CN112110910A - 制备利伐沙班中间体的方法及由其制备利伐沙班的方法 - Google Patents
制备利伐沙班中间体的方法及由其制备利伐沙班的方法 Download PDFInfo
- Publication number
- CN112110910A CN112110910A CN201910530922.6A CN201910530922A CN112110910A CN 112110910 A CN112110910 A CN 112110910A CN 201910530922 A CN201910530922 A CN 201910530922A CN 112110910 A CN112110910 A CN 112110910A
- Authority
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- China
- Prior art keywords
- magnesium
- acid
- formula
- organic solvent
- compound
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
- 238000000034 method Methods 0.000 title claims abstract description 41
- KGFYHTZWPPHNLQ-AWEZNQCLSA-N rivaroxaban Chemical compound S1C(Cl)=CC=C1C(=O)NC[C@@H]1OC(=O)N(C=2C=CC(=CC=2)N2C(COCC2)=O)C1 KGFYHTZWPPHNLQ-AWEZNQCLSA-N 0.000 title claims abstract description 29
- 229960001148 rivaroxaban Drugs 0.000 title claims abstract description 29
- DEXXSYVEWAYIGZ-LBPRGKRZSA-N 4-[4-[(5s)-5-(aminomethyl)-2-oxo-1,3-oxazolidin-3-yl]phenyl]morpholin-3-one Chemical compound O=C1O[C@@H](CN)CN1C1=CC=C(N2C(COCC2)=O)C=C1 DEXXSYVEWAYIGZ-LBPRGKRZSA-N 0.000 title claims abstract description 28
- 238000006243 chemical reaction Methods 0.000 claims description 73
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical group CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 66
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 66
- 150000001875 compounds Chemical class 0.000 claims description 47
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 43
- 238000003756 stirring Methods 0.000 claims description 32
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 31
- 239000003960 organic solvent Substances 0.000 claims description 27
- TWRXJAOTZQYOKJ-UHFFFAOYSA-L Magnesium chloride Chemical compound [Mg+2].[Cl-].[Cl-] TWRXJAOTZQYOKJ-UHFFFAOYSA-L 0.000 claims description 20
- 229910052751 metal Inorganic materials 0.000 claims description 20
- 239000002184 metal Substances 0.000 claims description 20
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 20
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 18
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical group [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 18
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 16
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 16
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 12
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 12
- 239000002253 acid Substances 0.000 claims description 12
- 239000011230 binding agent Substances 0.000 claims description 12
- 150000007524 organic acids Chemical class 0.000 claims description 12
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 claims description 12
- 239000004593 Epoxy Substances 0.000 claims description 11
- 159000000003 magnesium salts Chemical class 0.000 claims description 11
- ITMCEJHCFYSIIV-UHFFFAOYSA-N triflic acid Chemical compound OS(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-N 0.000 claims description 11
- RVDLHGSZWAELAU-UHFFFAOYSA-N 5-tert-butylthiophene-2-carbonyl chloride Chemical compound CC(C)(C)C1=CC=C(C(Cl)=O)S1 RVDLHGSZWAELAU-UHFFFAOYSA-N 0.000 claims description 10
- 150000004703 alkoxides Chemical class 0.000 claims description 10
- 229910001629 magnesium chloride Inorganic materials 0.000 claims description 10
- 229910001507 metal halide Inorganic materials 0.000 claims description 10
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 10
- 235000011181 potassium carbonates Nutrition 0.000 claims description 10
- 230000035484 reaction time Effects 0.000 claims description 10
- 239000002904 solvent Substances 0.000 claims description 9
- UCPYLLCMEDAXFR-UHFFFAOYSA-N triphosgene Chemical compound ClC(Cl)(Cl)OC(=O)OC(Cl)(Cl)Cl UCPYLLCMEDAXFR-UHFFFAOYSA-N 0.000 claims description 9
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 8
- KTVKQTNGWVJHFL-UHFFFAOYSA-N 2-ethylchromen-4-one Chemical compound C1=CC=C2OC(CC)=CC(=O)C2=C1 KTVKQTNGWVJHFL-UHFFFAOYSA-N 0.000 claims description 8
- QZLSBOVWPHXCLT-UHFFFAOYSA-N 5-chlorothiophene-2-carboxylic acid Chemical compound OC(=O)C1=CC=C(Cl)S1 QZLSBOVWPHXCLT-UHFFFAOYSA-N 0.000 claims description 8
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 claims description 8
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 claims description 8
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 claims description 8
- AMXOYNBUYSYVKV-UHFFFAOYSA-M lithium bromide Chemical compound [Li+].[Br-] AMXOYNBUYSYVKV-UHFFFAOYSA-M 0.000 claims description 8
- KWGKDLIKAYFUFQ-UHFFFAOYSA-M lithium chloride Chemical compound [Li+].[Cl-] KWGKDLIKAYFUFQ-UHFFFAOYSA-M 0.000 claims description 8
- VTHJTEIRLNZDEV-UHFFFAOYSA-L magnesium dihydroxide Chemical compound [OH-].[OH-].[Mg+2] VTHJTEIRLNZDEV-UHFFFAOYSA-L 0.000 claims description 8
- 239000000347 magnesium hydroxide Substances 0.000 claims description 8
- 229910001862 magnesium hydroxide Inorganic materials 0.000 claims description 8
- VLTRZXGMWDSKGL-UHFFFAOYSA-M perchlorate Inorganic materials [O-]Cl(=O)(=O)=O VLTRZXGMWDSKGL-UHFFFAOYSA-M 0.000 claims description 8
- VLTRZXGMWDSKGL-UHFFFAOYSA-N perchloric acid Chemical compound OCl(=O)(=O)=O VLTRZXGMWDSKGL-UHFFFAOYSA-N 0.000 claims description 8
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 8
- ZCPJBHYNOFIAPJ-AENDTGMFSA-N (2s)-1-amino-3-chloropropan-2-ol;hydrochloride Chemical compound Cl.NC[C@H](O)CCl ZCPJBHYNOFIAPJ-AENDTGMFSA-N 0.000 claims description 7
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 claims description 7
- 239000000395 magnesium oxide Substances 0.000 claims description 7
- CPLXHLVBOLITMK-UHFFFAOYSA-N magnesium oxide Inorganic materials [Mg]=O CPLXHLVBOLITMK-UHFFFAOYSA-N 0.000 claims description 7
- AXZKOIWUVFPNLO-UHFFFAOYSA-N magnesium;oxygen(2-) Chemical compound [O-2].[Mg+2] AXZKOIWUVFPNLO-UHFFFAOYSA-N 0.000 claims description 7
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical group ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 6
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 claims description 6
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 claims description 6
- 229910052749 magnesium Inorganic materials 0.000 claims description 6
- 239000011777 magnesium Substances 0.000 claims description 6
- CRGZYKWWYNQGEC-UHFFFAOYSA-N magnesium;methanolate Chemical compound [Mg+2].[O-]C.[O-]C CRGZYKWWYNQGEC-UHFFFAOYSA-N 0.000 claims description 6
- 150000005309 metal halides Chemical class 0.000 claims description 6
- 239000011736 potassium bicarbonate Substances 0.000 claims description 6
- 235000015497 potassium bicarbonate Nutrition 0.000 claims description 6
- 229910000028 potassium bicarbonate Inorganic materials 0.000 claims description 6
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 claims description 6
- 235000011118 potassium hydroxide Nutrition 0.000 claims description 6
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 6
- 235000017550 sodium carbonate Nutrition 0.000 claims description 6
- 235000011121 sodium hydroxide Nutrition 0.000 claims description 6
- MPCRDALPQLDDFX-UHFFFAOYSA-L Magnesium perchlorate Chemical compound [Mg+2].[O-]Cl(=O)(=O)=O.[O-]Cl(=O)(=O)=O MPCRDALPQLDDFX-UHFFFAOYSA-L 0.000 claims description 5
- UEGPKNKPLBYCNK-UHFFFAOYSA-L magnesium acetate Chemical compound [Mg+2].CC([O-])=O.CC([O-])=O UEGPKNKPLBYCNK-UHFFFAOYSA-L 0.000 claims description 5
- 239000011654 magnesium acetate Substances 0.000 claims description 5
- 235000011285 magnesium acetate Nutrition 0.000 claims description 5
- 229940069446 magnesium acetate Drugs 0.000 claims description 5
- ZLNQQNXFFQJAID-UHFFFAOYSA-L magnesium carbonate Chemical group [Mg+2].[O-]C([O-])=O ZLNQQNXFFQJAID-UHFFFAOYSA-L 0.000 claims description 5
- 239000001095 magnesium carbonate Substances 0.000 claims description 5
- 229910000021 magnesium carbonate Inorganic materials 0.000 claims description 5
- 239000000203 mixture Substances 0.000 claims description 5
- 238000000926 separation method Methods 0.000 claims description 5
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-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
- 229910052783 alkali metal Inorganic materials 0.000 claims description 4
- 150000001340 alkali metals Chemical class 0.000 claims description 4
- 229910052784 alkaline earth metal Inorganic materials 0.000 claims description 4
- 150000001342 alkaline earth metals Chemical class 0.000 claims description 4
- SRSXLGNVWSONIS-UHFFFAOYSA-N benzenesulfonic acid Chemical compound OS(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-N 0.000 claims description 4
- 229940092714 benzenesulfonic acid Drugs 0.000 claims description 4
- HSZCZNFXUDYRKD-UHFFFAOYSA-M lithium iodide Chemical compound [Li+].[I-] HSZCZNFXUDYRKD-UHFFFAOYSA-M 0.000 claims description 4
- OTCKOJUMXQWKQG-UHFFFAOYSA-L magnesium bromide Chemical compound [Mg+2].[Br-].[Br-] OTCKOJUMXQWKQG-UHFFFAOYSA-L 0.000 claims description 4
- 229910001623 magnesium bromide Inorganic materials 0.000 claims description 4
- HCWCAKKEBCNQJP-UHFFFAOYSA-N magnesium orthosilicate Chemical compound [Mg+2].[Mg+2].[O-][Si]([O-])([O-])[O-] HCWCAKKEBCNQJP-UHFFFAOYSA-N 0.000 claims description 4
- 239000000391 magnesium silicate Substances 0.000 claims description 4
- 229910052919 magnesium silicate Inorganic materials 0.000 claims description 4
- 235000019792 magnesium silicate Nutrition 0.000 claims description 4
- WNJYXPXGUGOGBO-UHFFFAOYSA-N magnesium;propan-1-olate Chemical compound CCCO[Mg]OCCC WNJYXPXGUGOGBO-UHFFFAOYSA-N 0.000 claims description 4
- 229940098779 methanesulfonic acid Drugs 0.000 claims description 4
- MFRIHAYPQRLWNB-UHFFFAOYSA-N sodium tert-butoxide Chemical compound [Na+].CC(C)(C)[O-] MFRIHAYPQRLWNB-UHFFFAOYSA-N 0.000 claims description 4
- ZXEKIIBDNHEJCQ-UHFFFAOYSA-N isobutanol Chemical compound CC(C)CO ZXEKIIBDNHEJCQ-UHFFFAOYSA-N 0.000 claims description 3
- MHCFAGZWMAWTNR-UHFFFAOYSA-M lithium perchlorate Chemical compound [Li+].[O-]Cl(=O)(=O)=O MHCFAGZWMAWTNR-UHFFFAOYSA-M 0.000 claims description 3
- 229910001486 lithium perchlorate Inorganic materials 0.000 claims description 3
- -1 preferably Chemical class 0.000 claims description 3
- WHQOKFZWSDOTQP-UHFFFAOYSA-N 2,3-dihydroxypropyl 4-aminobenzoate Chemical compound NC1=CC=C(C(=O)OCC(O)CO)C=C1 WHQOKFZWSDOTQP-UHFFFAOYSA-N 0.000 claims description 2
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 claims description 2
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 2
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 claims description 2
- UXVMQQNJUSDDNG-UHFFFAOYSA-L Calcium chloride Chemical compound [Cl-].[Cl-].[Ca+2] UXVMQQNJUSDDNG-UHFFFAOYSA-L 0.000 claims description 2
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 2
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 claims description 2
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 claims description 2
- NTIZESTWPVYFNL-UHFFFAOYSA-N Methyl isobutyl ketone Chemical compound CC(C)CC(C)=O NTIZESTWPVYFNL-UHFFFAOYSA-N 0.000 claims description 2
- UIHCLUNTQKBZGK-UHFFFAOYSA-N Methyl isobutyl ketone Natural products CCC(C)C(C)=O UIHCLUNTQKBZGK-UHFFFAOYSA-N 0.000 claims description 2
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 claims description 2
- 150000001263 acyl chlorides Chemical class 0.000 claims description 2
- 125000000217 alkyl group Chemical group 0.000 claims description 2
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 2
- 229910052794 bromium Inorganic materials 0.000 claims description 2
- 239000011575 calcium Substances 0.000 claims description 2
- 229910052791 calcium Inorganic materials 0.000 claims description 2
- 229910001622 calcium bromide Inorganic materials 0.000 claims description 2
- 239000001110 calcium chloride Substances 0.000 claims description 2
- 229910001628 calcium chloride Inorganic materials 0.000 claims description 2
- WGEFECGEFUFIQW-UHFFFAOYSA-L calcium dibromide Chemical compound [Ca+2].[Br-].[Br-] WGEFECGEFUFIQW-UHFFFAOYSA-L 0.000 claims description 2
- JHLCADGWXYCDQA-UHFFFAOYSA-N calcium;ethanolate Chemical compound [Ca+2].CC[O-].CC[O-] JHLCADGWXYCDQA-UHFFFAOYSA-N 0.000 claims description 2
- AMJQWGIYCROUQF-UHFFFAOYSA-N calcium;methanolate Chemical compound [Ca+2].[O-]C.[O-]C AMJQWGIYCROUQF-UHFFFAOYSA-N 0.000 claims description 2
- 125000004432 carbon atom Chemical group C* 0.000 claims description 2
- 230000003197 catalytic effect Effects 0.000 claims description 2
- 239000000460 chlorine Substances 0.000 claims description 2
- 229910052801 chlorine Inorganic materials 0.000 claims description 2
- 229910052736 halogen Inorganic materials 0.000 claims description 2
- 150000002367 halogens Chemical group 0.000 claims description 2
- 238000003402 intramolecular cyclocondensation reaction Methods 0.000 claims description 2
- 229910052740 iodine Inorganic materials 0.000 claims description 2
- 239000011630 iodine Substances 0.000 claims description 2
- 229910052744 lithium Inorganic materials 0.000 claims description 2
- LZWQNOHZMQIFBX-UHFFFAOYSA-N lithium;2-methylpropan-2-olate Chemical compound [Li+].CC(C)(C)[O-] LZWQNOHZMQIFBX-UHFFFAOYSA-N 0.000 claims description 2
- AZVCGYPLLBEUNV-UHFFFAOYSA-N lithium;ethanolate Chemical compound [Li+].CC[O-] AZVCGYPLLBEUNV-UHFFFAOYSA-N 0.000 claims description 2
- YCCQFVKDUYOJJL-UHFFFAOYSA-N magnesium 2-methylbutan-2-olate Chemical compound CCC(C)([O-])C.[Mg+2].CCC(C)([O-])C YCCQFVKDUYOJJL-UHFFFAOYSA-N 0.000 claims description 2
- BLQJIBCZHWBKSL-UHFFFAOYSA-L magnesium iodide Chemical compound [Mg+2].[I-].[I-] BLQJIBCZHWBKSL-UHFFFAOYSA-L 0.000 claims description 2
- 229910001641 magnesium iodide Inorganic materials 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 claims description 2
- 229910052700 potassium Inorganic materials 0.000 claims description 2
- 239000011591 potassium Substances 0.000 claims description 2
- BDAWXSQJJCIFIK-UHFFFAOYSA-N potassium methoxide Chemical compound [K+].[O-]C BDAWXSQJJCIFIK-UHFFFAOYSA-N 0.000 claims description 2
- 229910052708 sodium Inorganic materials 0.000 claims description 2
- 239000011734 sodium Substances 0.000 claims description 2
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 claims description 2
- YJPVTCSBVRMESK-UHFFFAOYSA-L strontium bromide Chemical compound [Br-].[Br-].[Sr+2] YJPVTCSBVRMESK-UHFFFAOYSA-L 0.000 claims description 2
- 229910001625 strontium bromide Inorganic materials 0.000 claims description 2
- 229940074155 strontium bromide Drugs 0.000 claims description 2
- 229910001631 strontium chloride Inorganic materials 0.000 claims description 2
- AHBGXTDRMVNFER-UHFFFAOYSA-L strontium dichloride Chemical compound [Cl-].[Cl-].[Sr+2] AHBGXTDRMVNFER-UHFFFAOYSA-L 0.000 claims description 2
- 125000003944 tolyl group Chemical group 0.000 claims description 2
- 238000009833 condensation Methods 0.000 claims 1
- 230000005494 condensation Effects 0.000 claims 1
- 239000012535 impurity Substances 0.000 abstract description 9
- 238000002360 preparation method Methods 0.000 abstract description 6
- 230000015572 biosynthetic process Effects 0.000 abstract description 4
- 238000003786 synthesis reaction Methods 0.000 abstract description 3
- 239000000543 intermediate Substances 0.000 description 46
- 239000000243 solution Substances 0.000 description 41
- 238000001914 filtration Methods 0.000 description 20
- 238000001816 cooling Methods 0.000 description 15
- 239000012065 filter cake Substances 0.000 description 14
- 239000000047 product Substances 0.000 description 14
- 239000012043 crude product Substances 0.000 description 12
- 238000004537 pulping Methods 0.000 description 12
- 238000005160 1H NMR spectroscopy Methods 0.000 description 11
- 238000001228 spectrum Methods 0.000 description 9
- 238000001035 drying Methods 0.000 description 7
- 239000000706 filtrate Substances 0.000 description 6
- 239000012046 mixed solvent Substances 0.000 description 6
- 239000007787 solid Substances 0.000 description 5
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 4
- 239000007791 liquid phase Substances 0.000 description 4
- 229910000402 monopotassium phosphate Inorganic materials 0.000 description 4
- 235000019796 monopotassium phosphate Nutrition 0.000 description 4
- 239000012071 phase Substances 0.000 description 4
- PJNZPQUBCPKICU-UHFFFAOYSA-N phosphoric acid;potassium Chemical compound [K].OP(O)(O)=O PJNZPQUBCPKICU-UHFFFAOYSA-N 0.000 description 4
- 125000000612 phthaloyl group Chemical group C(C=1C(C(=O)*)=CC=CC1)(=O)* 0.000 description 4
- 238000004809 thin layer chromatography Methods 0.000 description 4
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-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
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 3
- 238000005481 NMR spectroscopy Methods 0.000 description 3
- 238000004458 analytical method Methods 0.000 description 3
- 239000003795 chemical substances by application Substances 0.000 description 3
- 238000004587 chromatography analysis Methods 0.000 description 3
- 238000010511 deprotection reaction Methods 0.000 description 3
- 238000004128 high performance liquid chromatography Methods 0.000 description 3
- 125000006239 protecting group Chemical group 0.000 description 3
- 238000007142 ring opening reaction Methods 0.000 description 3
- 150000003839 salts Chemical class 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- KCOPAESEGCGTKM-UHFFFAOYSA-N 1,3-oxazol-4-one Chemical compound O=C1COC=N1 KCOPAESEGCGTKM-UHFFFAOYSA-N 0.000 description 2
- BAVYZALUXZFZLV-UHFFFAOYSA-N Methylamine Chemical compound NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 230000007547 defect Effects 0.000 description 2
- 238000007872 degassing Methods 0.000 description 2
- 238000001514 detection method Methods 0.000 description 2
- 239000003085 diluting agent Substances 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 238000010438 heat treatment Methods 0.000 description 2
- 238000002386 leaching Methods 0.000 description 2
- 239000012528 membrane Substances 0.000 description 2
- 239000011259 mixed solution Substances 0.000 description 2
- 238000007086 side reaction Methods 0.000 description 2
- 239000000741 silica gel Substances 0.000 description 2
- 229910002027 silica gel Inorganic materials 0.000 description 2
- 238000001308 synthesis method Methods 0.000 description 2
- 238000002604 ultrasonography Methods 0.000 description 2
- 238000005303 weighing Methods 0.000 description 2
- BRLQWZUYTZBJKN-VKHMYHEASA-N (-)-Epichlorohydrin Chemical compound ClC[C@H]1CO1 BRLQWZUYTZBJKN-VKHMYHEASA-N 0.000 description 1
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 1
- OMOBWMBJNNCUFO-UHFFFAOYSA-N 5-chlorothiophene-2-carboxamide Chemical compound NC(=O)C1=CC=C(Cl)S1 OMOBWMBJNNCUFO-UHFFFAOYSA-N 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- WOYBPWHILGLKFA-UHFFFAOYSA-N ClC1(SC=CC1)C(=O)O Chemical compound ClC1(SC=CC1)C(=O)O WOYBPWHILGLKFA-UHFFFAOYSA-N 0.000 description 1
- 208000005189 Embolism Diseases 0.000 description 1
- 229940123583 Factor Xa inhibitor Drugs 0.000 description 1
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Abstract
本发明提供了一种制备式(VI)所示利伐沙班中间体的方法以及制备利伐沙班的方法。所述中间体的制备方法具有步骤简单、条件易控、选择性好、收率高、杂质少等优点,可实现利伐沙班的绿色合成。
Description
技术领域
本发明涉及制药技术领域,具体涉及制备利伐沙班中间体的方法及由其制备利法沙班的方法。通过利用该中间体制备利伐沙班的方法原料易得、工艺简洁、反应条件温和且适合工业化。
背景技术
利伐沙班是拜耳公司开发的全球第一个可口服的抗凝药,为Xa因子抑制剂,主要用于成人静脉血栓的防治,也能降低部分卒中和全身性栓塞的风险。利伐沙班具有生物利用度高,治疗疾病谱广,量效关系稳定,出血风险低等优点,自上市以来,受到广泛认可,已成为最具市场前景的抗栓药物之一。
关于利伐沙班的制备,目前国内外报道了多种方法,但这些的方法都存在一定缺点,如下所示:
路线一是原研公司在已获授权专利(CN1434822、CN1906191)中公开的合成路线,式(V)化合物和含邻苯二甲酰保护基的环氧化合物(1a)反应,得到中间体1b,中间体1b与羰基二咪唑反应形成恶唑啉酮1c,随后经甲胺脱保护及成盐得到中间体1d;最后,中间体1d与2-氯-噻吩-2-甲酸(I)缩合,得到利伐沙班。在该路线中,中间体1c脱保护,生成大量含邻苯二甲酰基片段的副产物,这些副产物可残留在中间体1d中,最终影响产品的纯度。此外,1c脱保护后,反应液用过量盐酸酸化,导致了大量污水产生,不符合“绿色、清洁”的生产理念。
路线一:原研公司报道的合成路线
专利WO2012032533所公开的路线,与原研路线大体相同,关键中间体的合成仍需利用邻苯二甲酰作为保护基,同样具有上述路线的缺点。
路线二:WO2012032533中的合成路线
加拿大APOTEX PHARMACHEM公司在中国申请的专利CN102844309中,报道了一条利伐沙班新的合成路线。化合物(V)先与氯甲酸甲酯3a反应得到中间体3b,3b再与R-环氧氯丙烷发生取代反应,得到中间体3c。在强碱存在下,3c与5-氯噻吩-2-甲酰胺发生环氧开环及分子内环合反应,得到终产物。该路线虽然步骤少,但中间体3c及目标产物的收率都比较低,而且需无水操作,不适合工业化应用。
路线三:CN102844309中的合成路线
路线四是BAYER HEALTHCARE AG公司在其美国专利US2010081807中报道的一条避免使用邻苯二甲酰做保护基的利伐沙班的合成路线。在该路线中,中间体4d到(VI)的合成为关键步骤,但该步骤收率偏低,并且4d的制备需使用醋酐与强腐蚀性的氢溴酸溶液,氢溴酸溶液具高挥发性,易造成设备损坏,也有安全隐患。
路线四:US2010081807中的合成路线
另一篇专利CN102753537报道的合成方法,虽然避免使用氢溴酸,但由于4c的两个羟基都有反应活性,在制备中间体5a的过程中,不可避免存在副反应,加之5a为油状物,杂质不易除去,最终会影响关键中间体和最终产品的纯度。
路线五:CN102753537中的合成路线
印度制药公司RANBAXY LAB在专利WO2013156936中公开的利伐沙班合成路线也无需利用邻苯二甲酰保护的中间体。该路线中,中间体(III)先转为化学反应活性更高的环氧化合物(IV),该活性中间体再与化合物(V)反应,得到关键中间体(VI),两步收率50%左右。随后一篇专利(WO2015000617)报道,在环氧开环这步反应中,通过加入金属盐,如高氯酸锂、高氯酸镁或三氟甲磺酸镁等可显著提高中间体(VI)的收率。然而,这些金属盐并非工业上常用到的,市场上不易大量获取,质量也难以保证。另外,由于环氧中间体(IV)的化学稳定性较差,分离之后再投入反应,很容易引入杂质,不能长期储存,这些问题使该路线的工业应用受到限制。
路线六:WO2013156936中的合成路线
现有利伐沙班的制备方法都不够理想,鉴于其良好的市场前景及潜在的需求,开发简单、经济、环保、易于工业化的工艺路线具有现实意义。
发明内容
针对现有技术不足,本发明提供了一种制备式(VI)所示的利伐沙班中间体的方法,
所述方法选自以下方法中的一种:
方法一:
B-1)式(III)化合物先经分子内环合,形成式(IV)环氧中间体,该中间体不经分离,与式(V)化合物在镁盐或氧化镁或氢氧化镁和有机酸预先反应形成的体系的介导下反应,得到利伐沙班关键中间体(VI)
或者,
方法二:
B-2)式(III)化合物与式(V)化合物在金属醇盐M(OR)n、金属卤化物MYn或金属高氯酸盐M(ClO4)n的存在下直接反应,得到利伐沙班关键中间体(VI)
在方法一中,所述镁盐为碳酸镁、乙酸镁、甲醇镁、乙醇镁、叔丁醇镁、硅酸镁、氯化镁,所述有机酸优选为三氟乙酸、三氟甲磺酸、甲磺酸、对甲苯磺酸或苯磺酸;
在方法二中,M选自碱金属或碱土金属中的任意一种,优选地,所述碱金属为钠、钾或锂;所述碱土金属为镁或钙,R选自碳原子为1~5的烷基,n为1或2;
Y选自卤素,优选为氯、溴或碘。
优选地,上述步骤B-1)包括:
B-1.1)镁盐或氧化镁或氢氧化镁加入到含水的有机溶剂中,一定温度下,加入有机酸,搅拌,直至形成澄清或部分澄清的溶液。其中,所述的镁盐为碳酸镁、乙酸镁、甲醇镁、乙醇镁、叔丁醇镁、硅酸镁、氯化镁,所用有机溶剂为丙酮、乙腈、四氢呋喃或1,4-二氧六环,水的量为有机酸用量的0.1-10倍摩尔量,所用有机酸为三氟乙酸、三氟甲磺酸、甲磺酸、对甲苯磺酸或苯磺酸,优选三氟甲磺酸或对甲苯磺酸,反应温度为0-50℃,优选0-20℃,反应时间为0.1-5h;
B-1.2)式(III)化合物在有机溶剂和缚酸剂存在下,形成中间体(IV),该中间体不经分离,与式(V)化合物一起加入到步骤B-1.1的溶液中,一定温度下反应,生成式(VI)中间体。其中,所用有机溶剂为丙酮、乙腈、四氢呋喃或1,4-二氧六环,所述缚酸剂选自氢氧化钠、氢氧化钾、碳酸氢钠、碳酸氢钾、碳酸钠和碳酸钾,反应温度为10-50℃,优选20-40℃,反应时间为8-24h。
优选地,上述步骤B-2)包括:
式(III)化合物和式(V)化合物,在有机溶剂中,通过加入金属醇盐M(OR)n、金属卤化物MYn或金属高氯酸盐M(ClO4)n中的一种或多种,在一定温度下反应,直接生成中间体(VI)。其中,所述的金属醇盐M(OR)n选自甲醇钠、甲醇钾、乙醇锂、乙醇钠、甲醇镁、乙醇镁、正丙醇镁、甲醇钙、乙醇钙、叔丁醇钠、叔丁醇锂、叔丁醇镁、异丁醇镁或叔戊醇镁;优选地,所述的金属醇盐M(OR)n选自乙醇镁、正丙醇镁、叔丁醇镁或异丁醇镁;更优选地,所述的金属醇盐M(OR)n为乙醇镁或叔丁醇镁。所述的金属卤化物MYn选自氯化锂、溴化锂、碘化锂、氯化镁、溴化镁、碘化镁、氯化钙、溴化钙、氯化锶或溴化锶;优选地,所述金属卤化物MYn为溴化锂、氯化锂、溴化镁或氯化镁;更优选地,所述的金属卤化物MYn为氯化镁。所述金属高氯酸盐M(ClO4)n选自高氯酸锂、高氯酸镁、高氯酸钙;优选地,所述金属高氯酸盐为高氯酸镁。所述的有机溶剂选自乙腈、乙醇、异丙醇、1-丁醇、叔丁醇、甲苯、丙酮、4-甲基-2-戊酮、N,N-二甲基甲酰胺中的一种或多种的组合;优选地,所述有机溶剂为乙腈或甲苯或叔丁醇;反应温度为50-150℃;反应时间为8-24h。
所述式(III)化合物由5-氯噻吩-2-甲酸(I)与(S)-1-氨基-3-氯-2-丙醇盐酸盐(II)缩合得到:
具体地,5-氯噻吩-2-甲酸(I)先通过三光气和催化量的DMF活化为酰氯,再在溶剂和缚酸剂存在下,与(S)-1-氨基-3-氯-2-丙醇盐酸盐(II)反应,制备式(III)化合物。其中,三光气用量为5-氯噻吩-2-甲酸的0.3-0.5倍摩尔量,DMF用量为5-氯噻吩-2-甲酸的0.01-0.3倍摩尔量,所述溶剂为有机溶剂与水的混合物,水与有机溶剂的重量比例为5:1-1:20,有机溶剂选自二氯甲烷、甲苯、丙酮、乙腈、四氢呋喃和1,4-二氧六环,所述缚酸剂选自氢氧化钠、氢氧化钾、碳酸氢钠、碳酸氢钾、碳酸钠和碳酸钾,反应温度为-10-50℃,反应时间为1-10h。
本发明的又一目的是提供了一种制备利伐沙班的方法,其包括如下步骤:
步骤1:根据上述方法制备利伐沙班中间体(VI);
步骤2:
中间体(VI)与三光气在含水溶剂和缚酸剂存在下反应,经后处理,得到利伐沙班,其中,所述含水溶剂是指水与有机溶剂按一定比例的混合物,有机溶剂选自甲苯、丙酮、乙腈、四氢呋喃和1,4-二氧六环,水与有机溶剂的重量比例为1:50-1:2,所述缚酸剂选自氢氧化钠、氢氧化钾、碳酸氢钠、碳酸氢钾、碳酸钠和碳酸钾,反应温度为0-150℃,反应时间为1-10h。
有益效果
由于以上技术方案的实施,本发明与现有技术相比具有如下优点:
本发明提供了两种制备利伐沙班关键中间体(VI)的方法,方法一:式(III)化合物在一定条件下转变成环氧,该中间体不经分离,与式(V)化合物在镁盐或氧化镁或氢氧化镁和有机酸预先反应形成的体系的介导下反应,高收率得到利伐沙班中间体(VI)。该方法在很大程度上可减少因环氧中间体不稳定而引起的副反应,镁盐或氧化镁或氢氧化镁和有机酸预先反应形成的体系对环氧开环具有显著的促进作用,与现有技术相比,可明显降低物料成本、提高产物收率及产品质量,更适合工业化应用。方法二:式(III)化合物与式(V)化合物在镁盐的存在下直接反应,得到利伐沙班关键中间体(VI),该方法的收率与现有合成方法的相当,但无需将式(III)化合物转成环氧活性中间体,操作更加简洁,一定程度上也降低物料消耗及废物的产生。本发明提供的利伐沙班的制备方法,可以达到95%的摩尔收率,粗品纯度≥99%,单个杂质≤0.10%,显著优于现有合成方法。
附图说明
图1为式(VI)化合物的H-NMR图谱;
图2为式(VI)化合物的红外图谱;
图3为式(VI)化合物的HPLC图谱;
图4为利伐沙班的H-NMR图谱;
图5为利伐沙班的HPLC图谱。
具体实施方式
以下结合具体的实施例对本发明做进一步详细的说明,但本发明不限于以下实施例。
样品数据由以下仪器测定:核磁共振氢谱(1H NMR)和核磁共振碳谱(13C NMR)用Bruker Avance III 400核磁共振仪测定,以TMS为内标,化学位移单位为ppm;质谱用Finnigan LCQ/DECA和Micromass Ultra Q-TOF(ESI)质谱仪测定;纯度分析使用的液相型号为Waters2489;显色使用的精科WFH-203B三用紫外分析仪,波长为254nm和365nm。所有温度以℃(摄氏度)表示,室温或环境温度是指20-25℃。
TLC硅胶板为烟台化工厂生产的HSGF-254型薄层层析硅胶板,薄层层析使用的层析板厚度为0.2±0.03mm,丙酮、乙腈、乙酸乙酯、乙醇、碳酸氢钠、碳酸钾、叔丁醇镁、氢氧化镁试剂均为分析纯,由国药集团化学试剂有限公司提供,所用试剂和溶剂除特别说明外,均未经特别处理。
式(III)化合物纯度分析的HPLC测定条件
色谱条件:
色谱柱:Phenomenex Gemini C18,4.6×250mm,5μm或者等同的色谱柱。
流动相A:0.02M磷酸二氢钾溶液(pH4.0):称取磷酸二氢钾2.72g至950mL水中,超声溶解,用磷酸调节pH至4.0,加水至1000mL,用0.45μm滤膜过滤,脱气。
流动相B:乙腈
流速:1.0mL/min;检测波长:250nm;柱温:30℃;进样体积:5μl;稀释剂:水:乙腈=50:50(v/v);样品浓度:1mg/mL
利伐沙班纯度分析的HPLC测定条件
色谱条件:
色谱柱:Phenomenex Gemini C18,4.6×250mm,5μm或者等同的色谱柱。
流动相A:0.02M磷酸二氢钾溶液(pH=4.0):称取磷酸二氢钾2.72g至950mL水中,超声溶解,用磷酸调节pH至4.0,加水至1000mL,用0.45μm滤膜过滤,脱气。
流动相B:乙腈
洗脱梯度:
流速:1.0mL/min;检测波长:250nm;柱温:30℃;进样体积:5μl;稀释剂:水:乙腈=50:50(v/v);样品浓度:0.5mg/mL
实施例1
式(I)化合物(20g,0.12mol,1当量)中加入甲苯(100mL),加入三光气(14.26g,0.048mol,0.4当量),加入DMF(0.88g,0.012mol,0.1当量),升温至50±5℃反应。反应完全后反应液减压浓缩至干,得到黄色油状物,备用。
将式(II)化合物(17.52g,0.12mol,1当量)加入到甲苯(60mL)和水(100mL)混合溶液中,加入碳酸氢钠(21.17g,0.0.25mol,2.1当量),搅拌均匀,冷却至5±5℃,缓慢滴加上步产物的甲苯溶液(40mL)。滴加完全后,反应液在5±5℃下搅拌1-2小时,然后缓慢升温至室温,继续搅拌直至反应结束。过滤,收集滤饼,常压55±5℃烘干得到式(III)化合物,浅黄色至类白色固体28.46g,摩尔收率91%,纯度大于99.0%。H-NMR(DMSO-d6,400Hz)δ8.65(t,J=5.7Hz,1H),7.68(d,J=4.0Hz,1H),7.18(d,J=4.0Hz,1H),5.43(d,J=5.3Hz,1H),3.90–3.80(m,1H),3.64(dd,J=11.2,4.4Hz,1H),3.54(dd,J=11.2,5.8Hz,1H),3.43–3.34(m,1H),3.28–3.18(m,1H)。
实施例2
将式(III)化合物(20g,0.079mol,1当量)加入到丙酮(200mL)中,再加入碳酸钾(16.56g,0.12mol,1.5当量),维持反应液内温在30-40℃范围内,搅拌,直至反应结束。过滤除去不溶物,滤液备用(含式IV中间体)。
将氢氧化镁(1.40g,0.024mol,0.3当量)加入到丙酮(100mL),再加入水(0.86g,0.048mol,0.6当量),在0-10℃下搅拌半小时后,滴加三氟甲磺酸(7.20g,0.048mol,0.6当量),在滴加过程中,控制反应液温度在0-10℃范围内。滴加完毕,反应液变澄清后,继续搅拌0.5-1小时。
将式(V)化合物(15.18g,0.079mol,1.0当量)加入到第一步反应后的滤液中,再一起加入到第二步的反应液中,控制内温在25-35℃范围内,搅拌,直至反应结束。将反应液浓缩至小体积(约60mL),加入水(140mL),60±5℃打浆2-3小时后,将反应液降温至0-10℃,搅拌、析晶2-3小时,过滤,得到化合物VI的粗品。将粗品加入到丙酮和水的混合溶剂(1:1,240mL)中,60±5℃打浆2-3小时,再降温至0-10度,搅拌2-3小时;过滤,滤饼常压60±5℃烘干,得到中间体VI纯品,白色至类白色固体产品24.31g,摩尔收率75%,纯度大于99.5%,单杂小于0.1%。H-NMR(DMSO-d6,400Hz)δ8.61(t,J=5.7Hz,1H),7.69(d,J=4.1Hz,1H),7.18(d,J=4.0Hz,1H),7.02(d,J=8.7Hz,2H),6.60(d,J=8.8Hz,2H),5.65(t,J=6.0Hz,1H),5.08(d,J=5.1Hz,1H),4.14(s,2H),3.97–3.87(m,2H),3.86–3.76(m,1H),3.64–3.55(m,2H),3.40–3.44(m,1H),3.30–3.21(m,1H),3.16–3.06(m,1H),3.03–2.93(m,1H)。
实施例3
第一步反应与实施例1中第一步反应相同。
将氯化镁(2.3g,0.024mol,0.3当量)加入到丙酮(100mL)中,再加入水(0.86g,0.048mol,0.6当量),在0-10℃搅拌半小时后,滴加三氟甲磺酸(7.2g,0.048mol,0.6当量),在滴加过程中,维持反应液内温在0-10℃。滴加完毕,反应液变澄清后,继续搅拌0.5-1小时。
将化合物V(15.18g,0.079mol,1.0当量)加入到第一步反应后的滤液中,再一起加入到第二步的反应液中,控制内温在25-35℃之间,搅拌直至反应结束。将反应液浓缩至小体积(约60mL),加入水(140mL),60±5℃打浆2-3小时后,反应液降温至0-10℃,搅拌、析晶2-3小时,过滤,得到化合物VI的粗品。将粗品加入到(丙酮和水的混合溶剂(1:1,240mL)中,60±5℃打浆2-3小时,再降温至0-10度,搅拌2-3小时;过滤,滤饼常压60±5℃烘干,得到中间体VI纯品,白色至类白色固体17.41g,摩尔收率54%,纯度大于99.5%,单杂小于0.1%。H-NMR谱图数据与实施例2相同。
实施例4
第一步反应与实施例2中第一步反应相同。
将碳酸镁(2.02g,0.024mol,0.3当量)加入到丙酮(100mL)中,再加入水(0.86g,0.048mol,0.6当量),在0-10℃搅拌半小时后,滴加三氟甲磺酸(7.2g,0.048mol,0.6当量),在滴加过程中,维持反应液内温在0-10℃。滴加完毕,反应液变澄清后,继续搅拌0.5-1小时。
将化合物V(15.18g,0.079mol,1.0当量)加入到第一步反应后的滤液中,再一起加入到第二步的反应液中,控制内温在25-35℃之间,搅拌直至反应结束。将反应液浓缩至小体积(约60mL),加入水(140mL),60±5℃打浆2-3小时后,反应液降温至0-10℃,搅拌、析晶2-3小时,过滤,得到化合物VI的粗品。将粗品加入到(丙酮和水的混合溶剂(1:1,240mL)中,60±5℃打浆2-3小时,再降温至0-10度,搅拌2-3小时;过滤,滤饼常压60±5℃烘干,得到中间体VI纯品,白色至类白色固体22.47g,摩尔收率69%,纯度大于99.5%,单杂小于0.1%。H-NMR谱图数据与实施例2相同。
实施例5
第一步反应与实施例2中第一步反应相同。
将乙酸镁(3.73g,0.024mol,0.3当量)加入到丙酮(100mL)中,再加入水(0.86g,0.048mol,0.6当量),在0-10℃搅拌半小时后,滴加三氟甲磺酸(7.2g,0.048mol,0.6当量),在滴加过程中,维持反应液内温在0-10℃。滴加完毕,反应液变澄清后,继续搅拌0.5-1小时。
将化合物V(15.18g,0.079mol,1.0当量)加入到第一步反应后的滤液中,再一起加入到第二步的反应液中,控制内温在25-35℃之间,搅拌直至反应结束。将反应液浓缩至小体积(约60mL),加入水(140mL),60±5℃打浆2-3小时后,反应液降温至0-10℃,搅拌、析晶2-3小时,过滤,得到化合物VI的粗品。将粗品加入到(丙酮和水的混合溶剂(1:1,240mL)中,60±5℃打浆2-3小时,再降温至0-10度,搅拌2-3小时;过滤,滤饼常压60±5℃烘干,得到中间体VI纯品,白色至类白色固体19.67g,摩尔收率61%,纯度大于99.5%,单杂小于0.1%。H-NMR谱图数据与实施例2相同。
实施例6
第一步反应与实施例2中第一步反应相同。
将氧化镁(0.97g,0.024mol,0.3当量)加入到丙酮(100mL)中,再加入水(0.86g,0.048mol,0.6当量),在0-10℃搅拌半小时后,滴加三氟甲磺酸(7.2g,0.048mol,0.6当量),在滴加过程中,维持反应液内温在0-10℃。滴加完毕,反应液变澄清后,继续搅拌0.5-1小时。
将化合物V(15.18g,0.079mol,1.0当量)加入到第一步反应后的滤液中,再一起加入到第二步的反应液中,控制内温在25-35℃之间,搅拌直至反应结束。将反应液浓缩至小体积(约60mL),加入水(140mL),60±5℃打浆2-3小时后,反应液降温至0-10℃,搅拌、析晶2-3小时,过滤,得到化合物VI的粗品。将粗品加入到(丙酮和水的混合溶剂(1:1,240mL)中,60±5℃打浆2-3小时,再降温至0-10度,搅拌2-3小时;过滤,滤饼常压60±5℃烘干,得到中间体VI纯品,白色至类白色固体20.1g,摩尔收率62%,纯度大于99.5%,单杂小于0.1%。H-NMR谱图数据与实施例2相同。
实施例7
将化合物V(3g,0.016mol,1当量)和叔丁醇镁(2.8g,0.016mol,1当量)加入到甲苯(30mL)中,70-80℃温度下搅拌。0.5小时后,加入化合物III(5.3g,0.021mol,1.3当量),升温回流反应,直至反应结束。反应液降至室温(15-25℃),搅拌1-2小时后,过滤;滤饼加入到乙醇(15mL)和水(15mL)的混合溶液中,稀盐酸(6N)调节溶液pH至6.5-7.5,随后升温回流;1~2小时后,降温至0-10度,搅拌1-2小时后,过滤;滤饼用过少量95%乙醇淋洗,60-70℃烘干,得到产品3.9g,摩尔收率60%,液相纯度98.6%。H-NMR谱图数据与实施例2相同。
实施例8
将中间体VI(1g,0.0024mol,1当量)和碳酸钾(0.42g,0.003mol,1.2当量)加入到乙腈(10mL)中,搅拌半小时后,加入三光气(0.3g,0.4当量),控制反应液温度在40-50℃范围内,直至反应结束。将反应液降温至室温(15-25℃),搅拌1-2小时后,过滤;滤饼加入到水(10mL)中,室温打浆1-2小时,过滤;滤饼60-70℃烘干,得到产品0.93g,摩尔收率88%,液相纯度99.6%。H-NMR(DMSO-d6,400Hz)δ8.97(t,J=5.7Hz,1H),7.69(d,J=4.1Hz,1H),7.56(d,J=9.0Hz,2H),7.40(d,J=8.9Hz,2H),7.19(d,J=4.0Hz,1H),4.91–4.79(m,1H),4.25–4.13(m,3H),4.01–3.92(m,2H),3.85(dd,J=9.1,6.2Hz,1H),3.76–3.65(m,2H),3.61(t,J=5.5Hz,2H)。
实施例9
中间体VI(10g,0.024mol,1当量)加入到乙腈(85mL)和水(15mL)中,搅拌均匀,随后加入碳酸钾(5.4g,1.6当量),混合物冷至5±5℃,加入三光气固体(3.6g,0.5当量),在5±5℃下搅拌1-2小时,然后缓慢升温至40±5℃,继续搅拌4-6小时,TLC反应完全。反应液冷至5±5℃,保温搅拌1-2小时,过滤,滤饼分别用水,乙腈淋洗。收集湿滤饼,得到粗品。湿滤饼加入到乙腈/水(1:1,50mL)中,升温至60±5℃,搅拌打浆3±1小时。降温至25±5℃,保持此温度,继续搅拌1-2小时。过滤,滤饼用少量乙腈/水的混合溶剂淋洗。收集滤饼,60±5℃常压烘干得到10g纯品利伐沙班,摩尔收率95%,液相纯度99.8%。H-NMR谱图数据与实施例8的相同。
Claims (5)
1.一种制备式(VI)所示利伐沙班中间体的方法,
其可通过选自以下方法中的一种制备得到:
方法一:
B-1)式(III)化合物先经分子内环合,形成式(IV)环氧中间体,该中间体不经分离,与式(V)化合物在镁盐或氧化镁或氢氧化镁和有机酸预先反应形成的体系的介导下反应,得到利伐沙班关键中间体(VI)
方法二:
B-2)式(III)化合物与式(V)化合物在金属醇盐M(OR)n、金属卤化物MYn或金属高氯酸盐M(ClO4)n的存在下直接反应,得到利伐沙班关键中间体(VI)
在方法一中,所述镁盐为碳酸镁、乙酸镁、甲醇镁、乙醇镁、叔丁醇镁、硅酸镁、氯化镁,所述有机酸为三氟乙酸、三氟甲磺酸、甲磺酸、对甲苯磺酸或苯磺酸;
在方法二中,M选自碱金属或碱土金属中的任意一种,优选地,所述碱金属为钠、钾或锂,所述碱土金属为镁或钙,R选自碳原子为1~5的烷基,n为1或2,Y选自卤素,优选为氯、溴或碘。
2.根据权利要求1所述的方法,其中,上述步骤B-1)包括:
B-1.1)镁盐或氧化镁或氢氧化镁加入到含水的有机溶剂中,加入有机酸,搅拌,直至形成澄清或部分澄清的溶液;
其中,所述的镁盐为碳酸镁、乙酸镁、甲醇镁、乙醇镁、叔丁醇镁、硅酸镁、氯化镁,所用有机溶剂为丙酮、乙腈、四氢呋喃或1,4-二氧六环;在所述含水的有机溶剂中,水的量为所述有机酸用量的0.1-10倍摩尔量,所述有机酸为三氟乙酸、三氟甲磺酸、甲磺酸、对甲苯磺酸或苯磺酸,优选三氟甲磺酸或对甲苯磺酸,反应温度为0-50℃,优选0-20℃,反应时间为0.1-5h;
B-1.2)式(III)化合物在有机溶剂和缚酸剂存在下,形成中间体(IV),该中间体不经分离,与式(V)化合物一起加入到步骤B-1.1)的溶液中,生成式(VI)中间体;
其中,所用有机溶剂为丙酮、乙腈、四氢呋喃或1,4-二氧六环,所述缚酸剂选自氢氧化钠、氢氧化钾、碳酸氢钠、碳酸氢钾、碳酸钠和碳酸钾,反应温度为10-50℃,优选20-40℃,反应时间为8-24h。
3.根据权利要求1所述的方法,其中,上述步骤B-2)包括:
式(III)化合物和式(V)化合物,在有机溶剂中,通过加入金属醇盐M(OR)n、金属卤化物MYn或金属高氯酸盐M(ClO4)n中的一种或多种,直接生成中间体(VI);
其中,所述的金属醇盐M(OR)n选自甲醇钠、甲醇钾、乙醇锂、乙醇钠、甲醇镁、乙醇镁、正丙醇镁、甲醇钙、乙醇钙、叔丁醇钠、叔丁醇锂、叔丁醇镁、异丁醇镁或叔戊醇镁;优选地,所述的金属醇盐M(OR)n选自乙醇镁、正丙醇镁、叔丁醇镁或异丁醇镁;更优选地,所述的金属醇盐M(OR)n为乙醇镁或叔丁醇镁;
所述的金属卤化物MYn选自氯化锂、溴化锂、碘化锂、氯化镁、溴化镁、碘化镁、氯化钙、溴化钙、氯化锶或溴化锶;优选地,所述金属卤化物MYn为溴化锂、氯化锂、溴化镁或氯化镁;更优选地,所述的金属卤化物MYn为氯化镁;
所述金属高氯酸盐M(ClO4)n选自高氯酸锂、高氯酸镁、高氯酸钙;优选地,所述金属高氯酸盐为高氯酸镁。所述的有机溶剂选自乙腈、乙醇、异丙醇、1-丁醇、叔丁醇、甲苯、丙酮、4-甲基-2-戊酮、N,N-二甲基甲酰胺中的一种或多种的组合;优选地,所述有机溶剂为乙腈或甲苯或叔丁醇;
反应温度为50-150℃;反应时间为8-24h。
4.根据权利要求1所述的方法,其中,所述式(III)化合物通过5-氯噻吩-2-甲酸(I)与(S)-1-氨基-3-氯-2-丙醇盐酸盐(II)缩合得到:
具体地,5-氯噻吩-2-甲酸(I)先通过三光气和催化量的DMF活化为酰氯,再在溶剂和缚酸剂存在下,与(S)-1-氨基-3-氯-2-丙醇盐酸盐(II)反应,制备式(III)化合物;
其中,三光气用量为5-氯噻吩-2-甲酸的0.3-0.5倍摩尔量,DMF用量为5-氯噻吩-2-甲酸的0.01-0.3倍摩尔量,所述溶剂为有机溶剂与水的混合物,水与有机溶剂的重量比例为5:1-1:20,有机溶剂选自二氯甲烷、甲苯、丙酮、乙腈、四氢呋喃和1,4-二氧六环,所述缚酸剂选自氢氧化钠、氢氧化钾、碳酸氢钠、碳酸氢钾、碳酸钠和碳酸钾,
反应温度为-10-50℃,反应时间为1-10h。
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