US3546212A - Oxidation of benzodiazepines with ruthenium tetroxide - Google Patents
Oxidation of benzodiazepines with ruthenium tetroxide Download PDFInfo
- Publication number
- US3546212A US3546212A US736250A US3546212DA US3546212A US 3546212 A US3546212 A US 3546212A US 736250 A US736250 A US 736250A US 3546212D A US3546212D A US 3546212DA US 3546212 A US3546212 A US 3546212A
- Authority
- US
- United States
- Prior art keywords
- ruthenium tetroxide
- dihydro
- phenyl
- benzodiazepin
- added
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Lifetime
Links
- 229910001927 ruthenium tetroxide Inorganic materials 0.000 title abstract description 35
- 238000007254 oxidation reaction Methods 0.000 title abstract description 12
- 230000003647 oxidation Effects 0.000 title abstract description 11
- 229940049706 benzodiazepine Drugs 0.000 title description 9
- 150000001557 benzodiazepines Chemical class 0.000 title description 5
- 238000006243 chemical reaction Methods 0.000 abstract description 9
- 229940125681 anticonvulsant agent Drugs 0.000 abstract description 3
- 239000001961 anticonvulsive agent Substances 0.000 abstract description 3
- 229940035363 muscle relaxants Drugs 0.000 abstract description 3
- 239000003158 myorelaxant agent Substances 0.000 abstract description 3
- 229940125723 sedative agent Drugs 0.000 abstract description 3
- 239000000932 sedative agent Substances 0.000 abstract description 3
- UDLAUVFRZXIQJS-UHFFFAOYSA-N 1,3-dihydro-1,4-benzodiazepin-2-one Chemical class N1C(=O)CN=CC2=CC=CC=C21 UDLAUVFRZXIQJS-UHFFFAOYSA-N 0.000 abstract description 2
- GUJAGMICFDYKNR-UHFFFAOYSA-N 1,4-benzodiazepine Chemical class N1C=CN=CC2=CC=CC=C12 GUJAGMICFDYKNR-UHFFFAOYSA-N 0.000 abstract description 2
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 27
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 26
- 150000001875 compounds Chemical class 0.000 description 25
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 24
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 18
- 239000000203 mixture Substances 0.000 description 15
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 14
- 238000000034 method Methods 0.000 description 14
- -1 alkyl radical Chemical class 0.000 description 13
- 239000000047 product Substances 0.000 description 13
- 230000001590 oxidative effect Effects 0.000 description 12
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 9
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 9
- 239000011541 reaction mixture Substances 0.000 description 8
- 239000000706 filtrate Substances 0.000 description 7
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 7
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 6
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-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
- 239000000460 chlorine Substances 0.000 description 6
- 238000001914 filtration Methods 0.000 description 5
- 238000002844 melting Methods 0.000 description 5
- 230000008018 melting Effects 0.000 description 5
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 5
- 238000002360 preparation method Methods 0.000 description 5
- 150000003254 radicals Chemical class 0.000 description 5
- KJTLSVCANCCWHF-UHFFFAOYSA-N Ruthenium Chemical compound [Ru] KJTLSVCANCCWHF-UHFFFAOYSA-N 0.000 description 4
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 4
- 238000002425 crystallisation Methods 0.000 description 4
- 230000008025 crystallization Effects 0.000 description 4
- 230000000694 effects Effects 0.000 description 4
- 229910052707 ruthenium Inorganic materials 0.000 description 4
- 239000002904 solvent Substances 0.000 description 4
- MEXNZUOOCNBUJU-UHFFFAOYSA-N (2-chlorophenyl)-pyrimidin-2-ylmethanone Chemical compound ClC1=CC=CC=C1C(=O)C1=NC=CC=N1 MEXNZUOOCNBUJU-UHFFFAOYSA-N 0.000 description 3
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- 125000000217 alkyl group Chemical group 0.000 description 3
- PNEYBMLMFCGWSK-UHFFFAOYSA-N aluminium oxide Inorganic materials [O-2].[O-2].[O-2].[Al+3].[Al+3] PNEYBMLMFCGWSK-UHFFFAOYSA-N 0.000 description 3
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 3
- 239000003153 chemical reaction reagent Substances 0.000 description 3
- 229910052801 chlorine Inorganic materials 0.000 description 3
- 238000004821 distillation Methods 0.000 description 3
- 229910052739 hydrogen Inorganic materials 0.000 description 3
- 239000001257 hydrogen Substances 0.000 description 3
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 3
- 230000007935 neutral effect Effects 0.000 description 3
- 239000012429 reaction media Substances 0.000 description 3
- 238000001953 recrystallisation Methods 0.000 description 3
- 239000012312 sodium hydride Substances 0.000 description 3
- 229910000104 sodium hydride Inorganic materials 0.000 description 3
- 239000007787 solid Substances 0.000 description 3
- ZAICQJHRVHLVEY-UHFFFAOYSA-N 2-(2-chlorophenyl)-2-pyrimidin-2-ylacetonitrile Chemical compound ClC1=CC=CC=C1C(C#N)C1=NC=CC=N1 ZAICQJHRVHLVEY-UHFFFAOYSA-N 0.000 description 2
- AOQMKLMZECLOEZ-UHFFFAOYSA-N 7-nitro-5-phenyl-2,3-dihydro-1h-1,4-benzodiazepine Chemical compound C12=CC([N+](=O)[O-])=CC=C2NCCN=C1C1=CC=CC=C1 AOQMKLMZECLOEZ-UHFFFAOYSA-N 0.000 description 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 2
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 2
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 2
- MZVQCMJNVPIDEA-UHFFFAOYSA-N [CH2]CN(CC)CC Chemical group [CH2]CN(CC)CC MZVQCMJNVPIDEA-UHFFFAOYSA-N 0.000 description 2
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 2
- 229910052794 bromium Inorganic materials 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- SPWVRYZQLGQKGK-UHFFFAOYSA-N dichloromethane;hexane Chemical compound ClCCl.CCCCCC SPWVRYZQLGQKGK-UHFFFAOYSA-N 0.000 description 2
- 239000000284 extract Substances 0.000 description 2
- 229910052736 halogen Inorganic materials 0.000 description 2
- 150000002367 halogens Chemical class 0.000 description 2
- GTVRLHPVICIJFQ-UHFFFAOYSA-N hexane;tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl.CCCCCC GTVRLHPVICIJFQ-UHFFFAOYSA-N 0.000 description 2
- 125000004356 hydroxy functional group Chemical group O* 0.000 description 2
- 125000001570 methylene group Chemical group [H]C([H])([*:1])[*:2] 0.000 description 2
- 239000002480 mineral oil Substances 0.000 description 2
- 235000010446 mineral oil Nutrition 0.000 description 2
- 239000012452 mother liquor Substances 0.000 description 2
- 239000003921 oil Substances 0.000 description 2
- 239000002244 precipitate Substances 0.000 description 2
- HEMHJVSKTPXQMS-UHFFFAOYSA-M sodium hydroxide Inorganic materials [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N sulfuric acid Substances OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- ROXAFEIDZVHGFX-UHFFFAOYSA-N 1,3,4,5-tetrahydro-1,4-benzodiazepin-2-one Chemical class N1C(=O)CNCC2=CC=CC=C21 ROXAFEIDZVHGFX-UHFFFAOYSA-N 0.000 description 1
- CLUHZXYQKUXOOL-UHFFFAOYSA-N 1-methyl-7-nitro-5-pyrimidin-2-yl-2,3-dihydro-1,4-benzodiazepine Chemical compound C12=CC([N+]([O-])=O)=CC=C2N(C)CCN=C1C1=NC=CC=N1 CLUHZXYQKUXOOL-UHFFFAOYSA-N 0.000 description 1
- MRDUURPIPLIGQX-UHFFFAOYSA-N 2-(2-chlorophenyl)acetonitrile Chemical compound ClC1=CC=CC=C1CC#N MRDUURPIPLIGQX-UHFFFAOYSA-N 0.000 description 1
- UNCQVRBWJWWJBF-UHFFFAOYSA-N 2-chloropyrimidine Chemical compound ClC1=NC=CC=N1 UNCQVRBWJWWJBF-UHFFFAOYSA-N 0.000 description 1
- 125000004198 2-fluorophenyl group Chemical group [H]C1=C([H])C(F)=C(*)C([H])=C1[H] 0.000 description 1
- WNVLMUAFJWJKBH-UHFFFAOYSA-N 3-methyl-5-phenyl-1,4-benzodiazepin-2-one Chemical compound C=12C=CC=CC2=NC(=O)C(C)=NC=1C1=CC=CC=C1 WNVLMUAFJWJKBH-UHFFFAOYSA-N 0.000 description 1
- VSALAFOSJBZZFM-UHFFFAOYSA-N 7-chloro-1-methyl-5-phenyl-1,4-benzodiazepine-2,3-dione Chemical compound N=1C(=O)C(=O)N(C)C2=CC=C(Cl)C=C2C=1C1=CC=CC=C1 VSALAFOSJBZZFM-UHFFFAOYSA-N 0.000 description 1
- CNXUJSZPLRNZKN-UHFFFAOYSA-N 7-chloro-5-phenyl-1h-1,4-benzodiazepine-2,3-dione Chemical compound C12=CC(Cl)=CC=C2NC(=O)C(=O)N=C1C1=CC=CC=C1 CNXUJSZPLRNZKN-UHFFFAOYSA-N 0.000 description 1
- JZWOKDTXYPEJEW-UHFFFAOYSA-N 7-chloro-5-phenyl-2,3-dihydro-1h-1,4-benzodiazepine Chemical compound C12=CC(Cl)=CC=C2NCCN=C1C1=CC=CC=C1 JZWOKDTXYPEJEW-UHFFFAOYSA-N 0.000 description 1
- BSFOWENCYDHTPW-UHFFFAOYSA-N 7-nitro-5-pyrimidin-2-yl-2,3-dihydro-1h-1,4-benzodiazepine Chemical compound C12=CC([N+](=O)[O-])=CC=C2NCCN=C1C1=NC=CC=N1 BSFOWENCYDHTPW-UHFFFAOYSA-N 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 1
- PIICEJLVQHRZGT-UHFFFAOYSA-N Ethylenediamine Chemical compound NCCN PIICEJLVQHRZGT-UHFFFAOYSA-N 0.000 description 1
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 1
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 1
- YZCKVEUIGOORGS-IGMARMGPSA-N Protium Chemical compound [1H] YZCKVEUIGOORGS-IGMARMGPSA-N 0.000 description 1
- CZPWVGJYEJSRLH-UHFFFAOYSA-N Pyrimidine Chemical compound C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 description 1
- FIULGFJIHJJXMT-UHFFFAOYSA-N [C]1[N]C=CC=C1 Chemical compound [C]1[N]C=CC=C1 FIULGFJIHJJXMT-UHFFFAOYSA-N 0.000 description 1
- 150000001338 aliphatic hydrocarbons Chemical class 0.000 description 1
- 125000003282 alkyl amino group Chemical group 0.000 description 1
- 125000003277 amino group Chemical group 0.000 description 1
- 229910021529 ammonia Inorganic materials 0.000 description 1
- SLUNEGLMXGHOLY-UHFFFAOYSA-N benzene;hexane Chemical compound CCCCCC.C1=CC=CC=C1 SLUNEGLMXGHOLY-UHFFFAOYSA-N 0.000 description 1
- 125000005998 bromoethyl group Chemical group 0.000 description 1
- 235000011089 carbon dioxide Nutrition 0.000 description 1
- 125000001309 chloro group Chemical group Cl* 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- VAYGXNSJCAHWJZ-UHFFFAOYSA-N dimethyl sulfate Chemical compound COS(=O)(=O)OC VAYGXNSJCAHWJZ-UHFFFAOYSA-N 0.000 description 1
- 239000011363 dried mixture Substances 0.000 description 1
- IDGUHHHQCWSQLU-UHFFFAOYSA-N ethanol;hydrate Chemical compound O.CCO IDGUHHHQCWSQLU-UHFFFAOYSA-N 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 125000005843 halogen group Chemical group 0.000 description 1
- 125000005059 halophenyl group Chemical group 0.000 description 1
- 239000002035 hexane extract Substances 0.000 description 1
- 150000002430 hydrocarbons Chemical group 0.000 description 1
- 150000002431 hydrogen Chemical group 0.000 description 1
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 1
- 239000005457 ice water Substances 0.000 description 1
- 229910001867 inorganic solvent Inorganic materials 0.000 description 1
- 239000003049 inorganic solvent Substances 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 239000012280 lithium aluminium hydride Substances 0.000 description 1
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 1
- 235000019341 magnesium sulphate Nutrition 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 238000006386 neutralization reaction Methods 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- 239000007800 oxidant agent Substances 0.000 description 1
- 239000003208 petroleum Substances 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 125000004076 pyridyl group Chemical group 0.000 description 1
- 125000000246 pyrimidin-2-yl group Chemical group [H]C1=NC(*)=NC([H])=C1[H] 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 230000000717 retained effect Effects 0.000 description 1
- 239000002002 slurry Substances 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 238000004809 thin layer chromatography Methods 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- 239000008096 xylene Substances 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
- A61K31/551—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having two nitrogen atoms, e.g. dilazep
- A61K31/5513—1,4-Benzodiazepines, e.g. diazepam or clozapine
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
- C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
- C07D239/26—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
- C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
- C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
- C07D239/30—Halogen atoms or nitro radicals
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
- C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
- C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
- C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
- C07D239/52—Two oxygen atoms
- C07D239/54—Two oxygen atoms as doubly bound oxygen atoms or as unsubstituted hydroxy radicals
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- D—TEXTILES; PAPER
- D06—TREATMENT OF TEXTILES OR THE LIKE; LAUNDERING; FLEXIBLE MATERIALS NOT OTHERWISE PROVIDED FOR
- D06P—DYEING OR PRINTING TEXTILES; DYEING LEATHER, FURS OR SOLID MACROMOLECULAR SUBSTANCES IN ANY FORM
- D06P1/00—General processes of dyeing or printing textiles, or general processes of dyeing leather, furs, or solid macromolecular substances in any form, classified according to the dyes, pigments, or auxiliary substances employed
- D06P1/44—General processes of dyeing or printing textiles, or general processes of dyeing leather, furs, or solid macromolecular substances in any form, classified according to the dyes, pigments, or auxiliary substances employed using insoluble pigments or auxiliary substances, e.g. binders
-
- D—TEXTILES; PAPER
- D06—TREATMENT OF TEXTILES OR THE LIKE; LAUNDERING; FLEXIBLE MATERIALS NOT OTHERWISE PROVIDED FOR
- D06P—DYEING OR PRINTING TEXTILES; DYEING LEATHER, FURS OR SOLID MACROMOLECULAR SUBSTANCES IN ANY FORM
- D06P3/00—Special processes of dyeing or printing textiles, or dyeing leather, furs, or solid macromolecular substances in any form, classified according to the material treated
- D06P3/80—Inorganic fibres
-
- D—TEXTILES; PAPER
- D06—TREATMENT OF TEXTILES OR THE LIKE; LAUNDERING; FLEXIBLE MATERIALS NOT OTHERWISE PROVIDED FOR
- D06P—DYEING OR PRINTING TEXTILES; DYEING LEATHER, FURS OR SOLID MACROMOLECULAR SUBSTANCES IN ANY FORM
- D06P3/00—Special processes of dyeing or printing textiles, or dyeing leather, furs, or solid macromolecular substances in any form, classified according to the material treated
- D06P3/82—Textiles which contain different kinds of fibres
- D06P3/854—Textiles which contain different kinds of fibres containing modified or unmodified fibres, i.e. containing the same type of fibres having different characteristics, e.g. twisted and not-twisted fibres
Definitions
- the present invention relates to the oxidation of benzodiazepines with ruthenium tetroxide.
- the present invention relates to a process which comprises oxidizing a compound of the formula:
- the present invention relates to oxidizing compounds of the formula:
- Illustrative of typical radicals represented by the character R which are stable under the oxidation conditions described herein to effect the preparation of compounds of the Formula II above are the hydrogen radical, the lower alkyl radical, the halo lower alkyl radical, e.g. chloropropyl, bromoethyl and the like, a basic side chain containing radical such as the dilower alkyl-amino-lower alkyl radical (dimethylaminoethyl, diethylaminoethyl, dimethylaminopropyl and the like), or any other radical which would be stable under the oxidation conditions utilized; that is to say, that would be uneffected by oxidation in the manner described herein utilizing ruthenium tetroxide.
- lower alkyl as utilized herein, both branched and straight chain C -C preferably C -C hydrocarbon groups are contemplated such as methyl, ethyl propyl, isobutyl and the like.
- halogen as utilized herein, all four forms thereof are contemplated unless otherwise specified, e.g. chlorine, bromine, iodine and fluorine.
- a particularly advantageous process aspect of the present invention results in the preparation of compounds of the Formula II above wherein R and R are hydrogen and B is phenyl or halophenyl, preferably, 2-halophenyl, most preferentially, 2-fluorophenyl.
- R R and B are as above and R is halogen, preferably chlorine or bromine, most preferably, chlorine.
- R, R and R represent the groups preferred above
- B is the phenyl group
- R is selected from the group consisting of hydrogen, lower alkyl, most preferentially, methyl and dilower alkyl amino lower alkyl, most preferentially, diethylaminoethyl. If B is pyridyl, a 2-pyridyl radical is preferred.
- the oxidation with ruthenium tetroxide proceeds readily and facily to the desired product of the Formula II above.
- ruthenium tetroxide is added to the reaction zone in a molar excess.
- the re action is effected at below room temperature, e.g., at a temperature range of from about -20 to about 15, most preferably, from about 0 to about 10.
- the reaction proceeds most suitably in the presence of an inert inorganic solvent and among the many solvents suitable for the purposes of the present invention there may be included halogenated aliphatic hydrocarbons such as chloroform, dichloromethane and the like.
- any suitable reagent may be added to the reaction medium to destroy any excess ruthenium tetroxide present therein.
- a preferred reagent for this purpose is a lower alkanol such as Z-propanol.
- the compounds of the Formula II above are known compounds and are useful as anticonvulsants, muscle relaxants and sedative agents. Their pharmacological usefulness is well document in the literature.
- R, R R and B are as above.
- an excess of ruthenium tetroxide is preferentially utilized in the preferred embodiment. If a slight excess is utilized, the compound of the Formula II is the major product and its preparation is preferred. If a great excess of ruthenium tetroxide is utilized, the compound of the Formula IV can be obtained in major amounts. The amount of ruthenium tetroxide utilized to achieve the desired end is readily ascertainable by those skilled in the art. As the particularly preferred embodiment of this invention relates to the preparation of a compound of the Formula II above, it is of course evi dent that a slight excess of ruthenium tetroxide is preferentially utilized for the purposes of the present invention.
- the process of the present invention in a preferred embodiment therefore relates to a novel oxidation procedure for efiecting the conversion of certain benzodiazepines into other 2,3-dihydro-1,4-benzodiazepin-2-ones in unexpectedly good yields and in a facile and convenient manner.
- EXAMPLE 1 Into a 500 ml. 3-necked round bottom flask equipped with magnetic stirrer and immersed in an ice-salt bath at l was placed 7-chloro-2,3-dihydro-5-phenyl-1H-l,4- benzodiazepine (642 mg., 2.5 mmoles). A chloroform solution of ruthenium tetroxide (158 ml. of 0.07 M, 11 mmole, 4.4 equivalents) was added dropwise over a 30 minute period and stirred for an additional period of 30 minutes. 2-propanol ml.) was added to the re- 4 action medium and the reaction mixture was filtered.
- 7-chloro-2,3-dihydro-5-phenyl-1H-l,4- benzodiazepine (642 mg., 2.5 mmoles).
- a chloroform solution of ruthenium tetroxide 158 ml. of 0.07 M, 11 mmole, 4.4 equivalent
- EXAMPLE 2 Into a 500 ml. 3-necked round bottom flask equipped with magnetic stirrer and immersed in an ice-salt bath at 10 was placed 7-chloro-2,3-dihydro-1-methyl-5- phenyl-lH-l,4-benzodiazepine (732 mg., 2.7 mmole). A solution of ruthenium tetroxide (180 m1. of 0.054 M, 9.7 mmole, 3.6 equivalents) was added dropwise over a 30 minute period and stirred for an additional 30 minutes. 2-propanol (5 ml.) and water (200 ml.) was added to the reaction medium and the mixture was filtered through Celite.
- the starting material 2,3-dihydro-1-methyl-7-nitro-5 (Z-pyrimidinyl)-1H-1,4-benzodiazepine is not part of the present invention, but its preparation is disclosed herein in order that the disclosure may be complete.
- EXAMPLE 6 Into a 500 ml. 3-necked round bottom flask equipped with magnetic stirrer and immersed in an ice-salt bath at -10 was placed 7-ch1oro-1,3,4,5-tetrahydro-5-phenyl- 2H-1,4-benzodiazepin-2-one (681 mg., 2.5 mmole). A solution of ruthenium tctroxide ml. of 0.067 M, 7.0 mmole, 2.8 equivalents) was added dropwise over a 30 minute period and stirred for an additional 30 minutes.
- EXAMPLE 7 A stirred solution of 0.5 g. (0.00166 M) of 7-chloro- 1,3 dihydro 3 hydroxy 1 methyl 5 phenyl 2H- 1,4-benzodiazepin-2-one in 12 ml. of chloroform cooled in an ice bath was treated with the dropwise addition of 51 m1. (0.00332 M) of a 0.0647 M ruthenium tctroxide solution. After 18 hrs., 15 ml, of water was added and the mixture was filtered through celite. The chloroform layer was separated, dried over anhydrous sodium sulfate and evaporated to dryness. To the oil so obtained there was added a mixture of dichloromethane and hexane (2x).
- EXAMPLE 8 A stirred suspension of 3 g. (0.0105 M) of 7-chloro-1,3- dihydro 3 hydroxy 5 phenyl 2H 1,4 benzodiazcpin-2-one in 10 ml. of CHCl in an ice bath was treated with 200 ml. (0.013 M) of a 0.0647 M solution of ruthenium tctroxide in chloroform. After 18 hrs. at room temperature, 25 ml. of water was added and the solution was filtered through celite.
- EXAMPLE 9 A solution of 1 g. (0.00348 M) of 7-chloro-l,3,4,5- tetrahydro 1 methyl 5 phenyl 2H 1,4 benzodi azepin-Z-one in 25 ml. of chloroform was stirred in an ice bath and was treated with 108 ml. (0.00696 M) of a 0.0047 M solution of ruthenium tctroxide in chloroform over a 10-minute period. After standing 18 hours at room temperature an additional 75 ml. (0.00485 M) of ruthenium tetroxide was added and the reaction was allowed to stand for an additional 18 hours. Water (50 ml.) was added and the mixture was filtered through Celite.
- Z is selected from the group consisting of carbonyl and methylene
- A is selected from the group consisting of with the proviso that when Z is carbonyl, A is with ruthenium tetroxide whereby to prepare the corresponding compound of the formula:
- a process as defined in claim 1 which comprises oxidizing 7-halo-2,3-dihydro-5-phenyl-1H-1,4-benzodiazepine with ruthenium tetroxide whereby to obtain 7-halo- 2,3-dihydro-5-phenyl-2H 1,4-benzodiazepin-2-one.
- a process as defined in claim 1 which comprises oxidizing 7-chloro-2,3-dihydro-5-phenyl-1H-1,4-benzodiazepine with ruthenium tetroxide whereby to obtain 7- chloro-Z,3-dihydro-5-phenyl-2H-l ,4-benzodiazepin-2-one.
- process as defined in claim 1 which comprises oxidizing 7-halo-2,3-dihydro-l-methyl-S-phenyl-IH-1,4- benzodiazepine with ruthenium tetroxide whereby to obtain 7-halo-2,3-dihydro-l-methyl-S-phenyl-ZH-1,4-benzodiazepin-Z-one.
- a process as defined in claim 1 which comprises oxidizing 2,3 dihydro-7-nitro-5-phenyl-lH-1,4 benzodiazepine with ruthenium tetroxide whereby to obtain 2,3- dihydro7-nitro-5-pheny1-2H-1,4-benzodiazepin-2-one.
- a process as defined in claim 1 which comprises oxidizing a compound of the formula 7-halo-l,3,4,5- tetrahydro-S-phenyl-ZH-1,4-benzodiazepin-2-one with ruthenium tetroxide whereby to prepare 7-halo-2,3-dihydro- 5-phenyl-2I-I-1,4-benzodiazepin-2-one.
- a process as defined in claim 1 which comprises oxidizing a compound of the formula 7-chlor0-1,3,4,5- tetrahydro-S-phenyl-ZH-1,4-benzodiazepin-2-one with ruthenium tetroxide whereby to prepare 7-chloro-2,3-dihydro-S-phenyl-ZH-l,4-benzodiazepin-2-one.
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Abstract
Conversion of 1,4-benzodiazepines (A) and tetrahydrol,4-benzodiazepin-2-ones (B) into 2,3-dihydro-1,4-benzodiazepin-2-ones (C) by oxidation of (A) or (B) with ruthenium tetroxide. (C) are useful as anticonvulsants, muscle relaxants and sedatives
Description
United States Patent 3,546,212 OXIDATION OF BENZODIAZEPINES WITH RUTHENIUM TETROXIDE Arthur Martin Felix, Clifton, Rodney Ian Fryer, North Caldwell, and Leo Henryk Sternbach, Upper Montclair, N.J., assignors to Hotfmann-La Roche Inc., Nutley, N.J., a corporation of New Jersey No Drawing. Filed June 12, 1968, Ser. No. 736,250 Int. Cl. C0711 53/06 US. Cl. 260-2393 8 Claims ABSTRACT OF THE DISCLOSURE Conversion of 1,4-benzodiazepines (A) and tetrahydro- 1,4-benzodiazepin-2-ones (B) into 2,3-dihydro-l,4-benzodiazepin-Z-ones (C) by oxidation of (A) or (B) with ruthenium tetroxide. (C) are useful as anticonvulsants, muscle relaxants and sedatives.
BACKGROUND The reagent ruthenium tetroxide was first discovered more than a century ago. However, it appears thatlittle effort was made to explore its capabilities as evidenced by the relative paucity of literature articles reporting on studies of reactions with ruthenium tetroxide. Certain workers in the art [Berkowitz et al., I. Am. Chem. Soc., 80, 6682 (1952)] have shown that ruthenium tetroxide is usable as an oxidant. However, it was not known until the discovery by the present applicants that ruthenium tetroxide could be efficaciously utilized in oxidizing amino group containing compounds such as benzodiazepines into corresponding compounds containing the carbonyl group in position-2 and the so-called Schifis base, i.e. the
I radical. This discovery is particularly surprising due to the relative difficulty of converting a CH grouping in a heterocyclic amino to a C 0 grouping and the well known propensity of the |3= radical to be unstable under conditions of the type inherent in an oxidation reaction.
DETAILED DESCRIPTION OF THE INVENTION As is evident from the above, the present invention relates to the oxidation of benzodiazepines with ruthenium tetroxide. In one aspect, the present invention relates to a process which comprises oxidizing a compound of the formula:
Patented Dec. 8, 1970 with ruthenium tetroxide whereby to prepare the corresponding compound of the formula:
wherein B, R, R R and R are as described hereinabove.
In another aspect, the present invention relates to oxidizing compounds of the formula:
wherein B, R, R R and R with ruthenium tetroxide to thereby obtain the corresponding compound of the Formula II above.
Illustrative of typical radicals represented by the character R which are stable under the oxidation conditions described herein to effect the preparation of compounds of the Formula II above are the hydrogen radical, the lower alkyl radical, the halo lower alkyl radical, e.g. chloropropyl, bromoethyl and the like, a basic side chain containing radical such as the dilower alkyl-amino-lower alkyl radical (dimethylaminoethyl, diethylaminoethyl, dimethylaminopropyl and the like), or any other radical which would be stable under the oxidation conditions utilized; that is to say, that would be uneffected by oxidation in the manner described herein utilizing ruthenium tetroxide.
By the term lower alkyl as utilized herein, both branched and straight chain C -C preferably C -C hydrocarbon groups are contemplated such as methyl, ethyl propyl, isobutyl and the like. By the term halogen as utilized herein, all four forms thereof are contemplated unless otherwise specified, e.g. chlorine, bromine, iodine and fluorine.
A particularly advantageous process aspect of the present invention results in the preparation of compounds of the Formula II above wherein R and R are hydrogen and B is phenyl or halophenyl, preferably, 2-halophenyl, most preferentially, 2-fluorophenyl. In a more preferred embodiment R R and B are as above and R is halogen, preferably chlorine or bromine, most preferably, chlorine. In the most preferred embodiment, R, R and R represent the groups preferred above, B is the phenyl group, R is selected from the group consisting of hydrogen, lower alkyl, most preferentially, methyl and dilower alkyl amino lower alkyl, most preferentially, diethylaminoethyl. If B is pyridyl, a 2-pyridyl radical is preferred.
In either of the process aspects set forth above, the oxidation with ruthenium tetroxide proceeds readily and facily to the desired product of the Formula II above. In a preferred aspect, ruthenium tetroxide is added to the reaction zone in a molar excess. Preferably, the re action is effected at below room temperature, e.g., at a temperature range of from about -20 to about 15, most preferably, from about 0 to about 10. The reaction proceeds most suitably in the presence of an inert inorganic solvent and among the many solvents suitable for the purposes of the present invention there may be included halogenated aliphatic hydrocarbons such as chloroform, dichloromethane and the like.
Advantageously, after the reaction is permitted to proceed for the time necessary to effect the desired end, i.e. to the point where compounds of the Formula II above are prepared, any suitable reagent may be added to the reaction medium to destroy any excess ruthenium tetroxide present therein. A preferred reagent for this purpose is a lower alkanol such as Z-propanol.
The compounds of the Formula II above are known compounds and are useful as anticonvulsants, muscle relaxants and sedative agents. Their pharmacological usefulness is well document in the literature.
When pursuing the reaction described above, i.e. the oxidation of a compound of the Formula I or 111 above wherein R is hydrogen with ruthenium tetroxide, it has been observed that there is obtained as a minor product, a compound of the formula:
wherein R, R R and B are as above.
As is noted above, an excess of ruthenium tetroxide is preferentially utilized in the preferred embodiment. If a slight excess is utilized, the compound of the Formula II is the major product and its preparation is preferred. If a great excess of ruthenium tetroxide is utilized, the compound of the Formula IV can be obtained in major amounts. The amount of ruthenium tetroxide utilized to achieve the desired end is readily ascertainable by those skilled in the art. As the particularly preferred embodiment of this invention relates to the preparation of a compound of the Formula II above, it is of course evi dent that a slight excess of ruthenium tetroxide is preferentially utilized for the purposes of the present invention.
Compounds of the Formula IV above can also be prepared by treating the corresponding compound of the wherein R, R R and B are as above with ruthenium tetroxide in the manner described above.
Compounds of the Formula IV above can be converted into the known compounds of the Formula II above or into the corresponding compounds which contain a methylene group in position-2 with lithium aluminum hydride according to known procedures.
The process of the present invention in a preferred embodiment therefore relates to a novel oxidation procedure for efiecting the conversion of certain benzodiazepines into other 2,3-dihydro-1,4-benzodiazepin-2-ones in unexpectedly good yields and in a facile and convenient manner.
The following examples are illustrative but not limitative of the present invention. All temperatures are stated in degrees centigrade.
EXAMPLE 1 Into a 500 ml. 3-necked round bottom flask equipped with magnetic stirrer and immersed in an ice-salt bath at l was placed 7-chloro-2,3-dihydro-5-phenyl-1H-l,4- benzodiazepine (642 mg., 2.5 mmoles). A chloroform solution of ruthenium tetroxide (158 ml. of 0.07 M, 11 mmole, 4.4 equivalents) was added dropwise over a 30 minute period and stirred for an additional period of 30 minutes. 2-propanol ml.) was added to the re- 4 action medium and the reaction mixture was filtered. The Ru0 which precipitated was washed with hot tetrahydrofuran and the combined filtrate evaporated to dryness yielding 7-chloro-2,3-dihydro-5-phenyl-2H-1,4-benzodiazepin-Z-one. After crystallization from carbon tetrachloride-hexane, the product melted at 2150-2170".
EXAMPLE 2 Into a 500 ml. 3-necked round bottom flask equipped with magnetic stirrer and immersed in an ice-salt bath at 10 was placed 7-chloro-2,3-dihydro-1-methyl-5- phenyl-lH-l,4-benzodiazepine (732 mg., 2.7 mmole). A solution of ruthenium tetroxide (180 m1. of 0.054 M, 9.7 mmole, 3.6 equivalents) was added dropwise over a 30 minute period and stirred for an additional 30 minutes. 2-propanol (5 ml.) and water (200 ml.) was added to the reaction medium and the mixture was filtered through Celite. The filtrate was transferred to a separa- Jtory funnel and the chloroform layer retained. The aqueous layer was washed three times with chloroform. The chloroform washings were added to the said chloroform layer. The so-obtained medium was dried over magnesium sulfate, filtered and evaporated to a small volume. Hexane was added to the resulting medium. It was then allowed to stand. Crystals of 7-chloro-2,3- dihydro-l-methyl-S-phenyl-ZH-l,4-benzodiazepin 2-one, M.P. 127-1305 formed which was separated by filtration.
EXAMPLE 3 Into a 500 ml. 3-necked round bottom flask equipped with magnetic stirrer and immersed in an ice-salt bath at l0 was placed 2,3-dihydro-1-methyl-7-nitro-5-phenyl- 1I-I-1,4-benzodiazepine (678 mg, 2.5 mmole). A solution of ruthenium tetroxide ml. of 0.077 M, 12.7 mmole, 5.1 equivalents) was added dropwise over a 30 minute period and stirred for an additional 30 minutes. 2-propanol (5 ml.) was then added and the reaction mixture was filtered. The RuO which precipitated was washed with chloroform and the combined filtrate evaporated to dryness yielding 2,3-dihydro-1-methyl-7-nitro-5-pheny1- 2H-1,4-benzodiazepin-2-one. After crystallization from ethanol-water the product was found to have a M.P. of 153158.
EXAMPLE 4 Into a 250 ml. 3-necked round bottom flask equipped with magnetic stirrer and immersed in an ice bath was placed 2,3 dihydro 7-nitro-5-phenyl-1H-1,4-benzodiazepine (1.34 g., 5.0 mmole). A solution of ruthenium tetroxide -(271 ml. of 0.074 M, 20 mmole, 4 equivalents) was added dropwise over a 30 minute period and stirred for an additional hour. 2-propanol (5 ml.) was added to the reaction medium and the resulting reaction mixture was fil tered and washed with tetrahydrofuran. The combined filtrate was evaporated to dryness. There was obtained a yellow solid, which upon crystallization from ethanol afforded 2,3 dihydro-7-nitro-5-phenyl-2H-1,4-benzodiazepin-2-one as off-white prisms, M.P. 221Q27.
EXAMPLE 5 Into a 500 ml. 3-necked round bottom flask equipped with magnetic stirrer and immersed in an ice bath was placed 2,3 dihydro 1-methyl-7-nitro-5-(2-pyrimidinyl)- 1H-1,4-benzodiazepine (944 mg., 3.33 mmole). A solution of ruthenium tetroxide (260 ml. of 0.058 M, 15 mmole, 4.5 equivalents) was added dropwise over a 30 minute period and stirred for an additional 30 minutes. 2-propanol (5 ml.) was added and the reaction mixture was filtered and evaporated to dryness. The resultant oil was crystallized from methylene chloride-hexane giving 2,3- dihydro l methyl-7-nitro-5-(2-pyrimidinyl)-2H-1,4- benzodiazepin-Z-one, M.P. 194.0-196.5 dec.
The starting material 2,3-dihydro-1-methyl-7-nitro-5 (Z-pyrimidinyl)-1H-1,4-benzodiazepine is not part of the present invention, but its preparation is disclosed herein in order that the disclosure may be complete.
To a solution of 54.4 g. (0.36 moles) of o-chlorophenylacetonitrile in 900 ml. of anhydrous tetrahydrofuran, 17.2 g. (0.36 moles) of sodium hydride (50:50 by wt. in mineral oil) was added. The resulting mixture was heated to reflux for 30 min. while stirring. The temperature was lowered to 60 and a solution of 41.1 g. (0.36 moles) of 2-chloropyrimidine in 216 ml. of tetrahydrofuran was added slowly. The reaction mixture was then refluxed for 3 hrs. After cooling, 100 ml. of water was added cautiously and tetrahydrof-uran was removed by distillation under reduced pressure. The residue was extracted with methylene chloride, washed with water and dried (Na- SO Removal of solvent by distillation gave a residue which was extracted twice with 375 ml. of hot hexane. The hexane insoluble fraction was crystallized from a mixture of henzene and hexane to give 2-(2-pyrimidyl)-2-(2-chlorophenyl)acetonitrile; M.P. 7981. Additional amounts of the product were obtained from the mother liquor and the hexane extract. Recrystallization of the product from hexane gave colorless rhombs melting at 81-82.
To a solution of 3.0 g. (0.013 moles) of 2-(2-pyrimidyl)-2-(2-chlorophenyl)acetonitrile in 250 g. of dry tetrahydrofuran, 0.76 g. (0.016 moles) of sodium hydride (50 percent by weight in mineral oil) was added and the mixture stirred and refluxed for 2 hrs. It was then cooled to room temperature and stirred for 16 hrs. while passing a stream of dry air through the mixture. Methanol (10 m1.) and water (20 ml.) were added to destroy excess sodium hydride and the mixture was then concentrated under reduced pressure to remove tetrahydrofuran. On addition of water to the residue, 2-(2-chlorobenzoyl) pyrimidine crystallized (M.P. 1247). An additional amount of the product was obtained from the filtrate. Recrystallization from a mixture of benzene and hexane gave colorless plates of 2-(2-chlorobenzoyl)pyrimidine, M.P. l279.
A solution of 11.9 g. of 2-(2-chlorobenzoyl) pyrimidine in 60 ml. of concentrated sulfuric acid was cooled to and a solution of 3.1 ml. of 90 percent nitric acid in 7.7 ml. of concentrated sulfuric acid was added dropwise during 1 hr. The reaction mixture was then stirred for an additional hour at 0 and for 1 hr. at room temperature, then poured onto ice. On neutralization with dilute ammonia, a while solid formed. Filtration separated 2-(2- chloro-S-nitrobenzoyl)pyrimidine, M.P. 1436. Recrystallization from benzene gave light yellow rhombs melting at 147-9".
A mixture of 2-(2-chloro-5-nitrobenzoyl)-pyrimidine (446.2 gm., 1.70 mols.), ethylenediamine (510 gm., 8.5 mols.) and anhydrous pyridine (1700 ml.) was stirred and heated on the steam-bath for hrs. Most of the solvents were removed by concentration under reduced pressure, followed by successive co-distillation with xylene and toluene. The resulting tarry residue was mixed with methanol (200 ml.) and aqueous 3 N-sodium hydroxide. The crude produce precipitated, and was recovered by filtration, washed with water, and dried. Purification was effected by addition of Woelm activity I neutral alumina (1 kg.) to a slurry of the product in methanol, followed by removal of the solvent :under reduced pressure. The dried mixture of product and alumina was then continuously extracted with hot methylene chloride, in a Soxhlet extractor, until no further product was recovered in the extract (4-5 days were required). Filtration of the extract gave 2,3 dihydro 7-nitro-5-(2-pyrimidinyl)-lH-1,4-benzodiazepine (M.P. 222-224 C).
A solution of 2,3-dihydro-7-nitro-5-(Z-pyrimidinyl)- 1H-l,4-benzodiazepine (147.7 gm., 0.55 mols.) and sodium methoxide (33.0 gm., 0.61 mols.) in anhydrous N,N-dimethylformamide (1300 ml.) was stirred for 1 hour at room temperature and was then treated dropwise with a solution of dimethyl sulfate (77.0 gm., 0.61 mols.) in dry dimethylformamide (260 ml.) during 2 hours, maintaining the temperature of the reaction mixture at 05 C., by cooling in an ice bath. Stirring was continued for 24 hours at room temperature, and then the mixture was poured into ice water (6 liters). Dry ice was added until the mixture was approximately neutral (pH 5-6); the crude product was recovered by extraction with methylene chloride, and was obtained as a largely crystalline solid. This material was extracted with cold methylene chloride and filtered. The filtrate was passed through a bed of Woelm activity III neutral alumina (785 gm.). The methylene chloride eluate was evaporated, and the resulting residue was crystallized from benzene-hexane to give 2,3-dihydro-1-methyl-7-nitro-5- (2-pyrimidinyl)-lH-l,4-benzodiazepine (M.P. 179-181 C.). A further crop was obtained fror the mother liquors. The product was recrystallized from methylene chloridehexane as yellow rods, M.P. 181-l83 C. (dec.).
EXAMPLE 6 Into a 500 ml. 3-necked round bottom flask equipped with magnetic stirrer and immersed in an ice-salt bath at -10 was placed 7-ch1oro-1,3,4,5-tetrahydro-5-phenyl- 2H-1,4-benzodiazepin-2-one (681 mg., 2.5 mmole). A solution of ruthenium tctroxide ml. of 0.067 M, 7.0 mmole, 2.8 equivalents) was added dropwise over a 30 minute period and stirred for an additional 30 minutes. 2-propanol (5 ml.) was then added and the reaction mixture was filtered and evaporated to dryness giving 7 chloro 2,3 dihydro 5 phenyl 2H 1,4 benzodiazepin-Z-one which after crystallization from carbon tetrachloride-hexane melted at 2155-2175".
EXAMPLE 7 A stirred solution of 0.5 g. (0.00166 M) of 7-chloro- 1,3 dihydro 3 hydroxy 1 methyl 5 phenyl 2H- 1,4-benzodiazepin-2-one in 12 ml. of chloroform cooled in an ice bath was treated with the dropwise addition of 51 m1. (0.00332 M) of a 0.0647 M ruthenium tctroxide solution. After 18 hrs., 15 ml, of water was added and the mixture was filtered through celite. The chloroform layer was separated, dried over anhydrous sodium sulfate and evaporated to dryness. To the oil so obtained there was added a mixture of dichloromethane and hexane (2x). The precipitate which formed each time was removed. The mother liquors were then crystallized from ether and the product recrystallized from a mixture of dichloromethane and hexane to give 7-chloro-l-methyl-5- phenyl-IH-1,4-benzodiazepine-2,3-dione as white prisms, melting at 169-174".
EXAMPLE 8 A stirred suspension of 3 g. (0.0105 M) of 7-chloro-1,3- dihydro 3 hydroxy 5 phenyl 2H 1,4 benzodiazcpin-2-one in 10 ml. of CHCl in an ice bath was treated with 200 ml. (0.013 M) of a 0.0647 M solution of ruthenium tctroxide in chloroform. After 18 hrs. at room temperature, 25 ml. of water was added and the solution was filtered through celite. A precipitate which then formed in the filtrates was removed by filtration and recrystallized first from ethyl acetate and then from a mixture of dichloro-methane and petroleum ether to give 7-chloro-5- phenyl-1H-1,4-benzodiazepine-2,3-dione as yellow plates melting at 243-251".
EXAMPLE 9 A solution of 1 g. (0.00348 M) of 7-chloro-l,3,4,5- tetrahydro 1 methyl 5 phenyl 2H 1,4 benzodi azepin-Z-one in 25 ml. of chloroform was stirred in an ice bath and was treated with 108 ml. (0.00696 M) of a 0.0047 M solution of ruthenium tctroxide in chloroform over a 10-minute period. After standing 18 hours at room temperature an additional 75 ml. (0.00485 M) of ruthenium tetroxide was added and the reaction was allowed to stand for an additional 18 hours. Water (50 ml.) was added and the mixture was filtered through Celite. The chloroform layer was separated, dried over anhydrous sodium sulfate and evaporated to dryness. The residue was crystallized from ether to give 7-chloro-2,3-dihydrol-methyl-S-phenyl-ZH-l,4-benzodiazepin-2-one as white prisms melting at 128-32. An examination of the mother liquor by thin layer chromatography showed the presence of considerable amounts of 7-chloro-l-methyl-S-phenyl- 1H- 1 ,4-benzodiazepine-2,3-dionc.
What is claimed is:
1. A process which comprises oxidizing a compound of the formula:
wherein Z is selected from the group consisting of carbonyl and methylene, A is selected from the group consisting of with the proviso that when Z is carbonyl, A is with ruthenium tetroxide whereby to prepare the corresponding compound of the formula:
RaO I ll R l x w R1 R; I
wherein B, R, R R and R are as described hereinabove.
2. A process as defined in claim 1 which comprises oxidizing 7-halo-2,3-dihydro-5-phenyl-1H-1,4-benzodiazepine with ruthenium tetroxide whereby to obtain 7-halo- 2,3-dihydro-5-phenyl-2H 1,4-benzodiazepin-2-one.
3. A process as defined in claim 1 which comprises oxidizing 7-chloro-2,3-dihydro-5-phenyl-1H-1,4-benzodiazepine with ruthenium tetroxide whereby to obtain 7- chloro-Z,3-dihydro-5-phenyl-2H-l ,4-benzodiazepin-2-one.
4 A. process as defined in claim 1 which comprises oxidizing 7-halo-2,3-dihydro-l-methyl-S-phenyl-IH-1,4- benzodiazepine with ruthenium tetroxide whereby to obtain 7-halo-2,3-dihydro-l-methyl-S-phenyl-ZH-1,4-benzodiazepin-Z-one.
5. A process as defined in claim 1 which comprises oxidizing 7-chloro-2,3-dihydro-l-methyl-S-phenyl-1H-1,4- benzodiazepine with ruthenium tetroxide whereby to obtain 7-chloro2,3-dihydro-1-methyl5-phenyl-2H-1,4=benzodiazepin-Z-one.
6. A process as defined in claim 1 which comprises oxidizing 2,3 dihydro-7-nitro-5-phenyl-lH-1,4 benzodiazepine with ruthenium tetroxide whereby to obtain 2,3- dihydro7-nitro-5-pheny1-2H-1,4-benzodiazepin-2-one.
7. A process as defined in claim 1 which comprises oxidizing a compound of the formula 7-halo-l,3,4,5- tetrahydro-S-phenyl-ZH-1,4-benzodiazepin-2-one with ruthenium tetroxide whereby to prepare 7-halo-2,3-dihydro- 5-phenyl-2I-I-1,4-benzodiazepin-2-one.
8. A process as defined in claim 1 which comprises oxidizing a compound of the formula 7-chlor0-1,3,4,5- tetrahydro-S-phenyl-ZH-1,4-benzodiazepin-2-one with ruthenium tetroxide whereby to prepare 7-chloro-2,3-dihydro-S-phenyl-ZH-l,4-benzodiazepin-2-one.
References Cited UNITED STATES PATENTS 3,371,085 2/1968 Reeder et a1. 260239.3
HENRY R. JILES, Primary Examiner R. T. BOND, Assistant Examiner US. Cl. X.R. 260-239, 999
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US73625068A | 1968-06-12 | 1968-06-12 | |
US80346169A | 1969-02-28 | 1969-02-28 |
Publications (1)
Publication Number | Publication Date |
---|---|
US3546212A true US3546212A (en) | 1970-12-08 |
Family
ID=27113017
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US736250A Expired - Lifetime US3546212A (en) | 1968-06-12 | 1968-06-12 | Oxidation of benzodiazepines with ruthenium tetroxide |
Country Status (12)
Country | Link |
---|---|
US (1) | US3546212A (en) |
AT (2) | AT289125B (en) |
BE (1) | BE734376A (en) |
CA (1) | CA950453A (en) |
CH (3) | CH523267A (en) |
DE (1) | DE1929910A1 (en) |
ES (1) | ES368239A1 (en) |
FR (1) | FR2010744A1 (en) |
GB (1) | GB1239380A (en) |
IE (1) | IE33286B1 (en) |
NL (3) | NL143927B (en) |
SE (1) | SE347510B (en) |
Cited By (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US3723414A (en) * | 1970-02-13 | 1973-03-27 | Schering Corp | 1-polyfluoroalkyl benzodiazepines |
US3896109A (en) * | 1971-09-30 | 1975-07-22 | Upjohn Co | 2,3-dehydro-1h-1,4-benzodiazepines |
US4083948A (en) * | 1977-04-04 | 1978-04-11 | Hoffmann-La Roche, Inc. | Benzodiazepine radioimmunoassay using I125-label |
US4280993A (en) * | 1978-01-19 | 1981-07-28 | Claus Braestrup | Process for determining the concentration of benzodiazepines in a body fluid |
US4497740A (en) * | 1981-06-19 | 1985-02-05 | Kali-Chemie Pharma Gmbh | 2-Azidomethyl-1,4-benzodiazepine compounds |
US5137564A (en) * | 1989-07-27 | 1992-08-11 | Schering Agrochemicals Limited | Pyrimidinyl herbicides |
Families Citing this family (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
DE3621551C1 (en) * | 1986-06-27 | 1987-07-02 | Eckard 5810 Witten De Feller | Cutting tool for lathe - has carrier arm and screw cooperating to retain lower packer plate and upper cutting insert in tool |
DE3836538A1 (en) * | 1988-10-27 | 1990-05-03 | Christian Rinke | Packaging container, in particular bottle |
BR9307264A (en) * | 1992-10-16 | 1999-05-11 | Nippon Soda Co | Pyrimidine derivatives herbicide and fungicide |
Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US3371085A (en) * | 1959-12-10 | 1968-02-27 | Hoffmann La Roche | 5-aryl-3h-1,4-benzodiazepin-2(1h)-ones |
-
1968
- 1968-06-12 US US736250A patent/US3546212A/en not_active Expired - Lifetime
-
1969
- 1969-05-28 CH CH806669A patent/CH523267A/en not_active IP Right Cessation
- 1969-05-28 CH CH583472A patent/CH550185A/en not_active IP Right Cessation
- 1969-06-06 CH CH872369A patent/CH523898A/en not_active IP Right Cessation
- 1969-06-06 NL NL696908658A patent/NL143927B/en unknown
- 1969-06-10 SE SE08239/69A patent/SE347510B/xx unknown
- 1969-06-10 GB GB1239380D patent/GB1239380A/en not_active Expired
- 1969-06-11 FR FR6919321A patent/FR2010744A1/fr not_active Withdrawn
- 1969-06-11 ES ES368239A patent/ES368239A1/en not_active Expired
- 1969-06-11 AT AT554069A patent/AT289125B/en not_active IP Right Cessation
- 1969-06-11 IE IE797/69A patent/IE33286B1/en unknown
- 1969-06-11 AT AT167371A patent/AT299960B/en not_active IP Right Cessation
- 1969-06-11 BE BE734376D patent/BE734376A/xx unknown
- 1969-06-11 NL NL6908866A patent/NL6908866A/xx unknown
- 1969-06-12 CA CA054,138,A patent/CA950453A/en not_active Expired
- 1969-06-12 NL NL6908966A patent/NL6908966A/xx unknown
- 1969-06-12 DE DE19691929910 patent/DE1929910A1/en active Pending
Patent Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US3371085A (en) * | 1959-12-10 | 1968-02-27 | Hoffmann La Roche | 5-aryl-3h-1,4-benzodiazepin-2(1h)-ones |
Cited By (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US3723414A (en) * | 1970-02-13 | 1973-03-27 | Schering Corp | 1-polyfluoroalkyl benzodiazepines |
US3896109A (en) * | 1971-09-30 | 1975-07-22 | Upjohn Co | 2,3-dehydro-1h-1,4-benzodiazepines |
US4083948A (en) * | 1977-04-04 | 1978-04-11 | Hoffmann-La Roche, Inc. | Benzodiazepine radioimmunoassay using I125-label |
US4280993A (en) * | 1978-01-19 | 1981-07-28 | Claus Braestrup | Process for determining the concentration of benzodiazepines in a body fluid |
US4497740A (en) * | 1981-06-19 | 1985-02-05 | Kali-Chemie Pharma Gmbh | 2-Azidomethyl-1,4-benzodiazepine compounds |
US5137564A (en) * | 1989-07-27 | 1992-08-11 | Schering Agrochemicals Limited | Pyrimidinyl herbicides |
Also Published As
Publication number | Publication date |
---|---|
NL6908966A (en) | 1969-12-16 |
AT299960B (en) | 1972-07-10 |
AT289125B (en) | 1971-04-13 |
IE33286B1 (en) | 1974-05-15 |
ES368239A1 (en) | 1971-06-16 |
NL6908866A (en) | 1969-12-22 |
SE347510B (en) | 1972-08-07 |
DE1929910A1 (en) | 1970-01-02 |
CH550185A (en) | 1974-06-14 |
NL6908658A (en) | 1969-12-16 |
FR2010744A1 (en) | 1970-02-20 |
IE33286L (en) | 1969-12-12 |
CH523898A (en) | 1972-06-15 |
CA950453A (en) | 1974-07-02 |
NL143927B (en) | 1974-11-15 |
BE734376A (en) | 1969-12-11 |
CH523267A (en) | 1972-05-31 |
GB1239380A (en) | 1971-07-14 |
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