CN115433159A - Related substance of canagliflozin and preparation method and application thereof - Google Patents
Related substance of canagliflozin and preparation method and application thereof Download PDFInfo
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- CN115433159A CN115433159A CN202110611961.6A CN202110611961A CN115433159A CN 115433159 A CN115433159 A CN 115433159A CN 202110611961 A CN202110611961 A CN 202110611961A CN 115433159 A CN115433159 A CN 115433159A
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- Prior art keywords
- compound
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- formula
- acid
- canagliflozin
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- VHOFTEAWFCUTOS-TUGBYPPCSA-N canagliflozin hydrate Chemical compound O.CC1=CC=C([C@H]2[C@@H]([C@@H](O)[C@H](O)[C@@H](CO)O2)O)C=C1CC(S1)=CC=C1C1=CC=C(F)C=C1.CC1=CC=C([C@H]2[C@@H]([C@@H](O)[C@H](O)[C@@H](CO)O2)O)C=C1CC(S1)=CC=C1C1=CC=C(F)C=C1 VHOFTEAWFCUTOS-TUGBYPPCSA-N 0.000 title claims abstract description 45
- 229960001713 canagliflozin Drugs 0.000 title claims abstract description 44
- 239000000126 substance Substances 0.000 title claims abstract description 34
- 238000002360 preparation method Methods 0.000 title claims abstract description 33
- 239000012535 impurity Substances 0.000 claims abstract description 16
- 239000003814 drug Substances 0.000 claims abstract description 11
- VLRIERSBZHUCOW-UHFFFAOYSA-N 2-[(5-bromo-2-methylphenyl)methyl]-5-(4-fluorophenyl)thiophene Chemical class CC1=CC=C(Br)C=C1CC1=CC=C(C=2C=CC(F)=CC=2)S1 VLRIERSBZHUCOW-UHFFFAOYSA-N 0.000 claims abstract description 10
- 229940079593 drug Drugs 0.000 claims abstract description 10
- 238000006243 chemical reaction Methods 0.000 claims description 51
- 150000001875 compounds Chemical class 0.000 claims description 51
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 35
- 239000000243 solution Substances 0.000 claims description 29
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 claims description 26
- 238000003756 stirring Methods 0.000 claims description 25
- 239000012044 organic layer Substances 0.000 claims description 18
- 150000007530 organic bases Chemical class 0.000 claims description 16
- 238000010791 quenching Methods 0.000 claims description 15
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 14
- 239000007864 aqueous solution Substances 0.000 claims description 14
- 239000003960 organic solvent Substances 0.000 claims description 14
- 238000001816 cooling Methods 0.000 claims description 13
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical group CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 claims description 12
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 claims description 12
- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 claims description 12
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 claims description 12
- 230000002378 acidificating effect Effects 0.000 claims description 12
- 238000000034 method Methods 0.000 claims description 12
- 230000000171 quenching effect Effects 0.000 claims description 12
- AQRLNPVMDITEJU-UHFFFAOYSA-N triethylsilane Chemical compound CC[SiH](CC)CC AQRLNPVMDITEJU-UHFFFAOYSA-N 0.000 claims description 12
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 11
- 239000003153 chemical reaction reagent Substances 0.000 claims description 11
- 229940125904 compound 1 Drugs 0.000 claims description 11
- 239000007788 liquid Substances 0.000 claims description 11
- 230000002829 reductive effect Effects 0.000 claims description 11
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 claims description 10
- KZMGYPLQYOPHEL-UHFFFAOYSA-N Boron trifluoride etherate Chemical compound FB(F)F.CCOCC KZMGYPLQYOPHEL-UHFFFAOYSA-N 0.000 claims description 10
- 239000002841 Lewis acid Substances 0.000 claims description 10
- 150000007517 lewis acids Chemical class 0.000 claims description 10
- 239000000203 mixture Substances 0.000 claims description 10
- ZCSHNCUQKCANBX-UHFFFAOYSA-N lithium diisopropylamide Chemical compound [Li+].CC(C)[N-]C(C)C ZCSHNCUQKCANBX-UHFFFAOYSA-N 0.000 claims description 9
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 claims description 8
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 8
- 230000021736 acetylation Effects 0.000 claims description 8
- 238000006640 acetylation reaction Methods 0.000 claims description 8
- 239000003638 chemical reducing agent Substances 0.000 claims description 8
- 239000000047 product Substances 0.000 claims description 8
- 230000009471 action Effects 0.000 claims description 7
- 229940125782 compound 2 Drugs 0.000 claims description 7
- 229910052757 nitrogen Inorganic materials 0.000 claims description 7
- 230000008569 process Effects 0.000 claims description 7
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 6
- 229940098779 methanesulfonic acid Drugs 0.000 claims description 6
- 238000003908 quality control method Methods 0.000 claims description 6
- 238000005406 washing Methods 0.000 claims description 6
- 239000002904 solvent Substances 0.000 claims description 5
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 claims description 5
- MIOPJNTWMNEORI-GMSGAONNSA-N (S)-camphorsulfonic acid Chemical compound C1C[C@@]2(CS(O)(=O)=O)C(=O)C[C@@H]1C2(C)C MIOPJNTWMNEORI-GMSGAONNSA-N 0.000 claims description 4
- PAMIQIKDUOTOBW-UHFFFAOYSA-N 1-methylpiperidine Chemical compound CN1CCCCC1 PAMIQIKDUOTOBW-UHFFFAOYSA-N 0.000 claims description 4
- 229960000549 4-dimethylaminophenol Drugs 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
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 4
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 claims description 4
- 239000002253 acid Substances 0.000 claims description 4
- 239000002168 alkylating agent Substances 0.000 claims description 4
- 229940100198 alkylating agent Drugs 0.000 claims description 4
- 230000002152 alkylating effect Effects 0.000 claims description 4
- 229910052786 argon Inorganic materials 0.000 claims description 4
- 239000007795 chemical reaction product Substances 0.000 claims description 4
- YNESATAKKCNGOF-UHFFFAOYSA-N lithium bis(trimethylsilyl)amide Chemical compound [Li+].C[Si](C)(C)[N-][Si](C)(C)C YNESATAKKCNGOF-UHFFFAOYSA-N 0.000 claims description 4
- -1 naHMDS Chemical compound 0.000 claims description 4
- 230000007935 neutral effect Effects 0.000 claims description 4
- ITMCEJHCFYSIIV-UHFFFAOYSA-N triflic acid Chemical compound OS(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-N 0.000 claims description 4
- JIAARYAFYJHUJI-UHFFFAOYSA-L zinc dichloride Chemical compound [Cl-].[Cl-].[Zn+2] JIAARYAFYJHUJI-UHFFFAOYSA-L 0.000 claims description 4
- IUBQJLUDMLPAGT-UHFFFAOYSA-N potassium bis(trimethylsilyl)amide Chemical compound C[Si](C)(C)N([K])[Si](C)(C)C IUBQJLUDMLPAGT-UHFFFAOYSA-N 0.000 claims description 3
- 150000003839 salts Chemical class 0.000 claims description 3
- 239000012453 solvate Substances 0.000 claims description 3
- 239000007858 starting material Substances 0.000 claims description 3
- VFWCMGCRMGJXDK-UHFFFAOYSA-N 1-chlorobutane Chemical compound CCCCCl VFWCMGCRMGJXDK-UHFFFAOYSA-N 0.000 claims description 2
- 229910021627 Tin(IV) chloride Inorganic materials 0.000 claims description 2
- WETWJCDKMRHUPV-UHFFFAOYSA-N acetyl chloride Chemical compound CC(Cl)=O WETWJCDKMRHUPV-UHFFFAOYSA-N 0.000 claims description 2
- 239000012346 acetyl chloride Substances 0.000 claims description 2
- 239000012345 acetylating agent Substances 0.000 claims description 2
- VSCWAEJMTAWNJL-UHFFFAOYSA-K aluminium trichloride Chemical compound Cl[Al](Cl)Cl VSCWAEJMTAWNJL-UHFFFAOYSA-K 0.000 claims description 2
- QYJXDIUNDMRLAO-UHFFFAOYSA-N butyl 4-methylbenzenesulfonate Chemical compound CCCCOS(=O)(=O)C1=CC=C(C)C=C1 QYJXDIUNDMRLAO-UHFFFAOYSA-N 0.000 claims description 2
- KMGBZBJJOKUPIA-UHFFFAOYSA-N butyl iodide Chemical compound CCCCI KMGBZBJJOKUPIA-UHFFFAOYSA-N 0.000 claims description 2
- LFLBHTZRLVHUQC-UHFFFAOYSA-N butyl methanesulfonate Chemical compound CCCCOS(C)(=O)=O LFLBHTZRLVHUQC-UHFFFAOYSA-N 0.000 claims description 2
- ORPJQHHQRCLVIC-UHFFFAOYSA-N magnesium;propan-2-olate Chemical compound CC(C)O[Mg]OC(C)C ORPJQHHQRCLVIC-UHFFFAOYSA-N 0.000 claims description 2
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 claims description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 2
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 claims description 2
- HPGGPRDJHPYFRM-UHFFFAOYSA-J tin(iv) chloride Chemical compound Cl[Sn](Cl)(Cl)Cl HPGGPRDJHPYFRM-UHFFFAOYSA-J 0.000 claims description 2
- XJDNKRIXUMDJCW-UHFFFAOYSA-J titanium tetrachloride Chemical compound Cl[Ti](Cl)(Cl)Cl XJDNKRIXUMDJCW-UHFFFAOYSA-J 0.000 claims description 2
- ZGYICYBLPGRURT-UHFFFAOYSA-N tri(propan-2-yl)silicon Chemical compound CC(C)[Si](C(C)C)C(C)C ZGYICYBLPGRURT-UHFFFAOYSA-N 0.000 claims description 2
- UHUUYVZLXJHWDV-UHFFFAOYSA-N trimethyl(methylsilyloxy)silane Chemical compound C[SiH2]O[Si](C)(C)C UHUUYVZLXJHWDV-UHFFFAOYSA-N 0.000 claims description 2
- 239000011592 zinc chloride Substances 0.000 claims description 2
- 235000005074 zinc chloride Nutrition 0.000 claims description 2
- 238000009472 formulation Methods 0.000 claims 2
- 239000012670 alkaline solution Substances 0.000 claims 1
- XONPDZSGENTBNJ-UHFFFAOYSA-N molecular hydrogen;sodium Chemical compound [Na].[H][H] XONPDZSGENTBNJ-UHFFFAOYSA-N 0.000 claims 1
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 abstract description 6
- 230000015572 biosynthetic process Effects 0.000 abstract description 3
- 238000003786 synthesis reaction Methods 0.000 abstract description 3
- 238000001514 detection method Methods 0.000 abstract description 2
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 25
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 21
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 20
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 20
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 15
- 239000000543 intermediate Substances 0.000 description 13
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 13
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 12
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 10
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 9
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 6
- 238000005070 sampling Methods 0.000 description 6
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 5
- 239000008213 purified water Substances 0.000 description 5
- 239000011780 sodium chloride Substances 0.000 description 5
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 4
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 4
- 239000012141 concentrate Substances 0.000 description 4
- NOESYZHRGYRDHS-UHFFFAOYSA-N insulin Chemical compound N1C(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(NC(=O)CN)C(C)CC)CSSCC(C(NC(CO)C(=O)NC(CC(C)C)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CCC(N)=O)C(=O)NC(CC(C)C)C(=O)NC(CCC(O)=O)C(=O)NC(CC(N)=O)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CSSCC(NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2C=CC(O)=CC=2)NC(=O)C(CC(C)C)NC(=O)C(C)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2NC=NC=2)NC(=O)C(CO)NC(=O)CNC2=O)C(=O)NCC(=O)NC(CCC(O)=O)C(=O)NC(CCCNC(N)=N)C(=O)NCC(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC(O)=CC=3)C(=O)NC(C(C)O)C(=O)N3C(CCC3)C(=O)NC(CCCCN)C(=O)NC(C)C(O)=O)C(=O)NC(CC(N)=O)C(O)=O)=O)NC(=O)C(C(C)CC)NC(=O)C(CO)NC(=O)C(C(C)O)NC(=O)C1CSSCC2NC(=O)C(CC(C)C)NC(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CC(N)=O)NC(=O)C(NC(=O)C(N)CC=1C=CC=CC=1)C(C)C)CC1=CN=CN1 NOESYZHRGYRDHS-UHFFFAOYSA-N 0.000 description 4
- 239000012074 organic phase Substances 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
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-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
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 238000004440 column chromatography Methods 0.000 description 3
- 238000001914 filtration Methods 0.000 description 3
- 239000008103 glucose Substances 0.000 description 3
- 229910000027 potassium carbonate Inorganic materials 0.000 description 3
- 230000009467 reduction Effects 0.000 description 3
- 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 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 2
- 102000004877 Insulin Human genes 0.000 description 2
- 108090001061 Insulin Proteins 0.000 description 2
- WTEOIRVLGSZEPR-UHFFFAOYSA-N boron trifluoride Chemical compound FB(F)F WTEOIRVLGSZEPR-UHFFFAOYSA-N 0.000 description 2
- 229940126214 compound 3 Drugs 0.000 description 2
- 206010012601 diabetes mellitus Diseases 0.000 description 2
- 238000001035 drying Methods 0.000 description 2
- 230000002526 effect on cardiovascular system Effects 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 238000000605 extraction Methods 0.000 description 2
- 239000012634 fragment Substances 0.000 description 2
- 235000012209 glucono delta-lactone Nutrition 0.000 description 2
- 239000000182 glucono-delta-lactone Substances 0.000 description 2
- 229960003681 gluconolactone Drugs 0.000 description 2
- FFUAGWLWBBFQJT-UHFFFAOYSA-N hexamethyldisilazane Chemical compound C[Si](C)(C)N[Si](C)(C)C FFUAGWLWBBFQJT-UHFFFAOYSA-N 0.000 description 2
- 230000001771 impaired effect Effects 0.000 description 2
- 229940125396 insulin Drugs 0.000 description 2
- 210000003734 kidney Anatomy 0.000 description 2
- 230000007246 mechanism Effects 0.000 description 2
- OPGQKSHKFCOBGF-UHFFFAOYSA-N methanesulfonic acid;methanol Chemical compound OC.CS(O)(=O)=O OPGQKSHKFCOBGF-UHFFFAOYSA-N 0.000 description 2
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 description 2
- 239000013558 reference substance Substances 0.000 description 2
- 238000000926 separation method Methods 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 125000000026 trimethylsilyl group Chemical group [H]C([H])([H])[Si]([*])(C([H])([H])[H])C([H])([H])[H] 0.000 description 2
- ZFFBIQMNKOJDJE-UHFFFAOYSA-N 2-bromo-1,2-diphenylethanone Chemical compound C=1C=CC=CC=1C(Br)C(=O)C1=CC=CC=C1 ZFFBIQMNKOJDJE-UHFFFAOYSA-N 0.000 description 1
- 206010067484 Adverse reaction Diseases 0.000 description 1
- TWCMVXMQHSVIOJ-UHFFFAOYSA-N Aglycone of yadanzioside D Natural products COC(=O)C12OCC34C(CC5C(=CC(O)C(O)C5(C)C3C(O)C1O)C)OC(=O)C(OC(=O)C)C24 TWCMVXMQHSVIOJ-UHFFFAOYSA-N 0.000 description 1
- PLMKQQMDOMTZGG-UHFFFAOYSA-N Astrantiagenin E-methylester Natural products CC12CCC(O)C(C)(CO)C1CCC1(C)C2CC=C2C3CC(C)(C)CCC3(C(=O)OC)CCC21C PLMKQQMDOMTZGG-UHFFFAOYSA-N 0.000 description 1
- 229910015900 BF3 Inorganic materials 0.000 description 1
- 208000024172 Cardiovascular disease Diseases 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- XUIMIQQOPSSXEZ-UHFFFAOYSA-N Silicon Chemical compound [Si] XUIMIQQOPSSXEZ-UHFFFAOYSA-N 0.000 description 1
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-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
- 102000000070 Sodium-Glucose Transport Proteins Human genes 0.000 description 1
- 108010080361 Sodium-Glucose Transport Proteins Proteins 0.000 description 1
- 229940123518 Sodium/glucose cotransporter 2 inhibitor Drugs 0.000 description 1
- 125000000218 acetic acid group Chemical group C(C)(=O)* 0.000 description 1
- 230000002411 adverse Effects 0.000 description 1
- 230000006838 adverse reaction Effects 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 125000003118 aryl group Chemical group 0.000 description 1
- 210000000227 basophil cell of anterior lobe of hypophysis Anatomy 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- XGIUDIMNNMKGDE-UHFFFAOYSA-N bis(trimethylsilyl)azanide Chemical compound C[Si](C)(C)[N-][Si](C)(C)C XGIUDIMNNMKGDE-UHFFFAOYSA-N 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 230000006196 deacetylation Effects 0.000 description 1
- 238000003381 deacetylation reaction Methods 0.000 description 1
- MYTMXVHNEWBFAL-UHFFFAOYSA-L dipotassium;carbonate;hydrate Chemical compound O.[K+].[K+].[O-]C([O-])=O MYTMXVHNEWBFAL-UHFFFAOYSA-L 0.000 description 1
- 230000029142 excretion Effects 0.000 description 1
- 239000012065 filter cake Substances 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 230000002641 glycemic effect Effects 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- PFOARMALXZGCHY-UHFFFAOYSA-N homoegonol Natural products C1=C(OC)C(OC)=CC=C1C1=CC2=CC(CCCO)=CC(OC)=C2O1 PFOARMALXZGCHY-UHFFFAOYSA-N 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 230000003301 hydrolyzing effect Effects 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 229940121068 invokana Drugs 0.000 description 1
- 239000010410 layer Substances 0.000 description 1
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 208000010125 myocardial infarction Diseases 0.000 description 1
- 239000003921 oil Substances 0.000 description 1
- 239000003538 oral antidiabetic agent Substances 0.000 description 1
- 230000020477 pH reduction Effects 0.000 description 1
- 238000004537 pulping Methods 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 230000009103 reabsorption Effects 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 230000000717 retained effect Effects 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 229910052710 silicon Inorganic materials 0.000 description 1
- 239000010703 silicon Substances 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- WRIKHQLVHPKCJU-UHFFFAOYSA-N sodium bis(trimethylsilyl)amide Chemical compound C[Si](C)(C)N([Na])[Si](C)(C)C WRIKHQLVHPKCJU-UHFFFAOYSA-N 0.000 description 1
- 239000012312 sodium hydride Substances 0.000 description 1
- 229910000104 sodium hydride Inorganic materials 0.000 description 1
- 238000010025 steaming Methods 0.000 description 1
- 238000000967 suction filtration Methods 0.000 description 1
- 208000001072 type 2 diabetes mellitus Diseases 0.000 description 1
- 210000002700 urine Anatomy 0.000 description 1
Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
- C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
- C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
- C07D333/06—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to the ring carbon atoms
- C07D333/22—Radicals substituted by doubly bound hetero atoms, or by two hetero atoms other than halogen singly bound to the same carbon atom
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- 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
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H1/00—Processes for the preparation of sugar derivatives
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H15/00—Compounds containing hydrocarbon or substituted hydrocarbon radicals directly attached to hetero atoms of saccharide radicals
- C07H15/02—Acyclic radicals, not substituted by cyclic structures
- C07H15/04—Acyclic radicals, not substituted by cyclic structures attached to an oxygen atom of the saccharide radical
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N1/00—Sampling; Preparing specimens for investigation
- G01N1/28—Preparing specimens for investigation including physical details of (bio-)chemical methods covered elsewhere, e.g. G01N33/50, C12Q
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Biochemistry (AREA)
- Life Sciences & Earth Sciences (AREA)
- Health & Medical Sciences (AREA)
- Genetics & Genomics (AREA)
- Biotechnology (AREA)
- Engineering & Computer Science (AREA)
- Molecular Biology (AREA)
- Crystallography & Structural Chemistry (AREA)
- Physics & Mathematics (AREA)
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- General Physics & Mathematics (AREA)
- Immunology (AREA)
- Pathology (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
Abstract
The invention discloses a related substance of canagliflozin and a preparation method and application thereof, belongs to the technical field of drug synthesis, and solves the problem that n-butyl impurities of canagliflozin are not researched in the prior art. The structure of the related substance of canagliflozin provided by the invention is shown as a formula I. The invention also provides a preparation method of the related substance and application of the related substance in detection of canagliflozin intermediates, bulk drugs and/or preparations.
Description
Technical Field
The invention belongs to the technical field of drug synthesis, and particularly relates to related substances of canagliflozin and a preparation method and application thereof.
Background
Canagliflozin (Canagliflozin) under the trade name Invokana, chemical name: (1S) -1,5-anhydro-1- [3- [ [5- (4-fluorophenyl) -2-thienyl ] methyl ] -4-methylphenyl ] -D-glucitol hemihydrate, CAS: 5363 and 928672-86-0, the structural formula is shown as follows.
Canagliflozin is a selective sodium-glucose cotransporter type 2 (SGLT-2) inhibitor developed by mitsubishi, gunson, bang, for glycemic control in adult type ii diabetics. The medicine is approved by FDA in 3 months in 2013 and is marketed in the United states, and is marketed in 7 months in 2018 in China, and can be used for treating type II diabetes of adult patients.
The canagliflozin is the first SGLT-2 inhibitor approved by FDA to be on the market, and is expected to become the first new mechanism oral hypoglycemic drug with kidney protection effect proved by large-scale clinical research in the world. It reduces the blood glucose level in diabetic patients by inhibiting the reabsorption of glucose by the kidneys, which promotes the excretion of large amounts of glucose from the urine. The action mechanism of canagliflozin is independent of insulin, and the curative effect of the canagliflozin is not reduced because of the impaired function of islet beta cells or the impaired utilization of insulin of a patient. Canagliflozin can also reduce the risk of major cardiovascular adverse events, including heart attack, stroke or death from cardiovascular causes, and is particularly suitable for type ii diabetic adult patients with cardiovascular disease. Therefore, the canagliflozin has high research value and wide application prospect.
The preparation method of canagliflozin has more reports in documents, and the commonly adopted synthesis strategy is that an aryl aglycone fragment and a sugar ring fragment are butted under the action of n-butyl lithium, then a methanesulfonic acid methanol solution is used for acidification, and finally the obtained intermediate is subjected to reduction demethoxylation; or acetylation is carried out before reduction, methoxy is removed through reduction, and finally hydrolysis and deacetylation are carried out to obtain the product.
Patent CN101573368B discloses a preparation method of canagliflozin, which uses 2- (4-fluorophenyl) -5- [ (5-bromo-2-methylphenyl) methyl ] thiophene (compound 1) as a starting material, condenses with silicon-based protected gluconic acid-delta-lactone (compound 2) under the action of n-butyllithium, processes with methanesulfonic acid methanol solution, reacts to generate compound 3, reduces with boron trifluoride diethyl etherate/triethylsilane system to generate canagliflozin, and obtains high-purity canagliflozin through crystallization. The specific synthetic route is as follows:
patent CN200980151648.6 discloses a preparation method of canagliflozin, which comprises the steps of performing acetylation protection on a compound 3 on the basis of the route, reducing the compound by a boron trifluoride diethyl etherate/triethylsilane system, and finally hydrolyzing to remove acetyl to obtain the canagliflozin.
In the process of preparing canagliflozin by adopting n-butyl lithium, n-butyl impurities with higher safety risk are introduced. The n-butyl impurity is provided and researched and controlled, and has important significance in the quality control of canagliflozin and preparation products thereof.
Disclosure of Invention
The invention discovers that four impurities with higher risks, namely n-butyl impurities (compounds of formulas II-V), are introduced into an intermediate and a final product of the canagliflozin in the process of preparing the canagliflozin by adopting the n-butyl lithium.
One of the purposes of the invention is to provide a related substance of canagliflozin, which is generated in the process of preparing the canagliflozin by adopting n-butyl lithium, and solve the problem that the n-butyl impurity is not researched in the prior art.
Another object of the present invention is to provide a process for producing the substance.
The third object of the present invention is to provide the use of the related substance.
In order to achieve the purpose, the technical scheme adopted by the invention is as follows:
the invention provides a related substance of canagliflozin shown in a formula I, which comprises a salt or a solvate thereof:
wherein R is selected from
In some embodiments of the invention, the related substances or salts or solvates thereof have the structure shown below:
the nature of the compound of formula II determines its existence in two forms which cannot be separately obtained, and the other form has the following structure as shown in formula II':
the preparation method of the related substances provided by the invention comprises the following steps: taking a compound 1 as a starting material, adding a first organic base and an alkylating reagent for reaction, condensing an obtained reaction product with a compound 2 under the action of n-butyllithium, and treating the reaction product with an acidic aqueous solution to react to generate a compound shown in a formula II;
the preparation method of the related substance provided by the invention comprises the following steps: reacting the compound shown in the formula II with an acidic methanol solution to generate a compound shown in the formula III:
the preparation method of the related substance provided by the invention comprises the following steps: reacting the compound shown in the formula III with a second organic base and an acetylation reagent, and generating a compound shown in the formula IV by the obtained product under the action of a reducing agent and Lewis acid;
the preparation method of the related substance provided by the invention comprises the following steps: reacting a compound shown in the formula IV under an alkaline condition to generate a compound shown in the formula V;
in some embodiments of the invention, the first organic base is selected from one or more of sodium methoxide, sodium ethoxide, magnesium isopropoxide, sodium hydride, potassium tert-butoxide, LDA, LHMDS, naHMDS, KHMDS;
or/and the alkylating agent is selected from one or more of n-chlorobutane, n-bromobutane, n-iodobutane, n-butyl methanesulfonate and n-butyl p-toluenesulfonate;
or/and the acid in the acidic aqueous solution is selected from one or more of methanesulfonic acid, trifluoroacetic acid, trifluoromethanesulfonic acid, camphorsulfonic acid, hydrochloric acid and sulfuric acid;
or/and the acid in the acidic methanol solution is selected from one or more of methanesulfonic acid, trifluoroacetic acid, trifluoromethanesulfonic acid, camphorsulfonic acid, hydrochloric acid and sulfuric acid;
or/and the second organic base is selected from one or more of triethylamine, diisopropylethylamine, pyridine, N-methylmorpholine, N-methylpiperidine and DMAP;
or/and the acetylating agent is selected from acetic anhydride or acetyl chloride;
or/and the reducing agent is selected from one or more of triethylsilane, triisopropylsilane and tetramethyldisiloxane;
and/or the Lewis acid is selected from one or more of boron trifluoride diethyl etherate, aluminum trichloride, zinc chloride, stannic chloride and titanium tetrachloride.
In some embodiments of the invention, the preparation of the compound of formula II comprises the steps of: under the protection of nitrogen or argon, dissolving the compound 1 in a first organic solvent, and cooling; adding a first organic base and an alkylating reagent, reacting, quenching, separating liquid, collecting an organic layer, and concentrating to obtain a first oily substance; under the protection of nitrogen or argon, adding a second organic solvent into the obtained first oily matter for dissolving, cooling, adding n-butyl lithium, and stirring for reaction; adding the compound 2, and stirring for reaction; adding an acidic aqueous solution, and stirring for reaction; quenching reaction, separating liquid, collecting an organic layer, and volatilizing the solvent to obtain a compound shown in the formula II;
preferably, the molar equivalent ratio of compound 1 to first organic base is 1;
preferably, the molar equivalent ratio of compound 1 to alkylating agent is 1;
preferably, the temperature is reduced to below-30 ℃ and the first organic base is added;
preferably, n-butyllithium is added gradually down to-70 ℃ or below.
Preferably, the compound is dissolved to prepare a solution, and then the solution is added, and the reaction is stirred.
Or/and the preparation of the compound of formula III comprises the following steps: adding the compound of the formula II into an acidic methanol solution, stirring for reaction, quenching for reaction, separating liquid, collecting an organic layer, and volatilizing the solvent to obtain a compound of the formula III;
and/or the preparation of the compound of formula IV comprises the following steps: dissolving the compound shown in the formula III in a third organic solvent, adding a second organic base, adding an acetylation reagent, and stirring for reaction; quenching reaction, washing, separating liquid, collecting an organic layer, and concentrating to obtain a second oily substance; dissolving the obtained second oily substance in a fourth organic solvent, adding a reducing agent and Lewis acid, stirring for reaction, quenching for reaction, separating liquid, collecting an organic layer, and volatilizing the solvent to obtain a compound shown in the formula IV;
preferably, the molar equivalent ratio of the compound of formula iii to the reducing agent is 1:4;
preferably, the molar equivalent ratio of the compound of formula iii to lewis acid is 1:4;
preferably, adding an acetylation reagent, and then stirring for reaction at 20-30 ℃;
preferably, after adding the Lewis acid, stirring the mixture for reaction at the temperature of between 0 and 10 ℃;
or/and the preparation of the compound of formula V comprises the steps of: dissolving the compound shown in the formula IV in a fifth organic solvent, adding an alkaline aqueous solution, and stirring for reaction; quenching reaction, separating, collecting an organic layer, and concentrating to obtain a compound shown in the formula V;
preferably, adding an alkaline aqueous solution, and then stirring and reacting at normal temperature; further preferably, the alkali in the alkaline aqueous solution is selected from one or more of sodium hydroxide, potassium hydroxide and lithium hydroxide.
In some embodiments of the present invention, the first organic solvent and the second solvent are both selected from one or more of tetrahydrofuran, diethyl ether, toluene, and ethylene glycol dimethyl ether;
the third organic solvent is selected from one or more of ethyl acetate, dichloromethane, acetonitrile and tetrahydrofuran;
the fourth organic solvent is selected from one or more of chloroform, dichloromethane, acetonitrile and tetrahydrofuran;
the fifth organic solvent is selected from one or more of tetrahydrofuran, methanol and ethanol.
The invention provides application of related substances in quality control of canagliflozin intermediates, bulk drugs and/or preparations.
The related substances provided by the invention are used as impurity reference substances and are applied to the quality control of canagliflozin intermediates, bulk drugs and/or preparations.
The English abbreviation of the invention corresponds to the Chinese name:
LDA: lithium diisopropylamide;
EA: acetic acid ethyl ester;
DCM: dichloromethane;
DMAP: 4-dimethylaminopyridine;
LHMDS: lithium hexamethyldisilazide;
NaHMDS: bis (trimethylsilyl) amide;
KHMDS: hexamethyldisilazane based potassium amide.
Compared with the prior art, the invention has the following beneficial effects:
the invention provides the n-butyl impurity of canagliflozin and the preparation method thereof for the first time, can quickly and efficiently obtain the impurity reference substance, and has important significance for the quality research and control of the canagliflozin and the intermediate and the adverse reaction of medicines.
The preparation method of the related substance of canagliflozin provided by the invention is simple and convenient to operate, easily available in raw materials and high in yield.
Detailed Description
In order to make the objects, technical solutions and advantages of the embodiments of the present invention clearer, the technical solutions in the embodiments of the present invention will be clearly and completely described below. The examples, in which specific conditions are not specified, were conducted under conventional conditions or conditions recommended by the manufacturer. The reagents or instruments used are not indicated by the manufacturer, and are all conventional products available commercially.
EXAMPLE 1 preparation of the Compound of formula II
10g of 2- (4-fluorophenyl) -5- [ (5-bromo-2-methylphenyl) methyl ] thiophene (compound 1) and 50mL of tetrahydrofuran were added to a 250mL three-necked flask, and the mixture was purged with nitrogen and cooled to-20 ℃. 16.62mL of LDA (2.0 mol/L) was added dropwise, and the reaction was continued for 30min. 4.17g of n-bromobutane is added dropwise and the reaction is carried out for about 2h. 10mL of water was added dropwise, and 30mL of EA was added. Add 1N HCl 50mL wash once and wash with water to pH 6-7. Vacuum concentrating at 50 deg.C to obtain 11.6g product.
500mL four-necked bottle was charged with the above10g of product, 70g of tetrahydrofuran and 70g of toluene, and cooling to below-70 ℃ under the protection of nitrogen. 16.58mL of n-butyllithium (2.5 mol/L) is added dropwise, the internal temperature is kept lower than-70 ℃, and the reaction is stirred for 30-60 min. 14.59g of trimethylsilyl protected glucono-delta-lactone (compound 2) dissolved in 20g of toluene is added dropwise, and the reaction is stirred for about 2 hours after the dropwise addition. 6.03g of trifluoroacetic acid solution dissolved in 8g of water is added dropwise, the cooling bath is removed, the temperature is naturally raised to 0-10 ℃, and the reaction is stirred for about 3 hours. Potassium carbonate 5.6g dissolved in water 50mL is added to quench the reaction, stirred for 5min, and the solution is allowed to stand for liquid separation. The organic phase was charged with 35.6g of tetrahydrofuran, washed twice with 10% NaCl solution, concentrated under reduced pressure at 50 ℃ and purified by silica gel column (DCM: meOH = 100) to obtain 6.8g of the compound represented by formula II. Yield 55%, purity: 94.1 percent. MS-ESI (m/z): [ M + H-H ] 2 O] + 499.2。 1 H NMR(400MHz，DMSO-d6)：δ7.57-7.60(m，2H)，7.17-7.30(m，4H)，7.06-7.08(d，J＝8.0Hz，1H)，6.84-6.85(d，J＝4.0Hz，1H)，6.19-6.21(d，J＝4.0Hz，1H)，4.84-4.87(m，1H)，4.61-4.65(d，J＝8.0Hz，1H)，4.32-4.37(m，3H)，3.50-3.67(m，4H)，3.20-3.30(m，1H)，2.94-3.02(m，1H)，2.38-2.42(m，1H)，2.29(s，3H)，1.95-2.10(m，2H)，1.25-1.31(m，4H)，0.83-0.87(m，3H)。
EXAMPLE 2 preparation of the Compound of formula III
Taking 6g of impurity shown in formula II, adding 36ml of methanol, cooling to 0-10 ℃, and adding 556mg of methanesulfonic acid. The reaction was stirred for 2h. 200ml of methylene chloride and 120ml of an aqueous potassium carbonate solution were added thereto, and the mixture was stirred and separated. The organic phase was retained and concentrated under reduced pressure to give 6g of an oil. And (5) performing column chromatography purification to obtain 5.7g of the compound shown in the formula III. Yield 92.5%, purity: 97.0 percent. MS-ESI (m/z): [ M + H-MeOH ]] + 499.2。 1 H NMR(400MHz，DMSO-d6)：δ7.57-7.61(m，2H)，7.54-7.56(d，J＝4.0Hz，1H)，7.30-7.31(dd，J＝4.0Hz，J＝8.0Hz，1H)，7.18-7.22(m，3H)，7.11-7.13(d，J＝8.0Hz，1H)，6.82-6.84(d，J＝8.0Hz，1H)，4.97-4.98(d，J＝4.0Hz，1H)，4.67-4.72(m，2H)，4.52-4.54(d，J＝8.0Hz，1H)，4.31-4.33(t，J＝8.0Hz，1H)，3.74-3.80(d，J＝8.0Hz，1H)，3.55-3.58(m，2H)，3.38-3.39(m，1H)，3.19-3.26(m，1H)，2.96(s，3H)，2.89-2.96(m，1H)，2.29(s，3H)，2.03-2.04(m，2H)，1.26-1.31(m，4H)，0.83(t，J＝8.0Hz，3H)。
EXAMPLE 3 preparation of the Compound of formula IV
Taking 5g of impurities shown in the formula III, adding 20mL of ethyl acetate, 72mg of DMAP and 6.4g of N-methylmorpholine, cooling to 0 ℃, dropwise adding 6g of acetic anhydride, and stirring at room temperature for reacting overnight after dropwise adding. The reaction mixture was quenched with 25mL of water, extracted with 100mL of ethyl acetate, and separated. The organic phase was washed with 1N HCl (50 mL), saturated sodium bicarbonate solution (50 mL) and saturated sodium chloride (50 mL). Concentrating under reduced pressure at 45 deg.C to dry, adding acetonitrile 20mL to dissolve, adding triethylsilane 5g, and cooling to-5 deg.C. Dropwise adding 6.2g of boron trifluoride diethyl etherate, stirring for reacting for 6h, adding 3.6g of potassium carbonate solution dissolved in 50mL of water to quench the reaction, extracting with 200mL of ethyl acetate, washing an organic phase with a saturated sodium chloride solution (80 mL multiplied by 2), concentrating under reduced pressure, and purifying by column chromatography to obtain 4.2g of a compound shown in the formula IV. The yield is 66.7 percent, and the purity is 88.2 percent. MS-ESI (m/z): [ M + NH4 ]] + 686.3。 1 H NMR(400MHz，CDCl3)：δ7.45-7.49(m，2H)，7.22-7.23(d，J＝4.0Hz，1H)，7.15-7.10(m，5H)，6.75-6.76(d，J＝4.0Hz，1H)，5.17-5.32(m，3H)，4.25-4.38(m，4H)，3.86-3.88(m，1H)，2.33(s，3H)，2.06(s，3H)，2.05(s，3H)，2.01(s，3H)，1.97(s，3H)，1.56-1.68(m，2H)，1.33-1.36(m，4H)，0.89(t，J＝8.0Hz，3H)。
EXAMPLE 4 preparation of the Compound of formula V
Taking 4g of impurities shown in the formula IV, adding 22g of methanol and 18g of tetrahydrofuran, cooling to 5-10 ℃, adding 0.84g of lithium hydroxide solution dissolved in 12g of water, and stirring at room temperature for reaction overnight. 40g of methylene chloride and 24g of purified water were added thereto, and the mixture was extracted and separated. Washing the purified water to pH 6-7. Concentrating under reduced pressure, and purifying by column chromatography to obtain 2.4g of compound shown in formula V. The yield is 80.3 percent, and the purity is 96.8 percent. MS-ESI (m/z): [ M + NH4 ]] + 518.3。 1 H NMR(400MHz，CDCl3)：δ7.57-7.61(m，2H)，7.11-7.31(m，6H)，6.86-6.88(t，J＝4.0Hz，1H)，4.93-4.95(t，J＝4.0Hz，2H)，4.71-4.73(dd，1H)，4.42-4.47(m，1H)，4.31-4.35(t，J＝8.0Hz，1H)，3.97-4.01(dd，1H)，3.68-3.73(m，1H)，3.41-3.47(m，1H)，3.09-3.31(m，4H)，2.30(s，3H)，1.96-2.09(m，2H)，1.23-1.35(m，4H)，0.83-0.87(t，J＝8.0Hz，3H)。
EXAMPLE 5 preparation of Canagliflozin
The method comprises the following steps: into a 2L reaction flask were added 330g of tetrahydrofuran, 320g of toluene, and 45g of 2- (4-fluorophenyl) -5- [ (5-bromo-2-methylphenyl) methyl ] thiophene (compound 1), and the mixture was stirred to dissolve it, and cooled to-70 ℃ under nitrogen protection. N-butyllithium was added dropwise. After the dropwise addition, the internal temperature is controlled to be minus 70 ℃, and the stirring reaction is carried out for about 30min. Adding a toluene solution of trimethylsilyl protected glucono-delta-lactone (compound 2); after the addition, the temperature is controlled at-70 ℃ for reaction for 2h. Stopping cooling, dropwise adding a trifluoroacetic acid aqueous solution, and after dropwise adding, heating to 20-30 ℃ for reacting for 3h. Adding potassium carbonate water solution to adjust the pH value to be neutral. Standing, layering, and washing with sodium chloride solution. The organic layer was concentrated under reduced pressure until the solution became cloudy, and the concentration was stopped, and 330g of toluene was added to the residue, followed by stirring overnight. Filtering, and drying a filter cake in vacuum to obtain the canagliflozin intermediate A (sampling point 1).
Step two: and (3) adding 550g of methanol and 100g of canagliflozin intermediate A into a 2L reaction bottle, cooling to 10 ℃, adding 10g of methanesulfonic acid, and stirring for reacting for about 3 hours. Aqueous potassium carbonate was added to adjust the pH to near neutrality, and 1330g of methylene chloride was added for extraction to separate an organic layer, which was washed with sodium chloride solution. The organic layer was concentrated until no significant fraction flowed out, then 260g of toluene was added, dissolved, and concentrated until no significant fraction flowed out, to give canagliflozin intermediate B (sample point 2).
Step three: and adding 540g of ethyl acetate, 100g of canagliflozin intermediate B and 120g of N-methylmorpholine into a 1L reaction bottle, dropwise adding 120g of acetic anhydride at the internal temperature of less than or equal to 25 ℃, and reacting for about 6 hours after dropwise adding. 240g of purified water is added dropwise to quench the reaction, and the mixture is allowed to stand and separated. Washing the organic layer with dilute hydrochloric acid, sodium bicarbonate solution and sodium chloride solution in sequence, drying with anhydrous sodium sulfate, filtering, concentrating the filtrate under reduced pressure until no obvious fraction flows out, steaming acetonitrile for two times, and concentrating until no obvious fraction flows out to obtain the concentrate.
850g of acetonitrile was added to the concentrate obtained in the above step, and the mixture was dissolved and transferred to a 3L reaction flask, and 110g of triethylsilane was added. And cooling to 0 ℃, dropwise adding 130g of boron trifluoride ether solution, and reacting for about 6 hours after dropwise adding. Adjusting pH to be nearly neutral by potassium carbonate aqueous solution, filtering solid in a water layer, adding 1Kg of purified water into the obtained solid, pulping, and performing suction filtration to dryness to obtain the canagliflozin intermediate C (sampling point 3).
Step four: to a 2L reaction flask, 550g of methanol, 450g of tetrahydrofuran, and 100g of canagliflozin intermediate C were added. Controlling the internal temperature to be less than or equal to 25 ℃, adding lithium hydroxide aqueous solution, and reacting for 3 hours after the addition is finished. 600g of purified water and 530g of methylene chloride were added thereto, followed by extraction and separation. The organic layer was washed twice with sodium chloride solution. The organic layer was concentrated under reduced pressure until no significant fraction flowed, and then was distilled once with ethyl acetate, and concentrated to give a crude cargliflozin concentrate D (sample point 4).
Respectively taking the canagliflozin intermediates prepared in the steps, and carrying out HPLC detection, wherein the compounds of the formulas II-V are detected as follows:
| sampling point | Intermediates | Impurity compound | Amount of examination |
| Sampling point 1 | Canagliflozin intermediate A | Formula II | 0.97％ |
| Sampling point 2 | Canagliflozin intermediate B | Formula III | 0.93％ |
| Sampling point 3 | Canagliflozin intermediate C | Formula IV | 1.23％ |
| Sample point 4 | Canagliflozin crude concentrate D | Formula V | 0.92％ |
It can be seen that during the preparation of canagliflozin, more impurity compounds of formulae ii to v are produced, which need to be controlled. The impurity compound provided by the application has important significance on quality control and product safety of canagliflozin intermediates, bulk drugs and preparation drugs.
The above-mentioned embodiment is only one of the preferred embodiments of the present invention, and should not be used to limit the scope of the present invention, but all the insubstantial modifications or changes made within the spirit and scope of the main design of the present invention, which still solve the technical problems consistent with the present invention, should be included in the scope of the present invention.
Claims (10)
1. Related substances of canagliflozin represented by formula I, including salts or solvates thereof:
wherein R is selected from
2. The canagliflozin related substance according to claim 1, having a structure as shown below:
3. the method of preparing the related substance according to claim 1 or 2, characterized by comprising the steps of: taking a compound 1 as a starting material, adding a first organic base and an alkylating reagent for reaction, condensing an obtained reaction product with a compound 2 under the action of n-butyllithium, and treating the reaction product with an acidic aqueous solution to react to generate a compound shown in a formula II;
4. the method of preparing the related substance according to claim 1 or 2, characterized by comprising the steps of: reacting a compound of formula II with an acidic methanol solution to produce a compound of formula III:
5. the method of preparing the related substance according to claim 1 or 2, characterized by comprising the steps of: reacting a compound shown in the formula III with a second organic base and an acetylation reagent, and generating a compound shown in the formula IV by the obtained product under the action of a reducing agent and Lewis acid;
6. the method of preparing the related substance according to claim 1 or 2, characterized by comprising the steps of: reacting a compound shown in the formula IV under an alkaline condition to generate a compound shown in the formula V;
7. the process according to any one of claims 3 to 6, wherein the first organic base is selected from one or more of sodium methoxide, sodium ethoxide, magnesium isopropoxide, sodium hydrogen, potassium tert-butoxide, LDA, LHMDS, naHMDS, KHMDS;
or/and the alkylating agent is selected from one or more of n-chlorobutane, n-bromobutane, n-iodobutane, n-butyl methanesulfonate and n-butyl p-toluenesulfonate;
or/and the acid in the acidic aqueous solution is selected from one or more of methanesulfonic acid, trifluoroacetic acid, trifluoromethanesulfonic acid, camphorsulfonic acid, hydrochloric acid and sulfuric acid;
or/and the acid in the acidic methanol solution is selected from one or more of methanesulfonic acid, trifluoroacetic acid, trifluoromethanesulfonic acid, camphorsulfonic acid, hydrochloric acid and sulfuric acid;
or/and the second organic base is selected from one or more of triethylamine, diisopropylethylamine, pyridine, N-methylmorpholine, N-methylpiperidine and DMAP;
or/and the acetylating agent is selected from acetic anhydride or acetyl chloride;
or/and the reducing agent is selected from one or more of triethylsilane, triisopropylsilane and tetramethyldisiloxane;
and/or the Lewis acid is selected from one or more of boron trifluoride diethyl etherate, aluminum trichloride, zinc chloride, stannic chloride and titanium tetrachloride.
8. The process of claim 6, wherein the preparation of the compound of formula ii comprises the steps of: dissolving the compound 1 in a first organic solvent under the protection of nitrogen or argon, and cooling; adding a first organic base and an alkylating reagent, reacting, quenching, separating liquid, collecting an organic layer, and concentrating to obtain a first oily substance; under the protection of nitrogen or argon, adding a second organic solvent into the obtained first oily matter for dissolving, cooling, adding n-butyl lithium, and stirring for reaction; adding the compound 2, and stirring for reaction; adding an acidic aqueous solution, and stirring for reaction; quenching reaction, separating liquid, collecting an organic layer, and volatilizing the solvent to obtain a compound shown in the formula II;
preferably, the molar equivalent ratio of compound 1 to first organic base is 1;
preferably, the molar equivalent ratio of compound 1 to alkylating agent is 1;
preferably, the temperature is reduced to below-30 ℃ and the first organic base is added;
preferably, n-butyllithium is added gradually to below-70 ℃;
or/and the preparation of the compound of formula III comprises the following steps: adding the compound of the formula II into an acidic methanol solution, stirring for reaction, adding an alkaline aqueous solution for quenching reaction, adjusting the pH of a reaction solution to be nearly neutral, separating liquid, collecting an organic layer, and concentrating to obtain a compound of a formula III;
and/or the preparation of the compound of formula IV comprises the following steps: dissolving the compound shown in the formula III in an organic solvent, adding a second organic base, adding an acetylation reagent, and stirring for reaction; quenching reaction, washing, separating liquid, collecting an organic layer, and concentrating to obtain an oily substance; dissolving the obtained oily matter in an organic solvent, adding a reducing agent and Lewis acid, stirring for reaction, quenching for reaction, adjusting the pH of a reaction solution to be nearly neutral, separating, collecting an organic layer, and concentrating to obtain a compound shown in the formula IV;
preferably, the molar equivalent ratio of the compound of formula iii to the reducing agent is 1:4;
preferably, the molar equivalent ratio of the compound of formula iii to lewis acid is 1:4;
preferably, adding an acetylation reagent, and stirring for reaction at 20-30 ℃;
preferably, after adding the Lewis acid, stirring the mixture for reaction at the temperature of between 0 and 10 ℃;
or/and the preparation of the compound of formula V comprises the steps of: dissolving a compound shown in the formula IV in an organic solvent, adding an alkaline aqueous solution, and stirring for reaction; quenching reaction, separating liquid, collecting an organic layer, and concentrating to obtain a compound shown in the formula V;
preferably, the reaction is stirred at room temperature after the addition of the aqueous alkaline solution.
9. Use of a related substance as defined in claim 1 or 2 for quality control of canagliflozin intermediates, bulk drugs and/or formulations.
10. Use of a related substance as defined in claim 1 or 2 as an impurity control substance in the quality control of canagliflozin intermediates, bulk drugs and/or formulations.
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