WO1992008706A1 - Verfahren zur herstellung von 4,5,6,7-tetrahydro-imidazo-(4,5,ljk) (1,4)-benzodiazepin-2-(1h)-thionen sowie zwischenprodukte - Google Patents
Verfahren zur herstellung von 4,5,6,7-tetrahydro-imidazo-(4,5,ljk) (1,4)-benzodiazepin-2-(1h)-thionen sowie zwischenprodukte Download PDFInfo
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- WO1992008706A1 WO1992008706A1 PCT/EP1991/002038 EP9102038W WO9208706A1 WO 1992008706 A1 WO1992008706 A1 WO 1992008706A1 EP 9102038 W EP9102038 W EP 9102038W WO 9208706 A1 WO9208706 A1 WO 9208706A1
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- Prior art keywords
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- compounds
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- 238000000034 method Methods 0.000 title claims abstract description 21
- 239000013067 intermediate product Substances 0.000 title abstract description 3
- 150000001875 compounds Chemical class 0.000 claims abstract description 72
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims abstract description 26
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 19
- 239000001257 hydrogen Substances 0.000 claims abstract description 19
- 125000004432 carbon atom Chemical group C* 0.000 claims abstract description 16
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims abstract description 10
- 229910052736 halogen Inorganic materials 0.000 claims abstract description 7
- 150000002367 halogens Chemical class 0.000 claims abstract description 7
- 125000005843 halogen group Chemical group 0.000 claims abstract description 6
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims abstract description 6
- CIUQDSCDWFSTQR-UHFFFAOYSA-N [C]1=CC=CC=C1 Chemical compound [C]1=CC=CC=C1 CIUQDSCDWFSTQR-UHFFFAOYSA-N 0.000 claims abstract description 3
- 125000001844 prenyl group Chemical group [H]C([*])([H])C([H])=C(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 12
- 238000002360 preparation method Methods 0.000 claims description 9
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 6
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 5
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 5
- 229910052801 chlorine Inorganic materials 0.000 claims description 5
- 239000000460 chlorine Substances 0.000 claims description 5
- ZOXJGFHDIHLPTG-UHFFFAOYSA-N Boron Chemical compound [B] ZOXJGFHDIHLPTG-UHFFFAOYSA-N 0.000 claims description 4
- 229910052796 boron Inorganic materials 0.000 claims description 4
- 239000000543 intermediate Substances 0.000 claims description 4
- UMGDCJDMYOKAJW-UHFFFAOYSA-N thiourea Chemical compound NC(N)=S UMGDCJDMYOKAJW-UHFFFAOYSA-N 0.000 claims description 4
- 125000003277 amino group Chemical group 0.000 claims description 3
- RAFNCPHFRHZCPS-UHFFFAOYSA-N di(imidazol-1-yl)methanethione Chemical compound C1=CN=CN1C(=S)N1C=CN=C1 RAFNCPHFRHZCPS-UHFFFAOYSA-N 0.000 claims description 3
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 3
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Natural products NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 claims description 2
- 238000007112 amidation reaction Methods 0.000 claims description 2
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 2
- 229910052794 bromium Inorganic materials 0.000 claims description 2
- QGJOPFRUJISHPQ-NJFSPNSNSA-N carbon disulfide-14c Chemical compound S=[14C]=S QGJOPFRUJISHPQ-NJFSPNSNSA-N 0.000 claims description 2
- ZWZVWGITAAIFPS-UHFFFAOYSA-N thiophosgene Chemical compound ClC(Cl)=S ZWZVWGITAAIFPS-UHFFFAOYSA-N 0.000 claims description 2
- FCSKOFQQCWLGMV-UHFFFAOYSA-N 5-{5-[2-chloro-4-(4,5-dihydro-1,3-oxazol-2-yl)phenoxy]pentyl}-3-methylisoxazole Chemical compound O1N=C(C)C=C1CCCCCOC1=CC=C(C=2OCCN=2)C=C1Cl FCSKOFQQCWLGMV-UHFFFAOYSA-N 0.000 claims 1
- 125000001246 bromo group Chemical group Br* 0.000 claims 1
- 238000004519 manufacturing process Methods 0.000 abstract description 3
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 abstract description 2
- 125000004191 (C1-C6) alkoxy group Chemical group 0.000 abstract 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 36
- -1 3-nitro-benzyl Chemical group 0.000 description 18
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 15
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 15
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 11
- OKKJLVBELUTLKV-UHFFFAOYSA-N methanol Natural products OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 10
- 239000000203 mixture Substances 0.000 description 10
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 10
- BVHCYKZSWOWXPO-UHFFFAOYSA-N 1,3-dihydro-1,4-benzodiazepine-2-thione Chemical class N1C(=S)CN=CC2=CC=CC=C21 BVHCYKZSWOWXPO-UHFFFAOYSA-N 0.000 description 9
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 9
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 8
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 8
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 8
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 6
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- 238000006243 chemical reaction Methods 0.000 description 5
- 239000012442 inert solvent Substances 0.000 description 5
- 229910000027 potassium carbonate Inorganic materials 0.000 description 5
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 4
- WGYKZJWCGVVSQN-UHFFFAOYSA-N propylamine Chemical compound CCCN WGYKZJWCGVVSQN-UHFFFAOYSA-N 0.000 description 4
- 238000010992 reflux Methods 0.000 description 4
- 229910052938 sodium sulfate Inorganic materials 0.000 description 4
- 235000011152 sodium sulphate Nutrition 0.000 description 4
- 239000002904 solvent Substances 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 4
- QGJOPFRUJISHPQ-UHFFFAOYSA-N Carbon disulfide Chemical compound S=C=S QGJOPFRUJISHPQ-UHFFFAOYSA-N 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 3
- 241001061127 Thione Species 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 239000007795 chemical reaction product Substances 0.000 description 3
- 239000003795 chemical substances by application Substances 0.000 description 3
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 3
- 238000001704 evaporation Methods 0.000 description 3
- 238000007363 ring formation reaction Methods 0.000 description 3
- 239000000741 silica gel Substances 0.000 description 3
- 229910002027 silica gel Inorganic materials 0.000 description 3
- 229910000029 sodium carbonate Inorganic materials 0.000 description 3
- AUAXYMOBWXOEQD-UHFFFAOYSA-N 2,5-dichloro-3-nitrobenzoic acid Chemical compound OC(=O)C1=CC(Cl)=CC([N+]([O-])=O)=C1Cl AUAXYMOBWXOEQD-UHFFFAOYSA-N 0.000 description 2
- AFABGHUZZDYHJO-UHFFFAOYSA-N 2-Methylpentane Chemical compound CCCC(C)C AFABGHUZZDYHJO-UHFFFAOYSA-N 0.000 description 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 2
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 2
- 125000000217 alkyl group Chemical group 0.000 description 2
- 229910021529 ammonia Inorganic materials 0.000 description 2
- 229940049706 benzodiazepine Drugs 0.000 description 2
- MCQRPQCQMGVWIQ-UHFFFAOYSA-N boron;methylsulfanylmethane Chemical compound [B].CSC MCQRPQCQMGVWIQ-UHFFFAOYSA-N 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 238000007796 conventional method Methods 0.000 description 2
- 239000003480 eluent Substances 0.000 description 2
- ROBXZHNBBCHEIQ-SCSAIBSYSA-N ethyl (2r)-2-aminopropanoate Chemical compound CCOC(=O)[C@@H](C)N ROBXZHNBBCHEIQ-SCSAIBSYSA-N 0.000 description 2
- ROBXZHNBBCHEIQ-BYPYZUCNSA-N ethyl (2s)-2-aminopropanoate Chemical compound CCOC(=O)[C@H](C)N ROBXZHNBBCHEIQ-BYPYZUCNSA-N 0.000 description 2
- 230000008020 evaporation Effects 0.000 description 2
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 2
- 125000004491 isohexyl group Chemical group C(CCC(C)C)* 0.000 description 2
- 125000001972 isopentyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 description 2
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 2
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 2
- 125000001280 n-hexyl group Chemical group C(CCCCC)* 0.000 description 2
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 2
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- 125000002813 thiocarbonyl group Chemical group *C(*)=S 0.000 description 2
- PARSQALDHYECKE-SSDOTTSWSA-N (2r)-2-n-[(2-bromo-3-nitrophenyl)methyl]propane-1,2-diamine Chemical compound NC[C@@H](C)NCC1=CC=CC([N+]([O-])=O)=C1Br PARSQALDHYECKE-SSDOTTSWSA-N 0.000 description 1
- QDQCVMLOCFOFAG-SSDOTTSWSA-N (2r)-2-n-[(2-chloro-3-nitrophenyl)methyl]propane-1,2-diamine Chemical compound NC[C@@H](C)NCC1=CC=CC([N+]([O-])=O)=C1Cl QDQCVMLOCFOFAG-SSDOTTSWSA-N 0.000 description 1
- WCVGASUFZCFEIZ-SSDOTTSWSA-N (3R)-3-methyl-9-nitro-2,3,4,5-tetrahydro-1H-1,4-benzodiazepine Chemical compound C[C@@H]1CNC2=C(CN1)C=CC=C2[N+]([O-])=O WCVGASUFZCFEIZ-SSDOTTSWSA-N 0.000 description 1
- IWPWEJWPWXDFSP-ZCFIWIBFSA-N (3R)-7-chloro-3-methyl-9-nitro-2,3,4,5-tetrahydro-1H-1,4-benzodiazepine Chemical compound ClC=1C=C(C2=C(CN[C@@H](CN2)C)C=1)[N+](=O)[O-] IWPWEJWPWXDFSP-ZCFIWIBFSA-N 0.000 description 1
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- LOYZVRIHVZEDMW-UHFFFAOYSA-N 1-bromo-3-methylbut-2-ene Chemical compound CC(C)=CCBr LOYZVRIHVZEDMW-UHFFFAOYSA-N 0.000 description 1
- OISVCGZHLKNMSJ-UHFFFAOYSA-N 2,6-Lutidine Substances CC1=CC=CC(C)=N1 OISVCGZHLKNMSJ-UHFFFAOYSA-N 0.000 description 1
- WTDJEGSXLFHZPY-UHFFFAOYSA-N 2-bromo-3-nitrobenzoic acid Chemical compound OC(=O)C1=CC=CC([N+]([O-])=O)=C1Br WTDJEGSXLFHZPY-UHFFFAOYSA-N 0.000 description 1
- BETVLJMOJDGFLC-UHFFFAOYSA-N 2-bromo-3-nitrobenzoyl chloride Chemical compound [O-][N+](=O)C1=CC=CC(C(Cl)=O)=C1Br BETVLJMOJDGFLC-UHFFFAOYSA-N 0.000 description 1
- 125000000069 2-butynyl group Chemical group [H]C([H])([H])C#CC([H])([H])* 0.000 description 1
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 description 1
- 125000001494 2-propynyl group Chemical group [H]C#CC([H])([H])* 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
- 125000000474 3-butynyl group Chemical group [H]C#CC([H])([H])C([H])([H])* 0.000 description 1
- GAMYYCRTACQSBR-UHFFFAOYSA-N 4-azabenzimidazole Chemical compound C1=CC=C2NC=NC2=N1 GAMYYCRTACQSBR-UHFFFAOYSA-N 0.000 description 1
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-dimethylaminopyridine Substances CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 1
- 208000030507 AIDS Diseases 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- 241000450599 DNA viruses Species 0.000 description 1
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 1
- 208000031886 HIV Infections Diseases 0.000 description 1
- 241000713772 Human immunodeficiency virus 1 Species 0.000 description 1
- 241000713340 Human immunodeficiency virus 2 Species 0.000 description 1
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 1
- YUDRVAHLXDBKSR-UHFFFAOYSA-N [CH]1CCCCC1 Chemical compound [CH]1CCCCC1 YUDRVAHLXDBKSR-UHFFFAOYSA-N 0.000 description 1
- GJEAMHAFPYZYDE-UHFFFAOYSA-N [C].[S] Chemical compound [C].[S] GJEAMHAFPYZYDE-UHFFFAOYSA-N 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 125000003545 alkoxy group Chemical group 0.000 description 1
- 150000003973 alkyl amines Chemical class 0.000 description 1
- 125000002947 alkylene group Chemical group 0.000 description 1
- 125000000304 alkynyl group Chemical group 0.000 description 1
- 238000010640 amide synthesis reaction Methods 0.000 description 1
- 150000001408 amides Chemical class 0.000 description 1
- CPNLKFUZPSLDMM-UHFFFAOYSA-N boron;1,4-oxathiane Chemical class [B].C1CSCCO1 CPNLKFUZPSLDMM-UHFFFAOYSA-N 0.000 description 1
- PVYPHUYXKVVURH-UHFFFAOYSA-N boron;2-methylpropan-2-amine Chemical compound [B].CC(C)(C)N PVYPHUYXKVVURH-UHFFFAOYSA-N 0.000 description 1
- KXTGULZDUSATCW-UHFFFAOYSA-N boron;4-methylmorpholine Chemical compound [B].CN1CCOCC1 KXTGULZDUSATCW-UHFFFAOYSA-N 0.000 description 1
- YJROYUJAFGZMJA-UHFFFAOYSA-N boron;morpholine Chemical compound [B].C1COCCN1 YJROYUJAFGZMJA-UHFFFAOYSA-N 0.000 description 1
- KHYAFFAGZNCWPT-UHFFFAOYSA-N boron;n,n-diethylaniline Chemical compound [B].CCN(CC)C1=CC=CC=C1 KHYAFFAGZNCWPT-UHFFFAOYSA-N 0.000 description 1
- RJTANRZEWTUVMA-UHFFFAOYSA-N boron;n-methylmethanamine Chemical compound [B].CNC RJTANRZEWTUVMA-UHFFFAOYSA-N 0.000 description 1
- UWTDFICHZKXYAC-UHFFFAOYSA-N boron;oxolane Chemical compound [B].C1CCOC1 UWTDFICHZKXYAC-UHFFFAOYSA-N 0.000 description 1
- XYWGMXHWFVLTHI-UHFFFAOYSA-N boron;piperazine Chemical compound [B].C1CNCCN1 XYWGMXHWFVLTHI-UHFFFAOYSA-N 0.000 description 1
- NNTOJPXOCKCMKR-UHFFFAOYSA-N boron;pyridine Chemical compound [B].C1=CC=NC=C1 NNTOJPXOCKCMKR-UHFFFAOYSA-N 0.000 description 1
- 239000003638 chemical reducing agent Substances 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 1
- 241001493065 dsRNA viruses Species 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 125000006038 hexenyl group Chemical group 0.000 description 1
- 125000005394 methallyl group Chemical group 0.000 description 1
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 1
- 125000002255 pentenyl group Chemical group C(=CCCC)* 0.000 description 1
- 125000005981 pentynyl group Chemical group 0.000 description 1
- 229920000885 poly(2-vinylpyridine) Polymers 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- WTTIBCHOELPGFK-LBPRGKRZSA-N r82150 Chemical compound C1N(CC=C(C)C)[C@@H](C)CN2C(=S)NC3=CC=CC1=C32 WTTIBCHOELPGFK-LBPRGKRZSA-N 0.000 description 1
- 150000003254 radicals Chemical class 0.000 description 1
- 230000010076 replication Effects 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- 125000005207 tetraalkylammonium group Chemical group 0.000 description 1
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Substances C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/06—Peri-condensed systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C211/00—Compounds containing amino groups bound to a carbon skeleton
- C07C211/01—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to acyclic carbon atoms
- C07C211/26—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to acyclic carbon atoms of an unsaturated carbon skeleton containing at least one six-membered aromatic ring
- C07C211/29—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to acyclic carbon atoms of an unsaturated carbon skeleton containing at least one six-membered aromatic ring the carbon skeleton being further substituted by halogen atoms or by nitro or nitroso groups
Definitions
- the invention relates to 2- [(3-nitro-benzyl) amino] alkyl-a ine and a process for the preparation of 4,5,6,7-tetra-hydro-imidazo- [4,5, ljk] [1.4] -benzodiazepin-2 (IH) thiones via the 2- [(3-nitro-benzyl) amino] alkylamines as intermediates.
- the invention relates to an improved process for the preparation of 4,5,6,7-tetrahydro-imidazo- [4,5, ljk] [1.4] - benzodiazepine-2 (IH) thiones of the general formula I
- R1 is a hydrogen atom or a straight-chain or branched alkyl radical having 1-6 carbon atoms
- R2 represents a hydrogen atom, a straight-chain or branched alkyl radical having 1-6 carbon atoms, a straight-chain or branched alkenyl radical having 3-6 carbon atoms, a C 3 -C 6 alkynyl radical, a C 3 -C 5 cycloalkyl radical or a C ⁇ _-Cg- Alkyl radical which can also be substituted by a phenyl radical or a C3-Cg-cycloalkyl radical, 3 and R4 are identical or different and, independently of one another, denote hydrogen, halogen, hydroxyl, Ci-Cg-alkoxy, Cx-Cg-alkyl or amino.
- R * L represents a hydrogen atom or a straight-chain or branched alkyl group with 1-6 carbon atoms.
- the methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, n-pentyl, isopentyl, n-hexyl and isohexyl groups are preferred
- 2 can represent a hydrogen atom or a straight-chain or branched C 1 -C 6 -alkyl group.
- the methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, n-pentyl, isopentyl, n-hexyl and isohexyl group are preferred.
- R2 can also be a straight-chain or branched C3-C6-
- Alkylene group mean.
- the allyl, 2-methylallyl, isobutenyl, pentenyl, isopentenyl, hexenyl and isohexenyl group are preferred.
- R2 can also mean a straight-chain or branched C3-C6 alkynyl group. This means in particular a 2-propynyl, 2-butynyl, 3-butynyl, pentynyl or hexynyl radical.
- a C3 ⁇ C5-C cloalkyl radical for R3 means a cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl radical.
- R3 and R4 can be the same or different and independently of one another are hydrogen, halogen, such as fluorine, chlorine or bromine, hydroxy, alkyl, such as methyl or ethyl, or alkoxy, such as methoxy or ethoxy,
- the compounds of general formula I can have one or more
- REPLACEMENT LEAF have asymmetric carbon atoms.
- the invention therefore also relates to all optically active and diastereomeric forms and racemic and diastereomeric mixtures.
- R * j_, 2, R 3 and R4 have the meanings given, are prepared by using a compound of the general formula II,
- R ⁇ _, R 2 , R3 and R4 have the meanings given, according to a conventional method with a reagent which transfers the thiocarbonyl group, such as, for example, carbon disulfide, thiocarbonyldiimidazole, thiophosgene or thiourea.
- a reagent which transfers the thiocarbonyl group such as, for example, carbon disulfide, thiocarbonyldiimidazole, thiophosgene or thiourea.
- R 1, R 2, R 3 and R 4 have the meanings indicated and convert the nitro group into an amino group by a conventional method known to the person skilled in the art.
- the compounds of general formula III can be prepared by using a compound of general
- X represents a halogen atom or a sulfonic ester grouping.
- the compounds of general formula IV can be prepared by using a compound of general formula VI,
- REPLACEMENT LEAF in which R_, 3 and 4 have the meanings given and Y represents a halogen atom, is subjected to a cyclization reaction.
- R] _, R3, R4 and Y have the meanings given, is subjected to a reduction using hydrogen boron or diborane.
- the compounds of the general formula VII can be prepared by using a compound of the general formula VII
- R, R 3 , R4 and Y have the meanings given, and R5 is hydrogen or an alkyl radical, is subjected to an amidation reaction by methods known to those skilled in the art.
- the compounds of the general formula VIII can be prepared by using a compound of the general formula VIII
- Ri has the meanings given and R 5 is hydrogen or an alkyl radical, brings about the reaction in the customary manner.
- the compounds of the general formula IX are known from the literature or can be prepared by methods known from the literature.
- REPLACEMENT LEAF are and relate to racemates or optically active compounds.
- the reactions of the compounds of the general formula II with a reagent transferring a thiocarbonyl group to a compound of the general formula I are carried out by, for example, reacting a compound of the general formula II with carbon disulfide in an aqueous-alcoholic solution in the presence of alkali by a method known to those skilled in the art or by reacting a compound of the general formula II with thiocarbonyldiimidazole in an inert solvent, such as, for example, Dimethylformamide brings to reaction.
- the compounds of the general formula II are prepared by converting the nitro group into an amino group in a compound of the general formula by a method known to those skilled in the art.
- the compounds of the general formula IV are reacted with compounds of the general formula V to give compounds of the general formula III by reacting the compounds of the general formula IV with compounds of the general formula V in an inert solvent, such as, for example, dimethylformamide, dimethylacetamide, acetone, methyl ethyl ketone or alcohol at at temperatures between room temperature and reflux temperature of the solvent, tion agent such as sodium carbonate or potassium carbonate to the skilled person by methods known brings preferably between 40 "C and 60 C in the presence of a ⁇ alkaline Kondensa ⁇ to the reaction.
- an inert solvent such as, for example, dimethylformamide, dimethylacetamide, acetone, methyl ethyl ketone or alcohol
- the cyclization of a compound of general formula VI to a compound of general formula IV can be carried out by using a compound of general Formula VI in an inert solvent such as dimethyl formamide, dimethylacetamide, acetone, methyl ethyl ketone or alcohol in the presence of an alkaline condensing agent such as sodium carbonate or potassium carbonate to react at temperatures between room temperature and the reflux temperature of the solvent.
- an inert solvent such as dimethyl formamide, dimethylacetamide, acetone, methyl ethyl ketone or alcohol
- an alkaline condensing agent such as sodium carbonate or potassium carbonate
- the cyclization reaction of a compound of the general formula VI to a compound of the general formula IV can also be carried out by heating a compound of the general formula IV in the presence of an alkaline condensing agent, such as, for example, sodium carbonate or potassium carbonate, without the addition of a solvent to temperatures between 100 "C and 200 ⁇ C, preferably between 130 ⁇ C and 170 ° C.
- an alkaline condensing agent such as, for example, sodium carbonate or potassium carbonate
- the compounds of the general formula VI are shown in that a compound of the general formula VII with hydrogen boron or diborane in an inert solvent, such as e.g. Tetrahydrofuran, dioxane, diethyl ether or methylene chloride at temperatures between room temperature and reflux temperature of the solvent or by reacting a compound of general formula VI in an inert solvent such as e.g. Subjects methylene chloride reduction with a tetraalkylammonium borohydride.
- an inert solvent such as e.g. Tetrahydrofuran, dioxane, diethyl ether or methylene chloride
- B a borane-ammonia complex, borane-tert-butylamine complex, borane-N, N-diethylaniline complex, borane-dimethylamine complex, borane-4-dimethylaminopyridine complex, borane-dimethyl sulfide complex, borane -Dimethyl sulfide complex, borane-N-ethyldiisopropylamine complex, borane-N-ethylmorpholine complex, borane-2,6-lutidine complex, borane-N-methylmorpholine complex, borane-morpholine complex, borane-1,4 -Oxathian complex, borane-N-phenylmorpholine complex, borane-piperazine complex,
- the compounds of the general formula VII are illustrated by subjecting a compound of the general formula VIII to an amide formation reaction according to the person skilled in the art and methods known from the literature.
- the compounds of general formula VIII can be prepared by reacting a compound of general formula IX with a compound of general formula X by methods known to those skilled in the art.
- the invention relates in particular to a new and economical process for the production of
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP3517660A JPH06502400A (ja) | 1990-11-16 | 1991-10-29 | ４，５，６，７−テトラヒドロ−イミダゾ−（４，５，１ｊｋ）（１，４）−ベンゾジアゼピン−２−（１Ｈ）−チオン並びに中間生成物の製造方法 |
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE4036552A DE4036552C1 (enrdf_load_stackoverflow) | 1990-11-16 | 1990-11-16 | |
| DEP4036552.2 | 1990-11-16 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| WO1992008706A1 true WO1992008706A1 (de) | 1992-05-29 |
Family
ID=6418388
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/EP1991/002038 WO1992008706A1 (de) | 1990-11-16 | 1991-10-29 | Verfahren zur herstellung von 4,5,6,7-tetrahydro-imidazo-(4,5,ljk) (1,4)-benzodiazepin-2-(1h)-thionen sowie zwischenprodukte |
Country Status (9)
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6936610B2 (en) | 1996-11-08 | 2005-08-30 | Astrazeneca Uk Limited | Heterocyclic derivatives |
Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| NZ238664A (en) * | 1990-07-06 | 1992-12-23 | Janssen Pharmaceutica Nv | Substituted tetrahydroimidazo(1,4)benzodiazepin-2-(thi)ones and pharmaceutical anti-viral compositions |
| ATE160147T1 (de) * | 1991-09-24 | 1997-11-15 | Janssen Pharmaceutica Nv | Verfahren zur herstellung von enantiomer reinem imidazo (4,5,1-jk) (1,4)-benzodiazepin-2(1h)- thionen |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0336466A1 (en) * | 1988-03-18 | 1989-10-11 | Janssen Pharmaceutica N.V. | Antiviral tetrahydroimidazo (1,4) benzodiazepin-2-ones |
| EP0384522A1 (en) * | 1989-02-23 | 1990-08-29 | Janssen Pharmaceutica N.V. | Antiviral tetrahydroimidazo[1,4]benzodiazepin-2-thiones |
-
1990
- 1990-11-16 DE DE4036552A patent/DE4036552C1/de not_active Expired - Lifetime
-
1991
- 1991-10-29 EP EP91918424A patent/EP0557307A1/de not_active Withdrawn
- 1991-10-29 JP JP3517660A patent/JPH06502400A/ja active Pending
- 1991-10-29 AU AU88559/91A patent/AU8855991A/en not_active Abandoned
- 1991-10-29 CA CA002096238A patent/CA2096238A1/en not_active Abandoned
- 1991-10-29 WO PCT/EP1991/002038 patent/WO1992008706A1/de not_active Application Discontinuation
- 1991-11-11 IL IL100033A patent/IL100033A0/xx unknown
- 1991-11-15 IE IE397991A patent/IE913979A1/en unknown
- 1991-11-15 ZA ZA919050A patent/ZA919050B/xx unknown
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0336466A1 (en) * | 1988-03-18 | 1989-10-11 | Janssen Pharmaceutica N.V. | Antiviral tetrahydroimidazo (1,4) benzodiazepin-2-ones |
| EP0384522A1 (en) * | 1989-02-23 | 1990-08-29 | Janssen Pharmaceutica N.V. | Antiviral tetrahydroimidazo[1,4]benzodiazepin-2-thiones |
Non-Patent Citations (1)
| Title |
|---|
| The Journal of Organic Chemistry, Band 56, Nr. 15, 19. Juli 1991 (Easton, US), K.A. Parker et al.: "A four-step synthesis of TIBO R82150", Seiten 4600-4601, siehe Seite 4600 * |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6936610B2 (en) | 1996-11-08 | 2005-08-30 | Astrazeneca Uk Limited | Heterocyclic derivatives |
Also Published As
| Publication number | Publication date |
|---|---|
| DE4036552C1 (enrdf_load_stackoverflow) | 1992-02-06 |
| AU8855991A (en) | 1992-06-11 |
| CA2096238A1 (en) | 1992-05-17 |
| ZA919050B (en) | 1992-08-26 |
| EP0557307A1 (de) | 1993-09-01 |
| JPH06502400A (ja) | 1994-03-17 |
| IL100033A0 (en) | 1992-08-18 |
| IE913979A1 (en) | 1992-05-20 |
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