TWI384981B - 製備經葡萄哌喃糖基取代的苄基苯衍生物及其中間物 - Google Patents
製備經葡萄哌喃糖基取代的苄基苯衍生物及其中間物 Download PDFInfo
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- TWI384981B TWI384981B TW095116447A TW95116447A TWI384981B TW I384981 B TWI384981 B TW I384981B TW 095116447 A TW095116447 A TW 095116447A TW 95116447 A TW95116447 A TW 95116447A TW I384981 B TWI384981 B TW I384981B
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- Taiwan
- Prior art keywords
- formula
- group
- alkyl
- compound
- tetrahydrofuran
- Prior art date
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- 238000000034 method Methods 0.000 title claims description 74
- 230000008569 process Effects 0.000 title claims description 15
- 239000000543 intermediate Chemical class 0.000 title description 21
- CZZYITDELCSZES-UHFFFAOYSA-N diphenylmethane Chemical class C=1C=CC=CC=1CC1=CC=CC=C1 CZZYITDELCSZES-UHFFFAOYSA-N 0.000 title description 8
- 238000006243 chemical reaction Methods 0.000 claims description 113
- -1 tetrahydropyran-4-yl Chemical group 0.000 claims description 102
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 76
- 150000001875 compounds Chemical class 0.000 claims description 73
- 229910052751 metal Inorganic materials 0.000 claims description 65
- 239000002184 metal Substances 0.000 claims description 64
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 56
- 125000003118 aryl group Chemical group 0.000 claims description 55
- 239000000460 chlorine Substances 0.000 claims description 49
- 229910052739 hydrogen Inorganic materials 0.000 claims description 44
- 239000001257 hydrogen Substances 0.000 claims description 42
- 239000002253 acid Substances 0.000 claims description 38
- 125000003147 glycosyl group Chemical group 0.000 claims description 22
- 150000002431 hydrogen Chemical class 0.000 claims description 22
- 229910052794 bromium Inorganic materials 0.000 claims description 21
- 239000003054 catalyst Substances 0.000 claims description 21
- 239000003638 chemical reducing agent Substances 0.000 claims description 20
- 238000012546 transfer Methods 0.000 claims description 20
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 19
- 239000002841 Lewis acid Substances 0.000 claims description 19
- 150000007517 lewis acids Chemical class 0.000 claims description 19
- 229910052801 chlorine Inorganic materials 0.000 claims description 18
- 229910052740 iodine Inorganic materials 0.000 claims description 18
- JFDZBHWFFUWGJE-UHFFFAOYSA-N benzonitrile Chemical compound N#CC1=CC=CC=C1 JFDZBHWFFUWGJE-UHFFFAOYSA-N 0.000 claims description 17
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 17
- 125000001424 substituent group Chemical group 0.000 claims description 17
- DIOQZVSQGTUSAI-UHFFFAOYSA-N decane Chemical compound CCCCCCCCCC DIOQZVSQGTUSAI-UHFFFAOYSA-N 0.000 claims description 16
- 150000002902 organometallic compounds Chemical class 0.000 claims description 16
- 229910052736 halogen Inorganic materials 0.000 claims description 15
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 15
- 125000006239 protecting group Chemical group 0.000 claims description 15
- 125000005129 aryl carbonyl group Chemical group 0.000 claims description 14
- 150000002148 esters Chemical class 0.000 claims description 14
- KWGKDLIKAYFUFQ-UHFFFAOYSA-M lithium chloride Chemical compound [Li+].[Cl-] KWGKDLIKAYFUFQ-UHFFFAOYSA-M 0.000 claims description 14
- KUZXQXCWRNFIHK-UHFFFAOYSA-N 3,3-diethyldodecane Chemical compound CCCCCCCCCC(CC)(CC)CC KUZXQXCWRNFIHK-UHFFFAOYSA-N 0.000 claims description 13
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 13
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims description 13
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 13
- 125000005740 oxycarbonyl group Chemical group [*:1]OC([*:2])=O 0.000 claims description 13
- RWCCWEUUXYIKHB-UHFFFAOYSA-N benzophenone Chemical class C=1C=CC=CC=1C(=O)C1=CC=CC=C1 RWCCWEUUXYIKHB-UHFFFAOYSA-N 0.000 claims description 12
- 229910052731 fluorine Inorganic materials 0.000 claims description 11
- 125000000217 alkyl group Chemical group 0.000 claims description 10
- PHOQVHQSTUBQQK-SQOUGZDYSA-N D-glucono-1,5-lactone Chemical compound OC[C@H]1OC(=O)[C@H](O)[C@@H](O)[C@@H]1O PHOQVHQSTUBQQK-SQOUGZDYSA-N 0.000 claims description 9
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 9
- 229910052710 silicon Inorganic materials 0.000 claims description 9
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 claims description 8
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical group [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 claims description 8
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 claims description 8
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 8
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 8
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 8
- 239000011737 fluorine Substances 0.000 claims description 8
- 229960003681 gluconolactone Drugs 0.000 claims description 8
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 claims description 8
- 235000012209 glucono delta-lactone Nutrition 0.000 claims description 7
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 7
- 125000001624 naphthyl group Chemical group 0.000 claims description 7
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 6
- 150000002576 ketones Chemical class 0.000 claims description 6
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 6
- 150000002367 halogens Chemical group 0.000 claims description 5
- 239000003795 chemical substances by application Substances 0.000 claims description 4
- 150000005171 halobenzenes Chemical class 0.000 claims description 4
- 238000003780 insertion Methods 0.000 claims description 4
- 230000037431 insertion Effects 0.000 claims description 4
- TWRXJAOTZQYOKJ-UHFFFAOYSA-L magnesium chloride Substances [Mg+2].[Cl-].[Cl-] TWRXJAOTZQYOKJ-UHFFFAOYSA-L 0.000 claims description 4
- NOGFHTGYPKWWRX-UHFFFAOYSA-N 2,2,6,6-tetramethyloxan-4-one Chemical compound CC1(C)CC(=O)CC(C)(C)O1 NOGFHTGYPKWWRX-UHFFFAOYSA-N 0.000 claims description 3
- 239000011630 iodine Substances 0.000 claims description 3
- 229910001623 magnesium bromide Inorganic materials 0.000 claims description 3
- 229910001629 magnesium chloride Inorganic materials 0.000 claims description 3
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 2
- KZBUYRJDOAKODT-UHFFFAOYSA-N Chlorine Chemical compound ClCl KZBUYRJDOAKODT-UHFFFAOYSA-N 0.000 claims description 2
- 150000003937 benzamidines Chemical class 0.000 claims description 2
- 125000006267 biphenyl group Chemical group 0.000 claims description 2
- 150000001768 cations Chemical class 0.000 claims description 2
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 2
- YCKRFDGAMUMZLT-UHFFFAOYSA-N Fluorine atom Chemical compound [F] YCKRFDGAMUMZLT-UHFFFAOYSA-N 0.000 claims 2
- REOPPMSCFNBULP-UHFFFAOYSA-N C(C)(C)Cl.[Li] Chemical compound C(C)(C)Cl.[Li] REOPPMSCFNBULP-UHFFFAOYSA-N 0.000 claims 1
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 126
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 103
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 90
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 87
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 84
- 239000002904 solvent Substances 0.000 description 74
- 239000000203 mixture Substances 0.000 description 70
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 68
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 66
- 239000000243 solution Substances 0.000 description 65
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 54
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 49
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 46
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 42
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 42
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 39
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 35
- 235000019439 ethyl acetate Nutrition 0.000 description 34
- 238000001819 mass spectrum Methods 0.000 description 33
- 239000000047 product Substances 0.000 description 33
- 238000003786 synthesis reaction Methods 0.000 description 31
- 230000015572 biosynthetic process Effects 0.000 description 30
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 29
- 239000002585 base Substances 0.000 description 29
- 229910052744 lithium Inorganic materials 0.000 description 27
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 26
- KZMGYPLQYOPHEL-UHFFFAOYSA-N Boron trifluoride etherate Chemical compound FB(F)F.CCOCC KZMGYPLQYOPHEL-UHFFFAOYSA-N 0.000 description 26
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 25
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 25
- 150000003839 salts Chemical class 0.000 description 25
- 229910052723 transition metal Inorganic materials 0.000 description 25
- 150000003624 transition metals Chemical class 0.000 description 22
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 21
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 20
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 19
- VSCWAEJMTAWNJL-UHFFFAOYSA-K aluminium trichloride Chemical compound Cl[Al](Cl)Cl VSCWAEJMTAWNJL-UHFFFAOYSA-K 0.000 description 19
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 18
- 238000006722 reduction reaction Methods 0.000 description 18
- 239000011777 magnesium Substances 0.000 description 17
- 229910052749 magnesium Inorganic materials 0.000 description 17
- 239000012074 organic phase Substances 0.000 description 17
- 229910052725 zinc Inorganic materials 0.000 description 16
- 239000011701 zinc Chemical group 0.000 description 16
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical group [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 15
- 230000008859 change Effects 0.000 description 15
- 229910052738 indium Inorganic materials 0.000 description 15
- 230000009467 reduction Effects 0.000 description 15
- 235000011121 sodium hydroxide Nutrition 0.000 description 15
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 14
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 14
- 238000001704 evaporation Methods 0.000 description 13
- 230000008020 evaporation Effects 0.000 description 13
- APFVFJFRJDLVQX-UHFFFAOYSA-N indium atom Chemical group [In] APFVFJFRJDLVQX-UHFFFAOYSA-N 0.000 description 13
- ZOXJGFHDIHLPTG-UHFFFAOYSA-N Boron Chemical group [B] ZOXJGFHDIHLPTG-UHFFFAOYSA-N 0.000 description 12
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 12
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical group [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 12
- 239000012267 brine Substances 0.000 description 12
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 12
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 11
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 11
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 11
- 229940113088 dimethylacetamide Drugs 0.000 description 11
- 239000012039 electrophile Substances 0.000 description 11
- ITMCEJHCFYSIIV-UHFFFAOYSA-M triflate Chemical compound [O-]S(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-M 0.000 description 11
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 description 10
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 10
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 10
- 229960000583 acetic acid Drugs 0.000 description 10
- UORVGPXVDQYIDP-UHFFFAOYSA-N borane Chemical class B UORVGPXVDQYIDP-UHFFFAOYSA-N 0.000 description 10
- 229910052796 boron Inorganic materials 0.000 description 10
- 239000003153 chemical reaction reagent Substances 0.000 description 10
- 230000013595 glycosylation Effects 0.000 description 10
- 238000006206 glycosylation reaction Methods 0.000 description 10
- 239000003960 organic solvent Substances 0.000 description 10
- 239000011541 reaction mixture Substances 0.000 description 10
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 9
- 238000005859 coupling reaction Methods 0.000 description 9
- 238000002360 preparation method Methods 0.000 description 9
- 229910052938 sodium sulfate Inorganic materials 0.000 description 9
- 235000011152 sodium sulphate Nutrition 0.000 description 9
- DIIIISSCIXVANO-UHFFFAOYSA-N 1,2-Dimethylhydrazine Chemical compound CNNC DIIIISSCIXVANO-UHFFFAOYSA-N 0.000 description 8
- OAKJQQAXSVQMHS-UHFFFAOYSA-N Hydrazine Chemical compound NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 description 8
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 8
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 8
- 229910052799 carbon Inorganic materials 0.000 description 8
- 229910052802 copper Inorganic materials 0.000 description 8
- 239000010949 copper Substances 0.000 description 8
- 238000000354 decomposition reaction Methods 0.000 description 8
- 239000011734 sodium Substances 0.000 description 8
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 8
- LWIHDJKSTIGBAC-UHFFFAOYSA-K tripotassium phosphate Chemical compound [K+].[K+].[K+].[O-]P([O-])([O-])=O LWIHDJKSTIGBAC-UHFFFAOYSA-K 0.000 description 8
- JIAARYAFYJHUJI-UHFFFAOYSA-L zinc dichloride Chemical compound [Cl-].[Cl-].[Zn+2] JIAARYAFYJHUJI-UHFFFAOYSA-L 0.000 description 8
- 229930182476 C-glycoside Natural products 0.000 description 7
- 150000000700 C-glycosides Chemical class 0.000 description 7
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 7
- VYZAMTAEIAYCRO-UHFFFAOYSA-N Chromium Chemical group [Cr] VYZAMTAEIAYCRO-UHFFFAOYSA-N 0.000 description 7
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 7
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 description 7
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 7
- PXHVJJICTQNCMI-UHFFFAOYSA-N Nickel Chemical compound [Ni] PXHVJJICTQNCMI-UHFFFAOYSA-N 0.000 description 7
- 239000007864 aqueous solution Substances 0.000 description 7
- 229910000085 borane Inorganic materials 0.000 description 7
- 229930195733 hydrocarbon Natural products 0.000 description 7
- 150000002430 hydrocarbons Chemical class 0.000 description 7
- 239000007800 oxidant agent Substances 0.000 description 7
- 229910052760 oxygen Inorganic materials 0.000 description 7
- 229910052763 palladium Inorganic materials 0.000 description 7
- 229910000027 potassium carbonate Inorganic materials 0.000 description 7
- 235000011181 potassium carbonates Nutrition 0.000 description 7
- 238000006467 substitution reaction Methods 0.000 description 7
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 6
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 6
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 6
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 description 6
- 238000005727 Friedel-Crafts reaction Methods 0.000 description 6
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 6
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 6
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 6
- XYFCBTPGUUZFHI-UHFFFAOYSA-N Phosphine Chemical compound P XYFCBTPGUUZFHI-UHFFFAOYSA-N 0.000 description 6
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 6
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 6
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 description 6
- PXXJHWLDUBFPOL-UHFFFAOYSA-N benzamidine Chemical compound NC(=N)C1=CC=CC=C1 PXXJHWLDUBFPOL-UHFFFAOYSA-N 0.000 description 6
- UAOMVDZJSHZZME-UHFFFAOYSA-N diisopropylamine Chemical compound CC(C)NC(C)C UAOMVDZJSHZZME-UHFFFAOYSA-N 0.000 description 6
- USIUVYZYUHIAEV-UHFFFAOYSA-N diphenyl ether Chemical class C=1C=CC=CC=1OC1=CC=CC=C1 USIUVYZYUHIAEV-UHFFFAOYSA-N 0.000 description 6
- 125000005843 halogen group Chemical group 0.000 description 6
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 6
- 238000011065 in-situ storage Methods 0.000 description 6
- 239000012442 inert solvent Substances 0.000 description 6
- JMMWKPVZQRWMSS-UHFFFAOYSA-N isopropanol acetate Natural products CC(C)OC(C)=O JMMWKPVZQRWMSS-UHFFFAOYSA-N 0.000 description 6
- 229940011051 isopropyl acetate Drugs 0.000 description 6
- GWYFCOCPABKNJV-UHFFFAOYSA-M isovalerate Chemical compound CC(C)CC([O-])=O GWYFCOCPABKNJV-UHFFFAOYSA-M 0.000 description 6
- PYLWMHQQBFSUBP-UHFFFAOYSA-N monofluorobenzene Chemical compound FC1=CC=CC=C1 PYLWMHQQBFSUBP-UHFFFAOYSA-N 0.000 description 6
- 239000012044 organic layer Substances 0.000 description 6
- 239000012279 sodium borohydride Substances 0.000 description 6
- 229910000033 sodium borohydride Inorganic materials 0.000 description 6
- 239000004215 Carbon black (E152) Substances 0.000 description 5
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- SRSXLGNVWSONIS-UHFFFAOYSA-M benzenesulfonate Chemical compound [O-]S(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-M 0.000 description 1
- CHIHQLCVLOXUJW-UHFFFAOYSA-N benzoic anhydride Chemical compound C=1C=CC=CC=1C(=O)OC(=O)C1=CC=CC=C1 CHIHQLCVLOXUJW-UHFFFAOYSA-N 0.000 description 1
- PASDCCFISLVPSO-UHFFFAOYSA-N benzoyl chloride Chemical compound ClC(=O)C1=CC=CC=C1 PASDCCFISLVPSO-UHFFFAOYSA-N 0.000 description 1
- KCXMKQUNVWSEMD-UHFFFAOYSA-N benzyl chloride Chemical compound ClCC1=CC=CC=C1 KCXMKQUNVWSEMD-UHFFFAOYSA-N 0.000 description 1
- 229940073608 benzyl chloride Drugs 0.000 description 1
- DAMJCWMGELCIMI-UHFFFAOYSA-N benzyl n-(2-oxopyrrolidin-3-yl)carbamate Chemical compound C=1C=CC=CC=1COC(=O)NC1CCNC1=O DAMJCWMGELCIMI-UHFFFAOYSA-N 0.000 description 1
- OQFSQFPPLPISGP-UHFFFAOYSA-N beta-carboxyaspartic acid Natural products OC(=O)C(N)C(C(O)=O)C(O)=O OQFSQFPPLPISGP-UHFFFAOYSA-N 0.000 description 1
- 239000004305 biphenyl Substances 0.000 description 1
- 235000010290 biphenyl Nutrition 0.000 description 1
- 150000001638 boron Chemical class 0.000 description 1
- YMEKEHSRPZAOGO-UHFFFAOYSA-N boron triiodide Chemical compound IB(I)I YMEKEHSRPZAOGO-UHFFFAOYSA-N 0.000 description 1
- 239000001273 butane Substances 0.000 description 1
- KDYFGRWQOYBRFD-NUQCWPJISA-N butanedioic acid Chemical compound O[14C](=O)CC[14C](O)=O KDYFGRWQOYBRFD-NUQCWPJISA-N 0.000 description 1
- 125000004369 butenyl group Chemical group C(=CCC)* 0.000 description 1
- AIYUHDOJVYHVIT-UHFFFAOYSA-M caesium chloride Chemical compound [Cl-].[Cs+] AIYUHDOJVYHVIT-UHFFFAOYSA-M 0.000 description 1
- HUCVOHYBFXVBRW-UHFFFAOYSA-M caesium hydroxide Inorganic materials [OH-].[Cs+] HUCVOHYBFXVBRW-UHFFFAOYSA-M 0.000 description 1
- XQPRBTXUXXVTKB-UHFFFAOYSA-M caesium iodide Chemical compound [I-].[Cs+] XQPRBTXUXXVTKB-UHFFFAOYSA-M 0.000 description 1
- 150000001721 carbon Chemical group 0.000 description 1
- 125000004432 carbon atom Chemical group C* 0.000 description 1
- 150000007942 carboxylates Chemical class 0.000 description 1
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 1
- ZDQWVKDDJDIVAL-UHFFFAOYSA-N catecholborane Chemical compound C1=CC=C2O[B]OC2=C1 ZDQWVKDDJDIVAL-UHFFFAOYSA-N 0.000 description 1
- KXZJHVJKXJLBKO-UHFFFAOYSA-N chembl1408157 Chemical compound N=1C2=CC=CC=C2C(C(=O)O)=CC=1C1=CC=C(O)C=C1 KXZJHVJKXJLBKO-UHFFFAOYSA-N 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 150000001805 chlorine compounds Chemical class 0.000 description 1
- 125000004803 chlorobenzyl group Chemical group 0.000 description 1
- XTHPWXDJESJLNJ-UHFFFAOYSA-M chlorosulfate Chemical compound [O-]S(Cl)(=O)=O XTHPWXDJESJLNJ-UHFFFAOYSA-M 0.000 description 1
- 238000003776 cleavage reaction Methods 0.000 description 1
- 230000002860 competitive effect Effects 0.000 description 1
- DOBRDRYODQBAMW-UHFFFAOYSA-N copper(i) cyanide Chemical compound [Cu+].N#[C-] DOBRDRYODQBAMW-UHFFFAOYSA-N 0.000 description 1
- OPQARKPSCNTWTJ-UHFFFAOYSA-L copper(ii) acetate Chemical compound [Cu+2].CC([O-])=O.CC([O-])=O OPQARKPSCNTWTJ-UHFFFAOYSA-L 0.000 description 1
- SBTSVTLGWRLWOD-UHFFFAOYSA-L copper(ii) triflate Chemical compound [Cu+2].[O-]S(=O)(=O)C(F)(F)F.[O-]S(=O)(=O)C(F)(F)F SBTSVTLGWRLWOD-UHFFFAOYSA-L 0.000 description 1
- 150000003983 crown ethers Chemical class 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 238000005695 dehalogenation reaction Methods 0.000 description 1
- 230000001419 dependent effect Effects 0.000 description 1
- 239000002274 desiccant Substances 0.000 description 1
- 239000012954 diazonium Substances 0.000 description 1
- 150000001989 diazonium salts Chemical class 0.000 description 1
- LHCGBIFHSCCRRG-UHFFFAOYSA-N dichloroborane Chemical compound ClBCl LHCGBIFHSCCRRG-UHFFFAOYSA-N 0.000 description 1
- 125000004177 diethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- DENRZWYUOJLTMF-UHFFFAOYSA-N diethyl sulfate Chemical compound CCOS(=O)(=O)OCC DENRZWYUOJLTMF-UHFFFAOYSA-N 0.000 description 1
- 229940008406 diethyl sulfate Drugs 0.000 description 1
- ZHXTWWCDMUWMDI-UHFFFAOYSA-N dihydroxyboron Chemical group O[B]O ZHXTWWCDMUWMDI-UHFFFAOYSA-N 0.000 description 1
- SRXOCFMDUSFFAK-UHFFFAOYSA-N dimethyl peroxide Chemical group COOC SRXOCFMDUSFFAK-UHFFFAOYSA-N 0.000 description 1
- VAYGXNSJCAHWJZ-UHFFFAOYSA-N dimethyl sulfate Chemical compound COS(=O)(=O)OC VAYGXNSJCAHWJZ-UHFFFAOYSA-N 0.000 description 1
- 150000002013 dioxins Chemical class 0.000 description 1
- 229910001882 dioxygen Inorganic materials 0.000 description 1
- ZZVUWRFHKOJYTH-UHFFFAOYSA-N diphenhydramine Chemical group C=1C=CC=CC=1C(OCCN(C)C)C1=CC=CC=C1 ZZVUWRFHKOJYTH-UHFFFAOYSA-N 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 125000001033 ether group Chemical group 0.000 description 1
- 150000002170 ethers Chemical class 0.000 description 1
- 125000003754 ethoxycarbonyl group Chemical group C(=O)(OCC)* 0.000 description 1
- 125000005745 ethoxymethyl group Chemical group [H]C([H])([H])C([H])([H])OC([H])([H])* 0.000 description 1
- 125000004672 ethylcarbonyl group Chemical group [H]C([H])([H])C([H])([H])C(*)=O 0.000 description 1
- 125000002534 ethynyl group Chemical group [H]C#C* 0.000 description 1
- OJCSPXHYDFONPU-UHFFFAOYSA-N etoac etoac Chemical compound CCOC(C)=O.CCOC(C)=O OJCSPXHYDFONPU-UHFFFAOYSA-N 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 238000001640 fractional crystallisation Methods 0.000 description 1
- 239000001530 fumaric acid Substances 0.000 description 1
- 239000012362 glacial acetic acid Substances 0.000 description 1
- 239000000174 gluconic acid Substances 0.000 description 1
- 235000012208 gluconic acid Nutrition 0.000 description 1
- 125000005640 glucopyranosyl group Chemical group 0.000 description 1
- 239000004220 glutamic acid Substances 0.000 description 1
- 235000013922 glutamic acid Nutrition 0.000 description 1
- 150000002343 gold Chemical class 0.000 description 1
- 229940093915 gynecological organic acid Drugs 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- SPRIOUNJHPCKPV-UHFFFAOYSA-N hydridoaluminium Chemical compound [AlH] SPRIOUNJHPCKPV-UHFFFAOYSA-N 0.000 description 1
- 229910000040 hydrogen fluoride Inorganic materials 0.000 description 1
- 238000005984 hydrogenation reaction Methods 0.000 description 1
- 238000007327 hydrogenolysis reaction Methods 0.000 description 1
- 150000004679 hydroxides Chemical class 0.000 description 1
- WGCNASOHLSPBMP-UHFFFAOYSA-N hydroxyacetaldehyde Natural products OCC=O WGCNASOHLSPBMP-UHFFFAOYSA-N 0.000 description 1
- 150000002460 imidazoles Chemical class 0.000 description 1
- 150000004693 imidazolium salts Chemical class 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 230000002083 iodinating effect Effects 0.000 description 1
- PCEBAZIVZVIQEO-UHFFFAOYSA-N iodocyclopentane Chemical compound IC1CCCC1 PCEBAZIVZVIQEO-UHFFFAOYSA-N 0.000 description 1
- HVTICUPFWKNHNG-UHFFFAOYSA-N iodoethane Chemical compound CCI HVTICUPFWKNHNG-UHFFFAOYSA-N 0.000 description 1
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 1
- 125000000654 isopropylidene group Chemical group C(C)(C)=* 0.000 description 1
- 239000004310 lactic acid Substances 0.000 description 1
- 235000014655 lactic acid Nutrition 0.000 description 1
- 150000002596 lactones Chemical class 0.000 description 1
- 229960004873 levomenthol Drugs 0.000 description 1
- 239000012280 lithium aluminium hydride Substances 0.000 description 1
- XGZVUEUWXADBQD-UHFFFAOYSA-L lithium carbonate Chemical compound [Li+].[Li+].[O-]C([O-])=O XGZVUEUWXADBQD-UHFFFAOYSA-L 0.000 description 1
- 229910052808 lithium carbonate Inorganic materials 0.000 description 1
- 150000002642 lithium compounds Chemical class 0.000 description 1
- OTCKOJUMXQWKQG-UHFFFAOYSA-L magnesium bromide Chemical compound [Mg+2].[Br-].[Br-] OTCKOJUMXQWKQG-UHFFFAOYSA-L 0.000 description 1
- 150000002681 magnesium compounds Chemical class 0.000 description 1
- LWLPYZUDBNFNAH-UHFFFAOYSA-M magnesium;butane;bromide Chemical compound [Mg+2].[Br-].CCC[CH2-] LWLPYZUDBNFNAH-UHFFFAOYSA-M 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 239000011976 maleic acid Substances 0.000 description 1
- 239000001630 malic acid Substances 0.000 description 1
- 235000011090 malic acid Nutrition 0.000 description 1
- 229960002510 mandelic acid Drugs 0.000 description 1
- 238000004949 mass spectrometry Methods 0.000 description 1
- 239000011159 matrix material Substances 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- COTNUBDHGSIOTA-UHFFFAOYSA-N meoh methanol Chemical compound OC.OC COTNUBDHGSIOTA-UHFFFAOYSA-N 0.000 description 1
- 229910001507 metal halide Inorganic materials 0.000 description 1
- 150000005309 metal halides Chemical class 0.000 description 1
- 229910052987 metal hydride Inorganic materials 0.000 description 1
- 150000004681 metal hydrides Chemical class 0.000 description 1
- 229910044991 metal oxide Inorganic materials 0.000 description 1
- 150000004706 metal oxides Chemical class 0.000 description 1
- 238000006263 metalation reaction Methods 0.000 description 1
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 1
- UZKWTJUDCOPSNM-UHFFFAOYSA-N methoxybenzene Substances CCCCOC=C UZKWTJUDCOPSNM-UHFFFAOYSA-N 0.000 description 1
- CXHHBNMLPJOKQD-UHFFFAOYSA-M methyl carbonate Chemical compound COC([O-])=O CXHHBNMLPJOKQD-UHFFFAOYSA-M 0.000 description 1
- 125000004674 methylcarbonyl group Chemical group CC(=O)* 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 239000002808 molecular sieve Substances 0.000 description 1
- 229910000403 monosodium phosphate Inorganic materials 0.000 description 1
- 235000019799 monosodium phosphate Nutrition 0.000 description 1
- IJDNQMDRQITEOD-UHFFFAOYSA-N n-butane Chemical group CCCC IJDNQMDRQITEOD-UHFFFAOYSA-N 0.000 description 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- XIKYYQJBTPYKSG-UHFFFAOYSA-N nickel Chemical compound [Ni].[Ni] XIKYYQJBTPYKSG-UHFFFAOYSA-N 0.000 description 1
- 150000002825 nitriles Chemical class 0.000 description 1
- 239000012454 non-polar solvent Substances 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 238000006053 organic reaction Methods 0.000 description 1
- 150000002901 organomagnesium compounds Chemical class 0.000 description 1
- 238000006864 oxidative decomposition reaction Methods 0.000 description 1
- 150000002923 oximes Chemical class 0.000 description 1
- BJEYNNFDAPPGST-UHFFFAOYSA-N oxirene Chemical compound O1C=C1 BJEYNNFDAPPGST-UHFFFAOYSA-N 0.000 description 1
- HBEQXAKJSGXAIQ-UHFFFAOYSA-N oxopalladium Chemical compound [Pd]=O HBEQXAKJSGXAIQ-UHFFFAOYSA-N 0.000 description 1
- MUMZUERVLWJKNR-UHFFFAOYSA-N oxoplatinum Chemical compound [Pt]=O MUMZUERVLWJKNR-UHFFFAOYSA-N 0.000 description 1
- 229910003445 palladium oxide Inorganic materials 0.000 description 1
- NXJCBFBQEVOTOW-UHFFFAOYSA-L palladium(2+);dihydroxide Chemical compound O[Pd]O NXJCBFBQEVOTOW-UHFFFAOYSA-L 0.000 description 1
- PIBWKRNGBLPSSY-UHFFFAOYSA-L palladium(II) chloride Chemical compound Cl[Pd]Cl PIBWKRNGBLPSSY-UHFFFAOYSA-L 0.000 description 1
- YJVFFLUZDVXJQI-UHFFFAOYSA-L palladium(ii) acetate Chemical compound [Pd+2].CC([O-])=O.CC([O-])=O YJVFFLUZDVXJQI-UHFFFAOYSA-L 0.000 description 1
- INIOZDBICVTGEO-UHFFFAOYSA-L palladium(ii) bromide Chemical compound Br[Pd]Br INIOZDBICVTGEO-UHFFFAOYSA-L 0.000 description 1
- QNGNSVIICDLXHT-UHFFFAOYSA-N para-ethylbenzaldehyde Natural products CCC1=CC=C(C=O)C=C1 QNGNSVIICDLXHT-UHFFFAOYSA-N 0.000 description 1
- 125000000538 pentafluorophenyl group Chemical group FC1=C(F)C(F)=C(*)C(F)=C1F 0.000 description 1
- 239000003208 petroleum Substances 0.000 description 1
- 229940044652 phenolsulfonate Drugs 0.000 description 1
- 125000003884 phenylalkyl group Chemical group 0.000 description 1
- ZUOUZKKEUPVFJK-UHFFFAOYSA-N phenylbenzene Natural products C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 description 1
- 229910052697 platinum Inorganic materials 0.000 description 1
- 229910003446 platinum oxide Inorganic materials 0.000 description 1
- 239000002798 polar solvent Substances 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 235000011056 potassium acetate Nutrition 0.000 description 1
- 235000003270 potassium fluoride Nutrition 0.000 description 1
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical class [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 description 1
- OTYBMLCTZGSZBG-UHFFFAOYSA-L potassium sulfate Chemical compound [K+].[K+].[O-]S([O-])(=O)=O OTYBMLCTZGSZBG-UHFFFAOYSA-L 0.000 description 1
- 229910052939 potassium sulfate Inorganic materials 0.000 description 1
- 239000001120 potassium sulphate Substances 0.000 description 1
- 235000011151 potassium sulphates Nutrition 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 1
- 230000005588 protonation Effects 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- ILVXOBCQQYKLDS-UHFFFAOYSA-N pyridine N-oxide Chemical compound [O-][N+]1=CC=CC=C1 ILVXOBCQQYKLDS-UHFFFAOYSA-N 0.000 description 1
- 230000009257 reactivity Effects 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 229910052703 rhodium Inorganic materials 0.000 description 1
- 239000010948 rhodium Substances 0.000 description 1
- MHOVAHRLVXNVSD-UHFFFAOYSA-N rhodium atom Chemical compound [Rh] MHOVAHRLVXNVSD-UHFFFAOYSA-N 0.000 description 1
- 230000007017 scission Effects 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 150000003378 silver Chemical class 0.000 description 1
- URGAHOPLAPQHLN-UHFFFAOYSA-N sodium aluminosilicate Chemical compound [Na+].[Al+3].[O-][Si]([O-])=O.[O-][Si]([O-])=O URGAHOPLAPQHLN-UHFFFAOYSA-N 0.000 description 1
- WRIKHQLVHPKCJU-UHFFFAOYSA-N sodium bis(trimethylsilyl)amide Chemical compound C[Si](C)(C)N([Na])[Si](C)(C)C WRIKHQLVHPKCJU-UHFFFAOYSA-N 0.000 description 1
- BEOOHQFXGBMRKU-UHFFFAOYSA-N sodium cyanoborohydride Chemical compound [Na+].[B-]C#N BEOOHQFXGBMRKU-UHFFFAOYSA-N 0.000 description 1
- AJPJDKMHJJGVTQ-UHFFFAOYSA-M sodium dihydrogen phosphate Chemical compound [Na+].OP(O)([O-])=O AJPJDKMHJJGVTQ-UHFFFAOYSA-M 0.000 description 1
- PUZPDOWCWNUUKD-UHFFFAOYSA-M sodium fluoride Chemical compound [F-].[Na+] PUZPDOWCWNUUKD-UHFFFAOYSA-M 0.000 description 1
- 235000009518 sodium iodide Nutrition 0.000 description 1
- 229910001415 sodium ion Inorganic materials 0.000 description 1
- KKCBUQHMOMHUOY-UHFFFAOYSA-N sodium oxide Chemical compound [O-2].[Na+].[Na+] KKCBUQHMOMHUOY-UHFFFAOYSA-N 0.000 description 1
- 229910001948 sodium oxide Inorganic materials 0.000 description 1
- 229960001922 sodium perborate Drugs 0.000 description 1
- 229910052979 sodium sulfide Inorganic materials 0.000 description 1
- GRVFOGOEDUUMBP-UHFFFAOYSA-N sodium sulfide (anhydrous) Chemical compound [Na+].[Na+].[S-2] GRVFOGOEDUUMBP-UHFFFAOYSA-N 0.000 description 1
- RZWQDAUIUBVCDD-UHFFFAOYSA-M sodium;benzenethiolate Chemical compound [Na+].[S-]C1=CC=CC=C1 RZWQDAUIUBVCDD-UHFFFAOYSA-M 0.000 description 1
- YKLJGMBLPUQQOI-UHFFFAOYSA-M sodium;oxidooxy(oxo)borane Chemical compound [Na+].[O-]OB=O YKLJGMBLPUQQOI-UHFFFAOYSA-M 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 230000002269 spontaneous effect Effects 0.000 description 1
- KXCAEQNNTZANTK-UHFFFAOYSA-N stannane Chemical compound [SnH4] KXCAEQNNTZANTK-UHFFFAOYSA-N 0.000 description 1
- 229910000080 stannane Inorganic materials 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 125000000020 sulfo group Chemical group O=S(=O)([*])O[H] 0.000 description 1
- 150000003871 sulfonates Chemical class 0.000 description 1
- PUGUQINMNYINPK-UHFFFAOYSA-N tert-butyl 4-(2-chloroacetyl)piperazine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CCN(C(=O)CCl)CC1 PUGUQINMNYINPK-UHFFFAOYSA-N 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
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- JRMUNVKIHCOMHV-UHFFFAOYSA-M tetrabutylammonium bromide Chemical compound [Br-].CCCC[N+](CCCC)(CCCC)CCCC JRMUNVKIHCOMHV-UHFFFAOYSA-M 0.000 description 1
- WHRNULOCNSKMGB-UHFFFAOYSA-N tetrahydrofuran thf Chemical compound C1CCOC1.C1CCOC1 WHRNULOCNSKMGB-UHFFFAOYSA-N 0.000 description 1
- 125000001412 tetrahydropyranyl group Chemical group 0.000 description 1
- AWDBHOZBRXWRKS-UHFFFAOYSA-N tetrapotassium;iron(6+);hexacyanide Chemical compound [K+].[K+].[K+].[K+].[Fe+6].N#[C-].N#[C-].N#[C-].N#[C-].N#[C-].N#[C-] AWDBHOZBRXWRKS-UHFFFAOYSA-N 0.000 description 1
- 238000009210 therapy by ultrasound Methods 0.000 description 1
- HNKJADCVZUBCPG-UHFFFAOYSA-N thioanisole Chemical compound CSC1=CC=CC=C1 HNKJADCVZUBCPG-UHFFFAOYSA-N 0.000 description 1
- 150000003568 thioethers Chemical class 0.000 description 1
- 125000003396 thiol group Chemical group [H]S* 0.000 description 1
- 150000007944 thiolates Chemical class 0.000 description 1
- XJDNKRIXUMDJCW-UHFFFAOYSA-J titanium tetrachloride Chemical compound Cl[Ti](Cl)(Cl)Cl XJDNKRIXUMDJCW-UHFFFAOYSA-J 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
- 230000032258 transport Effects 0.000 description 1
- 125000005270 trialkylamine group Chemical group 0.000 description 1
- JKNHZOAONLKYQL-UHFFFAOYSA-K tribromoindigane Chemical compound Br[In](Br)Br JKNHZOAONLKYQL-UHFFFAOYSA-K 0.000 description 1
- FAQYAMRNWDIXMY-UHFFFAOYSA-N trichloroborane Chemical compound ClB(Cl)Cl FAQYAMRNWDIXMY-UHFFFAOYSA-N 0.000 description 1
- FMRGMCNQJPJPPJ-UHFFFAOYSA-K trichlorostannane Chemical compound Cl[SnH](Cl)Cl FMRGMCNQJPJPPJ-UHFFFAOYSA-K 0.000 description 1
- IMNIMPAHZVJRPE-UHFFFAOYSA-N triethylenediamine Chemical compound C1CN2CCN1CC2 IMNIMPAHZVJRPE-UHFFFAOYSA-N 0.000 description 1
- 150000008648 triflates Chemical class 0.000 description 1
- AHZJKOKFZJYCLG-UHFFFAOYSA-K trifluoromethanesulfonate;ytterbium(3+) Chemical compound [Yb+3].[O-]S(=O)(=O)C(F)(F)F.[O-]S(=O)(=O)C(F)(F)F.[O-]S(=O)(=O)C(F)(F)F AHZJKOKFZJYCLG-UHFFFAOYSA-K 0.000 description 1
- WHAFDJWJDDPMDO-UHFFFAOYSA-N trimethyl(phenyl)phosphanium Chemical compound C[P+](C)(C)C1=CC=CC=C1 WHAFDJWJDDPMDO-UHFFFAOYSA-N 0.000 description 1
- QMGCGMCWRCSEPP-UHFFFAOYSA-N trimethylphosphane;hydrochloride Chemical compound [Cl-].C[PH+](C)C QMGCGMCWRCSEPP-UHFFFAOYSA-N 0.000 description 1
- YWWDBCBWQNCYNR-UHFFFAOYSA-N trimethylphosphine Substances CP(C)C YWWDBCBWQNCYNR-UHFFFAOYSA-N 0.000 description 1
- OBAJXDYVZBHCGT-UHFFFAOYSA-N tris(pentafluorophenyl)borane Chemical compound FC1=C(F)C(F)=C(F)C(F)=C1B(C=1C(=C(F)C(F)=C(F)C=1F)F)C1=C(F)C(F)=C(F)C(F)=C1F OBAJXDYVZBHCGT-UHFFFAOYSA-N 0.000 description 1
- 125000002221 trityl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1C([*])(C1=C(C(=C(C(=C1[H])[H])[H])[H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 229940102001 zinc bromide Drugs 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C39/00—Compounds having at least one hydroxy or O-metal group bound to a carbon atom of a six-membered aromatic ring
- C07C39/24—Halogenated derivatives
- C07C39/367—Halogenated derivatives polycyclic non-condensed, containing only six-membered aromatic rings as cyclic parts, e.g. halogenated poly-hydroxyphenylalkanes
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C43/00—Ethers; Compounds having groups, groups or groups
- C07C43/02—Ethers
- C07C43/20—Ethers having an ether-oxygen atom bound to a carbon atom of a six-membered aromatic ring
- C07C43/225—Ethers having an ether-oxygen atom bound to a carbon atom of a six-membered aromatic ring containing halogen
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C43/00—Ethers; Compounds having groups, groups or groups
- C07C43/02—Ethers
- C07C43/235—Ethers having an ether-oxygen atom bound to a carbon atom of a six-membered aromatic ring and to a carbon atom of a ring other than a six-membered aromatic ring
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Description
本發明係關於一種用於製備式I之經葡萄哌喃糖基取代的苄基苯衍生物之方法,
其中取代基R1
及R3
如下文中所定義。此外本發明係關於用於製備經葡萄哌喃糖基取代之苄基苯衍生物之方法之中間物及起始材料的製備方法。另外本發明係關於該等中間物及起始材料。
在國際專利申請案WO 2005/092877中描述通式為
之經葡萄哌喃糖基取代之苯衍生物,其中基團R1
至R6
及R7 a
、R7 b
、R7 c
於本文中定義。該等化合物對於鈉離子依賴性葡萄糖共輸送體SGLT(尤其SGLT2)具有有價值之抑制效應。
本發明之目標在於找到用於製備式I之經葡萄哌喃糖基取代之苄基苯衍生物之新穎方法;尤其使用之方法可以高產率、高鏡像異構或非對映體純度獲得產物,且其允許在低技術支出及高空間/時間產率下以工業規模製造該產物。
本發明之另一目標在於提供上述製造方法中起始材料之製備方法。
本發明之進一步目標係關於根據本發明方法中之新穎中間物及起始材料。
對於熟習此項技術者,直接從以上及以下描述將顯而易見本發明之其它目標。
在第一態樣中,本發明係關於一種製備通式I化合物之方法,
其中R1
表示環丁基、環戊基、環己基、R-四氫呋喃-3-基、S-四氫呋喃-3-基或四氫哌喃-4-基;且R3
表示氫;其特徵在於在通式II化合物中將不為氫之保護基團R2
分解,特定言之水解,
其中R1
如上文所定義且R2
彼此獨立地表示氫、(C1 - 1 8
-烷基)羰基、(C1 - 1 8
-烷基)氧基羰基、芳基羰基、芳基-(C1 - 3
-烷基)-羰基、芳基-C1 - 3
-烷基、烯丙基、Ra
Rb
Rc
Si、CRa
Rb
ORc
,其中兩相鄰基團R2
可相互連接以形成橋聯基團SiRa
Rb
、CRa
Rb
或CRa
ORb
-CRa
ORb
;限制條件為至少一個取代基R2
不為氫。
Ra
、Rb
、Rc
彼此獨立地表示C1 - 4
-烷基、芳基或芳基-C1 - 3
-烷基,同時該烷基可經鹵素單取代或多取代;L1係彼此獨立地選自氟、氯、溴、C1 - 3
-烷基、C1 - 4
-烷氧基及硝基;同時以上基團之定義中提及之芳基意謂苯基或萘基,較佳為苯基,其可經L1單取代或多取代。
在第二態樣中,本發明係關於一種製備通式II化合物之方法,
其中R1
表示環丁基、環戊基、環己基、R-四氫呋喃-3-基、S-四氫呋喃-3-基或四氫哌喃-4-基;且R2
彼此獨立地表示氫、(C1 - 1 8
-烷基)羰基、(C1 - 1 8
-烷基)氧基羰基、芳基羰基、芳基-(C1 - 3
-烷基)-羰基、芳基-C1 - 3
-烷基、烯丙基、Ra
Rb
Rc
Si、CRa
Rb
ORc
,其中兩相鄰基團R2
可相互連接以形成橋聯基團SiRa
Rb
、CRa
Rb
或CRa
ORb
-CRa
ORb
;Ra
、Rb
、Rc
彼此獨立地表示C1 - 4
-烷基、芳基或芳基-C1 - 3
-烷基,同時該等烷基可經鹵素單取代或多取代;L1係彼此獨立地選自氟、氯、溴、C1 - 3
-烷基、C1 - 4
-烷氧基及硝基;同時以上基團之定義中提及之芳基意謂苯基或萘基,較佳為苯基,其可經L1單取代或多取代;其特徵在於使通式III化合物與還原劑反應,
其中R1
及每個R2
如上文所定義且R'表示氫、C1 - 6
-烷基、(C1 - 4
-烷基)羰基、(C1 - 4
-烷基)氧基羰基、芳基羰基、芳基-(C1 - 3
-烷基)-羰基;同時術語"芳基"如上文所定義。
在第三態樣中,本發明係關於一種製備通式III化合物之方法,
其中R1
表示環丁基、環戊基、環己基、R-四氫呋喃-3-基、S-四氫呋喃-3-基或四氫哌喃-4-基;且R2
彼此獨立地表示氫、(C1 - 1 8
-烷基)羰基、(C1 - 1 8
-烷基)氧基羰基、芳基羰基、芳基-(C1 - 3
-烷基)-羰基、芳基-C1 - 3
-烷基、烯丙基、Ra
Rb
Rc
Si、CRa
Rb
ORc
,其中兩相鄰基團R2
可相互連接以形成橋聯基團SiRa
Rb
、CRa
Rb
或CRa
ORb
-CRa
ORb
;且Ra
、Rb
、Rc
彼此獨立地表示C1 - 4
-烷基、芳基或芳基-C1 - 3
-烷基,同時該等烷基可經鹵素單取代或多取代;L1係彼此獨立地選自氟、氯、溴、C1 - 3
-烷基、C1 - 4
-烷氧基及硝基;R'表示氫、C1 - 6
-烷基、(C1 - 4
-烷基)羰基、(C1 - 4
-烷基)氧基羰基、芳基羰基、芳基-(C1 - 3
-烷基)-羰基;同時以上基團之定義中提及之芳基意謂苯基或萘基,較佳為苯基,其可經L1單取代或多取代;其特徵在於將式VI之有機金屬化合物
其中R1
如上文所定義,且M表示Li或MgHal,其中Hal表示Cl、Br或I;或其藉由金屬轉移作用而獲得之衍生物;(其中式VI化合物可藉由下法獲得:鹵素-金屬交換或藉由將金屬插入通式V之鹵素-苄基苯化合物之碳-鹵素鍵中
其中R1
如上文所定義,且X表示Br或I;且視情況繼以金屬轉移作用)予以加至通式IV之葡萄糖酸內酯
其中R2
如上文所定義,隨後將所得加合物與水或醇R'-OH(其中R'表示C1 - 6
-烷基)於酸存在下反應,且視情況將與水(其中R'表示氫)反應所得之產物在隨後與醯化劑之反應中轉化為式III之產物,其中R'表示(C1 - 4
-烷基)羰基、(C1 - 4
-烷基)氧基羰基、芳基羰基或芳基-(C1 - 3
-烷基)-羰基,其中術語"芳基"如上文中所定義。
在第四態樣中,本發明係關於一種製備通式XXXIII化合物之方法,
其中R1
、R2
如上文及下文中所定義;其特徵在於將式XXX之受保護D-葡萄烯糖
其中R2
如上文所定義;予以金屬化以生成式XXXI之金屬化D-葡萄烯糖
其中R2
如上文中所定義,且M表示鋰或鎂部分;視情況將其金屬轉移以生成式XXXI之金屬化D-葡萄烯糖,其中M表示鎂、鋅、銦、硼、錫、矽或鉻部分;及將式XXXI之經金屬化或經金屬轉移之D-葡萄烯糖與式V之配醣基在過渡金屬催化劑存在下反應
其中R1
如上文所定義,且X表示脫離基;生成式XXXII之葡萄烯糖衍生物
其中R1
及R2
如上文中所定義;及藉由添加水至葡萄烯糖部分之雙鍵,特別是藉由該雙鍵之硼氫化作用及隨後之碳-硼鍵分解,或藉由該雙鍵之環氧化作用或二羥基化作用及隨後所得變旋異構碳-氧鍵之還原,將式XXXII之葡萄烯糖衍生物轉化為式XXXIII之產物。
在第五態樣中,本發明係關於一種製備通式XXXIII化合物之方法,
其中R1
、R2
如上文及下文中所定義;其特徵在於將式XXX之受保護D-葡萄烯糖
其中R2
如上文所定義;予以環氧化以生成相應之式XXXIV之氧化葡萄烯糖
其中R2
如上文所定義;及將式XXXIV之氧化葡萄烯糖與式VI之金屬化配醣基反應
其中R1
如上文中所定義,且M表示鋰、鎂、鋅、銦、鋁或硼部分;以生成式XXXIII之產物。
在第六態樣中,本發明係關於一種製備通式II化合物之方法,
其中R1
、R2
如上文及下文中所定義;其特徵在於使式XXXV之葡萄糖衍生物
其中R2
如上文所定義且Hal表示F、Cl、Br、C1 - 3
-烷基羰氧基、C1 - 3
-烷氧基羰氧基或C1 - 3
-烷氧基;與式VI之金屬化配醣基反應
其中R1
如上文中所定義,且M表示鋰、鎂、鋅、銦或硼部分;以生成式II之產物。
在第七態樣中,本發明係關於一種製備通式V化合物之方法,
其中R1
表示環丁基、環戊基、環己基、R-四氫呋喃-3-基、S-四氫呋喃-3-基或四氫哌喃-4-基;且X表示溴原子或碘原子;其特徵在於使式XII之氯化苯甲醯衍生物
其中X如上文所定義;或諸如苯甲醯酐、酯、或苯甲腈之其衍生物;在催化劑存在下與式XXVII之鹵苯反應
其中Z5
表示氟、氯或碘原子;獲得式XXVI之中間物化合物
其中X及Z5
如上文中所定義;且在鹼存在下,較佳在一溶劑或溶劑混合物中,使式XXVI之中間物化合物與R1
-OH(其中R1
如上文中所定義)或其陽離子反應,以生成式VII之二苯基酮衍生物
其中X及R1
如上文中所定義;且在路易斯酸存在下,較佳在一溶劑或溶劑混合物中,將式VII之二苯基酮衍生物與還原劑反應以提供如上文中所定義之式V化合物。
在第八態樣中,本發明係關於一種製備通式II化合物之方法,
其中R1
及R2
如上文中所定義,其特徵在於藉由根據本發明之第七態樣之方法獲得式V之配醣基
其中X及R1
如上文中所定義,且將通式V之該鹵苯-苄基苯化合物藉由鹵素-金屬交換或藉由將金屬插入通式V之鹵素-苄基苯化合物之碳-鹵素鍵中,及視情況隨後進行金屬轉移作用而轉化為式VI之有機金屬化合物
其中R1
如上文中所定義,且M表示Li或MgHal,其中Hal表示Cl、Br或I;且根據本發明之第三態樣之方法使該式VI之該有機金屬化合物與通式IV之葡萄糖酸內酯反應
其中R2
如上文中所定義,以獲得式III之中間物,
其中R2
、R'及R1
如上文中所定義,且使該式III之該中間物根據本發明之第二態樣與還原劑反應,以獲得式II化合物。
在第九態樣中,本發明係關於通式II化合物
其中R1
表示環丁基、環戊基、環己基、R-四氫呋喃-3-基、S-四氫呋喃-3-基或四氫哌喃-4-基;且R2
彼此獨立地表示氫、(C1 - 1 8
-烷基)羰基、(C1 - 1 8
-烷基)氧基羰基、芳基羰基、芳基-(C1 - 3
-烷基)-羰基、芳基-C1 - 3
-烷基、烯丙基、Ra
Rb
Rc
Si、CRa
Rb
ORc
,其中兩相鄰基團R2
可相互連接以形成橋聯基團SiRa
Rb
、CRa
Rb
或CRa
ORb
-CRa
ORb
;限制條件為至少一個取代基R2
不表示氫;Ra
、Rb
、Rc
彼此獨立地表示C1 - 4
-烷基、芳基或芳基-C1 - 3
-烷基,同時該等烷基可經鹵素單取代或多取代;L1係彼此獨立地選自氟、氯、溴、C1 - 3
-烷基、C1 - 4
-烷氧基及硝基;同時以上基團之定義中提及之芳基意謂苯基或萘基,較佳為苯基,其可經L1單取代或多取代。
在另一態樣中,本發明係關於通式III化合物
其中R1
表示環丁基、環戊基、環己基、R-四氫呋喃-3-基、S-四氫呋喃-3-基或四氫哌喃-4-基;且R2
彼此獨立地表示氫、(C1 - 1 8
-烷基)羰基、(C1 - 1 8
-烷基)氧基羰基、芳基羰基、芳基-(C1 - 3
-烷基)-羰基、芳基-C1 - 3
-烷基、烯丙基、Ra
Rb
Rc
Si、CRa
Rb
ORc
,其中兩相鄰基團R2
可相互連接以形成橋聯基團SiRa
Rb
、CRa
Rb
或CRa
ORb
-CRa
ORb
;Ra
、Rb
、Rc
彼此獨立地表示C1 - 4
-烷基、芳基或芳基-C1 - 3
-烷基,同時該等烷基或芳基可經鹵素單取代或多取代;L1係彼此獨立地選自氟、氯、溴、C1 - 3
-烷基、C1 - 4
-烷氧基及硝基;R'表示氫、C1 - 6
-烷基、(C1 - 4
-烷基)羰基、(C1 - 4
-烷基)氧基羰基、芳基羰基、芳基-(C1 - 3
-烷基)-羰基;同時以上基團之定義中提及之芳基意謂苯基或萘基,較佳為苯基,其可經L1單取代或多取代。
在另一態樣中,本發明係關於通式VI化合物
其中R1
表示環丁基、環戊基、環己基、R-四氫呋喃-3-基、S-四氫呋喃-3-基或四氫哌喃-4-基;且M表示Li或MgHal,其中Hal表示Cl、Br或I。在另一態樣中,本發明係關於通式V化合物
其中R1
表示環丁基、環戊基、環己基、R-四氫呋喃-3-基、S-四氫呋喃-3-基或四氫哌喃-4-基;且X表示Br或I。在另一態樣中,本發明係關於式VII化合物
或式XIX化合物
其中R1
表示環丁基、環戊基、環己基、R-四氫呋喃-3-基、S-四氫呋喃-3-基或四氫哌喃-4-基;且X表示Br或I。
在另一態樣中,本發明係關於式XXVI化合物
其中X表示Br或I;且Z表示羥基、氟、氯、溴、碘、C1 - 4
-烷基-磺醯基氧基、芳基磺醯基氧基、芳基-C1 - 3
-烷基-磺醯基氧基、二-(C1 - 6
-烷氧基)-硼基、二-羥基-硼基、KF3
B、NaF3
B或LiF3
B;且術語"芳基"如上文中所定義。
在另一態樣中,本發明係關於式XXXII化合物
其中R1
表示環丁基、環戊基、環己基、R-四氫呋喃-3-基、S-四氫呋喃-3-基或四氫哌喃-4-基;且R2
彼此獨立地表示氫、(C1 - 1 8
-烷基)羰基、(C1 - 1 8
-烷基)氧基羰基、芳基羰基、芳基-(C1 - 3
-烷基)-羰基、芳基-C1 - 3
-烷基、烯丙基、Ra
Rb
Rc
Si、CRa
Rb
ORc
,其中兩相鄰基團R2
可相互連接以形成橋聯基團SiRa
Rb
、CRa
Rb
或CRa
ORb
-CRa
ORb
;Ra
、Rb
、Rc
彼此獨立地表示C1 - 4
-烷基、芳基或芳基-C1 - 3
-烷基,同時該等烷基可經鹵素單取代或多取代;L1係彼此獨立地選自氟、氯、溴、C1 - 3
-烷基、C1 - 4
-烷氧基及硝基;同時以上基團之定義中提及之芳基意謂苯基或萘基,較佳為苯基,其可經L1單取代或多取代。
除非另外說明,否則基團、殘基及取代基,尤其R1
、R2
、R3
、R'、Ra
、Rb
、Rc
、L1、M、X及Z,均如上文及下文中所定義。
若殘基、取代基或基團在一化合物中出現若干次,則其可具有相同或不同之意義。
在根據本發明之方法及化合物中,以下基團及取代基之意義為較佳:R1
較佳表示R-四氫呋喃-3-基或S-四氫呋喃-3-基。
R2
較佳表示氫、甲基羰基、乙基羰基或三甲基矽烷基。
Ra
、Rb
、Rc
彼此獨立地較佳表示甲基、乙基、正丙基或異丙基、第三丁基或苯基;最佳為甲基。
R'較佳表示氫、甲基或乙基。
在下文中詳細描述根據本發明之方法。
流程0描述經由移除存在於化合物II中的不為氫之保護基團R2
,將化合物II轉化為化合物I,其中R1
、R2
及R3
如上文中所定義。
流程0:經由移除保護基團來合成式I之C-糖苷
將使用之任一醯基保護基團R2
分解,例如於0至120℃,較佳10至100℃之間溫度下,在諸如三氟乙酸、鹽酸或硫酸之酸或諸如氫氧化鋰、氫氧化鈉或氫氧化鉀之鹼金屬鹼存在下或在例如碘基三甲基矽烷之非質子性試劑存在下,在例如水、異丙醇/水、乙酸/水、四氫呋喃/水、或二噁烷/水之水性溶劑中水解。
藉由使用諸如鹽酸之酸,視情況在諸如乙酸之溶劑存在下,於50至120℃之間溫度下處理,或藉由使用氫氧化鈉溶液,視情況在如四氫呋喃或甲醇之溶劑存在下,於0至50℃之間溫度下處理,較佳將三氟乙醯基團R2
分解。
將使用之任一醯基或縮酮保護基團R2
分解,例如於0至120℃,較佳10至100℃之間溫度下,在諸如三氟乙酸、鹽酸或硫酸之酸存在下或在例如碘基三甲基矽烷之非質子性試劑存在下,在例如水、異丙醇/水、乙酸/水、四氫呋喃/水、或二噁烷/水之水性溶劑或水性溶劑混合物中水解。
在例如水、水性溶劑混合物或諸如甲醇或乙醇之低級醇中,在諸如氫氧化鋰、氫氧化鈉、碳酸鉀或甲氧化鈉之鹼存在下,將例如三甲基矽烷基之矽烷基R2
分解。
在水性或醇性溶劑中,諸如鹽酸、三氟乙酸或乙酸之酸亦合適。對於在諸如二乙醚、四氫呋喃或二氯甲烷之有機溶劑中分解而言,亦適於使用諸如氟化四丁基銨之氟化試劑。
將苄基、甲氧苄基或苄氧羰基R2
有利地經氫解作用裂解,例如在諸如鈀/木炭之催化劑存在下在諸如甲醇、乙醇、乙酸乙酯或冰醋酸之合適溶劑中使用氫,視情況在0至100℃之間之溫度下,但較佳在20至60℃之間之環境溫度下,且在1至7巴(bar),但較佳為3至5巴,之氫壓力下添加諸如鹽酸之酸。然而在苯甲醚作用下,較佳使2,4-二甲氧基苄基在三氟乙酸中分解。
較佳藉由使用諸如三氟乙酸或鹽酸之酸處理或使用碘基三甲基矽烷處理,視情況使用諸如二氯甲烷、二噁烷、甲醇或二乙醚之溶劑使第三丁基或第三丁氧基羰基R2
分解。
可經由化合物III之變旋異構碳-氧鍵之還原來合成式II之葡萄糖衍生物(流程1)。
流程1:化合物III之還原
R'及R1
如上文中所定義。R2
如上文中所定義,且表示例如氫、乙醯基、三甲基乙醯基、苯甲醯基、第三丁氧基羰基、苄氧基羰基、三烷基矽烷基、苄基或經取代苄基。若兩相鄰基團R2
相互連接以形成橋聯基團,則其較佳形成諸如亞苄基縮醛之縮醛、諸如亞異丙基縮酮之縮酮或導致形成二噁烷之伸乙基,例如與2,3-二甲氧基-丁烯結合,(其經由丁烯基之2及3位連接至哌喃醣之氧原子)。R2
之較佳意義為氫或三-(C1 - 3
-烷基)矽烷基,諸如三甲基矽烷基或三異丙基矽烷基。R'較佳表示氫或C1 - 4
-烷基,特定言之為甲基或乙基。
可使用還原劑在路易斯酸存在或不存在情況下進行該還原反應。合適之還原劑包括例如諸如三乙基矽烷、三丙基矽烷、三異丙基矽烷,或二苯基矽烷之矽烷類、硼氫化鈉、氰基硼氫化鈉、硼氫化鋅、硼錯合物、氫化鋰鋁、二異丁基氫化鋁或碘化釤。合適之路易斯酸為諸如醚合三氟化硼、三氟甲磺酸三甲基矽烷酯、四氯化鈦、四氯化錫、三氟甲磺酸鈧鹽、三氟甲磺酸銅(II)鹽,或碘化鋅;或合適之路易斯酸為諸如鹽酸、甲苯磺酸、三氟乙酸或乙酸之布忍斯特酸(BrΦnsted acid)。視還原劑而定,可在不使用路易斯酸時進行該還原反應。可在諸如二氯甲烷、氯仿、乙腈、甲苯、己烷、二乙醚、四氫呋喃、二噁烷、乙醇、水或其混合物之溶劑中進行該反應。較佳根據還原劑及視情況之路易斯酸來選擇溶劑。較佳反應溫度在-80℃與120℃之間,更佳在-30與80℃之間。
一種尤其合適之試劑組合包括例如三乙基矽烷及醚合三氟化硼,其可在-60℃至60℃溫度下方便地用於乙腈、二氯甲烷或其混合物中。
該還原反應較佳在無水時進行,特定言之該反應混合物中水含量低於2000 ppm,更佳低於1000 ppm。
除上述還原劑外,氫可用於所要之還原反應。在諸如鈀/木炭、氧化鈀、氧化鉑或雷氏鎳(Raney nickel)之過渡金屬催化劑存在下,在諸如四氫呋喃、乙酸乙酯、甲醇、乙醇、水或乙酸之溶劑中,於-40℃至100℃溫度及1至10托(Torr)氫壓力下可完成此轉換。
可藉由將所需苄基苯化合物以有機金屬化合物之形式反應來從D-葡萄糖酸內酯或其衍生物合成式II之葡萄糖衍生物(流程2a)。
流程2a:將有機金屬化合物添加到葡萄糖酸內酯中
該流程2a及以下部分描述根據本發明第三態樣方法之較佳條件及實施例。
可經由所謂鹵素-金屬交換反應或藉由將金屬插入碳-鹵素鍵中而從相應溴化或碘化苄基苯V製備苄基苯(VI)之格林納(Grignard)試劑或鋰試劑。可使用例如正丁基鋰、第二丁基鋰或第三丁基鋰之有機鋰化合物進行該鹵素-金屬交換,以合成相應鋰化合物VI。較佳量之有機鋰化合物在約1至2莫耳之範圍內,更佳約與該苄基苯V等莫耳。
使用合適格林納試劑(諸如C3 - 4
-烷基鎂氯化物或溴化物,例如異丙基-或第二丁基鎂溴化物或氯化物或二異丙基-或二第二丁基鎂),在不存在或存在諸如氯化鋰之可加速金屬化過程之額外鹽類的情況下,藉由鹵素-金屬交換亦可生成類似鎂化合物。該特定金屬轉移有機鎂化合物亦可由合適前驅體原位形成(參閱如Angew.Chem. 2004
,116
,3396-3399及Angew.Chem. 2006
,118
,165-169及其中所引用之文獻)。該格林納試劑較佳用量為每毫升苄基苯V約1至5莫耳範圍內。
該鹵素-金屬交換反應較佳在-100℃與40℃之間,尤其較佳在-80℃與10℃之間進行。該鹵素-鋰交換反應之更佳溫度範圍為-80℃至-15℃。
該鹵素-金屬交換反應較佳在惰性溶劑或其混合物中進行,例如二乙醚、二噁烷、四氫呋喃、二乙二醇二甲醚、甲苯、己烷、二甲亞碸、二氯甲烷或其混合物。尤其較佳之溶劑係選自四氫呋喃、二乙二醇二甲醚、二噁烷及其混合物。
由此獲得之鎂或鋰衍生化合物可視情況使用諸如三氯化鈰、氯化鋅或溴化鋅、氯化銦或溴化銦之金屬鹽進行金屬轉移,以形成適於添加之其他有機金屬化合物(VI)。
此外,亦可藉由將金屬插入鹵代芳族化合物V之碳-鹵素鍵中來製備該有機金屬化合物VI。鋰及鎂為此轉換之合適金屬元素。可在諸如二乙醚、二噁烷、四氫呋喃、甲苯、己烷、二甲亞碸及其混合物之溶劑中,於-80至100℃,較佳為-70至40℃之溫度範圍內實現該插入。在無自發性反應發生之情況下,金屬之先前活化可為必須,諸如使用1,2-二溴乙烷、碘、三甲基氯矽烷、乙酸、鹽酸處理及/或超音波處理。
較佳在-100℃與40℃之間,尤其較佳-80至-10℃之溫度下,在惰性溶劑或其混合物中將有機金屬化合物VI添加到葡萄糖酸內脂或其衍生物(IV)中,以獲得式III化合物。若化合物VI為鋰有機化合物,則更佳在-80至-20℃之溫度範圍內進行該添加。若化合物VI為鎂有機化合物,則在添加過程中之尤其較佳溫度在-30℃至-15℃之範圍內。
儘管在惰性氣體環境下進行較佳,但是所有以上反應均可在空氣中進行。氬氣及氮氣為較佳惰性氣體。
亦可在啟用高交換率之微反應器及/或微混合器中進行金屬化及/或偶合反應;如類似於WO 2004/076470中所描述之方法。
用於將金屬化化合物VI添加到適當保護之葡萄糖酸內脂IV中之合適溶劑為例如二乙醚、甲苯、二氯甲烷、己烷、四氫呋喃、二噁烷、N
-甲基吡咯啶酮及其混合物。
無需更多佐劑,或在有利於惰性反應偶合搭配物的諸如BF3
*OEt2
或Me3
SiCl之促進劑存在下進行該加成反應(參閱M.Schlosser,Organometallics in Synthesis,John Wiley & Sons,Chichester/New York/Brisbane/Toronto/Singapore,1994)。
流程2a中取代基R2
之較佳定義為苄基、經取代苄基、三烷基矽烷基、尤其較佳為三-(C1 - 3
-烷基)矽烷基,諸如三甲基矽烷基、三異丙基矽烷基、4-甲氧基苄基及苄基。若兩相鄰取代基R2
連接在一起,則該等兩取代基較佳部分為亞苄基縮醛、4-甲氧基亞苄基縮醛、異丙基縮酮或與2,3-二甲氧基-丁烯組成二噁烷(其經由丁烷之2及3位與哌喃醣之氧原子連接)。基團R'較佳表示氫、C1 - 4
-烷基、C1 - 4
-烷基羰基或C1 - 4
-烷氧基羰基,尤其較佳為氫、甲基或乙基。
將有機金屬化合物VI或其衍生物添加到葡萄糖酸內脂IV之後,引入基團R'。若R'等於氫或C1 - 4
-烷基,則將該反應溶液在諸如乙酸、甲磺酸、甲苯磺酸、硫酸、三氟乙酸或鹽酸之酸存在情況下用醇,尤其諸如甲醇或乙醇之C1 - 4
-烷醇或水處理。使用醇或水之此反應較佳在約0℃至80℃,尤其約20℃至60℃之溫度範圍內進行。在加入R'過程中,保護基團R2
若在所用反應條件下不穩定則會分解,生成相應質子化化合物,即化合物III,其中R2
等於H。例如保護基團(其中R2
表示三烷基矽烷基,諸如三甲基矽烷基)通常在使用醇及/或水在酸存在情況下分解,以獲得化合物III,其中R2
表示H。
在製備氫化合物III(R'=H)後,藉由使變旋異構羥基與諸如碘代甲烷、硫酸二甲酯、碘代乙烷、硫酸二乙酯、乙醯氯或乙酸酐之合適親電子劑在諸如三乙基胺、乙基二異丙基胺、碳酸鈉或碳酸鉀或碳酸銫、氫氧化鈉或氫氧化鉀或氫氧化銫之鹼存在下,亦可連接R'。在添加親電子劑前使用例如氫化鈉亦可將羥基去質子化。
流程2b:C-糖苷之合成--方法2
流程2b中所描述之方法2說明C-糖苷之合成,其開始於適當保護之D-葡萄烯糖XXX(參閱Synlett 2004
,第1235-1238頁;Org.Lett. 2003
,5
,第405-2408頁及其中所引用對類似方法之文獻)。將該受保護之D-葡萄烯糖XXX金屬化以生成D-葡萄烯糖衍生物XXXI,其中M表示鋰、鎂、鋅、銦、硼、錫、矽或鉻部分;特定言之鋰、鹵化鎂、鹵化鋅、鹵化銦、酸、酸酯。藉由使用強鹼去質子化可實現葡萄烯糖XXX在C-1處之金屬化。能夠將該葡萄烯糖去質子化之強鹼可為諸如正丁基鋰、第二丁基鋰或第三丁基鋰之鋰鹼。由此所得之C-1鋰化葡萄烯糖可使用傳輸相應之C-1金屬化葡萄烯糖衍生物之不同親電子金屬源進行金屬轉移。適用於隨後轉移、與配醣基部分偶合之金屬種類係來源於例如鋰、鎂、鋅、銦、硼、錫、矽及鉻。該葡萄烯糖化合物從鋰至上述金屬之一之金屬轉移作用可使用相應的例如諸如氯化物、溴化物及碘化物之鹵化物、諸如三氟甲磺酸鹽之磺酸鹽及烴氧化物(諸如待引入的金屬種類之甲氧化物、乙氧化物、丙氧化物及其丙氧化物)來進行。視金屬轉移至之金屬而定,該金屬可載有一種以上葡萄烯糖殘基,諸如在相應三葡萄糖酸銦或二葡萄糖酸鋅中。相應之單葡萄烯糖取代金屬衍生物亦為可用。該葡萄烯糖與強鹼(特定言之為鋰鹼)之金屬化較佳在惰性溶劑(如四氫呋喃、醚、二噁烷、二甲氧基乙烷、己烷及甲苯)中進行。較佳溫度在-80℃與50℃間之範圍內。視相同溫度範圍內之親電子金屬種類而定,該金屬轉移可在相同溶劑中進行。在金屬轉移作用中可用之親電子金屬種類中,以下最為合適:三烷基氯化錫烷、四氯錫烷、三烷基氯化矽烷、三烷氧基氯化矽烷基氯化物或溴化物、三氯化硼、三烷基硼酸鹽、二烷基氯化硼烷、三氯化銦、氯化鋅、三氟甲磺酸鹽或溴化物、氯化鎂或溴化鎂。此編集決不意謂將該等可用金屬親電子劑限制為以上所述,而是提供一種可使用親電子劑之概念。在以上及以下所描述之反應中,該等保護基團R2
較佳根據其在鹼性條件下之穩定性而選擇,特定言之該等基團R2
彼此獨立地表示-SiRa
Rb
Rc
,其中兩相鄰基團R2
可相互連接以形成橋聯基團SiRa
Rb
,其中Ra
、Rb
、Rc
如上文中所定義,較佳表示異丙基。
由此所得式XXXI之金屬化葡萄烯糖衍生物可與配醣基V偶合,其中基團X表示脫離基,較佳選自由下列各物組成之群:氯、溴、碘、諸如三氟甲磺酸鹽、甲苯磺酸鹽、苯磺酸鹽及甲磺酸鹽、氯磺酸鹽之磺酸鹽、硫酸或其鹽類、羥基羰基或其鹽類、腈及重氮鹽。該偶合反應較佳在過渡金屬催化劑(如鈀、銅、鐵及鎳之鹽類、錯合物或元素改質)存在下進行。錯合物可原位形成或在將過渡金屬添加到該反應混合物之前形成。過渡金屬之錯合物中之配位體可為如三芳基膦、芳基二烷基膦、三烷基膦、亞磷酸鹽、1,3-二取代二氫咪唑鎓碳烯、1,3-二取代咪唑鎓碳烯及烯烴。該反應較佳在惰性有機溶劑或其混合物中進行。合適之溶劑可為例如四氫呋喃、二噁烷、二甲氧基乙烷、己烷、甲苯、苯、二甲基甲醯胺、二甲基乙醯胺、N-甲基吡咯啶酮、丙酮、乙酸乙酯、水、甲醇、乙醇、丙醇、異丙醇、乙二醇、聚乙二醇。該偶合反應較佳在-80℃與180℃之間進行,更佳為-20℃至120℃。流程2b中之結束合成步驟為將水克式量添加至葡萄烯糖部分之雙鍵中。可藉由如硼氫化反應(其導致2-硼-2-脫氧葡萄糖衍生物之形成,其可藉由碳-硼鍵之氧化作用轉化為相應葡萄糖化合物)完成此過程。用於硼氫化反應之合適硼烷為如硼烷或醚、硫醚或其胺加合物、烷基硼烷或二烷基硼烷(如己基硼烷、第三己基硼烷、二乙基硼烷及9-BBN、四甲基乙二醇硼烷、兒茶酚硼烷、鹵化或諸如二氯硼烷之二鹵化硼烷。該硼氫化反應可在例如四氫呋喃、己烷、環己烷、醚、甲苯、苯、二氯甲烷中進行。較佳溫度範圍在-50℃與150℃之間,較佳在-20℃與50℃之間。可使用氧化試劑(如過氧化氫、第三丁基過氧化氫、過硼酸鈉及N-氧化三烷基胺)進行該碳-硼鍵之氧化性分解。視氧化試劑而定,該反應在諸如氫氧化鈉之鹼存在下有利地進行。該反應較佳在惰性有機溶劑或其混合物中進行。較佳溶劑係選自四氫呋喃、水、醇、二噁烷、二甲氧基乙烷、環己烷、己烷、甲苯、二氯甲烷及其混合物。較佳溫度範圍在-30℃至150℃之間,較佳為0℃至110℃。一種旨在將水添加到雙鍵之硼氫化反應的替代方法為雙鍵之環氧化或雙羥基化,及所得變旋異構碳-氧鍵之還原。在過渡金屬催化劑存在下用於環氧化之合適氧化試劑為例如二甲基二氧、三氟二甲基二氧、3-氯過氧苯甲酸、過氧化氫及氧。另一合適氧化劑為過氧單硫酸、過氧二硫酸及其鹽類,在至少一種酮存在下(特定言之為式2 KHSO5
×KHSO4
×K2
SO4
之三合鹽,其以OXONE(商標E.I.du Pont de Nemours)及CAROAT(商標Degussa,Peroxid-Chemie GmbH & Co.KG,Dr.-Gustav-Adolph-Str.3,D-82049 Pullach,Germany)之商標名市售)與較佳為丙酮之酮組合之情況下。可使用如四氧化鋨及二鉀四氧化鋨,較佳在其氧化劑(如六氰鐵酸鉀、過氧化氫及N-氧化N-甲基嗎啉)存在下完成二羥基化作用;由環氧化作用所得之氧水解亦提供該二羥基化產物。該氧化反應可在惰性有機溶劑或其混合物(如二氯甲烷、四氫呋喃、醚、己烷、環己烷、二噁烷、丙酮、乙酸乙酯、乙腈、水、醇及其混合物)中進行。較佳溫度範圍在-80℃與100℃之間,較佳在-50℃與50℃之間。可使用還原劑例如諸如三乙基矽烷之三烷基矽烷、諸如硼氫化鈉之硼氫化物及諸如二異丁基氫化鋁之氫化鋁完成氧或地二羥基化產物中變旋異構碳-氧鍵之還原。視還原劑而定,諸如醚合三氟化硼、氯化鋅、氯化三甲基矽烷或三氟甲磺酸鹽、烷基鹵化物、二烷基鹵化物或鹵化鋁、三氟甲磺酸銅之路易斯酸,及諸如鹽酸、乙酸、烷基磺酸或芳磺酸、三氟乙酸之布忍斯特酸為必需或至少有利的。二氯甲烷、乙腈、四氫呋喃、醚、己烷屬於較佳溶劑。較佳溫度範圍在-80℃與120℃內。氫亦可與過渡金屬催化劑(諸如鈀/木炭、雷氏鎳及氫氧化鈀)組合使用。
隨後,可藉由分解(特定言之水解)將式XXXIII之產物轉移至式I之產物中,保護基團R2
不為氫,有利地使用上文中所描述之方法。
流程2c:C-糖苷之合成-方法3
流程2c說明了起始於葡萄烯糖XXX的得到C-糖苷之替代方法(參閱如Synlett 2003
,870-872頁;Tetrahedron 2002
,58
,1997-2009頁及其中所引用對類似方法之文獻)。使用合適氧化試劑之環氧化作用將葡萄烯糖XXX轉化為相應之氧化葡萄烯糖XXXIV。已描述與流程2b中所示葡萄烯糖XXXII類似轉化率之轉換之合適反應條件。在所述氧化劑中,分別或原位形成之二甲基二氧及三氟二甲基二氧為較佳。可使用如過氧單硫酸、過氧二硫酸及其鹽類,在至少一種酮存在下(特定言之以式2 KHSO5
×KHSO4
×K2
SO4
之三合鹽,其以OXONE(商標E.I.du Pont de Nemours)及CAROAT(商標Degussa,Peroxid-Chemie GmbH & Co.KG,Dr.-Gustav-Adolph-Str.3,D-82049 Pullach,Germany)之商標名市售)與較佳為丙酮之酮組合之情況下,獲得該氧化劑。較佳在-80與0℃溫度範圍內,在惰性有機溶劑或其混合物中進行該反應。較佳溶劑係選自由下列各物組成之群:二噁烷、1,2-二甲氧基乙烷、甲苯、己烷、四氫呋喃、二乙醚、二氯甲烷及其混合物。在上文及下文所述之反應中,該等保護基團R2
較佳係彼此獨立地選自由下列各物組成之群:C1 - 4
-烷基羰基、C1 - 4
-烷氧基羰基、芳基甲基及Ra
Rb
Rc
Si,其中芳基、Ra
、Rb
及Rc
如上文中所定義。
隨後使用式VI之金屬化配醣基之反應、環氧化物開環(其中M表示鋰、鎂、鋅、銦、鋁或硼部分)提供所要之C-糖苷。對於該轉換,M之較佳含義為鋰、鹵化鎂、鹵化鋅、鹵化銦、鹵化鋁、鹵化二烷基鋁或酸化合物。流程2a中詳細描述了化合物VI之鋰或鎂衍生物之合成,而該等化合物至替代金屬種類之一之金屬轉移可類似於流程2b中鋰化葡萄烯糖至相同金屬衍生物之金屬轉移而完成。無需佐劑或在過渡金屬鹽或錯合物(如氰化銅或鹵化銅)存在或在如醚合三氟化硼或氯化三甲基矽烷或三氟甲磺酸鹽之路易斯酸存在情況下,可發生該環氧化物開環反應。合適惰性溶劑可為如丙酮、醚、四氫呋喃、乙腈、二氯甲烷、甲苯、己烷及其混合物。較佳溫度範圍在-80℃至60℃之間。
隨後,可藉由分解(特定言之水解)將式XXXIII之產物轉移至式I之產物中,保護基團R2
不為氫,有利地使用上文中所描述之方法。
流程2d:C-糖苷之合成-方法4
在變旋異構碳上載有潛在脫離基Hal之葡萄糖衍生物XXXV亦可作為起始材料用於與金屬化芳基配醣基VI偶合(參閱J.Carbohydr.Chem. 1994
,13
,303-321頁及其中所引用對類似方法之文獻)。合適之脫離基Hal可為鹵化物、烴氧化物、醯基(如羧酸鹽及碳酸鹽);特定言之為F、Cl、Br、C1 - 3
-烷基羰基氧基、C1 - 3
-烷氧基羰基氧基或C1 - 3
-烷氧基,諸如Cl、Br、甲氧化物、乙酸酯及碳酸甲酯。連接至芳基部分之合適金屬M為如鋰、諸如鹵化鎂之鎂、諸如鹵化鋅之鋅、諸如二鹵化銦之銦、諸如酸或酸酯之硼。流程2c中已描述由相應鹵化芳族製備該等金屬化芳基化合物。視所使用金屬種類及葡萄糖基供體而定,無需或在額外路易斯酸(如醚合三氟化硼、氯化三甲基矽烷或三氟甲磺酸鹽)存在情況下可進行該取代反應。該反應較佳在惰性有機溶劑或其混合物中進行。較佳考慮金屬化配醣基、葡萄糖基供體及所需佐劑而選擇較佳溶劑;以下溶劑可為有利:四氫呋喃、二噁烷、甲苯、己烷、醚、N-甲基吡咯啶酮、二甲基乙醯胺、二甲基甲醯胺、乙腈、二氯甲烷及其混合物。該偶合反應通常在-80℃與120℃之間進行,較佳為-60℃至60℃。在上文及下文所述之反應中,該等保護基團R2
較佳係彼此獨立地選自由下列各物組成之群:C1 - 4
-烷基羰基、C1 - 4
-烷氧基羰基、芳基甲基及Ra
Rb
Rc
Si,其中芳基、Ra
、Rb
及Rc
如上文中所定義。
隨後,可藉由分解(特定言之水解)將式II之產物轉移至式I之產物中,保護基團R2
不為氫,有利地使用上文中所描述之方法。
使用有機化學中標準轉換或至少一種由有機合成中專題文獻所知之方法,可進行鹵化芳烴化合物V之合成(參閱inter alia J.March,Advanced Organic Reactions,Reactions,Mechanisms,and Structure,4th Edition,John Wiley & Sons,Chichester/New York/Brisbane/Toronto/Singapore,1992及其中所引用文獻)。以下所描述之該合成策略提供其示範,作為實例。
在以下流程中除非另外說明,否則X表示溴或碘,Alk表示C1 - 4
-烷基,R表示C1 - 4
-烷基、C1 - 4
-烷氧基、CF3
、芳基或芳基-C1 - 3
-烷基,其中芳基可經L1單取代或多取代;R1
如上文中所定義;且L1如上文中所定義。
流程3顯示起始於二苯基酮衍生物IX之配醣基V之合成,該二苯基酮衍生物IX可由苯甲酸衍生物及苯基烷基醚或金屬化苯基烷基醚製備(見流程5、8及9)。第一步驟為化合物IX中醚部分之分解,其可在中性、酸性及鹼性條件下完成。用於此轉換之合適酸試劑為例如三氯化硼或三溴化硼或三碘化硼或碘基三甲基矽烷、氯化鋁或溴化鋁、氫溴酸、鹽酸、氯化鈰、三氟乙酸及三氟甲磺酸,其可與諸如金屬鹵化物之親核試劑一起使用(如碘化鈉、水、烷硫醇、硫代苯甲醚及硫化二烷,其可除去脫離基團。根據所使用酸,選自由下列各物組成之群之溶劑為較佳:鹵化烴(如二氯甲烷、氯仿或1,2-二氯乙烷)、乙腈、甲苯、己烷、乙酸及其混合物。無額外溶劑之反應亦可行。該等反應通常在-90至150℃下進行,較佳為-80至50℃。使用如金屬硫醇鹽(如硫化鈉、乙硫醇鈉、三甲基硫醇矽鈉、苯硫酚鉀、氰化鈉及碘化鋰),在溶劑(如二甲基甲醯胺、二甲基乙醯胺、1,3-二甲基-2-氧代六氫化嘧啶、N-甲基吡咯啶酮、四氫呋喃、三甲基吡啶及喹啉),於0與250℃之間溫度下(較佳50至180℃),可完成中性或鹼性條件下之分解。流程3中概述之第二步驟包含將殘基R1
連接到化合物VIII之苯酚氧。如同經典親核取代反應,該轉換可在鹼性條件下進行。因此,藉由鹼將該苯酚去質子化以形成相應苯酚鹽。合適鹼為如基團I或II之金屬鹽,特定言之為碳酸鹽、氫氧化物、醇化物(如甲氧化物、乙氧化物或第三丁氧化物)及諸如氫化鈉之金屬氫化物。可在極性及非極性溶劑中以及無需溶劑,較佳在醇(如乙醇、異丙醇或丁醇)、丙酮、水、二甲基甲醯胺、二甲基乙醯胺、N-甲基吡咯啶酮、二甲亞碸、四氫呋喃、二氯甲烷及其混合物中進行該反應。隨後在20與180℃,較佳40與120℃溫度之間將所得酚鹽與R1
之親電子劑反應。合適之R1
親電子劑為如鹵化物(如氯化物、溴化物或碘化物)、烷基磺酸鹽(如甲磺酸鹽)、三氟甲磺酸鹽、芳基磺酸鹽(如4-溴苯基磺酸鹽、4-甲基苯基磺酸鹽或酚磺酸鹽)。將R1
連接至苯酚VIII之一替代方法為將苯酚VIII添加至載有合適位置C=C雙鍵之基團R1
。在布忍斯特酸(如三氟甲磺酸、鹽酸、硫酸)或過渡金屬催化劑(如鉑、釕、鈀或金之鹽類及其錯合物)作用下,可進行改反應;較佳鹽類為三氟甲磺酸鹽、氯化物、溴化物及碘化物(參閱如Cai-Guang Yang及Chuang He;J.Am Chem.Soc. 2005
,127
,及其中所引用之文獻)。最適於該添加之溶劑取決於所使用之酸或過渡金屬。如甲苯、苯、二氯甲烷、1,2-二氯乙烷、乙腈、四氫呋喃、二甲基乙醯胺、N-甲基吡咯啶酮、己烷及乙酸乙酯之溶劑係合適。該反應在0至200℃,較佳20至140℃下進行。流程3以二苯基酮VII之還原作為結束,以提供配醣基V。用於該轉化之合適還原劑為諸如Et3
SiH及三異丙基矽烷之矽烷、諸如NaBH4
之硼氫化物及諸如LiAlH4
之氫化鋁,在路易斯酸(如BF3
* OEt2
、三(五氟苯基)硼烷、三氟乙酸、鹽酸、氯化鋁或InCl3
)存在下。較佳在溶劑如鹵化烴(如二氯甲烷及1,2-二氯乙烷)、甲苯、苯、己烷、乙腈及其混合物中,在-30至150℃,較佳20至100℃溫度下進行該反應。在諸如Pd/炭之過渡金屬催化劑作用下加氫還原為另一可能之合成方法,但由於在剩餘分子中之競爭性還原,可能不太適用。根據沃夫-奇希諾(Wolff-Kishner)或其變體方法之還原亦為可能。因此將該酮與肼或其衍生物(如1,2-二(叔丁基二甲基矽基)肼)轉化為腙,其在強鹼性反應條件及加熱下分解,以釋放二苯基甲烷V及氮氣。可在一罐中或在腙或其衍生物分離後在兩獨立反應步驟中進行。合適鹼包括如在溶劑(如乙二醇、甲苯、DMSO、2-(2-丁氧基乙氧基)乙醇或第三丁基丁醇)中之KOH、NaOH或KOtBu;無溶劑反應亦為可能。該反應可在20與250℃,較佳80與200℃之間之溫度下進行。對於沃夫-奇希諾(Wolff-Kishner)還原鹼性條件之替代方法為克萊門森(Clemmensen)還原,其在酸性條件下進行,若無並行脫鹵作用發生,則亦可在此使用該方法。
流程3:配醣基V之合成--方法1
流程4概述與流程3略為不同之配醣基V合成方法。然而,大體上可在與關於化合物VIII及VII之上述合成類似之反應條件下進行流程4中描述之醚分解及隨後之醚化作用。
流程4:配醣基V之合成--方法2
流程5描述配醣基V之合成,其起始於已知氯化苯甲醯XII及苯基醚衍生物XIII。第一步,製備二苯基酮VII,其特徵在於作為有機合成中為人熟知且廣泛使用的方法之弗瑞德-克來福特(Friedel-Crafts)或弗瑞德-克來福特型醯化作用。大體上,該氯化苯甲醯XII可由其它苯甲酸衍生物(如苯甲醯酸酐、酯或苯甲腈)替代。該經典反應具有廣泛基質範圍且通常在以催化量或化學計量之催化劑(諸如AlCl3
、FeCl3
、碘、鐵、ZnCl2
、硫酸或三氟甲磺酸)存在下進行。該反應較佳在諸如二氯甲烷或1,2-二氯乙烷之氯化烴、諸如己烷之烴中,於-30至140℃,較佳30至100℃之溫度範圍內進行。然而,其它溶劑及溶劑混合物以及無溶劑反應或微波爐內之反應亦為可能。流程5中第二反應步驟類似於上文中所述流程3之最後反應。
流程5:配醣基V之合成--方法3
流程6說明配醣基V之替代合成,其經由苯基醚XIII與苄基親電子劑XIV之弗瑞德-克來福特型烷基化(參閱Angew.Chem. 2005
,117
,第242-246頁及Syn.Commun. 2004
,34
,第3161-3165頁及其中所引用之文獻)。該反應通常在催化劑存在下進行,催化劑特定言之為諸如氯化鈧、氯化鋅、氯化鋁或三氟化硼之路易斯酸、諸如硫酸、鹽酸或氟化氫之布忍斯特酸、諸如硫酸鈰或氯化鐿之鑭族鹽、錒族鹽、過渡金屬鹽或諸如IrCl3
* nH2
O、RhCl3
* nH2
O、H2
[PtCl6
]* 6H2
O或H2
[PdCl6
]* 6H2
O之錯合物。該等催化劑可以化學計量量或過量應用,但在多數情況下以化學計量量或甚至催化量即足夠。該反應通常使用與無溶劑苄基親電子劑相關之過量芳族化合物XIII進行;然而亦可使用諸如鹵化烴或烴之惰性溶劑。該反應通常在0與200℃(較佳為20至140℃)之間溫度下進行。
流程6:配醣基V之合成--方法4
流程7中所表示之方法開始於自單取代酚XV合成苯醚XVI,其可類似於流程3中所示之醚化反應之合成而進行。在流程7之第二步驟中,殘基Z2
與金屬或經取代金屬殘基交換。按照流程2a中描述金屬化配醣基VI之相同方法,可由氯化、溴化或碘化芳族化合物XV製備鋰或鎂取代之芳族化合物XVII。藉由與合適硼親電子劑(諸如酸酯、鹵代酸酯、烷基酸酯、二烷基酸酯、三鹵代硼烷及其衍生物)反應,可由該等金屬化苯基XVII獲得相應硼取代化合物,如酸、酸酯或二烷基芳基硼烷。此外,亦可由相應氯化、溴化、碘化或准鹵化物(諸如三氟甲磺酸鹽及甲苯磺酸鹽前驅體)及二硼化合物(諸如雙(四甲基乙二醇基)二硼及雙(新戊基-乙二醇基)二硼)或諸如四甲基乙二醇硼烷之硼烷,經由過渡金屬催化反應製備該硼化芳族化合物XVII(參閱Tetrahedron Lett. 2003
,第4895-4898頁及其中所引用之文獻)。該過渡金屬為例如作為元素、鹽或錯合物使用之鈀;常用Pd源為例如鈀/木炭、乙酸鈀、氯化鈀、溴化鈀、二亞苄基丙酮鈀,其如此使用或與配位子組合使用,該配位子為諸如膦(如三環己基膦、三苯基膦、1,1'-雙(二苯基膦基)二茂鐵及三甲苯基膦)或亞磷酸鹽或咪唑鎓鹽(如1,3-二芳基或二烷基咪唑鎓鹵化物或准鹵化物)或二氫咪唑鎓鹽。所得過渡金屬之錯合物及配位子可原位或在獨立步驟中製備。較佳在諸如三乙胺、乙酸鉀、碳酸鉀、磷酸鉀、氫氧化鈉、三乙胺或乙基二異丙基胺之鹼存在下在諸如乙腈、四氫呋喃、二甲亞碸、二甲基甲醯胺、二甲基乙醯胺、N-甲基吡咯啶酮、二噁烷、甲苯及其混合物之溶劑中,於0至180℃(較佳60至140℃)下進行該等反應。鋰或鎂取代苯基化合物XVII自發添加至苯甲醛XVIII,提供二芳基甲醇XIX。可在諸如二乙醚、四氫呋喃、甲苯、二氯甲烷、二噁烷、諸如己烷之烴及其混合物之溶劑中,於-100至20℃,較佳-80至0℃之溫度範圍內進行該反應。可藉由銠催化反應將芳基酸XVII添加至苯甲醛衍生物XVIII中,提供相應二芳基甲醇XIX(參閱Adv.Synth.Catal. 2001
,343-350頁及其中所引用之文獻)。流程7之結束步驟為對配醣基V而言二芳基甲醇XIX之還原。用於此轉換之合適還原劑為例如NaBH4
、LiAlH4
、iBu2
AlH、Et3
SiH、iPr3
SiH或Ph2
SiClH。該反應通常在諸如BF3
* OEt2
、三氟乙酸、鹽酸、InCl3
或AlCl3
之路易斯酸存在下,在諸如鹵化烴(例如二氯甲烷或1,2-二氯乙烷)、甲苯、例如己烷之烴、乙腈或其混合物之溶劑中,於-80至150℃、較佳-20至100℃之溫度下進行。以氫在諸如鈀/木炭之過渡金屬催化劑存在下進行之還原大體上亦為可能,但尤其必須注意使用此方法以保持分子之其它部分的充分完整性。
流程7:配醣基V之合成--方法5
流程8中所概述之合成開始於將金屬化苯基醚衍生物XXI添加至苯甲酸或其衍生物(XX)(諸如苯甲酸酯、苯甲酸酐)、苯甲醯胺(如Weinreb型、苯甲腈或氯化苯甲醯)以生成二苯基酮VII。大體上可將鋰或鎂衍生苯基醚XXI添加至苯甲醯胺、苯甲酸酯、氯化苯甲醯、苯甲酸酐及苯甲腈,以提供所需二苯基酮VII,而僅有鋰化苯基醚與苯甲酸反應以生產相同化合物。後一反應可在例如四氫呋喃、二噁烷、二乙醚、苯、甲苯、己烷及其混合物中,於-80至100℃,較佳-30至40℃下進行。苯甲腈及苯甲醯胺(諸如相應之Weinreb型胺或其相近衍生物)較佳在四氫呋喃、二噁烷、甲苯、己烷、醚及其混合物中,於-90至50℃,較佳-80至20℃溫度下進行反應。氯化苯甲醯或酸酐及苯甲酸酯通常在低溫(較佳為-80至0℃)下用於諸如四氫呋喃、二乙醚、甲苯、二氯甲烷、二噁烷、諸如己烷之烴及其混合物之惰性溶劑。要防止對氯化苯甲醯、苯甲醯酸酐或苯甲酸酯之有機金屬化合物之雙加成而生成相應之醇,該加成可在諸如氯化三甲基矽烷之捕捉試劑存在下優先進行。用於防止上述情況中雙加成之替代選擇可為對較低反應性親核劑XXI之金屬轉移。合適金屬為如鋅、鈰、鉻、或銦,將其作為氯化、溴化、碘化或諸如三氟甲磺酸鹽之准鹵化鹽引入以使鋰或鎂化合物金屬轉移,以提供相應較低反應性更高選擇性之金屬化合物XXI。較佳在其中生成初始有機金屬化合物之溶劑(見上文)中,於-90至0℃之溫度下執行該金屬轉移。金屬轉移不限於上述金屬及已在流程7中描述之硼衍生化合物,但亦可提供例如錫烷或矽烷。某些金屬轉移化合物自發與相應苯甲醯基親電子劑(特定言之為氯化苯甲醯及酸酐)反應,但添加過渡金屬催化劑較為有利。特定言之,芳基酸、其酯、二烷基芳基硼烷、芳基三氟硼烷、錫烷、矽烷、銦、鉻及鋅衍生化合物XXI與由過渡金屬(如鈀、銅、鐵、鎳)調節之氯化苯甲醯衍生物XX偶合,其中過渡金屬可用作元素或與配位子(諸如亞磷酸鹽、例如三苯基膦、三環己基膦、三甲苯基膦之膦、1,3-取代咪唑鎓或二氫咪唑鎓化合物)結合的鹽(諸如乙酸鹽、氯化物、溴化物、碘化物、乙醯基丙酮酸鹽、三氟甲磺酸鹽及氰化物),生成二芳基酮VII。不僅在添加至偶合搭配物之前,而且在原位反應搭配物存在情況下,可製備活性過渡金屬種類。合適溶劑為例如二甲基甲醯胺、二甲基乙醯胺、N-甲基吡咯啶酮、二甲亞碸、二噁烷、醚、己烷、甲苯、四氫呋喃、二氯甲烷或其混合物,其較佳在-50至150℃,尤其較佳為0至120℃之溫度下使用。用於獲得配醣基V之結束轉化已在上文中詳細描述且可在此類似地應用。
流程8:配醣基V之合成--方法6
根據流程9,可按如上所述合成之金屬化芳基XXIII亦可與苄基親電子劑XXII(諸如苄基氯化物、溴化物、碘化物、磺酸鹽、磷酸鹽、碳酸鹽或羧酸鹽)反應,得到二芳基甲烷V。鋰或鎂衍生苯基化合物XXIII較佳(但不總為必須)在過渡金屬(如銅、鐵、鎳或鈀)作用下進行反應(參閱如Org.Lett. 2001
,3
,2871-2874 andTetrahedron Lett. 2004
,第8225-8228頁及其中所引用之文獻)。有用溶劑為例如四氫呋喃、二噁烷、甲苯、二氯甲烷、己烷、醚或其化合物。反應溫度之範圍為-90至20℃,較佳為-80至-20℃。該過渡金屬可作為諸如木炭之元素、作為鹽(如乙酸鹽、乙醯基丙酮酸鹽、氰化物、氯化物、溴化物、碘化物、三氟甲磺酸鹽)或作為諸如二亞苄基丙酮、亞磷酸鹽之錯合物、諸如三苯基膦、三環己基膦及三甲苯基膦之膦、或來源於如1,3-二取代咪唑或二氫咪唑化合物之碳烯而使用。在反應搭配物存在情況下,或在添加至偶合搭配物之前,可原位製備活性過渡金屬種類。載有如硼、錫、矽、鋅、銦、鉻殘基之芳基金屬化合物XXIII較佳與過渡金屬催化劑組合使用。此種類型之合適金屬化合物為例如酸、酸酯、二烷基硼烷、三氟硼烷、三烷基錫烷、三氯錫烷、三烷氧基矽烷、二鹵化銦取代或鹵化鋅取代化合物。金屬取代化合物XXIII可按上文所述藉由從相應鋰或鎂衍生化合物金屬轉移而合成,或在鋅、鉻及銦之情況下亦藉由元素金屬之插入直接來自相應芳基氯化物、溴化物或碘化物。可在四氫呋喃、二甲基甲醯胺、二甲基乙醯胺、N
-甲基吡咯啶酮、二甲亞碸、甲苯、醚、二噁烷、二氯甲烷、乙腈、己烷、水、諸如甲醇、異丙醇之醇或其混合物中,於-30至180℃,較佳20至150℃之反應溫度下進行與苄基親電子劑之偶合反應。視該金屬而定,額外之鹼(諸如三乙基胺、乙基二異丙基胺、碳酸銫或碳酸鉀或碳酸鈉或碳酸鋰、第三丁氧化鉀或第三丁氧化鈉或第三丁氧化鋰、磷酸鉀、氟化鉀或氟化銫或氟化四丁銨、氫氧化鈉、氫氧化鉈、甲醇鈉)及/或其它添加劑,諸如氯化鋰、諸如碳酸鹽或氧化物之銀鹽、溴化四丁銨及溴化鈉將可為有利的甚至必需的(例如M.Schlosser,Organometallics in Synthesis,John Wiley & Sons,Chichester/New York/Brisbane/Toronto,1994及其中所引用之文獻)。
流程9:配醣基V之合成--方法7
流程10顯示經由中間物XXVI(其可根據流程8製備)獲得配醣基V之路徑。若Z5
表示諸如F之鹵素,則中間物XXVI可根據流程5另外由弗瑞德-克來福特醯化作用製備。可經由不同方法實現以O-R1
置換化合物XXVI中Z5
。在Z5
較佳表示氟、氯、碘、三氟甲磺酸之情況下,可根據親核取代將O-R1
連接至苯環,其中R1
-OH或其陰離子在加成/消除序列中置換Z5
。通常在諸如二甲基甲醯胺、二甲基乙醯胺、二甲亞碸、四氫呋喃、二噁烷、第三丁基醇、甲苯、N
-甲基吡咯啶酮、水、醇或其混合物之溶劑中,在如第三丁氧化鋰或第三丁氧化鈉或第三丁氧化鉀、碳酸鈉或碳酸鉀或碳酸銫、氫氧化鈉或氫氧化鉀、磷酸三鉀、三乙胺、乙基二異丙基胺、二氮雜二環十一烯之鹼存在下,於0至180℃,較佳40至140℃範圍內之溫度下進行該反應。R1
-OH亦可作為溶劑使用且可使用例如氫化鈉或鈉去質子化,以在添加化合物XXVI前形成烷氧化物。要增強R1
-O-金屬之親核性,添加冠醚(如18-冠-6)係有用。可分離中間物XXVI與R1
-OH之偶合亦可在例如來源於Pd或Cu之過渡金屬鹽或錯合物中進行(Ullmann或Ullmann型反應)。其中Z5
較佳表示碘或三氟甲磺酸鹽。對於無催化反應所描述之相同溶劑、鹼、添加劑及溫度可用於催化反應,除非後者較佳在諸如氬氣或氮氣之惰性氣體環境中進行。該催化劑通常作為元素(如此或在木炭上)、作為鹽(如氯化物、溴化物、碘化物、乙酸鹽、氰化物)或作為與配位子(如亞磷酸鹽、膦、1,3-二取代咪唑或二氫咪唑碳烯)之錯合物而使用。若Z5
表示芳基酸或三氟酸鹽,則在諸如三乙胺或吡啶之鹼中,在溶劑(如四氫呋喃、二氯甲烷、1,2-二氯乙烷、乙腈、二噁烷、二甲基甲醯胺、二甲基乙醯胺及N-甲基吡咯啶酮)中,R1
-OH可經由銅(II)催化反應連接至諸如二乙酸銅之銅源。可使用化學計量之銅催化劑或在其氧化劑(如氧氣、吡啶-N-氧化物或環氧四甲基哌啶)與僅以催化計量之催化劑作用下進行該反應。乾燥溶劑及諸如分子篩之乾燥劑之存在係有利(參閱例如Angew.Chem. 2003
,115
,5558-5607頁及其中所引用之文獻)。
流程10:配醣基V之合成--方法8
流程11顯示獲取對應於流程10之配醣基V之較佳方法,其中中間物XXVI較佳根據流程5由弗瑞德-克來福特醯化製備。流程11及以下部分描述了本發明第七態樣之較佳條件及實施例。
配醣基V之合成起始於已知氯化苯甲醯XII及鹵苯XXVII。取代基X較佳表示溴或碘原子。取代基Z5
之較佳含義為氟原子。第一步,製備二苯基酮XXVI,其特徵在於有機合成中為人熟知之弗瑞德-克來福特或弗瑞德-克來福特型醯化作用。大體上,該氯化苯甲醯XII可由其它苯甲酸衍生物(例如苯甲醯酸酐、酯或苯甲腈)替代。在催化劑(例如AlCl3
、FeCl3
、碘、鐵、ZnCl2
、硫酸或三氟甲磺酸,其均以催化量或至多化學計量量使用)存在下有利地進行該反應。一種較佳之催化劑為AlCl3
。可使用或不使用額外溶劑進行該反應。較佳之額外溶劑為諸如二氯甲烷或1,2-二氯乙烷之氯化烴、諸如己烷之烴或其混合物。根據一較佳實施例,使用額外充當溶劑之過量鹵苯XXVII進行該反應。反應期間之較佳溫度為-30至140℃,較佳為30至85℃。在反應完成後可用水中止該反應混合物較佳地將該等有機溶劑移除。較佳藉由結晶將該中間物XXVI從例如水中分離。
流程11中之第二反應步驟為用O-R1
置換Z5
,其類似於如上文中所述之流程10之第二反應步驟。根據一較佳實施例,根據親核取代將O-R1
連接到芳環上,其中R1
-OH或其陰離子以加成/消除序列取代Z5
。該反應有利地在諸如二甲基甲醯胺、二甲基乙醯胺、二甲亞碸、四氫呋喃、二噁烷、第三丁基醇、甲苯、庚烷、N-甲基吡咯啶酮、水、醇或其混合物溶劑中進行。較佳溶劑係選自二甲基甲醯胺、四氫呋喃及二甲基乙醯胺。
此反應較佳在諸如鹼性C1 - 4
-烷氧化物、鹼性碳酸鹽、鹼性氫氧化物、鹼性磷酸鹽、三(C1 - 3
烷基)胺之鹼及其它N-含有機鹼作用下進行。較佳鹼之實例為第三丁氧化鋰或第三丁氧化鈉或第三丁氧化鉀、碳酸鈉或碳酸鉀或碳酸銫、氫氧化鈉或氫氧化鉀、磷酸三鉀、三乙胺、乙基二異丙胺、雙(三甲基矽烷基)醯胺鈉(NaHMDS)、二氮雜二環十一烯(DBU)、1,4-二氮雜二環[2.2.2]辛烷(DABCO)或其混合物。更佳鹼係選自第三丁氧基鈉或第三丁氧基鉀、氫氧化鈉或氫氧化鉀、碳酸銫、碳酸銫及碳酸鉀之混合物或其混合物。鹼用量較佳在每莫耳中間物XXVI自1至5莫耳鹼之範圍內。在該鹼為碳酸鹽、磷酸鹽或其混合物之情況下,該鹼總量更佳在每莫耳中間物XXVI自2至4莫耳鹼之範圍內,最佳在每莫耳中間物XXVI約3莫耳鹼之範圍內。
該反應較佳在約-20至60℃,更佳約-10至40℃,甚至更佳約0至30℃範圍內之溫度下進行。
該中間物VII可較佳藉由結晶從反應混合物中分離,例如從乙醇與水之混合物中分離。
根據流程11之合成途徑以二苯基酮VII之還原作為結束,以得到配醣基V。在諸如BF3
* OEt2
、三(五氟苯基)硼烷、三氟乙酸、鹽酸、氯化鋁或InCl3
之路易斯酸存在下,用於此轉化之合適還原劑為矽烷,特定言之為三(C1 - 3
-烷基)矽烷(例如三乙基矽烷、二甲基乙基矽烷及三異丙基矽烷)、諸如NaBH4
之硼氫化物及諸如LiAlH4
之氫化鋁。在諸如BF3
* OEt2
之路易斯酸存在下,尤其較佳之還原劑為Et3
SiH。在諸如三氟乙酸之路易斯酸存在下,另一尤其較佳之還原劑為NaBH4
。
該還原劑(特定言之為Et3
SiH)之用量較佳為每莫耳二苯基酮VII約1至5莫耳,更佳約2至4莫耳,最佳約3莫耳。該路易斯酸(特定言之為BF3
* OEt2
)之用量較佳為每莫耳二苯基酮VII約1至5莫耳,更佳約1至3莫耳。
該反應較佳在諸如鹵代烴(例如二氯甲烷及1,2-二氯乙烷)、甲苯、苯、己烷、乙腈及其混合物之溶劑中進行。
較佳地,在約-30至100℃,較佳約-20至50℃,更佳約-10至25℃之溫度下進行該還原。
式V之配醣基可分離及純化或可不經純化用於式I之最終產物之合成。
起始於式V之配醣基,可使用上文中所述方法(較佳使用流程2a中描述及說明之方法)獲得式I之產物。
流程11:配醣基V之合成--較佳實施例
在上文所述之反應中,任何存在之反應性基團(如乙炔基、羥基、胺基、烷胺基或亞胺基)均可藉由習知保護基(其在反應後再次分解)在反應期間得到保護。
例如,羥基之保護基團可為三甲基矽烷基、乙醯基、三苯甲基、苄基或四氫哌喃基。
胺基、烷胺基或亞胺基之保護基團可為例如甲醯基、乙醯基、三氟乙醯基、乙氧羰基、第三丁氧羰基、苄氧羰基、苄基、甲氧基苄基或2,4-二甲氧基苄基。
此外,如上文所述,所得該等化合物及中間物可溶於其對映異構物及/或非對映體中。因此,例如順/反混合物可溶於其順及反異構體中,且可將具有至少一種光學活性碳原子之化合物分離為其對映異構物。
因此,例如順/反混合物可藉由層析法溶於其順及反異構體中,所得以外消旋體形式存在之化合物及中間物可藉由本身已知(cf.Allinger N.L.and Eliel E.L.in"Topics in Stereochemistry",Vol.6,Wiley Interscience,1971)之方法分離為其光學對映體,且具有至少兩個不對稱碳原子之化合物或中間物可根據其物理-化學差異使用本身已知之方法(例如藉由層析法及/或分步結晶)溶於其非對映體中,且若該等化合物以外消旋形式獲得,則其可隨後溶於上述對映異構物中。
較佳藉由手性相上之柱分離或藉由從光學活性溶劑重結晶或藉由與光學活性基質(其形成鹽或衍生物,例如具有外消旋化合物之酯或醯胺,特定言之為酸及其活性衍生物或醇)反應且分離由此所得之鹽或衍生物之非對映體混合物(例如根據其溶解性差異)分離該等對映異構物,同時游離對映體可藉由合適試劑之操縱從純非對映體鹽或衍生物中釋放。通常所用之光學活性酸為例如酒石酸或二苯甲醯基酒石酸之D-及L-形式、二-鄰甲苯基酒石酸、蘋果酸、扁桃酸、樟腦磺酸、麩胺酸、天冬胺酸或奎尼酸。光學活性醇可為例如(+)或(-)-薄荷醇及醯胺中光學活性醯基,例如可為(+)-或(-)-薄荷基氧基羰基。
此外,本發明之化合物及中間物可轉化為其鹽類,特定言之用於醫藥上之用途轉化為具有無機或有機酸之生理可接受鹽類。可用於此目的之酸包括例如鹽酸、氫溴酸、硫酸、甲磺酸、磷酸、反丁烯二酸、丁二酸、乳酸、檸檬酸、酒石酸或順丁烯二酸。
亦可使用以下實例中所述方法有利地獲得本發明之化合物,由此目的該等方法亦可與文獻中為熟習此項技術者所知之方法(特定言之,WO 98/31697、WO 01/27128、WO 02/083066、WO 03/099836及WO 2004/063209中所述之方法)組合。
在上文及下文中,羥基之H原子並未在每個結構式中明顯顯示。以下實例預期說明本發明而非對其限制。若壓力以單位"托"表示,則藉由使用1托=133.322 Pa可將相應值轉化為國際單位。該術語"室溫"或"環境溫度"表示約20℃之溫度。
Ac 乙醯基,Bu 丁基,Et 乙基,EtOAc 乙酸乙酯,i-Pr 異丙基,Me 甲基,MeOH 甲醇,MTBE 甲基第三丁基醚,THF 四氫呋喃。
(5-溴-2-氯-苯基)-(4-甲氧基-苯基)-甲酮
將38.3毫升乙二醯氯及0.8毫升二甲基甲醯胺添加至於500毫升二氯甲烷中之100公克5-溴-2-氯-苯甲酸之混合物中。將該反應混合物攪拌14小時,隨後過濾且在一旋轉式汽化器中與所有揮發性組分分離。將該殘餘物溶於150毫升二氯甲烷中,將所得溶液冷卻至-5℃且添加46.5公克苯甲醚。隨後分批添加51.5公克三氯化鋁,以使溫度不超過5℃。再將該溶液在1至5℃下攪拌1小時,隨後傾倒在碎冰上。將有機相分離,且以二氯甲烷將水相萃取三次。以1 M鹽酸水溶液、兩次以1 M氫氧化鈉溶液及以鹽水洗滌該合併之有機相。將該有機相乾燥,在真空中移除溶劑且將殘餘物從乙醇中重結晶。
產量:86.3公克(理論上64%)質譜(ESI+
):m/z=325/327/329(Br+Cl)[M+H]]+
類似於實例I可獲得以下化合物:(1)(5-溴-2-氯苯基)-(4-(R)-四氫呋喃-3-基氧基-苯基)-甲酮除了使用2當量三氯化鋁之外,根據上述程序進行該反應。在添加三氯化鋁後將該反應混合物在室溫下攪拌。
質譜(ESI+
):m/z=382/384/386(Br+Cl)[M+H]]+
(2)(5-溴-2-氯-苯基)-(4-(S)-四氫呋喃-3-基氧基-苯基)-甲酮除了使用2當量三氯化鋁之外,根據上述程序進行該反應。在添加三氯化鋁後將該反應混合物在室溫下攪拌。
(5-溴-2-氯-苯基)-(4-氟-苯基)-甲酮變化A:
將8.7毫升乙二醯氯及0.3毫升二甲基甲醯胺添加至於150毫升二氯甲烷中之24公克5-溴-2-氯-苯甲酸之混合物中。將該反應混合物攪拌14小時,隨後過濾且在一旋轉式汽化器中與所有揮發性組分分離。將殘餘物溶於105毫升氟代苯中且加熱至85℃。隨後分批添加13.3公克三氯化鋁且將所得混合物在85℃下攪拌16小時。冷卻至環境溫度後,將該反應混合物傾倒於300公克碎冰與100毫升濃鹽酸之混合物上。以乙酸乙酯將所得混合物萃取兩次。以1 M氫氧化鈉水溶液、1 M鹽酸水溶液及鹽水洗滌該合併之有機萃取物。經硫酸鎂乾燥後,在真空中移除溶劑。用石油醚洗滌凝固之殘餘物且在真空中乾燥。
產量:25.0公克(理論上80%)質譜(ESI+
):m/z=313/315/317(Br+Cl)[M+H]+
]
變化B:
於0至10℃下將4毫升乙二醯氯添加至於40毫升氟代苯及0.1毫升N,N
-二甲基甲醯胺中之9.42公克5-溴-2-氯-苯甲酸之溶液中。將該溶液在約20℃下攪拌2小時。將過量乙二醯氯蒸發。將該殘餘物在38毫升氟代苯中稀釋,且在0℃下分五部分添加5.87公克氯化鋁。將該溶液在80℃下攪拌5小時,且在0至25℃下以60毫升水驟冷。在50毫升乙酸異丙酯中萃取該產物且以40毫升3重量%之鹽水洗滌兩次。經由蒸發移除溶劑且從庚烷及水中重結晶該產物。
產量:11.94公克(理論上92.4%)質譜(ESI+
):m/z=314/316(Cl)[M+H]]+
(2-氯-5-碘-苯基)-(4-氟-苯基)-甲酮
於0至10℃下將16.2毫升乙二醯氯添加至於180毫升氟代苯及0.3毫升N,N
-二甲基甲醯胺中之48.94公克2-氯-5-碘-苯甲酸之溶液中。將該溶液在約20℃下攪拌2小時。將過量乙二醯氯蒸發。將該殘餘物在166毫升氟代苯中稀釋,且在0℃下分五部分添加25.93公克氯化鋁。將該溶液在75℃下攪拌1.5小時,且在0至25℃下以300毫升水驟冷。在300毫升乙酸異丙酯中萃取該產物且用200毫升鹽水(3重量%)洗滌兩次。經由蒸發移除殘餘水分及溶劑。
產量:60.56公克(理論上95%)質譜(ESI+
):m/z=361/363(Cl)[M+H]]+
(5-溴-2-氯-苯基)-(4-(S)-四氫呋喃-3-基氧基-苯基)-甲酮變化A:
將10.3公克第三丁氧化鉀添加至於200毫升二甲基甲醯胺中之8.1公克(S)-3-羥基-四氫呋喃之溶液中。在室溫下將該混合物攪拌10分鐘,隨後添加24.0公克(5-溴-2-氯苯基)-(4-氟苯基)-甲酮,同時在水浴中冷卻以使該溶液溫度保持在35℃以下。將該反應混合物在室溫下攪拌14小時且隨後以1000毫升水稀釋。以乙酸乙酯萃取所得混合物且以水及鹽水洗滌合併之萃取物。用硫酸鎂乾燥後,將溶劑移除且由乙醇將殘餘物重結晶。
產量:22.5公克(理論上77%)質譜(ESI+
):m/z=382/384/386(Br+Cl)[M+H]]+
變化B:
於0至5℃下將於90毫升四氫呋喃中之9.60公克第三丁氧化鉀添加至於60毫升四氫呋喃及5.87公克(S)-3-羥基四氫呋喃中之19.00公克(5-溴-2-氯苯基)-(4-氟苯基)-甲酮溶液中。將該溶液在10℃下攪拌0.5小時。以60毫升水及40毫升甲基第三丁基醚在0至25℃下中止該反應。以80毫升鹽水(3重量%)洗滌該產物。經由蒸發移除溶劑且在135毫升之2:1乙酸異丙醇酯/水中結晶。
產量:20.1公克(理論上87%)質譜(ESI+
):m/z=382/384(Cl)[M+H]]+
(2-氯-5-碘苯基)-{4-[(S)-(四氫呋喃-3-基)-氧基]-苯基}-甲酮
於0至5℃下將於250毫升四氫呋喃中之26公克第三丁氧化鉀添加至於170毫升四氫呋喃及16.46公克(S)-3-羥基四氫呋喃中之60.56公克(2-氯-5-碘苯基)-(4-氟苯基)-甲酮溶液中。將該溶液在10℃下攪拌0.5小時。用170毫升水及170毫升甲基第三丁基醚在0至25℃下中止該反應。用170毫升鹽水(3重量%)洗滌該產物。經由蒸發移除溶劑且在220毫升之2:1乙酸異丙酯中結晶。
產量:65.1公克(理論上90%)質譜(ESI+
):m/z=428/430(Cl)[M+H]+
4-溴-2-溴甲基-1-氯-苯
將4.0公克N-溴代丁二醯亞胺緩慢添加至於50毫升冷卻至5℃之四氫呋喃中的5.0公克4-溴-1-氯-2-羥甲基-苯及5.9公克三苯基膦之溶液中。在環境溫度下攪拌1小時後將該沉澱過濾且在真空中除去溶劑。藉由矽膠(環己烷/乙酸乙酯50:1)上之層析法將殘餘物純化。
產量:4.9公克(理論上76%)質譜(EI):m/z=282/284/286(Br+Cl)[M]]+
4-溴-1-氯-2-(4-甲氧基-苄基)-苯
將於75毫升二氯甲烷及150毫升乙腈中之86.2公克(5-溴-2-氯苯基)-(4-甲氧基苯基)-甲酮及101.5毫升三乙基矽烷冷卻至10℃。添加50.8毫升醚合三氟化硼以使溫度不超過20℃。將該溶液在環境溫度下攪拌14小時,隨後再添加9毫升三乙基矽烷及4.4毫升醚合三氟化硼。進一步將該溶液在45至50℃下攪拌3小時且隨後冷卻至環境溫度。添加70毫升水中28公克氫氧化鉀之溶液,且將所得混合物攪拌2小時。隨後將有機相分離,且用二異丙基醚將水相萃取三次。用2 M氫氧化鉀溶液洗滌合併之有機相兩次,用鹽水洗滌一次,隨後經由硫酸鈉乾燥。將溶劑移除後,用乙醇洗滌殘餘物且在60℃下乾燥。
產量:50.0公克(理論上61%)質譜(ESI+
):m/z=310/312/314(Br+Cl)[M+H]]+
類似於實例VII可獲得以下化合物:(1)4-溴-1-氯-2-(4-環戊基氧基-苄基)-苯
(2)(S
)-4-溴-1-氯-2-(4-四氫呋喃-3-基氧基-苄基)-苯
(3)(R
)-4-溴-1-氯-2-(4-四氫呋喃-3-基氧基-苄基)-苯
(4)4-溴-1-氯-2-(4-四氫哌喃-4-基氧-苄基)-苯
(5)4-溴-1-氯-2-(4-環己基氧基-苄基)-苯
(6)4-溴-1-氯-2-(4-環丁氧基-苄基)-苯
4-(5-溴-2-氯-苄基)-酚
將於150毫升二氯甲烷中14.8公克4-溴-1-氯-2-(4-甲氧基-苄基)-苯之溶液在冰浴中冷卻。隨後添加於二氯甲烷中之50毫升1 M三溴化硼溶液,且將該溶液在環境溫度下攪拌2小時。隨後將該溶液再次在冰浴中冷卻,且逐滴添加飽和碳酸鉀溶液。在環境溫度下用1 M鹽酸水溶液將該混合物調節至pH約為1,分離有機相且以乙酸乙酯將水相再萃取三次。經硫酸鈉將該合併之有機相乾燥,且將溶劑完全移除。
產量:13.9公克(理論上98%)質譜(ESI-
):m/z=295/297/299(Br+Cl)[M-H]-
4-溴-1-氯-2-(4-環戊基氧基-苄基)-苯
將23毫升碘代環戊烷添加至於300毫升乙醇中之40.0公克4-(5-溴-2-氯-苄基)-酚及71.0公克碳酸銫之混合物中。將該混合物在60℃下攪拌隔夜且隨後冷卻至環境溫度。將乙醇蒸發,且將水添加至殘餘物。以乙酸乙酯萃取所得混合物,經硫酸鈉乾燥合併之萃取物,且將溶劑移除。經由矽膠(環己烷/乙酸乙酯100:1->10:1)過濾該殘餘物。
產量:34.4公克(理論上70%)質譜(ESI+
):m/z=364/366/368(Br+Cl)[M]]+
類似於實例IX可獲得以下化合物:(1)(S)-4-溴-1-氯-2-(4-四氫呋喃-3-基氧基-苄基)-苯
質譜(ESI+
):m/z=366/368/370(Br+Cl)[M+H]]+
(2)(R
)-4-溴-1-氯-2-(4-四氫呋喃-3-基氧苄基)-苯
質譜(ESI+
):m/z=366/368/370(Br+Cl)[M]+
(3)4-溴-1-氯-2-(4-四氫哌喃-4-基氧基-苄基)-苯
(4)4-溴-1-氯-2-(4-環己基氧基-苄基)-苯
(5)4-溴-1-氯-2-(4-環丁基氧基-苄基)-苯
(S)-4-溴-1-氯-2-(4-四氫呋喃-3-基氧基-苄基)-苯變化A:
於20℃下將93毫升二乙醚合三氟化硼添加至於1.33公升乙腈及314毫升三乙基矽烷中之250公克(5-溴-2-氯-苯基)-{4-[(S)-(四氫呋喃-3-基)氧基]-苯基}-甲酮之懸浮液中。將該溶液在20℃下攪拌16小時。將該混合物過濾且以1.5升1.5 M氫氧化鈉溶液在0至20℃下驟冷濾液。經由蒸發移除溶劑且以1.3公升甲基第三丁基醚將殘餘物稀釋。使用1.2公升0.1 M之NaOH(隨後用1公升水)洗滌該產物。經由蒸發移除溶劑且經由甲苯之蒸餾移除大部分三乙基矽烷醇。
產量:218公克(理論上90%)質譜(ESI+
):m/z=368/370(Cl)[M+H]]+
變化B:
於20℃下將20.45公克三氟化硼合二乙醚添加至於260毫升乙腈及34.68公克二甲基矽烷中之50.00公克(5-溴-2-氯-苯基)-{4-[(S)-(四氫呋喃-3-基)氧基]-苯基}-甲酮之懸浮液中。將該溶液在20℃下攪拌16小時。將該混合物過濾且用290毫升1.5 M氫氧化鈉溶液在0至20℃下驟冷濾液。經由蒸發移除溶劑且用260毫升甲基第三丁基醚將殘餘物稀釋。以240毫升0.1 M之NaOH、隨後用200毫升水洗滌該產物。經由蒸發移除溶劑且經由庚烷之蒸餾移除大部分二甲基乙基矽烷醇。
產量:45.76公克(理論上95%)質譜(ESI+
):m/z=368/370(Cl)[M+H]]+
變化C:
於0℃下將5.92公克三氟乙酸添加至於10毫升二氯甲烷(或者氟代苯)中之1.91公克(5-溴-2-氯-苯基)-{4-[(S)-(四氫呋喃-3-基)氧基]-苯基}-甲酮與0.38公克硼氫化鈉之懸浮液中。將該溶液在20℃下攪拌16小時,且在0至20℃下用20毫升水及20毫升MTBE驟冷。用20毫升水洗滌該產物。經由蒸發移除溶劑。
產量:1.6至1.75公克(理論上87至95%)
變化D:
於0℃下將11.4公克三氟乙酸添加至於10毫升乙酸異丙酯中之1.91公克(5-溴-2-氯-苯基)-{4-[(S)-(四氫呋喃-3-基)氧基]-苯基}-甲酮與0.8公克硼氫化鈉之懸浮液中。將該溶液在20℃下攪拌16小時,且在0至20℃下用20毫升水及20毫升MTBE驟冷。用20毫升水洗滌該產物。經由蒸發移除溶劑。
產量:1.6~1.75公克(理論上87~95%)
變化E:
於20℃下將0.04公克硼氫化鈉添加至於5毫升四氫呋喃中之0.19公克(5-溴-2-氯-苯基)-{4-[(S)-(四氫呋喃-3-基)氧基]-苯基}-甲酮之溶液中。將該溶液在20℃下攪拌16小時且將溶液交換至5毫升二氯甲烷。於0℃下分別將0.35毫升1 M三氯化硼二氯甲烷、0.02毫升水及0.24毫升三氟乙酸添加至該研磨漿中。將該混合物在環境溫度下攪拌4小時,且在0至20℃下用10毫升水及10毫升MTBE驟冷。用10毫升水洗滌該產物。經由蒸發移除溶劑。
產量:0.18公克(理論上97%)
(S)-4-碘-1-氯-2-(4-四氫呋喃-3-基氧基-苄基)-苯變化A:
於10℃下將23.66公克二乙醚合三氟化硼添加至於300毫升乙腈及40.14公克二甲基乙基矽烷中之63.12公克(2-氯-5-碘-苯基)-{4-[(S)-(四氫呋喃-3-基)氧基]-苯基}-甲酮之懸浮液中。將該溶液在20℃下攪拌16小時。以350毫升1.5 M氫氧化鈉溶液在0至20℃下中止該反應。將該產物在200毫升乙酸乙酯中稀釋。以200毫升水洗滌該產物。經由蒸發移除溶劑且在1:2乙腈/水中結晶。
產量:54.9公克(理論上90%)質譜(ESI+
):m/z=414/416(Cl)[M+H]]+
變異體B:
於20℃下將0.04公克硼氫化鈉添加至於5毫升四氫呋喃中之0.22公克(2-氯-5-碘-苯基)-{4-[(S)-(四氫呋喃-3-基)氧基]-苯基}-甲酮之溶液中。將該溶液在20℃下攪拌16小時且將溶液交換至5毫升二氯甲烷。於0℃下分別將0.35毫升1 M三氯化硼二氯甲烷、0.02毫升水及0.24毫升三氟乙酸添加至該漿液中。將該混合物在20℃下攪拌4小時,且在0至20℃下以10毫升水及10毫升MTBE驟冷。用10毫升水洗滌該產物。經由蒸發移除溶劑且在1:2乙腈/水中結晶。
產量:0.18公克(理論上86%)質譜(ESI+
):m/z=414/416(Cl)[M+H]]+
2,3,4,6-四-O-(三甲基矽烷基)-D-葡萄哌喃酮
將於200毫升四氫呋喃中之20公克D-葡萄糖酸-1,5-內酯與98.5毫升N-甲基嗎啉之溶液冷卻至-5℃。隨後逐滴添加85毫升三甲基氯化矽烷,以使溫度不超過5℃。隨後將該溶液在環境溫度下攪拌1小時,在35℃下攪拌5小時及再在環境溫度下攪拌14小時。添加300毫升甲苯後,將該溶液在冰浴中冷卻,且添加500毫升水以使溫度不超過10℃。隨後將有機相分離且用水性磷酸二氫鈉溶液、水及鹽水洗滌。在真空中移除溶劑,殘餘物在250毫升甲苯中吸收,且再次完全移除溶劑。
產量:52.5公克(約90%純)質譜(ESI+
):m/z=467[M+H]]+
實例XIII
1-氯-4-(1-甲氧基-D-葡萄哌喃糖-1-基)-2-(4-(R)-四氫呋喃-3-基氧基-苄基)-苯
將於85毫升無水二乙醚中之5.40公克(R)-4-溴-1-氯-2-(4-四氫呋喃-3-基氧基-苄基)-苯之溶液在氬氣下冷卻至-78℃。將18.5毫升於戊烷中之1.7 M第三丁基鋰溶液緩慢逐滴添加至該冷卻溶液,且隨後將該溶液在-78℃下攪拌45分鐘。隨後經由一傳輸針將7.50公克(計算值為90%純)之2,3,4,6-四-O-(三甲基矽烷基)-D-葡萄哌喃酮之-78℃-冷溶液添加至35毫升二乙醚中。將所得溶液在-78℃下攪拌2小時,且隨後將2.5毫升甲磺酸溶液添加至65毫升甲醇中。將冷卻浴移除,且將該溶液在環境溫度下攪拌16小時。隨後用固體碳酸氫鈉中和該溶液,將大部分溶劑移除且將碳酸氫鈉水溶液添加至殘餘物中。以乙酸乙酯萃取所得混合物,經硫酸鈉乾燥合併之萃取物,且將溶劑移除以提供粗產物(其將經受還原而不經進一步純化)。
產量:6.95公克(粗產物)質譜(ESI+
):m/z=503/505(Cl)[M+Na]+
類似於實例XIII可獲得以下化合物:(1)1-氯-4-(1-甲氧基-D-葡萄哌喃糖-1-基)-2-(4-(S)-四氫呋喃-3-基氧基-苄基)-苯
(2)1-氯-4-(1-甲氧基-D-葡萄哌喃糖-1-基)-2-(4-環戊基氧基-苄基)-苯
質譜(ESI+
):m/z=501/503(Cl)[M+Na]+
1-氯-4-(2,3,4,6-四-O-乙醯基-D-葡萄哌喃糖-1-基)-2-(4-(R)-四氫呋喃-3-基氧基-苄基)-苯
將6.95公克1-氯-4-(1-甲氧基-D-葡萄哌喃糖-1-基)-2-(4-(R)-四氫呋喃基氧基-苄基)-苯與4.7毫升三乙基矽烷在40毫升二氯甲烷及80毫升乙腈中之溶液冷卻至-10℃。隨後逐滴添加1.25毫升醚合三氟化硼以使該溶液之溫度保持在0℃以下。將該溶液在冰浴中攪拌3小時。添加碳酸氫鈉水溶液,且以乙酸乙酯萃取所得混合物。經硫酸鈉乾燥有機相,將溶劑移除且在80毫升二氯甲烷中吸收殘餘物。隨後添加8.5毫升比啶、7.8毫升乙酸酐及100毫克4-二甲胺基比啶。將該溶液在環境溫度下攪拌1小時,隨後用水稀釋。以二氯甲烷萃取該混合物,用1 M鹽酸洗滌有機相且經由硫酸鈉乾燥。移除溶劑後將殘餘物由乙醇重結晶以提供作為白色晶體之產物。
產量:2.20公克(理論上25%)質譜(ESI+
):m/z=619/621(Cl)[M+H]]+
類似於實例XIV可獲得以下化合物:(1)1-氯-4-(2,3,4,6-四-O-乙醯基-D-葡萄哌喃糖-1-基)-2-(4-(S)-四氫呋喃-3-基氧基-苄基)-苯
(2)1-氯-4-(2,3,4,6-四-O-乙醯基-D-葡萄哌喃糖-1-基)-2-(4-環戊基氧基-苄基)-苯
質譜(ESI+
):m/z=640/642(Cl)[M+Na]+
1-氯-4-(2,3,4,6-四-O-苄基-D-葡萄哌喃糖-1-基)-2-(4-(S)-四氫呋喃-3-基氧基-苄基)-苯
將0.37公克1-氯-4-(1-甲氧基-2,3,4,6-四-O-苄基-D-葡萄哌喃糖-1-基)-2-(4-(S)-四氫呋喃-3-基氧基-苄基)-苯與0.21毫升三乙基矽烷在2.5毫升二氯甲烷及7.5毫升乙腈中之溶液冷卻至-20℃。隨後經1分鐘逐滴添加0.13毫升醚合三氟化硼。允許將所得混合物經1小時溫至-10℃。添加碳酸氫鈉水溶液,且以乙酸乙酯萃取所得混合物。將有機相以鹽水洗滌,經硫酸鈉乾燥且在真空下濃縮。藉由管柱層析法純化所得殘餘物以定量產率獲得呈稠油狀之a及b異構體之混合物(a:b比率約為1:3)。
產量:0.36公克(理論上100%)質譜(ESI+
):m/z=833/835(Cl)[M+Na]+
1-氯-4-(2,3,4,6-四-O-烯丙基-D-葡萄哌喃糖-1-基)-2-(4-(S)-四氫呋喃-3-基氧基-苄基)-苯
將0.37公克1-氯-4-(1-甲氧基-2,3,4,6-四-O-烯丙基-D-葡萄哌喃糖-1-基)-2-(4-(S)-四氫呋喃-3-基氧基-苄基)-苯與0.28毫升三乙基矽烷在2.5毫升二氯甲烷及7.5毫升乙腈中之溶液冷卻至-20℃。隨後經1分鐘逐滴添加0.16毫升醚合三氟化硼。允許將所得混合物經1小時溫至-10℃。添加碳酸氫鈉水溶液,且用乙酸乙酯萃取所得混合物。將有機相用鹽水洗滌,經硫酸鈉乾燥且在真空下濃縮。藉由管柱層析法純化所得殘餘物以提供呈稠油狀之a及b異構體之混合物(a:b比率約為1:9)。
產量:0.30公克(理論上85%)質譜(ESI+
):m/z=633/635(Cl)[M+Na]+
1-氯-4-(β-D-葡萄哌喃糖-1-基)-2-(4-(R)-四氫呋喃-3-基氧基-苄基)-苯
將4毫升4 M氫氧化鉀水溶液添加至於30毫升甲醇中之2.20公克1-氯-4-(2,3,4,6-四-O-乙醯基-D-葡萄哌喃糖-1-基)-2-(4-(R)-四氫呋喃-3-基氧基-苄基)-苯之溶液中。將該溶液在環境溫度下攪拌1小時,隨後以4 M鹽酸中和。將甲醇蒸發,且以鹽水稀釋殘餘物及以乙酸乙酯萃取。經硫酸鈉將該合併之有機萃取物乾燥,且將溶劑移除。在矽膠(二氯甲烷/甲醇1:0->4:1)上層析該殘餘物。
產量:1.45公克(理論上90%)質譜(ESI+
):m/z=451/453(Cl)[M+H]+
類似於實例XVII可獲得以下化合物:(1)1-氯-4-(β-D-葡萄哌喃糖-1-基)-2-(4-(S)-四氫呋喃-3-基氧基-苄基)-苯
質譜(ESI+
):m/z=451/453(Cl)[M+H]+
(2)1-氯-4-(β-D-葡萄哌喃糖-1-基)-2-(4-環戊基氧基-苄基)-苯
質譜(ESI+
):m/z=466/468(Cl)[M+NH4
]+
(3)1-氯-4-(b-D-葡萄哌喃糖-1-基)-2-(4-四氫哌喃-4-基氧基-苄基)-苯
質譜(ESI+
):m/z=487/489(Cl)[M+Na]+
(4)1-氯-4-(β-D-葡萄哌喃糖-1-基)-2-(4-環己氧基-苄基)-苯
質譜(ESI+
):m/z=480/482(Cl)[M+NH4
]+
(5)1-氯-4-(β-D-葡萄哌喃糖-1-基)-2-(4-環丁基氧基-苄基)-苯
質譜(ESI+
):m/z=452/454(Cl)[M+NH4
]+
1-氯-4-(β-D-葡萄哌喃糖-1-基)-2-(4-(S)-四氫呋喃-3-基氧-苄基)-苯變化A:步驟i)
於-15至-5℃下將於己烷中之12毫升2.5 M之BuLi添加至於30毫升四氫呋喃中於THF中的5.5毫升2.0 M之BuMgCl溶液中,且在-10℃下攪拌20分鐘。將10.00公克(S)-3-[4-(5-溴-2-氯-苄基)-苯氧基]-四氫呋喃在-23至-20℃下添加至10毫升THF中,且在-22℃下攪拌20分鐘。將20.32公克2,3,4,6-四-O-(三甲基矽烷基)-D-葡萄哌喃糖在-20至-18℃下添加至7毫升THF中。隨後將該反應在-20℃下攪拌1小時且在另1小時中溫至-12℃。添加60毫升25重量%之NH4
Cl水溶液以中止該反應。添加40毫升MTBE且將有機層分離。以30毫升EtOAc萃取水層。經由MgSO4
乾燥合併之有機相且濃縮。
步驟ii)將步驟i)之殘餘物溶於100毫升MeOH及0.52公克MeSO3
H中,且在43℃下攪拌4小時。隨後將該反應冷卻至5℃且用20毫升10重量%之NaHCO3
水溶液中止該反應。將MeOH減壓蒸餾且添加25毫升水及25毫升EtOAc。將有機層分離,且以20毫升EtOAc萃取水相。將合併之有機相乾燥且濃縮至乾燥狀態。
步驟iii)將步驟ii)之殘餘物溶於63毫升MeCN及43毫升CH2
Cl2
中且冷卻至-20℃。添加7.59公克三乙基矽烷,隨後添加6.95公克醚合三氟化硼。將該反應經2小時自-20℃逐漸溫至10℃。添加40公克10重量%之NaHCO3
以中止該反應。在減壓下移除有機溶劑。注入50毫升乙酸異丙酯及12毫升水且將該混合物在環境溫度下攪拌隔夜。將該產物過濾及乾燥。
產量:13.5公克(理論上55%)質譜(ESI+
):m/z=451/453(Cl)[M+H]]+
變化B:
使用i-PrMgCl替代變化A中步驟i)中之BuMgCl。步驟ii)及iii)與變化A中相同。
變化C:
使用i-PrMgCl/LiCl替代變化A中步驟i)中之BuMgCl。步驟ii)及iii)與變化A中相同。
變化D:步驟i)
於0至20℃下(或者在20℃下)將於THF中之8.4毫升1.0 M之i-PrMgCl/LiCl緩慢注入於4毫升THF中之2.90公克(S)-3-[4-(5-溴-2-氯-苄基)-苯氧基]-四氫呋喃溶液中。將該反應在20℃下攪拌16小時且冷卻至-23℃。將4.3公克2,3,4,6-四-O-(三甲基矽烷基)-D-葡萄哌喃酮逐滴添加至2毫升THF中。隨後將該反應在-20℃下攪拌2小時。添加NH4
Cl水溶液(25重量%,12毫升)以中止該反應。添加MTBE(8毫升)且將有機層分離。以EtOAc(30毫升)萃取水層。經MgSO4
乾燥合併之有機相且濃縮。
步驟ii)
將步驟i)之殘餘物溶於MeOH(20毫升)及MeSO3
H(260毫克,2.8毫莫耳)中且在43℃下攪拌3小時。隨後將該反應冷卻至5℃且以10重量%之NaHCO3
水溶液(12毫升)中止該反應。將MeOH減壓蒸餾且添加水(4毫升)及EtOAc(30毫升)。將有機層分離,且以EtOAc(20毫升)萃取水相。將合併之有機相乾燥且濃縮至乾燥狀態。
步驟iii)
將步驟ii)之殘餘物溶於MeCN(17毫升)及CH2
Cl2
(11毫升)中且冷卻至-20℃。添加三乙基矽烷(2.08公克,17.9毫莫耳),隨後添加醚合三氟化硼(1.9公克,13.4毫莫耳)。將該反應經2小時自-20℃逐漸溫至10℃。添加10%之NaHCO3
(25毫升)以中止該反應。在減壓下移除有機溶劑。注入乙酸異丙酯(15毫升)及水(5毫升)且將該混合物在環境溫度下攪拌隔夜。將該產物過濾及乾燥。
產量:0.91公克(理論上27%)質譜(ESI+
):m/z=451/453(Cl)[M+H]+
變化E:步驟i)
於-23℃下將於THF中之8.4毫升1.0 M之i-PrMgCl/LiCl緩慢注入於4毫升THF中之2.90公克(S)-3-[4-(5-碘-2-氯-苄基)-苯氧基]-四氫呋喃溶液中。將該反應在-22℃下攪拌20分鐘。逐滴添加於2毫升THF中之4.3公克2,3,4,6-四-O-(三甲基矽烷基)-D-葡萄哌喃酮。隨後將該反應在-20℃下攪拌2小時。添加NH4
Cl水溶液(25重量%,12毫升)以中止該反應。添加MTBE(8毫升)且將有機層分離。以EtOAc(30毫升)萃取水層。經MgSO4
乾燥合併之有機相且濃縮。
步驟ii)
將步驟i)之殘餘物溶於MeOH(20毫升)及MeSO3
H(260毫克,2.8毫莫耳)中且在43℃下攪拌3小時。隨後將該反應冷卻至5℃且以10重量%之NaHCO3
水溶液(12毫升)中止該反應。將MeOH減壓蒸餾且添加水(4毫升)及EtOAc(30毫升)。將有機層分離,且以EtOAc(20毫升)萃取水相。將合併之有機相乾燥且濃縮至乾燥狀態。
步驟iii)
將步驟ii)之殘餘物溶於MeCN(17毫升)及CH2
Cl2
(11毫升)中且冷卻至-20℃。添加三乙基矽烷(2.08公克,17.9毫莫耳),隨後添加醚合三氟化硼(1.9公克,13.4毫莫耳)。將該反應經2小時自-20℃逐漸溫至10℃。添加25毫升10重量%之NaHCO3
水溶液以中止該反應。在減壓下移除有機溶劑。注入乙酸異丙酯(15毫升)及水(5毫升)且將該混合物在環境溫度下攪拌隔夜。將該產物過濾及乾燥。
產量:2.2公克(理論上65%)質譜(ESI+
):m/z=451/453(Cl)[M+H]]+
Claims (14)
- 一種製備通式III化合物之方法,
- 一種製備通式II化合物之方法,
- 如請求項2之方法,其中在式II中該取代基R2 表示氫,且在該式IV中該取代基R2 表示如請求項1所定義之保護基團,且在該式III中該取代基R2 具有與式IV中相同之含義或表示氫。
- 如請求項1之方法,其中R1 表示R-四氫呋喃-3-基或S-四氫呋喃-3-基。
- 如請求項2之方法,其中R1 表示R-四氫呋喃-3-基或S-四氫呋喃-3-基。
- 如請求項3之方法,其中R1 表示R-四氫呋喃-3-基或S-四氫呋喃-3-基。
- 如請求項2之方法,其中在式II中該取代基R2 表示氫,且在式IV中該取代基R2 表示三甲基矽烷基,且在式III中該取代基R2 具有與式IV中相同之含義或表示氫。
- 如請求項2之方法,其中基團X表示碘。
- 如請求項2之方法,其中基團R'表示氫、甲基或乙基。
- 如請求項2之方法,其中基團Z5 表示氟。
- 如請求項2之方法,其中該式V化合物係藉由以C3-4 -烷基 鎂氯化物或溴化物在氯化鋰存在或不存在之情況下之鹵素-金屬交換,轉化為式VI之有機金屬化合物,其中該鹵素-金屬交換係在-80℃與10℃之間進行。
- 如請求項2之方法,其中該式V化合物係藉由以異丙基鎂氯化物在氯化鋰存在下之鹵素-金屬交換,轉化為式VI之有機金屬化合物,其中該鹵素-金屬交換係在-80℃與10℃之間進行。
- 如請求項2之方法,其中該式III之中間物與作為還原劑之矽烷在路易斯酸存在或不存在情況下進行反應,以獲得式II化合物。
- 如請求項2之方法,其中該式III之中間物與作為還原劑之三乙基矽烷在路易斯酸存在下進行反應,以獲得式II化合物。
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Families Citing this family (133)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CA2557801C (en) * | 2004-03-16 | 2013-06-25 | Boehringer Ingelheim International Gmbh | Glucopyranosyl-substituted benzol derivatives, drugs containing said compounds, the use thereof and method for the production thereof |
WO2006064033A2 (en) * | 2004-12-16 | 2006-06-22 | Boehringer Ingelheim International Gmbh | Glucopyranosyl-substituted benzene derivatives, medicaments containing such compounds, their use and process for their manufacture |
ATE445608T1 (de) * | 2005-02-23 | 2009-10-15 | Boehringer Ingelheim Int | Glucopyranosylsubstituierte ((hetero)arylethynyl- benzyl)-benzenderivative und deren verwendung als inhibitoren des natriumabhängigen glucose- cotransporters typ 2 (sglt2) |
ES2338041T3 (es) * | 2005-04-15 | 2010-05-03 | Boehringer Ingelheim International Gmbh | Derivados de (heteroariloxi-bencil)-benceno sustituidos con glucopiranosilo en calidad de inhibidores de sglt. |
UA91546C2 (uk) | 2005-05-03 | 2010-08-10 | Бьорінгер Інгельхайм Інтернаціональ Гмбх | КРИСТАЛІЧНА ФОРМА 1-ХЛОР-4-(β-D-ГЛЮКОПІРАНОЗ-1-ИЛ)-2-[4-((S)-ТЕТРАГІДРОФУРАН-3-ІЛОКСИ)-БЕНЗИЛ]-БЕНЗОЛУ, СПОСІБ ЇЇ ОДЕРЖАННЯ ТА ЇЇ ЗАСТОСУВАННЯ ПРИ ПРИГОТУВАННІ ЛІКАРСЬКИХ ЗАСОБІВ |
US7723309B2 (en) * | 2005-05-03 | 2010-05-25 | Boehringer Ingelheim International Gmbh | Crystalline forms of 1-chloro-4-(β-D-glucopyranos-1-yl)-2-[4-((R)-tetrahydrofuran-3-yloxy)-benzyl]-benzene, a method for its preparation and the use thereof for preparing medicaments |
US7772191B2 (en) | 2005-05-10 | 2010-08-10 | Boehringer Ingelheim International Gmbh | Processes for preparing of glucopyranosyl-substituted benzyl-benzene derivatives and intermediates therein |
TW200726755A (en) * | 2005-07-07 | 2007-07-16 | Astellas Pharma Inc | A crystalline choline salt of an azulene derivative |
CA2616294A1 (en) * | 2005-07-27 | 2007-02-08 | Boehringer Ingelheim International Gmbh | Glucopyranosyl-substituted ((hetero)cycloalkylethynyl-benzyl)-benzene derivatives and use thereof as sodium-dependent glucose cotransporter (sglt) inhibitors |
DE602006017566D1 (de) * | 2005-08-30 | 2010-11-25 | Boehringer Ingelheim Pharma | Glucopyranosyl-substituierte benzyl-derivate, medikamente mit solchen verbindungen, ihre verwendung und herstellungsverfahren dafür |
TW200745075A (en) * | 2005-09-08 | 2007-12-16 | Boehringer Ingelheim Int | Crystalline forms of 1-chloro-4-(β-D-glucopyranos-1-yl)-2-(4-ethynyl-benzyl)-benzene, methods for its preparation and the use thereof for preparing medicaments |
AR056195A1 (es) * | 2005-09-15 | 2007-09-26 | Boehringer Ingelheim Int | Procedimientos para preparar derivados de (etinil-bencil)-benceno sustituidos de glucopiranosilo y compuestos intermedios de los mismos |
AR059489A1 (es) * | 2006-02-15 | 2008-04-09 | Boehringer Ingelheim Vetmed | Derivados de benzonitrilo sustituidos con glucopiranosilo, composiciones farmaceuticas que contienen compuestos de este tipo, su uso y procedimiento para su fabricacion |
PE20080697A1 (es) * | 2006-05-03 | 2008-08-05 | Boehringer Ingelheim Int | Derivados de benzonitrilo sustituidos con glucopiranosilo, composiciones farmaceuticas que contienen compuestos de este tipo, su uso y procedimiento para su fabricacion |
JP5230613B2 (ja) * | 2006-05-23 | 2013-07-10 | テラコス・インコーポレイテッド | グルコース輸送体阻害剤およびその使用方法 |
US8039441B2 (en) * | 2006-08-15 | 2011-10-18 | Boehringer Ingelheim International Gmbh | Glucopyranosyl-substituted cyclopropylbenzene derivatives, pharmaceutical compositions containing such compounds, their use as SGLT inhibitors and process for their manufacture |
CA2664095A1 (en) * | 2006-09-21 | 2008-03-27 | Boehringer Ingelheim International Gmbh | Glucopyranosyl-substituted difluorobenzyl-benzene derivatives, medicaments containing such compounds, their use and process for their manufacture |
JP2010507629A (ja) * | 2006-10-27 | 2010-03-11 | ベーリンガー インゲルハイム インターナショナル ゲゼルシャフト ミット ベシュレンクテル ハフツング | 4−(β−D−グルコピラノス−1−イル)−1−メチル−2−[4−((S)−テトラヒドロフラン−3−イルオキシ)−ベンジル]−ベンゼンの結晶形、その製造方法及び医薬品を製造するための使用 |
US7879806B2 (en) | 2006-11-06 | 2011-02-01 | Boehringer Ingelheim International Gmbh | Glucopyranosyl-substituted benzyl-benzonitrile derivates, medicaments containing such compounds, their use and process for their manufacture |
UY30730A1 (es) | 2006-12-04 | 2008-07-03 | Mitsubishi Tanabe Pharma Corp | Forma cristalina del hemihidrato de 1-(b (beta)-d-glucopiranosil) -4-metil-3-[5-(4-fluorofenil) -2-tienilmetil]benceno |
CN101568537A (zh) | 2006-12-21 | 2009-10-28 | 安斯泰来制药有限公司 | C-糖苷衍生物的制造方法及其合成中间体 |
US7795228B2 (en) * | 2006-12-28 | 2010-09-14 | Theracos, Inc. | Spiroheterocyclic glycosides and methods of use |
US20100081625A1 (en) | 2007-01-26 | 2010-04-01 | Boehringer Ingelheim International Gmbh | Methods for preventing and treating neurodegenerative disorders |
CA2679310A1 (en) | 2007-02-21 | 2008-08-28 | Boehringer Ingelheim International Gmbh | Tetrasubstituted glucopyranosylated benzene derivatives, medicaments containing such compounds, their use and process for their manufacture |
PE20090938A1 (es) * | 2007-08-16 | 2009-08-08 | Boehringer Ingelheim Int | Composicion farmaceutica que comprende un derivado de benceno sustituido con glucopiranosilo |
SG188800A1 (en) | 2007-08-23 | 2013-04-30 | Theracos Inc | Benzylbenzene derivatives and methods of use |
KR101552187B1 (ko) * | 2007-09-10 | 2015-09-10 | 얀센 파마슈티카 엔.브이. | Sglt 억제제로서 유용한 화합물의 제조 방법 |
US8648085B2 (en) | 2007-11-30 | 2014-02-11 | Boehringer Ingelheim International Gmbh | 1, 5-dihydro-pyrazolo (3, 4-D) pyrimidin-4-one derivatives and their use as PDE9A mudulators for the treatment of CNS disorders |
UA101004C2 (en) | 2007-12-13 | 2013-02-25 | Теракос, Инк. | Derivatives of benzylphenylcyclohexane and use thereof |
CL2008003653A1 (es) | 2008-01-17 | 2010-03-05 | Mitsubishi Tanabe Pharma Corp | Uso de un inhibidor de sglt derivado de glucopiranosilo y un inhibidor de dppiv seleccionado para tratar la diabetes; y composicion farmaceutica. |
JP5302900B2 (ja) * | 2008-01-31 | 2013-10-02 | アステラス製薬株式会社 | 脂肪性肝疾患の治療用医薬組成物 |
UA105362C2 (en) | 2008-04-02 | 2014-05-12 | Бьорингер Ингельхайм Интернациональ Гмбх | 1-heterocyclyl-1, 5-dihydro-pyrazolo [3, 4-d] pyrimidin-4-one derivatives and their use as pde9a modulators |
TWI523652B (zh) | 2008-07-15 | 2016-03-01 | 泰瑞克公司 | 氘化苄基苯衍生物及使用方法 |
CN102177147A (zh) | 2008-08-22 | 2011-09-07 | 泰拉科斯有限公司 | 制备sglt2抑制剂的方法 |
BRPI0918841B8 (pt) | 2008-08-28 | 2021-05-25 | Pfizer | derivados de dioxa-biciclo[3.2.1]octano-2,3,4-triol, seus cristais, composições farmacêuticas e usos |
NZ590788A (en) | 2008-09-08 | 2012-11-30 | Boehringer Ingelheim Int | Pyrazolopyrimidines and their use for the treatment of cns disorders |
US9056850B2 (en) * | 2008-10-17 | 2015-06-16 | Janssen Pharmaceutica N.V. | Process for the preparation of compounds useful as inhibitors of SGLT |
JP5600328B2 (ja) | 2009-02-13 | 2014-10-01 | ベーリンガー インゲルハイム インターナショナル ゲゼルシャフト ミット ベシュレンクテル ハフツング | グルコピラノシルジフェニルメタン誘導体を含む医薬組成物、その医薬剤形、それらの調製方法及び患者の血糖コントロールを改善するためのそれらの使用 |
CN102307577A (zh) | 2009-02-13 | 2012-01-04 | 贝林格尔.英格海姆国际有限公司 | 包含sglt2抑制剂、dpp-iv抑制剂和任选的另一种抗糖尿病药的药物组合物及其用途 |
UY32427A (es) | 2009-02-13 | 2010-09-30 | Boheringer Ingelheim Internat Gmbh | Composicion farmaceutica, forma farmaceutica, procedimiento para su preparacion, metodos de tratamiento y usos de la misma |
PE20120002A1 (es) | 2009-02-13 | 2012-02-12 | Boehringer Ingelheim Int | Derivados de benceno sustituido con glucopiranosilo como inhibidores de sglt2 |
RS53167B (en) | 2009-03-31 | 2014-06-30 | Boehringer Ingelheim International Gmbh | 1-HETEROCYCLYL-1,5-DIHYDRO-PYRAZOLO [3,4-D] PYRIMIDIN-4-ONE DERIVATIVES AND THEIR APPLICATIONS AS A PDE9A MODULATOR |
US20110009347A1 (en) * | 2009-07-08 | 2011-01-13 | Yin Liang | Combination therapy for the treatment of diabetes |
CA2767258C (en) | 2009-07-10 | 2016-09-13 | Janssen Pharmaceutica Nv | Crystallisation process for 1-(.beta.-d-glucopyranosyl)-4-methyl-3-[5-(4-fluorophenyl)-2-thienylmethyl] benzene |
JP5736377B2 (ja) | 2009-09-30 | 2015-06-17 | ベーリンガー インゲルハイム インターナショナル ゲゼルシャフト ミット ベシュレンクテル ハフツング | 1−クロロ−4−(β−D−グルコピラノス−1−イル)−2−[4−((S)−テトラヒドロフラン−3−イルオキシ)ベンジル]ベンゼンの結晶形の調製方法 |
WO2011039108A2 (en) * | 2009-09-30 | 2011-04-07 | Boehringer Ingelheim International Gmbh | Processes for preparing of glucopyranosyl-substituted benzyl-benzene derivatives |
US10610489B2 (en) * | 2009-10-02 | 2020-04-07 | Boehringer Ingelheim International Gmbh | Pharmaceutical composition, pharmaceutical dosage form, process for their preparation, methods for treating and uses thereof |
EA024368B1 (ru) * | 2009-10-14 | 2016-09-30 | Янссен Фармацевтика Нв | Процесс получения соединений для применения в качестве ингибиторов sglt2 |
AP3099A (en) | 2009-11-02 | 2015-01-31 | Pfizer | Dioxa-bicyclo[3.2.1]octane-2,3,4-triol de derivatives |
WO2011120923A1 (en) | 2010-03-30 | 2011-10-06 | Boehringer Ingelheim International Gmbh | Pharmaceutical composition comprising an sglt2 inhibitor and a ppar- gamma agonist and uses thereof |
JP6227406B2 (ja) | 2010-05-11 | 2017-11-08 | ヤンセン ファーマシューティカ エヌ.ベー. | SGLTの阻害剤としての1−(β−D−グルコピラノシル)−2−チエニル−メチルベンゼン誘導体を含有する医薬製剤 |
WO2011153712A1 (en) | 2010-06-12 | 2011-12-15 | Theracos, Inc. | Crystalline form of benzylbenzene sglt2 inhibitor |
WO2012003811A1 (en) * | 2010-07-09 | 2012-01-12 | Zhejiang Beta Pharma Inc. | C-aryl glucoside sglt2 inhibitors and method |
GEP20156217B (en) | 2010-08-12 | 2015-01-12 | Boehringer Ingelheim Int | 6-cycloalkyl-1, 5-dihydro-pyrazolo [3, 4-d] pyrimidin-4-one derivatives and their use as pde9a inhibitors |
JP2013540801A (ja) | 2010-11-02 | 2013-11-07 | ベーリンガー インゲルハイム インターナショナル ゲゼルシャフト ミット ベシュレンクテル ハフツング | 代謝異常の治療のための組合せ医薬 |
US20120283169A1 (en) | 2010-11-08 | 2012-11-08 | Boehringer Ingelheim International Gmbh | Pharmaceutical composition, methods for treating and uses thereof |
US20130035281A1 (en) | 2011-02-09 | 2013-02-07 | Boehringer Ingelheim International Gmbh | Pharmaceutical composition, methods for treating and uses thereof |
US8809345B2 (en) | 2011-02-15 | 2014-08-19 | Boehringer Ingelheim International Gmbh | 6-cycloalkyl-pyrazolopyrimidinones for the treatment of CNS disorders |
AR085689A1 (es) | 2011-03-07 | 2013-10-23 | Boehringer Ingelheim Int | Composiciones farmaceuticas de metformina, linagliptina y un inhibidor de sglt-2 |
CA2832938C (en) | 2011-04-13 | 2019-09-03 | Janssen Pharmaceutica Nv | Process for the preparation of compounds useful as inhibitors of sglt2 |
US9035044B2 (en) | 2011-05-09 | 2015-05-19 | Janssen Pharmaceutica Nv | L-proline and citric acid co-crystals of (2S, 3R, 4R, 5S,6R)-2-(3-((5-(4-fluorophenyl)thiopen-2-yl)methyl)4-methylphenyl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol |
MX2013014135A (es) | 2011-06-03 | 2014-01-23 | Boehringer Ingelheim Int | Inhibidores de sglt2 para tratar trastornos metabolicos en pacientes tratados con agentes neurolepticos. |
CN102875503B (zh) | 2011-06-25 | 2016-05-25 | 山东轩竹医药科技有限公司 | C-糖苷衍生物 |
US20130035298A1 (en) | 2011-07-08 | 2013-02-07 | Boehringer Ingelheim International Gmbh | Pharmaceutical composition, methods for treating and uses thereof |
JP2014530186A (ja) | 2011-09-13 | 2014-11-17 | パナセア バイオテック リミテッド | 新規sglt阻害剤 |
CN102408459B (zh) * | 2011-09-29 | 2014-07-23 | 天津药物研究院 | 一类含异头位烷基的苯基c-葡萄糖苷衍生物、其制备方法和用途 |
US9555001B2 (en) | 2012-03-07 | 2017-01-31 | Boehringer Ingelheim International Gmbh | Pharmaceutical composition and uses thereof |
US9192617B2 (en) | 2012-03-20 | 2015-11-24 | Boehringer Ingelheim International Gmbh | Pharmaceutical composition, methods for treating and uses thereof |
US9193751B2 (en) | 2012-04-10 | 2015-11-24 | Theracos, Inc. | Process for the preparation of benzylbenzene SGLT2 inhibitors |
EA201401231A1 (ru) | 2012-05-09 | 2015-08-31 | Бёрингер Ингельхайм Интернациональ Гмбх | Фармацевтические комбинации, предназначенные для лечения метаболических нарушений |
CN104045513A (zh) * | 2013-03-14 | 2014-09-17 | 爱康药业有限公司 | 4-取代-1-氯-2-(4-氟苄基)苯及其制备方法和作为中间体在制备抗ii型糖尿病药物中的应用 |
DK2981269T3 (da) | 2013-04-04 | 2023-10-23 | Boehringer Ingelheim Vetmedica Gmbh | Behandling af stofskifteforstyrrelser hos hestedyr |
US20140303098A1 (en) | 2013-04-05 | 2014-10-09 | Boehringer Ingelheim International Gmbh | Pharmaceutical composition, methods for treating and uses thereof |
US11813275B2 (en) | 2013-04-05 | 2023-11-14 | Boehringer Ingelheim International Gmbh | Pharmaceutical composition, methods for treating and uses thereof |
US20140303097A1 (en) | 2013-04-05 | 2014-10-09 | Boehringer Ingelheim International Gmbh | Pharmaceutical composition, methods for treating and uses thereof |
AU2014255727B2 (en) | 2013-04-18 | 2019-07-25 | Boehringer Ingelheim International Gmbh | Pharmaceutical composition, methods for treating and uses thereof |
CN104250272B (zh) * | 2013-06-27 | 2018-10-09 | 上海方楠生物科技有限公司 | 一种利用微反应器制备列净类药物中间体的方法 |
WO2015051484A1 (en) | 2013-10-12 | 2015-04-16 | Theracos, Inc. | Preparation of hydroxy-benzylbenzene derivatives |
EP3063116A1 (en) * | 2013-10-31 | 2016-09-07 | Sun Pharmaceutical Industries Ltd | Process for the preparation of 4-bromo-1-chloro-2-(4-ethoxybenzyl)benzene |
SI3862003T1 (sl) | 2013-12-17 | 2024-02-29 | Boehringer Ingelheim Vetmedica Gmbh | Inhibitor SGLT-2 za uporabo pri zdravljenju metabolične motnje pri mačjih živalih |
US9902751B2 (en) | 2013-12-30 | 2018-02-27 | Mylan Laboratories Limited | Process for the preparation of empagliflozin |
US9315438B2 (en) | 2014-01-03 | 2016-04-19 | Xuanzhu Pharma Co., Ltd | Optically pure benzyl-4-chlorophenyl-C-glucoside derivative |
CN104761522B (zh) * | 2014-01-03 | 2017-02-15 | 山东轩竹医药科技有限公司 | 光学纯的苄基‑4‑氯苯基的c‑糖苷衍生物 |
EP3485890B1 (en) * | 2014-01-23 | 2023-05-10 | Boehringer Ingelheim Vetmedica GmbH | Sglt2 inhibitors for treatment of metabolic disorders in canine animals |
PT3125882T (pt) | 2014-04-01 | 2020-08-17 | Boehringer Ingelheim Vetmedica Gmbh | Tratamento de distúrbios metabólicos em animais equinos |
AU2015320975B2 (en) | 2014-09-25 | 2020-10-08 | Boehringer Ingelheim Vetmedica Gmbh | Combination treatment of SGLT2 inhibitors and dopamine agonists for preventing metabolic disorders in equine animals |
US20170319539A1 (en) * | 2014-10-01 | 2017-11-09 | Mylan Laboratories Ltd. | Amorphous Empagliflozin |
CN105753827A (zh) * | 2014-12-17 | 2016-07-13 | 中美华世通生物医药科技(武汉)有限公司 | 制备化合物的方法 |
US10508128B2 (en) | 2015-02-09 | 2019-12-17 | Indoco Remedies Limited | Process for the preparation of SGLT inhibitor compounds |
CN104788438B (zh) * | 2015-05-04 | 2018-02-02 | 南京华威医药科技集团有限公司 | 恩格列净b晶型及其制备 |
CN106336403A (zh) * | 2015-07-14 | 2017-01-18 | 江苏豪森药业集团有限公司 | 依帕列净的工业制备方法 |
EA201890592A1 (ru) | 2015-08-27 | 2018-09-28 | Бёрингер Ингельхайм Ветмедика Гмбх | Жидкие фармацевтические композиции, содержащие ингибиторы sglt-2 |
US20170071970A1 (en) | 2015-09-15 | 2017-03-16 | Janssen Pharmaceutica Nv | Co-therapy comprising canagliflozin and phentermine for the treatment of obesity and obesity related disorders |
CN105153137A (zh) * | 2015-09-17 | 2015-12-16 | 上海应用技术学院 | 一种艾格列净的制备方法 |
EP3362055B1 (en) | 2015-10-15 | 2023-01-18 | Boehringer Ingelheim International GmbH | Sglt-2 inhibitor for use in the treatment of a metabolic myopathy |
WO2017141202A1 (en) | 2016-02-17 | 2017-08-24 | Lupin Limited | Complex of sglt2 inhibitor and process for preparation thereof |
CN106117192B (zh) * | 2016-06-23 | 2018-11-23 | 甘肃成纪生物药业有限公司 | 一种恩格列净的合成方法 |
DK3526229T3 (da) | 2016-10-13 | 2021-07-19 | Boehringer Ingelheim Int | Fremgangsmåde til at fremstille glucopyranosyl-substituerede benzyl-benzen-derivater. |
KR20190070956A (ko) | 2016-10-19 | 2019-06-21 | 베링거 인겔하임 인터내셔날 게엠베하 | Ssao/vap-1 억제제 및 sglt2 억제제를 포함하는 복합제제 및 이의 용도 |
CA3039745A1 (en) | 2016-11-10 | 2018-05-17 | Boehringer Ingelheim International Gmbh | Pharmaceutical composition, methods for treating and uses thereof |
CN108285439B (zh) * | 2017-01-09 | 2023-05-02 | 江苏天士力帝益药业有限公司 | 一种碳糖苷类钠葡萄糖转运蛋白体2抑制剂 |
CN106905305B (zh) * | 2017-02-09 | 2020-04-07 | 杭州科巢生物科技有限公司 | 一种恩格列净的制备方法 |
CN106938998B (zh) * | 2017-04-07 | 2018-07-03 | 四川智强医药科技开发有限公司 | 卡格列净有关物质的合成方法 |
CN108794548B (zh) * | 2017-04-28 | 2023-06-16 | 正大天晴药业集团股份有限公司 | 制备恩格列净及其中间体的方法 |
WO2018207113A1 (en) | 2017-05-09 | 2018-11-15 | Piramal Enterprises Limited | A process for the preparation of sglt2 inhibitor and intermediates thereof |
US11046676B2 (en) | 2017-06-05 | 2021-06-29 | Laurus Labs Limited | Process for preparation of empagliflozin or its co-crystals, solvates and their polymorphs thereof |
TWI797133B (zh) | 2017-06-09 | 2023-04-01 | 丹麥商諾佛 儂迪克股份有限公司 | 用於經口投予的固體組成物 |
CN107652276A (zh) * | 2017-08-09 | 2018-02-02 | 江苏工程职业技术学院 | 一种sglt2抑制剂依帕列净的制备方法 |
CN109988161A (zh) * | 2017-12-29 | 2019-07-09 | 徐州万邦金桥制药有限公司 | 一种适合工业化生产恩格列净的制备方法 |
WO2019201752A1 (en) | 2018-04-17 | 2019-10-24 | Boehringer Ingelheim International Gmbh | Pharmaceutical composition, methods for treating and uses thereof |
EP3826642A1 (en) | 2018-07-25 | 2021-06-02 | Boehringer Ingelheim International GmbH | Empagliflozin for use in treating alport syndrome |
WO2020039394A1 (en) | 2018-08-24 | 2020-02-27 | Novartis Ag | New drug combinations |
JP2022506579A (ja) * | 2018-11-09 | 2022-01-17 | アールエムディー サイエンシズ インコーポレイテッド | がん及び他の状態の治療用組成物 |
WO2020242253A1 (ko) * | 2019-05-30 | 2020-12-03 | 동아에스티 주식회사 | Sglt-2 억제제인 신규 엠파글리플로진 유도체 |
CN110305118B (zh) * | 2019-06-20 | 2024-04-02 | 四川科伦药物研究院有限公司 | 一种适合工业生产恩格列净的合成方法 |
WO2021089752A1 (en) | 2019-11-07 | 2021-05-14 | Novo Nordisk A/S | Solid compositions comprising a glp-1 agonist, an sglt2 inhibitor and a salt of n-(8-(2-hydroxybenzoyl)amino)caprylic acid |
CN114727624A (zh) | 2019-11-28 | 2022-07-08 | 勃林格殷格翰动物保健有限公司 | Sglt-2抑制剂在非人哺乳动物的停奶中的用途 |
CA3167531A1 (en) | 2020-02-17 | 2021-08-26 | Boehringer Ingelheim Vetmedica Gmbh | Use of sglt-2 inhibitors for the prevention and/or treatment of cardiac diseases in felines |
CN111253346A (zh) * | 2020-04-01 | 2020-06-09 | 安徽联创生物医药股份有限公司 | 一种制备依帕列净中间体的合成方法 |
US20230110193A1 (en) | 2020-04-07 | 2023-04-13 | Boehringer Ingelheim International Gmbh | Methods for the treatment of headache disorders |
WO2021250565A1 (en) * | 2020-06-10 | 2021-12-16 | Hikal Limited | An improved process for preparation of empagliflozin and its crystalline polymorph |
CN112248572A (zh) * | 2020-10-30 | 2021-01-22 | 深圳烯湾科技有限公司 | 碳纳米管增强碳纤维复合材料及其制备方法 |
KR20220068805A (ko) | 2020-11-19 | 2022-05-26 | 한미약품 주식회사 | 신규한 글루코스 유도체 |
EP4023644A1 (en) | 2020-12-30 | 2022-07-06 | Zaklady Farmaceutyczne Polpharma SA | Process for the preparation of a pharmaceutical agent |
CN113121476A (zh) * | 2021-04-02 | 2021-07-16 | 江苏阿尔法药业股份有限公司 | 一种恩格列净中间体的制备工艺 |
CN113480497B (zh) * | 2021-07-27 | 2023-02-28 | 山东铂源药业股份有限公司 | 一种恩格列净关键中间体的合成方法 |
WO2023006745A1 (en) | 2021-07-28 | 2023-02-02 | Boehringer Ingelheim Vetmedica Gmbh | Use of sglt-2 inhibitors for the prevention and/or treatment of hypertension in non-human mammals |
CN117715639A (zh) | 2021-07-28 | 2024-03-15 | 勃林格殷格翰动物保健有限公司 | Sglt-2抑制剂用于预防和/或治疗非人哺乳动物中的肾脏病的用途 |
AU2022319909A1 (en) | 2021-07-28 | 2024-02-22 | Boehringer Ingelheim Vetmedica Gmbh | Use of sglt-2 inhibitors for the prevention and/or treatment of cardiac diseases in non-human mammals excluding felines, in particular canines |
CN114195611B (zh) * | 2021-12-24 | 2024-05-28 | 合肥工业大学 | 一种二芳基甲烷类化合物的合成方法 |
WO2023129595A1 (en) | 2021-12-30 | 2023-07-06 | Newamsterdam Pharma B.V. | Obicetrapib and sglt2 inhibitor combination |
WO2023217058A1 (zh) * | 2022-05-12 | 2023-11-16 | 浙江华海药业股份有限公司 | 一种制备含吡喃葡萄糖基化合物的方法 |
US20230381101A1 (en) | 2022-05-25 | 2023-11-30 | Boehringer Ingelheim Vetmedica Gmbh | Aqueous pharmaceutical compositions comprising sglt-2 inhibitors |
Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2002083066A2 (en) * | 2001-04-11 | 2002-10-24 | Bristol-Myers Squibb Company | Amino acid complexes of c-aryl glucosides for treatment of diabetes and method |
Family Cites Families (149)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US3174901A (en) | 1963-01-31 | 1965-03-23 | Jan Marcel Didier Aron Samuel | Process for the oral treatment of diabetes |
NL167151C (nl) | 1971-04-09 | 1981-11-16 | Acf Chemiefarma Nv | Werkwijze ter bereiding van geneesmiddelen met anti-parasitaire werking op basis van halogeen bevatten- de 2,2'-methyleendifenolderivaten, alsmede werkwijze ter bereiding van deze geneeskrachtige verbindingen. |
NO154918C (no) | 1977-08-27 | 1987-01-14 | Bayer Ag | Analogifremgangsmaate til fremstilling av terapeutisk aktive derivater av 3,4,5-trihydroksypiperidin. |
DE2758025A1 (de) | 1977-12-24 | 1979-07-12 | Bayer Ag | Neue derivate von 3,4,5-trihydroxypiperidin, verfahren zu ihrer herstellung und ihre verwendung |
DE2951135A1 (de) | 1979-12-19 | 1981-06-25 | Hoechst Ag, 6230 Frankfurt | Sulfonylharnstoffe, verfahren zu ihrer herstellung, pharmazeutische praeparate auf basis dieser verbindungen und ihre verwendung |
JPS5639056A (en) | 1980-07-16 | 1981-04-14 | Kanebo Ltd | Preparation of n,n,n',n'-tetraacylated nucleus halogenated aromatic diamine |
JPS58164502A (ja) | 1982-03-26 | 1983-09-29 | Chugai Pharmaceut Co Ltd | 除草用組成物 |
US4786755A (en) * | 1985-06-03 | 1988-11-22 | Warner-Lambert Company | Diphenic acid monoamides |
US4602023A (en) | 1985-06-03 | 1986-07-22 | Warner-Lambert Company | Diphenic acid monoamides |
US4786023A (en) * | 1987-08-19 | 1988-11-22 | Harris Leverett D | Drafting implement holder |
US6297273B1 (en) | 1996-04-02 | 2001-10-02 | Mars, Inc. | Use of cocoa solids having high cocoa polyphenol content in tabletting compositions and capsule filling compositions |
JPH1085502A (ja) | 1996-09-19 | 1998-04-07 | Konica Corp | 晶析方法 |
AU6024998A (en) | 1997-01-15 | 1998-08-07 | Glycomed Incorporated | Aryl c-glycoside compounds and sulfated esters thereof |
JPH11124392A (ja) | 1997-10-21 | 1999-05-11 | Sankyo Co Ltd | C−グリコシル化されたアリールスズ化合物 |
US6613806B1 (en) * | 1999-01-29 | 2003-09-02 | Basf Corporation | Enhancement of the efficacy of benzoylbenzenes |
TR200201082T2 (tr) | 1999-08-31 | 2002-07-22 | Kissei Pharmaceutical Co., Ltd. | Glikopriranoziloksipirazol türevleri |
US6515117B2 (en) * | 1999-10-12 | 2003-02-04 | Bristol-Myers Squibb Company | C-aryl glucoside SGLT2 inhibitors and method |
PH12000002657B1 (en) | 1999-10-12 | 2006-02-21 | Bristol Myers Squibb Co | C-aryl glucoside SGLT2 inhibitors |
US6627611B2 (en) * | 2000-02-02 | 2003-09-30 | Kotobuki Pharmaceutical Co Ltd | C-glycosides and preparation of thereof as antidiabetic agents |
JP4456768B2 (ja) | 2000-02-02 | 2010-04-28 | 壽製薬株式会社 | C−配糖体を含有する薬剤 |
SK287183B6 (sk) * | 2000-03-17 | 2010-02-08 | Kissei Pharmaceutical Co., Ltd. | Glukopyranozyloxybenzylbenzenový derivát, farmaceutická kompozícia s jeho obsahom, ich použitie a medziprodukt |
US6683056B2 (en) | 2000-03-30 | 2004-01-27 | Bristol-Myers Squibb Company | O-aryl glucoside SGLT2 inhibitors and method |
US6627634B2 (en) | 2000-04-08 | 2003-09-30 | Boehringer Ingelheim Pharma Kg | Bicyclic heterocycles, pharmaceutical compositions containing them, their use, and processes for preparing them |
PT1329456E (pt) | 2000-09-29 | 2006-12-29 | Kissei Pharmaceutical | Derivados de glucopiranosiloxibenzilbenzeno e composições medicinais que os contêm. |
CA2429833A1 (en) | 2000-11-30 | 2002-06-06 | Kissei Pharmaceutical Co., Ltd. | Glucopyranosyloxybenzylbenzene derivatives, medicinal compositions containing the same and intermediates in the production thereof |
US7019012B2 (en) | 2000-12-20 | 2006-03-28 | Boehringer Ingelheim International Pharma Gmbh & Co. Kg | Quinazoline derivatives and pharmaceutical compositions containing them |
TWI255817B (en) | 2001-02-14 | 2006-06-01 | Kissei Pharmaceutical | Glucopyranosyloxybenzylbenzene derivatives and medicinal use thereof |
EP1360172A1 (en) | 2001-02-15 | 2003-11-12 | Pfizer Products Inc. | Ppar agonists |
CA2438595C (en) | 2001-02-27 | 2011-08-09 | Kissei Pharmaceutical Co., Ltd. | Glucopyranosyloxypyrazole derivatives and medicinal use thereof |
US6936590B2 (en) * | 2001-03-13 | 2005-08-30 | Bristol Myers Squibb Company | C-aryl glucoside SGLT2 inhibitors and method |
JP3698067B2 (ja) * | 2001-03-30 | 2005-09-21 | Jsr株式会社 | 電子吸引性基および電子供与性基を有するモノマー、それを用いた共重合体、ならびにプロトン伝導膜 |
JP2002338471A (ja) | 2001-05-23 | 2002-11-27 | Asahi Kasei Corp | 勃起機能不全のための治療薬 |
DE10139416A1 (de) | 2001-08-17 | 2003-03-06 | Aventis Pharma Gmbh | Aminoalkyl substituierte aromatische Bicyclen, Verfahren zu ihrer Herstellung und ihre Verwendung als Arzneimittel |
US20030087843A1 (en) | 2001-09-05 | 2003-05-08 | Washburn William N. | O-pyrazole glucoside SGLT2 inhibitors and method of use |
WO2003031458A1 (en) | 2001-10-12 | 2003-04-17 | Dana-Farber Cancer Institute | Methods for synthesis of diarylmethanes |
BR0306980A (pt) | 2002-02-01 | 2004-11-09 | Novo Nordisk As | Composto, uso de um composto, composição farmacêutica, e, método para o tratamento de distúrbios ou doenças relacionadas com o receptor de histamina h3 |
GB0206215D0 (en) | 2002-03-15 | 2002-05-01 | Novartis Ag | Organic compounds |
DE10231370B4 (de) | 2002-07-11 | 2006-04-06 | Sanofi-Aventis Deutschland Gmbh | Thiophenglycosidderivate, diese Verbindungen enthaltende Arzneimittel und Verfahren zur Herstellung dieser Arzneimittel |
TWI254635B (en) | 2002-08-05 | 2006-05-11 | Yamanouchi Pharma Co Ltd | Azulene derivative and salt thereof |
RU2356906C2 (ru) | 2002-08-08 | 2009-05-27 | Киссеи Фармасьютикал Ко., Лтд. | Производные пиразола, лекарственные композиции, содержащие эти производные, их применение в медицине и промежуточные соединения для их получения |
EP2308878A3 (de) | 2002-08-21 | 2011-10-26 | Boehringer Ingelheim Pharma GmbH & Co. KG | 8-[3-Amino-Piperidin-1-YL] -Xanthine, deren Herstellung und deren Verwendung als Arzneimittel |
US7407955B2 (en) | 2002-08-21 | 2008-08-05 | Boehringer Ingelheim Pharma Gmbh & Co., Kg | 8-[3-amino-piperidin-1-yl]-xanthines, the preparation thereof and their use as pharmaceutical compositions |
JP3567162B1 (ja) | 2002-11-20 | 2004-09-22 | 日本たばこ産業株式会社 | 4−オキソキノリン化合物及びそのhivインテグラーゼ阻害剤としての利用 |
CZ2004764A3 (cs) | 2002-11-20 | 2005-02-16 | Japan Tobacco Inc | 4-Oxochinolinová sloučenina a její použití jako inhibitoru HIV-integrázy |
JP4651934B2 (ja) * | 2002-12-04 | 2011-03-16 | キッセイ薬品工業株式会社 | ベンジルフェノール誘導体、それを含有する医薬組成物およびその医薬用途 |
DE10258008B4 (de) | 2002-12-12 | 2006-02-02 | Sanofi-Aventis Deutschland Gmbh | Heterocyclische Fluorglycosidderivate, diese Verbindungen enthaltende Arzneimittel und Verfahren zur Herstellung dieser Arzneimittel |
DE10258007B4 (de) | 2002-12-12 | 2006-02-09 | Sanofi-Aventis Deutschland Gmbh | Aromatische Fluorglycosidderivate, diese Verbindungen enthaltende Arzneimittel und Verfahren zur Herstellung dieser Arzneimittel |
CA2512389A1 (en) | 2003-01-03 | 2004-07-29 | Bristol-Myers Squibb Company | Methods of producing c-aryl glucoside sglt2 inhibitors |
US7164015B2 (en) | 2003-02-27 | 2007-01-16 | Bristol-Myers Squibb Company | Non-cryogenic process for forming glycosides |
PL1980560T3 (pl) | 2003-03-14 | 2011-11-30 | Astellas Pharma Inc | Pochodne C-glikozydowe do leczenia cukrzycy |
WO2005000860A2 (en) | 2003-06-03 | 2005-01-06 | The Regents Of The University Of California | Compositions and methods for treatment of disease with acetylated disaccharides |
JP2004359630A (ja) | 2003-06-06 | 2004-12-24 | Yamanouchi Pharmaceut Co Ltd | ジフルオロジフェニルメタン誘導体及びその塩 |
PL1651658T5 (pl) | 2003-08-01 | 2020-11-30 | Mitsubishi Tanabe Pharma Corporation | Nowe związki o działaniu inhibitującym transporter zależny od sodu |
EP1679965A4 (en) | 2003-08-01 | 2009-05-27 | Janssen Pharmaceutica Nv | SUBSTITUTED FUSED HETEROCYCLIC C-GLYCOSIDES |
RS20060320A (en) | 2003-08-01 | 2008-08-07 | Janssen Pharmaceutica N.V., | Substituted indazole-o-glucosides |
JP4131216B2 (ja) * | 2003-08-20 | 2008-08-13 | Jsr株式会社 | ポリアリーレンおよびその製造方法、ならびに高分子固体電解質およびプロトン伝導膜 |
DE502004008951D1 (de) | 2003-08-26 | 2009-03-19 | Boehringer Ingelheim Pharma | Glucopyranosyloxy-pyrazole, diese verbindungen enthaltende arzneimittel, deren verwendung und verfahren zu ihrer herstellung |
US7375090B2 (en) * | 2003-08-26 | 2008-05-20 | Boehringer Ingelheim International Gmbh | Glucopyranosyloxy-pyrazoles, pharmaceutical compositions containing these compounds, the use thereof and processed for the preparation thereof |
US20050085680A1 (en) | 2003-10-21 | 2005-04-21 | Joseph Auerbach | Method for industrial decontamination |
US20050134555A1 (en) * | 2003-12-19 | 2005-06-23 | Kye Systems Corp. | Pointing device for detecting hand-movement |
DE10361133A1 (de) | 2003-12-22 | 2005-07-21 | Boehringer Ingelheim Pharma Gmbh & Co. Kg | Glucopyranosyloxy-substituierte Aromaten, diese Verbindungen enthaltende Arzneimittel, deren Verwendung und Verfahren zu ihrer Herstellung |
US7371732B2 (en) * | 2003-12-22 | 2008-05-13 | Boehringer Ingelheim International Gmbh | Glucopyranosyloxy-substituted aromatic compounds, medicaments containing such compounds, their use and process for their manufacture |
US8058245B2 (en) | 2004-03-04 | 2011-11-15 | Kissei Pharmaceutical Co., Ltd. | Fused heterocycle derivative, medicinal composition containing the same, and medicinal use thereof |
JP5078350B2 (ja) | 2004-03-04 | 2012-11-21 | キッセイ薬品工業株式会社 | 縮合ヘテロ環誘導体、それを含有する医薬組成物およびその医薬用途 |
DE102004012676A1 (de) | 2004-03-16 | 2005-10-06 | Boehringer Ingelheim Pharma Gmbh & Co. Kg | Glucopyranosyl-substituierte Phenyle, diese Verbindungen enthaltende Arzneimittel, deren Verwendung und Verfahren zu ihrer Herstellung |
CA2557801C (en) | 2004-03-16 | 2013-06-25 | Boehringer Ingelheim International Gmbh | Glucopyranosyl-substituted benzol derivatives, drugs containing said compounds, the use thereof and method for the production thereof |
US7393836B2 (en) | 2004-07-06 | 2008-07-01 | Boehringer Ingelheim International Gmbh | D-xylopyranosyl-substituted phenyl derivatives, medicaments containing such compounds, their use and process for their manufacture |
KR20070048188A (ko) | 2004-07-08 | 2007-05-08 | 아스텔라스세이야쿠 가부시키가이샤 | 아줄렌 유도체의 제조방법 및 이의 합성 중간체 |
DE102004034690A1 (de) * | 2004-07-17 | 2006-02-02 | Boehringer Ingelheim Pharma Gmbh & Co. Kg | Methyliden-D-xylopyranosyl-und Oxo-D-xylopyranosyl-substituierte Phenyle, diese Verbindungen enthaltende Arzneimittel, deren Verwendung und Verfahren zu ihrer Herstellung |
TW200606129A (en) | 2004-07-26 | 2006-02-16 | Chugai Pharmaceutical Co Ltd | Novel cyclohexane derivative, its prodrug, its salt and diabetic therapeutic agent containing the same |
WO2006010557A1 (de) * | 2004-07-27 | 2006-02-02 | Boehringer Ingelheim International Gmbh | D-glucopyranosyl-phenyl-substituierte cyclen, diese verbindungen enthaltende arzneimittel, deren verwendung und verfahren zu ihrer herstellung |
WO2006018150A1 (de) | 2004-08-11 | 2006-02-23 | Boehringer Ingelheim International Gmbh | D-xylopyranosyl-phenyl-substituierte cyclen, diese verbindungen enthaltende arzneimittel, deren verwendung und verfahren zu ihrer herstellung |
AR051446A1 (es) | 2004-09-23 | 2007-01-17 | Bristol Myers Squibb Co | Glucosidos de c-arilo como inhibidores selectivos de transportadores de glucosa (sglt2) |
WO2006035796A1 (ja) | 2004-09-29 | 2006-04-06 | Kissei Pharmaceutical Co., Ltd. | 1-(β-D-グリコピラノシル)-3-置換含窒素ヘテロ環化合物、それを含有する医薬組成物及びその医薬用途 |
DE102004048388A1 (de) | 2004-10-01 | 2006-04-06 | Boehringer Ingelheim Pharma Gmbh & Co. Kg | D-Pyranosyl-substituierte Phenyle, diese Verbindungen enthaltende Arzneimittel, deren Verwendung und Verfahren zu ihrer Herstellung |
WO2006064033A2 (en) | 2004-12-16 | 2006-06-22 | Boehringer Ingelheim International Gmbh | Glucopyranosyl-substituted benzene derivatives, medicaments containing such compounds, their use and process for their manufacture |
JP2006176443A (ja) | 2004-12-22 | 2006-07-06 | Shionogi & Co Ltd | メラニン凝集ホルモン受容体アンタゴニスト |
GT200600008A (es) | 2005-01-18 | 2006-08-09 | Formulacion de compresion directa y proceso | |
ATE445608T1 (de) * | 2005-02-23 | 2009-10-15 | Boehringer Ingelheim Int | Glucopyranosylsubstituierte ((hetero)arylethynyl- benzyl)-benzenderivative und deren verwendung als inhibitoren des natriumabhängigen glucose- cotransporters typ 2 (sglt2) |
ES2338041T3 (es) * | 2005-04-15 | 2010-05-03 | Boehringer Ingelheim International Gmbh | Derivados de (heteroariloxi-bencil)-benceno sustituidos con glucopiranosilo en calidad de inhibidores de sglt. |
US7723309B2 (en) | 2005-05-03 | 2010-05-25 | Boehringer Ingelheim International Gmbh | Crystalline forms of 1-chloro-4-(β-D-glucopyranos-1-yl)-2-[4-((R)-tetrahydrofuran-3-yloxy)-benzyl]-benzene, a method for its preparation and the use thereof for preparing medicaments |
UA91546C2 (uk) | 2005-05-03 | 2010-08-10 | Бьорінгер Інгельхайм Інтернаціональ Гмбх | КРИСТАЛІЧНА ФОРМА 1-ХЛОР-4-(β-D-ГЛЮКОПІРАНОЗ-1-ИЛ)-2-[4-((S)-ТЕТРАГІДРОФУРАН-3-ІЛОКСИ)-БЕНЗИЛ]-БЕНЗОЛУ, СПОСІБ ЇЇ ОДЕРЖАННЯ ТА ЇЇ ЗАСТОСУВАННЯ ПРИ ПРИГОТУВАННІ ЛІКАРСЬКИХ ЗАСОБІВ |
US7772191B2 (en) | 2005-05-10 | 2010-08-10 | Boehringer Ingelheim International Gmbh | Processes for preparing of glucopyranosyl-substituted benzyl-benzene derivatives and intermediates therein |
WO2007000445A1 (en) | 2005-06-29 | 2007-01-04 | Boehringer Ingelheim International Gmbh | Glucopyranosyl-substituted benzyl-benzene derivatives, medicaments containing such compounds, their use and process for their manufacture |
CA2616294A1 (en) | 2005-07-27 | 2007-02-08 | Boehringer Ingelheim International Gmbh | Glucopyranosyl-substituted ((hetero)cycloalkylethynyl-benzyl)-benzene derivatives and use thereof as sodium-dependent glucose cotransporter (sglt) inhibitors |
US7452872B2 (en) | 2005-08-24 | 2008-11-18 | Salix Pharmaceuticals, Inc. | Formulations and uses of 2-hydroxy-5-phenylazobenzoic acid derivatives |
DE602006017566D1 (de) | 2005-08-30 | 2010-11-25 | Boehringer Ingelheim Pharma | Glucopyranosyl-substituierte benzyl-derivate, medikamente mit solchen verbindungen, ihre verwendung und herstellungsverfahren dafür |
TW200745075A (en) * | 2005-09-08 | 2007-12-16 | Boehringer Ingelheim Int | Crystalline forms of 1-chloro-4-(β-D-glucopyranos-1-yl)-2-(4-ethynyl-benzyl)-benzene, methods for its preparation and the use thereof for preparing medicaments |
AR056195A1 (es) * | 2005-09-15 | 2007-09-26 | Boehringer Ingelheim Int | Procedimientos para preparar derivados de (etinil-bencil)-benceno sustituidos de glucopiranosilo y compuestos intermedios de los mismos |
JOP20180109A1 (ar) | 2005-09-29 | 2019-01-30 | Novartis Ag | تركيبة جديدة |
AR059489A1 (es) * | 2006-02-15 | 2008-04-09 | Boehringer Ingelheim Vetmed | Derivados de benzonitrilo sustituidos con glucopiranosilo, composiciones farmaceuticas que contienen compuestos de este tipo, su uso y procedimiento para su fabricacion |
PE20080697A1 (es) | 2006-05-03 | 2008-08-05 | Boehringer Ingelheim Int | Derivados de benzonitrilo sustituidos con glucopiranosilo, composiciones farmaceuticas que contienen compuestos de este tipo, su uso y procedimiento para su fabricacion |
PE20110235A1 (es) | 2006-05-04 | 2011-04-14 | Boehringer Ingelheim Int | Combinaciones farmaceuticas que comprenden linagliptina y metmorfina |
EP1852108A1 (en) | 2006-05-04 | 2007-11-07 | Boehringer Ingelheim Pharma GmbH & Co.KG | DPP IV inhibitor formulations |
TW200817424A (en) | 2006-08-04 | 2008-04-16 | Daiichi Sankyo Co Ltd | Benzylphenyl glucopyranoside derivatives |
US8039441B2 (en) | 2006-08-15 | 2011-10-18 | Boehringer Ingelheim International Gmbh | Glucopyranosyl-substituted cyclopropylbenzene derivatives, pharmaceutical compositions containing such compounds, their use as SGLT inhibitors and process for their manufacture |
US20100227809A1 (en) | 2006-08-17 | 2010-09-09 | Wellstat Therapeutics Corporation | Combination treatment for metabolic disorders |
CA2664095A1 (en) | 2006-09-21 | 2008-03-27 | Boehringer Ingelheim International Gmbh | Glucopyranosyl-substituted difluorobenzyl-benzene derivatives, medicaments containing such compounds, their use and process for their manufacture |
JP2010507629A (ja) | 2006-10-27 | 2010-03-11 | ベーリンガー インゲルハイム インターナショナル ゲゼルシャフト ミット ベシュレンクテル ハフツング | 4−(β−D−グルコピラノス−1−イル)−1−メチル−2−[4−((S)−テトラヒドロフラン−3−イルオキシ)−ベンジル]−ベンゼンの結晶形、その製造方法及び医薬品を製造するための使用 |
US7879806B2 (en) | 2006-11-06 | 2011-02-01 | Boehringer Ingelheim International Gmbh | Glucopyranosyl-substituted benzyl-benzonitrile derivates, medicaments containing such compounds, their use and process for their manufacture |
US20100298243A1 (en) | 2006-11-09 | 2010-11-25 | Boehringer Ingelheim International Gmbh | Combination therapy with sglt-2 inhibitors and their pharmaceutical compositions |
ATE514692T1 (de) | 2007-01-26 | 2011-07-15 | Sanofi Aventis | Phenothiazin derivate, verfahren zu ihrer herstellung und ihre verwendung als arzneimittel |
US20100081625A1 (en) | 2007-01-26 | 2010-04-01 | Boehringer Ingelheim International Gmbh | Methods for preventing and treating neurodegenerative disorders |
CA2679310A1 (en) | 2007-02-21 | 2008-08-28 | Boehringer Ingelheim International Gmbh | Tetrasubstituted glucopyranosylated benzene derivatives, medicaments containing such compounds, their use and process for their manufacture |
WO2008101938A1 (en) | 2007-02-21 | 2008-08-28 | Boehringer Ingelheim International Gmbh | Glucopyranosyl-substituted benzyl-benzonitrile derivatives, medicaments containing such compounds, their use and process for their manufacture |
ITFI20070042A1 (it) | 2007-02-21 | 2008-08-22 | Laboratori Guidotti Spa | Formulazione farmaceutica e compressa comprendente detta formulazione. |
TW200904405A (en) | 2007-03-22 | 2009-02-01 | Bristol Myers Squibb Co | Pharmaceutical formulations containing an SGLT2 inhibitor |
TW200904454A (en) | 2007-03-22 | 2009-02-01 | Bristol Myers Squibb Co | Methods for treating obesity employing an SGLT2 inhibitor and compositions thereof |
PE20090696A1 (es) | 2007-04-20 | 2009-06-20 | Bristol Myers Squibb Co | Formas cristalinas de saxagliptina y procesos para preparar las mismas |
CN101754972A (zh) | 2007-05-18 | 2010-06-23 | 百时美施贵宝公司 | Sglt2抑制剂的晶体结构及其制备方法 |
PE20090938A1 (es) | 2007-08-16 | 2009-08-08 | Boehringer Ingelheim Int | Composicion farmaceutica que comprende un derivado de benceno sustituido con glucopiranosilo |
PE20090603A1 (es) | 2007-08-16 | 2009-06-11 | Boehringer Ingelheim Int | Composicion farmaceutica que comprende un inhibidor de sglt2 y un inhibidor de dpp iv |
KR101552187B1 (ko) | 2007-09-10 | 2015-09-10 | 얀센 파마슈티카 엔.브이. | Sglt 억제제로서 유용한 화합물의 제조 방법 |
CL2008003653A1 (es) | 2008-01-17 | 2010-03-05 | Mitsubishi Tanabe Pharma Corp | Uso de un inhibidor de sglt derivado de glucopiranosilo y un inhibidor de dppiv seleccionado para tratar la diabetes; y composicion farmaceutica. |
CN101503399B (zh) | 2008-02-04 | 2012-06-27 | 白鹭医药技术(上海)有限公司 | C-芳基葡萄糖苷sglt2抑制剂 |
US20110015225A1 (en) | 2008-04-01 | 2011-01-20 | Takeda Pharmaceutical Company Limited | Heterocyclic compound |
PE20140960A1 (es) | 2008-04-03 | 2014-08-15 | Boehringer Ingelheim Int | Formulaciones que comprenden un inhibidor de dpp4 |
WO2010045656A2 (en) | 2008-10-17 | 2010-04-22 | Nectid, Inc. | Novel sglt2 inhibitor dosage forms |
PE20120002A1 (es) | 2009-02-13 | 2012-02-12 | Boehringer Ingelheim Int | Derivados de benceno sustituido con glucopiranosilo como inhibidores de sglt2 |
CN102307577A (zh) | 2009-02-13 | 2012-01-04 | 贝林格尔.英格海姆国际有限公司 | 包含sglt2抑制剂、dpp-iv抑制剂和任选的另一种抗糖尿病药的药物组合物及其用途 |
JP5600328B2 (ja) | 2009-02-13 | 2014-10-01 | ベーリンガー インゲルハイム インターナショナル ゲゼルシャフト ミット ベシュレンクテル ハフツング | グルコピラノシルジフェニルメタン誘導体を含む医薬組成物、その医薬剤形、それらの調製方法及び患者の血糖コントロールを改善するためのそれらの使用 |
AU2010212823B2 (en) | 2009-02-13 | 2016-01-28 | Boehringer Ingelheim International Gmbh | Antidiabetic medications comprising a DPP-4 inhibitor (linagliptin) optionally in combination with other antidiabetics |
UY32427A (es) | 2009-02-13 | 2010-09-30 | Boheringer Ingelheim Internat Gmbh | Composicion farmaceutica, forma farmaceutica, procedimiento para su preparacion, metodos de tratamiento y usos de la misma |
MY182720A (en) | 2009-04-16 | 2021-02-03 | Taisho Pharmaceutical Co Ltd | Pharmaceutical compositions |
JP2012528170A (ja) | 2009-05-27 | 2012-11-12 | ブリストル−マイヤーズ スクイブ カンパニー | 別の抗糖尿病薬を用いた先の治療に抵抗性を有する2型糖尿病患者をsglt2阻害剤およびその組成物を用いて治療する方法 |
US20110077212A1 (en) | 2009-09-25 | 2011-03-31 | Theracos, Inc. | Therapeutic uses of sglt2 inhibitors |
JP5736377B2 (ja) | 2009-09-30 | 2015-06-17 | ベーリンガー インゲルハイム インターナショナル ゲゼルシャフト ミット ベシュレンクテル ハフツング | 1−クロロ−4−(β−D−グルコピラノス−1−イル)−2−[4−((S)−テトラヒドロフラン−3−イルオキシ)ベンジル]ベンゼンの結晶形の調製方法 |
WO2011039108A2 (en) | 2009-09-30 | 2011-04-07 | Boehringer Ingelheim International Gmbh | Processes for preparing of glucopyranosyl-substituted benzyl-benzene derivatives |
US10610489B2 (en) | 2009-10-02 | 2020-04-07 | Boehringer Ingelheim International Gmbh | Pharmaceutical composition, pharmaceutical dosage form, process for their preparation, methods for treating and uses thereof |
JP5784623B2 (ja) | 2009-11-13 | 2015-09-24 | アストラゼネカ・アクチエボラーグAstrazeneca Aktiebolag | 速放性錠剤製剤 |
WO2011120923A1 (en) | 2010-03-30 | 2011-10-06 | Boehringer Ingelheim International Gmbh | Pharmaceutical composition comprising an sglt2 inhibitor and a ppar- gamma agonist and uses thereof |
US20120283169A1 (en) | 2010-11-08 | 2012-11-08 | Boehringer Ingelheim International Gmbh | Pharmaceutical composition, methods for treating and uses thereof |
AR083878A1 (es) | 2010-11-15 | 2013-03-27 | Boehringer Ingelheim Int | Terapia antidiabetica vasoprotectora y cardioprotectora, linagliptina, metodo de tratamiento |
US20130035281A1 (en) | 2011-02-09 | 2013-02-07 | Boehringer Ingelheim International Gmbh | Pharmaceutical composition, methods for treating and uses thereof |
AR085689A1 (es) | 2011-03-07 | 2013-10-23 | Boehringer Ingelheim Int | Composiciones farmaceuticas de metformina, linagliptina y un inhibidor de sglt-2 |
MX2013014135A (es) | 2011-06-03 | 2014-01-23 | Boehringer Ingelheim Int | Inhibidores de sglt2 para tratar trastornos metabolicos en pacientes tratados con agentes neurolepticos. |
US20130035298A1 (en) | 2011-07-08 | 2013-02-07 | Boehringer Ingelheim International Gmbh | Pharmaceutical composition, methods for treating and uses thereof |
US9555001B2 (en) | 2012-03-07 | 2017-01-31 | Boehringer Ingelheim International Gmbh | Pharmaceutical composition and uses thereof |
US9192617B2 (en) | 2012-03-20 | 2015-11-24 | Boehringer Ingelheim International Gmbh | Pharmaceutical composition, methods for treating and uses thereof |
US20140303097A1 (en) | 2013-04-05 | 2014-10-09 | Boehringer Ingelheim International Gmbh | Pharmaceutical composition, methods for treating and uses thereof |
US20140303098A1 (en) | 2013-04-05 | 2014-10-09 | Boehringer Ingelheim International Gmbh | Pharmaceutical composition, methods for treating and uses thereof |
US20160000816A1 (en) | 2013-04-05 | 2016-01-07 | Boehringer Ingelheim International Gmbh | Pharmaceutical composition, methods for treating and uses thereof |
AU2014255727B2 (en) | 2013-04-18 | 2019-07-25 | Boehringer Ingelheim International Gmbh | Pharmaceutical composition, methods for treating and uses thereof |
PT3125882T (pt) | 2014-04-01 | 2020-08-17 | Boehringer Ingelheim Vetmedica Gmbh | Tratamento de distúrbios metabólicos em animais equinos |
JP6561136B2 (ja) | 2015-04-30 | 2019-08-14 | ベーリンガー インゲルハイム インターナショナル ゲゼルシャフト ミット ベシュレンクテル ハフツング | 勃起機能不全を治療又は改善するための方法及びsglt2阻害薬を含む医薬組成物 |
EP3362055B1 (en) | 2015-10-15 | 2023-01-18 | Boehringer Ingelheim International GmbH | Sglt-2 inhibitor for use in the treatment of a metabolic myopathy |
WO2017093419A1 (en) | 2015-12-04 | 2017-06-08 | Boehringer Ingelheim International Gmbh | Pharmaceutical composition, methods for treating and uses thereof |
KR20230028568A (ko) | 2016-03-16 | 2023-02-28 | 베링거 인겔하임 인터내셔날 게엠베하 | 엠파글리플로진을 포함하는 약제학적 조성물 및 이의 용도 |
CA3039745A1 (en) | 2016-11-10 | 2018-05-17 | Boehringer Ingelheim International Gmbh | Pharmaceutical composition, methods for treating and uses thereof |
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Patent Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2002083066A2 (en) * | 2001-04-11 | 2002-10-24 | Bristol-Myers Squibb Company | Amino acid complexes of c-aryl glucosides for treatment of diabetes and method |
Non-Patent Citations (1)
Title |
---|
Revesz Laszlo et al;"SAR of benzoylpyridines and benzophenones as p38alpha MAP kinase inhibitors with oral activity";Bioorganic & Medicinal Chemistry Letters,14(13),3601-3605. * |
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