JP2013541498A - ピラノ−[2,3−c]ピリジン誘導体の調製方法 - Google Patents
ピラノ−[2,3−c]ピリジン誘導体の調製方法 Download PDFInfo
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- JP2013541498A JP2013541498A JP2013520798A JP2013520798A JP2013541498A JP 2013541498 A JP2013541498 A JP 2013541498A JP 2013520798 A JP2013520798 A JP 2013520798A JP 2013520798 A JP2013520798 A JP 2013520798A JP 2013541498 A JP2013541498 A JP 2013541498A
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- 238000000034 method Methods 0.000 title claims abstract description 23
- BVIHAADUZBOGSJ-UHFFFAOYSA-N 2h-pyrano[2,3-c]pyridine Chemical class N1=CC=C2C=CCOC2=C1 BVIHAADUZBOGSJ-UHFFFAOYSA-N 0.000 title description 3
- 150000001875 compounds Chemical class 0.000 claims abstract description 80
- 239000003153 chemical reaction reagent Substances 0.000 claims abstract description 37
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 21
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical group C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 16
- 229910052799 carbon Inorganic materials 0.000 claims description 12
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 8
- 150000007530 organic bases Chemical class 0.000 claims description 7
- SIPUZPBQZHNSDW-UHFFFAOYSA-N bis(2-methylpropyl)aluminum Chemical group CC(C)C[Al]CC(C)C SIPUZPBQZHNSDW-UHFFFAOYSA-N 0.000 claims description 6
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 6
- 230000001590 oxidative effect Effects 0.000 claims description 6
- FBPINGSGHKXIQA-UHFFFAOYSA-N 2-amino-3-(2-carboxyethylsulfanyl)propanoic acid Chemical compound OC(=O)C(N)CSCCC(O)=O FBPINGSGHKXIQA-UHFFFAOYSA-N 0.000 claims description 5
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 5
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 4
- NKLCNNUWBJBICK-UHFFFAOYSA-N dess–martin periodinane Chemical compound C1=CC=C2I(OC(=O)C)(OC(C)=O)(OC(C)=O)OC(=O)C2=C1 NKLCNNUWBJBICK-UHFFFAOYSA-N 0.000 claims description 4
- 229910010082 LiAlH Inorganic materials 0.000 claims description 3
- 125000001475 halogen functional group Chemical group 0.000 claims description 3
- FIYYMXYOBLWYQO-UHFFFAOYSA-N ortho-iodylbenzoic acid Chemical compound OC(=O)C1=CC=CC=C1I(=O)=O FIYYMXYOBLWYQO-UHFFFAOYSA-N 0.000 claims description 3
- 238000006859 Swern oxidation reaction Methods 0.000 claims description 2
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 2
- 230000003647 oxidation Effects 0.000 claims 3
- 238000007254 oxidation reaction Methods 0.000 claims 3
- 229910052760 oxygen Inorganic materials 0.000 claims 2
- 208000035143 Bacterial infection Diseases 0.000 abstract description 3
- 208000022362 bacterial infectious disease Diseases 0.000 abstract description 3
- 239000000543 intermediate Substances 0.000 abstract description 3
- 239000000126 substance Substances 0.000 abstract description 2
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 66
- 239000000203 mixture Substances 0.000 description 41
- 238000005481 NMR spectroscopy Methods 0.000 description 28
- 239000010410 layer Substances 0.000 description 18
- 239000012044 organic layer Substances 0.000 description 17
- 238000003756 stirring Methods 0.000 description 16
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 12
- PFKFTWBEEFSNDU-UHFFFAOYSA-N carbonyldiimidazole Chemical compound C1=CN=CN1C(=O)N1C=CN=C1 PFKFTWBEEFSNDU-UHFFFAOYSA-N 0.000 description 9
- 238000006243 chemical reaction Methods 0.000 description 9
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 9
- -1 n- propyl Chemical group 0.000 description 9
- 239000011734 sodium Substances 0.000 description 9
- 239000000243 solution Substances 0.000 description 9
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 9
- 229940126062 Compound A Drugs 0.000 description 8
- NLDMNSXOCDLTTB-UHFFFAOYSA-N Heterophylliin A Natural products O1C2COC(=O)C3=CC(O)=C(O)C(O)=C3C3=C(O)C(O)=C(O)C=C3C(=O)OC2C(OC(=O)C=2C=C(O)C(O)=C(O)C=2)C(O)C1OC(=O)C1=CC(O)=C(O)C(O)=C1 NLDMNSXOCDLTTB-UHFFFAOYSA-N 0.000 description 8
- 239000012455 biphasic mixture Substances 0.000 description 8
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 6
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 6
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 6
- 239000007787 solid Substances 0.000 description 6
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 4
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 4
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 4
- 150000001412 amines Chemical class 0.000 description 4
- FKZCJUZAVSQWNQ-UHFFFAOYSA-N ethyl 2-[(2-hex-5-enoxy-2-oxoethyl)amino]-2-oxoacetate Chemical compound CCOC(=O)C(=O)NCC(=O)OCCCCC=C FKZCJUZAVSQWNQ-UHFFFAOYSA-N 0.000 description 4
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 3
- VRPJIFMKZZEXLR-UHFFFAOYSA-N 2-[(2-methylpropan-2-yl)oxycarbonylamino]acetic acid Chemical compound CC(C)(C)OC(=O)NCC(O)=O VRPJIFMKZZEXLR-UHFFFAOYSA-N 0.000 description 3
- QXVCUSYHDODUGS-UHFFFAOYSA-N 3,4-dihydro-2h-pyrano[2,3-c]pyridin-6-ylmethanol Chemical compound C1CCOC2=C1C=C(CO)N=C2 QXVCUSYHDODUGS-UHFFFAOYSA-N 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 239000002253 acid Substances 0.000 description 3
- 230000002378 acidificating effect Effects 0.000 description 3
- 238000009833 condensation Methods 0.000 description 3
- 230000005494 condensation Effects 0.000 description 3
- 238000010511 deprotection reaction Methods 0.000 description 3
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 3
- 0 *C(*)(C(*)(C1(*)O)S)Oc2c1c(*)c(C=O)nc2* Chemical compound *C(*)(C(*)(C1(*)O)S)Oc2c1c(*)c(C=O)nc2* 0.000 description 2
- DSOLBHZRAGNEPO-UHFFFAOYSA-N 3,4-dihydro-2h-pyrano[2,3-c]pyridine-6-carbaldehyde Chemical compound C1CCOC2=C1C=C(C=O)N=C2 DSOLBHZRAGNEPO-UHFFFAOYSA-N 0.000 description 2
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 2
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 2
- 229940098779 methanesulfonic acid Drugs 0.000 description 2
- ZGNCFTGDZPAKLP-ONEGZZNKSA-N methyl 2-[[2-[(e)-hex-4-enoxy]-2-oxoethyl]amino]-2-oxoacetate Chemical compound COC(=O)C(=O)NCC(=O)OCCC\C=C\C ZGNCFTGDZPAKLP-ONEGZZNKSA-N 0.000 description 2
- BJRREYNGXNOFPY-UHFFFAOYSA-N methyl 2-oxo-2-[(2-oxo-2-pent-4-enoxyethyl)amino]acetate Chemical compound COC(=O)C(=O)NCC(=O)OCCCC=C BJRREYNGXNOFPY-UHFFFAOYSA-N 0.000 description 2
- MIYJIDZRMVVQCP-UHFFFAOYSA-N methyl 3,4-dihydro-2h-pyrano[2,3-c]pyridine-6-carboxylate Chemical compound C1CCOC2=C1C=C(C(=O)OC)N=C2 MIYJIDZRMVVQCP-UHFFFAOYSA-N 0.000 description 2
- LQAVWYMTUMSFBE-UHFFFAOYSA-N pent-4-en-1-ol Chemical compound OCCCC=C LQAVWYMTUMSFBE-UHFFFAOYSA-N 0.000 description 2
- UOKJRXXHZJOPAL-UHFFFAOYSA-N pent-4-enyl 2-[(2-ethoxy-2-oxoacetyl)amino]-3-phenylpropanoate Chemical compound C=CCCCOC(=O)C(NC(=O)C(=O)OCC)CC1=CC=CC=C1 UOKJRXXHZJOPAL-UHFFFAOYSA-N 0.000 description 2
- 229920006395 saturated elastomer Polymers 0.000 description 2
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 2
- WJKHJLXJJJATHN-UHFFFAOYSA-N triflic anhydride Chemical compound FC(F)(F)S(=O)(=O)OS(=O)(=O)C(F)(F)F WJKHJLXJJJATHN-UHFFFAOYSA-N 0.000 description 2
- ZYJPUMXJBDHSIF-NSHDSACASA-N (2s)-2-[(2-methylpropan-2-yl)oxycarbonylamino]-3-phenylpropanoic acid Chemical compound CC(C)(C)OC(=O)N[C@H](C(O)=O)CC1=CC=CC=C1 ZYJPUMXJBDHSIF-NSHDSACASA-N 0.000 description 1
- QVHJQCGUWFKTSE-YFKPBYRVSA-N (2s)-2-[(2-methylpropan-2-yl)oxycarbonylamino]propanoic acid Chemical compound OC(=O)[C@H](C)NC(=O)OC(C)(C)C QVHJQCGUWFKTSE-YFKPBYRVSA-N 0.000 description 1
- DTVMQRSVGNABQJ-UHFFFAOYSA-N 2-[(2-ethoxy-2-oxoacetyl)amino]-3-phenylpropanoic acid Chemical compound CCOC(=O)C(=O)NC(C(O)=O)CC1=CC=CC=C1 DTVMQRSVGNABQJ-UHFFFAOYSA-N 0.000 description 1
- KHMNCHDUSFCTGK-UHFFFAOYSA-N 2-aminophenylacetic acid Chemical compound NC1=CC=CC=C1CC(O)=O KHMNCHDUSFCTGK-UHFFFAOYSA-N 0.000 description 1
- JWUJQDFVADABEY-UHFFFAOYSA-N 2-methyltetrahydrofuran Chemical compound CC1CCCO1 JWUJQDFVADABEY-UHFFFAOYSA-N 0.000 description 1
- WTQJVYWOYHZLSP-UHFFFAOYSA-N 2h-pyrano[2,3-c]pyridine-6-carbaldehyde Chemical compound C1=CCOC2=C1C=C(C=O)N=C2 WTQJVYWOYHZLSP-UHFFFAOYSA-N 0.000 description 1
- VTIODUHBZHNXFP-NSCUHMNNSA-N 4-Hexen-1-ol, (E)- Chemical compound C\C=C\CCCO VTIODUHBZHNXFP-NSCUHMNNSA-N 0.000 description 1
- QZRHDMKYWOXBLB-UHFFFAOYSA-N CCOC(C(NC(C(OCCCC=C)=O)c1ccccc1)=O)=O Chemical compound CCOC(C(NC(C(OCCCC=C)=O)c1ccccc1)=O)=O QZRHDMKYWOXBLB-UHFFFAOYSA-N 0.000 description 1
- MVLWTBBHPRPPOX-UHFFFAOYSA-N CCOC(C(NC(C)C(OCCCC=C)=O)=O)=O Chemical compound CCOC(C(NC(C)C(OCCCC=C)=O)=O)=O MVLWTBBHPRPPOX-UHFFFAOYSA-N 0.000 description 1
- LOMVENUNSWAXEN-UHFFFAOYSA-N Methyl oxalate Chemical compound COC(=O)C(=O)OC LOMVENUNSWAXEN-UHFFFAOYSA-N 0.000 description 1
- XBDQKXXYIPTUBI-UHFFFAOYSA-N Propionic acid Chemical compound CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 1
- 229910004298 SiO 2 Inorganic materials 0.000 description 1
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 1
- XYEJARFTZQJJLM-AATRIKPKSA-N [(e)-hex-4-enyl] 2-[(2-methylpropan-2-yl)oxycarbonylamino]acetate Chemical compound C\C=C\CCCOC(=O)CNC(=O)OC(C)(C)C XYEJARFTZQJJLM-AATRIKPKSA-N 0.000 description 1
- 125000000217 alkyl group Chemical group 0.000 description 1
- 230000002051 biphasic effect Effects 0.000 description 1
- 239000012267 brine Substances 0.000 description 1
- 125000004432 carbon atom Chemical group C* 0.000 description 1
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 1
- VEVRNHHLCPGNDU-MUGJNUQGSA-O desmosine Chemical compound OC(=O)[C@@H](N)CCCC[N+]1=CC(CC[C@H](N)C(O)=O)=C(CCC[C@H](N)C(O)=O)C(CC[C@H](N)C(O)=O)=C1 VEVRNHHLCPGNDU-MUGJNUQGSA-O 0.000 description 1
- YWEUIGNSBFLMFL-UHFFFAOYSA-N diphosphonate Chemical compound O=P(=O)OP(=O)=O YWEUIGNSBFLMFL-UHFFFAOYSA-N 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- IGIPRDHXEPLCFT-UHFFFAOYSA-N ethyl 2,3,4,5-tetrahydrooxepino[2,3-c]pyridine-7-carboxylate Chemical compound C1CCCOC2=C1C=C(C(=O)OCC)N=C2 IGIPRDHXEPLCFT-UHFFFAOYSA-N 0.000 description 1
- OWZFULPEVHKEKS-UHFFFAOYSA-N ethyl 2-chloro-2-oxoacetate Chemical compound CCOC(=O)C(Cl)=O OWZFULPEVHKEKS-UHFFFAOYSA-N 0.000 description 1
- IDLNDVZFBKVVSL-UHFFFAOYSA-N ethyl 5-methyl-3,4-dihydro-2h-pyrano[2,3-c]pyridine-6-carboxylate Chemical compound O1CCCC2=C(C)C(C(=O)OCC)=NC=C21 IDLNDVZFBKVVSL-UHFFFAOYSA-N 0.000 description 1
- WMAYYLMRRFSMFO-UHFFFAOYSA-N ethyl 8-benzyl-3,4-dihydro-2h-pyrano[2,3-c]pyridine-6-carboxylate Chemical compound N=1C(C(=O)OCC)=CC=2CCCOC=2C=1CC1=CC=CC=C1 WMAYYLMRRFSMFO-UHFFFAOYSA-N 0.000 description 1
- DETIBGSHGAPUKI-UHFFFAOYSA-N ethyl 8-methyl-3,4-dihydro-2h-pyrano[2,3-c]pyridine-6-carboxylate Chemical compound C1CCOC2=C1C=C(C(=O)OCC)N=C2C DETIBGSHGAPUKI-UHFFFAOYSA-N 0.000 description 1
- PGZDIXARNADHDQ-UHFFFAOYSA-N ethyl 8-phenyl-3,4-dihydro-2h-pyrano[2,3-c]pyridine-6-carboxylate Chemical compound N=1C(C(=O)OCC)=CC=2CCCOC=2C=1C1=CC=CC=C1 PGZDIXARNADHDQ-UHFFFAOYSA-N 0.000 description 1
- 235000019439 ethyl acetate Nutrition 0.000 description 1
- 238000003818 flash chromatography Methods 0.000 description 1
- ZXUQEPZWVQIOJE-UHFFFAOYSA-N methyl 2-chloro-2-oxoacetate Chemical compound COC(=O)C(Cl)=O ZXUQEPZWVQIOJE-UHFFFAOYSA-N 0.000 description 1
- HZOMNCROTGWGJK-UHFFFAOYSA-N methyl 5-methyl-3,4-dihydro-2h-pyrano[2,3-c]pyridine-6-carboxylate Chemical compound O1CCCC2=C(C)C(C(=O)OC)=NC=C21 HZOMNCROTGWGJK-UHFFFAOYSA-N 0.000 description 1
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- DLYUQMMRRRQYAE-UHFFFAOYSA-N phosphorus pentoxide Inorganic materials O1P(O2)(=O)OP3(=O)OP1(=O)OP2(=O)O3 DLYUQMMRRRQYAE-UHFFFAOYSA-N 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 125000006239 protecting group Chemical group 0.000 description 1
- 238000010791 quenching Methods 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- VTIODUHBZHNXFP-UHFFFAOYSA-N trans-hex-4-en-1-ol Natural products CC=CCCCO VTIODUHBZHNXFP-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
- C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
- C07D491/04—Ortho-condensed systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
- C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
- C07D491/04—Ortho-condensed systems
- C07D491/044—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
- C07D491/052—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring the oxygen-containing ring being six-membered
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
- A61K31/436—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a six-membered ring having oxygen as a ring hetero atom, e.g. rapamycin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
- C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
- C07D491/04—Ortho-condensed systems
- C07D491/044—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Medicinal Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Oncology (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Communicable Diseases (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Epidemiology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Cephalosporin Compounds (AREA)
Abstract
Description
R2はC1〜C4-アルキルであり、
R3は、H、C1〜C4-アルキル、ベンジル、-フェニル-(R10)x又は-C1〜C4-アルキル-COO-C1〜C4-アルキルであり、
各R4は独立に、H又はC1〜C4-アルキルであり、
各R5及び各R6は独立にH、C1〜C4-アルキル、-O-C1〜C4-アルキル又は-S-C1〜C4-アルキルであり、
R7はR8又は-CH2-R9であり、
R8は、H、C1〜C4-アルキル、-フェニル-(R10)x又は-COO-C1〜C4-アルキルであり、
R9は、H、C1〜C3-アルキル、-フェニル-(R10)x又は-COO-C1〜C4-アルキルであり、
各R10は独立に、ハロ、C1〜C4-アルキル、-O-C1〜C6-アルキル又は-S-C1〜C4-アルキルであり、
各xは独立に、0、1又は2である)
を生成させるステップを含む方法である。
を生成させるステップを含む方法である。式(II)の化合物は、細菌感染症の治療に有用な化合物への中間体として有望であることが分かっている。
を生成させるステップを含む方法である。
と反応させることによって調製することができる。
スキーム1は本発明の一つの態様を例示する。化合物(3)は、適切な縮合条件下、例えば1,1'-カルボニルジイミダゾールの存在下で酸(1)をアルコール(2)と接触させることによって調製することができる。保護基を、適切な脱保護条件下、好ましくはHCl、H2SO4、MsOH又はTsOHなどの強酸との反応によって化合物(3)から除去してアミン(4)を生成させる。
メチル2-オキソ-2-((2-オキソ-2-(ペンタ-4-エン-1-イルオキシ)エチル)アミノ)アセテート(42.5g、1eq)及びジクロロメタン(DCM)(425mL)を撹拌しながら容器に加え、続いてピリジン(17.6g、1.2eq)を加えた。Tf2O(78.5g、1.5eq)を、内温を約25℃に保ちながら45分かけてその混合物に加えた。混合物を6時間撹拌し、その時点で、20wt%NaOAc水溶液(255mL)を加えて反応物を注意深くクエンチして二相溶液を生成させた。水層をDCM(85mL)で抽出した。一緒にした有機層を最初に水(127.5mL)で洗浄し、10wt%クエン酸溶液(170mL)で洗浄した。6N HCl(127.5mL)をその混合物に加えて二相混合物を生成させた。二つの層を分離し、有機層を6N HCl(85mL)で抽出した。酸性水層を一緒にし、DCM(127.5mL)を加えた。温度を25℃未満に保持しながら、水層のpHが3〜5に達するまで28wt%NH4OH水溶液を徐々に加えた。二つの層を分離し、水層をDCM(85mL)で抽出した。一緒にした有機層を水(85mL)で洗浄した。有機溶液を減圧下で濃縮して表題化合物を油状物として得た。静置するとこれは固化した。1H NMR (400MHz, CDCl3) δ ppm 8.17 (s, 1H), 7.80-7.86 (m, 1H), 4.26 (t, J=5.19Hz, 2H), 3.92 (s, 3H), 2.79 (t, J=6.44Hz, 2H), 1.97-2.09 (m, 2H); 13C NMR (75MHz, CDCl3) δ ppm 165.11, 154.25, 138.95, 138.64, 130.06, 126.13, 65.55, 51.99, 23.57, 20.67;HRMS (M+Na) m/z, 計算値: C10H11NO3Na, 216.0637; 実測値, 216.0643。
ペンタ-4-エン-1-イル2-(2-エトキシ-2-オキソアセトアミド)プロパノエート(1.05g、1eq)及びDCM(15mL)を撹拌しながら容器に加えた。次いでピリジン(0.39g、1.2eq)を加え、混合物を15℃に冷却した。Tf2O(1.7g、1.5eq)をその混合物に15分かけて加え、混合物を周囲温度に加温して1.5時間撹拌した。反応物を、DCM及び20wt%NaOAc水溶液を加えてクエンチして二相混合物を生成させた。層を分離し、有機層を水で洗浄した。次いで有機層を減圧下で濃縮して表題化合物を黄色固体として得た。1H NMR (300MHz, CDCl3) δ ppm 7.62 (s, 1H), 4.32 (q, J=7.12Hz, 2H), 4.16-4.25 (m, 2H), 2.70 (t, J=6.44Hz, 2H), 2.37 (s, 3H), 1.86 - 2.03 (m, 2H), 1.31 (t, J=7.12Hz, 3H); 13C NMR (75MHz, CDCl3) δ ppm 165.15, 152.44, 147.98, 137.72, 128.73, 124.80, 66.85, 61.09, 23.98, 21.06, 18.98, 14.11;HRMS (M+H) m/z, 計算値: C12H16NO3, 222.1130; 実測値, 222.1133。
ペンタ-4-エン-1-イル2-(2-エトキシ-2-オキソアセトアミド)-3-フェニルプロパノエート(0.80g、1eq)及びDCM(15mL)を撹拌しながら容器に加えた。次いでピリジン(0.23g、1.2eq)を加え、混合物を15℃に冷却した。Tf2O(1.0g、1.5eq)をその混合物に15分かけて加え、混合物を周囲温度に加温した。溶液を3.5時間撹拌し、次いで反応物を、DCM及び20wt%NaOAc水溶液を加えてクエンチして二相混合物を生成させた。層を分離し、有機層を6N HCl(3×10mL)で抽出した。一緒にした酸性層をDCMで洗浄し、pHを固体K2CO3で約9に調節した。塩基性の水層をDCMで抽出した。有機層を減圧下で濃縮して表題化合物を得た。1H NMR (300MHz, CDCl3) δ ppm 7.74 (s, 1H), 7.10-7.35 (m, 5H), 4.43 (q, J=7.12Hz, 2H), 4.22-4.29 (m, 2H), 4.21 (s, 2H), 2.78 (t, J=6.41Hz, 2H), 1.93-2.06 (m, 2H), 1.41 (t, J=7.12Hz, 3H); 13C NMR (75MHz, CDCl3) δ ppm 165.08, 152.25, 149.62, 138.86, 138.06, 129.62, 128.61, 127.80, 125.61, 125.23, 66.70, 60.97, 38.55, 23.93, 20.92, 14.10;HRMS (M+H) m/z, 計算値: C18H20NO3, 298.1443; 実測値: 298.1450。
エチル8-フェニル-3,4-ジヒドロ-2H-ピラノ[2,3-c]ピリジン-6-カルボキシレートを、エチル2-オキソ-2-((2-オキソ-2-(ペンタ-4-エン-1-イルオキシ)-1-フェニルエチル)アミノ)アセテート(0.91g)から出発して、実施例3(b)と同様の仕方で調製した。1H NMR (300MHz, CDCl3) δ ppm 7.91-7.98 (m, 2H), 7.84 (s, 1H), 7.34-7.49 (m, 3H), 4.44 (q, J=7.12Hz, 2H), 4.29-4.38 (m, 2H), 2.91 (t, J=6.44Hz, 2H), 2.02-2.18 (m, 2H), 1.43 (t, J=7.12Hz, 3H); 13C NMR (75MHz, CDCl3) δ ppm 165.11, 152.06, 149.30, 146.60, 138.65, 136.72, 135.82, 130.64, 129.30, 128.06, 127.59, 125.48, 66.89, 61.07, 24.37, 20.84, 14.09;HRMS (M+H) m/z, 計算値: C17H18NO3, 284.1287; 実測値: 284.1301。
(E)-メチル2-((2-(ヘキサ-4-エン-1-イルオキシ)-2-オキソエチル)アミノ)-2-オキソアセテート(0.24g、1eq)及びDCM(2.4mL)を撹拌しながら容器に加え、続いてピリジン(95mg、1.2eq)を加えた。次いでTf2O(0.42g、1.5eq)を周囲温度で45分かけて加え、混合物を周囲温度で48時間撹拌した。混合物を20wt%NaOAc水溶液(2×1.5mL)、10wt%クエン酸水溶液(3×1.5mL)及び水(1×1.5mL)で洗浄した。次いで有機層を減圧下で濃縮して表題化合物を固体として得た。1H NMR (300MHz, CDCl3) δ ppm 8.10 (s, 1H), 4.15-4.25 (m, 2H), 3.94 (s, 3H), 2.71 (t, J=6.56Hz, 2H), 2.47 (s, 3H), 2.00-2.18 (m, 2H); 13C NMR (75MHz, CDCl3) δ ppm 166.71, 153.50, 138.69, 136.72, 135.67, 130.36, 65.93, 52.35, 22.18, 21.49, 14.57;HRMS (M+H) m/z, 計算値: C11H14NO3, 208.0974; 実測値: 208.0981。
(3,4-ジヒドロ-2H-ピラノ[2,3-c]ピリジン-6-イル)メタノール(300g、1.0eq)、DCM(1.5L)及びジメチルスルホキシド(216mL、2.05eq)を、撹拌しながら約0〜5℃に保持した容器に加えた。混合物の温度を約0〜7℃に保持しながら、トリエチルアミン(858mL、4.1eq)、次いで固体ピリジン三酸化硫黄(474g、2.0eq)を混合物に徐々に加えた。混合物を約0〜7℃で約5〜8時間撹拌し、次いで5wt%NaHCO3水溶液(3L)でクエンチして二相混合物を生成させた。層を分離し、水層をDCM(0.9L)で抽出した。一緒にした有機層を5wt%クエン酸水溶液(3.0L)及びブライン(300mL)で洗浄し、無水硫酸ナトリウムで乾燥し、ろ過してDCM溶液中の表題化合物を得た。1H NMR (300MHz, CDCl3) δ ppm 9.94 (s, 1H), 8.21-8.32 (m, 1H), 7.72 (s, 1H), 4.25-4.40 (m, 2H), 2.85 (t, J=6.50Hz, 2H), 1.97-2.19 (m, 2H)。
Claims (17)
- 式(I)の化合物:
R2はC1〜C4-アルキルであり、
R3はH、C1〜C4-アルキル、ベンジル、-フェニル-(R10)x又は-C1〜C4-アルキル-COO-C1〜C4-アルキルであり、
各R4は独立にH又はC1〜C4-アルキルであり、
各R5及び各R6は独立にH、C1〜C4-アルキル、-O-C1〜C4-アルキル又は-S-C1〜C4-アルキルであり、
R7はR8又は-CH2-R9であり、
R8はH、C1〜C4-アルキル、-フェニル-(R10)x又は-COO-C1〜C4-アルキルであり、
R9はH、C1〜C3-アルキル、-フェニル-(R10)x又は-COO-C1〜C4-アルキルであり、
各R10は独立にハロ、C1〜C6-アルキル、-O-C1〜C4-アルキル又は-S-C1〜C4-アルキルであり、
各xは独立に0、1又は2である)
を生成させるステップを含む方法。 - 脱水試薬がTf2O又はP2O5であり、R4、R5及びR6がそれぞれ独立にH又はC1〜C4-アルキルであり、さらに有機塩基の存在下で実施する、請求項1に記載の方法。
- R4、R5及びR6がそれぞれ独立にH又はメチルであり、有機塩基がピリジン、トリエチルアミン又はジイソプロピルエチルアミンである、請求項2に記載の方法。
- R4、R5及びR6のそれぞれがHであり、脱水試薬がTf2Oであり、有機塩基を化合物(I)に対して少なくとも1当量の量で、且つ当量で脱水試薬の量より少ない量で使用する、請求項2又は3に記載の方法。
- 脱水試薬がTf2O又はP2O5である、請求項7に記載の方法。
- 脱水試薬がTf2Oであり、R2がメチル又はエチルである、請求項7又は8に記載の方法。
- 化合物(V)に対して少なくとも1当量の量で、且つ当量で脱水試薬の量より少ない量の有機塩基の存在下で実施する、請求項7、8又は9に記載の方法。
- 還元試薬がジイソブチルアルミニウムヒドリド、LiAlH4、LiBH4又はNaBH4である、請求項5又は11に記載の方法。
- 還元試薬がLiBH4である、請求項5、11又は13に記載の方法。
- 酸化試薬が、MnO2、スワーン酸化試薬、2-ヨードキシ安息香酸、ピリジン三酸化硫黄又はデス-マーチンペルヨージナンである、請求項5、11、13又は14に記載の方法。
- 酸化試薬がピリジン三酸化硫黄である、請求項5、11、13、14又は15に記載の方法。
- 還元試薬がジイソブチルアルミニウムヒドリドである、請求項6又は12に記載の方法。
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