CN114195748A - Preparation method of sodium-glucose cotransporter 2 inhibitor - Google Patents
Preparation method of sodium-glucose cotransporter 2 inhibitor Download PDFInfo
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- CN114195748A CN114195748A CN202111090450.0A CN202111090450A CN114195748A CN 114195748 A CN114195748 A CN 114195748A CN 202111090450 A CN202111090450 A CN 202111090450A CN 114195748 A CN114195748 A CN 114195748A
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- 238000002360 preparation method Methods 0.000 title claims abstract description 16
- 229940123518 Sodium/glucose cotransporter 2 inhibitor Drugs 0.000 title abstract description 9
- 150000001875 compounds Chemical class 0.000 claims abstract description 117
- 238000000746 purification Methods 0.000 claims abstract description 7
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 60
- 238000000034 method Methods 0.000 claims description 38
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 32
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 24
- 238000006243 chemical reaction Methods 0.000 claims description 24
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 21
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 21
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 18
- 239000000126 substance Substances 0.000 claims description 17
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 14
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 13
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 12
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 11
- 229940024606 amino acid Drugs 0.000 claims description 11
- 229910052739 hydrogen Inorganic materials 0.000 claims description 11
- 239000001257 hydrogen Substances 0.000 claims description 11
- 230000008569 process Effects 0.000 claims description 11
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 10
- 150000001413 amino acids Chemical class 0.000 claims description 10
- 229910052736 halogen Inorganic materials 0.000 claims description 10
- 150000002367 halogens Chemical class 0.000 claims description 10
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 10
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 9
- 229930182821 L-proline Natural products 0.000 claims description 8
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 8
- 229960002429 proline Drugs 0.000 claims description 8
- 238000001953 recrystallisation Methods 0.000 claims description 8
- ONIBWKKTOPOVIA-BYPYZUCNSA-N L-Proline Chemical compound OC(=O)[C@@H]1CCCN1 ONIBWKKTOPOVIA-BYPYZUCNSA-N 0.000 claims description 7
- 125000003545 alkoxy group Chemical group 0.000 claims description 7
- 238000010009 beating Methods 0.000 claims description 7
- 150000002431 hydrogen Chemical class 0.000 claims description 7
- 239000012046 mixed solvent Substances 0.000 claims description 7
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 7
- YZCKVEUIGOORGS-OUBTZVSYSA-N Deuterium Chemical compound [2H] YZCKVEUIGOORGS-OUBTZVSYSA-N 0.000 claims description 6
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 claims description 6
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 6
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 claims description 6
- 229910052805 deuterium Inorganic materials 0.000 claims description 6
- 239000003153 chemical reaction reagent Substances 0.000 claims description 5
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 5
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-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
- 229910000024 caesium carbonate Inorganic materials 0.000 claims description 4
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 4
- 229910052808 lithium carbonate Inorganic materials 0.000 claims description 4
- XGZVUEUWXADBQD-UHFFFAOYSA-L lithium carbonate Chemical group [Li+].[Li+].[O-]C([O-])=O XGZVUEUWXADBQD-UHFFFAOYSA-L 0.000 claims description 4
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 4
- -1 nitro, cyano, phenyl Chemical group 0.000 claims description 4
- 238000007254 oxidation reaction Methods 0.000 claims description 4
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 4
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 4
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 2
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 2
- 230000002378 acidificating effect Effects 0.000 claims description 2
- 150000001298 alcohols Chemical class 0.000 claims description 2
- RQPZNWPYLFFXCP-UHFFFAOYSA-L barium dihydroxide Chemical compound [OH-].[OH-].[Ba+2] RQPZNWPYLFFXCP-UHFFFAOYSA-L 0.000 claims description 2
- 239000007810 chemical reaction solvent Substances 0.000 claims description 2
- 239000012973 diazabicyclooctane Substances 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 claims description 2
- 238000010791 quenching Methods 0.000 claims description 2
- 230000000171 quenching effect Effects 0.000 claims description 2
- 239000002904 solvent Substances 0.000 claims description 2
- UDYFLDICVHJSOY-UHFFFAOYSA-N sulfur trioxide pyridine complex Chemical compound O=S(=O)=O.C1=CC=NC=C1 UDYFLDICVHJSOY-UHFFFAOYSA-N 0.000 claims description 2
- IMNIMPAHZVJRPE-UHFFFAOYSA-N triethylenediamine Chemical compound C1CN2CCN1CC2 IMNIMPAHZVJRPE-UHFFFAOYSA-N 0.000 claims description 2
- LWIHDJKSTIGBAC-UHFFFAOYSA-K tripotassium phosphate Chemical compound [K+].[K+].[K+].[O-]P([O-])([O-])=O LWIHDJKSTIGBAC-UHFFFAOYSA-K 0.000 claims description 2
- 229910000404 tripotassium phosphate Inorganic materials 0.000 claims description 2
- 150000004682 monohydrates Chemical class 0.000 claims 2
- 125000000174 L-prolyl group Chemical group [H]N1C([H])([H])C([H])([H])C([H])([H])[C@@]1([H])C(*)=O 0.000 claims 1
- 230000003647 oxidation Effects 0.000 claims 1
- 239000002994 raw material Substances 0.000 abstract description 2
- 238000009776 industrial production Methods 0.000 abstract 1
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 16
- 239000000243 solution Substances 0.000 description 13
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical class [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 11
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 9
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 9
- 239000007864 aqueous solution Substances 0.000 description 9
- 239000007787 solid Substances 0.000 description 9
- 239000012043 crude product Substances 0.000 description 8
- 239000000203 mixture Substances 0.000 description 8
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 8
- 239000012074 organic phase Substances 0.000 description 8
- 229920006395 saturated elastomer Polymers 0.000 description 8
- 125000000217 alkyl group Chemical group 0.000 description 7
- 125000000753 cycloalkyl group Chemical group 0.000 description 7
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 7
- 235000017557 sodium bicarbonate Nutrition 0.000 description 7
- CZDYPVPMEAXLPK-UHFFFAOYSA-N tetramethylsilane Chemical compound C[Si](C)(C)C CZDYPVPMEAXLPK-UHFFFAOYSA-N 0.000 description 7
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 6
- IJOOHPMOJXWVHK-UHFFFAOYSA-N chlorotrimethylsilane Chemical compound C[Si](C)(C)Cl IJOOHPMOJXWVHK-UHFFFAOYSA-N 0.000 description 6
- 238000000926 separation method Methods 0.000 description 6
- 239000000741 silica gel Substances 0.000 description 6
- 229910002027 silica gel Inorganic materials 0.000 description 6
- 238000004809 thin layer chromatography Methods 0.000 description 6
- 238000005160 1H NMR spectroscopy Methods 0.000 description 5
- 238000005481 NMR spectroscopy Methods 0.000 description 5
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 5
- 125000004432 carbon atom Chemical group C* 0.000 description 5
- 239000007788 liquid Substances 0.000 description 5
- 239000012071 phase Substances 0.000 description 5
- 238000003756 stirring Methods 0.000 description 5
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 4
- OKKJLVBELUTLKV-MZCSYVLQSA-N Deuterated methanol Chemical compound [2H]OC([2H])([2H])[2H] OKKJLVBELUTLKV-MZCSYVLQSA-N 0.000 description 4
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 4
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 4
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 4
- 238000004440 column chromatography Methods 0.000 description 4
- 238000001816 cooling Methods 0.000 description 4
- 238000005984 hydrogenation reaction Methods 0.000 description 4
- 239000000047 product Substances 0.000 description 4
- 208000001072 type 2 diabetes mellitus Diseases 0.000 description 4
- 239000003643 water by type Substances 0.000 description 4
- HTSGKJQDMSTCGS-UHFFFAOYSA-N 1,4-bis(4-chlorophenyl)-2-(4-methylphenyl)sulfonylbutane-1,4-dione Chemical compound C1=CC(C)=CC=C1S(=O)(=O)C(C(=O)C=1C=CC(Cl)=CC=1)CC(=O)C1=CC=C(Cl)C=C1 HTSGKJQDMSTCGS-UHFFFAOYSA-N 0.000 description 3
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-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
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 3
- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 description 3
- 239000000460 chlorine Substances 0.000 description 3
- 238000001035 drying Methods 0.000 description 3
- 239000012065 filter cake Substances 0.000 description 3
- 238000001914 filtration Methods 0.000 description 3
- 239000008103 glucose Substances 0.000 description 3
- 238000004128 high performance liquid chromatography Methods 0.000 description 3
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 3
- 238000010992 reflux Methods 0.000 description 3
- VPZQPVZMZHUTTF-WCCKRBBISA-N (2s)-pyrrolidine-2-carboxylic acid;hydrate Chemical compound O.OC(=O)[C@@H]1CCCN1 VPZQPVZMZHUTTF-WCCKRBBISA-N 0.000 description 2
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 2
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- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 2
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- 238000013459 approach Methods 0.000 description 2
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- 230000009286 beneficial effect Effects 0.000 description 2
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 2
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- 206010012601 diabetes mellitus Diseases 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- NLFBCYMMUAKCPC-KQQUZDAGSA-N ethyl (e)-3-[3-amino-2-cyano-1-[(e)-3-ethoxy-3-oxoprop-1-enyl]sulfanyl-3-oxoprop-1-enyl]sulfanylprop-2-enoate Chemical compound CCOC(=O)\C=C\SC(=C(C#N)C(N)=O)S\C=C\C(=O)OCC NLFBCYMMUAKCPC-KQQUZDAGSA-N 0.000 description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 2
- 238000000605 extraction Methods 0.000 description 2
- 239000011737 fluorine Substances 0.000 description 2
- 229910052731 fluorine Inorganic materials 0.000 description 2
- 238000010438 heat treatment Methods 0.000 description 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 2
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- 238000004949 mass spectrometry Methods 0.000 description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 2
- 125000002950 monocyclic group Chemical group 0.000 description 2
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- 235000011152 sodium sulphate Nutrition 0.000 description 2
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 2
- 230000001225 therapeutic effect Effects 0.000 description 2
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- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical class [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 1
- 101100096578 Arabidopsis thaliana SQD2 gene Proteins 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
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- PBAYDYUZOSNJGU-UHFFFAOYSA-N chelidonic acid Natural products OC(=O)C1=CC(=O)C=C(C(O)=O)O1 PBAYDYUZOSNJGU-UHFFFAOYSA-N 0.000 description 1
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- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
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- 125000002433 cyclopentenyl group Chemical group C1(=CCCC1)* 0.000 description 1
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- 125000003187 heptyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
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- 150000002500 ions Chemical class 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 210000003734 kidney Anatomy 0.000 description 1
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 1
- 235000019341 magnesium sulphate Nutrition 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 230000010534 mechanism of action Effects 0.000 description 1
- 230000001404 mediated effect Effects 0.000 description 1
- 229940098779 methanesulfonic acid Drugs 0.000 description 1
- 239000011259 mixed solution Substances 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 229910000403 monosodium phosphate Inorganic materials 0.000 description 1
- 235000019799 monosodium phosphate Nutrition 0.000 description 1
- 238000006386 neutralization reaction Methods 0.000 description 1
- 238000005580 one pot reaction Methods 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 125000003232 p-nitrobenzoyl group Chemical group [N+](=O)([O-])C1=CC=C(C(=O)*)C=C1 0.000 description 1
- 229910052763 palladium Inorganic materials 0.000 description 1
- 229920002866 paraformaldehyde Polymers 0.000 description 1
- 230000008506 pathogenesis Effects 0.000 description 1
- 229910052698 phosphorus Inorganic materials 0.000 description 1
- 239000011574 phosphorus Substances 0.000 description 1
- 125000003367 polycyclic group Chemical group 0.000 description 1
- 230000001376 precipitating effect Effects 0.000 description 1
- 238000004321 preservation Methods 0.000 description 1
- 125000006239 protecting group Chemical group 0.000 description 1
- 238000004537 pulping Methods 0.000 description 1
- 230000009103 reabsorption Effects 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- AJPJDKMHJJGVTQ-UHFFFAOYSA-M sodium dihydrogen phosphate Chemical compound [Na+].OP(O)([O-])=O AJPJDKMHJJGVTQ-UHFFFAOYSA-M 0.000 description 1
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 description 1
- 235000010265 sodium sulphite Nutrition 0.000 description 1
- 125000003003 spiro group Chemical group 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- ILMRJRBKQSSXGY-UHFFFAOYSA-N tert-butyl(dimethyl)silicon Chemical compound C[Si](C)C(C)(C)C ILMRJRBKQSSXGY-UHFFFAOYSA-N 0.000 description 1
- 125000001981 tert-butyldimethylsilyl group Chemical group [H]C([H])([H])[Si]([H])(C([H])([H])[H])[*]C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- CZIRZNRQHFVCDZ-UHFFFAOYSA-L titan yellow Chemical compound [Na+].[Na+].C1=C(C)C(S([O-])(=O)=O)=C2SC(C3=CC=C(C=C3)/N=N/NC3=CC=C(C=C3)C3=NC4=CC=C(C(=C4S3)S([O-])(=O)=O)C)=NC2=C1 CZIRZNRQHFVCDZ-UHFFFAOYSA-L 0.000 description 1
- 239000005051 trimethylchlorosilane Substances 0.000 description 1
- 125000000026 trimethylsilyl group Chemical group [H]C([H])([H])[Si]([*])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 238000004704 ultra performance liquid chromatography Methods 0.000 description 1
- 238000001291 vacuum drying Methods 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- 230000003820 β-cell dysfunction Effects 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D309/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings
- C07D309/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
- C07D309/08—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D309/10—Oxygen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D493/00—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system
- C07D493/02—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system in which the condensed system contains two hetero rings
- C07D493/08—Bridged systems
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
Abstract
The invention relates to a preparation method of a sodium-glucose cotransporter 2 inhibitor. The invention relates to a preparation method of a compound shown in formula I' and formula I, which comprises the steps of selectively removing one molecule of TMS protecting group from a compound shown in formula II under alkaline conditions to obtain a compound shown in formula III, and then reacting the compound shown in formula III serving as a raw material to obtain a target product. The compound of formula I' can also be derivatized to obtain a compound of formula VI, which is convenient for purification. The preparation method has the advantages of few steps, low cost, suitability for industrial production and high purity of the obtained product.
Description
Technical Field
The disclosure belongs to the field of medicines, and relates to a preparation method of a sodium-glucose cotransporter 2(SGLT-2) inhibitor.
Background
In recent years, intensive research on the pathogenesis of diabetes provides more and more ways for treating type II diabetes. The discovery of sodium-glucose cotransporter 2(SGLT-2) inhibitors provides another new idea for treating diabetes. SGLT-2 functions to transport glucose. The therapeutic mechanism of SGLT-2 inhibitors is to lower blood glucose by selectively inhibiting the activity of SGLT-2. SGLT-2 was chosen as a target, on the one hand because of its absolute reabsorption of glucose and on the other hand because it is expressed only in the kidney. Since SGLT-2 inhibitors do not intervene in glucose metabolism, this therapeutic approach is a novel approach to glycemic control. It has also been found that the mechanism of action of SGLT-2 is independent of the degree of β cell dysfunction or insulin resistance, and its efficacy does not decline with β cell function failure or severe insulin resistance. Therefore, it is reasonable to consider SGLT-2 inhibitors with good prospects for current treatment of type II diabetes.
WO2012019496 discloses a novel SGLT-2 inhibitor, the structure of which is shown as formula I',
WO2016050134 discloses an L-proline complex of the compound, the structure of which is shown in formula I,
WO2012019496 discloses a preparation method of a compound of formula I', which is complicated in synthesis process, requires to perform tert-butyldimethylsilyl (TBS) and benzyl (Bn) protection on four hydroxyl groups of a tetrahydropyran ring respectively, and sequentially removes the four hydroxyl groups in the reaction process, thereby prolonging the process route. Meanwhile, the process route has the steps of column chromatography purification, which is not beneficial to large-scale production, and the removal of benzyl protection needs to utilize an expensive palladium reagent, so that the cost is high.
CN107686496A discloses a method for constructing five-membered heterocyclic ring by adopting a one-pot method, which has improved synthesis efficiency, but still fails to effectively solve the problems.
Disclosure of Invention
In order to overcome the deficiencies of the prior art, the present disclosure aims to provide a novel preparation method of SGLT-2 inhibitors.
In one aspect, the present disclosure provides novel reaction intermediates, compounds of formula a:
wherein R is1、R2Independently selected from H, -CH2OH、-CH2OTMS or-CH (═ O),
R3、R4、R5independently selected from H or TMS, and when R is1is-CH2OH and R2When is H, R3、R4、R5At least one of them is TMS.
In some embodiments, the compound of formula a is specifically selected from the following compounds:
the present disclosure also provides novel reaction intermediates, such as compounds of formula VI:
R6、R7、R8、R9independently selected from H or Q, Q is
Wherein R is10Independently selected from hydrogen, deuterium, halogen, nitro, cyano, phenyl, C optionally substituted by halogen3-C6Cycloalkyl, C optionally substituted by halogen1-C6Alkyl and optionally halogen-substituted C1-C6An alkoxy group,
n is an integer selected from 1 to 5.
In some embodiments, R6Is Q, R7、R8、R9Independently selected from H or Q; preferably R6、R7、R8、R9Is Q;
R10may be independently selected from hydrogen, halogen, nitro, cyano, C optionally substituted by halogen3-C6Cycloalkyl, C optionally substituted by halogen1-C3Alkyl and optionally halogen-substituted C1-C3An alkoxy group;
in some embodiments, R10May be independently selected from hydrogen, halogen, nitro, cyano and C1-C3An alkoxy group.
In some embodiments, Q may be specifically selected from the following structures:
in some embodiments, Q is specifically selected from
Preference is given to
More preferably
The disclosure also provides a preparation method of the compound shown in the formula III, which comprises the step of preparing the compound shown in the formula II in the presence of alkaline substances to obtain the compound shown in the formula III,
in some embodiments, the reaction solvent is selected from water, C1～C6One or more of alcohols, acetone, dichloromethane, chloroform, ethyl acetate, tetrahydrofuran, dioxane, acetonitrile, N-dimethylformamide, N-dimethylsulfoxide, preferably one or more of water, methanol, ethanol, acetone, dichloromethane, more preferably methanol;
the alkaline substance is selected from Li2CO3、Na2CO3、Ba(OH)2、K3PO4、Cs2CO3、K2CO3、KF、CsF、Bu4One or more of NF, LiOH, NaOH, KOH, triethylamine, pyridine, DIPEA, DABCO, NaOR and KOR, wherein R is independently selected from C1～C6Alkyl, wherein the basic substance is preferably Li2CO3、Na2CO3、K2CO3、Cs2CO3One or two of them, furtherPreferably Na2CO3；
The molar ratio of the compound represented by the formula II to the basic substance is 1: 0.1 to 5, preferably 1: 0.15-2, more preferably 1: 0.2-0.5;
in some embodiments, the reaction further comprises the step of quenching by the addition of an acidic species, preferably acetic acid.
The present disclosure also provides a method for preparing a compound of formula I' or a pharmaceutically acceptable amino acid complex thereof, comprising the step of preparing a compound of formula III according to the method of the present disclosure,
in some embodiments, the pharmaceutically acceptable amino acid complex of the compound of formula I' is specifically selected from the group consisting of the L-proline complex shown in formula I; l-proline monohydrate is preferred.
Further, the preparation method of the compound shown in formula I' or the pharmaceutically acceptable amino acid complex thereof, or the preparation method of the compound shown in formula I, which is disclosed by the disclosure, can also comprise a step of preparing the compound shown in formula II from the compound shown in formula a,
further, the method can also comprise a step of preparing the compound shown in the formula IV from the compound shown in the formula III through oxidation reaction,
in some embodiments, the reagent used for the oxidation reaction comprises sulfur trioxide-pyridine;
further, the method can also comprise a step of preparing the compound shown in the formula V from the compound shown in the formula IV,
further, the scheme may further comprise a step of preparing a compound represented by formula I' from a compound represented by formula V,
further, the method comprises the steps of converting the compound of formula I 'into a compound of formula VI as described in the present disclosure, purifying the compound of formula VI, and converting it into a compound of formula I',
the present disclosure also provides a method of purifying a compound of formula I', the method comprising the steps of: converting the compound of formula I 'to a compound of formula VI as described in the disclosure, purifying the compound of formula VI, and converting it to a compound of formula I'.
The present disclosure also provides a method for preparing a compound represented by formula I' or a pharmaceutically acceptable amino acid complex thereof, the method comprising the steps of: converting a compound of formula I 'to a compound of formula VI as described in the disclosure, purifying the compound of formula VI, and converting it to a compound of formula I',
in some embodiments, the purification preferably comprises recrystallization and/or beating;
further, the purified solvent is a mixed solvent of acetonitrile/isopropanol, and the mixture ratio is acetonitrile: isopropanol ═ 1:0.5-2, preferably acetonitrile: 1:1-1.5 of isopropanol; more preferably acetonitrile: isopropanol-1: 1.5.
The disclosure also provides a preparation method of the compound shown in the formula I 'or the pharmaceutically acceptable amino acid compound thereof, which comprises the step of preparing the compound shown in the formula I' from the compound shown in the formula VI,
in some embodiments, the pharmaceutically acceptable amino acid complex of the compound of formula I' is specifically selected from the group consisting of the L-proline complex shown in formula I; l-proline monohydrate is preferred.
The present disclosure also provides a method for preparing a compound represented by formula II from a compound represented by formula b, comprising the steps of:
the present disclosure also generally provides a method of preparing a compound of formula I' and formula I:
in order to further improve the purity of the product, in some embodiments, the methods of preparing compounds of formula I ' and formula I further comprise the step of derivatizing the compound of formula I ' to obtain a compound of formula VI, and purifying the compound of formula VI to recover the compound of formula I ':
the technical scheme of the disclosure has the following beneficial effects:
(1) only one protecting group TMS needs to be used and removed in the process of synthesizing the compound of the formula I', so that the process steps are shortened, and the production cost is reduced; (2) the compound of the formula III obtained by selectively removing single TMS from the compound of the formula II has high reaction specificity, and the compound of the formula III has high purity and can be directly used for the next reaction; (3) the derivative compound of formula VI can be purified by recrystallization and/or pulping, and the purity of the final product obtained in the subsequent steps is increased, thus meeting the purity requirement of the medicine; (4) the preparation method does not need column chromatography in the whole process, and is suitable for large-scale production.
Unless stated to the contrary, terms used in the specification and claims have the following meanings.
"optionally" or "optionally" means that the subsequently described event or circumstance may, but need not, occur, and that the description includes instances where the event or circumstance occurs or does not. For example "optionally halogen-substituted C1-C6Alkyl "means that a halogen may, but need not, be present, and the description includes the case where an alkyl is substituted with a halogen and the case where an alkyl is not substituted with a halogen.
"A and/or B" means any of the following: a; b; a and B, and in the case of "A and B", the order of A and B before and after is not limited. For example, "including recrystallization and/or beating" means any of the following: "including recrystallization"; "including beating"; "includes recrystallization and beating", and when "includes recrystallization and beating", the order of recrystallization and beating before and after is not limited.
In the chemical structure of the compound of the present invention, a bond
Denotes an unspecified configuration, i.e. a bond if a chiral isomer is present in the chemical structure
Can be that
Or at the same time contain
Two configurations.
Any isotopically-labeled derivative of a compound described in this disclosure or a pharmaceutically acceptable salt thereof, or an isomer thereof, is encompassed by this disclosure. Atoms that can be isotopically labeled include, but are not limited to, hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, chlorine, iodine, and the like. Each of which can be isotopically substituted2H(D)、3H、11C、13C、14C、15N、18F、31P、32P、35S、36Cl and125i, and the like. Unless otherwise indicated, when a position is specifically designated as deuterium (D), that position is understood to be deuterium having an abundance that is at least 3000 times greater than the natural abundance of deuterium (which is 0.015%) (i.e., at least 45% deuterium incorporation).
"halogen" refers to fluorine, chlorine, bromine and iodine.
"alkyl" refers to a saturated aliphatic hydrocarbon group, including straight and branched chain groups of 1 to 20 carbon atoms. Alkyl groups having 1 to 10 carbon atoms such as methyl, ethyl, propyl, 2-propyl, n-butyl, isobutyl, tert-butyl or pentyl and the like are preferred. More preferred are lower alkyl groups having 1 to 6 carbon atoms, such as methyl, ethyl, propyl, 2-propyl, n-, iso-or tert-butyl, pentyl, heptyl, and the like.
"cycloalkyl" means a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent, the cycloalkyl ring containing from 3 to 20 carbon atoms, preferably from 3 to 6 carbon atoms. Non-limiting examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, and the like; polycyclic cycloalkyl groups include spiro, fused and bridged cycloalkyl groups.
"alkoxy" refers to-O- (alkyl) and-O- (cycloalkyl), wherein alkyl and cycloalkyl are as defined above. Non-limiting examples include methoxy, ethoxy, propoxy, butoxy, cyclopropoxy, cyclobutoxy, cyclopentyloxy, cyclohexyloxy and the like.
"TMS" refers to trimethylsilyl and "TMS-Cl" refers to trimethylchlorosilane.
"PNB" refers to p-nitrobenzoyl and "PNB-Cl" refers to p-nitrobenzoyl chloride.
Detailed Description
The present invention will be explained in detail with reference to specific examples below so that those skilled in the art can more fully understand the present invention. The specific examples are only for illustrating the technical solutions of the present invention and do not limit the present invention in any way.
Experimental procedures, in which specific conditions are not noted in the examples of the present disclosure, are generally performed under conventional conditions, or under conditions recommended by manufacturers of raw materials or commercial products. Reagents of specific sources are not indicated, and conventional reagents are purchased in the market.
The structure of the compounds is determined by Nuclear Magnetic Resonance (NMR) or/and Mass Spectrometry (MS). NMR shift (. delta.) of 10-6The units in (ppm) are given. NMR was measured using a Bruker AVANCE-400 NMR spectrometer using deuterated dimethyl sulfoxide (DMSO-d6), deuterated chloroform (CDCl3), deuterated methanol (CD3OD) and Tetramethylsilane (TMS) as the internal standard. The spatial configuration of the optical isomers (isomers) of the compounds can be further confirmed by measuring parameters of the single crystal.
HPLC measurements were performed using Waters ACQUITY ultra high Performance LC, Shimadzu LC-20A systems, Shimadzu LC-2010HT series or Agilent 1200LC high pressure liquid chromatography (ACQUITY UPLC BEH C181.7UM 2.1.1X 50MM column, Ultimate XB-C183.0. 150mm column or xtmate C182.1. 30mm column).
MS is measured by a Waters SQD2 mass spectrometer, scanning is carried out in a positive/negative ion mode, and the mass scanning range is 100-1200.
Chiral HPLC analysis and determination using Chiralpak IC-3100 × 4.6mm I.D., 3um, Chiralpak AD-3150 × 4.6mm I.D., 3um, Chiralpak AD-350 × 4.6mm I.D., 3um, Chiralpak AS-3150 × 4.6mm I.D., 3um, Chiralpak AS-4.6 mm I.D., 3 μm, Chiralcel OD-3150 × 4.6mm I.D., 3um, Chiralcel OD- × 4.6mm I.D., 3 μm, Chiralcel OJ-H150 × 4.6mm I.D., 5um, Chiralcel OJ-3150 × 4.6mm I.D., 3um chromatographic column;
the thin layer chromatography silica gel plate adopts HSGF254 of tobacco yellow sea or GF254 of Qingdao, the specification of the silica gel plate used by Thin Layer Chromatography (TLC) is 0.15 mm-0.2 mm, and the specification of the thin layer chromatography separation and purification product is 0.4 mm-0.5 mm.
The flash column purification system used either Combiflash Rf150(TELEDYNE ISCO) or Isolara one (Biotage).
The forward column chromatography generally uses 100-200 mesh, 200-300 mesh or 300-400 mesh silica gel of the Titan yellow sea silica gel as a carrier, or uses a hyperpure normal phase silica gel column (40-63 μm, 60, 12g, 25g, 40g, 80g or other specifications) pre-filled by Santai in Changzhou.
Reverse phase column chromatography typically uses a column of ultrapure C18 silica gel (20-45 μm,
40g, 80g, 120g, 220g or other specifications).
The high pressure Column purification system used Waters AutoP in combination with Waters Xbridge BEH C18 OBD Prep Column,
5 μm, 19mm X150 mm or Atlantis T3OBD Prep Column,
5μm，19mm X 150mm。
the chiral preparative column used DAICEL CHIRALPAK IC (250 mm. times.30 mm,10um) or Phenomenex-Amylose-1(250 mm. times.30 mm,5 um).
Known starting materials in this disclosure can be synthesized using or according to methods known in the art, or can be purchased from companies such as Shanghai Tantan science, ABCR GmbH & Co. KG, Acros Organics, Aldrich Chemical Company, Shaoshi Chemicals (Accela ChemBio Inc), Darri Chemicals, and the like.
In the examples, the reaction can be carried out in an argon atmosphere or a nitrogen atmosphere, unless otherwise specified.
An argon atmosphere or nitrogen atmosphere means that the reaction flask is connected to a balloon of argon or nitrogen with a volume of about 1L.
The hydrogen atmosphere refers to a reaction flask connected with a hydrogen balloon with a volume of about 1L.
The pressure hydrogenation reaction used a hydrogenation apparatus of Parr 3916EKX type and a hydrogen generator of Qinglan QL-500 type or a hydrogenation apparatus of HC2-SS type.
The hydrogenation reaction was usually evacuated and charged with hydrogen and repeated 3 times.
The microwave reaction was carried out using a CEM Discover-S908860 type microwave reactor.
In the examples, the solution means an aqueous solution unless otherwise specified.
In the examples, the reaction temperature is, unless otherwise specified, from 20 ℃ to 30 ℃ at room temperature.
The progress of the reaction in the examples was monitored by Thin Layer Chromatography (TLC).
Example 1
Compound b (30.0g, 0.168mol) was dissolved in 300ml tetrahydrofuran and N-methylmorpholine (136.3g, 1347.2mmol, 8.0eq) was added to a 1L three-necked flask. TMS-Cl (109.8g, 1010.46mmol,6.0eq) was added dropwise over an ice-water bath, and after the addition was complete, the mixture was warmed to room temperature and stirred for 18 h. After the reaction, n-heptane, a saturated sodium bicarbonate solution and water were added, liquid separation was performed, and the organic layer was washed with water, a sodium dihydrogen phosphate aqueous solution and a saturated common salt in this order, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain 84.51g of a light-colored oily substance, which was used as a crude product in the next step.
Example 2
Compound d (50.0g, 145.5mmol,1.0eq) was charged in a 3L multi-necked flask, tetrahydrofuran (240mL), toluene (200mL), and n-hexane (600mL) were added, and the mixture was stirred to dissolve, n-butyllithium (95.9mL, 152.8mmol, 1.05eq, 1.6M/L) was added dropwise at-65 ℃ or lower, and stirred for 1 hour with heat preservation. A toluene solution of compound c (79.08g, 160.1mmol, 1.1eq) was added dropwise to the reaction mixture, and stirred for 2h with constant temperature. A solution of methanesulfonic acid (26.6g, 276.4mmol, 1.9eq) in methanol was added dropwise to the reaction solution under ice-bath conditions, and the mixture was stirred at room temperature for 16 hours. After the reaction, a saturated aqueous solution of sodium bicarbonate was added, liquid separation was performed, the organic phase was extracted with a saturated aqueous solution of sodium bicarbonate, the aqueous phases were combined and extracted with ethyl acetate, the ethyl acetate phase was washed with water, the ethyl acetate phase was combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain 57.82g of a foamy solid, and the crude product was used directly in the next step.
Example 3
Compound a (57.8g, 126.51mmol, 1.0eq) was dissolved in dichloromethane (578mL) and imidazole (68.89g, 1012.08mmol, 8.0eq) was added. The temperature was reduced to 0 ℃ and after addition of chlorotrimethylsilane (82.46g, 759.06mmol, 6.0eq) stirring was carried out at room temperature for 16 h. After the reaction, a saturated aqueous sodium bicarbonate solution and water were added, the mixture was separated, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to dryness to obtain 86.07g of an oil, and the crude product was used in the next step.
1H NMR(400MHz,CDCl3)d 7.29-7.45(m,1H),7.29-7.44(m,2H),6.81-6.95(m,3H),3.93-4.16(m,5H),3.82-3.90(m,1H),3.71-3.81(m,1H),3.60-3.68(m,1H),3.46-3.57(m,1H),3.19-3.28(m,1H),2.98-3.16(m,3H),1.37-1.48(m,3H),-0.03-0.25(m,28H),-0.35(s,8H)
Example 4
Compound II (86.07g, 115.44mmol, 1.0eq) was dissolved in methanol (396mL), cooled to-5 deg.C, sodium carbonate (3.42g, 32.32mmol, 0.28eq) was added and stirred for 4 h. After the reaction, acetic acid is added and stirred. The reaction mixture was concentrated under reduced pressure, followed by addition of MTBE and an aqueous solution of sodium hydrogencarbonate, liquid separation, washing of the organic phase with saturated brine, drying over anhydrous sodium sulfate, filtration and concentration under reduced pressure to give 84.25g of an oil with a purity of 86.74%, which was used as a crude product in the next step.
1H NMR(400MHz,CDCl3)d＝7.39(d,J＝8.8Hz,1H),7.34-7.28(m,2H),6.95-6.82(m,3H),4.16-3.95(m,5H),3.86(m,1H),3.79-3.71(m,1H),3.68-3.59(m,1H),3.55-3.46(m,1H),3.22(s,2H),3.16-3.01(m,3H),1.43(t,J＝7.0Hz,3H),0.31-0.13(m,19H),-0.35(s,8H)
Example 5
Compound III (84.25g, 100.13mmol, 1.0eq) was dissolved in dichloromethane (840mL), dimethyl sulfoxide (337mL), triethylamine (65.5mL), pyridine trioxide added, and reaction at 25 ℃ for 2 h. The reaction solution was diluted with MTBE, poured into a 5% aqueous sodium sulfite solution, and the organic phase was washed successively with an aqueous sodium bicarbonate solution and a saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain 85.2g of an oily substance having a purity of 82.4%, and the crude product was used directly in the next step.
1H NMR(400MHz,CDCl3)d＝9.77-8.59(m,1H),7.74-7.68(m,2H),7.32-7.28(m,1H),6.97-6.69(m,3H),4.26-3.75(m,6H),3.74-3.42(m,1H),3.33-3.17(m,1H),3.13-2.79(m,3H),1.48-1.32(m,3H),0.25--0.45(m,27H)
Example 6
Compound IV (85.2g, 100.13mmol, 1.0eq) was dissolved in ethanol (850mL), paraformaldehyde (66.08g, 2202.86mmol, 22eq) was added at 20 deg.C, 20% sodium ethoxide solution (187.38g, 550.72mmol, 5.5eq) was added, stirring was continued at room temperature for 4h, and then at 55 deg.C for 2.5 h. After the reaction, the dried ethanol is concentrated under reduced pressure, MTBE is added, liquid separation is carried out, the organic phase is washed by water, the water phases are combined, extraction is carried out by the MTBE, the organic phase is combined, anhydrous sodium sulfate is added for drying, filtration and concentration under reduced pressure are carried out, 58.46g of foamy solid is obtained, the purity is 64.5%, and the crude product is directly used in the next step.
1H NMR(400MHz,CDCl3)d＝7.45-7.30(m,1H),7.26-7.13(m,2H),6.87-6.66(m,3H),5.75-5.18(m,2H),4.54(d,J＝7.8Hz,1H),4.10(t,J＝9.8Hz,1H),4.04-3.91(m,4H),3.86-3.75(m,3H),3.73-3.62(m,4H),3.17(d,J＝9.8Hz,1H),3.01-2.74(m,3H),1.37-1.28(m,3H)
Example 7
Compound V (19.30g, 39.64mmol) was dissolved in dichloromethane (386mL), concentrated hydrochloric acid (4.8mL) was added, stirred at room temperature for 16h, anhydrous sodium sulfate was added, stirred for 2h, filtered, and the filtrate was concentrated under reduced pressure to dryness to give a foamy solid 17.73g, purity 72.05%, crude was used directly in the next step.
Example 8
Compound I' (17.73g, 38.98mmol, 1.0eq) was dissolved in dichloromethane (177mL), triethylamine (35.50g,350.82mmol, 9.0eq) and PNB-Cl (43.40g,233.88mmol, 6.0eq) were added at 0-5 deg.C, and the reaction was carried out at room temperature for 4 hours. After the reaction, a saturated aqueous solution of sodium bicarbonate was added dropwise, the mixture was separated, and the organic phase was washed with a saturated aqueous solution of sodium bicarbonate and a saturated aqueous solution of sodium chloride, respectively, dried over sodium sulfate, and concentrated under reduced pressure to dryness to obtain 36.94g of a foamy solid with a purity of 65.9%.
The crude compound VI-1 (29.00g) was added to a single-neck flask, followed by addition of a mixed solvent of acetonitrile/isopropanol (acetonitrile: isopropanol ═ 2:3), heating to reflux, natural cooling to room temperature, stirring for 18 hours, filtration, rinsing the filter cake with a mixed solvent of acetonitrile/isopropanol (acetonitrile: isopropanol ═ 2:3), and vacuum drying to give an off-white solid 15.63g with a purity of 97.6%. The obtained off-white solid was added to a single-neck flask, and then a mixed solvent of acetonitrile/isopropanol (acetonitrile: isopropanol: 2:3) was added thereto, and the mixture was heated to reflux, naturally cooled to room temperature, stirred for 18 hours, filtered, and the filter cake was rinsed with a mixed solvent of acetonitrile/isopropanol (acetonitrile: isopropanol: 2:3), and then dried under vacuum to obtain 14.83g of a white solid with a purity of 98.7% and a total yield of 45.1% in five steps from compound II.
1H NMR(400MHz,CDCl3)d＝8.34(d,J＝8.8Hz,2H),8.30-8.21(m,4H),8.17(t,J＝9.3Hz,4H),8.08(d,J＝8.8Hz,2H),8.01(d,J＝8.8Hz,2H),7.94(d,J＝8.8Hz,2H),7.48-7.41(m,2H),7.35(d,J＝8.1Hz,1H),6.79-6.70(m,2H),6.66-6.57(m,1H),6.19-6.02(m,2H),5.88(d,J＝8.1Hz,1H),4.88-4.71(m,2H),4.61(d,J＝12.7Hz,1H),4.14-3.99(m,3H),3.95(s,2H),1.43(t,J＝7.0Hz,3H)
Example 9
Dissolving compound VI-1(14.83g, 14.11mmol, 1.0eq) in THF (74mL), adding water (74mL), cooling to 0-5 deg.C, adding LiOH. H2O (2.96g,70.55mmol, 5.0eq), naturally warmed to room temperature for reaction for 3 hours, after the reaction is finished, saturated ammonium chloride is added for neutralization reaction, extraction is carried out by ethyl acetate, an organic layer is washed by saturated sodium bicarbonate and saturated saline (593mL), dried by sodium sulfate and concentrated under reduced pressure to dryness to obtain 7.03g of foamy solid with the purity of 99.2%.
Example 10
Compound I' (7.03g, theoretical 14.11mmol, 1.0eq) was placed in ethanol (70mL) and n-hexane (35mL), L-proline (1.79g, 15.52mmol, 1.1eq) and water (0.7mL) were added, the temperature was raised to 70 ℃, stirred for 30 minutes, cooled naturally to room temperature and stirred for 18 hours, filtered, the filter cake was rinsed with ethanol/n-hexane mixed solvent (ethanol/n-hexane ═ 2:1), then dried under vacuum to give 7.53g of white solid, yield in two steps 90.8%, (calculated from compound VI-1) purity 99.6%, single impurity less than 0.1%.
Comparative example 1
Dissolving compound II (2.0g, 2.68mmol, 1.0eq) in methanol (9.2mL), cooling to-5 deg.C, adding potassium carbonate (104mg, 0.75mmol, 0.28eq), stirring for 4h, HPLC-mediated, compound III accounting for 22%, compound a accounting for 48%, and most of TMS being removed.
Comparative example 2
Compound I' (1g, 2.198mmol, 1.0eq) was dissolved in toluene (10mL), pyridine (1.39g,17.59mmol, 8.0eq) was added at 0-5 deg.C, acetic anhydride (1.35g,13.19mmol, 6.0eq) was added dropwise, and the mixture was allowed to warm to room temperature naturally for 16 hours. After the reaction, a saturated aqueous solution of sodium bicarbonate was added dropwise, followed by liquid separation, and the organic phase was washed once with water, dried over magnesium sulfate, and concentrated to dryness to obtain 1.23g of a brown oily substance with a yield of 89.70% and a purity of 66.5%.
Adding isopropanol into the crude product, heating to 60 ℃, stirring, cooling to room temperature, precipitating brown oily matter which is not solidified, and spin-drying the solution.
The crude product is added with a mixed solution of acetonitrile and isopropanol (acetonitrile: isopropanol-2: 3), heated to reflux, naturally cooled to room temperature and stirred for 18 hours, and no product is precipitated.
Since the invention has been described in terms of specific embodiments thereof, certain modifications and equivalent variations will be apparent to those skilled in the art and are intended to be included within the scope of the invention.
Claims (26)
1. A compound of formula A:
wherein R is1、R2Independently selected from H, -CH2OH、-CH2OTMS or-CH (═ O),
R3、R4、R5independently selected from H or TMS, and when R is1is-CH2OH and R2When is H, R3、R4、R5At least one of them is TMS.
2. The compound according to claim 1, which is in particular selected from the following compounds:
3. a compound of formula VI:
R6、R7、R8、R9independently selected from H or Q, Q is
Wherein R is10Independently selected from hydrogen, deuterium, halogen, nitro, cyano, phenyl, C optionally substituted by halogen3-C6Cycloalkyl, C optionally substituted by halogen1-C6Alkyl and optionally halogen-substituted C1-C6An alkoxy group,
n is an integer selected from 1 to 5.
4. A compound of claim 3, wherein R is6Is Q, R7、R8、R9Is independently selected fromH or Q; preferably R6、R7、R8、R9Is Q.
5. A compound according to claim 3 or 4, wherein R is10Independently selected from hydrogen, halogen, nitro, cyano, C optionally substituted by halogen3-C6Cycloalkyl, C optionally substituted by halogen1-C3Alkyl and optionally halogen-substituted C1-C3An alkoxy group.
6. A compound of claim 5, wherein R is10Independently selected from hydrogen, halogen, nitro, cyano and C1-C3An alkoxy group.
7. A compound according to claim 3 or 4, wherein Q is selected in particular from the following structures:
8. a compound according to claim 7, wherein Q is specifically selected from
Preference is given to
More preferably
9. A preparation method of a compound shown in a formula III comprises the step of preparing the compound shown in the formula III from a compound shown in a formula II in the presence of an alkaline substance,
10. the process according to claim 9, wherein the reaction solvent is selected from water and C1～C6One or more of alcohols, acetone, dichloromethane, chloroform, ethyl acetate, tetrahydrofuran, dioxane, acetonitrile, N-dimethylformamide, N-dimethylsulfoxide, preferably one or more of water, methanol, ethanol, acetone, dichloromethane, more preferably methanol.
11. The production method according to claim 9, wherein the basic substance is selected from Li2CO3、Na2CO3、Ba(OH)2、K3PO4、Cs2CO3、K2CO3、KF、CsF、Bu4One or more of NF, LiOH, NaOH, KOH, triethylamine, pyridine, DIPEA, DABCO, NaOR and KOR, wherein R is independently selected from C1～C6Alkyl, wherein the basic substance is preferably Li2CO3、Na2CO3、K2CO3、Cs2CO3One or more of them, more preferably Na2CO3。
12. The method of claim 9, further comprising the step of quenching the reaction by adding an acidic substance, preferably acetic acid.
13. The method according to claim 9, wherein the molar ratio of the compound represented by formula II to the basic substance is 1: 0.1 to 5, preferably 1: 0.15-2, more preferably 1: 0.2-0.5.
14. A process for the preparation of a compound of formula I' or a pharmaceutically acceptable amino acid complex thereof, comprising the step of preparing a compound of formula III according to the process of any one of claims 9 to 13,
15. the method according to claim 14, wherein the pharmaceutically acceptable amino acid complex is selected from the group consisting of an L-proline complex represented by formula I; preferably the monohydrate of L-proline, and preferably,
16. the method according to claim 14 or 15, further comprising a step of preparing a compound represented by formula II from the compound represented by formula a,
17. the method according to claim 14 or 15, further comprising a step of preparing a compound represented by formula IV from a compound represented by formula III by oxidation,
18. the process of claim 17, wherein the reagent used in the oxidation reaction comprises sulfur trioxide-pyridine.
19. The method according to claim 14 or 15, further comprising a step of preparing a compound represented by formula V from a compound represented by formula IV,
20. the method according to claim 14 or 15, further comprising a step of preparing a compound represented by formula I' from a compound represented by formula V,
21. the process according to claim 14 or 15, further comprising the steps of preparing a compound of formula VI as defined in any one of claims 3 to 8 from the compound of formula I ', purifying the compound of formula VI and then reacting the purified compound of formula VI to obtain the compound of formula I',
22. a method for purifying a compound of formula I', comprising the steps of: converting a compound of formula I 'to a compound of formula VI as defined in any one of claims 3 to 8, purifying the compound of formula VI, and converting it to a compound of formula I'; said purification preferably comprises recrystallization and/or beating,
23. the method according to claim 22, wherein the purified solvent is a mixed solvent of acetonitrile/isopropanol, and the ratio of acetonitrile: isopropanol ═ 1:0.5-2, preferably acetonitrile: 1:1-1.5 of isopropanol; more preferably acetonitrile: isopropanol-1: 1.5.
24. A process for the preparation of a compound of formula I 'or a pharmaceutically acceptable amino acid complex thereof, comprising the step of preparing a compound of formula I' from a compound of formula VI as claimed in any one of claims 3 to 8,
25. a method for preparing a compound shown as a formula I' or a pharmaceutically acceptable amino acid complex thereof, which is characterized by comprising the following steps: converting a compound of formula I 'into a compound of formula VI as claimed in any of claims 3 to 8, purifying the compound of formula VI and converting it into a compound of formula I',
26. the method according to claim 24 or 25, wherein the pharmaceutically acceptable amino acid complex is selected from the group consisting of L-proline complex represented by formula I; preferably the monohydrate of L-proline, and preferably,
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| CN102372722A (en) * | 2010-08-10 | 2012-03-14 | 江苏恒瑞医药股份有限公司 | C-aryl glucoside derivative, preparation method thereof and application of C-aryl glucoside derivative in medicine |
| CN104017031A (en) * | 2014-06-21 | 2014-09-03 | 李友香 | Hypoglycemic drug and composition |
| CN104031098A (en) * | 2014-06-21 | 2014-09-10 | 李友香 | Hypoglycemic medicine |
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| CN102149717A (en) * | 2008-08-28 | 2011-08-10 | 辉瑞大药厂 | Dioxa-bicyclo[3.2.1]octane-2,3,4-triol derivatives |
| CN102372722A (en) * | 2010-08-10 | 2012-03-14 | 江苏恒瑞医药股份有限公司 | C-aryl glucoside derivative, preparation method thereof and application of C-aryl glucoside derivative in medicine |
| CN104017031A (en) * | 2014-06-21 | 2014-09-03 | 李友香 | Hypoglycemic drug and composition |
| CN104031098A (en) * | 2014-06-21 | 2014-09-10 | 李友香 | Hypoglycemic medicine |
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