CN110204541B - Preparation method of apixaban - Google Patents
Preparation method of apixaban Download PDFInfo
- Publication number
- CN110204541B CN110204541B CN201810167381.0A CN201810167381A CN110204541B CN 110204541 B CN110204541 B CN 110204541B CN 201810167381 A CN201810167381 A CN 201810167381A CN 110204541 B CN110204541 B CN 110204541B
- Authority
- CN
- China
- Prior art keywords
- formula
- solvent
- compound shown
- compound
- oxo
- 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.)
- Active
Links
- QNZCBYKSOIHPEH-UHFFFAOYSA-N Apixaban Chemical compound C1=CC(OC)=CC=C1N1C(C(=O)N(CC2)C=3C=CC(=CC=3)N3C(CCCC3)=O)=C2C(C(N)=O)=N1 QNZCBYKSOIHPEH-UHFFFAOYSA-N 0.000 title claims abstract description 40
- 229960003886 apixaban Drugs 0.000 title claims abstract description 39
- 238000002360 preparation method Methods 0.000 title claims abstract description 29
- 238000006268 reductive amination reaction Methods 0.000 claims abstract description 16
- 238000007112 amidation reaction Methods 0.000 claims abstract description 15
- 238000000034 method Methods 0.000 claims abstract description 15
- 238000005984 hydrogenation reaction Methods 0.000 claims abstract description 13
- TYMLOMAKGOJONV-UHFFFAOYSA-N 4-nitroaniline Chemical compound NC1=CC=C([N+]([O-])=O)C=C1 TYMLOMAKGOJONV-UHFFFAOYSA-N 0.000 claims abstract description 11
- 230000002140 halogenating effect Effects 0.000 claims abstract description 9
- 238000006722 reduction reaction Methods 0.000 claims abstract description 9
- FQHCPFMTXFJZJS-UHFFFAOYSA-N (4-methoxyphenyl)hydrazine;hydrochloride Chemical compound Cl.COC1=CC=C(NN)C=C1 FQHCPFMTXFJZJS-UHFFFAOYSA-N 0.000 claims abstract description 8
- 239000003153 chemical reaction reagent Substances 0.000 claims abstract description 7
- 150000001875 compounds Chemical class 0.000 claims description 67
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 66
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 39
- 239000002904 solvent Substances 0.000 claims description 36
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 33
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 22
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 22
- -1 sodium triacetoxyborohydride Chemical compound 0.000 claims description 18
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 claims description 16
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 16
- 238000006243 chemical reaction Methods 0.000 claims description 16
- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Chemical compound ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 claims description 16
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 claims description 14
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 12
- 239000003638 chemical reducing agent Substances 0.000 claims description 12
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 11
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 10
- 229910000564 Raney nickel Inorganic materials 0.000 claims description 9
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 9
- JWUJQDFVADABEY-UHFFFAOYSA-N 2-methyltetrahydrofuran Chemical compound CC1CCCO1 JWUJQDFVADABEY-UHFFFAOYSA-N 0.000 claims description 8
- 239000007868 Raney catalyst Substances 0.000 claims description 8
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 claims description 8
- SKTCDJAMAYNROS-UHFFFAOYSA-N methoxycyclopentane Chemical compound COC1CCCC1 SKTCDJAMAYNROS-UHFFFAOYSA-N 0.000 claims description 8
- 239000012279 sodium borohydride Substances 0.000 claims description 8
- 229910000033 sodium borohydride Inorganic materials 0.000 claims description 8
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 7
- 239000003513 alkali Substances 0.000 claims description 7
- 229910052739 hydrogen Inorganic materials 0.000 claims description 7
- 239000001257 hydrogen Substances 0.000 claims description 7
- UKVIEHSSVKSQBA-UHFFFAOYSA-N methane;palladium Chemical group C.[Pd] UKVIEHSSVKSQBA-UHFFFAOYSA-N 0.000 claims description 7
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 6
- 239000002585 base Substances 0.000 claims description 6
- 229910052794 bromium Inorganic materials 0.000 claims description 6
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 6
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 6
- 239000012321 sodium triacetoxyborohydride Substances 0.000 claims description 6
- 230000009435 amidation Effects 0.000 claims description 5
- 239000003054 catalyst Substances 0.000 claims description 5
- 238000006555 catalytic reaction Methods 0.000 claims description 5
- 239000000460 chlorine Substances 0.000 claims description 5
- 229910052801 chlorine Inorganic materials 0.000 claims description 5
- 238000005658 halogenation reaction Methods 0.000 claims description 5
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 5
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 5
- 235000011181 potassium carbonates Nutrition 0.000 claims description 5
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 claims description 4
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 4
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 claims description 4
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 claims description 4
- UHZYTMXLRWXGPK-UHFFFAOYSA-N phosphorus pentachloride Chemical compound ClP(Cl)(Cl)(Cl)Cl UHZYTMXLRWXGPK-UHFFFAOYSA-N 0.000 claims description 4
- 239000011591 potassium Substances 0.000 claims description 4
- 229910052700 potassium Inorganic materials 0.000 claims description 4
- SCVFZCLFOSHCOH-UHFFFAOYSA-M potassium acetate Chemical compound [K+].CC([O-])=O SCVFZCLFOSHCOH-UHFFFAOYSA-M 0.000 claims description 4
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 claims description 4
- GETQZCLCWQTVFV-UHFFFAOYSA-N trimethylamine Chemical compound CN(C)C GETQZCLCWQTVFV-UHFFFAOYSA-N 0.000 claims description 4
- 239000008096 xylene Substances 0.000 claims description 4
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 3
- NPXOKRUENSOPAO-UHFFFAOYSA-N Raney nickel Chemical compound [Al].[Ni] NPXOKRUENSOPAO-UHFFFAOYSA-N 0.000 claims description 3
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 3
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 3
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 3
- 239000003795 chemical substances by application Substances 0.000 claims description 3
- 238000006482 condensation reaction Methods 0.000 claims description 3
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 3
- OGFAWKRXZLGJSK-UHFFFAOYSA-N 1-(2,4-dihydroxyphenyl)-2-(4-nitrophenyl)ethanone Chemical compound OC1=CC(O)=CC=C1C(=O)CC1=CC=C([N+]([O-])=O)C=C1 OGFAWKRXZLGJSK-UHFFFAOYSA-N 0.000 claims description 2
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 2
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 claims description 2
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 claims description 2
- XSTXAVWGXDQKEL-UHFFFAOYSA-N Trichloroethylene Chemical group ClC=C(Cl)Cl XSTXAVWGXDQKEL-UHFFFAOYSA-N 0.000 claims description 2
- VSGNNIFQASZAOI-UHFFFAOYSA-L calcium acetate Chemical compound [Ca+2].CC([O-])=O.CC([O-])=O VSGNNIFQASZAOI-UHFFFAOYSA-L 0.000 claims description 2
- 239000001639 calcium acetate Substances 0.000 claims description 2
- 235000011092 calcium acetate Nutrition 0.000 claims description 2
- 229960005147 calcium acetate Drugs 0.000 claims description 2
- NKWPZUCBCARRDP-UHFFFAOYSA-L calcium bicarbonate Chemical compound [Ca+2].OC([O-])=O.OC([O-])=O NKWPZUCBCARRDP-UHFFFAOYSA-L 0.000 claims description 2
- 229910000020 calcium bicarbonate Inorganic materials 0.000 claims description 2
- 229910000019 calcium carbonate Inorganic materials 0.000 claims description 2
- 235000010216 calcium carbonate Nutrition 0.000 claims description 2
- 235000011056 potassium acetate Nutrition 0.000 claims description 2
- 239000011736 potassium bicarbonate Substances 0.000 claims description 2
- 235000015497 potassium bicarbonate Nutrition 0.000 claims description 2
- 229910000028 potassium bicarbonate Inorganic materials 0.000 claims description 2
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 claims description 2
- 239000001632 sodium acetate Substances 0.000 claims description 2
- 235000017281 sodium acetate Nutrition 0.000 claims description 2
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 claims description 2
- 235000011121 sodium hydroxide Nutrition 0.000 claims description 2
- YBBRCQOCSYXUOC-UHFFFAOYSA-N sulfuryl dichloride Chemical compound ClS(Cl)(=O)=O YBBRCQOCSYXUOC-UHFFFAOYSA-N 0.000 claims description 2
- WMOVHXAZOJBABW-UHFFFAOYSA-N tert-butyl acetate Chemical compound CC(=O)OC(C)(C)C WMOVHXAZOJBABW-UHFFFAOYSA-N 0.000 claims description 2
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 2
- IMFACGCPASFAPR-UHFFFAOYSA-N tributylamine Chemical compound CCCCN(CCCC)CCCC IMFACGCPASFAPR-UHFFFAOYSA-N 0.000 claims description 2
- UBOXGVDOUJQMTN-UHFFFAOYSA-N trichloroethylene Natural products ClCC(Cl)Cl UBOXGVDOUJQMTN-UHFFFAOYSA-N 0.000 claims description 2
- 150000002148 esters Chemical class 0.000 claims 2
- 229940070710 valerate Drugs 0.000 claims 2
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims 1
- 238000004519 manufacturing process Methods 0.000 claims 1
- 125000000636 p-nitrophenyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)[N+]([O-])=O 0.000 abstract description 24
- 239000002994 raw material Substances 0.000 abstract description 11
- BVOCPVIXARZNQN-UHFFFAOYSA-N nipecotamide Chemical compound NC(=O)C1CCCNC1 BVOCPVIXARZNQN-UHFFFAOYSA-N 0.000 abstract description 2
- 150000003869 acetamides Chemical class 0.000 abstract 1
- 230000035484 reaction time Effects 0.000 description 14
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 12
- 239000007791 liquid phase Substances 0.000 description 12
- PXHVJJICTQNCMI-UHFFFAOYSA-N Nickel Chemical compound [Ni] PXHVJJICTQNCMI-UHFFFAOYSA-N 0.000 description 10
- 238000010992 reflux Methods 0.000 description 10
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 8
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 8
- 238000004821 distillation Methods 0.000 description 8
- 238000005406 washing Methods 0.000 description 8
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 8
- 238000001914 filtration Methods 0.000 description 7
- DLFVBJFMPXGRIB-UHFFFAOYSA-N Acetamide Chemical compound CC(N)=O DLFVBJFMPXGRIB-UHFFFAOYSA-N 0.000 description 6
- 235000019270 ammonium chloride Nutrition 0.000 description 6
- 238000001816 cooling Methods 0.000 description 6
- 238000001035 drying Methods 0.000 description 5
- 239000012065 filter cake Substances 0.000 description 5
- 239000000203 mixture Substances 0.000 description 5
- 239000012074 organic phase Substances 0.000 description 5
- 125000004172 4-methoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C([H])C([H])=C1* 0.000 description 4
- ZHNUHDYFZUAESO-UHFFFAOYSA-N Formamide Chemical compound NC=O ZHNUHDYFZUAESO-UHFFFAOYSA-N 0.000 description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 description 4
- 239000007864 aqueous solution Substances 0.000 description 4
- 230000009286 beneficial effect Effects 0.000 description 4
- 230000015572 biosynthetic process Effects 0.000 description 4
- 230000000052 comparative effect Effects 0.000 description 4
- 238000009776 industrial production Methods 0.000 description 4
- 239000007788 liquid Substances 0.000 description 4
- 229910052757 nitrogen Inorganic materials 0.000 description 4
- 238000003786 synthesis reaction Methods 0.000 description 4
- 230000002829 reductive effect Effects 0.000 description 3
- 239000002351 wastewater Substances 0.000 description 3
- OYDSTJMVOOOYDW-UHFFFAOYSA-N 1-(4-iodophenyl)piperidin-2-one Chemical compound C1=CC(I)=CC=C1N1C(=O)CCCC1 OYDSTJMVOOOYDW-UHFFFAOYSA-N 0.000 description 2
- 125000006306 4-iodophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1I 0.000 description 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 2
- 206010014522 Embolism venous Diseases 0.000 description 2
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 2
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 2
- 238000007098 aminolysis reaction Methods 0.000 description 2
- 238000005915 ammonolysis reaction Methods 0.000 description 2
- 238000005660 chlorination reaction Methods 0.000 description 2
- 238000006352 cycloaddition reaction Methods 0.000 description 2
- 238000010812 external standard method Methods 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 2
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 2
- 150000007529 inorganic bases Chemical class 0.000 description 2
- 229910052759 nickel Inorganic materials 0.000 description 2
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 2
- 150000007530 organic bases Chemical class 0.000 description 2
- 229910052763 palladium Inorganic materials 0.000 description 2
- XUWHAWMETYGRKB-UHFFFAOYSA-N piperidin-2-one Chemical compound O=C1CCCCN1 XUWHAWMETYGRKB-UHFFFAOYSA-N 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 239000011541 reaction mixture Substances 0.000 description 2
- 238000007363 ring formation reaction Methods 0.000 description 2
- 239000012312 sodium hydride Substances 0.000 description 2
- 229910000104 sodium hydride Inorganic materials 0.000 description 2
- 229910001220 stainless steel Inorganic materials 0.000 description 2
- 239000010935 stainless steel Substances 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- 238000006467 substitution reaction Methods 0.000 description 2
- 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 description 2
- 208000004043 venous thromboembolism Diseases 0.000 description 2
- 239000002699 waste material Substances 0.000 description 2
- PPUHOTDYJQGTAE-UHFFFAOYSA-N 1-(4-methoxyphenyl)-7-oxo-6-[4-(2-oxopiperidin-1-yl)phenyl]-4,5-dihydropyrazolo[3,4-c]pyridine-3-carboxylic acid Chemical compound C1=CC(OC)=CC=C1N1C(C(=O)N(CC2)C=3C=CC(=CC=3)N3C(CCCC3)=O)=C2C(C(O)=O)=N1 PPUHOTDYJQGTAE-UHFFFAOYSA-N 0.000 description 1
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- YOETUEMZNOLGDB-UHFFFAOYSA-N 2-methylpropyl carbonochloridate Chemical compound CC(C)COC(Cl)=O YOETUEMZNOLGDB-UHFFFAOYSA-N 0.000 description 1
- 125000004637 2-oxopiperidinyl group Chemical group O=C1N(CCCC1)* 0.000 description 1
- WKZRYUVJFYDZTP-UHFFFAOYSA-N 4,5,6,7-tetrahydro-1h-pyrazolo[3,4-c]pyridine-3-carboxylic acid Chemical compound C1NCCC2=C1NN=C2C(=O)O WKZRYUVJFYDZTP-UHFFFAOYSA-N 0.000 description 1
- VBKPPDYGFUZOAJ-UHFFFAOYSA-N 5-oxopentanoic acid Chemical compound OC(=O)CCCC=O VBKPPDYGFUZOAJ-UHFFFAOYSA-N 0.000 description 1
- 206010003658 Atrial Fibrillation Diseases 0.000 description 1
- OBYFVISULYVYNB-UHFFFAOYSA-N ClC1=CC=CC=C1.P(Cl)(Cl)(Cl)(Cl)Cl Chemical compound ClC1=CC=CC=C1.P(Cl)(Cl)(Cl)(Cl)Cl OBYFVISULYVYNB-UHFFFAOYSA-N 0.000 description 1
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical group [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 1
- 229940123688 Direct Factor Xa inhibitor Drugs 0.000 description 1
- 238000010958 [3+2] cycloaddition reaction Methods 0.000 description 1
- 229910021529 ammonia Inorganic materials 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- LOGJGIGNTMIGTB-UHFFFAOYSA-N benzyl 5-oxopentanoate Chemical compound O=CCCCC(=O)OCC1=CC=CC=C1 LOGJGIGNTMIGTB-UHFFFAOYSA-N 0.000 description 1
- 238000009833 condensation Methods 0.000 description 1
- 230000005494 condensation Effects 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 229940047562 eliquis Drugs 0.000 description 1
- 230000007613 environmental effect Effects 0.000 description 1
- 230000032050 esterification Effects 0.000 description 1
- 238000005886 esterification reaction Methods 0.000 description 1
- WUPBOSISFPJABC-UHFFFAOYSA-N ethyl 5-oxopentanoate Chemical compound CCOC(=O)CCCC=O WUPBOSISFPJABC-UHFFFAOYSA-N 0.000 description 1
- 125000000524 functional group Chemical group 0.000 description 1
- 238000011540 hip replacement Methods 0.000 description 1
- 239000013067 intermediate product Substances 0.000 description 1
- 238000013150 knee replacement Methods 0.000 description 1
- LSNSJCKGQREPDW-UHFFFAOYSA-N methyl 3-amino-3-oxopropanoate Chemical compound COC(=O)CC(N)=O LSNSJCKGQREPDW-UHFFFAOYSA-N 0.000 description 1
- YBTZROCKNUIONO-UHFFFAOYSA-N methyl 5-oxopentanoate Chemical compound COC(=O)CCCC=O YBTZROCKNUIONO-UHFFFAOYSA-N 0.000 description 1
- BHAAPTBBJKJZER-UHFFFAOYSA-N p-anisidine Chemical compound COC1=CC=C(N)C=C1 BHAAPTBBJKJZER-UHFFFAOYSA-N 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- QJXPVSVXECBALX-UHFFFAOYSA-N propan-2-yl 5-oxopentanoate Chemical compound CC(C)OC(=O)CCCC=O QJXPVSVXECBALX-UHFFFAOYSA-N 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- OJLCOAYTPHMGTM-UHFFFAOYSA-N tert-butyl 5-oxopentanoate Chemical compound CC(C)(C)OC(=O)CCCC=O OJLCOAYTPHMGTM-UHFFFAOYSA-N 0.000 description 1
- CMSYDJVRTHCWFP-UHFFFAOYSA-N triphenylphosphane;hydrobromide Chemical compound Br.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 CMSYDJVRTHCWFP-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
Abstract
The invention provides a preparation method of apixaban, which comprises the steps of using 3-formylmethyl n-glutaric acid monoester monoamide (II) and 4-nitroaniline as raw materials, generating 1- (4-nitrophenyl) piperidine-2-ketone-4-acetamide (III) through reductive amination and intramolecular amidation reaction, then reacting with a halogenating reagent to obtain 1- (4-nitrophenyl) piperidine-2-ketone-3, 3-dihalogenated-4-dihalogenated acetamide (IV), condensing with 4-methoxyphenylhydrazine hydrochloride to obtain l- (4-methoxyphenyl) -7-oxo-6- (4-nitrophenyl) -4,5,6, 7-tetrahydro-1H-pyrazolo [3,4-c ] pyridine-3-formamide (V), and then the piperidine-3-formamide (V) is subjected to hydrogenation reduction reaction and is subjected to reductive amination and intramolecular amidation reaction with 5-oxo-n-valerate to generate apixaban (I). The method has the advantages of simple and convenient operation, safety, greenness, low cost, high selectivity and high yield and purity of the product.
Description
Technical Field
The invention relates to a preparation method of apixaban, belonging to the technical field of medical chemistry.
Background
Apixaban (Apixaban, i), chemically known as l- (4-methoxyphenyl) -7-oxo-6- [4- (2-oxopiperidin-1-yl) phenyl ] -4,5,6, 7-tetrahydro-1H-pyrazolo [3,4-c ] pyridine-3-carboxamide, is a novel direct factor Xa inhibitor developed by the combination of behme, sequardt and fevere, and was approved by the european union in 3 months of 2011 and approved by the FDA in the united states in 28 months of 2012, under the trade name Eliquis, for the prevention of Venous Thromboembolism (VTE) and atrial fibrillation in adult patients with hip or knee replacement.
The chemical structural formula of apixaban is shown as follows:
patent documents WO2003049681 and WO2004083177 propose two routes for preparing apixaban, one of which is to use piperidine-2-ketone as raw material, obtain 3, 3-dichloropiperidine-2-ketone by phosphorus pentachloride chlorination, eliminate one molecule of hydrogen chloride under the action of potassium carbonate to obtain 3-chloro-5, 6-dihydropyridine-2 (1H) -ketone, obtain 3-morpholin-4-yl-5, 6-dihydropyridine-2 (1H) -ketone by substitution reaction with morpholine, cycloaddition with (Z) -2-chloro-2- [2- (4-methoxyphenyl) hydrazono ] ethyl acetate, generate 1- (4-methoxyphenyl) 7-oxo-4, 5,6, 7-tetrahydro-1H-pyrazolo [3 by the action of trifluoroacetic acid, 4-c ] pyridine-3-ethyl formate, then condensing with 1- (4-iodophenyl) -2-piperidone to obtain 1- (4-methoxyphenyl) -7-oxo-6- [4- (2-oxopiperidinyl) phenyl ] -4,5,6, 7-tetrahydro-1H-pyrazolo [3,4-c ] -pyridine-3-formic acid, and obtaining apixaban by isobutyl chloroformate esterification and ammonia ammonolysis with the total yield of 5.2 percent. Secondly, 1- (4-iodophenyl) -3, 3-dichloropiperidine-2-ketone is used as a raw material, the raw material and morpholine are subjected to substitution reaction to obtain 1- (4-iodophenyl) -3-morpholin-4-yl-5, 6-dihydropyridine-2 (1H) -ketone, then the 1- [4- (2-oxopiperidinyl) phenyl ] -3-morpholin-4-yl-5, 6-dihydropyridine-2 (1H) -ketone and piperidine-2-ketone are prepared under the catalysis of cuprous bromide-triphenylphosphine, and the 1- [4- (2-oxopiperidine) phenyl ] -3-morpholin-4-yl-5, 6-dihydropyridine-2 (1H) -ketone and (Z) -2-chloro-2- [2- (4-methoxyphenyl) hydrazono ] ethyl acetate are subjected to cycloaddition and hydrochloric acid to generate 1- (4-methoxyphenyl) -7-oxo-6- 4- (2-oxo-piperidyl) phenyl ] -4,5,6, 7-tetrahydro-1H-pyrazolo [3,4-c ] -pyridine-3-carboxylic acid ethyl ester is subjected to aminolysis by formamide catalyzed by sodium methoxide to obtain the apixaban, and the total yield is 31.1-32.0%. The reaction equations for the two routes described above are depicted as synthetic scheme 1 below.
Synthesis scheme 1
In the two preparation routes of apixaban, the used raw materials (Z) -2-chloro-2- [2- (4-methoxyphenyl) hydrazono ] ethyl acetate and 1- (4-iodophenyl) -2-piperidone are high in price, multiple in reaction steps, complex in operation, low in total yield, large in wastewater amount and not beneficial to industrial production.
Chinese patent document CN10267531A uses p-nitroaniline as raw material, and the p-nitroaniline is jected to amidation reaction by 5-chloro-n-valeryl chloride and condensation by strong base sodium hydride to obtain 1- (4-nitrophenyl) piperidine-2-ketone, then chlorination is carried out under the action of phosphorus pentachloride-chlorobenzene to obtain 3, 3-dichloro-1- (4-nitrophenyl) piperidine-2-ketone, hydrogen chloride is eliminated under the action of potassium carbonate to obtain 1- (4-nitrophenyl) -3-chloro-5, 6-dihydropyridine-2 (1H) -ketone, and the reaction with (Z) -2-chloro-2- [2- (4-methoxyphenyl) hydrazono ] ethyl acetate is jected to cyclization reaction by [3+2], and nitro is catalyzed and hydrogenated to obtain l- (4-methoxyphenyl) -7-oxo-6- (4-aminophenyl) Ethyl (4, 5,6, 7-tetrahydro-1H-pyrazolo [3,4-c ] pyridine-3-carboxylate) is amidated with 5-chloro-n-valeryl chloride and condensed with strong base sodium hydride to obtain l- (4-methoxyphenyl) -7-oxo-6- [4- (2-oxopiperidin-1-yl) phenyl ] -4,5,6, 7-tetrahydro-1H-pyrazolo [3,4-c ] pyridine-3-carboxylate, and the total yield is about 14.5% by aminolysis with formamide catalyzed by sodium methoxide to prepare apixaban, and the corresponding reaction equation is described as the following synthetic scheme 2.
Synthesis scheme 2
The raw material (Z) -2-chloro-2- [2- (4-methoxyphenyl) hydrazono ] ethyl acetate used by the method has high price, complex operation, low total yield and large amount of three wastes, and is not beneficial to industrial production.
"J.China pharmaceutical chemistry, vol.23, 5, 383-. The key intermediate and p-anisidine are subjected to Japp-Klingmann reaction to obtain an intermediate ethyl 2-chloro-2- [2- (4-methoxyphenyl) hydrazone acetate, and the ethyl l- (4-methoxyphenyl) -7-oxo-6- (4-nitrophenyl) -4,5,6, 7-tetrahydro-1H-pyrazolo [3,4-c ] pyridine-3-carboxylate is obtained through [3+2] cycloaddition and de-morpholino, the nitro is reduced to amino, 5-chloro-n-valeryl chloride is amidated, cyclization is carried out under strong base, and ammonolysis is carried out to obtain apixaban, wherein the total yield is 32.5%. The corresponding reaction equation is depicted as scheme 3 below.
Synthesis scheme 3
However, the route has long steps, complicated operation and large amount of waste water, and is not beneficial to green industrial production.
Disclosure of Invention
Aiming at the defects of the prior art, the invention provides the preparation method of apixaban, which is simple and convenient to operate, safe, green, low in cost, high in yield and high in purity.
Description of terms:
a compound of formula II: 3-formylmethyl-n-glutarate monoamide;
a compound of formula III: 1- (4-nitrophenyl) piperidin-2-one-4-acetamide;
a compound of formula IV: 1- (4-nitrophenyl) piperidin-2-one-3, 3-dihalo-4-dihaloacetamide;
a compound of formula V: l- (4-methoxyphenyl) -7-oxo-6- (4-nitrophenyl) -4,5,6, 7-tetrahydro-1H-pyrazolo [3,4-c ] pyridine-3-carboxamide;
a compound of formula VI: l- (4-methoxyphenyl) -7-oxo-6- (4-aminophenyl) -4,5,6, 7-tetrahydro-1H-pyrazolo [3,4-c ] pyridine-3-carboxamide.
The compound numbers in the specification are completely consistent with the structural formula numbers, have the same reference relationship, and are based on the structural formula.
The technical scheme of the invention is as follows:
a preparation method of apixaban comprises the following steps:
(1) in a solvent A, under the action of a reducing agent, carrying out reductive amination and intramolecular amidation on a compound shown in a formula II and 4-nitroaniline to generate a compound shown in a formula III;
wherein, in the structural formula of the compound shown in the formula II,r is-CH3、-C2H5、-C3H7、-C4H9、-CH2Ph; wherein Ph represents phenyl;
(2) in a solvent B, performing halogenation reaction on the compound shown in the formula III and a halogenating reagent to obtain a compound shown in a formula IV;
wherein in the structural formula of the compound shown in the formula IV, X is Cl or Br;
(3) in a solvent C, under the catalysis of alkali, condensing a compound shown in the formula IV and 4-methoxy phenylhydrazine hydrochloride to obtain a compound shown in the formula V;
(4) dissolving the compound in the solvent D, and preparing a compound shown in the formula VI by a compound shown in the formula V through hydrogenation reduction reaction under the catalysis of a hydrogenation catalyst;
(5) in a solvent E, under the action of a reducing agent F, the compound shown in the formula VI and 5-oxo-n-valerate undergo reductive amination and intramolecular amidation reaction to generate apixaban (I).
According to the present invention, preferably, in step (1), the solvent a is one or a combination of two or more of methanol, ethanol, tetrahydrofuran, 2-methyltetrahydrofuran, methylcyclopentyl ether, 1, 2-dimethoxyethane, toluene, xylene, 1, 2-dichloroethane, or chlorobenzene; the mass ratio of the solvent A to the compound shown in the formula II in the step (1) is (5-20): 1; preferably, the mass ratio of the solvent A to the compound of the formula II in the step (1) is (5-10): 1.
According to the present invention, preferably, the reducing agent in step (1) is one or a combination of two or more of sodium triacetoxyborohydride, potassium triacetoxyborohydride, sodium borohydride and potassium borohydride.
According to the present invention, it is preferred that the compound of formula II in step (1) is one of 3-formylmethyl-n-glutarate mono-methyl ester mono-amide, 3-formylmethyl-n-glutarate mono-ethyl ester mono-amide, 3-formylmethyl-n-glutarate mono-isopropyl ester mono-amide, 3-formylmethyl-n-glutarate mono-tert-butyl ester mono-amide or 3-formylmethyl-n-glutarate mono-benzyl ester mono-amide.
According to the invention, the molar ratio of the reducing agent, the 4-nitroaniline and the compound of the formula II in step (1) is preferably (0.5-2.0): (0.9-1.5): 1.
According to the present invention, it is preferred that the reductive amination reaction temperature in step (1) is 20 to 100 ℃; preferably, the reductive amination reaction temperature in step (1) is 40-70 ℃. The reaction time is 2-10 hours; preferably, the reaction time is 5 to 7 hours.
According to the present invention, it is preferable that the intramolecular amidation reaction temperature in step (1) is 50 to 130 ℃; preferably, the temperature of the intramolecular amidation reaction in step (1) is 90-110 ℃. The reaction time is 2-8 hours; preferably, the reaction time is 4 to 6 hours.
According to the present invention, preferably, the solvent B in step (2) is one or a combination of two or more of dichloromethane, chloroform, carbon tetrachloride, 1, 2-dichloroethane, trichloroethylene or chlorobenzene; the mass ratio of the solvent B to the compound shown in the formula III in the step (2) is (5-50): 1; preferably, the mass ratio of the solvent B to the compound of the formula III in the step (2) is (15-20): 1.
According to the invention, preferably, the halogenating reagent in the step (2) is one of chlorine, phosphorus pentachloride, sulfuryl chloride, bromine or phosphorus pentabromide; the molar ratio of the halogenating agent to the compound of formula III in step (2) is (1.0-8.0): 1; preferably, the molar ratio of the halogenating agent to the compound of formula III in step (2) is (2.0-4.0): 1.
according to the present invention, it is preferable that the halogenation reaction temperature in the step (2) is 20 to 90 ℃; preferably, the halogenation reaction temperature in the step (2) is 40-70 ℃. The reaction time is 2-8 hours; preferably, the reaction time is 3 to 5 hours.
According to the present invention, preferably, in the step (3), the solvent C is one or a combination of two or more of methanol, ethanol, tetrahydrofuran, 2-methyltetrahydrofuran, methylcyclopentyl ether, 1, 2-dimethoxyethane, acetonitrile or chlorobenzene; the mass ratio of the solvent C to the compound shown in the formula IV in the step (3) is (5-30) to 1; preferably, the mass ratio of the solvent C to the compound of the formula IV in the step (3) is (5-10): 1.
According to the present invention, preferably, the base in step (3) is an inorganic base or an organic base, the inorganic base is selected from one or a combination of potassium carbonate, sodium methoxide, sodium ethoxide, calcium carbonate, sodium hydroxide, potassium bicarbonate, sodium bicarbonate, calcium bicarbonate, potassium acetate, sodium acetate and calcium acetate, and the organic base is selected from one or a combination of trimethylamine, triethylamine and tri-n-butylamine; the molar ratio of the base to the compound of formula IV in step (3) is (3.0-6.0): 1.
According to the present invention, it is preferred that the molar ratio of the 4-methoxyphenylhydrazine hydrochloride salt to the compound of the formula IV in step (3) is (1.0 to 1.5): 1.
according to the present invention, it is preferable that the condensation reaction in step (3) is carried out at a temperature of 30 to 100 ℃; preferably, the temperature of the condensation reaction in step (3) is 50 to 80 ℃. The reaction time is 2-10 hours; preferably, the reaction time is 3 to 6 hours.
According to the present invention, preferably, the solvent D in step (4) is one or a combination of two or more of methanol, ethanol, isopropanol, acetonitrile, ethyl acetate, tert-butyl acetate, tetrahydrofuran, 2-methyltetrahydrofuran, methylcyclopentyl ether or 1, 2-dimethoxyethane; the mass ratio of the solvent D to the compound of the formula V in the step (4) is (5-25) to 1; preferably, the mass ratio of the solvent D and the compound of the formula V in the step (4) is (10-20): 1.
According to the present invention, it is preferable that the hydrogenation catalyst in the step (4) is palladium carbon or Raney nickel.
Preferably, the mass of the palladium carbon is 0.5-10% of that of the compound of the formula V; more preferably, the mass of the palladium carbon is 1-5% of that of the compound of the formula V, and the mass content of palladium in the palladium carbon is 5%.
Preferably, the mass of the Raney nickel is 5-25% of that of the compound of the formula V; more preferably, the mass of the Raney nickel is 10-15% of that of the compound of the formula V, and the mass content of nickel in the Raney nickel is 50%.
According to the present invention, it is preferable that the temperature of the hydrogenation reduction reaction in the step (4) is 0 to 80 ℃ and the hydrogen pressure is 0.1 to 0.5 MPa; preferably, the temperature of the hydrogenation reduction reaction in the step (4) is 40-65 ℃, and the hydrogen pressure is 0.2-0.4 MPa. The hydrogenation reduction reaction time in the step (4) is 3-10 hours; preferably, the hydrogenation reduction reaction time in the step (4) is 4 to 8 hours.
According to the present invention, preferably, in the step (5), the solvent E is one or a combination of two or more of tetrahydrofuran, 2-methyltetrahydrofuran, methylcyclopentyl ether, 1, 2-dimethoxyethane, toluene, xylene, 1, 2-dichloroethane, or chlorobenzene; the mass ratio of the solvent E to the compound shown in the formula VI in the step (5) is (10-30) to 1; preferably, the mass ratio of the solvent E to the compound of the formula VI in the step (5) is (15-22): 1.
According to the present invention, preferably, the reducing agent F in step (5) is one or a combination of two or more of sodium triacetoxyborohydride, potassium triacetoxyborohydride, sodium borohydride or potassium borohydride.
According to the present invention, it is preferable that the 5-oxo-n-pentanoate in the step (5) is one of methyl 5-oxo-n-pentanoate, ethyl 5-oxo-n-pentanoate, isopropyl 5-oxo-n-pentanoate, tert-butyl 5-oxo-n-pentanoate, or benzyl 5-oxo-n-pentanoate.
According to the present invention, it is preferred that the molar ratio of the reducing agent F, the 5-oxo-n-valerate and the compound of the formula VI in step (5) is (1.0-4.0): (0.9-1.6): 1.
According to the present invention, it is preferred that the reductive amination reaction temperature in step (5) is 20 to 100 ℃; preferably, the reductive amination reaction temperature in step (5) is 40-70 ℃. The reaction time is 2-10 hours; preferably, the reaction time is 5 to 7 hours.
According to the present invention, it is preferable that the intramolecular amidation reaction temperature in step (5) is 50 to 130 ℃; preferably, the temperature of the intramolecular amidation reaction in step (5) is 90-110 ℃. The reaction time is 2-8 hours; preferably, the reaction time is 4 to 6 hours.
The process of the present invention is depicted as scheme 4 below:
synthesis scheme 4
Wherein in the structural formula of the compound shown in the formula II, R is-CH3、-C2H5、-C3H7、-C4H9、-CH2Ph; wherein Ph represents phenyl; in the structural formula of the compound shown in the formula IV, X is Cl or Br.
The invention has the technical characteristics and beneficial effects that:
1. the invention provides a novel preparation route of apixaban, which uses 3-formylmethyl-n-glutaric acid monoester monoamide (II) and 4-nitroaniline as raw materials to generate 1- (4-nitrophenyl) piperidine-2-ketone-4-acetamide (III) through reductive amination and intramolecular amidation reactions, then the 1- (4-nitrophenyl) piperidine-2-ketone-3, 3-dihalogen-4-dihalogen acetamide (IV) reacts with a halogenating reagent to obtain a halogenated compound, and the halogenated compound is condensed with 4-methoxyphenylhydrazine hydrochloride to obtain l- (4-methoxyphenyl) -7-oxo-6- (4-nitrophenyl) -4,5,6, 7-tetrahydro-1H-pyrazolo [3,4-c ] pyridine-3-formamide (V), and then the piperidine-3-formamide (V) is subjected to hydrogenation reduction reaction and is subjected to reductive amination and intramolecular amidation reaction with 5-oxo-n-valerate to generate apixaban (I).
2. The raw materials used in the invention are cheap, the stability of the raw materials and the intermediate products is good, and the cost is low; the method has simple steps and simple and convenient operation, can prepare the apixaban by only 5 steps, and has short process flow and mild reaction conditions; the method has the advantages of less wastewater amount in each step, less three wastes, environmental protection and contribution to the industrial production of apixaban.
3. The method has the advantages of single reaction site of each step of reaction functional group, high reaction selectivity, high product purity and yield (the total yield reaches 66.4%), and high atom economy in the reaction process.
Detailed Description
The present invention is described in detail below with reference to examples, but the present invention is not limited thereto.
The raw materials and reagents used in the examples are all commercially available products. In the examples, "%" is a mass percentage unless otherwise specified.
Example 1: preparation of 1- (4-nitrophenyl) piperidin-2-one-4-acetamide (III)
To a 500 ml four-necked flask equipped with a stirrer, a thermometer, a reflux condenser and a dropping funnel, 50 g of methanol, 60 g of toluene, 13.8 g (0.1 mol) of 4-nitroaniline, 4.5 g of sodium borohydride, 19.0 g (0.1 mol) of 3-formylmethyl-n-methylglutaryl monoamide (II) were added, and the mixture was stirred at 60 to 65 ℃ for 5 hours, at 95 to 100 ℃ for 5 hours, while recovering methanol by distillation. Cooling to 20 to 25 ℃, acidifying the system pH value with 20 wt% ammonium chloride aqueous solution to 4.0-4.5, adding 100 g dichloromethane, demixing, extracting the water layer with dichloromethane for 3 times, each time 20 g, combining the organic phases, distilling and recovering dichloromethane and toluene to obtain 24.6 g 1- (4-nitrophenyl) piperidin-2-one-4-acetamide, the yield is 88.8%, and the purity of the liquid phase is 99.3%.
Example 2: preparation of 1- (4-nitrophenyl) piperidin-2-one-4-acetamide (III)
To a 500 ml four-necked flask equipped with a stirrer, a thermometer, a reflux condenser and a dropping funnel, 50 g of tetrahydrofuran, 60 g of toluene, 13.8 g (0.1 mol) of 4-nitroaniline, 30.5 g of sodium triacetoxyborohydride, 19.0 g (0.1 mol) of 3-formylmethyl-n-glutaric acid monomethyl ester monoamide (II) were charged, stirred and reacted at 50 to 55 ℃ for 6 hours, stirred and reacted at 95 to 100 ℃ for 5 hours, while tetrahydrofuran was recovered by distillation. Cooling to 20 to 25 ℃, acidifying the system pH value with 20 wt% ammonium chloride aqueous solution to 4.0-4.5, adding 100 g dichloromethane, layering, extracting the water layer with dichloromethane for 3 times, each time 20 g, combining the organic phases, distilling and recovering dichloromethane, tetrahydrofuran and toluene to obtain 24.9 g 1- (4-nitrophenyl) piperidin-2-one-4-acetamide, with the yield of 89.9% and the liquid phase purity of 99.4%.
Example 3: preparation of 1- (4-nitrophenyl) piperidin-2-one-3, 3-dichloro-4-dichloroacetamide (IV 1)
To a 500 ml four-necked flask equipped with a stirrer, a thermometer, a reflux condenser and a dropping funnel were charged 220 g of 1, 2-dichloroethane, 13.9 g (0.1 mol) of 1- (4-nitrophenyl) piperidin-2-one-4-acetamide (III) prepared in example 1, 52.5 g of phosphorus pentachloride, and the reaction was stirred at 50 to 55 ℃ for 5 hours. The reaction mixture was cooled to 20 to 25 ℃ and slowly added to 100 g of 1, 2-dichloroethane and 300 g of crushed ice with constant stirring, the layers were separated, the aqueous layer was extracted 3 times with 20 g of 1, 2-dichloroethane, the organic phases were combined and the 1, 2-dichloroethane was recovered by distillation to give 21.2 g of 1- (4-nitrophenyl) piperidin-2-one-3, 3-dichloro-4-dichloroacetamide as a pale brown viscous liquid which was used directly in the next step (example 5).
Example 4: preparation of 1- (4-nitrophenyl) piperidin-2-one-3, 3-dibromo-4-dibromoacetamide (IV 2)
To a 500 ml four-necked flask equipped with a stirrer, a thermometer, a reflux condenser and a dropping funnel were charged 220 g of 1, 2-dichloroethane, 13.9 g (0.1 mol) of 1- (4-nitrophenyl) piperidin-2-one-4-acetamide (III) prepared in example 2, 35 g of bromine, and the reaction was stirred at 40 to 45 ℃ for 5 hours. The reaction mixture was cooled to 20 to 25 ℃ and slowly added to 100 g of 1, 2-dichloroethane and 300 g of crushed ice with constant stirring, the layers were separated, the aqueous layer was extracted 3 times with 20 g of 1, 2-dichloroethane, the organic phases were combined and the 1, 2-dichloroethane was recovered by distillation to give 30.5 g of 1- (4-nitrophenyl) piperidin-2-one-3, 3-dibromo-4-dibromoacetamide as a brown viscous liquid which was used directly in the next step (example 6).
Example 5: preparation of l- (4-methoxyphenyl) -7-oxo-6- (4-nitrophenyl) -4,5,6, 7-tetrahydro-1H-pyrazolo [3,4-c ] pyridine-3-carboxamide (V)
Into a 500 ml four-necked flask equipped with a stirrer, a thermometer, a reflux condenser and a dropping funnel were charged 180 g of methanol, 10.5 g (0.06 mol) of 4-methoxyphenylhydrazine hydrochloride, 21.2 g of a light brown viscous liquid 1- (4-nitrophenyl) piperidin-2-one-3, 3-dichloro-4-dichloroacetamide (IV 1) (obtained in example 3), 40.0 g of potassium carbonate, and stirred at 70 to 75 ℃ for 5 hours, followed by filtration, washing the filter cake twice with water, 20 g each, and 20 g of methanol in that order, followed by drying, to obtain 17.2 g of l- (4-methoxyphenyl) -7-oxo-6- (4-nitrophenyl) -4,5,6, 7-tetrahydro-1H-pyrazolo [3,4-c ] pyridine-3-carboxamide, the yield was 84.6% (calculated on the compound of formula III as starting material) and the liquid phase purity was 99.1%.
Example 6: preparation of l- (4-methoxyphenyl) -7-oxo-6- (4-nitrophenyl) -4,5,6, 7-tetrahydro-1H-pyrazolo [3,4-c ] pyridine-3-carboxamide (V)
Into a 500 ml four-necked flask equipped with a stirrer, a thermometer, a reflux condenser and a dropping funnel were charged 180 g of methanol, 10.5 g (0.06 mol) of 4-methoxyphenylhydrazine hydrochloride, 30.5 g of a brown viscous liquid 1- (4-nitrophenyl) piperidin-2-one-3, 3-dibromo-4-dibromoacetamide (IV 2) (obtained in example 4), 30.5 g of triethylamine, and stirred at 60 to 65 ℃ for 6 hours, followed by filtration, washing the filter cake twice with water, 20 g each time, and 20 g of methanol in that order, followed by drying, to obtain 17.4 g of l- (4-methoxyphenyl) -7-oxo-6- (4-nitrophenyl) -4,5,6, 7-tetrahydro-1H-pyrazolo [3,4-c ] pyridine-3-carboxamide, the yield was 85.5% (calculated on the compound of formula III as starting material) and the liquid phase purity was 98.9%.
Example 7: preparation of l- (4-methoxyphenyl) -7-oxo-6- (4-aminophenyl) -4,5,6, 7-tetrahydro-1H-pyrazolo [3,4-c ] pyridine-3-carboxamide (VI)
Into a 500 ml stainless steel autoclave were charged 120 g of methanol, 8.2 g (0.02 mol) of l- (4-methoxyphenyl) -7-oxo-6- (4-nitrophenyl) -4,5,6, 7-tetrahydro-1H-pyrazolo [3,4-c ] pyridine-3-carboxamide (V) prepared in example 6, 0.3 g of 5 wt% palladium on carbon catalyst (palladium content 5% by mass in palladium on carbon), and after three times of replacement with nitrogen, hydrogen was introduced while maintaining a hydrogen pressure of 0.2 to 0.3MPa, and the reaction was carried out at 50 to 55 ℃ for 6 hours. The nitrogen is replaced for three times, the palladium carbon is removed by filtration, the filtrate is concentrated and dried to obtain 7.3 g of l- (4-methoxyphenyl) -7-oxo-6- (4-aminophenyl) -4,5,6, 7-tetrahydro-1H-pyrazolo [3,4-c ] pyridine-3-formamide, the yield is 96.8 percent and the liquid phase purity is 99.7 percent.
Example 8: preparation of l- (4-methoxyphenyl) -7-oxo-6- (4-aminophenyl) -4,5,6, 7-tetrahydro-1H-pyrazolo [3,4-c ] pyridine-3-carboxamide (VI)
150 g of isopropanol, 8.2 g (0.02 mol) of l- (4-methoxyphenyl) -7-oxo-6- (4-nitrophenyl) -4,5,6, 7-tetrahydro-1H-pyrazolo [3,4-c ] pyridine-3-carboxamide (V) prepared in example 5, 1.1 g of a 50 wt% Raney nickel catalyst (the mass content of nickel in Raney nickel is 50%) were placed in a 500 ml stainless steel autoclave and, after three replacements with nitrogen, hydrogen was introduced and the pressure of hydrogen was maintained at 0.2-0.3MPa for 5 hours at 60-65 ℃. The nitrogen is replaced for three times, the Raney nickel is removed by filtration, the filtrate is concentrated and dried to obtain 7.2 g of l- (4-methoxyphenyl) -7-oxo-6- (4-aminophenyl) -4,5,6, 7-tetrahydro-1H-pyrazolo [3,4-c ] pyridine-3-formamide, the yield is 95.5 percent and the liquid phase purity is 99.6 percent.
Example 9: preparation of Apixaban (I)
To a 500 ml four-necked flask equipped with a stirrer, a thermometer, a reflux condenser and a dropping funnel, 30 g of methanol, 30 g of toluene, 3.8 g (0.01 mol) of l- (4-methoxyphenyl) -7-oxo-6- (4-aminophenyl) -4,5,6, 7-tetrahydro-1H-pyrazolo [3,4-c ] pyridine-3-carboxamide (vi) prepared in example 7, 1.2 g of sodium borohydride, 1.8 g (0.014 mol) of methyl 5-oxo-n-valerate were added, and the mixture was stirred at 50 to 55 ℃ for 6 hours, then stirred at 95 to 100 ℃ for 5 hours while recovering methanol by distillation. Cooling to 20-25 deg.c, acidifying with 20 wt% concentration ammonium chloride aqua system pH value of 4.0-4.5, filtering, washing the filter cake twice with water, 20 g each time, washing with 20 g methanol once, and drying to obtain 4.1 g apixaban in 89.2% yield and liquid phase purity of 99.7%.
1H NMR (frequency 400MHz, solvent is deuterated dimethyl sulfoxide):
1.4-1.6 (multiplet, 4H), 2.2 (triplet, 2H),2.7 (triplet, 2H),3.2 (triplet, 2H),3.3 (triplet, 2H), 3.7 (singlet, 3H), 4.7 (broad, 2H),6.7 (doublet, 2H),7.0 (doublet, 2H), 7.1 (doublet, 2H),7.6 (doublet, 2H).
Example 10: preparation of Apixaban (I)
To a 500 ml four-necked flask equipped with a stirrer, a thermometer, a reflux condenser and a dropping funnel, 30 g of ethanol, 30 g of toluene, 3.8 g (0.01 mol) of l- (4-methoxyphenyl) -7-oxo-6- (4-aminophenyl) -4,5,6, 7-tetrahydro-1H-pyrazolo [3,4-c ] pyridine-3-carboxamide (vi) prepared in example 8, 3.5 g of sodium triacetoxyborohydride, 2.2 g (0.015 mol) of ethyl 5-oxo-n-valerate were added, and the mixture was stirred at 50 to 55 ℃ for 6 hours, then stirred at 95 to 100 ℃ for 5 hours, while recovering ethanol by distillation. Cooling to 20-25 deg.c, acidifying with 20 wt% concentration ammonium chloride aqua system pH value of 4.0-4.5, filtering, washing the filter cake twice with water, 20 g each time, washing with 20 g methanol once, and drying to obtain 4.0 g apixaban in yield of 87.1% and liquid phase purity of 99.8%.
Comparative example 1: preparation of 1- (4-nitrophenyl) piperidin-2-one-4-acetamide (III)
To a 500 ml four-necked flask equipped with a stirrer, a thermometer, a reflux condenser and a dropping funnel, 50 g of methanol, 60 g of toluene, 13.8 g (0.1 mol) of 4-nitroaniline, 4.5 g of sodium borohydride, 19.0 g (0.1 mol) of 3-formylmethyl-n-glutaric acid monomethyl ester monoamide (II) were added, and the mixture was stirred at 15 to 20 ℃ for 8 hours, stirred at 95 to 100 ℃ for 5 hours, while recovering methanol by distillation. Cooling to 20-25 deg.C, acidifying system pH value with 20 wt% ammonium chloride aqueous solution 4.0-4.5, adding 100 g dichloromethane, layering, extracting water layer with dichloromethane for 3 times, each time 20 g, combining organic phases, distilling to recover dichloromethane and toluene to obtain 30.2 g dope, analyzing content of 1- (4-nitrophenyl) piperidin-2-one-4-acetamide by liquid phase external standard method to 11.6%, and obtaining liquid phase yield of 12.6%.
It can be seen from this comparative example that the reductive amination temperature is important, and that the yield of 1- (4-nitrophenyl) piperidin-2-one-4-acetamide is greatly reduced due to the excessively low temperature.
Comparative example 2: preparation of Apixaban (I)
To a 500 ml four-necked flask equipped with a stirrer, a thermometer, a reflux condenser and a dropping funnel, 30 g of methanol, 30 g of toluene, 3.8 g (0.01 mol) of l- (4-methoxyphenyl) -7-oxo-6- (4-aminophenyl) -4,5,6, 7-tetrahydro-1H-pyrazolo [3,4-c ] pyridine-3-carboxamide (vi) prepared in example 7, 1.2 g of sodium borohydride, 1.8 g (0.014 mol) of methyl 5-oxo-n-valerate were added, and the mixture was stirred at 15 to 20 ℃ for 10 hours, then stirred at 95 to 100 ℃ for 5 hours while recovering methanol by distillation. Cooling to 20-25 ℃, acidifying the system pH value by using 20 wt% ammonium chloride aqueous solution to be 4.0-4.5, filtering, washing a filter cake twice by using water in sequence, washing 20 g of methanol each time, and drying to obtain 4.9 g of sticky matter, wherein the content of apixaban is 9.2% and the yield of a liquid phase is 9.8% according to the analysis of a liquid phase external standard method.
Compared with the comparative example, the reductive amination reaction temperature is important, the temperature is too low, and the yield of apixaban is greatly reduced.
Claims (10)
1. A preparation method of apixaban comprises the following steps:
(1) in a solvent A, under the action of a reducing agent, carrying out reductive amination and intramolecular amidation on a compound shown in a formula II and 4-nitroaniline to generate a compound shown in a formula III;
wherein in the structural formula of the compound shown in the formula II, R is-CH3、-C2H5、-C3H7、-C4H9、-CH2Ph; wherein Ph represents phenyl;
(2) in a solvent B, performing halogenation reaction on the compound shown in the formula III and a halogenating reagent to obtain a compound shown in a formula IV;
wherein in the structural formula of the compound shown in the formula IV, X is Cl or Br;
(3) in a solvent C, under the catalysis of alkali, condensing a compound shown in the formula IV and 4-methoxy phenylhydrazine hydrochloride to obtain a compound shown in the formula V;
(4) in a solvent D, under the catalysis of a hydrogenation catalyst, a compound of a formula V is subjected to hydrogenation reduction reaction to prepare a compound of a formula VI;
(5) in a solvent E, under the action of a reducing agent F, carrying out reductive amination and intramolecular amidation on a compound shown in a formula VI and 5-oxo-n-valerate to generate apixaban (I);
2. process for the preparation of apixaban according to claim 1, characterized in that in step (1) any one or more of the following conditions are included:
a. the solvent A is one or the combination of more than two of methanol, ethanol, tetrahydrofuran, 2-methyltetrahydrofuran, methyl cyclopentyl ether, 1, 2-dimethoxyethane, toluene, xylene, 1, 2-dichloroethane or chlorobenzene; the mass ratio of the solvent A to the compound shown in the formula II is (5-20) to 1;
b. the reducing agent is one or the combination of more than two of sodium triacetoxyborohydride, potassium triacetoxyborohydride, sodium borohydride or potassium borohydride;
c. the compound of the formula II is one of 3-formylmethyl-n-glutaric acid monomethyl ester monoamide, 3-formylmethyl-n-glutaric acid monoethyl ester monoamide, 3-formylmethyl-n-glutaric acid monoisopropyl ester monoamide, 3-formylmethyl-n-glutaric acid mono-tert-butyl ester monoamide or 3-formylmethyl-n-glutaric acid monobenzyl ester monoamide;
d. the mol ratio of the reducing agent, the 4-nitroaniline and the compound shown in the formula II is (0.5-2.0): (0.9-1.5): 1.
3. Process for the preparation of apixaban according to claim 1, characterized in that in step (1) any one or more of the following conditions are included:
a. the temperature of the reductive amination reaction is 20-100 ℃;
b. the reaction temperature of the intramolecular amidation is 50-130 ℃.
4. Process for the preparation of apixaban according to claim 1, characterized in that in step (2) any one or more of the following conditions is included:
a. the solvent B is one or the combination of more than two of dichloromethane, chloroform, carbon tetrachloride, 1, 2-dichloroethane, trichloroethylene or chlorobenzene; the mass ratio of the solvent B to the compound shown in the formula III is (5-50) to 1;
b. the halogenating reagent is one of chlorine, phosphorus pentachloride, sulfuryl chloride, bromine or phosphorus pentabromide; the molar ratio of the halogenating agent to the compound of formula III is (1.0-8.0): 1;
c. the temperature of the halogenation reaction is 20-90 ℃.
5. Process for the preparation of apixaban according to claim 1, characterized in that in step (3) any one or more of the following conditions are included:
a. the solvent C is one or the combination of more than two of methanol, ethanol, tetrahydrofuran, 2-methyltetrahydrofuran, methyl cyclopentyl ether, 1, 2-dimethoxyethane, acetonitrile or chlorobenzene; the mass ratio of the solvent C to the compound shown in the formula IV is (5-30) to 1;
b. the alkali is inorganic alkali or organic alkali, the inorganic alkali is selected from one or the combination of potassium carbonate, sodium methoxide, sodium ethoxide, calcium carbonate, sodium hydroxide, potassium bicarbonate, sodium bicarbonate, calcium bicarbonate, potassium acetate, sodium acetate and calcium acetate, and the organic alkali is selected from one or the combination of trimethylamine, triethylamine and tri-n-butylamine; the molar ratio of the base to the compound of formula IV is (3.0-6.0) to 1;
c. the molar ratio of the 4-methoxy phenylhydrazine hydrochloride to the compound shown in the formula IV is (1.0-1.5): 1.
6. the process for the preparation of apixaban according to claim 1, characterized in that the temperature of the condensation reaction in step (3) is 30-100 ℃.
7. Process for the preparation of apixaban according to claim 1, characterized in that in step (4) any one or more of the following conditions is included:
a. the solvent D is one or the combination of more than two of methanol, ethanol, isopropanol, acetonitrile, ethyl acetate, tert-butyl acetate, tetrahydrofuran, 2-methyltetrahydrofuran, methyl cyclopentyl ether or 1, 2-dimethoxyethane; the mass ratio of the solvent D to the compound of the formula V is (5-25) to 1;
b. the hydrogenation catalyst is palladium carbon or Raney nickel;
the mass of the palladium carbon is 0.5-10% of that of the compound of the formula V;
the mass of the Raney nickel is 5-25% of that of the compound of the formula V.
8. The process for preparing apixaban according to claim 1, wherein the temperature of the hydrogenation reduction reaction in step (4) is 0 to 80 ℃ and the hydrogen pressure is 0.1 to 0.5 MPa.
9. Process for the preparation of apixaban according to claim 1, characterized in that in step (5) any one or more of the following conditions are included:
a. the solvent E is one or the combination of more than two of tetrahydrofuran, 2-methyltetrahydrofuran, methyl cyclopentyl ether, 1, 2-dimethoxyethane, toluene, xylene, 1, 2-dichloroethane or chlorobenzene; the mass ratio of the solvent E to the compound shown in the formula VI is (10-30) to 1;
b. the reducing agent F is one or the combination of more than two of sodium triacetoxyborohydride, potassium triacetoxyborohydride, sodium borohydride or potassium borohydride;
c. the 5-oxo-n-valerate is one of 5-oxo-n-methyl valerate, 5-oxo-n-ethyl valerate, 5-oxo-n-isopropyl valerate, 5-oxo-n-tert-butyl valerate or 5-oxo-n-benzyl valerate;
d. the mol ratio of the reducing agent F, the 5-oxo-n-valerate and the compound shown in the formula VI is (1.0-4.0): (0.9-1.6): 1.
10. Process for the preparation of apixaban according to claim 1, characterized in that in step (5) any one or more of the following conditions are included:
a. the temperature of the reductive amination reaction is 20-100 ℃;
b. the reaction temperature of the intramolecular amidation is 50-130 ℃.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201810167381.0A CN110204541B (en) | 2018-02-28 | 2018-02-28 | Preparation method of apixaban |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201810167381.0A CN110204541B (en) | 2018-02-28 | 2018-02-28 | Preparation method of apixaban |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN110204541A CN110204541A (en) | 2019-09-06 |
| CN110204541B true CN110204541B (en) | 2020-06-23 |
Family
ID=67778651
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201810167381.0A Active CN110204541B (en) | 2018-02-28 | 2018-02-28 | Preparation method of apixaban |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN110204541B (en) |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102675314A (en) * | 2012-06-14 | 2012-09-19 | 南京正科制药有限公司 | Method for synthesizing apixaban |
Family Cites Families (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP2238127B1 (en) * | 2007-12-26 | 2012-08-15 | Sanofi | Pyrazole-carboxamide derivatives as p2y12 antagonists |
| WO2014072884A1 (en) * | 2012-11-12 | 2014-05-15 | Alembic Pharmaceuticals Limited | Process for the synthesis of apixaban |
| WO2014108919A2 (en) * | 2013-01-09 | 2014-07-17 | Msn Laboratories Limited | NOVEL INTERMEDIATE AND POLYMORPHS OF 1-(4-METHOXYPHENYL)-7-OXO-6-[4-(2-OXOPIPERIDIN-1-YL)PHENYL]-4,5,6,7-TETRAHYDRO-1H-PYRAZOLO[3,4-c] PYRIDINE-3-CARBOXAMIDE AND PROCESS THEREOF |
| EP3212620B1 (en) * | 2014-10-28 | 2020-11-25 | Jubilant Generics Limited (Formerly Jubilant Life Sciences Division) | Process for the preparation of apixaban and intermediates thereof |
-
2018
- 2018-02-28 CN CN201810167381.0A patent/CN110204541B/en active Active
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102675314A (en) * | 2012-06-14 | 2012-09-19 | 南京正科制药有限公司 | Method for synthesizing apixaban |
Non-Patent Citations (4)
| Title |
|---|
| "Environment-friendly Synthesis of Bioactive Pyrazoles";Lucas Pizzutia et al.;《Current Organic Chemistry》;20140101;第18卷;第115-126页 * |
| "Identification of 4,5-Dihydro-1H-pyrazolo[4,3-h]quinazoline Derivatives as a New Class of Orally and";Italo Beria et al.;《J. Med. Chem.》;20100416;第53卷;第3532-3551页 * |
| "The Synthesis of Some Fused Pyrazolo-1,4-Naphthoquinones";Aurora Molinari et al.;《J. Heterocyclic Chem.》;20140527;第52卷;第620-622页 * |
| "阿哌沙班( apixaban)";高雅莉;《中国药物化学杂志》;20130630;第23卷(第3期);第251页 * |
Also Published As
| Publication number | Publication date |
|---|---|
| CN110204541A (en) | 2019-09-06 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| US6452019B1 (en) | Preparation of 4,5-diamino-1-(2′-hydroxyethyl)-pyrazole and acid addition salts thereof | |
| CN107200741B (en) | Preparation method of anaplastic lymphoma kinase inhibitor | |
| KR20150118146A (en) | Vortioxetine manufacturing process | |
| TWI382975B (en) | Process for preparing 1-[3-[3-(4-chlorophenyl)propoxy]propyl]-piperidine | |
| CN110204541B (en) | Preparation method of apixaban | |
| KR20120053011A (en) | Method for synthesis of n-alkyl carbazole and derivatives thereof | |
| CN103601645A (en) | Preparation method of 1-(phenethylamino) propane-2-alcoholic compounds or salts thereof | |
| CN113636973A (en) | Industrial preparation method of 4- (6-aminopyridine-3-yl) piperazine-1-carboxylic acid tert-butyl ester | |
| KR20030078038A (en) | Process for producing diamines | |
| CN102532109A (en) | Synthetic method of lapatinib and salt of lapatinib | |
| CN101218244A (en) | Processes for preparing pyrazole-O-glycoside derivatives and novel intermediates of said processes | |
| CN109503473B (en) | Synthesis method of 2-methoxy-3-amino-5-pyridine boronic acid pinacol ester and intermediate thereof | |
| WO2006080401A1 (en) | Method for producing fluorinated proline derivative | |
| CN109651286B (en) | High-selectivity synthesis method of 4- (4-aminophenyl) morpholine-3-one | |
| CN109810052B (en) | Simple and convenient preparation method of high-selectivity apatinib | |
| JP2646907B2 (en) | Method for producing 6-amino-7-fluoro-2H-1,4-benzoxazin-3 (4H) -one | |
| JP3088561B2 (en) | Method for producing 2,3-diaminopyridines | |
| EA004922B1 (en) | Method for preparing polyhalogenated paratrifluoromethylanilines | |
| JPH0414096B2 (en) | ||
| CN110128401B (en) | Simple preparation method of alogliptin benzoate | |
| CN115784922B (en) | Preparation method of (2S) -2-amino-4- (cyclopropyl/cyclobutyl) butyric acid | |
| CN109096128A (en) | A kind of preparation method of amino-polyethyleneglycols propionic acid | |
| CN109928975B (en) | Industrial preparation method of Riboxini | |
| WO2023100110A1 (en) | Process for preparing brivaracetam | |
| JP3981894B2 (en) | Process for producing 4,6-diaminoresorcinol and / or a salt thereof |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant | ||
| PE01 | Entry into force of the registration of the contract for pledge of patent right |
Denomination of invention: A preparation method of apixaban Effective date of registration: 20231205 Granted publication date: 20200623 Pledgee: Hengfeng bank Limited by Share Ltd. Dongying branch Pledgor: Xinfa pharmaceutical Co.,Ltd. Registration number: Y2023980069314 |
|
| PE01 | Entry into force of the registration of the contract for pledge of patent right |