ES2875411T3 - Síntesis de trans-8-cloro-5-metil-1-[4-(piridin-2-iloxi)-ciclohexil]-5,6-dihidro-4h-2,3,5,10b-tetraazabenzo[e]azuleno y formas cristalinas del mismo - Google Patents
Síntesis de trans-8-cloro-5-metil-1-[4-(piridin-2-iloxi)-ciclohexil]-5,6-dihidro-4h-2,3,5,10b-tetraazabenzo[e]azuleno y formas cristalinas del mismo Download PDFInfo
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- ES2875411T3 ES2875411T3 ES14805290T ES14805290T ES2875411T3 ES 2875411 T3 ES2875411 T3 ES 2875411T3 ES 14805290 T ES14805290 T ES 14805290T ES 14805290 T ES14805290 T ES 14805290T ES 2875411 T3 ES2875411 T3 ES 2875411T3
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- 230000015572 biosynthetic process Effects 0.000 title description 12
- 238000003786 synthesis reaction Methods 0.000 title description 6
- GMPZPHGHNDMRKL-RZDIXWSQSA-N O([C@H]1CC[C@@H](CC1)C1=NN=C2CN(CC3=CC(Cl)=CC=C3N21)C)C1=CC=CC=N1 Chemical compound O([C@H]1CC[C@@H](CC1)C1=NN=C2CN(CC3=CC(Cl)=CC=C3N21)C)C1=CC=CC=N1 GMPZPHGHNDMRKL-RZDIXWSQSA-N 0.000 title description 2
- 150000001875 compounds Chemical class 0.000 claims abstract description 229
- 238000000034 method Methods 0.000 claims abstract description 83
- 230000008569 process Effects 0.000 claims abstract description 79
- 230000002194 synthesizing effect Effects 0.000 claims abstract description 45
- 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 abstract description 5
- NLFBCYMMUAKCPC-KQQUZDAGSA-N ethyl (e)-3-[3-amino-2-cyano-1-[(e)-3-ethoxy-3-oxoprop-1-enyl]sulfanyl-3-oxoprop-1-enyl]sulfanylprop-2-enoate Chemical compound CCOC(=O)\C=C\SC(=C(C#N)C(N)=O)S\C=C\C(=O)OCC NLFBCYMMUAKCPC-KQQUZDAGSA-N 0.000 claims abstract description 3
- 150000003839 salts Chemical class 0.000 claims description 13
- 239000012458 free base Substances 0.000 claims description 7
- HTSGKJQDMSTCGS-UHFFFAOYSA-N 1,4-bis(4-chlorophenyl)-2-(4-methylphenyl)sulfonylbutane-1,4-dione Chemical compound C1=CC(C)=CC=C1S(=O)(=O)C(C(=O)C=1C=CC(Cl)=CC=1)CC(=O)C1=CC=C(Cl)C=C1 HTSGKJQDMSTCGS-UHFFFAOYSA-N 0.000 claims 1
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 102
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 99
- 239000000725 suspension Substances 0.000 description 57
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 55
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- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 44
- 229960004592 isopropanol Drugs 0.000 description 41
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 39
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 39
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 37
- 230000002829 reductive effect Effects 0.000 description 37
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 33
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- 239000012074 organic phase Substances 0.000 description 29
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- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 27
- 239000011541 reaction mixture Substances 0.000 description 27
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 27
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- 238000006243 chemical reaction Methods 0.000 description 25
- 239000002904 solvent Substances 0.000 description 25
- BAVYZALUXZFZLV-UHFFFAOYSA-N Methylamine Chemical compound NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 description 24
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 24
- 239000012065 filter cake Substances 0.000 description 23
- 239000000543 intermediate Substances 0.000 description 23
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 22
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 22
- 239000000047 product Substances 0.000 description 22
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 22
- 235000017557 sodium bicarbonate Nutrition 0.000 description 22
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 20
- NLKNQRATVPKPDG-UHFFFAOYSA-M potassium iodide Chemical compound [K+].[I-] NLKNQRATVPKPDG-UHFFFAOYSA-M 0.000 description 19
- 229920006395 saturated elastomer Polymers 0.000 description 19
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 18
- 239000011780 sodium chloride Substances 0.000 description 18
- 238000002425 crystallisation Methods 0.000 description 17
- 230000008025 crystallization Effects 0.000 description 17
- 239000013078 crystal Substances 0.000 description 16
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 15
- 239000012043 crude product Substances 0.000 description 15
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- 150000002466 imines Chemical class 0.000 description 14
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- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 12
- RENMDAKOXSCIGH-UHFFFAOYSA-N Chloroacetonitrile Chemical compound ClCC#N RENMDAKOXSCIGH-UHFFFAOYSA-N 0.000 description 12
- 239000012279 sodium borohydride Substances 0.000 description 12
- 229910000033 sodium borohydride Inorganic materials 0.000 description 12
- 0 CN1Cc2cc(Cl)ccc2N2C(C(CC3)CCC3Oc3ccccn3)=N*C2C1 Chemical compound CN1Cc2cc(Cl)ccc2N2C(C(CC3)CCC3Oc3ccccn3)=N*C2C1 0.000 description 11
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 11
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 11
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 11
- 235000019341 magnesium sulphate Nutrition 0.000 description 11
- OAKJQQAXSVQMHS-UHFFFAOYSA-N Hydrazine Chemical compound NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 description 10
- -1 triazole compounds Chemical class 0.000 description 10
- 230000029936 alkylation Effects 0.000 description 9
- 238000000634 powder X-ray diffraction Methods 0.000 description 9
- ROHOPJILCIIOET-UHFFFAOYSA-N 4-chloro-2-(methylaminomethyl)aniline Chemical compound CNCC1=CC(Cl)=CC=C1N ROHOPJILCIIOET-UHFFFAOYSA-N 0.000 description 8
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 8
- KWYHDKDOAIKMQN-UHFFFAOYSA-N N,N,N',N'-tetramethylethylenediamine Chemical compound CN(C)CCN(C)C KWYHDKDOAIKMQN-UHFFFAOYSA-N 0.000 description 8
- 238000001237 Raman spectrum Methods 0.000 description 8
- RHQDFWAXVIIEBN-UHFFFAOYSA-N Trifluoroethanol Chemical compound OCC(F)(F)F RHQDFWAXVIIEBN-UHFFFAOYSA-N 0.000 description 8
- 238000005804 alkylation reaction Methods 0.000 description 8
- 239000006227 byproduct Substances 0.000 description 8
- 229910052799 carbon Inorganic materials 0.000 description 8
- 239000001257 hydrogen Substances 0.000 description 8
- 229910052739 hydrogen Inorganic materials 0.000 description 8
- 238000002329 infrared spectrum Methods 0.000 description 8
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical class CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 8
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 8
- 239000000376 reactant Substances 0.000 description 8
- 208000029560 autism spectrum disease Diseases 0.000 description 7
- 239000000539 dimer Substances 0.000 description 7
- GMPZPHGHNDMRKL-UHFFFAOYSA-N 8-chloro-5-methyl-1-(4-pyridin-2-yloxycyclohexyl)-4,6-dihydro-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine Chemical compound N12C3=CC=C(Cl)C=C3CN(C)CC2=NN=C1C(CC1)CCC1OC1=CC=CC=N1 GMPZPHGHNDMRKL-UHFFFAOYSA-N 0.000 description 6
- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 description 6
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 6
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 6
- 239000002585 base Substances 0.000 description 6
- 239000003153 chemical reaction reagent Substances 0.000 description 6
- 239000000706 filtrate Substances 0.000 description 6
- 238000006138 lithiation reaction Methods 0.000 description 6
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 6
- 239000003960 organic solvent Substances 0.000 description 6
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 description 6
- 238000000746 purification Methods 0.000 description 6
- 238000003756 stirring Methods 0.000 description 6
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- 150000001299 aldehydes Chemical class 0.000 description 5
- PFKFTWBEEFSNDU-UHFFFAOYSA-N carbonyldiimidazole Chemical compound C1=CN=CN1C(=O)N1C=CN=C1 PFKFTWBEEFSNDU-UHFFFAOYSA-N 0.000 description 5
- 238000002474 experimental method Methods 0.000 description 5
- 238000000605 extraction Methods 0.000 description 5
- 238000004128 high performance liquid chromatography Methods 0.000 description 5
- 238000010992 reflux Methods 0.000 description 5
- 230000002269 spontaneous effect Effects 0.000 description 5
- GLQPMEFDVJDHIN-UHFFFAOYSA-N 1-(5-chloro-2-nitrophenyl)-n-methylmethanamine Chemical compound CNCC1=CC(Cl)=CC=C1[N+]([O-])=O GLQPMEFDVJDHIN-UHFFFAOYSA-N 0.000 description 4
- OKDGRDCXVWSXDC-UHFFFAOYSA-N 2-chloropyridine Chemical compound ClC1=CC=CC=N1 OKDGRDCXVWSXDC-UHFFFAOYSA-N 0.000 description 4
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 4
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 4
- KXKVLQRXCPHEJC-UHFFFAOYSA-N acetic acid trimethyl ester Natural products COC(C)=O KXKVLQRXCPHEJC-UHFFFAOYSA-N 0.000 description 4
- WETWJCDKMRHUPV-UHFFFAOYSA-N acetyl chloride Chemical compound CC(Cl)=O WETWJCDKMRHUPV-UHFFFAOYSA-N 0.000 description 4
- 239000012346 acetyl chloride Substances 0.000 description 4
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- 150000001409 amidines Chemical class 0.000 description 4
- 238000004458 analytical method Methods 0.000 description 4
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- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 3
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 3
- QCQCHGYLTSGIGX-GHXANHINSA-N 4-[[(3ar,5ar,5br,7ar,9s,11ar,11br,13as)-5a,5b,8,8,11a-pentamethyl-3a-[(5-methylpyridine-3-carbonyl)amino]-2-oxo-1-propan-2-yl-4,5,6,7,7a,9,10,11,11b,12,13,13a-dodecahydro-3h-cyclopenta[a]chrysen-9-yl]oxy]-2,2-dimethyl-4-oxobutanoic acid Chemical compound N([C@@]12CC[C@@]3(C)[C@]4(C)CC[C@H]5C(C)(C)[C@@H](OC(=O)CC(C)(C)C(O)=O)CC[C@]5(C)[C@H]4CC[C@@H]3C1=C(C(C2)=O)C(C)C)C(=O)C1=CN=CC(C)=C1 QCQCHGYLTSGIGX-GHXANHINSA-N 0.000 description 3
- AVIOWTWKTMGTCW-UHFFFAOYSA-N 4-pyridin-2-yloxy-N'-(4-pyridin-2-yloxycyclohexanecarbonyl)cyclohexane-1-carbohydrazide Chemical compound N1=C(C=CC=C1)OC1CCC(CC1)C(=O)NNC(=O)C1CCC(CC1)OC1=NC=CC=C1 AVIOWTWKTMGTCW-UHFFFAOYSA-N 0.000 description 3
- MCNMIKLFMPMXNY-UHFFFAOYSA-N 7-chloro-4-methyl-3,5-dihydro-1,4-benzodiazepin-2-amine Chemical compound CN1CC2=C(C=CC(Cl)=C2)N=C(N)C1 MCNMIKLFMPMXNY-UHFFFAOYSA-N 0.000 description 3
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 3
- 206010003805 Autism Diseases 0.000 description 3
- 208000020706 Autistic disease Diseases 0.000 description 3
- OCQUVZIPPPRRFW-RZDIXWSQSA-N ClC1=CC(=C(N)C=C1)CN(CC=1OC(=NN1)[C@@H]1CC[C@H](CC1)OC1=NC=CC=C1)C Chemical compound ClC1=CC(=C(N)C=C1)CN(CC=1OC(=NN1)[C@@H]1CC[C@H](CC1)OC1=NC=CC=C1)C OCQUVZIPPPRRFW-RZDIXWSQSA-N 0.000 description 3
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 3
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- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 238000002441 X-ray diffraction Methods 0.000 description 3
- 239000000654 additive Substances 0.000 description 3
- 230000000996 additive effect Effects 0.000 description 3
- 150000001298 alcohols Chemical class 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 238000004090 dissolution Methods 0.000 description 3
- 238000001704 evaporation Methods 0.000 description 3
- 230000008020 evaporation Effects 0.000 description 3
- 235000019253 formic acid Nutrition 0.000 description 3
- WGOPGODQLGJZGL-UHFFFAOYSA-N lithium;butane Chemical compound [Li+].CC[CH-]C WGOPGODQLGJZGL-UHFFFAOYSA-N 0.000 description 3
- BSCCSDNZEIHXOK-UHFFFAOYSA-N phenyl carbamate Chemical compound NC(=O)OC1=CC=CC=C1 BSCCSDNZEIHXOK-UHFFFAOYSA-N 0.000 description 3
- IUGYQRQAERSCNH-UHFFFAOYSA-N pivalic acid Chemical compound CC(C)(C)C(O)=O IUGYQRQAERSCNH-UHFFFAOYSA-N 0.000 description 3
- 235000015497 potassium bicarbonate Nutrition 0.000 description 3
- 229910000028 potassium bicarbonate Inorganic materials 0.000 description 3
- 239000011736 potassium bicarbonate Substances 0.000 description 3
- IOLCXVTUBQKXJR-UHFFFAOYSA-M potassium bromide Inorganic materials [K+].[Br-] IOLCXVTUBQKXJR-UHFFFAOYSA-M 0.000 description 3
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 description 3
- 230000009257 reactivity Effects 0.000 description 3
- 239000011734 sodium Substances 0.000 description 3
- MFRIHAYPQRLWNB-UHFFFAOYSA-N sodium tert-butoxide Chemical compound [Na+].CC(C)(C)[O-] MFRIHAYPQRLWNB-UHFFFAOYSA-N 0.000 description 3
- 239000007787 solid Substances 0.000 description 3
- 239000007858 starting material Substances 0.000 description 3
- DIYBTHVWQJYHOY-UHFFFAOYSA-N tert-butyl N-[4-chloro-2-(methylaminomethyl)phenyl]carbamate Chemical compound ClC1=CC(=C(C=C1)NC(OC(C)(C)C)=O)CNC DIYBTHVWQJYHOY-UHFFFAOYSA-N 0.000 description 3
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 3
- PXLIDLJRIOVOTR-UHFFFAOYSA-N 1-(4-pyridin-2-yloxycyclohexyl)-5,6-dihydro-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine Chemical class C1CC(CCC1OC1=NC=CC=C1)C1=NN=C2CNCC3=C(C=CC=C3)N12 PXLIDLJRIOVOTR-UHFFFAOYSA-N 0.000 description 2
- BWZVCCNYKMEVEX-UHFFFAOYSA-N 2,4,6-Trimethylpyridine Chemical compound CC1=CC(C)=NC(C)=C1 BWZVCCNYKMEVEX-UHFFFAOYSA-N 0.000 description 2
- 150000005749 2-halopyridines Chemical class 0.000 description 2
- JQQUCVRHWINPAR-UHFFFAOYSA-N 4-chloro-2-(methylaminomethyl)aniline dihydrochloride Chemical compound Cl.Cl.ClC1=CC(=C(N)C=C1)CNC JQQUCVRHWINPAR-UHFFFAOYSA-N 0.000 description 2
- RBLOMVCPJAWDNW-UHFFFAOYSA-N 4-chloro-2-(methylaminomethyl)aniline hydrochloride Chemical compound Cl.ClC1=CC(=C(N)C=C1)CNC RBLOMVCPJAWDNW-UHFFFAOYSA-N 0.000 description 2
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- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 2
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- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 2
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- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
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- 229940066842 petrolatum Drugs 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- 229910052697 platinum Inorganic materials 0.000 description 1
- 239000003880 polar aprotic solvent Substances 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 235000011181 potassium carbonates Nutrition 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 238000012545 processing Methods 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 238000005932 reductive alkylation reaction Methods 0.000 description 1
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Classifications
-
- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
- A61K31/551—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having two nitrogen atoms, e.g. dilazep
- A61K31/5513—1,4-Benzodiazepines, e.g. diazepam or clozapine
- A61K31/5517—1,4-Benzodiazepines, e.g. diazepam or clozapine condensed with five-membered rings having nitrogen as a ring hetero atom, e.g. imidazobenzodiazepines, triazolam
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
-
- 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/13—Crystalline forms, e.g. polymorphs
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Animal Behavior & Ethology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Medicinal Chemistry (AREA)
- Epidemiology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Neurosurgery (AREA)
- Neurology (AREA)
- Engineering & Computer Science (AREA)
- General Chemical & Material Sciences (AREA)
- Biomedical Technology (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Other In-Based Heterocyclic Compounds (AREA)
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| EP13195864 | 2013-12-05 | ||
| PCT/EP2014/076041 WO2015082370A1 (en) | 2013-12-05 | 2014-12-01 | Synthesis of trans-8-chloro-5-methyl-1 -[4-(pyridin-2-yloxy)-cyclohexyl]-5,6-dihydro-4h-2,3,5,10b-tetraaza-benzo[e]azulene and crytalline forms thereof |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| ES2875411T3 true ES2875411T3 (es) | 2021-11-10 |
Family
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Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| ES14805290T Active ES2875411T3 (es) | 2013-12-05 | 2014-12-01 | Síntesis de trans-8-cloro-5-metil-1-[4-(piridin-2-iloxi)-ciclohexil]-5,6-dihidro-4h-2,3,5,10b-tetraazabenzo[e]azuleno y formas cristalinas del mismo |
Country Status (19)
| Country | Link |
|---|---|
| US (3) | US10246460B2 (OSRAM) |
| EP (1) | EP3077396B1 (OSRAM) |
| JP (1) | JP6454707B2 (OSRAM) |
| KR (3) | KR102384629B1 (OSRAM) |
| CN (1) | CN105793263B (OSRAM) |
| AR (1) | AR098592A1 (OSRAM) |
| AU (2) | AU2014359409A1 (OSRAM) |
| CA (2) | CA3142754C (OSRAM) |
| ES (1) | ES2875411T3 (OSRAM) |
| HR (1) | HRP20210966T1 (OSRAM) |
| IL (2) | IL245450A0 (OSRAM) |
| MX (1) | MX372971B (OSRAM) |
| MY (1) | MY175464A (OSRAM) |
| NZ (1) | NZ720340A (OSRAM) |
| PL (1) | PL3077396T3 (OSRAM) |
| SG (1) | SG11201604502SA (OSRAM) |
| SI (1) | SI3077396T1 (OSRAM) |
| WO (1) | WO2015082370A1 (OSRAM) |
| ZA (1) | ZA201603304B (OSRAM) |
Families Citing this family (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| HRP20210966T1 (hr) | 2013-12-05 | 2021-09-17 | F. Hoffmann - La Roche Ag | Sinteza trans-8-kloro-5-metil-1-[4-(piridin-2-iloksi)-cikloheksil]-5,6-dihidro-4h-2,3,5,10b-tetraazabenzo[e]azulena i njegovih kristalnih oblika |
| WO2017191117A1 (en) | 2016-05-03 | 2017-11-09 | Bayer Pharma Aktiengesellschaft | V1a receptor antagonists for use in the treatment of renal diseases |
| TWI816718B (zh) | 2017-12-08 | 2023-10-01 | 瑞士商赫孚孟拉羅股份公司 | 醫藥調配物 |
| WO2020139670A1 (en) | 2018-12-27 | 2020-07-02 | Teva Pharmaceuticals International Gmbh | Solid state forms of balovaptan |
| US20240154207A1 (en) | 2021-10-06 | 2024-05-09 | Lg Energy Solution, Ltd. | Battery module |
Family Cites Families (11)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CA1197242A (en) * | 1983-03-02 | 1985-11-26 | Jean A. Gauthier | Pyrimido¬1,2-a|pyrrolo¬2,1-c|¬1, 4|benzodiazepine-3-carboxylic acid derivatives |
| DE602004003914T2 (de) * | 2003-02-19 | 2007-05-31 | Pfizer Inc. | Für die therapie geeignete triazolverbindungen |
| GB0303852D0 (en) | 2003-02-19 | 2003-03-26 | Pfizer Ltd | Triazole compounds useful in therapy |
| GB0400700D0 (en) | 2004-01-13 | 2004-02-18 | Pfizer Ltd | Compounds useful in therapy |
| WO2006021882A1 (en) | 2004-08-25 | 2006-03-02 | Pfizer Limited | Triazolobenzodiazepines and their use as vasopressin antagonists |
| US7601715B2 (en) * | 2005-06-22 | 2009-10-13 | Bristol-Myers Squibb Company | Process for preparing triazole substituted azaindoleoxoacetic piperazine derivatives and novel salt forms produced therein |
| KR101385433B1 (ko) * | 2008-11-18 | 2014-04-14 | 에프. 호프만-라 로슈 아게 | 다이하이드로테트라아자벤조아줄렌의 알킬사이클로헥실에터 |
| DK2370441T3 (da) * | 2008-11-28 | 2013-10-21 | Hoffmann La Roche | Arylcyclohexylethere af dihydrotetraazabenzoazulener til anvendelse som vasopressin v1a-receptorantagonister |
| US8492376B2 (en) | 2010-04-21 | 2013-07-23 | Hoffmann-La Roche Inc. | Heteroaryl-cyclohexyl-tetraazabenzo[e]azulenes |
| CN105492010B (zh) | 2013-08-19 | 2020-01-03 | 豪夫迈·罗氏有限公司 | 用于治疗相移睡眠障碍的V1a拮抗剂 |
| HRP20210966T1 (hr) * | 2013-12-05 | 2021-09-17 | F. Hoffmann - La Roche Ag | Sinteza trans-8-kloro-5-metil-1-[4-(piridin-2-iloksi)-cikloheksil]-5,6-dihidro-4h-2,3,5,10b-tetraazabenzo[e]azulena i njegovih kristalnih oblika |
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2014
- 2014-12-01 HR HRP20210966TT patent/HRP20210966T1/hr unknown
- 2014-12-01 SI SI201431838T patent/SI3077396T1/sl unknown
- 2014-12-01 MX MX2016006558A patent/MX372971B/es active IP Right Grant
- 2014-12-01 WO PCT/EP2014/076041 patent/WO2015082370A1/en not_active Ceased
- 2014-12-01 AU AU2014359409A patent/AU2014359409A1/en not_active Abandoned
- 2014-12-01 MY MYPI2016000870A patent/MY175464A/en unknown
- 2014-12-01 NZ NZ720340A patent/NZ720340A/en unknown
- 2014-12-01 KR KR1020217034768A patent/KR102384629B1/ko active Active
- 2014-12-01 PL PL14805290T patent/PL3077396T3/pl unknown
- 2014-12-01 CN CN201480065960.4A patent/CN105793263B/zh active Active
- 2014-12-01 SG SG11201604502SA patent/SG11201604502SA/en unknown
- 2014-12-01 CA CA3142754A patent/CA3142754C/en active Active
- 2014-12-01 KR KR1020167017925A patent/KR102384608B1/ko active Active
- 2014-12-01 JP JP2016536746A patent/JP6454707B2/ja active Active
- 2014-12-01 EP EP14805290.5A patent/EP3077396B1/en active Active
- 2014-12-01 ES ES14805290T patent/ES2875411T3/es active Active
- 2014-12-01 CA CA2931016A patent/CA2931016C/en active Active
- 2014-12-01 KR KR1020217034765A patent/KR102384630B1/ko active Active
- 2014-12-03 AR ARP140104488A patent/AR098592A1/es unknown
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2016
- 2016-05-03 IL IL245450A patent/IL245450A0/en unknown
- 2016-05-16 ZA ZA2016/03304A patent/ZA201603304B/en unknown
- 2016-06-03 US US15/172,542 patent/US10246460B2/en active Active
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2019
- 2019-02-18 IL IL264891A patent/IL264891B/en active IP Right Grant
- 2019-02-20 AU AU2019201183A patent/AU2019201183B2/en active Active
- 2019-03-04 US US16/291,887 patent/US11040977B2/en active Active
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2021
- 2021-06-03 US US17/337,547 patent/US12459947B2/en active Active
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