CN100537549C - N-芳基吗啉酮的制备方法 - Google Patents
N-芳基吗啉酮的制备方法 Download PDFInfo
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- CN100537549C CN100537549C CNB2004800225813A CN200480022581A CN100537549C CN 100537549 C CN100537549 C CN 100537549C CN B2004800225813 A CNB2004800225813 A CN B2004800225813A CN 200480022581 A CN200480022581 A CN 200480022581A CN 100537549 C CN100537549 C CN 100537549C
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- China
- Prior art keywords
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- compound
- phenyl
- hal
- salt
- Prior art date
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- 238000004519 manufacturing process Methods 0.000 title claims abstract description 4
- 150000001875 compounds Chemical class 0.000 claims abstract description 54
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 45
- 238000000034 method Methods 0.000 claims description 38
- 238000006243 chemical reaction Methods 0.000 claims description 27
- 238000002360 preparation method Methods 0.000 claims description 24
- 150000003839 salts Chemical class 0.000 claims description 23
- 125000004432 carbon atom Chemical group C* 0.000 claims description 19
- 238000007363 ring formation reaction Methods 0.000 claims description 8
- 230000008569 process Effects 0.000 claims description 7
- 239000012442 inert solvent Substances 0.000 claims description 6
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Substances [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 6
- 235000015320 potassium carbonate Nutrition 0.000 claims description 6
- OXVFGUUCIPAZSM-UHFFFAOYSA-N 4-(2-nitrophenyl)morpholin-3-one Chemical compound [O-][N+](=O)C1=CC=CC=C1N1C(=O)COCC1 OXVFGUUCIPAZSM-UHFFFAOYSA-N 0.000 claims description 5
- NGYPJPFTRGWDID-UHFFFAOYSA-N 4-(3-nitrophenyl)morpholin-3-one Chemical compound [O-][N+](=O)C1=CC=CC(N2C(COCC2)=O)=C1 NGYPJPFTRGWDID-UHFFFAOYSA-N 0.000 claims description 5
- OWMGEFWSGOTGAU-UHFFFAOYSA-N 4-(4-nitrophenyl)morpholin-3-one Chemical compound C1=CC([N+](=O)[O-])=CC=C1N1C(=O)COCC1 OWMGEFWSGOTGAU-UHFFFAOYSA-N 0.000 claims description 5
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 claims description 5
- RANQDGYXXRUFEF-UHFFFAOYSA-N methyl 4-(3-oxomorpholin-4-yl)benzoate Chemical compound C1=CC(C(=O)OC)=CC=C1N1C(=O)COCC1 RANQDGYXXRUFEF-UHFFFAOYSA-N 0.000 claims description 5
- ACWSFMHEFXSIIZ-UHFFFAOYSA-N 4-(4-benzoylphenyl)morpholin-3-one Chemical compound C=1C=C(N2C(COCC2)=O)C=CC=1C(=O)C1=CC=CC=C1 ACWSFMHEFXSIIZ-UHFFFAOYSA-N 0.000 claims description 4
- VTEJHZFMTZOSFD-UHFFFAOYSA-N [N+](=O)([O-])C1=CC(=C(C=C1)N1C(COCC1)=O)CN Chemical compound [N+](=O)([O-])C1=CC(=C(C=C1)N1C(COCC1)=O)CN VTEJHZFMTZOSFD-UHFFFAOYSA-N 0.000 claims description 4
- 150000001412 amines Chemical class 0.000 claims description 4
- 229910000024 caesium carbonate Inorganic materials 0.000 claims description 4
- 150000002148 esters Chemical class 0.000 claims description 4
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 claims description 3
- 150000003818 basic metals Chemical class 0.000 claims description 2
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 claims 2
- 229910052784 alkaline earth metal Inorganic materials 0.000 claims 1
- 150000001342 alkaline earth metals Chemical class 0.000 claims 1
- 229910052728 basic metal Inorganic materials 0.000 claims 1
- 239000011877 solvent mixture Substances 0.000 claims 1
- 239000002243 precursor Substances 0.000 abstract description 3
- -1 and for example Substances 0.000 description 76
- 239000002585 base Substances 0.000 description 24
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 21
- 239000000203 mixture Substances 0.000 description 20
- 239000002253 acid Substances 0.000 description 17
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 16
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 15
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 14
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 12
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 12
- 125000000217 alkyl group Chemical group 0.000 description 11
- 108010074860 Factor Xa Proteins 0.000 description 9
- 229910052760 oxygen Inorganic materials 0.000 description 9
- 238000003756 stirring Methods 0.000 description 9
- 238000005160 1H NMR spectroscopy Methods 0.000 description 8
- DLFVBJFMPXGRIB-UHFFFAOYSA-N Acetamide Chemical compound CC(N)=O DLFVBJFMPXGRIB-UHFFFAOYSA-N 0.000 description 8
- 125000004430 oxygen atom Chemical group O* 0.000 description 8
- 125000004434 sulfur atom Chemical group 0.000 description 8
- CEWVATDHWSVYRG-UHFFFAOYSA-N 5-chloro-2,3-dihydro-1,4-dioxine Chemical compound ClC1=COCCO1 CEWVATDHWSVYRG-UHFFFAOYSA-N 0.000 description 7
- 239000013078 crystal Substances 0.000 description 7
- 238000010438 heat treatment Methods 0.000 description 7
- 238000001953 recrystallisation Methods 0.000 description 7
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 7
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 6
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 6
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 6
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical class Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- 230000002785 anti-thrombosis Effects 0.000 description 6
- 230000015572 biosynthetic process Effects 0.000 description 6
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 6
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 6
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 6
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 6
- PRAJOOPKIIUZRM-UHFFFAOYSA-N 2,2-dichloro-1,4-dioxane Chemical compound ClC1(Cl)COCCO1 PRAJOOPKIIUZRM-UHFFFAOYSA-N 0.000 description 5
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 5
- 230000005764 inhibitory process Effects 0.000 description 5
- 239000001301 oxygen Substances 0.000 description 5
- 239000011541 reaction mixture Substances 0.000 description 5
- 239000002904 solvent Substances 0.000 description 5
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 4
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 4
- XNWFRZJHXBZDAG-UHFFFAOYSA-N 2-METHOXYETHANOL Chemical compound COCCO XNWFRZJHXBZDAG-UHFFFAOYSA-N 0.000 description 4
- ZNQVEEAIQZEUHB-UHFFFAOYSA-N 2-ethoxyethanol Chemical compound CCOCCO ZNQVEEAIQZEUHB-UHFFFAOYSA-N 0.000 description 4
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 4
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 4
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 4
- 108010054265 Factor VIIa Proteins 0.000 description 4
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 4
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 4
- WGQKYBSKWIADBV-UHFFFAOYSA-N benzylamine Chemical compound NCC1=CC=CC=C1 WGQKYBSKWIADBV-UHFFFAOYSA-N 0.000 description 4
- 238000006073 displacement reaction Methods 0.000 description 4
- 229940012414 factor viia Drugs 0.000 description 4
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 4
- 125000004433 nitrogen atom Chemical group N* 0.000 description 4
- 239000000047 product Substances 0.000 description 4
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 4
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 3
- 229940123583 Factor Xa inhibitor Drugs 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 208000007536 Thrombosis Diseases 0.000 description 3
- 239000003513 alkali Substances 0.000 description 3
- 229960004676 antithrombotic agent Drugs 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
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 3
- 239000000706 filtrate Substances 0.000 description 3
- 235000019253 formic acid Nutrition 0.000 description 3
- 125000000623 heterocyclic group Chemical group 0.000 description 3
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 3
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 3
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 3
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 3
- 230000035479 physiological effects, processes and functions Effects 0.000 description 3
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 3
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 2
- 125000003682 3-furyl group Chemical group O1C([H])=C([*])C([H])=C1[H] 0.000 description 2
- 125000001541 3-thienyl group Chemical group S1C([H])=C([*])C([H])=C1[H] 0.000 description 2
- XYGUMYSLDJVROG-UHFFFAOYSA-N 4-(3-oxomorpholin-4-yl)benzonitrile Chemical compound O=C1COCCN1C1=CC=C(C#N)C=C1 XYGUMYSLDJVROG-UHFFFAOYSA-N 0.000 description 2
- 125000000339 4-pyridyl group Chemical group N1=C([H])C([H])=C([*])C([H])=C1[H] 0.000 description 2
- WREVVZMUNPAPOV-UHFFFAOYSA-N 8-aminoquinoline Chemical compound C1=CN=C2C(N)=CC=CC2=C1 WREVVZMUNPAPOV-UHFFFAOYSA-N 0.000 description 2
- LSNNMFCWUKXFEE-UHFFFAOYSA-M Bisulfite Chemical compound OS([O-])=O LSNNMFCWUKXFEE-UHFFFAOYSA-M 0.000 description 2
- 239000004215 Carbon black (E152) Substances 0.000 description 2
- QGJOPFRUJISHPQ-UHFFFAOYSA-N Carbon disulfide Chemical compound S=C=S QGJOPFRUJISHPQ-UHFFFAOYSA-N 0.000 description 2
- RGHNJXZEOKUKBD-SQOUGZDYSA-N D-gluconic acid Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C(O)=O RGHNJXZEOKUKBD-SQOUGZDYSA-N 0.000 description 2
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 2
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 2
- 239000005977 Ethylene Substances 0.000 description 2
- BWGVNKXGVNDBDI-UHFFFAOYSA-N Fibrin monomer Chemical group CNC(=O)CNC(=O)CN BWGVNKXGVNDBDI-UHFFFAOYSA-N 0.000 description 2
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 2
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 2
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 2
- 239000002841 Lewis acid Substances 0.000 description 2
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 2
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 2
- UFWIBTONFRDIAS-UHFFFAOYSA-N Naphthalene Chemical compound C1=CC=CC2=CC=CC=C21 UFWIBTONFRDIAS-UHFFFAOYSA-N 0.000 description 2
- 206010028980 Neoplasm Diseases 0.000 description 2
- PVNIIMVLHYAWGP-UHFFFAOYSA-N Niacin Chemical compound OC(=O)C1=CC=CN=C1 PVNIIMVLHYAWGP-UHFFFAOYSA-N 0.000 description 2
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 description 2
- 108010000499 Thromboplastin Proteins 0.000 description 2
- 102000002262 Thromboplastin Human genes 0.000 description 2
- XSTXAVWGXDQKEL-UHFFFAOYSA-N Trichloroethylene Chemical compound ClC=C(Cl)Cl XSTXAVWGXDQKEL-UHFFFAOYSA-N 0.000 description 2
- HDUHSISAGHHYRW-UHFFFAOYSA-N [N].N1=CC=CC2=CC=CC=C21 Chemical compound [N].N1=CC=CC2=CC=CC=C21 HDUHSISAGHHYRW-UHFFFAOYSA-N 0.000 description 2
- 150000001298 alcohols Chemical class 0.000 description 2
- 150000001336 alkenes Chemical class 0.000 description 2
- 150000001408 amides Chemical class 0.000 description 2
- 229910021529 ammonia Inorganic materials 0.000 description 2
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 2
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 2
- 238000010523 cascade reaction Methods 0.000 description 2
- 230000008859 change Effects 0.000 description 2
- 150000008280 chlorinated hydrocarbons Chemical class 0.000 description 2
- 230000015271 coagulation Effects 0.000 description 2
- 238000005345 coagulation Methods 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- MTHSVFCYNBDYFN-UHFFFAOYSA-N diethylene glycol Chemical compound OCCOCCO MTHSVFCYNBDYFN-UHFFFAOYSA-N 0.000 description 2
- SBZXBUIDTXKZTM-UHFFFAOYSA-N diglyme Chemical compound COCCOCCOC SBZXBUIDTXKZTM-UHFFFAOYSA-N 0.000 description 2
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 2
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 2
- 208000035475 disorder Diseases 0.000 description 2
- 150000002170 ethers Chemical class 0.000 description 2
- 239000004744 fabric Substances 0.000 description 2
- 238000010265 fast atom bombardment Methods 0.000 description 2
- 229930195733 hydrocarbon Natural products 0.000 description 2
- 150000002430 hydrocarbons Chemical class 0.000 description 2
- 235000011167 hydrochloric acid Nutrition 0.000 description 2
- SUMDYPCJJOFFON-UHFFFAOYSA-N isethionic acid Chemical compound OCCS(O)(=O)=O SUMDYPCJJOFFON-UHFFFAOYSA-N 0.000 description 2
- 150000002576 ketones Chemical class 0.000 description 2
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 2
- 150000007517 lewis acids Chemical class 0.000 description 2
- 238000004949 mass spectrometry Methods 0.000 description 2
- QPJVMBTYPHYUOC-UHFFFAOYSA-N methyl benzoate Chemical compound COC(=O)C1=CC=CC=C1 QPJVMBTYPHYUOC-UHFFFAOYSA-N 0.000 description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 2
- 210000003097 mucus Anatomy 0.000 description 2
- 150000002825 nitriles Chemical class 0.000 description 2
- 150000002828 nitro derivatives Chemical class 0.000 description 2
- LQNUZADURLCDLV-UHFFFAOYSA-N nitrobenzene Chemical compound [O-][N+](=O)C1=CC=CC=C1 LQNUZADURLCDLV-UHFFFAOYSA-N 0.000 description 2
- LYGJENNIWJXYER-UHFFFAOYSA-N nitromethane Chemical compound C[N+]([O-])=O LYGJENNIWJXYER-UHFFFAOYSA-N 0.000 description 2
- 239000003921 oil Substances 0.000 description 2
- BHAAPTBBJKJZER-UHFFFAOYSA-N p-anisidine Chemical compound COC1=CC=C(N)C=C1 BHAAPTBBJKJZER-UHFFFAOYSA-N 0.000 description 2
- 235000011007 phosphoric acid Nutrition 0.000 description 2
- WLJVNTCWHIRURA-UHFFFAOYSA-N pimelic acid Chemical compound OC(=O)CCCCCC(O)=O WLJVNTCWHIRURA-UHFFFAOYSA-N 0.000 description 2
- 230000002265 prevention Effects 0.000 description 2
- 125000004940 pyridazin-4-yl group Chemical group N1=NC=C(C=C1)* 0.000 description 2
- 230000035484 reaction time Effects 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 150000003462 sulfoxides Chemical class 0.000 description 2
- 230000009424 thromboembolic effect Effects 0.000 description 2
- 238000005406 washing Methods 0.000 description 2
- 239000008096 xylene Substances 0.000 description 2
- NHOWDZOIZKMVAI-UHFFFAOYSA-N (2-chlorophenyl)(4-chlorophenyl)pyrimidin-5-ylmethanol Chemical compound C=1N=CN=CC=1C(C=1C(=CC=CC=1)Cl)(O)C1=CC=C(Cl)C=C1 NHOWDZOIZKMVAI-UHFFFAOYSA-N 0.000 description 1
- RBKHNGHPZZZJCI-UHFFFAOYSA-N (4-aminophenyl)-phenylmethanone Chemical compound C1=CC(N)=CC=C1C(=O)C1=CC=CC=C1 RBKHNGHPZZZJCI-UHFFFAOYSA-N 0.000 description 1
- RMSGQZDGSZOJMU-UHFFFAOYSA-N 1-butyl-2-phenylbenzene Chemical group CCCCC1=CC=CC=C1C1=CC=CC=C1 RMSGQZDGSZOJMU-UHFFFAOYSA-N 0.000 description 1
- 125000006218 1-ethylbutyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C([H])([H])[H] 0.000 description 1
- ZMZGFLUUZLELNE-UHFFFAOYSA-N 2,3,5-triiodobenzoic acid Chemical compound OC(=O)C1=CC(I)=CC(I)=C1I ZMZGFLUUZLELNE-UHFFFAOYSA-N 0.000 description 1
- NQOXBEQDOSTNES-UHFFFAOYSA-N 2-(2-chloroethoxy)-n-(3-nitrophenyl)acetamide Chemical class [O-][N+](=O)C1=CC=CC(NC(=O)COCCCl)=C1 NQOXBEQDOSTNES-UHFFFAOYSA-N 0.000 description 1
- AYXBRISMAGJWQK-UHFFFAOYSA-N 2-(2-chloroethoxy)-n-(4-cyanophenyl)acetamide Chemical class ClCCOCC(=O)NC1=CC=C(C#N)C=C1 AYXBRISMAGJWQK-UHFFFAOYSA-N 0.000 description 1
- OXQGTIUCKGYOAA-UHFFFAOYSA-N 2-Ethylbutanoic acid Chemical compound CCC(CC)C(O)=O OXQGTIUCKGYOAA-UHFFFAOYSA-N 0.000 description 1
- RPGKFFKUTVJVPY-UHFFFAOYSA-N 2-amino-4-methylbenzoic acid Chemical compound CC1=CC=C(C(O)=O)C(N)=C1 RPGKFFKUTVJVPY-UHFFFAOYSA-N 0.000 description 1
- 125000006176 2-ethylbutyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(C([H])([H])*)C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000002941 2-furyl group Chemical group O1C([*])=C([H])C([H])=C1[H] 0.000 description 1
- FICOOHIRQQCVKR-UHFFFAOYSA-N 2-methyl-4-(4-nitrophenyl)morpholin-3-one Chemical compound O=C1C(C)OCCN1C1=CC=C([N+]([O-])=O)C=C1 FICOOHIRQQCVKR-UHFFFAOYSA-N 0.000 description 1
- 125000004493 2-methylbut-1-yl group Chemical group CC(C*)CC 0.000 description 1
- 125000004105 2-pyridyl group Chemical group N1=C([*])C([H])=C([H])C([H])=C1[H] 0.000 description 1
- KHEVPDFAQFJIGK-UHFFFAOYSA-N 2-sulfooxyethanesulfonic acid Chemical compound OS(=O)(=O)CCOS(O)(=O)=O KHEVPDFAQFJIGK-UHFFFAOYSA-N 0.000 description 1
- 125000000175 2-thienyl group Chemical group S1C([*])=C([H])C([H])=C1[H] 0.000 description 1
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- 239000003814 drug Substances 0.000 description 1
- CCIVGXIOQKPBKL-UHFFFAOYSA-N ethanesulfonic acid Chemical compound CCS(O)(=O)=O CCIVGXIOQKPBKL-UHFFFAOYSA-N 0.000 description 1
- HCPOCMMGKBZWSJ-UHFFFAOYSA-N ethyl 3-hydrazinyl-3-oxopropanoate Chemical compound CCOC(=O)CC(=O)NN HCPOCMMGKBZWSJ-UHFFFAOYSA-N 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
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- 229910000042 hydrogen bromide Inorganic materials 0.000 description 1
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- 125000004464 hydroxyphenyl group Chemical group 0.000 description 1
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- ROXKHDSFZFKVAU-UHFFFAOYSA-N methyl 4-nitro-2-(3-oxomorpholin-4-yl)benzoate Chemical compound COC(=O)C1=CC=C([N+]([O-])=O)C=C1N1C(=O)COCC1 ROXKHDSFZFKVAU-UHFFFAOYSA-N 0.000 description 1
- 229940095102 methyl benzoate Drugs 0.000 description 1
- 125000000325 methylidene group Chemical group [H]C([H])=* 0.000 description 1
- GRVDJDISBSALJP-UHFFFAOYSA-N methyloxidanyl Chemical group [O]C GRVDJDISBSALJP-UHFFFAOYSA-N 0.000 description 1
- 239000011707 mineral Substances 0.000 description 1
- 235000010755 mineral Nutrition 0.000 description 1
- 230000004784 molecular pathogenesis Effects 0.000 description 1
- 125000004312 morpholin-2-yl group Chemical group [H]N1C([H])([H])C([H])([H])OC([H])(*)C1([H])[H] 0.000 description 1
- 125000004572 morpholin-3-yl group Chemical group N1C(COCC1)* 0.000 description 1
- 125000004573 morpholin-4-yl group Chemical group N1(CCOCC1)* 0.000 description 1
- 208000010125 myocardial infarction Diseases 0.000 description 1
- QQBMJUYLNIYJSZ-UHFFFAOYSA-N n-(2-chloroethoxy)acetamide Chemical compound CC(=O)NOCCCl QQBMJUYLNIYJSZ-UHFFFAOYSA-N 0.000 description 1
- YZMHQCWXYHARLS-UHFFFAOYSA-N naphthalene-1,2-disulfonic acid Chemical compound C1=CC=CC2=C(S(O)(=O)=O)C(S(=O)(=O)O)=CC=C21 YZMHQCWXYHARLS-UHFFFAOYSA-N 0.000 description 1
- 125000001971 neopentyl group Chemical group [H]C([*])([H])C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 229960003512 nicotinic acid Drugs 0.000 description 1
- 235000001968 nicotinic acid Nutrition 0.000 description 1
- 239000011664 nicotinic acid Substances 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- SFJGCXYXEFWEBK-UHFFFAOYSA-N oxazepine Chemical class O1C=CC=CC=N1 SFJGCXYXEFWEBK-UHFFFAOYSA-N 0.000 description 1
- 125000000636 p-nitrophenyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)[N+]([O-])=O 0.000 description 1
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- 125000003538 pentan-3-yl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])C([H])([H])[H] 0.000 description 1
- 229940075930 picrate Drugs 0.000 description 1
- OXNIZHLAWKMVMX-UHFFFAOYSA-M picrate anion Chemical compound [O-]C1=C([N+]([O-])=O)C=C([N+]([O-])=O)C=C1[N+]([O-])=O OXNIZHLAWKMVMX-UHFFFAOYSA-M 0.000 description 1
- 235000019260 propionic acid Nutrition 0.000 description 1
- 125000003373 pyrazinyl group Chemical group 0.000 description 1
- 125000002206 pyridazin-3-yl group Chemical group [H]C1=C([H])C([H])=C(*)N=N1 0.000 description 1
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 1
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- 125000003548 sec-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D265/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom and one oxygen atom as the only ring hetero atoms
- C07D265/28—1,4-Oxazines; Hydrogenated 1,4-oxazines
- C07D265/30—1,4-Oxazines; Hydrogenated 1,4-oxazines not condensed with other rings
- C07D265/32—1,4-Oxazines; Hydrogenated 1,4-oxazines not condensed with other rings with oxygen atoms directly attached to ring carbon atoms
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/02—Non-specific cardiovascular stimulants, e.g. drugs for syncope, antihypotensives
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/04—Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/08—Vasodilators for multiple indications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/14—Vasoprotectives; Antihaemorrhoidals; Drugs for varicose therapy; Capillary stabilisers
Abstract
式(I)化合物N-芳基吗啉酮及其前体的制备方法,其中X的含义在权利要求1中指明。
Description
本发明涉及式I化合物及其盐的制备方法
其中
X代表
R1代表NO2、CN、COOR3、CON(R3)2、COR3、SO2R4、SO2N(R3)2、CF3、F或Cl,
R2代表H、Hal、A、OR3、N(R3)2、NO2、CN、COOR3、CON(R3)2、NR3COA、NR3CON(R3)2、NR3COOR3、NR3SO2A、-[C(R5)2]n-Ar、-[C(R5)2]n-Het、-[C(R5)2]n-环烷基、COR3、SO2N(R3)2或SO2R4,
R3代表H、A、-[C(R5)2]n-Ar或-[C(R5)2]n-Het,
R4代表A、-[C(R5)2]n-Ar或-[C(R5)2]n-Het,
R5代表H或A′,
Ar代表苯基,其为未取代的,或被以下取代基单-、二-或三取代:Hal、A、OR5、N(R5)2、NO2、CN、COOR5、CON(R5)2、NR5COA、NR5SO2A、COR5、SO2N(R5)2或S(O)nA,
Het代表具有1-4个N、O和/或S原子的单环或二环饱和、不饱和或芳香杂环,其为未取代的,或被以下取代基单-或二取代:Hal、A、OR5、N(R5)2、NO2、CN、COOR5、CON(R5)2、NR5COA、NR5SO2A、COR5、SO2N(R5)2、S(O)nA和/或羰基氧(=O),
A′代表具有1-6个C原子的无支链或支链烷基,
A代表具有1-12个C原子的无支链、支链或环状烷基,其中一个或两个CH2基团可被O或S原子和/或被-CH=CH-基团置换,和/或另外1-7个H原子可被F置换,
Hal代表F、Cl、Br或I,
n代表0、1或2,
m代表0、1、2、3或4,
其特征为
a)式II化合物
X-NH2 II
其中X的含义同前,
与5-氯-2,3-二氢-1,4-二氧杂环己二烯(dioxin)反应
得到式III化合物
其中X的含义同前,
b)然后式III化合物经环化生成式I化合物,
并且
c)通过将式I的碱或酸转化成其一种盐,任选将b)中的后者转化成其盐。
本发明的目的是发现因子Xa抑制剂前体的新型改进制备方法。
与现有技术的已知方法相比较,本发明所提供的方法更简洁、更有效。
因子Xa抑制剂可用来对抗、预防血栓栓塞疾病,如血栓形成、心肌梗塞、动脉硬化、炎症、中风、心绞痛、血管成形术后的再狭窄和间歇性跛行。
因子Xa是血凝固这个复杂过程中的蛋白酶之一。因子Xa催化凝血酶原转化为凝血酶。凝血酶将血纤维蛋白原分裂成血纤蛋白单体,其交联是促成血栓形成的基本原因。凝血酶的激活会导致引发血栓栓塞疾病。然而,抑制了凝血酶就可抑制血栓形成过程中的血纤蛋白的形成。
凝血酶的抑制是可测量的,例如采用G.F.Cousin等“Circulation”1996,94,1705-1712中的方法。
抑制了因子Xa就可阻止凝血酶的形成。
因子Xa的抑制、抗凝剂测定值和抗血栓形成的活性可通过常规的体外或体内方法测得。适当的方法如J.Hauptmann等“Thrombosisand Haemostasis”1990,63,220-223所述。
因子Xa的抑制是可测量的,例如采用T.Hara等“Thromb.Haemostas”1994,71,314-319的方法。
凝血因子VIIa与组织因子结合后,就引发外部凝血级联反应,并激活因子X,形成因子Xa。抑制了因子VIIa从而阻止因子Xa的形成,继而阻止凝血酶的形成。
因子VIIa的抑制、抗凝剂测定值和抗血栓形成的活性可通过常规的体外或体内方法测得。因子VIIa抑制的常规测定值方法如H.F.Ronning等“Thrombosis Research”1996,84,73-81所述。
凝血因子IXa产生于内部凝血级联反应,同样激活因子X,形成因子Xa。因此,抑制了因子IXa就可以另外一种方式阻止因子Xa的形成。
因子IXa的抑制、抗凝剂测定值和抗血栓形成的活性可通过常规的体外或体内方法测得。适当的方法如J.Chang等“Journal ofBiological Chemistry”1998,273,12089-12094所述。
T.Taniguchi和N.R.Lemoine在“Biomed.Health Res.”(2000),41(Molecular pathogenesis of Pancreatic Cancer),57-59中已经阐述了组织因子TF/因子VIIa与各型癌症发展之间的相关性。下列出版物描述了各型肿瘤TF-VII抗肿瘤作用和因子Xa抑制剂:
K.M.Donnelly等“Thromb.Haemost.”1998;79:1041-1047;
E.G.Fischer等“Clin.Invest.”104:1213-1221(1999);
B.M.Mueller等“Clin.Invest.”101:1372-1378(1998);
M.E.Bromberg等“Thromb.Haemost.”1999;82:88-92。
WO 02/057236描述了其他方法及吗啉酮前体。
如下制备2-(2-氯乙氧基)乙酰胺的方法已有文献记载:
如US 3074939、BE776767及DE1922613中已描述了该方法。
如G.May、D.Peteri、Arzneim.-Forsch.(Drug Res.)23,718(1973)中已描述了该方法。
如DE2150075中已描述了该方法。
然而,这些方法都存在弊端。因此,需要许多反应步骤或起始原料很贵。
M.J.Astle、J.D.Welks、J.Org.Chem.26,4325(1961)公开了如下反应:
R=烷基、苯基
我们惊奇的发现,只要芳胺的pKa值低于或等于3,其也与5-氯-2,3-二氢-1,4-二氧杂环己二烯(2-chlorodioxene)发生反应,生成2-(2-氯乙氧基)乙酰胺。
鉴于M.J.Astle、J.D.Welks、J.Org.Chem.26,4325(1961),该反应是难以预料的,因为胺,如氨、苄胺、8-氨基-喹啉或4-甲氧基苯胺不发生反应或反应不充分。
pKa值的比较:
苄胺 9.5
氨 9.24
8-氨基-喹啉 0.7(NH2基团)和4.0(喹啉氮)。
碱性喹啉氮阻止反应。
4-甲氧基苯胺 5.4
4-硝基苯胺 1.0
4-氰基苯胺 1.7
3-硝基苯胺 2.5
2-甲基-4-硝基苯胺 1.04
4-氨基苯甲酸甲酯 1.5
4-氨基二苯甲酮 2.2
2-硝基苯胺 -0.23
在该反应中,加入例如布朗斯台得酸(Bronsted acid)有利于反应,诸如盐酸、或路易斯酸,或加入文献(R.K.Summerbell,H.E.Lunk,J.Am.Chem.Soc.79,P.4802,1957)中所提到的化合物2,2-二氯二氧杂环己一烯(2,2-dichlorodioxene),其容易分解为氯化氢和5-氯-2,3-二氢-1,4-二氧杂环己二烯。反应可在许多溶剂中进行,例如,甲苯、乙腈、二氧六环,也可在固质中(in mass)进行,即,不加溶剂。典型反应温度为0-150℃,通常为约80℃,例如在70至90℃之间。
该方法的优点在于5-氯-2,3-二氢-1,4-二氧杂环己二烯或2,2-二氯二氧六环容易制得。
例如M.Lyoda等“Heterocycles”,54,P.833,2001中已描述了2,3-二氯二氧六环的制备。氯化氢的热消除在US 2756240中已有描述。这些方法制得的5-氯-2,3-二氢-1,4-二氧杂环己二烯都含有一定比例的2,2-二氯二氧六环杂质(典型的为5%至50%)。
N.V.Kuznetsov,I.I.Krasavtsev,Sov.Prog.Chem.(Engl.Transl.)44,P.77,1987描述了采用氢氧化钠由2,3-二氯二氧六环制备5-氯-2,3-二氢-1,4-二氧杂环己二烯的方法。
氯乙氧基乙酰胺发生环化生成吗啉酮,迄今为止,已有如下两个出版物有所描述:DE922613和L.Fumagalli等“Pharmazie”30,78(1975)。
两例都涉及三碘苯甲酸和三碘苯基链烷酸衍生物。
然而,该方法只适用于水溶性反应物,正如上述文献所述,其中R总含有一个游离羧基。
我们发现采用弱碱如碳酸铯或碳酸钾,在合适的溶剂如乙腈中,氯乙氧基乙酰胺可优选被环化生成吗啉酮。
上文及下文,A代表烷基,是具有1、2、3、4、5、6、7、8、9或10个C原子的无支链(直链)或支链结构。A优选代表甲基,还可代表乙基、丙基、异丙基、丁基、异丁基、仲丁基或叔丁基,此外,还可代表戊基、1-、2-或3-甲基丁基,1,1-、1,2-或2,2-二甲基-丙基,1-乙基丙基、己基、1-、2-、3-或4-甲基戊基,1,1-、1,2-、1,3-、2,2-、2,3-或3,3-二甲基丁基,1-或2-乙基丁基、1-乙基-1-甲基丙基、1-乙基-2-甲基丙基、1,1,2-或1,2,2-三甲基丙基,还可优选代表如三氟甲基。
A非常特别优选代表具有1、2、3、4、5或6个C原子的烷基,优选甲基、乙基、丙基、异丙基、丁基、异丁基、仲丁基、叔丁基、戊基、己基或三氟甲基。
A′优选代表具有1、2、3、4、5或6个C原子的烷基,优选甲基、乙基、丙基、异丙基、丁基、异丁基、仲丁基、叔丁基、戊基、己基或三氟甲基。
环烷基具有3-7个C原子,优选代表环丙基、环丁基、环戊基或环己基。
Hal优选代表F、Cl、Br或I。
R1优选代表NO2、CN、COOH、COOR3、COR3或Cl。
R2优选代表H、Hal或A。
R3优选代表H、A′或-[C(R5)2]n-Ar。
R4优选代表A。
Ar代表如苯基,邻、间或对甲苯基,邻、间或对乙基苯基,邻、间或对丙基苯基,邻、间或对异丙基苯基,邻、间或对叔丁基-苯基,邻、间或对氢氧基苯基,邻、间或对硝基苯基,邻、间或对氨基苯基,邻、间或对(N-甲氨基)苯基,邻、间或对(N-甲基-氨基羰基)苯基,邻、间或对乙酰胺基苯基,邻、间或对甲氧基-苯基,邻、间或对乙氧基苯基,邻、间或对乙氧羰基苯基,邻、间或对(N,N-二甲氨基)苯基,邻、间或对(N,N-二甲氨羰基)苯基,邻、间或对(N-乙基氨基)苯基,邻、间或对(N,N-二乙基氨基)-苯基,邻、间或对氟苯基,邻、间或对溴苯基,邻、间或对氯苯基,邻、间或对(甲基亚磺酰氨基)苯基,邻、间或对(甲基-磺酰基)苯基,还优选代表2,3-、2,4-、2,5-、2,6-、3,4-或3,5-二氟苯基,2,3-、2,4-、2,5-、2,6-、3,4-或3,5-二氯苯基,2,3-、2,4-、2,5-、2,6-、3,4-或3,5-二溴苯基,2,4-或2,5-二硝基苯基,2,5-或3,4-二甲氧基苯基,3-硝基-4-氯苯基,3-氨基-4-氯-,2-氨基-3-氯-,2-氨基-4-氯-,2-氨基-5-氯-或2-氨基-6-氯苯基,2-硝基-4-N,N-二甲基氨基-或3-硝基-4-N,N-二甲基氨苯基,2,3-二氨基苯基,2,3,4-、2,3,5-、2,3,6-、2,4,6-或3,4,5-三氯苯基,2,4,6-三甲氧基苯基,2-氢氧基-3,5-二氯苯基,对碘苯基,3,6-二氯-4-氨基苯基,4-氟-3-氯苯基,2-氟-4-溴苯基,2,5-二氟-4-溴苯基,3-溴-6-甲氧基苯基,3-氯-6-甲氧基苯基,3-氯-4-乙酰氨基苯基,3-氟-4-甲氧基苯基,3-氨基-6-甲基苯基,3-氯-4-乙酰氨基苯基或2,5-二甲基-4-氯苯基。
Ar优选代表如苯基,其为未取代的,或被以下取代基单-、二-或三取代:Hal、A、OR5、SO2A、COOR5或CN。Ar特别优选代表如苯基,其为未取代的,或被以下取代基单-或二取代:Hal、A、OA、SO2A、SO2NH2、COOR5或CN。例如苯基,2-甲基磺酰基苯基,2-氨基磺酰基苯基,2-、3-或4-氯苯基,4-甲基苯基,4-溴苯基,3-氟-4-甲氧基苯基,4-三氟甲氧基苯基,4-乙氧基苯基,2-甲氧基苯基,3-氰基苯基或4-乙氧羰基-苯基。
Ar非常特别优选代表未取代的苯基。
Het为未取代的,或被以下取代基单或二取代:Hal、A、OR5、N(R5)2、NO2、CN、COOR5、CON(R5)2、NR5COA、NR5SO2A、COR5、SO2N(R5)2、S(O)nA和/或羰基氧(=O)取代的基团,并代表如2-或3-呋喃基,2-或3-噻吩基,1-、2-或3-吡咯基,1-、2、4-或5-咪唑基,1-、3-、4-或5-吡唑基,2-、4-或5-噁唑基,3-,4-或5-异噁唑基,2-、4-或5-噻唑基,3-、4-或5-异噻唑基,2-、3-或4-吡啶基,2-、4-、5-或6-嘧啶基,还优选代表1,2,3-三唑-1-、-4-或-5-基,1,2,4-三唑-1-、-3-或5-基,1-或5-四唑基,1,2,3-噁二唑-4-或-5-基,1,2,4-噁二唑-3-或-5-基,1,3,4-噻二唑-2-或-5-基,1,2,4-噻二唑-3-或-5-基,1,2,3-噻二唑-4-或-5-基,3-或4-哒嗪基,吡嗪基,1-、2-、3-、4-、5-、6-或7-吲哚基,4-或5-异吲哚基,1-、2-、4-或5-苯并咪唑基,1-、3-、4-、5-、6-或7-苯并吡唑基,2-、4-、5-、6-或7-苯并噁唑基,3-、4-、5-、6-或7-苯并异噁唑基,2-、4-、5-、6-或7-苯并噻唑基,2-、4-、5-、6-或7-苯并异噻唑基,4-、5-、6-或7-苯并-2,1,3-噁二唑基,2-、3-、4-、5-、6-、7-或8-喹啉基,1-、3-、4-、5-、6-、7-或8-异喹啉基,3-、4-、5-、6-、7-或8-噌啉基,2-、4-、5-、6-、7-或8-喹唑啉基,5-或6-喹喔啉基,2-、3-、5-、6-、7-或8-2H-苯并-1,4-噁嗪基,还优选代表1,3-苯并间二氧杂环戊烷-5-基、1,4-苯并二氧六环-6-基、2,1,3-苯并噻二唑-4-或-5-基或2,1,3-苯并噁二唑-5-基。
杂环基团也可部分或全部氢化。Het也可代表如2,3-二氢-2-、-3-、-4-或-5-呋喃基,2,5-二氢-2-、-3-、-4-或-5-呋喃基,四氢-2-或-3-呋喃基,1,3-二氧戊环-4-基,四氢-2-或-3-噻吩基,2,3-二氢-1-、-2-、-3-、-4-或-5-吡咯基,2,5-二氢-1-、-2-、-3-、-4-或-5-吡咯基,1-、2-或3-吡咯烷基,四氢-1-、-2-或-4-咪唑基,2,3-二氢-1-、-2-、-3-、-4-或-5-吡唑基,四氢-1-、-3-或-4-吡唑基,1,4-二氢-1-、-2-、-3-或-4-吡啶基,1,2,3,4-四氢-1-、-2-、-3-、-4-、-5-或-6-吡啶基,1-、2-、3-或4-哌啶基,2-、3-或4-吗啉基,四氢-2-、-3-或-4-吡喃基,1,4-二氧六环基,1,3-二氧六环-2-、-4-或-5-基,六氢-1-、-3-或-4-哒嗪基,六氢-1-、-2-、-4-或-5-嘧啶基,1-、2-或3-哌嗪基,1,2,3,4-四氢-1-、-2-、-3-、-4-、-5-、-6-、-7-或-8-喹啉基,1,2,3,4-四氢-1-、-2-、-3-、-4-、-5-、-6-、-7-或-8-异喹啉基,2-、3-、5-、6-、7-或8-3,4-二氢-2H-苯并-1,4-噁嗪基,还更优选2,3-亚甲基二羟苯基,3,4-亚甲基二羟苯基,2,3-亚乙基二羟苯基,3,4-亚乙基二羟苯基,3,4-(二氟亚甲基二羟基)苯基,2,3-二氢苯并呋喃-5-或6-基,2,3-(2-氧代亚甲基二羟基)-苯基或3,4-二氢-2H-1,5-苯并二氧杂氮杂-6-或-7-基,还优选2,3-二氢苯并呋喃基或2,3-二氢-2-氧代-呋喃基。
n优选代表0或1。
m优选代表0、1或2。
本发明优选涉及权利要求1的式I化合物的制备方法,其中
R1代表NO2、CN、COOR3、COR3或Cl,
R2代表H、Hal或A。
还优选权利要求1或2的式I化合物的制备方法,其中
R1代表NO2、CN、COOR3、CON(R3)2、COR3、SO2R4、SO2N(R3)2、CF3、F或Cl,
R2代表H、Hal或A,
R3代表H、A、-[C(R5)2]n-Ar或-[C(R5)2]n-Het。
还优选权利要求1的式I化合物的制备方法,其中Ar代表苯基。
还优选式I化合物的制备方法,其中R4代表A。
还优选式I化合物的制备方法,其中
R1代表NO2、CN、COOR3、CON(R3)2、COR3、CF3、F或Cl,
R2代表H、Hal或A′,
R3代表H、A′或-[C(R5)2]n-Ar,
Ar代表苯基,
R5代表H或A′,
A′代表具有1-6个C原子的无支链或支链烷基,
Hal代表F、Cl、Br或I,
n代表0、1或2。
非常特别优选权利要求1的化合物的制备方法,所述化合物选自
1)4-(4-硝基苯基)-3-氧代吗啉,
2)4-(3-硝基苯基)-3-氧代吗啉,
3)4-(2-硝基苯基)-3-氧代吗啉,
4)2-甲基-4-(4-硝基苯基)-3-氧代吗啉,
5)4-(4-甲氧基羰基苯基)-3-氧代吗啉,
6)4-(4-苯甲酰基苯基)-氧代吗啉。
还优选权利要求1-6中一项或多项的式I化合物的制备方法,其中式II胺的pKa值≤3。
式I化合物可优选采用如下方法制得,在步骤a)中,将式II化合物与5-氯-2,3-二氢-1,4-二氧杂环己二烯反应,生成式III化合物。
反应通常在惰性溶剂中进行,但也可在无溶剂的固质中进行。
在该反应中,加入例如布朗斯台得酸有利于反应,像盐酸、或路易斯酸,或加入文献(R.K.Summerbell,H.E.Lunk,J.Am.Chem.Soc.79,P.4802,1957)中所提到的化合物2,2-二氯二氧杂环己一烯,其易分解为氯化氢和5-氯-2,3-二氢-1,4-二氧杂环己二烯。
根据所用条件,反应时间在数分钟至14天之间,优选在1至10小时,反应温度在0℃至150℃之间,通常在20℃至130℃之间,优选在60℃至110℃之间,最优选在70℃至90℃之间。
合适的惰性溶剂如水;烃,如己烷、石油醚、苯、甲苯、二甲苯;氯化烃,如三氯乙烯、1,2-二氯乙烷、四氯化碳、氯仿或二氯甲烷;醇类,如甲醇、乙醇、异丙醇、正丙醇、正丁醇或叔丁醇;醚类,如二乙醚、二异丙醚、四氢呋喃(THF)或二氧六环;乙二醇醚,如乙二醇一甲醚或乙二醇一乙醚(甲基乙二醇或乙基乙二醇)、乙二醇二甲醚(二甘醇二甲醚);酮类,如丙酮或丁酮;酰胺类,如乙酰胺、二甲基乙酰胺或二甲基甲酰胺(DMF);腈类,如乙腈;亚砜,如二甲亚砜(DMSO);二硫化碳;羧酸,如甲酸或乙酸;硝基化合物,如硝基甲烷或硝基苯;酯类,如乙酸乙酯,或上述溶剂的混合物。特别优选乙腈。
在第二步b)中,式III化合物经环化,得到式I化合物。
反应通常在惰性溶剂中进行,优选有碱金属或碱土金属氢氧化物、碳酸盐或碳酸氢盐。最优选弱碱,如碳酸铯或碳酸钾。
根据所用条件,反应时间在数分钟至14天之间,优选在1至20小时,反应温度在0℃至150℃之间,通常在0℃至90℃之间,优选在10℃至70℃之间,更优选在20℃至50℃之间。
合适的惰性溶剂有如烃,如己烷、石油醚、苯、甲苯、二甲苯;氯化烃,如三氯乙烯、1,2-二氯乙烷、四氯化碳、氯仿或二氯甲烷;醇类,如甲醇、乙醇、异丙醇、正丙醇、正丁醇或叔丁醇;醚类,如二乙醚、二异丙醚、四氢呋喃(THF)或二氧六环;乙二醇醚,如乙二醇一甲醚或乙二醇一乙醚(甲基乙二醇或乙基乙二醇)、乙二醇二甲醚(二甘醇二甲醚);酮类,如丙酮或丁酮;酰胺类,如乙酰胺、二甲基乙酰胺或二甲基甲酰胺(DMF);腈类,如乙腈;亚砜,如二甲亚砜(DMSO);二硫化碳;羧酸,如甲酸或乙酸;硝基化合物,如硝基甲烷或硝基苯;酯类,如乙酸乙酯,或上述溶剂的混合物。特别优选乙腈。
步骤a)与b)也可作为一锅法反应进行。当胺与5-氯-2,3-二氢-1,4-二氧杂环己二烯反应完全后,溶液温度降低。此时,加入过量的碱金属碳酸盐(典型为1.5至4当量),搅拌反应混合物直至转化完全。
用酸可使得式I的碱转化为相关的酸加成盐,如等量的碱与酸在惰性溶剂如乙醇中反应,然后进行蒸发。适合该反应的酸特别是生成生理学上可接受盐类的酸。因此,可用无机酸,如硫酸、硝酸、氢卤酸如氢氯酸或氢溴酸、磷酸如正磷酸、氨基磺酸,还有有机酸,尤其脂肪酸、脂环酸、芳烷酸(araliphatic acid)、芳香族或杂环单或多元羧酸、磺酸或硫酸,如甲酸、乙酸、丙酸、三甲基醋酸、二乙基乙酸、丙二酸、琥珀酸、庚二酸、富马酸、马来酸、乳酸、酒石酸、苹果酸、枸橼酸、葡萄糖酸、抗坏血酸、烟酸、异烟酸、甲或乙磺酸、乙二磺酸、2-羟乙基磺酸、苯磺酸、对甲苯磺酸、萘单磺酸和萘二磺酸、月桂基硫酸。生理学上不可接受的盐类,如苦味酸盐,可用来分离和/或纯化式I化合物。
另一方面,式I化合物可用碱转化为相应的金属盐,尤其为碱金属盐或碱土金属盐,或相应的铵盐(如氢氧化钠、氢氧化钾、碳酸钠或碳酸钾)。
亦可能采用生理学上可接受的有机碱,如乙醇胺。
本发明还涉及式III的中间体化合物及其盐
其中
X代表
R1代表NO2或CN,
R2代表H、Hal、A、OR3、N(R3)2、NO2、CN、COOR3、CON(R3)2、NR3COA、NR3CON(R3)2、NR3COOR3、NR3SO2A、-[C(R5)2]n-Ar、-[C(R5)2]n-Het、-[C(R5)2]n-环烷基、COR3、SO2N(R3)2或SO2R4,
R3代表H、A、-[C(R5)2]n-Ar或-[C(R5)2]n-Het,
R4代表A、-[C(R5)2]n-Ar或-[C(R5)2]n-Het,
R5代表H或A′,
Ar代表苯基,其为未取代的,或被以下取代基单-、二-或三取代:Hal、A、OR5、N(R5)2、NO2、CN、COOR5、CON(R5)2、NR5COA、NR5SO2A、COR5、SO2N(R5)2或S(O)nA,
Het代表具有1-4个N、O和/或S原子的单环或二环饱和、不饱和或芳香杂环,其为未取代的,或被以下取代基单-或二取代:Hal、A、OR5、N(R5)2、NO2、CN、COOR5、CON(R5)2、NR5COA、NR5SO2A、COR5、SO2N(R5)2、S(O)nA和/或羰基氧(=O),
A′代表具有1-6个C原子的无支链或支链烷基,
A代表具有1-12个C原子的无支链、支链或环状烷基,其中一个或两个CH2基团可被O或S原子和/或被-CH=CH-基团置换,和/或另外1-7个H原子可被F置换,
Hal代表F、Cl、Br或I,
n代表0、1或2,
m代表0、1、2、3或4。
中间体化合物对于式I化合物的制备很重要。
相应基团的优选含义如上所述,除非另有说明。
本发明还涉及权利要求15的中间体化合物及其盐,其中
R1代表NO2或CN,
R2代表H、Hal或A。
还优选权利要求15的中间体化合物及其盐,其中
R1代表NO2或CN,
R2代表H、Hal或A,
R3代表H、A、-[C(R5)2]n-Ar或-[C(R5)2]n-Het。
还优选权利要求15、16或17的中间体化合物及其盐,其中
Ar代表苯基。
还优选权利要求15-18中一项或多项的中间体化合物及其盐,其中
R4代表A。
尤其优选权利要求15-19中一项或多项的中间体化合物及其盐,其中
R1代表NO2或CN,
R2代表H、Hal或A′,
R3代表H、A′或-[C(R5)2]n-Ar,
Ar代表苯基,
R5代表H或A′,
A′代表具有1-6个C原子的无支链或支链烷基,
Hal代表F、Cl、Br或I,
n代表0、1或2,
m代表0、1或2。
尤其优选权利要求20的中间体化合物及其盐,其中
R1代表NO2,
R2代表H、Hal或A′,
R3代表H、A′或-[C(R5)2]n-Ar,
Ar代表苯基,
R5代表H或A′,
A′代表具有1-6个C原子的无支链或支链烷基,
Hal代表F、Cl、Br或I,
n代表0、1或2,
m代表0、1或2。
本发明还涉及式III的中间体化合物及其盐的制备方法
其中
X代表
R1代表NO2、CN、COOR3、CON(R3)2、COR3、SO2R4、SO2N(R3)2、CF3、F或Cl,
R2代表H、Hal、A、OR3、N(R3)2、NO2、CN、COOR3、CON(R3)2、NR3COA、NR3CON(R3)2、NR3COOR3、NR3SO2A、-[C(R5)2]n-Ar、-[C(R5)2]n-Het、-[C(R5)2]n-环烷基、COR3、SO2N(R3)2或SO2R4,
R3代表H、A、-[C(R5)2]n-Ar或-[C(R5)2]n-Het,
R4代表A、-[C(R5)2]n-Ar或-[C(R5)2]n-Het,
R5代表H或A′,
Ar代表苯基,其为未取代的,或被以下取代基单-、二-或三取代:Hal、A、OR5、N(R5)2、NO2、CN、COOR5、CON(R5)2、NR5COA、NR5SO2A、COR5、SO2N(R5)2或S(O)nA,
Het代表具有1-4个N、O和/或S原子的单环或二环饱和、不饱和或芳香杂环,其为未取代的,或被以下取代基单-或二取代:Hal、A、OR5、N(R5)2、NO2、CN、COOR5、CON(R5)2、NR5COA、NR5SO2A、COR5、SO2N(R5)2、S(O)nA和/或羰基氧(=O),
A′代表具有1-6个C原子的无支链或支链烷基,
A代表具有1-12个C原子的无支链、支链或环状烷基,其中一个或两个CH2基团可被O或S原子和/或被-CH=CH-基团置换,和/或另外1-7个H原子可被F置换,
Hal代表F、Cl、Br或I,
n代表0、1或2,
m代表0、1、2、3或4,
其特征为
a)式II化合物
X-NH2 II
其中X的含义同前,
与5-氯-2,3-二氢-1,4-二氧杂环己二烯反应
并且
式III化合物被任选转化为其盐类。
该方法的反应条件,尤其优选的与前所述的式I化合物的制备条件相同。
相应基团的优选含义如上所述,除非另有说明。
优选权利要求22的式III的中间体化合物的制备方法,其中
R1代表NO2或CN,
R2代表H、Hal、A、OR3、N(R3)2、NO2、CN、COOR3、CON(R3)2、NR3COA、NR3CON(R3)2、NR3COOR3、NR3SO2A、-[C(R5)2]n-Ar、-[C(R5)2]n-Het、-[C(R5)2]n-环烷基、COR3、SO2N(R3)2或SO2R4,
R3代表H、A、-[C(R5)2]n-Ar或-[C(R5)2]n-Het,
R4代表A、-[C(R5)2]n-Ar或-[C(R5)2]n-Het,
R5代表H或A′,
Ar代表苯基,其为未取代的,或被以下取代基单-、二-或三取代:Hal、A、OR5、N(R5)2、NO2、CN、COOR5、CON(R5)2、NR5COA、NR5SO2A、COR5、SO2N(R5)2或S(O)nA,
Het代表具有1-4个N、O和/或S原子的单环或二环饱和、不饱和或芳香杂环,其为未取代的,或被以下取代基单-或二取代:Hal、A、OR5、N(R5)2、NO2、CN、COOR5、CON(R5)2、NR5COA、NR5SO2A、COR5、SO2N(R5)2、S(O)nA和/或羰基氧(=O),
A′代表具有1-6个C原子的无支链或支链烷基,
A代表具有1-12个C原子的无支链、支链或环状烷基,其中一个或两个CH2基团可被O或S原子和/或被-CH=CH-基团置换,和/或另外1-7个H原子可被F置换,
Hal代表F、Cl、Br或I,
n代表0、1或2,
m代表0、1、2、3或4。
还优选权利要求23的式III的中间体化合物的制备方法,其中
R1代表NO2或CN,
R2代表H、Hal或A。
还优选权利要求23的式III的中间体化合物的制备方法,其中
R1代表NO2或CN,
R2代表H、Hal或A,
R3代表H、A、-[C(R5)2]n-Ar或-[C(R5)2]n-Het。
还优选权利要求23的式III的中间体化合物的制备方法,其中
Ar代表苯基。
还优选权利要求23的式III的中间体化合物的制备方法,其中
R4代表A。
尤其优选权利要求23的式III的中间体化合物的制备方法,其中
R1代表NO2或CN,
R2代表H、Hal或A′,
R3代表H、A′或-[C(R5)2]n-Ar,
Ar代表苯基,
R5代表H或A′,
A′代表具有1-6个C原子的无支链或支链烷基,
Hal代表F、Cl、Br或I,
n代表0、1或2,
m代表0、1或2。
上文和下文,所有的温度都指的是℃。
质谱法(MS):EI(电子碰撞电离)M+;
ESI(电子喷雾电离)(M+H)+;
FAB(快速原子轰击)(M+H)+
实施例1
4-(4-硝基苯基)-3-氧代吗啉
制备方法与如下方案类似:
1.1 无溶剂:
将1.53克5-氯-2,3-二氢-1,4-二氧杂环己二烯和2,2-二氯二氧六环(摩尔比率为1:1)的混合物加入1.00克(7.24mmol)的4-硝基苯胺中,边搅拌边将混合物加热至80℃。1小时内形成一种褐色固体,再变为液体,随后12小时内结晶。粗制产物从乙醇加水重结晶,得到1.80克淡黄色晶体2-(2-氯乙氧基)-N-(4-硝基苯基)乙酰胺(“Al”),熔点为
101-102℃.1H-NMR(d6-DMSO):δ=3.82(m;4H),4.23(s;2H),7.91(d,J=9Hz,2H),8.23(d,J=9Hz,2H),10.34(s,1H)。
1.2 在乙腈中:
将310毫克5-氯-2,3-二氢-1,4-二氧杂环己二烯和2,2-二氯二氧六环(摩尔比率为1:1)的混合物加入276毫克(2.00mmol)4-硝基苯胺的2毫升乙腈溶液中,搅拌下于80℃加热溶液18小时。蒸发反应混合物,残余物从乙醇/水重结晶:360毫克淡黄色晶体“A1”。
1.3 室温下,将1千克的“A1”溶于5升乙腈,加入835克碳酸钾,在此温度搅拌混合物18小时。将混合物加温至50℃,采用类似于实施例6的方法处理,得到4-(4-硝基苯基)-3-氧代吗啉(“A2”),熔点150-152℃。
实施例2
4-(4-硝基-2-甲基苯基)-3-氧代吗啉
将1.05克5-氯-2,3-二氢-1,4-二氧杂环己二烯和2,2-二氯二氧六环(摩尔比率为1:1)的混合物加入1.10克(7.24mmol)2-甲基-4-硝基苯胺的20毫升THF溶液中,加热混合物至沸腾。蒸馏除去溶剂,残留物为褐色粘液,加热至80℃,并持续18小时。冷却后,残余物从甲苯/叔丁基甲基醚重结晶:1.50克淡黄色晶体2-(2-氯乙氧基)-N-(2-甲基-4-硝基苯基)乙酰胺,熔点
113-114℃.1H-NMR(d6-DMSO):δ=2.35(s;3H),3.82(m;4H),4.23(s;2H),8.05(d,J=8Hz,1H)8.09(dd,J=9Hz,J=1Hz,1H),8.16(d,J=1Hz,1H),9.33(s,1H).
进行类似于1.3的环化反应,得到4-(4-硝基-2-甲基苯基)-3-氧代吗啉,ESI 237。
实施例3
4-(2-硝基苯基)-3-氧代吗啉
将1.12克5-氯-2,3-二氢-1,4-二氧杂环己二烯和2,2-二氯二氧六环(摩尔比率为89:11)的混合物加入含1.12克(8.12mmol)2-硝基苯胺中,边搅拌边将混合物加热至80℃。形成粘液,搅拌3小时。冷却至室温,产物结晶:2.1克淡黄色晶体2-(2-氯乙氧基)-N-(2-硝基苯基)乙酰胺。
1H-NMR(d6-DMSO):δ=3.84(m;4H),4.25(s;2H),7.35(t,J=8Hz,1H),7.77(t,J=8Hz,1H),8.14(d,J=8Hz,1H),8.30(d,J=8Hz,1H),10.74(s,1H).
进行类似于1.3的环化反应,得到4-(2-硝基苯基)-3-氧代吗啉,ESI 223。
实施例4
4-(4-氰基苯基)-3-氧代吗啉
将959毫克(8.12mmol)4-氨基苄腈、1.12克5-氯-2,3-二氢-1,4-二氧杂环己二烯和2,2-二氯二氧六环(摩尔比率为89:11)的混合物搅拌下于80℃加热18小时。冷却至室温,产物重结晶:1.9克淡黄色晶体2-(2-氯乙氧基)-N-(4-氰基苯基)-乙酰胺。
1H-NMR(d6-DMSO):δ=3.82(m;4H),4.19(s;2H),7.78(d,J=8Hz,2H),7.85(d,J=8Hz,2H),10.22(s,1H).
进行类似于1.3的环化反应,得到4-(4-氰基苯基)-3-氧代吗啉,ESI 203。
实施例5
4-(4-甲氧基羰基苯基)-3-氧代吗啉
将1.23毫克(8.12mmol)4-氨基苯甲酸甲酯、1.12克5-氯-2,3-二氢-1,4-二氧杂环己二烯和2,2-二氯二氧六环(摩尔比率为89:11)的混合物搅拌下于80℃加热18小时。冷却至室温,产物重结晶:2.2克淡黄色晶体4-[2-(2-氯乙氧基)乙酰氨基]苯甲酸甲酯。
1H-NMR(d6-DMSO):δ=3.82(m;7H),4.20(s;2H),7.82(d,J=8Hz,2H),7.93(d,J=8Hz,2H),10.15(s,1H).
进行类似于1.3的环化反应,得到4-(4-甲氧基羰基苯基)-3-氧代吗啉,ESI 236。
实施例6
一锅法反应制备“A2”
将6.40克5-氯-2,3-二氢-1,4-二氧杂环己二烯(含有6%的2,2-二氯二氧六环)加入6.00克(24.9mmol)4-硝基苯胺的40毫升的乙腈溶液中,混合物于80℃搅拌18小时。将反应溶液冷却至40℃,加入18.0克(130mmol)碳酸钾,在该温度搅拌混合物14小时。过滤反应混合物,残余物用乙腈充分洗涤,蒸发滤液。残余物从乙腈重结晶:8.2克褐色晶体(“A2”),熔点
150-152℃.1H-NMR(d6-DMSO):δ=3.86(t,J=5Hz;2H),4.02(t,J=5Hz;2H),4.28(s;2H),7.77(d,J=9Hz,2H),8.28(d,J=9Hz,2H).
实施例7
4-(3-硝基苯基)-3-氧代吗啉
将1.12克(8.12mmol)3-硝基苯胺和1.11克5-氯-2,3-二氢-1,4-二氧杂环己二烯(含有6%的2,2-二氯二氧六环)的混合物搅拌80℃加热24小时,得到2.1克褐色油状物2-(2-氯乙氧基)-N-(3-硝基苯基)-乙酰胺。ESI 259。
进行类似于1.3的环化反应,得到4-(3-硝基苯基)-3-氧代吗啉,ESI 223。
实施例8
4-(4-苯甲酰基苯基)-3-氧代吗啉
将1.60克(8.12mmol)4-氨基二苯酮和1.11克5-氯-2,3-二氢-1,4-二氧杂环己二烯(含有6%的2,2-二氯二氧六环)的混合物搅拌下于80℃加热24小时,得到2.6克褐色油状物N-(4-苯甲酰基苯基)-2-(2-氯乙氧基)乙酰胺。ESI 318。
进行类似于1.3的环化反应,得到4-(4-苯甲酰基苯基)-3-氧代吗啉,ESI 282。
实施例9
4-(3-氟苯基)-3-氧代吗啉
将12.0克(108mmol)3-氟苯胺和16克5-氯-2,3-二氢-1,4-二氧杂环己二烯(含有6%的2,2-二氯二氧六环)的混合物于100℃加热,持续24小时。冷却混合物,在减压状态下除去过量的5-氯-2,3-二氢-1,4-二氧杂环己二烯,得到25克褐色油状物2-(2-氯乙氧基)-N-(3-氟苯基)乙酰胺;ESI 232。将该油状物溶于400毫升乙腈,加入84.7克(260mmol)碳酸铯。在室温下,搅拌形成的悬浮液18小时。过滤反应混合物,蒸发滤液,得到21.0克褐色油状物4-(3-氟苯基)吗啉-3-酮;
ESI196.1H-NMR(d6-DMSO):δ=3.77(t,J=5Hz;2H),3.97(t,J=5Hz;2H),4.23(s;2H),7.11(dddd,J1=8Hz,J2=8Hz,J3=2Hz,J4=0.5Hz,1H),7.26(ddd,J1=8Hz,J2=2Hz,J3=0.5Hz,1H),7.34(ddd,J1=10Hz,J2=2Hz,J3=2Hz,1H),7.45(ddd,J1=8Hz,J2=8Hz,J3=7Hz,1H).
实施例10
4-(3-甲基-4-硝基苯基)-3-氧代吗啉
将12.8克5-氯-2,3-二氢-1,4-二氧杂环己二烯(含有6%的2,2-二氯二氧六环)加入10.0克(65.7mmol)3-甲基-4-硝基苯胺的250毫升的乙腈溶液中,在80℃下,搅拌混合物66小时。冷却反应溶液至室温,加入42.8克(13]mmol)碳酸铯,在室温下搅拌混合物18小时。过滤反应混合物,残余物经乙腈充分洗涤,蒸发滤液。残余物从少量乙腈重结晶,得到12.8克(83%)淡黄色固体的4-(3-甲基-4-硝基苯基)吗啉-3-酮。
ESI 236.1H-NMR(d6-DMSO):δ=2.54(s;2H),δ=3.82(t,J=5Hz;2H),4.00(t,J=5Hz;2H),-4.25(s;2H),7.57(m;2H),8.04(d,J.=8Hz;1H).
4-(2-氯-5-氟-4-硝基苯基)-3-氧代吗啉按照类似方法得到
实施例11
按照类似于实施例7的方法得到4-(2-溴-5-硝基苯基)-3-氧代吗啉
按照类似于实施例7的方法得到4-(2-甲氧基羰基-5-硝基苯基)-3-氧代吗啉
Claims (11)
2.权利要求1的方法,所述方法用于制备式I化合物,其中式II的胺的pKa值≤3。
3.权利要求1的方法,其中方法步骤a)和b)进行一锅式反应。
4.权利要求1的方法,其中方法步骤a)在0℃至150℃下进行。
5.权利要求4的方法,其中方法步骤a)在70℃至90℃下进行。
6.权利要求1的方法,其中所述环化反应在碱金属或碱土金属的氢氧化物、碳酸盐或碳酸氢盐存在下,在惰性溶剂或溶剂混合物中进行。
7.权利要求1的方法,其中所述环化反应在碳酸铯或碳酸钾存在下进行。
8.权利要求1的方法,其中所述方法在乙腈中作为一锅法反应进行。
9.权利要求1的方法,所述方法用于制备选自以下的化合物或其盐
(1)4-(4-硝基苯基)-3-氧代吗啉
(2)4-(3-硝基苯基)-3-氧代吗啉
(3)4-(2-硝基苯基)-3-氧代吗啉
(4)4-(4-硝基-2-甲基苯基)-3-氧代吗啉
(5)4-(4-甲氧基羰基苯基)-3-氧代吗啉
(6)4-(4-苯甲酰基苯基)-3-氧代吗啉。
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CN103804221B (zh) * | 2014-02-25 | 2016-09-14 | 湖北迅达药业股份有限公司 | 一种4-(4-氨基苯基)-3-吗啉酮的制备方法及其中间体 |
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CH512247A (de) * | 1968-05-02 | 1971-09-15 | Bracco Ind Chimica Spa | Neue Röntgenkontrastmittel und Verfahren zu ihrer Herstellung |
DE19962924A1 (de) * | 1999-12-24 | 2001-07-05 | Bayer Ag | Substituierte Oxazolidinone und ihre Verwendung |
DE10102322A1 (de) * | 2001-01-19 | 2002-07-25 | Merck Patent Gmbh | Phenylderivate |
DE10129725A1 (de) * | 2001-06-20 | 2003-01-02 | Bayer Ag | Kombinationstherapie substituierter Oxazolidinone |
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CN103804222A (zh) * | 2014-02-25 | 2014-05-21 | 湖北迅达药业股份有限公司 | 一种4-(4-氨基苯基)-3-吗啉酮的合成方法及其中间体 |
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ES2275233T3 (es) | 2007-06-01 |
AU2004265056B2 (en) | 2011-03-17 |
JP2007501818A (ja) | 2007-02-01 |
KR101119940B1 (ko) | 2012-03-19 |
EP1654240A1 (de) | 2006-05-10 |
ZA200602068B (en) | 2007-05-30 |
ATE344252T1 (de) | 2006-11-15 |
BRPI0413484A (pt) | 2006-10-17 |
PL1654240T3 (pl) | 2007-02-28 |
DK1654240T3 (da) | 2007-03-26 |
RU2006107291A (ru) | 2007-09-20 |
RU2343149C2 (ru) | 2009-01-10 |
CA2535412C (en) | 2012-08-28 |
AU2004265056A1 (en) | 2005-02-24 |
CA2535412A1 (en) | 2005-02-24 |
EP1654240B1 (de) | 2006-11-02 |
MXPA06001567A (es) | 2006-05-15 |
PT1654240E (pt) | 2007-02-28 |
JP4668903B2 (ja) | 2011-04-13 |
CN1832933A (zh) | 2006-09-13 |
AR045244A1 (es) | 2005-10-19 |
HK1095145A1 (en) | 2007-04-27 |
KR20060066086A (ko) | 2006-06-15 |
US7687624B2 (en) | 2010-03-30 |
DE10336716A1 (de) | 2005-03-10 |
DE502004001923D1 (de) | 2006-12-14 |
US20100210864A1 (en) | 2010-08-19 |
WO2005016899A1 (de) | 2005-02-24 |
US20060217550A1 (en) | 2006-09-28 |
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