CN103980263A - New synthesis process of canagliflozin - Google Patents
New synthesis process of canagliflozin Download PDFInfo
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- CN103980263A CN103980263A CN201410153116.9A CN201410153116A CN103980263A CN 103980263 A CN103980263 A CN 103980263A CN 201410153116 A CN201410153116 A CN 201410153116A CN 103980263 A CN103980263 A CN 103980263A
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- 238000000034 method Methods 0.000 title claims abstract description 31
- 230000015572 biosynthetic process Effects 0.000 title abstract description 5
- 229960001713 canagliflozin Drugs 0.000 title abstract description 5
- 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 abstract description 5
- 238000003786 synthesis reaction Methods 0.000 title abstract description 5
- 238000006243 chemical reaction Methods 0.000 claims abstract description 34
- 239000002253 acid Substances 0.000 claims abstract description 29
- VNDYJBBGRKZCSX-UHFFFAOYSA-L zinc bromide Chemical compound Br[Zn]Br VNDYJBBGRKZCSX-UHFFFAOYSA-L 0.000 claims abstract description 26
- 239000002994 raw material Substances 0.000 claims abstract description 25
- 239000003054 catalyst Substances 0.000 claims abstract description 21
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 claims abstract description 21
- 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
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Chemical compound BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims abstract description 13
- 229940102001 zinc bromide Drugs 0.000 claims abstract description 13
- 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
- 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 9
- 239000003153 chemical reaction reagent 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
- 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
- IYYIVELXUANFED-UHFFFAOYSA-N bromo(trimethyl)silane Chemical compound C[Si](C)(C)Br IYYIVELXUANFED-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
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 30
- 239000000047 product Substances 0.000 claims description 30
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 21
- VSCWAEJMTAWNJL-UHFFFAOYSA-K aluminium trichloride Chemical compound Cl[Al](Cl)Cl VSCWAEJMTAWNJL-UHFFFAOYSA-K 0.000 claims description 18
- 239000012043 crude product Substances 0.000 claims description 14
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 14
- 239000012535 impurity Substances 0.000 claims description 13
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 12
- 230000002378 acidificating effect Effects 0.000 claims description 12
- 229910052794 bromium Inorganic materials 0.000 claims description 12
- -1 iodo-2-tolyl Chemical group 0.000 claims description 12
- 239000002904 solvent Substances 0.000 claims description 11
- AMXOYNBUYSYVKV-UHFFFAOYSA-M lithium bromide Chemical compound [Li+].[Br-] AMXOYNBUYSYVKV-UHFFFAOYSA-M 0.000 claims description 10
- 125000003261 o-tolyl group Chemical group [H]C1=C([H])C(*)=C(C([H])=C1[H])C([H])([H])[H] 0.000 claims description 10
- 238000001816 cooling Methods 0.000 claims description 9
- 238000001914 filtration Methods 0.000 claims description 9
- 239000002808 molecular sieve 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
- 125000001207 fluorophenyl group Chemical group 0.000 claims description 7
- UQSXHKLRYXJYBZ-UHFFFAOYSA-N iron oxide Inorganic materials [Fe]=O UQSXHKLRYXJYBZ-UHFFFAOYSA-N 0.000 claims description 7
- 239000007788 liquid Substances 0.000 claims description 7
- NDLPOXTZKUMGOV-UHFFFAOYSA-N oxo(oxoferriooxy)iron hydrate Chemical compound O.O=[Fe]O[Fe]=O NDLPOXTZKUMGOV-UHFFFAOYSA-N 0.000 claims description 7
- 239000012141 concentrate Substances 0.000 claims description 6
- 238000005516 engineering process Methods 0.000 claims description 6
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 claims description 6
- XEEYBQQBJWHFJM-UHFFFAOYSA-N iron Substances [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 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
- 229940059936 lithium bromide Drugs 0.000 claims description 5
- 239000012046 mixed solvent Substances 0.000 claims description 5
- 239000000843 powder Substances 0.000 claims description 5
- 125000006239 protecting group Chemical group 0.000 claims description 5
- GYCHYNMREWYSKH-UHFFFAOYSA-L iron(ii) bromide Chemical compound [Fe+2].[Br-].[Br-] GYCHYNMREWYSKH-UHFFFAOYSA-L 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
- ZWLPBLYKEWSWPD-UHFFFAOYSA-N o-toluic acid Chemical compound CC1=CC=CC=C1C(O)=O ZWLPBLYKEWSWPD-UHFFFAOYSA-N 0.000 abstract description 6
- 238000004519 manufacturing process Methods 0.000 abstract description 5
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 abstract description 2
- 229910052740 iodine Inorganic materials 0.000 abstract description 2
- 239000011630 iodine Substances 0.000 abstract description 2
- QFWPJPIVLCBXFJ-UHFFFAOYSA-N glymidine Chemical compound N1=CC(OCCOC)=CN=C1NS(=O)(=O)C1=CC=CC=C1 QFWPJPIVLCBXFJ-UHFFFAOYSA-N 0.000 abstract 1
- 238000009776 industrial production Methods 0.000 abstract 1
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 30
- 239000000243 solution Substances 0.000 description 17
- 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 9
- JIGUQPWFLRLWPJ-UHFFFAOYSA-N Ethyl acrylate Chemical compound CCOC(=O)C=C JIGUQPWFLRLWPJ-UHFFFAOYSA-N 0.000 description 8
- PNJWIWWMYCMZRO-UHFFFAOYSA-N pent‐4‐en‐2‐one Natural products CC(=O)CC=C PNJWIWWMYCMZRO-UHFFFAOYSA-N 0.000 description 8
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 7
- 239000007787 solid Substances 0.000 description 7
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-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
- 238000003756 stirring 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
- 239000012065 filter cake Substances 0.000 description 4
- 239000010410 layer Substances 0.000 description 4
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 3
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 3
- 238000009835 boiling Methods 0.000 description 3
- 230000003197 catalytic effect Effects 0.000 description 3
- 238000000605 extraction Methods 0.000 description 3
- 239000012452 mother liquor Substances 0.000 description 3
- 238000001556 precipitation Methods 0.000 description 3
- 238000005070 sampling Methods 0.000 description 3
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 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
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- 238000005906 dihydroxylation reaction Methods 0.000 description 2
- LDCRTTXIJACKKU-ONEGZZNKSA-N dimethyl fumarate Chemical compound COC(=O)\C=C\C(=O)OC LDCRTTXIJACKKU-ONEGZZNKSA-N 0.000 description 2
- 229960004419 dimethyl fumarate Drugs 0.000 description 2
- 229960004756 ethanol Drugs 0.000 description 2
- 235000019441 ethanol Nutrition 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
- 238000012544 monitoring process Methods 0.000 description 2
- 239000012074 organic phase Substances 0.000 description 2
- 238000002360 preparation method Methods 0.000 description 2
- 238000002203 pretreatment Methods 0.000 description 2
- 239000011734 sodium Substances 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 229960000549 4-dimethylaminophenol Drugs 0.000 description 1
- 208000013016 Hypoglycemia Diseases 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
- DWAQJAXMDSEUJJ-UHFFFAOYSA-M Sodium bisulfite Chemical class [Na+].OS([O-])=O DWAQJAXMDSEUJJ-UHFFFAOYSA-M 0.000 description 1
- 229940123518 Sodium/glucose cotransporter 2 inhibitor Drugs 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
- 230000006978 adaptation Effects 0.000 description 1
- 230000003579 anti-obesity Effects 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
- 230000015556 catabolic process Effects 0.000 description 1
- 239000007810 chemical reaction solvent Substances 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 229960000935 dehydrated alcohol Drugs 0.000 description 1
- 206010012601 diabetes mellitus Diseases 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
- 239000003814 drug Substances 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 238000003912 environmental pollution Methods 0.000 description 1
- 238000003810 ethyl acetate extraction Methods 0.000 description 1
- 239000004744 fabric Substances 0.000 description 1
- 239000010419 fine particle 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
- 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
- 238000010907 mechanical stirring Methods 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
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 238000013517 stratification Methods 0.000 description 1
- 238000000967 suction filtration Methods 0.000 description 1
- 239000003930 superacid Substances 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)
- Catalysts (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The present invention discloses a new synthesis process of canagliflozin. The new synthesis process comprises: adopting 2-methyl benzoic acid as a starting raw material, and adopting a self-made catalyst, iodic acid and iodine to carry out a reaction to produce an intermediate 1, or adopting 2-methyl benzoic acid as a starting raw material, and adding liquid bromine under effects of a metal reagent and a catalyst to synthesize an intermediate 2; optionally selecting the intermediate 1 or 2 to carry out an acylation reaction with thionyl chloride, and then carrying out a Friedel-Crafts reaction to produce an intermediate 3; adopting ALPHA-D-glucose as a raw material, carrying out a reaction with pivaloyl chloride to protect all hydroxyl, and carrying out a reaction with zinc bromide and bromotrimethylsilane to produce an intermediate 4; linking the intermediate 3 and the intermediate 4 to produce an intermediate 5; and finally under an acid condition, removing the pivaloyl to produce the target compound. The new synthesis process has characteristics of high yield, mild condition, safety, reliability, cheap and easily available raw material, and easy production cost control, and is suitable for industrial production.
Description
Technical field
The present invention relates to the clean new synthetic process of a kind of Ka Gelie.
Background technology
The clean Canagliflozin of Kan Gelie is first SGLT2 inhibitor medicaments of being ratified by FDA, can be used for the treatment of adult's diabetes B by the mode excreting by kidney after breakdown of glucose is reduced to blood sugar, has broad prospects.Except good glycemic control, the antiobesity action of Canagliflozin is more remarkable, and compares with glimepiride, and hypoglycemia event that canagliflozin causes is far away few many.
The existing synthetic route processing condition of reported in literature are harsh, as adopt high warm filter, and high to production unit requirement, industrialized cost is higher; Because syntheti c route is longer, the yield of each step is lower, causes total recovery low, and environmental pollution is large, is unfavorable for suitability for industrialized production.Therefore, need to provide a kind of new technical scheme to solve the problems referred to above.
Summary of the invention
For addressing the above problem, the invention provides the clean new synthetic process of a kind of Ka Gelie.
The technical solution used in the present invention:
The new synthetic process that Ka Gelie is clean, comprises the following steps:
A, take 2-tolyl acid as starting raw material, use self-control catalyst molecule sieve load ferric oxide, the Iod R that is 0.5 ~ 1.0 with acid iodide and mole multiple generates the iodo-2-tolyl acid of intermediate one 5-, and aftertreatment technology adopts the rear cold filtration of cooling, the way of mother liquid recycle;
B or take 2-tolyl acid as starting raw material, under the effect of metal reagent and super acidic catalyst, adding mole multiple is 1.05 ~ 1.5 bromine, and adopts molecular sieve definitely without water pretreatment to solvent bromine, the bromo-2-tolyl acid of synthetic intermediate two 5-;
C, optional intermediate one or intermediate two first carry out acylation reaction with the thionyl chloride of 1.1 equivalents as fragment, then under the effect of catalyzer aluminum chloride with the 2-(of equimolar ratio to fluorophenyl)-thiophene carries out Friedel-Crafts reaction and generates intermediate three;
D, take ALPHA-D-glucose as raw material, through react all hydroxyls of protection with pivaloyl chloride after, then at-10 ~ 25 ℃, react generation intermediate four with zinc bromide, bromotrimethylsilane;
E, intermediate three and intermediate four mol ratio 1:1, under anhydrous and oxygen-free condition, subzero 76-80 degree Celsius connects and generates intermediate five under the effect from controlling catalyst zinc bromide, lithiumbromide butyl ether solution;
F, target product are further sloughed pivaloyl group under acidic conditions; generate target compound; reaction is finished; first normal pressure steams after the feature impurity that is difficult for removing; concentrate to obtain crude product; the method of repeatedly pulling an oar with different solvents is more progressively removed various impurity, obtains purity higher than 98% target product.
In b step, metal reagent is Fe powder or iron bromide, and super acidic catalyst is trifluoromethanesulfonic acid or tosic acid.
In d step, take ALPHA-D-glucose as raw material, through react all hydroxyls of protection with pivaloyl chloride, in the technique of upper protecting group, add a small amount of sulfur oxychloride.
In f step, solvent is the mixed solvent of methyl alcohol, acetic acid or methyl alcohol, acetic acid and water.
For the generation of above-mentioned each intermediate, then explain by following chemical equation, chemical equation is:
Intermediate one
Intermediate two
Intermediate three
Intermediate four
Intermediate five
Product
Advantage of the present invention is: yield is high, and mild condition is safe and reliable, is applicable to suitability for industrialized production, and raw material is cheaply easy to get, and is conducive to production control cost.
Embodiment
Following embodiment is only for the present invention is described, but can not limit protection scope of the present invention.
Embodiment 1
The new synthetic process that Ka Gelie is clean, comprises the following steps:
A, take 2-tolyl acid as starting raw material, use self-control catalyst molecule sieve load ferric oxide, the Iod R that is 0.5 with acid iodide and mole multiple generates the iodo-2-tolyl acid of intermediate one 5-, aftertreatment technology adopts the rear cold filtration of cooling, the way of mother liquid recycle, specific as follows: temperature of reaction is down to 20 degrees Celsius, a large amount of solids are separated out, at this temperature, the product that is mixed with catalyzer is filtered, mother liquor is applied mechanically next time, can connected set 5 times, after filter cake dissolves with ethyl propenoate, normal temperature filters, catalyzer is leached and applied mechanically next time, can apply mechanically 5 times, after filtrate precipitation, the ethyl propenoate recrystallization of 2.5 times of weight for crude product, obtain white products and obtain product, yield is more than 88%,
B or take 2-tolyl acid as starting raw material, under the effect of metal reagent Fe powder and super acidic catalyst trifluoromethanesulfonic acid, adding mole multiple is 1.05 bromine, and adopt molecular sieve definitely without water pretreatment to solvent bromine, the bromo-2-tolyl acid of synthetic intermediate two 5-, yield is more than 85%;
C, optional intermediate one or intermediate two first carry out acylation reaction with the thionyl chloride of 1.1 equivalents as fragment, then under the effect of catalyzer aluminum chloride with the 2-(of equimolar ratio to fluorophenyl)-thiophene carries out Friedel-Crafts reaction and generates intermediate three, yield 78%;
D, take ALPHA-D-glucose as raw material, through react all hydroxyls of protection with pivaloyl chloride after, react and generate intermediate four at-10 ℃ with zinc bromide, bromotrimethylsilane again, in the technique of upper protecting group, add a small amount of sulfur oxychloride, make pivaloyl chloride consumption reduce half, yield is without impact, and two step yields are all more than 82%, and total recovery is greater than 67%;
E, intermediate three and intermediate four mol ratio 1:1, under anhydrous and oxygen-free condition, subzero 76 degrees Celsius, under the effect from controlling catalyst zinc bromide, lithiumbromide butyl ether solution, connect and generate intermediate five, yield is more than 71%;
F, target product are further sloughed pivaloyl group under acidic conditions; generate target compound; reaction is finished; first normal pressure steams after the feature impurity that is difficult for removing; concentrate to obtain crude product; the method of repeatedly pulling an oar with methyl alcohol is more progressively removed various impurity, obtains purity higher than 98% target product, and yield is more than 85%.
Embodiment 2
The new synthetic process that Ka Gelie is clean, comprises the following steps:
A, take 2-tolyl acid as starting raw material, use self-control catalyst molecule sieve load ferric oxide, the Iod R that is 0.7 with acid iodide and mole multiple generates the iodo-2-tolyl acid of intermediate one 5-, aftertreatment technology adopts the rear cold filtration of cooling, the way of mother liquid recycle, specific as follows: temperature of reaction is down to 18 degrees Celsius, a large amount of solids are separated out, at this temperature, the product that is mixed with catalyzer is filtered, mother liquor is applied mechanically next time, can connected set 3 times, after filter cake dissolves with ethyl propenoate, normal temperature filters, catalyzer is leached and applied mechanically next time, can apply mechanically 3 times, after filtrate precipitation, the ethyl propenoate recrystallization of 2.5 times of weight for crude product, obtain white products and obtain product, yield is more than 88%,
B or take 2-tolyl acid as starting raw material, under the effect of metal reagent iron bromide and super acidic catalyst tosic acid, adding mole multiple is 1.25 bromine, and adopt molecular sieve definitely without water pretreatment to solvent bromine, the bromo-2-tolyl acid of synthetic intermediate two 5-, yield is more than 85%;
C, optional intermediate one or intermediate two first carry out acylation reaction with the thionyl chloride of 1.1 equivalents as fragment, then under the effect of catalyzer aluminum chloride with the 2-(of equimolar ratio to fluorophenyl)-thiophene carries out Friedel-Crafts reaction and generates intermediate three, yield 78-80%;
D, take ALPHA-D-glucose as raw material, through react all hydroxyls of protection with pivaloyl chloride after, react and generate intermediate four at 10 ℃ with zinc bromide, bromotrimethylsilane again, in the technique of upper protecting group, adopt the way that adds a small amount of sulfur oxychloride, make pivaloyl chloride consumption reduce half, yield is without impact, and two step yields are all more than 82%, and total recovery is greater than 67%;
E, intermediate three and intermediate four mol ratio 1:1, under anhydrous and oxygen-free condition, subzero 78 degrees Celsius, under the effect from controlling catalyst zinc bromide, lithiumbromide butyl ether solution, connect and generate intermediate five, yield is more than 71%;
F, target product are further sloughed pivaloyl group under acidic conditions; generate target compound; reaction is finished; first normal pressure steams after the feature impurity that is difficult for removing; concentrate to obtain crude product; the method of repeatedly pulling an oar with acetic acid is more progressively removed various impurity, obtains purity higher than 98% target product, and yield is more than 85%.
Embodiment 3
The new synthetic process that Ka Gelie is clean, comprises the following steps:
A, take 2-tolyl acid as starting raw material, use self-control catalyst molecule sieve load ferric oxide, the Iod R that is 1.0 with acid iodide and mole multiple generates the iodo-2-tolyl acid of intermediate one 5-, aftertreatment technology adopts the rear cold filtration of cooling, the way of mother liquid recycle, specific as follows: temperature of reaction is down to 22 degrees Celsius, a large amount of solids are separated out, at this temperature, the product that is mixed with catalyzer is filtered, mother liquor is applied mechanically next time, can connected set 4 times, after filter cake dissolves with ethyl propenoate, normal temperature filters, catalyzer is leached and applied mechanically next time, can apply mechanically 4 times, after filtrate precipitation, the ethyl propenoate recrystallization of 2.5 times of weight for crude product, obtain white products and obtain product, yield is more than 88%,
B or take 2-tolyl acid as starting raw material, under the effect of metal reagent Fe powder and super acidic catalyst trifluoromethanesulfonic acid, adding mole multiple is 1.5 bromine, and adopt molecular sieve definitely without water pretreatment to solvent bromine, the bromo-2-tolyl acid of synthetic intermediate two 5-, yield is more than 85%;
C, optional intermediate one or intermediate two first carry out acylation reaction with the thionyl chloride of 1.1 equivalents as fragment, then under the effect of catalyzer aluminum chloride with the 2-(of equimolar ratio to fluorophenyl)-thiophene carries out Friedel-Crafts reaction and generates intermediate three, yield 80%;
D, take ALPHA-D-glucose as raw material, through react all hydroxyls of protection with pivaloyl chloride after, react and generate intermediate four at 25 ℃ with zinc bromide, bromotrimethylsilane again, in the technique of upper protecting group, adopt the way that adds a small amount of sulfur oxychloride, make pivaloyl chloride consumption reduce half, yield is without impact, and two step yields are all more than 82%, and total recovery is greater than 67%;
E, intermediate three and intermediate four mol ratio 1:1, under anhydrous and oxygen-free condition, subzero 80 degrees Celsius, under the effect from controlling catalyst zinc bromide, lithiumbromide butyl ether solution, connect and generate intermediate five, yield is more than 71%;
F, target product are further sloughed pivaloyl group under acidic conditions; generate target compound; reaction is finished; first normal pressure steams after the feature impurity that is difficult for removing; concentrate to obtain crude product; the method of repeatedly pulling an oar with methyl alcohol and water mixed solvent is more progressively removed various impurity, obtains purity higher than 98% target product, and yield is more than 85%.
In f step, mixed solvent can also be the mixed solvent of acetic acid and water.
Be below the preparation process of each intermediate:
Prepare intermediate one: in 500ml reaction flask, add, 2-methyl-phenylformic acid 40g, 0.113mol iodine, the 70% acid iodide aqueous solution, catalyst molecule sieve load ferric oxide, acetic acid, acetic anhydride, is warming up to backflow, in LC, controls, and cooling crystallization, filters mother liquid recycle.Crude product adds ethyl propenoate entirely molten to product, removes by filter zeolite, is spin-dried for, and the ethyl propenoate recrystallization of 2.5 times of weight for crude product, obtains white products 67.76g, yield 88%, purity 94%(LC).
Prepare intermediate and in ml reaction flask add 2-methyl-phenylformic acid 40g at two: 250, iron powder, trifluoromethanesulfonic acid, bromine/methylene dichloride (through molecular sieve pre-treatment), be warming up to backflow, drip 0.388mol bromine/dichloromethane solution, drip and finish, backflow is spent the night, in TLC, control to reaction finishes, cooling, drips saturated sodium bisulfite to redness and takes off, separatory, water layer 30ml dichloromethane extraction, merge organic layer, washing, is spin-dried for to obtain crude product 53g, ethyl alcohol recrystallization, obtain product 54.09g, yield 85%, purity 95%(LC).
Prepare intermediate three: in 250ml four-hole boiling flask, add the iodo-2-tolyl acid of 5-20g, methylene dichloride, dimethyl fumarate, be warming up to 20 ℃, drip sulfur oxychloride.Drip and finish, be warming up to backflow, after 1.5h, sampling LC monitoring is without raw material.Be cooled to 2 ℃, add aluminum chloride, stir 15min, drip 13.6g2-(to fluorophenyl) the DCM solution of-thiophene.Drip to finish, react 3h at 20 ℃, in LC, control is without raw material.Be cooled to 2 ℃, add aluminum chloride, stir 15min, drip the acetonitrile solution of TMDSO, be warming up to back flow reaction 5h, in LC, control to reaction finishes.Reaction solution is poured in 5% hydrochloric acid soln, stirred, dichloromethane extraction twice water layer for, merges organic layer, washing, and anhydrous sodium sulfate drying, is spin-dried for, use ethyl acetate and Virahol recrystallization, obtain product 21.75g, yield 70%, purity 98%(LC).
Prepare intermediate three: in 10L four-hole boiling flask, add the bromo-2-tolyl acid of 5-800g, methylene dichloride, dimethyl fumarate, is warming up to backflow, drips sulfur oxychloride, and in sampling LC, control to reaction finishes.Be cooled to 2 ℃, add aluminum chloride, drip equimolar 2-(to fluorophenyl) the DCM solution of-thiophene.Drip to finish, react 3 hours at 20 ℃, LC monitors without raw material.Be cooled to 2 ℃, add aluminum chloride.Drip acetonitrile, drip and finish, drip fast the acetonitrile solution of TMDSO, be warming up to back flow reaction 5h, in LC, control to reaction finishes.Reaction solution is poured in 10% hydrochloric acid soln, stirred 15min, water layer 3L dichloromethane extraction, merges organic layer, and washing, is spin-dried for, and use ethyl acetate and Virahol recrystallization, obtain product 1009.6g, yield 75%, purity 96%(LC).
Prepare intermediate four: in 10L four-hole reaction flask, add 384g alpha-D-glucose, pyridine, methylene dichloride, DMAP, mechanical stirring, is heated to 48 ℃.Close heating, add 10ml sulfur oxychloride.Start to drip pivaloyl chloride 1412g, 2h dropwises, and temperature maintains 50 ℃ of back flow reaction.Control during HPLC detects.Reaction finishes rear negative pressure and is concentrated into dryly, adds methylene dichloride and dilute hydrochloric acid stirring and dissolving, stratification, separatory.After organic phase washing, use anhydrous Na
2sO
4dry, filtration.Organic phase negative pressure is concentrated into dry, obtains light yellow solid 1830g.Crude product dehydrated alcohol recrystallization, obtains white solid 1096g, purity 98%, and yield 82%, standby.
In 20L four-hole reaction flask, pass into N
2, add 750g Calcium Chel 330, methylene dichloride, zinc bromide, stirs.Reaction solution is cooled to 10 ℃, starts to drip the mixture of bromotrimethylsilane and methylene dichloride, and 1.5h dropwises.Control temperature 20-25 ℃, stirring reaction 1.5h.HPLC detects to reaction end.Suction filtration goes out zinc bromide, obtains yellow clarified liq.Be cooled to 0 ℃, drip sodium bicarbonate aqueous solution, monitoring pH value is at 7-8.Separatory obtains organic layer and adds anhydrous Na
2sO
4dry, filter.Organic layer negative pressure concentrates to obtain lurid solid 700g, crude product purity 88%.Virahol 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, in 500ml reaction flask, add intermediate three 40.8g, n-butyl ether, toluene, logical nitrogen, cools to-40 ℃, drips butyllithium, drips Bi Baowen 2h.Drip zinc bromide lithiumbromide butyl ether solution, drip and finish, 30 ℃ of insulation 2h.The toluene solution that drips intermediate four, is warming up to 90 ℃ of insulations after dripping, in sampling LC, control to reaction finishes.After cooling, reaction solution is poured in the hydrochloric acid that 500ml is rare, separatory, 120ml*3 ethyl acetate extraction for water layer, merges organic layer, and washing, separatory, the concentrated brown oil of doing to obtain, add ethyl alcohol recrystallization to obtain product 55.5g.Purity 95%, yield 71%.
In the four-hole boiling flask of the preparation that Ka Gelie is clean: 2L, add 150g intermediate five, methyl alcohol, stirring at room 15min.Drip the methanol solution of 30% sodium methylate, dropwise and be warming up to backflow.In LC, control is to reacting complete.Normal pressure steams after the feature impurity that is difficult for removing, and concentrated to obtain crude product, then adds the method that methyl alcohol, Acetic Acid-Water, water, methanol-water equal solvent repeatedly pulls an oar and progressively remove various impurity, filter, recrystallizing methanol obtains solid 72.6g, yield 85%, purity 98%(LC) more than.
The clean new synthetic process of Ka Gelie of the present invention advantage specific as follows:
1) intermediate one is synthetic, adopts catalytic synthetic techniques, uses the molecular sieve carried ferric oxide catalyst of self-control to participate in reaction, and the selectivity of 5 upper iodine is increased to almost absolutely from 60%.This step yield is brought up to more than 88%, greatly improved yield, reduced impurity.In this external aftertreatment, evaded the comparatively step of complicated fine particle high temperature heat filtering, because this step is high to equipment requirements, temperature is slightly low, and product is just separated out from filtrate, stops up filter cloth.Present method changes it, adopts the rear cold filtration of cooling, the way of mother liquid recycle.Filter cake adopts the stripping of lower step solvent, after filtration catalizer, containing product filtrate, participates in the next step directly.Technique is simple to operation, greatly reduces treatment time and difficulty, and producing feasibility obviously improves, and also can improve yield, and has reduced the pollution to environment.
2) intermediate two is synthetic by the groping of reaction conditions and synthesis mechanism, and makes 3 special adaptations.The one, molecular sieve to carry out pre-treatment to reaction solvent, make it definitely anhydrous; The metal reagents such as the two Fe powder that will add catalytic amount, iron bromide; The super acids such as three trifluoromethanesulfonic acids that will add wherein catalytic amount, tosic acid, can will originally almost accomplish high yield without the reaction of product.
3) upper pivaloyl group one step during synthetic intermediate four, adds a small amount of sulfur oxychloride, in the situation that yield does not fall, the consumption of pivaloyl chloride can be reduced to 50%, reduce the pollution to environment.
4), during synthetic intermediate five, evaded traditional TMS protection glucose and dock the method for dehydroxylation of reducing afterwards with intermediate three, with 2; 3,4,6-O-, tetra-pivaloyl groups-ALPHA-D-bromo Glucopyranose docks with intermediate three; can avoid dehydroxylation, improve total recovery, greatly cost-saving.And adopting homemade bridge joint catalyzer to connecting, make yield improve 20% than original.
Claims (4)
1. the clean new synthetic process of Ka Gelie, is characterized in that, comprises the following steps:
A, take 2-tolyl acid as starting raw material, use self-control catalyst molecule sieve load ferric oxide, the Iod R that is 0.5 ~ 1.0 with acid iodide and mole multiple generates the iodo-2-tolyl acid of intermediate one 5-, and aftertreatment technology adopts the rear cold filtration of cooling, the way of mother liquid recycle;
B or take 2-tolyl acid as starting raw material, under the effect of metal reagent and super acidic catalyst, adding mole multiple is 1.05 ~ 1.5 bromine, and adopts molecular sieve definitely without water pretreatment to solvent bromine, the bromo-2-tolyl acid of synthetic intermediate two 5-;
C, optional intermediate one or intermediate two first carry out acylation reaction with the thionyl chloride of 1.1 equivalents as fragment, then under the effect of catalyzer aluminum chloride with the 2-(of equimolar ratio to fluorophenyl)-thiophene carries out Friedel-Crafts reaction and generates intermediate three;
D, take ALPHA-D-glucose as raw material, through react all hydroxyls of protection with pivaloyl chloride after, then at-10 ~ 25 ℃, react generation intermediate four with zinc bromide, bromotrimethylsilane;
E, intermediate three and intermediate four mol ratio 1:1, under anhydrous and oxygen-free condition, subzero 76-80 degree Celsius connects and generates intermediate five under the effect from controlling catalyst zinc bromide, lithiumbromide butyl ether solution;
F, target product are further sloughed pivaloyl group under acidic conditions; generate target compound; reaction is finished; first normal pressure steams after the feature impurity that is difficult for removing; concentrate to obtain crude product; the method of repeatedly pulling an oar with different solvents is more progressively removed various impurity, obtains purity higher than 98% target product.
2. the clean new synthetic process of Ka Gelie according to claim 1, is characterized in that: in b step, metal reagent is Fe powder or iron bromide, and super acidic catalyst is trifluoromethanesulfonic acid or tosic acid.
3. the clean new synthetic process of Ka Gelie according to claim 1, is characterized in that: in d step, take ALPHA-D-glucose as raw material, through react all hydroxyls of protection with pivaloyl chloride, add a small amount of sulfur oxychloride in the technique of upper protecting group.
4. the clean new synthetic process of Ka Gelie according to claim 1, is characterized in that: in f step, solvent is the mixed solvent of methyl alcohol, acetic acid or methyl alcohol, acetic acid and water.
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