CA2157234C - Stereoselective process for producing dihydro-2-3-benzodiazepine derivatives - Google Patents
Stereoselective process for producing dihydro-2-3-benzodiazepine derivatives Download PDFInfo
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- CA2157234C CA2157234C CA002157234A CA2157234A CA2157234C CA 2157234 C CA2157234 C CA 2157234C CA 002157234 A CA002157234 A CA 002157234A CA 2157234 A CA2157234 A CA 2157234A CA 2157234 C CA2157234 C CA 2157234C
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- Prior art keywords
- compound
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- group
- hydrogen
- nitrophenyl
- Prior art date
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- 238000000034 method Methods 0.000 title claims abstract description 47
- 230000000707 stereoselective effect Effects 0.000 title description 3
- 229940053197 benzodiazepine derivative antiepileptics Drugs 0.000 title 1
- -1 N-substituted dihydro-2,3 benzodiazepines Chemical class 0.000 claims abstract description 84
- 150000001875 compounds Chemical class 0.000 claims description 116
- 239000001257 hydrogen Substances 0.000 claims description 36
- 229910052739 hydrogen Inorganic materials 0.000 claims description 36
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 20
- 125000000636 p-nitrophenyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)[N+]([O-])=O 0.000 claims description 19
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 17
- 125000003118 aryl group Chemical group 0.000 claims description 16
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 claims description 15
- 238000006243 chemical reaction Methods 0.000 claims description 15
- 125000004429 atom Chemical group 0.000 claims description 13
- 125000002485 formyl group Chemical group [H]C(*)=O 0.000 claims description 13
- 125000002252 acyl group Chemical group 0.000 claims description 12
- UKJLNMAFNRKWGR-UHFFFAOYSA-N cyclohexatrienamine Chemical group NC1=CC=C=C[CH]1 UKJLNMAFNRKWGR-UHFFFAOYSA-N 0.000 claims description 12
- 125000005843 halogen group Chemical group 0.000 claims description 11
- 125000006239 protecting group Chemical group 0.000 claims description 11
- 125000000008 (C1-C10) alkyl group Chemical group 0.000 claims description 10
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 10
- 150000003839 salts Chemical class 0.000 claims description 10
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical group C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 claims description 10
- 239000002585 base Substances 0.000 claims description 9
- 125000003107 substituted aryl group Chemical group 0.000 claims description 9
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 8
- 229910052736 halogen Inorganic materials 0.000 claims description 8
- 150000002367 halogens Chemical class 0.000 claims description 8
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 7
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 7
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 7
- 125000001501 propionyl group Chemical group O=C([*])C([H])([H])C([H])([H])[H] 0.000 claims description 7
- 238000004519 manufacturing process Methods 0.000 claims description 6
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 5
- 229910052783 alkali metal Inorganic materials 0.000 claims description 5
- 239000003153 chemical reaction reagent Substances 0.000 claims description 5
- 238000011065 in-situ storage Methods 0.000 claims description 5
- 125000001424 substituent group Chemical group 0.000 claims description 5
- BDHFUVZGWQCTTF-UHFFFAOYSA-M sulfonate Chemical compound [O-]S(=O)=O BDHFUVZGWQCTTF-UHFFFAOYSA-M 0.000 claims description 5
- 125000000229 (C1-C4)alkoxy group Chemical group 0.000 claims description 4
- 229910000288 alkali metal carbonate Inorganic materials 0.000 claims description 3
- 150000008041 alkali metal carbonates Chemical class 0.000 claims description 3
- 229910000102 alkali metal hydride Inorganic materials 0.000 claims description 3
- 150000008046 alkali metal hydrides Chemical class 0.000 claims description 3
- 150000008044 alkali metal hydroxides Chemical group 0.000 claims description 3
- FAMRKDQNMBBFBR-BQYQJAHWSA-N diethyl azodicarboxylate Substances CCOC(=O)\N=N\C(=O)OCC FAMRKDQNMBBFBR-BQYQJAHWSA-N 0.000 claims description 3
- FAMRKDQNMBBFBR-UHFFFAOYSA-N ethyl n-ethoxycarbonyliminocarbamate Chemical group CCOC(=O)N=NC(=O)OCC FAMRKDQNMBBFBR-UHFFFAOYSA-N 0.000 claims description 3
- 239000007800 oxidant agent Substances 0.000 claims description 3
- 238000007363 ring formation reaction Methods 0.000 claims description 3
- 150000003461 sulfonyl halides Chemical class 0.000 claims description 3
- 125000005951 trifluoromethanesulfonyloxy group Chemical group 0.000 claims description 3
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 claims description 2
- 125000005948 methanesulfonyloxy group Chemical group 0.000 claims 1
- 229940098747 AMPA receptor antagonist Drugs 0.000 abstract 1
- 239000000775 AMPA receptor antagonist Substances 0.000 abstract 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 69
- 239000000203 mixture Substances 0.000 description 57
- 239000000243 solution Substances 0.000 description 54
- 239000000543 intermediate Substances 0.000 description 37
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 28
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 27
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 26
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 26
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 24
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 23
- 239000000047 product Substances 0.000 description 23
- HEMHJVSKTPXQMS-UHFFFAOYSA-M sodium hydroxide Inorganic materials [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 23
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 22
- 239000007787 solid Substances 0.000 description 22
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 21
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 18
- 238000004128 high performance liquid chromatography Methods 0.000 description 18
- 238000003786 synthesis reaction Methods 0.000 description 16
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 15
- 230000015572 biosynthetic process Effects 0.000 description 14
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 13
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 12
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 12
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 12
- 239000012267 brine Substances 0.000 description 11
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 10
- 125000000217 alkyl group Chemical group 0.000 description 10
- 229910052757 nitrogen Inorganic materials 0.000 description 10
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 9
- 150000002431 hydrogen Chemical group 0.000 description 9
- 238000010992 reflux Methods 0.000 description 9
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 9
- 239000000463 material Substances 0.000 description 8
- 239000012074 organic phase Substances 0.000 description 8
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 8
- 239000002904 solvent Substances 0.000 description 8
- 101150041968 CDC13 gene Proteins 0.000 description 7
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 7
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 7
- 238000003556 assay Methods 0.000 description 7
- 239000002244 precipitate Substances 0.000 description 7
- 239000011541 reaction mixture Substances 0.000 description 7
- 235000011121 sodium hydroxide Nutrition 0.000 description 7
- 238000003756 stirring Methods 0.000 description 7
- 238000003828 vacuum filtration Methods 0.000 description 7
- 238000005160 1H NMR spectroscopy Methods 0.000 description 6
- 241000222120 Candida <Saccharomycetales> Species 0.000 description 6
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 6
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 6
- 240000004808 Saccharomyces cerevisiae Species 0.000 description 6
- 235000014680 Saccharomyces cerevisiae Nutrition 0.000 description 6
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 6
- WFIZEGIEIOHZCP-UHFFFAOYSA-M potassium formate Chemical compound [K+].[O-]C=O WFIZEGIEIOHZCP-UHFFFAOYSA-M 0.000 description 6
- 239000011347 resin Substances 0.000 description 6
- 229920005989 resin Polymers 0.000 description 6
- 239000007858 starting material Substances 0.000 description 6
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 5
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 5
- 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 5
- 125000001931 aliphatic group Chemical group 0.000 description 5
- 229940049706 benzodiazepine Drugs 0.000 description 5
- 230000008030 elimination Effects 0.000 description 5
- 238000003379 elimination reaction Methods 0.000 description 5
- 239000006260 foam Substances 0.000 description 5
- 150000007857 hydrazones Chemical class 0.000 description 5
- 150000002576 ketones Chemical class 0.000 description 5
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 5
- 235000019341 magnesium sulphate Nutrition 0.000 description 5
- 238000001819 mass spectrum Methods 0.000 description 5
- 125000001570 methylene group Chemical group [H]C([H])([*:1])[*:2] 0.000 description 5
- 239000012044 organic layer Substances 0.000 description 5
- 238000002390 rotary evaporation Methods 0.000 description 5
- 239000000725 suspension Substances 0.000 description 5
- XIYKRJLTYKUWAM-UHFFFAOYSA-N 3,4-methylenedioxyphenylpropan-2-one Chemical class CC(=O)CC1=CC=C2OCOC2=C1 XIYKRJLTYKUWAM-UHFFFAOYSA-N 0.000 description 4
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 4
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 4
- 150000001298 alcohols Chemical class 0.000 description 4
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 description 4
- 239000003124 biologic agent Substances 0.000 description 4
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 4
- 229910052794 bromium Inorganic materials 0.000 description 4
- 239000003054 catalyst Substances 0.000 description 4
- 210000003169 central nervous system Anatomy 0.000 description 4
- 239000000039 congener Substances 0.000 description 4
- 230000000694 effects Effects 0.000 description 4
- 239000011521 glass Substances 0.000 description 4
- 239000005457 ice water Substances 0.000 description 4
- 229960004592 isopropanol Drugs 0.000 description 4
- QARBMVPHQWIHKH-UHFFFAOYSA-N methanesulfonyl chloride Chemical compound CS(Cl)(=O)=O QARBMVPHQWIHKH-UHFFFAOYSA-N 0.000 description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Substances [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 4
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 description 3
- BXRFQSNOROATLV-UHFFFAOYSA-N 4-nitrobenzaldehyde Chemical group [O-][N+](=O)C1=CC=C(C=O)C=C1 BXRFQSNOROATLV-UHFFFAOYSA-N 0.000 description 3
- FBOYMIDCHINJKC-UHFFFAOYSA-N 5-bromo-1,3-benzodioxole Chemical compound BrC1=CC=C2OCOC2=C1 FBOYMIDCHINJKC-UHFFFAOYSA-N 0.000 description 3
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 description 3
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 3
- 239000012359 Methanesulfonyl chloride Substances 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- GOOHAUXETOMSMM-VKHMYHEASA-N S-propylene oxide Chemical compound C[C@H]1CO1 GOOHAUXETOMSMM-VKHMYHEASA-N 0.000 description 3
- 241000235017 Zygosaccharomyces Species 0.000 description 3
- 241000235033 Zygosaccharomyces rouxii Species 0.000 description 3
- OFLXLNCGODUUOT-UHFFFAOYSA-N acetohydrazide Chemical group C\C(O)=N\N OFLXLNCGODUUOT-UHFFFAOYSA-N 0.000 description 3
- 125000003282 alkyl amino group Chemical group 0.000 description 3
- 125000005115 alkyl carbamoyl group Chemical group 0.000 description 3
- 150000001502 aryl halides Chemical class 0.000 description 3
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 description 3
- 150000002170 ethers Chemical class 0.000 description 3
- 239000000706 filtrate Substances 0.000 description 3
- 238000001914 filtration Methods 0.000 description 3
- IKDUDTNKRLTJSI-UHFFFAOYSA-N hydrazine monohydrate Substances O.NN IKDUDTNKRLTJSI-UHFFFAOYSA-N 0.000 description 3
- LZWQNOHZMQIFBX-UHFFFAOYSA-N lithium;2-methylpropan-2-olate Chemical compound [Li+].CC(C)(C)[O-] LZWQNOHZMQIFBX-UHFFFAOYSA-N 0.000 description 3
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 3
- 150000002924 oxiranes Chemical class 0.000 description 3
- 229920006395 saturated elastomer Polymers 0.000 description 3
- 239000002002 slurry Substances 0.000 description 3
- 229910052708 sodium Inorganic materials 0.000 description 3
- 239000011734 sodium Substances 0.000 description 3
- 125000006273 (C1-C3) alkyl group Chemical group 0.000 description 2
- HZNVUJQVZSTENZ-UHFFFAOYSA-N 2,3-dichloro-5,6-dicyano-1,4-benzoquinone Chemical compound ClC1=C(Cl)C(=O)C(C#N)=C(C#N)C1=O HZNVUJQVZSTENZ-UHFFFAOYSA-N 0.000 description 2
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 2
- 229910021595 Copper(I) iodide Inorganic materials 0.000 description 2
- 241000235036 Debaryomyces hansenii Species 0.000 description 2
- BDAGIHXWWSANSR-UHFFFAOYSA-M Formate Chemical compound [O-]C=O BDAGIHXWWSANSR-UHFFFAOYSA-M 0.000 description 2
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 2
- OAKJQQAXSVQMHS-UHFFFAOYSA-N Hydrazine Chemical compound NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 description 2
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 2
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 2
- OFBQJSOFQDEBGM-UHFFFAOYSA-N Pentane Chemical compound CCCCC OFBQJSOFQDEBGM-UHFFFAOYSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- 241000582914 Saccharomyces uvarum Species 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- 101100054666 Streptomyces halstedii sch3 gene Proteins 0.000 description 2
- PPBRXRYQALVLMV-UHFFFAOYSA-N Styrene Chemical compound C=CC1=CC=CC=C1 PPBRXRYQALVLMV-UHFFFAOYSA-N 0.000 description 2
- JACAAXNEHGBPOQ-LLVKDONJSA-N Talampanel Chemical compound C([C@H](N(N=1)C(C)=O)C)C2=CC=3OCOC=3C=C2C=1C1=CC=C(N)C=C1 JACAAXNEHGBPOQ-LLVKDONJSA-N 0.000 description 2
- QTBSBXVTEAMEQO-UHFFFAOYSA-N acetic acid Substances CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- 235000019270 ammonium chloride Nutrition 0.000 description 2
- VZTDIZULWFCMLS-UHFFFAOYSA-N ammonium formate Chemical compound [NH4+].[O-]C=O VZTDIZULWFCMLS-UHFFFAOYSA-N 0.000 description 2
- 125000003310 benzodiazepinyl group Chemical group N1N=C(C=CC2=C1C=CC=C2)* 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- 238000004296 chiral HPLC Methods 0.000 description 2
- 239000000460 chlorine Substances 0.000 description 2
- 229910052801 chlorine Inorganic materials 0.000 description 2
- 235000008504 concentrate Nutrition 0.000 description 2
- 239000012141 concentrate Substances 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- LSXDOTMGLUJQCM-UHFFFAOYSA-M copper(i) iodide Chemical compound I[Cu] LSXDOTMGLUJQCM-UHFFFAOYSA-M 0.000 description 2
- 239000013078 crystal Substances 0.000 description 2
- 238000004821 distillation Methods 0.000 description 2
- 238000001035 drying Methods 0.000 description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 2
- 239000008103 glucose Substances 0.000 description 2
- WGOPGODQLGJZGL-UHFFFAOYSA-N lithium;butane Chemical compound [Li+].CC[CH-]C WGOPGODQLGJZGL-UHFFFAOYSA-N 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
- RKNBYEDXBCUNQB-UHFFFAOYSA-N methylaminourea Chemical compound CNNC(N)=O RKNBYEDXBCUNQB-UHFFFAOYSA-N 0.000 description 2
- 235000011181 potassium carbonates Nutrition 0.000 description 2
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 2
- 230000003389 potentiating effect Effects 0.000 description 2
- 238000001556 precipitation Methods 0.000 description 2
- 238000000425 proton nuclear magnetic resonance spectrum Methods 0.000 description 2
- 239000000741 silica gel Substances 0.000 description 2
- 229910002027 silica gel Inorganic materials 0.000 description 2
- 238000010898 silica gel chromatography Methods 0.000 description 2
- 229910000104 sodium hydride Inorganic materials 0.000 description 2
- 239000012258 stirred mixture Substances 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- JRMUNVKIHCOMHV-UHFFFAOYSA-M tetrabutylammonium bromide Chemical compound [Br-].CCCC[N+](CCCC)(CCCC)CCCC JRMUNVKIHCOMHV-UHFFFAOYSA-M 0.000 description 2
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 2
- 239000002699 waste material Substances 0.000 description 2
- NWZSZGALRFJKBT-KNIFDHDWSA-N (2s)-2,6-diaminohexanoic acid;(2s)-2-hydroxybutanedioic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O.NCCCC[C@H](N)C(O)=O NWZSZGALRFJKBT-KNIFDHDWSA-N 0.000 description 1
- FTNJQNQLEGKTGD-UHFFFAOYSA-N 1,3-benzodioxole Chemical compound C1=CC=C2OCOC2=C1 FTNJQNQLEGKTGD-UHFFFAOYSA-N 0.000 description 1
- FFRBMBIXVSCUFS-UHFFFAOYSA-N 2,4-dinitro-1-naphthol Chemical compound C1=CC=C2C(O)=C([N+]([O-])=O)C=C([N+]([O-])=O)C2=C1 FFRBMBIXVSCUFS-UHFFFAOYSA-N 0.000 description 1
- 125000006276 2-bromophenyl group Chemical group [H]C1=C([H])C(Br)=C(*)C([H])=C1[H] 0.000 description 1
- 125000005916 2-methylpentyl group Chemical group 0.000 description 1
- MQXDOEPVEGRMQZ-UHFFFAOYSA-N 3-(4-nitrophenyl)-1h-1,2-benzodiazepine Chemical compound C1=CC([N+](=O)[O-])=CC=C1C1=NNC2=CC=CC=C2C=C1 MQXDOEPVEGRMQZ-UHFFFAOYSA-N 0.000 description 1
- 125000006305 3-iodophenyl group Chemical group [H]C1=C([H])C(I)=C([H])C(*)=C1[H] 0.000 description 1
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- 125000001312 palmitoyl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
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- NTTOTNSKUYCDAV-UHFFFAOYSA-N potassium hydride Chemical compound [KH] NTTOTNSKUYCDAV-UHFFFAOYSA-N 0.000 description 1
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- AKHNMLFCWUSKQB-UHFFFAOYSA-L sodium thiosulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=S AKHNMLFCWUSKQB-UHFFFAOYSA-L 0.000 description 1
- 235000019345 sodium thiosulphate Nutrition 0.000 description 1
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- FKHIFSZMMVMEQY-UHFFFAOYSA-N talc Chemical compound [Mg+2].[O-][Si]([O-])=O FKHIFSZMMVMEQY-UHFFFAOYSA-N 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 150000003512 tertiary amines Chemical class 0.000 description 1
- 125000001544 thienyl group Chemical group 0.000 description 1
- 230000008733 trauma Effects 0.000 description 1
- 125000005208 trialkylammonium group Chemical group 0.000 description 1
- PTMFUWGXPRYYMC-UHFFFAOYSA-N triethylazanium;formate Chemical compound OC=O.CCN(CC)CC PTMFUWGXPRYYMC-UHFFFAOYSA-N 0.000 description 1
- 238000005292 vacuum distillation Methods 0.000 description 1
- 125000003774 valeryl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
- C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
- C07D491/04—Ortho-condensed systems
- C07D491/056—Ortho-condensed systems with two or more oxygen atoms as ring hetero atoms in the oxygen-containing ring
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
- C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
- C07D491/04—Ortho-condensed systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/04—Centrally acting analgesics, e.g. opioids
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D317/00—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms
- C07D317/08—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3
- C07D317/44—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D317/46—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems condensed with one six-membered ring
- C07D317/48—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring
- C07D317/50—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to atoms of the carbocyclic ring
- C07D317/58—Radicals substituted by nitrogen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D493/00—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system
- C07D493/02—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system in which the condensed system contains two hetero rings
- C07D493/04—Ortho-condensed systems
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Neurology (AREA)
- Neurosurgery (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Engineering & Computer Science (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Veterinary Medicine (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Biomedical Technology (AREA)
- Public Health (AREA)
- Pain & Pain Management (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Plural Heterocyclic Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Applications Claiming Priority (4)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US29864594A | 1994-08-31 | 1994-08-31 | |
| US08/298,645 | 1994-08-31 | ||
| US08/413,036 US5665878A (en) | 1994-08-31 | 1995-03-28 | Stereoselective process for producing dihydro-2,3-benzodiazepine derivatives |
| US08/413,036 | 1995-03-28 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CA2157234A1 CA2157234A1 (en) | 1996-03-01 |
| CA2157234C true CA2157234C (en) | 2005-05-03 |
Family
ID=26970799
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002157234A Expired - Fee Related CA2157234C (en) | 1994-08-31 | 1995-08-30 | Stereoselective process for producing dihydro-2-3-benzodiazepine derivatives |
Country Status (21)
| Country | Link |
|---|---|
| US (3) | US5919954A (en, 2012) |
| EP (1) | EP0699677B1 (en, 2012) |
| JP (1) | JP3481019B2 (en, 2012) |
| KR (1) | KR100399518B1 (en, 2012) |
| CN (1) | CN1086705C (en, 2012) |
| AT (1) | ATE231867T1 (en, 2012) |
| AU (1) | AU702658B2 (en, 2012) |
| BR (1) | BR9503845A (en, 2012) |
| CA (1) | CA2157234C (en, 2012) |
| CZ (1) | CZ295675B6 (en, 2012) |
| DE (1) | DE69529499T2 (en, 2012) |
| DK (1) | DK0699677T3 (en, 2012) |
| ES (1) | ES2189819T3 (en, 2012) |
| FI (1) | FI113269B (en, 2012) |
| HU (1) | HU223776B1 (en, 2012) |
| IL (1) | IL115100A (en, 2012) |
| IN (1) | IN190402B (en, 2012) |
| NO (1) | NO312838B1 (en, 2012) |
| PL (3) | PL190640B1 (en, 2012) |
| RU (1) | RU2151149C1 (en, 2012) |
| TR (1) | TR199501071A2 (en, 2012) |
Families Citing this family (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE69820081D1 (de) * | 1997-08-12 | 2004-01-08 | Egyt Gyogyszervegyeszeti Gyar | 1-3 dioxolo/4.5-h//2,3-benzodiazepin derivate als ampa/kainate-rezeptor-hemmer |
| UA67749C2 (uk) * | 1997-08-12 | 2004-07-15 | Егіш Дьйодьсердьяр Рт. | Похідна 8-заміщеного-9н-1,3-діоксол/4,5-h//2,3/бензодіазепіну з властивостями амра/каїнатного антагоніста, спосіб одержання похідних, фармацевтична композиція (варіанти), спосіб її одержання та спосіб лікування |
| WO1999023242A1 (en) * | 1997-11-04 | 1999-05-14 | Eli Lilly And Company | Ketoreductase gene and protein from yeast |
| US20030219456A1 (en) * | 2002-05-21 | 2003-11-27 | Taing Ok | Method of utilization of zygosaccharomyces rouxii |
| US6858605B2 (en) | 2003-02-04 | 2005-02-22 | Ivax Drug Research Institute, Ltd. | Substituted 2,3-benzodiazepine derivatives |
| ES2322069T3 (es) * | 2005-12-05 | 2009-06-16 | Deutsche Post Ag | Procedimiento para la clasificacion de envios postales y dispositivo con una estructura de datos para un plan de clasificacion. |
| AU2006334172A1 (en) * | 2005-12-30 | 2007-07-12 | Egis Gyogyszergyar Nyilvanosan Mukodo Reszvenytarsasag | Optical isomers of dihydro-2,3-benzodiazepines and their stereoselective synthesis |
| KR100841592B1 (ko) | 2007-04-16 | 2008-06-26 | 한양대학교 산학협력단 | 벤조디옥솔 유도체와 이의 제조방법 |
Family Cites Families (14)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3748342A (en) * | 1971-05-06 | 1973-07-24 | Sandoz Ag | Intermediates for preparing quinazolinones |
| US3794642A (en) * | 1973-01-15 | 1974-02-26 | Lilly Co Eli | Oxidation of substituted methanes to the corresponding substituted methanols |
| DE2816475A1 (de) * | 1978-04-15 | 1979-10-25 | Bayer Ag | Isochroman-derivate, verfahren zu ihrer herstellung und ihre verwendung als synergisten in insektiziden und akariziden mitteln |
| US4358041A (en) | 1980-06-12 | 1982-11-09 | Olin Corporation | Powder-actuated tool with power adjustment and angle-fire control |
| HU191702B (en) * | 1984-06-27 | 1987-03-30 | Gyogyszerkutato Intezet | New process for preparing 1-aryl-5 h-2,3-benzodiazepines |
| HU191698B (en) * | 1984-07-27 | 1987-03-30 | Gyogyszerkutato Intezet | Process for producing new 1-aryl-5h-2beta-benzodiazepines |
| HU198494B (en) | 1986-08-15 | 1989-10-30 | Gyogyszerkutato Intezet | Process for producing new 3,4-dihydro-5h-2,3-benzodiazepine derivative and acid addition salts thereof, as well as pharmaceutical compositions comprising same |
| EP0357787B1 (en) * | 1988-02-12 | 1996-05-08 | Daicel Chemical Industries, Ltd. | Process for preparing optically active 2-hydroxy acid derivatives |
| JP2679145B2 (ja) * | 1988-09-02 | 1997-11-19 | ダイセル化学工業株式会社 | オキシケトンの製造法 |
| HU219778B (hu) * | 1990-12-21 | 2001-07-30 | Gyógyszerkutató Intézet Közös Vállalat | Eljárás N-acil-2,3-benzodiazepin-származékok, savaddíciós sóik és az ezeket tartalmazó gyógyászati készítmények előállítására, valamint a vegyületek egy csoportja, és az ezeket tartalmazó gyógyászati készítmények |
| HU206719B (en) | 1990-12-21 | 1992-12-28 | Gyogyszerkutato Intezet | Process for producing 1-/4-acylamino-phenyl/-7,8-methylenedioxy-5h-2,3-benzodiazepine derivatives, acid addicional salts and pharmaceutical compositions containing them |
| JP3061422B2 (ja) * | 1990-12-27 | 2000-07-10 | ダイセル化学工業株式会社 | 光学活性（ｓ）−２−クロロ−１−フェニルプロパノールの製造法 |
| JPH04271789A (ja) * | 1991-01-10 | 1992-09-28 | Takeda Chem Ind Ltd | Ｄ−パントラクトンの製造方法 |
| HU219777B (hu) * | 1993-07-02 | 2001-07-30 | Gyógyszerkutató Intézet Kft. | Optikailag aktív 1-(4-nitro-fenil)-4-metil-7,8-metiléndioxi-3,4-dihidro-5H-2,3-benzodiazepin és eljárás előállítására |
-
1995
- 1995-08-29 TR TR95/01071A patent/TR199501071A2/xx unknown
- 1995-08-30 CA CA002157234A patent/CA2157234C/en not_active Expired - Fee Related
- 1995-08-30 DE DE69529499T patent/DE69529499T2/de not_active Expired - Lifetime
- 1995-08-30 FI FI954064A patent/FI113269B/fi active
- 1995-08-30 AT AT95306051T patent/ATE231867T1/de not_active IP Right Cessation
- 1995-08-30 PL PL95369079A patent/PL190640B1/pl not_active IP Right Cessation
- 1995-08-30 PL PL95369080A patent/PL190318B1/pl not_active IP Right Cessation
- 1995-08-30 BR BR9503845A patent/BR9503845A/pt not_active IP Right Cessation
- 1995-08-30 JP JP22157095A patent/JP3481019B2/ja not_active Expired - Fee Related
- 1995-08-30 IN IN1044CA1995 patent/IN190402B/en unknown
- 1995-08-30 AU AU30355/95A patent/AU702658B2/en not_active Ceased
- 1995-08-30 ES ES95306051T patent/ES2189819T3/es not_active Expired - Lifetime
- 1995-08-30 KR KR1019950027526A patent/KR100399518B1/ko not_active Expired - Fee Related
- 1995-08-30 IL IL11510095A patent/IL115100A/xx not_active IP Right Cessation
- 1995-08-30 CN CN95116311A patent/CN1086705C/zh not_active Expired - Fee Related
- 1995-08-30 NO NO19953396A patent/NO312838B1/no not_active IP Right Cessation
- 1995-08-30 CZ CZ19952219A patent/CZ295675B6/cs not_active IP Right Cessation
- 1995-08-30 PL PL95310226A patent/PL188796B1/pl not_active IP Right Cessation
- 1995-08-30 RU RU95114549/04A patent/RU2151149C1/ru not_active IP Right Cessation
- 1995-08-30 HU HU9502545A patent/HU223776B1/hu not_active IP Right Cessation
- 1995-08-30 EP EP95306051A patent/EP0699677B1/en not_active Expired - Lifetime
- 1995-08-30 DK DK95306051T patent/DK0699677T3/da active
-
1997
- 1997-04-14 US US08/843,307 patent/US5919954A/en not_active Expired - Fee Related
-
1999
- 1999-03-02 US US09/260,449 patent/US5986114A/en not_active Expired - Fee Related
- 1999-07-02 US US09/346,795 patent/US6160133A/en not_active Expired - Fee Related
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