012141 concentrate Substances 0.000 description 2
- 238000002425 crystallisation Methods 0.000 description 2
- 230000008025 crystallization Effects 0.000 description 2
- VAYGXNSJCAHWJZ-UHFFFAOYSA-N dimethyl sulfate Chemical compound COS(=O)(=O)OC VAYGXNSJCAHWJZ-UHFFFAOYSA-N 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 239000012259 ether extract Substances 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- 239000008187 granular material Substances 0.000 description 2
- 238000010438 heat treatment Methods 0.000 description 2
- 239000013067 intermediate product Substances 0.000 description 2
- 238000002955 isolation Methods 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 2
- NEUAPOAFUOOCQR-UHFFFAOYSA-N n'-(4-chlorophenyl)-n'-methylethane-1,2-diamine Chemical compound NCCN(C)C1=CC=C(Cl)C=C1 NEUAPOAFUOOCQR-UHFFFAOYSA-N 0.000 description 2
- 229910052757 nitrogen Inorganic materials 0.000 description 2
- 239000003208 petroleum Substances 0.000 description 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 2
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 2
- 239000012429 reaction media Substances 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- 239000000725 suspension Substances 0.000 description 2
- 150000003512 tertiary amines Chemical class 0.000 description 2
- UFRGXRPHKUXLIU-UHFFFAOYSA-N 1,4-benzodiazepine-2-thione Chemical compound S=C1C=NC=C2C=CC=CC2=N1 UFRGXRPHKUXLIU-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
- QSNSCYSYFYORTR-UHFFFAOYSA-N 4-chloroaniline Chemical compound NC1=CC=C(Cl)C=C1 QSNSCYSYFYORTR-UHFFFAOYSA-N 0.000 description 1
- QEPNNAVXGTYUCT-UHFFFAOYSA-N 7-chloro-1-methyl-5-phenyl-3,5-dihydro-2H-1,4-benzodiazepine-4-carbaldehyde Chemical compound C12=CC(Cl)=CC=C2N(C)CCN(C=O)C1C1=CC=CC=C1 QEPNNAVXGTYUCT-UHFFFAOYSA-N 0.000 description 1
- LZIAQNOAIDLPMN-UHFFFAOYSA-N 7-chloro-5-(2-fluorophenyl)-1,3,4,5-tetrahydro-1,4-benzodiazepin-2-one Chemical compound ClC=1C=CC2=C(C(NCC(N2)=O)C2=C(C=CC=C2)F)C1 LZIAQNOAIDLPMN-UHFFFAOYSA-N 0.000 description 1
- JZWOKDTXYPEJEW-UHFFFAOYSA-N 7-chloro-5-phenyl-2,3-dihydro-1h-1,4-benzodiazepine Chemical compound C12=CC(Cl)=CC=C2NCCN=C1C1=CC=CC=C1 JZWOKDTXYPEJEW-UHFFFAOYSA-N 0.000 description 1
- PIICEJLVQHRZGT-UHFFFAOYSA-N Ethylenediamine Chemical compound NCCN PIICEJLVQHRZGT-UHFFFAOYSA-N 0.000 description 1
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-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
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 1
- HKNSIVFWRXBWCK-UHFFFAOYSA-N [N].NC1=CC=CC=C1 Chemical group [N].NC1=CC=CC=C1 HKNSIVFWRXBWCK-UHFFFAOYSA-N 0.000 description 1
- WETWJCDKMRHUPV-UHFFFAOYSA-N acetyl chloride Chemical compound CC(Cl)=O WETWJCDKMRHUPV-UHFFFAOYSA-N 0.000 description 1
- 239000012346 acetyl chloride Substances 0.000 description 1
- 229910001854 alkali hydroxide Inorganic materials 0.000 description 1
- 150000008044 alkali metal hydroxides Chemical class 0.000 description 1
- 125000005037 alkyl phenyl group Chemical group 0.000 description 1
- WNROFYMDJYEPJX-UHFFFAOYSA-K aluminium hydroxide Chemical compound [OH-].[OH-].[OH-].[Al+3] WNROFYMDJYEPJX-UHFFFAOYSA-K 0.000 description 1
- 230000001773 anti-convulsant effect Effects 0.000 description 1
- 125000003118 aryl group Chemical group 0.000 description 1
- CSKNSYBAZOQPLR-UHFFFAOYSA-N benzenesulfonyl chloride Chemical compound ClS(=O)(=O)C1=CC=CC=C1 CSKNSYBAZOQPLR-UHFFFAOYSA-N 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000004432 carbon atom Chemical group C* 0.000 description 1
- 238000001311 chemical methods and process Methods 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 238000005695 dehalogenation reaction Methods 0.000 description 1
- UVCOILFBWYKHHB-UHFFFAOYSA-N desalkylflurazepam Chemical compound FC1=CC=CC=C1C1=NCC(=O)NC2=CC=C(Cl)C=C12 UVCOILFBWYKHHB-UHFFFAOYSA-N 0.000 description 1
- AAOVKJBEBIDNHE-UHFFFAOYSA-N diazepam Chemical compound N=1CC(=O)N(C)C2=CC=C(Cl)C=C2C=1C1=CC=CC=C1 AAOVKJBEBIDNHE-UHFFFAOYSA-N 0.000 description 1
- 238000010828 elution Methods 0.000 description 1
- 239000002038 ethyl acetate fraction Substances 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 235000019253 formic acid Nutrition 0.000 description 1
- 230000005484 gravity Effects 0.000 description 1
- 150000004820 halides Chemical class 0.000 description 1
- 150000004678 hydrides Chemical class 0.000 description 1
- 150000002430 hydrocarbons Chemical group 0.000 description 1
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 1
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 239000005457 ice water Substances 0.000 description 1
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 description 1
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 239000000155 melt Substances 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 239000003158 myorelaxant agent Substances 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- TWNQGVIAIRXVLR-UHFFFAOYSA-N oxo(oxoalumanyloxy)alumane Chemical compound O=[Al]O[Al]=O TWNQGVIAIRXVLR-UHFFFAOYSA-N 0.000 description 1
- QNGNSVIICDLXHT-UHFFFAOYSA-N para-ethylbenzaldehyde Natural products CCC1=CC=C(C=O)C=C1 QNGNSVIICDLXHT-UHFFFAOYSA-N 0.000 description 1
- 239000002798 polar solvent Substances 0.000 description 1
- 125000006239 protecting group Chemical group 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 239000000932 sedative agent Substances 0.000 description 1
- 230000001624 sedative effect Effects 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
- 159000000000 sodium salts Chemical class 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000012265 solid product Substances 0.000 description 1
- 239000012258 stirred mixture Substances 0.000 description 1
- FKHIFSZMMVMEQY-UHFFFAOYSA-N talc Chemical compound [Mg+2].[O-][Si]([O-])=O FKHIFSZMMVMEQY-UHFFFAOYSA-N 0.000 description 1
- YBRBMKDOPFTVDT-UHFFFAOYSA-N tert-butylamine Chemical compound CC(C)(C)N YBRBMKDOPFTVDT-UHFFFAOYSA-N 0.000 description 1
- 125000003944 tolyl group Chemical group 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D243/00—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms
- C07D243/06—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms having the nitrogen atoms in positions 1 and 4
- C07D243/10—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms having the nitrogen atoms in positions 1 and 4 condensed with carbocyclic rings or ring systems
- C07D243/14—1,4-Benzodiazepines; Hydrogenated 1,4-benzodiazepines
- C07D243/16—1,4-Benzodiazepines; Hydrogenated 1,4-benzodiazepines substituted in position 5 by aryl radicals
- C07D243/18—1,4-Benzodiazepines; Hydrogenated 1,4-benzodiazepines substituted in position 5 by aryl radicals substituted in position 2 by nitrogen, oxygen or sulfur atoms
- C07D243/24—Oxygen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D243/00—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms
- C07D243/06—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms having the nitrogen atoms in positions 1 and 4
- C07D243/10—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms having the nitrogen atoms in positions 1 and 4 condensed with carbocyclic rings or ring systems
- C07D243/14—1,4-Benzodiazepines; Hydrogenated 1,4-benzodiazepines
- C07D243/16—1,4-Benzodiazepines; Hydrogenated 1,4-benzodiazepines substituted in position 5 by aryl radicals
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Description
Fremgangsmåte for fremstilling av benzodiazepin-derivater. Process for the production of benzodiazepine derivatives.
Oppfinnelsen vedrorer en ny kjemisk fremgangsmåte for fremstilling av benzodiazepin-derivater med muskelrelakserende, sedativ og antikonvulsiv virkning. Disse derivater innehar den generelle formel The invention relates to a new chemical process for the production of benzodiazepine derivatives with muscle relaxant, sedative and anticonvulsant effects. These derivatives have the general formula
hvor B betyr karbonyl eller metylen, where B means carbonyl or methylene,
halogen, fortrinnsvis klor eller brom, halogen, preferably chlorine or bromine,
R2hydrogen eller lavere alkyl og R2hydrogen or lower alkyl and
R^hydrogen eller halogen. R^hydrogen or halogen.
Uttrykket "halogen" vedrorer alle former, dvs. klor, brom, fluor og jod, unntagen hvor spesielt angis. Ved uttrykket"lavere alkyl" (enten alene eller i kombinasjon med andre radi-kaler) dreier det seg om rettkjedede eller forgrenede hydrokar-bongrupper med 1-7 karbonatomer. Eksempler på slike lavere alkylgrupper er metyl, etyl, isopropyl, tert.butyl og lignende. Uttrykket "aryl", som det anvendes i det folgende, vedrorer fenylgrupper, substituerte fenylgrupper, f.eks. lavere alkyl-fenyl, som tolyl og lignende. The term "halogen" refers to all forms, i.e. chlorine, bromine, fluorine and iodine, except where specifically stated. The term "lower alkyl" (either alone or in combination with other radicals) refers to straight-chain or branched hydrocarbon groups with 1-7 carbon atoms. Examples of such lower alkyl groups are methyl, ethyl, isopropyl, tert.butyl and the like. The term "aryl", as used in the following, refers to phenyl groups, substituted phenyl groups, e.g. lower alkyl-phenyl, such as tolyl and the like.
Fremgangsmåten ifolge oppfinnelsen består i at man behandler en forbindelse med den generelle formel hvor B, , R2og R^har foran angitte betydning og X betyr en arylsulfonyl-, lavere alkylsulfonyl-eller en lavere alkanoylgruppe, The method according to the invention consists in treating a compound with the general formula where B, , R 2 and R 2 have the above meaning and X means an arylsulfonyl, lower alkylsulfonyl or a lower alkanoyl group,
med en base i nærvær av et inert organisk opplosningsmiddel. with a base in the presence of an inert organic solvent.
I det franske patent nr. 1.405.699 beskrives fremstillingen av forbindelser med formel I, hvor B betyr karbonyl, ved oksyda-sjon av tilsvarende 1,2,3,4-tetrahydro-derivater. Denne fremgangsmåte er dog bare anvendelig på 1-usubstituerte forbindelser. Hvis en 1-alkyl-substituert forbindelse onskes, må denne alkylgruppe innfores etterpå. Ifolge oppfinnelsen kan også 1-substituerte forbindelser oppnås, hvorved utbyttet på disse forbindelser dessuten forbedres vesentlig. French patent no. 1,405,699 describes the preparation of compounds of formula I, where B means carbonyl, by oxidation of corresponding 1,2,3,4-tetrahydro derivatives. However, this method is only applicable to 1-unsubstituted compounds. If a 1-alkyl-substituted compound is desired, this alkyl group must be introduced afterwards. According to the invention, 1-substituted compounds can also be obtained, whereby the yield of these compounds is also significantly improved.
Det amerikanske patent nr. 3.243.427 beskriver forbindelser med formel I, hvor B betyr metylen, såvel som metoder for disses fremstilling. En metode omfatter reduksjonen av et tilsvarende benzodiazepin-2-on, hvorved dog i stor grad også den tilsvarende 1,2,3,4-tetrahydroforbindelse faller ut som ikke ytterligere anvendelig biprodukt. Foreliggende oppfinnelse sikrer nå en mulighet for viderebearbeidelse av disse biprodukter til de onskede forbindelser med formel I. Den ytterligere i dette patentskrift beskrevne omsetning av 2-aminobenzofenon med etylenimin og avsvovlingen av et tilsvarende 1,4-benzodiazepin-2-tion har likeledes ulemper, hvorved på den ene side anvendelsen av det meget giftige etylenimin, på den annen side den alltid samtidig med avsvovlingen med Raney-nikkel inntredende dehalo- genering av en halogensubstituent i 5-fenylringen er å anse som uonsket. Reaksjonen av et 2-halogenzofenon med etylendiamin har den ulempe at bare i 1-stilling usubstituerte forbindelser oppnås, hvorved, hvis 1-substituerte derivater er onsket, en etterfolgende alkylering må skje, hvorved utbyttet reduseres betrak-telig. Reaksjonen av et 2-amino-benzofenon med et p-acylamino-alkylhalogenid og etterfolgende hydrolyse av beskyttelsesgrup-pen har endelig den ulempe at alkyleringen av anilinnitrogen-atomet, for det tilfellet at 1-substituerte forbindelser er onsket, forloper med meget dårlige utbytter. Den etterfolgende alkylering reduserer, som allerede nevnt, utbyttet likeledes vesentlig. US Patent No. 3,243,427 describes compounds of formula I, where B is methylene, as well as methods for their preparation. One method involves the reduction of a corresponding benzodiazepine-2-one, whereby, however, to a large extent the corresponding 1,2,3,4-tetrahydro compound also falls out as a by-product that is not further applicable. The present invention now ensures an opportunity for further processing of these by-products into the desired compounds of formula I. The further reaction described in this patent document of 2-aminobenzophenone with ethyleneimine and the desulphurisation of a corresponding 1,4-benzodiazepine-2-thione also have disadvantages, whereby on the one hand the use of the highly toxic ethyleneimine, on the other hand the dehalogenation of a halogen substituent in the 5-phenyl ring, which always occurs simultaneously with the desulphurisation with Raney nickel, is to be considered undesirable. The reaction of a 2-halogenophenone with ethylenediamine has the disadvantage that only in the 1-position unsubstituted compounds are obtained, whereby, if 1-substituted derivatives are desired, a subsequent alkylation must take place, whereby the yield is reduced considerably. The reaction of a 2-amino-benzophenone with a p-acylamino-alkyl halide and subsequent hydrolysis of the protecting group finally has the disadvantage that the alkylation of the aniline nitrogen atom, in the case that 1-substituted compounds are desired, proceeds with very poor yields. The subsequent alkylation, as already mentioned, also significantly reduces the yield.
Som sagt gjennomfores fremgangsmåten ifolge oppfinnelsen i nærvær av en base og et inert organisk opplosningsmiddel. Kravene, som er stilt til basen, består utelukkende i at den bevirker omdannelsen av en forbindelse med formel II til den tilsvarende forbindelse med formel I. Eksempler på slike baser er lavere alkalialkylater, som natriummetoksyd, kaliumtertiærbutoksyd og lignende, alkalihydrider, som natriumhydrid; vandige alkali-hydroksyder, som vandig natriumhydroksyd og vandig kaliumhydroksyd og lignende kan også anvendes med fordel, når X er arylsulfonyl eller alkylsulfonyl. Et eller annet vanlig disponibelt inert organisk opplosningsmiddel kan anvendes ved omdannelsen av forbindelser med formel II til de tilsvarende forbindelser med formel I. Som eksempler skal nevnes: dimetylformamid, dimetylsulfoksyd, tetrahydrofuran og lignende. Temperatur og trykk er ingen kritiske faktorer ved denne omdannelse. Det ble dog fastslått at temperaturer mellom ca. 0° og ca. 80°, hensiktsmessig mellom ca. 25° og ca. 80° er fordelaktig, da de sikrer hoye utbytter av det onskede sluttprodukt. As said, the method according to the invention is carried out in the presence of a base and an inert organic solvent. The requirements set for the base consist exclusively in that it effects the conversion of a compound of formula II into the corresponding compound of formula I. Examples of such bases are lower alkali alkylates, such as sodium methoxide, potassium tertiary butoxide and the like, alkali hydrides, such as sodium hydride; aqueous alkali hydroxides, such as aqueous sodium hydroxide and aqueous potassium hydroxide and the like can also be used with advantage when X is arylsulfonyl or alkylsulfonyl. One or another commonly available inert organic solvent can be used in the conversion of compounds of formula II to the corresponding compounds of formula I. Examples include: dimethylformamide, dimethylsulfoxide, tetrahydrofuran and the like. Temperature and pressure are not critical factors in this transformation. However, it was determined that temperatures between approx. 0° and approx. 80°, suitable between approx. 25° and approx. 80° is advantageous, as they ensure high yields of the desired end product.
Når man fra en forbindelse med formel II, hvor B betyr en karbonylgruppe, med én base fremstiller en tilsvarende forbindelse med formel I, hvor B betyr en karbonylgruppe, så fastslås det at som mellomprodukt opptrer en forbindelse med formel When a corresponding compound of formula I, where B denotes a carbonyl group, is prepared with one base from a compound of formula II, where B denotes a carbonyl group, it is established that a compound of formula appears as an intermediate product
hvor ^, R2 og har foran angitte betydning. where ^, R 2 and have the above meaning.
Den kan med eller uten isolering fra reaksjonsmediet, hvor den oppnås, ved behandling med en base overfores til den tilsvarende forbindelse med formel I. It can, with or without isolation from the reaction medium, where it is obtained, be transferred to the corresponding compound of formula I by treatment with a base.
Fra det foranstående folger at man kan omsette en forbindelse med formel II, hvor B betyr en karbonylgruppe, med en base tilsvarende de foranstående angivelser i et inert organisk opplosningsmiddel og avbryter reaksjonen etter dannelse av en forbindelse med formel III. Denne forbindelse med formel III kan deretter omsettes med en base, fortrinnsvis i nærvær av et polart opplosningsmiddel, som vann, en lavere alkano1, f.eks. etanol eller lignende, idet denne base kan være identisk med den forst anvendte base eller forskjellig fra denne, hvorved man endelig oppnår en forbindelse med formel I, hvor B betyr en karbonylgruppe. På den annen side er det også mulig å omsette en forbindelse med formel II, hvor B er en karbonylgruppe, med en base inntil dannelse av forbindelsen med formel I, uten at man avbryter reaksjonen eller isolerer mellomproduktet med formel III. For disse variasjoner er det redegjort i eksemp-lene. Isolasjonen av en forbindelse med formel III oppnår man på enkel måte, når man anvender et vannfritt medium som reak-sjonsmedium. From the foregoing it follows that one can react a compound of formula II, where B means a carbonyl group, with a base corresponding to the above indications in an inert organic solvent and interrupt the reaction after formation of a compound of formula III. This compound of formula III can then be reacted with a base, preferably in the presence of a polar solvent, such as water, a lower alkano1, e.g. ethanol or the like, as this base may be identical to the first base used or different from this, whereby a compound of formula I is finally obtained, where B means a carbonyl group. On the other hand, it is also possible to react a compound of formula II, where B is a carbonyl group, with a base until the compound of formula I is formed, without interrupting the reaction or isolating the intermediate product of formula III. These variations are explained in the examples. The isolation of a compound of formula III is achieved in a simple way, when an anhydrous medium is used as reaction medium.
Fremstillingen av forbindelser med formel II kan bevirkes ved omsetning av en forbindelse med den generelle formel The preparation of compounds of formula II can be effected by reacting a compound of the general formula
hvor B, , R2og R^har foran angitte betydning, where B, , R2 and R^ have the above meaning,
med et arylsulfonylhalogenid, et lavere alkylsulfonylhalogenid eller et middel som innforer en lavere alkanoylgruppe. Eksempler på arylsulfonylhalogenider, som kan anvendes for dette formål, er tosylhalogenider, som p-toluensulfonylklorid og benzen-sulfonylklorid. Egnede lavere alkylsulfonylhalogenider er with an arylsulfonyl halide, a lower alkylsulfonyl halide or an agent introducing a lower alkanoyl group. Examples of arylsulfonyl halides, which can be used for this purpose, are tosyl halides, such as p-toluenesulfonyl chloride and benzenesulfonyl chloride. Suitable lower alkylsulfonyl halides are
f.eks. mesylhalogenider, som metansulfonylklorid. Egnede mid-ler som innforer lavere alkanoylgrupper er f.eks. eddiksyreanhydrid, acetylklorid og lignende. Hensiktsmessig anvender man for denne fremstilling av forbindelser med formel II arylsulfonylhalogenider og lavere alkylsulfonylhalogenider. Spesielt foretrukket er tosylklorid og mesylklorid. e.g. mesyl halides, such as methanesulfonyl chloride. Suitable agents which introduce lower alkanoyl groups are e.g. acetic anhydride, acetyl chloride and the like. Appropriately, arylsulfonyl halides and lower alkylsulfonyl halides are used for this preparation of compounds of formula II. Particularly preferred are tosyl chloride and mesyl chloride.
Fremstillingen av forbindelser med formel II gjennomfores hensiktsmessig i nærvær av et inert organisk opplosningsmiddel, som en alkanol, f.eks. etanol, metanol, en eter, som dietyleter eller tetrahydrofuran, dimetylformamid, pyridin, et tertiært amin, som tertiær butylamin eller trietylamin og lignende. The preparation of compounds of formula II is conveniently carried out in the presence of an inert organic solvent, such as an alkanol, e.g. ethanol, methanol, an ether, such as diethyl ether or tetrahydrofuran, dimethylformamide, pyridine, a tertiary amine, such as tertiary butylamine or triethylamine and the like.
Det er hensiktsmessig å sorge for en syreakseptor i reaksjons-miljo til å oppta den dannede saltsyre, som danner seg ved anvendelsen av et halogenid som reagens. Egnede syreakseptorer er tertiære aminer, pyridin og lignende. I en foretrukken ut-fbreisesform anvender man syreakseptoren i stort overskudd, idet den tjener to formål, for det forste som opplosningsmiddel og for det annet som syreakseptor. Også for dette formål er pyridin foretrukket. Temperatur og trykk er ikke kritisk ved denne•fremstilling av forbindelser med formel 11$hensiktsmessig arbeider man ved ca. romtemperatur eller over. It is appropriate to provide an acid acceptor in the reaction environment to absorb the formed hydrochloric acid, which is formed when a halide is used as a reagent. Suitable acid acceptors are tertiary amines, pyridine and the like. In a preferred form of expansion, the acid acceptor is used in large excess, as it serves two purposes, firstly as a solvent and secondly as an acid acceptor. Also for this purpose, pyridine is preferred. Temperature and pressure are not critical in this • preparation of compounds with formula 11 $ expediently work at approx. room temperature or above.
De folgende eksempler anskueliggjor fremgangsmåten ifolge oppfinnelsen. Alle temperaturer er angitt i Celsiusgrader. The following examples illustrate the method according to the invention. All temperatures are given in degrees Celsius.
EKSEMPEL 1 EXAMPLE 1
En opplosning av 3,0 g (0,007 mol) 7-klor-2,3,4,5-tetrahydro-l-metyl-5-fenyl-4-(p-toluensulfonyl)-1H-1,4-benzodiazepin i 35 ml torr N,N-dimetylformamid behandles med 0,3 g (0,008 mol) av en 60 %{ iq natriumhydriddispersjon i en mineralolje. Reaksjonsblandingen rores ved romtemperatur i 2 timer og står så A solution of 3.0 g (0.007 mol) of 7-chloro-2,3,4,5-tetrahydro-1-methyl-5-phenyl-4-(p-toluenesulfonyl)-1H-1,4-benzodiazepine in 35 ml of dry N,N-dimethylformamide is treated with 0.3 g (0.008 mol) of a 60%{iq sodium hydride dispersion in a mineral oil. The reaction mixture is stirred at room temperature for 2 hours and then allowed to stand
til henstand i 48 timer. Reaksjonsblandingen helles i 100 ml vann og ekstraheres to ganger hver gang med 75 ml diklormetan. Diklormetanekstraktene forenes, vaskes tre ganger hver gang med 200 ml vann og en gang med lOO ml mettet koksaltopplosning, torkes over vannfritt natriumsulfat, filtreres og inndampes til torrhet. Den dannede gule olje opploses i 30 ml absolutt etanol og behandles med 1,2 ml av en 5,56-n opplosning av hydrogen-klorid i etanol. Etanolen avdampes og den tilbakeblivende olje krystalliseres fra en blanding av isopropanol og eter, hvorved man oppnår 7-klor-2,3-dihydro-l-metyl-5-fenyl-lH-1,4-benzodiazepin- hy droklorid i form av gule prismer med smeltepunkt 240 - 250°. for a grace period of 48 hours. The reaction mixture is poured into 100 ml of water and extracted twice each time with 75 ml of dichloromethane. The dichloromethane extracts are combined, washed three times each time with 200 ml of water and once with 100 ml of saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered and evaporated to dryness. The yellow oil formed is dissolved in 30 ml of absolute ethanol and treated with 1.2 ml of a 5.56-n solution of hydrogen chloride in ethanol. The ethanol is evaporated and the remaining oil is crystallized from a mixture of isopropanol and ether, whereby 7-chloro-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepine hydrochloride is obtained in the form of yellow prisms with melting point 240 - 250°.
Utgangsmaterialet kan fremstilles på folgende måte: The starting material can be produced in the following way:
En opplosning av 14,0 g (0,051 mol) 7-klor-l-metyl-5-fenyl-2,3,4,5-tetrahydro-lH-l,4-benzodiazepin i 50 ml pyridin behandles ved tilbakelopstemperatur med en opplosning av 11,7 g (0,0615 mol) p-toluensulfonylklorid i 50 ml pyridin (tilset-ningstid 20 minutter) og oppvarmes så i 1,5 timer under tilbakelop. Den varme reaksjonsblanding helles i 500 ml vann, hvorved en svart olje skiller seg ut. Vannet avdekanteres, og oljen opploses i 200 ml diklormetan. Diklormetanopplosningen vaskes tre ganger hver gang med 400 ml vann og en gang med 100 ml mettet koksaltopplosning, torkes over vannfritt natriumsulfat, filtreres og inndampes nesten til torrhet. Man tilsetter benzen og inndamper oppløsningen ennå en gang, hvorved man oppnår en mork olje. Den tilbakeblivende olje opploses i et lite volum benzen og filtreres gjennom et skikt Florisil, som man har fuktet med heksan. Man oppnår en svak gul opplosning etter fortsatt eluering med benzen. Oppløsningen inndampes deretter til en olje. Etter krystallisasjon fra eter/heksan oppnår man 7-klor-2,3,4,5-tetrahydro-l-metyl-5-fenyl-4-(p-toluensulfonyl)-1H-1,4-benzodiazepin i form av hvite krystaller med smeltepunkt 110 - 117°. Etter omkrystallisasjonen fra diklormetan/heksan smelter produktet ved 127 - 130°. A solution of 14.0 g (0.051 mol) of 7-chloro-1-methyl-5-phenyl-2,3,4,5-tetrahydro-1H-1,4-benzodiazepine in 50 ml of pyridine is treated at reflux temperature with a solution of 11.7 g (0.0615 mol) of p-toluenesulfonyl chloride in 50 ml of pyridine (addition time 20 minutes) and then heated for 1.5 hours under reflux. The hot reaction mixture is poured into 500 ml of water, whereby a black oil separates. The water is decanted off, and the oil is dissolved in 200 ml of dichloromethane. The dichloromethane solution is washed three times each time with 400 ml of water and once with 100 ml saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered and evaporated almost to dryness. Benzene is added and the solution is evaporated once more, whereby a dark oil is obtained. The remaining oil is dissolved in a small volume of benzene and filtered through a layer of Florisil, which has been moistened with hexane. A faint yellow solution is obtained after continued elution with benzene. The solution is then evaporated to an oil. After crystallization from ether/hexane, 7-chloro-2,3,4,5-tetrahydro-1-methyl-5-phenyl-4-(p-toluenesulfonyl)-1H-1,4-benzodiazepine is obtained in the form of white crystals with melting point 110 - 117°. After recrystallization from dichloromethane/hexane, the product melts at 127 - 130°.
EKSEMPEL 2 EXAMPLE 2
En opplosning av 4,0 g (0,009 mol) 7-klor-l,3,4,5-tetrahydro-1-metyl-5-fenyl-4-(p-toluensulfonyl)-2H-1,4-benzodiazepin-2-on i 35 ml N,N-dimetylformamid behandles med 0,4 g (0,01 mol) av en 60 %'ig natriumhydriddispersjon i en mineralolje. Den så-ledes erholdte reaksjonsblanding lar man stå til henstand i 55 timer ved romtemperatur og heller deretter i 100 ml vann, som man så ekstraherer med 100 ml diklormetan. Diklormetanekstraktet vaskes tre ganger hver gang med 100 ml vann og med mettet koksaltopplosning, torkes over vannfritt natriumsulfat og inndampes til torrhet. Den erholdte olje krystalliseres fra aceton/heksan og gir 7-klor-l,3-dihydro-l-metyl-5-fenyl-2H-1,4-benzodiazepin-2-on i form av hvite prismer med smeltepunkt 127 - 130°. A solution of 4.0 g (0.009 mol) 7-chloro-1,3,4,5-tetrahydro-1-methyl-5-phenyl-4-(p-toluenesulfonyl)-2H-1,4-benzodiazepine-2 -one in 35 ml of N,N-dimethylformamide is treated with 0.4 g (0.01 mol) of a 60% sodium hydride dispersion in a mineral oil. The reaction mixture thus obtained is allowed to stand for 55 hours at room temperature and then poured into 100 ml of water, which is then extracted with 100 ml of dichloromethane. The dichloromethane extract is washed three times each time with 100 ml of water and saturated sodium chloride solution, dried over anhydrous sodium sulfate and evaporated to dryness. The obtained oil is crystallized from acetone/hexane and gives 7-chloro-1,3-dihydro-1-methyl-5-phenyl-2H-1,4-benzodiazepine-2-one in the form of white prisms with a melting point of 127 - 130° .
Utgangsmaterialet kan fremstilles på folgende måte: The starting material can be produced in the following way:
En opplosning av 50,0 g (0,184 mol) 7-klor-l,3,4,5-tetrahydro-5-fenyl-2H-1,4-benzodiazepin-2-on i 100 ml pyridin oppvarmes under tilbakelop. En varm opplosning av 42,0 g (0,22 mol) p-toluensulfonylklorid i 100 ml pyridin tilsettes i lopet av 20 minutter til reaksjonsblåndingen. Reaksjonsblåndingen oppvarmes deretter i 1,5 timer under tilbakelop og helles så i liter vann. Man rorer inntil et brunt bunnfall har dannet seg. Dette skilles fra ved filtrering og vaskes fire ganger hver gang med 500 ml vann, to ganger hver gang med 300 ml etanol og med 200 ml eter. Bunnfallet omkrystalliseres deretter fra en blanding av kloroform og etanol, hvorved man oppnår 7-klor-1,3,4,5-tetrahydro-5-fenyl-4-(p-toluensulfonyl)-2H-1,4-benzodiazepin- 2-on i form av hvite prismer med smeltepunkt 244 - 250°. Ved omkrystallisasjon fra kloroform/etanol oppnår man hvite prismer med smeltepunkt 246 - 25 2°. A solution of 50.0 g (0.184 mol) of 7-chloro-1,3,4,5-tetrahydro-5-phenyl-2H-1,4-benzodiazepine-2-one in 100 ml of pyridine is heated under reflux. A hot solution of 42.0 g (0.22 mol) of p-toluenesulfonyl chloride in 100 ml of pyridine is added over 20 minutes to the reaction mixture. The reaction mixture is then heated for 1.5 hours under reflux and then poured into liters of water. Stir until a brown precipitate has formed. This is separated by filtration and washed four times each time with 500 ml of water, twice each time with 300 ml of ethanol and with 200 ml of ether. The precipitate is then recrystallized from a mixture of chloroform and ethanol, whereby 7-chloro-1,3,4,5-tetrahydro-5-phenyl-4-(p-toluenesulfonyl)-2H-1,4-benzodiazepine-2- on in the form of white prisms with a melting point of 244 - 250°. By recrystallization from chloroform/ethanol, white prisms with a melting point of 246 - 25 2° are obtained.
En opplosning av 10 g (0,0 234 mol) 7-klor-l,3,4,5-tetrahydro-5-fenyl-4-(p-toluensulfonyl)-2H-1,4-benzodiazepin-2-on i 65 ml N,N-dimetylformamid behandles med en opplosning av natriummetoksyd i metanol (0,028 mol NaOCH^) ved romtemperatur. Den erholdte gule opplosning rores i 20 minutter, avkjoles til 5° og behandles så med 2,9 ml (0,047 mol) metyljodid. Den erholdte reaksjonsblanding rores så i 10 minutter ved 5 - 10° og så i 1,5 timer ved romtemperatur. Deretter heller man reaksjonsblandingen i 200 ml vann og ekstraherer med 200 ml diklormetan .-Diklormetanet vaskes tre ganger hver gang med 300 ml vann og med mettet koksaltopplosning, torkes over vannfritt natriumsulfat og inndampes til torrhet. Den erholdte gule olje omkrystalliseres fra diklormetan/eter og gir 7-klor-l,3,4,5-tetrahydro-l-metyl-5-fenyl-4-(p-toluensulfonyl)-2H-1,4-benzodiazepin-2-on i form av hvite nåler med smeltepunkt 260 - 262°. A solution of 10 g (0.0 234 mol) of 7-chloro-1,3,4,5-tetrahydro-5-phenyl-4-(p-toluenesulfonyl)-2H-1,4-benzodiazepine-2-one in 65 ml of N,N-dimethylformamide is treated with a solution of sodium methoxide in methanol (0.028 mol NaOCH^) at room temperature. The yellow solution obtained is stirred for 20 minutes, cooled to 5° and then treated with 2.9 ml (0.047 mol) of methyl iodide. The resulting reaction mixture is then stirred for 10 minutes at 5 - 10° and then for 1.5 hours at room temperature. The reaction mixture is then poured into 200 ml of water and extracted with 200 ml of dichloromethane. The dichloromethane is washed three times each time with 300 ml of water and with saturated sodium chloride solution, dried over anhydrous sodium sulfate and evaporated to dryness. The yellow oil obtained is recrystallized from dichloromethane/ether to give 7-chloro-1,3,4,5-tetrahydro-1-methyl-5-phenyl-4-(p-toluenesulfonyl)-2H-1,4-benzodiazepine-2 -on in the form of white needles with a melting point of 260 - 262°.
EKSEMPEL 3 EXAMPLE 3
En opplosning av 19,5 g (0,0456 mol) 7-klor-l,3,4,5-tetrahydro-5-fenyl-4-(p-toluensulfonyl)-2H-1,4-benzodiazepin-2-on i 150 ml torr benzen behandles med 4,0 g (0,10 mol) av en 60 %'ig natriumhydrid-dispersjon i en mineralolje. Reaksjonsblåndingen oppvarmes i 20 timer under tilbakelop og helles så i 300 ml vann. Man tilsetter saltsyre inntil pH-verdien utgjor ca. 7. Skiktene skilles og det vandige skikt ekstraheres to ganger hver gang med 1 liter diklormetan. De organiske skikt forenes, vaskes tre ganger hver gang med 500 ml vann og med 100 ml mettet koksaltopplosning, torkes over vannfritt natriumsulfat, filtreres og inndampes til torrhet. Den erholdte olje krystalliseres fra en blanding av kiklormetan/heksan og gir 7-klor-1,5-dihydro-5-fenyl-2H-l,4-benzodiazepin-2-on i form av hvite A solution of 19.5 g (0.0456 mol) of 7-chloro-1,3,4,5-tetrahydro-5-phenyl-4-(p-toluenesulfonyl)-2H-1,4-benzodiazepine-2-one in 150 ml of dry benzene is treated with 4.0 g (0.10 mol) of a 60% sodium hydride dispersion in a mineral oil. The reaction mixture is heated for 20 hours under reflux and then poured into 300 ml of water. Hydrochloric acid is added until the pH value is approx. 7. The layers are separated and the aqueous layer is extracted twice each time with 1 liter of dichloromethane. The organic layers are combined, washed three times each time with 500 ml of water and with 100 ml of saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered and evaporated to dryness. The oil obtained is crystallized from a mixture of cyclochloromethane/hexane and gives 7-chloro-1,5-dihydro-5-phenyl-2H-1,4-benzodiazepine-2-one in the form of white
prismer med smeltepunkt 20 2 - 210°. prisms with melting point 20 2 - 210°.
En opplosning av 0,5 g (0,002 mol) 7-klor-l,5-dihydro-5-fenyl-2H-1,4-benzodiazepin-2-on i 15 ml N,N-dimetylformamid behandles med en opplosning av natriummetoksyd i metanol (0,011 mol NaOCH^). Reaksjonsblåndingen står til henstand i 1/2 time ved romtemperatur og helles så i 50 ml vann. Man tilsetter salt- A solution of 0.5 g (0.002 mol) of 7-chloro-1,5-dihydro-5-phenyl-2H-1,4-benzodiazepine-2-one in 15 ml of N,N-dimethylformamide is treated with a solution of sodium methoxide in methanol (0.011 mol NaOCH^). The reaction mixture is allowed to stand for 1/2 hour at room temperature and is then poured into 50 ml of water. Salt is added
syre inntil pH-verdien når ca. 7 og ekstraherer deretter reak-sjonsbl åndingen to ganger hver gang med 40 ml diklormetan. De forente diklormetanekstrakter vaskes tre ganger hver gang med 60 ml vann og en gang med 30 ml mettet koksaltopplosning, tor- acid until the pH value reaches approx. 7 and then extracts the reaction mixture twice each time with 40 ml of dichloromethane. The combined dichloromethane extracts are washed three times each time with 60 ml of water and once with 30 ml of saturated sodium chloride solution, dried
kes over vannfritt natriumsulfat, filtreres og inndampes til torrhet. Den tilbakeblivende olje krystalliseres fra en blanding av diklormetan og heksan og gir 7-klor-l,3-dihydro-5-fenyl-2H-l,4-benzodiazepin-2-on i form av hvite prismer med smeltepunkt 215 - 221°. kes over anhydrous sodium sulfate, filtered and evaporated to dryness. The remaining oil is crystallized from a mixture of dichloromethane and hexane and gives 7-chloro-1,3-dihydro-5-phenyl-2H-1,4-benzodiazepine-2-one in the form of white prisms with a melting point of 215 - 221°.
EKSEMPEL 4 EXAMPLE 4
En opplosning av 5,0 g (0,0117 mol) 7-klor-l,3,4,5-tetrahydro-5-fenyl-4-(p-toluensulfonyl)-2H-1,4-benzodiazepin-2-on i 35 ml N,N-dimetylformamid behandles med 1,0 g (0,026 mol) av en A solution of 5.0 g (0.0117 mol) of 7-chloro-1,3,4,5-tetrahydro-5-phenyl-4-(p-toluenesulfonyl)-2H-1,4-benzodiazepine-2-one in 35 ml of N,N-dimethylformamide is treated with 1.0 g (0.026 mol) of a
60 %'ig natriumhydrid-dispersjon i en mineralolje. Man rorer den brunfargede opplosning i 1 time ved romtemperatur og lar den deretter stå til henstand i 48 timer. Reaksjonsblåndingen helles så i 200 ml vann og ekstraheres med 100 ml diklormetan. Diklormetanekstraktene vaskes tre ganger hver gang med 500 ml vann og med 100 ml mettet koksaltopplosning, torkes over vannfritt natriumsulfat og inndampes til torrhet. Den erholdte olje opploses i diklormetan, og den erholdte opplosning konsentreres og avkjoles. Det erholdte konsentrat filtreres og omkrystalliseres fra aceton, hvorved man oppnår 7-klor-l,3-di-hydro-5-fenyl-2H-1,4-benzodiazepin-2-on i form av hvite pris- 60% sodium hydride dispersion in a mineral oil. The brown solution is stirred for 1 hour at room temperature and then left to stand for 48 hours. The reaction mixture is then poured into 200 ml of water and extracted with 100 ml of dichloromethane. The dichloromethane extracts are washed three times each time with 500 ml of water and with 100 ml of saturated sodium chloride solution, dried over anhydrous sodium sulfate and evaporated to dryness. The resulting oil is dissolved in dichloromethane, and the resulting solution is concentrated and cooled. The resulting concentrate is filtered and recrystallized from acetone, whereby 7-chloro-1,3-dihydro-5-phenyl-2H-1,4-benzodiazepine-2-one is obtained in the form of white pris-
mer med smeltepunkt 212 - 214°. more with melting point 212 - 214°.
EKSEMPEL 5 EXAMPLE 5
En opplosning av 3,0 g (0,007 mol) 7-klor-l,3,4,5-tetrahydroT5-fenyl-4-(p-toluensulfonyl)-2H-1,4-benzodiazepin-2-on i 35 ml N,N-dimetylformamid avkjoles til 5° og behandles med en opplos ning av natriummetoksyd i metanol (0,0154 mol NaOCH^). Reak-sjonsbl åndingen lar man stå til henstand i 79 timer og heller så i 200 ml vann. Man bringer pH-verdien med saltsyre på ca. 7 og ekstraherer så opplosningen med 100 ml diklormetan. Det organiske skikt avskilles og vaskes tre ganger hver gang med 300 ml vann og med 100 ml mettet koksaltopplosning, torkes over vannfritt natriumsulfat, filtreres og inndampes til torrhet. Den erholdte olje krystalliserer man fra en blanding av diklormetan og heksan og oppnår 7-klor-l,3-dihydro-5-fenyl-2H-1,4-benzodiazepin-2-on i form av hvite prismer med smeltepunkt 213 - 217°. A solution of 3.0 g (0.007 mol) of 7-chloro-1,3,4,5-tetrahydroT5-phenyl-4-(p-toluenesulfonyl)-2H-1,4-benzodiazepine-2-one in 35 ml of N ,N-dimethylformamide is cooled to 5° and treated with a solution of sodium methoxide in methanol (0.0154 mol NaOCH^). The reaction mixture is allowed to stand for 79 hours and then in 200 ml of water. The pH value is brought with hydrochloric acid to approx. 7 and then extract the solution with 100 ml of dichloromethane. The organic layer is separated and washed three times each time with 300 ml of water and with 100 ml of saturated sodium chloride solution, dried over anhydrous sodium sulphate, filtered and evaporated to dryness. The obtained oil is crystallized from a mixture of dichloromethane and hexane and 7-chloro-1,3-dihydro-5-phenyl-2H-1,4-benzodiazepine-2-one is obtained in the form of white prisms with a melting point of 213 - 217° .
EKSEMPEL 6 EXAMPLE 6
En opplosning av 3,0 g (0,007 mol) 7-klor-l,3,4,5-tetrahydro-5-fenyl-4-(p-toluensulfonyl)-2H-1,4-benzodiazepin-2-on i 35 ml N,N-dimetylformamid avkjoles til 5° og behandles med 1,7 g (0,0154 mol) kaliumtertiærbutoksyd, hvorved opplosningen blir dypgul. Man rorer reaksjonsblandingen i 1,5 timer ved 5°, lar den så oppvarmes til romtemperatur og står til henstand i 79 timer. Reaksjonsblandingen helles deretter i 200 ml vann og bringes med saltsyre på en pH-verdi på ca. 7. Deretter ekstraherer man opplosningen med 100 ml diklormetan. Diklormetan-skiktet skilles fra og vaskes fire ganger hver gang med 300 ml vann og med 100 ml mettet koksaltopplosning, torkes over vannfritt natriumsulfat, filtreres og inndampes til torrhet. Den erholdte olje krystalliserer man fra en blanding av diklormetan og heksan, hvorved man oppnår 7-klor-l,3-dihydro-5-fenyl-2H-1,4-benzodiazepin-2-on i form av hvite prismer med smeltepunkt 212 - 216°. A solution of 3.0 g (0.007 mol) of 7-chloro-1,3,4,5-tetrahydro-5-phenyl-4-(p-toluenesulfonyl)-2H-1,4-benzodiazepine-2-one in 35 ml of N,N-dimethylformamide is cooled to 5° and treated with 1.7 g (0.0154 mol) of potassium tertiary butoxide, whereby the solution becomes deep yellow. The reaction mixture is stirred for 1.5 hours at 5°, then allowed to warm to room temperature and allowed to stand for 79 hours. The reaction mixture is then poured into 200 ml of water and brought to a pH value of approx. 7. The solution is then extracted with 100 ml of dichloromethane. The dichloromethane layer is separated and washed four times each time with 300 ml of water and with 100 ml of saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered and evaporated to dryness. The obtained oil is crystallized from a mixture of dichloromethane and hexane, whereby 7-chloro-1,3-dihydro-5-phenyl-2H-1,4-benzodiazepine-2-one is obtained in the form of white prisms with a melting point of 212 - 216°.
EKSEMPEL 7 EXAMPLE 7
En opplosning av 2,0 g (0,0047 mol) 7-klor-l,3,4,5-tetrahydro-5-fenyl-4-(p-toluensulfonyl)-2H-1,4-benzodiazepin-2-on i 30 ml N,N-dimetylformamid behandles med 0,5 ml av en 0,1-n natriumhydroksydopplosning. Blandingen rores i 4 timer ved romtemperatur og står så til henstand i 55 timer. Reaksjonsblandingen helles i 100 ml vann og pH-verdien bringes på ca. 7 med saltsyre. Den erholdte opplosning ekstraheres deretter tre ganger hver gang med 50 ml diklormetan. De forente diklormetanekstrakter vaskes tre ganger hver gang med 200 ml vann og med 100 ml mettet koksaltopplosning, torkes over vannfritt natriumsulfat, filtreres og inndampes til torrhet. Den erholdte- olje krystalliseres fra en blanding av diklormetan og heksan. Deretter om-krystalliserer man to ganger fra aceton og oppnår 7-klor-l,3-dihydro-5-fenyl-2H-1,4-benzodiazepin-2-on i form av hvite prismer med smeltepunkt 211 - 214°. A solution of 2.0 g (0.0047 mol) of 7-chloro-1,3,4,5-tetrahydro-5-phenyl-4-(p-toluenesulfonyl)-2H-1,4-benzodiazepine-2-one in 30 ml of N,N-dimethylformamide is treated with 0.5 ml of a 0.1-n sodium hydroxide solution. The mixture is stirred for 4 hours at room temperature and then allowed to stand for 55 hours. The reaction mixture is poured into 100 ml of water and the pH value is brought to approx. 7 with hydrochloric acid. The solution obtained is then extracted three times each time with 50 ml of dichloromethane. The combined dichloromethane extracts are washed three times each time with 200 ml of water and with 100 ml of saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered and evaporated to dryness. The oil obtained is crystallized from a mixture of dichloromethane and hexane. It is then recrystallized twice from acetone and 7-chloro-1,3-dihydro-5-phenyl-2H-1,4-benzodiazepine-2-one is obtained in the form of white prisms with a melting point of 211 - 214°.
EKSEMPEL 8 EXAMPLE 8
En opplosning av 5,0 g (0,117 mol) 7-klor-l,3,4,5-tetrahydro-5-fenyl-4-(p-toluensulfonyl)-2H-1,4-benzodiazepin-2-on i 40 ml tetrahydrofuran behandles med 1,0 g (0,0258 mol) av en 60 %'ig dispersjon av natriumhydrid i en mineralolje. Man rorer reaksjonsblandingen forst ved romtemperatur og deretter i 5 timer ved 60°. Reaksjonsblandingen helles i 200 ml vann og ekstraheres med 100 ml diklormetan. Diklormetanekstraktene vaskes tre ganger hver gang med 300 ml vann og med 100 ml mettet koksaltopplosning, torkes over vannfritt natriumsulfat, filtreres og inndampes til torrhet. Den erholdte olje krystalliseres fra diklormetan og gir 7-klor-l,3-dihydro-5-fenyl-2H-1,4-benzodiazepin- 2-on i form av hvite prismer med smeltepunkt 210 - 214°. A solution of 5.0 g (0.117 mol) of 7-chloro-1,3,4,5-tetrahydro-5-phenyl-4-(p-toluenesulfonyl)-2H-1,4-benzodiazepine-2-one in 40 ml of tetrahydrofuran is treated with 1.0 g (0.0258 mol) of a 60% dispersion of sodium hydride in a mineral oil. The reaction mixture is stirred first at room temperature and then for 5 hours at 60°. The reaction mixture is poured into 200 ml of water and extracted with 100 ml of dichloromethane. The dichloromethane extracts are washed three times each time with 300 ml of water and with 100 ml of saturated sodium chloride solution, dried over anhydrous sodium sulphate, filtered and evaporated to dryness. The oil obtained is crystallized from dichloromethane and gives 7-chloro-1,3-dihydro-5-phenyl-2H-1,4-benzodiazepine-2-one in the form of white prisms with a melting point of 210 - 214°.
EKSEMPEL 9 EXAMPLE 9
En opplosning av 5,0 g (0,0117 mol) 7-klor-l,3,4,5-tetrahydro-5-fenyl-4-(p-toluensulfonyl)-2H-1,4-benzodiazepin-2-on i 40 ml dimetylsulfoksyd behandles med 1,0g (0,0258 mol) av en 60 %'ig dispersjon av natriumhydrid i en mineralolje. Reaksjonsblandingen rores i 1 time ved romtemperatur og står så til henstand i 40 timer, hvorved opplosningen blir ravfarget. Reaksjonsblandingen helles så i 150 ml vann og ekstraheres med 100 ml diklormetan. Diklormetanekstraktet vaskes tre ganger hver gang med 300 ml vann og med 100 ml mettet koksaltopplosning, torkes over vannfritt natriumsulfat, filtreres og inndampes til torrhet. A solution of 5.0 g (0.0117 mol) of 7-chloro-1,3,4,5-tetrahydro-5-phenyl-4-(p-toluenesulfonyl)-2H-1,4-benzodiazepine-2-one in 40 ml of dimethyl sulfoxide is treated with 1.0 g (0.0258 mol) of a 60% dispersion of sodium hydride in a mineral oil. The reaction mixture is stirred for 1 hour at room temperature and then allowed to stand for 40 hours, whereby the solution becomes amber colored. The reaction mixture is then poured into 150 ml of water and extracted with 100 ml of dichloromethane. The dichloromethane extract is washed three times each time with 300 ml of water and with 100 ml of saturated sodium chloride solution, dried over anhydrous sodium sulphate, filtered and evaporated to dryness.
Den erholdte olje krystalliseres fra en blanding av diklormetan og heksan, hvorved man oppnår 7-klor-l,3-dihydro-5-fenyl-2H-1,4-benzodiazepin-2-on i form av hvite prismer med smeltepunkt 210 - 214°. The obtained oil is crystallized from a mixture of dichloromethane and hexane, whereby 7-chloro-1,3-dihydro-5-phenyl-2H-1,4-benzodiazepine-2-one is obtained in the form of white prisms with a melting point of 210 - 214 °.
EKSEMPEL 10 EXAMPLE 10
En opplosning av 3,0 g (0,0086 mol) 7-klor-l,3,4,5-tetrahydro-4- metansulfonyl-5-fenyl-2H-1,4-benzodiazepin-2-on i 30 ml N,N-dimetylformamid behandles med 0,76 g (0,019 mol) av en 60 %'ig natriumhydrid-dispersjon i en mineralolje. Reaksjonsblandingen rores i 2 timer ved romtemperatur og så i 4 timer ved 45°. Etter avkjolingen til romtemperatur helles reaksjonsblandingen i 200 ml vann og innstiller pH-verdien på ca. 7 med saltsyre. Den erholdte blanding ekstraheres to ganger hver gang med 75 ml diklormetan. De forente diklormetanekstrakter vaskes tre ganger hver gang med 300 ml vann og med 100 ml mettet koksaltopplosning, torkes over vannfritt natriumsulfat, filtreres og inndampes til torrhet. Den erholdte olje krystalliseres fra en blanding av diklormetan og heksan.Moderlutene inndampes til torrhet og krystalliseres fra en blanding av diklormetan og heksan, hvorved man oppnår 7-klor-l,3-dihydro-5-fenyl-2H-1,4-benzodiazepin-2-on i form av hvite prismer med smeltepunkt 210 - 214°. A solution of 3.0 g (0.0086 mol) of 7-chloro-1,3,4,5-tetrahydro-4-methanesulfonyl-5-phenyl-2H-1,4-benzodiazepine-2-one in 30 ml of N ,N-dimethylformamide is treated with 0.76 g (0.019 mol) of a 60% sodium hydride dispersion in a mineral oil. The reaction mixture is stirred for 2 hours at room temperature and then for 4 hours at 45°. After cooling to room temperature, the reaction mixture is poured into 200 ml of water and the pH value is adjusted to approx. 7 with hydrochloric acid. The resulting mixture is extracted twice each time with 75 ml of dichloromethane. The combined dichloromethane extracts are washed three times each time with 300 ml of water and with 100 ml of saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered and evaporated to dryness. The oil obtained is crystallized from a mixture of dichloromethane and hexane. The mother liquors are evaporated to dryness and crystallized from a mixture of dichloromethane and hexane, whereby 7-chloro-1,3-dihydro-5-phenyl-2H-1,4-benzodiazepine is obtained -2-one in the form of white prisms with a melting point of 210 - 214°.
Utgangsmaterialet kan fremstilles på folgende måte: The starting material can be produced in the following way:
En suspensjon av 50 g (0,183 mol) 7-klor-l,3,4,5-tetrahydro-5-fenyl-2H-1,4-benzodiazepin-2-on i 380 ml pyridin avkjoles til 5° og behandles med 15,6 ml (0,201 mol) metansulfonylklorid i 15 minutter. Den klare gule opplosning oppvarmes til 28° og rores så ved romtemperatur i 2,5 timer. Reaksjonsblandingen helles deretter i 1,3 liter vann og rores kraftig. Det kry-stalline bunnfall filtreres fra og vaskes fire ganger hver gang med 300 ml vann og to ganger hver gang med 200 ml eter. Ved omkrystallisasjon av reaksjonsproduktet fra en blanding av kloroform og etanol oppnår man 7-klor-l,3,4,5-tetrahydro-4-metansulfonyl-5-fenyl-2H-1,4-benzodiazepin-2-on som hvite prismer med smeltepunkt 203 - 206°. A suspension of 50 g (0.183 mol) of 7-chloro-1,3,4,5-tetrahydro-5-phenyl-2H-1,4-benzodiazepine-2-one in 380 ml of pyridine is cooled to 5° and treated with 15 .6 ml (0.201 mol) of methanesulfonyl chloride for 15 minutes. The clear yellow solution is heated to 28° and then stirred at room temperature for 2.5 hours. The reaction mixture is then poured into 1.3 liters of water and stirred vigorously. The crystalline precipitate is filtered off and washed four times each time with 300 ml of water and twice each time with 200 ml of ether. By recrystallization of the reaction product from a mixture of chloroform and ethanol, 7-chloro-1,3,4,5-tetrahydro-4-methanesulfonyl-5-phenyl-2H-1,4-benzodiazepine-2-one is obtained as white prisms with melting point 203 - 206°.
EKSEMPEL 11 EXAMPLE 11
En opplosning av 3,0 g (0,0068 mol) 7-klor-l,3,4,5-tetrahydro-5- (2-fluorfenyl)-4-(p-toluensulfonyl)-2H-1,4-benzodiazepin-2-on i 35 ml N,N-dimetylformamid behandles med 0,6 g (0,015 mol) av en 60 %'ig natriumhydrid-dispersjon i en mineralolje og rores i 19 timer ved romtemperatur. Reaksjonsblandingen helles så i 200 ml vann og pH innstilles på ca. 7 med saltsyre. Reaksjonsblandingen ekstraheres deretter to ganger med 75 ml diklormetan. De forente diklormetanekstrakter vaskes fire ganger hver gang med 600 ml vann og med lOO ml mettet koksaltopplosning, torkes over vannfritt natriumsulfat, filtreres og inndampes til torrhet. Den tilbakeblivende gule olje krystalliseres fra en blanding av diklormetan og heksan. Moderlutene inndampes deretter til torrhet og krystalliseres fra en blanding av benzen og heksan, hvorved man oppnår 7-klor-l,3-di-hydro-5-(2-fluorfenyl)-2H-1,4-benzodiazepin-2-on i form av hvite prismer med smeltepunkt 196 - 20 2°. A solution of 3.0 g (0.0068 mol) of 7-chloro-1,3,4,5-tetrahydro-5-(2-fluorophenyl)-4-(p-toluenesulfonyl)-2H-1,4-benzodiazepine -2-one in 35 ml of N,N-dimethylformamide is treated with 0.6 g (0.015 mol) of a 60% sodium hydride dispersion in a mineral oil and stirred for 19 hours at room temperature. The reaction mixture is then poured into 200 ml of water and the pH is adjusted to approx. 7 with hydrochloric acid. The reaction mixture is then extracted twice with 75 ml of dichloromethane. The combined dichloromethane extracts are washed four times each time with 600 ml of water and with 100 ml of saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered and evaporated to dryness. The remaining yellow oil is crystallized from a mixture of dichloromethane and hexane. The mother liquors are then evaporated to dryness and crystallized from a mixture of benzene and hexane, whereby 7-chloro-1,3-dihydro-5-(2-fluorophenyl)-2H-1,4-benzodiazepine-2-one is obtained in form of white prisms with melting point 196 - 20 2°.
Utgangsmaterialet kan fremstilles på folgende måte: The starting material can be produced in the following way:
En opplosning av 10,0 g (0,034 mol) 7-klor-l,3,4,5-tetrahydro-5-(2-fluorfenyl)-2H-1,4-benzodiazepin-2-on i 100 ml pyridin behandles med en opplosning av 9,5 g (0,051 mol) p-toluensulfonylklorid i 50 ml pyridin. Reaksjonsblandingen oppvarmes i 2 timer under tilbakelop og helles så i 750 ml vann. Etter roringen i 1/2 time skiller et oljeaktig bunnfall seg ut. Krystallene filtreres fra og opploses i en stor mengde diklormetan, som torkes over vannfritt natriumsulfat, filtreres og deretter konsentreres på et dampbad til et lite volum. Den erholdte opplosning avkjoles. Man oppnår 7-klor-l,3,4,5-tetrahydro-5-(2-fluorfenyl)-4-(p-toluensulfonyl)-2H-1,4-benzodiazepin- 2-on, som filtreres fra. Etter omkrystallisasjon fra en blanding av diklormetan/petroleter (kokeområde 30 - 60°) krystalliserer produktet i form av hvite prismer med smeltepunkt 242 - 243°. A solution of 10.0 g (0.034 mol) of 7-chloro-1,3,4,5-tetrahydro-5-(2-fluorophenyl)-2H-1,4-benzodiazepine-2-one in 100 ml of pyridine is treated with a solution of 9.5 g (0.051 mol) of p-toluenesulfonyl chloride in 50 ml of pyridine. The reaction mixture is heated for 2 hours under reflux and then poured into 750 ml of water. After stirring for 1/2 hour, an oily sediment separates. The crystals are filtered off and dissolved in a large amount of dichloromethane, which is dried over anhydrous sodium sulfate, filtered and then concentrated on a steam bath to a small volume. The obtained solution is cooled. 7-chloro-1,3,4,5-tetrahydro-5-(2-fluorophenyl)-4-(p-toluenesulfonyl)-2H-1,4-benzodiazepine-2-one is obtained, which is filtered off. After recrystallization from a mixture of dichloromethane/petroleum ether (boiling range 30 - 60°), the product crystallizes in the form of white prisms with a melting point of 242 - 243°.
EKSEMPEL 12 EXAMPLE 12
Til en opplosning av 1 g (3,3 mmol) 7-klor-l,2,3,5-tetrahydro-1-metyl-5-fenyl-4H-1,4-benzodiazepin-4-karboksaldehyd i 25 ml N,N-dimetylformamid tilsetter man 300 mg natriumhydrid (7,5 mmol av en 60 %'ig suspensjon i en mineralolje). Reaksjonsblandingen rores under nitrogen i 90 minutter og helles så på is. Etter smeltning av isen skilles det erholdte bunnfall fra og oppslemmes i en l-n eddiksyreopplosning. Blandingen filtreres fra, og filtratet innstilles alkalisk med fortynnet natronlut, hvorved man oppnår rå 7-klor-2,3-dihydro-l-metyl-5-fenyl-1H-1,4-benzodiazepin-hydroklorid i form av en olje, som ved ekstraksjon utvinnes med eter. For ytterligere rensning filtreres ekstraktet av en benzenopplosning ved 10 g aluminium-oksyd (aktivitet III noytral). Man inndamper filtratet og oppnår et gummilignende produkt, som man behandler med metanolisk saltsyre og eter, hvorved man oppnår 7-klor-2,3-dihydro-l-metyl-5-fenyl-lH-l,4-benzodiazepin-hydroklorid. Ved omkrystallisasjon av hydrokloridet fra metanol/eter oppnår man orangefargede krystaller med smeltepunkt 256 - 257° (lukket ror). To a solution of 1 g (3.3 mmol) of 7-chloro-1,2,3,5-tetrahydro-1-methyl-5-phenyl-4H-1,4-benzodiazepine-4-carboxaldehyde in 25 ml of N, 300 mg of sodium hydride (7.5 mmol of a 60% suspension in a mineral oil) is added to N-dimethylformamide. The reaction mixture is stirred under nitrogen for 90 minutes and then poured onto ice. After melting the ice, the precipitate obtained is separated and suspended in a l-n acetic acid solution. The mixture is filtered off, and the filtrate is made alkaline with dilute caustic soda, whereby crude 7-chloro-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepine hydrochloride is obtained in the form of an oil, which by extraction is recovered with ether. For further purification, the extract is filtered from a benzene solution through 10 g of aluminum oxide (activity III neutral). The filtrate is evaporated and a gum-like product is obtained, which is treated with methanolic hydrochloric acid and ether, whereby 7-chloro-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepine hydrochloride is obtained. On recrystallization of the hydrochloride from methanol/ether, orange-coloured crystals with a melting point of 256 - 257° (closed stirrer) are obtained.
Utgangsmaterialet kan fremstilles på folgende måte: The starting material can be produced in the following way:
En blanding av 63,8 g (0,5 mol) p-kloranilin og 114 g (0,6 mol) p-toluensulfonylklorid i 400 ml pyridin rores ved romtemperatur natten over. Deretter fjerner man det meste av pyridinet i vakuum og heller resten i 2 liter isvann og ekstraherer destil-latet med eter. Eteren ekstraheres med l-n natriumhydroksydopplosning, vandig saltsyre og vann, torkes over magnesiumsul-fat og konsentreres. Den erholdte olje omkrystalliseres fra eter og gir tosylamido-4-klorbenzen med smeltepunkt 119,5-120,5 . A mixture of 63.8 g (0.5 mol) p-chloroaniline and 114 g (0.6 mol) p-toluenesulfonyl chloride in 400 ml pyridine is stirred at room temperature overnight. Most of the pyridine is then removed under vacuum and the remainder is poured into 2 liters of ice water and the distillate is extracted with ether. The ether is extracted with 1-1 sodium hydroxide solution, aqueous hydrochloric acid and water, dried over magnesium sulphate and concentrated. The oil obtained is recrystallized from ether and gives tosylamido-4-chlorobenzene with a melting point of 119.5-120.5.
En blanding av 70,4 g (0,25 mol) tosylamido-4-klorbenzen, A mixture of 70.4 g (0.25 mol) tosylamido-4-chlorobenzene,
700 ml toluen og 0,3 mol natriummetoksyd i 200 ml metanol rores og oppvarmes i 1 time under tilbakelop. Man destillerer hoved-mengden av metanolen fra og tilsetter 47,3 ml (0,5 mol) dimetylsulfat. Man fortsetter roringen og oppvarmningen under tilbakelop i ytterligere 5 timer. Det utskilte natriumsalt opp-loser seg langsomt. Overskytende dimetylsulfat odelegges ved oppvarmning under tilbakelop i 1,5 timer med 400 ml 3-n natriumhydroksydopplosning. Fasene skilles og toluenet avdestilleres, hvorved et hvitt krystallint bunnfall blir tilbake. Ved omkrystallisasjon fra etanol oppnår man N-metyl-tosylamido-4-klor-benzen med smeltepunkt 92 - 93°. 700 ml of toluene and 0.3 mol of sodium methoxide in 200 ml of methanol are stirred and heated for 1 hour under reflux. The main amount of methanol is distilled off and 47.3 ml (0.5 mol) of dimethylsulphate is added. Stirring and heating during reflux are continued for a further 5 hours. The secreted sodium salt dissolves slowly. Excess dimethyl sulfate is decomposed by heating under reflux for 1.5 hours with 400 ml of 3-n sodium hydroxide solution. The phases are separated and the toluene is distilled off, whereby a white crystalline precipitate remains. By recrystallization from ethanol, N-methyl-tosylamido-4-chloro-benzene is obtained with a melting point of 92 - 93°.
61,5 g (0,208 mol) N-metyl-tosylamido-4-klorbenzen tilsettes til 580 ml svovelsyre (spesifikk vekt 1,74) ved 105°. Reaksjonsblandingen rores, oppvarmes til 145° og "holdes ved denne temperatur i 1 time. Etter avkjoling innstilles opplosningen sterkt alkalisk med 50 %'ig natronlut, og den organiske base ekstraheres med eter. De organiske ekstrakter torkes over kaliumhydroksyd-småkorn, konsentreres og resten destilleres i vakuum, hvorved man oppnår p-klor-N-metylanilin med kokepunkt 74 _ 75<0>ved 0,7 Torr. 61.5 g (0.208 mol) of N-methyl-tosylamido-4-chlorobenzene are added to 580 ml of sulfuric acid (specific gravity 1.74) at 105°. The reaction mixture is stirred, heated to 145° and kept at this temperature for 1 hour. After cooling, the solution is made strongly alkaline with 50% caustic soda, and the organic base is extracted with ether. The organic extracts are dried over potassium hydroxide granules, concentrated and the residue is distilled in vacuum, whereby p-chloro-N-methylaniline with boiling point 74 - 75<0> at 0.7 Torr is obtained.
I en 50 ml trehalskolbe, som er utrustet med tilbakelopskjoler, dråpetrakt og rorer, tildryppes til 13,3 g aluminiumklorid og 20 ml torr benzen 14,1 g (0,1 mol) p-klor-N-metylanilin omhyggelig under roring. Etter fullstendig tilsetning oppvarmes reaksjonsblandingen inntil begynnende tilbakelop og holdes en kort periode ved denne temperatur. Man destillerer deretter inn friskt destillert etylenimin (4,3 g, 0,1 mol) langsomt i reaksjonskaret. Etter fullstendig tilsetning rores reaksjonsblandingen videre i 30 minutter og helles så i 200 g is, som befinner seg i en 1-liter-kolbe, forsynt med en tilbakelopskjoler. Man tilsetter deretter det erholdte faste produkt i små deler 50 g fast kaliumhydroksyd, hvorved man iakttar at materialet går i opplosning. Det avkjoles deretter og ekstraheres tre ganger med benzen. De forente benzenekstrakter torkes over kaliumhydroksydsmåkorn og konsentreres. Resten destilleres i vakuum gjennom en 10 cm Vigreux-kolonne, hvorved man oppnår N-(p-klorfenyl)-N-metyl-etylendiamin med kokepunkt 126 - 127° ved 0,05 Torr. In a 50 ml wooden-necked flask, which is equipped with reflux skirts, dropping funnel and stirrer, to 13.3 g of aluminum chloride and 20 ml of dry benzene, 14.1 g (0.1 mol) of p-chloro-N-methylaniline is carefully added dropwise while stirring. After complete addition, the reaction mixture is heated until it begins to reflux and is kept for a short period at this temperature. Freshly distilled ethyleneimine (4.3 g, 0.1 mol) is then slowly distilled into the reaction vessel. After complete addition, the reaction mixture is further stirred for 30 minutes and then poured into 200 g of ice, which is in a 1 liter flask fitted with a reflux condenser. 50 g of solid potassium hydroxide is then added in small portions to the solid product obtained, whereby it is observed that the material dissolves. It is then cooled and extracted three times with benzene. The combined benzene extracts are dried over potassium hydroxide granules and concentrated. The residue is distilled in vacuum through a 10 cm Vigreux column, whereby N-(p-chlorophenyl)-N-methyl-ethylenediamine with a boiling point of 126 - 127° at 0.05 Torr is obtained.
100 ml 98 %'ig maursyre tilsettes under roring og under avkjoling i et isbad omhyggelig til 70 g (0,4 mol) N-(p-klor-fenyl) -N-metyl-etylendiamin. Det erholdte reaksjonsblanding lar man oppvarme til 25° og tilsetter så 40 g (0,375 mol) benzaldehyd. Den erholdte blanding oppvarmes i 17 timer til 95°. Etter avkjoling tilsettes reaksjonsblandingen langsomt til en omrort blanding av is, 3-n natriumhydroksydopplosning og eter. Det alkaliske vandige skikt skilles fra, ekstraheres ytterligere tre ganger hver gang med 100 ml eter og avbrytes. 100 ml of 98% formic acid is carefully added while stirring and while cooling in an ice bath to 70 g (0.4 mol) of N-(p-chloro-phenyl)-N-methyl-ethylenediamine. The resulting reaction mixture is allowed to warm to 25° and then 40 g (0.375 mol) benzaldehyde is added. The resulting mixture is heated for 17 hours to 95°. After cooling, the reaction mixture is slowly added to a stirred mixture of ice, 3-n sodium hydroxide solution and ether. The alkaline aqueous layer is separated, extracted a further three times each time with 100 ml of ether and discarded.
De forente eterekstrakter vaskes med vann, torkes over magnesium-sulfat og inndampes. Man oppnår en olje, som opploses i en blanding av 500 ml n-saltsyre og 250 ml eter. Eterskiktet skilles fra og det vandige sure skikt ekstraheres ennå en gang med to ganger hver 250 ml eter. De forente eterekstrakter vaskes med mettet natriumhydrogenkarbonatopplosning, torkes over magne-siumsulfat og inndampes. Ved krystallisasjon av resten fra isopropanol oppnår man 7-klor-l,3,4,5-tetrahydro-l-metyl-5-fenyl-4H-1,4-benzodiazepin-4-karboksaldehyd i to utbytter av krystaller som smelter ved 114 - 115° og ved 120 - 121°. Ved omkrystallisasjon av de forente krystallene fra heksan oppnår man krem-fargede prismer med smeltepunkt 121 - 122°. The combined ether extracts are washed with water, dried over magnesium sulphate and evaporated. An oil is obtained, which is dissolved in a mixture of 500 ml of n-hydrochloric acid and 250 ml of ether. The ether layer is separated and the aqueous acidic layer is extracted once more with 250 ml each of ether twice. The combined ether extracts are washed with saturated sodium bicarbonate solution, dried over magnesium sulphate and evaporated. Crystallization of the residue from isopropanol yields 7-chloro-1,3,4,5-tetrahydro-1-methyl-5-phenyl-4H-1,4-benzodiazepine-4-carboxaldehyde in two yields of crystals melting at 114 - 115° and at 120 - 121°. By recrystallization of the combined crystals from hexane, cream-coloured prisms with a melting point of 121 - 122° are obtained.
EKSEMPEL 13 EXAMPLE 13
En opplosning av 1 g (0,00318 mol) 4-acetyl-7-klor-2,3,4,5-tetrahydro-l-metyl-5-fenyl-lH-1,4-benzodiazepin i 25 ml torr N,N-dimetylformamid under nitrogen behandles med 0,14 g A solution of 1 g (0.00318 mol) 4-acetyl-7-chloro-2,3,4,5-tetrahydro-1-methyl-5-phenyl-1H-1,4-benzodiazepine in 25 ml torr N, N-dimethylformamide under nitrogen is treated with 0.14 g
(0,00349 mol) av en 56,9 %'ig natriumhydrid-dispersjon i en mineralolje. Reaksjonsblandingen lar man stå til henstand i 60 timer. Den rores deretter om i 5 timer ved 40 - 45° og opp-losningsmidlet fjernes under forminsket trykk. Resten opploses i 50 ml eter og ekstraheres to ganger hver gang med 40 ml l-n saltsyre. De sure skikt forenes, innstilles basisk med airano-niumhydroksyd og ekstraheres med 100 ml diklormetan. Det organiske skikt vaskes med 50 ml av en mettet koksaltopplosning, torkes over vannfritt natriumsulfat og inndampes til torrhet. Den erholdte olje opploses i diklormetan, filtreres over 75 g silicagel og elueres med 400 ml diklormetan og 500 ml etylacetat. Etylacetatfraksjonen tilsettes overskytende etanolisk saltsyre, hvorpå man inndamper til torrhet. Reaksjonsproduktet omkrystalliseres to ganger fra isopropanol/eter og gir 7-klor-2,3-dihydro-l-metyl-5-fenyl-lH-1,4-benzodiazepin-hydroklorid i form av orangefargede prismer med smeltepunkt 250 - 254° (lukket ror) . (0.00349 mol) of a 56.9% sodium hydride dispersion in a mineral oil. The reaction mixture is allowed to stand for 60 hours. It is then stirred for 5 hours at 40 - 45° and the solvent is removed under reduced pressure. The residue is dissolved in 50 ml of ether and extracted twice each time with 40 ml of 1-n hydrochloric acid. The acidic layers are combined, made basic with aluminum hydroxide and extracted with 100 ml of dichloromethane. The organic layer is washed with 50 ml of a saturated sodium chloride solution, dried over anhydrous sodium sulfate and evaporated to dryness. The oil obtained is dissolved in dichloromethane, filtered over 75 g of silica gel and eluted with 400 ml of dichloromethane and 500 ml of ethyl acetate. Excess ethanolic hydrochloric acid is added to the ethyl acetate fraction, after which it is evaporated to dryness. The reaction product is recrystallized twice from isopropanol/ether and gives 7-chloro-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepine hydrochloride in the form of orange-colored prisms with a melting point of 250 - 254° (closed rudder).
Utgangsmaterialet kan fremstilles på folgende måte: The starting material can be produced in the following way:
Til en opplosning av 69 g (0,25 mol) rå 7-klor-2,3,4,5-tetra hydro-l-metyl-5-fenyl-lH-1,4-benzodiazepin i 200 ml pyridin tilsetter man 125 ml eddiksyreanhydrid. Reaksjonsblandingen står til henstand i 15 minutter ved romtemperatur og oppvarmes så i et dampbad i 35 minutter. Deretter konsentrerer man i vakuum til torrhet. Resten opploses i en blanding av eter og iskald fortynnet saltsyre. Eterskiktet skilles fra, vaskes med vann og fortynnet iskald natronlut, torkes og inndampes i vakuum til torrhet. Resten krystalliseres til blandingen av eter og petroleter og gir 4-acetyl-7-klor-2,3,4,5-tetrahydro-l-metyl-5-fenyl-lH-1,4-benzodiazepin med smeltepunkt 106 - 108°. To a solution of 69 g (0.25 mol) of crude 7-chloro-2,3,4,5-tetra hydro-1-methyl-5-phenyl-1H-1,4-benzodiazepine in 200 ml of pyridine 125 ml of acetic anhydride is added. The reaction mixture stand for 15 minutes at room temperature and heat then in a steam bath for 35 minutes. Then you concentrate in vacuum to dryness. The residue is dissolved in a mixture of ether and ice-cold dilute hydrochloric acid. The ether layer is separated, washed with water and diluted ice-cold caustic soda, dried and evaporated in vacuum to dryness. The residue is crystallized into the mixture of ether and petroleum ether and gives 4-acetyl-7-chloro-2,3,4,5-tetrahydro-1-methyl-5-phenyl-1H-1,4-benzodiazepine with melting point 106 - 108°.
Claims (1)
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CH (1) | CH492723A (en) |
DE (1) | DE1695223A1 (en) |
DK (1) | DK137494B (en) |
ES (1) | ES350159A1 (en) |
FI (1) | FI48469C (en) |
FR (1) | FR1553404A (en) |
GB (3) | GB1199863A (en) |
IE (1) | IE31935B1 (en) |
NL (2) | NL143567B (en) |
NO (1) | NO121545B (en) |
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US4002611A (en) * | 1968-02-13 | 1977-01-11 | Sumitomo Chemical Company, Limited | Preparation of benzodiazepines |
JPS515395B1 (en) * | 1971-04-12 | 1976-02-19 |
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1968
- 1968-02-01 CH CH163468A patent/CH492723A/en not_active IP Right Cessation
- 1968-02-03 DE DE19681695223 patent/DE1695223A1/en active Pending
- 1968-02-05 GB GB3850969A patent/GB1199863A/en not_active Expired
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- 1968-02-05 GB GB570668A patent/GB1199862A/en not_active Expired
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- 1968-02-05 FR FR1553404D patent/FR1553404A/fr not_active Expired
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FI48469B (en) | 1974-07-01 |
ES350159A1 (en) | 1969-04-16 |
IE31935B1 (en) | 1973-02-21 |
SE341190B (en) | 1971-12-20 |
NL6801612A (en) | 1968-08-07 |
FI48469C (en) | 1974-10-10 |
YU25768A (en) | 1978-05-15 |
CH492723A (en) | 1970-06-30 |
GB1199863A (en) | 1970-07-22 |
YU34128B (en) | 1978-12-31 |
DK137494B (en) | 1978-03-13 |
NL143567C (en) | |
DK137494C (en) | 1978-08-28 |
IE31935L (en) | 1968-08-06 |
GB1199862A (en) | 1970-07-22 |
GB1199864A (en) | 1970-07-22 |
FR1553404A (en) | 1969-01-10 |
NL143567B (en) | 1974-10-15 |
DE1695223A1 (en) | 1972-02-03 |
BE710301A (en) | 1968-08-05 |
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