CN1356996A - 苯并呋喃衍生物 - Google Patents
苯并呋喃衍生物 Download PDFInfo
- Publication number
- CN1356996A CN1356996A CN00809308A CN00809308A CN1356996A CN 1356996 A CN1356996 A CN 1356996A CN 00809308 A CN00809308 A CN 00809308A CN 00809308 A CN00809308 A CN 00809308A CN 1356996 A CN1356996 A CN 1356996A
- Authority
- CN
- China
- Prior art keywords
- compound
- formula
- piperazinyl
- base carbonyl
- benzyl
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
- IANQTJSKSUMEQM-UHFFFAOYSA-N 1-benzofuran Chemical class C1=CC=C2OC=CC2=C1 IANQTJSKSUMEQM-UHFFFAOYSA-N 0.000 title claims abstract 3
- 150000003839 salts Chemical class 0.000 claims abstract description 24
- 239000003814 drug Substances 0.000 claims abstract description 9
- 150000001875 compounds Chemical class 0.000 claims description 91
- 239000002585 base Substances 0.000 claims description 86
- -1 1-piperazinyl Chemical group 0.000 claims description 56
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 49
- 125000006239 protecting group Chemical group 0.000 claims description 39
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 37
- 229910052794 bromium Inorganic materials 0.000 claims description 31
- 229910052801 chlorine Inorganic materials 0.000 claims description 31
- 229910052740 iodine Inorganic materials 0.000 claims description 30
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 28
- 239000002253 acid Substances 0.000 claims description 23
- 229910052799 carbon Inorganic materials 0.000 claims description 22
- 238000006243 chemical reaction Methods 0.000 claims description 21
- 150000001721 carbon Chemical group 0.000 claims description 20
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 claims description 17
- 238000000034 method Methods 0.000 claims description 16
- 125000000217 alkyl group Chemical group 0.000 claims description 12
- 229910052736 halogen Inorganic materials 0.000 claims description 12
- 150000002367 halogens Chemical class 0.000 claims description 12
- 238000002360 preparation method Methods 0.000 claims description 10
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 claims description 8
- QARVLSVVCXYDNA-UHFFFAOYSA-N bromobenzene Chemical compound BrC1=CC=CC=C1 QARVLSVVCXYDNA-UHFFFAOYSA-N 0.000 claims description 8
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 8
- 238000004519 manufacturing process Methods 0.000 claims description 7
- 150000001907 coumarones Chemical class 0.000 claims description 6
- 150000002576 ketones Chemical class 0.000 claims description 6
- 239000003513 alkali Substances 0.000 claims description 5
- QHKJIJXBJCOABP-UHFFFAOYSA-N 1-benzofuran-2-carboxamide Chemical class C1=CC=C2OC(C(=O)N)=CC2=C1 QHKJIJXBJCOABP-UHFFFAOYSA-N 0.000 claims description 4
- 229910021529 ammonia Inorganic materials 0.000 claims description 4
- 125000001246 bromo group Chemical group Br* 0.000 claims description 4
- NJJWMEJWFYRORL-UHFFFAOYSA-N 3-(4-chlorobutyl)-1h-indole-5-carbonitrile Chemical compound C1=C(C#N)C=C2C(CCCCCl)=CNC2=C1 NJJWMEJWFYRORL-UHFFFAOYSA-N 0.000 claims description 3
- 210000003169 central nervous system Anatomy 0.000 claims description 3
- 229940079593 drug Drugs 0.000 claims description 3
- 230000000694 effects Effects 0.000 claims description 3
- 238000010306 acid treatment Methods 0.000 claims description 2
- 238000005904 alkaline hydrolysis reaction Methods 0.000 claims description 2
- 230000032050 esterification Effects 0.000 claims description 2
- 238000005886 esterification reaction Methods 0.000 claims description 2
- 229910052731 fluorine Inorganic materials 0.000 claims description 2
- 229910052757 nitrogen Inorganic materials 0.000 claims description 2
- 230000007704 transition Effects 0.000 claims description 2
- 108010021119 Trichosanthin Proteins 0.000 claims 1
- 230000015572 biosynthetic process Effects 0.000 abstract 1
- 239000013067 intermediate product Substances 0.000 abstract 1
- 238000003786 synthesis reaction Methods 0.000 abstract 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical group CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 24
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 22
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 21
- 229910052760 oxygen Inorganic materials 0.000 description 16
- 239000001301 oxygen Substances 0.000 description 16
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 15
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 12
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 12
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 12
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 11
- 239000000203 mixture Substances 0.000 description 11
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 11
- 125000004390 alkyl sulfonyl group Chemical group 0.000 description 10
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 10
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 9
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 9
- 239000012074 organic phase Substances 0.000 description 7
- 239000002904 solvent Substances 0.000 description 7
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 6
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 6
- 239000012442 inert solvent Substances 0.000 description 6
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 6
- VLTRZXGMWDSKGL-UHFFFAOYSA-N perchloric acid Chemical compound OCl(=O)(=O)=O VLTRZXGMWDSKGL-UHFFFAOYSA-N 0.000 description 6
- 239000000243 solution Substances 0.000 description 6
- 125000002252 acyl group Chemical group 0.000 description 5
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 5
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 4
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical group CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 4
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 4
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 4
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 4
- 125000004391 aryl sulfonyl group Chemical group 0.000 description 4
- 238000002425 crystallisation Methods 0.000 description 4
- 230000008025 crystallization Effects 0.000 description 4
- UFWIBTONFRDIAS-UHFFFAOYSA-N naphthalene-acid Natural products C1=CC=CC2=CC=CC=C21 UFWIBTONFRDIAS-UHFFFAOYSA-N 0.000 description 4
- QVINPSQORHCFEX-UHFFFAOYSA-N $l^{1}-oxidanylsulfonylbenzene Chemical compound [O]S(=O)(=O)C1=CC=CC=C1 QVINPSQORHCFEX-UHFFFAOYSA-N 0.000 description 3
- 125000000590 4-methylphenyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)C([H])([H])[H] 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical group CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 3
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical group CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- LSNNMFCWUKXFEE-UHFFFAOYSA-M Bisulfite Chemical compound OS([O-])=O LSNNMFCWUKXFEE-UHFFFAOYSA-M 0.000 description 3
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 150000001408 amides Chemical class 0.000 description 3
- 150000003818 basic metals 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
- 239000012043 crude product Substances 0.000 description 3
- 239000000706 filtrate Substances 0.000 description 3
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 3
- 239000011541 reaction mixture Substances 0.000 description 3
- 238000010898 silica gel chromatography Methods 0.000 description 3
- 229910052938 sodium sulfate Inorganic materials 0.000 description 3
- 235000011152 sodium sulphate Nutrition 0.000 description 3
- 238000005406 washing Methods 0.000 description 3
- 125000003088 (fluoren-9-ylmethoxy)carbonyl group Chemical group 0.000 description 2
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 2
- XNWFRZJHXBZDAG-UHFFFAOYSA-N 2-METHOXYETHANOL Chemical compound COCCO XNWFRZJHXBZDAG-UHFFFAOYSA-N 0.000 description 2
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 2
- MKKSTJKBKNCMRV-UHFFFAOYSA-N 5-bromo-2-hydroxybenzaldehyde Chemical compound OC1=CC=C(Br)C=C1C=O MKKSTJKBKNCMRV-UHFFFAOYSA-N 0.000 description 2
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-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
- BWLUMTFWVZZZND-UHFFFAOYSA-N Dibenzylamine Chemical compound C=1C=CC=CC=1CNCC1=CC=CC=C1 BWLUMTFWVZZZND-UHFFFAOYSA-N 0.000 description 2
- ROSDSFDQCJNGOL-UHFFFAOYSA-N Dimethylamine Chemical compound CNC ROSDSFDQCJNGOL-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
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 2
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 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
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 2
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- 125000001931 aliphatic group Chemical group 0.000 description 2
- 125000004453 alkoxycarbonyl group Chemical group 0.000 description 2
- 125000003118 aryl group Chemical group 0.000 description 2
- 229910052728 basic metal Inorganic materials 0.000 description 2
- SRSXLGNVWSONIS-UHFFFAOYSA-N benzenesulfonic acid Chemical compound OS(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-N 0.000 description 2
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 2
- 239000013078 crystal Substances 0.000 description 2
- 238000002242 deionisation method Methods 0.000 description 2
- HPNMFZURTQLUMO-UHFFFAOYSA-N diethylamine Chemical compound CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 description 2
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 2
- 125000003754 ethoxycarbonyl group Chemical group C(=O)(OCC)* 0.000 description 2
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 2
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 2
- 238000007327 hydrogenolysis reaction Methods 0.000 description 2
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-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
- 239000000047 product Substances 0.000 description 2
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 2
- 239000002994 raw material Substances 0.000 description 2
- 229910052708 sodium Inorganic materials 0.000 description 2
- 239000011734 sodium Substances 0.000 description 2
- 235000017550 sodium carbonate Nutrition 0.000 description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 description 2
- MFRIHAYPQRLWNB-UHFFFAOYSA-N sodium tert-butoxide Chemical compound [Na+].CC(C)(C)[O-] MFRIHAYPQRLWNB-UHFFFAOYSA-N 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- 239000000725 suspension Substances 0.000 description 2
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 description 2
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 2
- 238000001291 vacuum drying Methods 0.000 description 2
- DRFJJKOQBRMRCL-UHFFFAOYSA-N 1-(3-bromophenyl)-2,5-dimethylpyrrole Chemical compound CC1=CC=C(C)N1C1=CC=CC(Br)=C1 DRFJJKOQBRMRCL-UHFFFAOYSA-N 0.000 description 1
- ZEMZPXWZVTUONV-UHFFFAOYSA-N 2-(2-dicyclohexylphosphanylphenyl)-n,n-dimethylaniline Chemical group CN(C)C1=CC=CC=C1C1=CC=CC=C1P(C1CCCCC1)C1CCCCC1 ZEMZPXWZVTUONV-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
- ZNQVEEAIQZEUHB-UHFFFAOYSA-N 2-ethoxyethanol Chemical compound CCOCCO ZNQVEEAIQZEUHB-UHFFFAOYSA-N 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
- 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 1
- 229960000549 4-dimethylaminophenol Drugs 0.000 description 1
- DLFVBJFMPXGRIB-UHFFFAOYSA-N Acetamide Chemical compound CC(N)=O DLFVBJFMPXGRIB-UHFFFAOYSA-N 0.000 description 1
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- 239000004215 Carbon black (E152) Substances 0.000 description 1
- QGJOPFRUJISHPQ-UHFFFAOYSA-N Carbon disulfide Chemical compound S=C=S QGJOPFRUJISHPQ-UHFFFAOYSA-N 0.000 description 1
- RGHNJXZEOKUKBD-UHFFFAOYSA-N D-gluconic acid Natural products OCC(O)C(O)C(O)C(O)C(O)=O RGHNJXZEOKUKBD-UHFFFAOYSA-N 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 1
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 1
- VGGSQFUCUMXWEO-UHFFFAOYSA-N Ethene Chemical compound C=C VGGSQFUCUMXWEO-UHFFFAOYSA-N 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 1
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 1
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 1
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 1
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 1
- 239000005662 Paraffin oil Substances 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 1
- SMWDFEZZVXVKRB-UHFFFAOYSA-N Quinoline Chemical compound N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 1
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 description 1
- XSTXAVWGXDQKEL-UHFFFAOYSA-N Trichloroethylene Chemical group ClC=C(Cl)Cl XSTXAVWGXDQKEL-UHFFFAOYSA-N 0.000 description 1
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 1
- CGIHPACLZJDCBQ-UHFFFAOYSA-N acibenzolar Chemical compound SC(=O)C1=CC=CC2=C1SN=N2 CGIHPACLZJDCBQ-UHFFFAOYSA-N 0.000 description 1
- 238000013019 agitation Methods 0.000 description 1
- 125000002723 alicyclic group Chemical group 0.000 description 1
- 229910052784 alkaline earth metal Inorganic materials 0.000 description 1
- 229910001860 alkaline earth metal hydroxide Inorganic materials 0.000 description 1
- 150000001342 alkaline earth metals Chemical class 0.000 description 1
- 125000005257 alkyl acyl group Chemical group 0.000 description 1
- 230000029936 alkylation Effects 0.000 description 1
- 238000005804 alkylation reaction Methods 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 238000007281 aminoalkylation reaction Methods 0.000 description 1
- 150000003863 ammonium salts Chemical class 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 125000003435 aroyl group Chemical group 0.000 description 1
- 125000003710 aryl alkyl group Chemical group 0.000 description 1
- 125000005161 aryl oxy carbonyl group Chemical group 0.000 description 1
- 125000004104 aryloxy group Chemical group 0.000 description 1
- 229910001038 basic metal oxide Inorganic materials 0.000 description 1
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
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- 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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Classifications
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
- C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D307/78—Benzo [b] furans; Hydrogenated benzo [b] furans
- C07D307/79—Benzo [b] furans; Hydrogenated benzo [b] furans with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the hetero ring
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- C07D307/82—Benzo [b] furans; Hydrogenated benzo [b] furans with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the hetero ring
- C07D307/84—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
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Abstract
式(I)苯并呋喃衍生物及其盐适于用作合成药物中的中间产物,其中R和R′具有在权利要求书中给出的含义。
Description
本申请涉及式I苯并呋喃衍生物及其盐：其中R是1-哌嗪基、4-R1-哌嗪基或L，R′是2-R2-5-R3-吡咯-1-基羰基、4-R4-哌嗪-1-基羰基、N，N-二(叔丁氧基羰基)氨基羰基、-CH＝C(R5R6)、苯并呋喃-2-基-C≡C-、-C(卤素)3、-CO-C(卤素)3、1，4-二氢苯并[d][1，2]噁嗪-3-基羰基或3，4-二氢苯并-1H-酞嗪-2-基羰基，L是Cl、Br、I或游离或反应性官能修饰的OH，R1、R4彼此独立地为H、苄基或另一氨基保护基，R2、R3彼此独立地为H或具有1-6个碳原子的烷基，R5、R6彼此独立地为具有1-6个碳原子的烷基，Hal是F、Cl、Br或I。
类似的化合物公开在DE 4333254和DE 19514567中。
本发明是基于下述目的：即发现可用作特别是合成药物的中间体，但是也可以直接用于制备药物的新化合物。
已经发现，式I化合物及其盐是用于制备药物、并且同时具有药理活性的重要中间体。因此，它们表现出例如对中枢神经系统的作用。
本发明涉及式I苯并呋喃衍生物及其盐。
在本申请上下文中，除非另外特定指出，否则基团R1、R2、R3、R4、R5、R6、R、R′、L、Q和Q′具有在式I-V中给出的含义。在上式中，A具有1-4个，优选1、2或3个碳原子。A优选为甲基或乙基，和丙基或异丙基，还可以是丁基、异丁基、仲丁基或叔丁基。
基团Ph是苯基。
在式I、II、V、VI和VII化合物中，L、Q和Q′优选为Cl、Br、I或反应性修饰的OH，例如活化酯、咪唑交酯(imidazolide)或具有1-6个碳原子的烷基磺酰基氧基(优选甲基磺酰基氧基)或具有6-10个碳原子的芳基磺酰基氧基(优选苯基磺酰基氧基或对甲苯基磺酰基氧基)。
术语“氨基保护基”是通常已知的，并涉及适于在化学反应中保护(封锁)氨基，但是在分子的其它位点上进行完所需化学反应后易于除去的基团。这样的基团特别是未取代的酰基、芳基、芳烷氧基甲基或芳烷基。因为氨基保护基在所需反应(或反应顺序)后被除去，所以其性质和大小不重要；然而，优选的基团是具有1-20个、特别是1-8个碳原子的基团。在本发明方法和本发明化合物中，术语“酰基”应作最广义的理解。其包括源自脂族、芳脂族、芳族或杂环羧酸或磺酸的酰基，以及特别是烷氧基羰基、芳氧基羰基、和尤其是芳烷氧基羰基。这类酰基的实例有链烷酰基例如乙酰基、丙酰基、丁酰基；芳烷酰基例如苯基乙酰基；芳酰基例如苯甲酰基或甲苯甲酰基；芳氧基烷酰基例如苯氧基乙酰基；烷氧基羰基例如甲氧基羰基、乙氧基羰基、2，2，2-三氯乙氧基羰基、BOC(叔丁氧基羰基)、2-碘乙氧基羰基；芳烷氧基羰基例如CBZ(苄氧羰基，还称为“Z”)、4-甲氧基苄氧基羰基、FMOC(9-芴基甲氧基羰基)；芳基磺酰基例如Mtr(4-甲氧基-2，3，6-三甲基苯基磺酰基)。优选的氨基保护基是BOC和Mtr，以及CBZ或FMOC。
式I化合物可具有一个或多个手性中心，并因此可以以不同立体异构形式存在。式I包括所有这些形式。
本发明还涉及制备权利要求1的式I苯并呋喃衍生物及其盐的方法，其特征在于a)为了制备式I化合物其中R是Cl、Br、I、1-哌嗪基、或-R1-哌嗪基，且R′是2-R2-5-R3-吡咯-1-基羰基、4-R4-哌嗪-1-基羰基、1，4-二氢苯并[d][1，2]噁嗪-3-基羰基或3，4-二氢苯并-1H-酞嗪-2-基羰基，将式II化合物其中R是Cl、Br、I、1-哌嗪基、或4-R1-哌嗪基，Q是Cl、Br、I或游离或反应性官能修饰的OH，且R1具有在权利要求1中给出的含义，与式III化合物反应
R′-H III其中R′是2-R2-5-R3-吡咯-1-基、4-R4-哌嗪-1-基、1，4-二氢苯并[d][1，2]噁嗪-3-基或3，4-二氢苯并-1H-酞嗪-2-基，且R2、R3和R4具有在权利要求1中给出的含义，或者b)为了制备式I化合物其中R是Cl、Br、I、1-哌嗪基、或4-R1-哌嗪基，且R′是-CH＝C(R5R6)、苯并呋喃-2-基-C≡C-、-C(卤素)3、或-CO-C(卤素)3，且R1、R5和R6具有在权利要求1中给出的含义，i)将式IV化合物
其中R是Cl、Br、I、1-哌嗪基、或4-R1-哌嗪基，与式V化合物反应
Q′-CH2-CO-R′ V其中R′是-CH＝C(R5R6)、苯并呋喃-2-基-C≡C-、-C(卤素)3、或-CO-C(卤素)3，Q′是Cl、Br、I或游离或反应性官能修饰的OH，且R5和R6具有在权利要求1中给出的含义，或者ii)将式Va化合物环化
其中R和R′具有在i)下面给出的含义，或者c)通过引入氨基保护基将其中R是1-哌嗪基的式I化合物转化成其中R是4-R1-哌嗪基，且R1是氨基保护基的另一式I化合物，或者d)通过除去苄基或氨基保护基将其中R是4-R1-哌嗪基，且R1是苄基或另一氨基保护基的式I化合物转化成其中R1是1-哌嗪基的式I化合物，或者e)通过例如下述方法将式I化合物中的基团R转化成另一基团Ri)用OH代替Br原子，ii)将OH酯化，或iii)用4-R1-哌嗪基代替Br原子，其中R1是苄基或氨基保护基，和/或通过用酸处理将式I碱转化成一种其盐。
式I化合物以及用于其制备的原料是通过其自身已知的方法，例如在文献中描述的方法(例如在标准著作如Houben-Weyl，Methodder organischen Chemie[有机化学方法]，Georg-Thieme-Verlag，Stuttgart中描述的方法)，即在已知且适于所提及反应的反应条件下制得的。对于这种情况，可使用自身已知但是在本文中没有更详细地提及的方法变型。
如果需要的话，原料可在原位形成，这样它们就不用从反应混合物中分离出来，而是可以直接进一步反应以生成式I化合物。
在式II化合物中，基团Q优选为Cl或Br；然而，其也可以是I、OH或反应性修饰的OH例如具有1-6个碳原子的烷基磺酰基氧基(优选甲基磺酰基氧基)或具有6-10个碳原子的芳基磺酰基氧基(优选苯基磺酰基氧基或对甲苯基磺酰基氧基、1-萘磺酰基氧基或2-萘磺酰基氧基)。在式II化合物中，基团R优选为Br或4-苄基哌嗪基。
某些式II化合物是已知的；未知的式II化合物可易于通过类似于制备已知化合物的方法制得。
依据本发明方法进行的式II化合物与式III化合物的反应是例如关于胺烷基化的文献中已知的。可将反应组分在没有溶剂存在的情况下彼此融合，需要时在封闭的试管或高压反应釜中进行。然而，也可以将化合物在惰性溶剂存在下反应。合适的惰性溶剂是例如烃如己烷、石油醚、苯、甲苯或二甲苯；氯代烃例如三氯乙烯、1，2-二氯乙烷、四氯化碳、氯仿或二氯甲烷；醇例如甲醇、乙醇、异丙醇、正丙醇、正丁醇或叔丁醇；醚例如乙醚、二异丙基醚、四氢呋喃(THF)或二氧杂环己烷；二醇醚例如乙二醇一甲醚或一乙醚(甲基乙二醇或乙基乙二醇)、乙二醇二甲醚(二甘醇二甲醚)；酮例如丙酮或丁酮；酰胺例如乙酰胺、二甲基乙酰胺或二甲基甲酰胺(DMF)；腈例如乙腈；亚砜例如二甲亚砜(DMSO)；二硫化碳；硝基化合物例如硝基甲烷或硝基苯；酯例如乙酸乙酯，以及任选所述溶剂彼此的混合物或者与水的混合物。
加入酸结合剂例如碱金属或碱土金属氢氧化物、碳酸盐或碳酸氢盐，或者碱金属或碱土金属优选钾、钠或钙的弱酸盐，或者加入有机碱例如三乙胺、二甲基胺、吡啶或喹啉或过量的胺组分可能是有利的。根据所用的条件，反应时间可以为几分钟-14天，并且反应温度可以为0-150℃、一般为20-130℃。
在式V化合物中，基团Q′优选为Cl或Br；然而，其也可以是I、OH或反应性修饰的OH例如具有1-6个碳原子的烷基磺酰基氧基(优选甲基磺酰基氧基)或具有6-10个碳原子的芳基磺酰基氧基(优选苯基磺酰基氧基或对甲苯基磺酰基氧基、1-萘磺酰基氧基或2-萘磺酰基氧基)。
在式IV化合物中，基团R优选为Br或4-苄基哌嗪基。
依据本发明方法进行的式IV化合物与式V化合物的反应是例如关于苯酚烷基化的文献中已知的。
某些式VI化合物是已知的；未知的化合物可易于通过类似于制备已知化合物的方法制得。环化是依据通常已知的方法进行的。
根据所用的保护基，使用例如强酸，方便起见使用TFA(三氟乙酸)或高氯酸，但是也可以使用其它无机强酸例如盐酸或硫酸，有机强羧酸例如三氯乙酸或磺酸如苯磺酸或对甲苯磺酸将氨基保护基从式I化合物上除去。可存在另外的惰性溶剂，但不总是必需的。合适的惰性溶剂优选为有机溶剂，例如羧酸如乙酸，醚例如四氢呋喃或二氧杂环己烷，酰胺例如二甲基甲酰胺，卤代烃例如二氯甲烷，以及醇例如甲醇、乙醇或异丙醇，和水。此外，可使用上述溶剂的混合物。优选使用过量的THF、同时不加入另外的溶剂，呈与乙酸混合物形式的高氯酸，和比例为9∶1的70％高氯酸。方便起见，反应温度为大约0-大约50℃；反应优选在15-30℃进行。
优选使用在二氯甲烷中的TFA或者使用在二氧杂环己烷中的大约3-5N盐酸于15-30℃除去基团BOC。
可氢解除去的保护基(例如CBZ或苄基)可通过在催化剂(例如方便起见在载体如碳上的贵金属催化剂例如钯)存在下用氢处理来除去。合适的溶剂是上述溶剂，特别是例如醇如甲醇或乙醇，或酰胺例如DMF。氢解一般在约0-100℃温度和约1-200巴压力下，优选在20-30℃温度和1-10巴压力下进行。
其中R′是N，N-二(叔丁氧基羰基)氨基羰基的式I化合物可优选这样获得：在加入碱例如二乙胺和优选催化量的二甲基氨基吡啶的惰性溶剂例如THF或二氧杂环己烷中，将其中R是-R1-哌嗪基或L，L具有在权利要求1中给出的含义，且R1是苄基或另一氨基保护基的未保护氨基羰基化合物与(BOC)2O反应。
可使用酸将式I碱转化成相应的酸加成盐，例如将等当量的式I碱与酸在惰性溶剂例如乙醇中反应，然后蒸发。适用于该反应的酸特别是能生成生理可接受盐的酸。因此，可使用无机酸，例如硫酸、硝酸、氢卤酸如盐酸或氢溴酸、磷酸例如正磷酸、氨基磺酸，和有机酸，特别是脂族、脂环族、芳脂族、芳香族或杂环一元或多元羧酸、磺酸或硫酸，例如甲酸、乙酸、丙酸、新戊酸、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、柠檬酸、葡萄糖酸、抗坏血酸、烟酸、异烟酸、甲磺酸或乙磺酸、乙二磺酸、2-羟基乙磺酸、苯磺酸、对甲苯磺酸、萘一磺酸和萘二磺酸、和十二烷基硫酸。与生理不可接受酸形成的盐例如苦味酸盐可用于分离和/或纯化式I化合物。
另一方面，可用碱(例如钠或钾氢氧化物或碳酸盐)将式I化合物转化成相应的金属、特别是碱金属或碱土金属盐，或转化成相应的铵盐。
本发明还涉及式I化合物作为合成药物的中间体的应用。相应的药物描述在例如DE4333254中。
本发明特别涉及式I化合物作为合成表现出中枢神经系统作用的药物的中间体的应用。可非常特别优选提及1-[4-(5-氰基吲哚-3-基)丁基]-4-(2-氨基甲酰基苯并呋喃-5-基)哌嗪及其盐。
因此，本发明特别涉及权利要求1的式I化合物其中R是Cl、Br、I或4-R1-哌嗪基，R′是2-R2-5-R3-吡咯-1-基羰基、4-R4-哌嗪-1-基羰基、1，4-二氢苯并[d][1，2]噁嗪-3-基羰基或3，4-二氢苯并-1H-酞嗪-2-基羰基，R1是苄基或另一氨基保护基，R4是H、苄基或另一氨基保护基，R2、R3彼此独立地为H或具有1-6个碳原子的烷基，在合成1-[4-(5-氰基吲哚-3-基)丁基]-4-(2-氨基甲酰基苯并呋喃-5-基)哌嗪及其盐中的应用，其特征在于将其中R是Cl、Br或I的3-R-6-羟基苯甲醛与式VI化合物反应
X-CH2-CO-Q VI其中X是Cl、Br、I或游离或官能修饰的OH，Q是OH或OR″，且R″是具有1-6个碳原子的烷基，以生成式VII化合物其中R是Cl、Br或I，且Q具有上述含义，将由此获得的化合物中的Q转化成Cl、Br、I或游离或官能修饰的OH，将由此获得的化合物与式III化合物反应
R′-H III其中R′是2-R2-5-R3-吡咯-1-基羰基、4-R4-哌嗪-1-基羰基、1，4-二氢苯并[d][1，2]噁嗪-3-基羰基或3，4-二氢苯并-1H-酞嗪-2-基羰基，且R2、R3和R4具有上述含义，以生成式I化合物其中R是Cl、Br或I，R′是2-R2-5-R3-吡咯-1-基羰基、4-R4-哌嗪-1-基羰基、1，4-二氢苯并[d][1，2]噁嗪-3-基羰基或3，4-二氢苯并-1H-酞嗪-2-基羰基，R4是H、苄基或另一氨基保护基，R2、R3彼此独立地为H或具有1-6个碳原子的烷基，通过下述方法将由此获得的式I化合物中的基团R转化成另一基团R：在过渡金属催化下与式VIII化合物反应
4-R1-哌嗪 VIII其中R1是苄基或另一氨基保护基，以生成式I化合物其中R是-R1-哌嗪基，R′是2-R2-5-R3-吡咯-1-基羰基、4-R4-哌嗪-1-基羰基、1，4-二氢苯并[d][1，2]噁嗪-3-基羰基或3，4-二氢苯并-1H-酞嗪-2-基羰基，R1是苄基或另一氨基保护基，R4是H、苄基或另一氨基保护基，R2、R3彼此独立地为H或具有1-6个碳原子的烷基，对于由此获得的式I化合物i)首先通过碱性水解将式I化合物转化成式IX化合物和/或其酸加成盐
其中R是4-R1-哌嗪基，且R1是苄基或另一氨基保护基，然后使用氨将其转化成式X化合物
其中R是4-R1-哌嗪基，且R1是苄基或另一氨基保护基，或者ii)使用氨将式I化合物直接转化成式X化合物
其中R是4-R1-哌嗪基，且R1是苄基或另一氨基保护基，通过除去氨基保护基R1将由此获得的式X化合物转化成5-(1-哌嗪基)苯并呋喃-2-甲酰胺或其酸加成盐，并将5-(1-哌嗪基)苯并呋喃-2-甲酰胺与3-(4-氯丁基)-5-氰基吲哚反应，以生成1-[4-(5-氰基吲哚-3-基)丁基]-4-(2-氨基甲酰基苯并呋喃-5-基)哌嗪，并任选将其转化成其酸加成盐。
3-(4-氯丁基)-5-氰基吲哚公开在DE 4101686中；1-[4-(5-氰基吲哚-3-基)丁基]-4-(2-氨基甲酰基苯并呋喃-5-基)哌嗪公开在DE4333254中。
在本申请上下文中，所有温度都是以℃为单位给出的。在下述实施例中，“常规后处理”是表示：如果需要的话加入水，如果需要的话根据终产物的组成将溶液调节至pH2-10，用乙酸乙酯或二氯甲烷萃取，分离出有机相，用硫酸钠干燥，蒸发，并通过硅胶色谱法和/或结晶来纯化。Rf是指在硅胶上的值。
实施例1(2，5-二甲基吡咯-1-基)-5-溴苯并呋喃-2-基甲酮
将0.3g氢化钠(60％在石蜡油中的悬浮液)置于10ml THF中，并滴加在10ml THF中的0.5mL 2，5-二甲基吡咯(5分钟)。在50℃搅拌1小时后，获得了微红的悬浮液。在25℃滴加在10ml THF中的1.3g 5-溴苯并呋喃-2-甲酰氯(5分钟)，然后将该混合物搅拌2小时。加入100ml完全去离子化的水和100ml乙酸乙酯。将分离出的有机相用2×100ml水洗涤，并真空干燥。硅胶色谱(用庚烷/乙酸乙酯4∶1洗脱)纯化后，残余的油状物给出了700mg黄色结晶(收率44％)，熔点115-116℃。
实施例25-溴苯并呋喃-2-甲酸二乙基酰胺
将1.3g 5-溴苯并呋喃-2-甲酰氯、1mL乙基二异丙基胺和30mL甲苯混合，在搅拌下向该棕色溶液中加入0.62ml二乙胺。形成了沉淀，并且反应有轻微放热。5分钟后，用30ml完全去离子化的水处理该混合物，并分离各相。将有机相依次用1)20ml 1N HCl、2)20ml 1N NaOH、3)20ml水和20ml饱和NaCl溶液洗涤，然后真空除去溶剂组分。硅胶色谱纯化后，在洗脱液MtB醚/庚烷2∶1中形成了残余的淡黄色油状物。最终重量：1.3g无色结晶(收率88％)，熔点79-81℃。
实施例3N-(5-溴苯并呋喃-2-羰基)亚氨二甲酸二叔丁酯
在20℃将12g 5-溴苯并呋喃-2-甲酰胺、23.5ml BOC2O、600mg DMAP和8ml三乙胺置于100ml THF中。在吸热反应中于3小时内形成了澄清的橙色溶液。将其温热至25℃，并用100ml水和100ml乙酸乙酯处理。分离出有机相，用100ml水和100ml饱和氯化钠溶液洗涤2次。将有机相浓缩，形成了油状物与结晶的混合物(22g/收率40％)。用160ml乙醇将粗产物结晶后，获得了9.0g黄色结晶，熔点138-139℃。
实施例45-溴苯并呋喃-2-甲酸二苄基酰胺
在50-60℃、搅拌下，用10分钟将50ml甲苯与7.9g二苄基胺的溶液滴加到在100ml甲苯内的5.2g 5-溴苯并呋喃-2-甲酰氯中。获得了无色固体。滴加完成后，将该混合物在100-110℃搅拌3小时。冷却至10℃后，抽滤出固体产物(氯化二苄基铵)。然后将滤液用150ml水和10g碳酸钠处理，并充分振摇。分离出有机相，再用100ml水洗涤，用硫酸钠干燥并过滤。将滤液在旋转蒸发仪中真空浓缩，获得了残余物(残余物：9.5g)。用100ml甲醇重结晶，分离后获得了6.5g产物(收率77％)。熔点114-115℃。
实施例55-(4-苄基哌嗪-1-基)溴苯并呋喃-2-甲酸二苄基酰胺
在氮气氛下将0.06mg Pd2DBA3和0.007g 2-二环己基膦基-2′-二甲基氨基联苯在40ml甲苯中于25℃搅拌20分钟。然后加入1.58g5-溴-2，3-二氢苯并呋喃-2-甲酸二苄基酰胺、0.98g 1-苄基哌嗪和1.43g叔丁醇钠，并将该混合物在120℃搅拌2小时。将冷却的该反应混合物在150ml水与5ml 37％盐酸的混合物中搅拌。用1.5g碳酸钠将该反应混合物中和，并用100ml乙酸乙酯将该水相萃取3次。用5g硫酸钠将合并的有机相干燥，将滤液真空浓缩，获得了树脂状残余物(1.8g粗产物)。将粗产物溶于100ml乙酸乙酯中，用活性炭使其变澄清，并过滤。通过加入25ml 2M氯化氢乙醇溶液将哌嗪产物作为盐酸盐沉淀出来，过滤，将结晶用10ml乙酸乙酯洗涤，在40℃真空干燥。最终重量：1.5g/收率53％，熔点196-198℃。
实施例6顺式/反式-1，2-二(5-溴苯并呋喃)-2-基乙烯
A)制备二醚
该化合物是通过将5-溴水杨醛与Cl-CH2-CH＝CH-CH2-Cl反应而获得的。B)通过环化获得二苯并呋喃衍生物。
实施例72，2′-乙炔二基二-5-溴苯并呋喃
A)制备二醚
将5-溴水杨醛与Cl-CH2-CC-CH2-Cl反应。B)将该二醚环化。
Claims (6)
1.式I苯并呋喃衍生物及其盐：
其中R是1-哌嗪基、4-R1-哌嗪基或L，R′是2-R2-5-R3-吡咯-1-基羰基、4-R4-哌嗪-1-基羰基、N，N-二(叔丁氧基羰基)氨基羰基、-CH＝C(R5R6)、苯并呋喃-2-基-C≡C-、-C(卤素)3、-CO-C(卤素)3、1，4-二氢苯并[d][1，2]噁嗪-3-基羰基或3，4-二氢苯并-1H-酞嗪-2-基羰基，L是Cl、Br、I或游离或反应性官能修饰的OH，R1、R4彼此独立地为H、苄基或另一氨基保护基，R2、R3彼此独立地为H或具有1-6个碳原子的烷基，R5、R6彼此独立地为具有1-6个碳原子的烷基，Hal是F、Cl、Br或I。
2.权利要求1的化合物，其中所述化合物是a)(5-溴苯并呋喃-2-基)-(2，5-二甲基吡咯-1-基)甲酮；b)(4-苄基哌嗪-1-基)-[5-(4-苄基哌嗪-1-基)苯并呋喃-2-基]甲酮；c)[5-(4-苄基哌嗪-1-基)苯并呋喃-2-基]-(1，4-二氢苯并[d][1，2]噁嗪-3-基)甲酮；d)[5-(4-苄基哌嗪-1-基)苯并呋喃-2-基]-(3，4-二氢-1H-酞嗪-2-基)甲酮；e)5-溴-2-(2-甲基丙烯基)苯并呋喃；和它们的盐。
3.制备权利要求1的式I苯并呋喃衍生物及其盐的方法，其特征在于a)为了制备式I化合物其中R是Cl、Br、I、1-哌嗪基、或4-R1-哌嗪基，且R′是2-R2-5-R3-吡咯-1-基羰基、4-R4-哌嗪-1-基羰基、1，4-二氢苯并[d][1，2]噁嗪-3-基羰基或3，4-二氢苯并-1H-酞嗪-2-基羰基，将式II化合物其中R是Cl、Br、I、1-哌嗪基、或4-R1-哌嗪基，Q是Cl、Br、I或游离或反应性官能修饰的OH，且R1具有在权利要求1中给出的含义，与式III化合物反应
R′-H III其中R′是2-R2-5-R3-吡咯-1-基、4-R4-哌嗪-1-基、1，4-二氢苯并[d][1，2]噁嗪-3-基或3，4-二氢苯并-1H-酞嗪-2-基，且R2、R3和R4具有在权利要求1中给出的含义，或者b)为了制备式I化合物其中R是Cl、Br、I、1-哌嗪基、或4-R1-哌嗪基，且R′是-CH＝C(R5R6)、苯并呋喃-2-基-C≡C-、-C(卤素)3、或-CO-C(卤素)3，且R1、R5和R6具有在权利要求1中给出的含义，i)将式IV化合物其中R是Cl、Br、I、1-哌嗪基、或4-R1-哌嗪基，与式V化合物反应
Q′-CH2-CO-R′ V其中R′是-CH＝C(R5R6)、苯并呋喃-2-基-C≡C-、-C(卤素)3、或-CO-C(卤素)3，Q′是Cl、Br、I或游离或反应性官能修饰的OH，且R5和R6具有在权利要求1中给出的含义，或者ii)将式Va化合物环化其中R和R′具有在i)中给出的含义，或者c)通过引入氨基保护基将其中R是1-哌嗪基的式I化合物转化成其中R是4-R1-哌嗪基，且R1是氨基保护基的另一式I化合物，或者d)通过除去苄基或氨基保护基将其中R是4-R1-哌嗪基，且R1是苄基或另一氨基保护基的式I化合物转化成其中R1是1-哌嗪基的式I化合物，或者e)通过例如下述方法将式I化合物中的基团R转化成另一基团Ri)用OH代替Br原子，ii)将OH酯化，或iii)用4-R1-哌嗪基代替Br原子，其中R1是苄基或氨基保护基，和/或通过用酸处理将式I碱转化成一种其盐。
4.权利要求1的式I化合物作为合成药物的中间体的应用。
5.权利要求1的式I化合物作为合成表现出中枢神经系统作用的药物的中间体的应用。
6.权利要求1的式I化合物其中R是Cl、Br、I或4-R1-哌嗪基，R′是2-R2-5-R3-吡咯-1-基羰基、4-R4-哌嗪-1-基羰基、1，4-二氢苯并[d][1，2]噁嗪-3-基羰基或3，4-二氢苯并-1H-酞嗪-2-基羰基，R1是苄基或另一氨基保护基，R4是H、苄基或另一氨基保护基，R2、R3彼此独立地为H或具有1-6个碳原子的烷基，在合成1-[4-(5-氰基吲哚-3-基)丁基]-4-(2-氨基甲酰基苯并呋喃-5-基)哌嗪及其盐中的应用，其特征在于将其中R是Cl、Br或I的3-R-6-羟基苯甲醛与式VI化合物反应
X-CH2-CO-Q VI其中X是Cl、Br、I或游离或官能修饰的OH，Q是OH或OR″，且R″是具有1-6个碳原子的烷基，以生成式VII化合物
其中R是Cl、Br或I，且Q具有上述含义，将由此获得的化合物中的Q转化成Cl、Br、I或游离或官能修饰的OH，将由此获得的化合物与式III化合物反应
R′-H III其中R′是2-R2-5-R3-吡咯-1-基羰基、4-R4-哌嗪-1-基羰基、1，4-二氢苯并[d][1，2]噁嗪-3-基羰基或3，4-二氢苯并-1H-酞嗪-2-基羰基，且R2、R3和R4具有上述含义，以生成式I化合物其中R是Cl、Br或I，R′是2-R2-5-R3-吡咯-1-基羰基、4-R4-哌嗪-1-基羰基、1，4-二氢苯并[d][1，2]噁嗪-3-基羰基或3，4-二氢苯并-1H-酞嗪-2-基羰基，R4是H、苄基或另一氨基保护基，R2、R3彼此独立地为H或具有1-6个碳原子的烷基，通过下述方法将由此获得的式I化合物中的基团R转化成另一基团R：在过渡金属催化下与式VIII化合物反应
4-R1-哌嗪 VIII其中R1是苄基或另一氨基保护基，以生成式I化合物其中R是4-R1-哌嗪基，R′是2-R2-5-R3-吡咯-1-基羰基、4-R4-哌嗪-1-基羰基、1，4-二氢苯并[d][1，2]噁嗪-3-基羰基或3，4-二氢苯并-1H-酞嗪-2-基羰基，R1是苄基或另一氨基保护基，R4是H、苄基或另一氨基保护基，R2、R3彼此独立地为H或具有1-6个碳原子的烷基，对于由此获得的式I化合物i)首先通过碱性水解将式I化合物转化成式IX化合物和/或其酸加成盐其中R是4-R1-哌嗪基，且R1是苄基或另一氨基保护基，然后使用氨将其转化成式X化合物
其中R是4-R1-哌嗪基，且R1是苄基或另一氨基保护基，或者ii)使用氨将式I化合物直接转化成式X化合物
其中R是4-R1-哌嗪基，且R1是苄基或另一氨基保护基，通过除去保护基R1将由此获得的式X化合物转化成5-(1-哌嗪基)苯并呋喃-2-甲酰胺或其酸加成盐，并将5-(1-哌嗪基)苯并呋喃-2-甲酰胺与3-(4-氯丁基)-5-氰基吲哚反应，以生成1-[4-(5-氰基吲哚-3-基)丁基]-4-(2-氨基甲酰基苯并呋喃-5-基)哌嗪，然后任选将其转化成其酸加成盐。
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| DE19932314.3 | 1999-07-10 | ||
| DE19932314A DE19932314A1 (de) | 1999-07-10 | 1999-07-10 | Benzofuranderivate |
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| US (1) | US6531503B1 (zh) |
| EP (1) | EP1194426B1 (zh) |
| JP (1) | JP4908706B2 (zh) |
| KR (1) | KR100709378B1 (zh) |
| CN (1) | CN1178934C (zh) |
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| AT (1) | ATE273973T1 (zh) |
| AU (1) | AU767413B2 (zh) |
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| CA (1) | CA2378603C (zh) |
| CZ (1) | CZ301441B6 (zh) |
| DE (2) | DE19932314A1 (zh) |
| DK (1) | DK1194426T3 (zh) |
| ES (1) | ES2226884T3 (zh) |
| HK (1) | HK1047275B (zh) |
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| MX (1) | MXPA02000316A (zh) |
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| NO (1) | NO328209B1 (zh) |
| PL (1) | PL196477B1 (zh) |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101990535A (zh) * | 2008-04-18 | 2011-03-23 | 默克专利有限公司 | 作为fxr调节剂的苯并呋喃、苯并噻吩、苯并噻唑衍生物 |
| CN105308024A (zh) * | 2013-06-10 | 2016-02-03 | 安斯泰来制药株式会社 | 二环式含氮芳香族杂环酰胺化合物 |
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| DE102006060597A1 (de) | 2006-12-21 | 2008-06-26 | Merck Patent Gmbh | Verfahren zur Herstellung von Benzofuran-2-carboxamiden |
| PL2406243T3 (pl) * | 2009-03-10 | 2014-10-31 | Takeda Pharmaceuticals Co | Pochodne benzofuranu |
| CA2798610A1 (en) | 2010-05-06 | 2011-11-10 | Bristol-Myers Squibb Company | Bicyclic heteroaryl compounds as gpr119 modulators |
| WO2011140161A1 (en) | 2010-05-06 | 2011-11-10 | Bristol-Myers Squibb Company | Benzofuranyl analogues as gpr119 modulators |
| CN102964323B (zh) * | 2012-11-13 | 2015-03-25 | 苏州永健生物医药有限公司 | 一种5-（哌嗪-1-基）苯并呋喃-2-甲酰胺的合成方法 |
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| US2724915A (en) * | 1955-11-29 | Snow remover | ||
| DE2757532A1 (de) * | 1977-12-23 | 1979-07-05 | Hoechst Ag | N,n'-disubstituiertes cyclisches diamin und verfahren zu dessen herstellung |
| CN1129443A (zh) * | 1993-06-14 | 1996-08-21 | 美国辉瑞有限公司 | 仲胺用作治糖尿病和治肥胖病药物 |
| DE4333254A1 (de) | 1993-09-30 | 1995-04-06 | Merck Patent Gmbh | Piperidine und Piperazine |
| DE19514567A1 (de) * | 1995-04-20 | 1996-10-24 | Merck Patent Gmbh | Benzofurane |
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101990535A (zh) * | 2008-04-18 | 2011-03-23 | 默克专利有限公司 | 作为fxr调节剂的苯并呋喃、苯并噻吩、苯并噻唑衍生物 |
| CN101990535B (zh) * | 2008-04-18 | 2013-06-19 | 默克专利有限公司 | 作为fxr调节剂的苯并呋喃、苯并噻吩、苯并噻唑衍生物 |
| CN105308024A (zh) * | 2013-06-10 | 2016-02-03 | 安斯泰来制药株式会社 | 二环式含氮芳香族杂环酰胺化合物 |
| CN105308024B (zh) * | 2013-06-10 | 2017-10-27 | 安斯泰来制药株式会社 | 二环式含氮芳香族杂环酰胺化合物 |
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