NO156483B - CLOSURE Capsule for liquid medicine bottle - Google Patents
CLOSURE Capsule for liquid medicine bottle Download PDFInfo
- Publication number
- NO156483B NO156483B NO844193A NO844193A NO156483B NO 156483 B NO156483 B NO 156483B NO 844193 A NO844193 A NO 844193A NO 844193 A NO844193 A NO 844193A NO 156483 B NO156483 B NO 156483B
- Authority
- NO
- Norway
- Prior art keywords
- compound
- phenyl
- benzothiazepine
- water
- mixture
- Prior art date
Links
- 239000007788 liquid Substances 0.000 title description 4
- 239000002775 capsule Substances 0.000 title description 2
- 239000003814 drug Substances 0.000 title description 2
- 150000001875 compounds Chemical class 0.000 claims description 96
- -1 trifluoromethyl-phenyl Chemical group 0.000 claims description 70
- 239000002253 acid Chemical group 0.000 claims description 22
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 claims description 20
- 239000001257 hydrogen Substances 0.000 claims description 19
- 229910052739 hydrogen Inorganic materials 0.000 claims description 19
- 125000000217 alkyl group Chemical group 0.000 claims description 16
- 238000000034 method Methods 0.000 claims description 14
- 239000012280 lithium aluminium hydride Substances 0.000 claims description 13
- 150000003839 salts Chemical class 0.000 claims description 12
- 239000003960 organic solvent Substances 0.000 claims description 11
- 150000004965 peroxy acids Chemical class 0.000 claims description 11
- 238000006243 chemical reaction Methods 0.000 claims description 10
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims description 10
- 239000003054 catalyst Substances 0.000 claims description 9
- 229910052736 halogen Inorganic materials 0.000 claims description 9
- 150000002367 halogens Chemical class 0.000 claims description 9
- 238000002360 preparation method Methods 0.000 claims description 8
- KHIWWQKSHDUIBK-UHFFFAOYSA-N periodic acid Chemical compound OI(=O)(=O)=O KHIWWQKSHDUIBK-UHFFFAOYSA-N 0.000 claims description 7
- 238000005984 hydrogenation reaction Methods 0.000 claims description 6
- 125000006239 protecting group Chemical group 0.000 claims description 6
- 125000003277 amino group Chemical group 0.000 claims description 5
- 150000008064 anhydrides Chemical class 0.000 claims description 5
- 239000000460 chlorine Substances 0.000 claims description 5
- 238000010438 heat treatment Methods 0.000 claims description 5
- 229910000510 noble metal Inorganic materials 0.000 claims description 5
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 5
- 239000007858 starting material Substances 0.000 claims description 5
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 4
- 125000005037 alkyl phenyl group Chemical group 0.000 claims description 4
- 150000007514 bases Chemical class 0.000 claims description 4
- 238000009903 catalytic hydrogenation reaction Methods 0.000 claims description 4
- 229910052801 chlorine Inorganic materials 0.000 claims description 4
- 125000005059 halophenyl group Chemical group 0.000 claims description 4
- 229910052757 nitrogen Inorganic materials 0.000 claims description 4
- SJGALSBBFTYSBA-UHFFFAOYSA-N oxaziridine Chemical compound C1NO1 SJGALSBBFTYSBA-UHFFFAOYSA-N 0.000 claims description 4
- 150000001204 N-oxides Chemical class 0.000 claims description 3
- 239000007868 Raney catalyst Substances 0.000 claims description 3
- NPXOKRUENSOPAO-UHFFFAOYSA-N Raney nickel Chemical compound [Al].[Ni] NPXOKRUENSOPAO-UHFFFAOYSA-N 0.000 claims description 3
- 229910000564 Raney nickel Inorganic materials 0.000 claims description 3
- 125000002252 acyl group Chemical group 0.000 claims description 3
- 125000003545 alkoxy group Chemical group 0.000 claims description 3
- 150000007657 benzothiazepines Chemical class 0.000 claims description 3
- 239000003638 chemical reducing agent Substances 0.000 claims description 3
- PXQLVRUNWNTZOS-UHFFFAOYSA-N sulfanyl Chemical class [SH] PXQLVRUNWNTZOS-UHFFFAOYSA-N 0.000 claims description 3
- 125000000475 sulfinyl group Chemical group [*:2]S([*:1])=O 0.000 claims description 3
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 3
- 229940085242 benzothiazepine derivative selective calcium channel blockers with direct cardiac effects Drugs 0.000 claims description 2
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 2
- 125000004430 oxygen atom Chemical group O* 0.000 claims description 2
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 2
- 125000004076 pyridyl group Chemical group 0.000 claims description 2
- 125000001424 substituent group Chemical group 0.000 claims description 2
- 230000036571 hydration Effects 0.000 claims 1
- 238000006703 hydration reaction Methods 0.000 claims 1
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 123
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 99
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 98
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 91
- 239000000243 solution Substances 0.000 description 86
- 239000000203 mixture Substances 0.000 description 75
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 47
- 239000000047 product Substances 0.000 description 35
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 33
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 30
- 238000002844 melting Methods 0.000 description 30
- 230000008018 melting Effects 0.000 description 30
- 238000001953 recrystallisation Methods 0.000 description 29
- 239000000706 filtrate Substances 0.000 description 27
- 239000011541 reaction mixture Substances 0.000 description 27
- 238000001914 filtration Methods 0.000 description 25
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 23
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 22
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 21
- 239000002244 precipitate Substances 0.000 description 21
- 239000000725 suspension Substances 0.000 description 19
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 18
- 239000012044 organic layer Substances 0.000 description 18
- LPXPTNMVRIOKMN-UHFFFAOYSA-M sodium nitrite Chemical compound [Na+].[O-]N=O LPXPTNMVRIOKMN-UHFFFAOYSA-M 0.000 description 16
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 15
- 239000013078 crystal Substances 0.000 description 15
- 238000003756 stirring Methods 0.000 description 15
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 14
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 12
- 238000001816 cooling Methods 0.000 description 12
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 11
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 9
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 9
- BQVVSSAWECGTRN-UHFFFAOYSA-L copper;dithiocyanate Chemical compound [Cu+2].[S-]C#N.[S-]C#N BQVVSSAWECGTRN-UHFFFAOYSA-L 0.000 description 9
- 239000003208 petroleum Substances 0.000 description 9
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 9
- 229960000583 acetic acid Drugs 0.000 description 8
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 8
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 8
- 235000010288 sodium nitrite Nutrition 0.000 description 8
- JQWHASGSAFIOCM-UHFFFAOYSA-M sodium periodate Chemical compound [Na+].[O-]I(=O)(=O)=O JQWHASGSAFIOCM-UHFFFAOYSA-M 0.000 description 8
- 229910052938 sodium sulfate Inorganic materials 0.000 description 8
- 235000011152 sodium sulphate Nutrition 0.000 description 8
- 239000007787 solid Substances 0.000 description 8
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 7
- 229910052783 alkali metal Inorganic materials 0.000 description 7
- 239000012259 ether extract Substances 0.000 description 7
- 239000000284 extract Substances 0.000 description 7
- ZNNZYHKDIALBAK-UHFFFAOYSA-M potassium thiocyanate Chemical compound [K+].[S-]C#N ZNNZYHKDIALBAK-UHFFFAOYSA-M 0.000 description 7
- 229940116357 potassium thiocyanate Drugs 0.000 description 7
- MQVLYJDRCCOSTE-UHFFFAOYSA-N 5-phenyl-2,3-dihydro-1,4-benzothiazepine Chemical compound C1(=CC=CC=C1)C1=NCCSC2=C1C=CC=C2 MQVLYJDRCCOSTE-UHFFFAOYSA-N 0.000 description 6
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 6
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 6
- 238000009835 boiling Methods 0.000 description 6
- 239000012141 concentrate Substances 0.000 description 6
- 238000002425 crystallisation Methods 0.000 description 6
- 230000008025 crystallization Effects 0.000 description 6
- 239000000155 melt Substances 0.000 description 6
- 239000012991 xanthate Substances 0.000 description 6
- SJEIHUFTTDSXFW-UHFFFAOYSA-N Cl.ClC=1C=CC2=C(C(=NCCS2)C2=CC=CC=C2)C1 Chemical compound Cl.ClC=1C=CC2=C(C(=NCCS2)C2=CC=CC=C2)C1 SJEIHUFTTDSXFW-UHFFFAOYSA-N 0.000 description 5
- 150000007513 acids Chemical class 0.000 description 5
- 239000002585 base Substances 0.000 description 5
- 230000015572 biosynthetic process Effects 0.000 description 5
- 238000000354 decomposition reaction Methods 0.000 description 5
- 239000012954 diazonium Substances 0.000 description 5
- IJGRMHOSHXDMSA-UHFFFAOYSA-O diazynium Chemical compound [NH+]#N IJGRMHOSHXDMSA-UHFFFAOYSA-O 0.000 description 5
- ZOOODBUHSVUZEM-UHFFFAOYSA-N ethoxymethanedithioic acid Chemical compound CCOC(S)=S ZOOODBUHSVUZEM-UHFFFAOYSA-N 0.000 description 5
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 5
- 239000012458 free base Substances 0.000 description 5
- 150000002431 hydrogen Chemical class 0.000 description 5
- KGKWXEGYKGTMAK-UHFFFAOYSA-N 1-(2-amino-4,5-dimethoxyphenyl)ethanone Chemical compound COC1=CC(N)=C(C(C)=O)C=C1OC KGKWXEGYKGTMAK-UHFFFAOYSA-N 0.000 description 4
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 4
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 4
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 4
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 4
- KFSLWBXXFJQRDL-UHFFFAOYSA-N Peracetic acid Chemical compound CC(=O)OO KFSLWBXXFJQRDL-UHFFFAOYSA-N 0.000 description 4
- ARUVKPQLZAKDPS-UHFFFAOYSA-L copper(II) sulfate Chemical compound [Cu+2].[O-][S+2]([O-])([O-])[O-] ARUVKPQLZAKDPS-UHFFFAOYSA-L 0.000 description 4
- PSLIMVZEAPALCD-UHFFFAOYSA-N ethanol;ethoxyethane Chemical compound CCO.CCOCC PSLIMVZEAPALCD-UHFFFAOYSA-N 0.000 description 4
- 229910052500 inorganic mineral Inorganic materials 0.000 description 4
- 235000010755 mineral Nutrition 0.000 description 4
- 239000011707 mineral Substances 0.000 description 4
- JCBJVAJGLKENNC-UHFFFAOYSA-M potassium ethyl xanthate Chemical compound [K+].CCOC([S-])=S JCBJVAJGLKENNC-UHFFFAOYSA-M 0.000 description 4
- JVBXVOWTABLYPX-UHFFFAOYSA-L sodium dithionite Chemical compound [Na+].[Na+].[O-]S(=O)S([O-])=O JVBXVOWTABLYPX-UHFFFAOYSA-L 0.000 description 4
- MAOBFOXLCJIFLV-UHFFFAOYSA-N (2-aminophenyl)-phenylmethanone Chemical compound NC1=CC=CC=C1C(=O)C1=CC=CC=C1 MAOBFOXLCJIFLV-UHFFFAOYSA-N 0.000 description 3
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 3
- TVMFDIOFLJRSSD-UHFFFAOYSA-N 7,8-dimethoxy-5-methyl-2,3-dihydro-1,4-benzothiazepine hydrochloride Chemical compound Cl.COC=1C(=CC2=C(C(=NCCS2)C)C1)OC TVMFDIOFLJRSSD-UHFFFAOYSA-N 0.000 description 3
- HHKGMIFLDWRDQW-UHFFFAOYSA-N 7-chloro-5-phenyl-2,3-dihydro-1lambda6,4-benzothiazepine 1,1-dioxide Chemical compound ClC=1C=CC2=C(C(=NCCS2(=O)=O)C2=CC=CC=C2)C1 HHKGMIFLDWRDQW-UHFFFAOYSA-N 0.000 description 3
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 3
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 3
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 3
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 3
- 239000003513 alkali Substances 0.000 description 3
- 229910052784 alkaline earth metal Inorganic materials 0.000 description 3
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 3
- 229910052794 bromium Inorganic materials 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- QPOWUYJWCJRLEE-UHFFFAOYSA-N dipyridin-2-ylmethanone Chemical compound C=1C=CC=NC=1C(=O)C1=CC=CC=N1 QPOWUYJWCJRLEE-UHFFFAOYSA-N 0.000 description 3
- 239000005457 ice water Substances 0.000 description 3
- 239000010410 layer Substances 0.000 description 3
- TWNQGVIAIRXVLR-UHFFFAOYSA-N oxo(oxoalumanyloxy)alumane Chemical compound O=[Al]O[Al]=O TWNQGVIAIRXVLR-UHFFFAOYSA-N 0.000 description 3
- 108090000623 proteins and genes Proteins 0.000 description 3
- 150000003385 sodium Chemical class 0.000 description 3
- 239000011734 sodium Substances 0.000 description 3
- 229910052708 sodium Inorganic materials 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- RMVRSNDYEFQCLF-UHFFFAOYSA-N thiophenol Chemical compound SC1=CC=CC=C1 RMVRSNDYEFQCLF-UHFFFAOYSA-N 0.000 description 3
- 239000008096 xylene Substances 0.000 description 3
- YWEZSJXVHWNVEM-UHFFFAOYSA-N (5-chloro-2-sulfanylphenyl)-phenylmethanone Chemical compound SC1=C(C(=O)C2=CC=CC=C2)C=C(C=C1)Cl YWEZSJXVHWNVEM-UHFFFAOYSA-N 0.000 description 2
- MWSPMQMEJPJFIN-UHFFFAOYSA-N 2-[2-(2-benzoyl-4-nitrophenyl)sulfanylethyl]isoindole-1,3-dione Chemical compound C(C1=CC=CC=C1)(=O)C1=C(C=CC(=C1)[N+](=O)[O-])SCCN1C(C=2C(C1=O)=CC=CC2)=O MWSPMQMEJPJFIN-UHFFFAOYSA-N 0.000 description 2
- OGMADIBCHLQMIP-UHFFFAOYSA-N 2-aminoethanethiol;hydron;chloride Chemical compound Cl.NCCS OGMADIBCHLQMIP-UHFFFAOYSA-N 0.000 description 2
- LSYWVVHWSXDAKU-UHFFFAOYSA-N 5-phenyl-2,3,4,5-tetrahydro-1,4-benzothiazepine Chemical compound N1CCSC2=CC=CC=C2C1C1=CC=CC=C1 LSYWVVHWSXDAKU-UHFFFAOYSA-N 0.000 description 2
- JVOTYNTXFDAYPZ-UHFFFAOYSA-N 5-phenyl-7-(trifluoromethyl)-2,3-dihydro-1,4-benzothiazepine Chemical compound C1(=CC=CC=C1)C1=NCCSC2=C1C=C(C=C2)C(F)(F)F JVOTYNTXFDAYPZ-UHFFFAOYSA-N 0.000 description 2
- ZOHWIKYKTASKEP-UHFFFAOYSA-N 5-phenyl-7-(trifluoromethyl)-2,3-dihydro-1,4-benzothiazepine hydrochloride Chemical compound Cl.C1(=CC=CC=C1)C1=NCCSC2=C1C=C(C=C2)C(F)(F)F ZOHWIKYKTASKEP-UHFFFAOYSA-N 0.000 description 2
- GCJRNWHDAJWEDM-UHFFFAOYSA-N 7,8-dimethoxy-5-methyl-2,3,4,5-tetrahydro-1,4-benzothiazepine Chemical compound COC=1C(=CC2=C(C(NCCS2)C)C1)OC GCJRNWHDAJWEDM-UHFFFAOYSA-N 0.000 description 2
- OYJSAYMYPKRXAE-UHFFFAOYSA-N 7,8-dimethoxy-5-methyl-2,3,4,5-tetrahydro-1,4-benzothiazepine hydrochloride Chemical compound Cl.COC=1C(=CC2=C(C(NCCS2)C)C1)OC OYJSAYMYPKRXAE-UHFFFAOYSA-N 0.000 description 2
- KPSPYIGRPWPSPY-UHFFFAOYSA-N 8-chloro-9b-phenyl-3,4-dihydrooxazireno[2,3-d][1,4]benzothiazepine 5,5-dioxide Chemical compound C=1C(Cl)=CC=C(S(CCN2O3)(=O)=O)C=1C23C1=CC=CC=C1 KPSPYIGRPWPSPY-UHFFFAOYSA-N 0.000 description 2
- LCGLNKUTAGEVQW-UHFFFAOYSA-N Dimethyl ether Chemical compound COC LCGLNKUTAGEVQW-UHFFFAOYSA-N 0.000 description 2
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 description 2
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 2
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 2
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 2
- GQPLMRYTRLFLPF-UHFFFAOYSA-N Nitrous Oxide Chemical compound [O-][N+]#N GQPLMRYTRLFLPF-UHFFFAOYSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 2
- ZMZDMBWJUHKJPS-UHFFFAOYSA-M Thiocyanate anion Chemical compound [S-]C#N ZMZDMBWJUHKJPS-UHFFFAOYSA-M 0.000 description 2
- 150000001340 alkali metals Chemical class 0.000 description 2
- 150000001342 alkaline earth metals Chemical class 0.000 description 2
- 150000001350 alkyl halides Chemical class 0.000 description 2
- 230000029936 alkylation Effects 0.000 description 2
- 238000005804 alkylation reaction Methods 0.000 description 2
- 239000003610 charcoal Substances 0.000 description 2
- 239000007795 chemical reaction product Substances 0.000 description 2
- 238000004090 dissolution Methods 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 229940093915 gynecological organic acid Drugs 0.000 description 2
- ZMZDMBWJUHKJPS-UHFFFAOYSA-N hydrogen thiocyanate Natural products SC#N ZMZDMBWJUHKJPS-UHFFFAOYSA-N 0.000 description 2
- 230000007062 hydrolysis Effects 0.000 description 2
- 238000006460 hydrolysis reaction Methods 0.000 description 2
- 239000012442 inert solvent Substances 0.000 description 2
- 238000002955 isolation Methods 0.000 description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 2
- 235000019341 magnesium sulphate Nutrition 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 229910052751 metal Inorganic materials 0.000 description 2
- 239000002184 metal Substances 0.000 description 2
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 2
- NALMPLUMOWIVJC-UHFFFAOYSA-N n,n,4-trimethylbenzeneamine oxide Chemical compound CC1=CC=C([N+](C)(C)[O-])C=C1 NALMPLUMOWIVJC-UHFFFAOYSA-N 0.000 description 2
- 229910017604 nitric acid Inorganic materials 0.000 description 2
- 239000003921 oil Substances 0.000 description 2
- 235000019198 oils Nutrition 0.000 description 2
- 150000007524 organic acids Chemical class 0.000 description 2
- 235000005985 organic acids Nutrition 0.000 description 2
- 239000007800 oxidant agent Substances 0.000 description 2
- MUMZUERVLWJKNR-UHFFFAOYSA-N oxoplatinum Chemical compound [Pt]=O MUMZUERVLWJKNR-UHFFFAOYSA-N 0.000 description 2
- 239000000825 pharmaceutical preparation Substances 0.000 description 2
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 description 2
- 229910003446 platinum oxide Inorganic materials 0.000 description 2
- 238000007363 ring formation reaction Methods 0.000 description 2
- 239000012279 sodium borohydride Substances 0.000 description 2
- 229910000033 sodium borohydride Inorganic materials 0.000 description 2
- 229910000104 sodium hydride Inorganic materials 0.000 description 2
- 239000012312 sodium hydride Substances 0.000 description 2
- 239000011697 sodium iodate Substances 0.000 description 2
- 235000015281 sodium iodate Nutrition 0.000 description 2
- 229940032753 sodium iodate Drugs 0.000 description 2
- VGTPCRGMBIAPIM-UHFFFAOYSA-M sodium thiocyanate Chemical compound [Na+].[S-]C#N VGTPCRGMBIAPIM-UHFFFAOYSA-M 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- KDYFGRWQOYBRFD-UHFFFAOYSA-N succinic acid Chemical compound OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 2
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 2
- ZUWXHHBROGLWNH-UHFFFAOYSA-N (2-amino-5-chlorophenyl)-phenylmethanone Chemical compound NC1=CC=C(Cl)C=C1C(=O)C1=CC=CC=C1 ZUWXHHBROGLWNH-UHFFFAOYSA-N 0.000 description 1
- RLZGJZACKNYMHL-UHFFFAOYSA-N (2-benzoylphenyl) thiocyanate Chemical compound S(C#N)C1=C(C(=O)C2=CC=CC=C2)C=CC=C1 RLZGJZACKNYMHL-UHFFFAOYSA-N 0.000 description 1
- HRPHZUAPQWJPCZ-UHFFFAOYSA-N (2-chloro-5-nitrophenyl)-phenylmethanone Chemical compound [O-][N+](=O)C1=CC=C(Cl)C(C(=O)C=2C=CC=CC=2)=C1 HRPHZUAPQWJPCZ-UHFFFAOYSA-N 0.000 description 1
- UAHUVUPAWHHOLG-UHFFFAOYSA-N (5-nitro-2-sulfanylphenyl)-phenylmethanone Chemical compound SC1=C(C(=O)C2=CC=CC=C2)C=C(C=C1)[N+](=O)[O-] UAHUVUPAWHHOLG-UHFFFAOYSA-N 0.000 description 1
- TUPGNPRENOAMPM-UHFFFAOYSA-N 1$l^{4},4-benzothiazepine 1-oxide Chemical class O=S1C=CN=CC2=CC=CC=C12 TUPGNPRENOAMPM-UHFFFAOYSA-N 0.000 description 1
- FHGWEHGZBUBQKL-UHFFFAOYSA-N 1,2-benzothiazepine Chemical compound S1N=CC=CC2=CC=CC=C12 FHGWEHGZBUBQKL-UHFFFAOYSA-N 0.000 description 1
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- KYVHGCKMVJDCNV-UHFFFAOYSA-N 1,4-benzothiazepine Chemical class S1C=CN=CC2=CC=CC=C12 KYVHGCKMVJDCNV-UHFFFAOYSA-N 0.000 description 1
- XYPISWUKQGWYGX-UHFFFAOYSA-N 2,2,2-trifluoroethaneperoxoic acid Chemical compound OOC(=O)C(F)(F)F XYPISWUKQGWYGX-UHFFFAOYSA-N 0.000 description 1
- YIBLPFQAJZNUGU-UHFFFAOYSA-N 2-[2-(4-amino-2-benzoylphenyl)sulfanylethyl]isoindole-1,3-dione Chemical compound NC1=CC(=C(C=C1)SCCN1C(C=2C(C1=O)=CC=CC2)=O)C(C2=CC=CC=C2)=O YIBLPFQAJZNUGU-UHFFFAOYSA-N 0.000 description 1
- RILZRCJGXSFXNE-UHFFFAOYSA-N 2-[4-(trifluoromethoxy)phenyl]ethanol Chemical compound OCCC1=CC=C(OC(F)(F)F)C=C1 RILZRCJGXSFXNE-UHFFFAOYSA-N 0.000 description 1
- WJAXXWSZNSFVNG-UHFFFAOYSA-N 2-bromoethanamine;hydron;bromide Chemical compound [Br-].[NH3+]CCBr WJAXXWSZNSFVNG-UHFFFAOYSA-N 0.000 description 1
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 1
- 125000004080 3-carboxypropanoyl group Chemical group O=C([*])C([H])([H])C([H])([H])C(O[H])=O 0.000 description 1
- KJDGYQDHCKSNGO-UHFFFAOYSA-M 4,5-dimethoxy-2-(3-phenylpropanoyl)benzenediazonium chloride Chemical compound [Cl-].COC1=CC(=C(C=C1OC)[N+]#N)C(CCC1=CC=CC=C1)=O KJDGYQDHCKSNGO-UHFFFAOYSA-M 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
- AJOGEZHHNFUDSH-UHFFFAOYSA-N 7-bromo-5-pyridin-2-yl-2,3-dihydro-1,4-benzothiazepine Chemical compound BrC=1C=CC2=C(C(=NCCS2)C2=NC=CC=C2)C1 AJOGEZHHNFUDSH-UHFFFAOYSA-N 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 1
- KCYYFZUVEOVXGL-UHFFFAOYSA-N Br.NCBr Chemical compound Br.NCBr KCYYFZUVEOVXGL-UHFFFAOYSA-N 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 1
- MYIUIDSJQOGWOH-UHFFFAOYSA-N C1(=CC=CC=C1)C1=NCCS(C2=C1C=CC=C2)=O Chemical compound C1(=CC=CC=C1)C1=NCCS(C2=C1C=CC=C2)=O MYIUIDSJQOGWOH-UHFFFAOYSA-N 0.000 description 1
- LOZHAUIBHUXAJC-UHFFFAOYSA-N COC(C=C(C(CC(CC(C1=CC=CC=C1)C(C(N)=C1)=CC(OC)=C1OC)=O)C1=CC=CC=C1)C(N)=C1)=C1OC Chemical compound COC(C=C(C(CC(CC(C1=CC=CC=C1)C(C(N)=C1)=CC(OC)=C1OC)=O)C1=CC=CC=C1)C(N)=C1)=C1OC LOZHAUIBHUXAJC-UHFFFAOYSA-N 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- 239000004215 Carbon black (E152) Substances 0.000 description 1
- CVLNPAUGPYBWLR-UHFFFAOYSA-N Cl.FC(C=1C=CC2=C(C(NCCS2)C2=CC=CC=C2)C1)(F)F Chemical compound Cl.FC(C=1C=CC2=C(C(NCCS2)C2=CC=CC=C2)C1)(F)F CVLNPAUGPYBWLR-UHFFFAOYSA-N 0.000 description 1
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- KRHYYFGTRYWZRS-UHFFFAOYSA-M Fluoride anion Chemical compound [F-] KRHYYFGTRYWZRS-UHFFFAOYSA-M 0.000 description 1
- 108010010803 Gelatin Proteins 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 1
- LQXVIMBHDPRUHQ-UHFFFAOYSA-N NCCSC1=C(C(=O)C2=CC=CC=C2)C=C(C=C1)C(F)(F)F Chemical compound NCCSC1=C(C(=O)C2=CC=CC=C2)C=C(C=C1)C(F)(F)F LQXVIMBHDPRUHQ-UHFFFAOYSA-N 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 1
- NRMOBHGSHDKJLW-UHFFFAOYSA-N [2-amino-5-(trifluoromethyl)phenyl]-phenylmethanone Chemical compound NC1=CC=C(C(F)(F)F)C=C1C(=O)C1=CC=CC=C1 NRMOBHGSHDKJLW-UHFFFAOYSA-N 0.000 description 1
- QHDJJBSLUFDASY-UHFFFAOYSA-N [2-chloro-5-(trifluoromethyl)phenyl]-phenylmethanone Chemical compound FC(F)(F)C1=CC=C(Cl)C(C(=O)C=2C=CC=CC=2)=C1 QHDJJBSLUFDASY-UHFFFAOYSA-N 0.000 description 1
- CIUQDSCDWFSTQR-UHFFFAOYSA-N [C]1=CC=CC=C1 Chemical class [C]1=CC=CC=C1 CIUQDSCDWFSTQR-UHFFFAOYSA-N 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- PBCJIPOGFJYBJE-UHFFFAOYSA-N acetonitrile;hydrate Chemical compound O.CC#N PBCJIPOGFJYBJE-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
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 125000004442 acylamino group Chemical group 0.000 description 1
- 230000010933 acylation Effects 0.000 description 1
- 238000005917 acylation reaction Methods 0.000 description 1
- 229910000102 alkali metal hydride Inorganic materials 0.000 description 1
- 150000008046 alkali metal hydrides Chemical class 0.000 description 1
- 150000008044 alkali metal hydroxides Chemical class 0.000 description 1
- 239000012670 alkaline solution Substances 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 239000000908 ammonium hydroxide Substances 0.000 description 1
- 150000001450 anions Chemical group 0.000 description 1
- 229940125681 anticonvulsant agent Drugs 0.000 description 1
- 239000001961 anticonvulsive agent Substances 0.000 description 1
- 125000004429 atom Chemical group 0.000 description 1
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 description 1
- 239000000872 buffer Substances 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- 125000001589 carboacyl group Chemical group 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 125000004432 carbon atom Chemical group C* 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 229910052802 copper Inorganic materials 0.000 description 1
- 239000010949 copper Substances 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 150000008050 dialkyl sulfates Chemical class 0.000 description 1
- 150000001989 diazonium salts Chemical class 0.000 description 1
- QGGZBXOADPVUPN-UHFFFAOYSA-N dihydrochalcone Chemical compound C=1C=CC=CC=1C(=O)CCC1=CC=CC=C1 QGGZBXOADPVUPN-UHFFFAOYSA-N 0.000 description 1
- VAYGXNSJCAHWJZ-UHFFFAOYSA-N dimethyl sulfate Chemical compound COS(=O)(=O)OC VAYGXNSJCAHWJZ-UHFFFAOYSA-N 0.000 description 1
- 239000008298 dragée Substances 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 238000010828 elution Methods 0.000 description 1
- 239000003995 emulsifying agent Substances 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- MDKXBBPLEGPIRI-UHFFFAOYSA-N ethoxyethane;methanol Chemical compound OC.CCOCC MDKXBBPLEGPIRI-UHFFFAOYSA-N 0.000 description 1
- 230000004992 fission Effects 0.000 description 1
- 235000013312 flour Nutrition 0.000 description 1
- 235000019253 formic acid Nutrition 0.000 description 1
- 239000000499 gel Substances 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- 239000012362 glacial acetic acid Substances 0.000 description 1
- 150000004820 halides Chemical class 0.000 description 1
- 125000005843 halogen group Chemical group 0.000 description 1
- 229930195733 hydrocarbon Natural products 0.000 description 1
- 150000002430 hydrocarbons Chemical class 0.000 description 1
- 230000003301 hydrolyzing effect Effects 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 1
- 229910052742 iron Inorganic materials 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 150000002576 ketones Chemical class 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 231100000053 low toxicity Toxicity 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 239000011976 maleic acid Substances 0.000 description 1
- 229940098779 methanesulfonic acid Drugs 0.000 description 1
- GBMDVOWEEQVZKZ-UHFFFAOYSA-N methanol;hydrate Chemical compound O.OC GBMDVOWEEQVZKZ-UHFFFAOYSA-N 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 229940035363 muscle relaxants Drugs 0.000 description 1
- 239000003158 myorelaxant agent Substances 0.000 description 1
- 239000012299 nitrogen atmosphere Substances 0.000 description 1
- VQTGUFBGYOIUFS-UHFFFAOYSA-N nitrosylsulfuric acid Chemical compound OS(=O)(=O)ON=O VQTGUFBGYOIUFS-UHFFFAOYSA-N 0.000 description 1
- 239000001272 nitrous oxide Substances 0.000 description 1
- 230000003204 osmotic effect Effects 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- GCSHUYKULREZSJ-UHFFFAOYSA-N phenyl(pyridin-2-yl)methanone Chemical compound C=1C=CC=NC=1C(=O)C1=CC=CC=C1 GCSHUYKULREZSJ-UHFFFAOYSA-N 0.000 description 1
- SPEXCGKGVJUPGG-UHFFFAOYSA-N phenyl-(2-sulfanylphenyl)methanone Chemical compound SC1=CC=CC=C1C(=O)C1=CC=CC=C1 SPEXCGKGVJUPGG-UHFFFAOYSA-N 0.000 description 1
- FAIAAWCVCHQXDN-UHFFFAOYSA-N phosphorus trichloride Chemical compound ClP(Cl)Cl FAIAAWCVCHQXDN-UHFFFAOYSA-N 0.000 description 1
- 125000000612 phthaloyl group Chemical group C(C=1C(C(=O)*)=CC=CC1)(=O)* 0.000 description 1
- 229910052697 platinum Inorganic materials 0.000 description 1
- 229920001515 polyalkylene glycol Polymers 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 125000001501 propionyl group Chemical group O=C([*])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 239000012429 reaction media Substances 0.000 description 1
- 238000006798 ring closing metathesis reaction Methods 0.000 description 1
- 239000005060 rubber Substances 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- RZFBEFUNINJXRQ-UHFFFAOYSA-M sodium ethyl xanthate Chemical compound [Na+].CCOC([S-])=S RZFBEFUNINJXRQ-UHFFFAOYSA-M 0.000 description 1
- 239000011877 solvent mixture Substances 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 239000001384 succinic acid Substances 0.000 description 1
- 150000003467 sulfuric acid derivatives Chemical class 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 238000010408 sweeping Methods 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 235000012222 talc Nutrition 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 1
- 235000015112 vegetable and seed oil Nutrition 0.000 description 1
- 239000008158 vegetable oil Substances 0.000 description 1
- 238000009736 wetting Methods 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
Classifications
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B65—CONVEYING; PACKING; STORING; HANDLING THIN OR FILAMENTARY MATERIAL
- B65D—CONTAINERS FOR STORAGE OR TRANSPORT OF ARTICLES OR MATERIALS, e.g. BAGS, BARRELS, BOTTLES, BOXES, CANS, CARTONS, CRATES, DRUMS, JARS, TANKS, HOPPERS, FORWARDING CONTAINERS; ACCESSORIES, CLOSURES, OR FITTINGS THEREFOR; PACKAGING ELEMENTS; PACKAGES
- B65D47/00—Closures with filling and discharging, or with discharging, devices
- B65D47/04—Closures with discharging devices other than pumps
- B65D47/06—Closures with discharging devices other than pumps with pouring spouts or tubes; with discharge nozzles or passages
- B65D47/12—Closures with discharging devices other than pumps with pouring spouts or tubes; with discharge nozzles or passages having removable closures
- B65D47/122—Threaded caps
- B65D47/123—Threaded caps with internal parts
Landscapes
- Engineering & Computer Science (AREA)
- Mechanical Engineering (AREA)
- Medical Preparation Storing Or Oral Administration Devices (AREA)
- Closures For Containers (AREA)
- Medicinal Preparation (AREA)
- Containers And Packaging Bodies Having A Special Means To Remove Contents (AREA)
Description
Fremgangsmåte for fremstilling av farmasøytisk anvendbare benzothiazepin-derivater. Process for the preparation of pharmaceutically usable benzothiazepine derivatives.
Oppfinnelsen vedrører en fremgangsmåte for fremstilling av hittil ukjente 1,4-benzothiazepiner med den generelle formel The invention relates to a process for the production of hitherto unknown 1,4-benzothiazepines with the general formula
hvor X betegner -S-, -SO- eller -SOa-, where X denotes -S-, -SO- or -SOa-,
R og R, hydrogen, halogen, lavere al- R and R, hydrogen, halogen, lower al-
kyl, lavere alkoxy eller trifluor-methyl, kyl, lower alkoxy or trifluoromethyl,
R2 fenyl, halofenyl, lavere alkylfenyl, trifluormethylfenyl eller pyridyl, R.,, R2 phenyl, halophenyl, lower alkylphenyl, trifluoromethylphenyl or pyridyl, R.,,
R,, og R5 hydrogen eller lavere alkyl, R 1 and R 5 are hydrogen or lower alkyl,
R(i hydrogen, R- hydrogen, lavere alkyl R(in hydrogen, R- hydrogen, lower alkyl
eller lavere alkanoyl, eller R(i og R7 betegner en ytterligere C-N-binding eller, or lower alkanoyl, or R(i and R7 represent an additional C-N bond or,
når X betegner gruppen -S02-, en C-N-binding og et oxygenatom bundet til nitrogenatomet. when X denotes the group -SO2-, a C-N bond and an oxygen atom bonded to the nitrogen atom.
Fremstilling av syreaddisjonssalter av basiske forbindelser med foran nevnte for- Preparation of acid addition salts of basic compounds with the aforementioned
mel omfattes også av nærværende oppfinnelse. flour is also covered by the present invention.
I formel I er R, fortrinnsvis bundet In formula I, R is preferably bonded
til benzothiazepin-kjernen i 7-stilling og R er hydrogen. Hvis R2 er et substituert fenyl-radikal, er en slik substituent fortrinnsvis bundet i 2'-stilling i nevnte fe- to the benzothiazepine nucleus in the 7-position and R is hydrogen. If R2 is a substituted phenyl radical, such a substituent is preferably attached in the 2'-position in said fe-
nyl-radikal, R3 og R,, er fortrinnsvis hydro- nyl radical, R3 and R1, are preferably hydro-
gen, og likeledes er R- fortrinnsvis hydrogen. gene, and likewise R- is preferably hydrogen.
En foretrukket klasse av forbindelser A preferred class of compounds
er forbindelser med formel I, hvor X er -S-, are compounds of formula I, where X is -S-,
R og R, har ovenfor nevnte betydning, R2 betegner fenyl, halofenyl, lavere alkyl-fenyl eller trifluormethylfenyl, R3, R4 og Rg hydrogen eller lavere alkyl og" R6 og R7 en C-N-binding. R and R have the above meaning, R 2 denotes phenyl, halophenyl, lower alkyl-phenyl or trifluoromethylphenyl, R 3 , R 4 and R 8 hydrogen or lower alkyl and R 6 and R 7 a C-N bond.
Spesielt foretrukne forbindelser med særlig sterk virkning og lav toksisitet er: 7-klor-2,3-dihydro-5-fenyl-l,4-benzothiazepin, 7-klor-2,3-dihydro-5-fenyl-l,4-benzothiazepin-1,1 -dioxyd, 7-klor-2,3-dihydro-5-fenyl-l,4-benzothiazepin-l-oxyd. Particularly preferred compounds with particularly strong effects and low toxicity are: 7-chloro-2,3-dihydro-5-phenyl-1,4-benzothiazepine, 7-chloro-2,3-dihydro-5-phenyl-1,4- benzothiazepine-1,1-dioxide, 7-chloro-2,3-dihydro-5-phenyl-1,4-benzothiazepine-1-oxide.
Uttrykket «lavere alkyl» som anvendt The term "lower alkyl" as used
i nærværende beskrivelse enten alene eller i forbindelser (f. eks. «lavere alkoxy»), tilsikter å betegne både rette og forgrenete lavere alkylgrupper med høyst 4 karbon-atomer f. eks. methyl, ethyl, propyl og isopropyl. in the present description, either alone or in compounds (e.g. "lower alkoxy"), is intended to denote both straight and branched lower alkyl groups with no more than 4 carbon atoms, e.g. methyl, ethyl, propyl and isopropyl.
Uttrykket «halogen» tilsikter å betegne The term "halogen" is intended to denote
alle fire halogenene, nemlig klor, brom, all four halogens, namely chlorine, bromine,
jod og fluor. Foretrukket blant halogenene er brom og klor. iodine and fluoride. Preferred among the halogens are bromine and chlorine.
I sin mest omfattende utførelsesform karakteriseres fremgangsmåten ifølge nærværende oppfinnelse ved at man behand- In its most extensive embodiment, the method according to the present invention is characterized by treating
ler en forbindelse med den generelle formel Ila ler a compound of the general formula IIa
med en forbindelse med den generelle formel Hb with a compound of the general formula Hb
hvor i formlene Ila og Hb et av symbolene Y og 2 betegner halogen og det andre mercapto, R, R,, Rs, R.„ R., og R5 har den foran angitte betydning, og R,, betegner amino eller en beskyttet where in formulas Ia and Hb one of the symbols Y and 2 denotes halogen and the other mercapto, R, R,, Rs, R.
aminogruppe, amino group,
avspalter eventuelt tilstedeværende beskyttende grupper, cykliserer åpenkjedete forbindelser ved anvendelse av varme og, hvis ønsket, underkaster den oppnådde forbindelse med den generelle formel III cleaves any protecting groups present, cyclizes open-chain compounds using heat and, if desired, subjects the resulting compound of the general formula III
hvor R, R,, R„, R.„ R, og R- har foran where R, R,, R„, R.„ R, and R- are preceded
angitte betydning, stated meaning,
et eller flere av reaksjonstrinnene som består i: behandling av en forbindelse med formel III med hydrogenperoxyd eller en persyre fulgt av oppvarming av et således oppnådd oxaziran i nærvær av et inert organisk oppløsningsmiddel, deoxydering av et således oppnådd N-oxyd ved behandling; med et reduksjonsmiddel eller ved hydrering i nærvær av Raney-nikkel, reduksjon av en således oppnådd forbindelse i nærvær av en hydreringskatalysator, behandling av en forbindelse med formel III med et perjodat eller en beregnet mengde av en persyre til dannelse av en sulfinylgruppe i 1-stilling, reduksjon av en forbindelse med formel III med lithiumaluminiumhydrid eller ved katalytisk hydrering i nærvær av en edelmetallkatalysator, behandling av en således oppnådd forbindelse med perjodat eller med hydrogenperoxyd eller en persyre, behandling av et oppnådd 1,1,4-trioxyd som bærer et hydro- one or more of the reaction steps consisting of: treating a compound of formula III with hydrogen peroxide or a peracid followed by heating a thus obtained oxaziran in the presence of an inert organic solvent, deoxidizing a thus obtained N-oxide by treatment; with a reducing agent or by hydrogenation in the presence of Raney nickel, reduction of a compound thus obtained in the presence of a hydrogenation catalyst, treatment of a compound of formula III with a periodate or a calculated amount of a peracid to form a sulfinyl group in 1- position, reduction of a compound of formula III with lithium aluminum hydride or by catalytic hydrogenation in the presence of a noble metal catalyst, treatment of a thus obtained compound with periodate or with hydrogen peroxide or a peracid, treatment of an obtained 1,1,4-trioxide bearing a hydro-
genatom i 2-stilling, med et anhydrid av en alkansyre fulgt av behandling av en således oppnådd forbindelse med lithiumaluminiumhydrid, innføring av en lavere alkyl eller alkanoylgruppe i en forbindelse som feierer et hydrogenatom i 4-stilling, omvandling av en basisk forbindelse til et syreaddisjonssalt. gene atom in the 2-position, with an anhydride of an alkanoic acid followed by treatment of a compound thus obtained with lithium aluminum hydride, introduction of a lower alkyl or alkanoyl group into a compound sweeping a hydrogen atom in the 4-position, conversion of a basic compound into an acid addition salt .
En spesiell utførelsesform av fremgangsmåten ifølge oppfinnelsen består i å anvende som utgangsmaterialer forbindelser med formel Ila og Hb, hvor et av symbolene Y og Z betegner halogen og det andre mercapto, R betegner hydrogen, R, hydrogen, halogen, lavere alkyl eller trifluormethyl, R2 fenyl, halofenyl, lavere alkyl-fenyl eller trifluormethylfenyl, R.,, R, og R- hydrogen eller lavere alkyl og R,, amino eller en beskyttet aminogruppe, hvis ønsket, avspaltning av eventuelt beskyttende grupper, cyklisering av åpenkjedete forbindelser og, hvis ønsket, underkaste det oppnådde produkt en eller flere av de eventuelle reaksjonstrinn omtalt i foregå-ende avsnitt unntagen katalytisk hydrering av en forbindelse med formel III i nærvær av en edelmetallkatalysator og inn-føring av en lavere alkyl. A special embodiment of the method according to the invention consists in using as starting materials compounds of formula Ila and Hb, where one of the symbols Y and Z denotes halogen and the other mercapto, R denotes hydrogen, R, hydrogen, halogen, lower alkyl or trifluoromethyl, R2 phenyl, halophenyl, lower alkyl-phenyl or trifluoromethylphenyl, R.,, R, and R- hydrogen or lower alkyl and R,, amino or a protected amino group, if desired, removal of any protecting groups, cyclization of open-chain compounds and, if if desired, subject the obtained product to one or more of the possible reaction steps mentioned in the preceding paragraph except catalytic hydrogenation of a compound of formula III in the presence of a noble metal catalyst and introduction of a lower alkyl.
Ifølge et trekk ved nærværende oppfinnelse reagerer en forbindelse med den generelle formel IVa According to a feature of the present invention, a compound of the general formula IVa reacts
hvor R, R, og R2 er som foran beskrevet, med en forbindelse med den generelle formel IVb hvor Rs, R4 og R-, er som foran beskrevet, og hvor haloatomet fortrinnsvis er klor og brom, fortrinnsvis i nærvær av et vanlig inert oppløsningsmiddel som kan være vann, en alkohol f. eks. methanol og lignende og en base f. eks. natriumhydroxyd, og gir derved en blanding som inneholder en forbindelse med formel III og en forbindelse med formel V wherein R, R, and R 2 are as described above, with a compound of the general formula IVb wherein R s , R 4 and R-, are as described above, and wherein the halo atom is preferably chlorine and bromine, preferably in the presence of a common inert solvent which can be water, an alcohol e.g. methanol and the like and a base, e.g. sodium hydroxide, thereby giving a mixture containing a compound of formula III and a compound of formula V
hvor R, R,, R2, R;j, R4 og Rr, er som foran beskrevet. where R, R1, R2, R;j, R4 and Rr, are as described above.
Forbindelser med formel V kan videre reagere med eller uten isolering fra reak-sjonsmediet i hvilket de er fremstilt, for å gi forbindelser med formel III. F. eks. kan reaksjonsblandingen som inneholder forbindelsene med formel III og V, uten isolering enten oppvarmes i nærvær av et inert organisk oppløsningsmiddel som pyridin og lignende for å bevirke cyklisering av forbindelser med formel V. Således økes utbytte av av forbindelser med formel III. Compounds of formula V can further react with or without isolation from the reaction medium in which they are prepared, to give compounds of formula III. For example the reaction mixture containing the compounds of formula III and V, without isolation, can either be heated in the presence of an inert organic solvent such as pyridine and the like to effect cyclization of compounds of formula V. Thus, the yield of compounds of formula III is increased.
Forbindelser med formel V kan altså fremstilles ved reaksjon av en forbindelse med den generelle formel Via Compounds of formula V can thus be prepared by reaction of a compound with the general formula Via
hvor R, R, og R:, er som foran beskrevet, med en forbindelse med formel VIb fortrinnsvis i nærvær av en sterk base, helst et alkalimetallhydroxyd eller et alka-limetallalkylat eller et alkalimetallhydrid, f. eks. natriumhydrid og et inert organisk oppløsningsmiddel som pyridin. De således dannede forbindelser med formel V kan så oppvarmes i nærvær av et inert organisk oppløsningsmiddel som pyridin og lignende, hvorved ringslutning til forbindelser med formel III opptrer. I en alternativ metode for fremstilling av forbindelser med formel V (forbindelser som ved oppvarming i nærvær av et inert organisk oppløsningsmiddel som pyridin og lignende cykliserer til forbindelser med formel III) reagerer en forbindelse med formel IVa med en forbindelse med formel IVc where R, R, and R:, are as described above, with a compound of formula VIb preferably in the presence of a strong base, preferably an alkali metal hydroxide or an alkali metal alkylate or an alkali metal hydride, e.g. sodium hydride and an inert organic solvent such as pyridine. The thus formed compounds of formula V can then be heated in the presence of an inert organic solvent such as pyridine and the like, whereby ring closure to compounds of formula III occurs. In an alternative method for the preparation of compounds of formula V (compounds which on heating in the presence of an inert organic solvent such as pyridine and the like cyclize to compounds of formula III) a compound of formula IVa reacts with a compound of formula IVc
hvor R3, R, og R- er som foran beskrevet og R9 er en beskyttet aminogruppe, d.v.s. en acylamino eller en diacylaminogruppe. Slike beskyttende grupper er f. eks. propionyl, acetyl, benzoyl, fthaloyl, succinyl og lignende. Alt det som i det vesentlige kreves av beskyttelsesgruppene, er at de er lett hyd-rolyserbare ved anvendelse av vanlige fremgangsmåter. where R3, R, and R- are as described above and R9 is a protected amino group, i.e. an acylamino or a diacylamino group. Such protective groups are e.g. propionyl, acetyl, benzoyl, phthaloyl, succinyl and the like. All that is essentially required of the protecting groups is that they are easily hydrolysable using conventional methods.
Den resulterende forbindelse som har The resulting compound that has
formel VII formula VII
hvor R, R,, R2, R,,, R, og R3 er som foran beskrevet og RS) er en beskyttet aminogruppe, kan hydrolyseres til forbindelser med formel V f. eks. under sure betingelser. Det følgende er en generell beskrivelse av metodene for fremstilling av noen utgangsmaterialer. Fremgangsmåten for fremstilling av forbindelser med formel IVa omfatter først reaksjon av det tilsvarende 2-aminobenzenketon med salpe-tersyrling i nærvær av et overskudd av en sterk mineralsyre, f. eks. saltsyre, svovelsyre og lignende. Den resulterende blanding kan behandles med et salt av fluor-borsyre som et alkalimetallsalt, f. eks. natriumfluorborat. På denne måte fremstilles diazoniumforbindelser med formel VIII where R, R,, R2, R,, R, and R3 are as described above and RS) is a protected amino group, can be hydrolyzed to compounds of formula V e.g. under acidic conditions. The following is a general description of the methods for producing some starting materials. The process for preparing compounds of formula IVa first comprises reaction of the corresponding 2-aminobenzene ketone with nitrous oxide in the presence of an excess of a strong mineral acid, e.g. hydrochloric acid, sulfuric acid and the like. The resulting mixture can be treated with a salt of fluoroboric acid as an alkali metal salt, e.g. sodium fluoroborate. Diazonium compounds of formula VIII are prepared in this way
hvor R, R, og Rc, er som foran beskrevet og X er et anion av en sterk mineralsyre eller radikalet BF4- where R, R, and Rc are as described above and X is an anion of a strong mineral acid or the radical BF4-
Ved dannelse av forbindelser med formel VIII kan salpetersyrlingen forenes med mineralsyrene for å danne en forbindelse som nitrosylsulfat og lignende og en slik forbindelse kan spille en rolle i dannelsen av forbindelser med formel VIII. In the formation of compounds of formula VIII, the nitric acid can combine with the mineral acids to form a compound such as nitrosyl sulfate and the like, and such a compound can play a role in the formation of compounds of formula VIII.
De således dannede forbindelser med formel VIII reagerer så med et xanthat, det vil si et salt av xanthogensyre f. eks. et alkalimetallxanthat, f. eks. natriumxanthat og kalsiumxanthat eller et jordalkalisk metallxanthat, for å fremskaffe forbindelse med formel IX The thus formed compounds of formula VIII then react with a xanthate, that is to say a salt of xanthogenic acid, e.g. an alkali metal xanthate, e.g. sodium xanthate and calcium xanthate or an alkaline earth metal xanthate, to provide compound of formula IX
hvor R, R, og R2 er som foran beskrevet, som så kan hydrolyseres, fortrinnsvis under basiske betingelser ved anvendelse av vanlig hydrolyse-teknikk til forbindelser med formel IVa. Egnete xanthater er jord-alkalimetall eller alkalimetallsalter av al-kylxanthater. Forbindelser med formel IVa kan altså fremstilles fra forbindelser med formel VIII ved behandling av forbindelser med formel VIII med et metall-thiocyanat, f. eks. kobberthiocyanat, til en forbindelse med den generelle formel X where R, R, and R2 are as described above, which can then be hydrolysed, preferably under basic conditions using the usual hydrolysis technique for compounds of formula IVa. Suitable xanthates are alkaline earth metal or alkali metal salts of alkyl xanthates. Compounds of formula IVa can thus be prepared from compounds of formula VIII by treating compounds of formula VIII with a metal thiocyanate, e.g. copper thiocyanate, to a compound of the general formula X
hvor R, R1 og R2 er som foran beskrevet, og deretter hydrolysering, fortrinnsvis under basiske betingelser, av den resulterende forbindelse med formel X til forbindelser med formel IVa ved anvendelse av vanlig hydrolyse-teknikk. where R, R1 and R2 are as described above, and then hydrolyzing, preferably under basic conditions, the resulting compound of formula X to compounds of formula IVa using conventional hydrolysis techniques.
Den cykliserte forbindelse med formel III kan underkastes en rekke av de etter-følgende trinn og sekvente trinn som skis-sert i alminnelighet ovenfor. En mer detal-jert forklaring er gitt senere. The cyclized compound of formula III may be subjected to a series of subsequent steps and sequential steps as outlined generally above. A more detailed explanation is given later.
Ved en metode behandles en forbindelse med formel III med enhver hensikts-messig persyre som pereddiksyre eller hydrogenperoxyd ved en temperatur på 0— 150°C, fortrinnsvis 10—60°C i nærvær av en syre som eddiksyre og lignende for å fremstille et oxaziran med den generelle formel XI In one method, a compound of formula III is treated with any suitable peracid such as peracetic acid or hydrogen peroxide at a temperature of 0-150°C, preferably 10-60°C in the presence of an acid such as acetic acid and the like to produce an oxaziran with the general formula XI
hvor R, R1( R2, R3, Rj og R5 er foran beskrévet. Den resulterende forbindelse gir ved oppvarming i nærvær av et inert organisk oppløsningsmiddel som xylen, toluen og lignende forbindelser med den generelle formel XII hvor R, R,, R2, R3, R4 og R5 er som foran beskrevet. Forbindelser med formel XII kan de-oxyderes i 4-stilling ved behandling med reduksjonsmiddel som fosfortriklorid eller ved hydrering i nærvær av Raney-nikkel. Denne resulterende forbindelse som har den generelle formel XIII hvor R, R,, R2, R;j, R4 og R5 er som foran beskrevet, kan videre reduseres ved hydrering i nærvær av en vanlig hydreringskatalysator som en edelmetallkatalysator, f. eks. pla-tinaoxyd og lignende eller et alkalimetall-eller et jordalkalimetallborhydrid som natriumborhydrid, for å gi forbindelser med den generelle formel XIV hvor R, Rv <R>2, R:), R4 og R5 er som foran beskrevet. Forbindelser med formel III kan altså behandles med et oxydasjonsmiddel som et perjodat, f. eks. et alkalimetallperjodat, eller med en beregnet mengde av en persyre for å danne en forbindelse med den generelle formel XV hvor R, R4, R2, R.j, R, og R5 er som foran beskrevet. Ved enda en annen metode kan forbindelser med formel III reduseres med lithiumaluminiumhydrid eller ved katalytisk hydrering i nærvær av en edelmetallkatalysator som platina, for å gi forbindelser med formel XVI where R, R1( R2, R3, Rj and R5 are as previously described. The resulting compound on heating in the presence of an inert organic solvent such as xylene, toluene and similar compounds of the general formula XII where R, R1, R2, R3 . ,, R2, R;j, R4 and R5 are as described above, can be further reduced by hydrogenation in the presence of a common hydrogenation catalyst such as a noble metal catalyst, e.g. platinum oxide and the like or an alkali metal or an alkaline earth metal borohydride such as sodium borohydride, to give compounds of the general formula XIV where R, Rv<R>2, R:), R4 and R5 are as described above. Compounds of formula III can thus be treated with an oxidizing agent such as a periodate, e.g. an alkali metal periodate, or with a calculated amount of a peracid to form a compound of the general formula XV wherein R, R 4 , R 2 , R 1 , R 1 , and R 5 are as previously described. In yet another method, compounds of formula III can be reduced with lithium aluminum hydride or by catalytic hydrogenation in the presence of a noble metal catalyst such as platinum to give compounds of formula XVI
hvor R, R,, R„ R3, R,, og R5 er som foran beskrevet. where R, R1, R„ R3, R1, and R5 are as described above.
Forbindelser med formel XVI kan videre selektivt behandles med enten et me-tallperjodat for å gi de tilsvarende forbindelser med en sulfinylgruppe i 1-stilling eller med et sterkt oxydasjonsmiddel, f. eks. en persyre som pereddiksyre eller trifluor-pereddiksyre eller hydrogenperoxyd, for å gi de tilsvarende forbindelser med en sul-fonylgruppe i 1-stilling. Compounds of formula XVI can further be selectively treated with either a metal periodate to give the corresponding compounds with a sulfinyl group in the 1-position or with a strong oxidizing agent, e.g. a peracid such as peracetic acid or trifluoroperacetic acid or hydrogen peroxide, to give the corresponding compounds with a sulphonyl group in the 1-position.
Behandlingen med lithiumaluminiumhydrid som beskrevet ovenfor, d.v.s. dan- The treatment with lithium aluminum hydride as described above, i.e. dan-
nelsen av 2,3,4,5-tetrahydro-l,4-benzothi-azepiner, utføres i et hvert tilfelle ved en temperatur på -h20 til +90°C, fortrinnsvis H-5 til -f40°C, i nærvær av ethvert vanlig tilgjengelig inert organisk oppløsningsmid-del som tetrahydrofuran eller en ether som diethylether, dimethylether og lignende. Behandlingen med. et alkalimetallperjodat som beskrevet ovenfor, dvs. dannelsen av 1,4-benzothiazepin-l-oxyder, utføres i et hvert tilfelle fortrinnsvis i nærvær av et inert organisk oppløsningsmiddel som en alkohol, f. eks. methanol, ethanol og lignende, et keton som aceton og methyl-ethylketon, dioxan og lignende ved en temperatur i området h-10 til + 60°C, fortrinnsvis H-5 til +40°C. The synthesis of 2,3,4,5-tetrahydro-1,4-benzothi-azepines is carried out in each case at a temperature of -h20 to +90°C, preferably -5 to -f40°C, in the presence of any commonly available inert organic solvent such as tetrahydrofuran or an ether such as diethyl ether, dimethyl ether and the like. The treatment with. an alkali metal periodate as described above, i.e. the formation of 1,4-benzothiazepine-1-oxides, is carried out in each case preferably in the presence of an inert organic solvent such as an alcohol, e.g. methanol, ethanol and the like, a ketone such as acetone and methyl ethyl ketone, dioxane and the like at a temperature in the range h-10 to +60°C, preferably H-5 to +40°C.
Forbindelser med den generelle formel XVII Compounds of the general formula XVII
hvor R, Rt, R2, R3, R4 og R0 er som foran beskrevet, where R, Rt, R2, R3, R4 and R0 are as described above,
kan behandles med f. eks. et anhydrid av en alkansyre, f. eks. acetanhydrid, for å gi forbindelser med den generelle formel can be treated with e.g. an anhydride of an alkanoic acid, e.g. acetic anhydride, to give compounds of the general formula
XVIII XVIII
hvor R, Rj, R2, R3 og R5 som foran beskrevet. where R, Rj, R2, R3 and R5 as described above.
Forbindelser med formel XVIII kan videre behandles forsiktig med lithiumaluminiumhydrid for derved å fremstille den tilsvarende forbindelse med formel XIII, hvor R4 er hydrogen. Compounds of formula XVIII can further be carefully treated with lithium aluminum hydride to thereby produce the corresponding compound of formula XIII, where R4 is hydrogen.
Forbindelser tilsvarende formel I, hvor R7 er lavere alkyl, kan syntetiseres fra de tilsvarende forbindelser med formel I, hvor R7 er hydrogen ved alkylering av slike forbindelser. Alkyleringen kan foregå f. eks. ved dannelse av natriumderivatet av forbindelser med formel I, hvor R7 er hydrogen, med et natriumalkylat som natrium-methoxyd i et inert organisk oppløs-ningsmiddel som toluen og så la natriumderivatet reagere med f. eks. dialkylsul-fat eller et alkylhalogenid i et inert opp-løsningsmiddel f. eks. et hydrokarbon eller dimethylformamid. Egnede dialkylsulfater kan være dimethylsulfat. Lignende egnede alkylhalogenider kan være methyljodid. Alternativt kan innføringen av alkylgrup-pen derfor utføres under analoge reak-sjonsbetingelser uten først å danne det nevnte natriumderivat. Compounds corresponding to formula I, where R7 is lower alkyl, can be synthesized from the corresponding compounds of formula I, where R7 is hydrogen by alkylation of such compounds. The alkylation can take place e.g. by forming the sodium derivative of compounds of formula I, where R7 is hydrogen, with a sodium alkylate such as sodium methoxy in an inert organic solvent such as toluene and then allowing the sodium derivative to react with e.g. dialkyl sulfate or an alkyl halide in an inert solvent, e.g. a hydrocarbon or dimethylformamide. Suitable dialkyl sulphates can be dimethyl sulphate. Similarly suitable alkyl halides may be methyl iodide. Alternatively, the introduction of the alkyl group can therefore be carried out under analogous reaction conditions without first forming the aforementioned sodium derivative.
Alkanoylering i 4-stilling kan utføres ved hjelp av vanlige alkanoyleringsmidler som alkansyrehalogenider eller anhydri-der, f. eks. eddiksyreanhydrid eller acetyl-klorid. Alkanoylation in the 4-position can be carried out using common alkanoylating agents such as alkanoic acid halides or anhydrides, e.g. acetic anhydride or acetyl chloride.
Forbindelser tilsvarende formel I er i alminnelighet basiske av natur og slike basiske forbindelser danner syreaddisjonssalter med uorganiske eller organiske syrer. Blant syrene som er egnet for saltdan-ningsformål omfattes slike syrer som mine-ralsyrer, f. eks. halogenhydrogensyrer som saltsyre, hydrobromidsyre og lignende, sal-petersyre, svovelsyre, fosforsyre, eddiksyre etc, og organiske syrer som maursyre, met-hansulfonsyre, p-toluensulfonsyre, ravsyre. sitronsyre, vinsyre, maleinsyre og lignende. Compounds corresponding to formula I are generally basic in nature and such basic compounds form acid addition salts with inorganic or organic acids. Among the acids which are suitable for salt formation purposes are included such acids as mineral acids, e.g. halogenated acids such as hydrochloric acid, hydrobromic acid and the like, nitric acid, sulfuric acid, phosphoric acid, acetic acid, etc., and organic acids such as formic acid, methanesulfonic acid, p-toluenesulfonic acid, succinic acid. citric acid, tartaric acid, maleic acid and the like.
Forbindelser med formel I er verdifulle som muskelrelakserende og antikon-vulserende midler. De farmakologisk virk-somme forbindelser kan anvendes som me-dikamenter i form av farmasøytiske pre-parater som inneholder forbindelsene eller saltene derav i blanding med en farma-søytisk organisk eller uorganisk, fast eller flytende bærer egnet for enteral, f .eks. oral eller parenteral administrasjon. For fremstilling av preparatene kan det anvendes substanser som ikke reagerer med forbindelsene, som vann, gelatin, lactose, stivelse, magnesiumstearat, talkum, vege-tabilske oljer, gummi, polyalkylenglykoler, petroleum, géler eller enhver annen kjent bærer anvendt for fremstillingen av medi-kamenter. De farmasøytiske preparatene kan foreligge i fast form, f. eks. som tab-letter, dragéer, suppositorier eller kapsler, eller i flytende form, f. eks. oppløsninger, emulsjoner eller suspensjoner. Hvis ønsket kan de steriliseres og/eller inneholde hjel-pemidler som konserverings-, stabiliser-ings-, fuktnings- eller emulgeringsmidler, salter til forandring av det osmotiske trykk eller puffere. De kan også inneholde i kombinasjon andre terapeutisk verdifulle substanser. Compounds of formula I are valuable as muscle relaxants and anticonvulsants. The pharmacologically active compounds can be used as medicines in the form of pharmaceutical preparations containing the compounds or their salts in admixture with a pharmaceutical organic or inorganic, solid or liquid carrier suitable for enteral use, e.g. oral or parenteral administration. For the preparation of the preparations, substances that do not react with the compounds can be used, such as water, gelatin, lactose, starch, magnesium stearate, talc, vegetable oils, rubber, polyalkylene glycols, petroleum, gels or any other known carrier used for the preparation of medi- comments. The pharmaceutical preparations can be in solid form, e.g. as tablets, dragées, suppositories or capsules, or in liquid form, e.g. solutions, emulsions or suspensions. If desired, they can be sterilized and/or contain auxiliaries such as preservatives, stabilisers, wetting or emulsifying agents, salts to change the osmotic pressure or buffers. They may also contain, in combination, other therapeutically valuable substances.
De følgende eksempler 3, 5—13, 19, 21— 26, 30—33 og 36—38 er illustrerende for The following examples 3, 5—13, 19, 21—26, 30—33 and 36—38 are illustrative of
oppfinnelsen, mens eksemplene 1, 2, 4, 14— 18, 20, 27—29, 34 og 35 viser fremstillingen av noen utgangsstoffer som kan anvendes. Alle temperaturene er angitt i Celsiusgra-der. the invention, while examples 1, 2, 4, 14-18, 20, 27-29, 34 and 35 show the preparation of some starting materials that can be used. All temperatures are given in degrees Celsius.
Eksempel 1. Example 1.
Til 450 ml konsentrert svovelsyre, av-kjølt til 10° tilsettes langsomt 76 g (1 mol) natriumnitrit under omrøring. Blandingen oppvarmes derpå til ca. 80° inntil en klar oppløsning er dannet. Ef ter avkjøling til 30° tilsettes 232 g (1 mol) 2-amino-5-klor-benzofenon porsjonsvis idet temperaturen holdes mellom 30—40°. Efter omrøring i 1 time helles oppløsningen langsomt til 3 1 isvann. Efter filtrering tilsettes en oppløs-ning av 200 g natriumfluorborat i 800 ml vann. 2-benzoyl-4-klor-benzendiazonium-fluorborat faller ut. Produktet skilles fra ved filtrering og vaskes med en liten mengde vann. To 450 ml of concentrated sulfuric acid, cooled to 10°, slowly add 76 g (1 mol) of sodium nitrite while stirring. The mixture is then heated to approx. 80° until a clear solution is formed. After cooling to 30°, 232 g (1 mol) of 2-amino-5-chloro-benzophenone are added in portions, keeping the temperature between 30-40°. After stirring for 1 hour, the solution is slowly poured into 3 1 of ice water. After filtration, a solution of 200 g of sodium fluoroborate in 800 ml of water is added. 2-benzoyl-4-chloro-benzenediazonium fluoroborate precipitates. The product is separated by filtration and washed with a small amount of water.
Eksempel 2. Example 2.
Fluorborat i eksempel 1 tilsettes i lø-pet av 5 minutter til en heftig omrørt opp-løsning av 240 g (1,5 mol) kaliumethylxanthat i 1,5 1 vann oppvarmet til 75°. The fluoroborate in example 1 is added over the course of 5 minutes to a vigorously stirred solution of 240 g (1.5 mol) of potassium ethyl xanthate in 1.5 l of water heated to 75°.
Efter at tilsetningen var avsluttet røres After the addition has finished, stir
blandingen om i 15 minutter, avkjøles og ekstraheres med ether. Etherekstraktet tør-kes over natriumsulfat, filtreres og filtratet konsentreres i vakuum til tørrhet og gir ethylxanthosyre 2-benzoyl-4-klorfenyl-esteren som rest. the mixture is stirred for 15 minutes, cooled and extracted with ether. The ether extract is dried over sodium sulphate, filtered and the filtrate is concentrated in vacuo to dryness and gives the ethyl xanthosic acid 2-benzoyl-4-chlorophenyl ester as a residue.
Eksempel 3. Example 3.
Resten i eksempel 2 tilsettes til en opp-løsning av 240 g kaliumhydroxyd i en blanding av 600 ml vann og 600 ml ethanol. Reaksjonsblandingen røres om og tilbake-løpsbehandles i 15 minutter, mens 35 g sinkstøv omhyggelig tilsettes. En liter vann tilsettes derpå og blandingen filtreres over et filter og vaskes med 500 ml vann. Filtratet som inneholder thiofenolet, 5-klor-2-mercaptobenzofenon, kjøles til romtemperatur og en oppløsning av 204 g bromethylaminhydrobromid i 350 ml vann tilsettes. Efter omrøring i 15 minutter ekstraheres reaksjonsblandingen med methylenklorid og det organiske lag tørkes over natriumsulfat og filtreres. Filtratet ansyres med methanolisk saltsyre og konsentreres i vakuum. Til resten som består av 7-klor-2,3-dihydro-5-fenyl-l,4-benzothiazepin og 5-klor-2-(2-aminoethylthio)benzofenon, tilsettes 1 liter pyridin. Oppløsningen til-bakeløpsbehandles i 1 time, konsentreres derefter i vakuum og residuet oppløses i en blanding av methylenklorid og vann. Det organiske lag separeres, tørkes, filtreres, og filtratet ansyres med ethanolisk saltsyre og fortynnes med ca. 300 ml ethanol. Opp-løsningen konsentreres i vakuum for å fjerne methylenklorid. 7-klor-2,3-dihydro-5-fenyl-l,4-benzothiazepinhydroklorid, som smelter ved ca. 230°, separeres ved filtrering og vaskes med en liten mengde ethanol. Omkrystallisering fra en blanding av ethanol og ether ga gule prismer av produktet som smelter ved 233—234° (spaltning). The residue in example 2 is added to a solution of 240 g of potassium hydroxide in a mixture of 600 ml of water and 600 ml of ethanol. The reaction mixture is stirred and refluxed for 15 minutes, while 35 g of zinc dust is carefully added. One liter of water is then added and the mixture is filtered over a filter and washed with 500 ml of water. The filtrate containing the thiophenol, 5-chloro-2-mercaptobenzophenone, is cooled to room temperature and a solution of 204 g of bromomethylamine hydrobromide in 350 ml of water is added. After stirring for 15 minutes, the reaction mixture is extracted with methylene chloride and the organic layer is dried over sodium sulphate and filtered. The filtrate is acidified with methanolic hydrochloric acid and concentrated in vacuo. To the residue consisting of 7-chloro-2,3-dihydro-5-phenyl-1,4-benzothiazepine and 5-chloro-2-(2-aminoethylthio)benzophenone, 1 liter of pyridine is added. The solution is refluxed for 1 hour, then concentrated in vacuo and the residue dissolved in a mixture of methylene chloride and water. The organic layer is separated, dried, filtered, and the filtrate is acidified with ethanolic hydrochloric acid and diluted with approx. 300 ml of ethanol. The solution is concentrated in vacuo to remove methylene chloride. 7-chloro-2,3-dihydro-5-phenyl-1,4-benzothiazepine hydrochloride, which melts at approx. 230°, separated by filtration and washed with a small amount of ethanol. Recrystallization from a mixture of ethanol and ether gave yellow prisms of the product melting at 233-234° (decomposition).
Eksempel 4. Example 4.
En oppløsning av 125 g kobbersulfat i 500 ml vann (90°) forenes med en oppløs-ning av 95 g natriumthiocyanat i 250 ml vann. Det utfelte kobberthiocyanat skilles fra ved filtrering, vaskes med vann og suspenderes i 500 ml vann. Til denne blanding tilsettes 50 g natriumthiocyanat og 2-benzoyl-4-klor-benzendiazonium-fluorborat fremstilt fra y2 mol av aminobenzofeno-net som i eksempel 1. Blandingen røres om i 24 timer ved romtemperatur. De faste stoffer som inneholder reaksjonsproduk-tet skilles fra ved filtrering, vaskes med koldt vann og ekstraheres med kokende alkohol (ca. 1 liter). Den varme alkohol - oppløsning filtreres for å fjerne kobber-thiocyanatet. Ved kjøling krystalliserte 5-klor-2-thiocyanobenzofenon fra alkohol-oppløsningen. Produktet renses ved omkrystallisasjon fra ethanol og dannet krem-farvede nåler som smelter ved 98—99°. • A solution of 125 g of copper sulphate in 500 ml of water (90°) is combined with a solution of 95 g of sodium thiocyanate in 250 ml of water. The precipitated copper thiocyanate is separated by filtration, washed with water and suspended in 500 ml of water. To this mixture are added 50 g of sodium thiocyanate and 2-benzoyl-4-chloro-benzenediazonium fluoroborate prepared from y2 mol of the aminobenzophenone as in example 1. The mixture is stirred for 24 hours at room temperature. The solids containing the reaction product are separated by filtration, washed with cold water and extracted with boiling alcohol (approx. 1 litre). The hot alcohol solution is filtered to remove the copper thiocyanate. On cooling, 5-chloro-2-thiocyanobenzophenone crystallized from the alcohol solution. The product is purified by recrystallization from ethanol and forms cream-coloured needles which melt at 98-99°. •
Eksempel 5. Example 5.
En blanding av 78 g 5-klor-2-thiocya-nobenzofenon i 800 ml alkohol, 200 ml 40 pst.'s natriumhydroxyd og 60 g natriumhydrosulfit tilbakeløpsbehandles i y2 time. 2-mercapto-5-klorbenzofenon dannes og al-kyleres derefter med bromethylamin-hy-drobromid som beskrevet i eksempel 3. Ytterligere behandling med pyridin, slik som beskrevet i eksempel 3, gir 7-klor-2,3-di-hydro-5-fenyl-l,4-benzothiazepinhydroklorid som efter omkrystallisasjon viste seg å ha et smeltepunkt på 233—234° (spaltning). A mixture of 78 g of 5-chloro-2-thiocyanobenzophenone in 800 ml of alcohol, 200 ml of 40% sodium hydroxide and 60 g of sodium hydrosulphite is refluxed for y2 hours. 2-mercapto-5-chlorobenzophenone is formed and then alkylated with bromethylamine hydrobromide as described in Example 3. Further treatment with pyridine, as described in Example 3, gives 7-chloro-2,3-dihydro- 5-phenyl-1,4-benzothiazepine hydrochloride which after recrystallization was found to have a melting point of 233-234° (decomposition).
Den frie base frigjøres fra det ovenfor nevnte hydroklorid med natriumhydroxyd og ekstraheres med ether. Etheropp-løsningen konsentreres i vakuum og 7-klor-2,3-dihydro-5-fenyl-l,4-benzothiazepin krystalliserer fra ether som farveløse prismer som smelter ved 79—80°. The free base is liberated from the above-mentioned hydrochloride with sodium hydroxide and extracted with ether. The ether solution is concentrated in vacuo and 7-chloro-2,3-dihydro-5-phenyl-1,4-benzothiazepine crystallizes from ether as colorless prisms melting at 79-80°.
Eksempel 6. Example 6.
En oppløsning av 34 g (0,125 mol) 7-klor-2,3-dihydro-5-fenyl-l,4-benzothiazepinhydroklorid i 200 ml tørt tetrahydrofuran tilsettes omhyggelig ved romtemperatur til en omrørt suspensjon av 10 g (0,25 mol) lithiumaluminiumhydrid i 600 ml tetrahydrofuran. Reaksjonsblandingen tilbakeløpsbehandles i 2 timer og avkjøles derpå i et isbad. En liter fuktig ether tilsettes langsomt og blandingen filtreres gjennom et filter. Filtratet tørkes, konsentreres i vakuum til tørrhet og resten opplø-ses i ethanol. Oppløsningen ansyres med et overskudd av methanolisk klorhydrogen. Ved tilsetning av ether oppnåes 7-klor-5-fenyl-2,3,4,5-tetrahydro-l,4-benzothiazepinhydroklorid. A solution of 34 g (0.125 mol) of 7-chloro-2,3-dihydro-5-phenyl-1,4-benzothiazepine hydrochloride in 200 ml of dry tetrahydrofuran is carefully added at room temperature to a stirred suspension of 10 g (0.25 mol) lithium aluminum hydride in 600 ml of tetrahydrofuran. The reaction mixture is refluxed for 2 hours and then cooled in an ice bath. One liter of moist ether is added slowly and the mixture is filtered through a filter. The filtrate is dried, concentrated in vacuo to dryness and the residue dissolved in ethanol. The solution is acidified with an excess of methanolic hydrogen chloride. By adding ether, 7-chloro-5-phenyl-2,3,4,5-tetrahydro-1,4-benzothiazepine hydrochloride is obtained.
Omkrystallisasjon av produktet fra en blanding av ethanol og ether gir svakt gule nåler som smelter ved 267—268°. Recrystallization of the product from a mixture of ethanol and ether gives faint yellow needles melting at 267-268°.
Eksempel 7. Example 7.
Til en omrørt oppløsning av 5,4 g (0,02 mol) 7-klor-2,3-dihydro-5-fenyl-1,4-benzothiazepinhydroklorid i 200 ml methanol av-kjølt i et isbad, tilsettes 4,5 g (0,02 mol) natrium-meta-perjodat oppløst i 42 ml vann. Reaksjonsblandingen røres om i 6 timer med isavkjøling og 14 timer ved romtemperatur. Det utfelte natriumjodat skilles fra ved filtrering og filtratet konsentreres i vakuum til et lite volum. Konsentratet ekstraheres med methylenklorid og det organiske lag skilles fra, tørkes og konsentreres i vakuum til tørrhet. Den således oppnådde rest oppløses i methanol og ansyres med methanolisk hydrogenklorid. Tilsetning av ether gir 7-klor-2,3-dihydro-5-fenyl-l,4-benzothiazepin 1-oxyd-hydroklorid. Omkrystallisasjon av produktet fra en blanding av methanol og ether gir svakt gule prismer som smelter ved 206—207°. To a stirred solution of 5.4 g (0.02 mol) 7-chloro-2,3-dihydro-5-phenyl-1,4-benzothiazepine hydrochloride in 200 ml methanol cooled in an ice bath, add 4.5 g (0.02 mol) of sodium meta-periodate dissolved in 42 ml of water. The reaction mixture is stirred for 6 hours with ice cooling and 14 hours at room temperature. The precipitated sodium iodate is separated by filtration and the filtrate is concentrated in a vacuum to a small volume. The concentrate is extracted with methylene chloride and the organic layer is separated, dried and concentrated in vacuo to dryness. The residue thus obtained is dissolved in methanol and acidified with methanolic hydrogen chloride. Addition of ether gives 7-chloro-2,3-dihydro-5-phenyl-1,4-benzothiazepine 1-oxyd-hydrochloride. Recrystallization of the product from a mixture of methanol and ether gives faint yellow prisms melting at 206-207°.
Eksempel 8. Example 8.
Til en omrørt oppløsning av 4 g (0,014 mol) 7-klor-5-fenyl-2,3,4,5-tetrahydro-l,4-benzothiazepinhydroklorid i 100 ml methanol avkjølt i et isbad tilsettes 3,2 g (0,015 mol) natrium-meta-perjodat opp-løst i 28 ml vann. Reaksjonsblandingen røres om i 5 timer under isavkjøling og 23 timer ved romtemperatur. Det utfelte natriumjodat skilles fra ved filtrering og filtratet konsentreres i vakuum til et lite volum. Konsentratet ekstraheres med methylenklorid og det organiske lag skilles fra, tørkes og konsentreres i vakuum til tørrhet. En methanolisk oppløsning av resten ansyres med methanolisk hydrogenklorid. Ved tilsetning av ether krystalliserer 7-klor-2,3,4,5-tetrahydro-5-fenyl-l,4-benzothiazepin 1-oxyd-hydroklorid. Omkrystallisasjon fra en blanding av methanol og ether gir farveløse prismer av produktet som smelter ved 230—231°. To a stirred solution of 4 g (0.014 mol) 7-chloro-5-phenyl-2,3,4,5-tetrahydro-1,4-benzothiazepine hydrochloride in 100 ml methanol cooled in an ice bath is added 3.2 g (0.015 mol ) sodium meta-periodate dissolved in 28 ml of water. The reaction mixture is stirred for 5 hours under ice cooling and 23 hours at room temperature. The precipitated sodium iodate is separated by filtration and the filtrate is concentrated in a vacuum to a small volume. The concentrate is extracted with methylene chloride and the organic layer is separated, dried and concentrated in vacuo to dryness. A methanolic solution of the residue is acidified with methanolic hydrogen chloride. On addition of ether, 7-chloro-2,3,4,5-tetrahydro-5-phenyl-1,4-benzothiazepine 1-oxide hydrochloride crystallizes. Recrystallization from a mixture of methanol and ether gives colorless prisms of the product melting at 230-231°.
Basen frigjøres fra hydrokloridet med alkali og krystalliseres fra ether som far-veløse prismer som smelter ved 116—117°. The base is liberated from the hydrochloride with alkali and crystallized from ether as colorless prisms melting at 116-117°.
Eksempel 9. Example 9.
En oppløsning av 43,2 g (0,158 mol) 7-klor-2,3-dihydro-5-fenyl-l,4-benzothiazepinhydroklorid i 400 ml eddiksyre og 70 ml 30 pst.'s hydrogenperoxyd får henstå ved romtemperatur utsatt for dagslys i 14 dager. 7-klor-4,5-epoxy-2,3,4,5-tetrahydro-5-fenyl-l,4-benzothiazepin-l,l-dioxyd faller ut og skilles fra ved filtrering. Ved omkrystallisasjon fra methylenklorid oppnåes farveløse prismer av produktet som, når de innføres i et smeltepunktapparat ved 200°, smelter ved 205°, blir igjen faste og smelter igjen ved 265—266°. A solution of 43.2 g (0.158 mol) 7-chloro-2,3-dihydro-5-phenyl-1,4-benzothiazepine hydrochloride in 400 ml acetic acid and 70 ml 30% hydrogen peroxide is left at room temperature exposed to daylight for 14 days. 7-Chloro-4,5-epoxy-2,3,4,5-tetrahydro-5-phenyl-1,4-benzothiazepine-1,1-dioxide precipitates and is separated by filtration. On recrystallization from methylene chloride, colorless prisms of the product are obtained which, when introduced into a melting point apparatus at 200°, melt at 205°, become solid again and melt again at 265—266°.
En blanding av 5 g 7-klor-4,5-epoxy-2,3,4,5-tetrahydro-5-fenyl-l,4-benzothiazepin-l,l-dioxyd i 100 ml kokende xylen tilbakeløpsbehandles i 10 minutter og av-kjøles derpå. 7-klor-2,3-dihydro-5-fenyl-l,4-benzothiazepin-l,l,4-trioxyd dannes og skilles fra ved filtrering. Produktet krystalliseres fra methylenklorid som farveløse nåler som smelter ved 265—266°. A mixture of 5 g of 7-chloro-4,5-epoxy-2,3,4,5-tetrahydro-5-phenyl-1,4-benzothiazepine-1,1-dioxide in 100 ml of boiling xylene is refluxed for 10 minutes and then cool down. 7-chloro-2,3-dihydro-5-phenyl-1,4-benzothiazepine-1,1,4-trioxide is formed and separated by filtration. The product is crystallized from methylene chloride as colorless needles melting at 265-266°.
Eksempel 10. Example 10.
Til en omrørt suspensjon av 7,3 g (0,022 mol) 7-klor-2,3-dihydro-5-fenyl-l,4-benzothiazepin-l,l,4-trioxyd i 300 ml kloroform tilsettes 9 ml (0,1 mol) fosfortriklorid. Reaksjonsblandingen tilbakeløpsbehandles i 1 time, avkjøles derpå og isbehandles, og et overskudd av 50 pst.'s kaliumhydroxyd tilsettes. Blandingen røres om ved romtemperatur inntil fullstendig oppløsning er oppnådd. Det organiske lag skilles fra, tørkes og konsentreres i vakuum til tørrhet. Resten krystalliserte fra aceton og gir 7-klor-2,3-dihydro-5-fenyl-l,4-benzothiazepin-1,1-dioxyd. Omkrystallisasjon fra aceton gir farveløse prismer av produktet, hvilke smelter ved 164—165°. 9 ml (0, 1 mol) phosphorus trichloride. The reaction mixture is refluxed for 1 hour, then cooled and treated with ice, and an excess of 50% potassium hydroxide is added. The mixture is stirred at room temperature until complete dissolution is achieved. The organic layer is separated, dried and concentrated in vacuo to dryness. The residue crystallized from acetone to give 7-chloro-2,3-dihydro-5-phenyl-1,4-benzothiazepine-1,1-dioxyd. Recrystallization from acetone gives colorless prisms of the product, which melt at 164-165°.
Eksempel 11. Example 11.
En oppløsning av 21,3 g (0,07 mol) 7-klor-2,3-dihydro-5-fenyl-l,4-benzothiazepin-l,l-dioxyd i 200 ml eddiksyre og 200 ml vann hydreres ved romtemperatur og atmosfærisk trykk i nærvær av 1,8 g pla-tinaoxyd. Efter absorbsjon av 1,2 liter hydrogen (21 timer) skilles katalysatoren fra ved filtrering og filtratet konsentreres i vakuum til tørrhet. Resten oppløses i methylenklorid, vaskes med fortynnet alkali og det organiske lag tørkes og konsentreres til et lite volum. Konsentratet (ca. 50 ml) adsorberes på en kolonne fremstilt av 200 g grad I aluminiumoxyd. Ved eluering av kolonnen med methylenklorid gir de første 250 ml av eluatet (efter konsentrasjon til tørrhet i vakuum) en rest som kry-stallisert fra ether gir 7-klor-2,3,4,5-tetra-hydro-5-fenyl-l,4-benzothiazepin-l,l-dioxyd. Omkrystallisasjon fra ether gir far-veløse plater av produktet som smelter ved 159—160,5°. A solution of 21.3 g (0.07 mol) of 7-chloro-2,3-dihydro-5-phenyl-1,4-benzothiazepine-1,1-dioxide in 200 ml of acetic acid and 200 ml of water is hydrated at room temperature and atmospheric pressure in the presence of 1.8 g of platinum oxide. After absorption of 1.2 liters of hydrogen (21 hours), the catalyst is separated by filtration and the filtrate is concentrated in vacuo to dryness. The residue is dissolved in methylene chloride, washed with dilute alkali and the organic layer is dried and concentrated to a small volume. The concentrate (approx. 50 ml) is adsorbed on a column made of 200 g of grade I aluminum oxide. When elution of the column with methylene chloride, the first 250 ml of the eluate (after concentration to dryness in vacuum) gives a residue which crystallized from ether gives 7-chloro-2,3,4,5-tetra-hydro-5-phenyl- 1,4-benzothiazepine-1,1-dioxide. Recrystallization from ether gives colorless plates of the product melting at 159-160.5°.
Eksempel 12. Example 12.
En omrørt suspensjon av 19,2 g (0,06 mol) 7-klor-2,3-dihydro-5-fenyl-l,4-benzothiazepin-l,l,4-trioxyd i 200 ml acetanhydrid tilbakeløpsbehandles i 5 timer. Efter konsentrasjon av reaksjonsblandingen i vakuum til tørrhet krystalliseres resten fra benzen og gir 7-klor-5-fenyl-l,4-benzothiazepin-l,l-dioxyd. Produktet omkrystalliseres fra en blanding av methylenklorid og ether som gule prismer som har et smeltepunkt på 207—208°. A stirred suspension of 19.2 g (0.06 mol) of 7-chloro-2,3-dihydro-5-phenyl-1,4-benzothiazepine-1,1,4-trioxide in 200 ml of acetic anhydride is refluxed for 5 hours. After concentration of the reaction mixture in vacuo to dryness, the residue is crystallized from benzene to give 7-chloro-5-phenyl-1,4-benzothiazepine-1,1-dioxyd. The product is recrystallized from a mixture of methylene chloride and ether as yellow prisms which have a melting point of 207-208°.
Eksempel 13. Example 13.
Til en suspensjon av 0,8 g (0,021 mol) lithiumaluminiumhydrid i 90 ml tørt tetrahydrofuran tilsettes 1,5 g (0,005 mol) 7-klor-5-fenyl-l,4-benzothiazepin-l,l-dioxyd. Reaksjonsblandingen røres om ved romtemperatur i 30 minutter, avkjøles derpå i et isbad og overskuddet av lithiumaluminiumhydrid ble ødelagt ved den gradvise tilsetning av fuktig ether. Reaksjonsblandingen filtreres gjennom et filter og filtratet tørkes og konsentreres i vakuum til tørr-het. Resten oppløses i ethanolisk hydrogenklorid, og hydrokloridet feller ut ved tilsetningen av aceton. Det rå salt skilles fra og omdannes til 7-klor-2,3-dihydro-5-fenyl-l,4-benzothiazepin-l,l-dioxyd ved behandling med alkali og krystallisasjon fra aceton. Omkrystallisasjon fra aceton gir far-veløse prismer av produktet som smelter ved 164—165°. To a suspension of 0.8 g (0.021 mol) of lithium aluminum hydride in 90 ml of dry tetrahydrofuran is added 1.5 g (0.005 mol) of 7-chloro-5-phenyl-1,4-benzothiazepine-1,1-dioxyd. The reaction mixture was stirred at room temperature for 30 minutes, then cooled in an ice bath and the excess lithium aluminum hydride was destroyed by the gradual addition of moist ether. The reaction mixture is filtered through a filter and the filtrate is dried and concentrated in vacuo to dryness. The residue is dissolved in ethanolic hydrogen chloride, and the hydrochloride is precipitated by the addition of acetone. The crude salt is separated and converted into 7-chloro-2,3-dihydro-5-phenyl-1,4-benzothiazepine-1,1-dioxide by treatment with alkali and crystallization from acetone. Recrystallization from acetone gives colorless prisms of the product melting at 164-165°.
Eksempel 14. Example 14.
Til en omrørt oppløsning av 6,8 g (0,06 mol) 2-mercaptoethylamin-hydroklorid i 150 ml dimethylformamid tilsettes 6,6 g (0,122 mol) natriummethoxyd. Blandingen oppvarmes ved 40—50° i 15 minutter, derpå tilsettes 15,6 g (0,06 mol) 2-klor-5-nitro-benzofenon og omrøring fortsettes i 3 timer ved romtemperatur. Fortynnet natriumhydroxyd tilsettes og produktet ekstraheres med methylenklorid. Det organiske lag skilles fra, tørkes og konsentreres i vakuum til et lite volum. 5-nitro-2-(amino-ethylthio)benzofenon krystalliserer og skilles fra ved filtrering. Omkrystallisasjon fra methylenklorid gir produktet som gule nåler som smelter ved 189—190°. To a stirred solution of 6.8 g (0.06 mol) of 2-mercaptoethylamine hydrochloride in 150 ml of dimethylformamide is added 6.6 g (0.122 mol) of sodium methoxy. The mixture is heated at 40-50° for 15 minutes, then 15.6 g (0.06 mol) of 2-chloro-5-nitro-benzophenone are added and stirring is continued for 3 hours at room temperature. Dilute sodium hydroxide is added and the product is extracted with methylene chloride. The organic layer is separated, dried and concentrated in vacuo to a small volume. 5-nitro-2-(amino-ethylthio)benzophenone crystallizes and is separated by filtration. Recrystallization from methylene chloride gives the product as yellow needles melting at 189-190°.
Eksempel 15. Example 15.
En blanding av 10,4 g (0,04 mol) 2-mercapto-5-nitro-benzofenon, 800 ml methanol, 2,2 g (0,04 mol) natriummethoxyd og 10 g (0,04 mol) |3-bromethylfthalimid tilbakeløpsbehandles i 17 timer og konsentreres derefter i vakuum til tørrhet. Resten ekstraheres med methylenklorid og vaskes med fortynnet natriumhydroxyd. Det organiske lag tørkes og konsentreres i vakuum til et lite volum. Konsentratet fortynnes med petrolether. N-[2-(2-benzoyl-4-nitro-fenylthio)-ethyl]fthalimid feller ut og vi-seg seg å ha et smeltepunkt ved 120—123°. Omkrystallisasjon fra en blanding av methylenklorid og petrolether gir gule prismer av produktet som smelter ved 126 —127°. A mixture of 10.4 g (0.04 mol) 2-mercapto-5-nitro-benzophenone, 800 ml methanol, 2.2 g (0.04 mol) sodium methoxide and 10 g (0.04 mol) |3- bromomethylphthalimide is refluxed for 17 hours and then concentrated in vacuo to dryness. The residue is extracted with methylene chloride and washed with dilute sodium hydroxide. The organic layer is dried and concentrated in vacuo to a small volume. The concentrate is diluted with petroleum ether. N-[2-(2-benzoyl-4-nitro-phenylthio)-ethyl]phthalimide precipitates and appears to have a melting point at 120-123°. Recrystallization from a mixture of methylene chloride and petroleum ether gives yellow prisms of the product melting at 126 —127°.
Eksempel 16. Example 16.
Til en omrørt suspensjon av 10 g (0,023 mol) N- [2- (2-benzoyl-4-nitrof enylthio) - ethyl]fthalimid i en blanding av 100 ml eddiksyre og 100 ml vann oppvarmet på et dampbad tilsettes forsiktig 7,5 g jernspon i løpet av en tidsperiode på 45 minutter. Reaksjonsblandingen oppvarmes ytterligere 30 minutter, filtreres derpå gjennom et filter. Filtratet fortynnes med vann og ekstraheres med methylenklorid. Det organiske lag vaskes med koldt fortynnet kaliumhydroxyd, tørkes og konsentreres i vakuum til tørrhet. Krystallisasjon av resten fra en blanding av ethanol, ether og petrolether gir N-[2-(4-amino-2-benzoylfen-ylthio)ethyl]fthalimid som smelter ved 107—113°. Lysgule prismer av produktet som smelter ved 115—116° oppnåes ved krystallisasjon fra ethanol. To a stirred suspension of 10 g (0.023 mol) of N-[2-(2-benzoyl-4-nitrophenylthio)-ethyl]phthalimide in a mixture of 100 ml of acetic acid and 100 ml of water heated on a steam bath, carefully add 7.5 g of iron filings during a time period of 45 minutes. The reaction mixture is heated for a further 30 minutes, then filtered through a filter. The filtrate is diluted with water and extracted with methylene chloride. The organic layer is washed with cold dilute potassium hydroxide, dried and concentrated in vacuo to dryness. Crystallization of the residue from a mixture of ethanol, ether and petroleum ether gives N-[2-(4-amino-2-benzoylphenylthio)ethyl]phthalimide which melts at 107-113°. Light yellow prisms of the product melting at 115-116° are obtained by crystallization from ethanol.
Eksempel 17. Example 17.
Til en avkjølt suspensjon av 4 g (0,01 mol) N- [2- (4-amino-2-benzoylfenylthio) - To a cooled suspension of 4 g (0.01 mol) N-[2-(4-amino-2-benzoylphenylthio)-
ethyljfthalimid i 60 ml 3n saltsyre tilsettes 11 ml 1 n natriumnitrit i løpet av 10 minutter ved 0—5°. Reaksjonsblandingen rø-res om ved 0—5° i 45 minutter og tilsettes derpå til en oppløsning av 2 g (0,02 mol) cuproklorid i 40 ml konsentrert saltsyre ved romtemperatur. Reaksjonsblandingen røres om i 2 timer ved romtemperatur, helles derpå på is, gjøres alkalisk med et overskudd av ammoniumhydroxyd og ekstraheres med methylenklorid. Methylenklorid-laget tørkes, konsentreres i vakuum til et volum på ca. 50 ml og filtreres derefter gjennom 30 g grad I aluminiumoxyd. Filterresten vaskes med methylenklorid og filtratet samles i fraksjoner. De første 50 ml filtrat konsentreres i vakuum til tørr-het og resten krystalliserer fra ether og gir N- [2- (2-benzoyl-4-klor-fenylthio) ethyl]fthalimid. Farveløse prismer av produktet som smelter ved 106—107° oppnåes ved omkrystallisasjon fra ether. of ethyl jphthalimide in 60 ml of 3N hydrochloric acid is added to 11 ml of 1N sodium nitrite during 10 minutes at 0-5°. The reaction mixture is stirred at 0-5° for 45 minutes and is then added to a solution of 2 g (0.02 mol) of cuprochloride in 40 ml of concentrated hydrochloric acid at room temperature. The reaction mixture is stirred for 2 hours at room temperature, then poured onto ice, made alkaline with an excess of ammonium hydroxide and extracted with methylene chloride. The methylene chloride layer is dried, concentrated in vacuo to a volume of approx. 50 ml and then filtered through 30 g of grade I aluminum oxide. The filter residue is washed with methylene chloride and the filtrate is collected in fractions. The first 50 ml of filtrate are concentrated in vacuo to dryness and the residue crystallizes from ether to give N-[2-(2-benzoyl-4-chloro-phenylthio)ethyl]phthalimide. Colorless prisms of the product melting at 106-107° are obtained by recrystallization from ether.
Eksempel 18. Example 18.
En oppløsning av 0,8 g (0,002 mol) N-[2-(2-benzoyl-4-klorfenylthio)ethyl]fthal-imid i en blanding av 35 ml eddiksyre og konsentrert saltsyre tilbakeløpsbehandles i 17 timer. Reaksjonsblandingen helles på is, gjøres alkalisk med 50 pst.'s kaliumhydroxyd og ekstraheres med methylenklorid. Det organiske lag skilles fra, tørkes, ansyres med hydrogenklorid og konsentreres i vakuum til tørrhet. Resten krystalliserer fra en blanding av ethanol og ether og gir 5-klor-2-(2-aminoethylthio)benzofenon-hydroklorid. Omkrystallisasjon fra en blanding av ethanol og ether gir produktet som svakt gule nåler som smelter ved 168—169°. A solution of 0.8 g (0.002 mol) N-[2-(2-benzoyl-4-chlorophenylthio)ethyl]phthalimide in a mixture of 35 ml of acetic acid and concentrated hydrochloric acid is refluxed for 17 hours. The reaction mixture is poured onto ice, made alkaline with 50% potassium hydroxide and extracted with methylene chloride. The organic layer is separated, dried, acidified with hydrogen chloride and concentrated in vacuo to dryness. The residue crystallizes from a mixture of ethanol and ether to give 5-chloro-2-(2-aminoethylthio)benzophenone hydrochloride. Recrystallization from a mixture of ethanol and ether gives the product as pale yellow needles melting at 168-169°.
Eksempel 19. Example 19.
Til 450 ml konsentrert svovelsyre, avkjølt til 10°, tilsettes 69 g (1 mol) natriumnitrit langsomt under omrøring. Blandingen oppvarmes derpå til ca. 80°, inntil en klar opp-løsning dannes. Efter avkjøling til 30° tilsettes 197 g (1 mol) 2-aminobenzofenon porsjonsvis og temperaturen holdes mellom 30—40°. Efter omrøring i 1 time helles opp-løsningen langsomt i 3 liter isvann. Efter filtrering tilsettes langsomt en oppløsning av 200 g natriumfluorborat i 800 ml vann til filtratet under omrøring. 2-benzoyl-ben-zendiazonium-fluorborat feller ut og skilles fra ved filtrering. Bunnfallet vaskes med en liten mengde vann. Det således vaskede bunnfall tilsettes over en tidsperiode på 10 minutter til en kraftig omrørt opp-løsning av 240 g (1,5 mol) omkrystallisert kaliumethylxanthat (Teknisk ethylxanthat omkrystalliseres fra en fem ganger så stor mengde kokende ethanol) i 1,5 liter vann oppvarmet til 75°. Efter tilsetningens full-førelse røres blandingen om i 5 minutter, avkjøles og ekstraheres med ether. Etherekstraktet tørkes over natriumsulfat, filtreres og filtratet konsentreres i vakuum til tørrhet og gir en rå 2-benzoylfenylester som inneholder ethylxanthosyre. En oppløsning av 240 g kaliumhydroxyd i en blanding av 600 ml vann og 600 ml ethanol tilsettes til det rå stoff. Reaksjonsblandingen røres derpå om og tilbakeløpsbehandles i 15 minutter, mens 35 g sinkstøv omhyggelig inn-føres. En liter vann tilsettes derefter, og blandingen filtreres over et filter og vaskes med 500 ml vann. Det filtratholdige 2-mer-captobenzofenon avkjøles til romtemperatur, og en oppløsning av 204 g bromethyl-aminohydrobromid i 350 ml vann tilsettes. Etter omrøring i 15 minutter ekstraheres reaksjonsblandingen med methylenklorid, og det organiske lag tørkes over natriumsulfat og filtreres. Filtratet ansyres med methanolisk saltsyre og konsentreres i vakuum. Til resten, som inneholder 2-(2-aminoethylthio)-benzofenon og 2,3-di-hydro-5-fenyl-l,4-benzothiazepin tilsettes en liter pyridin. Oppløsningen tilbakeløps-behandles i 1 time, konsentreres derpå i vakuum og resten oppløses i en blanding av methylenklorid og vann. Det organiske lag skilles fra, tørkes og konsentreres i vakuum til tørrhet. Den oljeaktige rest opp-løses i ether og filtreres over 500 g av grad I aluminiumoxyd. Filterresten vaskes derefter med ether. Filtratet konsentreres i vakuum til tørrhet og resten krystalliseres fra en blanding av ether og petrolether. Det rå produkt renses ved omkrystallisasjon fra den samme oppløsningsmiddelblanding og gir 2,3-dihydro-5-fenyl-l,4-benzothiazepin som farveløse prismer som smelter ved 64—65°. To 450 ml of concentrated sulfuric acid, cooled to 10°, 69 g (1 mol) of sodium nitrite are added slowly while stirring. The mixture is then heated to approx. 80°, until a clear solution is formed. After cooling to 30°, 197 g (1 mol) of 2-aminobenzophenone are added in portions and the temperature is kept between 30-40°. After stirring for 1 hour, the solution is poured slowly into 3 liters of ice water. After filtration, a solution of 200 g of sodium fluoroborate in 800 ml of water is slowly added to the filtrate while stirring. 2-benzoyl-benzenediazonium-fluoroborate precipitates and is separated by filtration. The precipitate is washed with a small amount of water. The thus washed precipitate is added over a period of 10 minutes to a vigorously stirred solution of 240 g (1.5 mol) of recrystallized potassium ethyl xanthate (Technical ethyl xanthate is recrystallized from a five times larger amount of boiling ethanol) in 1.5 liters of water heated to 75°. After the addition is complete, the mixture is stirred for 5 minutes, cooled and extracted with ether. The ether extract is dried over sodium sulphate, filtered and the filtrate is concentrated in vacuo to dryness and gives a crude 2-benzoylphenyl ester containing ethylxanthosic acid. A solution of 240 g of potassium hydroxide in a mixture of 600 ml of water and 600 ml of ethanol is added to the crude substance. The reaction mixture is then stirred and refluxed for 15 minutes, while 35 g of zinc dust is carefully introduced. One liter of water is then added, and the mixture is filtered over a filter and washed with 500 ml of water. The filtrate-containing 2-mer-captobenzophenone is cooled to room temperature, and a solution of 204 g of bromethylaminohydrobromide in 350 ml of water is added. After stirring for 15 minutes, the reaction mixture is extracted with methylene chloride, and the organic layer is dried over sodium sulfate and filtered. The filtrate is acidified with methanolic hydrochloric acid and concentrated in vacuo. One liter of pyridine is added to the residue, which contains 2-(2-aminoethylthio)-benzophenone and 2,3-dihydro-5-phenyl-1,4-benzothiazepine. The solution is refluxed for 1 hour, then concentrated in vacuo and the residue dissolved in a mixture of methylene chloride and water. The organic layer is separated, dried and concentrated in vacuo to dryness. The oily residue is dissolved in ether and filtered over 500 g of grade I aluminum oxide. The filter residue is then washed with ether. The filtrate is concentrated in vacuo to dryness and the residue is crystallized from a mixture of ether and petroleum ether. The crude product is purified by recrystallization from the same solvent mixture to give 2,3-dihydro-5-phenyl-1,4-benzothiazepine as colorless prisms melting at 64-65°.
En oppløsning av 7 g 2,3-dihydro-5-fenyl-l,4-benzothiazepin i et overskudd av methanolisk hydrogenklorid konsentreres i vakuum til tørrhet. Resten krystalliseres to ganger fra en blanding av methylenklorid og ether og danner gule prismer av 2,3-dihydro-5-fenyl-l,4-benzothiazepinhydroklorid som smelter ved 201—202°. A solution of 7 g of 2,3-dihydro-5-phenyl-1,4-benzothiazepine in an excess of methanolic hydrogen chloride is concentrated in vacuo to dryness. The residue is crystallized twice from a mixture of methylene chloride and ether and forms yellow prisms of 2,3-dihydro-5-phenyl-1,4-benzothiazepine hydrochloride melting at 201-202°.
Eksempel 20. Example 20.
En oppløsning av 250 g kobbersulfat i 1 liter varmt vann forenes med en oppløs-ning av 223 g kaliumthiocyanat i 500 ml vann. Det utfelte kobberthiocyanat skilles fra ved filtrering, vaskes med vann og suspenderes i 1 liter vann. Til denne blanding tilsettes 100 g kaliumthiocyanat og rått 2-benzoyl-benzendiazoniumfluorborat fremstilt fra 1 mol aminobenzofenon som i eksempel 23. Blandingen røres om over nat-ten. Et bunnfall som danner seg skilles fra ved filtrering. Bunnfallet vaskes med koldt vann og ekstraheres med ca. 1 liter kokende ether. Etherlaget tørkes og filtreres. Til denne oppløsning (ca. 1 liter) tilsettes ca. 2 liter petrolether. Blandingen avkjøles, oppløsningen som flyter ovenpå, dekanteres og den gjenværende uoppløselige olje fjer-nes. Den dekanterte oppløsning avsetter krystaller som filtreres fra (s.p. 80—91°). Den slik filtrerte oppløsning konsentreres og den gjenværende olje omkrystalliseres fra ethanol og gir krystaller, s.p. 73—87°. Krystallene med s.p. 80—91° og med s.p. 73—78° forenes. Efter krystallisasjon av kombinasjonen fra en ether- og petrol-etherblanding og derpå fra fortynnet alkohol oppnåes svakt gule krystaller av 2-thiocyano-benzofenon, s.p. 82—82,5°. A solution of 250 g of copper sulphate in 1 liter of warm water is combined with a solution of 223 g of potassium thiocyanate in 500 ml of water. The precipitated copper thiocyanate is separated by filtration, washed with water and suspended in 1 liter of water. To this mixture are added 100 g of potassium thiocyanate and crude 2-benzoyl-benzenediazonium fluoroborate prepared from 1 mol of aminobenzophenone as in example 23. The mixture is stirred overnight. A precipitate that forms is separated by filtration. The precipitate is washed with cold water and extracted with approx. 1 liter of boiling ether. The ether layer is dried and filtered. To this solution (approx. 1 litre) add approx. 2 liters of petroleum ether. The mixture is cooled, the solution that floats on top is decanted and the remaining insoluble oil is removed. The decanted solution deposits crystals which are filtered off (m.p. 80-91°). The solution thus filtered is concentrated and the remaining oil is recrystallized from ethanol to give crystals, m.p. 73-87°. The crystals with s.p. 80-91° and with m.p. 73-78° unite. After crystallization of the combination from an ether and petroleum ether mixture and then from dilute alcohol, slightly yellow crystals of 2-thiocyano-benzophenone are obtained, m.p. 82-82.5°.
Eksempel 21. Example 21.
Til en omrørt oppløsning av 4,7 g (0,02 mol) 2,3-dihydro-5-fenyl-l,4-benzothiazepin i 10 ml methanol avkjølt i et isbad tilsettes 4,2 g (0,02 mol) natrium-meta-perjodat oppløst i 40 ml vann. Reaksjonsblandingen røres om i 1 time ved 30°C og 4 timer ved romtemperatur. Den resulterende blanding filtreres. Filtratet konsentreres i vakuum til et lite volum. Konsentratet ekstraheres med methylenklorid, og det organiske lag skilles fra, tørkes og konsentreres i vakuum til tørrhet. Den slik oppnådde rest oppløses i ether og gir krystallinsk 2,3-dihydro-5-fenyl-l,4-benzothiazepin-l-oxyd. Omkrystallisasjon av produktet fra ether gir farveløse prismer som smelter ved 158—160°. To a stirred solution of 4.7 g (0.02 mol) 2,3-dihydro-5-phenyl-1,4-benzothiazepine in 10 ml methanol cooled in an ice bath is added 4.2 g (0.02 mol) sodium -meta-periodate dissolved in 40 ml of water. The reaction mixture is stirred for 1 hour at 30°C and 4 hours at room temperature. The resulting mixture is filtered. The filtrate is concentrated in vacuo to a small volume. The concentrate is extracted with methylene chloride, and the organic layer is separated, dried and concentrated in vacuo to dryness. The residue thus obtained is dissolved in ether and gives crystalline 2,3-dihydro-5-phenyl-1,4-benzothiazepine-1-oxide. Recrystallization of the product from ether gives colorless prisms melting at 158-160°.
Eksempel 22. Example 22.
En oppløsning av 12 g (0,05 mol) 2,3-dihydro-5-fenyl-l,4-benzothiazepin i en blanding av 130 ml eddiksyre og 20 ml 30 pst.'s hydrogenperoxyd får henstå ved romtemperatur, utsatt for dagslys i 17 dager. Reaksjonsblandingen fortynnes med vann og 4,5-epoxy-2,3,4,5-tetrahydro-5-fenyl-l,4-benzothiazepin-l,l-dioxyd som feller ut skilles ved filtrering. Produktet renses ved krystallisasjon fra en blanding av methylenklorid og ether og danner farveløse prismer som smelter ved 169—170°. A solution of 12 g (0.05 mol) of 2,3-dihydro-5-phenyl-1,4-benzothiazepine in a mixture of 130 ml of acetic acid and 20 ml of 30% hydrogen peroxide is allowed to stand at room temperature, exposed to daylight for 17 days. The reaction mixture is diluted with water and the 4,5-epoxy-2,3,4,5-tetrahydro-5-phenyl-1,4-benzothiazepine-1,1-dioxide which precipitates is separated by filtration. The product is purified by crystallization from a mixture of methylene chloride and ether and forms colorless prisms which melt at 169-170°.
En oppløsning av 2 g 4,5-epoxy-2,3,4,5-tetrahydro-5-fenyl-l,4-benzothiazepin-1,1-dioxyd i 60 mi xylen tilbakeløpsbehand-les i y2 time og avkjøles derpå. Det krystal-linske reaksjonsprodukt skilles fra ved filtrering. Omkrystallisasjon fra en blanding av methylenklorid og ether gir farveløse nåler av 2,3-dihydro-5-fenyl-l,4-benzothiazepin-l,l,4-trioxyd, s.p. 238—239°. A solution of 2 g of 4,5-epoxy-2,3,4,5-tetrahydro-5-phenyl-1,4-benzothiazepine-1,1-dioxide in 60 ml of xylene is refluxed for y2 hours and then cooled. The crystalline reaction product is separated by filtration. Recrystallization from a mixture of methylene chloride and ether gives colorless needles of 2,3-dihydro-5-phenyl-1,4-benzothiazepine-1,1,4-trioxyd, m.p. 238—239°.
Eksempel 23. Example 23.
En oppløsning av 23,9 g (0,1 mol) 2,3-dihydro-5-fenyl-l,4-benzothiazepin i 200 ml tørt tetrahydrofuran tilsettes langsomt ved romtemperatur til en omrørt suspensjon av 8 g (0,2 mol) lithiumaluminiumhydrid i 600 ml tetrahydrofuran. Reaksjonsblandingen tilbakeløpsbehandles i 2 timer og avkjøles derefter i et isbad. 1 liter våt ether tilsettes langsomt og blandingen filtreres gjennom et filter. Filtratet tørkes, konsentreres i vakuum til tørrhet og resten oppløses i ether. Ved henstand oppnåes krystallinsk 2,3,4,5-tetrahydro-5-fenyl-l,4-benzothiazepin. Omkrystallisasjon fra ether gir farveløse nåler av produktet, s.p. 89 —90°. A solution of 23.9 g (0.1 mol) of 2,3-dihydro-5-phenyl-1,4-benzothiazepine in 200 ml of dry tetrahydrofuran is added slowly at room temperature to a stirred suspension of 8 g (0.2 mol) lithium aluminum hydride in 600 ml of tetrahydrofuran. The reaction mixture is refluxed for 2 hours and then cooled in an ice bath. 1 liter of wet ether is added slowly and the mixture is filtered through a filter. The filtrate is dried, concentrated in vacuo to dryness and the residue dissolved in ether. On standing, crystalline 2,3,4,5-tetrahydro-5-phenyl-1,4-benzothiazepine is obtained. Recrystallization from ether gives colorless needles of the product, m.p. 89 -90°.
Eksempel 24. Example 24.
Til en omrørt oppløsning av 4,8 g (0,020 mol) 2,3,4,5-tetrahydro-5-fenyl-l,4-benzothiazepin i 100 ml methanol avkjølt i et isbad tilsettes 4,2 g (0,020 mol) natrium-meta-perjodat oppløst i 40 ml vann. Reaksjonsblandingen røres om i 4 timer ved romtemperatur. Den resulterende blanding filtreres og filtratet konsentreres i vakuum til et lite volum. Konsentratet ekstraheres med methylenklorid og det organiske lag skilles fra, tørkes og konsentreres i vakuum til tørrhet. Ved tilsetning av ether krystalliserer rått 2,3,4,5-tetrahydro-5-fenyl-l,4-benzothiazepin-l-oxyd. Omkrystallisasjon fra en blanding av CH2Cla og ether gir far-veløse nåler av produktet, s.p. 147—148°. To a stirred solution of 4.8 g (0.020 mol) 2,3,4,5-tetrahydro-5-phenyl-1,4-benzothiazepine in 100 ml methanol cooled in an ice bath is added 4.2 g (0.020 mol) sodium -meta-periodate dissolved in 40 ml of water. The reaction mixture is stirred for 4 hours at room temperature. The resulting mixture is filtered and the filtrate is concentrated in vacuo to a small volume. The concentrate is extracted with methylene chloride and the organic layer is separated, dried and concentrated in vacuo to dryness. On addition of ether, crude 2,3,4,5-tetrahydro-5-phenyl-1,4-benzothiazepine-1-oxide crystallizes. Recrystallization from a mixture of CH 2 Cl 2 and ether gives colorless needles of the product, m.p. 147-148°.
Eksempel 25. Example 25.
Til 60 ml konsentrert svovelsyre, av-kjølt til 10°, tilsettes 6,9 g (0,1 mol) natriumnitrit langsomt under omrøring. Blandingen oppvarmes derpå til ca. 80° inntil en klar oppløsning danner seg. Efter av-kjøling til 45° tilsettes 26,5 g (0,1 mol) 2-amino-5-trifluormethylbenzofenon porsjonsvis, og temperaturen holdes mellom 45—50°. Efter omrøring i 1 time helles opp-løsningen langsomt til 400 ml is-vann. Efter filtrering tilsettes en oppløsning av 20 g natriumfluorborat i 80 ml vann til filtratet. 2-benzoyl-4-trifluormethyl-benzendiazo-niumfluorborat feller ut. Det skilles fra ved filtrering og vaskes derefter med en liten mengde vann. Det slik vaskede bunnfall tilsettes i løpet av 5 minutter til en kraftig omrørt oppløsning av 24 g (0,15 mol) omkrystallisert kaliumethylxanthat (Teknisk ethylxanthat omkrystalliseres fra en fem ganger så stor mengde kokende ethanol) i 200 ml vann oppvarmet til 70°. Efter at tilsetningen er fullført, røres blandingen om i 5 minutter, avkjøles og ekstraheres med ether. Etherekstraktet tørkes over natriumsulfat, filtreres og filtratet konsentreres i vakuum til tørrhet. Den oljeaktige rest som inneholder ethylxanthosyre 2-benzoyl-4-trifluormethylfenylester oppnåes. En oppløsning av 20 g kaliumhydroxyd i en blanding på 60 ml vann og 60 ml ethanol tilsettes til den oljeaktige rå rest. Reaksjonsblandingen røres derpå om og tilbakeløpsbehandles i 10 minutter, mens 3,5 g sinkstøv omhyggelig innføres. 150 ml vann tilsettes derpå, og blandingen filtreres over et filter og vaskes med 50 ml vann. Filtratet som inneholder 2-mercapto-5-tri-fluormethylbenzofenon avkjøles til romtemperatur, og en oppløsning av 20 g brom-ethylaminohydrobromid i 35 ml vann tilsettes. Efter omrøring i 30 minutter ekstraheres reaksjonsblandingen med methylenklorid og det organiske lag tørkes over natriumsulfat og filtreres. Filtratet ansyres med methanolisk saltsyre og konsentreres i vakuum. Til resten, som består av 2-(2-ami-noethylthio)-5-trifluormethylbenzofenon og 2,3-dihydro-5-fenyl-7-trifluormethyl-1,4-benzothiazepin, tilsettes 100 ml pyridin. Oppløsningen tilbakeløpsbehandles i 2 timer og konsentreres derpå i vakuum. Resten oppløses derefter i en blanding av ether og vann. Det organiske lag skilles fra, tør-kes og konsentreres i vakuum til tørrhet. Resten oppløses i et overskudd av methanolisk hydrogenklorid og konsentreres i vakuum til tørrhet. Den slik oppnådde rest krystalliseres fra en blanding av methylenklorid, ether og petroleumether og gir rått 2,3-dihydro-5-fenyl-7-trifluormethyl-l,4-benzothiazepinhydroklorid. Produktet omkrystalliseres fra isopropanol og gir gule prismer av produktet, s.p. 231—232°. Basen, nemlig 2,3-dihydro-5-fenyl-7-trifluormethyl-l,4-benzothiazepin, frigjøres fra hydrokloridet i en iskold blanding av ether og fortynnet natriumhydroxyd. Det organiske lag tørkes og konsentreres i vakuum til tørrhet. Resten omkrystalliseres fra petroleumether og gir farveløse prismer av den frie base, s.p. 90—91°. To 60 ml of concentrated sulfuric acid, cooled to 10°, 6.9 g (0.1 mol) of sodium nitrite are added slowly while stirring. The mixture is then heated to approx. 80° until a clear solution forms. After cooling to 45°, 26.5 g (0.1 mol) of 2-amino-5-trifluoromethylbenzophenone are added in portions, and the temperature is kept between 45-50°. After stirring for 1 hour, the solution is poured slowly into 400 ml of ice water. After filtration, a solution of 20 g of sodium fluoroborate in 80 ml of water is added to the filtrate. 2-benzoyl-4-trifluoromethyl-benzenediazonium fluoroborate precipitates. It is separated by filtration and then washed with a small amount of water. The precipitate washed in this way is added within 5 minutes to a vigorously stirred solution of 24 g (0.15 mol) of recrystallized potassium ethyl xanthate (Technical ethyl xanthate is recrystallized from a five times larger amount of boiling ethanol) in 200 ml of water heated to 70°. After the addition is complete, the mixture is stirred for 5 minutes, cooled and extracted with ether. The ether extract is dried over sodium sulphate, filtered and the filtrate is concentrated in vacuo to dryness. The oily residue containing ethyl xanthosic acid 2-benzoyl-4-trifluoromethylphenyl ester is obtained. A solution of 20 g of potassium hydroxide in a mixture of 60 ml of water and 60 ml of ethanol is added to the oily crude residue. The reaction mixture is then stirred and refluxed for 10 minutes, while 3.5 g of zinc dust is carefully introduced. 150 ml of water is then added, and the mixture is filtered over a filter and washed with 50 ml of water. The filtrate containing 2-mercapto-5-trifluoromethylbenzophenone is cooled to room temperature, and a solution of 20 g of bromoethylaminohydrobromide in 35 ml of water is added. After stirring for 30 minutes, the reaction mixture is extracted with methylene chloride and the organic layer is dried over sodium sulphate and filtered. The filtrate is acidified with methanolic hydrochloric acid and concentrated in vacuo. To the residue, which consists of 2-(2-aminoethylthio)-5-trifluoromethylbenzophenone and 2,3-dihydro-5-phenyl-7-trifluoromethyl-1,4-benzothiazepine, 100 ml of pyridine is added. The solution is refluxed for 2 hours and then concentrated in vacuo. The residue is then dissolved in a mixture of ether and water. The organic layer is separated, dried and concentrated in vacuo to dryness. The residue is dissolved in an excess of methanolic hydrogen chloride and concentrated in vacuo to dryness. The residue thus obtained is crystallized from a mixture of methylene chloride, ether and petroleum ether and gives crude 2,3-dihydro-5-phenyl-7-trifluoromethyl-1,4-benzothiazepine hydrochloride. The product is recrystallized from isopropanol and gives yellow prisms of the product, m.p. 231—232°. The base, namely 2,3-dihydro-5-phenyl-7-trifluoromethyl-1,4-benzothiazepine, is liberated from the hydrochloride in an ice-cold mixture of ether and dilute sodium hydroxide. The organic layer is dried and concentrated in vacuo to dryness. The residue is recrystallized from petroleum ether and gives colorless prisms of the free base, m.p. 90-91°.
Eksempel 26. Example 26.
Til en oppløsning av 2,2 g 2-mercapto-ethylaminhydroklorid i 125 ml pyridin tilsettes 1 g 53 pst. natriumhydrid og 5,6 g 2-klor-5-trifluormethylbenzofenon. Reaksjonsblandingen oppvarmes på dampbad i 3 timer og konsentreres derpå i vakuum til tørrhet. Kold fortynnet saltsyre og ether tilsettes til resten av 5-trifluormethyl-2-(2-aminoethylthio)benzofenonhydroklorid som feller ut skilles fra ved filtrering. Omkrystallisasjon av produktet fra isopropanol gir farveløse nåler som smelter ved 178—179°. To a solution of 2.2 g of 2-mercapto-ethylamine hydrochloride in 125 ml of pyridine, 1 g of 53% sodium hydride and 5.6 g of 2-chloro-5-trifluoromethylbenzophenone are added. The reaction mixture is heated on a steam bath for 3 hours and then concentrated in vacuo to dryness. Cold dilute hydrochloric acid and ether are added to the residue of 5-trifluoromethyl-2-(2-aminoethylthio)benzophenone hydrochloride which precipitates and is separated by filtration. Recrystallization of the product from isopropanol gives colorless needles melting at 178-179°.
Dette produkt kan sykliseres til 2,3-di-hydro-5-fenyl-7-trifluormethyl-l,4-benzothiazepinhydroklorid ved behandling med kokende pyridin. This product can be cyclized to 2,3-dihydro-5-phenyl-7-trifluoromethyl-1,4-benzothiazepine hydrochloride by treatment with boiling pyridine.
Eksempel 27. Example 27.
7,5 g 6'-amino-3',4'-dimetoxyaceto-fenon tilsettes til 70 ml fortynnet saltsyre (1:1). Den resulterende blanding oppvarmes ved 50° inntil fullstendig oppløsning, anbringes derpå i et isbad og røres om inntil den indre temperatur er falt under +5°-Til den slik oppnådde fine suspensjon tilsettes dråpevis en oppløsning av 2,9 g natriumnitrit i 5 ml vann i en slik mengde for å holde temperaturen ved 0 til +5°. Efter tilsetningens fullførelse røres blandingen om i isbadet i iy2 time. En filtrert oppløsning av 7,7 g natriumfluorborat i 30 ml vann tilsettes, og blandingen røres om i 30 minutter. 2-acetyl-4,5-dimethoxy-ben-zendiazoniumfluorborat som feller ut samles opp ved filtrering og vaskes med vann. 7.5 g of 6'-amino-3',4'-dimethoxyacetophenone is added to 70 ml of diluted hydrochloric acid (1:1). The resulting mixture is heated at 50° until complete dissolution, then placed in an ice bath and stirred until the internal temperature has fallen below +5°-To the thus obtained fine suspension is added dropwise a solution of 2.9 g of sodium nitrite in 5 ml of water in such an amount as to keep the temperature at 0 to +5°. After the addition is complete, the mixture is stirred in the ice bath for 12 hours. A filtered solution of 7.7 g of sodium fluoroborate in 30 ml of water is added, and the mixture is stirred for 30 minutes. The 2-acetyl-4,5-dimethoxy-benzenediazonium fluoroborate that precipitates is collected by filtration and washed with water.
8,5 g av det utfelte diazoniumfluor-borat, mens ennå fuktig, tilsettes i små porsjoner til en oppløsning av 8 g kaliumethylxanthat i 50 ml vann. Under tilsetningen holdes temperaturen ved 70—75°. Efter tilsetningens fullførelse fortsettes opp-varmning i 15 minutter. Den avkjølte blanding ekstraheres med ether. Etherekstraktet vaskes med 5 pst.'s natriumhydroxyd-oppløsning, derpå med vann og tørkes over natriumsulfat. Den oljeaktige rest, oppnådd efter fjerning av oppløsningsmidlet, tas opp i en liten mengde ether. Ethyl-xanthogensyre-2-acetyl-4,5-dimethoxy-fenylesteren med s.p. 92—93° faller ut og isoleres ved filtrering. Omkrystallisasjon fra fortynnet ethanol hever smeltepunktet for produktet til 94—95°. 8.5 g of the precipitated diazonium fluoroborate, while still moist, are added in small portions to a solution of 8 g of potassium ethyl xanthate in 50 ml of water. During the addition, the temperature is kept at 70-75°. After completion of the addition, heating is continued for 15 minutes. The cooled mixture is extracted with ether. The ether extract is washed with 5% sodium hydroxide solution, then with water and dried over sodium sulphate. The oily residue obtained after removal of the solvent is taken up in a small amount of ether. The ethyl xanthogenic acid 2-acetyl-4,5-dimethoxy-phenyl ester with m.p. 92-93° precipitates and is isolated by filtration. Recrystallization from dilute ethanol raises the melting point of the product to 94-95°.
Eksempel 28. Example 28.
Til en oppløsning av 37,5 g kobbersul- To a solution of 37.5 g of copper sul-
fat i 150 ml vann (90°) tilsettes en opp-løsning av 34,5 g kaliumthiocyanat i 75 ml vann. Det utfelte kobberthiocyanat filtreres fra, vaskes med vann og suspenderes i 150 ml vann som inneholder 90 g kaliumthiocyanat. Til den omrørte suspensjon tilsettes dråpevis diazoniumkloridoppløs-ningen som er fremstilt fra 30 g 6'-amino-3',4'-dimethoxyacetofenon. (Diazoniumklo-ridet fremstilles ved dråpevis tilsetning ved en temperatur på 0 til 5° av en oppløsning av 11,6 g natriumnitrit i 40 ml vann til en barrel in 150 ml of water (90°), a solution of 34.5 g of potassium thiocyanate in 75 ml of water is added. The precipitated copper thiocyanate is filtered off, washed with water and suspended in 150 ml of water containing 90 g of potassium thiocyanate. The diazonium chloride solution prepared from 30 g of 6'-amino-3',4'-dimethoxyacetophenone is added dropwise to the stirred suspension. (The diazonium chloride is prepared by the dropwise addition at a temperature of 0 to 5° of a solution of 11.6 g of sodium nitrite in 40 ml of water to a
oppløsning av 30 g 6'-amino-3',4'-dimeth-oxyacetofenon i 280 ml fortynnet saltsyre solution of 30 g of 6'-amino-3',4'-dimeth-oxyacetophenone in 280 ml of dilute hydrochloric acid
(1:8)). Under tilsetningen holdes temperaturen for reaksjonsblandingen ved 70— 75°. Efter tilsetningens fullførelse røres blandingen om og oppvarmes i 15 minutter. Bunnfallet som danner seg, filtreres fra, vaskes med vann og tørkes i vakuum (1:8)). During the addition, the temperature of the reaction mixture is kept at 70-75°. After the addition is complete, the mixture is stirred and heated for 15 minutes. The precipitate that forms is filtered off, washed with water and dried in a vacuum
ved 50°. De tørrede faste stoffer ekstraheres tre ganger med 200 ml ethanol. De forenede ekstrakter, ved avkjøling, avsetter 3,4-dimethoxy-6-thiocyanatoacetofenon i krystallinsk form. Efter omkrystallisasjon at 50°. The dried solids are extracted three times with 200 ml of ethanol. The combined extracts, on cooling, deposit 3,4-dimethoxy-6-thiocyanatoacetophenone in crystalline form. After recrystallization
fra acetonitril-vann smelter 3,4-dimeth-oxy-6-thiocyanatoaceto-fenonet ved 144— 146°. from acetonitrile-water, the 3,4-dimeth-oxy-6-thiocyanatoaceto-phenone melts at 144— 146°.
Eksempel 29. Example 29.
3,4-dimethoxy-6-thiocyanatoaceto-fenon fremstilles som i eksempel 28, men i 3,4-dimethoxy-6-thiocyanatoacetophenone is prepared as in example 28, but in
stedet for å anvende diazoniumkloridopp-løsningen anvendes det tilsvarende fluor-boratsalt i reaksjonen. Det tilsettes til kobberthiocyanatsuspensjonen ved 70 til 75° og reaksjonsblandingen opparbeides som beskrevet i eksempel 28. 60 g 6'-amino-3',4'-dimethoxyacetofenon anvendes som ut-gangsmateriale. instead of using the diazonium chloride solution, the corresponding fluoroborate salt is used in the reaction. It is added to the copper thiocyanate suspension at 70 to 75° and the reaction mixture is worked up as described in example 28. 60 g of 6'-amino-3',4'-dimethoxyacetophenone is used as starting material.
Eksempel 30. Example 30.
Til en suspensjon av 18 g 3,4-dimeth-oxy-6-thiocyanatoacetofenon og 14 g natriumhydrosulfit i 220 ml ethanol tilsettes 54 ml 40 pst.'s natriumhydroxydoppløsning. Den resulterende blanding tilbakeløpsbe-handles i 30 minutter i nitrogenatmosfære. Til den avkjølte blanding tilsettes en opp-løsning av 20 g 2-bromethylaminhydrobromid i 40 ml vann. Blandingen røres om ved romtemperatur i en time og oppvarmes derefter på dampbad i ytterligere en time. Blandingen filtreres derpå. Filtratet fortynnes med 1 liter vann og ekstraheres med methylenklorid. Ekstraktet tørkes over natriumsulfat, filtreres, ansyres med ethanolisk saltsyre og fordampes til tørrhet i vakuum. Resten oppløses i varm ethanol, filtreres og avkjøles. Tilsetning av over-skytende ether feller ut 2,3-dihydro-7,8-di-methoxy-5-methyl-1,4-benzothiazepinhydroklorid i form av gule krystaller. Efter omkrystallisasjon fra ethanol-ether ble forbindelsen funnet å ha et smeltepunkt på 201—203° (spaltning). To a suspension of 18 g of 3,4-dimeth-oxy-6-thiocyanatoacetophenone and 14 g of sodium hydrosulphite in 220 ml of ethanol, 54 ml of 40% sodium hydroxide solution is added. The resulting mixture is refluxed for 30 minutes in a nitrogen atmosphere. A solution of 20 g of 2-bromomethylamine hydrobromide in 40 ml of water is added to the cooled mixture. The mixture is stirred at room temperature for one hour and then heated on a steam bath for a further hour. The mixture is then filtered. The filtrate is diluted with 1 liter of water and extracted with methylene chloride. The extract is dried over sodium sulphate, filtered, acidified with ethanolic hydrochloric acid and evaporated to dryness in vacuo. The residue is dissolved in hot ethanol, filtered and cooled. Addition of excess ether precipitates 2,3-dihydro-7,8-di-methoxy-5-methyl-1,4-benzothiazepine hydrochloride in the form of yellow crystals. After recrystallization from ethanol-ether, the compound was found to have a melting point of 201-203° (decomposition).
Den frie base oppnåes ved å oppløse 2,3-dihydro-7,8-dimethoxy-5-methyl-l,4-benzothiazepin-hydrokloridet i vann, gjøre oppløsningen alkalisk og ekstrahere med ether. Det tørrede etherekstrakt fordampes til tørrhet, og resten omkrystalliserer fra heptan for å gi basen med smeltepunkt 101—103°. The free base is obtained by dissolving the 2,3-dihydro-7,8-dimethoxy-5-methyl-1,4-benzothiazepine hydrochloride in water, making the solution alkaline and extracting with ether. The dried ether extract is evaporated to dryness, and the residue is recrystallized from heptane to give the base, melting at 101-103°.
Eksempel 31. Example 31.
7 g ethylxanthogensyre-2-acetyl-4,5-dimethoxyfenylester oppløses i 20 ml 30 pst.'s ethanolisk kaliumhydroxyd og til-bakeløpsbehandles i 1 time under nitrogen. Til den avkjølte oppløsning tilsettes 6,2 g 2-bromethylaminhydrobromid. Den resulterende blanding røres om i 1 time ved romtemperatur, filtreres og bringes til tørr-het. Til resten tilsettes kloroform og vann. Kloroformlaget skilles fra, tørkes og fordampes til tørrhet. Resten oppløses i 25 ml pyridin og tilbakeløpsbehandles i 2 timer, hvorefter den resulterende oppløsnin-gen fordampes til tørrhet. Resten tas opp i vann og kloroform og derpå skilles det organiske lag fra, tørkes og tas til tørrhet. Resten oppløses i et minimum av ethanol og ansyres med saltsyre. 2,3-dihydro-7,8-dimethoxy-5-methyl-l,4-benzothiazepinhydroklorid som feller ut, skilles fra ved filtrering. Efter omkrystallisasjon fra ethanol-ether ble forbindelsen funnet å ha et smeltepunkt på 200—201° (spaltning). 7 g of ethyl xanthogenic acid-2-acetyl-4,5-dimethoxyphenyl ester are dissolved in 20 ml of 30% ethanolic potassium hydroxide and refluxed for 1 hour under nitrogen. 6.2 g of 2-bromomethylamine hydrobromide is added to the cooled solution. The resulting mixture is stirred for 1 hour at room temperature, filtered and brought to dryness. Chloroform and water are added to the residue. The chloroform layer is separated, dried and evaporated to dryness. The residue is dissolved in 25 ml of pyridine and refluxed for 2 hours, after which the resulting solution is evaporated to dryness. The residue is taken up in water and chloroform and then the organic layer is separated, dried and taken to dryness. The residue is dissolved in a minimum of ethanol and acidified with hydrochloric acid. The precipitated 2,3-dihydro-7,8-dimethoxy-5-methyl-1,4-benzothiazepine hydrochloride is separated by filtration. After recrystallization from ethanol-ether, the compound was found to have a melting point of 200-201° (decomposition).
Eksempel 32. Example 32.
ll,8g2,3-dihydro-7,8-dimethoxy-5-methyl-1,4-benzothiazepin-hydroklorid opp-løses i 200 ml vann. 44 ml ln natriumhydroxyd tilsettes og blandingen homogeniseres ved tilsetningen av 100 ml ethanol. Til den alkaliske oppløsning tilsettes en oppløsning av 9,5 g natriumborhydrid i 75 ml vann. Den resulterende blanding får henstå ved romtemperatur i 18 timer. Oppløsningen ansyres, fortynnes med 500 ml vann, gjøres alkalisk igjen og ekstraheres med methylenklorid. Ekstraktet vaskes med vann, tør-kes over magnesiumsulfat og filtreres. Filtratet ansyres med saltsyre og fordampes til tørrhet. 7,8-dimethoxy-5-methyl-2,3,4,5-tetrahydro-1,4-benzothiazepinhydroklorid 11,8g2,3-dihydro-7,8-dimethoxy-5-methyl-1,4-benzothiazepine hydrochloride is dissolved in 200 ml of water. 44 ml of sodium hydroxide is added and the mixture is homogenised by the addition of 100 ml of ethanol. A solution of 9.5 g of sodium borohydride in 75 ml of water is added to the alkaline solution. The resulting mixture is allowed to stand at room temperature for 18 hours. The solution is acidified, diluted with 500 ml of water, made alkaline again and extracted with methylene chloride. The extract is washed with water, dried over magnesium sulphate and filtered. The filtrate is acidified with hydrochloric acid and evaporated to dryness. 7,8-dimethoxy-5-methyl-2,3,4,5-tetrahydro-1,4-benzothiazepine hydrochloride
oppnåes som et hvitt fast stoff som smelter is obtained as a white solid which melts
ved 259—261°. Omkrystallisasjon fra ethanol-ether hever smeltepunktet til 261— 263°. at 259-261°. Recrystallization from ethanol-ether raises the melting point to 261-263°.
Den frie base fremstilles ved å oppløse det sistnevnte hydroklorid i vann, gjøre oppløsningen alkalisk og ekstrahere med ether. Det tørrede etherekstrakt fordampes til tørrhet og resten omkrystalliseres fra methanol-vann og gir 7,8-dimethoxy-5-methyl-2,3,4,5-tetrahydro-l,4-benzothiazepin som hvite krystaller, s.p. 57—59°. The free base is prepared by dissolving the latter hydrochloride in water, making the solution alkaline and extracting with ether. The dried ether extract is evaporated to dryness and the residue recrystallized from methanol-water to give 7,8-dimethoxy-5-methyl-2,3,4,5-tetrahydro-1,4-benzothiazepine as white crystals, m.p. 57-59°.
Eksempel 33. Example 33.
2,7 g 7,8-dimethoxy-5-methyl-2,3,4,5-tetrahydro-l,4-benzothiazepinhydroklorid oppløses i 25 ml iseddik. 4,4 g 30 pst.'s hydrogenperoxyd tilsettes, og blandingen får henstå ved romtemperatur i 2 uker. Efter 2.7 g of 7,8-dimethoxy-5-methyl-2,3,4,5-tetrahydro-1,4-benzothiazepine hydrochloride are dissolved in 25 ml of glacial acetic acid. 4.4 g of 30% hydrogen peroxide is added, and the mixture is allowed to stand at room temperature for 2 weeks. After
fjerning av oppløsningsmidlet behandles removal of the solvent is processed
resten med varm methylenklorid og de the residue with hot methylene chloride and those
faste stoffer isoleres ved filtrering. Efter solids are isolated by filtration. After
omkrystallisasjon fra methanol-ether oppnåes 7,8-dimethoxy-5-methyl-2,3,4,5-tetra-hydro-1,4-benzothiazepin 1,1 -dioxydhydro-klorid med smeltepunkt 252—254° (spaltning). recrystallization from methanol ether yields 7,8-dimethoxy-5-methyl-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxydhydrochloride with melting point 252-254° (decomposition).
Den frie base fremstilles ved å oppløse sistnevnte hydroklorid i vann, gjøre opp-løsningen alkalisk og ekstrahere med ether. Det tørrede etherekstrakt fordampes til tørrhet og resten tilsettes til benzen og krystalliseres fra y2 mol benzen og gir krystaller med smeltepunkt 151—153°. The free base is prepared by dissolving the latter hydrochloride in water, making the solution alkaline and extracting with ether. The dried ether extract is evaporated to dryness and the residue is added to benzene and crystallized from y2 mol of benzene and gives crystals with a melting point of 151-153°.
Efter tørring i 24 timer i vakuum ved 110° oppnåes 7,8-dimethoxy-5-methyl-2,3, After drying for 24 hours in a vacuum at 110°, 7,8-dimethoxy-5-methyl-2,3 is obtained,
4,5-tetrahydro-1,4-benzothiazepin-1,1-dioxyd i ren form, s.p. 151—153°. 4,5-tetrahydro-1,4-benzothiazepine-1,1-dioxide in pure form, m.p. 151—153°.
Eksempel 34. Example 34.
Til en oppløsning av 10 g kobbersulfat i 50 ml vann (90°) tilsettes en oppløsning av 5 g kaliumthiocyanat i 20 ml vann. Det A solution of 5 g of potassium thiocyanate in 20 ml of water is added to a solution of 10 g of copper sulphate in 50 ml of water (90°). The
utfelte kobberthiocyanat filtreres fra, vaskes med vann og suspenderes i 100 ml vann som inneholder 25 g kaliumthiocyanat, 12,6 precipitated copper thiocyanate is filtered off, washed with water and suspended in 100 ml of water containing 25 g of potassium thiocyanate, 12.6
g 6-amino-3,4-dimetoxyfenylfenethylketon g 6-amino-3,4-dimethoxyphenylphenethyl ketone
suspenderes i 300 ml ln saltsyre og suspensjonen oppvarmes på dampbad i 15 minutter. Efter avkjøling tilsettes en oppløs-ning av 3,5 g natriumnitrit i 20 ml vann dråpevis under omrøring ved en temperatur på 0 til +5°. Efter fullførelse av slik tilsetning røres suspensjonen om i et kjøle-bad i 1 time og gir 4,5-dimethoxy-2-(3-fenylpropionyl)-benzendiazoniumklorid. Denne suspensjon tilsettes omhyggelig til is suspended in 300 ml of hydrochloric acid and the suspension is heated on a steam bath for 15 minutes. After cooling, a solution of 3.5 g of sodium nitrite in 20 ml of water is added dropwise with stirring at a temperature of 0 to +5°. After completion of such addition, the suspension is stirred in a cooling bath for 1 hour and gives 4,5-dimethoxy-2-(3-phenylpropionyl)-benzenediazonium chloride. This suspension is added carefully to
kobberthiocyanatsuspensjonen mens temperaturen for reaksjonsblandingen holdes ved 70—75° under slik tilsetning. Efter til- the copper thiocyanate suspension while the temperature of the reaction mixture is maintained at 70-75° during such addition. After to-
setningens fullførelse røres blandingen om og oppvarmes i 20 minutter. Bunnfallet som danner seg filtreres fra, vaskes med vann og tørkes i vakuum ved 50°. De tørkede faste stoffer ekstraheres gjentatte ganger med acetonitril. De forenede ekstrakter, the sentence's completion, the mixture is stirred and heated for 20 minutes. The precipitate that forms is filtered off, washed with water and dried in a vacuum at 50°. The dried solids are extracted repeatedly with acetonitrile. The combined extracts,
ved kjøling, avsetter krystaller av 3,4-di-methoxy-6-thiocyanatfenylfenethylketon. on cooling, precipitates crystals of 3,4-di-methoxy-6-thiocyanate phenylphenethyl ketone.
Efter omkrystallisasjon fra acetonitril- After recrystallization from acetonitrile-
vann smelter produktet ved 145—146°. water melts the product at 145-146°.
Eksempel 35. Example 35.
Til en oppløsning av 16 g kobbersulfat To a solution of 16 g of copper sulphate
i 65 ml vann (90°) tilsettes en oppløsning av 14,5 g kaliumthiocyanat i 35 ml vann. Kobberthiocyanat feller ut. Bunnfallet filt- in 65 ml of water (90°) add a solution of 14.5 g of potassium thiocyanate in 35 ml of water. Copper thiocyanate precipitates. The precipitate felt-
reres fra, vaskes med vann og suspenderes i 65 ml vann som inneholder 25 g kalium- is removed, washed with water and suspended in 65 ml of water containing 25 g of potassium
thiocyanat. Til den omrørte suspensjon til- thiocyanate. To the stirred suspension to-
settes dråpevis en 4-brom-2-(2-picolynoyl)-benzendiazoniumkloridoppløsning fremstilt ved å oppløse 14 g 6-amino-3-bromfenyl 2- is added dropwise a 4-bromo-2-(2-picolynoyl)-benzenediazonium chloride solution prepared by dissolving 14 g of 6-amino-3-bromophenyl 2-
pyridylketon i 130 ml fortynnet salt- pyridyl ketone in 130 ml of dilute saline
syre (1:8), avkjøle den slik dannede opp- acid (1:8), cool the thus formed
løsning, tilsette denne til en oppløsning av 4 g natriumnitrit i 15 ml vann ved et tem-peraturområde på 0 til -(-5° og efter full- solution, add this to a solution of 4 g of sodium nitrite in 15 ml of water at a temperature range of 0 to -(-5° and after complete
førelse av slik tilsetning røre om i 1 time i kjølebadet. Under tilsetningen av diazoni-umkloridoppløsningen til den omrørte sus- carrying out such an addition stir for 1 hour in the cooling bath. During the addition of the diazonium chloride solution to the stirred sus-
pensjon holdes temperaturen for reaksjons- pension is kept the temperature for reaction
blandingen ved 70—75°. Efter tilsetningens fullførelse tilsettes 8 g natriumbicarbonat og blandingen avkjøles. Bunnfallet som. the mixture at 70-75°. After completion of the addition, 8 g of sodium bicarbonate are added and the mixture is cooled. The precipitate which.
danner seg filtreres fra, vaskes med vann og tørkes i vakuum ved 50°. De forenede ekstrakter gir ved avkjøling krystaller av 3-brom-6-thiocyanatfenyl 2-pyridylketon. formed is filtered off, washed with water and dried in a vacuum at 50°. The combined extracts give crystals of 3-bromo-6-thiocyanatephenyl 2-pyridyl ketone on cooling.
Efter omkrystallisasjon fra ethanol smel- After recrystallization from ethanol melt-
ter det sistnevnte produkt ved 159—161°. gives the latter product at 159-161°.
Eksempel 36. Example 36.
Til en suspensjon av 6,3 g 3-brom-6-thiocyanatfenyl 2-pyridylketon og 3,5 g natriumhydrosulfit i 60 ml ethanol tilset- To a suspension of 6.3 g of 3-bromo-6-thiocyanatephenyl 2-pyridyl ketone and 3.5 g of sodium hydrosulphite in 60 ml of ethanol add
tes 15 ml 40 pst.'s natriumhydroxydopp- 15 ml of 40% sodium hydroxide solution
løsning. Den resulterende blanding tilbake-løpsbehandles i 30 minutter under nitro- solution. The resulting mixture is refluxed for 30 minutes under nitro-
gen. Til den avkjølte blanding tilsettes en oppløsning av 4,4 g 2-bromethylaminhydro- gen. To the cooled mixture is added a solution of 4.4 g of 2-bromomethylamine hydro-
bromid i 10 ml vann. Blandingen røres om i 1 time ved romtemperatur og oppvarmes i en time på dampbad. Blandingen fortyn- bromide in 10 ml of water. The mixture is stirred for 1 hour at room temperature and heated for one hour in a steam bath. The mixture dilut-
nes med 200 ml vann og ekstraheres med methylenklorid. Ekstraktet behandles med trekull, ansyres med ethanolisk saltsyre og bringes til tørrhet. Til resten tilsettes et minimum av ethanol. Krystaller av 7-brom-2,3-dihydro-5- (2-pyridyl) - 1,4-ben- nes with 200 ml of water and extracted with methylene chloride. The extract is treated with charcoal, acidified with ethanolic hydrochloric acid and brought to dryness. A minimum of ethanol is added to the residue. Crystals of 7-bromo-2,3-dihydro-5-(2-pyridyl)-1,4-ben-
zothiazepin-hydroklorid som danner seg, zothiazepine hydrochloride that forms,
filtreres fra. Modervæskene, ved henstand i 24 timer, gir ytterligere krystaller av det sistnevnte produkt. Krystallene forenes og omkrystalliseres fra ethanol-ether for å gi gule krystaller av produktet, s.p. 205—210° are filtered out. The mother liquors, on standing for 24 hours, give additional crystals of the latter product. The crystals are combined and recrystallized from ethanol-ether to give yellow crystals of the product, m.p. 205-210°
(spaltning). (fission).
Eksempel 37. Example 37.
Til en suspensjon av 2,1 g 3-brom-6-thiocyanatfenyl-2-pyridylketon og 1,1 g natriumhydrosulfit i 20 ml ethanol tilsettes 5 ml 40 pst.'s natriumhydroxydoppløsning. To a suspension of 2.1 g of 3-bromo-6-thiocyanate phenyl-2-pyridyl ketone and 1.1 g of sodium hydrosulphite in 20 ml of ethanol, 5 ml of 40% sodium hydroxide solution is added.
Blandingen oppvarmes i 30 minutter under The mixture is heated for 30 minutes below
nitrogen. Til den avkjølte blanding tilset- nitrogen. To the cooled mixture add-
tes en oppløsning av 1,5 g 2-brom-ethyl-aminhydrobromid i 3 ml vann. Efter om- test a solution of 1.5 g of 2-bromo-ethylamine hydrobromide in 3 ml of water. After about-
røring i 1 time ved romtemperatur tilsettes 75 ml vann. Blandingen ekstraheres med stirring for 1 hour at room temperature, 75 ml of water is added. The mixture is extracted with
methylenklorid. Ekstraktet behandles med trekull, tørkes over magnesiumsulfat og konsentreres i vakuum til et lite volum. methylene chloride. The extract is treated with charcoal, dried over magnesium sulphate and concentrated in vacuo to a small volume.
Tilsetning av en liten mengde ethanol fører Addition of a small amount of ethanol leads
til krystallisasjon. 7-brom-2,3-dihydro-5-(2-pyridyl)-l,4-benzothiazepin i form av krystaller isoleres ved filtrering. Fra mo- to crystallization. 7-bromo-2,3-dihydro-5-(2-pyridyl)-1,4-benzothiazepine in the form of crystals is isolated by filtration. From mo-
dervæskene oppnåes en ytterligere mengde av produktet i krystallinsk form. Krystal- the liquids, a further quantity of the product in crystalline form is obtained. crystal
lene forenes og efter omkrystallisasjon fra isopropanol smelter produktet ved 166— lene are combined and after recrystallization from isopropanol the product melts at 166—
168°. 168°.
Eksempel 38. Example 38.
En oppløsning av 12,2 g (0,04 mol) 2,3-dihydro-7-trifluor-methyl-5-fenyl-l,4- A solution of 12.2 g (0.04 mol) of 2,3-dihydro-7-trifluoro-methyl-5-phenyl-1,4-
benzothiazepin i 200 ml tørt tetrahydro- benzothiazepine in 200 ml dry tetrahydro-
furan tilsettes langsomt ved romtempera- furan is added slowly at room temperature
tur til en omrørt suspensjon av 3,0 g (0,08 turn to a stirred suspension of 3.0 g (0.08
mol) lithiumaluminiumhydrid i 200 ml tetrahydrofuran. Reaksjonsblandingen til-bakeløpsbehandles i 2 timer og avkjøles derpå i et isbad. 1 liter fuktig ether til- mol) of lithium aluminum hydride in 200 ml of tetrahydrofuran. The reaction mixture is refluxed for 2 hours and then cooled in an ice bath. 1 liter of moist ether to
settes langsomt og derpå filtreres blandin- is set slowly and then the mixture is filtered
gen gjennom et filter. Filtratet tørkes og konsentreres i vakuum til tørrhet. Resten oppløses i isopropanol og ansyres med en oppløsning av klorhydrogen i isopropanol. gene through a filter. The filtrate is dried and concentrated in vacuo to dryness. The residue is dissolved in isopropanol and acidified with a solution of hydrogen chloride in isopropanol.
Ved henstand oppnåes krystallinsk 2,3,4,5-tetrahydro-7-trifluormethyl-5-fenyl-l,4-benzothiazepinhydroklorid. Omkrystallisa- On standing, crystalline 2,3,4,5-tetrahydro-7-trifluoromethyl-5-phenyl-1,4-benzothiazepine hydrochloride is obtained. Recrystallize
sjon av produktet fra isopropanol gir farve- tion of the product from isopropanol gives colour-
løse prismer som smelter ved 255—257° loose prisms melting at 255—257°
Claims (4)
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
FI833832A FI68792C (en) | 1983-10-20 | 1983-10-20 | Sealing cap for a liquid medicine bottle. |
Publications (3)
Publication Number | Publication Date |
---|---|
NO844193L NO844193L (en) | 1985-04-22 |
NO156483B true NO156483B (en) | 1987-06-22 |
NO156483C NO156483C (en) | 1987-09-30 |
Family
ID=8517954
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
NO844193A NO156483C (en) | 1983-10-20 | 1984-10-19 | CLOSURE Capsule for liquid medicine bottle. |
Country Status (5)
Country | Link |
---|---|
DE (1) | DE8407149U1 (en) |
DK (1) | DK160360C (en) |
FI (1) | FI68792C (en) |
NO (1) | NO156483C (en) |
SE (1) | SE457444B (en) |
-
1983
- 1983-10-20 FI FI833832A patent/FI68792C/en not_active IP Right Cessation
-
1984
- 1984-03-08 DE DE8407149U patent/DE8407149U1/en not_active Expired
- 1984-10-18 SE SE8405211A patent/SE457444B/en not_active IP Right Cessation
- 1984-10-18 DK DK499084A patent/DK160360C/en not_active IP Right Cessation
- 1984-10-19 NO NO844193A patent/NO156483C/en not_active IP Right Cessation
Also Published As
Publication number | Publication date |
---|---|
NO844193L (en) | 1985-04-22 |
FI68792C (en) | 1987-04-13 |
FI68792B (en) | 1985-07-31 |
SE8405211L (en) | 1985-04-21 |
SE457444B (en) | 1988-12-27 |
DK160360C (en) | 1991-07-22 |
DK499084D0 (en) | 1984-10-18 |
DK160360B (en) | 1991-03-04 |
DE8407149U1 (en) | 1984-06-28 |
DK499084A (en) | 1985-04-21 |
NO156483C (en) | 1987-09-30 |
SE8405211D0 (en) | 1984-10-18 |
FI833832A0 (en) | 1983-10-20 |
FI833832A (en) | 1985-04-21 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
CA1103246A (en) | Thiazine derivatives | |
RU2129549C1 (en) | Pyrimidine derivatives and methods of preparing thereof | |
NO122814B (en) | ||
EP0208510A2 (en) | 1-Substituted oxindole-3-carboxamines as antiinflammatory and analgesic agents | |
US3362962A (en) | Certain benzothiazepine derivatives | |
FI59253C (en) | PROCEDURE FOR THERAPEUTIC PREPARATION OF THERAPEUTIC 4-HYDROXY-2H-THIENO (2,3-E) OCH (3,4-E) -1,2-THIAZINE-3-CARBOXAMIDE-1,1-DIOXIDE DERIVATIVES | |
US4076709A (en) | Thienothiazines | |
NO162414B (en) | Flexible container for transport and storage of bulk goods. | |
NO153530B (en) | ANALOGUE PROCEDURE FOR THE PREPARATION OF THERAPEUTIC ACTIVE SUBSTITUTED HETEROCYCLIC BENZAMIDES. | |
EP0204215A1 (en) | 2-[(1H-benzimidazol-2-ylsulfinyl)methyl]-benzenamines | |
NO147809B (en) | POWER TURBINE. | |
US3080364A (en) | 3, 6, 8-triketopyrimido [5, 4-] 1, 4-thiazines and process | |
FI89267C (en) | Process for the preparation of therapeutically active 4,5-dihydrooxazoles | |
CA1217187A (en) | Thiazine derivatives | |
CA2004911A1 (en) | 4,5,6,7-tetrahydrobenzimidazole derivatives | |
NZ222805A (en) | Triazine derivatives and pharmaceutical compositions | |
NO156483B (en) | CLOSURE Capsule for liquid medicine bottle | |
PL145873B1 (en) | Method of obtaining novel 2-oxindole-1-carbonamides | |
US4090020A (en) | Thienothiazine derivatives | |
US4348519A (en) | Thiazine derivatives | |
US4175085A (en) | Thienothiazine derivatives | |
NO159905B (en) | HARDENABLE BINDING MIXTURE FOR FORMABLE CASTLE MIXTURES. | |
US3314948A (en) | Heterocyclic compounds | |
KR0128975B1 (en) | 9-acylamino-tetrahydroacridine derivatives and memory euhancing agent containing said derivative as active ingredient | |
FI69461C (en) | ANALOGIFICANT FARING FOR FRAMSTAELLNING AV NYA SAOSOM LAEKEMEDELSAKTIVAEMNEN ANVAENDBARA BENSOTIOFEN-2-ON-3-CARBOXAMIDER |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
MM1K | Lapsed by not paying the annual fees |