CN104693114B - A kind of improved preparation method of betrixaban - Google Patents
A kind of improved preparation method of betrixaban Download PDFInfo
- Publication number
- CN104693114B CN104693114B CN201310664433.2A CN201310664433A CN104693114B CN 104693114 B CN104693114 B CN 104693114B CN 201310664433 A CN201310664433 A CN 201310664433A CN 104693114 B CN104693114 B CN 104693114B
- Authority
- CN
- China
- Prior art keywords
- compound
- preparation
- acid
- salt
- betrixaban
- 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.)
- Expired - Fee Related
Links
- 229950011103 betrixaban Drugs 0.000 title claims abstract description 60
- XHOLNRLADUSQLD-UHFFFAOYSA-N betrixaban Chemical compound C=1C=C(Cl)C=NC=1NC(=O)C1=CC(OC)=CC=C1NC(=O)C1=CC=C(C(=N)N(C)C)C=C1 XHOLNRLADUSQLD-UHFFFAOYSA-N 0.000 title claims abstract description 56
- 238000002360 preparation method Methods 0.000 title claims abstract description 44
- 238000006243 chemical reaction Methods 0.000 claims abstract description 76
- ROSDSFDQCJNGOL-UHFFFAOYSA-N Dimethylamine Chemical compound CNC ROSDSFDQCJNGOL-UHFFFAOYSA-N 0.000 claims abstract description 72
- 150000003839 salts Chemical class 0.000 claims abstract description 59
- 150000001875 compounds Chemical class 0.000 claims abstract description 55
- 238000000034 method Methods 0.000 claims abstract description 55
- 229910052725 zinc Inorganic materials 0.000 claims abstract description 8
- 239000000376 reactant Substances 0.000 claims abstract description 7
- 239000002904 solvent Substances 0.000 claims abstract description 6
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 42
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 36
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 22
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 21
- -1 Hydrogen furans Chemical class 0.000 claims description 20
- RDOXTESZEPMUJZ-UHFFFAOYSA-N anisole Chemical group COC1=CC=CC=C1 RDOXTESZEPMUJZ-UHFFFAOYSA-N 0.000 claims description 15
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 claims description 15
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 claims description 10
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 claims description 10
- 229910052739 hydrogen Inorganic materials 0.000 claims description 10
- 239000001257 hydrogen Substances 0.000 claims description 10
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims description 9
- 239000012046 mixed solvent Substances 0.000 claims description 9
- JWUJQDFVADABEY-UHFFFAOYSA-N 2-methyltetrahydrofuran Chemical compound CC1CCCO1 JWUJQDFVADABEY-UHFFFAOYSA-N 0.000 claims description 8
- IUYHWZFSGMZEOG-UHFFFAOYSA-M magnesium;propane;chloride Chemical compound [Mg+2].[Cl-].C[CH-]C IUYHWZFSGMZEOG-UHFFFAOYSA-M 0.000 claims description 8
- 239000011701 zinc Substances 0.000 claims description 7
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 claims description 6
- HQWPLXHWEZZGKY-UHFFFAOYSA-N diethylzinc Chemical compound CC[Zn]CC HQWPLXHWEZZGKY-UHFFFAOYSA-N 0.000 claims description 6
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 claims description 5
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 claims description 5
- NKDDWNXOKDWJAK-UHFFFAOYSA-N dimethoxymethane Chemical compound COCOC NKDDWNXOKDWJAK-UHFFFAOYSA-N 0.000 claims description 5
- 125000004836 hexamethylene group Chemical group [H]C([H])([*:2])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[*:1] 0.000 claims description 5
- 229910001623 magnesium bromide Inorganic materials 0.000 claims description 5
- XWCQLLDGXBLGMD-UHFFFAOYSA-M magnesium;pentane;bromide Chemical compound [Mg+2].[Br-].CCCC[CH2-] XWCQLLDGXBLGMD-UHFFFAOYSA-M 0.000 claims description 5
- LVKCSZQWLOVUGB-UHFFFAOYSA-M magnesium;propane;bromide Chemical compound [Mg+2].[Br-].C[CH-]C LVKCSZQWLOVUGB-UHFFFAOYSA-M 0.000 claims description 5
- UZKWTJUDCOPSNM-UHFFFAOYSA-N methoxybenzene Substances CCCCOC=C UZKWTJUDCOPSNM-UHFFFAOYSA-N 0.000 claims description 5
- TWRXJAOTZQYOKJ-UHFFFAOYSA-L Magnesium chloride Chemical compound [Mg+2].[Cl-].[Cl-] TWRXJAOTZQYOKJ-UHFFFAOYSA-L 0.000 claims description 4
- 150000002012 dioxanes Chemical class 0.000 claims description 4
- LGRLWUINFJPLSH-UHFFFAOYSA-N methanide Chemical compound [CH3-] LGRLWUINFJPLSH-UHFFFAOYSA-N 0.000 claims description 4
- PHSPFUQAZNIVCH-UHFFFAOYSA-M [Mg].[I-].C[N+]1=CC=CC=C1 Chemical compound [Mg].[I-].C[N+]1=CC=CC=C1 PHSPFUQAZNIVCH-UHFFFAOYSA-M 0.000 claims description 3
- OTCKOJUMXQWKQG-UHFFFAOYSA-L magnesium bromide Chemical compound [Mg+2].[Br-].[Br-] OTCKOJUMXQWKQG-UHFFFAOYSA-L 0.000 claims description 3
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 2
- 229910001629 magnesium chloride Inorganic materials 0.000 claims description 2
- PCHJSUWPFVWCPO-UHFFFAOYSA-N gold Chemical compound [Au] PCHJSUWPFVWCPO-UHFFFAOYSA-N 0.000 claims 1
- 239000010931 gold Substances 0.000 claims 1
- 229910052737 gold Inorganic materials 0.000 claims 1
- 150000002894 organic compounds Chemical class 0.000 claims 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 abstract description 47
- 125000000217 alkyl group Chemical group 0.000 abstract description 12
- 125000003118 aryl group Chemical group 0.000 abstract description 9
- 230000006872 improvement Effects 0.000 abstract description 9
- 238000004519 manufacturing process Methods 0.000 abstract description 8
- 229910052749 magnesium Inorganic materials 0.000 abstract description 7
- 238000012545 processing Methods 0.000 abstract description 5
- 238000000746 purification Methods 0.000 abstract description 5
- 239000002994 raw material Substances 0.000 abstract description 5
- 230000007812 deficiency Effects 0.000 abstract description 4
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 abstract description 4
- 229910000041 hydrogen chloride Inorganic materials 0.000 abstract description 4
- 229910052740 iodine Inorganic materials 0.000 abstract description 4
- 239000007789 gas Substances 0.000 abstract description 2
- 238000005498 polishing Methods 0.000 abstract 1
- 235000002639 sodium chloride Nutrition 0.000 description 51
- 239000000243 solution Substances 0.000 description 37
- 238000004128 high performance liquid chromatography Methods 0.000 description 28
- 239000012065 filter cake Substances 0.000 description 19
- 238000001914 filtration Methods 0.000 description 14
- 238000003756 stirring Methods 0.000 description 13
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 13
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 12
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 12
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 12
- 150000007522 mineralic acids Chemical class 0.000 description 12
- 150000007524 organic acids Chemical class 0.000 description 12
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 11
- 239000012535 impurity Substances 0.000 description 11
- 239000000047 product Substances 0.000 description 11
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 10
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 10
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 10
- 239000002585 base Substances 0.000 description 10
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 9
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 9
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 9
- 238000006298 dechlorination reaction Methods 0.000 description 9
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 9
- IWYDHOAUDWTVEP-SSDOTTSWSA-N (R)-mandelic acid Chemical compound OC(=O)[C@H](O)C1=CC=CC=C1 IWYDHOAUDWTVEP-SSDOTTSWSA-N 0.000 description 8
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 8
- 239000002253 acid Substances 0.000 description 8
- 238000010791 quenching Methods 0.000 description 8
- 230000000171 quenching effect Effects 0.000 description 8
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 7
- HQQARYRCDMYLHW-UHFFFAOYSA-N N,N-diethyl-2-[(2-methoxy-5-methylsulfonylbenzoyl)amino]ethanamine oxide Chemical compound CC[N+]([O-])(CC)CCNC(=O)C1=CC(S(C)(=O)=O)=CC=C1OC HQQARYRCDMYLHW-UHFFFAOYSA-N 0.000 description 7
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 7
- 239000011976 maleic acid Substances 0.000 description 7
- HTSGKJQDMSTCGS-UHFFFAOYSA-N 1,4-bis(4-chlorophenyl)-2-(4-methylphenyl)sulfonylbutane-1,4-dione Chemical compound C1=CC(C)=CC=C1S(=O)(=O)C(C(=O)C=1C=CC(Cl)=CC=1)CC(=O)C1=CC=C(Cl)C=C1 HTSGKJQDMSTCGS-UHFFFAOYSA-N 0.000 description 6
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 6
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 6
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 6
- SRSXLGNVWSONIS-UHFFFAOYSA-N benzenesulfonic acid Chemical compound OS(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-N 0.000 description 6
- 229940092714 benzenesulfonic acid Drugs 0.000 description 6
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 6
- 239000007788 liquid Substances 0.000 description 6
- 239000011777 magnesium Substances 0.000 description 6
- 229910017604 nitric acid Inorganic materials 0.000 description 6
- 238000001953 recrystallisation Methods 0.000 description 6
- 238000000926 separation method Methods 0.000 description 6
- SWWQQSDRUYSMAR-UHFFFAOYSA-N 1-[(4-hydroxyphenyl)methyl]-1,2,3,4-tetrahydroisoquinoline-6,7-diol;hydrochloride Chemical group Cl.C1=CC(O)=CC=C1CC1C2=CC(O)=C(O)C=C2CCN1 SWWQQSDRUYSMAR-UHFFFAOYSA-N 0.000 description 5
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 5
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 5
- 230000008859 change Effects 0.000 description 5
- 125000002147 dimethylamino group Chemical group [H]C([H])([H])N(*)C([H])([H])[H] 0.000 description 5
- 235000019441 ethanol Nutrition 0.000 description 5
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 5
- 229940071870 hydroiodic acid Drugs 0.000 description 5
- 229940098779 methanesulfonic acid Drugs 0.000 description 5
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- 239000007787 solid Substances 0.000 description 5
- 239000000126 substance Substances 0.000 description 5
- 238000005406 washing Methods 0.000 description 5
- OBTZDIRUQWFRFZ-UHFFFAOYSA-N 2-(5-methylfuran-2-yl)-n-(4-methylphenyl)quinoline-4-carboxamide Chemical compound O1C(C)=CC=C1C1=CC(C(=O)NC=2C=CC(C)=CC=2)=C(C=CC=C2)C2=N1 OBTZDIRUQWFRFZ-UHFFFAOYSA-N 0.000 description 4
- FNRMMDCDHWCQTH-UHFFFAOYSA-N 2-chloropyridine;3-chloropyridine;4-chloropyridine Chemical compound ClC1=CC=NC=C1.ClC1=CC=CN=C1.ClC1=CC=CC=N1 FNRMMDCDHWCQTH-UHFFFAOYSA-N 0.000 description 4
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 4
- RGHNJXZEOKUKBD-SQOUGZDYSA-N D-gluconic acid Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C(O)=O RGHNJXZEOKUKBD-SQOUGZDYSA-N 0.000 description 4
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- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 4
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 4
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- 239000000010 aprotic solvent Substances 0.000 description 4
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- 238000002425 crystallisation Methods 0.000 description 4
- 230000008025 crystallization Effects 0.000 description 4
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 4
- 235000021050 feed intake Nutrition 0.000 description 4
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- GSJRUEBQWPLHSN-UHFFFAOYSA-N n-methylmethanamine;oxolane Chemical compound CNC.C1CCOC1 GSJRUEBQWPLHSN-UHFFFAOYSA-N 0.000 description 4
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- DTSJEZCXVWQKCL-BTJKTKAUSA-N (z)-but-2-enedioic acid;n-(5-chloropyridin-2-yl)-2-[[4-(n,n-dimethylcarbamimidoyl)benzoyl]amino]-5-methoxybenzamide Chemical compound OC(=O)\C=C/C(O)=O.C=1C=C(Cl)C=NC=1NC(=O)C1=CC(OC)=CC=C1NC(=O)C1=CC=C(C(=N)N(C)C)C=C1 DTSJEZCXVWQKCL-BTJKTKAUSA-N 0.000 description 3
- 238000005160 1H NMR spectroscopy Methods 0.000 description 3
- STNAQENUCOFEKN-UHFFFAOYSA-N 2-cyanobenzoyl chloride Chemical compound ClC(=O)C1=CC=CC=C1C#N STNAQENUCOFEKN-UHFFFAOYSA-N 0.000 description 3
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- 239000001361 adipic acid Substances 0.000 description 2
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- 235000013985 cinnamic acid Nutrition 0.000 description 2
- 238000007796 conventional method Methods 0.000 description 2
- MKRVHLWAVKJBFN-UHFFFAOYSA-N diphenylzinc Chemical compound C=1C=CC=CC=1[Zn]C1=CC=CC=C1 MKRVHLWAVKJBFN-UHFFFAOYSA-N 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- NLFBCYMMUAKCPC-KQQUZDAGSA-N ethyl (e)-3-[3-amino-2-cyano-1-[(e)-3-ethoxy-3-oxoprop-1-enyl]sulfanyl-3-oxoprop-1-enyl]sulfanylprop-2-enoate Chemical compound CCOC(=O)\C=C\SC(=C(C#N)C(N)=O)S\C=C\C(=O)OCC NLFBCYMMUAKCPC-KQQUZDAGSA-N 0.000 description 2
- 239000001530 fumaric acid Substances 0.000 description 2
- XOXYHGOIRWABTC-UHFFFAOYSA-N gentisin Chemical compound C1=C(O)C=C2C(=O)C3=C(O)C=C(OC)C=C3OC2=C1 XOXYHGOIRWABTC-UHFFFAOYSA-N 0.000 description 2
- 239000000174 gluconic acid Substances 0.000 description 2
- 235000012208 gluconic acid Nutrition 0.000 description 2
- 229940097043 glucuronic acid Drugs 0.000 description 2
- 150000002431 hydrogen Chemical class 0.000 description 2
- 238000006460 hydrolysis reaction Methods 0.000 description 2
- 239000004310 lactic acid Substances 0.000 description 2
- 235000014655 lactic acid Nutrition 0.000 description 2
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 2
- 229910052744 lithium Inorganic materials 0.000 description 2
- YDGSUPBDGKOGQT-UHFFFAOYSA-N lithium;dimethylazanide Chemical compound [Li+].C[N-]C YDGSUPBDGKOGQT-UHFFFAOYSA-N 0.000 description 2
- IWCVDCOJSPWGRW-UHFFFAOYSA-M magnesium;benzene;chloride Chemical compound [Mg+2].[Cl-].C1=CC=[C-]C=C1 IWCVDCOJSPWGRW-UHFFFAOYSA-M 0.000 description 2
- NXPHGHWWQRMDIA-UHFFFAOYSA-M magnesium;carbanide;bromide Chemical compound [CH3-].[Mg+2].[Br-] NXPHGHWWQRMDIA-UHFFFAOYSA-M 0.000 description 2
- GFTXWCQFWLOXAT-UHFFFAOYSA-M magnesium;cyclohexane;bromide Chemical compound [Mg+2].[Br-].C1CC[CH-]CC1 GFTXWCQFWLOXAT-UHFFFAOYSA-M 0.000 description 2
- FRIJBUGBVQZNTB-UHFFFAOYSA-M magnesium;ethane;bromide Chemical compound [Mg+2].[Br-].[CH2-]C FRIJBUGBVQZNTB-UHFFFAOYSA-M 0.000 description 2
- BRKADVNLTRCLOW-UHFFFAOYSA-M magnesium;fluorobenzene;bromide Chemical compound [Mg+2].[Br-].FC1=CC=[C-]C=C1 BRKADVNLTRCLOW-UHFFFAOYSA-M 0.000 description 2
- SCEZYJKGDJPHQO-UHFFFAOYSA-M magnesium;methanidylbenzene;chloride Chemical compound [Mg+2].[Cl-].[CH2-]C1=CC=CC=C1 SCEZYJKGDJPHQO-UHFFFAOYSA-M 0.000 description 2
- YAMQOOCGNXAQGW-UHFFFAOYSA-M magnesium;methylbenzene;bromide Chemical compound [Mg+2].[Br-].CC1=CC=CC=[C-]1 YAMQOOCGNXAQGW-UHFFFAOYSA-M 0.000 description 2
- MPMNUCMJDPWNCV-UHFFFAOYSA-M magnesium;phenoxybenzene;bromide Chemical compound [Mg+2].[Br-].C=1C=[C-]C=CC=1OC1=CC=CC=C1 MPMNUCMJDPWNCV-UHFFFAOYSA-M 0.000 description 2
- 229960002510 mandelic acid Drugs 0.000 description 2
- ZKUUVVYMPUDTGJ-UHFFFAOYSA-N methyl 5-hydroxy-4-methoxy-2-nitrobenzoate Chemical compound COC(=O)C1=CC(O)=C(OC)C=C1[N+]([O-])=O ZKUUVVYMPUDTGJ-UHFFFAOYSA-N 0.000 description 2
- WBYWAXJHAXSJNI-UHFFFAOYSA-N methyl p-hydroxycinnamate Natural products OC(=O)C=CC1=CC=CC=C1 WBYWAXJHAXSJNI-UHFFFAOYSA-N 0.000 description 2
- 238000002156 mixing Methods 0.000 description 2
- 239000012071 phase Substances 0.000 description 2
- 235000019260 propionic acid Nutrition 0.000 description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 2
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 2
- 230000035484 reaction time Effects 0.000 description 2
- 229910052711 selenium Inorganic materials 0.000 description 2
- 239000011669 selenium Substances 0.000 description 2
- 235000015170 shellfish Nutrition 0.000 description 2
- TXUICONDJPYNPY-UHFFFAOYSA-N (1,10,13-trimethyl-3-oxo-4,5,6,7,8,9,11,12,14,15,16,17-dodecahydrocyclopenta[a]phenanthren-17-yl) heptanoate Chemical compound C1CC2CC(=O)C=C(C)C2(C)C2C1C1CCC(OC(=O)CCCCCC)C1(C)CC2 TXUICONDJPYNPY-UHFFFAOYSA-N 0.000 description 1
- LCPVQAHEFVXVKT-UHFFFAOYSA-N 2-(2,4-difluorophenoxy)pyridin-3-amine Chemical compound NC1=CC=CN=C1OC1=CC=C(F)C=C1F LCPVQAHEFVXVKT-UHFFFAOYSA-N 0.000 description 1
- FCSKOFQQCWLGMV-UHFFFAOYSA-N 5-{5-[2-chloro-4-(4,5-dihydro-1,3-oxazol-2-yl)phenoxy]pentyl}-3-methylisoxazole Chemical compound O1N=C(C)C=C1CCCCCOC1=CC=C(C=2OCCN=2)C=C1Cl FCSKOFQQCWLGMV-UHFFFAOYSA-N 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- 206010003658 Atrial Fibrillation Diseases 0.000 description 1
- LSNNMFCWUKXFEE-UHFFFAOYSA-M Bisulfite Chemical compound OS([O-])=O LSNNMFCWUKXFEE-UHFFFAOYSA-M 0.000 description 1
- YSRKIFIAXKTQLN-UHFFFAOYSA-N CC[Zn]N(C)C Chemical compound CC[Zn]N(C)C YSRKIFIAXKTQLN-UHFFFAOYSA-N 0.000 description 1
- FITVBGDDRFHFKJ-UHFFFAOYSA-N CN(C)[Zn]C Chemical compound CN(C)[Zn]C FITVBGDDRFHFKJ-UHFFFAOYSA-N 0.000 description 1
- DJEYBELNUUJBQS-UHFFFAOYSA-N CN(C)[Zn]C1=CC=CC=C1 Chemical compound CN(C)[Zn]C1=CC=CC=C1 DJEYBELNUUJBQS-UHFFFAOYSA-N 0.000 description 1
- 244000025254 Cannabis sativa Species 0.000 description 1
- 238000007445 Chromatographic isolation Methods 0.000 description 1
- CDEMHJCJMMOFMB-UHFFFAOYSA-M ClC1=CC=C([Mg]Br)C=C1 Chemical compound ClC1=CC=C([Mg]Br)C=C1 CDEMHJCJMMOFMB-UHFFFAOYSA-M 0.000 description 1
- 206010051055 Deep vein thrombosis Diseases 0.000 description 1
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 1
- 238000005481 NMR spectroscopy Methods 0.000 description 1
- ZQSCEMYEJFSARK-UHFFFAOYSA-M O1CCCC1.[Br-].C(CCCC)[Mg+] Chemical compound O1CCCC1.[Br-].C(CCCC)[Mg+] ZQSCEMYEJFSARK-UHFFFAOYSA-M 0.000 description 1
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 description 1
- 208000010378 Pulmonary Embolism Diseases 0.000 description 1
- 229910021626 Tin(II) chloride Inorganic materials 0.000 description 1
- 206010047249 Venous thrombosis Diseases 0.000 description 1
- FEEHGGSSPLTALT-UHFFFAOYSA-M [Mg].C(C)(C)[Mg]Br Chemical compound [Mg].C(C)(C)[Mg]Br FEEHGGSSPLTALT-UHFFFAOYSA-M 0.000 description 1
- 150000001335 aliphatic alkanes Chemical class 0.000 description 1
- 150000001408 amides Chemical group 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 230000031709 bromination Effects 0.000 description 1
- 238000005893 bromination reaction Methods 0.000 description 1
- 125000003739 carbamimidoyl group Chemical group C(N)(=N)* 0.000 description 1
- 239000003518 caustics Substances 0.000 description 1
- WWMCURUJBADGMN-UHFFFAOYSA-N chlorobenzene;hydrobromide Chemical compound Br.ClC1=CC=CC=C1 WWMCURUJBADGMN-UHFFFAOYSA-N 0.000 description 1
- 238000011097 chromatography purification Methods 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 230000007797 corrosion Effects 0.000 description 1
- 238000005260 corrosion Methods 0.000 description 1
- 230000008878 coupling Effects 0.000 description 1
- 238000010168 coupling process Methods 0.000 description 1
- 238000005859 coupling reaction Methods 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 230000006837 decompression Effects 0.000 description 1
- 125000004177 diethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- XHFGWHUWQXTGAT-UHFFFAOYSA-N dimethylamine hydrochloride Natural products CNC(C)C XHFGWHUWQXTGAT-UHFFFAOYSA-N 0.000 description 1
- IQDGSYLLQPDQDV-UHFFFAOYSA-N dimethylazanium;chloride Chemical compound Cl.CNC IQDGSYLLQPDQDV-UHFFFAOYSA-N 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 150000002240 furans Chemical class 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- FUKUFMFMCZIRNT-UHFFFAOYSA-N hydron;methanol;chloride Chemical compound Cl.OC FUKUFMFMCZIRNT-UHFFFAOYSA-N 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 1
- 150000002500 ions Chemical class 0.000 description 1
- 229960002337 magnesium chloride Drugs 0.000 description 1
- BXHREGOYAAJTCJ-UHFFFAOYSA-M magnesium;dimethylazanide;bromide Chemical compound [Br-].CN(C)[Mg+] BXHREGOYAAJTCJ-UHFFFAOYSA-M 0.000 description 1
- SMDZDLANMQKORU-UHFFFAOYSA-M magnesium;dimethylazanide;chloride Chemical compound [Cl-].CN(C)[Mg+] SMDZDLANMQKORU-UHFFFAOYSA-M 0.000 description 1
- GRYDGXUVWLGHPL-UHFFFAOYSA-M magnesium;heptane;bromide Chemical compound [Mg+2].[Br-].CCCCCC[CH2-] GRYDGXUVWLGHPL-UHFFFAOYSA-M 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 235000013372 meat Nutrition 0.000 description 1
- 208000010125 myocardial infarction Diseases 0.000 description 1
- 125000003136 n-heptyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- XTMWXULZPRKUTG-UHFFFAOYSA-N n-iodo-n-methylmethanamine Chemical compound CN(C)I XTMWXULZPRKUTG-UHFFFAOYSA-N 0.000 description 1
- 239000012074 organic phase Substances 0.000 description 1
- 125000002524 organometallic group Chemical group 0.000 description 1
- 229910052698 phosphorus Inorganic materials 0.000 description 1
- 239000011574 phosphorus Substances 0.000 description 1
- 230000002980 postoperative effect Effects 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 230000000069 prophylactic effect Effects 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 238000007670 refining Methods 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 238000004904 shortening Methods 0.000 description 1
- CHQMHPLRPQMAMX-UHFFFAOYSA-L sodium persulfate Substances [Na+].[Na+].[O-]S(=O)(=O)OOS([O-])(=O)=O CHQMHPLRPQMAMX-UHFFFAOYSA-L 0.000 description 1
- 238000010183 spectrum analysis Methods 0.000 description 1
- 235000011150 stannous chloride Nutrition 0.000 description 1
- 239000001119 stannous chloride Substances 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- CZDYPVPMEAXLPK-UHFFFAOYSA-N tetramethylsilane Chemical compound C[Si](C)(C)C CZDYPVPMEAXLPK-UHFFFAOYSA-N 0.000 description 1
- 238000012546 transfer Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/72—Nitrogen atoms
- C07D213/75—Amino or imino radicals, acylated by carboxylic or carbonic acids, or by sulfur or nitrogen analogues thereof, e.g. carbamates
Abstract
The present invention relates to organic chemistry fileds and pharmaceutical field, and in particular to a kind of improvement preparation method of betrixaban (Fig. 1).Compared with prior art, the deficiencies of which overcomes the use of highly corrosive hydrogen chloride gas, " three wastes " processing load is heavier, product is not easy polishing purification.The main feature of the preparation method are as follows: in non-protonic solvent, use metallo-organic compound RMR ' (M is selected from Mg, Zn, and R is selected from Cl, Br, I, alkyl or aryl, and R ' is selected from alkyl or aryl) and dimethylamine or its reactant salt；Then, resulting reaction solution is reacted with Formula II compound or its salt, betrixaban is made.Improvement new method raw material are easy to get, reaction condition is mild, easy to operate for this, and good quality of product, cost is relatively low, is more suitable for industrialized production.
Description
Technical field
The present invention relates to organic chemistry fileds and pharmaceutical field, and in particular to a kind of improved preparation side of betrixaban
Method.
Background technique
Betrixaban (Betrixaban), chemical name are as follows: N- (5- chloro-2-pyridyl) -2- [[4- [(dimethylamino) imido
Ylmethyl] benzoyl] amino] -5- methoxy benzamide, structure is shown in formula I:
Betrixaban, a kind of oral small molecule compound, direct Xa factor inhibitor are developed by Millennium earliest,
After transfer U.S. Portola Pharmaceuticals.This product be mainly used for prevent and treat deep vein thrombosis formed and
The postoperative pulmonary embolisms of orthopaedic srugery, at the same can be used for prevention atrial fibrillation caused by apoplexy, be furthermore alternatively arranged as myocardial infarction and
The two wires prophylactic of apoplexy.Foreign countries are in III phase clinical research at present.
Patent document CN1391555A, CN101595092A, CN102762538A etc. successively disclose the system of betrixaban
Preparation Method.
Patent document CN1391555A discloses (square case 1) following preparation method earliest:
As shown in scheme 1, which is with 2- amino -5- chloropyridine (VII) and 5- methoxyl group -2- nitrobenzoic acid (VI)
Compound V is obtained through amidation process under the conditions of phosphorus oxychloride and pyridine for raw material；Compound V restores to obtain through stannous chloride
Compound IV；Compound IV obtains compound II with to cyano-benzoyl chloride (III) generation amidation process；Thereafter, compound
II first reacts in the hydrogen chloride methanol solution of high concentration, then sloughs the hydrogen chloride in reaction system, then react with dimethylamine,
Most betrixaban I is obtained through column chromatographic isolation and purification afterwards.The preparation process final step need to use and handle a large amount of high corrosion
Property hydrogen chloride gas, equipment anticorrosion is required high, and " three wastes " processing load is heavier；In addition, last column chromatography for separation is pure
Change is also unfavorable for industrialized implementation.
For the deficiency of 1 technique of scheme, patent document CN101595092A improves technique, wherein the most significant
Be that the acid reaction condition of final step has been substituted for basic reaction conditions, i.e., first in tetrahydrofuran with just base lithium and
Dimethylamino lithium is made in dimethylamine, and then dimethylamino lithium is reacted with compound II, post-treated isolated betrixaban I,
Yield wherein contains dechlorination impurity about 1% shown in Formula VIII up to 77%, HPLC purity about 98%.(square case 2).
As shown in scheme 2, this method not only avoids the use of strong caustic gas hydrogen chloride, reduces equipment anticorrosion and " three
It is useless " burden of processing；And post-processing operation is simplified, be conducive to industrial applications.But reagent is just used in this method
Base lithium is expensive and transport storage requirement is more harsh, causes the production cost of product higher.In addition, made from this method
Product contains the impurity of some more difficult removings, if dechlorination impurity content is up to 1%；Further, patent document CN102762538A
It points out, two kinds of by-products easily generated, i.e. dechlorination impurity VIII and demethyl impurity IX when preparing betrixaban I with this method, i.e.,
Make by being purified at salt, their content may also be up to 0.25% respectively, the production of these impurity similar with betrixaban I structure
The raw raising for being further purified and refining yield for being unfavorable for betrixaban.
Patent document CN102762538A discloses another preparation route (square case 3) of betrixaban.
As shown in Scheme 3, which is to be condensed that high-purity is made in the presence of coupling reagent through compound X and compound IV
Betrixaban I.Wherein compound X is made using two methods: method is first is that under the alkaline condition in similar above scheme 2
Compound XI-I is converted by paracyanobenzoic acid ethyl ester (XII-I), then compound XI-I is hydrolyzed in the presence of lithium hydroxide
Obtain compound X；Method is second is that by paracyanobenzoic acid methyl esters under the acid condition of similar 1 final step of above scheme
(XII-II) it is converted into compound XI-II, then compound XI-II is hydrolyzed in the presence of lithium hydroxide and obtained compound X.The party
Method prepares betrixaban using the route of convergence type, is conducive to the shortening of manufacturing cycle.But its key intermediate compound X is used
The method preparation of similar above scheme one or scheme two, the deficiency with the above method.In addition, compound XI-I or compound
When XI-II hydrolyzes prepare compound X, the amidino groups facile hydrolysis in molecular structure is amide, leads to more by-product XIII's
It generates, is unfavorable for the raising of reaction yield；In addition, since the polarity of compound X is big, good water solubility, when it is by compound XI-I
Or compound XI-II is hydrolyzed in lithium hydroxide aqueous solution after being made, and is not easy to separate it from reacting solution, is caused to separate
Yield is lower；Experiment shows one-step hydrolysis reaction gained compound X crude product to compound XI-I or compound XI-II separation yield
About 50%.
Based on the deficiency of the above betrixaban preparation method, the present inventor studies preparation method, is developed
A kind of improvement new method preparing betrixaban, this improvement new method raw material are easy to get, reaction condition is mild, easy to operate,
Good quality of product, cost is relatively low, is more suitable for industrialized production.
Summary of the invention
The purpose of the present invention is to provide a kind of new methods of the improved preparation of betrixaban.The improvement new method raw material
Be easy to get, reaction condition is mild, easy to operate, good quality of product, cost is relatively low, is more suitable for industrialized production.
In order to achieve the above-mentioned object of the invention, present invention employs following technical solutions:
The present invention provides a kind of preparation methods of compound of formula I, this method comprises: by RMN (CH3)2With Formula II compound
Or its reactant salt；
Wherein:
M is selected from Mg, Zn；R is selected from Cl, Br, I, alkyl or aryl；Wherein when R is alkyl, preferably C1-C7 straight chain or branch
Alkyl group；When R is aryl, preferably phenyl or substituted-phenyl.In one embodiment, RMN (CH3)2For RMgN (CH3)2, choosing
From ClMgN (CH3)2(dimethylamino magnesium chloride), BrMgN (CH3)2(dimethylamino magnesium bromide), IMgN (CH3)2(dimethylamino iodine
Change magnesium) etc.；In another embodiment, RMN (CH3)2For RZnN (CH3)2, it is selected from CH3ZnN(CH3)2(dimethylamino methyl
Zinc), CH3CH2ZnN(CH3)2(dimethylamino ethyl zinc), C6H5ZnN(CH3)2(dimethylaminophenyl zinc) etc..
In the above method, RMN (CH3)2It is obtained by metallo-organic compound RMR ' and dimethylamine or its reactant salt；Wherein M and
R is defined as above, and R ' is selected from alkyl or aryl；Wherein when R ' is alkyl, preferred C1-C7 linear or branched alkyl group；Working as R ' is
When aryl, preferably phenyl or substituted-phenyl.In one embodiment, metallo-organic compound RMR ' is RMgR ', is selected from n-propyl
Magnesium chloride, isopropylmagnesium chloride, cyclohexyl magnesium chloride, phenyl-magnesium-chloride, benzylmagnesium chloride, methyl-magnesium-bromide, ethylmagnesium bromide,
Isopropyl magnesium bromide, selenium alkynide, n-pentyl magnesium bromide, cyclopenta magnesium bromide, cyclohexyl magnesium bromide, n-heptyl bromination
Magnesium, o-tolyl magnesium bromide, 4- diphenyl magnesium bromide, 4- Phenoxyphenyl magnesium bromide, 4- flourophenyl magnesium bromide, 4- chlorobenzene bromide
Change magnesium, methylpyridinium iodide magnesium etc., wherein it is preferred that isopropylmagnesium chloride, isopropyl magnesium bromide or n-pentyl magnesium bromide；In an embodiment party
In case, metallo-organic compound RMR ' is RZnR ', selected from zinc methide, diethyl zinc, diphenyl zinc etc., wherein it is preferred that diethyl
Base zinc.
The salt of dimethylamine refers to the salt that dimethylamine and suitable inorganic acid or organic acid are formed；Wherein suitable inorganic acid choosing
From hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, phosphoric acid or sulfuric acid etc.；Suitable organic acid is selected from oxalic acid, acetic acid, trifluoroacetic acid, first
Sulfonic acid, benzene sulfonic acid, p-methyl benzenesulfonic acid etc..
The solvent of metallo-organic compound RMR ' and dimethylamine or its reactant salt is generally aprotic solvent, is selected from tetrahydro furan
It mutters, methyltetrahydrofuran, ether, methyl phenyl ethers anisole, methyl tertiary butyl ether(MTBE), glycol dimethyl ether, dimethoxymethane, dioxanes, first
Benzene, dimethylbenzene, hexane, heptane, hexamethylene etc. or their mixed solvent, wherein preferably tetrahydrofuran, methyltetrahydrofuran,
Toluene.
The reaction temperature of metallo-organic compound RMR ' and dimethylamine or its salt is generally -10 DEG C to 40 DEG C, preferably 0 DEG C
To 30 DEG C.
The molar ratio of metallo-organic compound RMR ' and dimethylamine is generally 1:1 to 1:3, preferably 1:1.1 to 1:
1.5；If dimethylamine is to feed intake in a salt form, RMR ' generally needs Excess quantities to eliminate the active of dimethylamine salt introducing
The influence of hydrogen, the molal quantity of excessive portion are generally not less than the molal quantity of active hydrogen in dimethylamine salt.
Metallo-organic compound RMR ' and dimethylamine or its salt after the reaction was completed, can directly carry out subsequent anti-without processing
It answers.
In the above method, Formula II compound or its salt can be according in patent document CN1391555A, CN101595092A etc.
Published method is made.
In the above method, the salt of Formula II compound refers to what Formula II compound and suitable inorganic acid or organic acid were formed
Salt；Wherein suitable inorganic acid is selected from hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, phosphoric acid or sulfuric acid etc.；Suitable organic acid is selected from
Oxalic acid, trifluoroacetic acid, methanesulfonic acid, benzene sulfonic acid, p-methyl benzenesulfonic acid etc..
In the above method, Formula II compound and RMN (CH3)2Molar ratio be generally 1:1 to 1:7, wherein it is preferred that 1:2
To 1:6, if Formula II compound is to feed intake in a salt form, RMN (CH3)2Generally Excess quantities is needed to carry out cancelling II chemical combination
The influence for the active hydrogen that object salt introduces, the molal quantity of excessive portion are generally not less than mole of active hydrogen in Formula II compound salt
Number.
In the above method, Formula II compound or its salt and RMN (CH3)2Reaction dissolvent be generally aprotic solvent, be selected from
Tetrahydrofuran, methyltetrahydrofuran, ether, methyl phenyl ethers anisole, methyl tertiary butyl ether(MTBE), glycol dimethyl ether, dimethoxymethane, two dislike
Alkane, toluene, dimethylbenzene, hexane, heptane, hexamethylene etc. or their mixed solvent, wherein preferably tetrahydrofuran, methyl tetrahydro
Furans, toluene.
In the above method, Formula II compound or its salt and RMN (CH3)2Reaction temperature be generally -10 DEG C to 40 DEG C, preferably
It is 0 DEG C to 30 DEG C.
In the above method, the method that this field routine can be used in the determination in reaction time is carried out, and is such as supervised using TLC, HPLC
Control etc..
In the above method, after the completion of reaction, can further comprise product is separated with the conventional methods in the field,
The post-processing such as purifying；For example, after reaction, with sour (such as hydrochloric acid, maleic acid) quenching reaction, using conventional concentration,
It is filtered, washed etc. and to operate isolated betrixaban or its salt.In one embodiment, after reaction, with sour (such as hydrochloric acid
Deng) quenching reaction using the isolated betrixaban I of operation such as being concentrated, being filtered, washed is greater than the yield of compound II
80%, HPLC purity are greater than 98%；Betrixaban can further be purified by conventional purification methods such as recrystallizations, example
Such as, further recrystallization purifying can be carried out to betrixaban with n,N-dimethylacetamide/toluene mixed solvent, HPLC is pure
Degree can be improved to 99.0% or 99.5% or 99.7% or more.In another embodiment, after reaction, with commonly use it is medicinal acid (such as
Maleic acid, hydrochloric acid etc.) quenching reaction, using the salt of the isolated betrixaban of the operation such as conventional concentration, filtering, to chemical combination
The yield of object II is greater than 80%, HPLC purity and is greater than 98%；It further can be by conventional purification methods such as recrystallizations to shellfish Qu Xi
The salt of class is purified, for example, can further be recrystallized with salt of alcohol/water mixed solvent to betrixaban, HPLC purity
It can be improved to 99.0% or 99.5% or 99.7% or more.
In the above method, optionally, by resulting betrixaban further at salt.Formed salt generally refers to betrixaban
The salt formed with suitable inorganic acid or organic acid；Wherein suitable inorganic acid is selected from hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, phosphorus
Acid or sulfuric acid etc.；Suitable organic acid be selected from maleic acid, lactic acid, phenoxy acetic acid, propionic acid, succinic acid, adipic acid, ascorbic acid,
Camphoric acid, gluconic acid, citric acid, methanesulfonic acid, fumaric acid, glycolic, naphthalene -1,5- disulfonic acid, gentianic acid, benzene sulfonic acid, camphor
Sulfonic acid, Alpha-hydroxy caproic acid, benzoic acid, glucuronic acid, ketoglutaric acid, malonic acid, mandelic acid, pyroglutamic acid, cinnamic acid etc..At
The mode of salt generally comprises two kinds: one is after the completion of reaction, directly using suitable sour quenching reaction simultaneously at salt；It is another
Being will after reaction, first isolated betrixaban free alkali, then again with suitable acid at salt.At salt or at salt
The method that this field routine can be used in separation carries out.
In one embodiment, the present invention provides a kind of preparation methods of compound of formula I, this method comprises:
(1), by metallo-organic compound RMR ' and dimethylamine or its reactant salt；Wherein M be selected from Mg, Zn, R be selected from Cl, Br,
I, alkyl or aryl, R ' are selected from alkyl or aryl；
(2), the resulting dimethylamine reaction solution of step (1) is reacted with Formula II compound or its salt.
It is for convenience of description, metallo-organic compound RMR ' and dimethylamine or its salt is anti-in above method step (1)
Resulting reaction solution is answered to be referred to as " dimethylamine reaction solution ".
In above method step (1), when R or R ' is alkyl, preferred C1-C7 linear or branched alkyl group；When R is aryl
When, preferably phenyl or substituted-phenyl.
In above method step (1), when metallo-organic compound RMR ' is RMgR ', it is selected from n-propyl magnesium chloride, isopropyl
Base magnesium chloride, cyclohexyl magnesium chloride, phenyl-magnesium-chloride, benzylmagnesium chloride, methyl-magnesium-bromide, ethylmagnesium bromide, isopropylmagnesium bromide
Magnesium, selenium alkynide, n-pentyl magnesium bromide, cyclopenta magnesium bromide, cyclohexyl magnesium bromide, n-heptyl magnesium bromide, o-tolyl
Magnesium bromide, 4- diphenyl magnesium bromide, 4- Phenoxyphenyl magnesium bromide, 4- flourophenyl magnesium bromide, 4- chlorophenylmagnesium bromide, methyl iodide
Change magnesium etc., wherein it is preferred that isopropylmagnesium chloride, isopropyl magnesium bromide or n-pentyl magnesium bromide；When metallo-organic compound RMR ' is
RZnR ', selected from zinc methide, diethyl zinc, diphenyl zinc etc., wherein it is preferred that diethyl zinc.
In above method step (1), the salt of dimethylamine refers to the salt that dimethylamine and suitable inorganic acid or organic acid are formed；
Wherein suitable inorganic acid is selected from hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, phosphoric acid or sulfuric acid etc.；Suitable organic acid is selected from grass
Acid, acetic acid, trifluoroacetic acid, methanesulfonic acid, benzene sulfonic acid, p-methyl benzenesulfonic acid etc..
In above method step (1), reaction dissolvent is generally aprotic solvent, selected from tetrahydrofuran, methyltetrahydrofuran,
Ether, methyl phenyl ethers anisole, methyl tertiary butyl ether(MTBE), glycol dimethyl ether, dimethoxymethane, dioxanes, toluene, dimethylbenzene, hexane, heptan
Alkane, hexamethylene etc. or their mixed solvent, wherein preferably tetrahydrofuran, methyltetrahydrofuran, toluene.
In above method step (1), reaction temperature is generally -10 DEG C to 40 DEG C, preferably 0 DEG C to 30 DEG C.
In above method step (1), the molar ratio of metallo-organic compound RMR ' and dimethylamine is generally 1:1 to 1:
3, preferably 1:1.1 to 1:1.5；If dimethylamine is to feed intake in a salt form, RMR ' generally needs Excess quantities to eliminate
The influence for the active hydrogen that dimethylamine salt introduces, the molal quantity of excessive portion are generally not less than mole of active hydrogen in dimethylamine salt
Number.
In above method step (1), metallo-organic compound RMR ' and dimethylamine or its salt after the reaction was completed, can be without
Processing is directly used in the reaction of step (2).
In above method step (2), the salt of Formula II compound refers to Formula II compound and suitable inorganic acid or organic acid
The salt of formation；Wherein suitable inorganic acid is selected from hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, phosphoric acid or sulfuric acid etc.；Suitable is organic
Acid is selected from oxalic acid, trifluoroacetic acid, methanesulfonic acid, benzene sulfonic acid, p-methyl benzenesulfonic acid etc..
In above method step (2), the molar ratio of metallo-organic compound RMR ' in Formula II compound and step (1)
Generally 1:1 to 1:7, wherein it is preferred that 1:2 to 1:6；If Formula II compound is to feed intake in a salt form, Organometallic
Closing object RMR ' and corresponding dimethylamine or its salt and corresponding metallo-organic compound RMR ' generally needs Excess quantities to carry out cancelling
The influence for the active hydrogen that II compound salt introduces, the molal quantity of excessive portion are generally not less than active hydrogen in Formula II compound salt
Molal quantity.
In above method step (2), reaction dissolvent is generally aprotic solvent, selected from tetrahydrofuran, methyltetrahydrofuran,
Ether, methyl phenyl ethers anisole, methyl tertiary butyl ether(MTBE), glycol dimethyl ether, dimethoxymethane, dioxanes, toluene, dimethylbenzene, hexane, heptan
Alkane, hexamethylene etc. or their mixed solvent, wherein preferably tetrahydrofuran, methyltetrahydrofuran, toluene.
In above method step (2), reaction temperature is generally -10 DEG C to 40 DEG C, preferably 0 DEG C to 30 DEG C.
In above method step (2), the determination in reaction time can be used this field routine method carry out, such as using TLC,
HPLC monitoring etc..
In above method step (2), after the completion of reaction, can further comprise with the conventional methods in the field to product into
The post-processings such as row separation, purifying；For example, after reaction, with sour (such as hydrochloric acid, maleic acid) quenching reaction, using routine
Concentration, be filtered, washed etc. and to operate isolated betrixaban or its salt.In one embodiment, after reaction, it uses
Sour (such as hydrochloric acid) quenching reaction, using the isolated betrixaban I of operation such as being concentrated, being filtered, washed, to compound II's
Yield is greater than 80%, HPLC purity and is greater than 98%；Betrixaban can further be carried out by conventional purification methods such as recrystallizations
Purifying, for example, further recrystallization purifying can be carried out to betrixaban with n,N-dimethylacetamide/toluene mixed solvent,
Its HPLC purity can be improved to 99.0% or 99.5% or 99.7% or more.In another embodiment, after reaction, it uses
Medicinal sour (such as hydrochloric acid, maleic acid) quenching reaction is commonly used, using the isolated shellfish Qu Xi of the operation such as conventional concentration, filtering
The salt of class is greater than 80%, HPLC purity to the yield of compound II and is greater than 98%；The general purifications such as recrystallization can further be passed through
Method purifies the salt of betrixaban, for example, can further be tied again with salt of alcohol/water mixed solvent to betrixaban
Crystalline substance, HPLC purity can be improved to 99.0% or 99.5% or 99.7% or more.
It, optionally, can be further at salt by resulting betrixaban in above method step (2).Formed salt is usually
Refer to the salt that betrixaban and suitable inorganic acid or organic acid are formed；Wherein suitable inorganic acid is selected from hydrochloric acid, hydrobromic acid, hydrogen iodine
Acid, nitric acid, phosphoric acid or sulfuric acid etc.；Suitable organic acid be selected from maleic acid, lactic acid, phenoxy acetic acid, propionic acid, succinic acid, adipic acid,
Ascorbic acid, camphoric acid, gluconic acid, citric acid, methanesulfonic acid, fumaric acid, glycolic, naphthalene -1,5- disulfonic acid, gentianic acid, benzene
Sulfonic acid, camphorsulfonic acid, Alpha-hydroxy caproic acid, benzoic acid, glucuronic acid, ketoglutaric acid, malonic acid, mandelic acid, pyroglutamic acid, meat
Cinnamic acid etc..Generally comprise two kinds at the mode of salt: one is after the completion of reaction, with directly with suitable sour quenching reaction simultaneously
At salt；Another kind is the first isolated betrixaban free alkali by after reaction, then again with suitable acid at salt.At
Salt or at the separation of salt can be used this field routine method carry out.
Above-mentioned betrixaban provided by the invention improves preparation method, compared with the immediate prior art, in reaction item
Part, product quality, product cost etc. have improvement effect.Such as:
From upper table comparison as can be seen that improvements preparation method provided by the invention used in reagent safety more preferably, valence
Lattice are cheaper, are conducive to the reduction of production cost；And product purity made from the improvement preparation method improves, wherein compared with
The dechlorination impurity VIII and demethyl impurity IX that hardly possible removes are significantly reduced, and are conducive to drug grade high-purity betrixaban or its salt
Preparation.
Generally speaking, the improvement preparation method raw material of above-mentioned betrixaban provided by the invention be easy to get, reaction condition temperature
With it is easy to operate, good quality of product, cost is relatively low, is more suitable for industrialized production.
Detailed description of the invention
Fig. 1 betrixaban structural formula
Fig. 2 Formula II structural formula of compound
Specific embodiment
Specific embodiment with reference to embodiments is described in further detail above content of the invention again.
But the range that this should not be interpreted as to the above-mentioned theme of the present invention is only limitted to example below.The above-mentioned thought feelings of the present invention are not being departed from
Under condition, the various replacements or change made according to ordinary skill knowledge and customary means, should all include of the invention
In range.
Mass spectral analysis is surveyed by the ESI ion source holotype of Agilent 6120B single quadrupole mass spectrometer in following embodiment
Fixed；Nmr analysis is at room temperature, with BRUKER AVANCE III HD400 Nuclear Magnetic Resonance, deuterated dimethyl sulfoxide
(DMSO-d6) make test solvent, tetramethylsilane makees what internal standard measurement was completed.
The preparation of 1 betrixaban of embodiment
Under stirring, 15~20 DEG C of temperature control, isopropylmagnesium chloride tetrahydrofuran solution (the commercially viable purchase of 2mol/L is added dropwise
) 308ml(0.615mol, 5eq) to dimethylamine tetrahydrofuran solution (commercially viable to buy) 339ml of 2mol/L
In (0.677mol, 5.5eq), dimethylamine reaction solution is obtained.
It is 15~20 DEG C of temperature control, Formula II compound 50.0g(0.123mol, 1eq) and tetrahydrofuran 500ml is mixed under stirring
It closes, then above-mentioned dimethylamine reaction solution is added dropwise；After being added dropwise continue be stirred to react at 25~30 DEG C, with HPLC monitoring react into
Journey.When after reaction, at 15~20 DEG C, reaction solution is added in about 2mol/L aqueous hydrochloric acid solution 700ml, then with hydrochloric acid tune
Section system pH to 2~3；Reduced pressure steams organic solvent, the solid being precipitated in filtering and concentrating liquid, the suitable washing of filter cake
It washs；Filter cake and acetone 500ml are stirred, with triethylamine regulation system pH to 7~8；Filtering；Filter cake subtracts at 40~45 DEG C
It press dry dry, obtains betrixaban 45.5g.Yield: 82.0%；HPLC purity: 98.9%, wherein dechlorination impurity VIII is 0.05%, piptonychia
Base impurity IX is not detected.
Above-mentioned betrixaban 45.0g is taken, stirs and is dissolved in n,N-dimethylacetamide 180ml at about 70 DEG C, first is added dropwise
Benzene 360ml；Cool down crystallization, filtering, and filter cake is washed with proper amount of acetone, is dried under reduced pressure at 40~45 DEG C；Gained betrixaban
HPLC purity 99.7%.
(+) LC-MS:m/z=452 ([M+H]+)。1H NMR(400MHz, DMSO-d6) δ: 2.96 (s, 6H), 3.83 (s,
3H),7.06-7.09(dd,1H),7.55-7.59(m,3H),7.80-7.83(dd,1H),8.21-8.23(d,1H),8.27-
8.30(d,2H),8.37-8.40(d,1H),8.41-8.43(d,1H),10.54(br.,2H)。
The preparation of 2 betrixaban maleate of embodiment
Under stirring, 0~5 DEG C of temperature control, the isopropylmagnesium chloride tetrahydrofuran solution (commercially viable to buy) of 2mol/L is added dropwise
105ml(0.21mol, 8.4eq) to dimethylamine hydrochloride 8.91g(0.11mol, 4.4eq) tetrahydrofuran 60ml suspension
In, obtain dimethylamine reaction solution.
Under stirring, 0~5 DEG C of temperature control, Formula II compound 10.0g(0.025mol, 1eq) is mixed with tetrahydrofuran 100ml,
Above-mentioned dimethylamine reaction solution is added dropwise again；Continue to be stirred to react at 10~15 DEG C after being added dropwise, monitors reaction process with HPLC.
When after reaction, at 10~15 DEG C, reaction solution being added in the solution that maleic acid 45g and aqueous solution 100ml are made into；Decompression
Concentration steams organic solvent, the solid being precipitated in filtering and concentrating liquid, the suitable water washing of filter cake.Filter cake subtracts at 40~45 DEG C
It press dry dry, obtains betrixaban maleate 12.1g.Yield: 85.4%；HPLC purity: 98.6%, wherein dechlorination impurity VIII be
0.03%, demethyl impurity IX is not detected.
Above-mentioned betrixaban maleate 10.0g is taken, stirring is dissolved in the mixing of ethyl alcohol 50ml Yu water 25ml at about 70 DEG C
In solvent, water 150ml is added dropwise；Cool down crystallization, filtering, and filter cake is dried under reduced pressure at 40~45 DEG C；Gained betrixaban maleic acid
Salt HPLC purity 99.9%.
1H NMR(400MHz, DMSO-d6) δ: 3.25 (s, 3H), 3.32 (s, 3H), 3.87 (s, 3H), 6.02 (s, 2H),
7.19-7.21(dd,1H),7.44-7.45(1H),7.75-7.77(d,2H),7.97-9.98(d,2H),8.08-8.13(m,
3H),8.44-8.45(d,1H),9.01(br.,1H),9.37(br.,1H),11.04(s,1H),11.13(s,1H).
The preparation of 3 betrixaban of embodiment
Under stirring, 25~30 DEG C of temperature control, isopropylmagnesium chloride tetrahydrofuran solution (the commercially viable purchase of 2mol/L is added dropwise
) 81ml(0.161mol, 7eq) to dimethylamine tetrahydrofuran solution (commercially viable to buy) 121ml of 2mol/L
In (0.242mol, 10.5eq), dimethylamine reaction solution is obtained.
Under stirring, 25~30 DEG C of temperature control, by Formula II compound hydrochloride 10.0g(0.023mol, 1eq) and tetrahydrofuran
100ml mixing, then above-mentioned dimethylamine reaction solution is added dropwise；Continue to be stirred to react at 25~30 DEG C after being added dropwise, be supervised with HPLC
Survey reaction process.When after reaction, at 15~20 DEG C, reaction solution is added in about 2mol/L aqueous hydrochloric acid solution 210ml, then
With hydrochloric acid regulation system pH to 2~3；Reduced pressure steams organic solvent, and the solid being precipitated in filtering and concentrating liquid, filter cake is in right amount
Water washing；Filter cake and acetone 90ml are stirred, with triethylamine regulation system pH to 7~8；Filtering；Filter cake is 45~50
It is dried under reduced pressure at DEG C, obtains betrixaban 8.35g.Yield: 80.5%.HPLC purity: 98.7%, wherein dechlorination impurity VIII be
0.03%, demethyl impurity IX is not detected.
The preparation of 4 betrixaban hydrochloride of embodiment
Under stirring, 15~20 DEG C of temperature control, n-pentyl magnesium bromide tetrahydrofuran solution (the commercially viable purchase of 1mol/L is added dropwise
) 75ml(0.075mol, 3eq) to dimethylamine tetrahydrofuran solution (commercially viable to buy) 56ml(0.113mol of 2mol/L,
In 4.5eq), dimethylamine reaction solution is obtained.
It is 15~20 DEG C of temperature control, Formula II compound 10.0g(0.025mol, 1eq) and tetrahydrofuran 100ml is mixed under stirring
It closes, then above-mentioned dimethylamine reaction solution is added dropwise；After being added dropwise continue be stirred to react at 25~30 DEG C, with HPLC monitoring react into
Journey.When after reaction, at 15~20 DEG C, reaction solution is added in about 2mol/L aqueous hydrochloric acid solution 100ml, then with hydrochloric acid tune
Section system pH to 2~3；Reduced pressure steams organic solvent, the solid being precipitated in filtering and concentrating liquid, the suitable washing of filter cake
It washs.Filter cake is dried under reduced pressure at 40~45 DEG C, obtains betrixaban hydrochloride 10.1g, yield: 82.9%；HPLC purity: 99.0%,
Wherein dechlorination impurity VIII is 0.02%, and demethyl impurity IX is not detected.
Above-mentioned betrixaban hydrochloride 10.0g is taken, stirs and is dissolved in n,N-dimethylacetamide 40ml at about 70 DEG C, is dripped
Add toluene 80ml；Cool down crystallization, filtering, and filter cake is dried under reduced pressure at 40~45 DEG C；Gained betrixaban hydrochloride HPLC purity
99.8%。
The preparation of 5 betrixaban of embodiment
Under stirring, 0~5 DEG C of temperature control, toluene solution (commercially viable to buy) 50ml of the diethyl zinc of 1mol/L is added dropwise
(0.050mol, 2eq) to 2mol/L dimethylamine tetrahydrofuran solution (commercially viable to buy) 28ml(0.055mol, 2.2eq)
In, obtain dimethylamine reaction solution.
Under stirring, 0~5 DEG C of temperature control, Formula II compound 10.0g(0.025mol, 1eq) is mixed with tetrahydrofuran 100ml,
Above-mentioned dimethylamine reaction solution is added dropwise again；Continue to be stirred to react at 5~10 DEG C after being added dropwise, monitors reaction process with HPLC.
When after reaction, at 5~10 DEG C, reaction solution is added in about 2mol/L diluted hydrochloric acid aqueous solution 70ml, then is adjusted with hydrochloric acid
System pH to 2~3；Reduced pressure steams organic solvent, the solid being precipitated in filtering and concentrating liquid, and filter cake successively uses suitable washing
It washs；Filter cake and acetone 100ml are stirred, with triethylamine regulation system pH to 7~8；Filtering；Filter cake subtracts at 40~45 DEG C
It press dry dry, obtains betrixaban 9.03g.Yield: 80.1%；HPLC purity: 99.0%, wherein dechlorination impurity VIII is 0.02%, piptonychia
Base impurity IX is not detected.
The preparation of 1 Formula II compound of preparation example
(1) preparation of N- (the chloro- pyridine -2- base of 5-) -5- methoxyl group -2- nitro-benzamide (compound V)
It is stirred at room temperature down, by 5- methoxyl group -2- nitrobenzoic acid (compound VI, commercially viable to buy) 250g
(1.27mol, 1eq) and 2- amino -5- chloropyridine (compound VII) 163g(1.27mol, 1eq) it is suspended in acetonitrile 1700ml,
Pyridine 301g(3.81mol, 3eq is added), phosphorus oxychloride 231g(1.52mol, 1.2eq is then added dropwise)；After being stirred to react 1 hour
Water 3500ml is added, crystallization is quenched；Filtering, filter cake are washed with water 1700ml × 2；It is dried under reduced pressure to obtain compound V349g.
(2) preparation of 2- amino-N- (the chloro- pyridine -2- base of 5-) -5- methoxy-b enzamide (compound IV)
It is stirred at room temperature down, by N- (the chloro- pyridine -2- base of 5-) -5- methoxyl group -2- nitro-benzamide (compound V) 300g
(0.977mol, 1.0eq) is dissolved in acetic acid 3000ml, and iron powder 546g(9.77mol, 10eq is added portionwise)；After adding iron powder
Continue to be stirred to react 3 hours, ethyl acetate 6000ml and water 3000ml, liquid separation is then added；The water phase ethyl acetate separated
3000ml × 2 is extracted；Merge organic phase, is successively washed with water, saturated aqueous solution of sodium bicarbonate, saturated sodium-chloride water solution, nothing
Aqueous sodium persulfate is dry, is concentrated under reduced pressure, obtains compound IV244g.
(3) N- (the chloro- pyridine -2- base of 5-) -2- (4- cyano-benzoyl-amino) -5- methoxy-b enzamide (chemical combination
Object II) preparation
At 10~20 DEG C, by formula IV compound 200g(0.72mol, 1.0eq) and triethylamine 109g(1.08mol,
It 1.5eq) is dissolved in tetrahydrofuran 2000ml, is added dropwise thereto to cyano-benzoyl chloride (compound III, commercially viable to buy)
130g(0.79mol, 1.1eq) and the solution that is made into of tetrahydrofuran 1000ml, HPLC monitor reaction process；It crosses after reaction
Filter, filter cake are washed through ethanol in proper amount, are dried under reduced pressure to obtain compound II263g.HPLC purity: 98.7%.
(+) LC-MS:m/z=407 ([M+H]+)。1H NMR(400MHz, DMSO-d6) δ: 3.85 (s, 3H), 7.16-7.19
(dd,1H),7.39-7.41(d,1H),7.93-7.96(d,2H),8.02-8.04(m,4H),8.13-8.14(d,2H),8.42-
8.43(d,1H),11.06(br.2H)。
The preparation of 2 Formula II compound hydrochloride of preparation example
At 10~20 DEG C, formula IV compound 40.0g(0.14mol, 1.0eq) is dissolved in tetrahydrofuran 400ml, Xiang Qi
It is middle to be added dropwise to cyano-benzoyl chloride (compound III, commercially viable to buy) 24.8g(0.15mol, 1.1eq) and tetrahydrofuran
The solution that 200ml is made into, HPLC monitor reaction process；It filters after reaction, filter cake is washed through ethanol in proper amount, is dried under reduced pressure
Formula II compound hydrochloride.HPLC purity: 99.5%.
Claims (12)
1. a kind of improved preparation method of betrixaban, it is characterised in that by RMN (CH3)2It is anti-with II compound or its salt of formula
It answers；
RMN (the CH3)2Selected from ClMgN (CH3)2、BrMgN(CH3)2、IMgN(CH3)2、CH3ZnN(CH3)2Or CH3CH2ZnN
(CH3)2。
2. preparation method according to claim 1, it is characterised in that II compound of formula and RMN (CH3)2Molar ratio
For 1:1 to 1:7.
3. preparation method according to claim 2, it is characterised in that II compound of formula and RMN (CH3)2Molar ratio
For 1:2 to 1:6.
4. preparation method according to claim 1, it is characterised in that the temperature of the reaction is 0 DEG C to 30 DEG C.
5. preparation method according to claim 1, it is characterised in that the RMN (CH3)2Be by metallo-organic compound RMR ' with
Dimethylamine or its reactant salt obtain；The metallo-organic compound RMR ' is selected from isopropylmagnesium chloride, isopropyl magnesium bromide, positive penta
Base magnesium bromide, methylpyridinium iodide magnesium, zinc methide or diethyl zinc.
6. a kind of improved preparation method of betrixaban, it is characterised in that use following methods:
(1), metallo-organic compound RMR ' and dimethylamine or its reactant salt, the metallo-organic compound RMR ' are selected from isopropyl
Base magnesium chloride, isopropyl magnesium bromide, n-pentyl magnesium bromide, methylpyridinium iodide magnesium, zinc methide, diethyl zinc；
(2), the resulting dimethylamine reaction solution of step (1) is reacted with II compound or its salt of formula,
7. according to claim 1,5 or 6 any preparation method, it is characterised in that the solvent of the reaction is selected from tetrahydro furan
It mutters, methyltetrahydrofuran, ether, methyl phenyl ethers anisole, methyl tertiary butyl ether(MTBE), glycol dimethyl ether, dimethoxymethane, dioxanes, first
Benzene, dimethylbenzene, hexane, heptane, hexamethylene or their mixed solvent.
8. preparation method according to claim 7, it is characterised in that the solvent of the reaction is selected from tetrahydrofuran, methyl four
Hydrogen furans, toluene.
9. according to the preparation method of claim 5 or 6, it is characterised in that the metallo-organic compound RMR ' and dimethylamine or its
The reaction temperature of salt is 0 DEG C to 30 DEG C.
10. according to the preparation method of claim 5 or 6, it is characterised in that the metallo-organic compound RMR ' and dimethylamine
Molar ratio is 1:1.1 to 1:1.5.
11. preparation method according to claim 6, it is characterised in that gold in II compound of step (2) Chinese style and step (1)
The molar ratio for belonging to organic compound RMR ' is 1:2 to 1:6.
12. preparation method according to claim 6, it is characterised in that step (2) reaction temperature is 0 DEG C to 30 DEG C.
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| CN106518758A (en) * | 2015-09-11 | 2017-03-22 | 扬子江药业集团江苏紫龙药业有限公司 | Preparation method of Betrixaban intermediate N-(5-chloro-2-pyridyl)-2-(4-cyanobenzeneformamido)-5-metoxybenzamide |
| CN106831553A (en) * | 2015-09-11 | 2017-06-13 | 天津科伦药物研究有限公司 | The preparation method of betrixaban or its analog |
| CN105348187B (en) * | 2015-12-02 | 2017-12-08 | 安徽省逸欣铭医药科技有限公司 | A kind of betrixaban analogue and its production and use |
| WO2017117189A1 (en) * | 2015-12-30 | 2017-07-06 | Tetraphase Pharmaceuticals, Inc. | Preparation of mixed amidomagnesium halides |
| CN107098853A (en) * | 2016-02-20 | 2017-08-29 | 天津科伦药物研究有限公司 | The preparation method of betrixaban maleate |
| CN105732490A (en) * | 2016-03-25 | 2016-07-06 | 重庆医科大学 | Preparation method of betrixaban |
| CN107778224B (en) * | 2016-08-31 | 2020-06-26 | 鲁南制药集团股份有限公司 | Preparation method of betrixaban intermediate |
| CN108586325A (en) * | 2017-03-16 | 2018-09-28 | 上海度德医药科技有限公司 | A kind of preparation method of Betrixaban intermediates |
| WO2018229796A2 (en) | 2017-06-14 | 2018-12-20 | Mylan Laboratories Limited | A process for betrixaban hydrochloride and betrixaban maleate salt |
| CN108530349A (en) * | 2018-04-09 | 2018-09-14 | 重庆三圣实业股份有限公司 | The preparation method and products thereof of betrixaban intermediate and betrixaban |
| CN113620869B (en) * | 2020-05-06 | 2023-04-18 | 江西同和药业股份有限公司 | Preparation method of betrixaban |
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| CN101595092A (en) * | 2006-11-02 | 2009-12-02 | 米伦纽姆医药公司 | The method of the pharmaceutical salts of composition-factor XA inhibitor |
| WO2010132999A1 (en) * | 2009-05-21 | 2010-11-25 | Chlorion Pharma, Inc. | Methyl sulfanyl pyrmidmes useful as antiinflammatories, analgesics, and antiepileptics |
| CN103261161A (en) * | 2010-09-01 | 2013-08-21 | 博尔托拉制药公司 | Crystalline forms of a factor Xa inhibitor |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101595092A (en) * | 2006-11-02 | 2009-12-02 | 米伦纽姆医药公司 | The method of the pharmaceutical salts of composition-factor XA inhibitor |
| WO2010132999A1 (en) * | 2009-05-21 | 2010-11-25 | Chlorion Pharma, Inc. | Methyl sulfanyl pyrmidmes useful as antiinflammatories, analgesics, and antiepileptics |
| CN103261161A (en) * | 2010-09-01 | 2013-08-21 | 博尔托拉制药公司 | Crystalline forms of a factor Xa inhibitor |
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