CN106336403A - Industrial preparation method for empagliflozin - Google Patents
Industrial preparation method for empagliflozin Download PDFInfo
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- CN106336403A CN106336403A CN201510413692.7A CN201510413692A CN106336403A CN 106336403 A CN106336403 A CN 106336403A CN 201510413692 A CN201510413692 A CN 201510413692A CN 106336403 A CN106336403 A CN 106336403A
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- Prior art keywords
- palie
- acid
- compound
- formula
- net preparation
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- 238000002360 preparation method Methods 0.000 title claims abstract description 29
- OBWASQILIWPZMG-QZMOQZSNSA-N empagliflozin Chemical compound O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@H]1C1=CC=C(Cl)C(CC=2C=CC(O[C@@H]3COCC3)=CC=2)=C1 OBWASQILIWPZMG-QZMOQZSNSA-N 0.000 title abstract description 5
- 229960003345 empagliflozin Drugs 0.000 title abstract description 5
- 238000000034 method Methods 0.000 claims abstract description 15
- 150000001875 compounds Chemical class 0.000 claims description 33
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical group CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 21
- 238000006243 chemical reaction Methods 0.000 claims description 21
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 18
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 18
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 17
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 12
- 239000002253 acid Substances 0.000 claims description 12
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 9
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-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
- VSCWAEJMTAWNJL-UHFFFAOYSA-K aluminium trichloride Chemical compound Cl[Al](Cl)Cl VSCWAEJMTAWNJL-UHFFFAOYSA-K 0.000 claims description 8
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 7
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 claims description 6
- 239000002841 Lewis acid Substances 0.000 claims description 6
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 claims description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical group [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 6
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 claims description 6
- WTEOIRVLGSZEPR-UHFFFAOYSA-N boron trifluoride Chemical compound FB(F)F WTEOIRVLGSZEPR-UHFFFAOYSA-N 0.000 claims description 6
- 150000007517 lewis acids Chemical class 0.000 claims description 6
- 150000002902 organometallic compounds Chemical class 0.000 claims description 6
- 239000003513 alkali Substances 0.000 claims description 5
- KZMGYPLQYOPHEL-UHFFFAOYSA-N Boron trifluoride etherate Chemical compound FB(F)F.CCOCC KZMGYPLQYOPHEL-UHFFFAOYSA-N 0.000 claims description 4
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 4
- BLRPTPMANUNPDV-UHFFFAOYSA-N Silane Chemical group [SiH4] BLRPTPMANUNPDV-UHFFFAOYSA-N 0.000 claims description 4
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 4
- 239000000654 additive Substances 0.000 claims description 4
- 230000000996 additive effect Effects 0.000 claims description 4
- 239000003638 chemical reducing agent Substances 0.000 claims description 4
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 claims description 4
- 239000012046 mixed solvent Substances 0.000 claims description 4
- 239000000203 mixture Substances 0.000 claims description 4
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 4
- 239000001117 sulphuric acid Substances 0.000 claims description 4
- 235000011149 sulphuric acid Nutrition 0.000 claims description 4
- GETQZCLCWQTVFV-UHFFFAOYSA-N trimethylamine Chemical compound CN(C)C GETQZCLCWQTVFV-UHFFFAOYSA-N 0.000 claims description 4
- 229910015900 BF3 Inorganic materials 0.000 claims description 3
- 238000005917 acylation reaction Methods 0.000 claims description 3
- 150000008044 alkali metal hydroxides Chemical class 0.000 claims description 3
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 3
- 229910052500 inorganic mineral Inorganic materials 0.000 claims description 3
- 229940098779 methanesulfonic acid Drugs 0.000 claims description 3
- 239000011707 mineral Substances 0.000 claims description 3
- 150000007524 organic acids Chemical class 0.000 claims description 3
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 claims description 2
- 235000019253 formic acid Nutrition 0.000 claims description 2
- 229910000765 intermetallic Inorganic materials 0.000 claims description 2
- GLXDVVHUTZTUQK-UHFFFAOYSA-M lithium;hydroxide;hydrate Chemical compound [Li+].O.[OH-] GLXDVVHUTZTUQK-UHFFFAOYSA-M 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 claims description 2
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 claims description 2
- 239000002904 solvent Substances 0.000 claims description 2
- 239000003795 chemical substances by application Substances 0.000 claims 2
- 241001597008 Nomeidae Species 0.000 claims 1
- 238000013341 scale-up Methods 0.000 claims 1
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 abstract description 7
- 238000011031 large-scale manufacturing process Methods 0.000 abstract description 3
- 229960002920 sorbitol Drugs 0.000 abstract 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 15
- 208000035126 Facies Diseases 0.000 description 14
- 239000000376 reactant Substances 0.000 description 11
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 10
- 238000003756 stirring Methods 0.000 description 10
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 9
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 8
- 239000002585 base Substances 0.000 description 8
- 239000000243 solution Substances 0.000 description 8
- 235000002639 sodium chloride Nutrition 0.000 description 7
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 6
- 150000002118 epoxides Chemical class 0.000 description 6
- 239000000047 product Substances 0.000 description 6
- -1 t-Butyldimethylsilyl Epoxide Chemical class 0.000 description 6
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 5
- 239000007864 aqueous solution Substances 0.000 description 5
- 239000000706 filtrate Substances 0.000 description 5
- 239000011780 sodium chloride Substances 0.000 description 5
- 229960002668 sodium chloride Drugs 0.000 description 5
- 238000005406 washing Methods 0.000 description 5
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 4
- YLQBMQCUIZJEEH-UHFFFAOYSA-N Furan Chemical compound C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 4
- 239000008346 aqueous phase Substances 0.000 description 4
- 239000003153 chemical reaction reagent Substances 0.000 description 4
- 239000007788 liquid Substances 0.000 description 4
- 239000008213 purified water Substances 0.000 description 4
- 235000017557 sodium bicarbonate Nutrition 0.000 description 4
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 4
- PHOQVHQSTUBQQK-SQOUGZDYSA-N D-glucono-1,5-lactone Chemical compound OC[C@H]1OC(=O)[C@H](O)[C@@H](O)[C@@H]1O PHOQVHQSTUBQQK-SQOUGZDYSA-N 0.000 description 3
- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 description 3
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 3
- 238000001035 drying Methods 0.000 description 3
- 239000012065 filter cake Substances 0.000 description 3
- 235000012209 glucono delta-lactone Nutrition 0.000 description 3
- 239000000182 glucono-delta-lactone Substances 0.000 description 3
- 229960003681 gluconolactone Drugs 0.000 description 3
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 3
- 229910052751 metal Inorganic materials 0.000 description 3
- 239000002184 metal Substances 0.000 description 3
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 3
- 229960000549 4-dimethylaminophenol Drugs 0.000 description 2
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 2
- 229910052799 carbon Inorganic materials 0.000 description 2
- 230000018044 dehydration Effects 0.000 description 2
- 238000006297 dehydration reaction Methods 0.000 description 2
- 229960004756 ethanol Drugs 0.000 description 2
- 238000000605 extraction Methods 0.000 description 2
- 229910052736 halogen Inorganic materials 0.000 description 2
- 238000010438 heat treatment Methods 0.000 description 2
- 230000000977 initiatory effect Effects 0.000 description 2
- DLEDOFVPSDKWEF-UHFFFAOYSA-N lithium butane Chemical compound [Li+].CCC[CH2-] DLEDOFVPSDKWEF-UHFFFAOYSA-N 0.000 description 2
- KWGKDLIKAYFUFQ-UHFFFAOYSA-M lithium chloride Chemical compound [Li+].[Cl-] KWGKDLIKAYFUFQ-UHFFFAOYSA-M 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 238000001465 metallisation Methods 0.000 description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 2
- MZRVEZGGRBJDDB-UHFFFAOYSA-N n-Butyllithium Substances [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 2
- 229910052757 nitrogen Inorganic materials 0.000 description 2
- 125000001979 organolithium group Chemical group 0.000 description 2
- 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- 238000001953 recrystallisation Methods 0.000 description 2
- 150000003839 salts Chemical class 0.000 description 2
- 238000001291 vacuum drying Methods 0.000 description 2
- 238000010792 warming Methods 0.000 description 2
- 0 *C(C[C@@]1O*)(c(cc2Cc(cc3)ccc3O[C@@]3COCC3)ccc2Cl)O[C@](CO)[C@]1O Chemical compound *C(C[C@@]1O*)(c(cc2Cc(cc3)ccc3O[C@@]3COCC3)ccc2Cl)O[C@](CO)[C@]1O 0.000 description 1
- LCPVQAHEFVXVKT-UHFFFAOYSA-N 2-(2,4-difluorophenoxy)pyridin-3-amine Chemical compound NC1=CC=CN=C1OC1=CC=C(F)C=C1F LCPVQAHEFVXVKT-UHFFFAOYSA-N 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 description 1
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Chemical compound OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 1
- 239000007818 Grignard reagent Substances 0.000 description 1
- 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 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- 229940123518 Sodium/glucose cotransporter 2 inhibitor Drugs 0.000 description 1
- 102100037202 Sodium/myo-inositol cotransporter 2 Human genes 0.000 description 1
- 101710090560 Sodium/myo-inositol cotransporter 2 Proteins 0.000 description 1
- 235000009392 Vitis Nutrition 0.000 description 1
- 241000219095 Vitis Species 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 150000008064 anhydrides Chemical class 0.000 description 1
- 229910052786 argon Inorganic materials 0.000 description 1
- UHOVQNZJYSORNB-UHFFFAOYSA-N benzene Substances C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 1
- 229960002246 beta-d-glucopyranose Drugs 0.000 description 1
- 150000001721 carbon Chemical group 0.000 description 1
- 239000000460 chlorine Substances 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 125000004803 chlorobenzyl group Chemical group 0.000 description 1
- NEHMKBQYUWJMIP-UHFFFAOYSA-N chloromethane Chemical class ClC NEHMKBQYUWJMIP-UHFFFAOYSA-N 0.000 description 1
- 239000012141 concentrate Substances 0.000 description 1
- 238000009833 condensation Methods 0.000 description 1
- 230000005494 condensation Effects 0.000 description 1
- 229960000935 dehydrated alcohol Drugs 0.000 description 1
- 206010012601 diabetes mellitus Diseases 0.000 description 1
- 235000005911 diet Nutrition 0.000 description 1
- 230000037213 diet Effects 0.000 description 1
- 238000002651 drug therapy Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000010828 elution Methods 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- KCWYOFZQRFCIIE-UHFFFAOYSA-N ethylsilane Chemical compound CC[SiH3] KCWYOFZQRFCIIE-UHFFFAOYSA-N 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 239000000284 extract Substances 0.000 description 1
- 229930182478 glucoside Natural products 0.000 description 1
- 150000008131 glucosides Chemical class 0.000 description 1
- 229930182470 glycoside Natural products 0.000 description 1
- 150000004795 grignard reagents Chemical class 0.000 description 1
- 150000002367 halogens Chemical class 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
- 150000002500 ions Chemical class 0.000 description 1
- 239000007791 liquid phase Substances 0.000 description 1
- FUJCRWPEOMXPAD-UHFFFAOYSA-N lithium oxide Chemical compound [Li+].[Li+].[O-2] FUJCRWPEOMXPAD-UHFFFAOYSA-N 0.000 description 1
- 229910001947 lithium oxide Inorganic materials 0.000 description 1
- UBJFKNSINUCEAL-UHFFFAOYSA-N lithium;2-methylpropane Chemical compound [Li+].C[C-](C)C UBJFKNSINUCEAL-UHFFFAOYSA-N 0.000 description 1
- WGOPGODQLGJZGL-UHFFFAOYSA-N lithium;butane Chemical compound [Li+].CC[CH-]C WGOPGODQLGJZGL-UHFFFAOYSA-N 0.000 description 1
- TWRXJAOTZQYOKJ-UHFFFAOYSA-L magnesium chloride Substances [Mg+2].[Cl-].[Cl-] TWRXJAOTZQYOKJ-UHFFFAOYSA-L 0.000 description 1
- 229910001629 magnesium chloride Inorganic materials 0.000 description 1
- 150000002681 magnesium compounds Chemical class 0.000 description 1
- 150000002736 metal compounds Chemical class 0.000 description 1
- 235000010755 mineral Nutrition 0.000 description 1
- 229910000402 monopotassium phosphate Inorganic materials 0.000 description 1
- 235000019796 monopotassium phosphate Nutrition 0.000 description 1
- 229910052756 noble gas Inorganic materials 0.000 description 1
- 150000002835 noble gases Chemical class 0.000 description 1
- 125000002734 organomagnesium group Chemical group 0.000 description 1
- AICOOMRHRUFYCM-ZRRPKQBOSA-N oxazine, 1 Chemical compound C([C@@H]1[C@H](C(C[C@]2(C)[C@@H]([C@H](C)N(C)C)[C@H](O)C[C@]21C)=O)CC1=CC2)C[C@H]1[C@@]1(C)[C@H]2N=C(C(C)C)OC1 AICOOMRHRUFYCM-ZRRPKQBOSA-N 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-O oxonium Chemical compound [OH3+] XLYOFNOQVPJJNP-UHFFFAOYSA-O 0.000 description 1
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N phenol group Chemical group C1(=CC=CC=C1)O ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 1
- PJNZPQUBCPKICU-UHFFFAOYSA-N phosphoric acid;potassium Chemical compound [K].OP(O)(O)=O PJNZPQUBCPKICU-UHFFFAOYSA-N 0.000 description 1
- 238000011020 pilot scale process Methods 0.000 description 1
- 238000011946 reduction process Methods 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- CHQMHPLRPQMAMX-UHFFFAOYSA-L sodium persulfate Substances [Na+].[Na+].[O-]S(=O)(=O)OOS([O-])(=O)=O CHQMHPLRPQMAMX-UHFFFAOYSA-L 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 238000010200 validation analysis Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D407/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00
- C07D407/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings
- C07D407/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- 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)
Abstract
The invention discloses an industrial preparation method for empagliflozin. Specifically, the invention relates to a preparation method for empagliflozin as shown in formula as defined in the specification, i.e., (1S)-1,5-dehydro-1-(4-chloro-3{4-[(3S)-tetrahydrofuran-3-yloxy]benzyl}pheyl)-D-glucitol, and an intermediate prepared by using the method. The preparation method for empagliflozin in the invention is stable in process, good in reproducibility and suitable for large-scale production.
Description
Technical field
The present invention relates to medicinal chemistry arts and in particular to a kind of Yi Palie be only (1s) 1,5 take off
The work of water 1 (4 chlorine 3 { 4 [(3s) oxolane 3 base epoxide] benzyl } phenyl) d glucitol
Industry preparation method.
Background technology
The diabetes epidemiology of 200 years diabetology branch of Chinese Medical Association (cds) tissues
Survey result shows, estimates that China adult prevalence rate of more than 20 years old is 9.7%, adult patient
Sum reaches 92,400,000 people, and China is likely to become the most country of number of patients in the world.China
More than 90% diabeticss are ii patients with type Ⅰ DM, except fraction is through Diet Therapy and motion
Treat beyond the ii patients with type Ⅰ DM patient that can control, all need Drug therapy.Yi Palie is net, full name:
(1s) -1,5- dehydration -1- (the chloro- 3- of 4- { 4- [(3s)-oxolane -3- base epoxide] benzyl } phenyl)-d- Portugal
Grape sugar alcohol, English name: empagliflozin, its structural formula is as follows:
Yi Palie, only by boehringeringelheim and eli lilly joint development, is a kind of sodium
Dependent glucose cotransporter sglt2 inhibitor, for treating ii patients with type Ⅰ DM,
This product has very big market potential and growth space.
Document with regard to Yi Palie net system Preparation Method and patent have two methods, are summarized as follows:
Method 1:
Patent cn103030617a reports the net preparation method of following Yi Palie:
This route is with glucono-δ-lactone and the chloro- 4- of 1- bromo- 2- [4- (t-Butyldimethylsilyl
Epoxide)-benzyl]-benzene be initiation material, the ratio of addition compound product beta/alpha mixture after silica gel purification
Example is 6:1, needs the dichloromethane solution through acetic anhydride and pyridine by its hydroxyl completely acylated,
And in ethanol recrystallization and be converted into pure beta isomer, then in methyl alcohol with potassium hydroxide
Solution reaction.In this route, final step reaction is related to the change of chiral carbon atom configuration, that is,
Phenolic hydroxyl group intermediate is reacted with (r)-oxolane -3- base -4- toluene sulfonic acide ester under alkali effect
Obtain finished product, the content of isomer of finished product is difficult to control to, this route yield is relatively low simultaneously, thus
Be not suitable for amplifying and produce.
Method 2:
It is net that patent cn102574829a and cn101193903b report following Yi Palie
Preparation method:
This route with glucono-δ-lactone and (s) -3- (4- (the chloro- benzyl of the iodo- 2- of 5-) phenoxy group) -
Oxolane be initiation material, sequentially pass through the three-step reactions such as protection, condensation, reduction obtain according to
Handkerchief row are net, but reduce in this route counter need to carry out in anhydrous conditions, moisture presence can be led
Cause to produce impurity (structure is as follows) in reduction process, therefore this technique is not suitable for amplifying and produces.
The invention that aims at of the present invention a kind of prepares the net new method of Yi Palie.
Content of the invention
It is an object of the invention to solution above-mentioned technical problem, provide that a kind of to prepare Yi Palie net
New method, this process is simple is stable, reliable product quality, be applicable to commercial production.
The technical scheme is that and realize in the following manner:
Formula i compound is removed protection group and Yi Palie is obtained only, wherein r1Represent (c1-4- alkyl)
Carbonyl.
Preferably, the method removing formula i protection group is at a temperature of between 0 to 100 DEG C,
Under the acid conditions such as trifluoroacetic acid, hydrochloric acid or sulphuric acid, or sodium hydroxide, Lithium hydrate,
In the presence of the alkali metal hydroxides such as potassium hydroxide, hydrolysis removes.
Formula i compound is to be obtained by the reduction of formula ii compound, wherein r1And r2As above
Defined.
Preferably, the method for described formula ii compound reduction is in lewis acid such as boron trifluoride
Ether or aluminum chloride and reaction dissolvent such as acetonitrile, acetonitrile/toluene Mixed Solvent or acetonitrile/bis-
In the presence of chloromethanes mixed solvent, at 0～50 DEG C of temperature, formula i is reduced by reducing agent
Compound, described reducing agent is selected from silane derivative, preferably trialkylsilane, and more preferably three
Ethylsilane.
Formula ii compound is to be acylated formula iii compound with acylating reagents such as carboxylic acid halides, anhydride
Reaction is obtained.
Preferably, acylation reaction is carried out in the presence of a base: described alkali be selected from triethylamine,
Trimethylamine, n, n- diisopropylethylamine, pyridine and DMAP.
Formula (iii) compound is to be prepared into its organo-metallic compound (v) by formula (iv) compound,
Additive reaction is occurred to be obtained by metallic compound (v) and formula (vi) again, r2、r3、x
With m as hereinbefore defined.
Preferably, formula v compound be by formula iv compound through halogen-metal exchange reaction or
Metal is inserted in carbon-halogen bond and is obtained.Preferably, formula v metal compound can use
The organolithium reagents such as n-BuLi, s-butyl lithium or tert-butyl lithium, described organolithium reagent is preferred
Amount be in the range of about 1 to 2 mole.Alternatively, formula v metallization
Thing can also use Grignard reagent, preferably c3-4- alkyl magnesium chloride thing or bromide, in lithium chloride
Do not exist etc. the other salts that can accelerate metallization processes or in the presence of, by halogen
- metal exchange can generate similar magnesium compound, and it is about 1 to 5 to rub that organomagnesium reagent is preferably measured
In the range of you.
Preferably between -100 to 40 DEG C, more preferably between -80 to -10 DEG C, in inertia
In solvent or its mixture, formula v compound is added in formula vi compound or derivatives thereof,
Then hydroxyl protecting group is removed by addition compound product in acid condition, and form sugar with alcohol
Glycosides.Preferably, described acid is selected from the mineral acids such as hydrochloric acid, sulphuric acid；Formic acid, acetic acid, trifluoro
The organic acid such as acetic acid, methanesulfonic acid；The lewis acids such as boron trifluoride, aluminum chloride.For being formed
The alcohol of glucosides is selected from the alkylols such as methanol, ethanol, normal propyl alcohol.
All above reactions all can be carried out in atmosphere, preferably in the noble gases such as argon or nitrogen
Carry out under environment.
Inventor passes through lot of experiment validation, the stable processing technique of the present invention, and reproducibility is good,
Suitable large-scale production, especially goes for pilot scale and workshop large-scale production.
Specific embodiment
In order to further illustrate the present invention, below in conjunction with specific embodiment, the present invention is had
Body illustrates, but protection scope of the present invention is not limited to specific embodiment.
Embodiment 1:2,3,4,6- tetra--o- trimethyl silicon substrate-d- glucono-δ-lactone
3.6kg glucono-δ-lactone, 36l tetrahydrochysene furan is added in 100l low-temp reaction kettle
Mutter and 16kg n- methyl morpholine, stirring and dissolving, reactant liquor is cooled to Deca 12kg after -5～5 DEG C
Trim,ethylchlorosilane.Completion of dropping, reactant liquor is transferred in 100l reactor, 10～30 DEG C of temperature control
Reaction 16～18 hours.
Reactant liquor is cooled to 0～10 DEG C, adds 30l purified water, point liquid, collect organic faciess,
Aqueous phase 30l normal heptane extraction, merges organic faciess and uses 5% potassium dihydrogen phosphate aqueous solution successively
Washing (20l × 2), 20% sodium-chloride water solution washing (20l × 1).Organic faciess anhydrous slufuric acid
Sodium is dried, and filters, and filtrate reduced in volume is extremely dry to obtain title compound 9.5kg, molar yield
100.7%.
Embodiment 2: methyl isophthalic acid-c- (the chloro- 3- of 4- { 4- [(3s)-oxolane -3- base epoxide] benzyl }
Phenyl)-d- pyranglucoside
15l oxolane, 15l toluene and 4.8kg (s) -3- (4- (5- is added in 100l reactor
Iodo- 2- chlorobenzyl) phenoxy group) oxolane, stirring and dissolving, under nitrogen protection, reactant liquor is lowered the temperature
To -80～-70 DEG C, Deca 7l 2.5m n-BuLi hexane solution, completion of dropping temperature control reacts
1～1.5 hour.Control -80～-70 DEG C of Deca 2,3,4,6- of temperature tetra--o- trimethyl silicon substrate-d- Fructus Vitis viniferae
The toluene solution (9.5kg, 10l) of saccharic acid-delta-lactone, the reaction 2～2.5 of completion of dropping temperature control is little
When.It is slowly added to the methanol solution (5kg, 40l) of methanesulfonic acid, after adding, be warming up to 20～30 DEG C
Reaction 16～18 hours.
Reactant liquor is transferred in 300l reactor, add 50l 8% sodium bicarbonate aqueous solution and
50l ethyl acetate, collects organic faciess, and aqueous phase extracts twice (40l × 2) with ethyl acetate again,
Merge organic faciess.Organic faciess are successively using 50l purification water washing, 50l 20% aqueous sodium chloride
Liquid wash, organic faciess anhydrous sodium sulfate drying, filter, filtrate reduced in volume to about 20l, plus
Enter the stirring of 8l toluene, be slowly added in 200l normal heptane, rejection filter after stirring 0.5～1 hour,
Collection solid obtains title compound and directly throws next step.
Embodiment 3: methyl -2,3,4,6- four-o- acetyl group -1-c- (the chloro- 3- of 4- { 4- [(3s)-tetrahydrochysene furan
Mutter -3- base epoxide] benzyl } phenyl)-d- pyranglucoside
Add embodiment 2 gained compound and 50l dichloromethane in 100l reactor, stir
Mix dissolving, reactant liquor is cooled to after -5～5 DEG C and sequentially adds 7.5l pyridine, 8.7l acetic anhydride
With 50g DMAP.Reactant liquor is transferred in 200l reactor, temperature control
10～30 DEG C are reacted 1.5～2 hours.
Add 75l purified water in reactant liquor, point liquid, collect organic faciess, aqueous phase uses 50l again
Dichloromethane extraction, merges organic faciess.Organic faciess use 1mol/l salt acid elution successively
(50l × 2), 8% sodium bicarbonate aqueous solution washing (50l × 1), 20% sodium chloride solution washing
(50l × 2), collect organic faciess and use anhydrous sodium sulfate drying, filter, filtrate reduced in volume is extremely
Do to obtain title compound 4.7kg, molar yield 62.6% is (with (s) -3- (4- (5- iodo- 2- chlorobenzyl)
Phenoxy group) oxolane) calculate, two step molar yields).
Embodiment 4:2,3,4,6- tetra--o- acetyl group -1-c- (the chloro- 3- of 4- { 4- [(3s)-oxolane -3-
Base epoxide] benzyl } phenyl)-β-d- Glucopyranose.
Add embodiment 3 gained compound, 18l acetonitrile and 130g pure in 50l reactor
Change water, stirring and dissolving, reactant liquor be cooled to 0～10 DEG C, add 2.68kg triethyl silicane,
0～10 DEG C of Deca 4.1kg boron trifluoride diethyl etherate of temperature control, 0～10 DEG C of reaction of completion of dropping temperature control
1～1.5 hour, reactant liquor was warming up to 20～30 DEG C again and continues stirring reaction 18～20 hours.
Reactant liquor is transferred in 200l reactor, add 20l 8% sodium bicarbonate aqueous solution and
60l ethyl acetate, stirs 5～10 minutes, point liquid, and aqueous phase uses 60l ethyl acetate to extract again,
Merge organic faciess and use 30l 8% sodium bicarbonate aqueous solution and 30l 20% aqueous sodium chloride successively
Liquid washs, and collects organic faciess and uses anhydrous sodium sulfate drying, filters, and filtrate reduced in volume is extremely dry.
By concentrate with, after 100l dehydrated alcohol heating for dissolving, continuing to stir after being cooled to 0～10 DEG C
Mix 2.5～3 hours, rejection filter；Filter cake again recrystallization twice, the vacuum drying 36 of 60 DEG C of filter cake is little
When obtain title compound 2.5kg, molar yield 40.3%.
Embodiment 5:(1s) -1,5- dehydration -1- (the chloro- 3- of 4- { 4- [(3s)-oxolane -3- base epoxide]
Benzyl } phenyl)-d- glucitol
12l oxolane, 18l absolute methanol, 6l purified water is added in 50l reactor
With embodiment 4 gained compound, stirring is lower to add a hydronium(ion) lithium oxide 195g, and temperature control 10～
40 DEG C are reacted 2.5～3 hours.It is evaporated to dry, residue is dissolved in 50l ethyl acetate,
Washed with 10l purified water and 10l 20% sodium-chloride water solution successively, collect organic faciess and with no
Aqueous sodium persulfate is dried, and filters, and filtrate reduced in volume is extremely dry.
Residue 18l methylene chloride/methanol mixed solvent heating for dissolving (5/1, v/v), plus
Enter dichloromethane 75l, be stirred at room temperature 2 hours, filter, 50 DEG C of vacuum drying 12 of filter cake are little
When obtain title compound 1.25kg, molar yield 68.8%, hplc purity 99.8%.
1h nmr(500mhz,dmso-d6): δ=1.90-1.95 (m, 1h), 2.14-2.21 (m,
1h),3.09-3.32(m,4h),3.43-3.48(m,1h),3.69-3.75(m,3h),3.78-3.87
(m,2h),3.94-4.02(m,3h),4.42(t,1h),4.80-4.81(d,1h),4.91-4.96(m,
3h), 6.81-6.83 (d, j=8.7hz, 2h), 7.10-7.11 (d, j=8.6hz, 2h), 7.22-7.25
(dd,j1=1.9hz, j2=8.3hz, 1h), 7.33-7.34 (d, j=1.8hz, 1h), 7.36-7.37
(d, j=8.2hz, 1h).
13c nmr(125mhz,dmso-d6): δ=32.4,37.6,61.3,66.3,70.3,
72.2,74.7,76.9,78.3,80.6,81.1,115.2,127.3,128.6,129.6,
130.8,131.5,131.9,137.7,139.6,155.5.
Ir (kbr): 3427,3255,3038,2931,2869,1613,1580,1510,
1437,1350,1279,1241,1063,843,798.
ms(m/z):473.1339[m+na]+.
Claims (20)
1. the net preparation method of Yi Palie,
It is characterized in that, using formula (i) compound be hydrolyzed reaction remove protection group be obtained,
Wherein r1Represent (c1-4- alkyl) carbonyl.
2. the net preparation method of Yi Palie according to claim 1 it is characterised in that
The described method removing protection group is at a temperature of between 0 to 100 DEG C, exists in acid or alkali
Under conditions of remove.
3. the net preparation method of Yi Palie according to claim 2 it is characterised in that
Described acid is selected from alkali metal hydroxide selected from trifluoroacetic acid, hydrochloric acid or sulphuric acid, described alkali.
4. the net preparation method of Yi Palie according to claim 3 it is characterised in that
Described alkali metal hydroxide is selected from sodium hydroxide, Lithium hydrate or potassium hydroxide.
5. the net preparation method of Yi Palie according to claim 1 it is characterised in that
Formula (i) compound is prepared by reducing formula (ii) compound,
Wherein r1Represent (c1-4- alkyl) carbonyl；And r2Represent c1-6- alkyl.
6. the net preparation method of Yi Palie according to claim 5 it is characterised in that
The method of described formula (ii) compound reduction is in the presence of lewis acid and reaction dissolvent, leads to
Cross reducing agent to be reduced.
7. the net preparation method of Yi Palie according to claim 6 it is characterised in that
Described lewis acid is selected from boron trifluoride diethyl etherate and/or aluminum chloride.
8. the net preparation method of Yi Palie according to claim 6 it is characterised in that
It is molten that described reaction dissolvent is selected from acetonitrile, acetonitrile/toluene Mixed Solvent or acetonitrile/dichloromethane mixing
Agent.
9. the net preparation method of Yi Palie according to claim 6 it is characterised in that
Described reaction is carried out at 0～50 DEG C of temperature.
10. the net preparation method of Yi Palie according to claim 6 it is characterised in that
Described reducing agent is selected from silane derivative, preferably trialkylsilane, more preferably triethyl silicane.
The net preparation method of 11. Yi Palie according to claim 5 it is characterised in that
Formula (ii) compound is by formula (iii) compound is carried out acylation reaction, with acylated examination
Agent protection prepares,
The net preparation method of 12. Yi Palie according to claim 11 it is characterised in that
Described acylation reaction is carried out in the basic conditions.
The net preparation method of 13. Yi Palie according to claim 12 it is characterised in that
Described alkali is selected from triethylamine, trimethylamine, n, n- diisopropylethylamine, pyridine and 4- dimethylamino
Pyridine.
The net preparation method of 14. Yi Palie according to claim 11 it is characterised in that
Formula (iii) compound is to be prepared into its organo-metallic compound (v) by formula (iv) compound,
Again by metallic compound (v) and formula (vi) compound or derivatives thereof generation additive reaction,
Wherein x represents br or i；
Wherein m represents li or mg；
Wherein r3Represent three-(c1-3- alkyl) silicyl；
Subsequently by this adduct of gained after additive reaction and alcohol r2Oh reacts in presence of an acid, its
Middle r2Represent c1-6- alkyl.
The net preparation method of 15. Yi Palie according to claim 14 it is characterised in that
The temperature of described additive reaction between -100 to 40 DEG C, more preferably between -80 to -10 DEG C.
The net preparation method of 16. Yi Palie according to claim 14 it is characterised in that
In atent solvent or its mixture by formula (v) compound be added to formula (vi) compound or
In its derivant.
The net preparation method of 17. Yi Palie according to claim 14 it is characterised in that
Described acid is selected from mineral acid, organic acid or lewis acid.
The net preparation method of 18. Yi Palie according to claim 17 it is characterised in that
Described mineral acid is selected from hydrochloric acid or sulphuric acid；Described organic acid is selected from formic acid, acetic acid, trifluoroacetic acid
Or methanesulfonic acid；Described lewis acid is selected from boron trifluoride or aluminum chloride.
The net preparation method of 19. Yi Palie according to claim 17 it is characterised in that
Described alcohol is selected from methanol, ethanol or normal propyl alcohol.
The net preparation method of 20. Yi Palie according to any one in claim 1～19,
It is characterized in that, described preparation method goes for scale up test or industrial mass production.
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| CN107556302A (en) * | 2017-11-02 | 2018-01-09 | 中国医药集团总公司四川抗菌素工业研究所 | It is a kind of to prepare the net methods of Yi Palie |
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| CN112194655A (en) * | 2020-10-15 | 2021-01-08 | 通化东宝药业股份有限公司 | Preparation method of empagliflozin intermediate |
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