HU188071B - Process for producing pyrrolo-benzodiazepine derivatives - Google Patents
Process for producing pyrrolo-benzodiazepine derivatives Download PDFInfo
- Publication number
- HU188071B HU188071B HU812247A HU224781A HU188071B HU 188071 B HU188071 B HU 188071B HU 812247 A HU812247 A HU 812247A HU 224781 A HU224781 A HU 224781A HU 188071 B HU188071 B HU 188071B
- Authority
- HU
- Hungary
- Prior art keywords
- hydrogen
- formula
- alkenyl
- group
- lower alkyl
- Prior art date
Links
- 238000000034 method Methods 0.000 title claims description 33
- YUOCYTRGANSSRY-UHFFFAOYSA-N pyrrolo[2,3-i][1,2]benzodiazepine Chemical class C1=CN=NC2=C3C=CN=C3C=CC2=C1 YUOCYTRGANSSRY-UHFFFAOYSA-N 0.000 title 1
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 169
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims abstract description 77
- 125000003545 alkoxy group Chemical group 0.000 claims abstract description 20
- 125000004029 hydroxymethyl group Chemical group [H]OC([H])([H])* 0.000 claims abstract description 17
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims abstract description 10
- 125000003282 alkyl amino group Chemical group 0.000 claims abstract description 8
- 125000004423 acyloxy group Chemical group 0.000 claims abstract description 7
- 150000001450 anions Chemical class 0.000 claims abstract description 4
- 239000000932 sedative agent Substances 0.000 claims abstract description 4
- 230000001624 sedative effect Effects 0.000 claims abstract description 4
- 125000004953 trihalomethyl group Chemical group 0.000 claims abstract description 4
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims abstract 9
- 150000001408 amides Chemical class 0.000 claims abstract 2
- 150000002148 esters Chemical class 0.000 claims abstract 2
- 229910052739 hydrogen Inorganic materials 0.000 claims description 260
- 239000001257 hydrogen Substances 0.000 claims description 259
- 150000001875 compounds Chemical class 0.000 claims description 221
- 150000002431 hydrogen Chemical class 0.000 claims description 184
- 125000003342 alkenyl group Chemical group 0.000 claims description 162
- 239000000203 mixture Substances 0.000 claims description 78
- 125000000304 alkynyl group Chemical group 0.000 claims description 67
- 238000006243 chemical reaction Methods 0.000 claims description 53
- 238000002360 preparation method Methods 0.000 claims description 50
- -1 hydroxy- Chemical class 0.000 claims description 46
- 239000007787 solid Substances 0.000 claims description 41
- 125000004453 alkoxycarbonyl group Chemical group 0.000 claims description 36
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 32
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 23
- 150000003839 salts Chemical class 0.000 claims description 22
- 239000002253 acid Substances 0.000 claims description 12
- 229910052783 alkali metal Inorganic materials 0.000 claims description 12
- XUUSYXJGMRQBKQ-UHFFFAOYSA-N 2h-2-benzazepine Chemical class N1C=CC=C2C=CC=CC2=C1 XUUSYXJGMRQBKQ-UHFFFAOYSA-N 0.000 claims description 11
- VHNOGETZDZESKL-UHFFFAOYSA-N 8-chloro-6-(2-fluorophenyl)-2,4-dihydropyrrolo[3,4-d][2]benzazepine Chemical compound FC1=CC=CC=C1C1=NCC2=CNC=C2C2=CC=C(Cl)C=C12 VHNOGETZDZESKL-UHFFFAOYSA-N 0.000 claims description 11
- 150000001340 alkali metals Chemical class 0.000 claims description 11
- 125000002485 formyl group Chemical group [H]C(*)=O 0.000 claims description 11
- 239000007858 starting material Substances 0.000 claims description 11
- 150000001412 amines Chemical group 0.000 claims description 10
- LILHFUJGFBQZPM-UHFFFAOYSA-N 8-chloro-6-(2-chlorophenyl)-2,4-dihydropyrrolo[3,4-d][2]benzazepine Chemical compound C12=CC(Cl)=CC=C2C2=CNC=C2CN=C1C1=CC=CC=C1Cl LILHFUJGFBQZPM-UHFFFAOYSA-N 0.000 claims description 9
- 206010029897 Obsessive thoughts Diseases 0.000 claims description 8
- 125000004432 carbon atom Chemical group C* 0.000 claims description 8
- YYSPSNXIOBATFQ-UHFFFAOYSA-N 8-chloro-6-(2-chlorophenyl)-1-methyl-2,4-dihydropyrrolo[3,4-d][2]benzazepine Chemical compound C12=CC(Cl)=CC=C2C2=C(C)NC=C2CN=C1C1=CC=CC=C1Cl YYSPSNXIOBATFQ-UHFFFAOYSA-N 0.000 claims description 7
- 239000004480 active ingredient Substances 0.000 claims description 7
- 239000003795 chemical substances by application Substances 0.000 claims description 6
- 239000008194 pharmaceutical composition Substances 0.000 claims description 6
- 150000008044 alkali metal hydroxides Chemical class 0.000 claims description 5
- 230000000949 anxiolytic effect Effects 0.000 claims description 5
- 229910052799 carbon Inorganic materials 0.000 claims description 5
- BTSGZYKXPCTZMC-UHFFFAOYSA-N 8-chloro-6-(2-chlorophenyl)-2-methyl-4h-pyrrolo[3,4-d][2]benzazepine Chemical compound C12=CC(Cl)=CC=C2C2=CN(C)C=C2CN=C1C1=CC=CC=C1Cl BTSGZYKXPCTZMC-UHFFFAOYSA-N 0.000 claims description 4
- 125000005843 halogen group Chemical group 0.000 claims description 4
- 238000007254 oxidation reaction Methods 0.000 claims description 4
- RVMFVFNTEFQYCF-UHFFFAOYSA-N 2-[8-chloro-6-(2-fluorophenyl)-4h-pyrrolo[3,4-d][2]benzazepin-2-yl]ethanol Chemical compound C12=CC(Cl)=CC=C2C2=CN(CCO)C=C2CN=C1C1=CC=CC=C1F RVMFVFNTEFQYCF-UHFFFAOYSA-N 0.000 claims description 3
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 claims description 3
- 125000002252 acyl group Chemical group 0.000 claims description 3
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 3
- 125000001841 imino group Chemical group [H]N=* 0.000 claims description 3
- 230000003647 oxidation Effects 0.000 claims description 3
- DAXJNUBSBFUTRP-RTQNCGMRSA-N (8r,9s,10r,13s,14s)-6-(hydroxymethyl)-10,13-dimethyl-7,8,9,11,12,14,15,16-octahydro-6h-cyclopenta[a]phenanthrene-3,17-dione Chemical compound O=C1C=C[C@]2(C)[C@H]3CC[C@](C)(C(CC4)=O)[C@@H]4[C@@H]3CC(CO)C2=C1 DAXJNUBSBFUTRP-RTQNCGMRSA-N 0.000 claims description 2
- 125000005431 alkyl carboxamide group Chemical group 0.000 claims description 2
- 125000004429 atom Chemical group 0.000 claims description 2
- 239000007788 liquid Substances 0.000 claims description 2
- 239000000463 material Substances 0.000 claims description 2
- UUEVFMOUBSLVJW-UHFFFAOYSA-N oxo-[[1-[2-[2-[2-[4-(oxoazaniumylmethylidene)pyridin-1-yl]ethoxy]ethoxy]ethyl]pyridin-4-ylidene]methyl]azanium;dibromide Chemical compound [Br-].[Br-].C1=CC(=C[NH+]=O)C=CN1CCOCCOCCN1C=CC(=C[NH+]=O)C=C1 UUEVFMOUBSLVJW-UHFFFAOYSA-N 0.000 claims description 2
- 125000001309 chloro group Chemical group Cl* 0.000 claims 2
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims 1
- 229940100198 alkylating agent Drugs 0.000 claims 1
- 239000002168 alkylating agent Substances 0.000 claims 1
- 125000004103 aminoalkyl group Chemical group 0.000 claims 1
- 125000005392 carboxamide group Chemical group NC(=O)* 0.000 claims 1
- 229940125904 compound 1 Drugs 0.000 claims 1
- 239000003937 drug carrier Substances 0.000 claims 1
- 125000001153 fluoro group Chemical group F* 0.000 claims 1
- ZZUFCTLCJUWOSV-UHFFFAOYSA-N furosemide Chemical compound C1=C(Cl)C(S(=O)(=O)N)=CC(C(O)=O)=C1NCC1=CC=CO1 ZZUFCTLCJUWOSV-UHFFFAOYSA-N 0.000 claims 1
- 238000004519 manufacturing process Methods 0.000 claims 1
- 231100000252 nontoxic Toxicity 0.000 claims 1
- 230000003000 nontoxic effect Effects 0.000 claims 1
- 239000000651 prodrug Substances 0.000 claims 1
- 229940002612 prodrug Drugs 0.000 claims 1
- 125000001424 substituent group Chemical group 0.000 claims 1
- 229910052736 halogen Inorganic materials 0.000 abstract description 13
- 150000002367 halogens Chemical class 0.000 abstract description 11
- AGOHXMSGPOYHLT-UHFFFAOYSA-N pyrrolo[3,4-d][2]benzazepine Chemical compound N1=CC2=CC=CC=C2C2=CN=CC2=C1 AGOHXMSGPOYHLT-UHFFFAOYSA-N 0.000 abstract description 5
- 125000003187 heptyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 abstract 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 345
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 296
- 239000000243 solution Substances 0.000 description 118
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 94
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 90
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 83
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 74
- 238000002844 melting Methods 0.000 description 52
- 230000008018 melting Effects 0.000 description 52
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 51
- 239000011541 reaction mixture Substances 0.000 description 40
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 36
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 36
- 238000001953 recrystallisation Methods 0.000 description 35
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 31
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 30
- HEMHJVSKTPXQMS-UHFFFAOYSA-M sodium hydroxide Inorganic materials [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 28
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 26
- 239000003921 oil Substances 0.000 description 26
- 235000019198 oils Nutrition 0.000 description 26
- 238000003756 stirring Methods 0.000 description 26
- 238000004440 column chromatography Methods 0.000 description 25
- 239000000047 product Substances 0.000 description 23
- 239000000741 silica gel Substances 0.000 description 23
- 229910002027 silica gel Inorganic materials 0.000 description 23
- 125000004182 2-chlorophenyl group Chemical group [H]C1=C([H])C(Cl)=C(*)C([H])=C1[H] 0.000 description 22
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 21
- 239000013078 crystal Substances 0.000 description 21
- 239000002904 solvent Substances 0.000 description 21
- 229920006395 saturated elastomer Polymers 0.000 description 18
- 239000002244 precipitate Substances 0.000 description 17
- 239000003480 eluent Substances 0.000 description 16
- 239000012280 lithium aluminium hydride Substances 0.000 description 16
- 239000003208 petroleum Substances 0.000 description 15
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 14
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 14
- 239000003826 tablet Substances 0.000 description 14
- 125000004198 2-fluorophenyl group Chemical group [H]C1=C([H])C(F)=C(*)C([H])=C1[H] 0.000 description 13
- 229960000583 acetic acid Drugs 0.000 description 13
- 229960001760 dimethyl sulfoxide Drugs 0.000 description 13
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 13
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 12
- 238000002425 crystallisation Methods 0.000 description 10
- 230000008025 crystallization Effects 0.000 description 10
- 239000000706 filtrate Substances 0.000 description 10
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 10
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 10
- 238000010992 reflux Methods 0.000 description 10
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 9
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 9
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 9
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 8
- PXHVJJICTQNCMI-UHFFFAOYSA-N Nickel Chemical compound [Ni] PXHVJJICTQNCMI-UHFFFAOYSA-N 0.000 description 8
- 239000007868 Raney catalyst Substances 0.000 description 8
- 229910000564 Raney nickel Inorganic materials 0.000 description 8
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 8
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 8
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 8
- 239000000908 ammonium hydroxide Substances 0.000 description 8
- 239000002585 base Substances 0.000 description 8
- 238000009835 boiling Methods 0.000 description 8
- NUJOXMJBOLGQSY-UHFFFAOYSA-N manganese dioxide Chemical compound O=[Mn]=O NUJOXMJBOLGQSY-UHFFFAOYSA-N 0.000 description 8
- 239000012312 sodium hydride Substances 0.000 description 8
- 229910000104 sodium hydride Inorganic materials 0.000 description 8
- 239000000725 suspension Substances 0.000 description 8
- 125000004356 hydroxy functional group Chemical group O* 0.000 description 7
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 7
- 235000017557 sodium bicarbonate Nutrition 0.000 description 7
- SMWPBMJVUOELBM-UHFFFAOYSA-N 3-(2-benzoyl-4-chlorophenyl)prop-2-enenitrile Chemical compound ClC1=CC=C(C=CC#N)C(C(=O)C=2C=CC=CC=2)=C1 SMWPBMJVUOELBM-UHFFFAOYSA-N 0.000 description 6
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 6
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 6
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 6
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 6
- 239000007864 aqueous solution Substances 0.000 description 6
- 239000006071 cream Substances 0.000 description 6
- 229940098779 methanesulfonic acid Drugs 0.000 description 6
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 6
- 238000000746 purification Methods 0.000 description 6
- 239000012279 sodium borohydride Substances 0.000 description 6
- 229910000033 sodium borohydride Inorganic materials 0.000 description 6
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 5
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 5
- 239000000460 chlorine Substances 0.000 description 5
- 239000012442 inert solvent Substances 0.000 description 5
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 5
- 239000008101 lactose Substances 0.000 description 5
- 235000019359 magnesium stearate Nutrition 0.000 description 5
- BEOOHQFXGBMRKU-UHFFFAOYSA-N sodium cyanoborohydride Chemical compound [Na+].[B-]C#N BEOOHQFXGBMRKU-UHFFFAOYSA-N 0.000 description 5
- 229910052938 sodium sulfate Inorganic materials 0.000 description 5
- 235000011152 sodium sulphate Nutrition 0.000 description 5
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 4
- DQFQCHIDRBIESA-UHFFFAOYSA-N 1-benzazepine Chemical compound N1C=CC=CC2=CC=CC=C12 DQFQCHIDRBIESA-UHFFFAOYSA-N 0.000 description 4
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 description 4
- NHQDETIJWKXCTC-UHFFFAOYSA-N 3-chloroperbenzoic acid Chemical compound OOC(=O)C1=CC=CC(Cl)=C1 NHQDETIJWKXCTC-UHFFFAOYSA-N 0.000 description 4
- WIXOADQWUHTLKI-UHFFFAOYSA-N 8-chloro-6-(2-fluorophenyl)-1-methyl-2,4-dihydropyrrolo[3,4-d][2]benzazepine Chemical compound C12=CC(Cl)=CC=C2C2=C(C)NC=C2CN=C1C1=CC=CC=C1F WIXOADQWUHTLKI-UHFFFAOYSA-N 0.000 description 4
- ZKXFBTJZHZYVJW-UHFFFAOYSA-N 8-chloro-6-phenyl-2,4-dihydropyrrolo[3,4-d][2]benzazepine Chemical compound C12=CC(Cl)=CC=C2C2=CNC=C2CN=C1C1=CC=CC=C1 ZKXFBTJZHZYVJW-UHFFFAOYSA-N 0.000 description 4
- NLHHRLWOUZZQLW-UHFFFAOYSA-N Acrylonitrile Chemical compound C=CC#N NLHHRLWOUZZQLW-UHFFFAOYSA-N 0.000 description 4
- 241000282326 Felis catus Species 0.000 description 4
- 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 4
- 241001465754 Metazoa Species 0.000 description 4
- 241000699670 Mus sp. Species 0.000 description 4
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 4
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 4
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 4
- 230000002152 alkylating effect Effects 0.000 description 4
- 239000002775 capsule Substances 0.000 description 4
- 239000003638 chemical reducing agent Substances 0.000 description 4
- 229940117975 chromium trioxide Drugs 0.000 description 4
- WGLPBDUCMAPZCE-UHFFFAOYSA-N chromium trioxide Inorganic materials O=[Cr](=O)=O WGLPBDUCMAPZCE-UHFFFAOYSA-N 0.000 description 4
- GAMDZJFZMJECOS-UHFFFAOYSA-N chromium(6+);oxygen(2-) Chemical compound [O-2].[O-2].[O-2].[Cr+6] GAMDZJFZMJECOS-UHFFFAOYSA-N 0.000 description 4
- ORTQZVOHEJQUHG-UHFFFAOYSA-L copper(II) chloride Chemical compound Cl[Cu]Cl ORTQZVOHEJQUHG-UHFFFAOYSA-L 0.000 description 4
- 238000000354 decomposition reaction Methods 0.000 description 4
- 230000000694 effects Effects 0.000 description 4
- 239000012467 final product Substances 0.000 description 4
- 229910052731 fluorine Inorganic materials 0.000 description 4
- 229910052500 inorganic mineral Inorganic materials 0.000 description 4
- 239000010410 layer Substances 0.000 description 4
- ZCSHNCUQKCANBX-UHFFFAOYSA-N lithium diisopropylamide Chemical compound [Li+].CC(C)[N-]C(C)C ZCSHNCUQKCANBX-UHFFFAOYSA-N 0.000 description 4
- 229910052987 metal hydride Inorganic materials 0.000 description 4
- 150000004681 metal hydrides Chemical class 0.000 description 4
- 235000010755 mineral Nutrition 0.000 description 4
- 239000011707 mineral Substances 0.000 description 4
- 239000002480 mineral oil Substances 0.000 description 4
- 235000010446 mineral oil Nutrition 0.000 description 4
- 229910052700 potassium Inorganic materials 0.000 description 4
- 239000011591 potassium Substances 0.000 description 4
- 229910000029 sodium carbonate Inorganic materials 0.000 description 4
- 239000011780 sodium chloride Substances 0.000 description 4
- QAEDZJGFFMLHHQ-UHFFFAOYSA-N trifluoroacetic anhydride Chemical compound FC(F)(F)C(=O)OC(=O)C(F)(F)F QAEDZJGFFMLHHQ-UHFFFAOYSA-N 0.000 description 4
- NRKYWOKHZRQRJR-UHFFFAOYSA-N 2,2,2-trifluoroacetamide Chemical class NC(=O)C(F)(F)F NRKYWOKHZRQRJR-UHFFFAOYSA-N 0.000 description 3
- CQSGINBFYDVOOQ-UHFFFAOYSA-N 3-[4-chloro-2-(2-chlorobenzoyl)phenyl]prop-2-enenitrile Chemical compound ClC1=CC=C(C=CC#N)C(C(=O)C=2C(=CC=CC=2)Cl)=C1 CQSGINBFYDVOOQ-UHFFFAOYSA-N 0.000 description 3
- JSUANPBAYQHQBN-UHFFFAOYSA-N 3-[4-chloro-2-(2-fluorobenzoyl)phenyl]prop-2-enenitrile Chemical compound FC1=CC=CC=C1C(=O)C1=CC(Cl)=CC=C1C=CC#N JSUANPBAYQHQBN-UHFFFAOYSA-N 0.000 description 3
- XPTWRNPCTUBIMY-UHFFFAOYSA-N 8-chloro-6-(2-chlorophenyl)-2,4-dihydropyrrolo[3,4-d][2]benzazepine-3-carboxylic acid Chemical compound OC(=O)C=1NC=C(C2=CC=C(Cl)C=C22)C=1CN=C2C1=CC=CC=C1Cl XPTWRNPCTUBIMY-UHFFFAOYSA-N 0.000 description 3
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 3
- YXHKONLOYHBTNS-UHFFFAOYSA-N Diazomethane Chemical compound C=[N+]=[N-] YXHKONLOYHBTNS-UHFFFAOYSA-N 0.000 description 3
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 3
- 229920002472 Starch Polymers 0.000 description 3
- 229910000288 alkali metal carbonate Inorganic materials 0.000 description 3
- 150000008041 alkali metal carbonates Chemical class 0.000 description 3
- 229910021529 ammonia Inorganic materials 0.000 description 3
- 239000002249 anxiolytic agent Substances 0.000 description 3
- 229910052786 argon Inorganic materials 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- 230000003197 catalytic effect Effects 0.000 description 3
- 229910052801 chlorine Inorganic materials 0.000 description 3
- 238000001816 cooling Methods 0.000 description 3
- NPOMSUOUAZCMBL-UHFFFAOYSA-N dichloromethane;ethoxyethane Chemical compound ClCCl.CCOCC NPOMSUOUAZCMBL-UHFFFAOYSA-N 0.000 description 3
- 238000010828 elution Methods 0.000 description 3
- MDKXBBPLEGPIRI-UHFFFAOYSA-N ethoxyethane;methanol Chemical compound OC.CCOCC MDKXBBPLEGPIRI-UHFFFAOYSA-N 0.000 description 3
- 239000006260 foam Substances 0.000 description 3
- 239000012362 glacial acetic acid Substances 0.000 description 3
- 239000005457 ice water Substances 0.000 description 3
- OFSVXQSEYSHGQO-UHFFFAOYSA-N methyl 8-chloro-6-(2-chlorophenyl)-5-oxido-4h-pyrrolo[3,4-d][2]benzazepin-5-ium-2-carboxylate Chemical compound C12=CC(Cl)=CC=C2C2=CN(C(=O)OC)C=C2C[N+]([O-])=C1C1=CC=CC=C1Cl OFSVXQSEYSHGQO-UHFFFAOYSA-N 0.000 description 3
- 229910000027 potassium carbonate Inorganic materials 0.000 description 3
- 235000011181 potassium carbonates Nutrition 0.000 description 3
- NLKNQRATVPKPDG-UHFFFAOYSA-M potassium iodide Chemical compound [K+].[I-] NLKNQRATVPKPDG-UHFFFAOYSA-M 0.000 description 3
- 239000008107 starch Substances 0.000 description 3
- 235000019698 starch Nutrition 0.000 description 3
- BDHFUVZGWQCTTF-UHFFFAOYSA-M sulfonate Chemical compound [O-]S(=O)=O BDHFUVZGWQCTTF-UHFFFAOYSA-M 0.000 description 3
- NGOUPILQFWOEET-UHFFFAOYSA-N 1-(1-isocyanoethylsulfonyl)-4-methylbenzene Chemical compound [C-]#[N+]C(C)S(=O)(=O)C1=CC=C(C)C=C1 NGOUPILQFWOEET-UHFFFAOYSA-N 0.000 description 2
- DJNDTMJICQUTSN-UHFFFAOYSA-N 2-benzyl-4-chlorobenzaldehyde Chemical compound ClC1=CC=C(C=O)C(CC=2C=CC=CC=2)=C1 DJNDTMJICQUTSN-UHFFFAOYSA-N 0.000 description 2
- KGHIGKJJSTWDMM-UHFFFAOYSA-N 2-benzyl-4-chlorobenzoic acid Chemical compound OC(=O)C1=CC=C(Cl)C=C1CC1=CC=CC=C1 KGHIGKJJSTWDMM-UHFFFAOYSA-N 0.000 description 2
- YAQLSKVCTLCIIE-UHFFFAOYSA-N 2-bromobutyric acid Chemical compound CCC(Br)C(O)=O YAQLSKVCTLCIIE-UHFFFAOYSA-N 0.000 description 2
- MONMFXREYOKQTI-UHFFFAOYSA-N 2-bromopropanoic acid Chemical compound CC(Br)C(O)=O MONMFXREYOKQTI-UHFFFAOYSA-N 0.000 description 2
- YMDNODNLFSHHCV-UHFFFAOYSA-N 2-chloro-n,n-diethylethanamine Chemical compound CCN(CC)CCCl YMDNODNLFSHHCV-UHFFFAOYSA-N 0.000 description 2
- KWMBADTWRIGGGG-UHFFFAOYSA-N 2-diethoxyphosphorylacetonitrile Chemical compound CCOP(=O)(CC#N)OCC KWMBADTWRIGGGG-UHFFFAOYSA-N 0.000 description 2
- ZQDBTVYWVDEAOT-UHFFFAOYSA-N 3-(2-benzyl-4-chlorophenyl)prop-2-enenitrile Chemical compound ClC1=CC=C(C=CC#N)C(CC=2C=CC=CC=2)=C1 ZQDBTVYWVDEAOT-UHFFFAOYSA-N 0.000 description 2
- UVEYDKXPEBFCFZ-UHFFFAOYSA-N 3-[8-chloro-6-(2-fluorophenyl)-4h-pyrrolo[3,4-d][2]benzazepin-2-yl]-n,n-dimethylpropan-1-amine;dihydrochloride Chemical compound Cl.Cl.C12=CC(Cl)=CC=C2C2=CN(CCCN(C)C)C=C2CN=C1C1=CC=CC=C1F UVEYDKXPEBFCFZ-UHFFFAOYSA-N 0.000 description 2
- MJBDDUZFQWJYLY-UHFFFAOYSA-N 4-(2-benzoyl-4-chlorophenyl)-1h-pyrrole-3-carbonitrile Chemical compound C=1C=CC=CC=1C(=O)C1=CC(Cl)=CC=C1C1=CNC=C1C#N MJBDDUZFQWJYLY-UHFFFAOYSA-N 0.000 description 2
- ZAJIWEWPHTZSMZ-UHFFFAOYSA-N 4-[4-chloro-2-(2-chlorobenzoyl)phenyl]-5-ethyl-1h-pyrrole-3-carbonitrile Chemical compound N1C=C(C#N)C(C=2C(=CC(Cl)=CC=2)C(=O)C=2C(=CC=CC=2)Cl)=C1CC ZAJIWEWPHTZSMZ-UHFFFAOYSA-N 0.000 description 2
- LYDRFZTZHFLADZ-UHFFFAOYSA-N 4-[4-chloro-2-(2-chlorobenzoyl)phenyl]-5-methyl-1h-pyrrole-3-carbonitrile Chemical compound N1C=C(C#N)C(C=2C(=CC(Cl)=CC=2)C(=O)C=2C(=CC=CC=2)Cl)=C1C LYDRFZTZHFLADZ-UHFFFAOYSA-N 0.000 description 2
- ASDAHLYZLZIMRB-UHFFFAOYSA-N 4-[4-chloro-2-(2-fluorobenzoyl)phenyl]-1h-pyrrole-3-carbonitrile Chemical compound FC1=CC=CC=C1C(=O)C1=CC(Cl)=CC=C1C1=CNC=C1C#N ASDAHLYZLZIMRB-UHFFFAOYSA-N 0.000 description 2
- KUKAOBDDLANOSV-UHFFFAOYSA-N 8-chloro-6-(2-fluorophenyl)-2,4-dihydropyrrolo[3,4-d][2]benzazepine methanesulfonic acid Chemical compound CS(=O)(=O)O.ClC1=CC2=C(C=3C(CN=C2C2=C(C=CC=C2)F)=CNC3)C=C1 KUKAOBDDLANOSV-UHFFFAOYSA-N 0.000 description 2
- DLFVBJFMPXGRIB-UHFFFAOYSA-N Acetamide Chemical compound CC(N)=O DLFVBJFMPXGRIB-UHFFFAOYSA-N 0.000 description 2
- JIKVAVYCZZBFLM-UHFFFAOYSA-N ClC1=CC=2C(=C3C(C=NC2C2=C(C=CC=C2)F)=CNC3C)C=C1 Chemical compound ClC1=CC=2C(=C3C(C=NC2C2=C(C=CC=C2)F)=CNC3C)C=C1 JIKVAVYCZZBFLM-UHFFFAOYSA-N 0.000 description 2
- 229910021592 Copper(II) chloride Inorganic materials 0.000 description 2
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 2
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 2
- BAVYZALUXZFZLV-UHFFFAOYSA-N Methylamine Chemical compound NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 description 2
- 229920000881 Modified starch Polymers 0.000 description 2
- OFBQJSOFQDEBGM-UHFFFAOYSA-N Pentane Chemical compound CCCCC OFBQJSOFQDEBGM-UHFFFAOYSA-N 0.000 description 2
- KAESVJOAVNADME-UHFFFAOYSA-N Pyrrole Chemical compound C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 description 2
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 2
- LMGIXQZNOPHFTH-UHFFFAOYSA-N [2-[4-(aminomethyl)-2-methyl-1h-pyrrol-3-yl]-5-chlorophenyl]-(2-fluorophenyl)methanol Chemical compound N1C=C(CN)C(C=2C(=CC(Cl)=CC=2)C(O)C=2C(=CC=CC=2)F)=C1C LMGIXQZNOPHFTH-UHFFFAOYSA-N 0.000 description 2
- 150000003973 alkyl amines Chemical class 0.000 description 2
- 150000001350 alkyl halides Chemical class 0.000 description 2
- BHELZAPQIKSEDF-UHFFFAOYSA-N allyl bromide Chemical compound BrCC=C BHELZAPQIKSEDF-UHFFFAOYSA-N 0.000 description 2
- 238000004458 analytical method Methods 0.000 description 2
- 125000002785 azepinyl group Chemical group 0.000 description 2
- UORVGPXVDQYIDP-UHFFFAOYSA-N borane Chemical compound B UORVGPXVDQYIDP-UHFFFAOYSA-N 0.000 description 2
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 2
- 239000003054 catalyst Substances 0.000 description 2
- VXIVSQZSERGHQP-UHFFFAOYSA-N chloroacetamide Chemical compound NC(=O)CCl VXIVSQZSERGHQP-UHFFFAOYSA-N 0.000 description 2
- 239000012230 colorless oil Substances 0.000 description 2
- ARUVKPQLZAKDPS-UHFFFAOYSA-L copper(II) sulfate Chemical compound [Cu+2].[O-][S+2]([O-])([O-])[O-] ARUVKPQLZAKDPS-UHFFFAOYSA-L 0.000 description 2
- 229910000366 copper(II) sulfate Inorganic materials 0.000 description 2
- YKGMKSIHIVVYKY-UHFFFAOYSA-N dabrafenib mesylate Chemical compound CS(O)(=O)=O.S1C(C(C)(C)C)=NC(C=2C(=C(NS(=O)(=O)C=3C(=CC=CC=3F)F)C=CC=2)F)=C1C1=CC=NC(N)=N1 YKGMKSIHIVVYKY-UHFFFAOYSA-N 0.000 description 2
- WBKFWQBXFREOFH-UHFFFAOYSA-N dichloromethane;ethyl acetate Chemical compound ClCCl.CCOC(C)=O WBKFWQBXFREOFH-UHFFFAOYSA-N 0.000 description 2
- 239000006185 dispersion Substances 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 150000002170 ethers Chemical class 0.000 description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 2
- 239000011737 fluorine Substances 0.000 description 2
- 238000009472 formulation Methods 0.000 description 2
- 150000004820 halides Chemical class 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-M hydroxide Chemical compound [OH-] XLYOFNOQVPJJNP-UHFFFAOYSA-M 0.000 description 2
- 150000007975 iminium salts Chemical group 0.000 description 2
- 229910052744 lithium Inorganic materials 0.000 description 2
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 2
- SYSQUGFVNFXIIT-UHFFFAOYSA-N n-[4-(1,3-benzoxazol-2-yl)phenyl]-4-nitrobenzenesulfonamide Chemical class C1=CC([N+](=O)[O-])=CC=C1S(=O)(=O)NC1=CC=C(C=2OC3=CC=CC=C3N=2)C=C1 SYSQUGFVNFXIIT-UHFFFAOYSA-N 0.000 description 2
- 150000007524 organic acids Chemical class 0.000 description 2
- CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 description 2
- 239000007800 oxidant agent Substances 0.000 description 2
- 150000004965 peroxy acids Chemical class 0.000 description 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 2
- 239000003880 polar aprotic solvent Substances 0.000 description 2
- 239000002798 polar solvent Substances 0.000 description 2
- 229910000028 potassium bicarbonate Inorganic materials 0.000 description 2
- 235000015497 potassium bicarbonate Nutrition 0.000 description 2
- 239000011736 potassium bicarbonate Substances 0.000 description 2
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 description 2
- 239000012286 potassium permanganate Substances 0.000 description 2
- LJCNRYVRMXRIQR-OLXYHTOASA-L potassium sodium L-tartrate Chemical compound [Na+].[K+].[O-]C(=O)[C@H](O)[C@@H](O)C([O-])=O LJCNRYVRMXRIQR-OLXYHTOASA-L 0.000 description 2
- 229940074439 potassium sodium tartrate Drugs 0.000 description 2
- 125000006239 protecting group Chemical group 0.000 description 2
- LVTJOONKWUXEFR-FZRMHRINSA-N protoneodioscin Natural products O(C[C@@H](CC[C@]1(O)[C@H](C)[C@@H]2[C@]3(C)[C@H]([C@H]4[C@@H]([C@]5(C)C(=CC4)C[C@@H](O[C@@H]4[C@H](O[C@H]6[C@@H](O)[C@@H](O)[C@@H](O)[C@H](C)O6)[C@@H](O)[C@H](O[C@H]6[C@@H](O)[C@@H](O)[C@@H](O)[C@H](C)O6)[C@H](CO)O4)CC5)CC3)C[C@@H]2O1)C)[C@H]1[C@H](O)[C@H](O)[C@H](O)[C@@H](CO)O1 LVTJOONKWUXEFR-FZRMHRINSA-N 0.000 description 2
- LEHBURLTIWGHEM-UHFFFAOYSA-N pyridinium chlorochromate Chemical compound [O-][Cr](Cl)(=O)=O.C1=CC=[NH+]C=C1 LEHBURLTIWGHEM-UHFFFAOYSA-N 0.000 description 2
- PLKKXWBJOVTVEU-UHFFFAOYSA-N pyrrolo[2,3-i][1]benzazepine Chemical class C1=CC=NC2=C3C=CN=C3C=CC2=C1 PLKKXWBJOVTVEU-UHFFFAOYSA-N 0.000 description 2
- 239000000376 reactant Substances 0.000 description 2
- 239000000377 silicon dioxide Substances 0.000 description 2
- 229910052708 sodium Inorganic materials 0.000 description 2
- 239000011734 sodium Substances 0.000 description 2
- LPXPTNMVRIOKMN-UHFFFAOYSA-M sodium nitrite Chemical compound [Na+].[O-]N=O LPXPTNMVRIOKMN-UHFFFAOYSA-M 0.000 description 2
- 235000011006 sodium potassium tartrate Nutrition 0.000 description 2
- 239000000454 talc Substances 0.000 description 2
- 229910052623 talc Inorganic materials 0.000 description 2
- 238000004809 thin layer chromatography Methods 0.000 description 2
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 2
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 2
- 230000001988 toxicity Effects 0.000 description 2
- 231100000419 toxicity Toxicity 0.000 description 2
- 125000003866 trichloromethyl group Chemical group ClC(Cl)(Cl)* 0.000 description 2
- 239000011701 zinc Substances 0.000 description 2
- 229910052725 zinc Inorganic materials 0.000 description 2
- FAVKIHMGRWRACA-UHFFFAOYSA-N (2,5-dichlorophenyl)-phenylmethanone Chemical compound ClC1=CC=C(Cl)C(C(=O)C=2C=CC=CC=2)=C1 FAVKIHMGRWRACA-UHFFFAOYSA-N 0.000 description 1
- ZUWXHHBROGLWNH-UHFFFAOYSA-N (2-amino-5-chlorophenyl)-phenylmethanone Chemical compound NC1=CC=C(Cl)C=C1C(=O)C1=CC=CC=C1 ZUWXHHBROGLWNH-UHFFFAOYSA-N 0.000 description 1
- MEIFVWINIHKENC-UHFFFAOYSA-N (2-iodophenyl)-phenylmethanone Chemical class IC1=CC=CC=C1C(=O)C1=CC=CC=C1 MEIFVWINIHKENC-UHFFFAOYSA-N 0.000 description 1
- GHDUWHHOYQOLEI-UHFFFAOYSA-N (5-chloro-2-iodophenyl)-(2-fluorophenyl)methanone Chemical compound FC1=CC=CC=C1C(=O)C1=CC(Cl)=CC=C1I GHDUWHHOYQOLEI-UHFFFAOYSA-N 0.000 description 1
- CUMYCBZGJLFFQC-UHFFFAOYSA-N (8-chloro-6-phenyl-2,4-dihydropyrrolo[3,4-d][2]benzazepin-1-yl)methanol Chemical compound C12=CC(Cl)=CC=C2C2=C(CO)NC=C2CN=C1C1=CC=CC=C1 CUMYCBZGJLFFQC-UHFFFAOYSA-N 0.000 description 1
- XZDSWNRFXYZQKW-UHFFFAOYSA-N (8-chloro-6-phenyl-2,4-dihydropyrrolo[3,4-d][2]benzazepin-3-yl)methanol Chemical compound OCC=1NC=C(C2=CC=C(Cl)C=C22)C=1CN=C2C1=CC=CC=C1 XZDSWNRFXYZQKW-UHFFFAOYSA-N 0.000 description 1
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 description 1
- 125000006531 (C2-C5) alkyl group Chemical group 0.000 description 1
- OEZHRMOVCQGFOJ-UHFFFAOYSA-N 1-(1-isocyanobut-3-enylsulfonyl)-4-methylbenzene Chemical compound CC1=CC=C(S(=O)(=O)C(CC=C)[N+]#[C-])C=C1 OEZHRMOVCQGFOJ-UHFFFAOYSA-N 0.000 description 1
- HLITUPWOVBUZQH-UHFFFAOYSA-N 1-(1-isocyanopropylsulfonyl)-4-methylbenzene Chemical compound CCC([N+]#[C-])S(=O)(=O)C1=CC=C(C)C=C1 HLITUPWOVBUZQH-UHFFFAOYSA-N 0.000 description 1
- PCYWMDGJYQAMCR-UHFFFAOYSA-N 1h-pyrrole-3-carbonitrile Chemical compound N#CC=1C=CNC=1 PCYWMDGJYQAMCR-UHFFFAOYSA-N 0.000 description 1
- ZUMNVZWXCHVAKW-UHFFFAOYSA-N 2,2,2-trichloro-1-[8-chloro-6-(2-fluorophenyl)-1-methyl-2,4-dihydropyrrolo[3,4-d][2]benzazepin-3-yl]ethanone Chemical compound C12=CC(Cl)=CC=C2C2=C(C)NC(C(=O)C(Cl)(Cl)Cl)=C2CN=C1C1=CC=CC=C1F ZUMNVZWXCHVAKW-UHFFFAOYSA-N 0.000 description 1
- GZBWEJAEZUFQJZ-UHFFFAOYSA-N 2,2,2-trichloro-1-[8-chloro-6-(2-fluorophenyl)-2,4-dihydropyrrolo[3,4-d][2]benzazepin-3-yl]ethanone Chemical compound FC1=CC=CC=C1C1=NCC2=C(C(=O)C(Cl)(Cl)Cl)NC=C2C2=CC=C(Cl)C=C12 GZBWEJAEZUFQJZ-UHFFFAOYSA-N 0.000 description 1
- UTQNKKSJPHTPBS-UHFFFAOYSA-N 2,2,2-trichloroethanone Chemical group ClC(Cl)(Cl)[C]=O UTQNKKSJPHTPBS-UHFFFAOYSA-N 0.000 description 1
- RRPSAVQWRHUOGF-UHFFFAOYSA-N 2-(8-chloro-6-phenyl-4h-pyrrolo[3,4-d][2]benzazepin-2-yl)acetamide Chemical compound C12=CC(Cl)=CC=C2C2=CN(CC(=O)N)C=C2CN=C1C1=CC=CC=C1 RRPSAVQWRHUOGF-UHFFFAOYSA-N 0.000 description 1
- JYVCICWVRWCAIC-UHFFFAOYSA-N 2-(bromomethyl)butanoic acid Chemical compound CCC(CBr)C(O)=O JYVCICWVRWCAIC-UHFFFAOYSA-N 0.000 description 1
- HUHXLHLWASNVDB-UHFFFAOYSA-N 2-(oxan-2-yloxy)oxane Chemical group O1CCCCC1OC1OCCCC1 HUHXLHLWASNVDB-UHFFFAOYSA-N 0.000 description 1
- XODHJLRPEZMYMY-UHFFFAOYSA-N 2-[8-chloro-6-(2-chlorophenyl)-4h-pyrrolo[3,4-d][2]benzazepin-2-yl]-n,n-diethylethanamine Chemical compound C12=CC(Cl)=CC=C2C2=CN(CCN(CC)CC)C=C2CN=C1C1=CC=CC=C1Cl XODHJLRPEZMYMY-UHFFFAOYSA-N 0.000 description 1
- PNYLBJWQZWZIIM-UHFFFAOYSA-N 2-[8-chloro-6-(2-fluorophenyl)-4h-pyrrolo[3,4-d][2]benzazepin-2-yl]-n,n-diethylethanamine;dihydrochloride Chemical compound Cl.Cl.C12=CC(Cl)=CC=C2C2=CN(CCN(CC)CC)C=C2CN=C1C1=CC=CC=C1F PNYLBJWQZWZIIM-UHFFFAOYSA-N 0.000 description 1
- CSDWIZPFVOSPBM-UHFFFAOYSA-N 2-benzazepine-2-carboxylic acid Chemical compound OC(=O)N1C=CC=C2C=CC=CC2=C1 CSDWIZPFVOSPBM-UHFFFAOYSA-N 0.000 description 1
- SJBXMBRSTWBJRN-UHFFFAOYSA-N 2-benzoyl-4-chlorobenzoic acid Chemical compound OC(=O)C1=CC=C(Cl)C=C1C(=O)C1=CC=CC=C1 SJBXMBRSTWBJRN-UHFFFAOYSA-N 0.000 description 1
- MAUOLJVNWSALFX-UHFFFAOYSA-N 2H-2-benzazepin-3-ylmethanol Chemical compound C=1NC(=CC=C2C=1C=CC=C2)CO MAUOLJVNWSALFX-UHFFFAOYSA-N 0.000 description 1
- UZWSOZPVAYLXCA-UHFFFAOYSA-N 4-[4-chloro-2-(2-chlorobenzoyl)phenyl]-1h-pyrrole-3-carbonitrile Chemical compound C=1C=CC=C(Cl)C=1C(=O)C1=CC(Cl)=CC=C1C1=CNC=C1C#N UZWSOZPVAYLXCA-UHFFFAOYSA-N 0.000 description 1
- IKAMPYOAPGTRQW-UHFFFAOYSA-N 4-[4-chloro-2-(2-fluorobenzoyl)phenyl]-5-methyl-1h-pyrrole-3-carbonitrile Chemical compound N1C=C(C#N)C(C=2C(=CC(Cl)=CC=2)C(=O)C=2C(=CC=CC=2)F)=C1C IKAMPYOAPGTRQW-UHFFFAOYSA-N 0.000 description 1
- VCHBFTABRRYRKH-UHFFFAOYSA-N 4-[4-chloro-2-(2-fluorobenzoyl)phenyl]-5-prop-2-enyl-1h-pyrrole-3-carbonitrile Chemical compound FC1=CC=CC=C1C(=O)C1=CC(Cl)=CC=C1C1=C(CC=C)NC=C1C#N VCHBFTABRRYRKH-UHFFFAOYSA-N 0.000 description 1
- SOOUEJQPNKCQGA-UHFFFAOYSA-N 4-[4-chloro-3-(2-fluorobenzoyl)phenyl]-5-methyl-1h-pyrrole-3-carbonitrile Chemical compound N1C=C(C#N)C(C=2C=C(C(Cl)=CC=2)C(=O)C=2C(=CC=CC=2)F)=C1C SOOUEJQPNKCQGA-UHFFFAOYSA-N 0.000 description 1
- PSGXORCIZDTNHM-UHFFFAOYSA-N 8-chloro-6-(2-chlorophenyl)-1,2-dimethyl-4h-pyrrolo[3,4-d][2]benzazepine Chemical compound C=1N(C)C(C)=C(C2=CC=C(Cl)C=C22)C=1CN=C2C1=CC=CC=C1Cl PSGXORCIZDTNHM-UHFFFAOYSA-N 0.000 description 1
- ASQKOWPSPOCCQP-UHFFFAOYSA-N 8-chloro-6-(2-chlorophenyl)-1-methyl-2,4-dihydropyrrolo[3,4-d][2]benzazepine-3-carbaldehyde Chemical compound C12=CC(Cl)=CC=C2C2=C(C)NC(C=O)=C2CN=C1C1=CC=CC=C1Cl ASQKOWPSPOCCQP-UHFFFAOYSA-N 0.000 description 1
- ZISHUIMSWPBOSO-UHFFFAOYSA-N 8-chloro-6-(2-chlorophenyl)-2,4-dihydropyrrolo[3,4-d][2]benzazepine-3-carbaldehyde Chemical compound C12=CC(Cl)=CC=C2C2=CNC(C=O)=C2CN=C1C1=CC=CC=C1Cl ZISHUIMSWPBOSO-UHFFFAOYSA-N 0.000 description 1
- MCGWTWWSPDWNCX-UHFFFAOYSA-N 8-chloro-6-(2-chlorophenyl)-2,5-dimethyl-4,6-dihydropyrrolo[3,4-d][2]benzazepine Chemical compound CN1CC2=CN(C)C=C2C2=CC=C(Cl)C=C2C1C1=CC=CC=C1Cl MCGWTWWSPDWNCX-UHFFFAOYSA-N 0.000 description 1
- HMXAVTQZFQBWGR-UHFFFAOYSA-N 8-chloro-6-(2-chlorophenyl)-4-methoxy-2,4-dihydropyrrolo[3,4-d][2]benzazepine Chemical compound C12=CC(Cl)=CC=C2C2=CNC=C2C(OC)N=C1C1=CC=CC=C1Cl HMXAVTQZFQBWGR-UHFFFAOYSA-N 0.000 description 1
- HIXHXOHAIJBLCQ-UHFFFAOYSA-N 8-chloro-6-(2-chlorophenyl)-4h-pyrrolo[3,4-d][2]benzazepine-2-carboxylic acid Chemical compound C12=CC(Cl)=CC=C2C2=CN(C(=O)O)C=C2CN=C1C1=CC=CC=C1Cl HIXHXOHAIJBLCQ-UHFFFAOYSA-N 0.000 description 1
- WVCIGTWVDACBHJ-UHFFFAOYSA-N 8-chloro-6-(2-fluorophenyl)-1-methyl-3-prop-2-ynyl-2,4-dihydropyrrolo[3,4-d][2]benzazepine Chemical compound C12=CC(Cl)=CC=C2C2=C(C)NC(CC#C)=C2CN=C1C1=CC=CC=C1F WVCIGTWVDACBHJ-UHFFFAOYSA-N 0.000 description 1
- NPKUDLCWKWOJAO-UHFFFAOYSA-N 8-chloro-6-(2-fluorophenyl)-1-prop-2-enyl-2,4-dihydropyrrolo[3,4-d][2]benzazepine Chemical compound FC1=CC=CC=C1C1=NCC2=CNC(CC=C)=C2C2=CC=C(Cl)C=C12 NPKUDLCWKWOJAO-UHFFFAOYSA-N 0.000 description 1
- VMOQUBBQGBNGBD-UHFFFAOYSA-N 8-chloro-6-(2-fluorophenyl)-2-methyl-4h-pyrrolo[3,4-d][2]benzazepine Chemical compound C12=CC(Cl)=CC=C2C2=CN(C)C=C2CN=C1C1=CC=CC=C1F VMOQUBBQGBNGBD-UHFFFAOYSA-N 0.000 description 1
- NYRIVPPDMHFCLI-UHFFFAOYSA-N 8-chloro-6-(2-fluorophenyl)-2-prop-2-enyl-4h-pyrrolo[3,4-d][2]benzazepine Chemical compound FC1=CC=CC=C1C1=NCC2=CN(CC=C)C=C2C2=CC=C(Cl)C=C12 NYRIVPPDMHFCLI-UHFFFAOYSA-N 0.000 description 1
- JQJTZPYVYCLDNT-UHFFFAOYSA-N 8-chloro-6-(2-fluorophenyl)-3-prop-2-enyl-2,4-dihydropyrrolo[3,4-d][2]benzazepine Chemical compound FC1=CC=CC=C1C1=NCC2=C(CC=C)NC=C2C2=CC=C(Cl)C=C12 JQJTZPYVYCLDNT-UHFFFAOYSA-N 0.000 description 1
- XWRCZLSZZBEESY-UHFFFAOYSA-N 8-chloro-6-(2-fluorophenyl)-n,1-dimethyl-2,4-dihydropyrrolo[3,4-d][2]benzazepine-3-carboxamide Chemical compound CNC(=O)C=1NC(C)=C(C2=CC=C(Cl)C=C22)C=1CN=C2C1=CC=CC=C1F XWRCZLSZZBEESY-UHFFFAOYSA-N 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- 206010003591 Ataxia Diseases 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- COVZYZSDYWQREU-UHFFFAOYSA-N Busulfan Chemical compound CS(=O)(=O)OCCCCOS(C)(=O)=O COVZYZSDYWQREU-UHFFFAOYSA-N 0.000 description 1
- SYAHIHKAZUTIDI-UHFFFAOYSA-N C1=NC=C2CNC=C3C(=C21)C=CC=C3 Chemical compound C1=NC=C2CNC=C3C(=C21)C=CC=C3 SYAHIHKAZUTIDI-UHFFFAOYSA-N 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 description 1
- OFIAVPVZYUSKHL-UHFFFAOYSA-N Cl.Cl.C1=NC=C2CNC=C3C(=C21)C=CC=C3 Chemical compound Cl.Cl.C1=NC=C2CNC=C3C(=C21)C=CC=C3 OFIAVPVZYUSKHL-UHFFFAOYSA-N 0.000 description 1
- NWQGCHPOTGJFGR-UHFFFAOYSA-N ClC1=CC=2C(=C3C(CNC2C2=CC=CC=C2)=C(N=C3)C=O)C=C1 Chemical compound ClC1=CC=2C(=C3C(CNC2C2=CC=CC=C2)=C(N=C3)C=O)C=C1 NWQGCHPOTGJFGR-UHFFFAOYSA-N 0.000 description 1
- 229940126062 Compound A Drugs 0.000 description 1
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 description 1
- 108010010803 Gelatin Proteins 0.000 description 1
- NLDMNSXOCDLTTB-UHFFFAOYSA-N Heterophylliin A Natural products O1C2COC(=O)C3=CC(O)=C(O)C(O)=C3C3=C(O)C(O)=C(O)C=C3C(=O)OC2C(OC(=O)C=2C=C(O)C(O)=C(O)C=2)C(O)C1OC(=O)C1=CC(O)=C(O)C(O)=C1 NLDMNSXOCDLTTB-UHFFFAOYSA-N 0.000 description 1
- 239000004368 Modified starch Substances 0.000 description 1
- 241000699666 Mus <mouse, genus> Species 0.000 description 1
- BUIQRTDBPCHRIR-UHFFFAOYSA-L O[Cr](Cl)(=O)=O Chemical compound O[Cr](Cl)(=O)=O BUIQRTDBPCHRIR-UHFFFAOYSA-L 0.000 description 1
- 229930040373 Paraformaldehyde Natural products 0.000 description 1
- YGYAWVDWMABLBF-UHFFFAOYSA-N Phosgene Chemical compound ClC(Cl)=O YGYAWVDWMABLBF-UHFFFAOYSA-N 0.000 description 1
- 101100070542 Podospora anserina het-s gene Proteins 0.000 description 1
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 1
- DWAQJAXMDSEUJJ-UHFFFAOYSA-M Sodium bisulfite Chemical compound [Na+].OS([O-])=O DWAQJAXMDSEUJJ-UHFFFAOYSA-M 0.000 description 1
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 description 1
- 241001122767 Theaceae Species 0.000 description 1
- GKRCPQIVLRQANZ-UHFFFAOYSA-N [8-chloro-6-(2-chlorophenyl)-1-methyl-2,4-dihydropyrrolo[3,4-d][2]benzazepin-3-yl]methanol Chemical compound C12=CC(Cl)=CC=C2C2=C(C)NC(CO)=C2CN=C1C1=CC=CC=C1Cl GKRCPQIVLRQANZ-UHFFFAOYSA-N 0.000 description 1
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 1
- 125000003668 acetyloxy group Chemical group [H]C([H])([H])C(=O)O[*] 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 239000000443 aerosol Substances 0.000 description 1
- 229910001854 alkali hydroxide Inorganic materials 0.000 description 1
- 125000005596 alkyl carboxamido group Chemical group 0.000 description 1
- 230000029936 alkylation Effects 0.000 description 1
- 238000005804 alkylation reaction Methods 0.000 description 1
- PNEYBMLMFCGWSK-UHFFFAOYSA-N aluminium oxide Inorganic materials [O-2].[O-2].[O-2].[Al+3].[Al+3] PNEYBMLMFCGWSK-UHFFFAOYSA-N 0.000 description 1
- 125000004202 aminomethyl group Chemical group [H]N([H])C([H])([H])* 0.000 description 1
- 150000008064 anhydrides Chemical class 0.000 description 1
- 239000011260 aqueous acid Substances 0.000 description 1
- 239000008346 aqueous phase Substances 0.000 description 1
- 150000004945 aromatic hydrocarbons Chemical class 0.000 description 1
- 239000012298 atmosphere Substances 0.000 description 1
- CBHOOMGKXCMKIR-UHFFFAOYSA-N azane;methanol Chemical compound N.OC CBHOOMGKXCMKIR-UHFFFAOYSA-N 0.000 description 1
- 230000000903 blocking effect Effects 0.000 description 1
- 229910000085 borane Inorganic materials 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- 239000000872 buffer Substances 0.000 description 1
- 125000004063 butyryl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 150000001244 carboxylic acid anhydrides Chemical class 0.000 description 1
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- FZFAMSAMCHXGEF-UHFFFAOYSA-N chloro formate Chemical compound ClOC=O FZFAMSAMCHXGEF-UHFFFAOYSA-N 0.000 description 1
- 150000001844 chromium Chemical class 0.000 description 1
- 238000003776 cleavage reaction Methods 0.000 description 1
- 229910052802 copper Inorganic materials 0.000 description 1
- 239000010949 copper Substances 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- WLXALCKAKGDNAT-UHFFFAOYSA-N diazoethane Chemical compound CC=[N+]=[N-] WLXALCKAKGDNAT-UHFFFAOYSA-N 0.000 description 1
- 239000012954 diazonium Substances 0.000 description 1
- 150000001989 diazonium salts Chemical class 0.000 description 1
- SYZWSSNHPZXGML-UHFFFAOYSA-N dichloromethane;oxolane Chemical compound ClCCl.C1CCOC1 SYZWSSNHPZXGML-UHFFFAOYSA-N 0.000 description 1
- 125000000118 dimethyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 125000002147 dimethylamino group Chemical group [H]C([H])([H])N(*)C([H])([H])[H] 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 239000012153 distilled water Substances 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 239000008298 dragée Substances 0.000 description 1
- 239000003995 emulsifying agent Substances 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- PSLIMVZEAPALCD-UHFFFAOYSA-N ethanol;ethoxyethane Chemical compound CCO.CCOCC PSLIMVZEAPALCD-UHFFFAOYSA-N 0.000 description 1
- GCFHZZWXZLABBL-UHFFFAOYSA-N ethanol;hexane Chemical compound CCO.CCCCCC GCFHZZWXZLABBL-UHFFFAOYSA-N 0.000 description 1
- 239000012259 ether extract Substances 0.000 description 1
- CHDFNIZLAAFFPX-UHFFFAOYSA-N ethoxyethane;oxolane Chemical compound CCOCC.C1CCOC1 CHDFNIZLAAFFPX-UHFFFAOYSA-N 0.000 description 1
- BIEKZLXXKLEPNI-UHFFFAOYSA-N ethyl 2-(8-chloro-6-phenyl-4h-pyrrolo[3,4-d][2]benzazepin-2-yl)acetate Chemical compound C12=CC(Cl)=CC=C2C2=CN(CC(=O)OCC)C=C2CN=C1C1=CC=CC=C1 BIEKZLXXKLEPNI-UHFFFAOYSA-N 0.000 description 1
- OAYLNYINCPYISS-UHFFFAOYSA-N ethyl acetate;hexane Chemical compound CCCCCC.CCOC(C)=O OAYLNYINCPYISS-UHFFFAOYSA-N 0.000 description 1
- 239000000284 extract Substances 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 235000019253 formic acid Nutrition 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- 239000011521 glass Substances 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 229940093915 gynecological organic acid Drugs 0.000 description 1
- UKJFVOWPUXSBOM-UHFFFAOYSA-N hexane;oxolane Chemical compound C1CCOC1.CCCCCC UKJFVOWPUXSBOM-UHFFFAOYSA-N 0.000 description 1
- 150000002430 hydrocarbons Chemical group 0.000 description 1
- 150000002483 hydrogen compounds Chemical class 0.000 description 1
- 239000012433 hydrogen halide Substances 0.000 description 1
- 229910000039 hydrogen halide Inorganic materials 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 125000002768 hydroxyalkyl group Chemical group 0.000 description 1
- 150000002466 imines Chemical class 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 238000011065 in-situ storage Methods 0.000 description 1
- 239000003701 inert diluent Substances 0.000 description 1
- 150000002527 isonitriles Chemical class 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 235000012054 meals Nutrition 0.000 description 1
- 239000000155 melt Substances 0.000 description 1
- WPRDIODXFXULLB-UHFFFAOYSA-N methyl 2-(2-benzazepin-2-yl)acetate Chemical compound COC(CN1C=C2C(=CC=C1)C=CC=C2)=O WPRDIODXFXULLB-UHFFFAOYSA-N 0.000 description 1
- GBQPMNYEQWHXKV-UHFFFAOYSA-N methyl 2-[8-chloro-6-(2-fluorophenyl)-4h-pyrrolo[3,4-d][2]benzazepin-2-yl]acetate Chemical compound C12=CC(Cl)=CC=C2C2=CN(CC(=O)OC)C=C2CN=C1C1=CC=CC=C1F GBQPMNYEQWHXKV-UHFFFAOYSA-N 0.000 description 1
- UOHPNIOVYZDNMX-UHFFFAOYSA-N methyl 2H-2-benzazepine-3-carboxylate Chemical compound COC(=O)C=1NC=C2C(=CC=1)C=CC=C2 UOHPNIOVYZDNMX-UHFFFAOYSA-N 0.000 description 1
- VSDOHBJJRMWLOY-UHFFFAOYSA-N methyl 8-chloro-6-(2-chlorophenyl)-4h-pyrrolo[3,4-d][2]benzazepine-2-carboxylate Chemical compound C12=CC(Cl)=CC=C2C2=CN(C(=O)OC)C=C2CN=C1C1=CC=CC=C1Cl VSDOHBJJRMWLOY-UHFFFAOYSA-N 0.000 description 1
- XMJHPCRAQCTCFT-UHFFFAOYSA-N methyl chloroformate Chemical compound COC(Cl)=O XMJHPCRAQCTCFT-UHFFFAOYSA-N 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 235000019426 modified starch Nutrition 0.000 description 1
- 238000012544 monitoring process Methods 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 239000012044 organic layer Substances 0.000 description 1
- 230000003204 osmotic effect Effects 0.000 description 1
- MUJIDPITZJWBSW-UHFFFAOYSA-N palladium(2+) Chemical class [Pd+2] MUJIDPITZJWBSW-UHFFFAOYSA-N 0.000 description 1
- 229920002866 paraformaldehyde Polymers 0.000 description 1
- 235000019271 petrolatum Nutrition 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- JAMNHZBIQDNHMM-UHFFFAOYSA-N pivalonitrile Chemical compound CC(C)(C)C#N JAMNHZBIQDNHMM-UHFFFAOYSA-N 0.000 description 1
- 229920001515 polyalkylene glycol Polymers 0.000 description 1
- 159000000001 potassium salts Chemical class 0.000 description 1
- 230000001376 precipitating effect Effects 0.000 description 1
- 238000012746 preparative thin layer chromatography Methods 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 238000003825 pressing Methods 0.000 description 1
- 125000001501 propionyl group Chemical group O=C([*])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- JUJWROOIHBZHMG-UHFFFAOYSA-O pyridinium Chemical compound C1=CC=[NH+]C=C1 JUJWROOIHBZHMG-UHFFFAOYSA-O 0.000 description 1
- JIYKTSNKLRCIOV-UHFFFAOYSA-N pyrrolo[3,4-d][2]benzazepine-3-carbaldehyde Chemical compound C1=NC(=C2C=NC=C3C(=C21)C=CC=C3)C=O JIYKTSNKLRCIOV-UHFFFAOYSA-N 0.000 description 1
- 125000000168 pyrrolyl group Chemical group 0.000 description 1
- 230000007017 scission Effects 0.000 description 1
- 230000035939 shock Effects 0.000 description 1
- ODZPKZBBUMBTMG-UHFFFAOYSA-N sodium amide Chemical compound [NH2-].[Na+] ODZPKZBBUMBTMG-UHFFFAOYSA-N 0.000 description 1
- 235000010267 sodium hydrogen sulphite Nutrition 0.000 description 1
- 235000010288 sodium nitrite Nutrition 0.000 description 1
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
- 238000004611 spectroscopical analysis Methods 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 230000001954 sterilising effect Effects 0.000 description 1
- 238000004659 sterilization and disinfection Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 150000003462 sulfoxides Chemical class 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 235000012222 talc Nutrition 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- CFOAUYCPAUGDFF-UHFFFAOYSA-N tosmic Chemical compound CC1=CC=C(S(=O)(=O)C[N+]#[C-])C=C1 CFOAUYCPAUGDFF-UHFFFAOYSA-N 0.000 description 1
- 229910052723 transition metal Inorganic materials 0.000 description 1
- 150000003624 transition metals Chemical class 0.000 description 1
- 235000015112 vegetable and seed oil Nutrition 0.000 description 1
- 239000008158 vegetable oil Substances 0.000 description 1
- 210000003462 vein Anatomy 0.000 description 1
- 238000005550 wet granulation Methods 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C29/00—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring
- C07C29/132—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring by reduction of an oxygen containing functional group
- C07C29/136—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring by reduction of an oxygen containing functional group of >C=O containing groups, e.g. —COOH
- C07C29/147—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring by reduction of an oxygen containing functional group of >C=O containing groups, e.g. —COOH of carboxylic acids or derivatives thereof
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C255/00—Carboxylic acid nitriles
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
- C07C45/27—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by oxidation
- C07C45/30—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by oxidation with halogen containing compounds, e.g. hypohalogenation
- C07C45/305—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by oxidation with halogen containing compounds, e.g. hypohalogenation with halogenochromate reagents, e.g. pyridinium chlorochromate
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C63/00—Compounds having carboxyl groups bound to a carbon atoms of six-membered aromatic rings
- C07C63/68—Compounds having carboxyl groups bound to a carbon atoms of six-membered aromatic rings containing halogen
- C07C63/72—Polycyclic acids
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/30—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
- C07D207/32—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two 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
- C07D207/33—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two 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 with substituted hydrocarbon radicals, directly attached to ring carbon atoms
- C07D207/335—Radicals substituted by nitrogen atoms not forming part of a nitro radical
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/30—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
- C07D207/34—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two 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, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Plural Heterocyclic Compounds (AREA)
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US17555580A | 1980-08-05 | 1980-08-05 | |
| US06/286,124 US4354973A (en) | 1980-08-05 | 1981-07-23 | Pyrrolo[3,4-d][2]benzazepines |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| HU188071B true HU188071B (en) | 1986-03-28 |
Family
ID=26871324
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| HU812247A HU188071B (en) | 1980-08-05 | 1981-08-03 | Process for producing pyrrolo-benzodiazepine derivatives |
Country Status (25)
| Country | Link |
|---|---|
| US (1) | US4354973A (enExample) |
| EP (1) | EP0045519B1 (enExample) |
| AR (1) | AR230639A1 (enExample) |
| AT (1) | ATE13888T1 (enExample) |
| AU (1) | AU545298B2 (enExample) |
| CA (1) | CA1174674A (enExample) |
| CH (1) | CH648849A5 (enExample) |
| DE (2) | DE3171021D1 (enExample) |
| DK (1) | DK347681A (enExample) |
| ES (4) | ES504525A0 (enExample) |
| FI (1) | FI71149C (enExample) |
| FR (1) | FR2488257A1 (enExample) |
| GB (1) | GB2083460B (enExample) |
| HU (1) | HU188071B (enExample) |
| IE (1) | IE51466B1 (enExample) |
| IL (1) | IL63487A (enExample) |
| IT (1) | IT1138133B (enExample) |
| LU (1) | LU83531A1 (enExample) |
| MC (1) | MC1409A1 (enExample) |
| NL (1) | NL8103655A (enExample) |
| NO (1) | NO812647L (enExample) |
| NZ (1) | NZ197920A (enExample) |
| PH (1) | PH16814A (enExample) |
| PT (1) | PT73481B (enExample) |
| SE (1) | SE8104659L (enExample) |
Families Citing this family (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE3372369D1 (de) * | 1982-05-18 | 1987-08-13 | Hoffmann La Roche | Pyrrole (3,4-d)(2)benzazepine derivatives |
| US4436662A (en) | 1982-06-28 | 1984-03-13 | Hoffmann-La Roche Inc. | Pyrrolo[3,4-d][2]benzazepinones |
| US5098901A (en) * | 1991-09-10 | 1992-03-24 | Sterling Drug Inc. | Imidazo [1,2-b][2]benzazepine and pyrimido [1,2-b][2]benzazepine antiarrhythmic agents |
Family Cites Families (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3523947A (en) * | 1966-11-23 | 1970-08-11 | Hoffmann La Roche | 1-cyclic amidine-5-aryl-1,4-benzodiazepine and process |
| US3947585A (en) * | 1974-06-03 | 1976-03-30 | Ciba-Geigy Corporation | Pyrazolobenzazepines |
| US4022801A (en) * | 1974-06-03 | 1977-05-10 | Ciba-Geigy Corporation | Pyrazolobenzazepines |
| US4169150A (en) * | 1975-11-12 | 1979-09-25 | Teijin Limited | Benzodiazepine derivatives and pharmaceutical compositions containing said derivatives |
-
1981
- 1981-07-23 US US06/286,124 patent/US4354973A/en not_active Expired - Fee Related
- 1981-07-27 CH CH4869/81A patent/CH648849A5/de not_active IP Right Cessation
- 1981-08-03 NZ NZ197920A patent/NZ197920A/en unknown
- 1981-08-03 SE SE8104659A patent/SE8104659L/xx unknown
- 1981-08-03 IT IT23347/81A patent/IT1138133B/it active
- 1981-08-03 HU HU812247A patent/HU188071B/hu unknown
- 1981-08-03 LU LU83531A patent/LU83531A1/de unknown
- 1981-08-03 IL IL63487A patent/IL63487A/xx unknown
- 1981-08-03 NL NL8103655A patent/NL8103655A/nl not_active Application Discontinuation
- 1981-08-04 FI FI812416A patent/FI71149C/fi not_active IP Right Cessation
- 1981-08-04 PH PH26000A patent/PH16814A/en unknown
- 1981-08-04 PT PT73481A patent/PT73481B/pt unknown
- 1981-08-04 ES ES504525A patent/ES504525A0/es active Granted
- 1981-08-04 FR FR8115107A patent/FR2488257A1/fr active Granted
- 1981-08-04 DK DK347681A patent/DK347681A/da not_active Application Discontinuation
- 1981-08-04 CA CA000383108A patent/CA1174674A/en not_active Expired
- 1981-08-04 MC MC811533A patent/MC1409A1/fr unknown
- 1981-08-04 NO NO812647A patent/NO812647L/no unknown
- 1981-08-04 GB GB8123763A patent/GB2083460B/en not_active Expired
- 1981-08-05 AT AT81106137T patent/ATE13888T1/de not_active IP Right Cessation
- 1981-08-05 AR AR286350A patent/AR230639A1/es active
- 1981-08-05 EP EP81106137A patent/EP0045519B1/de not_active Expired
- 1981-08-05 DE DE8181106137T patent/DE3171021D1/de not_active Expired
- 1981-08-05 DE DE19813131064 patent/DE3131064A1/de not_active Withdrawn
- 1981-08-05 AU AU73825/81A patent/AU545298B2/en not_active Ceased
- 1981-08-14 IE IE1775/81A patent/IE51466B1/en unknown
-
1982
- 1982-07-01 ES ES513621A patent/ES513621A0/es active Granted
- 1982-07-01 ES ES513622A patent/ES513622A0/es active Granted
- 1982-07-01 ES ES513620A patent/ES8304983A1/es not_active Expired
Also Published As
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| EP0150040B1 (de) | Imidazodiazepin-Derivate | |
| US4563525A (en) | Process for preparing pyrazolopyridine compounds | |
| JPH02191281A (ja) | 新規チエノ―トリアゾロ―１，４―ジアゼピノ―２―カルボン酸 | |
| DE3833008A1 (de) | Pyrrolocarbozol-derivate, verfahren zu deren herstellung und deren verwendung als arzneimittel | |
| DE69428546T2 (de) | 3-acylaminobenzazepine | |
| EP0022078B1 (de) | Pyrazolochinoline, Verfahren zu ihrer Herstellung, und pharmazeutische Präparate enthaltend diese Verbindungen | |
| US4210648A (en) | II-Aminoacyl-5,11-dihydro-6H-pyrido(2,3-B) (1,4)benzodiazepin-6-ones and salts thereof | |
| EP0023707B1 (de) | Substituierte Tetraazatricyclen, Verfahren zu ihrer Herstellung, ihre Verwendung und sie enthaltende Arzneimittel | |
| DE3535927A1 (de) | 3-vinyl- und 3-ethinyl-ss-carbolinderivate, ihre herstellung und ihre verwendung als arzneimittel | |
| EP0294599A2 (de) | Tricyclische Pyridonderivate | |
| NZ204203A (en) | Pyrazolopyridine derivatives,methods for their preparation and pharmaceutical compositions | |
| NZ204569A (en) | Pyrazolo(3,4-b)pyridine derivatives and pharmaceutical compositions | |
| US3732212A (en) | 1,2,3,10,11,11a-hexahydro-5h-pyrrolo(2,1-c)(1,4)benzodiazepine-5,11-diones | |
| Hino et al. | Agents Acting on the Central Nervous System.: Synthesis of 3-Phenyl-2-piperazinyl-1-benzazocines, 3-Substituted-2-piperazinyl-1-benzazepines and Related Compounds | |
| HUT54162A (en) | Process for producing new substituted thienopyran derivatives and pharmaceutical compositions comprising such compounds | |
| HU188071B (en) | Process for producing pyrrolo-benzodiazepine derivatives | |
| GB1586655A (en) | Pyrido-indole transquilising agents | |
| EP0232675B1 (de) | 5-Aminoalkyl-Beta-Carbolinderivate, ihre Herstellung und Verwendung als Arzneimittel | |
| US4431823A (en) | 1H-Pyrrole-3-carbonitrile-4(2-benzoyl)phenyl derivatives as intermediates for pyrrolo[3,4-D][2]benzazepines | |
| US4409390A (en) | Pyrrolo[3,4-D][2]Benzazepines | |
| US4405518A (en) | Pyrrolo[3,4-d] [2] benzazepines | |
| HU185633B (en) | Process for preparing phenyl-quinolizidine derivatives | |
| US4428879A (en) | Pyrrolo[3,4,-d][2]benzazepines | |
| US4428878A (en) | Pyrrolo[3,4-d][2]benzazepines | |
| Costanzo et al. | Synthesis of derivatives of pyrazolo [1, 5‐a] pyrrolo [1, 2‐c][1, 3, 6]‐benzotriazocine, a new class of compounds with potential CNS activity |