CN116283911A - Preparation method of dabigatran etexilate - Google Patents
Preparation method of dabigatran etexilate Download PDFInfo
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- CN116283911A CN116283911A CN202310048173.XA CN202310048173A CN116283911A CN 116283911 A CN116283911 A CN 116283911A CN 202310048173 A CN202310048173 A CN 202310048173A CN 116283911 A CN116283911 A CN 116283911A
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- KSGXQBZTULBEEQ-UHFFFAOYSA-N dabigatran etexilate Chemical compound C1=CC(C(N)=NC(=O)OCCCCCC)=CC=C1NCC1=NC2=CC(C(=O)N(CCC(=O)OCC)C=3N=CC=CC=3)=CC=C2N1C KSGXQBZTULBEEQ-UHFFFAOYSA-N 0.000 title claims abstract description 42
- 229960000288 dabigatran etexilate Drugs 0.000 title claims abstract description 41
- 238000002360 preparation method Methods 0.000 title abstract description 21
- 150000001875 compounds Chemical class 0.000 claims abstract description 113
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims abstract description 18
- 239000003960 organic solvent Substances 0.000 claims abstract description 17
- 229910052757 nitrogen Inorganic materials 0.000 claims abstract description 9
- 239000003054 catalyst Substances 0.000 claims abstract description 8
- 239000012467 final product Substances 0.000 claims abstract description 7
- 238000006555 catalytic reaction Methods 0.000 claims abstract description 6
- 239000002253 acid Substances 0.000 claims abstract description 5
- 150000003863 ammonium salts Chemical class 0.000 claims abstract description 5
- 238000005915 ammonolysis reaction Methods 0.000 claims abstract description 5
- 238000006243 chemical reaction Methods 0.000 claims description 67
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 54
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 42
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 37
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 28
- 238000000034 method Methods 0.000 claims description 24
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 18
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 15
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 14
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 13
- UAOMVDZJSHZZME-UHFFFAOYSA-N diisopropylamine Chemical compound CC(C)NC(C)C UAOMVDZJSHZZME-UHFFFAOYSA-N 0.000 claims description 9
- PWKSKIMOESPYIA-BYPYZUCNSA-N L-N-acetyl-Cysteine Chemical compound CC(=O)N[C@@H](CS)C(O)=O PWKSKIMOESPYIA-BYPYZUCNSA-N 0.000 claims description 8
- 229960004308 acetylcysteine Drugs 0.000 claims description 8
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 claims description 8
- USFZMSVCRYTOJT-UHFFFAOYSA-N Ammonium acetate Chemical compound N.CC(O)=O USFZMSVCRYTOJT-UHFFFAOYSA-N 0.000 claims description 7
- 239000005695 Ammonium acetate Substances 0.000 claims description 7
- 229940043376 ammonium acetate Drugs 0.000 claims description 7
- 235000019257 ammonium acetate Nutrition 0.000 claims description 7
- ATRRKUHOCOJYRX-UHFFFAOYSA-N Ammonium bicarbonate Chemical compound [NH4+].OC([O-])=O ATRRKUHOCOJYRX-UHFFFAOYSA-N 0.000 claims description 6
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 6
- BVCZEBOGSOYJJT-UHFFFAOYSA-N ammonium carbamate Chemical compound [NH4+].NC([O-])=O BVCZEBOGSOYJJT-UHFFFAOYSA-N 0.000 claims description 6
- 239000001099 ammonium carbonate Substances 0.000 claims description 6
- 229940059913 ammonium carbonate Drugs 0.000 claims description 6
- 235000012501 ammonium carbonate Nutrition 0.000 claims description 6
- KXDHJXZQYSOELW-UHFFFAOYSA-N carbonic acid monoamide Natural products NC(O)=O KXDHJXZQYSOELW-UHFFFAOYSA-N 0.000 claims description 6
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 claims description 6
- 239000002994 raw material Substances 0.000 claims description 5
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 claims description 4
- 235000019253 formic acid Nutrition 0.000 claims description 4
- 238000007254 oxidation reaction Methods 0.000 claims description 4
- 125000006239 protecting group Chemical group 0.000 claims description 4
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 3
- 229940043279 diisopropylamine Drugs 0.000 claims description 3
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 3
- 125000003277 amino group Chemical group 0.000 claims description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 2
- 239000003513 alkali Substances 0.000 claims 1
- 239000000047 product Substances 0.000 abstract description 40
- 238000004519 manufacturing process Methods 0.000 abstract description 10
- 239000006227 byproduct Substances 0.000 abstract description 7
- 239000003814 drug Substances 0.000 abstract description 4
- 229940079593 drug Drugs 0.000 abstract description 2
- 230000015572 biosynthetic process Effects 0.000 abstract 1
- 238000003786 synthesis reaction Methods 0.000 abstract 1
- 238000003756 stirring Methods 0.000 description 26
- 238000001035 drying Methods 0.000 description 23
- 239000000243 solution Substances 0.000 description 21
- 238000001914 filtration Methods 0.000 description 13
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 12
- 239000012065 filter cake Substances 0.000 description 12
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 10
- 239000012074 organic phase Substances 0.000 description 10
- -1 amidine compound Chemical class 0.000 description 9
- 238000000605 extraction Methods 0.000 description 8
- 239000000203 mixture Substances 0.000 description 8
- 238000001953 recrystallisation Methods 0.000 description 8
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 7
- KIWBRXCOTCXSSZ-UHFFFAOYSA-N hexyl carbonochloridate Chemical compound CCCCCCOC(Cl)=O KIWBRXCOTCXSSZ-UHFFFAOYSA-N 0.000 description 7
- 239000007787 solid Substances 0.000 description 7
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 6
- 235000019441 ethanol Nutrition 0.000 description 6
- 238000005406 washing Methods 0.000 description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 5
- 239000012046 mixed solvent Substances 0.000 description 5
- 239000002904 solvent Substances 0.000 description 5
- 238000001291 vacuum drying Methods 0.000 description 5
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 4
- 238000001816 cooling Methods 0.000 description 4
- 239000000706 filtrate Substances 0.000 description 4
- 238000010438 heat treatment Methods 0.000 description 4
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 4
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 4
- 238000004321 preservation Methods 0.000 description 4
- DYHSDKLCOJIUFX-UHFFFAOYSA-N tert-butoxycarbonyl anhydride Chemical compound CC(C)(C)OC(=O)OC(=O)OC(C)(C)C DYHSDKLCOJIUFX-UHFFFAOYSA-N 0.000 description 4
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 4
- YBAZINRZQSAIAY-UHFFFAOYSA-N 4-aminobenzonitrile Chemical compound NC1=CC=C(C#N)C=C1 YBAZINRZQSAIAY-UHFFFAOYSA-N 0.000 description 3
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 3
- 239000012043 crude product Substances 0.000 description 3
- 238000002425 crystallisation Methods 0.000 description 3
- 230000008025 crystallization Effects 0.000 description 3
- 230000006837 decompression Effects 0.000 description 3
- 238000011010 flushing procedure Methods 0.000 description 3
- 239000012044 organic layer Substances 0.000 description 3
- 238000001556 precipitation Methods 0.000 description 3
- FKLJPTJMIBLJAV-UHFFFAOYSA-N Compound IV Chemical compound O1N=C(C)C=C1CCCCCCCOC1=CC=C(C=2OCCN=2)C=C1 FKLJPTJMIBLJAV-UHFFFAOYSA-N 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- 102000009123 Fibrin Human genes 0.000 description 2
- 108010073385 Fibrin Proteins 0.000 description 2
- BWGVNKXGVNDBDI-UHFFFAOYSA-N Fibrin monomer Chemical compound CNC(=O)CNC(=O)CN BWGVNKXGVNDBDI-UHFFFAOYSA-N 0.000 description 2
- SWLVFNYSXGMGBS-UHFFFAOYSA-N ammonium bromide Chemical compound [NH4+].[Br-] SWLVFNYSXGMGBS-UHFFFAOYSA-N 0.000 description 2
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 2
- 229940011182 cobalt acetate Drugs 0.000 description 2
- QAHREYKOYSIQPH-UHFFFAOYSA-L cobalt(II) acetate Chemical compound [Co+2].CC([O-])=O.CC([O-])=O QAHREYKOYSIQPH-UHFFFAOYSA-L 0.000 description 2
- 229940125904 compound 1 Drugs 0.000 description 2
- 230000007797 corrosion Effects 0.000 description 2
- 238000005260 corrosion Methods 0.000 description 2
- 229960003850 dabigatran Drugs 0.000 description 2
- YBSJFWOBGCMAKL-UHFFFAOYSA-N dabigatran Chemical compound N=1C2=CC(C(=O)N(CCC(O)=O)C=3N=CC=CC=3)=CC=C2N(C)C=1CNC1=CC=C(C(N)=N)C=C1 YBSJFWOBGCMAKL-UHFFFAOYSA-N 0.000 description 2
- 230000007547 defect Effects 0.000 description 2
- 238000004090 dissolution Methods 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
- MHYCRLGKOZWVEF-UHFFFAOYSA-N ethyl acetate;hydrate Chemical compound O.CCOC(C)=O MHYCRLGKOZWVEF-UHFFFAOYSA-N 0.000 description 2
- 238000001704 evaporation Methods 0.000 description 2
- 229950003499 fibrin Drugs 0.000 description 2
- 150000002466 imines Chemical class 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 238000012423 maintenance Methods 0.000 description 2
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 2
- 229940127216 oral anticoagulant drug Drugs 0.000 description 2
- CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 description 2
- 230000003647 oxidation Effects 0.000 description 2
- 239000001301 oxygen Substances 0.000 description 2
- 229910052760 oxygen Inorganic materials 0.000 description 2
- 239000012071 phase Substances 0.000 description 2
- 229910000027 potassium carbonate Inorganic materials 0.000 description 2
- 238000010898 silica gel chromatography Methods 0.000 description 2
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 238000000967 suction filtration Methods 0.000 description 2
- 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 1
- XKIXLCDXGSNKEI-UHFFFAOYSA-N 2-(chloromethyl)-1,5-dimethylbenzimidazole Chemical compound CC1=CC=C2N(C)C(CCl)=NC2=C1 XKIXLCDXGSNKEI-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
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 1
- 241001137307 Cyprinodon variegatus Species 0.000 description 1
- 108010049003 Fibrinogen Proteins 0.000 description 1
- 102000008946 Fibrinogen Human genes 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- 101000712605 Theromyzon tessulatum Theromin Proteins 0.000 description 1
- 108090000190 Thrombin Proteins 0.000 description 1
- 208000007536 Thrombosis Diseases 0.000 description 1
- 206010047249 Venous thrombosis Diseases 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 230000001154 acute effect Effects 0.000 description 1
- 230000010100 anticoagulation Effects 0.000 description 1
- SOGXBRHOWDEKQB-UHFFFAOYSA-N benzyl 2-chloroacetate Chemical compound ClCC(=O)OCC1=CC=CC=C1 SOGXBRHOWDEKQB-UHFFFAOYSA-N 0.000 description 1
- 230000000903 blocking effect Effects 0.000 description 1
- 230000023555 blood coagulation Effects 0.000 description 1
- 235000011089 carbon dioxide Nutrition 0.000 description 1
- 230000000052 comparative effect Effects 0.000 description 1
- JNGZXGGOCLZBFB-IVCQMTBJSA-N compound E Chemical compound N([C@@H](C)C(=O)N[C@@H]1C(N(C)C2=CC=CC=C2C(C=2C=CC=CC=2)=N1)=O)C(=O)CC1=CC(F)=CC(F)=C1 JNGZXGGOCLZBFB-IVCQMTBJSA-N 0.000 description 1
- 238000009833 condensation Methods 0.000 description 1
- 230000005494 condensation Effects 0.000 description 1
- 238000006264 debenzylation reaction Methods 0.000 description 1
- MHDVGSVTJDSBDK-UHFFFAOYSA-N dibenzyl ether Chemical compound C=1C=CC=CC=1COCC1=CC=CC=C1 MHDVGSVTJDSBDK-UHFFFAOYSA-N 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 229940012952 fibrinogen Drugs 0.000 description 1
- 238000003818 flash chromatography Methods 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 230000002496 gastric effect Effects 0.000 description 1
- 238000005984 hydrogenation reaction Methods 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 239000010410 layer Substances 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 230000014508 negative regulation of coagulation Effects 0.000 description 1
- 125000002560 nitrile group Chemical group 0.000 description 1
- BSCHIACBONPEOB-UHFFFAOYSA-N oxolane;hydrate Chemical compound O.C1CCOC1 BSCHIACBONPEOB-UHFFFAOYSA-N 0.000 description 1
- 235000015320 potassium carbonate Nutrition 0.000 description 1
- 235000011181 potassium carbonates Nutrition 0.000 description 1
- 229940066336 pradaxa Drugs 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- LVTJOONKWUXEFR-FZRMHRINSA-N protoneodioscin Natural products O(C[C@@H](CC[C@]1(O)[C@H](C)[C@@H]2[C@]3(C)[C@H]([C@H]4[C@@H]([C@]5(C)C(=CC4)C[C@@H](O[C@@H]4[C@H](O[C@H]6[C@@H](O)[C@@H](O)[C@@H](O)[C@H](C)O6)[C@@H](O)[C@H](O[C@H]6[C@@H](O)[C@@H](O)[C@@H](O)[C@H](C)O6)[C@H](CO)O4)CC5)CC3)C[C@@H]2O1)C)[C@H]1[C@H](O)[C@H](O)[C@H](O)[C@@H](CO)O1 LVTJOONKWUXEFR-FZRMHRINSA-N 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 238000010791 quenching Methods 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 238000007363 ring formation reaction Methods 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 229910000033 sodium borohydride Inorganic materials 0.000 description 1
- 239000012279 sodium borohydride Substances 0.000 description 1
- 239000012265 solid product Substances 0.000 description 1
- 230000009870 specific binding Effects 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- 229960004072 thrombin Drugs 0.000 description 1
- 229960005080 warfarin Drugs 0.000 description 1
- PJVWKTKQMONHTI-UHFFFAOYSA-N warfarin Chemical compound OC=1C2=CC=CC=C2OC(=O)C=1C(CC(=O)C)C1=CC=CC=C1 PJVWKTKQMONHTI-UHFFFAOYSA-N 0.000 description 1
- 238000010626 work up procedure Methods 0.000 description 1
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C257/00—Compounds containing carboxyl groups, the doubly-bound oxygen atom of a carboxyl group being replaced by a doubly-bound nitrogen atom, this nitrogen atom not being further bound to an oxygen atom, e.g. imino-ethers, amidines
- C07C257/10—Compounds containing carboxyl groups, the doubly-bound oxygen atom of a carboxyl group being replaced by a doubly-bound nitrogen atom, this nitrogen atom not being further bound to an oxygen atom, e.g. imino-ethers, amidines with replacement of the other oxygen atom of the carboxyl group by nitrogen atoms, e.g. amidines
- C07C257/18—Compounds containing carboxyl groups, the doubly-bound oxygen atom of a carboxyl group being replaced by a doubly-bound nitrogen atom, this nitrogen atom not being further bound to an oxygen atom, e.g. imino-ethers, amidines with replacement of the other oxygen atom of the carboxyl group by nitrogen atoms, e.g. amidines having carbon atoms of amidino groups bound to carbon atoms of six-membered aromatic rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C327/00—Thiocarboxylic acids
- C07C327/58—Derivatives of thiocarboxylic acids, the doubly-bound oxygen atoms being replaced by nitrogen atoms, e.g. imino-thio ethers
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention relates to a preparation method of dabigatran etexilate, and belongs to the technical field of drug synthesis. In order to solve the problem of improving the product yield, a preparation method of dabigatran etexilate is provided, which comprises the steps of reacting a compound shown in a formula 9 under the action of a catalyst in an organic solvent to generate a compound shown in a formula 8, carrying out ammonolysis reaction on the compound shown in the formula 8 under the catalysis of ammonium salt to generate a compound shown in a formula 7, reacting the compound shown in the formula 7 with the compound shown in the formula 6 under the catalysis of acid in the organic solvent to generate a compound shown in the formula 5, reacting the compound shown in the formula 5 with the compound shown in the formula 4 under the protection of nitrogen to generate a compound shown in the formula 3, and reacting the compound shown in the formula 3 with the compound shown in the formula 2 in an alkaline environment in the organic solvent to generate the final product dabigatran etexilate; the invention has the advantages of high product yield, less byproduct generation, lower production cost, higher product purity and the like.
Description
Technical Field
The invention relates to a preparation method of dabigatran etexilate, belonging to the field of medicine preparation.
Background
Dabigatran etexilate (dabigatran etexilate), which is a novel anticoagulation medicine developed by Bolin invahn company in Germany, month 4 in 2008, is marketed in Germany and British first, with the trade name Pradaxa, for preventing and treating acute venous thrombosis. The oral anticoagulant drug is the first new class of oral anticoagulant drugs marketed 50 years after warfarin, belongs to a non-peptide thrombin inhibitor, is a precursor drug of dabigatran, and is converted into dabigatran with direct anticoagulant activity in vivo after being orally taken through gastrointestinal absorption, and is combined with a fibrin specific binding site of thrombin to prevent fibrinogen from being cracked into fibrin, thereby blocking the last step of a blood coagulation waterfall network and thrombosis.
The chemical name of the compound shown in the formula 1, namely dabigatran etexilate, is ethyl 3- [ [ [2- [ [ [4- [ [ [ (hexyloxy) carbonyl ] amino ] iminomethyl ] phenyl ] amino ] methyl ] -1-methyl-1H-benzimidazole-5-yl ] carbonyl ] (pyridine-2-yl) amino ] propionate, and the chemical structural formula is shown as follows:
in the patent CN104418839B, an amidine compound is prepared by treating a cyano compound with a saturated ethanol solution of hydrogen chloride and an ethanol solution of ammonium carbonate successively, and then the amidine compound and n-hexyl chloroformate are subjected to the action of triethylamine to prepare dabigatran etexilate. The synthetic route is as follows:
in the patent CN103626740A, a preparation method of dabigatran etexilate is disclosed, a compound VII and benzyl chloroacetate are reacted and condensed to obtain a compound VI, the compound VI is subjected to ammonolysis to generate a compound V, the compound V is further reacted and condensed with n-hexyl chloroformate to obtain a compound IV, the compound IV is subjected to hydrogenation debenzylation to generate a compound III, and finally the compound III and the compound II are reacted to synthesize dabigatran etexilate. The synthetic route is as follows:
from the above documents, it can be seen that the current dabigatran etexilate production and preparation have the defects of difficult post-production treatment, high production cost, low product yield and the like.
Therefore, there is a need to find a synthetic method with less byproduct generation, high product yield and low production cost.
Disclosure of Invention
Aiming at the defects in the prior art, the invention provides a preparation method of dabigatran etexilate, which solves the problems of how to realize the preparation method for increasing the yield of the product and reducing the generation of byproducts.
The invention aims at realizing the following technical scheme, namely a preparation method of dabigatran etexilate, which comprises the following steps:
s1: in an organic solvent, reacting a raw material compound of formula 9 under the action of a catalyst to generate a compound of formula 8;
s2: converting the compound of the formula 8 obtained in the step S1 into a compound of the formula 7 through ammonolysis reaction under the catalysis of ammonium salt;
s3: in an organic solvent, reacting the compound of the formula 7 obtained in the step S2 with the compound of the formula 6 under the catalysis of acid, and then performing oxidation reaction to generate the compound of the formula 5;
s4: in an organic solvent, reacting the compound of the formula 5 obtained in the step S4 with the compound of the formula 4 under the protection of nitrogen to generate a compound of the formula 3;
s5: in an organic solvent, the compound of the formula 3 obtained in the step S5 is reacted with the compound of the formula 2 in an alkaline environment to generate a final product, namely dabigatran etexilate, which is the compound of the formula 1.
The synthetic route of the compound of formula 1 is as follows:
according to the invention, the nitrile group of the para-aminobenzonitrile is ammonolyzed to obtain the para-aminobenzonitrile, a large amount of hydrogen chloride is not used in the reaction process, the corrosion to equipment is reduced, the subsequent maintenance cost is reduced, the compound shown in the formula 6 is condensed with the compound shown in the formula 7, the compound shown in the formula 5 is generated through the oxidation of benzyl oxide after removing the protecting group, the compound shown in the formula 7 can be obtained through the oxidation of 2-chloromethyl-1, 5-dimethyl-1H-benzimidazole, the compound shown in the formula 5 is reacted with the compound shown in the formula 4, N-2 pyridine-B-alanine ethyl ester to generate the dabigatran etexilate intermediate shown in the formula 3, and the compound shown in the formula 3 is reacted with the compound shown in the formula 2, namely the N-hexyl chloroformate to obtain the final product dabigatran etexilate.
In the above method for preparing dabigatran etexilate, preferably, the organic solvent in the step S1 is one of absolute ethanol or acetone. Most preferably, absolute ethyl alcohol is selected as solvent for more stable reaction.
In the above method for preparing dabigatran etexilate, preferably, the catalyst in the step S1 is one of N-acetylcysteine, ammonium carbonate or ammonium acetate. Most preferably, N-acetylcysteine is selected to catalyze the reaction so that the product yield is high.
In the above-mentioned dabigatran etexilate production method, the reaction temperature in the step S1 is preferably 20 to 65 ℃. Most preferably, the reaction rate is high at 45℃and the product yield is high.
In the above method for preparing dabigatran etexilate, preferably, the ammonium salt in the step S2 may be one of ammonium carbamate and ammonium acetate. Most preferably, the reaction rate is faster when ammonium carbamate is selected.
In the above method for preparing dabigatran etexilate, preferably, the organic solvent in the step S3 is selected from one of tetrahydrofuran, dichloromethane and ethyl acetate. Most preferably, tetrahydrofuran is used as the solvent to stabilize the reaction.
In the above-mentioned dabigatran etexilate preparation method, preferably, the amino group linked to the methyl group in the compound of formula 7 in the step S3 is attached with a protecting group. Most preferably, boc is used as the protecting group.
In the above-mentioned dabigatran etexilate preparation method, preferably, the acid in the step S3 is selected from one of formic acid, acetic acid and p-toluenesulfonic acid. Most preferably, formic acid is used with less by-products and is easy to work up.
In the above-mentioned dabigatran etexilate preparation method, preferably, the organic solvent in the step S4 is selected from one of dichloromethane, tetrahydrofuran and dioxane. Most preferably, dichloromethane is used as a solvent, so that byproducts can be reduced, and the reaction stability can be improved.
In the above method for preparing dabigatran etexilate, preferably, the base in step S5 is one of triethylamine, diisopropylamine and pyridine. Most preferably, triethylamine is selected with fewer byproducts.
In summary, compared with the prior art, the invention has the following advantages:
1. in the invention, the para-aminobenzonitrile generates the compound shown in the formula 8 through the catalyst and then carries out ammonolysis reaction to generate the para-aminobenzoamidine, and saturated hydrogen chloride solution is not needed in the reaction process, so that the corrosion of hydrogen chloride to production equipment is avoided, the equipment maintenance cost is reduced, the product yield is higher, and the production cost is reduced due to high conversion rate;
2. compared with the compound of the formula 3 generated by cyclization reaction in other reaction processes, the compound of the formula 3 is generated by the reaction condensation of the compound of the formula 5 and the compound of the formula 4, the reaction is simpler, the byproducts are easier to treat, the post-treatment cost is reduced, and the production cost is reduced.
Drawings
FIG. 1 is a general synthetic route of the present invention.
Detailed Description
The technical scheme of the present invention will be further specifically described by means of specific examples, but the present invention is not limited to these examples.
Example 1
Preparation of Compounds of formula 7
300ml of absolute ethanol is placed in a beaker, 59.07g of the compound of formula 9 is added, and the mixture is stirred until the compound is completely dissolved; in another beaker, 300ml of absolute ethyl alcohol is put, 81.6g of N-acetylcysteine is added, after the absolute ethyl alcohol is stirred and dissolved completely, the p-aminobenzonitrile ethanol solution and the N-acetylcysteine ethanol solution are poured into a three-mouth flask, the temperature is raised to 45 ℃, and the stirring reaction is carried out for 20 hours. 15.61g of ammonium carbamate is slowly added into a three-neck flask in batches, the reaction is carried out for 20 hours under heat preservation, after the complete reaction, the reaction is carried out for 48 hours, the filtrate is pumped out after the completion of the reaction, the filter cake is washed by ethanol, 10g of anhydrous magnesium sulfate is added for drying, and the product is obtained by recrystallisation and drying, wherein 64.43g of the compound of formula 7 is white solid, the product yield is 95.4%, and the product purity is 99.6%.
Example 2
Preparation of Compounds of formula 5
Adding 40.52g of a compound of formula 7 into a beaker, dropwise adding 200ml of tetrahydrofuran solution containing 65.47g of Boc anhydride, stirring for 1h at room temperature, adding 67.21g of the compound of formula 6 and 500ml of tetrahydrofuran, adding 23.01g of formic acid, heating to 45 ℃, stirring for reacting for 2h, adding 200ml of ethyl acetate for extraction, decompressing and desolventizing, filtering, flushing a filter cake by using saturated saline water, drying, adding 500ml of tetrahydrofuran, adding 53.11g of cobalt acetate, heating to 120 ℃, regulating the pressure to 0.3-1.5 MPa, adding 29.38g of ammonium bromide, introducing oxygen for reacting for 5h, dropwise adding 200ml of dichloromethane solution of 25% trifluoroacetic acid after the reaction is completed, reacting for 30min at room temperature, standing for layering, adding 200ml of ethyl acetate for extraction, combining organic phases, washing the organic phases by using saturated saline solution, decompressing and desolventizing, recrystallizing, and drying to obtain a final product of 86.96g of the compound of formula 5, wherein the product yield is 89.7%, and the product purity is 99.5%.
Example 3
Preparation of Compounds of formula 3
96.94g of the compound of formula 5 is added into 500mL of dichloromethane under the protection of nitrogen, the reaction temperature is controlled between 0 ℃ and 5 ℃, 58.23g of the compound of formula 4 is slowly added, stirring is carried out for 30min, the temperature is raised to room temperature, the reaction is continued, TLC tracking is carried out until the consumption of the raw materials is completed, 200mL of ethyl acetate is added for extraction, the organic phases are combined, the filtration is carried out, the filter cake is washed by saturated saline solution, 15g of anhydrous sodium sulfate is added for drying, the compound of formula 3 is 132.7g, the product yield is 88.6%, and the product purity is 99.1% after recrystallization and drying are carried out.
Example 4
Preparation of Compounds of formula 1
1500mL of a 5:1 tetrahydrofuran-water mixed solvent is prepared, 149.77g of a compound of formula 3 is added, stirring is carried out for 20min, 30.36g of triethylamine is added, stirring is carried out for 30min at room temperature, 65.85g of n-hexyl chloroformate is slowly added dropwise, stirring is carried out for 12h, an organic layer is separated out by standing, 300mL of ethyl acetate is used for extracting 3 times of water phase, the organic phases are combined, anhydrous magnesium sulfate is added for drying, concentrated precipitation is carried out, a crude product of the compound of formula 1 is obtained by filtering, 150mL of ethyl acetate is added, the temperature is raised to 65 ℃, standing is carried out for 3h at room temperature, cooling is carried out to 4 ℃, crystallization is carried out, filtering is carried out, vacuum drying is carried out, and 170.51g of the compound of formula 1, namely dabigatran etexilate, is obtained, the product yield is 90.6%, and the product purity is 99.7%.
Example 5
300ml of acetone is placed in a beaker, 59.07g of the compound of formula 9 is added, and the mixture is stirred until the mixture is completely dissolved; in another beaker, 300ml of acetone is put, 81.6g of N-acetylcysteine is added, after the solution is stirred and completely dissolved, the p-aminobenzonitrile solution and the N-acetylcysteine solution are poured into a three-neck flask, the temperature is raised to 45 ℃, and the reaction is stirred for 20 hours. 15.42g of ammonium acetate is slowly added into a three-neck flask in batches, the reaction is carried out for 20 hours under heat preservation, after the complete reaction, the reaction is carried out for 48 hours, the filtrate is pumped out after the completion of the reaction, the filter cake is washed by ethanol, 10g of anhydrous magnesium sulfate is added for drying, and the product is obtained by recrystallisation and drying, 62.61g of the compound of formula 7 is white solid, the product yield is 92.7%, and the product purity is 99.2%.
Example 6
300ml of absolute ethanol is placed in a beaker, 59.07g of the compound of formula 9 is added, and the mixture is stirred until the compound is completely dissolved; in another beaker, 300ml of absolute ethyl alcohol is put, 81.6g of N-acetylcysteine is added, after the absolute ethyl alcohol is stirred and dissolved completely, the p-aminobenzonitrile ethanol solution and the N-acetylcysteine ethanol solution are poured into a three-mouth flask, the temperature is raised to 20 ℃, and the stirring reaction is carried out for 20 hours. 15.61g of ammonium carbamate is slowly added into a three-neck flask in batches, the reaction is carried out for 20 hours under heat preservation, after the complete reaction, the reaction is carried out for 48 hours, the filtrate is pumped out after the completion of the reaction, the filter cake is washed by ethanol, 10g of anhydrous magnesium sulfate is added for drying, and 59.03g of compound of formula 7 is obtained as a white solid product after recrystallization and drying, the product yield is 87.4%, and the product purity is 97.3%.
Example 7
300ml of absolute ethanol is placed in a beaker, 59.07g of the compound of formula 9 is added, and the mixture is stirred until the compound is completely dissolved; in another beaker, 300ml of absolute ethyl alcohol is put, 81.6g of N-acetylcysteine is added, after the absolute ethyl alcohol is stirred and dissolved completely, the p-aminobenzonitrile ethanol solution and the N-acetylcysteine ethanol solution are poured into a three-mouth flask, the temperature is raised to 65 ℃, and the stirring reaction is carried out for 20 hours. 15.61g of ammonium carbamate is slowly added into a three-neck flask in batches, the reaction is carried out for 20 hours under heat preservation, after the complete reaction, the reaction is carried out for 48 hours, the filtrate is pumped out after the completion of the reaction, the filter cake is washed by ethanol, 10g of anhydrous magnesium sulfate is added for drying, and the product is obtained by recrystallisation and drying, wherein 60.11g of the compound of formula 7 is white solid, the product yield is 89%, and the product purity is 98.5%.
Example 8
67.21g of the compound of formula 6 is placed in a beaker, 500ml of dichloromethane is added, 51.04g of acetic acid is added, the temperature is raised to 45 ℃, 40.52g of the compound of formula 7 is added dropwise, after the dropwise addition, stirring reaction is carried out for 2h, 200ml of ethyl acetate is added for extraction, decompression and desolventizing are carried out, filtration is carried out, a saturated saline solution is used for flushing a filter cake, 15g of anhydrous sodium sulfate is added for drying, recrystallization and drying are carried out, and the final product of 84.24g of the compound of formula 5 is obtained, the product yield is 86.9%, and the product purity is 98.5%.
Example 9
Adding 40.52g of a compound of formula 7 into a beaker, dropwise adding 200ml of tetrahydrofuran solution containing 65.47g of Boc anhydride, stirring for 1h at room temperature, adding 67.21g of the compound of formula 6 and 500ml of tetrahydrofuran, adding 51.66g of p-toluenesulfonic acid, heating to 45 ℃, stirring for reacting for 2h, adding 200ml of ethyl acetate for extraction, decompressing and desolventizing, filtering, flushing a filter cake by saturated saline solution, drying, adding 500ml of tetrahydrofuran, adding 53.11g of cobalt acetate, heating to 120 ℃, adjusting the pressure to 0.3-1.5 MPa, adding 29.38g of ammonium bromide, introducing oxygen for reacting for 5h, dropwise adding 200ml of dichloromethane solution of 25% trifluoroacetic acid after the reaction is completed, reacting for 30min at room temperature, standing for layering, adding 200ml of ethyl acetate into a water layer for extraction, merging organic phases, washing the organic phases by using saturated saline solution, decompressing and desolventizing, recrystallizing, and drying to obtain a final product of the compound of formula 5, 84.82g, wherein the product yield is 87.5%, and the product purity is 98.9%.
Example 10
96.94g of the compound of formula 5 is added into 500mL of tetrahydrofuran under the protection of nitrogen, the reaction temperature is controlled to be between 0 and 5 ℃, 58.23g of the compound of formula 4 is slowly added, stirring is carried out for 30min, the temperature is raised to room temperature, the reaction is continued, TLC tracking is carried out until the consumption of raw materials is completed, 200mL of ethyl acetate is added for extraction, decompression desolventizing and filtration are carried out, saturated saline solution is used for washing filter cakes, 15g of anhydrous sodium sulfate is added for drying, recrystallization and drying are carried out, and 132.09g of the compound of formula 3 is obtained, the product yield is 88.2%, and the product purity is 98.8%.
Example 11
96.94g of the compound of formula 5 is added into 500mL of dioxane under the protection of nitrogen, the reaction temperature is controlled to be between 0 and 5 ℃, 58.23g of the compound of formula 4 is slowly added, stirring is carried out for 30min, the temperature is raised to room temperature, the reaction is continued, TLC tracking is carried out until the consumption of raw materials is completed, 200mL of ethyl acetate is added for extraction, decompression desolventizing and filtration are carried out, saturated saline solution is used for washing filter cakes, 15g of anhydrous sodium sulfate is added for drying, recrystallization and drying are carried out, 130.9g of the compound of formula 3 is obtained, the product yield is 87.4%, and the product purity is 98.1%.
Example 12
1500mL of a 5:1 ethyl acetate-water mixed solvent is prepared, 149.77g of a compound of formula 3 is added, stirring is carried out for 20min, 30.36g of diisopropylamine is added, stirring is carried out for 30min at room temperature, 65.85g of n-hexyl chloroformate is slowly added dropwise, stirring is carried out for 12h, an organic layer is separated out by standing, 300mL of ethyl acetate is used for extracting 3 times, the organic phases are combined, anhydrous magnesium sulfate is added for drying, concentrated precipitation is carried out, a crude product of the compound 1 is obtained by filtering, 150mL of ethyl acetate is added, the temperature is raised to 65 ℃, standing is carried out for 3h at room temperature, cooling is carried out to 4 ℃, crystallization is carried out, filtering is carried out, vacuum drying is carried out, 167.49g of the compound of formula 1, namely dabigatran etexilate is obtained, and the product yield is 89%, and the product purity is 99.2%.
Example 13
1500mL of a 5:1 ethyl acetate-water mixed solvent is prepared, 149.77g of a compound of formula 3 is added, stirring is carried out for 20min, 23.73g of pyridine is added, stirring is carried out for 30min at room temperature, 65.85g of n-hexyl chloroformate is slowly added dropwise, stirring is carried out for 12h, an organic layer is separated out by standing, 300mL of ethyl acetate is used for extracting 3 times of water phase, the organic phases are combined, anhydrous magnesium sulfate is added for drying, concentrated precipitation is carried out, a crude product of the compound 1 is obtained by filtering, 150mL of ethyl acetate is added, the temperature is raised to 65 ℃, standing is carried out for 3h at room temperature, cooling is carried out to 4 ℃, crystallization is carried out, filtering is carried out, vacuum drying is carried out, 165.24g of the compound of formula 1, namely dabigatran etexilate is obtained, and the product yield is 87.8%, and the product purity is 98.4%.
Example 14
Preparation of Compounds of formula 7 Using ammonium carbonate as catalyst
300ml of absolute methanol is put into a three-mouth bottle, the temperature is reduced to 5 ℃ under the protection of nitrogen, 30ml of thionyl chloride is stirred and added dropwise, 59.07g of p-aminobenzonitrile is added after the dripping, the container is sealed, and the reaction is stirred for 24 hours at room temperature. Desolventizing under reduced pressure, adding 400ml of absolute methanol, stirring at room temperature for dissolution, evaporating for desolventizing, adding 39.53g of ammonium carbonate, and stirring at room temperature for reaction for 16h. Suction filtration, washing of the filter cake with saturated saline and vacuum drying gave 54.7g of the compound of formula 7 with a product yield of 81% and a product purity of 97.9%.
Example 15
Preparation of Compounds of formula 7 Using ammonium acetate as catalyst
300ml of absolute methanol is put into a three-mouth bottle, the temperature is reduced to 5 ℃ under the protection of nitrogen, 30ml of thionyl chloride is stirred and added dropwise, 59.07g of p-aminobenzonitrile is added after the dripping, the container is sealed, and the reaction is stirred for 24 hours at room temperature. Desolventizing under reduced pressure, adding 400ml of absolute methanol, stirring at room temperature for dissolution, evaporating for desolventizing, adding 38.54g of ammonium acetate, and stirring at room temperature for reaction for 16h. Suction filtration, washing of the filter cake with saturated saline and vacuum drying gave 53.49g of the compound of formula 7 with a yield of 79.2% and a purity of 97.9%.
Comparative example
This embodiment is an embodiment of the disclosed patent CN104418839B
Under the protection of nitrogen, 60mL of a methylene chloride (dried) solution of redistilled oxalyl chloride (6.3 mL,0.072mol,1.2 eq) is firstly added into a 500mL three-necked flask, the temperature of the reaction system is controlled to be minus 50 ℃ by using a dry ice/acetone bath, 70mL of a methylene chloride solution of DMSO (11.6 mL,0.072mmol,1.2 eq) is slowly added dropwise, the temperature of the reaction system is kept below minus 50 ℃, 120mL of a methylene chloride solution of a compound C (22.1 g,0.06 mol) is slowly added dropwise after 5min, the reaction is continuously kept below minus 50 ℃, 50mL of a methylene chloride solution of triethylamine (30.6 mL,0.22mol,3 eq) is slowly added after 20min, the reaction is slowly returned to room temperature for 30min, and the reaction is continuously carried out until the reaction is completed. After the reaction is finished, saturated NH is used 4 The reaction was quenched with aqueous Cl, extracted with 60mL×3 with dichloromethane, the organic phases combined, washed 2 times with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure to give compound D, which was purified by flash silica gel chromatography to give 19.6g of a pale yellow viscous liquid in 89% yield.
A mixture of Compound D (11 g,0.03 mol) and Compound E (3.9 g,0.033 mol) was dissolved in 100mL of absolute ethanol, and 0.1mL of AcOH was added thereto to react at 50℃for 2 hours. During the reaction, white solid is separated out, after the reaction is finished, the mixture is cooled to room temperature, filtered by suction, washed by water, absolute ethyl alcohol and absolute ethyl ether in turn, and dried to obtain a pale yellow imine intermediate which is directly used for the subsequent reaction. The resulting pale yellow imine intermediate was dissolved in 150mL of Tetrahydrofuran (THF), and K2CO3 (5 g,0.036mol,1.2 eq), meI (1.87 mL,0.3mol,1 eq) were added in this order and stirred at room temperature to react, followed by TLC until the reaction was complete. After the completion of the reaction, insoluble matters were removed by filtration, concentrated under reduced pressure, and recrystallized from absolute ethanol to obtain 11.5g of Compound F in 80% yield.
Compound G (9.6G, 0.02 mol) was dissolved in 100mL of absolute ethanol, the temperature of the system was controlled between 0-5 using an ice bath, sodium borohydride (0.92G, 0.025 mol) was slowly added, the reaction was continued for 30min, then slowly returned to room temperature, and TLC followed by completion. After the reaction, 50mL of absolute ethyl alcohol was removed under reduced pressure, and under ice-bath cooling, 0.05mol/L of AcOH was slowly added to quench the reaction, the mixture was extracted with 50mL×3 of ethyl acetate, the organic phase was combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give an oily liquid, which was recrystallized from a mixed solvent of ethyl acetate and n-hexane to give 7.5G of compound G as a pale yellow solid in 78% yield.
Compound G (0.012 mol, 5.7G) was dissolved in 90mL of 0℃absolute ethanol, and the solution was continuously purged with dry hydrogen chloride gas for 1 hour, followed by stirring at room temperature for 5 hours. After the completion of the reaction, the solvent was removed under reduced pressure, and 90mL of absolute ethanol and ammonium carbonate ((NH) were added to the reaction flask 4 ) 2 CO 3 0.015mol,1.2 eq) at room temperature. After the reaction, the solvent was removed under reduced pressure, and purified by flash silica gel column chromatography to give compound H as a white solid 3.6g in 59% yield.
2.5g (0.005 mol) of Compound H was dissolved in a mixed solvent of 70mL of HF and 5mL of water, and 1.4g (0.01 mol) of potassium carbonate was added thereto, followed by stirring at room temperature for 20 minutes. 1.0g (0.006 mmol) of n-hexyl chloroformate (Compound J) was slowly added, and the reaction was continued at room temperature until completion after the completion of the dropwise addition. Purification by flash chromatography on silica gel gave 2.5g of a colourless solid (compound T) in 81% yield.
Compared with the preparation method in the invention, the yield is lower in the embodiment, which is unfavorable for mass production.
The embodiments of the present invention are not limited to the examples described above, and those skilled in the art can make various changes and modifications in form and detail without departing from the spirit and scope of the present invention, which are considered to fall within the scope of the present invention.
Claims (10)
1. A method for preparing dabigatran etexilate, which is characterized by comprising the following steps:
s1: in an organic solvent, reacting a raw material compound of formula 9 under the action of a catalyst to generate a compound of formula 8;
s2: converting the compound of the formula 8 obtained in the step S1 into a compound of the formula 7 through ammonolysis reaction under the catalysis of ammonium salt;
s3: in an organic solvent, reacting the compound of the formula 7 obtained in the step S2 with the compound of the formula 6 under the catalysis of acid, and then performing oxidation reaction to generate the compound of the formula 5;
s4: in an organic solvent, reacting the compound of the formula 5 obtained in the step S4 with the compound of the formula 4 under the protection of nitrogen to generate a compound of the formula 3;
s5: in an organic solvent, the compound of the formula 3 obtained in the step S5 is reacted with the compound of the formula 2 in an alkaline environment to generate a final product, namely dabigatran etexilate, which is the compound of the formula 1.
2. The method for preparing dabigatran etexilate according to claim 1, wherein the method comprises the following steps: in the step S1, the organic solvent may be one of absolute ethyl alcohol or acetone.
3. The method for preparing dabigatran etexilate according to claim 1, wherein the method comprises the following steps: in the step S1, the catalyst can be selected from one of N-acetylcysteine, ammonium carbonate or ammonium acetate.
4. The method for preparing dabigatran etexilate according to claim 1, wherein the method comprises the following steps: the reaction temperature in the step S1 is 20-65 ℃.
5. The method for preparing dabigatran etexilate according to claim 1, wherein the method comprises the following steps: in the step S2, ammonium salt can be selected from ammonium carbamate or ammonium acetate.
6. The method for preparing dabigatran etexilate according to claim 1, wherein the method comprises the following steps: in the step S3, the organic solvent may be one of tetrahydrofuran, dichloromethane or ethyl acetate.
7. The method for preparing dabigatran etexilate according to claim 1, wherein the method comprises the following steps: in the step S3, the acid can be selected from one of formic acid, acetic acid or p-toluenesulfonic acid.
8. The method for preparing dabigatran etexilate according to claim 1, wherein the method comprises the following steps: the amino group connected with the methyl group on the compound in the formula 7 in the step S3 is connected with a protecting group.
9. The method for preparing dabigatran etexilate according to claim 1, wherein the method comprises the following steps: in the step S4, the organic solvent may be selected from one of dichloromethane, tetrahydrofuran or dioxane.
10. The method for preparing dabigatran etexilate according to claim 1, wherein the method comprises the following steps: in the step S5, the alkali can be selected from one of triethylamine, diisopropylamine or pyridine.
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| CN105523999A (en) * | 2014-10-21 | 2016-04-27 | 重庆医药工业研究院有限责任公司 | Dabigatran etexilate intermediate synthesis method |
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| CN105985264A (en) * | 2015-02-02 | 2016-10-05 | 江南大学 | Novel preparation method of hexatamidine |
| CN105669651A (en) * | 2016-03-07 | 2016-06-15 | 山东罗欣药业集团股份有限公司 | Preparation technique of dabigatran methanesulfonate |
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