NZ759478B2 - 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 crystalline forms thereof - Google Patents
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 crystalline forms thereofInfo
- Publication number
- NZ759478B2 NZ759478B2 NZ759478A NZ75947814A NZ759478B2 NZ 759478 B2 NZ759478 B2 NZ 759478B2 NZ 759478 A NZ759478 A NZ 759478A NZ 75947814 A NZ75947814 A NZ 75947814A NZ 759478 B2 NZ759478 B2 NZ 759478B2
- Authority
- NZ
- New Zealand
- Prior art keywords
- compound
- formula
- mmol
- added
- methyl
- Prior art date
Links
- 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 abstract 2
- 230000015572 biosynthetic process Effects 0.000 title description 10
- 238000003786 synthesis reaction Methods 0.000 title description 5
- 230000002194 synthesizing Effects 0.000 title description 5
- 150000001875 compounds Chemical class 0.000 claims abstract description 260
- 238000000034 method Methods 0.000 claims abstract description 83
- 239000000543 intermediate Substances 0.000 abstract description 25
- 238000004519 manufacturing process Methods 0.000 abstract 1
- OKKJLVBELUTLKV-UHFFFAOYSA-N methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 64
- VEXZGXHMUGYJMC-UHFFFAOYSA-N HCl Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 60
- WYURNTSHIVDZCO-UHFFFAOYSA-N tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 54
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 52
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 52
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 49
- 239000000725 suspension Substances 0.000 description 46
- KFZMGEQAYNKOFK-UHFFFAOYSA-N iso-propanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 45
- XEKOWRVHYACXOJ-UHFFFAOYSA-N acetic acid ethyl ester Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 41
- -1 TRANSCHLOROMETHYL-1 -[4-(PYRIDINYLOXY)- CYCLOHEXYL]-5,6-DIHYDRO-4H-2,3,5,10B-TETRAAZA-BENZO[E]AZULENE Chemical compound 0.000 description 40
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 39
- UIIMBOGNXHQVGW-UHFFFAOYSA-M NaHCO3 Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 38
- FAPWRFPIFSIZLT-UHFFFAOYSA-M sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 37
- QTBSBXVTEAMEQO-UHFFFAOYSA-N acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 36
- 239000011780 sodium chloride Substances 0.000 description 35
- 230000002829 reduced Effects 0.000 description 33
- 238000000634 powder X-ray diffraction Methods 0.000 description 29
- HEMHJVSKTPXQMS-UHFFFAOYSA-M sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 27
- 239000000203 mixture Substances 0.000 description 26
- 239000012074 organic phase Substances 0.000 description 26
- 238000006243 chemical reaction Methods 0.000 description 25
- 239000011541 reaction mixture Substances 0.000 description 24
- BZLVMXJERCGZMT-UHFFFAOYSA-N MeOtBu Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 23
- 239000012065 filter cake Substances 0.000 description 23
- NLKNQRATVPKPDG-UHFFFAOYSA-M Potassium iodide Chemical compound [K+].[I-] NLKNQRATVPKPDG-UHFFFAOYSA-M 0.000 description 22
- YMWUJEATGCHHMB-UHFFFAOYSA-N methylene dichloride Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 22
- 239000000047 product Substances 0.000 description 21
- WEVYAHXRMPXWCK-UHFFFAOYSA-N acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 20
- 239000002904 solvent Substances 0.000 description 20
- 235000017557 sodium bicarbonate Nutrition 0.000 description 19
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 19
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 16
- 238000002425 crystallisation Methods 0.000 description 16
- 230000005712 crystallization Effects 0.000 description 16
- 150000003839 salts Chemical class 0.000 description 16
- 238000001237 Raman spectrum Methods 0.000 description 15
- 239000000843 powder Substances 0.000 description 15
- YOQDYZUWIQVZSF-UHFFFAOYSA-N sodium borohydride Substances [BH4-].[Na+] YOQDYZUWIQVZSF-UHFFFAOYSA-N 0.000 description 15
- 239000008346 aqueous phase Substances 0.000 description 14
- 150000002466 imines Chemical class 0.000 description 14
- BAVYZALUXZFZLV-UHFFFAOYSA-N methylamine Chemical compound NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 description 13
- CSNNHWWHGAXBCP-UHFFFAOYSA-L mgso4 Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 13
- MZRVEZGGRBJDDB-UHFFFAOYSA-N n-Butyllithium Substances [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 13
- CSCPPACGZOOCGX-UHFFFAOYSA-N acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 12
- 238000002329 infrared spectrum Methods 0.000 description 12
- 238000006722 reduction reaction Methods 0.000 description 12
- 229910000033 sodium borohydride Inorganic materials 0.000 description 12
- 239000012043 crude product Substances 0.000 description 11
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 11
- 235000019341 magnesium sulphate Nutrition 0.000 description 11
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- OAKJQQAXSVQMHS-UHFFFAOYSA-N hydrazine Chemical compound NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 description 10
- SECXISVLQFMRJM-UHFFFAOYSA-N n-methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 10
- YXFVVABEGXRONW-UHFFFAOYSA-N toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 10
- 239000000539 dimer Substances 0.000 description 9
- 229940093499 ethyl acetate Drugs 0.000 description 9
- 235000019439 ethyl acetate Nutrition 0.000 description 9
- BDAGIHXWWSANSR-UHFFFAOYSA-N formic acid Chemical compound OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 9
- 239000012458 free base Substances 0.000 description 9
- IMNFDUFMRHMDMM-UHFFFAOYSA-N n-heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 9
- ODGROJYWQXFQOZ-UHFFFAOYSA-N sodium;boron(1-) Chemical compound [B-].[Na+] ODGROJYWQXFQOZ-UHFFFAOYSA-N 0.000 description 9
- RHQDFWAXVIIEBN-UHFFFAOYSA-N 2,2,2-trifluoroethyl alcohol Chemical compound OCC(F)(F)F RHQDFWAXVIIEBN-UHFFFAOYSA-N 0.000 description 8
- 238000007792 addition Methods 0.000 description 8
- 238000005804 alkylation reaction Methods 0.000 description 7
- KXKVLQRXCPHEJC-UHFFFAOYSA-N Methyl acetate Natural products COC(C)=O KXKVLQRXCPHEJC-UHFFFAOYSA-N 0.000 description 6
- KWYHDKDOAIKMQN-UHFFFAOYSA-N Tetramethylethylenediamine Chemical compound CN(C)CCN(C)C KWYHDKDOAIKMQN-UHFFFAOYSA-N 0.000 description 6
- 239000002253 acid Substances 0.000 description 6
- 239000006227 byproduct Substances 0.000 description 6
- 239000003153 chemical reaction reagent Substances 0.000 description 6
- 239000000706 filtrate Substances 0.000 description 6
- UFHFLCQGNIYNRP-UHFFFAOYSA-N hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 6
- 239000001257 hydrogen Substances 0.000 description 6
- 229910052739 hydrogen Inorganic materials 0.000 description 6
- 238000006138 lithiation reaction Methods 0.000 description 6
- 239000003960 organic solvent Substances 0.000 description 6
- 239000012071 phase Substances 0.000 description 6
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 description 6
- KWYUFKZDYYNOTN-UHFFFAOYSA-M potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 6
- 238000010992 reflux Methods 0.000 description 6
- 239000002002 slurry Substances 0.000 description 6
- 239000011734 sodium Substances 0.000 description 6
- 229910052708 sodium Inorganic materials 0.000 description 6
- CDBYLPFSWZWCQE-UHFFFAOYSA-L sodium carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 6
- DTQVDTLACAAQTR-UHFFFAOYSA-N trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 6
- 150000001409 amidines Chemical class 0.000 description 5
- 239000002585 base Substances 0.000 description 5
- 210000004027 cells Anatomy 0.000 description 5
- 238000001704 evaporation Methods 0.000 description 5
- 238000005755 formation reaction Methods 0.000 description 5
- 238000004128 high performance liquid chromatography Methods 0.000 description 5
- 150000002500 ions Chemical class 0.000 description 5
- 238000000746 purification Methods 0.000 description 5
- 239000000376 reactant Substances 0.000 description 5
- KEAYESYHFKHZAL-UHFFFAOYSA-N sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 5
- 238000001228 spectrum Methods 0.000 description 5
- 230000002269 spontaneous 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
- AFABGHUZZDYHJO-UHFFFAOYSA-N 2-Methylpentane Chemical class CCCC(C)C AFABGHUZZDYHJO-UHFFFAOYSA-N 0.000 description 4
- WETWJCDKMRHUPV-UHFFFAOYSA-N Acetyl chloride Chemical compound CC(Cl)=O WETWJCDKMRHUPV-UHFFFAOYSA-N 0.000 description 4
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate dianion Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 description 4
- DIYBTHVWQJYHOY-UHFFFAOYSA-N ClC1=CC(=C(C=C1)NC(OC(C)(C)C)=O)CNC Chemical compound ClC1=CC(=C(C=C1)NC(OC(C)(C)C)=O)CNC DIYBTHVWQJYHOY-UHFFFAOYSA-N 0.000 description 4
- 239000012346 acetyl chloride Substances 0.000 description 4
- 150000001299 aldehydes Chemical class 0.000 description 4
- 238000004458 analytical method Methods 0.000 description 4
- HUYREUUJFLHEDE-UHFFFAOYSA-N cyclohexanecarbohydrazide Chemical compound NNC(=O)C1CCCCC1 HUYREUUJFLHEDE-UHFFFAOYSA-N 0.000 description 4
- 201000010099 disease Diseases 0.000 description 4
- 238000004090 dissolution Methods 0.000 description 4
- 238000000605 extraction Methods 0.000 description 4
- 239000008079 hexane Substances 0.000 description 4
- SJRJJKPEHAURKC-UHFFFAOYSA-N n-methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 description 4
- IOLCXVTUBQKXJR-UHFFFAOYSA-M potassium bromide Inorganic materials [K+].[Br-] IOLCXVTUBQKXJR-UHFFFAOYSA-M 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- 239000000758 substrate Substances 0.000 description 4
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 3
- JWUJQDFVADABEY-UHFFFAOYSA-N 2-Methyltetrahydrofuran Chemical compound CC1CCCO1 JWUJQDFVADABEY-UHFFFAOYSA-N 0.000 description 3
- XVFQUYFLVVKQLO-OVCLIPMQSA-N ClC1=CC(=C(C=C1)NC(OC(C)(C)C)=O)/C=N/C Chemical compound ClC1=CC(=C(C=C1)NC(OC(C)(C)C)=O)/C=N/C XVFQUYFLVVKQLO-OVCLIPMQSA-N 0.000 description 3
- CYYOZYIZQCTUKF-UHFFFAOYSA-N ClC1=CC(=C(C=C1)NC(OC(C)(C)C)=O)CN(C)CC#N Chemical compound ClC1=CC(=C(C=C1)NC(OC(C)(C)C)=O)CN(C)CC#N CYYOZYIZQCTUKF-UHFFFAOYSA-N 0.000 description 3
- FXHOOIRPVKKKFG-UHFFFAOYSA-N DMA Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-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
- MFRIHAYPQRLWNB-UHFFFAOYSA-N Sodium tert-butoxide Chemical compound [Na+].CC(C)(C)[O-] MFRIHAYPQRLWNB-UHFFFAOYSA-N 0.000 description 3
- 238000002441 X-ray diffraction Methods 0.000 description 3
- 230000004913 activation Effects 0.000 description 3
- 239000000654 additive Substances 0.000 description 3
- 230000000996 additive 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
- 238000001035 drying Methods 0.000 description 3
- 235000019253 formic acid Nutrition 0.000 description 3
- 150000003840 hydrochlorides Chemical class 0.000 description 3
- 239000007788 liquid Substances 0.000 description 3
- LRHPLDYGYMQRHN-UHFFFAOYSA-N n-butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 3
- BDERNNFJNOPAEC-UHFFFAOYSA-N propanol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 3
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 3
- 229910000029 sodium carbonate Inorganic materials 0.000 description 3
- 235000017550 sodium carbonate Nutrition 0.000 description 3
- 239000007787 solid Substances 0.000 description 3
- 239000007858 starting material Substances 0.000 description 3
- 150000004684 trihydrates Chemical class 0.000 description 3
- VZCYOOQTPOCHFL-OWOJBTEDSA-N (E)-but-2-enedioate;hydron Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-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
- UIIJZQVROQHLAP-UHFFFAOYSA-N 2-methyl-2-(2-methylbutan-2-yloxy)butane;sodium Chemical compound [Na].CCC(C)(C)OC(C)(C)CC UIIJZQVROQHLAP-UHFFFAOYSA-N 0.000 description 2
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonium chloride Substances [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 2
- 206010003805 Autism Diseases 0.000 description 2
- TVFDJXOCXUVLDH-UHFFFAOYSA-N Cesium Chemical compound [Cs] TVFDJXOCXUVLDH-UHFFFAOYSA-N 0.000 description 2
- VGBKIVYOXOPKMH-XYPYZODXSA-N ClCC=1OC(=NN=1)[C@@H]1CC[C@H](CC1)OC1=NC=CC=C1 Chemical compound ClCC=1OC(=NN=1)[C@@H]1CC[C@H](CC1)OC1=NC=CC=C1 VGBKIVYOXOPKMH-XYPYZODXSA-N 0.000 description 2
- FUZZWVXGSFPDMH-UHFFFAOYSA-N Hexanoic acid Chemical compound CCCCCC(O)=O FUZZWVXGSFPDMH-UHFFFAOYSA-N 0.000 description 2
- AVIOWTWKTMGTCW-UHFFFAOYSA-N N1=C(C=CC=C1)OC1CCC(CC1)C(=O)NNC(=O)C1CCC(CC1)OC1=NC=CC=C1 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 2
- 229960003975 Potassium Drugs 0.000 description 2
- TYJJADVDDVDEDZ-UHFFFAOYSA-M Potassium bicarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 description 2
- 239000007868 Raney catalyst Substances 0.000 description 2
- 229910000564 Raney nickel Inorganic materials 0.000 description 2
- AKHNMLFCWUSKQB-UHFFFAOYSA-L Sodium thiosulphate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=S AKHNMLFCWUSKQB-UHFFFAOYSA-L 0.000 description 2
- 239000008186 active pharmaceutical agent Substances 0.000 description 2
- 235000019270 ammonium chloride Nutrition 0.000 description 2
- 201000002055 autistic disease Diseases 0.000 description 2
- 229910052792 caesium Inorganic materials 0.000 description 2
- OKTJSMMVPCPJKN-UHFFFAOYSA-N carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 2
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 2
- 239000003054 catalyst Substances 0.000 description 2
- 238000004587 chromatography analysis Methods 0.000 description 2
- 238000004891 communication Methods 0.000 description 2
- 230000000875 corresponding Effects 0.000 description 2
- 230000003247 decreasing Effects 0.000 description 2
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 2
- 239000002270 dispersing agent Substances 0.000 description 2
- 239000006185 dispersion Substances 0.000 description 2
- AINBZKYUNWUTRE-UHFFFAOYSA-N ethanol;propan-2-ol Chemical compound CCO.CC(C)O AINBZKYUNWUTRE-UHFFFAOYSA-N 0.000 description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 2
- IKDUDTNKRLTJSI-UHFFFAOYSA-N hydrazine hydrate Chemical compound O.NN IKDUDTNKRLTJSI-UHFFFAOYSA-N 0.000 description 2
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Substances C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 2
- 238000011065 in-situ storage Methods 0.000 description 2
- 238000002955 isolation Methods 0.000 description 2
- WGOPGODQLGJZGL-UHFFFAOYSA-N lithium;butane Chemical compound [Li+].CC[CH-]C WGOPGODQLGJZGL-UHFFFAOYSA-N 0.000 description 2
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- 230000001264 neutralization Effects 0.000 description 2
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- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
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- 230000001131 transforming Effects 0.000 description 2
- WJKHJLXJJJATHN-UHFFFAOYSA-N triflic anhydride Chemical compound FC(F)(F)S(=O)(=O)OS(=O)(=O)C(F)(F)F WJKHJLXJJJATHN-UHFFFAOYSA-N 0.000 description 2
- 230000001755 vocal Effects 0.000 description 2
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- GXMBHQRROXQUJS-UHFFFAOYSA-N (2-hept-2-ynylsulfanylphenyl) acetate Chemical compound CCCCC#CCSC1=CC=CC=C1OC(C)=O GXMBHQRROXQUJS-UHFFFAOYSA-N 0.000 description 1
- PFKFTWBEEFSNDU-UHFFFAOYSA-N 1,1'-Carbonyldiimidazole Substances C1=CN=CN1C(=O)N1C=CN=C1 PFKFTWBEEFSNDU-UHFFFAOYSA-N 0.000 description 1
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- OBETXYAYXDNJHR-UHFFFAOYSA-N 2-Ethylhexanoic acid Chemical compound CCCCC(CC)C(O)=O OBETXYAYXDNJHR-UHFFFAOYSA-N 0.000 description 1
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- MTAODLNXWYIKSO-UHFFFAOYSA-N 2-fluoropyridine Chemical compound FC1=CC=CC=N1 MTAODLNXWYIKSO-UHFFFAOYSA-N 0.000 description 1
- YOETUEMZNOLGDB-UHFFFAOYSA-N 2-methylpropyl carbonochloridate Chemical compound CC(C)COC(Cl)=O YOETUEMZNOLGDB-UHFFFAOYSA-N 0.000 description 1
- CNJLMVZFWLNOEP-UHFFFAOYSA-N 4,7,7-trimethylbicyclo[4.1.0]heptan-5-one Chemical compound O=C1C(C)CCC2C(C)(C)C12 CNJLMVZFWLNOEP-UHFFFAOYSA-N 0.000 description 1
- HCFRWBBJISAZNK-UHFFFAOYSA-N 4-Hydroxycyclohexylcarboxylic acid Chemical compound OC1CCC(C(O)=O)CC1 HCFRWBBJISAZNK-UHFFFAOYSA-N 0.000 description 1
- UPPAITGJPSHRNY-UHFFFAOYSA-N 4-pyridin-2-yloxycyclohexane-1-carbohydrazide Chemical compound C1CC(C(=O)NN)CCC1OC1=CC=CC=N1 UPPAITGJPSHRNY-UHFFFAOYSA-N 0.000 description 1
- 206010001488 Aggression Diseases 0.000 description 1
- MMCPOSDMTGQNKG-UHFFFAOYSA-N Anilinium chloride Chemical compound Cl.NC1=CC=CC=C1 MMCPOSDMTGQNKG-UHFFFAOYSA-N 0.000 description 1
- 210000004556 Brain Anatomy 0.000 description 1
- PXLIDLJRIOVOTR-UHFFFAOYSA-N C1CC(CCC1OC1=NC=CC=C1)C1=NN=C2CNCC3=C(C=CC=C3)N12 Chemical class C1CC(CCC1OC1=NC=CC=C1)C1=NN=C2CNCC3=C(C=CC=C3)N12 PXLIDLJRIOVOTR-UHFFFAOYSA-N 0.000 description 1
- ABVXUOGYISONHH-UHFFFAOYSA-N CC(C)(C)OC(=O)N(Cl)c1ccccc1 Chemical compound CC(C)(C)OC(=O)N(Cl)c1ccccc1 ABVXUOGYISONHH-UHFFFAOYSA-N 0.000 description 1
- GRJYSZPQKJLBQD-UHFFFAOYSA-N CC(O)=O.CNCC1=C(NC(=O)OC(C)(C)C)C=CC(Cl)=C1 Chemical compound CC(O)=O.CNCC1=C(NC(=O)OC(C)(C)C)C=CC(Cl)=C1 GRJYSZPQKJLBQD-UHFFFAOYSA-N 0.000 description 1
- ZJLWFTUEMINHAP-UHFFFAOYSA-N CN=CC1=C(C=CC(Cl)=C1)[N+]([O-])=O Chemical compound CN=CC1=C(C=CC(Cl)=C1)[N+]([O-])=O ZJLWFTUEMINHAP-UHFFFAOYSA-N 0.000 description 1
- 206010008522 Childhood disintegrative disease Diseases 0.000 description 1
- VGCXGMAHQTYDJK-UHFFFAOYSA-N Chloroacetyl chloride Chemical compound ClCC(Cl)=O VGCXGMAHQTYDJK-UHFFFAOYSA-N 0.000 description 1
- CQSAQPJDRJUUMC-UHFFFAOYSA-N Cl.ClC=1C=CC(=C(C1)CNC)[N+](=O)[O-] Chemical compound Cl.ClC=1C=CC(=C(C1)CNC)[N+](=O)[O-] CQSAQPJDRJUUMC-UHFFFAOYSA-N 0.000 description 1
- GDZCIESJLLVZEG-UHFFFAOYSA-M ClC(=O)C1=CC=C(C=C1)NC([O-])=O Chemical compound ClC(=O)C1=CC=C(C=C1)NC([O-])=O GDZCIESJLLVZEG-UHFFFAOYSA-M 0.000 description 1
- NZNMSOFKMUBTKW-UHFFFAOYSA-N Cyclohexanecarboxylic acid Chemical compound OC(=O)C1CCCCC1 NZNMSOFKMUBTKW-UHFFFAOYSA-N 0.000 description 1
- 210000004544 DC2 Anatomy 0.000 description 1
- 206010012401 Depressive disease Diseases 0.000 description 1
- 238000005033 Fourier transform infrared spectroscopy Methods 0.000 description 1
- 102100014726 MECP2 Human genes 0.000 description 1
- 101700029603 MECP2 Proteins 0.000 description 1
- BJEPYKJPYRNKOW-UHFFFAOYSA-N Malic acid Chemical compound OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 description 1
- FEWJPZIEWOKRBE-XIXRPRMCSA-N Mesotartaric acid Chemical compound OC(=O)[C@@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-XIXRPRMCSA-N 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- NVSOSQNIJKZFBR-UHFFFAOYSA-N N'-[2-(ethylamino)ethyl]ethane-1,2-diamine Chemical compound CCNCCNCCN NVSOSQNIJKZFBR-UHFFFAOYSA-N 0.000 description 1
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 1
- OSVUJQHZNJQNRQ-UHFFFAOYSA-N N1=C(C=CC=C1)OC1(CCCCC1)C(=O)O Chemical compound N1=C(C=CC=C1)OC1(CCCCC1)C(=O)O OSVUJQHZNJQNRQ-UHFFFAOYSA-N 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-N P-Toluenesulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
- UKODFQOELJFMII-UHFFFAOYSA-N PMDTA Chemical compound CN(C)CCN(C)CCN(C)C UKODFQOELJFMII-UHFFFAOYSA-N 0.000 description 1
- LPNYRYFBWFDTMA-UHFFFAOYSA-N Potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 1
- 102000014961 Protein Precursors Human genes 0.000 description 1
- 108010078762 Protein Precursors Proteins 0.000 description 1
- 238000001069 Raman spectroscopy Methods 0.000 description 1
- 208000006289 Rett Syndrome Diseases 0.000 description 1
- CBXWGGFGZDVPNV-UHFFFAOYSA-N SO4-SO4 Chemical compound OS(O)(=O)=O.OS(O)(=O)=O CBXWGGFGZDVPNV-UHFFFAOYSA-N 0.000 description 1
- VATDYQWILMGLEW-UHFFFAOYSA-N Sec-Butyllithium Chemical compound [Li]C(C)CC VATDYQWILMGLEW-UHFFFAOYSA-N 0.000 description 1
- 206010040984 Sleep disease Diseases 0.000 description 1
- 230000002378 acidificating Effects 0.000 description 1
- 125000002252 acyl group Chemical group 0.000 description 1
- 230000016571 aggressive behavior Effects 0.000 description 1
- 230000001476 alcoholic Effects 0.000 description 1
- 125000000217 alkyl group Chemical group 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- USFZMSVCRYTOJT-UHFFFAOYSA-N ammonium acetate Chemical compound N.CC(O)=O USFZMSVCRYTOJT-UHFFFAOYSA-N 0.000 description 1
- 239000000010 aprotic solvent Substances 0.000 description 1
- KBZOIRJILGZLEJ-LGYYRGKSSA-N argipressin Chemical compound C([C@H]1C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CSSC[C@@H](C(N[C@@H](CC=2C=CC(O)=CC=2)C(=O)N1)=O)N)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CCCN=C(N)N)C(=O)NCC(N)=O)C1=CC=CC=C1 KBZOIRJILGZLEJ-LGYYRGKSSA-N 0.000 description 1
- 125000003118 aryl group Chemical group 0.000 description 1
- 239000012298 atmosphere Substances 0.000 description 1
- 201000007185 autism spectrum disease Diseases 0.000 description 1
- 150000001545 azulenes Chemical class 0.000 description 1
- 230000006399 behavior Effects 0.000 description 1
- 230000003542 behavioural Effects 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-M bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 1
- KXDHJXZQYSOELW-UHFFFAOYSA-M carbamate Chemical compound NC([O-])=O KXDHJXZQYSOELW-UHFFFAOYSA-M 0.000 description 1
- AOGYCOYQMAVAFD-UHFFFAOYSA-M carbonochloridate Chemical compound [O-]C(Cl)=O AOGYCOYQMAVAFD-UHFFFAOYSA-M 0.000 description 1
- 238000009903 catalytic hydrogenation reaction Methods 0.000 description 1
- 150000001768 cations Chemical class 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
- IXCSERBJSXMMFS-UHFFFAOYSA-M chloride;hydrochloride Chemical compound Cl.[Cl-] IXCSERBJSXMMFS-UHFFFAOYSA-M 0.000 description 1
- 229910052681 coesite Inorganic materials 0.000 description 1
- 230000001149 cognitive Effects 0.000 description 1
- 229910052906 cristobalite Inorganic materials 0.000 description 1
- 239000000287 crude extract Substances 0.000 description 1
- 238000010511 deprotection reaction Methods 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 230000002708 enhancing Effects 0.000 description 1
- 238000011067 equilibration Methods 0.000 description 1
- FFLYUXVZEPLMCL-UHFFFAOYSA-N ethylchloranuidyl formate Chemical group CC[Cl-]OC=O FFLYUXVZEPLMCL-UHFFFAOYSA-N 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 239000000284 extract Substances 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- VZCYOOQTPOCHFL-UHFFFAOYSA-N fumaric acid Chemical compound OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 1
- 239000001530 fumaric acid Substances 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 238000004817 gas chromatography Methods 0.000 description 1
- 230000002068 genetic Effects 0.000 description 1
- 239000011521 glass Substances 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- XMBWDFGMSWQBCA-UHFFFAOYSA-M iodide Chemical compound [I-] XMBWDFGMSWQBCA-UHFFFAOYSA-M 0.000 description 1
- 230000002530 ischemic preconditioning Effects 0.000 description 1
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 1
- 239000004310 lactic acid Substances 0.000 description 1
- 235000014655 lactic acid Nutrition 0.000 description 1
- 230000000670 limiting Effects 0.000 description 1
- WHXSMMKQMYFTQS-UHFFFAOYSA-N lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 1
- 229910052744 lithium Inorganic materials 0.000 description 1
- CETVQRFGPOGIQJ-UHFFFAOYSA-N lithium;hexane Chemical compound [Li+].CCCCC[CH2-] CETVQRFGPOGIQJ-UHFFFAOYSA-N 0.000 description 1
- 239000011976 maleic acid Substances 0.000 description 1
- 239000001630 malic acid Substances 0.000 description 1
- 235000011090 malic acid Nutrition 0.000 description 1
- 229940099690 malic acid Drugs 0.000 description 1
- 229940098779 methanesulfonic acid Drugs 0.000 description 1
- WDWDWGRYHDPSDS-UHFFFAOYSA-N methanimine Chemical compound N=C WDWDWGRYHDPSDS-UHFFFAOYSA-N 0.000 description 1
- NQMRYBIKMRVZLB-UHFFFAOYSA-N methylamine hydrochloride Chemical compound [Cl-].[NH3+]C NQMRYBIKMRVZLB-UHFFFAOYSA-N 0.000 description 1
- UAVOCTDYPKOULU-UHFFFAOYSA-N methylchloranuidyl formate Chemical compound C[Cl-]OC=O UAVOCTDYPKOULU-UHFFFAOYSA-N 0.000 description 1
- 239000002480 mineral oil Substances 0.000 description 1
- 235000010446 mineral oil Nutrition 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- QDHHCQZDFGDHMP-UHFFFAOYSA-N monochloramine Chemical compound ClN QDHHCQZDFGDHMP-UHFFFAOYSA-N 0.000 description 1
- 239000012452 mother liquor Substances 0.000 description 1
- GRYLNZFGIOXLOG-UHFFFAOYSA-N nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 1
- 150000002825 nitriles Chemical class 0.000 description 1
- 238000010899 nucleation Methods 0.000 description 1
- 230000000269 nucleophilic Effects 0.000 description 1
- 238000010534 nucleophilic substitution reaction Methods 0.000 description 1
- 201000008430 obsessive-compulsive disease Diseases 0.000 description 1
- 238000005580 one pot reaction Methods 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- WCPAKWJPBJAGKN-UHFFFAOYSA-N oxadiazole Chemical compound C1=CON=N1 WCPAKWJPBJAGKN-UHFFFAOYSA-N 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- 239000003880 polar aprotic solvent Substances 0.000 description 1
- 229940094025 potassium bicarbonate Drugs 0.000 description 1
- 239000001184 potassium carbonate Substances 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 229940086066 potassium hydrogencarbonate Drugs 0.000 description 1
- OZAIFHULBGXAKX-UHFFFAOYSA-N precursor Substances N#CC(C)(C)N=NC(C)(C)C#N OZAIFHULBGXAKX-UHFFFAOYSA-N 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 230000003449 preventive Effects 0.000 description 1
- 229910052904 quartz Inorganic materials 0.000 description 1
- 238000010791 quenching Methods 0.000 description 1
- 230000000171 quenching Effects 0.000 description 1
- 239000003638 reducing agent Substances 0.000 description 1
- 238000006268 reductive amination reaction Methods 0.000 description 1
- 230000003252 repetitive Effects 0.000 description 1
- 230000003989 repetitive behavior Effects 0.000 description 1
- 201000000980 schizophrenia Diseases 0.000 description 1
- 238000007790 scraping Methods 0.000 description 1
- 230000028327 secretion Effects 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- 235000012239 silicon dioxide Nutrition 0.000 description 1
- 230000003997 social interaction Effects 0.000 description 1
- 229910052682 stishovite Inorganic materials 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 229960001367 tartaric acid Drugs 0.000 description 1
- UDRAXSCYIYYSLE-UHFFFAOYSA-N tert-butyl N-(4-carbonochloridoylphenyl)carbamate Chemical compound CC(C)(C)OC(=O)NC1=CC=C(C(Cl)=O)C=C1 UDRAXSCYIYYSLE-UHFFFAOYSA-N 0.000 description 1
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 230000001225 therapeutic Effects 0.000 description 1
- 210000001519 tissues Anatomy 0.000 description 1
- 229910052905 tridymite Inorganic materials 0.000 description 1
- 229960003726 vasopressin Drugs 0.000 description 1
- 239000002699 waste material Substances 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
- A61K31/551—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having two nitrogen atoms, e.g. dilazep
- A61K31/5513—1,4-Benzodiazepines, e.g. diazepam or clozapine
- 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
- 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
-
- 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
- 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
Abstract
The present invention provides processes for the manufacture of trans-8-chloro-5-methyl-1-[4-(pyridin-2-yloxy)-cyclohexyl]-5,6-dihydro-4H-2,3,5,10b-tetraaza-benzo[e]azulene (formula I) and crystalline forms thereof. Also disclosed are compounds useful as intermediates in the methods of the invention. .
Description
SYNTHESIS OF TRANSCHLOROMETHYL-1 -[4-(PYRIDINYLOXY)-
CYCLOHEXYL]-5,6-DIHYDRO-4H-2,3,5,10B-TETRAAZA-BENZO[E]AZULENE AND
CRYTALLINE FORMS THEREOF
This application is a divisional of New d patent application , which is the national
phase entry in New Zealand of PCT international application (published as
). The entire contents of each of these applications are incorporated by
reference herein.
Field of the invention
The present invention provides processes to cture tuted 1-[4-(Pyridin
yloxy)-cyclohexyl]-5,6-dihydro-4H-2,3,5,10b-tetraaza-benzo[e]azulenes. Also disclosed are
compounds useful as ediates in the methods of the invention.
Background of the invention
Autistic Spectrum Disorders (ASD) are a clinically geneous condition characterized
by defects in socialization and language. ASD include a wide range of abnormalities including a
genuine incapacity to organize affective relations, behavioral ies in reciprocal social
interactions, verbal and non-verbal communication, limited interest in the surrounding
environment associated with stereotyped movements and repetitive plays (Bourreau et al, .
Research to date indicates that a genetic predisposition may be involved, but also environmental
factors have to be taken into consideration (Bourgeron, 2009)2. There is at present no efficient
biological/ pharmaceutical treatment of ASD.
Pyridinyloxy)-cyclohexyl]-5,6-dihydro-4H-2,3,5,10b-tetraaza-benzo[e]azulenes
have previously been described in the art3.
r WO2004074291 and WO20050684664 describe triazole compounds and a process
of cturing the same.
It has surprisingly been found that by using the processes according to the present
invention 8-chloromethyl[4-(2-pyridyloxy)cyclohexyl]-4,6-dihydro-[1,2,4]triazolo[4,3-
a][1,4]benzodiazepine and its pharmaceutically acceptable salts can be prepared more
economically with less process steps under moderate reaction conditions with an outstanding
yield. Additionally or atively, the processes according to the present invention at least
provide the public with a useful choice. Further, crude intermediate products can mostly be used
in subsequent reaction steps without the need of any additional cation steps.
Further, several forms have been identified and it has surprisingly been found that form F
is the most preferred one.
Summary of the invention
Accordingly, the present invention provides a process to synthesize a compound of formula I,
comprising the following steps:
XII XX XIX I .
In the description in this ication reference may be made to subject matter which is not
within the scope of the appended claims. That subject matter should be readily identifiable by a
person skilled in the art and may assist in putting into practice the invention as defined in the
appended claims.
Definitions
The following definitions of the general terms used in the present description apply
irrespectively of whether the terms in question appear alone or in combination with other groups.
The term “room temperature” (RT) refers to 18-30°C, in particular 20-25°C, more
particular to 20°C.
“Solution” as used herein is meant to encompass liquids wherein a reagent or reactant is
present in a solvent in dissolved form (as a solute) or is present in particulate, un-dissolved form,
or both. Thus, in a "solution", it is contemplated that the solute may not be entirely dissolved
therein and solid solute may be present in dispersion or slurry form. Accordingly, a "solution" of
a particular reagent or nt is meant to encompass slurries and dispersions, as well as
solutions, of such reagents or reactants. "Solution" and "Slurry" may be used hangeable
herein.
nt” as used herein is meant to encompass liquids that fully dissolve a reagent or
nt exposed to the solvent, as well as liquids which only lly ve the t or
reactant or which act as dispersants for the reagent or reactant. Thus, when a particular reaction
is carried out in a nt", it is plated that some or all of the reagents or reactants
present may not be in dissolved form.
The term “approximately” in connection with degrees 2-theta values refers to ±0.2 degrees
2-theta.
The terms “crystalline form” or “form” refer to polymorphic forms and solvates of a
compound.
The term aceutically acceptable salts" refers to salts that are suitable for use in
contact with the tissues of humans and animals. Examples of le salts with inorganic and
organic acids are, but are not limited to acetic acid, citric acid, formic acid, fumaric acid,
hydrochloric acid, lactic acid, maleic acid, malic acid, methane-sulfonic acid, nitric acid,
phosphoric acid, p-toluenesulphonic acid, ic acid, sulfuric acid (sulphuric acid), tartaric
acid, trifluoroacetic acid and the like. Preferred are formic acid, trifluoroacetic acid and
hydrochloric acid. Most preferred is hydrochloric acid.
The terms “Autistic Spectrum” and “Autistic Spectrum Disorders” summarize conditions
fied as pervasive developmental disorders, which include but are not limited to autism,
Asperger me, pervasive developmental disorder not otherwise specified (PDD-NOS),
childhood disintegrative disorder, Rett syndrome and Fragile X, in particular autism. These
disorders are typically characterized by social deficits, communication difficulties, stereotyped
or repetitive behaviors and interests, and cognitive .
The term “comprising” as used in this specification and claims means sting at least
in part of”. When interpreting statements in this specification and claims which include the term
“comprising”, other features besides the features prefaced by this term in each statement can also
be present. Related terms such as “comprise” and “comprises” are to be interpreted in similar
manner.
The nomenclature used in this Application is based on IUPAC systematic nomenclature,
unless indicated otherwise.
Detailed Description of the Invention
In detail, the present invention is ned with a process to synthesize a crystalline form
of a nd of formula I
Described is the lline form A of the compound of formula I as described herein,
characterized by a X-ray powder diffraction pattern having the characteristic peaks expressed in
values of s a at approximately
degree 2-theta degree 2-theta degree 2-theta
13.0 18.1 21.9
13.5 18.9 23.9
14.5 19.5 27.2
.9 20.6
17.8 21.0 .
Described is the crystalline form A of the compound of formula I as described herein,
characterized by the X-ray powder diffraction pattern as shown in figure 1.
Described is the crystalline form A of the compound of formula I as described herein,
characterized by the Infrared um shown in as shown in figure2.
Described is the crystalline form A of the compound of a I as described herein,
characterized by the Raman spectrum shown in as shown in figure 3.
Described is the lline form B of the compound of a I as described herein,
characterized by a X-ray powder diffraction pattern having the characteristic peaks expressed in
values of degrees 2-theta at approximately
degree a degree a degree 2-theta
7.5 15.1 20.0
9.9 15.9 21.2
12.4 16.6 24.8
14.3 18.1 25.5 .
bed is the crystalline form B of the compound of formula I as described herein,
characterized by the X-ray powder diffraction pattern as shown in figure 4.
Described is the crystalline form B of the compound of formula I as described herein,
characterized by the Infrared spectrum shown in as shown in figure 5.
Described is the crystalline form B of the compound of formula I as described herein,
terized by the Raman spectrum shown in as shown in figure 6.
Described is the crystalline form B of the compound of formula I as described herein,
characterized by the following unit cell parameters
A 12.01 Å
B 17.91 Å
C 10.52 Å .
alpha 90 deg
beta 101.14 deg
gamma 90 deg
Described is the crystalline form C of the compound of formula I as bed herein,
characterized by a X-ray powder diffraction n having the characteristic peaks expressed in
values of degrees 2-theta at approximately
degree 2-theta degree 2-theta degree 2-theta
9.0 18.1 20.2
12.6 18.4 20.8
13.7 19.4 22.5
16.6 19.7 23.0 .
Described is the crystalline form C of the compound of formula I as described herein,
characterized by the X-ray powder diffraction pattern as shown in figure 7.
Described is the crystalline form C of the compound of formula I as described herein,
characterized by the ed spectrum shown in as shown in figure 8.
Described is the crystalline form C of the compound of formula I as described herein,
characterized by the Raman spectrum shown in as shown in figure 9.
Described is the crystalline form C of the compound of formula I as described herein,
characterized by the following unit cell parameters
A 10.80 Å
B 18.16 Å
C 18.42 Å
alpha 108.64 deg
beta 99.57 deg
gamma 106.79 deg .
Described is the crystalline form D of the nd of formula I as described herein,
characterized by a X-ray powder diffraction pattern having the characteristic peaks expressed in
values of degrees 2-theta at imately
degree a degree 2-theta degree 2-theta
7.8 15.8 22.6
9.4 18.2 26.3
12.3 19.7 26.9 .
13.6 20.8
.2 21.6
Described is the crystalline form D of the compound of formula I as bed herein,
characterized by the X-ray powder diffraction n as shown in figure 10.
Described is the crystalline form D of the compound of formula I as described herein,
characterized by the Infrared spectrum shown in as shown in figure 11.
Described is the crystalline form D of the compound of formula I as described herein,
terized by the Raman spectrum shown in as shown in figure 12.
bed is the crystalline form D of the
A 11.74 Å
B 9.08 Å
C 22.93 Å
alpha 90 deg
beta 103.84 deg
gamma 90 deg .
Described is the crystalline form E of the compound of formula I as described herein,
characterized by a X-ray powder diffraction pattern having the characteristic peaks expressed in
values of s 2-theta at approximately
degree 2-theta degree 2-theta degree 2-theta
9.7 16.7 25.0
12.4 17.8 23.3
14.1 18.1 28.9
.2 19.7 29.4
.7 21.1 .
Described is the crystalline form E of the compound of formula I as described herein,
characterized by the X-ray powder diffraction pattern as shown in figure 13.
Described is the crystalline form E of the nd of formula I as described herein,
characterized by the Infrared spectrum shown in as shown in figure 14.
Described is the crystalline form E of the compound of formula I as described herein,
terized by the Raman spectrum shown in as shown in figure 15.
Described is the crystalline form F of the compound of formula I as described herein,
characterized by a X-ray powder diffraction pattern having the characteristic peaks expressed in
values of degrees 2-theta at approximately
degree 2-theta degree 2-theta degree 2-theta
8.6 15.7 23.0
8.9 17.9 24.0
11.4 19.5 26.5
12.2 20.7 27.0
.2 22.6 .
Described is the crystalline form F of the compound of formula I as described herein,
characterized by the X-ray powder ction pattern as shown in figure 16.
Described is the crystalline form F of the compound of formula I as described herein,
characterized by the Infrared spectrum shown in as shown in figure 17.
Described is the crystalline form F of the compound of formula I as described herein,
characterized by the Raman spectrum shown in as shown in figure 18.
bed is the crystalline form F of the compound of formula I as described herein,
characterized by the following unit cell parameters
A 8.98 Å
B 11.30 Å
C 12.02 Å
alpha 117.01 deg
beta 102.48 deg
gamma 94.76 deg .
Described is the crystalline form G of the nd of a I as bed herein,
characterized by a X-ray powder diffraction pattern having the characteristic peaks expressed in
values of s 2-theta at approximately
degree 2-theta degree 2-theta degree 2-theta
7.4 15.8 21.1
9.8 16.4 22.5
12.3 17.9 24.5
14.1 18.1 25.3
14.9 20.0 29.2 .
Described is the crystalline form G of the compound of formula I as described herein,
characterized by the X-ray powder diffraction pattern as shown in figure 19.
Described is the crystalline form G of the compound of formula I as described herein,
characterized by the ed spectrum shown in as shown in figure 20.
Described is the crystalline form G of the nd of formula I as described herein,
characterized by the Raman spectrum shown in as shown in figure 21.
Described is the crystalline form G of the compound of formula I as bed herein,
characterized by the following unit cell parameters
A 12.02 Å
B 18.04 Å
C 10.29 Å
alpha 90 deg.
beta 100.63 deg.
gamma 90 deg. .
Described is the crystalline form H of the compound of formula I as described herein,
characterized by a X-ray powder diffraction pattern having the characteristic peaks expressed in
values of degrees 2-theta at approximately
degree 2-theta degree 2-theta degree a
12.8 18.6 23.6
14.2 20.8 25.3
17.0 21.2 28.4
17.7 22.2 .
Described is the crystalline form H of the compound of formula I as described ,
characterized by the X-ray powder diffraction pattern as shown in figure 22.
Described is the crystalline form H of the compound of formula I as described herein,
characterized by the Raman spectrum shown in as shown in figure 23.
bed is the crystalline form H of the compound of formula I as described herein,
characterized by the following unit cell parameters
A 22.76 Å
B 8.52 Å
C 12.55 Å
alpha 90 deg
beta 99.18 deg
gamma 90 deg .
Described is a process to transform form A to form F.
Form A Form F
Described is the trihydrate of a compound of formula I.
Described is a process to size a compound of formula I as bed herein,
sing reacting a compound of formula II with a compound of formula VI
II free base VI I
III bis-hydrochloride salt .
The amidine free base II can be reacted thermally with the compound of formula VI to
provide the compound of formula I. The presence of an acid enhances the reactivity and the
purity of the crude API. This is conveniently achieved by using the amidine bis-hydrochloride
III as a substrate. III can be isolated as crystalline intermediate which thus provides a good
purification point in that synthesis.
Described is a process to size a compound of formula I as described herein,
comprising reacting a compound of formula III with a compound of formula VI.
Described is a s to synthesize a nd of formula I as described herein,
comprising reacting a nd of formula III with a compound of formula VI, whereby they
are reacted thermally, in particular at a temperature of 95°C ± 35°C, more particular 85°C
±15°C, most particular 80°C ±5°C. Specific atures are 75°C, 76°C, 77°C, 78°C, 79°C,
80°C, 81°C, 82°C, 83°C, 84°C and 85°C.
Described is a process to synthesize a compound of formula I as described herein,
comprising reacting a compound of a III with a compound of formula VI in an organic
solvent like THF, dioxane, DMF, NMP, acetonitrile and alcohols, in particular an alcoholic
solvent like ethanol, n-propanol, isopropanol, n-butanol, more ularly isopropanol and npropanol
, even more particularly panol. Compound I can be directly isolated as
hydrochloride by tion when the on is performed in a suitable solvent like isopropanol.
Alternatively, I as free base can be isolated by addition of an aqueous base like aqueous sodium
hydroxide, aqueous potassium hydroxide, aqueous sodium onate, aqueous potassium
bicarbonate, aqueous sodium carbonate, aqueous potassium carbonate, in particular, s
sodium hydroxide, aqueous potassium hydroxide, more particular aqueous sodium hydroxide.
The compound I is then isolated as trihydrate (form H) which leads to the anhydrous form A
upon drying.
Described is a process to synthesize a compound of formula I as described herein,
comprising reacting a compound of formula II with a compound of formula VI, whereby the
free base of the product I is isolated at pH > 8, in particular, at pH > 10, more particularly at pH
> 12.
Described is isolation of the free base of the product I at pH > 8, in particular, at pH > 10,
more particularly at pH > 12 using an appropriate solvent e like an alcohol/water mixture,
in particular ethanol/water, isopropanol/water, n-propanol/water, more particular
isopropanol/water, free of un-desired uct yridyloxy)-N'-[4-(2-pyridyloxy)
cyclohexanecarbonyl]cyclohexane-carbohydrazide (VI’).
Described is a process to synthesize a compound of a I as described herein,
sing reacting a compound of formula II with a compound of formula VI, whereby 4-(2-
pyridyloxy)-N'-[4-(2-pyridyloxy) cyclohexanecarbonyl] cyclohexane-carbohydrazide VI’ is the
byproduct.
VI’.
Described is the process as described above, further comprising reacting a compound of formula
XI or a hydrochloride salt thereof to a compound of formula III:
. 2 HCl
XI III
or a hydrochloride salt
thereof .
Described is the process as described above further comprising ng a compound of
formula X to a compound of formula XI via the following steps:
X XXV IX VIII
. 2 HCl
XI.2 HCl VII
Compound of formula XI can be isolated as a bis-hydrochloride. Alternatively, it can be
prepared in-situ and directly further ted to compound of formula III.
bed is the process as described above further comprising reacting a compound of
formula X to a compound of formula III via the following steps:
X IX VIII
. 2 HCl
III VII
Described is the process to synthesize a compound of formula I comprising the following
steps:
X XXV IX VIII VII
. 2 HCl
I III XI or XI. n HCl (n = 0, 1, 2)
de of formula XXV has been described in the art (Aubé et al.)5 being prepared by
ortho-lithiation with sec-butyl lithium (s-BuLi) at -78°C then raising the temperature to -20°C
prior to quenching with DMF. The product was obtained in 54% yield after chromatography.
Present reaction is med at higher temperature (up to -30°C) and with l lithium (n-
BuLi) to obtain a higher yield of > 80% yield without chromatography and after crystallization.
The process described herein is much more efficient and scalable.
Described is the process to synthesize a nd of formula XXV from a compound of
formula X, whereby the lithiation takes place in tetrahydrofuran (THF), 2-methyl-
tetrahydrofuran (2-Me-THF) or methyl tert-butyl ether (MBTE), in ular THF and MBTE,
most particular MTBE.
Described is the process to synthesize a compound of formula XXV from a compound of
formula X, whereby the lithiation takes place at -60°C to -10°C, in particular between -40°C and
-20°C, most particular at -30 ± 2°C.
Described is the process to synthesize a compound of formula XXV from a compound of
formula X, whereby the lithiation takes place in the presence of an additive like (but not limited
to) tetramethylethylendiamine (TMEDA) or ethyldiethylenetriamine (PMDTA), in
particular TMEDA.
Described is the process to synthesize a compound of formula XXV from a compound of
a X, whereby the lithiation takes place with n-butyl lithium, n-hexyl lithium or s-butyl
lithium, in particular n-butyl lithium.
Described is the process to synthesize a compound of formula XXV from a nd of
formula X, whereby the lithiation takes place with n-BuLi, in the presence of
tetramethylethylendiamine (TMEDA) in MTBE and at -30 ± 2°C.
Compound of a XXV can be isolated as a crystalline intermediate and then
converted in a second step to the imine of formula IX. The crystallization can be performed for
example in ethanol or panol.
Alternatively, the crude extract of compound XXV can be telescoped with the imine
formation step by performing a solvent ge to the target solvent ed by imine
formation and isolation of compound of formula IX.
Described is the process as described above comprising reacting a compound of formula
XXV to a compound of formula IX, whereby imine formation is conducted in an alcohol like
methanol, ethanol, isopropanol or n-propanol, in particular ethanol or methanol or mixture
thereof.
The imine of a IX is isolated as a crystalline intermediate by direct crystallization
from the reaction mixture. It was gratifyingly found that the imine crystallization provides a
very efficient purification point in the synthesis.
The imine of a IX can be reduced by catalytic hydrogenation to provide the
intermediate of formula VIII.
Described is the process as described above sing ng a compound of formula IX
to a compound of formula VIII whereby the ion is performed with hydrogen in a the
presence of a catalyst like Platinum on charcoal, in particular with hydrogen and Pt/C in
methanol.
Described is the s as described above comprising reacting a compound of formula IX
to a compound of formula VIII whereby the reduction is performed with en over Pt/C at
a temperature between 15°C and 50°C, in particular n 20 and 30°C, most particular
between 20 and 25°C.
Described is the process as described above comprising reacting a nd of formula IX
to a compound of formula VIII whereby the reduction is performed with hydrogen over Pt/C at
a pressure n 1 and 10 bar, in particular at 5 bar.
Described is the process as described above comprising reacting a compound of formula IX
to a compound of formula VIII whereby the ion is performed with hydrogen over Pt/C in
methanol at a re of 5 bar and at room temperature.
Alternatively, the imine of formula IX can be reduced to the intermediate of formula VIII
by the use of sodium borohydride.
Although the reduction does proceed in an aprotic solvent like THF in the presence of a
carboxylic acid (acetic acid, caproic acid, 2-ethyl-hexanoic acid and pivalic acid, in particular
acetic acid and pivalic acid), better results can be obtained in protic organic solvents like
methanol or ethanol, in particular ol.
Working in a homogenous reaction system like THF/methanol mixtures, and in the
presence of methyl amine as additive minimizes the formation of the following 2 major
byproducts dimer 1 and dimer 2.
dimer 1 dimer 2
The homogenous system maximizes the tration of the imine of formula IX in
solution, hence increasing the rate of the productive reduction vs dimer ion. Due to the
moderate to low solubility of the imine substrate in methanol, an additive like for e THF
is used to provide a clear solution prior to the dosing of the reducing agent.
The presence of methyl amine es with the t of formula VIII for the reaction
with the imine substrate of formula IX hence decreasing the amount of side products dimer 1
and/or dimer 2.
Described is the process as described above comprising reacting a compound of a IX
to a compound of formula VIII whereby the reduction is performed with sodium borohydride in
a mixture of THF and methanol, in particular with enough methanol to ensure reactivity and
enough THF to ensure solubility of the imine substrate.
Described is the process as bed above comprising reacting a compound of formula IX
to a compound of formula VIII whereby the reduction is performed with sodium borohydride in
methanol or a e of THF and methanol, in ular a mixture of THF and methanol, most
particular in a 2:1 mixture of methanol and THF.
Described is the process as bed above comprising reacting a compound of formula IX
to a compound of formula VIII whereby the reduction with sodium borohydride is conducted in
the presence of a carboxylic acid like (but not limited to) acetic acid or pivalic acid, in particular
acetic acid.
Described is the s as described above comprising ng a compound of formula IX
to a compound of formula VIII whereby the reduction with sodium borohydride is conducted in
the presence methyl amine. Described is the process as described above sing reacting a
nd of formula IX to a compound of formula VIII whereby the reduction with sodium
dride is conducted in a 2:1 methanol/THF mixture, in the presence of acetic acid and
methyl amine.
bed is the process comprising the reduction of the imine of formula IX to the
intermediate of formula VIII whereby dimer 1 and dimer 2 are formed as by-products in
amounts of <1%. The intermediate of formula VIII can be isolated by crystallization for
example from a mixture of iPrOH and water or as a salt, for example its acetic acid salt.
Extraction of the crude t of formula VIII (from the sodium borohydride reduction) in
the aqueous phase at acidic pH (for example but not limited to pH from 4-6), followed by a
wash-out of the impurities with an organic solvent, ed by an extraction of the product in
an organic solvent at neutral to basic pH gives a product of very high purity. The extract can
then be introduced in the next step (alkylation) without the need of crystallization and drying
steps.
Described is the process as bed above comprising reacting a compound of formula IX
to a compound of formula VIII whereby the purification of the crude intermediate of formula is
performed by an extractive work-up, in particular an acid extraction of the product in the
aqueous phase, followed by a wash with an organic solvent, followed by extracting the product
with an organic solvent at neutral to basic pH.
The alkylation of a compound of formula VIII to provide a compound of formula VII can
be performed with chloro-, bromo-, or cetonitrile. The reactivity of the chloroacetonitrile
can be enhanced by using a bromide or iodide source like for example potassium iodide or
bromide.
Described is the process as described above comprising reacting a compound of formula
VIII to a nd of a VII whereby the alkylation is performed with acetonitrile,
in particular with chloroacetonitrile in the presence of potassium iodide or potassium bromide,
most particular with chloroacetonitrile in the presence of potassium iodide.
Although the alkylation can be performed in polar aprotic solvents like DMF, NMP, DMA
or DMSO, alternative solvents are preferred for better waste stream processing. Suitable
ts are THF, 2-Me-THF, acetone, toluene, acetonitrile, or ethyl acetate. For kinetic reasons,
acetonitrile, acetone and ethyl acetate are used in particular, more particularly ethyl acetate.
Described is the process as described above comprising reacting a compound of formula
VIII to a compound of formula VII whereby the alkylation is performed with chloroacetonitrile
and potassium iodide, in acetone, acetonitrile or ethyl acetate, in particular in ethyl e.
Ethyl e offers the additional advantage of ng a direct tive work-up without
any solvent exchange prior to the extraction, or the use of an additional phase splitting solvent.
Described is the process as described above comprising reacting a compound of formula
VIII to a compound of formula VII whereby the tion is performed with chloroacetonitrile
in the presence of a suitable base like sodium en carbonate, sodium carbonate, potassium
hydrogen carbonate, sodium hydrogen carbonate, cesium en carbonate or cesium
ate, in particular with sodium hydrogen carbonate or potassium en carbonate, most
particularly with sodium hydrogen carbonate.
Described is the process as described above sing reacting a compound of a
VIII to a compound of formula VII whereby the alkylation is performed with chloroacetonitrile,
in refluxing ethyl acetate, in the presence of potassium iodide and sodium hydrogen ate
as base.
Product of formula VII can be isolated by crystallization for example in isopropanol or
ethanol/water mixtures.
Described is the process as described above comprising reacting a compound of formula
VII to a nd of formula III, y the reaction takes place in the presence of excess
HCl, in an alcohol like methanol, ethanol, trifluoroethanol, isopropanol, in particular
isopropanol or trifluoroethanol, more particular isopropanol, or an alcohol/dichloromethane
mixture, in ular trifluoroethanol/dichloromethane (for the use of trifluoroethanol as solvent
for the preparation of amidines from nitrile see Caron et al.6).
bed is the process as described above comprising reacting a compound of formula
VII to a nd of formula III, whereby nd of formula VII is converted to compound
of formula XI. 2 HCl which is not isolated but is in situ further converted to compound of
formula III.
Described is the process as described above comprising reacting a compound of formula
VII to a compound of formula III, whereby an alkyl 2-[(2-aminochloro-phenyl)methylmethyl-amino
]acetate, the corresponding e or othoester byproducts are formed, the RO
fragment coming from the l being used.
III' III'' III'''
Compared to the use of linear alcohols like ethanol, the amount of these byproducts (III’,
III’’, III’’’) is decreased by using less nucleophilic alcohols like isopropanol or trifluoroethanol.
Isopropanol represents a greener and cheaper alternative to trifluoroethanol.
Described is the process as bed above comprising reacting a compound of a
VII to a compound of formula III, whereby the reaction takes place in the presence of excess
HCl, in isopropanol.
Described is the s as described above comprising reacting a compound of formula
VII to a compound of formula III, y the starting material is dosed onto the solution upon
which Boc deprotection to a compound of formula XI (as hydrochloride salt) occurs in a
controlled manner allowing the control of the CO2 off-gas.
Described is the process to synthesize a compound of formula I r comprising reacting
a compound of formula X to a compound of formula XI via the following steps:
. 2 HCl
X XXV IX VIII XII . 2 HCl
Described is the process to synthesize a compound of formula I comprising the ing
steps:
. 2 HCl
X XXV IX VIII XII . 2 HCl
. 2 HCl
I III XI
Described is the process to synthesize a compound of formula I further comprising ng
a compound of formula XV to a compound of formula XI via the following steps:
XV XIV XIII XII XI .
Compound of formula XII can also be isolated as a hydrochloride salt.
The transformation of compound of formula XV to nd of formula XII was adapted
from WO2005/684667.
Described is the process to synthesize a compound of formula I comprising the following
steps:
XV XIV XIII XII XI
. 2 HCl
I III
Described is the process to synthesize a compound of formula I further comprising reacting
a compound of formula XVI to a compound of formula XI via the following steps:
. HCl . HCl
XVI XIII.HCl XII.HCl XI
Described is the process to size a compound of formula I sing the following
steps:
. HCl
. HCl
XVI XIII.HCl XII.HCl XI
. 2 HCl
I III
Described is the sis of a compound of formula I comprising reacting a compound of
formula XXVI to a compound of formula XI via the following steps
XXVI XII XI .
Compound of formula XII has been described in the art by Venkov et al. 8 as an
intermediate which was not isolated and used directly in a subsequent reaction.
Described is the process as described above sing reacting a compound of formula
XXVI to a compound of a XII, whereby compound of formula XII is isolated from the
reaction mixture.
Described is the process as described above comprising ng a compound of formula
XXVI to a compound of formula XI, whereby the reductive amination and the alkylation step
are conducted in one pot.
Described is intermediate XI.
Described is the process to synthesize a compound of a I comprising the following
steps:
XXVI XII XI
. 2 HCl
I III .
A certain embodiment of the invention relates to a process to synthesize a nd of
formula I as described herein, comprising the following steps:
XXIV XXIII VI
A certain embodiment of the invention relates to a process to synthesize a compound of
formula I as described herein, sing reacting a compound of formula XXIII to a
compound of formula VI by aromatic nucleophilic substitution of a 2-halopyridine with 4-
hydroxycyclohexanecarboxylic acid.
A certain embodiment of the invention relates to a process to synthesize a compound of
formula I as described , comprising reacting a compound of a XXIV to a
compound of formula XXIII, whereby bases like are sodium tert-amyl alcoholate (tAmONa),
potassium myl alcoholate (tAmOK), sodium tert-butoxide (tBuONa), potassium tertbutoxide
(tBuOK), in particular tAmONa can be used.
A certain embodiment of the ion relates to a process to synthesize a compound of
formula I as described herein, comprising reacting a compound of formula XXIV to a
compound of formula XXIII, y the t is N-methylpyrrolidone (NMP) or
dimethylacetamide (DMA), in particular NMP.
A certain embodiment of the invention relates to a process to synthesize a compound of
formula I as described herein, comprising reacting a nd of formula XXIV to a
compound of formula XXIII, whereby the reaction is performed at 80-120°C, in particular at 88-
92°C.
A certain embodiment of the invention relates to a process to synthesize a compound of
formula I as described , comprising reacting a compound of formula XXIV to a
compound of formula XXIII, whereby the 2-halopyridines are selected from 2-fluoropyridine
and 2-chloropyridine, in particular 2-chloropyridine.
A certain embodiment of the invention relates to a s to synthesize a compound of
formula I as described herein, comprising reacting a compound of formula XXIV to a
compound of formula XXIII, whereby compound of formula XXIV is reacted with 2-
chloropyridine, in NMP, in the presence of sodium tert-amyloxide at C.
A certain embodiment of the invention relates to a process to synthesize a compound of
formula I as described herein, comprising reacting a compound of formula XXIII to a
compound of formula VI, y XXIII is activated by reaction with a suitable alkyl
chloroformate like yl-, ethyl or methyl chloroformate, in particular isobutyl chloroformate.
A certain embodiment of the invention relates to a process to synthesize a compound of
a I as described herein, comprising reacting a compound of formula XXIII to a
nd of formula VI, whereby XXIII is activated with a suitable alkyl formate in the
presence of a suitable base like ylamine, Hünig’s base, pyridine, collidine or N-
methylmorpholine, in ular N-methylmorpholine.
A certain embodiment of the invention relates to a s to synthesize a compound of
formula I as described herein, comprising reacting a compound of formula XXIII to a
compound of formula VI, whereby XXIII is ted with carbonyldimimidazole (CDI) to give
the corresponding acyl ole intermediate which is further reacted with hydrazine.
A certain embodiment of the invention relates to a process to synthesize a compound of
formula I as described herein, sing reacting a compound of formula XXIII to a
compound of formula VI, whereby the reaction takes place in a suitable solvent like DMF, NMP,
THF, 2-MeTHF, in particular THF.
A certain embodiment of the ion relates to a process to synthesize a compound of
formula I as described herein, comprising reacting a compound of a XXIII to a
compound of formula VI, whereby the activation with CDI is performed at 10°C to 50°C, in
particular between 20°C and 30°C, more particular at 25°C.
A certain ment of the invention relates to a process to synthesize a compound of
a I as bed herein, comprising reacting a compound of formula XXIII to a
compound of formula VI, whereby the acyl imidazole intermediate is then reacted with
hydrazine, in particular excess hydrazine is used, most particular at least 2 time the excess of
CDI used in the activation step.
A certain embodiment of the invention relates to a process to synthesize a compound of
formula I as described , comprising reacting a compound of a XXIII to a
compound of a VI, whereby the order of addition involves the addition of the ted
acid to hydrazine.
A certain ment of the invention relates to a process to synthesize a compound of
formula I as described herein, comprising reacting a compound of formula XXIII to a
nd of formula VI, whereby the acyl imidazole reaction mixture can be degassed after the
activation and prior to the reaction with hydrazine to remove the solubilized CO2.
A certain embodiment of the invention relates to a process to synthesize a compound of
a I as described herein, comprising reacting a compound of formula XXIII to a
compound of formula VI, whereby 4-(2-pyridyloxy)-N'-[4-(2-pyridyloxy) cyclohexanecarbonyl]
cyclohexane- carbohydrazide (VI’) is formed as uct.
A certain embodiment of the invention relates to a process to size a compound of
formula I, comprising the following steps:
Certain oxadiazole precursors have been described in the art9.
A certain embodiment of the invention relates to a s to synthesize a compound of
formula I as described herein, comprising the following steps:
XXIV XXIII VI
XX XXI
A certain embodiment of the invention relates to the process to synthesize a compound of
formula I comprising the following steps:
XXIV XXIII VI
XX XXI
XIX I .
Described is the process to synthesize a nd of a I, whereby a compound of
formula INT, a tautomer or a salt thereof, is formed as intermediate:
INT.
bed is the intermediate compound INT, a tautomer or a salt thereof. Described is the
intermediate compound INT.
Described is the process to synthesize a compound of formula I, whereby a compound of
formula III is formed as intermediate.
Described is the intermediate nd II, a tautomer or a salt thereof:
II: free base, III: .2HCl.
Described is the intermediate compound II, or a salt thereof.
Described is the intermediate compound III.
Described is a process to synthesize a compound of formula VI.
XXIV XXIII VI .
Described is the s to synthesize a compound of formula I comprising the following
steps:
XXIV XXIII VI
. 2 HCl
A certain embodiment of the invention relates to a compound of formula I or a
pharmaceutically acceptable salt, whenever prepared by a s of the invention.
Described is a compound of formula I as described herein for use as a medicament.
Described is a compound of formula I as described herein for use in the therapeutic and/or
preventive ent of inappropriate secretion of vasopressin, y, depressive disorders,
obsessive compulsive disorder, autistic um disorders, schizophrenia, aggressive behavior
and phase shift sleep disorders, in particular .
Brief description of the Figures
The FTIR data has been collected as a Nujol mull so additional peaks due to the mineral oil
dispersing agent are visible in the IR spectra.
Figure 1: XRPD pattern of form A.
Figure 2: IR spectrum of form A.
Figure 3: Raman spectrum of form A.
Figure 4: XRPD pattern of form B.
Figure 5: IR spectrum of form B.
Figure 6: Raman spectrum of form B.
Figure 7: XRPD pattern of form C.
Figure 8: IR spectrum of form C.
Figure 9: Raman spectrum of form C.
Figure 10: XRPD pattern of form D.
Figure 11: IR spectrum of form D.
Figure 12: Raman spectrum of form D.
Figure 13: XRPD pattern of form E.
Figure 14: IR spectrum of form E.
Figure 15: Raman spectrum of form E.
Figure 16: XRPD pattern of form F.
Figure 17: IR spectrum of form F.
Figure 18: Raman um of form F.
Figure 19: XRPD pattern of form G.
Figure 20: IR spectrum of form G.
Figure 21: Raman spectrum of form G.
Figure 22: XRPD pattern of form H.
Figure 23: Raman spectrum of form H.
Experimental Part
The following experiments are provided for ration of the invention. They should not
be considered as limiting the scope of the invention, but merely as being entative thereof.
Form A of I
100 mg of I were dissolved in a closed vial, at 22°C, in 5.0 mL of a mixture of
ethanol/water 1:1 (v/v). After dissolution, the solution was filtered with a 0.45 µm filter unit.
Subsequently, the clear on was allowed to evaporate at 22°C for 10 days. After complete
evaporation the product was dried (50°C/<20 mbar for >24 h) and analyzed.
Form B of I
100 mg of I were dissolved in a closed vial, at 22°C, in 3.0 mL of ethyl acetate. After
dissolution, the solution was filtered with a 0.45 µm filter unit. Subsequently, the clear solution
was allowed to evaporate at 22°C for 10 days. The ment led to single crystals of form B
suitable for single crystal structure analysis. After complete evaporation the product was dried
<20 mbar for >24 h) and analyzed.
Form C of I
100 mg of I were dissolved in a closed vial, at 22°C, in 1.4 mL of a mixture of water
saturated butanol (ca. 20% v/v). After dissolution, the solution was filtered with a 0.45 µm filter
unit. Subsequently, the clear solution was allowed to evaporate at 22°C for 1 month. The
experiment led to single crystals of form C suitable for single crystal structure analysis. After
te evaporation the product was dried (50°C/<20 mbar for >24 h) and analyzed.
Form D (p-xylene hemi-solvate) of I
100 mg of I were suspended in a closed vial, at 22°C, in 0.35 mL of ne and allowed
to agitate at 60°C. After 14 days equilibration at 60 °C, the slurry was filtered and the product
dried (50°C/<20 mbar for >24 h) and analyzed. The evaporation of the te (3 days at 22°C)
led to single crystals of form D suitable for single crystal structure analysis.
Form E (acetic acid hemi-solvate) of I
100 mg of I were dissolved in a closed vial, at 22°C, in 0.4 mL of acetic acid. After
dissolution, the solution was filtered with a 0.45 µm filter unit. Subsequently, the clear solution
was allowed to evaporate at 22°C for 14 days. The ment led to an oily residuum which
transform in to a powder after scraping with a spattel. The product was dried (50°C/<20 mbar for
>24 h) and analyzed.
Form F of I
100 mg of Form B were suspended in a closed vial, at 22°C, in 0.3 mL of isopropanol
and allowed to agitate at 22°C. After 1 day agitation, 10 mg of API / form C were added and the
slurry still agitates at 22°C. After 14 days equilibration at 22 °C, the slurry was filtered and the
product dried (50°C/<20 mbar for >24 h) and ed.
Form G (butyronitrile solvate) of I
100 mg of I were dissolved in a closed vial, at 22°C, in 1.5 mL of butyronitrile.
Immediately after ution, the solution began, under agitation, to precipitate. The slurry was
allowed, still under agitation, to partially evaporate at 22°C for 10 days.
After partially evaporation (ca. 50 %), the slurry was filtered and the product dried (50°C/<20
mbar for >24 h) and ed. The evaporation of the filtrate (2 weeks at 22°C) led to single
ls of form G suitable for single crystal structure analysis.
Form H (trihydrate) of I
100 mg of I were dissolved in 1.9 mL of a mixture of ethanol/water 1:1 (v/v) at 65°C in a
closed vial. The clear solution was linearly cooled from 65°C to -20°C within 8 h without
agitation. The experiment led to single crystals of form H suitable for single l structure
analysis. The product was isolated by removing the mother liquor with a pipette and analyzed in
wet stage.
utyl N-(4-chloroformyl-phenyl)carbamate XXV
X XXV
tert-Butyl rophenylcarbamate (40 g, 175 mmol, Eq: 1.00) was dissolved in THF
(248 g, 280 mL). The solution was cooled to -30°C. ,N'-tetramethylethylenediamine (44.5
g, 57.8 mL, 379 mmol, Eq: 2.17) was added dropwise. After 5 min, n-butyllithium 2.5 M in
hexanes (210 mL, 524 mmol, Eq: 3.00) was added dropwise over 60 min at -30°C to -20°C.
After 5 h at -30°, DMF (38.4 g, 40.5 mL, 524 mmol, Eq: 3.00) were added over 35 min. After 1
h at -30°C, cold (0-5°C) methyl t-butyl ether (MTBE) (207 g, 280 mL) was added (0°C). 25%
aqueous hydrogen chloride (HCl) (178 g, 149 mL, 1.22 mol, Eq: 7.0) was added over 30 min at -
° to 0°C. The aqueous phase was separated and extracted with MTBE (74.0 g, 100 mL). The
organic phases were washed sequentially with 10% aqueous sodium chloride (NaCl) (100 mL),
% aqueous sodium hydrogen carbonate (NaHCO3) (100 mL) and half saturated aqueous NaCl
(100 mL). The organic phases were combined, dried over magnesium sulfate (MgSO4) and
concentrated under reduced pressure (40°C/ down to 10 mbar) to give 45.2 g of crude t.
The crude t was dissolved in 2-propanol (157 g, 200 mL) at 80°C. The clear solution was
slowly cooled to 0°C during which product started to crystallize. The suspension was stirred 1 h
at 0°C and was ed. The filter cake was washed with cold (0-5°C) 2-propanol (15.7 g, 20 mL)
dried at 50°C/10 mbar to give 38.8 g of title compound.
tert-Butyl N-[4-chloro[(E)-methyliminomethyl]phenyl]carbamate IX
X IX
MTBE process
N-Bocchloroaniline (121 g, 531 mmol, Eq: 1.00) was dissolved in MTBE (648 g, 875
mL). The on was cooled to -25°C. TMEDA (72 g, 92.9 mL, 620 mmol, Eq: 1.17) was
added. 2.5 M n-Butyllithium (BuLi) in hexanes (398 g, 572 mL, 1.43 mol, Eq: 2.69) was added
over 70 min, keeping the temperature below -20°C. After 2.5 h, dimethylformamide (DMF) (113
g, 120 mL, 1.55 mol, Eq: 2.91) was added over 30-45 min, keeping the temperature between -
°C and -20°C. After 1 h, 25% s HCl (526 g, 470 mL, 3.61 mol, Eq: 6.79) was added at
a rate that the internal temperature is kept between -30°C and 0°C. The reaction mixture was
warmed up to room temperature (RT) over 30 min. The aqueous phase was separated and
extracted with MTBE (333 g, 450 mL). The organic phases were combined and washed
sequentially with saturated aqueous NaCl (600 mL), 10% s NaHCO3 (600 mL) and
aqueous NaCl (600 mL). The organic phase was trated to circa 550 mL and the MTBE
was solvent exchanged to ethanol (EtOH) at constant volume (Tj max 55°C). The crude aldehyde
suspension was diluted with EtOH (250 mL). 33% Methylamine in EtOH (150 g, 1.59 mol, Eq: 3)
was added and the reaction mixture was stirred for > 2 h at 25°C (until < 2% aldehyde are left,
IPC). If required, the reaction mixture is seeded at 20°C. The resulting suspension was cooled
over 1 h to -10°C. After 3 h at -10°C, the suspension was filtered. The filter cake was washed
with cold (circa -10°C) EtOH and was dried at 60°C/5 mbar to give 109 g of title compound as
light yellow crystals.
THF process
Alternatively, tert-butyl rophenylcarbamate (120 g, 511 mmol, Eq: 1.00) was
dissolved in tetrahydrofuran (THF) (745 g, 840 mL). The solution was cooled to -30°C.
,N'-tetramethylethylenediamine (129 g, 168 mL, 1.1 mol, Eq: 2.15) was added. NButyllithium
2.5 M in hexanes (613 mL, 1.53 mol, Eq: 3.00) was added over 60 min between -
°C and -20°C. After 5 h at -30°C, DMF (112 g, 118 mL, 1.53 mol, Eq: 3.00) was added over
45 min between -30° and -20°C. 25% HCl (522 g, 435 mL, 3.58 mol, Eq: 7.0) was added over 30
min at -30°C to 0°C (pH 4-5). The aqueous phase was ted and extracted with a mixture of
THF (106 g, 120 mL) and hexanes (79.1 g, 120 mL). The organic phases were washed
sequentially with half saturated aqueous NaCl (240 mL), 5% aqueous NaHCO3 (240 mL) and
half saturated aqueous NaCl (240 mL). The organic phases were combined and concentrated to
circa 300 mL and split in two.
Part 1 was diluted with THF (887 g, 1 L) and azeotroped at 45°C / 400 mbar. The
solution was t exchanged to methanol to give 285 g of a yellow suspension (residual water:
0.14 %). 9.8 M Methylamine in methanol (36.5 mL, 358 mmol, Eq: 1.4 ve to theoretical
aldehyde content) were added. A clear yellow solution was obtained. After 15 min the imine
started to crystallize (in case no spontaneous crystallization is observed, seeding is performed).
After 2 h at 20-25°C the suspension was stirred for 1 h at 40°C, cooled to -10°C for 1 h and
filtered. The filter cake was washed with cold (-10°C) methanol (47.5 g, 60 mL) and dried at
40°C under reduced pressure to give 57 g of the title compound as a light yellow powder.
Part 2 was azeotroped and solvent exchanged to ethanol at 45°C / 200 mbar to give 281 g
of a yellow suspension : < 0.1 %). 9.8 M Methylamine in methanol (36.5 mL, 358 mmol,
Eq: 1.4 to theoretical aldehyde t) was added at RT. After 4 h at RT and 1 h at -10°C, the
suspension was filtered. The filter cake was washed with cold (-10°C) ethanol (47.4 g, 60 mL)
and was dried at 40°C under reduced pressure to give 51.5 g of the title compound as a yellow
powder.
utyl hloro[(E)-methyliminomethyl]phenyl]carbamate IX
XXV IX
tert-Butyl 4-chloroformylphenylcarbamate (38 g, 149 mmol, Eq: 1.00) was suspended
in methanol (195 g, 247 mL). 9.8 M methylamine solution in methanol (21.2 mL, 208 mmol, Eq:
1.40) was added over 30 min at RT. The reaction mixture was d 1 h and the resulting
solution was cooled to -10°C (at circa 0°C the product started to crystallized spontaneously).
After 2 h at -10°C, the suspension was filtered. The filter cake was washed with cold (-10°C)
methanol (15.0 g, 19.0 mL) and dried under reduced pressure (10 0°C to give) 36.4 g of
the title compound as a white crystalline powder.
tert-Butyl N-[4-chloro(methylaminomethyl)phenyl]carbamate VIII
IX VIII
tert-Butyl N-[4-chloro[(E)-methyliminomethyl]phenyl]carbamate (50 g, 184 mmol, Eq:
1.00) was dissolved in a mixture of ol (253 g, 320 mL) and THF (142 g, 160 mL). The
solution was cooled to RT. 40% Methylamine in methanol (MeOH) (14.4 g, 185 mmol, Eq: 1.01)
was added followed by acetic acid (AcOH) (22.0 g, 21.0 mL, 365 mmol, Eq: 1.98). Venpure 20-
(sodium borohydride (NaBH4) 20% / sodium hydroxide (NaOH) 20% in water, 35 g, 28.8 mL,
185 mmol, Eq: 1.00) was added at 0°C for 45-60 min. After 30 min, acetone (21.4 g, 27.0 mL,
366 mmol, Eq: 1.99) was added over 30 min at 0°C. After > 0.5 h at 0°C, the reaction mixture
was added to a mixture consisting of 5% aqueous Na2CO3 (500 mL), half saturated aqueous
NaCl (125 mL) and MTBE (370 g, 500 mL). The organic phase was separated and washed with
% aqueous NaCl (210 g, 200 mL). The organic phase was extracted twice with a mixture
consisting of 9 mL formic acid in 0.5 L water. The aqueous phases were combined and washed
twice with MTBE (370 g, 500 mL). The c phases were discarded. MTBE (0.5 L) was
added and the pH was ed to 12-13 by addition of 32 % aqueous NaOH (41.9 g, 31 mL, 335
mmol, Eq: 1.82). The aqueous phase was separated and extracted with MTBE (250 mL). The
c phases were combined and washed with saturated aqueous NaHCO3 (209 g, 200 mL)
and 10% aqueous NaCl (210 g, 200 mL) (pH: 7-8). The crude product on was concentrated
to circa half the volume (KFT < 0.5 % water). The crude product mixture was ed to remove
salts. The solution was concentrated under reduced pressure to give 51 g of crude product (>
99.5 a% by high-performance liquid chromatography (HPLC), contains circa 8% al
MTBE). The crude product solution is solvent exchanged to ethyl acetate (AcOEt) and
introduced in the next step without further purification.
The t can be crystallized from isopropanol (iPrOH)/water:
1.0 g tert-Butyl N-[4-chloro(methylaminomethyl)phenyl]carbamate was dissolved at 40°C in
2-propanol (3.92 g, 5 mL). The clear solution was cooled to RT and water (3.00 g, 3 mL) was
added. The solution was seeded (crude, dried product did slowly crystallize upon standing
providing the first seed crystals) and the crystallization started slowly. After 30 min, water (7.00
g, 7 mL) was added dropwise over 10 min. The white suspension was stirred 1 h at RT and
filtered. The filter cake was washed with water and dried at 40°C/5 mbar to give 1 g of product
as white crystals.
Alternatively, tert-butyl N-[4-chloro[(E)-methyliminomethyl]phenyl]carbamate (2 g, 7.29
mmol, Eq.: 1) was suspended in methanol (20 mL). Pt/C 5% (185 mg) was added, the mixture
was pressurized with hydrogen (5 bar) and stirred at RT. After completion of the reaction, the
catalyst was filtered and the solution was concentrated under reduced re to give 1.85 g of
crude tert-butyl N-[4-chloro(methylaminomethyl)-phenyl]carbamate. The title compound can
be crystallized as described above.
tert-Butyl N-[4-chloro[[cyanomethyl(methyl)amino]methyl]phenyl]carbamate
VIII VII
tert-Butyl N-[4-chloro(methylaminomethyl)phenyl]carbamate (49.9 g, 184 mmol, Eq:
1.00) was dissolved in AcOEt (226 g, 250 mL). Sodium hydrogen carbonate (16.6 g, 198 mmol,
Eq: 1.07) and potassium iodide (KI) (6 g, 36.0 mmol, Eq: 0.196) were added in one portion. 2-
chloroacetonitrile (15.4 g, 13.0 mL, 200 mmol, Eq: 1.09) was added in one portion and the
reaction e was heated at reflux for 15 h (< 2% starting material). The on e was
cooled to RT. 10% Aqueous NaCl (262 g, 250 mL) was added. The organic phase was separated
and washed with half saturated aqueous NaHCO3 (261 g, 250 mL). The organic phase was
d ght together with 10% aqueous sodium thiosulfate (291 g, 250 mL, 184 mmol, Eq:
1.00) and tetrabutylamonium chloride (1 g, 3.6 mmol, Eq: 0.02). The organic phase was
separated and washed with 10% aqueous NaCl (262 g, 250 mL). The organic phase was
concentrated to circa half the volume and was filtered. The volume was adjusted to circa 200 mL
with EtOH and the solution was solvent exchanged to EtOH at constant volume. The on
was cooled to circa 28-30°C and was seeded. After 30 min, the suspension was cooled to RT and
water (40 mL) was added dropwise. The suspension was stirred overnight at RT and 2 h at 0-5°C.
The suspension was filtered. The filter cake was washed with EtOH/water 1:1 (100 mL) and was
dried at 60°C/5 mbar to give 46.8 g of title compound as white crystals.
tert-Butyl N-[4-chloro[[cyanomethyl(methyl)amino]methyl]phenyl]carbamate VI
VIII VII
tert-Butyl 4-chloro((methylamino)methyl)phenylcarbamate (9.0 g, 31.6 mmol, Eq:
1.00) was dissolved in ethyl acetate (40.6 g, 45.0 mL). Sodium onate (3.18 g, 37.9 mmol,
Eq: 1.2) was added followed by potassium iodide (1.06 g, 6.34 mmol, Eq: 0.201). 2-
chloroacetonitrile (2.92 g, 2.46 mL, 37.9 mmol, Eq: 1.2) was added, the suspension was heated
up to 78°C (oil bath 80°C) and stirred overnight. The reaction mixture was cooled to RT, and
water (22.5 g, 22.5 mL) was added. The organic phase was separated and washed with half
saturated aqueous NaHCO3 (22.5 mL), a 10% aqueous sodiumthiosulfate solution (22.5 mL) and
water (22.5 g, 22.5 mL). The organic phase was concentrated under d pressure (45°C/ 180
mbar, circa 50 mL) to circa half the volume. The crude product solution was solvent ged
to 2-propanol (final volume circa 30 mL). The 2-propanol-solution was seeded and stirred for 1 h
at RT, then the white sion was cooled to 0°-2°C, stirred for another hour and filtered over
a glass sintered funnel. The crystals were washed with cold 2-propanol (7.84 g, 10 mL) and dried
until constant weight (5 mbar/ 50°C) to give 8.8 g of the title compound as a white crystalline
powder.
7-Chloromethyl-3,5-dihydro-1,4-benzodiazepinamine dihydrochloride III
. 2 HCl
VII III
2-Propanol (312 g, 400 mL) was charged in the reactor at 20-25°C. Acetyl chloride
(AcCl) (255 g, 231 mL, 3.22 mol, Eq: 9.97) was added dropwise over 45 min. After 15 min a
warm (45-55°C) solution of tert-butyl N-[4-chloro
[[cyanomethyl(methyl)amino]methyl]phenyl]carbamate in anol (468 g, 600 mL) was
added over 45-60 min keeping the temperature between C during which most of the Bocdeprotection
happens and the ation step started. After 2 h at 40°C, AcCl (127 g, 115 mL,
1.6 mol, Eq: 4.97) was added dropwise at 35-40°C. After 4 h at 40°C,
AcCl (127 g, 115 mL, 1.6 mol, Eq: 4.97) was added at 35-40°C. The suspension was stirred
ght at 40°C. The reaction mixture was concentrated at C, under reduced pressure to
a volume of circa 400 mL. The suspension was solvent exchanged at constant volume with
further anol (936 g, 1.2 l) and was stirred > 1 h at RT. The suspension was filtered and the
filter cake was washed with 2-propanol (195 g, 250 mL). The crystals were dried at 60°C/10
mbar to give 85.8 g of t as white crystals (99.2 a% purity by HPLC).
8-Chloromethyl[4-(2-pyridyloxy)cyclohexyl]-4,6-dihydro-[1,2,4]triazolo[4,3-
a][1,4]benzodiazepine I, form A
. 2 HCl
. n HCl
pH adjustement
drying filtration
I, Form A I, Form H . HCl
romethyl-3,5-dihydro-1,4-benzodiazepinamine dihydrochloride (92.3 g, 326
mmol, Eq: 1.00) and 4-(2-pyridyloxy)cyclohexanecarbohydrazide (76.8 g, 326 mmol, Eq: 1.00)
were charged in the reactor followed by 2-propanol (504 g, 646 mL). The suspension was heated
at reflux for 18 h at C (until complete conversion of the amidine and the intermediate).
The reaction mixture was cooled down to RT while water (775 g, 775 mL) was added. The
almost clear solution was filtered. The filter was washed with water (24.9 g, 24.9 mL) to give 1.5
L of crude product solution (pH 4).
The filtrate (1.5 L) was split in 2 portions: 1 L into reactor B (217 mmol theory) and 0.5
L into reactor A (109 mmol theory).
Compound I is best isolated as free base. However, its hydrochloride can also be isolated:
after complete conversion of the amidine and the intermediate, the reaction mixture is cooled to
0-5°C. The resulting suspension is stirred for 1 h at 0-5°C and filtered. The filter cake is washed
with cold panol and dried under reduced pressure 50°C/10 mbar to give I.HCl.
Reactor A, pH 9-10 crystallization.- 1.7 equiv NaOH
8% Aqueous NaOH (Ca. 95 g,,corresponds to circa 1.7 equiv.) was added over 15 min,
maintaining the temperature between 20-25°C (spontaneous cryst. at 79g addition, pH 10 at end
of addition). Seed crystals of I, form A (75 mg) were added (in case the crystallization is not
spontaneous). The light yellow suspension was stirred for 1.5 h at RT and was cooled to 0-5°C
within 30 min. After 5 h stirring at 0-5°C, the suspension was filtered. The filter cake (form H)
was washed with cold (0-5°C) 2-propanol / water 1:2 (123 mL), and water (42.0 g, 42 mL), and
dried at 60°C under reduced pressure to give 38.4 g of the title compound as a white crystalline
powder (crystalline form A by powder X-Ray analysis, 99.3 a% purity by HPLC, 0.4 a%
compound of formula VI’).
Reactor B, pH ≥12 crystallization:
The pH was set to ≥ 12 by addition of 222 g of a circa 8% aqueous NaOH (circa 2 equiv.)
over 30 min maintaining the temperature between 20-25°C (pH 10-11 after 201 g added,
spontaneous cryst. after addition of 130 g). Seed crystals of I, form A (75 mg) were added (in
case the crystallization is not spontaneous). The yellow sion was stirred for 2 h at RT then
cooled to 0-5°C for 30 min. After 5 h stirring at 0-5°C, the suspension was filtered. The filter
cake (form H) was washed with cold ) 2-propanol / water 1:2 (246 mL), and water (83.0 g,
83 mL), and dried at 60°C under reduced re to give 74.6 g of the title compound as white
crystalline powder % purity by HPLC, nd of formula VI’ was not detected, form A
by powder X-Ray analysis).
8-chloromethyl[4-(2-pyridyloxy)cyclohexyl]-4,6-dihydro-[1,2,4]triazolo[4,3-
a][1,4]benzodiazepine I, form F
I, Form A I, Form F
8-Chloromethyl[4-(2-pyridyloxy)cyclohexyl]-4,6-dihydro-[1,2,4]triazolo[4,3-
a][1,4]benzodiazepine (38.1 g, 92.8 mmol, Eq: 1.00) was suspended in methyl acetate (698 g,
750 mL), the suspension was heated to 55°C. The resulting turbid solution was filtered and
cooled to C within 30 min. The solution was seeded with 0.75 g of nd with
a I, form F and cooled over 2 h to RT. The suspension was stirred overnight and circa 550
mL methyl acetate (MeOAc) was exchanged at constant volume (Tj max 45°C / 400-450 mbar)
with n-heptane (374 g, 550 mL) targeting circa 45-55% m/m MeOAc content.
The suspension was cooled to 0°C and stirred at 0°C for > 4 h. The suspension was filtered. The
filter cake was washed with n-heptane (102 g, 150 mL) and dried at 60°C under reduced pressure
to give 36 g of the title nd as crystalline form F (by powder X-ray analysis).
8-Chloromethyl[4-(2-pyridyloxy)cyclohexyl]-4,6-dihydro-[1,2,4]triazolo[4,3-
a][1,4]benzodiazepine I, form F
8-Chloromethyl[4-(2-pyridyloxy)cyclohexyl]-4,6-dihydro-[1,2,4]triazolo[4,3-
a][1,4]benzodiazepine (13.6g) was dissolved in anol (213 g, 272 mL) at 55°C. The hot
solution was filtered. The solution was concentrated to circa 130-140 mL. n-Heptane (93.0 g,
136 mL) was added at 55°C for 15 min. The clear solution was cooled to circa 45°C and was
seeded with 300 mg of crystalline I, form F. The mixture was cooled within 20 h to 0°C. The
ing sion was filtered. The filter cake was washed with cold (0°C) 2-propanol / n -
heptane 1:1 (54.4 mL) and dried to give 11.7 g of the title compound as crystalline form F (by
powder X-ray is).
Trans(2-pyridyloxy)cyclohexanecarboxylic acid XXIII
XXIV XXIII
Sodium tert-amyloxide (tAmONa) (444 g, 3.83 mol, Eq: 2.26) was charged in the reactor
followed by N-methylpyrrolidone (NMP) (2.06 kg, 2 L) and heated at Tj=90°C. A on of
transhydroxycyclohexanecarboxylic acid (244 g, 1.69 mol, Eq: 1.00) in NMP (515 g, 500 mL)
was added over 15 min at 80-85°C. 2-Chloropyridine (239 g, 2.11 mol, Eq: 1.24) was added over
5 min at 80-85°C. After > 60 h, the reaction mixture was cooled to 50°C and water (8.00 kg, 8 L)
at 50°C. The reaction mixture was cooled to RT. The pH was adjusted to circa 5 with 25%
aqueous HCl (280 g, 250 mL). The suspension was cooled to 0-5°C, stirred for > 2 h and was
filtered. The filter cake was washed with water (8.00 kg, 8 L) and was dried at 50°C under
reduced pressure to give 245 g of the title compound (>99 a% purity by gas chromatography
(GC)).
Trans(2-pyridyloxy)cyclohexanecarbohydrazide VI
XXIII VI
1,1'-Carbonyldiimidazole (CDI) (215 g, 1.32 mol, Eq: 1.21) was ded in THF (1.07
kg, 1.2 L) at 20°C. A solution of trans (2-pyridyloxy)cyclohexanecarboxylic acid (243 g, 1.1
mol, Eq: 1.00) in THF (1.07 kg, 1.2 L, Eq: -) was added over 70 mi n. After 16 h, the reaction
e was degassed (vacuum/N2 cycles). About 100 mL of solvent were distilled off under
reduced pressure at Tr < 30°C. The resulting activated acid solution was added at 15-25°C to a
solution of hydrazine monohydrate (75.2 g, 73 mL, 1.5 mol, Eq: 1.4) in THF (1.07 kg, 1.3 L) /
water (1.2 kg, 1.3 L). After > 2 h stirring at 20-25°C, 3.2 L of solvent were distilled at Tj 50-
55°C / 300 - 200 mbar while continuously adding 3.5 L of water. The resulting suspension was
stirred overnight at RT and filtered. The filter cake was washed with water (750 g, 0.75 L) and
dried at 50°C under reduced pressure to give 223 g of the title compound (98.9 a% by HPLC,
0.4% of compound of a VI’).
1-(5-Chloronitro-phenyl)-N-methyl-methanimine XIV
XV XIV
ronitrobenzaldehyde (45 g, 243 mmol, Eq: 1.00) was treated with 2 M
methylamine in MeOH (141 g, 180 mL, 360 mmol, Eq: 1.48). The reaction mixture was stirred
at RT for 5 h and concentrated under reduced re to give 48.06 g of the title compound. The
crude product is introduced directly in the next step without further purification.
1-(5-Chloronitro-phenyl)-N-methyl-methanamine XIII
reduction
XIV XIII
(E)-N-(5-Chloronitrobenzylidene)methanimine (47.5 g, 239 mmol, Eq: 1.00) was
dissolved in methanol (447 g, 565 mL). The solution was cooled to 0°C and sodium borohydride
(7.64 g, 194 mmol, Eq: 0.811) was added in portions over 25 min. The reaction mixture was
stirred overnight at RT (circa 98% conversion). Further sodium borohydride (1.77 g, 44.9 mmol,
Eq: 0.19) was added and the reaction mixture was stirred for 3 h. The t ged to
dichloromethane (DCM) (final volume circa 400 mL) and washed with saturated aqueous
NaHCO3 (200 mL). The aqueous phase was separated and extracted twice with
DCM (318 g, 240 mL). The organic phases were washed sequentially twice with half saturated
aqueous NaHCO3 (200 mL). The organic phases were combined, dried over magnesium sulfate
(MgSO4) and trated under reduced pressure to give 47.1 g of the title compound.
4-Chloro(methylaminomethyl)aniline XII
XIII XII
1-(5-Chloronitro-phenyl)-N-methyl-methanamine (23 g, 109 mmol, Eq.: 1) was
ved in methanol (690 mL), 46% Raney-Nickel (6.91 g, 55 mmol, 0.5 equiv.) was added
and the mixture was stirred under a en here (1 bar) at RT. After completion of the
reaction, the suspension was filtered and the filtrate was concentrated under d pressure to
give 19 g of the crude title compound.
1-(5-Chloronitro-phenyl)-N-methyl-methanamine hydrochloride XIII.HCl
. HCl
XVI XIII.HCl
40% Methylamine in methanol (90.0 mL, 882 mmol, Eq: 12.1) was charged in the reactor
and a solution of ro(chloromethyl)nitrobenzene (15 g, 72.8 mmol, Eq: 1.00) in
MeOH (94.8 g, 120 mL) was added dropwise over 50 min at RT The light yellow solution was
stirred at RT for 5.5 h (until completion of the reaction). The reaction mixture was concentrated
under reduced pressure to give 21.5 g of a yellow solid which was taken up in AcOEt (108 g,
120 mL). The resulting suspension was filtered. The filter cake (methylamine hydrochloride)
was washed three times with AcOEt (135 g, 150 mL). The filtrate was evaporated to afford 14.6
g of a yellow oil. The crude 1-(5-chloronitro-phenyl)-N-methyl-methanamine was dissolved
in AcOEt (108 g, 120 mL). 4.4 M en chloride (HCl) in AcOEt (33.6 mL, 147 mmol, Eq:
2.02) was added slowly. The resulting pale yellow suspension was stirred overnight at RT. The
suspension was filtered. The filter cake was washed twice with AcOEt and dried at 10 mbar,
50°C to give 15.6 g of the title compound as a light yellow powder.
4-Chloro(methylaminomethyl)aniline hydrochloride l
. HCl . HCl
XIII.HCl XII.HCl
1-(5-Chloronitro-phenyl)-N-methyl-methanamine hloride (50 g, 208 mmol, Eq.:
1) was dissolved in methanol (790 mL), 46% Raney-Nickel (13 g,104 mmol, 0.5 equiv.) was
added and the mixture was stirred under a hydrogen atmosphere (1 bar) at RT. After completion
of the reaction, the suspension was filtered and the filtrate was concentrated under reduced
pressure to give 43 g of the crude title compound.
The crude t can be crystallized:
The crude product (22.5 g) was dissolved in methanol (400 mL). Water (3.7 mL) and
activated charcoal (2.5 g) were added. The suspension was heated to 50°C, then cooled to RT
and filtered. The filtrate was concentrated under reduced pressure to circa half the volume.
Isopropanol (200 mL) was added and the solution was concentrated under reduced pressure to
circa 220 g during which crystallization d leading to a thick suspension. Isopropanol (50
mL) was added. The suspension was stirred 2 h at RT and was filtered. The filter cake was
washed with isopropanol (30 mL) and was dried at 50°C/10 mbar to give 15 g of the title
compound as an off-white powder.
2-[(2-Aminochloro-phenyl)methyl-methyl-amino]acetonitrile XI
. HCl
XII.HCl XI
ro((methylamino)methyl)aniline hydrochloride (10 g, 48.3 mmol, Eq: 1.00) was
suspended in acetonitrile (78.0 g, 100 mL). Sodium hydrogen ate (8.92 g, 106 mmol, Eq:
2.2) was added and the suspension was heated to 85°C. 2-chloroacetonitrile (3.91 g, 3.28 mL,
50.7 mmol, Eq: 1.05) was added and the reaction mixture was stirred for 24 h. The reaction
mixture was cooled to RT and water (150 g, 150 mL) was added. Toluene (173 g, 200 mL) was
added and most of the acetonitrile was removed at the rotavapor. The aqueous phase was
separated and extracted with toluene (86.7 g, 100 mL). The organic phases were washed with
half saturated aqueous NaHCO3 (100 mL) and half saturated aqueous NaCl. The organic phases
were combined, dried over MgSO4, filtered and concentrated under d pressure to give 9.95
g of the tile compound as a light yellow solid. Alternatively, the tion can also be performed
using the free base XII as starting material.
Trans-N'-(2-chloroacetyl)(2-pyridyloxy)cyclohexanecarbohydrazide XXI
VI XXI
Trans(2-pyridyloxy)cyclohexanecarbohydrazide (4 g, 17.0 mmol, Eq: 1.00) was
suspended in DCM (66.2 g, 50.0 mL). 2,4,6-Trimethylpyridine (sym-collidine) (2.29 g, 2.5 mL,
18.7 mmol, Eq: 1.1) was added. The sion was cooled to 0°C and 2-chloroacetyl chloride
(2.04 g, 1.43 mL, 17.9 mmol, Eq: 1.05) was added se over 30 min at 0-5°C. After 1 h at
0-5°C, the suspension was filtered. The filter cake was washed with cold dichloromethane (40
mL) and dried under reduced pressure at 40°C to give 5.1 g of the title compound.
Trans(chloromethyl)[4-(2-pyridyloxy)cyclohexyl]-1,3,4-oxadiazole XX
XXI XX
N'-(2-Chloroacetyl)(2-pyridyloxy)cyclohexanecarbohydrazide (44 g, 141 mmol, Eq:
1.00) was suspended in itrile (257 g, 330 mL, Eq: -). The suspension was cooled to 0°C
and triflic anhydride (48.8 g, 28.7 mL, 169 mmol, Eq: 1.2) was added over 30 min. The reaction
was stirred at RT until > 95% conversion (> 15 h). The ing solution was cooled to 0°C and
a solution of sodium hydrogen carbonate (27.0 g, 322 mmol, Eq: 2.28) in water (440 g, 440 mL)
was added followed by dichloromethane (437 g, 330 mL). The aqueous phase was extracted
twice with dichloromethane (662 g, 500 mL). The organic phases were washed sequentially with
half saturated aqueous NaCl (500 mL). The organic phases were combined, dried over MgSO4,
filtered and concentrated under reduced pressure to give 44.0 g of the crude title compound.
Crystallization: The crude product (39.0 g) was crystallized from isopropanol to give 19.08 g of
the title compound.
Transchloro[[methyl-[[5-[4-(2-pyridyloxy)cyclohexyl]-1,3,4-oxadiazol
yl]methyl] amino] methyl]aniline XIX
XX XIX
Trans(chloromethyl)[4-(2-pyridyloxy)cyclohexyl]-1,3,4-oxadiazole (6.7 g, 21.9
mmol, Eq: 1.00), 4-chloro((methylamino)methyl)aniline (4.33 g, 24.1 mmol, Eq: 1.1), sodium
en carbonate (2.21 g, 26.3 mmol, Eq: 1.2) and acetonitrile (54.8 g, 70.3 mL) were charged
in the reactor and heated at reflux for 4 h. onal 4-chloro((methylamino)methyl)aniline
(393 mg, 2.19 mmol, Eq: 0.1) was added and the reaction mixture was stirred for 20 h at reflux.
The reaction mixture was cooled to RT. Water (20.0 g, 20.0 mL) and dichloromethane (79.5 g,
60.0 mL) were added. The aqueous phase was separated and extracted with dichloromethane
(26.5 g, 20.0 mL). The organic phases were washed sequentially with saturated s
ammonium chloride (NH4Cl) (25.0 mL), 10% aqueous NaCl (25.0 mL) and saturated aqueous
NaCl (25.0 mL). The organic phases were combined, dried over MgSO4 and filtered. The te
was filtered over 25 g of silica gel (SiO2) and concentrated under reduced re to give 5.3 g
of the title compound.
Transchloromethyl[4-(2-pyridyloxy)cyclohexyl]-4,6-dihydro-
[1,2,4]triazolo[4,3-a][1,4] benzodiazepine I
XIX I
Transchloro[[methyl-[[5-[4-(2-pyridyloxy)cyclohexyl]-1,3,4-oxadiazolyl]methyl]
amino] methyl]aniline (5 g, 10.1 mmol, Eq: 1.00) was dissolved in tetrahydrofuran
(44.4 g, 50 mL). Trifluoroacetic acid (2.02 g, 1.36 mL, 17.4 mmol, Eq: 1.72) was added and the
reaction mixture was heated to 60°C for 2.5 h. The reaction was cooled to RT, saturated aqueous
NaHCO3 (25 mL) was added (pH=8) and the e was stirred for 15 min (formation of a
yellow suspension). Water (25.0 g, 25 mL) and AcOEt (36.1 g, 40 mL) were added. After 30 min
stirring, the aqueous phase was separated and extracted with AcOEt (18.0 g, 20 mL). The
organic phases were washed twice with saturated aqueous NaCl (17 mL) (pH ~7). The c
phases were combined, dried over MgSO4, ed and concentrated under reduced pressure to
give 5.03 g of the crude title compound. The crude product was taken up in isopropanol (20 mL)
and evaporated, redissolved again in isopropanol (20 mL) and evaporated. The residue was
dissolved in isopropanol (11.8 g, 15 mL) and seeded with I, form F. The crystallization started
and the sion was stirred for 18 h at RT. The suspension was filtered. The filter cake was
washed twice with isopropanol (7.84 g, 10 mL) and dried under reduced pressure to give 3.11 g
of the title compound (form F by X-Ray powder diffraction).
4-Chloro(methylaminomethyl)aniline dihydrochloride XII.2HCl
. 2 HCl
VIII XII.2HCl
tert-Butyl 4-chloro((methylamino)methyl)phenylcarbamate (1.0 g, 3.69 mmol, Eq:
1.00) was ved in AcOEt (4.5 g, 5.00 mL). 4 M HCl in AcOEt (4.62 mL, 18.5 mmol, Eq:
.00) was added. The resulting sion was heated overnight at 40°C. The suspension was
cooled to RT, stirred for 1 h and filtered. The filter cake was washed with AcOEt (20 mL) and
was dried under reduced pressure at 50°C to give 0.9 g of the title compound.
2-[(2-Aminochloro-phenyl)methyl-methyl-amino]acetonitrile
. 2 HCl
XII.2HCl XI
4-Chloro((methylamino)methyl)aniline dihydrochloride from us step (0.8 g,
3.28 mmol, Eq: 1.00) was suspended in acetonitrile (6.24 g, 8.00 mL). Sodium hydrogen
carbonate (883 mg, 10.5 mmol, Eq: 3.2) was added. The white suspension was heated to 85°C.
2-chloroacetonitrile (266 mg, 223 µl, 3.45 mmol, Eq: 1.05) was added and stirred overnight at
85°C. The reaction mixture was cooled to RT, water (12.0 g, 12.0 mL) was added and the
mixture was stirred for 10 min. Toluene (13.9 g, 16.0 mL) was added and most of the acetonitrile
was removed under reduced pressure. The aqueous phase was separated and extracted with
toluene (6.94 g, 8.00 mL). The organic phases were washed with half saturated aqueous
NaHCO3 (8.00 mL) and half saturated NaCl (8.00 mL), dried over MgSO4, filtered and
concentrated under reduced pressure to give 840 mg of the title nd. The crude product
was ved in MTBE (5 mL) at reflux. The ess solution was slowly cooled to RT. The
resulting white suspension was filtered. The filter cake was washed with n-heptane (20 mL) and
dried under reduced pressure to give 410 mg of the title compound as a white powder.
4-Chloro(methylaminomethyl)aniline XII
1. MeNH2
2. NaBH4
XXVI XII
2-Aminochlorobenzaldehyde (500 mg, 3.12 mmol, Eq: 1.00) was dissolved at RT in
ethanol (5.93 g, 7.50 mL). 41% Aqueous methylamine on (472 mg, 527 µl, 6.23 mmol, Eq:
2.00) was added and the yellow solution was stirred for 1 h at RT. NaBH4 (118 mg, 3.12 mmol,
Eq: 1.00) was added and the suspension was stirred for 18 h at RT. Ethylacetate (18.0 g, 20 mL)
and half saturated s NaCl (20 mL) were added. The organic phase was separated, dried
over MgSO4, filtered and was evaporated to dryness to give 550 mg of the title compound.
7-Chloromethyl-3,5-dihydro-1,4-benzodiazepinamine II
. 2 HCl
III II
7-Chloromethyl-4,5-dihydro-1H-benzo[e][1,4]diazepin-2(3H)-imine ochloride
(1.75 g, 6.19 mmol, Eq: 1.00) was suspended in AcOEt (50 mL). Saturated aqueous sodium
hydrogen carbonate (30 mL) was added and the mixture was stirred for 30 min at RT. The
aqueous phase was ted and extracted twice with AcOEt (20 mL). The organic phases were
combined, dried over MgSO4, filtered and concentrated under reduced pressure to give 930 mg
of the title compound.
7-Chloromethyl-3,5-dihydro-1,4-benzodiazepinamine dihydrochloride III
. 2 HCl
XI III
2-((2-Aminochlorobenzyl)(methyl)amino)acetonitrile (11.1 g, 51.4 mmol, Eq: 1.00)
was dissolved with trifluoroethanol (138 g, 100 mL). 4M HCl in dioxane (38.5 mL, 154 mmol,
Eq: 3.0) was added. The on mixture was stirred 6 h at 40°C until completion then
concentrated under reduced pressure to give 17.95 g of the title compound (contains ca 9%
dioxane and 11% residual trifluoroethanol).
Alternatively, compound of formula XI can be reacted to compound of formula III under
conditions similar to the one used for the direct transformation of compound of formula VII to
compound of formula III as described in a us example.
tert-Butyl N-[4-chloro(methylaminomethyl)phenyl]carbamate acetic acid salt
VIII.AcOH
. AcOH
VIII VIII. AcOH
utyl 4-chloro((methylamino)methyl)phenylcarbamate (1.0 g, 3.1 mmol, Eq: 1.00)
was dissolved in MTBE (8.21 g, 12 mL) at RT. Acetic acid (206 mg, 196 µl, 3.41 mmol, Eq: 1.1)
was added dropwise during which the product started to crystallize. After 2 h at RT, the
suspension was filtered. The filter cake was washed with MTBE and dried under d
pressure (10 0°C) to give 0.58 g of the title compound.
1 Genes, Brain and Behavior (2011) 10: 228–235
2 Curr. Opin. Neurobiol. 19, 231-234 (2009)
3 WO2010060836
4 WO2004074291 and WO2005068466
Aubé et al, J. Org. Chem., Vol. 65, No. 3, 2000
6 Caron, L. Wei, J. Douville, A. Ghosh, J. Org. Chem. 2010, 75, 945–947
7 WO2005/68466
8 Venkov et al, Synthesis, 1990, 253
9 WO2004074291, WO2005068466 and WO2006021882
The following ed aphs define some particular embodiments of the present
disclosure:
1. A crystalline form of a compound of formula I
2. The lline form A of the compound of formula I according to paragraph 1,
terized by a X-ray powder diffraction pattern having the teristic peaks expressed in
values of degrees 2-theta at approximately
degree 2-theta degree 2-theta degree 2-theta
13.0 18.1 21.9
13.5 18.9 23.9
14.5 19.5 27.2
.9 20.6
17.8 21.0 .
3. The crystalline form A according to any one of paragraphs 1-2, characterized by the X-ray
powder diffraction pattern as shown in figure 1.
4. The crystalline form F of the compound of formula I according to paragraph 1,
characterized by a X-ray powder diffraction pattern having the characteristic peaks expressed in
values of degrees 2-theta at approximately
degree 2-theta degree 2-theta degree 2-theta
8.6 15.7 23.0
8.9 17.9 24.0
11.4 19.5 26.5
12.2 20.7 27.0
.2 22.6 .
. The crystalline form F according to any one of paragraphs 1 or 4, characterized by the X-
ray powder diffraction pattern as shown in figure 16.
6. A process to synthesize a compound of a I according to paragraph 1, comprising
reacting a compound of formula II with a compound of formula VI
. 2 HCl
III VI I .
7. The process according to paragraph 6, further sing reacting a compound of formula
XI to a compound of formula III:
. 2 HCl
XI III .
8. The s according to any one of paragraphs 6-7 further comprising reacting a
compound of formula X to a nd of formula XI or a pharmaceutically acceptable salt
f via the following steps:
X IX VIII VII XI .
9. The process according to any one of paragraphs 6-7 further comprising reacting a
compound of formula XV to a compound of formula XI or a pharmaceutically acceptable salt
thereof via the following steps:
XV XIV XIII XII XI .
The process according to any one of paragraphs 6-7 further comprising reacting a compound of
formula XXVI to a compound of formula XI or a pharmaceutically acceptable salt thereof via the
following steps
XXVI XII XI .
11. A process to synthesize a compound of a I, comprising the step of reacting a
nd of formula XII with a compound of formula XX
XII XX XIX I
12. A process to size a compound of formula I according to paragraph 11, further
comprising the following steps:
XXIV XXIII VI
XX XXI
The process according to any one of paragraphs 6-7, whereby a compound of formula INT is
formed as intermediate:
INT.
14. Intermediate compound II or a salt thereof III:
II: free base, III: .2HCl.
. A compound of formula I or a pharmaceutically acceptable salt, whenever prepared by a
process ing to any one of paragraphs 6-13.
16. The crystalline form H of the compound of formula I according to paragraph 1,
characterized by a X-ray powder diffraction pattern having the characteristic peaks expressed in
values of degrees 2-theta at approximately
degree 2-theta degree 2-theta degree 2-theta
12.8 18.6 23.6
14.2 20.8 25.3
17.0 21.2 28.4
17.7 22.2 .
In this specification where nce has been made to patent specifications, other external
documents, or other sources of information, this is generally for the purpose of providing a
context for discussing the features of the invention. Unless specifically stated otherwise,
nce to such external documents is not to be construed as an admission that such documents,
or such s of ation, in any jurisdiction, are prior art, or form part of the common
general knowledge in the art.
Claims (3)
1. A process to size a compound of formula I, comprising the following steps: XII XX XIX I .
2. A process to synthesize a compound of formula I according to claim 1, further sing 5 the following steps: XXIV XXIII VI XX XXI .
3. The process according to any one of claims 1–2 substantially as herein described with reference to any example thereof.
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
EP13195864.7 | 2013-12-05 | ||
EP13195864 | 2013-12-05 | ||
NZ720340A NZ720340A (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 crystalline forms thereof |
Publications (2)
Publication Number | Publication Date |
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NZ759478A NZ759478A (en) | 2021-06-25 |
NZ759478B2 true NZ759478B2 (en) | 2021-09-28 |
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