ES2898336T3 - Derivado de difenilmetano en forma cristalina - Google Patents
Derivado de difenilmetano en forma cristalina Download PDFInfo
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- ES2898336T3 ES2898336T3 ES20152959T ES20152959T ES2898336T3 ES 2898336 T3 ES2898336 T3 ES 2898336T3 ES 20152959 T ES20152959 T ES 20152959T ES 20152959 T ES20152959 T ES 20152959T ES 2898336 T3 ES2898336 T3 ES 2898336T3
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- CZZYITDELCSZES-UHFFFAOYSA-N diphenylmethane Chemical class C=1C=CC=CC=1CC1=CC=CC=C1 CZZYITDELCSZES-UHFFFAOYSA-N 0.000 title description 9
- 150000001875 compounds Chemical class 0.000 claims abstract description 386
- 238000001228 spectrum Methods 0.000 claims abstract description 31
- 238000002441 X-ray diffraction Methods 0.000 claims abstract 8
- 229910002483 Cu Ka Inorganic materials 0.000 claims description 8
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Natural products CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 175
- 239000000203 mixture Substances 0.000 description 143
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 137
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 115
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 110
- 239000000243 solution Substances 0.000 description 102
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 94
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 87
- 235000019439 ethyl acetate Nutrition 0.000 description 82
- 239000013078 crystal Substances 0.000 description 79
- 238000006243 chemical reaction Methods 0.000 description 77
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 62
- 239000011541 reaction mixture Substances 0.000 description 60
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 58
- 238000003756 stirring Methods 0.000 description 57
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 56
- 239000012074 organic phase Substances 0.000 description 55
- 238000000034 method Methods 0.000 description 50
- 239000007787 solid Substances 0.000 description 50
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 47
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 47
- 235000019341 magnesium sulphate Nutrition 0.000 description 47
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 45
- 238000005160 1H NMR spectroscopy Methods 0.000 description 42
- 239000002904 solvent Substances 0.000 description 40
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 39
- 239000000706 filtrate Substances 0.000 description 37
- 238000000746 purification Methods 0.000 description 36
- 230000002829 reductive effect Effects 0.000 description 35
- 238000004519 manufacturing process Methods 0.000 description 34
- 239000000047 product Substances 0.000 description 34
- 239000011734 sodium Substances 0.000 description 33
- 239000000725 suspension Substances 0.000 description 32
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 31
- KORCWPOBTZTAFI-YVTYUBGGSA-N (2s,3r,4r,5s,6r)-2-[7-chloro-6-[(4-cyclopropylphenyl)methyl]-2,3-dihydro-1-benzofuran-4-yl]-6-(hydroxymethyl)oxane-3,4,5-triol Chemical compound O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@H]1C1=CC(CC=2C=CC(=CC=2)C2CC2)=C(Cl)C2=C1CCO2 KORCWPOBTZTAFI-YVTYUBGGSA-N 0.000 description 29
- -1 diphenylmethane derivative compound Chemical class 0.000 description 29
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 28
- 229910052736 halogen Inorganic materials 0.000 description 28
- 150000002367 halogens Chemical group 0.000 description 28
- 238000007363 ring formation reaction Methods 0.000 description 27
- 239000002244 precipitate Substances 0.000 description 26
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 24
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 24
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 24
- 239000012043 crude product Substances 0.000 description 24
- 230000015572 biosynthetic process Effects 0.000 description 23
- 238000006722 reduction reaction Methods 0.000 description 23
- 238000010898 silica gel chromatography Methods 0.000 description 23
- 238000003786 synthesis reaction Methods 0.000 description 23
- 125000000217 alkyl group Chemical group 0.000 description 21
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 19
- 125000003545 alkoxy group Chemical group 0.000 description 19
- 239000012153 distilled water Substances 0.000 description 19
- 125000006239 protecting group Chemical group 0.000 description 19
- 230000009467 reduction Effects 0.000 description 19
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 17
- 239000007810 chemical reaction solvent Substances 0.000 description 17
- 238000010511 deprotection reaction Methods 0.000 description 17
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 16
- 239000003153 chemical reaction reagent Substances 0.000 description 16
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 16
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 16
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 16
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 15
- 239000002841 Lewis acid Substances 0.000 description 14
- 150000007517 lewis acids Chemical class 0.000 description 14
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 13
- 238000000113 differential scanning calorimetry Methods 0.000 description 13
- 229910052760 oxygen Inorganic materials 0.000 description 13
- 239000012279 sodium borohydride Substances 0.000 description 12
- 229910000033 sodium borohydride Inorganic materials 0.000 description 12
- 238000012360 testing method Methods 0.000 description 12
- AQRLNPVMDITEJU-UHFFFAOYSA-N triethylsilane Chemical compound CC[SiH](CC)CC AQRLNPVMDITEJU-UHFFFAOYSA-N 0.000 description 12
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 11
- 239000008346 aqueous phase Substances 0.000 description 11
- 239000012267 brine Substances 0.000 description 11
- 238000002425 crystallisation Methods 0.000 description 11
- 230000008025 crystallization Effects 0.000 description 11
- 229910052757 nitrogen Inorganic materials 0.000 description 11
- LEHBURLTIWGHEM-UHFFFAOYSA-N pyridinium chlorochromate Chemical compound [O-][Cr](Cl)(=O)=O.C1=CC=[NH+]C=C1 LEHBURLTIWGHEM-UHFFFAOYSA-N 0.000 description 11
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 11
- 239000007858 starting material Substances 0.000 description 11
- ILJSQTXMGCGYMG-UHFFFAOYSA-N triacetic acid Chemical compound CC(=O)CC(=O)CC(O)=O ILJSQTXMGCGYMG-UHFFFAOYSA-N 0.000 description 11
- 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 10
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 10
- 239000002253 acid Substances 0.000 description 10
- 238000001816 cooling Methods 0.000 description 10
- 239000008103 glucose Substances 0.000 description 10
- 230000008569 process Effects 0.000 description 10
- 238000010183 spectrum analysis Methods 0.000 description 10
- 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 10
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 9
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 9
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 9
- 239000000460 chlorine Substances 0.000 description 9
- 239000001301 oxygen Substances 0.000 description 9
- KZMGYPLQYOPHEL-UHFFFAOYSA-N Boron trifluoride etherate Chemical compound FB(F)F.CCOCC KZMGYPLQYOPHEL-UHFFFAOYSA-N 0.000 description 8
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 8
- 108091006269 SLC5A2 Proteins 0.000 description 8
- 102000058081 Sodium-Glucose Transporter 2 Human genes 0.000 description 8
- 101710090560 Sodium/myo-inositol cotransporter 2 Proteins 0.000 description 8
- 102100037202 Sodium/myo-inositol cotransporter 2 Human genes 0.000 description 8
- 150000001299 aldehydes Chemical class 0.000 description 8
- 239000007864 aqueous solution Substances 0.000 description 8
- 238000001914 filtration Methods 0.000 description 8
- 125000001072 heteroaryl group Chemical group 0.000 description 8
- 238000006462 rearrangement reaction Methods 0.000 description 8
- 229910052717 sulfur Inorganic materials 0.000 description 8
- UMGDCJDMYOKAJW-UHFFFAOYSA-N thiourea Chemical compound NC(N)=S UMGDCJDMYOKAJW-UHFFFAOYSA-N 0.000 description 8
- KORCWPOBTZTAFI-SKTPTLSNSA-N (3R,4R,5S,6R)-2-[7-chloro-6-[(4-cyclopropylphenyl)methyl]-2,3-dihydro-1-benzofuran-4-yl]-6-(hydroxymethyl)oxane-3,4,5-triol Chemical compound OC[C@H]1OC([C@H](O)[C@@H](O)[C@@H]1O)c1cc(Cc2ccc(cc2)C2CC2)c(Cl)c2OCCc12 KORCWPOBTZTAFI-SKTPTLSNSA-N 0.000 description 7
- ICSHUVKDARHDBY-UHFFFAOYSA-N 4-bromo-7-chloro-6-[(4-cyclopropylphenyl)methyl]-2,3-dihydro-1-benzofuran Chemical compound ClC1=C2OCCC2=C(Br)C=C1CC(C=C1)=CC=C1C1CC1 ICSHUVKDARHDBY-UHFFFAOYSA-N 0.000 description 7
- 229960000549 4-dimethylaminophenol Drugs 0.000 description 7
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 7
- 238000007112 amidation reaction Methods 0.000 description 7
- 125000003118 aryl group Chemical group 0.000 description 7
- 238000012790 confirmation Methods 0.000 description 7
- 125000002791 glucosyl group Chemical group C1([C@H](O)[C@@H](O)[C@H](O)[C@H](O1)CO)* 0.000 description 7
- 238000010438 heat treatment Methods 0.000 description 7
- 125000000592 heterocycloalkyl group Chemical group 0.000 description 7
- 230000007774 longterm Effects 0.000 description 7
- PWBYYFFYBSILOC-UHFFFAOYSA-N methyl 4-bromo-7-chloro-2,3-dihydro-1-benzofuran-6-carboxylate Chemical compound COC(=O)C1=CC(Br)=C2CCOC2=C1Cl PWBYYFFYBSILOC-UHFFFAOYSA-N 0.000 description 7
- 235000017557 sodium bicarbonate Nutrition 0.000 description 7
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 7
- 239000000126 substance Substances 0.000 description 7
- 125000001424 substituent group Chemical group 0.000 description 7
- TWCMVXMQHSVIOJ-UHFFFAOYSA-N Aglycone of yadanzioside D Natural products COC(=O)C12OCC34C(CC5C(=CC(O)C(O)C5(C)C3C(O)C1O)C)OC(=O)C(OC(=O)C)C24 TWCMVXMQHSVIOJ-UHFFFAOYSA-N 0.000 description 6
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical class [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 6
- PLMKQQMDOMTZGG-UHFFFAOYSA-N Astrantiagenin E-methylester Natural products CC12CCC(O)C(C)(CO)C1CCC1(C)C2CC=C2C3CC(C)(C)CCC3(C(=O)OC)CCC21C PLMKQQMDOMTZGG-UHFFFAOYSA-N 0.000 description 6
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 6
- 239000007983 Tris buffer Substances 0.000 description 6
- 230000002378 acidificating effect Effects 0.000 description 6
- 125000004414 alkyl thio group Chemical group 0.000 description 6
- 125000000304 alkynyl group Chemical group 0.000 description 6
- VSCWAEJMTAWNJL-UHFFFAOYSA-K aluminium trichloride Chemical compound Cl[Al](Cl)Cl VSCWAEJMTAWNJL-UHFFFAOYSA-K 0.000 description 6
- 230000009435 amidation Effects 0.000 description 6
- 229910052796 boron Inorganic materials 0.000 description 6
- 229910052799 carbon Inorganic materials 0.000 description 6
- 239000003638 chemical reducing agent Substances 0.000 description 6
- QQVDYSUDFZZPSU-UHFFFAOYSA-M chloromethylidene(dimethyl)azanium;chloride Chemical compound [Cl-].C[N+](C)=CCl QQVDYSUDFZZPSU-UHFFFAOYSA-M 0.000 description 6
- 125000000392 cycloalkenyl group Chemical group 0.000 description 6
- PFOARMALXZGCHY-UHFFFAOYSA-N homoegonol Natural products C1=C(OC)C(OC)=CC=C1C1=CC2=CC(CCCO)=CC(OC)=C2O1 PFOARMALXZGCHY-UHFFFAOYSA-N 0.000 description 6
- IUYHWZFSGMZEOG-UHFFFAOYSA-M magnesium;propane;chloride Chemical compound [Mg+2].[Cl-].C[CH-]C IUYHWZFSGMZEOG-UHFFFAOYSA-M 0.000 description 6
- 239000012299 nitrogen atmosphere Substances 0.000 description 6
- 239000003921 oil Substances 0.000 description 6
- 239000012044 organic layer Substances 0.000 description 6
- 239000003960 organic solvent Substances 0.000 description 6
- 239000012086 standard solution 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
- FCAAQAQGPIWLJV-UHCQXOBWSA-N (3R,4S,5S,6R)-2-[7-chloro-6-[(4-cyclopropylphenyl)methyl]-2,3-dihydro-1-benzofuran-4-yl]-6-(hydroxymethyl)-2-methoxyoxane-3,4,5-triol Chemical compound COC1(O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O)c1cc(Cc2ccc(cc2)C2CC2)c(Cl)c2OCCc12 FCAAQAQGPIWLJV-UHCQXOBWSA-N 0.000 description 5
- 125000006376 (C3-C10) cycloalkyl group Chemical group 0.000 description 5
- 239000012359 Methanesulfonyl chloride Substances 0.000 description 5
- 238000006751 Mitsunobu reaction Methods 0.000 description 5
- PCLIMKBDDGJMGD-UHFFFAOYSA-N N-bromosuccinimide Substances BrN1C(=O)CCC1=O PCLIMKBDDGJMGD-UHFFFAOYSA-N 0.000 description 5
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 5
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 5
- 239000012345 acetylating agent Substances 0.000 description 5
- 239000002585 base Substances 0.000 description 5
- 238000004364 calculation method Methods 0.000 description 5
- 239000012141 concentrate Substances 0.000 description 5
- 230000008878 coupling Effects 0.000 description 5
- 238000010168 coupling process Methods 0.000 description 5
- 238000005859 coupling reaction Methods 0.000 description 5
- 238000000605 extraction Methods 0.000 description 5
- 150000004820 halides Chemical class 0.000 description 5
- 238000004811 liquid chromatography Methods 0.000 description 5
- UBJFKNSINUCEAL-UHFFFAOYSA-N lithium;2-methylpropane Chemical compound [Li+].C[C-](C)C UBJFKNSINUCEAL-UHFFFAOYSA-N 0.000 description 5
- WGOPGODQLGJZGL-UHFFFAOYSA-N lithium;butane Chemical compound [Li+].CC[CH-]C WGOPGODQLGJZGL-UHFFFAOYSA-N 0.000 description 5
- DKPSECUCTBPLBV-UHFFFAOYSA-N methyl 5-bromo-2-chloro-3-hydroxy-4-(2-hydroxyethyl)benzoate Chemical compound COC(=O)c1cc(Br)c(CCO)c(O)c1Cl DKPSECUCTBPLBV-UHFFFAOYSA-N 0.000 description 5
- IEMDCTKBMXAVHF-UHFFFAOYSA-N methyl 5-bromo-2-chloro-3-methoxybenzoate Chemical compound COC(=O)C1=CC(Br)=CC(OC)=C1Cl IEMDCTKBMXAVHF-UHFFFAOYSA-N 0.000 description 5
- 238000007069 methylation reaction Methods 0.000 description 5
- 239000012071 phase Substances 0.000 description 5
- 238000010992 reflux Methods 0.000 description 5
- 239000000523 sample Substances 0.000 description 5
- 239000012488 sample solution Substances 0.000 description 5
- 229920006395 saturated elastomer Polymers 0.000 description 5
- 239000011593 sulfur Substances 0.000 description 5
- 238000001308 synthesis method Methods 0.000 description 5
- 239000003039 volatile agent Substances 0.000 description 5
- VNGTZLYNGGLPIZ-WCXIOVBPSA-N (3r,4s,5r,6r)-3,4,5-tris(trimethylsilyloxy)-6-(trimethylsilyloxymethyl)oxan-2-one Chemical compound C[Si](C)(C)OC[C@H]1OC(=O)[C@H](O[Si](C)(C)C)[C@@H](O[Si](C)(C)C)[C@@H]1O[Si](C)(C)C VNGTZLYNGGLPIZ-WCXIOVBPSA-N 0.000 description 4
- QHRRVAVLHNUMCG-UHFFFAOYSA-N (4-bromo-7-chloro-2,3-dihydro-1-benzofuran-6-yl)methanol Chemical compound BrC1=CC(=C(C2=C1CCO2)Cl)CO QHRRVAVLHNUMCG-UHFFFAOYSA-N 0.000 description 4
- HDEUNQGNKCNQIB-VEDZAQCTSA-N 7-chloro-6-[(4-methoxyphenyl)methyl]-4-[(2S,3R,4R,5S,6R)-3,4,5-tris(phenylmethoxy)-6-(phenylmethoxymethyl)thian-2-yl]-2,3-dihydro-1-benzofuran Chemical compound ClC1=C(C=C(C=2CCOC=21)[C@@H]1S[C@@H]([C@H]([C@@H]([C@H]1OCC1=CC=CC=C1)OCC1=CC=CC=C1)OCC1=CC=CC=C1)COCC1=CC=CC=C1)CC1=CC=C(C=C1)OC HDEUNQGNKCNQIB-VEDZAQCTSA-N 0.000 description 4
- 239000007818 Grignard reagent Substances 0.000 description 4
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 4
- NFHFRUOZVGFOOS-UHFFFAOYSA-N Pd(PPh3)4 Substances [Pd].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 NFHFRUOZVGFOOS-UHFFFAOYSA-N 0.000 description 4
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 4
- DHXVGJBLRPWPCS-UHFFFAOYSA-N Tetrahydropyran Chemical compound C1CCOCC1 DHXVGJBLRPWPCS-UHFFFAOYSA-N 0.000 description 4
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Natural products NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 description 4
- CDTWFPKHHCCLSV-UHFFFAOYSA-M [Br-].C1=CC([Mg+])=CC=C1C1CC1 Chemical compound [Br-].C1=CC([Mg+])=CC=C1C1CC1 CDTWFPKHHCCLSV-UHFFFAOYSA-M 0.000 description 4
- 150000001350 alkyl halides Chemical class 0.000 description 4
- 239000006227 byproduct Substances 0.000 description 4
- 238000012812 general test Methods 0.000 description 4
- 150000004795 grignard reagents Chemical class 0.000 description 4
- 125000004029 hydroxymethyl group Chemical group [H]OC([H])([H])* 0.000 description 4
- 229910010272 inorganic material Inorganic materials 0.000 description 4
- 239000011147 inorganic material Substances 0.000 description 4
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 4
- 238000002844 melting Methods 0.000 description 4
- 230000008018 melting Effects 0.000 description 4
- QARBMVPHQWIHKH-UHFFFAOYSA-N methanesulfonyl chloride Chemical compound CS(Cl)(=O)=O QARBMVPHQWIHKH-UHFFFAOYSA-N 0.000 description 4
- 238000006385 ozonation reaction Methods 0.000 description 4
- 150000003214 pyranose derivatives Chemical group 0.000 description 4
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 4
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 4
- ITMCEJHCFYSIIV-UHFFFAOYSA-N triflic acid Chemical compound OS(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-N 0.000 description 4
- XEUOMEGOBLAVOZ-UVPIGPOJSA-N (2s,3r,4r,5s,6r)-2-(6-benzyl-7-chloro-2,3-dihydro-1-benzofuran-4-yl)-6-(hydroxymethyl)oxane-3,4,5-triol Chemical compound O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@H]1C1=CC(CC=2C=CC=CC=2)=C(Cl)C2=C1CCO2 XEUOMEGOBLAVOZ-UVPIGPOJSA-N 0.000 description 3
- RXRRMUXGMNWNGL-KQDNOMNESA-N (2s,3r,4r,5s,6r)-2-[7-chloro-6-[(4-methoxyphenyl)methyl]-2,3-dihydro-1-benzofuran-4-yl]-6-(hydroxymethyl)thiane-3,4,5-triol Chemical compound C1=CC(OC)=CC=C1CC1=CC([C@H]2[C@@H]([C@@H](O)[C@H](O)[C@@H](CO)S2)O)=C(CCO2)C2=C1Cl RXRRMUXGMNWNGL-KQDNOMNESA-N 0.000 description 3
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- DGODWNOPHMXOTR-UHFFFAOYSA-N dipotassium;dioxido(dioxo)osmium;dihydrate Chemical compound O.O.[K+].[K+].[O-][Os]([O-])(=O)=O DGODWNOPHMXOTR-UHFFFAOYSA-N 0.000 description 1
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- C07D407/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings
- C07D407/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
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- A61P3/00—Drugs for disorders of the metabolism
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
- A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
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- B01D9/00—Crystallisation
- B01D9/005—Selection of auxiliary, e.g. for control of crystallisation nuclei, of crystal growth, of adherence to walls; Arrangements for introduction thereof
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
- C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D307/78—Benzo [b] furans; Hydrogenated benzo [b] furans
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
- C07D409/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/13—Crystalline forms, e.g. polymorphs
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B51/00—Introduction of protecting groups or activating groups, not provided for in the preceding groups
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Diabetes (AREA)
- Medicinal Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- Bioinformatics & Cheminformatics (AREA)
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- Endocrinology (AREA)
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- Hematology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Saccharide Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Pyrane Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
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| DE102011054773A1 (de) | 2011-10-25 | 2013-04-25 | Vb Autobatterie Gmbh & Co. Kgaa | Anschlusspol für einen Akkumulator, Akkumulatorgehäuse und Maschine zur Herstellung eines Anschlusspols |
| MX2021001732A (es) * | 2018-08-13 | 2021-06-23 | Daewoong Pharmaceutical Co Ltd | Preparacion de intermedio util para la sintesis de inhibidor de sglt. |
| CN112341416A (zh) * | 2019-08-09 | 2021-02-09 | 天津津艺医药科技发展有限责任公司 | 一种制备苯并含氧脂杂环衍生物的方法 |
| MX2022010220A (es) * | 2020-02-27 | 2022-10-10 | Daewoong Pharmaceutical Co Ltd | Intermedio util para la sintesis de un inhibidor de sglt y metodo para preparar un inhibidor de sglt utilizando el mismo. |
| CN112094253B (zh) * | 2020-09-10 | 2023-01-10 | 株式会社大熊制药 | 用于制备sglt抑制剂中间体的合成方法 |
| PE20231373A1 (es) * | 2020-09-10 | 2023-09-07 | Daewoong Pharmaceutical Co Ltd | Metodo de sintesis para la preparacion de un intermedio de inhibidores de sglt |
| CN113200860B (zh) * | 2021-04-29 | 2024-07-30 | 爱斯特（成都）生物制药股份有限公司 | 一种sglt2抑制剂中间体的制备方法 |
| KR20230046784A (ko) * | 2021-09-30 | 2023-04-06 | 주식회사 대웅제약 | 이나보글리플로진을 포함하는 약학 조성물 |
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| KR102853437B1 (ko) * | 2024-11-13 | 2025-09-04 | 대웅바이오(주) | 연속반응 공정을 이용한 이나보글리플로진 합성방법 |
| KR102837941B1 (ko) * | 2024-11-13 | 2025-07-25 | 대웅바이오(주) | Inline quenching 공정을 도입한 연속반응 공정을 이용한 이나보글리플로진 합성방법 |
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| ES2719656T3 (es) * | 2011-06-01 | 2019-07-11 | Green Cross Corp | Derivados de difenilmetano novedosos como inhibidores del SGLT2 |
| US9340521B2 (en) * | 2013-03-18 | 2016-05-17 | Green Cross Corporation | Method for dual inhibition of SGLT1 and SGLT2 using diphenylmethane derivatives |
| FR3017868A1 (fr) * | 2014-02-21 | 2015-08-28 | Servier Lab | Derives d'isoquinoleine, leur procede de preparation et les compositions pharmaceutiques qui les contiennent |
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