JP6571644B2 - ヒドロキシ−ベンジルベンゼン誘導体の調製 - Google Patents
ヒドロキシ−ベンジルベンゼン誘導体の調製 Download PDFInfo
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- JP6571644B2 JP6571644B2 JP2016521973A JP2016521973A JP6571644B2 JP 6571644 B2 JP6571644 B2 JP 6571644B2 JP 2016521973 A JP2016521973 A JP 2016521973A JP 2016521973 A JP2016521973 A JP 2016521973A JP 6571644 B2 JP6571644 B2 JP 6571644B2
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- Prior art keywords
- alkoxy
- compound
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- alkyl
- reaction mixture
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- 238000002360 preparation method Methods 0.000 title claims description 22
- CDMGNVWZXRKJNS-UHFFFAOYSA-N 2-benzylphenol Chemical class OC1=CC=CC=C1CC1=CC=CC=C1 CDMGNVWZXRKJNS-UHFFFAOYSA-N 0.000 title 1
- 150000001875 compounds Chemical class 0.000 claims description 191
- 238000000034 method Methods 0.000 claims description 119
- 239000011541 reaction mixture Substances 0.000 claims description 91
- 239000002904 solvent Substances 0.000 claims description 64
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 53
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 51
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 claims description 49
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 claims description 41
- 238000000634 powder X-ray diffraction Methods 0.000 claims description 41
- 239000003638 chemical reducing agent Substances 0.000 claims description 38
- BLRPTPMANUNPDV-UHFFFAOYSA-N Silane Chemical compound [SiH4] BLRPTPMANUNPDV-UHFFFAOYSA-N 0.000 claims description 37
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 36
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 36
- 239000002253 acid Substances 0.000 claims description 36
- 239000003054 catalyst Substances 0.000 claims description 36
- 229910000077 silane Inorganic materials 0.000 claims description 36
- JWUJQDFVADABEY-UHFFFAOYSA-N 2-methyltetrahydrofuran Chemical compound CC1CCCO1 JWUJQDFVADABEY-UHFFFAOYSA-N 0.000 claims description 33
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 32
- 229910052739 hydrogen Inorganic materials 0.000 claims description 31
- 239000001257 hydrogen Substances 0.000 claims description 31
- WYURNTSHIVDZCO-UHFFFAOYSA-N tetrahydrofuran Substances C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 29
- UHUUYVZLXJHWDV-UHFFFAOYSA-N trimethyl(methylsilyloxy)silane Chemical compound C[SiH2]O[Si](C)(C)C UHUUYVZLXJHWDV-UHFFFAOYSA-N 0.000 claims description 28
- 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 26
- 125000005843 halogen group Chemical group 0.000 claims description 25
- 150000002431 hydrogen Chemical class 0.000 claims description 23
- 230000008569 process Effects 0.000 claims description 22
- 125000003118 aryl group Chemical group 0.000 claims description 21
- 125000000217 alkyl group Chemical group 0.000 claims description 20
- OFBQJSOFQDEBGM-UHFFFAOYSA-N Pentane Chemical compound CCCCC OFBQJSOFQDEBGM-UHFFFAOYSA-N 0.000 claims description 17
- 125000003545 alkoxy group Chemical group 0.000 claims description 17
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims description 16
- 229910052736 halogen Inorganic materials 0.000 claims description 16
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 claims description 16
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims description 15
- 125000001309 chloro group Chemical group Cl* 0.000 claims description 15
- YYROPELSRYBVMQ-UHFFFAOYSA-N 4-toluenesulfonyl chloride Chemical compound CC1=CC=C(S(Cl)(=O)=O)C=C1 YYROPELSRYBVMQ-UHFFFAOYSA-N 0.000 claims description 14
- RGSFGYAAUTVSQA-UHFFFAOYSA-N Cyclopentane Chemical compound C1CCCC1 RGSFGYAAUTVSQA-UHFFFAOYSA-N 0.000 claims description 14
- 125000001072 heteroaryl group Chemical group 0.000 claims description 14
- 125000003808 silyl group Chemical group [H][Si]([H])([H])[*] 0.000 claims description 14
- 150000002367 halogens Chemical class 0.000 claims description 13
- AEMRFAOFKBGASW-UHFFFAOYSA-N Glycolic acid Chemical compound OCC(O)=O AEMRFAOFKBGASW-UHFFFAOYSA-N 0.000 claims description 12
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 claims description 12
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 claims description 12
- XUKFPAQLGOOCNJ-UHFFFAOYSA-N dimethyl(trimethylsilyloxy)silicon Chemical compound C[Si](C)O[Si](C)(C)C XUKFPAQLGOOCNJ-UHFFFAOYSA-N 0.000 claims description 12
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 11
- 125000006677 (C1-C3) haloalkoxy group Chemical group 0.000 claims description 10
- 238000001237 Raman spectrum Methods 0.000 claims description 10
- 125000002346 iodo group Chemical group I* 0.000 claims description 10
- 125000006656 (C2-C4) alkenyl group Chemical group 0.000 claims description 9
- 125000005133 alkynyloxy group Chemical group 0.000 claims description 9
- 125000001246 bromo group Chemical group Br* 0.000 claims description 9
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 claims description 8
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 8
- 235000011054 acetic acid Nutrition 0.000 claims description 8
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 8
- 235000019253 formic acid Nutrition 0.000 claims description 8
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 claims description 8
- 229920001843 polymethylhydrosiloxane Polymers 0.000 claims description 8
- 239000011780 sodium chloride Substances 0.000 claims description 8
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 claims description 7
- DMEGYFMYUHOHGS-UHFFFAOYSA-N heptamethylene Natural products C1CCCCCC1 DMEGYFMYUHOHGS-UHFFFAOYSA-N 0.000 claims description 7
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 7
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 6
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims description 6
- 125000003302 alkenyloxy group Chemical group 0.000 claims description 6
- 229910052796 boron Inorganic materials 0.000 claims description 6
- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Chemical compound ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 claims description 6
- 125000000000 cycloalkoxy group Chemical group 0.000 claims description 6
- 125000005113 hydroxyalkoxy group Chemical group 0.000 claims description 6
- OVAWAJRNDPSGHE-UHFFFAOYSA-N 2-methyloxolane;hydrate Chemical compound O.CC1CCCO1 OVAWAJRNDPSGHE-UHFFFAOYSA-N 0.000 claims description 5
- YZCKVEUIGOORGS-OUBTZVSYSA-N Deuterium Chemical group [2H] YZCKVEUIGOORGS-OUBTZVSYSA-N 0.000 claims description 5
- 229910052805 deuterium Inorganic materials 0.000 claims description 5
- 229910052740 iodine Inorganic materials 0.000 claims description 5
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 5
- DPKBAXPHAYBPRL-UHFFFAOYSA-M tetrabutylazanium;iodide Chemical compound [I-].CCCC[N+](CCCC)(CCCC)CCCC DPKBAXPHAYBPRL-UHFFFAOYSA-M 0.000 claims description 5
- 229910052794 bromium Inorganic materials 0.000 claims description 4
- 235000015165 citric acid Nutrition 0.000 claims description 4
- 125000004356 hydroxy functional group Chemical group O* 0.000 claims description 4
- 239000004310 lactic acid Substances 0.000 claims description 4
- 235000014655 lactic acid Nutrition 0.000 claims description 4
- 235000006408 oxalic acid Nutrition 0.000 claims description 4
- GETTZEONDQJALK-UHFFFAOYSA-N (trifluoromethyl)benzene Chemical compound FC(F)(F)C1=CC=CC=C1 GETTZEONDQJALK-UHFFFAOYSA-N 0.000 claims description 3
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 claims description 3
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 claims description 3
- 229910000147 aluminium phosphate Inorganic materials 0.000 claims description 3
- 235000011167 hydrochloric acid Nutrition 0.000 claims description 3
- 229910017604 nitric acid Inorganic materials 0.000 claims description 3
- 239000008096 xylene Substances 0.000 claims description 3
- 229910052799 carbon Inorganic materials 0.000 claims description 2
- 230000003197 catalytic effect Effects 0.000 claims description 2
- 230000005855 radiation Effects 0.000 claims description 2
- -1 benzophenone ketone Chemical class 0.000 description 67
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 64
- 239000000243 solution Substances 0.000 description 63
- 239000000203 mixture Substances 0.000 description 49
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 48
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 46
- 229910052757 nitrogen Inorganic materials 0.000 description 34
- MTPPJFHIYMURGK-UHFFFAOYSA-N 2-cyclopropyloxyethyl 4-methylbenzenesulfonate Chemical compound C1=CC(C)=CC=C1S(=O)(=O)OCCOC1CC1 MTPPJFHIYMURGK-UHFFFAOYSA-N 0.000 description 27
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 27
- 238000006243 chemical reaction Methods 0.000 description 21
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 17
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 16
- 125000001424 substituent group Chemical group 0.000 description 16
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 15
- 238000003756 stirring Methods 0.000 description 15
- 239000003586 protic polar solvent Substances 0.000 description 13
- KYERPXJVHWYNIT-UHFFFAOYSA-N 4-[(2-chloro-5-iodophenyl)methyl]phenol Chemical compound C1=CC(O)=CC=C1CC1=CC(I)=CC=C1Cl KYERPXJVHWYNIT-UHFFFAOYSA-N 0.000 description 12
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 12
- 150000007513 acids Chemical class 0.000 description 12
- 239000003208 petroleum Substances 0.000 description 12
- 239000011777 magnesium Substances 0.000 description 11
- 238000002425 crystallisation Methods 0.000 description 10
- 238000000113 differential scanning calorimetry Methods 0.000 description 10
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Substances [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 10
- GGZQLTVZPOGLCC-UHFFFAOYSA-N 2-(2-bromoethyl)-1,3-dioxolane Chemical compound BrCCC1OCCO1 GGZQLTVZPOGLCC-UHFFFAOYSA-N 0.000 description 9
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 9
- 125000001931 aliphatic group Chemical group 0.000 description 9
- 239000003153 chemical reaction reagent Substances 0.000 description 9
- 239000013078 crystal Substances 0.000 description 9
- 238000010438 heat treatment Methods 0.000 description 9
- 238000001228 spectrum Methods 0.000 description 9
- FCEHBMOGCRZNNI-UHFFFAOYSA-N 1-benzothiophene Chemical compound C1=CC=C2SC=CC2=C1 FCEHBMOGCRZNNI-UHFFFAOYSA-N 0.000 description 8
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 8
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 8
- KYQCOXFCLRTKLS-UHFFFAOYSA-N Pyrazine Chemical compound C1=CN=CC=N1 KYQCOXFCLRTKLS-UHFFFAOYSA-N 0.000 description 8
- YTPLMLYBLZKORZ-UHFFFAOYSA-N Thiophene Chemical compound C=1C=CSC=1 YTPLMLYBLZKORZ-UHFFFAOYSA-N 0.000 description 8
- 125000003342 alkenyl group Chemical group 0.000 description 8
- 125000000304 alkynyl group Chemical group 0.000 description 8
- 239000012065 filter cake Substances 0.000 description 8
- 229910052749 magnesium Inorganic materials 0.000 description 8
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 8
- 239000007787 solid Substances 0.000 description 8
- 238000005481 NMR spectroscopy Methods 0.000 description 7
- 125000004432 carbon atom Chemical group C* 0.000 description 7
- 239000011521 glass Substances 0.000 description 7
- 125000000592 heterocycloalkyl group Chemical group 0.000 description 7
- 238000004519 manufacturing process Methods 0.000 description 7
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 6
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 6
- 238000001069 Raman spectroscopy Methods 0.000 description 6
- 239000007864 aqueous solution Substances 0.000 description 6
- 238000001816 cooling Methods 0.000 description 6
- 235000019439 ethyl acetate Nutrition 0.000 description 6
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 6
- 239000012044 organic layer Substances 0.000 description 6
- 239000000047 product Substances 0.000 description 6
- 239000011877 solvent mixture Substances 0.000 description 6
- FTVLMFQEYACZNP-UHFFFAOYSA-N trimethylsilyl trifluoromethanesulfonate Chemical compound C[Si](C)(C)OS(=O)(=O)C(F)(F)F FTVLMFQEYACZNP-UHFFFAOYSA-N 0.000 description 6
- 0 *C(CCC(Cc1cc(*)c(*)cc1*)CC1)C1/C1=C\C=C\C=C\C=C1 Chemical compound *C(CCC(Cc1cc(*)c(*)cc1*)CC1)C1/C1=C\C=C\C=C\C=C1 0.000 description 5
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 5
- 108091006269 SLC5A2 Proteins 0.000 description 5
- 102000058081 Sodium-Glucose Transporter 2 Human genes 0.000 description 5
- 239000013543 active substance Substances 0.000 description 5
- 239000012267 brine Substances 0.000 description 5
- 239000000460 chlorine Substances 0.000 description 5
- 230000008025 crystallization Effects 0.000 description 5
- 125000001153 fluoro group Chemical group F* 0.000 description 5
- 239000008103 glucose Substances 0.000 description 5
- 230000001404 mediated effect Effects 0.000 description 5
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 5
- 229910000027 potassium carbonate Inorganic materials 0.000 description 5
- 230000009467 reduction Effects 0.000 description 5
- 238000007363 ring formation reaction Methods 0.000 description 5
- 238000007142 ring opening reaction Methods 0.000 description 5
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 5
- VLLMWSRANPNYQX-UHFFFAOYSA-N thiadiazole Chemical compound C1=CSN=N1.C1=CSN=N1 VLLMWSRANPNYQX-UHFFFAOYSA-N 0.000 description 5
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 5
- 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 5
- JENZZAGOSSIJAZ-UHFFFAOYSA-N (2-chloro-5-iodophenyl)-(4-methoxyphenyl)methanone Chemical compound C1=CC(OC)=CC=C1C(=O)C1=CC(I)=CC=C1Cl JENZZAGOSSIJAZ-UHFFFAOYSA-N 0.000 description 4
- AYQHCHVTMZTXKS-UHFFFAOYSA-N 2-cyclopropyloxyethanol Chemical compound OCCOC1CC1 AYQHCHVTMZTXKS-UHFFFAOYSA-N 0.000 description 4
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 4
- SIKJAQJRHWYJAI-UHFFFAOYSA-N Indole Chemical compound C1=CC=C2NC=CC2=C1 SIKJAQJRHWYJAI-UHFFFAOYSA-N 0.000 description 4
- 206010028980 Neoplasm Diseases 0.000 description 4
- PCNDJXKNXGMECE-UHFFFAOYSA-N Phenazine Natural products C1=CC=CC2=NC3=CC=CC=C3N=C21 PCNDJXKNXGMECE-UHFFFAOYSA-N 0.000 description 4
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 4
- KAESVJOAVNADME-UHFFFAOYSA-N Pyrrole Chemical compound C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 description 4
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 description 4
- 229910000024 caesium carbonate Inorganic materials 0.000 description 4
- 201000011510 cancer Diseases 0.000 description 4
- 210000004027 cell Anatomy 0.000 description 4
- 239000008367 deionised water Substances 0.000 description 4
- 229910021641 deionized water Inorganic materials 0.000 description 4
- 229910052731 fluorine Inorganic materials 0.000 description 4
- 150000002500 ions Chemical class 0.000 description 4
- 239000012454 non-polar solvent Substances 0.000 description 4
- 239000003921 oil Substances 0.000 description 4
- 239000004033 plastic Substances 0.000 description 4
- 229920003023 plastic Polymers 0.000 description 4
- 239000000843 powder Substances 0.000 description 4
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 4
- 229940002612 prodrug Drugs 0.000 description 4
- 239000000651 prodrug Substances 0.000 description 4
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 4
- 238000002411 thermogravimetry Methods 0.000 description 4
- 229930192474 thiophene Natural products 0.000 description 4
- PAAZPARNPHGIKF-UHFFFAOYSA-N 1,2-dibromoethane Chemical compound BrCCBr PAAZPARNPHGIKF-UHFFFAOYSA-N 0.000 description 3
- CTYLJKCSPCSNKD-UHFFFAOYSA-N 1-chloro-2-[[4-(2-cyclopropyloxyethoxy)phenyl]methyl]-4-iodobenzene Chemical compound ClC1=CC=C(I)C=C1CC(C=C1)=CC=C1OCCOC1CC1 CTYLJKCSPCSNKD-UHFFFAOYSA-N 0.000 description 3
- ZOXJGFHDIHLPTG-UHFFFAOYSA-N Boron Chemical compound [B] ZOXJGFHDIHLPTG-UHFFFAOYSA-N 0.000 description 3
- 125000000882 C2-C6 alkenyl group Chemical group 0.000 description 3
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 3
- 150000001298 alcohols Chemical class 0.000 description 3
- 125000005189 alkyl hydroxy group Chemical group 0.000 description 3
- 239000012043 crude product Substances 0.000 description 3
- 238000004090 dissolution Methods 0.000 description 3
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 3
- 239000011737 fluorine Substances 0.000 description 3
- 239000007789 gas Substances 0.000 description 3
- 125000002883 imidazolyl group Chemical group 0.000 description 3
- 229910052500 inorganic mineral Chemical class 0.000 description 3
- 125000002183 isoquinolinyl group Chemical group C1(=NC=CC2=CC=CC=C12)* 0.000 description 3
- 150000002576 ketones Chemical class 0.000 description 3
- 239000010410 layer Substances 0.000 description 3
- 239000007788 liquid Substances 0.000 description 3
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 3
- 239000011707 mineral Chemical class 0.000 description 3
- 235000010755 mineral Nutrition 0.000 description 3
- 125000001624 naphthyl group Chemical group 0.000 description 3
- 125000004076 pyridyl group Chemical group 0.000 description 3
- 125000002943 quinolinyl group Chemical group N1=C(C=CC2=CC=CC=C12)* 0.000 description 3
- 150000003839 salts Chemical class 0.000 description 3
- 229910052717 sulfur Inorganic materials 0.000 description 3
- 239000000725 suspension Substances 0.000 description 3
- 125000003831 tetrazolyl group Chemical group 0.000 description 3
- 125000000335 thiazolyl group Chemical group 0.000 description 3
- 125000001544 thienyl group Chemical group 0.000 description 3
- 125000001425 triazolyl group Chemical group 0.000 description 3
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 2
- 125000006017 1-propenyl group Chemical group 0.000 description 2
- 125000000530 1-propynyl group Chemical group [H]C([H])([H])C#C* 0.000 description 2
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 description 2
- 125000001494 2-propynyl group Chemical group [H]C#CC([H])([H])* 0.000 description 2
- 125000004105 2-pyridyl group Chemical group N1=C([*])C([H])=C([H])C([H])=C1[H] 0.000 description 2
- MGADZUXDNSDTHW-UHFFFAOYSA-N 2H-pyran Chemical compound C1OC=CC=C1 MGADZUXDNSDTHW-UHFFFAOYSA-N 0.000 description 2
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- 125000003453 indazolyl group Chemical group N1N=C(C2=C1C=CC=C2)* 0.000 description 1
- 239000011261 inert gas Substances 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 150000007529 inorganic bases Chemical class 0.000 description 1
- 230000000968 intestinal effect Effects 0.000 description 1
- 238000005040 ion trap Methods 0.000 description 1
- 229910052742 iron Inorganic materials 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 125000001972 isopentyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000000555 isopropenyl group Chemical group [H]\C([H])=C(\*)C([H])([H])[H] 0.000 description 1
- 125000003253 isopropoxy group Chemical group [H]C([H])([H])C([H])(O*)C([H])([H])[H] 0.000 description 1
- 210000003734 kidney Anatomy 0.000 description 1
- 238000002514 liquid chromatography mass spectrum Methods 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 201000005202 lung cancer Diseases 0.000 description 1
- 208000020816 lung neoplasm Diseases 0.000 description 1
- OTCKOJUMXQWKQG-UHFFFAOYSA-L magnesium bromide Chemical compound [Mg+2].[Br-].[Br-] OTCKOJUMXQWKQG-UHFFFAOYSA-L 0.000 description 1
- 230000002503 metabolic effect Effects 0.000 description 1
- 239000002207 metabolite Substances 0.000 description 1
- 229940098779 methanesulfonic acid Drugs 0.000 description 1
- 210000000110 microvilli Anatomy 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
- PYLWMHQQBFSUBP-UHFFFAOYSA-N monofluorobenzene Chemical compound FC1=CC=CC=C1 PYLWMHQQBFSUBP-UHFFFAOYSA-N 0.000 description 1
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000003136 n-heptyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001280 n-hexyl group Chemical group C(CCCCC)* 0.000 description 1
- 238000000238 one-dimensional nuclear magnetic resonance spectroscopy Methods 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 125000006353 oxyethylene group Chemical group 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 125000005010 perfluoroalkyl group Chemical group 0.000 description 1
- 125000005062 perfluorophenyl group Chemical group FC1=C(C(=C(C(=C1F)F)F)F)* 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 230000000704 physical effect Effects 0.000 description 1
- 125000004193 piperazinyl group Chemical group 0.000 description 1
- 239000003880 polar aprotic solvent Substances 0.000 description 1
- 239000002798 polar solvent Substances 0.000 description 1
- 229920001296 polysiloxane Polymers 0.000 description 1
- 239000001103 potassium chloride Substances 0.000 description 1
- 235000011164 potassium chloride Nutrition 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 210000000512 proximal kidney tubule Anatomy 0.000 description 1
- 238000010926 purge Methods 0.000 description 1
- 125000000719 pyrrolidinyl group Chemical group 0.000 description 1
- 125000001567 quinoxalinyl group Chemical group N1=C(C=NC2=CC=CC=C12)* 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 230000008085 renal dysfunction Effects 0.000 description 1
- 208000007278 renal glycosuria Diseases 0.000 description 1
- 239000013557 residual solvent Substances 0.000 description 1
- 239000012266 salt solution Substances 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 229930195734 saturated hydrocarbon Natural products 0.000 description 1
- 239000012047 saturated solution Substances 0.000 description 1
- 238000006748 scratching Methods 0.000 description 1
- 230000002393 scratching effect Effects 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 210000002966 serum Anatomy 0.000 description 1
- 125000004469 siloxy group Chemical group [SiH3]O* 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- SNOOUWRIMMFWNE-UHFFFAOYSA-M sodium;6-[(3,4,5-trimethoxybenzoyl)amino]hexanoate Chemical compound [Na+].COC1=CC(C(=O)NCCCCCC([O-])=O)=CC(OC)=C1OC SNOOUWRIMMFWNE-UHFFFAOYSA-M 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- 238000000967 suction filtration Methods 0.000 description 1
- 150000003460 sulfonic acids Chemical class 0.000 description 1
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 description 1
- 239000011593 sulfur Substances 0.000 description 1
- 208000011580 syndromic disease Diseases 0.000 description 1
- 125000001973 tert-pentyl group Chemical group [H]C([H])([H])C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 125000003718 tetrahydrofuranyl group Chemical group 0.000 description 1
- 125000001412 tetrahydropyranyl group Chemical group 0.000 description 1
- DDFYFBUWEBINLX-UHFFFAOYSA-M tetramethylammonium bromide Chemical compound [Br-].C[N+](C)(C)C DDFYFBUWEBINLX-UHFFFAOYSA-M 0.000 description 1
- RXMRGBVLCSYIBO-UHFFFAOYSA-M tetramethylazanium;iodide Chemical compound [I-].C[N+](C)(C)C RXMRGBVLCSYIBO-UHFFFAOYSA-M 0.000 description 1
- 239000011135 tin Substances 0.000 description 1
- 229910052718 tin Inorganic materials 0.000 description 1
- 150000003606 tin compounds Chemical class 0.000 description 1
- 238000003354 tissue distribution assay Methods 0.000 description 1
- 239000010936 titanium Substances 0.000 description 1
- 229910052719 titanium Inorganic materials 0.000 description 1
- 238000007070 tosylation reaction Methods 0.000 description 1
- ITMCEJHCFYSIIV-UHFFFAOYSA-N triflic acid Chemical compound OS(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-N 0.000 description 1
- 238000001665 trituration Methods 0.000 description 1
- 230000002485 urinary effect Effects 0.000 description 1
- 210000002700 urine Anatomy 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
- 239000011701 zinc Substances 0.000 description 1
- 229910052726 zirconium Inorganic materials 0.000 description 1
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Description
本出願は2013年10月12日に出願されたPCT出願番号PCT/CN2013/001227の外国優先権を主張し、その全体を全ての目的のために本明細書中に取り込む。
ナトリウム依存性(「活性」)グルコース共輸送体(SGLT)(SGLT1(腸管刷子縁において主として見られる)及びSGLT2 (腎近位尿細管に局在化している)を含む)は大きく評価されている。特に、SGLT2は腎臓によるグルコース再取り込みの大部分の役割を担っていることが発見されている。腎臓SGLTの阻害は尿中に排泄されるグルコースの量を増加させることによる高血糖症の治療に有用なアプローチと現在考えられている(Arakawa Kら, Br J Pharmacol 132: 578-86, 2001; Oku Aら, Diabetes 48: 1794-1800, 1999)。この治療アプローチの可能性は最近の発見によりさらに支持されており、 その発見は正常血清グルコースレベルの存在下でかつ一般的な腎機能障害又は他の疾患の非存在下での尿糖排泄を特徴とする、見かけ上良性の症候群である家族性腎性糖尿の場合に、SGLT2遺伝子の突然変異が起こることである(Santer Rら, J Am Soc Nephrol 14: 2873-82, 2003) 。それゆえ、SGLT、特にSGLT2を阻害する化合物は抗糖尿病薬としての使用に有望な候補である(Washburn WN, Expert Opin Ther Patents 19: 1485-99, 2009においてレビュー)。さらに、癌細胞はその正常な対照物と比較して、増加したグルコース取り込みを示すので、SGLT阻害は癌細胞を餓死させることによる癌の治療法として提案されている。例えば、研究はSGLT2が肺癌の転移巣におけるグルコース取り込みの役割を果たすことを示唆している(Ishikawa Nら, Jpn J Cancer Res 92: 874-9, 2001)。このように、SGLT2阻害剤は抗がん剤としても有用であることができる。
幾つかの実施形態において、本発明は、式I:
本方法は、式II:
反応混合物はまた、シラン還元剤、触媒及び溶媒を含む。反応混合物は式Iの化合物を調製するのに適した条件下にある。
該方法は
Mg及び
本方法は工程(a)の中間体が2−メチルテトラヒドロフラン中に実質的に溶解されるようにして、第一の反応混合物を水及び2−メチルテトラヒドロフランと接触させる工程(b)を含む。本方法はまた、式IIIの化合物を生成するのに適した条件下で、4−メチルベンゼン−1−スルホニルクロリド(トシル-Cl)及び工程(a)の中間体を含有する工程(b)の2−メチルテトラヒドロフランを含む第二の反応混合物を形成する工程(c)を含む。
I.一般
本発明はナトリウム依存性グルコース供輸送体SGLT阻害剤の調製のための中間体化合物の調製方法を提供する。幾つかの化合物は、トルエン中でホウ素触媒及びテトラメチルジシロキサンを用いて、同時のベンゾフェノンケトンの還元及びメトキシフェニル基の脱アルキル化を行うことにより高い収率及び純度で調製されうる。他の中間体化合物はバービアー様マグネシウムを媒介とする分子内環開環/環化を用いて調製でき、ここで、生成物は2−メチルテトラヒドロフランを用いて分離され、これは濃縮なしに次の工程で溶媒として使用され、生成物を高純度及び収率で提供する。最後に、本発明はまた、結晶性化合物、結晶性化合物の調製方法を提供する。
「反応混合物を形成すること (Forming a reaction mixture)」は、一緒に混合しそして反応することができるように少なくとも2つの区別される化学種を接触させるプロセスを指す。しかしながら、得られる反応生成物は、添加された試薬の間の反応から直接的に生成されることができ、又は、反応混合物において生成されうる、1種以上の添加された試薬から得られる中間体形態から生成されうることが理解されるべきである。
本発明は同時にケトンを還元しそして−OR基を脱アルキル化して−OHを形成することにより化合物を調製する方法を提供する。幾つかの実施形態において、本発明は式I:
反応混合物はまた、シラン還元剤、触媒及び溶媒を含む。反応混合物は式Iの化合物を調製するのに適した条件下にある。
幾つかの実施形態において、本発明は、
該方法は工程(a)2−シクロプロポキシエチル−4−メチルベンゼンスルホネート及び極性プロトン性溶媒である第一の溶媒を混合して、溶液を形成すること、及び、工程(b)前記化合物の結晶形態を形成するのに適した条件下に、前記溶液に第二の溶媒を添加して、混合物を提供すること、
の工程を含む。
本発明はまた、式IIIの化合物の製造方法を提供する。式IIIの化合物は、以前に調製されている (米国特許第7,838,499号明細書を参照されたい)。以前に記載されたバービアー様マグネシウム媒介分子内開環/環化工程に従って、本発明の方法は2−メチルテトラヒドロフランを用いた抽出工程を含み、ここで、中間体化合物の2−シクロプロポキシエタノールを含む抽出溶媒はさらなる濃縮なしにトシル化工程で直接使用される。
該方法は工程(a):Mg及び
該方法はまた、工程(b):工程(a)の中間体が2−メチルテトラヒドロフラン中に実質的に溶解されるようにして、第一の反応混合物を水及び2−メチルテトラヒドロフランと接触させることを含む。該方法はまた、(c)式IIIの化合物を生成するのに適した条件下で、4−メチルベンゼン−1−スルホニルクロリド(トシル-Cl)及び工程(a)の中間体を含有する工程(b)の2−メチルテトラヒドロフランを含む第二の反応混合物を形成することを含む。
本発明はまた、他の化合物の調製のための式IIIの化合物の使用方法を提供する。例えば、式IIIの化合物は式Ic:
下記の実施例は例示の目的のために提供され、いかなる方法によっても本発明を限定することは意図されない。当業者は様々な重要ではないパラメータに変更又は修飾がなされ、本質的に同一の結果を生じうることを容易に認識するであろう。
還元−脱メチル化反応を開発した。この方法はテトラメチルジシロキサンを還元剤として用い、そしてトリス(ペンタフルオロフェニル)ボランを触媒として使用する。シロキサン加水分解の後に、粗製4−(2−クロロ−5−ヨードベンジル)フェノールをn−ヘプタン又は石油エーテル中での研和により容易に精製し(30〜60℃(主にヘキサン異性体画分)又は90〜100℃(主としてヘプタン異性体画分) )、それにより、不純物及びオルト異性体を容易に除去した。両方の画分は不純物を良好に除去したが、ヘプタン画分は安全上の理由から好ましい。
溶液1:2Lフラスコに石油エーテル(1 L, 90〜100℃画分)及びトリス(ペンタフルオロフェニル)ボラン(3.44 g, 6.71 mmol)を窒素下に撹拌しながら装填した。溶液を0〜5℃に冷却し、そしてTMDS (143 g, 2.42 mol)を添加ファンネル内で15分にわたって滴下して加えた。
溶液1:グラスライニング反応器 (glass lined reactor)中に、(2−クロロ−5−ヨードフェニル) (4−メトキシフェニル)メタノン(15.8 kg)及びトルエン(94.8 kg)を窒素下に装填し、そして反応混合物を還流して濃縮し、水及びアルコールトレースを除去した。室温への冷却の後に、蒸留物の重量を新鮮な無水トルエンで置き換えた。テトラメチルジシロキサン(5.7 kg)を、次いで、装填し、そして溶液を窒素下にプラスチックドラムに移した。
溶液1:グラスライニング反応器中に、(2−クロロ−5−ヨードフェニル) (4−メトキシフェニル)メタノン(200.0kg/1.0当量)及びトルエン(1200 kg)を窒素下に装填し、そして溶液を200kgの溶媒が反応混合物から除去されるまで蒸留し、潜在的な水及びアルコールトレースをパージした。室温への冷却の後に、テトラメチルジシロキサン(72 kg/1.0当量)を装填し、そして溶液を窒素下にプラスチックドラムに移し、そして詰めた。
題記の化合物をバービアー (Barbier)様マグネシウム媒介分子内開環/環化を用いて2−(2−ブロモエチル)−1, 3−ジオキソランから2工程で調製した。
題記の化合物をバービアー様マグネシウム媒介分子内開環/環化を用いて2−(2−ブロモエチル)−1, 3−ジオキソランから2工程で調製した。
題記の化合物をバービアー様マグネシウム媒介分子内開環/環化を用いて、2−(2−ブロモエチル)−1, 3-ジオキソランから2工程で調製した。
本例は2−シクロプロポキシエチル4−メチルベンゼンスルホネートと4−(2−クロロ−5−ヨードベンジル)フェノールとのカップリングによる2−(4−(2−シクロプロポキシエトキシ)ベンジル)−1−クロロ−4−ヨードベンゼンの調製を記載する。
Claims (45)
- 式I
式II
シラン還元剤、
B(C6F5)3、BF3−THF、BF3−Bu2O、BF3−MeCN、BF3AcOH、BF3H3PO4及びBF3からなる群より選ばれる触媒、及び、
溶媒、
を含む反応混合物を、式Iの化合物を調製するのに適した条件下で形成することを含み、
上式中、Xはブロモ又はヨードであり、
R1は、水素、ハロゲン、C1〜C3アルキル、C2〜C4アルケン、C2〜C4アルキン、C3〜C6シクロアルキル及び−CNからなる群より選ばれ、
各R2及びR3は、独立して、水素、ハロ、ヒドロキシ、C1〜C3アルキル、C2〜C4アルケニル、C1〜C3アルコキシ、C1〜C3アルキル−ヒドロキシ、C3〜C6シクロアルキル、(C1〜C3アルコキシ)C1〜C3アルキル、(C1〜C3ハロアルコキシ)C1〜C3アルキル、(C2〜C4アルケニルオキシ)C1〜C3アルキル、(C2〜C4アルキニルオキシ)C1〜C3アルキル、(C3〜C6シクロアルコキシ)C1〜C3アルキル、C1〜C3ヒドロキシアルコキシ、C3〜C6シクロアルコキシ、C3〜C6ヘテロシクロアルコキシ、(C1〜C3アルコキシ)C1〜C3アルコキシ、(C1〜C3ハロアルコキシ)C1〜C3アルコキシ、(C2〜C4アルケニルオキシ)C1〜C3アルコキシ、(C2〜C4アルキニルオキシ)C1〜C3アルコキシ、(C3〜C6シクロアルコキシ)C1〜C3アルコキシ、(C3〜C6ヘテロシクロアルコキシ)C1〜C3アルコキシ、(C3〜C6シクロアルキル)C1〜C3アルコキシ、(C3〜C6シクロアルキル)C2〜C4アルケニルオキシ、(C3〜C6シクロアルキル)C2〜C4アルキニルオキシ、−C(O)H、−C(O)OH及び−C(O)O−C1〜C3アルキルからなる群より選ばれ、
ここで、少なくとも1つのR3はC1〜C3アルコキシ、C1〜C3ヒドロキシアルコキシ、C3〜C6シクロアルコキシ、C3〜C6ヘテロシクロアルコキシ、(C1〜C3アルコキシ)C1〜C3アルコキシ、(C1〜C3ハロアルコキシ)C1〜C3アルコキシ、(C2〜C4アルケニルオキシ)C1〜C3アルコキシ、(C2〜C4アルキニルオキシ)C1〜C3アルコキシ、(C3〜C6シクロアルコキシ)C1〜C3アルコキシ、(C3〜C6ヘテロシクロアルコキシ)C1〜C3アルコキシ、(C3〜C6シクロアルキル)C1〜C3アルコキシ、(C3〜C6シクロアルキル)C2〜C4アルケニルオキシ及び(C3〜C6シクロアルキル)C2〜C4アルキニルオキシからなる群より選ばれ、
各R4は、独立して、水素、ハロ、−OR4a、C1〜C3アルキル、C2〜C4アルケニル、C1〜C3アルコキシ、C1〜C3アルキルヒドロキシ、C3〜C6シクロアルキル、(C1〜C3アルコキシ)C1〜C3アルキル、(C1〜C3ハロアルコキシ)C1〜C3アルキル、(C2〜C4アルケニルオキシ)C1〜C3アルキル、(C2〜C4アルキニルオキシ)C1〜C3アルキル、(C3〜C6シクロアルコキシ)C1〜C3アルキル、C1〜C3ヒドロキシアルコキシ、C3〜C6シクロアルコキシ、C3〜C6ヘテロシクロアルコキシ、(C1〜C3アルコキシ)C1〜C3アルコキシ、(C1〜C3ハロアルコキシ)C1〜C3アルコキシ、(C2〜C4アルケニルオキシ)C1〜C3アルコキシ、(C2〜C4アルキニルオキシ)C1〜C3アルコキシ、(C3〜C6シクロアルコキシ)C1〜C3アルコキシ、(C3〜C6ヘテロシクロアルコキシ)C1〜C3アルコキシ、(C3〜C6シクロアルキル)C1〜C3アルコキシ、(C3〜C6シクロアルキル)C2〜C4アルケニルオキシ、(C3〜C6シクロアルキル)C2〜C4アルキニルオキシ、−C(O)H、−C(O)OH及び−C(O)O−C1〜C3アルキルからなる群より選ばれ、
R4aは、水素及びシリル基からなる群より選ばれ、
少なくとも1つのR4は−OR4aであり、
環Cは、アリール及びヘテロアリールからなる群より選ばれ、
環Dは、存在しないか、又は、アリール及びヘテロアリールからなる群より選ばれ、
添字nは1〜4の整数であり、
前記アルキル、アルコキシ、シクロアルキル、アルケニルオキシ、アルキニルオキシ、シクロアルコキシ、ヒドロキシアルコキシ及びヘテロシクロアルコキシ又はそれらの部分は、場合により、部分的に又は完全にフッ素化されていてよく、及び、
1個以上の水素原子は場合により、重水素で置換されていてよい、
方法。 - R1はハロゲンである、請求項1〜3のいずれか1項記載の方法。
- R3はC1〜C3アルコキシ及びC3〜C6シクロアルコキシからなる群より選ばれる、請求項1〜4のいずれか1項記載の方法。
- R1はクロロであり、
R2はHであり、
R3はC1〜C3アルコキシであり、そして、
R4は−OR4aである、請求項1〜5のいずれか1項記載の方法。 - R3はメトキシである、請求項1〜6のいずれか1項記載の方法。
- 前記シラン還元剤はテトラメチルジシロキサン(TMDS)、ペンタメチルジシロキサン(PMDS)、ポリメチルヒドロシロキサン(PMHS)及びEt3SiHからなる群より選ばれる、請求項1〜7のいずれか1項記載の方法。
- 前記シラン還元剤はテトラメチルジシロキサン(TMDS)である、請求項1〜8のいずれか1項記載の方法。
- 前記シラン還元剤は式IIの化合物に対して1.0当量〜5.0当量(モル/モル)の量で存在する、請求項1〜9のいずれか1項記載の方法。
- 前記シラン還元剤は式IIの化合物に対して1.0当量〜2.0(モル/モル)の量で存在する、請求項1〜10のいずれか1項記載の方法。
- 前記触媒はB(C6F5)3である、請求項1〜11のいずれか1項記載の方法。
- 前記触媒は式IIの化合物に対して0.1当量(モル/モル)未満の量で存在する、請求項1〜12のいずれか1項記載の方法。
- 前記触媒は式IIの化合物に対して0.01当量(モル/モル)未満の量で存在する、請求項1〜13のいずれか1項記載の方法。
- 前記溶媒はペンタン、ヘキサン、ヘプタン、シクロペンタン、シクロヘキサン、ベンゼン、トルエン、キシレン、トリフルオロメチルベンゼン及びクロロベンゼンからなる群より選ばれる少なくとも1つの要素又はそれらの組み合わせを含む、請求項1〜14のいずれか1項記載の方法。
- 前記溶媒はトルエンを含む、請求項1〜15のいずれか1項記載の方法。
- 前記反応混合物は−25℃〜50℃の温度である、請求項1〜16のいずれか1項記載の方法。
- 前記反応混合物は−10℃〜25℃の温度である、請求項1〜17のいずれか1項記載の方法。
- 前記反応混合物は0℃〜20℃の温度である、請求項1〜18のいずれか1項記載の方法。
- 式Iの化合物は少なくとも75%の収率で調製される、請求項1〜19のいずれか1項記載の方法。
- 式Iの化合物は少なくとも90%の収率で調製される、請求項1〜20のいずれか1項記載の方法。
- 式Iの化合物は少なくとも95%の収率で調製される、請求項1〜21のいずれか1項記載の方法。
- 式Iの化合物は少なくとも95%の純度で調製される、請求項1〜22のいずれか1項記載の方法。
- 式Iの化合物は少なくとも98%の純度で調製される、請求項1〜23のいずれか1項記載の方法。
- R4aはシリル基であり、前記方法は、R4が−OHである式Iの化合物を調製するのに十分な条件下に、前記反応混合物に酸を添加することを含む、請求項1〜24のいずれか1項記載の方法。
- 前記酸は塩酸、硫酸、リン酸及び硝酸からなる群より選ばれる、請求項25記載の方法。
- 前記酸は塩酸である、請求項26記載の方法。
- 反応混合物を加熱し、それにより、R4が−OHである式Iの化合物を調製することをさらに含む、請求項25〜27のいずれか1項記載の方法。
- 式III
該方法は
(a)Mg、及び
(b)工程(a)の中間体が2−メチルテトラヒドロフラン中に実質的に溶解されるようにして、第一の反応混合物を水及び2−メチルテトラヒドロフランと接触させること、及び、
(c)式IIIの化合物を生成するのに適した条件下で、4−メチルベンゼン−1−スルホニルクロリド(トシル-Cl)及び工程(a)の中間体を含有する工程(b)の2−メチルテトラヒドロフランを含む第二の反応混合物を形成すること、
を含む、方法。 - (a)テトラヒドロフラン溶媒中に、
(b)工程(a)の中間体が2−メチルテトラヒドロフラン中に実質的に溶解されるようにして、第一の反応混合物を水及び2−メチルテトラヒドロフランと接触させること、及び、
(c)式IIIの化合物を生成するのに適した条件下で、4−メチルベンゼン−1−スルホニルクロリド(トシル-Cl)及び工程(a)の中間体を含有する工程(b)の2−メチルテトラヒドロフランを含む第二の反応混合物を形成すること、
を含む、請求項30記載の方法。 - 工程(b)は、工程(a)の中間体が2−メチルテトラヒドロフラン中に実質的に溶解されるようにして、第一の反応混合物を水、酸、及び2−メチルテトラヒドロフランと接触させることを含む、請求項30又は31に記載の方法。
- 工程(b)は、工程(a)の中間体が2−メチルテトラヒドロフラン中に実質的に溶解されるようにして、第一の反応混合物を水、酸、塩化ナトリウム及び2−メチルテトラヒドロフランと接触させることを含む、請求項30又は31に記載の方法。
- 前記酸は塩酸、ギ酸、酢酸、クエン酸、乳酸、シュウ酸及びグリコール酸からなる群より選ばれる、請求項33又は34に記載の方法。
- 前記酸は塩酸である、請求項33〜35のいずれか1項に記載の方法。
- 式IIIの化合物は少なくとも50%の収率で調製される、請求項30〜36のいずれか1項記載の方法。
- 式IIIの化合物は少なくとも65%の収率で調製される、請求項30〜37のいずれか1項記載の方法。
- 濃縮中間体を形成するために2−メチルテトラヒドロフランを除去することなく、工程(a)の中間体を含有する2−メチルテトラヒドロフランを工程(c)で使用する、請求項30〜38のいずれか1項記載の方法。
- 式Ic
該方法は
(a)Mg、及び
(b)工程(a)の中間体が2−メチルテトラヒドロフラン中に実質的に溶解されるようにして、第一の反応混合物を水及び2−メチルテトラヒドロフランと接触させること、及び、
(c)式IIIの化合物:
(d)式Icの化合物を調製するのに適した条件下で、
少なくとも90%の純度を有する式III
式Ib
を含み、
上式中、Xはブロモ及びヨードからなる群より選ばれ、
R1は、水素、ハロ、ヒドロキシ、C1〜C3アルキル又はC1〜C3アルコキシからなる群より選ばれ、
R2は、水素、ハロ、ヒドロキシ、C1〜C3アルキル、C1〜C3アルコキシ、C3〜C6シクロアルキル、(C1〜C3アルコキシ)C1〜C3アルキル、(C1〜C3ハロアルコキシ)C1〜C3アルキル、(C2〜C4アルケニルオキシ)C1〜C3アルキル、(C2〜C4アルキニルオキシ)C1〜C3アルキル、(C3〜C6シクロアルコキシ)C1〜C3アルキル、C1〜C3ヒドロキシアルコキシ、C3〜C6シクロアルコキシ、C3〜C6ヘテロシクロアルコキシ、(C1〜C3アルコキシ)C1〜C3アルコキシ、(C1〜C3ハロアルコキシ)C1〜C3アルコキシ、(C2〜C4アルケニルオキシ)C1〜C3アルコキシ、(C2〜C4アルキニルオキシ)C1〜C3アルコキシ、(C3〜C6シクロアルコキシ)C1〜C3アルコキシ、(C3〜C6ヘテロシクロアルコキシ)C1〜C3アルコキシ、(C3〜C6シクロアルキル)C1〜C3アルコキシ、(C3〜C6シクロアルキル)C2〜C4アルケニルオキシ及び(C3〜C6シクロアルキル)C2〜C4アルキニルオキシからなる群より選ばれる、方法。 - 式IIIの化合物は少なくとも95%の純度を有する、請求項40記載の方法。
- 式IIIの化合物は結晶性である、請求項40記載の方法。
- 式IIIの化合物の結晶形態は、14.3、21.1及び21.9度2θ(±0.1度2θ)のピークを含むX線粉末回折(XRPD)パターンを特徴とし、前記XRPDはCuK α1 線を用いて行われ、あるいは、110、778、1170及び1206cm -1 のピークを含むラマンスペクトルを特徴とする、請求項42記載の方法。
- 式Ibの化合物は、請求項1記載の方法によって調製される、請求項43記載の方法。
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---|---|---|---|---|
CN1020944C (zh) | 1990-01-30 | 1993-05-26 | 阿图尔-费希尔股份公司费希尔厂 | 紧固件 |
EP0671953A4 (en) | 1992-11-13 | 1996-01-10 | Univ Ohio State Res Found | ANALOGS OF N- (4-HYDROXYPHENYL) RETINAMIDE-O-GLUCURONIDE ARYLAMIDE. |
AU6024998A (en) | 1997-01-15 | 1998-08-07 | Glycomed Incorporated | Aryl c-glycoside compounds and sulfated esters thereof |
US6069238A (en) | 1998-09-30 | 2000-05-30 | Eli Lilly And Company | Spirocyclic C-glycosides |
US7407978B2 (en) | 1999-04-06 | 2008-08-05 | Theracos, Inc. | Heterocyclic analogs of diphenylethylene compounds |
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 |
US6555519B2 (en) | 2000-03-30 | 2003-04-29 | Bristol-Myers Squibb Company | O-glucosylated benzamide SGLT2 inhibitors and method |
US6683056B2 (en) | 2000-03-30 | 2004-01-27 | Bristol-Myers Squibb Company | O-aryl glucoside SGLT2 inhibitors and method |
EP1340749A4 (en) | 2000-11-17 | 2007-09-05 | Takeda Pharmaceutical | isoxazole |
TWI255817B (en) | 2001-02-14 | 2006-06-01 | Kissei Pharmaceutical | Glucopyranosyloxybenzylbenzene derivatives and medicinal use thereof |
US6936590B2 (en) | 2001-03-13 | 2005-08-30 | Bristol Myers Squibb Company | C-aryl glucoside SGLT2 inhibitors and method |
ES2258141T3 (es) | 2001-04-11 | 2006-08-16 | Bristol-Myers Squibb Company | Complejos de aminoacidos de glucosidos c-arilo para el tratamiento de la diabetes y procedimiento. |
WO2003020737A1 (en) | 2001-09-05 | 2003-03-13 | Bristol-Myers Squibb Company | O-pyrazole glucoside sglt2 inhibitors and method of use |
PL210710B1 (pl) | 2002-03-22 | 2012-02-29 | Kissei Pharmaceutical | Krystaliczne postaci 2-(4-metoksybenzylo) fenylo-6-O-etoksykarbonylo-ß-D-glukopiranozydu, ich zastosowanie oraz zawierająca je kompozycja farmaceutyczna |
TWI254635B (en) | 2002-08-05 | 2006-05-11 | Yamanouchi Pharma Co Ltd | Azulene derivative and salt thereof |
DE60332743D1 (de) | 2002-08-08 | 2010-07-08 | Kissei Pharmaceutical | Pyrazolderivat, dieses enthaltende medizinische zusammensetzung, medizinische verwendung davon, und zwischenprodukt für dessen herstellung |
EP1528066A4 (en) | 2002-08-09 | 2007-05-02 | Taisho Pharmaceutical Co Ltd | ARYL-t-THIO-B-GLUCOPYRANOSIDE DERIVATIVES AND DIABETES CONTAINING THEM |
DE10258007B4 (de) | 2002-12-12 | 2006-02-09 | Sanofi-Aventis Deutschland Gmbh | Aromatische Fluorglycosidderivate, diese Verbindungen enthaltende Arzneimittel und Verfahren zur Herstellung dieser Arzneimittel |
DE10258008B4 (de) | 2002-12-12 | 2006-02-02 | Sanofi-Aventis Deutschland Gmbh | Heterocyclische Fluorglycosidderivate, diese Verbindungen enthaltende Arzneimittel und Verfahren zur Herstellung dieser Arzneimittel |
US7375213B2 (en) | 2003-01-03 | 2008-05-20 | 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 |
WO2004080990A1 (ja) | 2003-03-14 | 2004-09-23 | Astellas Pharma Inc. | C-グリコシド誘導体又はその塩 |
JP2004300102A (ja) | 2003-03-31 | 2004-10-28 | Kissei Pharmaceut Co Ltd | 縮合複素環誘導体、それを含有する医薬組成物およびその医薬用途 |
TWI308261B (en) | 2003-07-08 | 2009-04-01 | Tokyo Ohka Kogyo Co Ltd | Resin for positive photoresist composition, positive photoresist composition using the same, stacked body and resist pattern formation method |
AR048376A1 (es) | 2003-08-01 | 2006-04-26 | Janssen Pharmaceutica Nv | C- glicosidos heterociclos fusionados sustituidos |
EP1679966A4 (en) | 2003-08-01 | 2009-05-27 | Janssen Pharmaceutica Nv | BENZIMIDAZOLE-, BENZTRIAZOLE- AND BENZIMIDAZOLONE-SUBSTITUTED O-GLUCOSIDES |
DK2896397T4 (da) | 2003-08-01 | 2020-11-16 | Mitsubishi Tanabe Pharma Corp | Nye forbindelser med hæmmende aktivitet mod natriumafhængig glukosetransportør |
WO2005021566A2 (de) | 2003-08-26 | 2005-03-10 | Boehringer Ingelheim International Gmbh | 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 |
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 |
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 |
US20070185197A1 (en) | 2004-03-31 | 2007-08-09 | Hideki Fujikura | Phenol derivative, medicinal composition containing the same, and medicinal use 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 |
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 |
EP1773800A1 (de) | 2004-07-27 | 2007-04-18 | 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) |
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 |
US7687469B2 (en) | 2004-12-16 | 2010-03-30 | Boehringer Ingelheim International Gmbh | Glucopyranosyl-substituted benzene derivatives, medicaments containing such compounds, their use and process for their manufacture |
TW200637839A (en) | 2005-01-07 | 2006-11-01 | Taisho Pharmaceutical Co Ltd | 1-thio-d-glucitol derivatives |
TW200637869A (en) | 2005-01-28 | 2006-11-01 | Chugai Pharmaceutical Co Ltd | The spiroketal derivatives and the use as therapeutical agent for diabetes of the same |
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) |
MY145694A (en) | 2005-04-11 | 2012-03-30 | Xenon Pharmaceuticals Inc | Spiroheterocyclic compounds and their uses as therapeutic agents |
ATE453656T1 (de) | 2005-04-15 | 2010-01-15 | Boehringer Ingelheim Int | Glucopyranosyl-substituierte (heteroaryloxy- benzyl)-benzen-derivate als sglt-inhibitoren |
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 |
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 |
TW200726755A (en) | 2005-07-07 | 2007-07-16 | Astellas Pharma Inc | A crystalline choline salt of an azulene derivative |
JP5128474B2 (ja) | 2005-07-27 | 2013-01-23 | 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−置換((ヘテロ)シクロアルキルエチニル−ベンジル)−ベンゼン誘導体、該化合物を含有する薬剤、それらの使用及びそれらの製造方法 |
GB0516156D0 (en) | 2005-08-05 | 2005-09-14 | Eisai London Res Lab Ltd | JNK 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 |
EP1926720B1 (en) | 2005-09-08 | 2010-12-15 | Boehringer Ingelheim International GmbH | CRYSTALLINE FORMS OF 1-CHLORO-4-(ß-D-GLUCOPYRANOS-1-YL)-2-(4-ETHYNYL-BENZYL)-BENZENE, METHODS FOR ITS PREPARATION AND THE USE THEREOF FOR PREPARING MEDICAMENTS |
TWI370818B (en) | 2006-04-05 | 2012-08-21 | Astellas Pharma Inc | Cocrystal of c-glycoside derivative and l-proline |
AU2007252432B2 (en) | 2006-05-19 | 2011-11-17 | Taisho Pharmaceutical Co., Ltd. | C-phenyl glycitol compound |
US7803778B2 (en) | 2006-05-23 | 2010-09-28 | Theracos, Inc. | Glucose transport inhibitors and methods of use |
US7919598B2 (en) | 2006-06-28 | 2011-04-05 | Bristol-Myers Squibb Company | Crystal structures of SGLT2 inhibitors and processes for preparing same |
US20080027014A1 (en) | 2006-07-28 | 2008-01-31 | Tanabe Seiyaku Co., Ltd. | Novel SGLT inhibitors |
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 |
CA2667550A1 (en) | 2006-10-27 | 2008-05-02 | Boehringer Ingelheim International Gmbh | Crystalline form of 4-(.beta.-d-glucopyranos-1-yl)-1-methyl-2-[4-((s)-tetrahydrofuran-3-yloxy)-benzyl]-benzene, a method for its preparation and the use thereof for preparing medicaments |
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 |
AU2008232419B2 (en) | 2007-04-02 | 2013-06-20 | Theracos, Inc. | Benzylic glycoside derivatives and methods of use |
WO2008144346A2 (en) | 2007-05-18 | 2008-11-27 | Bristol-Myers Squibb Company | Crystal structures of sglt2 inhibitors and processes for their preparation |
EP2183263B1 (en) | 2007-07-26 | 2011-10-26 | Lexicon Pharmaceuticals, Inc. | Methods and compounds useful for the preparation of sodium glucose co-transporter 2 inhibitors |
JP4809931B2 (ja) * | 2007-08-23 | 2011-11-09 | セラコス・インコーポレイテッド | ベンジルベンゼン誘導体およびその使用方法 |
ES2647504T3 (es) | 2007-09-10 | 2017-12-21 | Janssen Pharmaceutica N.V. | Proceso para la preparación de compuestos útiles como inhibidores de SGLT |
UA101004C2 (en) | 2007-12-13 | 2013-02-25 | Теракос, Инк. | Derivatives of benzylphenylcyclohexane and use thereof |
JP6071198B2 (ja) | 2008-07-15 | 2017-02-01 | テラコス,インコーポレーテッド | 重水素化ベンジルベンゼン誘導体及び使用方法 |
NZ591818A (en) * | 2008-08-22 | 2013-01-25 | Theracos Inc | Processes for the preparation of sglt2 inhibitors |
JP4825322B1 (ja) | 2008-08-28 | 2011-11-30 | ファイザー・インク | ジオキサ−ビシクロ[3.2.1]オクタン−2,3,4−トリオール誘導体 |
WO2010147430A2 (en) | 2009-06-19 | 2010-12-23 | Green Cross Corporation | Novel c-aryl glucoside sglt2 inhibitors and pharmaceutical composition comprising same |
WO2011153712A1 (en) | 2010-06-12 | 2011-12-15 | Theracos, Inc. | Crystalline form of benzylbenzene sglt2 inhibitor |
WO2012025857A1 (en) * | 2010-08-23 | 2012-03-01 | Hetero Research Foundation | Cycloalkyl methoxybenzyl phenyl pyran derivatives as sodium dependent glucose co transporter (sglt2) inhibitors |
CN102757415B (zh) * | 2011-04-25 | 2015-07-29 | 北京普禄德医药科技有限公司 | 一种钠依赖性葡萄糖转运蛋白抑制剂及其制备方法和用途 |
US9034921B2 (en) * | 2011-06-01 | 2015-05-19 | Green Cross Corporation | Diphenylmethane derivatives as SGLT2 inhibitors |
US9193751B2 (en) * | 2012-04-10 | 2015-11-24 | Theracos, Inc. | Process for the preparation of benzylbenzene SGLT2 inhibitors |
CN105611920B (zh) | 2013-10-12 | 2021-07-16 | 泰拉科斯萨普有限责任公司 | 羟基-二苯甲烷衍生物的制备 |
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JP2016533357A (ja) | 2016-10-27 |
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US20150210634A1 (en) | 2015-07-30 |
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CN105611920B (zh) | 2021-07-16 |
SG11201602861QA (en) | 2016-05-30 |
NZ718211A (en) | 2021-04-30 |
EP3055281A1 (en) | 2016-08-17 |
CN105611920A (zh) | 2016-05-25 |
WO2015051484A1 (en) | 2015-04-16 |
CA2925034A1 (en) | 2015-04-16 |
CA2925034C (en) | 2021-12-07 |
EP3055281B1 (en) | 2020-01-08 |
AU2014334416A1 (en) | 2016-04-14 |
US10093616B2 (en) | 2018-10-09 |
RU2671493C2 (ru) | 2018-11-01 |
MX2016004565A (es) | 2016-07-12 |
AU2014334416B2 (en) | 2018-08-09 |
AR098002A1 (es) | 2016-04-27 |
ZA201602198B (en) | 2020-11-25 |
KR102295683B1 (ko) | 2021-08-27 |
KR20160070795A (ko) | 2016-06-20 |
TWI655181B (zh) | 2019-04-01 |
WO2015051597A1 (en) | 2015-04-16 |
IL244758B (en) | 2020-01-30 |
US9464043B2 (en) | 2016-10-11 |
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