CN104109157A - Preparation method of canagliflozin - Google Patents
Preparation method of canagliflozin Download PDFInfo
- Publication number
- CN104109157A CN104109157A CN201410377806.2A CN201410377806A CN104109157A CN 104109157 A CN104109157 A CN 104109157A CN 201410377806 A CN201410377806 A CN 201410377806A CN 104109157 A CN104109157 A CN 104109157A
- Authority
- CN
- China
- Prior art keywords
- preparation
- palladium
- sodium
- reaction
- methyl
- 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.)
- Granted
Links
- 238000002360 preparation method Methods 0.000 title claims abstract description 29
- 229960001713 canagliflozin Drugs 0.000 title abstract description 7
- 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 7
- 238000006243 chemical reaction Methods 0.000 claims abstract description 35
- 150000001875 compounds Chemical class 0.000 claims abstract description 26
- 239000003054 catalyst Substances 0.000 claims abstract description 9
- 238000007336 electrophilic substitution reaction Methods 0.000 claims abstract description 4
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims description 36
- -1 iodo-2-aminomethyl phenyl Chemical group 0.000 claims description 22
- PIBWKRNGBLPSSY-UHFFFAOYSA-L palladium(II) chloride Chemical group Cl[Pd]Cl PIBWKRNGBLPSSY-UHFFFAOYSA-L 0.000 claims description 19
- 229910052763 palladium Inorganic materials 0.000 claims description 18
- ZZPNDIHOQDQVNU-UHFFFAOYSA-N 2-hydroxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane Chemical compound CC1(C)OB(O)OC1(C)C ZZPNDIHOQDQVNU-UHFFFAOYSA-N 0.000 claims description 17
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 claims description 14
- YTPLMLYBLZKORZ-UHFFFAOYSA-N Thiophene Chemical compound C=1C=CSC=1 YTPLMLYBLZKORZ-UHFFFAOYSA-N 0.000 claims description 14
- 239000003153 chemical reaction reagent Substances 0.000 claims description 13
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 12
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 12
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 12
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical class OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 claims description 12
- YQTCQNIPQMJNTI-UHFFFAOYSA-N 2,2-dimethylpropan-1-one Chemical group CC(C)(C)[C]=O YQTCQNIPQMJNTI-UHFFFAOYSA-N 0.000 claims description 10
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 10
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 8
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 8
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 8
- YXFVVABEGXRONW-UHFFFAOYSA-N toluene Substances CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 8
- GETQZCLCWQTVFV-UHFFFAOYSA-N trimethylamine Chemical compound CN(C)C GETQZCLCWQTVFV-UHFFFAOYSA-N 0.000 claims description 8
- 239000002253 acid Substances 0.000 claims description 7
- SCVFZCLFOSHCOH-UHFFFAOYSA-M potassium acetate Chemical compound [K+].CC([O-])=O SCVFZCLFOSHCOH-UHFFFAOYSA-M 0.000 claims description 7
- 229930192474 thiophene Natural products 0.000 claims description 7
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 6
- 239000003513 alkali Substances 0.000 claims description 6
- 230000035484 reaction time Effects 0.000 claims description 6
- 239000011734 sodium Substances 0.000 claims description 6
- 229910052708 sodium Inorganic materials 0.000 claims description 6
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 claims description 6
- 229910052500 inorganic mineral Inorganic materials 0.000 claims description 5
- 239000011707 mineral Substances 0.000 claims description 5
- 235000010755 mineral Nutrition 0.000 claims description 5
- 150000007530 organic bases Chemical group 0.000 claims description 5
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Substances [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 5
- 235000015320 potassium carbonate Nutrition 0.000 claims description 5
- XYFCBTPGUUZFHI-UHFFFAOYSA-N Phosphine Chemical compound P XYFCBTPGUUZFHI-UHFFFAOYSA-N 0.000 claims description 4
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 claims description 4
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 claims description 4
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 claims description 4
- GCUVBACNBHGZRS-UHFFFAOYSA-N cyclopenta-1,3-diene cyclopenta-2,4-dien-1-yl(diphenyl)phosphane iron(2+) Chemical compound [Fe++].c1cc[cH-]c1.c1cc[c-](c1)P(c1ccccc1)c1ccccc1 GCUVBACNBHGZRS-UHFFFAOYSA-N 0.000 claims description 4
- WMKGGPCROCCUDY-PHEQNACWSA-N dibenzylideneacetone Chemical compound C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1 WMKGGPCROCCUDY-PHEQNACWSA-N 0.000 claims description 4
- GPNDARIEYHPYAY-UHFFFAOYSA-N palladium(ii) nitrate Chemical compound [Pd+2].[O-][N+]([O-])=O.[O-][N+]([O-])=O GPNDARIEYHPYAY-UHFFFAOYSA-N 0.000 claims description 4
- 150000003053 piperidines Chemical class 0.000 claims description 4
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 claims description 4
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 4
- 239000001632 sodium acetate Substances 0.000 claims description 4
- 229960004249 sodium acetate Drugs 0.000 claims description 4
- 235000017281 sodium acetate Nutrition 0.000 claims description 4
- ODZPKZBBUMBTMG-UHFFFAOYSA-N sodium amide Chemical compound [NH2-].[Na+] ODZPKZBBUMBTMG-UHFFFAOYSA-N 0.000 claims description 4
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 4
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 claims description 4
- YFTHZRPMJXBUME-UHFFFAOYSA-N tripropylamine Chemical compound CCCN(CCC)CCC YFTHZRPMJXBUME-UHFFFAOYSA-N 0.000 claims description 4
- 238000010511 deprotection reaction Methods 0.000 claims description 3
- KTWOOEGAPBSYNW-UHFFFAOYSA-N ferrocene Chemical compound [Fe+2].C=1C=C[CH-]C=1.C=1C=C[CH-]C=1 KTWOOEGAPBSYNW-UHFFFAOYSA-N 0.000 claims description 3
- VYXHVRARDIDEHS-UHFFFAOYSA-N 1,5-cyclooctadiene Chemical compound C1CC=CCCC=C1 VYXHVRARDIDEHS-UHFFFAOYSA-N 0.000 claims description 2
- 239000004912 1,5-cyclooctadiene Substances 0.000 claims description 2
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 2
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 claims description 2
- TWKVUTXHANJYGH-UHFFFAOYSA-L allyl palladium chloride Chemical class Cl[Pd]CC=C.Cl[Pd]CC=C TWKVUTXHANJYGH-UHFFFAOYSA-L 0.000 claims description 2
- JFDZBHWFFUWGJE-UHFFFAOYSA-N benzonitrile Chemical compound N#CC1=CC=CC=C1 JFDZBHWFFUWGJE-UHFFFAOYSA-N 0.000 claims description 2
- 239000000460 chlorine Substances 0.000 claims description 2
- 229910052801 chlorine Inorganic materials 0.000 claims description 2
- 125000003963 dichloro group Chemical group Cl* 0.000 claims description 2
- FSRXIRGQJIHEFB-UHFFFAOYSA-N diphenylphosphane;ethane Chemical compound CC.C=1C=CC=CC=1PC1=CC=CC=C1 FSRXIRGQJIHEFB-UHFFFAOYSA-N 0.000 claims description 2
- ONDPGJBEBGWAKI-UHFFFAOYSA-N diphenylphosphane;propane Chemical compound CCC.C=1C=CC=CC=1PC1=CC=CC=C1 ONDPGJBEBGWAKI-UHFFFAOYSA-N 0.000 claims description 2
- NXJCBFBQEVOTOW-UHFFFAOYSA-L palladium(2+);dihydroxide Chemical compound O[Pd]O NXJCBFBQEVOTOW-UHFFFAOYSA-L 0.000 claims description 2
- NFHFRUOZVGFOOS-UHFFFAOYSA-N palladium;triphenylphosphane Chemical compound [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 claims description 2
- UQPUONNXJVWHRM-UHFFFAOYSA-N palladium;triphenylphosphane Chemical compound [Pd].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 UQPUONNXJVWHRM-UHFFFAOYSA-N 0.000 claims description 2
- 229910000073 phosphorus hydride Inorganic materials 0.000 claims description 2
- 238000010931 ester hydrolysis Methods 0.000 claims 1
- 238000004519 manufacturing process Methods 0.000 abstract description 9
- 238000000034 method Methods 0.000 abstract description 9
- 239000002994 raw material Substances 0.000 abstract description 6
- 230000009471 action Effects 0.000 abstract description 2
- 230000008569 process Effects 0.000 abstract description 2
- MGXZKAYHSITHMW-UHFFFAOYSA-N 2-(4-fluorophenyl)-5-[(5-iodo-2-methylphenyl)methyl]thiophene Chemical compound CC1=CC=C(I)C=C1CC1=CC=C(C=2C=CC(F)=CC=2)S1 MGXZKAYHSITHMW-UHFFFAOYSA-N 0.000 abstract 2
- FKLJPTJMIBLJAV-UHFFFAOYSA-N Compound IV Chemical compound O1N=C(C)C=C1CCCCCCCOC1=CC=C(C=2OCCN=2)C=C1 FKLJPTJMIBLJAV-UHFFFAOYSA-N 0.000 abstract 2
- IPWKHHSGDUIRAH-UHFFFAOYSA-N bis(pinacolato)diboron Chemical compound O1C(C)(C)C(C)(C)OB1B1OC(C)(C)C(C)(C)O1 IPWKHHSGDUIRAH-UHFFFAOYSA-N 0.000 abstract 1
- 230000003301 hydrolyzing effect Effects 0.000 abstract 1
- 238000009776 industrial production Methods 0.000 abstract 1
- 125000006239 protecting group Chemical group 0.000 abstract 1
- 238000004904 shortening Methods 0.000 abstract 1
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 18
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 11
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 9
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 9
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 9
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 8
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 6
- 229960001701 chloroform Drugs 0.000 description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 5
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 5
- 238000011084 recovery Methods 0.000 description 5
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 4
- OKKJLVBELUTLKV-MZCSYVLQSA-N Deuterated methanol Chemical compound [2H]OC([2H])([2H])[2H] OKKJLVBELUTLKV-MZCSYVLQSA-N 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 4
- XTNGUQKDFGDXSJ-ZXGKGEBGSA-N Canagliflozin Chemical compound 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 XTNGUQKDFGDXSJ-ZXGKGEBGSA-N 0.000 description 3
- 239000004215 Carbon black (E152) Substances 0.000 description 3
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 3
- 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 3
- 108091006269 SLC5A2 Proteins 0.000 description 3
- 102000058081 Sodium-Glucose Transporter 2 Human genes 0.000 description 3
- 239000007810 chemical reaction solvent Substances 0.000 description 3
- 239000008103 glucose Substances 0.000 description 3
- 229930195733 hydrocarbon Natural products 0.000 description 3
- 239000012046 mixed solvent Substances 0.000 description 3
- YKXCWZVUWWQSAV-BTVCFUMJSA-N (2r,3s,4r,5r)-2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C=O YKXCWZVUWWQSAV-BTVCFUMJSA-N 0.000 description 2
- KZPYGQFFRCFCPP-UHFFFAOYSA-N 1,1'-bis(diphenylphosphino)ferrocene Chemical compound [Fe+2].C1=CC=C[C-]1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=C[C-]1P(C=1C=CC=CC=1)C1=CC=CC=C1 KZPYGQFFRCFCPP-UHFFFAOYSA-N 0.000 description 2
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 2
- 238000005160 1H NMR spectroscopy Methods 0.000 description 2
- 229910002666 PdCl2 Inorganic materials 0.000 description 2
- 229940123518 Sodium/glucose cotransporter 2 inhibitor Drugs 0.000 description 2
- 239000008280 blood Substances 0.000 description 2
- 210000004369 blood Anatomy 0.000 description 2
- WTEOIRVLGSZEPR-UHFFFAOYSA-N boron trifluoride Chemical compound FB(F)F WTEOIRVLGSZEPR-UHFFFAOYSA-N 0.000 description 2
- 239000013078 crystal Substances 0.000 description 2
- 206010012601 diabetes mellitus Diseases 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 238000001035 drying Methods 0.000 description 2
- 238000002330 electrospray ionisation mass spectrometry Methods 0.000 description 2
- 239000003112 inhibitor Substances 0.000 description 2
- 229940121068 invokana Drugs 0.000 description 2
- 239000010410 layer Substances 0.000 description 2
- 229910052757 nitrogen Inorganic materials 0.000 description 2
- 238000011017 operating method Methods 0.000 description 2
- 239000012044 organic layer Substances 0.000 description 2
- 210000005239 tubule Anatomy 0.000 description 2
- 208000001072 type 2 diabetes mellitus Diseases 0.000 description 2
- 238000003809 water extraction Methods 0.000 description 2
- AITNMTXHTIIIBB-UHFFFAOYSA-N 1-bromo-4-fluorobenzene Chemical compound FC1=CC=C(Br)C=C1 AITNMTXHTIIIBB-UHFFFAOYSA-N 0.000 description 1
- PURJRGMZIKXDMW-UHFFFAOYSA-N 2-(4-fluorophenyl)thiophene Chemical compound C1=CC(F)=CC=C1C1=CC=CS1 PURJRGMZIKXDMW-UHFFFAOYSA-N 0.000 description 1
- TUCRZHGAIRVWTI-UHFFFAOYSA-N 2-bromothiophene Chemical compound BrC1=CC=CS1 TUCRZHGAIRVWTI-UHFFFAOYSA-N 0.000 description 1
- GSFNQBFZFXUTBN-UHFFFAOYSA-N 2-chlorothiophene Chemical compound ClC1=CC=CS1 GSFNQBFZFXUTBN-UHFFFAOYSA-N 0.000 description 1
- BUBVLQDEIIUIQG-UHFFFAOYSA-N 3,4,5-tris(phenylmethoxy)-6-(phenylmethoxymethyl)oxan-2-one Chemical compound C=1C=CC=CC=1COC1C(OCC=2C=CC=CC=2)C(OCC=2C=CC=CC=2)C(=O)OC1COCC1=CC=CC=C1 BUBVLQDEIIUIQG-UHFFFAOYSA-N 0.000 description 1
- PWTUNOWHNRYMOB-UHFFFAOYSA-N 3-iodo-2-methylbenzoyl chloride Chemical compound CC1=C(I)C=CC=C1C(Cl)=O PWTUNOWHNRYMOB-UHFFFAOYSA-N 0.000 description 1
- 229910015900 BF3 Inorganic materials 0.000 description 1
- ZOXJGFHDIHLPTG-UHFFFAOYSA-N Boron Chemical compound [B] ZOXJGFHDIHLPTG-UHFFFAOYSA-N 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 1
- DKPFZGUDAPQIHT-UHFFFAOYSA-N Butyl acetate Natural products CCCCOC(C)=O DKPFZGUDAPQIHT-UHFFFAOYSA-N 0.000 description 1
- 101100393023 Crocus sativus GLT2 gene Proteins 0.000 description 1
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical group CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 1
- LCGLNKUTAGEVQW-UHFFFAOYSA-N Dimethyl ether Chemical group COC LCGLNKUTAGEVQW-UHFFFAOYSA-N 0.000 description 1
- 206010013710 Drug interaction Diseases 0.000 description 1
- 102000018711 Facilitative Glucose Transport Proteins Human genes 0.000 description 1
- 108091052347 Glucose transporter family Proteins 0.000 description 1
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 1
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical group [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 1
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 1
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 1
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 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
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 230000008901 benefit Effects 0.000 description 1
- 229910052796 boron Inorganic materials 0.000 description 1
- 229940043232 butyl acetate Drugs 0.000 description 1
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 239000012141 concentrate Substances 0.000 description 1
- 230000003247 decreasing effect Effects 0.000 description 1
- 238000001647 drug administration Methods 0.000 description 1
- 229940000406 drug candidate Drugs 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 238000003810 ethyl acetate extraction Methods 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- FUZZWVXGSFPDMH-UHFFFAOYSA-N hexanoic acid Chemical compound CCCCCC(O)=O FUZZWVXGSFPDMH-UHFFFAOYSA-N 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 210000003734 kidney Anatomy 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- PQDJYEQOELDLCP-UHFFFAOYSA-N trimethylsilane Chemical compound C[SiH](C)C PQDJYEQOELDLCP-UHFFFAOYSA-N 0.000 description 1
- 229940094989 trimethylsilane Drugs 0.000 description 1
- 238000007039 two-step reaction Methods 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
-
- 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)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
Abstract
The invention relates to the technical field of canagliflozin preparation and particularly relates to a preparation method of canagliflozin. The preparation method comprises the steps: with tetrapivoloyl-alpha-D-bromo-glucopyranose as a raw material, enabling the tetrapivoloyl-alpha-D-bromo-glucopyranose and bis(pinacolato)diboron to be subjected to electrophilic substitution reaction to generate a compound IV; with 2-(4-fluorophenyl)-5-[(5-iodo-2-methylphenyl)methyl]thiofuran as a raw material, enabling the 2-(4-fluorophenyl)-5-[(5-iodo-2-methylphenyl)methyl]thiofuran to react with the compound IV under the action of a catalyst to generate a compound VI; and hydrolyzing the compound VI under an alkaline condition, and removing a protecting group to obtain canagliflozin. The preparation method of canagliflozin, provided by the invention, is greatly shortened in synthetic route and only comprises three steps, so that the operation process is simplified; the preparation method is relatively mild in reaction condition, simple, convenient and feasible in aftertreatment, capable of well meeting the requirement of industrial production, shortening the production time, reducing the labor cost and the production cost and greatly increasing the reaction yield and high in total yield (more than 60%) due to the adoption of the route.
Description
technical field
The present invention relates to the clean preparing technical field of Ka Gelie, particularly the clean preparation method of a kind of Ka Gelie.
background technology
Ka Gelie clean (canagliflozin), commodity are called Invokana, the New type of S GLT2 inhibitor of being researched and developed by Johson & Johnson, be used for the treatment of type II diabetes, on March 29th, 2013, U.S. FDA has been ratified the Invokana of Johnson & Johnson sheet (canagliflozin) and has been used for the treatment of diabetes B adult patient; In September, 2013, Ka Gelie has only obtained European drug administration (EMA) approval and has been used for the treatment of adult's diabetes B.In addition, Ka Gelie has also obtained Australian approval only.Ka Gelie Jing Shi Johson & Johnson is one of the most promising drug candidate person.Under Johson & Johnson Yang Sen department have this medicine in North America, the selling right of South America, Europe, the Middle East, Africa, Australia, New Zealand and some Asian countries.
The clean chemical name of Ka Gelie is (1S)-1,5-dehydrogenation-1-C-[3-[[5-(4-fluorophenyl)-2-thienyl] methyl]-4-aminomethyl phenyl]-D-Glucose alcohol, No. CAS is 842133-18-0, structural formula is as shown in I.
（Ⅰ）
First SGLT2 inhibitor that Ka Gelie ratifies for FDA only, belong to selectivity sodium-glucose body 2(SGLT2 that cotransports) kind new medicine of inhibitor, sodium-glucose body that cotransports is that a kind of glucose transporter has two kinds of hypotypes, SGLT2 is one of them hypotype, at nearly uriniferous tubules, express, participate in the heavily absorption of the glucose that filters in most tube chamber, Ka Gelie net energy suppresses SGLT2, make the glucose in uriniferous tubules can not suction smoothly receipts, reduce kidney glucose threshold (RTG), thereby reduce blood sugar concentration.Clinical in type II diabetes.Ka Gelie is first SGLT2 inhibitor of listing only, and day clothes once, can reach blood sugar decreasing effect and have good tolerance, and drug interaction is low, has wide potential applicability in clinical practice.At present in the listing of a plurality of countries.
At present, the preparation method clean to Ka Gelie has bibliographical information both at home and abroad, and WO2005012326 discloses, the bromo-2-tolyl aldehyde of the 5-of take is starting raw material, through reacting with 2-chlorothiophene, with 2,3,4,6-tetra--O-TMS-maltonic acid-1,5-lactone reaction, then react and obtain thick methyl ether compound with the methanol solution of methylsulphonic acid, react and obtain target product I with trimethyl silane and boron trifluoride ether solution again
Concrete synthetic route is as follows:
WO2009035969 and WO2012140120 disclose, and take p-Fluoro bromo benzene as starting raw material, with magnesium powder form format reagent; react with 2-bromothiophene again and obtain 2-(4-fluorophenyl)-thiophene; the latter reacts with the iodo-2-methyl benzoyl chloride of 5-, and the product obtaining removes carbonyl through reduction; with 2; the reaction of 3,4,6-O-, tetra-pivaloyl groups-alpha-D-Glucopyranose bromide; hydrolysis Deprotection obtains target product I, and concrete synthetic route is as follows:
The clean equal more complicated of synthetic method of above prior art disclosed preparation Ka Gelie, step is longer, has extended the production cycle, and reaction conditions is comparatively harsh, and aftertreatment is comparatively loaded down with trivial details, and route total recovery is not high.
summary of the invention
In order to solve, in above prior art, prepare that Ka Gelie the accounts show a surplus of reactions steps is long, technique is loaded down with trivial details, severe reaction conditions, aftertreatment is complicated, route total recovery is not high problem, the invention provides a kind of reactions steps shorter, the clean novel method of preparation Ka Gelie that yield is high.
The present invention is achieved by the following measures:
The preparation method that Ka Gelie is clean, comprises the following steps
(1) take four pivaloyl groups-alpha-D-bromo Glucopyranose (II) as raw material and connection boric acid pinacol ester (III) generation electrophilic substitution reaction generation compound (IV);
(2) take the iodo-2-aminomethyl phenyl of 2-(4-fluorophenyl)-5-[(5-) methyl] compound (IV) reacting generating compound (VI) that obtains with step (1) under catalyst action as raw material of thiophene (V);
(3) get the compound (VI) that step (2) obtains and be hydrolyzed under alkaline condition, it is that Ka Gelie is clean that Deprotection obtains compound (I).
Whole reaction process as shown in the formula:
The clean novel method of preparation Ka Gelie provided by the invention, the palladium catalyst wherein using in step (1) can be one of following reagent: Palladous chloride, palladium hydroxide, palladium, Palladous nitrate, allyl palladium chloride dimer, two (cyanobenzene) Palladous chloride, two (dibenzalacetones) close palladium, 1, two (diphenylphosphino) ferrocene of 1'-] close Palladous chloride, two (triphenylphosphine) ferrocene closes Palladous chloride, four (triphen phosphino-) palladium, three (dibenzalacetone) two palladiums, two (1, two (diphenylphosphine) ethane of 2-) palladium, dichloro two (thricyclohexyl is seen) palladium, two (three-O-toluene phosphine) palladiums of trans-dichloro, (1, 5-cyclooctadiene) palladium chloride, chlorine palladium acid sodium, three (dibenzalacetone) two palladiums-chloroform adducts, triphenylphosphine palladium acetate, two (acetonitrile) Palladous chloride, [1, the two diphenylphosphine propane of 3-] Palladous chloride, tetrakis triphenylphosphine palladium etc.Preferably 1, two (diphenylphosphino) ferrocene of 1'-] close Palladous chloride (PdCl2 (dppf)).Wherein the consumption mol ratio of halogenated aryl hydrocarbon, that acid esters of connection boron frequency is 1:1-1:2, and the consumption mol ratio of halogenated aryl hydrocarbon and palladium catalyst is 20:1-100:1.
Wherein step (1) reaction solvent is the mixed solvent of one or both and multiple mentioned reagent for DMF, dioxane, tetrahydrofuran (THF), DMSO, methylene dichloride, trichloromethane (chloroform), toluene, acetone.Temperature of reaction can be 20 ℃-60 ℃ as preferable reaction temperature at 0 ℃-160 ℃, and the reaction times is as the criterion to react completely, and can be 30 minutes to 24 hours.Wherein the alkaline reagents of the use of step (1) one of is following reagent: organic bases, as sodium methylate, sodium ethylate, sodium-acetate, Potassium ethanoate, sodium amide, trityl sodium, potassium tert.-butoxide, pyridine, piperidines, Trimethylamine 99, triethylamine, tripropyl amine or diisopropyl ethyl amine etc.; Mineral alkali, as salt of wormwood, sodium carbonate, saleratus, sodium bicarbonate, sodium hydroxide, potassium hydroxide, preferably alkaline reagents is Potassium ethanoate, the consumption mol ratio of halogenated aryl hydrocarbon and Potassium ethanoate is 1:1-1:3.
The clean method of Ka Gelie of preparing provided by the invention, wherein step (2) starting compound used (V) can be for one of following: the iodo-2-aminomethyl phenyl of 2-(4-fluorophenyl)-5-[(5-) methyl] thiophene, the bromo-2-aminomethyl phenyl of 2-(4-fluorophenyl)-5-[(5-) methyl] thiophene.
Wherein the alkaline reagents of the use of step (2) one of is following reagent: organic bases, as sodium methylate, sodium ethylate, sodium-acetate, Potassium ethanoate, sodium amide, trityl sodium, potassium tert.-butoxide, pyridine, piperidines, Trimethylamine 99, triethylamine, tripropyl amine or diisopropyl ethyl amine etc.; Mineral alkali, as salt of wormwood, sodium carbonate, saleratus, sodium bicarbonate, sodium hydroxide, potassium hydroxide, compound (V) is 1:1-1:3 with the consumption mol ratio of alkali.
Wherein the reaction solvent of step (2) is the mixed solvent of one or both and multiple mentioned reagent of DMF, dioxane, tetrahydrofuran (THF), DMSO, methylene dichloride, trichloromethane (chloroform), toluene, acetone.Temperature of reaction can be 0 ℃-60 ℃ as preferable reaction temperature at 0 ℃-200 ℃, and the reaction times is as the criterion to react completely, and can be 30 minutes to 24 hours.
The clean preparation method of a kind of Ka Gelie provided by the invention, wherein step (3) alkaline reagents used is one of following: organic bases, as sodium methylate, sodium ethylate, sodium-acetate, Potassium ethanoate, sodium amide, trityl sodium, potassium tert.-butoxide, pyridine, piperidines, Trimethylamine 99, triethylamine, tripropyl amine or diisopropyl ethyl amine etc.; Mineral alkali, as salt of wormwood, sodium carbonate, saleratus, sodium bicarbonate, sodium hydroxide, potassium hydroxide, preferably alkaline reagents is sodium methylate.
Wherein the reaction solvent of step (3) is the mixed solvent of one or both and multiple mentioned reagent of methyl alcohol, ethanol, Virahol, propyl carbinol, the trimethyl carbinol, methylene dichloride, ethyl acetate, butylacetate, ether, methyl tertiary butyl ether, isopropyl ether, trichloromethane (chloroform), acetone etc.Temperature of reaction can be 20 ℃-80 ℃ as preferable reaction temperature at 0 ℃-200 ℃, and the reaction times is as the criterion to react completely, and can be 30 minutes to 24 hours.
Advantage of the present invention:
(1) the clean method of Ka Gelie of preparing of the present invention, adopt palladium catalyst catalytic synthetic techniques, synthetic route shortens dramatically, and only has three steps, simplified operating procedure, reaction conditions is comparatively gentle, and aftertreatment is simple and easy to do, is more suitable for industrialization production requirements, not only save production time and labour cost, and reduced production cost, and having increased substantially the yield of reaction, this route total recovery reaches more than 60%;
(2) when preparing compound (VI), this route is taked first by compound (II) four pivaloyl groups-alpha-D-bromo Glucopyranose and connection boric acid pinacol ester generation substitution reaction, boric acid pinacol ester group in the compound obtaining (IV) is more easily left away, and has improved reaction yield;
(3) by compound (II), obtained in the process of compound (VI), this route adopts the method for carrying out two-step reaction in same reaction system, at compound (II) through reacting and obtain after compounds Ⅳ with connection boric acid pinacol ester, without aftertreatment, directly in former reaction system, add compound (V) to react and obtain compound (VI), simplified operating procedure, shortened the production cycle, aftertreatment is simple and easy to do, improved the yield of reaction, reduced production cost, after the catalyst reaction using in route, be easy to remove, be more suitable for industrialized production.
embodiment:
Following examples are to further illustrate of the present invention, include but not limited to following examples.Below with reference to embodiment, elaborate the present invention, but it will be appreciated by those skilled in the art that the present invention is not limited to the preparation method of these embodiment and use.And those skilled in the art can be equal to replacement, combination, improvement or modify the present invention according to description of the invention, but these all will comprise within the scope of the invention.
embodiment 1
The preparation of (1) four pivaloyl groups-alpha-D-Glucopyranose boric acid pinacol ester (IV)
Under nitrogen protection, in 50ml reaction flask, by [1, two (diphenylphosphino) ferrocene of 1'-] palladium chloride (PdCl2 (dppf)) (0.22g, 0.3mmol), Potassium ethanoate (3.0g, 30mmol) and connection boric acid pinacol ester (2.8g, 10mmol) be dissolved in 12ml DMSO, separately add four pivaloyl groups-alpha-D-bromo Glucopyranose (5.8g, 10mmol), temperature control, in 80 ℃, reacts 8 hours, reacts complete, without aftertreatment, directly carry out next step reaction;
(2) three (PAs)-(2S, 3S, 4R, 5R, 6R)-2-(3-((5-(4-fluorophenyl) thiophene-2-yl) methyl)-4-aminomethyl phenyl)-6-(oxy acid methyl neopentyl) tetrahydrochysene-2H-pyrans-3, the preparation of 4,5-, tri-base esters (VI)
In the reaction solution of above-mentioned reaction, add the iodo-2-aminomethyl phenyl of compound (V) 2-(4-fluorophenyl)-5-[(5-) methyl] thiophene (4.9g, 12mmol), temperature control, in 15 ℃, reacts 4 hours, react complete, with ethyl acetate/water extraction (V/V=1:1), water layer, with ethyl acetate washed twice, merges organic layer, anhydrous sodium sulfate drying, concentrated (7.7g) total recovery of compound (VI) that obtains: 85%;
(3) (1S)-1,5-dehydrogenation-1-C-[3-[[5-(4-fluorophenyl)-2-thienyl] methyl]-4-aminomethyl phenyl] preparation of-D-Glucose alcohol (Ka Gelie is clean)
In 50ml reaction flask, add compound VI (4.0g, 5mmol) and 20ml methyl alcohol, stirring at room, dissolves, and adds sodium methylate (28% methanol solution), temperature control is in 60 ℃, react 16 hours, be cooled to room temperature, the yellow solution obtaining adds 7ml water and crystal seed, in-5 ℃, stir 1 hour, filtration obtains target compound Ka Gelie clean (1. 8g), yield 88%, purity 94%.m.p:105-107℃;ESI-MS:445(MH
+).
1HNMR(CD3OD)?δ7.5(m,2H),7.3(m,1H),7.25(d,1H,J=7.8Hz),7.15(d,1H,J=7.8Hz),7.0(m,3H),6.7(m,1H),4.9(s,4H),4.2(s,2H),4.1(m,1H),3.9(d,1H,J=12.0Hz),3.7(d,1H,J=12.0Hz),3.45(m,4H),2.3(s,3H)。
embodiment 2
The preparation of (1) four pivaloyl groups-alpha-D-Glucopyranose boric acid pinacol ester (IV)
Under nitrogen protection, in 50ml reaction flask, two (triphenylphosphine) ferrocene are closed to Palladous chloride (0.21g, 0.3mmol), salt of wormwood (4.1g, 30mmol) and connection boric acid pinacol ester (2.8g, 10mmol) be dissolved in 12ml DMF, separately add four pivaloyl groups-alpha-D-bromo Glucopyranose (5.8g, 10mmol), temperature control is in 80 ℃, react 10 hours, react complete, without aftertreatment, directly carry out next step reaction;
(2) three (PAs)-(2S, 3S, 4R, 5R, 6R)-2-(3-((5-(4-fluorophenyl) thiophene-2-yl) methyl)-4-aminomethyl phenyl)-6-(oxy acid methyl neopentyl) tetrahydrochysene-2H-pyrans-3, the preparation of 4,5-, tri-base esters (VI)
In the reaction solution of above-mentioned reaction, add the bromo-2-aminomethyl phenyl of compound (V) 2-(4-fluorophenyl)-5-[(5-) methyl] thiophene (4.9g, 12mmol), temperature control is in 20 ℃, react 8 hours, react complete, with methylene dichloride/water extraction (V/V=1:1), water layer is with twice of washed with dichloromethane, merge organic layer, anhydrous magnesium sulfate drying, concentrates and obtains compound (VI) (7.0g), total recovery: 75%;
(3) (1S)-1,5-dehydrogenation-1-C-[3-[[5-(4-fluorophenyl)-2-thienyl] methyl]-4-aminomethyl phenyl] preparation of-D-Glucose alcohol (Ka Gelie is clean)
In 50ml reaction flask, add in compound VI (4.0g, 5mmol) and 20ml methyl alcohol, stirring at room makes it to dissolve, add sodium methylate (28% methanol solution), temperature control, in 60 ℃, reacts 16 hours, be cooled to room temperature, the yellow solution obtaining adds 7ml water and crystal seed, in-5 ℃ of stirrings 1 hour, filters and obtains target compound Ka Gelie clean (1.7g), yield 85%, purity 90%.m.p:105-107℃;ESI-MS:445(MH
+).
1HNMR(CD3OD)?δ7.5(m,2H),7.3(m,1H),7.25(d,1H,J=7.8Hz),7.15(d,1H,J=7.8Hz),7.0(m,3H),6.7(m,1H),4.9(s,4H),4.2(s,2H),4.1(m,1H),3.9(d,1H,J=12.0Hz),3.7(d,1H,J=12.0Hz),3.45(m,4H),2.3(s,3H)。
Above-described embodiment is preferably embodiment of the present invention; but embodiments of the present invention are not subject to the restriction of embodiment; other is any does not deviate from change, modification, the combination made under spirit of the present invention and principle, substitute, simplify and all should be equivalent substitute mode, within being included in protection scope of the present invention.
Claims (8)
1. the clean preparation method of Yi Zhong Ka Gelie, is characterized in that comprising the following steps:
(1) four pivaloyl groups-alpha-D-bromo Glucopyranose generates four pivaloyl groups-alpha-D-Glucopyranose boric acid pinacol ester with connection boric acid pinacol ester generation electrophilic substitution reaction;
(2) the iodo-2-aminomethyl phenyl of 2-(4-fluorophenyl)-5-[(5-) methyl] thiophene or the bromo-2-aminomethyl phenyl of 2-(4-fluorophenyl)-5-[(5-) methyl] thiophene reacts with four pivaloyl groups-alpha-D-Glucopyranose boric acid pinacol ester and generates three (2,2-neopentanoic acid)-(2S, 3S, 4R, 5R, 6R)-2-(3-((5-(4-fluorophenyl) thiophene-2-yl) methyl)-4-aminomethyl phenyl)-6-(oxy acid methyl neopentyl) tetrahydrochysene-2H-pyrans-3,4,5-, tri-base esters;
(3) three (2; 2-neopentanoic acid)-(2S; 3S; 4R; 5R; 6R)-2-(3-((5-(4-fluorophenyl) thiophene-2-yl) methyl)-4-aminomethyl phenyl)-6-(oxy acid methyl neopentyl) tetrahydrochysene-2H-pyrans-3, it is clean that 4,5-, tri-base ester hydrolysis Deprotections obtain compound Ka Gelie.
2. preparation method according to claim 1, is characterized in that in electrophilic substitution reaction, using palladium catalyst in (1), and the mol ratio of four pivaloyl groups-alpha-D-bromo Glucopyranose and palladium catalyst is 20-100:1.
3. preparation method according to claim 2, it is characterized in that described palladium catalyst is Palladous chloride, palladium hydroxide, palladium, Palladous nitrate, allyl palladium chloride dimer, two (cyanobenzene) Palladous chloride, two (dibenzalacetones) close palladium, 1, two (diphenylphosphino) ferrocene of 1'-] close Palladous chloride, two (triphenylphosphine) ferrocene closes Palladous chloride, four (triphen phosphino-) palladium, three (dibenzalacetone) two palladiums, two (1, two (diphenylphosphine) ethane of 2-) palladium, dichloro two (thricyclohexyl is seen) palladium, two (three-O-toluene phosphine) palladiums of trans-dichloro, (1, 5-cyclooctadiene) palladium chloride, chlorine palladium acid sodium, three (dibenzalacetone) two palladiums-chloroform adducts, triphenylphosphine palladium acetate, two (acetonitrile) Palladous chloride, [1, the two diphenylphosphine propane of 3-] Palladous chloride or tetrakis triphenylphosphine palladium.
4. preparation method according to claim 1, is characterized in that in step (1), temperature of reaction is 0 ℃-160 ℃, and the reaction times is 30 minutes to 24 hours.
5. preparation method according to claim 1, is characterized in that in step (2), temperature of reaction is 0 ℃-200 ℃, and the reaction times is 30 minutes to 24 hours.
6. preparation method according to claim 1, is characterized in that step (3) is to be hydrolyzed under alkaline condition, and the alkaline reagents of use is organic bases or mineral alkali.
7. preparation method according to claim 6, is characterized in that organic bases is sodium methylate, sodium ethylate, sodium-acetate, Potassium ethanoate, sodium amide, trityl sodium, potassium tert.-butoxide, pyridine, piperidines, Trimethylamine 99, triethylamine, tripropyl amine or diisopropyl ethyl amine; Mineral alkali is salt of wormwood, sodium carbonate, saleratus, sodium bicarbonate, sodium hydroxide or potassium hydroxide.
8. preparation method according to claim 1, is characterized in that in step (3), temperature of reaction is 0 ℃-200 ℃, and the reaction times is 30 minutes to 24 hours.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201410377806.2A CN104109157B (en) | 2014-08-04 | 2014-08-04 | The preparation method that Ka Gelie is clean |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201410377806.2A CN104109157B (en) | 2014-08-04 | 2014-08-04 | The preparation method that Ka Gelie is clean |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN104109157A true CN104109157A (en) | 2014-10-22 |
| CN104109157B CN104109157B (en) | 2016-05-25 |
Family
ID=51706163
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201410377806.2A Active CN104109157B (en) | 2014-08-04 | 2014-08-04 | The preparation method that Ka Gelie is clean |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN104109157B (en) |
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104926803A (en) * | 2015-06-17 | 2015-09-23 | 南通常佑药业科技有限公司 | Preparation method for novel SGLT2 inhibitor medicine |
| CN105541815A (en) * | 2015-12-24 | 2016-05-04 | 寿光富康制药有限公司 | Preparation method for canagliflozin |
| CN110655511A (en) * | 2019-05-31 | 2020-01-07 | 北京莱瑞森医药科技有限公司 | Preparation and refining method of high-purity empagliflozin |
| CN112375076A (en) * | 2020-11-23 | 2021-02-19 | 黄冈鲁班药业股份有限公司 | Novel method for synthesizing canagliflozin |
| CN115028616A (en) * | 2022-05-24 | 2022-09-09 | 上海予君生物科技发展有限公司 | Canagliflozin impurity, preparation process and application thereof, and preparation process of compounds of formula II and formula III |
Citations (3)
| 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 |
| CN102459185A (en) * | 2009-04-20 | 2012-05-16 | 田边三菱制药株式会社 | Novel thyroid hormone beta receptor agonist |
| 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 |
-
2014
- 2014-08-04 CN CN201410377806.2A patent/CN104109157B/en active Active
Patent Citations (3)
| 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 |
| CN102459185A (en) * | 2009-04-20 | 2012-05-16 | 田边三菱制药株式会社 | Novel thyroid hormone beta receptor agonist |
| 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 |
Non-Patent Citations (1)
| Title |
|---|
| JUN YI ET AL.: "Alkylboronic Esters from Palladium- and Nickel-Catalyzed Borylation of Primary and Secondary Alkyl Bromides", 《ADVANCED SYNTHESIS & CATALYSIS》, vol. 354, 30 March 2012 (2012-03-30), pages 1685 - 1691 * |
Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104926803A (en) * | 2015-06-17 | 2015-09-23 | 南通常佑药业科技有限公司 | Preparation method for novel SGLT2 inhibitor medicine |
| CN104926803B (en) * | 2015-06-17 | 2017-12-22 | 南通常佑药业科技有限公司 | A kind of preparation method of new SGLT2 inhibitor medicine |
| CN105541815A (en) * | 2015-12-24 | 2016-05-04 | 寿光富康制药有限公司 | Preparation method for canagliflozin |
| CN105541815B (en) * | 2015-12-24 | 2018-07-13 | 寿光富康制药有限公司 | A kind of preparation method of canagliflozin |
| CN110655511A (en) * | 2019-05-31 | 2020-01-07 | 北京莱瑞森医药科技有限公司 | Preparation and refining method of high-purity empagliflozin |
| CN112375076A (en) * | 2020-11-23 | 2021-02-19 | 黄冈鲁班药业股份有限公司 | Novel method for synthesizing canagliflozin |
| CN115028616A (en) * | 2022-05-24 | 2022-09-09 | 上海予君生物科技发展有限公司 | Canagliflozin impurity, preparation process and application thereof, and preparation process of compounds of formula II and formula III |
Also Published As
| Publication number | Publication date |
|---|---|
| CN104109157B (en) | 2016-05-25 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN104109157A (en) | Preparation method of canagliflozin | |
| CN1984898A (en) | Process for production of azulene derivatives and intermediates for the synthesis of the same | |
| CN104327119A (en) | Preparation method of tedizolid phosphate | |
| CN104926803B (en) | A kind of preparation method of new SGLT2 inhibitor medicine | |
| CN108675976A (en) | A kind of halogenated glucose carbon glycosides of 6- and its preparation method and application | |
| CN104529970A (en) | Method for preparing Dapagliflozin | |
| CN103159662B (en) | Method for preparing pyrrole derivative with sulfonyl group on beta-substituent | |
| CN102952135A (en) | Synthesis method for medicine entecavir for treating hepatitis B | |
| CN109456315A (en) | Carbon-aryl glycoside class SGLT-2 inhibitor precursor and its synthetic method | |
| CN104177331A (en) | Preparation method of bilastine | |
| CN102153601A (en) | Method for preparing gemcitabine hydrochloride and intermediate thereof with high selectivity | |
| CN102180914A (en) | Preparation method of 2-deoxidizing-D-glucose | |
| CN105732648A (en) | Nitrogen heterocyclic ring compound of pyrrolofuran and synthetic method | |
| CN101735300B (en) | Method for preparing 6beta,7beta-methylene-steride-3beta,5beta-diol | |
| CN102807563B (en) | Method for preparing voriconazole and intermediate thereof | |
| CN101993464B (en) | Preparation method of capecitabine | |
| CN105541815B (en) | A kind of preparation method of canagliflozin | |
| CN103709030A (en) | Environmentally-friendly preparation method of ciprofibrate | |
| CN105669513A (en) | Preparation method of polysubstituted 3-alkynyl pyrrole derivative | |
| CN105017284A (en) | Preparation method for ceftizoxime alapivoxil, intermediates thereof and preparation method for intermediates | |
| CN102079720B (en) | Method for preparing 1-benzylpiperidine-4-carboxaldehyde | |
| CN102093247B (en) | Preparation method of 2-methyl-4-N-(2-methylbenzoyl)benzoic acid | |
| CN104610215A (en) | Preparation method of nebivolol intermediates and preparation method of nebivolol | |
| CN104513225A (en) | Preparation method of 2-thiopheneacetonitrile | |
| CN114751864B (en) | Polysubstituted imidazole derivative and preparation method thereof |
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 | ||
| TR01 | Transfer of patent right |
Effective date of registration: 20191204 Address after: 257400 Shandong city of Dongying province Lijin County Jin Road No. 198 two Patentee after: SHANDONG PHOENIX PHARMACEUTICAL Co.,Ltd. Address before: 250101 production building, No. 2766, show Road, hi tech Zone, Shandong, Ji'nan 1-101-501 Patentee before: SHANDONG KANGMEILE PHARMACEUTICAL TECHNOLOGY Co.,Ltd. |
|
| TR01 | Transfer of patent right | ||
| PE01 | Entry into force of the registration of the contract for pledge of patent right |
Denomination of invention: Preparation method of canagliflozin Effective date of registration: 20231124 Granted publication date: 20160525 Pledgee: Shandong Lijin Rural Commercial Bank Co.,Ltd. Pledgor: SHANDONG PHOENIX PHARMACEUTICAL Co.,Ltd. Registration number: Y2023980067591 |
|
| PE01 | Entry into force of the registration of the contract for pledge of patent right |