CN101010321B - 吡咯并[3,2-b]吡啶衍生物及其制备方法 - Google Patents
吡咯并[3,2-b]吡啶衍生物及其制备方法 Download PDFInfo
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- CN101010321B CN101010321B CN200580029375XA CN200580029375A CN101010321B CN 101010321 B CN101010321 B CN 101010321B CN 200580029375X A CN200580029375X A CN 200580029375XA CN 200580029375 A CN200580029375 A CN 200580029375A CN 101010321 B CN101010321 B CN 101010321B
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- China
- Prior art keywords
- pyrrolo
- dimethyl
- benzyloxy
- pyridine hydrochloride
- pyridine
- 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.)
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- 238000000034 method Methods 0.000 title claims abstract description 19
- 238000002360 preparation method Methods 0.000 title abstract description 158
- XWIYUCRMWCHYJR-UHFFFAOYSA-N 1h-pyrrolo[3,2-b]pyridine Chemical class C1=CC=C2NC=CC2=N1 XWIYUCRMWCHYJR-UHFFFAOYSA-N 0.000 title abstract description 7
- 150000003839 salts Chemical class 0.000 claims abstract description 27
- AOJFQRQNPXYVLM-UHFFFAOYSA-N pyridine hydrochloride Substances [Cl-].C1=CC=[NH+]C=C1 AOJFQRQNPXYVLM-UHFFFAOYSA-N 0.000 claims description 297
- 150000001875 compounds Chemical class 0.000 claims description 175
- 229910052731 fluorine Inorganic materials 0.000 claims description 125
- 239000011737 fluorine Substances 0.000 claims description 125
- 239000000460 chlorine Substances 0.000 claims description 62
- 229910052801 chlorine Inorganic materials 0.000 claims description 62
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical class OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 40
- -1 acetoxyl group Chemical group 0.000 claims description 38
- 125000000051 benzyloxy group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])O* 0.000 claims description 34
- 229940073608 benzyl chloride Drugs 0.000 claims description 30
- 150000001412 amines Chemical class 0.000 claims description 27
- 238000006243 chemical reaction Methods 0.000 claims description 22
- 229910052736 halogen Inorganic materials 0.000 claims description 22
- 150000002367 halogens Chemical class 0.000 claims description 22
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 12
- 239000001257 hydrogen Substances 0.000 claims description 10
- 229910052739 hydrogen Inorganic materials 0.000 claims description 10
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 9
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 6
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 6
- 125000005956 isoquinolyl group Chemical group 0.000 claims description 6
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 6
- 239000001301 oxygen Substances 0.000 claims description 6
- 229910052760 oxygen Inorganic materials 0.000 claims description 6
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 6
- 239000008194 pharmaceutical composition Substances 0.000 claims description 5
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 claims description 5
- HGUFODBRKLSHSI-UHFFFAOYSA-N 2,3,7,8-tetrachloro-dibenzo-p-dioxin Chemical compound O1C2=CC(Cl)=C(Cl)C=C2OC2=C1C=C(Cl)C(Cl)=C2 HGUFODBRKLSHSI-UHFFFAOYSA-N 0.000 claims description 4
- 125000003601 C2-C6 alkynyl group Chemical group 0.000 claims description 4
- 229910002651 NO3 Inorganic materials 0.000 claims description 4
- 125000003545 alkoxy group Chemical group 0.000 claims description 4
- 125000000217 alkyl group Chemical group 0.000 claims description 4
- 229940077388 benzenesulfonate Drugs 0.000 claims description 4
- 239000003937 drug carrier Substances 0.000 claims description 4
- 125000001160 methoxycarbonyl group Chemical group [H]C([H])([H])OC(*)=O 0.000 claims description 4
- 125000001624 naphthyl group Chemical group 0.000 claims description 4
- 229960005235 piperonyl butoxide Drugs 0.000 claims description 4
- MZKUGCOENXBMFR-UHFFFAOYSA-N pyridin-1-ium;phosphate Chemical compound [O-]P([O-])([O-])=O.C1=CC=[NH+]C=C1.C1=CC=[NH+]C=C1.C1=CC=[NH+]C=C1 MZKUGCOENXBMFR-UHFFFAOYSA-N 0.000 claims description 4
- 125000004076 pyridyl group Chemical group 0.000 claims description 4
- 229950004288 tosilate Drugs 0.000 claims description 4
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 4
- HAFVXEXJWPBGDC-UHFFFAOYSA-N FC1=CC=C(CC1(C(=O)O)C)C(=O)O Chemical compound FC1=CC=C(CC1(C(=O)O)C)C(=O)O HAFVXEXJWPBGDC-UHFFFAOYSA-N 0.000 claims description 3
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 3
- JPRPJUMQRZTTED-UHFFFAOYSA-N 1,3-dioxolanyl Chemical group [CH]1OCCO1 JPRPJUMQRZTTED-UHFFFAOYSA-N 0.000 claims description 2
- HRDGDCUMSQBHDL-UHFFFAOYSA-N 2-(1-ethyl-2,3-dimethylpyrrolo[3,2-b]pyridin-7-yl)-3,4-dihydro-1h-isoquinoline;hydrochloride Chemical compound Cl.C1CC2=CC=CC=C2CN1C1=C2N(CC)C(C)=C(C)C2=NC=C1 HRDGDCUMSQBHDL-UHFFFAOYSA-N 0.000 claims description 2
- DWOWGZLLPMSAMD-UHFFFAOYSA-N 2-[1-(1,3-dioxolan-2-ylmethyl)-2,3-dimethylpyrrolo[3,2-b]pyridin-7-yl]-3,4-dihydro-1h-isoquinoline;hydrochloride Chemical compound Cl.CC1=C(C)C2=NC=CC(N3CC4=CC=CC=C4CC3)=C2N1CC1OCCO1 DWOWGZLLPMSAMD-UHFFFAOYSA-N 0.000 claims description 2
- NWEYOUNTRUPQFH-UHFFFAOYSA-N 2-[1-(2-methoxyethyl)-2,3-dimethylpyrrolo[3,2-b]pyridin-7-yl]-3,4-dihydro-1h-isoquinoline;hydrochloride Chemical compound Cl.C1CC2=CC=CC=C2CN1C1=C2N(CCOC)C(C)=C(C)C2=NC=C1 NWEYOUNTRUPQFH-UHFFFAOYSA-N 0.000 claims description 2
- HNVFXONRCMZZGV-UHFFFAOYSA-N 2-[1-[(3-methoxyphenyl)methyl]-2,3-dimethylpyrrolo[3,2-b]pyridin-7-yl]-3,4-dihydro-1h-isoquinoline;hydrochloride Chemical compound Cl.COC1=CC=CC(CN2C3=C(N4CC5=CC=CC=C5CC4)C=CN=C3C(C)=C2C)=C1 HNVFXONRCMZZGV-UHFFFAOYSA-N 0.000 claims description 2
- JEXJQNLPEIKFGK-UHFFFAOYSA-N 2-[1-[(4-methoxyphenyl)methyl]-2,3-dimethylpyrrolo[3,2-b]pyridin-7-yl]-3,4-dihydro-1h-isoquinoline;hydrochloride Chemical compound Cl.C1=CC(OC)=CC=C1CN1C2=C(N3CC4=CC=CC=C4CC3)C=CN=C2C(C)=C1C JEXJQNLPEIKFGK-UHFFFAOYSA-N 0.000 claims description 2
- SPGVJNFBITVCLC-UHFFFAOYSA-N 2-[1-[2-(1,3-dioxolan-2-yl)ethyl]-2,3-dimethylpyrrolo[3,2-b]pyridin-7-yl]-3,4-dihydro-1h-isoquinoline;hydrochloride Chemical compound Cl.CC1=C(C)C2=NC=CC(N3CC4=CC=CC=C4CC3)=C2N1CCC1OCCO1 SPGVJNFBITVCLC-UHFFFAOYSA-N 0.000 claims description 2
- PGJGOYFKFOLYSY-UHFFFAOYSA-N 2-[2,3-dimethyl-1-(3-methylbut-1-en-2-yl)pyrrolo[3,2-b]pyridin-7-yl]-3,4-dihydro-1h-isoquinoline;hydrochloride Chemical compound Cl.C1CC2=CC=CC=C2CN1C1=C2N(C(=C)C(C)C)C(C)=C(C)C2=NC=C1 PGJGOYFKFOLYSY-UHFFFAOYSA-N 0.000 claims description 2
- XAOMTJGIZDJMBU-UHFFFAOYSA-N 2-[2,3-dimethyl-1-(naphthalen-2-ylmethyl)pyrrolo[3,2-b]pyridin-7-yl]-3,4-dihydro-1h-isoquinoline;hydrochloride Chemical compound Cl.C1=CC=CC2=CC(CN3C4=C(N5CC6=CC=CC=C6CC5)C=CN=C4C(C)=C3C)=CC=C21 XAOMTJGIZDJMBU-UHFFFAOYSA-N 0.000 claims description 2
- SDWOBSTZEYFLDA-UHFFFAOYSA-N 2-[2,3-dimethyl-1-[(3-methylphenyl)methyl]pyrrolo[3,2-b]pyridin-7-yl]-3,4-dihydro-1h-isoquinoline;hydrochloride Chemical compound Cl.CC1=C(C)C2=NC=CC(N3CC4=CC=CC=C4CC3)=C2N1CC1=CC=CC(C)=C1 SDWOBSTZEYFLDA-UHFFFAOYSA-N 0.000 claims description 2
- AKUSZFPCJFNRSZ-UHFFFAOYSA-N 3,4-dimethyl-1,2-oxazole Chemical compound CC1=CON=C1C AKUSZFPCJFNRSZ-UHFFFAOYSA-N 0.000 claims description 2
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 2
- 229950005953 camsilate Drugs 0.000 claims description 2
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 2
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 2
- 125000002147 dimethylamino group Chemical group [H]C([H])([H])N(*)C([H])([H])[H] 0.000 claims description 2
- 125000001207 fluorophenyl group Chemical group 0.000 claims description 2
- 125000000842 isoxazolyl group Chemical group 0.000 claims description 2
- SOJSYOXMFGDLHY-UHFFFAOYSA-N methyl acetate;hydrochloride Chemical compound Cl.COC(C)=O SOJSYOXMFGDLHY-UHFFFAOYSA-N 0.000 claims description 2
- MZDGXTXYHXDWIM-UHFFFAOYSA-N methyl benzoate;hydrochloride Chemical compound Cl.COC(=O)C1=CC=CC=C1 MZDGXTXYHXDWIM-UHFFFAOYSA-N 0.000 claims description 2
- 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 claims description 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 2
- RQDTYPWUPFMCQO-UHFFFAOYSA-N 1-(2-methoxyethyl)-2,3-dimethyl-7-[(3-methylphenyl)methoxy]pyrrolo[3,2-b]pyridine;hydrochloride Chemical compound Cl.C=12N(CCOC)C(C)=C(C)C2=NC=CC=1OCC1=CC=CC(C)=C1 RQDTYPWUPFMCQO-UHFFFAOYSA-N 0.000 claims 1
- QLSHSXTWJAGZNC-UHFFFAOYSA-N 1-(cyclobutylmethyl)-7-[(3,5-difluorophenyl)methoxy]-2,3-dimethylpyrrolo[3,2-b]pyridine;hydrochloride Chemical compound Cl.C=12N(CC3CCC3)C(C)=C(C)C2=NC=CC=1OCC1=CC(F)=CC(F)=C1 QLSHSXTWJAGZNC-UHFFFAOYSA-N 0.000 claims 1
- IYKAWIYSOMPHKJ-UHFFFAOYSA-N 1-[(3-methoxyphenyl)methyl]-2,3-dimethyl-7-[(3-methylphenyl)methoxy]pyrrolo[3,2-b]pyridine;hydrochloride Chemical compound Cl.COC1=CC=CC(CN2C3=C(OCC=4C=C(C)C=CC=4)C=CN=C3C(C)=C2C)=C1 IYKAWIYSOMPHKJ-UHFFFAOYSA-N 0.000 claims 1
- GMXZXVUBJOAKBN-UHFFFAOYSA-N 1-[(3-methoxyphenyl)methyl]-2,3-dimethyl-7-[[4-(trifluoromethyl)phenyl]methoxy]pyrrolo[3,2-b]pyridine;hydrochloride Chemical compound Cl.COC1=CC=CC(CN2C3=C(OCC=4C=CC(=CC=4)C(F)(F)F)C=CN=C3C(C)=C2C)=C1 GMXZXVUBJOAKBN-UHFFFAOYSA-N 0.000 claims 1
- RWIJRYYIZRYLAC-UHFFFAOYSA-N 1-benzyl-2,3-dimethyl-7-[(3-methylphenyl)methoxy]pyrrolo[3,2-b]pyridine;hydrochloride Chemical compound Cl.C=12N(CC=3C=CC=CC=3)C(C)=C(C)C2=NC=CC=1OCC1=CC=CC(C)=C1 RWIJRYYIZRYLAC-UHFFFAOYSA-N 0.000 claims 1
- PXMOGFUOTUPKPE-UHFFFAOYSA-N 1-benzyl-7-[(3,5-difluorophenyl)methoxy]-2,3-dimethylpyrrolo[3,2-b]pyridine;hydrochloride Chemical compound Cl.C=12N(CC=3C=CC=CC=3)C(C)=C(C)C2=NC=CC=1OCC1=CC(F)=CC(F)=C1 PXMOGFUOTUPKPE-UHFFFAOYSA-N 0.000 claims 1
- PHJBNCZOJKZYGK-UHFFFAOYSA-N 1-ethyl-2,3-dimethyl-7-[(3-methylphenyl)methoxy]pyrrolo[3,2-b]pyridine;hydrochloride Chemical compound Cl.C=12N(CC)C(C)=C(C)C2=NC=CC=1OCC1=CC=CC(C)=C1 PHJBNCZOJKZYGK-UHFFFAOYSA-N 0.000 claims 1
- IABNZPXHQVXQNX-UHFFFAOYSA-N 2,3-dimethyl-1-[(4-methylphenyl)methyl]-7-[[4-(trifluoromethyl)phenyl]methoxy]pyrrolo[3,2-b]pyridine;hydrochloride Chemical compound Cl.C=12N(CC=3C=CC(C)=CC=3)C(C)=C(C)C2=NC=CC=1OCC1=CC=C(C(F)(F)F)C=C1 IABNZPXHQVXQNX-UHFFFAOYSA-N 0.000 claims 1
- SBEVVKNODRXRNV-UHFFFAOYSA-N 2,3-dimethyl-7-[(3-methylphenyl)methoxy]-1-[(4-methylphenyl)methyl]pyrrolo[3,2-b]pyridine;hydrochloride Chemical compound Cl.C=12N(CC=3C=CC(C)=CC=3)C(C)=C(C)C2=NC=CC=1OCC1=CC=CC(C)=C1 SBEVVKNODRXRNV-UHFFFAOYSA-N 0.000 claims 1
- WRVMOCZDIXEPKW-UHFFFAOYSA-N 2-(1-benzyl-2,3-dimethylpyrrolo[3,2-b]pyridin-7-yl)-3,4-dihydro-1h-isoquinoline;hydrochloride Chemical compound Cl.CC1=C(C)C2=NC=CC(N3CC4=CC=CC=C4CC3)=C2N1CC1=CC=CC=C1 WRVMOCZDIXEPKW-UHFFFAOYSA-N 0.000 claims 1
- BYWFTNNHMPKFAI-UHFFFAOYSA-N 7-(1,3-benzodioxol-5-ylmethoxy)-1-(1,3-dioxolan-2-ylmethyl)-2,3-dimethylpyrrolo[3,2-b]pyridine;hydrochloride Chemical compound Cl.CC1=C(C)C2=NC=CC(OCC=3C=C4OCOC4=CC=3)=C2N1CC1OCCO1 BYWFTNNHMPKFAI-UHFFFAOYSA-N 0.000 claims 1
- IUBZJYDRAYJBKO-UHFFFAOYSA-N 7-(1,3-benzodioxol-5-ylmethoxy)-1-(2-methoxyethyl)-2,3-dimethylpyrrolo[3,2-b]pyridine;hydrochloride Chemical compound Cl.C1=C2OCOC2=CC(COC=2C=CN=C3C(C)=C(C)N(C=23)CCOC)=C1 IUBZJYDRAYJBKO-UHFFFAOYSA-N 0.000 claims 1
- CKVRLXKXIKPXSA-UHFFFAOYSA-N 7-(1,3-benzodioxol-5-ylmethoxy)-1-[(3-methoxyphenyl)methyl]-2,3-dimethylpyrrolo[3,2-b]pyridine;hydrochloride Chemical compound Cl.COC1=CC=CC(CN2C3=C(OCC=4C=C5OCOC5=CC=4)C=CN=C3C(C)=C2C)=C1 CKVRLXKXIKPXSA-UHFFFAOYSA-N 0.000 claims 1
- ISELRLIAPVOKOL-UHFFFAOYSA-N 7-(1,3-benzodioxol-5-ylmethoxy)-1-benzyl-2,3-dimethylpyrrolo[3,2-b]pyridine;hydrochloride Chemical compound Cl.CC1=C(C)C2=NC=CC(OCC=3C=C4OCOC4=CC=3)=C2N1CC1=CC=CC=C1 ISELRLIAPVOKOL-UHFFFAOYSA-N 0.000 claims 1
- HBOWBGFXUZYNOW-UHFFFAOYSA-N 7-(1,3-benzodioxol-5-ylmethoxy)-1-ethyl-2,3-dimethylpyrrolo[3,2-b]pyridine;hydrochloride Chemical compound Cl.C1=C2OCOC2=CC(COC=2C=CN=C3C(C)=C(C)N(C=23)CC)=C1 HBOWBGFXUZYNOW-UHFFFAOYSA-N 0.000 claims 1
- QHUWUUQWOYKEEN-UHFFFAOYSA-N 7-(1,3-benzodioxol-5-ylmethoxy)-2,3-dimethyl-1-(2-methylpropyl)pyrrolo[3,2-b]pyridine;hydrochloride Chemical compound Cl.C1=C2OCOC2=CC(COC=2C=CN=C3C(C)=C(C)N(C=23)CC(C)C)=C1 QHUWUUQWOYKEEN-UHFFFAOYSA-N 0.000 claims 1
- JMVHTODYRRSVIP-UHFFFAOYSA-N 7-(1,3-benzodioxol-5-ylmethoxy)-2,3-dimethyl-1-[(3-methylphenyl)methyl]pyrrolo[3,2-b]pyridine;hydrochloride Chemical compound Cl.CC1=C(C)C2=NC=CC(OCC=3C=C4OCOC4=CC=3)=C2N1CC1=CC=CC(C)=C1 JMVHTODYRRSVIP-UHFFFAOYSA-N 0.000 claims 1
- FFNSSHFIEMTKFL-UHFFFAOYSA-N 7-(1,3-benzodioxol-5-ylmethoxy)-2,3-dimethyl-1-[(4-methylphenyl)methyl]pyrrolo[3,2-b]pyridine;hydrochloride Chemical compound Cl.CC1=C(C)C2=NC=CC(OCC=3C=C4OCOC4=CC=3)=C2N1CC1=CC=C(C)C=C1 FFNSSHFIEMTKFL-UHFFFAOYSA-N 0.000 claims 1
- NSLZKPAMUYDNGL-UHFFFAOYSA-N 7-[(3,5-difluorophenyl)methoxy]-1-(2-methoxyethyl)-2,3-dimethylpyrrolo[3,2-b]pyridine;hydrochloride Chemical compound Cl.C=12N(CCOC)C(C)=C(C)C2=NC=CC=1OCC1=CC(F)=CC(F)=C1 NSLZKPAMUYDNGL-UHFFFAOYSA-N 0.000 claims 1
- RQAVTBUKNYSXAV-UHFFFAOYSA-N 7-[(3,5-difluorophenyl)methoxy]-2,3-dimethyl-1-[(4-methylphenyl)methyl]pyrrolo[3,2-b]pyridine;hydrochloride Chemical compound Cl.C=12N(CC=3C=CC(C)=CC=3)C(C)=C(C)C2=NC=CC=1OCC1=CC(F)=CC(F)=C1 RQAVTBUKNYSXAV-UHFFFAOYSA-N 0.000 claims 1
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 claims 1
- 230000000694 effects Effects 0.000 abstract description 19
- 102100021904 Potassium-transporting ATPase alpha chain 1 Human genes 0.000 abstract description 12
- 108010083204 Proton Pumps Proteins 0.000 abstract description 12
- 239000000203 mixture Substances 0.000 abstract description 11
- 230000005764 inhibitory process Effects 0.000 abstract description 7
- 230000002401 inhibitory effect Effects 0.000 abstract description 4
- 230000002441 reversible effect Effects 0.000 abstract description 3
- 238000005160 1H NMR spectroscopy Methods 0.000 description 328
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 87
- 239000007787 solid Substances 0.000 description 76
- 239000002585 base Substances 0.000 description 58
- 239000011541 reaction mixture Substances 0.000 description 44
- 239000000243 solution Substances 0.000 description 36
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 31
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 30
- 230000002829 reductive effect Effects 0.000 description 28
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 27
- 238000003756 stirring Methods 0.000 description 23
- QSSXJPIWXQTSIX-UHFFFAOYSA-N 1-bromo-2-methylbenzene Chemical compound CC1=CC=CC=C1Br QSSXJPIWXQTSIX-UHFFFAOYSA-N 0.000 description 22
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 22
- LCGLNKUTAGEVQW-UHFFFAOYSA-N Dimethyl ether Chemical compound COC LCGLNKUTAGEVQW-UHFFFAOYSA-N 0.000 description 18
- JOTRPRKONYTVBV-UHFFFAOYSA-N 4-chloro-3-nitropyridine Chemical compound [O-][N+](=O)C1=CN=CC=C1Cl JOTRPRKONYTVBV-UHFFFAOYSA-N 0.000 description 17
- 238000001035 drying Methods 0.000 description 17
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 15
- PVWOIHVRPOBWPI-UHFFFAOYSA-N n-propyl iodide Chemical compound CCCI PVWOIHVRPOBWPI-UHFFFAOYSA-N 0.000 description 15
- 239000012044 organic layer Substances 0.000 description 15
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- 238000010898 silica gel chromatography Methods 0.000 description 14
- LVZWSLJZHVFIQJ-UHFFFAOYSA-N Cyclopropane Chemical compound C1CC1 LVZWSLJZHVFIQJ-UHFFFAOYSA-N 0.000 description 13
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 13
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 12
- 239000002253 acid Substances 0.000 description 12
- BHELZAPQIKSEDF-UHFFFAOYSA-N allyl bromide Chemical compound BrCC=C BHELZAPQIKSEDF-UHFFFAOYSA-N 0.000 description 12
- UORHQLNXWYFBIL-UHFFFAOYSA-N tert-butyl carbamate hydrochloride Chemical compound Cl.CC(C)(C)OC(N)=O UORHQLNXWYFBIL-UHFFFAOYSA-N 0.000 description 12
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical class Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 10
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 10
- 102000004190 Enzymes Human genes 0.000 description 9
- 108090000790 Enzymes Proteins 0.000 description 9
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 9
- 238000013016 damping Methods 0.000 description 9
- 239000012530 fluid Substances 0.000 description 9
- XBDXMDVEZLOGMC-UHFFFAOYSA-N 1-(chloromethyl)-3-fluorobenzene Chemical compound FC1=CC=CC(CCl)=C1 XBDXMDVEZLOGMC-UHFFFAOYSA-N 0.000 description 8
- DMHZDOTYAVHSEH-UHFFFAOYSA-N 1-(chloromethyl)-4-methylbenzene Chemical compound CC1=CC=C(CCl)C=C1 DMHZDOTYAVHSEH-UHFFFAOYSA-N 0.000 description 8
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 8
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 8
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 8
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- 150000002431 hydrogen Chemical class 0.000 description 1
- 230000003301 hydrolyzing effect Effects 0.000 description 1
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- 230000004054 inflammatory process Effects 0.000 description 1
- 229910052500 inorganic mineral Inorganic materials 0.000 description 1
- 229910052816 inorganic phosphate Inorganic materials 0.000 description 1
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 1
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- NLWBJPPMPLPZIE-UHFFFAOYSA-N methyl 4-(bromomethyl)benzoate Chemical compound COC(=O)C1=CC=C(CBr)C=C1 NLWBJPPMPLPZIE-UHFFFAOYSA-N 0.000 description 1
- SATDLKYRVXFXRE-UHFFFAOYSA-N methyl 4-(chloromethyl)benzoate Chemical compound COC(=O)C1=CC=C(CCl)C=C1 SATDLKYRVXFXRE-UHFFFAOYSA-N 0.000 description 1
- KMBKANUKRRDMII-UHFFFAOYSA-N methyl 4-[[7-(3,4-dihydro-1h-isoquinolin-2-yl)-2,3-dimethylpyrrolo[3,2-b]pyridin-1-yl]methyl]benzoate;hydrochloride Chemical compound Cl.C1=CC(C(=O)OC)=CC=C1CN1C2=C(N3CC4=CC=CC=C4CC3)C=CN=C2C(C)=C1C KMBKANUKRRDMII-UHFFFAOYSA-N 0.000 description 1
- 229920000609 methyl cellulose Polymers 0.000 description 1
- 239000001923 methylcellulose Substances 0.000 description 1
- GRVDJDISBSALJP-UHFFFAOYSA-N methyloxidanyl Chemical group [O]C GRVDJDISBSALJP-UHFFFAOYSA-N 0.000 description 1
- 210000001589 microsome Anatomy 0.000 description 1
- 235000010755 mineral Nutrition 0.000 description 1
- 239000011707 mineral Substances 0.000 description 1
- 150000004712 monophosphates Chemical class 0.000 description 1
- PSHKMPUSSFXUIA-UHFFFAOYSA-N n,n-dimethylpyridin-2-amine Chemical compound CN(C)C1=CC=CC=N1 PSHKMPUSSFXUIA-UHFFFAOYSA-N 0.000 description 1
- 239000013642 negative control Substances 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- ZWLPBLYKEWSWPD-UHFFFAOYSA-N o-toluenecarboxylic acid Natural products CC1=CC=CC=C1C(O)=O ZWLPBLYKEWSWPD-UHFFFAOYSA-N 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- OIGWAXDAPKFNCQ-UHFFFAOYSA-N p-Isopropylbenzyl alcohol Natural products CC(C)C1=CC=C(CO)C=C1 OIGWAXDAPKFNCQ-UHFFFAOYSA-N 0.000 description 1
- UQPUONNXJVWHRM-UHFFFAOYSA-N palladium;triphenylphosphane Chemical compound [Pd].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 UQPUONNXJVWHRM-UHFFFAOYSA-N 0.000 description 1
- VEDDBHYQWFOITD-UHFFFAOYSA-N para-bromobenzyl alcohol Chemical compound OCC1=CC=C(Br)C=C1 VEDDBHYQWFOITD-UHFFFAOYSA-N 0.000 description 1
- 208000000689 peptic esophagitis Diseases 0.000 description 1
- UHZYTMXLRWXGPK-UHFFFAOYSA-N phosphorus pentachloride Chemical compound ClP(Cl)(Cl)(Cl)Cl UHZYTMXLRWXGPK-UHFFFAOYSA-N 0.000 description 1
- 229920002451 polyvinyl alcohol Polymers 0.000 description 1
- 230000002980 postoperative effect Effects 0.000 description 1
- YORCIIVHUBAYBQ-UHFFFAOYSA-N propargyl bromide Chemical compound BrCC#C YORCIIVHUBAYBQ-UHFFFAOYSA-N 0.000 description 1
- 235000019260 propionic acid Nutrition 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 229940083082 pyrimidine derivative acting on arteriolar smooth muscle Drugs 0.000 description 1
- 150000003230 pyrimidines Chemical class 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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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
Abstract
本发明提供新的吡咯并[3,2-b]吡啶衍生物或者其药学可接受的盐、其制备方法和含有其的组合物。本发明的吡咯并[3,2-b]吡啶衍生物或者其药学可接受的盐具有极好的质子泵抑制作用并具有达到可逆的质子泵抑制作用的能力。
Description
技术领域
本发明涉及具有极好的抗胃酸分泌的抑制活性的新的吡咯并[3,2-b]吡啶衍生物或者其药学可接受的盐、其制备方法和含有其的药物组合物。
背景技术
当涉及胃酸分泌的攻击因子强或者胃粘膜的防御因子弱时发生消化性溃疡疾病。各种药物例如抗酸药、抗胆碱能药、H2-受体拮抗剂和质子泵抑制剂已经用于治疗消化性溃疡疾病。质子泵抑制剂奥美拉唑的出现重新引起了该领域的研究活动。
然而,已经指出,奥美拉唑的质子泵抑制作用是不可逆的,因此导致胃酸分泌的长期抑制,这会产生副作用。因此,正在进行各种尝试以开发可逆性的质子泵抑制剂。例如,WO 98/37,080(AstraZenecaAB)、WO 00/17,200(Byk Gulden Lomberg Chem.)和美国专利No.4,450,164(Schering Corporation)中公开了将咪唑并吡啶衍生物作为可逆性质子泵抑制剂。而且,欧洲专利No.775,120(Yuhan Corp.)还公开了嘧啶衍生物。
发明内容
技术问题
本发明提供具有极好的质子泵抑制作用并具有实现可逆性质子泵抑制作用的能力的新的吡咯并[3,2-b]吡啶衍生物或者其药学可接受的盐。
技术方案
根据本发明的一个方面,提供吡咯并[3,2-b]吡啶衍生物或者其药学可接受的盐。
而且,根据本发明的另一个方面,提供吡咯并[3,2-b]吡啶衍生物或者其药学可接受的盐的制备方法。
而且,根据本发明的另一个方面,提供包含作为活性成分的吡咯并[3,2-b]吡啶衍生物或者其药学可接受的盐和药学可接受的载体的药物组合物。
具体实施方式
根据本发明的一个方面,提供通式(I)的化合物或者其药学可接受的盐:
其中:
R1是氢;任选用一个或者多个选自C1-C5烷氧基、羟基、C3-C7环烷基、乙酰氧基、C2-C6烯氧基、C1-C3烷氧羰基、任选用C1-C3烷基单或双取代的氨基、氰基、萘基、吡啶基、环氧乙烷基、噁唑烷酮基、任选用C1-C3烷基单或双取代的异噁唑基、1,3-二氧戊环基和2,3-二氢苯并[1,4]二噁烯基的取代基取代的直链或者支链C1-C6烷基;直链或者支链C2-C6烯基;直链或者支链C2-C6炔基;或者任选用一个或者多个选自卤素、C1-C3烷基、C1-C3烷氧基、氰基、C1-C3烷氧羰基和三氟-C1-C3烷基的取代基取代的苄基,
R2是直链或者支链C1-C6烷基,
R3是任选用羟基取代的直链或者支链C1-C6烷基,
R4是氢;直链或者支链C1-C6烷基;卤素;氰基;羟基羰基;氨基羰基;或者C3-C7环烷基-氨基羰基,
R5是任选用卤素或者C1-C5烷基单或多取代的1,2,3,4-四氢异喹啉基;任选用一个或者多个选自卤素、C1-C5烷基、C1-C5烷氧基和三氟-C1-C3烷基的取代基取代的苄氧基;任选用一个或者两个选自C1-C5烷氧-羰基和任选用卤素取代的苄基的取代基取代的氨基;任选用卤素单或多取代的苯基;任选用卤素单或多取代的苯氧基;吡啶基-C1-C3烷氧基;或者胡椒基氧基,和
n是1或者2。
本发明的通式(I)的化合物或者其药学可接受的盐中,优选那些其中:
R1是氢;直链或者支链C1-C6烷基;用一个或者多个选自甲氧基、羟基、环丙基、环丁基、乙酰氧基、乙烯氧基、甲氧基羰基、二甲基氨基、氰基、萘基、吡啶基、环氧乙烷基、噁唑烷酮基、二甲基异噁唑基、1,3-二氧戊环基和2,3-二氢苯并[1,4]二噁烯基的取代基取代的C1-C3烷基;直链或者支链C2-C6烯基;直链或者支链C2-C6炔基;或者任选用一个或者多个选自卤素、C1-C3烷基、C1-C3烷氧基、氰基、甲氧基羰基和三氟甲基的取代基取代的苄基,
R2是甲基,
R3是甲基或者羟甲基,
R4是氢;甲基;卤素;氰基;羟基羰基;氨基羰基;或者环丙基氨基羰基,
R5是1,2,3,4-四氢异喹啉基;6-氟-1-甲基-1,2,3,4-四氢异喹啉基;用一个或者多个选自卤素、C1-C5烷基、C1-C5烷氧基和三氟甲基的取代基取代的苄氧基;用叔-丁氧基羰基或者氟苄基单或双取代的氨基;氟苯基;氟苯氧基;吡啶基-甲氧基;或者胡椒基氧基,和
n是1或者2。
本发明的化合物可以是药学可接受的无毒盐形式。所述无毒盐可以包括在抗溃疡药领域中使用的常规酸加成盐,例如源于诸如盐酸、氢溴酸、硫酸、氨基磺酸、磷酸或者硝酸的无机酸和诸如乙酸、丙酸、琥珀酸、羟基乙酸、硬脂酸、柠檬酸、马来酸、丙二酸、甲磺酸、酒石酸、苹果酸、苯乙酸、谷氨酸、苯甲酸、水杨酸、2-乙酰氧基苯甲酸、富马酸、樟脑磺酸、苯磺酸、对甲苯磺酸、草酸或者三氟乙酸的有机酸的盐。可以根据任何常规的方法制备这些酸加成盐。
本发明在其范围内包括根据下面的方案1制备通式(I)的化合物或者其药学可接受的盐的方法:
方案1.
其中,R1、R2、R3、R4、R5和n与上述定义的相同且X是卤素。
具体而言,可以使用以下方法制备通式(I)的化合物或者其药学可接受的盐,所述方法包括:使通式(II)的化合物和R5-H反应得到通式(III)的化合物,使通式(III)的化合物和通式(IV)的化合物反应得到通式(Ia)的化合物,和使通式(Ia)的化合物和R1-X反应得到通式(I)的化合物。
在方案1的方法中,通式(II)和(IV)的化合物是可以从市场上购买的。通式(II)的化合物和R5-H的反应可以在碱例如氢化钠、叔丁醇钾、碳酸钠或者氢氧化钾的存在下进行。而且,该反应可以在有机溶剂例如无水四氢呋喃和N,N-二甲基甲酰胺中并且在室温或者加热例如在温度40℃~140℃下进行。
通式(III)的化合物和通式(IV)的化合物的环化反应可以在有机酸例如无水四氢呋喃中进行。而且,该反应可以在温度-78℃~-20℃或者室温下进行。
通式(Ia)的化合物和R1-X反应得到通式(I)的化合物。通式(Ia)的化合物和R1-X的反应可以在碱例如氢化钠或者叔丁醇钾的存在下进行。而且,该反应可以在有机溶剂例如四氢呋喃或者N,N-二甲基甲酰胺中并且在室温或者在温度40℃~100℃下进行。为了增加反应速率和/或者反应产率,可以使用催化量的18-冠-6。
根据本发明的另一个方面,可以根据下述方案2制备通式(Ic)的化合物或者其药学可接受的盐:
方案2.
其中,R1、R2、R4和R5与上述定义的相同。
具体而言,可以使用以下方法制备通式(Ic)的化合物或者其药学可接受的盐,所述方法包括:在硝酸铈(IV)铵和乙酸存在下,用水解剂例如氢氧化锂水解通式(Ib)的化合物。
根据本发明的另一个方面,可以使用以下方法制备通式(Ig)的化合物或者其药学可接受的盐,所述方法包括:使通式(Id)的化合物和氰化铜(CuCN)反应得到通式(Ie)的化合物;水解通式(Ie)的化合物得到通式(If)的化合物;和使通式(If)的化合物和通式(V)的化合物反应得到通式(Ig)的化合物,如下述方案3:
方案3.
其中,R1、R2、R3、R5和X与上述定义的相同,R6和R7互相独立地是氢或者C3-C7环烷基。
在方案3的方法中,可以通过在有机溶剂例如N,N-二甲基甲酰胺中回流通式(Id)的化合物和氰化铜(CuCN)得到通式(Ie)的化合物。
在酸性或者碱性条件下水解通式(Ie)的化合物,产生通式(If)的化合物。可以在50℃~100℃下用氢氧化钾溶液进行水解反应。
可以在偶联剂例如N-(3-二甲氨基丙基)-N’-乙基碳二亚胺(EDC)或者1-羟基-7-氮杂苯并***(HOBT)存在下进行通式(If)的化合物和通式(V)的化合物的反应。偶联反应可以在有机溶剂例如二氯甲烷或者N,N-二甲基甲酰胺中进行。
在其范围内,本发明还包括药物组合物,所述药物组合物包含治疗有效量的任意如上所述的通式(I)的化合物或者其药学可接受的盐和药学可接受的载体。通式(I)的化合物或者其药学可接受的盐可以用于预防和治疗哺乳动物包括人的胃肠道炎症疾病和与胃酸相关的疾病例如胃炎、胃溃疡、十二指肠溃疡、反流性食管炎和佐林格-埃利森综合征。而且,本发明的化合物或者其盐可以用于治疗其它需要胃抗分泌作用的胃肠道紊乱例如胃泌素瘤患者、急性上胃肠出血患者体内的。本发明的化合物或者其盐还可以用于重病特别护理状态的患者以及术前和术后用于预防酸吸入和应激性溃疡。
本发明的组合物可以包括添加剂例如乳糖或者玉米淀粉、润滑剂例如硬脂酸镁、乳化剂、助悬剂、稳定剂和等渗剂。如果需要,可以加入甜味剂和/或调味剂。
本发明的组合物可以口服或者胃肠外施用,包括静脉内、腹膜内、皮下、直肠和局部施用途径。因此,本发明的组合物可以配制成各种各样的形式例如片剂、胶囊、水溶液或者混悬剂。在片剂用于口服的情况下,通常添加载体例如乳糖、玉米淀粉和润滑剂例如硬脂酸镁。在胶囊用于口服的情况下,乳糖和/或者干燥的玉米淀粉可以用作稀释剂。当需要水混悬剂用于口服时,活性成分可以和乳化剂和/或者助悬剂组合。如果需要,可以添加某些甜味剂和/或调味剂。肌肉内、腹膜内、皮下和静脉内使用时,通常制备成活性成分的灭菌溶液,并且应该适当调节和缓冲该溶液的pH。静脉内使用时,为了使制剂等渗,应该控制溶质的总浓度。本发明的组合物可以是包含药学可接受的载体的水溶液的形式,例如盐水,pH水平为7.4。可以通过局部团注将该溶液引入到患者的肌肉内血流中。
可以以有效量范围从每日约0.1mg/kg到约500mg/kg向对象患者施用本发明的化合物。当然,可以根据患者的年龄、体重、感受性或者症状改变该剂量。
下述实施例仅仅是为了详细说明目的而提供的,并且不希望限制本发明的范围。
制备1.2-(3-硝基吡啶-4-基)-1,2,3,4-四氢异喹啉
步骤1:4-氯-3-硝基吡啶
将4-羟基-3-硝基吡啶(10.0g、71.38mmol)加入到100ml磷酰氯中,然后在搅拌下回流1h。减压浓缩反应混合物。将所得剩余物加入到500ml冰水中,然后用2N氢氧化钠溶液中和。用二氯甲烷(300ml)萃取该反应混合物。用无水硫酸镁干燥分离的有机层并减压浓缩得到浅黄色固体的标题化合物(9.2g、92.0%)。
TLC:正己烷/乙酸乙酯=2/1(v/v):Rf=0.5
1H-NMR(CDCl3)δ9.12(s,1H),8.69(d,1H),7.55(d,1H)
步骤2:2-(3-硝基吡啶-4-基)-1,2,3,4-四氢异喹啉
在0℃下,将氢化钠(60%、386.4mg、9.66mmol)加入到1,2,3,4-四氢异喹啉(1.06ml、8.05mmol)在N,N-二甲基甲酰胺(30ml)中的溶液中,并且在相同的温度下搅拌10min。将步骤1制备的4-氯-3-硝基吡啶(1.124g、7.09mmol)加入到该反应混合物中,室温下搅拌2h,用水(10ml)和乙酸乙酯(100ml)的混合物稀释,然后用水(100ml)洗涤2次。用无水硫酸镁干燥分离的有机层并减压浓缩得到黄色固体的标题化合物(1.13g、89.3%)。
TLC:正己烷/乙酸乙酯=2/1(v/v):Rf=0.3
1H-NMR(CDCl3)δ8.86(s,1H),8.36(d,2H),7.22(m,3H),7.12(m,1H),6.96(d,1H),4.35(s,2H),3.53(t,2H),3.03(t,2H)
制备2.4-(4-氟苄氧基)-3-硝基吡啶
将制备1的步骤1中制备的4-氯-3-硝基吡啶(2.0g、12.62mmol)加入到4-氟苄基醇(2.04ml、18.92mmol)、碳酸钾(1.74g、12.62mmol)和氢氧化钾(2.38g、50.48mmol)在无水甲苯(100ml)中的混悬液中。将催化量的三[2-(2-甲氧基乙氧基)乙基]胺加入到反应混合物中,然后室温下搅拌1h。过滤该反应混合物,然后减压浓缩。用硅胶柱色谱纯化所得的剩余物(乙酸乙酯/正己烷=1/1、(v/v))得到白色固体的标题化合物(2.5g、86.3%)。
TLC:正己烷/乙酸乙酯(2/1):Rf=0.4
1H-NMR(CDCl3)δ8.57(s,1H),7.28(m,3H),7.16(m,2H),6.70(d,1H),5.05(s,2H)
制备3.(2,3-二甲基-1H-吡咯并[3,2-b]吡啶-7-基)-(4-氟苄基)氨基甲酸叔丁酯
步骤1:(4-氟苄基)-(3-硝基吡啶-4-基)-胺
将碳酸钠(3.20g、30.27mmol)和4-氟苄基胺(2.14ml、18.92mmol)加入到制备1的步骤1制备的4-氯-3-硝基吡啶(3.0g、18.92mmol)在30ml无水N,N-二甲基甲酰胺中的溶液中,然后将该反应混合物在80℃下搅拌1h。用水(10ml)和乙酸乙酯(100ml)的混合物稀释该反应混合物,然后用水(100ml)洗涤2次。用无水硫酸镁干燥分离的有机层,然后减压浓缩,得到黄色固体的标题化合物(3.01g、83.5%)。
1H-NMR(CDCl3)δ8.60(s,1H),7.29(m,3H),7.18(m,2H),6.70(d,1H),5.20(s,2H)
步骤2.(4-氟苄基)-(3-硝基吡啶-4-基)-氨基甲酸叔丁酯
将二-叔丁基-碳酸氢盐(8.13g、37.25mmol)和N,N-二甲基氨基吡啶(2.27g、18.63mmol)加入到步骤1制备的(4-氟苄基)-(3-硝基吡啶-4-基)-胺(3.07g,12.42mmol)在100ml四氢呋喃中的溶液中,然后将该反应混合物搅拌24h。减压浓缩该反应混合物。用硅胶柱色谱纯化所得的剩余物(乙酸乙酯/正己烷=1/1,(v/v))得到黄色油的标题化合物(2.9g、75.6%)。
1H-NMR(CDCl3)δ8.60(s,1H),7.29(m,3H),7.18(m,2H),6.70(d,1H),5.10(s,2H),1.3(s,9H)
步骤3.(2,3-二甲基-1H-吡咯并[3,2-b]吡啶-7-基)-(4-氟苄基)-氨基甲酸叔丁酯
在氮气氛下,将步骤2制备的(4-氟苄基)-(3-硝基吡啶-4-基)-氨基甲酸叔丁酯(10.2g)溶解在无水四氢呋喃(200ml)中。-78℃下,将1-甲基-1-丙烯基溴化镁(0.5M在四氢呋喃溶液中,110ml,130.5mmol)加入到该溶液中,并在-20℃下搅拌5h。将20ml 20%的氯化铵溶液加入到该反应混合物中,然后用乙酸乙酯(200ml)萃取2次。用无水硫酸镁干燥分离的有机层并减压浓缩。用硅胶柱色谱纯化所得的剩余物(乙酸乙酯/甲醇=10/1、(v/v))得到浅黄色固体的标题化合物(3.8g,28.9%)。
1H-NMR(CDCl3)δ8.31(d,1H),8.12(s,1H),7.40(m,1H),7.18(d,2H),7.09(d,2H),3.16(s,3H),2.53(s,3H),2.48(s,3H),1.41(s,9H)
实施例1.1-(4-氯苄基)-7-(1,2,3,4-四氢异喹啉-2-基)-(2,3-二甲基-1H-吡咯并[3,2-b]吡啶盐酸盐
步骤1.2-(2,3-二甲基-1H-吡咯并[3,2-b]吡啶-7-基)-1,2,3,4-四氢异喹啉
在氮气氛下,将制备1制备的2-(3-硝基吡啶-4-基)-1,2,3,4-四氢异喹啉(5g、19.58mmol)溶解在无水四氢呋喃(200ml)中。-78℃下,将1-甲基-1-丙烯基溴化镁(0.5M在四氢呋喃溶液中,80ml、117.5mmol)加入到该溶液中,然后在-20℃下搅拌5h。将20ml 20%的氯化铵溶液加入到该反应混合物中,然后用乙酸乙酯(200ml)萃取2次。用无水硫酸镁干燥分离的有机层并减压浓缩。用硅胶柱色谱纯化所得的剩余物(乙酸乙酯/二氯甲烷/甲醇=10/10/1、(v/v/v))得到浅黄色固体的标题化合物(2.1g、25.3%)。
1H-NMR(CDCl3)δ8.26(d,1H),7.77(s,1H),7.19(m,4H),6.59(d,1H),4.46(s,2H),3.64(t,2H),3.04(t,2H),2.41(s,3H),2.30(s,3H)
步骤2.1-(4-氯苄基)-7-(1,2,3,4-四氢异喹啉-2-基)-2,3-二甲基-1H-吡咯并[3,2-b]吡啶盐酸盐
将步骤1制备的2-(2,3-二甲基-1H-吡咯并[3,2-b]吡啶-7-基)-1,2,3,4-四氢异喹啉(30mg、0.108mmol)、叔丁醇钾(13.6mg、0.162mmol)和催化量的18-冠-6加入到无水四氢呋喃(2ml)中。将4-氯苄基氯(0.09ml、0.162mmol)加入到反应混合物中,然后室温下搅拌12h。减压浓缩该反应混合物。所得的剩余物用硅胶柱色谱纯化(乙酸乙酯/二氯甲烷/甲醇=10/10/1、(v/v/v)),溶于乙酸乙酯(1ml)中,然后用氯化氢气体饱和。过滤所得的沉淀,得到白色固体的标题化合物(6.9mg、15.8%)。
1H-NMR(CDCl3)δ8.34(d,1H),7.17(m,5H),6.98(m,1H),6.89(m,1H),6.54(d,2H),5.51(s,2H),4.39(s,2H),3.57(s,2H),2.93(d,2H),2.59(s,3H),2.25(s,3H)
实施例2~29
根据实施例1中步骤2的相同步骤,使用实施例1中步骤1制备的2-(2,3-二甲基-1H-吡咯并[3,2-b]吡啶-7-基)-1,2,3,4-四氢异喹啉,和2-(溴甲基)萘、2-溴甲基-1,3-二氧戊环、(溴甲基)环丙烷、2-溴乙基甲醚、苄基溴、烯丙基溴、3-甲氧基苄基氯、2-氟苄基氯、4-甲氧基苄基氯、1-碘代丙烷、3-甲基苄基氯、碘代乙烷、2-(2-溴乙基)-1,3-二氧戊环、2-溴甲基-1,4-苯并二噁烷、4-溴-2-甲基-2-丁烯、4-溴甲基-3,5-二甲基异噁唑、2-氯苄基氯、乙酸1-溴乙酯、溴甲基甲醚、4-叔丁基苄基氯、(溴甲基)环丁烷、3-氰基苄基溴、乙酸溴甲酯、2,4-二甲基苄基溴、4-甲氧基羰基苄基溴、2-(溴乙基)乙烯基醚、1-溴-2-甲基-丙烷或者环氧溴丙烷,制备实施例2~29的标题化合物。
实施例2
1-(2-萘基甲基)-7-(1,2,3,4-四氢异喹啉-2-基)-2,3-二甲基-1H-吡咯并[3,2-b]吡啶盐酸盐
1H-NMR(CDCl3)δ8.36(d,1H),7.82(m,1H),7.73(m,1H),7.65(m,1H),7.50(m,2H),7.15(m,5H),6.78(m,2H),5.67(s,2H),4.43(s,2H),3.59(m,2H),2.88(m,2H),2.64(s,3H),2.35(s,3H);
(收率:78.9%)
实施例3
1-(1,3-二氧戊环-2-基甲基)-7-(1,2,3,4-四氢异喹啉-2-基)-2,3-二甲基-1H-吡咯并[3,2-b]吡啶盐酸盐
1H-NMR(CDCl3)δ8.30(d,1H),7.21(m,3H),7.14(m,2H),4.83(t,1H),4.74(m,4H),3.85(m,3H),3.35(m,2H),3.05(m,3H),2.59(s,3H),2.50(s,3H);
(收率:86.3%)
实施例4
1-环丙基甲基-7-(1,2,3,4-四氢异喹啉-2-基)-2,3-二甲基-1H-吡咯并[3,2-b]吡啶盐酸盐
1H-NMR(CDCl3)δ8.31(d,1H),7.22(m,3H),7.11(m,2H),4.54(d,2H),4.14(s,2H),3.70(m,2H),3.08(m,2H),2.54(s,2H),2.41(s,3H),2.35(s,3H),0.83(m,1H),0.32(m,2H),0.08(m,2H);
(收率:69.8%)
实施例5
1-(2-甲氧基乙基)-7-(1,2,3,4-四氢异喹啉-2-基)-2,3-二甲基-1H-吡咯并[3,2-b]吡啶盐酸盐
1H-NMR(CDCl3)δ8.34(d,1H),7.22(m,3H),7.11(m,2H),4.44(m,4H),3.66(m,2H),3.38(m,2H),3.07(s,3H),2.50(s,3H),2.42(s,3H);(收率:78.6%)
实施例6.1-苄基-7-(1,2,3,4-四氢异喹啉-2-基)-2,3-二甲基-1H-吡咯并[3,2-b]吡啶盐酸盐
1H-NMR(CDCl3)δ8.34(m,1H),7.18(m,4H),7.02(m,5H),6.93(m,1H),5.56(s,2H),4.37(s,2H),3.56(m,2H),2.98(m,2H),2.59(s,3H),2.25(s,3H);
(收率:68.7%)
实施例7.1-烯丙基-7-(1,2,3,4-四氢异喹啉-2-基)-2,3-二甲基-1H-吡咯并[3,2-b]吡啶盐酸盐
1H-NMR(CDCl3)δ8.26(s,1H),7.20(m,3H),6.88(m,1H),6.67(m,1H),5.88d,2H),5.66(m,1H),4.49(s,2H),4.33(d,1H),4.25(d,1H),3.63(s,2H),3.05(s,2H),2.55(s,3H),2.42(s,3H);
(收率:73.5%)
实施例8.
1-(3-甲氧基苄基)-7-(1,2,3,4-四氢异喹啉-2-基)-2,3-二甲基-1H-吡咯并[3,2-b]吡啶盐酸盐
1H-NMR(CDCl3)δ8.31(m,1H),7.03(m,4H),6.86(m,3H),6.20(m,2H),5.58(s,2H),4.52(s,2H),3.68(s,3H),3.45(m,2H),2.95(m,2H),2.55(s,3H),2.34(s,3H);
(收率:77.0%)
实施例9.
1-(2-氟苄基)-7-(1,2,3,4-四氢异喹啉-2-基)-2,3-二甲基-1H-吡咯并[3,2-b]吡啶盐酸盐
1H-NMR(CDCl3)δ836(d,1H),7.00(m,4H),6.91(m,4H),6.86(m,1H),6.39(s,1H),5.63(s,2H),4.47(m,2H),3.63(m,2H),2.96(m,2H),2.53(s,3H),2.47(s,3H);
(收率:74.5%)
实施例10.
1-(4-甲氧基苄基)-7-(1,2,3,4-四氢异喹啉-2-基)-2,3-二甲基-1H-吡咯并[3,2-b]吡啶盐酸盐
1H-NMR(CDCl3)δ8.27(d,1H),7.32(m,3H),7.00(m,3H),6.77(m,3H),5.51(s,2H),4.55(m,2H),3.77(s,3H),2.97(m,4H),2.45(s,3H),2.33(s,3H);
(收率:86.9%)
实施例11.
1-丙基-7-(1,2,3,4-四氢异喹啉-2-基)-2,3-二甲基-1H-吡咯并[3,2-b]吡啶盐酸盐
1H-NMR(CDCl3)δ8.35(d,1H),7.12(m,5H),4.56(s,2H),4,33(t,2H),3,32(m,2H),2.80(m,2H),2.34(s,3H),2,28(s,3H),1.98(m,2H),1.53(d,3H);
(收率:78.0%)
实施例12.
1-(3-甲基苄基)-7-(1,2,3,4-四氢异喹啉-2-基)-2,3-二甲基-1H-吡咯并[3,2-b]吡啶盐酸盐
1H-NMR(CDCl3)δ8.42(d,1H),6.92(m,4H),6.87(m,1H),6.48(m,4H),5.66(s,2H),4.59(m,2H),3.72(m,2H),3.08(m,2H),2.64(s,3H),2.48(s,3H),2.10(s,3H);
(收率:75.6%)
实施例13.
1-乙基-7-(1,2,3,4-四氢异喹啉-2-基)-2,3-二甲基-1H-吡咯并[3,2-b]吡啶盐酸盐
1H-NMR(CDCl3)δ8.29(d,1H),7.23(m,4H),7.00(d,1H),4.56(d,2H),4.32(m,2H),3.67(m,2H),3.08(m,2H),2.59(s,3H),2.48(s,3H),1.06(t,3H);
(收率:77.0%)
实施例14.
1-[2-(1,3-二氧戊环-2-基)乙基]-7-(1,2,3,4-四氢异喹啉-2-基)-2,3-二甲基-1H-吡咯并[3,2-b]吡啶盐酸盐
1H-NMR(CDCl3)δ8.34(s,1H),7.17(m,4H),7.10(s,1H),4.83(m,2H),4.39(s,2H),4.01(m,1H),3.57(s,2H),3.12(m,4H),2.93(m,2H),2.56(s,3H),2.47(s,3H),1.89(m,2H);
(收率:58.4%)
实施例15.
1-(2,3-二氢苯并[1,4]-二噁烯-6-基甲基)-7-(1,2,3,4-四氢异喹啉-2-基)-2,3-二甲基-1H-吡咯并[3,2-b]吡啶盐酸盐
1H-NMR(CDCl3)δ8.34(s,1H),7.16(m,4H),7.10(m,4H),5.41(s,2H),4.21(s,2H),4.01(m,4H),3.69(s,2H),2.93(m,2H),2.57(s,3H),2.48(s,3H);
(收率:58.6%)
实施例16.
1-(3-甲基丁烯-2-基)-7-(1,2,3,4-四氢异喹啉-2-基)-2,3-二甲基-1H-吡咯并[3,2-b]吡啶盐酸盐
1H-NMR(CDCl3)δ8.35(s,1H),7.51(m,4H),7.10(s,1H),4.86(d,2H),4.39(s,2H),4.10(m,1H),3.57(m,2H),2.95(m,2H),2.56(s,3H),2.35(s,3H),1.89(s,6H);
(收率:78.5%)
实施例17.
1-(3,5-二甲基异噁唑-4-基甲基)-7-(1,2,3,4-四氢异喹啉-2-基)-2,3-二甲基-1H-吡咯并[3,2-b]吡啶盐酸盐
1H-NMR(CDCl3)δ8.37(d,1H),7.19(m,3H),6.88(m,2H),5.40(s,2H),4.40(s,2H),3.49(m,2H),3.03(m,2H),2.58(s,3H),2.32(s,3H),1.91(s,3H),1.65(s,3H);
(收率:57.8%)
实施例18.
1-(2-氯苄基)-7-(1,2,3,4-四氢异喹啉-2-基)-2,3-二甲基-1H-吡咯并[3,2-b]吡啶盐酸盐
1H-NMR(CDCl3)δ8.35(d,1H),7.21(m,4H),6.98(m,6H),5.66(s,2H),4.82(s,2H),4.54(m,2H),3.51(m,2H),2.54(s,3H),2.33(s,3H);
(收率:75.4%)
实施例19.
1-甲氧基羰基乙基-7-(1,2,3,4-四氢异喹啉-2-基)-2,3-二甲基-1H-吡咯并[3,2-b]吡啶盐酸盐
1H-NMR(CDCl3)δ8.09(m,1H),7.21(m,5H),4.45(m,4H),4.11(m,4H),3.83(m,2H),3.07(s,3H),2.65(s,3H),2.55(s,3H);
(收率:83.0%)
实施例20.
1-甲氧基甲基-7-(1,2,3,4-四氢异喹啉-2-基)-2,3-二甲基-1H-吡咯并[3,2-b]吡啶盐酸盐
1H-NMR(CDCl3)δ8.30(m,1H),7.23(m,3H),6.98(m,2H),5.524(s,2H),4.55(s,2H),3.89(m,2H),3.48(m,2H),3.09(s,3H),2.53(s,3H),2.50(s,3H);
(收率:69.3%)
实施例21.
1-(4-叔丁基苄基)-7-(1,2,3,4-四氢异喹啉-2-基)-2,3-二甲基-1H-吡咯并[3,2-b]吡啶盐酸盐
1H-NMR(CDCl3)δ8.31(s,1H),7.20(m,4H),6.99(m,4H),5.65(s,2H),4.51(s,2H),3.77(m,2H),3.06(m,2H),2.59(s,3H),2.32(s,3H),1.27(s,9H);
(收率:72.0%)
实施例22.
1-环丁基甲基-7-(1,2,3,4-四氢异喹啉-2-基)-2,3-二甲基-1H-吡咯并[3,2-b]吡啶盐酸盐
1H-NMR(CDCl3)δ8.27(s,1H),7.17(m,3H),7.00(m,2H),4.45(s,2H),4.27(s,2H),3.70(m,2H),3.09(m,2H),2.57(s,3H),2.465(s,3H),2.84(m,1H),1.66(m,4H),1.43(m,2H);
(收率:83.5%)
实施例23.
1-(3-氰基苄基)-7-(1,2,3,4-四氢异喹啉-2-基)-2,3-二甲基-1H-吡咯并[3,2-b]吡啶盐酸盐
1H-NMR(CDCl3)δ7.79-7.50(m,5H),7.48(m,2H),7.21(m,3H),5.61(s,2H),4.40(m,2H),3.51(m,2H),2.96(m,2H),2.43(s,3H),2.36(s,3H);
(收率:58.4%)
实施例24.
1-甲氧基羰基甲基-7-(1,2,3,4-四氢异喹啉-2-基)-2,3-二甲基-1H-吡咯并[3,2-b]吡啶盐酸盐
1H-NMR(CDCl3)δ8.39(m,1H),7.11-7.09(m,5H),5.21(s,2H),4.46(s,2H),3.74(s,3H),3.47(m,2H),3.07(m,2H),2.58(s,3H),2.51(s,3H);
(收率:66.8%)
实施例25.
1-(2,4-二甲基苄基)-7-(1,2,3,4-四氢异喹啉-2-基)-2,3-二甲基-1H-吡咯并[3,2-b]吡啶盐酸盐
1H-NMR(CDCl3)δ8.38(m,1H),7.09(m,6H),6.40(m,1H),6.02(s,1H),5.46(m,2H),4.20(m,2H),3.53(m,2H),2.97(m,2H),2.65(s,3H),2.28(s,3H),1.77(s,6H);
(收率:78.5%)
实施例26.
1-(4-甲氧基羰基苄基)-7-(1,2,3,4-四氢异喹啉-2-基)-2,3-二甲基-1H-吡咯并[3,2-b]吡啶盐酸盐
1H-NMR(CDCl3)δ8.21(d,1H),7.98(d,1H),7,20(m,4H),6,98(m,4H),5,60(s,2H),4.68(s,2H),3.67(s,3H),3.05(m,2H),2.88(m,2H),2.34(s,3H),2.28(s,3H)
(收率:65.0%)
实施例27.
1-(2-乙烯氧基乙基)-7-(1,2,3,4-四氢异喹啉-2-基)-2,3-二甲基-1H-吡咯并[3,2-b]吡啶盐酸盐
1H-NMR(CDCl3)δ8.36(s,1H),7.50(m,4H),7.10(s,1H),4.80(d,2H),4.72(s,2H),4.23(m,1H),3.78(m,2H),3.60(m,2H),3.49(m,2H),2.93(m,2H),2.35(s,3H),2.28(s,3H);
(收率:48.7%)
实施例28.
1-异丁基-7-(1,2,3,4-四氢异喹啉-2-基)-2,3-二甲基-1H-吡咯并[3,2-b]吡啶盐酸盐
1H-NMR(CDCl3)δ8.35(s,1H),7.38(m,4H),7.14(s,1H),4.89(s,2H),4.75(d,2H),3.69(m,2H),2.98(m,2H),2.58(s,3H),2.55(s,3H),1.99(m,1H),1.57(d,6H);
(收率:75.1%)
实施例29.
1-环氧乙烷基甲基-7-(1,2,3,4-四氢异喹啉-2-基)-2,3-二甲基-1H-吡咯并[3,2-b]吡啶盐酸盐
1H-NMR(CDCl3)δ8.36(s,1H),7.48(m,4H),7.12(s,1H),5.11(s,2H),4.89(s,2H),3.68(m,2H),3.60(m,2H),3.55(m,1H),2.89(m,2H),2.58(s,3H),2.55(s,3H);
(收率:57.4%)
实施例30.
1-苄基-7-(1,2,3,4-四氢异喹啉-2-基)-3-羟甲基-2-甲基-1H-吡咯并[3,2-b]吡啶盐酸盐
用饱和碳酸氢钠溶液处理实施例6中制备的化合物(501.1mg、1.23mmol)得到1-苄基-7-(1,2,3,4-四氢异喹啉-2-基)-2,3-二甲基-1H-吡咯并[3,2-b]吡啶(433.6mg、1.18mmol)。室温下将硝酸铈(IV)铵(1.94g,3.54mmol)加入到1-苄基-7-(1,2,3,4-四氢异喹啉-2-基)-2,3-二甲基-1H-吡咯并[3,2-b]吡啶(433.6mg、1.18mmol)在乙酸(10ml)中的溶液中。55℃下搅拌反应混合物4h,冷却至室温,倒入水中,然后用乙酸乙酯萃取。用饱和氯化钠溶液洗涤所得的有机层,用无水硫酸镁干燥然后减压浓缩。将所得的剩余物溶解在甲醇(20ml)中。将2N氢氧化锂(5.0ml)加入到该溶液中,然后室温下搅拌1h。用1N的盐酸中和该反应混合物,减压浓缩除去甲醇,然后用乙酸乙酯萃取。所得的有机层用无水硫酸镁干燥然后减压浓缩。用硅胶柱色谱纯化所得的剩余物得到1-苄基-7-(1,2,3,4-四氢异喹啉-2-基)-3-羟甲基-2-甲基-1H-吡咯并[3,2-b]吡啶,然后溶解在乙酸乙酯中。用氯化氢气体饱和该溶液然后过滤得到白色固体的标题化合物(69mg,13.9%)。
1H-NMR(CDCl3)δ8.75(d,1H),7.95(d,1H),7.13(m,4H),6.74(m,5H),5.79(s,2H),4.14(m,2H),3.26(m,2H),4.10(s,2H),2.80(m,2H),2.34(s,3H)
实施例31.
2-(2,3-二甲基-1H-吡咯并[3,2-b]吡啶-7-基)-6-氟-1-甲基-1,2,3,4-四氢异喹啉
步骤1:6-氟-1-甲基-2-(3-硝基吡啶-4-基)-1,2,3,4-四氢异喹啉
除了使用根据WO 94/14795中公开的方法制备的6-氟-1-甲基-1,2,3,4-四氢异喹啉以外,根据制备1中步骤2的相同步骤,得到浅黄色固体的标题化合物(收率:85.3%)。该产物不需要进一步纯化而用于后续的步骤。
步骤2:2-(2,3-二甲基-1H-吡咯并[3,2-b]吡啶-7-基)-6-氟-1-甲基-1,2,3,4-四氢异喹啉
除了使用步骤1中制备的6-氟-1-甲基-2-(3-硝基吡啶-4-基)-1,2,3,4-四氢异喹啉以外,根据实施例1中步骤1的相同步骤,得到白色固体的标题化合物(收率:15.7%)。
1H-NMR(CDCl3)δ10.23(s,1H),8.51(d,1H),7.87(d,1H),7.21(m,2H),7.06(s,1H),4.36(s,2H),3.37(t,1H),3.14(t,2H),2.37(d,3H),2.53(s,3H),2.23(s,3H)
实施例32:2-(1-苄基-2,3-二甲基-1H-吡咯并[3,2-b]吡啶-7-基)-6-氟-1-甲基-1,2,3,4-四氢异喹啉盐酸盐
除了使用实施例31中步骤2中制备的2-(2,3-二甲基-1H-吡咯并[3,2-b]吡啶-7-基)-6-氟-1-甲基-1,2,3,4-四氢异喹啉和苄基溴以外,根据实施例1中步骤2的相同步骤,得到白色固体的标题化合物(收率:65.8%)。
1H-NMR(CDCl3)δ8.50(d,1H),7.84(d,1H),7.53(m,5H),7.20(m,2H),7.04(s,1H),4.36(s,2H),3.35(t,1H),3.12(t,2H),2.34(d,3H),2.40(s,3H),2.35(s,3H)
实施例33:1-(4-氯苄基-7-(4-氟苄氧基)-2,3-二甲基-1H-吡咯并[3,2-b]吡啶盐酸盐
步骤1:7-(4-氟苄氧基)-2,3-二甲基-1H-吡咯并[3,2-b]吡啶
在氮气氛下,将制备2制备的4-(4-氟苄氧基)-3-硝基吡啶(4.8g、19.34mmol)溶解在无水四氢呋喃(200ml)中。-78℃下,将1-甲基-1-丙烯基溴化镁(0.5M在四氢呋喃溶液中,116ml、58.02mmol)加入到该溶液中,然后在-20℃下搅拌5h。将20%的氯化铵溶液(20ml)加入到该反应混合物中,然后用乙酸乙酯(200ml)萃取2次。用无水硫酸镁干燥分离的有机层并减压浓缩。用硅胶柱色谱(乙酸乙酯/二氯甲烷/甲醇=10/10/1、(v/v/v))纯化所得的剩余物得到浅黄色固体的标题化合物(2.45g,28.3%)。
1H-NMR(CDCl3)δ8.29(d,1H),7.97(s,1H),7.43(m,2H),7.10(m,2H),6.60(d,1H),5.18(s,2H),2.39(s,3H),2.30(s,3H)
步骤2.1-(4-氯苄基)-7-(4-氟苄氧基)-2,3-二甲基-1H-吡咯并[3,2-b]吡啶盐酸盐
将步骤1制备的7-(4-氟苄氧基)-2,3-二甲基-1H-吡咯并[3,2-b]吡啶(25mg、0.105mmol)、叔丁醇钾(13.6mg、0.163mmol)和催化量的18-冠-6加入到无水四氢呋喃(2ml)中。将4-氯苄基氯(0.089ml、0.160mmol)加入到反应混合物中,然后室温下搅拌12h。减压浓缩该反应混合物。所得的剩余物用硅胶柱色谱纯化(乙酸乙酯/二氯甲烷/甲醇=10/10/1、(v/v/v)),溶解于乙酸乙酯(1ml)中,然后用氯化氢气体饱和。过滤所得的沉淀得到白色固体的标题化合物(6.9mg、15.8%)。
1H-NMR(CDCl3)δ8.38(s,1H),7.24(d,2H),7.03(m,4H),6.87(s,1H),6.52(d,2H),5.50(s,2H),5.22(s,2H),2.60(s,3H),2.37(s,3H)
实施例34~62
根据实施例33中步骤2的相同步骤,使用实施例33的步骤1中制备的7-(4-氟苄氧基)-2,3-二甲基-1H-吡咯并[3,2-b]吡啶,和4-甲基苄基氯、4-溴甲基甲基苯甲酸酯、4-叔丁基苄基氯、2-(溴甲基)-萘、2-(溴乙基)乙烯基醚、2-溴甲基-1,3-二氧戊环、3-氟苄基氯、2,5-二甲基苄基氯、4-溴甲基-3,5-二甲基异噁唑、3-氯苄基氯、2-氯甲基吡啶、6-氯甲基-2,3-二氢苯并[1,4]-二噁烯、3-氰基苄基氯、环氧溴丙烷、3-氯甲基吡啶、烯丙基溴、1-碘-2-甲基丙烷、炔丙基溴、3-甲氧基苄基溴、3-甲基苄基溴、苄基溴、(溴甲基)环丁烷、4-溴-2-甲基-2-丁烯、甲基-3-溴丙酸酯、4-甲氧基苄基氯、2-氟苄基氯、(溴甲基)环丙烷、2-溴乙基甲醚或者1-碘代丙烷,制备实施例34~62中的标题化合物。
实施例34.7-(4-氟苄氧基)-2,3-二甲基-1-(4-甲基苄基)-1H-吡咯并[3,2-b]吡啶盐酸盐
1H-NMR(CDCl3)δ8.32(d,1H),7.01(m,6H),6.59(m,3H),5.68(s,2H),5.35(s,2H),2.64(s,3H),2.33(s,3H),1.90(s,3H);
(收率:68.7%)
实施例35.4-[7-(4-氟苄氧基)-2,3-二甲基-吡咯并[3,2-b]吡啶-1-基甲基]-苯甲酸甲酯盐酸盐
1H-NMR(CDCl3)δ8.38(s,1H),8.06(d,1H),7.94(m,2H),7.60(d,1H),7.08(m,4H),6.71(m,2H),5.59(s,2H),5.23(s,2H),3.93(s,3H),2.62(s,3H),2.38(s,3H);
(收率:63.4%)
实施例36.1-(4-叔丁基苄基)-7-(4-氟苄氧基)-2,3-二甲基-1H-吡咯并[3,2-b]吡啶盐酸盐
1H-NMR(CDCl3)δ8.35(s,1H),7.29(d,2H),6.99(m,4H),6.90(s,1H),6.61(s,2H),5.60(s,2H),5.22(s,2H),2.60(s,3H),2.38(s,3H),1.32(s,9H);
(收率:58.4%)
实施例37.7-(4-氟苄氧基)-2,3-二甲基-1-(萘-2-基甲基)-1H-吡咯并[3,2-b]吡啶盐酸盐
1H-NMR(CDCl3)δ8.36(s,1H),7.50(m,4H),7,20(m,4H),7.01(m,4H),5.42(s,2H),5.33(s,2H),2.48(s,3H),2.33(s,3H);
(收率:59.4%)
实施例38.7-(4-氟苄氧基)-2,3-二甲基-1-(2-乙烯氧基乙基)-1H-吡咯并[3,2-b]吡啶盐酸盐
1H-NMR(CDCl3)δ8.12(s,1H),7.52(m,2H),7.16(m,2H),6.95(s,1H),5.41(s,2H),5.40(s,2H),4.43(s,2H),3.90(s,2H),2.48(s,3H),2.37(s,3H);
(收率:48.7%)
实施例39.1-(1,3-二氧戊环-2-基甲基)-7-(4-氟苄氧基)-2,3-二甲基-1H-吡咯并[3,2-b]吡啶盐酸盐
1H-NMR(CDCl3)δ8.36(s,1H),7.47(m,4H),7.12(s,1H),5.68(s,2H),4.98(d,2H),4.58(m,1H),4.10(m,4H),2.68(s,3H),2.59(s,3H);
(收率:53.2%)
实施例40.1-(3-氟苄基)-7-(4-氟苄氧基)-2,3-二甲基-1H-吡咯并[3,2-b]吡啶盐酸盐
1H-NMR(CDCl3)δ8.37(t,1H),7.24-6.91(m,7H),6.39(m,2H),5.52(s,2H),5.24(s,2H),2.59(s,3H),2.38(s,3H);
(收率:68.3%)
实施例41.1-(2,5-二甲基苄基)-7-(4-氟苄氧基)-2,3-二甲基-1H-吡咯并[3,2-b]吡啶盐酸盐
1H-NMR(CDCl3)δ8.32(d,1H),7.05(m,7H),5.76(s,1H),5.41(s,2H),5.15(s,2H),2.70(s,3H),2.54(s,3H),2.13(s,3H),1.99(s,3H);
(收率:53.0%)
实施例42.1-(3,5-二甲基异噁唑-4-基甲基)-7-(4-氟苄氧基)-2,3-二甲基-1H-吡咯并[3,2-b]吡啶盐酸盐
1H-NMR(CDCl3)δ8.46(s,1H),7.13(m,4H),6.97(s,1H),5.30(s,4H),2.59(s,3H),2.32(s,3H),1.75(s,3H),1.71(s,3H);
(收率:78.4%)
实施例43.1-(3-氯苄基)-7-(4-氟苄氧基)-2,3-二甲基-1H-吡咯并[3,2-b]吡啶盐酸盐
1H-NMR(CDCl3)δ8.39(s,1H),7.39(d,1H),7.24(m,1H),7.12(m,1H),6.95(m,5H),6.02(s,1H),5.58(s,2H),5.18(s,2H),2.63(s,3H),2.36(s,3H);
(收率:81.0%)
实施例44.1-(吡啶-2-基甲基)-7-(4-氟苄氧基)-2,3-二甲基-1H-吡咯并[3,2-b]吡啶盐酸盐
1H-NMR(CDCl3)δ8.35(s,1H),7.29(d,2H),6.99(m,4H),6.90(s,1H),6.61(s,2H),5.60(s,2H),5.22(s,2H),2.60(s,3H),2.38(s,3H);
(收率:82.3%)
实施例45.1-(2,3-二氢苯并[1,4]-二噁烯-6-基甲基)-7-(4-氟苄氧基)-2,3-二甲基-1H-吡咯并[3,2-b]吡啶盐酸盐
1H-NMR(CDCl3)δ8.43(s,1H),7.48(m,3H),7.19(m,2H),6.86(m,2H),6.74(s,1H),5.37(s,2H),4.42(s,2H),3.76(d,2H),3.59(d,2H),2.53(s,3H),2.46(s,3H);
(收率:67.0%)
实施例46.1-(3-氰基苄基)-7-(4-氟苄氧基)-2,3-二甲基-1H-吡咯并[3,2-b]吡啶盐酸盐
1H-NMR(CDCl3)δ8.42(s,1H),7.59(m,2H),7.38(m,2H),7.14(m,4H),7.00(s,1H),5.53(s,2H),5.22(s,2H),2.74(s,3H),2.40(s,3H);
(收率:83.2%)
实施例47.1-环氧乙烷基甲基-7-(4-氟苄氧基)-2,3-二甲基-1H-吡咯并[3,2-b]吡啶盐酸盐
1H-NMR(CDCl3)δ8.34(s,1H),7.48(m,4H),7.13(s,1H),5.68(s,2H),4.89(s,2H),3.98(m,1H),3.33(m,2H),2.59(s,3H),2.50(s,3H);
(收率:65.4%)
实施例48.1-(吡啶-3-基甲基)-7-(4-氟苄氧基)-2,3-二甲基-1H-吡咯并[3,2-b]吡啶盐酸盐
1H-NMR(CDCl3)δ8.36(s,1H),7.85(m,4H),7.47(m,4H),7.12(s,1H),5.68(s,2H),5.12(s,2H),2.68(s,3H),2.59(s,3H);
(收率:54.0%)
实施例49.1-烯丙基-7-(4-氟苄氧基)-2,3-二甲基-1H-吡咯并[3,2-b]吡啶盐酸盐
1H-NMR(CDCl3)δ8.43(d,1H),7.47(m,3H),7.00(m,2H),5.84(m,1H),5.48(s,2H),5.22(d,1H),5.14(s,2H),4.55(d,1H),2.58(s,3H),2.40(s,3H);
(收率:79.0%)
实施例50.7-(4-氟苄氧基)-1-异丁基-2,3-二甲基-1H-吡咯并[3,2-b]吡啶盐酸盐
1H-NMR(CDCl3)δ8.34(d,1H),7.25(m,5H),5.68(s,2H),4.85(d,2H),2.56(s,3H),2.33(s,3H),1.78(m,1H),1.58(d,6H);
(收率:86.0%)
实施例51.7-(4-氟苄氧基)-2,3-二甲基-1-(丙-2-炔基)-1H-吡咯并[3,2-b]吡啶盐酸盐
1H-NMR(CDCl3)δ8.37(s,3H),7.53(m,2H),7.16(m,2H),6.94(s,1H),5.41(s,2H),5.12(s,2H),2.56(s,3H),2.50(s,3H),2.38(s,1H);
(收率:58.6%)
实施例52.7-(4-氟苄氧基)-1-(3-甲氧基苄基)-2,3-二甲基-1H-吡咯并[3,2-b]吡啶盐酸盐
1H-NMR(CDCl3)δ8.35(s,1H),7.20(m,3H),7.00(m,3H),6.91(s,1H),6.22(s,2H),5.54(s,2H),5.29(s,2H),3.72(s,3H),2.63(s,3H),2.40(s,3H);
(收率:71.5%)
实施例53.7-(4-氟苄氧基)-1-(3-甲基苄基)-2,3-二甲基-1H-吡咯并[3,2-b]吡啶盐酸盐
1H-NMR(CDCl3)δ8.36(s,1H),7.04(m,1H),7.01(m,5H),6.83(s,1H),6.47(s,1H),6.44(m,1H),5.52(s,2H),5.22(s,2H),2.60(s,3H),2.37(s,3H),2.26(s,3H);
(收率:88.5%)
实施例54.1-苄基-7-(4-氟苄氧基)-2,3-二甲基-1H-吡咯并[3,2-b]吡啶盐酸盐
1H-NMR(CDCl3)δ8.37(s,1H),7.29(m,3H),7.01(m,4H),6.84(s,1H),6.66(m,2H),5.56(s,2H),5.22(s,2H),2.61(s,3H),2.38(s,3H);
(收率:89.3%)
实施例55.1-环丁基甲基-7-(4-氟苄氧基)-2,3-二甲基-1H-吡咯并[3,2-b]吡啶盐酸盐
1H-NMR(CDCl3)δ8.37(s,1H),7.50(m,2H),7.18(m,3H),5.37(s,2H),4.28(s,2H),2.54(m,1H),2.55(s,3H),2.45(s,3H),1.79(m,3H),1.57(m,3H);
(收率:78.6%)
实施例56.7-(4-氟苄氧基)-2,3-二甲基-1-(3-甲基-2-丁烯-2-基)-1H-吡咯并[3,2-b]吡啶盐酸盐
1H-NMR(CDCl3)δ8.35(s,1H),7.43(m,2H),7.14(m,2H),6.85(s,1H),5.36(s,2H),5.04(m,1H),4.94(s,2H),2.54(s,3H),2.39(s,3H),1.58(s,6H);
(收率:59.8%)
实施例57.1-[2-(甲氧基羰基)乙基]-7-(4-氟苄氧基)-2,3-二甲基-1H-吡咯并[3,2-b]吡啶盐酸盐
1H-NMR(CDCl3)δ8.36(s,1H),7.48(m,2H),7.12(m,2H),6.93(s,1H),5.39(s,2H),4.51(s,2H),4.23(s,2H),2.55(s,3H),2.45(s,3H),1.95(s,3H);
(收率:67.9%)
实施例58.7-(4-氟苄氧基)-1-(4-甲氧基苄基)-2,3-二甲基-1H-吡咯并[3,2-b]吡啶盐酸盐
1H-NMR(CDCl3)δ8.36(s,1H),7.11(s,2H),7.01(m,2H),6.80(m,3H),6.61(d,2H),5.49(s,2H),5.25(s,2H),3.79(s,3H),2.59(s,3H),2.38(s,3H);
(收率:78.4%)
实施例59.1-(2-氟苄基)-7-(4-氟苄氧基)-2,3-二甲基-1H-吡咯并[3,2-b]吡啶盐酸盐
1H-NMR(CDCl3)δ8.43(s,1H),7.53(m,2H),7.27(m,1H),7.05(m,4H),6.23(m,2H),5.61(s,2H),5.30(s,2H),2.63(s,3H),2.49(s,3H);
(收率:86.3%)
实施例60.1-环丙基甲基-7-(4-氟苄氧基)-2,3-二甲基-1H-吡咯并[3,2-b]吡啶盐酸盐
1H-NMR(CDCl3)δ8.36(s,1H),7.50(m,2H),7.24(s,1H),7.10(m,2H),5.84(s,2H),5.10(s,2H),2.54(s,3H),2.35(s,3H),0.78(m,1H),0.62(m,2H),0.17(m,2H);
(收率:79.6%)
实施例61.7-(4-氟苄氧基)-1-(2-甲氧基乙基)-2,3-二甲基-1H-吡咯并[3,2-b]吡啶盐酸盐
1H-NMR(CDCl3)δ8.38(s,1H),7.46(m,2H),7.18(m,2H),6.91(s,1H),5.36(s,2H),4.44(s,2H),3.51(s,2H),3.19(s,3H),2.54(s,3H),2.43(s,3H);
(收率:69.0%)
实施例62.7-(4-氟苄氧基)-2,3-二甲基-1-丙基-1H-吡咯并[3,2-b]吡啶盐酸盐
1H-NMR(CDCl3)δ8.36(s,1H),7.48(m,2H),7.17(m,2H),6.89(s,1H),5.34(s,2H),4.17(t,2H),2.54(s,3H),2.40(s,3H),1.66(m,2H),0.72(t,3H);
(收率:78.5%)
实施例63.1-苄基-7-(4-氟苄氧基)-2,3-二甲基-1H-吡咯并[3,2-b]吡啶甲磺酸盐
用饱和碳酸氢钠溶液处理实施例54中制备的化合物(219mg、0.58mmol)得到1-苄基-7-(4-氟苄氧基)-2,3-二甲基-1H-吡咯并[3,2-b]吡啶(200mg、0.55mmol)。室温下将甲磺酸(0.034ml、0.55mmol)加入到1-苄基-7-(4-氟苄氧基)-2,3-二甲基-1H-吡咯并[3,2-b]吡啶(200mg、0.55mmol)在10ml乙酸乙酯中的溶液中。在相同的温度下搅拌反应混合物24h,过滤所得的固体得到白色固体的标题化合物(收率:89.7%)。
1H-NMR(CDCl3)δ8.37(s,1H),7.29(m,3H),7.01(m,4H),6.84(s,1H),6.66(m,2H),5.56(s,2H),5.22(s,2H),2.61(s,3H),2.38(s,3H)
实施例64~71
根据实施例63中的相同步骤,使用通过用饱和碳酸氢钠溶液处理实施例54中制备的化合物得到的1-苄基-7-(4-氟苄氧基)-2,3-甲基-1H-吡咯并[3,2-b]吡啶,和苯磺酸、对甲苯磺酸、硝酸、硫酸、马来酸、磷酸、丙二酸或者氢溴酸,制备实施例64~71的标题化合物。
实施例64.1-苄基-7-(4-氟苄氧基)-2,3-二甲基-1H-吡咯并[3,2-b]吡啶苯磺酸盐
1H-NMR(CDCl3)δ8.67(s,1H),8.01(s,2H),7.38(s,3H),7.26(m,4H),6.98(m,3H),6.87(d,1H),6.65(s,2H),5.55(s,2H),5.21(s,2H),2.44(s,3H),2.36(s,3H);
(收率:95.8%)
实施例65.1-苄基-7-(4-氟苄氧基)-2,3-二甲基-1H-吡咯并[3,2-b]吡啶对甲苯磺酸盐
1H-NMR(CDCl3)δ8.68(s,1H),7.91(d,2H),7.27(m,4H),7.18(d,2H),6.99(m,3H),6.87(d,1H),6.66(d,2H),5.55(s,2H),5.21(s,2H),2.44(s,3H),2.36(s,6H);
(收率:88.4%)
实施例66.1-苄基-7-(4-氟苄氧基)-2,3-二甲基-1H-吡咯并[3,2-b]吡啶硝酸盐
1H-NMR(CDCl3)δ8.53(s,1H),7.29(m,4H),7.00(m,4H),6.88(d,1H),6.68(s,2H),5.58(s,2H),5.25(s,2H),2.42(s,3H),2.38(s,3H);
(收率:79.8%)
实施例67.1-苄基-7-(4-氟苄氧基)-2,3-二甲基-1H-吡咯并[3,2-b]吡啶硫酸盐
1H-NMR(DMSO-d6)δ8.45(s,1H),7.25(s,6H),7.11(t,2H),6.78(s,2H),5.61(s,2H),5.44(s,2H),2.36(s,3H),2.28(s,3H);
(收率:86.9%)
实施例68.1-苄基-7-(4-氟苄氧基)-2,3-二甲基-1H-吡咯并[3,2-b]吡啶马来酸盐
1H-NMR(CDCl3)δ8.62(d,1H),7.28(m,4H),6.99(m,3H),6.84(d,1H),6.67(s,2H),6.38(s,2H),5.57(s,2H),5.22(s,2H),2.44(s,3H),2.38(s,3H);
(收率:95.4%)
实施例69.1-苄基-7-(4-氟苄氧基)-2,3-二甲基-1H-吡咯并[3,2-b]吡啶磷酸盐
1H-NMR(DMSO-d6)δ8.02(s,1H),7.09(m,5H),6.95(m,2H),6.70(s,1H),6.64(s,2H),5.43(s,2H),5.09(s,2H),2.14(s,3H),2.08(s,3H);
(收率:85.8%)
实施例70.1-苄基-7-(4-氟苄氧基)-2,3-二甲基-1H-吡咯并[3,2-b]吡啶丙二酸盐
1H-NMR(DMSO-d6)δ8.58(d,1H),7.28(m,4H),7.00(m,3H),6.82(d,1H),6.68(s,2H),5.58(s,2H),5.22(s,2H),3.32(s,2H),2.44(s,3H),2.38(s,3H);
(收率:91.2%)
实施例71.1-苄基-7-(4-氟苄氧基)-2,3-二甲基-1H-吡咯并[3,2-b]吡啶氢溴酸盐
1H-NMR(CDCl3)δ8.38(s,1H),7.29(m,4H),7.00(m,3H),6.92(d,1H),6.66(s,2H),5.56(s,2H),5.25(s,2H),2.60(s,3H),2.38(s,3H);
(收率:79.8%)
实施例72.1-烯丙基-7-(4-氯苄氧基)-2,3-二甲基-1H-吡咯并[3,2-b]吡啶盐酸盐
步骤1:4-(4-氯苄氧基)-3-硝基吡啶
除了使用制备1中步骤1制备的4-氯-3-硝基吡啶和4-氯苄基醇以外,根据制备2的相同步骤,得到白色固体的标题化合物(收率:78.0%)。
1H-NMR(CDCl3)δ9.04(s,1H),8.62(d,1H),7.40(m,4H),7.04(d,1H),5.28(d,1H)
步骤2:7-(4-氯苄氧基)-2,3-二甲基-1H-吡咯并[3,2-b]吡啶
除了使用步骤1制备的4-(4-氯苄氧基)-3-硝基吡啶以外,根据实施例33中步骤1的相同步骤,得到白色固体的标题化合物(收率:23.8%)。
1H-NMR(CDCl3)δ8.28(d,1H),8.02(s,1H),7.38(m,4H),6.58(d,1H),5.19(s,2H),2.40(s,3H),2.30(s,3H)
步骤3:1-烯丙基-7-(4-氯苄氧基)-2,3-二甲基-1H-吡咯并[3,2-b]吡啶盐酸盐
除了使用步骤2制备的7-(4-氯苄氧基)-2,3-二甲基-1H-吡咯并[3,2-b]吡啶和烯丙基溴以外,根据实施例33中步骤2的相同步骤,得到白色固体的标题化合物(收率:75.3%)。
1H-NMR(CDCl3)δ8.35(d,1H),7.44(d,2H),7.38(d,2H),6.85(d,1H),5.87(m,1H),5.33(s,2H),5.14(d,1H),4.93(s,2H),4.53(d,1H),2.56(s,3H),2.38(s,3H)
实施例73~97
根据实施例33中步骤2的相同步骤,使用实施例72中步骤2制备的7-(4-氯苄氧基)-2,3-二甲基-1H-吡咯并[3,2-b]吡啶,和苄基溴、溴甲基甲醚、2-氰基苄基溴、2-氯苄基氯、溴乙腈、4-三氟甲基苄基溴、4-叔丁基苄基氯、4-氯甲基吡啶、5-氯甲基-2-噁唑烷酮、2,5-二甲基苄基氯、溴乙酸甲酯、4-溴-2-甲基-2-丁烯、乙酸2-溴乙酯、2-溴乙基甲醚、2-溴甲基-1,3-二氧戊环、4-氟苄基溴、2-氟苄基溴、碘代乙烷、4-氟苄基氯、3-甲氧基苄基氯、4-氟苄基氯、甲基-4-(溴甲基)苯甲酸酯、3-甲基苄基氯、4-甲基苄基氯或者(溴甲基)环丙烷,制备实施例73~97中的标题化合物。
实施例73.1-苄基-7-(4-氯苄氧基)-2,3-二甲基-1H-吡咯并[3,2-b]吡啶盐酸盐
1H-NMR(CDCl3)δ8.36(d,1H),7.30(m,5H),6.98(d,2H),6.84(d,1H),6.68(d,2H),5.57(s,2H),5.23(s,2H),2.60(s,3H),2.38(s,3H);
(收率:69.5%)
实施例74.7-(4-氯苄氧基)-1-甲氧基甲基-2,3-二甲基-1H-吡咯并[3,2-b]吡啶盐酸盐
1H-NMR(CDCl3)δ8.36(d,1H),7.45(m,4H),6.97(d,1H),5.61(s,2H),5.40(s,2H),3.17(s,3H),2.55(s,3H),2.49(s,3H);
(收率:67.3%)
实施例75.1-(2-氰基苄基)-7-(4-氯苄氧基)-2,3-二甲基-1H-吡咯并[3,2-b]吡啶盐酸盐
1H-NMR(CDCl3)δ8.40(d,1H),7.64(d,1H),7.42(m,3H),6.96(m,3H),6.32(s,1H),5.75(s,2H),5.23(s,2H),2.62(s,3H),2.39(s,3H);
(收率:75.4%)
实施例76.1-(2-氯苄基)-7-(4-氯苄氧基)-2,3-二甲基-1H-吡咯并[3,2-b]吡啶盐酸盐
1H-NMR(CDCl3)δ8.37(s,1H),7.41(d,2H),7.25(m,3H),7.14(m,1H),6.90(m,3H),5.59(s,2H),5.18(s,2H),2.63(s,3H),2.36(s,3H);
(收率:68.4%)
实施例77.1-氰基甲基-7-(4-氯苄氧基)-2,3-二甲基-1H-吡咯并[3,2-b]吡啶盐酸盐
1H-NMR(CDCl3)δ8.36(s,1H),7.48(m,4H),7.03(s,1H),5.44(s,2H),5.26(s,2H),2.53(s,6H);
(收率:54.1%)
实施例78.7-(4-氯苄氧基)-2,3-二甲基-1-(4-三氟甲基苄基)-1H-吡咯并[3,2-b]吡啶盐酸盐
1H-NMR(CDCl3)δ8.38(s,1H),7.53(d,2H),7.29(d,2H),6.99(d,2H),6.88(s,1H),6.76(d,2H),5.59(s,2H),5.20(s,2H),2.61(s,3H),2.38(s,3H);(收率:68.7%)
实施例79.1-(4-叔丁基苄基)-7-(4-氯苄氧基)-2,3-二甲基-1H-吡咯并[3,2-b]吡啶盐酸盐
1H-NMR(CDCl3)δ8.34(s,1H),7.28(m,4H),6.98(d,2H),6.81(s,1H),6.62(d,2H),5.53(s,2H),5.23(s,2H),2.59(s,3H),2.38(s,3H),1.30(s,9H);
(收率:58.9%)
实施例80.7-(4-氯苄氧基)-2,3-二甲基-1-(吡啶-4-基甲基)-1H-吡咯并[3,2-b]吡啶盐酸盐
1H-NMR(CDCl3)δ8.51(d,1H),8.41(s,1H),7.34(d,2H),7.01(d,2H),6.86(s,1H),6.58(s,2H),5.53(s,2H),5.16(s,2H),2.62(s,3H),2.38(s,3H);
(收率:68.0%)
实施例81.5-[7-(4-氯苄氧基)-2,3-二甲基-吡咯并[3,2-b]吡啶-1-基甲基]-噁唑烷-2-酮盐酸盐
1H-NMR(CDCl3)δ9.27(s,1H),8.32(s,1H),7.52(m,3H),6.87(s,1H),5.45(s,2H),5.02(s,1H),4.86(s,1H),3.77(m,2H),3.63(m,1H),2.50(s,6H);
(收率:61.1%)
实施例82.7-(4-氯苄氧基)-1-(2,5-二甲基苄基)-2,3-二甲基-1H-吡咯并[3,2-b]吡啶盐酸盐
1H-NMR(CDCl3)δ8.36(s,1H),7.21(m,3H),7.08(m,2H),6.84(d,2H),5.67(s,1H),5.41(s,2H),5.14(s,2H),2.63(s,3H),2.35(s,3H),2.17(s,3H),2.01(s,3H);
(收率:59.8%)
实施例83.[7-(4-氯苄氧基)-2,3-二甲基-吡咯并[3,2-b]吡啶-1-基]乙酸甲酯盐酸盐
1H-NMR(CDCl3)δ8.36(s,1H),7.45(d,2H),7.36(d,2H),6.88(s,1H),5.32(s,2H),5.03(s,2H),3.65(s,3H),2.56(s,3H),2.36(s,3H);
(收率:63.3%)
实施例84.7-(4-氯苄氧基)-2,3-二甲基-1-(3-甲基丁-2-烯基)-1H-吡咯并[3,2-b]吡啶盐酸盐
1H-NMR(CDCl3)δ8.33(d,1H),7.41(m,4H),6.85(d,1H),5.39(s,2H),5.05(m,1H),4.95(d,2H),2.54(s,3H),2.32(s,3H),1.41(s,6H);
(收率:58.6%)
实施例85.1-(2-乙酰氧基乙基)-7-(4-氯苄氧基)-2,3-二甲基-1H-吡咯并[3,2-b]吡啶盐酸盐
1H-NMR(CDCl3)δ8.33(d,1H),7.45(m,4H),6.92(d,1H),5.38(s,2H),4.59(d,2H),4.25(d,2H),2.62(s,3H),2.45(s,3H),2.06(s,3H);
(收率:77.6%)
实施例86.7-(4-氯苄氧基)-1-(2-甲氧基乙基)-2,3-二甲基-1H-吡咯并[3,2-b]吡啶盐酸盐
1H-NMR(CDCl3)δ8.38(d,1H),7.59(m,4H),6.93(d,1H),5.34(s,2H),4.40(s,2H),3.47(s,2H),3.21(s,3H),2.55(s,3H),2.46(s,3H);
(收率:77.0%)
实施例87.7-(4-氯苄氧基)-1-(1,3-二氧戊环-2-基甲基)-2,3-二甲基-1H-吡咯并[3,2-b]吡啶盐酸盐
1H-NMR(CDCl3)δ8.28(d,1H),7.44(m,4H),6.86(d,1H),5.38(s,2H),5.09(m,1H),4.53(s,2H),3.76(s,2H),3.60(s,2H),2.58(s,3H),2.46(s,3H);
(收率:58.4%)
实施例88.7-(4-氯苄氧基)-1-(4-氯苄基)-2,3-二甲基-1H-吡咯并[3,2-b]吡啶盐酸盐
1H-NMR(CDCl3)δ8.36(s,1H),7.30(m,4H),7.04(d,2H),6.88(s,1H),6.60(d,2H),5.51(s,2H),5.23(s,2H),2.59(s,3H),2.37(s,3H);
(收率:85.3%)
实施例89.7-(4-氯苄氧基)-1-(2-氟苄基)-2,3-二甲基-1H-吡咯并[3,2-b]吡啶盐酸盐
1H-NMR(CDCl3)δ8.38(s,1H),7.28(m,3H),6.99(m,4H),6.73(s,1H),6.13(s,1H),5.62(s,2H),5.30(s,2H),2.61(s,3H),2.38(s,3H);
(收率:86.0%)
实施例90.7-(4-氯苄氧基)-1-乙基-2,3-二甲基-1H-吡咯并[3,2-b]吡啶盐酸盐
1H-NMR(CDCl3)δ8.33(s,1H),7.44(m,4H),6.89(s,1H),5.38(s,2H),4.35(m,2H),2.53(s,3H),2.42(s,3H),1.29(t,3H);
(收率:88.3%)
实施例91.7-(4-氯苄氧基)-1-(4-氟苄基)-2,3-二甲基-1H-吡咯并[3,2-b]吡啶盐酸盐
1H-NMR(CDCl3)δ8.36(s,1H),7.37(d,2H),7.06(d,2H),6.99(d,2H),6.87(s,1H),6.64(s,2H),5.52(s,2H),5.24(s,2H),2.59(s,3H),2.38(s,3H);
(收率:81.1%)
实施例92.7-(4-氯苄氧基)-1-(3-甲氧基苄基)-2,3-二甲基-1H-吡咯并[3,2-b]吡啶盐酸盐
1H-NMR(CDCl3)δ8.35(s,1H),7.39(m,1H),7.27(s,1H),7.18(t,1H),7.00(d,2H),6.82(d,2H),6.22(d,2H),5.52(s,2H),5.22(s,2H),3.77(s,3H),2.59(s,3H),2.37(s,3H);
(收率:79.8%)
实施例93.7-(4-氯苄氧基)-1-(3-氟苄基)-2,3-二甲基-1H-吡咯并[3,2-b]吡啶盐酸盐
1H-NMR(CDCl3)δ8.37(s,1H),7.29(m,3H),7.02(m,3H),6.87(s,1H),6.40(t,2H),5.53(s,2H),5.22(s,2H),2.60(s,3H),2.38(s,3H);
(收率:80.1%)
实施例94.7-(4-氯苄氧基)-1-(4-甲氧基羰基苄基)-2,3-二甲基-1H-吡咯并[3,2-b]吡啶盐酸盐
1H-NMR(CDCl3)δ8.38(s,1H),7.94(d,2H),7.28(d,2H),7.00(d,2H),6.85(s,1H),6.70(d,2H),5.59(s,2H),5.19(s,2H),3.93(s,3H),2.61(s,3H),2.37(s,3H);
(收率:78.9%)
实施例95.7-(4-氯苄氧基)-1-(3-甲基苄基)-2,3-二甲基-1H-吡咯并[3,2-b]吡啶盐酸盐
1H-NMR(CDCl3)δ8.35(s,1H),7.27(d,2H),7.18(t,1H),7.10(d,1H),6.97(d,2H),6.82(s,1H),6.48(m,2H),5.53(s,2H),5.22(s,2H),2.60(s,3H),2.37(s,3H),2.22(s,3H);
(收率:75.3%)
实施例96.7-(4-氯苄氧基)-1-(4-甲基苄基)-2,3-二甲基-1H-吡咯并[3,2-b]吡啶盐酸盐
1H-NMR(CDCl3)δ8.35(s,1H),7.27(d,2H),7.08(d,2H),7.01(d,2H),6.81(s,1H),6.56(d,2H),5.52(s,2H),5.23(s,2H),2.59(s,3H),2.37(s,3H),2.34(s,3H);
(收率:78.8%)
实施例97.7-(4-氯苄氧基)-1-环丙基甲基-2,3-二甲基-1H-吡咯并[3,2-b]吡啶盐酸盐
1H-NMR(CDCl3)δ8.34(d,1H),7.44(m,4H),6.89(d,1H),5.36(s,2H),4.22(d,2H),2.55(s,3H),2.44(s,3H),1.10(m,1H),0.48(d,2H),0.20(d,2H);
(收率:88.1%)
实施例98.1-烯丙基-7-(苯并[1,3]间二氧杂环戊烯-5-基甲氧基)-2,3-二甲基-1H-吡咯并[3,2-b]吡啶盐酸盐
步骤1:4-(苯并[1,3]间二氧杂环戊烯-5-基甲氧基)-3-硝基吡啶
除了使用制备1中步骤1制备的4-氯-3-硝基吡啶(3.0g、18.92mmol)和胡椒基醇(3.45ml、18.92mmol)以外,根据制备2中的相同步骤,得到黄色固体的标题化合物(3.08g、88.6%)。
1H-NMR(CDCl3)δ9.02(s,1H),8.60(d,1H),7.06(d,1H),6.91(t,2H),6.84(d,1H),5.99(s,2H),5.21(s,2H)
步骤2:7-(苯并[1,3]间二氧杂环戊烯-5-基甲氧基)-2,3-二甲基-1H-吡咯并[3,2-b]吡啶
除了使用步骤1制备的4-(苯并[1,3]间二氧杂环戊烯-5-基甲氧基)-3-硝基吡啶以外,根据实施例33中步骤1的相同步骤,得到白色固体的标题化合物(收率:28.9%)。
1H-NMR(CDCl3)δ8.28(d,1H),7.94(s,1H),6.94(m,2H),6.82(d,1H),6.60(d,1H),5.99(s,2H),5.11(s,2H),2.39(s,3H),2.21(s,3H)
步骤3:1-烯丙基-7-(苯并[1,3]间二氧杂环戊烯-5-基甲氧基)-2,3-二甲基-1H-吡咯并[3,2-b]吡啶盐酸盐
除了使用步骤2制备的7-(苯并[1,3]间二氧杂环戊烯-5-基甲氧基)-2,3-二甲基-1H-吡咯并[3,2-b]吡啶和烯丙基溴以外,根据实施例33中步骤2的相同步骤,得到白色固体的标题化合物(收率:53.8%)。
1H-NMR(CDCl3)δ8.33(s,1H),6.86(m,4H),6.03(s,2H),5.90(m,1H),5.27(s,2H),5.15(d,1H),4.96(s,2H),4.56(d,1H),2.56(s,3H),2.39(s,3H)
实施例99~121
根据实施例33中步骤2的相同步骤,使用实施例98中步骤2制备的7-(苯并[1,3]间二氧杂环戊烯-5-基甲氧基)-2,3-二甲基-1H-吡咯并[3,2-b]吡啶,和2-溴乙基甲基醚、2-溴甲基-1,3-二氧戊环、2-氟苄基氯、4-叔丁基苄基氯、溴乙酸甲酯、4-氯甲基-3,5-二甲基异噁唑、5-氯甲基-2-噁唑烷酮、2-氯苄基氯、4-三氟甲基苄基氯、2-溴乙醇、溴甲基甲醚、2,5-二甲基苄基氯、4-甲氧羰基苄基氯、4-溴-2-甲基-2-丁烯、3-甲基苄基氯、4-甲基苄基氯、苄基溴、3-氟苄基溴、碘代乙烷、4-氟苄基溴、3-甲氧基苄基溴、1-溴-2-甲基丙烷或者(溴甲基)环丙烷,制备实施例99~121中的标题化合物。
实施例99.7-(苯并[1,3]间二氧杂环戊烯-5-基甲氧基)-1-(2-甲氧基乙基)-2,3-二甲基-1H-吡咯并[3,2-b]吡啶盐酸盐
1H-NMR(CDCl3)δ8.32(s,1H),6.87(m,4H),6.03(s,2H),5.28(s,2H),4.46(s,2H),3.55(s,2H),3.21(s,3H),2.53(s,3H),2.40(s,3H);
(收率:59.6%)
实施例100.7-(苯并[1,3]间二氧杂环戊烯-5-基甲氧基)-1-([1,3]-二氧戊环-2-基甲基)-2,3-二甲基-1H-吡咯并[3,2-b]吡啶盐酸盐
1H-NMR(CDCl3)δ8.34(s,1H),6.93(m,4H),6.01(s,2H),5.29(d,2H),5.13(m,1H),4.55(s,2H),3.78(d,2H),3.60(d,2H),2.53(s,3H),2.32(s,3H);
(收率:61.4%)
实施例101.7-(苯并[1,3]间二氧杂环戊烯-5-基甲氧基)-1-(2-氟苄基)-2,3-二甲基-1H-吡咯并[3,2-b]吡啶盐酸盐
1H-NMR(CDCl3)δ8.34(m,1H),7.07(m,3H),6.82(m,1H),6.73(d,1H),6.61(d,1H),6.39(s,1H),6.221(m,1H),5.99(s,2H),5.61(s,1H),5.15(s,2H),2.60(s,3H),2.29(s,3H);
(收率:58.8%)
实施例102.7-(苯并[1,3]间二氧杂环戊烯-5-基甲氧基)-1-(4-叔丁基苄基)-2,3-二甲基-1H-吡咯并[3,2-b]吡啶盐酸盐
1H-NMR(CDCl3)δ8.32(s,1H),7.30(m,2H),6.79(m,2H),6.64(m,3H),6.43(s,1H),5.99(s,2H),5.53(s,2H),5.15(s,2H),2.58(s,3H),2.38(s,3H),1.29(s,9H);
(收率:83.0%)
实施例103.7-(苯并[1,3]间二氧杂环戊烯-5-基甲氧基)-1-甲氧基羰基甲基-2,3-二甲基-1H-吡咯并[3,2-b]吡啶盐酸盐
1H-NMR(CDCl3)δ8.34(s,1H),6.95(m,4H),6.03(s,2H),5.25(s,2H),5.05(s,2H),3.69(s,3H),2.55(s,3H),2.44(s,3H);
(收率:68.1%)
实施例104.7-(苯并[1,3]间二氧杂环戊烯-5-基甲氧基)-1-(3,5-二甲基异噁唑-4-基甲基)-2,3-二甲基-1H-吡咯并[3,2-b]吡啶盐酸盐
1H-NMR(CDCl3)δ8.38(s,1H),6.95(m,3H),6.71(s,1H),6.00(s,2H),5.34(s,2H),5.24(s,2H),2.56(s,3H),2.35(s,3H),1.81(s,3H),1.64(s,3H);
(收率:74.0%)
实施例105.7-(苯并[1,3]间二氧杂环戊烯-5-基甲氧基)-1-(2-噁唑烷酮-5-基甲基)-2,3-二甲基-1H-吡咯并[3,2-b]吡啶盐酸盐
1H-NMR(CDCl3)δ8.35(s,1H),6.93(m,4H),6.01(s,2H),5.28(s,2H),4.89(s,2H),3.84(m,2H),3.57(m,1H),2.51(s,3H),2.48(s,3H);
(收率:65.4%)
实施例106.7-(苯并[1,3]间二氧杂环戊烯-5-基甲氧基)-1-(2-氯苄基)-2,3-二甲基-1H-吡咯并[3,2-b]吡啶盐酸盐
1H-NMR(CDCl3)δ8.36(d,1H),7.40(d,1H),6.93(m,1H),6.85(m,3H),6.71(d,1H),6.54(m,1H),6.24(s,1H),5.99(s,2H),5.58(s,2H),5.08(s,2H),2.62(s,3H),2.36(s,3H);
(收率:73.2%)
实施例107.7-(苯并[1,3]间二氧杂环戊烯-5-基甲氧基)-2,3-二甲基-1-(4-三氟甲基苄基)-1H-吡咯并[3,2-b]吡啶盐酸盐
1H-NMR(CDCl3)δ8.37(d,1H),7.52(d,2H),6.77(m,4H),6.57(d,1H),6.44(s,1H),6.00(s,2H),5.60(s,2H),5.12(s,2H),2.61(s,3H),2.39(s,3H);
(收率:83.5%)
实施例108.7-(苯并[1,3]间二氧杂环戊烯-5-基甲氧基)-1-(2-羟乙基)-2,3-二甲基-1H-吡咯并[3,2-b]吡啶盐酸盐
1H-NMR(CDCl3)δ8.33(d,1H),7.03(m,2H),6.89(m,2H),6.03(s,2H),5.33(t,2H),4.44(t,2H),3.87(m,2H),2.53(s,3H),2.49(s,3H);
(收率:46.5%)
实施例109.7-(苯并[1,3]间二氧杂环戊烯-5-基甲氧基)-1-甲氧基甲基-2,3-二甲基-1H-吡咯并[3,2-b]吡啶盐酸盐
1H-NMR(CDCl3)δ8.35(d,1H),6.95(m,2H),6.88(m,2H),6.04(s,2H),5.62(s,2H),5.36(s,2H),3.19(s,3H),2.55(s,3H),2.48(s,3H);
(收率:79.5%)
实施例110.7-(苯并[1,3]间二氧杂环戊烯-5-基甲氧基)-1-(2,5-二甲基苄基)-2,3-二甲基-1H-吡咯并[3,2-b]吡啶盐酸盐
1H-NMR(CDCl3)δ8.35(s,1H),6.94(m,2H),6.69(m,1H),6.52(s,1H),6.21(s,1H),6.01(s,1H),5.99(s,2H),5.65(s,1H),5.30(s,2H),5.21(s,2H),5.06(s,2H),2.63(s,3H),2.31(s,3H),2.11(s,3H),2.05(s,3H);
(收率:63.5%)
实施例111.7-(苯并[1,3]间二氧杂环戊烯-5-基甲氧基)-1-(4-甲氧基羰基苄基)-2,3-二甲基-1H-吡咯并[3,2-b]吡啶盐酸盐
1H-NMR(CDCl3)δ8.33(s,1H),7.93(s,1H),6.95(m,3H),6.65(m,3H),6.38(s,1H),5.99(s,2H),5.61(s,2H),5.13(s,2H),3.91(s,3H),2.51(s,3H),2.39(s,3H);
(收率:65.0%)
实施例112.7-(苯并[1,3]间二氧杂环戊烯-5-基甲氧基)-1-(3-甲基丁-2-烯基)-2,3-二甲基-1H-吡咯并[3,2-b]吡啶盐酸盐
1H-NMR(CDCl3)δ8.29(s,1H),6.88(m,5H),6.01(s,2H),5.29(s,2H),5.04(t,1H),4.96(d,2H),2.53(s,3H),2.39(s,3H),1.70(s,3H),1.62(s,3H);
(收率:74.1%)
实施例113.7-(苯并[1,3]间二氧杂环戊烯-5-基甲氧基)-2,3-二甲基-1-(3-甲基苄基)-1H-吡咯并[3,2-b]吡啶盐酸盐
1H-NMR(CDCl3)δ8.33(d,1H),7.16(t,1H),7.09(d,1H),6.78(m,2H),6.64(d,1H),6.44(m,3H),5.99(s,2H),5.54(s,2H),5.16(s,2H),2.60(s,3H),2.38(s,3H),2.27(s,3H);
(收率:66.8%)
实施例114.7-(苯并[1,3]间二氧杂环戊烯-5-基甲氧基)-1-(4-甲基苄基)-2,3-二甲基-1H-吡咯并[3,2-b]吡啶盐酸盐
1H-NMR(CDCl3)δ8.33(d,1H),7.08(d,2H),6.88(m,2H),6.63(m,3H),6.42(s,1H),5.99(s,2H),5.52(s,2H),5.16(s,2H),2.58(s,3H),2.47(s,3H),2.32(s,3H);
(收率:66.0%)
实施例115.7-(苯并[1,3]间二氧杂环戊烯-5-基甲氧基)-1-苄基-2,3-二甲基-1H-吡咯并[3,2-b]吡啶盐酸盐
1H-NMR(CDCl3)δ8.33(s,1H),7.28(m,3H),6.81(s,1H),6.72(m,3H),6.60(d,1H),6.43(s,1H),5.99(s,2H),5.57(s,2H),5.15(s,2H),2.59(s,3H),2.38(s,3H);
(收率:70.5%)
实施例116.7-(苯并[1,3]间二氧杂环戊烯-5-基甲氧基)-1-(3-氟苄基)-2,3-二甲基-1H-吡咯并[3,2-b]吡啶盐酸盐
1H-NMR(CDCl3)δ8.37(s,1H),6.99(t,2H),6.88(m,2H),6.65(s,1H),6.41(m,3H),6.01(s,2H),5.53(s,2H),5.14(s,2H),2.60(s,3H),2.31(s,3H);
(收率:69.8%)
实施例117.7-(苯并[1,3]间二氧杂环戊烯-5-基甲氧基)-1-乙基-2,3-二甲基-1H-吡咯并[3,2-b]吡啶盐酸盐
1H-NMR(CDCl3)δ8.32(d,1H),6.87(m,5H),6.03(s,2H),5.29(s,2H),4.35(m,2H),2.53(s,3H),2.42(s,3H),1.30(t,3H);
(收率:73.3%)
实施例118.7-(苯并[1,3]间二氧杂环戊烯-5-基甲氧基)-1-(4-氟苄基)-2,3-二甲基-1H-吡咯并[3,2-b]吡啶盐酸盐
1H-NMR(CDCl3)δ8.34(d,1H),7.04(m,3H),6.87(m,1H),6.76(m,3H),6.55(s,1H),6.00(s,2H),5.52(s,2H),5.16(s,2H),2.59(s,3H),2.38(s,3H);
(收率:72.1%)
实施例119.7-(苯并[1,3]间二氧杂环戊烯-5-基甲氧基)-1-(3-甲氧基苄基)-2,3-二甲基-1H-吡咯并[3,2-b]吡啶盐酸盐
1H-NMR(CDCl3)δ8.33(d,1H),6.91(m,3H),6.65(m,2H),6.45(s,1H),6.24(m,2H),6.02(s,2H),5.40(s,2H),5.13(s,2H),3.72(s,3H),2.62(s,3H),2.36(s,3H);
(收率:73.2%)
实施例120.7-(苯并[1,3]间二氧杂环戊烯-5-基甲氧基)-1-异丁基-2,3-二甲基-1H-吡咯并[3,2-b]吡啶盐酸盐
1H-NMR(CDCl3)δ8.41(d,1H),6.93(m,4H),6.03(s,2H),5.25(s,2H),4.03(s,2H),2.63(s,3H),2.40(s,3H),1.99(m,1H),0.67(s,6H);
(收率:80.3%)
实施例121.7-(苯并[1,3]间二氧杂环戊烯-5-基甲氧基)-1-环丙基甲基-2,3-二甲基-1H-吡咯并[3,2-b]吡啶盐酸盐
1H-NMR(CDCl3)δ8.34(s,1H),6.93(s,2H),6.87(d,2H),6.04(s,2H),5.28(s,2H),4.23(d,2H),2.55(s,3H),2.44(s,3H),111(m,1H),0.49(d,2H),0.22(d,2H);
(收率:72.5%)
实施例122.7-(4-氟苄氧基)-1-(2-甲氧基乙基)-2,3-二甲基-1H-吡咯并[3,2-b]吡啶
用饱和碳酸氢钠溶液处理实施例61中制备的化合物(2.1g、6.05mmol),得到白色固体的标题化合物(收率:99.4%)。
1H-NMR(CDCl3)δ8.34(d,1H),7.47(s,2H),7.16(t,2H),6.91(d,1H),5.39(s,2H),4.44(s,2H),3.51(s,2H),3.19(s,3H),2.52(s,3H),2.43(s,3H)
实施例123.7-(4-氟苄氧基)-1-(2-甲氧基乙基)-2,3-二甲基-1H-吡咯并[3,2-b]吡啶甲磺酸盐
室温下将0.039ml甲磺酸加入到实施例122中制备的7-(4-氟苄氧基)-1-(2-甲氧基乙基)-2,3-二甲基-1H-吡咯并[3,2-b]吡啶(200mg、0.609mmol)在10ml乙酸乙酯中的溶液中,然后在相同的温度下搅拌24h。过滤所得的固体得到白色固体的标题化合物(收率:85.1%)。
1H-NMR(DMSO-d6)δ8.48(s,1H),7.64(s,2H),7.33(m,3H),5.55(s,2H),4.47(s,2H),3.52(s,2H),3.11(s,3H),2.43(s,3H),2.32(s,3H),2.26(s,3H)
实施例124~133
根据实施例123中的相同步骤,使用实施例122中制备的7-(4-氟苄氧基)-1-(2-甲氧基乙基)-2,3-二甲基-1H-吡咯并[3,2-b]吡啶,和苯磺酸、对甲苯磺酸、硝酸、硫酸、马来酸、磷酸、丙二酸、樟脑磺酸、草酸或者氢溴酸,制备实施例124~133中的标题化合物。
实施例124.7-(4-氟苄氧基)-1-(2-甲氧基乙基)-2,3-二甲基-1H-吡咯并[3,2-b]吡啶苯磺酸盐
1H-NMR(DMSO-d6)δ8.50(s,1H),7.63(m,4H),7.31(s,6H),5.55(s,2H),4.47(s,2H),3.52(s,2H),3.11(s,3H),2.43(s,3H),2.26(s,3H);
(收率:92.3%)
实施例125.7-(4-氟苄氧基)-1-(2-甲氧基乙基)-2,3-二甲基-1H-吡咯并[3,2-b]吡啶对甲苯磺酸盐
1H-NMR(DMSO-d6)δ8.50(s,1H),7.63(s,2H),(s,3H),7.46(d,2H),7.32(m,3H),7.12(d,2H),5.55(s,2H),4.47(s,2H),3.52(s,2H),3.11(s,3H),2.43(s,3H),2.28(s,3H),2.26(s,3H),
(收率:95.4%)
实施例126.7-(4-氟苄氧基)-1-(2-甲氧基乙基)-2,3-二甲基-1H-吡咯并[3,2-b]吡啶硝酸盐
1H-NMR(DMSO-d6)δ8.48(s,1H),7.64(s,2H),7.32(m,3H),5.55(s,2H),4.47(s,2H),3.52(s,2H),3.11(s,3H),2.43(s,3H),2.26(s,3H);
(收率:88.4%)
实施例127.7-(4-氟苄氧基)-1-(2-甲氧基乙基)-2,3-二甲基-1H-吡咯并[3,2-b]吡啶硫酸盐
1H-NMR(DMSO-d6)δ8.24(s,1H),7.41(s,2H),7.08(m,3H),5.31(s,2H),4.24(s,2H),3.33(s,2H),2.88(s,3H),2.20(s,3H),2.03(s,3H);
(收率:89.4%)
实施例128.7-(4-氟苄氧基)-1-(2-甲氧基乙基)-2,3-二甲基-1H-吡咯并[3,2-b]吡啶马来酸盐
1H-NMR(DMSO-d6)δ8.44(s,1H),7.63(s,2H),7.30(m,3H),6.05(s,2H),5.52(s,2H),4.46(s,2H),3.51(s,2H),3.11(s,3H),2.42(s,3H),2.25(s,3H)
(收率:96.5%)
实施例129.7-(4-氟苄氧基)-1-(2-甲氧基乙基)-2,3-二甲基-1H-吡咯并[3,2-b]吡啶磷酸盐
1H-NMR(DMSO-d6)δ8.14(s,1H),7.58(s,2H),7.28(t,2H),6.86(s,1H),5.31(s,2H),4.39(s,2H),3.55(s,2H),3.11(s,3H),2.34(s,3H),2.18(s,3H);
(收率:88.2%)
实施例130.7-(4-氟苄氧基)-1-(2-甲氧基乙基)-2,3-二甲基-1H-吡咯并[3,2-b]吡啶丙二酸盐
1H-NMR(DMSO-d6)δ8.23(s,1H),7.60(s,2H),7.29(t,2H),6.98(s,1H),5.37(s,2H),4.40(s,2H),3.56(s,2H),3.11(s,3H),3.04(s,2H),2.36(s,3H),2.20(s,3H);
(收率:79.9%)
实施例131.7-(4-氟苄氧基)-1-(2-甲氧基乙基)-2,3-二甲基-1H-吡咯并[3,2-b]吡啶樟脑磺酸盐
1H-NMR(DMSO-d6)δ8.48(d,1H),7.64(s,2H),7.32(m,3H),5.55(s,2H),4.47(s,2H),3.52(s,2H),3.11(s,3H),2.89(d,1H),2.68(m,1H),2.43(s,3H),2.36(d,1H),2.26(s,3H),2.20(s,1H),1.92(s,1H),1.84(m,2H),1.28(m,2H),1.04(s,3H),0.73(s,3H),
(收率:86.9%)
实施例132.7-(4-氟苄氧基)-1-(2-甲氧基乙基)-2,3-二甲基-1H-吡咯并[3,2-b]吡啶草酸盐
1H-NMR(DMSO-d6)δ8.33(s,1H),7.61(s,2H),7.28(t,2H),7.12(s,1H),5.44(s,2H),4.43(s,2H),3.51(s,2H),3.11(s,3H),2.34(s,3H),2.16(s,3H);
(收率:95.2%)
实施例133.7-(4-氟苄氧基)-1-(2-甲氧基乙基)-2,3-二甲基-1H-吡咯并[3,2-b]吡啶氢溴酸盐
1H-NMR(DMSO-d6)δ8.37(s,1H),7.53(s,2H),7.21(m,3H),5.45(s,2H),4.36(s,2H),3.41(d,2H),3.00(s,3H),2.33(s,3H),2.16(s,3H);
(收率:75.8%)
实施例134.7-(2,4-二氯苄氧基)-1-甲氧基甲基-2,3-二甲基-1H-吡咯并[3,2-b]吡啶盐酸盐
步骤1:4-(2,4-二氯苄氧基)-3-硝基吡啶
除了使用制备1中步骤1制备的4-氯-3-硝基吡啶和2,4-二氯苄基醇以外,根据制备2中的相同步骤,得到白色固体的标题化合物(收率:89.3%)。
1H-NMR(CDCl3)δ9.05(s,1H),8.60(d,1H),7.13(d,1H),5.29(d,1H)
步骤2:7-(2,4-二氯苄氧基)-2,3-二甲基-1H-吡咯并[3,2-b]吡啶
除了使用步骤1制备的4-(2,4-二氯苄氧基)-3-硝基吡啶以外,根据实施例33中步骤1的相同步骤,得到白色固体的标题化合物(收率:28.6%)。
1H-NMR(CDCl3)δ8.29(d,1H),8.01(s,1H),7.52(m,3H),6.53(d,1H),5.18(s,2H),2.41(s,3H),2.31(s,3H)
步骤3:7-(2,4-二氯苄氧基)-1-甲氧基甲基-2,3-二甲基-1H-吡咯并[3,2-b]吡啶盐酸盐
除了使用步骤2制备的7-(2,4-二氯苄氧基)-2,3-二甲基-1H-吡咯并[3,2-b]吡啶和溴甲基甲醚以外,根据实施例33中步骤2的相同步骤,得到白色固体的标题化合物(收率:58.9%)。
1H-NMR(CDCl3)δ8.38(d,1H),7.54(m,2H),7.51(m,2H),5.61(s,2H),5.50(s,2H),3.17(s,3H),2.56(s,3H),2.49(s,3H)
实施例135~143
根据实施例33中步骤2的相同步骤,使用实施例134中步骤2制备的7-(2,4-二氯苄氧基)-2,3-二甲基-1H-吡咯并[3,2-b]吡啶,和4-溴-2-甲基-2-丁烯、苄基溴、碘代乙烷、乙酸溴甲酯、(溴甲基)环丙烷、4-氟苄基溴、3-甲氧基苄基溴、2-氯苄基溴或者4-叔丁基苄基氯,制备实施例135~143中的标题化合物。
实施例135.7-(2,4-二氯苄氧基)-2,3-二甲基-1-(3-甲基丁-2-烯基)-1H-吡咯并[3,2-b]吡啶盐酸盐
1H-NMR(CDCl3)δ8.36(s,1H),7.52(s,1H),7.43(m,3H),5.60(s,2H),5.14(t,1H),4.80(s,2H),2.55(s,3H),2.41(s,3H),1.59(s,6H);
(收率:75.9%)
实施例136.1-苄基-7-(2,4-二氯苄氧基)-2,3-二甲基-1H-吡咯并[3,2-b]吡啶盐酸盐
1H-NMR(CDCl3)δ8.33(d,1H),7.43(s,3H),7.11(m,2H),6.89(m,1H),6.67(m,2H),5.58(s,2H),5.32(s,2H),2.64(s,3H),2.41(s,3H);
(收率:86.4%)
实施例137.7-(2,4-二氯苄氧基)-1-乙基-2,3-二甲基-1H-吡咯并[3,2-b]吡啶盐酸盐
1H-NMR(CDCl3)δ8.37(d,1H),7.55(s,1H),7.52(d,1H),7.43(d,1H),6.93(d,1H),5.45(s,2H),4.34(m,2H),2.58(s,3H),2.42(s,3H),1.11(t,3H);(收率:75.9%)
实施例138.7-(2,4-二氯苄氧基)-1-甲氧基羰基甲基-2,3-二甲基-1H-吡咯并[3,2-b]吡啶盐酸盐
1H-NMR(CDCl3)δ8.37(d,1H),7.54(s,1H),7.39(m,2H),6.89(s,1H),5.40(s,2H),5.04(s,2H),3.61(s,3H),2.57(s,3H),2.36(s,3H);
(收率:69.7%)
实施例139.1-环丙基甲基-7-(2,4-二氯苄氧基)-2,3-二甲基-1H-吡咯并[3,2-b]吡啶盐酸盐
1H-NMR(CDCl3)δ8.41(d,1H),7.60(m,2H),7.52(m,1H),7.38(m,1H),5.45(s,2H),4.33(d,2H),2.56(s,3H),2.47(s,3H),1.11(m,1H),0.48(m,2H),0.19(m,2H);
(收率:78.3%)
实施例140.7-(2,4-二氯苄氧基)-1-(4-氟苄基)-2,3-二甲基-1H-吡咯并[3,2-b]吡啶盐酸盐
1H-NMR(CDCl3)δ8.40(d,1H),7.44(s,1H),7.19(m,2H),6.90(m,3H),6.38(m,2H),5.52(s,2H),5.32(s,2H),2.61(s,3H),2.39(s,3H);
(收率:75.5%)
实施例141.7-(2,4-二氯苄氧基)-1-(3-甲氧基苄基)-2,3-二甲基-1H-吡咯并[3,2-b]吡啶盐酸盐
1H-NMR(CDCl3)δ8.33(d,1H),7.42(s,1H),7.13(m,3H),6.86(m,3H),6.20(s,1H),5.52(s,2H),5.31(s,2H),3.70(s,3H),2.55(s,3H),2.38(s,3H);
(收率:78.6%)
实施例142.1-(2-氯苄基)-7-(2,4-二氯苄氧基)-2,3-二甲基-1H-吡咯并[3,2-b]吡啶盐酸盐
1H-NMR(CDCl3)δ8.39(d,1H),7.38(s,1H),7.31(m,2H),7.14(m,2H),6.84(d,2H),6.01(d,1H),5.57(d,2H),5.26(s,2H),2.63(s,3H),2.36(s,3H);
(收率:58.5%)
实施例143.1-(4-叔丁基苄基)-7-(2,4-二氯苄氧基)-2,3-二甲基-1H-吡咯并[3,2-b]吡啶盐酸盐
1H-NMR(CDCl3)δ8.37(d,1H),7.43(s,1H),7.23(m,2H),7.10(s,1H),6.92(m,2H),6.60(d,2H),5.29(s,2H),5.33(s,2H),2.61(s,3H),2.44(s,3H),1.28(s,9H);
(收率:68.8%)
实施例144.1-苄基-2,3-二甲基-7-(3-甲基苄氧基)-1H-吡咯并[3,2-b]吡啶盐酸盐
步骤1:4-(3-甲基苄氧基)-3-硝基吡啶
除了使用制备1中步骤1制备的4-氯-3-硝基吡啶和3-甲基苄基醇以外,根据制备2中的相同步骤,得到黄色固体的标题化合物(收率:89.8%)。
1H-NMR(CDCl3)δ9.03(s,1H),8.62(d,1H),7.45(m,4H),7.09(d,1H),5.35(d,1H),1.53(s,3H)
步骤2:7-(3-甲基苄氧基)-2,3-二甲基-1H-吡咯并[3,2-b]吡啶
除了使用步骤1中制备的4-(3-甲基苄氧基)-3-硝基吡啶以外,根据实施例33中步骤1的相同步骤,得到浅黄色固体的标题化合物(收率:28.3%)。
1H-NMR(CDCl3)δ8.29(d,1H),8.01(s,1H),7.40(m,4H),6.58(d,1H),5.23(s,2H),2.40(s,3H),2.30(s,3H),1.55(s,1H)
步骤3:1-苄基-2,3-二甲基-7-(3-甲基苄氧基)-1H-吡咯并[3,2-b]吡啶盐酸盐
除了使用步骤2制备的7-(3-甲基苄氧基)-2,3-二甲基-1H-吡咯并[3,2-b]吡啶和苄基溴以外,根据实施例33中步骤2的相同步骤,得到白色固体的标题化合物(收率:89.3%)。
1H-NMR(CDCl3)δ8.33(d,1H),7.20(m,3H),6.89(d,2H),6.81(d,1H),6.72(d,2H),5.59(s,2H),5.23(s,2H),2.60(s,3H),2.32(s,3H),2.24(s,3H)
实施例145~159
根据实施例33中步骤2的相同步骤,使用实施例144中步骤2制备的7-(3-甲基苄氧基)-2,3-二甲基-1H-吡咯并[3,2-b]吡啶,和碘代乙烷、3-氟苄基氯、4-氯苄基氯、3-甲基苄基氯、2-氯甲基吡啶、2,5-二甲基苄基氯、4-叔丁基苄基氯、4-溴-2-甲基-2-丁烯、1-碘代丙烷、(溴甲基)环丙烷、烯丙基溴、4-甲基苄基氯、2-溴乙基甲醚、4-氟苄基氯或者3-甲氧基苄基氯,制备实施例145~159中的标题化合物。
实施例145.1-乙基-2,3-二甲基-7-(3-甲基苄氧基)-1H-吡咯并[3,2-b]吡啶盐酸盐
1H-NMR(CDCl3)δ8.31(s,1H),7.34(m,4H),6.86(d,1H),5.37(s,2H),4.38(m,2H),2.53(s,3H),2.42(s,3H),2.40(s,3H),1.29(t,3H);
(收率:69.0%)
实施例146.1-(3-氟苄基)-2,3-二甲基-7-(3-甲基苄氧基)-1H-吡咯并[3,2-b]吡啶盐酸盐
1H-NMR(CDCl3)δ8.36(d,1H),7.18(m,3H),6.97(m,3H),6.83(d,1H),6.64(m,2H),5.54(s,2H),5.23(s,2H),2.60(s,3H),2.37(s,3H),2.30(s,3H);
(收率:58.9%)
实施例147.1-(4-氯苄基)-2,3-二甲基-7-(3-甲基苄氧基)-1H-吡咯并[3,2-b]吡啶盐酸盐
1H-NMR(CDCl3)δ8.34(t,1H),7.19(m,4H),6.90(m,3H),6.61(d,2H),5.57(s,2H),5.22(s,2H),2.59(s,3H),2.37(s,3H),2.30(s,3H);
(收率:51.4%)
实施例148.2,3-二甲基-1-(3-甲基苄基)-7-(3-甲基苄氧基)-1H-吡咯并[3,2-b]吡啶盐酸盐
1H-NMR(CDCl3)δ8.33(d,1H),7.34(m,1H),7.14(m,2H),7.09(d,1H),6.91(m,3H),6.50(m,2H),5.56(s,2H),5.25(s,2H),2.59(s,3H),2.40(s,3H),2.37(s,3H),2.27(s,3H);
(收率:63.3%)
实施例149.2,3-二甲基-7-(3-甲基苄氧基)-1-(吡啶-2-基甲基)-1H-吡咯并[3,2-b]吡啶盐酸盐
1H-NMR(CDCl3)δ8.36(d,1H),7.18(m,3H),6.97(m,3H),6.83(d,1H),6.64(m,2H),5.54(s,2H),5.23(s,2H),2.60(s,3H),2.37(s,3H),2.30(s,3H);
(收率:85.4%)
实施例150.1-(2,5-二甲基苄基)-2,3-二甲基-7-(3-甲基苄氧基)-1H-吡咯并[3,2-b]吡啶盐酸盐
1H-NMR(CDCl3)δ8.34(d,1H),7.33(m,1H),7.16(m,2H),6.99(m,2H),6.79(m,3H),5.44(s,2H),5.15(s,2H),2.63(s,3H),2.40(s,3H),2.27(s,6H),2.00(s,3H);
(收率:72.0%)
实施例151.1-(4-叔丁基苄基)-2,3-二甲基-7-(3-甲基苄氧基)-1H-吡咯并[3,2-b]吡啶盐酸盐
1H-NMR(CDCl3)δ8.34(d,1H),7.34(m,4H),7.19(d,1H),6.97(s,1H),6.87(m,1H),6.65(d,1H),5.56(s,2H),5.25(s,2H),2.59(s,3H),2.54(s,3H),2.37(s,3H),1.29(s,9H);
(收率:80.1%)
实施例152.2,3-二甲基-7-(3-甲基苄氧基)-1-(3-甲基丁-2-烯基)-1H-吡咯并[3,2-b]吡啶盐酸盐
1H-NMR(CDCl3)δ8.40(d,1H),7.31(m,4H),5.40(s,2H),5.21(m,1H),4.99(s,2H),2.57(s,3H),2.38(s,6H),1.81(s,6H);
(收率:74.6%)
实施例153.2,3-二甲基-7-(3-甲基苄氧基)-1-丙基-1H-吡咯并[3,2-b]吡啶盐酸盐
1H-NMR(CDCl3)δ8.34(s,1H),7.34(m,4H),6.88(s,1H),5.33(s,2H),4.20(t,2H),2.40(s,3H),2.30(s,3H),2.17(s,3H),1.69(m,2H),0.75(t,3H);
(收率:78.2%)
实施例154.1-环丙基甲基-2,3-二甲基-7-(3-甲基苄氧基)-1H-吡咯并[3,2-b]吡啶盐酸盐
1H-NMR(CDCl3)δ8.35(d,1H),7.34(m,4H),6.89(d,1H),5.35(s,2H),4.13(d,2H),2.56(s,3H),2.45(s,3H),2.41(s,3H),1.13(m,1H),0.48(m,2H),0.22(m,2H);
(收率:66.9%)
实施例155.1-烯丙基-2,3-二甲基-7-(3-甲基苄氧基)-1H-吡咯并[3,2-b]吡啶盐酸盐
1H-NMR(CDCl3)δ8.33(d,1H),7.31(m,3H),6.85(d,1H),5.90(m,1H),5.35(s,2H),5.15(d,1H),4.97(s,2H),4.57(d,1H),2.57(s,3H),2.39(s,6H);
(收率:72.3%)
实施例156.2,3-二甲基-1-(4-甲基苄基)-7-(3-甲基苄氧基)-1H-吡咯并[3,2-b]吡啶盐酸盐
1H-NMR(CDCl3)δ8.32(d,1H),7.19(m,2H),7.09(d,2H),6.92(m,3H),6.62(d,2H),5.55(s,2H),5.25(s,2H),2.58(s,3H),2.37(s,3H),2.27(s,3H),2.27(s,3H);
(收率:93.5%)
实施例157.1-(2-甲氧基乙基)-2,3-二甲基-7-(3-甲基苄氧基)-1H-吡咯并[3,2-b]吡啶盐酸盐
1H-NMR(CDCl3)δ8.33(d,1H),7.34(m,4H),6.87(d,1H),5.36(s,2H),4.47(m,2H),3.50(m,2H),3.20(s,3H),2.54(s,3H),2.44(s,3H),2.40(s,3H);
(收率:86.3%)
实施例158.1-(4-氟苄基)-2,3-二甲基-7-(3-甲基苄氧基)-1H-吡咯并[3,2-b]吡啶盐酸盐
1H-NMR(CDCl3)δ8.35(t,1H),7.20(m,3H),7.00(m,3H),6.85(d,1H),6.42(m,2H),5.55(s,2H),5.23(s,2H),2.60(s,3H),2.37(s,3H),2.29(s,3H);
(收率:91.0%)
实施例159.1-(3-甲氧基苄基)-2,3-二甲基-7-(3-甲基苄氧基)-1H-吡咯并[3,2-b]吡啶盐酸盐
1H-NMR(CDCl3)δ8.33(d,1H),7.33(m,1H),7.17(m,2H),6.91(s,2H),6.81(d,2H),6.27(s,1H),5.56(s,2H),5.24(s,2H),3.70(s,3H),2.52(s,3H),2.49(s,3H),2.17(s,3H);
(收率:88.5%)
实施例160.1-(3-氯苄基)-7-(2-乙氧基苄氧基)-2,3-二甲基-1H-吡咯并[3,2-b]吡啶盐酸盐
步骤1:4-(2-乙氧基苄氧基)-3-硝基吡啶
除了使用制备1中步骤1制备的4-氯-3-硝基吡啶和2-乙氧基苄基醇以外,根据制备2中的相同步骤,得到黄色固体的标题化合物(收率:65.9%)。
1H-NMR(CDCl3)δ9.04(s,1H),8.62(d,1H),7.32(m,4H),7.04(d,1H),5.33(d,1H),2,87(m,2H),1.2(t,3H)
步骤2:7-(2-乙氧基苄氧基)-2,3-二甲基-1H-吡咯并[3,2-b]吡啶
除了使用步骤1中制备的4-(2-乙氧基苄氧基)-3-硝基吡啶以外,根据实施例33中步骤1的相同步骤,得到白色固体的标题化合物(收率:25.5%)。
1H-NMR(CDCl3)δ8.30(d,1H),8.01(s,1H),7.25(m,4H),6.58(d,1H),5.30(s,2H),3.12(m,2H),2.41(s,3H),2.26(s,3H),1.21(t,3H)
步骤3:1-(3-氯苄基)-7-(2-乙氧基苄氧基)-2,3-二甲基-1H-吡咯并[3,2-b]吡啶盐酸盐
除了使用步骤2制备的7-(2-乙氧基苄氧基)-2,3-二甲基-1H-吡咯并[3,2-b]吡啶和3-氯苄基溴以外,根据实施例33中步骤2的相同步骤,得到白色固体的标题化合物(收率:79.8%)。
1H-NMR(CDCl3)δ8.26(d,1H),7.88(d,1H),7.23(m,3H),7.04(t,3H),6.97(d,4H),6.63(m,2H),5.28(m,2H),3.01(s,3H),2.36(s,3H),2.33(s,3H),
实施例161~178
根据实施例33中步骤2的相同步骤,使用实施例160中步骤2制备的7-(2-乙氧基苄氧基)-2,3-二甲基-1H-吡咯并[3,2-b]吡啶,和(溴甲基)环丙烷、2-溴乙基甲醚、(溴甲基)环丁烷、烯丙基溴、碘代乙烷、3,4-二氯苄基氯、2-甲氧基苄基氯、2-氯苄基氯、2-氟苄基氯、1-碘代丙烷、4-甲氧基苄基氯、4-氯苄基氯、3-甲基苄基氯、4-甲基苄基氯、4-氟苄基氯、2-溴甲基-1,3-二氧戊环、3-甲氧基苄基溴或3-氟苄基溴,制备实施例161~178中的标题化合物。
实施例161.1-环丙基甲基-7-(2-乙氧基苄氧基)-2,3-二甲基-1H-吡咯并[3,2-b]吡啶盐酸盐
1H-NMR(CDCl3)δ8.33(t,1H),7.39(m,2H),6.96(m,3H),5.44(s,2H),4.23(d,2H),4.12(m,2H),2.55(s,3H),2.43(s,3H),1.41(t,3H),1.12(m,1H),0.43(m,2H),0.20(m,2H);
(收率:82.5%)
实施例162.7-(2-乙氧基苄氧基)-1-(2-甲氧基乙基)-2,3-二甲基-1H-吡咯并[3,2-b]吡啶盐酸盐
1H-NMR(CDCl3)δ8.31(t,1H),7.36(m,2H),6.96(m,3H),5.45(s,2H),4.45(t,2H),4.11(m,2H),3.54(t,2H),3.17(s,3H),2.52(s,3H),2.42(s,3H),1.40(t,3H);
(收率:78.4%)
实施例163.1-环丁基甲基-7-(2-乙氧基苄氧基)-2,3-二甲基-1H-吡咯并[3,2-b]吡啶盐酸盐
1H-NMR(CDCl3)δ8.32(s,1H),7.39(m,2H),6.97(m,3H),5.45(s,2H),4.30(s,2H),4.12(d,2H),2.63(m,1H),2.54(s,3H),2.41(s,3H),1.77~1.55(m,6H),1.25(t,3H);
(收率:69.7%)
实施例164.1-烯丙基-7-(2-乙氧基苄氧基)-2,3-二甲基-1H-吡咯并[3,2-b]吡啶盐酸盐
1H-NMR(CDCl3)δ8.31(d,1H),7.36(m,2H),6.97(m,3H),5.58(m,1H),5.49(s,2H),5.11(d,1H),4.97(s,2H),4.61(d,1H),4.12(m,2H),2.55(s,3H),2.38(s,3H),1.42(t,3H);
(收率:51.0%)
实施例165.7-(2-乙氧基苄氧基)-1-乙基-2,3-二甲基-1H-吡咯并[3,2-b]吡啶盐酸盐
1H-NMR(CDCl3)δ8.30(t,1H),7.37(d,1H),6.98(m,3H),5.46(s,2H),4.36(m,2H),4.12(m,2H),2.53(s,3H),2.40(s,3H),1.40(t,3H),1.28(t,3H);
(收率:65.8%)
实施例166.1-(3,4-二氯苄基)-7-(2-乙氧基苄氧基)-2,3-二甲基-1H-吡咯并[3,2-b]吡啶盐酸盐
1H-NMR(CDCl3)δ8.36(d,1H),7.38(m,2H),6.99(t,2H),6.89(t,2H),6.78(s,1H),6,42(d,1H),5.48(s,2H),5.32(s,2H),3.99(m,2H),2.53(s,3H),2.35(s,3H),1.29(t,3H);
(收率:74.0%)
实施例167.7-(2-乙氧基苄氧基)-1-(2-甲氧基苄基)-2,3-二甲基-1H-吡咯并[3,2-b]吡啶盐酸盐
1H-NMR(CDCl3)δ8.32(t,1H),7.21(m,3H),6.82(m,5H),6.02(d,1H),5.58(s,2H),5.30(s,2H),3.98(m,2H),3.76(s,3H),2.58(s,3H),2.31(s,3H),1.32(t,3H);
(收率:63.5%)
实施例168.1-(2-氯苄基)-7-(2-乙氧基苄氧基)-2,3-二甲基-1H-吡咯并[3,2-b]吡啶盐酸盐
1H-NMR(CDCl3)δ8.33(t,1H),7.36(d,1H),7.21(m,2H),7.10(t,1H),6.92(d,1H),6.82(d,1H),6.75(s,2H),6.02(d,2H),5.64(s,2H),5.30(s,2H),3.96(m,2H),2.60(s,3H),2.33(s,3H),1.31(1,3H);
(收率:74.2%)
实施例169.7-(2-乙氧基苄氧基)-1-(2-氟苄基)-2,3-二甲基-1H-吡咯并[3,2-b]吡啶盐酸盐
1H-NMR(CDCl3)δ8.32(t,1H),7.30(m,1H),6.96(m,4H),6.85(m,3H),6.24(t,1H),5.65(s,2H),5.35(s,2H),4.01(m,2H),2.58(s,3H),2.35(s,3H),1.34(t,3H);
(收率:63.0%)
实施例170.7-(2-乙氧基苄氧基)-1-丙基-2,3-二甲基-1H-吡咯并[3,2-b]吡啶盐酸盐
1H-NMR(CDCl3)δ8.33(d,1H),7.39(m,2H),7.00(m,3H),5.43(d,2H),4.21(m,2H),4.11(m,2H),2.54(s,3H),2.40(s,3H),1.58(m,2H),1.39(m,3H),0.74(m,3H);
(收率:68.8%)
实施例171.7-(2-乙氧基苄氧基)-1-(4-甲氧基苄基)-2,3-二甲基-1H-吡咯并[3,2-b]吡啶盐酸盐
1H-NMR(CDCl3)δ8.31(t,1H),7.32(t,1H),6.96(m,4H),6.77(d,2H),6.64(d,2H),5.52(s,2H),5.36(s,2H),4.04(m,2H),3.81(s,3H),2.56(s,3H),2.36(s,3H),1.34(t,3H);
(收率:84.0%)
实施例172.1-(4-氯苄基)-7-(2-乙氧基苄氧基)-2,3-二甲基-1H-吡咯并[3,2-b]吡啶盐酸盐
1H-NMR(CDCl3)δ8.34(t,1H),7.35(t,1H),7.19(d,2H),6.94(d,1H),6.87(d,1H),6.60(d,1H),5.52(s,2H),5.33(s,2H),3.98(m,2H),2.59(s,3H),2.36(s,3H),1.31(t,3H);
(收率:75.0%)
实施例173.7-(2-乙氧基苄氧基)-1-(3-甲基苄基)-2,3-二甲基-1H-吡咯并[3,2-b]吡啶盐酸盐
1H-NMR(CDCl3)δ8.31(t,1H),7.30(m,1H),7.15(m,2H),7.11(m,1H),6.92(m,2H),6.87(m,1H),6.49(m,2H),5.50(s,2H),5.35(s,2H),4.01(m,2H),2.58(s,3H),2.47(s,3H),2.29(s,3H),1.34(t,3H);
(收率:83.0%)
实施例174.7-(2-乙氧基苄氧基)-1-(4-甲基苄基)-2,3-二甲基-1H-吡咯并[3,2-b]吡啶盐酸盐
1H-NMR(CDCl3)δ8.30(d,1H),7.52(m,1H),7.05(d,2H),6.88(m,4H),6.62(d,2H),5.55(s,2H),5.35(s,2H),4.02(m,2H),2.58(s,3H),2.35(s,3H),2.31(s,3H),1.34(t,3H);
(收率:75.0%)
实施例175.1-(4-氟苄基)-7-(2-乙氧基苄氧基)-2,3-二甲基-1H-吡咯并[3,2-b]吡啶盐酸盐
1H-NMR(CDCl3)δ8.34(d,1H),7.34(t,1H),6.93(m,6H),6.67(t,2H),5.53(s,2H),5.34(s,2H),4.01(m,2H),2.57(s,3H),2.36(s,3H),1.32(t,3H);
(收率:64.0%)
实施例176.1-(1,3-二氧戊环-2-基甲基)-7-(2-乙氧基苄氧基)-2,3-二甲基-1H-吡咯并[3,2-b]吡啶盐酸盐
1H-NMR(CDCl3)δ8.86(s,1H),8.33(m,1H),7.42(m,2H),6.95(m,2H),5.48(d,2H),5.10(m,1H),4.53(d,2H),4.11(m,2H),3.71(m,4H),2.52(s,3H),2.45(s,3H),1.40(m,3H);
(收率:75.4%)
实施例177.7-(2-乙氧基苄氧基)-1-(3-甲氧基苄基)-2,3-二甲基-1H-吡咯并[3,2-b]吡啶盐酸盐
1H-NMR(CDCl3)δ8.32(t,1H),7.31(m,1H),7.16(t,1H),6.92(d,2H),6.84(m,3H),6.26(s,2H),5.57(s,2H),5.35(s,2H),4.01(m,2H),3.68(s,3H),2.57(s,3H),2.35(s,3H),1.34(t,3H);
(收率:79.5%)
实施例178.1-(3-氟苄基)-7-(2-乙氧基苄氧基)-2,3-二甲基-1H-吡咯并[3,2-b]吡啶盐酸盐
1H-NMR(CDCl3)δ8.33(d,1H),7.33(t,1H),7.19(m,1H),6.94(t,3H),6.85(m,2H),6.43(m,2H),5.55(s,2H),5.34(s,2H),3.99(m,2H),2.59(s,3H),2.36(s,3H),1.34(t,3H);
(收率:86.7%)
实施例179.1-环丁基甲基-7-(3,5-二氟苄氧基)-2,3-二甲基-1H-吡咯并[3,2-b]吡啶盐酸盐
步骤1:4-(3,5-二氟苄氧基)-3-硝基吡啶
除了使用制备1中步骤1制备的4-氯-3-硝基吡啶和3,5-二氟苄基醇以外,根据制备2中的相同步骤,得到黄色固体的标题化合物(收率:78.0%)。
1H-NMR(CDCl3)δ9.06(s,1H),8.73(s,1H),8.65(d,1H),7.40(s,1H),7.35(s,1H),7.04(d,1H),5.28(d,1H)
步骤2:7-(3,5-二氟苄氧基)-2,3-二甲基-1H-吡咯并[3,2-b]吡啶
除了使用步骤1中制备的4-(3,5-二氟苄氧基)-3-硝基吡啶以外,根据实施例33中步骤1的相同步骤,得到白色固体的标题化合物(收率:20.4%)。
1H-NMR(CDCl3)δ8.75(s,1H),8.66(d,1H),8.01(s,1H),7.40(s,1H),7.35(s,1H),7.04(d,1H),5.28(d,1H),2.11(s,3H),2.35(s,3H)
步骤3:1-环丁基甲基-7-(3,5-二氟苄氧基)-2,3-二甲基-1H-吡咯并[3,2-b]吡啶盐酸盐
除了使用步骤2制备的7-(3,5-二氟苄氧基)-2,3-二甲基-1H-吡咯并[3,2-b]吡啶和(溴甲基)环丁烷以外,根据实施例33中步骤2的相同步骤,得到白色固体的标题化合物(收率:70.5%)。
1H-NMR(CDCl3)δ8.36(s,1H),7.02(m,2H),6.91(m,1H),6.82(m,1H),5.36(s,2H),4.35(d,2H),2.67(m,1H),2.55(s,3H),2.44(s,3H),1.73(m,2H),1.67(m,2H)
实施例180~199
根据实施例33中步骤2的相同步骤,使用实施例179中步骤2制备的7-(3,5-二氟苄氧基)-2,3-二甲基-1H-吡咯并[3,2-b]吡啶,和(溴甲基)环丙烷、2-溴乙基甲醚、1-碘代丙烷、4-氯苄基氯、4-氟苄基溴、碘代乙烷、3,4-二氯苄基氯、碘代甲烷、2-氯苄基氯、3,4-二甲氧基苄基氯、2-甲氧基苄基氯、2-氟苄基氯、3-氯苄基氯、4-甲氧基苄基氯、3-甲氧基苄基氯、苄基溴、4-甲基苄基溴、2-氯甲基吡啶、3-氯甲基吡啶或者2-氯-N,N-二甲基乙基胺盐酸盐,制备实施例180~199中的标题化合物。
实施例180.1-环丙基甲基-7-(3,5-二氟苄氧基)-2,3-二甲基-1H-吡咯并[3,2-b]吡啶盐酸盐
1H-NMR(CDCl3)δ8.37(d,1H),7.04(m,2H),6.89(m,2H),5.39(s,2H),4.34(d,2H),2.57(s,3H),2.47(s,3H),1.15(m,1H),0.56(m,2H),0.27(m,2H);
(收率:86.0%)
实施例181.7-(3,5-二氟苄氧基)-1-(2-甲氧基乙基)-2,3-二甲基-1H-吡咯并[3,2-b]吡啶盐酸盐
1H-NMR(CDCl3)δ8.33(d,1H),7.02(d,2H),6.89(m,2H),5.33(s,2H),4.53(t,2H),3.59(t,2H),3.27(s,3H),2.55(s,3H),2.43(s,3H);
(收率:75.6%)
实施例182.7-(3,5-二氟苄氧基)-2,3-二甲基-1-丙基-1H-吡咯并[3,2-b]吡啶盐酸盐
1H-NMR(CDCl3)δ8.35(d,1H),7.01(d,2H),6.91(m,1H),6.83(m,1H),5.35(s,2H),4.24(t,2H),2.55(s,3H),2.43(s,3H),1.73(m,2H),0.83(t,3H);
(收率:58.7%)
实施例183.1-(4-氯苄基)-7-(3,5-二氟苄氧基)-2,3-二甲基-1H-吡咯并[3,2-b]吡啶盐酸盐
1H-NMR(CDCl3)δ8.37(s,1H),7.37(m,1H),7.03(d,1H),6.85(t,2H),6.59(m,4H),5.56(s,2H),5.23(s,2H),2.53(s,3H),2.39(s,3H);
(收率:63.3%)
实施例184.7-(3,5-二氟苄氧基)-1-(4-氟苄基)-2,3-二甲基-1H-吡咯并[3,2-b]吡啶盐酸盐
1H-NMR(CDCl3)δ8.38(d,1H),7.06(m,2H),6.84(m,2H),6.59(s,2H),6.42(m,2H),5.85(s,2H),5.24(s,2H),2.54(s,3H),2.40(s,3H);
(收率:71.2%)
实施例185.7-(3,5-二氟苄氧基)-1-乙基-2,3-二甲基-1H-吡咯并[3,2-b]吡啶盐酸盐
1H-NMR(CDCl3)δ8.34(s,1H),6.99(s,2H),6.89(m,1H),6.82(m,1H),5.38(s,2H),4.40(m,2H),2.55(s,3H),2.44(s,3H),1.27(t,3H);
(收率:83.6%)
实施例186.7-(3,5-二氟苄氧基)-1-(3,4-二氯苄基)-2,3-二甲基-1H-吡咯并[3,2-b]吡啶盐酸盐
1H-NMR(CDCl3)δ8.40(s,1H),7.49(m,1H),6.82(m,2H),6.65(d,2H),6.50(m,2H),5.49(s,2H),5.24(s,2H),2.54(s,3H),2.39(s,3H);
(收率:65.1%)
实施例187.7-(3,5-二氟苄氧基)-1,2,3-三甲基-1H-吡咯并[3,2-b]吡啶盐酸盐
1H-NMR(CDCl3)δ8.33(t,1H),7.00(d,2H),6.91(t,1H),6.81(s,1H),5.37(s,2H),4.00(s,3H),2.55(s,3H),2.43(s,3H);
(收率:75.6%)
实施例188.1-(2-氯苄基)-7-(3,5-二氟苄氧基)-2,3-二甲基-1H-吡咯并[3,2-b]吡啶盐酸盐
1H-NMR(CDCl3)δ8.40(t,1H),7.43(m,2H),7.16(m,1H),6.81(m,2H),6.46(s,2H),6.03(m,1H),5.61(s,2H),5.16(s,2H),2.60(s,3H),2.39(s,3H);
(收率:63.8%)
实施例189.7-(3,5-二氟苄氧基)-1-(3,4-二甲氧基苄基)-2,3-二甲基-1H-吡咯并[3,2-b]吡啶盐酸盐
1H-NMR(CDCl3)δ7.98(d,1H),7.61(d,1H),7.01(d,2H),6.91(s,4H),6.82(s,2H),5.71(s,2H),5.64(s,2H),3.81(s,3H),2.34(s,3H),2.27(s,3H);
(收率:72.5%)
实施例190.7-(3,5-二氟苄氧基)-1-(2-甲氧基苄基)-2,3-二甲基-1H-吡咯并[3,2-b]吡啶盐酸盐
1H-NMR(CDCl3)δ7.92(d,1H),7.56(d,1H),7.38(t,1H),7.21(t,1H),6.97(m,2H),6.75(t,1H),6.58(d,1H),6.22(d,1H),5.78(s,2H),5.67(s,2H),3.89(s,3H),2.25(s,3H),2.17(s,3H);
(收率:64.2%)
实施例191.7-(3,5-二氟苄氧基)-1-(2-氟苄基)-2,3-二甲基-1H-吡咯并[3,2-b]吡啶盐酸盐
1H-NMR(CDCl3)δ8.37(s,1H),7.36(m,1H),7.05(m,3H),6.81(m,2H),6.56(d,2H),5.63(s,2H),5.30(s,2H),2.56(s,3H),2.39(s,3H);
(收率:58.4%)
实施例192.1-(3-氯苄基)-7-(3,5-二氟苄氧基)-2,3-二甲基-1H-吡咯并[3,2-b]吡啶盐酸盐
1H-NMR(CDCl3)δ8.39(d,1H),7.23(m,1H),6.847(m,3H),6.72(s,1H),6.61(m,2H),6.52(m,1H),5.56(s,2H),5.19(s,2H),2.63(s,3H),2.40(s,3H);
(收率:85.4%)
实施例193.7-(3,5-二氟苄氧基)-1-(4-甲氧基苄基)-2,3-二甲基-1H-吡咯并[3,2-b]吡啶盐酸盐
1H-NMR(CDCl3)δ8.34(d,1H),6.91(m,4H),6.64(m,4H),5.54(s,2H),5.24(s,2H),3.73(s,3H),2.61(s,3H),2.39(s,3H);
(收率:65.3%)
实施例194.7-(3,5-二氟苄氧基)-1-(3-甲氧基苄基)-2,3-二甲基-1H-吡咯并[3,2-b]吡啶盐酸盐
1H-NMR(CDCl3)δ7.97(d,1H),7.64(d,1H),7.19(t,1H),6.89(d,1H),6.78(d,1H),6.56(m,2H),6.46(s,2H),5.76(s,2H),5.68(s,2H),3.76(s,3H),2.35(s,3H),2.31(s,3H);
(收率:69.4%)
实施例195.1-苄基-7-(3,5-二氟苄氧基)-2,3-二甲基-1H-吡咯并[3,2-b]吡啶盐酸盐
1H-NMR(CDCl3)δ8.35(d,1H),7.42(m,4H),6.80(m,4H),6.55(d,1H),5.60(s,2H),5.25(s,2H),2.62(s,3H),2.45(s,3H);
(收率:80.9%)
实施例196.7-(3,5-二氟苄氧基)-1-(4-甲基苄基)-2,3-二甲基-1H-吡咯并[3,2-b]吡啶盐酸盐
1H-NMR(CDCl3)δ8.34(brs,1H),7.10(m,3H),6.79(m,2H),6.59(m,3H),5.56(s,2H),5.22(s,2H),2.59(s,3H),2.40(s,3H),2.32(s,3H);
(收率:91.5%)
实施例197.1-(吡啶-2-基甲基)-7-(3,5-二氟苄氧基)-2,3-二甲基-1H-吡咯并[3,2-b]吡啶盐酸盐
1H-NMR(CDCl3)δ8.33(brs,1H),7.14(m,3H),6.87(m,2H),6.54(m,3H),5.53(s,2H),5.24(s,2H),2.40(s,3H),2.32(s,3H);
(收率:85.4%)
实施例198.1-(吡啶-3-基甲基)-7-(3,5-二氟苄氧基)-2,3-二甲基-1H-吡咯并[3,2-b]吡啶盐酸盐
1H-NMR(CDCl3)δ8.37(brs,1H),8.01(s,1H),7.14(m,2H),6.94(m,2H),6.32(m,3H),5.54(s,2H),5.35(s,2H),2.39(s,3H),2.28(s,3H);
(收率:75.6%)
实施例199.1-(2,2-二甲基氨乙基)-7-(3,5-二氟苄氧基)-2,3-二甲基-1H-吡咯并[3,2-b]吡啶盐酸盐
1H-NMR(CDCl3)δ8.45(brs,1H),8.01(s,1H),7.87(m,2H),6.94(d,1H),5.35(s,2H),4.35(d,2H),4.01(d,2H),2.88(s,6H),2.84(m,2H),2.39(s,3H),2.28(s,3H);
(收率:66.3%)
实施例200.2,3-二甲基-1-(4-甲基苄基)-7-(4-三氟甲基苄氧基)-1H-吡咯并[3,2-b]吡啶盐酸盐
步骤1:4-(4-三氟甲基苄氧基)-3-硝基吡啶
除了使用制备1中步骤1制备的4-氯-3-硝基吡啶和4-三氟甲基苄基醇以外,根据制备2中的相同步骤,得到黄色固体的标题化合物(收率:89.5%)。
1H-NMR(CDCl3)δ9.03(s,1H),8.66(d,1H),7.38(m,4H),7.02(d,1H),5.29(d,1H)
步骤2:7-(4-三氟甲基苄氧基)-2,3-二甲基-1H-吡咯并[3,2-b]吡啶
除了使用步骤1中制备的4-(4-三氟甲基苄氧基)-3-硝基吡啶以外,根据实施例33中步骤1的相同步骤,得到白色固体的标题化合物(收率:29.5%)。
1H-NMR(CDCl3)δ8.28(d,1H),8.01(s,1H),7.36(m,4H),6.57(d,1H),5.20(s,2H),2.41(s,3H),2.31(s,3H)
步骤3:2,3-二甲基-1-(4-甲基苄基)-7-(4-三氟甲基苄氧基)-1H-吡咯并[3,2-b]吡啶盐酸盐
除了使用步骤2制备的7-(4-三氟甲基苄氧基)-2,3-二甲基-1H-吡咯并[3,2-b]吡啶和4-甲基苄基溴以外,根据实施例33中步骤2的相同步骤,得到白色固体的标题化合物(收率:88.6%)。
1H-NMR(CDCl3)δ8.37(d,1H),7.55(d,2H),7.16(m,2H),7.13(d,2H),6.81(m,1H),6.58(d,2H),5.55(s,2H),5.32(s,2H),2.61(s,3H),2.38(s,3H),2.35(s,3H)
实施例201~208
根据实施例33中步骤2的相同步骤,使用实施例200中步骤2制备的7-(4-三氟甲基苄氧基)-2,3-二甲基-1H-吡咯并[3,2-b]吡啶,和3-甲氧基苄基溴、2-氯苄基氯、碘代乙烷、4-氯苄基氯、(溴甲基)环丙烷、4-甲氧基苄基氯、3-氟苄基氯或者3,4-二氯苄基氯,制备实施例201~208中的标题化合物。
实施例201.1-(3-甲氧基苄基)-2,3-二甲基-7-(4-三氟甲基苄氧基)-1H-吡咯并[3,2-b]吡啶盐酸盐
1H-NMR(CDCl3)δ8.36(t,1H),7.55(d,2H),7.18(m,3H),6.83(d,2H),6.22(s,2H),5.54(s,2H),5.30(s,2H),3.70(s,3H),2.60(s,3H),2.38(s,3H);
(收率:89.0%)
实施例202.1-(2-氯苄基)-2,3-二甲基-7-(4-三氟甲基苄氧基)-1H-吡咯并[3,2-b]吡啶盐酸盐
1H-NMR(CDCl3)δ8.39(d,1H),7.54(d,2H),7.37(d,1H),7.11(m,3H),6.83(m,2H),6.03(d,1H),5.61(s,2H),5.26(s,2H),2.62(s,3H),2.37(s,3H);
(收率:75.4%)
实施例203.1-乙基-2,3-二甲基-7-(4-三氟甲基苄氧基)-1H-吡咯并[3,2-b]吡啶盐酸盐
1H-NMR(CDCl3)δ8.34(d,1H),7.75(d,2H),7.62(d,2H),6.89(s,1H),5.48(s,2H),4.38(m,2H),2.54(s,3H),2.43(s,3H),1.33(t,3H);
(收率:63.8%)
实施例204.1-(4-氯苄基)-2,3-二甲基-7-(4-三氟甲基苄氧基)-1H-吡咯并[3,2-b]吡啶盐酸盐
1H-NMR(CDCl3)δ8.37(d,1H),7.60(d,2H),7.38(m,2H),7.24(m,2H),6.86(m,1H),6.60(d,2H),5.50(s,2H),5.31(s,2H),2.60(s,3H),2.37(s,3H);
(收率:85.2%)
实施例205.1-环丙基甲基-2,3-二甲基-7-(4-三氟甲基苄氧基)-1H-吡咯并[3,2-b]吡啶盐酸盐
1H-NMR(CDCl3)δ8.08(d,2H),7.99(d,1H),7.37(m,2H),6.45(s,1H),5.25(s,1H),4.59(m,1H),4.41(m,1H),4.15(d,1H),2.53(s,3H),2.47(s,3H),1.34(m,1H),0.72(d,1H),0.61(d,1H),0.35(m,2H);
(收率:77.4%)
实施例206.1-(4-甲氧基苄基)-2,3-二甲基-7-(4-三氟甲基苄氧基)-1H-吡咯并[3,2-b]吡啶盐酸盐
1H-NMR(CDCl3)δ8.36(d,1H),7.58(d,2H),6.94(m,3H),6.84(m,2H),6.79(m,2H),6.60(d,2H),5.52(s,2H),5.29(s,2H),3.78(s,3H),2.60(s,3H),2.38(s,3H);
(收率:65.4%)
实施例207.1-(3-氟苄基)-2,3-二甲基-7-(4-三氟甲基苄氧基)-1H-吡咯并[3,2-b]吡啶盐酸盐
1H-NMR(CDCl3)δ8.38(d,1H),7.56(d,2H),7.15(d,2H),7.032(m,3H),6.83(m,1H),6.22(m,1H),5.62(s,2H),5.24(s,2H),2.62(s,3H),2.39(s,3H);
(收率:68.7%)
实施例208.1-(3,4-二氯苄基)-2,3-二甲基-7-(4-三氟甲基苄氧基)-1H-吡咯并[3,2-b]吡啶盐酸盐
1H-NMR(CDCl3)δ8.40(s,1H),7.64(d,2H),7.32(m,4H),6.88(s,1H),6.79(s,1H),6.43(d,1H),5.48(s,2H),5.22(s,2H),2,61(s,3H),2.39(s,3H);
(收率:74.2%)
实施例209.1-苄基-2,3-二甲基-7-(吡啶-3-基甲氧基)-1H-吡咯并[3,2-b]吡啶盐酸盐
步骤1:4-(吡啶-3-基甲氧基)-3-硝基吡啶
除了使用制备1中步骤1制备的4-氯-3-硝基吡啶和3-吡啶甲醇以外,根据制备2中的相同步骤,得到黄色固体的标题化合物(收率:78.5%)。
1H-NMR(CDCl3)δ9.06(s,1H),8.70(s,1H),8.65(m,2H),7.87(m,1H),7.39(m,1H),7.10(d,2H),5.32(s,2H)
步骤2:2,3-二甲基-7-(吡啶-3-基甲氧基)-1H-吡咯并[3,2-b]吡啶
除了使用步骤1中制备的4-(吡啶-3-基甲氧基)-3-硝基吡啶以外,根据实施例33中步骤1的相同步骤,得到白色固体的标题化合物(收率:18.4%)。
1H-NMR(CDCl3)δ8.74(s,1H),8.64(s,1H),8.30(s,1H),8.04(brs,1H),7.79(d,1H),7.35(d,1H),6.63(s,1H),5.30(s,2H),2.40(s,3H),2.31(s,3H)
步骤3:1-苄基-2,3-二甲基-7-(吡啶-3-基甲氧基)-1H-吡咯并[3,2-b]吡啶盐酸盐
除了使用步骤2制备的2,3-二甲基-7-(吡啶-3-基甲氧基)-1H-吡咯并[3,2-b]吡啶和苄基溴以外,根据实施例33中步骤2的相同步骤,得到白色固体的标题化合物(收率:78.4%)。
1H-NMR(DMSO-d6)δ8.59(s,2H),8.37(s,1H),7.78(s,1H),7.53(s,1H),7.21(s,1H),7.10(s,3H),6.64(s,2H),5.57(s,2H),5.47(s,2H),2.25(s,3H),2.14(s,3H)
实施例210~214
根据实施例33中步骤2的相同步骤,使用实施例209中步骤2制备的2,3-二甲基-7-(吡啶-3-基甲氧基)-1H-吡咯并[3,2-b]吡啶,和1-碘代丙烷、1-碘代-2-甲基丙烷、烯丙基溴、2-溴乙基甲醚或者(溴甲基)环丁烷,制备实施例210~214中的标题化合物。
实施例210.2,3-二甲基-1-丙基-7-(吡啶-3-基甲氧基)-1H-吡咯并[3,2-b]吡啶盐酸盐
1H-NMR(DMSO-d6)δ8.72(s,1H),8.55(s,1H),8.27(d,1H),8.08(d,1H),7.53(s,1H),7.15(d,1H),5.43(s,2H),3.97(t,2H),2.20(s,3H),2.06(s,3H),1.35(m,2H),0.39(t,3H);
(收率:78.5%)
实施例211.1-异丁基-2,3-二甲基-7-(吡啶-3-基甲氧基)-1H-吡咯并[3,2-b]吡啶盐酸盐
1H-NMR(DMSO-d6)δ8.75(s,1H),8.58(s,1H),8.31(d,1H),8.10(d,1H),7.56(s,1H),7.18(d,1H),5.44(s,2H),3.86(d,2H),2.22(s,3H),2.10(s,3H),1.74(m,1H),0.39(d,6H);
(收率:69.8%)
实施例212.1-烯丙基-2,3-二甲基-7-(吡啶-3-基甲氧基)-1H-吡咯并[3,2-b]吡啶盐酸盐
1H-NMR(DMSO-d6)δ8.92(s,1H),8.79(s,1H),8.51(d,1H),8.31(s,1H),7.80(s,1H),7.37(s,1H),5.97(m,1H),5.370(s,2H),5.08(d,1H),5.01(s,2H),4.56(s,1H),2.50(s,3H),2.32(s,3H);
(收率:57.9%)
实施例213.1-(2-甲氧基乙基)-2,3-二甲基-7-(吡啶-3-基甲氧基)-1H-吡咯并[3,2-b]吡啶盐酸盐
1H-NMR(DMSO-d6)δ9.00(s,1H),8.84(s,1H),8.49(d,1H),8.43(d,1H),7.88(s,1H),7.37(d,1H),5.71(s,2H),4.49(s,2H),3.50(d,2H),3,12(s,3H),2.44(s,3H),2.31(s,3H);
(收率:78.4%)
实施例214.1-环丁基甲基-2,3-二甲基-7-(吡啶-3-基甲氧基)-1H-吡咯并[3,2-b]吡啶盐酸盐
1H-NMR(DMSO-d6)δ8.99(s,1H),8.81(s,1H),8.50(d,1H),8.37(s,1H),7.82(s,1H),7.39(d,1H),5.69(s,2H),4.33(d,2H),2.61(m,1H),2.44(s,3H),2.30(s,3H),1.66(m,6H);
(收率:83.4%)
实施例215.1-苄基-2,3-二甲基-7-(吡啶-2-基甲氧基)-1H-吡咯并[3,2-b]吡啶盐酸盐
步骤1:4-(吡啶-2-基甲氧基)-3-硝基吡啶
除了使用制备1中步骤1制备的4-氯-3-硝基吡啶和2-吡啶甲醇以外,根据制备2中的相同步骤,得到黄色固体的标题化合物(收率:68.3%)。
1H-NMR(CDCl3)δ9.06(s,1H),8.61(m,2H),7.78(m,1H),7.64(d,1H),7.31(m,1H),7.15(d,1H),5.41(s,2H)
步骤2:2,3-二甲基-7-(吡啶-2-基甲氧基)-1H-吡咯并[3,2-b]吡啶
除了使用步骤1中制备的4-(吡啶-2-基甲氧基)-3-硝基吡啶以外,根据实施例33中步骤1的相同步骤,得到白色固体的标题化合物(收率:21.5%)。
1H-NMR(CDCl3)δ8.64(s,1+1H),8.26(d,1H),7.73(t,1H),7.48(d,1H),7.29(s,1H),6.63(d,1H),5.40(s,2H),2.43(s,3H),2.33(s,3H)
步骤3:1-苄基-2,3-二甲基-7-(吡啶-2-基甲氧基)-1H-吡咯并[3,2-b]吡啶盐酸盐
除了使用步骤2制备的2,3-二甲基-7-(吡啶-2-基甲氧基)-1H-吡咯并[3,2-b]吡啶和苄基溴以外,根据实施例33中步骤2的相同步骤,得到白色固体的标题化合物(收率:78.4%)。
1H-NMR(DMSO-d6)δ8.59(s,1H),8.47(d,1H),7.78(t,1H),7.42(t,1H),7.31(d,1H),7.24(s,3H),7.19(d,1H),6.89(s,2H),5.72(s,2H),5.62(s,2H),2.40(s,3H),2.33(s,3H)
实施例216~217
根据实施例33中步骤2的相同步骤,使用实施例215中步骤2制备的2,3-二甲基-7-(吡啶-2-基甲氧基)-1H-吡咯并[3,2-b]吡啶,和1-碘代丙烷或者2-溴乙基甲醚,制备实施例216~217中的标题化合物。
实施例216.2,3-二甲基-1-丙基-7-(吡啶-2-基甲氧基)-1H-吡咯并[3,2-b]吡啶盐酸盐
1H-NMR(DMSO-d6)δ8.59(s,1H),8.38(d,1H),7.90(t,1H),7.62(d,1H),7.41(s,1H),7.27(d,1H),5.59(s,2H),4.21(t,2H),2.37(s,3H),2.22(s,3H),1.57(m,2H),0.61(t,3H);
(收率:63.8%)
实施例217.1-(2-甲氧基乙基)-2,3-二甲基-7-(吡啶-2-基甲氧基)-1H-吡咯并[3,2-b]吡啶盐酸盐
1H-NMR(DMSO-d6)δ8.65(s,1H),8.44(d,1H),7.96(t,1H),7.67(d,1H),7.47(s,1H),7.32(d,1H),5.69(s,2H),4.55(s,2H),3.60(s,2H),3.19(s,3H),2.45(s,3H),2.29(s,3H);
(收率:79.8%)
实施例218.7-(4-溴苄氧基)-2,3-二甲基-1H-吡咯并[3,2-b]吡啶
步骤1:4-溴苄氧基-3-硝基吡啶
除了使用制备1中步骤1制备的4-氯-3-硝基吡啶和4-溴苄基醇以外,根据制备2中的相同步骤,得到黄色固体的标题化合物(收率:78.9%)。
1H-NMR(CDCl3)δ9.04(s,1H),8.62(d,1H),7.56(d,2H),7.34(d,2H),7.04(d,1H),5.26(s,2H)
步骤2:7-(4-溴苄氧基)-2,3-二甲基-1H-吡咯并[3,2-b]吡啶
除了使用步骤1中制备的4-溴苄氧基-3-硝基吡啶以外,根据实施例33中步骤1的相同步骤,得到白色固体的标题化合物(收率:15.8%)。
1H-NMR(CDCl3)δ8.28(d,1H),8.21(brs,1H),7.52(d,2H),7.31(d,2H),6.56(d,1H),5.16(s,2H),2.39(s,3H),2.30(s,3H)
实施例219~230
根据实施例33中步骤2的相同步骤,使用实施例218中步骤2制备的7-(4-溴苄氧基)-2,3-二甲基-1H-吡咯并[3,2-b]吡啶,和苄基溴、烯丙基溴、4-氟苄基氯、3-氟苄基氯、3-甲基苄基溴、4-甲基苄基溴、2-氟苄基溴、3-氯苄基溴、(溴甲基)环丁烷、1-碘-2-甲基丙烷、1-碘代丙烷或者2-甲氧基苄基氯,制备实施例219~230中的标题化合物。
实施例219.1-苄基-7-(4-溴苄氧基)-2,3-二甲基-1H-吡咯并[3,2-b]吡啶盐酸盐
1H-NMR(CDCl3)δ8.35(t,1H),7.43(d,1H),7.29(m,3H),6.91(d,2H),6.81(d,1H),6.67(d,2H),5.57(s,2H),5.20(s,2H),2.60(s,3H),2.32(s,3H);
(收率:48.9%)
实施例220.1-烯丙基-7-(4-溴苄氧基)-2,3-二甲基-1H-吡咯并[3,2-b]吡啶盐酸盐
1H-NMR(CDCl3)δ8.33(t,1H),7.60(d,2H),7.33(d,2H),6.88(d,1H),5.88(m,1H),5.33(s,2H),5.14(d,1H),4.94(d,2H),4.54(d,1H),2.56(s,3H),2.32(s,3H);
(收率:58.8%)
实施例221.7-(4-溴苄氧基)-1-(4-氟苄基)-2,3-二甲基-1H-吡咯并[3,2-b]吡啶盐酸盐
1H-NMR(CDCl3)δ8.34(t,1H),7.47(d,2H),6.96(m,4H),6.87(d,1H),6.63(m,2H),5.21(s,2H),5.23(s,2H),2.59(s,3H),2.37(s,3H)
(收率:65.3%)
实施例222.7-(4-溴苄氧基)-1-(3-氟苄基)-2,3-二甲基-1H-吡咯并[3,2-b]吡啶盐酸盐
1H-NMR(CDCl3)δ8.36(t,1H),7.47(d,2H),7.22(m,1H),7.01(m,3H),6.90(d,1H),6.41(t,2H),5.53(s,2H),5.22(s,2H),2.60(s,3H),2.38(s,3H);
(收率:78.0%)
实施例223.7-(4-溴苄氧基)-2,3-二甲基-1-(3-甲基苄基)-1H-吡咯并[3,2-b]吡啶盐酸盐
1H-NMR(DMSO-d6)δ8.29(d,1H),7.31(d,2H),7.06(d,1H),6.92(m,3H),6.85(m,1H),6.48(s,1H),6.32(d,1H),5.40(s,2H),5.27(s,2H),2.19(s,3H),2.12(s,3H),1.99(s,3H);
(收率:63.3%)
实施例224.7-(4-溴苄氧基)-2,3-二甲基-1-(4-甲基苄基)-1H-吡咯并[3,2-b]吡啶盐酸盐
1H-NMR(CDCl3)δ8.34(t,1H),7.43(d,2H),7.07(d,2H),6.93(d,2H),6.82(d,1H),6.58(d,2H),5.53(s,2H),5.22(s,2H),2.59(s,3H),2.37(s,3H),2.32(s,3H);
(收率:78.9%)
实施例225.7-(4-溴苄氧基)-1-(2-氟苄基)-2,3-二甲基-1H-吡咯并[3,2-b]吡啶盐酸盐
1H-NMR(CDCl3)δ8.36(t,1H),7.43(d,2H),7.30(d,1H),7.03(m,2H),6.92(d,2H),6.83(d,1H),6.23(t,1H),5.61(s,2H),521(s,2H),2.60(s,3H),2.38(s,3H)
(收率:68.0%)
实施例226.7-(4-溴苄氧基)-1-(3-氯苄基)-2,3-二甲基-1H-吡咯并[3,2-b]吡啶盐酸盐
1H-NMR(CDCl3)δ8.36(t,1H),7.49(d,1H),7.27(s,1H),7.20(t,1H),6.98(d,2H),6.88(d,1H),6.71(s,1H),6.46(d,1H),5.54(s,2H),5.24(s,2H),2.60(s,3H),2.33(s,3H);
(收率:68.8%)
实施例227.7-(4-溴苄氧基)-1-环丁基甲基-2,3-二甲基-1H-吡咯并[3,2-b]吡啶盐酸盐
1H-NMR(CDCl3)δ8.34(brs,1H),7.63(d,2H),7.38(d,2H),6.88(d,1H),5.34(s,2H),4.30(d,2H),2.54(s,3H),2.38(s,3H),1.77(m,3H),1.66(m,4H);
(收率:55.4%)
实施例228.7-(4-溴苄氧基)-1-异丁基-2,3-二甲基-1H-吡咯并[3,2-b]吡啶盐酸盐
1H-NMR(CDCl3)δ8.39(t,1H),7.63(d,2H),7.38(d,2H),6.96(d,1H),5.37(s,2H),4.04(d,2H),2.55(s,3H),2.42(s,3H),1.81(m,1H),0.71(d,6H);
(收率:70.0%)
实施例229.7-(4-溴苄氧基)-2,3-二甲基-1-丙基-1H-吡咯并[3,2-b]吡啶盐酸盐
1H-NMR(CDCl3)δ8.33(t,1H),7.61(d,2H),7.38(d,2H),7.01(d,1H),5.38(s,2H),4.31(t,2H),2.52(s,3H),2.41(s,3H),1.67(m,2H),0.75(t,3H);
(收率:65.5%)
实施例230.7-(4-溴苄氧基)-1-(2-甲氧基苄基)-2,3-二甲基-1H-吡咯并[3,2-b]吡啶盐酸盐
1H-NMR(CDCl3)δ8.35(t,1H),7.41(d,2H),6.84(m,6H),5.97(d,1H),5.68(s,2H),5.14(s,2H),3.75(s,3H),2.60(s,3H),2.25(s,3H);
(收率:78.0%)
实施例231.1-苄基-7-(4-异丙基苄氧基)-2,3-二甲基-1H-吡咯并[3,2-b]吡啶盐酸盐
步骤1:4-异丙基苄氧基-3-硝基吡啶
除了使用制备1中步骤1制备的4-氯-3-硝基吡啶和4-异丙基苄基醇以外,根据制备2中的相同步骤,得到白色固体的标题化合物(收率:67.8%)。
1H-NMR(CDCl3)δ9.02(s,1H),8.59(d,1H),7.37(d,2H),7.28(d,2H),7.07(d,1H),5.28(s,2H),2.90(m,1H),1.26(d,6H)
步骤2:7-(4-异丙基苄氧基)-2,3-二甲基-1H-吡咯并[3,2-b]吡啶
除了使用步骤1中制备的4-异丙基苄氧基-3-硝基吡啶以外,根据实施例33中步骤1的相同步骤,得到白色固体的标题化合物(收率:25.8%)。
1H-NMR(CDCl3)δ8.31(d,1H),7.20(d,2H),7.05(d,2H),6.82(d,1H),5.23(s,2H),2.90(m,1H),2.54(s,3H),2.35(s,3H),1.24(d,6H)
步骤3:1-苄基-7-(4-异丙基苄氧基)-2,3-二甲基-1H-吡咯并[3,2-b]吡啶盐酸盐
除了使用步骤2制备的7-(4-异丙基苄氧基)-2,3-二甲基-1H-吡咯并[3,2-b]吡啶和苄基溴以外,根据实施例33中步骤2的相同步骤,得到白色固体的标题化合物(收率:78.5%)。
1H-NMR(CDCl3)δ8.32(t,1H),7.27(m,3H),7.16(d,2H),7.00(d,2H),6.83(d,1H),6.67(m,2H),5.57(s,2H),5.22(s,2H),2.91(m,1H),2.59(s,3H),2.37(s,3H),1.26(d,6H)
实施例232~240
根据实施例33中步骤2的相同步骤,使用实施例231中步骤2制备的7-(4-异丙基苄氧基)-2,3-二甲基-1H-吡咯并[3,2-b]吡啶,和4-氟苄基氯、3-甲基苄基氯、3-氟苄基氯、4-甲基苄基氯、2-甲氧基苄基溴、3-氯苄基溴、2-氟苄基溴、(溴甲基)环丁烷或者1-碘代丙烷,制备实施例232~240中的标题化合物。
实施例232.1-(4-氟苄基)-7-(4-异丙基苄氧基)-2,3-二甲基-1H-吡咯并[3,2-b]吡啶盐酸盐
1H-NMR(CDCl3)δ8.34(t,1H),7.20(d,2H),7.05(d,2H),6.93(t,2H),6.86(d,1H),6.62(m,2H),5.52(s,2H),5.23(s,2H),2.93(m,1H),2.58(s,3H),2.37(s,3H),1.27(d,6H);
(收率:85.4%)
实施例233.7-(4-异丙基苄氧基)-2,3-二甲基-1-(3-甲基苄基)-1H-吡咯并[3,2-b]吡啶盐酸盐
1H-NMR(CDCL3)δ8.32(t,1H),7.17(m,3H),7.10(d,1H),7.02(d,2H),6.83(d,1H),6.50(s,1H),6.47(d,1H),5.55(s,2H),5.24(s,2H),2.92(m,1H),2.59(s,3H),2.37(s,3H),2.26(s,3H),1.26(d,6H);
(收率:65.7%)
实施例234.1-(3-氟苄基)-7-(4-异丙基苄氧基)-2,3-二甲基-1H-吡咯并[3,2-b]吡啶盐酸盐
1H-NMR(CDCl3)δ8.35(t,1H),7.19(m,3H),7.01(m,3H),6.86(d,1H),6.39(m,2H),5.53(s,2H),5.21(s,2H),2.92(m,1H),2.59(s,3H),2.37(s,3H),1.25(d,6H);
(收率:78.4%)
实施例235.7-(4-异丙基苄氧基)-2,3-二甲基-1-(4-甲基苄基)-1H-吡咯并[3,2-b]吡啶盐酸盐
1H-NMR(CDCl3)δ8.32(t,1H),7.17(d,2H),7.07(d,2H),7.01(d,2H),6.83(d,1H),6.59(d,2H),5.54(s,2H),5.24(s,2H),2.92(m,1H),2.58(s,3H),2.37(s,3H),2.33(s,3H),1.28(d,6H);
(收率:84.2%)
实施例236.7-(4-异丙基苄氧基)-1-(2-甲氧基苄基)-2,3-二甲基-1h-吡咯并[3,2-b]吡啶盐酸盐
1H-NMR(CDCl3)δ8.32(t,1H),7.29(m,1H),7.12(d,2H),6.89(m,3H),6.79(m,2H),6.01(d,1H),5.55(s,2H),5.18(s,2H),3.73(s,3H),2.89(m,1H),2.59(s,3H),2.33(s,3H),1.24(d,6H);
(收率:65.7%)
实施例237.1-(3-氯苄基)-7-(4-异丙基苄氧基)-2,3-二甲基-1H-吡咯并[3,2-b]吡啶盐酸盐
1H-NMR(CDCl3)δ8.36(t,1H),7.20(d,2H),7.05(d,2H),6.93(t,2H),6.86(d,1H),6.62(m,2H),5.52(s,2H),5.23(s,2H),2.91(m,1H),2.58(s,3H),2.37(s,3H),1.27(d,6H);
(收率:74.5%)
实施例238.1-(2-氟苄基)-7-(4-异丙基苄氧基)-2,3-二甲基-1H-吡咯并[3,2-b]吡啶盐酸盐
1H-NMR(CDCl3)δ8.34(t,1H),7.35-6.96(m,7H),6.84(d,1H),6.23(t,1H),5.63(s,2H),5.23(s,2H),2.88(m,1H),2.59(s,3H),2.36(s,3H),1.25(d,6H);
(收率:63.8%)
实施例239.1-环丁基甲基-7-(4-异丙基苄氧基)-2,3-二甲基-1H-吡咯并[3,2-b]吡啶盐酸盐
1H-NMR(CDCl3)δ8.32(t,1H),7.40(d,2H),7.33(d,2H),6.88(d,1H),5.34(s,2H),4.29(d,1H),2.98(m,1H),2.63(m,1H),2.53(s,3H),2.40(s,3H),1.77-1.56(m,7H),1.28(d,6H);
(收率:81.0%)
实施例240.7-(4-异丙基苄氧基)-1-丙基-2,3-二甲基-1H-吡咯并[3,2-b]吡啶盐酸盐
1H-NMR(CDCl3)δ8.32(t,1H),7.38(d,2H),7.30(d,2H),6.88(d,1H),5.33(s,2H),4.20(t,2H),2.97(m,1H),2.53(s,3H),2.39(s,3H),1.68(m,2H),1.28(d,6H),0.71(t,3H);
(收率:78.5%)
实施例241.1-苄基-7-(4-氟苯氧基)-2,3-二甲基-1H-吡咯并[3,2-b]吡啶盐酸盐
步骤1:4-氟苯氧基-3-硝基吡啶
在0℃下将氢化钠(7.2g、180.4mmol)缓慢加入到4-氟苯酚(17.11g、152.6mmol)在200ml N,N-二甲基甲酰胺中的溶液中,然后室温下搅拌该反应混合物30min。0℃下将制备1中步骤1制备的4-氯-3-硝基吡啶(22.0g、138.8mmol)加入到该反应混合物中,室温下搅拌1h,用200ml乙酸乙酯稀释,然后用200ml水洗涤3次。用无水硫酸镁干燥分离的有机层并减压浓缩得到浅黄色固体的标题化合物(25.2g、76.8%)。
1H-NMR(CDCl3)δ9.13(s,1H),8.57(d,1H),7.15(m,4H),6.76(d,1H)
步骤2:7-(4-氟苯氧基)-2,3-二甲基-1H-吡咯并[3,2-b]吡啶
除了使用步骤1中制备的4-氟苯氧基-3-硝基吡啶以外,根据实施例33中步骤1的相同步骤,得到白色固体的标题化合物(收率:18.5%)。
1H-NMR(CDCl3)δ8.22(d,1H),7.99(brs,1H),7.08(m,4H),6.38(d,1H),2.55(s,3H),2.32(s,3H)
步骤3:1-苄基-7-(4-氟苯氧基)-2,3-二甲基-1H-吡咯并[3,2-b]吡啶盐酸盐
除了使用步骤2制备的7-(4-氟苯氧基)-2,3-二甲基-1H-吡咯并[3,2-b]吡啶和苄基溴以外,根据实施例33中步骤2的相同步骤,得到白色固体的标题化合物(收率:63.8%)。
1H-NMR(CDCl3)δ8.27(t,1H),7.31(m,3H),7.13(t,2H),6.87(m,4H),6.44(d,1H),5.71(s,2H),2.64(s,3H),2.47(s,3H)
实施例242~243
根据实施例33中步骤2的相同步骤,使用实施例241中步骤2制备的7-(4-氟苯氧基)-2,3-二甲基-1H-吡咯并[3,2-b]吡啶,和烯丙基溴或者(溴甲基)环丁烷,制备实施例242~243中的标题化合物。
实施例242.1-烯丙基-7-(4-氟苯氧基)-2,3-二甲基-1H-吡咯并[3,2-b]吡啶盐酸盐
1H-NMR(CDCl3)δ8.25(t,1H),7.20-7.12(m,4H),6.47(d,1H),6.04(m,1H),5.22(d,1H),5.10(d,2H),4.72(d,1H),2.61(s,3H),2.46(s,3H);
(收率:73.3%)
实施例243.1-环丁基甲基-7-(4-氟苯氧基)-2,3-二甲基-1H-吡咯并[3,2-b]吡啶盐酸盐
1H-NMR(CDCl3)δ8.22(t,1H),7.23-7.17(m,4H),6.42(d,1H),4.50(d,2H),2.74(m,1H),2.58(s,3H),2.48(s,3H),1.91-1.76(m,7H);
(收率:83.4%)
实施例244.(2,3-二甲基-1-丙基-1H-吡咯并[3,2-b]吡啶-7-基)-(4-氟苄基)氨基甲酸叔丁酯盐酸盐
将制备3中制备的(2,3-二甲基-1H-吡咯并[3,2-b]吡啶-7-基)-(4-氟苄基)氨基甲酸叔丁酯(20mg、0.089mmol)、叔丁醇钾(10.6mg、0.143mmol)和催化量的18-冠-6加入到无水四氢呋喃(2ml)中。将1-碘代丙烷(0.089ml、0.130mmol)加入到反应混合物中,然后室温下搅拌12h。减压浓缩该反应混合物。所得的剩余物用硅胶柱色谱纯化(乙酸乙酯/二氯甲烷/甲醇=10/10/1、(v/v/v)),溶解在乙酸乙酯(1ml)中,然后用氯化氢气体饱和。过滤所得的沉淀得到白色固体的标题化合物(16.3mg,58.6%)。
1H-NMR(CDCl3)δ8.32(d,1H),7.38(m,1H),7.15(d,2H),7.03(d,2H),5.29(m,2H),4.35(m,2H),3.40(m,2H),3.16(s,3H),2.53(s,3H),2.48(s,3H),1.41(s,9H)
实施例245~253
根据实施例244中的相同步骤,使用制备3制备的(2,3-二甲基-1H-吡咯并[3,2-b]吡啶-7-基)-(4-氟苄基)氨基甲酸叔丁酯,和2-溴乙基甲醚、(溴甲基)环丙烷、碘代乙烷、苄基溴、3-氟苄基氯、3-甲氧基苄基氯、4-甲氧基苄基氯、3-甲基苄基氯或者4-甲基苄基氯,制备实施例245~253中的标题化合物。
实施例245.[2,3-二甲基-1-(2-甲氧基乙基)-1H-吡咯并[3,2-b]吡啶-7-基]-(4-氟苄基)氨基甲酸叔丁酯盐酸盐
1H-NMR(CDCl3)δ8.32(d,1H),7.38(m,1H),7.15(d,2H),7.03(d,2H),5.29(m,2H),4.35(m,2H),3.40(m,2H),3.16(s,3H),2.53(s,3H),2.48(s,3H),1.41(s,9H);
(收率:75.8%)
实施例246.(2,3-二甲基-1-环丙基甲基-1H-吡咯并[3,2-b]吡啶-7-基)-(4-氟苄基)氨基甲酸叔丁酯盐酸盐
1H-NMR(CDCl3)δ8.27(t,1H),7.06(m,2H),6.98(m,2H),6.68(m,1H),5.32(m,2H),4.20(m,2H),2.64(s,3H),2.55(s,3H),1.42(s,9H),0.97(m,1H),0.55(m,2H),0.28(m,2H);
(收率:63.8%)
实施例247.(2,3-二甲基-1-乙基-1H-吡咯并[3,2-b]吡啶-7-基)-(4-氟苄基)氨基甲酸叔丁酯盐酸盐
1H-NMR(CDCl3)δ8.29(m,1H),7.11(t,2H),6.99(t,2H),6.70(m,1H),5.28(m,2H),4.28(m,2H),4.17(m,2H),2.62(s,3H),2.50(s,3H),1.34(s,9H),1.18(t,3H);
(收率:58.4%)
实施例248.1-苄基-(2,3-二甲基-1H-吡咯并[3,2-b]吡啶-7-基)-(4-氟苄基)氨基甲酸叔丁酯盐酸盐
1H-NMR(CDCl3)δ8.31(t,1H),7.30(m,2H),7.02(m,2H),6.98(m,2H),6.62(m,3H),5.45(m,4H),2.62(s,3H),2.38(s,3H),1.41(s,9H);
(收率:75.0%)
实施例249.[2,3-二甲基-1-(3-氟苄基)-1H-吡咯并[3,2-b]吡啶-7-基]-(4-氟苄基)氨基甲酸叔丁酯盐酸盐
1H-NMR(CDCl3)δ8.35(t,1H),7.00(m,3H),6.91(m,2H),6.70(m,2H),6.37(m,2H),5.48(m,4H),2.67(s,3H),2.36(s,3H),1.41(s,9H);
(收率:63.3%)
实施例250.[2,3-二甲基-1-(3-甲氧基苄基)-1H-吡咯并[3,2-b]吡啶-7-基]-(4-氟苄基)氨基甲酸叔丁酯盐酸盐
1H-NMR(CDCl3)δ8.31(t,1H),7.22(t,1H),7.02(m,2H),6.92(m,2H),6.80(d,1H),6.66(m,1H),6.17(s,2H),5.44(m,2H),4.96(br,s,2H),3.73(s,3H),2.66(s,3H),2.38(s,3H),1.34(s,9H);
(收率:58.8%)
实施例251.[2,3-二甲基-1-(4-甲氧基苄基)-1H-吡咯并[3,2-b]吡啶-7-基]-(4-氟苄基)氨基甲酸叔丁酯盐酸盐
1H-NMR(CDCl3)δ8.31(t,1H),7.03(m,2H),6.99(m,2H),6.81(m,3H),6.55(d,2H),5.43(m,4H),3.79(s,3H),2.55(s,3H),2.40(s,3H),1.30(s,9H);
(收率:75.0%)
实施例252.[2,3-二甲基-1-(3-甲基苄基)-1H-吡咯并[3,2-b]吡啶-7-基]-(4-氟苄基)氨基甲酸叔丁酯盐酸盐
1H-NMR(CDCl3)δ8.31(t,1H),7.18(m,1H),7.15(m,1H),7.09(m,2H),6.96(m,2H),6.64(m,1H),6.44(s,1H),6.37(m,1H),5.50(m,4H),2.63(s,3H),2.41(s,3H),2.24(s,3H),1.31(s,9H);
(收率:63.8%)
实施例253.[2,3-二甲基-1-(4-甲基苄基)-1H-吡咯并[3,2-b]吡啶-7-基]-(4-氟苄基)氨基甲酸叔丁酯盐酸盐
1H-NMR(CDCl3)δ8.30(t,1H),7.09(d,2H),7.02(m,3H),6.91(t,2H),6.64(d,2H),5.45(m,4H),2.56(s,3H),2.41(s,3H),2.34(s,3H),1.16(s,9H);
(收率:61.0%)
实施例254.N-(1-烯丙基-2,3-二甲基-1H-吡咯并[3,2-b]吡啶-7-基)-4-氟苄基胺盐酸盐
步骤1:(1-烯丙基-2,3-二甲基-1H-吡咯并[3,2-b]吡啶-7-基)-(4-氟苄基)氨基甲酸叔丁酯盐酸盐
除了使用制备3中制备的(2,3-二甲基-1H-吡咯并[3,2-b]吡啶-7-基)-(4-氟苄基)氨基甲酸叔丁酯和烯丙基溴以外,根据实施例244中的相同步骤,得到白色固体的标题化合物(收率:88.6%)。该产物不需要进一步纯化而用于后续的反应。
步骤2:N-(1-烯丙基-2,3-二甲基-1H-吡咯并[3,2-b]吡啶-7-基)-4-氟苄基胺盐酸盐
将步骤1中制备的(1-烯丙基-2,3-二甲基-1H-吡咯并[3,2-b]吡啶-7-基)-(4-氟苄基)氨基甲酸叔丁酯盐酸盐(101.3mg)在乙酸乙酯(10ml)中的溶液用氯化氢气体饱和,然后室温下搅拌1小时。将所得沉淀过滤,然后干燥,得到白色固体的标题化合物(35.3mg,44.1%)。
1H-NMR(CDCl3)δ7.91(t,1H),7.11(m,2H),6.48(s,1H),6.48(m,1H),6.35(m,1H),6.11(m,1H),5.26(d,1H),5.05(s,2H),4.71(d,1H),4.56(d,2H),2.42(s,3H),2.28(s,3H)
实施例255~263
根据实施例244和/或者实施例254中步骤2的相同步骤,使用制备3制备的(2,3-二甲基-1H-吡咯并[3,2-b]吡啶-7-基)-(4-氟苄基)氨基甲酸叔丁酯,和(溴甲基)环丙烷、2-溴乙基甲醚、3-甲氧基苄基溴、4-甲氧基苄基溴、碘代乙烷、1-碘代丙烷、苄基溴、3-氟苄基氯或者4-甲基苄基氯,制备实施例255~263中的标题化合物。
实施例255.N-(1-环丙基甲基-2,3-二甲基-1H-吡咯并[3,2-b]吡啶-7-基)-4-氟苄基胺盐酸盐
1H-NMR(CDCl3)δ7.87(t,1H),7.38(m,2H),7.08(t,2H),6.59(s,1H),6.27(d,1H),4.63(d,2H),4.39(d,2H),2.37(s,3H),2.32(s,3H),1.04(m,1H),0.54(m,2H),0.24(m,2H);
(收率:53.8%)
实施例256.N-[1-(2-甲氧基乙基)-2,3-二甲基-1H-吡咯并[3,2-b]吡啶-7-基]-4-氟苄基胺盐酸盐
1H-NMR(CDCl3)δ8.04(t,1H),7.71(t,1H),7.34(m,2H),7.10(t,2H),6.40(d,1H),4.49(d,2H),4.39(t,2H),3.75(t,2H),3.19(s,3H),2.47(s,3H),2.35(s,3H);
(收率:48.3%)
实施例257.N-[1-(3-甲氧基苄基)-2,3-二甲基-1H-吡咯并[3,2-b]吡啶-7-基]-4-氟苄基胺盐酸盐
1H-NMR(CDCl3)δ8.02(s,1H),7.20(t,1H),6.95(t,2H),6.85(m,2H),6.37(d,2H),6.25(s,1H),5.60(s,1H),5.49(s,2H),4.27(s,2H),3.65(s,3H),2.53(s,3H),2.40(s,3H);
(收率:55.1%)
实施例258.N-[1-(4-甲氧基苄基)-2,3-二甲基-1H-吡咯并[3,2-b]吡啶-7-基]-4-氟苄基胺盐酸盐
1H-NMR(CDCl3)δ7.94(s,1H),6.93(t,2H),6.85(m,2H),6.76(s,3H),6.18(s,1H),5.89(s,1H),5.51(s,2H),4.29(s,2H),3.78(s,3H),2.51(s,3H),2.40(s,3H);
(收率:44.2%)
实施例259.N-(1-乙基-2,3-二甲基-1H-吡咯并[3,2-b]吡啶-7-基)-4-氟苄基胺盐酸盐
1H-NMR(CDCl3)δ7.77(s,1H),7.34(s,2H),7.03(t,2H),6.87(s,1H),6.19(s,1H),4.66(s,2H),4.52(s,2H),2.35(s,3H),2.34(s,3H),1.28(t,3H);
(收率:65.3%)
实施例260.N-(2,3-二甲基-1-丙基-1H-吡咯并[3,2-b]吡啶-7-基)-4-氟苄基胺盐酸盐
1H-NMR(CDCl3)δ7.85(t,1H),7.36(m,2H),7.07(t,2H),6.36(s,1H),6.21(d,1H),4.60(d,2H),4.30(t,2H),2.38(s,3H),2.33(s,3H),1.72(m,2H),0.84(t,3H);
(收率:70.8%)
实施例261.N-(1-苄基-2,3-二甲基-1H-吡咯并[3,2-b]吡啶-7-基)-4-氟苄基胺盐酸盐
1H-NMR(CDCl3)δ8.00(t,1H),7.33(m,2H),6.93(t,2H),6.81(m,4H),6.23(d,1H),5.60(m,1H),5.53(s,2H),4.26(d,2H),2.54(s,3H),2.40(s,3H);
(收率:89.3%)
实施例262.N-(1-(3-氟苄基)-2,3-二甲基-1H-吡咯并[3,2-b]吡啶-7-基)-4-氟苄基胺盐酸盐
1H-NMR(CDCl3)δ7.88(s,1H),7.21(m,1H),6.99(t,1H),6.91(t,2H),6.83(m,1H),6.65(d,1H),6.50(d,1H),6.23(s,1H),6.14(s,1H),5.70(s,2H),4.35(s,2H),2.49(s,3H),2.39(s,3H);
(收率:77.5%)
实施例263.N-[1-(4-甲基苄基)-2,3-二甲基-1H-吡咯并[3,2-b]吡啶-7-基]-4-氟苄基胺盐酸盐
1H-NMR(CDCl3)δ7.97(s,1H),7.07(d,2H),6.92(t,2H),6.81(d,2H),6.73(d,2H),6.20(s,1H),5.75(s,1H),5.51(s,2H),4.27(s,2H),2.53(s,3H),2.40(s,3H),2.34(s,3H);
(收率:69.3%)
实施例264.1-苄基-7-(4-氟苄氧基)-2,3,5,6-四甲基-1H-吡咯并[3,2-b]吡啶盐酸盐
步骤1:2,3-二甲基-4-硝基吡啶-N-氧化物
将30%过氧化氢(100ml)加入到2,3-二甲基吡啶(2g)在50ml乙酸中的溶液中,90℃下搅拌12h,然后减压浓缩该反应混合物。将所得的剩余物加入到浓硫酸和硝酸(7∶3)的混合物(30ml)中。搅拌下回流该反应混合物3.5h,冷却到室温,然后加入到冰水中。用氢氧化钠溶液碱化该反应混合物,用二氯甲烷萃取,无水硫酸钠干燥,然后减压浓缩。用乙醇重结晶所得的剩余物得到2.4g浅黄色固体的标题化合物。
步骤2:2,3-二甲基-4-硝基吡啶
将步骤1制备的2,3-二甲基-4-硝基吡啶-N-氧化物(75.6g、0.45mol)溶解在300ml二氯甲烷中。-15℃~-20℃下经30min将三氯化磷(44ml)在二氯甲烷(60ml)中的溶液缓慢加入到该溶液中。在相同的温度下,搅拌该反应混合物15min,然后在室温下进一步搅拌15min。将反应混合物冷却到-78℃。将50ml水加入到反应混合物中,用氢氧化钠溶液中和,然后用二氯甲烷萃取。用无水硫酸镁干燥分离的有机层并减压浓缩得到浅黄色固体的标题化合物(65g、95%)。
1H-NMR(CDCl3)δ2.43(s,3H),2.66(s,3H),7.43(d,1H),8.55(d,1H)
步骤3:2,3-二甲基-4-羟基-5-硝基吡啶
将无水乙酸钾(49g、0.5mol)加入到步骤2中制备的2,3-二甲基-4-硝基吡啶(45.6g、0.3mol)在300ml乙酸酐中的溶液中,然后搅拌下回流16h。将该反应混合物冷却到室温,然后向其中加入无水醚。搅拌该反应混合物1h,用硅藻土过滤,然后减压浓缩得到4-乙酰氧基-2,3-二甲基吡啶(45g、91%)。将所得的剩余物加入到250ml水中,搅拌下回流4h,然后室温下过夜。减压浓缩该反应混合物得到32.6g液体形式的2,3-二甲基-4-羟基吡啶。将该液体产物溶解在120ml浓硫酸中并加热到60℃。经45min将90%硝酸(40ml)和硫酸(30ml)的混合物缓慢加入到该反应混合物中,并维持温度在60~65℃。在65℃加热该反应混合物2h然后在75℃加热30min。将反应混合物冷却至室温,然后加入到冰水中。用氢氧化铵将所得的溶液调节至pH5~6,得到浅黄色固体。将所得的固体过滤,用冷水洗涤,然后80~90℃下干燥得到34.5g标题化合物。
1H-NMR(CDCl3)δ2.54(s,3H),2.87(s,3H),9.35(s,1H)
步骤4:2,3-二甲基-4-氯-5-硝基吡啶
将步骤3制备的2,3-二甲基-4-羟基-5-硝基吡啶(26.8g、0.16mol)加入到85ml磷酰氯中。将五氯化磷(33.3g、0.16mol)加入到该反应混合物中,然后搅拌下回流2h。将反应混合物在室温下过夜,加入到冰水中,用28%氢氧化铵调节至pH5,然后用醚萃取。用无水硫酸镁干燥分离的有机层并浓缩得到28.3g标题化合物。
1H-NMR(CDCl3)δ2.47(s,3H),2.66(s,3H),8.77(s,1H)
步骤5:4-(4-氟苄氧基)-2,3-二甲基-5-硝基吡啶
除了使用步骤4中制备的2,3-二甲基-4-氯-5-硝基吡啶(1.0g、5.36mmol)以外,根据制备2中的相同步骤,得到浅黄色油的标题化合物(收率:85.4%)。
1H-NMR(CDCl3)δ8.80(s,1H),7.43(m,2H),7.04(m,2H),4.99(s,2H),2.56(s,3H),2.19(s,3H)
步骤6:7-(4-氟苄氧基)-2,3,5,6-四甲基-1H-吡咯并[3,2-b]吡啶
除了使用步骤5中制备的4-(4-氟苄氧基)-2,3-二甲基-5-硝基吡啶以外,根据实施例33中步骤1的相同步骤,得到白色固体的标题化合物(收率:23.4%)。
1H-NMR(CDCl3)δ7.31(m,2H),6.67(m,2H),5.48(s,2H),4.78(s,2H),3.04(s,3H),2.70(s,3H),2.33(s,3H),2.25(s,3H)
步骤7:1-苄基-7-(4-氟苄氧基)-2,3,5,6-四甲基-1H-吡咯并[3,2-b]吡啶盐酸盐
除了使用步骤6中制备的7-(4-氟苄氧基)-2,3,5,6-四甲基-1H-吡咯并[3,2-b]吡啶以外,根据实施例33中步骤2的相同步骤,得到白色固体的标题化合物(收率:85.1%)。
1H-NMR(CDCl3)δ7.27(m,3H),7.09(m,4H),6.67(m,2H),5.499(s,2H),4.77(s,2H),3.05(s,3H),2.69(s,3H),2.32(s,3H),2.28(s,3H)
实施例265~266
根据实施例33中步骤2的相同步骤,使用实施例264中步骤6制备的7-(4-氟苄氧基)-2,3,5,6-四甲基-1H-吡咯并[3,2-b]吡啶,和1-碘代丙烷或者2-溴乙基甲醚,制备实施例265~266中的标题化合物。
实施例265.1-丙基-7-(4-氟苄氧基)-2,3,5,6-四甲基-1H-吡咯并[3,2-b]吡啶盐酸盐
1H-NMR(CDCl3)δ7.41(m,2H),7.14(m,2H),5.07(s,2H),4.02(t,2H),3.03(s,3H),2.63(s,3H),2.38(s,3H),2.34(s,3H)(,0.18(m,2H),0.72(t,3H);
(收率:66.4%)
实施例266.7-(4-氟苄氧基)-1-(2-甲氧基乙基)-2,3,5,6-四甲基-1H-吡咯并[3,2-b]吡啶盐酸盐
1H-NMR(CDCl3)δ7.39(m,2H),7.15(m,2H),5.11(s,2H),4.29(s,2H),3.47(s,2H),3.16(s.3H),3.04(s,3H),2.64(s,3H),2.41(s,3H),2.36(s,3H);
(收率:77.4%)
实施例267.N-(1-烯丙基-2,3,5,6-四甲基-1H-吡咯并[3,2-b]吡啶-7-基)-4-氟苄基胺盐酸盐
步骤1:(4-氟苄基)-(2,3,5,6-四甲基-1H-吡咯并[3,2-b]吡啶-7-基)-氨基甲酸叔丁酯
除了使用实施例264中步骤4制备的2,3-二甲基-4-氯-5-硝基吡啶和4-氟苄基胺以外,根据制备3中的相同步骤,得到白色固体的标题化合物(收率:12.4%)。
1H-NMR(CDCl3)δ8.31(d,1H),8.12(s,1H),7.40(m,1H),7.18(d,2H),7.09(d,2H),3.16(s,3H),2.53(s,3H),2.48(s,3H),1.41(s,9H)
步骤2:N-(1-烯丙基-2,3,5,6-四甲基-1H-吡咯并[3,2-b]吡啶-7-基)-4-氟苄基胺盐酸盐
除了使用步骤1制备的(4-氟苄基)-(2,3,5,6-四甲基-1H-吡咯并[3,2-b]吡啶-7-基)氨基甲酸叔丁酯和烯丙基溴以外,根据实施例244和/或者实施例254中步骤2的相同步骤,得到白色固体的标题化合物(收率:58.5%)。
1H-NMR(CDCl3)δ7.06(t,2H),6.96(t,2H),5.77(m,1H),5.12(m,2H),4.704(m,3H),4.31(m,1H),2.95(s,3H),2.68(s,3H),2.40(s,3H),1.67(s,3H)
实施例268~271
根据实施例244和/或者实施例254中步骤2的相同步骤,使用实施例267中步骤1制备的(4-氟苄基)-(2,3,5,6-四甲基-1H-吡咯并[3,2-b]吡啶-7-基)-氨基甲酸叔丁酯,和苄基溴、(溴甲基)环丙烷、1-碘代丙烷或者2-溴乙基甲醚,制备实施例268~271中的标题化合物。
实施例268.N-(1-苄基-2,3,5,6-四甲基-1H-吡咯并[3,2-b]吡啶-7-基)-4-氟苄基胺盐酸盐
1H-NMR(CDCl3)δ7.56(m,4H),7.24(m,2H),7.08(t,1H),6.94(t,1H),6.76(d,1H),5.52(d,1H),5.24(d,1H),5.02(d,1H),4.18(d,1H),2.90(s,3H),2.62(s,3H),2.30(s,3H),1.70(s,3H);
(收率:75.6%)
实施例269.N-(1-环丙基甲基-2,3,5,6-四甲基-1H-吡咯并[3,2-b]吡啶-7-基)-4-氟苄基胺盐酸盐
1H-NMR(CDCl3)δ7.01(t,2H),6.94(t,2H),5.22(d,1H),4.19(m,2H),3.86(m,2H),2.88(s,3H),2.69(s,3H),2.49(s,3H),1.65(s,3H),0.97(m,1H),0.53(m,1H),0.44(m,1H),0.25(brs,1H);
(收率:45.9%)
实施例270.N-(1-丙基-2,3,5,6-四甲基-1H-吡咯并[3,2-b]吡啶-7-基)-4-氟苄基胺盐酸盐
1H-NMR(CDCl3)δ7.03(t,2H),6.95(t,2H),5.19(d,1H),4.27(d,1H),4.03(m,1H),3.90(m,1H),2.95(s,3H),2.67(s,3H),2.45(s,3H),1.67(s,3H),1.55(m,2H),0.88(t,3H),
(收率:74.1%)
实施例271.N-(1-(2-甲氧基乙基)-2,3,5,6-四甲基-1H-吡咯并[3,2-b]吡啶-7-基)-4-氟苄基胺盐酸盐
1H-NMR(CDCl3)δ7.03(d,2H),6.94(t,2H),5.20(d,1H),4.26(d,2H),4.21(d,1H),3.47(d,2H),3.15(s,3H),2.92(s,3H),2.66(s,3H),2.47(s,3H),1.63(s,3H);
(收率:65.3%)
实施例272.6-溴-7-(4-氟苄氧基)-2,3-二甲基-1H-吡咯并[3,2-b]吡啶
步骤1:3-溴-5-硝基吡啶-4-醇
将4-羟基-3-硝基吡啶(40g、0.285mol)加入到200ml水中,然后在室温下缓慢向其中加入溴(18.44ml、0.36mol)。50℃加热下搅拌反应混合物2h,然后冷却到室温。将所得的沉淀过滤,用水洗涤,然后干燥得到浅黄色固体的标题化合物(49.8g、87.8%)。该产物不需要进一步纯化而用于后续的步骤。
步骤2:3-溴-4-氯-5-硝基吡啶
0℃下,缓慢将步骤1制备的3-溴-5-硝基吡啶-4-醇(49.8g、0.227mol)加入到200ml三氯化磷中。在相同的温度下,缓慢向其中加入N,N-二乙基苯胺(34.65ml、0.227mol)。搅拌下回流该反应混合物2h,然后减压浓缩。将所得的剩余物加入到冰水中,然后用300ml醚萃取。用无水硫酸镁干燥分离的有机层并减压浓缩得到32.4g浅黄色固体的标题化合物。该产物不需要进一步纯化而用于后续的步骤。
步骤3:3-溴-4-(4-氟苄氧基)-5-硝基吡啶
除了使用步骤2制备的3-溴-4-氯-5-硝基吡啶(1.0g、4.21mmol)以外,根据制备2中的相同步骤,得到白色固体的标题化合物(收率:78.3%)。
1H-NMR(CDCl3)δ8.75(s,1H),8.26(s,1H),7.43(m,2H),7.04(m,2H),5.04(s,2H),
步骤4:6-溴-7-(4-氟苄氧基)-2,3-二甲基-1H-吡咯并[3,2-b]吡啶
除了使用步骤3制备的3-溴-4-(4-氟苄氧基)-5-硝基吡啶(1.28g、3.91mmol)以外,根据实施例33中步骤1的相同步骤,得到白色固体的标题化合物(收率:18.3%)。
1H-NMR(CDCl3)δ8.43(s,1H),7.71(s,1H),7.40(m,2H),7.06(m,2H),5.22(s,2H),2.30(s,3H),2.24(s,3H)
实施例273~275
根据实施例33中步骤2的相同步骤,使用实施例272中步骤4制备的6-溴-7-(4-氟苄氧基)-2,3-二甲基-1H-吡咯并[3,2-b]吡啶,和苄基溴、1-碘代丙烷或者2-溴乙基甲醚,制备实施例273~275中的标题化合物。
实施例273.1-苄基-6-溴-7-(4-氟苄氧基)-2,3-二甲基-1H-吡咯并[3,2-b]吡啶盐酸盐
1H-NMR(CDCl3)δ8.66(s,1H),7.31(m,3H),7.12(m,2H),7.01(t,2H),6.65(brs,2H),5.50(s,2H),5.11(s,2H),2.61(s,3H),2.11(s,3H);
(收率:45.3%)
实施例274.6-溴-7-(4-氟苄氧基)-1-丙基-2,3-二甲基-1H-吡咯并[3,2-b]吡啶盐酸盐
1H-NMR(CDCl3)δ8.60(s,1H),7.45(m,2H),7.14(t,2H),5.44(s,2H),4.01(t,2H),2.55(s,3H),2.41(s,3H),1.59(m,2H),0.70(t,3H);
(收率:65.3%)
实施例275.6-溴-7-(4-氟苄氧基)-1-(2-甲氧基乙基)-2,3-二甲基-1H-吡咯并[3,2-b]吡啶盐酸盐
1H-NMR(CDCl3)δ8.60(s,1H),7.44(m,2H),7.14(t,2H),5.47(s,2H),4.28(t,2H),3.44(t,2H),3.17(s,3H),2.55(s,3H),2.40(s,3H);
(收率:45.8%)
实施例276.1-苄基-7-(4-氟苄氧基)-2,3-二甲基-1H-吡咯并[3,2-b]吡啶-6-腈
用饱和碳酸钠溶液中和实施例273中制备的1-苄基-6-溴-7-(4-氟苄氧基)-2,3-二甲基-1H-吡咯并[3,2-b]吡啶盐酸盐,得到1-苄基-6-溴-7-(4-氟苄氧基)-2,3-二甲基-1H-吡咯并[3,2-b]吡啶(1.4g、3.18mmol)。1-苄基-6-溴-7-(4-氟苄氧基)-2,3-二甲基-1H-吡咯并[3,2-b]吡啶(1.4g、3.18mmol)和氰化亚铜(700mg、7.52mmol)在无水N,N-二甲基甲酰胺(30ml)中的溶液回流48h,然后冷却至室温。将乙酸乙酯加入到该反应混合物中,然后过滤除去不溶解的固体。将水加入到所得的溶液中,然后用乙酸乙酯萃取。用无水硫酸镁干燥所得的有机层并减压浓缩。用硅胶柱色谱(乙酸乙酯/甲醇=10/1、v/v)纯化所得的剩余物得到278mg白色固体的标题化合物。
1H-NMR(CDCl3)δ8.54(s,1H),7.28(m,3H),7.11(m,2H),7.05(t,2H),6.45(s,2H),5.43(s,2H),5.21(s,2H),2.53(s,3H),2.12(s,3H)
实施例277.1-苄基-7-(4-氟苄氧基)-2,3-二甲基-1H-吡咯并[3,2-b]吡啶-6-酰胺
用乙醇(8ml)和水(2ml)的混合物稀释实施例276中制备的1-苄基-7-(4-氟苄氧基)-2,3-二甲基-1H-吡咯并[3,2-b]吡啶-6-腈(500mg、1.30mmol)。将氢氧化钾(650mg、13.0mmol)加入到该反应混合物中,然后回流2h。将水加入到反应混合物中,然后用乙酸乙酯萃取。用无水硫酸镁干燥分离的有机层并减压浓缩。用硅胶柱色谱(乙酸乙酯/甲醇=10/1、(v/v))纯化所得的剩余物得到350mg白色固体的标题化合物。
1H-NMR(CDCl3)δ8.32(s,1H),7.33(m,3H),7.21(m,2H),7.12(t,2H),6.35(s,2H),5.43(s,2H),5.21(s,2H),4.01(brs,2H),2.41(s,3H),2.23(s,3H)
实施例278.7-(4-氟苯基)-1-(2-甲氧基乙基)-2,3-二甲基-1H-吡咯并[3,2-b]吡啶盐酸盐
步骤1:4-(4-氟苯基)-3-硝基吡啶
将制备1中步骤1制备的4-氯-3-硝基吡啶(3g、18.9mmol)、4-氟苯基硼酸(2.9g、20.79mmol)、四(三苯膦)钯(0)(2.1g、1.89mmol)和碳酸钾(7.8g、56.7mmol)混悬在120ml的1,4-二噁烷中。搅拌下回流所得的悬液24h,用硅藻土过滤,然后减压浓缩。用硅胶柱色谱纯化所得的剩余物得到1.76g浅黄色固体的标题化合物。
1H-NMR(CDCl3)δ9.09(s,1H),8.82(d,1H),7.40(d,1H),7.34(m,2H),7.20(m,2H)
步骤2:7-(4-氟苯基)-2,3-二甲基-1H-吡咯并[3,2-b]吡啶
除了使用步骤1制备的4-(4-氟苯基)-3-硝基吡啶以外,根据实施例33中步骤1的相同步骤,得到白色固体的标题化合物(收率:14.8%)。该产物不需要进一步纯化而用于后续的步骤。
步骤3:7-(4-氟苯基)-1-(2-甲氧基乙基)-2,3-二甲基-1H-吡咯并[3,2-b]吡啶盐酸盐
除了使用步骤2制备的7-(4-氟苯基)-2,3-二甲基-1H-吡咯并[3,2-b]吡啶和2-溴乙基甲醚以外,根据实施例33中步骤2的相同步骤,得到白色固体的标题化合物(收率:82.3%)。
1H-NMR(CDCl3)δ8.43(t,1H),7.44(m,2H),7.28(m,2H),7.13(d,1H),4.00(t,2H),3.08(t,2H),3.05(s,3H),2.64(s,3H),2.50(s,3H)
实施例279~287
根据实施例33中步骤2的相同步骤,使用实施例278中步骤2制备的7-(4-氟苯基)-2,3-二甲基-1H-吡咯并[3,2-b]吡啶,和(溴甲基)环丙烷、3-氟苄基氯、碘代乙烷、1-碘代丙烷、3-甲氧基苄基氯、4-甲基苄基氯、4-氟苄基氯、烯丙基溴或者3-氯苄基溴,制备实施例279~287中的标题化合物。
实施例279.7-(4-氟苯基)-1-环丙基甲基-2,3-二甲基-1H-吡咯并[3,2-b]吡啶盐酸盐
1H-NMR(CDCl3)δ8.45(t,1H),7.45(m,2H),7.28(m,2H),7.15(d,1H),3.76(d,2H),2.67(s,3H),2.52(s,3H),0.62(m,1H),0.30(m,2H),0.11(m,2H);
(收率:66.0%)
实施例280.7-(4-氟苯基)-1-(3-氟苄基)-2,3-二甲基-1H-吡咯并[3,2-b]吡啶盐酸盐
1H-NMR(CDCl3)δ8.48(t,1H),7.17(m,1H),7.11(m,3H),7.03(t,2H),6.95(t,1H),6.11(t,2H),5.03(s,2H),2.73(s,3H),2.42(s,3H);
(收率:78.0%)
实施例281.1-乙基-7-(4-氟苯基)-2,3-二甲基-1H-吡咯并[3,2-b]吡啶盐酸盐
1H-NMR(CDCl3)δ8.44(t,1H),7.46(m,2H),7.28(m,2H),7.13(d,1H),3.83(q,2H),2.65(s,3H),2.48(s,3H),0.92(t,3H);
(收率:65.5%)
实施例282.7-(4-氟苯基)-1-丙基-2,3-二甲基-1H-吡咯并[3,2-b]吡啶盐酸盐
1H-NMR(CDCl3)δ8.44(t,1H),7.45(m,2H),7.29(m,2H),7.13(d,1H),3.75(t,2H),2.65(s,3H),2.50(t,3H),2.47(s,3H),0.85(m,2H);
(收率:66.2%)
实施例283.7-(4-氟苯基)-1-(3-甲氧基苄基)-2,3-二甲基-1H-吡咯并[3,2-b]吡啶盐酸盐
1H-NMR(CDCl3)δ8.46(t,1H),7.09(m,4H),7.01(t,2H),6.76(d,1H),5.91(s,2H),4.99(s,2H),3.69(s,3H),2.71(s,3H),2.41(s,3H);
(收率:70.5%)
实施例284.7-(4-氟苯基)-1-(4-甲基苄基)-2,3-二甲基-1H-吡咯并[3,2-b]吡啶盐酸盐
1H-NMR(CDCl3)δ8.46(t,1H),7.10(m,3H),7.03(m,3H),7.91(d,1H),4.98(s,2H),4.71(s,2H),2.38(s,3H),2.40(s,3H),2.29(s,3H);
(收率:63.9%)
实施例285.7-(4-氟苯基)-1-(4-氟苄基)-2,3-二甲基-1H-吡咯并[3,2-b]吡啶盐酸盐
1H-NMR(CDCl3)δ8.47(t,1H),7.12(m,3H),7.01(t,2H),6.89(t,2H),6.30(m,2H),5.01(s,2H),2.72(s,3H),2.42(s,3H);
(收率:72.5%)
实施例286.1-烯丙基-7-(4-氟苯基)-2,3-二甲基-1H-吡咯并[3,2-b]吡啶盐酸盐
1H-NMR(CDCl3)δ8.47(t,1H),7.38(m,2H),7.22(t,2H),7.13(d,1H),5.54(m,1H),5.09(d,1H),4.36(s,2H),4.32(d,1H),2.67(s,3H),2.44(s,3H);
(收率:66.5%)
实施例287.1-(3-氯苄基)-7-(4-氟苯基)-2,3-二甲基-1H-吡咯并[3,2-b]吡啶盐酸盐
1H-NMR(CDCl3)δ8.48(t,1H),7.20(d,1H),7.09(m,6H),6.35(s,1H),6.17(d,1H),5.02(s,2H),2.73(s,3H),2.43(s,3H);
(收率:78.8%)
实施例288.1-苄基-7-(4-氟苄氧基)-2,3-二甲基-1H-吡咯并[3,2-b]吡啶-6-羧酸
用乙醇(8ml)和水(2ml)的混合物稀释实施例276中制备的1-苄基-7-(4-氟苄氧基)-2,3-二甲基-1H-吡咯并[3,2-b]吡啶-6-腈(500mg、1.30mmol)。将氢氧化钾(650mg、13.0mmol)加入到该溶液中,然后回流24h。将水加入到反应混合物中,然后用乙酸乙酯萃取。用无水硫酸镁干燥分离的有机层并减压浓缩。用硅胶柱色谱(乙酸乙酯/甲醇=5/1、(v/v))纯化所得的剩余物得到280mg白色固体的标题化合物。
1H-NMR(DMSO-d6)δ10.7(brs,1H),8.33(s,1H),7.35(m,3H),7.25(m,2H),7.11(t,2H),6.45(s,2H),5.33(s,2H),5.11(s,2H),2.42(s,3H),2.28(s,3H)
实施例289.1-苄基-7-(4-氟苄氧基)-2,3-二甲基-N-环丙基-1H-吡咯并[3,2-b]吡啶-6-酰胺
将实施例288中制备的1-苄基-7-(4-氟苄氧基)-2,3-二甲基-1H-吡咯并[3,2-b]吡啶-6-羧酸(24.16mg、0.056mmol)、1-羟基苯并***水合物(11.4mg、0.085mmol)、1-(3-二甲基氨基丙基)-3-乙基碳二亚胺盐酸盐(16.3mg、0.085mmol)、二异丙基乙胺(0.029ml、0.168mmol)和环丙胺(5.8μl、0.084mmol)溶解在二氯甲烷(1ml)中。室温下,搅拌所得的溶液2h,然后减压浓缩。用硅胶柱色谱(乙酸乙酯/甲醇=10/1、(v/v))纯化所得的剩余物得到白色固体的标题化合物(12.3mg、58%)。
1H-NMR(DMSO-d6)δ8.34(s,1H),7.36(m,3H),7.28(m,2H),7.15(t,2H),6.55(s2H),5.38(s,2H),5.11(s,2H),4.24(d,2H),2.42(s,3H),2.28(s,3H),1.38(m,1H),0.78(m,2H),0.14(m,2H)
试验实施例1.对质子泵(H+/K+-ATP酶)活性的抑制作用
1-1.胃质子泵囊泡的制
备用载玻片刮猪的含有壁细胞和消化细胞的胃底区(fundicregion)。将收集的细胞混悬在10ml的0.25M蔗糖缓冲液中并用紧密配合的特氟隆-玻璃匀浆器匀化。8,000rpm下将该匀浆离心35min,除去丸形团块。进一步在25,000rpm下将上清液离心75min。将所得的丸形团块再次混悬在蔗糖缓冲液(10ml)中,然后将悬液置于由0.25M蔗糖缓冲液和含有9%Ficoll(w/w)的分离介质组成的非连续密度梯度中。100,000xg下离心3小时15min后,收集蔗糖缓冲液和Ficoll溶液的界面处的物质,然后100,000xg下离心40min。将所得的丸形团块再次混悬在1ml的5mM Hepes/Tris缓冲液(pH6.1)中。冻干该物质并储存在-70℃,用作质子泵体外酶反应分析的酶源。
1-2.质子泵(H+/K+-ATP酶)活性的抑制作用的检测
用96-孔板评价本发明的化合物的对质子泵活性的抑制作用。在本分析中,基于含有K+和不含有K+的H+/K+-ATP酶活性的活性差计算K+特异性H+/K+-ATP酶活性。在96-孔板中,将缓冲液中的1%二甲基亚砜(DMSO)加入到阴性和阳性对照组中,将缓冲液中本发明的稀释化合物加入到试验组中。室温下,在100μl反应体积中进行所有的分析,在使用之前,将猪胃囊泡保存在冰中。反应开始时,将含有1%DMSO的10μl反应缓冲液加入到阴性和阳性对照组和每个化合物浓度的试验组中。然后在各种浓度试验化合物的存在下,预培养在5mM Pipes/Tris缓冲液(pH6.1)中的冻干囊泡。培养5min后,分别将阴性和阳性缓冲液加入到前面的反应混合物中。将作为底物的ATP加入到反应缓冲液中,37℃下,培养30min。添加比色试剂(2X孔雀石绿、1X钼酸铵、1X聚乙烯醇、2X H2O)终止酶活性,使用微孔读数板(Genios Pro、TECAN)在620nm处检测该反应中一磷酸盐(Pi)的量。将含有K+和不含有K+的Pi产量差视为K+激发的H+/K+-ATP酶活性。使用Litchfield-Wilicoxon法(J.Pharmacol.Exp.Ther(1949)96,99)从化合物的每个%抑制值计算试验化合物的IC50。结果如表1所示。
表1
实施例 | IC50(uM) | 实施例 | IC50(uM) |
1 | 0.65 | 2 | 1.06 |
3 | 0.64 | 5 | 0.32 |
6 | 0.20 | 7 | 0.22 |
8 | 0.44 | 9 | 0.33 |
10 | 0.69 | 12 | 0.97 |
13 | 0.80 | 14 | 0.53 |
15 | 3.81 | 16 | 0.19 |
23 | 2.29 | 33 | 0.65 |
34 | 0.23 | 35 | 1.09 |
37 | 1.26 | 38 | 1.31 |
39 | 0.22 | 40 | 0.19 |
50 | 2.44 | 54 | 2.30 |
55 | 0.07 | 56 | 0.57 |
57 | 0.27 | 58 | 0.23 |
61 | 0.10 | 62 | 0.11 |
64 | 0.05 | 65 | 0.06 |
66 | 0.05 | 67 | 0.05 |
68 | 0.06 | 69 | 0.06 |
70 | 0.04 | 71 | 0.06 |
72 | 0.03 | 73 | 0.04 |
74 | 1.08 | 79 | 1.59 |
80 | 2.87 | 81 | 1.25 |
82 | 4.70 | 83 | 3.82 |
84 | 0.39 | 85 | 0.17 |
86 | 0.05 | 87 | 0.16 |
88 | 0.67 | 89 | 0.34 |
90 | 0.14 | 91 | 0.46 |
92 | 0.05 | 93 | 0.05 |
94 | 0.89 | 95 | 0.52 |
96 | 0.13 | 97 | 0.09 |
98 | 0.62 | 99 | 0.63 |
100 | 2.82 | 101 | 1.01 |
113 | 1.42 | 114 | 0.07 |
115 | 0.13 | 116 | 0.15 |
117 | 0.72 | 118 | 0.46 |
119 | 0.23 | 120 | 0.12 |
121 | 0.32 | 122 | 0.02 |
123 | 0.06 | 124 | 0.05 |
125 | 0.05 | 126 | 0.05 |
127 | 0.04 | 128 | 0.05 |
129 | 0.04 | 130 | 0.04 |
131 | 0.06 | 132 | 0.05 |
133 | 0.06 | 134 | 0.54 |
135 | 0.15 | 136 | 0.05 |
137 | 0.06 | 138 | 0.46 |
139 | 0.02 | 140 | 0.08 |
141 | 0.09 | 144 | 0.24 |
145 | 0.53 | 146 | 3.15 |
147 | 3.45 | 153 | 1.03 |
154 | 0.24 | 155 | 0.57 |
156 | 0.61 | 157 | 0.57 |
158 | 0.32 | 159 | 0.88 |
161 | 0.58 | 162 | 1.15 |
163 | 1.01 | 164 | 3.00 |
177 | 0.29 | 178 | 0.84 |
179 | 0.57 | 180 | 0.83 |
181 | 4.71 | 182 | 3.88 |
183 | 1.21 | 184 | 1.07 |
195 | 0.68 | 196 | 0.38 |
200 | 0.60 | 201 | 0.68 |
218 | 3.28 | 219 | 0.06 |
220 | 0.05 | 221 | 0.18 |
222 | 0.06 | 223 | 1.21 |
224 | 0.12 | 225 | 0.62 |
226 | 0.45 | 227 | 0.09 |
228 | 0.03 | 229 | 0.07 |
254 | 0.21 | 255 | 0.55 |
256 | 2.08 | 260 | 1.21 |
261 | 2.06 | 263 | 1.45 |
264 | 3.07 | 268 | 1.25 |
如表1所示,本发明的化合物对胃H+/K+-ATP酶具有极好的抑制作用。
试验实施例2.对幽门结扎大鼠的基础胃酸分泌的抑制作用
根据Shay’s大鼠模型进行本发明的化合物对基础胃酸分泌的抑制作用(Shay,H.,et al.,1945,gastroenterology,5,43-61)。将雄性Sprague Dawley(SD)大鼠(200±10g体重)分成3组(n=5),自由饮水下,禁食24h。对照组单独口服施用0.5%甲基纤维素,其它组在幽门结扎前1h,口服施用1、3和10mg/kg/5ml剂量的混悬在0.5%甲基纤维素溶液中的试验化合物。
醚麻醉下,切开大鼠腹部,然后结扎幽门。结扎后5h,处死动物,收集胃内容物。1,000xg下将收集的内容物离心10min得到胃液。通过0.01N NaOH体积(ueq/ml)自动滴定胃液到pH7.0,检测酸的总产量,使用Litchfield-Wilicoxon法计算试验化合物的ED50。通过下述公式计算%抑制活性,结果如表2所示。
试验化合物的%抑制活性=(对照组的酸的总产量-试验化合物处理组的酸的总产量)/对照组的酸的总产量×100
表2.
实施例 | ED50(mg/kg) |
50 | 2.4 |
54 | 2.3 |
55 | 1.3 |
61 | 3.0 |
62 | 1.6 |
72 | 2.0 |
73 | 2.5 |
86 | 1.1 |
97 | 2.0 |
139 | 1.6 |
如表2所示,本发明的化合物对幽门结扎大鼠具有有效的抗基础胃酸分泌的抑制活性。
试验实施例3.对猪胃H+/K+-ATP酶的可逆性抑制
3-1.胃囊泡的制备
使用Sacconmani等人的方法(Saccomani G,Stewart HB,ShqwD,Lewin M and Sachs G,Characterization of gastric mucosalmembranes.IX.Fraction and purification of K-ATPase-containingvesicles by zonal centrifugation and free-flow electrophoresistechinque.Biochem.Biophy.Acta.(BBA)-Biomembranes 465,311-330,1977.)从猪基底粘膜制备胃囊泡。冻干该物质并在-70℃中储存。使用牛血清白蛋白作为标准物,通过Bradford法测定胃囊泡的蛋白含量(Bradford MM, A rapid and sensitive method for the quantitation ofmicrogram quantities of protein utilizing the p
3-2.猪胃H+/K+-ATP酶的可逆性抑制的测定
在试验化合物具有50%质子泵抑制的浓度下,使用一步比色测定法,通过ATP释放的无机磷酸盐检测猪微粒体(冻干囊泡)的H+/K+-ATP酶活性(Chan KM,Delfert D,and Junger KD,A directcolorimetric assay for Ca2+-stimulated ATPase activity.Anal Biochem,157,375-380,1986)。根据Washout法考察试验化合物对H+/K+-ATP酶的作用模式(Beil W,Staar U,and Sewing KF,Substitutedthieno[3,4-d]imidazoles,a novel group of H+/K+-ATPase inhibitors.Differentiation of their inhibition characteristics from those ofomeprazole.Eur.J.Pharmacol,187,455-67,1990)。
在试验化合物(实施例50、64和94的化合物)以具有50%质子泵抑制的浓度的存在下,预培养在5mM Pipes/Tris缓冲液溶液中的冻干囊泡。在前述的反应缓冲液中添加2mM MgCl2、50mM KCl、5μM凡林霉素和0.5mM ATP,然后在37℃下培养30min。使用比色测定法检测H+/K+-ATP酶活性,然后在100,000xg下,将试验样品离心1h。囊泡以丸形团块形式存在于试验样品中。将其上清液用不含有试验化合物的相同缓冲液代替。室温下,将试验样品预培养5min,然后在37℃下进一步培养30min。同样使用比色测定法检测H+/K+-ATP酶活性。分析清洗前和清洗后试验样品中的H+/K+-ATP酶活性,与未处理组的那些进行对比。
结果,实施例50、64和94的化合物在清洗前抑制H+/K+-ATP酶活性的50%,在清洗后不抑制H+/K+-ATP酶活性;清洗后,实施例50、64和94的化合物的胃H+/K+-ATP酶活性完全恢复到未处理组的水平。这些结果证明通式(I)的化合物显示可逆的胃H+/K+-ATP酶抑制作用。
Claims (5)
1.通式(I)的化合物或者其药学可接受的盐:
其中:
R1是氢;任选用一个或者多个选自C1-C5烷氧基、羟基、C3-C7环烷基、乙酰氧基、C2-C6烯氧基、C1-C3烷氧羰基、任选用C1-C3烷基单或双取代的氨基、氰基、萘基、吡啶基、环氧乙烷基、噁唑烷酮基、任选用C1-C3烷基单或多取代的异噁唑基、1,3-二氧戊环基和2,3-二氢苯并[1,4]二噁烯基的取代基取代的直链或者支链C1-C6烷基;直链或者支链C2-C6烯基;直链或者支链C2-C6炔基;或者任选用一个或者多个选自卤素、C1-C3烷基、C1-C3烷氧基、氰基、C1-C3烷氧羰基和三氟-C1-C3烷基的取代基取代的苄基,
R2是直链或者支链C1-C6烷基,
R3是任选用羟基取代的直链或者支链C1-C6烷基,
R4是氢;直链或者支链C1-C6烷基;卤素;氰基;羟基羰基;氨基羰基;或者C3-C7环烷基-氨基羰基,
R5是任选用卤素或者C1-C5烷基单或多取代的1,2,3,4-四氢异喹啉基;任选用一个或者多个选自卤素、C1-C5烷基、C1-C5烷氧基和三氟-C1-C3烷基的取代基取代的苄氧基;任选用一个或者两个选自C1-C5烷氧-羰基和任选用卤素取代的苄基的取代基取代的氨基;任选用卤素单或多取代的苯基;任选用卤素单或多取代的苯氧基;吡啶基-C1-C3烷氧基;或者胡椒基氧基,和
n是1或者2。
2.权利要求1的化合物或者其药学可接受的盐,其中R1是氢;直链或者支链C1-C6烷基;用一个或者多个选自甲氧基、羟基、环丙基、环丁基、乙酰氧基、乙烯氧基、甲氧基羰基、二甲基氨基、氰基、萘基、吡啶基、环氧乙烷基、噁唑烷酮基、二甲基异噁唑基、1,3-二氧戊环基和2,3-二氢苯并[1,4]二噁烯基的取代基取代的C1-C3烷基;直链或者支链C2-C6烯基;直链或者支链C2-C6炔基;或者任选用一个或者多个选自卤素、C1-C3烷基、C1-C3烷氧基、氰基、甲氧基羰基和三氟甲基的取代基取代的苄基,
R2是甲基,
R3是甲基或者羟甲基,
R4是氢;甲基;卤素;氰基;羟基羰基;氨基羰基;或者环丙基氨基羰基,
R5是1,2,3,4-四氢异喹啉基;6-氟-1-甲基-1,2,3,4-四氢异喹啉基;用一个或者多个选自卤素、C1-C5烷基、C1-C5烷氧基和三氟甲基的取代基取代的苄氧基;用叔丁氧羰基或者氟苄基单或双取代的氨基;氟苯基;氟苯氧基;吡啶基-甲氧基;或者胡椒基氧基,和n是1或者2。
3.权利要求1的化合物或者其药学可接受的盐,其选自:
1-(4-氯苄基)-7-(1,2,3,4-四氢异喹啉-2-基)-2,3-二甲基-1H-吡咯并[3,2-b]吡啶盐酸盐;
1-(2-萘基甲基)-7-(1,2,3,4-四氢异喹啉-2-基)-2,3-二甲基-1H-吡咯并[3,2-b]吡啶盐酸盐;
1-(1,3-二氧戊环-2-基甲基)-7-(1,2,3,4-四氢异喹啉-2-基)-2,3-二甲基-1H-吡咯并[3,2-b]吡啶盐酸盐;
1-(2-甲氧基乙基)-7-(1,2,3,4-四氢异喹啉-2-基)-2,3-二甲基-1H-吡咯并[3,2-b]吡啶盐酸盐;
1-苄基-7-(1,2,3,4-四氢异喹啉-2-基)-2,3-二甲基-1H-吡咯并[3,2-b]吡啶盐酸盐;
1-烯丙基-7-(1,2,3,4-四氢异喹啉-2-基)-2,3-二甲基-1H-吡咯并[3,2-b]吡啶盐酸盐;
1-(3-甲氧基苄基)-7-(1,2,3,4-四氢异喹啉-2-基)-2,3-二甲基-1H-吡咯并[3,2-b]吡啶盐酸盐;
1-(2-氟苄基)-7-(1,2,3,4-四氢异喹啉-2-基)-2,3-二甲基-1H-吡咯并[3,2-b]吡啶盐酸盐;
1-(4-甲氧基苄基)-7-(1,2,3,4-四氢异喹啉-2-基)-2,3-二甲基-1H-吡咯并[3,2-b]吡啶盐酸盐;
1-(3-甲基苄基)-7-(1,2,3,4-四氢异喹啉-2-基)-2,3-二甲基-1H-吡咯并[3,2-b]吡啶盐酸盐;
1-乙基-7-(1,2,3,4-四氢异喹啉-2-基)-2,3-二甲基-1H-吡咯并[3,2-b]吡啶盐酸盐;
1-[2-(1,3-二氧戊环-2-基)乙基]-7-(1,2,3,4-四氢异喹啉-2-基)-2,3-二甲基-1H-吡咯并[3,2-b]吡啶盐酸盐;
1-(2,3-二氢苯并[1,4]-二噁烯-6-基甲基)-7-(1,2,3,4-四氢异喹啉-2-基)-2,3-二甲基-1H-吡咯并[3,2-b]吡啶盐酸盐;
1-(3-甲基丁烯-2-基)-7-(1,2,3,4-四氢异喹啉-2-基)-2,3-二甲基-1H-吡咯并[3,2-b]吡啶盐酸盐;
1-(3-氰基苄基)-7-(1,2,3,4-四氢异喹啉-2-基)-2,3-二甲基-1H-吡咯并[3,2-b]吡啶盐酸盐;
1-(4-氯苄基)-7-(4-氟苄氧基)-2,3-二甲基-1H-吡咯并[3,2-b]吡啶盐酸盐;
7-(4-氟苄氧基)-2,3-二甲基1-(4-甲基苄基)-1H-吡咯并[3,2-b]吡啶盐酸盐;
4-[7-(4-氟苄氧基)-2,3-二甲基-吡咯并[3,2-b]吡啶-1-基甲基]-苯甲酸甲酯盐酸盐;
7-(4-氟苄氧基)-2,3-二甲基-1-(萘-2-基甲基)-1H-吡咯并[3,2-b]吡啶盐酸盐;
7-(4-氟苄氧基)-2,3-二甲基-1-(2-乙烯氧基乙基)-1H-吡咯并[3,2-b]吡啶盐酸盐;
1-(1,3-二氧戊环-2-基甲基)-7-(4-氟苄氧基)-2,3-二甲基-1H-吡咯并[3,2-b]吡啶盐酸盐;
1-(3-氟苄基)-7-(4-氟苄氧基)-2,3-二甲基-1H-吡咯并[3,2-b]吡啶盐酸盐;
7-(4-氟苄氧基)-1-异丁基-2,3-二甲基-1H-吡咯并[3,2-b]吡啶盐酸盐;
1-苄基-7-(4-氟苄氧基)-2,3-二甲基-1H-吡咯并[3,2-b]吡啶盐酸盐;
1-环丁基甲基-7-(4-氟苄氧基)-2,3-二甲基-1H-吡咯并[3,2-b]吡啶盐酸盐;
7-(4-氟苄氧基)-2,3-二甲基-1-(3-甲基-2-丁烯-2-基)-1H-吡咯并[3,2-b]吡啶盐酸盐;
1-[2-(甲氧基羰基)乙基]-7-(4-氟苄氧基)-2,3-二甲基-1H-吡咯并[3,2-b]吡啶盐酸盐;
7-(4-氟苄氧基)-1-(4-甲氧基苄基)-2,3-二甲基-1H-吡咯并[3,2-b]吡啶盐酸盐;
7-(4-氟苄氧基)-1-(2-甲氧基乙基)-2,3-二甲基-1H-吡咯并[3,2-b]吡啶盐酸盐;
7-(4-氟苄氧基)-2,3-二甲基-1-丙基-1H-吡咯并[3,2-b]吡啶盐酸盐;
1-苄基-7-(4-氟苄氧基)-2,3-二甲基-1H-吡咯并[3,2-b]吡啶苯磺酸盐;
1-苄基-7-(4-氟苄氧基)-2,3-二甲基-1H-吡咯并[3,2-b]吡啶对甲苯磺酸盐;
1-苄基-7-(4-氟苄氧基)-2,3-二甲基-1H-吡咯并[3,2-b]吡啶硝酸盐;
1-苄基-7-(4-氟苄氧基)-2,3-二甲基-1H-吡咯并[3,2-b]吡啶硫酸盐;
1-苄基-7-(4-氟苄氧基)-2,3-二甲基-1H-吡咯并[3,2-b]吡啶马来酸盐;
1-苄基-7-(4-氟苄氧基)-2,3-二甲基-1H-吡咯并[3,2-b]吡啶磷酸盐;
1-苄基-7-(4-氟苄氧基)-2,3-二甲基-1H-吡咯并[3,2-b]吡啶丙二酸盐;
1-苄基-7-(4-氟苄氧基)-2,3-二甲基-1H-吡咯并[3,2-b]吡啶氢溴酸盐;
1-烯丙基-7-(4-氯苄氧基)-2,3-二甲基-1H-吡咯并[3,2-b]吡啶盐酸盐;
1-苄基-7-(4-氯苄氧基)-2,3-二甲基-1H-吡咯并[3,2-b]吡啶盐酸盐;
7-(4-氯苄氧基)-1-甲氧基甲基-2,3-二甲基-1H-吡咯并[3,2-b]吡啶盐酸盐;
1-(4-叔丁基苄基)-7-(4-氯苄氧基)-2,3-二甲基-1H-吡咯并[3,2-b]吡啶盐酸盐;
7-(4-氯苄氧基)-2,3-二甲基-1-(吡啶-4-基甲基)-1H-吡咯并[3,2-b]吡啶盐酸盐;
5-[7-(4-氯苄氧基)-2,3-二甲基-吡咯并[3,2-b]吡啶-1-基甲基]-噁唑烷-2-酮盐酸盐;
7-(4-氯苄氧基)-1-(2,5-二甲基苄基)-2,3-二甲基-1H-吡咯并[3,2-b]吡啶盐酸盐;
[7-(4-氯苄氧基)-2,3-二甲基-吡咯并[3,2-b]吡啶-1-基]乙酸甲酯盐酸盐;
7-(4-氯苄氧基)-2,3-二甲基-1-(3-甲基丁-2-烯基)-1H-吡咯并[3,2-b]吡啶盐酸盐;
1-(2-乙酰氧基乙基)-7-(4-氯苄氧基)-2,3-二甲基-1H-吡咯并[3,2-b]吡啶盐酸盐;
7-(4-氯苄氧基)-1-(2-甲氧基乙基)-2,3-二甲基-1H-吡咯并[3,2-b]吡啶盐酸盐;
7-(4-氯苄氧基)-1-(1,3-二氧戊环-2-基甲基)-2,3-二甲基-1H-吡咯并[3,2-b]吡啶盐酸盐;
7-(4-氯苄氧基)-1-(4-氯苄基)-2,3-二甲基-1H-吡咯并[3,2-b]吡啶盐酸盐;
7-(4-氯苄氧基)-1-(2-氟苄基)-2,3-二甲基-1H-吡咯并[3,2-b]吡啶盐酸盐;
7-(4-氯苄氧基)-1-乙基-2,3-二甲基-1H-吡咯并[3,2-b]吡啶盐酸盐;
7-(4-氯苄氧基)-1-(4-氟苄基)-2,3-二甲基-1H-吡咯并[3,2-b]吡啶盐酸盐;
7-(4-氯苄氧基)-1-(3-甲氧基苄基)-2,3-二甲基-1H-吡咯并[3,2-b]吡啶盐酸盐;
7-(4-氯苄氧基)-1-(3-氟苄基)-2,3-二甲基-1H-吡咯并[3,2-b]吡啶盐酸盐;
7-(4-氯苄氧基)-1-(4-甲氧基羰基苄基)-2,3-二甲基-1H-吡咯并[3,2-b]吡啶盐酸盐;
7-(4-氯苄氧基)-1-(3-甲基苄基)-2,3-二甲基-1H-吡咯并[3,2-b]吡啶盐酸盐;
7-(4-氯苄氧基)-1-(4-甲基苄基)-2,3-二甲基-1H-吡咯并[3,2-b]吡啶盐酸盐;
7-(4-氯苄氧基)-1-环丙基甲基-2,3-二甲基-1H-吡咯并[3,2-b]吡啶盐酸盐;
1-烯丙基-7-(苯并[1,3]间二氧杂环戊烯-5-基甲氧基)-2,3-二甲基-1H-吡咯并[3,2-b]吡啶盐酸盐;
7-(苯并[1,3]间二氧杂环戊烯-5-基甲氧基)-1-(2-甲氧基乙基)-2,3-二甲基-1H-吡咯并[3,2-b]吡啶盐酸盐;
7-(苯并[1,3]间二氧杂环戊烯-5-基甲氧基)-1-(1,3-二氧戊环-2-基甲基)-2,3-二甲基-1H-吡咯并[3,2-b]吡啶盐酸盐;
7-(苯并[1,3]间二氧杂环戊烯-5-基甲氧基)-1-(2-氟苄基)-2,3-二甲基-1H-吡咯并[3,2-b]吡啶盐酸盐;
7-(苯并[1,3]间二氧杂环戊烯-5-基甲氧基)-2,3-二甲基-1-(3-甲基苄基)-1H-吡咯并[3,2-b]吡啶盐酸盐;
7-(苯并[1,3]间二氧杂环戊烯-5-基甲氧基)-1-(4-甲基苄基)-2,3-二甲基-1H-吡咯并[3,2-b]吡啶盐酸盐;
7-(苯并[1,3]间二氧杂环戊烯-5-基甲氧基)-1-苄基-2,3-二甲基-1H-吡咯并[3,2-b]吡啶盐酸盐;
7-(苯并[1,3]间二氧杂环戊烯-5-基甲氧基)-1-(3-氟苄基)-2,3-二甲基-1H-吡咯并[3,2-b]吡啶盐酸盐;
7-(苯并[1,3]间二氧杂环戊烯-5-基甲氧基)-1-乙基-2,3-二甲基-1H-吡咯并[3,2-b]吡啶盐酸盐;
7-(苯并[1,3]间二氧杂环戊烯-5-基甲氧基)-1-(4-氟苄基)-2,3-二甲基-1H-吡咯并[3,2-b]吡啶盐酸盐;
7-(苯并[1,3]间二氧杂环戊烯-5-基甲氧基)-1-(3-甲氧基苄基)-2,3-二甲基-1H-吡咯并[3,2-b]吡啶盐酸盐;
7-(苯并[1,3]间二氧杂环戊烯-5-基甲氧基)-1-异丁基-2,3-二甲基-1H-吡咯并[3,2-b]吡啶盐酸盐;
7-(苯并[1,3]间二氧杂环戊烯-5-基甲氧基)-1-环丙基甲基-2,3-二甲基-1H-吡咯并[3,2-b]吡啶盐酸盐;
7-(4-氟苄氧基)-1-(2-甲氧基乙基)-2,3-二甲基-1H-吡咯并[3,2-b]吡啶;
7-(4-氟苄氧基)-1-(2-甲氧基乙基)-2,3-二甲基-1H-吡咯并[3,2-b]吡啶甲磺酸盐;
7-(4-氟苄氧基)-1-(2-甲氧基乙基)-2,3-二甲基-1H-吡咯并[3,2-b]吡啶苯磺酸盐;
7-(4-氟苄氧基)-1-(2-甲氧基乙基)-2,3-二甲基-1H-吡咯并[3,2-b]吡啶对甲苯磺酸盐;
7-(4-氟苄氧基)-1-(2-甲氧基乙基)-2,3-二甲基-1H-吡咯并[3,2-b]吡啶硝酸盐;
7-(4-氟苄氧基)-1-(2-甲氧基乙基)-2,3-二甲基-1H-吡咯并[3,2-b]吡啶硫酸盐;
7-(4-氟苄氧基)-1-(2-甲氧基乙基)-2,3-二甲基-1H-吡咯并[3,2-b]吡啶马来酸盐;
7-(4-氟苄氧基)-1-(2-甲氧基乙基)-2,3-二甲基-1H-吡咯并[3,2-b]吡啶磷酸盐;
7-(4-氟苄氧基)-1-(2-甲氧基乙基)-2,3-二甲基-1H-吡咯并[3,2-b]吡啶丙二酸盐;
7-(4-氟苄氧基)-1-(2-甲氧基乙基)-2,3-二甲基-1H-吡咯并[3,2-b]吡啶樟脑磺酸盐;
7-(4-氟苄氧基)-1-(2-甲氧基乙基)-2,3-二甲基-1H-吡咯并[3,2-b]吡啶草酸盐;
7-(4-氟苄氧基)-1-(2-甲氧基乙基)-2,3-二甲基-1H-吡咯并[3,2-b]吡啶氢溴酸盐;
7-(2,4-二氯苄氧基)-1-甲氧基甲基-2,3-二甲基-1H-吡咯并[3,2-b]吡啶盐酸盐;
7-(2,4-二氯苄氧基)-2,3-二甲基-1-(3-甲基丁-2-烯基)-1H-吡咯并[3,2-b]吡啶盐酸盐;
1-苄基-7-(2,4-二氯苄氧基)-2,3-二甲基-1H-吡咯并[3,2-b]吡啶盐酸盐;
7-(2,4-二氯苄氧基)-1-乙基-2,3-二甲基-1H-吡咯并[3,2-b]吡啶盐酸盐;
7-(2,4-二氯苄氧基)-1-甲氧基羰基甲基-2,3-二甲基-1H-吡咯并[3,2-b]吡啶盐酸盐;
1-环丙基甲基-7-(2,4-二氯苄氧基)-2,3-二甲基-1H-吡咯并[3,2-b]吡啶盐酸盐;
7-(2,4-二氯苄氧基)-1-(4-氟苄基)-2,3-二甲基-1H-吡咯并[3,2-b]吡啶盐酸盐;
7-(2,4-二氯苄氧基)-1-(3-甲氧基苄基)-2,3-二甲基-1H-吡咯并[3,2-b]吡啶盐酸盐;
1-苄基-2,3-二甲基-7-(3-甲基苄氧基)-1H-吡咯并[3,2-b]吡啶盐酸盐;
1-乙基-2,3-二甲基-7-(3-甲基苄氧基)-1H-吡咯并[3,2-b]吡啶盐酸盐;
1-(3-氟苄基)-2,3-二甲基-7-(3-甲基苄氧基)-1H-吡咯并[3,2-b]吡啶盐酸盐;
1-(4-氯苄基)-2,3-二甲基-7-(3-甲基苄氧基)-1H-吡咯并[3,2-b]吡啶盐酸盐;
2,3-二甲基-7-(3-甲基苄氧基)-1-丙基-1H-吡咯并[3,2-b]吡啶盐酸盐;
1-环丙基甲基-2,3-二甲基-7-(3-甲基苄氧基)-1H-吡咯并[3,2-b]吡啶盐酸盐;
1-烯丙基-2,3-二甲基-7-(3-甲基苄氧基)-1H-吡咯并[3,2-b]吡啶盐酸盐;
2,3-二甲基-1-(4-甲基苄基)-7-(3-甲基苄氧基)-1H-吡咯并[3,2-b]吡啶盐酸盐;
1-(2-甲氧基乙基)-2,3-二甲基-7-(3-甲基苄氧基)-1H-吡咯并[3,2-b]吡啶盐酸盐;
1-(4-氟苄基)-2,3-二甲基-7-(3-甲基苄氧基)-1H-吡咯并[3,2-b]吡啶盐酸盐;
1-(3-甲氧基苄基)-2,3-二甲基-7-(3-甲基苄氧基)-1H-吡咯并[3,2-b]吡啶盐酸盐;
1-环丙基甲基-7-(2-乙氧基苄氧基)-2,3-二甲基-1H-吡咯并[3,2-b]吡啶盐酸盐;
7-(2-乙氧基苄氧基)-1-(2-甲氧基乙基)-2,3-二甲基-1H-吡咯并[3,2-b]吡啶盐酸盐;
1-环丁基甲基-7-(2-乙氧基苄氧基)-2,3-二甲基-1H-吡咯并[3,2-b]吡啶盐酸盐;
1-烯丙基-7-(2-乙氧基苄氧基)-2,3-二甲基-1H-吡咯并[3,2-b]吡啶盐酸盐;
7-(2-乙氧基苄氧基)-1-(3-甲氧基苄基)-2,3-二甲基-1H-吡咯并[3,2-b]吡啶盐酸盐;
1-(3-氟苄基)-7-(2-乙氧基苄氧基)-2,3-二甲基-1H-吡咯并[3,2-b]吡啶盐酸盐;
1-环丁基甲基-7-(3,5-二氟苄氧基)-2,3-二甲基-1H-吡咯并[3,2-b]吡啶盐酸盐;
1-环丙基甲基-7-(3,5-二氟苄氧基)-2,3-二甲基-1H-吡咯并[3,2-b]吡啶盐酸盐;
7-(3,5-二氟苄氧基)-1-(2-甲氧基乙基)-2,3-二甲基-1H-吡咯并[3,2-b]吡啶盐酸盐;
7-(3,5-二氟苄氧基)-2,3-二甲基-1-丙基-1H-吡咯并[3,2-b]吡啶盐酸盐;
1-(4-氯苄基)-7-(3,5-二氟苄氧基)-2,3-二甲基-1H-吡咯并[3,2-b]吡啶盐酸盐;
7-(3,5-二氟苄氧基)-1-(4-氟苄基)-2,3-二甲基-1H-吡咯并[3,2-b]吡啶盐酸盐;
1-苄基-7-(3,5-二氟苄氧基)-2,3-二甲基-1H-吡咯并[3,2-b]吡啶盐酸盐;
7-(3,5-二氟苄氧基)-1-(4-甲基苄基)-2,3-二甲基-1H-吡咯并[3,2-b]吡啶盐酸盐;
2,3-二甲基-1-(4-甲基苄基)-7-(4-三氟甲基苄氧基)-1H-吡咯并[3,2-b]吡啶盐酸盐;
1-(3-甲氧基苄基)-2,3-二甲基-7-(4-三氟甲基苄氧基)-1H-吡咯并[3,2-b]吡啶盐酸盐;
7-(4-溴苄氧基)-2,3-二甲基-1H-吡咯并[3,2-b]吡啶;
1-苄基-7-(4-溴苄氧基)-2,3-二甲基-1H-吡咯并[3,2-b]吡啶盐酸盐;
1-烯丙基-7-(4-溴苄氧基)-2,3-二甲基-1H-吡咯并[3,2-b]吡啶盐酸盐;
7-(4-溴苄氧基)-1-(4-氟苄基)-2,3-二甲基-1H-吡咯并[3,2-b]吡啶盐酸盐;
7-(4-溴苄氧基)-1-(3-氟苄基)-2,3-二甲基-1H-吡咯并[3,2-b]吡啶盐酸盐;
7-(4-溴苄氧基)-2,3-二甲基-1-(3-甲基苄基)-1H-吡咯并[3,2-b]吡啶盐酸盐;
7-(4-溴苄氧基)-1-(4-甲基苄基)-2,3-二甲基-1H-吡咯并[3,2-b]吡啶盐酸盐;
7-(4-溴苄氧基)-1-(2-氟苄基)-2,3-二甲基-1H-吡咯并[3,2-b]吡啶盐酸盐;
7-(4-溴苄氧基)-1-(3-氯苄基)-2,3-二甲基-1H-吡咯并[3,2-b]吡啶盐酸盐;
7-(4-溴苄氧基)-1-环丁基甲基-2,3-二甲基-1H-吡咯并[3,2-b]吡啶盐酸盐;
7-(4-溴苄氧基)-1-异丁基-2,3-二甲基-1H-吡咯并[3,2-b]吡啶盐酸盐;
7-(4-溴苄氧基)-2,3-二甲基-1-丙基-1H-吡咯并[3,2-b]吡啶盐酸盐;
N-(1-烯丙基-2,3-二甲基-1H-吡咯并[3,2-b]吡啶-7-基)-4-氟苄基胺盐酸盐;
N-(1-环丙基甲基-2,3-二甲基-1H-吡咯并[3,2-b]吡啶-7-基)-4-氟苄基胺盐酸盐;
N-[1-(2-甲氧基乙基)-2,3-二甲基-1H-吡咯并[3,2-b]吡啶-7-基]-4-氟苄基胺盐酸盐;
N-(2,3-二甲基-1-丙基-1H-吡咯并[3,2-b]吡啶-7-基)-4-氟苄基胺盐酸盐;
N-(1-苄基-2,3-二甲基-1H-吡咯并[3,2-b]吡啶-7-基)-4-氟苄基胺盐酸盐;
N-[1-(4-甲基苄基)-2,3-二甲基-1H-吡咯并[3,2-b]吡啶-7-基]-4-氟苄基胺盐酸盐;
1-苄基-7-(4-氟苄氧基)-2,3,5,6-四甲基-1H-吡咯并[3,2-b]吡啶盐酸盐;和
N-(1-苄基-2,3,5,6-四甲基-1H-吡咯并[3,2-b]吡啶-7-基)-4-氟苄基胺盐酸盐。
5.一种药物组合物,其包含治疗有效量的任意根据权利要求1的通式(I)的化合物或者其药学可接受的盐,和药学可接受的载体。
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PCT/KR2005/002926 WO2006038773A1 (en) | 2004-09-03 | 2005-09-03 | Pyrrolo[3,2-b]pyridine derivatives and processes for the preparation thereof |
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EP (1) | EP1784403B1 (zh) |
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CN (1) | CN101010321B (zh) |
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TWI732785B (zh) | 2015-09-21 | 2021-07-11 | 美商普雷辛肯公司 | 雜環化合物及其用途 |
CN105622495A (zh) * | 2016-03-23 | 2016-06-01 | 叶芳 | 4-氯-3-硝基吡啶及其制备方法 |
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DE3269604D1 (en) | 1981-06-26 | 1986-04-10 | Schering Corp | Novel imidazo(1,2-a)pyridines and pyrazines, processes for their preparation and pharmaceutical compositions containing them |
KR0144833B1 (ko) | 1992-12-28 | 1998-07-15 | 김태훈 | 신규의 퀴나졸린 유도체 및 그의 제조방법 |
JP3465827B2 (ja) * | 1993-02-24 | 2003-11-10 | 株式会社日清製粉グループ本社 | アザインドール誘導体およびこれを有効成分とする抗潰瘍薬 |
ATE229020T1 (de) * | 1994-01-19 | 2002-12-15 | Sankyo Co | Pyrrolopyridazin-derivate |
DE69530989T2 (de) | 1994-08-13 | 2004-05-19 | Yuhan Corp. | Neue pyrimidinderivate und verfahren zu ihrer herstellung |
SE9700661D0 (sv) | 1997-02-25 | 1997-02-25 | Astra Ab | New compounds |
CN1155598C (zh) | 1998-09-23 | 2004-06-30 | 奥坦纳医药公司 | 四氢吡啶醚化合物 |
TWI287014B (en) | 1999-06-15 | 2007-09-21 | Sankyo Co | Optically active pyrrolopyridazine compound |
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US5714495A (en) * | 1995-04-14 | 1998-02-03 | Adir Et Compagnie | Pyridine compounds as melatonergic agents |
CN1284078A (zh) * | 1997-11-28 | 2001-02-14 | 阿斯特拉曾尼卡有限公司 | 抑制胃酸分泌的杂环化合物、其制备方法及其药物组合物 |
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EP1784403A4 (en) | 2009-11-11 |
CN101010321A (zh) | 2007-08-01 |
KR20060051004A (ko) | 2006-05-19 |
US20070213358A1 (en) | 2007-09-13 |
BRPI0514695A (pt) | 2008-06-17 |
ES2426920T3 (es) | 2013-10-25 |
AU2005290360A1 (en) | 2006-04-13 |
JP2008511620A (ja) | 2008-04-17 |
CA2579127C (en) | 2011-08-02 |
EP1784403A1 (en) | 2007-05-16 |
RU2397170C2 (ru) | 2010-08-20 |
US7642269B2 (en) | 2010-01-05 |
MX2007002219A (es) | 2007-05-04 |
AU2005290360B2 (en) | 2011-06-30 |
JP4989478B2 (ja) | 2012-08-01 |
KR100958828B1 (ko) | 2010-05-24 |
EP1784403B1 (en) | 2013-07-17 |
HK1105976A1 (en) | 2008-02-29 |
RU2007112109A (ru) | 2008-10-10 |
WO2006038773A1 (en) | 2006-04-13 |
DK1784403T3 (da) | 2013-10-21 |
CA2579127A1 (en) | 2006-04-13 |
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