CN103980263B - The synthesis technique of canagliflozin - Google Patents
The synthesis technique of canagliflozin Download PDFInfo
- Publication number
- CN103980263B CN103980263B CN201410153116.9A CN201410153116A CN103980263B CN 103980263 B CN103980263 B CN 103980263B CN 201410153116 A CN201410153116 A CN 201410153116A CN 103980263 B CN103980263 B CN 103980263B
- Authority
- CN
- China
- Prior art keywords
- acid
- canagliflozin
- reaction
- catalyst
- under
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Active
Links
- 238000000034 method Methods 0.000 title claims abstract description 31
- 229960001713 canagliflozin Drugs 0.000 title claims abstract description 19
- VHOFTEAWFCUTOS-TUGBYPPCSA-N canagliflozin hydrate Chemical compound O.CC1=CC=C([C@H]2[C@@H]([C@@H](O)[C@H](O)[C@@H](CO)O2)O)C=C1CC(S1)=CC=C1C1=CC=C(F)C=C1.CC1=CC=C([C@H]2[C@@H]([C@@H](O)[C@H](O)[C@@H](CO)O2)O)C=C1CC(S1)=CC=C1C1=CC=C(F)C=C1 VHOFTEAWFCUTOS-TUGBYPPCSA-N 0.000 title claims abstract description 19
- 230000015572 biosynthetic process Effects 0.000 title claims abstract description 10
- 238000003786 synthesis reaction Methods 0.000 title claims abstract description 10
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 claims abstract description 30
- 239000003054 catalyst Substances 0.000 claims abstract description 27
- VNDYJBBGRKZCSX-UHFFFAOYSA-L zinc bromide Chemical compound Br[Zn]Br VNDYJBBGRKZCSX-UHFFFAOYSA-L 0.000 claims abstract description 26
- 230000000694 effects Effects 0.000 claims abstract description 16
- JVSFQJZRHXAUGT-UHFFFAOYSA-N 2,2-dimethylpropanoyl chloride Chemical compound CC(C)(C)C(Cl)=O JVSFQJZRHXAUGT-UHFFFAOYSA-N 0.000 claims abstract description 13
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims abstract description 13
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims abstract description 13
- 229910052794 bromium Inorganic materials 0.000 claims abstract description 13
- 239000002994 raw material Substances 0.000 claims abstract description 13
- 229940102001 zinc bromide Drugs 0.000 claims abstract description 13
- 230000000977 initiatory effect Effects 0.000 claims abstract description 12
- 239000000463 material Substances 0.000 claims abstract description 12
- 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 claims abstract description 11
- 239000002253 acid Substances 0.000 claims abstract description 9
- 229910052751 metal Inorganic materials 0.000 claims abstract description 9
- 239000002184 metal Substances 0.000 claims abstract description 9
- WQZGKKKJIJFFOK-DVKNGEFBSA-N alpha-D-glucose Chemical compound OC[C@H]1O[C@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-DVKNGEFBSA-N 0.000 claims abstract description 8
- 239000003153 chemical reaction reagent Substances 0.000 claims abstract description 8
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims abstract description 8
- YQTCQNIPQMJNTI-UHFFFAOYSA-N 2,2-dimethylpropan-1-one Chemical group CC(C)(C)[C]=O YQTCQNIPQMJNTI-UHFFFAOYSA-N 0.000 claims abstract description 7
- QFWPJPIVLCBXFJ-UHFFFAOYSA-N glymidine Chemical compound N1=CC(OCCOC)=CN=C1NS(=O)(=O)C1=CC=CC=C1 QFWPJPIVLCBXFJ-UHFFFAOYSA-N 0.000 claims abstract description 7
- 238000005727 Friedel-Crafts reaction Methods 0.000 claims abstract description 6
- 238000005917 acylation reaction Methods 0.000 claims abstract description 6
- 150000001875 compounds Chemical class 0.000 claims abstract description 6
- 239000000047 product Substances 0.000 claims description 34
- 238000006243 chemical reaction Methods 0.000 claims description 32
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical group OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 30
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 18
- VSCWAEJMTAWNJL-UHFFFAOYSA-K aluminium trichloride Chemical compound Cl[Al](Cl)Cl VSCWAEJMTAWNJL-UHFFFAOYSA-K 0.000 claims description 18
- 239000000243 solution Substances 0.000 claims description 17
- 239000012043 crude product Substances 0.000 claims description 14
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 claims description 11
- 239000002904 solvent Substances 0.000 claims description 11
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 11
- 239000012535 impurity Substances 0.000 claims description 10
- AMXOYNBUYSYVKV-UHFFFAOYSA-M lithium bromide Chemical compound [Li+].[Br-] AMXOYNBUYSYVKV-UHFFFAOYSA-M 0.000 claims description 10
- 238000001816 cooling Methods 0.000 claims description 9
- 239000003795 chemical substances by application Substances 0.000 claims description 8
- 238000001914 filtration Methods 0.000 claims description 8
- 239000002808 molecular sieve Substances 0.000 claims description 8
- 239000010413 mother solution Substances 0.000 claims description 8
- URGAHOPLAPQHLN-UHFFFAOYSA-N sodium aluminosilicate Chemical compound [Na+].[Al+3].[O-][Si]([O-])=O.[O-][Si]([O-])=O URGAHOPLAPQHLN-UHFFFAOYSA-N 0.000 claims description 8
- DURPTKYDGMDSBL-UHFFFAOYSA-N 1-butoxybutane Chemical compound CCCCOCCCC DURPTKYDGMDSBL-UHFFFAOYSA-N 0.000 claims description 7
- 230000002378 acidificating effect Effects 0.000 claims description 7
- 125000001207 fluorophenyl group Chemical group 0.000 claims description 7
- 238000005516 engineering process Methods 0.000 claims description 6
- 239000012046 mixed solvent Substances 0.000 claims description 6
- ITMCEJHCFYSIIV-UHFFFAOYSA-N triflic acid Chemical group OS(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-N 0.000 claims description 6
- 239000012634 fragment Substances 0.000 claims description 5
- 239000000843 powder Substances 0.000 claims description 5
- 238000006555 catalytic reaction Methods 0.000 claims 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 claims description 4
- FEONEKOZSGPOFN-UHFFFAOYSA-K tribromoiron Chemical compound Br[Fe](Br)Br FEONEKOZSGPOFN-UHFFFAOYSA-K 0.000 claims description 4
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 claims 2
- 239000005711 Benzoic acid Substances 0.000 claims 1
- 235000010233 benzoic acid Nutrition 0.000 claims 1
- 239000000052 vinegar Substances 0.000 claims 1
- 235000021419 vinegar Nutrition 0.000 claims 1
- 230000002194 synthesizing effect Effects 0.000 abstract description 8
- 238000004519 manufacturing process Methods 0.000 abstract description 5
- IYYIVELXUANFED-UHFFFAOYSA-N bromo(trimethyl)silane Chemical compound C[Si](C)(C)Br IYYIVELXUANFED-UHFFFAOYSA-N 0.000 abstract description 2
- 150000007513 acids Chemical class 0.000 abstract 2
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 31
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 9
- 238000001953 recrystallisation Methods 0.000 description 9
- 238000010792 warming Methods 0.000 description 8
- JIGUQPWFLRLWPJ-UHFFFAOYSA-N Ethyl acrylate Chemical compound CCOC(=O)C=C JIGUQPWFLRLWPJ-UHFFFAOYSA-N 0.000 description 7
- PNJWIWWMYCMZRO-UHFFFAOYSA-N pent‐4‐en‐2‐one Natural products CC(=O)CC=C PNJWIWWMYCMZRO-UHFFFAOYSA-N 0.000 description 7
- 239000007787 solid Substances 0.000 description 7
- 238000003756 stirring Methods 0.000 description 7
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 6
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 6
- 239000012044 organic layer Substances 0.000 description 6
- 238000011084 recovery Methods 0.000 description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 5
- 239000000706 filtrate Substances 0.000 description 5
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 description 5
- 238000005406 washing Methods 0.000 description 5
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 4
- VQRQVAQXEZYREW-UHFFFAOYSA-N bromomethane silane Chemical compound [SiH4].CBr VQRQVAQXEZYREW-UHFFFAOYSA-N 0.000 description 4
- 239000012065 filter cake Substances 0.000 description 4
- 239000010410 layer Substances 0.000 description 4
- 239000007788 liquid Substances 0.000 description 4
- ZWLPBLYKEWSWPD-UHFFFAOYSA-N o-toluic acid Chemical compound CC1=CC=CC=C1C(O)=O ZWLPBLYKEWSWPD-UHFFFAOYSA-N 0.000 description 4
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 3
- 238000009835 boiling Methods 0.000 description 3
- 230000003197 catalytic effect Effects 0.000 description 3
- -1 dichloromethane Alkane Chemical class 0.000 description 3
- 238000001556 precipitation Methods 0.000 description 3
- 239000000376 reactant Substances 0.000 description 3
- 238000005070 sampling Methods 0.000 description 3
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- 208000035126 Facies Diseases 0.000 description 2
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- 239000002585 base Substances 0.000 description 2
- 230000008901 benefit Effects 0.000 description 2
- 238000001514 detection method Methods 0.000 description 2
- 229960004756 ethanol Drugs 0.000 description 2
- 235000019441 ethanol Nutrition 0.000 description 2
- 239000001530 fumaric acid Substances 0.000 description 2
- 239000008103 glucose Substances 0.000 description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 2
- 238000009413 insulation Methods 0.000 description 2
- 238000002360 preparation method Methods 0.000 description 2
- 230000008569 process Effects 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 2
- SMZOUWXMTYCWNB-UHFFFAOYSA-N 2-(2-methoxy-5-methylphenyl)ethanamine Chemical compound COC1=CC=C(C)C=C1CCN SMZOUWXMTYCWNB-UHFFFAOYSA-N 0.000 description 1
- NIXOWILDQLNWCW-UHFFFAOYSA-N 2-Propenoic acid Natural products OC(=O)C=C NIXOWILDQLNWCW-UHFFFAOYSA-N 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- 241000196324 Embryophyta Species 0.000 description 1
- 239000007832 Na2SO4 Substances 0.000 description 1
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 1
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 1
- 229940123518 Sodium/glucose cotransporter 2 inhibitor Drugs 0.000 description 1
- 235000009392 Vitis Nutrition 0.000 description 1
- 241000219095 Vitis Species 0.000 description 1
- 229910021536 Zeolite Inorganic materials 0.000 description 1
- PQLVXDKIJBQVDF-UHFFFAOYSA-N acetic acid;hydrate Chemical compound O.CC(O)=O PQLVXDKIJBQVDF-UHFFFAOYSA-N 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 230000006978 adaptation Effects 0.000 description 1
- 238000013019 agitation Methods 0.000 description 1
- 229910021529 ammonia Inorganic materials 0.000 description 1
- 230000003579 anti-obesity Effects 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- AYFCVLSUPGCQKD-UHFFFAOYSA-L calcium;trisodium;2-[bis[2-[bis(carboxylatomethyl)azaniumyl]ethyl]azaniumyl]acetate Chemical compound [Na+].[Na+].[Na+].[Ca+2].[O-]C(=O)C[NH+](CC([O-])=O)CC[NH+](CC(=O)[O-])CC[NH+](CC([O-])=O)CC([O-])=O AYFCVLSUPGCQKD-UHFFFAOYSA-L 0.000 description 1
- 238000000354 decomposition reaction Methods 0.000 description 1
- 229960000935 dehydrated alcohol Drugs 0.000 description 1
- 239000002027 dichloromethane extract Substances 0.000 description 1
- 238000005906 dihydroxylation reaction Methods 0.000 description 1
- HNPSIPDUKPIQMN-UHFFFAOYSA-N dioxosilane;oxo(oxoalumanyloxy)alumane Chemical compound O=[Si]=O.O=[Al]O[Al]=O HNPSIPDUKPIQMN-UHFFFAOYSA-N 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 238000003912 environmental pollution Methods 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 239000002024 ethyl acetate extract Substances 0.000 description 1
- 239000000284 extract Substances 0.000 description 1
- 239000004744 fabric Substances 0.000 description 1
- WIGIZIANZCJQQY-RUCARUNLSA-N glimepiride Chemical compound O=C1C(CC)=C(C)CN1C(=O)NCCC1=CC=C(S(=O)(=O)NC(=O)N[C@@H]2CC[C@@H](C)CC2)C=C1 WIGIZIANZCJQQY-RUCARUNLSA-N 0.000 description 1
- 229960004346 glimepiride Drugs 0.000 description 1
- 230000002641 glycemic effect Effects 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 230000002218 hypoglycaemic effect Effects 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- UQSXHKLRYXJYBZ-UHFFFAOYSA-N iron oxide Inorganic materials [Fe]=O UQSXHKLRYXJYBZ-UHFFFAOYSA-N 0.000 description 1
- 210000003734 kidney Anatomy 0.000 description 1
- DCHYHZGBCSNKQN-UHFFFAOYSA-L lithium zinc dibromide Chemical compound [Br-].[Zn+2].[Br-].[Li+] DCHYHZGBCSNKQN-UHFFFAOYSA-L 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- GBMDVOWEEQVZKZ-UHFFFAOYSA-N methanol;hydrate Chemical compound O.OC GBMDVOWEEQVZKZ-UHFFFAOYSA-N 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 238000012544 monitoring process Methods 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- NDLPOXTZKUMGOV-UHFFFAOYSA-N oxo(oxoferriooxy)iron hydrate Chemical compound O.O=[Fe]O[Fe]=O NDLPOXTZKUMGOV-UHFFFAOYSA-N 0.000 description 1
- 238000012805 post-processing Methods 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 150000003222 pyridines Chemical class 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- GEHJYWRUCIMESM-UHFFFAOYSA-L sodium sulfite Chemical class [Na+].[Na+].[O-]S([O-])=O GEHJYWRUCIMESM-UHFFFAOYSA-L 0.000 description 1
- 238000013517 stratification Methods 0.000 description 1
- 239000003930 superacid Substances 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 208000001072 type 2 diabetes mellitus Diseases 0.000 description 1
- 239000010457 zeolite Substances 0.000 description 1
Classifications
-
- 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
- C07D409/10—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 linked by a carbon chain containing aromatic rings
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
- Catalysts (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention discloses the synthesis technique of canagliflozin, with 2 ar-Toluic acids as initiation material, use self-control catalyst, iodic acid and Iod R to generate intermediate one, or with 2 ar-Toluic acids as initiation material, under the effect of metal reagent and catalyst, add bromine, synthetic intermediate two；Optionally intermediate one or intermediate two first carries out acylation reaction with thionyl chloride, carries out Friedel-Crafts reaction and generates intermediate three；With ALPHA D glucose as raw material, after reacting all hydroxyls of protection with pivaloyl chloride, then react generation intermediate four with zinc bromide, bromotrimethylsilane；Intermediate three and intermediate four, connect and generate intermediate five；Under last acid condition, pivaloyl group is sloughed, generate target compound.The new technique for synthesizing yield of the canagliflozin of the present invention is high, and mild condition is safe and reliable, is suitable for industrialized production, and raw material is cheap and easily-available, is conducive to controlling production cost.
Description
Technical field
The present invention relates to the new technique for synthesizing of a kind of canagliflozin.
Background technology
Canagliflozin Canagliflozin is first SGLT2 inhibitor medicaments ratified by FDA, can be by by Fructus Vitis viniferae
By the way of kidney excrete, reduce blood glucose after sugar decomposition, be used for treating adult's type 2 diabetes mellitus, have wide before
Scape.Except good glycemic control, the antiobesity action of Canagliflozin is more notable, and compared with glimepiride,
Far much less for the hypoglycemic event that canagliflozin causes.
The existing synthetic route process conditions of reported in literature are harsh, as used high-temperature hot filter, high to producing equipment requirements, work
Industry relatively costly；Owing to syntheti c route is longer, the yield of each step is relatively low, causes total recovery low, and environmental pollution is big, is unfavorable for
Industrialized production.Accordingly, it is desirable to provide a kind of new technical scheme solves the problems referred to above.
Summary of the invention
For solving the problems referred to above, the present invention provides the new technique for synthesizing of a kind of canagliflozin.
The technical solution used in the present invention:
The new technique for synthesizing of canagliflozin, comprises the following steps:
A, with 2-ar-Toluic acid as initiation material, use catalyst molecule sieve load ferrum oxide, with iodic acid and mole again
Number is the Iod R generation intermediate one 5-iodo-2-ar-Toluic acid of 0.5 ~ 1.0, and aftertreatment technology uses cold filtration after cooling,
The way of mother liquid recycle；
B or with 2-ar-Toluic acid as initiation material, under the effect of metal reagent and super acidic catalyst, addition rubs
Your multiple is the bromine of 1.05 ~ 1.5, and solvent bromine is used molecular sieve absolute pretreatment, and 5-is bromo-for synthetic intermediate two
2-ar-Toluic acid；
C, optional intermediate one or intermediate two carry out acylation reaction, so as the first thionyl chloride with 1.1 equivalents of fragment
After under the effect of catalyst aluminum chloride with the 2-(of equimolar ratio to fluorophenyl)-thiophene carries out Friedel-Crafts reaction and generates intermediate
Three；
D, with ALPHA-D-glucose as raw material, through with pivaloyl chloride react protection all hydroxyls after, then with zinc bromide, three
Methyl bromide silane generates intermediate four-10 ~ 25 DEG C of reactions；
E, intermediate three and intermediate four mol ratio 1:1, under the conditions of anhydrous and oxygen-free, subzero 76-80 degree Celsius, in self-control
Catalyst zinc bromide, lithium bromide butyl ether solution effect under connect generate intermediate five；
Pivaloyl group is sloughed by f, target product the most in acid condition, generates target compound, and reaction is finished, the most often
After pressure steams the feature impurity being difficult to remove, it is concentrated to give crude product, then the method repeatedly pulled an oar with different solvents is progressively removed respectively
Plant impurity, obtain the purity target product higher than 98%.
In b step, metal reagent is Fe powder or ferric bromide, and super acidic catalyst is trifluoromethanesulfonic acid or p-methyl benzenesulfonic acid.
In Step d, with ALPHA-D-glucose as raw material, through reacting all hydroxyls of protection, upper protection with pivaloyl chloride
The technique of base adds a small amount of thionyl chloride.
In f step, solvent is the mixed solvent of methanol, acetic acid or methanol, acetic acid and water.
For the generation of each intermediate above-mentioned, then being explained by following chemical equation, chemical equation is:
Intermediate one
；
Intermediate two
；
Intermediate three
；
Intermediate four
；
Intermediate five
；
Product
。
The invention have the advantage that yield is high, mild condition, safe and reliable, it is suitable for industrialized production, raw material is cheap and easily-available,
Be conducive to controlling production cost.
Detailed description of the invention
Following embodiment is merely to illustrate the present invention, but can not limit protection scope of the present invention.
Embodiment 1
The new technique for synthesizing of canagliflozin, comprises the following steps:
A, with 2-ar-Toluic acid as initiation material, use catalyst molecule sieve load ferrum oxide, with iodic acid and mole again
Number is the Iod R generation intermediate one 5-iodo-2-ar-Toluic acid of 0.5, and aftertreatment technology uses cold filtration after cooling, mother solution
The way applied mechanically, specific as follows: reaction temperature is down to 20 degrees Celsius, a large amount of solids separate out, and will be mixed with catalysis at this temperature
The product of agent filters, and mother solution is applied mechanically next time, can connected set 5 times, after filter cake dissolves with ethyl acrylate, room temperature filters, by catalyst
Leach and apply mechanically next time, can apply mechanically 5 times, after filtrate precipitation, the crude product ethyl acrylate recrystallization of 2.5 times of weight, obtain white product
Product obtain product, yield more than 88%；
B or with 2-ar-Toluic acid as initiation material, in metal reagent Fe powder and super acidic catalyst trifluoromethanesulfonic acid
Under effect, adding mol times is the bromine of 1.05, and solvent bromine is used molecular sieve absolute pretreatment, synthetic mesophase
Body two 5-bromo-2-ar-Toluic acid, yield is more than 85%；
C, optional intermediate one or intermediate two carry out acylation reaction, so as the first thionyl chloride with 1.1 equivalents of fragment
After under the effect of catalyst aluminum chloride with the 2-(of equimolar ratio to fluorophenyl)-thiophene carries out Friedel-Crafts reaction and generates intermediate
Three, yield 78%；
D, with ALPHA-D-glucose as raw material, through with pivaloyl chloride react protection all hydroxyls after, then with zinc bromide, three
Methyl bromide silane generates intermediate four-10 DEG C of reactions, adds a small amount of thionyl chloride, make pivaloyl chloride in the technique of upper protection group
Consumption reduces half, and yield is without impact, and two step yields are all more than 82%, and total recovery is more than 67%；
E, intermediate three and intermediate four mol ratio 1:1, under the conditions of anhydrous and oxygen-free, subzero 76 degrees Celsius, urge in self-control
Agent zinc bromide, lithium bromide butyl ether solution effect under connect generate intermediate five, yield more than 71%；
Pivaloyl group is sloughed by f, target product the most in acid condition, generates target compound, and reaction is finished, the most often
After pressure steams the feature impurity being difficult to remove, being concentrated to give crude product, the method that again with methanol is repeatedly pulled an oar progressively is removed various miscellaneous
Matter, obtains the purity target product higher than 98%, yield more than 85%.
Embodiment 2
The new technique for synthesizing of canagliflozin, comprises the following steps:
A, with 2-ar-Toluic acid as initiation material, use catalyst molecule sieve load ferrum oxide, with iodic acid and mole again
Number is the Iod R generation intermediate one 5-iodo-2-ar-Toluic acid of 0.7, and aftertreatment technology uses cold filtration after cooling, mother solution
The way applied mechanically, specific as follows: reaction temperature is down to 18 degrees Celsius, a large amount of solids separate out, and will be mixed with catalysis at this temperature
The product of agent filters, and mother solution is applied mechanically next time, can connected set 3 times, after filter cake dissolves with ethyl acrylate, room temperature filters, by catalyst
Leach and apply mechanically next time, can apply mechanically 3 times, after filtrate precipitation, the crude product ethyl acrylate recrystallization of 2.5 times of weight, obtain white product
Product obtain product, yield more than 88%；
B or with 2-ar-Toluic acid as initiation material, at metal reagent ferric bromide and super acidic catalyst p-methyl benzenesulfonic acid
Effect under, add mol times be the bromine of 1.25, and to solvent bromine use molecular sieve absolute pretreatment, in synthesis
Mesosome two 5-bromo-2-ar-Toluic acid, yield is more than 85%；
C, optional intermediate one or intermediate two carry out acylation reaction, so as the first thionyl chloride with 1.1 equivalents of fragment
After under the effect of catalyst aluminum chloride with the 2-(of equimolar ratio to fluorophenyl)-thiophene carries out Friedel-Crafts reaction and generates intermediate
Three, yield 78-80%；
D, with ALPHA-D-glucose as raw material, through with pivaloyl chloride react protection all hydroxyls after, then with zinc bromide, three
Methyl bromide silane generates intermediate four 10 DEG C of reactions, uses the way adding a small amount of thionyl chloride in the technique of upper protection group,
Making pivaloyl chloride consumption reduce half, yield is without impact, and two step yields are all more than 82%, and total recovery is more than 67%；
E, intermediate three and intermediate four mol ratio 1:1, under the conditions of anhydrous and oxygen-free, subzero 78 degrees Celsius, urge in self-control
Agent zinc bromide, lithium bromide butyl ether solution effect under connect generate intermediate five, yield more than 71%；
Pivaloyl group is sloughed by f, target product the most in acid condition, generates target compound, and reaction is finished, the most often
After pressure steams the feature impurity being difficult to remove, it is concentrated to give crude product, then the method repeatedly pulled an oar with acetic acid is progressively removed various miscellaneous
Matter, obtains the purity target product higher than 98%, yield more than 85%.
Embodiment 3
The new technique for synthesizing of canagliflozin, comprises the following steps:
A, with 2-ar-Toluic acid as initiation material, use catalyst molecule sieve load ferrum oxide, with iodic acid and mole again
Number is the Iod R generation intermediate one 5-iodo-2-ar-Toluic acid of 1.0, and aftertreatment technology uses cold filtration after cooling, mother solution
The way applied mechanically, specific as follows: reaction temperature is down to 22 degrees Celsius, a large amount of solids separate out, and will be mixed with catalysis at this temperature
The product of agent filters, and mother solution is applied mechanically next time, can connected set 4 times, after filter cake dissolves with ethyl acrylate, room temperature filters, by catalyst
Leach and apply mechanically next time, can apply mechanically 4 times, after filtrate precipitation, the crude product ethyl acrylate recrystallization of 2.5 times of weight, obtain white product
Product obtain product, yield more than 88%；
B or with 2-ar-Toluic acid as initiation material, in metal reagent Fe powder and super acidic catalyst trifluoromethanesulfonic acid
Under effect, adding mol times is the bromine of 1.5, and solvent bromine is used molecular sieve absolute pretreatment, synthetic mesophase
Body two 5-bromo-2-ar-Toluic acid, yield is more than 85%；
C, optional intermediate one or intermediate two carry out acylation reaction, so as the first thionyl chloride with 1.1 equivalents of fragment
After under the effect of catalyst aluminum chloride with the 2-(of equimolar ratio to fluorophenyl)-thiophene carries out Friedel-Crafts reaction and generates intermediate
Three, yield 80%；
D, with ALPHA-D-glucose as raw material, through with pivaloyl chloride react protection all hydroxyls after, then with zinc bromide, three
Methyl bromide silane generates intermediate four 25 DEG C of reactions, uses the way adding a small amount of thionyl chloride in the technique of upper protection group,
Making pivaloyl chloride consumption reduce half, yield is without impact, and two step yields are all more than 82%, and total recovery is more than 67%；
E, intermediate three and intermediate four mol ratio 1:1, under the conditions of anhydrous and oxygen-free, subzero 80 degrees Celsius, urge in self-control
Agent zinc bromide, lithium bromide butyl ether solution effect under connect generate intermediate five, yield more than 71%；
Pivaloyl group is sloughed by f, target product the most in acid condition, generates target compound, and reaction is finished, the most often
After pressure steams the feature impurity being difficult to remove, be concentrated to give method that crude product, again with methanol and water mixed solvent repeatedly pull an oar by
Step removes various impurity, obtains the purity target product higher than 98%, yield more than 85%.
In f step, mixed solvent can also be the mixed solvent of acetic acid and water.
It is below the preparation process of each intermediate:
Prepare in intermediate one: 500ml reaction bulb and add, 2-methyl-benzoic acid 40g, 0.113mol iodine, 70% iodic acid water
Solution, catalyst molecule sieve load ferrum oxide, acetic acid, acetic anhydride, it is warming up to backflow, LC is controlled, crystallize of lowering the temperature, filters, mother solution
Apply mechanically.It is the most molten to product that crude product adds ethyl acrylate, is filtered to remove zeolite, is spin-dried for, the crude product acrylic acid second of 2.5 times of weight
Ester recrystallization, obtains white products 67.76g, yield 88%, purity 94%(LC).
Prepare and intermediate two: 250 ml reaction bulb adds 2-methyl-benzoic acid 40g, iron powder, trifluoromethanesulfonic acid, bromine/
Dichloromethane (through molecular sieve pretreatment), is warming up to backflow, drips 0.388mol bromine/dichloromethane solution, drips and finishes, refluxed
At night, in TLC, control terminates to reaction, and cooling drips saturated sodium sulfite and takes off to redness, separatory, water layer 30ml dichloromethane
Alkane extracts, and merges organic layer, washing, is spin-dried for obtaining crude product 53g, ethyl alcohol recrystallization, obtains product 54.09g, yield 85%, purity 95%
(LC).
Prepare addition 5-iodo-2-ar-Toluic acid 20g, dichloromethane, fumaric acid in intermediate three: 250ml four-hole boiling flask
Two formicesters, are warming up to 20 DEG C, drip thionyl chloride.Dropping is finished, and is warming up to backflow, and after 1.5h, sampling LC monitors without raw material.Cooling
To 2 DEG C, adding aluminum chloride, stir 15min, dropping 13.6g2-(is to fluorophenyl) the DCM solution of-thiophene.Dropping is finished, 20 DEG C
Lower reaction 3h, in LC, control is without raw material.It is cooled to 2 DEG C, adds aluminum chloride, stir 15min, the acetonitrile solution of dropping TMDSO, rise
Temperature is to back flow reaction 5h, and in LC, control terminates to reaction.Reactant liquor is poured in the hydrochloric acid solution of 5%, stirring, water layer dichloromethane
Alkane is extracted twice, and merges organic layer, and washing, anhydrous sodium sulfate is dried, and is spin-dried for, and with ethyl acetate and recrystallisation from isopropanol, obtains product
Product 21.75g, yield 70%, purity 98%(LC).
Prepare addition 5-bromo-2-ar-Toluic acid 800g, dichloromethane, fumaric acid two in intermediate three: 10L four-hole boiling flask
Formicester, is warming up to backflow, drips thionyl chloride, and in sampling LC, control terminates to reaction.It is cooled to 2 DEG C, adds aluminum chloride, dropping
Equimolar 2-(is to fluorophenyl) the DCM solution of-thiophene.Dropping is finished, and reacts 3 hours at 20 DEG C, and LC monitors without raw material.It is cooled to
2 DEG C, add aluminum chloride.Dropping acetonitrile, dropping is complete, and the acetonitrile solution of fast drop TMDSO is warming up to back flow reaction 5h, LC
Middle control terminates to reaction.Being poured into by reactant liquor in the hydrochloric acid solution of 10%, stir 15min, water layer 3L dichloromethane extracts, and closes
And organic layer, washing, it is spin-dried for, with ethyl acetate and recrystallisation from isopropanol, obtains product 1009.6g, yield 75%, purity 96%
(LC).
Prepare addition 384g alpha-D-glucose, pyridine, dichloromethane, 4-diformazan ammonia in four: 10L tetra-mouthful of reaction bulb of intermediate
Yl pyridines, mechanical agitation, it is heated to 48 DEG C.Close heating, add 10ml thionyl chloride.Start to drip pivaloyl chloride 1412g, 2h
Dripping complete, temperature maintains 50 DEG C of back flow reaction.HPLC detection is controlled.Reaction terminates rear negative pressure and is concentrated to dryness, and adds dichloromethane
Alkane and dilute hydrochloric acid stirring and dissolving, stratification, separatory.Anhydrous Na is used after organic facies washing2SO4It is dried, filters.Organic facies negative pressure
It is concentrated to dryness, obtains light yellow solid 1830g.Crude product dehydrated alcohol recrystallization, obtains white solid 1096g, purity 98%, yield
82%, standby.
In tetra-mouthfuls of reaction bulbs of 20L, it is passed through N2, add 750g Calcium Chel 330, dichloromethane, zinc bromide, stir.Instead
Answering liquid to be cooled to 10 DEG C, start the mixture dripping bromotrimethylsilane with dichloromethane, 1.5h dropping is complete.Control temperature
20-25 DEG C, stirring reaction 1.5h.HPLC detection terminates to reaction.Sucking filtration goes out zinc bromide, obtains yellow supernatant liquid.It is cooled to 0
DEG C, dripping sodium bicarbonate aqueous solution, monitoring pH value is at 7-8.Separatory obtains organic layer and adds anhydrous Na2SO4It is dried, filters.Organic layer is born
Pressure is concentrated to give lurid solid 700g, crude product purity 88%.Isopropanol is washed and starched, and obtains product 599.7g, yield 83%, purity
97.5%.Total recovery 68.06%.
Prepare intermediate five: anhydrous and oxygen-free device, 500ml reaction bulb adds intermediate three 40.8g, n-butyl ether, toluene,
Logical nitrogen, cools to-40 DEG C, drips butyl lithium, drips Bi Baowen 2h.Dropping zinc bromide lithium bromide butyl ether solution, dropping is complete,
30 DEG C of insulation 2h.The toluene solution of dropping intermediate four, is warming up to 90 DEG C of insulations, controls to reacting knot in sampling LC after dripping
Bundle.Being poured into by reactant liquor after cooling in the dilute hydrochloric acid of 500ml, separatory, water layer 120ml*3 ethyl acetate extracts, and merges organic
Layer, washing, separatory, concentration are done to obtain brown oil, are added ethyl alcohol recrystallization and obtain product 55.5g.Purity 95%, yield 71%.
The four-hole boiling flask of the preparation of canagliflozin: 2L adds 150g intermediate five, methanol, 15min is stirred at room temperature.Dropping
The methanol solution of 30% Feldalat NM, drips complete being warming up to and refluxes.LC is controlled to reacting complete.Normal pressure steams the spy being difficult to remove
After levying impurity, be concentrated to give crude product, then add methanol, method that Acetic Acid-Water, water, methanol-water equal solvent are repeatedly pulled an oar progressively is removed
Various impurity, filter, and recrystallizing methanol obtains solid 72.6g, yield 85%, purity 98%(LC) more than.
The canagliflozin new technique for synthesizing advantage specific as follows of the present invention:
1) synthesis of intermediate one, uses catalytic synthetic techniques, uses and makes the participation of molecular sieve carried ferric oxide catalyst by oneself
Reaction, makes the selectivity of 5 upper iodine increase to almost absolutely from 60%.This step yield is made to bring up to more than 88%, greatly
Improve greatly yield, reduce impurity.The step that complex fine grained high-temperature hot filters has been evaded in this external post processing,
Because this step is high to equipment requirements, temperature is slightly lower, and product just separates out from filtrate, blocks filter cloth.It is changed by this method
Become, use cold filtration after cooling, the way of mother liquid recycle.Filter cake then uses lower step solvent dissolution, contains product after filtering catalyst
Filtrate directly participates in the next step.Technique is simple to operation, greatly reduces process time and difficulty, and producing feasibility substantially carries
Height, also can improve yield, and decrease the pollution to environment.
2) synthesis of intermediate two is by groping with synthesis mechanism reaction condition, makes 3 special adaptations.One is
Want molecular sieve that reaction dissolvent is carried out pretreatment so that it is absolute；The metal examinations such as the Fe powder of two catalytic amounts to be added, ferric bromide
Agent；The super acids such as the trifluoromethanesulfonic acid of three catalytic amounts to be added thereto to, p-methyl benzenesulfonic acid, can be by original anti-almost without product
High yield should be accomplished.
3) upper pivaloyl group one step during synthetic intermediate four, adds a small amount of thionyl chloride, can in the case of yield does not drops
The consumption of pivaloyl chloride is reduced 50%, reduces the pollution to environment.
4), during synthetic intermediate five, reduction dehydroxylation after traditional TMS protection glucose docks has been evaded with intermediate three
Method, with 2,3,4,6-O-tetra-pivaloyl group-ALPHA-D-bromo Glucopyranose .s dock with intermediate three, can avoid deshydroxy
Base, improves total recovery, is greatly saved cost.And to connecting the homemade bridge joint catalyst of employing so that yield carried than originally
High by 20%.
Claims (3)
1. the synthesis technique of canagliflozin, it is characterised in that comprise the following steps:
A, with 2-ar-Toluic acid as initiation material, use catalyst molecule sieve load ferrum oxide, with iodic acid and mol times be
The Iod R of 0.5 ~ 1.0 generates intermediate one 5-iodo-2-ar-Toluic acid, and aftertreatment technology uses cold filtration after cooling, mother solution
The way applied mechanically；
B or with 2-ar-Toluic acid as initiation material, under the effect of metal reagent and super acidic catalyst, adds mole times
Number is the bromine of 1.05 ~ 1.5, and solvent bromine is used molecular sieve absolute pretreatment, synthetic intermediate two 5-bromo-2-first
Yl benzoic acid；
C, optional intermediate one or intermediate two carry out acylation reaction as the first thionyl chloride with 1.1 equivalents of fragment, then exist
With the 2-(of equimolar ratio to fluorophenyl under the effect of catalyst aluminum chloride)-thiophene carries out Friedel-Crafts reaction and generates intermediate three；
D, with ALPHA-D-glucose as raw material, through with pivaloyl chloride react protection all hydroxyls after, then with zinc bromide, trimethyl
Bromo-silicane generates intermediate four-10 ~ 25 DEG C of reactions；
E, intermediate three and intermediate four mol ratio 1:1, under the conditions of anhydrous and oxygen-free, subzero 76-80 degree Celsius, in self-control catalysis
Agent zinc bromide, lithium bromide butyl ether solution effect under connect generate intermediate five；
Pivaloyl group is sloughed by f, target product the most in acid condition, generates target compound, and reaction is finished, and first normal pressure steams
After going out the feature impurity being difficult to remove, it is concentrated to give crude product, then the method repeatedly pulled an oar with different solvents is progressively removed various miscellaneous
Matter, obtains the purity target product higher than 98%；
In b step, metal reagent is Fe powder or ferric bromide, and super acidic catalyst is trifluoromethanesulfonic acid or p-methyl benzenesulfonic acid.
The synthesis technique of canagliflozin the most according to claim 1, it is characterised in that: in Step d, with ALPHA-D-Portugal
Grape sugar is raw material, through reacting all hydroxyls of protection with pivaloyl chloride, adds a small amount of thionyl chloride in the technique of upper protection group.
The synthesis technique of canagliflozin the most according to claim 1, it is characterised in that: in f step, solvent is methanol, vinegar
The mixed solvent of acid, methanol and water, acetic acid and the one in the mixed solvent of water.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201410153116.9A CN103980263B (en) | 2014-04-17 | 2014-04-17 | The synthesis technique of canagliflozin |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201410153116.9A CN103980263B (en) | 2014-04-17 | 2014-04-17 | The synthesis technique of canagliflozin |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN103980263A CN103980263A (en) | 2014-08-13 |
| CN103980263B true CN103980263B (en) | 2016-08-03 |
Family
ID=51272456
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201410153116.9A Active CN103980263B (en) | 2014-04-17 | 2014-04-17 | The synthesis technique of canagliflozin |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN103980263B (en) |
Families Citing this family (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104311532B (en) * | 2014-10-31 | 2016-04-20 | 山东大学 | The preparation method of 2-(4-fluorophenyl)-5-[(the bromo-2-aminomethyl phenyl of 5-) methyl] thiophene |
| CN104557895B (en) * | 2015-01-27 | 2017-10-31 | 江苏嘉逸医药有限公司 | The synthesis technique of 1 (β D glycopyranosyls) 4 methyl 3 [5 (4 fluorophenyl) 2 thienyl methyls] benzene |
| CN104744449B (en) * | 2015-03-21 | 2018-02-09 | 北京工业大学 | A kind of preparation method of canagliflozin semihydrate and its monocrystalline |
| US10370365B2 (en) | 2015-09-16 | 2019-08-06 | Optimus Drugs (P) Limited | Process for the preparation of Canagliflozin |
| CN105399735A (en) * | 2015-12-29 | 2016-03-16 | 上海应用技术学院 | Empagliflozin intermediate, and preparation method and application thereof |
| CN108017612B (en) * | 2017-11-29 | 2020-06-09 | 南通常佑药业科技有限公司 | Preparation method of canagliflozin intermediate |
| CN114591313A (en) * | 2020-12-04 | 2022-06-07 | 南京圣鼎医药科技有限公司 | Preparation method of canagliflozin |
| CN113149828A (en) * | 2021-03-31 | 2021-07-23 | 山东寿光增瑞化工有限公司 | Preparation method of 5-bromo-2-methylbenzoic acid |
| CN118026843B (en) * | 2024-01-31 | 2024-09-03 | 连云港冠昕医药科技有限公司 | Preparation method of 9-fluorenylmethyl chloroformate |
Citations (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2005012326A1 (en) * | 2003-08-01 | 2005-02-10 | Tanabe Seiyaku Co., Ltd. | Novel compounds having inhibitory activity against sodium-dependant transporter |
| CN101362681A (en) * | 2003-02-10 | 2009-02-11 | 三菱瓦斯化学株式会社 | Process for production of iodine compounds |
| CN101611032A (en) * | 2006-12-04 | 2009-12-23 | 詹森药业有限公司 | Glycopyranosyl derivatives as the thienyl-containing of antidiabetic drug |
| WO2011079772A1 (en) * | 2009-12-31 | 2011-07-07 | 上海特化医药科技有限公司 | Method for preparation of 2,5-disubstituted thiophene compound |
| US20120258913A1 (en) * | 2003-08-01 | 2012-10-11 | Sumihiro Nomura | Glucopyranoside compound |
| CN102781915A (en) * | 2009-12-31 | 2012-11-14 | 皮拉马尔有限公司 | Inhibitors of diacylglycerol acyl transferase |
| CN103596944A (en) * | 2011-04-13 | 2014-02-19 | 詹森药业有限公司 | Process for the preparation of compounds useful as inhibitors of SGLT2 |
| CN103649033A (en) * | 2011-05-26 | 2014-03-19 | Tf化学公司 | Family of aryl, heteroaryl, O-aryl and O-heteroaryl carbasugars |
-
2014
- 2014-04-17 CN CN201410153116.9A patent/CN103980263B/en active Active
Patent Citations (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101362681A (en) * | 2003-02-10 | 2009-02-11 | 三菱瓦斯化学株式会社 | Process for production of iodine compounds |
| WO2005012326A1 (en) * | 2003-08-01 | 2005-02-10 | Tanabe Seiyaku Co., Ltd. | Novel compounds having inhibitory activity against sodium-dependant transporter |
| US20120258913A1 (en) * | 2003-08-01 | 2012-10-11 | Sumihiro Nomura | Glucopyranoside compound |
| CN101611032A (en) * | 2006-12-04 | 2009-12-23 | 詹森药业有限公司 | Glycopyranosyl derivatives as the thienyl-containing of antidiabetic drug |
| WO2011079772A1 (en) * | 2009-12-31 | 2011-07-07 | 上海特化医药科技有限公司 | Method for preparation of 2,5-disubstituted thiophene compound |
| CN102781915A (en) * | 2009-12-31 | 2012-11-14 | 皮拉马尔有限公司 | Inhibitors of diacylglycerol acyl transferase |
| CN103596944A (en) * | 2011-04-13 | 2014-02-19 | 詹森药业有限公司 | Process for the preparation of compounds useful as inhibitors of SGLT2 |
| CN103649033A (en) * | 2011-05-26 | 2014-03-19 | Tf化学公司 | Family of aryl, heteroaryl, O-aryl and O-heteroaryl carbasugars |
Non-Patent Citations (2)
| Title |
|---|
| Discovery of Canagliflozin, a Novel C-Glucoside with Thiophene Ring, as Sodium-Dependent Glucose Cotransporter 2 Inhibitor for the Treatment of Type 2 Diabetes Mellitus;Sumihiro Nomura,等;《J. Med. Chem.》;20100608;第53卷;第6355-6360 * |
| Stereoselective C-Glycosylation Reactions with Arylzinc Reagents;Sebastien Lemaire，et al.;《ORGANIC LETTERS》;20120203;第14卷(第6期);第1480-1483页 * |
Also Published As
| Publication number | Publication date |
|---|---|
| CN103980263A (en) | 2014-08-13 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN103980263B (en) | The synthesis technique of canagliflozin | |
| CN104892509B (en) | Nuo get Si Ta preparation method | |
| CN108794397A (en) | A kind of his synthetic methods and its midbody compound of Luo Shasi | |
| CN106256824B (en) | Preparation method of high-purity delafloxacin meglumine salt | |
| CN102395591B (en) | Method for preparing prasugrel | |
| CN103864802B (en) | The preparation method of maleic acid asenapine | |
| CN105254544A (en) | Preparing method for bisphenol S | |
| CN101560228B (en) | Method for synthesizing trichloroacetyl sucrose | |
| CN103664923B (en) | The preparation method of Nifuratel | |
| CN104086545A (en) | Synthesis method of 1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridyl-3-formamidine hydrochloride | |
| CN110156684A (en) | A kind of synthesis technology of demethyl coclaurine and its pharmaceutical salts | |
| CN105693802A (en) | Preparation method of 16 beta-methyl steroid | |
| CN106748721B (en) | A kind of preparation method of the chloro- 5- iodo-benzoic acid of 2- | |
| CN110467592B (en) | A kind of semi-synthetic method of luteolin | |
| CN101270124A (en) | Novel method for purifying and preparing high-purity fluorandiol and fluorandiol salt | |
| CN103665084A (en) | Method for preparing abiraterone acetate | |
| CN103739662B (en) | A kind of preparation method of sodium tanshinone IIA sulfate | |
| CN101696185B (en) | Synthesizing method of 6-nitro-S-(-)-indoline-2-carboxylic acid | |
| CN106045995B (en) | A kind of synthetic method of 5 bromine 1H pyrrolo-es [2,3 b] pyridines | |
| CN112939814B (en) | Preparation method of deuterated dacarbazine intermediate | |
| CN107382785A (en) | One planting sand storehouse must bent key intermediate preparation method | |
| CN102010325A (en) | Method for synthesizing p-hydroxyphenylacetic acid | |
| CN102167667A (en) | Method for synthesizing pentaerythritol tetrabenzoate | |
| CN100522936C (en) | Synthesis process of 2,4-dichloro-5-sulfonyl benzoic acid | |
| CN106588888A (en) | High-purity L-sunitinib malate preparation method |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C14 | Grant of patent or utility model | ||
| GR01 | Patent grant |