CA1100960A - 3-fluorobenzodiazepines - Google Patents
3-fluorobenzodiazepinesInfo
- Publication number
- CA1100960A CA1100960A CA242,041A CA242041A CA1100960A CA 1100960 A CA1100960 A CA 1100960A CA 242041 A CA242041 A CA 242041A CA 1100960 A CA1100960 A CA 1100960A
- Authority
- CA
- Canada
- Prior art keywords
- dihydro
- benzodiazepin
- phenyl
- fluoro
- methyl
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired
Links
- PZOZHMBWLDUJCP-UHFFFAOYSA-N 3-fluoro-1H-1,2-benzodiazepine Chemical class FC1=NNC2=C(C=C1)C=CC=C2 PZOZHMBWLDUJCP-UHFFFAOYSA-N 0.000 title claims 3
- 150000001875 compounds Chemical class 0.000 claims abstract description 95
- 239000002253 acid Substances 0.000 claims abstract description 33
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims abstract description 31
- 125000004432 carbon atom Chemical group C* 0.000 claims abstract description 28
- 229910052801 chlorine Inorganic materials 0.000 claims abstract description 26
- 229910052731 fluorine Inorganic materials 0.000 claims abstract description 26
- 238000006243 chemical reaction Methods 0.000 claims abstract description 22
- 150000003839 salts Chemical class 0.000 claims abstract description 21
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 18
- JCXJVPUVTGWSNB-UHFFFAOYSA-N nitrogen dioxide Inorganic materials O=[N]=O JCXJVPUVTGWSNB-UHFFFAOYSA-N 0.000 claims abstract description 14
- 229910052794 bromium Inorganic materials 0.000 claims abstract description 12
- 239000000203 mixture Substances 0.000 claims description 81
- -1 trifluoromethane-sulfonyloxy, trichloromethanesulfonyloxy, p-nitrobenzene-sulfonyloxy Chemical group 0.000 claims description 80
- 238000000034 method Methods 0.000 claims description 74
- 230000008569 process Effects 0.000 claims description 58
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 45
- 239000000126 substance Substances 0.000 claims description 30
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 28
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 claims description 27
- 125000004182 2-chlorophenyl group Chemical group [H]C1=C([H])C(Cl)=C(*)C([H])=C1[H] 0.000 claims description 25
- 239000000460 chlorine Substances 0.000 claims description 25
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 24
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 22
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 21
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 claims description 18
- 125000004198 2-fluorophenyl group Chemical group [H]C1=C([H])C(F)=C(*)C([H])=C1[H] 0.000 claims description 15
- 229960003529 diazepam Drugs 0.000 claims description 15
- AAOVKJBEBIDNHE-UHFFFAOYSA-N diazepam Chemical compound N=1CC(=O)N(C)C2=CC=C(Cl)C=C2C=1C1=CC=CC=C1 AAOVKJBEBIDNHE-UHFFFAOYSA-N 0.000 claims description 13
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 12
- IEAZSLKYQNZPRN-UHFFFAOYSA-N 7-chloro-3-fluoro-5-phenyl-1,3-dihydro-1,4-benzodiazepin-2-one Chemical compound C12=CC(Cl)=CC=C2NC(=O)C(F)N=C1C1=CC=CC=C1 IEAZSLKYQNZPRN-UHFFFAOYSA-N 0.000 claims description 11
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 claims description 10
- PCLIMKBDDGJMGD-UHFFFAOYSA-N N-bromosuccinimide Chemical compound BrN1C(=O)CCC1=O PCLIMKBDDGJMGD-UHFFFAOYSA-N 0.000 claims description 10
- 229910052736 halogen Inorganic materials 0.000 claims description 10
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 claims description 10
- 239000003054 catalyst Substances 0.000 claims description 7
- 239000003795 chemical substances by application Substances 0.000 claims description 7
- 125000005843 halogen group Chemical group 0.000 claims description 7
- 150000002367 halogens Chemical class 0.000 claims description 7
- UFQZSHDUEUWIQF-UHFFFAOYSA-N 3-fluoro-5-(2-fluorophenyl)-7-nitro-1,3-dihydro-1,4-benzodiazepin-2-one Chemical compound C12=CC([N+](=O)[O-])=CC=C2NC(=O)C(F)N=C1C1=CC=CC=C1F UFQZSHDUEUWIQF-UHFFFAOYSA-N 0.000 claims description 6
- 229910021529 ammonia Inorganic materials 0.000 claims description 6
- JPJALAQPGMAKDF-UHFFFAOYSA-N selenium dioxide Chemical compound O=[Se]=O JPJALAQPGMAKDF-UHFFFAOYSA-N 0.000 claims description 6
- 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 6
- OKXVLIUXLUDLCV-UHFFFAOYSA-N 5-(2-chlorophenyl)-3,7-difluoro-1,3-dihydro-1,4-benzodiazepin-2-one Chemical compound C12=CC(F)=CC=C2NC(=O)C(F)N=C1C1=CC=CC=C1Cl OKXVLIUXLUDLCV-UHFFFAOYSA-N 0.000 claims description 5
- WGLPBDUCMAPZCE-UHFFFAOYSA-N chromium trioxide Inorganic materials O=[Cr](=O)=O WGLPBDUCMAPZCE-UHFFFAOYSA-N 0.000 claims description 5
- 229910052739 hydrogen Inorganic materials 0.000 claims description 5
- 229910052744 lithium Inorganic materials 0.000 claims description 5
- 229910052700 potassium Inorganic materials 0.000 claims description 5
- KOMKSSWORSXLBP-UHFFFAOYSA-N 7-chloro-5-(2-chlorophenyl)-3-fluoro-1,3-dihydro-1,4-benzodiazepin-2-one Chemical compound C12=CC(Cl)=CC=C2NC(=O)C(F)N=C1C1=CC=CC=C1Cl KOMKSSWORSXLBP-UHFFFAOYSA-N 0.000 claims description 4
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 4
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 claims description 4
- 125000002947 alkylene group Chemical group 0.000 claims description 4
- 125000003118 aryl group Chemical group 0.000 claims description 4
- 125000005279 aryl sulfonyloxy group Chemical group 0.000 claims description 4
- 239000012025 fluorinating agent Substances 0.000 claims description 4
- 238000010438 heat treatment Methods 0.000 claims description 4
- 239000001257 hydrogen Substances 0.000 claims description 4
- ANRQGKOBLBYXFM-UHFFFAOYSA-M phenylmagnesium bromide Chemical compound Br[Mg]C1=CC=CC=C1 ANRQGKOBLBYXFM-UHFFFAOYSA-M 0.000 claims description 4
- 239000012286 potassium permanganate Substances 0.000 claims description 4
- 239000001632 sodium acetate Substances 0.000 claims description 4
- 235000017281 sodium acetate Nutrition 0.000 claims description 4
- LPXPTNMVRIOKMN-UHFFFAOYSA-M sodium nitrite Chemical compound [Na+].[O-]N=O LPXPTNMVRIOKMN-UHFFFAOYSA-M 0.000 claims description 4
- SZJYHCIVEVNIOT-UHFFFAOYSA-N 3-fluoro-1-methyl-5-phenyl-3h-1,4-benzodiazepin-2-one Chemical compound N=1C(F)C(=O)N(C)C2=CC=CC=C2C=1C1=CC=CC=C1 SZJYHCIVEVNIOT-UHFFFAOYSA-N 0.000 claims description 3
- JWGBSFCQLZTKGI-UHFFFAOYSA-N 3-fluoro-7-nitro-5-phenyl-1,3-dihydro-1,4-benzodiazepin-2-one Chemical compound C12=CC([N+](=O)[O-])=CC=C2NC(=O)C(F)N=C1C1=CC=CC=C1 JWGBSFCQLZTKGI-UHFFFAOYSA-N 0.000 claims description 3
- YYROPELSRYBVMQ-UHFFFAOYSA-N 4-toluenesulfonyl chloride Chemical compound CC1=CC=C(S(Cl)(=O)=O)C=C1 YYROPELSRYBVMQ-UHFFFAOYSA-N 0.000 claims description 3
- FZABLTNUBRBKJP-UHFFFAOYSA-N 5-(2-chlorophenyl)-3,7-difluoro-1-methyl-3h-1,4-benzodiazepin-2-one Chemical compound N=1C(F)C(=O)N(C)C2=CC=C(F)C=C2C=1C1=CC=CC=C1Cl FZABLTNUBRBKJP-UHFFFAOYSA-N 0.000 claims description 3
- 230000009471 action Effects 0.000 claims description 3
- 125000004423 acyloxy group Chemical group 0.000 claims description 3
- 125000003545 alkoxy group Chemical group 0.000 claims description 3
- 125000005278 alkyl sulfonyloxy group Chemical group 0.000 claims description 3
- 239000002168 alkylating agent Substances 0.000 claims description 3
- 229940100198 alkylating agent Drugs 0.000 claims description 3
- 150000001244 carboxylic acid anhydrides Chemical class 0.000 claims description 3
- 150000001734 carboxylic acid salts Chemical class 0.000 claims description 3
- ZCDOYSPFYFSLEW-UHFFFAOYSA-N chromate(2-) Chemical compound [O-][Cr]([O-])(=O)=O ZCDOYSPFYFSLEW-UHFFFAOYSA-N 0.000 claims description 3
- 229940117975 chromium trioxide Drugs 0.000 claims description 3
- GAMDZJFZMJECOS-UHFFFAOYSA-N chromium(6+);oxygen(2-) Chemical compound [O-2].[O-2].[O-2].[Cr+6] GAMDZJFZMJECOS-UHFFFAOYSA-N 0.000 claims description 3
- 239000012024 dehydrating agents Substances 0.000 claims description 3
- 230000002140 halogenating effect Effects 0.000 claims description 3
- 229910052740 iodine Inorganic materials 0.000 claims description 3
- 230000000802 nitrating effect Effects 0.000 claims description 3
- 229960001454 nitrazepam Drugs 0.000 claims description 3
- 229910000510 noble metal Inorganic materials 0.000 claims description 3
- XHFXMNZYIKFCPN-UHFFFAOYSA-N perchloryl fluoride Chemical compound FCl(=O)(=O)=O XHFXMNZYIKFCPN-UHFFFAOYSA-N 0.000 claims description 3
- 239000011734 sodium Substances 0.000 claims description 3
- SMBZJSVIKJMSFP-UHFFFAOYSA-N trifluoromethyl hypofluorite Chemical compound FOC(F)(F)F SMBZJSVIKJMSFP-UHFFFAOYSA-N 0.000 claims description 3
- JCTRZVYVOAHMBS-UHFFFAOYSA-N 10-chloro-5-fluoro-7-methyl-11b-phenyl-3,5-dihydro-2h-[1,3]oxazolo[3,2-d][1,4]benzodiazepin-6-one Chemical compound O1CCN2C(F)C(=O)N(C)C3=CC=C(Cl)C=C3C21C1=CC=CC=C1 JCTRZVYVOAHMBS-UHFFFAOYSA-N 0.000 claims description 2
- JVUXTXPYITVPJS-UHFFFAOYSA-N 3-chloro-7-nitro-5-phenyl-1,3-dihydro-1,4-benzodiazepin-2-one Chemical compound C12=CC([N+](=O)[O-])=CC=C2NC(=O)C(Cl)N=C1C1=CC=CC=C1 JVUXTXPYITVPJS-UHFFFAOYSA-N 0.000 claims description 2
- HRLGKYRXSGZLTB-UHFFFAOYSA-N 3-fluoro-5-(2-fluorophenyl)-1-methyl-7-nitro-3h-1,4-benzodiazepin-2-one Chemical compound N=1C(F)C(=O)N(C)C2=CC=C([N+]([O-])=O)C=C2C=1C1=CC=CC=C1F HRLGKYRXSGZLTB-UHFFFAOYSA-N 0.000 claims description 2
- MOEOWSMHYGOHDP-UHFFFAOYSA-N 5,7-dichloro-3-fluoro-1-methyl-3h-1,4-benzodiazepin-2-one Chemical compound ClC1=NC(F)C(=O)N(C)C2=CC=C(Cl)C=C21 MOEOWSMHYGOHDP-UHFFFAOYSA-N 0.000 claims description 2
- 150000001204 N-oxides Chemical class 0.000 claims description 2
- MDFFNEOEWAXZRQ-UHFFFAOYSA-N aminyl Chemical compound [NH2] MDFFNEOEWAXZRQ-UHFFFAOYSA-N 0.000 claims description 2
- 150000001450 anions Chemical class 0.000 claims description 2
- CHIFCDOIPRCHCF-UHFFFAOYSA-N delorazepam Chemical compound C12=CC(Cl)=CC=C2NC(=O)CN=C1C1=CC=CC=C1Cl CHIFCDOIPRCHCF-UHFFFAOYSA-N 0.000 claims description 2
- SOCTUWSJJQCPFX-UHFFFAOYSA-N dichromate(2-) Chemical compound [O-][Cr](=O)(=O)O[Cr]([O-])(=O)=O SOCTUWSJJQCPFX-UHFFFAOYSA-N 0.000 claims description 2
- 230000007062 hydrolysis Effects 0.000 claims description 2
- 238000006460 hydrolysis reaction Methods 0.000 claims description 2
- ADIMAYPTOBDMTL-UHFFFAOYSA-N oxazepam Chemical compound C12=CC(Cl)=CC=C2NC(=O)C(O)N=C1C1=CC=CC=C1 ADIMAYPTOBDMTL-UHFFFAOYSA-N 0.000 claims description 2
- 235000010288 sodium nitrite Nutrition 0.000 claims description 2
- NINGMRSNYNFRCB-UHFFFAOYSA-N 7-chloro-3-fluoro-1-methyl-5-phenyl-3h-1,4-benzodiazepin-2-one Chemical compound N=1C(F)C(=O)N(C)C2=CC=C(Cl)C=C2C=1C1=CC=CC=C1 NINGMRSNYNFRCB-UHFFFAOYSA-N 0.000 claims 2
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 claims 2
- BPWINVKSLHXFPN-UHFFFAOYSA-N 5-(2-chlorophenyl)-1-methyl-3h-1,4-benzodiazepin-2-one Chemical compound N=1CC(=O)N(C)C2=CC=CC=C2C=1C1=CC=CC=C1Cl BPWINVKSLHXFPN-UHFFFAOYSA-N 0.000 claims 1
- SCTARSBTRQNRBA-UHFFFAOYSA-N 7-chloro-3-fluoro-4-hydroxy-1-methyl-5-phenyl-3,5-dihydro-1,4-benzodiazepin-2-one Chemical compound ON1C(F)C(=O)N(C)C2=CC=C(Cl)C=C2C1C1=CC=CC=C1 SCTARSBTRQNRBA-UHFFFAOYSA-N 0.000 claims 1
- 229910006124 SOCl2 Inorganic materials 0.000 claims 1
- VMPVEPPRYRXYNP-UHFFFAOYSA-I antimony(5+);pentachloride Chemical compound Cl[Sb](Cl)(Cl)(Cl)Cl VMPVEPPRYRXYNP-UHFFFAOYSA-I 0.000 claims 1
- 238000004519 manufacturing process Methods 0.000 claims 1
- CIMMBUKJPRGPHD-UHFFFAOYSA-N n-[4-chloro-2-(n-hydroxy-c-phenylcarbonimidoyl)phenyl]-2-fluoro-n-methylacetamide Chemical compound FCC(=O)N(C)C1=CC=C(Cl)C=C1C(=NO)C1=CC=CC=C1 CIMMBUKJPRGPHD-UHFFFAOYSA-N 0.000 claims 1
- 229910052708 sodium Inorganic materials 0.000 claims 1
- 239000007858 starting material Substances 0.000 abstract description 8
- ZZIFIRFDVGBHEA-UHFFFAOYSA-N 3-fluoro-1,3-dihydro-1,4-benzodiazepin-2-one Chemical class N1C(=O)C(F)N=CC2=CC=CC=C21 ZZIFIRFDVGBHEA-UHFFFAOYSA-N 0.000 abstract description 3
- 239000003874 central nervous system depressant Substances 0.000 abstract description 3
- 239000000243 solution Substances 0.000 description 66
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 39
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 36
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 36
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 24
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 23
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 22
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 22
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 21
- 238000003756 stirring Methods 0.000 description 21
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 18
- 238000000354 decomposition reaction Methods 0.000 description 16
- 238000010992 reflux Methods 0.000 description 16
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 15
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 14
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 13
- 239000002585 base Substances 0.000 description 13
- 239000000047 product Substances 0.000 description 13
- REYHXKZHIMGNSE-UHFFFAOYSA-M silver monofluoride Chemical compound [F-].[Ag+] REYHXKZHIMGNSE-UHFFFAOYSA-M 0.000 description 13
- 235000017550 sodium carbonate Nutrition 0.000 description 11
- 229910000029 sodium carbonate Inorganic materials 0.000 description 11
- 229940001593 sodium carbonate Drugs 0.000 description 11
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 11
- 239000002904 solvent Substances 0.000 description 10
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 9
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 9
- 125000001153 fluoro group Chemical group F* 0.000 description 9
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 9
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 8
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 description 8
- VKYKSIONXSXAKP-UHFFFAOYSA-N hexamethylenetetramine Chemical compound C1N(C2)CN3CN1CN2C3 VKYKSIONXSXAKP-UHFFFAOYSA-N 0.000 description 8
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 7
- 150000001408 amides Chemical class 0.000 description 7
- 238000003682 fluorination reaction Methods 0.000 description 7
- 229930195733 hydrocarbon Natural products 0.000 description 7
- 150000002430 hydrocarbons Chemical class 0.000 description 7
- 239000007788 liquid Substances 0.000 description 7
- 229910052757 nitrogen Inorganic materials 0.000 description 7
- 229910000069 nitrogen hydride Inorganic materials 0.000 description 7
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 6
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 6
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 6
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 6
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 6
- 239000012442 inert solvent Substances 0.000 description 6
- LQNUZADURLCDLV-UHFFFAOYSA-N nitrobenzene Chemical compound [O-][N+](=O)C1=CC=CC=C1 LQNUZADURLCDLV-UHFFFAOYSA-N 0.000 description 6
- 239000011698 potassium fluoride Substances 0.000 description 6
- 238000002360 preparation method Methods 0.000 description 6
- 239000003826 tablet Substances 0.000 description 6
- GUNJVIDCYZYFGV-UHFFFAOYSA-K antimony trifluoride Chemical compound F[Sb](F)F GUNJVIDCYZYFGV-UHFFFAOYSA-K 0.000 description 5
- 239000002775 capsule Substances 0.000 description 5
- 239000003814 drug Substances 0.000 description 5
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 5
- 239000000725 suspension Substances 0.000 description 5
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 4
- 239000002841 Lewis acid Substances 0.000 description 4
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 4
- QARVLSVVCXYDNA-UHFFFAOYSA-N bromobenzene Chemical compound BrC1=CC=CC=C1 QARVLSVVCXYDNA-UHFFFAOYSA-N 0.000 description 4
- 150000002170 ethers Chemical class 0.000 description 4
- 239000004312 hexamethylene tetramine Substances 0.000 description 4
- 235000010299 hexamethylene tetramine Nutrition 0.000 description 4
- 239000005457 ice water Substances 0.000 description 4
- 238000011065 in-situ storage Methods 0.000 description 4
- 229910001506 inorganic fluoride Inorganic materials 0.000 description 4
- 150000007517 lewis acids Chemical class 0.000 description 4
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 4
- 238000007363 ring formation reaction Methods 0.000 description 4
- DURPTKYDGMDSBL-UHFFFAOYSA-N 1-butoxybutane Chemical compound CCCCOCCCC DURPTKYDGMDSBL-UHFFFAOYSA-N 0.000 description 3
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 3
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 3
- KRHYYFGTRYWZRS-UHFFFAOYSA-N Fluorane Chemical compound F KRHYYFGTRYWZRS-UHFFFAOYSA-N 0.000 description 3
- KRHYYFGTRYWZRS-UHFFFAOYSA-M Fluoride anion Chemical compound [F-] KRHYYFGTRYWZRS-UHFFFAOYSA-M 0.000 description 3
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 3
- OFOBLEOULBTSOW-UHFFFAOYSA-N Malonic acid Chemical compound OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 3
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 3
- 241000700159 Rattus Species 0.000 description 3
- 150000007513 acids Chemical class 0.000 description 3
- 230000029936 alkylation Effects 0.000 description 3
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- 150000002823 nitrates Chemical class 0.000 description 1
- KJONHKAYOJNZEC-UHFFFAOYSA-N nitrazepam Chemical compound C12=CC([N+](=O)[O-])=CC=C2NC(=O)CN=C1C1=CC=CC=C1 KJONHKAYOJNZEC-UHFFFAOYSA-N 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- JBCXQJHXIYZCNI-UHFFFAOYSA-N nitro benzoate Chemical compound [O-][N+](=O)OC(=O)C1=CC=CC=C1 JBCXQJHXIYZCNI-UHFFFAOYSA-N 0.000 description 1
- 125000004971 nitroalkyl group Chemical group 0.000 description 1
- LYGJENNIWJXYER-UHFFFAOYSA-N nitromethane Chemical compound C[N+]([O-])=O LYGJENNIWJXYER-UHFFFAOYSA-N 0.000 description 1
- 239000003921 oil Substances 0.000 description 1
- 235000019198 oils Nutrition 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 150000004812 organic fluorine compounds Chemical class 0.000 description 1
- 150000002900 organolithium compounds Chemical class 0.000 description 1
- 230000003204 osmotic effect Effects 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 230000001590 oxidative effect Effects 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 125000004430 oxygen atom Chemical group O* 0.000 description 1
- 125000003854 p-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Cl 0.000 description 1
- 125000001037 p-tolyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)C([H])([H])[H] 0.000 description 1
- FJKROLUGYXJWQN-UHFFFAOYSA-N papa-hydroxy-benzoic acid Natural products OC(=O)C1=CC=C(O)C=C1 FJKROLUGYXJWQN-UHFFFAOYSA-N 0.000 description 1
- 239000003208 petroleum Substances 0.000 description 1
- 239000003444 phase transfer catalyst Substances 0.000 description 1
- 150000003016 phosphoric acids Chemical class 0.000 description 1
- IUGYQRQAERSCNH-UHFFFAOYSA-N pivalic acid Chemical compound CC(C)(C)C(O)=O IUGYQRQAERSCNH-UHFFFAOYSA-N 0.000 description 1
- 229920002647 polyamide Polymers 0.000 description 1
- 229920000728 polyester Polymers 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- BITYAPCSNKJESK-UHFFFAOYSA-N potassiosodium Chemical compound [Na].[K] BITYAPCSNKJESK-UHFFFAOYSA-N 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 235000003270 potassium fluoride Nutrition 0.000 description 1
- FYRHIOVKTDQVFC-UHFFFAOYSA-M potassium phthalimide Chemical compound [K+].C1=CC=C2C(=O)[N-]C(=O)C2=C1 FYRHIOVKTDQVFC-UHFFFAOYSA-M 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 235000019260 propionic acid Nutrition 0.000 description 1
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 230000009257 reactivity Effects 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 230000002040 relaxant effect Effects 0.000 description 1
- 229960004889 salicylic acid Drugs 0.000 description 1
- ADZWSOLPGZMUMY-UHFFFAOYSA-M silver bromide Chemical compound [Ag]Br ADZWSOLPGZMUMY-UHFFFAOYSA-M 0.000 description 1
- HKZLPVFGJNLROG-UHFFFAOYSA-M silver monochloride Chemical compound [Cl-].[Ag+] HKZLPVFGJNLROG-UHFFFAOYSA-M 0.000 description 1
- ODZPKZBBUMBTMG-UHFFFAOYSA-N sodium amide Chemical compound [NH2-].[Na+] ODZPKZBBUMBTMG-UHFFFAOYSA-N 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 239000012312 sodium hydride Substances 0.000 description 1
- 235000010267 sodium hydrogen sulphite Nutrition 0.000 description 1
- CMXPERZAMAQXSF-UHFFFAOYSA-M sodium;1,4-bis(2-ethylhexoxy)-1,4-dioxobutane-2-sulfonate;1,8-dihydroxyanthracene-9,10-dione Chemical compound [Na+].O=C1C2=CC=CC(O)=C2C(=O)C2=C1C=CC=C2O.CCCCC(CC)COC(=O)CC(S([O-])(=O)=O)C(=O)OCC(CC)CCCC CMXPERZAMAQXSF-UHFFFAOYSA-M 0.000 description 1
- 238000003797 solvolysis reaction Methods 0.000 description 1
- 230000008925 spontaneous activity Effects 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 229960002317 succinimide Drugs 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 150000003871 sulfonates Chemical class 0.000 description 1
- 150000003467 sulfuric acid derivatives Chemical class 0.000 description 1
- YBBRCQOCSYXUOC-UHFFFAOYSA-N sulfuryl dichloride Chemical compound ClS(Cl)(=O)=O YBBRCQOCSYXUOC-UHFFFAOYSA-N 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 229960003188 temazepam Drugs 0.000 description 1
- 125000004213 tert-butoxy group Chemical group [H]C([H])([H])C(O*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- QSUJAUYJBJRLKV-UHFFFAOYSA-M tetraethylazanium;fluoride Chemical compound [F-].CC[N+](CC)(CC)CC QSUJAUYJBJRLKV-UHFFFAOYSA-M 0.000 description 1
- 229910052716 thallium Inorganic materials 0.000 description 1
- BKVIYDNLLOSFOA-UHFFFAOYSA-N thallium Chemical compound [Tl] BKVIYDNLLOSFOA-UHFFFAOYSA-N 0.000 description 1
- LSJNBGSOIVSBBR-UHFFFAOYSA-N thionyl fluoride Chemical compound FS(F)=O LSJNBGSOIVSBBR-UHFFFAOYSA-N 0.000 description 1
- 238000007070 tosylation reaction Methods 0.000 description 1
- 239000000196 tragacanth Substances 0.000 description 1
- 235000010487 tragacanth Nutrition 0.000 description 1
- 229940116362 tragacanth Drugs 0.000 description 1
- RYVBINGWVJJDPU-UHFFFAOYSA-M tributyl(hexadecyl)phosphanium;bromide Chemical compound [Br-].CCCCCCCCCCCCCCCC[P+](CCCC)(CCCC)CCCC RYVBINGWVJJDPU-UHFFFAOYSA-M 0.000 description 1
- CYRMSUTZVYGINF-UHFFFAOYSA-N trichlorofluoromethane Chemical compound FC(Cl)(Cl)Cl CYRMSUTZVYGINF-UHFFFAOYSA-N 0.000 description 1
- BDZBKCUKTQZUTL-UHFFFAOYSA-N triethyl phosphite Chemical compound CCOP(OCC)OCC BDZBKCUKTQZUTL-UHFFFAOYSA-N 0.000 description 1
- 238000007514 turning Methods 0.000 description 1
- 235000015112 vegetable and seed oil Nutrition 0.000 description 1
- 239000008158 vegetable oil Substances 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
- 239000008096 xylene Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D243/00—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms
- C07D243/06—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms having the nitrogen atoms in positions 1 and 4
- C07D243/10—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms having the nitrogen atoms in positions 1 and 4 condensed with carbocyclic rings or ring systems
- C07D243/14—1,4-Benzodiazepines; Hydrogenated 1,4-benzodiazepines
- C07D243/16—1,4-Benzodiazepines; Hydrogenated 1,4-benzodiazepines substituted in position 5 by aryl radicals
- C07D243/18—1,4-Benzodiazepines; Hydrogenated 1,4-benzodiazepines substituted in position 5 by aryl radicals substituted in position 2 by nitrogen, oxygen or sulfur atoms
- C07D243/24—Oxygen atoms
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
Applications Claiming Priority (4)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE19742460360 DE2460360A1 (de) | 1974-12-20 | 1974-12-20 | 3-fluorbenzodiazepine und verfahren zu ihrer herstellung |
| DEP2460360.9 | 1974-12-20 | ||
| DEP2542251.9 | 1975-09-23 | ||
| DE19752542251 DE2542251A1 (de) | 1975-09-23 | 1975-09-23 | 3-fluorbenzodiazepine und verfahren zu ihrer herstellung |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1100960A true CA1100960A (en) | 1981-05-12 |
Family
ID=25768130
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA242,041A Expired CA1100960A (en) | 1974-12-20 | 1975-12-18 | 3-fluorobenzodiazepines |
Country Status (18)
| Country | Link |
|---|---|
| US (1) | US4232016A (en, 2012) |
| JP (1) | JPS5188985A (en, 2012) |
| AT (1) | AT353794B (en, 2012) |
| AU (1) | AU8760075A (en, 2012) |
| CA (1) | CA1100960A (en, 2012) |
| CH (3) | CH617193A5 (en, 2012) |
| CS (1) | CS188984B2 (en, 2012) |
| DD (1) | DD122382A5 (en, 2012) |
| DK (1) | DK583775A (en, 2012) |
| ES (1) | ES443692A1 (en, 2012) |
| FR (1) | FR2294708A1 (en, 2012) |
| GB (1) | GB1480559A (en, 2012) |
| IE (1) | IE42383B1 (en, 2012) |
| IL (1) | IL48665A (en, 2012) |
| IT (1) | IT7948446A0 (en, 2012) |
| LU (1) | LU74049A1 (en, 2012) |
| NL (1) | NL7514861A (en, 2012) |
| SE (1) | SE7514344L (en, 2012) |
Families Citing this family (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS6032775A (ja) * | 1983-07-30 | 1985-02-19 | Daikin Ind Ltd | 含フッ素ベンゾジアゼピン類 |
| US4479901A (en) * | 1983-08-15 | 1984-10-30 | E. I. Du Pont De Nemours And Company | Fluorination of carbanions with N-fluoro-N-alkylsulfonamides |
| US4690934A (en) * | 1985-09-25 | 1987-09-01 | Nippon Kayaku Kabushiki Kaisha | N-phenylsulfonylisonicotinamide derivatives and their use as fungicides or bactericides |
| US5030632A (en) * | 1986-09-23 | 1991-07-09 | Sandoz Pharm. Corp. | Low dose temazepam |
| US5211954A (en) * | 1986-09-23 | 1993-05-18 | Sandoz Ltd. | Low dose temazepam |
| US5629310A (en) * | 1986-09-23 | 1997-05-13 | Sterling; William R. | Low dose temazepam |
| FR2620449B1 (fr) * | 1987-09-16 | 1991-04-19 | Sanofi Sa | Procede de preparation de derives de benzodiazepine-1,4 one-2 |
| US20090068325A1 (en) * | 2007-09-10 | 2009-03-12 | Gil Depicciotto | Method of treatment of fresh produce |
Family Cites Families (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3121076A (en) * | 1964-02-11 | Benzodiazepinones and processes | ||
| US3371085A (en) * | 1959-12-10 | 1968-02-27 | Hoffmann La Roche | 5-aryl-3h-1,4-benzodiazepin-2(1h)-ones |
| US3296251A (en) * | 1963-02-26 | 1967-01-03 | American Home Prod | 3-mercapto and 3-substituted mercapto-1, 3-dihydro-2h-1, 4-benzodiazepin-2-ones |
| NL298071A (en, 2012) * | 1963-06-04 | |||
| GB1052144A (en, 2012) * | 1964-02-11 | |||
| US3429874A (en) * | 1966-12-22 | 1969-02-25 | Schering Corp | 1-polyhalogenoalkyl-2-oxo-1,3-dihydro-2h-1,4-benzodiazepines |
-
1975
- 1975-12-09 US US05/639,163 patent/US4232016A/en not_active Expired - Lifetime
- 1975-12-11 FR FR7537935A patent/FR2294708A1/fr active Granted
- 1975-12-14 IL IL48665A patent/IL48665A/xx unknown
- 1975-12-16 AU AU87600/75A patent/AU8760075A/en not_active Expired
- 1975-12-17 CS CS758626A patent/CS188984B2/cs unknown
- 1975-12-18 GB GB51893/75A patent/GB1480559A/en not_active Expired
- 1975-12-18 SE SE7514344A patent/SE7514344L/xx unknown
- 1975-12-18 CA CA242,041A patent/CA1100960A/en not_active Expired
- 1975-12-18 LU LU74049A patent/LU74049A1/xx unknown
- 1975-12-18 DD DD190285A patent/DD122382A5/xx unknown
- 1975-12-19 JP JP50152699A patent/JPS5188985A/ja active Pending
- 1975-12-19 ES ES443692A patent/ES443692A1/es not_active Expired
- 1975-12-19 AT AT968875A patent/AT353794B/de not_active IP Right Cessation
- 1975-12-19 NL NL7514861A patent/NL7514861A/xx not_active Application Discontinuation
- 1975-12-19 CH CH1654475A patent/CH617193A5/de not_active IP Right Cessation
- 1975-12-19 DK DK583775A patent/DK583775A/da unknown
- 1975-12-19 IE IE2767/75A patent/IE42383B1/en unknown
-
1979
- 1979-03-22 IT IT7948446A patent/IT7948446A0/it unknown
- 1979-10-16 CH CH930679A patent/CH620685A5/de not_active IP Right Cessation
- 1979-10-16 CH CH930579A patent/CH618433A5/de not_active IP Right Cessation
Also Published As
| Publication number | Publication date |
|---|---|
| CH617193A5 (en, 2012) | 1980-05-14 |
| FR2294708A1 (fr) | 1976-07-16 |
| IL48665A0 (en) | 1976-02-29 |
| SE7514344L (sv) | 1976-06-21 |
| DD122382A5 (en, 2012) | 1976-10-05 |
| FR2294708B1 (en, 2012) | 1979-09-21 |
| ATA968875A (de) | 1979-05-15 |
| IT7948446A0 (it) | 1979-03-22 |
| US4232016A (en) | 1980-11-04 |
| CH620685A5 (en, 2012) | 1980-12-15 |
| NL7514861A (nl) | 1976-06-22 |
| ES443692A1 (es) | 1977-10-01 |
| JPS5188985A (en) | 1976-08-04 |
| CH618433A5 (en, 2012) | 1980-07-31 |
| LU74049A1 (en, 2012) | 1977-07-01 |
| CS188984B2 (en) | 1979-03-30 |
| GB1480559A (en) | 1977-07-20 |
| AT353794B (de) | 1979-12-10 |
| DK583775A (da) | 1976-06-21 |
| IE42383B1 (en) | 1980-07-30 |
| AU8760075A (en) | 1977-06-23 |
| IL48665A (en) | 1979-11-30 |
| IE42383L (en) | 1976-06-20 |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| MKEX | Expiry |